Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:13]=[CH:12][O:11][CH:10]=1)[CH2:5][CH2:6]O)[CH:2]=[CH2:3].C(N(CC)CC)C.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([Cl:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([N:4]([CH2:5][CH2:6][Cl:30])[CH2:8][C:9]1[CH:13]=[CH:12][O:11][CH:10]=1)[CH:2]=[CH2:3].[C:21]1([CH3:31])[CH:22]=[CH:23][C:24]([S:27]([Cl:30])(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: C=CCN(CCO)Cc1ccoc1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=CCN(CCCl)Cc1ccoc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 9.255 g (51.07 mmol) of the above 2-[allyl-(3-furylmethyl)amino]ethanol, 10.7 ml (76.6 mmol) of triethylamine and 0.1 g of 4-dimethylaminopyridine in 150 ml of dichloromethane, 11.7 g (61.3 mmol) of p-toluenesulfonyl chloride was added at room temperature, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1 to 9/1) to yield N-allyl-N-(3-furylmethyl)-2-chloroethylamine as a mixture with p-toluenesulfonyl chloride.
Reaction SMILES: [CH3:1][C@@H:2]([OH:5])[C:3]#[CH:4].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:6][C:7]1[C:8]([C:4]#[C:3][C@H:2]([OH:5])[CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]
Reactant: C#C[C@@H](C)O
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H](C)O)c21

Procedure:
Using Method C above, (R)-But-3-yn-2-ol (189 mg, 2.71 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (100 mg, 0.27 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (30 mg, 0.03 mmol) and CuI (2 mg) in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 4 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (R)-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-butynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-10% MeOH in CH2Cl2 gradient and trituration with Et2O. (Yield 40 mg, 47%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8](/[N:10]=C/N(C)C)[N:7]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].NN.C(O)(=O)C>O1CCOCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)/C=N/c1cc(C(C)(C)C)nn1CC1CCCCO1
Agent: NN
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(N)n(CC2CCCCO2)n1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To a solution of Example 63B (0.9 g, 3.1 mmol) in dioxane (10 mL) were added hydrazine (0.12 mL, 3.7 mmol, Aldrich) and acetic acid (0.35 mL, 6.2 mmol). After stirring at 85° C. for 16 hours, the reaction mixture was cooled and quenched with saturated NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the title compound. MS (APCI+) m/z 238 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[CH:21]1[CH:22]=[CH:23][C:24]2[N:29](O)N=N[C:25]=2[CH:26]=1.[Cl:31][C:32]1[CH:36]=[CH:35][NH:34][C:33]=1[C:37]([OH:39])=O.NC1C=C2C([CH:45]=[CH:46][N:47]2[CH2:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=CC=1>C(Cl)Cl>[Cl:31][C:32]1[CH:36]=[CH:35][NH:34][C:33]=1[C:37]([NH:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[N:47]([CH2:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH:46]=[CH:45]2)=[O:39]
Reactant: O=C(O)c1[nH]ccc1Cl
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(N)cc21
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Cn1ccc2cc(NC(=O)c3[nH]ccc3Cl)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
DIPEA (4.0 equiv.), EDCI (1.5 equiv.) and HOBt (1.0 equiv.) were added at 0° C. to a solution of 3-chloro-1H-pyrrole-2-carboxylic acid (5.24 mmol, 1.0 equiv.) in DCM (25 ml). The mixture was stirred for 15 min at 25° C. and then cooled to 0° C. again. A solution of tert-butyl 2-(6-amino-1H-indol-1-yl)acetate (intermediate A—for synthesis see above) (5.24 mmol, 1.0 equiv.) in DCM (10 ml) was added, and the reaction mixture was stirred for 16 h at 25° C. It was then diluted with DCM (200 ml), washed with sat. ammonium chloride solution (2×50 ml), sat. sodium hydrogen carbonate solution (2×50 ml) and sat. NaCl solution (2×50 ml), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (6% methanol in DCM). Yield: 56%
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH3:2].P([O-])([O-])([O-])=O.C([O-])(=O)C>>[CH2:1]([O:3][C@@H:4]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)[C:5]([OH:7])=[O:6])[CH3:2].[CH2:1]([O:3][C@H:4]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(Cc1ccc(O)cc1)C(=O)OC(C)C
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: CCO[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: CCO[C@H](Cc1ccc(O)cc1)C(=O)OC(C)C
Temperature: 25 °C

