Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2].[CH3:19][C:20]([CH3:25])=[CH:21][C:22](Cl)=[O:23]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:22](=[O:23])[CH:21]=[C:20]([CH3:25])[CH3:19])[CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2]
Reactant: CC(C)=CC(=O)Cl
Reactant: CCCCCC(C(=O)OCC)c1cccc(N)c1
Solvent: ClC(Cl)Cl
Product: CCCCCC(C(=O)OCC)c1cccc(NC(=O)C=C(C)C)c1

Procedure:
A solution of 2-(3-amino-phenyl)-heptanoic acid ethyl ester (3.866 g, 15.5 mmole) in 40 mL of chloroform was treated with 1.73 mL of 3,3-dimethylacryloyl chloride. The mixture was heated at reflux for four hours, quenched by the addition of 100 mL water and extracted with three 50 mL portions of chloroform. The combined organic extracts were washed with 100 mL of saturated aqueous sodium bicarbonate solution, 100 mL of water and 100 mL of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 15% ethyl acetate in hexanes) to yield 3.822 g of 2-[3-(3-methyl-but-2-enoylamino)-phenyl]-heptanoic acid ethyl ester as a pale yellow oil.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]1[CH:22]=[N:21][C:8]2[CH2:9][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:12][O:13][C:7]=2[N:6]=1)[CH3:3].C[Si](C)(C)[N-][Si](C)(C)C.[K+].I[CH2:34][CH3:35].O>O1CCCC1>[CH2:34]([N:4]([CH:2]([CH3:1])[CH3:3])[C:5]1[CH:22]=[N:21][C:8]2[CH2:9][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:12][O:13][C:7]=2[N:6]=1)[CH3:35]
Reactant: CCI
Reactant: CC(C)Nc1cnc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(c1cnc2c(n1)OCCN(C(=O)OC(C)(C)C)C2)C(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 7 %

Procedure:
To a solution of tert-butyl 3-[(1-methylethyl)amino]-6,7-dihydropyrazino[2,3-f][1,4]oxazepine-8(9H)-carboxylate (137 mg) in tetrahydrofuran (3 mL) was added dropwise potassium hexamethyl disilazide (1.06 mL, 0.5 M toluene solution) at 0° C. The mixture was stirred at 0° C. for 15 min, and iodoethane (105 μL) was added dropwise thereto. The mixture was stirred at 0° C. for 1.5 hr, and further at room temperature overnight. Water (5 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10→40% ethyl acetate/hexane) to give the title compound (10 mg, 7%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:36]=[CH:35][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][N:18]3[C:26]([O:27]C)=[N:25][C:24]4[C:19]3=[N:20][C:21]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[N:22][C:23]=4[NH2:29])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)[CH3:3].CO.Cl.N>O1CCOCC1>[NH2:29][C:23]1[N:22]=[C:21]([O:30][CH2:31][CH2:32][O:33][CH3:34])[N:20]=[C:19]2[C:24]=1[NH:25][C:26](=[O:27])[N:18]2[CH2:17][CH2:16][CH:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:36][CH:35]=2)[CH2:11][CH2:12]1
Reactant: COCCOc1nc(N)c2nc(OC)n(CCC3CCN(Cc4ccc(CN(C)C)cc4)CC3)c2n1
Agent: Cl
Agent: N
Solvent: CO
Solvent: C1COCCO1
Product: COCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(Cc4ccc(CN(C)C)cc4)CC3)c2n1
Temperature: 0 °C
Yield: 33.3 %

Procedure:
To the compound (0.28 g, 0.57 mmol) obtained in Step (iii) were added methanol (3 ml) and a 4N hydrochloric acid in dioxane (3 ml), and the mixture was stirred at room temperature for one hour. The mixture was cooled to 0° C., and neutralized with 4% aqueous ammonia. The precipitated solid was collected by filtration, and washed with water to give the title compound (0.18 g, 0.19 mmol) as a white solid. Yield: 65%.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:40])=[C:5]([C:21]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][N:29]2C(=O)C3=CC=CC=C3C2=O)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].O.NN>C(O)C>[CH3:40][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:5]=1[C:21]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][NH2:29])=[O:22]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1
Agent: NN
Solvent: CCO
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOCCN)C1c1cccc([N+](=O)[O-])c1
Yield: 68.8 %

