Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>[Pd].O>[CH2:11]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CC[C@H](NCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.4 %

Procedure:
A mixture of 74.5 g (0.5 mol) of L-glutamic acid, 54 g (0.5 mol) of benzaldehyde, 41 g (1.0 mol) of sodium hydroxide, and 1 liter of water was stirred at room temperature for 3 hours. A 5 g portion of 10% palladium on carbon catalyst was added and the mixture hydrogenated for 83 minutes at 51 psig. The catalyst was filtered and the pH of the filtrate was adjusted to 4.2 with 1 N HCl. The solids were filtered, washed with water and dried to give 55.1 g of N-benzyl-L-glutamic acid mp 151°-153° dec., [α]D23 +16° (c4, 1 N HCl). (c 4.1, 1 N HCl). Concentration of the filtrate gave a second crop of 24.9 g, mp 157°-158° dec., [α]D23 +16° (c 4, 1 N HCl).
Reaction SMILES: O.[N:2]([N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH:14]=[C:13]([C:21]#[N:22])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]2=3)[CH2:6][CH2:5]1)=O.[OH-].[NH4+]>[Zn].C(O)(=O)C>[NH2:2][N:4]1[CH2:5][CH2:6][N:7]([CH:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH:14]=[C:13]([C:21]#[N:22])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]2=3)[CH2:8][CH2:9]1
Reactant: N#CC1=Cc2ccccc2C(N2CCN(N=O)CC2)c2ccccc21
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: N#CC1=Cc2ccccc2C(N2CCN(N)CC2)c2ccccc21
Reaction time: 1 h

Procedure:
Approximately 500 parts of water is slowly added to a solution of 98 parts of 5-(4-nitroso-1-piperazinyl)-5H-dibenzo[a,d]cycloheptene-10-carbonitrile in 1200 parts of glacial acetic acid. To the resultant mixture is added, at a rate such that the temperature does not exceed 35°, approximately 150 parts of zinc dust. When the addition is complete, the reaction mixture is stirred at 28°-30° for 1 hour, whereupon insoluble solids are filtered out and washed with 300 parts of 65% acetic acid. Washings and filtrate are combined and diluted with 3 volumes of water. The solution thus obtained is cooled to 5°-10° and maintained thereat while sufficient 30% ammonium hydroxide is added to induce alkalinity. The resultant mixture is extracted with chloroform. The chloroform extract is dried over anhydrous potassium carbonate and stripped of solvent by vacuum distillation. The residual viscous oil crystallizes from hexane to give 5-(4-amino-1-piperazinyl)-5H-dibenzo[a,d]cycloheptene-10-carbonitrile as a colorless solid which, dried in air, melts at 137°-146°.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]([CH3:16])([CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:5]([O:7][CH3:8])=[O:6].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:27]=[C:26](Cl)[C:25]3=[CH:29][C:30]([CH3:32])=[CH:31][N:24]3[CH2:23][C:22]=2[CH:33]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:27]=[C:26]([N:13]3[CH2:14][CH2:15][N:10]([CH2:9][C:4]([CH3:16])([CH3:3])[C:5]([O:7][CH3:8])=[O:6])[CH2:11][CH2:12]3)[C:25]3=[CH:29][C:30]([CH3:32])=[CH:31][N:24]3[CH2:23][C:22]=2[CH:33]=1
Reactant: COC(=O)C(C)(C)CN1CCNCC1
Reactant: Cc1cc2n(c1)Cc1cc(Cl)ccc1N=C2Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(C)(C)CN1CCN(C2=Nc3ccc(Cl)cc3Cn3cc(C)cc32)CC1
Temperature: 140 °C
Reaction time: 3.5 h
Yield: 58.3 %

