Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH3:22])[C:5]([N:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:17][C:10]=2[CH2:9][CH2:8]1)=[O:6].[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.Cl>O.CC(C)=O>[CH:23]1([NH:29][C:30]([NH:21][S:18]([C:16]2[CH:15]=[CH:14][C:11]3[CH2:12][CH2:13][N:7]([C:5](=[O:6])[N:4]([CH3:22])[CH3:3])[CH2:8][CH2:9][C:10]=3[CH:17]=2)(=[O:20])=[O:19])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C=NC1CCCCC1
Reactant: CN(C)C(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CN(C)C(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2CC1
Temperature: 25 °C

Procedure:
8.8 Ml. of 2N sodium hydroxide are added while stirring at 25° C. to a mixture of 5.2 g. of 3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide in 180 ml. of acetone, during which the solid material first dissolves and then a new crystalline precipitate immediately results. 2.26 Ml. of cyclohexylisocyanate are then added thereto while cooling externally with ice and stirring, whereupon the solid material passes completely into solution and then a crystalline precipitate soon reappears. The mixture is subsequently stirred for 16 hours at 25° C., then diluted with 350 ml. of water, acidified to pH 2 with 3N hydrochloric acid and finally extracted twice with 500 ml. of chloroform each time. The chloroform extracts are dried over sodium sulfate and evaporated in vacuo at 60° C. The residue is dissolved in 25 ml. of acetone and crystallized by trituration. There is obtained 1-cyclohexyl-3-[(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]urea, m.p. 113° C. (with decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.Cl[CH2:17][CH2:18][CH2:19][N:20]1[C:25](=[O:26])[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:23](=[O:35])[C:22]([CH3:36])=[N:21]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:17][CH2:18][CH2:19][N:20]3[C:25](=[O:26])[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[C:23](=[O:35])[C:22]([CH3:36])=[N:21]3)[CH2:12][CH2:13]2)=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: COc1cc(F)ccc1N1CCNCC1
Reactant: Cc1nn(CCCCl)c(=O)n(COCC[Si](C)(C)C)c1=O
Product: COc1cc(F)ccc1N1CCN(CCCn2nc(C)c(=O)n(COCC[Si](C)(C)C)c2=O)CC1

Procedure:
substituting 1-(4-fluoro-2-methoxyphenyl)piperazine and 2-(3-chloropropyl)-6-methyl-4-[2-(trimethylsilyl)ethoxymethyl]-1,2,4-triazine-3,5(2H,4H)-dione gave 2-{3-[4-(4-fluoro-2-methoxyphenyl)piperazin-1-yl]propyl}-6-methyl-4-[2-(trimethylsilyl)ethoxymethyl]-1,2,4-triazine-3,5(2H,4H)-dione;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][OH:34])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][OH:34])[CH2:30][CH2:31]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)cnn1-c1cccc(Cl)c1
Reactant: N#Cc1cc(N)ccc1N1CCN(CCO)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(CCO)CC3)c(C#N)c2)cnn1-c1cccc(Cl)c1
Yield: 12.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(3-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (2 g) and 5-amino-2-[4-(2-hydroxyethyl) piperazin-1-yl]benzonitrile (2.5 g), the title compound (0.5 g) was obtained, melting point: 176–177° C.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12.C([O-])([O-])=O.[K+].[K+].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24].C(OCC)(=O)C>CN1CCCC1=O>[C:19]1([CH3:24])[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12
Reactant: Cc1ccccc1Br
Reactant: O=C1CN2C(=O)CCC2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccccc1N1C(=O)CN2C(=O)CCC21
Yield: 15.4 %

Procedure:
To a solution of tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione (1.3 g, 9.28 mmol, prepared as described in J. Med. Chem. 36, 4214, 1994) in N-methylpyrrolidone (NMP, 12 cc), Cul (0.5 g, 2.62 mmol), K2CO3 (1.3 g, 9.28 mmol) and 2-bromotoluene (6 g, 35 mmol) were added under stirring. The suspension was heated in a microwave apparatus (250 Watt) for 1 h. Ethyl acetate was added to the suspension and the solid was filtered. The organic phase was washed with water and the aqueous phase was re-extracted with CH2Cl2. The organic phases were gathered and dried over Ma2SO4, filtered and concentrated to dryness. The residue was triturated with Et2O. The solid was filtered, and crystallized the first time with IPrOH and then with AcOEt to yield 0.33 g of the title compound, mp=138-139° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>O>[C:23]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=1)(=[O:25])[CH3:24]
Reactant: Nc1cccc(-c2nc3ncccc3o2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cccc(-c2nc3ncccc3o2)c1

