Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:6]([CH3:33])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[O:22][C:23]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=4[C:25]=3[CH3:26])=[O:20])=[CH:14][C:13]=2[F:32])[C:9]=1[CH3:10].[OH-].[Na+].Cl>O1CCOCC1.O.O>[F:32][C:13]1[CH:14]=[C:15]([NH:18][C:19]([C:21]2[O:22][C:23]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=3[C:25]=2[CH3:26])=[O:20])[CH:16]=[CH:17][C:12]=1[CH2:11][N:8]1[C:9]([CH3:10])=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[C:6]([CH3:33])=[N:7]1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(NC(=O)c3oc4ccc(F)cc4c3C)cc2F)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nn(Cc2ccc(NC(=O)c3oc4ccc(F)cc4c3C)cc2F)c(C)c1CC(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
To a solution of 5-fluoro-3-methyl-1-benzofuran-2-carboxylic acid (194 mg, 1 mmol) in 5 mL dimethylformamide is added diisopropylethylamine (0.516 mL, 3 mmol) and HATU (399 mg, 1.05 mmol) is added. After stirring at room temperature for 25 minutes dimethylformamide (1 mL) and then intermediate [1-(4-amino-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]acetic acid methyl ester (291 mg, 1 mmol) is added. Subsequently diisopropylethylamine (0.344 mL, 2 mmol) and dimethylformamide (2 mL) is added, and the mixture is stirred at room temperature for 48 hours. Then ethyl acetate and water are added and the precipitate is filtered off. The organic layer is extracted twice with acetic acid (1 N), once with an aqueous solution of NaHCO3 (5% by weight) and twice with water, dried over MgSO4. The solvent is removed by evaporation in vacuo. The residue is purified by MPLC (dichloromethane/methanol 96:4) to yield 120 mg of (1-(2-fluoro-4-[(5-fluoro-3-methylbenzofuran-2-carbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (ESI mass spectrum: [M+H]+=468; TLC: Rf=0.72 (dichloromethane/methanol 9:1, silicagel 60 F254)). b) To a solution of (1-(2-fluoro-4-[(5-fluoro-3-methylbenzofuran-2-carbonyl)-amino]-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester (119 mg, 0.26 mmol) in dioxane/water (7 mL/7 mL) is added an aqueous solution of NaOH (1 M, 2.3 mL) and the mixture is stirred at room temperature for 12 hours and at 60° C. for 2 hours. The mixture is diluted with water, acidified with hydrochloric acid (1 M, 1 mL) and extracted with ethyl acetate. The organic layer is dried over MgSO4, the solvent evaporated in vacuo, the residue is crystallized with diisopropyl ether and the precipitate is isolated by filtration to yield 69 mg of the title compound (ESI mass spectrum: [M+H]+=454; Retention time HPLC: 0.90 min (method D)).
Reaction SMILES: [N:1]1([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:20][CH:21]([F:25])[C:22](Cl)=[O:23]>C1(C)C=CC=CC=1>[F:20][CH:21]([F:25])[C:22](=[O:23])[C:8](=[CH:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C(Cl)C(F)F
Reactant: COC(=O)C=CN1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C(=CN1CCCCC1)C(=O)C(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
Methyl 3-piperidin-1-ylacrylate (99%, 26.6 g, 155 mmol) and triethylamine (17.3 g, 171 mmol) were initially charged in toluene (300 ml) and cooled to −30° C. At this temperature, difluoroacetyl chloride (20 g, 171 mmol) was introduced. The reaction mixture was stirred at −30° C. for 3 h, another 200 ml of toluene were added to keep the suspension stirrable and the mixture was then warmed to room temperature over a period of 1 hour. The reaction mixture was washed with deionized water (200 ml). After separation of the phases, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined and washed with an aqueous saturated NaCl solution (100 ml), and the solvent was then removed under reduced pressure. This gave methyl 4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate as an orange oil (amount: 37.6 g; purity according to quant. NMR: 82.2%; yield: 80.3%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[Br:13]Br>C(O)(=O)C>[Br:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2[nH]nc(Br)c2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
5-Nitroindazole (10 g, 61.3 mmol) was dissolved in acetic acid (170 mL) and the mixture heated to 80° C. Bromine (3.1 mL, 60.7 mmol) was added slowly and the mixture heated to reflux. After 2 hours, the reaction mixture was allowed to cool to room temperature, and the resulting precipitate filtered off. Additional product was isolated by concentrating the filtrate, partitioning the residue between chloroform and saturated sodium bicarbonate solution, separating and drying the organic phase over sodium sulfate. Concentration gave a solid which was combined with the original precipitate to give the title compound as a yellow solid (11.4 g, 77%). 1H NMR δ 7.74 (1H, d), 8.21 (1H, dd), 8.40 (1H, d), 14.06 (1H, brs); MS (ES−) m/e=240.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[N:22]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1.[OH:29]OS([O-])=O.[K+].C([O-])(O)=O.[Na+]>C1COCC1.O>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[N:22]=3)=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[N:13]=2)=[CH:5][CH:4]=1)=[O:29]
Reactant: O=S([O-])OO
Reactant: COc1nccc(-c2[nH]c(-c3ccc(SC)cc3)nc2-c2ccc(F)cc2)n1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nccc(-c2[nH]c(-c3ccc(S(C)=O)cc3)nc2-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.3 %

