Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:30])[C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[CH:6][C:5]=12.[Cl:31]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:31][C:3]1[N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:30])[C:13]3[CH:14]=[CH:15][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[CH2:21][CH2:20]4)=[CH:17][CH:18]=3)=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: CC(C)C(=O)N1CCC(c2ccc(C(=O)NCc3ccn4ccnc4c3)cc2)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)N1CCC(c2ccc(C(=O)NCc3ccn4c(Cl)cnc4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(1-isobutyrylpiperidin-4-yl)benzamide (0.025 g, 0.062 mmol) in chloroform (1.030 ml) was treated with N-chlorosuccinimide (9.49 mg, 0.071 mmol) and the reaction was stirred at ambient temperature for 16 hours. The reaction was concentrated under a stream of warm nitrogen. The residue was purified by normal phase chromatography to give the title compound. 1H NMR (500 MHz, methanol-d4) δ ppm 8.67 (d, J=7.0 Hz, 1H), 8.11 (s, 1H), 7.89-7.83 (m, 2H), 7.81 (s, 1H), 7.57 (dd, J=7.1, 1.5 Hz, 1H), 7.43-7.37 (m, 2H), 4.80-4.75 (m, 2H), 4.75-4.67 (m, 1H), 4.25-4.16 (m, 1H), 3.28-3.18 (m, 1H), 3.07-2.88 (m, 2H), 2.79-2.66 (m, 1H), 2.02-1.85 (m, 2H), 1.75-1.53 (m, 2H), 1.17-1.08 (m, 6H); MS (ESI(+)) m/e 439 (M+H)+.
Reaction SMILES: C([N+:8]1[CH:17]=[CH:16][C:15]2[C:14]3[N:18]([CH3:31])[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])=[C:20]([C:21](=[O:23])[NH2:22])[C:13]=3[CH2:12][CH2:11][C:10]=2[CH:9]=1)C1C=CC=CC=1.[Br-].CC(C)([O-])C.[K+]>CS(C)=O.C1COCC1>[CH3:31][N:18]1[C:14]2[C:15]3[CH:16]=[CH:17][N:8]=[CH:9][C:10]=3[CH2:11][CH2:12][C:13]=2[C:20]([C:21]([NH2:22])=[O:23])=[C:19]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]
Reactant: Cc1ccccc1-c1c(C(N)=O)c2c(n1C)-c1cc[n+](Cc3ccccc3)cc1CC2
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1ccccc1-c1c(C(N)=O)c2c(n1C)-c1ccncc1CC2

Procedure:
To a solution of 7-benzyl-3-carbamoyl-1-methyl-2-o-tolyl-4,5-dihydro-1H-pyrrolo[2,3-f]isoquinolin-7-ium; bromide XXV (1.64 mmol) in dry DMSO (1 mL), 1M potassium tert-butoxide (11.5 mmol) in THF was added. The solution was bubbled with dry air overnight. Volatiles were removed, the residue was suspended in DCM, washed with water, dried (Na2SO4), filtered and the solvent evaporated. Chromatography on silica gel (eluant: DCM/MeOH 20:1) afforded the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]([NH2:18])=[O:17])[N:11]=1)[CH2:7][CH2:6][O:5]2.[CH3:19][N:20]([CH:22](OC)OC)[CH3:21]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16](/[N:18]=[CH:19]/[N:20]([CH3:22])[CH3:21])=[O:17])[N:11]=1)[CH2:7][CH2:6][O:5]2
Reactant: NC(=O)c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Reactant: COC(OC)N(C)C
Solvent: C1COCCO1
Product: CN(C)/C=N/C(=O)c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Temperature: 100 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a solution of 12-chloro-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene-4-carboxamide (0.380 mmol, 100 mg) in 1,4-dioxane (3 mL) was added DMF-DMA (1.14 mmol, 147 mg). The mixture was stirred at 100° C. for 1 hour under nitrogen atmosphere. Then solvent was evaporated under reduced pressure, the residue was washed by ether to give 12-chloro-N-[(1E)-(dimethylamino)methylidene]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene-4-carboxamide (80 mg, 68% yield), which was used in the next step without further purification. LCMS (ESI) m/z: 320.1 [M+H+]
