Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:17][C:18]2[C:19]3[C:26]4[CH2:27][CH2:28][C:29]5([CH2:34][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)OCC[O:30]5)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>C(O)(=O)C.O>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([NH:17][C:18]2[C:19]3[C:26]4[CH2:27][CH2:28][C:29](=[O:30])[CH2:34][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Clc1cc(Nc2ncnc3sc4c(c23)CCC2(C4)OCCO2)ccc1OCc1ccccn1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 177.3 %

Procedure:
To a stirring acetic acid/H2O solution (4:1, 250 mL) was added N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5,8-dihydro-6H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolan]-4-amine hydrochloride (10.0 g, 19.3 mmol), and the contents heated at 80° C. for 40 h. The dark colored mixture was cooled to rt, and the solvent removed under reduced pressure. The crude residue was suspended in water (200 mL), stirred for 10 min., and filtered. The collected solid was further washed with H2O (300 mL) and ether (100 mL) to afford the desired product as a brown solid (8.1 g, 89%). 1H-NMR (DMSO-d6) δ 8.71 (d, 1H), 8.54 (s, 1H), 8.42 (s, 1H), 8.10 (td, 1H), 7.78 (d, 1H), 7.75 (d, 1H), 7.56 (m, 2H), 7.25 (d, 1H), 5.38 (s, 2H), 5.08 (br, 1H), 3.76 (s, 2H), 3.50 (t, 2H), 2.69 (t, 2H); LCMS RT=2.44 min; [M+H]+=437.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.S(Cl)([Cl:19])(=O)=O.[OH-].[Na+]>C(Cl)Cl.CO>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]([Cl:19])[C:6](=[O:14])[C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=1
Reactant: COC(=O)CCC(=O)c1ccc(C)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CC(Cl)C(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A stirred solution of 152.6 g (0.74 mole) of 3-(4-methylbenzoyl)propionic methyl ester in 225 mL of methylene chloride was cooled to -5° C. in methanol:ice bath. A solution of 109.9 g (66 mL, 0.81 mole) of sulfuryl chloride (97%) in 65 mL of methylene chloride was added dropwise at a rate which maintained the temperature at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was cooled to 0° C. in an ice bath and treated with 3N sodium hydroxide until just basic. The organic portion was separated, dried over magnesium sulfate and concentrated in vacuo (172.9 g). The oil was distilled at 125° C. (150 mm Hg) in 4 fractions. A sample of fraction 2 was sent for elemental analysis.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[CH:16]([C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)[C:15](=O)[C:14]2[C:13]([C:24](OCC)=[O:25])=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8]1.O.[NH2:30][NH2:31]>CO>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]1[NH:8][C:9]2[C:14]3[C:15](=[N:30][NH:31][C:24](=[O:25])[C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:16]1[C:17]1[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1nccn1C)N2
Solvent: O
Solvent: CO
Product: Cn1ccnc1C1Nc2cccc3c(=O)[nH]nc(c23)C1c1nccn1C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 41 %

Procedure:
A mixture of ethyl 2,3-bis(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (120 mg) in 85% hydrazine monohydrate (2 mL) and methanol (3 mL) was stirred at room temperature for 3.5 h. Evaporated the solvent and methanol (1 mL) was added, filtered and washed the cake by methanol (2 mL) to obtain a white solid. The solid was dried in vacuum at 50° C. to obtain 8,9-bis(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (45 mg, yield 41%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 3.46 (s, 3H), 3.49 (s, 3H), 4.78-4.81 (d, J=12.0 Hz, 1H), 5.08-5.11 (d, J =12.0 Hz, 1H), 6.69 (s, 1H), 6.76-6.79 (m, 3H), 6.99-7.02 (d, J=7.6 Hz, 1H), 7.42-7.49 (m, 2H); LC-MS (ESI) m/z: 348 (M+1)+.
Reaction SMILES: C(Cl)(C)(C)C.Cl.[CH:7]1(Cl)[CH2:11][CH2:10][CH2:9][CH2:8]1.C1([SiH](Cl)Cl)CCCC1.C1([Si:26]([Cl:29])([Cl:28])[Cl:27])CCCC1>>[CH:7]1[CH2:11][CH2:10][CH2:9][CH:8]=1.[Cl:27][SiH:26]([Cl:29])[Cl:28]
Reactant: Cl[Si](Cl)(Cl)C1CCCC1
Reactant: ClC1CCCC1
Agent: Cl
Agent: Cl[SiH](Cl)C1CCCC1
Solvent: CC(C)(C)Cl
Product: C1=CCCC1
Product: Cl[SiH](Cl)Cl
Yield: 58.4 %

