Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH:51]1[CH2:55][CH2:54][CH:53]([OH:56])[CH2:52]1>ClCCl.O>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:51]2[CH2:55][CH2:54][CH:53]([OH:56])[CH2:52]2)=[O:17])=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccc(Cc2nc3ccccc3[nH]2)cc1
Reactant: OC1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(Cc2nc3ccccc3[nH]2)cc1)N1CCC(O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
A solution of methyl 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoate (5 g, 0.019 mol) in methanol was treated with sodium hydroxide (1.50 g, 0.037 mol) and water, heated to 65° C., stirred for 3 h and concentrated under reduced pressure. The resultant residue was dissolved in water and acidified with concentrated HCl. The resultant precipitate was removed by filtration and dried under vacuum overnight to provide 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoic acid (82.0%). 1H NMR-(400 MHz, DSMO-d6): 7.96 (d, J=8 Hz, 2H), 7.91 (m, J=9 Hz, 2H), 7.60 (d, J=8 Hz, 2H), 7.52 (m, J=6 Hz, 2H), 4.65 (s, 2H). LCMS (ESI+) 253 (M+H). A portion of 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoic acid (5.0 g, 0.020 mol) was dissolved in dichloromethane, cooled to 0° C., treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.50 g, 0.023 mol), 1-hydroxybenzotriazole (HOBT) (3.21 g, 0.024 mol), and diisopropylethylamine (6.41 g, 0.049 mol), stirred at room temperature for 30 min, cooled to 0° C., treated with a solution of 3-pyrrolidinol (1.89 g, 0.021 mol) in dichloromethane, stirred at room temperature for 24 h and diluted with water. The phases were separated and the organic phase was washed sequentially with saturated aqueous NaHCO3, saturated aqueous NaCl, dried over sodium sulfate and concentrated to dryness under reduced pressure to provide [4-(1H-benzoimidazol-2-ylmethyl)-phenyl]-(3-hydroxy-pyrrolidin-1-yl)-methanone (34%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): 7.47 (s, 4H), 7.38 (d, J=7.6 Hz, 2H), 4.87 (s, J=4.2 Hz, 1H), 4.21 (d, 2H), 3.48 (m, 4 H), 1.85 (m, 2H). LCMS (ESI+) 322 (M+H).
Reaction SMILES: [CH3:1][C:2]1([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7]C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C.Br>C(O)(=O)C>[CH3:1][C:2]1([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH2:7]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)Nc1ccc(C(F)(F)F)cn1
Agent: Br
Solvent: CC(=O)O
Product: CC1(Nc2ccc(C(F)(F)F)cn2)CCCC1N
Temperature: 90 °C

Procedure:
To a solution of (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl N-(2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl)carbamate in acetic acid (3 ml) was added HBr (6 M, 1.68 ml, 10.10 mmol). The reaction was sealed and heated at 90° C. for 24 hours. To this was then added further HBr (6 M, 1.68 ml, 10.10 mmol) and the reaction was heated at 90° C. for 24 hours. The reaction was concentrated in vacuo and the resulting residue was purified by SCX chromatography (2M ammonia in methanol). The product was purified by reverse phase chromatography (C18 silica, 5-100% water (with 0.05% ammonia)/acetonitrile) to afford the title compound as a single trans-enantiomer.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([NH:20][NH2:21])=[O:19])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:22]1[CH2:27][CH2:26][CH:25]([CH2:28][N:29]=[C:30]=[O:31])[CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[CH:25]1([CH2:28][NH:29][C:30]([NH:21][NH:20][C:18](=[O:19])[CH2:17][CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:11][CH2:12]2)=[O:31])[CH2:26][CH2:27][CH2:22][CH2:23][CH2:24]1
Reactant: NNC(=O)CCN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Reactant: O=C=NCC1CCCCC1
Solvent: Cc1ccccc1
Product: O=C(CCN1CCN(c2cccc([N+](=O)[O-])c2)CC1)NNC(=O)NCC1CCCCC1
Temperature: 70 °C
Yield: 86.5 %

