Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH2:11][CH2:12][CH:13]([CH3:41])[CH:14]([OH:40])[CH:15]([CH3:39])[C:16](=[O:38])[CH:17]([CH2:36][CH3:37])[CH:18]2[CH:22]([CH3:23])[CH2:21][C:20]([CH2:34][CH3:35])([CH:24]3[CH2:29][CH2:28][C:27]([CH2:31][CH3:32])([OH:30])[CH:26]([CH3:33])[O:25]3)[O:19]2)=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:42])=[C:4]([CH3:43])[CH:3]=1.[C:44](OC(=O)C)(=[O:46])[CH3:45].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[C:44]([NH:1][C:2]1[C:10]([CH2:11][CH2:12][CH:13]([CH3:41])[CH:14]([OH:40])[CH:15]([CH3:39])[C:16](=[O:38])[CH:17]([CH2:36][CH3:37])[CH:18]2[CH:22]([CH3:23])[CH2:21][C:20]([CH2:34][CH3:35])([CH:24]3[CH2:29][CH2:28][C:27]([CH2:31][CH3:32])([OH:30])[CH:26]([CH3:33])[O:25]3)[O:19]2)=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:42])=[C:4]([CH3:43])[CH:3]=1)(=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(C(=O)C(C)C(O)C(C)CCc1c(N)cc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC(C(=O)C(C)C(O)C(C)CCc1c(NC(C)=O)cc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C

Procedure:
To a suspension of 1.21 g. (2 mmole) of 5-amino-3-methyl-6-{7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]-heptyl}salicylic acid in 50 ml. glacial acetic acid was added 1 ml. acetic anhydride (~10 mmoles). On warming the mixture to 70° on a steam bath, the amine dissolved and after a further half an hour at room temperature, the solution was poured on to crushed ice. The mixture was carefully made alkaline with sodium carbonate solution and extracted twice with 400 ml. ether. After drying (NaSO4) the ethereal solution was evaporated to approximately 100 ml. The resulting microcrystalline product had m.p. 189°-190°, [α]D -17.45° (1%, MeOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:17]([NH:19][CH3:20])=[O:18])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][N:32]([CH:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][N:32]([CH:40]3[CH2:45][CH2:44][N:43]([CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[C:7]([C:17]([NH:19][CH3:20])=[O:18])=[CH:8][C:9]4=[O:16])[CH2:42][CH2:41]3)[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1
Reactant: CNC(=O)c1cc(=O)n(CC=O)c2cc(OC)ccc12
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CNC(=O)c1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To 2 mL of dichloromethane suspension containing 77 mg of 7-methoxy-N-methyl-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-4-carboxamide, 2 mL of dichloromethane solution containing 98 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 16 μL of acetic acid were added and stirred at room temperature for 2 hours. To the reaction mixture, 89 mg of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 min. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=10:1] to give 0.16 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-4-((methylamino)carbonyl)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a light brown foam.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]1[C@@H:18](/[CH:19]=[CH:20]/[CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:17][CH2:16][C:15]1=[O:28]>C1COCC1>[CH2:1]([S:3][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]1[C@@H:18](/[CH:19]=[CH:20]/[CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH2:17][CH2:16][C:15]1=[O:28])[CH3:2]
Reactant: CCS
Reactant: O=C1CC[C@H](/C=C/CC2CCCCC2)[C@H]1CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSCCCCCCC[C@H]1C(=O)CC[C@@H]1/C=C/CC1CCCCC1
Reaction time: 3 h

