Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([CH:20]([CH3:22])C)[NH:5][S:6]([NH:9]C(OCC1C=CC=CC=1)=O)(=[O:8])=[O:7].[CH3:24]O>[Pd]>[CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:5][S:6]([NH2:9])(=[O:7])=[O:8])[CH2:20][CH2:22][CH3:24]
Reactant: COC(=O)C(NS(=O)(=O)NC(=O)OCc1ccccc1)C(C)C
Reactant: CO
Agent: [Pd]
Product: CCCC(NS(N)(=O)=O)C(=O)OC
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of N- (carbobenzyloxyaminosulfonyl) -DL-valine methyl ester (28.5 g) in methanol (200 ml) under nitrogen was cooled to 0° C. and 1.8 g of 10% Pd/C was added. The mixture was placed into a Parr Apparatus and hydrogenated at 55 psi for 2 hours. The catalyst was removed on a pad of CELITE® and the filtrate was concentrated in vacuo and purified by flash silica gel chromatography (ethyl acetate/hexane, 1:1) to afford 17.2 g (96%) of N-(aminosulfonyl)-DL-valine methyl ester (Formula VII: R=CH3 ; R1 =H; R2 =isopropyl; R3 =H) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[C:35](=[O:42])[CH:36]=[C:37]([CH2:40][OH:41])[O:38][CH:39]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[C:35](=[O:42])[CH:36]=[C:37]([CH2:40][OH:41])[O:38][CH:39]=1)=[CH:13][CH:12]=[C:11]([C:17]([F:20])([F:18])[F:19])[CH:10]=2)=[O:5])[CH3:2]
Reactant: O=c1cc(CO)occ1OCCCCCBr
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OCCCCCOc1coc(CO)cc1=O
Reaction time: 0.17 h
Yield: 31 %

Procedure:
4-Hydroxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (0.86 g, 3.02 mmol) was dissolved in DMF (10 mL). Cs2CO3 (0.98 g, 3.02 mmol) was added at RT and the mixture was stirred for 10 min. A solution of 5-(5-bromo-pentyloxy)-2-hydroxymethyl-pyran-4-one 10 (0.86 g, 3.02 mmol) in DMF (5 mL) was added via syringe. This mixture was stirred at 50° C. for 22 h. Water (10 mL) was added and the mixture extracted with EtOAc (2×50 mL), washed with water (3×50 mL), brine (3×50 mL) dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent (CH2Cl2:MeOH)=90:10. 4-[5-(6-Hydroxymethyl-4-oxo-4H-pyran-3-yloxy)-pentyloxy]-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester 13 was obtained (0.43 g, 31% yield) as a pale yellow foam.
Reaction SMILES: C12(C3C=C[C:14]([O:15]CC(O)=O)=[CH:13]C=3)CC3CC(CC(C3)C1)C2.[NH2:22][C:23]1[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C>[S:29]([C:25]1[CH:24]=[C:23]([NH:22][C:14](=[O:15])[CH3:13])[CH:28]=[CH:27][CH:26]=1)(=[O:30])(=[O:31])[NH2:32]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(S(N)(=O)=O)c1
Reaction time: 8 h
Yield: 38.5 %

