Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[N:24](OCCCC)=[O:25].C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.O>[N:24]([N:12]1[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][CH2:8][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:25]
Reactant: CCCCON=O
Reactant: c1ccc(C2COc3ccccc3N2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=NN1c2ccccc2OCC1c1ccccc1
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a mixture of 3-phenyl-3,4-dihydro-2H-1,4-benzoxazine (17 g, 80.5 mmol) in ethyl ether (100 mL) is added trifluoroacetic acid (6.2 mL 80.5 mmol). The resulting solution is chilled to 5° C. in an ice bath, to which n-butyl nitrite (9.4 mL 80.5 mmol) is added dropwise. The mixture is stirred for 1 h and transferred to a separatory funnel to which is slowly added potassium carbonate (2.6 g, 18.8 mmol) in water (200 mL). Solids formed in the ether layer. The layers are separated and ethyl ether (100 mL) is added to dissolve the solids. The ether layer is washed twice with water (200 mL), dried over magnesium sulfate, filtered and concentrated. The resulting oil is chilled in the refrigerator overnight. The solids formed from the oil are ground-up in hexanes and collected by filtration to give 15.7 g (81%) of 4-nitroso-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine.
Reaction SMILES: Cl[C@H:2]1[C@H:6]([Cl:7])[C:5]2[CH:8]=[CH:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:4]=2[O:3]1.[C:16]([O-])([O-])=O.[K+].[K+]>CCO>[Cl:7][C:6]1[C:5]2[CH:8]=[CH:9][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:11][C:4]=2[O:3][CH:2]=1
Reactant: COC(=O)c1ccc2c(c1)O[C@@H](Cl)[C@@H]2Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1ccc2c(Cl)coc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
trans-Methyl 2,3-dichloro-2,3-dihydro-1-benzofuran-6-carboxylate (58 mg, 0.23 mmol) is dissolved in EtOH (2 ml), treated with K2CO3 (187 mg, 1.35 mmol) and stirred at RT overnight. The mixture is concentrated to dryness, the residue is dissolved in 50% saturated NaCl (10 ml) and extracted with CH2Cl2 (3×10 ml). The combined organics are dried (K2CO3), filtered, and concentrated in vacuo to a yellow oil. The crude material is chromatographed over 10 g slurry-packed silica gel, eluting with 25% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 30 mg (58%) of ethyl 3-chloro-1-benzofuran-6-carboxylate as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.44, 4.43, 7.66, 7.79, 8.07, 8.21 ppm.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([S:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH2:30]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:25]=3)[NH:20][N:19]=2)(=[O:17])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.O>CN(C=O)C>[N:1]([CH2:30][CH2:29][CH2:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[S:15]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)(=[O:16])=[O:17])=[N+:2]=[N-:3]
Reactant: Cc1ccc(S(=O)(=O)OCCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCOc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 87.5 %

Procedure:
Sodium azide (0.425 g, 6.54 mmol) was added to a solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (1.16 g, 2.16 mmol) in DMF (20 mL). The reaction mixture was stirred at 80° C. for 15 hours in a sealed tube. After cooling to ambient temperature, it was poured into excess water and extracted with ethyl acetate. The organic phase was washed with 10% ammonium chloride/water solution, water and brine. It was dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 73° C. in vacuo for 45 minutes to yield 5-(3-azido-propoxy)-3-(naphthalene-1-sulfonyl)-1H-indazole as an amber gum (0.770 g, 87.7%); Mass Spectrum (−EI, [M−H]−) m/z 406. 1HNMR (400 MHz, DMSO-d6): δ14.05 (br, 1H), 8.64-8.68 (m, 1H), 8.53 (dd, 1H, J=7.42 Hz and 1.16 Hz), 8.25-8.28 (m, 1H), 8.01-8.05 (m, 1H), 7.70-7.74 (m, 1H), 7.52-7.64 (m, 3H), 7.26 (d, 1H, J=2.08 Hz), 7.08 (dd, 1H, J=9.16 Hz and 2.32 Hz), 4.06 (t, 2H, J=6.14 Hz), 3.49-3.52 (m, 2H), 1.96-1.99 ppm (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13](=[O:31])[CH:14]=[C:15]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C(O)(=O)C.[Fe]>[CH3:1][CH:2]([NH:12][C:13](=[O:31])[CH:14]=[C:15]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC(C)NC(=O)C=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: CCCCCCCCCC(C)NC(=O)C=C(c1ccccc1)c1ccc(N)cc1

