Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CS(O[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:23]3[N:24]=[CH:25][N:26]=[C:27]([NH2:28])[C:22]=3[C:21]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:31][CH:30]=3)=[CH:20]2)[CH2:15][CH2:14]1)(=O)=O.[H-].[Na+]>CN(C)C=O>[N:1]1([CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[N:24]=[CH:25][N:26]=[C:27]([NH2:28])[C:22]=4[C:21]([C:29]4[CH:30]=[CH:31][C:32]([O:35][C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)=[CH:33][CH:34]=4)=[CH:20]3)[CH2:15][CH2:14]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CS(=O)(=O)OCCC1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(CCn2ccnc2)CC1
Temperature: 40 °C
Reaction time: 5 h
Yield: 63 %

Procedure:
Imidazole (0.070 g, 1.03 mmol) was added into a solution of 2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}ethyl methanesulfonate (0.052 g, 0.10 mmol) in N,N-dimethylformamide (2 mL). The mixture was stirred at 40° C. for 5 hours. 60% Sodium hydride in mineral oil (0.021 g, 052 mmol) was added and the mixture was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the residue was purified by preparative RP-HPLC to yield 7-{4-[2-(1H-1-imidazolyl)ethyl]cyclohexyl}-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.030 g, 0.063 mmol) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.30(s, 1H), 7.55(br, 1H), 7.44(d, 2H), 7.42(t, 2H), 7.16(t, 1H), 7.08(m, 6H), 6.95(br, 1H), 5.49(br, 2H), 4.72(m, 1H), 4.01(t, 2H), 1.99-1.71 (m, 11H); RP-HPLC (Hypersil C18, 5 μm, 100 A, 250×4.6 mm; 25%-100% over 10 min acetonitrile-0.05M ammonium acetate, 1 mL/min) Rt 9.18 min; MS: MH+ 479.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS([O-])=O.[Na+].[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([NH2:31])[CH:25]=1.C(O)C>O>[O:1]([C:8]1[CH:15]=[CH:14][C:11]([C:12]2[NH:30][C:27]3[CH:28]=[CH:29][C:24]([C:23]([O:22][CH3:21])=[O:32])=[CH:25][C:26]=3[N:31]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc2[nH]c(-c3ccc(Oc4ccccc4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To 4-phenoxybenzaldehyde (3.0 g, 0.02 mol) was added 21 mL of 40% NaHSO3 (aq). The mixture was stirred for 1 h at 25° C. Methyl-3,4-diaminobenzoate (2.5 g, 0.02 mol) and ethanol (15 mL) were added. The mixture was refluxed for 4 h. The reaction was then poured into water. The precipitate filtered and recrystallized from EtOAc to afford 2-(4-phenoxyphenyl)-1H-benzimidazole-5-carboxylic acid, methyl ester (5.06 g, 97%) as a white solid.
Reaction SMILES: [OH-:1].[Na+].[C:3]([C:5]1[N:6]=[N:7][N:8]([CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[CH:9]=1)#[N:4]>O>[F:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([F:18])[C:11]=1[CH2:10][N:8]1[CH:9]=[C:5]([C:3]([NH2:4])=[O:1])[N:6]=[N:7]1
Reactant: [OH-]
Reactant: N#Cc1cn(Cc2c(F)cccc2F)nn1
Agent: [Na+]
Solvent: O
Product: NC(=O)c1cn(Cc2c(F)cccc2F)nn1
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
1 N sodium hydroxide solution (0.11 ml) is added to a mixture of 4-cyano-1-(2,6-difluorobenzyl)-1H-1,2,3-triazole (2.20 g) and water (44 ml) at an external temperature of 95-100°C. while stirring. After 90 minutes, the suspension is cooled to 10°C. and the product is isolated by filtration, washed with water and dried at about 60°C. in vacuo. 1-(2,6-Difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide is obtained in this manner; yield: 99.2% by weight modification A.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30]>>[CH2:29]([NH:31][C:32]([N:20]1[CH2:21][CH2:22][C:16]2[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[N:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=3)=[N:18][C:17]=2[CH2:19]1)=[O:33])[CH3:30]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)NCC)C3)cc1

