Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[C:7]1([S:13][CH:14]=[CH:15][C:16](Cl)=[O:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[CH2:20]([O:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([O:27][NH:28][C:16](=[O:17])[CH:15]=[CH:14][S:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NOCc1ccccc1
Reactant: O=C(Cl)C=CSc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(C=CSc1ccccc1)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
Pyridine (2.7 ml) was added to THF (80 ml) solution of 3-(phenylthio)acryloyl chloride (3.0 g) and hydrochloric acid salt of O-benzylhydroxylamine (2.6 g) under ice-cooling and stirred at the same temperature for one hour and at room temperature for three hours. The reaction mixture was concentrated under reduced pressure. Chloroform (150 ml) was added to the residue, washed successively with 1N hydrochloric acid, pure water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate 2:1) to obtain N-benzyloxy-3-(phenylthio)acrylamide (3.5 g) as colorless oil. N-benzyloxy-3-(phenylthio)acrylamide (1.0 g) was dissolved to acetonitrile (70 ml), carbon tetrabromide (2.3 g) and triphenylphosphine (1.8 g) were added thereto under ice-cooling, then heat refluxing for four hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate 20:1) to obtain N-benzyloxy-3-(phenylthio)acrylimidoyl bromide (1.1 g) as light yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:37][C:38]1[CH:42]=[C:41]([CH2:43][C:44](O)=[O:45])[O:40][N:39]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH:24]1([NH:23][C:21]([C:16]2[CH:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:6]4[O:7][C:3]([CH2:2][NH:1][C:44](=[O:45])[CH2:43][C:41]5[O:40][N:39]=[C:38]([CH3:37])[CH:42]=5)=[N:4][N:5]=4)=[CH:13][CH:12]=3)[C:19]([CH3:20])=[CH:18][CH:17]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: Cc1cc(CC(=O)O)on1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(CC(=O)NCc2nnc(-c3ccc(-c4cc(C(=O)NC5CC5)ccc4C)cc3)o2)on1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4′-[5-(Aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Example 53) (30 mg), EDC (19.8 mg), HOBt (11.7 mg), 3-methyl-5-isoxazoleacetic acid (12.2 mg) and DIPEA (0.02 ml) were mixed in DMF (5 ml). The reaction was stirred at room temperature for 48 hours, the DMF evaporated under vacuum and the residue dissolved in DCM. The solution was washed with water (2×10 ml) and the DCM was evaporated under vacuum. The residue was dissolved in methanol and filtered through a bond-elut (SCX, 2 g). The solvent was evaporated from the filtrate and the residue applied to a bond-elut (silica) and eluted with an ethyl acetate/cyclohexane gradient to give, after evaporation of the solvent, N-cyclopropyl-6-methyl-4′-[5-({[(3-methylisoxazol-5-yl)acetyl]amino}methyl)-1,3,4-oxadiazol-2-yl]-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14].N[CH2:17][CH2:18][O:19]CCO.C(CN)O>>[OH:19][CH2:18][CH2:17][O:1][CH2:2][CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14]
Reactant: N#Cc1ccc(NCCO)c([N+](=O)[O-])c1
Reactant: NCCOCCO
Solvent: NCCO
Product: N#Cc1ccc(NCCOCCO)c([N+](=O)[O-])c1

Procedure:
Preparation is similar to the synthesis in (a) above, except that 2-(2-aminoethoxy)ethanol is used in lieu of monoethanolamine.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH2:24]([CH2:26][NH2:27])[OH:25].N12CCCNC1=NCCC2>C1(C)C=CC=CC=1>[OH:25][CH2:24][CH2:26][NH:27][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Reactant: NCCO
Agent: C1CN=C2NCCCN2C1
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NCCO)[nH]n1
Temperature: 90 °C
Yield: 27.4 %

Procedure:
To a solution of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.32 mmol) and ethanolamine (29 mg, 0.47 mmol) in toluene (1 mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (16 mg, 0.11 mmol) and the reaction was heated at 90° C. under argon overnight. After cooling to room temperature, the mixture was evaporated and purification by chromatography (silica, dichloromethane:methanol=100:0 to 9:1) afforded the title compound (30 mg, 28%), which was obtained as a white solid. MS: m/e=343.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Reactant: Fc1cc(F)cc(CBr)c1