Procedure:
A solution of 0.63 g. of 2-(3-aminophenyl)oxazolo[4,5-b]pyridine in 10 ml. of pyridine was treated with 0.35 ml. of acetic anhydride with stirring. After stirring over the weekend the mixture was diluted to 50 ml. with water. After stirring a short time and cooling, the precipitate was collected, washed with water and dried. Recrystallization from ethyl acetate gave 2-(3-acetamidophenyl)oxazolo[4,5-b]pyridine, m.p. 201.5°-202.5°.
Reaction SMILES: Cl.[C:2]([C@@H:5]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][CH:23]([NH:26][CH3:27])[CH2:22][CH2:21]4)[C:9]=3[C:8]1=2)(=[O:4])[NH2:3].C=O.[BH3-][C:42]#N.[Na+]>CO>[C:2]([C@@H:5]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:21][CH2:22][CH:23]([N:26]([CH3:42])[CH3:27])[CH2:24][CH2:25]4)[C:9]=3[C:8]1=2)(=[O:4])[NH2:3]
Reactant: [BH3-]C#N
Reactant: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](NC(=O)OCc2ccccc2)C(N)=O)CC4)CC1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](NC(=O)OCc2ccccc2)C(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
A solution of benzyl N-[(1S)-1-carbamoyl-2-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethyl]carbamate hydrochloride (100 mg, 0.18 mmol, 1.00 equiv) in methanol (10 mL) was added HCHO (37%, 2 mL) and stirred for 0.5 h at room temperature. This was followed by the addition of NaBH3CN (33.6 mg, 0.53 mmol, 2.99 equiv) at 0° C. and the resulting solution was allowed to react, with stirring, for an additional 2 h at room temperature. The reaction was then quenched by the addition of 20 mL of water and extracted with 3×50 mL of dichloromethane and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was applied onto a silica gel column with CH2Cl2: CH3OH (10:1) to provide benzyl N-[(1S)-1-carbamoyl-2-[(3R)-12-[[4-(dimethylamino)cyclohexyl]oxy]7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethyl]carbamate (50 mg, 52%) as a white solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[C:9]([C:13]1[C:22]2[O:21][CH2:20][CH2:19][CH2:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl>[C:9]([C:13]1[C:22]2[O:21][CH2:20][CH2:19][CH2:18][C:17]=2[CH:16]=[C:15]([C:5](=[O:7])[CH3:6])[CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1cccc2c1OCCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a suspension of AlCl3 (0.54 g, 4.05 mmol, 1.1 equiv) in CH2Cl2 (20 mL) is added acetyl chloride (0.28 mL, 4.05 mmol, 1.1 equiv). The resulting suspension is allowed to stir at -78° C. for 30 min, and a solution of 8-tert-butyl-2,3-dihydrobenzopyran (0.70 g, 3.68 mmol) in CH2Cl2 (5 mL) is added dropwise using an addition funnel. After the addition is complete, the reaction mixture (pale yellow precipitate) is allowed to warm to room temperature over 4 h. The resulting suspension is cooled to 0° C and quenched with water, washed with water and brine. The aqueous layers are extracted with CH2Cl2, the combined organic layer is dried (MgSO4), filtered and concentrated. The resulting off-white solid is recrystallized using hexanes to give the title compound (0.67 g, 79%) as white crystals.
Reaction SMILES: CN(C=O)C.[CH3:6][CH:7]([OH:16])[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[H-].[Na+].F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>O>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([O:16][CH:7]([CH3:6])[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: CC(O)CCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCN1CCOCC1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
To 100 mL of DMF is added α-methyl-4-morpholinepropanol (15.9 g, 0.1 mol) and 7.2 g (50% in mineral oil, 0.15 mol) of NaH followed by 14.1 g (0.1 mol) of 1-fluoro4-nitrobenzene. Heat the reaction at 80° C. and monitor the reaction by thin-layer chromatography. Upon completion of the reaction add 100 mL of water and extract with ether. Dry the organic phase over Na2SO4. Filter off the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.CN(C)C=O.N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>N1C=CC=CC=1>[Si:32]([O:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Temperature: -20 °C
Reaction time: 12 h
Yield: 91.1 %

