Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:10](=[O:19])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]1[CH:37]=[CH:36][C:32](C(O)=O)=[CH:31][CH:30]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(CC)C(C)C)(C)C.[C:47](OCC)(=[O:49])C>ClCCl.CN(C)C1C=CN=CC=1>[Cl:18][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:19])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][C:47]([CH:28]([NH:27][C:25](=[O:26])[O:24][C:20]([CH3:21])([CH3:22])[CH3:23])[C:29]3[CH:30]=[CH:31][CH:32]=[CH:36][CH:37]=3)=[O:49])=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(C)=O
Reactant: Nc1nonc1-c1noc(=O)n1-c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(C(=O)Nc1nonc1-c1noc(=O)n1-c1cccc(Cl)c1)c1ccccc1
Reaction time: 16 h

Procedure:
A solution of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one (0.5 g, 1.8 mmol) and 4-{[(tert-butoxycarbonyl)amino]methyl}benzoic acid (0.67 g, 2.7 mmol) in dichloromethane (35 mL) was treated with 4-dimethylaminopyridine (0.13 g, 1.1 mmol) and N,N-diisopropylethylamine (0.93 mL, 5.4 mmol) followed by bromotris(pyrrolydino)phosphonium hexafluorophosphate (1.3 g, 2.7 mmol) and additional N,N-diisopropylethylamine (0.93 mL, 5.4 mmol). The reaction mixture was stirred for 16 h, diluted with ethyl acetate (˜200 mL) and washed with 0.1 M HCl (2×100 mL) and brine (25 mL), dried with sodium sulfate, filtered, and concentrated. Purification of the crude reaction mixture on silica gel gave the intermediate tert-butyl {-[({4-[4-(3-chlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)carbonyl]benzyl}carbamate. This material was diluted with dichloromethane (30 mL), treated with 4.0 M HCl in 1,4-dioxane (4.5 mL), and stirred for 1 h. The reaction mixture was concentrated and purified by preparative LCMS to give the desired product (542 mg, 58%). LCMS for C18H14ClN6O4 (M+H)+: m/z=413.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:18]=[CH:19][C:20]([N+:25]([O-:27])=[O:26])=[C:21]([CH:24]=1)[CH:22]=[O:23].O>ClC1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:24]=[C:21]([C:20]([N+:25]([O-:27])=[O:26])=[CH:19][CH:18]=1)[CH:22]=[O:23]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Solvent: Clc1ccccc1
Solvent: O
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])c(C=O)c3)c2cc1OC
Temperature: 25 °C
Yield: 66.3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (200 mg) and 5-hydroxy-2-nitrobenzaldehyde (299 mg) were suspended in chlorobenzene (2 ml), and the suspension was heated under reflux for 8 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using ethyl acetate-hexane to give 3-[(6,7-dimethoxy-4-quinolyl)oxy]-6-nitrobenzaldehyde (210 mg, yield 66%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[CH3:21][S:22][CH2:23][CH2:24][CH2:25][NH2:26]>>[CH3:21][S:22][CH2:23][CH2:24][CH2:25][NH:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cnc2cc(-c3ccccc3)ccc2c1Cl
Reactant: CSCCCN
Product: CSCCCNc1c([N+](=O)[O-])cnc2cc(-c3ccccc3)ccc12
Yield: 93.3 %

Procedure:
4—Chloro-3-nitro-7-phenylquinoline (5.3 g, 18.8 mmol) and 3-methylsulfanyl-propylamine (2.17 g, 20.6 mmol) were combined and treated according to the general procedure described in Part E of Example 1. Recrystallization from isopropanol afforded 6.2 g of (3-methylsulfanylpropyl)-(3-nitro-7-phenylquinolin-4-yl)amine as gold plates.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1.B(Br)(Br)Br.O>C(Cl)Cl>[F:13][C:12]([F:14])([F:15])[C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Temperature: -80 °C
Reaction time: 72 h
Yield: 33.6 %

