Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][CH:7]([C:14]1([NH:19][CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Si:29]([O:36][CH2:37][CH:38]=O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:24]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][CH:7]([C:14]1([N:19]([CH2:38][CH2:37][O:36][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CNC1(C(NC(=O)c2cccc(C(F)(F)F)c2Cl)c2ccccc2)CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(CCO[Si](C)(C)C(C)(C)C)C1(C(NC(=O)c2cccc(C(F)(F)F)c2Cl)c2ccccc2)CCCC1
Yield: 99.9 %

Procedure:
The title compound (0.390 g, 99%) was prepared from (±)-2-chloro-N-[[1-(methylamino)cyclopentyl](phenyl)methyl]-3-(trifluoromethyl)benzamide (0.282 g; 0.686 mmol), (tert-butyldimethylsilyloxy acetaldehyde (90%; 0.265 g; 1.52 mmol) and sodium triacetoxyborohydride (0.290 g; 1.52 mmol) in DCM (5 ml) in a similar manner to that described in E30. Mass Spectrum (Electrospray LC/MS). Found 569 (MH+). C29H4035ClF3N2O2Si requires 568. Ret. time: 3.04 min.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)[S:6][CH:7]=1.[OH-].[Na+:23]>O>[F:21][C:2]([F:1])([F:20])[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C@H:15]([CH3:19])[C:16]([O-:18])=[O:17])=[CH:13][CH:14]=2)[S:6][CH:7]=1.[Na+:23]
Reactant: C[C@H](C(=O)O)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@H](C(=O)[O-])c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
In a 100 ml round-bottomed flask equipped with a magnetic stirrer, compound 3 (7.26 gr, 22.9 mmol) was suspended in water (30 ml) and 2N NaOH (11.45 ml, 22.9 mol) was slowly added. The resulting dark red solution was stirred for 1 h at room temperature, filtered on a 0.45μ filter and freeze dried. Pure sodium (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate 3a (7.51 g, 22.2 mmol) was obtained as white solid (97%). m.p. 142°-145° C. [α]D=−8.7 (c=0.62; CH3OH); 1H-NMR (D2O): δ 9.00 (bs, 1H, NH), 7.30 (m, 4H), 7.28 (s, 1H), 3.55 (q, 1H, J=7 Hz), 1.35 (d, 3H, J=7 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])=[O:17])[CH3:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH2:29][CH2:30][CH3:31]>CS(C)=O.O>[CH2:28]([O:20][C:19](=[O:21])[CH2:18][S:16]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1)[CH3:15])=[O:17])[CH2:29][CH2:30][CH3:31]
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCOC(=O)CS(=O)C(C)c1ccc(-c2ccccc2F)cc1

Procedure:
1.5 gm (5 millimols) of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid, m.p. 164° - 165° C, were stirred with 1.05 gm of potassium carbonate and 0.9 ml of n-butyl bromide in 15 ml of dimethyl sulfoxide for 60 hours. The mixture was subsequently diluted with water, and the reaction product was extracted with toluene. After washing, drying and evaporating the extract, the residue (1.7 gm) was recrystallized from cyclohexane. Yield: 1.2 gm (67% of theory); m.p.: 72° - 74° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:18]([NH:22][OH:23])([CH3:21])([CH3:20])[CH3:19]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[N+:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[O-:23])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)NO
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)(C)[N+]([O-])=Cc1ccc(OCc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared by refluxing a benzene solution of 4-(4-fluorobenzyloxy)benzaldehyde and N-tert-butylhydroxylamine for 21 hours with p-toluenesulfonic acid as a catalyst. The title compound was obtained as a solid in 98.5% yield, m.p. 180.3° C. (Rf=0.16 on a silica gel plate using hexanes: EtOAc, 1:1, v/v, as an eluant).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].NN>[Ni].CO>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: [Ni]
Agent: NN
Solvent: CO
Product: CC(=O)c1c[nH]c2ccc(N)cc12
Reaction time: 1 h
Yield: 99 %

Procedure:
A suspension of 3-acetyl-5-nitroindole (3.0 g, 14.7 mmol) and Raney Nickel (3.0 g) in methanol is treated dropwise with hydrazine (0.7 g, 21.9 mmol) at 0° C., stirred under N2 for 1 h and filtered. The filtrate is concentrated in vacuo to afford the title product as an oil, 2.5 g (99% yield) identified by NMR and mass spectral analyses.
Reaction SMILES: O(C([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH:12]=2)[CH:7]=1)(C)C)O.CC(C)=[O:22]>S(=O)(=O)(O)O>[OH:22][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH:12]=2)[CH:7]=1
Reactant: CC(C)=O
Reactant: COC(=O)c1ccc2cc(C(C)(C)OO)ccc2c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2cc(O)ccc2c1

