Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)(=[O:3])[CH3:2].[Br:13]CC(C1N=CC2CCCCC=2C=1)=O>>[Br:13][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)=[O:3]
Reactant: O=C(CBr)c1cc2c(cn1)CCCC2
Reactant: CC(=O)c1ccc2c(c1)CCO2
Product: O=C(CBr)c1ccc2c(c1)CCO2

Procedure:
*5-Bromoacetyl-2,3-dihydro-1-benzofuran was prepared from 5-acetyl-2,3-dihydro-1-benzofuran according to the procedure for preparing 3-bromoacetyl-5,6,7,8-tetrahydroisoquinoline described in Example 1.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][N:12](C(OC(C)(C)C)=O)[C:11](=[O:21])[C:10]2[CH:22]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)[NH:24][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([CH:8]1[CH2:13][NH:12][C:11](=[O:21])[C:10]2[CH:22]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)[NH:24][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(Cc2ccccc2)c2[nH]c(-c3cccc4cccnc34)cc2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCC(Cc2ccccc2)c2[nH]c(-c3cccc4cccnc34)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.3 %

Procedure:
A mixture of rac-tert-butyl 7-benzyl-4-oxo-2-(quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridine-5(4H)-carboxylate (200 mg, 0.441 mmol), DCM (10 mL), and TFA (2 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo, and the residue was suspended in 1N aq. HCl (10 mL) and washed with EtOAc (5 mL). The aq. layer was neutralized with sat. aq. NaHCO3 (5 mL) and extracted with EtOAc (2×10 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by preparative TLC (80% EtOAc/petroleum ether) afforded rac-7-benzyl-2-(quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (30 mg, 0.085 mmol, 19% yield) as a pale green solid: 1H NMR (400 MHz, DMSO-d6) δ 12.29 (1H, br s), 8.92 (1H, dd, J=1.6 Hz & 2.8 Hz), 8.47 (1H, dd, J=1.6 Hz & 6.8 Hz), 8.21 (1H, d, J=7.2 Hz), 7.86 (1H, d, J=8 Hz), 7.67-7.62 (2H, m), 7.43-7.40 (4H, m), 7.33-7.30 (1H, m), 7.18 (1H, d, J=2 Hz), 7.06 (1H, br s), 3.48-3.40 (1H, m), 3.20-3.10 (2H, m), 2.92-2.86 (2H, m). m/z (ESI, +ve) 353.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(Cl)cc3)c1)N2
Yield: 78.6 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (4.0 g, 10.3 mmol), 4-chlorophenylboronic acid (2.1 g, 13.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.1 mmol) in dioxane (10 mL) was added 2 M sodium carbonate solution in water (10 mL, 20 mmol). The resulting mixture was subjected to microwave irradiation for 60 min at 110° C. The mixture was diluted with ethyl acetate (150 mL), washed with saturated aqueous sodium bicarbonate solution (30 mL×2), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) afforded 2-(4′-chloro-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.4 g, 80%) as a white solid: LC/MS m/e calcd for C26H26ClNO2 (M+H)+: 420.96, observed: 420.5.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH3:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:29][C:30]([CH3:32])=O.C(O)(=O)C>CN(C=O)C.O>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:30]([CH3:32])[CH3:29])[CH2:10][C@H:9]1[CH3:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)=O
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)OC(C)(C)C)[C@H](C)C1
Temperature: 60 °C

