Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:21])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH2:4][CH2:3]1.[H][H]>CO.[C].[Pd]>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:21])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1O
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N[C@H]2CC[C@H](C)CC2)ccc1O

Procedure:
0.075 g of 10% palladium-carbon was added to a solution of 1.5 g of N-(trans-4-methylcyclohexyl)-4-hydroxy -3-methoxycinnamamide (Example 131) in 100 ml of methanol. The solution was vigorously stirred for 16 hours under normal-pressure hydrogen gas. After reaction, the catalyst was filtered out, and the solvent was removed in vacuo from the flitrate, yielding 1.33 g of N-(trans-4-methylcyclohexyl)-3-(4-hydroxy-3-methoxyphenyl)propionamide (a compound of the present as a colorless oil, which had the following physiochemical properties:
Reaction SMILES: C([CH:8]([CH:10]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:12]=2[O:11]1)[NH2:9])C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>>[CH2:38]([O:37][C:35](=[O:36])[NH:9][CH2:8][CH:10]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:12]=2[O:11]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(Cc1ccccc1)C1Cc2cccc(-c3ccccc3)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3ccccc3)c2O1)OCc1ccccc1

Procedure:
Treatment of (±)-benzyl(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine (1.5 g, 1.43 mmol) with diisopropylethylamine (0.277 g, 2.14 mmol) followed by benzyl chloroformate (0.268 g, 1.572 mmol) generally according to the procedure described for Intermediate 12 provided 1.64 (79%) of (±)-benzyl[7-phenyl-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a clear oil. Rf=0.68 (silica, ethyl acetate:hexanes 1:2); Anal. calcd. for C23H21NO3: C, 76.86; H, 5.89; N, 3.90. Found: C, 75.10H, 5.71; N, 3.90. Chiral HPLC separation of (±)-benzyl[7-phenyl-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralpak AD, ethanol:hexane 1:1) provided two fractions. Fraction 1 (Rt=10.746 min, Chiralpak AD, ethanol:hexane 1:1); Fraction 2 (Rt=13.433 min, Chiralpak AD ethanol:hexane 1:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[OH:20][C:21]1[CH:34]=[C:33]([OH:35])[CH:32]=[CH:31][C:22]=1[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].[OH-].[Na+].C(Cl)(Cl)Cl>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([O:35][C:33]4[CH:32]=[CH:31][C:22]([C:23](=[O:24])[C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[C:21]([OH:20])[CH:34]=4)=[O:18])=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Reactant: Cc1ccc(-c2nc3cc(C(=O)Cl)ccc3o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccc(-c2nc3cc(C(=O)Oc4ccc(C(=O)c5ccccc5)c(O)c4)ccc3o2)cc1

Procedure:
A solution containing 5.42 g. (0.02 mole) of 1c, 4.28 g. (0.02 mole) of 2,4-dihydroxybenzophenone, and 0.8 g. (0.02 mole) of sodium hydroxide in 50 ml. of chloroform and 15 ml. of water was refluxed for 3 hours. After cooling, the layers were separated and the organic layer was concentrated to given 5.27 g. (59%) of 1e as a white crystalline solid: UV (CH2Cl2) λmax 306 nm (31,000), ε325 =18,500.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:10][C:11]([CH:17]=O)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([O:34][C:35]([NH:37][CH:38](P(OC)(OC)=O)[C:39]([O:41][CH3:42])=[O:40])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C)C(=N)N(C)C>C1COCC1.C(OCC)(=O)C>[CH2:27]([O:34][C:35]([NH:37]/[C:38](=[CH:17]\[C:11]1[N:10]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1)/[C:39]([O:41][CH3:42])=[O:40])=[O:36])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
To a solution of 5-phenyl-4-(pyridin-2-ylmethylamino)quinazoline-2-carbaldehyde (0.9 g, 3 mmol) in THF (10 mL) was added methyl 2-benzyloxycarbonylamino-2(dimethoxyphosphinyl)acetate (0.96 g, 2.9 mmol) followed by tetramethyguanidine (0.66 mL. 5.3 mmol). The resulting solution was stirred at RT for 3 h. After this time, the reaction mixture was diluted with ethyl acetate, washed successively with water and brine, dried over Na2SO4, filtered then and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (30% ethyl acetate in hexane) to yield (Z)-methyl 2-(benzyloxycarbonylamino)-3-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)acrylate (0.7 g (48% yield). LCMS Method V: retention time 1.94 min; [M+1]=546.0.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:10][NH2:11]>C(O)C>[CH3:1][C:2]([NH:11][CH3:10])([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CN
Reactant: CCOC(=O)C=C(C)C
Solvent: CCO
Product: CCOC(=O)CC(C)(C)NC

