Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([C:28]([NH:30][CH3:31])=[O:29])[C:13](=[O:27])[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[C:15]=2[CH3:16])=[CH:4][CH:3]=1.C(O)=[O:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:10]2[CH:11]=[C:12]([C:28]([NH:30][CH3:31])=[O:29])[C:13](=[O:27])[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[C:15]=2[CH3:16])=[O:33])=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: CNC(=O)c1cc(C#Cc2ccc(Cl)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Product: CNC(=O)c1cc(C(=O)Cc2ccc(Cl)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 120 °C
Yield: 66 %

Procedure:
5-[(4-Chlorophenyl)ethynyl]-N,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (111 mg, 0.25 mmol) was mixed with formic acid (1 ml) and heated in a microwave oven to 120° C. for 1 h. The formic acid was evaporated off and the residue was purified on an Xterra C8 column using a gradient of acetonitrile/water. Freeze drying of the mixture afforded 5-[(4-chlorophenyl)acetyl]-N,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (77 mg, 66%).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[N:30]=[CH:31][C:24]=12>C1COCC1.C(OCC)(=O)C>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[N:29]1[C:25]2=[N:26][CH:27]=[N:28][C:23]([O:3][C@@H:4]([CH2:15][O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:5]([NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])=[C:24]2[CH:31]=[N:30]1
Reactant: COC[C@H](C)OC[C@H](O)C(=O)Nc1cnc(C)cn1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC[C@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1cnc(C)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.6 %

Procedure:
Sodium hydride (23.17 mg, 0.58 mmol) was added in one portion to a stirred solution of (S)-2-hydroxy-3-((S)-1-methoxypropan-2-yloxy)-N-(5-methylpyrazin-2-yl)propanamide (Intermediate Y3) (78 mg, 0.29 mmol) in anhydrous THF (5 mL) at 0° C. The resulting mixture was stirred for 10 minutes and then a solution of 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (115 mg, 0.43 mmol) in dry THF (2 mL) added dropwise over 1 minute and the reaction was allowed to warm up to ambient temperature and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), and washed sequentially with water (10 mL) and saturated brine (5 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0-100% ethyl acetate in isohexane to afford the product (115 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 1.20 (d, 3H), 2.53 (s, 3H), 3.35-3.50 (m, 5H), 3.79-3.88 (m, 1H), 4.08-4.16 (m, 1H), 4.21-4.28 (m, 1H), 5.94-5.99 (m, 1H), 7.43-7.55 (m, 3H), 7.60-7.63 (m, 1H), 8.12-8.13 (m, 1H), 8.40 (s, 1H), 8.58 (s, 1H), 9.18 (s, 1H), 9.42 (d, 1H). m/z (ESI+) (M+H)+=498.36; HPLC tR=2.25 min.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)=[O:25]>CS(C)=O>[CH3:33][O:32][C:28]1[CH:27]=[C:26]([C:24](=[O:25])[CH2:23][O:1][C:2]2[CH:15]=[CH:14][C:5]([CH2:6][CH:7]3[S:11][C:10](=[O:12])[NH:9][C:8]3=[O:13])=[CH:4][CH:3]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Reactant: COc1cccc(C(=O)CBr)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cccc(C(=O)COc2ccc(CC3SC(=O)NC3=O)cc2)c1
Reaction time: 1 h
Yield: 47.1 %

