Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:25]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:11]=3[O:20][CH2:21][CH:22]([F:24])[F:23])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:26]([O:30][C:31]([N:33]1[CH2:39][CH2:38][C:37]2[CH:40]=[CH:41][C:42]([NH2:44])=[CH:43][C:36]=2[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:39][CH2:38][C:37]2[CH:40]=[CH:41][C:42]([NH:44][C:2]3[N:25]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:11]=5[O:20][CH2:21][CH:22]([F:24])[F:23])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:43][C:36]=2[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)c(OCC(F)F)c1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
7-{8-[2-(2,2-Difluoro-ethoxy)-4-methanesulfonyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-[2-(2,2-difluoro-ethoxy)-4-methanesulfonyl-phenyl]-[1,2,4]-triazolo[1,5-a]pyridine (0.371 g, 1.20 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.253 g, 652 mmol) in a manner analogous to Example 311a and 311b to give product (0.285 g, 71%): 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.58 (s, 1H), 8.82 (d, 1H), 7.94 (d, 1H), 7.74 (s, 1H), 7.68 (m, 2H), 7.48 (d, 1H), 7.37 (s, 1H), 7.05 (m, 2H), 6.27 (br m, 1H), 4.52 (m, 2H), 3.45 (m, 4H), 2.77 (m, 4H), 2.50 (s, 3H), 1.41 (s, 9H). MS=614 (MH)+.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][C:14](=[O:16])[CH2:13][CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[C:1]([O:9][C@H:10]1[CH2:15][C@@H:14]([OH:16])[CH2:13][CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1nccc1[C@H]1CCC(=O)C[C@@H]1OC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cn1nccc1[C@H]1CC[C@H](O)C[C@@H]1OC(=O)c1ccccc1
Yield: 65.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 162d by using the (1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)-5-oxocyclohexyl benzoate (441 mg, 1.48 mmol) prepared in Example 163c, sodium borohydride (168 mg, 4.44 mmol) and ethanol (7.0 mL), to yield the title compound (290 mg, 65%) as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([C:12]2([CH3:16])[CH2:15][O:14][CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([C:12]3([CH3:16])[CH2:15][O:14][CH2:13]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC1(C(=O)NCc2nccnc2Cl)COC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(c2ncc3c(Cl)nccn23)COC1
Temperature: 25 °C
Yield: 128.7 %

Procedure:
To a stirred solution of N-((3-chloropyrazin-2-yl)methyl)-3-methyloxetane-3-carboxamide (1.945 mmol, 0.47 g) in dichloromethane (10 ml) cooled in an ice-bath was added pyridine (27.2 mmol, 2.198 ml) and trifluoromethane sulfonic anhydride (11.67 mmol, 1.971 ml). The ice-bath was removed and the reaction was stirred at room temperature. After 2 hours the reaction mixture was cooled in ice-bath, diluted with ethyl acetate (5 mL) and quenched with aqueous sodium hydrogencarbonate. The organic layer separated and the aqueous layer washed four times with ethyl acetate. The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo. Purification by column chromatography (silica gel, ethyl acetate) yielded 8-chloro-3-(3-methyloxetan-3-yl)imidazo[1,5-a]pyrazine (0.56 g).
Reaction SMILES: C(O[C:4](=O)[NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC>C1COCC1>[CH3:4][NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)NC1CCCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN[C@H]1CCCc2ccccc21
Temperature: 75 °C
Reaction time: 2 h

Procedure:
(1,2,3,4-Tetrahydro-naphthalen-1-yl)-carbamic acid ethyl ester (5.0 g, 22.8 mmol) is added slowly under nitrogen to a suspension of LiAlH4 (2.6 g, 68 mmol) in THF (50 mL). The resulting mixture is heated at 75° C. with stirring for 2 hours. On cooling, Na2SO4.10H2O (15.0 g) and ether (100 mL) are added to the mixture. The resulting mixture is stirred at room temperature for 1 hour, filtered through celite, and concentrated in vacuo. 1 N HCl (20 mL) and ether (20 mL) are added to the residue. The organic layer is separated and discarded. The aqueous layer is basified with 1 N NaOH and extracted with CH2Cl2 (2×25 mL). The combined extract is washed with water (2×), dried (Na2SO4) and concentrated to give (S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine as an oil. [α]RT=−10.6 (0.02, EtOH). 1H NMR (CDCl3) 7.30 (m, 1H), 7.06-7.20 (m, 3H), 3.66 (t, 1H), 2.78 (m, 2H), 2.50 (s, 3H), 1.70-2.00 (m, 4H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Br[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]>CN(C)C=O>[N:1]1([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[C:16]3[C:15](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]2=[O:23])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCn1cncn1
Reaction time: 1.5 h
Yield: 86.4 %

