Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COCCOC.[F:7][C:8]1[C:13](B(O)O)=[CH:12][CH:11]=[CH:10][N:9]=1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[C:19]=1[F:26]>O.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:26][C:19]1[C:20]([NH2:25])=[N:21][C:22]([CH3:24])=[N:23][C:18]=1[C:13]1[C:8]([F:7])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1nc(N)c(F)c(Cl)n1
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Product: Cc1nc(N)c(F)c(-c2cccnc2F)n1
Temperature: 100 °C
Yield: 59.7 %

Procedure:
DME (6.00 mL, 57722 μmol) and water (0.6 mL, 3152 μmol) were added to a mixture of 2-fluoropyridin-3-ylboronic acid (666 mg, 4728 μmol), 6-chloro-5-fluoro-2-methylpyrimidin-4-amine (0.5093 g, 3152 μmol), and Pd(Ph3P)4 (364 mg, 315 μmol) under nitrogen. The mixture was sealed and heated at 100° C. for 60 min under microwave irradiation. After cooling, the mixture was diluted with water and the precipitate was collected, washed with DCM, and 5-fluoro-6-(2-fluoropyridin-3-yl)-2-methylpyrimidin-4-amine (418 mg, 60%) was isolated as an off-white powder. LCMS (API-ES) m/z 223 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 8.39 (d, J=4.02 Hz, 1H) 8.18 (t, J=8.03 Hz, 1H) 7.53 (t, J=5.27 Hz, 1H) 7.38 (br. s., 2H) 2.37 (s, 3H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1>CC(C)=O>[C:13]([C:12]1[CH:16]=[CH:17][C:9]([N:8]2[C:1](=[O:7])[CH:2]=[CH:3][C:4]2=[O:6])=[CH:10][CH:11]=1)([OH:15])=[O:14]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C1C=CC(=O)O1
Solvent: CC(C)=O
Product: O=C(O)c1ccc(N2C(=O)C=CC2=O)cc1

Procedure:
N-(para-carboxyphenyl)maleimide was prepared as follows. Maleic anhydride (45.2 grams (g)) was dissolved in from 300-400 milliliters (ml) of acetone. To this solution, an equimolar amount of para-aminobenzoic acid (63.2 g) was added with rapid stirring. The reaction mixture solidified within a few seconds. Excess solvent was removed by evaporation to yield the amic acid intermediate which was then dried overnight at 65° C. under vacuum.
Reaction SMILES: [NH2:1][C:2]1[C:9]([NH:10][CH3:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:12])[CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:20]=O)[CH:17]=[N:18][CH:19]=1.OOS([O-])=O.[K+]>CN(C=O)C.O.C([O-])([O-])=O.[K+].[K+]>[F:12][C:4]1[C:5]([C:6]#[N:7])=[CH:8][C:9]2[N:10]([CH3:11])[C:20]([C:16]3[CH:17]=[N:18][CH:19]=[C:14]([F:13])[CH:15]=3)=[N:1][C:2]=2[CH:3]=1
Reactant: CNc1cc(C#N)c(F)cc1N
Reactant: O=Cc1cncc(F)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(-c2cncc(F)c2)nc2cc(F)c(C#N)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-amino-2-fluoro-5-methylamino-benzonitrile (0.15 g, 0.00090 mol) and 5-Fluoro-pyridine-3-carbaldehyde (0.11 g, 0.0090 mol) in DMF (5 mL) and H2O (2 mL) was added OXONE® monopersulphate (0.19 g, 0.0012 mol). The reaction mixture was stirred at room temperature for 5 h, and was diluted with 10% K2CO3 solution to PH˜8-10 and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to afford the crude compound, which was purified by column chromatography to obtain title compound 5-fluoro-2-(5-fluoropyridin-3-yl)-1-methyl-1H-benzimidazole-6-carbonitrile (398) as a brown solid. C14H8F2N4; 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.83 (d, J=2.4 Hz, 1H), 8.47 (d, 5.4 Hz, 1H), 8.29 (d, J=9.6 Hz, 1H), 7.88 (d, J=9.6 Hz, 1H), 3.98 (s, 3H); MS (M+1): 271.1. HPLC purity: 99.44%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:17])[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)=[O:4].[CH3:18][CH2:19][O:20]C(C)=O.O>CN(C1C=CN=CC=1)C.C(OC(=O)C)(=O)C.CCOCC>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:17])[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:19](=[O:20])[CH3:18])[CH:11]=1)=[O:4]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1nc(C)sc1-c1cccc(N)c1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1nc(C)sc1-c1cccc(NC(C)=O)c1

