Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:2]=[C:3]([NH2:22])[C:4]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:14][C@@H:13]4[CH2:15][O:16][P:17]([OH:20])([O:19][C@H:12]4[C@H:11]3[OH:21])=[O:18])[C:5]=2[N:6]=1.C(O)C(N)(CO)C[OH:26].CN1C(=O)N(C)C(=O)C2NC=NC1=2.CN1C(=O)N(C)C(=O)C2NC=NC1=2.C(N)CN.SCCO.C>>[CH:1]1[N:2]=[C:3]([NH2:22])[C:4]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:14][C@H:13]([CH2:15][O:16][P:17]([OH:20])([OH:19])=[O:18])[C@@H:12]([OH:26])[C@H:11]3[OH:21])[C:5]=2[N:6]=1
Reactant: NC(CO)(CO)CO
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@@H]2COP(=O)(O)O[C@H]2[C@H]1O
Agent: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: OCCS
Solvent: NCCN
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Reaction time: 2.5 h

Procedure:
Samples of cAMP standards (0-10 pmol) are added to each test tube containing the incubation buffer (trizma base 0.1 M; aminophylline 8.0 mM; 2-mercaptoethanol 6.0 mM, pH 7.4) and [3H]-cAMP in a total volume of 0.5 mL. The binding protein, previously prepared from beef adrenals, is added to the samples previously incubated at 4° C. for 150 min. and, after the addition of charcoal are centrifuged at 2,000 g for 10 min. The clear supernatant (0.2 mL) is mixed with 4 mL of atomlight in a LS-1800 Beckman scintillation counter.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][CH2:16][O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>C(Cl)Cl>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]#[C:15][CH2:16][O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#CCOS(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)OCC#CC1CCNCC1
Reaction time: 0.5 h

Procedure:
A solution of 2.96 g (9.4 mmol) of 4-(3-Methanesulfonyloxy-prop-1-ynyl)-piperidine-1-carboxylic acid tert-butyl ester in 50 ml CH2Cl2 was treated at 0° C. with 25.2 ml of TFA (for 20 min). After 30 min at this temperature, the reaction was evaporated, evaporated again with toluene (4 times) and dried to give 3.6 g (quantitative) of methanesulfonic acid 3-piperidin-4-yl-prop-2-ynyl ester; compound with trifluoro-acetic acid, MS: 218 (MH+).
Reaction SMILES: [C:1]([NH:5][C:6]1[O:7][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:15]=[C:14]3B2OC(C)(C)C(C)(C)O2)=[N:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:40]1[N:45]=[C:44]([CH:46]2[CH2:48][CH2:47]2)[C:43]([F:49])=[CH:42][N:41]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[C:1]([NH:5][C:6]1[O:7][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:15]=[C:14]3[C:40]2[N:45]=[C:44]([CH:46]3[CH2:48][CH2:47]3)[C:43]([F:49])=[CH:42][N:41]=2)=[N:9][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)(C)C)o4)ccc32)cc1
Reactant: Fc1cnc(Cl)nc1C1CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(C4CC4)n3)c3cc(-c4nnc(NC(C)(C)C)o4)ccc32)cc1
Temperature: 130 °C
Yield: 76.4 %

