Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:36][C:37]1[CH:46]=[C:45]2[CH:40]([CH2:41][CH2:42][N:43]([C:47](=[O:52])[C:48]([F:51])([F:50])[F:49])[CH2:44]2)[CH2:39][CH:38]=1.Cl>O1CCOCC1.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:21]1[CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:36][C:37]4[CH:46]=[C:45]5[C:40]([CH2:41][CH2:42][N:43]([C:47](=[O:52])[C:48]([F:51])([F:49])[F:50])[CH2:44]5)=[CH:39][CH:38]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35])=[O:33]
Reactant: NC1=CCC2CCN(C(=O)C(F)(F)F)CC2=C1
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)c1c(F)cccc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CN(C(=O)C(F)(F)F)CC4)n2)cc1NC(=O)c1c(F)cccc1F
Temperature: 80 °C
Yield: 44.7 %

Procedure:
To a solution of N-[5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-(methyloxy)phenyl]-2,6-difluorobenzamide (158 mg, 0.32 mmol) in 1,4-dioxane (6 mL) and 2-propanol (2 mL) was added 7-amino-N-trifluoroacetyl tetrahydroisoquinoline (158 mg, 0.64 mmol) followed by catalytic 12M HCl. After heating overnight at 80° C., reaction was quenched with saturated NaHCO3 (25 mL), solvent removed by rotary evaporation, aqueous layer extracted with DCM (25 mL), the organic layer was concentrated and purified by column chromatography (5-50% EtOAc in hexanes) to provide the product (100 mg, 44%) as an off-white solid. ESIMS (M+H)+=700.
Reaction SMILES: Cl.[CH3:2][Si:3]([CH3:29])([CH3:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.C(Cl)Cl.[OH:33][CH:34]([CH2:39][CH3:40])[C:35]([O:37][CH3:38])=[O:36].C(N(CC)CC)C>CCOCC>[CH3:2][Si:3]([CH3:29])([CH3:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:33][CH:34]([C:35]([O:37][CH3:38])=[O:36])[CH2:39][CH3:40])=[O:24])=[CH:21][CH:20]=1
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reactant: CCC(O)C(=O)OC
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(OC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 10.0 g. 4-[14-(trimethylsilyl)tetradecylamino]benzoyl chloride hydrochloride in 200 ml. methylene chloride is added dropwise a solution of 3 g. methyl α-hydroxybutyrate and 5 g. triethylamine in 100 ml. ether. After 17 hours stirring at room temperature, the precipitate is collected and washed with several portions of ether. The ether solution is washed with water, dried and evaporated to yield the product as a white solid.
Reaction SMILES: [NH:1]([C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:7]([C:13]1[CH:18]=[CH:17][C:16]([C:19]3([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=1)=[N:8]2)[NH2:2].[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCOCC1>[OH:38][C:37]1[N:12]2[C:3]([C:4]3[CH:5]=[C:6]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:7]([C:13]4[CH:18]=[CH:17][C:16]([C:19]5([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[N:8][C:9]=3[CH:10]=[CH:11]2)=[N:1][N:2]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(NN)c4cc3-c3ccccc3)cc2)CCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccn5c(O)nnc5c4cc3-c3ccccc3)cc2)CCC1
Temperature: 95 °C

Procedure:
To a round bottom flask was added tert-butyl {1-[4-(5-hydrazino-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-6) (2.77 g, 5.75 mmol), and 1,1′-carbonylbis(1H-imidazole) (4.10 g, 4.40 mmol), in 1,4 Dioxane (30 mL). The sealed reaction mixture was then heated at 95° C. under an atmosphere of nitrogen. To the crude reaction mixture was added a saturated solution of sodium bicarbonate (100 mL) and ethyl acetate. The organic layer was washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was then purified by silica gel chromatography eluting with 0-10% IPA/DCM. The appropriate fractions were then combined and the solvent was removed in vacuo to give tert-butyl {1-[4-(3-hydroxy-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (1-6a) as a tan solid. MS (M+H)+: observed=508.1, calculated=508.6.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][CH2:5][N:6]=1.[C:7](Cl)(Cl)=[O:8].[OH-:11].[Na+]>O.C(Cl)Cl>[C:2]([O:3][CH2:4][CH2:5][N:6]=[C:7]=[O:8])(=[O:11])[CH3:1]
Reactant: O=C(Cl)Cl
Reactant: [OH-]
Reactant: CC1=NCCO1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCCN=C=O
Temperature: 0 °C
Reaction time: 0.92 h