Procedure:
The mixture of [4-(1-adamantyl)-phenoxy]acetic acid (80.7 mg, 0.28 mmol), 3-amino-benzenesulfonamide (72.3 mg, 0.42 mmol), N,N-diisopropylethylamine, redistilled (DIPEA) (0.1 ml, 0.56 mmol) and benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (pybop) (291.4 mg, 0.56 mmol) in DMF (5 mL) was stirred overnight and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by Prep-TLC (n-Hexane:EtoAc:MeOH=6:3:1) to give 244-Adamantyl-1-yl-phenoxyl)-N-(3-sulfamoyl-phenyl)-acetamide as a white solid (23.1 mg, 18.7% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:4]=1N)[CH3:2].[BrH:13].N([O-])=O.[Na+]>O>[Br:13][C:4]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2]
Reactant: Br
Reactant: CCc1cccc([N+](=O)[O-])c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1cccc([N+](=O)[O-])c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
A suspension of 2-ethyl-6-nitroaniline (1.7 g, 10 mmol) in water (10 mL) and aqueous HBr (5 mL, 40%, 25 mmol) was refluxed for 10 minutes and then cooled to 0° C. A solution of NaNO2 (0.7 g, 10 mmol) in H2O (4 mL) was added dropwise at a temperature <10° C. The diazonium-containing solution was stirred for 30 minutes at a temperature of 0° C. to 5° C. and was then slowly added to a stirred mixture of CuBr (1.4 g, 10 mmol) in aqueous HBr (4 mL, 40%, 20 mmol) and water (8 mL) at RT. The mixture was stirred at RT for 30 minutes and then on a steam bath for 1 hour. The mixture was subsequently washed with aqueous saturated NaHCO3 and brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography eluting with petroleum ether to give the title compound as a pale yellow oil (1.7 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.50 (1H, dd, J=7.6, 1.6 Hz), 7.43 (1H, dd, J=8.0, 1.6 Hz), 7.37 (1H, dd, J=8.0, 7.6 Hz), 2.88 (2H, q, J=7.6 Hz), 1.28 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][P:7](O)(O)=O)[C:2]([OH:4])=[O:3].[C:11]([O-:16])(=[O:15])[C:12]([O-:14])=[O:13].[NH4+:17].[NH4+].N>O>[CH2:1]([NH:5][CH2:6][PH2:7])[C:2]([O-:4])=[O:3].[NH4+:17].[C:11]([O-:16])(=[O:15])[C:12]([O-:14])=[O:13].[NH4+:5].[NH4+:5]
Reactant: O=C(O)CNCP(=O)(O)O
Agent: N
Agent: O=C([O-])C(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: O=C([O-])CNCP

Procedure:
35 lb/hr of glyphosate acid wet cake containing approximately 12–13% by weight moisture and 7.3 lb/hr of di-ammonium oxalate are pre-blended and then metered into the mixer at a rate of approximately 42.3 lb/hr. The surfactant is injected into the mixer at a rate of approximately 0.7 lb/hr. Liquid anhydrous ammonia is injected into the mixer at a rate of approximately 2.6 lb/hr. Water is injected into the reactor at a rate of about 2 lb/hr to attain a total moisture content of approximately 20% by weight of all of the components added to the mixer. The ammonia reacts with the glyphosate acid to produce an ammonium glyphosate/di-ammonium oxalate paste. Water vapor is flashed from the paste product at the exit of the mixer. The moisture content of the ammonium glyphosate/di-ammonium oxalate paste is approximately 8–10% by weight. The pH of a 1% solution of the paste in water is approximately pH 4.5.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:18]([F:29])[CH:17]=2)=[N:4][C:5]([C@@H:8]2[CH2:13][CH2:12][C:11](=[O:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.[BH4-].[Na+]>CO>[NH2:1][C:2]1[C:3]([C:16]2[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])=[C:18]([F:29])[CH:17]=2)=[N:4][C:5]([C@@H:8]2[CH2:13][CH2:12][C@@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc([C@@H]3CCC(=O)[C@@H](F)C3)cnc2N)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2nc([C@@H]3CC[C@@H](O)[C@@H](F)C3)cnc2N)cc1F
Reaction time: 2 h
Yield: 35.8 %

Procedure:
To a solution of (+/−)-tert-butyl 4-(3-amino-6-((1R,3S)-3-fluoro-4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (208 mg, 0.516 mmol) in MeOH (3.017 mL) was added NaBH4 (29.3 mg, 0.773 mmol) at 0° C. The reaction mixture was stirred for 2 h. LCMS showed ˜4:1 ratio of two diastereomers. After quenched with NaHCO3 solution, the reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, filtered off and concentrated in vacuo. The major diastereomer was separated by neutral prep HPLC. After lyophilzation, (+/−)-tert-butyl 4-(3-amino-6-((1R,3S,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoate was obtained in 35.8% yield. (74.9 mg). LCMS (m/z): 406.3 (MH+), 0.80 min. The relative stereochemistry of (+/−)-tert-butyl 4-(3-amino-6-((1R,3S,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoate was confirmed by NMR.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Si:9]([O:16][CH:17]([CH:39]=[CH2:40])[CH2:18][N:19]1[C:23]2[N:24]=[CH:25][N:26]=[C:27]([NH2:28])[C:22]=2[C:21]([C:29]2[CH:30]=[N:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:20]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:1][C:20]1[N:19]([CH2:18][CH:17]([O:16][Si:9]([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11])[CH:39]=[CH2:40])[C:23]2[N:24]=[CH:25][N:26]=[C:27]([NH2:28])[C:22]=2[C:21]=1[C:29]1[CH:30]=[N:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CC(Cn1cc(-c2cnc3ccccc3c2)c2c(N)ncnc21)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC(Cn1c(Br)c(-c2cnc3ccccc3c2)c2c(N)ncnc21)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
N-Bromosuccinimide (894 mg) was added to a solution of 7-(2-(tert-butyldimethylsilyloxy)-3-butenyl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (2.13 g) obtained in Step 5 in DMF (25 ml) at room temperature. After stirring at the same temperature for 30 minutes, the mixture was poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a yellow solid (2.26 g).
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:30][CH3:31])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[OH-].[Li+].Cl>CO>[O:32]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:30][CH3:31])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)CCc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(CC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(CCC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.5 %

