Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][NH:11][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:44][CH2:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([C:54](=[O:65])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2[C:61]([F:64])([F:63])[F:62])[CH2:50][CH2:49]1)=[O:47].Cl>CN(C=O)C.O>[CH3:10][NH:11][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:44][CH2:45][C:46](=[O:47])[N:48]2[CH2:49][CH2:50][N:51]([C:54](=[O:65])[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=3[C:61]([F:64])([F:62])[F:63])[CH2:52][CH2:53]2)=[O:18])=[CH:15][CH:14]=1
Reactant: CNC(=O)c1ccc(C(=O)O)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CNC(=O)c1ccc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.74 %

Procedure:
DIPEA (165 mg, 0.2 mL, 1.2 mmol) was added drop wise to N-methyl-terephthalamic acid (80 mg, 0.4 mmol) in DMF (5 mL). EDCI (100 mg, 0.5 mmol) and HOBT (67 mg, 0.5 mmol) were added consecutively and, after 10 minutes, 2-Amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone in its HCl salt form (150 mg, 0.4 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using basic alumina and 10% MeOH in CHCl3 as eluent) to afford 30 mg (15.74% yield) of N-methyl-N′-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-terephthalamide. LCMS Purity: 97.3%. 1H NMR (CDCl3): δ 8.7 (d, 2H), 8.2 (d, 2H), 7.8 (m, 1H), 7.7 (m, 3H), 7.2 (m, 2H), 4.4 (m, 2H), 4.1 (s, 1H), 3.8 (s, 3H), 3.4 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([CH2:12][N:13]([CH3:20])[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:3]=1.[NH2:21][C:22]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]2[C:25]([CH:26]3[CH2:36][CH:27]3[CH2:28][O:29]2)=[CH:24][CH:23]=1>C(Cl)Cl.N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:21][C:22]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]3[C:25]([CH:26]4[CH2:36][CH:27]4[CH2:28][O:29]3)=[CH:24][CH:23]=2)(=[O:10])=[O:9])=[C:4]([CH2:12][N:13]([CH3:20])[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:3]=1
Reactant: CN(Cc1cc(F)ccc1S(=O)(=O)Cl)C(=O)C(F)(F)F
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CN(C)C(=O)C(F)(F)F)ccc2c1OCC1CC21
Yield: 109.1 %

Procedure:
A mixture of 4-fluoro-2-[N-methyl-N-(2,2,2-trifluoroacetyl)aminomethyl]benzenesulfonyl chloride (Intermediate 158, 0.182 g) was added to a solution of methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42, 0.100 g) in DCM (3 mL) and pyridine (1 mL) and the resultant mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-40% to give methyl (1aRS,7bSR)-5-(4-fluoro-2-[N-methyl-N-(2,2,2-trifluoroacetyl)aminomethyl]benzenesulfonyl-amino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.257 g) as a solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][N:7]=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]=1)[CH3:2].[CH2:19]([OH:21])C>[C].[Pd]>[CH2:1]([N:3]1[C:19](=[O:21])[NH:10][C:9]2[C:4]1=[N:5][C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:7][CH:8]=2)[CH3:2]
Reactant: CCNc1nc(-c2ccccc2)ncc1[N+](=O)[O-]
Reactant: CCO
Agent: [Pd]
Product: CCn1c(=O)[nH]c2cnc(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 4-ethylamino-5-nitro-2-phenylpyrimidine (2.7 g), palladium-carbon (0.3 g), and ethanol (50 ml) is stirred at room temperature under hydrogen atmosphere for five hours, and the reaction mixture is filtered. The filtrate is concentrated under reduced pressure, and to the resulting residue is added urea (1.4 g). The mixture is stirred at 200° C. for two hours. After cooling, water is added to the reaction mixture, and the precipitates are collected by filtration, washed with water, and washed with ethanol to give the desired compound (2.4 g).