Procedure:
In the case where 1.0 g of the present compound, methyl 2-(2-hydroperoxy-2-propyl)naphthalene-6-carboxylate are heated in 10.0 g of acetone for 30 min at a temperature between 50° and 70° C. in the presence of 0.02 g of sulfuric acid as a catalyst, methyl 2-hydroxynaphthalene-6-carboxylate is formed nearly quantitatively. The thus formed compound is hydrolyzed nearly quantitatively into 2-hydroxynaphthalene-6-carboxylic acid (acid-6) by heating the thus formed compound for 30 min at a temperature between 20° and 50° C. in an aqueous about 1N alkali solution.
Reaction SMILES: Cl[C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.Cl.Cl.[CH2:19]([N:26]1[C:34]2[CH2:33][CH2:32][NH:31][CH2:30][C:29]=2[N:28]=[CH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>COCCO.O>[CH2:19]([N:26]1[C:34]2[CH2:33][CH2:32][N:31]([C:2]3[NH:11][C:10](=[O:12])[C:9]4[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=4)[N:3]=3)[CH2:30][C:29]=2[N:28]=[CH:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(Cn2cnc3c2CCNC3)cc1
Reactant: COc1cc2nc(Cl)[nH]c(=O)c2cc1OC
Agent: Cl
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc2nc(N3CCc4c(ncn4Cc4ccccc4)C3)[nH]c(=O)c2cc1OC
Temperature: 120 °C
Reaction time: 6 h
Yield: 29.9 %

Procedure:
A mixture of 2-chloro-6,7-dimethoxy-3H-quinazolin-4-one 1 (wherein R is methyl and Z is —C(O)—, 296 mg, 1.24 mmol), 1-benzyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine dihydrochloride 15a (440 mg, 1.54 mmol)) and diisopropylethylamine (1.2 g, 9.26 mmol) in 2-methoxyethanol (10 mL) was stirred at 120° C. for 6 hours. The reaction mixture was concentrated in vacuo to give an oil residue, which was diluted with water. The white precipitate that formed was collected by filtration to give 155 mg of 2-(1-benzyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-6,7-dimethoxy-3H-quinazolin-4-one 501, [M+H]+=418.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[CH2:12]([CH:30]([CH2:34][C:35]([O-])=[O:36])[C:31]([O-])=[O:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C.S(=O)(=O)(O)O>[CH2:12]([CH:30]1[CH2:34][C:35](=[O:36])[N:1]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[OH:11])[C:31]1=[O:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CCCCCCCCCCCCCCCCCCC(CC(=O)[O-])C(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCC1CC(=O)N(c2ccc([N+](=O)[O-])cc2O)C1=O
Temperature: 25 °C

