Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)=[CH:5][CH:4]=1)[CH3:2].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(O[C@@H:31]1[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[C@@H:42]([O:43][C:44](=[O:46])[CH3:45])[C@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]1[O:33][C:34](=[O:36])[CH3:35])(=O)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(#N)C.ClC(Cl)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:11]=[N:12][N:13]([C@@H:31]3[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[C@@H:42]([O:43][C:44](=[O:46])[CH3:45])[C@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]3[O:33][C:34](=[O:36])[CH3:35])[CH:14]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCc1ccc(Cc2cn[nH]c2)cc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CC(Cl)Cl
Product: CCc1ccc(Cc2cnn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2)cc1
Temperature: 60 °C
Yield: 44.4 %

Procedure:
To a solution of 4-(4-ethylphenylmethyl)pyrazole 36 (495 mg) in acetonitrile (2.0 ml) was added N,O-bis(trimethylsilyl)acetamide (1.05 ml), and the mixture was stirred under heating at 60° C. for 2.5 hours under argon atmosphere. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give crude 4-(4-ethylphenylmethyl)-1-trimethylsilylpyrazole 37, which was used in the subsequent reaction without further purification. (2) The above N-silyl compound 37 was dissolved in dichloroethane (7.0 ml), and added thereto were molecular sieve 4A powder (500 mg), 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose 38 (1.04 g) and trimethylsilyl trifluoromethanesulfonate (0.51 ml). The mixture was stirred under heating at heating at 80° C. for 3 hours under argon atmosphere. The reaction mixture was cooled to room temperature, and insoluble materials were filtered off. Subsequently, the filtrate was poured into a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted twice with dichloromethane, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20-50:50) to give 4-(4-ethylphenylmethyl)-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)pyrazole 39 (610 mg) as a colorless semisolid. APCI-Mass m/Z 517 (M+H). (3) From the above tetraacetate compound 39, the desired 4-(4-ethylphenylmethyl)-1-(β-D-glucopyranosyl)pyrazole 40 was prepared in a manner similar to Example 106-(3) as colorless oil. APCI-Mass m/Z 349 (M+H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([CH3:21])[C:19]([C:22](=[O:25])[CH2:23][CH3:24])=[CH:18][C:17]=2[CH3:26])=[CH:12][CH:11]=1>C1COCC1.C(OCC)(=O)C>[Br:1][C:18]1[C:17]([CH3:26])=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[N:20]([CH3:21])[C:19]=1[C:22](=[O:25])[CH2:23][CH3:24]
Reactant: CCC(=O)c1cc(C)c(-c2ccc(Cl)cc2)n1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(=O)c1c(Br)c(C)c(-c2ccc(Cl)cc2)n1C
Temperature: -78 °C
Reaction time: 5 h
Yield: 89.6 %

Procedure:
A solution of N-bromosuccinimide (4.42 g, 24.83 mmol) in THF (62.5 ml) was added dropwise to a stirred solution of 1-(5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrol-2-yl)propan-1-one (compound 49a, 6.5 g, 24.83 mmol) in THF (100 ml) at −78° C. The resulting reaction mixture was then stirred at a temperature of −78° C. for 5 hr. The reaction mixture was allowed to warm to 25° C. slowly during further 3 to 4 hr. The progress of the reaction was monitored by TLC. The solvent from the reaction mixture was evaporated under reduced pressure and residue so obtained was mixed in ethyl acetate (200 ml). The resulting mixture was washed with saturated sodium bicarbonate solution (1×100 ml) which was followed by washing with water (1×100 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 10% ethyl acetate in hexanes to obtain the title compound (7.58 g, 90%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH2:45])O1>C([P+]([Pd](Cl)(Cl)[P+](C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.O>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH2:45])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: C=C(B1OC(C)(C)C(C)(C)O1)c1ccccc1
Agent: CN(C)c1ccc([P+](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[P+](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(c1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Temperature: 80 °C
Yield: 91 %