Procedure:
To (R)-1-Boc-2-methylpiperazine (200.0 mg, 0.999 mmol) and sodium triacetoxyborohydride (444.5 mg, 2.097 mmol) in DMF (5 mL) was added acetone (116 mg, 0.147 mL, 1.997 mmol) and acetic acid (90.0 mg, 86 μL, 1.498 mmol). The reaction mixture was heated at 60° C. for 1 h. The reaction mixture was diluted with water and extracted three times with diethyl ether. The combined organics were dried over sodium sulfate, filtered, concentrated, and used without further purification. LCMS-ESI+: calc'd for C13H27N2O2 (M+H+): 243.2; Found: 243.1 (M+H+).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[C:16]([F:17])=[CH:15][C:14]([C:18]#[N:19])=[C:13]([O:20][CH3:21])[C:12]=2[F:22])[N:8]=[CH:7][C:6]=1[Cl:23])(=O)C.[OH-:24].[Na+].Cl.[CH3:27][OH:28]>O>[NH2:4][C:5]1[CH:10]=[C:9]([C:11]2[C:16]([F:17])=[CH:15][C:14]([C:18]#[N:19])=[C:13]([O:20][CH3:21])[C:12]=2[F:22])[N:8]=[C:7]([C:27]([OH:28])=[O:24])[C:6]=1[Cl:23]
Reactant: [OH-]
Reactant: CO
Reactant: COc1c(C#N)cc(F)c(-c2cc(NC(C)=O)c(Cl)cn2)c1F
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1c(C#N)cc(F)c(-c2cc(N)c(Cl)c(C(=O)O)n2)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A slurry of 4-acetylamino-3-chloro-6-(4-cyano-2,6-difluoro-3-methoxyphenyl)pyridine (0.13 g, 0.33 mmol) in methanol (5 mL) was treated with 1N sodium hydroxide (1.7 mL) and stirred at ambient temperature for 1 hour. The solution was diluted with water (15 mL) and acidified with 1N hydrochloric acid (1.7 mL) and the solid collected (0.095 g). Analysis by 1H NMR showed the 4-amino-3-chloro-6-(4-cyano-2,6-difluoro-3-methoxyphenyl)pyridine-2-carboxylic acid and an impurity. This material was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.[C:13](Cl)(=[O:15])[CH3:14].O.Cl>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC(=O)Cl
Reactant: CC1(C)CCSc2ccccc21
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCS2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 14.3 g (80.21 mmol) of 4,4-dimethyl thiochroman (from Example 2) and 6.76 g (86.12 mmol) of acetyl chloride in 65 ml benzene was cooled in an ice bath and treated dropwise with 26.712 g (102.54 mmol) of stannic chloride. The mixture was stirred at room temperature for 12 hours, then treated with 65 ml water and 33 ml conc. hydrogen chloride and heated at reflux for 0.5 hours. After being cooled to room temperature, the organic layer was separated and the aqueous layer extracted with 5×50 ml benzene. The recovered organic fractions were combined and washed with 5% sodium carbonate solution, water, saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) followed by kugelrohr distillation (150° C., 0.7 mm) to give the title compound as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Cl>CN(C)C=O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9]
Reactant: COc1cccc(CCl)c1
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(CN2CCCCC2=O)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 108.9 %

Procedure:
In 6 ml of N,N-dimethylformamide was suspended 0.8 g of 60% sodium hydride and thereto was added dropwise a solution of 1.98 g of 2-piperidone in 8 ml of N,N-dimethylformamide under a stream of argon and with ice cooling. Then, to the mixture was added dropwise a solution of 2.82 g of 3-methoxybenzyl chloride in 8 ml of N,N-dimethylformamide at room temperature. The mixture was stirred at 65° C. for 8 hours. After cooling, to the reaction mixture were added ice-cold water and the mixture was extracted with diethyl ether. The extract was purified by a silica gel column chromatography (chloroform:methanol=20:1) to give 4.3 g of 1-(3-methoxybenzyl)-2-piperidone. This compound was heated in 10 ml of 47% hydrobromic acid for 12 hours. The mixture was made alkaline with addition of sodium carbonate and extracted with chloroform. After removing the solvent at a reduced pressure, 2.3 g (yield 57%) of 1-(3-hydroxybenzyl)-2-piperidone was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]2[CH2:15][O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S-:17].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]([OH:14])[CH2:15][S:17][CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]([C@H]2CO2)C1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC[C@@H](O)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
(R)—(S)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (1.0 g, 4.7 mmol, 1.0 eq.) in DMF (10 mL) was combined with sodium methyl mercaptide (2.5 g, 14.1 mmol, 3.0 eq.), and the resulting mixture was stirred at 50° C. for 3 hours under nitrogen. Upon completion of the reaction, the mixture was concentrated under vacuum, extracted with EtOAc, washed with saturated aqueous NaCl and water, dried, and concentrated. The crude product was purified by preparative HPLC (MeCN:EtOH=4:6) to yield the title compound (700 mg).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:18][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[N:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:11][CH:6]2[CH2:5][CH2:4]1.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[CH:23]2.Cl>>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH2:2][CH:3]1[CH2:18][N:7]3[CH2:8][CH2:9][N:10]([C:12]4[N:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[CH2:11][CH:6]3[CH2:5][CH2:4]1)[CH:24]=[CH:23]2
Reactant: OCC1CCC2CN(c3ncccn3)CCN2C1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: Cl
Product: Fc1ccc2c(ccn2CC2CCC3CN(c4ncccn4)CCN3C2)c1

Procedure:
The title compound was synthesized according to Example 9 from (7RS,9aSR)-7-hydroxymethyl-2-(pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 3) and 5-fluoroindole. mp (.HCl) 70–72° C. HRMS calcd for C21H25FN5(MH+): 366.2094, found: 366.2104.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](C)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([CH2:36][CH3:37])=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:36]([C:33]1[N:32]=[CH:31][C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:38])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:35][CH:34]=1)[CH3:37]
Reactant: CCc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (2-{3-[3-(6-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M174) (287 mg, 0.53 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (184 mg, 82%).
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[C:6]([O:9][C:10](=[O:12])[CH3:11])(=[O:8])[CH3:7]>>[C:1]1(=[O:8])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:6]([O:9][CH:10]1[CH2:11][CH2:5][CH:1]=[CH:2][O:12]1)(=[O:8])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: C1=CCCC1
Product: CC(=O)OC1CCC=CO1
Product: O=C1C=CCC1