Procedure:
3-Methoxy-5-nitrobenzotrifluoride (5 g, 23 mmol) was dissolved in anhydrous methylene chloride (100 mL) and cooled to −80° C. under a nitrogen atmosphere. To this solution was added via dropping fimnel a 1 M solution of BBr3 in methylene chloride (68 mL, 68 mmol). This solution was allowed to warm to room temperature and stirred for 3 days. Water was slowly added to the mixture and mixed well to quench the excess BBr3. To this mixture ether (500 mL) was added. The organic layer was separated and extracted with 2 N NaOH (240 mL). The alkaline extract was neutralized with dilute HC1 and extracted with diethyl ether (3×300 mL). The ether extracts were combined, washed with saturated NaCl and dried over anhydrous MgSO4. Evaporation of diethyl ether gave a brownish yellow oil which was chromatographed on a silica column to give 1.6 g (34%) of a yellow solid. 1H-NMR (CDCl3/CD3OD; 300 MHz) δ7.38-7.40 (m, 1 H), 7.82 (t, 1 H, J=2.2 Hz), and 7.95-7.96 (m, 1 H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([NH:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C.[Br:36][C:37]1[C:38]([NH2:44])=[N:39][CH:40]=[C:41]([Br:43])[N:42]=1>CN(C)C=O.ClCCl>[Br:36][C:37]1[C:38]([NH:44][C:22](=[O:24])[C:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:26])[CH3:25])=[N:39][CH:40]=[C:41]([Br:43])[N:42]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: Nc1ncc(Br)nc1Br
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)Nc1ncc(Br)nc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.8 %

Procedure:
1,1′-Carbonyldiimidazole (2.63 g, 16.24 mmol) was added to a stirred solution of 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (3.00 g, 14.76 mmol) in N,N-dimethylformamide (4 mL) and dichloromethane (8 mL) at room temperature. The resulting clear colorless mixture was stirred at room temperature under nitrogen for 3 h. N,N-Diisopropylethylamine (3.86 mL, 22.14 mmol) was added followed by 3,5-dibromopyrazin-2-amine (5.60 g, 22.14 mmol). The resulting mixture was heated at 50° C. under a reflux condenser under nitrogen for 71 h. Dichloromethane was removed under reduced pressure. The residue was diluted with ethyl acetate and washed with water. The water layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with 30% ethyl acetate in hexane and solids collected by vacuum filtration. The filtrate was concentrated under reduced pressure and purified using flash chromatography (5-50% ethyl acetate in hexane). Fractions containing the desired product were combined with the solids obtained by filtration and concentrated under reduced pressure. The residue was dried under high vacuum to give the desired product (2.38 g, 5.43 mmol, 37% yield) as an off-white solid. MS (ESI) m/z 439.3 [M+1]+, 461.1 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=[CH:12][N:11]=1.Cl.[CH3:23][N:24]1[CH2:29][CH2:28][C:27](=[CH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][C:32]=2[C:40]([F:43])([F:42])[F:41])[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:29][CH2:28][C:27](=[CH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([NH:9][C:10]4[N:15]=[C:14]([C:16]5[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=5)[CH:13]=[CH:12][N:11]=4)[CH:4]=3)=[O:36])=[CH:33][C:32]=2[C:40]([F:41])([F:43])[F:42])[CH2:26][CH2:25]1
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CN1CCC(=Cc2ccc(C(=O)Cl)cc2C(F)(F)F)CC1
Agent: Cl
Product: Cc1ccc(NC(=O)c2ccc(C=C3CCN(C)CC3)c(C(F)(F)F)c2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
This compound was prepared in the same manner as in Example 1, except that 4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]aniline (Patent Document 1) and 4-(1-methylpiperidin-4-ylidenemethyl)-3-trifluoromethylbenzoyl chloride hydrochloride (Reference Example 7) were used.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH2:17][C:18](=[O:20])[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=O)=[CH:4][C:3]=1[CH2:21][CH2:22][C:23]([OH:25])=[O:24].O.[OH-].[Na+].Cl>CO>[Cl:11][C:10]1[C:2]([Cl:1])=[C:3]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:4]=[C:5]2[C:9]=1[C:8]1[C:7]([CH2:13][CH2:14][CH3:15])([CH2:6]2)[CH2:16][CH2:17][C:18](=[O:20])[CH:19]=1
Reactant: CCCC1(CCC(C)=O)Cc2cc(CCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC12CCC(=O)C=C1c1c(cc(CCC(=O)O)c(Cl)c1Cl)C2