Procedure:
A mixture of 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1: 3 g, 9.18 mmol), dioxane (32.1 ml) and water (9.64 ml) was degassed and to this was added mono(bis(di-tert-butyl(4-(dimethylamino)phenyl)phosphonio)palladium(IV)) dichloride (0.195 g, 0.275 mmol), cesium carbonate (10.14 g, 31.1 mmol) and 4,4,5,5-tetramethyl-2-(1-phenylethenyl)-1,3,2-dioxaborolane (3 g, 13.04 mmol). The mixture was heated to 80° C. for 6 hours and upon cooling was partitioned between dichloromethane and water. The organic portion was dried (MgSO4), filtered and concentrated to give an orange oil. The crude oil was purified by silica chromatography eluting with 0-60% ethyl acetate in petrol to afford 3,4-bis(benzyloxy)-6-(1-phenylethenyl)pyridazine as a brown oil (yield=91%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[F:17])=[N:6][CH:7]=1>C(O)C.ClCCl.[Pt](=O)=O>[F:17][C:9]1[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccc(F)cn2)c1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: ClCCl
Product: Nc1ccc(F)c(-c2ccc(F)cn2)c1
Reaction time: 1 h

Procedure:
To a solution of 5-fluoro-2-(2-fluoro-5-nitrophenyl)pyridine (1.23 g) in ethanol (70 ml) and dichloromethane (30 ml) was added platinum(IV) oxide (150 mg) and the mixture shaken on a Parr hydrogenation apparatus under an atmosphere of hydrogen at 45 psi for 1 h. Filtration and evaporation of the filtrate afforded 4-fluoro-3-(5-fluoropyridin-2-yl)phenylamine: MS (ES+) m/z 207.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[NH2:22][C:23]1[C:24]([NH:44][CH3:45])=[CH:25][C:26]([O:39][CH2:40][CH:41]([F:43])[F:42])=[C:27]([CH:38]=1)[C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=1)=[O:29].CC(C)N=C=NC(C)C>CN(C=O)C>[Br:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:28]([C:27]2[C:26]([O:39][CH2:40][CH:41]([F:42])[F:43])=[CH:25][C:24]3[N:44]([CH3:45])[C:20]([NH:19][C:3]4[CH:4]=[C:5]([CH2:6][NH:7][C:8]([C:10]5([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]5)=[O:9])[CH:17]=[CH:18][C:2]=4[F:1])=[N:22][C:23]=3[CH:38]=2)=[O:29])=[CH:32][CH:33]=1
Reactant: CNc1cc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)cc1N
Reactant: O=C(NCc1ccc(F)c(N=C=S)c1)C1(C(F)(F)F)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2F)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21

Procedure:
The title compound was prepared in accordance with the procedure in Example 72, step (a) using N-(4-fluoro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (160 mg; 0.50 mmol), 5-amino-N-(4-bromophenyl)-2-(2,2-difluoroethoxy)-4-(methylamino)benzamide (200 mg; 0.50 mmol), DIC (63 mg; 0.50 mmol) and DMF (4 mL). Yield: 25 mg (7%). 400 MHz 1H-NMR (DMSO-d6, ppm) 10.06 (1H, s) 8.61 (1H, s) 8.39 (1H, t, J=5.8 Hz) 7.87-7.81 (1H, m) 7.73-7.65 (3H, m) 7.52-7.48 (2H, m) 7.29-7.26 (1H, m) 7.21-7.14 (1H, m) 6.91-6.86 (1H, m) 6.65-6.36 (1H, m) 4.55-4.46 (2H, m) 4.24 (2H, d, J=5.8 Hz) 3.71 (3H, s) 1.39-1.32 (2H, m) 1.23-1.20 (2H, m). MS m/z: 684, 686 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:26]=[CH:25][C:9]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([C:18]3[N:19]=[C:20]([NH2:23])[S:21][CH:22]=3)=[C:13]([CH3:24])[CH:12]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.Cl.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([C:18]3[N:19]=[C:20]([NH:23][C:35](=[O:42])[C:36]4[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=4)[S:21][CH:22]=3)=[C:13]([CH3:24])[CH:12]=2)=[CH:25][CH:26]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COCCOc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOc1ccc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a solution of 4-{4-(4-(2-methoxyethoxy)phenoxy)-2,6-dimethylphenyl}thiazol-2-amine (12-6, 322.3 mg, 0.90 mmol) in CH2Cl2 (10.0 ml) was added triethylamine (0.40 mL, 2.6 mmol) followed by isonicotinoyl chloride hydrochloride (387.2 mg, 2.1 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with hot water. The resultant precipitate was filtered and dried under vacuum to give N-(4-{4-(4-(2-methoxyethoxy)phenoxy)-2,6-dimethylphenyl}thiazol-2-yl)isonicotinamide (12, 230 mg) as white solids in 56% yield: 1H NMR (500 MHz, DMSO-d6) δ 13.0 (brs, 1 H), 8.78 (d, J=5.8 Hz, 2 H), 7.98 (d, J=5.8 Hz, 2 H), 7.12 (s, 1 H), 6.96-7.00 (m, 4 H), 6.67 (s, 2 H), 4.01-4.07 (m, 2 H), 3.63-3.64 (m, 2 H), 3.26 (s, 3 H), 2.03 (s, 6 H). ESI-MS: m/z 476.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[S:9][C:10](Br)=[CH:11][C:12]=1[S:13](=[O:27])(=[O:26])[N:14]([CH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[OH:18])[CH3:15])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:35]([O:37]CC)=[CH2:36])CCC.[F-].[Cs+].C(OCC)(=O)C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[S:9][C:10]([C:35](=[O:37])[CH3:36])=[CH:11][C:12]=1[S:13](=[O:27])(=[O:26])[N:14]([CH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[OH:18])[CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1cc(Br)sc1NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1cc(S(=O)(=O)N(C)CC(O)c2ccc(F)cc2)c(NC(=O)OC(C)(C)C)s1
Reaction time: 0.17 h