Product: Cc1nc(-c2ccn(Cc3cc(F)cc(F)c3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-bromomethyl-3,5-difluoro-benzene as described in Example 49 and isolated as a white solid (0.071 mg, 51% yield). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.56 (d, J=4 Hz, 1H), 7.71 (d, J=8 Hz, 1H), 7.45 (d, J=2 Hz, 1H), 7.28-7.34 (m, 1H), 6.89 (d, J=2 Hz, 1H), 6.70-6.79 (m, 3H), 6.12-6.18 (m, 1H), 5.32 (s, 2H), 4.63 (d, J=8 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=425.9; Rt=1.25 min; HRMS (M+H)+=426.12.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]2.S(=O)(=O)(O)O>COCCOCCOC>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[C:14](=[CH:2][C:1]([OH:5])=[O:4])[CH2:13][CH2:12]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: O=CC(=O)O
Agent: O=S(=O)(O)O
Solvent: COCCOCCOC
Solvent: O
Product: COc1ccc2c(c1)CCC(=CC(=O)O)C2=O
Temperature: 110 °C
Yield: 88.5 %

Procedure:
Glyoxalic acid (190 mL, 1702 mmol) and water (180 mL) were added to a stirred solution of 6-methoxy tetralone (300 g, 1702 mmol) in diglyme (600 mL) followed by sulfuric acid (80 mL, 1500 mmol). The reaction mixture was heated to 110° C. overnight. The reaction mixture was cooled to 0° C., and resulting solids were filtered off and washed with water (3×200 mL), dried under reduced pressure to afford the title compound (350 g, 88%) as a solid. 1H NMR (300 MHz, DMSO-d6): δ 12.9 (bs, 1H), 7.9 (d, J=8.4 Hz, 1H), 7.0 (m, 2H), 6.6 (s, 1H), 3.8 (s, 3H), 3.3 (m, 2H), 3.0 (m, 2H). ESI-MS m/z: 233 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][C@H:17]([F:20])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:27])[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][C@H:17]([F:20])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CC[C@H](F)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CC[C@H](F)C1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[(3S)-3-fluoropyrrolidin-l-yl]quinolin-7-yl}ethanone (0.10 g, 0.34 mmol) and ammonium acetate (0.263 g, 3.42 mmol) in methanol (1.5 mL) and acetonitrile (1.5 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, sodium cyanoborohydride (0.064 g, 1.0 mmol). The reaction was heated at 65° C. overnight, cooled to room temperature and quenched with sat. NaHCO3 solution and extracted with Ethyl acetate. The combined organic layers were dried over MgSO4, concentrated and purified on a preparative LCMS (pH=10) to give the desired product. LCMS calculated for C15H18ClFN3 (M+H)+: m/z=294.1; Found: 294.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:20][NH2:21].[H][H]>[Pt]=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:13][CH2:12][CH:11]([NH:21][CH3:20])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COC(=O)C1(c2cccc(OC)c2)CCCC(=O)C1
Reactant: CN
Agent: O=[Pt]
Solvent: CO
Product: CNC1CCCC(C(=O)OC)(c2cccc(OC)c2)C1

Procedure:
A mixture of 0.52 g of methyl 1-(3-methoxyphenyl)-3-oxo-cyclohexane-1-carboxylate, 0.5 ml of 30% aqueous methylamine, 8 ml of methanol and 0.025 g of platinum oxide is shaken for 48 hours in a hydrogen atmosphere. After the reaction, the mixture is filtered to remove the catalyst. The filtrate is concentrated under reduced pressure to remove solvent, whereby methyl 1-(3-methoxyphenyl)-3-methylamino-cyclohexane-1-carboxylate is obtained as crude oil. 7 ml of xylene are added to the crude oil and the mixture is refluxed for 20 hours under heating. Then, the mixture is concentrated under reduced pressure to remove solvent. The residue is dissolved in ether. The ether solution is washed with 10 % hydrochloric acid and water, successively, dried and then evaporated to remove solvent. The residue thus obtained is recrystallized from n-hexane. 