Procedure:
To a 5 mL glass microwave tube containing N-tert-butyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (166 mg, 0.309 mmol) was added 2-chloro-4-cyclopropyl-5-fluoropyrimidine (69.4 mg, 0.402 mmol), potassium phosphate (197 mg, 0.928 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (8.9 mg, 0.019 mmol), and Pd2(dba)3 (8.5 mg, 9.28 μmol). The tube was purged with argon, the solids were treated with dioxane (3 mL) and Water (0.3 mL), the tube was sealed, and the contents were heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 130° C. for 30 min. The mixture was treated with H2O and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (eluting with 5-60% EtOAc in Hex) affording N-tert-butyl-5-(3-(4-cyclopropyl-5-fluoropyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (129 mg, 76%) as a light yellow viscous oil. MS (ESI, pos. ion) m/z: 547.1 (M+1).
Reaction SMILES: C(NC(=O)[O-])C.C[O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]([CH3:21])[CH:14]3[CH2:18][NH:17][CH2:16][CH:15]3[C:19]=2[CH:20]=1>Cl.O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]([CH3:21])[CH:14]3[CH2:18][NH:17][CH2:16][CH:15]3[C:19]=2[CH:20]=1
Reactant: COc1ccc2c(c1)C1CNCC1C2C
Agent: CCNC(=O)[O-]
Agent: Cl
Solvent: O
Product: CC1c2ccc(O)cc2C2CNCC12
Temperature: 120 °C
Reaction time: 20 h

Procedure:
N-Ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (12 mg, 0.045 mmol) was dissolved in concentrated HCl (2 mL) and stirred for 20 hours at 120° C. The reaction solution was cooled to room temperature, diluted with H2O (2 mL), and washed with EtOAc (5 mL). The aqueous solution was concentrated on a speed vac to afford the title compound as the hydrochloride salt. MS calculated for C12H15NO+H: 190, observed: 190.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][C:18]1[CH:28]=[C:21]2[C:22]([CH:26]=O)=[CH:23][CH:24]=[CH:25][N:20]2[N:19]=1.O>O1CCCC1>[CH3:17][C:18]1[CH:28]=[C:21]2[C:22](/[CH:26]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:23][CH:24]=[CH:25][N:20]2[N:19]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1cc2c(C=O)cccn2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cccn2nc(C)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (2.70 g, 61.8 mmol) in tetrahydrofuran (42 mL) was added a solution of ethyl diethylphosphonoacetate (13.8 g, 61.8 mmol) in tetrahydrofuran (20 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 2-methylpyrazolo[1,5-a]pyridine-4-carbaldehyde (9.00 g, 56.2 mmol) in tetrahydrofuran (50 mL), and the mixture was warmed to room temperature over 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/1) to give the title compound (11.8 g, yield 91%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][S:7][C:6]=2[CH:17]=1.[C:18]([O:22][C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][CH2:36]O)[N:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:18]([O:22][C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][CH2:36][O:1][C:2]3[CH:3]=[CH:4][C:5]4[C:9]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][S:7][C:6]=4[CH:17]=3)[N:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCO)nc21
Reactant: CCOC(=O)CCc1csc2cc(O)ccc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1csc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 0.8 %

Procedure:
Ethyl 3-(6-hydroxybenzo[b]thiophen-3-yl)propanoate (207 mg, 82.6 mmol), 7-(2-hydroxy-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (276 mg, 99.2 mmol) and triphenylphosphine (435 mg, 165 mmol) were dissolved in THF (15 ml) and stirred for 15 minutes under argon atmosphere at 0° C. Then, diisopropyl azodicarboxylate (0.325 ml, 165 mmol) was added to the mixture. After stirring overnight under argon, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried with sodium sulfate, filtered and evaporated under vacuum. The crude product was chromatographied over silica gel to yield 338 mg (80%) of 7-{2-[3-(2-Ethoxycarbonyl-ethyl)-benzo[b]thiophen-6-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester. NMR 1H Cl3CD δ: 7.59 (d, 1H, J=8.8 Hz), 7.33 (m, 2H), 7.00 (dd, 1H, J=2.3, 8.8 Hz), 6.93 (m, 2H), 4.42 (t, 2H, J=6.7 Hz), 4.14 (m, 2H), 3.76 (m, 2H), 3.22 (m, 2H), 3.12 (m, 2H), 2.73 (m, 4H), 1.92 (m, 2H) 1.51 (s, 9H), 1.26 (m, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH:25]4[CH2:27][CH2:26]4)(=[O:24])=[O:23])[CH:19]=3)[CH2:15]2)[CH2:11][O:10][C@@H:9]1[C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=1[F:36])(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[F:36][C:29]1[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:28]=1[C@@H:9]1[C@@H:8]([NH2:7])[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH:25]4[CH2:27][CH2:26]4)(=[O:24])=[O:23])[CH:19]=3)[CH2:15]2)[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(S(=O)(=O)C4CC4)nc3C2)CO[C@@H]1c1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@@H](N2Cc3cn(S(=O)(=O)C4CC4)nc3C2)CO[C@@H]1c1cc(F)c(F)cc1F
Reaction time: 1.5 h