Procedure:
(5-Bromo-3-{[2-(4-fluorophenyl)-2-hydroxy-ethyl]-methyl-sulfamoyl}-thiophene-2-yl)carbamic acid tert-butyl ester (the compound of Preparation Example 97) (5.5 g), tributyl(1-ethoxyvinyl)tin (6.7 g), cesium fluoride (5.3 g) and tetrakis(triphenylphosphine)palladium (0.73 g) were stirred in 1,4-dioxane (50 mL) at 100° C. for 2 hours. After ethyl acetate was added and insoluble matter was removed by filtration, 2N hydrochloric acid was added, and the solution was stirred for 10 minutes. After washing the organic layer with water, an aqueous solution of sodium bicarbonate and saturated sodium chloride water, and was dried with anhydrous magnesium sulfate. The residue resulting from the removal of the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (3.2 g9 was obtained as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([CH2:11][CH3:12])([CH3:10])[CH2:8][CH3:9])=[N:5][N:6]=1.[CH2:13]([C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[C:16]=1[C:17](Cl)=[O:18])[CH3:14]>C1(C)C=CC=CC=1>[CH2:8]([C:7]([C:4]1[S:3][C:2]([NH:1][C:17](=[O:18])[C:16]2[C:20]([CH2:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:15]=2[CH2:13][CH3:14])=[N:6][N:5]=1)([CH3:10])[CH2:11][CH3:12])[CH3:9]
Reactant: CCc1cccc(CC)c1C(=O)Cl
Reactant: CCC(C)(CC)c1nnc(N)s1
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1C(=O)Nc1nnc(C(C)(CC)CC)s1
Yield: 36.2 %

Procedure:
A solution of 1.85 g of 2-amino-5-(1- ethyl-1-methylproyl)-1,3,4-thiadiazole and 2.21 g of 2,6-diethylbenzoyl chloride in 50 ml of toluene was heated at reflux for sixteen hours and then cooled and the solvent was removed by evaporation under reduced pressure to provide a solid residue. The solid was crystallized from 2B ethanol to give 1.25 g of N-[5-(1-ethyl-1-methylpropyl)-1,3,4-thiadiazol-2-yl]-2,6-diethylbenzamide.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-:5]C(C)C)C.C[O:10][C:11]([C:13]1([CH2:16][OH:17])[CH2:15][CH2:14]1)=O.CC#N>C1COCC1>[OH:17][CH2:16][C:13]1([C:11](=[O:10])[CH2:2][C:3]#[N:5])[CH2:15][CH2:14]1
Reactant: COC(=O)C1(CO)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCOC1
Product: N#CCC(=O)C1(CO)CC1