Reaction SMILES: [CH3:1][N:2]([CH3:39])[C:3](=[O:38])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([O:30]CC3C=CC=CC=3)[CH2:19][CH2:18][N:17]([C:20]3[C:21]4[C:28]([CH3:29])=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1.FC(F)(F)C(O)=O>CO.[OH-].[OH-].[Pd+2]>[CH3:39][N:2]([CH3:1])[C:3](=[O:38])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([OH:30])[CH2:19][CH2:18][N:17]([C:20]3[C:21]4[C:28]([CH3:29])=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1
Reactant: Cc1c[nH]c2ncnc(N3CCC(OCc4ccccc4)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1c[nH]c2ncnc(N3CCC(O)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Reaction time: 24 h
Yield: 14.5 %

Procedure:
Crude 3-(4-(benzyloxy)-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamido)phenyl dimethylcarbamate from example 24, step F (85% pure, approximately 80 mg) was taken up in methanol (2 mL), and a catalytic amount of Pearlman's catalyst was added. The system was hydrogenated at 60 psi for 24 hours, after which a small amount of product was observed. Trifluoroacetic acid (0.1 mL) was added, and the hydrogenation was continued at 60 psi H2 for 3 days, after which the reaction was approximately one third of the way completed. The reaction was filtered, and the product was isolated by prep HPLC (30×100 mm C18 column, 10-100% acetonitrile:water (10 mM ammonium acetate), 15 min, 45 mL/min) to afford the title compound (9.6 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](O)=O)[CH:6]=[CH:7][CH:8]=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:29]1[C:33]2[CH:34]=[CH:35][C:36]([C:38]([NH:40][NH2:41])=O)=[CH:37][C:32]=2[NH:31][CH:30]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:51])=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][CH2:10][C:11]1[S:51][C:38]([C:36]2[CH:35]=[CH:34][C:33]3[NH:29][CH:30]=[N:31][C:32]=3[CH:37]=2)=[N:40][N:41]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cccc(CCC(=O)O)c1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: COc1cccc(CCc2nnc(-c3ccc4[nH]cnc4c3)s2)c1

Procedure:
The compound was synthesized starting from 3-(3-methoxyphenyl)propionic acid (181 mg; 1 mmol), DCC (206 mg; 1 mmol), benzimidazol-5-carbohydrazide (176 mg; 1 mmol) and Lawesson's reagent (606 mg; 1.5 mmol) as described in method 2; yield: 0.019 g (5.7%); MS m/z: 337.3 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.08 (t, 2H, 3J=7.5 Hz); 3.46 (t, 2H, 3J=7.5 Hz); 3.72 (s, 3H); 6.76-6.78 (m, 1H); 6.85-6.88 (m, 2H); 7.20 (t, 1H, 3J=7.9 Hz); 7.81 (d, 1H, 3J=8.7 Hz); 7.89 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 8.20 (d, 1H, 4J=1.7 Hz); 8.83 (s, 1H); HPLC (METHOD [A]): rt 12.24 min (95.9%)
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH2:8])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O>[CH2:25]([O:24][C:22](=[O:23])[NH:8][CH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([OH:1])[CH2:3]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NC1CCCC(O)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC1CCCC(O)C1)OCc1ccccc1
Yield: 88.1 %

Procedure:
Treat a mixture of 3-hydroxycyclohexyl amine (10 g, 86.96 mmol), potassium carbonate (18 g, 130 mmol), ethyl acetate (150 mL) and water (70 mL) with benzyl chloroformate (22.17 g, 130 mmol). Stir the reaction at room temperature for 12 hours. Separate the organic layer, dry the organic over sodium sulfate, filter and concentrate. Add diethyl ether to the residuer. Filter the resulting white precipitate and air dry to afford 19.1 g of the title compound (88%). MS (m/z): 250 (M+).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([CH3:11])[C:8]([OH:10])=O)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[CH:25]=[N:24]2)=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:31]3[CH2:30][CH2:29][CH2:28][N:27]([C:8](=[O:10])[CH:7]([N:6]4[C:2]([CH3:1])=[N:3][C:4]([C:12]([F:15])([F:14])[F:13])=[N:5]4)[CH3:11])[C:26]=3[CH:25]=[N:24]2)=[CH:21][CH:22]=1
