Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH3:17])[C:3](=[O:6])[CH:4]=[CH2:5].[CH2:18]([O:20][C:21]([C:23]1[C:24](=[O:34])[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29](Br)=[CH:28][N:27]=2)=[O:22])[CH3:19].CCN(C(C)C)C(C)C>C(C#N)C.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:18]([O:20][C:21]([C:23]1[C:24](=[O:34])[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29](/[CH:5]=[CH:4]/[C:3](=[O:6])[N:2]([CH3:1])[CH2:7][C:8]1[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=1[CH3:17])=[CH:28][N:27]=2)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1cc2cc(Br)cnc2[nH]c1=O
Reactant: C=CC(=O)N(C)Cc1sc2ccccc2c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(/C=C/C(=O)N(C)Cc3sc4ccccc4c3C)cnc2[nH]c1=O
Temperature: 25 °C
Yield: 56.3 %

Procedure:
A suspension of N-methyl-N-(3-methyl-benzo[b]thiophen-2-ylmethyl)acrylamide (500 mg, 2.04 mmol), 6-bromo-2-oxo-1,2-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (665 mg, 2.24 mmol), (o-tol)3P (135 mg, 0.44 mmol) and DIEA (0.4 mL, 2.45 mmol) in EtCN (10 mL) and DMF (10 mL) was deoxygenated with argon for 30 min. Pd(OAc)2 (50 mg, 0.22 mmol) was added, the mixture was deoxygenated with argon for 20 min and then heated to reflux overnight. The mixture was cooled to room temperature and concentrated. The residue was partitioned between CH2Cl2 and H2O. The organic layer was washed with satd NaCl, dried (Na2SO4) and concentrated. Purification by column chromatography (silica gel, 89:10:1 CH2Cl2/MeOH/conc NH4OH) gave the title compound (530 mg, 56%) as a yellow solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.98 (d, J=2.1 Hz, 1H), 8.67 (s, 1H), 8.44-8.42 (m, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.75-7.52 (m, 2H), 7.43-7.31 (m, 3H), 5.14-4.91 (m, 2H), 4.32-4.25 (m, 2H), 3.18-2.96 (m, 3H), 2.43 (s, 3H), 1.33-1.27 (m, 3H); MS (ESI) m/e 462 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[F:6][C:7]([F:25])([F:24])[C:8]([N:10]([CH2:17][P:18]([O:22]Cl)([O:20]Cl)=[O:19])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9].[C:26]1([SH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>CCOCC>[F:6][C:7]([F:25])([F:24])[C:8]([N:10]([CH:17]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[P:18]([OH:22])([O:20][S:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:19])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9]
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Reactant: CCNCC
Reactant: Sc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C(=O)C(F)(F)F)C(N(CC)CC)P(=O)(O)OSc1ccccc1
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A solution of diethylamine (5.0 ml, 0.05 mole) in 50 ml. of ether was added to a solution of ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (8.25 g, 0.025 mole) in 150 ml. of ether at 0° C. The solution was stirred for two hours, then filtered and the filtrate treated with a solution of thiophenol (2.4 ml, 0.025 mole) and triethylamine (3.4 ml, 0.025 mole) in 50 ml. of ether at 0° C. After stirring overnight, the solution was filtered and the filtrate was washed with 0.3% aqueous hydrochloric acid, dried over sodium sulfate and concentrated in vacuo to yield ethyl N-trifluoroacetyl-N-(diethylamino(phenylthio)phosphonomethyl)glycinate (8.7 g) as a yellow oil, ND22 =1.5049.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:4](=[N:5][CH:6]=[N:7][C:8]=2[NH2:11])[N:3]=1.[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:17][CH2:16]1)(=[O:14])[CH3:13]>C1COCC1>[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][N:3]2[C:2]([Br:1])=[N:10][C:9]3[C:4]2=[N:5][CH:6]=[N:7][C:8]=3[NH2:11])[CH2:17][CH2:16]1)(=[O:14])[CH3:13].[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][N:5]2[C:4]3[C:9]([N:10]=[C:2]([Br:1])[N:3]=3)=[C:8]([NH2:11])[N:7]=[CH:6]2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CCC(CCOS(=O)(=O)c2ccc(C)cc2)CC1
Reactant: Nc1ncnc2nc(Br)[nH]c12
Solvent: C1CCOC1
Product: CC(=O)N1CCC(CCn2c(Br)nc3c(N)ncnc32)CC1
Product: CC(=O)N1CCC(CCn2cnc(N)c3nc(Br)nc2-3)CC1
Temperature: 100 °C
Yield: 42 %
Yield: 21 %