Procedure:
TEA (14.2 mmol) and DMAP (4.05 mmol) are added successively to a solution of 5-(3-amino-phenyl)-2-methyl-thiazole-4-carboxylic acid methyl ester (4.05 mmol) in acetic anhydride (25 mL). After stirring for 30 min EtOAc and water are added, the layers are separated and the aq. layer is extracted once with EtOAc. The combined organic layers are washed with sat. aq. NH4Cl solution, sat. aq. NaHCO3 solution and water, dried over MgSO4 and concentrated in vacuo to give a crude product which is diluted with ether. The obtained suspension is filtered. The residue is washed with ether and dried in vacuo to give the desired product which is used without further purification. LC-MS: tR=0.81 min; [M+H]+=291.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH:12]1[CH2:14][CH2:13]1)[CH:6]=[C:5]2[CH2:15][C:16]([OH:18])=[O:17].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.CCO.O>[CH:12]1([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:20]4[S:19][CH:23]=[CH:22][CH:21]=4)=[CH:10][CH:9]=3)[C:5]([CH2:15][C:16]([OH:18])=[O:17])=[CH:6]2)[CH2:14][CH2:13]1
Reactant: O=C(O)Cc1cn(CC2CC2)c2ccc(Br)cc12
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CCO
Product: O=C(O)Cc1cn(CC2CC2)c2ccc(-c3cccs3)cc12
Temperature: 85 °C
Yield: 79.3 %

Procedure:
To a sealed tube containing 2-[5-bromo-1-(cyclopropylmethyl)-1H-indol-3-yl]acetic acid (100 mg, 0.32 mmol), 2-thiopheneboronic acid (124 mg, 0.97 mmol), (C6H5)4Pd (37 mg, 0.032 mmol), Na2CO3 (2.6 mmol) in a mixture of benzene/EtOH/H2O (5/1/3, 4.5 mL) was heated at 85° C. for 19 h. The mixture was poured onto diethyl ether and adjusted to pH 3 before extracting with diethyl ether. The mixture was washed with NaH2PO4, dried over MgSO4 and evaporated to give the crude product which was purified on silica gel column (33% EtOAc in hexane with 1% HCOOH) to give 79 mg (78% yield) of the product.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[N:33]=[C:34]=[O:35].C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:34]([NH:33][C:24]3[CH:25]=[CH:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:23]=3)=[O:35])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccc2ccccc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)Nc4ccc5ccccc5c4)c3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 63 %