Procedure:
Isopropyl (2RS) (+/−) 2-ethoxy-3-(4-hydroxyphenyl)propanoate (0.5 ml of a solution containing 2 mg/ml in a phosphate, pH 7; 0.1 M, or acetate buffer, pH 5; 0.1 M) was added to the reaction vessel followed by an enzyme (0.5 ml enzyme solution). The reaction mixture was shaken at room temperature and analysed at different times (maximum 28 h). The reaction mixture was analysed without work up by the gradient HPLC method 1, chiral HPLC methods 3 and 5, and by the CCE method 1.
Reaction SMILES: [CH3:1][Si:2]([CH3:27])([CH3:26])[C:3]1[S:4][C:5]([C:8]23[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[CH2:13][C@@H:12]2[CH2:11][O:10][NH:9]3)=[CH:6][N:7]=1.[C:28]([N:36]=[C:37]=[S:38])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[C:28]([NH:36][C:37]([N:9]1[C:8]2([C:5]3[S:4][C:3]([Si:2]([CH3:27])([CH3:26])[CH3:1])=[N:7][CH:6]=3)[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:13][CH:12]2[CH2:11][O:10]1)=[S:38])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[Si](C)(C)c1ncc(C23CN(C(=O)OCc4ccccc4)C[C@@H]2CON3)s1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ncc(C23CN(C(=O)OCc4ccccc4)CC2CON3C(=S)NC(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a mixture of benzyl(3aS)-6a-(2-trimethylsilylthiazol-5-yl)-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5-carboxylate (0.218 g, 0.54 mmol) in THF (3.60 mL) is added benzoyl isothiocyanate (0.088 g, 0.54 mmol). The mixture is stirred for 1 hour at room temperature and more benzoyl isothiocyanate (0.044 g, 0.27 mmol) is added. The reaction is stirred for 3 hours at room temperature, concentrated under reduced pressure, and purified by silica gel chromatography eluting with a gradient of 5% to 100% ethyl acetate in hexanes to give title compound (0.204 g, 67%). ES/MS (m/e): 404 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Mn]([O-])(=O)(=O)=[O:10].[K+].[OH2:15]>>[Br:1][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:15]
Reactant: O
Reactant: Cc1cccnc1Br
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: O=C(O)c1cccnc1Br
Reaction time: 5 h
Yield: 62 %

Procedure:
2-bromo-3-methylpyridine (25.0 mL, 213 mmol) was added to a solution of potassium permanganate (87.7 g, 555 mmol) in 800 mL of water and the mixture was stirred under reflux. After 5 hours, 600 mL of water was distilled off and the remaining suspension was filtered. The residue was washed with two 50 mL portions of hot water and the combined filtrates were acidified with concentrated HCl. The white precipitate was filtered and dried in a vacuum oven to give 26.8 g of 2-bromonicotinic acid (62% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]=1[NH2:30].[C:32](Cl)(=[O:35])[CH2:33][CH3:34].C(N(CC)CC)C>ClCCl.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:7]=[CH:6][C:5]=1[NH:30][C:32](=[O:35])[CH2:33][CH3:34]
Reactant: COC(=O)c1cc(C2=C(c3cc(Cl)ccc3OCc3ccccc3)CCC2)ccc1N
Reactant: CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1ccc(C2=C(c3cc(Cl)ccc3OCc3ccccc3)CCC2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A mixture of 5-[2-(2-benzyloxy-5-chlorophenyl)-cyclopent-1-enyl]-2-aminobenzoic acid methyl ester (55 mg, 0.12 mmol), propionyl chloride (13 mg, 0.14 mmol), and triethylamine (15 mg, 0.14 mmol) in dichloromethane (2 ml) was stirred at room temperature for 30 minutes. The reaction mixture was diluted with EtOAc (10 ml) and washed with 5% NaHCO3 (10 ml), 2M HCl (10 ml), water (10 ml) and brine (10 ml). The organic phase was dried and evaporated to give the product as a colourless glass 50 mg 85%. LC/MS: Rt=4.09[M+H] 490 (1 Cl).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH:7]=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](Br)[CH:23]=1>CS(C)=O>[Br:21][C:22]1[CH:23]=[C:24]([N:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:14])[CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:25]=[CH:26][CH:27]=1
Reactant: Brc1cccc(Br)c1
Reactant: CN(C)c1ccc2c(=O)[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C)c1ccc2c(=O)n(-c3cccc(Br)c3)ccc2c1
Temperature: 150 °C
Yield: 61.9 %