Procedure:
To a solution of LDA (115 mmol) in THF (300 mL), at −78° C., a solution of 1-hydroxymethyl-cyclopropanecarboxylic acid methyl ester (5 g, 28.4 mmol) in CH3CN (5.91 mL, 115 mmol) is added. The reaction is allowed to reach rt. At this point it is quenched with 1N HCl (200 mL) and extracted with EtOAc (200 mL, ×3). It is then dried and evaporated to give 3-(1-hydroxymethyl-cyclopropyl)-3-oxo-propionitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.26 (s, 2 H) 4.03 (s, 1 H) 3.58 (br. s., 2 H) 1.15-1.16 (m, 2 H) 0.92-0.95 (m, 2 H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:26][C:7]2=[CH:8][N:9]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:10]3[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:5]([C:6]=32)[C:4]1=[O:27].[F:28][C:29]([F:34])([F:33])[C:30](O)=[O:31].C(N(CC)CC)C>ClCCl>[CH3:15][O:14][C:13]1[CH:12]=[CH:11][C:10]2[N:9]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=[C:7]3[CH2:26][CH:3]([NH:2][C:30](=[O:31])[C:29]([F:34])([F:33])[F:28])[C:4](=[O:27])[C:5]=1[C:6]=23
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc2c3c(cn2S(=O)(=O)c2ccc(C)cc2)CC(N)C(=O)c13
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c3c(cn2S(=O)(=O)c2ccc(C)cc2)CC(NC(=O)C(F)(F)F)C(=O)c13
Yield: 73.5 %

Procedure:
To a suspension of 4-amino-3,4-dihydro-6-methoxy-1-p-toluenesulfonylbenz[cd]indol-5(1H)-one hydrochloride (1.45 g, 3.50 mmol) in dichloromethane (30 ml) were added, while stirring under ice-cooling, anhydrous trifluoroacetic acid (0.61 ml, 4.27 mmol) and triethylamine (1.18 ml, 16.1 mmol). The mixture was stirred for 30 minutes as it was. After completion of the reaction, the reaction mixture was subjected to distillation under reduced pressure. The residue was shaken together with ethyl acetate (40 ml)-1N HCl (30 ml) to allow two layers to be formed. The organic layer was washed with an aqueous saline solution and dried (anhydrous Na2SO4). The solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to afford the title compound (1.2 g, 73%, m.p.189°-190° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32]1([C:38]2([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:41]3[CH2:42][CH2:43][C:38]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:48])([CH3:50])[CH3:49])([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:39][CH2:40]3)=[O:22])[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccccc2)CCNCC1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(C(=O)N2CCC(NC(=O)OC(C)(C)C)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 87 %

Procedure:
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1 eq., 201 mg, 0.53 mmol), triethylamine (3 eq, 0.22 mL, 0.157 mmol), tert-butyl N-(4-phenyl piperidin-4-yl)carbamate (1 eq, 146 mg, 0.53 mmol), and Benzotriazole-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (1 eq, 233 mg, 0.53 mmol) was stirred in tetrahydrofuran (10 mL) for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure tert-butyl N-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-yl)carbamate (295 mg, 87%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.37 (br. s., 9H) 2.11 (dd, J=12.67, 4.00 Hz, 2H) 2.21 (s, 3H) 2.24-2.34 (m, 1H) 2.34-2.56 (m, 1H) 3.26 (t, J=12.01 Hz, 1H) 3.56 (t, J=12.39 Hz, 1H) 4.32 (d, J=13.75 Hz, 1H) 4.64 (d, J=13.56 Hz, 1H) 4.96 (br. s., 1H) 7.08 (d, J=8.38 Hz, 2H) 7.13-7.49 (m, 10H).
Reaction SMILES: [CH3:1][C:2]([NH2:13])([CH3:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[O:14]([CH2:21][CH2:22][CH2:23]Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[ClH:25].CO>C(#N)C>[ClH:25].[O:14]([CH2:21][CH2:22][CH2:23][NH:13][C:2]([CH3:1])([CH3:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCCOc1ccccc1
Reactant: COc1ccc(CC(C)(C)N)cc1
Agent: Cl
Solvent: CO
Solvent: CC#N
Product: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 62 h

