Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])[C:6](=[O:12])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O>[C:1]([N:5]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])[C:6](=[O:12])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCCCCN(C(=O)C(=O)OCC)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C#CCCCCN(C(=O)C(=O)O)C(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
A solution of 0.7 g of 17d in 8 ml of dioxane was mixed with a solution of 0.3 g of KOH in 3 ml of water. The mixture was stirred for 2 h at 50° C. and then diluted with 30 ml of water and acidified to pH3 with 0.5 N HCl. The product was extracted with ethyl acetate. The extract was washed with water, dried and concentrated, to give 0.50 g of 19a as a colorless oil. NMR (CDCl3) δ 1.53 (s and m, 11, tertC4H9 and CH2), 1.78 (m, 2, CH2), 1.97 (t, 1, acetylene), 2.20 (m, 2, CH2), 3.56 (m, 2, CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6](/[CH:12]=[CH:13]/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([O:18]C)=[O:17])=[CH:5]2.[OH-].[K+].CCO.CC(O)=O.Cl>CCO.O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6](/[CH:12]=[CH:13]/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([OH:18])=[O:17])=[CH:5]2
Reactant: COC(=O)/C(=C/C=C/c1cc2cc(Cl)c(Cl)cc2[nH]1)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CO/C(=C\C=C\c1cc2cc(Cl)c(Cl)cc2[nH]1)C(=O)O
Temperature: 25 °C
Yield: 99 %

Procedure:
A suspension of methyl (2Z,4E)-5-(5,6-dichloroindol-2-yl)-2-methoxy-2,4-pentadienoate (10 g, 30.7 mmol) and KOH (3.6 g, 64.2 mmol) in EtOH/water {fraction (1/1)} (460 ml) was refluxed for 3 h. The suspension after cooling to RT was poured into water (1.5 l), it was acidified with 2N HCl and extracted with AcOEt (2×1 l). The organic phase was washed with water and dried (MgSO4), then concentrated and the residue taken up with CH2Cl2. Filtration and drying in the oven at 50° produced 9.5 g of pure title compound (30.4 mmol, yield 99.1%), m.p.=249-250° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([O-:7])=[O:6].Cl[C:13]1[C:18]([I:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1.O1CC[CH2:25][CH2:24]1>CCOC(C)=O.O.CC(O)=O>[I:19][C:18]1[C:13]([CH:4]([C:5]([O:7][CH2:24][CH3:25])=[O:6])[C:3]([O:9][CH2:10][CH3:11])=[O:8])=[N:14][CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=1
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1cnc(Cl)c(I)c1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(C(=O)OCC)c1ncc([N+](=O)[O-])cc1I
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74 %

Procedure:
To a round-bottom flask containing sodium hydride (0.56 g, 0.014 mol) suspended in tetrahydrofuran (25 mL) was added ethyl malonate (2.0 mL, 0.013 mol) dropwise, and was stirred at 25° C. for 5 minutes. To this reaction mixture was added 2-chloro-3-iodo-5-nitropyridine (2.5 g, 0.00879 mol) and was stirred at 25° C. for 4 hours. The reaction was diluted with EtOAc and water and was acidified with a few drops of AcOH. Then it was extracted with EtOAc and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and stripped in vacuo. The reaction was chromatographed on silica gel using 10% EtOAc/hexanes, followed by 20% EtOAc/hexanes to give the product (2.66 g, 74%). 1H NMR (400 MHZ, CDCl3): δ 9.35 (d, 1H), 8.89 (d, 1H), 5.27 (s, 1H), 4.31 (q, 4H), 1.30 (t, 6H); MS (ES) (M+H)=409.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)cc4Cl)cc3)c2cc1OC
Yield: 85.4 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (53 mg) was dissolved in toluene (5 ml) with heat, 2,4-dichlorophenyl isocyanate (115 mg) was added, and the admixture was refluxed with heat for 20 minutes. The separated crystals were filtered and then washed with toluene to obtain 74 mg of the title compound (yield: 85%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([Cl:16])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1Cl)=[O:5])[CH3:2].C(O)C.[CH2:21]([NH2:23])[CH3:22]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([Cl:16])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[NH:23][CH2:21][CH3:22])=[O:5])[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCNc1c(C(=O)OCC)c(C)nc(Cl)c1[N+](=O)[O-]
Yield: 69 %

Procedure:
27.9 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.1 mol.) are dissolved in 100 ml. of ethyl alcohol and 12 g. of triethylamine. At reflux temperature a solution of 4.5 g. of ethylamine in 50 ml. of alcohol is slowly added dropwise with continual stirring. After the addition is completed, the reaction mixture is refluxed for an additional 30 minutes. The solvent is then removed in vacuo and the residue is dissolved in 300 ml. of petroleum ether. The triethylamine hydrochloride is filtered off and the filtrate cooled to 0°; 6-chloro-4-ethylamino-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester crystallizes, yield: 69%, m.p. 36°-37° (methanol).