Procedure:
In 3 liters of ethyl acetate and 50 ml of concentrated sulfuric acid were dissolved by heating 150 g of 2-amino-5-nitro-phenol and 350 g of octadecylsuccinate and the resulting solution was boiled under reflux for further 30 hours. Thereafter, the solution was cooled up to room temperature and washed twice with 2 liters of 10% hydrochloric acid and twice with 10% sodium carbonate solution. Then, ethyl acetated was distilled off and the residue was recrystallized from hexane to afford light yellow powdery crystal melting at 115°-120° C. in the yield of 153 g.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[O:13][C:12]([CH2:14][N:15]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[N:16]3)=[N:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[O:13][C:12]([CH2:14][N:15]3[CH:19]=[CH:18][C:17]([NH2:20])=[N:16]3)=[N:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2cnc(Cn3ccc([N+](=O)[O-])n3)o2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1(c2cnc(Cn3ccc(N)n3)o2)OCCO1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(2-methyl-[1,3]dioxolan-2-yl)-2-(3-nitro-pyrazol-1-ylmethyl)-oxazole (23 mg, 0.08 mmol), iron powder (14 mg, 0.25 mmol) and NH4Cl (22 mg, 0.41 mmol) in a mixture of EtOH (1.0 mL) and water (0.5 mL) was stirred at 85° C. for 15 min. The reaction mixture was filtered while hot, dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.56 min; [M+H]+=251.38.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Cl:13][C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1>CCOCC>[Cl:13][C:14]1[N:19]=[C:18]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Clc1ncccn1
Reactant: Ic1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Clc1nccc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of iodobenzene (3.53 ml) in ether (10 ml) was added n-butyllithium (1.6M in hexane, 20 ml), and the mixture was stirred at room temperature for 20 minutes. The above solution was added to a solution of 2-chloropyrimidine (3.52 g) in ether (90 ml) at −30° C. The mixture was stirred at −30° C. for 30 minutes and then at 0° C. for 30 minutes, quenched with a solution of acetic acid (1.83 ml) and water (0.31 ml) in tetrahydrofuran (6 ml), and treated with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (7.26 g) in tetrahydrofuran (30 ml). The mixture was stirred at 0° C. for 5 minutes, cooled to 0° C., treated with a cold aqueous solution of sodium hydroxide (3M, 9.2 ml), and stirred at 0° C. for 5 minutes. The organic phase was separated, washed with water and brine, dried over magnesium sulfate, concentrated and subjected to silica gel column chromatography (hexane-ethyl acetate, 7:3) to afford 2-chloro-4-phenylpyrimidine (3.39 g) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1)#[N:2].[C:16](OC)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[SH:19].C(N(CC)CC)C.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:12]([N:9]([CH2:10][CH3:11])[C:7](=[O:8])[C:6]1[CH:14]=[CH:15][C:3]([C:1]2[S:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:16](=[O:24])[N:2]=2)=[CH:4][CH:5]=1)[CH3:13]
Reactant: CCN(CC)C(=O)c1ccc(C#N)cc1
Reactant: COC(=O)c1ccccc1S
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc(-c2nc(=O)c3ccccc3s2)cc1
Yield: 30.5 %

Procedure:
A mixture of 4-cyano-N,N-diethylbenzamide (0.60 g, 3.0 mmol), methyl thiosalicylate (0.75 g, 4.5 mmol), triethylamine (0.54 g, 5.3 mmol) and toluene (5 ml) was heated and refluxed under a nitrogen flow for 70 hours. To the reaction solution, ethyl acetate was added and the solid precipitated was removed by filtration. After the filtrate was ice-cooled, the crystals precipitated were taken by filtration and recrystallized from ethyl acetate to give the title compound (0.31 g, 30%) as crystals.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>ClCCl.Cl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[CH:7][CH:8]=1
Reactant: C1=COCCC1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Product: FC(F)(F)c1ccc(OC2CCCCO2)cc1
Yield: 133.3 %

Procedure:
A solution of 4-(Trifluoromethyl)-phenol (40 g) in dichloromethane (100 ml) was added at 0° C. dropwise to a solution of dihydropyran (53 g) in dichloromethane (100 ml) and aqueous HCl (200 μl) The reaction was allowed to reach room temperature, then quenched with saturated sodium bicarbonate (×1). The organic layer was separated and dried (MgSO4), concentrated in vacuo to give the sub-title compound (81 g)
Reaction SMILES: C([C:3]1[Se:7][C:6]([C@@H:8]2[O:30][C@H:29]([CH2:31][O:32]C(=O)C3C=CC=CC=3)[C@@H:19]([O:20]C(=O)C3C=CC=CC=3)[C@H:9]2[O:10]C(=O)C2C=CC=CC=2)=[N:5]C=1C(N)=O)C.C[O-].[Na+].C1(C)C=CC=CC=1.[C:54]([O:57][CH2:58]C)(=[O:56])[CH3:55]>CO>[C@@H:8]1([C:6]2[Se:7][CH:3]=[C:55]([C:54]([O:57][CH3:58])=[O:56])[N:5]=2)[O:30][C@H:29]([CH2:31][OH:32])[C@@H:19]([OH:20])[C@H:9]1[OH:10]
Reactant: CCOC(C)=O
Reactant: CCc1[se]c([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)nc1C(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1c[se]c([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Temperature: 25 °C