Procedure:
To a solution of 2-(4-methylthiophenyl)-4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl)imidazole (0.10 g, 0.25 mmol) in 10 mL of THF at 0° C. was added a cooled solution of Oxone (0.084 g, 0.28 mmol)in 10 mL of H2O. The solution was warmed to room temperature and stirred for 20 min. Next, 20 mL of NaHCO3 sat was added and the mixture was extracted thrice with 20 mL of CH2Cl2. The combined organic layers were washed with 20 mL of 20% NaS2O5 and brine and then dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was then purified by silica gel chromatography with 2-6% CH3OH/CH2Cl2 to give the title compound as a light yellow solid (0.084 g, 82%). ES(+) MS m/e=409 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)([CH2:12][CH3:13])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:37])C=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24]([CH3:25])=[O:37])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)([CH2:12][CH3:13])[CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC(CCO)(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12
Solvent: CO
Solvent: ClCCl
Product: CCC(CCO)(c1ccc(Cl)cc1)c1c[nH]c2c(CS(C)=O)cccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
60 mg (0.16 mmol) of the compound from Example 140 were introduced into 6 ml of dichloromethane at 0° C., 40 mg (0.16 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 62 mg (99% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>CCOC(C)=O>[OH:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: OCCCc1cccc(B(O)O)c1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(CCCO)c3)nc12

Procedure:
1-{2-[3-(3-Hydroxy-propyl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 3-(3-hydroxypropyl)benzeneboronic acid following general procedures as described in these Examples. Silica gel chromatography using 20-100% EtOAc in hexanes as eluant provided 80 mg (48%) of a yellow solid. MP 170-171° C., M+H=338.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[Br:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=1[CH2:20]Br.O>C1COCC1>[Br:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=1[CH2:20][CH2:2][C:1]#[N:3]
Reactant: COc1cc(Br)c(CBr)cc1OC
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Br)c(CCC#N)cc1OC
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.3 mL of acetonitrile (5.8 mmoles, 1.8 eq.) in 15 mL of THF there are added, at −60° C., 1.77 mL of n-butyllithium (2M in cyclohexane, 3.5 mmoles, 1.1 eq.). The solution is stirred for 15 minutes at −60° C. and then 1 g of 1-bromo-2-(bromomethyl)-4,5-dimethoxybenzene (3.2 mmoles) dissolved in 5 mL of THF is added. The reaction mixture is stirred for 1 hour and then hydrolysed using 10 mL of water and extracted twice with ethyl acetate. The organic phases are combined and evaporated under reduced pressure. The crude reaction product is purified by chromatography on silica gel (eluant: methylcyclohexane/ethyl acetate (70/30)). After evaporating off the solvent under reduced pressure, 505 mg of an orange oil which crystallises in the form of a beige solid are obtained.
Reaction SMILES: [CH2:1]([CH:3]1[NH:12][C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([F:13])[CH:10]=2)[N:5]2[CH:15]=[CH:16][CH:17]=[C:4]12)[CH3:2].N1C=CC=CC=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][C:27]=1[CH3:36]>C(Cl)Cl>[CH2:1]([CH:3]1[N:12]([S:32]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[C:27]([CH3:36])[CH:28]=2)(=[O:34])=[O:33])[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([F:13])[CH:10]=2)[N:5]2[CH:15]=[CH:16][CH:17]=[C:4]12)[CH3:2]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C
Reactant: CCC1Nc2cc(F)c(F)cc2-n2cccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1c2cccn2-c2cc(F)c(F)cc2N1S(=O)(=O)c1ccc(OC)c(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.6 %