Procedure:
6-Dimethylamino-2H-isoquinolin-1-one (39 mg, 0.21 mmol), cuprous iodide (8.0 mg, 0.041 mmol), and potassium carbonate (29 mg, 0.21 mmol) were deposited in sealed vessel. 3 mL DMSO and 1,3-dibromobenzene (98 mg, 0.42 mmol) were added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150° C. for 5 hours. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (25% ethyl acetate/hexanes) to yield 2-(3-Bromo-phenyl)-6-dimethylamino-2H-isoquinolin-1-one (45 mg, 0.13 mmol). MS (ESI) 345.0 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[CH:26][C:27]=1[Cl:28].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][C:27]([Cl:28])=[C:22]([Cl:21])[CH:23]=3)[CH2:34][CH2:33]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(Cl)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)cc1-c1ccc(Cl)cc1

Procedure:
Example 1 by using 3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg, 0.275 mmol), 1-(3,4-dichlorophenyl)piperazine (64 mg, 0.275 mmol), DIPEA (0.072 mL, 0.413 mmol) and NaBH(OAc)3 (175 mg, 0.825 mmol).
Reaction SMILES: C[C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.[C:26]([CH2:29][CH2:30][CH2:31][CH2:32]CCCCCCC(Cl)=O)(=O)[NH2:27].[C:42](CCCCCCCCCCC(O)=O)(=O)[NH2:43].[CH2:58](Cl)Cl>N1C=CC=CC=1>[CH3:58][N:43]([C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=1)[CH3:42]
Reactant: NC(=O)CCCCCCCCCCC(=O)O
Reactant: ClCCl
Reactant: NC(=O)CCCCCCCCCCC(=O)Cl
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: c1ccncc1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 1, but using 365 mg of radicicol, 11-carbamoylundecanoyl chloride prepared from 900 mg of 11-carbamoylundecanoic acid, 8 ml of dry methylene chloride, 0.97 ml of pyridine and a catalytic amount of dimethylaminopyridine, 273 mg of the title compound were obtained.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH2:16]([N:4]1[CH:5]=[CH:6][C:7]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:3]1=[O:2])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)CCc1ccnc(O)c1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCc1ccn(Cc2ccccc2)c(=O)c1
Reaction time: 0.75 h
Yield: 81.7 %