Procedure:
A solution of the product obtained in Step A above (74 mg, 0.14 mmol) in dichloromethane (6 mL) was treated with trifluoroacetic acid (3 mL) at room temperature. After 1.5 h, the reaction mixture was concentrated to give the title compound. 1H NMR (500 MHz, CD3OD): δ 1.18-1.24 (m, 2H); 1.35-1.40 (m, 2H); 2.12 (q, 1H, J=12 Hz); 2.79-2.86 (m, 1H); 2.92-2.98 (m, 1H); 3.64 (td, 1H, J=12, 6 Hz); 3.79 (t, 1H, J=12 Hz); 3.90-3.98 (m, 1H); 4.48-4.54 (m, 1H); 4.57-4.72 (m, 5H); 7.25-7.32 (m, 1H); 7.46-7.53 (m, 1H); 8.08 (s, 1H). LC-MS: 443.04 (M+1).
Reaction SMILES: [N+](C1C=CC(C(OCCC(C)(C)CC=C)=O)=CC=1)([O-])=O.C(OCCC(OC1C=CC([N+]([O-])=O)=CC=1)=O)C=C.[N+](C1C=CC(C(OCCC(C)(C)CC(O[N+]([O-])=O)CO[N+]([O-])=O)=O)=CC=1)([O-])=O.[N+:67]([O:70][CH:71]([CH2:88][O:89][N+:90]([O-:92])=[O:91])[CH2:72][O:73][CH2:74][CH2:75][C:76]([O:78]C1C=CC([N+]([O-])=O)=CC=1)=[O:77])([O-:69])=[O:68]>>[N+:67]([O:70][CH:71]([CH2:88][O:89][N+:90]([O-:92])=[O:91])[CH2:72][O:73][CH2:74][CH2:75][C:76]([OH:78])=[O:77])([O-:69])=[O:68]
Reactant: O=C(CCOCC(CO[N+](=O)[O-])O[N+](=O)[O-])Oc1ccc([N+](=O)[O-])cc1
Agent: C=CCC(C)(C)CCOC(=O)c1ccc([N+](=O)[O-])cc1
Agent: C=CCOCCC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CC(C)(CCOC(=O)c1ccc([N+](=O)[O-])cc1)CC(CO[N+](=O)[O-])O[N+](=O)[O-]
Product: O=C(O)CCOCC(CO[N+](=O)[O-])O[N+](=O)[O-]

Procedure:
The title compound was prepared by following the procedure described in EXAMPLE 8 Step A,B except that the reagent 3,3-dimethylhex-5-enyl 4-nitrobenzoate was replaced by 4-nitrophenyl 3-(allyloxy)propanoate and the reagent 3,3-dimethyl-5,6-bis(nitrooxy)hexyl 4-nitrobenzoate was replaced by 4-nitrophenyl 3-(2,3-bis(nitrooxy)propoxy)propanoate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][OH:21])[CH:18]=3)[CH:13]=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1.O>ClCCl>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][O:21][C:23](=[O:25])[CH3:24])[CH:18]=3)[CH:13]=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1ccc(-n2ccc3ccc(CO)cc32)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-n2ccc3ccc(COC(C)=O)cc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.1 %

