Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]([CH3:57])[C:20](=[O:56])[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-])=O)[C:31]=2[NH:39][C:40]([CH2:42][N:43]2[C:47](=[O:48])[C:46]3=[CH:49][CH:50]=[CH:51][CH:52]=[C:45]3[C:44]2=[O:53])=O)=[O:29])=[C:23]([O:54][CH3:55])[CH:22]=1)=[O:5])[CH3:2].C(O)(=O)C>C(O)C.[Fe]>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]([CH3:57])[C:20](=[O:56])[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[C:31]3[N:39]=[C:40]([CH2:42][N:43]4[C:47](=[O:48])[C:46]5=[CH:49][CH:50]=[CH:51][CH:52]=[C:45]5[C:44]4=[O:53])[NH:36][C:32]=3[CH:33]=[CH:34][CH:35]=2)=[O:29])=[C:23]([O:54][CH3:55])[CH:22]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCCCOc1cc(C)ccc1N(C)C(=O)c1ccc(NC(=O)c2cccc([N+](=O)[O-])c2NC(=O)CN2C(=O)c3ccccc3C2=O)c(OC)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CCCCCOc1cc(C)ccc1N(C)C(=O)c1ccc(NC(=O)c2cccc3[nH]c(CN4C(=O)c5ccccc5C4=O)nc23)c(OC)c1
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
A mixture of N-[2-(5-ethoxycarbonylpent-1-yloxy)-4-methylphenyl]-3-methoxy-N-methyl-4-(3-nitro-2-phthalimidomethylcarbonylaminophenyl)carbonylaminobenzamide (3.96 g), iron powder (1.42 g) and acetic acid (3.05 g) in ethanol (50 ml) was refluxed for 4 hours and the solvent was removed under reduce pressure. The residue was stirred in a mixture of chloroform (100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml) for 30 minutes and the solution was filtered through a bed of celite. The organic phase was separated and washed with brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was solidified with diethyl ether to give N-[2-(5-ethoxycarbonylpent-1-yloxy)-4-methylphenyl]-3-methoxy-N-methyl-4-(2-phthalimidomethyl-1H-benzimidazol-4-yl)carbonylaminobenzamide (3.64 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:9][CH:8]=1)=[O:6])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[C:5]([C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]2[C:19]([NH2:20])=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:11][CH:12]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(Nc2ncccc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(=O)c1ccc(Nc2ncccc2N)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
10% Pd/C (9 mg) is added to a solution of [4-(3-nitro-pyridin-2-ylamino)-phenyl]oxo-acetic acid ethyl ester (26 7 mg, 0.847 mmol) in ethanol (2 mL). The mixture is stirred at rt for 1.5 h under H2. The reaction mixture is filtered through celite and the solvent removed under vacuum to afford [4-(3-amino-pyridin-2-ylamino)-phenyl]oxo-acetic acid ethyl ester as a yellow solid. Title compound: ES-MS: 286.10 [M+H]+; tR=0.9 min (System 2).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)C>[CH2:15]([N:22]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: CCOCC
Product: O=c1c2cccc([N+](=O)[O-])c2ccn1Cc1ccccc1
Temperature: 80 °C

Procedure:
5-Nitro-isochromen-1-one (1.0 g, 5.23 mmol) from step 2 was dissolved in excess benzylamine (5 mL) and heated to 80° C. for 4 hours. The mixture was then diluted in diethyl ether and washed several times with (0.5 N) HCl. The organic layer was concentrated in vacuo to give 2-benzyl-5-nitro-2H-isoquinolin-1-one as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:29][CH2:30][C:31]([OH:33])=O)[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:16]1(=[O:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.[CH:56]([NH:59][CH3:60])([CH3:58])[CH3:57]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:29][CH2:30][C:31]([N:59]([CH:56]([CH3:58])[CH3:57])[CH3:60])=[O:33])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])[S:16]1(=[O:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(C)C
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCC(=O)O)cc2OCc2ccccc2)S1(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N(C)C(=O)CCc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid (0.10 g, 0.2 mmol), EDCl (0.38 g, 0.20 mmol) and HOAt (0.027 g, 0.20 mmol) in DMF (1 mL) is added N-isopropyl-N-methylamine (0.15 g, 0.2 mmol). The mixture is stirred at RT for 18 h, then poured into water. The mixture is extracted into EtOAc and the organic phase washed with water (3×) and sat. NaCl (1×). The organic solution is dried over Na2SO4 and the solvent removed under reduced pressure to afford the title compound. This is used directly in the next step.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)O1.Cl[C:18]1[N:19]=[C:20]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]2[CH3:34])[C:21]2[CH2:26][N:25]([CH3:27])[CH2:24][C:22]=2[N:23]=1>>[CH3:27][N:25]1[CH2:26][C:21]2[C:20]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])=[N:19][C:18]([C:9]3[CH:10]=[CH:11][C:12]([NH2:13])=[CH:14][CH:15]=3)=[N:23][C:22]=2[CH2:24]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C)C2
Product: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc2c1CN(C)C2
Yield: 72 %