Procedure:
Dissolve methyl 2,2-dimethyl-3-(piperazin-1-yl)propanoate dihydrochloride (1.61 g, 5.89 mmoles) in water and load on to two SCX-2 (10 g) cartridges. Wash the cartridges with methanol and elute with 2M ammonia in methanol. Concentrate in vacuo, then dissolve the resultant oil in acetonitrile (40 mL). Add 7,11-dichloro-2-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.167 g, 4.4 mmoles) to the acetonitrile solution. Divide the acetonitrile solution and place in to 2 microwave tubes, add potassium carbonate (0.89 g, 6.79 mmoles) to each microwave tube and heat and stir at 140° C. in the microwave for 3.5 hr. Allow the reaction mixture to cool, filter, wash the solid collected on the sinter with acetonitrile then concentrate the filtrate in vacuo, add methanol and then evaporate to dryness. Treat with more methanol and collect the resultant precipitate, wash the precipitate with methanol to give methyl 3-[4-(7-chloro-2-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-2,2-dimethylpropanoate as a crystalline solid (1.1 g). MS (m/z): 429.18 (M+1).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[N:14]=[CH:13][C:12]2[CH:11]=[CH:10][C:9]3[C:15]([C:19]([O:21]CC)=O)=[N:16][N:17]([CH3:18])[C:8]=3[C:7]=2[N:6]=1)=[O:3].CO.C[N:27](C)C=O.[OH-].[NH4+]>>[NH2:1][C:2]([NH:4][C:5]1[N:14]=[CH:13][C:12]2[CH:11]=[CH:10][C:9]3[C:15]([C:19]([NH2:27])=[O:21])=[N:16][N:17]([CH3:18])[C:8]=3[C:7]=2[N:6]=1)=[O:3]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1nn(C)c2c1ccc1cnc(NC(N)=O)nc12
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cn1nc(C(N)=O)c2ccc3cnc(NC(N)=O)nc3c21
Temperature: 65 °C
Reaction time: 48 h
Yield: 50 %

Procedure:
A suspension of 0.20 g (0.63 mmol) of ethyl 8-[(aminocarbonyl)amino]-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate in 15 mL of a mixture methanol/dimethylformamide/ammonium hydroxide 30% 1/1/1 was stirred in a close bottle at 65° C. for 48 hours. The solvent was then evaporated under reduced pressure, the residue redissolved with a mixture dichloromethane/methanol 9/1 and washed with water. The organic layer was dried over anhydrous Na2SO4 and evaporated to dryness. The product was purified by chromatography on a silica gel column (eluant dichloromethane/acetone/methanol) giving 0.09 g (50% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[N:14]=[CH:15][C:16]([C:27]([O:29]C)=O)=[N:17][C:18]=1[O:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)(=[O:11])=[O:10].[NH3:31]>CO>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[N:14]=[CH:15][C:16]([C:27]([NH2:31])=[O:29])=[N:17][C:18]=1[O:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)(=[O:10])=[O:11]
Reactant: N
Reactant: COC(=O)c1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2cccnc2)n1
Solvent: CO
Product: NC(=O)c1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2cccnc2)n1