Procedure:
3-[6,7-Dichloro-2,3-dihydro-1-oxo-2-(3-oxobutyl)-2-propyl-inden-5-yl]propionic acid (3.1 g, 0.00805 mole) was stirred at 25° C. in a mixture of methanol (2 ml), water (6 ml) and 1N sodium hydroxide (25 ml) for 96 hours. After dilution with water, the mixture was acidified with hydrochloric acid and extracted with a mixture of diethyl ether and tetrahydrofuran. The organic extracts were washed with water, dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from acetic acid-acetonitrile (1:1) to obtain the product mp 201°-3° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([CH3:14])=[CH:11][C:12]#[N:13])[CH:6]=[CH:7][CH:8]=1.[CH:17]([C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1)=O.[C:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])#[N:28].N1CCCCC1>C(O)C>[NH2:28][C:27]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:15])([F:16])[F:1])[CH:4]=2)[C:10]([CH3:14])=[C:11]([C:12]#[N:13])[CH:17]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(=CC#N)Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(N)N(c2cccc(C(F)(F)F)c2)C(C)=C(C#N)C1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
Under argon, 100 mg (0.44 mmol) of the compound of Example 2A, 57.97 mg (0.44 mmol) 4-formylbenzonitrile and 50.01 mg (0.44 mmol) ethyl cyanoacetate are dissolved in 2 ml ethanol. 3.76 mg (4.4 μl, 0.04 mmol) piperidine are added, and the mixture is stirred at reflux overnight. After cooling down to room temperature, the formed crystals are filtered and washed twice with ethanol. The crude product is purified by column chromatography with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][CH2:8][C:9]2(C(OCC)=O)[CH2:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:31]([O:33]CC)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH2:8][CH:9]2[CH2:13][C:12]3[CH:14]=[C:15]([CH2:31][OH:33])[CH:16]=[CH:17][C:11]=3[O:10]2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1(COCc2ccc(F)cc2)Cc2ccccc2O1
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1ccc2c(c1)CC(COCc1ccc(F)cc1)O2
Yield: 83 %

Procedure:
Following the process described in example 18 (point C), starting from ethyl 2-(4'-fluorobenzyloxymethyl)-2,3-dihydrobenzofuran-2-carboxylate (7.00 g, 23.2 mmol), LiAlH4 (3.51 g, 92.6 mmol) and dry ethyl ether (300 ml), the title compound was prepared (83% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][C:17]([CH:21]=[O:22])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].N1C=CN=C1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)(=O)C.O.ClCCl>[Si:23]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][C:17]([CH:21]=[O:22])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: O=Cc1ccc2c(c1)c1ccccc1n2CCCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCn1c2ccccc2c2cc(C=O)ccc21
Yield: 64.9 %

Procedure:
9-(6-hydroxyhexyl)-9H-carbazole-3-carbaldehyde (12.0 g, 0.0406 mol) and dichloromethane (100 ml) were loaded into a three-neck flask, stirred, added with tert-butyldimethylsilyl chloride (7.35 g, 0.0487 mol) and imidazole (3.04 g, 0.0447 mol), and allowed to react at room temperature for 24 hours with stirring. The reaction product was transferred into a separate funnel, and was then added with water and ethyl acetate, after which the organic layer was isolated therefrom, dehydrated using sodium sulfate, and then distilled under reduced pressure. Then, the obtained viscous liquid was separated through silica column chromatography, thus obtaining 10.8 g of a liquid as the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:19])=[N:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[CH3:20].C([O:23][C:24]([C:26]12[CH2:43][CH:42]1[CH:41]=[CH:40][CH2:39][CH2:38][CH2:37][CH2:36][N:35]([CH3:44])[C:34](=[O:45])[N:33]1[CH:29]([CH2:30][CH:31](O)[CH2:32]1)[C:28](=[O:47])[NH:27]2)=[O:25])C>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:19][CH:31]3[CH2:30][CH:29]4[N:33]([C:34](=[O:45])[N:35]([CH3:44])[CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[CH:41][CH:42]5[C:26]([C:24]([OH:25])=[O:23])([NH:27][C:28]4=[O:47])[CH2:43]5)[CH2:32]3)=[N:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[CH3:20]
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)N1CC(O)CC1C(=O)N2
Reactant: COc1cc2nc(-c3ccccc3)nc(O)c2cc1C
Product: COc1cc2nc(-c3ccccc3)nc(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)c2cc1C
Yield: 11.3 %

