Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]([O:15]CC)=[O:14])=[O:12])[S:8][CH:9]=1)([CH3:4])[CH3:3].O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:4][C:2]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]([OH:15])=[O:14])=[O:12])[S:8][CH:9]=1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)C(=O)Nc1nc(C(C)(C)C)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1csc(NC(=O)C(=O)O)n1

Procedure:
Ethyl 4-(2-methyl-2-propyl)thiazol-2-ylcarbamoylcarboxylate (1.3 g., 5 mmoles) was combined with 40 ml. of water, 20 ml. of ethanol and 5 ml. of 1 N potassium carbonate and the mixture heated on a steam bath for 10 minutes. Completion of reaction was determined by tlc. The solution was stripped of ethanol and the aqueous residue clarified by filtration. The filtrate was cooled in an ice-water bath and the product (1.02 g.) precipitated by acidification with 1 N hydrochloric acid. Recrystallization from ethyl acetate provided purified 4-(2-methyl-2-propyl)thiazol-2-ylcarbamoylcarboxylic acid [0.72 g.; m.p. 198°-200° C. dec.)].
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2([CH3:15])[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=[CH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[H][H]>CN(C=O)C.[Pt]>[Cl:1][C:2]1[C:3]([C:8]2([CH3:15])[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(c2ncccc2Cl)C=CC(=O)CC1
Reactant: [H][H]
Agent: [Pt]
Solvent: CN(C)C=O
Product: CC1(c2ncccc2Cl)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
A solution of the product of Example 38E (0.225 g, 1.015 mmol) in DMF was added to 5% Pt—C, wet (225 mg, 1.153 mmol) in a 50 ml pressure bottle. The mixture was pressurized with hydrogen (40 psi), stirred for 16 hours at ambient temperature, filtered to remove catalyst, and concentrated. The residue was chromatographed on silica gel eluting with 30% ethyl acetate-hexanes to give the title compound (90 mg, 40%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.55 (dd, J=1.5, 4.6, 1H), 7.91 (dd, J=1.5, 8.0, 1H), 7.36 (dd, J=4.6, 8.0, 1H), 2.96-2.77 (m, 2H), 2.26 (dd, J=5.4, 8.1, 4H), 2.03-1.84 (m, 2H), 1.46 (s, 3H). MS (DCI) m/z 224 (M+H)+.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](COC)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.[C:31]([C@@H:33]1[CH:50]2[C@:45]([CH3:52])([CH2:46][CH2:47][C:48](=[O:51])[CH2:49]2)[C@@H:44]2[C@H:35]([C@H:36]3[C@@:40]([CH2:42][CH2:43]2)([CH3:41])[C:39](=[O:53])[CH2:38][CH2:37]3)[CH2:34]1)#N>>[CH3:1][O:2][CH2:31][C@@H:33]1[CH:50]2[C@:45]([CH3:52])([CH2:46][CH2:47][C:48](=[O:51])[CH2:49]2)[C@@H:44]2[C@H:35]([C@H:36]3[C@@:40]([CH2:42][CH2:43]2)([CH3:41])[C:39](=[O:53])[CH2:38][CH2:37]3)[CH2:34]1
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: COC[C@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Product: COC[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 88 %

Procedure:
The title compound II-ap was prepared in 88% yield from 3,3:17,17-bis(ethylendioxy)-6α-methoxymethylandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.25 (s, 3H), 3.24 (m, 2H), 2.53-0.75 (m, 21H), 1.11 (s, 3H), 0.87 (s, 3H).
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[CH2:9]([C:11]1[NH:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][CH:12]=1)[CH3:10].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:8][C:12]1[N:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:15][C:11]=1[CH2:9][CH3:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1ncc(CC)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nc(Cl)c(CC)[nH]1
Temperature: 25 °C
Reaction time: 28 h
Yield: 44.8 %

Procedure:
NCS (3.15 g, 23.59 mmol) was added to a solution of ethyl 5-ethyl-1H-imidazole-2-carboxylate obtained in Example (1b) (3.35 g, 19.92 mmol) in chloroform (100 mL), and the mixture was stirred at room temperature for 28 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, followed by extraction with chloroform. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 3/1) to obtain 1.81 g of the title compound as a pale yellow solid (45%).
Reaction SMILES: CS(O[C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:7])(=O)=O.C(N(CC)C(C)C)(C)C.[N:23]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CS(C)=O.O>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C@@H:6]([N:26]1[CH2:25][CH2:24][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27]1)[CH3:7]
Reactant: C[C@@H](OS(C)(=O)=O)c1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccccn1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 75 %

