Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N+:10]([O-])=[O:11])([C:4]([CH3:9])([N+:6]([O-])=[O:7])[CH3:5])[CH3:3].[NH4+].[Cl-]>C1COCC1.O.[Zn]>[OH:7][NH:6][C:4]([CH3:9])([C:2]([NH:10][OH:11])([CH3:3])[CH3:1])[CH3:5]
Reactant: CC(C)([N+](=O)[O-])C(C)(C)[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(NO)C(C)(C)NO
Temperature: 9 °C
Reaction time: 1 h
Yield: 18376.1 %

Procedure:
2,3-Dimethyl-2,3-dinitrobutane (82.56 g, 0.47 mmol) was dissolved in a mixture of THF (1407 mL) and water (235 mL). To this solution cooled to 8-10° C., Zn powder (126.9 g, 1.95 mol) was added in one portion. A solution of NH4Cl (202.1 g, 3.77 mol) in H2O (705 mL) was added dropwise to this slurry, with continued stirring for 1 h at 10° C., and the flask was stored in cooled water for 16 h. The slurry was filtered, and the precipitate was carefully washed with THF (4×200 mL). The precipitate was then dried by three washings with diethyl ether and collected. The solution was evaporated under vacuum until THF ceased to distill off. Then the solution was protected from air, and sodium carbonate (235 g) and sodium chloride (141 g) were added with cooling. Continuous extraction with chloroform (1880 mL) was performed over 18 h. The filtrate was concentrated to give oil product, then added petroleum ether to this mixture and stirred for 30 min at room temperature, filtered, dried, to afford a white powder (12.8 g, 18.4% yield). 1HNMR (400 MHz, DMSO): δ 6.89 (s, 1H), 5.34 (s, 1H), 0.96 (s, 3H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:37]=[CH:36][CH:35]=[CH:34][C:7]=1[C:8]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[S:17]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=O)(=[O:19])=[O:18])=[O:9]>C1C=CC=CC=1>[Cl:5][C:6]1[CH:37]=[CH:36][CH:35]=[CH:34][C:7]=1[C:8]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[S:17]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([Cl:3])=[O:33])(=[O:19])=[O:18])=[O:9]
Reactant: O=C(O)CCCCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)CCCCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
19 g of redistilled thionyl chloride are added to 10.3 g of 11-[2-(2-chlorobenzoyl)-4-chlorobenzenesulphonamido]undecanoic acid in 130 ml of anhydrous benzene. After refluxing for 2 hours, the reaction medium is evaporated to dryness under vacuum and it gives a colourless oil which is used without further purification.
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH:23]2[CH2:32][C:31]3[N:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:25][CH2:24]2)=[CH:17][CH:16]=1)(=O)=O)([O-])=O.[NH:40]1[CH:44]=[CH:43][N:42]=[C:41]1[CH:45]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][NH:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]([CH2:45][C:41]2[NH:42][CH:43]=[CH:44][N:40]=2)[CH:23]2[CH2:32][C:31]3[N:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:25][CH2:24]2)=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCc3cccnc3C2)cc1)Cc1ccccn1
Reactant: O=Cc1ncc[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNCc2ccc(CN(Cc3ncc[nH]3)C3CCc4cccnc4C3)cc2)nc1
Yield: 120.4 %

Procedure:
Using general procedure B: Reaction of N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-7-quinolinyl)-1,4-benzenedimethanamine (175 mg, 0.32 mmol), imidazole-2-carboxaldehyde (155 mg, 1.6 mmol) and NaBH(OAc)3 (137 mg, 0.64 mmol) in MeOH (3 mL) for 8 hours at 60° C., followed by purification of the crude material by column chromatography on silica gel (CHCl3/MeOH/NH4OH 20:2:1) gave the desired product (169 mg, 84%) as a yellow/green foam.
Reaction SMILES: [C:1](=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:3])[CH3:2].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:3][C:1](=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)=C(C)CBr

