Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH:5]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C@H:26]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]2)=[CH:21][CH:20]=1)[CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([C:17]#[N:18])=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2].[NH2-].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:38])[C@H:5]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C@H:26]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]2)=[CH:21][CH:20]=1)[CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([C:17]#[N:18])=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc2ccc(C#N)cc2c1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: [NH2-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@@H](Cc1ccc2ccc(C#N)cc2c1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Yield: 77.7 %

Procedure:
2-[4-[[(3S)-1-(tert-Butoxycarbonyl)-3-pyrrolidinyl]oxy]phenyl]-3-(7-cyano-2-naphthyl)propionic acid ethyl ester (1.90 g, 3.7 mmol) was heated and dissolved in ethanol (6 ml), and the resultant solution was cooled to room temperature with stirring to settle crystals. Subsequently, sodium amide (22 mg, 0.6 mmol) was added thereto, followed by stirring at the same temperature for 30 minutes, then sodium amide (22 mg, 0.6 mmol) was further added, followed by stirring for 18 hours. The crystals were collected through filtration to obtain 1.48 g of the title compound (78% yield). The diastereomer purity of the crystals was 92.3%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O>O1CCCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1c(-c2ccccc2)ccnc1Cl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: OCc1c(-c2ccccc2)ccnc1Cl
Yield: 71.7 %

Procedure:
To a solution of 2-chloro-4-phenylnicotinic acid (22.4 g) in tetrahydrofuran (200 ml) was added thionyl chloride (21 ml), and the mixture was heated under reflux for 3 hrs. The solvent was evaporated under reduced pressure, and the precipitated solid was collected by filtration and washed with hexane. The obtained powdery solid was dissolved in tetrahydrofuran (200 ml), and lithium aluminum hydride (4.5 g) was added by small portions while cooling in a dry ice-acetone bath. The mixture was stirred under cooling for 5 min. and water was added to quench the reaction. The precipitated solid was filtered off, and the filtrate was concentrated and extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (15.1 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13]#[N:14])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[OH-:17].[Na+].OO>CO>[F:1][C:2]([F:15])([F:16])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:13]([NH2:14])=[O:17])[CH2:11][CH2:12]2)=[CH:8][CH:9]=1
Reactant: N#CC1(c2ccc(OC(F)(F)F)cc2)CC1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: NC(=O)C1(c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 55 °C

Procedure:
A mixture of 1-(4-trifluoromethoxyphenyl)cyclopropanecarbonitrile (4.0 g), 25% aqueous sodium hydroxide (0.46 mL), 30% aqueous hydrogen peroxide (25 mL), and methanol (100 mL) was heated at 55° C. for 1 h with stirring. The reaction mixture was concentrated under reduced pressure, the precipitated crystals were collected by filtration, to obtain white solid 1-(4-(trifluoromethoxy)phenyl)cyclopropanecarbamide (4.5 g). (3) A mixture of 1-(4-trifluoromethoxyphenyl)cyclopropanecarbamide (4.5 g), 15% aqueous sodium hydroxide (150 mL), and methanol (60 mL) was heated at 78° C. for 18 h with stirring. The reaction mixture was left stand for cooling, then the reaction solution was adjusted to pH 2 using 15% hydrochloric acid and concentrated under reduced pressure. The precipitated crystals were collected by filtration to obtain white solid 1-(4-(trifluoromethoxy)phenyl)cyclopropanecarboxylic acid (4.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@H:6]([CH3:15])[N:7]2[C:12](=[O:14])[CH3:13].[Br:16]N1C(=O)CCC1=O>C(#N)C>[Br:16][C:11]1[C:2]([OH:1])=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:12](=[O:14])[CH3:13])[C@@H:6]([CH3:15])[CH2:5][CH2:4]2
Reactant: CC(=O)N1c2cccc(O)c2CC[C@@H]1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
A solution of (S)-1-(5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (1.2 g, 5.85 mmol) in acetonitrile (24 mL) was cooled to 0° C. and treated with N-bromosuccinimide (1.041 g, 5.85 mmol) in one portion. The solution turned dark yellow-orange in color initially, then faded to a pale orange color over the next 10-15 min. After 30 min, the solution was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 8:1 dichloromethane-ethyl acetate followed by 7:1 dichloromethane-ethyl acetate) to afford (S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (1.37 g, 82%). MS (ESI, pos. ion) m/z 284, 286 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]Br)=[CH:4][CH:3]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([O-:20])=[CH:16][CH:15]=1)([O-:13])=[O:12].[Na+]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:20][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CCBr)cc1
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CCOc2ccc([N+](=O)[O-])cc2)cc1
Yield: 73.8 %

