Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:10][N:11]([CH:13]=O)[CH3:12]>CC(N(C)C)=O>[CH3:10][N:11]([CH3:13])/[CH:12]=[CH:2]/[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccccc1
Reactant: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: CN(C)/C=C/C(=O)c1ccccc1
Yield: 29.1 %

Procedure:
A mixture of acetophenone (8.0 g, 66.58 mmol, 1.0 eq) and DMF (5.8 g, 79.90 mmol, 1.2 eq.) in 10.0 mL of DMA in a 25-mL microwave vial was irradiated at 115° C. for 0.5-1 h. The crude reaction mixture was triturated with n-hexane, and the resultant solid was filtered to afford the title compound as a pale yellow solid (3.4 g. 29.3% yield). [M+H] Calc'd for C11H13NO, 176. Found, 176.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13]Br)=[N:5]1)(=[O:3])[CH3:2].Cl.[CH2:16]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][N:27]2[CH2:28][CH2:29][CH:24]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25][CH2:26]2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1nc(CBr)c2ccccc21
Reactant: c1ccc(CCC2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)n1nc(CN2CCC(CCc3ccccc3)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 13.7 %

Procedure:
1-Acetyl-3-bromomethyl-1H-indazole (0.50 g, 1.98 mmol) in CH2Cl2 (25 mL) was treated with 4-phenethylpiperidine hydrochloride (0.893 g, 3.96 mmol) and Hunig's base (0.78 g, 5.94 mmol) and the mixture stirred at 20° C. for 16 h. The mixture was poured into saturated aqueous sodium bicarbonate solution (25 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried (MgSO4), concentrated and the residue purified by flash chromatography (0%→10% EtOAc in hexane) to give 1-acetyl-3-(4-phenethylpiperidin-1-ylmethyl)-1H-indazole as a colourless oil (98 mg, 14%). This was dissolved in CH2Cl2 /methanol (1:1, 10 mL), treated with NaOMe (2 mg) and stirred for 15 min at 20° C. The mixture was poured into saturated aqueous sodium bicarbonate solution (25 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried (MgSO4), concentrated and the residue recrystallised from EtOAc/hexane to give the title compound (55 mg, 69%) as colourless crystals; mp 153°-155° C. (from EtOAc/hexane); 1H NMR (360 MHz, d6 -DMSO) δ 12.75 (bs, 1H, NH), 7.84 (d, J=8.1 Hz, 1H, indazole), 7.46 (d, J=8.4 Hz, 1H, indazole), 7.31 (t, J=6.7 Hz, 1H, indazole), 7.27-7.12 (m, 5H, Ph), 7.07 (t, J=7.1 Hz, 1H, indazole), 3.78 (s, 2 H, Ar--CH2N), 2.85 (m, 2 H, aliphatic), 2.56 (m, 2 H, aliphatic), 1.94 (m, 2H, aliphatic), 1.65 (m, 2H, aliphatic), 1.47 (m, 2H, aliphatic), 1.16 (m, 3H, aliphatic); MS (CI+) m/e 320 (M+H+); Anal. calcd for C21H25N3 : C, 78.96; H, 7.89; N, 13.15. Found: C, 78.94; H, 7.96; N, 12.89.
Reaction SMILES: N1C=CN=CC=1C1C=CN=[C:9]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18](C(O)=O)=[CH:17][CH:16]=2)N=1.[NH:24]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)[C:25]([NH2:27])=[NH:26].CN(/C=C/C(C1C=NC=CN=1)=O)C.CN(C)/C=C/C(C1C=NC=CC=1)=O>>[N:13]1[CH:9]=[CH:17][CH:16]=[C:15]([C:23]2[CH:22]=[CH:18][N:27]=[C:25]([NH:24][C:28]3[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=3)[N:26]=2)[CH:14]=1
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: O=C(O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Agent: CN(C)/C=C/C(=O)c1cccnc1
Agent: CN(C)/C=C/C(=O)c1cnccn1
Product: O=C(O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1