Procedure:
Step 2 Method as intermediate 5, using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and (S)-4-(2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine. The crude reaction mixture was partitioned between water and EtOAc, the phases separated and the organic layer dried over magnesium sulphate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (0-15% MeOH/DCM), to yield a pale yellow oil (477 mg, 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][CH:4]=1.[Br:11]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:11][CH2:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cccc(CO)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc(CBr)n1
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To (6-methoxypyridin-2-yl)methanol (3.36 g, 24.1 mmol) in DCM (30 mL) was added perbromomethane (12.0 g, 36.2 mmol) and triphenylphosphine (9.50 g, 36.2 mmol). The reaction mixture was stirred for 1 hour, concentrated and silica gel chromatography (EtOAc/Hexane 1:5) to provide the desired product (4.23 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[CH:22][C:12]([CH:13]=[C:14]([N:19]=[N+]=[N-])[C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:23]=[C:22]2[C:12]([CH:13]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[NH:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(=Cc1ccc(OCc2ccccc2)cc1)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2ccc(OCc3ccccc3)cc2[nH]1

Procedure:
Methyl 4-benzyloxy-α-azidocinnamate (EXAMPLE 246, 5.8 g) is dissolved in 376 ml of toluene and the reaction is heated to reflux for 1 hr. Then the reaction is cooled, concentrated under reduced pressure and the solids are recrystallized from ethyl acetate/hexane to provide the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:18][C:17]=1[NH2:29]>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]2)=[CH:18][C:17]=1[NH:29][S:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:13])=[O:12]
Reactant: CN1CCN(c2ccc(Br)c(N)c2)CC1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: CN1CCN(c2ccc(Br)c(NS(=O)(=O)c3ccc4ccccc4c3)c2)CC1

Procedure:
The title compound (E118) was prepared from naphthalene-2-sulfonyl chloride (100 mg, 0.44 mmol) and 2-bromo-5-(4-methylpiperazin-1-yl)phenylamine (D27) (120 mg, 0.44 mmol) using the method of Example 1 (85 mg, 35%) MH+=460/462.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)[OH:4].O.C(=O)(O)[O-].[Na+].[Cl:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[Cl:22][CH2:23][C:24]([NH:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:15])([F:13])[F:14])[CH:6]=1)[OH:4])=[O:25]
Reactant: O=C(Cl)CCl
Reactant: NC[C@H](O)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)NC[C@H](O)c1ccc(F)c(C(F)(F)F)c1