Procedure:
To a stirring solution of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione (100 mg, 0.4 mmol) in DMSO (2 ml), potassium tert-butoxide (106 mg, 0.941 mmol) was added. Stirring continued at RT for about 1 hour. 2-Bromo-3′-methoxyacetophenone (100 mg, 0.5 mmol) was then added to the mixture. After 2 hours, LCMS showed that the reaction was complete. The reaction mixture was partitioned between EtOAc and water, and the aqueous phase was extracted with EtOAc. Combined extracts were washed with brine, dried on (Na2SO4), filtered, and evaporated in vacuo. The residue was chromatographed on a small RediSep column eluting with 0-10% acetone/DCM. Fractions containing the product were combined and evaporated in vacuo to afford 70 mg of 5-{4-[2-(3-methoxyphenyl)-2-oxoethoxy]benzyl}-1,3-thiazolidine-2,4-dione as a pale yellow solid. 1H-NMR (DMSO-d6): δ 12.49 (brs, 1H), 7.72(s, 1H), 7.59(m, 1H), 7.53-7.46(m, 4H), 7.24(dd, J=8.2, 2.4 Hz, 1H), 7.10(d, J=8.7 Hz, 2H), 5.66(s, 2H), (3.80(s, 3H). HPLC: 3.969 min., 61 area % @2540 nm; 3.969 min., 62 area % @210 nm. MS (ESI−) for C19H15NO5S m/z 368.4 (M−H)−.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:28])[CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1>CCCCCC.C1(C)C=CC=CC=1>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)([OH:28])[CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:19]=1
Reactant: Brc1ccccn1
Reactant: Cc1ccc(C(=O)CCN2CCCC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(O)(CCN2CCCC2)c2ccccn2)cc1
Temperature: -40 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
400 ml of toluene is charged into a round-bottom flask, which is cooled to −40° C. and then solution of n-butyllithium (76.6 g) in hexane is added and the temperature of the reaction mixture is maintained at −40° to −50° C. 2-Bromopyridine (189.2 g) is then added to the reaction mixture and the temperature is maintained at −65° to −55° C. for 35 to 45 minutes. 200 g of 4′-methyl-3-pyrrolidinopropiophenone in 200 ml of toluene is added to the reaction mixture in the R.B. flask. The reaction mass is stirred at −65° to −55° C. for 2 hours and it is further stirred for 1 hour at −40° to −50° C. The reaction mass is quenched in ice water and HCl is added slowly at 10° to 20° C. to get a clear solution. The aqueous layer is separated and it is added slowly to NaOH in the R.B. flask at 15° C.-20° C. The reaction mass is stirred for half an hour and the precipitated solid is filtered off. The solid is transferred into a round-bottom flask and then 500 ml of methanol is added. The reaction mass is refluxed at 60° C. for half an hour and the mass is cooled to 10°-20° C. The solid mass is filtered and dried under suction for one hour. On drying the solid compound at 70°-80° C. for 4 hours, 1-(4-methylphenyl)-1-(2-pyridyl)-3-pyrrolidinopropan-1-ol (220 g, 80.5% yield) with 99.3% HPLC purity is obtained whose melting point is in the range of 115°-119° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH:34]1[C:43]2[C:38](=[CH:39][C:40]([NH2:44])=[CH:41][CH:42]=2)[CH:37]=[CH:36][N:35]=1>CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:44][C:40]4[CH:39]=[C:38]5[C:43](=[CH:42][CH:41]=4)[CH:34]=[N:35][CH:36]=[CH:37]5)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:33]
Reactant: Nc1ccc2cnccc2c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Solvent: CC(C)O
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4cnccc4c3)n2)c1)c1c(F)cccc1F