Procedure:
To a solution of ethyl 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]propanoate (100 mg, 0.22 mmol) in methanol (2 mL) was added an aqueous solution of lithium hydroxide (20.6 mg in 2 mL of water) and the resulting mixture was stirred at room temperature for 4 hours. The reacting mixture was acidified to pH 4 with an aqueous solution of hydrochloric acid (5 N), and then extracted with ethyl acetate (10 mL×3). The organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 1-10% methanol in dichlorometane) to afford 50 mg of the product as a white solid. MS (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.08 (brs, 2 H), 7.94 (d, J=7.58 Hz, 1 H), 7.80 (brs, 1 H), 7.72 (t, J=7.07 Hz, 1 H), 7.57 (d, J=7.33 Hz, 2 H), 7.37 (brs, 1 H), 5.38 (m, 2 H), 4.56 (brs, 2 H), 3.94-3.69 (m, 2 H), 3.26 (brs, 2 H), 2.81-2.64 (m, 4 H), 1.22 (t, J=7.58 Hz, 3 H).
Reaction SMILES: FC(F)(F)S([N:6]1[CH2:12][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][S:16][C:9]=2[CH2:8][CH2:7]1)(=O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[S:16]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:12][CH:11]([OH:13])[C:10]=2[CH:14]=[CH:15]1
Reactant: O=C1CN(S(=O)(=O)C(F)(F)F)CCc2sccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CNCCc2sccc21
Temperature: 0 °C
Yield: 48.8 %

Procedure:
A solution of 2.5 g of 6-trifluoromethanesulfonyl-4,5,7,8-tetrahydro-thieno[2,3-d]azepin-4-one prepared in the step 4 in 30 mL of dry THF was slowly dropped into an ice-cooled solution of 0.63 g of lithium aluminum hydride in 20 mL of dry THF. The reaction solution was gradually heated followed by heating to reflux overnight. Then the reaction solution was cooled, ice was gradually added thereto so that an excess of lithium aluminum hydride was decomposed and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo. The residue was purified by silica gel column chromatography to give 0.69 g of the objective compound.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[C:18]2[C:9]=1[S:10][C:11]1[C:12]([CH2:29][C:30]([OH:32])=[O:31])=[C:13]([O:27][CH3:28])[CH:14]=[C:15]([CH2:25][NH2:26])[C:16]=1[N:17]2[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33](O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[C:1]([O:5][C:6]([C:8]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[C:18]2[C:9]=1[S:10][C:11]1[C:12]([CH2:29][C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[C:13]([O:27][CH3:28])[CH:14]=[C:15]([CH2:25][NH2:26])[C:16]=1[N:17]2[CH3:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(CN)c2c(c1CC(=O)O)Sc1c(ccc(OC)c1C(=O)OC(C)(C)C)N2C
Reactant: OCc1ccccc1
Solvent: ClCCl
Product: COc1cc(CN)c2c(c1CC(=O)OCc1ccccc1)Sc1c(ccc(OC)c1C(=O)OC(C)(C)C)N2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
A solution of 158 mg (0.77 mmol) of N,N-dicyclohexylcarbodiimide in methylene chloride was added dropwise to an ice-cooled solution of 3.20 mg (0.695 mmol) of (6-tert.-butoxycarbonyl-aminomethyl-3,7-dimethoxy-10-methyl-phenothiazin-4-yl)-acetic acid, 90.2 mg (0.84 mmol) of benzyl alcohol and 20 mg of N,N-dimethylaminopyridine in 2.5 ml of methylene chloride. The reaction mixture was stirred at room temperature overnight and filtered. The filter residue was washed with methylene chloride. The combined filtrates were washed with saturated sodium bicarbonate solution, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane (1:4), whereupon, after recrystallization from ethanol and drying, 280 mg (73.3%) of benzyl (6-tert.-butoxycarbonyl-aminomethyl-3,7-dimethoxy-10-methyl-phenothiazin-4-yl)-acetate were obtained as white crystals of m.p. 131°-132°.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C(O)=O)[CH:15]=2)[C:10]([CH3:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)[C:22]([Cl:24])=[O:23]>ClCCl.CN(C)C=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:20])([C:22]([Cl:24])=[O:23])[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nn(Cc2ccccc2)c2cc(C(=O)O)ccc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C(=O)Cl)NN(Cc2ccccc2)c2ccccc21
Reaction time: 2 h