Procedure:
(R)-2-amino-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanol (2.27 g, 10.2 mmol) was dissolved in 50 mL of dichloromethane. Water (50 mL) containing sodium bicarbonate (1.11 g, 13.2 mmol) was added. The mixture was stirred under ice bath and 2-chloroacetyl chloride (1.38 g, 12.2 mmol) in dichloromethane (10 mL) was added dropwise. The mixture was stirred for 20 min. The pH value was checked and concentrated sodium bicarbonate solution was added (15 mL) to adjust pH to basic. The ice bath was removed and the mixture was stirred for 15 min. TLC indicated consumption of the starting material. The mixture was extracted with dichloromethane and sodium bicarbonate solution. The organic layer was washed with brine and dried. Solvents were evaporated and the resulting material was purified through ISCO flash column chromatography (40 g silica gel, 20% to 90% ethyl acetate in hexanes gradient) to give 2-chloro-N—[(R)-2-(4-fluoro-3-trifluoromethylphenyl)-2-hydroxy-ethyl]-acetamide as an oily material, which gradually solidified (2.64 g). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.18 (br. s., 1H) 3.40 (ddd, J=14.07, 8.21, 5.29 Hz, 1H) 3.72 (ddd, J=14.16, 6.99, 3.40 Hz, 1H) 4.09 (s, 2H) 4.95 (dd, J=7.93, 3.02 Hz, 1H) 7.03 (br. s., 1H) 7.16-7.26 (m, 1H) 7.54-7.62 (m, 1H) 7.66 (dd, J=6.61, 2.08 Hz, 1H).
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH2:16][CH:15]([CH3:17])[CH2:14][C:13](=[O:18])[CH:12]=1>C(OCC)C.Cl[Cu]>[CH2:1]([C:11]1([CH3:10])[CH2:16][CH:15]([CH3:17])[CH2:14][C:13](=[O:18])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1=CC(=O)CC(C)C1
Reactant: Br[Mg]Cc1ccccc1
Agent: Cl[Cu]
Solvent: CCOCC
Product: CC1CC(=O)CC(C)(Cc2ccccc2)C1
Reaction time: 0.08 h
Yield: 53 %

Procedure:
To a cooled (−20° C.) 1M benzylmagnesium bromide solution in diethyl ether (50 ml) under argon was added CuCl (0.52 g, 5.3 mmol) and the mixture was stirred for 5 min. Then a solution of 3,5-dimethyl-2-cyclohexen-1-one (12) (4.4 g, 35.1 mmol) in diethyl ether (15 ml) was added dropwise keeping the temperature below −10° C. The mixture was stirred for 2 h and quenched with 10% aqueous acetic acid (40 ml). The organic layer was separated, washed with water, saturated aqueous NaHCO3 and saturated aqueous NaCl, and dried over MgSO4. Filtration and concentration in vacuo afforded oily residue what was separated by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 10:1). Cyclohexanone 13 (4.0 g, 53%) was obtained as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:5]=1.O.[OH-].[Li+].Cl>C1COCC1.O.CO>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]=1[CH2:11][O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][N:7]=1)[C:3]([OH:24])=[O:2]
Reactant: COC(=O)c1ccnc(OCc2c(-c3ccccc3)noc2C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a suspension of 2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isonicotinic acid methyl ester (759 mg, 2.3 mmol) in THF (6.3 mL) was added a solution of lithium hydroxide monohydrate (196 mg, 4.7 mmol) in water (6.3 mL) and methanol (1.4 mL) added and the resulting mixture stirred at room temperature for 2 h. The mixture was acidified to pH 4 with HCl (25%, 3 drops and the resulting precipitate filtered off and dried to afford the title compound (641 mg, 88%) which was obtained as a white solid. MS: m/e=309.5 [M−H]−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:13][CH:14]=2)[C:9]1=[O:31].C(=O)([O-])[O-].[K+].[K+].[F:38][C:39]([F:62])([F:61])[CH2:40][NH:41][C:42]([C:44]1([CH2:57][CH2:58][CH2:59]Br)[C:56]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[C:50]2[C:45]1=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:43]>CN(C=O)C.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:19][CH2:20][N:21]([CH2:59][CH2:58][CH2:57][C:44]4([C:42](=[O:43])[NH:41][CH2:40][C:39]([F:38])([F:61])[F:62])[C:56]5[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=5[C:50]5[C:45]4=[CH:46][CH:47]=[CH:48][CH:49]=5)[CH2:22][CH2:23]3)=[CH:13][CH:14]=2)[C:9]1=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)C(=O)N(Cc2ccccn2)CC3)CC1
Reactant: O=C(NCC(F)(F)F)C1(CCCBr)c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2cc(N3CCN(CCCC4(C(=O)NCC(F)(F)F)c5ccccc5-c5ccccc54)CC3)ccc2CCN1Cc1ccccn1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 44 %