Procedure:
Diethyl isopropylidenemalonate (4, 50g, 0.25 mol) was refluxed with stirring with N-bromosuccinimide (44.3 g, 0.25 mol) and dibenzoyl peroxide (1.0 g, 4.1 mmol) in carbon tetrachloride (100 mL) with illumination using Kodak Ectagraphic slide projector lamp ELH (300 Watt) for 1.5 h. The reaction was completed as indicated by a negative starch-iodine test for N-bromosuccinimide. The resulting mixture was diluted with carbon tetrachloride (100 mL) and it was cooled in an ice-bath. The precipitated succinimide was filtered off and the filtrate was evaporated in vacuo at room temperature. The residual pale yellow oil of diethyl bromo-isopropylidene-malonate (5, 71.1 g) was used without purification in the Example 2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N+:8]=2[O-])[CH:3]=[C:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].C[Si](C)(C)N[Si](C)(C)C.[Cl:25]C(OC)=O>C1COCC1>[Cl:25][C:7]1[N:8]=[C:9]2[C:4]([CH:3]=[C:2]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:1]2)=[CH:5][CH:6]=1
Reactant: COC(=O)Cl
Reactant: CCOC(=O)c1cc2ccc[n+]([O-])c2[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(Cl)nc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
To a stirred solution of ethyl 7-azaindole-2-carboxylate-7-oxide (1.32 g, 6.4 mmol) and hexamethyldisilazane (1.4 mL, 6.6 mmol) in THF (30 mL) at 0° C. was added dropwise over 30 min a solution of methyl chloroformate (12 mL, 15.5 mmol) in THF (5 mL). The mixture was warmed to room temperature, stirred for 2 h and partitioned between ether (50 mL) and water (50 mL). The aqueous layer was extracted with ether (30 mL). The combined organic extracts were washed (water, brine), dried (sodium sulfate) and purified by column chromatography [SiO2; heptane—ether (3:1)1 to give ethyl 6-chloro-7-azaindole-2-carboxylate as a white solid (0.38 g, 26%). mp 144-145° C. Found: C, 53.69; H, 4.05; N, 12.39%. C10H9N2ClO2 requires: C, 53.47; H, 4.04; N, 12.46%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[OH:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[N:14]1[CH:15]=[CH:16][C:11]([CH:10]=[CH:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][O:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)=[CH:4][CH:5]=2)=[CH:12][CH:13]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: ClCc1ccc(C=Cc2ccncc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#Cc1ccc(OCc2ccc(C=Cc3ccncc3)cc2)cc1
Yield: 64 %

Procedure:
A mixture of 2.3 g (10 mmol) 4-[2-(4-chloromethylphenyl)-ethenyl]-pyridine, 1.2 g (10 mmol) 4-hydroxybenzonitrile, 1.4 g potassium carbonate and 10 ml butanone is heated under reflux for 18 h, filtered, the filtrate evaporated, taken up in ethyl acetate, washed with water, dried and evaporated. One obtains 2.0 g of title compound (64% of theory) of the m.p. 147°-149° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([OH:14])[CH2:13][CH2:12][CH2:11]2)=[C:6]([F:15])[CH:5]=1.Br[CH2:17][C:18]([OH:20])=[O:19]>CN(C)C(=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([O:14][CH2:17][C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13]2)=[C:6]([F:15])[CH:5]=1
Reactant: OC1(c2ccc(Br)cc2F)CCC1
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(O)COC1(c2ccc(Br)cc2F)CCC1
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
A 50 mL round-bottomed flask was charged with NaH (361 mg, 9.04 mmol) and N,N-dimethylacetamide (5 mL). A solution of the product from Example 60A (443 mg; 1.808 mmol) in N,N-dimethylacetamide (5 mL) was added dropwise, and the reaction was stirred at 22° C. for 30 min. A solution of 2-bromoacetic acid (502 mg, 3.62 mmol) in N,N-dimethylacetamide (5 mL) was added dropwise. The reaction was stirred at 22° C. for 16 hours and was then quenched by the slow addition of water (15 mL). The aqueous was extracted with 1:1 diethyl ether/hexanes (2×20 mL), and the organics discarded. The aqueous layer was acidified to pH 1 with 1M HCl and extracted with ethyl acetate (2×75 mL). The combined organics were washed with water (4×20 mL) and brine (1×20 mL), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title product. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54-1.70 (m, 1 H), 1.91-2.10 (m, 1 H), 2.34-2.47 (m, 4 H), 3.65 (s, 2 H), 7.34-7.43 (m, 2 H), 7.49-7.53 (m, 1 H), 12.45 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:18]([F:21])=[CH:19][CH:20]=1)[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].[F:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1.Cl>O1CCCC1.N1C=CC=CC=1>[C:16]([C:13]1[CH:14]=[C:15]2[C:7]([C:5]([C:4]3[C:3]([F:22])=[C:2]([NH:1][S:30]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=4)(=[O:32])=[O:31])[CH:20]=[CH:19][C:18]=3[F:21])=[O:6])=[CH:8][NH:9][C:10]2=[N:11][CH:12]=1)#[N:17]
Reactant: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(N)c3F)c2c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(NS(=O)(=O)c4cccc(F)c4)c3F)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.9 %

