Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC=CC=3)(=O)=O)[N:9]=[CH:10][C:3]=12.C[N:21]1[CH:25]=[C:24](C)[C:23]([C:27]([NH:29][C:30]2[CH:38]=[C:37]([Sn](C)(C)C)[CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][N:34]3S(C2C=CC=CC=2)(=O)=O)=[O:28])=[N:22]1.[C:52]1(S)[CH:57]=CC=C[CH:53]=1>CN(C=O)C>[CH3:53][CH:52]([N:22]1[C:23]([C:27]([NH:29][C:30]2[CH:38]=[C:37]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[NH:8][N:9]=[CH:10][C:3]=34)[CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)=[O:28])=[CH:24][CH:25]=[N:21]1)[CH3:57]
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(I)ccnc21
Reactant: Sc1ccccc1
Reactant: Cc1cn(C)nc1C(=O)Nc1cc([Sn](C)(C)C)cc2c1cnn2S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)n1nccc1C(=O)Nc1cc(-c2ccnc3[nH]ncc23)cc2[nH]ncc12
Temperature: 135 °C
Reaction time: 8 h

Procedure:
4-Iodo-1-(phenylsulfonyl)-1H-pyrazolo[3,4-b]pyridine (69 mg) in DMF (0.4 ml) was added to 1,4-dimethyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1H-pyrazole-3-carboxamide (100 mg) in DMF (0.4 ml). Solvias catalyst (4 mg) was added and the sealed vessel was heated in the Anton Paar microwave at 135° C. for 20 min. PS-thiophenol resin was added and the reaction was stirred overnight before being filtered onto a C18SPE cartridge, pre-washed with 0.1% TFA, with acetonitrile. The cartridge was washed with 0.1% TFA in acetonitrile and the collected solvent was removed under a stream of nitrogen. The residue was dissolved in DMSO (1 ml) and purified by MDAP (method C). The solvent was evaporated in vacuo. The residue was dissolved in isopropanol (0.3 ml), 2M sodium hydroxide (aq) (0.3 ml) was added and the reaction was left at room temperature overnight. The solvent was removed under a stream of nitrogen and the residue was dissolved in DMSO (0.5 ml) and purified by MDAP (method C). The solvent was evaporated in vacuo to give title compound, 9 mg.
Reaction SMILES: [CH2:1]([C@@H:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([C@@H:8]1[NH:13][C@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][O:10][C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCC(c2ccccc2)=N[C@H]1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C1OC[C@@H](c2ccccc2)N[C@H]1Cc1ccccc1
Reaction time: 5 h
Yield: 32.7 %

Procedure:
To a solution of (3S)-3-Benzyl-5-phenyl-3,6-dihydro-2H-1,4-oxazin-2-one (1.56 g, 5.88 mmol, 1.0 equiv.) in anhydrous methanol (40 mL) under an atmosphere of nitrogen was added palladium on activated carbon (156 mg, 0.1 equiv. by mass). The mixture was consecutively degassed and purged three times with hydrogen and then stirred for 5 hours under an atmosphere of hydrogen. Filtration through a short pad of CELITE® diatomaceous earth and removal of solvent from the filtrate in vacuo yielded the crude product which was purified by flash column chromatography on silica eluting with petrol and diethyl ether (4:1) to furnish the title product as a white solid (514 mg, 33%); m.p. 75.0-76.0° C. (lit. 76.0-78.0° C.); v(max)(KBr) 3321 (N—H), 2949 (C—H), 1731 (C═O), cm−1; δH (250 MHz, CDCl3) 7.36-7.21 (10H, m, Ph), 4.34-4.15 (3H, m, PhCHCH2), 3.97 (1H, dd, J 3.2, T 10.0 Hz, NHCH), 3.56, (1H, dd, J 3.2, J 13.6 Hz, CHPh×1), 3.00, (1H, dd, /10.0, T 13.6 Hz, CH2Ph×1), 1.84 (1H, br, NH); δH, (62.5 MHz, CDCl3) 169.6, 138.0, 137.8, 129.8, 129.3, 129.2, 129.1, 127.5, 127.4, 75.3, 60.6, 57.9, 39.4; m/z (CL, NH3), 268 (MH+, 40%), 267 (80%, M+), 223 (100%), and 209 (57%); HRMS for C17H17NO2 requires 267.1259 found 267.1263. [α]D20 −156.4 (c 1.02 CHCl3) (lit. [α]D20-157.9 (c 2.00 CHCl3)).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]=2)[O:3]1.[ClH:23]>CC(OC)(C)C.CCOCC>[ClH:23].[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:22])[O:3][B:4]([C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]=2)[O:5]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: CC1(C)OB(C2=CCNCC2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2 g, 6.47 mmol) was suspended in MTBE (8.1 mL) and 2M HCl in Et2O (24 mL). The reaction was stirred rt overnight, the white precipitate formed collected by filtration and washed with Et2O to give the title compound (1.434 g, 90%).