Procedure:
To a suspension of 8-bromoadenine (0.042 g, 0.197 mmol) and toluene-4-sulfonic 2-(1-acetyl-piperidin-4-yl)-ethyl ester (0.077 g, 0.237 mmol) in THF was added Barton's base (50 μl, 0.237 mmol) at room temperature. The reaction mixture was heated at 100° C. for 15 min in microwave reactor, at the end of this period reaction was cooled to room temperature and the crude was purified by Isco silica gel flash column using 0-5% gradient of methanol in dichloromethane to give 0.030 g (42%) of 9-[2-(1-acetylpiperidin-4-yl)-ethyl]-8-bromo-9H-purin-6-amine, LC-MS [M+H]+ 366.2 and 0.015 g (21%) of 3-[2-(1-acetylpiperidin-4-yl)-ethyl]-8-bromo-3H-purin-6-amine, LC-MS [M+H]+ 366.2
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([O:12][C:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:30]([O:34][C:35]([NH:37][NH2:38])=[O:36])([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl>[CH2:5]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:1]([N:37]([C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])[NH2:38])=[O:2])[CH2:17][CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(N)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a phosgene solution (20% solution in toluene) at 0° C. was added piperazine-1-carboxylic acid benzyl ester (0.385 mL, 1.996 mmol) and diisopropylethyl amine (0.383 mL, 4.397 mmol) in 5 mL of CH2Cl2 dropwise. The resulting pale yellow mixture was stirred 2 h warming to room temperature under Ar. The phosgene solution was removed by vacuum distillation. 20 mL of anhydrous CH2Cl2 was added. The reaction vessel was cooled to 0° C. and hydrazinecarboxylic acid tert-butyl ester and diisopropylethyl amine (0.383 mL, 4.397 mmol) was added in one portion. The reaction was warmed to room temperature and stirred for 1 h. The reaction was quenched with 10 mL of saturated NaHCO3, diluted with 30 mL of EtOAc, then washed with 2×30 mnL of saturated NH4Cl solution and 30 mL of brine. The organic phase was dried over MgSO4, filtered and concentrated to provide 720 mg of 4-(N-tert-butoxycarbonyl-hydrazinocarbonyl)-piperazine-1-carboxylic acid benzyl ester as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]3[C:33]([N:34]=2)=[CH:32][CH:31]=[C:30]([C:35]2([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:37][CH2:36]2)[N:29]=3)=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[S:27][C:28]4[C:33]([N:34]=3)=[CH:32][CH:31]=[C:30]([C:35]3([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:36][CH2:37]3)[N:29]=4)=[CH:24][CH:25]=2)[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: Fc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2)C[C@H]1C(=O)O
Temperature: 95 °C

Procedure:
A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (162.1 mg, 0.701 mmol) in DMF (4.0 mL) was slowly added to a suspension of sodium hydride (60% w/w in mineral oil) (58 mg, 1.45 mmol) in DMF (4.0 mL), and the resulting mixture was heated at 95° C. for 5 min. 2-(4-Fluorophenyl)-5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine (75.3 mg, 0.217 mmol) was then added, and the resulting solution was heated at 95° C. for 18 h. The reaction mixture was subsequently cooled to 25° C. and diluted with EtOAc (5 mL). Excess NaH was quenched with water (5 mL), and the resulting mixture was diluted with 0.1N aq. HCl (40 mL) and extracted with EtOAc. The combined extracts were sequentially washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to provide (2S,4R)-1-(tert-butoxycarbonyl)-4-(4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenoxy)pyrrolidine-2-carboxylic acid as a yellow solid. MS (ESI) m/z: Calculated: 557.2; Observed: 557.8 (M++1).
Reaction SMILES: [C:1](OC)(=O)[C:2]([CH3:4])=O.[CH3:8][O:9][C:10](=[O:24])[C@H:11]([CH3:23])[NH:12][C:13]1[CH:18]=[CH:17][C:16]2[O:19][CH2:20][CH2:21][O:22][C:15]=2[CH:14]=1>C(O)C(C)C>[CH2:8]([O:9][C:10](=[O:24])[C@H:11]([CH3:23])[NH:12][C:13]1[CH:18]=[CH:17][C:16]2[O:19][CH2:20][CH2:21][O:22][C:15]=2[CH:14]=1)[CH:2]([CH3:4])[CH3:1]
Reactant: COC(=O)[C@H](C)Nc1ccc2c(c1)OCCO2
Reactant: COC(=O)C(C)=O
Solvent: CC(C)CO
Product: CC(C)COC(=O)[C@H](C)Nc1ccc2c(c1)OCCO2

