Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.Cl[CH:26](Cl)C>CN(C)C=O>[C:1]1([S:7][C:8]2[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][C:9]=2[C:10]([O:12][CH3:26])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(Cl)Cl
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Sc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(F)(F)F)cc1Sc1ccccc1

Procedure:
A mixture of 2-phenylsulphenyl-4-trifluoromethylbenzoic acid (11.5 g), thionyl chloride (11.4 g), dimethylformamide (0.2 ml) and dichloroethane was heated at reflux for 90 minutes. The solution was then concentrated under reduced pressure and the residue was dissolved in methanol and heated at reflux for one hour. The resulting solution was poured into aqueous sodium bicarbonate and extracted with ether. The organic phase was dried over anhydrous sodium sulphate, filtered and evaporated. The resulting material was crystallised from hexane to give methyl 2-phenylsulphenyl-4-trifluoromethylbenzoate (10.5 g) as white crystals, m.p. 58° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][CH:11]2[CH2:16][O:15][C:14]3([CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[O:13][CH2:12]2)[CH:5]=[CH:4][N+:3]=1[O-].C(OC(=O)C)(=[O:25])C.[OH-].[Na+]>CO>[CH3:8][C:7]1[C:2]([CH2:1][OH:25])=[N:3][CH:4]=[CH:5][C:6]=1[O:9][CH2:10][CH:11]1[CH2:16][O:15][C:14]2([CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[O:13][CH2:12]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(OCC2COC3(CCOCC3)OC2)cc[n+]([O-])c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(OCC2COC3(CCOCC3)OC2)ccnc1CO
Temperature: 85 °C
Reaction time: 0.92 h
Yield: 59.5 %

Procedure:
The 2,3-dimethyl-4-(1,5,9-trioxaspiro[5.5]undec-3-ylmethoxy)pyridine 1-oxide (3.31 g, 10.7 mmol) obtained in the step (10b) was mixed with acetic anhydride (30 ml, 331 mmol). The mixture was stirred at 85° C. for 1 hour and 55 minutes. After cooled to a room temperature, the reaction mixture was concentrated. To the residue, methanol (50 ml) and a 5N aqueous sodium hydroxide solution (30 ml, 150 mmol) were added and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated and the residue was separated between water and ethyl acetate. The organic layer was washed twice with a 1N aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the title compound (1.97 g, yield: 59.5%) as a brown oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:14][C:15]1[CH:22]=[CH:21][C:18]([NH:19][CH3:20])=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:22]=[CH:21][C:18]([N:19]([CH3:20])[S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNc1ccc(F)cc1
Product: CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1

Procedure:
4-(chlorosulfonyl)benzoic acid (0.5 g, 2.27 mmol) was treated with 4-fluoro-N-methylaniline (851 mg, 6.80 mmol) using method A to give 4-(N-(4-fluorophenyl)-N-methylsulfamoyl)benzoic acid as a white solid. Yield: 534 mg (76%). 1H-NMR: 8.10 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.23-7.11 (m, 4H), 3.15 (s, 3H).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][S:11][CH2:10][C@@H:9]([C:19]([OH:21])=[O:20])[NH:8][C:7]1=[O:22])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O>[C:1]([S:4][CH2:5][CH:6]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][S:11][CH2:10][C@@H:9]([C:19]([O:21][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:20])[NH:8][C:7]1=[O:22])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC1CCCCCCCSC[C@@H](C(=O)O)NC1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CC(=O)SCC1CCCCCCCSC[C@@H](C(=O)OCc2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3R)-6-(Acetylthiomethyl)-5-oxo-1-thia-4-azacyclotridecane-3-carboxylic acid (0.62 g, 1.78 mmol) is dissolved in dimethylformide (8 ml) and cesium carbonate (0.64 g, 1.96 mmol) is added, followed by benzyl bromide (0.31 g, 1.78 mmol). The mixture is stirred overnight at room temperature, poured into water (300 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers are washed with water (2×100 ml), brine (1×200 ml), dried (MgSO4) and the solvent is evaporated. Silica gel chromatography (5% ethyl acetate/hexane) gives benzyl (3R)-6-(acetylthiomethyl)-5-oxo-1-thia-4-azacyclotridecane-3-carboxylate, m.p. 192°-193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:39])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[C:31]([Cl:38])[CH:30]=1)[CH3:25].CCN(CC)CC>ClCCCl>[CH2:24]([O:26][C:27](=[O:39])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:37])=[C:31]([Cl:38])[CH:30]=1)[CH3:25]
Reactant: CCOC(=O)Cc1ccc(N=C=O)c(Cl)c1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOC(=O)Cc1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 11.1) was reacted with (3-chloro-4-isocyanato-phenyl)-acetic acid ethyl ester in 1,2-dichloroethane in the presence of Et3N (1.4 eq.) for 2 d under reflux conditions to give the title compound as brown gum. MS: m/e=565.3 [M+H+].
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:26])[CH:6]=[C:7]([CH2:24][CH3:25])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]([Cl:38])=[CH:35][CH2:36]Cl>CN(C)C=O>[CH2:24]([C:7]1[CH:6]=[C:5]([O:26][CH2:36][CH:35]=[C:34]([Cl:38])[Cl:33])[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][N:15]=1)[CH3:25]
Reactant: CCc1cc(O)cc(CC)c1OCCCOc1ccc(C(F)(F)F)cn1
Reactant: ClCC=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 0.45 g of 3,5-diethyl-4-[3-(5-trifluoromethyl-2-pyridyloxy)propyloxy]phenol and 0.17 g of potassium carbonate, to which a solution of 0.18 g of 1,1,3-trichloropropene dissolved in 5 ml of N,N-dimethylformamide was added dropwise, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice-water, and extracted twice with 100 ml of diethyl ether. The combined diethyl ether was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude produce was subjected to silica gel chromatography, which afforded 0.35 g of 3,5-diethyl-4-[3-(5-trifluoromethyl-2-pyridyloxy)propyloxy]-1-(3,3-dichloro-2-propenyloxy)benzene (60% yield), nD20.0 1.5192.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)\[CH3:7])[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)\[CH2:7][Br:17])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)Oc1cccc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1cccc(Br)c1
Yield: 31.6 %

