Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:6]([Li])[CH2:7][CH2:8][CH3:9].O>C1(C)C=CC=CC=1>[CH3:4][CH:3]=[CH:2][CH:1]([OH:5])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C/C=C/C=O
Reactant: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CC=CC(O)CCCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
31.5 g of crotonaldehyde are added dropwise, at -20° C. in the course of 75 minutes, to 32 g of butyllithium, dissolved in 145.8 g of toluene. After the reaction has proceeded for two hours, the temperature increasing slowly to 0° C., 250 ml of water are carefully added dropwise. The aqueous phase is separated off and washed once with 100 ml of toluene. The combined organic phases are washed neutral with water, dried over sodium sulphate and distilled. 46 g of oct-2-en-4-ol of boiling point 68°-72° C./13 mb are obtained. According to the gas chromatogram, the purity is 96%. The NMR spectrum confirms the expected structure.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]1([S:16]([N:19]=[C:20]=[S:21])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:20](=[S:21])[NH:19][S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[N:3]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: O=S(=O)(N=C=S)c1ccccc1
Solvent: CC#N
Product: Cc1cc(C)nc(NC(=S)NS(=O)(=O)c2ccccc2)n1

Procedure:
To a dry suspension of 12.4 g of 2-amino-4,-6-dimethypyrimidine in 60 ml of acetonitrile was added 19.9 g of benzenesulfonyl isothiocyanate. The heavy white precipitate which formed was removed by filtration and washed with anhydrous ethyl ether. It melted at 165°170°. The product was N-[(4,6-dimethylpyrimidin-2-yl)-aminothioxomethyl]benzenesulfonamide.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:25]([NH:24][CH2:22][CH3:23])=[O:26])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CCN=C=O
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2ccccc2)C1
Product: CCNC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of N-(1-Boc-piperidin-3-ylmethyl)aniline 1 (102 mg, 0.35 mmol) in 1 mL of dry CH2Cl2was added ethyl isocyanate (95%, 35 μL, 1.2 eq.) at room temperature. After being shaken at room temperature for overnight, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2. Removal of the CH2Cl2 afforded N-(1-Boc-piperidin-3-yl-methyl)-N-phenyl-N′-ethylurea (2) (120 mg, 95%). LRMS 285 (M-100)+ 261.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([OH:31])=O)[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH:32]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH2:34][CH2:33]1>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[CH2:26][C:25]([CH3:27])([CH3:28])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([NH:38][S:35]([CH:32]5[CH2:34][CH2:33]5)(=[O:37])=[O:36])=[O:31])[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: NS(=O)(=O)C1CC1
Reactant: CC(C)Oc1ccc(-c2cccc(C3CC(C)(C)c4cc(C(=O)O)ccc4N3)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2cccc(C3CC(C)(C)c4cc(C(=O)NS(=O)(=O)C5CC5)ccc4N3)c2)cc1
Yield: 29.9 %

Procedure:
A mixture of 2-(4′-isopropoxy-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (120 mg, 0.29 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (83 mg, 0.43 mmol), 4-dimethylaminopyridine (52.5 mg, 0.43 mmol), cyclopropane sulfonic acid amide (110 mg, 0.87 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [2-(4′-isopropoxy-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (45 mg, 30%) as a light yellow solid: MS (ESI) M+1=519.1.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=[O:2].CS(C)=[O:20].C(=O)([O-])[O-].[K+].[K+].OO>O>[CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]([NH2:13])=[O:20])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: CS(C)=O
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
Combine 4-(4-Formyl-phenoxy)-benzonitrile (3.6 g, 16.1 mmol), dimethylsulfoxide (25 mL), potassium carbonate (2.1 g, 15.2 mmol), and 3 mL of 30% hydrogen peroxide solution. Stir 18 h at ambient temperature. Dilute with 100 mL of water, extract with ethyl acetate (3× 100 mL). Wash the organic phase with 100 mL of water, and 50 mL of brine. Dry the organic phase over sodium sulfate, filter, and concentrate under vacuum. Purify via a Biotage Flash 40L system using 75:25 hexanes/ethyl acetate as eluting solvent to give 3.0 g (77%) of the title compound: 1H NMR (chloroform-d): 9.95 (s, 1H), 7.88 (m, 4H), 7.12 (m, 4H), 5.29-5.14 (br m, 2H).
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][C:8]=1[C:9]([O:11]C)=O)=[C:2]=[S:3].[CH3:20][C:21]1[N:22]=[CH:23][N:24]([CH2:26][CH2:27][CH2:28][NH2:29])[CH:25]=1>>[CH2:13]([C:6]1[S:5][C:4]2[NH:1][C:2](=[S:3])[N:29]([CH2:28][CH2:27][CH2:26][N:24]3[CH:25]=[C:21]([CH3:20])[N:22]=[CH:23]3)[C:9](=[O:11])[C:8]=2[CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cn(CCCN)cn1
Reactant: COC(=O)c1cc(Cc2ccccc2)sc1N=C=S
Product: Cc1cn(CCCn2c(=S)[nH]c3sc(Cc4ccccc4)cc3c2=O)cn1

