Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].Br[C:12]1[CH:13]=[CH:14][C:15]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]2)=[O:19])=[N:16][CH:17]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:28][CH2:27][CH2:26][N:23]1[CH2:22][CH2:21][N:20]([C:18]([C:15]2[CH:14]=[CH:13][C:12]([NH:10][C:7]3[N:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=3)=[CH:17][N:16]=2)=[O:19])[CH2:25][CH2:24]1
Reactant: O=C(c1ccc(Br)cn1)N1CCN(CCO)CC1
Reactant: Nc1ncc([N+](=O)[O-])cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: O=C(c1ccc(Nc2ncc([N+](=O)[O-])cn2)cn1)N1CCN(CCO)CC1
Temperature: 25 °C
Yield: 39.5 %

Procedure:
A mixture of 5-nitro-pyrimidin-2-ylamine (0.85 g, 6.1 mmol), intermediate 46 (Example 95) (2.5 g, 8.0 mmol), Pd(OAc)2 (0.40 g, 0.44 mmol), Xantphos (0.5 g, 0.86 mmol) and cesium carbonate (4.0 g, 12 mmol) was suspended in dioxane (30 mL) and heated at reflux under the argon atmosphere for 18 h. The mixture was allowed to cool to room temperature, filtered and washed with DCM. The filtrate was concentrated and the crude product purified by flash chromatography on silica gel (5% MeOH/DCM to 15% MeOH/DCM) to afford the title compound (0.90 g, 40%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[C:24]([O:25]COC)=[CH:23][C:22]3[C:21]([CH3:30])([CH3:29])[CH2:20][CH2:19][C:18]([CH3:32])([CH3:31])[C:17]=3[CH:16]=2)=[O:14])[CH:9]=[C:8]([F:33])[C:3]=1[C:4]([O:6]C)=[O:5]>CO.Cl>[F:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[C:24]([OH:25])=[CH:23][C:22]3[C:21]([CH3:29])([CH3:30])[CH2:20][CH2:19][C:18]([CH3:32])([CH3:31])[C:17]=3[CH:16]=2)=[O:14])[CH:9]=[C:8]([F:33])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COCOc1cc2c(cc1C(=O)Nc1cc(F)c(C(=O)OC)c(F)c1)C(C)(C)CCC2(C)C
Agent: Cl
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3cc(F)c(C(=O)O)c(F)c3)c(O)cc21

Procedure:
A solution of methyl 2,6-difluoro-4-[(3-methoxymethoxy-5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carbonyl)-amino]-benzoate (Compound A, 113 mg, 0.26 mmol) in 6 ml of methanol and 3 drops of conc. HCl was stirred at room temperature for overnight and then concentrated to dryness. The solid was recrystallized from ethyl ether: hexane to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.S(Cl)([Cl:16])(=O)=O>>[Cl:1][C:2]1[C:10]([Cl:16])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Reactant: O=S(=O)(Cl)Cl
Product: O=C1Nc2ccc(Cl)c(Cl)c2C1=O
Yield: 70 %

Procedure:
Chlorination of 4-chloroisatin with sulfuryl chloride by the method of B. R. Baker, et al., J. Org. Chem., 17, 149 (1952), gave a 70% yield of the title compound.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:21]=[C:19]([OH:20])[C:17]([OH:18])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:22](=O)(ON1C(=O)CCC1=O)[O:23]N1C(=O)CCC1=O.C(N(CC)CC)C>ClCCl>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]2[O:18][C:22](=[O:23])[O:20][C:19]=2[CH:21]=1)[C:10]([OH:12])=[O:11])=[O:2])([CH3:6])([CH3:7])[CH3:5]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2oc(=O)oc2c1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
Boc-L-DOPA (22.3 g, 75 mmol) and disuccinimidyl carbonate (DSC, 80% pure, 24 g, 75 mmol) were suspended in anhydrous dichloromethane (500 mL) and triethylamine (21 mL, 150 mmol) was added dropwise at 0° C. The resulting reaction mixture was stirred at 0° C. for 30 min. The suspension became a clear solution. HPLC indicated a completed reaction. The reaction mixture was washed with 10% citric acid (200 mL) and water (200 mL×5) to remove triethylamine and N-hydroxysuccinamide. The organic layer was collected, dried over MgSO4, and concentrated to provide the title compound (16) (22 g, 91% yield), 1H NMR (400 MHz, CDCl3): δ 1.43 (s, 9H), 3.11 (dd, 1H, J=14, 6.8 Hz), 3.27 (dd, 1H, J=14, 6.8 Hz), 4.59 (dd, 1H, J=14, 6.8 Hz), 5.03 (d, 1H, NH, J=8.0 Hz), 7.05 (dd, 1H, J=8, 2 Hz), 7.11 (d, 1H, J=2 Hz), 7.18 (d, 1H, J=8 Hz). MS (ESI) m/z 321.9 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:36]([NH:35][CH2:33][CH3:34])=[O:37])[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: CCN=C=O
Product: CCNC(=O)N1CCN(c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)CC1