Procedure:
1.35 g (5.0 mmol) of the product from Example 3 was dissolved in 40 ml of methylene chloride and 1 ml of pyridine added. To this solution was added 1.20 g (5.4 mmol) of 4-methoxy-3-methyl benzenesulfonyl chloride. The solution was stirred at room temperature for 6 hours, after which it was concentrated, then diluted with 5 ml of 2N HCl. The residue was extracted 2 times with ethyl acetate, dried (MgSO4) and concentrated. The crude solid so obtained was chromatographed on silica gel, eluting with 20% ethyl acetate:hexane to afford a light yellow solid, which can be recrystallized from ethyl acetate:hexane to yield 1.52 g (72%) of product.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH2:26][C:27]([NH2:29])=[O:28])=[C:14]([CH3:25])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+]>CCO.O>[NH2:29][C:27](=[O:28])[CH2:26][C:13]1[C:12]2[C:16](=[CH:17][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:30])=[O:3])=[CH:10][CH:11]=2)[N:15]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:14]=1[CH3:25]
Reactant: CCOC(=O)CCCOc1ccc2c(CC(N)=O)c(C)n(Cc3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(CC(N)=O)c2ccc(OCCCC(=O)O)cc2n1Cc1ccccc1
Yield: 47.2 %

Procedure:
A solution of 100 mg (0.245 mmol) of 4-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-6-yl]oxy]butanoic acid ethyl ester and 2 mL of 1N NaOH in 5 mL of EtOH was stirred for 1.5 hours, diluted with water and extracted with EtOAc. The aqueous layer was made acidic to pH 6 with 1N HCl and extracted with EtOAc, the EtOAc dried (MgSO4), and concentrated at reduced pressure. The residue was crystallized from MeOH/CH2Cl2 to give 44 mg (47% yield) of 4-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-6-yl]oxy]butanoic acid, mp, 180°-184° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[CH:12]=[N:13][OH:14]>CN(C)C=O.C(OC)(C)(C)C>[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([Cl:1])=[N:13][OH:14]
Reactant: ON=Cc1ccccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: ON=C(Cl)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
N-Chlorosuccinimide (56.1 g) was added slowly to a 0° C. solution of the compound prepared in Example 4 (65.4 g) in N,N-dimethylformamide (1.2 L). The reaction was stirred at room temperature overnight and then diluted with ice water and methyl tert-butyl ether. The layers were separated and the aqueous phase was extracted once more with methyl tert-butyl ether. The organic phases were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (79.5 g) having the following physical data.
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[N:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([O-:5])=O.[Na+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42]([NH2:44])=[O:43].CN(C=O)C>CCOC(C)=O>[F:13][C:2]([F:1])([C:6]1[N:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([NH:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42]([NH2:44])=[O:43])=[O:5]
Reactant: O=C([O-])C(F)(F)c1ncc(F)cn1
Reactant: NC(=O)c1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1NC(=O)C(F)(F)c1ncc(F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To sodium 2,2-difluoro-2-(5-fluoropyrimidin-2-yl)acetate (400 mg, 1.87 mmol), HATU (850 mg, 2.24 mmol), and 2-aminobenzamide (305 mg, 2.24 mmol) was added DMF (7 mL) and the mixture was stirred at rt overnight. The mixture was diluted with EtOAc and washed with saturated aq NH4Cl, saturated aq NaHCO3, and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-12% MeOH/DCM to afford 2-(2,2-difluoro-2-(5-fluoropyrimidin-2-yl)acetamido)benzamide (374 mg, 44%); LC-MS (ESI) m/z 333 (M+Na)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[C:8]([N:26]2[CH:30]=[N:29][CH:28]=[N:27]2)[CH:7]=1)=[CH2:5])C.