Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[H-].[Na+].[CH:17]([N:20]([CH:24]([CH3:26])[CH3:25])[C:21](Cl)=[O:22])([CH3:19])[CH3:18]>O1CCCC1.C(OCC)(=O)C>[CH:17]([N:20]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:22])[O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][CH2:5][N:4]2[CH2:1][C:2]#[CH:3])=[CH:9][CH:10]=1)([CH3:19])[CH3:18]
Reactant: C#CCN1CCCc2ccc(O)cc21
Reactant: CC(C)N(C(=O)Cl)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CCN1CCCc2ccc(OC(=O)N(C(C)C)C(C)C)cc21
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
A solution of 1-(prop-2-ynyl)-1,2,3,4-tetrahydroquinolin-7-ol (400 mg, 2.14 mM) in dry tetrahydrofuran (THF; 5 mL) was added to the stirred solution of sodium hydride in dry THF at −10° C. during 5 minutes under nitrogen environment at room temperature (25° C.). The reaction, mixture was stirred for 30 minutes. Then, N,N-diisopropyl carbamoyl chloride (510 mg) was added to the stirring reaction mixture. The mixture was stirred further for 7 hours during which the temperature was allowed to reach the room temperature (35° C.). The reaction mixture was diluted with ethyl acetate, washed with water, and dried over sodium sulphate. The combined fractions of ethyl acetate were concentrated under vacuum and chromatographed using ethyl acetate:hexane (1:49) to afford 10h as semisolid. Yield: 72.6%.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[S:19][C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:21][C:8]=2[C:7]=1[OH:28])=[O:5])C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32]>C[O-].[Na+].CO>[CH2:12]([C:10]1[C:9]2[S:19][C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:21][C:8]=2[C:7]([OH:28])=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[N:11]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(Cc2ccccc2)c2sc(-c3ccccc3)nc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1nc(Cc2ccccc2)c2sc(-c3ccccc3)nc2c1O
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A mixture of 4-benzyl-7-hydroxy-2-phenyl-thiazolo[5,4-c]pyridine-6-carboxylic acid ethyl ester (48 mg, 0.12 mmole) and glycine (185 mg, 2.46 mmole) in 0.5 M sodium methoxide/methanol (4.7 ml) was refluxed for 45 h before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (15 ml) and extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (3.5 ml). The resulting precipitate was filtered, washed with water and dried in vacuo to give the title compound as a yellow solid (38 mg). 1H NMR (DMSO-d6, 200 MHz): δ=13.13 (br s, 1H), 9.34 (t, 1H, J=6.0 Hz), 8.08 (m, 2H), 7.58 (m, 3H), 7.33 (m, 5H), 4.36 (s, 2H), 4.06 (d, 2H, J=5.8 Hz); MS: (+) m/z 420.29 (M+1), MS: (−) m/z 418.29 (M−1).
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][C:13](O)=[O:14])[C:10](=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:22]1.[ClH:41].[CH3:42][O:43][C:44](=[O:47])[CH2:45][NH2:46].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O>[ClH:41].[O:1]=[C:2]1[N:11]([CH2:12][C:13]([NH:46][CH2:45][C:44]([O:43][CH3:42])=[O:47])=[O:14])[C:10](=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:23][CH2:22]1
Reactant: O=C(O)Cn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Reactant: COC(=O)CN
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)Cn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 61.3 %