Procedure:
A solution of 3-[4-(3-nitrophenyl)piperazino]propanohydrazide D7 (0.55 g, 1.87 mmol) in toluene (30 mL) was heated at 70° C. and cyclohexanemethyl isocyanate (0.28 g, 0.30 mL, 1.96 mmol) was added at once. The slurry was heated at 70° C. until all solid went into solution (15 min) and then cooled to room temperature. The resulting solid was filtered and washed with toluene to afford 0.70 g (95%) N-(cyclohexylmethyl)-2-{3-[4-(3-nitrophenyl)piperazin-1-yl]propanoyl}hydrazine carboxamide D8 as an orange semi-solid.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:5][C:6](=[O:29])[C@H:7]([CH2:23][C:24]1[N:28]=[CH:27][NH:26][CH:25]=1)[NH:8][C:9](=[O:22])[CH2:10][NH:11][C:12]([O:14]CC1C=CC=CC=1)=O.Br.[C:36]([OH:39])(=O)[CH3:37]>>[OH:39][C:36]1[CH:37]=[CH:31][C:30]([C:12](=[O:14])[NH:11][CH2:10][C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:34])[CH2:30][CH:31]([CH3:32])[CH3:33])=[O:29])[CH2:23][C:24]2[N:28]=[CH:27][NH:26][CH:25]=2)=[O:22])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CNC(=O)OCc1ccccc1
Reactant: CC(=O)O
Agent: Br
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CNC(=O)c1ccc(O)cc1)C(=O)O
Reaction time: 1 h

Procedure:
20 g of carbobenzoxyglycyl-L-histidyl-L-leucine methyl ester is added to 100 ml of 25% HBr solution in acetic acid and this mixture is stirred for one hour to split off the carbobenzoxy group, and then 2000 ml of absolute ether is added. The precipitate thus produced is filtered off and washed with ethyl ether and dried in a desiccator.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[CH2:17][C@H:16]3[NH:18]C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)C.O>[F:1][C:2]([F:26])([F:27])[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[CH2:17][C@H:16]3[NH2:18])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: N[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)cc1
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of tert-butyl(trans)-2-(3′-(trifluoromethyl)biphenyl-4-yl)cyclopropylcarbamate (5 g) in diethyl ether (50 mL) at 0° C., HCl in Diethyl ether (20 mL) was added and stirred for 1 h. After completion, the solvent was evaporated and residue was triturated with Et2O (20 mL) to give crude salt. The crude salt was dissolved in water (50 mL), basified with Na2CO3 solution, extracted with EtOAc (3×50 mL). The combined extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and evaporated to get crude (trans)-2-(3′-(trifluoromethyl)biphenyl-4-yl)cyclopropanamine (3.6 g, 98.09%) as a white solid
Reaction SMILES: [NH2:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)([CH3:7])[C:3]([O:5]C)=O.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27])#[N:16]>>[O:25]=[C:24]1[NH:1][C:2]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)([CH3:7])[C:3](=[O:5])[N:23]1[C:20]1[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=1
Reactant: COC(=O)C(C)(N)c1ccc(O)cc1
Reactant: N#Cc1ccc(N=C=O)cc1C(F)(F)F
Product: CC1(c2ccc(O)cc2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O