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20](=[O:21])[N:11]2[CH2:12][CH:13]=[CH:14][CH:15]([C:16]([O:18]C)=[O:17])[N:10]2[C:9]1=[O:22])(=O)C>C(OCC)(=O)C.CCCCCC>[SH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20](=[O:21])[N:11]2[CH2:12][CH:13]=[CH:14][CH:15]([C:16]([OH:18])=[O:17])[N:10]2[C:9]1=[O:22]
Reactant: COC(=O)C1C=CCn2c(=O)n(CCCSC(C)=O)c(=O)n21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)C1C=CCn2c(=O)n(CCCS)c(=O)n21
Yield: 35 %

Procedure:
In a manner analogous to that described in Example 32, from methyl 2,3,5,8-tetrahydro-2-(3-acetylthiopropyl)-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate there was obtained in 35% yield 2,3,5,8-tetrahydro-2-(3-mercaptopropyl)-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylic acid of melting point 119°-121° C. (from ethyl acetate/hexane).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:23])[N:4]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][CH:13]=2)=[O:11])[N:5]=[CH:6][C:7]=1Cl.[CH2:24]1[CH:31]2[C:27]3([NH2:33])[CH2:28][CH:29]([CH2:32][CH:25]1[CH2:26]3)[CH2:30]2.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C(=O)C>[Cl:1][C:2]1[C:3](=[O:23])[N:4]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][CH:13]=2)=[O:11])[N:5]=[CH:6][C:7]=1[NH:33][C:27]12[CH2:28][CH:29]3[CH2:32][CH:25]([CH2:24][CH:31]1[CH2:30]3)[CH2:26]2
Reactant: CCN(CC)c1ccc(C(=O)Cn2ncc(Cl)c(Cl)c2=O)cc1
Reactant: NC12CC3CC(CC1C3)C2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCN(CC)c1ccc(C(=O)Cn2ncc(NC34CC5CC(CC3C5)C4)c(Cl)c2=O)cc1
Yield: 18.2 %

Procedure:
4,5-Dichloro-2-{2-[4-(diethylamino)phenyl]-2-oxoethyl}pyridazin-3(2H)-one (30 mg, 0.0846 mmol), hexahydro-2,5-methanopentalen-3a(1H)-amine (22 mg, 0.126 mmol) and triethylamine (59 μL, 0.423 mmol) were stirred in N,N-dimethylacetamide (1 mL) at 90° C. for 3 days. After completion of the reaction, the reaction solution was mixed with aqueous ammonium chloride and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to give the desired product (7 mg, 17% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([N:32]2[C:37](=[O:38])[N:36](COCC[Si](C)(C)C)[C:35](=[O:47])[CH:34]=[N:33]2)[CH:29]=[C:28]([Cl:48])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:26]C)=[C:9]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[O:13])[CH:10]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[C:30]([N:32]2[C:37](=[O:38])[NH:36][C:35](=[O:47])[CH:34]=[N:33]2)[CH:29]=[C:28]([Cl:48])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:26])=[C:9]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=2)=[O:13])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)n(COCC[Si](C)(C)C)c3=O)cc2Cl)cc1NC(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)Nc1cc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.5 %

Procedure:
To a solution of 1-{5-[2,6-dichloro-4-(3,5-dioxo-4-(2-trimethylsilanyl-ethoxy-methyl)4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-2-methoxy-phenyl}-3-(4-trifluoromethoxy-phenyl)-urea (72 mg, 0.1 mmol) in CH2Cl2 was added dropwise BBr3 (1M in CH2Cl2, 4.0 mL, 0.4 mmol). The mixture was stirred at room temperature for 18 h and quenched with water (10 mL). After stirring at room temperature for 1 h, the quenched mixture was extracted with CH2Cl2 (3×10 mL). The combined CH2Cl2 extracts were dried and concentrated. The residue was purified by preparative TLC (10% MeOH in CH2Cl2) to afford the title compound (25.4 mg) of this EXAMPLE. MS Calc.:584.3 Found:581.8 (M−1).
