Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])=O.[NH4+].[C:5]([O:10][CH:11]([O:13][C:14]([NH:16][CH2:17][C:18]1([CH2:24][C:25]([O:27]CC=C)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:15])[CH3:12])(=[O:9])[CH:6]([CH3:8])[CH3:7]>C(O)C.[Pd]>[C:5]([O:10][CH:11]([O:13][C:14]([NH:16][CH2:17][C:18]1([CH2:24][C:25]([OH:27])=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:15])[CH3:12])(=[O:9])[CH:6]([CH3:8])[CH3:7]
Reactant: C=CCOC(=O)CC1(CNC(=O)OC(C)OC(=O)C(C)C)CCCCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(OC(=O)NCC1(CC(=O)O)CCCCC1)OC(=O)C(C)C
Reaction time: 1 h

Procedure:
To a stirred suspension of ammonium formate (3.4 g, 54 mmol) in ethanol (34 mL), was added compound (15) (10 g, 27 mmol) together with 10% Pd/C (1 g) under a nitrogen atmosphere. After one hour, the reaction mixture was filtered and the catalyst washed with ethanol (2×10 mL). The filtrates were combined and evaporated. The crude product was dissolved in diethyl ether (150 mL) and the organic phase was washed with 2N HCl (100 mL), water (100 mL) and brine (100 mL). The ether layer was dried over anhydrous sodium sulfate and concentrated to give a viscous liquid that crystallized upon standing. The product was recrystallized using 1:10 ethyl acetate:heptane (100 mL) to give the product (11) as a white, crystalline solid (7.9 g, 88%), m.p 63-64° C.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][CH2:32][C:33](Cl)=[O:34]>C(Cl)Cl.CN(C1C=CC=CN=1)C>[Cl:31][CH2:32][C:33]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1)=[O:34]
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
To a stirred solution of 0.91 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 10 ml of methylene chloride is added 0.46 g of triethylamine and 36 mg of dimethylamino-pyridine followed by the slow addition of 0.42 g of chloroacetyl chloride in 5 ml of methylene chloride. The resulting mixture is stirred at room temperature for 3 hours then partitioned with 10 ml of 50% NaHCO3 and the methylene chloride evaporated in vacuo. The remaining suspension is filtered, washed with 50% NaHCO3, H2O, EtOAc (2×2 ml), ether (2×5 ml) and dried in vacuo to give 1.14 g of beige solid. MS(CI): 380(M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH3:13]O.S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:13])=[O:9])=[CH:11][CH:12]=1
Reactant: Nc1ccc(C=CC(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)C=Cc1ccc(N)cc1
Yield: 72 %

Procedure:
4-Aminocinnamic acid (15.0 g, 77.6 mmol) was added to a mixed solvent of methanol (250 ml) and chloroform (150 ml), and sulfuric acid (3 ml) was added, which was followed by refluxing under heating for 47 hours. The reaction mixture was concentrated under reduced pressure, and the residue was made weak alkaline with a saturated aqueous sodium hydrogencarbonate and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give 7.84 g of methyl 4-aminocinnamate as a yellow solid (72%). This solid (7.80 g, 44.1 mmol) was dissolved in methanol (250 ml) and 10% palladium-carbon (780 mg) was added. The mixture was stirred at room temperature for 19 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite and low boiling matters were distilled away from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) to give 5.98 g of methyl 3-(4-aminophenyl)propionate as a colorless solid (76%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12](=O)[CH2:13][CH3:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:16][NH:17][S:18](Cl)(=[O:20])=[O:19].[BH4-].[Na+]>>[CH2:13]([CH:12]1[C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[N:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[NH:1][S:18](=[O:20])(=[O:19])[N:17]1[CH3:16])[CH3:14]
Reactant: CNS(=O)(=O)Cl
Reactant: CCC(=O)c1ccc2cccnc2c1N
Agent: [BH4-]
Agent: [Na+]
Product: CCC1c2ccc3cccnc3c2NS(=O)(=O)N1C
Yield: 9 %