Procedure:
Following reductive amination General Procedure A above and using 1,4-benzodioxa-6-amine (Aldrich) and methyl pyruvate (Aldrich), N-(3,4-ethylenedioxyphenyl)alanine methyl ester was prepared. The methyl ester was then transesterified following General Procedure Q above using isobutanol to provide the title compound. Purification was by preparative plate chromatography.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:8]2[CH:9]=[C:10]([OH:21])[C:11]([C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].O>CCOCC>[C:13]([C:11]1[C:10]([OH:21])=[CH:9][C:8]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[CH:12]=1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)C1=Cc2cc(C(=O)c3ccccc3)c(O)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(O)C1=Cc2cc(C(=O)c3ccccc3)c(O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
14 g of 4-benzoyl-5-hydroxybenzocyclobutene-1-carboxylic acid methyl ester are dissolved in 150 ml of ether and the solution is added to 62 ml of 2N aqueous sodium hydroxide solution and 25 ml of water. This mixture is vigorously stirred for 1 hour at room temperature. The ether phase is separated off and extracted once with 75 ml of water. The aqueous phase is washed once with 75 ml of ether. The combined aqueous phases are rendered acidic with 2N aqueous hydrochloric acid and extracted 3 times with 100 ml of methylene chloride each time. The combined methylene chloride extracts are dried over magnesium sulphate and concentrated by evaporation. Crystallisation of the residue from ether/petroleum ether yields 4-benzoyl-5-hydroxybenzocyclobutene-1-carboxylic acid in the form of yellow crystals having a melting point of 167°-169°.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][N:11]=2)=[CH:6][CH:5]=1.[C:21]([O:25][C:26](=[O:41])[CH:27]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[CH:35][CH:34]=1)[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22].O>C1COCC1.CN(C=O)C>[C:21]([O:25][C:26](=[O:41])[CH:27]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:12]2[N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=3)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:20])=[CH:35][CH:34]=1)[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)c2ccccc12
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(c1ccc(Cn2nc(-c3ccc(Cl)cc3)c3ccccc3c2=O)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 54 mg (2.14 mmol) of sodium hydride were added a little at a time to a solution of 500 mg (1.95 mmol) of 4-(4-chlorophenyl)phthalazin-1(2H)-one [CAS Reg. No. 51334-86-2] in 7.6 ml of THF. After the evolution of gas had ended, 688 mg (1.95 mmol) of tert-butyl[4-(bromomethyl)phenyl](cyclopentyl)acetate, dissolved in 4.5 ml of DMF, were slowly added dropwise at 0° C., and the reaction solution was then stirred at room temperature overnight. Water was then added carefully to the reaction mixture. The reaction mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent was removed to dryness under reduced pressure. The crude product obtained was purified by flash chromatography on silica gel (mobile phase: initially cyclohexane/ethyl acetate 3:1, then ethyl acetate). This gave 630 mg (93% pure, 1.11 mmol, 57% of theory) of a colorless solid.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([O:18][C:19]2[C:27]([CH:28]3[CH2:30][CH2:29]3)=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([F:31])[CH:20]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[CH3:43][S:44]([NH2:47])(=[O:46])=[O:45]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][C:19]2[C:27]([CH:28]3[CH2:30][CH2:29]3)=[CH:26][C:22]([C:23]([NH:47][S:44]([CH3:43])(=[O:46])=[O:45])=[O:24])=[C:21]([F:31])[CH:20]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(C2CC2)c(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.7 %

Procedure:
A mixture of 4-(1-benzhydrylazetidin-3-yloxy)-5-cyclopropyl-2-fluorobenzoic acid (100 mg, 0.24 mmol), EDCI (69 mg, 0.36 mmol), DMAP (44 mg, 0.36 mmol) and methanesulfonamide (34 mg, 0.36 mmol) in DCM (15 mL) was stirred at room temperature for 18 h. The mixture was diluted with DCM (10 mL) and washed with HCl (2 N, 15 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Combiflash (20%-50% CH3CN/H2O in 0.1% NH4HCO3) to give target compound (40 mg, 34%) as a pale yellow solid. LCMS (ESI) Method A: RT=5.29 min, m/z: 495.1 [M+H]+. 1H-NMR (500 MHz, MeOH-d4,): δ 7.54-7.46 (m, 10H), 7.29 (d, J=8.0 Hz, 1H), 6.64 (d, J=12.0 Hz, 1H), 5.83 (s, 1H), 5.29-5.26 (m, 1H), 4.75-4.71 (m, 2H), 4.41-4.38 (m, 2H), 3.37 (s, 3H), 2.22-2.18 (m, 1H), 1.03-0.99 (m, 2H), 0.75-0.42 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[S:11]([Cl:15])(=[O:14])(=[O:13])[NH2:12].C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[ClH:15].[CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([O:9][S:11](=[O:14])(=[O:13])[NH2:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)c1cccc(O)c1
Reactant: NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(C)c1cccc(OS(N)(=O)=O)c1
Product: Cl
Temperature: 15 °C