Procedure:
A gummy suspension of 206.3 g (75.1% pure by HPLC; 0.239 mol) of the blocked ethyl ester, IV, in 700 ml of methanol was heated and stirred on the steam bath until solution occurred. The solution was allowed to cool to room temperature during which time a finely dispersed oily suspension formed. To this suspension was added 17.2 g (318 mmol) of sodium methoxide. The addition was slightly exothermic and resulted in a brown solution. The solution was stirred at room temperature overnight. TLC (SiO2, toluene-ethyl acetate, 10:1) indicated that no starting material remained. To the reaction solution was added 100 g of Dowex 50 W×4 resin (H+) (washed with methanol) and the suspension was stirred for one hour. The resin was filtered off, washed well with methanol, and discarded. The filtrate and washings were evaporated under reduced pressure to give a two phase mixture. The upper, more liquid phase (mainly methyl benzoate) was decanted. The remaining brown viscous gum was triturated two times with ether. (The methyl benzoate was combined with the ether triturates and upon standing yielded some desired product as a solid). The brown viscous gum was treated with approximately 1 l of warm ethanol and triturated. A dark brown material was filtered from the suspension. TLC (SiO2; dichloromethane-methanol, 10:1) indicated that the dark brown material was mostly slower moving impurities in the filtrate and was discarded.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:12])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[OH:4].C(NC(C)C)(C)C.Br[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[O:37])=[C:32]([S:43][CH:44]([CH3:46])[CH3:45])[CH:31]=2)=[CH:26][CH:25]=1.O1CCOCC1.[ClH:53]>CN(C)C=O>[ClH:53].[OH:4][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[C@@H:2]([NH:1][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[O:37])=[C:32]([S:43][CH:44]([CH3:45])[CH3:46])[CH:31]=2)=[CH:28][CH:29]=1)[CH3:12]
Reactant: CC(C)Sc1cc(-c2ccc(OCCBr)cc2)ccc1C(=O)NS(C)(=O)=O
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: C1COCCO1
Product: CC(C)Sc1cc(-c2ccc(OCCN[C@@H](C)[C@H](O)c3ccc(O)cc3)cc2)ccc1C(=O)NS(C)(=O)=O
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of 4-[(1R,2S)-2-amino-1-hydroxypropyl]-phenol (96.6 mg) in N,N-dimethylformamide (1.00 ml) were added diisopropylamine (156 μl) and 4′-(2-bromoethoxy)-3-(isopropylthio)-N-(methylsulfonyl)-4-biphenylcarboxamide (210 mg) at room temperature and stirred at 100° C. for 5 hours. To the reaction mixture was added hydrogen chloride 1,4-dioxane solution (4M, 464 μl) and stirred at 0° C. The mixture was filtrated and the filtrate was concentrated in vacuo. The residue was washed with ethyl ether three times, dried and purified with reverse phase silica gel column chromatography. To the resulting solution was added hydrogen chloride ethyl acetate solution (4M, 111 μl) and concentrated in vacuo to give 4′-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethoxy]-3-(isopropylthio)-N-(methylsulfonyl)-4-biphenylcarboxamide hydrochloride (108 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([O:21]CC)=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].O[Li].O>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2]
Reactant: CCOC(=O)c1cnc(N2CCC[C@@H](Oc3ccccc3OCC)C2)nc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Temperature: 22.5 °C
Reaction time: 24 h
Yield: 78.5 %

Procedure:
To a solution of ethyl (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylate (71.5 g, 193 mmol) in THF/H2O (1:1, 2 L) was added LiOH.H2O (24.2 g, 578 mmol) at 20-25° C. The reaction mixture was stirred at 20-25° C. for 24 hours. The mixture was concentrated, and the aqueous phase was washed with diethyl ether (2 times with 500 mL). The aqueous phase was acidified to pH 2 with 1N HCl (˜400 mL). The precipitated solid was filtered and dried to afford (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (52 g, 78%). MS (ES+) 344.18 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][CH:9]([CH3:12])[C:8]2[N:7]=[C:6]([C:13]3[O:14][CH:15]=CC=3)[CH:5]=[CH:4][C:3]1=2.[O:18]=[O+][O-].O=O.CSC.CI.C([O-])([O-])=O.[K+].[K+]>CO.CC(N(C)C)=O.O>[CH3:1][CH:2]1[CH2:11][CH2:10][CH:9]([CH3:12])[C:8]2[N:7]=[C:6]([C:13]([O:14][CH3:15])=[O:18])[CH:5]=[CH:4][C:3]1=2
Reactant: O=[O+][O-]
Reactant: CC1CCC(C)c2nc(-c3ccco3)ccc21
Agent: O=C([O-])[O-]
Agent: O=O
Agent: [K+]
Solvent: CO
Solvent: CSC
Solvent: CI
Product: COC(=O)c1ccc2c(n1)C(C)CCC2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5,8-Dimethyl-2-(2-furyl)-5,6,7,8-tetrahydroquinoline (3 g) was dissolved in 100 ml of methanol. Ozone generated from oxygen at −78° C. was introduced into the obtained solution for 10 minutes. The resulting system was saturated with nitrogen gas, followed by the addition of 7 ml of dimethyl sulfide. The temperature of the mixture was raised to room temperature and the resulting reaction mixture was concentrated to give about 3 g of a crude product. This crude product containing a caroxylic acid was dissolved in 10 ml of DMA, followed by the addition of 1 ml of methyl iodide and 3.6 g of K2CO3. The obtained mixture was stirred at room teperature for one hour, followed by the addition of 30 ml of water. The obtained mixture was extracted with ethyl acetate (50 ml×2) and the organic phase was washed with a saturated aqueous solution of common salt, dried over MgSO4 and concentrated. The obtained mixture was purified by column chromatography to give 1.6 g of the objective compound.
Reaction SMILES: [Br:1][C:2]1[C:3]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][C:4]=2[C:5](=O)[NH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].P(Cl)(Cl)([Cl:26])=O>>[Br:1][C:2]1[C:3]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][C:4]=2[C:5]([Cl:26])=[N:6][CH:7]=1
Reactant: O=c1[nH]cc(Br)c2sc(-c3ccccc3)cc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Clc1ncc(Br)c2sc(-c3ccccc3)cc12