Procedure:
2-(4-Methylphenyl)ethyl bromide (X: X=Br) (10 g, 0.05 mole) and sodium 4-nitrophenolate (XI) (8.1 g, 0.05 mole) were added to dimethylformamide (60 ml), and the mixture was reacted at 90° C. for 5 hours. Thereafter, the reaction mixture was treated in the same manner as in Example 12 to obtain 9.5 g of 4-[2-(4-methylphenyl)ethoxy]-nitrobenzene (VI) as white crystals (yield, 73.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(CC(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(OC)cc1

Procedure:
A solution of 4-Methoxyphenylacetic acid (2 g) and para-toluenesulfonic acid (230 mg) in 30 ml of ethanol is refluxed for 2 hours. The solvent is evaporated under reduced pressure and the residue is suspended in a saturated aqueous solution of sodium hydrogencarbonate and extracted twice with ethyl acetate. The organic extracts are collected, washed with water and dried over sodium sulfate to give, after evaporation of the solvent under reduced pressure, 2.14 g of the product.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:23][N:7]2[C:8](=[O:22])[N:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[CH2:10][C@@H:6]2[CH2:5]1)=[N+]=[N-]>C1COCC1.[Pd]>[NH2:1][C@@H:4]1[CH2:23][N:7]2[C:8](=[O:22])[N:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=3)[CH2:10][C@@H:6]2[CH2:5]1
Reactant: [N-]=[N+]=N[C@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Agent: [Pd]
Solvent: C1CCOC1
Product: N[C@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Yield: 84.5 %

Procedure:
A mixture of crude (6S,7aS)-6-Azido-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 20, step c) (0.90 g) and 10% Pd/C (0.18 g) was stirred in anhydrous THF (20 mL) at the H2 atmosphere for 1 h at 15° C. The mixture was filtered, concentrated and purified by silica gel column chromatography (eluting with DCM/MeOH=50:1˜10:1) to yield 0.70 g of the title compound as a grey solid. 1H NMR (300 MHz, d6-DMSO): δ 7.67 (d, 2H, J=3 Hz), 7.31 (d, 2H, J=9 Hz), 3.96 (d, 1H, J=12 Hz), 3.86 (d, 1H, J=12 Hz), 3.77-3.73 (m, 1H), 3.54-3.52 (m, 1H), 3.18-3.17 (m, 1H), 3.10-3.06 (m, 1H), 2.15-2.11 (m, 1H), 1.69 (s, 2H), 1.35-1.31 (m, 1H); LC-MS: 302.1 [M+1]+.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:13]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)[CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].S(Cl)(Cl)=O>C(COC)OC.C(Cl)Cl.CC(N(C)C)=O>[CH2:13]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[O:34])=[CH:36][CH:37]=1)[CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCC=CCCCNc1ccc(C(=O)O)cc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCC=CCCCNc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 31.4 g. of benzenesulfonamide in 250 ml. of dry dimethylacetamide is added dropwise, with stirring and cooling, to a suspension of 5.5 g. of sodium hydride in 100 ml. of dry dimethylacetamide over 30 minutes at room temperature. Stirring is continued for a further 30 minutes. In the meantime, a mixture of 36.2 g. of 4-(4-pentadecenylamino)benzoic acid in 1200 ml. of methylene chloride, 300 ml. of dimethoxyethane, and 40 ml. of thionyl chloride is refluxed for 1 hour and 15 minutes. The solution is evaporated to an oil which is co-evaporated twice with added dioxane to remove excess thionyl chloride. To the resulting oily residue of 4-(4-pentadecenylamino)benzoyl chloride hydrochloride is added, in one portion, the previously prepared mixture of sodium benzenesulfonamide in dimethylacetamide. The mixture is stirred for 30 minutes, without cooling, and is then filtered through a bed of diatomaceous earth. The filtrate is poured into 2 l. of water, and 250 ml. of saturated sodium chloride solution is added to coagulate the precipitate. The mixture is filtered and the product is washed with water and partially air dried. The product is dissolved in methylene chloride, the mixture is filtered through diatomaceous earth, and brine is added to break the emulsion. The layers are separated, the organic phase is dried over anhydrous sodium sulfate and filtered through a bed of 300 g. of hydrous magnesium silicate. The product is eluted with an additional 3 l. of methylene chloride. The first approximately 1 l. of filtrate is set aside and the remainder is evaporated to dryness. The residue is crystallized three times from toluene and the product is dried in the Abderhalden at 65° C. to provide the title compound as colorless crystals.
Reaction SMILES: [ClH:1].[F:2][C:3]1[C:22]2[O:21][C@H:10]3[CH2:11][N:12](CC4C=CC=CC=4)[CH2:13][C@@H:9]3[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1>CO.[Pd]>[ClH:1].[F:2][C:3]1[C:22]2[O:21][C@H:10]3[CH2:11][NH:12][CH2:13][C@@H:9]3[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Fc1cccc2c1O[C@H]1CN(Cc3ccccc3)C[C@@H]1C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Fc1cccc2c1O[C@H]1CNC[C@@H]1C2
Yield: 73.1 %

