Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[N:12]([CH3:13])[C:11](=[O:14])[N:10]([CH3:15])[C:9](=[O:16])[CH:8]=1.[N+:17]([O-])([OH:19])=[O:18]>>[Cl:6][C:7]1[N:12]([CH3:13])[C:11](=[O:14])[N:10]([CH3:15])[C:9](=[O:16])[C:8]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: Cn1c(Cl)cc(=O)n(C)c1=O
Agent: O=S(=O)(O)O
Product: Cn1c(Cl)c([N+](=O)[O-])c(=O)n(C)c1=O
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To 25 ml of sulfuric acid was slowly added 8.5 g (0.049 mol) of 6-chloro-1,3-dimethyluracil as prepared in Synthesis Example 1 at 10° to 15° C. To this solution was gradually added 8.5 ml of fuming nitric acid at 0° to 5° C. After stirring for 5 minutes, the reaction mixture was poured onto ice and extracted twice with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The resulting crystals were recrystallized from a mixed solvent of ethyl acetate and hexane to give 7.5 g (70%) of 6-chloro-1,3-dimethyl-5-nitrouracil having a melting point of 91° to 92° C.
Reaction SMILES: [O-2].[Zn+2:2].[C:3]1([P:9](=[O:12])([OH:11])[OH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C.O>[C:3]1([P:9](=[O:10])([O-:12])[O-:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Zn+2:2]
Reactant: O=P(O)(O)c1ccccc1
Agent: [O-2]
Agent: [Zn+2]
Solvent: CCO
Solvent: O
Product: O=P([O-])([O-])c1ccccc1

Procedure:
A slurry in ethanol-water of zinc oxide was prepared by charging a 300 mL reaction flask equipped with a stirrer with 10.0 g (123 mmol) of zinc oxide (JIS grade 2, available from HakusuiTech Ltd.) and 90.0 g of 50% by mass ethanol-water. A solution of 1.9 g (12 mmol) of phenylphosphonic acid (Nissan Chemical Industries, Ltd.) dissolved in 11.0 g of 50% by mass ethanol-water was gradually added dropwise at room temperature (about 25° C.) to this slurry with stirring, thereby effecting a reaction for one hour. The slurry was then filtered and the wet cake was thoroughly rinsed with ethanol. The wet cake was subsequently dried at 120° C. for at least 12 hours, yielding a white powder of zinc phenylphosphonate-containing zinc oxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1[CH:41]=[CH:40][C:39]([C:42]2([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:45]3[CH2:46][CH2:47][C:42]([C:39]4[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=4)([C:48]([NH2:50])=[O:49])[CH2:43][CH2:44]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccncc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccncc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 88.6 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (7.5 mmol) and 4-(pyridin-4-yl)-piperidine-4-carboxylic acid amide hydrochloride (5 mmol). Chromatograph on silica gel eluting with 10% methanol/dichloromethane to give the title compound: Rf =0.28 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[NH:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[O:15].C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:1]=[C:19]1[NH:13][C:14](=[O:15])[NH:16][C:17]1=[O:18]
Reactant: O=C1CNC(=O)N1
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C=C2NC(=O)NC2=O)cc1OC

Procedure:
It was previously reported by Deulofeu and Mendivelzua, Z. physiol, Chem. 219, 233 (1933) that the condensation of veratraldehyde (3,4-dimethoxybenzaldehyde) with hydantoin in acetic anhydride in the presence of fused anhydrous sodium acetate gave 5-(3',4'-dimethoxybenzal) hydantoin. We have now found, however, that this reaction leads to the formation of a corresponding acetylated product.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][OH:21])[C:4]1[N:9]=[C:8]([N:10]([CH2:13][OH:14])[CH2:11][OH:12])[N:7]=[C:6]([N:15]([CH2:18][OH:19])[CH2:16][OH:17])[N:5]=1)[OH:2].[C:22]1(=[O:32])[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12>O>[C:22]([OH:27])(=[O:32])[C:23]1[C:24](=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:25]([OH:2])=[O:26].[CH2:13]([N:10]([CH2:11][OH:12])[C:8]1[N:9]=[C:4]([N:3]([CH2:1][OH:2])[CH2:20][OH:21])[N:5]=[C:6]([N:15]([CH2:18][OH:19])[CH2:16][OH:17])[N:7]=1)[OH:14]
Reactant: O=C1OC(=O)c2ccccc21
Agent: OCN(CO)c1nc(N(CO)CO)nc(N(CO)CO)n1
Solvent: O
Product: O=C(O)c1ccccc1C(=O)O
Reaction time: 5 h

