Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])[CH2:4][CH2:3]1.[F:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:20][CH:19]=1
Reactant: Oc1ccc(F)cc1
Reactant: CN1CCN(CC(O)c2ccccc2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCN(CC(Oc2ccc(F)cc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76 %

Procedure:
2-(4-Methyl-piperazin-1-yl)-1-phenyl-ethanol (38) (2.0 g, 9.09 mmol) was dissolved in 50 mL of THF. 4-fluorophenol was added to the solution and then triphenylphosphine. After complete dissolution, the mixture was cooled to 0° C. and after 10 minutes DIAD was added dropwise. Ice-bath was removed and the reaction mixture was stirred at room temperature for 48 hours. The product was purified using flash chromatography, eluting pure ethyl acetate to recover any starting materials. Polarity of the solvent was then increased using 30:70 methanol/ethyl acetate. The product 13a (2.18 g, 6.94 mmol, 76%) was afforded as a orange-brown oil. 1H-NMR (CDCl3): δ 7.33 (5H, m), 6.80 (4H, m), 5.21 (1H, dd, J=3.08, 3.07 Hz), 3.00 (1H, dd, J=8.49, 8.48), 2.67 (5H, b), 2.45 (4H, b), 2.27 (3H, s).
Reaction SMILES: [ClH:1].Cl.[CH:3]1([N:7]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)[S:24][CH:25]=2)=[CH:17][CH:16]=1>>[ClH:1].[CH:3]1([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([C:30]([C:29]3[CH:28]=[CH:27][C:26]([C:23]4[S:24][CH:25]=[C:21]([C:18]5[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=5)[N:22]=4)=[CH:34][CH:33]=3)=[O:31])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: C1CC(N2CCCNCC2)C1
Reactant: O=C(O)c1ccc(-c2nc(-c3ccc(F)cc3)cs2)cc1
Agent: Cl
Product: O=C(c1ccc(-c2nc(-c3ccc(F)cc3)cs2)cc1)N1CCCN(C2CCC2)CC1

Procedure:
The title compound (E8) was prepared from 1-(cyclobutyl)-hexahydro-1H-1,4-diazepine dihydrochloride (D4) and 4-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]benzoic acid using the procedure described in Example 7. MS APCI-436 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.Cl[C:8]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=1[CH2:10]Br>>[Cl:16][C:14]1[CH:15]=[CH:8][C:9]([CH2:10][N:4]2[CH:5]=[CH:6][C:2]([NH2:1])=[N:3]2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(CBr)c(Cl)c1
Reactant: Nc1cc[nH]n1
Product: Nc1ccn(Cc2ccc(Cl)cc2)n1

Procedure:
Prepared in analogy to example 10a) starting with 3-amino-1H-pyrazole and 2,4-dichlorobenzyl bromide. The title compound was obtained as a light yellow solid (Yield=29%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:10][C:11]1([N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]4[NH:33][CH:34]=[CH:35][C:28]=34)[CH:24]=[N:23]2)[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1)#[N:9]>C(Cl)Cl>[NH:33]1[C:29]2=[N:30][CH:31]=[CH:32][C:27]([C:25]3[CH:24]=[N:23][N:22]([C:11]4([CH2:10][C:8]#[N:9])[CH2:12][NH:13][CH2:14]4)[CH:26]=3)=[C:28]2[CH:35]=[CH:34]1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ccnc4[nH]ccc34)cn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCC1(n2cc(-c3ccnc4[nH]ccc34)cn2)CNC1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (7.0 mL) was added to tert-butyl 3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (0.90 g, 2.4 mmol) in methylene chloride (7.0 mL). The reaction mixture was stirred at 30° C. for 2 h. The volatiles were removed under reduced pressure to afford the desired product (quantitative) as TFA salt which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z 279.1.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CO[C:19](=[O:28])[C:20]1[C:21](=[CH:23][CH:24]=[C:25]([Cl:27])[CH:26]=1)[OH:22].Cl>C1COCC1.CCCCCCC.O.C(Cl)Cl>[OH:6][CH2:1][CH2:2][C:3]1[C:4](=[O:5])[O:22][C:21]2[C:20]([C:19]=1[OH:28])=[CH:26][C:25]([Cl:27])=[CH:24][CH:23]=2
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: O=C1CCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: O
Product: O=c1oc2ccc(Cl)cc2c(O)c1CCO
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 64.9 %

