Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][NH:9][C:10]([CH2:12][CH2:13][C:14]1[CH:44]=[CH:43][C:17]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([NH:32][S:33]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1)=[O:11])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][NH:9][C:10]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH:26]([NH:32][S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=3)(=[O:35])=[O:34])[C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[CH:23][CH:24]=2)=[CH:43][CH:44]=1)=[O:11]
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)NC(Cc2ccc(Oc3ccc(CCC(=O)NOCc4ccccc4)cc3)cc2)C(=O)N(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(Cc2ccc(Oc3ccc(CCC(=O)NO)cc3)cc2)C(=O)N(C)C)cc1
Yield: 58.6 %

Procedure:
Palladium on BaSO4 (5%, 0.5 g) was added to a degassed solution of the benzyl hydroxamate 26 (0.8 g) in MeOH (50 mL) and the suspension was treated with hydrogen at atmospheric pressure for 4 h. The suspension was filtered over a Celite® bed and concentrated to yield the desired hydroxamate 27 (0.4 g, 59%). 1H NMR (400 MHz, DMSO-d6): 10.36 (s, 1H), 8.70 (br, 1H), 8.05 (d, J=9.2 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.29 (d, J=7.6 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H), 4.29 (m, 1H), 2.73-2.80 (m, 3H), 2.67 (s, 3H), 2.59 (dd, J=13.2 and 7.6 Hz, 1H), 2.99 (s, 3H), 2.24 (t, J=8.0 Hz, 2H). LCMS (m/e): Obsd. 511, Calcd. 510.6
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9][C:10](=[CH2:12])[CH3:11]>C1(C)C(C)=CC=CC=1>[C:10]([C:5]1[CH:6]=[CH:7][C:8]([C:10]([CH3:12])([CH3:11])[CH3:9])=[C:1]([OH:2])[C:3]=1[OH:4])([CH3:11])([CH3:9])[CH3:12]
Reactant: C=C(C)C
Reactant: Oc1ccccc1O
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1ccc(C(C)(C)C)c(O)c1O

Procedure:
A mixture of freshly distilled TiCl4 (11 g, 58 mmol) and pyrocatechol (13.7 g, 0.124 mol) was refluxed in 80 mL of xylene during 20 hours. The resulting dark-brown solid was filtered, washed by xylene and dried under vacuum. Titanium catecholate (10.24 g, 66%) was isolated. This salt (2.3 g, 8.7 mmol), pyrocatechol (82.5 g, 0.749 mol), xylene (80 mL) and isobutylene (150 mL) were heated in autoclave during 1.5 hours at 140° C. The solvent was removed and the residue was distilled under vacuum (b.p. −140-145° C., ˜1 mm Hg; m.p. 96-96.5° C.). Yield: 157.4 g (95%). (Also see “Organic Chemistry of Free Radicals”, Moscow, Khimia, 1979, p. 134.)
Reaction SMILES: [CH2:1]([O:43][CH:44]1[C@H:48]2[C@H:49](O[Si](C(C)(C)C)(C)C)[N:50](C(OCC(Cl)(Cl)Cl)=O)[C:51]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:52]=3[C:53](=[O:54])[N:47]2[CH:46]=[C:45]1[C:77]1[S:78][CH:79]=[CH:80][CH:81]=1)[CH2:2][CH2:3][O:4][CH:5]1[C@H:9]2[C@H:10](O[Si](C(C)(C)C)(C)C)[N:11](C(OCC(Cl)(Cl)Cl)=O)[C:12]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:13]=3[C:14](=[O:15])[N:8]2[CH:7]=[C:6]1[C:38]1[S:39][CH:40]=[CH:41][CH:42]=1>C1COCC1>[CH2:3]([O:4][CH:5]1[C@@H:9]2[CH:10]=[N:11][C:12]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:13]=3[C:14](=[O:15])[N:8]2[CH:7]=[C:6]1[C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)[CH2:2][CH2:1][O:43][CH:44]1[C@@H:48]2[CH:49]=[N:50][C:51]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:52]=3[C:53](=[O:54])[N:47]2[CH:46]=[C:45]1[C:77]1[S:78][CH:79]=[CH:80][CH:81]=1
Reactant: COc1ccc2c(c1)C(=O)N1C=C(c3cccs3)C(OCCCOC3C(c4cccs4)=CN4C(=O)c5cc(OC)ccc5N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]34)[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)N2C(=O)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)N1C=C(c3cccs3)C(OCCCOC3C(c4cccs4)=CN4C(=O)c5cc(OC)ccc5N=C[C@@H]34)[C@@H]1C=N2
Yield: 71 %