Procedure:
A mixture of 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.50 g, 1.6 mmol), 2-naphthyl isocyanate (0.26 g, 1.6 mmol), and diisopropylethylamine (0.40 g, 3.1 mmol) in 10 mL pyridine was warmed to 40° C. with stirring under N2, and the resulting solution was stirred at the same temperature for 2 hours. The mixture was cooled, and the solvent was evaporated under vacuum. The residue was chromatographed, eluting with 96:4 methylene chloride-methanol, to provide 0.46 g of the product in 70% yield: mp 201-203° C.; 1H NMR (DMSO-d6) δ 2.07-2.11 (m, 1H), 2.54-2.66 (m, 2H), 2.85-2.91 (m, 1H), 4.75 (d, J=6.0 Hz, 2H), 5.18 (dd, J=12.6 Hz, d=5.4 Hz, 1H), 6.88 (t, J=6.0 Hz, 1H), 7.28-7.34 (m, 1H), 7.38-7.45 (m, 2H), 7.70-7.88 (m, 6H), 8.05 (d, J=1.6 Hz, 1H), 9.05 (s, 1H), 11.20 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 31.0, 38.8, 48.9, 112.7, 119.4, 121.9, 123.6, 126.2, 126.8, 127.2, 127.4, 128.3, 128.8, 131.7, 133.8, 134.8, 137.9, 140.2, 155.3, 167.0, 167.6, 169.8, 172.8; Anal. calcd. for C25H20N4O5.0.5H2O: C, 64.51; H, 4.54; N, 12.03. Found: C, 64.87; H, 4.88; N, 11.59.
Reaction SMILES: Cl.Cl.Cl.Cl[C:5]1([C:11]2[C:12]([O:17][CH:18]3[CH2:21][N:20]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:19]3)=[N:13][CH:14]=[CH:15][N:16]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[C:32](N1C=CN=C1)(=[O:34])[CH3:33].CCN(C(C)C)C(C)C.[OH2:49]>C(Cl)Cl>[C:32]([N:8]1[CH2:9][CH2:10][C:5]([C:11]2[C:12]([O:17][CH:18]3[CH2:21][N:20]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:19]3)=[N:13][CH:14]=[CH:15][N:16]=2)([OH:49])[CH2:6][CH2:7]1)(=[O:34])[CH3:33]
Reactant: O
Reactant: O=C(OCc1ccccc1)N1CC(Oc2nccnc2C2(Cl)CCNCC2)C1
Reactant: CC(=O)n1ccnc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(O)(c2nccnc2OC2CN(C(=O)OCc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of benzyl 3-((3-(4-chloropiperidin-4-yl)pyrazin-2-yl)oxy)azetidine-1-carboxylate trihydrochloride salt, 1-acetylimidazole (0.204 g, 1.851 mmol), DIEA (1.58 mL, 9.25 mmol), and 1-acetylimidazole (0.204 g, 1.851 mmol) in DCM (10 mL) was stirred at room temperature for 16 hours. H2O was added, and layers were separated. The organic extracts were dried over Na2SO4, concentrated and purified by silica gel chromatography using ISCO™ (0-60% EtOAc/Hexanes) to give the title compound. MS (M+1): 427 calc.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[CH:18][C:13]=2[CH:12]=1)=[O:10].C(N(C(C)C)CC)(C)C.Cl.[NH2:41][CH:42]([CH3:47])[C:43]([CH3:46])([OH:45])[CH3:44]>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:14]2[N:15]=[C:16]([NH:41][CH:42]([CH3:47])[C:43]([OH:45])([CH3:46])[CH3:44])[N:17]=[CH:18][C:13]=2[CH:12]=1)=[O:10]
Reactant: CC(N)C(C)(C)O
Reactant: CS(=O)(=O)c1ncc2cc(C(=O)Nc3ccccc3Cl)n(-c3ccc(F)cc3)c2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(Nc1ncc2cc(C(=O)Nc3ccccc3Cl)n(-c3ccc(F)cc3)c2n1)C(C)(C)O
Temperature: 140 °C

