Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[C:16]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)([CH2:21][CH3:22])[C:17]([O:19][CH3:20])=[O:18].CN1CCOCC1>C(Cl)Cl>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:16]([N:11]2[C:12]3[C:8](=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)([CH2:21][CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[CH:28][CH:27]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (1.59 mL, 20.4 mmol) was added to a stirred solution of 3b (6.67 g, 19.5 mmol) and 4-methylmorpholine (2.78 mL, 25.3 mmol) in DCM (100 mL) at 0° C. After 30 min, an additional portion of methanesulfonyl chloride (0.80 mL, 10.2 mmol) was added. After 1 h, the reaction mixture was partitioned between DCM and saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with DCM. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-50% EtOAc/hexanes as eluent) to afford the title compound 25. m/z (ES) 421 (MH)+; IP=A rating
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C[Si](C)(C)C[C:21](F)([F:23])[F:22].[I-].[Na+]>O1CCCC1>[F:22][C:21]1([F:23])[C:1]2([CH2:7][O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: COc1ccc(COCC2=CCCCC2)cc1
Reactant: C[Si](C)(C)CC(F)(F)F
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COCC23CCCCC2C3(F)F)cc1
Temperature: 115 °C
Yield: 79.7 %

Procedure:
To a microwave 5 mL vial was added 1-((cyclohexenylmethoxy)- methyl)-4-methoxybenzene (0.46 g, 2.00 mmol), trimethyl(2,2,2-trifluoroethyl)silane (0.57 g, 4.00 mmol) and sodium iodide (0.66 g, 4.40 mmol) in anhydrous tetrahydrofuran (1.0 mL). The vial was degassed with nitrogen and sealed. The reaction mixture was heated in the microwave reactor at 115° C. for 1 hour. The reaction vial was cooled and the TLC showed presence of starting material. To the reaction vial was added trimethyl(2,2,2-trifluoroethyl)silane (0.5 mL) and continued heating in the microwave at the same temperature for another 1 hour. The reaction was filtered, washed with ethyl acetate (10 ml). The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (20%) to afford the title compound as colourless liquid (0.45 g, 80%).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([C:18]([OH:20])=O)[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][N:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:23]>>[CH:1]1([C:6]2[CH:7]=[C:8]([C:18]([NH:23][N:22]([CH3:21])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:20])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reactant: CN(N)c1ccccc1
Product: CN(NC(=O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 14c) and 1-methyl-1-phenyl-hydrazine (CAN 618-40-6) as starting materials; LC-MS (UV peak area/ESI) 98.0%, 394.1737 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[C:21]([Cl:37])=[CH:20][N:19]=1>>[Cl:37][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[N:23][C:18]([NH:1][C:2]2[CH:16]=[CH:15][C:5]3[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:19][CH:20]=1
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3C)ncc1Cl
Yield: 28.8 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (35 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (50 mgs) gave the title compound as an off-white solid (22 mgs). 1H-NMR (CDCl3, 400 MHz): 9.65 (s, 1H), 8.55 (d, J=8.3 Hz, 1H); 8.19 (s, 2H), 7.94 (d, J=8.1 Hz, 1H), 7.65-7.58 (m, 2H), 7.37 (s, 1H), 7.30-7.26 (m, 1H); 7.14-7.10 (m, 2H); 3.31 (s, 3H); 3.28-3.23 (m, 1H), 2.33-2.30 (m, 2H), 2.03 (broad s, 2H), 1.34 (d, J=7.1 Hz, 6H), 1.27 (s, 6H). LC/MS: found 528.15 (M+H)+; MP: 195-197° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:16][Li]>C1(C)C=CC=CC=1.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:16])=[CH:6][CH:7]=1
Reactant: Brc1ccc(N=Cc2ccccc2)cc1
Reactant: [Li]C
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(Nc1ccc(Br)cc1)c1ccccc1
Temperature: -40 °C
Reaction time: 3 h

Procedure:
To a solution of N-(4-bromophenyl)-N-(1-phenylmethylidene)amine (1.0 g, 0.00385 mol) in toluene (30 mL) cooled to −78° C., a 1.4M solution of methyl lithium in diethyl ether (5.5 mL) was added dropwise keeping the temperature below −75° C. The solution was warmed up to −40° C. and stirred at this temperature under an atmosphere of nitrogen for 3 hours. The reaction mixture was quenched by a dropwise addition of water and the layers were separated. The organic phase was washed with brine (50 mL), dried with magnesium sulfate and concentrated under reduced pressure to yield N-(4-bromophenyl)-N-(1-phenylethyl)amine (1.03 g, 0.00373 mol) as an off-white solid.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.[N:10]([C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([CH3:24])=[CH2:23])[CH:17]=1)([CH3:15])[CH3:14])=[C:11]=[O:12]>C(Cl)(Cl)Cl>[CH2:23]=[C:22]([C:18]1[CH:17]=[C:16]([C:13]([NH:10][C:11]([N:4]2[CH:5]3[CH2:8][CH2:9][N:1]([CH2:7][CH2:6]3)[CH2:2][CH2:3]2)=[O:12])([CH3:15])[CH3:14])[CH:21]=[CH:20][CH:19]=1)[CH3:24]
Reactant: C1CN2CCC(CC2)N1
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Solvent: ClC(Cl)Cl
Product: C=C(C)c1cccc(C(C)(C)NC(=O)N2CCN3CCC2CC3)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
To a solution of 1,4-diazabicyclo[3.2.2]nonane (350 mg, 2.77 mmol) and 1-(2-isocyanatopropan-2-yl)-3-(prop-1-en-2-yl)benzene (1.09 mL, 5.55 mmol) in chloroform (2 mL) was added 3-4 pieces of molecular sieves. The reaction mixture was stirred at room temperature for 18 h and then concentrated. The crude material was purified on a combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH) to afford the corresponding urea as an off-white solid (650 mg, 36%). 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.31-7.26 (m, 3H), 5.34(s, 1H), 5.07 (s, 1H), 4.73 (br s, 1H), 4.03 (BR s, 1H), 3.64 (m, 2H), 3.14-3.03 (m, 6H), 2.15 (s, 3H) 2.06 (m, 2H), 1.72 (m, 8H) ppm. 13C NMR (100 MHz, CDCl3) δ 155.7, 148.3, 143.8, 141.3, 128.5, 124.1, 123.9, 122.0, 112.5, 57.8, 55.8, 48.1, 46.4 (2×), 41.2, 30.2 (2×), 27.3 (2×), 22.1 ppm. Purity: >98% UPLCMS (210 nm); retention time 0.71 min; (M+1) 328
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].BrCC1OC(C(F)(F)F)=CC=1.[F:18][C:19]1[C:20]([F:37])=[CH:21][C:22]2[O:36][CH2:35][C:25]3([C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:34])[C:23]=2[CH:24]=1.CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[F:18][C:19]1[C:20]([F:37])=[CH:21][C:22]2[O:36][CH2:35][C:25]3([C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])[C:26]3=[O:34])[C:23]=2[CH:24]=1
Reactant: O=C1Nc2ccccc2C12COc1cc(F)c(F)cc12
Reactant: CC(C)CCBr
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: CC(C)CCN1C(=O)C2(COc3cc(F)c(F)cc32)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 1-bromo-3-methylbutane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1H)-one, 5,6-difluoro-1′-(3-methylbutyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (96%) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.34 (t, J=7.7 Hz, 1H), 7.16-7.04 (m, 2H), 6.93 (d, J=7.8 Hz, 1H), 6.77 (dd, J=10.3, 6.3 Hz, 1H), 6.50 (t, J=8.5 Hz, 1H), 4.95 (d, J=9.1 Hz, 1H), 4.70 (d, J=9.1 Hz, 1H), 3.88-3.67 (m, 2H), 1.72-1.60 (m, 3H), 1.01 (d, 6.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ176.3, 156.6 (d, JC-F=11.0 Hz), 151.1 (dd, JC-F=248.1, 14.5 Hz), 145.6 (dd, JC-F=241.3, 14.0 Hz), 142.3, 131.6, 129.2, 123.8, 123.3, 111.5 (d, J=20.5 Hz), 108.7, 99.9 (d, J=22.3 Hz), 80.7, 57.7, 38.8, 36.0, 26.0, 22.4, 22.3; MS (ES+) m/z 344.4 (M+1).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([O:16][C:17]([N:19]1[C@H:23]([CH2:24][F:25])[C@@H:22]([C:26]2[CH:31]=[CH:30][C:29]([S:32][CH3:33])=[CH:28][CH:27]=2)[O:21][C:20]1([CH3:35])[CH3:34])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)(O)[O-].[Na+]>ClCCl>[F:25][CH2:24][C@@H:23]1[C@@H:22]([C:26]2[CH:27]=[CH:28][C:29]([S:32]([CH3:33])=[O:9])=[CH:30][CH:31]=2)[O:21][C:20]([CH3:35])([CH3:34])[N:19]1[C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18]