Procedure:
A mixture of about 9.0 g of 1H-1,2,4-triazole, about 6.24 g of approximately 50% sodium hydride in oil and about 130 ml of dimethylformamide was stirred for about 1.5 hours, then about 33 g of N-(4-bromobutyl)phthalimide was added and this mixture was heated on a steam bath for about 6 hours then concentrated to a solid residue. Water and methylene chloride were added, the organic layer was separated, washed with water, dried and concentrated to a residue. This residue was crystallized from ethanol, giving about 27.3 g of 2-[4-(1H-1,2,4-triazol-1-yl)butyl]-1H-isoindol-1,3(2H)-dione.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[CH3:27][N:28]([CH3:35])[C@H:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1>>[CH3:27][N:28]([CH3:35])[C@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[CH2:30]1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN(C)[C@H]1CCCNC1
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCC[C@H](N(C)C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)—N,N-dimethylpiperidin-3-amine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (d, J=13.39 Hz, 1 H) 1.83 (br. s., 2 H) 2.06-2.23 (m, 1 H) 2.43 (s, 3 H) 2.81 (br. s., 7 H) 3.04-3.25 (m, 1 H) 3.35-3.42 (m, 1 H) 3.54 (br. s., 1 H) 4.02 (br. s., 1 H) 4.44 (br. s., 1 H) 7.67 (d, J=8.22 Hz, 1 H) 7.74 (s, 1 H) 7.78 (d, J=7.83 Hz, 1 H) 8.11 (dd, J=8.59, 1.77 Hz, 1 H) 8.17 (br. s., 1 H) 8.42 (br. s., 1 H) 8.58 (d, J=1.52 Hz, 1 H); ESI-MS m/z [M+H]+ 431.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29]C)=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=3[O:39][CH3:40])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:25])[CH3:26])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=3[O:39][CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(C)ccc2OC)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 70 °C
Yield: 21.6 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-methyl-2-methoxy-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (100 mg, 0.167 mmol), NaOH (33.5 mg, 0.837 mmol), H2O (2 mL) and methanol (3 mL) was heated at 70° C. for 1 h. Then methanol was removed by vacuum and the aqueous solution was acidified to “pH” 1-2 by addition of concentrated HCl aqueous solution. The precipitate was collected by filtration and washed with CH2Cl2 twice to give the title compound as a white solid (21 mg).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([O:13][CH3:14])=[CH:6][C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)=[CH:18][CH:17]=1>C1COCC1.[OH-].[Na+]>[Cl:32][C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][CH2:22][C:19]2[CH:20]=[CH:21][C:16]([NH:15][C:5]3[CH:6]=[C:7]([O:13][CH3:14])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=3[C:3]([OH:33])=[O:2])=[CH:17][CH:18]=2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1Nc1ccc(CCCc2ccc(Cl)c(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(Nc2ccc(CCCc3ccc(Cl)c(Cl)c3)cc2)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 36 h
Yield: 70.5 %