Procedure:
5-(2,3-Dichlorobenzenesulphonylamino)-6-(3-pyridinylmethoxy)pyrazine-2-carboxylic acid, methyl ester (Example 134) (0.05 g) was heated at 60° C. in 7M ammonia in methanol for 4 days. The solution was evaporated to dryness and the product crystallised from methyl acetate. Yield 0.027 g.
Reaction SMILES: N[C:2]1[C:7]([O:8][C:9]([F:17])([F:16])[CH:10]([F:15])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=[CH:4][N:3]=1.S(=O)(=O)(O)[OH:19].N([O-])=O.[Na+]>O>[F:16][C:9]([F:17])([O:8][C:7]1[C:2]([OH:19])=[N:3][CH:4]=[CH:5][CH:6]=1)[CH:10]([F:15])[C:11]([F:14])([F:13])[F:12]
Reactant: Nc1ncccc1OC(F)(F)C(F)C(F)(F)F
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ncccc1OC(F)(F)C(F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
2.6 g (10 mmol) of 2-amino-3-(1,1,2,3,3,3-hexafluoro-1propyloxy)pyridine were diazotized at 0° C. in 35 ml of 2N sulfuric acid using 0.76 g (11 mmol) of sodium nitrite in 5 ml of water. The reaction mixture was stirred for 30 minutes and the product was extracted using ethyl acetate. The organic phase was washed until neutral, dried using MgSO4 and concentrated by evaporation.
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[H-].[Na+]>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 2-hydroxybenzimidazole (4.00 g, 29.8 mmol) and tert-butyl bromoacetate (5.53 g, 28.3 mmol) in DMF (50 mL) at 0° C. was added sodium hydride (1.31 g of a 60% dispersion in mineral oil, 32.8 mmol). The mixture was stirred at 0° C. for 1 h, then quenched with saturated aqueous NaHCO3 and concentrated in vacuo. The residue was partitioned between EtOAc (500 mL) and H2O (300 mL) and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc-100:0 to 0:100, to give the title compound. MS: m/z=249 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[C:12]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([OH:3])=[O:2].[CH3:26]O>>[OH:10][C:9]1[CH:8]=[CH:7][C:6]([N:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[C:12]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:5][C:4]=1[C:1]([O:3][CH3:26])=[O:2]
Reactant: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCCC3)ccc1O
Reactant: CO
Product: COC(=O)c1cc(-n2c(-c3ccccc3)cc3c2CCCC3)ccc1O

Procedure:
Hydrogen chloride gas was bubbled through a boiling mixture of 25.0 g. (0.075 mole) of 1-(3-carboxy-4-hydroxyphenyl) 2-phenyl-4,5,6,7-tetrahydroindole and 750 ml. of methanol for 2 hours. The mixture was heated under reflux for 18.5 hours, cooled and filtered to provide 19.6 g. (75%) of white solid. Recrystallization from methanol gave colorless crystals, m.p. 141°-142°.
Reaction SMILES: N1[CH2:12][CH2:11]NCCNCCNCC1.[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:15][CH2:14][CH2:13][CH2:18][CH2:17][CH2:13][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:11][CH3:12]
Reactant: C1CNCCNCCNCCN1
Reactant: c1ccccc1
Product: CCCCCCCCCCCCC

Procedure:
reacting 1,4,7,10-tetraazacyclododecane with dimethylformamidedimethylacetal in the presence of benzene to yield 1,4,7,10-tetraazatricyclo(5.5.1.0)tridecane,
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13]([CH3:15])=O.S([O-])([O-])(=O)=O.[Ca+2].C(O)(=O)C>C(O)C>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:13]([CH3:15])=[CH:12][C:11]([O:17][CH2:18][CH3:19])=[O:16])[CH:10]=2)[CH:6]=[N:7]1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ccc2cn[nH]c2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C=C(C)Nc1ccc2cn[nH]c2c1
Reaction time: 24 h
Yield: 84.5 %

Procedure:
To a suspension of 6-aminoindazole (40.0 g, 0.30 mol) in absolute ethanol (500 ml) was added ethyl acetoacetate (70.37 g, 54 mol), calcium sulfate (CaSO4) (20 g) and acetic acid (2 ml). The reaction mixture was heated to reflux and after 24 hours more calcium sulfate (10 g) and ethyl acetoacetate (19 ml) was added and the reflux continued for another 24 hour period. It was necessary to add more CaSO4 (5 g) and ethyl acetoacetate (10 ml) and to reflux the reaction mixture for an additional 24 hours to complete the conversion of 6-aminoindazole to product. The solid was removed by filtration and the filtrate subjected to rotary evaporation. Ethanol was added and the slurry cooled in a refrigerator. The solid was collected by filtration, washed with hexanes and dried in a vacuum oven to give the cyclization precursor ethyl 3-(indazol-6-ylamino)but-2-enoate as a light brown solid (62.19 g, 84%).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[N:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:9][N:10]2[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([OH:18])[CH2:12][C:11]2([CH3:20])[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:28](Cl)(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](Cl)=[O:38]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:22]1([NH:21][C:8]([O:9][N:10]2[C:11]([CH3:20])([CH3:19])[CH2:12][CH:13]([O:18][C:28](=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:18][CH:13]3[CH2:12][C:11]([CH3:19])([CH3:20])[N:10]([O:9][C:8](=[N:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[NH:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[C:15]([CH3:17])([CH3:16])[CH2:14]3)=[O:38])[CH2:14][C:15]2([CH3:16])[CH3:17])=[N:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: O=C(Cl)CCCCCCCCC(=O)Cl
Reactant: CC1(C)CC(O)CC(C)(C)N1OC(=NC1CCCCC1)NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OC(=NC3CCCCC3)NC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC(=NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 100.3 %

