Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[Al](C)C.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@@:25]([OH:51])([CH2:45][N:46]1[CH:50]=[N:49][CH:48]=[N:47]1)[C@H:26]([S:28][C@@H:29]1[CH2:34][O:33][C@@H:32]([C:35]2[CH:44]=[CH:43][C:38]([C:39](OC)=[O:40])=[CH:37][CH:36]=2)[O:31][CH2:30]1)[CH3:27]>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@@:25]([OH:51])([CH2:45][N:46]1[CH:50]=[N:49][CH:48]=[N:47]1)[C@H:26]([S:28][C@@H:29]1[CH2:34][O:33][C@@H:32]([C:35]2[CH:36]=[CH:37][C:38]([C:39]([NH:12][CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)=[O:40])=[CH:43][CH:44]=2)[O:31][CH2:30]1)[CH3:27]
Reactant: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)cc1
Reactant: NCc1cccc2ccccc12
Agent: C[Al](C)C
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)NCc3cccc4ccccc34)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(4), a reaction was carried out using commercially available 1-naphthylmethylamine (187 mg, 1.2 mmol), trimethylaluminium (1.1 ml, 1.07M n-hexane solution, 1.2 mmol) and methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (150 mg, 0.30 mmol), obtained in Example 12(1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (170 mg, yield 91%) as a white solid which was recrystallized from dichloromethane-hexane to give white powdery crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1F)[C:5]([C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6].[C-:21]#[N:22].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[C:21]#[N:22])[C:5]([C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6]
Reactant: COCOc1cccnc1C(=O)c1ccc(F)c(Br)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COCOc1cccnc1C(=O)c1ccc(C#N)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
To a solution of 2-(3-bromo-4-fluorobenzoyl)-3-methoxymethoxypyridine (4.68 g) in dimethyl sulfoxide (50 mL) was added potassium cyanide (2.7 g) at 0° C. The mixture was stirred for 3 hours while raising the temperature to room temperature. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The extract solution was washed with water and a saturated aqueous saline solution, successively, and dried (sodium sulfate) and then concentrated. The concentrate was purified by means of a silica gel column (ethyl acetate--hexane) to afford 2-(3-bromo-4-cyanobenzoyl)-3-methoxymethoxypyridine (4.59 g) (compound B-6). Physical properties and spectrum date of the product are shown in Table 3 and Table 4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O>C(O)C.N1CCCC1>[CH2:1]([O:3][C:4](=[O:8])[C:5]([C:6]#[N:7])=[CH:13][C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([F:9])[CH:11]=1)[CH3:2]
Reactant: O=Cc1cccc(F)c1
Reactant: CCOC(=O)CC#N
Solvent: C1CCNC1
Solvent: CCO
Product: CCOC(=O)C(C#N)=Cc1cccc(F)c1
Yield: 98.5 %