Procedure:
To a solution of 7-(4-fluoro-phenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (2-chloro-phenyl)-amide, 27, (0.11 g, 0.25 mmol) in N-methyl-pyrrolidinone (3 mL) is added diisopropylethylamine (0.22 mL, 1.28 mmol) and 3-amino-2-methyl-butan-2-ol hydrochloride salt (0.11 g, 0.77 mmol). The mixture is heated to 140° C. for 4 hours and the resulting solution purified by preparative HPLC to afford the desired product as a yellowish solid: 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.33 (d, J=8.1 Hz, 1H), 8.23 (s, 1H), 7.45-7.40 (m, 3H), 7.32-7.22 (m, 3H), 7.13 (t, J=8.1 Hz, 2H), 3.92-3.82 (m, 1H), 1.26 (d, J=9.1 Hz, 6H), 1.20 (d, J=6.8 Hz, 3H); ESI+ MS: m/z (rel intensity) 468.0.0 (100, M++H).
Reaction SMILES: C([S:4][CH2:5][S:6][C:7]1[N:8]=[N:9][NH:10][CH:11]=1)(=O)C.C[O-].[Na+].[C:15]1([CH:21]([O:28][C:29]([C:31]2[N:36]3[C:37](=[O:59])[C@@H:38](NC(=O)/C(/C4N=C(NC(OC(C)(C)C)=O)SC=4)=C\CC)[C@H:35]3[S:34][CH2:33][C:32]=2OS(C)(=O)=O)=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.CO.Cl.O>[C:15]1([CH:21]([O:28][C:29]([C:31]2[N:36]3[C:37](=[O:59])[CH2:38][C@H:35]3[S:34][CH2:33][C:32]=2[S:4][CH2:5][S:6][C:7]2[N:8]=[N:9][NH:10][CH:11]=2)=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)SCSc1c[nH]nn1
Reactant: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(C)(=O)=O)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(SCSc2c[nH]nn2)CS[C@@H]2CC(=O)N12
Reaction time: 0.33 h
Yield: 111.4 %

Procedure:
To a solution of 4-acetylthiomethylthio-1,2,3-triazole (230 mg : 1.22 mMol.) in dimethylformamide (6 ml) is dropwise added a 1.26N-sodium methoxide in methanol (1.9 ml) at -60° C., and the mixture is stirred for 20 minutes, mixed with a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol -4-yl)-2-pentenoylamino]-3-methanesulfonyloxy-3-cephem -4- carboxylic acid diphenylmethyl ester (740 mg : 1 mMol.) in dimethylformamide (3 ml), and stirred at the same temperature for 40 minutes. The reaction mixture is diluted with 10% hydrochloric acid (2 ml) and water (30 ml) and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and purified by silica gel chromatography (toluene : ethyl acetate=2:1) to give 7β-(Z)-2-(2- t-butoxycarbonylaminothiazol-4-yl)-2-pentenoylamino]-3-(1,2,3-triazol-4- ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (553 mg) as colorless foam. Yield : 70%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=1.[C:18]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)(=[O:20])[CH3:19].CCOC(C)=O>C(#N)C.N1C=CC=CC=1>[C:18]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:17][C:12]2[CH:11]=[C:10]([C:2]3[O:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)[CH:15]=[CH:14][C:13]=2[NH2:16])=[O:27])=[CH:24][CH:23]=1)(=[O:20])[CH3:19]
Reactant: Nc1ccc(-c2nc3ccccc3o2)cc1N
Reactant: CC(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(=O)Nc1ccc(C(=O)Nc2cc(-c3nc4ccccc4o3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 0.8 %

Procedure:
To a stirred suspension of 227 (350 mg, 1.55 mmol) in acetonitrile (20 mL) and pyridine (2 ml) was added 4-acetamidobenzoyl chloride (307 mg, 1.55 mmol) in acetonitrile (5 ml) at 0° C. The solution was warmed up to room temperature and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel, eluents hexane-EtOAc (1:3), then EtOAc (100%), to afford 228 as a beige solid (5 mg, 1% yield). 1H NMR: (DMSO) δ (ppm): 10.22 (s, 1H), 9.62 (s, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.80 (1H, dd, J=2.0, 8.4 Hz, 1H), 7.68-7.73 (m, 4H), 7.33-7.35 (m, 2H), 6.91 (d, J=8.4 Hz, 1H), 5.86 (bs, 2H), 2.12 (s, 3H). MS: (calc.) 386.41; (obt.) 387.1 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[C:19]([CH3:20])=[CH:18][C:5]2[CH:6](C3C=CC=CC=3)[NH:7][CH2:8][CH2:9][NH:10][CH2:11][C:4]=2[CH:3]=1.CC(C)=[O:23].Cl([O-])(=O)=O.[K+]>O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:18][C:19]=1[CH3:20])[C:6]1=[N:7][CH2:8][CH2:9][N:10]1[CH:11]2[OH:23]
Reactant: Cc1cc2c(cc1C)C(c1ccccc1)NCCNC2
Reactant: CC(C)=O
Agent: [K+]
Agent: [O-][Cl+2]([O-])[O-]
Solvent: O
Product: Cc1cc2c(cc1C)C(O)N1CCN=C21