Procedure:
Ethyl mercaptan (0.1 ml) was injected dropwise into a slurry of 1.0 ml THF and 62.5 mg of sodium hydride (50% in oil). The resultant slurry was stirred for 1.0 hour at 25° whereupon a solution of 167 mg 1-Bromo-16,20-methanoprost-13E-en-9-one in 1.0 ml of THF was injected and the reaction mixture was stirred for 3.0 hours at 25°. The reaction mixture was quenched by the addition of 10% aqueous HCl and extracted twice with chloroform. The chloroform extracts were washed with saturated aqueous NaHCO3 and then brine. They were dried (Na2SO4), filtered and evaporated in vacuo to yield 135 mg of an orange oil. The oil was chromatographed (85:15 silicic acid-Celite, benzene-ethyl acetate gradient elution) to afford 70.1 mg of a clear oil having the following structure: ##STR58## The structure of this material was confirmed by nuclear magnetic resonance and mass spectral analysis.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[C:11]=1[NH:12][N:13]1[CH:18]=[CH:17][C:16](=[O:19])[NH:15][C:14]1=[O:20]>C(O)(=O)C>[Br:1][C:17]1[C:16](=[O:19])[NH:15][C:14](=[O:20])[N:13]([NH:12][C:11]2[C:21]([Cl:26])=[CH:22][C:23]([Cl:25])=[CH:24][C:10]=2[Cl:9])[CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1ccn(Nc2c(Cl)cc(Cl)cc2Cl)c(=O)[nH]1
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)n(Nc2c(Cl)cc(Cl)cc2Cl)cc1Br
Temperature: 25 °C

Procedure:
An excess of N-bromosuccinimide in acetic acid is added to 1-(2,4,6-trichloroanilino)-2,4-pyrimidinedione and the mixture is refluxed for 10 hours. It is cooled to RT and is then poured into ice and filtered to give 5-bromo-1-(2,4,6-trichloroanilino)-2,4-pyrimidinedione.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC(C)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CC(C)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 62.4 %

Procedure:
7-[2-(2-formamidothiazol-4-yl)-2-iso-butoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 4.1 g.), conc. hydrochloric acid (3.65 g.) and methanol (61.5 ml.) were treated in a similar manner to that of Example 15-(3) to give 7-[2-(2-aminothiazol-4-yl)-2-iso-butoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.4 g.).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][NH2:8])[CH3:2].C(OC(N1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])=O)C>O1CCCC1>[CH2:10]([O:9][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][CH2:7][N:8]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])[CH3:11]
Reactant: CCOC(CCCN)OCC
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: C1CCOC1
Product: CCOC(CCCN1C(=O)c2ccccc2C1=O)OCC
Temperature: 0 °C
Reaction time: 18 h
Yield: 104.1 %

Procedure:
A solution of 4-aminobutyraldehyde diethyl acetal (48.5 g, 0.3 mol) in tetrahydrofuran (60 ml) was added dropwise to a stirred slurry of N-(ethoxycarbonyl) phthalimide (65.93 g, 0.3 mol) in tetrahydrofuran (250 ml) at 0° C. After stirring at 0° C. for 0.16 h and at room temperature for 18 h the solvent was removed in vacuo and the residue distilled at 1 mmHg to remove the ethyl carbamate by-product. The residual brown oil was allowed to cool to afford the title compound (91 g, 93%).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([OH:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.[ClH:24]>>[ClH:24].[NH:8]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([OH:17])=[O:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C1CCCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Perhydro-azepine-1,4-dicarboxylic acid 1-tert-butyl ester (1 g, 4 mmol) was dissolved in 4 M of Hydrogen chloride in 1,4-Dioxane (10 mL, 40 mmol) and stirred at room temperature for 1 hour. Crude reaction was concentrated to dryness and used without additional purification.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1.[C:20]([C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1)(=[O:22])[CH3:21]>>[C:20]([C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])=[C:7]([C:13]3[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=3)[CH:8]=2)=[O:31])[CH:26]=[CH:27][CH:28]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cccc(N=C=O)c1
Reactant: CN(C)CCOc1ccc(N)cc1-c1ccnn1C
Product: CC(=O)c1cccc(NC(=O)Nc2ccc(OCCN(C)C)c(-c3ccnn3C)c2)c1
Yield: 64.3 %

