Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].[Mg+2].[Cl-].[Cl-].[F:14][C:15]1[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[CH:20][C:16]=1C(Cl)=O>C(#N)C>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3](=[O:5])[C:20]1[CH:16]=[C:15]([F:14])[C:23]([F:24])=[C:22]([F:25])[C:21]=1[F:26])[CH3:9]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium ethyl malonate (3.66 g, 21.5 mmol), MgCl2 (2.44 g, 25.7 mmol) and TEA (2.05 g, 20.3 mmol) were mixed in acetonitrile (70 ml) at 10-15° C. for 2.5 hr. 2,3,4,5-tetrafluorobenzoyl chloride (2.00 g, 10.3 mmol) in acetonitrile (10 ml) was added at 0° C. over 15 min followed by a second addition of TEA (0.23 g, 2.3 mmol). After allowing to warm to RT, the mixture was stirred for 16 hr. After removal of volatiles in vaccuo Toluene (30 ml) was added and removed in vacuo. Following the addition of toluene (60 ml), HCl 1.5 M (40 ml) was added cautiously, ensuring the temperature did not exceed 25° C. The organic fraction was washed with HCl 1.5 M (2×25 ml) and water (2×25 ml), dried over MgSO4 and reduced to a light orange oil in vacuo ([M+1]+ 265, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.Cl[C:34]1[C:43]2[C:38](=[CH:39][C:40]([F:45])=[C:41]([F:44])[CH:42]=2)[N:37]=[CH:36][N:35]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([C:34]2[C:43]3[C:38](=[CH:39][C:40]([F:45])=[C:41]([F:44])[CH:42]=3)[N:37]=[CH:36][N:35]=2)[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Fc1cc2ncnc(Cl)c2cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ncnc3cc(F)c(F)cc23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 37 %

Procedure:
A solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (1.27 g, 5.23 mmol) in dry THF (2 mL) was added dropwise over 2 minutes with stirring to 1.01M LiHMDS/THF (5.75 mL, 5.81 mmol) at −78° C. under argon. After 5 min at −78° C., the cold bath was removed and the reaction was allowed to stir at “rt” for 30 min. A portion of this enolate solution (5.1 mL, 3 mmol enolate) was added dropwise over 2-3 min to a stirred homogeneous solution of 4-chloro-6,7-difluoroquinazoline (600 mg, 2.99 mmol) in dry THF (3 mL) at 0° C. under argon. The reaction was stirred for 30 min at 0° C., and was then quenched with 1M NaH2PO4 (50 mL) and extracted with EtOAc (1×50 mL). The organic layer was washed with 4M NaCl (1×50 mL), dried (Na2SO4), and concentrated. The residue was purified with silica flash chromatography (3:1 hexanes/EtOAc) to afford the title compound as a yellow oil (451 mg, 37%). LC/MS (ESI): calcd mass 407.2, found 408.2 (MH)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH2:17])[CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O[CH:21](O)[C:22]([F:25])([F:24])[F:23])C.O>C1C=CC=CC=1>[Si:1]([O:8][CH2:9][C@@H:10](/[N:17]=[CH:21]/[C:22]([F:25])([F:24])[F:23])[CH2:11][CH2:12][C:13]([F:14])([F:16])[F:15])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](N)CCC(F)(F)F
Reactant: CCOC(O)C(F)(F)F
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H](CCC(F)(F)F)/N=C/C(F)(F)F

