Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([OH:15])=O)[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:44]1[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45]1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:49][CH:46]3[CH2:47][CH2:48][O:44][CH2:45]3)=[O:15])[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: NC1CCOC1
Reactant: O=C(O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CN1C[C@@H]2COCCN2c2nc(Cl)ncc21)NC1CCOC1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x26 using (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetic acid (PREPARATION x25, 50 mg, 0.176 mmol), HATU (87 mg, 0.228 mmol), tetrahydro-furan-3-ylamine (23 mg, 0.263 mmol) and triethylamine (0.073 mL, 0.527 mmol) in DMF (2 mL). ESI-MS m/z [M+H]+ calc'd for C15H20ClN6O3, 354.13; found 354.2.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[CH3:22])=[O:13])=[CH:4]1.I[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C=O)C>[CH2:24]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[CH3:22])=[O:13])=[CH:4]1)[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CN1CCCCC1COC(=O)c1c[nH]c2ccccc12
Reactant: CCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCn1cc(C(=O)OCC2CCCCN2C)c2ccccc21
Reaction time: 0.75 h
Yield: 56.7 %

Procedure:
To a DMF (5 ml) suspension of 60% sodium hydride (0.10 g, 2.5 mmol) was dropwise added a DMF (7 ml) solution of (1-methyl-2-piperidyl)methyl 1H-indole-3-carboxylate (0.50 g, 1.7 mmol) at room temperature over a period of 10 min. The mixture was stirred for 45 min., onto which was then poured 1-iodopentane (0.38 g, 1.9 mmol) followed by stirring for additional 4 hours. A reaction solution was poured onto ice water followed by extraction with ethyl acetate (50 ml). The extract was washed successively with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give a pale yellow crude product (0.52 g). Purification of the product by column chromatography on silica gel (SiO2 : 20 g, CHCl3 /MeOH=20/1) afforded the title compound (0.33 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:14].Cl>C1COCC1.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:14])=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
A solution of 6-bromo-1H-indole (2.34 g, 11.9 mmol) in dry THF (25 mL) was cooled in an ice bath. Sodium hydride (1.12 g of 60% dispersion in oil, 28.0 mmol) was added. The mixture was stirred for 30 minutes under nitrogen at room temperature, then cooled in an ice bath. Iodomethane (1.6 mL, 26 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature, poured into excess water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography using hexane as an eluant to yield 6-bromo-1-methyl-1H-indole 2.04 g (81.6%, 9.71 mmol) as a yellow oil. 1HNMR (200 MHz, DMSO-d6): δ 7.7 (s, 1H), 7.5 (d, 1H, J=8.6 Hz), 7.35 (d, 1H, J=2.1 Hz), 7.15 (d, 1H, 7.3 Hz), 6.4 (d, 1H, J=1.3 Hz), and 3.75 ppm (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[CH:7][N:6]2[CH:14]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C1COCC1>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH2:24][CH2:25][N:26]([CH2:2][C:3]2[N:4]=[C:5]3[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[CH:7][N:6]3[CH:14]=2)[CH2:27][CH2:28]1
Reactant: CCOc1ccc2nc(CCl)cn2c1
Reactant: Clc1ccc(N2CCNCC2)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1ccc2nc(CN3CCN(c4ccc(Cl)cc4Cl)CC3)cn2c1
Temperature: 75 °C
Yield: 23.8 %

Procedure:
A mixture of 2-(chloromethyl)-6-ethoxyimidazo[1,2-α]pyridine (0.204 g), 1-(2,4-dichlorophenyl) piperazine (Example 31, Step 1; 0.2283 g), triethylamine (Aldrich; 0.15 mL), and THF (1.3 mL) is stirred at 75° C. until the reaction is judged complete by thin layer chromatography. The cooled mixture is concentrated under reduced pressure and partitioned between dichloromethane and saturated aq. sodium bicarbonate. The combined organic layers are dried with MgSO4 and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (2/98) and crystallized from ethyl acetate/ether to give 0.0936 g of the title compound; mp 171-172° C.; MS m/z 404, 406; IR (mineral oil) 1478, 1189, 797, 1508, 1273 cm-1 ; 1H NMR (CDCl3) δ1.45, 2.77, 3.08, 3.77, 3.98, 6.94, 7.17, 7.34, 7.45, 7.47, 7.60.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:12][C:11]=1[NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.C(N(CC)CC)C.Cl[C:45]([O:47][CH3:48])=[O:46]>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([CH:17]2[CH2:18][CH2:19][N:20]([C:45]([O:47][CH3:48])=[O:46])[CH2:21][CH2:22]2)=[N:12][C:11]=1[NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nc(C3CCNCC3)[nH]c(=O)c2-c2nc3ccccc3s2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(c2nc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c(-c3nc4ccccc4s3)c(=O)[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.9 %