Procedure:
Method as example 33 using 1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (example 82) and ethyl isocyanate as starting materials.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH:4]2[C:3]1=[O:12].[CH3:13][N:14]([CH3:18])[C:15](Cl)=[S:16]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[O:7]=[C:6]1[CH:5]2[CH:4]([CH2:11][CH2:10][CH2:9][CH2:8]2)[C:3](=[O:12])[N:2]1[O:1][C:15](=[S:16])[N:14]([CH3:18])[CH3:13]
Reactant: CN(C)C(=S)Cl
Reactant: O=C1C2CCCCC2C(=O)N1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CN(C)C(=S)ON1C(=O)C2CCCCC2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
To a solution of 25.38 g (0.15 mol) of N-hydroxy-hexahydrophthalimide (prepared as described in Chem. Pharm. Bull., 16, (1968), 622) and 0.5 g 4-dimethylaminopyridine in 100 ml pyridine were added 18.54 g (0.15 mol) of dimethylthiocarbamoyl chloride. The mixture was stirred at room temperature during 3 h and then poured into 1000 ml of ice water. The precipitate was filtered off and recrystallized from 120 ml of ethanol to give 28.38 g of white crystals, mp. 124-126° C.
Reaction SMILES: C1([N:7]=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1[CH2:22][CH2:21][CH2:20][C:19]([CH3:24])([CH3:23])[C:18]=1/[CH:25]=[CH:26]/[C:27](/[CH3:37])=[CH:28]/[CH:29]=[CH:30]/[C:31](/[CH3:36])=[CH:32]/[C:33](O)=[O:34].ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:16][C:17]1[CH2:22][CH2:21][CH2:20][C:19]([CH3:24])([CH3:23])[C:18]=1/[CH:25]=[CH:26]/[C:27](/[CH3:37])=[CH:28]/[CH:29]=[CH:30]/[C:31](/[CH3:36])=[CH:32]/[C:33]([NH2:7])=[O:34]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(N)=O)C(C)(C)CCC1
Yield: 62 %

Procedure:
3 g (0.0146 mole) of dicyclohexylcarbodiimide (DCC) was added to the solution of 4.48 g (0.0112 mole) of 1-amino-polyethylene glyco (molecular weight 400), 3.98 g (0.0133 mole) of retinoic acid and 1.51 g (0.0112 mole) of 1 -hydroxybenzotriazole in 40 ml of dry dichloromethane, and the reaction solution was then treated according to the same procedure as described in Example 1(A) to obtain the title compound (Yield 62%, Tm=−14° C., Rf=0.15).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])/[CH:14]=[C:15](\[C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)/[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2].[C:31]([O:35][C:36](=[O:52])[CH2:37][N:38]=[C:39]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([CH3:34])([CH3:33])[CH3:32].[OH-].[Na+].O>C(#N)C>[C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])[CH2:14][C:15]([CH:37]([N:38]=[C:39]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:52])([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:16]([F:17])([F:19])[F:18])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1cc(C(=O)CC(c2cc(Cl)cc(Cl)c2)(C(N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.2 %

Procedure:
To a solution of 4-[(E)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (1 g) and (benzhydrylidene-amino)-acetic acid tert-butyl ester (643 mg) in acetonitrile (5 mL) was added a solution of sodium hydroxide (0.6 mL, 32%) at room temperature. The reaction was stirred at ambient temperature for 18 hours, then water was added and the reaction mixture was extracted with dichloromethane and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 05% ethyl acetate in cyclohexane) to afford 4-[3-[(Benzhydrylidene-amino)-tert-butoxycarbonyl-methyl]-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-benzoic acid tert-butyl ester (1.12 g) as a yellow foam. 19F NMR (376 MHz, CDCl3) δ −60.99 and −61.88 ppm (mixture of 2 diastereoisomers).
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:12]1[CH:13]=[C:14]([C:18]2([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=3)[C:20]([NH2:28])=[N:19]2)[CH:15]=[CH:16][CH:17]=1>>[F:27][C:24]1[CH:25]=[C:26]2[C:21]([C:20]([NH2:28])=[N:19][C:18]2([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:7]3[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[CH:13]=2)[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[CH:22][CH:23]=1
Reactant: OB(O)c1cccnc1F
Reactant: NC1=NC(c2ccncc2)(c2cccc(Br)c2)c2cc(F)ccc21
Product: NC1=NC(c2ccncc2)(c2cccc(-c3cccnc3F)c2)c2cc(F)ccc21