Procedure:
10% Cd/Pb couple (288 mg, 2.35 mmol, 20 eq) was added to a rapidly stirring mixture of 20 (154 mg, 0.12 mmol), THF (3 mL) and 1 N NH4OAc (3 mL). The reaction mixture was allowed to stir for 3 hours when TLC showed complete consumption of the starting material. The solids were filtered and rinsed with H2O and DCM. The aqueous layer was extracted with DCM (3×15 mL) and the organic extracts were combined, washed with brine (40 mL) and dried (MgSO4). Filtration and evaporation of solvent afforded the crude product which was purified by flash column chromatography (99:1 v/v CHCl3/MeOH then gradient to 98:2 v/v CHCl3/MeOH) to afford 21 as a yellow glass (59 mg, 72%): 1H NMR (400 MHz, CDCl3) δ 7.90 (d, 2H, J=4.0 Hz, H11), 7.51 (s, 2H, H6), 7.36 (s, 2H, H3), 7.22 (d, 2H, J=5.2 Hz, Harom), 7.02 (dd, 2H, J=3.6, 5.0 Hz, Harom), 6.98 (d, 2H, J=3.4 Hz, Harom), 6.88 (s, 2H, H9), 4.43-4.23 (m, 6H, H11a and OCH2CH2CH2O), 3.94 (s, 6H, OCH3×2), 3.59 (ddd, 2H, J=2.0, 11.5, 16.0 Hz, H1), 2.85 (ddd, 2H, J=1.5, 5.2, 16.0 Hz, H1), 2.49-2.40 (m, 2H, OCH2CH2CH2O).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.[CH2:18]([NH2:23])[CH2:19][CH:20]([CH3:22])[CH3:21].[BH4-].[Na+]>CO>[CH3:21][CH:20]([CH3:22])[CH2:19][CH2:18][NH:23][CH2:1][C:3]1[O:7][C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH2:15])=[O:14])=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)o2)cc1
Reactant: CC(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCc1ccc(Oc2ccc(C(N)=O)cc2)o1
Yield: 67.8 %

Procedure:
Combine 4-(5-Formyl-furan-2-yloxy)-benzamide (0.18 g, 0.78 mmol), isoamylamine (0.10 g, 0.1.17 mmol), 3 Å molecular sieves (2 g) in methanol (30 mL), agitate 18 hours at ambient temperature. Add sodium borohydride (0.058 g, 1.52 mmol), agitate 20 hours at ambient temperature. Filter through Celite, then concentrate in vacuo. Partition the residue between water (50 mL), and ethyl acetate (150 mL). Drain the organic layer, and dry over sodium sulfate. Purify via ISCO™ 100 c (40 g silica) using a gradient of 95:5:0.5 to 90:10:1 chloroform/ethanol/ammonium hydroxide to afford the title compound (0.160 g, 68%): mass spectrum (ion spray): m/z=303.18 (M+1); HPLC retention time: 5.79 min (HPLC method in this experiment: 5:95-95:5 ACN/0.1% TFA in water over 10 minutes using a 15 cm Zorbax column, running at 1 mL/minute, ultraviolet detector set at 254 nM).
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[CH2:4][C:5]([O:7][CH2:8][O:9][C:10](=[O:17])[CH2:11][CH:12](OC)[O:13][CH3:14])=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:14][O:13][CH:12]=[CH:11][C:10]([O:9][CH2:8][O:7][C:5](=[O:6])[CH:4]=[CH:3][O:2][CH3:1])=[O:17]
Reactant: COC(CC(=O)OCOC(=O)CC(OC)OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC=CC(=O)OCOC(=O)C=COC
Yield: 78.8 %