Procedure:
Into a solution of tert-butyl (3R)-3-[[5-(1,3-benzothiazol-2-yl)-6-oxo-2-(piperidin-4-yl)-1,6-dihydropyrimidin-4-yl]amino]piperidine-1-carboxylate (100 mg, 0.20 mmol, 1.00 equiv) and triethylamine (29.7 mg, 0.29 mmol, 1.50 equiv) in dichloromethane (5 ml) was added methyl chloroformate (14.8 mg, 0.16 mmol, 0.80 equiv). The resulting mixture was stirred for 2 h at room temperature. Concentration under reducing pressure gave 100 mg of the title compound as a crude product, which was used directly for next step without further purification. MS m/z [M+H]+ (ESI): 569.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.[I:12]Cl>ClCCl>[I:12][C:11]1[C:5]2[C:6](=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:9][CH:10]=1
Reactant: ClI
Reactant: COc1cnc2[nH]ccc2c1
Solvent: ClCCl
Product: COc1cnc2[nH]cc(I)c2c1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
To a solution of 5-methoxy-1H-pyrrolo[2,3-b]pyridine (14, 300 mg, 2.0 mmol) in 30 mL of dichloromethane under nitrogen, iodine monochloride (3 mL, 1.0 M in dichloromethane, 3.0 mmol) was added at −40° C. The reaction was stirred to room temperature, then quenched with 10 mL of 1 M aqueous sodium thiosulfate pentahydrate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with water, brine, then dried over sodium sulfate, decolored with activated carbon, filtered and the filtrate concentrated under vacuum. The resulting solid was washed with 20% ethyl acetate in hexane to provide the desired compound (15, 371 mg). MS (ESI) [M+H+]+=275.03.
Reaction SMILES: [CH3:1][N:2]([C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:12])[CH2:10]Br)[N:8]=1)[CH3:3].C(=O)([O-])O.[K+].Cl.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([NH2:32])[CH3:31])=[CH:25][CH:24]=1)([O:21][CH3:22])=[O:20]>CC(C)=O>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([NH:32][CH2:10][CH:9]([OH:12])[C:7]2[N:8]=[C:4]([N:2]([CH3:3])[CH3:1])[S:5][CH:6]=2)[CH3:31])=[CH:25][CH:24]=1)([O:21][CH3:22])=[O:20]
Reactant: CN(C)c1nc(C(=O)CBr)cs1
Reactant: COC(=O)c1ccc(CC(C)N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CC(C)NCC(O)c2csc(N(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5 g of 2-(N,N-dimethylamino)-4-bromoacetyl-thiazole in 250 ml of acetone are heated to reflux with 10 g of potassium hydrogen carbonate and 9.5 g of 2-(4-carbomethoxyphenyl)-1-methylethylamine-hydrochloride for 3 hours. After the reaction mixture has been cooled the inorganic products are removed by filtration, and the filtrate is concentrated in a rotary evaporator. The resulting oil residue is taken up in 150 ml of absolute methanol and, at 0°-5° C., 1.75 g of sodium borohydride are added in small poritons. The mixture is then stirred at 0°-5° C. for one hour and at room temperature for 24 hours. Then ice-water are added to the reaction mixture, and it is acidified with concentrated hydrochloric acid, made alkaline with ammonia, while cooling in ice, and extracted with methylene chloride. The extract is dried over sodium sulphate, concentrated and purified on a silica gel column using ethyl acetate/methanol=8:2 as eluant.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:16][C@H:15]([OH:17])[C@@H:14]([CH2:18][OH:19])[O:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:23]>P([O-])([O-])([O-])=O>[NH:3]1[C:4](=[O:23])[C:5]2[N:6]=[CH:7][N:8]([C@H:11]3[CH2:16][C@H:15]([OH:17])[C@@H:14]([CH2:18][OH:19])[O:13][CH2:12]3)[C:9]=2[N:10]=[C:2]1[NH2:1]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Nc1nc(Cl)c2ncn([C@@H]3CO[C@H](CO)[C@@H](O)C3)c2n1
Agent: O=P([O-])([O-])[O-]
Product: Nc1nc2c(ncn2[C@@H]2CO[C@H](CO)[C@@H](O)C2)c(=O)[nH]1
Reaction time: 4 h