Reactant: Cc1nc(C(F)(F)F)nn1C(C)C(=O)O
Reactant: Clc1ccc(-n2ncc3c2CCCN3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)nn1C(C)C(=O)N1CCCc2c1cnn2-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a mixture of 2-[5-methyl-3-(trifluoromethyl)-1,2,4-triazol-1-yl]propanoic acid (0.048 g, 0.21 mmol) and 1-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.050 g, 0.21 mmol) in DMF (1 mL) were added Hunig's base (0.055 g, 0.42 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uranium hexafluorophosphate methanaminium (HATU) (0.090 g, 0.23 mmol). The mixture was stirred at room temperature for 1 hour, and then partitioned between water (4 mL) and ethyl acetate (6 mL). The organic layer was washed with brine, dried (Na2SO4), filtered, concentrated in vacuo, and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the desired product as a white solid (0.028 g, 0.063 mmol, 30%). 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.43 (s, 4H), 5.60 (q, J=7.1 Hz, 1H), 3.77 (ddd, J=12.6, 7.5, 3.0 Hz, 1H), 3.52 (ddd, J=12.3, 8.3, 3.0 Hz, 1H), 2.84 (tt, J=6.9, 3.3 Hz, 2H), 2.52 (s, 3H), 2.09-1.81 (m, 5H); MS: (ES) m/z calculated for C19H18ClF3N6O [M+H]+ 439.1, found 438.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[F:11][C:12]1[C:13](=[NH:20])[N:14]([CH3:19])[C:15](=[O:18])[NH:16][CH:17]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:16]2[CH:17]=[C:12]([F:11])[C:13](=[NH:20])[N:14]([CH3:19])[C:15]2=[O:18])=[S:10])=[CH:4][CH:3]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Cn1c(=O)[nH]cc(F)c1=N
Solvent: CN(C)C=O
Product: Cn1c(=N)c(F)cn(C(=S)Nc2ccc(Cl)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
1-Chloro-4-isothiocyanatobenzene (78 mg, 0.46 mmol) was added to a stirred mixture of 5-fluoro-4-imino-3-methyl-3,4-dihydropyrimidin-2(1H)-one (60 mg, 0.42 mmol) and DMF (1.0 mL) and stirred at room temperature overnight. The solvent was removed and the residue was purified on normal phase chromatography (gradient, 0 to 10% MeOH-DCM). A second purification (gradient, 2 to 6% [10% NH4OH-MeOH]-DCM) gave the title compound as a yellow gum (68 mg, 52%); 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 10.99 (s, 1H), 7.75 (d, J=39.7 Hz, 2H), 7.48-7.15 (m, 3H), 3.22 (d, J=13.8 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) 6148.96, 144.90, 138.17, 136.27, 135.90, 128.51, 124.11, 123.07, 29.88; ESIMS m/z 311 ([M−H]+).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5](=[O:15])[CH:4]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:2].ClC1C(=O)C(C#N)=[C:26](C#N)[C:27](=[O:30])C=1Cl>C(OC(C)=C)(=O)C.C(Cl)Cl>[C:27]([O:15][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2)[CH:12]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:30])[CH3:26]
Reactant: CCC1Cc2cc(OC)ccc2C(=O)C1c1ccccc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: C=C(C)OC(C)=O
Solvent: ClCCl
Product: CCc1cc2cc(OC)ccc2c(OC(C)=O)c1-c1ccccc1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