Reactant: CSc1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]2CF)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]2CF)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of m-chloroperbenzoic acid (14.3 g, 1.2 eq) in 100 ml of dichloromethane was added drop wise to the solution of 13 (17.3 g) in 150 ml of dichloromethane at −20° C. The temperature was maintained at −20° C. for an additional 40 minutes. A saturated solution of sodium bicarbonate (80 ml) was added and stirred for 30 minutes. The organic layer was separated and washed with brine (50 ml) and dried over sodium sulfate. After purification (via a column) 13.4 g of the desired product (as a heavy oil) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[C:15]([CH2:17][NH2:18])[CH:14]=[CH:13][C:12]=2[Cl:19])=[CH:5][C:4]=1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)=[O:22].[CH:31]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32]1.N1C=CC=CC=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[C:15]([CH2:17][NH:18][S:34]([CH:31]3[CH2:33][CH2:32]3)(=[O:36])=[O:35])[CH:14]=[CH:13][C:12]=2[Cl:19])=[CH:5][C:4]=1[C:21]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([Br:30])=[CH:28][CH:29]=1)=[O:22]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: COc1ccc(NC(=O)c2cc(CN)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2cc(CNS(=O)(=O)C3CC3)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1
Reaction time: 8 h

Procedure:
A mixture of 52.5 mg N-[4-methoxy-3-(4-bromophenyl)aminocarbonyl-phenyl]-2-chloro-5-aminomethyl-benzamide (0.10 mmol), 16.8 mg cyclopropylsulphonic acid chloride (0.12 mmol), 1.0 mL pyridine and 4.0 mL acetonitrile was stirred overnight, concentrated, dissolved in 3 mL DMF and purified by prep. HPLC.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([O:17][CH3:18])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[F:25][CH:26]([F:28])Cl>O1CCCC1.O>[F:25][CH:26]([F:28])[C:13]1([C:15]([O:17][CH3:18])=[O:16])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: FC(F)Cl
Reactant: COC(=O)C1c2ccccc2Oc2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(C(F)F)c2ccccc2Oc2ccccc21
Reaction time: 72 h

Procedure:
16.8 g (0.07 mol) of methyl 9-xanthenecarboxylate (obtainable according to step 1.1.a) are dissolved in 300 mL of tetrahydrofuran and 9.1 g (0.077 mol) of potassium tert-butoxide are added batchwise while cooling. Then difluorochloromethane is piped in at 0° C. over a period of 1.5 hours. After all the gas has been piped in, the reaction mixture is left to stand for 72 hours at ambient temperature. The reaction mixture is then diluted with water to a total volume of about 2000 mL, extracted with ethyl acetate, the organic phase is separated off and washed with 5% aqueous sodium carbonate solution. After being extracted again with water, the organic phase is dried over magnesium sulfate and the solvent is removed by distillation. The crude product is purified by chromatography on silica gel (eluent: cyclohexane-ethyl acetate (98:2)) or by recrystallization from cyclohexane. Yield: 5.35 g of white crystals (26% of theoretical yield); melting point: 101° C.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[H-].[Na+].Br[C:14]1[N:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([OH:31])[C:23]=2[CH2:32][CH2:33][CH3:34])[CH:17]=[CH:16][CH:15]=1.C(OCC)C>CN(C)C=O>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:18]2[N:19]=[C:14]([S:1][C:2]3[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=3)[C:5]([OH:7])=[O:6])[CH:15]=[CH:16][CH:17]=2)=[C:23]([CH2:32][CH2:33][CH3:34])[C:24]=1[OH:31])(=[O:30])[CH3:29]
Reactant: O=C(O)c1cccc(S)c1
Reactant: CCCc1c(OCc2cccc(Br)n2)ccc(C(C)=O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCc1c(OCc2cccc(Sc3cccc(C(=O)O)c3)n2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.1 %

Procedure:
To a solution of 3-mercaptobenzoic acid (361 mg, 2.35 mmol) in dimethylformamide (15 mL) add sodium hydride (23 mg, 9.38 mmol) at 0° C., stir 10 min. Add 1-[4-(6-bromo-pyridin-2-ylmethoxy)-2-hydroxy-3-propyl-phenyl]-ethanone (854 mg, 2.35 mmol), heat to 100° C. for 6 hours. Cool to ambient temperature and add diethyl ether, collect the resulting red precipitate by filtration (290 mg). Purify by the residue by preparative LC (inject 110 mg) to yield the title compound as a white solid (50 mg, 0.12 mmol): 1H NMR (DMSO-d6) δ 0.88 (t, 3H), 1.50 (q, 2H), 2.55 (s, 3H), 2.61 (m, 2H), 5.25 (s, 2H), 6.65 (d, 1H), 6.97 (d, 1H), 7.26 (d, 1H), 7.62 (t, 1H), 7.76 (m, 1H), 7.83 (m, 1H), 8.02 (m, 1H), 8.07 (m, 1H), 12.85 (s, 1H), 13.25 (br s, 1H); MS (m/z): 436 (M−1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][N:23]([C:25]2([CH2:29][OH:30])[CH2:28][CH2:27][CH2:26]2)[CH:24]=1.C(O)(=O)C>CC(O)C>[CH:15]1([C@:10]2([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]4[CH:21]=[N:22][N:23]([C:25]5([CH2:29][OH:30])[CH2:28][CH2:27][CH2:26]5)[CH:24]=4)[N:7]=3)[C:9]2=[O:18])[CH2:17][CH2:16]1
Reactant: Nc1cnn(C2(CO)CCC2)c1
Reactant: N#C[C@@]1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: N#C[C@@]1(C2CC2)CCN(c2ccnc(Nc3cnn(C4(CO)CCC4)c3)n2)C1=O
Yield: 62.6 %

Procedure:
A solution of (3S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (150 mg) obtained in Step E of Example 103, (1-(4-amino-1H-pyrazol-1-yl)cyclobutyl)methanol (95 mg) obtained in Step C of Example 127 and acetic acid (34 mg) in propan-2-ol (4.0 mL) was stirred in a microwave reactor at 160° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate), and recrystallized (diisopropyl ether/ethyl acetate) to give the title compound (140 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N:17]1[C:21](=[O:22])[N:20]([CH:23]([F:25])[F:24])[C:19]([CH3:26])=[N:18]1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][CH:34](Br)[C:35]([O:37][CH3:38])=[O:36].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([N:17]2[C:21](=[O:22])[N:20]([CH:23]([F:24])[F:25])[C:19]([CH3:26])=[N:18]2)=[CH:4][C:5]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:34]([CH3:33])[C:35]([O:37][CH3:38])=[O:36])=[CH:12][CH:11]=1
Reactant: COC(=O)C(C)Br
Reactant: Cc1nn(-c2cc(Sc3ccc(O)cc3)c(Cl)cc2Cl)c(=O)n1C(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccc(Sc2cc(-n3nc(C)n(C(F)F)c3=O)c(Cl)cc2Cl)cc1
Temperature: 0 °C
Yield: 45.7 %

Procedure:
A stirred mixture of 1.5 g (0.0036 mole) of 1-[2,4-dichloro-5-(4-hydroxyphenylthio)phenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, 0.75 g (0.0054 mole) of potassium carbonate, 0.90 g (0.0054 mole) of methyl DL-2-bromopropionate, and 0.20 g (8×10-4 mole) of 18-crown-6 in 30 mL of N,N-dimethylformamide was heated at 100°-120° C. for approximately 18 hours. The reaction mixture was allowed to cool and was poured into ice-water. This aqueous mixture was extracted with diethyl ether and ethyl acetate. The organic extracts were combined and washed with water. The organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure, leaving a yellow oil. This oil was purified by column chromatography on silica gel, eluting with diethyl ether:petroleum ether (40:60) to yield 0.83 g of methyl 2-[4-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl- 5-oxo-1H-1,2,4-triazol-1-yl)phenylthio]phenoxy]propionate as a solid, m.p. 100°-101° C. The nmr spectrum was consistent with the proposed compound.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[CH:8]=[CH:7]1)(C)(C)C.Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH:29]2[CH2:34][C:33]([CH3:36])([CH3:35])[NH:32][C:31]([CH3:38])([CH3:37])[CH2:30]2)[N:23]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:35][C:33]1([CH3:36])[CH2:34][CH:29]([NH:28][C:24]2[N:23]=[C:22]([C:8]3[C:9]4[C:14](=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=4)[NH:6][CH:7]=3)[CH:27]=[CH:26][N:25]=2)[CH2:30][C:31]([CH3:38])([CH3:37])[NH:32]1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2ccc(C(F)(F)F)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc(C(F)(F)F)ccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from 1-(tert-butyl-dimethyl-silanyl)-6-trifluoromethyl-1H-indole (prepared by TBDMS protection of 6-trifluoromethyl-1H-indole) and (4-chloro-pyrimidin-2-yl)(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ cleavage of the TBDMS protecting group with catalytic amounts of TBAF. Yield: 640 mg (77%).