Procedure:
In a similar fashion using route 27 general procedure 71, 1-(8-amino-quinolin-7-yl)-propan-1-one 410 (300 mg, 1.6 mmol), N-methylsulfamyl chloride 213 (1 g, 7.7 mmol) and NaBH4 (20 mg, 0.54 mmol) gave the title compound (40 mg, 10%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C@@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[C:9]2[C:8](=[O:18])[N:7]([CH3:19])[CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].CC(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:19][N:7]1[C:8](=[O:18])[C:9]2[C:10]([NH:12][C@@H:13]3[CH2:17][CH2:16][O:15][CH2:14]3)=[N:11][C:2]([C:30]3[CH:29]=[CH:28][C:27]([N:24]4[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]4)=[CH:32][CH:31]=3)=[CH:3][C:4]=2[N:5]=[CH:6]1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cn1cnc2cc(Cl)nc(N[C@@H]3CCOC3)c2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CN1CCN(c2ccc(-c3cc4ncn(C)c(=O)c4c(N[C@@H]4CCOC4)n3)cc2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-7-chloro-3-methyl-5-(tetrahydrofuran-3-ylamino)pyrido[4,3-d]pyrimidin-4(3H)-one (16 mg, 0.057 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (19 mg, 0.063 mmol), Pd(PPh3)4 (6.6 mg, 0.0057 mmol), K2CO3 (24 mg, 0.17 mmol), 2-propanol (3 mL) and H2O (1 mL) was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature and worked-up. The residue was purified using slilica gel flash column chromatography (eluent: 0-10% methanol in dichloromethane) to afford (R)-3-methyl-7-(4-(4-methylpiperazin-1-yl)phenyl)-5-(tetrahydrofuran-3-ylamino) pyrido[4,3-d]pyrimidin-4(3H)-one as a slightly yellow solid. HPLC-MS calculated C23H28N6O2(M+H+): 421.24, found: 421.20.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:11]([F:27])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C)C=O>[N:28]([C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:11]([F:27])[CH:10]=2)[N:5]=[CH:4][N:3]=1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Nc1cc(F)c(Oc2cc(Cl)ncn2)cc1F)OCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cc(Oc2cc(F)c(NC(=O)OCc3ccccc3)cc2F)ncn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
Benzyl [4-(4-chloropyrimidin-6-yloxy)-2,5-difluorophenyl]carbamate (1.96 g) was dissolved in N,N-dimethylformamide (20 ml). Sodium azide (650 mg) was added thereto, followed by stirring at 60° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=3:1). Fractions containing the target compound were concentrated under reduced pressure and the residue was dried under reduced pressure to provide the titled compound as white crystals (685 mg, 34%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([N+:18]([O-])=O)[CH:14]=[CH:15][CH:16]=3)[C:11]([CH:21]=[CH2:22])=[N:10]2)=[N:3]1>CCO.C(Cl)Cl.[OH-].[OH-].[Pd+2]>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([CH2:8][N:9]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:18])[C:12]=3[C:11]([CH2:21][CH3:22])=[N:10]2)=[N:3]1
Reactant: C=Cc1nn(Cc2cc(C)n(C)n2)c2cccc([N+](=O)[O-])c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCc1nn(Cc2cc(C)n(C)n2)c2cccc(N)c12
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To 1-((1,5-dimethyl-1H-pyrazol-3-yl)methyl)-4-nitro-3-vinyl-1H-indazole (5.15 g, 17.3 mmol) in EtOH/DCM (100 mL/10 mL) was cautiously added palladium hydroxide on carbon (2.2 g, 20% wt). The reaction mixture was purged with nitrogen and hydrogen three times each. The reaction was agitated under H2 (45 psi) for 3 hours. The system was evacuated and purged with nitrogen. The mixture was filtered through Celite and the filter pad was washed with MeOH/DCM (10:1, 300 mL). The solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography (EtOAc/Hexane 2:1) to provide the product (4.35 g).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])(O)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[O:43]1[C:47]2([CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[O:46][CH2:45][CH2:44]1>C(#N)C>[O:43]1[C:47]2([CH2:52][CH2:51][N:50]([C:1](=[O:2])[CH2:4][N:5]3[CH2:27][CH2:26][CH2:25][C@H:6]3[C:7]([N:9]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])[CH2:49][CH2:48]2)[O:46][CH2:45][CH2:44]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)N1CCC2(CC1)OCCO2
Yield: 83.5 %