Procedure:
To 3α-hydroxy-5α-androstan-17-one (25.22 g, 290.5 g/mol, 86.8 mmol) dissolved in 65 mL of dry pyridine was added 65 mL of dry dimethylformamide, imidazole (14.77 g, 68.1 g/mol, 217 mmol), and t-butyldimethylsilylchloride (16.36 g, 151 g/mol, 109 mmol), and the reaction was allowed to stand at room temperature for 12 hours. The reaction mixture was then partitioned between 220 mL of water and 220 mL of ethyl acetate and the combined organic layers were washed with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and absolute ethanol was added with cooling to -20° C. to give the titled compound (32 g, 91% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:6][CH2:5]2.[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[N:24][CH:25]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH:7]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:6][CH2:5]3)[CH:23]=[N:24][CH:25]=1
Reactant: CC(C)S(=O)(=O)NC1CCc2cc(O)ccc21
Reactant: COc1cncc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cncc(Oc2ccc3c(c2)CCC3NS(=O)(=O)C(C)C)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of N-(5-hydroxy-2,3-dihydro-1H-inden-1-yl)propane-2-sulfonamide (50.0 mg, 0.196 mmol), 5-methoxypyridin-3-ylboronic acid (90 mg, 0.587 mmol), Copper(II)acetate (35.6 mg, 0.196 mmol), triethylamine (0.136 mL, 0.979 mmol), and crushed 4 Å molecular sieves (150 mg) in Dichloromethane (2 mL) was stirred at rt for 3 days. After this time the reaction mixture was filtered and solvent evaporated in vacuo. Purification by flash chromatography (heptane:EtOAc 3:1) afforded the title compound as a white solid. (6.7 mg, 9.4%). MS (ESI): m/z [M−H]− 361.0
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7](Cl)[C:8]2[N:9]([C:11](=[O:14])[NH:12][N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([CH2:18][NH2:19])[OH:17]>C1COCC1>[C:1]([C:5]1[N:6]=[C:7]([NH:19][CH2:18][CH2:16][OH:17])[C:8]2[N:9]([C:11](=[O:14])[NH:12][N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cn2c(=O)[nH]nc2c(Cl)n1
Reactant: NCCO
Solvent: C1CCOC1
Product: CC(C)(C)c1cn2c(=O)[nH]nc2c(NCCO)n1
Temperature: 25 °C

Procedure:
A solution of 0.50 g of the product of Step F and 0.40 g of ethanolamine in THF (6 mL) was heated at reflux for 16 h. After cooling the reaction mixture to ambient temperature, solvents were removed and the residue was purified by silica gel chromatography to yield the title compound as a white solid. MS (M+H+)=252.3.
Reaction SMILES: [CH3:1][CH:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40](Cl)(=[O:42])=[O:41])#[N:33]>>[N:18]1[C:17]2[NH:21][CH:22]=[CH:23][C:16]=2[C:15]([C:13]2[CH:12]=[N:11][N:10]([CH:2]([CH3:1])[CH2:3][N:4]3[CH2:5][CH2:6][N:7]([S:40]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[C:32]#[N:33])(=[O:42])=[O:41])[CH2:8][CH2:9]3)[CH:14]=2)=[N:20][CH:19]=1
Reactant: CC(CN1CCNCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Product: CC(CN1CCN(S(=O)(=O)c2ccccc2C#N)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1