Procedure:
A solution of 9.14 g of methyl 2-(2-phthalimidoethoxy)ethyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 4,2 g of hydrazine monohydrate in 100 ml of ethanol was refluxed for 2 hours under heating. After cooling the reaction solution with ice and then adding thereto 100 ml of chloroform, precipitates were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The product was eluted with chloroform-methanol (8:2 v/v) and 4.8 g of 2-(2-aminoethoxy)ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate was obtained as liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:21]=[CH:22][C:23]=2[S:24]([OH:27])(=[O:26])=O)[C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH3:20])=[O:5])[CH3:2].[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[CH:28]1([NH:31][S:24]([C:23]2[CH:22]=[N:21][N:10]3[C:11]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=4[CH3:20])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8][C:9]=23)(=[O:26])=[O:27])[CH2:30][CH2:29]1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)O)cnn2c1Nc1ccc(F)cc1C
Reactant: NC1CC1
Product: CCOC(=O)c1cnc2c(S(=O)(=O)NC3CC3)cnn2c1Nc1ccc(F)cc1C
Yield: 99.9 %

Procedure:
Using 6-ethoxycarbonyl-7-(4-fluoro-2-methylphenylamino)pyrazolo[1,5-a]pyrimidine-3-sulfonic acid (0.400 g, 1.145 mmol) obtained in Example 1 step 2 and cyclopropylamine (0.261 g, 4.580 mmol) instead of tert-butylamine, and in the same manner as in Example 1 step 3, the title compound (0.496 g, 100%) was obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.O1CCOCC1.[F:25][C:26]([F:62])([F:61])[C:27]1[CH:28]=[C:29]([CH:54]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:56]=1)[CH2:30][N:31]1[CH2:38][CH2:37][CH2:36][NH:35][C:34]2[N:39]=[C:40](S(C)(=O)=O)[N:41]=[C:42]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:33]=2[C:32]1=[O:53]>C(OCC)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:40]2[N:41]=[C:42]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:33]3[C:32](=[O:53])[N:31]([CH2:30][C:29]4[CH:54]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:56]=[C:27]([C:26]([F:62])([F:25])[F:61])[CH:28]=4)[CH2:38][CH2:37][CH2:36][NH:35][C:34]=3[N:39]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)c1nc2c(c(-c3ccccc3)n1)C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Reactant: CC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2nc3c(c(-c4ccccc4)n2)C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCN3)CC1
Yield: 69.2 %

Procedure:
1-acetylpiperazine(23.1 mg), diisopropylethylamine(0.1 mL), and 1,4-dioxane (1 mL) were added to 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-2-(methylsulfonyl)-5-oxo-4-phenylpyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 16; 83.8 mg). While heated, the mixture was refluxed for 5 hours. Subsequently, the reaction mixture was diluted with ethyl acetate, was sequentially washed with water and a saturated aqueous solution of sodium chloride, and was then dried over anhydrous sodium sulfate. Following removal of the solvent, the residue was purified on a silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain 2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-5-oxo-4-phenylpyrimido[4,5-b][1,5]diazocine (63.0 mg, 69%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:16]1([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][N:5]3[C:9](=[O:10])[C:8]4=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]4[C:6]3=[O:15])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCN1CCN(c2ccccc2)CC1
Reaction time: 4.5 h
Yield: 90 %

Procedure:
To the solution of N-(3-bromopropyl)phthalimide (15.6 g) in acetone (150 ml) were added 1-phenylpiperazine (10.4 g) and potassium carbonate (12.0 g). The resulting mixture was refluxed with stirring for 4.5 hours. The reaction mixture was cooled and then filtered. The filter cake was washed with acetone. The filtrate and washing were combined and evaporated under reduced pressure. The residue was recrystallized from ethanol to give an oil of N-[3-(4-phenyl-1-piperazinyl)propyl]phthalimide (18.3 g), mp 129° to 134° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:19])[C:9]([O:14]CC(C)=C)=[CH:10][C:11]=2[CH3:13])[CH2:6][CH:5]1[CH3:20])(=[O:3])[CH3:2]>C(N(CC)C1C=CC=CC=1)C.C(OCC)C>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:19])[C:9]([OH:14])=[C:10]([CH2:8][C:7]([CH3:12])=[CH2:6])[C:11]=2[CH3:13])[CH2:6][CH:5]1[CH3:20])(=[O:3])[CH3:2]
Reactant: C=C(C)COc1cc(C)c2c(c1C)CC(C)N2C(C)=O
Solvent: CCN(CC)c1ccccc1
Solvent: CCOCC
Product: C=C(C)Cc1c(C)c2c(c(C)c1O)CC(C)N2C(C)=O
Yield: 174.2 %

