Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(O)(C)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][CH:6]=1.[H-].[Na+].O>C1(C)C=CC=CC=1>[CH2:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4]#[CH:3])=[CH:10][CH:9]=1)[CH2:12][CH3:13]
Reactant: CCCc1ccc(C#CC(C)(C)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C#Cc1ccc(CCC)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
3-Methyl-1-(4'-propylphenyl)-1-butyne-3-ol (33 g) was dissolved in toluene (320 ml) under nitrogen atmosphere, and then sodium hydride (60% in 2 g of paraffin liquid) was added thereto. The mixture was stirred at 60° C. for 6 hours. The reaction solution was poured into water (300 ml), and then extracted with chloroform, followed by washing with water three times. After distilling off toluene and chloroform, the resultant was distilled under reduced pressure (b.p. 60° to 63° C./4 mmHg) to give 4-propylphenylacetylene (16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]([OH:34])([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[C:10](=[O:19])[C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N+:35](=[CH2:37])=[N-:36].CN(N=O)S(C1C=CC(C)=CC=1)(=O)=O.[OH-].[K+]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][C:25]([OH:34])([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:26][CH2:27]2)[C:10]([C:11]2[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:36][NH:35][CH:37]=2)=[O:19])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=[N+]=[N-]
Reactant: O=C(C#Cc1ccccc1)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(c1c[nH]nc1-c1ccccc1)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-(3,4-dichlorophenyl)-6-(4-hydroxy-4-phenylpiperidino)-1-phenyl-hex-1-yne-3-one (0.30 g) in diethyl ether (25 mL) was cooled to 0° C. and was treated with diazomethane (generated by the reaction of and ethereal solution of N-methyl-N-nitroso-p-toluenesulfonamide with ethanolic potassium hydroxide (Anal. Chem., 45, 2302, 1973)). The resulting mixture was allowed to warm to room temperature and stirred for 3 days. The solvent was evaporated. Radial chromatography, eluting with dichloromethane:methanol (gradient 97.5:2.5, 95:5), afforded the title compound (50 mg) as a white powder; mp 112°-114° C.; NMR: 8.13 (s,1), 7.56-7.26 (m, 12), 7.08 (d,1), 4.33 (broad s,1), 2.68 (m,2), 2.37 (m,3), 2.05 (broad s,1), 1.86 (broad s,1), 1.73-1.43 (m, 5); MS: m/z=534(M+l). Analysis for C30H29Cl2N3O2 ·0.75 H2O: Calculated: C, 65.75; H, 5.61; N, 7.67; Found: C, 65.71; H, 5.60; N, 7.83.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[C:7]([CH2:29]O)=[N:8][CH:9]=[CH:10][C:11]=1[S:12][CH2:13][CH2:14][CH2:15][S:16][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([N+:26]([O-:28])=[O:27])=[CH:24][N:25]=2)[N:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:3][CH2:29][C:7]1[C:6]([CH3:5])=[C:11]([S:12][CH2:13][CH2:14][CH2:15][S:16][C:17]2[CH:18]=[CH:19][C:20]3[N:21]([C:23]([N+:26]([O-:28])=[O:27])=[CH:24][N:25]=3)[N:22]=2)[CH:10]=[CH:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CCl
Temperature: 0 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
A solution of 3.6 ml (49.8 mmol) of thionyl chloride in 30 ml of dichloromethane is added dropwise at room temperature to a solution of 15.0 g (38.3 mmol) of {3-methyl-4-[3-(3-nitroimidazo[1,2-b]pyridazin-6-yl-sulfanyl)propylsulfanyl]pyridin-2-yl}methanol in 400 ml of anhydrous dichloromethane and the mixture is then stirred for a further 18 h. It is then cooled to 0° C. and aqueous sodium carbonate solution (100 ml) is cautiously added dropwise. The dichloromethane is distilled off. The suspension is then treated with 400 ml of water and stirred at 0° C. for 30 min. The precipitate is filtered off, washed with water, dried at 40° C. in vacuo and then suspended in 300 ml of acetone. After filtration and drying, 15.3 g (97%) of the title compound are isolated as a beige powder. M.p.: 155-156° C.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:24])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=4)[CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Br[CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:24])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH:26]5[CH2:30][CH2:29][CH2:28][CH2:27]5)[CH:19]=4)[CH2:14]3)[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2]1
Reactant: BrC1CCCC1
Reactant: O=C(CN1CCc2cc(O)ccc2C1)N1CCN(C2CCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCc2cc(OC3CCCC3)ccc2C1)N1CCN(C2CCC2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-1,2,3,4-tetrahydroisoquinolin-6-ol (145 mg, 0.44 mmol) in DMF (10.0 ml) is added 1-bromo-cyclopentane (72 mg, 0.48 mmol), and K2CO3 (60 mg, 0.44 mmol). The resulting mixture is stirred at 50° C. overnight. Water (10.0 ml) is added to quench the reaction, and the mixture is extracted with DCM (10 ml×3). The combined organic phase is dried over sodium sulfate, and the solvent is removed under reduced pressure to give a residue that is purified by PTLC (EtOAc/4% TEA) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 6.84-6.94 (1H, m), 6.60-6.70 (2H, m), 4.68-4.74 (1H, m), 3.60-3.74 (6H, m), 3.36 (2H, s), 2.62-2.86 (5H, m), 2.22-2.34 (4H, m), 1.56˜2.10 (14H, m); MS (+VE) m/z 398.3 (M++1).
Reaction SMILES: Cl.[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:4])[CH3:3].[CH3:21][O:22][C:23]1[CH:43]=[CH:42][C:26]([CH2:27][NH:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([C:39](O)=[O:40])[CH:37]=3)[CH:32]=[CH:31][N:30]=2)=[CH:25][CH:24]=1>>[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][N:17]([C:39]([C:36]4[CH:37]=[C:38]5[C:33]([CH:32]=[CH:31][N:30]=[C:29]5[NH:28][CH2:27][C:26]5[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:43][CH:42]=5)=[CH:34][CH:35]=4)=[O:40])[CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2
Reactant: COc1ccc(CNc2nccc3ccc(C(=O)O)cc23)cc1
Agent: Cl
Product: COc1ccc(CNc2nccc3ccc(C(=O)N4CCC5(CC4)Cc4cn(C(C)(C)C)nc4C(=O)N5)cc23)cc1