3-Ethyl-6-(methyloxy)-2-phenyl-3,4-dihydro-1(2H)-naphthalenone (55) (0.84 g, 3.00 mmol) was dissolved in isopropenyl acetate (30 mL). pTsOH monohydrate (100 mg) was added. The mixture was refluxed under nitrogen for 3 days. Cooled to room temperature, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.74 g, 7.50 mmol) was added. The resulting mixture was refluxed under nitrogen overnight. Cooled to room temperature and diluted with CH2Cl2 (150 mL). The mixture was washed with 0.2 N NaOH (4×20 mL), water (2×20 mL), brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a dark brown tar. The crude product was purified by flash chromatography over SiO2 with hexanes:acetone (50:1) to give 0.61 g (64%) of the title compound (56) as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.11 (t, J=7.5 Hz, 3H), 1.97 (s, 3H), 2.55 (q, J=7.5 Hz, 2H), 3.93 (s, 3H), 7.10-7.16 (m, 2H), 7.20-7.25 (m, 2H), 7.30-7.45 (m, 3H), 7.57 (s, 1H), 7.62 (d, J=8.9 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([C@:8]1([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][C@H:12]([OH:14])[C@@H:11]2[C@H:9]1[C@H:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.S([O-])(O)(=O)=O.[K+].O>CN(C)C1C=CN=CC=1.ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([C@:8]1([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][C@H:12]([O:14][S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=2)(=[O:38])=[O:37])[C@@H:11]2[C@H:9]1[C@H:10]2[C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@H](O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@](NC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)[C@@H]3[C@@H](C(=O)OC(C)(C)C)[C@@H]32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.7 %

Procedure:
Charge a 2-necked round bottom flask under nitrogen atmosphere with ditert-butyl(1S,2S,4S,5R,6R)-2-(tert-butoxycarbonylamino)-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (20.7 g, 0.5 mol, see WO03/104217/A2 for synthesis details), 4-dimethylaminopyridine (10.4 g, 0.85 mol), triethylamine (6.98 mL, 0.5 mmol) and p-toluenesulfonyl chloride (10.6 g, 0.55 mol) in dichloromethane (200 mL), and stir the mixture at room temperature overnight. Add 1N solution of potassium hydrogen sulfate (200 mL), water (100 mL) and extract the organic layer. Wash with water (200 mL), brine (200 mL), dry over magnesium sulfate, filter and evaporate to dryness. Add tetrahydrofuran (30 mL) then heptanes (90 mL). Heat the mixture at 60° C. and slowly add more heptanes (200 mL). Cool the mixture to room temperature. Filter the solid and dry under reduced pressure to yield the title compound as a white solid (24.6 g, 87%). MS (m/z): 590 (M+23).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]=[CH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[N+:16]([CH2:19][CH2:20][CH3:21])([O-:18])=[O:17].C1CCN2C(=NCCC2)CC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH:19]([N+:16]([O-:18])=[O:17])[CH2:20][CH3:21])[CH2:9][C:8]2=[O:13])=[CH:14][CH:15]=1
Reactant: CCC[N+](=O)[O-]
Reactant: O=C1C=CCCN1Cc1ccc(F)cc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(C1CCN(Cc2ccc(F)cc2)C(=O)C1)[N+](=O)[O-]
Reaction time: 24 h

Procedure:
To a solution 1-(4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one (2.0 g, 10 mmol) in 1-nitropropane (8.68 g, 97.5 mmol) was added DBU (1.48 g, 9.75 mmol). After stirring for 24 hours, the reaction mixture was concentrated under vacuum. The residual material was purified by silica gel column chromatography eluting with 1% methanol in CH2Cl2. The appropriate fractions were combined and concentrated to afford the title compound as mixture of diastereomers. The diastereomers co-eluted with a retention time of 3.01 min. The HPLC method was performed on a Hewlett-Packard Zorbax SB-C8 column (75×4.6 mm, 3.5 micron) eluting with 5%-100% CH3CN (0.1% TFA) in H2O (0.1% TFA). ES MS M+1=295.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:9]2[CH2:12][CH:11]([NH2:13])[CH2:10]2)=[CH:4][CH:3]=1.[C:21]1([S:31](Cl)(=[O:33])=[O:32])[CH:26]=[CH:25][CH:24]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:22]=1.C([N:37](CC)CC)C.N>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:9]2[CH2:10][CH:11]([NH:13][S:31]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([S:27](=[O:29])(=[O:28])[NH2:37])[CH:22]=3)(=[O:33])=[O:32])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: CCN(CC)CC