Procedure:
To a solution of γ-butyrolactone (15.5 g, 178.0 mmol) in THF (100 mL) at −78° C. was added a 1.0 M THF solution of LiHMDS (356 mL, 356 mmol), and the resulting mixture stirred at −78° C. for 1.5 hours. A solution of 5-chlorosalicylic methyl ester (16.6 g, 98% purity, 89.0 mmol) in THF (95 mL) was added. After stirring for 1 hour at 0° C., the mixture was warmed to room temperature overnight to ensure complete reaction. After cooling to 0° C., conc. HCl (12 N, 150 mL) was slowly added to bring the pH to 1. The reaction solution was stirred until HPLC analysis indicated the absence of the keto-ester intermediate. To the mixture was added 400 mL CH2Cl2 and 300 mL H2O; the organic phase was separated and the aqueous layer was extracted with CH2Cl2 (100 mL). The organic layers were combined and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to give a solid. Heptane (165 mL) was added to a solution of the solid in THF (290 mL) to crystallize the product. After cooling to 0-5° C. for about 3 hours, the product was isolated by filtration and washed with heptane. After drying in vacuo, a total of 13.9 g (66% yield) of the title compound as off-white crystals was obtained. m.p. 185-186° C.; MS m/z 240;
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15](O)=[O:16])[CH:12]=[CH:11][C:10]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:5][C:4]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30].ON1C(=O)CCC1=O.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.[NH2:61][C@H:62]([C:71]([CH3:74])([CH3:73])[CH3:72])[CH2:63][C:64]([O:66]C(C)(C)C)=[O:65].Cl>CN(C=O)C.C(O)=O>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]([NH:61][C@H:62]([C:71]([CH3:74])([CH3:73])[CH3:72])[CH2:63][C:64]([OH:66])=[O:65])=[O:16])[CH:12]=[CH:11][C:10]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:5][C:4]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(C)(C)C
Reactant: CN(C)CCCOc1cc(-c2nc(C(=O)O)ccc2-c2ccccc2Cl)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCCOc1cc(-c2nc(C(=O)N[C@@H](CC(=O)O)C(C)(C)C)ccc2-c2ccccc2Cl)ccc1Cl
Reaction time: 18 h
Yield: 117.3 %