Procedure:
The compound was synthesized starting from methyl 2-isothiocyanato-5-benzylthiophene-3-carboxylate (0.102 g. 0.35 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (0.049 g, 0.35 mmol) as described above.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:9])([CH3:8])[O:4][CH:5]([CH3:7])[CH3:6].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:19]([CH:28]=[O:29])=[CH:20][C:21]3[NH:25][CH:24]=[N:23][C:22]=3[C:26]=2[F:27])=[C:13]([Cl:30])[CH:12]=1>C1COCC1>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:19]([CH:28]([OH:29])[CH2:2][Si:3]([O:4][CH:5]([CH3:7])[CH3:6])([CH3:9])[CH3:8])=[CH:20][C:21]3[NH:25][CH:24]=[N:23][C:22]=3[C:26]=2[F:27])=[C:13]([Cl:30])[CH:12]=1
Reactant: CC(C)O[Si](C)(C)CCl
Reactant: O=Cc1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Solvent: C1CCOC1
Product: CC(C)O[Si](C)(C)CC(O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of the Grignard reagent prepared from Mg and chloromethyl dimethylisopropoxy silane (Org. Synth. 1992, 69, 96) [4.4 mL, 3.26 mmol, 0.74 M solution (based on 90% purity)] in THF, is added a solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde 10f (200 mg, 0.54 mmol) in THF (1 mL) at −78° C. After stirring for 1 hour at −78° C., the reaction is quenched with saturated aqueous NH4Cl, and extracted with EtOAc. The organic layer is dried over MgSO4, filtered, concentrated in vacuo to afford the crude desired product which is directly used without further purification.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[F:29][CH:30]([F:41])[C:31]1[CH:36]=[C:35](F)[CH:34]=[CH:33][C:32]=1[N+:38]([O-:40])=[O:39].C([O-])([O-])=O.[K+].[K+]>CN(P(N(C)C)(N(C)C)=O)C.CCOC(C)=O.O>[CH:1]1([C:4]2[C:5]([N:24]([C:35]3[CH:34]=[CH:33][C:32]([N+:38]([O-:40])=[O:39])=[C:31]([CH:30]([F:29])[F:41])[CH:36]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)F
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(F)F)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 101.5 %