Procedure:
A solution of cyanoacetic acid ethyl ester (1.1 g), 3-fluorobenzaldehyde (1.5 g) and pyrolidine (0.043 g) in ethanol (10 mL) was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, and this obtained solid was washed with ethanol (40 mL) to give the title compound (2.1 g).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:30](O)[CH2:31][CH:32]([CH3:34])[CH3:33])=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[N:21]=[CH:22][C:15]=2[N:14]([CH3:36])[C:13]1=[O:37])(C(C)(C)C)(C)C.[CH:38](O)=[O:39]>CC(=O)OCC.O.[Zn]>[CH:38]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[N:21]=[CH:22][C:15]=2[N:14]([CH3:36])[C:13]1=[O:37])=[O:39]
Reactant: CC(C)CC(O)c1c(-c2cccc(Cl)c2)ncc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Reactant: O=CO
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CCc1c(-c2cccc(Cl)c2)ncc2c1c(=O)n(CCCOC=O)c(=O)n2C
Temperature: 50 °C
Yield: 70 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-(3-chlorophenyl)-5-(1-hydroxy-3-methylbutyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 0.055 mmol) in HCOOH (1 mL) was added Zn dust (35.6 mg, 0.55 mmol). The reaction was heated at 50° C. for 1 h, cooled to RT and diluted with EA (5 mL) and water (1 mL). The organic layer was washed with brine (1 mL), dried over Na2SO4 and concentrated to give 3-(6-(3-chlorophenyl)-5-isopentyl-1-methyl-2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate. LCMS MH+ 444 and TR=1.738 min and 3-(6-(3-chlorophenyl)-5-isopentyl-1-methyl-2,4-dioxo-1,2,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate. LCMS: MH+ 446 and TR=1.956 min, (21 mg, 70% yield) as a solid. Used without further purification.
Reaction SMILES: [CH3:1][CH:2]([C:10]#[N:11])[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:18]=[O:19].[OH-].C([N+](CC)(CC)CC)C1C=CC=CC=1>O>[C:10]([C:2]([C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[CH:7][CH:8]=1)([CH3:1])[CH2:18][OH:19])#[N:11]
Reactant: CC(C#N)c1ccc(Cl)cc1
Reactant: C=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CC(C#N)(CO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To an ice cold stirred solution of α-methyl-4-chlorobenzyl cyanide* (50g., 0.3 mole) in 500 ml. of pyridine containing a suspension of paraformaldehyde (36g., 1.2 mole) is added 1 ml. of benzyl triethylammonium hydroxide. The mixture is stirred under nitrogen at room temperature for 72 hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give a thick oil, 58.4g., which is identified by nmr.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:6]1[C:11]([C:12]([CH2:14][CH2:15][CH2:16]Cl)=[O:13])=[CH:10][CH:9]=[C:8]([Cl:18])[CH:7]=1>CN(C)C=O>[Cl:18][C:8]1[CH:7]=[CH:6][C:11]([C:12](=[O:13])[CH2:14][CH2:15][CH2:16][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:10][CH:9]=1
Reactant: c1c[nH]cn1
Reactant: O=C(CCCCl)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: O=C(CCCn1ccnc1)c1ccc(Cl)cc1

Procedure:
To a 0° C. slurry of 10.5 g. of imidazole in 15 ml. dry dimethylformamide was added 6.5 g. of γ,p-dichlorobutyrophenone and the mixture was stirred overnight at room temperature then one day at 60° C. The above solution was poured into 400 ml. of water and extracted three times with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and the solvent evaporated to afford 1-[4-(4-chlorophenyl)butan-4-onyl]imidazole, which was used in the next step. This material may be further purified, if necessary, through the nitrate salt.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)[CH3:2].CN(C)CCN(C)CCN(C)C.C([Li])CCC.CCCCCC.C[O:35]B(OC)OC>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:10])=[C:8]([OH:35])[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(F)cc1
Reactant: COB(OC)OC
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(O)c1
Temperature: -60 °C
Reaction time: 1 h
Yield: 139.2 %

Procedure:
To 4-ethoxy-1-fluorobenzene (1.0 g, 7.1 mmol) in THF (8.0 mL) was added freshly distilled N,N,N′,N″,N″-pentamethyldiethylenetriamine (0.8 mL) and 1.6 M n-butyllithium in hexane (5.13 ml, 8.2 mmol) at −78° C. After stirred at −60° C. for 1 h, trimethylborate (0.52 mL, 4.6 mmol) was introduced at −78° C. and the solution was warmed up to rt for 2 h. The reaction was quenched by acetic acid (1.5 ml) at 0° C. After 15 min, 30% hydrogen peroxide (1.2 ml) was introduced and the mixture was stirred from 0° C. to rt overnight. The mixture was extracted by EtOAc (3×30 mL). The combined organic layer was washed by brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography to give 1.0 g colorless oil of 74A. 1H NMR (400 MHz, CDCl3) δ ppm 1.39 (t, J=6.81 Hz, 3 H) 3.96 (q, J=7.03 Hz, 2H) 5.30 (d, J=2.20 Hz, 1H) 6.28-6.43 (m, 1H) 6.55 (dd, J=7.47, 3.08 Hz, 1H) 6.90-7.01 (m, 1H).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH3:15][S:16][CH2:17][N:18]1[C:23](=[O:24])[N:22]2[CH:25]=[N:26][C:27]([C:28]([NH2:30])=O)=[C:21]2[N:20]=[N:19]1.C[Si](C)(C)O[Si](C)(C)C>C(Cl)Cl>[CH3:15][S:16][CH2:17][N:18]1[C:23](=[O:24])[N:22]2[CH:25]=[N:26][C:27]([C:28](=[S:2])[NH2:30])=[C:21]2[N:20]=[N:19]1
Reactant: CSCn1nnc2c(C(N)=O)ncn2c1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: ClCCl
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: CSCn1nnc2c(C(N)=S)ncn2c1=O
Yield: 36 %