Procedure:
A mixture containing ethyl 3,3-dimethylacrylate (100 g) and methylamine (140 ml of a 33% solution in ethanol) in ethanol (400 ml) was allowed to stand at room temperature for 2 weeks. The mixture was concentrated in vacuo to give an oil which was fractionally distilled in vacuo to give the title compound as a colourless, mobile oil, yield, 95.0 g, b.p. 68°-75°/20 mm.Hg.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1.C1C(=O)N([Br:19])C(=O)C1.C([O-])(O)=O.[Na+]>C(#N)C>[Br:19][C:7]1[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[C:4]([NH2:9])=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(Br)cc1C(F)(F)F
Temperature: 23 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of 3-trifluoromethyl-pyridin-2-ylamine (16.21 g, 100 mmol) in acetonitrile (300 mL) at 5° C. was added NBS (17.8 g, 100 mmol) and the mixture was stirred at 23° C. for 1 h. Poured onto ice and sat. NaHCO3 soln., extracted with EtOAc, washed with brine, dried over Na2SO4. Removal of the solvent in vacuum left a yellow solid. Silica gel & cotton wool column filtratation with DCM gave the product as a yellow solid (23.71 g, 98%). MS (ISP) 240.1 [(M+H)+].
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]([C:12]2[NH:13][C:14]([C:17]([C:19]3[C:20](Cl)=[N:21][CH:22]=[CH:23][CH:24]=3)=O)=[CH:15][CH:16]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:27][NH2:28]>C(O)C>[C:1]1([C@@H:7]([NH:9][C:10]([C:12]2[NH:13][C:14]([C:17]3[C:19]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[NH:28][N:27]=3)=[CH:15][CH:16]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: C[C@H](NC(=O)c1ccc(C(=O)c2cccnc2Cl)[nH]1)c1ccccc1
Solvent: O
Solvent: CCO
Product: C[C@H](NC(=O)c1ccc(-c2n[nH]c3ncccc23)[nH]1)c1ccccc1
Temperature: 80 °C
Yield: 19 %

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-2-carboxylic acid ((S)-1-phenyl-ethyl)-amide (450 mg, 1.3 mmol) and hydrazine hydrate (2 mL) in ethanol (20 mL) was heated at 80° C. for 24 hours. The reaction was concentrated, the residue was triturated with water. The precipitate was collected by vacuum filtration, washed with water and DCM to give 80 mg (19%) of the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](C2C=CC=CC=2)[N:30]=1.BrC1C=CC=C(Br)N=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([Br:28])[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cccc(-c2ccccc2)n1
Agent: Brc1cccc(Br)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and a mixture of (2-bromo-6-phenyl-pyridine and 2,6-dibromo-pyridine). The products were purified on silica but not separated from one another. The mixture was used in the next step.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]2[CH:18]=[CH:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][O:23][C:24](=[O:26])[CH3:25])[C:12]=2[N:13]=[CH:14][N:15]=1.O>C(Cl)Cl>[Cl:9][C:10]1[C:11]2[C:18]([Cl:1])=[CH:17][N:16]([CH2:19][O:20][CH2:21][CH2:22][O:23][C:24](=[O:26])[CH3:25])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CC(=O)OCCOCn1ccc2c(Cl)ncnc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCCOCn1cc(Cl)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 192 h