Procedure:
A mixture of 7-bromo-2-phenyl-5H-thieno[3,2-c]pyridin-4-one 3 (2.28 g, 7.5 mmol) in phosphorus oxychloride (27 mL) was heated at reflux for 21 h. The reaction mixture was basified to pH 5–6 by the addition of saturated aqueous sodium carbonate and extracted with dichloromethane (1×). The organic layer was dried over Na2SO4, filtered, and the filtrate was purified by silica gel column chromatography (eluent: hexane:EtOAc, 97:3) to give 95. 1H NMR (400 MHz, CDCl3) δ: 7.41–7.52 (m, 3H), 7.72–7.78 (m, 3H), 8.28 (s, 1H). MS (EI) m/z (M+H+) 324.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28].N1C=CC=CC=1.O>ClCCCl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:27](=[O:28])[C:23]2[S:22][CH:26]=[CH:25][CH:24]=2)[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: O=C(Cl)c1cccs1
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Solvent: O
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)c1cccs1
Yield: 47.2 %

Procedure:
2-oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.0 g) obtained from Referential Example 7 was suspended in 1,2-dichloroethane (20 ml), 2-thiophencarbonyl chloride (1.11 g) and pyridine (0.60 g) were added to the suspension, and the mixture was refluxed for 3 hours. The reaction mixture was allowed to cool, water was added to the mixture, extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 1.30 g of the title compound as a light yellow crystal.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[C:5]([NH:7][C:8]1[CH:33]=[C:32]([CH3:34])[C:11]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18](C(=O)C(OCC)=O)[N:17]=[C:16]3[CH:29]([CH3:31])C)=[C:10]([CH3:35])[CH:9]=1)=[O:6])[CH3:2].[O-][CH2:38]C.[Na+].[Cl-].[NH4+]>C(O)C>[CH3:35][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]([O:3][CH2:1][CH3:2])=[O:36])[CH:33]=[C:32]([CH3:34])[C:11]=1[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[CH2:29][CH2:31][CH3:38]
Reactant: CC[O-]
Reactant: CCOC(=O)C(=O)Nc1cc(C)c(Oc2ccc3c(c2)c(C(C)C)nn3C(=O)C(=O)OCC)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: CCCc1n[nH]c2ccc(Oc3c(C)cc(NC(=O)C(=O)OCC)cc3C)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of 56 mg (0.113 mmol) of ethyl [5-(4-{[ethoxy(oxo)acetyl]amino}-2,6-dimethylphenoxy)-3-isopropyl-1H-indazol-1-yl](oxo)acetate in 6 ml of ethanol is treated with a spatula-tipful of sodium ethoxide and stirred at room temperature for 30 min. 5 ml of satd ammonium chloride solution are added, the aqueous phase is extracted 2× with ethyl acetate, and the combined organic phases are washed 1× with water, dried over sodium sulphate and concentrated in vacuo and dried. 28 mc, (63%) of ethyl ({3,5-dimethyl-4-[(3-propyl-1H-indazol-5-yl)oxy]phenyl}amino)(oxo)-acetate are obtained.