Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].[H-].[Na+].I[CH3:18]>CN(C)C=O>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:9]([CH3:18])[C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
A solution of 3-nitrophthalimide (Aldrich)(1.78 g, 0.01 mol) in dry N,N-dimethylformamide (20 ml) was added dropwise to a stirred suspension of sodium hydride (0.36 g of an 80% dispersion in oil; 0.012 mol) in dry N,N-dimethylformamide (10 ml) under argon. The mixture was stirred at room temperature for 30 min and then treated with iodomethane (0.75 ml, 0.012 mol). After stirring overnight the reaction was poured into ice-water and extracted with dichloromethane (4×50 ml). The combined extracts were washed with water followed by brine, then dried over sodium sulfate and concentrated in vacuo. The residue was treated with water, and the resulting precipithate was removed by filtration and washed with water. After drying in a vacuum dessicator over silica gel the title compound was obtained as a yellow solid (1.64 g).
Reaction SMILES: C([O:3][C:4]([C:6]([CH3:30])([CH3:29])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:17]([F:28])=[CH:16][N:15]=2)=[CH:9][CH:8]=1)=O)C.CC(C[AlH]CC(C)C)C>>[F:28][C:17]1[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)=[N:19][C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([CH3:30])([CH3:29])[CH2:4][OH:3])=[CH:8][CH:9]=2)=[N:15][CH:16]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: CC(C)(CO)c1ccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc1

Procedure:
In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine, N2-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine was reduced with DIBALH to provide 5-fluoro-N2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.89 (d, 1H, J=2.9 Hz), 7.57 (s, 1H), 7.41 (d, 2H, J=8.8 Hz), 7.29 (d, 2H, J=8.2 Hz), 7.16 (d, 1H, J=8.2 Hz), 7.10 (d, 1H, J=8.8 Hz), 6.80-6.55 (m, 2H), 5.58 (s, 2H), 1.30 (s, 6H); LCMS: ret. time: 18.01 min.; purity: 98%; MS (m/e): 369 (MH+).
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[CH2:15][CH2:16]Cl)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:21]([C:28]1([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([C:28]1([OH:34])[CH2:33][CH2:32][N:31]([CH2:16][CH2:15][C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:20])[CH3:19])=[CH:8][CH:9]=2)=[O:18])[CH2:30][CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)CCCl)cc1
Reactant: OC1(Cc2ccccc2)CCNCC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)CCN2CCC(O)(Cc3ccccc3)CC2)cc1

Procedure:
The title compound, MS: m/e=468 (M+), was prepared from N-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-3-chloro-propionamide and 4-benzyl-4-hydroxypiperidin.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=1.[CH2:21]=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][N:14]([CH3:21])[CH2:13][CH2:12]3)=[CH:4][CH:3]=1
Reactant: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Reactant: C=O
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCN(C)CC2