Procedure:
Reduction of 6.4 g. of N-(1-methyldecyl)-3-phenyl-3-(4-nitrophenyl)propenamide with 4.2 g. of iron powder in glacial acetic acid, according to the procedure of Preparation 25, afforded the title compound as an oil. This product was chromatographed on 220 g. of silica gel, eluting with 1:1 ethyl acetate-hexane containing 2% triethylamine. This gave 2.0 g. of trans-N-(1-methyldecyl)-3-phenyl-3-(4-aminophenyl)propenamide and 2.5 g. of cis-N-(1-methyldecyl)-3-phenyl-3-(4-aminophenyl)propenamide. The NMR spectrum of the trans-isomer (in CDCl3) showed absorptions at 0.90 (m), 1.20 (s), 3.80 (b), 5.15 (b), 6.30 (s), 6.85 (m) and 7.30 (s) ppm.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9]2.[CH3:18]I>C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([CH3:18])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9]2
Reactant: CCOC(=O)c1cc2cccc(F)c2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cccc(F)c2n1C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (73.2% dispersion in oil; 962 mg) in dry THF (50 ml) under nitrogen at 0° was added ethyl 7-fluoro-1H-indole-2-carboxylate (5.5 g) in dry THF (50 ml), and the mixture was stirred for 1 h. Methyl iodide (2.16 ml) was added, and the mixture was stirred for 2 h, then at 50° for 3 h. The mixture was quenched with 10% aqueous THF (5 ml), diluted with ether (500 ml), washed with saturated brine solution (2×500 ml), dried and evaporated in vacuo to leave an oil. This was purified by FCC eluting with hexane:ether (20:1) to give the title compound (4.53 g) as a liquid, t.l.c. (hexane:ether, 20:1) Rf 0.37.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>>[ClH:23].[Br:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2Br)CC1
Agent: Cl
Product: O=C(c1ccccc1Br)N1CCNCC1
Reaction time: 4 h
Yield: 95 %

Procedure:
HCl (50 mL) was added to 4-(2-bromo-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (9 g, 24.4 mmol) at 0° C. The resulting mixture was stirred for 4 hours, then concentrated. The resulting residue was washed with 1% MeOH in ethyl acetate and dried under reduced pressure to afford 7.1 g (95%) of (2-bromo-phenyl)-piperazin-1-yl-methanone hydrochloride salt, LCMS: 306.6 (M+1)+, 86.8%, 1H NMR: (DMSO-d6): δ 9.6 (s, 2H), 7.7 (d, 1H), 7.45 (m, 3H), 4.0 (m, 1H), 3.76 (m, 1H), 3.18 (bs, 2H), 3.06 (bs, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH:11]([C:18]1[N:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:20]2[C:25]([C:26](=[O:28])[CH:27]=1)=[C:24]([CH3:29])[CH:23]=[C:22]([Cl:30])[N:21]=2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[Cl:30][C:22]1[N:21]=[C:20]2[C:25]([C:26](=[O:28])[CH:27]=[C:18]([N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:10])[N:19]2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:24]([CH3:29])[CH:23]=1
Reactant: Cc1cc(Cl)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: Cc1cc(Cl)nc2c1c(=O)cc(N(C(=O)Nc1ccc(F)cc1)c1ccccc1)n2-c1ccccc1
Reaction time: 16 h
Yield: 1.6 %