Procedure:
A solution of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-5,5,5-trifluoro-pentan-2-amine (3.00 g, 11.06 mmol) and trifluoroacetaldehyde ethyl hemiacetal (1.6 g, 11.1 mmol) in benzene (20 mL) was refluxed for 2 hours during which time water was collected in a Dean-Stark trap. The solvent was removed in vacuo yielding crude (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-5,5,5-trifluoro-N-[(1E)-2,2,2-trifluoroethylidene]pentan-2-amine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[C:12]([NH2:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:24]#[C:25]Br.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)[C:25]([NH2:24])=[N:23][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CBr
Reactant: Nc1ccc(OCc2ccccc2)nc1Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2ccc(OCc3ccccc3)nc2n1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 6-(benzyloxy)-N2-(4-bromophenyl)pyridine-2,3-diamine (3.86 g, 10.4 mmol) in H2O was added cyanogen bromide (1.44 g, 13.5 mmol) and TFA (200 μL). The reaction mixture was stirred at room temperature for 2.5 h, added 2 M aqueous Na2CO3 and extracted with DCM. The organic extract was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography to give 5-(benzyloxy)-3-(4-bromophenyl)-3H-imidazo[4,5-b]pyridin-2-amine intermediate. The benzyl group was removed in a similar manner as the one described in Example 1.102 to give the title compound. LCMS m/z=305.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 6.22 (broad s, 2H), 6.29 (d, J=8.2 Hz, 1H), 7.39-7.46 (m, 3H), 7.77 (m, 2H), 9.96 (s, 1H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].N1CCOCC1>C1COCC1.CS(C)=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>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Solvent: CS(C)=O
Product: CCCCn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.35 mmol) in anhydrous THF (4 ml) and anhydrous DMSO (0.4 ml) was treated with Pd(PPh3)4 (61 mg, 0.053 mmol). The mixture was degassed under gentle vacuum, morpholine (308 uL, 3.5 mmol) was added, and left to stir at rt under nitrogen for 4 hours. The yellow solution was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The residue was taken up in MeOH and passed down an amino-propyl SPE (5 g), eluting with MeOH followed by 5% AcOH/MeOH. The product fractions were combined and concentrated in vacuo to afford the title compound as an off white solid (30 mg, 35%). NMR; δH (400 MHz, d6-DMSO) 0.89 (t, 3H, J=7.5 Hz), 1.23-1.34 (m, 2H), 1.55-1.65 (m, 2H), 3.85 (t, 2H, J=7 Hz), 11.17 (s, 1H), 14.37 (br.s, 1H); m/z 243.3[MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:15][CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:15][CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:14])[S:10][CH:11]=1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCn1ncc(Cl)c1-c1csc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1ncc(Cl)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (0.26 g, 1.0 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (0.35 g, 1.1 mmol) and DIPEA (0.5 mL, 2.86 mmol) in DCM (5 mL) at 25° C. was added PyBrOP (0.6 g, 1.2 mmol) in one portion. After 2 h, the solution was concentrated and purified via column chromatography (silica, 20-50% EtOAc/hexane) affording the title compound (0.54 g, 91%) as a white solid: LC-MS (ES) m/z=588 (M+H)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](Cl)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:5]1)(=O)C.[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1>N1C=CC=CC=1>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:13]([NH:23][CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[O:14])[CH:8]=3)[NH:4][N:5]=2)=[CH:21][CH:20]=1
Reactant: NCc1cccnc1
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Solvent: c1ccncc1
Product: O=C(NCc1cccnc1)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 40.7 %

Procedure:
To a flask containing 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (300 mg, 0.95 mmol) dissolved in pyridine (4 mL) was added 3-aminomethyl pyridine (106 μl, 1.05 mmol). The reaction was allowed to stir under a nitrogen atmosphere overnight. LCMS indicated the reaction was complete. Solvent was removed and water was added to the flask. A solid crashed out of solution that was collected by filtration. The solid was taken up in a 3% ammonia in methanol solution (8 mL) and allowed to reflux at 60° C. for three hours. The reaction was neutralized with 1 N HCl solution and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated to yield the title compound (134 mg, 41% yield). 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 9.2 (s, 1H), 8.6 (m, 2H), 8.5 (s, 1H), 8.1 (m, 2H), 7.95 (d, 1H), 7.65 (d, 1H), 7.6 (m, 1H), 7.4 (m, 3H), 4.6 (m, 2H) ES-MS m/z 347 [M+1]+.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1>C(O)C>[CH:19]1([CH2:18][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([NH2:10])=[O:9])[CH2:21][CH2:20]1
Reactant: BrCC1CC1
Reactant: NC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=O)c1ccccc1OCC1CC1
Yield: 70.7 %