Procedure:
The title compound (113 mg) was prepared from 3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 190) and paraformaldehyde as in Example 35. MS (ESI): exact mass calculated for C17H22FN3, 287.18; found, m/z 288.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.42-7.40 (m, 2H), 7.34-7.30 (m, 2H), 4.42 (m, 1H), 3.77-3.74 (m, 1H), 3.67-3.62 (m, 2H), 3.36-3.34 (m, 1H), 3.27-3.21 (m, 3H), 3.03 (s, 3H), 2.92-2.89 (m, 1H), 2.80-2.76 (m, 1H), 1.49-1.29 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]([NH2:20])=[CH:4][CH:3]=1.[N:21]([O-])=O.[Na+].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)[N:21]=[N:20][C:5]2=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1NCc1ccc2ncccc2c1
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
Intermediate 9 (0.220 g, 0.772 mmol) was dissolved in acetic acid (1.3 ml) and cooled to 5° C. Sodium nitrite (0.063 g, 0.927 mmol) in 0.35 ml water was added slowly followed by sulphuric acid (0.09 ml). The reaction mixture was warmed to RT and stirred for 30 min. The reaction mixture was poured into ice water and pH adjusted to ca. 8 with sodium bicarbonate solution, extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated to afford the title compound as a brown solid (0.220 g, 96%). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.88 (s, 1H), 8.69 (d, J=8.6 Hz, 1H), 8.35 (d, J=8.1 Hz, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.90 (s, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.53 (dd, J=8.0, 4.0 Hz, 1H), 6.12 (s, 2H).
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:33]=[C:32]([CH3:34])[O:31][N:30]=4)=[CH:25][C:24]=3[CH3:35])=[CH:19][CH:18]=2)=[O:16])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].ClC(OC(Cl)C)=O.C(N(C(C)C)CC)(C)C>ClCCCl>[CH3:1][NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:33]=[C:32]([CH3:34])[O:31][N:30]=4)=[CH:25][C:24]=3[CH3:35])=[CH:21][CH:22]=2)=[O:16])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)cc1OCCN(C)C
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNCCOc1cc(NC(=O)c2ccc(-c3ccc(-c4noc(C)n4)cc3C)cc2)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A solution of N-[3-(2-dimethylaminoethoxy)-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide (E1, 0.2 g, 0.41 mmole) in 1,2-dichloroethane (5 ml) was treated at room temperature with 1-chloroethyl chloroformate (0.12 ml, 1.12 mmole) followed by diisopropylethylamine (0.15 ml, 0.86 mmole). The mixture was stirred for 2 hours at room temperature. After removal of solvent in vacuo the residue was treated with methanol (8 ml) and heated under reflux for 30 minutes. The reaction mixture was concentrated in vacuo and the residue treated with saturated aqueous potassium carbonate (10 ml) and extracted with dichloromethane (3×10 ml). The combined organic extracts were dried and concentrated in vacuo. Flash column chromatography on silica gel eluting with 5% MeOH/CH2Cl2 gave the title compound as a light pink solid (0.13 g, 68%) mp 97°-99° C.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][N:19]3[C:28](=[O:29])[CH2:27][C:22]4([CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:21][C:20]3=[O:30])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:31][OH:32].[BH4-].[Na+]>C(Cl)Cl>[CH3:31][O:32][C:4]1[CH:3]=[CH:8][CH:7]=[CH:6][C:5]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][N:19]2[C:20](=[O:30])[CH2:21][C:22]3([CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:27][CH:28]2[OH:29])[CH2:13][CH2:14]1
Reactant: CO
Reactant: COc1cccc(N2CCN(CCCON3C(=O)CC4(CCCC4)CC3=O)CC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCON2C(=O)CC3(CCCC3)CC2O)CC1

Procedure:
To a solution prepared from 8-[3-[4-(3-methoxyphenyl)-1-piperazinyl]propyloxy]-8-azaspiro[4.5]decan-7,9-dione (5.0 g), 300 ml of CH3OH and 100 CH2Cl2 was added NaBH4 (1.8 g) with stirring. The mixture was stirred at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[N+:23]([C:26]1[CH:27]=[C:28]([N:35]=[C:36]=[O:37])[CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[CH:31]=1)([O-:25])=[O:24]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:36]([NH:35][C:28]2[CH:27]=[C:26]([N+:23]([O-:25])=[O:24])[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=2)=[O:37])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cc([N+](=O)[O-])cc([N+](=O)[O-])c4)cc3)c2cc1OC
Yield: 57.5 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (54 mg) was dissolved in toluene (5 ml) with heat, 3,5-dinitrophenyl isocyanate (81 mg) was added, and the admixture was refluxed with heat for 20 minutes. The reaction solution was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 53 mg of the title compound (yield: 57%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.C([Mg]Cl)(C)C.C[CH2:18][S:19](=S)([O-])=O>C1COCC1>[Cl:11][C:9]1[C:10]2[C:2]([S:19][CH3:18])=[CH:3][S:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Clc1ncnc2scc(Br)c12
Reactant: CCS(=O)([O-])=S
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CSc1csc2ncnc(Cl)c12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 127.7 %