Procedure:
To a solution of 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}-4-methoxy-5-nitrobenzoic acid methyl ester (0.30 g, 0.061 mol) in THF (5 mL), 1N NaOH (aq.) (2.5 mL) was added, and the mixture was stirred for 36 hours at room temperature. The solvent was removed, and the residue was acidified with concentrated HCl to pH 3. The precipitate was collected by filtration and dried in vacuum for 16 hours. Recrystallization with MeOH gave the title compound as an orange solid 0.21 g (0.043 mol. 70%). mp 200-201° C.
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].[Br:5][C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([Cl:13])[CH:7]=1.O>CN(C)C=O>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([S:3][CH2:1][CH3:2])=[C:8]([Cl:13])[CH:7]=1
Reactant: Fc1ccc(Br)cc1Cl
Reactant: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1ccc(Br)cc1Cl
Temperature: 65 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
Sodium ethanethiolate (2.0 g) was added to a solution of 4-bromo-2-chloro-1-fluorobenzene (5.0 g) in N,N-dimethylformamide (20 mL), and the mixture was stirred at 65° C. for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:1→0:100) to give the title compound as a colorless oil (4.8 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[C:9]([CH3:15])[CH:8]=1)[CH3:2].[C:20]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:31][C:32]([CH3:38])=[C:33]([CH2:35][CH2:36]O)[N:34]=2)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]([CH3:15])[C:10]([O:14][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([C:27]3[CH:26]=[CH:25][C:24]([C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:29][CH:28]=3)[S:31][C:32]=2[CH3:38])=[C:11]([CH3:13])[CH:12]=1)[CH3:2]
Reactant: Cc1sc(-c2ccc(C(C)(C)C)cc2)nc1CCO
Reactant: CCOC(=O)C(Cc1cc(C)c(O)c(C)c1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cc(C)c(OCCc2nc(-c3ccc(C(C)(C)C)cc3)sc2C)c(C)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(4-hydroxy-3,5-dimethyl-phenyl)-propionic acid ethyl ester was reacted with 2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethanol (example 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3,5-dimethyl-phenyl)-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3,5-dimethyl-phenyl)-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]1[CH2:10][CH:9](O)[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[O:6][CH2:5]1.N>Cl>[CH3:2][NH:3][CH:4]1[CH:10]=[CH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[O:6][CH2:5]1
Reactant: CNC1COc2ccccc2C(O)C1
Agent: Cl
Agent: N
Product: CNC1C=Cc2ccccc2OC1
Temperature: 0 °C
Yield: 99.2 %