Procedure:
A solution of 1-acetyl-2,3-dihydro-2,4,7-trimethyl-5-[(2-methyl-2-propenyl)oxy]-1H-indole (3.8 g, 14.7 mmol) in N,N-diethylaniline (30 ml) was stirred for 2 hours at 200° C. under nitrogen atmosphere. The reaction mixture was diluted with diethyl ether, and washed with 1N hydrochloric acid, water and saturated brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 3.5 g of the title compound as an oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[N+:13]([C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([NH:20][NH2:21])=[O:19])([O-:15])=[O:14]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:21][NH:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=1[N+:13]([O-:15])=[O:14]
Reactant: NNC(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=Cc1ccc2ccccc2n1
Solvent: CCO
Product: O=C(NN=Cc1ccc2ccccc2n1)c1ccccc1[N+](=O)[O-]
Yield: 32.4 %

Procedure:
A mixture of 2.99 gm (0.019 mole) of 2-quinolinecarboxaldehyde, 3.44 gm (0.019 mole) of o-nitrobenzhydrazide and 150 ml of absolute ethanol is refluxed 9 hrs. The solvent is evaporated in vacuo. The solid is crystallized from methanol to give 1.97 gm (32%) of title compound, having a melting point of 195°-196° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[BH4-].[Na+].[C:22]([N:26]([CH3:33])[S:27]([CH2:30][C:31]#[N:32])(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23].[H-].[Na+].Br[C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[N:42]([S:46]([C:49]1[CH:55]=[CH:54][C:52]([CH3:53])=[CH:51][CH:50]=1)(=[O:48])=[O:47])[CH:41]=[C:40]2[CH2:56][C@H:57]1[CH2:61][CH2:60][CH2:59][N:58]1[CH3:62]>COCCOC.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.O>[C:22]([N:26]([CH3:33])[S:27]([CH:30]([C:31]#[N:32])[C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[N:42]([S:46]([C:49]1[CH:55]=[CH:54][C:52]([CH3:53])=[CH:51][CH:50]=1)(=[O:47])=[O:48])[CH:41]=[C:40]2[CH2:56][C@H:57]1[CH2:61][CH2:60][CH2:59][N:58]1[CH3:62])(=[O:28])=[O:29])([CH3:25])([CH3:24])[CH3:23]
Reactant: CN(C(C)(C)C)S(=O)(=O)CC#N
Reactant: Cc1ccc(S(=O)(=O)n2cc(C[C@H]3CCCN3C)c3cc(Br)ccc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [H-]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(C[C@H]3CCCN3C)c3cc(C(C#N)S(=O)(=O)N(C)C(C)(C)C)ccc32)cc1
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 44.2 %

