Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2Br)=[CH:3][CH:2]=1.[C:16]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=O)([O:18][CH2:19][CH3:20])=[O:17].Cl.C1C[O:32]CC1>CCCCCCC>[C:16]([N:21]1[CH2:26][CH2:25][C:24]([OH:32])([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][C:4]2[CH:5]=[CH:6][C:1]([CH3:15])=[CH:2][CH:3]=2)[CH2:23][CH2:22]1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Cc1ccc(Sc2ccccc2Br)cc1
Reactant: C1CCOC1
Reactant: CCOC(=O)N1CCCCC1=O
Agent: Cl
Solvent: CCCCCCC
Product: CCOC(=O)N1CCC(O)(c2ccccc2Sc2ccc(C)cc2)CC1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
In anhydrous equipment under a nitrogen atmosphere was stirred a mixture of 2-(4-tolylsulfanyl)-phenyl bromide (600 g, 2.15 mol) in heptanes (4.5 L) at room temperature (25° C.). n-Bu-lithium (10 M, 236 mL) solution in heptane was then added by canulation. After stirring at room temperature for 30 minutes the reaction mixture was cooled to −50° C. before a solution of carbetoxypiperidone in THF (1.5 L) was added dropwise while maintaining the temperature under −40° C. Once the addition was completed, reaction was allowed to warm to 0° C. before dilute HCl (1 L) was added maintaining the temperature below 10° C. Once addition was complete reaction was stirred for a further 15 minutes before phases where allowed to separate. Phases were separated, the water layer was extracted with ethyl acetate (1 L) and the organic layers combined. The combined organic layer was washed with NaCl solution (15%) (1 L), dried over magnesium sulphate, evaporated to dryness and slurried in diethyl ether (250 mL) for 30 minutes, filtered and dried at 40° C. in a vacuum oven. Yield 55-60%.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([C:19]2[C:20]([CH3:31])=[N:21][O:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=2)[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43]([C:27]3[CH:28]=[CH:29][C:24]([C:23]4[O:22][N:21]=[C:20]([CH3:31])[C:19]=4[CH:13]([C:11]4[N:10]=[N:9][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:12]=4)[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:25][CH:26]=3)=[CH:42][CH:41]=2)[CH2:38][CH2:39]1)=[O:36])[CH3:33]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(NS(C)(=O)=O)c1cn(Cc2ccccc2)nn1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(NS(C)(=O)=O)c4cn(Cc5ccccc5)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using N-{(1-benzyl-1H-[1,2,3]triazol-4-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methyl}-methanesulfonamide and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[C@@H:19]3[C@@H:14]([C:15]4[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[C:16]=4[CH2:17][CH2:18]3)[CH2:13][CH2:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:25]([N:27]([CH2:30]C)[CH2:28]C)C.CC(N(C)[Cl:36])=[O:34].Cl>ClCCCl.CN(C)C1C=CN=CC=1.CCOCC.O>[ClH:36].[CH3:25][N:27]([CH3:30])[C:28](=[O:34])[O:24][C:20]1[C:16]2[CH2:17][CH2:18][C@H:19]3[C@H:14]([CH2:13][CH2:12][N:11]3[CH2:10][CH2:9][CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:15]=2[CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)N(C)Cl
Reactant: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCC1CCCCC1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCCl
Solvent: O
Product: CN(C)C(=O)Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
3.30 g (0.01008 mol) of rac-cis-3-(4-cyclohexyl-butyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-ol were dissolved in 70 ml of 1,2-dichloroethane. 3.05 g (4.2 ml, 0.0301 mol) of triethylamine and 330 mg (2.70 mmol, 0.27 eq.) of 4-dimethylaminopyridine were added thereto in succession and then 2.8 ml (0.03024 mol) of dimethyl chloroformamide were added dropwise thereto. The mixture was boiled under reflux for 1 hour, then cooled, poured into water and extracted with CH2Cl2. The organic phase was washed with saturated aqueous sodium chloride solution, dried with MgSO4, filtered and concentrated, whereupon the residue was chromatographed over silica gel with n-hexane/ethyl acetate 1:1. The oil obtained (3.2 g) was dissolved in 100 ml of ether. 1.85 ml (8.83 mmol) of 4.78N ethanolic HCl solution were added dropwise thereto and the oily suspension was sonicated for 15 minutes in an ultrasonics bath. Then, it was stirred at room temperature for 1 hour and the separated crystals were filtered off under suction. After recrystallization from 120 ml of hot ethyl acetate and drying at 100°/0.02 Torr for 3 hours there were obtained 2.90 g (83%) of rac-cis-3-(4-cyclohexyl-butyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-yl dimethylcarbamate hydrochloride as white crystals with m.p. 145°-147°.
Reaction SMILES: [N:1]([C:4]([C:7]([C:10]([C:19]([F:22])([F:21])[F:20])([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[O:11][Na])([F:9])[F:8])([F:6])[F:5])=[N+:2]=[N-:3].S(OC)(O[CH3:27])(=O)=O>>[N:1]([C:4]([F:6])([F:5])[C:7]([F:9])([F:8])[C:10]([O:11][CH3:27])([C:19]([F:22])([F:21])[F:20])[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N+:2]=[N-:3]
Reactant: COS(=O)(=O)OC
Reactant: [N-]=[N+]=NC(F)(F)C(F)(F)C(O[Na])(OCC(F)(F)F)C(F)(F)F
Product: COC(OCC(F)(F)F)(C(F)(F)F)C(F)(F)C(F)(F)N=[N+]=[N-]
Yield: 72 %