0.33 g of 1-(14 3-methoxyphenyl)-6-methyl-6-azabicyclo[3,2,1]octane-7-one is obtained. M.p. 68° - 70°C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@H:7]([O:16][C:17](=[O:19])[CH3:18])[C@@H:8]([O:12][C:13](=[O:15])[CH3:14])[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[Cl:32][CH2:33][CH2:34][NH:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=1>C(Cl)Cl.N1C=CC=CC=1>[C:17]([O:16][C@H:7]([C@@H:8]([O:12][C:13](=[O:15])[CH3:14])[C:9]([N:35]([CH2:34][CH2:33][Cl:32])[C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:44])([F:45])[F:43])=[CH:38][CH:37]=1)=[O:11])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:20])(=[O:19])[CH3:18]
Reactant: CC(=O)O[C@@H](C(=O)O)[C@@H](OC(C)=O)C(=O)OC(C)(C)C
Reactant: FC(F)(F)c1ccc(NCCCl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@@H](C(=O)OC(C)(C)C)[C@@H](OC(C)=O)C(=O)N(CCCl)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.8 %

Procedure:
To a solution of (R,R)-2,3-bis(acetyloxy)-butanedioic acid mono tert-butyl ester (3.25 g: Tetrahedron, 45, 3071-3080, 1989) in CH2Cl2 (65 mL), were added oxalyl chloride (1.06 mL) and DMF (50 microL) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes then pyridine (3.82 mL) was added into the mixture at the same temperature. The reaction mixture was stirred at the same temperature for 5 minutes. To the mixture, was added a solution of compound 54-2 (2.5 g) in CH2Cl2 (12.5 mL) at 0° C. The mixture was stirred for 1 hour at the same temperature. Then the mixture was concentrated in vacuo and the resulting residue was suspended in water. The mixture was extracted with EtOAc and the organic layer was washed with 1N HCl aq., sat. NaHCO3 aq., brine, and it was dried with anhyd. Na2SO4. The solvent was removed under reduced pressure to obtain compound 54-3 (5.7 g) as brown oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH:18]=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C.O1CCCC1>[CH2:20]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH2:18][OH:19])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=Cc1c(N(Cc2ccccc2)Cc2ccccc2)cccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(N(Cc2ccccc2)Cc2ccccc2)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
The product from Example 46A (1.5 g, 4.33 mmoles) in ethanol (10 mL) and tetrahydrofuran (4 mL) was treated with sodium borohydride (0.164 g, 4.33 mmoles). After stirring for 30 minutes at room temperature, the mixture was quenched with saturated ammonium chloride and diluted with diethyl ether. The diethyl ether was washed with saturated ammonium chloride, brine, dried with sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10:1 to 4:1 hexanes:ethyl acetate) to provide the title compound (1.39 g, 92%). MS (ESI+) m/z 348 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=3)[C:9]([S:25][CH2:26][CH2:27][CH3:28])=[N:8][C:7]=2[N:29]=1.Cl.N1C=CC=CC=1.CN(C)C=O>O>[CH2:26]([S:25][C:9]1[N:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:22])([F:24])[F:23])=[CH:15][CH:14]=2)[C:11](=[O:12])[C:6]2[CH:5]=[CH:4][C:3](=[O:2])[NH:29][C:7]=2[N:8]=1)[CH2:27][CH3:28]
Reactant: CCCSc1nc2nc(OC)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: CCCSc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
A mixture of 7-methoxy-2-(propylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidin-4(3H)-one (213 mg), pyridine hydrochloride (1156 mg) and N,N-dimethylformamide (10 ml) was stirred at 120° C. for 3 hr. The mixture was allowed to be cooled to room temperature, and to the reaction mixture was added water thereto, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (183 mg).