Procedure:
Methylene bis(3,3-dimethoxypropionate) (14.01 g, 50 mmol) prepared as described in Example 19 and a catalytic amount of p-toluene sulfonic acid is added to toluene (250 ml). The methanol is removed by warming the reaction under an N2 atmosphere. When the reaction is complete the toluene is distilled off under reduced pressure. Diethyl ether (250 ml) is added and the mixture is washed with saturated aqueous sodium hydrogen carbonate (5×50 ml) and water (3×50 ml). The organic layer is dried (MgSO4) before evaporation to give 8.52 g (79%) product. 1H NMR (300 MHz, CDCl3): δ 3.65 (2×CH3, s), 5.2 (2×CH, d), 5.8 (O--CH2 --O), 7.65 (2×CH2, d).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH:4]([OH:6])[CH3:5].[CH:7](=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:8]([CH:7]1[S:1][CH2:2][CH2:3][CH:4]([CH3:5])[O:6]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(O)CCS
Reactant: CCCCCCCCCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCCC1OC(C)CCS1

Procedure:
75 ml of dichloromethane is placed in a 100 ml round-bottom flask. To the dichloromethane is added 5.3 grams (0.05 moles) of 4-mercapto-2-butanol. 8.58 grams (0.055 moles) n-decanal is then added followed by 0.1 grams of p-toluene sulfonic acid. Boiling chips are added to the flask. A Dean-Starke distilling receiver is placed on the flask, and a reflux condenser is placed on the receiver. The flask is then heated slowly until reflux occurs, and then the temperature is increased for a more vigorous reflux. The reflux lasts for a period of 2 hours before water of reaction ceases to be formed. The reaction mass is then cooled and neutralized with 10% aqueous sodium bicarbonate to a pH of 8. The reaction mass is filtered through fluted filter paper, and the dichloromethane solvent is removed by means of rotary evaporation. 11.8 grams of crude product are recovered after the rotary evaporation operation. The crude product is then distilled by means of vacuum distillation yielding the following 4 fractions:
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:5][C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)([C:6]([O:8]C)=[O:7])[CH2:3]1.[OH-].[Na+]>CO.O.C1COCC1>[F:17][C:2]1([F:1])[CH2:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)([C:6]([OH:8])=[O:7])[CH2:5]1
Reactant: COC(=O)C1(c2ccc(F)cc2)CC(F)(F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1(c2ccc(F)cc2)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.3 %

Procedure:
To a stirred solution of Intermediate 308D (400 mg, 1.638 mmol) in MeOH (5 mL), water (2 mL) and THF (2 mL) was added NaOH (197 mg, 4.91 mmol) and stirred for 12 h at RT. The reaction mixture was concentrated under vacuo and the pH of the residue was adjusted to 2.0 using 1.5 N HCl and the compound was extracted with ethyl acetate (3×10 mL) The combined organic layer was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to afford Intermediate 308E as a pale yellow solid (250 mg, 66%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.03 (bs, 1H), 7.33-7.43 (m, 2H), 7.21 (m, 2H), 3.32-3.37 (m, 2H), 2.99-3.15 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:14][C:13](=O)[C:12]3[CH:11]=[C:10]([CH3:16])[S:9][C:8]=3[NH:7][C:6]=2[CH:17]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:27]2)=CC=1>ClCCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:14][C:13](=[S:27])[C:12]3[CH:11]=[C:10]([CH3:16])[S:9][C:8]=3[NH:7][C:6]=2[CH:17]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc2c(s1)Nc1cc(F)ccc1NC2=O
Solvent: ClCCCl
Product: Cc1cc2c(s1)Nc1cc(F)ccc1NC2=S
Temperature: 81.5 °C