Procedure:
A solution of Example 3 (1.2 g) in methanol (50 mls) was hydrogenated over 10% palladium on charcoal (0.2 g) for 17 hours. The catalyst was filtered off, and the filtrate was evaporated to dryness. Crystallisation of the resulting solid from isopropyl alcohol/methanol gave the title compound (0.63 g). M.p. 259°. NMR (DMSOd6) δ 9.9 (2H, Br S, NH2+), 7.2-6.85 (3H, m, aromatic), 4.24 (1H, d of t, 3a-H), 3.8-2.78 (6H, m, 1-H2, 3-H2, 9-H2), 2.27 (1H, m, 9a-H).
Reaction SMILES: [NH2:1][C:2]1([C:30]#[N:31])[CH2:7][CH2:6][N:5]([S:8](/[CH:11]=[CH:12]/[C:13]2[C:18]([CH3:19])=[CH:17][C:16]([N:20]3[C:24]([CH3:26])([CH3:25])[C:23](=[O:27])[NH:22][C:21]3=[O:28])=[CH:15][C:14]=2[CH3:29])(=[O:10])=[O:9])[CH2:4][CH2:3]1.[OH-:32].[Na+].OO.[Cl-].[NH4+]>CO.CS(C)=O.CCCCCC.C(OCC)(=O)C>[NH2:1][C:2]1([C:30]([NH2:31])=[O:32])[CH2:7][CH2:6][N:5]([S:8](/[CH:11]=[CH:12]/[C:13]2[C:14]([CH3:29])=[CH:15][C:16]([N:20]3[C:24]([CH3:26])([CH3:25])[C:23](=[O:27])[NH:22][C:21]3=[O:28])=[CH:17][C:18]=2[CH3:19])(=[O:9])=[O:10])[CH2:4][CH2:3]1
Reactant: Cc1cc(N2C(=O)NC(=O)C2(C)C)cc(C)c1/C=C/S(=O)(=O)N1CCC(N)(C#N)CC1
Reactant: [OH-]
Agent: OO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(N2C(=O)NC(=O)C2(C)C)cc(C)c1/C=C/S(=O)(=O)N1CCC(N)(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a solution of (E)-4-amino-1-((4-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2,6-dimethylstyryl)sulfonyl)piperidine-4-carbonitrile (675 mg, 1.50 mmol) in methanol (7.5 mL) and dimethylsulfoxide (0.195 mL) at room temperature, a 2 N aqueous sodium hydroxide solution (1.6 ml, 1.6 mmol) was added and then a 30% aqueous hydrogen peroxide solution (0.2 mL, 1.95 mmol) were slowly added dropwise. The mixture was stirred at room temperature for one hour. Ethyl acetate, hexane, and a saturated aqueous ammonium chloride solution were added to the reaction mixture. The solid was collected by filtration, washed, and dried to afford (E)-4-amino-1-((4-(5,5-dimethyl-2,4-dioxoimidazolidine-1-yl)-2,6-dimethylstyryl)sulfonyl)piperidine-4-carboxamide (498 mg, 72%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:6][CH:5]=1.O=[CH:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>C(O)CCC.C(OCC)(=O)C>[C:25]([O:24][C:23](=[O:29])[NH:22][CH2:21][CH:20]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[CH2:11][CH2:10][N:9]1[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:18][CH:17]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: COc1ccc(CNCCc2ccsc2)cc1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: COc1ccc(CN2CCc3ccsc3C2CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 44.4 %

