Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[N:8]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Clc1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)c(Cl)c1
Product: O=[N+]([O-])c1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1

Procedure:
2-(4-Bromo-benzyl)-4-(2,4-dichlorophenyl)-1H-imidazole (3.27 g, 8.6 mmol) was treated as described in general procedure B using 4-fluoronitrobenzene to provide 2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1H-imidazole, which was treated with 4-hydroxyphenyl boronic acid according to general procedure G to provide 4′-[4-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1H-imidazol-2-ylmethyl]-biphenyl-4-ol (996 mg, 22% for two steps). To a solution of the phenol in THF (0.5 M) was added N-boc-4-hydroxypiperidine (2 eq) and triphenylphosphine (2 eq) under nitrogen, then while sonicating this mixture diisopropyl azodicarboxylate (2 eq) was added. After sonicating 1 hour the reaction mixture was evaporated in vacuo and the reside was purified by silica gel column chromatography to afford 4-{4′-[4-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1H-imidazol-2-ylmethyl]-biphenyl-4-yloxy}-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [OH-].[Na+:2].Cl[C:4]1[S:5][C:6]([Cl:12])=[CH:7][C:8]=1[C:9]([OH:11])=[O:10].[S:13]([O-:16])([OH:15])=[O:14].[Na+]>O>[Cl:12][C:6]1[S:5][C:4]([S:13]([OH:16])(=[O:15])=[O:14])=[C:8]([C:9]([O-:11])=[O:10])[CH:7]=1.[Na+:2]
Reactant: O=S([O-])O
Reactant: O=C(O)c1cc(Cl)sc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1cc(Cl)sc1S(=O)(=O)O
Reaction time: 24 h

Procedure:
59 g. of sodium hydroxide are dissolved in 637 ml. of water. The solution is heated to 90°, and 290.7 g. of 2,5-dichlorothiophene-3-carboxylic acid are added and dissolved by stirring. 156 g. of sodium hydrogen sulfite dissolved in 430 ml. of water is added to the solution and the pH thereof is adjusted to 7.5-7.7 with approximately 167 ml. of 30% caustic soda. 12 g. of finely powdered cuprous chloride are added to the clear solution, which is then boiled for 24 hours under reflux. The solution is filtered hot from the copper oxide and the filtrate is acidified with 400 ml. of concentrated HCl and cooled to 5°. The precipitate that has separated out is suction filtered without rewashing and dried in vacuo at 110° to constant weight. The precipitate is then boiled up with 3×500 ml. portions of methylene chloride. The residue is dried at 70° in vacuo, and sodium 5-chloro-2-sulfothiophene- 3-carboxylate is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=O)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[NH:9]2)=[C:4]([F:18])[CH:3]=1.C(Cl)([Cl:21])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([Cl:21])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[C:4]([F:18])[CH:3]=1
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1F)CCCC2
Reactant: O=C(Cl)Cl
Product: Fc1cc(Cl)ccc1-n1nc2c(c1Cl)CCCC2
Temperature: 140 °C
Reaction time: 1 h

Procedure:
Fifty parts of 2-(4-chloro-2-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-indazol-3-one and 26 parts of mixed xylenes were charged to a 3-neck, round-bottomed flask fitted with a mechanical stirrer, dry ice condenser, an addition funnel with a gas inlet and dry ice condenser above it. The mixture was heated to 140° C with agitation under a nitrogen atmosphere. Phosgene was condensed into the addition funnel from a pressurized cylinder, and 20.9 parts of phosgene was added dropwise over several minutes. After 1 hour, the temperature of the reaction mixture was raised to 150° and held there for 2 hours. The solvent was then removed by vacuum distillation and the melted product was poured into a dish and allowed to cool. There was obtained 52.1 parts of 2-(4-chloro-2-fluorophenyl)-3-chloro-4,5,6,7-tetrahydro-2H-indazole, m.p. 72°-80° (70.3% pure as determined by gas chromatography).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[NH:2]2.[NH2:15][C:16]1[S:17][C:18]([C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[C:19]([C:21](O)=[O:22])[N:20]=1>>[NH2:15][C:16]1[S:17][C:18]([C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[C:19]([C:21]([N:2]2[C@H:3]([CH2:7][NH:8][C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:22])[N:20]=1
Reactant: Cc1cccc(-c2sc(N)nc2C(=O)O)c1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)C(F)(F)F
Product: Cc1cccc(-c2sc(N)nc2C(=O)N2[C@H](CNC(=O)C(F)(F)F)C[C@@H]3C[C@@H]32)c1