Reaction SMILES: COC([C:5]1([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:9][CH2:8][C:7]([CH2:11][O:12][S:13]([CH3:16])(=[O:15])=[O:14])([CH3:10])[C:6]1=[O:17])=O.CS(O)(=O)=O>O>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH:5]2[CH2:9][CH2:8][C:7]([CH2:11][O:12][S:13]([CH3:16])(=[O:15])=[O:14])([CH3:10])[C:6]2=[O:17])=[CH:24][CH:23]=1
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(COS(C)(=O)=O)C1=O
Agent: CS(=O)(=O)O
Solvent: O
Product: CC1(COS(C)(=O)=O)CCC(Cc2ccc(Cl)cc2)C1=O
Temperature: 110 °C
Reaction time: 3.5 h

Procedure:
To 1.26 g of Compound 3-1-1 obtained in Production Example 2, 0.255 ml of methanesulfonic acid and 88.3 mg of water were added, and the resulting mixture was stirred at 110° C. for 3.5 hours. After the reaction, water was added to the reaction solution thus obtained, and extraction with ethyl acetate was then carried out. The extract was washed with an aqueous solution of sodium hydrogen carbonate and saturated brine. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled away.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH:11][CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15].[F:18][C:19]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[C:20]=1[C:21]([C:23]1[CH:24]=[C:25]([C:28](O)=[O:29])[NH:26][CH:27]=1)=[O:22].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:12][CH:13]([O:14][CH3:15])[O:16][CH3:17])[C:28]([C:25]1[NH:26][CH:27]=[C:23]([C:21](=[O:22])[C:20]2[C:19]([F:18])=[CH:34][C:33]([F:35])=[CH:32][C:31]=2[F:36])[CH:24]=1)=[O:29]
Reactant: COC(CNCc1nc2ccccc2[nH]1)OC
Reactant: O=C(O)c1cc(C(=O)c2c(F)cc(F)cc2F)c[nH]1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(CN(Cc1nc2ccccc2[nH]1)C(=O)c1cc(C(=O)c2c(F)cc(F)cc2F)c[nH]1)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a DMF 5 mL solution of product obtained in step A (693 mg, 2.95 mmol) were added 4-(2,4,6-trifluoro-benzoyl)-1H-pyrrole-2-carboxylic acid (793 mg, 2.95 mmol), EDC (678 mg, 3.53 mmol), HOBt (541 mg, 3.53 mmol) and triethylamine (0.821 mL, 5.89 mmol). The reaction mixture was stirred overnight at room temperature. Resulting suspension was filtered and diluted with EtOAc. The organic layer was washed with sat. ammonium chloride aq., sat. sodium bicarbonate aq. and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the title compound as oil (930 mg). LC/MS: m/z 487(M+H). 1H-NMR (500 MHz, CDCl3): δ 3.39 (s, 6H), 3.86 (br.s, 2H), 4.69 (d, 1H), 5.21 (s, 2H), 6.74 (t, 2H), 7.01 (br.s, 1H), 7.28 (s, 1H), 7.45 (dd, 2H), 7.65 (dd, 2H), 11.23 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:36](=[O:38])[CH3:37])[C:10]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([OH:32])[C:24]=3[CH2:33][CH2:34][CH3:35])=[CH:11][CH:12]=2)[CH:7]=1.[OH-].[Na+]>CO>[C:36]([C:9]1[C:10]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([OH:32])[C:24]=2[CH2:33][CH2:34][CH3:35])=[CH:11][CH:12]=[C:13]2[C:8]=1[CH:7]=[C:6]([O:5][CH2:4][C:3]([OH:39])=[O:2])[CH:15]=[CH:14]2)(=[O:38])[CH3:37]