Procedure:
To a stirred mixture of (E)-3-(3-bromo-phenoxy)-but-2-enoic acid ethyl ester (5.80 g, 0.020 mol) in carbon tetrachloride (30 mL) under a nitrogen atmosphere was added N-bromosuccinimide (5.51 g, 0.031 mol) and benzoyl peroxide (500 mg, 0.002 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(3-bromo-phenoxy)-but-2-enoic acid ethyl ester (2.30 g, 31%) as a yellow oil.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15](/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])\[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=1>O1CCCC1>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1/[C:15](/[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]1[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=1)=[O:10]
Reactant: NCCCCc1cccnc1
Reactant: COc1ccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2OC)cc1
Solvent: C1CCOC1
Product: COc1ccc(/C(=C\C=C\C(=O)NCCCCc2cccnc2)c2ccccc2OC)cc1
Yield: 81.2 %

Procedure:
As before in Example 134, a solution of (E,E)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.5 g) an 3-pyridinebutanamine (0.64 g) in tetrahydrofuran (15 mL) was stirred overnight at room temperature. After the usual workup. the crude product was crystallized from ethyl acetate to furnish 1.25 g of (E,E)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide, mp 164°-165° C.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])[CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:39][C:35]1[C:34]([F:40])=[C:33]([C@@H:14]2[C@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:16]([CH2:18][C:19]([CH3:22])([CH3:20])[CH3:21])[CH2:17][N:13]2[C:11]([NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:41])=[O:2])=[O:12])[CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)c1cccc(NC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1CN(C(=O)Nc2cccc(C(=O)O)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.8 %

Procedure:
To a mixture of 3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid methyl ester (20.0 mg, 0.03 mmol) in THF/MeOH (0.6 mL/0.2 mL) was added 4 N LiOH (0.2 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 NH2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid (19.5 mg, 100%). HRMS (ES+) m/z Calcd for C30H27Cl2F2N3O3+H [(M+H): 586.1471; Found: 586.1473.
Reaction SMILES: O[N:2]=[C:3]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][CH2:5][C:6]([OH:8])=[O:7]>C(O)C.[Pd]>[NH2:2][CH:3]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)CCC(CCc1ccccc1)=NO
Agent: [Pd]
Solvent: CCO
Product: NC(CCC(=O)O)CCc1ccccc1
Yield: 5.1 %

Procedure:
A solution of the oximes 100 (2.7 g 12.2 mmol) in ethanol (40 mL) was hydrogenated over 10% Pd—C at 40 psi and 50° C. for 3 days. The catalyst was filtered off and the solvent was evaporated. The residue was partitioned between ether and 0.1 M HCl and the aqueous layer was lyophilized giving 101 as a white powder (130 mg, 5%).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccc(Cl)cc3)CC2)cc1-c1ccc(F)cc1