Procedure:
prepared by reaction of N-[(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-2,2,2-trifluoro-acetamide with 2-amino-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (acidic): tR=0.87 min; [M+H]+=425.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH2:14][CH2:13][CH:12]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:11][CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: COc1ncccc1C1=CCC(=O)CC1
Product: COc1ncccc1C1=CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
The title compound was prepared as a white solid from reductive amination of 4-(2-methoxy-pyridin-3-yl)-cyclohex-3-enone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH2:11][CH2:12][O:13][C:14]1[C:24]2[CH2:23][CH2:22][N:21]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:20][CH2:19][C:18]=2[CH:17]=[CH:16][C:15]=1[Cl:31]>C(Cl)Cl>[Cl:31][C:15]1[CH:16]=[CH:17][C:18]2[CH2:19][CH2:20][N:21]([C:25](=[O:30])[C:26]([F:28])([F:27])[F:29])[CH2:22][CH2:23][C:24]=2[C:14]=1[O:13][CH2:12][CH2:11][NH:10][C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9]
Reactant: O=C=Nc1ccccc1
Reactant: NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Solvent: ClCCl
Product: O=C(NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)Nc1ccccc1

Procedure:
Combine phenyl isocyanate (16.3 mg, 0.137 mmol), 6-(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (46 mg, 0.137 mmol) in DCM (1.5 mL) and stir at ambient temperature for 16 h. Concentrate in vacuo. Purify by reverse phase HPLC (10-95% of solvent B in 12.8 min, 25 mL/min; solvent A: water, 0.1% trifluoroacetic acid; solvent B: acetonitrile, 0.1% trifluoroacetic acid; column: YMC SH-341-5, S-5μm, 12 nm, 100×20 mm) to give 7-chloro-6-[2-(3-phenyl-ureido)-ethoxy]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: CNOC
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1cc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.2 %

Procedure:
A solution of 2-amino-5-chlorobenzoic acid (5.0 g, 29.1 mmol), N,O-dimethylhydroxylamine hydrochloride (3.1 g, 32.0 mmol), and HOBt (3.9 g, 29.1 mmol) in CH2Cl2 (100 mL) was cooled to 0° C. and treated with EDCI (17.3 g, 87.3 mmol). The reaction was stirred at 25° C. for 12 h, diluted with H2O, and extracted with EtOAc. The organics were dried (Na2SO4), filtered, and concentrated. Chromatography (SiO2, 1:1 Hex/EtOAc) gave 8 (3.7 g, 60%) as a white solid.
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([CH2:17][O:18][C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:31])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:31])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1c[nH]c2c(COC(=O)c3ccc(OC)cc3)cccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCC(=O)c1cnc2c(COC(=O)c3ccc(OC)cc3)cccc2c1Cl

Procedure:
A solution of 3-butyryl-8-(4-methoxybenzoyloxymethyl)-4(1H)-quinolone (5.75 g, 15.1 mmol) in phosphoryl chloride (75 ml) was heated at reflux for 30 minutes, the phosphoryl chloride evaporated in vacuo, the residue poured onto ice, neutralised with sodium bicarbonate, and extracted into dichloromethane. Drying, evaporation, and trituration with ether gave the crude 3-butyryl-4-chloro-8-(4-methoxy-benzoyloxymethyl)quinoline, which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][NH2:9])=[O:7])#[N:2].C1COCC1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>CN(C=O)C>[Cl:18][CH2:19][C:20]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: N#Cc1cccc(C(=O)NN)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1cccc(C(=O)NNC(=O)CCl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
3-cyanobenzohydrazide (1.6 g, 10.0 mmol) was added to THF (40 ml) and DMF (10 ml). TEA (1.4 ml, 10.0 mmol) was added at 0° C. followed by chloroacetyl chloride (1.0 ml, 12.6 mmol) and the reaction mixture was stirred at 0° C. for 1 h and at rt for 2 h. The THF was evaporated, water was added to the remaining mixture, followed by filtratation over celite and purification with prep. HPLC to give the title compound (1.6 g, 69%). 1H NMR (DMSO-d6): 10.62 (br s, 2 H), 8.28 (m, 1 H), 8.18 (m, 1 H), 8.08 (m, 1 H), 7.75 (t, 1 H), 4.22 (s, 2 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][S:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])([O-:3])=[O:2].[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][S:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH:11][S:28]([C:20]1[O:19][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=1)(=[O:29])=[O:30])([O-:3])=[O:2]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: Nc1ccccc1SCc1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(CSc2ccccc2NS(=O)(=O)c2cc3ccccc3o2)c1
Yield: 41.4 %

