Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[C:2]([C:5]([CH3:30])([CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].CS(C)=O.[C:35]([C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1)(=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O>[CH3:29][C:5]([CH3:30])([CH2:6][CH2:7][CH2:8]/[CH:9]=[C:35](/[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)\[C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1)[C:2]([OH:4])=[O:3]
Reactant: CC(C)(CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: O=C(c1ccccc1)c1cccnc1
Agent: [Br-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(CCC/C=C(/c1ccccc1)c1cccnc1)C(=O)O
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (2.5 g, 60% oil dispersion) was washed with hexane, to make clean of the oil and dried under reduced pressure. Dimethylsulfoxide (25 ml) was added to it, and the mixture was heated under argon at 80° C. for 1 hour to produce dimsyl anions. The reaction solution was cooled at 10° C., and 5-carboxy-5,5-dimethylpentyltriphenylphosphonium bromide (8 g, 16 mmole) was added, followed by stirring at room temperature for another 10 minutes. A dimethylsulfoxide solution (5 ml) containing 3-benzoylpyridine (3 g, 16 mmole) was added dropwise to the mixture solution, and after the completion of the dropwise addition, stirring was continued at room temperature for 30 minutes. Water (50 ml) was added to the mixture, which was then shaken. The organic layer was separated, and the water layer was adjusted to pH 6.0 with 2N hydrochloric acid. The product was extracted three times with ethyl acetate (50 ml). The ethyl acetate layers were combined, washed with water, dried (over magnesium sulfate) and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel, and development was effected with ethyl acetate to yield (E)+(Z)-2,2-dimethyl-7-phenyl-7-(3-pyridyl)-6-heptenoic acid (2-a, 2-b) (2.2. g).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH3:20][N:21]([CH3:31])[CH2:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1.CC(C)=O.N>ClCCl.C1CCCCC1.CO.C(OCC)(=O)C>[CH3:31][N:21]([CH3:20])[CH2:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CN(C)CCCC1CCCCN1
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)CCCC1CCCCN1C(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 51 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-(dimethylamino)propyl]piperidine in a yield of 51% of theory. Colourless crystals, m.p. 142°-144° C. (from acetone and ethyl acetate), Rf 0.7 (Macherey-Nagel, Polygram® SIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/cyclohexane/methanol/conc. ammonia 68/15/15/2, v/v/v/v)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:25])(=[O:24])[NH:11][C@H:12]([C:21](=O)[NH2:22])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([O:26][CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][CH:33]=[N:34]3)[CH:5]=1.CCN(CC)CC.O(C(C(F)(F)F)=O)C(C(F)(F)F)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:24])(=[O:25])[NH:11][C@H:12]([C:21]#[N:22])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([O:26][CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][CH:33]=[N:34]3)[CH:5]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(N)=O)c(OCCc2cccc3ncccc23)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(S(=O)(=O)N[C@H](C#N)CC(=O)OC(C)(C)C)c(OCCc2cccc3ncccc23)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a solution of 4-((S)-2-tert-butoxycarbonyl-1-carbamoyl-ethylsulfamoyl)-3-(2-quinolin-5-yl-ethoxy)-benzoic acid methyl ester (1.20 g, 2.20 mmol) in dry THF (10 mL) at 0° C. was added Et3N (0.80 mL, 5.50 mmol). A solution of (CF3CO)2O in THF (0.5 M, 0.37 mL, 2.60 mmol) was added to the solution dropwise. After 30 min of stirring at 0° C., the ice bath was removed. The reaction mixture was allowed to warm up to room temperature over 4 h. The reaction mixture was worked up by addition of EtOAc (100 mL) then followed by washing the organic phase with saturated NaHCO3 (50 mL). Drying and removal of solvents under vacuum gave 0.90 g (76%) of 4-((S)-2-tert-butoxycarbonyl-1-cyano-ethylsulfamoyl)-3-(2-quinolin-5-yl-ethoxy)-benzoic acid methyl ester as a tan solid. MS m/z 540.3 (M+1).
Reaction SMILES: BrC1C=C(N[C@@H]2CCCN(C(OC(C)(C)C)=O)C2)C(OC)=NC=1.[Cl:24][CH2:25][C:26]([N:28]1CC[CH2:31][C@@H:30]([NH:34][C:35]2[C:40](=[O:41])[NH:39][CH:38]=[C:37]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)[CH:36]=2)[CH2:29]1)=[O:27]>>[Cl:24][CH2:25][C:26]([N:28]1[CH2:29][CH:30]([NH:34][C:35]2[C:40](=[O:41])[NH:39][CH:38]=[C:37]([C:42]3[CH:43]=[CH:44][N:45]=[CH:46][CH:47]=3)[CH:36]=2)[CH2:31]1)=[O:27]
Reactant: O=C(CCl)N1CCC[C@@H](Nc2cc(-c3ccncc3)c[nH]c2=O)C1
Agent: COc1ncc(Br)cc1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Product: O=C(CCl)N1CC(Nc2cc(-c3ccncc3)c[nH]c2=O)C1

