Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>CN(C)C1C=CN=CC=1.ClCCl>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][O:1][C:17](=[O:19])[CH3:18]
Reactant: O=C(CO)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-hydroxyaceto-phenone (10 g, 73.4 mmol), pyridine (17.4 g, 220.2 mmol), dichloromethane (734 mL), 3 crystals of 4-dimethylaminopyridine is cooled to −78° C. To this solution is added acetic anhydride (13.9 mL, 146.9 mmol) then warmed to room temperature and stirred for 18 h. The mixture is washed with water (200 mL) and brine (200 mL) then dried over sodium sulfate. The mixture is filtered and concentrated in vacuo to yield the title compound, 13 g (99%), as a colorless liquid.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][NH2:41])[CH2:34][CH2:33]1>>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][NH:41][C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27]([NH2:28])=[O:29])[CH2:34][CH2:33]1
Reactant: CN1CCN(CCCN)CC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCN3CCN(C)CC3)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 3-(4-methyl-piperazin-1-yl)-propylamine by the procedure analogous to Example 1. MS (APCl, m/z): 501 [M+H]+.
Reaction SMILES: [OH-].[NH4+].O.[C:4]([NH:7][C@H:8]([C:11]([OH:13])=[O:12])[CH2:9][SH:10])(=[O:6])[CH3:5]>C(O)(C)C>[NH4+:7].[C:4]([NH:7][C@H:8]([C:11]([O-:13])=[O:12])[CH2:9][SH:10])(=[O:6])[CH3:5]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)N[C@@H](CS)C(=O)[O-]
Temperature: 35 °C
Reaction time: 8 h

Procedure:
A solution of concentrated ammonium hydroxide (52 ml., 0.78 mole) and 20 ml. water is added in 10 minutes to a stirred mixture of N-acetyl-L-cysteine (114.2 g., 0.7 mole) in 1.2 liters of isopropanol under an atmosphere of nitrogen. During the addition the mixture thickens and the temperature increases to 35°C. The mixture is stirred overnight, collected and washed with isopropanol to yield 110 g. (87%) of product having a melting point of 156°-158°C. (dec.) (uncorr.). Crystallization of this product from water-isopropanol with cooling to -10°C. provides analytically pure N-acetyl-L-cysteine ammonium salt, M.P. 147.5°-150°C. (dec.) (corr.); [ α ]D25 + 20.6°(c 5,H2O).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:27])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:7]2[OH:26].C([O-])([O-])=O.[K+].[K+].Br[CH2:35][CH:36]([CH3:38])[CH3:37]>C(#N)C>[F:1][C:2]1[C:3]([O:27][CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:7]2[OH:26]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(O)c(F)c2C(C)(C)C1=O
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)COc1ccc2c(c1F)C(C)(C)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A mixture of 1,1-dimethylethyl N-((8-fluoro-4,7-dihydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (0.29 g, 0.76 mmol, see Example 23) and K2CO3 (0.21 g, 1.5 mmol) in 5 mL ACN stirred at room temperature, was treated with 1-bromo-2-methylpropane (0.52 g, 3.8 mmol). The mixture was stirred at room temperature for 12 hours. The mixture was then warmed to 80° C. and stirred for 24 hours. The mixture was concentrated in vacuo and purified by column chromatography eluting with 10-30% EtOAc/hexane to give 0.25 g of the title compound as a white solid. MS (m/z)=458 (M+Na)+.
Reaction SMILES: C(N(C(OC(C)(C)C)=O)[C@H]1C[C@@H](N2C=NC3C2=NC(Cl)=NC=3[Cl:23])C=C1)(OC(C)(C)C)=O.COC1C=CC(C(N[C:50]2[N:58]=[C:57]([Cl:59])[N:56]=[C:55]3[C:51]=2[N:52]=[CH:53][N:54]3[C@@H:60]2[CH2:64][C@H:63]([N:65]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[C@@H:62]([OH:80])[C@H:61]2[OH:81])C2C=CC(OC)=CC=2)=CC=1>>[C:73]([N:65]([C:66]([O:68][C:69]([CH3:71])([CH3:72])[CH3:70])=[O:67])[C@H:63]1[CH2:64][C@@H:60]([N:54]2[CH:53]=[N:52][C:51]3[C:55]2=[N:56][C:57]([Cl:59])=[N:58][C:50]=3[Cl:23])[C@H:61]([OH:81])[C@@H:62]1[OH:80])([O:75][C:76]([CH3:78])([CH3:79])[CH3:77])=[O:74]
Reactant: COc1ccc(C(Nc2nc(Cl)nc3c2ncn3[C@@H]2C[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[C@@H](O)[C@H]2O)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared from di-Boc-[(1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl]-amine using a procedure analogous to that use to prepare (1R,2S,3R,5S)-3-(6-{[bis-(4-methoxy-phenyl)-methyl]-amino}-2-chloro-purin-9-yl)-5-(di-Boc-amino)-cyclopentane-1,2-diol (Intermediate in the preparation of Intermediate ZA). 1H nmr (CDCl3, 400 MHz); 8.35 (s, 1H), 4.80 (m, 1H), 4.70 (m, 1H), 4.50 (m, 1H), 3.85 (m, 1H), 3.75 (m, 1H), 3.10 (m, 1H), 2.75 (m, 1H), 2.55 (m, 1H), 1.55 (s, 18H), MS (ES+) m/e 504 (MH+).
Reaction SMILES: OC([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]2)C(N1CCNCC1)CC.BrC1C=CC(N[N+]([O-])=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>COC(C)CCO.[Cu]>[NH:18]1[C:19]2[C:14](=[CH:13][CH:12]=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:22]
Reactant: CCC(C(O)c1ccc2c(c1)CCC(=O)N2)N1CCNCC1
Agent: [Cu]
Agent: COC(C)CCO
Agent: O=C([O-])[O-]
Product: O=C1CCc2ccccc2N1