Procedure:
Title compound was prepared according to the procedure described for the synthesis of compound 25a (scheme 6, step 3) replacing the guanindine 24 by 4-guanidinobenzoic acid (344) (Zlatoidsky P., Maliar T. Eur. J. Med. Chem Chim. Ther.; 1996, 31, 895-900) and (E)-3-(dimethylamino)-1-(pyrazin-2-yl)-prop-2-en-1-one (23a) by (E)-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one (345) (Zimmermann J., Buchdunger E., et al. Bioorg. Med. Chem. Lett., 1996, 6, 1221-1226). Yield of the product 28%. MS (m/z): 292.29 (calc) 293.1 (MH+) (found).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I:12]N1C(=O)CCC1=O.S(=O)(O)[O-].[Na+]>FC(F)(F)S(O)(=O)=O>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(O)c1cccc(F)c1F
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S([O-])O
Agent: [Na+]
Product: O=C(O)c1cc(I)cc(F)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.6 %

Procedure:
To a cold (0° C.), stirred solution of 4.74 g of 2,3-difluorobenzoic acid in 15.0 mL of trifluoromethanesulfonic acid is added in portions 8.1 g of powdered N-iodosuccinimide. Following the addition, the mixture is allowed to warm to room temperature, stirred for 5 h, then poured onto 200 mL of cracked ice containing 5 g of sodium bisulfite. The mixture is stirred well for 15 m, then filtered, and the solid washed well with water and dried under vacuum to provide 6.78 g of the title compound as a solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:7][CH2:8][C:9]([NH:11][CH2:12][C@@H:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14]2)=[O:10])=[CH:5][CH:6]=1.[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+]>COCCOC.O>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][N:15]1[CH2:16][CH2:17][O:18][C@@H:13]([CH2:12][NH:11][C:9](=[O:10])[CH2:8][S:7][C:4]2[S:3][C:2]([C:31]3[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=3)=[CH:6][CH:5]=2)[CH2:14]1
Reactant: O=C(CSc1ccc(Br)s1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(CSc1ccc(-c2ccncc2)s1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 100 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
The resultant product (500 mg) of Example 31 and 4-pyridylboronic acid (250 mg) were dissolved in a mixed solvent of ethylene glycol dimethyl ether (25 mL) and water (5 mL), sodium hydrogen carbonate (500 mg) and tetrakistriphenylphosphine palladium (60 mg) were added, and the mixture was stirred overnight at 100° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent, and the obtained residue was recrystallized from ethyl acetate to give the title compound (90 mg) as a pale-brown powder.
Reaction SMILES: [Cl:1][CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH:3]([CH3:5])[CH3:4].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:36](O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([O:20][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: OCc1ccccc1
Reactant: CC(C)C(Cl)OC(=O)NCC1(CC(=O)O)CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)C(Cl)OC(=O)NCC1(CC(=O)OCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of (93) (1.02 g, 3.34 mmol) in dichloromethane was added 1,3-dicyclohexylcarbodiimide (758 mg, 3.67 mmol). After stirring at room temperature for 30 min, benzyl alcohol (380 μL, 3.67 mmol) and 4-(dimethylamino)pyridine (catalytic amount) were added. The resulting mixture was stirred at room temperature of 16 h. After filtration, the filtrate was washed with 10% citric acid, dried over Na2SO4, and concentrated. Chromatography of the residue on silica gel, eluting with 10% ethyl acetate/hexane, gave 820 mg (62%) of the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.03 (d, J=6.4 Hz, 3H), 1.05 (d, J=6.4 Hz, 3H), 1.36-1.53 (m, 10H), 2.13 (m, 1H), 2.35 (s, 2H), 3.22 (m, 2H), 5.11 (s, 2H), 5.49 (t, 1H), 6.32 (d, J=4.8 Hz), 1H), 7.34 (m, 5H). MS (ESI) m/z 396.24 (M+H+).