Procedure:
The reaction was carried out under the same condition as in Example 3, except that the same amount of t-butyl chloride was used as the hydrogen chloride source. A mixture of cyclopentyl chloride and t-butyl chloride having the mixing ratio of 1:2 was reacted with metallic silicon at 280° C. to give 30.1 g of reaction products. The reaction products contained 6.2 g (39.1%) of cyclopentyldichlorosilane and 0.3 g (1.6%) of cyclopentyltrichlorosilane. There were not starting materials unreacted. As other by-products, 3.7 g (58.4%) of cyclopentene, 2.9 g of trichlorosilane and unconfirmed materials were obtained.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]#[N:9])[CH3:2].C(N(CC)CC)C.[SH2:17].O>N1C=CC=CC=1>[CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](=[S:17])[NH2:9])[CH3:2]
Reactant: CCn1cccc1C#N
Reactant: S
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCn1cccc1C(N)=S
Yield: 65 %

Procedure:
The 1-ethylpyrrole-2-carbonitrile obtained above (3.0 g, 25 mmole) is dissolved in a solution of triethylamine (12.5 g, 125 mmole) in pyridine (13 ml), and therein hydrogen sulfide is blown at 20° C. for 6 hours. To the reaction mixture is added water (300 ml). The precipitated crystals are separated by filtration, dried, and then recrystallized from ligroin to give 1-ethylpyrrole-2-carbothioamide (2.5 g, yield: 65%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([O:8]C)=O.[OH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[OH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:6](=[O:8])[CH2:5][C:4](=[O:10])[CH2:3][O:2][CH3:1])[CH2:14][CH2:13]1
Reactant: OC1CCNCC1
Reactant: COCC(=O)CC(=O)OC
Product: COCC(=O)CC(=O)N1CCC(O)CC1
Yield: 32.4 %

Procedure:
0.34 mol (48.7 g) of methyl 4-methoxy-acetoacetate and 0.36 mol (36.0 g) of 4-hydroxypiperidine were stirred for 5 h at 120° C. at a Dean-Stark apparatus. 45 g of the crude product was purified over 1 kg of silica gel with ethyl acetate/ethanol 9/1. 23.7 g of the title compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2I)=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34]#[CH:35]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34]#[C:35][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=1
Reactant: CCOC(=O)c1cnc(I)n1-c1ccc(F)cc1
Reactant: C#Cc1c(F)cccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(C#Cc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Ethyl 1-(4-fluorophenyl)-2-iodo-1H-imidazole-5-carboxylate (38) (847 mg, 2.35 mmol), PdCl2(PPh3)2 (82 mg, 0.12 mmol), copper (I) iodide (22 mg, 0.12 mmol), and THF (50 mL) were added to a pressure tube. Diisopropyl amine (6 mL) and 1-chloro-2-ethynyl-3-fluorobenzene (41) (400 mg, 2.59 mmol) were added to the pressure tube and the reaction was stirred at 50° C. overnight. The reaction was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to provide ethyl 2-((2-chloro-6-fluorophenyl)ethynyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (42).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:5]=[CH:6][C:7]=1[OH:8].[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCCCCC(=O)CCc1ccc(O)c(O)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCC(=O)CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 174.4 %