Procedure:
To 3-(3-amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (28, 130 mg, 0.436 mmol) in 3.5 mL of tetrahydrofuran, 0.31 mL of pyridine was added. 3-Fluoro-benzenesulfonyl chloride (30, 127 mg, 0.654 mmol) was added and the solution was stirred at room temperature for 48 hours. The reaction mixture was poured into 1 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and the solvent removed under reduced pressure to provide the desired compound (P-0005, 167 mg). MS(ESI)[M+H+]+=457.6.
Reaction SMILES: [NH2:1][C:2]1[C:11](=[S:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[C:11](=[S:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[O:4][CH:3]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1coc2ccccc2c1=S
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2coc3ccccc3c2=S)cc1
Temperature: 10 °C
Yield: 93.9 %

Procedure:
In order to do this, 3-aminothiochromone (7.4 g) is suspended in anhydrous pyridine (25 ml), the mixture is cooled to about 10° C. and para-toluenesulphonyl chloride (8.6 g) is then added, whist stirring. After dilution with distilled water (100 ml), precipitation, filtration, washing with ethanol and drying, 3-(p-toluenesulphonylamino)-thiochromone (13 g), which melts at 212° C., is obtained.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:20]([O:19][C:17]([CH:16]1[C:15](=[O:14])[C:7]2[C:5](=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=[C:2]([F:1])[CH:8]=2)[N:6]=[CH:22]1)=[O:18])[CH3:21]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)C1C=Nc2c(cc(F)cc2[N+](=O)[O-])C1=O
Yield: 45 %

Procedure:
Using an analogous procedure to that described in Example 2 in the section relating to the preparation of starting materials 4-fluoro-2-nitroaniline and diethyl ethoxymethylenemalonate were reacted, and then refluxed in diphenyl ether to give 3-ethoxycarbonyl-6-fluoro-8-nitro-4-oxo-3,4-dihydroquinoline in 45% yield, mp 278-280° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:22]2[S:26][C:25](=[S:27])[NH:24][N:23]=2)[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[O:11]COCCOC)([CH3:4])[CH3:3]>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([C:22]2[S:26][C:25](=[S:27])[NH:24][N:23]=2)[CH:8]=[C:9]([C:18]([CH3:19])([CH3:20])[CH3:21])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: COCCOCOc1c(C(C)(C)C)cc(-c2n[nH]c(=S)s2)cc1C(C)(C)C
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(C)(C)c1cc(-c2n[nH]c(=S)s2)cc(C(C)(C)C)c1O
Yield: 48.7 %

Procedure:
Anhydrous zinc bromide (7.3 g, 0.033 mole) is added to a suspension of 5-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]phenyl]1,3,4-thiadiazole-2(3H)-thione (2.7 g, 0.007 mole) in methylene chloride (10 ml). After 18 hours the mixture is diluted with methylene chloride (50 ml), washed with water (20 ml), saturated aqueous NaHCO3 (20 ml), saturated aqueous NaCl (20 ml), and dried over MgSO4. Filtration and concentration gives a solid which is recrystallized from ethyl acetate/hexane to provide 1.1 g (2.1 g theor., 52%) of 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione, mp 259.5°-260° C.
Reaction SMILES: [NH:1]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[N:8][C:9](O)=[C:10]([CH3:16])[C:11]=2[CH3:15])[N:6]=1)C(C)=O.P(Cl)(Cl)([Cl:20])=O>>[NH2:1][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[N:8][C:9]([Cl:20])=[C:10]([CH3:16])[C:11]=2[CH3:15])[N:6]=1
Reactant: CC(=O)Nc1ccc2c(C)c(C)c(O)nc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1c(Cl)nc2nc(N)ccc2c1C
Yield: 92 %