Procedure:
The title compound was prepared as described in Example 78 (Scheme #14, N) using (2-fluoropyridin-3-yl)boronic acid and 1-(3-bromophenyl)-6-fluoro-1-pyridin-4-yl-1H-isoindol-3-amine (Example 82) (22.5% yield): 1H NMR (CDCl3) δ 8.54 (m, 2 H), 8.18 (m, 1 H), 7.79 (m, 1 H), 7.50 (m, 1 H), 7.48-7.39 (m, 3 H), 7.32 (m, 1 H), 7.29-7.23 (m, 4 H), 7.18 (m, 1 H); MS (ESI) m/z 399 [M+1]+.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[N:29]=[C:28]([C:30]([O:32]CC)=[O:31])[O:27][N:26]=2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)C.O>[C:1]([N:20]1[CH:24]=[C:23]([C:25]2[N:29]=[C:28]([C:30]([OH:32])=[O:31])[O:27][N:26]=2)[N:22]=[CH:21]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1nc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)no1
Temperature: 0 °C

Procedure:
Ethyl 3-(1-trityl-1H-imidazol-4-yl)-1,2,4-oxadiazole-5-carboxylate (1.1 g, 2.442 mmol) was dissolved in ethanol (60 ml) and the resulting solution was cooled to 0° C. Cesium carbonate (6.36 g, 19.53 mmol) was dissolved in water (25 ml) and added into the solution. The reaction mixture was refluxed for 1 h. Ethanol was evaporated, diluted with water, filtered and washed with water. The solid was dried in vacuum at 40° C. The product was purified by recrystallization from THF and ethyl acetate, respectively. LC-MS: [M+1]=423.435.
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:21][O:22][C:23](=[O:25])[N:24]=2)[CH:15]=1.[N:28]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>N1C=CC=CC=1>[N:28]1([C:33]([N:24]2[C:23](=[O:25])[O:22][N:21]=[C:20]2[C:16]2[CH:15]=[C:14]([C:13]([F:12])([F:26])[F:27])[CH:19]=[CH:18][N:17]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: O=C(Cl)N1CCCC1
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(N1CCCC1)n1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Reaction time: 15 h
Yield: 63.4 %

Procedure:
To 1 ml of pyridine were added 0.3 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.26 g of 1-pyrrolidinecarbonyl chloride was added at room temperature. After stirring for 15 hours, the resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.27 g of 4-(1-pyrrolidinecarbonyl)-3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one (present compound (15)).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O(C(C)(C)C)[K]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ccc2ccccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[K]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc3ccccc3n2)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a degassed solution of 2-chloro-quinoline (1.00 g, 6.11 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.47 g, 7.33 mmol, 1.2 equiv; commercially available) in dimethoxyethane (15 mL) was added KOtert-Bu (0.96 g, 8.56 mmol, 1.4 equiv), (R)-(−)-1-[(S)-2-(dicyclohexyl-phosphino)-ferrocenyl]ethyl-di-tert-butylphosphine (3.39 mg, 0.0061 mmol, 0.1 mol %; Josiphos ligand [CAS RN 158923-11-6]; commercially available from Strem Chemicals, USA) and palladium(II) acetate (1.37 mg, 0.0061 mmol, 0.1 mol %). The reaction mixture was stirred at 90° C. for 4 h, concentrated by evaporation under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane (+1% triethylamine)/ethyl acetate providing 1.0 g (50%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.28-1.41 (m, 2H), 1.42 (s, 9H), 1.93-1.94 (m, 2H), 2.95-3.02 (m, 2H), 3.87-3.92 (m, 2H), 4.11-4.19 (m, 1H), 6.74 (d, J=8.9 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 7.10-7.16 (m, 1H), 7.42-7.51 (m, 2H), 7.59 (d, J=7.6 Hz, 1H), 7.83 (d, J=8.9 Hz, 1H). 13C NMR (75 MHz, DMSO): δ 28.07, 31.49, 42.41, 46.52, 78.52, 113.21, 121.03, 122.80, 125.52, 127.42, 128.89, 136.18, 147.82, 153.92, 156.13. MS (ISP): 328.5 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=O)=O.[I-:19].[Na+]>CC(C)=O.O>[F:14][C:13]([F:16])([F:15])[C:12]([F:18])([F:17])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][I:19]
Reactant: CS(=O)(=O)OCCCCCCC(F)(F)C(F)(F)F
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: FC(F)(F)C(F)(F)CCCCCCI
Reaction time: 8 h
Yield: 89.3 %