Procedure:
Prepared according to Procedure P using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50.0 mg, 0.11 mmol) and ethylisocyanate to give 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)-N-ethylpiperazine-1-carboxamide. 1H NMR (DMSO-d6) δ ppm 1.03 (t, J=6.4 Hz, 3H), 2.08 (br s, 3H), 3.05-3.11 (m, 6H), 3.25 (br s, 4H), 3.44-3.45 (m, 4H), 3.68-3.69 (m, 4H), 6.49 (br s, 1H), 6.59-6.56 (m, 1H), 7.13-7.18 (m, 1H), 7.28-7.30 (m, 1H), 7.53 (s, 1H), 7.78 (s, 1H), 8.36 (s, 1H). Mass Spectrum (ESI) m/e=512.1 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>O1CCOCC1>[CH2:13]([O:12][C:10]([NH:1][C@H:2]([CH2:3][CH2:4][OH:5])[C:6]([OH:8])=[O:7])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](CCO)C(=O)O
Solvent: C1COCCO1
Product: O=C(N[C@H](CCO)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of H-Hse-OH (5 g) in dioxane/2M NaOH (168 mL/42 mL) was added benzyl chloroformate (6.7 mL) dropwise over 15 min. The reaction mixture was allowed to warm to RT and was stirred overnight at RT. The solvent was evaporated off and the aq. residue was extracted with Et2O and acidified with a 2M HCl solution. The aq. phase was extracted with DCM. The DCM layers were combined, washed with water, dried (Na2SO4) and evaporated off to give the desired product as a white powder (6.2 g).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>C1COCC1>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])(=[O:12])=[O:13])=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(CN(Cc2ccccc2OC)S(=O)(=O)c2ccc(OC(C)=O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccccc1CN(Cc1ccc(C(=O)O)cc1)S(=O)(=O)c1ccc(O)cc1
Yield: 15 %

Procedure:
Methyl 4-((4-acetoxy-N-(2-methoxybenzyl)phenylsulfonamido)methyl)benzoate (crude) was dissolved in THF (1.0 mL) and treated with aqueous NaOH (1N, 2.0 mL, 2.0 mmol). The mixture was refluxed for an hour. Upon completion the THF was removed in vacuo and the resulting aqueous solution was acidified with 6 N aq HCl to a pH of ˜3. The aqueous phase was extracted with EtOAc (2×15 mL) and the combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The crude product was purified by reverse phase HPLC to afford 10.8 mg of the title compound (15% yield over two steps). MS (M−H, 426.1); 1H NMR (400 MHz, acetone-d6): δ, ppm: 3.65 (s, 3H), 4.37 (s, 2H), 4.43 (s, 2H), 6.79 (m, 2H), 7.01 (d, 2H, J=8.0 Hz), 7.17 (m, 2H), 7.28 (d, 2H, J=7.9 Hz), 7.73 (d, 2H, J=8.0 Hz), 7.87 (d, 2H, J=7.9 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][C@H:10]([NH:33]C(OCC1C=CC=CC=1)=O)[C:11]([NH:13][C@@H:14]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[O:25])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(O)C.[Pd]>[NH2:33][C@@H:10]([CH2:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:11]([NH:13][C@@H:14]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])=[O:25])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:12]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(=O)OCC[Si](C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(=O)OCC[Si](C)(C)C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
The product of step 7G (1.09 g) was dissolved in 2-propanol (75 mL) with 10% palladium on carbon (300 mg) and hydrogenated on a Parr shaker at 45 psi for one hour. The reaction mixture was filtered on a bed of Celite, washed with 2-propanol, and concentrated to yield the product (803 mg, 94%) as a clear oil. LRMS (ES): 489.5 [M+H]+, 977.7 [2M+H]+. 1HNMR (600.1343 MHz, CDCl3): 7.78 (m, 1H), 4.53 (m, 1H), 4.22 (m, 2H), 3.53 (m, 1H), 1.80-2.41 (m, 10H), 1.43 (s, 18H), 1.01 (m, 2H), 0.02 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.C(O)C.Cl.[NH2:19][OH:20]>CCCCCC>[OH:20]/[N:19]=[C:4](\[C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[CH3:1])/[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: NO
Reactant: CCOC(=O)C(=O)c1ccccc1C
Agent: Cl
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)/C(=N/O)c1ccccc1C
Yield: 68 %