Procedure:
5.0 Grams of 6-(1-hydroxy-2-piperazinylbutyl)-3,4-dihydrocarbostyril, 3.5 g of p-bromonitroaniline, 1.8 g of potassium carbonate and 0.2 g of copper powder were mixed in 60 ml of 3-methoxybutanol and refluxed by heating for 5 hours. The reaction mixture was filtered and the mother liquor was concentrated by distillation under a reduced pressure to dryness. The residue thus obtained was extracted with methanol-chloroform and the solvent was removed by distillation to obtain a residue. The residue was purified and separated by a preparative silica-gel thin layer chromatograph to obtain 0.21 g of 6-{1-hydroxy-2-[4-nitrophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril in yellow powdery crystals.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C:12](=[O:14])[CH3:13])(=O)[CH3:9].Cl.[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3C=C(O)[C:38]([Cl:42])=[CH:37][C:36]=3[F:43])=[N:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:44][CH3:45])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:12]([O:11][C:8]1[C:38]([Cl:42])=[CH:37][C:36]([F:43])=[C:35]([CH:9]=1)[NH:34][C:28]1[C:27]2[C:32](=[CH:33][C:24]([O:23][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:25]([O:44][CH3:45])[CH:26]=2)[N:31]=[CH:30][N:29]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(Nc3cc(O)c(Cl)cc3F)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(Nc3cc(OC(C)=O)c(Cl)cc3F)ncnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.9 %

Procedure:
Triethylamine (216 ml, 1.5 mmol) and then acetic anhydride (133 ml, 1.4 mmol) were added to a stirred suspension of 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy quinazoline hydrochloride (600 mg, 1.4 mmol) in methylene chloride (7 ml). The mixture was stirred at ambient temperature for 3 hours and insoluble material removed by filtration. Volatiles were removed from the filtrate by evaporation and the residue purified by flash chromatography eluting with methylene chloride/methanol (100/0 increasing in polarity to 97/3) to give 4-(5-acetoxy-4-chloro-2-fluoroanilino)-7-benzyloxy-6-methoxyquinazoline (340 mg, 52%) as a solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S([O-])([O-])(=O)=O.[CH3:19]O>>[CH3:19][O:12][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13]
Reactant: CO
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: O=S(=O)([O-])[O-]
Product: COC(=O)c1ccc2ncccc2c1
Temperature: 70 °C
Reaction time: 22 h