Procedure:
This compound was prepared according to the procedure of Example 92, using 4-[1-(1-methyl-2-piperazin-1-ylethyl)-1H-pyrazol-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine and 2-cyanobenzenesulfonyl chloride as the starting materials. 1H NMR (300 MHz, DMSO-D6): δ 12.05 (s, 1H); 8.61 (s, 1H); 8.58 (s, 1H); 8.21 (s, 1H); 8.07 (m, 1H); 7.95-7.78 (m, 3H); 7.53 (m, 1H); 6.88 (d, 1H); 4.62 (m, 1H); 2.98 (m, 4H); 2.82 (m, 1H); 2.59 (m, 3H); 2.36 (m, 2H); 1.40 (d, 3H); LCMS calculated for C23H25N8O2S(M+H)+: m/z=477.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]([CH3:21])([CH3:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:9][CH:8]=1.Br[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:31][C:30]=1[CH3:41])=[O:27].C(=O)(O)[O-].[Na+].O>CN(C)C=O>[CH:35]1([C:32]2[CH:33]=[CH:34][C:29]([NH:28][C:26](=[O:27])[CH2:25][N:5]([CH2:6][C:7]3[CH:23]=[CH:22][C:10]([O:11][C:12]([CH3:21])([CH3:20])[C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])=[CH:9][CH:8]=3)[CH2:4][CH2:3][O:2][CH3:1])=[C:30]([CH3:41])[CH:31]=2)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: Cc1cc(C2CCCCC2)ccc1NC(=O)CBr
Reactant: COCCNCc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCN(CC(=O)Nc1ccc(C2CCCCC2)cc1C)Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
0.303 g (0.94 mmol) of tert-butyl 2-(4-{[(2-methoxyethyl)amino]methyl}phenoxy)-2-methylpropanoate (Example III-33) is initially charged in 5 ml of dimethylformamide. At room temperature, 0.319 g (1.03 mmol) of 2-bromo-N-(4-cyclohexyl-2-methylphenyl)acetamide (Example III-19) and 0.086 g (1.03 mmol) of sodium bicarbonate are added. The mixture is stirred at 90° C. for 2 hours. The reaction mixture is then allowed to cool, and water is added. The mixture is extracted with ethyl acetate and the organic phase is washed with water and saturated sodium chloride solution. The organic phase is dried over sodium sulphate and freed from the solvent under reduced pressure. The residue is purified chromatographically on silica gel (cyclohexane/ethyl acetate 3:1) and the product is dried under reduced pressure. This gives 0.464 g (90% of theory) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:22]([O:29][C:30](=[O:33])[CH2:31]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30](=[O:33])[CH2:31][N:14]([S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])[C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]2)=[CH:13][CH:12]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: O=C(CBr)OCc1ccccc1
Product: CCCCS(=O)(=O)N(CC(=O)OCc1ccccc1)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from butane-1-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 228) and benzyl-2-bromoacetate according to the procedure of Example 251 as an orange oil; 1H NMR (300 MHz, CDCl3) δ 0.91 (t, J=7.29 Hz, 3H), 1.34–1.47 (m, 2H), 1.75–1.86 (m, 2H), 2.55 (t, J=6.09 Hz, 4H), 3.17–3.23 (m, 2H), 3.62 (t, J=6.00 Hz, 4H), 4.45 (s, 2H), 5.18 (s, 2H), 6.87–6.92 (m, 2H), 7.30–7.40 (m, 7H); MS (ES) m/z: 459.0 (MH+); HRMS found for C24H30N2O5S: 459.1944.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][NH2:9])[S:5][CH:6]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][NH:9][C:10](=[O:12])[CH3:11])[S:5][CH:6]=1
Reactant: Cc1csc(CCN)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCc1cc(C)cs1
Yield: 95 %

Procedure:
In close analogy to the procedure described above, 2-(4-Methyl-thiophen-2-yl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: C([O:4][CH2:5][CH:6]1[CH2:11][CH:10]([N:12]([C:17]([C:19]2[C:20]([NH:29][CH2:30][C:31]3[O:32][CH:33]=[CH:34][CH:35]=3)=[N:21][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[N:23][CH:24]=2)=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:9][N:8]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:7]1)(=O)C.O.[OH-].[Na+]>CO>[C:25]([C:22]1[N:21]=[C:20]([NH:29][CH2:30][C:31]2[O:32][CH:33]=[CH:34][CH:35]=2)[C:19]([C:17]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:10]2[CH2:11][CH:6]([CH2:5][OH:4])[CH2:7][N:8]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:9]2)=[O:18])=[CH:24][N:23]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(=O)OCC1CC(N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2NCc2ccco2)CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)C1CC(CO)CN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 7 h
Yield: 97.9 %