Procedure:
Add 6-fluoro-2-methyl-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulen-10-one (65.2 g, 0.263 mol) and 2,4-Bis-(4-methoxy-phenyl)-[1,3,2,4]dithiadiphosphetane 2,4-disulfide (Lawesson's Reagent, 63.7 g, 0.157 mol) to 1,2-dichloroethane (DCE, 3500 mL) with stirring. Heat to gentle reflux (80-83° C.) for 30 minutes, and then allow cooling to ambient temperature. Filter the product and rinse with DCE. Dry at 50-60° C. to give 61.9 (89%) the title compound: 1H NMR (400 MHz, DMSO-d6) δ 10.98 (bs, 1H), 8.87 (bs, 1H), 7.00 (m, 1H), 6.88 (s, 1H), 6.78(m, 1H), 6.56 (m, 1H), 2.22 (s, 3H). HRMS (ES) exact mass M+H calcd for C12H9FN2S2 265.0269; found 265.0276.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[C:12](=[O:15])[CH:11]=[C:10]([C:16]([O:18]C)=[O:17])[NH:9][C:8]=3[C:7](=[O:20])[C:6]=2[CH:21]=1>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[C:12](=[O:15])[CH:11]=[C:10]([C:16]([OH:18])=[O:17])[NH:9][C:8]=3[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: COC(=O)c1cc(=O)c2oc3ccc(Cl)cc3c(=O)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(=O)c2oc3ccc(Cl)cc3c(=O)c2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.2 %

Procedure:
A suspension of methyl 8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-2-carboxylate (1 g, 0.0034 mole) in 1N sodium hydroxide solution (20 ml) was stirred at room temperature for 24 hrs. The solid was filtered off, washed with water, with acetone, and suspended in 5N hydrochloric acid. The product was filtered off, washed with water, with acetone, and sucked dry. Recrystallization from DMF gave white crystals (0.775 g, 81%), m.p. 290°-320° (dec.).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([C:10]1([C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH2:11]1)=[C:8]=O>C1COCC1>[CH3:8][NH:7][C:10]1([C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)[CH2:19][CH2:18][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:12][CH2:11]1
Reactant: O=C=NC1(c2ccsc2)CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC1(c2ccsc2)CCC2(CC1)OCCO2
Reaction time: 1.5 h
Yield: 43.7 %