Procedure:
To a solution of 4-(6-formylindol-1-yl)benzoic acid ethyl ester in a mixed solvent of tetrahydrofuran (3 mL) and methanol (10 mL) was added sodium borohydride (0.075 g) at 0° C., and this mixture was stirred at room temperature for 0.5 hours. This reaction mixture was poured into a saturated aqueous ammonium chloride solution and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-(6-hydroxymethyl-indol-1-yl)benzoic acid ethyl ester (0.38 g). To a solution of 4-(6-hydroxymethyl-indol-1-yl)benzoic acid ethyl ester (0.09 g) in dichloromethane (1 mL) were added acetic anhydride (0.093 g) and pyridine (0.024 g), and this mixture was stirred at room temperature for 2 days. This mixture was poured into water and the resulting mixture was extracted with ethyl acetate. This organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.068 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[NH:16][C:15]4[CH2:18][CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][C:14]=4[C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[K+].I[CH3:32]>COCCOC>[CH3:32][N:16]1[C:17]2[C:9]([S:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19][CH2:18][C:15]1=2
Reactant: Cc1ccc(Sc2cccc3c4c([nH]c23)CCN(C(=O)OC(C)(C)C)C4)cc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1ccc(Sc2cccc3c4c(n(C)c23)CCN(C(=O)OC(C)(C)C)C4)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 95 %

Procedure:
Tert-butyl 6-[(4-methylphenyl)sulfanyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (22.6 mmol), potassium hydroxide (113 mmol), and iodomethane (226 mmol) were combined with dry DME (110 mL) and stirred at room temperature for 10 hours. The reaction was then filtered and the residue washed with chloroform. The filtrate was concentrated under reduced pressure to give tert-butyl 5-methyl-6-[(4-methylphenyl)sulfanyl]-1,3,4,5,-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (95%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([O:22][CH3:21])=[N:24][CH:25]=3)=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: COc1ccc(C(=O)O)cn1
Product: COc1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cn1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-methoxy-nicotinamide was prepared starting from intermediate D and 6-methoxy-nicotinic acid. MS calcd. for C23H18ClN3O3 [(M+H)+] 419.1, obsd. 420 [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22]
Reactant: C#CCCn1ccc2ccccc2c1=O
Reactant: Brc1ccccn1
Product: O=c1c2ccccc2ccn1CCC#Cc1ccccn1
Yield: 9841.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (100 mg, 0.63 mmol) and 2-but-3-ynyl-2H-isoquinolin-1-one (120 mg, 0.63 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 17 mg (62 mmol, 10%) of 2-(4-(pyridin-2-yl)but-3-ynyl)isoquinolin-1(2H)-one as a white solid (M.P.=85-90° C.).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C([N:32]1[C:36]([CH3:38])([CH3:37])[CH2:35][NH:34][C:33]1=[O:39])(=O)C1C=CC=CC=1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:34]4[CH2:35][C:36]([CH3:38])([CH3:37])[NH:32][C:33]4=[O:39])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: CC1(C)CNC(=O)N1C(=O)c1ccccc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)NC4=O)nc3)CC2)c(C)c1
Yield: 36.7 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 127 and 1-benzoyl-5,5-dimethylimidazolidin-2-one (105 mg) described in Preparation Example 58 and by the reaction and treatment in the same manner as in Example 509 to give the title compound (60 mg) produced by debenzoylation that simultaneously proceeded during the reaction.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.CN(C)[CH:16]=[O:17]>>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:16]=[O:17])[CH:11]=[CH:10]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CN(C)C=O
Product: COc1ccc2cc(C=O)ccc2c1