Procedure:
306 g of hexamethylol melamine, 148 g of phthalic anhydride and 5 L of water were placed into the a flask provided with a stirrer and a reflux tube, and were continuously refluxed-for 5 hours to form a crystal, which was then filtered out and dried to obtain hexamethylol melamine phthalate.
Reaction SMILES: C1(N)CCCCC1.[C:8]([O:12][C:13](/[C:15](/[CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:16]/[C:17]1([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(OC(N1C[C@@H](P(C2C=CC=CC=2)C2C=CC=CC=2)C[C@]1(P(C1C=CC=CC=1)C1C=CC=CC=1)CP(C1C=CC=CC=1)C1C=CC=CC=1)=O)(C)(C)C>C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[C:8]([O:12][C:13]([C@H:15]([CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:16][C:17]1([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:14])([CH3:10])([CH3:9])[CH3:11]
Reactant: COCCOC/C(=C\C1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: CC(C)(C)OC(=O)N1C[C@@H](P(c2ccccc2)c2ccccc2)C[C@@]1(CP(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Solvent: NC1CCCCC1
Solvent: C1=CCCC=CCC1
Product: COCCOC[C@H](CC1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Reaction time: 20.5 h
Yield: 100.4 %

Procedure:
(E)-1-[2-(tert-Butoxycarbonyl)-3-(2-methoxyethoxy)prop-1-enyl]-1-cyclopentanecarboxylic acid cyclohexylamine salt (100 mg, 0.22 mmole), chloro(1,5-cyclooctadiene)rhodium(I)dimer (3.0 mg, 0.0006 mmole) and (2S,4S)-tert-butyl-4-(diphenylphosphino)-2-(diphenylphosphino)-2-(diphenylphosphinomethyl)-1-pyrrolidinecarboxylate (7.6 mg, 0.013 mmole) were charged to a glass vial and the top sealed with a rubber septum. The system was purged with argon, methanol (2.5 mL) was added and the mixture purged with argon for 30 minutes. The reaction was hydrogenated at 104 kPa (15 p.s.i.) and room temperature for 20.5 hours. The reaction mixture was purged with nitrogen, Dowex 50W-X2 ion exchange resin (200 mesh, 100 mg) added and the mixture stirred for 15 minutes. The ion exchange resin was removed by filtration and the methanol removed by evaporation under reduced pressure to give the title compound as an oil (73 mg, quantitative) (ratio S:R 61:39), Rf =0.3 (ethyl acetate/hexane, 1:1+1% acetic acid).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@@H:6]([OH:8])[CH3:7])=[O:5].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1(C)C=CC=CC=1>[CH3:16][S:17]([O:8][C@@H:6]([CH3:7])[C:4]([O:3][CH2:2][CH3:1])=[O:5])(=[O:19])=[O:18]
Reactant: CCOC(=O)[C@H](C)O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H](C)OS(C)(=O)=O
Temperature: 20 °C
Yield: 96.6 %

Procedure:
To a solution of (L)-ethyl lactate (124 g, 1.05 mol) and triethyl amine (126 g, 1.25 mol) in toluene at 10-15° C. was added methanesulfonyl chloride (124 g, 1.08 mol) dropwise for about 2 hours. The mixture was allowed to warm to about 20° C. and the solid was filtered off. The solution was washed with water and dried, concentrated to afford the product (S)-ethyl 2-(methylsulfonyloxy)propanoate (199 g, yield 96.7%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:13])([F:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)C.[BH4-].[Na+]>C(O)C>[F:12][C:5]([F:13])([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:4][OH:3]
Reactant: CCOC(=O)C(F)(F)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC(F)(F)c1ccccc1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A stirred mixture of 2.2 g of difluoro-2-phenyl acetic acid ethyl ester (W. J. Middleton, E. M. Bingham, J. Org. Chem., 45, 2883-2887 (1980)), and 0.6 g of sodium borohydride in 75 mL of ethanol was kept at room temperature overnight, concentrated to near dryness under reduced pressure carefully acidified with 20 mL of 5% HCl and extracted into 3×50 mL of dichloromethane. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Drying under vacuum gave 1.7 g of product as an oil: 1H NMR (400 MHz, CDCl3) 7.5 (m, 5H), 4.0 (t, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[F:18][C:19]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][C:22]([NH2:23])=[C:21]([O:29][CH3:30])[CH:20]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N.O>O1CCOCC1>[F:18][C:19]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][C:22]([NH:23][C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH3:17])[CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[C:21]([O:29][CH3:30])[CH:20]=1
Reactant: Cn1cc(-c2ccnc(Cl)n2)c2ccccc21
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 85 °C
Reaction time: 3 h
Yield: 118.5 %