Reaction SMILES: C(C1C=C(C=CC=1O)N)(C)C.[OH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])[NH:18][C:17](=[O:25])[C:16]2=[O:26].[CH:27]1[C:32]([NH:33][NH2:34])=[CH:31][CH:30]=[C:29]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:28]=1.Cl>>[OH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])[NH:18][C:17](=[O:25])[C:16]2=[O:26].[OH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])[NH:18][C:17](=[O:25])[C:16]2=[N:34][NH:33][C:32]1[CH:31]=[CH:30][C:29]([S:35]([NH2:38])(=[O:36])=[O:37])=[CH:28][CH:27]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: CC(C)c1cc(N)ccc1O
Agent: CC(C)c1cc2c(cc1O)C(=O)C(=O)N2
Agent: Cl
Product: CC(C)c1cc2c(cc1O)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
5-Hydroxy-6-isopropyl-1H-indole-2,3-dione was prepared from 3-isopropyl-4-hydroxyaniline according to Procedure A: 1H NMR (DMSO-d6): δ1.12 (d, J=6.8 Hz, 6H), 3.21 (septet, J=6.9 Hz, 1H), 6.62 (s, 1H), 6.82 (s,1H), 9.51 (1H), 10.61 (s, 1H); ESI−MS m/z 204 (M−H)−. The title compound was prepared from 5-hydroxy-6-isopropyl-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ1.12 (d, J=7.0 Hz, 6H), 3.21 (septet, J=6.8 Hz, 1H), 6.62 (s, 1H), 6.97 (s, 1H), 7.21 (s, 2H), 7.45 (d, J=8.9 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 9.11 (s, 1H), 10.70 (s, 1H), 12.74 (s, 1H); ESI−MS m/z 373 (M−H)−. Anal. Calcd for C17H18N4O4S: C, 54.53; H, 4.85; N, 14.96; S, 8.56. Found: C, 54.37; H, 4.95; N, 14.84; S, 8.48.
Reaction SMILES: [C:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)OC1C=CC=CC=1.[NH2:17][C@H:18]([C:23]([O-:25])=[O:24])[CH2:19][CH2:20][S:21][CH3:22].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC.Cl>C(#N)C>[O:9]([C:1]([NH:17][C@H:18]([C:23]([OH:25])=[O:24])[CH2:19][CH2:20][S:21][CH3:22])=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: CSCC[C@H](N)C(=O)[O-]
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC#N
Product: CSCC[C@H](NC(=O)Oc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 428 mg (2 mmol) of diphenyl carbonate and 5 mL of acetonitrile were loaded into a round bottom flask having a volume of 100 mL, and then the mixture was stirred at room temperature. A solution prepared by dissolving 935 mg (2 mmol) of butyltriphenylphosphonium methionine salt in 15 mL of acetonitrile was dropped to the solution, and then the mixture was stirred for 50 minutes. After that, a 1M aqueous HCl solution was added to the reaction solution to terminate the reaction, and then the resultant was concentrated with an evaporator. Next, water was added to the concentrated product, and then the resultant was extracted with ethyl acetate. The resultant organic layer was washed with water and brine, and was then dried with sodium sulfate. After that, the dried product was concentrated with an evaporator. Thus, a crude product was obtained. Next, the crude product was purified by column chromatography. Thus, N-phenoxycarbonyl-L-methionine was obtained. An isolation amount and an isolation yield were 441.5 mg and 82%, respectively.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>S(=O)(=O)(O)O.O>[C:12]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(O)cc1F
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)O)c(F)c1
Temperature: 80 °C