Procedure:
A mixture of 145 mg (0.48 mmol) of compound 12 and 0.5 ml of a suspension of adenosine deaminase in 100 ml 0.05 M phosphate buffer, pH 7.5, was incubated for 4 hours at 30° C. The reaction mixture was concentrated to about 15 ml and the precipitate filtered off. Recrystallization from water provided 50 mg analytically pure compound 13. The filtrates were placed onto an XAD column (25×2 cm), which was eluted with water followed by MeOH-water (3:1). Evaporation gave an extra 70 mg of compound 13 as a white product to a total of 0.43 mmol (89%). mp >300° C.
Reaction SMILES: [Cl-].[NH4+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([OH:27])[C@@H:18]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH3:19])=[CH:13][C:12]=1[N+:28]([O-])=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C(O)C.[Zn]>[NH2:28][C:12]1[CH:13]=[C:14]([C@@H:17]([OH:27])[C@@H:18]([NH:20][C:21](=[O:26])[C:22]([F:23])([F:24])[F:25])[CH3:19])[CH:15]=[CH:16][C:11]=1[O:10][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H](NC(=O)C(F)(F)F)[C@H](O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: C[C@H](NC(=O)C(F)(F)F)[C@H](O)c1ccc(OCc2ccccc2)c(N)c1
Temperature: 70 °C
Yield: 91.8 %

Procedure:
A solution of ammonium chloride (29 g) in water (133 mL) was added to a solution of N-[(1S,2R)-2-(4-benzyloxy-3-nitrophenyl)-2-hydroxy-1-methylethyl]-2,2,2-trifluoroacetamide (73 g) in ethanol (487 mL) at room temperature with stirring. The mixture was cooled with an ice, and then zinc powder (95 g) was added to the mixture with stirring over 10 minutes. The gray suspension was heated up to 70° C. over 15 minutes, and stirred at that temperature for 1 hr. The insoluble materials were removed by filtration, and the filtrate was concentrated in vacuo. Ethyl acetate and water were added to the residue, and the insoluble materials were removed by filtration again. The organic layer in the filtrate was separated, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (62 g).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C(Cl)Cl>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])=[C:7]([C:13]3[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=3)[CH:8]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: CN(C)CCOc1ccc(N)cc1-c1ccnn1C
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
A solution of 4-(2-dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (26.0 mg, 0.1 mmol) in methylene chloride (1 mL) was treated with 4-chlorophenyl-isocyanate (13.3 μL, 0.105 mmol) then reaction mixture stirred at room temperature overnight and concentrated to give an oily residue that was subjected to a purification by flash chromatography (SiO2, CH2Cl2/MeOH gradient elution) to afford Compound 127 as a white solid in 69.8% yield. LCMS m/z (%)=414 (M+H 35Cl, 100), 416 (M+H 37Cl, 36). 1H NMR (400 MHz, acetone-d6) δ: 8.51 (s, 1H), 8.36 (s, 1H), 7.62-7.59 (m, 3H), 7.50 (s, 1H), 7.42 (s, 1H), 7.31 (d, J=8.90 Hz, 2H), 7.12 (d, J=8.92 Hz, 1H), 6.24 (s, 1H), 4.11 (t, J=5.86 Hz, 2H), 3.77 (s, 3H), 2.61 (t, J=5.85 Hz, 2H), 2.20 (s, 6H).
Reaction SMILES: [OH-].[Li+].[F:3][CH2:4][C:5]1[N:6]([C:17]2[C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:20]([CH3:27])=[CH:19][CH:18]=2)[C:7]([S:10][CH2:11][C:12]([O:14]CC)=[O:13])=[N:8][N:9]=1>C1COCC1.O>[F:3][CH2:4][C:5]1[N:6]([C:17]2[C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:20]([CH3:27])=[CH:19][CH:18]=2)[C:7]([S:10][CH2:11][C:12]([OH:14])=[O:13])=[N:8][N:9]=1
Reactant: CCOC(=O)CSc1nnc(CF)n1-c1ccc(C)c2c1CCCC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-n2c(CF)nnc2SCC(=O)O)c2c1CCCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Lithium hydroxide solution (1M aqueous, 0.59 mL, 0.59 mmol) is added to a solution of ethyl 2-(5-(fluoromethyl)-4-(4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate (107 mg, 0.294 mmol) in THF/water (3/1, 1.2 mL) and the mixture stirred at room temperature for 18 h. The crude reaction mixture is concentrated, acidified with HCl (1N, 3 mL) and extracted with ethyl acetate (3×3 mL). The combined organic extracts are dried over sodium sulfate, filtered and concentrated to afford 2-(5-(fluoromethyl)-4-(4-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid.
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]([N+:24]([O-])=O)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl>O>[NH2:24][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:27]
Reactant: O=C(c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: Nc1cc(C(=O)N(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1

