Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[C:22]1([CH2:28][S:29]([NH2:32])(=[O:31])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:17]=[C:16]([CH2:18][NH:32][S:29]([CH2:28][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)(=[O:30])=[O:31])[CH:15]=[N:14][CH:13]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)Cc1ccccc1
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Product: Cn1c(-c2cncc(CNS(=O)(=O)Cc3ccccc3)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and phenyl-methanesulfonamide are processed according to the method described in Example 170 to give N-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-C-phenyl-methanesulfonamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.77 (s, 3H), 4.31 (s, 2H), 4.44 (s, 2H), 7.30-7.41 (m, 6H), 7.73 (d, J=8.3 Hz, 1H), 7.83 (br. s., 1H), 7.97 (d, J=1.5 Hz, 1H), 8.03 (t, J=2.1 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.79 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 451.1006 [(M+H)+ Calcd for C23H20ClN4O2S: 451.0996].
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[ClH:5].[F:6][C:7]([F:11])([F:10])[CH2:8][NH2:9].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[ClH:5].[F:6][C:7]([F:11])([F:10])[CH2:8][NH:9][CH:2]([CH3:4])[CH3:1]
Reactant: CC(C)=O
Reactant: NCC(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)NCC(F)(F)F
Yield: 65.1 %

Procedure:
After briskly stirring a mixture of acetone (1.10 ml; 15 mmol), 2,2,2-trifluoroethylamine hydrochloride (1 g; 7.4 mmol), AcOH (2 ml) and 3 Å molecular sieves (5 g) in 30 ml of CH2Cl2 for 2 hour at room temperature, sodium triacetoxyborohydride (3.20 g; 15 mmol) was added. After stirring 18 hours at room temperature, the reaction mixture was filtered through celite and 5 ml of ethereal HCl were added. After removing the volatiles in vacuo the residue was partitioned between ether (100 ml) and 1N NaOH (100 ml). The organic layer was washed with brine (50 ml), dried (MgSO4) and filtered. Ethereal HCl (5 ml) was added and the volatiles were removed in vacuo to afford 855 mg (65%) of the title compound of this step as a white powder. mp (melting point)=80°-90° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6](Br)[CH:5]=1.B(O)(O)[C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:10][C:8]1[CH:9]=[C:4]([C:3]([O:2][CH3:1])=[O:12])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:7]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(O)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(O)cc(-c2ccc(C)cc2)c1

Procedure:
To a stirred solution of 3-bromo-5-hydroxy-benzoic acid methyl ester (4.09 g, 17.7 mmol) and p-tolylboronic acid (2.86 g, 21 mmol) in toluene (36 mL) was added cesium carbonate (7.14 g, 22 mmol) in water (3.6 mL) at room temperature. The mixture was purged with nitrogen, and tetrakis(triphenylphosphine)palladium(0) (1.05 g, 0.906 mmol) was added. The reaction mixture was subjected to microwave irradiation at 110° C. for 1 hour. After cooling, the mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH:13]=[C:14]3[CH:24]=[CH:23][C:17]([CH:18]=[CH:19][C:20]([O-:22])=[O:21])=[CH:16][CH2:15]3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1>FC(F)(F)C(O)=O>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH:13]=[C:14]3[CH:15]=[CH:16][C:17]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:23][CH2:24]3)[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: O=C([O-])C=CC1=CCC(=CN2CCN(c3ccncc3)CC2)C=C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C=CC1=CCC(=CN2CCN(c3ccncc3)CC2)C=C1
Yield: 104.7 %