Procedure:
4.3 Grams of 4-hydroxy-2-fluorobenzoic acid and 8.4 g of acetic anhydride were placed in a two-necked flask and mixed. While the mixture was cooled with water, 5 drops of sulfuric acid were added. After heat generation ended, the mixture was heated at 80° C. for 30 minutes. Thereafter, the reaction mixture was poured into cold water, and a precipitated crystal was recovered by filtration.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([NH:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)(=[O:19])=[O:18])=[CH:15][C:10]=3[N:9]=[C:8]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:35][O:36][C:37](=[O:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]Br.O>CN(C)C=O>[CH3:35][O:36][C:37](=[O:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:16]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C:14]1[CH:13]=[CH:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:9][C:10]=2[CH:15]=1
Reactant: O=S(=O)(Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)c1ccc(F)cc1
Reactant: COC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)S(=O)(=O)c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
150 mg of N-(1,2-diphenyl-1H-benzimidazol-5-yl)-4-fluorobenzenesulfonamide was suspended in 0.5 ml of N,N-dimethylformamide, mixed with 12 mg of sodium hydride and stirred for 30 minutes at 20° C. 98 mg of 6-bromohexanoic acid methyl ester was added, allowed to stir for 15 hours, mixed with water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=O>N1C=CC=CC=1>[CH2:19]([O:18][C:16]1[O:13][C:12](=[O:14])[C:3]2[CH:4]=[C:5]3[C:10]([CH2:9][CH2:8][CH2:7][CH2:6]3)=[CH:11][C:2]=2[N:1]=1)[CH3:20]
Reactant: Nc1cc2c(cc1C(=O)O)CCCC2
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOc1nc2cc3c(cc2c(=O)o1)CCCC3
Reaction time: 20 h

Procedure:
To a solution of 3-amino-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (1-2) (5.0 g, 26 mmol, 1 equiv) in pyridine (50 mL) at −10° C. under nitrogen was added ethyl chloroformate (10 mL, 11 g, 100 mmol, 4.0 equiv) dropwise over 1 h. The resulting solution was stirred from −10° C. to 23° C. over 20 h. The solvent was evaporated under reduced pressure and the solid residue was suspended in water (100 mL) with stirring for 1 h. The precipitate was filtered, washed with water and dried to yield 2-ethoxy-6,7,8,9-tetrahydro-4H-naphtho[2,3-d][1,3]oxazin-4-one (1-3) as a yellow solid. LRMS m/z (M+H) 246.4 found, 246.1 required.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=2[C:4]2[CH2:12][C:13]3[C:18]([C:3]1=2)=[CH:17][CH:16]=[CH:15][CH:14]=3.C([Li:23])CCC>C1(C)C=CC=CC=1.CCCCC>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=2[C:4]2[CH2:12][C:13]3[C:18]([C:3]1=2)=[CH:17][CH:16]=[CH:15][C:14]=3[Li:23]
Reactant: Cc1ccc2c(c1)c1c(n2C)-c2ccccc2C1
Reactant: [Li]CCCC
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: [Li]c1cccc2c1Cc1c-2n(C)c2ccc(C)cc12
Temperature: 25 °C

Procedure:
Under the nitrogen protection, 1.52 grams (0.0077 mole) of 5,8-dimethyl-5,10-dihydroindeno[1,2-b]indole is dissolved in 15 mL of toluene. To the solution is added 3.9 mL of n-butyllithium solution in pentane (2.0 mole/L). The mixture is refluxed for three hours and then cooled to 25° C. The precipitate is isolated by filtration, washed with hexane, and dried under vacuum, yielding 1.26 grams of 5,8-dimethyl-5,10-dihydroindeno [1,2-b]indolyllithium.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:20][CH2:21][C:22](Br)=[O:23]>ClCCl>[Br:20][CH2:21][C:22]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:23]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(NC(C)C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
To a solution of isopropyl-(4-methoxy-phenyl)-amine (25.11 g) in dichloromethane (250 mL) was added triethylamine (15.38 g) with stirring at ambient temperature. The solution was cooled in an ice bath (<3° C.) and bromoacetyl bromide (30.68 g) dissolved in dichloromethane (100 mL) was added dropwise over a 45 minute period with stirring and cooling in an ice bath. The reaction mix was stirred overnight at ambient temperature, washed with 0.3N HCl (300 mL) and brine (300 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give a dark brown oil. The oil was filtered through a pad of silica gel (150 g) which was eluted with ethyl acetate/hexane (1:1, 900 mL) and the filtrate evaporated under reduced pressure to afford the title compound (41.05 g) as a brown oil which crystallized on standing. 1H NMR (300 MHz, CDCl3): d 1.04(d, J=6.8 Hz, 6H), 3.53(s, 2H), 3.84(s, 3H), 4.93(m, 1H), 6.93(d, J=9.1 Hz, 2H), 7.10(d, J=9.1 Hz, 3H) TLC (EtOAc/Hexane(3:17)): Rf =0.18.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[NH:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1>C(#N)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]2[NH:13][C:1](=[O:2])[N:21]([CH:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:27]3)[C:15]=2[CH:16]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)N1CCC(Nc2cc(F)ccc2N)CC1
Solvent: CC#N
Product: CCOC(=O)N1CCC(n2c(=O)[nH]c3ccc(F)cc32)CC1
Temperature: 40 °C
Yield: 63.8 %