Procedure:
To a solution of 1.2 g of 1-(3,4-dihydroxyphenyl)-3-nonanone in 10 ml of dimethylformamide was added 200 mg of oily sodium hydride (60%) and after stirring the mixture for 15 minutes at room temperature, 0.9 g of benzyl bromide was added to the mixture followed by stirring for 15 minutes at room temperature. After further adding thereto 200 mg of oily sodium hydride (60%) and stirring the mixture for 15 minutes at room temperature, 0.9 g of benzyl bromide was added to the mixture followed by stirring for 1.5 hours at room temperature. After adding 50 ml of water to the reaction mixture, the product was extracted with toluene. The extract was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was applied to silica gel column chromatography and eluted with toluene to provide 1.8 g of 1-(3,4-dibenzyloxyphenyl)-3-nonanone as a sticky product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=3)[S:10][C:3]=12.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([O-:19])=[O:18].C([O-])([O-])=O.[K+].[K+].O(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[CH3:16][N:14]1[CH:15]=[C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:26][C:23]3[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=3)[CH:8]=2)[N:12]=[CH:13]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Cn1cnc(-c2cc3nccc(Cl)c3s2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4)c3s2)c1
Temperature: 190 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A mixture of 224 (950 mg, 3.81 mmol), 4-nitrophenol (795 mg, 5.72 mmol), K2CO3 (1.05 g, 7.62 mmol) and Ph2O (5 mL) was stirred at 190° C. for 2 h in a sealed tube, cooled and treated with additional amount of 4-nitrophenol (795 mg, 5.72 mmol). The mixture was stirred for another hour at the same conditions, cooled to room temperature and diluted with DCM. The DCM solution was extracted with 2N HCl; the aqueous phase was collected, basified with concentrated ammonium hydroxide solution (pH˜11) and extracted with EtOAc. The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 225 (860 mg, 64% yield) as an orange solid. MS (m/z): 353.1(M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:20](OC)(OC)(OC)[CH2:21][CH2:22][CH3:23]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:21]([C:20]1[N:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:22][CH3:23]
Reactant: CCOC(=O)CCNc1c(N)cnc2ccccc12
Reactant: CCCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Yield: 93.1 %

Procedure:
Ethyl N-(3-aminoquinolin-4-yl)-β-alaninate (33.3 g, 128 mmol) was treated according to a modification of the method described in Part B of Example 8. After the addition of trimethyl orthobutyrate (25.6 mL, 161 mmol) and pyridinium p-toluenesulfonate (0.200 g, 0.796 mmol), the reaction was heated at reflux for two hours and subjected to the work-up procedure to provide 37.1 g of ethyl 3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate, which was used without purification.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)[CH3:14].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[CH2:33]Br>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[CH2:33][CH:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)[CH3:14]
Reactant: COc1ccc(Br)c(CBr)c1
Reactant: CCc1ccc(C(=O)O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1ccc(Br)c(CC(C)c2ccc(C(=O)O)cc2)c1
Temperature: -5 °C
Reaction time: 8 h