Procedure:
A solution of 1-benzyl-3-methyl-indazole-6-carboxylic acid [0.15 g, Reference Example 28(o)] in dichloromethane (20 ml) was treated with dimethylformamide (2 drops) then with oxalyl chloride (1.69 ml). After stirring for 2 hours the reaction mixture was evaporated and the residue was dried under high vacuum to give the title compound (0.16 g) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)[CH2:15][C:14]1=[O:29].Cl.O1CCOCC1>CO>[NH2:21][CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][N:13]([C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=3)[N:9]=[CH:8][CH:7]=2)[C:14](=[O:29])[CH2:15]1
Reactant: COc1ccc2nccc(N3CCN(CCNC(=O)OC(C)(C)C)CC3=O)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2nccc(N3CCN(CCN)CC3=O)c2n1
Reaction time: 12 h
Yield: 0.1 %

Procedure:
To a solution of 1,1-dimethylethyl (2-{4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-3-oxo-1-piperazinyl}ethyl)carbamate (1.5 g, 3.74 mmol) in MeOH (19 mL) at 25° C. was added dropwise, a solution of HCl in dioxane (6.5 mL, 26.18 mmol, 4M HCl in dioxane). After 12 h, the solution was concentrated and the residue neutralized with excess MP carbonate resin affording the free amine (1.1 mg, 98%) as a red oil which was used without further purification: LCMS (ES) m/e 302 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH:21]([CH3:25])[CH2:22][O:23][CH3:24])=[C:12]([N+:17]([O-])=O)[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1>C(OCC)(=O)C.CS(C)=O.[Pd]>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH:21]([CH3:25])[CH2:22][O:23][CH3:24])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: COCC(C)Nc1c([N+](=O)[O-])cnc2cc(-c3c(C)noc3C)c(OC)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCC(C)Nc1c(N)cnc2cc(-c3c(C)noc3C)c(OC)cc12

Procedure:
7-(3, 5-Dimethylisoxazol-4-yl)-6-methoxy-N-(1-methoxypropan-2-yl)-3-nitroquinolin-4-amine (for a preparation see Intermediate 1) (25.8 g, 66.8 mmol) was dissolved in a mixture of ethyl acetate (1000 ml) and DMSO (50 ml) and the solution was hydrogenated using a flow-hydrogenation apparatus (H-Cube™) (settings: 20° C., 1 bar, 1 ml/min flow rate) and a 10% Pd/C CatCart 70 catalyst cartridge. The catalyst cartridge was changed whenever it became blocked. The reaction mixture was evaporated under reduced pressure and partitioned between ethyl acetate (750 ml) and water (3×750 ml). The aqueous layers were combined and extracted with ethyl acetate (750 ml). The organic layers were combined, dried (hydrophobic frit) and evaporated under reduced pressure. The residue was dissolved in DCM and applied to a silica cartridge (100 g). The cartridge was eluted with a 2M ammonia in methanol/DCM gradient (0-4%). The appropriate fractions were combined and evaporated under reduced pressure to give 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(1-methoxypropan-2-yl)quinoline-3,4-diamine and recovered 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N-(1-methoxypropan-2-yl)-3-nitroquinolin-4-amine (6.5 g)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1>>[C:27]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)/C=C/c2cn(C(=O)c3cccnc3)c3ccccc23)cc(OC)c1OC
Yield: 19.7 %