Procedure:
To a solution of 1,3-dicyclohexyl-2-(4-hydroxy-2,2,6,6-tetramethyl-piperidin-1-yl)-isourea [compound 8 prepared according to Example 8] (8.35 g, 22 mmol) and 4-dimethylaminopyridine (160 mg) in pyridine (20 ml) is added sebacoylchloride (2.5 g, 10.5 mmol). The mixture is stirred at room temperature for 22 hours and then diluted with ice-water (250 ml). The precipitate is filtered off, washed with water and dried to afford 9.75 g of the title compound as an off-white solid.
Reaction SMILES: Cl[C:2]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[O:3]1.Cl.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)([O-:22])=[O:21].C(N(CC)CC)C>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:2]2([OH:3])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:28]2[CH2:27][C:26]2[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:30][CH:29]=2)=[CH:13][CH:14]=1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: O=C1OC(Cl)(c2ccc(Cl)cc2)c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 65 %

Procedure:
Distilled THF (25 mL) was added to 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one (3.2 g, 11.5 mmol) followed by 4-nitrobenzylamine hydrochloride (2.3 g, 12.6 mmol) and triethylamine (4.8 mL, 34.5 mmol) as for general procedure A. The crude product was recrystallised in the minimum amount of boiling ethyl acetate to give 3-(4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one as a light yellow solid (2.95 g, 7.47 mmol, 65%); Rf=0.4 (40:60:EtOAc:petrol). 197.1-199.7° C. λmax (CH3OH)/nm 220, Abs 0.765. IR: 3215, 1676, 1517, 1395, 1341 cm−1. 1H NMR: (300 MHz, d6-DMSO) δ 4.35 (d, 1H, J=16.3 Hz, N—CH2), 4.61 (d, 1H, J=16.3 Hz, N—CH2), 7.28 (m, 4H, Ar—H), 7.45 (m, 3H, Ar—H), 7.58 (m, 2H, Ar—H), 7.79 (m, 1H, Ar—H), 8.05 (m, 2H, Ar—H). 13C NMR: (75 MHz, d6-DMSO) δ 42.1, 90.5, 123.1, 123.3, 128.4, 128.7, 129.1, 129.9, 130.3, 133.2, 133.3, 138.9, 146.4, 146.5, 149.4, 167.1. LC/MS-ES+ m/z 307.2, 368.2, 377.1. Anal. Calcd. for C21H15CN2O4: C, 63.89; H, 3.83; N, 7.10%. Found C, 63.78; H, 3.92; N, 7.12%. HRMS (EI) m/z Calcd. for C21H15ClN2O4: 394.0720. Found 394.0714.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[CH:33][C:34]([N:37]3[CH2:41][CH2:40][CH2:39][C:38]3=[O:42])=[N:35][CH:36]=2)O1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[CH:33][C:34]([N:37]4[CH2:41][CH2:40][CH2:39][C:38]4=[O:42])=[N:35][CH:36]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc(N3CCCC3=O)nc2)OC1(C)C
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(N5CCCC5=O)nc4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]pyrrolidin-2-one (from JPM2 Pharmaceuticals). LCMS calculated for C25H26N5O3 (M+H)+: m/z=444.2. Found 444.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[CH2:13]([C@H:15]1[O:17][CH2:16]1)[Cl:14]>CC#N>[Cl:14][CH2:13][C@@H:15]([OH:17])[CH2:16][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Reactant: ClC[C@@H]1CO1
Solvent: CC#N
Product: O=C1CSc2ccc(NC[C@H](O)CCl)cc2N1
Temperature: 45 °C
Reaction time: 24 h
Yield: 63.7 %