Procedure:
1-Methylsulfonyloxy-7,7,8,8,8-pentafluorooctane(14 g, 47.01 mmol) prepared in Step 1 was dissolved in acetone(200 ml), sodium iodide(19.62 g, 130 mmol) was added thereto, and the resulting mixture was stirred overnight under reflux-heating condition. The reaction solution was diluted with excess water(1 l), extracted twice with diethylether (100 ml), washed with 1% aqueous sodiumthiosulfate solution(100 ml) and saturated saline solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 14 g(42 mmol, Yield 89%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:9]2[CH2:12][CH:11]([C:13]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)(O)[C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH2:10]2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:20]3[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=3)[C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH2:10]2)=[CH:33][CH:32]=1
Reactant: CC(C)(C#N)C(O)(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C#N)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1

Procedure:
The reaction mixture of 128 mg (0.255 mmol) of 3-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3-(3,5-difluorophenyl)-3-hydroxy-2,2-dimethylpropanenitrile and 3 mL of phosphorus oxychloride in 5 mL of pyridine was heated at reflux for 48 h. The solution was concentrated, poured into 30 mL of ether, and washed with 5 mL of aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate=4:1 to afford the title compound. 1NMR (CDCl3) δ 1.47 (s, 6H), 3.48 (s, 2H), 4.18 (s, 2H), 4.47 (s, 1H), 6.66-6.77 (m, 2H), 7.25-6-7.35 (r, 8H); Mass Spectrum: m/e=483 (M+1 35Cl, 35Cl) and 485 (M+1 35Cl, 37Cl).
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([C:21]#[C:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][CH:16]=2)[C:11]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([CH2:21][CH2:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][CH:16]=2)[C:11]=1[C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2ccc(C#CC3CCCC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O
Solvent: O
Solvent: CC#N
Product: Cc1cc2ccc(CCC3CCCC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(2-cyclopentylethyl)-3-methylnaphthalen-2-yl)acetic acid (90) was prepared using the procedure of Example 87 from 2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(cyclopentylethynyl)-3-methylnaphthalen-2-yl)acetic acid. 1H-NMR: 400 MHz, (CD3OD) δ: 7.69 (d, J=9 Hz, 1H), 7.63 (s, 1H), 7.56 (m, 3H), 7.29 (m, 2H), 6.99 (s, 1H), 5.18 (s, 1H), 2.60 (m, 2H), 2.58 (s, 3H), 1.71 (m, 3H), 1.52 (m, 6H), 1.07 (m, 2H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 5.0 min run): tR (min)=4.54.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:9][C:10]1[S:11][C:12]2[CH2:13][N:14]([C:19](=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[CH2:15][CH2:16][C:17]=2[N:18]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([N:14]1[CH2:15][CH2:16][C:17]2[N:18]=[C:10]([CH2:9][O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[S:11][C:12]=2[CH2:13]1)=[O:27]
Reactant: Oc1ccccc1
Reactant: O=C(c1ccccc1F)N1CCc2nc(CCl)sc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1ccccc1F)N1CCc2nc(COc3ccccc3)sc2C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
