Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)([CH3:4])([CH3:3])[CH3:2].[OH:6][C:7]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].FC(F)(F)C(O)=O.S(=O)(=O)(O)O>CCCCCC>[C:1]([C:13]1[C:14]([OH:16])=[CH:15][C:7]([OH:6])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc(O)cc1O
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: CC(C)(C)c1cc(C(=O)O)c(O)cc1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.5 %

Procedure:
To a tert-butanol (14.3 mL, 11.12 g, 150 mmol) suspension of 2,4-dihydroxy-benzoic acid (F71-01: 2312 mg, 15.0 mmol), trifluoroacetic acid (8.0 mL, 11.84 g, 103.8 mmol) and sulfuric acid (0.43 mL, 0.79 g, 8.0 mmol) were added in this order under argon atmosphere while stirring at room temperature. The reacting solution was stirred at room temperature for 10 minutes and then at a bath temperature of 75° C. for 6 hours. Additional trifluoroacetic acid (8.0 mL, 11.84 g, 103.8 mmol) was added, and the reaction mixture was stirred at a bath temperature of 80° C. for further 2.5 hours. After completing the reaction, the reaction mixture was added to ice-water (160 mL) and stirred with the addition of hexane (20 mL). The deposited solids were collected by filtration, washed with water and hexane to obtain the title compound (F71-02: pale pink solid, 2.13 g, 68%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12][CH2:13][Cl:14])[C:4]=2[N:5]=[CH:6][N:7]=1>CCOC(C)=O.[Pd]>[Cl:14][CH2:13][CH2:12][CH:11]([N:8]1[C:4]2[N:5]=[CH:6][N:7]=[CH:2][C:3]=2[CH:10]=[CH:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCCC(c1ccccc1)n1ccc2c(Cl)ncnc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: ClCCC(c1ccccc1)n1ccc2cncnc21
Reaction time: 4 h
Yield: 81.7 %

Procedure:
A suspension of 4-chloro-7-(3-chloro-1-phenyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine (150 mg, 0.5 mmol) and Pd/C (10%, 50% water, 150 mg) in EtOAc (50 mL) was stirred under H2 atmosphere (balloon pressure) for 4 h. The reaction mixture was filtered through a celite pad, and the filter cake was washed with EtOAc (20 mL). The filtrate was concentrated and purified via flash chromatography (hexane/EtOAc), affording 7-(3-Chloro-1-phenyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine (111 mg, 83% yield).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:16]([C:26](=[O:41])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][C:35]3=[O:40])=[CH:30][CH:29]=2)[CH2:15]1.[N+:42]([C:45]1[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][CH:46]=1)([O-:44])=[O:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:22]([O:21][C:19]([N:17]1[CH2:18][C@@H:14]([O:13][C:49](=[O:50])[C:48]2[CH:47]=[CH:46][C:45]([N+:42]([O-:44])=[O:43])=[CH:53][CH:52]=2)[CH2:15][C@@H:16]1[C:26](=[O:41])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][C:35]2=[O:40])=[CH:30][CH:29]=1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C[C@@H]1C(=O)Nc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 211.1 %

Procedure:
8.1 5.51 ml (35 mmol) of diethyl azodicarboxylate (DEAD) are added dropwise at 0° C. under nitrogen to a solution of 7.0 g (7.26 mmol) of tert-butyl (2R,4R)-4-hydroxy-2-(4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate, 5.77 g (34.5 mmol) of p-nitrobenzoic acid and 9.18 g (35 mmol) of triphenylphosphine in 350 ml of tetrahydrofuran. The reaction mixture is subsequently left to stir at room temperature for 12 hours and evaporated to dryness-under reduced pressure, 20 ml of methylene chloride are added to the residue, and the methylene chloride solution is washed successively with 10 ml of saturated sodium chloride solution and 10 ml of water and dried over sodium sulfate. After the drying agent has been filtered off and the solvent has been stripped off in a rotary evaporator, the residue is triturated with 30 ml of diethyl ether, giving 8.5 g (88.8%) of tert-butyl-(2R,4S)-4-(4-nitrobenzoyloxy)-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate as slightly yellow crystals, ESI 555. 8.2 Analogously to Example 7, reaction of tert-butyl (2R,4S)-4-(4-nitro-benzoyloxy)-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate gives the compound (3S,5R)-1-(4-chlorophenylcarbamoyl)-5-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidin-3-yl 4-nitrobenzoate as yellowish crystals, ESI 608. 8.3 0.075 ml of 1N sodium hydroxide solution is added with ice cooling to the solution of 50 mg (0.082 mmol) of (3S,5R)-1-(4-chlorophenyl-carbamoyl)-5-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidin-3-yl 4-nitrobenzoate in 2 ml of methanol, and the reaction mixture is stirred for 15 minutes. The precipitate is filtered off and washed with 2 ml of methanol and dried, giving 35 mg (93%) of 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxamide as colourless crystals, ESI 459, m.p. 243° (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:6]([C:15]2[CH:16]=[C:17]([O:23][CH3:24])[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)=[N:7][C:8](S(C)(=O)=O)=[N:9][CH:10]=1.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32]>>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:6]([C:15]2[CH:16]=[C:17]([O:23][CH3:24])[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)=[N:7][C:8]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[N:9][CH:10]=1
Reactant: CS(N)(=O)=O
Reactant: COc1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(C)c1=O
Product: COc1cc(-c2nc(NS(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(C)c1=O