Procedure:
To a mixture of 674 mg (1.4 mmol) of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridine-2-carboxylic acid hydrochloride in 7 mL of anhydrous DMF are successively added, under argon and at room temperature, 240 mg (2.1 mmol) of N-hydroxysuccinimide and 401 mg (2.1 mmol) of EDC.HCl. After stirring for 18 hours, 1.31 mL (7.7 mmol) of DIEA and 304 mg (1.51 mmol) of tert-butyl(3S)-3-amino-4,4-dimethylpentanoate (J. Org. Chem., 1999, 64, 6411-6417) are successively added to the reaction medium. Stirring is continued for 18 hours at room temperature and the reaction mixture is then concentrated under reduced pressure. The residue obtained is then treated for 18 hours at room temperature with 0.25 mL (3 mmol) of aqueous 12N HCl solution in 30 mL of formic acid and then concentrated under reduced pressure. After purification by reverse-phase HPLC (RP18), eluting with an aqueous 10−2N HCl/acetonitrile gradient of from 5% to 100% acetonitrile, and after freeze-drying, 500 mg of (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}-amino)-4,4-dimethylpentanoic acid hydrochloride are obtained in the form of a white powder.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22].CN>>[C:12]([C:11]1[C:10](=[O:15])[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:4]=2)=[CH:22][N:21]([CH3:23])[CH:20]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)CC(=O)Cc1cccc(C(F)(F)F)c1
Reactant: COC(OC)N(C)C
Agent: CN
Product: CC(=O)c1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
Ten g. of 1-(3-trifluoromethylphenyl)-2,4-pentanedione was reacted with 40 ml. of N,N-dimethylformamide dimethyl acetal, and then with 10 ml. of 40% aqueous methylamine, as described in the examples above. The reaction mixture was evaporated under vacuum, and the residue was taken up in 1.5 liters of dichloromethane. The solution was washed with 1 liter of water, and the organic layer was dried with magnesium sulfate, treated with activated charcoal, filtered and evaporated under vacuum. The residue was triturated under diisopropyl ether, and a yellow powdery solid crystallized. The solid was found to be 4.56 g. of the desired product, m.p. 130°-131°, showing the following peaks in nmr analysis: δ8.10 (d, J=3 Hz, H2 of pyridine); 8.0-7.3 (m, 4H, aromatic); 7.43 (d, J=3 Hz, H6 of pyridine); 3.77 (s, 3H, N--CH3); 2.73 (s, 3H, COCH3).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14]CC)=[O:13])[CH:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[OH-].[Na+].CCO.Cl>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(Cl)cnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
Anal. Found: C, 53.27; H, 3.48; N, 5.14. Calc for C12H9Cl2NO2 : C, 53.36; H, 3.36; N, 5.19. ##STR169## Ethyl 1,4-dichloro-7-isoquinolinecarboxylate (500 mg, 1.85 mmol) in THF (2 mL) was treated with an aqueous solution of NaOH (3.7 mL, 1 M) and EtOH (few drops) added to give a single phase mixture. After stirring at room temperature overnight, HCl (3.7 mL, 1 M) was added to give a thick slurry which was filtered off, washed with water, and crystallised from i-PrOH. The fluffy white crystalline solid was triturated with hexane and dried to afford 1,4-dichloro-7-isoquinolinecarboxylic acid (240 mg, 0.99 mmol).
Reaction SMILES: C1(C2CC(=O)NN=2)CC1.ClC1C2C(=CC=C(OC)C=2)[N+]([O-])=CC=1.Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[NH:28]/[C:27](=[C:37]2/[C:38]([CH:43]3[CH2:45][CH2:44]3)=[N:39][NH:40][C:41]/2=[O:42])/[CH:26]=1.[C:46]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([SH:56])=[CH:52][CH:51]=1)(=[O:48])[CH3:47]>C(OC(=O)C)(=O)C.C(O)C>[CH:43]1([C:38]2=[N:39][NH:40][C:41](=[O:42])/[C:37]/2=[C:27]2\[NH:28][C:29]3[C:34]([C:25]([S:56][C:53]4[CH:52]=[CH:51][C:50]([NH:49][C:46](=[O:48])[CH3:47])=[CH:55][CH:54]=4)=[CH:26]\2)=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[CH2:45][CH2:44]1
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: COc1ccc2c(c1)C(Cl)=C/C(=C1/C(=O)NN=C1C1CC1)N2
Agent: COc1ccc2c(c1)c(Cl)cc[n+]2[O-]
Agent: O=C1CC(C2CC2)=NN1
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)C(Sc1ccc(NC(C)=O)cc1)=C/C(=C1/C(=O)NN=C1C1CC1)N2
Temperature: 180 °C