Procedure:
4-(2-Dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (26.0 mg, 0.1 mmol) was treated with 3-acetylphenyl isocyanate (16.9 μL, 0.105 mmol) in a similar manner as described in Example 1.2 to afford Compound 143 as a colorless waxy solid in 64.3% yield. LCMS m/z (%)=422 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ: 8.98 (s, 1H), 8.73 (s, 1H), 8.10 (s, 1H), 7.52-7.42 (m, 4H), 7.37 (d, J=8.06 Hz, 1H), 7.37 (d, J=6.75 Hz, 1H), 7.33-7.28 (m, 4H), 7.15 (d, J=8.98 Hz, 1H), 6.28 (s, 1H), 4.08 (t, J=5.80 Hz, 2H), 3.71 (s, 3H), 2.54 (m, 6H), 2.12 (s, 6H).
Reaction SMILES: [C:1]1([CH:7]([CH:9]([C:11]([NH2:13])=[O:12])[OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([C:22]([C:37]([OH:39])=[O:38])([OH:36])[C:23]([C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([OH:27])[C:24]([OH:26])=[O:25])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:28]([C:23]([C:24]([OH:26])=[O:25])([OH:27])[C:22]([C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([OH:36])[C:37]([OH:39])=[O:38])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:1]1([C@@H:7]([C@H:9]([C:11]([NH2:13])=[O:12])[OH:10])[NH2:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)C(O)C(N)c1ccccc1
Agent: O=C(O)C(O)(C(=O)c1ccccc1)C(O)(C(=O)O)C(=O)c1ccccc1
Solvent: CCO
Product: NC(=O)[C@H](O)[C@@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Racemic threo 3-phenylisoserine amide (IX) (120.0 g, 0.67 mole) and (−)-dibenzoyltartaric acid (240.1 g, 0.67 mole) were suspended in ethanol (1080.0 g). The suspension was refluxed for 2 hours, then cooled to room temperature and stirred for further 60 minutes. The product was filtered off, washed with ethanol (400.0 g) and vacuum dried at 50° C. Yield: 180.6 g (0.34 mole, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:18][CH2:19][C:20](Cl)=[O:21]>C(#N)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:20](=[O:21])[CH2:19][Cl:18])=[O:7])=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CCl)NNC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
To a mixture of 4-chlorobenzohydrazide 5 (1 g, 5.86 mmol) and K2CO3 (0.97 g, 7.03 mmol) in acetonitrile (30 mL) was added 2-chloroacetyl chloride (0.68 g, 6.08 mmol) dropwise at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 hours. The solid was collected, washed with H2O and ether, and dried to afford 4-chloro-N′-(2-chloroacetyl)benzohydrazide 6 (1.2 g, 82%) which was used for the next step without further purification. A mixture of 4-chloro-N′-(2-chloroacetyl)benzohydrazide 6 (0.6 g, 2.43 mmol) and phosphorous oxychloride (0.37 g, 2.43 mmol) in acetonitrile (20 mL) was stirred under reflux for 16 hours and concentrated. The residue was subjected to flush column chromatography eluting with 10-25% acetone/hexanes to give compound 7 (0.45 g). Yield: 82%.
Reaction SMILES: BrC=C([C:5]1[CH:6]=[C:7]([F:14])[C:8]([O:12]C)=[C:9]([F:11])[CH:10]=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH3:31][N:32]1[CH2:45][CH2:44][C:35]2[NH:36][C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][C:42]=3[C:34]=2[CH2:33]1>CN(C=O)C.[Cu]I>[CH3:31][N:32]1[CH2:45][CH2:44][C:35]2[N:36]([C:8]3([OH:12])[C:9]([F:11])=[CH:10][CH:5]=[CH:6][CH:7]3[F:14])[C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][C:42]=3[C:34]=2[CH2:33]1
Reactant: COc1c(F)cc(C(C)=CBr)cc1F
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2C2(O)C(F)=CC=CC2F)CCN(C)C1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
5-(1-Bromoprop-1-en-2-yl)-1,3-difluoro-2-methoxybenzene (223 mg, 1.2 mmol) was dissolved in DMF (5 mL) and potassium phosphate (424 mg, 2 mmol) was added followed by copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol). 2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was added and the mixture purged with nitrogen for 2 min. The reaction mixture was stirred at 85° C. overnight. Water was added and the solid mass was filtered under vacuum. The crude product was purified on silica gel (100-200 mesh) using 0-10% MeOH: DCM as eluent. Yield: 52 mg. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.30 (s, 1H), 7.24 (d, 2H), 7.10 (m, 2H), 7.0 (s, 1H), 4.70 (m, 1H), 4.40 (m, 1H), 3.82 (m, 1H), 3.60 (m, 1H), 3.18 (s, 3H), 3.14 (m, 2H), 2.42 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[I:5][C:6]1[C:7](=[O:23])[C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[C:9]=2[O:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:3][CH:2]([F:4])[O:14][C:10]1[N:11]=[CH:12][CH:13]=[C:8]2[C:7](=[O:23])[C:6]([I:5])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:15][C:9]=12
Reactant: O=c1c(I)c(-c2ccccc2)oc2c(=O)[nH]ccc12
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(I)c(-c2ccccc2)oc2c(OC(F)F)nccc12
Temperature: 40 °C
Reaction time: 48 h
Yield: 29 %