Procedure:
The title compound of Example 150 was treated with MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 11.37 (s, 1H), 8.34 (s, 1H), 8.26 (s, 1H), 7.58 (s, 1H), 7.54-7.50 (m, 1H), 7.28-7.23 (m, 1H), 7.10-7.06 (m, 1H), 3.74 (s, 3H), 3.52 (s, 3H), 3.39 (s, 3H). LCMS: 439.0 (M+1)+
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][C:24]=4[F:25])[NH:21][CH:20]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[O:30]1[CH2:35][CH2:34][CH2:33][CH:32]([CH:36]=O)[CH2:31]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][C:24]=4[F:25])[N:21]([CH2:36][CH:32]4[CH2:33][CH2:34][CH2:35][O:30][CH2:31]4)[CH:20]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=CC1CCCOC1
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)c(F)cc2N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)c(F)cc2N1CC1CCCOC1
Reaction time: 0.33 h
Yield: 50.5 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoroindolin-5-yl)cyclopropane-carboxamide (150 nag, 0.38 mmol) in anhydrous dichloromethane (2.3 mL) at room temperature under N2 was added tetrahydropyran-3-carbaldehyde (54 mg, 0.47 mmol). After 20 min of stirring, NaBH(OAc)3 (110 mg, 0.51 mmol) was added in one portion at room temperature. The reaction mixture was stirred for 6 h at room temperature before being purified by column chromatography on silica gel (5-20% ethyl acetate/hexanes) to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoro-1-((tetrahydro-2H-pyran-3-yl)methyl)indolin-5-yl)cyclopropanecarboxamide (95 mg, 50%). CDCl3 was added to the indoline and the solution was allowed to stir overnight at ambient temperature. The solution was concentrated to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoro-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-indol-5-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 493.0.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1CCCCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1CCCCN1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
A solution of tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}butyl)piperazine-1-carboxylate (0.0945 g, 0.177 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[4-(piperazin-1-yl)butyl]benzofuran-3(2H)-one (0.0524 g, 68%).
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH:26]([CH3:28])[CH3:27]>C(#N)C>[F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:14][CH2:13]1
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(methylsulfonyl)-phenyl]-piperidine (0.02 g, 0.078 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol), 1-bromo-2-methylpropane (0.009 ml, 0.082 mmol). MS m/z (relative intensity, 70 eV) 313 (M+, 1), 271 (15), 270 (bp), 147 (8) 133 (8).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[C:13](=[O:20])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:21]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:21][C:12]1[C:13](=[O:20])[N:14]([CH3:19])[C:15](=[O:18])[N:16]([CH3:17])[C:11]=1[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(-c2cc(=O)n(C)c(=O)n2C)cc1OC
Solvent: CC(=O)O
Product: COc1ccc(-c2c(Cl)c(=O)n(C)c(=O)n2C)cc1OC
Temperature: 100 °C
Reaction time: 5 h
Yield: 79.6 %

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (2.0 g) in acetic acid (100 ml) was added N-chlorosuccinimide (0.97 g), and the mixture was stirred at 100° C. for 5 hours. After cooling, the reaction mixture was evaporated, and dissolved in chloroform, The solution was washed with aqueous sodium bicarbonate, and dried over magnesium sulfate. After removal of the solvent, resulting mass was crystallized from ethanol, to give 5-chloro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (1.79 g).
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH2:11][O:12]C(=O)C)[CH2:6][O:7]C(=O)C)(=O)C.[OH-].[Na+].[ClH:40]>CO>[ClH:40].[NH2:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH2:6][OH:7])[CH2:11][OH:12]
Reactant: CCCCCCCCCCCCCCCCCCCCCCC(COC(C)=O)(COC(C)=O)NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCCCCCC(N)(CO)CO

Procedure:
2-Acetamido-1,3-diacetoxy-2-docosylpropane (1.5 g) was dissolved in 40 ml of methanol and 9.6 ml of a 1N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 6 hours. The mixture was neutralized with a 1N aqueous hydrochloric acid solution and concentrated under reduced pressure. The concentrate was washed with water and ethyl acetate:hexane=1:1 in order to give 846 mg of 2-amino-2-docosyl-1,3-propanediol hydrochloride.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([F:15])[S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:24])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]([O:4][CH2:5][CH:6]=[C:7]([F:15])[S:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:24])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCSC(F)=CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCS(=O)C(F)=CCOC(C)=O

