Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](N)=[O:12])=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:20].[K+].O>C(O)C>[CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:20])=[O:12])=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: NC(=O)c1ccc(C2CCCCC2)c(C(F)(F)F)c1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(C2CCCCC2)c(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
To a solution of 4-cyclohexyl-3-(trifluoromethyl)benzamide (D67) (822 mg, 3.03 mmol) in ethanol (40 ml) was added potassium hydroxide (1.700 g, 30.3 mmol) and water (5 ml) and the reaction heated to 90° C. block temperature for 3 h and stirred at room temperature for 16 h. Further potassium hydroxide (1.700 g, 30.3 mmol) was added and the reaction heated at reflux for 27 h. A further 5 mL of water was added and the reaction heated for 66 hours (weekend). The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (25 mL) and aqueous hydrochloric acid (2M, 25 mL). The aqueous layer was further extracted with ethyl acetate (25 mL) and the combined organic phases dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound as a white solid (737 mg). δH (methanol-d4, 400 MHz): 8.24 (1H, d), 8.18 (1H, dd), 7.68 (1H, d), 2.98 (1H, t), 1.72-1.95 (5H, m), 1.30-1.58 (5H, m). MS (ES): C14H15F3O2 requires 272; found 271 (M−H+).
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]=[CH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](O)=[O:44])=[CH:30][CH:29]=1.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:3][C:2]1[CH2:4][O:5][C:6](=[O:7])[C:1]=1[C:43](=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH:35]=[CH:34][C:31]1[CH:30]=[CH:29][C:28]([Cl:27])=[CH:33][CH:32]=1
Reactant: O=C(O)CCCCCCCC=Cc1ccc(Cl)cc1
Reactant: O=C1COC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCCCCCCC=Cc1ccc(Cl)cc1)C1=C(O)COC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
To a stirring solution of 189 mg (1.89 mmol) of tetronic acid in 15 mL of dimethylformamide is added 290 μL (2.08 mmol) of triethylamine and 8 mg (66 μmol) of 4-dimethylaminopyridine at 0° C. Next, 427 mg (2.22 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 690 mg (2.20 mmol) of 10-(4-chlorophenyl)dec-9-enoic acid as a mixture of E and Z isomers are added and the reaction mixture is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted three times with ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue is purified via flash chromatography on a 40 mm×150 mm silica gel column eluting with 5% methanol/ethyl acetate to give 400 mg (58%) of pure 4-hydroxy-3-[10-(4-chlorophenyl)-1-oxodec-9-enyl] -2(5H)-furanone as a mixture of E and Z isomers.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]([F:28])([F:27])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24](=[O:26])[CH3:25])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.O>CS(C)=O>[CH3:25][C:24]1([CH2:23][N:20]2[CH2:19][CH2:18][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:10]([F:9])([F:27])[F:28])=[CH:16][CH:15]=3)[CH2:22][CH2:21]2)[CH2:2][O:26]1
Reactant: C[S+](C)(C)=O
Reactant: CC(=O)CN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(CN2CCN(c3ccc(C(F)(F)F)cc3)CC2)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
Trimethylsulfoxonium iodide (2.5 g, 11.6 mmol) was gradually added to a suspension of sodium hydride (484 mg, 12.1 mmol) in dimethylsulfoxide (30 ml), and the mixture was stirred at room temperature for 1 hour. To which a solution of 1-{4-(4-trifluoromethylphenyl)piperazin-1-yl}propan-2-one (3.4 g, 11.9 mmol) in dimethylsulfoxide (20 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into iced water, and extracted with diethyl ether. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate, and then filtered. The resultant filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford 1-(2-methyl-2-oxiranylmethyl)-4-(4-trifluoromethylphenyl)piperazine (3.2 g, yield 98%)as a light yellow powder.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH2:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:18]=2[N:19]=1.[Cl-].[NH4+]>CN(C)C=O>[F:24][C:21]1[CH:22]=[CH:23][C:17]2[S:16][C:15]([CH2:14][O:12][C:9]3[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=3)=[N:19][C:18]=2[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Fc1ccc2sc(CBr)nc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2nc3cc(F)ccc3s2)cc1
