Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([F:10])[F:9].[Li]CCCC.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C.O>C1COCC1.C(OCC)(=O)C>[F:9][CH:8]([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1
Reactant: FC(F)c1ccccc1Br
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2ccccc2C(F)F)OC1(C)C
Temperature: -78 °C
Yield: 59.2 %

Procedure:
To a solution of 1-bromo-2-difluoromethyl-benzene (19.8 g, 95.7 mmol) in dry THF (200 ml) at −78° C. under a nitrogen atmosphere was added 2.5 M n-BuLi in hexanes (42 ml, 105 mmol) slowly. After completion of the addition, the resulting dark solution was stirred for an additional hour at −78° C. Subsequently, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (25 ml, 123 mmol) was added, and the solution was slowly warmed to room temperature. After stirring overnight at room temperature under a nitrogen atmosphere the solution was poured into 400 ml water. Ethyl acetate (300 ml) was added and the layers were separated. The aqueous layer was extracted twice with ethyl acetate (150 ml and 50 ml respectively), and the combined organic layers were washed with water, dried over Na2SO4, filtered, and evaporated to dryness under reduced pressure. The resulting brown oil (21 g) was purified by bulb-to-bulb-distillation at 3×10−3 mbar at 90-95° C. to yield 2-(2-difluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (14.4 g, 59%) as a slightly yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:23]([F:26])([F:25])[F:24])=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:29]I>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:23]([F:26])([F:25])[F:24])=[C:13]2[C:17]=1[N:16]([CH3:29])[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)ccc(OCc3ccccc3)c2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C(F)(F)F)ccc(OCc3ccccc3)c2n1C

Procedure:
The reaction was carried out in a manner similar to Reference Example 18 a) except for using 8.00 g (22.0 mmol) of ethyl 7-benzyloxy-4-trifluoromethyl-2-indolecarboxylate, 0.88 g (22.0 mmol) of 60% sodium hydride, 6.25 g (44.0 mmol) of methyl iodide and 150 ml of dimethylformamide. Ethyl 7-benzyloxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate was thus obtained in the yield of 7.40 g (89.1%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[S:7][C:8]([C:11]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22]>C1C=CC=CC=1.CCOC(C)=O>[CH2:1]([N:5]([C:6]1[S:7][C:8]([C:11]([OH:20])([C:12]([F:13])([F:14])[F:15])[C:16]([F:19])([F:17])[F:18])=[CH:9][N:10]=1)[C:24]([NH:23][CH2:21][CH3:22])=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Reactant: CCN=C=O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCCCN(C(=O)NCC)c1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Yield: 39 %

Procedure:
To a mixture of 2-[2-(butylamino)-1,3-thiazol-5-yl]-1,1,1,3,3,3-hexafluoropropan-2-ol (65 mg, 0.202 mmol) obtained from step 1 in benzene (2 ml) was added ethyl isocyanate (24 μL, 0.3 mmol) under a nitrogen atmosphere The reaction mixture was refluxed for 4 h. Solvent was removed under reduced pressure to obtain an oil, which was dissolved in EtOAc. The resulting solution was washed with H2O, saturated NaHCO3 and brine, and dried over MgSO4. The solvent was evaporated to yield a crude product which was purified by preparative TLC (EtOAC:hexanes, 1:3) to afford the corresponding product as a white solid (31 mg). 1H NMR δ0.92 (t, 3H), 1.20 (t, 3H), 1.37 (m, 2H) 1.67 (m, 2H), 3.37 (q, 2H), 3.83 (t, 2H), 4.24 (brs, 1H), 7.50 (s, 1H), 8.60 (brs, 1H); ESIMS: m/z 392 (M−H).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:20])[NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].O.Cl>CO>[C:1]1([NH:7][C:8](=[O:20])[NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(NC(=O)Nc2ccccc2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccccc1)Nc1ccc(C(=O)O)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
Methyl 6-(3-phenylureido)nicotinate (200 mg, 0.43 mmol) was dissolved in methanol (2 mL) at room temperature. Lithium hydroxide (100 mg, 4.17 mmol) was added, followed by water (10.5 mL). The mixture was heated to 50° C. and stirred overnight. The mixture was brought to pH 4-5 by addition of concentrated hydrochloric acid. The solid that had formed was then filtered and dried under vacuum to give the title compound (69 mg). MS (ESI) m/z 258.1[M+H]+
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=O.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[O:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH:32]([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]2)[CH2:31][CH2:30]1>C(Cl)Cl>[O:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[CH:32]([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][CH:44]([NH:47][C:11]([CH:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)=[O:13])[CH2:43][CH2:42]2)[CH2:31][CH2:30]1
Reactant: NC1CCN(CCC2CCOc3ccccc32)CC1
Reactant: O=C(O)C1CCc2ccccc2C1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCN(CCC2CCOc3ccccc32)CC1)C1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.4 %

