Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21](=[O:36])[C@@H:22]([NH2:35])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:26][CH:25]=1>C(OCC)(=O)C.CCCCCC>[CH3:19][O:20][C:21](=[O:36])[CH:22]([NH:35][C:12](=[O:14])[CH:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[CH:26][CH:25]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)C(CC(C)C)NC(=O)N1CCCCCC1
Yield: 81.2 %

Procedure:
A solution of the product from Example Z (2(S)-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid) (0.20 g, 0.78 mmol) and 2(S)-amino-3-(4-tert-butoxy-phenyl)-propionic acid methyl ester (Bachem, 0.247 g, 0.86 mmol) were coupled according to the procedure described in Example 42. The residue was passed through a plug of silica gel eluting with 70% ethyl acetate/hexane. The material obtained was purified by crystallization from hot hexane/ethyl acetate to give the title compound as a white solid (0.31 g, 81%), mp=96-99° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH:17][CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.[CH3:32][S-:33].[Na+]>CN(C)C=O.O>[C:20]1([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18][NH:17][C:4]2[N:3]=[C:2]([S:33][CH3:32])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[S-]
Reactant: Clc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 100 °C
Reaction time: 72 h
Yield: 99.8 %

Procedure:
A solution of 2-chloro-N-(2,2-diphenylethyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (Preparation 2) (49.7 g, 0.11 mol) in dry N,N-dimethylformamide (200 ml) was treated with sodium thiomethoxide (10 g, 0.14 mol) and the resulting mixture heated under an atmosphere of nitrogen at 100° C. for 90 minutes The mixture was stirred at room temperature for 72 hours and then reheated at 100° C. for a further 2 hours. The reaction mixture was cooled and diluted with water (1000 ml). A suspension was formed which was extracted with diethyl ether (×2). The combined organic layers were washed sequentially with water and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was azeotroped with diethyl ether followed by pentane to afford the title compound as a foam (48.9 g).
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][NH:6][C@H:7]([C@@H:10]([OH:14])[CH2:11][S:12][CH3:13])[CH2:8][OH:9].[CH2:15]([O:22][CH2:23][N:24]1[C:32]2[C:31]([Cl:33])=[N:30][CH:29]=[N:28][C:27]=2[C:26]([CH:34]=O)=[CH:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[CH2:15]([O:22][CH2:23][N:24]1[C:32]2[C:31]([Cl:33])=[N:30][CH:29]=[N:28][C:27]=2[C:26]([CH2:34][N:6]([CH3:5])[C@@H:7]([C@H:10]([OH:14])[CH2:11][S:12][CH3:13])[CH2:8][OH:9])=[CH:25]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1cn(COCc2ccccc2)c2c(Cl)ncnc12
Reactant: CN[C@@H](CO)[C@@H](O)CSC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CSC[C@@H](O)[C@@H](CO)N(C)Cc1cn(COCc2ccccc2)c2c(Cl)ncnc12
Reaction time: 48 h
Yield: 67 %

Procedure:
Sodium cyanoborohydride (68 mg, 1.1 mmol) was added to a stirred solution of (2S,3R)-2-(methylamino)-4-(methylthio)butane-1,3-diol (120 mg, 0.7 mmol) and 5-(benzyloxymethyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carbaldehyde (263 mg, 0.9 mmol) in methanol (2 ml) and the resulting reaction left for 48 h. The reaction was concentrated in vacuo and the resulting residue purified by flash chromatography on silica gel eluting with 5% MeOH/DCM=>10% MeOH/DCM to afford, presumably, (2S,3R)-2-(((5-(benzyloxymethyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)(methyl)amino)-4-(methylthio)butane-1,3-diol B.4 (220 mg, 67% yield) as a syrup which was used in the next step without purification.
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5]#[N:6].C1C=CC=CC=1.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[N:20]=[C:19]([C:34]([NH:36][NH2:37])=[O:35])[CH:18]=1>Cl.C(OCC)(=O)C.O>[C:5]([CH2:4][CH:3]=[N:37][NH:36][C:34](=[O:35])[C:19]1[CH:18]=[C:17]([O:16][CH3:15])[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)[N:20]=1)#[N:6]
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1
Reactant: COC(CC#N)OC
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN=CCC#N)c1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
3,3-dimethoxy propionitrile (0.35 g, 0.0015×2 mol) was dissolved in a 2N aqueous hydrochloric acid solution (about 10 ml). The obtained solution was stirred at a temperature of about 50 to 60° C. for about one hour. The solution was further mixed with benzene (about 10 ml) and 4-methoxy-6-[3-(trifluoromethyl)phenoxy] picolinic acid hydrazide (0.50 g, 0.0015 mol), and then the resultant mixture was stirred at that temperature for about one hour. The obtained reaction solution was distributed in ethyl acetate-water The organic phase separated from the solution was successively washed with saturated sodium bicarbonate water and with saturated brine, and then dried with anhydrous sodium sulfate. Thereafter, the resultant solution was concentrated and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[C:6]([CH3:12])[C:7]=1[O:8][CH2:9][O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]([Cl:25])=[CH:22][CH2:23]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:23][CH:22]=[C:21]([Cl:25])[Cl:20])[CH:5]=[C:6]([CH3:12])[C:7]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: COCOc1c(C)cc(O)cc1Cl
Reactant: ClCC=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1c(C)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Yield: 91.7 %