Reaction time: 0.08 h
Yield: 71 %

Procedure:
452.9 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 1.5 g of 4-nitrophenol in 30 ml of dimethylformamide cooled in an ice-water bath. The resulting mixture was stirred at this temperature for 5 minutes, after which a solution of 2.79 g of 2-bromomethyl-5-fluorobenzothiazole in 5 ml of dimethylformamide was added thereto. The temperature of the resulting mixture was elevated to room temperature and the mixture was then stirred for 3 hours. At the end of this time, a saturated aqueous ammonium chloride solution was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed consecutively with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was washed with a mixed solvent of methylene chloride and hexane to give 2.33 g of the title compound as a crude crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[N:3]=1
Reactant: NCCCCN
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: NCCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[(4-aminobutyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 1,4-diaminobutane, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([OH:18])([C@H:15]([OH:17])[CH3:16])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(OCC)(=O)C>[CH3:26][S:27]([O:17][C@H:15]([CH3:16])[C@:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([OH:18])[CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H](OS(C)(=O)=O)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (2R,3R)-2-(4-chlorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol (12.4 g) and triethylamine (7.6 ml) in ethyl acetate (200 ml) was added dropwise methanesulfonyl chloride (6.25 g) under ice-cooling. After stirring for 45 minutes at room temperature, the reaction mixture was washed with water and saturated saline, dried over magnesium sulfate and distilled under reduced pressure to give (2R,3R)-2-(4-chlorophenyl)-2-hydroxy-1-(1H-1,2,4-triazol-1-yl)-3-butyl methanesulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[NH:21][C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=2)=[CH:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1>O1CCCC1.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:13]2[NH:21][C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=2)[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C=C(c1cccc(Cl)c1)c1cc2cccnc2[nH]1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: CC(C)CC(c1cccc(Cl)c1)c1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.3 %

Procedure:
A solution of 2-(1-(3-chloro-phenyl)-3-methyl-but-1-enyl)-1H-pyrrolo[2,3-b]pyridine (1.3 g, 4.4 mmol) in tetrahydrofuran (50 mL) was treated with platinum dioxide (200 mg). The reaction was stirred at 25° C. under hydrogen atmosphere for 3 d. At this time, the reaction mixture was filtered and the filtrate was concentrated in vacuo. HPLC purification afforded 2-(1-(3-chloro-phenyl)-3-methyl-butyl)-1H-pyrrolo[2,3-b]pyridine (280 mg, 21.4%) as a colorless oil: 1H NMR (300 MHz, d6-DMSO): 6 ppm 11.83 (s, 1H), 8.17 (d, 1H, J=4.8 Hz), 7.96 (d, 1H, J=7.2 Hz), 7.46 (s, 1H), 7.36-7.25 (m, 3H), 7.11 (m, 1H), 6.40 (s, 1H), 4.25 (t, 1H, J=7.8 Hz), 2.11-2.04 (m, 1H), 1.93-1.86 (m, 1H), 1.40-1.36 (m, 1H), 0.91 (s, 3H), 0.88 (s, 3H).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][N:11]([S:37]([CH3:40])(=[O:39])=[O:38])[CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29]CC[Si](C)(C)C)=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C.Cl>C(#N)C.CCOC(C)=O>[OH:29][C:17]1[C:16]([CH2:15][CH:14]=[C:13]([CH3:36])[CH2:12][N:11]([S:37]([CH3:40])(=[O:38])=[O:39])[CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[C:24]([O:25][CH3:26])[C:23]([CH3:27])=[C:22]2[C:18]=1[C:19](=[O:28])[O:20][CH2:21]2
Reactant: CCOP(=O)(CCN(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)S(C)(=O)=O)OCC
Agent: C[Si](C)(C)Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: COc1c(C)c2c(c(O)c1CC=C(C)CN(CCP(=O)(O)O)S(C)(=O)=O)C(=O)OC2
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