Procedure:
To a stirred solution of 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (176 mg, 1 mmol) and triethylamine (0.25 ml) in methylene chloride (5 ml), isobutylchloroformate (136 mg, 1 mmol) was added. After 5 minutes N-[1-[2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4-aminopiperidine (260 mg, 1 mmol) in methylene chloride was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with 2N potassium hydroxide solution. The organic layer was separated, washed with distilled water and dried (Na2SO4). Evaporation of the solvent gave a white solid which was crystallized from diethyl ether to afford the title compound (140 mg, 33%), m.p.=130°-2°, Anal C27H34N2O2. 0.25 H2O, Calc, C, 76.65; H, 8.22, N, 6.62; Found C,76.34; H, 8.32; N, 6.59.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](C2C3C=C(C(OC)=O)NC=3CC=2)[CH:5]=[CH:6][CH:7]=1.[Mg:20].[Br:21]C1C=CC=C(Br)C=1.C1(CC2C3C=C(C(O)=O)NC=3CC2)CCCCC1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([Mg:20][Br:21])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2c([nH]1)CC=C2c1cccc(Br)c1
Reactant: [Mg]
Reactant: Brc1cccc(Br)c1
Agent: O=C(O)c1cc2c([nH]1)CCC2CC1CCCCC1
Solvent: C1CCOC1
Product: Br[Mg]c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.502 g, 2.80 mmol) and (3-bromophenyl)magnesium bromide (synthesized in situ) were reacted according to General Procedure 3 to give the endo olefin-containing compound methyl 4-(3-bromophenyl)-1,6-dihydrocyclopenta[b]pyrrole-2-carboxylate. (Note: (3-Bromophenyl)magnesium bromide was synthesized as follows: Activated magnesium (0.306 g, 12.6 mmol) was placed in a flask and anhydrous THF (50 mL) was added. 1,3-dibromobenzene (1.6 mL, 13.2 mmol) and a catalytic amount of 12 was added. The solution was stirred gently at ambient temperature for 30 min. Additional anhydrous THF (25 mL) was added and the solution refluxed for 3 h, and then allowed to cool to ambient temperature). Methyl 4-(3-bromophenyl)-1,6-dihydrocyclopenta[b]pyrrole-2-carboxylate was hydrogenated according to General Procedure 6 (with Pt2O), and was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-30% EtOAc/heptane affording a 1:1 mixture of the title compound and dehalogenated product as a slightly yellow solid: 0.315 g (67% yield). LCMS (ESI−) 318.0 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[CH3:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)=O>CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[CH3:18])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:15])([F:17])[F:16]
Reactant: FC(F)(F)c1cc(N2CCNCC2)ccc1Cl
Reactant: COc1ccc(C(C)=O)cc1OC
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: CO
Product: COc1ccc(C(C)N2CCN(c3ccc(Cl)c(C(F)(F)F)c3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A quantity of 0.17 g (0.6 mmole, 1 eq) of 1-(4-chloro-3-trifluoromethyl-phenyl)-piperazine and 0.1 g (0.6 mmole, 1 eq) of 3,4-dimethoxyacetophenone and 2 mL of Ti(OiPr)4 are warmed to 70° C. for 2 hours. The reaction solution is cooled to room temperature and 20 mL of anhydrous methanol is added followed by 1.0 g of NaBH and the resulting solution is stirred at room temperature for 2 hours. The reaction is quenched by the addition of 1 N NaOH and extracted with CH2Cl2. The CH2Cl2 extracts are dried over anhydrous MgSO4 and concentrated in vacuo. The residue is chromatographed on SiO2 with ethyl to afford 1-[4-chloro-3-(trifluoromethyl)phenyl]-4-[1-(3,4-dimethoxyphenyl)ethyl]piperazine (compound 2). Analysis 1H NMR (400 MHz, CDCl3): 7.31 (1H, d), 7.19 (1H, m), 6.90 (4H, m), 3.89 (6H, d), 3.38 (1H, m), 3.20 (4H, m), 2.61 (4H, m). MS (LC-MS): Calculated for C21H24ClF3N2O2 428.88. Found 429.30 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[C:14]=[N:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25].[F:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:30]=[CH:31][C:32]([N:35]2[CH2:40][CH2:39][N:38]([C:14]3[N:13]([C:4]4[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH:22]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:16]=4[N:15]=3)[CH2:37][CH2:36]2)=[CH:33][CH:34]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: COC(=O)/C=C/c1cnccc1N=C=Nc1cc(C(F)(F)F)ccc1OC