Procedure:
Phosphorus pentasulfide (25 mg, 0.11 mmol) was added in one portion to a suspension of 3-(methylthiomethyl)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide and hexamethyldisiloxane (85 mg; 0.112 mL, 0.525 mmol) in DCM (5 mL) and the mixture was refluxed overnight. The crude product was absorbed on silica and purified by flash chromatography using DCM:MeOH (95:5) as eluent to give 39 mg of the title compound as an orange solid (36% yield). δH (DMSO d6): 9.95 (1H, s), 9.47 (1H, s), 8.85 (1H, s), 5.43 (2H, s), 2.26 (3H, s).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CS(C)=O.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S([O-])c1ccc(F)cc1
Reactant: O=Cc1cccnc1Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cccnc1S(=O)(=O)c1ccc(F)cc1
Temperature: 100 °C
Yield: 545.7 %

Procedure:
2-Chloro-3-pyridinecarboxaldehyde (4.04 g, 2.86 mmol) and 4-fluorobenzenesulfinic acid sodium salt (5.73 g, 3.14 mmol) were dissolved in DMSO (100 ml) and the mixture was heated at 100° C. for 72 h under nitrogen. Upon cooling to ambient the mixture was diluted with water (500 ml) and extracted with EtOAc (3×). The combined organics were washed with water, brine, dried (MgSO4) and evaporated to dryness to afford 7.89 g of crude product. The crude compound was pre-absorbed onto silica and purified by dry pad suction column chromatography, eluting with heptane using an EtOAc gradient, to afford 4.14 g (41%) of the desired product as a yellow solid (plates) (MP=131-131.3° C.; IR=1691 cm−1; HPLC=7.21 min>99%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([O-])([O-])=O.[K+].[K+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Cl.O>CS(C)=O>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6]
Reactant: O=C1NCCN1
Reactant: Fc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1NCCN1Cc1ccccc1F
Reaction time: 1.8 h
Yield: 86 %

Procedure:
A 21.5 g (0.25 mole) portion of 2-imidazolidinone in 125 ml of dimethylsulfoxide was treated with 34.5 g (0.25 mole) of K2CO3, 20 g (0.12 mole) of KI and 36.3 g (0.25 mole) of 2-fluorobenzyl chloride. The reaction mixture was heated to 105° over 0.3 hours, held at 105° for 1.8 hours, and poured into 1.51 of water all with rapid stirring. The aqueous mixture was extracted with 1.3 l of chloroform. The chloroform extract was washed with 500 ml of H2O, dried over MgSO4 overnight and filtered. The filtrate was concentrated under reduced pressure to give 42 g (86%) of a light yellow oil. The crude product was washed with 100 ml of ether to give 10 g (20%) of a white solid m.p. 72°-76°.
Reaction SMILES: [C:1]1(C)C=CC=C[CH:2]=1.[N+:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)([O-:10])=[O:9]>O.FC(F)C(F)(F)S(O)(=O)=O.C(O)C>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH2:1][CH3:2])=[O:16])=[CH:18][CH:19]=1)([O-:10])=[O:9]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)C(F)(F)C(F)F
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1
Yield: 90 %