Procedure:
To a stirred solution of 0.35 g (1.7 mmol) of the title compound from Step A above in 3.5 mL of anhydrous dimethyl sulfoxide was added 0.60 mL (3.5 mmol) of N,N-diisopropylethylamine followed by 0.49 g (2.6 mmol) of tert-butyl piperazine-1-carboxylate. The resulting mixture was heated to 80° C. for 3 h then cooled to ambient temperature. The reaction was diluted with water and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography eluting with a 0-100% ethyl acetate in hexanes gradient to afford the title compound as a yellow gum (0.38 g, 75% yield. LC-MS: m/z (ES) 292.4 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.Cl[CH2:19][C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:23]([N:22]([CH2:25][CH3:26])[C:20](=[O:21])[CH2:19][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1)[CH3:24]
Reactant: CCN(CC)C(=O)CCl
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)C(=O)COc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Yield: 53.7 %

Procedure:
To a solution of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (0.905 g, 4.00 mmol) and 2-chloro-N,N-diethylacetamide (0.748 g, 5.00 mmol) in acetone (10 mL) was added potassium carbonate (0.663 g, 4.80 mmol), and the mixture was heated under reflux for 2 hr under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30%-70% ethyl acetate/hexane) to give the title compound (0.729 g, yield 54%) as a yellow oil.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)[C@@H]([C@@H](CO)S)S.Cl[CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:19]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:14][N:15]=2)=[O:9])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: ClCCN1CCCC1
Agent: OC[C@@H](S)[C@@H](S)CO
Product: O=C(Nc1ncc(SCCN2CCCC2)s1)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithio-erythritol and 1-(2-chloroethyl)-pyrrolidine
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22])([O-:17])=[O:16].C(=O)(O)[O-].[Na+]>ClCCl>[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22])([O-:17])=[O:16]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cooled (0° C.) solution of aniline (17 g, 180 mmol) and triethylamine (27 mL, 190 mmol) in dichloromethane (100 mL) was added a solution of 3-nitrobenzoyl chloride (30 g, 160 mmol) in dichloromethane (60 mL). The mixture was stirred for 15 min at 0° C. then overnight at room temperature. It was then poured into saturated sodium bicarbonate (1 L) and stirred vigorously for 15 min. The precipitate was collected, washed with water and dried (40 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][NH3+:16].[Cl-]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=[N:16][O:15][CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: CO[NH3+]
Agent: [Cl-]
Solvent: c1ccncc1
Product: CON=C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
27 ml of anhydrous pyridine were added to a mixture of 2.0 g of 1-(t-butoxycarbonyl)-3-pyrrolidone and 992 mg of o-methylhydroxylamine hydrochloride, and the mixture was kept stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off and saturated aqueous sodium bicarbonate solution was added to the residue until it was basic. The mixture was extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed over silica gel, using a 3/1 mixture of benzene and ethyl acetate as eluent, giving 2.3 g of 1-(t-butoxycarbonyl)-3-methoxyiminopyrrolidine as a mixture of syn- and anti-isomers.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[C:23]([NH:26][CH2:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)(=[O:25])[CH3:24]>>[C:23]([NH:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([NH:32][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])=[CH:33][CH:34]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)NCc1ccc(N)cc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: CC(=O)NCc1ccc(NC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1

Procedure:
N-[4-(Acetylaminomethyl)phenyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-(acetylaminomethyl)aniline using method I. LCMS; retention time 2.97 min, MH+ 441.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([C:12](O)=[O:13])[CH2:7]1)=[O:5]>C1COCC1>[OH:13][CH2:12][C@@H:8]1[CH2:9][CH2:10][CH2:11][N:6]([C:4](=[O:5])[CH2:3][CH:2]([CH3:1])[CH3:15])[CH2:7]1
Reactant: CC(C)CC(=O)N1CCC[C@@H](C(=O)O)C1
Solvent: C1CCOC1
Product: CC(C)CC(=O)N1CCC[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.8 %

Procedure:
To a solution of (R)-1-(3-methylbutanoyl)piperidine-3-carboxylic acid (Example 34d) (2.52 g, 11.84 mmol) in THF (20 mL) at 0° C., was added BH3Me2S (1.2 mL, 13.0 mmol) dropwise over 15 minutes. The reaction was warmed to room temperature and stirred overnight, cooled to 0° C., quenched with water, concentrated under reduced pressure to remove THF and extracted with EtOAc. The combined extracts were washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, concentrated under reduced pressure and purified by flash chromatography on silica gel (EtOAc/hexanes) to give the title compound (184 mg, 6%). MS 200 (MH+).
Reaction SMILES: C([N:8]1[CH:17]=[C:16]2[C:11]([N:12]([CH3:29])[C:13](=[O:28])[C:14]([C:18]3[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:19]=3[CH3:27])=[CH:15]2)=[C:10]2[CH:30]=[CH:31][N:32]=[C:9]12)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:24][C:22]1[CH:21]=[CH:20][C:19]([CH3:27])=[C:18]([C:14]2[C:13](=[O:28])[N:12]([CH3:29])[C:11]3[C:16](=[CH:17][N:8]=[C:9]4[NH:32][CH:31]=[CH:30][C:10]4=3)[CH:15]=2)[CH:23]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1-c1cc2cn(Cc3ccccc3)c3nccc-3c2n(C)c1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(N)cc1-c1cc2cnc3[nH]ccc3c2n(C)c1=O