Procedure:
To demonstrate that the product was N3CF2CF2C(ONa)(OCH2CF3)CF3, the reaction mixture was stirred overnight with 56.7 g (0.45 mol) of dimethyl sulfate, then heated to 40° (0.5 mm, 0.1 kPa) to remove volatiles. Fractionation of the volatiles gave 101.4 g (72%) of 6-azido-4-methoxy-4-trifluoromethyl-1,1,1,5,5,6,6-hepta fluoro-3-oxahexane, bp 60°-61° (15 mm, 2.0 kPa). IR (CCl4): 3010, 2970, and 2660 (sat'd CH), 2150 (N3), 1300-1100 cm-1 (CF, C--O). NMR (CCl4): 1H 4.10 (q, JFF 7.8 Hz, 2H, CH2CF3) and 3.67 ppm (s, 3H, OCH3); 19F-73.8 (t of t, JFF 9.3, 7.9 Hz, 3F, CF3), -75.3 (t, JHF 7.8 Hz, 3F, CF3CH2), -89.3 (q or t, JFF 7.9, 3.4 Hz, 2F, CF2N3), and 117.7 ppm (q of t, JFF 9.3, 3.4 Hz, CF2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=O)[NH:8][CH:7]=[C:6]2[C:16]#[N:17].P(Br)(Br)([Br:20])=O.C1(OC)C=CC=CC=1>>[Br:20][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)[C:6]([C:16]#[N:17])=[CH:7][N:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: COc1cc2c(C#N)c[nH]c(=O)c2cc1OC
Solvent: COc1ccccc1
Product: COc1cc2c(C#N)cnc(Br)c2cc1OC
Temperature: 110 °C
Yield: 22.7 %

Procedure:
To a mixture of 6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carbonitrile. (3.5 g, 15.2 mmol) and phosphorus oxybromide (30 g, 105 mmol) was added anisole (3.2 mL, 30.4 mmol). The reaction mixture was heated at 110° C. for 1 h. The excess phosphorus oxybromide was removed in vacuo. The mixture was then neutralized to pH=7 by addition of saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane (3×200 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (100 mL), dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was recrystallized from chloroform and diethyl ether to afford product 1-bromo-6,7-dimethoxy-isoquinoline-4-carbonitrile (1 g, 22.7% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](=[O:24])[NH:6][C:7]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=1[O:21][CH3:22]>C(O)(=O)C>[CH3:22][O:21][C:11]1[CH:12]=[C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:14]=[CH:15][C:10]=1[C:9]1[N:8]=[C:7]2[NH:6][C:5](=[O:24])[CH2:4][CH:3]=[C:2]2[N:1]=1
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)Nc1[nH]c(=O)ccc1N
Solvent: CC(=O)O
Product: COc1cc(NS(C)(=O)=O)ccc1C1=NC2=CCC(=O)NC2=N1

Procedure:
2.7 g of 5-amino-6-(2-methoxy-4-methanesulfonylaminobenzoyl-amino)-2-pyridone were refluxed in 50 acetic acid for 1.5 hours. The mixture was then concentrated by evaporation in vacuo, and the residue was purified on silica gel (eluant: methylene chloride/ethanol 1:0 to 1:0.1). Yield: 0.1 g (4% of theory). Melting point: above 255° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cc(O)ccc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(O)ccc1C(=O)OCc1ccccc1
Yield: 78.8 %