Procedure:
A mixture of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 6-isoquinolinamine and 6-isoquinolinamine in i-PrOH was heated in a microwave in a procedure analogous to that described in Example 64 to give, after purification, the title compound. LC MS (ES)+ 570.25. 1H NMR (400 MHz, DMSO-d6) δ 6.95 (s, 1H), 7.17-7.30 (m, 4H), 7.41 (d, 1H, J=7.5), 7.51-7.56 (m, 3H), 7.64 7.68 (m, 1H), 7.78-7.81 (m, 2H), 8.05 (s, 1H), 8.09 (bs, 2H), 8.19 (d, 1H, J=9.1), 8.41 (d, 1H, J=9.0), 8.85-8.89 (m, 2H), 8.96 (d, 1H, J=6.8), 9.8 (s, 1H), 10.94 (s, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH:15]([C:16]([O:18]CC)=[O:17])C(O)(C)CC(=O)[CH:11]3[C:24]([O:26]CC)=[O:25])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Na+]>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([CH2:11][C:24]([OH:26])=[O:25])[CH2:15][C:16]([OH:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)C1C(=O)CC(C)(O)C(C(=O)OCC)C1c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC(CC(=O)O)c1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
Diethyl 2-(1,3-benzodioxol-5-yl)-4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxylate (19 g) was suspended in ethanol (140 ml) and an aqueous solution of NaOH (50%, 270 ml). The mixture was heated at reflux for one hour. After the mixture was cooled to room temperature, the ethanol was removed under reduced pressure. Then, concentrated HCl was added until pH 1 was achieved while maintaining the temperature below 50° C. The mixture was filtered. The solid was washed with ether. The two layers were separated. The aqueous layer was extracted with ether (3×). The ether layers were combined, dried, and concentrated to give product. 1H NMR (DMSO-d6) δ 12.06 (br s, 2H), 6.88-6.68 (m, 3H), 5.98 (s, 2H), 3.4-3.3 (m, 1H), 2.62-2.42 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][CH:20]([CH3:23])[C:21]#[CH:22]>C(NCC)C.C(Cl)CCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:22]#[C:21][CH:20]([CH3:23])[CH3:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Reactant: C#CC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCCl
Product: CC(C)C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2

Procedure:
3.73 g (10 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to 100° in a pressure tube for 20 hours with 0.87 g of 3-methyl-1-butyne, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 19 mg of copper(I) iodide in 20 ml of diethylamine and 10 ml of ethylene chloride. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there was obtained a mixture of product and starting material of about 2:1. In order to remove the starting material, the mixture was heated under reflux the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there was obtained a mixture of product and starting material of about 2:1. In order to remove the starting material, the mixture was heated under reflux for 5 hours with 0.8 ml of 2-methyl-3-butyn-2-ol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 15 mg of copper(I) iodide in 15 ml of diethylamine. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate the byproduct can be separated from the desired product. After recrystallization from ether there was obtained 7-chloro-4,5-dihydro-5-methyl-3-(3-methyl-1-butynyl)-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 128°-130°.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CO.O.Cl[Pd]Cl>[C:12]1([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccnc(-c2ccccc2)c1
Temperature: 100 °C
Yield: 58.9 %

Procedure:
Methyl 2-chloroisonicotinate (2.5 g, 14.57 mmol), phenylboronic acid (2.66 g, 21.86 mmol), potassium carbonate (3.02 g, 21.86 mmol) and PdCl2 (dppf) (0.316 g, 0.44 mmol) were mixed in methanol (15 mL) in a 20 mL microwave vial. Two drops of water were added and the vial was capped and heated at 100° C. for 10 min in a single node microwave reactor. The solids were removed by filtration and the filtrate partly evaporated to yield a dark red slurry. DCM and water were added and the phases separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield a dark red oil. The compound was purified via Biotage, SNAP 340 g KP-SIL, eluent isocratic heptane/ethyl acetate 9:1 for 2 CV, then linear gradient heptane/ethyl acetate 9:1 to 6:4 over 5 CV to give methyl 2-phenylisonicotinate (1.83 g, 58%) as a colourless oil. 1H NMR (400 MHz, cdcl3) δ 3.98 (s, 3H), 7.39-7.54 (m, 3H), 7.76 (dd, 1H), 8.01-8.09 (m, 2H), 8.29 (s, 1H), 8.82 (d, 1H). MS m/z 214 (M+H)+
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C([NH:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:30]([C:37]([OH:40])([CH3:39])[CH3:38])[N:29]=[C:28]2[CH2:41][CH2:42][CH3:43])=[CH:22][CH:21]=1)=O)(C)(C)C>C(Cl)Cl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:30]([C:37]([OH:40])([CH3:38])[CH3:39])[N:29]=[C:28]2[CH2:41][CH2:42][CH3:43])=[CH:22][CH:21]=1)#[N:11]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)NC(C)(C)C)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 2 h
Yield: 80.9 %