Procedure:
In like manner, a 3-liter jacketed reaction vessel was charged with 288 ml of methylene chloride and cooled to 0° C. A solution of 2-methyl-2-oxazoline (77.5 g) in 137.7 ml of water, a solution of phosgene (131 g) in 280 ml of methylene chloride, and 250 ml of a 35 weight percent solution of aqueous sodium hydroxide were added simultaneously to the reaction vessel with cooling and stirring; the total additive time was approximately 55 minutes. Stirring was continued for 2 minutes after the addition was complete and the organic and aqueous layers then allowed to separate. The organic layer was isolated and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The desired product was then obtained from the concentrated organic layer by distillation at 55°/5 mm Hg to give 74.8 g (65 percent of theory) of the desired product as a clear, colorless liquid. The product structure was likewise confirmed by infrared and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C:7]1([CH3:31])[CH2:13][C:12]2[CH:14]=[C:15]3[O:20][CH2:19][O:18][C:16]3=[CH:17][C:11]=2[C:10]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([CH3:30])[CH:22]=2)=[N:9][NH:8]1)#[N:6]>>[C:1]([N:8]1[C:7]([C:5]#[N:6])([CH3:31])[CH2:13][C:12]2[CH:14]=[C:15]3[O:20][CH2:19][O:18][C:16]3=[CH:17][C:11]=2[C:10]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([CH3:30])[CH:22]=2)=[N:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C2=NNC(C)(C#N)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Product: CC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc3c(cc2CC1(C)C#N)OCO3
Yield: 67 %

Procedure:
To 60 ml of acetyl chloride 9.11 g (25.0 millimoles) of (±)-8-cyano-7,8-dihydro-8-methyl-5-(3-methyl-4-nitro-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine are added at 15° C. under stirring. The suspension formed turns into a solution within 5 minutes, but after a further period of 5 minutes a suspension is re-formed. The reaction mixture is stirred at 25° C. for 6 days, whereupon it is evaporated in vacuo. To the residue 90 ml of water are added and the mixture is stirred under cooling with icecold water for half an hour. The precipitated crystals are filtered and washed with icecold water. The crude product is crystallized from 150 ml of acetonitrile. The crystals are filtered, washed with acetonitrile and ether and dried. Thus 6.84 g of the desired compound are obtained, yield 67%, mp.: 253–255° C.
Reaction SMILES: [CH2:1]([CH:5]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[C:14]=1[Cl:21])[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:2][CH2:3][CH3:4].[CH2:22]([Br:25])[CH:23]=[CH2:24]>C(OCC)(=O)C>[Br-:25].[CH2:24]([N+:7]1([CH2:6][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[C:14]=2[Cl:21])[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH:23]=[CH2:22]
Reactant: CCCCC(Cc1ccc(Cl)c(Cl)c1Cl)CN1CCCC1
Reactant: C=CCBr
Solvent: CCOC(C)=O
Product: C=CC[N+]1(CC(CCCC)Cc2ccc(Cl)c(Cl)c2Cl)CCCC1
Product: [Br-]

Procedure:
A solution of 34.8 g of (XXII) and 36.3 g of allyl bromide in 250 ml of ethyl acetate was refluxed for 5 hours. The product, which was obtained as an oil, was washed several times with ethyl acetate and then freed from residual solvent under reduced pressure. Yield: 32 g of a yellowish brown resin (compound No. 60).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([C:17]([N:30]3[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:32][CH2:31]3)=[O:19])[CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(-c2cccc(C(=O)O)n2)cc1OC
Product: COc1ccc(-c2cccc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)n2)cc1OC