Procedure:
Following General Procedure B, the title compound (520 mg, 41%) was prepared from 2-((3-nitrobenzyl)thio)aniline (741 mg, 2.85 mmol), benzofuran-2-sulfonyl chloride (616 mg, 2.85 mmol) in pyridine (10 ml).
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>N.CO>[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c4c(ccc32)OCCNC4)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28.6 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 4-Methylbenzenesulfonyl chloride (19 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (4.9 mg). MS m/z 343 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][NH2:8])[CH:3]=1.[C:9]([N:13]1[C:17](=[O:18])[C:16](Cl)=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:14]1(=[O:27])=[O:26])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([N:13]1[C:17](=[O:18])[C:16]([NH:8][CH2:7][C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:14]1(=[O:26])=[O:27])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Cc1cc(CN)no1
Product: Cc1cc(CNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)no1
Yield: 56 %

Procedure:
The title compound was prepared as described for Example 24 from 1 equivalent of [(5-methylisoxazol-3-yl)methyl]-amine, 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1 equivalent TEA with a reaction time of 45 mins. The mixture was evaporated and purified by silica gel column chromatography (Horizons Biotage) using 35% EtOAc in pentane as eluent to give the title compound (0.070 g, 56%). 1H NMR (500 MHz CDCl3): δ 7.52-7.48 (m, 2H), 7.46-7.41 (m, 3H), 5.73 (s, 1H), 5.66 (t, 1H), 5.07 (d, 2H), 2.39 (s, 3H), 1.74 (s, 9H); 13C N (125 MHz CDCl3): δ 170.7, 159.9, 159.4, 134.8, 131.6, 130.1, 128.9, 124.7, 109.3, 100.4, 61.9, 40.4, 27.8, 12.5; Mass Spectrum: M+H+ 376
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:20]([NH2:22])=[O:21].[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=O)=[CH:26][CH:25]=1>>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[NH:22][C:20](=[O:21])[C:3]3[CH:4]=[N:5][N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:2]=3[N:1]=2)=[CH:26][CH:25]=1
Reactant: CC(O)C(CCCc1ccccc1)n1ncc(C(N)=O)c1N
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Product: CC(O)C(CCCc1ccccc1)n1ncc2c(=O)[nH]c(Cc3ccc(Br)cc3)nc21

Procedure:
Starting from 2.1 g (6.95 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-pyrazole-4-carboxamide and 4.05 mg (17.38 mmol) of 4-bromophenylacetyl chloride, the title compounds are prepared analogously to the protocol of Example 13. This gives 594 mg (18%) of the diastereomer which elutes more rapidly, M.p.: 117° C., and 372 mg (11%) of the diastereomer which elutes more slowly, M.p.: 116° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C@H:9]([NH:20][CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[CH2:8][C@@H:7]1[CH2:36][CH3:37])=[O:5])[CH3:2].N1C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:17])([F:18])[F:19])=[CH:13][CH:14]=2)[C@H:9]([N:20]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[C:24]([C:32]([F:35])([F:33])[F:34])[CH:23]=2)[C:4]([O:3][CH3:1])=[O:5])[CH2:8][C@@H:7]1[CH2:36][CH3:37])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 162 %