Procedure:
Following Example 1, but using tert-butyl 3-aminoazetidine-1-carboxylate (Example 1 Step 3) and reaction with chloroacetyl chloride (Example 1 Step 6) provided the desired compound after purification: 1H NMR (300 MHz, DMSO-d6) 11.87 (br s, 1H), 8.52 (d, J=5.4 Hz, 2H), 7.61 (d, J=6.0 Hz, 2H), 7.25-7.40 (m, 1H), 6.45-6.55 (m, 1H), 6.27 (d, J=6.3 Hz, 1H), 4.86 (apparent t, J=7.7 Hz, 1H), 4.25-4.44 (m, 2H), 4.13 (narrow m, 2H), 4.00-4.25 (m, 1H), 3.85-4.00 (m, 1H); MS (ES) m/z 319 (M+H).
Reaction SMILES: CO.[NH2:3][C:4]1[C:9]([F:10])=[C:8](Br)[C:7]([Cl:12])=[C:6]([F:13])[N:5]=1>[Pd].C(N(CC)CC)C>[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([Cl:12])=[C:6]([F:13])[N:5]=1
Reactant: Nc1nc(F)c(Cl)c(Br)c1F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1nc(F)c(Cl)cc1F
Reaction time: 1.5 h
Yield: 88.8 %

Procedure:
To 25 ml of methanol were added 2.7 g of 2-amino-4-bromo-5-chloro-3,6-difluoropyridine and 1.15 g of triethylamine together with 0.145 g of 10% palladium on carbon, and the mixture was hydrogenated at room temperature for 1.5 hours. The catalyst was separated by filtration, and the solvent and the like were distilled off under reduced pressure. To the residue was added 50 ml of chloroform, and the mixture was washed with 30 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting colorless flake crystals were dispersed in a mixed solution of diisopropylether and n-hexane (1:2), and collected by filtration to obtain 1.62 g of the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[CH3:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20]Cl)[N:19]=1.[H-].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]([N:5]([CH2:20][C:18]1[N:19]=[C:15]([CH3:14])[S:16][CH:17]=1)[C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4]
Reactant: Cc1nc(CCl)cs1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(CN(C(=O)CCl)c2c(C)cccc2C)cs1
Yield: 18 %

Procedure:
A mixture of 5.33 g N-chloroacetyl-2,6-dimethylaniline and 4 g 2-methyl-4-chloromethylthiazole (prepared in Example 4A above) in dry dimethylformamide was treated with 1.56 g sodium hydride as in Example 3 above. After workup, the solid product was purified by high-pressure liquid chromatography to yield 1.5 g pure product, m.p. 62°-64° C. This product is shown as Compound 3 in Table I. C15H17ClN2OS: calc., %C 58.35, %H 5.51, %N 9.08; found, %C 59.23, %H 5.79, %N 9.28.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:21])[NH:10][C:11](=S)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:21])[NH:10][C:11]([NH:23][NH2:24])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=S)[nH]c(-c2ccncc2)c1-c1ccc(F)cc1
Reactant: NN
Solvent: O
Product: NNc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c(=O)[nH]1
Temperature: 120 °C

Procedure:
A mixture of 5-(4-fluorophenyl)-6-(4-pyridyl)-2-thiouracil (500 mg, 1.66 mmol) and hydrazine hydrate (800 ml, ˜14 mmol) was heated at 120° C. for 60 min. It was evaporated and the reaction product was recrystallized from hot methanol to provide the title compound. MS (m/z): 298.0 (M+H)+; C15H12FN5O requir. 297.3. 1H-NMR (DMSO-d6): d 8.41, 7.12 (2m, each 2H, Pyrid.), 7.05, 7.00 (2m, each 2H, PhF). R1═NH—NH2
Reaction SMILES: [CH:1]1([NH:8][C:9]([C:11]2[C:23]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[CH:14]=[CH:13][CH:12]=2)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1COCC1.Cl.[OH-].[Na+]>CO>[CH:1]1([NH:8][CH2:9][C:11]2[C:23]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1CCCCCC1)c1cccc2c1Cc1ccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc2c(c1)Cc1c(CNC3CCCCCC3)cccc1-2
Temperature: 60 °C
Yield: 94.2 %