Procedure:
Using 6-(3,4-dimethoxyphenyl)pyridine-2-carboxylic acid and t-butoxycarbonylpiperazine, 1-{[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-(t-butoxycarbonyl) piperazine was obtained in a similar manner to Example 2 to be mentioned below. Further, a 4M hydrogen chloride/ethyl acetate solution was added thereto and the whole was reacted to obtain an objective compound.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([NH:12][C:13]2[CH:14]=[C:15]([C:20]3[N:24]=[C:23]([CH2:25][N:26](C)C(=O)OC(C)(C)C)[O:22][N:21]=3)[CH:16]=[CH:17][C:18]=2[CH3:19])=[O:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl>C(#N)C.O1CCOCC1.O>[NH2:26][CH2:25][C:23]1[O:22][N:21]=[C:20]([C:15]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([NH:12][C:10]([C:3]3[N:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]4=[N:1][CH:2]=3)=[O:11])[CH:14]=2)[N:24]=1
Reactant: Cc1ccc(-c2noc(CN(C)C(=O)OC(C)(C)C)n2)cc1NC(=O)c1cnc2ccccn12
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1ccc(-c2noc(CN)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirring suspension of tert-butyl (3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)methyl(methyl)carbamate (F54) (90 mg, 0.195 mmol) in acetonitrile (1 mL) was added 4N HCl in dioxane (1 mL) and water (0.5 mL). The reaction mixture was stirred at room temperature for 45 minutes. Then, the solvent was concentrated and the crude product was dried under high vacuum. The crude product N-(5-(5-(aminomethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (26) was used in the next step without further purification. 1H NMR (400 MHz, d6-DMSO) δ 10.04 (s, 1 H), 9.46-9.44 (m, 1 H), 8.74 (s, 2 H), 8.63 (s, 1 H), 8.15 (d, J=2.0 Hz, 1 H), 7.86-7.80 (m, 2 H), 7.59-7.54 (m, 1 H), 7.55 (d, J=8.4 Hz, 1 H), 7.23-7.20 (m, 1 H), 4.62 (s, 2 H), 2.39 (s, 3 H). MS m/z 349.4 (M+1)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]1[CH:36]=[C:37]([C:42]2[CH:43]=[C:44]([CH2:53]OS(C)(=O)=O)[C:45](=[O:52])[N:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[N:47]=2)[CH:38]=[CH:39][C:40]=1[F:41].CN1CCNCC1>>[F:34][C:35]1[CH:36]=[C:37]([C:42]2[CH:43]=[C:44]([CH2:53][N:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)[C:45](=[O:52])[N:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[N:47]=2)[CH:38]=[CH:39][C:40]=1[F:41]
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(COS(C)(=O)=O)c1=O
Agent: CN1CCNCC1
Product: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(CN2CCN(C)CC2)c1=O
Yield: 79.1 %

Procedure:
Following the procedure of Example 1 (10), 6-(3,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 79.1%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[O:18][C:19]=2[CH3:20])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].C(O)C.[BH4-].[Na+].O>O1CCCC1>[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:17]1[O:18][C:19]([CH3:20])=[C:15]([CH2:14][O:13][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][OH:2])=[CH:12][C:7]=2[C:8]([O:10][CH3:11])=[O:9])[N:16]=1
Reactant: COC(=O)c1cc(C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(CO)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a solution of methyl 5-formyl-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzoate (8.18 g) in tetrahydrofuran (50 mL)-ethanol (50 mL) was gradually added sodium borohydride (0.91 g) at room temperature. After stirring for 2 hrs, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-5-hydroxymethylbenzoate as pale-yellow crystals (6.53 g, yield 79%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 131-132° C.
Reaction SMILES: [C:1]1(=[O:20])[N:5]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][Br:12])=[CH:9][CH:8]=2)[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]12.[C:21]1([P:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1C=CC=CC=1>[Br-:12].[C:1]1(=[O:20])[N:5]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][P+:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:9][CH:8]=2)[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(CBr)cc1
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]
Yield: 67.8 %

Procedure:
To 29.2 g of 4-phthalimidomethylbenzyl bromide, were added 400 ml of benzene and 23.2 g of triphenylphosphine. The mixture was heated under reflux for 2 hours. The reaction mixture was cooled in ice. The crystals precipitated out of the reaction mixture were collected by filtration and washed thoroughly with benzene to yield 35.5 g of 4-phthalimidomethylbenzyltriphenylphosphonium bromide; m.p. 245°-246° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].C(N(C(C)C)CC)(C)C.[Cl:20][CH2:21][C:22](Cl)=[O:23].Cl>O1CCCC1>[Cl:20][CH2:21][C:22]([NH:4][C:3]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:2]=1[CH3:1])=[O:23]
Reactant: COc1ccc(C)c(N)c1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C)c(NC(=O)CCl)c1
Reaction time: 27 h