Procedure:
This product is prepared as in Example 5, starting from 10.71 g of methyl 2-amino-2-(4-hydroxyphenyl)propionate using 4-cyano-3-trifluoromethylphenyl isocyanate. 16.83 g of product are obtained (Yd=82%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:26][CH:27]([CH3:31])[C:28](Cl)=[O:29]>C1COCC1>[Cl:26][CH:27]([CH3:31])[C:28]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[CH:4][CH:3]=1)=[O:29]
Reactant: CC(Cl)C(=O)Cl
Reactant: Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(Cl)C(=O)Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of compound of example 15 (0.10 g, 0.39 mmol) in THF (10 mL), was added triethylamine (0.059 g, 0.58 mmol) and 2-chloropropanoyl chloride (0.074 g, 0.58 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 5% methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:43][O:44][CH3:45])[C:12]([NH:14][CH:15]2[C:41](=[O:42])[N:17]3[C:18]([C:25]([O:27][CH:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[C:19]([CH2:22][O:23][CH3:24])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=O.NC(N)=S.C(=O)(O)[O-].[Na+]>CC(N(C)C)=O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:43][O:44][CH3:45])[C:12]([NH:14][CH:15]2[C:41](=[O:42])[N:17]3[C:18]([C:25]([O:27][CH:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[C:19]([CH2:22][O:23][CH3:24])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: COCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(=O)CCl)n3)[C@H]2SC1
Agent: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 35.6 %

Procedure:
200 mg of benzhydryl 7-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate, followed by 45 mg of thiourea, were dissolved in 5 ml of dimethylacetamide. The solution was maintained at room temperature for 2 hours. after which a saturated aqueous solution of sodium bicarbonate was added. The reaction mixture was then extracted with 20 ml of ethyl acetate and the extract was washed with water to remove excess thiourea and then dried over anhydrous magnesium sulphate. After the drying agent had been filtered off, the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was chromatographed through 30 g of silica gel (Wacogel C-100), eluted with ethyl acetate, to afford 63 mg of benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:16](OCC)=[O:17].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH:16]([CH:10]([CH2:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:17]
Reactant: CCOC(=O)CCc1ccccc1
Reactant: CCOC=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.9 %

Procedure:
To a suspension solution containing 4.4 g of 60% NaH in 200 ml of THF, 17.8 g of ethyl 3-phenylpropionate and 8.2 g of ethyl formate were added dropwise under ice cool for one hour. Thereafter, the mixture was stirred at room temperature for 15 hours. Furthermore, 14 g of 60 % NaH and 25.9 g of ethyl formate were divided into three parts and each part was added separately. Afterwards, the solution mixture was stirred at room temperature for 15 hours. After a 10% citric acid solution was added to the resultant reaction solution, the reaction solution was extracted with ethyl acetate and the extract was concentrated under reduced pressure to obtain 32.4 g of a brown oily concentrate. The concentrate thus obtained was purified by silica gel column chromatography to obtain 17.9 g of the titled compound as a transparent oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[Si:18]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: Cc1ccc(CCCCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1ccc(CCCCO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 4 h

Procedure:
4-(4-Methylphenyl) butanol (0.5 g, 3.04 mmol) is dissolved in 5 ml DMF and to it is added imidazole (310 mg, 4.56 mmol) and tert-butyldimethylsilyl chloride (685 mg, 4.56 mmol). The reaction is stirred for 4 hrs after which it is extracted in ethyl acetate and washed with water to remove all DMF. The organic layer is then dried and concentrated. The crude mixture is then purified by flash chromatography using a mixture of ethyl acetate-hexanes as the eluting medium to afford the above mentioned product.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[F:9][C:10]1[CH:24]=[CH:23][C:13]([CH2:14][CH:15]([C:20](=O)[CH3:21])[C:16](OC)=[O:17])=[CH:12][CH:11]=1.O>CO>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][C:15]2[C:16]([OH:17])=[N:4][C:2]([CH3:3])=[N:5][C:20]=2[CH3:21])=[CH:23][CH:24]=1
Reactant: CC(=N)N
Reactant: COC(=O)C(Cc1ccc(F)cc1)C(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nc(C)c(Cc2ccc(F)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.2 %