Procedure:
Butyl lithium (1.6M hexanes, 35 mL, 56 mmol) was added dropwise to a THF (50 mL)/HMPA (10 mL) solution of diisopropylamine (7.9 mL, 56 mmol) cooled to −5° C. After stirring 10 minutes a THF solution (17 mL) of 4-ethylbenzoic acid (3.36 g, 22.4 mmol) was added dropwise. The red solution was kept at 5° C. overnight. A THF solution (17 mL) of 1-bromo-2-(bromomethyl)-4-methoxybenzene (60.27 g, 22.4 mmol) was added dropwise. The reaction solution was then allowed to warm to room temperature. The solution was then partitioned between ethyl acetate and aqueous 1N HCl. The organic phase was washed with water, brine and dried over MgSO4. The filtered solution was concentrated and the residue purified by silica gel chromatography using hexanes/ethyl acetate (with 1% AcOH) gradient to give the title compound. LCMS1 3.72 min. (M−17)=331
Reaction SMILES: C(O)(=O)C.NN.C([O:10][C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15])(=O)C>C1COCC1>[C:14]([O:13][C@@H:12]1[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:28][CH:11]1[OH:10])(=[O:16])[CH3:15]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: NN
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1OC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
Under nitrogen atmosphere, hydrazine acetate (197 mg, 2.19 mmol, 1.4 equiv) was added to a solution of β-D-galactopyranose pentaacetate (605 mg, 1.55 mmol) in anhydrous THF (10 mL) in presence of 4 Å molecular sieve. The reaction mixture was stirred at room temperature for 4 h 30, filtered, concentrated to dryness under reduced pressure and purified by chromatography on silica gel (25:1, dichloromethane/methanol) to afford 2,3,4,6-tetra-O-acetyl-D-galactopyranose (528 mg, 98%) as a yellow oil which was directly used in the next step. Under nitrogen atmosphere, trichloroacetonitrile (1.34 mL, 13.4 mmol, 8.8 equiv) and potassium carbonate (1.42 g, 10.3 mmol, 6.7 equiv) were added to a solution of 2,3,4,6-tetra-O-acetyl-D-galactopyranose (528 mg, 1.52 mmol) in anhydrous dichloromethane (20 mL) in presence of 4 Å molecular sieve. The reaction mixture was vigourously stirred at room temperature for 12 h, filtered and concentrated to dryness under reduced pressure to afford 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl trichloroacetamidate (707 mg, 95%) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:34])[CH2:31][C:32]#[N:33])[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.N1[CH2:40][CH2:39][CH2:38][CH2:37]C1.C1(C=O)CC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([C:31](=[CH:37][CH:38]4[CH2:40][CH2:39]4)[C:32]#[N:33])=[O:34])[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: C1CCNCC1
Reactant: N#CCC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: O=CC1CC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
A mixture of 3-[3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (120 mg, 0.26 mmol, 1.00 equiv), piperidine (27 mg, 0.28 mmol, 1.07 equiv) and cyclopropanecarbaldehyde (28 mg, 0.40 mmol, 1.51 equiv) in methanol (8 mL) was stirred in sealed tube at room temperature for 24 h. The resulting mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with dichloromethane/methanol (100/1) to give 85.4 mg (64%) of the title compound as a white solid. MS (ESI, pos. ion) m/z: 506 (M+1). 1HNMR (300 MHz, CDCl3, ppm) 8.392 (1H, s), 7.676˜7.581 (2H, t), 7.445˜7.393 (2H, t), 7.202˜7.097 (5H, m), 6.601˜6.566 (1H, d, J=10.5), 5.737 (2H, s), 5.010˜4.912 (1H, m), 4.691˜3.185 (4H, m), 2.464˜2.035 (5H, m), 1.275˜0.876 (4H, m).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=3)[C:15]=2[CH3:16])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:33]([O:37][C:38]([N:40]1[CH2:45][CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].O1CCOCC1>O>[C:33]([O:37][C:38]([N:40]1[CH2:41][CH:42]=[C:43]([C:2]2[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[CH:12]=[N:13][N:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=4)[C:15]=3[CH3:16])=[O:10])=[CH:4][CH:3]=2)[CH2:44][CH2:45]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: Cc1c(C(=O)Nc2ccc(Br)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 110 °C
Reaction time: 6.5 h
Yield: 94.9 %

Procedure:
To N-(6-bromopyridin-3-yl)-5-methyl-1-[5-(tri fluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (3.0 g), cesium carbonate (6.4 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloridedichloromethane complex (287 mg), and N-tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (2.28 g) were added 1,4-dioxane (26 ml) and water (7 ml), and stirred at 110° C. for 6.5 hours. To the reaction solution was added water, and the obtained solid was washed with a mixed solution of n-hexane and ethyl acetate to give N-[6-(1-tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (3.53 g) as a brown solid.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[C:36]([Br:41])[CH:35]=1)[CH2:18][N:19]([CH2:32][CH3:33])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Br:41][C:36]1[CH:35]=[C:34]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH2:32][CH3:33])[CH:39]=[CH:38][C:37]=1[F:40]
Reactant: CCN(C[C@@H](N)c1ccc(F)c(Br)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CCNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(F)c(Br)c1