Procedure:
A solution of 3-dimethylaminophenol (6.90 g, 0.05 mole) in 30 ml of acetonitrile was added in 13 minutes to a chilled (15° C.) stirred solution of 0.10 mole sulfamoyl chloride in 30 ml of acetonitrile. This was followed by the addition of 14 ml (0.10 mole) of triethylamine. The resultant mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (~60 ml) and then extracted twice with sodium bicarbonate solution. The combined aqueous layers were back extracted with 1:1 ethyl acetate/acetonitrile once. The organic layers were combined, dried over sodium sulfate, treated with charcoal, filtered, and evaporated to a black oil weighing 7.57 g.
Reaction SMILES: N[C@H:2]([CH:7]=O)[CH2:3]CSC.[CH3:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[CH3:19])[C:15](=[O:20])[N:14]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH:13]2[CH2:27][CH2:28][O:29]S(C)(=O)=O.O>C(O)CC>[CH3:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[CH3:19])[C:15](=[O:20])[N:14]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH:13]2[CH2:27][CH2:28][O:29][CH2:3][CH2:2][CH3:7]
Reactant: CSCC[C@H](N)C=O
Reactant: Cc1cc2c(cc1C)C(CCOS(C)(=O)=O)N(c1cccnc1)C2=O
Solvent: CCCO
Solvent: O
Product: CCCOCCC1c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Temperature: 90 °C
Yield: 26.4 %

Procedure:
Metal sodium (6.4 mg, 0.28 mmol) was stirred with heating in propanol (2 ml) at 110° C. for 1 hr, and 5,6-dimethyl-2-(3-pyridyl)-3-mesyloxyethylisoindolin-1-one (50 mg, 0.14 mmol) was added thereto, followed by stirring with heating at 90° C. for 3 hrs. To the reaction solution was added water, and extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:ethyl acetate=1:1) to give 12 mg of the title compound.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].[F:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:2][CH2:3][CH2:4][NH:5][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([F:6])=[CH:8][CH:9]=1
Reactant: NCCBr
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NCCBr)c1ccc(F)cc1
Temperature: 5 °C