Procedure:
3-Cyclopropyl-1H-pyrazol-5(4H)-one (0.2 mmol) and 4-chloro-6-methoxyquinoline 1-oxide (0.025 g, 0.2 mmol) were stirred in acetic anhydride (1.5 mL) at ambient temperature for 30-40 minutes. The reaction mixture was concentrated and the resulting solid filtered off and washed with a minimum amount of ether. (Z)-4-(4-chloro-6-methoxyquinolin-2(1H)-ylidene)-3-cyclopropyl-1H-pyrazol-5(4H)-one (0.04 g, 0.11 mmol) was dissolved in ethanol (1.5 mL) and 4-acetamidothiophenol (0.019 g, 0.11 mmol) was added. The reaction mixture was heated to 180° C. using a microwave reactor for 5-10 minutes. The mixture was then concentrated and the resulting solid filtered and washed with ether to give Example 47. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.46 (d, J=6.57 Hz, 2H) 0.65-0.71 (m, 2H) 1.43-1.54 (m, 1H) 2.11 (s, 3H) 3.98 (s, 3H) 7.18 (s, 1H) 7.45 (d, J=2.53 Hz, 1H) 7.63 (dd, J=9.09, 2.27 Hz, 1H) 7.70 (d, J=8.59 Hz, 2H) 7.82 (d, J=8.59 Hz, 2H) 8.07 (d, J=9.09 Hz, 1H) 10.39 (s, 1H); ESI-MS: m/z calc'd for C24H22N4O3S 446.52. found 447.2 (M+H)+.
Reaction SMILES: NC[C@@H]1C[C@H](O)C1.CS([O:12][C@H:13]1[CH2:16][C@@H:15]([CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[CH2:14]1)(=O)=O.[Cl:27][C:28]1[C:33]([CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:32]([Cl:40])[CH:31]=[CH:30][C:29]=1O.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOCC.O>[Cl:40][C:32]1[C:33]([CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:28]([Cl:27])[CH:29]=[CH:30][C:31]=1[O:12][C@H:13]1[CH2:16][C@H:15]([CH2:17][N:18]([CH3:19])[C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14]1
Reactant: Oc1ccc(Cl)c(CN2CCCC2)c1Cl
Reactant: CN(C[C@H]1C[C@@H](OS(C)(=O)=O)C1)C(=O)OC(C)(C)C
Agent: NC[C@H]1C[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: CN(C[C@H]1C[C@H](Oc2ccc(Cl)c(CN3CCCC3)c2Cl)C1)C(=O)OC(C)(C)C
Temperature: 92.5 °C

Procedure:
To a mixture of intermediate 6, cis-3-{[(tert-butoxycarbonyl)(methyl)amino]-methyl}cyclobutyl methanesulfonate (1.59 g, 5.42 mmol), intermediate 23, 2,4-dichloro-3-(pyrrolidin-1-ylmethyl)phenol (2 g, 8.13 mmol), and Cs2CO3 (2.65 g, 8.13 mmol) in DMSO (30 mL) was heated at 90-95° C. for 2 h under vigorous stirring in a flow of argon, and then cooled. Water (20 mL) and ether (50 mL) were added, and the layers were separated. The water layer was subjected to extraction with ether (2×50 mL). The combined organic layers were washed with water (30 mL), brine, dried with Na2SO4, and evaporated. The residue was purified by chromatography (silica gel, 63/100 μm, 50 g, CHCl3/hexane 20:80→100:0, CHCl3/MeOH 100:0→80:20) to furnish the title compound (1.7 g, 70%). LC/MS data: 443.1, 444.1, 445.1 (M+H) (calculated for C22H32Cl2N2O3 443.42). 1H NMR-data (DMSO-d6): 7.35 (d, 1H, J=9 Hz, Ar—H); 6.86 (d, 1H, J=9 Hz, Ar—H); 4.81-4.90 (m, 1H); 3.82 (brs, 2H, CH2); 3.33 (d, 2H, J=8 Hz, CH2); 2.78 (s, 3H, NCH3); 2.50-2.62 (m, 5H); 2.22-2.30 (m, 2H); 2.11-2.21 (m, 2H), 1.58-1.72 (m, 4H); 1.40 (brs, 9H, Boc).
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.C1(CN2C=CC(C3C=CC(CN)=CC=3)=N2)CC1.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]>[CH2:10]1[C:4]2[CH:3]=[CH:2][CH:18]=[CH:17][C:5]=2[CH2:6][CH2:7][NH:8][CH2:9]1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd]
Agent: NCc1ccc(-c2ccn(CC3CC3)n2)cc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)CCNCC2
Yield: 203.8 %