Procedure:
To a suspension of acetamidine hydrochloride (0.54 g, 5.71 mmol) in methanol (8 mL) was added a 30% solution of sodium methoxide in methanol (1.1 mL, 5.7 mmol), and the resulting solution was stirred at room temperature for 45 min. Then, a solution of methyl 2-(4-fluorobenzyl)-3-oxobutanoate (0.80 g, 3.57 mmol) in methanol (3 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 22 h. Water (100 mL) was added, and the mixture was extracted with chloroform (4×50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to provide 5-(4-fluorobenzyl)-2,6-dimethylpyrimidin-4-ol (0.74 g, 89% yield) as a colorless solid. 1H NMR (400 MHz, methanol-d4): 7.21 (m, 2H), 6.96 (m, 2H), 3.84 (s, 2H), 2.35 (s, 3H), 2.25 (s, 3H); MS (EI) for C13H13FN2O: 233 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([F:22])[CH:15]=2)=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:23][NH:24][S:25](Cl)(=[O:27])=[O:26].[BH4-].[Na+]>N1C=CC=CC=1>[F:22][C:16]1[CH:15]=[C:14]([CH:12]2[C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[N:10][CH:9]=[CH:8][CH:7]=4)[C:2]=3[NH:1][S:25](=[O:27])(=[O:26])[N:24]2[CH3:23])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COc1ccc(C(=O)c2ccc3cccnc3c2N)cc1F
Reactant: CNS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(C2c3ccc4cccnc4c3NS(=O)(=O)N2C)cc1F
Yield: 58 %

Procedure:
In a similar fashion using route 27 general procedure 71, (8-amino-quinolin-7-yl)-(3-fluoro-4-methoxy-phenyl)-methanone (Intermediate 381) (200 mg, 0.6 mmol), N-methylsulfamyl chloride (Intermediate 213) (260 mg, 2.0 mmol), NaBH4 (76 mg, 2.0 mmol) and pyridine (2 ml) gave the title compound (130 mg, 52%) after purification by column chromatography with n-hexane/EtOAc (50:50) as the eluent.
Reaction SMILES: I[C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Cl:12][C:13]1[C:18](B(O)O)=[CH:17][C:16]([F:22])=[CH:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:12][C:13]1[C:18]([C:2]2[C:3]([O:10][CH3:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=2)=[CH:17][C:16]([F:22])=[CH:15][N:14]=1
Reactant: COc1ncc(I)c(OC)n1
Reactant: OB(O)c1cc(F)cnc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: COc1ncc(-c2cc(F)cnc2Cl)c(OC)n1
Yield: 27 %

Procedure:
5-Iodo-2,4-dimethoxy-pyrimidine (868 mg, 3.3 mmol) was dissolved in degassed n-PrOH (30 ml) and then 2-chloro-5-fluoropyridine-3-boronic acid (858 mg, 4.9 mmol), Na2CO3 (700 mg, 6.6 mmol), PPh3 (88 mg, 0.33 mmol) and Pd(OAc)2 (90 mg) were added. The suspension was stirred at reflux for 4 hours. The solvent was evaporated under vacuum and the crude was partitioned between brine and ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether 2-8 affording 240 mg of the title compound (27% yield).
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][O:6][N:7]=[CH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[CH3:26]>C(O)C.C(O)(=O)C>[CH3:5][O:6][NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[CH3:26]
Reactant: CON=CCCCn1c(C)nc2c(N)nc3ccccc3c21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CONCCCCn1c(C)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
Sodium cyanoborohydride (16.0 g, 254 mmol) was added to a solution of 4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butanal O-methyloxime (prepared as described in Example 45, 15.1 g, 50.8 mmol) in ethanol (100 mL) and acetic acid (15 mL). The reaction mixture was stirred at room temperature for 2 hours, additional acetic acid (15 mL) was added, and stirring was continued for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and adjusted to pH 7 with saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane. The organic layers were combined, washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated to provide 12.1 g of 1-[4-(methoxyamino)butyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14](=[O:20])[NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:11]=2)[C:6]([CH2:21][C:22]2[CH:40]=[CH:39][C:25]([C:26]([NH:28][S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])(=[O:31])=[O:30])=[O:27])=[CH:24][C:23]=2[O:41][CH3:42])=[CH:5]1)[CH:2]=[CH2:3]>[OH-].[Na+].C(O)C.[Pd]>[CH2:16]([NH:15][C:14]([CH2:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH2:1][CH2:2][CH3:3])[CH:5]=[C:6]2[CH2:21][C:22]1[CH:40]=[CH:39][C:25]([C:26]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])(=[O:31])=[O:30])=[O:27])=[CH:24][C:23]=1[O:41][CH3:42])=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: C=CCn1cc(Cc2ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc2OC)c2cc(CC(=O)NCCCC)ccc21
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCNC(=O)Cc1ccc2c(c1)c(Cc1ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc1OC)cn2CCC
Yield: 76.9 %