Procedure:
To a solution of tert-butyl 3-[(acetyloxy)methyl]-5-[({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]piperidine-1-carboxylate (780 mg) in methanol (10 ml)-water (9 ml) was added 8 M aqueous sodium hydroxide solution (0.83 ml), and the mixture was stirred at 70° C. for 7 hr and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (5:95-100:0) was concentrated under reduced pressure to give the object compound (709 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[CH:8](Cl)Cl.C[O-:21].[Na+]>>[CH3:1][C:2]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[CH:8]=[O:21]
Reactant: C[O-]
Reactant: Cc1ccc(C)c(OCc2ccccc2C(Cl)Cl)c1
Agent: [Na+]
Product: Cc1ccc(C)c(OCc2ccccc2C=O)c1

Procedure:
As a process for producing 2-(aryloxymethyl)benzaldehyde, for example, the following method is described in JP 2009-215286 A (Example 5). In the method, 2-(2,5-dimethylphenoxymethyl)benzaldehyde is obtained by reacting 2-(2,5-dimethylphenoxymethyl)benzal chloride and sodium methoxide, and then a resulting acetal compound is extracted with xylene. Then, an organic layer obtained after liquid separation is mixed with an aqueous sulfuric acid solution to hydrolyze the acetal compound to obtain 2-(2,5-dimethylphenoxymethyl)benzaldehyde.
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[NH3:14]>O>[NH2:14][C@@H:3]([CH2:2][C:10]([OH:12])=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: N
Solvent: O
Product: N[C@@H](CC(=O)O)c1ccccc1

Procedure:
The reaction solution (250 g) containing 36 weight % (wt %) of L-phenylalanine, a bacterial cell (in an appropriate amount) of MT-11046 produced in Example 1 and water was reacted at each temperature shown in Table 6 for 24 hours or more. During the reaction, pH of the reaction solution was adjusted to 8.0 with 25% ammonia water. A solid of (S)-β-phenylalanine precipitated under all examined conditions was observed. The reaction yields of (S)-β-phenylalaninein respective temperatures are shown in Table 6.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:4].Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23].C(N(CC)CC)C>C(#N)C>[CH3:12][O:11][C:9]([C:8]1[CH:7]=[C:6]([CH:15]=[CH:14][CH:13]=1)[NH:5][C:3](=[O:4])[CH2:2][N:27]1[CH2:28][CH2:29][N:24]([C:22](=[O:23])[C:21]2[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:19]([O:18][CH3:17])[CH:20]=2)[CH2:25][CH2:26]1)=[O:10]
Reactant: COC(=O)c1cccc(NC(=O)CCl)c1
Reactant: COc1ccc(C(=O)N2CCNCC2)cc1OC
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(NC(=O)CN2CCN(C(=O)c3ccc(OC)c(OC)c3)CC2)c1

Procedure:
5 Grams of methyl m-(α-chloroacetylamino)benzoate, 7.56 g of N-(3,4-dimethoxybenzoyl)piperazine monohydrochloride, 7.76 g of triethylamine and 30 ml of acetonitrile were mixed together and reacted at 45° to 50° C. for 5 hours. After completion of the reaction, the reaction mixture was ice-cooled, and the crystals formed were removed by filtration. The mother liquor was concentrated to dryness, and extracted by adding 1 N-sodium hydroxide aqueous solution and chloroform. The chloroform layer was washed with water, dried and removed by distillation. The oily substance obtained was purified by a silica gel column chromatography to obtain 10.08 g of m-methoxycarbonyl-α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide in the form of colorless oily substance.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[C:10]([OH:18])[CH:9]=1.O>C1COCC1>[OH:13][CH2:12][C:11]1[CH:16]=[CH:17][C:8]([Cl:7])=[CH:9][C:10]=1[OH:18]
Reactant: COC(=O)c1ccc(Cl)cc1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a solution of lithium aluminum hydride (1.1 g) in THF (50 ml), methyl 4-chloro-2-hydroxybenzoate (5.38 g; prepared in Reference Example 46.) in THF (50 ml) was added dropwise in a stream of argon at 0° C. After the solution was warmed to at room temperature, the solution was stirred for 30 minutes. To the reaction mixture, water was added. The mixture was extracted with mixture solution of ether-AcOEt, washed, dried over and concentrated under the reduced pressure. The residue was recrystallized from mixture solution of hexane-AcOEt to give the title compound (3.92 g) having the following physical data.