Procedure:
N-Chlorosuccinimide was added to a solution of 4-chloro-7-(2-acetoxyethoxymethyl)pyrrolo[2,3-d]pyrimidine (3) (0.35 g) in dry methylene chloride (15 mL). The reaction mixture was stirred at room temperature for 8 days. At that time, TLC established a complete disappearance of starting material. Water (50 mL) was added to the mixture and the product was extracted with CHCL3 (3×30 mL). The chloroform extracts were combined and washed with water, then dried over anhydrous Na2SO4. The solvent was removed at 40 degrees C in vacuo and the resulting thick syrup was subjected to column chromatography. Elution of the silica gel column (15×2 cm) with benzene: chloroform (1:1), yielded a colorless oil (single spot on TLC) after evaporation of all the UV absorbing fractions at a reduced temperature and pressure, which was crystallized from ethyl alcohol to afford colorless needles of the acetylated intermediate, (7a, 0.23 g) (59.95%). 4,5-Dichloro-7-(2-acetoxyethoxymethyl)pyrrolo[2,3-d]pyrimidine (7a, 0.31 g) was then dissolved in dry methanol (15 mL) and to this solution was added methanol which had previously been saturated with ammonia at 0 degrees C. (25 mL). The reaction mixture was stirred in a pressure bottle at room temperature for 20 hours. The solvent was evaporated at 30 degrees C. in vacuo and the semi-solid mass was subjected to column chromatography. Elution of the product from a silica gel column (15×2 cm) with 2% MeOH in CHCl3 yielded a colorless compound, after evaporation of all the appropriate UV absorbing fractions. This solid was recrystallized from MeOH to furnish 0.11 g of 7. (40.74%), mp 142-143 degrees C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][C:9]2[N:10]=[CH:11][NH:12][C:13](=O)[C:8]=2[CH2:7]1)=[O:5])[CH3:2].C(OC(C1N(C(OC(C)(C)C)=O)CC2C(=O)NC=NC=2C1)=O)C.C(Cl)(Cl)(Cl)[Cl:48].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCCl>[CH2:1]([O:3][C:4]([CH:6]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][C:9]2[N:10]=[CH:11][N:12]=[C:13]([Cl:48])[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2c(nc[nH]c2=O)CN1C(=O)OC(C)(C)C
Reactant: ClC(Cl)(Cl)Cl
Agent: CCOC(=O)C1Cc2nc[nH]c(=O)c2CN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: CCOC(=O)C1Cc2c(Cl)ncnc2CN1C(=O)OC(C)(C)C

Procedure:
To a solution of the mixture of 4-Oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylic acid 7-tert-butyl ester 6-ethyl ester and 4-Oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6,7-dicarboxylic acid 6-tert-butyl ester 7-ethyl ester (1.5 g, 4.64 mmol) in DCE (25 mL), carbon tetrachloride (1.34 mL, 13.9 mmol) and triphenylphosphine (2.43 g, 9.28 mmol) are added. The reaction is heated at reflux and after completion of reaction as judged by LCMS. The solvents are removed and the products are isolated using FCC eluting with heptane:EtOAc 80:20. At this point the two products are separated. 4-Chloro-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylic acid 7-tert-butyl ester 6-ethyl ester MS (ESI) m/z 342.1 (M+1) and 4-chloro-7,8-dihydro-5H-pyrido[4,3-a]pyrimidine-6,7-dicarboxylic acid 6-tert-butyl ester 7-ethyl ester MS (ESI) m/z 342.1 (M+1) are isolated as an almost 4:1 ratio.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>ClCCl>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:27])=[CH:24][CH:23]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCCCN1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)NCCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
To a solution of N-3-aminopropylpiperidine (1.4 g, 10 mmol) in dichloromethane (20 mL) was added DIEA (1.9 mL, 11 mmol) followed by slow addition of 4-methoxy benzoyl chloride (1.9 g, 11 mmol). The reaction mixture was stirred at room temperature for 18 h. The solution was washed with 1 N KOH (aq.) (1×20 mL) and brine (1×20 mL). The organic phase was dried (K2CO3) and concentrated in vacuo to afford 4-methoxy-N-(3-piperidin-1-ylpropyl)benzamide (1.9 g, 6.9 mmol, 69%) as an oil.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[CH3:14][S:15][C:16]1[S:20][C:19]([NH2:21])=[N:18][CH:17]=1.C(N(CC)CC)C>C1COCC1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](=[O:8])[NH:21][C:19]1[S:20][C:16]([S:15][CH3:14])=[CH:17][N:18]=1)(=[O:3])[CH3:2]
Reactant: CSc1cnc(N)s1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1cnc(NC(=O)c2ccccc2OC(C)=O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
Under nitrogen a solution of acetylsalicyloyl chloride (1.24 g, 6.20 mmol, 1.3 eq) in THF (40 mL) was added to a stirred solution of 5-(methylthio)thiazol-2-amine 514 (700.0 mg, 4.79 mmol, 1.0 eq) in dry THF (5 mL). This was followed by the addition of triethylamine (0.67 mL, 4.79 mmol, 1.0 eq). The reaction mixture was stirred at room temperature and monitored by TLC. After two hours, reaction was filtered through sintered funnel and solvent removed in vacuo. The crude product was dissolved in EtOAc (150 mL) and washed twice each with 1M HCl and saturated aq. sodium hydrogen carbonate solutions. The organic fraction was dried over MgSO4 followed the removal of solvent. Flash column chromatography yielded the pure product 518 (1.450 g, 98%) as a solid.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:12]1([CH2:18][CH2:19][CH2:20][NH2:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)CC>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:21][CH2:20][CH2:19][CH2:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NCCCc1ccccc1
Reactant: Clc1ccc2ncc(Br)n2n1
Solvent: CCCO
Product: Brc1cnc2ccc(NCCCc3ccccc3)nn12
Temperature: 150 °C