Procedure:
108 mg (60%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg, 0.365 mmol), 1-(4-chlorophenyl)piperazine (98 mg, 0.365 mmol), DIPEA (0.1 mL, 0.548 mmol) and NaBH(OAc)3 (232 mg, 1.095 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([Li])CCC.[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18]>CCCCCC>[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]([OH:18])[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1
Reactant: Clc1ccc(Br)cc1
Reactant: O=Cc1ccccc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Product: OC(c1ccc(Cl)cc1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
A solution of 23.0 g (120 mmole) of 4-bromochlorobenzene in 150 ml of dry tetrahydrofura: was cooled to -78° C. under nitrogen and 78 ml (120 mmole) of 1.55M n-butyllithium in hexane was added dropwise at a rate to maintain temperature below -60° C. After stirring an additional 15 minutes, 14.0 ml (120 mmole) of 2-bromo-benzaldehyde was added and the reaction was stirred for 15 minutes. The reaction was quenched at -78° C. with saturated aqueous ammonium chloride and allowed to warm to room temperature. The reaction solution was diluted with 300 ml of diethyl ether and washed with three 75 ml portions of 1.0M sodium bisulfite, followed by 50 ml of 1.0M sodium hydroxide, 100 ml of water, and 50 ml of saturated sodium chloride. After drying over magnesium sulfate, the solvent was removed to give 35.3 g (99%) of crude 2-bromo-α -(4-chlorophenyl)benzyl alcohol as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:21])([F:20])[C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[CH2:18][OH:19])=[O:12])[CH2:7][CH2:6]1.Br[C:23]1[CH:24]=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1.O>CS(C)=O>[F:30][C:29]([F:32])([F:31])[C:27]1[CH:26]=[N:25][CH:24]=[C:23]([O:19][CH2:18][C@H:14]2[CH2:15][CH2:16][CH2:17][N:13]2[C:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([C:4]([F:3])([F:20])[F:21])[CH2:10][CH2:9]2)=[O:12])[CH:28]=1
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: O=C([C@H]1CC[C@H](C(F)(F)F)CC1)N1CCC[C@@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C([C@H]1CC[C@H](C(F)(F)F)CC1)N1CCC[C@@H]1COc1cncc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (60% oil dispersant, 11 mg, 0.27 mmol) was placed on the reaction tube, and a solution of [(2R)-1-{[trans-4-(trifluoromethyl)cyclohexyl]carbonyl}pyrrolidin-2-yl]methanol (68 mg, 0.24 mmol, EXAMPLE 31 Step 1) in DMSO (2.0 mL) was added at ambient temperature. After being stirred for 15 min at room temperature, 3-bromo-5-(trifluoromethyl)pyridine (50 mg, 0.22 mmol) was added to the mixture at ambient temperature. The mixture was heated stepwise with continuous stirring, at room temperature for 19 h, at 50° C. for 3 h, at 80° C. for 15 h, and at 100° C. for 15 h. After cooling to room temperature, water was added to the mixture. The mixture was extracted with ethyl acetate twice and washed with brine. The extracts were combined and dried over sodium sulfate and concentrated in vacuo to give an oil. The residual oil was purified by silica gel preparative thin layer chromatography (TLC) (ethyl acetate/hexane 3:2) to afford 40 mg (43%) of the title compound as a colorless viscous oil.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:26]([O:28][CH2:29][CH2:30][CH3:31])=[O:27])=[CH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.O>CN(C)C=O>[CH3:33][O:32][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:15][C:16]1[C:17]([C:26]([O:28][CH2:29][CH2:30][CH3:31])=[O:27])=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCCl)c(OC)cc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCN3CCOCC3)c(OC)cc12
Temperature: 60 °C
Reaction time: 48 h
Yield: 59 %

Procedure:
Propyl 3-[7-(2-chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-naphthalene-2-carboxylate (compound 322) (80 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (484 mg) and morpholine (0.15 ml) were added to the solution, and the mixture was stirred at 60° C. for 2 days. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (52 mg, yield 59%).
Reaction SMILES: [Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[CH:19]1([CH:22]([OH:36])[C:23]2[C:27]([C:28]([F:31])([F:30])[F:29])=[C:26]([C:32]([OH:34])=O)[N:25]([CH3:35])[N:24]=2)[CH2:21][CH2:20]1.[NH2:37][C:38]1[CH:39]=[CH:40][C:41]([Cl:50])=[C:42]([CH:49]=1)[C:43]([NH:45][CH:46]1[CH2:48][CH2:47]1)=[O:44]>O1CCCC1>[Cl:50][C:41]1[CH:40]=[CH:39][C:38]([NH:37][C:32]([C:26]2[N:25]([CH3:35])[N:24]=[C:23]([CH:22]([CH:19]3[CH2:20][CH2:21]3)[OH:36])[C:27]=2[C:28]([F:29])([F:30])[F:31])=[O:34])=[CH:49][C:42]=1[C:43](=[O:44])[NH:45][CH:46]1[CH2:48][CH2:47]1
Reactant: Nc1ccc(Cl)c(C(=O)NC2CC2)c1
Reactant: Cn1nc(C(O)C2CC2)c(C(F)(F)F)c1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cn1nc(C(O)C2CC2)c(C(F)(F)F)c1C(=O)Nc1ccc(Cl)c(C(=O)NC2CC2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 44 %