Procedure:
700 g of toluene, 190 g of ethanol, 350 g of 4-nitrobenzoic acid and 7 g of tetrafluoroethanesulfonic acid hydrate are weighed into a 2-1 four-necked flask equipped as described in Example 1. The procedure described in Example 1 is then repeated. Using the work-up described in Example 1 gives 368 g of ethyl 4-nitrobenzoate and, after drying, 361 g of dry ethyl 4-nitrobenzoate, which corresponds to a yield of 88.3% of theory, in a purity of 98.9% by HPLC.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH2:15])=[C:4]([NH2:16])[CH:3]=1.[C:17](=S)=[S:18].C(O)C.[K+].[Br-]>O>[F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:6][C:5]2[N:15]=[C:17]([SH:18])[NH:16][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)c(N2CCC(O)CC2)cc1N
Reactant: S=C=S
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: OC1CCN(c2cc3nc(S)[nH]c3cc2F)CC1
Yield: 62.3 %

Procedure:
6-Fluoro-5-(4-hydroxypiperidin-1-yl)-2-mercapto-1H-benzimidazole (4.5 g, 62%) was prepared by a similar procedure to that described in preparation 1 (step 5) using the diamine (6.0 g, 0.027 mol) (obtained in step 2 above), carbon disulfide (3.9 g, 0.052 mol), ethanol (30 mL) and water (5 mL). mp 268-269° C.; IR (KBr) 3397, 3124, 1487 cm-1 ; 1H NMR (DMSO-d6) δd 1.45-1.56 (m, 2H, CH2), 1.60-1.87 (m, 2H, CH2), 2.24 (s, 1H, SH), 2.64-3.92 (m, 2H, NCH2), 3.11-3.17 (m, 2H, NCH2), 3.30-3.60 (m, 1H, CH), 4.30 (brs, 1H, OH), 6.70 (d, J=7.4 Hz, 1H), 7.00 (d, J=12.6 Hz, 1H), 12.00 (brs, 1H, NH); Mass (m/z) 267 (M+.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:27])[NH:10][C:11](=[O:26])[C:12]=1[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][CH2:23][CH2:24]O)[CH:14]=1.[N:28]1[CH:33]=CC=C[CH:29]=1.CS(OS(C)(=O)=O)(=O)=O.CNC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:27])[NH:10][C:11](=[O:26])[C:12]=1[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][CH2:23][CH2:24][N:28]([CH3:33])[CH3:29])[CH:14]=1
Reactant: O=C1NC(=O)C(c2cn(CCCO)c3ncccc23)=C1c1ccccc1Cl
Reactant: c1ccncc1
Agent: CNC
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Product: CN(C)CCCn1cc(C2=C(c3ccccc3Cl)C(=O)NC2=O)c2cccnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.1 %

Procedure:
To a solution of Compound 1 (45 mg, 0.118 mmol) in THF (5 mL) was added pyridine (41 mg, 0.5 mmol). The mixture was stirred at room temperature for 15 min and then methanesulfonic anhydride (65 mg, 0.37 mmol) was added and the mixture was heated to 50° C. for 2 h. TLC and mass spectra showed the formation of Compound 2a. To the crude product was added excess 1.0 M solution of dimethylamine in THF (1 mL). The mixture was heated from 50 to 65° C. overnight. The solvent was concentrated in vacuo. The crude product was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated NaHCO3, brine, and evaporated in vacuo to give a crude product (50 mg). The crude product was separated by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, from 98:2:0.2 to 95:5:0.5) to give 15 mg (31%) of Compound 2 as a yellow solid. 1H NMR (DMSO-d6) δ 8.27 (s, 1H), 8.23 (m, 1H), 7.44-7.33 (m, 4H), 6.75-6.71 (m, 1H), 6.62-6.60 (m, 1H), 4.41-4.38 (m, 2H), 2.3-2.28 (m, 2H), 2.25 (s, 6H), 2.12-2.05 (m, 2H). ES-MS m/z 409 (MH+).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=O)(C)(C)C.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1O)[C:17]([O:19][CH3:20])=[O:18].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[O:11][CH2:10][C@@H:9]([NH2:8])[CH3:12])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@H](C)N)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.2 %