Procedure:
Lithium aluminium hydride (1.7 g) was added batchwise to 8-isocyanato-8-thiophen-3-yl-1,4-dioxa-spiro[4.5]decane (6 g; 22.6 mmole) dissolved in dry THF (70 ml) at 0 to 5° C. The reaction mixture was stirred for about 1.5 hours under reflux. On completion of the reaction (reaction monitored by thin layer chromatography), excess lithium aluminium hydride was destroyed with saturated aqueous sodium sulfate solution (20 ml). The resultant precipitate was filtered out over Celite. The filtrate was concentrated and extracted with ethyl acetate (3×100 ml). The organic phase was separated, dried (sodium sulfate) and concentrated under vacuum. Purification by column chromatography (silica gel, 50% ethyl acetate in n-hexane) yielded 2.5 g methyl-(8-thiophen-3-yl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine (43%; white low-melting solid).
Reaction SMILES: Br[C:2]1[C:3]([CH3:36])=[C:4]([NH:8][C:9]([C:11]2[C:19]3[N:18]=[C:17]([CH2:20][O:21][CH3:22])[NH:16][C:15]=3[CH:14]=[C:13]([NH:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[O:25])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:37][N:38](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:37]([C:2]1[C:3]([CH3:36])=[C:4]([NH:8][C:9]([C:11]2[C:19]3[N:18]=[C:17]([CH2:20][O:21][CH3:22])[NH:16][C:15]=3[CH:14]=[C:13]([NH:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:34])([F:33])[F:35])=[O:25])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1)#[N:38]
Reactant: COCc1nc2c(C(=O)Nc3cccc(Br)c3C)cc(NC(=O)c3ccccc3C(F)(F)F)cc2[nH]1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: COCc1nc2c(C(=O)Nc3cccc(C#N)c3C)cc(NC(=O)c3ccccc3C(F)(F)F)cc2[nH]1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a solution of N-(3-bromo-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (Example 38) (85 mg) in DMF (0.5 mL), was added zinc cyanide (60% content, 60 mg). After degassing, to the mixture was added tetrakis(triphenylphosphine) palladium (88 mg), and it was stirred at 100° C. for 24 hours. To the reaction mixture was added ice water, and it was extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified on preparative thin-layer chromatography to obtain the titled compound (14 mg) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][N:10]([S:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:19])=[O:18])[C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2[nH]ccc2n1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)n1ccc2nc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a suspension of 5-chloro-1H-pyrrolo[3,2-b]pyridine (5.0 g, 33 mmol, Adesis) in DCM (42 mL) was added benzenesulfonyl chloride (5.4 mL, 43 mmol, Aldrich), triethylamine (7.3 mL, 52 mmol) and 4-dimethylaminopyridine (0.40 g, 3.3 mmol). After stirring at room temperature for 1 hour, the mixture was diluted with EtOAc, washed with water (2×), brine, dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-20% EtOAc in hexanes to afford product as a white solid (8.7 g, 90%).
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][CH:7]1[CH2:8][CH2:9][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)C1CCC(=O)CC1
Reactant: NCc1ccccc1
Product: CC(C)C1CCC(NCc2ccccc2)CC1

Procedure:
Using the procedure outlined in Example 1, 4-isopropylcyclohexanone and benzylamine were converted to the title compound: RT=2.52 min; m/z (ES+)=232.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][O:25]2)[N:3]=1
Reactant: N#Cc1ccc2[nH]nc(Br)c2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Yield: 76.1 %

Procedure:
To a solution of 13.67 g (61.56 mmol) of 3-bromo-1H-indazole-5-carbonitrile and 2.06 g (10.8 mmol, 0.175 equiv.) of p-toluenesulfonic acid monohydrate in 247 mL of anhydrous tetrahydrofuran (THF) was added 11.2 mL (123 mmol, 2.00 equiv.) of 3,4-dihydro-2H-pyran. The mixture was refluxed under a nitrogen atmosphere for 14 h. The reaction was quenched with saturated aqueous sodium bicarbonate (sat. aq. NaHCO3). The mixture was extracted twice with EtOAc. The combined organics were washed with 2×sat. aq. NaHCO3, 1×sat. aq. NaCl, and dried over Na2SO4. Chromatography of the crude material on 200 g of silica gel using 30% EtOAc in hexanes afforded the title compound (14.34 g, 76% yield): ES-MS (m/z) 306 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.Cl.[Br:13][C:14]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:15]=1[O:16][CH:17]1[CH2:20][NH:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Br:13][C:14]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:15]=1[O:16][CH:17]1[CH2:20][N:19]([C:2]2[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=2)[CH2:18]1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Fc1ccc(Br)c(OC2CNC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CC(Oc3cc(F)ccc3Br)C2)cn1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a mixture of methyl 5-chloropyrazine-2-carboxylate (0.47 g, 2.7 mmol), 3-(2-bromo-5-fluorophenoxy)azetidine hydrochloride salt (0.80 g, 3.2 mmol) and potassium carbonate (0.75 g, 5.42 mmol) in dioxane (13 mL) was heated at 100° C. After a period of 4 h, the reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic phase was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The resulting solid was taken in ether and filtered to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]([C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][CH:29]=2)=[O:23])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][S-:32].[Na+]>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]([C:24]2[CH:25]=[N:26][C:27]([S:32][CH3:31])=[CH:28][CH:29]=2)=[O:23])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[S-]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccc(Cl)nc2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1
Temperature: 70 °C