Procedure:
The title compound was prepared by a method analogous to that described in Example 3, using 2′-tert-butyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one hydrochloride salt (Intermediate 4) and 1-(4-methoxybenzylamino)isoquinoline-7-carboxylic acid (Intermediate 27). +ESI (M+H) 553.5.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([CH2:14]Cl)=[CH:4][N:3]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:16]([CH2:14][C:5]1[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)CNc1nc(Cl)ncc1CCl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)CNc1nc(Cl)ncc1CN=[N+]=[N-]
Temperature: 30 °C
Reaction time: 2.5 h

Procedure:
A solution of 1.47 g (5.92 mmol) of (2-chloro-5-chloromethyl-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine and 0.46 g (7.1 mmol) NaN3 is dissolved in 6 ml of DMF and was stirred at 30° C. for 2.5 hours. Then the reaction mixture is cooled to rt., diluted with ethyl acetate and twice extracted with H2O. The organic layer is separated and dried over Na2SO4. Evaporation of the ethyl acetate yielded (5-azidomethyl-2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine as white crystalls.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)[CH:2]=1.[C:16](O)(=O)C.C=O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[S:9][C:10]3[CH2:16][NH:15][CH2:14][CH2:13][C:11]=3[N:12]=2)[CH:2]=1
Reactant: CC(=O)O
Reactant: NCCc1csc(Nc2cccnc2)n1
Agent: C=O
Solvent: CO
Product: c1cncc(Nc2nc3c(s2)CNCC3)c1
Reaction time: 2 h
Yield: 57.3 %