Procedure:
Four grams of 1,2,3,4,5,6-hexahydro-8,9-dimethyl1-phenyl-2,5-benzodiazocine is dissolved in 100 ml. of acetone. A solution of 2 g. of potassium chlorate in 100 ml. of water is added dropwise over a period of an hour. Thereafter, the mixture is filtered and evaporated to dryness to afford 2,3-dihydro-7,8-dimethyl-5H-imidazo[2,1-a]isoindol-5-ol which is recrystallized from methanol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=1>CCCCCC.C(OCC)(=O)C>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:3]=2)[CH:21]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: c1cncc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)c1

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 3-pyridineboronic acid pinacol ester with reaction time of 15 h. Chromatography (hexane/ethyl acetate 1:1) gave the title compound as a colorless solid.
Reaction SMILES: CN1CCCCC1.[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][CH3:21])[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[Cl:30][C:31]1[CH:41]=[CH:40][C:34]([O:35][CH2:36][CH:37]([NH2:39])[CH3:38])=[CH:33][CH:32]=1>C(Cl)Cl.O>[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][CH3:21])[C:17]([NH:39][CH:37]([CH3:38])[CH2:36][O:35][C:34]1[CH:40]=[CH:41][C:31]([Cl:30])=[CH:32][CH:33]=1)=[O:19])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(N)COc1ccc(Cl)cc1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)NC(C)COc1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
2.0 g of N-methylpiperidine was added to a solution containing 4.1 g of (2S)-2-tert-butoxycarbonylaminobutyric acid dissolved in 60 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 2.7 g of isobutyl chloroformate was added to the mixture at -40° C., and stirred for 1 hour at -20° C. 3.7 g of 2-(4-chlorophenoxy)-1-methylethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 5.6 g of the desired product in the form of a colorless glutinous substance (yield: 76%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C@@:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:13]([C:30]#[C:31][CH3:32])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[NH4+:34]>CCO>[NH2:34][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C@@:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:13]([C:30]#[C:31][CH3:32])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC#CC1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ccc([C@](C)(O)C(F)(F)F)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC#CC1CN(S(=O)(=O)c2ccc(N)nc2)CCN1c1ccc([C@](C)(O)C(F)(F)F)cc1
Temperature: 110 °C
Yield: 79.7 %

Procedure:
To a 20-mL vial was added (2S)-2-(4-(4-((6-chloro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.235 g, 0.482 mmol), EtOH (3.0 mL), and ammonium hydroxide (30%, 3.0 mL, 23 mmol, J. T. Baker, Philipsburg, N.J.). The vial was sealed and heated at 110° C. for 20 h. The reaction mixture was cooled to rt and the solvent was removed in vacuo. The residue was partitioned between water (20 mL) and DCM (40 mL). The aqueous layer was extracted with DCM (2×20 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude product was purified by column chromatography (40 g of silica, 10 to 30% acetone in hexanes) to afford (2S)-2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.180 g) as a mixture of two isomers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:19](OC3C=CC([N+]([O-])=O)=CC=3)=[O:20])[CH2:16][CH:15]([C:31]([O:33][CH3:34])=[O:32])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]([F:12])([F:11])[F:10].[NH:35]1[CH2:40][CH2:39][S:38][CH2:37][CH2:36]1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:19]([N:35]3[CH2:40][CH2:39][S:38][CH2:37][CH2:36]3)=[O:20])[CH2:16][CH:15]([C:31]([O:33][CH3:34])=[O:32])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]([F:10])([F:12])[F:11]
Reactant: COC(=O)C1CC(c2ccc(CC(F)(F)F)c(F)c2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reactant: C1CSCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)C1CC(c2ccc(CC(F)(F)F)c(F)c2)CN(C(=O)N2CCSCC2)C1
Temperature: 150 °C