Procedure:
515 mg (1.86 mmol) of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride are added to a solution of 410 mg (1.55 mmol) of 3-[cyclopropyl(hydroxy)methyl]-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid and 327 mg (1.55 mmol) of 5-amino-2-chloro-N-cyclopropylbenzamide in tetrahydrofuran (10 ml) and the mixture is stirred for six hours at room temperature. The reaction mixture is concentrated by evaporation, admixed with water, extracted with dichloromethane and the combined organic phases are dried over sodium sulphate. Following concentration by evaporation in vacuo, the solid is washed with dichloromethane to give 308 mg of (N-[4-chloro-3-(cyclopropylcarbamoyl)phenyl]-3-[cyclopropyl(hydroxy)methyl]-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (44%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([O:17]CC)=O)=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.Cl[C:21](=[O:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24]>>[CH2:8]([C:6]1[CH:7]=[C:2]2[C:3]([C:15]([OH:17])=[C:22]([C:23]([O:25][CH3:26])=[O:24])[C:21](=[O:27])[NH:1]2)=[N:4][CH:5]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)CC(=O)Cl
Reactant: CCOC(=O)c1ncc(Cc2ccccc2)cc1N
Product: COC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 3-amino-5-benzylpyridine-2-carboxylate and methyl 3-chloro-3-oxopropionate employing methods similar to those described in Example 1, Steps 10-11. The product was obtained as a tan solid: 1H NMR (d6-DMSO) δ 11.9 (1H, br), 11.59 (1H, s), 8.46 (1H, d, J=1.6 Hz), 7.43 (1H, d, J=1.6 Hz), 7.33-7.20 (5H, m), 4.11 (2H, s), 3.74 (3H, s); HRMS calcd for C17H14N2O4+H+: 311.1032. Found: 311.1025.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:18]=1.Cl.N1C=CC=CC=1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)=[CH:7][C:6]=2[CH:18]=1
Reactant: COc1ccc(-c2cc3cc(Br)ccc3o2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc(-c2cc3cc(Br)ccc3o2)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
A mixture of 81 (0.3 g, 1 mmol) and Pyridine HCl (5 g) was heated to 200° C. After 1 hr, the reaction was cooled and then diluted with water. The aqueous layer was extracted with EtOAc, dried over MgSO4 and concentrated to give a solid. The solid was triturated with CH2Cl2 and filtered to give a solid (0.11 g, 39%); Mp=228-229° C.; 1H NMR (DMSO-d6) δ 9.95 (br s, 1 H), 7.79 (d, 1 H, J=2.0 Hz), 7.74 (d, 2 H, J=8.8 Hz), 7.55 (d, 1 H, J=8.8 Hz), 7.39 (dd, 1 H, J=8.8 Hz, 2.4 Hz), 7.16 (s, 1 H), 6.88 (d, 2 H, J=8.8 Hz); MS 287/289 [M−H]−
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([F:16])[C:9]([F:17])=[C:8](F)[C:7]=1[F:19]>CC(C)=O.O>[N:1]([C:8]1[C:7]([F:19])=[C:6]([F:5])[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([F:16])[C:9]=1[F:17])=[N+:2]=[N-:3]
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1c(F)c(F)c(N=[N+]=[N-])c(F)c1F
Yield: 86 %

Procedure:
A mixture of NaN3 (0.6 g, 9.22 mmol) and methyl pentafluorobenzoate (1.76 g, 7.78 mmol) in acetone (16 mL) and water (6 mL) was refluxed for 8 hours. The mixture was cooled and then water (20 mL) was added, and the solution was extracted using diethyl ether (3×10 mL). The extracts were dried with Na2SO4 and the mixture was filtered. Solvent was evaporated to give 2 as a white power (1.67 g, yield=86%)
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[F:37])=[O:28])=[C:22]([Cl:38])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:39][CH3:40])C1C=CC=CC=1.[H][H].C(OCC)(=O)C>CN(C)C=O.[C].[Pd]>[Cl:38][C:22]1[CH:21]=[C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:39][CH3:40])[CH:11]=3)[N:16]=[CH:15][CH:14]=2)[CH:25]=[CH:24][C:23]=1[NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37])=[O:28]
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1O
Yield: 96.4 %

Procedure:
N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N′-(2,4-difluorophenyl)urea (215 mg) was dissolved in dimethylformamide (11 ml). Palladium-carbon (215 mg) was added to the solution, and the mixture was stirred in a hydrogen atmosphere at room temperature overnight. Ethyl acetate (30 ml) was added to the reaction solution, and the mixture was then filtered through Celite. The solvent was removed by distillation under the reduced pressure to give 174 mg (yield 96%) of the title compound.