A solution of [2-(methanesulfonyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonic acid diethyl ester (18 mg, 0.029 mmol) in acetonitrile (0.5 mL) was stirred with TMSBr (38 μL, 0.29 mmol) and 2,6-lutidine (34 μL, 0.29 mmol) for 2 hours at room temperature. The reaction was worked up by addition of EtOAc and aqueous 1N HCl. The organic layer was washed with brine and the solvent was removed in vacuo. The residue was suspended in a solution of 10% TFA-CH2Cl2 for 10 minutes before it was dried to provide 9.9 mg of the desired product (73%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.76 (s, 3H), 1.76-1.88 (m, 2H), 2.10 (s, 3H), 2.87 (s, 3H), 3.24-3.35 (m, 2H), 3.39 (d, 2H, J=7 Hz), 3.65 (s, 2H), 3.75 (s, 3H), 5.22 (s, 2H), 5.41-5.48 (m, 1H) ppm; 31P (121.4 MHz, DMSO-d6) δ 21.4 ppm; MS (m/z) 464.1 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([Cl:23])[CH:22]=1>>[Cl:16][C:17]1[CH:18]=[C:19]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: Nc1nnc(Br)c(-c2ccc(F)cc2)n1
Product: Nc1nnc(-c2cc(Cl)cc(Cl)c2)c(-c2ccc(F)cc2)n1
Yield: 27.8 %

Procedure:
6-(3,5-dichlorophenyl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (0.11 g, 17.6%) was prepared from 6-Bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (0.5 g, 1.18 mmol) and 3,5-dichloro phenylboronic acid (0.47 mg, 2.4 mmol) according to the general procedure of Example 1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C-:4]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH-:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Fe+2:16].CCN(CC)CC.[CH3:24][C:25](OC(C)=O)=[O:26]>CN(C1C=CN=CC=1)C.C1COCC1.CCOCC>[C:25]([O:1][CH2:2][C:3]1[C-:4]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1)(=[O:26])[CH3:24].[CH-:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Fe+2:16]
Reactant: CN(C)[c-]1cccc1CO
Reactant: CC(=O)OC(C)=O
Agent: [Fe+2]
Agent: CN(C)c1ccncc1
Agent: c1cc[cH-]c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)OCc1ccc[c-]1N(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
A solution of 61 (407 mg, 1.57 mmol), DMAP (19 mg, 0.16 mmol) and Et3N (0.65 mL, 4.70 mmol) in THF (8 mL) was treated with Ac2O (0.22 mL, 2.35 mmol) and allowed to stir at room temperature for 16 h. The reaction mixture was diluted with Et2O, washed with H2O (2×10 mL), brine (1×10 mL), dried over Na2SO4, filtered, and all volatiles were removed in vacuo. The crude product was taken up in hexanes and filtered through a pad of silica gel, eluting with 60:40 hexane/EtOAc. Evaporation of the filtrate afforded acetate 62 (413 mg, 88%) as a dark orange oil: Rf=0.44 (silica, 50:50 hex/EtOAc); IR (KBr, neat) vmax 3095, 3014, 2947, 2848, 2783, 1736, 1486, 1454 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.03 (AB q, 2H, J=12.0, 12.0 Hz), 4.16 (s, 5H), 4.10 (t, 1H, J=1.8 Hz), 4.02-3.93 (m, 2H), 2.61 (s, 6H), 2.03 (s, 1H), 13C NMR (75 MHz, CDCl3) δ 170.9, 114.4, 68.7, 67.7, 63.5, 61.9, 56.6, 45.2, 21.0; EIMS [m/z (%)] 301 (M+, 33), 121 (100); HRMS (EI) calcd for C15H19NO256Fe: 301.0765. Found 301.0766.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[S:5].Cl[CH:13]([C:17](=O)[CH3:18])[C:14](=[O:16])[CH3:15]>C(O)C>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]1[S:5][C:13]([C:14](=[O:16])[CH3:15])=[C:17]([CH3:18])[N:6]=1
Reactant: Cc1ccc(C(N)=S)c(C)c1
Reactant: CC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CC(=O)c1sc(-c2ccc(C)cc2C)nc1C
Temperature: 25 °C
Yield: 37 %

Procedure:
To ethanol (20 ml), 2,4-dimethylthiobenzamide (2.00 g) and 3-chloropentane-2,4-dione (1.79 g) were added, and the mixture was stirred under heat reflux for 4 hours. After the mixture was allowed to cool to a room temperature, from the mixture ethanol was distilled off under a reduced pressure. To the resulting residue, ethyl acetate was added, and the mixture was heated and stirred. After the mixture was allowed to cool to a room temperature, the precipitate was separated by filtration, washed with ethyl acetate, and then dried under a reduced pressure to give the title compound (1.10 g, 37%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([NH2:19])=[CH:17][C:6]2[CH2:7][CH2:8][CH:9]([NH:12][CH2:13][CH2:14][O:15][CH3:16])[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[C:38]3[CH2:37][N:36]([S:39]([CH3:42])(=[O:41])=[O:40])[CH2:35][C:34](=[O:43])[NH:33][C:32]=3[CH:31]=[CH:30][C:29]=2[O:44][CH3:45])[C:24]([Cl:46])=[CH:23][N:22]=1>>[Cl:46][C:24]1[C:25]([NH:27][C:28]2[C:38]3[CH2:37][N:36]([S:39]([CH3:42])(=[O:41])=[O:40])[CH2:35][C:34](=[O:43])[NH:33][C:32]=3[CH:31]=[CH:30][C:29]=2[O:44][CH3:45])=[N:26][C:21]([NH:19][C:18]2[C:3]([O:2][CH3:1])=[CH:4][C:5]3[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][O:15][CH3:16])[CH2:8][CH2:7][C:6]=3[CH:17]=2)=[N:22][CH:23]=1