Reaction SMILES: CC1C(N=C=O)=CC([N:8]=[C:9]=[O:10])=CC=1.C([C:16]([CH2:21][OH:22])(CO)CC)O.[C:23]([O:28][CH3:29])(=[O:27])[C:24]([CH3:26])=[CH2:25].C1(=O)C=CC(=O)C=C1.C(OCCO)(=O)C(C)=C>>[NH2:8][C:9]([O:22][CH2:21][CH3:16])=[O:10].[C:23]([O:28][CH3:29])(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: CCC(CO)(CO)CO
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Agent: C=C(C)C(=O)OC
Agent: C=C(C)C(=O)OCCO
Agent: O=C1C=CC(=O)C=C1
Product: CCOC(N)=O
Temperature: 70 °C
Reaction time: 10 h

Procedure:
A U.V. curable urethane composition is prepared by heating 104.4 grams (0.6 moles) of tolylene diisocyanate to 70° C. and, while maintaining this temperature adding dropwise over 2 hours a homogeneous solution, also heated to 70° C., consisting of 26.8 grams of trimethylolpropane, 79.0 grams of methyl methacrylate and 0.02 grams p-benzoquinone. At the end of the reaction period, the product is maintained at 70° C. for an additional 6 hours. There is, thereafter, added dropwise 57.2 grams of 2-hydroxyethyl methacrylate over a period of one-half hour, after which the reaction is continued for an additional 10 hours, followed by the addition of 43 grams methyl methacrylate, to obtain a methyl methacrylate solution of a light yellow, transparent photopolymerizable prepolymer containing approximately 1.8% by weight of isocyanate groups.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH:23](=[C:5]1/[C:4](=[O:6])[NH:3][C:2](=[O:7])[S:1]/1)\[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: O=C1CSC(=O)N1
Reactant: CCCCCCCCCCCCCCCC=O
Product: CCCCCCCCCCCCCCC/C=C1\SC(=O)NC1=O

Procedure:
TZD16 was prepared according to General Procedure A presented hereinabove using 2,4-thiazolidinedione and palmitaldehyde as reactants.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH2:9]/[C:10](/[CH3:18])=[CH:11]\[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13].[N+:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)([O-:21])=[O:20]>CC(O)C.ClCCl>[CH3:5][C:3]1[NH:9][C:10]([CH3:18])=[C:11]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[CH:25]([C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)[C:2]=1[C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: C/C(N)=C/C(=O)OC(C)C
Solvent: ClCCl
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+](=O)[O-])c1
Yield: 62.1 %

Procedure:
A solution of methyl acetoacetate (6.73 g, 58 mmol), 1-methylethyl 3-aminocrotonate (52) (8.34 g, 58 mmol) and 3-nitro-benzaldehyde (8.75 g, 58 mmol) in 2-propanol (80 mL0 was refluxed for 9 h. The mixture was diluted with dichloromethane (300 mL0 and dried (MgSo4), and the solvent was removed with a rotary evaporator. The crude product was recrystallized from ethyl acetate/hexane to afford 13.5 g (36 mmol, 62%) of 81 as a yellow crystalline solid: mp 142°-144° C. (lit.81 mp 147° C.); IR (CH2Cl2) 3440, 2960, 1695, 1622, 1530, 1470, 1352, 1215, 1100 cm-1 ; 1H NMR (CDCl3) δ 1.10 (d, J=6.2 Hz, 3H), 1.25 (d, J=6.2 Hz, 3H), 2.33 (s, 6H), 3.64 (s, 3 H), 4.95 (septet, J=6.2 Hz, 1H), 5.07 (s, 1H) 6.30 (s, 1H), 7.34-8.12 (m, 4H); 13C NMR (CDCl3) δ 19.95, 20.04, 22.35, 22.68, 40.53, 51.67. 67.98, 103.48, 104.19, 121.89, 123.61, 129.23, 135.07, 145.38, 145.91, 148.81, 150.61, 167.29, 168.35.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][C:16]([N:18]([C:20]4[CH:25]=[CH:24][N:23]=[C:22](Cl)[N:21]=4)[CH3:19])=[CH:17][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:31]=[C:32]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][C:16]([N:18]([CH3:19])[C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:29][C:30]5[CH:31]=[C:32]([S:36]([NH2:39])(=[O:37])=[O:38])[CH:33]=[CH:34][CH:35]=5)[N:21]=4)=[CH:17][C:10]=3[N:9]=2)=[CH:27][CH:28]=1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: CN(c1ccc2c(c1)nc(NCc1ccc(Cl)cc1)n2C)c1ccnc(Cl)n1