Procedure:
To N-cycloheptyl-1-fluorenecarboxamide (1.00 g, 3.28 mmol) was added a 1M solution of borane-tetrahydrofuran complex in THF (13 ml, 13 mmol) and the mixture was heated at 60° C. for 7.5 hrs. To this reaction mixture were added methanol (0.4 ml) and concentrated hydrochloric acid (3 ml) and the mixture was heated at 60° C. for 0.5 hr. Then, 1N aqueous sodium hydroxide solution (50 ml) was added at room temperature and the mixture was extracted with chloroform (80 ml×2 times). The organic layer was taken, dried and concentrated. To the residue were added ether (30 ml) and 4N hydrogen chloride in ethyl acetate (2 ml) and the resulting white solid was collected by filtration. This solid was dissolved in chloroform (80 ml) and washed with 1N aqueous sodium hydroxide solution (80 ml×1). The Organic layer was dried and concentrated to give 0.90 g of a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[N:9]=2)=[CH:4][C:3]=1[NH2:18].[C:19](Cl)(Cl)=[S:20]>O1CCCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[N:9]=2)=[CH:4][C:3]=1[N:18]=[C:19]=[S:20]
Reactant: Nc1cc(-c2nc(-c3ccco3)no2)ccc1Cl
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: S=C=Nc1cc(-c2nc(-c3ccco3)no2)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 27 %

Procedure:
To a solution of 4.8 g of 5-(4-chloro-3-aminophenyl)-3-(2-furyl)-1,2,4-oxadiazole in 400 ml of tetrahydrofuran, 5 ml of triethylamine and 2.1 g of thiophosgene are added. After stirring at room temperature for 4 hours, the reaction mixture is filtered and evaporated to dryness in vacuo. The residue is crystallized from petroleum ether to yield 1.5 g (27%) of the title product, m.p. 131°-132° .
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[N:12][C:13]=1[Cl:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:16]I>>[CH2:1]([C:8]1[CH:9]=[C:10]([OH:15])[C:11]([I:16])=[N:12][C:13]=1[Cl:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cnc(Cl)c(Cc2ccccc2)c1
Reactant: II
Product: Oc1cc(Cc2ccccc2)c(Cl)nc1I
Reaction time: 16 h

Procedure:
5-benzyl-6-chloropyridin-3-ol (0.73 g, 3.3 mmol) and I2 (0.21 mL, 4.0 mmol). The mixture became homogeneous and yellow after stirring for 16 h. The mixture was washed with sodium thiosulfate (100 mL), and then treated cautiously with conc. HCl until the pH was 2 by pH paper. The solution was extracted with EtOAc (3×50 mL), and the combined organic extracts were dried over MgSO4, filtered and concentrated to afford a pale yellow solid. The solid was purified by triturating with minimal DCM and ether to give a beige solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.90-11.09 (1H, br s), 7.30-7.37 (2H, m), 7.17-7.28 (3H, m), 6.99 (1H, s), 3.95 (2H, s); MS (ESI) m/z: Calculated: 344.9; Observed: 345.9 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([C:11]2[N:12]=[C:13]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:14]3[S:19][C:18]([CH2:20][N:21]4[CH2:26][C@@H]5CCCN5C[CH2:22]4)=[CH:17][C:15]=3[N:16]=2)[CH:3]=1.C(OC([N:43]1[CH2:50][CH:49]2[CH:45](CNC2)[CH2:44]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([C:11]2[N:12]=[C:13]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:14]3[S:19][C:18]([CH2:20][N:21]4[CH2:22][CH:49]5[CH:45]([CH2:44][NH:43][CH2:50]5)[CH2:26]4)=[CH:17][C:15]=3[N:16]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: Fc1cc(-c2nc(N3CCOCC3)c3sc(CN4CCN5CCC[C@H]5C4)cc3n2)c2cc[nH]c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cc(-c2nc(N3CCOCC3)c3sc(CN4CC5CNCC5C4)cc3n2)c2cc[nH]c2c1

Procedure:
Prepared according to the method used in the preparation of 2-(6-fluoro-1H-indol-4-yl)-6-[(S)-1-(hexahydro-pyrrolo[1,2-d]pyrazin-2-yl)methyl]-4-morpholin-4-yl-thieno-[3,2-d]pyrimidine using hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester in place of (S)-octahydro-pyrrolo[1,2-a]pyrazine, followed by BOC-deprotection using TFA:DCM (1:1). The title compound was obtained as a white solid (34 mg, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=[O:6].[C:13]([NH2:18])(=[O:17])[C@@H:14]([CH3:16])O>>[CH3:12][O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[C:4]=1[C@@H:5]1[NH:18][C:13](=[O:17])[CH:14]([CH3:16])[O:6]1
Reactant: C[C@@H](O)C(N)=O
Reactant: COc1cccc(OC)c1C=O
Product: COc1cccc(OC)c1[C@@H]1NC(=O)C(C)O1