Procedure:
A solution of 5.85 g (9.54 mmol, purity 80%) of the compound from Example 77A in 1-methyl-2-pyrrolidone (50 ml) was admixed with 5.43 ml (5.91 g, 57.2 mmol) of thiomorpholine and 4.99 ml (3.70 g, 28.6 mmol) of N,N-diisopropylethylamine and then heated in 4 portions in a single-mode microwave (Emrys Optimizer) at 150° C. for 45 min. For workup, the reaction solutions were combined and purified directly by means of preparative HPLC. Yield: 4.29 g (93% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]2[O:8][CH2:9][O:10][C:5]2=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([O:21][CH3:22])[C:15]([O:23][CH3:24])=[CH:14]2.[N:25]([O-])=O.[Na+].O.C(OCC)(=O)C>C(O)(=O)C.Cl>[CH3:22][O:21][C:16]1[C:15]([O:23][CH3:24])=[CH:14][C:13]2[C:18]([CH:17]=1)=[CH:19][CH:20]=[C:11]1[C:12]=2[N:25]=[N:1][C:2]2[CH:7]=[C:6]3[O:8][CH2:9][O:10][C:5]3=[CH:4][C:3]1=2
Reactant: COc1cc2ccc(-c3cc4c(cc3N)OCO4)cc2cc1OC
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2ccc3c4cc5c(cc4nnc3c2cc1OC)OCO5
Reaction time: 8 h
Yield: 46 %

Procedure:
6-(2-Amino-4,5-methylenedioxyphenyl)-2,3-dimethoxy-naphthalene (13, 40 mg, 0.13 mmol) in acetic acid (2 mL) and concentrated hydrochloric acid (0.3 mL) was cooled to 0° C. and diazotised with a solution of sodium nitrite (0.09 g in 1.5 mL water). The diazonium solution was allowed to rise slowly to room temperature and left overnight. Water (50 mL) was added to the red solution with some precipitate. The resulting mixture was extracted with ethyl acetate, washed with diluted sodium hydroxide solution, then with water, dried (anhydrous Na2SO4) and rotaevaporated to give the crude product. Chromatography on silica gel using 40:60 hexanes:ethyl acetate afforded the title compound (20 mg) in 50% yield; 1H NMR (CDCl3) d 4.09(3H, s), 4.22(3H, s), 6.24(2H, s), 7.31(1H, s), 7.80(1H s), 7.95(1H, s), 8.00(1H, d, J=9.2), 8.13(1H, d, J=8.9), 9.14(1H, s); 13C NMR d 56.5 56.9, 98.1, 102.9, 104.6, 107.5, 107.9, 117.1, 119.6, 120.6, 126.8, 128.5, 131.7, 141.9, 145.6, 150.2, 151.2, 152.1.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23]([C@H:25]1[CH2:29][CH2:28][C:27](=[O:30])[N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24])[NH2:22]>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:22][NH:21][C:23]([C@H:25]1[CH2:29][CH2:28][C:27](=[O:30])[N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@@H]1C(=O)NN
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Product: CC(C)(C)OC(=O)N1C(=O)CC[C@@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Yield: 60.9 %

Procedure:
Following a procedure analogous to Example 27, the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and (R)-tert-butyl 2-(hydrazinecarbonyl)-5-oxopyrrolidine-1-carboxylate (730 mg, prepared following a procedure analogous to Reference Example 6 from the compound described in Reference Example 4), 431.2 mg of the title compound was afforded (yield 60.9%).