Procedure:
A solution of 4-hydroxy-2-methylbenzoic acid (550 mg, 3.60 mmol), benzyl chloride (458 mg, 3.60 mmol) and N,N-diisopropylethylamine (465 mg, 3.6 mmol) was stirred at 70° C. for 22 h. A solution of saturated sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexanes/ethyl acetate) to afford phenylmethyl 4-hydroxy-2-methylbenzoate (687 mg, 79%). 1H NMR (400 MHz, DMSO): 10.21-10.18 (br. s, 1H), 7.84-7.77 (d, 1H), 7.48-7.31 (m, 5H), 6.71-6.64 (br. s, 2H), 5.26 (s, 2H), 2.47 (s, 3H). MS (EI) for C15H14O3: 243 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][C:17]=1F.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:15]=[CH:16][C:17]=1[O:10][C:7]1[CH:8]=[CH:9][C:4]2[CH:3]=[CH:2][O:1][C:5]=2[CH:6]=1
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Reactant: Oc1ccc2ccoc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(Oc2ccc3ccoc3c2)c(Cl)c1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-benzofuran-6-ol (418.5 mg, 3.1 mmol) in 6 ml of DMF was added 3-Chloro-4-fluorobenzotrifluoride (681.4 mg, 3.4 mmol) and cesium carbonate (1.5 g, 4.7 mmol). The reaction mixture was heated at 80° C. for 2 hours. After cooling to room temperature, it was diluted with ethyl acetate, washed with water (2×) and brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified on a silica gel column, eluting with ethyl acetate (0-30%) in hexane. The final product was collected as colorless oil. 1H NMR (CDCl3, δ ppm): 6.8 (s, 1H), 7.0 (two d, 2H), 7.2 (s, 1H), 7.4 (d, 1H), 7.6 (d, 1H), 7.7 (s, 1H), 7.8 (s, 1H).
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:15]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[C:14]=2[CH:31]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH2:9].[ClH:1].[OH:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:15]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[C:14]=2[CH:31]=1
Reactant: [H][H]
Reactant: CN1CCN(c2c(-c3ccccc3)oc3ccc(OCc4ccccc4)cc23)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN1CCN(c2c(-c3ccccc3)oc3ccc(O)cc23)CC1
Product: O

Procedure:
The mixture of 13.5 g of 1-(5-benzyloxy-2-phenyl-3-benzofuryl)-4-methylpiperazine hydrochloride, 125 ml of ethanol and 2.5 g of 10% palladium on charcoal is hydrogenated at a pressure of 2.7 atm and at ambient temperature until the hydrogen uptake ceases. The catalyst is filtered off, the filtrate evaporated and the residue triturated with acetone to afford the crystalline 1-(5-hydroxy-2-phenyl-3-benzofuryl)-4-methylpiperazine hydrochloride monohydrate melting at 253°-256° with decomposition.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([CH3:23])[CH:15]=2)[CH:10]=[CH:9][N:8]=1)=[O:5].[H][H]>CO.CC(O)=O.[Pt]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=2)=[CH:15][C:16]=1[CH3:23]
Reactant: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c(C)c2)ccn1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CO
Product: COCC(=O)Nc1cc(Oc2ccc(N)c(C)c2)ccn1

Procedure:
A solution of 2-methoxy-N-(4-(3-methyl-4-nitrophenoxy)pyridin-2-yl)acetamide (208 mg, 0.656 mmol) in a mixture of MeOH (10.0 mL) and AcOH (0.5 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, 40° C., 55 mm 10% Pt/C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo to afford the title compound, Intermediate H3, (192 mg, 97%); Rt 1.19 min (Method 2); m/z 288 (M+H)+ (ES+); which was used directly in the next step (below).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>O1CCCC1>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCCOc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1cccc(OCCO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 246 %