Procedure:
4.0 g of 6-quinolinecarboxylic acid were suspended in 30 ml of MeOH, 2.0 ml of conc. sulfate was added under ice cooling, and the mixture was stirred at 70° C. for 22 hours. The reaction solution was concentrated under reduced pressure, and the residue was mixed with water and neutralized with potassium carbonate. The thus-precipitated solid was filtered and dried to obtain 4.28 g of 6-quinolinecarboxylic acid methyl ester. 0.5 g of the obtained ester body was dissolved in 5 ml of formamide, 0.15 ml of conc. sulfate, 0.05 g of ferrous sulfate hepta-hydrate, and 0.4 ml of 31% hydrogen peroxide were sequentially added thereto, and the mixture was stirred at 80° C. for 50 minutes. The reaction solution was mixed with water and alkalinized with potassium carbonate. 10% MeOH-chloroform was added, and insoluble matter was filtered using celite. The obtained filtrate was separated, the obtained organic layer was dried over anhydrous sodium sulfate and concentrated, and the obtained residue was washed with EtOH to obtain 0.15 g of 6-methoxycarbonyl-2-quinolinecarboxamide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][CH:3]=1.[Br:10]C1C(CN2[C@@H](C)[C@@H](C3C=CC=C(OC(F)(F)F)C=3)OC2=O)=NC(SC)=NC=1>>[Br:9][C:5]1[C:6]([CH2:8][Br:10])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Cc1nc(Cl)ccc1Br
Reactant: CSc1ncc(Br)c(CN2C(=O)O[C@H](c3cccc(OC(F)(F)F)c3)[C@@H]2C)n1
Product: Clc1ccc(Br)c(CBr)n1

Procedure:
The preparation of this precursor from commercially available 6-chloro-3-bromo-2-methylpyridine has been described previously in WO2007081569, INTERMEDIATE 9 Step B.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].[C:35]12([CH2:45][OH:46])[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:43]C(C3)C1)[CH2:42]2.C12CC(CC1)CC2CO>>[CH:44]12[CH2:43][CH:41]([CH2:40][CH2:39]1)[CH2:42][CH:35]2[CH2:45][O:46][C:19]1[C:18]([Cl:17])=[CH:32][C:22]([C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24])=[C:21]([F:33])[CH:20]=1
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC1CC2CCC1C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CC3CCC2C3)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N-(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 2-Norbornanemethanol, the title compound was obtained as a colorless solid (0.17 g, 39%): 1H NMR (300 MHz, CDCl3) δ 8.72-8.54 (m, 1H), 8.12-8.01 (m, 1H), 6.77-6.61 (m, 1H), 4.15-3.67 (m, 2H), 3.01 (s, 6H), 2.49-2.21 (m, 3H), 2.10-1.74 (m, 1H), 1.64-1.05 (m, 6H), 0.83-0.71 (m, 1H); MS (ES−) m/z 403.2 (M−1), 405.2 (M−1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O>CO.C1COCC1.[Pd]>[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH2:9]
Reactant: Cc1nc(N)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(N)ccc1N

Procedure:
6-Methyl-5-nitropyridin-2-amine [CAS 22280-62-2] (0.38 g, 2.48 mmol) was hydrogenated at 50 psi with 10% Pd/C (0.35 g) in MeOH/THF (10 mL) overnight to give 6-methylpyridine-2,5-diamine as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1
Reactant: CSc1nccc(Cl)n1
Reactant: Brc1cccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(-n2ncc3c(Br)cccc32)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
To a solution of 4-bromo-1H-indazole (8.831 g, 44.82 mmol) in DMF (100 mL) was added NaH (60% suspension in mineral oil, 74.7 mmol, 2.988 g) followed by 4-chloro-2-methylsulfanyl-pyrimidine (4.34 mL, 37.35 mmol). The resulting mixture was allowed to stir at RT for 2 h; the solid precipitate was collected by filtration, washed and dried under reduced pressure to give 10.7 g (89% yield) of 4-bromo-1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.Cl.[O:12]([NH2:14])[CH3:13]>>[CH3:13][O:12][N:14]=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([Br:1])[CH:3]=1
Reactant: CON
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: Cl
Product: CON=Cc1ccc(F)c(Br)c1
Yield: 95 %

Procedure:
Reaction of 3-bromo-4-fluorobenzaldehyde with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a clear oil (95% yield). 1HNMR indicated a 95:5 mixture of E- to Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 3.97 (3H, s, OCH3), 7.12 (1H, m, aromatics), 7.48 (1H, m, aromatic), 7.82 (1H, m, aromatic), 7.97 (1H, s, CH).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:30]=[CH:29][C:21]([CH:22]=[CH:23][C:24]([O:26]CC)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+].O.C(O)C>C(O)(=O)C>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([CH:22]=[CH:23][C:24]([OH:26])=[O:25])=[CH:29][CH:30]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C=CC(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCNc1ccc(C=CC(=O)O)cc1