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:39])[C@H:16]2[CH2:20][C@H:19](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:18][N:17]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:40]([NH:48][C:49]1[CH:54]=[CH:53][NH:52][C:51](=[O:55])[N:50]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.ClCCl.C(OCC)(=O)C>[C:8]1([CH:7]([O:14][C:15](=[O:39])[C@H:16]2[CH2:20][C@@H:19]([N:52]3[CH:53]=[CH:54][C:49]([NH:48][C:40](=[O:47])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[N:50][C:51]3=[O:55])[CH2:18][N:17]2[C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](C(=O)OC(c3ccccc3)c3ccccc3)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: O=C(Nc1cc[nH]c(=O)n1)c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)C[C@@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A reaction mixture containing the trans-D tosylate (7) (1.10 g, 2.00 mmol), N4-benzoylcytosine (0.475 g, 2.20 mmol), anhydrous K2CO3 (0.300 g, 2.20 mmol) and 18-crown-6 (200 mg) in DMF (10 ml) was stirred at 70-80° C. under argon overnight. The white suspension was diluted with dichloromethane (75 ml), filtered through celite and the organic phase washed with water. Evaporation gave the crude product as an oil which was purfied by column chromatography (SiO2, ethyl acetate). The more polar fractions (Rf 0.33) were combined and evaporated to give the N1-isomer (0.299 g, 25%) as a white foam. Recrystallisation from ethanol-water gave white crystals of N-tert-butoxycarbonyl-cis-4-(N4-benzoylcytosin-1-yl)-D-proline diphenylmethyl ester (11), m.p. 133-135° C., (Found C, 65.8; H, 6.5; N, 8.8%; C34H34N4O6. C2HR5OH.H2O requires C, 65.6; H, 6.4; N, 8.5%), δH (200 MHz; CDCl3) 1.30 and 149 (9H, 2xs, Boc rotamers), 2.20 and 2.90 [2H, br m, CH2(3′)], 3.50-3.80 and 3.95-4.15 [2H, 2xbr m, CH2(5′)], 445-4.70 [1H, br m, CH(2′)], 5.28 [1H, br m, CH(4′)], 6.87 (1H, s, CHPh2), 7.15-7.40 (10H, m, phenyl CH), 7.40-7.75 [5H, m, CH(5), CH(6) and benzoyl m- and p-CH], 7.89 (2H, d, J=7.4 Hz, benzoyl o-CH), 8.83 (1H, br s, NH); δC (50.28 MHz; CDCl3) 27.7 and 28.0 (Boc CH3 rotamers), 34.4 and 36.0 [CH2(3′) rotamers], 49.6 and 50.5 [CH2(5′) rotamers], 54.3 and 54.9 [CH(4′) rotamers], 57.6 CH(2′)], 78.0 and 78.3 (CHPh2 rotamers), 81.3 (Boc C), 96.8 [CH(5)], 127.0-129.2 (aromatic CH), 133.4 (benzoyl C), 139.5 (aromatic C), 145.2 and 145.7 [CH(6) rotamers)], 153.8 (Boc CO rotamers), 155.6 [C(2)], 162.0 [C(4)], 166.8 (benzoyl CO), 171.3 (ester CO); m/z (ES MS) 595 (M+H+, 100%); νmax (KBr)/cm−1 1743 (C═O), 1704s (C═O); λmax (CHCl3)/nm 266 (ε/dm3.mol−1.cm−1 8.9×104), 312 (3.4×104); [α]D25 −13.6 (c=0.50, CHCl3).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[N:12]=[C:13]3[CH:19]=[CH:18][N:17]([S:20]([C:23]4[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[C:14]3=[N:15][CH:16]=2)=N)=[CH:5][CH:4]=1.Cl.C1C[O:34]CC1>>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[N:12]=[C:13]3[CH:19]=[CH:18][N:17]([S:20]([C:23]4[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[C:14]3=[N:15][CH:16]=2)=[O:34])=[CH:5][CH:4]=1
Reactant: CSc1ccc(C(=N)c2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n2)cc1
Reactant: C1CCOC1
Agent: Cl
Product: CSc1ccc(C(=O)c2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
(4-(Methylthio)phenyl)(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanimine (1.00 g, 2.37 mmol, prepared using AF from Preparation #AE.1 with (4-(methylthio)phenyl)magnesium bromide) was dissolved in THF (25 mL) then 6 N HCl (1.18 mL, 7.10 mmol) was added. The mixture was stirred rt for about 1 h then concentrated under reduced pressure. Saturated aqueous NaHCO3 (40 mL) and water (10 mL) were added then the mixture was extracted with DCM (50 mL and 15 mL). The combined organics were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give (4-(methylthio)phenyl)(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanone (0.754 g, 75%): LC/MS (Table 2, Method b) Rt=2.77 min; MS m/z 424 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-])=O)[CH:2]([CH3:4])[CH3:3]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC(C)Cc1c(N)cnc2ccccc12

Procedure:
The nitroxide group on the 4-isobutyl-3-nitro quinoline produced in Example 1 is reduced by catalytic reduction using toluene as solvent, Pd/C 5% (50% wet) as catalyst, at 40-45° C. and atmospheric pressure to produce 4-isobutyl 3-amino quinoline. The rate of reaction depends on efficiency of stirring. After catalyst filtration the solution is ready for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Br[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:13])[C:11]=1[O:12][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(OC2CCCC2)c(Cl)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
Methyl 3,5-dichloro-4-hydroxybenzoate (1) (1.00 g, 4.52 mmol) was dissolved in DMF (8 mL) and treated with bromocyclopentane (534 μL, 4.98 mmol), followed by potassium carbonate (937 mg, 6.79 mmol). The mixture was stirred at 80° C. for 3 h and then partitioned between EtOAc (100 mL) and H2O (100 mL). The aqueous phase was extracted with EtOAc (50 mL) and the combined organic phases washed successively with water (5×50 mL) and brine (50 mL), then dried over MgSO4 and filtered. The solvent was removed in vacuo to afford methyl 3,5-dichloro-4-(cyclopentyloxy)benzoate (2) (1.10 g, 84%): 1H NMR (400 MHz, CDCl3) δ: 7.97 (2H, s), 5.04 (1H, m), 3.90 (3H, s), 2.04-1.91 (4H, m), 1.82-1.75 (2H, m), 1.69-1.60 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]2[O:10][CH2:11][O:12][C:4]=2[CH:3]=1.[Mg].Br[CH2:15][CH2:16][CH3:17].[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[C:7]([CH:8]([OH:9])[CH2:15][CH2:16][CH3:17])=[CH:6][C:5]2[O:10][CH2:11][O:12][C:4]=2[CH:3]=1
Reactant: CCCBr
Reactant: Cc1cc2c(cc1C=O)OCO2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(O)c1cc2c(cc1C)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A solution of 5.0 g of (6-methyl-1,3-benzodioxol-5-yl)-carboxaldehyde in 20 ml of tetrahydrofuran was dropwise added at a room temperature to a Grignard reagent prepared from 0.86 g of magnesium ribbon, 10 ml of tetrahydrofuran and 4.4 g of 1-bromopropane. The obtained mixture was stirred at a room temperature for one hour, followed by the addition of a saturated aqueous solution of ammonium chloride. The obtained mixture was extracted with ether. The organic layer was washed with an aqueous solution of common salt, dried over magnesium sulfate and distilled to remove the solvent. 5.6 g of (6-methyl-1,3-benzodioxol-5-yl)butan-1-ol was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[CH:9]([CH3:12])[C:10]#[CH:11].ClS([N:24]=[C:25]=[O:26])(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:25](=[O:26])[NH2:24])=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[CH:9]([CH3:12])[C:10]#[CH:11]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: C#CC(C)c1ccc(-c2ccc(O)cc2)cc1OC
Solvent: ClCCl
Product: C#CC(C)c1ccc(-c2ccc(OC(N)=O)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.7 %

Procedure:
To a 25 mL flame dried flask with stir bar cooled to room temperature was added alkyne 20 (0.115 g, 0.46 mmol) dissolved in anhydrous CH2Cl2. The reactant was cooled to 0° C. and chlorosulfonyl isocyanate (0.08 mL, 0.92 mmol) was added dropwise. After 15 min, the reaction mixture was brought to room temperature and followed by TLC. The reaction was quenched with water and extracted with ether. The organic extracts were washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated and purified by flash column chromatography (SiO2, 7 g, 25% EtOAc/hexanes) to give the terminal acetylene 23 as a white solid (0.092 g, 68% yield): TLC Rf=0.1 (25% EtOAc/hexanes); mp 113.6-115.3° C.; 1H NMR (500 MHz, CDCl3) δ 7.61 (d, J=7.8 Hz, 1H), 7.56 (d, J=8.5 Hz, 2H), 7.19 (d, J=8.5 Hz, 2H), 7.15 (dd, J=7.8, 1.4 Hz, 1H), 7.01 (d, J=1.7 Hz, 1H), 4.21 (qd, J=7.0, 2.3 Hz, 1H), 3.88 (s, 3H), 2.23 (d, J=2.4 Hz, 1H), 1.47 (d, J=7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 189.2, 156.4, 155.6, 150.3, 140.6, 138.9, 133.1, 130.3, 128.3, 128.2, 122.1, 119.7, 109.6, 87.7, 69.6, 60.6, 55.7, 25.3, 22.8, 21.2, 14.4; IR (neat cm−1) 3423, 3308, 3268, 3199, 2969, 2341, 2105, 1698, 1606, 1494, 1378, 1213, 586; HRMS (DART, M++H) m/z 296.1300 (calculated for C18H18NO3, 296.1287).