Procedure:
Compound 30 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(3-bromo-4-fluoro-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [434 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.36 (s, 1H), 9.02 (d, J=4.5 Hz, 1H), 8.60 (s, 1H), 8.40 (d, J=4.4 Hz, 1H), 8.18 (s, 1H), 7.87 (d, J=4.9 Hz, 1H), 7.53 (d, J=5.5 Hz, 1H), 7.35 (t, J=8.7 Hz, 1H), 5.78-5.51 (m, 1H), 3.55-3.36 (m, 1H), 3.23-3.10 (m, 1H), 2.93-2.69 (m, 2H), 1.08 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[N:8][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].CCOC(C)=O>CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>[C:12]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:9]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:8]=1)(=[O:16])[CH:13]([CH3:14])[CH3:15]
Reactant: COc1ccc2c(C(=O)C(C)C)n[nH]c2c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(C(=O)C(C)C)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 5.456 g of 1-(6-methoxy-1H-indazol-3-yl)-2-methylpropan-1-one in 100 mL anhydrous DMF. Weigh in 8.96 g cesium carbonate followed by 4.593 g ethyl bromoacetate. The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. Partition the residue between EtOAc and water. Extract the aqueous layer with EtOAc several times. The combined organic extract was washed with water (3×) and saturated brine, dried over anhydrous Na2SO4, and evaporated to give the crude product. The title compound was obtained by recrystallization from 40 mL 4:1 hexanes and EtOAc. 1H NMR (CDCl3, 500 MHz) δ 8.26 (d, 8.9 Hz, 1H), 7.00 (dd, 2.1 & 9.0 Hz, 1H), 6.685 (d, 2.1 Hz, 1H), 5.17 (s, 2H), 4.28 (q, 7.1 Hz, 2H), 3.90 (s, 3H), 3.87 (heptet, 6.9 Hz, 1H), 1.29 (t, 7.1 Hz, 3H), 1.28 (d, 6.8 Hz, 6H). LC-MS: 3.51 min. (m/Z=305.1, 327.0).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH2:13][CH:14](O)[CH2:15][C:11]=2[C:10]([C:17]#[N:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:25])CC>ClCCl.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]2[CH2:13][CH:14]([F:25])[CH2:15][C:11]=2[C:10]([C:17]#[N:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1nn(Cc2ccccc2)c2c1CC(O)C2
Reactant: CCN(CC)S(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nn(Cc2ccccc2)c2c1CC(F)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.1 %

Procedure:
To a solution of 1-benzyl-5-hydroxy-1,4,5,6-tetrahydrocyclo-penta[c]pyrazole-3-carbonitrile (see Example 9.7, 30 mg, 0.125 mmol) in anhydrous dichloromethane (0.9 mL) was added DAST (33 μL, 0.25 mmol) under a nitrogen atmosphere. After stirring at room temperature for 15 minutes, the reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO3 solution and brine. The organic layer was dried over anhydrous Na2SO4 filtered and concentrated in vacuo. The residue was purified by PTLC (SiO2) using 30% ethyl acetate-hexanes to give the desired compound (16 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=1[C:27](Cl)=O.C(N(CC)CC)C>C(#N)C>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=1[C:27]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(Cl)ccc2Cl)n1
Temperature: 150 °C
Yield: 42 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.05 g, 0.154 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 2,5-dichlorobenzoyl chloride (0.111 g, 0.529 mmol) and triethylamine (1.0 mL, 13.6 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.031 g (42% yield) of pure product: MS (ES) m/z 479 (M+1).