Procedure:
To a solution of 3-(2-hydroxyethoxy)phenol (864 mg, 5 mmol) in tetrahydrofuran (20 ml) were added potassium carbonate (967 mg, 7 mmol) and t-butyl bromoacetate (0.89 ml, 6 mmol), and the mixture was stirred for 2 hours at room temperature. The reaction was quenched by 10% aqueous citric acid solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 10% aqueous citric acid solution, an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution. The organic layer was dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified with silica gel chromatography (hexane:ethyl acetate=3:1) to give the subject compound (3.30 g, 69%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[NH:6][CH:5]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[N:14]1([CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=3)[NH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: c1c[nH]cn1
Reactant: Fc1ccc2[nH]cc(CCBr)c2c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc2[nH]cc(CCn3ccnc3)c2c1

Procedure:
A solution of 3-(2-bromo-ethyl)-5-fluoro-1H-indole (4.84 g, 20 mmol), imidazole (1.36 g, 20 mmol) and ethyl-diisopropylamine (3.4 ml, 20 mmol) in abs. dioxane (50 ml) was stirred at 90° C. for 8 h until according to TLC educt was no longer present. The solvent was then removed i. vac., CHCl3 (100 ml) was added to the residue and the organic phase was washed twice with water. The organic phase was dried over Na2SO4 and concentrated i. vac. and the residue which remained was purified by flash chromatography with CHCl3/MeOH (9:1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[H-].[Na+].[CH2:14](Br)[CH2:15]Br.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN(C)C=O.O>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([O:1][CH2:24][CH2:23][N:22]2[CH2:15][CH2:14][N:19]([CH3:18])[CH2:20][CH2:21]2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: COc1cc(O)ccc1C=O
Reactant: CN1CCNCC1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCCN2CCN(C)CC2)ccc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
To a solution of 304 mg (2.00 mmol) of 4-hydroxy-2-methoxybenzaldehyde in N,N-dimethylformamide (4.0 mL) was added 105 mg (55%, 2.40 mmol) of sodium hydride at room temperature. The mixture was stirred at room temperature for 30 minutes, and 0.69 mL (8.0 mmol) of ethylene dibromide was added thereto. The mixture was stirred at 80° C. for 7 hours, and 2.2 mL (20 mmol) of 1-methylpiperazine was added thereto. The mixture was stirred at 80° C. overnight. Water was added to the reaction mixture under ice-cooling and extraction with ethyl acetate was performed. The resulting organic layer was washed with saturated sodium bicarbonate solution and then with saturated brine and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0 to 40/60) to give 115 mg (20% yield) of the title compound as a brown viscous matter.
Reaction SMILES: [Cl-].[CH3:2][NH2+:3][CH3:4].[C:5]1(=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C-:12]#[N:13].[K+]>O>[C:12]([C:5]1([N:3]([CH3:4])[CH3:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)#[N:13]
Reactant: [C-]#N
Reactant: C[NH2+]C
Reactant: O=C1CCCCC1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CN(C)C1(C#N)CCCCC1
Reaction time: 24 h

Procedure:
Dimethylammonium chloride (81.5 g, 1.0 mole) dissolved in water (150 ml.) was added to cyclohexanone (98.0 g., 1.0 mole), quickly followed by a solution of potassium cyanide (68.0 g, 1.045 mole) in water (150 ml.) added over a period of five minutes. The reaction mixture was stirred for 24 hours during which time a colourless crystalline solid was formed. The solid was filtered off, washed with ice cold water (200 ml.), dissolved in benzene (150 ml.) and rewashed with water (100 ml.). The aqueous layer was extracted with benzene (100 ml.), the benzene solutions then being combined, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The oily residue (144 g.) solidified to give 1-cyanocyclohexyldimethylamine, m.p. 36°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:31]=[CH:30][C:20]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][CH:18]=1.[Cl:32]N1C(=O)CCC1=O>CN(C=O)C>[Cl:32][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:31]=[CH:30][C:20]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Solvent: CN(C)C=O
Product: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Yield: 31.8 %