Product: COC(=O)CC1c2cnccc2N=C(N2CCN(c3ccc(F)cc3)CC2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
Starting from 565 mg (1.50 mmol) of the carbodiimide from Example 18A and 297 mg (1.65 mmol) of 4-fluorophenylpiperazine, general procedure [C] and purification by preparative HPLC result in 90 mg (10% of theory) of product.
Reaction SMILES: F[C:2](F)(F)C(O)=O.C(OC(=O)[NH:14][C@@H:15]([CH2:29][N:30]1[CH2:35][C:34](=[O:36])[N:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[Cl:43])[CH2:32][C:31]1([CH3:45])[CH3:44])[C@@H:16]([OH:28])[CH2:17][C@H:18]([C:21](=[O:27])[NH:22][CH2:23]C(C)C)[CH2:19][CH3:20])(C)(C)C.[C:47]([OH:54])(=[O:53])/[CH:48]=[CH:49]/[C:50]([OH:52])=[O:51].[CH2:55]([NH:59][C:60](=[O:86])[C@H:61]([CH2:84][CH3:85])[CH2:62][C@H:63]([OH:83])[C@@H:64]([NH2:82])[CH2:65][N:66]1[CH2:71][C:70](=[O:72])[N:69]([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][C:74]=2[Cl:79])[CH2:68][C:67]1([CH3:81])[CH3:80])[CH:56]([CH3:58])[CH3:57]>C(Cl)Cl.CO>[C:47]([OH:54])(=[O:53])/[CH:48]=[CH:49]/[C:50]([OH:52])=[O:51].[CH3:55][C:56]([CH3:58])([CH3:57])[CH2:23][NH:22][C:21](=[O:27])[C@H:18]([CH2:19][CH3:20])[CH2:17][C@H:16]([OH:28])[C@@H:15]([NH2:14])[CH2:29][N:30]1[CH2:35][C:34](=[O:36])[N:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[Cl:43])[CH2:32][C:31]1([CH3:44])[CH3:45].[NH2:82][C@@H:64]([CH2:65][N:66]1[CH2:71][C:70](=[O:72])[N:69]([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][C:74]=2[Cl:79])[CH2:68][C:67]1([CH3:80])[CH3:81])[C@@H:63]([OH:83])[CH2:62][C@@H:61]([CH2:84][CH3:85])[C:60]([NH:59][CH2:55][C:56]([CH3:2])([CH3:58])[CH3:57])=[O:86]
Reactant: CC[C@H](C[C@H](O)[C@H](CN1CC(=O)N(c2ccccc2Cl)CC1(C)C)NC(=O)OC(C)(C)C)C(=O)NCC(C)C
Reactant: CC[C@H](C[C@H](O)[C@@H](N)CN1CC(=O)N(c2ccccc2Cl)CC1(C)C)C(=O)NCC(C)C
Reactant: O=C(O)C(F)(F)F
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClCCl
Solvent: CO
Product: CC[C@H](C[C@H](O)[C@@H](N)CN1CC(=O)N(c2ccccc2Cl)CC1(C)C)C(=O)NCC(C)(C)C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
1.09 ml of trifluoroacetic acid (14.1 mmol) was added to a solution of 264 mg of {(1S,2S,4R)-4-(isobutylcarbamoyl)-1-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-ylmethyl]-2-hydroxyhexyl}carbamic acid t-butyl ester obtained in Example (107a) (0.47 mmol) in methylene chloride (2 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. After concentration under reduced pressure, a saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol/triethylamine=100/10/1). 26 mg of fumaric acid (0.22 mmol) was added to a solution of 210 mg of (2R,4S,5S)-5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-2-ethyl-4-hydroxyhexanoic acid isobutylamide obtained above (0.45 mmol) in methanol (3 ml), and the mixture was stirred at room temperature for five minutes. The reaction mixture was concentrated under reduced pressure, and methylene chloride (0.5 ml) was added to the residue. Diethyl ether (5 ml) was further added and the solid was collected by filtration to obtain 192 mg of the title compound (yield: 78%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:18](=O)[C:19]#[CH:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH:23]1([NH:28][C:29]([NH2:31])=[NH:30])[CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:18]3[CH:19]=[CH:20][N:31]=[C:29]([NH:28][CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[N:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N=C(N)NC1CCCC1
Reactant: C#CC(=O)c1c(-c2ccc(F)cc2)nc2c(Cl)cccn12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Fc1ccc(-c2nc3c(Cl)cccn3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 80 °C
Yield: 58.8 %