Procedure:
To a solution of 2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline-3-acetic acid (1.20 g, 2.22 mmol) obtained in Example 50 and glycine methyl ester hydrochloride (278 mg, 2.66 mmol) in N,N-dimethylformamide (20.0 ml), diethyl cyanophosphonate (425 ml, 2.66 mmol) and triethylamine (926 ml, 6.65 mmol) were added sequentially, and then the reaction mixture was stirred at room temperature for 17 hours. The solvent was distilled off under reduced pressure, and the residue was combined with water and extracted with ethyl acetate. After the extract was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure. The residue was subjected to a column chromatography on a silica gel eluting with n-hexane-ethyl acetate (5:1, v/v) to give the methyl ester of the title compound (883 mg, 65%) as an oil.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([OH:7])[CH:4]=[C:3]([CH2:8][CH:9]([NH2:13])[C:10]([OH:12])=[O:11])[CH:2]=1.[CH2:14]=O>Cl>[OH:7][C:5]1[CH:4]=[C:3]2[C:2](=[CH:1][CH:6]=1)[CH2:14][NH:13][CH:9]([C:10]([OH:12])=[O:11])[CH2:8]2
Reactant: NC(Cc1cccc(O)c1)C(=O)O
Reactant: C=O
Agent: Cl
Product: O=C(O)C1Cc2cc(O)ccc2CN1
Temperature: 90 °C
Yield: 155.8 %

Procedure:
To a suspension of DL-m-tyrosine (5.00 g, 11.0 mmol) in 0.05 N HCl (50 mL) was added 37% aq. formaldehyde (5.00 mL, 5.2 g, 64.0 mmol) and the resulting slurry was heated at 90° C. for 1 h and then cooled to RT. The mixture was filtered and the resulting solid was washed with H2O and acetone and dried in vacuo to yield 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (3.31 g, 52% yield) as an off-white solid. MS (EI) m/z: 194.0 (M+H+). 1H NMR (400 MHz, CD3OD): δ 7.03 (d, J=8.0 Hz, 1H), 6.69 (dd, J=8.8, and 2.4 Hz, 1H), 7.00 (s, 1H), 4.28-4.19 (m, 2H), 3.80 (dd, J=11.6, and 5.2 Hz, 1H), 3.31-3.27 (m, 1H), 3.05 (dd, J=16.8, and 11.2 Hz, 1H), acid, hydroxy and amine protons not visible.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:35][CH2:36]Br)=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[K+].[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:35][CH2:36][N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCBr)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCN4CCOCC4)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Temperature: 80 °C

Procedure:
A suspension of 2.0 g of 5-benzyloxy-3-[5-(2-bromoethoxy)-1-tert-butoxycarbonyl-1H-indol-2-yl]indazole-1-carboxylic acid tert-butyl ester and of 498 mg of potassium iodide in 90 ml of acetonitrile is heated at 80° C. for 7 hours. 394 μl of morpholine, 150 mg of potassium iodide and 1.24 g of potassium carbonate are then added and the mixture is heated at 80° C. for 15 hours. The reaction mixture is cooled to ambient temperature and then filtered. The filtrate is evaporated under reduced pressure in a rotary evaporator to obtain 1.90 g of 5-benzyloxy-3-[1-tert-butoxycarbonyl-5-(2-morpholin-4-ylethoxy)-1H-indol-2-yl]indazole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([S:27][CH3:28])[CH:22]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([S:27][CH3:28])[CH:22]=2)=[O:20])[CH2:7]1
Reactant: CSc1cccc(N=C=O)c1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: CSc1cccc(NC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)c1

Procedure:
Example 18 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-isocyanato-3-(methylthio)benzene (18.8 μl) to give the title compound (0.0352 g). LC-MS (System A): Rt 2.41 mins, Mass Spectrum m/z 440 [MH+].
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])[C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2.C(C(O)=O)(F)(F)F.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]Br)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:1]1[CH:5]=[C:4]([C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:34][CH2:33][C:30]3[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[CH2:12][CH2:13]2)=[O:7])[C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2
Reactant: O=C(c1csc2ccccc12)C1CCNCC1
Reactant: COc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CCN2CCC(C(=O)c3csc4ccccc34)CC2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Mix (benzo[b]thiophene-3-yl)(4-piperidinyl)methanone.CF3CO2H (2.0 g, 5.56 mmol), 2-(4-methoxyphenyl)ethyl bromide (1.27 g, 5.93 mmol), potassium carbonate (1.95 g, 1.41 mmol) and anhydrous dimethylformamide (20 mL). Warm to approximately 90° C. and stir overnight. Allow to cool to room temperature and partition between a 2:1 mixture of ethyl acetate:toluene and water. Separate the aqueous phase and wash the organic phase with water and saturated sodium chloride. Dry (Na2SO4) and evaporate the solvent in vacuo. Purify by chromatography (40% ethyl acetate/hexane) and recrystallize (cyclohexane) to give the title compound as pale yellow plates; mp 114°-116° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2=[N:13][C:14]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[CH:15][C:16](=[O:17])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:34]Br>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([Br:34])[C:10]2=[N:13][C:14]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[CH:15][C:16](=[O:17])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2nc(-c3ccncn3)cc(=O)n2CC1
Reactant: BrBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(Br)C1
Temperature: -30 °C
Reaction time: 0.08 h
Yield: 46.2 %