Procedure:
A mixture of 3-bromo-6-chloro-imidazo[1,2-b]pyridazine (232 mg, 1 mmol) and phenylpropyl amine (1 ml, 7 mmol) in n-PrOH (1 mL) was heated in a microwave at 150° C. for 20 min. Additional phenylpropyl amine (0.5 ml) was added and reaction mixture heated for additional 20 min. then 30 min. in a microwave. The reaction mixture was concentrated and the residue was subjected to ISCO (40 g column, DCM 3 min. then 0-10% MeOH in DCM over 30 min.) to gave the product (380 mg ˜90% pure and was used directly for next step).
Reaction SMILES: Cl/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[S:18][CH:19]=[C:20]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[CH:21]=2)[CH:10]=1)[CH2:6][CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N)CCC.[C:51]([C:55]#[CH:56])([CH3:54])([CH3:53])[CH3:52]>[Cu]I.[Pd](Cl)Cl.O1CCCC1>[CH3:52][C:51]([CH3:54])([CH3:53])[C:55]#[C:56]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[S:18][CH:19]=[C:20]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[CH:21]=2)[CH:10]=1)[CH2:6][CH3:7]
Reactant: CCN(C/C=C/Cl)Cc1cccc(OCc2cc(-c3ccsc3)cs2)c1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCN
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(OCc2cc(-c3ccsc3)cs2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 72 %

Procedure:
To 10 ml of tetrahydrofuran were added 1.01 g (2.5 mmol) of (E)-N-(3-chloro-2-propenyl)-N-ethyl-3-[4-(3-thienyl)-2-thienylmethyoxy]benzylamine, 23.8 mg (0.125 mmol) of copper (I) iodide, 8.9 mg (0.05 mmol) of palladium chloride and 26.2 mg (0.1 mmol) of triphenylphosphine, and further, 0.50 ml (5.0 mmol) of n-butylamine and 0.37 ml (3.0 mmol) of tert-butylacetylene under ice cooling. The mixture was stirred for 17 hours at room temperature, and extracted with a mixture of 70 ml of ethyl acetate and 30 ml of water. The organic layer was separated, washed with a mixture of 40 ml of water and 4 ml of 2N hydrochloric acid, a mixture of 40 ml of water and 6 ml of saturated sodium bicarbonate aqueous solution and 20 ml of saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. After ethyl acetate was evaporated under reduced pressure, the residue was treated with 3 ml of methanol, and stirred for 17 hours under ice cooling. The resulting crystals were collected by filtration, washed with 2 ml of methanol and dried under reduced pressure to obtain 0.81 g (yield: 72%) of the above identified compound as slightly yellowish brown crystalline powder.
Reaction SMILES: [CH2:1]([N:7]1[C:15]2[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=2[N:9]=[CH:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:19][O:20][C:21]1[CH:34]=[CH:33][C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)=[CH:23][CH:22]=1>>[CH2:1]([N:7]1[C:15]2[C:14](=[O:16])[N:13]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:24]3[CH:33]=[CH:34][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[C:12](=[O:17])[N:11]([CH3:18])[C:10]=2[N:9]=[CH:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COc1ccc(OCCCCCCBr)cc1
Reactant: CCCCCCn1cnc2c1c(=O)[nH]c(=O)n2C
Product: CCCCCCn1cnc2c1c(=O)n(CCCCCCOc1ccc(OC)cc1)c(=O)n2C
Yield: 71 %