Procedure:
A -5° C. solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (254 mg, 0.67 mmol, 1.0 eq), N-methylmorpholine (96 uL, 0.88 mmol, 1.30 eq) in acetonitrile (7 mL) was treated with isobutyl chloroformate (96 uL, 0.74 mmol, 1.1 eq) followed by 1,4-dioxa-8-aza-spiro[4.5] decane (0.193 g, 1.35 mmol, 2.0 eq). Purification by flash chromatography provided 280 mg (83%) of L-isoleucine, N-[1-(2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-oxoethyl)-L-Prolyl] benzylamide as a colorless oil
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[C:6]1([C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:13][NH:14][C:15](=[O:21])[CH:16]([CH3:20])[CH2:17]CO)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:5][CH2:1][CH2:17][CH:16]([CH3:20])[C:15]([NH:14][N:13]=[C:12]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:21]
Reactant: CC(CCO)C(=O)NN=C(c1ccccc1)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(CCBr)C(=O)NN=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., 8.1 g (24.3 mmol) of carbon tetrabromide are added to a solution of 6.0 g (20.2 mmol) of N′-(diphenylmethylene)-4-hydroxy-2-methylbutane hydrazide and 6.3 g (24.3 mmol) of triphenylphosphane in 150 ml of dichloromethane. The reaction mixture is stirred at 0° C. for 1 h and then concentrated and purified by column chromatography on silica gel (cyclohexane/ethyl acetate). This gives 2.7 g (37%) of the desired product; (log P(HCOOH): 3.76); 1H-NMR (ppm): δ (DMSO-d6)=1.12 (d, 3H), 1.79-1.86 (m, 1H), 2.33-2.38 (m, 1H), 2.62-2.67 (m, 1H), 4.10-4.14 (m, 1H), 4.25-4.29 (m, 1H), 7.29-7.65 (m, 10H); LC-MS: m/z=359 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8].[F:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25](F)[CH:26]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:25]3[CH:24]=[N:23][CH:22]=[C:21]([F:20])[CH:26]=3)=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8]
Reactant: Fc1cncc(F)c1
Reactant: Cc1ccc(N)c(C(=O)Nc2ccc(F)c(C)n2)n1
Product: Cc1ccc(Nc2cncc(F)c2)c(C(=O)Nc2ccc(F)c(C)n2)n1

Procedure:
The title compound, light yellow solid, MS (ISP): m/e=356.1 (M+H+), was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide and 3,5-Difluoropyridine in accordance with the general method of example 7.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[CH2:9][CH2:10][O:11][C:12]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:13]=3[C:14]=2[N:15]=1)=[O:5])C.[Li+].[OH-].C1COCC1>O>[Br:20][C:17]1[CH:18]=[CH:19][C:12]2[O:11][CH2:10][CH2:9][C:8]3[S:7][C:6]([C:4]([OH:5])=[O:3])=[N:15][C:14]=3[C:13]=2[CH:16]=1
Reactant: CCOC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester (2.52 g, 7.11 mmol) and LiOH (1.53 g, 36.6 mmol) was added THF (6.5 mL) and water (6.5 mL) and allowed to stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure to remove the THF. The reaction mixture was diluted with EtOAc and 1 N HCl and warmed in a water bath to solubilize the solid. The layers were separated and the organic extract was washed sequentially with water and brine. The combined organic extracts were dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid. LC/MS (ESI+): m/z 327 (M+H)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:27][C:24]([F:25])([F:26])[O:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1CCNCC1
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a cold (0 C) solution of 4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (1.15 g, 2.8 mmol) in DCM (3 ml) was added TFA (2 ml). The resulting solution was stirred for 1 hr. Solvent was then removed under reduced pressure. The crude solid was taken-up in AcOEt (15 ml) and washed with NaHCO3 sat (2×5 ml), water (5 ml) and finally with brine (5 ml). The organic layer was dried over MgSO4 and the solvent was removed under vacuo to yield the desired 1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine as a white solid (753 mg, 87% yield).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][NH2:13].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[Cl:11][C:4]1[N:3]=[C:2]([NH:13][CH3:12])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1nc(Cl)ccc1[N+](=O)[O-]
Reaction time: 24 h