Procedure:
4-Fluorophenyl isocyanate (45.0 mg, 0.33 mmol) was added to a stirred solution of 2-anilino-7-chloro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.276 mmol) in CH2Cl2 (3 mL). After 16 h, an additional equivalent of 4-fluorophenyl isocyanate (45.0 mg) was added, and the reaction stirred for an additional 16 h. The reaction was concentrated in vacuo and the residue was dissolved in EtOAc. The solution was washed with 1 N HCl, dried over MgSO4, and concentrated in vacuo. Purification of the residue using reverse phase prep-HPLC afforded N-(7-chloro-5-methyl-4-oxo-1-phenyl-1,4-dihydro-1,8-naphthyridin-2-yl)-N′-(4-fluorophenyl)-N-phenylurea (2.2 mg, 1.6%): LCMS RT: 3.47 min, MH+: 499.1, Rf=0.52 (1:1 EtOAc:Hex).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](S(C)(=O)=O)[N:29]=3)=[C:26]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[C:25](=[O:45])[N:24]2[CH3:46])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([O:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:29]=3)=[C:26]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[C:25](=[O:45])[N:24]2[CH3:46])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)c(-c2ccnc(S(C)(=O)=O)n2)n1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)c(-c2ccc(F)cc2)c(-c2ccnc(Oc3ccccc3)n2)n1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of phenol (0.11 g, 1.16 mmol) in THF (5 mL) is added NaH (0.024 g of a 60% dispersion in mineral oil, 0.58 mmol). After stirring for 5 min at room temp, a solution of 4-[4-(4-fluorophenyl)-2-methyl-5-(2-methanesulfonyl-pyrimidin-4-yl)-3-oxo-2,3-dihydro-pyrazol-1-yl]-piperidine-1 carboxylic acid tert-butyl ester, 12, (0.154 g, 0.29 mmol) in THF (3 mL) is added all at once. The reaction mixture is stirred at room temp for 14 hours and then quenched by pouring into aqueous saturated NaHCO3 solution. The aqueous phase is extracted three times with CH2Cl2, the combined organic phases washed with saturated sodium bicarbonate, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was used without further purification in the next step.
Reaction SMILES: Cl.Cl[CH2:3][C:4]([O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:5].[C:15]1([C:21]2[NH:22][C:23](=[S:32])[O:24][C:25]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:21]2[N:22]=[C:23]([S:32][CH2:3][C:4]([O:6][CH2:7][CH2:8][N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[O:5])[O:24][C:25]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(CCl)OCCN1CCOCC1
Reactant: S=c1[nH]c(-c2ccccc2)c(-c2ccccc2)o1
Agent: Cl
Product: O=C(CSc1nc(-c2ccccc2)c(-c2ccccc2)o1)OCCN1CCOCC1

Procedure:
A 7.3 g aliquot of the thus prepared 2-morpholinoethyl chloroacetate hydrochloride was then reacted according to the procedure of Example 1 with 7.6 g 4,5-diphenyl-4-oxazolin-2-thione to give 2.4 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:16][C:15](OC)([O:17]C)[C:13]=2[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1.O.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:16][C:15](=[O:17])[C:13]=2[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1(OC)Cc2ccc(OCc3ccccc3)cc21
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1Cc2ccc(OCc3ccccc3)cc21
Reaction time: 1 h