Procedure:
To a solution of 2-methyl-5-methoxyaniline (4.7 g) in tetrahydrofuran (50 ml), under nitrogen, was added diisopropylethylamine (12.6 ml) followed by dropwise addition of chloroacetyl chloride (2.7 ml) and the mixture stirred under nitrogen for 27 hours. The solution was poured into 2M aqueous hydrochloric acid (150 ml), extracted into diethyl ether (3×150 ml), washed with brine, dried (MgSO4), and concentrated to give the sub-title compound as a brown oil (5.15 g).
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=O.[NH2:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CCO>[CH3:15][C:2]1[N:16]=[C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]2[C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1
Reactant: Nc1ncccn1
Reactant: CC(Br)C(=O)c1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: Cc1nc2ncccn2c1-c1ccc(C(F)(F)F)cc1
Reaction time: 24 h
Yield: 46.8 %

Procedure:
Dissolve 2-bromo-1-[4-(trifluoromethyl)phenyl]propan-1-one (7.120 g, 25.332 mmol) and 2-aminopyrimidine (5.464 g, 55.729 mmol) in EtOH (40.0 mL). Heat the mixture to reflux, and stir for 24 hours. Concentrate in vacuo. Dissolve the residue in EtOAc (750 mL); and wash sequentially with saturated aqueous NaS2O3 (250 mL), saturated aqueous NaHCO3 (250 mL), and saturated NaCl (350 mL). Crystallize the orange residue from heptanes/EtOAc to give the title product as a white solid (3.29 g, 46.85% yield). 1H NMR (399.83 MHz, d6-DMSO) δ 8.84 (dd, J=1.9, 7.0 Hz, 1H), 8.54 (dd, J=2.0, 4.2 Hz, 1H), 8.06-8.04 (m, 2H), 7.83-7.81 (m, 2H), 7.10 (dd, J=4.1, 6.9 Hz, 1H), 2.68 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11]([NH:20][CH2:21]CO)=[N:10][C:9]=2[C:24]#[N:25])[CH:5]=[CH:6][CH:7]=1.NC[CH2:28][CH2:29][OH:30]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11]([NH:20][CH2:21][CH2:28][CH2:29][OH:30])=[N:10][C:9]=2[C:24]#[N:25])[CH:5]=[CH:6][CH:7]=1
Reactant: NCCCO
Reactant: COc1ccc2c(NCCO)nc(C#N)c(-c3cccc(F)c3)c2c1
Product: COc1ccc2c(NCCCO)nc(C#N)c(-c3cccc(F)c3)c2c1

Procedure:
Following the procedure for 4-(3-fluorophenyl)-1-[(2-hydroxyethyl)amino]-6-methoxyisoquinoline-3-carbonitrile, using 3-amino-1-propanol in place of 2-aminoethanol, the title compound was synthesized.
Reaction SMILES: C(O[C:4]1(O[Si](C)(C)C)[CH2:6][CH2:5]1)C.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C[Si]([C:22]#[N:23])(C)C>>[N:12]1([C:4]2([C:22]#[N:23])[CH2:5][CH2:6]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C[Si](C)(C)C#N
Reactant: C1CCNCC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Product: N#CC1(N2CCCCC2)CC1
Yield: 52 %

Procedure:
The reaction of (1-ethoxycyclopropoxy)trimethylsilane 13 and piperidine 14A with trimethylsilylcyanide yielded 1-(piperidin-1-yl)cyclopropanecarbonitrile as a yellow liquid (52%). MS ISP (m/e): 151.1 (68) [(M+H)]+, 149.2 (100).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6]([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)[O:5][N:4]=1)[CH3:2].S(=O)(=O)(O)O>>[CH2:1]([C:3]1[C:7]2[C:8](=[O:9])[N:10]([CH3:11])[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:12][C:6]=2[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(CC(=O)c2ccccc2)c1C(=O)NC
Agent: O=S(=O)(O)O
Product: CCc1noc2cc(-c3ccccc3)n(C)c(=O)c12