Procedure:
tButyl 4-[[4-(4-pyridyl)piperazin-1-yl]methylene]cinnamate (200 mg) was stirred in trifluoroacetic acid (5 ml) for 2 hours. The solvent was removed by evaporation and the resulting oil was titriated with anhydrous ether to give the title compound (210 mg) as a white solid: NMR (d6 DMSO) δ 3.05-3.25(m,4H), 3.7-4.1(bm,4H), 4.25(s,2H), 6.6(d,1H), 7.25(d,2H), 7.5(d,2H), 7.6(d,1H), 7.75(d,2H), 8.35(d,2H); m/e 324(M+H)+ ; calculated for C19H21N3 O2.2CF3COOH.0.5H2O: C, 49.5; H, 4.25; N, 7.4. Found: C, 49.1; H, 4.2; N, 7.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]OS(C1C=CC(C)=CC=1)(=O)=O)=[N+:17]=[N-:18].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([O:1][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][N:16]=[N+:17]=[N-:18])[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCN=[N+]=[N-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCCCCCCN=[N+]=[N-])cc(C(=O)OC)c1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
5-(6-Azidohexoxy)isophthalic Acid Dimethyl Ester was prepared as follows: A mixture of dimethyl 5-hydroxyisophthalate 4 (1.05 g, 5 mmol), 6-azido-1-(p-toluenesulfonyloxy)hexane (1.57 g, 5 mmol) and K2CO3 (1.38 g, 10 mmol) in DMF (15 mL) was stirred for 17 h at 80° C. After cooling down, H2O (150 mL) was added and the mixture was extracted with EtOAc, washed with water, dried (MgSO4), and the solvent was evaporated off. The pure title compound was obtained as a colorless oil (1.51 g, 90%) after column chromatography (SiO2: CH2Cl2).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH3:25].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC=O
Reactant: O=C1CSC(=O)N1CCCCOc1cccc2nccn12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCOc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.71 g (5.6 mmol) of 3-[4-(imidazo-[1,2-a]pyridin-5-yloxy)butyl]thiazolidine-2,4-dione and 0.51 ml (5.6 mmol) of n-butyraldehyde in 50 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate) to yield 1.79 g (88.9%, yellow oily substance) of the desired product.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[CH:4]=[CH:3][C:2]=1[C:11]([O:13]C)=[O:12].[OH:15]O>C(O)(=O)C>[CH3:10][O:9][C:7]([C:5]1[CH:6]=[N+:1]([O-:15])[C:2]([C:11]([OH:13])=[O:12])=[CH:3][CH:4]=1)=[O:8]
Reactant: OO
Reactant: COC(=O)c1ccc(C(=O)OC)nc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(=O)O)[n+]([O-])c1
Temperature: 100 °C

Procedure:
12 g (60 mmol) of dimethyl pyridine-2,5-dicarboxylate were suspended in 30 ml of glacial acetic acid, and after that 13 ml of hydrogen peroxide (35%) were added at and while stirring. The mixture was then heated to 100° C. (internal temperature), while stirring, with a clear solution being formed at 50° C. After the mixture had been stirred at 100° C. for 90 minutes, it was allowed to cool down to 20° C. and the crystalline precipitate was filtered off with suction and washed with water; after drying, 7.5 g of product were obtained, m.p. 160° C. (decomp.).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[C:4]([NH:6][C:7](=[N:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][N:19]=[C:20]2[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)SC)#[N:5]>CN(C=O)C>[NH2:5][C:4]1[N:6]=[C:7]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][N:19]=[C:20]3[N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:2]([CH3:1])[N:3]=1
Reactant: CSC(=NCCCOc1cccc2c(N3CCOCC3)nccc12)NC#N
Reactant: CNN
Solvent: CN(C)C=O
Product: Cn1nc(N)nc1NCCCOc1cccc2c(N3CCOCC3)nccc12
Temperature: 40 °C
Reaction time: 24 h