Procedure:
A stirred mixture of salicylamide (10.02 g., 0.074 mole), potassium carbonate (10.24 g., 0.074 mole) and bromomethylcyclopropane (10.0 g., 0.074 mole) in ethanol (15 ml.) was heated under reflux for 19 hours. The mixture was concentrated and the residue treated with water. The mixture was filtered and the collected solid recrystallized from benzene-Skellysolve B to give 2-cyclopropylmethoxybenzamide (10.0 g., 71.6%), m.p. 102°-105°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:15]([CH3:21])[CH2:16][C:17]([NH:19][NH2:20])=[O:18])[CH2:11][CH2:10]1.[CH2:22]1[CH2:27][CH2:26][CH:25]([CH2:28][N:29]=[C:30]=[O:31])[CH2:24][CH2:23]1.CCOC(C)=O>C1(C)C=CC=CC=1>[CH:25]1([CH2:28][NH:29][C:30]([NH:20][NH:19][C:17](=[O:18])[CH2:16][CH:15]([N:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:14][CH2:13]2)[CH3:21])=[O:31])[CH2:26][CH2:27][CH2:22][CH2:23][CH2:24]1
Reactant: O=C=NCC1CCCCC1
Reactant: COc1ccccc1N1CCN(C(C)CC(=O)NN)CC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCN(C(C)CC(=O)NNC(=O)NCC2CCCCC2)CC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 3-[4-(2-methoxyphenyl)piperazin-1-yl]butanohydrazide D12 (0.5 g, 1.71 mmol) in anhydrous toluene (7 mL), cyclohexanemethyl isocyanate (0.25 g, 1.80 mmol) was added dropwise at room temperature, the mixture was heated at 100° C. and stirred for 10 min. The solution was allowed to cool slowly to room temperature, AcOEt (15 mL) was added and the organic phase was washed with water (2×10 mL), dried over MgSO4 and evaporated under reduced pressure to afford 0.909 g N-(cyclohexylmethyl)-2-{3-[4-(2-methoxyphenyl)piperazin-1-yl]butanoyl}hydrazinecarboxamide D13 as an orange oil. The product containing little toluene was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C@H:12]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:13]([CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:14]([O:16]C(C)(C)C)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C@H:12]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@H:13]([CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:14]([OH:16])=[O:15])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)[C@H](CCCCc2ccccc2)[C@H](CCOc2ccccc2)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)[C@H](CCCCc2ccccc2)[C@H](CCOc2ccccc2)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 70.9 %

Procedure:
(±)-t-Butyl (2R*,3R*)-3-(4-methoxybenzenesulfonyl)-7-phenyl-2-(2-phenoxyethyl)heptanoate (0.3 g, 0.54 mmol) is dissolved in CH2Cl2 (7 mL), cooled to 0° C. and TFA (1 mL) is added slowly. The bath is removed and the reaction is stirred for 4 hours. The reaction is concentrated in vacuo and the residue purified by reverse phase HPLC (50-100% CH3CN in 0.1% TFA/H2O) to yield (±)-(2R*,3R*)-3-(4-methoxybenzenesulfonyl)-7-phenyl-2-(2-phenoxyethyl)heptanoic acid (0.19 g, 70%). 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J=8.8 Hz, 2H), 7.29-7.15 (m, 5H), 7.08 (d, J=7.3 Hz, 2H), 6.98-6.91 (m, 3H), 6.81 (d, J=8.3 Hz, 2H), 4.17-4.03 (m, 2H), 3.83 (s, 3H), 3.80-3.75 (m, 1H), 3.17-3.14 (m, 1H), 2.58-2.50 (m, 3H), 2.30-2.18 (m, 1H), 1.90-1.77 (m, 2H), 1.60-1.45 (m, 3H), 1.41-1.30 (m, 1H); MS (FAB) m/e 497 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:3]1.N1C=CN=C1.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C.O>[Si:26]([O:1][CH:2]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:3]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)NC1CC(O)CNC1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CC(O[Si](C)(C)C(C)(C)C)CNC1=O
Reaction time: 15 h
Yield: 85.8 %

Procedure:
To a stirred solution of compound 1C (0.355 g, 1.54 mmol) in 5 mL of DMF at room temperature was added imidazole (401 mg, 5.89 mmol) and then t-butyldimethyl chlorosilane (401 mg, 2.31 mmol). After 15 h, the reaction mixture is diluted with 25 mL water and extracted four times with 20 mL portions of ether. The combined organic extracts were washed three times with water, once with saturated NaCl. The organic layer was dried over MgSO4, and then filtered and evaporated under reduced pressure. Purification by silica gel chromatography (2:1 EtOAc/CH2Cl2) provided the title compound (455 mg, 86%) as a white solid. MS [M+H]+: found 345.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Br)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([Cl:12])=[CH:14][CH:15]=2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1nccnc1Br
Reactant: Nc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: COC(=O)c1nccnc1Nc1ccc(Cl)cc1
Reaction time: 96 h