Procedure:
34.6 g (0.15 mol) of 2-acetamino-7-hydroxy-5,6-dimethyl-1,8-naphthyridine and 380 ml of phosphorus oxychloride are boiled under reflux for 30 minutes, the starting material dissolving. Excess POCl3 is distilled off, the residue poured onto ice and concentrated hydrochloric acid is added. After the mixture has been boiled under reflux for 30 minutes, it is made alkaline with 50% strength sodium hydroxide solution. The precipitate is suction filtered and recrystallized from 4 liters of methanol. There is obtained 28.7 g (92%) of a pale brown solid which is further reacted without any purification.
Reaction SMILES: [H-].[Na+].CN(C)[CH:5]=[O:6].[CH2:8]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CI>O>[CH2:8]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:6][CH3:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCCCCCOCc1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCCCCCOCc1ccccc1
Temperature: 25 °C
Yield: 70 %

Procedure:
1.6 g (0.039 mol) of 55% sodium hydride in oil were added to 50 ml of dimethylformamide under stirring at room temperature. 5 ml (0.026 mol) of 5-benzyloxy-1-pentanol and 2.43 ml (0.039 mol) of methyl iodide were then added successively. After a night the excess of sodium hydride was decomposed with water and the solvent evaporated under vacuum. The residue was redissolved with methylene chloride and washed with water. The organic layer was finally dried over anhydrous sodium sulfate and evaporated to give 3.5 g (70% yield) of the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@:8]3([OH:25])[CH2:9][CH2:10][C@@H:11]2/[CH:12]=[CH:13]/[CH:14]=[O:15])[CH2:3]1>[Pd].C(O)C>[OH:1][C@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@:8]3([OH:25])[CH2:9][CH2:10][C@@H:11]2[CH2:12][CH2:13][CH:14]=[O:15])[CH2:3]1
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=O)CC[C@]12O
Agent: [Pd]
Solvent: CCO
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](CCC=O)CC[C@]12O
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
A mixture of 6.00 g of (E)-3β,14β-dihydroxy-5β-pregn-20-ene-21-carboxaldehyde (Fullerton D. S. and Pankaskie M. C., J. Med. Chem., 1976, 19, 1330) and 1.20 g of 5% palladium on charcoal in 1.20 l of ethanol was hydrogenated at room temperature and atmospheric pressure for 30 min. The mixture was then filtered through Celite and ethanol was evaporated to dryness to give 5.95 g of the title compound (II-c) as a white solid.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]([NH2:18])[CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]=1[O:11][CH3:12])=[O:5])C.CO[CH:21](OC)[CH2:22][C:23]#[N:24].CC1C=CC(S(O)(=O)=O)=CC=1.O.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH2:16]([O:15][C:13]([C:9]1[C:10]([O:11][CH3:12])=[C:6]2[C:4]([OH:5])=[C:22]([C:23]#[N:24])[CH:21]=[N:18][N:7]2[CH:8]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)c1cn(N)c(C(=O)OCC)c1OC
Reactant: COC(CC#N)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCOC(=O)c1cn2ncc(C#N)c(O)c2c1OC
Temperature: 80 °C
Yield: 10 %

Procedure:
To a mixture of amine 393E (0.34 g, 1.33 mmol) in toluene (2.6 ml) was added 3,3-dimethoxy-propionitrile (0.4 ml, 2.66 mmol) and TsOH.H2O (50 mg, 0.266 mmol), the mixture was heated at 80° C. for 4 h, then DBU (0.404 mg, 2.66 mmol) was added, and heated for another 0.5 h. The residue was purified by silica gel flash column chromatography to give 0.46 g of crude 393F (10% MeOH—CH2Cl2).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].CC(C)([O-])C.[K+].Br[CH2:21][CH2:22][CH2:23][Cl:24]>C1COCC1>[Cl:24][CH2:23][CH2:22][CH2:21][CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:12])([F:13])[F:1])[C:10]#[N:11]
Reactant: N#CCc1ccccc1C(F)(F)F
Reactant: ClCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC(CCCCl)c1ccccc1C(F)(F)F
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 132 %