Procedure:
To a solution of 3-fluoro-3-hexylthio-2-propenyl acetate (0.36 g, 1.5 mmol) in 5 ml of methylene chloride is added m-chloroperbenzoic acid (0.34 g, 1.7 mmol) at 5°. After the reaction is complete, the reaction mixture is diluted with methylene chloride, poured into aqueous saturated Na2CO3, extracted with methylene chloride (2X), washed with brine, dried and stripped of solvent to give 3-fluoro-3-hexylsulfinyl2-propenyl acetate. The product is purified by prep. TLC on silica gel eluting with 40% ethylacetate/hexane. The upper band is collected to give (E)-3-fluoro-3-hexylsulfinyl-2propenyl acetate (cpd. 1, Table A).
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[CH:22]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:29][C:20]2[O:8][CH2:9][C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=3[N:19]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCCCCC1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Product: O=[N+]([O-])c1ccc2c(c1)COC(NC1CCCCCC1)=N2
Yield: 99.1 %

Procedure:
Prepared from tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (5.0 g, 15 mmol) and cycloheptylamine (1.8 g, 16 mmol) according to the procedure described for Example 1. Obtained the title compound as a yellow foam (4.3 g, 100%), MS (ISP) m/e=288.3 [(M−H)+].
Reaction SMILES: C([NH:8][C@H:9]([C:11](O)=[O:12])[CH3:10])(OC(C)(C)C)=O.[ClH:14].[NH2:15][N:16]1[C:22](=[O:23])[CH:21]([CH3:24])[C:20]2[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=2[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]1=2>>[ClH:14].[NH2:8][C@H:9]([C:11]([NH:15][N:16]1[C:22](=[O:23])[CH:21]([CH3:24])[C:20]2[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=2[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]1=2)=[O:12])[CH3:10]
Reactant: CC1C(=O)N(N)c2ccccc2-c2ccccc21
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: CC1C(=O)N(NC(=O)[C@H](C)N)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using N-Boc-L-alanine (Aldrich) and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 1), the title compound was prepared.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:26][CH:27]1[NH:31][C:30](=[O:32])[CH2:29][CH2:28]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[CH:7][C:2]([N:31]5[CH:27]([CH3:26])[CH2:28][CH2:29][C:30]5=[O:32])=[N:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CC1CCC(=O)N1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(Br)cn2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(N3C(=O)CCC3C)cn2)CC1
Yield: 26.8 %

Procedure:
Using (5-bromopyrazin-2-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 243 and 5-methylpyrrolidin-2-one (44 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (42 mg) was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:16]=[C:15]([CH:17]=[N:18]C(OC)=O)[S:14][C:9]=2[N:10]([CH2:12][CH3:13])[CH:11]=1)=[O:5])C.[OH-:24].[Na+].Cl>O>[CH2:12]([N:10]1[CH:11]=[C:6]([C:4]([OH:3])=[O:5])[C:7](=[O:23])[C:8]2[CH:16]=[C:15]([CH:17]=[N:18][O:24][CH2:6][C:4]([OH:5])=[O:3])[S:14][C:9]1=2)[CH3:13]
Reactant: [OH-]
Reactant: CCOC(=O)c1cn(CC)c2sc(C=NC(=O)OC)cc2c1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(C=NOCC(=O)O)sc21
Reaction time: 3 h
Yield: 40 %

Procedure:
To the solution obtained in Example V containing 4,7-dihydro-7-ethyl-2-carbomethoxyiminomethyl-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester was added 0.15 g (3.7 mmols) of sodium hydroxide in 5 ml of water. The medium was maintained under stirring for 3 hours at room-temperature. The precipitate formed was filtered out, washed with ethanol and then with ethyl ether. The product so obtained was then taken up in 200 ml of water and the solution was acidified with concentrated hydrochloric acid. The precipitate so formed was filtered out, washed with water and then with ethanol. After drying, 4,7-dihydro-7-ethyl-2-carboxymethoxyiminomethyl-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid was obtained in a yield of 40%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][NH:16][C:15](=[N:19]N)[CH:14]=3)=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1>C(N)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:8][C:4]4[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=4)[CH:14]=3)=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN=c1cc(-c2c[nH]nc2-c2cccc(Cl)c2)cc[nH]1
Solvent: NCc1ccccc1
Product: Clc1cccc(-c2n[nH]cc2-c2ccnc(NCc3ccccc3)c2)c1
Yield: 121.9 %