Reactant: COc1ccc2c(c1Nc1nc(Cl)ncc1Cl)CN(S(C)(=O)=O)CC(=O)N2
Reactant: COCCNC1CCc2cc(N)c(OC)cc2CC1
Product: COCCNC1CCc2cc(Nc3ncc(Cl)c(Nc4c(OC)ccc5c4CN(S(C)(=O)=O)CC(=O)N5)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 3-Methoxy-N*7*-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine and 6-(2,5-Dichloro-pyrimidin-4-ylamino)-4-methanesulfonyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one in an analogous manner to example 730 (0.017 g, 11%). Mp 110-114° C.; LCMS (m/e) 660 (M); 1H-NMR (DMSO, 400 MHz) δ 10.28 (br, 1H), 8.58 (s, 1H), 8.05 (s, 1H), 7.42 (s, 1H), 7.35 (s, 1H), 7.20-7.14 (q, 2H, J=5.81 Hz), 6.70 (s, 1H), 6.56 (s, 1H), 6.39 (s, 1H), 4.40-4.24 (br, 3H), 3.74 (s, 3H), 3.70 (s, 6H), 3.98-3.45 (q, 3H, J=5.05 Hz), 3.25 (s, 2H), 2.80 (s, 2H), 2.79-2.70 (br, 2H), 2.70-2.57 (br, 2H), 2.35-2.10 (br, 2H), 1.98-1.81 (br, 3H), 1.25-0.90 (br, 4H).
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:18][C:19]([NH2:21])=[S:20].II.[O-]S([O-])(=S)=O.[Na+].[Na+]>CCO>[NH2:21][C:19]1[S:20][C:9]([C:10]#[N:11])=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:18]=1
Reactant: NC(N)=S
Reactant: N#CCC(=O)c1ccccc1
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: N#Cc1sc(N)nc1-c1ccccc1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a solution of benzoylacetonitrile derivative (1 eq.) in EtOH is added pyridine (1 eq.). The resulting mixture is stirred at 70° C. for 15 min then cooled at r.t. A previously stirred suspension of thiourea (2 eq.) and iodine (1 eq.) in EtOH is then slowly added. After 1 h at r.t. a cold 1 M Na2S2O3 solution is added under stirring. The resulting precipitate is filtered, washed with water, and finally dried under vacuo to afford the amino-4-phenyl-thiazole-5-carbonitrile derivative.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])/[C:10](/[CH3:27])=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]#[N:26])[CH:20]=3)[CH:13]=2)=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[CH2:33](N)[CH2:34][NH2:35]>C(O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])/[C:10](/[CH3:27])=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[NH:35][CH2:34][CH2:33][N:26]=4)[CH:20]=3)[CH:13]=2)=[CH:4][C:3]=1[C:29]([F:32])([F:30])[F:31]
Reactant: NCCN
Reactant: C/C(=C\c1cccc(Oc2ccnc(C#N)c2)c1)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: C/C(=C\c1cccc(Oc2ccnc(C3=NCCN3)c2)c1)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
(E)-N-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(3-(2-cyanopyridin-4-yloxy)phenyl)-2-methylacrylamide (500 mg, 1.09 mmol) and TEA (456 μL, 3.27 mmol) were combined and stirred in ethanol. H2S was bubbled into the solution for 2 min then the reaction mixture was sealed and allowed to stir at rt. Reaction completion was checked by LCMS and TLC. The mixture was diluted with EtOAc and washed with brine. The aqueous phase was extracted with EtOAc, and the organic solutions were combined, dried over Na2SO4, filtered, and concentrated to provide a yellow residue. The residue was redissolved in ethylene diamine (3 mL), heated to 60° C. for 5 min, and then allowed to cool to rt. The mixture was diluted with EtOAc and washed with brine. The aqueous phase was extracted with EtOAc, and the organic solutions were combined, dried over Na2SO4, filtered, and concentrated. Purification by column chromatography (SiO2, 0-10% MeOH with 1% NH4OH in DCM) provided B-12 (415 mg). LCMS, FA: Rt=1.34 min, [MH+ 501.0]. 1H NMR (400 MHz, CD3OD): δ 8.49 (d, 1H), 8.18 (d, 1H), 7.91-7.89 (dd, 1H), 7.57-7.53 (m, 3H), 7.40 (d, 1H), 7.35 (s, 1H), 7.23 (m, 1H), 7.16-7.13 (dd, 1H), 7.09-7.07 (m, 1H), 3.77 (s, 4H), and 2.16 (d, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:14][CH2:15][C:16](O)=[O:17]>O>[CH3:6][N:7]([C:16](=[O:17])[CH2:15][Cl:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CNc1ccccc1