Procedure:
To a stirred suspension of 50% KF-Celite (0.35 g, 3 mmol) in anhydrous acetonitrile (10 mL) was added 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (0.27 g, 1.5 mmol) and 3-phenoxypropyl bromide (0.484 g, 2.25 mmol). The reaction mixture was refluxed under nitrogen for 6 hours, followed by stirring at room temperature for 62 hours. The mixture was filtered and the filtrate, was evaporated. The hydrochloride was prepared by dissolving the residue in HCl/methanol. The resulting solution was concentrated and dried on a lyophilizer. The residue was redissolved in dry methanol and diluted with diethyl ether, which caused precipitation of 210 mg of the title compound as a white solid: GC/EI-MS, m/z (rel. int.) 298 (M-15, 2), 193 (15), 192 (100), 120 (13), 107. (5), 98 (9), 77 (8), 72 (7), 71 (8), 70 (6), 41 (4).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11]([Cl:13])=[N:10][CH:9]=[N:8][C:7]=2[C:6](Br)=[CH:5]1)[CH:2]=[CH2:3].[Li]CCCC.[F:20][C:21]([F:41])([F:40])[C:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[N:28]=[CH:27]2)=[O:23]>C1COCC1.O.[Cl-].[Na+].O>[CH2:1]([N:4]1[C:12]2[C:11]([Cl:13])=[N:10][CH:9]=[N:8][C:7]=2[C:6]([C:22]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[N:28]=[CH:27]3)([OH:23])[C:21]([F:40])([F:20])[F:41])=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cc(Br)c2ncnc(Cl)c21
Reactant: O=C(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ncnc(Cl)c21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 23.2 %

Procedure:
To a chilled (−78° C.) solution of 5-allyl-7-bromo-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (570 mg, 2.1 mmol) in 10 mL of THF was added n-BuLi (2.5 M in THF, 1.5 mL, 2.5 mmol) dropwise. After 5 minutes, a chilled (−78° C.) solution of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone (708 mg, 2.3 mmol) in 3 mL of THF was added in one portion. After 15 minutes, the mixture was diluted with water and warmed to room temperature, diluted with brine, and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography using EtOAc-hexanes (15-60% gradient) to provide 245 mg (23%) of the title compound as a beige solid. MS m/z 502.23 (MH+).
Reaction SMILES: N[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.N([O-])=[O:14].[Na+].[OH-].[Na+]>OS(O)(=O)=O.O>[OH:14][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2
Reactant: Cc1ccc2ncc(N)cc2c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2ncc(O)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
A solution of 3-Amino-6-methylquinoline [(1.21 g, 7.65 mmol), prepared according to J. Chem. Soc. 2024-2027(1948) Morley, J. S.; Simpson, J. C. E.] in 6N H2SO4 (25 ml) was cooled in an ice bath. To the solution NaNO2 (560 mg, 8.10 mmol) in water (2 ml) was added and stirred for 30 min at 0 degrees. Separately 5% H2SO4 was refluxed and above Diazo reaction mixture was added to this refluxing solution. After 30 min the reaction mixture was cooled to room temperature, and was neutralized by 6N NaOH. The resulting insoluble material was collected by filtration. This solid was recrystallized by CHCl3/AcOEt to afford compound (308) (348 mg, 29%).
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[C:10]([O:14][C:15]([N:17]1[CH2:22][C@H:21]([CH2:23]O)[N:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:19][C@H:18]1[CH3:32])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.[NH:40]1[CH:44]=[CH:43][CH:42]=[N:41]1>C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:22][C@H:21]([CH2:23][N:40]2[CH:44]=[CH:43][CH:42]=[N:41]2)[N:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:19][C@H:18]1[CH3:32])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CO)CN1C(=O)OC(C)(C)C
Reactant: c1cn[nH]c1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](Cn2cccn2)CN1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
A solution of methanesulfonic anhydride (0.65 g, 3.72 mmol) in DCM (5 mL) was added slowly to a solution of (2R,5R)-4-benzyl-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.08 g, 3.38 mmol) and triethylamine (1.42 mL, 1.02 g, 10.1 mmol) in DCM (10 mL) with stirring under nitrogen and external ice bath cooling. Stirring was continued at 0° C. for 2 h then pyrazole (0.3 g, 4.4 mmol) was added in one portion. Stirring at 20° C. was continued for 18 h, then mixture was partitioned between saturated aqueous NaHCO3 (40 mL) and DCM (3×20 mL). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-40% Et2O in 40-60 petroleum ether) gave the title compound (0.811 g) as an oil. MS: [M+H]+=371.