Procedure:
5-bromo-4-chlorothieno[2,3-d]pyrimidine (750 mg, 3.0 mmol) was partially dissolved in anh. THF (8 mL), cooled to 0° C. and treated in portions with a 2M THF solution of i-PrMgCl (2.0 mL, 4.0 mmol). After 20 minutes, this solution was treated dropwise with methylmethanethiosulfonate (460 μl, 570 mg, 4.5 mmol). The cooling bath was removed and the mixture was stirred for 4 hours at 25° C. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic phase was washed with water, brine, dried (Na2SO4) and evaporated to give 830 mg crude product-ca 80 percent pure by GC. The material was purified by recrystallization from hot heptane to give 350 mg (45 percent) yield of tan crystals.
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.Cl.[CH3:9][O:10][C:11](=[O:30])[C@H:12]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[N:13]1[CH2:18][CH:17](O)[C:16]2[S:20][CH:21]=[CH:22][C:15]=2[CH2:14]1.C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:9][O:10][C:11]([C@@H:12]([N:13]1[CH2:14][C:15]2[CH:22]=[CH:21][S:20][C:16]=2[CH2:17][CH2:18]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])=[O:30]
Reactant: COC(=O)[C@H](c1ccccc1Cl)N1Cc2ccsc2C(O)C1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of sodium iodide in acetonitrile is added chlorotrimethylsilane. The mixture is stirred at room temperature under nitrogen for 1 hour. (αS,7RS)-methyl-α-(7-hydroxy-4,5,6,7-tetrahydro-5-thieno[3,2-c]pyridyl)-o-chlorophenylacetate hydrochloride salt (10.0 g, 26.7 mmol) is added to the mixture at 0–5° C. After the addition is complete the mixture is warmed to room temperature and stirred for 18 hours. The reaction mixture is then basified with aqueous sodium bicarbonate solution. The organic layer is then washed with aqueous sodium thiosulfate solution, followed by water, then brine. The organic layer is then dried, filtered and concentrated to provide clopidogrel free base as an oily product (8.10 g). The product obtained was found to be identical to the product obtained in Example 1 by 1H-NMR.
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:8][N:7]([CH:9]2[CH2:13][CH2:12][C@@H:11]([CH3:14])[CH2:10]2)[C:6]2[N:15]=[C:16]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][C:21]=3[O:29][CH3:30])[N:17]=[CH:18][C:5]=2[N:4]([CH3:31])[C:3]1=[O:32].[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[F:33][C:2]1([F:1])[CH2:8][N:7]([CH:9]2[CH2:13][CH2:12][C@@H:11]([CH3:14])[CH2:10]2)[C:6]2[N:15]=[C:16]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH:41][CH:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)=[O:26])=[CH:22][C:21]=3[O:29][CH3:30])[N:17]=[CH:18][C:5]=2[N:4]([CH3:31])[C:3]1=[O:32]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CC[C@@H](C)C1)CC(F)(F)C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CC[C@@H](C)C1)CC(F)(F)C(=O)N2C
Reaction time: 0.5 h