Procedure:
prepared by reaction of 2,6-dimethoxybenzaldehyde with (R)-(+)-lactamide; LC-MS: tR=0.45 min; [M+H]+=238.21.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:18][CH:14]4[CH2:15][CH:16]([CH2:17]2)[C:12](C(O)=O)([CH2:13]4)[CH2:11]3)=[CH:6][CH:5]=1)([O-:3])=[O:2].OS(O)(=O)=O.[N-:27]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]23[CH2:18][CH:14]4[CH2:15][CH:16]([CH2:17]2)[C:12]([NH2:27])([CH2:13]4)[CH2:11]3)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)C12CC3CC1CC(c1ccc([N+](=O)[O-])cc1)(C3)C2
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: NC12CC3CC1CC(c1ccc([N+](=O)[O-])cc1)(C3)C2
Temperature: 45 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To the stirred solution of 1-(4-nitrophenyl)tricyclo[3.3.1.03,7]nonane-3-carboxylic acid (3.0 g, 10.45 mmol) obtained in step II, in CHCl3 (21 mL) was added conc. H2SO4 (4.2 mL, 78.9 mmol) then solid NaN3 was added in portions, so that the temperature of the reaction did not rise above 40° C. The reaction mixture was warmed to 45° C. and after stirring for 2 h it was cooled again to ice bath temperature, diluted with water and extracted with EtOAc. The aqueous layer was basified with 50% NaOH solution and extracted with CHCl3. The combined organic layer was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure to obtain 1-(4-nitrophenyl)tricyclo[3.3.1.03,7]nonan-3-amine as an off-white solid (2.0 g) in 74% yield. M.R: 201.0-205.9° C. m/z (M+1) 259; IR cm−1 3435, 2941, 1643, 1596, 1518, 1400, 1349, 1013, 750. 1H NMR (CDCl3) 300 MHz δ 8.14 (d, J=8.8 Hz, 2H), 7.39 (d, J=8.8 Hz, 2H), 3.70-3.60 (d (br), 2H), 2.62-2.50 (m, 2H), 2.38-2.23 (m, 3H), 2.15-2.0 (m, 3H), 1.95-1.60 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]3[C:22](=[N:23][CH:24]=2)[NH:21][CH2:20][CH2:19][CH2:18]3)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([N:33]=[C:34]=[O:35])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]3[C:22](=[N:23][CH:24]=2)[N:21]([C:34]([NH:33][C:25](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:35])[CH2:20][CH2:19][CH2:18]3)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2cncc(-c3cnc4c(c3)CCCN4)c2)cc1
Reactant: O=C=NC(=O)c1ccccc1
Solvent: ClCCl
Product: O=C(NC(=O)N1CCCc2cc(-c3cncc(OCc4ccccc4)c3)cnc21)c1ccccc1
Yield: 78.5 %

Procedure:
To a solution of 6-(5-benzyloxy-pyridin-3-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (530 mg, 1.7 mmol) in DCM (18 mL) is added benzoyl isocyanate (368 mg, 2.5 mmol). The resultant mixture is heated at reflux for 2 h. The solvent is removed under vacuum to obtain N-[6-(5-benzyloxy-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carbonyl]-benzamide (620 mg).
Reaction SMILES: C(OC(=O)C)(=O)C.C(O)(=O)C.[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([CH3:24])([CH3:23])[CH2:18][CH2:17][CH2:16]2>C1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[Br:12][C:13]1[CH:14]=[C:15]2[C:20]([C:19]([CH3:24])([CH3:23])[CH2:18][CH:17]=[CH:16]2)=[CH:21][CH:22]=1
Reactant: CC1(C)CCCc2cc(Br)ccc21
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC1(C)CC=Cc2cc(Br)ccc21
Reaction time: 1 h

Procedure:
To a cold mixture (0° C.) of 209 g (200 mmol) of chromium trioxide, 100 ml (1.06 mol) of acetic anhydride and 200 ml (3.5 mol) of acetic acid was added a solution of 10 g (41.8 mmol) of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F) in 125 ml of benzene. The reaction mixture was stirred for 1 hour, quenched with ice cold water and extracted with Et2O (3×100 ml). The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (silica, 10% EtOAc-hexane) to give the title compound as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15](=O)[C:14]2=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1>[C:7]1([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=c1[nH]c2ccccc2n(-c2ccccc2)c1=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: c1ccc(N2CCNc3ccccc32)cc1
Yield: 73.1 %