Procedure:
H7.1 (270 mg, 1.00 mmol) was dissolved in 6 mL 5:1 THF and water. To this solution was added 0.5 mL 1N HCl, and the resulting mixture was stirred for 1 hour. The resulting mixture was then diluted with 20 mL EtOAc and washed with saturated NaHCO3 and brine. The organic layer was dried over MgSO4, filtered, and concentrated in the presence of silica gel. The residue was then purified by column chromatography with 10% EtOAc/hexane to afford H7.2 (204 mg, yield, 91.1%). MS ESI (pos.) m/e: 225.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]([CH3:43])([CH3:42])[CH2:29][S:30]([CH2:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1)(=[O:32])=[O:31].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:13])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:39][CH2:38][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][S:30]([CH2:29][C:28]([CH3:43])([CH3:42])[CH3:27])(=[O:32])=[O:31])=[CH:41][CH:40]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(C)(C)CS(=O)(=O)Cc1ccc(CN)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)CS(=O)(=O)Cc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Temperature: 90 °C
Yield: 77.2 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (639 mg, 1.50 mmol) with 4-(2,2-dimethyl-propanesulfonylmethyl)-benzylamine (479 mg, 1.88 mmol), using tris(dibenzylideneacetone)dipalladium(0) (137 mg, 0.15 mmol), BINAP (187 mg, 0.3 mmol) and cesium carbonate (977 mg, 3 mmol) in toluene (20 mL). Heat the mixture at 90° C. overnight. Cool the mixture to room temperature and purify by chromatography on silica gel (80 g) eluting with hexane/EtOAc (1:0 to 4:1 gradient over 15 min; 50 mL/min) to give 7-chloro-6-[4-(2,2-dimethyl-propanesulfonyl-methyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (615 mg, 77%). MS (APCI+) m/z: 531 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:31])[N:14]([CH3:30])[N:15]=[C:16]([CH2:28][OH:29])[C:17]=1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:41][O:42][CH2:43]Cl.C(=O)([O-])O.[Na+]>C1COCC1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:31])[N:14]([CH3:30])[N:15]=[C:16]([CH2:28][O:29][CH2:41][O:42][CH3:43])[C:17]=1[S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)(=[O:20])=[O:19])[CH3:2]
Reactant: COCCl
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(=O)(=O)c2ccc(C)cc2)c(CO)nn(C)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C)cc(CC)c1-c1c(S(=O)(=O)c2ccc(C)cc2)c(COCOC)nn(C)c1=O
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a solution of 4-(2,6-diethyl-4-methylphenyl)-6-hydroxymethyl-5-(4-methylphenylsulfonyl)-2-methyl-3(2H)-pyridazinone (2.40 g, 5.45 mmol) and diisopropylethylamine (10 ml, 57.4 mmol) in THF (20 ml) was added chloromethyl methyl ether (2.4 ml, 31.6 mmol), and refluxed for 4 hours. After the reaction solution was cooled to room temperature, to the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate 2 times. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 2.11 g of 4-(2,6-diethyl-4-methylphenyl)-6-methoxymethoxymethyl-5-(4-methylphenylsulfonyl)-2-methyl-3(2H)-pyridazinone (yield: 80%) as solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=4[F:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:34][NH2:35]>>[CH3:34][NH:35][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=3[F:29])[C:15]=2[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(F)(F)F)cc(-c4cccc(F)c4F)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(C(F)(F)F)cc(-c3cccc(F)c3F)c2O1

Procedure:
The title compound was prepared (0.015 g, 19%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(2,3-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.12 g, 3.9 mmol). mp 123-125° C.
Reaction SMILES: [N:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:23]([CH2:30][CH2:31][CH3:32])[CH2:24][C:25]([O:27]CC)=[O:26].[O-]CC.[Na+].O>C(O)C>[C:14]1([CH2:13][CH2:12][CH2:11][NH:10][C:8]([C:7]2[CH:20]=[CH:21][C:4]([N:1]3[C:23]([CH2:30][CH2:31][CH3:32])=[C:24]([C:25]([OH:27])=[O:26])[N:3]=[N:2]3)=[CH:5][CH:6]=2)=[O:9])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: [N-]=[N+]=Nc1ccc(C(=O)NCCCc2ccccc2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
The pale-yellow solid of 4-azido-N-(3-phenylpropyl)benzamide obtained in Example 60a) and ethyl 3-oxohexanoate (1.08 ml, 6.43 mmol, 1.25 eq.) were dissolved in ethanol (20 ml), sodium ethoxide (486 mg, 6.43 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 10 min, and then at 60° C. for 13 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, washed with ethyl acetate-hexane (1:1, 30 ml), acidified with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a grayish white powder (1.99 g, 5.07 mmol, 98.7%)
Reaction SMILES: [CH:1]12[CH2:7][CH:6]1[CH2:5][CH:4]([C:8]([NH:10][C:11]1([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:13][CH2:12]1)=[O:9])[NH:3][CH2:2]2.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br.C([O-])([O-])=O.[Cs+].[Cs+]>>[F:24][C:25]([F:34])([F:35])[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:3]1[CH:4]([C:8]([NH:10][C:11]2([C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=3)[CH2:12][CH2:13]2)=[O:9])[CH2:5][CH:6]2[CH:1]([CH2:7]2)[CH2:2]1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC4CC4CN3)CC2)cc1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1ccc(C2(NC(=O)C3CC4CC4CN3Cc3cccc(C(F)(F)F)c3)CC2)cc1
Yield: 74.8 %