Procedure:
A solution of 1,1′-carbonyldiimidazole (12.6 g, 78 mmol) in acetonitrile (150 mL) was added portionwise over 10 minutes to a stirred solution of D2 (13.7 g, 49 mmol) in acetonitrile (250 mL) at 40° C. The reaction mixture was heated at 40° C. for 15 hours and then allowed to cool. The precipitate was collected by filtration and washed with acetonitrile (2×50 mL) to give the title compound (9.6 g, 69% yield) as a purple solid that was used without further purification. (Rf: 0.5 (ethyl acetate/hexane 7:8))
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1[N:18]=CC(COP(O)(O)=O)=C(C=O)C=1O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[C:1]1([CH2:7][CH2:8][CH:9]([NH2:18])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(N)CCc1ccccc1

Procedure:
In the same manner as in Example 12, a cell-dispersion solution was prepared. Into a flask in which substrates, that is, 504.6 mg of 1-phenyl-3-butanone and 618.8 mg of (S)-α-phenethylamine were added in advance, 3 ml of the cell-dispersion solution, 3.7 mg of pyridoxal phosphate, and 3 mL of a 1M potassium phosphate buffer (pH 6.8) were introduced. The whole volume was adjusted to 30 mL by adding deionized water therein. This was reacted at 30° C. for 16 hours with stirring. After the reaction is completed, 1-phenyl-3-butylamine thus produced in the reaction mixture was analyzed in the manner described below. This showed that 1-phenyl-3-butylamine was produced with a conversion rate of 68%, and it had a (S) configuration and optical purity of 95.8% e.e.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:16]=[C:15]2[C:6]([S:7][C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([C:17](O)=[O:18])[C:13]=3[NH:14]2)=[CH:5][CH:4]=1.C(Cl)(Cl)[Cl:23].P(Cl)(Cl)Cl>CN(C)C=O>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:16]=[C:15]2[C:6]([S:7][C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([C:17]([Cl:23])=[O:18])[C:13]=3[NH:14]2)=[CH:5][CH:4]=1
Reactant: ClC(Cl)Cl
Reactant: O=C(O)c1cccc2c1Nc1cc(C(F)(F)F)ccc1S2
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc2c1Nc1cc(C(F)(F)F)ccc1S2
Reaction time: 4 h