Procedure:
A solution of the bromopyridine compound prepared in step 3 of Example A-219 (150 mg, 0.5 mmol) in benzylamine (5 ml) was heated at 175° C. for six hours. After cooling, excess benzylamine was removed by high vacuum distillation and ethyl acetate added to the residue. After washing the organic phase with water and drying over magnesium sulfate, the solvent was removed in vacuo and the residue chromatographed on silica gel using mixtures of ethyl acetate and toluene to give 4-(3-(3-chlorophenyl)-1H-pyrazol-4-yl]-N-(phenylmethyl)-2-pyridinamine (110 mg, 61%) as a solid, m.p. 179-180° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[C:23]([O:35][CH3:36])=[CH:24][C:25]2[N:31]([CH3:32])[C:30](=[O:33])[O:29][CH2:28][CH2:27][C:26]=2[CH:34]=1.C(O)(C)C>Cl.O1CCOCC1>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:21][C:22]2[C:23]([O:35][CH3:36])=[CH:24][C:25]3[N:31]([CH3:32])[C:30](=[O:33])[O:29][CH2:28][CH2:27][C:26]=3[CH:34]=2)=[N:3][CH:4]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCOC(=O)N2C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CCOC(=O)N2C
Yield: 37.7 %

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (60.0 mg, 0.177 mmol), 2-Amino-3-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (39.3 mg, 0.177 mmol) and 5 drops of HCl/dioxane were stirred in isopropyl alcohol (2.00 mL, 26.1 mmol) at 120° C. in a sealed tube. After 24 hours the reaction mixture was concentrated and then extracted with DCM (20 mL) and washed with sat. NaHCO3 (20 mL) followed by water. The organic layer was dried over MgSO4, filtered and concentrated. The residue was chromatographed on ISCO flash system (0-10% DCM:MeOH) to obtain one peak by LC/MS. When analyzed by HPLC, two peaks were shown. The fractions were concentrated and the residue was chromatographed on ISCO flash system (0-100% Hex:EtOAc) to obtain the product and the decarboxylated side product. The product was isolated as a pale blue solid (35.0 mg, 37.7%). mp: 160-162° C., MS (ESI+): 525 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.11 (s, 1H), 7.95 (s, 1H), 7.68 (s, 1H), 7.15 (d, 1H), 7.01 (s, 1H), 6.85 (d, 1H), 4.36 (m, 2H), 3.88 (s, 3H), 3.30 (s, 3H), 2.90 (br s, 5H), 1.99 (br s, 3H), 1.7 (d, 2H), 1.5-1.1 (m, 5H).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:8]([OH:12])[CH2:9][CH:10]=[CH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C=O)C>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@@H:8]([O:12][CH2:23][CH:22]=[CH2:21])[CH2:9][CH:10]=[CH2:11])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C=CCBr
Reactant: C=CC[C@H](O)C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@@H](CC=C)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
(2S)-1,1-diphenyl-pent-4-en-2-ol 25a (0.37 g, 1.57 mmol) was dissolved in dry DMF (2 ml) and was added to a suspension of NaH (60% in mineral oil, 0.13 g, 3.14 mmol) in dry DMF (20 ml) at 0° C. The reaction mixture was allowed to reach room temperature over a period of 1 h. The reaction mixture was cooled again to 0° C. employing an ice-bath, and neat allyl bromide (0.57 g, 4.71 mmol) was added via syringe. The reaction mixture was removed from the ice-bath and stirred overnight at room temperature. The reaction was cooled again to 0° C. and quenched by slowly adding H2O (20 ml). The resulting mixture was extracted with Et2O (3×50 ml), and the combined organic phases were washed in turn with H2O, brine, and then dried over anhydrous Na2SO4. Filtration followed by concentration gave crude product as light orange oil. Purification by chromatography (hexane/ethyl ether=10:1) gave 0.37 g (2S)-1,1-Diphenyl-2-Allyloxy-Pent-4-en (85%, [α]D=(+)19.7, c=1, MeOH).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)(=[O:3])[CH3:2].[CH3:20][N:21]([CH:23](OC)OC)[CH3:22]>CN(C=O)C>[CH3:20][N:21]([CH3:23])/[CH:22]=[CH:2]/[C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH2:5]1)=[O:3]
Reactant: CC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C/C(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Yield: 110.1 %

Procedure:
A 250-mL round-bottom flask was charged with a solution of benzyl 3-acetylpiperidine-1-carboxylate (15 g, 54.53 mmol, 1.00 equiv, 95%) in DMF (100 mL). To the mixture was added DMF-DMA (17 g, 141.43 mmol, 2.50 equiv, 99%). The resulting solution was allowed to reflux for about 6 hours. The mixture was then cooled down to room temperature and concentrated on a rotary evaporator affording crude (E)-benzyl 3-(3-(dimethylamino)acryloyl)piperidine-1-carboxylate as brown oil (19 g).