Procedure:
0.345 ml of oxalyl chloride was added dropwise, whilst ice-cooling, to a solution of 1.00 g of ethyl 1-{4-[2-(t-butylaminocarbonyl)phenyl]phenyl }methyl -4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate [prepared as described in step (a) above] in 10 ml of methylene chloride, and the mixture was stirred at the same temperature for 2 hours. At the end of this time, the reaction mixture was diluted with an aqueous solution of sodium hydrogencarbonate and ethyl acetate, and the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 0.69 g of the title compound as crystals.
Reaction SMILES: Br[C:2]1[C:6]2[C:7]([NH2:11])=[N:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[F:12][C:13]1[C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=[C:18]2[C:14]=1[CH2:15][CH2:16][N:17]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(=O)(O)[O-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[NH2:11][C:7]1[C:6]2[C:2]([C:21]3[C:13]([F:12])=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:16][CH2:15]4)=[CH:3][O:4][C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c1ccc(B1OC(C)(C)C(C)(C)O1)c2F
Reactant: Nc1nccc2occ(Br)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c1ccc(-c1coc3ccnc(N)c13)c2F
Temperature: 100 °C
Reaction time: 15 h
Yield: 38.1 %

Procedure:
3-Bromofuro[3,2-c]pyridin-4-amine (310 mg, 1.455 mmol), 1,1-dimethylethyl 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole-1-carboxylate (577 mg, 1.589 mmol), PdCl2(dppf)-CH2Cl2 adduct (65 mg, 0.080 mmol), 1,4-Dioxane (15 mL), and saturated aqueous sodium bicarbonate (4.5 mL, 4.50 mmol) were added to a 200 mL flask equipped with a reflux condenser. The flask was evacuated and filled with nitrogen 4 times, and then the mixture was stirred at 100° C. under Nitrogen for 15 hours. LCMS showed complete and clean conversion, so it was cooled and filtered through celite, rinsing with EtOAc (50 mL). The filtrate was washed with half-saturated aqueous NaHCO3 (50 mL), and the aqueous phase was back-extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine (1×100 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 60 g SiO2, 10%-75% EtOAc in hexanes gradient over 60 minutes) to give 1,1-dimethylethyl 5-(4-aminofuro[3,2-c]pyridin-3-yl)-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate (205 mg, 0.555 mmol, 38.1% yield) as an off-white solid. LC/MS (ES) m/z=370 [M+H]+
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=3)[NH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].I.CS[C:24]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)=[NH:25]>C(O)C.[Pd]>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:24]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[NH:25])[CH:16]=3)[NH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Solvent: CCO
Product: CCN1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reaction time: 4 h
Yield: 65.5 %

Procedure:
A solution of 3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole (60) (0.1 g, 0.368 mmol) in dry ethanol (5 mL) was treated with 10% Pd—C (0.02 g), purged with hydrogen gas and stirred for 4 h under hydrogen atm. (balloon pressure). The solid was filtered off using celite bed and washed with dry ethanol (2×5 mL). The combined ethanol layer was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.21 g, 0.737 mmol) and stirred for 24 h at room temperature. The solvent was evaporated and product was precipitated with ether (100 mL). The solid was filtered and dissolved into sat. NaHCO3 sol.: CH2Cl2 (50 mL, 1:1). The org. layer was separated and aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography (2M NH3 in methanol: CH2Cl2, 5:95) to obtain N-(3-(1-ethylpiperidin-4-yl)-1H-indol-5-yl)thiophene-2-carboximidamide (61) (0.085 g, 66%) as a solid. mp 150-152° C.; 1H NMR (DMSO-d6) δ 1.01 (t, 3H, J=6.9 Hz), 1.59-1.75 (m, 2H), 1.90-2.05 (m, 4H), 2.35 (q, 2H), 2.65-2.73 (m, 1H), 2.94-2.97 (m, 2H), 6.23 (brs, 1H), 6.62 (dd, 1H, J=1.2, 8.4 Hz), 6.97 (s, 1H), 7.02 (d, 1H, J=2.1 Hz), 7.09 (t, 1H, J=4.2 Hz), 7.26 (d, 1H, J=8.4 Hz), 7.58 (d, 1H, J=5.4 Hz), 7.70 (d, 1H, J=3.6 Hz), 10.59 (s, 1H); ESI-MS m/z (%): 353 (M+, 100).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:22][CH2:23][NH2:24])[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.CO>C1(C)C=CC=CC=1.CCCCCCC>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:3])[NH:24][CH2:23][CH2:22]2)[CH2:7][CH2:8]1)(=[O:13])=[O:14]
Reactant: CCOC(=O)C1(CCN)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.4 %