Procedure:
23.0 g of 3-methylamino-2,3,4,5-tetrahydro-1-benzoxepin-5-ol hydrochloride were heated to 100 degrees C. for 30 minutes with stirring in 50 ml of 32 percent aqueous hydrochloric acid solution. Subsequently, the solution was poured over 100 g of ice, and the mixture was rendered alkaline with 70 ml of 25 percent aqueous ammonia solution. The mixture was thereafter extracted once with 100 ml and four times with 25 ml portions of methylene chloride. The combined methylene chloride extracts were dried over sodium sulfate, and the solvent was distilled off under reduced pressure. 17.4 g of 3-methylamino-2,3-dihydro-1-benzoxepine were obtained as a colorless oil.
Reaction SMILES: [F:1][CH:2]([F:15])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([OH:14])=O)[N:4]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=[O:31])[C:25]=1[CH:32]1[O:36][N:35]=[C:34]([C:37]2[N:38]=[C:39]([CH:42]3[CH2:47][CH2:46][NH2+:45][CH2:44][CH2:43]3)[S:40][CH:41]=2)[CH2:33]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl.CN(C)C=O>[F:15][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:9])[F:10])[N:5]([CH2:11][C:12]([N:45]2[CH2:44][CH2:43][CH:42]([C:39]3[S:40][CH:41]=[C:37]([C:34]4[CH2:33][CH:32]([C:25]5[C:24]([F:23])=[CH:29][CH:28]=[CH:27][C:26]=5[CH:30]=[O:31])[O:36][N:35]=4)[N:38]=3)[CH2:47][CH2:46]2)=[O:14])[N:4]=1
Reactant: O=C(O)Cn1nc(C(F)F)cc1C(F)F
Reactant: O=Cc1cccc(F)c1C1CC(c2csc(C3CC[NH2+]CC3)n2)=NO1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1cccc(F)c1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3,5-bis-(difluoromethyl)-1H-pyrazol-1-yl]acetic acid (58 mg) in dichloromethane (20 ml) were added, at 0° C., oxalyl chloride (94.5 mg) and one drop of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 2 hours. The solvent and the excess reagent were removed under reduced pressure. The solid residue was again dissolved in dichloromethane (5 ml) and, at 0° C., added dropwise to a solution of 4-{4-[5-(2-fluoro-6-formylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidinium chloride and triethylamine (5.0 eq.) in dichloromethane (15 ml). The reaction mixture was stirred at room temperature overnight. Then it was admixed with concentrated sodium hydrogencarbonate solution, and the aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated. Purification by column chromatography gave 2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}-3-fluorobenzaldehyde (55 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(OCCO)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)c1ccc(OCCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In an oven-dried flask placed under a nitrogen atmosphere, the product of Step 1 (121 g) and 3,4-dihydro-2H-pyran (106 mL) were stirred in dichloromethane (1100 mL). To this was added p-toluenesulfonic acid (4.4 g). The reaction mixture was stirred at room temperature for 2 hours. It was then transferred to a separatory funnel and washed with a saturated aqueous solution of sodium bicarbonate (1 L), dried over sodium sulfate and concentrated by rotary evaporation to yield an oil. 160 grams of 4-fluorophenyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl methanone was isolated. It was used in the next reaction as is without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>[Pd].CCO>[CH2:17]([O:16][C:14]([C@@H:3]1[N:2]([CH3:1])[C:6](=[O:7])[CH2:5][C@@H:4]1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C1C(c2ccccc2)=CC(=O)N1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H]1[C@@H](c2ccccc2)CC(=O)N1C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
A mixture of ethyl 1-methyl-5-oxo-3-phenyl-3-pyrroline-2-carboxylate (1 g, 4 mmol) and 10% palladium on carbon (0.1 g) in EtOH (30 mL) was stirred under a H2 atmosphere (1 Atm) for 1 hour. The reaction mixture was filtered through a pad of Celite® with the aid of CH2Cl2. The filtrate was concentrated under reduced pressure to yield (±)-(4R*,5R*)-5-(ethoxycarbonyl)-1-methyl-4-phenylpyrrolidin-2-one (1 g, 100%): TLC (40% EtOAc/hex) Rf 0.13; 1H NMR (CDCl3) δ 0.83 (t, J=7.4 Hz, 3H), 2.64-2.72 (dd, J=8.8, 16.5 Hz, 1H), 2.88-3.0 (m, 4H), 3.65-4.0 (m, 4H), 4.34-4.36 (d, J=8.9 Hz, 1H), 7.2-7.35 (m, 5H), HPLC ES-MS m/z (rel abundance) 248 (MH+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10].CON(C)[C:17]([CH:19]1CCCC[CH2:20]1)=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:13][CH2:12][CH2:20][CH2:19][CH2:17]1)=[O:10]
Reactant: CON(C)C(=O)C1CCCCC1
Reactant: Cc1ccc(N)c(C(=O)C2CC2)c1
Product: Cc1ccc(N)c(C(=O)C2CCCCC2)c1
Yield: 75 %

Procedure:
Crude (2-amino-5-methyl-phenyl)-cyclohexyl-methanone (75%, oil) was prepared in a similar fashion as described for (2-amino-5-methyl-phenyl)-cyclopropyl-methanone using cyclohexanecarboxylic acid methoxy-methyl-amide instead of cyclopropanecarboxylic acid methoxy-methyl-amide.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:21][N:20]=[CH:19][N:18]=3)(=[O:15])=[O:14])=[CH:9][C:8]=2[C:22]#[N:23])=[C:4](I)[CH:3]=1.CC1(C)C(C)(C)OB([N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)O1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:21][N:20]=[CH:19][N:18]=3)(=[O:15])=[O:14])=[CH:9][C:8]=2[C:22]#[N:23])=[C:4]([C:38]2[CH:39]=[N:35][NH:36][CH:37]=2)[CH:3]=1
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(Cl)cc1I
Reactant: CC1(C)OB(n2cccn2)OC1(C)C
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(Cl)cc1-c1cn[nH]c1