Procedure:
To a cooled solution of sodium (3.25 g) in ethanol (75 ml) was added a solution of ethyl β-(2-hydroxy-4-pyridyl)propionate (25.38 g) in ethanol (150 ml). This mixture was stirred for 45 minutes and then benzyl chloride (16.58 g) in ethanol (125 ml) was added. The reaction mixture was stirred under reflux for 9 hours, allowed to cool and evaporated under reduced pressure. The residue was taken up in water (150 ml) and diethyl ether (150 ml), the aqueous layer was separated and washed with diethyl ether (2×120 ml). The combined ether extracts were washed with water, dried over MgSO4 and evaporated under reduced pressure to yield ethyl β-(N-benzyl-2-oxo-4-pyridyl)propionate (30.29 g) as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:11]2([CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:10][CH:9]1[NH:16][C:17]([O:19][CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=1)=[O:18].F[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)=[CH:34][N:33]=1.C(N(CC)C(C)C)(C)C>>[F:44][C:41]1[CH:40]=[CH:39][C:38]([C:35]2[CH:36]=[CH:37][C:32]([N:13]3[CH2:14][CH2:15][C:11]4([CH2:10][CH:9]([NH:16][C:17]([O:19][CH2:20][C:21]5[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=5)=[O:18])[CH2:8]4)[CH2:12]3)=[N:33][CH:34]=2)=[CH:43][CH:42]=1
Reactant: CCOC(=O)c1cc(COC(=O)NC2CC3(CCNC3)C2)on1
Reactant: Fc1ccc(-c2ccc(F)nc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(COC(=O)NC2CC3(CCN(c4ccc(-c5ccc(F)cc5)cn4)C3)C2)on1
Yield: 19.4 %

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.3.). Starting with 0.45 g (1.04 mmol) of ethyl 5-(6-azaspiro[3.4]oct-2-ylcarbamoyloxymethyl)isoxazole-3-carboxylate trifluoroacetate, described in step 6.6., 0.198 g (1.04 mmol) of 2-fluoro-5-(4-fluorophenyl)pyridine, prepared in step 6.7. and 0.40 g (3.12 mmol) of N,N-diisopropylethylamine, and after purification by chromatography on preparative plates, eluting with a 96/4 mixture of dichloromethane and methanol, 0.10 g of pure product is obtained in the form of a wax, which is used without further purification in the following step.
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4].Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>CN(C)C=O.C(OCC)(=O)C>[C:3]([N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])[CH3:4]
Reactant: CC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: BrC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCN(c2ccc(OC3CCCCC3)cc2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60% suspension in mineral oil) (1.18 g) in dimethylformamide (25 ml) was added 1-acetyl-4-(4-hydroxyphenyl)piperazine (5 g) and bromocyclohexane (5.59 ml) and stirred for 1 hour at 100° C. The reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-acetyl-4-(4-cyclohexyloxyphenyl)piperazine (0.92 g).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[ClH:20]>C(O)C>[ClH:20].[CH:12](=[C:7]1[C:8](=[O:11])[C:9](=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCN1CCC(=O)CC1
Agent: Cl
Solvent: CCO
Product: CCCCN1CC(=Cc2ccccc2)C(=O)C(=Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
A stirred solution of 31 g of 1-butyl-4-piperidone and 64 g of benzaldehyde in 300 ml of ethanol is cooled to 15° C, treated dropwise with 66 ml of concentrated hydrochloric acid, refluxed for 5 hours, and maintained for about 16 hours at room temperature. The bulk of ethanol is evaporated and the syrupy residue is cooled, diluted to 600 ml with water, treated with 300 ml of ether, stirred, and rubbed; a solid gradually separates. After cooling for several hours, the solid is filtered, washed with ether, and air-dried; yielding 36.7 g of material, melting point 203°-205° C. Following crystallization from 100 ml of dimethylformamide, the material weighs 24.2 g; melting point 212°-214° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[CH2:14]([O:16][C:17]([C:19]1[N:24]=[CH:23][C:22]2[CH:25]=[C:26](Br)[S:27][C:21]=2[C:20]=1[OH:29])=[O:18])[CH3:15]>>[CH2:14]([O:16][C:17]([C:19]1[N:24]=[CH:23][C:22]2[CH:25]=[C:26]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=3)[S:27][C:21]=2[C:20]=1[OH:29])=[O:18])[CH3:15]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1ncc2cc(Br)sc2c1O
Product: CCOC(=O)c1ncc2cc(-c3cccc(C(F)(F)F)c3)sc2c1O