Procedure:
2-(3-Pyridyl)amino-4-(2-aminoethyl)thiazole (0.50 g, from preceding preparation) and acetic acid (0.19 ml, 3.3 mmol) were dissolved in methanol (23 ml) and treated with formaldehyde (0.19 ml of a 37% aqueous solution, 2.3 mmol). The reaction was allowed to stir at room temperature for 18 hours, at which point additional formaldehyde (0.02 ml of a 37% aqueous solution, 0.25 mmol) was added. After an additional 2 hours, the reaction mixture was filtered; the filtrate was concentrated in vacuo, dissolved in aqueous base, and extracted with methylene chloride. The organic extracts were dried over sodium sulfate and concentrated to provide the title product (310 mg, 1.3 mmol, 57% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]2[N:29]=[N:30][N:31]([CH2:32][C:33]([CH3:36])([OH:35])[CH3:34])[C:26]2=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[N:28]=[C:27]3[N:29]=[N:30][N:31]([CH2:32][C:33]([OH:35])([CH3:34])[CH3:36])[C:26]3=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)Cn1nnc2nc(Cl)ccc21
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)Cn1nnc2nc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)ccc21

Procedure:
The title compound was prepared as described in Example 1, Step 5 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (23 mg, 0.074 mmol) and 1-(5-chloro-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-2-methylpropan-2-ol (17 mg, 0.074 mmol) as starting materials.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:31])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH:19]=2)=[CH:10][CH:9]=1.ClC1C=CC=C(C(OO)=[O:40])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[O-:40][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:31])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH:19]=2)=[CH:12][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(Cc4ccccn4)cc3)c2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(Cc4cccc[n+]4[O-])cc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.3 %

Procedure:
To a solution of (E)-N-[4-(2-pyridylmethyl)phenyl]-3-(4-methylphenyl)cinnamamide (302 mg) in tetrahydrofuran (10 ml) was added 3-chloroperbenzoic acid (70%, 0.27 g) at 0° C., and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was recrystallized from ethanol to give (E)-N-[4-(1-oxidopyridin-2-ylmethyl)phenyl]-3-(4-methylphenyl)cinnamamide (Compound 191) (180 mg) as pale yellow crystals.
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].CCOC(C)=O>N1C=CC=CC=1>[C:21]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:8]2[CH:12]=[C:11]([CH2:13][O:14][C:27](=[O:29])[CH3:28])[N:10]=[CH:9]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)OC(C)=O
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 48 h

Procedure:
The alcohol from Step B (260 mmol, prepared above) was suspended in pyridine (500 mL). Acetic anhydride (74 mL, 780 mmol) was added dropwise, and the reaction was stirred for 48 hours during which it became homogeneous. The solution was poured into EtOAc, washed sequentially with water, 5% aq. HCl solution, sat. aq. NaHCO3, solution, and brine. The organic extracts were dried, (Na2SO4), and concentrated in vacuo to provide the product as a white powder, which was sufficiently pure for use in the next reaction.
Reaction SMILES: [SH:1][CH2:2][C:3]([CH2:5][SH:6])=[CH2:4].[CH3:7][C:8]([CH3:10])=O.[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[CH3:7][C:8]1([CH3:10])[S:6][CH2:5][C:3](=[CH2:4])[CH2:2][S:1]1
Reactant: C=C(CS)CS
Reactant: CC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: C=C1CSC(C)(C)SC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(Mercaptomethyl)-3-mercapto-1-propene (Z Chem. 1975, 15, 302)(0.83 g, 6.9 mmoles) and acetone (0.51 mL) were placed in about 15 mL of dichloromethane. Then anhydrous aluminium chloride (0.32 g) was added portionwise over one minute at room temperature. The solution was stirred at room temperature for 30 minutes. The reaction was worked up by addition of 20 mL of water followed by extraction with dichloromethane. The extracts were dried and evaporated to give 0.89 g clear oil with a penetrating smell. The oil was chromatographed to give 400 mg (40%) of clear oil.
Reaction SMILES: O[CH2:2][C@@H:3]1[CH2:9][C@H:8]2[C@H:6]([CH2:7]2)[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[O:41]=[C:39]1[C:38]2[C:37](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:36](=[O:46])[N:40]1[CH2:2][C@@H:3]1[CH2:9][C@H:8]2[C@H:6]([CH2:7]2)[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@H]2C[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H]2C[C@H]2C[C@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1,1-dimethylethyl (1S,4S,6S)-4-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate D27 (310 mg), triphenylphosphine (1073 mg, 4.09 mmol) and phthalimide (502 mg, 3.41 mmol) were collected together and dissolved in THF (7 ml). The mixture was brought to 50° C. and then DIAD (0.796 ml, 4.09 mmol) was added dropwise. The mixture was stirred for 1 hour at 50° C. then 1 ml of water were added. Volatiles were removed in vacuum and the resulting crude was purified by silica gel chromatography (column size 10 g) using Cy/EtOAc=8:2 to Cy/EtOAc=5:5 to EtOAc 100%. It was recovered the title compound D28 (488 mg). UPLC: (Acid Final_QC): rt=0.80 minutes, peaks observed: 357 (M+1). C20H24N2O4 requires 356.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:22][C:23](=[O:35])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:35]=[C:23]1[CH2:24][C:25]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=2)=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][C:9]=2[NH:22]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(C2=Nc3ccc(C#Cc4ccccc4)cc3NC(=O)C2)ccn1