Procedure:
A mixture of ethyl p-aminocinnamate, one equivalent of 1-bromohexadecene, one equivalent of anhydrous potassium carbonate in hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated to provide ethyl 4-hexadecylaminocinnamate. The ester is hydrolyzed with sodium hydroxide in a 1:1 water:ethanol solution at steam bath temperature for 10 hours. The hot solution is then acidified with acetic acid, cooled, filtered and the precipitate is washed with water. Recrystallization from chloroform yields 4-hexadecylaminocinnamic acid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:15][C:16]([CH3:18])=[CH2:17])=[C:4]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[N:7]([CH:13]=[O:14])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[Ca+2].[I:24](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl.CO>[I:24][CH2:17][C:16]1([CH3:18])[O:1][C:2]2[C:3](=[C:4]3[C:8](=[C:9]([CH3:12])[C:10]=2[CH3:11])[N:7]([CH:13]=[O:14])[CH2:6][CH2:5]3)[CH2:15]1
Reactant: O=I(=O)Cl
Reactant: C=C(C)Cc1c(O)c(C)c(C)c2c1CCN2C=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: Cc1c(C)c2c(c3c1OC(C)(CI)C3)CCN2C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a suspension of 2,3-dihydro-5-hydroxy-6,7-dimethyl-4-(2-methyl-2-propenyl)-1H-indole-1-carbaldehyde (4.91 g, 20.0 mmol) in dichloromethane (10 mL) and methanol (20 mL) was added calcium carbonate (2.60 g, 26.0 mmol), the mixture was ice-cooled, a solution of benzyltrimethylammonium dichloroiodate (7.66 g, 22.0 mmol) in dichloromethane (20 mL) was added dropwise over 10 minutes under nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered, and concentrated under reduced pressure. To the residue was added a solution of sodium hydrogen sulfite (2.50 g) in water (50 mL), and the mixture was extracted with ethyl acetate three times. The combined organic layers were washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 5;1 then 2:1), and recrystallized from ethyl acetate-diisopropyl ether to obtain 4.34 g of the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6](=O)[C@:7]([NH:12][C:13](=O)OC(C)(C)C)([CH3:11])[CH:8]([CH3:10])[CH3:9])[CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:11][C@:7]([NH:12][CH3:13])([CH:8]([CH3:10])[CH3:9])[CH2:6][N:4]1[CH2:3][CH:2]([OH:1])[CH2:5]1
Reactant: CC(C)[C@](C)(NC(=O)OC(C)(C)C)C(=O)N1CC(O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@](C)(CN1CC(O)C1)C(C)C
Temperature: 60 °C
Yield: 114.8 %

Procedure:
To a solution of (S)-tert-butyl 1-(3-hydroxyazetidin-1-yl)-2,3-dimethyl-1-oxobutan-2-ylcarbamate (Compound X) (1.07 g, 3.74 mmol) in THF (50 mL) was a 1M solution of LAH in THF (16 ml, 16.00 mmol) dropwise added (over approximately 2 min) at −20° C. under a nitrogen atmosphere. The resultant mixture was stirred at rt for 30 min and heated at 60° C. over night. Additional LAH in THF (1M solution, 2 mL, 2 mmol) was added and the mixture was heated at 70° C. over night. The solvent was removed. 1,4-Dioxane (60 mL) and a 0.5M solution of LAH in ethylene glycol dimethyl ether (10 mL) was added to the residue. The resultant mixture was heated at 100° C. over night. The mixture was diluted with diethyl ether (150 mL) and the reaction was quenched with Na2SO4×10H2O. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (0.8 g, quant.yield). The obtained crude product was used without further purification. LCMS (M+H)+: 187.
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](Cl)(=[O:44])[CH:41]([CH3:43])[CH3:42]>C(N(CC)CC)C.CN(C)C=O>[CH3:1][C@H:2]1[C@H:27]2[O:28][C@@:26]2([CH3:29])[C@@H:25]([O:30][C:40]([CH:41]([CH3:43])[CH3:42])=[O:44])[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(C)C(=O)Cl
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(=O)C(C)C)[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: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2cc(c1Cl)N(C)C(=O)C[C@H](OC(=O)C(C)C)[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: 2.5 h