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 (193 mg, 0.45 mmol) with 4-(1-cyclopropylmethyl-1H-pyrazol-3-yl)-benzylamine (207 mg, 0.91 mmol) using tris(dibenzylideneacetone)dipalladium(0) (83 mg, 0.091 mmol), BINAP (113 mg, 0.182 mmol) and cesium carbonate (207 mg, 0.627 mmol) in toluene (21 mL). Purify by chromatography on silica gel eluting with hexane:EtOAc (9:1) to give 7-chloro-6-[4-(1-cyclopropylmethyl-1H-pyrazol-3-yl)-benzylamino]trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (135 mg, 59%). MS (ES+) m/z: 503 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:12][N:13]([CH:15](OC)OC)[CH3:14]>CN(C=O)C>[CH3:12][N:13](/[CH:15]=[N:1]/[C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:14]
Reactant: CCOC(=O)c1[nH]cnc1N
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]cnc1/N=C/N(C)C

Procedure:
A solution of ethyl 4-amino-1H-imidazole-5-carboxylate (0.65 g, 4.19 mmol) and DMF-DMA (11.22 ml, 84 mmol) in DMF (3 mL) was stirred at RT under nitrogen for 3 days. The excess DMF-DMA and DMF were removed under vacuum to give the desired compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.34-13.68 (m, 1H), 8.09 (s, 1H), 7.36 (s, 1H), 4.12 (q, 2H), 2.96 (d, 6H), 1.22 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[C:14]([F:16])([F:15])[F:17])[CH2:9][CH2:10]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Fc1ccc(N2CCNCC2)c(C(F)(F)F)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCN(c2ccc(F)cc2C(F)(F)F)CC1
Yield: 69.2 %

Procedure:
Sulfonylation of 1-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine (386 mg, 1.55 mmol) with 4-chlorobenzene-1-sulfonyl chloride (328.2 mg, 1.555 mmol) was carried out according to the representative sulfonation procedure described in Example 1 using anhydrous dichloromethane (3 mL) as solvent and diisopropylethylamine (1.35 mL, 7.775 mmol) as base. 1-[(4-chlorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]piperazine was obtained in 69.2% yield (455 mg) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH2:23])=[N:14][C:15]=3[N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[S:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[CH:41]=[CH:40][C:34]([O:35][CH2:36][C:37](Cl)=[O:38])=[CH:33][CH:32]=1>O1CCOCC1>[NH2:23][C:13]1[N:12]=[C:11]2[S:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]2=[C:15]([N:17]2[CH2:18][CH2:19][N:20]([C:37](=[O:38])[CH2:36][O:35][C:34]3[CH:40]=[CH:41][C:31]([Cl:30])=[CH:32][CH:33]=3)[CH2:21][CH2:22]2)[N:14]=1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: Nc1nc(N2CCNCC2)c2c(-c3ccc(F)cc3)nsc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2c(-c3ccc(F)cc3)nsc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a suspension of Example 15 (0.2 mmol) and potassium carbonate (0.2 mmol) in 1,4-dioxane (5 mL) was added 4-chlorophenoxyacetyl chloride (0.2 mmol). The reaction mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the crude residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1:60), yielding the pure title compound (80 mg, 80%) as a yellowish solid. MS (m/z) 499.2 [M+H]+ (100%). 1H NMR δH (300 MHz, DMSO-d6, 25° C.) 7.72 (dd, J 8.4, 5.6 Hz, 2H), 7.38 (t, J 8.7 Hz, 2H), 7.30 (d, J 8.8 Hz, 2H), 7.08 (s, 2H, NH2), 6.89 (d, J 8.8 Hz, 2H), 4.76 (s, 2H), 3.34 (br s, 4H), 3.20 (br s, 4H).
Reaction SMILES: I[Si](C)(C)C.[Cl:6][C:7]1[C:11]([Cl:12])=[C:10]([CH3:13])[NH:9][C:8]=1[C:14]([NH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[S:24][C:25]([C:30]#[N:31])=[C:26]([O:28]C)[N:27]=2)[CH2:19][CH2:18]1)=[O:15]>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:6][C:7]1[C:11]([Cl:12])=[C:10]([CH3:13])[NH:9][C:8]=1[C:14]([NH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[S:24][C:25]([C:30]#[N:31])=[C:26]([OH:28])[N:27]=2)[CH2:19][CH2:18]1)=[O:15]
Reactant: COc1nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)sc1C#N
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1[nH]c(C(=O)NC2CCN(c3nc(O)c(C#N)s3)CC2)c(Cl)c1Cl
Reaction time: 1 h