Procedure:
To a solution of 4.5 g (14.27 mmol) of 4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester in dry tetrahydrofuran (140 mL) under argon at −30° C. was added 15.70 mL (15.70 mmol) of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran). The solution was stirred at −30° C. for 5 min and 0.77 mL (14.98 mmol) of bromine was added. The reaction was stirred at −30° C. to room temperature during 3 hours. The mixture was quenched with the addition of a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (dichloromethane with 1 to 3% of methanol) to afford 2.6 g (46%) of product.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:16]=1[CH:17]=O>>[Cl:14][C:15]1[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Cl
Product: O=c1cc(N2CCN(Cc3cc(C(F)(F)F)ccc3Cl)CC2)nc[nH]1

Procedure:
6-[4-(2-Chloro-5-trifluoromethyl-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2-chloro-5-(trifluoromethyl)benzaldehyde. Mass spectrum (ES) MH+=373.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.C([O:37][C:38](=[O:53])[CH2:39][CH2:40][C@@H:41]([C:50](O)=[O:51])[NH:42]C(OC(C)(C)C)=O)(C)(C)C>>[ClH:28].[NH2:42][C@H:41]([C:50](=[O:51])[NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:32])[F:30])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1)[CH2:40][CH2:39][C:38]([OH:53])=[O:37]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Product: N[C@@H](CCC(=O)O)C(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and tert-butoxycarbonyl-L-glutamic acid 5-tert-butyl ester by using the same method as in Example 96.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=O)[C:13]2[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=2[N:15]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=[S:25])[C:13]2[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=2[N:15]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3OCC)nc12
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCc1nn(C)c2c(=S)[nH]c(-c3ccccc3OCC)nc12
Reaction time: 0.5 h
Yield: 144.6 %

Procedure:
2-(2-ethoxy)-phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-one (50 g (0.16 mol)), phosphorus pentasulfide (17.8 g (0.08 mol)), pyridine (250 ml) were added into a 500 ml three-neck flask with a mechanical stirrer, stirred, heated and refluxed for 6 hours, TLC tracing was performed until the reactants were totally disappeared. The solvent pyridine was removed by distilling under reduced pressure, concentrated ammonia water ((25-28%) 75 ml) and ethanol 300 ml were added, heated and refluxed for 30 min. It was cooled, filtered, dried, and crude product (45 g) was obtained. The crude product was heated and solved into chloroform (150 ml), activated carbon (5 g) was added, stirring and reflux was performed for 30 min, it was filtered and the filtrate was washed with saturated brine and water consequently and dried with magnesium sulfate anhydrous, chloroform was removed by distilling, the obtained solid was re-crystallized with ethanol and dried, solid (38 g) was obtained with a yield of 72%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([C:14](=[C:18](SC)[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:15]([NH2:17])=[O:16])#[N:13]>>[NH2:13][C:12]1[N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[N:11]=[C:18]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[C:14]=1[C:15]([NH2:17])=[O:16]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Product: Cc1ccc(-c2nn(-c3ccc([N+](=O)[O-])cc3)c(N)c2C(N)=O)cc1