Procedure:
1,4-Dioxane (585 mL) was added to a mixture of 3-(2-chloropyrimidin-4-yl)-1-methylindole (Intermediate 177, 50 g, 160.04 mmol), 4-fluoro-2-methoxy-5-nitro-aniline (38.03 g, 192.04 mmol) and p-toluenesulfonic acid monohydrate (37.09 g, 192.04 mmol) at r.t. The resulting mixture was stirred at 85° C. for 3 h. After cooling to r.t., the mixture was quenched with 23% aqueous ammonia (39.59 mL, 480.1 mmol) and water (195 mL, 510.1 mmol) and a solid precipitated. The resulting slurry was stirred at r.t. for 3-4 h. The solid was collected by filtration and dried at 50° C. in vacuo for 12 h to give the title compound (74.6 g, 85%) as yellow solid; 1H NMR (CDCl3): 4.01 (6H, s), 6.90 (1H, d), 7.37-7.48 (4H, m), 8.05-8.12 (2H, m), 8.43 (1H, s), 8.90 (1H, s), 9.34 (1H, s); m/z: ES+ MH+ 394.12.
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[C@@H:13]([OH:26])[CH2:14][C@:15]4([CH3:25])[C@@:19]([OH:24])([C:20]([CH2:22][OH:23])=[O:21])[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2.[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:1][C@@:2]12[C@H:12]3[C@@H:13]([OH:26])[CH2:14][C@:15]4([CH3:25])[C@@:19]([OH:24])([C:20]([CH2:22][OH:23])=[O:21])[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2.[C:27]([O-:32])(=[O:33])[CH2:28][CH2:29][C:30]([O-:6])=[O:31]
Reactant: O=C1CCC(=O)O1
Agent: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C([O-])CCC(=O)[O-]
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of Hydrocortisone (3.65 g, 10 mmol) in acetonitrile (450 ml), succinic anhydride (1.65 g, 15 mmol) and DIEA (1.7 ml, 10 mmol) were added and the reaction mixture stirred at room temperature for 36 h. HPLC analysis of the reaction mixture showed 93% of the title compound. The solvent was evaporated and the residue redissolved in ethyl acetate and washed with water. The ethyl acetate phase was evaporated under reduced pressure and the residue triturated in diethyl ether to obtain 4.4 g of white powder in 95% yield. RtI 5.94′.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 120 °C
Reaction time: 48 h
Yield: 272.7 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (5.0 g, 29 mmol), piperazine-1-carboxylic acid tert-butyl ester (17 g, 9.1 mmol) and anhydrous potassium carbonate (4.4 g, 32 mmol) in N,N-dimethylacetamide (20 ml) was stirred at 120° C. under nitrogen for 2 days. Sample NMR analysis showed almost complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water (50 mL) and stirred vigorously for 2 hours. The resulting yellow precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting yellow brown solid was slurried in diethyl ether, filtered, washed with additional diethylether, dried to afford 4-(3-Amino-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (8.0 g, 85.7%) as a yellow powder, and used in the next step without further purification.
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].Cl.[CH3:7][N:8]1[CH2:14][C:13]2[CH:15]=[C:16](/[CH:19]=[CH:20]/[C:21](O)=O)[CH:17]=[N:18][C:12]=2NC(=O)[CH2:9]1.CNCC1C2C(=CC=CC=2)N(C)C=1>>[CH3:17][N:18]([CH2:12][C:13]1[C:15]2[C:9](=[CH:21][CH:20]=[CH:19][CH:16]=2)[N:8]([CH3:7])[CH:14]=1)[C:1](=[O:5])[CH:2]=[CH2:3]
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: C=CC(=O)O
Agent: CNCc1cn(C)c2ccccc12
Agent: Cl
Product: C=CC(=O)N(C)Cc1cn(C)c2ccccc12
Yield: 58 %