Procedure:
A solution of cis4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethy1-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (2.0 g, 3.7 mmol) and pyridine (0.58 g, 7.4 mmol) in 100 mL of dichloromethane was cooled in an icewater bath as methyl chlorofomate (0.87 g, 9.2 mmol) was added slowly. After stirring overnight at room temperature, the reaction mixture was washed twice with a 2N hydrochloric acid solution, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude product, which was purified by silica gel chromatography using 5-10% ethyl acetate/hexanes as eluent to afford 1.8 g of the title product. MS m/z 601 (M++1); 1H NMR (coalescing mixture of conformers, CDCl3) δ0.6-0.8 (bm, 3H), 1.2-1.3 (bm, 3H), 1.3-1.5 (bm, 2H), 1.6-1.75 (bm, 1H), 2.1-2.3 (bm, 1H), 3.7-3.9 (bs, 3H), 4.0-4.4 (bm, 4H), 5.0-5.6 (bm, 2H), 7.1 (s, 1H), 7.4-7.6 (bm, 2H), 7.6-7.8 (bm, 3H). [2R,4S]-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl -trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester was prepared in optically enriched form by resolution of the corresponding racemate, or an intermediate in its synthesis, using standard methods.
Reaction SMILES: [Cl:1][CH2:2][C:3]1([CH3:10])[CH2:7][N:6]([CH3:8])[C:5](=[O:9])[NH:4]1.C(O[Cl:16])(C)(C)C>CO>[Cl:16][N:4]1[C:3]([CH2:2][Cl:1])([CH3:10])[CH2:7][N:6]([CH3:8])[C:5]1=[O:9]
Reactant: CN1CC(C)(CCl)NC1=O
Reactant: CC(C)(C)OCl
Solvent: CO
Product: CN1CC(C)(CCl)N(Cl)C1=O
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A solution of 4-(chloromethyl)-1,4-dimethylimidazolidin-2-one (204 mg, 1.25 mmol) in MeOH (2.5 ml) was cooled to 0° C. tert-Butylhypochlorite (177 ul, 1.57 mmol) was added. The resulting solution was stirred for 60 min, during which time a white precipitate formed. The reaction mixture was concentrated under reduced pressure to half its initial volume and the solid was collected on a glass fritted filter and washed with water to give 168 mg of desired product (69% yield). 1H NMR (400 MHz, CDCl3) δ1.48 (s, 3H), 2.90 (s, 3H), 3.21-3.23 (d, J=8.8 Hz, 1H), 3.52-3.54 (d, J=8.9 Hz, 1H), 3.59-3.67 (q, J=11.1 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 19.9, 31.7, 47.6, 54.5, 63.1, 158.7. LRMS (ESI/APCI): 197 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([NH2:25])[CH:20]=1>O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:19]3[CH:20]=[C:21]([NH2:25])[N:22]=[CH:23][N:24]=3)=[CH:13][CH:12]=2)[CH2:4][CH2:3]1
Reactant: Nc1cc(Cl)ncn1
Reactant: CN1CCN(CCOc2ccc(N)cc2)CC1
Solvent: O
Product: CN1CCN(CCOc2ccc(Nc3cc(N)ncn3)cc2)CC1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
The title compound is prepared as described in Example 152A but using 4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylamine (300 mg, 1.28 mmol, 1 eq.), 6-chloro-pyrimidin-4-ylamine, water (0.5 ml), and stirring the reaction mixture for 2 h at 150° C. The crude product is purified by trituration in diethyl ether to afford the title compound as a white solid. ESI-MS: 329.1 [MH]+; tR=0.98 min (purity: 100%, gradient J).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:10]=[C:11]3[C:16]([N:17]4[CH2:22][CH:21]5[CH2:23][CH:18]4[CH2:19][NH:20]5)=[N:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:10]=[C:11]3[C:16]([N:17]4[CH2:22][CH:21]5[CH2:23][CH:18]4[CH2:19][N:20]5[S:39]([CH3:38])(=[O:41])=[O:40])=[N:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc(-c2c3ncnc(N4CC5CC4CN5)c3nn2-c2ccccc2Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC2CC1CN2c1ncnc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Yield: 101.9 %