Procedure:
To a stirred suspension of dichlorobis(triphenylphosphine)palladium (II) (704 mg, 1 mmol) and triphenylphosphine (525 mg, 2 mmol) in ethyleneglycol dimethylether (5 ml) at ambient temperature under an atmosphere of nitrogen was added sodium borohydride (38 mg, 1 mmol) in one portion. The green slurry was stirred for 5 min, then N-tert-butyl-cyano-N-methylmethanesulfonamide (from step (c), 1.04 g, 5.4 mmol) was added in one portion. The green slurry was then cooled to 0-5° C. and sodium hydride (60% dispersion in mineral oil) (441 mg, 11 mmol) was added portionwise, maintaining the temperature below 5° C. The brown solution was then warmed to ambient temperature over a 10 min period, before a solution of (R)-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1-tosyl-1H-indole (from step (d), 2.24 g, 5 mmol) in ethyleneglycol dimethyl ether (15 ml) was added dropwise. The brown slurry was then warmed to reflux. Reflux was maintained for 1.5 hr after which time the dark brown solution was cooled to ambient temperature. The reaction mixture was then poured into water (20 ml) and extracted with ethyl acetate (3×25 ml). The organic extracts were combined and evaporated in vacuo to yield a brown oil. This was purified by flash column chromatography (ethyl acetate:hexane:diethylamine 1:1:0.1 as eluant) to yield the subtitle compound (1.23 g, 45%) as a golden oil.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C@H:16]([CH3:17])[CH2:15][N:14]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])[C@@H:13]([CH3:28])[CH2:12]2)=[CH:7][C:6]=1[C:29]([F:32])([F:31])[F:30])#[N:4].[CH3:33]I.O>CN(C=O)C>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C@H:16]([CH3:17])[CH2:15][N:14]([C:18]([N:20]([CH3:33])[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])[C@@H:13]([CH3:28])[CH2:12]2)=[CH:7][C:6]=1[C:29]([F:31])([F:32])[F:30])#[N:4]
Reactant: CI
Reactant: C[C@@H]1CN(C(=O)Nc2ccc(F)cc2)[C@@H](C)CN1c1ccc(C#N)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CN(C(=O)N(C)c2ccc(F)cc2)[C@@H](C)CN1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
A 69 mg portion of 60% sodium hydride was suspended in 6 ml of DMF, 660 mg of trans-4-(4-cyano-3-trifluoromethylphenyl)-4′-fluoro-2,5-dimethylpiperazine-1-carboxanilide synthesized in Example 1-1 was added to the suspension under ice-cooling, and then the mixture was stirred at 50° C. for 10 minutes. The reaction solution was ice-cooled, 0.11 ml of methyl iodide was added dropwise thereto, and then the mixture was stirred at room temperature for 2 hours. The reaction mixture was mixed with water, extracted with ethyl acetate, washed with saturated brine and then dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by a silica gel column chromatography to obtain 620 mg of the title compound from ethyl acetate-hexane eluate.
Reaction SMILES: [CH2:1]([N:8]1[CH:30]=[N:29][C:28]2[N:13]([C@@H:14]3[O:27][C@H:17]([CH2:18][O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:16]=[CH:15]3)[CH:12]=[N:11][C:10]=2[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[C].[Pd].CO>[CH2:1]([N:8]1[CH:30]=[N:29][C:28]2[N:13]([C@@H:14]3[O:27][C@H:17]([CH2:18][O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)[CH:12]=[N:11][C:10]=2[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2ncn([C@H]3C=C[C@@H](COCc4ccccc4)O3)c2ncn1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=c1c2ncn([C@H]3CC[C@@H](COCc4ccccc4)O3)c2ncn1Cc1ccccc1
Yield: 90 %

Procedure:
To a methanol solution (1 mL) of N1,5′-O-dibenzyl-2′,3′-didehydro-2′,3′-dideoxyinosine (207 mg, 0.5 mmol), 5% palladium-carbon (20 mg) was added, and the mixture was stirred at room temperature for 2 hours in an atmosphere of hydrogen (1 atm). The palladium catalyst was removed from the obtained reaction mixture by filtration, and the resultant filtrate was concentrated under reduced pressure. After purification by chromatography (using 15 g of silica gel and ethyl acetate as an eluting solution), 187 mg of the intended product was obtained in a yield of 90% as a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1.[CH2:23]([CH:27]([Sn])C=C(CCCC)CCCC)[CH2:24]CC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:27]([C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1)[CH:23]=[CH2:24]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(Br)c2s1
Reactant: CCCCC(=CC([Sn])CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1cc(-c2cccnc2)cc2nc(NC(=O)NCC)sc12
Temperature: 120 °C

Procedure:
To a solution of 1-(7-bromo-5-pyridin-3-yl-benzothiazol-2-yl)-3-ethyl-urea (0.14 g, 0.37 mmol) in DMF (2 mL) was added tributylallyltin (0.15 g, 0.45 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was then degassed for half an hour followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.043 g, 0.0371 mmol). The reaction mixture was then again degassed for half an hour and heated at 120° C. for 20 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), DMF was distilled off; water was added to the reaction mixture and extracted with ethyl acetate (×3). The combined organic layer was dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude residue was purified over silica gel (230-400 M) using EtOAc-MeOH (95:5) to provide the title compound as off white solid (0.034 g, 27%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([CH3:28])=[CH:26][S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[C:27]([CH3:28])=[CH:26][S:25][C:15]=2[N:16]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1csc2nc(-c3cnccn3)nc(Cl)c12
Product: Cc1csc2nc(-c3cnccn3)nc(NCc3cccc([N+](=O)[O-])c3)c12