Procedure:
To a solution of 1-[8-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl]-2-propyn-1-one (740 mg, 2.5 mmol) in ethanol (20 mL) was added cyclopentyl guanidine hydrochloride (600 mg, 3.7 mmol), followed by solid potassium carbonate (510 mg, 3.7 mmol). The resulting solution was heated at 80° C. for 12 hours. The reaction mixture was concentrated to a solid. Water and dichloromethane were added. The phases were separated and the organics were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was crystallized from acetonitrile, to give 4-[8-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (600 mg, 59%) as a white solid. 1H NMR (CDCl3) δ 9.48 (d, 1H), 8.11 (d, 1H), 7.68 (q, 2H), 7.42 (d, 1H), 7.11 (t, 2H), 6.86 (t, 1H), 6.40 (d, 1H), 5.28 (d, 1H), 4.35 (m, 1H), 2.0–2.1 (m, 2H), 1.4–1.9 (m, 6H); 19F NMR (CDCl3) δ −113.0; MS m/z 408 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:16]([NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=1)(=[O:23])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(O)(=O)C.Cl>CO>[C:16]([NH:20][S:21]([C:24]1[CH:25]=[CH:26][C:27]([CH2:30][NH:15][C:13]2[NH:12][N:11]=[C:10]([NH:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=2)=[CH:28][CH:29]=1)(=[O:22])=[O:23])([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(C=O)cc1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)NS(=O)(=O)c1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (100 mg, 410 μmol) in MeOH (5 mL) was added N-tert-butyl-4-formylbenzenesulfonamide (109 mg, 451 μmol) followed by acetic acid (36.7 mg, 35 μl, 611 μmol). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (65.7 mg, 615 μmol) was added and the stirring was continued for 3 days. The reaction mixture was poured into 0.1N HCl solution (25 ml) and was extracted with EtOAc (3×30 ml). The combined organic solution was washed with brine, dried over Na2SO4 and concentrated to give a residue. The crude material was purified by flash chromatography (silica gel, 24 g, 3% to 5% MeOH in DCM) to give an off white solid as desired product (98 mg, 51% yield). MS +m/z: 469 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][CH2:9][OH:10])[N:3]=1.C(N(CC)CC)C.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CC#N>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:10][CH2:9][CH2:8][N:4]2[C:5]([CH3:7])=[CH:6][C:2]([CH3:1])=[N:3]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(C)n(CCO)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCCn2nc(C)cc2C)cc1
Yield: 46 %