Procedure:
To a mixture of 10 g of 3-chloro-4-methoxymethoxy-5-methylphenol, 7 g of potassium carbonate and 100 ml of N,N-dimethylformamide was added dropwise a solution of 8 g of 1,1,3-trichloro-1-propene dissolved in 30 ml of N,N-dimethylformamide, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice water, and extracted with 200 ml of diethyl ether. The combined ether was washed with water, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel chromatography, which afforded 14.1 g of 3-chloro-4-methoxymethoxy-5-methyl-1-(3,3-dichloro-2-propenyloxy)benzene (91% yield).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3].[CH3:14][NH:15][CH3:16]>C1COCC1>[CH3:14][N:15]([CH3:16])[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3]
Reactant: CNC
Reactant: O=C(Cl)c1ccc2c(c1)COC2=O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc2c(c1)COC2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 5-chlorocarbonylphthalid (32 g, 0.16 mole) in THF (300 ml) is added to dimethylamine (40% v/v in water, 300 ml) and ice (100 g). The mixture is stirred for 1 hour. THF is evaporated off in vacuo and precipitated crystals are filtred off at 5° C. and washed with water (100 ml).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:12]=3[C:13]=2[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:18][CH:17]=2)=[O:15])=[CH:5][CH:4]=1>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:12]=3[C:13]=2[CH:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:18][CH:17]=2)[OH:15])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2oc3cc(OC)ccc3c2C(=O)c2ccc(OCCN(C)C)cc2)cc1
Solvent: CO
Product: COc1ccc(-c2oc3cc(OC)ccc3c2C(O)c2ccc(OCCN(C)C)cc2)cc1
Yield: 68.5 %

Procedure:
1.335 g (3 mmol) of [2-(4-methoxyphenyl)-6-methoxybenzofuran-3-yl][4-[2-dimethylaminoethoxy]phenyl]methanone was reduced to the carbinol by the method described in Example 1. This yielded 920 mg of the title compound as an oil.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O=S(Cl)Cl.[NH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[OH:23].C([O-])([O-])=O.[Na+].[Na+]>N1C=CC=CC=1.O.CC(O)=O>[OH:23][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:17]=1[NH:16][C:9]([C:7]1[S:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:11]
Reactant: Nc1ccncc1O
Reactant: O=C(O)c1ccc([N+](=O)[O-])s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: O=C(Nc1ccncc1O)c1ccc([N+](=O)[O-])s1
Temperature: 10 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
A solution of 5-nitrothiophene-2carboxylic acid (5.0 g, 28.9 mmol) and SOCl2 (40 mL) was refluxed for 2 hrs. The solvent was removed in vacuo followed by addition of 4-amino-3-hydroxypyridine (2.65 g, 24.1 mmol) in pyridine (150 mL). The mixture was stirred at 10° C. overnight. Na2CO3 (1.53 g, 14.5 mmol) in water (100 mL) was added and stirred for 1 hr followed by adding AcOH to adjust pH=7. The precipitate was collected by filtration, washed with 10% AcOH (30 mL×2) and dried to give N-(3-hydroxypyridin-4-yl)-5-nitrothiophene-2-carboxamide as a yellow powder (5.0 g, yield 78%).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:11]=[C:10]([Br:12])[S:9][C:8]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[N+:18]([O-])([OH:20])=[O:19]>>[Br:6][C:7]1[C:11]([N+:18]([O-:20])=[O:19])=[C:10]([Br:12])[S:9][C:8]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1sc(Br)cc1Br
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1sc(Br)c([N+](=O)[O-])c1Br
Temperature: -5 °C
Reaction time: 1 h
Yield: 59.54 %