Procedure:
A solution of 4.11-A (5.6 g, 19.7 mmol) and t-butyl (2-oxoethyl)carbamate (12.6 g, 78.9 mmol) in butanol (118 mL) was heated to 140° C. for 16 h in a reaction vessel equiped with a Dean-Stark trap. The reaction mixture was cooled to 25° C. and diluted with ethyl acetate. The starting material 4.11-A precipitates as a white solid which was collected. The ethyl acetate filtrate was washed with saturated sodium bicarbonate (2×100 mL) and brine (100 mL), dried with Na2SO4, filtered, and concentrated to give a crude oil which was purified using flash column chromatography (100% hexane →30% EtOAc/hexane) to yield 4.11-B as an amber oil (3.4 g, 44%). 1H NMR (500 MHz, CDCl3): δ 7.26–7.25 (m, 2H), 7.18 (d, J=4.9 Hz, 1H), 6.88–6.85 (m, 2H), 6.81 (d, J=4.9 Hz, 1H), 5.05–5.00 (M, 1H), 3.81 (s, 3H), 3.80–3.78 (m, 1H), 3.72–3.64 (m, 2H), 3.57–3.53 (m, 1H), 3.20–3.15 (m, 1H), 3.15–3.08 (m, 1H), 2.90–2.78 (m, 2H), 2.48–2.45 (m, 1H), 1.42 (s, 9H); LCMS found for C21H29N2O3S (M+H)+: m/z=389.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[CH3:31][N:32]([CH3:38])[CH:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:35]5[CH2:36][CH2:37][CH:33]([N:32]([CH3:38])[CH3:31])[CH2:34]5)[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: CN(C)C1CCNC1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCC(N(C)C)C3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
A solution of 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (50 mg, 0.12 mmol) in 3(dimethylamino)pyrrolidine (1 ml) was heated at 120° C. for 18 h in a sealed tube. The reaction was concentrated under vacuum, the residue triturated with water to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(3-dimethylaminopyrrolidin-1-yl)isonicotinamide (38 mg). NMR; δH [2H6]—DMSO includes 10.28,(1H, s), 8.62,(1H, t), 8.20,(1H, d), 7.93,(2H, d), 7.71,(1H, dd), 7.65,(1H, d), 7.44,(2H, d), 7.30,(1H, d), 6.98,(1H, d), 6.87,(1H, s), 3.72,(1H, m), 3.62,(1H, m), 3.37,(1H, m), 3.16,(3H, m), 2.80,(1H, b), 2.21,(9H, m), 1.81,(1H, m), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 2.55 min, MH+498.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]([CH3:18])[CH3:17])[C:5]2[N:6]=[C:7]([S:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]([CH3:18])[CH3:17])[C:5]2[N:6]=[C:7]([S:11]([CH3:12])=[O:27])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(C)c2cc(Br)c(=O)n(C(C)C)c2n1
Solvent: ClCCl
Product: Cc1nc(S(C)=O)nc2c1cc(Br)c(=O)n2C(C)C
Yield: 47.6 %

Procedure:
To a stirred and cooled (−20° C.) solution of 6-bromo-8-isopropyl-4-methyl-2-(methylthio)-pyrido[2,3-d]pyrimidin-7(8H)-one (380 mg, 1.16 mmol) in CH2Cl2 (25 mL) was added MCPBA (340 mg, 77%, 1.52 mmol). After stirring for 30 min (−20° C. to 0° C.), the mixture was quenched with saturated aqueous NaHCO3, extracted with EtOAc, dried and evaporated. The crude product was washed with EtOAc/Hexane to give the title compound (190 mg, 48%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:16][C:15]=1[CH:26]([C:28]1[N:29]([S:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)(=[O:43])=[O:42])[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=2)[OH:27])([O-:13])=[O:12].C(N(CC)CC)C>ClCCl>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:16][C:15]=1[C:26]([C:28]1[N:29]([S:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)(=[O:42])=[O:43])[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[C:32]([C:37]([F:39])([F:40])[F:38])[CH:31]=2)=[O:27])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1C(O)c1cc2ccc(C(F)(F)F)cc2n1S(=O)(=O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(c1cc(N2CCCCC2)ccc1[N+](=O)[O-])c1cc2ccc(C(F)(F)F)cc2n1S(=O)(=O)c1ccccc1
Temperature: -80 °C
Yield: 99.6 %