Procedure:
To a mixture of the 4-(7,7-difluoro-5-methyl-9-((3R)-3-methylcyclopentyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid, 1-methylpiperidin-4-amine (1.1 equivalent) and DIEA (3-6 equivalent) in 20 mL of anhydrous DMF, was added HATU (1.5 to 2 equivalent). The reaction mixture was stirred for 30 min. The reaction mixture was then diluted with ethyl acetate, washed with water and brine. The organic layer dried over Na2SO4 followed by HPLC purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96-1.06 (m, 3H) 1.06-2.12 (m, 13H) 2.16 (s, 3H) 2.77 (d, J=11.87 Hz, 2H) 3.32 (br. s., 3H) 3.65-3.80 (m, 1H) 3.93 (s, 3H) 3.97-4.12 (m, 2H) 4.73-4.96 (m, 1H) 7.44-7.52 (m, 2H) 7.97 (d, J=6.06 Hz, 1H) 8.12 (d, J=7.83 Hz, 1H) 8.25 (d, 2H). [M+H] calc'd for C28H37F2N7O3 558. found 558.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[CH2:19]([O:26][C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27]1[S:28][C:29]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: c1ccc(COc2cccs2)cc1
Product: CC1(C)CC(Nc2nccc(-c3ccc(OCc4ccccc4)s3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2-benzyloxy-thiophene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:11]([N:13]([CH2:17][CH3:18])[C:14](Cl)=[O:15])[CH3:12]>O1CCCC1>[CH2:11]([N:13]([CH2:17][CH3:18])[C:14](=[O:15])[O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:12]
Reactant: CCN(CC)C(=O)Cl
Reactant: Oc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Oc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a solution of 3-chlorophenol (10 g; 78 mmol) in dry tetrahydrofuran (78 ml) under a nitrogen atmosphere was added sodium hydride (60% in oil) (6.22 g; 156 mmol) in small portions. The reaction was stirred at room temperature for 1 h and diethylcarbamic chloride (19.71 ml; 156 mmol) was slowly added and the reaction was stirred at room temperature for 21 h. The reaction was quenched with water, concentrated under reduced pressure, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (0-40%) in heptane furnished 9.86 g (56%) of 3-chlorophenyl diethylcarbamate.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[CH:13]=2)[O:3]1.[BH4-].[Na+]>CO>[CH3:1][C:2]1([CH3:20])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[OH:19])[CH:13]=2)[O:3]1
Reactant: CC1(C)OB(c2cnn(C3CCCC3=O)c2)OC1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)OB(c2cnn(C3CCCC3O)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclopentanone (W-1) (550 mg, 2 mmol) in methanol (5 mL) was added NaBH4 (150 mg, 4 mmol). The reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo, and the residue was extracted with EtOAc, washed with water, and purified by chromatography on silica gel to afford the title compound (200 mg). MS (m/z): 279 (M+1)+.
Reaction SMILES: [CH:1]12[O:6][CH:2]1[CH2:3][CH2:4][CH2:5]2.[NH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[N:7]1([C@@H:2]2[CH2:3][CH2:4][CH2:5][C@H:1]2[OH:6])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1CC2OC2C1
Reactant: C1CCNCC1
Product: O[C@@H]1CCC[C@H]1N1CCCCC1
Yield: 81 %

Procedure:
The title compound was prepared in 81% yield from cyclopentene oxide and piperidine by essentially following the procedures outlined in Example 20, Part A.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:24]=[CH:25][C:26]=1[C:27]1([OH:30])[CH2:29][CH2:28]1>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:32]([NH:31][C:23]3[CH:24]=[CH:25][C:26]([C:27]4([OH:30])[CH2:28][CH2:29]4)=[C:21]([F:20])[CH:22]=3)=[O:33])=[CH:12][C:11]([C:16]([F:17])([F:18])[F:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1ccc(C2(O)CC2)c(F)c1)Oc1ccccc1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(C2(O)CC2)c(F)c1
Reaction time: 8 h
Yield: 43.2 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (0.141 mg, 0.45 mmol, 1.0 eq) in DCM (5 mL) was added TEA (0.137 mg, 1.35 mmol, 3.0 eq) followed by phenyl 3-fluoro-4-(1-hydroxycyclopropyl)-phenylcarbamate (0.130 mg, 0.45 mmol, 1.0 eq) at RT and stirred overnight. The reaction mixture was diluted with DCM (20 mL), washed with water (10 mL), brine (5 mL), dried over anhydrous Na2SO4 and the solvents evaporated under vacuum. Crude product was purified by CC by using EtOAc/PE (1:1) to get 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(1-hydroxycyclopropyl)-phenyl)urea (0.0912 g; 43%) as pale yellow solid (TLC system: EtOAc/PE (3:1); Rf: 0.45).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1I)=[O:4].CC([O-])=O.[K+].[CH:23]1[CH:28]=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:24]=1>CN(C)C=O.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]([F:17])([F:16])[C:3]([N:5]1[CH2:28][C:23](=[CH2:24])[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(NCCc1ccc(Cl)cc1I)C(F)(F)F
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: C=C1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Temperature: 105 °C
Reaction time: 8 h
Yield: 437.3 %