Procedure:
4-Benzyl-9-methyl-7-(2-methyl-5-nitro-phenyl)-4,9-dihydro-3,4,9-triaza-cyclopenta[a]naphthalen-8-one (590 mg, 1.4 mmol) and 200 mg Pd(OH)2 in 20 ml ethanol is stirred under hydrogen atmosphere at room temperature for 12 hours. The reaction mixture is passed through a celite pad. The filtrate is concentrated and dried under vacuum to give the title compound as solid. MS m/z 305.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Br:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[C:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH:34]=[CH:33]2>>[F:1][C:2]([F:25])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:41]2[CH2:42][CH2:43][N:38]([C:35]3[CH:34]=[CH:33][C:32]4[C:37](=[C:28]([Br:27])[CH:29]=[CH:30][CH:31]=4)[N:36]=3)[CH2:39][CH2:40]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Brc1cccc2ccc(N3CCNCC3)nc12
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4cccc(Br)c4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 8-bromo-2-piperazin-1-yl-quinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:5][CH:4]=1.[BH4-].[Na+]>O=P(Cl)(Cl)Cl.C(Cl)Cl>[CH3:25][O:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[CH:7]([C:6]1[CH:26]=[CH:27][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:16][CH2:17]2
Reactant: COc1ccc(C(=O)N(CCc2cccc(OC)c2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C2c3ccc(OC)cc3CCN2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A stirred solution of 4-methoxy-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide in POCl3 under an atmosphere of N2 was heated at reflux for 14 hours. The solution was allowed to cool to rt and concentrated in vacuo. The residue was taken up in CH2Cl2 (30 ml) and washed with sat. NaHCO3 until CO2 evolution ceased. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (20 ml), cooled to 0° C., and NaBH4 (0.105 g, 2.77 mmol) was added in a portionwise manner. The reaction was stirred for 2 hours at 0° C., then additional NaBH4 (0.105 g, 2.77 mmol) was added. The reaction was stirred at rt overnight, diluted with CH2Cl2 (50 ml), and washed with sat. NaHCO3 solution (1×50 ml). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2, hexanes:EtOAc 10:1) to give the desired compound as a colorless oil (0.550 g, 1.59 mmol, 58% yield).
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.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>[N:1]([CH:4]([C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]=1[C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([F:17])[CH:23]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: Cc1nc2c(Br)c(C(C)N=[N+]=[N-])ccc2s1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc2c(-c3cccc(F)c3)c(C(C)N=[N+]=[N-])ccc2s1
Temperature: 100 °C
Yield: 83.8 %

Procedure:
To a mixture of 5-(1-azidoethyl)-4-bromo-2-methyl-1,3-benzothiazole (0.100 g, 0.336 mmol) and (3-fluorophenyl)boronic acid (56.5 mg, 0.404 mmol) in 1,4-dioxane (2 mL) was added a 1 M solution of sodium carbonate in water (0.40 mL, 22 mmol) and tetrakis(triphenylphosphine)palladium(0) (19.4 mg, 0.0168 mmol). The reaction mixture was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and then concentrated. The crude mixture was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to give the desired product (88 mg, 83%). LCMS calculated for C16H14FN4S(M+H)+: m/z=313.1; found: 313.0.
Reaction SMILES: C(=O)(O)[O-].[Na+].[F:6][C:7]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:8]=1[O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:32][CH2:33][CH2:34]Cl)=[CH:27][CH:26]=1>CN(C)C=O>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH:31]([C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)[CH2:32][CH2:33][CH2:34][N:13]2[CH2:14][CH2:15][CH:10]([O:9][C:8]3[C:16]([F:23])=[C:17]([F:22])[C:18]([F:21])=[C:19]([F:20])[C:7]=3[F:6])[CH2:11][CH2:12]2)=[CH:29][CH:30]=1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(C(CCCN2CCC(Oc3c(F)c(F)c(F)c(F)c3F)CC2)c2ccc(F)cc2)cc1
Temperature: 78 °C
Reaction time: 20 h