Procedure:
The title compound was prepared from 4-(4-chloro-2-iodophenoxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 355) and (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole using Method E above with microwave irradiation for 1 hour at 85° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@@H:28]1[CH3:33]>>[CH3:33][C@@H:28]1[N:27]([CH3:26])[CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:29]1
Reactant: C[C@H]1CNCCN1C
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCN(C)[C@@H](C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1,2-dimethylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (br. s., 3 H) 2.33 (d, J=2.27 Hz, 3 H) 2.84 (s, 3 H) 3.13-3.74 (m, 7 H) 7.63 (d, J=6.82 Hz, 1 H) 7.71-7.78 (m, 1 H) 7.90-8.67 (m, 4 H). ESI-MS m/z [M+H]+ 435.3.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([N+:9]([O-])=O)[CH:6]=[CH:7][CH:8]=1)=[CH2:2]>C(O)(=O)C.[Zn]>[CH:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[NH2:9])=[CH2:2]
Reactant: C=Cc1cccc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Product: C=Cc1cccc(N)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
To a solution of the above 3-ethenylnitrobenzene (10 g) in acetic acid (30 ml) was added zinc powder (10 g) and the mixture heated to 70° C. with stirring for two hours, then cooled to room temperature and filtered. Ethyl acetate (300 ml) was added to the filtrate, followed by 1M sodium hydroxide until pH 10. The organic layer was separated, washed with water (100 ml), brine (100 ml) and dried over magnesium sulphate. The solvent was removed under reduced pressure to give the crude product, which was purified by column chromatography to give 3-ethenylaniline (4.9 g), δ (60 MHz, CDCl3) 3.60 (2H, bs, NH2), 5.1, 5.2, 5.5 and 5.8 (3H, 4d, CH2 and CH) and 6.3 to 7.3 (4H, m, ArH).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([CH:9]=[N:10]O)[C:6]([C:12]2[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[N:5]1)([CH3:3])[CH3:2].S(Cl)(Cl)=O>ClCCCl>[CH:1]([N:4]1[CH:8]=[C:7]([C:9]#[N:10])[C:6]([C:12]2[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cc(C=NO)c(-c2ccc([N+](=O)[O-])o2)n1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: CC(C)n1cc(C#N)c(-c2ccc([N+](=O)[O-])o2)n1
Yield: 99 %

Procedure:
Stir an admixture of 3.4 g of finely pulverized 1-isopropyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehydeoxime in 15 ml of 1,2-dichloroethane with 1.8 g of thionyl chloride for 80 minutes at 55° C. Evaporate the resulting solution to dryness in vacuo and then evaporate to dryness twice more after mixing with 1,2-dichloroethane to obtain a 99% yield of 1-isopropyl-3-(5-nitro-2-furyl)pyrazole-4-carbonitrile [m.p. 181° to 182° C (from ethanol)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22](OCC)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([C:27]([F:30])([F:29])[F:28])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+:32].N>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:21][C:22]([NH2:32])=[O:23])=[CH:19][CH:20]=3)[CH:11]=[C:10]([C:27]([F:28])([F:30])[F:29])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: CCOC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc(C(F)(F)F)c2)cc1
Agent: N
Agent: [Cl-]
Solvent: CO
Product: NC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc(C(F)(F)F)c2)cc1
Temperature: 100 °C
Reaction time: 42 h
Yield: 44.4 %

Procedure:
A 10-mL vial was charged with ethyl 2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)amino)phenyl)acetate (0.064 g, 0.15 mmol) and ammonium chloride (0.024 g, 0.44 mmol) in methanol (2 mL). To this mixture was added NH3 (4.2 mL, 7N in methanol, 29.4 mmol). The vial was sealed and the resulting mixture was stirred at 100° C. for 42 h. After this time, the crude reaction solution concentrated under reduced pressure. The residue absorbed on silica (2 g) then purified by chromatography on silica using dichloromethane/methanol (10:0 to 9:1) as eluent to afford the title compound (0.027 g, 46%) as a light brown solid. MW=405.80. M.p. 97-99° C. 1H NMR (DMSO-d6, 500 MHz) δ 9.39 (s, 1H), 7.99-7.97 (m, 1H), 7.91-7.86 (m, 1H), 7.57-7.51 (m, 3H), 7.46 (br s, 1H), 7.33-7.29 (m, 2H), 7.27-7.23 (m, 2H), 7.19 (d, J=2.0 Hz, 1H), 6.88 (br s, 1H), 3.37 (s, 2H); APCI MS m/z 406 [M+H]+.