Procedure:
According to the procedure of Example 1 (a), except substituting acrylic acid for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(1-methyl-1H-indol-3-ylmethyl)amine for the methyl-(1-propyl-napthalen-2-ylmethyl)anine, the title compound (1.51 g, 58%) was prepared as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.71-7.50 (s, 1H), 7.34-7.21 (m, 2H), 7.15-6.90 (m, 2H), 6.80-6.53 (m, 1H), 6.45-6.35 (s, 1H), 5.72-5.67 (m, 1H), 4.80-4.75 (m, 2H), 3.77 (s, 3H), 3.05-2.99 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.CCO.[NH2:17][C:18]1[CH:52]=[CH:51][C:21]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]3[CH:29]=[C:30]([C:32]4[N:37]=[CH:36][C:35]([CH2:38][N:39]([CH2:47][CH2:48][O:49][CH3:50])[C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:34][CH:33]=4)[S:31][C:24]=23)=[C:20]([F:53])[CH:19]=1>C1(C)C=CC=CC=1>[F:53][C:20]1[CH:19]=[C:18]([NH:17][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[S:13])[CH:52]=[CH:51][C:21]=1[O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]2[CH:29]=[C:30]([C:32]3[N:37]=[CH:36][C:35]([CH2:38][N:39]([CH2:47][CH2:48][O:49][CH3:50])[C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[CH:34][CH:33]=3)[S:31][C:24]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a suspension of isothiocyanate 2 (5.50 g, 28.2 mmol) in a mixture of toluene (20 mL)/EtOH (20 mL) in a 500 mL round-bottom flask was added aniline 13 (10 g, 19.06 mmol) in a mixture of toluene (50 mL)/EtOH (50 mL). After 30 min, additional amount of isothiocyanate 2 (1 g, 5.12 mmol) in a mixture toluene (5 mL)/EtOH (5 mL) was added to the reaction mixture which was stirred at r.t. for an additional 45 min. The reaction mixture was concentrated under reduced pressure and the residue was co-evaporated with MeOH (40 mL) to dryness. Finally MeOH (80 mL) was added to the dry residue to produce a precipitate that was stirred at room temperature for 14 h, collected by filtration, dried for 2 h under vacuum to afford 14 as beige solid (7 g, 51% yield). MS (m/z): 720.3 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[C@@H:10]([CH3:12])[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CC1C=CC=CC=1.ClC(OC)=O.[C:31]1([CH2:37][O:38][NH2:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([NH:39][O:38][CH2:37][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:15])[C@@H:10]([CH3:12])[OH:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NOCc1ccccc1
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)Cc1ccccc1
Agent: COC(=O)Cl
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)NOCc1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 74.2 %

Procedure:
N-(t-Butyloxycarbonyl)-L-threonine (82.2 g) was dissolved in 1 liter of ethyl acetate and 40.5 g of dimethyl (phenylmethyl)amine was added. After stirring for 10 minutes the mixture was cooled to -10° C. and 31.05 g of methyl chloroformate were added dropwise. The mixture was stirred for 30 minutes at -10° C., after which a solution of 40.65 g of (phenylmethoxy)amine in 300 ml of ethyl acetate was added at -10° C. The temperature was then permitted to rise to 5° C. during a 90 minute period. The reaction mixture was evaporated in vacuo and redissolved in 1 liter of ethyl acetate the insoluble material was filtered off and the filtrate washed, with cooling, with water, dilute hydrochloric acid, (pH of aqueous phase not less than 2.5), sodium bicarbonate solution and brine. After drying (MgSO4) the solvent was removed in vacuo to yield an oil, which crystallized on treatment with petroleum ether, yielding 79.4 g of the title compound, melting point 87° C.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[O:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[O:40][NH2:41]>C(Cl)CCl.CN(C=O)C.C(N(CC)CC)C.O>[CH3:22][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([NH:41][O:40][CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39][O:34]3)=[O:21])=[CH:13]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: NOC1CCCCO1
Reactant: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)O)c2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1

Procedure:
Starting materials: (E)-3-[1-(4-dimethylamino-benzenesulfonyl)-1H-pyrrol-3-yl)-acrylic acid (compound B3) (0.150 g), HOBt?H2O (0.072 g), triethylamine (259 μl), DMF (10 ml), EDC?HCl (0.269 g), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.049 g). Reaction conditions: room temperature, 1 hour; room temperature, 17 hours.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][NH2:6].[S:7](N)(N)(=[O:9])=[O:8]>N1C=CC=CC=1>[CH3:1][N:2]1[CH2:3][CH2:4][CH2:5][NH:6][S:7]1(=[O:9])=[O:8]
Reactant: CNCCCN
Reactant: NS(N)(=O)=O
Solvent: c1ccncc1
Product: CN1CCCNS1(=O)=O
Temperature: 120 °C
Yield: 53.1 %