Agent: N
Solvent: CC#N
Product: NS(=O)(=O)c1cccc(S(=O)(=O)NC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.307 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylamine is added dropwise, at room temperature, to a solution of 0.412 g of 1,3-benzenedisulfonic acid dichloride and 0.165 cm3 of triethylamine in 10 cm3 of acetonitrile. After stirring for 3 hours at room temperature, 0.28 cm3 of a 20% solution of ammonia is added and the reaction mixture is left at room temperature. After 18 hours, the mixture is filtered and concentrated to dryness under reduced pressure (2.7 kPa). After chromatography on a silica gel column (particle size 0.06-0.200 mm, height 35 cm, diameter 2 cm), eluting under an argon pressure of 0.9 bar with dichloromethane and then a mixture of dichloromethane+1% methanol and then a mixture of dichloromethane+2% methanol by volume and collecting 30-cm3 fractions, fractions 23 to 34 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give 90 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3-sulfamoylphenylsulfonamide in the form of a white solid [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.78 (broad t, J=7 Hz: 2H); 3.35 (broad t, J=7 Hz: 2H); 4.01 (mt: 1H); 4.24 (s: 1H); 5.27 (unresolved complex: 2H); 5.61 (unresolved complex: 1H); from 7.15 to 7.35 (mt: 8H); 7.67 (t, J=8 Hz: 1H); 8.04 (broad d, J=8 Hz: 1H); 8.12 (broad d, J=8 Hz: 1H); 8.49 (broad s: 1H)].
Reaction SMILES: O([C@:9]([C@@H:21]([CH:23]([O:25][Si](C(C)(C)C)(C)C)O)[OH:22])([OH:20])[C:10]([F:19])([F:18])[C:11]([O:13]S(C)(=O)=O)=O)[Si](C(C)(C)C)(C)C.C[Si]([N:37]([Si](C)(C)C)[C:38]1[C:43]([I:44])=[CH:42][N:41]([Si](C)(C)C)[C:40](=[O:49])[N:39]=1)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.CO>ClCCCl>[NH2:37][C:38]1[C:43]([I:44])=[CH:42][N:41]([C:11]([C:10]([F:18])([F:19])[C@@H:9]([C@@H:21]([CH2:23][OH:25])[OH:22])[OH:20])=[O:13])[C:40](=[O:49])[N:39]=1
Reactant: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)OS(C)(=O)=O
Reactant: C[Si](C)(C)N(c1nc(=O)n([Si](C)(C)C)cc1I)[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Solvent: CO
Product: Nc1nc(=O)n(C(=O)C(F)(F)[C@H](O)[C@H](O)CO)cc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.8 %

Procedure:
To 1.99 g (0.0042 mol) of 3,5-bis(t-butyldimethylsiloxy)-1-methanesulfonyloxy-2-desoxy-2,2-difluororibose in 35 ml of dry 1,2-dichloroethane was added 2.08 g (0.0046 mol) of tris-trimethylsilyl-5-iodocytosine followed by 1.11 g (0.005 mol) of trifluoromethanesulfonyloxytrimethylsilane. The reaction mixture was refluxed for about 16 hours under a nitrogen atmosphere and cooled to room temperature. Five milliliters of methanol were added to the reaction mixture and the mixture was stirred for an additional 30 minutes. The mixture was filtered and the precipitated solid was collected by filtration. The filtrate was evaporated to dryness under reduced pressure, and the resulting residue was dissolved in 20 ml of dichloromethane saturated with anhydrous hydrogen bromide. This mixture was stirred for about 3 hours. The volatiles were removed in vacuo at 45° C. The residue was dissolved in 15 ml of water, neutralized to pH 7-8 with 10% sodium bicarbonate, and the resulting solution was washed once with 10 ml of ethyl acetate. The aqueous layer was chromatographed on a Whatman Prep ODS-3 reverse phase column in 2.0 ml portions using water/methanol (9:1, v:v) to afford 30 mg of 1-(4-amino-5-iodo-2-oxo-1H-pyrimidin-1-yl)-2-desoxy-2,2-difluororibose.