Procedure:
A stirring mixture of 10 g of sodium bicarbonate in 50 ml dimethylformamide was treated with 4.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine followed by a solution of 4.06 ml of 4,4-bis-(4-fluorophenyl)butyl chloride in 10 ml of dimethylformamide, and then stirred at 78° C. for 20 hours. After filtering, the filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Filtration followed by evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 20% ethyl acetate/dichloromethane) to afford 5.44 g of 1-[4,4-bis-(4-fluorophenyl)butyl]-4-(2,3,4,5,6-pentafluorophenoxy)piperidine as an oil. The oil was dissolved in hot isopropanol and acidified with an etheral solution of oxalic acid to precipitate the corresponding oxalate salt. Recrystallization from isopropanol afforded 2.75 g (30.0%) of 1-[4,4-bis-(4-fluorophenyl)butyl]-4-(2,3,4,5,6-pentafluorophenoxy)piperidine oxalate, m.p. 183°-185° C.
Reaction SMILES: N[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([CH:18]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:33])([F:32])[F:31].N([O-])=O.[Na+].CC#N.O.[ClH:42]>O.Cl[Cu]>[Cl:42][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([CH:18]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:33])([F:32])[F:31]
Reactant: Cl
Reactant: CCOC(=O)C(CC(C)C)c1cc(OCC(F)(F)F)c(N)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(CC(C)C)c1cc(OCC(F)(F)F)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
Ethyl 2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (640 mg, 1.3 mmol) was dissolved in a mixture of MeCN/H2O/HCl 15 mL/15 mL/1 mL at 0° C. A solution of NaNO2 (0.138 g, 2.0 mmol) in water (2 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (1.32 g, 13.4 mmol) in water (5 mL) was added drop wise at 0° C. The reaction mixture was heated to 80° C. for 2 h and the mixture was concentrated under reduced pressure. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na2SO4, filtered and concentrated to give crude black oil which was purified by chromatography over silica gel (hexane/EtOAc) to give the ethyl 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (380 mg) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][CH2:5][S:6]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[C:23]3[C:18](=[C:19]([C:32]([NH2:34])=[O:33])[CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=4)[CH:22]=3)[NH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])=[O:7].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:35][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][S:6]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[C:23]3[C:18](=[C:19]([C:32]([NH2:34])=[O:33])[CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[CH:26][CH:25]=4)[CH:22]=3)[NH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])=[O:7]
Reactant: CN(C)CCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)cc4)cc23)CC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CN(C)CCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CN5CCOCC5)cc4)cc23)CC1
Yield: 26.4 %

Procedure:
Following the general procedure of example (99), 3-(1-{[3-(dimethylamino)propyl]sulfonyl}-4-piperidinyl)-5-(4-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.1 mmol), morpholine (9 mg, 0.1 mmol) and NaBH(OAc)3 (64 mg, 0.3 mmol) were reacted to give the title compound (15 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.[Cl:11]N1C(=O)CCC1=O.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:11])=[N:7][OH:8])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 408 %

Procedure:
To a solution of 4-chloro-benzaldehyde oxime (20 g, 0.13 mol) in anhydrous dimethylformamide (80 ml) was added N-chlorosuccinimide (3.51 g, 0.03 mol, 0.2 eq) at room temperature. Subsequently, HCl gas drawn from the headspace of concentrated hydrochloric acid was bubbled through the reaction mixture. Then, additional N-chlorosuccinimide (14.06 g, 0.11 mol, 0.8 eq) was then added in four portions and the mixture was stirred at room temperature for twenty hours before it was poured into ice-water (200 ml) and extracted twice with methyl t-butyl ether. The combined organic layers were washed with water and brine, and then dried and concentrated to give the title compound as a white solid (23.26 g): 1H NMR (CDCl3, 200 MHz): δ=7.97 (s, 1H), 7.77 (m, 2H), 7.36 (m, 2 H). 13C NMR (CDCl3, 50 MHz): δ=139.37, 137.10, 130.99, 128.94, 128.57
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13](F)=[CH:12][CH:11]=1>O>[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:12][CH:11]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(F)cc1
Solvent: O
Product: COC(=O)c1ccc(N2CCOCC2)cc1
Temperature: 120 °C
Yield: 234.5 %

Procedure:
A mixture of morpholine (996 mg, 1 mL, 11.4 mmol) and 4-fluoro benzoic acid methyl ester (500 mg, 0.32 mmol) was stirred with heating at 120° C. for 48 hrs. Cold water then added, filtered the solid precipitated to afford 166 mg (23.15% yield) of 4-morpholin-4-yl-benzoic acid methyl ester. 1H NMR (CDCl3): δ 8.0 (d, 2H), 6.9 (d, 2H), 3.9 (m, 7H), 3.3 (t, 4H).