[Br:31]N1C(=O)CCC1=O>O1CCCC1.O>[N:26]1([C:8]2[CH:7]=[C:6]([C:4](=[O:5])[CH2:3][Br:31])[CH:11]=[CH:10][C:9]=2[C:12](=[O:13])[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[CH:30]=[N:29][CH:28]=[N:27]1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1ccc(C(=O)c2cc(OC)c(OC)c(OC)c2)c(-n2cncn2)c1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2ccc(C(=O)CBr)cc2-n2cncn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In the same manner as in the synthesis of Compound 515, 1,2,4-triazole was added to Compound 21 of Reaction 6. Then, tributyl(1-ethoxyvinyl)tin was added to the mixture, and the resulting mixture was reacted to obtain (4-(1-ethoxyvinyl)-2-(1H-1,2,4-triazol-1-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone. Thus obtained (4-(1-ethoxyvinyl)-2-(1H-1,2,4-triazol-1-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone was dissolved in a mixed solution of tetrahydrofuran and water (1/1), and N-bromosuccinimide (NBS) was added thereto. The mixture was stirred for 3 hours at room temperature. After completion of the reaction, the reaction mixture was extracted with EtOAc. The organic layer was washed with a saturated aqueous Na2 SO3 solution, water, and brine. The extracted organic layer was dried over anhydrous MgSO4, and the solid substance was filtered off. The filtrate was vacuum evaporated to remove the solvent. The resulting residue was purified by column chromatography (SiO2, n-Hex/EA=3/1→1/2) to obtain 1-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)-2-bromoethanone. Thus obtained 1-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)-2-bromoethanone (65 mg, 0.14 mmol) was dissolved in 3 ml of 95% ethanol, and thiourea (16 mg) was added thereto. The mixture was refluxed for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and vacuum evaporated to remove the solvent. The resulting residue was purified by column chromatography (SiO2, CH2Cl2/MeOH=30/1→10/1) to obtain Compound 516 (29.3 mg, 48%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([O:17][C:18](=[O:33])[CH:19]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10]2.C1C[O:37][CH2:36]C1>>[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([O:17][C:18](=[O:33])[C:19]([CH2:36][OH:37])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:10]2
Reactant: C1CCOC1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(Cc1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=C(O[C@H]1CN2CCC1CC2)C(CO)(Cc1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Lithium diisopropylamide (0.0048 mol) 2.40 ml of a 2M solution (in heptane/THF/ethylbenzene) was added to a stirred solution of 1.5 g (0.0045 mol) of 2,3-diphenylpropionic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester in 30 ml of THF at −70° C. under a N2 atmosphere. CH2O (gas) was bubbled into the reaction mixture via a steady stream of dry N2 during 10 min at −70° C. and then while the mixture was warmed at room temperature. The reaction was quenched by addition of saturated ammonium chloride solution (100 ml) and the resultant mixture was extracted twice with 100 ml of ethyl acetate. The organic layers were combined, dried over MgSO4 and evaporated to yield 1.9 g of an oil. This 1.9 g were combined with 3.28 g of a previous preparation and the product obtained (5.18 g) was purified by chromatography on silica gel eluting with chloroform/methanol/ammonia from 97.5:2.5:0.25 to 90:10:1. Appropriate fractions were combined and evaporated to obtain the two diastereomers: Intermediates I-22a and I-22b
Reaction SMILES: CS[C:3](SC)=[C:4]([C:7]#[N:8])[C:5]#[N:6].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].CO>C(O)C>[O:18]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:3]1=[C:4]([C:7]#[N:8])[C:5]#[N:6]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: Nc1ccccc1O
Solvent: CO
Solvent: CCO
Product: N#CC(C#N)=C1Nc2ccccc2O1

Procedure:
8.5 g. (0.05 M) of 3,3-bis(methylthio)-2-cyanoacrylonitrile and 6.0 g. (0.055 M) of 2-aminophenol in 200 ml. of methanol or ethanol are held under reflux for 4 hours, subsequently evaporated to dryness in vacuo and the resulting residue is made into a paste with 20 ml. of methanol or ethanol. The resulting crystals are filtered off under suction, washed with 10 ml. of ethanol and dried. There is obtained crude 2-benzoxazolinylidene-malononitrile of melting point ca. 240°-300° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[NH2:12][OH:13]>O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[N:12][OH:13])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: NO
Solvent: O
Product: O=[N+]([O-])c1cccc(C=NO)c1
Temperature: 70 °C
Yield: 96 %