Procedure:
Sulfuric acid (27.6 g, 15.0 ml, 281.0 mmol) was added in a dropwise manner to ethyl 3,5-dibromothiophene-2-carboxylate (Prepared according to procedure reported in JCS Perkin Trans-1: Organic and Bioorganic Chemistry (1972-1999), 1973, p 1766-1770), 5.0 g (15.92 mmol), at room temperature (about 25° C.). The reaction mixture was then cooled to −5° C. and to the cooled mixture was added nitric acid (2.0 g, 2.04 ml, 31.84 mmol) slowly. The reaction mixture was then stirred at 0° C. for 1 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then poured onto ice-water (150 ml). The mixture so obtained was extracted with ethyl acetate (2×100 ml). The combined organic layer was dried over sodium sulphate and was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 2% ethyl acetate in hexanes as an eluent to obtain the title compound (3.40 g, 59.54%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9](=O)[CH2:10][CH3:11])[CH:6]=[C:5]([CH2:13][CH3:14])[C:4]=1[OH:15])[CH3:2].Cl.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25]N)=[CH:21][CH:20]=1>>[CH2:13]([C:5]1[CH:6]=[C:7]([C:9]2[NH:25][C:22]3[C:23]([C:10]=2[CH3:11])=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[OH:15])[CH3:14]
Reactant: COc1ccc(NN)cc1
Reactant: CCC(=O)c1cc(CC)c(O)c(CC)c1
Agent: Cl
Product: CCc1cc(-c2[nH]c3ccc(OC)cc3c2C)cc(CC)c1O