Procedure:
4-tert-Butyl-N-[4-chloro-2-(6-chloro-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide (231 mg, 0.5 mmol) was dissolved in dry THF (5 mL) and treated with sodium thiomethoxide (175 mg, 2.5 mmol) and the mixture was heated at 70° C. for 4 h. The solvent was evaporated and the residue suspended in water (5 mL) and the product was precipitated by the drop wise addition of 3M HCl and purified by HPLC. 1H-NMR (400 MHz, CDCl3): δ 1.19 (s, 9H), 2.60 (s, 3H), 7.21-7.28 (m, 3H), 7.31 (m,1H), 7.50-7.54 (m, 3H), 7.65 (dd, 1H, J=8.4 Hz, 2.4 Hz), 7.78 (d, 1H, J=8.8 Hz), 8.19 (m, 1H), 9.62 (s, 1H). MS: m/z 476.0 (M++1).
Reaction SMILES: [N:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]2=[O:16])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[N:18]1[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=1.O.C(Cl)(Cl)Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1.[OH-].[Na+]>[N:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:24][C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)([CH2:24][C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[C:8]2=[O:16])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: ClCc1ccncc1
Reactant: O=C1Cc2ccccc2N1N1CCOCC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1N(N2CCOCC2)c2ccccc2C1(Cc1ccncc1)Cc1ccncc1
Temperature: 70 °C
Yield: 87.9 %

Procedure:
A mixture of 1,3-dihydro-1-(4-morpholinyl)-2H-indol-2-one (0.5g, 2.3 mmole), 4-picolyl chloride hydrochloride (0.83 g, 5.0 mmole), benzyltriethylammonium chloride (0.053 g, 0.23 mmole) in toluene (5 ml) and 50% sodium hydroxide solution (3.6 ml) were heated at 70° C. for three hours. The reaction was cooled to room temperature and poured into water/chloroform (30 ml each). The layers were separated and the aqueous layer extracted with additional chloroform (3×20 ml). The combined organic layers were washed with water (50 ml), brine (50 ml), dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The residue was chromatographed on silica gel using methanol/chloroform (7%), and recrystallized from chloroform/hexane to afford 0.81 g (88%) of the desired product as a solid, m.p. 200°-203° C.; IR (KBr): 1711 cm-1 ; 1H NMR (CDCl3, TMS) : δ8.26 (dd, J=4.4, 1.5 Hz, 2H), 7.37 (m, 1H), dd, J=7.7, 1.4 Hz, 2H), 6.80 (dd, J=4.4, 1.5 Hz, 4H), 6.61 (dd, J=7.7, 1.1 Hz, 1H), 3.77 (dd, J=5.5, 1.1 Hz, 2H), 3.59 (m, 2H), 3.43 (dd, J=11.4 Hz, 1.5 Hz, 2H), 3.37 (d, J=12.8 Hz, 2H), 3.14 (d, J=12.8 Hz,2H), 2.01 (br.d, J=10.2 Hz, 2H); mass spec. m/e 401 (M+H, 100%); Anal. (C24H24N4O2): C,H,N.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18][CH3:19])=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>CO>[C:20]([NH:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18][CH3:19])=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:3]1)(=[O:22])[CH3:21]
Reactant: COC(=O)[C@@H]1[C@@H]2C[C@@H](N)[C@@H](C2)N1C(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: COC(=O)[C@@H]1[C@H]2C[C@H]([C@H](NC(C)=O)C2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 166.7 %

Procedure:
To a solution of 2-tert-butyl 3-methyl (1R,3S,4R,6R)-6-amino-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate obtained in Example 29-3 (155 mg) in methanol (10 mL), was added acetic anhydride (30 mg). The mixture was stirred at room temperature for 1 hr. The resulting mixture was evaporated in vacuo and chromatographed on silica gel eluting with chloroform and methanol (19:1) to give the target compound (153 mg).