Reactant: CCCc1c(OCCCCCOc2ccc3ccc(OCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCCCOc2ccc3ccc(OCC(=O)O)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 77.9 %

Procedure:
To a suspension of 1.45 g of [[8-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-2-naphthalenyl]oxy]acetic acid methyl ester in 54 ml of methanol, was added 27 ml of 1N sodium hydroxide. The reaction mixture was stirred at reflux for one hour and 20 minutes. The methanol was removed in vacuo and the aqueous residue was acidified to pH3. The precipitate was dissolved in chloroform, dried (magnesium sulfate), and the solid obtained from the concentrated chloroform solution was recrystallized from ethylacetate-hexane to yield 1.1 g, mp 103°-106° C. (78%) of [[8-Acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy]-2-naphthalenyl]oxy]acetic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[C:9]([F:21])=[C:10]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:6].[H-].[Na+]>C1COCC1.CCOC(C)=O>[F:21][C:9]1[C:8]([N:7]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])=[CH:17][C:16]([N+:18]([O-:20])=[O:19])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(NC(=O)CCCCl)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])cc(N2CCCC2=O)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.8 %

Procedure:
To a solution of methyl 3-[(4-chlorobutanoyl)amino]-2-fluoro-5-nitrobenzoate (D139) (8.5 g, 26.7 mmol, 1 equiv) in THF (100 ml) was added NaH (60% dispersion in mineral oil, 1.17 g, 29.4 mmol, 1.1 equiv) and the resulting mixture was stirred at room temperature for 1.5 h then diluted with AcOEt. The organic phase was washed with H2O, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 2/1) gave methyl 2-fluoro-5-nitro-3-(2-oxo-1-pyrrolidinyl)benzoate (D140) (3.3 g, 43%) as a yellow solid. [M+H]+=283.1, RT=2.53 min.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][N:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:1][N:2]([CH3:13])[C:3]1[CH:12]=[CH:11][C:6]([CH2:7][OH:8])=[CH:5][N:4]=1
Reactant: COC(=O)c1ccc(N(C)C)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CN(C)c1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 6-dimethylamino-nicotinate (4.14 g, 23.0 mmol) in anhydrous ether (80 mL) at 0° C. was treated with lithium aluminum hydride (1 M in ether, 20 mL, 20 mmol). The mixture was stirred at rt for 0.5 h, cooled again to 0° C. and quenched slowly with sat. aq. NaHCO3 (10 mL). The resulting mixture was stirred at rt for 0.5 h, filtered, and washed with ether. The combined filtrates were dried over Na2SO4 and concentrated to give the title compound as a beige waxy solid (3.5 g, 100%). MS (ESI), (M+H)+153.4; 1H NMR (CDCl3) δ8.06 (d, 1H, J=2.4), 7.47 (dd, 1H, J=2.4, 8.8), 6.45 (d, 1H, J=8.8), 4.50 (s, 2H), 3.06 (s, 6H), 1.98 (br s, 1H).