Procedure:
Chlorodifluoromethane was bubbled into a solution of 3-iodo-2-phenyl-7H-pyrano[2,3-c]pyridine-4,8-dione (100 mg, 0.27 mmol) and potassium carbonate (55 mg, 0.40 mmol) in DMF (3.0 mL) over 2 min. The reaction mixture was stirred at 40° C., for 2 days under a chlorodifluoromethane balloon. The resulting mixture was partitioned between ethyl acetate (40 mL) and water (20 mL) and the phases were separated. The organic layer was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2, 20% ethyl acetate in cyclohexane) to give the title compound as a white solid (33 mg, 29%). LCMS (Method B): RT=4.46 min, [M+H]+=416.
Reaction SMILES: N#N.[Cl:3][C:4]1[C:5]([CH:10]([NH:24][C:25]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=O)[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][N:9]=1.CN(C=O)C.O=P(Cl)(Cl)Cl>O.CC#N>[Cl:3][C:4]1[C:5]2[N:6]([C:25]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:24][C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:7]=[CH:8][N:9]=1
Reactant: O=C(NC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl)C1CCCCC1
Agent: N#N
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nccn2c(C3CCCCC3)nc(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.5 %

Procedure:
In an oven-dried flask filled with N2 was added cyclohexanecarboxylic acid [(3-chloro-pyrazin-2-yl)-(4-phenoxyphenyl)-methyl]-amide (100 mg, 0.0002 mol), MeCN (6 mL) and DMF (1 mL, 0.01 mol). POCl3 was added dropwise at 0° C. The reaction mixture was allowed to warm up to rt and stirred at that temp overnight. The excess of POCl3 was removed under reduced pressure and the residue was quenched with 2 N NH3 in i-PrOH at 0° C. with vigorous stirring to adjust pH to 9. The crude reaction mixture was then charged with water and the aqueous layer was washed with DCM. The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain 82 mg of the title compound as a yellow oil. The compound was carried over to the next step. MS (ES+): m/z 404.09 (100)[MH+]. HPLC: tR=4.49 min (Open Lynx polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11](OC)=[O:12])=[O:6].O.[NH2:22][NH2:23]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([NH:22][NH2:23])=[O:12])=[O:6]
Reactant: COC(=O)c1cccc(NC(=O)c2cccc(Cl)c2)c1
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: NNC(=O)c1cccc(NC(=O)c2cccc(Cl)c2)c1
Temperature: 65 °C