Phenol (0.12 g, 1.24 mmol) was added to a stirred solution of 2-(chloromethyl)-5-(2-fluorobenzoyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine (0.19 g, 0.62 mmol) and K2CO3 (0.25 g, 1.86 mmol) in ACN (5 mL). The reaction mixture was stirred at 80° C. for 16 hours, filtered and the solvent evaporated in vacuo. The crude product was purified by HPLC on a C18 XBridge 30×100 mm, 5 μm column (gradient elution: 0.1% TFA in ACN/0.1% TFA in H2O). The desired fractions were collected and extracted with a saturated solution of NaHCO3 and the aqueous layer extracted with AcOEt. The combined organic layers were dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield 5-(2-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-thiazolo[5,4-c]pyridine (95 mg, 42% yield) as a solid. C20H17FN2O2S. 1H NMR (DMSO-d6, T=80° C.) δ ppm 2.81 (br. s., 2 H), 3.79 (br. s., 2 H), 4.76 (br. s., 2 H), 5.32 (s, 2 H), 6.85-7.09 (m, 3 H), 7.10-7.28 (m, 4 H), 7.30-7.39 (m, 1 H), 7.40-7.55 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][CH2:35]C4CC4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[CH3:39][O:40][CH2:41][CH2:42]NC>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][N:34]([CH2:42][CH2:41][O:40][CH3:39])[CH3:35])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:29])([F:31])[F:30])[CH:22]=4)[N:20]=3)[CH2:14][CH2:15]2)[N:5]=[CH:4][N:3]=1
Reactant: CNCCOC
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNCC2CC2)CC1
Product: COCCN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using N-(2-methoxyethyl)methylamine instead of cyclopropylmethylamine. LC-MS: (M+1=547, obsd.=547).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23]([CH:26]=O)[NH:22][C:21]=1[CH3:28])=[O:19])[CH3:13].N1CCCCC1>CCO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:26]\[C:23]1[NH:22][C:21]([CH3:28])=[C:20]([C:18]([NH:17][CH2:16][CH2:15][N:14]([CH2:29][CH3:30])[CH2:12][CH3:13])=[O:19])[C:24]=1[CH3:25]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(Br)cc32)c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To the solution of 5-bromoindolin-2-one (262 mg, 1.24 mmol) in EtOH (5 ml) was added N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (298 mg, 1.12 mmol) and piperidine (112 μL, 1.13 mmol). The mixture was stirred at 80° C. for 1 hour. After cooled down to room temperature, the reaction mixture was concentrated, filtrated, and washed with EtOH to give (Z)-5-((5-bromo-2-oxoindolin-3-ylidene)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (368 mg) as orange solid.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][C:5]1[CH:22]=[CH:21][C:8]2[N:9](COC)[C:10](=[O:17])[C:11]3[CH2:12][CH2:13][CH2:14][NH:15][C:16]=3[C:7]=2[CH:6]=1.[ClH:24]>C(O)C>[ClH:24].[ClH:24].[CH3:23][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:22]=[CH:21][C:8]2[NH:9][C:10](=[O:17])[C:11]3[CH2:12][CH2:13][CH2:14][NH:15][C:16]=3[C:7]=2[CH:6]=1
Reactant: COCn1c(=O)c2c(c3cc(CCN(C)C)ccc31)NCCC2
Agent: Cl
Solvent: CCO
Product: CN(C)CCc1ccc2[nH]c(=O)c3c(c2c1)NCCC3
Temperature: 80 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
The compound (20 mg, 0.06 mmol) prepared in step 7 was dissolved in ethanol (4 ml) and added with conc. hydrochloric acid (0.5 ml). The resulting mixture was stirred for 8 hours at 80° C. and cooled to room temperature. The mixture was then concentrated under reduced pressure to obtain the title compound (18 mg, yield: 82%, yellow solid).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:27]([C:24]2[CH:25]=[CH:26][C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:22][CH:23]=2)(=[O:29])=[O:28])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Br)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.27 (3, 9H), 7.41 (m, 3H), 7.50 (dd, 2H, J=4.8 Hz, 1.6 Hz), 7.67-72 (m, 4H), 8.85 (d, 2H, J=6 Hz), 10.19 (s, 1H). MS: m/z 473.9 (M++1).