Procedure:
A mixture of 21.7 g 3-bromo-pyrazine-2-carboxylic acid methyl ester and 25.5 g 4-chloroaniline in 150 ml ethyl acetate is boiled 4 days at reflux. The solution is washed with 4 N hydrochloric acid, water and then with 2 N sodium carbonate. The organic phase is dried over sodium sulphate and evaporated to give the heading compound (recrystallised from isopropanol) m.p. 135°-136°.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:6]([N+:19]([O-:21])=[O:20])=[CH:7][C:8]([CH3:18])=[C:9]([C:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH:12]=2)[CH:10]=1)([CH3:3])[CH3:2].[CH3:22][NH:23][CH3:24].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CO>[CH:1]([O:4][C:5]1[C:6]([N+:19]([O-:21])=[O:20])=[CH:7][C:8]([CH3:18])=[C:9]([C:11]2[CH2:16][CH2:15][CH:14]([N:23]([CH3:24])[CH3:22])[CH2:13][CH:12]=2)[CH:10]=1)([CH3:3])[CH3:2]
Reactant: CNC
Reactant: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1C1=CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1C1=CCC(N(C)C)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 4-(5-isopropoxy-2-methyl-4-nitrophenyl)cyclohex-3-enone (0.1 mmol) and dimethylamine (0.11 mmol) in 2 mL of 1,2-dicholoroethane, is added AcOH (0.1 mmol) and NaBH(OAc)3 (0.11 mmol). The reaction mixture is stirred at room temperature for 10 hours. After workup and silica flash chromatography (CH2Cl2/MeOH 9:1), 4-(5-isopropoxy-2-methyl-4-nitrophenyl)-N,N-dimethylcyclohex-3-enamine is obtained. MS (ES+): 319.19 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[C:4]([C:7]#[N:8])[C:3]=1[C:9]1[O:10][CH:11]=[CH:12][N:13]=1.[O:14]=[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:21]=2)[N:16]1[CH2:29][C:30](O)=[O:31]>>[C:7]([C:4]1[C:3]([C:9]2[O:10][CH:11]=[CH:12][N:13]=2)=[C:2]([NH:1][C:30](=[O:31])[CH2:29][N:16]2[C:17]3[C:22](=[CH:21][C:20]([C:25]([F:26])([F:28])[F:27])=[CH:19][CH:18]=3)[CH:23]=[CH:24][C:15]2=[O:14])[S:6][CH:5]=1)#[N:8]
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Reactant: N#Cc1csc(N)c1-c1ncco1
Product: N#Cc1csc(NC(=O)Cn2c(=O)ccc3cc(C(F)(F)F)ccc32)c1-c1ncco1

Procedure:
The title compound was synthesized from 5-amino-4-(oxazol-2-yl)thiophene-3-carbonitrile (21 mg, 0.11 mmol) and 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (30 mg, 0.11 mmol) according to protocol A. The product was purified by HPLC. LCMS method [7], retention time=6.70 min; MS(ESI) 445.0 (MH+); 1H NMR (300 MHz, CD3OD) δ 8.19 (d, J=9.8 Hz, 2H), 7.95-7.80 (m, 3H), 7.85 (d, J=1.8 Hz, 1H), 7.08 (d, J=0.8 Hz, 1H), 6.90 (d, J=9.6 Hz, 1H), 5.45 (s, 2H).
Reaction SMILES: CC(O)(C)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:7][CH:6]=1.[H-].[Na+].O>C1(C)C=CC=CC=1>[CH2:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4]#[CH:3])=[CH:10][CH:9]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCc1ccc(C#CC(C)(C)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C#Cc1ccc(CCCCC)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 78.3 %