Procedure:
Synder et al. J.A.C.S. 81, 4299-4300 (1959) claimed that the light-catalyzed liquid-phase autoxidation of cyclopentene in the presence of acetic anhydride gave cyclopentenone and 2-acetoxy-3,4-dihydro-[2H]-pyran.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:23])=[CH:5][C:6]([Cl:22])=[C:7]([C:9]2[NH:10][C:11](=[O:21])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:13]=2)[CH:8]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[Cl:22][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:21])[N:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:4]([F:23])[CH:5]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1cc(-c2nn(-c3ccc(Cl)cc3)c(=O)[nH]2)c(Cl)cc1F
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1cc(-c2nn(-c3ccc(Cl)cc3)c(=O)[nH]2)c(Cl)cc1F

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-chlorophenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-78, 0.120 g), pivaloyl chloride (0.5 mL), TEA (2.0 mL), dry THF (5 mL) to afford 0.033 g of the desired product. 1H NMR (300 MHz, DMSO): δ 1.12 (s, 9H), 4.30 (br s, 2H), 7.53-7.63 (m, 4H), 7.95 (d, J=12.8 Hz, 2H), 8.14 (s, 1H), 12.61 (s, 1H); MS (m/z): 437.47 (M+H)+.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-].[H-].[Na+].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:17]([C:22](=O)[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O.C(O)(=O)C>CN(C)C=O>[Cl:29][C:25]1[CH:24]=[C:23]([C:22]2[C:17]3[C:14](=[CH:13][C:12]([O:11][CH3:10])=[C:19]([O:20][CH3:21])[CH:18]=3)[CH:15]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[N:1]=2)[CH:28]=[CH:27][N:26]=1
Reactant: [C-]#[N+]CC(=O)OC
Reactant: COc1cc(C=O)c(C(=O)c2ccnc(Cl)c2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl isocyanoacetate (18 ml) in dimethylformamide (85 ml) is added sodium hydride (7.85 g, 62.4% in oil) with ice-cooling under nitrogen atmosphere, and the mixture is stirred at room temperature for 30 minutes. To a solution of 3,4-dimethoxy-6-(2-chloroisonicotinoyl)benzaldehyde (52.0 g) in dimethylformamide (170 ml) is added dropwise the above solution at 40-50° C., and then the mixture is stirred at 50° C. for one hour. The mixture is neutralized with 10% acetic acid, concentrated, and extracted with chloroform. The extract is washed, and the insoluble materials are collected by filtration, and the filtrate is dried and concentrated. The resultant and the collected insoluble materials are combined, and recrystallized from ether-methanol to give 2-chloro-4-(3-methoxycarbonyl-6,7-dimethoxyisoquinolin-1-yl)pyridine (16.1 g).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:33])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)C.[OH-].[K+]>C(O)C.O>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:34])=[O:3])[N:7]=2)=[O:33])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of {2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (prepared in Example 12B-a, 276 mg, 0.58 mmol) in ethanol (20 mL) at 25° C. was treated with a solution of potassium hydroxide (100 mg, 1.78 mmol) in water (6 mL). This light yellow solution was stirred at 25° C. for 2 h and then concentrated in vacuo to remove ethanol. The resulting aqueous solution was acidified to pH=2 with a 1N aqueous hydrochloric acid solution and then extracted with methylene chloride (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 10/90 hexanes/ethyl acetate plus 1% acetic acid) afforded {2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid (222 mg, 80%) as a white foam: FAB-HRMS m/e calcd for C25H26N2O4S (M+H)+ 451.1691, found 451.1686.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][SH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=1>O1CCCC1.O>[CH2:9]([S:10][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: SCc1ccccc1
Reactant: Fc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(SCc2ccccc2)nc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium hydride (60% in oil, 440 mg) in tetrahydrofuran (40 mL) was added dropwise phenylmethanethiol (1.37 g) at room temperature, 2-bromo-5-fluoropyridine (1.76 g) was added to the reaction mixture, and the mixture was stirred at 60° C. for 5 hr. The reaction mixture was diluted with water and concentrated under reduced pressure. The residual aqueous layer was extracted twice with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-hexane-ethyl acetate=97:3) to give the title compound as a crude brown oil (yield 244 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([O:30]C(CC(C)C)=O)[CH2:24][C:22](=[O:23])[N:21]([CH3:37])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:38])=[CH:9][CH:8]=[CH:7][CH:6]([O:39][CH3:40])[C:5]2([OH:45])[NH:41][C:42]([O:44][CH:3]1[CH2:4]2)=[O:43].Cl.[Al]>C(OCC)(=O)C.O.O1CCCC1>[CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([OH:30])[CH2:24][C:22](=[O:23])[N:21]([CH3:37])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:38])=[CH:9][CH:8]=[CH:7][CH:6]([O:39][CH3:40])[C:5]2([OH:45])[NH:41][C:42]([O:44][CH:3]1[CH2:4]2)=[O:43]
Reactant: COc1cc2cc(c1Cl)N(C)C(=O)CC(OC(=O)CC(C)C)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
Agent: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)/C=C/C=C(\C)C2
Agent: Cl
Agent: [Al]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
Temperature: -42 °C
Reaction time: 0.17 h