Procedure:
By reducing N,N-dibenzyl-4-benzyloxy-3-nitrobenzamide (melting point 131°-132° C.) in water-containing methanol with reduced iron powder-hydrochloric acid, 3-amino-N,N-dibenzyl-4-benzyloxybenzamide (melting point 81° C.) was obtained. Then, by reacting 3-amino-N,N-dibenzyl-4-benzyloxybenzamide with ethyl oxalyl chloride in the presence of pyridine in tetrahydrofuran, ethyl 2-benzyloxy-5-(N,N-dibenzylcarbamoyl)oxanilate (melting point 132°-133° C.) was obtained. A solution of 3.6 g of ethyl 2-benzyloxy-5-(N,N-dibenzylcarbamoyl)oxanilate thus obtained in 100 ml of ethanol was catalytically hydrogenated in the presence of 0.8 g of 10% palladium carbon until the absorption of hydrogen stopped. After the reaction was over, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to provide 2.7 g of ethyl 5-(N,N-dibenzylcarbamoyl)-2-hydroxyoxanilate, a gum.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:24])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Product: Cc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)c2)c(-c2ccccc2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.14 min; [M+H]+=413.07.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[CH2:22]1[O:30][CH:23]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[OH:30][CH:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][O:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17]
Reactant: c1ccc(C2CO2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cccc(O)c1
Product: O=C1c2ccccc2C(=O)N1CCOc1cccc(OCC(O)c2ccccc2)c1

Procedure:
Alkylation reaction of phenol 24 with styrene oxide gave 2-(2-(3-(2-hydroxy-2-phenylethoxy)phenoxy)ethyl)isoindoline-1,3-dione as yellow oil. Yield (0.85 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=7.2 Hz, 1H), 7.41-7.53 (m, 3H), 7.28-7.38 (m, 5H), 7.12-7.16 (m, 1H), 6.60-6.65 (m, 1H), 6.52 (s, 1H), 6.48 (dd, J=8.0, 2.0 Hz, 1H), 4.79-4.82 (m, 1H), 4.19 (t, J=5.4 Hz, 2H), 3.72-3.84 (m, 4H).
Reaction SMILES: C(OC([N:11]1C[C@H](O)C[C@H]1C(O)=O)=O)C1C=CC=CC=1.C(O[C:28]1[C:47]([O:48][CH3:49])=[CH:46][C:31]([C:32]([N:34]2[CH:38]=[C:37](CC(OC)=O)[CH2:36][C@H:35]2[CH2:44]O)=[O:33])=[C:30]([N+]([O-])=O)[CH:29]=1)C1C=CC=CC=1.NO.[N+](O)([O-])=O>C(Cl)(Cl)Cl>[CH3:49][O:48][C:47]1[C:46]2[N:11]=[CH:44][C@@H:35]3[CH2:36][CH2:37][CH2:38][N:34]3[C:32](=[O:33])[C:31]=2[CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)CC1=CN(C(=O)c2cc(OC)c(OCc3ccccc3)cc2[N+](=O)[O-])[C@H](CO)C1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: NO
Solvent: ClC(Cl)Cl
Solvent: O=[N+]([O-])O
Product: COc1cccc2c1N=C[C@@H]1CCCN1C2=O

Procedure:
Finely ground Cd/Pb couple (1.02 g). was added in small portions to a stirred solution of 100 (0.64 g, 1.51 mmol) in THF (10 mL) and 1M NH2OAc (10 mL). The reaction was followed by TLC (EtOAc), when no more starting material was observed, the mixture was poured into ethyl acetate (200 mL). The organic phase was dried over MgSO4 and evaporated to yield the product as a pale yellow oil (0.28 g, 80%): 1H NMR (270 MHz, CDCl3) δ 2.15 (m, 4H); 3.52 (m, 2H); 3.87 (s, 3H); 5.15 (m, 1H); 6.8-7.2 (m, 3H); 7.8 (d, J=4.7 Hz, 1H, imine H11). IR (Nujol): cm−1 3373, 2975, 1621, 1576, 1440, 1419, 1250, 1075, 750. MS: m/e (relative intensity) 230 (M+., 100), 215 (45), 201 (20), 187 (5), 160 (5), 146 (4), 133 (20), 105 (10), 76 (25), 70 (45), 63 (3), 51 (3). HRMS Calculated for C13H14N2O2: 230.1055. Found: 230.1055. [α]25D=+455.3° (c=0.6, CHCl3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)=[O:8])([O-])=O.[H][H]>[Pd].O1CCOCC1>[NH2:1][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)=[O:8]
Reactant: O=C(Nc1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1cccc(NC(=O)c2cccc(N)c2)c1