Procedure:
2,6-Diethyl-4-propionylphenol and 4-methoxyphenylhydrazine hydrochloride were treated in the same way as in Example 1 to give 2-(3,5-diethyl-4-hydroxyphenyl)-5-methoxy-3-methylindole.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10](=O)[N:11]=1)=[N:8][C:7]([CH3:13])=[C:6]([CH3:14])[N:5]=2.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][NH2:23])=[CH:19][CH:18]=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+].C(Cl)Cl>C[Si](C)(C)N[Si](C)(C)C.O>[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][NH:23][C:10]2[C:9]3[C:4](=[N:5][C:6]([CH3:14])=[C:7]([CH3:13])[N:8]=3)[N:3]=[C:2]([CH3:1])[N:11]=2)=[CH:19][CH:18]=1
Reactant: Cc1nc(=O)c2nc(C)c(C)nc2[nH]1
Reactant: COc1ccc(CCN)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CCNc2nc(C)nc3nc(C)c(C)nc23)cc1
Temperature: 115 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2,6,7-trimethylpteridin-4(1H)-one (1.1 g, 6.0 mmol), 4-methoxyphenethylamine (1.6 g, 11 mmol) and ammonium sulfate (0.56 g, 4.2 mmol) in hexamethyldisilazane (16 mL) was heated at 115° C. for 6 h. After cooling, the majority of solids were dissolved by addition of CH2Cl2 and H2O and the solvents removed in vacuo. The residue was slurried in a mixture of MeOH (5 mL) and H2O (50 mL) and stirred for 45 min. The bronze solid was collected by suction filtration and dried in vacuo at 50° C. The residue was dissolved in MeOH/CH2Cl2 and diluted with Et2O, causing crystallization. All solvent was allowed to evaporate, and the remaining solid dried in vacuo to afford [2-(4-methoxyphenyl)-ethyl]-(2,6,7-trimethylpteridin-4-yl)-amine as a brown powder (1.3 g; 67%): 1H NMR (300 MHz, CDCl3) δ 7.22-7.14 (m, 2H), 6.95 (t, J=6.3 Hz, 1H), 6.90-6.83 (m, 2H), 3.87 (dd, J=13.5, 6.8 Hz, 2H), 3.80 (s, 3H), 2.97 (t, J=7.2 Hz, 2H), 2.69 (s, 3H), 2.66 (s, 3H), 2.61 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:9][CH2:8][C:7]=2[C:6]([C:23](O)=[O:24])=[N:5][CH:4]=1.C1[CH:31]=[N:30][C:29]2N(O)N=NC=2C=1.CNC>C1COCC1.C(Cl)CCl>[CH3:1][O:2][C:3]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:9][CH2:8][C:7]=2[C:6]([C:23]([N:30]([CH3:31])[CH3:29])=[O:24])=[N:5][CH:4]=1
Reactant: On1nnc2cccnc21
Reactant: COc1ccc(CN2CCc3c(C(=O)O)ncc(OC)c3C2=O)cc1
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCCl
Product: COc1ccc(CN2CCc3c(C(=O)N(C)C)ncc(OC)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 250 mL THF suspension of 4-methoxy-6-(4-methoxybenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylic acid (11.0 g), 8.0 g EDC, 5.7 g HOAT, and 11.2 mL TEA was stirred at room temperature for 20 minutes, followed by addition of 45 mL of a 2M THF solution of dimethylamine and then stirring for 1.5 hours. The reaction was quenched with 200 mL of 1N aq HCl and stirred vigorously for 30 minutes. After concentrating in vacuo until an oil formed on the water layer, 200 mL chloroform was added. The water layer was washed again with chloroform then the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to pure product by HPLC/MS and NMR.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(SC(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@@H]1CCNC1
Product: O=C(Nc1ccc(SC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described infashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-((chlorodifluoromethyl)thio)phenyl)nicotinamide (Stage 217.2) and (R)-pyrrolidin-3-ol to afford an off-white crystalline solid. HPLC (Condition 4) tR=5.97 min, UPLC-MS (Condition 3) tR=1.19 min, m/z=478.2/480.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14].[O:17]1[CH2:21][CH2:20][CH:19]([CH:22]=O)[CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:22][CH:19]2[CH2:20][CH2:21][O:17][CH2:18]2)=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:15])([F:14])[F:16]
Reactant: NCCc1ccc(F)c(OCC(F)(F)F)c1
Reactant: O=CC1CCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(CCNCC2CCOC2)cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
A mixture of 500 mg (2.1 mmol) of 2-[4-fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethylamine, 210 mg (2.1 mmol) of tetrahydrofuran-3-carbaldehyde and 2 g of 4 Å molecular sieves in 30 ml of dry dichloromethane was stirred at room temperature for 30 minutes. 630 mg (2.9 mmol) of NaBH(OAc)3 were added portionwise. The reaction mixture was stirred for 4 hours at room temperature. An aqueous 5% solution of NaHCO3 was added and the product was extracted with dichloromethane. The crude product was purified by flash chromatography (dichloromethane/methanol/NH3 100:9:0.5 v:v:v). 300 mg (44% yield) of the title compound were isolated as an oil.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18](=O)[CH2:19][C:20]#[N:21])=[CH:13][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.NC1C=C[NH:26][N:25]=1.NN>CCO>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[CH:19]=[C:20]([NH2:21])[NH:25][N:26]=3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#CCC(=O)Cc1ccc(OCCCN2CCOCC2)cc1
Reactant: Nc1cc[nH]n1
Agent: NN
Solvent: CCO
Product: Nc1cc(Cc2ccc(OCCCN3CCOCC3)cc2)n[nH]1
Temperature: 65 °C

Procedure:
The 4-[4-(3-morpholin-4-yl-propoxy)-phenyl]-3-oxo-butyronitrile is then converted to the appropriate aminopyrazole by the following method: Under Ar(g), 0.095gms. of the 4-[4-(3-morpholin-4-yl-propoxy)-phenyl]-3-oxo-butyronitrile is dissolved in 2 mL of anhydrous EtOH and then is treated with 0.100 gms. anhydrous hydrazine. The reaction mixture is then heated overnight at 65° C., subsequently, cooled to room temperature and concentrated in vacuo providing 5-[4-(3-morpholin-4-yl-propoxy)-benzyl]-2H-pyrazol-3-ylamine which is use in crude form in the reaction of Example 58.
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:13][O:14][C:15]1[C:16]([N+:22]([O-:24])=[O:23])=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1.[Br:25]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:13][O:14][C:15]1[C:16]([N+:22]([O-:24])=[O:23])=[N:17][C:18]([CH2:21][Br:25])=[CH:19][CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C)nc1[N+](=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)nc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 21.3 %