Procedure:
To a solution of 1.0 gm (3.45 mmol) of methyl 3-(3-chlorobenzamido)benzoate in 24 mL of tetrahydrofuran was added 1.18 mL (34.5 mmol) of hydrazine hydrate. The reaction was heated overnight at 65° C. After cooling, the reaction mixture was concentrated under rotevaporation, and ether and water were added. The solid product was separated by filtration and dried in vacuo to give 3-(3-chlorobenzamido)benzhydrazide. MS m/z: 290.0 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([S:40](CCC(OC)=O)(=[O:42])=[O:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:49][CH3:50])=[O:5])[CH3:2].[OH-].[Na+].Cl.C(OCC)(=[O:56])C>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:37])([F:39])[F:38])[CH:29]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:31]=3)[C:22]([S:40]([OH:41])(=[O:42])=[O:56])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:49][CH3:50])=[O:5])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(S(=O)(=O)CCC(=O)OC)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(S(=O)(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(2-methoxycarbonyl-ethanesulfonyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (141 mg) and 2N aqueous NaOH solution (384 μl) are dissolved in ethanol (3 ml), and the mixture is stirred at 50° C. for 30 minutes. To the reaction solution is added 2N aqueous HCl solution (385 μl), and stirred overnight. To the reaction mixture is added ethyl acetate, and the organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=9:1→4:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-(5-sulfopyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (64 mg). MS (m/z): 662 [M−H]−.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C[O-].[Na+].[CH2:8](Br)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>CO.O>[CH2:21]([CH2:2][C:1]([OH:4])=[S:3])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: CC(O)=S
Reactant: CCCCCCCCCCCCCCBr
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCCC(O)=S
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.7 %

Procedure:
Thioacetic acid (3.32 g, 36.0 mmol) in MeOH (150 ml) was treated successively with NaOMe (25% in MeOH, 12 g, 0.08 mol) and tetradecyl bromide (10.0 g, 0.036 mol) and stirred vigorously at room temperature for 48 h. The mixture was poured into H2O, acidified to pH 2 (conc. HCl) and extracted with diethyl ether. Drying (MgSO4) and concentration in vacuo afforded a crude solid which was purified by flash column chromatography (FCC) (25% EtOAc in hexanes to 35% EtOAc in hexanes) to yield 3 as a colourless solid (8.6 g, 82%); m.p. 64-66° C. (lit. 65-67° C.); δH(300 M, CDCl3) 0.89 (t, 3H, J=6.7 Hz), 1.27 (m, 22H), 1.32 (m, 2H), 1.61 (m, 2H), 2.67 (t, 2H, J 7.4) and 3.28 (s, 2H); MS (FAB+) 289 (M+H)+, 288 M+; HRMS: Found M+0288.211823. Calc. for C16H32O2S: M+0288.212302.
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:20])[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]1)#[N:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl.O>[C:1]([CH2:3][CH:4]([O:20][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:8][CH2:7]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCCN(CC(O)CC#N)CC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCN(CC(CC#N)OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
A solution of tert-butyl 4-(3-cyano-2-hydroxypropyl)-1,4-diazepane-1-carboxylate (3.2 g, 11 mmol) and triethylamine (3.1 mL, 22 mmol) in DCM (60 mL) was cooled to 0° C. and treated with methanesulfonyl chloride (1.2 mL, 16 mmol). After stirring at 0° C. for 1 hour, the reaction solution was diluted with water and DCM. The organic layer was washed with water twice, dried over MgSO4, filtered, and concentrated to give the desired product as oil (4 g, 98%). The crude product was used immediately in the next step. LCMS calculated for C15H28N3O5S(M+H)+: m/z=362.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:12][CH2:11][CH2:10][NH:9]1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1ccccc1C1CCCN1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccccc2F)cc1

Procedure:
The title compound, white solid, m.p. 143° C. and MS: m/e=320.3 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(2-fluoro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.