Procedure:
A suspension of 6-amino-4H-benzo[1,4]thiazin-3-one (18.0 g, 100 mmol; commercial) and Ca(OTf)2 (0.5 eq.) in MeCN (800 mL) was heated at 50° for 1 h. (S)-epichlorohydrin (18.5 g, 200 mmol) was added and the mixture was stirred at rt for 72 h and at 45° C. for 24 h. The volatiles were removed under reduced pressure. After aqueous workup and extraction with EA, the title intermediate crystallized from EA to afford a beige solid (17.38 g, 64% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][N:15]=2)[CH3:13])=[O:10])=[CH:4][CH:3]=1.O[CH:27]1[CH2:31][CH2:30][O:29][CH2:28]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:29]1[CH2:30][CH2:31][CH:27]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:11][C@@H:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[CH:16][N:15]=3)[CH3:13])=[O:10])=[CH:6][CH:7]=2)[CH2:28]1
Reactant: OC1CCOC1
Reactant: C[C@@H](NC(=O)Cc1ccc(O)cc1)c1ccc(NCC(F)(F)F)cn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)Cc1ccc(OC2CCOC2)cc1)c1ccc(NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of the starting 2-(4-hydroxyphenyl)-N-((1R)-1-{5-[(2,2,2-trifluoroethyl)amino]pyridin-2-yl}ethyl)acetamide (60 mg, 0.17 mmol) in 0.5 ml of dry THF was added the 3-Hydroxytetrahydrofuran (14.92 mg, 0.169 mmol), Di-tert-butyl azodicarboxylate (58.5 mg, 0.254 mmol) and triphenylphosphine (66.6 mg, 0.254 mmol). The mixture was stirred at room temperature for Overnight. The reaction mixture was washed with saturated sodium bicarbonate solution and brine. Organics were extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated in vacuo. Purification by reverse phase chromatography gave 2-[4-(tetrahydrofuran-3-yloxy)phenyl]-N-((1R)-1-{5-[(2,2,2-trifluoroethyl)amino]pyridin-2-yl}ethyl)acetamide as a white solid (0.050 g, 70%). 1H NMR (CDCl3, 400 MHz) δ 8.212 (d, J=2.38 Hz, 1H); 7.189 (m, 4H); 6.830 (m, 2H); 6.624 (d, J=7.15 Hz, 1H); 5.103 (quintet, J=6.95 Hz, 1H); 4.924 (m, 1H); 4.379 (dd, J=8.06, 15.93 Hz, 2H); 3.999 (m, 3H); 3.905 (m, 1H); 3.519 (s, 2H); 2.187 (m, 2H); 1.387 (d, J=6.78 Hz, 3H); MS (ES): m/z 425.2 (M+H). FLIPR alpha1I IP=91 nM.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8]2)(=[O:4])=[O:3].[OH-].[NH4+:22]>C1COCC1.O>[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8]2)(=[O:4])(=[O:3])[NH2:22]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(S(=O)(=O)Cl)cc2C1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2ccc(S(N)(=O)=O)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a solution of tert-butyl 5-(chlorosulfonyl)isoindoline-2-carboxylate (D97) (400 mg, 1.259 mmol) in THF (12 mL) was added ammonium hydroxide (0.490 mL, 12.59 mmol) at 0° C. The mixture was left to stir for 1 hour at RT. The mixture was concentrated in vacuo and the residue obtained taken up in water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organics were dried and concentrated down to afford the title compound (335 mg). LCMS (A): m/z (M−H)− 297, C13H18N2O4S requires 298 (acidic).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl[CH:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1>CC#N>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([CH:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH2:7]1
Reactant: FC(F)(F)c1cccc(C(Cl)c2ccccc2)c1
Reactant: C[C@@H]1CNCCN1
Solvent: CC#N
Product: C[C@@H]1CN(C(c2ccccc2)c2cccc(C(F)(F)F)c2)CCN1
Temperature: 100 °C
Yield: 80.8 %