Procedure:
To a suspension of lithium aluminium hydride (3.99 g, 105.0 mmol, 5.0 equiv) in THF (30 mL) was added slowly a solution of 1-phenyl-1,4-dihydro-quinoxaline-2,3-dione (5.00 g, 21.0 mmol, 1.0 equiv; prepared as described by S.-K. Lin Molecules 1996, 1, 37-40) in THF (50 mL). After heating the reaction mixture to reflux for 16 h, a solution of 1 M NaOH (100 mL) was added. The reaction mixture was stirred for a few minutes, MgSO4 added and then filtered over Celite. Extraction of the filter cake with ethyl acetate (3×100 mL) and evaporation of the solvent under reduced pressure provided the crude reaction product which was purified by silica column chromatography eluting with a gradient of heptane/ethyl acetate to afford 3.23 g (73%) of the title compound as an orange solid. MS (ED: 210.0 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:26])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][CH:15]=1)=[C:7]2[CH3:25].[CH3:27][O:28][C:29](=[O:32])[CH2:30]Br>>[CH3:27][O:28][C:29](=[O:32])[CH2:30][O:26][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:25])=[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][CH:15]=1)[C:9](=[O:12])[NH:10]2
Reactant: COC(=O)CBr
Reactant: Cc1c(Cc2ccc(-n3cccn3)cc2)c(=O)[nH]c2c(Cl)ccc(O)c12
Product: COC(=O)COc1ccc(Cl)c2[nH]c(=O)c(Cc3ccc(-n4cccn4)cc3)c(C)c12

Procedure:
The title compound was prepared by the method of Preparation 7a using 8-chloro-5-hydroxy-4-methyl-3-(4-pyrazol-1-ylbenzyl)-1H-quinolin-2-one and bromoacetic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[CH2:27]([CH2:29][NH2:30])[OH:28].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:30][CH2:29][CH2:27][OH:28])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: NCCO
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NCCO)c(Cl)c32)c(F)cc1F
Temperature: 50 °C
Reaction time: 15.5 h
Yield: 85 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg), ethanolamine (35 mg) and triethylamine (200 mg) were added to pyridine (600 mg), and the mixture was stirred at 50° C. for 15.5 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (3 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Ethanol (1 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (188 mg) as a pale brown powder.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:3]=1.[F:17][C@@H:18]1[C@@H:22]([CH2:23][OH:24])[O:21][C@@H:20](N2C=CC(=O)NC2=O)[CH2:19]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:20]2[O:21][C@H:22]([CH2:23][OH:24])[C@@H:18]([F:17])[CH2:19]2)=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[N:3]=1
Reactant: Nc1nc(N2CCOCC2)c2nc[nH]c2n1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1nc(N2CCOCC2)c2ncn([C@H]3C[C@H](F)[C@@H](CO)O3)c2n1
Temperature: 45 °C
Reaction time: 192 h
Yield: 67.6 %

Procedure:
2-Amino-6-morpholino-9H-purine (0.58 g 2.6 moles) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 mmoles) were suspended in 50 ml 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky, et al., Biochemistry, 20, 3615, 1981 and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added and the suspension was stirred at 45° C. After 8 days, 100 ml MeOH was added to the reaction mixture. The resulting mixture was applied to a column containing AG1-X2 (OH-- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:methanol:acetone (96:2:2). Solvent was removed and lyophilization yielded 0.503 g of 2-amino-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-6-morpholino-9H-purine (68%): mp165°-167° C.; TLC Rf 0.70 (silica gel, MeCN:15N NH4OH:H2O/85:5:10); [α]D20 -16.4 (c=0.5, DMF); UV λmax (ε×10-3) at pH 7, 289 (16.6); at pH 13, 289 (16.5); 1H NMR (300 MHz, DMSO-d6) δ7.97 (s, 1H, H8), 6.22 (dd, 1H, H1', J=9.3 Hz, J=5.7 Hz), 5.93 (s, 2H, NH2), 5.37 (t, 1H, OH5', J=5.5 Hz), 5.3-5.5 (m, 1H, H3'), 4.0-4.23 (bm, 5H, H4' and morpholino ring), 3.63-3.66 (m, 4H, morpholino ring), 3.56 (t, 2H, H5' and H5", J=5.0 Hz), and 2.70-2.95 and 2.45-2.61 (m, 2H, H2' and H2"); MS (ci) 339 (M+1), 319 (M-F),221 (MH2 --C5H8FO2).