Procedure:
Substantially the same procedure as in Example 59 was repeated using Compound 1 (1.43 g) obtained in Example 1 and nicotinoyl chloride hydrochloride (1.51 g) to give Compound 60 (0.37 g).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][N:15]=[C:14]([CH2:17]Br)[C:13]=2[CH:19]=1>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][N:15]=[C:14]([CH2:17][N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)[C:13]=2[CH:19]=1
Reactant: Clc1ccc2onc(CBr)c2c1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc2onc(Cn3ccnc3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% in mineral oil, 276.6 g, 6.92 moles) is added in portions to a solution of imidazole (471 g, 6.92 moles) in dimethylformamide (4 L) over a period of 1 hour. After the addition is complete, the resulting suspension is stirred for 1 hour at ambient temperature. A solution of 5-chloro-3-bromomethyl-1,2-benzisoxazole (1.57 kg, 6.37 moles) in dimethylformamide (3 L) is then added over a period of 30 minutes, during which time there is an exotherm from 24° C. to 68° C. On completion of this addition, the reaction mixture is stirred and heated at 90° C. for 2 hours. The solvent is then removed in vacuo and the residue is taken up in methylene chloride (4 L). The resulting suspension is washed with water (2×2 L), which dissolves the solid material, and the organic solution is then dried over anhydrous sodium sulfate (1 kg), filtered and evaporated to give 5-chloro-3-[(1H-imidazol-1-yl)methyl]-1,2-benzisoxazole, m.p. 100-102° C.; hydrochloride salt, m.p. 201-203° C.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10]OS(C)(=O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16][NH2:17]>C1COCC1>[C:1]([NH:8][CH2:9][CH2:10][NH:17][CH3:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Reactant: CN
Solvent: C1CCOC1
Product: CNCCNC(=O)OC(C)(C)C
Temperature: 42.5 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
With reference to FIG. 10c, BocNHCH2CH2OMs (32) (1.42 g, 5.94 mmol) was transferred to a Chem-Glass pressure vessel using minimum amount of THF to which 60 mL of methylamine (MeNH2, P/N: Aldrich 395056, 2.0 M in THF, 120 mmol) solution was added, capped and heated (while stirring) at 40-45° C. for 3 h, then at RT for overnight (use safety shield). TLC analysis (1:1 EtOAc-hexanes) showed complete consumption of 32 and formation of a new product (Rf33=0.38; 1:1 DCM-MeOH+1% (v/v) Et3N; TLC plate was heated first for 5 min to remove Et3N then developed by heating with 3% (w/v) ninhydrin solution in EtOH). Reaction mixture then concentrated to an oil and purified by column chromatography (40 g SiO2 column Isco.; 40 mL/min, Column equilibrated with EtOAc, eluted with 1:1 MeOH-DCM+1% Et3N (v/v). 18 mL-fractions collected; fractions 13-19 had pure product) to give BocNH13CH213CH2NHMe 33 as colorless oil (0.79 g, 76%).). ES-MS (Direct infusion in MeOH) Calculated MH+ [13C2C6H18N2O2+H]+=177.14, observed MH+=177.14.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13][OH:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:16]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:21]=CC=C[CH:17]=1.C(=O)(OCC)OCC=C>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13][O:14][CH2:21][CH:16]=[CH2:17])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Agent: C=CCOC(=O)OCC
Solvent: C1CCOC1
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)OC

Procedure:
To a stirred solution of N-Boc-L-serine methyl ester (0.22 g, 1 mmol, 1 eq) in dry THF (2 ml) under N2 a mixture of π-allylpalladium chloride dimer (0.01 g, 0.02 mmol), triphenylphosphine (0.024 g, 0.09 mmol) and allyl ethyl carbonate (0.26 ml, 2 mmol, 2 eq) in dry THF (1 ml) was dropwise added at room temperature.
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[NH2:4].[C:11](OC)(=[O:14])[CH:12]=[CH2:13].C[O-].[Na+].[O-]CC.[Na+]>>[N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([N:3]2[CH2:13][CH2:12][C:11](=[O:14])[NH:4]2)[CH:6]=1
Reactant: C=CC(=O)OC
Reactant: NNc1cccnc1
Agent: CC[O-]
Agent: C[O-]
Agent: Cl
Product: O=C1CCN(c2cccnc2)N1

Procedure:
In step a of Scheme 1, 3-hydrazinopyridine dihydrochloride is reacted with methyl acrylate in the presence of a base such as sodium methoxide or sodium ethoxide to yield 1-(pyridin-3-yl)pyrazolidin-3-one followed by chlorination of 1-(pyridine-3-yl)pyrazolidin-3-one with phosphoryl chloride (POCl3) in a two-step process to yield dihydropyrazole chloride (5a). The first step may be conducted in a polar protic solvent such as, methanol (MeOH) or ethanol (EtOH), at a temperature from about 40° C. to about 80° C. The second step may be conducted neat in phosphoryl chloride at a temperature from about 40° C. to about 80° C. When the crude product from the first step was neutralized, the second step can also be conducted in a solvent like acetonitrile (MeCN) at a temperature from about 40° C. to about 80° C.