Procedure:
4-(2-Amino-ethyl)-1-(2-chloro-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (7.09 g) was suspended in toluene under an argon atmosphere, dimethylaluminium chloride in heptane (1 molar, 28.39 ml) was added and the mixture was stirred 5 minutes at RT then refluxed for 3 hours. It was then was cooled to RT, MeOH (40 ml) was added and the mixture was stirred for 30 minutes. The solvent was removed, the residue was adsorbed on silica gel and purified by flash chromatography over silica gel (eluents: AcOEt/CH2Cl2 5 to 50% then acetone/CH2Cl2 10 to 30%) to give the desired material (4.5 g) as light yellow solid. MS (ESI): 329.0 (MH+).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11])[CH2:3][CH2:2]1.[ClH:14]>O>[ClH:14].[S:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:3][CH2:2]1
Reactant: COC(=O)CCCN1CCSCC1
Agent: Cl
Solvent: O
Product: O=C(O)CCCN1CCSCC1
Yield: 91 %

Procedure:
A solution of 28.0 g. (0.138 mole) of methyl γ-thiomorpholinobutyrate in 300 ml. of concentrated hydrochloric acid and 250 ml. of water was stirred and heated at reflux for 18 hours. The solvents were removed on a rotary evaporator to give a colorless residue which crystallized upon trituration with acetone. The solid was filtered, washed with acetone, and dried in vacuo to give 28.2 g. (91%) of the desired product as colorless crystals, m.p. 242°-245°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH:12]2[CH2:14][CH2:13]2)=[CH:9][O:10]C)[C:3]=1[CH3:15].S(=O)(=O)(O)O.O.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH:12]2[CH2:14][CH2:13]2)[CH:9]=[O:10])[C:3]=1[CH3:15]
Reactant: COC=C(c1nccc(Cl)c1C)C1CC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cl)ccnc1C(C=O)C1CC1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 67.8 %

Procedure:
To a solution of 4-chloro-2-(1-cyclopropyl-2-methoxyvinyl)-3-methylpyridine (1.7 g, 7.60 mmol) in THF (15 mL) a 2M aqueous solution of sulfuric acid (15.20 mL, 30.4 mmol) was added and the reaction mixture was stirred at 50° C. for a total of 2.5 h. The resulting mixture was poured into water and neutralized with a saturated sodium bicarbonate solution, and thereafter, extracted with chloroform (3×20 mL). The resulting organic layers were washed with saturated salt water (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The resulting yellow solid was purified by silica gel column chromatography (hexane:ethyl acetate) (4:1) to obtain the aldehyde (1.08 g, 67.8%).
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:18])C=1.C([O-])(O)=O.[Na+]>ClC(Cl)C>[O:18]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]1=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1CCCCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C1CCCCCCCO1
Temperature: 80 °C
Reaction time: 18 h
Yield: 73.4 %

Procedure:
43.5 g (345 mmol) of cyclo-octanone is placed in solution in 430 ml of dichloroethane. 170 g (985 mmol) of meta-chloroperbenzoic acid is then added. The medium is heated to 80° C. for 48 hours. At room temperature, 400 ml of a Na2S2O5 and NaHCO3 saturated solution (1/1 v/v) are added. The medium is stirred vigorously for 18 hours. The organic phase is separated and contacted with Kl and H2O for 6 hours. The organic phase is separated and washed with a saturated solution of Na2S2O3, a saturated solution of NaCl then dried on MgSO4, filtered and concentrated under vacuum to give 36 g of the crude product.