Procedure:
Another embodiment of this invention comprises preparing 2-bromo-6-methoxynaphthalene as described herein, converting the 2-bromo-6-methoxynaphthalene into a Grignard reagent, and reacting the Grignard reagent with N,N-dimethylformamide (DMF) which yields after workup, 6-methoxy-2-naphthaldehyde. The Grignard reagent is formed by adding finely divided magnesium and, optionally a crystal of iodine, to a solution of 2-bromo-6-methoxynaphthalene in a suitable ether, such as diethyl ether or tetrahydrofuran in a dry, inert environment, and stirring the mixture at a temperature in the range of about 25° to about 80° C. The reaction of the resultant Grignard reagent with DMF is preferably conducted by adding the DMF portionwise to the Grignard reagent while stirring the mixture at a temperature in the range of about 25° to about 100° C., followed by acid hydrolysis. The following Example 57 is based in part on the procedure of A. Horeau, J. Jacques and R. Emiliozzi, Bull. Soc. Chim. Fr. 1959, at page 1857.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH2:14]([C:15]1[CH:16]=[CH:17][C:18]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:19][CH:20]=1)[CH2:13][CH3:12]
Reactant: CCCc1ccccc1
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: CCCc1ccc(C(O)C(=O)c2ccccc2)cc1

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and n-propylbenzene (0.56 ml, 4 mM) were dissolved in dichloroethane (6 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 2 hours. Using the same procedure as in Example 1, 4'-n-propylbenzoin was obtained as crystal (369.9 mg, 71.9% yield).
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][N:39]([CH3:43])[C:40](Cl)=[O:41]>C(Cl)Cl>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[N:29]=[CH:28][C:27]([NH:30][C:40](=[O:41])[N:39]([CH3:43])[CH3:38])=[CH:26][CH:25]=3)[CH2:22][CH2:23]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)Nc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.8 %

Procedure:
6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-ylamine (80 mg, 0.202 mmol), CH2Cl2 (0.5 mL), triethylamine (37 μL, 0.227 mmol), and dimethylcarbamoyl chloride (20 μL, 0.222 mmol) are combined and stirred at room temperature for 16 h. Concentrate the crude reaction mixture in vacuo. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (64 mg, 68%).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:22]=2)[CH2:14][C@H:13]1[O:29][CH3:30])=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:22]=2)[CH2:14][C@H:13]1[O:29][CH3:30]
Reactant: CCOC(=O)Cc1csc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)Cc1csc(N2CC[C@H](N)[C@H](OC)C2)n1

Procedure:
Ethyl cis(±)-[2-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazol-4-yl]acetate obtained in Example (64c) (124 mg, 0.29 mmol) was dissolved in ethanol (5 mL). A 10% palladium-carbon catalyst (75 mg) and ammonium formate (90 mg, 1.43 mmol) were added, and the mixture was heated under reflux for 15 hours. The reaction solution was filtered through celite. The filtrate was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16].Cl>C(Cl)(Cl)Cl>[C:15]([NH:19][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)(=[O:10])=[O:9])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)NC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.4 %

Procedure:
To a solution of 4-methyl-3-nitrobenzenesulfonyl chloride (5.40 g, 22.9 mmol) in chloroform (50 ml) was added tert-butylamine (6.00 ml, 57.1 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2.5 hr. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was successively washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and hexane was added to the residue. The precipitated solid was collected by filtration and dried in vacuo to give N-tert-butyl-4-methyl-3-nitrobenzenesulfonamide (5.89 g, yield 94.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[ClH:8].[C:9](=[NH:15])(OCC)[CH2:10][CH3:11]>C(#N)C>[ClH:8].[CH3:7][C:5]1[NH:4][N:3]=[C:2]([NH:1][C:9](=[NH:15])[CH2:10][CH3:11])[CH:6]=1
Reactant: CCOC(=N)CC
Reactant: Cc1cc(N)n[nH]1
Agent: Cl
Solvent: CC#N
Product: CCC(=N)Nc1cc(C)[nH]n1
Reaction time: 1 h

Procedure:
A 13.8 g portion of 3-amino-5-methyl-1H-pyrazole was dissolved in 52 ml of acetonitrile, and 22.0 g of ethyl propionimidate hydrochloride was added to the above solution with cooling on an ice bath. The resulting mixture was stirred for 1 hour at the same temperature and then overnight at room temperature.