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl)acetamide (464 mg, 2.0 mmol) and 4-nitrophenylhydrazine (337 mg, 2.2 mmol) following the procedure used for the compound of Example 12. The crude product was purified by column chromatography (SiO2, 2% acetic acid, 5% methanol in CH2Cl2) to give the title compound as a yellow solid (14 mg) m.p. 299-3000. δH (d6DMSO) 8.42 (2H, d, J 8.6 Hz), 8.21 (2H, d, J 8.7 Hz), 7.80 (2H, d, J 8.0 Hz) and 7.75 (2H, d, J 7.9 Hz).
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].ClC(OCC)=O.[OH:14][C@@H:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:16][CH2:17][C@@H:18]([O:27][CH2:28][CH:29]1[CH2:33][CH2:32][C:31](=[O:34])[NH:30]1)[C:19]1[S:23][C:22]([C:24]([OH:26])=O)=[CH:21][CH:20]=1.C(N)C>C(Cl)Cl>[CH2:1]([NH:3][C:24]([C:22]1[S:23][C:19]([C@H:18]([O:27][CH2:28][CH:29]2[CH2:33][CH2:32][C:31](=[O:34])[NH:30]2)[CH2:17][CH2:16][C@@H:15]([OH:14])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:20][CH:21]=1)=[O:26])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCCCC[C@H](O)CC[C@@H](OCC1CCC(=O)N1)c1ccc(C(=O)O)s1
Agent: CCN
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: CCCCC[C@H](O)CC[C@@H](OCC1CCC(=O)N1)c1ccc(C(=O)NCC)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.5 %

Procedure:
Triethylamine (9 mL, 0.065 mmol) and ethyl chloroformate (4.5 mL, 0.47 mmol) were added sequentially to a solution of acid 6 (12 mg, 0.031 mmol) in CH2Cl2 (0.2 mL) at 0° C., After 1 h at 0° C., ethylamine (2.0 M in THF, 0.15 mL, 0.30 mmol) was added and the mixture was allowed to warm to room temperature. After 18 h at room temperature, the reaction was quenched with 1.0 N HCl (5 mL) and extracted with EtOAc (3×10 mL). The combined extracts were washed with brine (5 mL), then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude residue by flash column chromatography on 4 g of silica gel (CH2Cl2→10% MeOH/CH2Cl2, gradient) afforded 7.7 mg (60%) of the title compound (8).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.C(NC(C)C)(C)C.[Li].[F:18][C:19]([F:23])([F:22])[CH2:20]I>C1COCC1>[F:18][C:19]([F:23])([F:22])[CH2:20][CH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]#[N:7])=[CH:8][CH:9]=1
Reactant: FC(F)(F)CI
Reactant: Cc1ccc(C#N)cn1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(CCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a solution of 6-methyl-nicotinonitrile (118 mg, 1.0 mmol) in anhydrous THF (20 mL) at −78 C under nitrogen was added lithium diisopropylamine (2M solution in THF/heptane/ethylbenzene, 550 μL, 1.1 mmol) drop-wise. The resulting solution was allowed to warm to room temperature for 5 min and then cooled back to −78 C. 1,1,1-Trifluoro-2-iodo-ethane (524 mg, 2.5 mmol) was then added to the solution drop-wise and the reaction mixture was allowed to warm to room temperature and stirred at this temperature for 2 h. The reaction mixture was cooled at 0 C and quenched with water; the resulting solution was extracted with EtOAc (3×25 mL). Combined organics were washed with brine (25 mL), dried over magnesium sulfate and purified by silica chromatography (25% EtOAc in heptane) to afford the title compound as a pale yellow oil (191 mg, 95%). Method C HPLC-MS: MH+ requires m/z=201. Found: m/z=201, Rt=1.22 min (86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[N:11][C:10]([CH3:26])=[N:9]2)=[CH:4][C:3]=1[CH3:27].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[C:30]([OH:32])([C:29]([F:34])([F:33])[F:28])=[O:31].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:11][C:10]([CH3:26])=[N:9]2)=[CH:4][C:3]=1[CH3:27]
Reactant: Cc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)n(-c2ccc(Cl)c(C)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(C2CCNCC2)n(-c2ccc(Cl)c(C)c2)n1