Product: CN(c1ccc2c(c1)nc(NCc1ccc(Cl)cc1)n2C)c1ccnc(Nc2cccc(S(N)(=O)=O)c2)n1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N2-(4-Chloro-benzyl)-N5-(2-chloro-pyrimidin-4-yl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (103 mg, 0.25 mmol) and 3-amino-benzenesulfonamide (43 mg, 0.25 mmol) as a white solid (68 mg, 470%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.89 (br s, 1H), 8.49 (s, 1H), 7.86 (d, J=6.3 Hz, 1H), 7.73 (m, 1H), 7.18-7.74 (m, 10H), 5.73 (d, J=6.3 Hz, 1H), 4.71 (d, J=5.7 Hz, 2H), 3.69 (s, 3H), 3.47 (s, 3H). MS (ESI) m/z=549 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl:18][C:19]1[C:20]([C:29]2[CH:34]=[CH:33][C:32](F)=[C:31]([N+:36]([O-:38])=[O:37])[CH:30]=2)=[N:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>CN(C)C=O>[Cl:18][C:19]1[C:20]([C:29]2[CH:34]=[CH:33][C:32]([CH:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:31]([N+:36]([O-:38])=[O:37])[CH:30]=2)=[N:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.9 g of an 80% strength by weight suspension of sodium hydride in mineral oil was added to 10 ml of anhydrous dimethylformamide. A solution of 5.1 g of di-tert-butyl malonate in 20 ml of dimethylformamide was added dropwise to this mixture, after which it was stirred for 30 minutes. A solution of 7.5 g of 3-chloro-2-(4-fluoro-3-nitrophenyl)-5-trifluoromethylpyridine in 20 ml of dimethylformamide was then added dropwise. The reaction mixture was stirred at 23° C. for 20 hours and at 80° C. for 5 hours. The cooled reaction mixture was then poured into 200 ml of ice water. The aqueous phase was extracted three times with 100 ml of tert-butyl methyl ether each time. The combined organic phases were washed with 100 ml of water, dried over sodium sulfate and concentrated. Yield: 10.8 g (79%) of a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]=[CH:6][CH:7](OC)OC)[CH3:2].C(#N)C.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:18]2[CH:19]=[C:20]([Br:23])[CH:21]=[CH:22][C:17]2=[N:16][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C=CC(OC)OC
Reactant: Nc1ccc(Br)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)Cc1cnc2ccc(Br)cn12
Yield: 107.1 %

Procedure:
Reflux a solution of 4,4-dimethoxy-but-2-enoic acid ethyl ester (3.3 g, 19.12 mmol) and toluene-4-sulfonic acid (0.02 g, 0.12 mmol) in a solution of 2:1 acetonitrile:water (90 mL) for 30 min. Add 2-amino-5-bromo-pyridine (1.65 g, 9.56 mmol) and reflux for 15 h. Cool and concentrate to ˜20 mL. Dilute the reaction with saturated aqueous sodium bicarbonate and extract into ethyl acetate. Combine and concentrate organic extracts. Flash chromatography using ethyl acetate/dichloromethane/methanol mixtures gives the subtitled compound as a brown oil (2.9 g). TOF MS ES+ exact mass calculated for C11H11BrN2O2 (p+1): m/z=283.0075 Found: 283.0082. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 7.55 (d, J=10 Hz, 1H), 7.49 (s, 1H), 7.34 (d, J=10 Hz, 1H), 4.15 (s, 2H), 4.09 (q, J=4 Hz, 2H), 1.18 (t, J=4 Hz, 3H). EA Calcd. For C11H11BrN2O2: C, 46.66; H, 3.92; N, 9.89; Found C, 46.56; H, 4.02; N, 9.60.