Procedure:
The title compound was prepared from 3-(trifluoromethyl)phenyl boronic acid and 2-bromo-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid ethyl ester, example 21.d, under conditions analogous to experimental example 21.e; MS: (+) m/z 368.0 (M+1)
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[F:24][C:25]1([F:37])[O:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34](O)=[O:35])[C:27]=2[O:26]1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:34]([C:33]3[C:27]4[O:26][C:25]([F:37])([F:24])[O:29][C:28]=4[CH:30]=[CH:31][CH:32]=3)=[O:35])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccc2c1OC(F)(F)O2
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4c3OC(F)(F)O4)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2,2-difluoro-benzo[1,3]dioxole-4-carboxylic acid. LC-MS (basic): tR=0.94 min; [M+H]+=516.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:11]([O:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.[Cl-].[NH4+].[N-:21]=[N+:22]=[N-:23].[Na+]>O>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]([OH:12])[CH:11]([N:21]=[N+:22]=[N-:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC2OC2CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)C(N=[N+]=[N-])CC1
Temperature: 75 °C
Yield: 78.6 %

Procedure:
To a stirred solution of 16.4 g 2,3,6,7-tetrahydro-azepine-1-carboxylic acid tert-butyl ester in 420 ml dichloromethane was added at −60° C. 35.8 g m-chloroperbenzoic acid (70% purity). The mixture was allowed to slowly warm to room temperature overnight, 1 l ethylacetate was added and the solution was extracted with aqueous sodium bicarbonate, 1N aqueous sodium hydroxide and brine. Evaporation of the solvent and chromatography yielded 14.5 g (82%) 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester as colorless liquid; MS (EI): m/e=213 (M+,5%), 158 (22%), 140 (12%), 57 (100%). To a solution of 14.3 g 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester in 750 ethanol was added 150 ml water, 35.8 g ammonium chloride and 43.6 g sodium azide. The mixture was stirred at 75° C. over night, the solvents were greatly removed by distillation under vacuum and the residue was suspended in ethanol and filtered. The ethanol was distilled off and the residue was suspended in ethylacetate and filtered. Removal of the solvent and chromatography on silicagel with ethylacetate/hexane 1:1, yielded 13.5 g (79%) 4-azido-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester as a viscous oil; MS (ISP): m/e=257 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([Sn](C)(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:18]>[NH4+].[OH-]>[NH:8]1[C:9]2[C:10](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:11]=[CH:12][C:13]1=[O:18].[C:6]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CC=C([Sn](C)(C)C)CC1
Agent: [NH4+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCCCC1
Product: O=c1ccc2ccccc2[nH]1
Reaction time: 16 h
Yield: 91 %

Procedure:
A modification of a procedure in the following reference herein incorporated by reference in its entirety, for all purposes as if fully set forth herein, was used: Boojamra, C. G.; Burow, K. M.; Thompson, L. A.; Ellman, J. A. J. Org. Chem., 1997, 62, 1240-1256. A solution of (NH4)2Fe(II)(SO4)2.6 H2O (24.4 g, 63 mmol) in water (60 mL) was added to a stirred solution of 4-bromo-2-nitro-benzoic acid (2) (3.05 g, 12.45 mmol) in concentrated aqueous NH4OH (40 mL) at room temperature. The iron sulfate solution flask was washed with an additional portion of water (20 mL) which was added to the reaction. After 16 hours, the reaction had changed from a dark green solution to a rusty-brown mixture which was filtered through a plug of Celite and washed with concentrated aqueous NH4OH (80 mL) and water (4×80 mL). The combined aqueous fractions were acidified to pH 1-2 with aqueous concentrated HCl and extracted with EtOAc (4×500 mL). The organic fractions were evaporated under reduced pressure to a brown solid. The crude product was dissolved in EtOAc (300 mL), washed with water (40 mL), brine (40 mL), dried with Na2SO4, filtered, and concentrated to dryness giving 2.47 g of product (3) as a brown solid in 91% yield and >90% purity by HPLC.