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH:16](C(=O)C)[CH2:15][CH:14](C(=O)C)[CH:13]1[C:23]#[N:24])([O:3][CH2:4][CH3:5])=[O:2].ClC1C=CC=[C:28]([C:32]([O:34]O)=[O:33])C=1.[I-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH:16]([O:3][C:1](=[O:2])[CH3:6])[CH2:15][CH:14]([O:34][C:32](=[O:33])[CH3:28])[CH:13]1[C:23]#[N:24])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CCCCCCC1C(C(C)=O)CC(C(C)=O)C1C#N
Agent: O=S([O-])([O-])=S
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCCCCC1C(OC(C)=O)CC(OC(C)=O)C1C#N
Reaction time: 96 h
Yield: 73 %

Procedure:
Five hundred milligrams of 2-(6'-carboethoxyhexyl)-3,5-diacetyl-cyclopentanecarbonitrile and 600 mg of meta-chloroperbenzoic acid were dissolved in 30 ml of chloroform, and the solution was allowed to stand for 4 days at room temperature. The reaction mixture was then treated with a 5% solution of sodium iodide and then with a 10% solution of sodium thiosulfate. Five hundred (500) milligrams of the resulting oily substance was purified by chromatography on silica gel to yield 200 mg of 2-(6'-carboethoxyhexyl)-3,5-diacetoxy-cyclopentanecarbonitrile which has the following characteristics: Infrared absorption (film method): 2250, 1735, 1235, 1180; Nuclear magnetic resonance (in CDCL3 solvent): the absorption of the methyne protons at the 3- and 5-position were observed at about 4.9 and about 5.2; 4.10 (2H, multiplet signal), 2.05 (6H, two singlet signals acetoxymethyl proton).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([OH:34])[C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[H-].[Na+].I[CH2:38][CH3:39]>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][CH:18]([O:34][CH2:38][CH3:39])[C:19]2[S:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:9])([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: CC(C)(Oc1ccc(CCC(O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Product: CCOC(CCc1ccc(OC(C)(C)C(=O)O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
2-(2,3-Dichloro-4-(3-ethoxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)-2-methylpropanoic acid is prepared from 2-(2,3-dichloro-4-(3-hydroxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid using 8 equivalents of sodium hydride and 2.1 equivalents of iodoethane according to general procedure H.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[CH:20]=[CH:21][C:22](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:22](/[CH:21]=[CH:20]/[C:19]3[CH:25]=[CH:26][CH:27]=[C:17]([C:16]([F:15])([F:28])[F:29])[CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(C(F)(F)F)c3)nc2n(CC)c1=O
Yield: 43.4 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 3.0 g (13.9 mmol) of 3-trifluoromethyl-cinnamic acid. Then, the resultant crude crystals were recrystallized from acetonitrile/water to give 2.07 g (yield 44%) of Compound 163 as white needles.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN(C)[C:19](N(C)C)=[O:20].[C]=O>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Ru].[Ru].[Ru].C1(C)C=CC=CC=1>[C:4]1([NH:1][C:19]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:20])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CN(C)C(=O)N(C)C
Agent: [Ru]
Agent: [C-]#[O+]
Agent: [C]=O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.3 %

Procedure:
Into a 200 ml autoclave equipped with a magnetic stirrer were introduced 5.6 g of nitrobenzene, 7.8 g of aniline, 27 ml of toluene, 6.3 g of N,N,N',N'-tetramethylurea (referred to hereafter as TMU), and 20 mg of Ru3 (CO)12. Thereafter the atmosphere within the system was changed to one of carbon monoxide, within was set at a pressure of 50 kg/cm2. Subsequently the reaction was carried out at 160° C. for 2 hours, with continuous stirring. After completion of the reaction, the system was cooled to room temperature, and following gas evacuation, the reaction liquor was filtered and 3.5 g of N,N'-diphenyl urea crystals obtained. The filtrate was analyzed by gas chromatography and high speed liquid chromatography, and found to contain 0.1 g of N,N'-diphenyl urea and 2.9 g of nitrobenzene. This indicated that the TOF (Turn Over Frequency) of N,N'-diphenyl urea production was 100 h-1 based on catalyst metal atoms, and the selectivity based on nitrobenzene was 94%.