Procedure:
A solution of N-allyl, N-trifluoroacetyl-2-iodo-4-chlorophenethylamine (0.76 g, 1.8 mmol) in dimethylformamide (20 mL) was treated with KOAc (0.53 g, 5.4 mmol), n-Bu4NBr (0.58 g, 1.8 mmol), PPh3 (0.047 g, 0.18 mmol), Pd(OAc)2 (0.041 g, 0.18 mmol) and stirred overnight at 105° C. The product mixture was cooled to 20° C., filtered, diluted with water (100 mL), extracted with ether (3×100 mL), the combined organic phases washed with water (100 mL), brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (10% EtOAc in hexane, silica) resulted in 0.228 g of a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 7.18 (m, 1H), 7.04 (m, 1H), 5.38 (m, 2H), 5.40 (d, J=16 Hz, 2H), 3.80 (m, 2H), 3.00 (m, 2H). MS calculated for C13H11ClF3NO+H: 290, observed: 290.
Reaction SMILES: C(O[C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[CH2:18]([C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23])[CH2:19][CH3:20]>CS(C)=O>[CH2:18]([C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[CH2:19][CH3:20]
Reactant: CCCc1ccccc1N
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Solvent: CS(C)=O
Product: CCCc1ccccc1Nc1c(Nc2ccccc2O)c(=O)c1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (50 mg, 0.21 mmol) in DMSO (1.5 mL) was added 2-propylaniline (0.030 mL, 0.21 mmol) and reaction was stirred at 110° C. overnight. Reaction was purified on HPLC (acetonitrile:water) and product was concentrated down. Solid was dried in vacuo. LC-MS (m/z) 323 (M+).
Reaction SMILES: [CH:1]1([C:7]2([C:12]3[CH:17]=[C:16]([O:18]C)[CH:15]=[C:14]([O:20]C)[CH:13]=3)[S:11][CH2:10][CH2:9][S:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1(C2C=C(O)C=C(O)C=2)SCCS1)CCC>CCCCCC.C(OCC)(=O)C>[CH:1]1([C:7]2([C:12]3[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([OH:20])[CH:13]=3)[S:8][CH2:9][CH2:10][S:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(OC)cc(C2(C3CCCCC3)SCCS2)c1
Agent: CCCCC1(c2cc(O)cc(O)c2)SCCS1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Oc1cc(O)cc(C2(C3CCCCC3)SCCS2)c1

Procedure:
Compound 18 was prepared from Compound 11 using the same procedure as described above for Compound 16. Yield 0.853 g (62.2%) as a waxy solid. Rf=0.27 (hexane:ethyl acetate 8:2); 1H NMR δ 6.78 (d, J=0.9 Hz, 2H), 6.19 (t, J=1.95 Hz, 1H), 4.14 (br s, 2H), 3.32–3.07 (m, 4H), 2.15–2.06 (m, 1H), 1.96–1.58 (m, 4H), 1.19–1.00 (m, 4H); 13C NMR δ 156.95, 147.94, 107.39, 101.12, 80.58, 60.83, 50.56, 38.82, 30.92, 26.77, 26.24, 21.08, 14.17; MS: (ESI, Neg.) m/z 295 ([M−H]−).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C.[OH:20][CH2:21][CH2:22][NH2:23]>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([S:9]([NH:23][CH2:22][CH2:21][OH:20])(=[O:11])=[O:10])[CH:6]=[N:7][CH:8]=1
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCCO)c1cncc(Br)c1

Procedure:
A cooled (0° C.) solution of 5-bromopyridine-3-sulfonyl chloride hydrochloride (3.00 g, 10.2 mmol) in DCM (50 ml) was slowly treated with triethylamine (4.3 ml) and stirred until a clear solution was obtained. This solution was treated dropwise with 2-hydroxyethylamine (0.68 g, 0.68 mL) and stirred at RT for 16 hours. The reaction mixture was washed successively with water and brine, the organic layer was dried with sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography (silica) eluting with 20% ethyl acetate in petroleum ether, to give the title compound.