Procedure:
(2-Trifluoromethylphenyl)acetonitrile (12.47 g, 67.3 mmol) was dissolved in THF (87.3 mL) at room temperature under nitrogen atmosphere. The reaction solution was cooled to −10° C. Then, potassium tert-butoxide (7.93 g, 70.7 mmol) was added to the reaction solution and the reaction mixture was stirred at −10° C. for 10 minutes. 1-Bromo-3-chloropropane (6.99 mL, 70.7 mmol) was added dropwise to the reaction mixture over 14 minutes, and the reaction mixture was stirred at 0° C. for 2 hours. The reaction was quenched with 10% NH4Cl aq. (8.6 mL). After the mixture was stirred, the aqueous layer was separated. The organic layer was concentrated under the reduced pressure to obtain the title compound (23.24 g). The yield was calculated as over 99% by HPLC external standard method.
Reaction SMILES: N.C([O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH:14]=[C:13]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH2:25][CH3:26])[CH:19]=2)[NH:12][C:11]1=[O:27])(=O)C>CO>[OH:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH:14]=[C:13]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([CH2:25][CH3:26])[CH:19]=2)[NH:12][C:11]1=[O:27]
Reactant: CCc1cc(Nc2cc(=O)n(CCCCOC(C)=O)c(=O)[nH]2)ccc1C
Agent: N
Solvent: CO
Product: CCc1cc(Nc2cc(=O)n(CCCCO)c(=O)[nH]2)ccc1C
Reaction time: 0.5 h
Yield: 118.2 %

Procedure:
Aqueous concentrated ammonia (150 ml) was added to a stirred suspension of 3-(4-acetoxybutyl)-6-(3-ethyl-4-methylanilino)uracil (10.5 g, 24 mmol) in 150 ml of methanol at room temperature. After 30 minutes, all solid was dissolved, and the solution was stirred for 72 hours. The solvent was removed, and the solid was co-evaporated three times with methanol, and filtered from methanol to give the product as a white solid (9.0 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:21])[CH2:12][O:13]CC2C=CC=CC=2)=[CH:6][CH:5]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:21])[CH2:12][OH:13])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(NC(=O)COCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(NC(=O)CO)cc1
Reaction time: 5 h

Procedure:
4-(2-benzyloxy-acetylamino)-benzoic acid methyl ester 12 (10 grams, 33.44 mmol) is dissolved in methanol (100 mL) in a pressure vessel. Pd/C (10%, 3 grams) is added, and the mixture is stirred under an atmosphere of hydrogen (4 Kg) for 5 hours. The catalyst is removed by filtration and the methanol distilled off. The crude 13 can be purified in a suitable solvent.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].[CH:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([S:15](Cl)(=[O:17])=[O:16])[C:9]=2[CH:8]=[CH:7][N:6]=1.CO.C(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[NH2:1][CH2:2][CH2:3][NH:4][S:15]([C:10]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:14]=2[CH:13]=[CH:12][CH:11]=1)(=[O:16])=[O:17]
Reactant: NCCN
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NCCNS(=O)(=O)c1cccc2cnccc12
Reaction time: 2 h
Yield: 65.7 %

Procedure:
In 200 ml of chloroform was dissolved 12.0 g of 1,2-diaminoethane, and to the solution was added dropwise 100 ml of a chloroform solution containing 4.55 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution was stirred at a temperature of 20° C. to 25° C. for two hours, and then the reaction solution was extracted with a 10% aqueous hydrochloric acid solution. The pH of the aqueous layer was adjusted to 10 with a 10% aqueous sodium hydroxide solution, and the aqueous layer was extracted with chloroform. The chloroform layer extracted was washed with water and dried with anhydrous potassium carbonate. Then the chloroform was distilled from the chloroform layer, and the residue obtained was subjected to a column chromatography [silica gel: 200 g; developing solvent: 2% methanol/chloroform (volume ratio)] to give 3.3 g of N-(2-aminoethyl)-5-isoquinolinesulfonamide as an oily substance in a yield of 66%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][CH2:15][OH:16])[CH2:12][N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:10](=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][CH2:15][O:16][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:12][N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:10](=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2cccc(Cl)c2)C[C@@H]1CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)N(c2cccc(Cl)c2)C[C@@H]1CCOS(C)(=O)=O
Reaction time: 0.75 h

Procedure:
To a solution of the alcohol from Step E (3.58 g, 10.1 mmol) in 50 mL of dichloromethane at 0° C. was added diisopropylethylamine (3.5 mL, 20.2 mmol), followed by methanesulfonyl chloride (0.936 mL, 12.1 mmol). The solution was stirred for 45 minutes, then quenched with 10% citlic acid. The solution was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product which was used in the next step without further purification.