Procedure:
Into a 50 mL 3-neck round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of dimethlysulfoxide (156 mg, 2.00 mmol, 3.73 equiv) in dichloromethane (5 mL). This was followed by the addition of oxalyl dichloride (127 mg, 1.00 mmol, 1.87 equiv) dropwise with stirring at −80° C. The resulting solution was stirred for 10 min at −80° C. in a liquid nitrogen bath. To this was added a solution of (2-nitro-5-(piperidin-1-yl)phenyl)(1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indol-2-yl)methanol (300 mg, 0.54 mmol, 1.00 equiv) in dichloromethane (5 mL) dropwise with stirring at −80° C. The resulting solution was stirred for an additional 60 min at −80° C. To the mixture was added triethylamine (400 mg, 3.96 mmol, 7.39 equiv) dropwise with stirring at −80° C. The resulting solution allowed to warm to −20° C. over 60 minutes. The solution was diluted with 50 mL of DCM. The mixture was washed with 1×30 mL of water and 1×30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 300 mg of intermediate if as orange oil.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:6][N:7]([C:29]1[N:34]=[CH:33][C:32](Br)=[CH:31][N:30]=1)[C@@H:8]1[CH2:12][N:11]([C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)[N:14]=2)[C@H:10]([CH2:27][CH3:28])[CH2:9]1.[NH:45]1[CH:49]=[CH:48][N:47]=[CH:46]1.C([O-])([O-])=O.[K+].[K+].CN(C)CC(O)=O.N.O>[Cu]I.CCOC(C)=O.CS(C)=O>[F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:6][N:7]([C:29]1[N:34]=[CH:33][C:32]([N:45]2[CH:49]=[CH:48][N:47]=[CH:46]2)=[CH:31][N:30]=1)[C@@H:8]1[CH2:12][N:11]([C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)[N:14]=2)[C@H:10]([CH2:27][CH3:28])[CH2:9]1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)CN1c1nc(N2CCC(O)CC2)ncc1Cl
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: N
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-n3ccnc3)cn2)CN1c1nc(N2CCC(O)CC2)ncc1Cl
Temperature: 25 °C
Yield: 20.5 %

Procedure:
A 15 ml round-bottom tube is charged with 1-(4-{(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidin-1-yl}-5-chloro-pyrimidin-2-yl)-piperidin-4-ol (32 mg, 0.044 mmol), imidazole (6 mg, 0.088 mmol), CuI (9 mg, 0.044 mmol), K2CO3 (12 mg, 0.088 mmol), N,N-dimethyl glycine (5 mg, 0.044 mmol) and DMSO (0.5 ml). Then the tube is sealed and heated to 110 degree for 18 hours. After cooling to rt, saturated NH3/H2O, EtOAc is added and then filtered through Celite pad. The solution is extracted with EtOAc and organic layer was dried over MgSO4. Removal of solvent and purification with reverse phase column give 1-(4-{(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-imidazol-1-yl-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidin-1-yl}-5-chloro-pyrimidin-2-yl)-piperidin-4-ol (6.5 mg, 0.009 mmol, 20%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:31][C:32]([C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:38]=[CH:37]2)=[NH:33]>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:31]=[C:32]([C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:38]=[CH:37]4)[N:33]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(C(=N)NO)ccc21
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(ccn4C(=O)OC(C)(C)C)c3)no2)cc1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59 %

Procedure:
Prepared using General Procedure 2. A flask containing 3-cyano-4-isopropoxybenzoic acid (135 mg, 0.66 mmol), HOBt (130 mg, 0.85 mmol) and EDC (164 mg, 0.85 mmol) in DMF (2.5 mL) was stirred for 1.5 h at room temperature under an atmosphere of N2. A solution of crude tert-butyl 5-(N-hydroxycarbamimidoyl)-1H-indole-1-carboxylate INT-66 (199 mg, 0.72 mmol) in DMF (2.5 mL) was added to the mixture. After 1 h at room temperature, the mixture was heated to 75° C. and stirred overnight. The reaction mixture was diluted with NaHCO3 and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated. The resulting crude material was chromatographed (EtOAc/hexanes) to provide 174 mg (59%) of tert-butyl 5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole-1-carboxylate INT-67 as a white solid. LCMS-ESI (m/z) calculated for C25H24N4O4: 444.5; found 445.1 [M+H]+, tR=3.67 min (Method 1).
Reaction SMILES: Cl.[C:2]1([C:8]2[C:12]3=[C:13]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:14]=[N:15][CH:16]=[C:11]3[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([C:32]2[CH:36]=[C:35]([CH:37]=O)[O:34][N:33]=2)[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([C:32]2[CH:36]=[C:35]([CH2:37][N:22]3[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:13]4[N:14]=[N:15][CH:16]=[C:11]5[O:10][N:9]=[C:8]([C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=6)[C:12]=45)[CH2:20][CH2:21]3)[O:34][N:33]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: O=Cc1cc(-c2cccc(Cl)c2)no1
Reactant: c1ccc(-c2noc3cnnc(NCC4CCNCC4)c23)cc1
Agent: Cl
Product: Clc1cccc(-c2cc(CN3CCC(CNc4nncc5onc(-c6ccccc6)c45)CC3)on2)c1

Procedure:
According to the same procedure described in Example 35, using the compound obtained in Example 84 instead of the compound obtained in Example 11 and 3-(3-chlorophenyl)isoxazole-5-carbaldehyde instead of 4-phenylthiophene-2-carbaldehyde, the title compound having the following physical data was obtained.