Procedure:
151 g (1 mol) of m-nitrobenzaldehyde was added to 1 l of water warmed at 70° C. and then, added with 72.6 g (1.1 mol) of a 50% aqueous solution of hydroxylamine under stirring. The mixture was stirred at the same temperature for one hour and cooled to room temperature and then, crystals deposited were filtered and dried. Thus 160 g of m-nitrobenzaldoxime was obtained. Yield 96%; M.P. 118°-121° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])=[CH:5][CH2:6][CH3:7].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])=[CH:5][CH:6]([Br:10])[CH3:7]
Reactant: CCC=C(C)C(=O)OC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)=CC(C)Br
Yield: 82.5 %

Procedure:
A solution of 2-methylpent-2-enoic acid methyl ester (1.20 g, 9.37 mmol) and N-bromosuccinimide (1.83 g, 10.2 mmol) in dry carbon tetrachloride (15 mL) irradiated with a 250 W sunlamp so as to achieve a state of reflux for 2.5 hours. After cooling, the succinimide was filtered off, the carbon tetrachloride was evaporated, and the product was distilled over a short path under reduced pressure to give the title compound (1.60 g, 82%) as a colourless oil.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[N:11]2[CH:12]=[CH:13][N:14]=[CH:15][C:10]2=[N:9][CH:8]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:6]([C:7]1[N:11]2[CH:12]=[CH:13][N:14]=[CH:15][C:10]2=[N:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cnc2cnccn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cnc2cnccn12
Reaction time: 0.25 h
Yield: 77.8 %

Procedure:
To a solution of 3-((Trimethylsilyl)ethynyl)imidazo [1,2-a]pyrazine (0.15 g, 0.7 mmol) in 3.5 mL of THF was added 1.05 mL (1.05 mmol) of tetrabutylammonium fluoride (1.0M in THF) at ambient temperature. The solution was stirred for 15 min, concentrated, and the crude product purified by silica gel flash chromatography (eluted with 50% EtOAc/hexanes) to provide 0.078 g of product.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:19][NH2:20])([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:11][CH:12]=2)[CH2:4][CH2:3]1.[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[N:30][CH:31]=[C:32]([CH:36]=2)[C:33](O)=[O:34])[N:24]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]([CH2:19][NH:20][C:33](=[O:34])[C:32]2[CH:36]=[C:28]([C:25]3[N:24]=[C:23]([C:22]([F:38])([F:37])[F:21])[O:27][N:26]=3)[CH:29]=[N:30][CH:31]=2)([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:11][CH:12]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(CN)(c2csc(-c3ccccc3)n2)CC1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: CN1CCC(CNC(=O)c2cncc(-c3noc(C(F)(F)F)n3)c2)(c2csc(-c3ccccc3)n2)CC1
Yield: 8 %

Procedure:
This compound was synthesized from (1-methyl-4-(2-phenylthiazol-4-yl)piperidin-4-yl)methanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (15 mg, yield 8%). 1H NMR (400 MHz, CDCl3) δ 9.43 (d, J=1.5 Hz, 1H), 9.22 (d, J=1.8 Hz, 1H), 8.76 (m, 1H), 7.92-7.90 (m, 3H), 7.42-7.41 (m, 3H), 7.19 (s, 1H), 3.92-3.87 (m, 2H), 3.00 (m, 2H), 2.84 (m, 2H), 2.57 (m, 5H), 2.25 (m, 2H). MS (ESI) m/z: Calculated for C25H23F3N6O2S: 528.55. found: 529.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.[CH:21]1([C:24](O)=[O:25])[CH2:23][CH2:22]1>>[CH3:19][N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:24]([CH:21]4[CH2:23][CH2:22]4)=[O:25])[CH:8]=[N:7][CH:6]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:13][C:14]1=[O:20]
Reactant: O=C(O)C1CC1
Reactant: CN1C(=O)CCc2cc(-c3cncc(CN)c3)ccc21
Product: CN1C(=O)CCc2cc(-c3cncc(CNC(=O)C4CC4)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 37, 6-(5-aminomethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one (example 36) has been reacted with cyclopropanecarboxylic acid to give the title compound as a white solid. MS: 336.3 (M+H+).