Procedure:
Quinazolinol derivative 112 (200 mg, 0.53 mmol) was coupled to compound 51 (268 mg, 0.7 mmol) followed by hydrolysis of the ethyl ester as described in example 52 which gave the title compound (36 mg, 11%). MS (M−H)+ 600.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:23]O.C(=O)([O-])[O-].[Na+].[Na+].C[O:32][C:33](OC)(N(C)C)[CH3:34]>C(O)C.O.C1(C)C(C)=CC=CC=1>[CH3:34][C:33]1[O:32][N:23]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]([C@@H:9]3[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]3)=[CH:7][CH:8]=2)[N:2]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C#N)cc2)C1
Reactant: COC(C)(OC)N(C)C
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1nc(-c2ccc([C@H]3CN(C(=O)OC(C)(C)C)CCO3)cc2)no1
Temperature: 80 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
To a solution of tert-butyl (2S)-2-(4-cyanophenyl)morpholine-4-carboxylate (intermediate 17, 17.6 g, 61.1 mmol) and hydroxylamine hydrochloride (12.8 g, 183 mmol) in ethanol (120 ml) was added sodium carbonate (32.4 g, 305 mmol) in water (120 ml) at room temperature and the mixture was stirred at 80° C. for 3 hours. After removal of the solvent under reduced pressure, the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was added with xylene (150 ml) and N,N-dimethylacetamide dimethylacetal (18.1 g, 122 mmol). After the solution was refluxed for 2 hours, water was azeotropically removed using a Dean-Stark water separator with molecular sieves 4A. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=3/1) to afford tert-butyl (2S)-2-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)morpholine-4-carboxylate (intermediate 18, 16.9 g, 80%)
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([O:10]C(C)C)=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH:22]=[C:21]([CH3:32])[C:20]=1[CH3:33].[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH:22]=[C:21]([CH3:32])[C:20]=1[CH3:33]
Reactant: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(OCC(=O)O)c2C)c1C
Reaction time: 3 h
Yield: 105.8 %

Procedure:
To a solution of isopropyl 2-[4-fluoro-3-[[5-(3-fluorophenyl)-2,3-dimethyl-phenyl]methylamino]-2-methyl-phenoxy]acetate (80 mg, 0.17 mmol, 1.0 eq) in a mixture of THF (5 mL) and MeOH (5 mL) was added NaOH (2M aqueous solution, 5 mL, 10 mmol). The reaction was stirred for 3 h then the organic solvent was removed under reduced pressure. The remaining aqueous solution was adjusted to pH 5 with diluted HCl and the mixture extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (CH2Cl2:MeOH, 400:1 to 4:1) to give the title compound as a white solid (74 mg, 97%).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C:5]1[CH:18]=[C:17]([O:19]CC2C=CC=CC=2)[C:8]2[N:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4].C(O)(=O)C>C(O)C.O1CCCC1.[Pd]>[CH3:1][N:2]([CH3:27])[C:3]([C:5]1[CH:18]=[C:17]([OH:19])[C:8]2[N:9]=[C:10]([C:13]([F:16])([F:14])[F:15])[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc(OCc2ccccc2)c2nc(C(F)(F)F)n(C)c2c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(O)c2nc(C(F)(F)F)n(C)c2c1
Yield: 100.9 %

Procedure:
A solution of 9.0 g (23.8 mmol) 7-benzyloxy-3-methyl-2-trifluoromethyl-3H-benzimidazole-5-carboxylic acid dimethylamide and 1.2 ml acetic acid in 300 ml ethanol-tetrahydrofuran (1:1) was hydrogenated over 1.1 g 10% Pd/C in autoclave (5 bar H2) at 50° C. for 16 h. The catalyst was filtered off and the filtrate concentrated in vacuo to afford 6.9 g (100%) of the title compound as a white solid.
Reaction SMILES: [C:1]([CH:5]1[CH2:9][S:8][CH:7]([CH3:10])[C:6]1=O)([O:3][CH3:4])=[O:2].Cl.[NH2:13][OH:14]>N1C=CC=CC=1>[C:1]([CH:5]1[CH2:9][S:8][CH:7]([CH3:10])[C:6]1=[N:13][OH:14])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1CSC(C)C1=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)C1CSC(C)C1=NO
Reaction time: 24 h
Yield: 99 %