Procedure:
To a suspension containing 0.23 mol of-bromoethylamine hydrobromide in 200 ml of chloroform, stirred at 5° C., is added dropwise a solution containing 0.21 mol of 4-fluorobenzoyl chloride in 50 ml of chloroform, followed by a solution containing 0.46 mol of triethylamine in 100 ml of chloroform. The mixture is then stirred at room temperature for 1 hour and then at reflux for 4 hours. After cooling and evaporation of the solvent, the residue is taken up in 200 ml of ether. After filtration of the salts and concentration of the solvent, the expected product is obtained by purification of the residue by chromatography on a column of silica, using a dichloromethane/acetone (98/2) mixture as eluent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[N:5]2.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:21]=[C:22]([C@H:26]([NH2:28])[CH3:27])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:28][C@@H:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([N:17]3[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]3)[CH:21]=1)[CH3:27])[CH:6]=[N:5]2
Reactant: C[C@@H](N)c1cccc(N2CCN(C)CC2)c1
Reactant: Clc1cnc2cc(Br)ccc2n1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H](Nc1cnc2cc(Br)ccc2n1)c1cccc(N2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-bromo-2-chloroquinoxaline (0.365 g 1.5 mmol) was dissolved in DMSO (10 mL) at room temperature and (R)-1-[3-(4-Methyl-piperazin-1-yl)-phenyl]-ethylamine (0.33 g, 1.5 mmol) and triethylamine (0.626 mL, 4.50 mmol) were added to the solution. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, water (100 mL) was added and the product was extracted with ethyl acetate (3×50 mL). The organic layer was washed with water (10 mL) followed by brine solution (10 mL) and dried over Na2SO4. The organic layer was concentrated in vacuo to afford the crude product.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl-].[NH4+:5].O=[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1.CO>N>[CH2:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][C:7]([NH2:5])([C:1]#[N:2])[CH2:8][CH2:9]1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [NH4+]
Reactant: [C-]#N
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: N#CC1(N)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
A solution of sodium cyanide (1052 mg, 21.5 mmol), ammonium chloride (1265 mg, 23.65 mmol), and benzyl 4-oxo-1-piperidine-carboxylate (5.0 gm, 21.5 mmol), was prepared in 5 M ammonia in methanol (8.6 mL, 43 mmol). The solution was brought to reflux for 4 h and then allowed to cool to room temperature. The solution was then filtered and washed with methanol (100 mL) and the filtrate was concentrated in vacuo. The resulting oil was taken up in MTBE (250 mL) and filtered again. The filter cake was washed with MTBE (100 mL) and the filtrate was concentrated in vacuo to yield 4-amino-4-cyano-piperidine-1-carboxylic acid benzyl ester as a clear oil (3.5 g) which was used without further purification.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:28]=[CH:27][N:14]3[C:15](=[O:26])[C:16]([O:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:17][N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.CO.O>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:28]=[CH:27][N:14]3[C:15](=[O:26])[C:16]([O:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)COc1cnc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)c1csc(CCc2ccn3c(=O)c(OCC(=O)O)cnc3c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The ethyl 2-{8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido[1,2-a]-pyrimidin-3-yloxy}acetate (41 mg) obtained in (A) was dissolved in tetrahydrofuran (1 ml) and methanol (300 ml), added with a solution of lithium hydroxide (5 mg) dissolved in water (300 ml), and then the mixture was stirred at room temperature for 1 hour, and the solvent was concentrated under reduced pressure. The residue was distributed between ether and water, and the aqueous layer was separated and made pH 3 with hydrochloric acid, and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate. After the solvent was evaporated, the residue was purified by silica gel column chromatography to obtain the title compound (quantitative).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]=1[C:19]#[N:20].[C:21]([C:27]([O:29][CH3:30])=[O:28])#[C:22][C:23]([O:25][CH3:26])=[O:24]>>[NH2:20][C:19]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([C:27]([O:29][CH3:30])=[O:28])[N:1]=[C:2]2[N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:5]=[C:4]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:3]=12
Reactant: N#Cc1c(-c2ccccc2)nn(-c2ccccc2)c1N
Reactant: COC(=O)C#CC(=O)OC
Product: COC(=O)c1nc2c(c(-c3ccccc3)nn2-c2ccccc2)c(N)c1C(=O)OC

Procedure:
Using 2.60 g (10 mmol) of 5-amino-1,3-diphenylpyrazole-4-carbonitrile [see J. Org. Chem., 29, 1915 (1964)] and 1.42 g (10 mmol) of dimethyl acetylenedicarboxylate, the entitled product having a melting point of 277° to 279° C. was obtained in the same manner as in Example 2-(2).
Reaction SMILES: [CH3:1][Li].[CH2:3]([O:7][C:8]1[CH:19]=[N:18][CH:17]=[CH:16][C:9]=1[C:10](N(OC)C)=[O:11])[CH:4]([CH3:6])[CH3:5].O>C1COCC1.Cl>[CH2:3]([O:7][C:8]1[CH:19]=[N:18][CH:17]=[CH:16][C:9]=1[C:10](=[O:11])[CH3:1])[CH:4]([CH3:5])[CH3:6]
Reactant: CON(C)C(=O)c1ccncc1OCC(C)C
Reactant: [Li]C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccncc1OCC(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl lithium (4.6 mL, 7.4 mmol, 1.6M in Et2O, Aldrich) was added dropwise to a solution of 3-isobutoxy-N-methoxy-N-methylisonicotinamide (0.88 g, 3.7 mmol) in 15 mL of THF at 0° C. The reaction mixture was allowed to stir at 0° C. for an additional 1 h. To the resulting mixture were added 1 mL of water and 2 drops of conc HCl. The layers were separated and the aqueous layer was washed twice with 20 mL portions of Et2O. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The product was purified by SiO2 flash chromatography (50:50 hexanes/ethyl acetate) to 450 mg (63%) of the title compound. 1H-NMR (400 MHz, d6-DMSO): δ 8.54 (s, 1H), 8.27 (d, 1H), 7.41 (d, 1H), 4.01 (d, 2H), 2.55 (s, 3H), 2.06 (m, 1H), 0.99 (d, 6H). MS (EI) for C12H18N2O2: 194 (MH+).