Procedure:
A solution of Rac-(S,S)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine 4A-1 (63 mg, 0.12 mmol) in dichloromethane (2 ml) was charged with triethylamine (0.1 ml). Methanesulfonyl chloride (0.01 ml, 0.14 mmol) was added via syringe, and the resultant mixture was stirred at 23° C. for 3 days. The reaction mixture was then washed with water (2 ml) and the layers were separated. The organic solution was dried over anhydrous magnesium sulfate and concentrated. Purification of the residue by reverse-phase HPLC afforded Rac-(S, S)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine 6A-1 (63 mg, quantitative): MS: 515.0 (M+1)+; 1H NMR (400 MHz, CD3OD) δ 8.3 (s, 0,5H), 8.1 (s, 0.5H), 7.6 (m, 4H), 7.4 (m, 4H), 6.1 (s, 0.5H), 5.2 (s, 0.5H), 4.7 (m, 1H), 4.4 (m, 0.5H), 4.2 (m, 0.5H), 4.0 (m, 1H), 3.8 (m, 1H), 3.5 (m, 3H), 3.0 (s, 3H).
Reaction SMILES: CCOCC.C1COCC1.[F:11][C:12]([F:20])([F:19])[C:13](=[O:18])[CH:14]=[C:15]([CH3:17])[CH3:16].[F:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1>[Cu]I.CCOCC>[F:11][C:12]([F:20])([F:19])[C:13](=[O:18])[CH2:14][C:15]([C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=1)([CH3:17])[CH3:16]
Reactant: CC(C)=CC(=O)C(F)(F)F
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(CC(=O)C(F)(F)F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 2 M ether/THF solution of the above 1,1,1-trifluoro-4-methylpent-3-en-2-one was added 3.8 g of CuI and 10 mL of 2 M ether solution of 4-fluorophenylmagnesium bromide at 0° C. The mixture was warmed to room temperature and stirred for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc three times. The combined organic layers were washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to yield 460 mg of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]=2[S:8][C:7]=1[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:40][S:41]([O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:9]=2[S:8][C:7]=1[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)c(Cc3cccc4ccccc34)sc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCOS(C)(=O)=O)c(Cc3cccc4ccccc34)sc21
Reaction time: 8 h

Procedure:
5-[(3-Hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (Example 4) (403 mg) was dissolved in dichloromethane (6 ml). Triethylamine (300 μl) was added followed by methanesulfonyl chloride (150 μl) and the mixture was stirred overnight. Sodium bicarbonate (aqueous) was added and the phases were separated. The aqueous phase was extracted twice with dichloromethane, the organic phases were combined, washed with brine, dried, filtered and evaporated to give the subtitle compound (0.57 g).
Reaction SMILES: [C:1]([O:7][CH:8]([C:13]([Cl:16])([Cl:15])[Cl:14])[CH:9]=[C:10]([CH3:12])[CH3:11])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(N(CC)CC)C.S(N=[N+]=[N-])([N:27]=[N+:28]=[N-])(=O)=O>C(#N)C>[N+:27](=[C:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH:8]([C:13]([Cl:14])([Cl:15])[Cl:16])[CH:9]=[C:10]([CH3:11])[CH3:12])=[O:6])=[N-:28]
Reactant: [N-]=[N+]=NS(=O)(=O)N=[N+]=[N-]
Reactant: CC(=O)CC(=O)OC(C=C(C)C)C(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)C(=[N+]=[N-])C(=O)OC(C=C(C)C)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of 1-trichloromethyl-3-methyl-2-butenyl acetoacetate (0.575 g, 2 mmole) and triethylamine (0.404 g, 4 mmole) in 10 ml of acetonitrile was added 1 g of polymer-bound sulfonyl azide (prepared by the method of Roush, et al., loc. cit.). The mixtre was stirred overnight at room temperature and filtered. The filter cake was washed with ether, and the slurry was filtered. Solvent was removed by evaporation from the combined filtrates to give 1-trichloromethyl-3-methyl-2-butenyl 2-diazoacetoacetate (0.60 g, 96% yield).