Procedure:
A solution of 37.26 g. (0.214 mole) of 4-carbomethoxy-3-keto-2-methyltetrahydrothiophene in 100 ml. anhydrous pyridine was treated with 18.0 g. (0.261 mole) hydroxylamine hydrochloride. The mixture was stirred 24 hours at 25°. The reaction was concentrated and partitioned between 1 N hydrochloric acid/methylene chloride. The aqueous phase was extracted two times with methylene chloride. The combined organic extracts were dried and evaporated to yield 40.1 g (99%) of pure 4-carbomethoxy-3-keto-2-methyltetrahydrothiophene oxime as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[N+:20]([O-:22])=[O:21])[N:5]=[CH:4][N:3]=1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29]>CN(C)C=O.C(OCC)(=O)C>[N+:20]([C:9]1[CH:10]=[CH:11][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:13][C:8]=1[C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:24]([F:23])([F:33])[F:34])[CH:26]=2)[CH:7]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Cl)ncn1
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ncn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-chloro-6-(2-nitro-5-(piperidin-1-yl)phenyl)pyrimidine (191 mg) in N,N-dimethylformamide (10 mL), and 3-(trifluoromethyl)benzylamine (210 mg). The resulting solution was stirred overnight at 50° C. The resulting mixture was dissolved in 50 mL of ethyl acetate and washed with 2×50 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatograpy to give 186 mg of product as yellow oil.
Reaction SMILES: CON(C)[C:4](=[O:17])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[CH3:16].[CH2:19]1COCC1>O>[CH3:16][C:7]1[CH:8]=[CH:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]=1[CH2:5][C:4](=[O:17])[CH3:19]
Reactant: C1CCOC1
Reactant: CON(C)C(=O)Cc1c(C)ccc2ccccc12
Solvent: O
Product: CC(=O)Cc1c(C)ccc2ccccc12
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 41 %

Procedure:
N-methoxy-N-methyl-2-(2-methyl-naphthalen-1-yl)-acetamide (1.01 g, 4.16 mmol) was dissolved in freshly distilled THF (17 mL) in an argon-purged, round-bottom flask. The mixture was chilled to 0° C. and methyl magnesium bromide (2.08 mL of 3.0 M soln in Et2O, 6.23 mmol) was added via syringe. The reaction was stirred at 0° C. for 75 minutes. TLC analysis (silica, 20% acetone-hexanes) indicated complete consumption of the starting material. The reaction was carefully quenched with a mixture of AcOH (1 mL) in EtOAc (5 mL). The quenched reaction was diluted with H2O and extracted three times with EtOAc. The organic extracts were combined, washed with brine solution, dried over Na2SO4, filtered through celite, and concentrated. Purification by flash chromatography (SiO2, 20% EtOAc-hexane) gave 1-(2-methyl-naphthalen-1-yl)-propan-2-one (343 mg, 1.73 mmol) in 41% yield. MS (APCI) m/z 199.1 (M+H). 1H NMR (300 MHz) CDCl3 δ 7.85 (m, 2H), 7.72 (d, J=9.4 Hz, 1H), 7.47 (m, 2H), 7.36 (d, J=8.2 Hz, 1H), 4.18 (s, 2H), 2.51 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH2:18][CH2:19][CH3:20])[C:3]1=[O:21].CC(C)([O-])C.[Na+].Cl[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:39]([F:42])([F:41])[F:40])[CH:37]=2)[N:32]=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[CH:15]([N:13]([CH3:14])[C@@H:10]1[CH2:11][CH2:12][C@H:7]([N:4]2[CH2:5][CH2:6][C@@H:2]([NH:1][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:39]([F:42])([F:40])[F:41])[CH:37]=4)[N:32]=[CH:31][CH:30]=3)[C:3]2=[O:21])[C@H:8]([CH2:18][CH2:19][CH3:20])[CH2:9]1)([CH3:16])[CH3:17].[CH:15]([N:13]([CH3:14])[C@@H:10]1[CH2:11][CH2:12][C@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:39]([F:42])([F:40])[F:41])[CH:37]=4)[N:32]=[CH:31][CH:30]=3)[C:3]2=[O:21])[C@H:8]([CH2:18][CH2:19][CH3:20])[CH2:9]1)([CH3:16])[CH3:17]
Reactant: FC(F)(F)c1ccc2nccc(Cl)c2c1
Reactant: CCC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@@H](Nc2ccnc3ccc(C(F)(F)F)cc23)C1=O
Product: CCC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](Nc2ccnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 80 °C

Procedure:
To a solution of (S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)pyrrolidin-2-one (100 mg) in toluene (2 mL) was added sodium tert-butoxide (42 mg), acetato(2′-di-t-butylphosphino-1,1′-diphenyl-2-yl)palladium(II) (7.8 mg), and 4-chloro-6-(trifluoromethyl)quinoline (102.3 mg). The mixture was heated at 80° C. for 14 h before it was filtered and concentrated in vacuo. The residue was purified by chiral chromatography (OD column, 80/20/0.1 hexane/iPrOH/Et2NH as mobile phase) to afford (R)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)-3-(6-(trifluoromethyl)quinolin-4-ylamino)pyrrolidin-2-one [8 mg; MS found: (M+H)+=491.3] and (S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)-3-(6-(trifluoromethyl)quinolin-4-ylamino)pyrrolidin-2-one [18 mg; MS found: (M+H)+=491.3].