Procedure:
3-Methyl-1-(4'-pentylphenyl)-1-butyne-3-ol (82 g) was dissolved in toluene (900 ml) under nitrogen atmosphere, and then sodium hydride (60% in paraffin liquid; 5.6 g) was added thereto, followed by stirring at 60° C. for 6 hours. The reaction solution was poured into water (500 ml), and extracted with chloroform, followed by washing with water three times. After distilling off toluene and chloroform, the resultant was distilled under reduced pressure (b.p. 85° to 90° C./3 mmHg) to give 4-pentylphenylacetylene (48 g).
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[CH2:22]([NH:25][C:26]([NH2:28])=[S:27])[CH2:23][CH3:24]>C(O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:28]=[C:26]([NH:25][CH2:22][CH2:23][CH3:24])[S:27][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: CCCNC(N)=S
Solvent: CCO
Product: CCCNc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (0.346 g, 0.932 mmol) (Example 26, Step 2) in ethanol (15 mL) in a 25 mL round bottom flask was added N-propylthiourea (0.116 g, 0.979 mmol) with stirring. The resulting solution was heated to reflux for 24 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in methylene chloride, washed successively with Na2CO3 (10% solution) and brine, dried over Na2SO4, filtered and reconcentrated in vacuo yielding 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(1-propylamino) thiazole as a yellow crystalline solid (0.276 g, 76%): mp 181°-182° C. 1H NMR (DMSO-d6) 400 mHz 5 7.97 (t, J=5.37 Hz, 1H), 7.78 (d, J=8.79 Hz, H), 7.42 (dd, J=5.86, 8.79, 2H), 7.37 (d, J=8.79, H), 7.15 (t, J=8.79 Hz, 2H), 3.21 (q, J=6.84, H), 3.18 (s, 3H), 1.60 (m, 2H), 0.91 (t, J=7.33, H). MS (EI): m/z 390 (M+). HRMS Δ=2.4 mmu.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[N:8]=[C:7]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[N:6]2[CH:31]=1.[CH2:32]([CH2:34][NH2:35])[OH:33]>>[OH:33][CH2:32][CH2:34][NH:35][CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[C:9]([S:11][C:12]3[CH:13]=[CH:14][C:15]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])=[CH:16][CH:17]=3)[N:8]=[C:7]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[N:6]2[CH:31]=1
Reactant: NCCO
Reactant: Cc1cc(Nc2nc(Sc3ccc(NC(=O)C4CC4)cc3)cc3nc(CO)cn23)n[nH]1
Product: Cc1cc(Nc2nc(Sc3ccc(NC(=O)C4CC4)cc3)cc3nc(CNCCO)cn23)n[nH]1

Procedure:
The title compound was synthesized using N-(4-(2-(hydroxymethyl)-5-(5-methyl-1H-pyrazol-3-ylamino)imidazo[1,2-c]pyrimidin-7-ylthio)phenyl)cyclopropanecarboxamide and ethanol amine using the procedure described in Example 283. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82 (d, J=6.32 Hz, 4H) 1.82 (dt, J=12.44, 6.28 Hz, 1H) 2.11 (s, 3H) 2.83-2.92 (m, 2H) 3.53-3.62 (m, 2H) 4.01 (s, 2H) 4.90 (s, 1H) 5.86 (s, 1H) 6.47 (s, 1H) 7.53 (d, J=8.08 Hz, 2H) 7.75 (d, J=7.83 Hz, 2H) 8.26 (s, 1H) 10.36 (s, 1H) 10.48 (s, 1H) 12.12 (s, 1H); ESI-MS: m/z calc'd for C23H26N8O2S 478.57; found 479.4 (M+H)+
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].Br[C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)=[CH:18]/[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:23]([CH3:34])[CH:22]=2)=[CH:13][CH:12]=1>C(N(CC)CC)C.C1C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:41][C:38]1[CH:37]=[CH:36][C:35](/[C:17](/[C:14]2[CH:13]=[CH:12][C:11]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[CH:16][CH:15]=2)=[CH:18]\[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:23]([CH3:34])[CH:22]=2)=[CH:40][CH:39]=1
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)C(C)c1ccc(OC/C=C(\c2ccc(Cl)cc2)c2ccc(Br)cc2)cc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)C(C)c1ccc(OC/C=C(\c2ccc(Cl)cc2)c2ccc(C#CCN3CCOCC3)cc2)cc1C

Procedure:
Under nitrogen atmosphere, 4-propargylmorpholine (550 mg, 4.4 mmol) bis(triphenylphosphine)palladium(II) dichloride (40 mg, 0.057 mmol) and copper(II) acetate (7 mg, 0.038 mmol) were added to a degassed solution of the above ester (280 mg, 0.55 mmol) in triethylamine (30 mL). The reaction mixture was refluxed for 8 h, diluted with benzene (100 mL), filtered and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, chloroform/methanol 9:1) yielding ethyl (Z)-[4-[3-(4-chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenyl]propionate.