Procedure:
A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (1.00 g, 2.49 mmol), 2-(difluoromethyl)-4-fluoro-1-nitrobenzene (1.13 g, 5.91 mmol) and K2CO3 (0.85 g, 6.15 mmol) in HMPA (6.2 mL) was stirred at 60° C. for 15 h. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-80% EtOAc/hexanes) to afford the title compound (1.45 g, 97%) as a yellow solid. LCMS (m/z, ES+)=574.3 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:5]([NH:15][C:16](=[O:29])[CH:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH:4]=1)#[N:2].I[CH2:31][CH2:32][OH:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[OH:33][CH2:32][CH2:31][O:13][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[NH:15][C:16](=[O:29])[CH:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[CH3:18]
Reactant: CC(C(=O)Nc1cc(C#N)ccc1CCCC(=O)O)c1cccc2ccccc12
Reactant: OCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C(=O)Nc1cc(C#N)ccc1CCCC(=O)OCCO)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution of the compound prepared in Example 2(6) (150 mg) and 2-iodoethanol (100 mg) in DMF (2 ml), potassium carbonate (65 mg) was added under an atmosphere of argon. The mixture was stirred for overnight at room temperature. Water was added to the reaction mixture, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over and concentrated to give the crude crystal. The crude crystal was recrystallized with ethyl acetate/hexane to give the title compound (95 mg) having the following physical data.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][OH:13])[CH:6]=1)[CH2:3][NH2:4].[C:14]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](=O)[CH3:32])=[CH:26][CH:25]=1)([O:16]CC1C=CC=CC=1)=[O:15].O>C1(C)C(C)=CC=CC=1>[C:14]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][OH:13])[CH:6]=2)[CH3:32])=[CH:26][CH:25]=1)([OH:16])=[O:15]
Reactant: CC(=O)Cc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: NCC(O)c1ccc(O)c(CO)c1
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(Cc1ccc(C(=O)O)cc1)NCC(O)c1ccc(O)c(CO)c1
Reaction time: 3 h

Procedure:
2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethanamine (1.09 g) and 1-(4-carbobenzyloxyphenyl)propan-2-one (1.6 g) were refluxed in xylene in a Dean and Stark apparatus until the theoretical amount of water had been collected. The solvent was removed, ethanol added and the mixture hydrogenated at 70 psi and 50° for 3 hours using 10% Pd/c as catalyst. Filtration of the catalyst and evaporation of the solvent gave the title compound as a foam τ (d6DMSO) 8.95 (3H, d, J=7 Hz), 6.8-7.4 (5H, m), 5.5 (2H, s+1H, t), 3.65 (5H, broad), 2.3-3.3 (5H, m), 2.0 (2H, d, J=8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][C:7]=1[O:15][CH3:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[S:31](Cl)([CH3:34])(=[O:33])=[O:32]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:12][S:31]([CH3:34])(=[O:33])=[O:32])=[O:11])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: COc1cc(C(N)=O)ccc1Cc1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)NS(C)(=O)=O)ccc1Cc1ccc(Cl)c(Cl)c1
Reaction time: 0.33 h

Procedure:
To a solution of 4-(3,4-dichlorobenzyl)-3-methoxybenzamide (Preparation 155, 155 mg, 0.50 mmol) in anyhydrous THF (5 mL) was added 1M LiHMDS (1.25 mL, 1.25 mmol) via syringe. The mixture was stirred for 20 minutes before adding mesyl chloride (0.116 mL, 1.50 mmol) and then stirred for 18 hours at room temperature. The reaction was quenched with the addition of 2M HCl (20 mL), and the aqueous was extracted with EtOAc (3×20 mL). The combined organics were concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with a gradient of 25% EtOAc in heptane to 100% EtOAc. The title compound was obtained as a white solid (40 mg, 21%).
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][CH:4]1[CH:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].Br[CH:14]([F:26])[C:15]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=1[F:25]>>[Cl:1][C:2]([Cl:12])=[CH:3][CH:4]1[CH:6]([C:7]([O:9][CH:14]([F:26])[C:15]2[C:16]([F:25])=[C:17]([F:24])[C:18]([F:23])=[C:19]([F:22])[C:20]=2[F:21])=[O:8])[C:5]1([CH3:10])[CH3:11]
Reactant: Fc1c(F)c(F)c(C(F)Br)c(F)c1F
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OC(F)c1c(F)c(F)c(F)c(F)c1F