Procedure:
8-Trifluoromethylphenothiazine-1-carboxylic acid (62.2 g., 0.20 mol.) was added to a stirred mixture of 300 ml. of chloroform and 300 ml. of phosphorus trichloride. The resulting brown suspension was cooled in an ice-bath while 50 ml. of dimethylformamide was added slowly until a reddish brown solution formed. After stirring the mixture for 4 hours at 25°, the chloroform and excess phosphorus trichloride were evaporated under reduced pressure. The resulting reddish brown solid residue was dissolved in 1500 ml. of boiling n-hexane. The hot, clear, reddish solution was decanted from a viscous, insoluble material and, on cooling, large red needles formed. The solid was collected by filtration and washed with hexane to give 8-trifluoromethylphenothiazine-1-carboxylic acid chloride, m.p. 124°-126°.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1)(=O)=O>C(N(CC)CC)C.ClCCl>[C:1]([O:9][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CS(=O)(=O)On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(On1nnc2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
Benzoic acid (2.44 g) is dissolved in a solution of triethylamine (2.80 ml) in dichloromethane (20 ml) under ice-cooling. To the solution is added 1-methanesulfonyloxy-1,2,3-benzotriazole (4.26 g) and the mixture is stirred at room temperature for 3 hours. The reaction mixture is washed with water, a saturated aqueous sodium hydrogen carbonate and water in order and dried to give crystals of 1-benzoyloxy-1,2,3-benzotriazole (5.0 g). The product is dissolved in dichloromethane (20 ml) and thereto are added triethylamine (2.80 ml) and methanol (4.8 ml) and the mixture is stirred at room temperature for 1 hour. The reaction mixture is washed with water, an aqueous sodium hydrogen carbonate and water in order, dried and then the solvent is distilled off to give methyl benzoate (2.39 g). Infrared spectrum: 1728 cm-1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].[F:11][C:12]([F:24])([F:23])[O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:10][C:9]1[C:2]([C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]([F:11])([F:23])[F:24])=[CH:19][CH:18]=2)=[CH:3][C:4]([C:5]#[N:6])=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(F)c(Br)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: N#Cc1ccc(F)c(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 80 °C
Reaction time: 0.13 h
Yield: 100.4 %

Procedure:
A 100 mL 3-necked flask equipped with a stir bar, a condenser, and a nitrogen inlet was flushed with nitrogen and then charged with 3-bromo-4-fluorobenzonitrile (2.507 g, 1.23×10−2 mol), 4-trifluoromethoxyphenyl boronic acid (2.825 g, 1.23×10−2mol, 1.01 equiv), bis(triphenylphosphine)-palladium(II) chloride (2.0 mg, 2.85×10−6 mol, 0.02 mol %), and sodium bicarbonate (1.577 g, 1.82×10−2 mol, 1.5 equiv). The flask was then evacuated and purged with nitrogen three times, and charged with deoxygenated toluene (6 mL) and deoxygenated water (6 mL). The mixture was heated to 80° C. until HPLC analysis indicated the disappearance of the aryl bromide (less than 16 hours; HPLC conditions: Eclipse XDB-C8 (4.6 mm×150 mm), flow rate: 1.5 mL/min.; mobile phase: 80:20 water(0.1%H3PO4)/CH3CN to 20:80 in 8 minutes, hold to 15 minutes with the column at 35° C. and UV detection: 210 nm. Retention time for the product is 8.88 min, retention time for aryl bromide is 6.47 min, retention time for excess boronic acid is 5.64 min, and retention time for homocoupled product is 10.58 minutes). The reaction was cooled to room temperature and the phases were separated. The organic phase was filtered through a plug of silica (2.5 g) and the silica plug was washed with toluene (25 mL). The filtrate was concentrated to provide the desired product (3.472 g, 92% potency, 93% potency adjusted yield). HRMS (FAB) calcd. for C14H7F4NO (M+H)+: 282.0542, found 282.0536; 1H NMR (CDCl3) δ 7.76 (dd, 1H), 7.68 (ddd, 1H), 7.56 (m, 2H), 7.34 (m, 2H), 7.30 (dd, 1H); 13C (CDCl3) δ 161.9, 149.5, 134.9, 133.5, 131.9, 130.4, 129.5, 121.2 (2), 120.4, 117.8, 117.7, 109.1; IR (KBr) 2230, 1514, 1490, 1265, 1256, 1223, 1210, 1157; Analytical: Pd 6 ppm, B <30ppm, Na <1ppm; mp 63.5-64.2° C.