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyrazin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3-nitrobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]1[NH:2][N:3]=[CH:4][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC.I[C:23]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]>CN(C=O)C.[Cu]I>[N:1]1[N:2]([C:23]2[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:35])[F:34])=[CH:28][C:24]=2[C:25]([OH:27])=[O:26])[N:3]=[CH:4][CH:5]=1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1I
Reactant: c1cn[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(C(F)(F)F)ccc1-n1nccn1

Procedure:
To a solution of 2H-1,2,3-triazole (CAS number 288-36-8; 1.0 g, 10.86 mmol) in DMF (4 ml) at 0-10° C. was added cesium carbonate (4.71 g, 14.49 mmol), copper (I) iodide (68 mg, 0.36 mmol), trans-1-N,2-N-dimethylcyclohexane-1,2-diamine (200 mg, 1.44 mmol) and 2-iodo-5-(trifluoromethyl)benzoic acid (CAS number 702641-04-1; 2.28 g, 7.24 mmol). The reaction was subjected to microwave irradiation at 120° C. for 15 minutes and was then partitioned between ethyl acetate (2×100 ml) and water (50 ml). The aqueous layer was acidified with HCl (aq, 2M) to give pH 2 and the organics were extracted with ethyl acetate (3×100 ml). The combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-3% methanol/DCM) to afford 2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37a; also commercially available CAS number 1384066-81-2). The mixed fractions were further purified by column chromatography (silica, 0-3% methanol/DCM) followed by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% formic acid) to afford 2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37b).
Reaction SMILES: Cl.Cl.[CH2:3]([N:5]1[C:9]2=[N:10][CH:11]=[C:12]([C:21]([NH:23][NH2:24])=[O:22])[C:13]([NH:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:8]2[CH:7]=[N:6]1)[CH3:4].CCN(C(C)C)C(C)C.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>C1COCC1>[CH:34]1([C:37]([NH:24][NH:23][C:21]([C:12]2[C:13]([NH:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[C:8]3[CH:7]=[N:6][N:5]([CH2:3][CH3:4])[C:9]3=[N:10][CH:11]=2)=[O:22])=[O:38])[CH2:36][CH2:35]1
Reactant: O=C(Cl)C1CC1
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)NN)cnc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)NNC(=O)C3CC3)cnc21
Yield: 45 %

Procedure:
A solution of Intermediate 19 (0.045 g) in THF (2 ml) was treated with DIPEA (0.045 ml), then with cyclopropylcarbonyl chloride (0.013 g) and stirred at room temperature for 16 h. The mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The layers were separated and the organic layer concentrated in vacuo, then applied to an SPE cartridge (aminopropyl, 1 g). The column was eluted with methanol to afford Intermediate 20 as a white solid (0.02 g). LCMS showed MH+=373; TRET=2.15 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[CH:32][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([N:26]3[CH2:31][CH2:30][S:29][CH2:28][CH2:27]3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:48])C=1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[CH:32][C:13]=2[C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([S:23]([N:26]3[CH2:27][CH2:28][S:29](=[O:48])[CH2:30][CH2:31]3)(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)Nc2ccc(S(=O)(=O)N3CCSCC3)cc2)cc1OC
Solvent: CC(C)=O
Product: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)Nc2ccc(S(=O)(=O)N3CCS(=O)CC3)cc2)cc1OC
Temperature: 25 °C

Procedure:
500 mg (0.82 mmol) of 2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide in 50 ml of acetone were cooled to 0° C. A solution of 371 mg (1.23 mmol) of 57% m-chloroperbenzoic acid in 20 ml of acetone was added and the mixture was stirred at room temperature over night. For working up it was poured onto water/ice and the precipitate was filtered off with suction. The two products obtained as a mixture were separated by chromatography over silica with methylene chloride/methanol (97:3).