Procedure:
In a mixture of 1 ml triethylamine and 50 ml of dimethylformamide was dissolved 100 mg of maytansinol and, while the solution was stirred under ice-cooling, 50 μl of isobutyryl chloride was added dropwise. The mixture was stirred under ice-cooling for 30 minutes and then, at room temperature for 2.5 hours, after which it was distilled under reduced pressure. The residue was dissolved in 10 ml of dichloromethane, washed with water and dried (Na2SO4). The solvent was distilled off under reduced pressure and the residue was chromatographed and recrystallized as in Reference Example 1. By the above procedure there was obtained 19.4 mg of Ansamitocin P-3.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9](OCC)=[O:10])=[CH:7][N:6]=[C:5]2[N:14]([CH2:17][CH3:18])[N:15]=[CH:16][C:4]=12)#[N:2].[NH2:19][NH2:20]>C(O)C>[NH2:2][C:1]1[C:3]2[C:4]3[CH:16]=[N:15][N:14]([CH2:17][CH3:18])[C:5]=3[N:6]=[CH:7][C:8]=2[C:9](=[O:10])[NH:19][N:20]=1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1C#N
Reactant: NN
Solvent: CCO
Product: CCn1ncc2c3c(N)n[nH]c(=O)c3cnc21
Temperature: 80 °C
Yield: 60 %

Procedure:
To a suspension of 4-cyano-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester (10.0 g, 40.1 mmol) in ethanol (100 mL) was added anhydrous hydrazine (5 eq). This suspension was then heated at 80° C. until starting material was consumed. The reaction was allowed to cool to rt and diluted with water (200 mL). The resulting solid was filtered and washed thoroughly with water until the filtrate was colorless. The solid was dried under vacuum to afford the title compound as a yellow solid (5.5 g, 60%). This material was >90% pure as judged by HPLC and was used directly.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.[C:25](O)(=[O:29])/[CH:26]=[CH:27]/[CH3:28]>CN(C)C1C=CN=CC=1.ClCCl>[C:25]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1)(=[O:29])/[CH:26]=[CH:27]/[CH3:28]
Reactant: C/C=C/C(=O)O
Reactant: O=Cc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C/C=C/C(=O)Oc1ccc(C=O)cc1
Reaction time: 8 h
Yield: 111.9 %

Procedure:
17.8 g of N,N'-dicyclohexylcarbodiimide were added while stirring within 5 minutes to a solution of 7.0 g of 4-hydroxybenzaldehyde, 7.4 g of (E)-but-2-enoic acid and 0.1 g of 4-(dimethylamino)pyridine in 50 ml of dichloromethane. The reaction mixture was stirred overnight, then filtered. The filtrate was washed with saturated sodium bicarbonate solution and with water and concentrated. Chomatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 3:7) and two-fold recrystallization of the fractions which were pure according to thin-layer chromatography gave 12.2 g of 4-[(E)-but-2-enoyloxy]benzaldehyde.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13].[I-].[Na+].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O>[N:16]([CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])=[N+:17]=[N-:18]
Reactant: O=c1[nH]c2ccccc2n1CCCl
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCn1c(=O)[nH]c2ccccc21
Temperature: 120 °C
Yield: 98.9 %

Procedure:
In 30 ml of dimethylformamide were dissolved 1.5 g of the above 1:1 (approx.) mixture of Compound h and Compound h', 1.5 g (9.9 mmol) of sodium iodide and 5.0 g (76.3 mmol) of sodium azide and the solution was heated at 120° C. for 48 hours. After cooling, the solvent was distilled off and 50 ml of ethyl acetate was added to the residue. The insolubles were filtered off and the filtrate was washed twice with 5% aqueous sodium thiosulfate solution and, then, three times with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 1.38 g (98.9%) of 1-(2-azidoethyl)-2,3-dihydro-2-oxo-1H-benzimidazole (Compound i) as light yellow crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[Cl:24][C:25]1[CH:30]=[C:29]([C:6]2[N:7]=[C:8]([N:10]3[C:14]4[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=4[N:12]=[CH:11]3)[S:9][C:5]=2[C:3]([OH:2])=[O:4])[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: OB(O)c1cccc(Cl)c1
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)O)s3)c2cc1OC
Yield: 20.7 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3-chlorophenylboronic acid (23.5 mg, 0.15 mmol) gave 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (8.6 mg, 21%) as a white solid. MS m/z 416 (M+1).