Procedure:
To a solution containing 19.2 g of ethyl 2-methylbenzoylformate (0.1 mol) and 100 ml of ethanol, 7.6 g of hydroxylamine hydrochloride (0.11 mol) was added and the resulting mixture was heated under reflux for 5 hours. Afterwards, the solvent was distilled off under reduced pressure as a work-up procedure to give a solid. The solid, to which hexane was added, was pulverized and 14.1 g of ethyl (E)-α-hydroxyimino-o-tolylacetate (yield; 68%) was filtered off. Furthermore, the concentrated residue of the filtrate, to which ethanol and a catalytic amount of thionyl chloride were added, was heated under reflux for 5 hours. The same work-up procedure as shown above was then employed to give 4.5 g of the objective product (yield; 21%). mp 88.0-89.0° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]([CH2:16][OH:17])=[CH:14][C:13]([CH2:18][OH:19])=[N:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1.C([N+](CCC)(CCC)CCC)CC>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]([CH:16]=[O:17])=[CH:14][C:13]([CH:18]=[O:19])=[N:12]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCn1nc(CO)cc1CO
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCn1nc(C=O)cc1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
To a stirred solution of 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-pyrazole-3,5-dimethanol (1.18 g, 4 mmol) in methylene chloride (20 ml), was added 4-methylmorpholine-N-oxide (2.89 g, 24 mmol) and molecular sieve 4 A (4 g). The reaction mixture was stirred at room temperature for 10 min. and then treated with tetrapropylammonium peruthenate (0.15 g, 0.4 mmol). Stirring was continued for 2 hr. The methylene chloride solution was concentrated and diluted with ether (40 ml). The mixture was filtered through a pad of silica gel (40 g) and the filter pad was eluted with 2×20 ml ether. The combined eluent was washed with 1N HCl and brine, dried over anhydrous sodium sulfate, and evaporated to give 0.79 g of a white solid; mp 63-64° C.; MS m/e 283 (MH+).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C([O-])(=O)C.[K+].O>CN(C)C(=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>[F:10][C:9]([F:12])([F:11])[C:8]([NH:7][CH2:6][C:5]1[CH:4]=[C:3]2[C:2](=[CH:15][CH:14]=1)[C:18]1=[CH:19][C:20]3[C:25]([N:17]1[CH2:16]2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:13]
Reactant: O=C(NCc1ccc(Br)c(Cn2ccc3ccccc32)c1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(NCc1ccc2c(c1)Cn1c-2cc2ccccc21)C(F)(F)F
Temperature: 130 °C