Procedure:
To a stirred mixture of N-methyl-1,3-diaminopropane (1.70 mL, 16.3 mmol) in pyridine (20 mL) was added sulfamide (1.877 g, 19.5 mmol). The mixture was heated in an oil bath at 120° C. for 16 hrs. After cooling to room temperature, the mixture was concentrated and the residue partitioned between ethyl acetate and saturated aqueous sodium chloride. The organic layer was washed with 1N aqueous hydrochloric acid, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate, filtered, and concentrated to afford a colorless oil (1.3 g, 53%). 1H NMR (300 MHz, CDCl3) δ 4.11 (br s, 1H), 3.60-3.48 (m, 2H), 3.32 (t, 2H, J=5.7 Hz), 2.78 (s, 3H), 1.85-1.72 (m, 2H).
Reaction SMILES: [ClH:1].[C:2]([CH2:4][C:5]1([N:16]2[CH:20]=[C:19]([B:21]3[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]3)[CH:18]=[N:17]2)[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)#[N:3]>O1CCOCC1.C(Cl)Cl>[ClH:1].[CH3:28][C:23]1([CH3:29])[C:24]([CH3:26])([CH3:27])[O:25][B:21]([C:19]2[CH:18]=[N:17][N:16]([C:5]3([CH2:4][C:2]#[N:3])[CH2:6][NH:7][CH2:8]3)[CH:20]=2)[O:22]1.[ClH:1]
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1(C)OB(c2cnn(C3(CC#N)CNC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.0 N HCl in 1,4-dioxane (2.0 mL) was added to solution of tert-butyl 3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (1.68 g, 4.33 mmol) in methylene chloride (10 mL). The reaction mixture was stirred at room temperature overnight, and then concentrated under reduced pressure to afford the desired product as HCl salt which was directly used in the next step reaction without further purification. LCMS cacld. for C14H22BN4O2 (M+1)+: m/z=289.2. Found: 289.1.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CN(C)C=O.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>>[Si:22]([O:11][C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][CH:2]=[N:1]2)=[CH:6][CH:7]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: Oc1ccc2cccnc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cccnc2c1

Procedure:
At room temperature to a solution of quinolin-7-ol (Matrix Scientific, Cat. No. 007603; 0.6 g, 4 mmol) in N,N-Dimethylformamide (10 mL, 100 mmol) was added 1H-imidazole (0.670 g, 9.84 mmol), followed by tert-butyldimethylsilyl chloride (0.934 g, 6.20 mmol) with stirring. The mixture was stirred at room temperature overnight, then quenched with sat'd NaHCO3 solution, and extracted with methylene chloride (3×). The combined extracts were washed with water and brine successively, and then dried over Na2SO4. After filtration, the filtrate was concentrated and purified with flash column using 15% ethyl acetate in hexane as eluent to yield 0.88 g of the product. LCMS (M+H)+: m/z=260.3.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC#N.C(=O)([O-])[O-].[Ag+2]>[CH2:13]([O:8][C:5]1[CH:4]=[C:3]([C:2]([Br:1])=[CH:7][N:6]=1)[C:9]([O:11][CH3:12])=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(=O)[nH]cc1Br
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COC(=O)c1cc(OCc2ccccc2)ncc1Br
Temperature: 65 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
To a suspension of methyl 5-bromo-2-oxo-1,2-dihydropyridine-4-carboxylate (2.5 g, 10.77 mmol) in MeCN (35 mL) was added silver carbonate (4.46 g, 16.16 mmol) and benzyl bromide (1.54 mL, 12.93 mmol). The reaction mixture was heated to 65° C. and stirred for 18 hours. The reaction mixture was filtered through a plug of Celite® and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 50-100% DCM in cyclohexane to give the title compound (3.31 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:14]([O-])=O)[CH:13]=1)[C:8]([OH:10])=[O:9])=[O:4]>CO.[OH-].[OH-].[Pd+2]>[NH2:14][C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cc(N)cc(C(=O)O)c1
Reaction time: 5 h
Yield: 92.3 %

Procedure:
20% Pd(OH)2 (0.50 g) was carefully wetted down under argon with methanol (5 mL) and then 3-(methoxycarbonyl)-5-nitrobenzoic acid (5.00 g, 22.2 mmol) in methanol (20 mL) was added. The mixture was then hydrogenated on a Parr Shaker apparatus for 5 hours at 50 psi. Under argon, the reaction was carefully filtered through a fiberglass filter paper. The filtrate was concentrated to give 3-amino-5-(methoxycarbonyl)benzoic acid (4.0 g, 20.5 mmol, 92% yield) of off-white solids as product. MS found: (M−H)+=194.