Procedure:
7-Hexyl-3-Methylxanthine and 6-(4-methoxyphenoxy)hexyl bromide were reacted and treated in substantially the same manner as described in Example 9 (a) to give 7-hexyl-1-[6-(4-methoxyphenoxy)hexyl]-3-methylxanthine (71%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[F:8][C:9]1[CH:10]=[C:11]([C:16](=O)[CH2:17][C:18](OCC)=[O:19])[CH:12]=[C:13]([F:15])[CH:14]=1>N1C=CC=CC=1>[F:8][C:9]1[CH:10]=[C:11]([C:16]2[N:4]3[N:3]=[C:2]([CH3:1])[CH:6]=[C:5]3[NH:7][C:18](=[O:19])[CH:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: CCOC(=O)CC(=O)c1cc(F)cc(F)c1
Reactant: Cc1cc(N)[nH]n1
Solvent: c1ccncc1
Product: Cc1cc2[nH]c(=O)cc(-c3cc(F)cc(F)c3)n2n1
Temperature: 25 °C
Yield: 36.8 %

Procedure:
3-Methylpyrazol-5-amine (526 mg) and ethyl 3-(3,5-difluorophenyl)-3-oxopropanoate (879 g) are stirred overnight in a pyridine (30 mL) solvent at 85° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield the target compound (521 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Br:12]Br>CC(O)=O.C(Cl)Cl.CCOC(C)=O>[Br:12][C:11]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: BrBr
Reactant: Oc1ccc2cccnc2c1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Oc1ccc2cccnc2c1Br
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
To a stirred solution of 7-hydroxyquinoline (59.0 g, 0.406 mol) in AcOH (120 mL) and CH2Cl2 (240 mL) was slowly added bromine (22.9 mL, 0.444 mol) in AcOH (120 mL) while maintaining the internal temperature at 0-5° C. The resulting suspension was stirred for 2 h at 0-5° C., and then diluted with EtOAc (100 mL) and filtered. The solid was washed with EtOAc (2×20 mL) and dried in vacuo to give 8-bromo-7-hydroxyquinoline (65 g, 76%).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:22]2[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:21]=2[NH:20][C:19](=O)[CH2:18][N:17]=1>CC(C)=O>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:22]2[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:21]=2[N:20]([CH3:19])[C:1](=[O:4])[CH2:18][N:17]=1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN1C(=O)CN=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
42.4 g of potassium carbonate and 18.5 ml of methyl iodide are added to a solution of 50 g (0.158 mol) of 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one in 600 ml of acetone and the mixture is stirred at room temperature for 16 hours. After filtering-off insoluble material, the filtrate is evaporated and the residue is taken up in methylene chloride. The organic phase is washed once with water, dried and evaporated, there being obtained 5-(o-chlorophenyl)-1,3-dihydro-1-methyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 220°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[N:17][C:12]=2[CH:11]=1.[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([S:38]([C:41]2[CH:46]=[CH:45][C:44](Br)=[CH:43][CH:42]=2)(=[O:40])=[O:39])[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([S:38]([C:41]2[CH:46]=[CH:45][C:44]([NH:18][C:15]3[N:16]=[N:17][C:12]4[CH:11]=[C:10]([C:3]5[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=5[Cl:1])[CH:20]=[C:19]([CH3:21])[C:13]=4[N:14]=3)=[CH:43][CH:42]=2)(=[O:39])=[O:40])[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)c2ccc(Br)cc2)CC1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(N)nnc3c2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Product: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(S(=O)(=O)C5CCN(C(=O)OCc6ccccc6)CC5)cc4)nnc3c2)c1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
In a dry 25 mL round bottom flask, 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.132 g, 0.44 mmol, 1 equiv), 4-(4-bromo-benzenesulfonyl)-piperidine-1-carboxylic acid benzyl ester (0.232 g, 0.529 mmol, 1.2 equiv), Cesium carbonate (0.432 g, 1.33 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.051 g, 0.088 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.040 g, 0.044 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (12 mL) and outfitted with a reflux condenser. The reaction was heated to reflux for 18 hours, then cooled to room temperature and slowly diluted with water. The resulting precipitate was collected and dried yielding a yellow powder (0.271 g, 93% yield). MS (ESI+): m/z=658.2, LC retention time: 3.41 min.