Procedure:
To a cooled (0° C.) solution of (S)-2-(N-tert-butoxycarbonylamino)-1-propanol (1.05 g, 5.99 mmol), methyl 3-chloro-4-hydroxybenzoate (1.12 g, 6.00 mmol), and PhP (2.36 g, 9.00 mmol) in THF (20 mL) was added diisopropyl azodicarboxylate (DIAD) (1.77 mL, 8.99 mmol), and the resulting mixture was heated under reflux for 2 days. The solution was evaporated off and the residue was dissolved in CH2Cl2 (20 mL) and TFA (10 mL). The resulting mixture was stirred at room temp for 1.5 hr. The solution was concentrated in vacuo, and the residue was dissolved in CHCl3. The mixture was extracted with H2O, and the aqueous layer was made basic by the addition of sat. NaHCO3. This basic aqueous layer was extracted with CHCl3. The extract was washed with brine, dried over Na2SO4 and evaporated to give 660 mg (2 steps, 32%) methyl (S)-3-chloro-4-(2-amino-1-propoxy)benzoate as a colorless oil. 1H-NMR (CDCl3) δ1.21 (d, 3 H, J=6.4 Hz), 3.41-3.48 (m, 1 H), 3.77-3.81 (m, 1 H), 3.89 (s, 3 H), 3.98-4.01 (m, 1 H), 6.91-6.94 (m, 1 H), 7.90-7.93 (m, 1 H), 8.05-8.06 (m, 1 H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:11]([O:13][CH2:14]Cl)[CH3:12]>C(#N)C>[CH2:11]([O:13][CH2:14][O:10][C:6]1[CH:5]=[C:4]([NH2:3])[CH:9]=[CH:8][CH:7]=1)[CH3:12]
Reactant: CCOCCl
Reactant: Nc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCOCOc1cccc(N)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
12 g (274.9 mmol) of a dispersion of sodium hydride (55% in oil) was added portionwise at 0° C. to a solution of 20.0 g (183.3 mmol) of 3-aminophenol in 450 mL of dried acetonitrile. The mixture was then allowed to agitate at 0° C. for 3 hours. A solution of 25 g (210.8 mmol) of chloromethyl ethyl ether in 30 mL of acetonitrile was added dropwise, and the mixture was allowed to agitate overnight at room temperature. The reaction mixture was then filtered and the filter cake was washed with a small amount of acetone and the filtrate was evaporated. This gave 32.3 g of 3-ethoxymethoxyphenylamine. The resulting product was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:4](=O)[CH:5]([N:7]2[CH:12]=[C:11]([I:13])[CH:10]=[CH:9][C:8]2=[N:14]S(C2C=CC(C)=CC=2)(=O)=O)[CH3:6])[CH2:3][CH2:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[CH:1]1([C:4]2[N:14]=[C:8]3[CH:9]=[CH:10][C:11]([I:13])=[CH:12][N:7]3[C:5]=2[CH3:6])[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)N=c2ccc(I)cn2C(C)C(=O)C2CC2)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(I)cn12
Reaction time: 3 h