Reactant: O=C(O)CCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C(=O)CCl)c1ccccc1
Reaction time: 1.25 h
Yield: 85.5 %

Procedure:
76.75g (0.50 moles) of phosphoryl chloride and 107g (1.00 moles) of N-methyl aniline were added to 99.2g (1.05 moles) of monochloracetic acid. Alternate additions of 10% of the total amount of each of the N-methyl aniline and of the phosphoryl chloride were made with stirring at a temperature of 60° to 70°C over a period of 75 minutes. The reaction mixture was then stirred at 100° to 110°C for 4 hours, after which the reaction mixture was cooled to 70° to 80°C and then poured into warm water. The aqueous suspension was stirred vigorously whilst cooling until the product crystallised and then cooled further until the temperature reached 30° to 35°C. The precipitated crystalline product was separated from the aqueous phase by filtration and then washed with water. The washed product was dried in an oven at a temperature of 50° to 60°C. 157g of dry off-white crystals of N-methyl chloro acetanilide having a melting point of 69°C were obtained. The yield was 85.5% based on the theoretical yield from the N-methyl aniline in the starting material.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[N:12]=[C:11]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[N:13]1[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:3]=2)[CH2:10][C:11]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])=[N:12]1
Reactant: C1COCCN1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccc(F)c(Br)c2)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccc(F)c(N3CCOCC3)c2)c(F)c1
Temperature: 100 °C
Reaction time: 7 h
Yield: 52.2 %

Procedure:
5-(3-Bromo-4-fluoro-phenyl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (30.0 mg, 0.06 mmol) prepared in Step 5 of Preparation 7, morpholine (7.0 uL, 0.08 mmol), Pd2(dba)3 (3.0 mg, cat.), BINAP (4.0 mg, cat.) and sodium t-butoxide (9.0 mg, 0.10 mmol) were added to toluene (1.0 mL). The reaction mixture was stirred at 100° C. for 7 hours and then filtered through celite pad. Ethyl acetate was added to the filtrate, which was washed with a saturated solution of sodium hydrogen carbonate and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/8) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.[Cl:11][C:12]1[CH:13]=[C:14]([S:19](Cl)(=[O:21])=[O:20])[CH:15]=[C:16]([Cl:18])[CH:17]=1>N1C=CC=CC=1.O>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[S:19]([C:14]1[CH:13]=[C:12]([Cl:11])[CH:17]=[C:16]([Cl:18])[CH:15]=1)(=[O:21])=[O:20]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 19 h
Yield: 87.9 %

Procedure:
L-Proline methyl ester hydrochloride (2.68 g, 16.2 mmol) was dissolved in pyridine (20 mL), 3,5-dichlorophenylsulfonyl chloride (3.57 g, 14.6 mmol) was added and the mixture was stirred for 19 hr. Water (5 mL) was added and the mixture was stirred for 45 min before diluting with water (200 mL). The mixture was extracted with Et2O (2×150 mL) and the combined extracts were washed with water (3×100 mL), 1N HCl (150 mL) and saturated aq NaHCO3 (150 mL), then dried (MgSO4), filtered and evaporated in vacuo to give 3,5-dichlorophenyl-sulfonyl-L-proline methyl ester as an oil (4.34 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2OS(C(F)(F)F)(=O)=O)[S:4][C:3]=1[C:19](=[O:21])[NH2:20].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.CO.C(Cl)Cl>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:4][C:3]=1[C:19]([NH2:20])=[O:21]
Reactant: NC(=O)c1sc2nccc(OS(=O)(=O)C(F)(F)F)c2c1N
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1sc2nccc(Nc3ccccc3)c2c1N

Procedure:
A solution of 20 mg trifluoromethanesulfonic acid 3-amino-2-carbamoyl-thieno[2,3-b]pyridin-4-yl ester and 27 microL aniline in 1 mL of THF was heated at 55° C. overnight under Ar. The reaction was applied to a 2 mm silica gel prep plate that was developed twice in 5% MeOH—CH2Cl2. The band was eluted with 50% MeOH—CH2Cl2 to get 18 mg. This was dissolved in 5% MeOH—CH2Cl2, filtered, concentrated, and dried in vacuo at 60° C. overnight to provide 10.5 mg of the title compound as a yellow-green solid.