Reaction SMILES: [CH2:1]([N:5]([CH2:37][CH2:38][CH2:39][CH3:40])[C:6]([C:8]1[CH:12]=[C:11]([CH3:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[C:23]([N:25]2[C@H:34]([CH2:35][OH:36])[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[Si:41](Cl)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42].N1C=CN=C1>C(Cl)Cl.O>[CH2:37]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[CH:12]=[C:11]([CH3:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[C:23]([N:25]2[C@H:34]([CH2:35][O:36][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[N:9]=1)=[O:7])[CH2:38][CH2:39][CH3:40]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.5 %

Procedure:
To a solution of (S)—N,N-dibutyl-1-(2-(3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-nitrophenyl)-5-methyl-1H-pyrazole-3-carboxamide (9.0 g, 16.4 mmol) in DCM (150 mL) were added TBDMS-chloride (2.98 g, 19.7 mmol), imidazole (2.23 g, 32.9 mmol) followed by stirring at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc (300 mL×2), twice. The combined organic layers were washed with water (300 mL), brine (100 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the title compound as a liquid 7 g (64%). Rf=0.74 (25% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 8.60-8.20 (m, 2H), 8.05-7.80 (m, 1H), 7.40-6.80 (m, 4H), 6.60-6.30 (m, 1H), 5.10-3.84 (m, 4H), 3.82-2.40 (m, 7H), 2.40-2.20 (m, 3H), 1.60-0.55 (m, 23H), 0.05-−0.40 (m, 6H); LC-MS: m/z 662.4 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[O:23][C:22](=[O:24])[C:21]3[C:16](=[C:17]([CH3:28])[CH:18]=[C:19]4[CH:27]=[N:26][NH:25][C:20]4=3)[N:15]=2)[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[N:6]=1.[CH:29]([NH2:32])([CH3:31])[CH3:30]>C(#N)C.O>[CH:29]([NH:32][C:22]([C:21]1[C:16]([NH:15][C:14]([C:4]2[N:5]([C:7]3[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=3)[N:6]=[C:2]([Br:1])[CH:3]=2)=[O:23])=[C:17]([CH3:28])[CH:18]=[C:19]2[C:20]=1[NH:25][N:26]=[CH:27]2)=[O:24])([CH3:31])[CH3:30]
Reactant: CC(C)N
Reactant: Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Solvent: CC#N
Solvent: O
Product: Cc1cc2cn[nH]c2c(C(=O)NC(C)C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a suspension of 600 mg of the above 7-[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazol-3-yl]-5-methyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 10 mL of acetonitrile/water (4:1, v/v) is added 1.11 mL (13.1 mmol) of isopropylamine. The reaction mixture is stirred for 9 hours at ambient temperature and then concentrated in vacuo. The residue is taken-up with brine and ethyl acetate. The phases are separated and the aqueous layer is washed with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexane/ethyl acetate 1:2) affords 110 mg (16% over two steps) of the product as a white solid; LC/MS:518/520 (M+H)+, m.p.: 163-166° C.