Procedure:
A mixture of 11.0 g. (0.0405 mole) of 3-ethyl-N-methyl-5-phenacyl-4-isoxazole carboxamide and 120 ml. of 2M sulfuric acid is refluxed for 18 hours. The mixture is cooled and extracted with methylene chloride. The methylene chloride layer is washed with water and then brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is triturated with ether and filtered to give 3-ethyl-5-methyl-6-phenyl-isoxazolo[4,5-c]pyridin4(5H)-one, m.p. 167° to 169° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[F:14][C:15]([F:25])([F:26])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:8]=[C:4]([O:5][CH2:6][CH3:7])[C:3]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:2]=1[Cl:1])=[O:19]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CCOC(=N)c1cc(Cl)ccc1Cl
Product: CCOC(=NC(=O)c1ccccc1C(F)(F)F)c1cc(Cl)ccc1Cl

Procedure:
starting from ethyl 2,5-dichlorobenzimidate and o-trifluoromethyl-benzoyl chloride there is obtained ethyl N-(o-trifluoromethyl-benzoyl)-2,5-dichlorobenzimidate and therefrom with methylhydrazine there is obtained 3-(2,5-dichlorophenyl)-1-methyl-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, m.p. 60°-63° C.;
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.F[C:23]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]>>[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:23]2[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:24]=2[C:25]([OH:27])=[O:26])=[CH:17][CH:16]=1
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: COc1ccc(N)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: COc1ccc(Nc2cc(F)c(F)cc2C(=O)O)cc1
Yield: 120.5 %

Procedure:
Using General Method 1, the reaction of 2.5 M solution of n-BuLi in hexanes (26 mL, 64 mmol), diisopropylamine (8.7 mL, 62 mmol), 4-methoxy-aniline (2.6 g, 17 mmol), and 2,4,5-trifluorobenzoic acid (3.6 g, 20.7 mmol) provided 5.72 g of the crude title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([NH:22]C(=O)OC(C)(C)C)[CH2:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[N:11]=2)[N:8]=1)[CH3:2].Cl.O1CCOCC1.[OH-].[Na+]>C(Cl)Cl.CO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([NH2:22])[CH2:19][CH2:20][CH2:21]4)=[CH:14][CH:13]=3)[N:11]=2)[N:8]=1)[CH3:2]
Reactant: CCc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: CCc1ccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a mixture of tert-butyl {1-[4-(6-ethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-2 (300 mg, 0.608 mmol, 1.0 eq) in DCM (3.9 mL) and MeOH (2.5 mL) was added a solution of 4 M hydrogen chloride in dioxane (3.0 mL, 12.2 mmol, 20.0 eq) and the mixture was stirred for overnight at rt. The mixture was poured onto ice, made alkaline with aqueous sodium hydroxide (2 N) and extracted with DCM. The combined organic phases were washed with brine, dried and concentrated in vacuo. Purification was achieved by crystallization from diisopropyl ether. The resulting solid was filtered and dried under high vacuum overnight to give 119 mg (52% yield) of the title compound.
Reaction SMILES: [Br:1][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.[CH2:17](O)[CH2:18][OH:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]3([C:12]([CH3:13])([CH3:15])[CH3:14])[O:19][CH2:18][CH2:17][O:16]3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: OCCO
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)C1(c2c[nH]c3ncc(Br)nc23)OCCO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.3 %

Procedure:
1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (1.5 g, 5.3 mmol) was partly dissolved in 18 ml toluene, and ethylene glycol (0.9 ml, 15.9 mmol) and then p-toluenesulfonic acid hydrate were added. The mixture was refluxed with a Dean-Stark-type trap attached for 24 hr. The reaction was cooled to room temperature and ammonium chloride solution, water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined ethyl acetate layers were washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration and evaporation the residue was purified by silica gel chromatography(ethyl acetate/hexanes to give 1.44 g (83%) of 2-bromo-7-(2-tert-butyl-[1,3]dioxolan-2-yl)-5H-pyrrolo[2,3-b]pyrazine.