Procedure:
The product from step b) (716 mg, 1.74 mmol) and potassium acetate (177 mg, 1.80 mmol) were dissolved in N,N-dimethylacetamide (17 mL). The solution was deoxygenated in vacuo and put under nitrogen atmosphere prior to addition of tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.17 mmol). The resulting suspension was heated on an oil bath at 130° C. for 3 h. Addition of water (100 mL) gave a white precipitate which was filtered, washed with water and dried to give the sub-title compound
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:33]=[CH:32][C:10]([O:11][CH2:12][CH:13]([OH:31])[CH2:14][N:15]2[CH2:22][CH:21]3[CH2:23][CH:17]([CH2:18][N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]3)[CH2:16]2)=[CH:9][CH:8]=1>N1C=CC=CC=1>[OH:31][CH:13]([CH2:12][O:11][C:10]1[CH:32]=[CH:33][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=1)[CH2:14][N:15]1[CH2:22][CH:21]2[CH2:23][CH:17]([CH2:18][N:19]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:20]2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC2CC(CN(CC(O)COc3ccc(N)cc3)C2)C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CC(O)COc3ccc(NS(C)(=O)=O)cc3)C2)C1
Reaction time: 2.5 h
Yield: 87 %

Procedure:
MsCl (0.50 g; 4.40 mmol) was added to a stirred solution of tert-butyl 7-[3-(4-aminophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.68 g; 4.29 mmol; see Example 13 above) in pyridine (20 mL). The reaction mixture was stirred for 2.5 h and subsequently concentrated. The residue was partitioned between DCM and NaHCO3 (sat.), the organic layer separated, dried and concentrated. Purification using column chromatography (gradient 0 to 10% MeOH in DCM) gave the title compound in a 87% yield. 13C NMR (CDCl3): δ 28.70, 28.70, 28.84, 29.09, 29.42, 31.93, 38.77, 47.64, 49.42, 57.01, 60.29, 61.84, 65.20, 70.79, 79.50, 115.48, 116.32, 124.53, 129.40, 155.94, 157.28.
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:3]([NH:5][C@@H:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([O:9]C)=[O:8])=[O:4].[OH-].[Li+].Cl>C1COCC1.O>[OH:1][C@@H:2]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:3]([NH:5][C@@H:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8])=[O:4]
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](O)CC(C)C)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@H](O)C(=O)N[C@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl (2S)-{[(2S)-2-hydroxy-4-methylpentanoyl]amino}(phenyl)acetate (76a) (4.185 g) in THF (30 ml) and water (15 ml) cooled to 0° C. was added lithium hydroxide (1.45 g) portion wise. The mixture was stirred at RT overnight. The reaction was acidified with 1N hydrochloric acid until pH=1. The mixture was concentrated to remove THF and extracted with Ethyl acetate (3×). The organic layers were washed with water, brine, dried, filtered and evaporated to afford the title compound as a tacky white solid. Trituration with dichloromethane/diethyl ether yielded a free flowing solid (3.85 g). 1H NMR (300 MHz, CDCl3) δ 0.89-0.94 (m, 6H), 1.45-1.63 (m, 2H), 1.76-1.83 (m, 1H), 3.25 (bs, 2H), 4.20-4.25 (m, 1H), 5.56 (d, 1H, J=7 Hz), 7.35-7.39 (m, 5H), 7.53 (d, 1H, J=7 Hz). MS APCI, m/z=266 (M+1). LC/MS: 1.68 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[CH3:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[CH:18]=O>C(O)C>[CH3:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[CH:18]=[N:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: Cc1ccsc1C=O
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: CCO
Product: Cc1ccsc1C=Nc1cc([N+](=O)[O-])ccc1O
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of 4-nitro-o-aminophenol (15.4 g, 0.1 mole) in 200 ml of ethanol, 3-methyl-2-thiophene carboxaldehyde (12.6 g, 0.1 mole) is added at room temperature. The mixture is allowed to stir for 1 hour and the precipitated yellow Schiff's Base is collected. Crystallization from acetonitrile yields 24.1 g of product, melting point 169°-171°C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].[C:12]([O:16][C:17]([NH:19][C@@H:20]1[CH2:25][C@H:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][NH:22][CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>CN(C=O)C>[C:12]([O:16][C:17]([NH:19][CH:20]1[CH2:25][CH:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][N:22]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=2)[CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CC(NC(=O)OC(C)(C)C)CN(c2cc(C(=O)O)c(Cl)nn2)C1
Temperature: 100 °C
Yield: 51.2 %