Reaction SMILES: [CH3:1][C:2]1([O:5][CH2:4]1)[CH3:3].[CH2:6]([N:9]1[C:17]2[C:12](=[N:13][C:14]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH:29]=[C:28]5[CH2:30][NH:31][CH2:32][C:27]5=[N:26]4)=[CH:21][CH:20]=3)=[C:15]([Cl:18])[CH:16]=2)[N:11]=[C:10]1[O:33][C@H:34]1[C@H:38]2[O:39][CH2:40][C@@H:41]([OH:42])[C@H:37]2[O:36][CH2:35]1)[CH:7]=[CH2:8].[NH4+].[OH-].CO.C(Cl)Cl>O1CCOCC1.CO.C(Cl)Cl>[CH2:6]([N:9]1[C:17]2[C:12](=[N:13][C:14]([C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH:29]=[C:28]5[CH2:30][N:31]([CH2:1][C:2]([OH:5])([CH3:4])[CH3:3])[CH2:32][C:27]5=[N:26]4)=[CH:23][CH:24]=3)=[C:15]([Cl:18])[CH:16]=2)[N:11]=[C:10]1[O:33][C@H:34]1[C@H:38]2[O:39][CH2:40][C@@H:41]([OH:42])[C@H:37]2[O:36][CH2:35]1)[CH:7]=[CH2:8]
Reactant: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-n4cc5c(n4)CNC5)cc3)c(Cl)cc21
Reactant: CC1(C)CO1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-n4cc5c(n4)CN(CC(C)(C)O)C5)cc3)c(Cl)cc21
Temperature: 80 °C
Reaction time: 72 h

Procedure:
Isobutylene oxide (17 μl, 0.191 mmol) was added to a stirred solution of (3R,3aR,6R,6aR)-6-[1-allyl-6-chloro-5-[4-(5,6-dihydro-4H-pyrrolo[3,4-c]pyrazol-2-yl)phenyl]imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (83.4 mg, 0.160 mmol) in dioxane (0.64 ml). The reaction mixture was a pale yellow solution that was heated to 80° C. After 3 days, additional isobutylene oxide (8 μl, 0.090 mmol) was added. After stirring an additional 16 h, the reaction mixture was cooled to room temperature. The reaction mixture was then diluted with MeOH/DCM and loaded onto two 500 micron 20 cm×20 cm silica gel plates, which were developed twice using 10% (10% NH4OH/MeOH)/DCM. The silica containing the product band was collected and eluted with 10% (10% NH4OH/MeOH)/DCM (80 ml). The solvent was evaporated under reduced pressure to give the desired product as a yellow residue. LC-MS: calculated for C30H33ClN6O5 592.22 observed m/e: 593.25 (M+H)+ (Rt 1.00/2 min)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([CH2:16][CH2:17][C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[NH:14][C:13]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].O>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([CH2:16][CH2:17][C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[N:14]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:13]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1CCc1ccco1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@H]1CCc1ccco1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.8 %

Procedure:
Triton B (1.94 mL, 4.3 mmols) was added dropwise to a stirred, cooled (-30° C.) solution of (3S,4R)-3-benzyloxycarbonylamino-4-[2-(2-furyl)ethyl]azetidin-2-one (1.35 g, 4.3 mmols) in N,N-dimethylformamide (15 mL). Stirring was continued for 0.25 hr. at -30° C. The mixture was allowed to warm to 0° C. during about 0.25 hr and then was recooled to -30° C. when a solution of t-butyl bromoacetate (0.764 mL, 4.73 mmols) in DMF (3 mL) was added dropwise. Stirring was continued at -30° C. for 0.25 hr., 1 hr at 0° C. and then for 2 hr at ambient temperatures, when additional t-butyl bromoacetate (0.3 mL) was added. The mixture was stirred for an additional 1 hr and was poured into H2O. The mixture was extracted twice with ethyl acetate. The extracts were washed twice with H2O, followed by saturated NaCl and then dried over MgSO4. The ethyl acetate was removed and the residue flash chromatographed on SiO2 (40 g) with methylene chloride-methanol (98:2) to afford 1.47 g (80% yield) of the title compound as a viscous oil which crystallized. Recrystallization from ethyl acetate-hexanes afforded colorless crystals, mp 82°-84° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22]([O:24]C)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[OH-].[Na+].Cl>CO.O1CCCC1>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22]([OH:24])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: COC(=O)c1cccc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
Methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate (from step 3) (10.0 g, 21.539 mmol) was dissolved in methanol (36 mL) and tetrahydrofuran (14 mL). 4N NaOH (13.5 mL, 53.847 mmol) was added. The resulting mixture was stirred for 1.5 hours at room temperature. The reaction was acidified (pH 2) with 4N HCl. The precipitate was collected by filtration to afford an off white solid (7.83 g, 81%) 1H NMR (400 MHz, DMSO-d6) δ 8.01 (dt, J=1.41, 7.65 Hz, 1H), 7.76 (app t, J=1.78 Hz, 1H), 7.76-7.15 (m, 5H), 6.66 (s, 1H), 5.32 (s, 2H), 1.92 (s, 3H) ES-HRMS m/z 450.0134 (M+H C20H14BrF2NO4 requires 450.0147).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH:17][C:16]2=[O:24])=[C:12]2[C:8]([C:9]([CH3:27])=[C:10]([CH3:26])[N:11]2[CH3:25])=[CH:7][CH:6]=1)=[O:4].[CH3:28][O:29][C:30](=[O:33])[CH:31]=[CH2:32].[OH-].[CH2:35]([N+](C)(C)C)C1C=CC=CC=1.O>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:13]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([CH2:32][CH2:31][C:30]([O:29][CH2:28][CH3:35])=[O:33])[C:16]2=[O:24])=[C:12]2[C:8]([C:9]([CH3:27])=[C:10]([CH3:26])[N:11]2[CH3:25])=[CH:7][CH:6]=1)=[O:4]
Reactant: C=CC(=O)OC
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: COC(=O)c1ccc2c(C)c(C)n(C)c2c1Cn1c(=O)[nH]c2ccccc21
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1c(=O)n(Cc2c(C(=O)OC)ccc3c(C)c(C)n(C)c23)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
To a stirred solution of 1,2,3-Trimethyl-7-(2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1H-indole-6-carboxylic acid methyl ester (70 mg, 0.19 mmol) in DMF (10 mL) was added the methylacrylate (0.035 mL, 0.39 mmol) followed by the benzyltrimethylammonium hydroxide (40% in MeOH) (0.13 mL, 0.29 mmol). The resulting solution was stirred at ambient temperature for 2 h after which time the reaction appeared complete. The reaction was poured into water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (2×). The combined organics were dried with MgSO4 and was filtered, concentrated. The residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the product 7-[3-(2-Ethoxycarbonyl-ethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl]-1,2,3-trimethyl-1H-indole-6-carboxylic acid methyl ester (66 mg, 76%) as a colorless oil.
Reaction SMILES: [I-].Cl[C:3]1[CH:8]=[CH:7]C=C[N+:4]=1C.C(N(CC)CC)C.C(N)CC.[C:21]([NH:24][CH2:25][CH2:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[CH:29]=[C:28]1[C:38]([OH:40])=O)(=[O:23])[CH3:22]>ClCCl>[C:21]([NH:24][CH2:25][CH2:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[CH:29]=[C:28]1[C:38]([NH:4][CH2:3][CH2:8][CH3:7])=[O:40])(=[O:23])[CH3:22]
Reactant: COc1ccc2cc(C(=O)O)n(CCNC(C)=O)c2c1
Reactant: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1cc2ccc(OC)cc2n1CCNC(C)=O

Procedure:
Under nitrogen, add 0.18 g of 2-chloro-1-methylpyridinium iodide, 0.25 ml of triethylamine and 0.06 ml of propylamine in dichloromethane to a solution of 0.20 g of the compound obtained in Step C of Example 1 in 20 ml of dichloromethane and then heat at reflux for 14 hours. Dilute the reaction mixture with dichloromethane and wash with saturated aqueous sodium chloride solution. Extract and dry the organic phase over sodium sulfate and then filter and evaporate. Purify the compound by column chromatography on silica gel using as eluant a 19/1 dichloromethane/ethanol mixture. After triturating in diisopropyl ether, the title compound is obtained in the form of a white solid.