Procedure:
α,2,3,4,5,6-Hexafluorobenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate was prepared from 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid and α-bromopentafluorobenzyl fluoride following the procedure described in Example 2 Method B. The product, a colourless oil, was characterised by p.m.r. spectroscopy. Chemical shift δ ppm (solvent CDCl3): 1.0-2.5(8H, m, (CH3)2 and cyclopropyl protons); 5.67 and 6.24(1H, both d of d, J=8Hz and J=2Hz, CH=); 7.53(1H, d, J=52Hz, CHF).
Reaction SMILES: ClC1C(Cl)=C(C2C=CC=CC=2)N=C(C(Cl)=O)C=1.[F-].[K+].[F:20][C:21]1[C:26]([F:27])=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:24]=[C:23]([C:34](F)=[O:35])[CH:22]=1.C(N(CC)CC)C.[CH:44]([OH:47])([CH3:46])[CH3:45]>S1(CCCC1)(=O)=O.O>[F:20][C:21]1[C:26]([F:27])=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:24]=[C:23]([C:34]([O:47][CH:44]([CH3:46])[CH3:45])=[O:35])[CH:22]=1
Reactant: CC(C)O
Reactant: O=C(F)c1cc(F)c(F)c(-c2ccccc2)n1
Agent: O=C(Cl)c1cc(Cl)c(Cl)c(-c2ccccc2)n1
Agent: [F-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CC(C)OC(=O)c1cc(F)c(F)c(-c2ccccc2)n1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
To a solution of 4,5-dichloro-6-phenylpicolinoyl chloride (1.76 g, 6.14 mmol) in sulfolane (40 mL, dried over 4 Å molecular sieves, ˜100 ppm H2O) was added potassium fluoride (2.14 g, 36.9 mmol). The reaction mixture was heated at 130° C. for 24 h. Reaction mixture was analyzed by GC-MS and 19F NMR. (Data for 4,5-difluoro-6-phenylpicolinoyl fluoride, GC-MS: m/z=237, 189; 19F NMR (376 MHz, Toluene-d8) δ 17.03 (s), −124.14 (d, J=19.1 Hz), −140.76 (d, J=19.1 Hz). Reaction was allowed to cool to room temperature and triethylamine (1.1 mL, 7.7 mmol) and isopropanol (0.7 mL, 9.2 mmol) were added. After stirring for 1.5 h, the reaction mixture was diluted with water (100 mL) and transferred to a separatory funnel. The reaction mixture was extracted with methyl tert-butyl ether (MTBE, 2×50 mL). The combined organic extracts were washed with water (3×50 mL) and saturated NaCl (50 mL) and concentrated under reduced pressure to provide a brown oil. The crude product oil was purified by silica gel flash chromatography (hexane/ethyl acetate gradient, 100% hexane→20% hexane/ethyl acetate) to provide 1.2 g (70% yield) of isopropyl 4,5-difluoro-6-phenyl-picolinate as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.07-7.99 (m, 2H), 7.89 (dd, J=9.4, 5.3 Hz, 1H), 7.56-7.42 (m, 3H), 5.31 (hept, J=6.3 Hz, 1H), 1.43 (d, J=6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 162.89 (d, J=3.4 Hz), 156.74 (dd, J=264.2, 12.5 Hz), 148.07 (dd, J=268.9, 10.8 Hz), 146.99 (dd, J=309.2, 10.8 Hz), 145.45 (s), 134.12-133.60 (m), 130.20 (s), 129.05 (d, J=5.9 Hz), 128.64 (s), 113.56 (d, J=16.0 Hz), 70.14 (s), 21.86 (s). 19F NMR (376 MHz, CDCl3) δ−125.22 (dd, J=17.7, 9.5 Hz), −144.74 (dd, J=17.7, 5.4 Hz). LRMS. Calcd. C15H13F2—NO2: 277.09. Found: m/z=277 (M+), 218, 191.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([OH:24])=O)[C:13]=2[CH2:12][NH:11][C:10]1=[O:34].[CH2:35]([NH2:38])[CH2:36][CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:32])[CH3:33])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([NH:38][CH2:35][CH2:36][CH3:37])=[O:24])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34]
Reactant: CN(C)CCNc1nc(-c2cccc(C(=O)O)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCNC(=O)c1cccc(-c2nc(NCCN(C)C)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 32.7 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoic acid (15 mg, 0.03 mmol) in CH2Cl2 (3 mL) were added propylamine (0.003 mL, 0.035 mmol), HATU (13 mg, 0.034 mmol) and diisopropyl ethyl amine (0.05 mL, 0.3 mmol). The reaction mixture was stirred over night. The reaction mixture was diluted with CH2Cl2 (5 mL) and water (5 mL) and shaked. The layers were separated and the organic layer was washed with brine (8 mL), dried over Na2SO4, filtered and concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) then provided the title compound as a white solid (5 mg, 31%). LC-MS m/z 510 (M+H)+; 1H-NMR (MeOD) δ 1.00 (t, 3H), 1.67 (m, 2H), 2.80 (s, 6H), 3.25 (m, 2H), 3.40 (m, 2H), 3.62 (m, 2H), 4.52 (s, 2H), 7.19 (m, 1H), 7.53 (m, 1H), 7.65 (m, 1H), 7.76 (d, 1H), 7.98 (d, 1H), 8.05 (s, 1H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]3[N:15]=[N:16][NH:17][N:18]=3)=[CH:12][N:11]=[C:10]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:34])(=[N:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27])=[CH:22][CH:21]=3)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[CH2:35]([N:17]1[N:16]=[N:15][C:14]([C:13]2[C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[N:9][C:10]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:34])(=[N:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27])=[CH:22][CH:21]=3)=[N:11][CH:12]=2)=[N:18]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3nn[nH]n3)c(NC3CCCCC3)n2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3nnn(Cc4ccccc4)n3)c(NC3CCCCC3)n2)cc1