Procedure:
A solution of tert-butyl 4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzylcarbamate (45 mg, 0.10 mmol) and N-chlorosuccinimide (17 mg, 0.13 mmol) in DMF (1 mL) was heated at 50° C. for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparatory HPLC (water/acetonitrile w 0.05% TFA gradient) to afford the desired product (15 mg, 32%) as a brown solid: ESI MS m/z 471 [C24H23ClN2O4S+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([CH2:21][CH2:22][CH2:23][CH:24]([CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25](O)=[O:26])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:25](=[O:26])[CH:24]([CH2:23][CH2:22][CH2:21][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:28][CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(CCCc1ccccc1)CCCc1ccccc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1CCN(Cc2ccccc2)CC1)C(CCCc1ccccc1)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
1-Benzyl-4-aminopiperidine (0.5 g; 2.63 mmol) is dissolved in DMF (25 mL) at ambient temperature. 5-Phenyl-2-(3-phenyl-propyl)-pentanoic acid (22) (0.78 g; 2.62 mmol), triethylamine (0.46 mL; 3.28 mmol), 1-hydroxybenzotriazole (0.444 g; 3.28 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.554 g; 2.89 mmol) are added sequentially. The mixture is stirred for 18 hours at ambient temperature then poured onto ethyl acetate (250 mL) and extracted successively with water (50 mL), saturated aqueous sodium bicarbonate (50 mL), and brine (50 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (10%→67% ethyl acetate in hexanes) affording the desired product (1.07 g) as a white solid. ESMS: MH+ 469.4 (base).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[S:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11]=1[CH2:19][C:20]#[N:21].I[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([F:29])[F:28].O>C1CCCCC1.O1CCCC1>[Cl:9][C:10]1[S:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11]=1[CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([F:29])[F:28])[C:20]#[N:21]
Reactant: FC(F)CCCCI
Reactant: N#CCc1c(Cl)sc2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: N#CC(CCCCC(F)F)c1c(Cl)sc2ccccc12
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
A solution of lithium diisopropylamide in cyclohexane (5.13 mmol, 3.42 ml of a 1.5M solution) was added dropwise to a solution of (2-chlorobenzo[b]thiophen-3-yl)acetonitrile (1.06 g, 5.13 mmol) in tetrahydrofuran (10 ml) cooled to -70° C. under nitrogen. The resulting solution was stirred at -70° C. for 20 min, then a solution of 5-iodo-1,1-difluoropentane (1.2 g, 5.13 mmol) in tetrahydrofuran (5 ml) was slowly added at -70° C. The reaction mixture was stirred at -70° C. for 1 hr, then slowly allowed to warm to room temperature and left at that temperature overnight. Water (60 ml) was added to the reaction solution and the resulting mixture was extracted with ethyl acetate (3×70 ml). The combined ethyl acetate extracts were washed with brine (80 ml), dried (sodium sulfate) and concentrated in vacuo. The crude product (2.1 g) was purified by column chromatography on silica gel (200 g), eluting with 4:1 hexane/dichloromethane followed by 7:3 hexane/dichloromethane to yield the title compound as an oil (950 mg, 59% yield). 1H NMR (300 MHz, CDCl3) δ1.4-1.7 (c, 4H), 1.7-2.05 (c, 3H), 2.2 (c, 1H) 4.3 (t, 1H), 5.6, 5.78, 5.98 (3t, total 1H), 7.42 (m, 2H), 7.75 (d, 1H), 7.95 (d, 1H).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:15])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:5].FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C([I:27])C=CC=1)=O.II.OS([O-])=O.[Na+]>C(Cl)Cl>[I:27][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:4]([N:3]([O:2][CH3:1])[CH3:15])=[O:5]
Reactant: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CON(C)C(=O)c1n[nH]c2ccccc12
Agent: II
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CON(C)C(=O)c1n[nH]c2ccc(I)cc12
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To the N-methoxy-N-methyl-1H-indazole-3-carboxamide (IX) (20 g, 97.4 mmol) in 1 L DCM was added bis(trifluoroacetoxy)iodobenzene (46 g, 107 mmol) followed by portionwise addition of iodine (14.84 g, 58.5 mmol) at r.t. After 1 hour, 600 mL of saturated NaHSO3 was added and a solid began to precipitate which was filtered and rinsed with excess DCM. The filtrate was washed with brine, dried over MgSO4, concentrated and the remaining solid was triturated with a minimal amount of DCM. The combined solids were dried under vacuum over KOH to produce 5-iodo-N-methoxy-N-methyl-1H-indazole-3-carboxamide (X) as a white solid (23.2 g, 70 mmol, 72% yield). 1H NMR (DMSO-d6) δ ppm 3.45 (s, 4H), 3.77 (s, 4H), 7.45-7.54 (m, 1H), 7.66 (dd, J=−8.81, 1.51 Hz, 1H), 8.40 (d, J=1.01 Hz, 1H); ESIMS found for C10H10IN3O2 m/z 331 (M+H).