Procedure:
A catalytic amount of α,α'-azobis(isobutyronitrile) was added to 3-methoxy-6-methyl-2-nitropyridine (described in Acta Chem. Scand., vol. 23, pages 1791-1796) (7.1 g), N-bromosuccinimide (7.1 g) and carbon tetrachloride (80 ml), and the mixture was refluxed for 16 hours. After the reaction, while the reaction mixture was still hot, it was suction-filtered to separate the insoluble succinimide. The filtrate was cooled to room temperature whereupon the unreacted 3-methoxy-6-methyl-2-nitropyridine precipitated as crystals. The crystals were separated by filtration. The residue was concentrated and then vacuum distilled to give 3-methoxy-2-nitro-6-pyridylmethyl bromide (2.1 g).
Reaction SMILES: C(O[C:4](=O)[NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12][C:11]2[CH:26]=[CH:27][CH:28]=[N:29][C:10]1=2)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:20]1([CH:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:9]([CH2:8][CH2:7][CH2:6][NH:5][CH3:4])[C:10]3[N:29]=[CH:28][CH:27]=[CH:26][C:11]=3[NH:12]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)NCCCN1c2ccccc2C(c2ccccc2)=Nc2cccnc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCCN1c2ccccc2C(c2ccccc2)Nc2cccnc21

Procedure:
To a solution of 1.4 g (0.0035 mole) of N-[3-[6-phenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine-11-yl]propyl]carbamic acid ethyl ester (from Example 29) in tetrahydrofuran under nitrogen gas was added 0.4 g (0.0105 mole) of lithium aluminum hydride and slight exothermic reaction occurred. The mixture was cooled to prevent overheating. The mixture was stirred at reflux temperature for 16 hr. Thin layer chromatography indicated only partial conversion had occurred. An additional 0.4 g (0.0105 mole) of lithium aluminum hydride was added and the mixture refluxed overnight. Thin-layer chromatography indicated the product was predominantly the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[S:19]1[CH:23]=[C:22]([C:24]([O-])=[O:25])[N:21]=[C:20]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:24]([C:22]3[N:21]=[C:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[S:19][CH:23]=3)=[O:25])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CCOC(=O)c1nc(C(=O)[O-])cs1
Product: CCOC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Yield: 82 %

Procedure:
(S)-ethyl 4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazole-2-carboxylate was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (540 mg, 2.071 mmol) and 2,4-thiazoledicarboxylic acid, 2-ethyl ester (500 mg, 2.485 mmol). Yield 82%. 1H-NMR (400 MHz; DMSO3): δ 1.18 (d, 3H), 1.35 (t, 3H), 4.35 (dd, 1H), 4.39-4.57 (m, 4H), 6.94 (d, 1H), 7.84 (d, 1H), 7.95 (m, 2H), 8.02 (m, 1H), 8.55 (s, 1H), 8.61 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:14]([O:1][C:2]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(F)(F)F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product from step (ii) (2.3 g), benzyl bromide (1.44 ml) and potassium carbonate (1.67 g) in DMF (20 ml) was stirred at RT for 2 h. The mixture was partitioned between diethylether and water, the organic layer dried, and the solvent evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 40/60 pet. ether/diethylether 4:1, yield 2.83 g.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[N:16]([CH3:17])[CH:10]([CH2:11][C:12](=O)[CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[CH2:1]([N:8]1[CH2:15][CH:14]2[N:16]([CH3:17])[CH:10]([CH2:11][C:12](=[N:20][OH:21])[CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1C2CC(=O)CC1CN(Cc1ccccc1)C2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: c1ccncc1
Product: CN1C2CC(=NO)CC1CN(Cc1ccccc1)C2
Temperature: 25 °C
Yield: 878.5 %

Procedure:
A mixture of 3-benzyl-9-methyl-7-oxo-3,9-diazabicyclo[3.3.1]nonane (9.33 g ), hydroxylamine hydrochloride (3.98 g ), pyridine (12.5 ml ) and ethanol was heated at reflux for 2 hrs. The reaction solution was cooled down to room temperature, potassium carbonate (15 g) and water (8 ml ) were added and the stirring was continued for a while. The resultant suspension was filtered through celite and the solvent was distilled off under reduced pressure. The resulting residue was mixed with chloroform (200 ml ) and filtered through Celite. The solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography and crystallized to afford the title compound (3. 87 g ).