Procedure:
A cooled (0° C.) mixture of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-ethanol (0.48 g, 3.4 mmol) and triethylamine (0.47 mL, 3.4 mmol) in MeCN (5 mL) was treated with 4-methylbenzenesulfonyl chloride (0.72 g, 3.8 mmol), after which the mixture was kept cool in a refrigerator for 2 days. The mixture was then concentrated in vacuo to give a residue which was purified by chromatography on silica gel, eluting with ethyl acetate hexane (1:1), to give 0.46 g (46%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:9]=2)[C:4](=[O:16])[NH:3]1.Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.O1CCOCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CCCCCC.[Cu](I)I.C(OC(=O)C)C>[CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([C:12]([F:13])([F:15])[F:14])=[CH:8][CH:9]=2)[C:4](=[O:16])[N:3]1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Brc1cccnc1
Reactant: CC1Cc2ccc(C(F)(F)F)cc2C(=O)N1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1COCCO1
Product: CC1Cc2ccc(C(F)(F)F)cc2C(=O)N1c1cccnc1
Yield: 61.8 %

Procedure:
3-Methyl-7-trifluoromethyl-3,4-dihydro-2H-isoquinolin-1-one (I-43d: 40 mg, 0.1745 mmol) was reacted with 3-bromo-pyridine (19 mg, 0.1163 mmol), 1,4-dioxane (5 mL), copper iodide (4 mg), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (8 mg) and potassium phosphate (93 mg, 0.4363 mmol). The reaction was monitored by TLC (50% ethylacetate in hexane). The reaction mass was concentrated under reduced pressure and partitioned between ethylacetate and water. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated. Purification by column chromatography on silica gel (100% ethylacetate in hexane) followed by washing with hexane and ether afforded 22 mg of the product (41.15% yield).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[C:10]([NH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:22])[F:21])=[O:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[C:10]([NH:12][N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:21])([F:22])[F:23])[C:2]([O:4][CH2:5][CH3:6])=[O:3])=[O:11]
Reactant: CCOC(=O)Cl
Reactant: O=C(NNc1ccccc1C(F)(F)F)c1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)N(NC(=O)c1ccccc1Cl)c1ccccc1C(F)(F)F

Procedure:
1.8 ml (19 mmol) of ethyl chloroformate are added dropwise while cooling to a mixture of 4.28 g (14 mmol) of 2-chloro-N'-(α,α,α-trifluoro-o-tolyl)-benzhydrazide and 2.7 ml (19 mmol) of triethylamine in 30 ml of toluene. The reaction mixture is heated at the reflux temperature for a further 4 hours and then extracted with diethyl ether against water and sodium bicarbonate solution. The organic phase is dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residual oil is then purified by chromatography using ethyl acetate/n-hexane (1:4) as the eluent. In this manner there is obtained ethyl 3-(2-chlorobenzoyl)-2-(α,α,α-trifluoro-o-tolyl)-carbazate as an almost colourless oil, IR spectrum (CHCl3): 3405, 1735, 1710 cm-1 ; 1H-NMR (CDCl3): 4.28 (q,OCH2CH3).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH2:15])[CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1.C(N(CC)CC)C.[O:24]=[C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[O:34])[N:26]1[CH2:35][CH2:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][S:37]([CH2:36][CH2:35][N:26]3[C:25](=[O:24])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]3=[O:34])(=[O:38])=[O:39])[CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Reactant: NC1CCCC(Nc2cc(I)cc(Cl)n2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)NC1CCCC(Nc2cc(I)cc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 145a (280 mg, 0.8 mmol) in CH2Cl2 (10 mL) was added triethylamine (110 mg, 1 mmol) and followed by 2-(1,3-dioxoisoindolin-2-yl)ethanesulfonyl chloride (262 mg, 0.95 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by flash chromophatography (EtOAc/hexanes=1:4) to give the title compound. Yield: 180 mg (32%). MS (DCI/NH3) m/z 589 (M+H)+.
Reaction SMILES: [OH-:1].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:19][C:20]#N)[N:7]([CH3:18])[C:8]=1[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.Cl.[OH2:23]>C(O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH2:19][C:20]([OH:23])=[O:1])[N:7]([CH3:18])[C:8]=1[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: [OH-]
Reactant: O
Reactant: Cn1c(CC#N)cc(Br)c1C(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cn1c(CC(=O)O)cc(Br)c1C(=O)c1ccc(Cl)cc1

Procedure:
A solution of 0.05 g (1.1 m mole) of sodium hydroxide in 2 ml of water and 2 ml of ethanol is combined with 0.19 g (0.56 m mole) of 4bromo-5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetnitrile, and the whole is stirred and refluxed for 4 hours. The resulting mixture is poured into 30 ml of cold 3N hydrochloric acid; the precipitate which forms is filtered off and washed well with water. Recrystallization of this precipitate from acetonitrile yields 4-bromo-5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetic acid as a pink solid; m.p. 190° C. (dec.)
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C@H:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C@@H:8]([NH2:10])[CH3:9])=[CH:3][CH:2]=1.[C:26](OCC)(=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O-:33])=[O:32]>>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([C@H:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C@@H:8]([NH:10][C:26]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:34])[CH3:9])=[CH:5][CH:6]=1
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)c(Cl)c1)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)CCCCC(=O)[O-]
Product: C[C@H](NC(=O)CCCCC(=O)O)[C@@H](Cc1ccc(Cl)c(Cl)c1)c1ccc(-c2ccccc2)cc1

Procedure:
Compounds of Examples 67 to 71 were prepared in the same manner as in Example 66 except that (1S, 2S)-2-(4-biphenylyl)-3-(3,4-dichlorophenyl)-1-methylpropylamine and monoethyl adipate used as the starting materials in the above reaction were changed to the respective corresponding amine compounds and/or monoester derivatives.