Procedure:
To a solution of N-(1-(1-cyclopropyl-1-oxopropan-2-yl)-5-iodopyridin-2(1H)-ylidene)-4-methylbenzenesulfonamide (30.5 g) in THF (300 mL) was added trifluoroacetic anhydride (18.3 mL) dropwise, and the mixture was stirred for 3 hr. The resulting precipitate was collected by filtration, and washed with diethyl ether to give a salt of the title compound as a white solid. The obtained solid was dissolved in 1 N sodium hydroxide, and the solution was extracted with ethyl acetate/THF. Then the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The obtained solid was washed with diisopropyl ether to give the title compound (17.7 g) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[S:5][C:4](=[S:21])[NH:3]1.[NH2:22][CH2:23][C@H:24]([OH:33])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[OH:33][C@H:24]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:23][NH:22][CH:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH:7]=[C:6]3[S:5][C:4](=[S:21])[NH:3][C:2]3=[O:1])=[CH:9][CH:10]=2)[CH2:15][CH2:16]1
Reactant: O=C1CCN(c2ccc(C=C3SC(=S)NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C1NC(=S)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-[4-(4-Oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidine-4-one (which was obtained in Example 34) (0.16 g, 0.5 mmol) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Example 3) (0.12 g, 0.75 mmol) were mixed in 1,2-dichloroethane (10 mL) and then treated with sodium triacetoxyborohydride (0.16 g, 0.75 mmol) and acetic acid (0.045 g, 0.75 mmol). After stirring at room temperature under a nitrogen atmosphere for one day the mixture was quenched with 1N sodium hydroxide (NaOH) and then poured into a saturated aqueous sodium bicarbonate (NaHCO3). The aqueous layer was extracted with dichloromethane and the combined organic layers were dried and concentrated. The residue was purified by preparative thin layer chromatography (16% MeOH/CH2CH2) to give the title compound as a pale yellowish solid; mp >220° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.50-1.70 (m, 2H), 1.90-2.10 (m, 2H), 2.60-3.40 (m, 7H), 3.90-4.20 (m, 3H), 6.70-7.15 (m, 6H), 7.30 (d, J=8.8 Hz, 2H), 7.38 (d, J=8.8 Hz, 2H); MS (ES) m/z: 470.0 (MH+); HRMS Calcd. for C24H27N3O3S2 (M+): 469.1494. Found: 469.1488.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([O:10][CH:11]=[CH2:12])(=O)[CH3:8].C[C:14]12[O:20][CH:19]1[CH2:18]C(CO)[CH2:16][CH2:15]2>C1(C)C=CC=CC=1>[CH3:12][C:11]12[O:10][CH:7]1[CH2:8][CH:14]([O:20][CH:19]=[CH2:18])[CH2:15][CH2:16]2
Reactant: C=COC(C)=O
Reactant: CC12CCC(CO)CC1O2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=COC1CCC2(C)OC2C1
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture (100 mL) of sodium carbonate (0.06 mol) and toluene was heated to 95° C. 4.2 g of vinyl acetate was added dropwise to the mixture. Next, maintaining the temperature of the reaction mixture, and fifteen minutes later, further the mixture was combined with di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (0.5 mmol). Next, (6-methyl-7-oxabicyclo[4.1.0]hept-3-yl)methanol (0.05 mol) was added dropwise over for two hours, and a reaction was carried out in a nitrogen atmosphere while adding dropwise 12.6 g of vinyl acetate and holding the reaction temperature at 95° C. After the completion of dropwise addition, the mixture was stirred for one hour. As the result of gas chromatography analysis of the mixture, it is confirmed that there was produced 1-methyl-4-vinyloxy-7-oxabicyclo[4.1.0]heptane represented by following Formula (14) in a yield of 95%. In 1H-NMR (CDCl3) analysis, signals specific to vinyl group were observed at 6.5 ppm, 4.2 ppm, and 4.05 ppm.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: C1CCNCC1
Product: Brc1ccc(-c2nsc3cc(OCCCCN4CCCCC4)ccc23)cc1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and piperidine were converted to yield 3-(4-Bromo-phenyl)-6-(4-piperidin-1-yl-butoxy)-benzo[d]isothiazole as white solid, MS: 445(MH+, 1Br).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[N:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=O)[O:5][C:6]=1[CH3:7].[NH3:18]>CO>[CH3:17][O:16][C:13]1[N:12]=[CH:11][C:10]([C:8]2[C:4]([OH:5])=[CH:3][C:2]([CH3:1])=[C:6]([CH3:7])[N:18]=2)=[CH:15][CH:14]=1
Reactant: N
Reactant: COc1ccc(C(=O)c2cc(C)c(C)o2)cn1
Solvent: CO
Product: COc1ccc(-c2nc(C)c(C)cc2O)cn1
Temperature: 160 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(6-methoxypyridin-3-yl)-methanone (650 mg), methanol (6 ml), and a 28% aqueous ammonia solution (6 ml) were placed in a sealed tube and was stirred at 160° C. overnight. The reaction solution was cooled to room temperature, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give 6′-methoxy-5,6-dimethyl-[2,3′]bipyridin-3-ol (109 mg, yield 86%).