Procedure:
50 mg (0.1 mmol) (RS)—S-(4-{[4-(cyclohexylamino)-5-(2H-tetrazol-5-yl)-pyrimidine-2-yl]amino}phenyl)-N-(ethoxycarbonyl)-S-methylsulfoximide, 18 mg (0.1 mmol) benzyl bromide, 71 mg (0.51 mmol) potassium carbonate and 17 mg (0.1 mmol) potassium iodide in 1.6 ml 2-butanone are stirred for 6 hours at 80° C. After cooling, the mixture is absorbed onto silica gel and purified chromatographically (DCM/EtOH 95:5). 43 mg (0.07 mmol; corresponding to 73% of theory) of the product is obtained.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:9]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[ClH:26].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CO>[ClH:26].[ClH:26].[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([CH:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(c1cccc(C(F)(F)F)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: CC(c1cccc(C(F)(F)F)c1)N1CCNCC1
Yield: 129.3 %

Procedure:
The product from Example 44A (0.071 g, 0.198 mmol) was added to HCl (2.0 Min dioxane) (0.991 mL, 1.981 mmol), and methanol was added dropwise until the reaction became nearly homogeneous. As the reaction was stirred, a precipitate formed. The reaction was concentrated to give the title compound (0.066 g, 0.256 mmol) as the dihydrochloride salt. MS (APCI) m/z 259 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH:15]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[CH:19]=[C:20]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:21]=[CH:22][C:23]=1[CH3:24].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]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH2:15][N:28]2[CH2:29][CH2:30][N:25]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[C:18]([CH3:17])[CH:19]=3)[CH2:26][CH2:27]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: CCCc1cc(CCC=O)nn1C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(C)c(C)c3)CC2)nn1C(C)(C)C

Procedure:
95 mg (98%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50 mg, 0.225 mmol), 1-(3,4-dimethylphenyl)piperazine (43 mg, 0.225 mmol), DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:26]CCl>S(Cl)(Cl)=O.CN(C)C=O>[Cl:26][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: ClCCl
Reactant: OCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(CCl)cc2)=NO1
Temperature: 0 °C

Procedure:
In a solution of 4.2 g of 5-(3,5-dichlorophenyl)-3-[4-(hydroxymethyl)phenyl]-5-trifluoromethyl-4,5-dihydro-isoxazole in 100 mL of dichloromethane, 1.2 mL of thionyl chloride and a catalytic amount (2 to 3 drops) of N,N-dimethylformamide were added, and stirred under reflux with heating for 3 hours. After the completion of the reaction, the reaction mixture was poured into 30 mL of ice water, the organic phase was collected, washed with water (50 mL×1) and saturated sodium hydrogen carbonate aqueous solution (30 mL×3), and thereafter dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluted with ethyl acetate-hexane (1:5) to obtain 4.1 g of the aimed product as pale yellow crystal.