Procedure:
This example describes reduction of ansamitocins with LiAl(OMe)3H using water followed by aqueous HCl. Ansamitocins (200 mg, 0.32 mmol) were weighed into a 25 mL round bottomed flask. Tetrahydrofuran (1.0 mL) was added to the flask with stirring, and the flask was cooled in a −42° C. cooling bath. After 10 min, a solution of 0.67 M LiAl(OMe)3H in tetrahydrofuran (3.8 mL, 2.52 mmol) was added dropwise by syringe. The bath temperature was maintained between −34° C. and −42° C. throughout the addition. After addition was complete, the reaction was stirred for 2 hours at between −32° C. and −37° C. 1 mL of deionized water was added dropwise to the reaction. After a 30 min holding period, 2 mL of 3 M HCl and 10 mL of ethyl acetate were quickly added to the flask. The cooling unit was turned off, and most of the aluminum byproducts went into solution. The contents were transferred to a separatory funnel and mixed well. The organic layer was retained and washed with 2 mL of saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, and solvent was removed by rotary evaporation. The residue was purified by silica chromatography using a mobile phase of dichloromethane:methanol 95:5 (v:v) to give 117 mg of maytansinol (66% yield by weight).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:9]=2[C:8]([O:18][CH:19]([F:21])[F:20])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].C(O)(=O)C>CO.O>[F:21][CH:19]([F:20])[O:18][C:8]1[C:9]2[O:17][C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[C:10]=2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OC(F)F)c2oc3ccncc3c12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OC(F)F)c2oc3ccncc3c12
Yield: 89.1 %

Procedure:
A solution of Methyl-6-difluoromethyloxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylate (6.5 g, 0.0221 moles), sodium hydroxide (4.0 g, 0.110 moles) and water (10.0 mL) in methanol (60.0 mL) was refluxed for 1-1.5 hrs. Methanol was removed under reduced pressure. The residue obtained was diluted with water (50.0 mL) and acidified with acetic acid. The solid separated was filtered, washed with water (2×100 mL) and dried to get 5.5 g of product as off-white solid.
Reaction SMILES: [CH3:1][Mg]I.[CH2:4]([C:8]1[N:9]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]([C:15]#[N:16])=C(C#N)[N:12]=1)[CH2:5][CH2:6][CH3:7].[Cl-].[NH4+].C([O:40][CH2:41][CH3:42])C>O1CCCC1>[C:41]([C:42]1[N:12]=[C:8]([CH2:4][CH2:5][CH2:6][CH3:7])[N:9]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]=1[C:15]#[N:16])(=[O:40])[CH3:1]
Reactant: CCOCC
Reactant: CCCCc1nc(C#N)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCc1nc(C(C)=O)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
11.1 ml of a 2M solution of methylmagnesium iodide in diethyl ether was slowly added dropwise at room temperature, in an atmosphere of nitrogen, to a solution of 4.5 g of 2-butyl-1-tritylimidazole-4,5-dicarbonitrile [prepared as described in step (i) above] in 45 ml of tetrahydrofuran, and the resulting mixture was stirred at room temperature for 3 hours. At the end of this time, a saturated aqueous solution of ammonium chloride was added dropwise, whilst ice-cooling, to the mixture. The tetrahydofuran layer was separated, washed with a saturated aqueous solution of sodium chloride and concentrated by evaporation under reduced pressure to give a concentrate. The aqueous layer was once again extracted with a small amount of ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried and concentrated by evaporation under reduced pressure. The resulting extract was combined with the above concentrate, and the resulting crude product was purified by column chromatography through silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, and the product was crystallized from a mixture of ethyl acetate and hexane, to give 1.46 g of the title compound, melting at 159°-160° C. (with decomposition).