Procedure:
A solution of 14.3 g. of 3,3'-dinitrobenzanilide in 150 ml. of dioxane is hydrogenated at three atmospheres of hydrogen using 1 g. of 10% palladium-on-charcoal catalyst. The catalyst is removed by filtration and the filtrate evaporated to dryness. The residue is recrystallized from ethanol. There is obtained 8.72 g. of material melting at 123°-4°.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C@@H](C2C=CC(OC)=CC=2)C)[CH:7]=1.[C:23](O)([C:25](F)(F)F)=O>>[NH:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[C:6]1[CH:7]=[C:2]([C:2]2[C:23]3[C:25](=[CH:5][CH:6]=[CH:8][CH:12]=3)[NH:4][CH:3]=2)[CH:3]=[N:4][CH:5]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc([C@@H](C)N2CCC[C@H]2c2cncc(Br)c2)cc1
Product: c1ccc2c(-c3cncc([C@@H]4CCCN4)c3)c[nH]c2c1

Procedure:
A solution of 3-Bromo-5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine 3 (3.64 g, 10.0 mmole) in 5 mL of TFA was heated at 120° C. in a microwave reactor for 30 minutes. The resulting solution was concentrated to remove TFA. The residue was dissolved in 150 mL of CH2Cl2 and basicfied by 5 mL of saturated NaHCO3. The solution was washed by 2×10 mL of water, dried over Na2SO4 and concentrated to give 3-((S)-5-Pyrrolidin-2-yl-pyridin-3-yl)-1H-indole 4 (2.4 g, crude) as deep brown gum without further purification for the next step reaction.
Reaction SMILES: C(OC(=O)CN1C2CCC[C@@H](N([S:17]([C:20]3C=C(C(F)(F)F)C=C(SCC)[CH:21]=3)(=[O:19])=[O:18])C)C=2C=N1)C.[CH2:34]([O:36][C:37](=[O:64])[CH2:38][N:39]1[C:47]2[CH2:46][CH2:45][CH2:44][C@@H:43]([N:48]([S:50]([C:53]3[CH:58]=[C:57]([C:59]([F:62])([F:61])[F:60])[CH:56]=[C:55](F)[CH:54]=3)(=[O:52])=[O:51])[CH3:49])[C:42]=2[CH:41]=[N:40]1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:64])[CH2:38][N:39]1[C:47]2[CH2:46][CH2:45][CH2:44][C@@H:43]([N:48]([S:50]([C:53]3[CH:58]=[C:57]([C:59]([F:60])([F:61])[F:62])[CH:56]=[C:55]([S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])[CH:54]=3)(=[O:52])=[O:51])[CH3:49])[C:42]=2[CH:41]=[N:40]1)[CH3:35]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(SCC)cc(C(F)(F)F)c1
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(F)cc(C(F)(F)F)c1
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)CC)c1

Procedure:
Starting with {(R)-4-[(3-ethylsulfanyl-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (1st step intermediate of example 8-1) using the method analogous to the one described for example 7-1, {(R)-4-[(3-ethanesulfonyl-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester was obtained as a white solid. MS cald. for C21H26F3N3O6S2 537, obsd. (ESI+) [(M+H)+] 538.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH2:7][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: Fc1ccc(Br)cc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.7 %

Procedure:
To 5-bromo-2-fluorobenzaldehyde (2.50 g, 12 mmol) and morpholine (1.61 mL, 1.61 g, 18 mmol) in 1,2-dichloroethane (100 mL) was added sodium triacetoxyborohydride (5.21 g, 2.5 mmol) portionwise with stirring at room temperature over 5 min. The mixture was stirred under nitrogen for 1 h, then 2 N sodium hydroxide solution (100 mL) was added, and the mixture was stirred for a further 5 min. The biphasic mixture was separated, and the aqueous layer was washed with dichloromethane (2×75 mL). The combined organic layers were washed with saturated sodium chloride solution (1×50 mL) and were concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 75% diethyl ether in isohexane (+1% triethylamine), to yield 4-(5-bromo-2-fluorobenzyl)morpholine (3.18 g, 94%).