Reaction SMILES: [C:1]([N:4]([C:12]1[C:16]2[CH:17]=[C:18]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[O:28][C:29]3[CH:34]=[C:33]([F:35])[C:32]([S:36](=[O:55])(=[O:54])[N:37](CC4C=CC(OC)=CC=4OC)[C:38]4[S:42][N:41]=[CH:40][N:39]=4)=[CH:31][C:30]=3[F:56])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)C(=O)OC(C)(C)C)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[S:42]1[C:38]([NH:37][S:36]([C:32]2[C:33]([F:35])=[CH:34][C:29]([O:28][C:22]3[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=3[C:18]3[CH:19]=[CH:20][C:15]4[O:14][N:13]=[C:12]([NH:4][C:1](=[O:3])[CH3:2])[C:16]=4[CH:17]=3)=[C:30]([F:56])[CH:31]=2)(=[O:54])=[O:55])=[N:39][CH:40]=[N:41]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4onc(N(C(C)=O)C(=O)OC(C)(C)C)c4c3)cc2F)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1noc2ccc(-c3cc(Cl)ccc3Oc3cc(F)c(S(=O)(=O)Nc4ncns4)cc3F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
A solution of tert-butyl acetyl(5-(5-chloro-2-(4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2,5-difluorophenoxy)phenyl)benzo[d]isoxazol-3-yl)carbamate (0.21 g, 0.25 mmol) in dichloromethane (20 mL) at 0° C., under nitrogen, was treated with trifluoroacetic acid (75 μL, 0.8 mmol) and stirred for 1 h. The reaction mixture was allowed to warm to ambient temperature, stirred for 3 h and concentrated in vacuo. The residue was purified by reverse phase HPLC to afford N-(5-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2,5-difluorophenoxy)-5-chlorophenyl)benzo[d]isoxazol-3-yl)acetamide as a colorless solid in 35% yield (0.05 g): 1H NMR (300 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.47 (s, 1H), 8.11 (s, 1H), 7.76-7.63 (m, 3H), 7.59, (d, J=2.3 Hz, 1H), 7.49 (dd, J=9.1, 2.7 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H), 7.13 (dd, J=10.3, 6.5 Hz, 1H), 2.12 (s, 3H), (Note: sulfonamide N—H not observed); MS (ES+) m/z 599.6 (M+23), 601.6 (M+23).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:39]([CH2:44][CH3:45])=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:39]([CH2:44][CH3:45])=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CCc1ncccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3CC)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(2-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K31) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (294 mg, 69%).