Procedure:
To a stirred solution of 10 g (52 mmol) of 2,6-dichloro-3-nitropyridine in 300 mL of N,N-dimethylformamide was added 26 mL (52 mmol) of methylamine (2M in tetrahydrofuran) and 9.3 g (88 mmol) of sodium carbonate and the resulting mixture was stirred for 24 h. The solution was diluted with 500 mL water and extracted with three 700 mL portions of ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, and evaporated in vacuo to yield a viscous oil. The crude material was purified by flash chromatography on a Biotage Horizon® system (silica gel, 0 to 10% ethyl acetate/hexanes gradient) to give 6-chloro-N-methyl-3-nitropyridin-2-amine as a yellow solid. LC/MS 188.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:14]([NH:17][CH2:18][CH2:19][CH2:20][NH2:21])([CH3:16])[CH3:15]>>[CH3:15][CH:14]([NH:17][CH2:18][CH2:19][CH2:20][NH:21][S:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:12])=[O:11])[CH3:16]
Reactant: CC(C)NCCCN
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Product: CC(C)NCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Following the procedure of Example 1, m-nitrobenzenesulfonyl chloride was reacted with N-isopropyl propane-1,3-diamine to provide the free base, m.r. 57°-59° C., converted to the hydrochloride salt, m.r. 184°-188° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.[S:13]([Cl:17])(=O)(=[O:15])[OH:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[S:13]([Cl:17])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Product: O=c1[nH]cc(S(=O)(=O)Cl)c2cc(Br)ccc12

Procedure:
A solution of 6-bromoisoquinolin-1(2H)-one (10 g) in chlorosulfuric acid (29.9 mL) was heated at 90° C. for 2 h. Chlorosulfuric acid (29.9 mL) was added, and the reaction mixture was poured onto ice (CAUTION). The resulting solid was filtered, washed with water, and dried in vacuo (25° C.) to give the subtitle compound as a beige solid (12.31 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1>>[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:26][CH:25]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: Cc1ccc(CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)cc1

Procedure:
Compound 120 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-(bromomethyl)-4-methylbenzene and conditions outlined in procedure V. M.p.=156-158° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 7.2 (dd, 4H), 3.55 (s, 2H), 2.9 (s, 2H), 2.75 (d, 2H), 2.5 (t, 2H), 2.35 (s, 3H), 2.1 (d, 2H), 1.85 (t, 2H); LCMS: 406 [M+H].
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:5](F)[CH:4]=1.[Cl:14]C1C=C(C=CC=1F)C=O>>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:5]([Cl:14])[CH:4]=1
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1F
Product: CS(=O)(=O)c1ccc(CBr)cc1Cl