Procedure:
Methyl hydrazine (7.3 g) is added to a stirred suspension of 1-cyano-2-methyl-3-[3-(1-morpholino-5-isoquinolyloxy)propyl]pseudothiourea (11.56 g) in DMF (91.5 ml). The reaction mixture is stirred at 40° C. under nitrogen for 24 hrs and evaporated in vacuo resulting in a red oil which partially crystallizes on standing. The residue is dissolved in boiling acetonitrile (150 ml) and the hot solution treated with Darco G-60, filtered through Celite, concentrated and cooled. The precipitate is collected, washed with acetonitrile and dried in vacuo at elevated temperature. The dried precipitate is recrystallized from absolute ethanol, dried in vacuo at 75° C. affording the desired product as a powder, M.P. 178°-180° C. Elemental analysis indicates the product as a 1/4 hydrate.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH:6]([O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:22])=O)=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:11]=1)([CH3:8])[CH3:7].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([N:3]([CH2:4][CH3:5])[C:20]([C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[C:10]([O:9][CH:6]([CH3:7])[CH3:8])=[N:11][C:12]([NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1)=[CH:13]2)=[O:22])[CH3:2]
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
Diethylamine (14 ul) and triethylamine (17 ul) in CH2Cl2 (5 ml) was added to 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid (33 mg), HOBt (18 mg), EDCI (25 mg) at 0° C. in order. The mixture was stirred at room temperature for 3 hrs and washed with 8% NaOH, water and brine, dried with anhydrous sodium sulfate and concentrated. The residue was purified by preparative LC-MS to give 31 mg of product as yellow solid. (80% yield). LC-MS: m/e 382 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[N:7]=3)[CH2:16][CH2:17]2)=[CH:22]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1nnc2ccc(N3CCC(c4c[nH]c5ccccc45)CC3)nn12
Yield: 30.8 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.223 g, 1.0 mmol), 3-(piperidin-4-yl)-1H-indole (0.240 g, 1.20 mmol) and DIPEA (0.257 mL, 1.50 mmol) in DMF (3 mL) was heated at 70° C. for 1 hour. The reaction mixture was run onto an SCX cartridge, which was washed with MeOH and eluted with 2M ammonia in methanol. The crude product was purified by MPLC silica chromatography, eluting with ethyl acetate. Pure fractions were evaporated to a gum which crystallised on trituration with ether to afford 6-[4-(1H-indol-3-yl)piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (0.119 g, 31%) as a colourless crystalline solid.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]2[NH:16][C:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][N:13]=2)[C:9]([OH:25])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][C:27]1=[O:32].O>CN1CCCC1=O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:15]2[NH:16][C:12]([C:10]3[C:9]([OH:25])=[C:8]4[C:3]([CH:4]=[CH:5][CH:6]=[N:7]4)=[C:2]([N:29]4[CH2:30][CH2:31][NH:26][C:27](=[O:32])[CH2:28]4)[N:11]=3)=[N:13][N:14]=2)=[CH:19][CH:20]=1
Reactant: Oc1c(-c2nnc(Cc3ccc(F)cc3)[nH]2)nc(Br)c2cccnc12
Reactant: O=C1CNCCN1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1CN(c2nc(-c3nnc(Cc4ccc(F)cc4)[nH]3)c(O)c3ncccc23)CCN1
Yield: 55.6 %