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1.ClC1C=CC=C(C(OO)=O)C=1.CS(C1N=NC(C#N)=C(N2CCC3C=CC=CC=3CC2)N=1)(=O)=O.[NH2:56][CH2:57][CH2:58][C:59]1[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=1>ClCCl.O1CCOCC1>[N:61]1[CH:62]=[CH:63][CH:64]=[C:59]([CH2:58][CH2:57][NH:56][C:3]2[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]3[CH2:15][CH2:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[CH2:11][CH2:10]3)[N:8]=2)[CH:60]=1
Reactant: CSc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Reactant: NCCc1cccnc1
Agent: CS(=O)(=O)c1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1nnc(NCCc2cccnc2)nc1N1CCc2ccccc2CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A solution of 120 mg (0.40 mmol) of 3-methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile in 5 ml of dichloromethane was treated at room temperature with 109 mg (0.44 mmol) of 3-chloro-perbenzoic acid (70%). After 2 hours the reaction mixture was evaporated under reduced pressure, and, without working-up and characterization, the resulting crude 3-methanesulfonyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile was directly treated with a solution of 108 mg (0.88 mmol) of 3-(2-aminoethyl)pyridine in 10 ml of dioxane. The reaction mixture was then stirred at 80° C. overnight. The reaction mixture was then evaporated under reduced pressure and the residue obtained directly chromatographed on silica gel with a 95:5:0.1 v/v/v mixture of dichloromethane, methanol and ammonium hydroxide as the eluent. There were obtained 55 mg (37% of theory) of 3-(2-pyridin-3-yl-ethylamino)-5 -(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile as a white amorphous solid; MS: 372 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:27][CH2:28][CH2:29][C:30]([O:32]C)=[O:31]>>[CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2ccc(-c3ccc(OC[C@@H]4CCCN4)cc3)s2)cc1
Reactant: COC(=O)CCCBr
Product: O=C(O)CCCN1CCC[C@H]1COc1ccc(-c2ccc(Cc3ccccc3)s2)cc1
Yield: 30 %

Procedure:
The title compound was prepared from the product of example 172 (100 mg, 0.22 mmol) and methyl 4-bromobutyrate (56 mg, 0.31 mmol) using the procedure of example 147 with 30% yield (30 mg). 1HNMR (CD3OD) 7.44 (br d, J=8 Hz, 2H), 7.32-7.20 (m, 5H), 7.01 (br d, J=3.6 Hz, 1H), 6.99 (br d, J=8 Hz, 2H), 6.73 (br d, J=3.6 Hz, 1H), 4.70 (br, 1H), 4.20 (br, 2H), 4.12 (s, 2H), 3.97 (br, 1H), 3.59 (br, 3H), 3.00 (br, 2H), 2.45 (br, 2H), 2.19-1.98 (br, 4H), LC/MS (ESI+) m/z: 92%; 437 (M+1, 100). Elemental analysis
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH:3]=[CH:2]1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:40](=[NH:42])[NH2:41])[CH:36]=2)[CH:31]=1)(=O)=O.C(OCC)C>N1C=CC=CC=1>[CH:1]1([CH2:6][C:7]([O:9][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([C:40](=[NH:41])[NH2:42])[CH:36]=3)[CH:31]=2)=[O:8])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: O=C(O)CC1C=CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: N=C(N)c1ccc2cc(OC(=O)CC3C=CCC3)ccc2c1
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
To a solution of 2.2 g of 2-cyclopentene-1-acetic acid in 50 ml of anhydrous pyridine, while being cooled in ice and stirred, was added 4.4 g of DCC. After 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture and stirred for 24 hours at room temperature. The precipitate formed by the addition of ethyl ether was collected by filtration, admixed with dimethylformamide, and filtered to remove the insolubles. Ethyl ether was added to the filtrate and the precipitate which was formed was collected by filtration and recrystallized from a dimethyl formamide-ethyl ether mixture to yield 2.1 g of a white powder of 6-amidino-2-naphthyl 2-cyclopenteneacetate methanesulfonate.