Procedure:
The titled compound is prepared analogously to 4-bromomethyl-2-fluoro-1-methanesulfonyl-benzene by replacing 3,4-difluorobenzaldehyde with 3-chloro-4-fluoro-benzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: O=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D1 starting from 3-fluoro-4-hydroxybenzaldehyde and 2-chloro-5-(trifluoromethyl)pyridine, LC-MS (ESI): m/z 286 [M+H]+; 3.37 min (ret time).
Reaction SMILES: [NH:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:8])=[CH:5][N:4]=1)[NH2:2].[Cl:19][C:20]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:21]=1[C:28](=[CH:34]N(C)C)[C:29](OCC)=[O:30]>>[Cl:19][C:20]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:21]=1[C:28]1[CH:34]=[N:2][N:1]([C:3]2[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[O:8])=[CH:5][N:4]=2)[C:29]=1[OH:30]
Reactant: NNc1ccc(C(=O)NCC2CCOCC2)cn1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1Cl
Product: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)c(Cl)c1

Procedure:
The title compound was prepared in a manner similar to Example 188 using 6-hydrazinyl-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide and ethyl 2-(2-chloro-4-cyanophenyl)-3-(dimethylamino)acrylate. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.39 (m, 4H) 1.68 (d, J=12.9 Hz, 2H) 3.20-3.37 (m, 6H) 3.63 (s, 1H) 3.92 (dd, J=11.2, 2.7 Hz, 2H) 7.90 (d, J=8.1 Hz, 1H) 8.15 (s, 1H) 8.49 (d, J=3.8 Hz, 2H) 8.73-8.87 (m, 1H) 8.98 (s, 1H). MS m/z [M+H]+ 438.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([N+:20]([O-])=O)[CH:11]=1.[H][H]>[Pd].CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([NH2:20])[CH:11]=1
Reactant: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1N
Yield: 88.7 %

Procedure:
Five-percent palladium on carbon (2.53 g) was added to a solution of 10.0 g of N-(2-pyridylmethyl)-4-acetylamino-3-nitrobenzamide in 150 ml of methanol, and the mixture was stirred in a hydrogen atmosphere at 60° C. for 15 hours. The solid material was separated through filtration, and the filtrate was concentrated. The resulting residue was purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 7:3) to give 8.02 g of N-(2-pyridylmethyl)-4-acetylamino-3-aminobenzamide.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:15]>C(Cl)Cl>[C:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1cc[n+]([O-])cc1

Procedure:
In a manner analogous to the preparation of the compound of Example 1, from 3,4,5-trimethoxyphenylguanidine nitrate (2.25 g, 7.81 mmol), 3-dimethylamino-1-(1-oxo-pyrid-4-yl)-2-propen-1-one (880 mg, 7.81 mmol) and sodium hydroxide (344 mg, 8.6 mmol) to give the title compound (1.2 g) as a green solid m.p. 220°. MS m/z 355 (M+H). The 3-dimethylamino-1-(1-oxopyrid-4-yl)-2-propen-1-one used as starting material was prepared by heating a solution of 4-acetylpyridine-N-oxide (2.5 g, 18.2 mmol) in dimethylformamide diethylacetal (30 ml) at reflux for 0.5 h. On cooling the resulting solid was collected and washed with diethyl ether to give the desired product (3.18 g) as an orange solid m.p. 181°. The 4-acetylpyridine-N-oxide was prepared by treating a solution of 4-acetylpyridine (3.0 g, 24.8 mmol) in CH2Cl2 with 3-chloro-peroxybenzoic acid [Aldrich 57-86%] (8.4 g) at room temperature for 12 h. The reaction was filtered, the filtrate concentrated under reduced pressure and the resulting residue subjected to column chromatography [silica 10% methanol-ethyl acetate] to give the desired product (3.2 g) as a white solid m.p. 101°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2.[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19](O)=[O:20])([CH3:15])[CH3:14]>>[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1)=[O:20])([CH3:15])[CH3:14]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: COc1ccc2c(c1)CCCN2
Product: COc1ccc2c(c1)CCCN2C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C

Procedure:
Prepared in analogy to example 1.1 from 6-methoxy-1,2,3,4-tetrahydro-quinoline (CA [120-15-0]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).