Procedure:
A mixture of 3,6-Dichloro-pyridazine-4-carboxylic acid (201) (400 mg, 2 mmol) and (3R,5S)-3,5-bis-tert butoxy carbonyl amino piperdine (4) (1.3 g, 4 mmol) in 14 ml DMF containing iPr2NEt (718 ∥l, 4 mmol) was heated at 100° C. for 25.6 h with shaking. The solvent was removed under reduced pressure. After HPLC purification, compound 207 (483 mg, 51.1%) was obtained as a solid. LC-MS (ESI): m/e=472.3 [M+1]+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=3[CH:17]=2)=[CH:3][CH:2]=1.Cl>CO.CCOCC.[Pt](=O)=O>[NH:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=3[CH:17]=2)[CH2:5][CH2:6]1
Reactant: O=C1COc2ccc(-c3ccncc3)cc2N1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=C1COc2ccc(C3CCNCC3)cc2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.8 %

Procedure:
A solution of 6-(4-pyridyl)-4H-benzo[1,4]oxazin-3-one (0.57 g, 2.52 mmol), in methanol (15 mL) was treated with platinum (IV) oxide (50 mg, 0.22 mmol) and 1M HCl in ether (2.7 mL) and stirred at room temperature under an atmosphere of hydrogen for 24 h. The reaction mixture was filtered through celite and the filtrate evaporated in vacuo to give the title compound (0.59 g, 87%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N:7]=1)[CH3:2].Cl[CH2:15][CH2:16][CH2:17][CH2:18]Cl>>[CH2:1]([O:3][C:4]([C:5]1([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N:7]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(C)cn1
Reactant: ClCCCCCl
Product: CCOC(=O)C1(c2ccc(C)cn2)CCCC1

Procedure:
The product of Step 1, above (43), was dialkylated as described in Example 1, Step 1, using 1,4-dichlorobutane to obtain the title compound (44).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].[SH:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C)C=O.C(OCC)(=O)C>[CH3:27][N:18]([S:19]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)(=[O:21])=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[NH:10][C:9]([C:7]1[S:8][CH:4]([CH2:3][CH2:2][S:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:5][N:6]=1)=[CH:17]2
Reactant: CCOC(=O)CS
Reactant: CN(c1cccc2cc(C3=NCC(CCCl)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CSCCC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 50 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of N-{2-[5-(2-chloroethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (100 mg) in N,N-dimethylformamide (3 mL) were added potassium carbonate (65 mg) and ethyl mercaptoacetate (50 μL), and the mixture was stirred overnight at 50° C. Potassium carbonate (20 mg) was added to the reaction mixture, and the mixture was stirred at 50° C. for 3 hr, and cooled to room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (60 mg, yield 50%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 524 (MH+).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:7]=[C:8]([C@@H:13]2[CH2:15][C@H:14]2[C:16]([OH:18])=O)[CH:9]=[CH:10][C:11]=1[F:12]>C1(C)C=CC=CC=1>[F:5][C:6]1[CH:7]=[C:8]([C@@H:13]2[CH2:15][C@H:14]2[C:16]([Cl:3])=[O:18])[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Solvent: Cc1ccccc1
Product: O=C(Cl)[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Temperature: 35 °C
Reaction time: 6 h

Procedure:
Thionyl chloride (72.65 g, 1.21 molar equivalents) was added to the stirred toluene solution of (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanecarboxylic acid (18 wt %, net 100.00 g, 504.62 mmol). The mixture was stirred at 35° C. for 6 hours, then concentrated under reduced pressure to give a solution of (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanecarbonyl chloride. To a mixture of 28% ammonia aqueous solution (122.55 g, 4.00 molar equivalents), water (300.4 g) and ethyl acetate (700.2 g), the solution of (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanecarbonyl chloride obtained above was gradually added with stirring below 10° C. The reaction mixture was allowed to stir below 10° C. for 1 hour. The mixture was neutralized with 35% hydrochloric acid, then the organic layer was separated and washed with water. The resultant solution was concentrated azeotropically under reduced pressure to give a slurry of (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanecarboxamide. The resultant slurry was heated to obtain a clear solution, and cooled for crystallization. Hexane was added to the slurry, then the precipitates were collected by filtration and dried to give (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanecarboxamide (net 91.12 g, Yield: 92%).