Procedure:
Iodotrimethylsilane (0.02 ml, 0.13 mmol) was added to a suspension of 3,4-dichloro-N-[1-(5-cyano-4-methoxy-1,3-thiazol-2-yl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Example 269, 0.04 g, 0.1 mmol) in DCM:CHCl3 (1:1). After stirring for one hour the reaction was complete. Partitioning with EtOAc and water, drying organic portion with MgSO4 and concentrating yielded a yellow oil which, after triturating with ether, gave a yellow solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:32])([F:31])[C:10]1[CH:30]=[CH:29][C:13]([C:14]([CH:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[O:15])=[CH:12][N:11]=1>C(Cl)Cl>[NH:19]1[CH2:20][CH2:21][CH:16]([C:14]([C:13]2[CH:12]=[N:11][C:10]([C:9]([F:32])([F:8])[F:31])=[CH:30][CH:29]=2)=[O:15])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(C(F)(F)F)nc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(C(F)(F)F)nc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
TFA (34.4 mL, 449.3 mmol) was added to a solution of tert-butyl 4-(6-(trifluoromethyl)nicotinoyl)piperidine-1-carboxylate (Intermediate 56: step b, 16.1 g, 44.9 mmol) in DCM (450 mL) and the resulting solution was stirred at room temperature for 3 hours. The mixture was concentrated to remove most of the TFA on the rotary evaporator and a mixture of EtOAc/hexanes was added. The white solid that precipitated was filtered and dried to provide the title compound which was used in the next step without purification.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[N+:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)([O-:32])=[O:31]>>[N+:30]([C:33]1[CH:38]=[C:37]([C:2]2[C:10]3[O:9][CH2:8][CH:7]([C:11]4[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=4)[C:6]=3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[C:3]=2[CH3:29])[CH:36]=[CH:35][CH:34]=1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cccc([N+](=O)[O-])c1)OCC2c1ccc(C(C)C)cc1
Yield: 59 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (3-nitrophenyl)boronic acid, the title compound was obtained in the same manner as in Example 107. Yield: 59%. Melting point: 209-210° C. (ethyl acetate-hexane).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:5]2.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.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.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH2:5]3)[CH2:27][CH2:26]1
Reactant: CN1CCNCC1
Reactant: O=C1c2ccc(Br)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc3c(c2)CN(Cc2ccc(OC(F)(F)F)cc2)C3=O)CC1
Yield: 15.5 %

Procedure:
A mixture of 5-bromo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.104 g, 0.27 mmol), 1-methyl piperazine (0.047 mL, 0.4 mmol), Pd2.dba3 (0.009 g, 0.01 mmol), BINAP (0.012 g, 0.02 mmol), and sodium tertiary-butoxide (0.040 g, 0.4 mmol) in toluene (3 mL) was heated to reflux for 3 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-(4-methyl-piperazin-1-yl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.017 g, 41%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.36 (s, 3H), 2:58 (m, 4H), 3.32 (m, 4H), 4.20 (s, 2H), 4.76 (s, 2H), 6.83-7.32 (m, 6H), 7.73 (d, 1H).