Procedure:
The compound (50 mg, 0.16 mmol) prepared in step (b) of Example 125 was dissolved in anhydrous DMF. Potassium carbonate (44 mg) and 66 mg of the compound prepared in step (a) of Example 93 were added to the solution. The mixture was stirred at 50° C. for 20 hr and further at 80° C. for 4.5 hr. The reaction solution was diluted with ethyl acetate, and the dilution was washed twice with water, followed by drying over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography (development system, methylene chloride:methanol=30:1) to give the title compound (46 mg, yield 71%) as a white foam.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[N:14]1[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]1>C(Cl)Cl>[N:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[N:14]1[CH2:15][CH2:16][CH:17]([NH2:20])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncccn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
TFA (7.87 mL, 103 mmol) was added to a solution of tert-butyl 1-(pyrimidine-2-yl)piperidin-4-ylcarbamate (2.86 g, 10.3 mmol) in DCM (60 mL) at at 0° C. The reaction mixture was stirred for 2 h at room temperature and removed the solvent under reduced pressure. The residue was re-dissolved in DCM, and neutralized with aq. Na2HCO3. The solvents were removed by evaporation, the resulting residue was purified by column chromatography (DCM:MeOH:NH4OH=10:1:0.1) to give 1-(pyrimidin-2-yl)piperidin-4-amine (1.68 g, 92%) as a white solid. 1H-NMR (CD3OD, Varian 400 MHz) δ 1.26-1.37 (2H, m), 1.75-1.99 (2H, m), 2.76-2.98 (2H, m), 2.86-3.05 (1H, m), 4.64-4.72 (2H, m), 6.53 (1H, t, J=4.8 Hz), 8.27 (2H, d, J=4.8 Hz). m/z=179.04 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.C([Li])CCC.[C:26](=[O:28])=[O:27].Cl>C(OCC)C.C(OCC)(=O)C.O>[CH3:9][S:8][C:6]1[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=[C:2]([C:26]([OH:28])=[O:27])[CH:7]=1
Reactant: O=C=O
Reactant: CSc1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Reaction time: 0.17 h

Procedure:
2-bromo-4-methylmercapto-6-[3-(trifluoromethyl)phenoxy] pyridine (5.00 g, 0.0137 mol) was dissolved in about 200 ml of diethyl ether. While cooling in a dry ice-acetone bath in an argon atmosphere, the obtained solution was mixed with n-butyl lithium [9.3 ml (ca. 1.63 M in hexane solution), 0.0137×1.1 mol] and then stirred for about 10 minutes. After the interior of the reactor was replaced with a carbon dioxide gas, the solution was removed from the bath and stirred at room temperature for about one hour. The obtained reaction solution was mixed with about 15 ml of a 4 N aqueous hydrochloric acid solution. The obtained solution was distributed in ethyl acetate-water and then washed with saturated brine. The organic phase separated from the solution was dried with anhydrous sodium sulfate, concentrated and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [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]([CH3:31])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:32])=[CH:9][CH:8]=[CH:7][CH:6]([O:33][CH3:34])[C:5]2([OH:39])[NH:35][C:36]([O:38][CH:3]1[CH2:4]2)=[O:37].[C:40](OC(=O)C)(=[O:42])[CH3:41].O>N1C=CC=CC=1.C(Cl)(Cl)Cl.CO>[CH3:1][C@H:2]1[C@@H:27]2[O:28][C@@:26]2([CH3:29])[C@@H:25]([O:30][C:40]([CH3:41])=[O:42])[CH2:24][C:22](=[O:23])[N:21]([CH3:31])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:32])=[CH:9][CH:8]=[CH:7][C@@H:6]([O:33][CH3:34])[C@:5]2([OH:39])[NH:35][C:36]([O:38][C@H:3]1[CH2:4]2)=[O:37]
Reactant: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
Reactant: CC(=O)OC(C)=O
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: COc1cc2cc(c1Cl)N(C)C(=O)C[C@H](OC(C)=O)[C@]1(C)O[C@H]1[C@H](C)[C@@H]1C[C@@](O)(NC(=O)O1)[C@H](OC)/C=C/C=C(\C)C2
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc2cc(c1Cl)N(C)C(=O)C[C@H](OC(C)=O)[C@]1(C)O[C@H]1[C@H](C)[C@@H]1C[C@@](O)(NC(=O)O1)[C@H](OC)C=CC=C(C)C2
Reaction time: 18 h