Procedure:
The product from step B (145.7 mg, 0.373 mmol) was dissolved in anhydrous dichloromethane (1 mL). Trifluoroacetic acid (100 uL, 1.298 mmol) was added dropwise with stirring. The reaction solution was stirred at room temperature for 16 h. The solution was concentrated and the crude residue was purified by RP-HPLC(C18; acetonitrile, water, 0.1% TFA) to afford the title compound. HPLC/MS: 291.0/293.0 (M+1), Rt=2.09 (LC4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([C:13]#[N:14])=[C:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=1.P(Cl)(Cl)([Cl:26])=O>O>[Cl:26][C:7]1[C:6]([C:13]#[N:14])=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: CC(C)c1cccc(-c2c(C#N)c(=O)[nH]c3ccc(Cl)cc23)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C)c1cccc(-c2c(C#N)c(Cl)nc3ccc(Cl)cc23)c1
Yield: 83.9 %

Procedure:
A mixture of 6-chloro-4-(3-isopropyl-phenyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile (142 mg, 440 μmol, Eq: 1.00) and phosphorus oxychloride (2.02 g, 1.23 ml, 13.2 mmol, Eq: 30) was heated to reflux for 3 h. The reaction mixture was then poured into water and extracted with DCM (3×). The combined organic layers were washed with water and brine, dried with Na2SO4 and evaporated to afford the title compound (126 mg, light yellow solid). MS (ESI): 343.1 (M+H)+.
Reaction SMILES: [N:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]2=[O:16])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N:24]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=1>CO>[N:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([CH2:30][C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)[C:8]2=[O:16])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C1Cc2ccccc2N1N1CCOCC1
Reactant: O=Cc1ccncc1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C1C(Cc2ccncc2)c2ccccc2N1N1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
A mixture of 1,3-dihydro-1-(4-morpholinyl)-2H-indol-2-one (301 mg, 1.38 mmole), triethylamine (0.22 ml, 1.52 mmole), 4-pyridinecarboxaldehyde (0.15 ml, 1.52 mmole) in methanol (3 ml) was refluxed for 30 minutes. The volatiles were evaporated and the crude product was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude red oil was characterized by mass spec., m/e 308 (M+H, 100%) for the aldol/dehydration product. The crude material was immediately dissolved in methanol (10 ml), cooled to 0° C., to which was added sodium borohydride (168 mg). After stirring 30 minutes, normal extractive workup afforded a yellow foam, which was purified by column chromatography using 5% methanol-chloroform. The product was recrystallized from hexane-ethyl acetate to give 259 mg of a powder, m.p. 108°-110° C. Anal (C18H19N3O2): C,H,N.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.C([O:21][B:22](OC(C)C)[O:23]C(C)C)(C)C>>[F:8][C:6]1[CH:7]=[C:2]([B:22]([OH:23])[OH:21])[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Product: OB(O)c1cc(F)cc(C(F)(F)F)c1

Procedure:
3-Bromo-5-fluorobenzotrifluoride was lithiated with n-butyllithium and treated with tri-isopropylborate to give 3-fluoro-5-trifluoromethylphenyl boronic acid. This was coupled to 5-bromopyrimidine, using Suzuki methodology to afford 3-fluoro-5-(pyrimidin-5-yl)benzotrifluoride. Hydrolysis with conc. sulphuric acid and chlorosulphonic acid afforded 3-fluoro-5-(pyrimidin-5-yl)benzoic acid. This was converted to the methyl ester by treatment with methanol and conc. sulphuric acid, and to the hydrazide by treatment with hydrazine hydrate. Diazotisation and treatment with potassium carbonate afforded the title compound.