Procedure:
To a solution of (R)-(−)-2-methylpiperazine (2.2 g, 22 mmol) in CH3CN (20 mL) was added 1-(chloro(phenyl)methyl)-3-(trifluoromethyl)benzene (2.0 g, 7.4 mmol) and heated to 100° C. for 12 h and concentrated under vacuum. The residue was dissolved in CH2Cl2 (150 mL) and washed with 1N NaOH (150 mL). The organic layer was dried with K2CO3 or Na2SO4, filtered, and concentrated. The crude product was purified by ISCO using 0-20% 2N NH3/MeOH solution in CH2Cl2 to give the title compound (2.00 g, 81% yield) as oil. MS (ESI, pos. ion) m/z: 335.1 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH2:12].[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[Br:10][C:8]1[CH:7]=[C:6]([CH3:11])[C:5]([NH:12][S:21]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[C:4]([CH:9]=1)[C:3]([OH:2])=[O:13]
Reactant: COC(=O)c1cc(Br)cc(C)c1N
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: Cc1cc(Br)cc(C(=O)O)c1NS(=O)(=O)c1ccc(F)cc1
Yield: 36 %

Procedure:
By following the procedure of Example 134 the product of Example 133 and 4-flurobenzenesulfonyl chloride provides 5-bromo-2-(4-fluoro-benzenesulfonylamino)-3methyl-benzoic acid as a yellow solid in 36% yield. Electrospray Mass Spec: 386.0 (M-H)-
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[N:20]1([CH2:26][CH2:27][NH2:28])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[N:20]1([CH2:26][CH2:27][NH:28][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NCCN1CCOCC1
Product: CCc1cc(-c2cncc(C(=O)NCCN3CCOCC3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-(morpholin-4-yl)-ethyl-amine to afford the title compound. MS: m/e=371 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[C:12](F)[CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].[OH:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1.Cl>CS(C)=O>[F:7][C:8]1[CH:13]=[C:12]([O:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]
Reactant: Cc1cc(O)n[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(Oc2ccc([N+](=O)[O-])c(F)c2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
Potassium carbonate (3.46 g, 25.0 mmol) and 2,4-difluoronitrobenzene (7.95 g, 50.0 mmol) were added to a solution of 3-hydroxy-5-methylpyrazole (4.91 g, 50.0 mmol) in DMSO (80 ml) at room temperature, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (100 ml) and extracted with ethyl acetate (100 ml×2). An organic layer was washed with water (100 ml×2), dried over anhydrous magnesium sulfate and filtered to remove magnesium sulfate, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a yellow solid of 3-(3-fluoro-4-nitrophenyloxy)-5-methylpyrazole (1.52 g, yield: 12.8%) [mp: 80-83° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.33 (d, J=0.5 Hz, 3H), 5.77 (d, J=0.5 Hz, 1H), 6.96-7.03 (m, 2H), 8.06-8.13 (m, 1H), 10.03 (br s, 1H)] and a yellow solid of 3-(5-fluoro-2-nitrophenyloxy)-5-methylpyrazole (0.97 g, yield: 8.2%) [mp: 95-97° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.31 (s, 3H), 5.77 (s, 1H), 6.90 (ddd, J=2.7, 5.8 and 9.1 Hz, 1H), 7.01 (dd, J=2.7 and 9.6 Hz, 1H), 8.03 (dd, J=5.8 and 9.1 Hz, 1H), 9.86 (br s, 1H)].