Procedure:
A solution of 4-[1-allyl-5-(butylcarbamoyl)methylindol-3-ylmethyl]-3-methoxy-N-(2-methylphenylsulfonyl)benzamide (0.35 g) in 1N sodium hydroxide (0.6 ml) and ethanol (10 ml) was hydrogenated at 3.45 bar in the presence of 10% (w/w) palladium-on-carbon (0.09 g) for 3 hours. The catalyst was removed by was evaporated. The residue was dissolved in H2O (10 ml) and the resultant aqueous solution was acidified with 10% (v/v) hydrochloric acid. The white precipitate which formed was collected by filtration, washed with water, and dried under vacuum to give the title compound (0.27 g, 77%) as a white powder; mp 100°-102°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:20]=1[O:21]C)[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:17])[CH2:9]1)=[O:7])#[N:2].[Cl-].[Li+].Cl>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([C:23]([F:26])([F:24])[F:25])[C:20]=1[OH:21])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:17])[CH2:9]1)=[O:7])#[N:2]
Reactant: COc1c(C#N)cc(C(=O)N2CS(=O)c3ccccc32)cc1C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)N2CS(=O)c3ccccc32)cc(C(F)(F)F)c1O
Temperature: 70 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
3-(3-cyano-4-methoxy-5-trifluoromethylbenzoyl)-1-oxo-2,3-dihydro-1,3-benzothiazole (619 mg) was dissolved in N,N-dimethylformamide (5 mL), and lithium chloride (276 mg) was added to the solution, and the mixture was stirred at 70° C. for 3 hours. To the reaction solution, 1N hydrochloric acid was added, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (494 mg) as a colorless crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:13](O)=[O:14])=[CH:5][CH:4]=1.B#B>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH:12]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH2:13][OH:14])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCC(CCc2ccc(OC)cc2)C(=O)O)cc1
Agent: B#B
Solvent: C1CCOC1
Product: COc1ccc(CCCC(CO)CCc2ccc(OC)cc2)cc1
Reaction time: 10 h

Procedure:
A solution of 5-(4-methoxyphenyl)-2-[2-(4-methoxy phenyl)ethyl]pentanoic acid (20 g, 0.058 mol) in dry tetrahydrofuran (50 ml) was treated with a solution of diborane in tetrahydrofuran (100 ml of 1M, 0.1 mol) and left to stand at room temperature for 10 hours. The solvent was evaporated off under reduced pressure and the residue was acidified with hydrochloric acid (2N) and extracted with chloroform. The combined extracts were dried (Na2SO4) and the solvent was evaporated off under reduced pressure to give the crude product which was further purified by column chromatography (silica gel, ethyl acetate) to give 5-(4-methoxyphenyl)-2-[2-(4-methoxyphenyl)ethyl]-1-pentanol as a colourless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:18][NH2:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][CH:14]([NH:19][CH3:18])[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CN
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 1.6 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and methylamine (20 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (1 mg) and a syn-form compound (1 mg).