Procedure:
The title compound (D141) (53 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-(1-(3-azabicyclo[4.1.0]heptane-4-carboxamido)cyclopropyl)benzoate (diastereoisomers mixture) (D100) (48 mg, 0.15 mmol) and 3-(Trifluoromethyl)benzyl bromide (0.040 ml, 0.17 mmol). (Cs2CO3:2 eq; reaction time: 4 hrs; reaction temperature: RT.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([OH:9])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:44][C:45]([F:56])([F:55])[C:46]1[CH:47]=[C:48]([C@@H:52]([NH2:54])[CH3:53])[CH:49]=[CH:50][CH:51]=1>CN(C=O)C.[Cl-].[NH4+]>[F:44][C:45]([F:55])([F:56])[C:46]1[CH:47]=[C:48]([C@@H:52]([NH:54][C:7]([C:3]2[CH:4]=[N:5][NH:6][C:2]=2[CH3:1])=[O:9])[CH3:53])[CH:49]=[CH:50][CH:51]=1
Reactant: C[C@H](N)c1cccc(C(F)(F)F)c1
Reactant: Cc1[nH]ncc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1[nH]ncc1C(=O)N[C@@H](C)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83.6 %

Procedure:
To 5-methyl-1H-pyrazole-4-carboxylic acid (390 mg, 3.1 mmol) in DMF (10 mL) is added triethylamine (1.2 mL, 9.4 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (PyBOP) (1.8 g, 3.5 mmol). After stirring for 5 min at room temperature, (S)-1-(3-trifluoromethyl-phenyl)-ethylamine (650 mg, 3.4 mmol) is added and the reaction is stirred at room temperature for 2 days. The mixture is then diluted with saturated ammonium chloride and extracted with EtOAc (4×15 mL). The combined organic layer is washed with saturated NaHCO3 solution (20 mL) followed by brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material is purified by flash chromatography on silica gel (eluted with 0 to 60% EtOAc/hexanes) followed by recrystallization from ether/hexanes to provide 5-methyl-1H-pyrazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-ethyl]-amide as a colorless solid (770 mg, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5](=[O:8])[NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[O:15]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C(#N)C>[CH3:1][O:2][C:3]1[N:4]([CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:23]=2)[C:5](=[O:8])[NH:6][N:7]=1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: COc1n[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1n[nH]c(=O)n1Cc1cccc(Oc2ccccc2)c1
Reaction time: 5.5 h
Yield: 18.2 %

Procedure:
To a solution of 575 mg (5 mmol) of 5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one in 7 ml of dry acetonitrile was added 726 mg (5.25 mmol) of potassium carbonate was added. A solution of 1.32 g (5 mmol) of 3-phenoxybenzylbromide in 9 ml of dry acetonitrile was added dropwise thereto at 55° C. After the mixture was stirred at the same temperature for additional 5.5 hours, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. To the resultant solid residue (1.36 g) was added a mixture of equal amounts of tert-butyl methyl ether and n-hexane. The mixture was cooled and the deposited solid was washed, ice-cooled, collected by filtration, and dried to obtain a residue. The residue was recrystallized from tert-butyl methyl ether to obtain 0.27 g of 5-methoxy-4-(3-phenoxybenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one as white powder.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[CH:12]([CH:14]=[CH2:15])=[O:13].O>C1COCC1.C(N(CC)CC)C>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([S:9][CH2:15][CH2:14][CH:12]=[O:13])=[CH:7][CH:8]=1
Reactant: C=CC=O
Reactant: FC(F)(F)c1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=CCCSc1ccc(C(F)(F)F)cc1
Yield: 99.6 %

Procedure:
Ten grams of 4-trifluoromethylthiophenol was dissolved in 15 ml of THF, and after adding 4.0 g of 95% acrolein under ice-cooling, 0.1 g of triethylamine was added while thoroughly stirring the reaction solution. After stirring for 1.5 hours under ice-cooling, the reaction solution was poured into water and extracted with ether. The ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 13.1 g of 3-(4-trifluoromethylphenylthio)propionaldehyde.