Procedure:
A solution of 5-bromo-7-[5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl)-1,6-naphthyridin-8-ol (10 mg, 0.03 mmol) and piperazin-2-one (60 mg, 0.60 mmol) in 1-methylpyrrolidin-2-one (2 mL) was heated at 150° C. for 18 hours. The resultant solution was cooled to room temperature and water was added. The solids which formed were removed by filtration and further purified by prep HPLC to give 4-{7-[5-(4-Fluorobenzyl)-4H-1,2,4-triazol-3-yl]-8-hydroxy-1,6-naphthyridin-5-yl}piperazin-2-one (7 mg, 67%) as a white solid. 1H NMR (CD3OD/CDCl3): δ 9.03 (d, J=4.4 Hz, 1 H), 8.48 (d, J=8.4 Hz, 1 H), 7.64 (dd, J=8.4, 4.4 Hz, 1 H), 7.32 (dd, J=8.4, 5.6Hz, 2 H), 6.97 (t, J=8.4Hz, 2 H). 4.13 (s, 2 H), 4.10 (5,2 H), 3.60 (m, 2 H), 3.42 (m, 2 H); 19F NMR (CD3OD/CDCl3): δ −117.93; MS m/z 420 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]#[C:7][CH2:8][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])(=[O:3])[CH3:2].[Cl:15][C:16]1[N:21]=[CH:20][C:19]([CH2:22][NH:23]C)=[CH:18][CH:17]=1>O1CCCC1>[C:1]([O:4][CH2:5][C:6]([NH:23][CH2:22][C:19]1[CH:20]=[N:21][C:16]([Cl:15])=[CH:17][CH:18]=1)=[CH:7][CH2:8][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC#CCC(=O)OC(C)C
Reactant: CNCc1ccc(Cl)nc1
Solvent: C1CCOC1
Product: CC(=O)OCC(=CCC(=O)OC(C)C)NCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an initial charge of 124 mg (0.672 mmol) of iso-propyl 4-acetoxybut-2-ynecarboxylate in 5 ml of anhydrous tetrahydrofuran (THF) are added dropwise 116 mg (0.739 mmol) of 1-(6-chloropyridin-3-yl)-N-methylmethanamine, dissolved in 1 ml of anhydrous THF, at room temperature. The reaction mixture is stirred at room temperature for 16 h and concentrated under reduced pressure. Subsequently, the residue is taken up with toluene and washed successively with dilute aqueous sulphuric acid and sodium hydrogencarbonate solution. After drying over magnesium sulphate and concentrating the organic phase under reduced pressure, 120 mg (50% of theory) of iso-propyl 4-acetoxy-3-[(4-chlorobenzyl)(methyl)amino]but-2-enecarboxylate are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.[C:16]([O:19][CH2:20][C:21]1[CH:22]=[C:23]([C:26](=[O:29])[CH2:27]Br)[O:24][CH:25]=1)(=[O:18])[CH3:17]>>[C:16]([O:19][CH2:20][C:21]1[CH:22]=[C:23]([C:26]([C:27]2[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]3[C:5]([C:6]=2[NH2:7])=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=3)=[O:29])[O:24][CH:25]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OCc1coc(C(=O)CBr)c1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2cc(COC(C)=O)co2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 employing 4-chloro-2-(ethoxycabonylamino)benzonitrile (Exampe 1, step 1) and 4-acetoxymethyl-2-(bromoacetyl)furan (step 1).
Reaction SMILES: C(N[C:5](=[O:12])[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=O)(=O)C.[NH2:13][NH:14][C:15]([NH:17][NH2:18])=[S:16]>C(O)C.Cl>[NH2:13][N:14]1[C:5](=[O:12])[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[N:18][N:17]=[C:15]1[SH:16]
Reactant: NNC(=S)NN
Reactant: CC(=O)NC(=O)C(=O)C(C)(C)C
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1nnc(S)n(N)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.5 %