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-])=O.C([O-])([O-])=O.[K+].[K+].[C:21]([O:25][CH3:26])(=[O:24])[CH2:22][SH:23]>CN(C=O)C>[CH3:26][O:25][C:21]([C:22]1[S:23][C:4]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=2[CH:6]=1)=[O:24]
Reactant: COC(=O)CS
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc([N+](=O)[O-])cc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2,4-dinitrobenzaldehyde (6.45 g, 32.9 mmol) and K2CO3 (5.45 g, 39.4 mmol) in DMF (60 mL) was slowly added methyl thioglycolate (3.0 mL, 32.9 mmol). The mixture was stirred at RT for 1 h, then at 50° C. for 2 hr. The resultant mixture was poured into H2O/ice and stirred until a precipitate formed. The solid was filtered and triturated with hot MeOH. The pale brown solid was filtered. 1H NMR (DMSO-d6) δ 9.13 (s, 1H), 8.33 (s, 1H), 8.30-8.17 (m, 2H), 3.89 (s, 3H). MS (EI): cal'd (MH+) 238.01, exp (MH+) 238.10.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH2:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.CS([C:13]1[N:18]=[C:17]([C:19]2[C:20]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([Cl:39])[CH:33]=3)=[N:21][N:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=23)[CH:16]=[CH:15][N:14]=1)(=O)=O>O>[Cl:39][C:34]1[CH:33]=[C:32]([C:20]2[C:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:18]=3)=[C:23]3[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:31])[F:29])=[CH:27][N:22]3[N:21]=2)[CH:37]=[CH:36][C:35]=1[F:38]
Reactant: NCCN1CCCC1
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)c(Cl)c3)nn3cc(C(F)(F)F)ccc23)n1
Solvent: O
Product: Fc1ccc(-c2nn3cc(C(F)(F)F)ccc3c2-c2ccnc(NCCN3CCCC3)n2)cc1Cl

Procedure:
2-Pyrrolidin-1-ylethylamine (0.04 mL) and 4-[2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl methyl sulfone (0.02 g) were mixed at room temperature and heated with an airgun until a homogenous melt was obtained (2 min). Upon cooling, water was added. The precipitated solid was filtered and dried to give the title compound as a beige solid (0.012 g); 1H NMR (d6-DMSO) δ 9.50(1H, s), 8.48(1H, bs), 8.18(1H, d), 7.83(1H, d), 7.68(1H, dd), 7.62(1H, m), 7.56(1H, dd), 7.12(1H, bs), 6.42(1H, bs), 2.44(2H, bs), 1.67(4H, bs); m/z 505 (M+1)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[S:51][C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=1.N1C=CC=CC=1>C(Cl)Cl.O>[S:51]1[C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=[C:50]1[NH:49][C:40](=[O:42])[CH:39]([C:31]1[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=1)[CH2:43][CH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: Nc1nc2ccccc2s1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3s2)cc1Cl
Temperature: 0 °C
Yield: 75.8 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it became homogeneous. The resulting light purple reaction mixture was then treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 16, 200 mg, 0.61 mmol). The resulting reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminobenzothiazole (136 mg, 0.91 mmol) and pyridine (0.15 mL, 1.8 mmol) and was stirred at 25° C. for 16 h. The reaction was then diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate) afforded N-benzothiazol-2-yl-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (214 mg, 77%) as an off-white foam: EI-HRMS m/e calcd for C22H23ClN2O3S2 (M+) 462.0839, found 462.0833.