Procedure:
In 0.7 ml of pyridine was dissolved 100 mg of maytansinol. To the solution, cooled with ice, was added 0.35 ml of acetic anhydride. The mixture was left standing for 18 hours at room temperature (23°-25° C.). The reaction solution was poured into 5 ml of cold water and stirred. The precipitate separated out was collected by filtration and dried to obtain 85 mg of powdery substance. This powdery substance was dissolved in 1 ml of chloroform/methanol 10:1 (V/V). To the solution was added 0.2 g of silica gel, and mixed sufficiently. The mixture was then applied to the top of a silica gel column (80 ml). Elution was carried out with ethyl acetate saturated with water. The eluate was collected in 10 ml fractions. The fractions of No. 37-44 were collected, concentrated under reduced pressure. To the residue was added a small volume of ethyl acetate (about 0.5 ml) to dissolve the precipitating crystals again, then was left standing at room temperature. Precipitating crystals were collected by filtration, whereupon 36.0 mg. of maytanacine was obtained. The melting point of this was 231° C. and, when compared with maytanacine obtained in Reference Example 22 in mass spectrum, IR spectrum, UV-spectrum and thin layer chromatogram, this product was found to be identical with the maytanacine obtained in the above.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=1)=[O:5])C.[OH-].[K+]>>[C:4]([C:6]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:7]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:14][CH:15]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1ccc(OCc2ccc(Cl)cc2C(=O)OCC)cc1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)Cc1ccc(OCc2ccc(Cl)cc2C(=O)O)cc1

Procedure:
Reaction of ethyl 4-(2-ethoxycarbonyl-4-chlorobenzyloxy)phenylacetate with potassium hydroxide as described in Example 1c provides 4-(2-carboxy-4-chlorobenzyloxy)phenylacetic acid, m.p. 205°-208°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([CH:21]=O)[N:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30].C(N(CC)CC)C.N1CCCCC1>C(O)C>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19](/[CH:21]=[C:28]3/[C:27](=[O:29])[NH:26][C:25](=[O:30])[S:24]/3)[N:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cc(C=O)ncn2)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)NCC1CCN(c2cc(/C=C3\SC(=O)NC3=O)ncn2)CC1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
An 8 mL round-bottomed vial was charged with tert-butyl((1-(6-formylpyrimidin-4-yl)piperidin-4-yl)methyl)carbamate (77.9 mg, 0.24 mmol, 1 equiv.), ethanol (1 mL), thiazolidine-2,4-dione (28.5 mg, 0.24 mmol, 1 equiv.) and triethylamine (68 μL, 0.48 mmol, 2 equiv.). Piperidine (1.04 mg, 23 μL of a solution of 52 μL in 0.95 mL ethanol, 0.012 mmol, 5% eq.) was added and Argon was bubbled through the solution. The reaction mixture was shaken at 85° C. for 18 h. LC-MS of the crude reaction mixture showed mostly the desired product. The solvent was evaporated. The residue was partitioned between EtOAc (10 mL) and 10% NH4Cl (5 mL). The organic layer was dried over Na2SO4. Evaporation of solvent gave the crude (Z)-tert-butyl((1-(6-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-4-yl)piperidin-4-yl)methyl)carbamate (79.8 mg, 78%). LC-MS: M+1=420.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.CN(C=O)C.S(Cl)([Cl:26])=O>>[Cl:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COCCOc1cc2nncc(O)c2cc1OC
Solvent: CN(C)C=O
Product: COCCOc1cc2nncc(Cl)c2cc1OC
Yield: 74 %

Procedure:
The starting material 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline was obtained by heating a solution of 4-hydroxy-6-methoxy-7-(2-methoxyethoxy)cinnoline (7.8 g, 0.031 mol) in thionyl chloride (130 ml) containing DMF (0.8 ml) at 80° C. for 2 hours. After dilution with toluene, the mixture was evaporated to dryness. The resulting solid was filtered off, washed with ether, and then dissolved in ethyl acetate. The ethyl acetate solution was washed with saturated aqueous sodium hydrogen carbonate solution and then brine, dried (MgSO4) and the solvent evaporated. The residue was purified by flash chromatography using methylene chloride/ethyl acetate (1/9) as eluent to give 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (6.2 g, 74%).