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]([Cl:18])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([NH2:29])(=[O:28])=[O:27].Cl>O.CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([NH:29][C:8]1[C:17]([Cl:18])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)(=[O:28])=[O:27]
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: Clc1nc2ccccc2nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccccc1Cl
Yield: 101 %

Procedure:
In the presence of potassium carbonate (625 mg), 2,3-dichloroquinoxaline (275 mg) and 2-chlorobenzenesulfonamide (264 mg) were allowed to react in the solution of dimethylformamide (4 mL) for 3 hours at 90° C. To the reaction mixture, water and hydrochloric acid were added and extracted with ethyl acetate. The residue was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate and concentrated to obtain the title compound (493 mg) having the following physical data.
Reaction SMILES: [CH2:1](Br)[CH3:2].[F:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[CH2:8][C@@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH2:1]([N:11]1[CH2:12][CH2:13][C@@H:9]([CH2:8][C:7]2[CH:14]=[CH:15][CH:16]=[C:5]([F:4])[CH:6]=2)[CH2:10]1)[CH3:2]
Reactant: Fc1cccc(C[C@@H]2CCNC2)c1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCN1CC[C@@H](Cc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 57.6 %

Procedure:
Ethyl bromide (0.22 g) was added to a suspension of 3-(R)-(3-fluorobenzyl)pyrrolidine (Intermediate 98, 0.36 g) and potassium carbonate (0.55 g) in acetonitrile and the mixture was stirred at room temperature for 2.5 hours. The mixture was diluted with ethyl acetate, filtered and the filtrate was evaporated to dryness. The residue was triturated with DCM, the solvent was decanted off and evaporated to dryness to give (R)-1-ethyl-3-(3-fluorobenzyl)pyrrolidine (0.24 g) as an oil.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].C1C=CC=CC=1.[Cl:11][C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][C:13]=1[N+:24]([O-:26])=[O:25].S(=O)(=O)(O)O>O>[CH2:1]([O:4][C:16](=[O:17])[C:15]1[CH:14]=[C:13]([N+:24]([O-:26])=[O:25])[C:12]([Cl:11])=[C:20]([N+:21]([O-:23])=[O:22])[CH:19]=1)[CH2:2][CH3:3]
Reactant: CCCO
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CCCOC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
Into a 1000 ml round-bottomed flask equipped with a stirrer, thermometer and Marcusson-condenser 180 g (3 moles) of n-propanol, and 380 g of benzene are weighed in, whereupon 493 g (2 moles) of 4-chloro-3,5-dinitro-benzoic acid and 20 g of concentrated sulfuric acid are added under stirring. The reaction mixture is heated to boiling on a water bath under stirring (86° C.) until no more water is distilled off. The water thus formed is collected in the Marcusson-condenser and removed if necessary. In the meantime the upper benzene/n-propanol phase is continuously re-introduced into the flask. The reaction having been completed the mixture is cooled to room temperature under stirring, the precipitated crystals are filtered off, washed with cold n-propanol and dried. Thus 490 g of the desired compound are obtained, yield 85%, purity 98%.