Reaction SMILES: C([NH:4][CH:5]1[CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]2[CH2:15][CH:16]=[CH:17][CH:18]=[C:7]2[S:6]1)(=O)C.CC(C1C=CC=CC=1)=C.N1CCCC1>C1(C)C(C)=CC=CC=1>[NH2:4][C:5]1[S:6][C:7]2[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=2[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C1C(NC(C)=O)SC2=CC=CCC21
Agent: C=C(C)c1ccccc1
Solvent: C1CCNC1
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1c(N)sc2ccccc12
Temperature: 102 °C
Reaction time: 20 h
Yield: 70.5 %

Procedure:
14.4 g of hydrogenation catalyst (Degussa-Hüls; E 101 R/W 5%) are added to a solution of 36 g of ethyl 2-acetylaminotetrahydrobenzothiophene-3-carboxylate in 250 ml of xylene (isomeric mixture) and the mixture is heated to a constant temperature of 139° C. to 141° C. 47 g of α-methylstyrene are metered in over a period of 5 h. The mixture is then refluxed for a further 36 h. It is cooled to 102° C., 32 g of pyrrolidine are added and the mixture is brought back to the reflux point (127° C.); it is stirred for 20 h at this temperature. After cooling to 20° C., the Pd/carbon is filtered off, the filtrate is concentrated to a residue, and the residue is taken up in 75 ml of ethyl acetate and washed with three times 12 ml of 10% hydrochloric acid. The organic phase is washed with twice 5 ml of water and then concentrated to a residue. This is recrystallized from 50 ml of isopropanol to give 21 g of ethyl 2-aminobenzothiophene-3-carboxylate in the form of slightly yellowish crystals (70.5% yield).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH3:16])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:28]1([CH3:36])[CH:33]=[CH:32][C:31]([CH:34]=[O:35])=[CH:30][CH:29]=1>O1CCCC1>[C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH2:16][CH:34]([OH:35])[C:31]3[CH:32]=[CH:33][C:28]([CH3:36])=[CH:29][CH:30]=3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNC(=O)c1c(-c2ccccc2)noc1C
Reactant: Cc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccccc2)noc1CC(O)c1ccc(C)cc1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A suspension of 75 g. (0.348 mole) of 3-phenyl-5,N-dimethyl-isoxazole-4-carboxamide and 1 liter of tetrahydrofuran is cooled to -65° C. and 478 ml. of 1.6M n-butyllithium in hexane (0.765 mole) is added dropwise maintaining the temperature between -60° and -70° C. After the addition is complete, the orange suspension is stirred for 11/2 hours at -60° to -70° C., and then 37.2 g. (0.350 mole) of p-tolualdehyde in 375 ml. tetrahydrofuran is added dropwise maintaining the temperature between -60° and -70° C. After addition is complete the mixture is stirred for 11/2 hrs. at -60° to -70° C. and then warmed to -30° C. and quenched by the addition of saturated ammonium chloride solution. The mixture is further diluted with tetrahydrofuran and the layers are separated. The tetrahydrofuran layer is washed twice with 50% brine, and once with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The solid residue is triturated with a 50:50 mixture of ether:petroleum ether, filtered and washed with cold ether to give 3-phenyl-5-(4-methyl-β-hydroxyphenethyl)-N-methyl-isoxazole-4-carboxamide; m.p. 148° to 150° C.
Reaction SMILES: [CH3:1][C:2]1([NH:21][C:22]2C=N[C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[N:19]=[CH:18][CH:17]=[N:16]1.Cl.[NH2:33][C:34]1(C)CCCC1NC(=O)C1C=CC=CC=1N1N=CC=N1.ClC1N=CC(C(F)(F)F)=CN=1>>[CH3:1][C:2]1([NH:21][C:22]2[N:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:34][N:33]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[N:16]=[CH:17][CH:18]=[N:19]1
Reactant: CC1(Nc2cnc(C(F)(F)F)cn2)CCCC1NC(=O)c1ccccc1-n1nccn1
Reactant: CC1(N)CCCC1NC(=O)c1ccccc1-n1nccn1
Agent: Cl
Agent: FC(F)(F)c1cnc(Cl)nc1
Product: CC1(Nc2ncc(C(F)(F)F)cn2)CCCC1NC(=O)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-(2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 82) from N-(2-amino-2-methylcyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 26; 200 mg, 0.70 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (CAS number 69034-12-4; 141 mg, 0.77 mmol) except this was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) followed by reverse phase chromatography (C18 silica, 0-100% water (with 0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: C(O/[N:5]=[C:6](/[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[F:23])\[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[OH:15])(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:23][C:17]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=1[C:6]1[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[O:15][N:5]=1
Reactant: COc1ccc(/C(=N\OC(C)=O)c2cc(F)ccc2F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(-c3cc(F)ccc3F)noc2c1
Reaction time: 0.75 h

Procedure:
To a mixture of 34 g of E-2',5'-difluoro-2-hydroxy-4-methoxybenzophenone O-acetyl oxime in 70 ml dimethylformamide at 65° C., 18.2 g of potassium carbonate is added. The mixture is stirred for 45 min and poured into water. The precipitate is collected and dried. Recrystallization from ether gives 3-(2,5-difluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 121°-122° C.