Procedure:
Prepared from {2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-4-phenylethynyl-phenyl}-carbamic acid tert.-butyl ester (Example K67) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (10 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9])=[C:4]([F:15])[CH:3]=1.Cl.C([N:19]=C=NCCCN(C)C)C.[OH-].[NH4+]>ClCCl>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([NH2:19])=[O:9])=[C:4]([F:15])[CH:3]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1F)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(Oc1ccc(Cl)cc1F)C(N)=O
Reaction time: 1 h

Procedure:
To a solution of Example 53B (14.6 g, 62.8 mmol) in dichloromethane (200 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (8.50 g, 55.5 mmol), and the reaction mixture was stirred for 1 hour. Ammonium hydroxide (87 mL, 628 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours and then quenched with water (100 mL). The aqueous layer was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with saturated NaHCO3, brine (100 mL), dried (MgSO4), filtered and concentrated. The residue was triturated with hexane/ethyl acetate (95/5) to provide the titled compound. MS (DCI+) m/z 232 (M+H)+.
Reaction SMILES: FC(F)(F)[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)N=1.Cl[C:20]1N=C(C(F)(F)F)C=C[N:21]=1>>[CH3:3][C:8]1[N:21]=[CH:20][C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)=[N:6][CH:7]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: FC(F)(F)c1ccnc(N2C[C@@H]3CCNC[C@@H]32)n1
Product: Cc1cnc(N2C[C@@H]3CCNC[C@@H]32)cn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 27, substituting 2-bromo-5-methylpyrazine for 2-chloro-4-(trifluoromethyl)pyrimidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8](C#CC3C=CC(C(OCC)=O)=CC=3)=[CH:7][C:6]=2[C:5]([C:25]#[C:26][CH2:27][CH2:28][CH3:29])=[CH:4][CH2:3]1.FC(F)(F)S(OC1C2C=CC([C:49]#[C:50][C:51]3[CH:61]=[CH:60][C:54]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:53][CH:52]=3)=CC=2C(C)(C)CC=1)(=O)=O>>[CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[C:9]([C:49]#[C:50][C:51]3[CH:61]=[CH:60][C:54]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:53][CH:52]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:25]#[C:26][CH2:27][CH2:28][CH3:29])=[CH:4][CH2:3]1
Reactant: CCCC#CC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc21
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3OS(=O)(=O)C(F)(F)F)cc1
Product: CCCC#CC1=CCC(C)(C)c2cc(C#Cc3ccc(C(=O)OCC)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl]benzoate (compound 75), 200 mg (0.42 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 87) was converted into the title compound (pale yellow oil) using 286 mg (4.2 mmol) of pentyne, 60 mg (0.08 mmol) of bis(triphenylphosphine)palladium (II) chloride and 20 mg (0.11 mmol) of cuprous iodide.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].O=C[C@H]([C@H]([C@@H](CO)O)O)O>>[O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C[C@@H](O)[C@@H](O)[C@H](O)CO
Product: O=C[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
D-xylose and D-lyxose: 2.8%
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]#[CH:19])=[CH:13][CH:14]=2)[C:9]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[N:8][C:7]1=[O:29].C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][O:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][O:44]1>CC(C)=O>[CH:26]([C:23]1[CH:24]=[CH:25][C:20]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]#[CH:19])[CH:11]=3)[N:6]([CH2:5][C:4]3[CH:30]=[CH:31][CH:32]=[C:2]([O:1][CH2:40][CH2:41][O:42][CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][O:44]4)[CH:3]=3)[C:7](=[O:29])[N:8]=2)=[CH:21][CH:22]=1)([CH3:27])[CH3:28]
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(O)c1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(OCCOC2CCCCO2)c1
Temperature: 25 °C