Procedure:
37.0 g (0.22 mol) of trimethylpyruvic acid N-acetylamide in 150 ml of ethanol were added dropwise to 23.2 g (0.22 mol) of thiocarbohydrazide in 400 ml of 1N HCl and the reaction mixture was subsequently stirred at room temperature for 5 hours. The product which had precipitated was filtered off, washed with water and dried. 41.2 g of the abovementioned product (VI) of melting point 210° C. were obtained, with a content, determined by gas chromatography, of >99% which corresponded to a yield of 95% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:41])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:23]3[CH2:28][CH2:27][NH:26][C:25](=[O:29])[CH2:24]3)=[O:22])[C:10]([C:30]3[C:31]([O:38][CH2:39][CH3:40])=[N:32][C:33](SC)=[N:34][CH:35]=3)=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.S(=O)(O)[O-].[Na+].[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>C(Cl)Cl.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:41])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:23]3[CH2:28][CH2:27][NH:26][C:25](=[O:29])[CH2:24]3)=[O:22])[C:10]([C:30]3[C:31]([O:38][CH2:39][CH3:40])=[N:32][C:33]([N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)=[N:34][CH:35]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1nc(SC)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1
Reactant: C1COCCN1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOc1nc(N2CCOCC2)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
To a solution of rac-4-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one (160 mg, 0.261 mmol) in methylene chloride cooled to 0° C. was added 100 mg of m-chloroperoxybenzoic acid (≦77%, Aldrich). After 10 min, sodium bisulfite solution was added to quench the reaction. The product was extracted with methylene chloride. The organic layer was washed with saturated solution of sodium bicarbonate, brine, dried over Na2SO4 and concentrated to give the crude sulphoxide as light yellow foam. The crude sulphoxide/sulphone was taken in 20 mL of tetrahydrofuran, and morpholine (200 uL, 3.34 mmol, Aldrich) was added. The mixture was heated at reflux overnight. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification of the crude residue by flash column chromatography (silica gel, eluting with 50-100% ethyl acetate in hexanes, then with 0-5% methanol in ethyl acetate) gave the tittle compound (94 mg, 55%). HR-MS (ES, m/z) calculated for C32H36N7O4Cl2 [(M+H)+] 652.2201, observed 652.2202.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.[NH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1)=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCCCN1CCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCCCN1CCCC1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 54.3 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), 1-(3-aminopropyl)pyrrolidine (11.89 mg, 0.093 mmol), and BOP (41.0 mg, 0.093 mmol). The reaction mixture was stirred overnight and was then concentrated. The resulting residue was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B; flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(3-(pyrrolidin-1-yl)propyl)acetamide (13.7 mg, 0.025 mmol, 53.5% yield): LCMS=542.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.18 (2 H, d, J=8.28 Hz), 7.50-7.81 (7 H, m), 5.14 (1 H, s), 3.33-3.41 (2 H, m), 2.90 (4 H, br. s.), 2.78 (2 H, t, J=7.65 Hz), 1.74-2.01 (6 H, m); Analytical LC/MS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 90:10 acetonitrile:water with 10 mM ammonium acetate; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.2 min.
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([N:21]=[C:22]=[O:23])[CH2:18][CH2:19][CH3:20]>C(C(C)=O)C>[CH2:17]([NH:21][C:22]([NH:10][S:7]([C:3]1[C:2]([CH3:1])=[CH:6][S:5][CH:4]=1)(=[O:9])=[O:8])=[O:23])[CH2:18][CH2:19][CH3:20]
Reactant: Cc1cscc1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1cscc1C
Reaction time: 8 h

Procedure:
4-Methyl-3-thiophenesulfonamide (22 g), 125 ml of methyl ethyl ketone, 16.6 g of potassium carbonate and 14.3 g of butyl isocyanate was stirred at reflux for six hours, allowed to stand overnight and then evaporated to a syrup. Water (150 ml) was added to the residue and the mixture was filtered to remove a small amount of solid. The filtrate was acidified, cooled and the resulting intermediate was filtered off. It melted at 126°-131° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][S:7](=[O:11])(=[O:10])[NH:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:18]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br)#[N:19].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][S:7](=[O:11])(=[O:10])[N:6]1[CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([C:18]#[N:19])[CH:21]=1)=[O:4]
Reactant: COC(=O)C1CCS(=O)(=O)N1
Reactant: N#Cc1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1CCS(=O)(=O)N1Cc1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 52.5 %

Procedure:
To a stirred solution of 1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid methyl ester (Intermediate 1, 0.200 g, 1.10 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (0.450 g, 3.20 mmol) at room temperature under nitrogen. The reaction mixture was cooled to 0° C. and 3-cyano benzyl bromide (available from Aldrich; 0.240 g, 1.22 mmol) was added into the reaction mixture slowly and followed by the addition of tetra-n-butylammonium (0.025 g, 0.07 mmol). The reaction was completed in 5 h at room temperature as monitored by silica TLC. The reaction mixture was diluted with ethyl acetate (25 mL), washed with water (3×15 mL), dried over sodium sulfate and concentrated under reduced pressure to provide crude material, which was purified by silica gel column chromatography (100-200 mesh) using a gradient of 20-30% ethyl acetate/hexanes to give 2-(3-cyano-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid methyl ester (0.170 g, 56%).