Reaction SMILES: [CH3:1][C:2](=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(OCC)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][CH:2]([OH:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCC(C)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Pentadecanone (200 g) was added a 3-litre three-necked flask under nitrogen, to which diethyl ether (1000 ml) was slowly added from a dropping funnel. Sodium borohydride (63.54 g) was then slowly added and the mixture stirred for two days at room temperature under nitrogen. Toluene was added to the reaction vessel and the contents transferred to a separating funnel. The organic layer was washed with water and the aqueous layer was collected. The aqueous layer was washed with toluene, which was combined with the previous organic layer. The product was dried with magnesium sulphate and filtered under vacuum. The solvent was then stripped on a rotary evaporator at 100° C. to yield the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[NH:32][C:33](=O)[O:34]C1C=CC=CC=1.O>CN(C)C=O.C(OCC)(=O)C>[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[NH:32][C:33]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:34]
Reactant: O=C(Nc1nccs1)Oc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc4c(ccn4C(=O)Nc4nccs4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
After dissolving 4-(1H-indol-5-yloxy)-6,7-dimethoxyquinoline (25 mg, 0.0780 mmol) in N,N-dimethylformamide (0.4 ml), sodium hydride (6 mg) was added and the mixture was stirred at room temperature for 15 minutes. Phenyl N-(2-thiazolyl)carbamate (30 mg, 0.1362 mmol) was further added and the mixture was stirred at 80° C. for 2 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the extract was washed with saturated saline and dried over anhydrous magnesium sulfate, and the filtrate was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate/ethanol system), the obtained crystals were suspended in ethanol and diluted with hexane, and then the crystals were filtered out, washed with hexane and dried by aspiration to obtain the title compound (23 mg, 0.0515 mmol, 66.04%) as light yellow crystals.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:36][C:37]1[C:45]([NH:46][S:47]([C:50]2[S:51][CH:52]=[CH:53][CH:54]=2)(=[O:49])=[O:48])=[C:44]2[C:40]([CH:41]=[C:42]([C:55]([NH:57][CH2:58][CH2:59][S:60]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=O)[NH:43]2)=[CH:39][CH:38]=1.C(=O)([O-])O.[Na+]>ClCCl>[S:60]1[CH2:59][CH2:58][N:57]=[C:55]1[C:42]1[NH:43][C:44]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[C:37]([CH3:36])[C:45]=2[NH:46][S:47]([C:50]1[S:51][CH:52]=[CH:53][CH:54]=1)(=[O:49])=[O:48]
Reactant: Cc1ccc2cc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]c2c1NS(=O)(=O)c1cccs1
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2cc(C3=NCCS3)[nH]c2c1NS(=O)(=O)c1cccs1
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
A mixture of triphenylphosphine oxide (1.5 g), trifluoromethanesulfonic anhydride (0.46 mL) and dichloromethane (25 mL) was stirred for 15 min under ice-cooling. 6-Methyl-7-[(2-thienylsulfonyl)amino]-N-[2-(tritylthio)ethyl]-1H-indole-2-carboxamide (0.57 g) was added, and the mixture was stirred for 4 hr under ice-cooling. The reaction mixture was poured into aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The aqueous layer was extracted with dichloromethane, and the combined dichloromethane layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were suspended in ethyl acetate-hexane, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-1:3), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (251 mg, yield 74%) as colorless prism crystals. melting point 183-184° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[OH:13][CH2:14][C:15]1([CH2:19][CH2:20][CH3:21])[CH2:18]O[CH2:16]1>>[CH3:1][O:2][CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]12[O:13][CH2:14][C:15]([CH2:19][CH2:20][CH3:21])([CH2:18][O:12]1)[CH2:16][O:11]2
Reactant: COCC#CCCCCC(=O)O
Reactant: CCCC1(CO)COC1
Product: CCCC12COC(CCCCC#CCOC)(OC1)OC2

Procedure:
1-(7-Methoxyhept-5-ynyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane was prepared from 8-methoxyoct-6-ynoic acid and 3-hydroxymethyl-3-n-propyloxetane using the methodology described in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:9]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][N:14]=2)[C:10](O)=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:9]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][N:14]=2)[CH2:10][Cl:29])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1nnnc1C(C(=O)O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: ClCCl
Product: Cn1nnnc1C(CCl)=C(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
To a solution of dry (0.1 mmHg at 80° C.) 3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)2-propenoic acid 3.8 g (11.0 mmoles) in 20 mL of dry methylene chloride was added 4 mL (46.0 mmoles) of purified oxalyl chloride (redistilled over CaH2) in one single portion. The reaction mixture was warmed gradually to reflux temperature for two hours. The mixture was evaporated under reduced pressure to remove volatile solvent, then excess oxalyl chloride was removed under vacuum (20 mmHg) at ambient temperature for 2 hours and under high vacuum (0.1 mmHg) at 50° C. for 16 hours to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:16][CH2:15][C:14]3(OCC(C)(C)C[O:17]3)[CH2:13][CH2:12]1)[C:7](=[O:24])[C:6]([C:25]([NH:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])=[O:26])=[C:5]2[OH:36]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)[C:7](=[O:24])[C:6]([C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[C:5]2[OH:36]
Reactant: CC1(C)COC2(CCC3(CC2)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C(O)c2cc(Cl)ccc23)OC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCC(=O)CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
A mixture of 1,1-dimethylethyl N-((6″-chloro-4″-hydroxy-5,5-dimethyl-2″-oxo-dispiro[1,3-dioxane-2,1′-cyclohexane-4′,1″-naphthalen]-3″-yl)carbonyl)glycinate (18 mg, 35 μmol) in 1 mL TFA was stirred at room temperature for 30 minutes, M+1=378. The mixture was concentrated in vacuo, and dried under high vacuum to give 11 mg of the product as an off-white solid. MS (m/z)=378 (M+H)+. Calculated for C18H16ClNO6 377.07.
Reaction SMILES: [CH3:1][N:2]1[C:18]2([CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[C:6]2=[CH:7][C:8]([C:14]([F:17])([F:16])[F:15])=[C:9]([C:10]([F:13])([F:12])[F:11])[N:5]2[CH2:4][CH2:3]1.Cl>C(Cl)Cl>[CH3:1][N:2]1[C:18]2([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:6]2=[CH:7][C:8]([C:14]([F:15])([F:16])[F:17])=[C:9]([C:10]([F:12])([F:11])[F:13])[N:5]2[CH2:4][CH2:3]1
Reactant: CN1CCn2c(cc(C(F)(F)F)c2C(F)(F)F)C12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: ClCCl
Product: CN1CCn2c(cc(C(F)(F)F)c2C(F)(F)F)C12CCNCC2
Reaction time: 0.5 h
Yield: 2 %

Procedure:
tert-Butyl 2-methyl-6,7-bis(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (from step 1) was taken up in CH2Cl2 (2 mL) and HCl (1.7 mL of 4 M, 6.8 mmol) was added. The mixture was allowed to stir for 30 min before it was concentrated under reduced pressure. The residue was taken up in ethyl acetate and was washed with sat. aq. NaHCO3, then brine. The organic layer was dried over sodium sulfate, filtered and concentrated to give 2-methyl-6,7-bis(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine] (22 mg, 2% over 2 steps). ESI-MS m/z calc. 341.1, found 342.3 (M+1)+; Retention time: 1.29 minutes.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[CH3:13][CH:14]1[CH2:19][CH:18]([CH3:20])[CH2:17][NH:16][CH2:15]1>C(O)C>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([N:16]2[CH2:17][CH:18]([CH3:20])[CH2:19][CH:14]([CH3:13])[CH2:15]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: CC1CNCC(C)C1
Solvent: CCO
Product: CC#CCOc1cc(N2CC(C)CC(C)C2)ncn1
Temperature: 25 °C
Reaction time: 10 h
Yield: 103.3 %

Procedure:
Into 3 ml of ethanol was resolved 0.3 g of 4-(2-butynyloxy)-6-chloropyrimidine, 0.56 g of 3,5-dimethylpiperidine (cis/trans=about 3/1) was added therein, and the mixture was stirred for 10 hours under reflux condition. The reaction mixture was cooled to near room temperature, and concentrated. Into the residue was added a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.44 g of 4-(2-butynyloxy)-6-(3,5-dimethylpiperidino)pyrimidine (hereinafter, referred to as Compound (7)). Compound (7) had the cis/trans diastereomer originated two methyls on the piperidine ring. The ratio of the cis/trans diastereomer was about 3.1/1.