Procedure:
To a solution of 640 mg (1.51 mmol) of 1-(3-hydroxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one in acetone (20 ml) is added potassium carbonate (2.08 g, 15.1 mmol) followed by 2-(2-bromo-ethoxy)-tetrahydropyran (475 μl, 3.02 mmol). The reaction mixture is heated at reflux for 2 days. After cooling to room temperature, the reaction mixture is quenched with water and extracted with EtOAc (2×20 ml). The combined organic layers are washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to provide a yellow oil which is purified by flash chromatography on silica gel using dichloromethane/t-butyl methyl ether (1:1) to provide the title compound as a yellow oil. Yield: 830 mg (71%).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[NH3:23].O>CS(C)=O>[NH2:23][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: N
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N
Temperature: 90 °C
Yield: 79.3 %

Procedure:
A mixture of 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (126) (0.30 g, 1.01 mmol) and ammonia (4.05 mL, 8.10 mmol) in DMSO (5 mL) was heated at 90° C. in a sealed tube for 16 h. The reaction mixture was cooled to RT, treated with water, and extracted with DCM (3×). The extracts were dried over Na2SO4, concentrated. The residue was purified by silica gel chromatography (0-10% MeOH/DCM) to give 2-(3-amino-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (445a, 235 mg, 79%). m/z (ESI, +ve) 294 (M+H)+. A mixture of 2-(3-amino-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (445a, 50 mg, 0.17 mmol) and Ac2O (0.016 mL, 0.17 mmol) in pyridine (2 mL) was heated at 50° C. for 16 h. It was concentrated under reduced pressure. The residue was purified by reverse phase HPLC. The pure fractions were combined and concentrated to dryness. The solid was dissolved in MeOH and neutralized by pass through Stratosphere SPE (PL-HCO3 MP-Resin) to give N-(3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)acetamide as a tan solid (445) (10 mg, 17%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.21 (1H, br. s.), 10.22 (1H, s), 8.07-8.20 (1H, m), 7.71 (1H, dd, J=8.2, 1.2 Hz), 7.63 (1H, t, J=7.8 Hz), 7.09 (1H, d, J=2.3 Hz), 6.99 (1H, br. s.), 3.41-3.51 (2H, t, J=6.8 Hz), 2.94 (2H, t, J=6.8 Hz), 2.75 (3H, s), 2.36 (3H, s). m/z (ESI, +ve) 336 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][N:25]=3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H][H]>C(O)C.[Pd]>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:15]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1ccc(Br)cn1
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1ccccn1

Procedure:
The more polar compound, 3-(4-phenoxyphenyl)-1-(5-bromo-2-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, was suspended in absolute ethanol (10 mL) and N,N-dimethylformamide (5 mL) and 10% palladium on carbon (0.007 g) was added. The mixture was stirred under a balloon atmosphere of hydrogen for 18 hours. The mixture was filtered through pad of Celite® 521, washing with absolute ethanol. The solvent was removed in vacuo to give 3-(4-phenoxyphenyl)-1-(2-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.030 g, 0.00007 mol) as a white solid.