Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[O:20][CH3:21])=O.[C:22]([O:29][CH3:30])(=[O:28])[CH2:23][CH2:24][C:25]([CH3:27])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:30][O:29][C:22](=[O:28])[CH2:23][C:24]1[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[O:20][CH3:21])=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:25]=1[CH3:27]
Reactant: COc1cc(C)ccc1C(=O)c1c(N)sc2c1CCCC2
Reactant: COC(=O)CCC(C)=O
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1OC)CCCC3
Yield: 79.8 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(2-methoxy-4-methylphenyl)methanone (0.602 g; 2 mmol), methyl levulinate (0.282 mL; 2.2 mmol), chlorotrimethylsilane (1.02 mL; 8 mmol) in DMF (8 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane furnished 0.631 g (80%) of the title compound as a yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[CH:10]1(B(O)O)[CH2:12][CH2:11]1.N1C=CC=CC=1C1C=CC=CN=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:10]1([N:1]2[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]2)[CH2:12][CH2:11]1
Reactant: COC(=O)c1cc[nH]c1
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: COC(=O)c1ccn(C2CC2)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 57.1 %

Procedure:
A mixture of methyl 1H-pyrrole-3-carboxylate (500 mg, 4.00 mmol), cyclopropylboronic acid (686 mg, 7.99 mmol), copper(II) acetate (726 mg, 4.00 mmol), 2,2′-bipyridyl (624 mg, 4.00 mmol), sodium carbonate (847 mg, 7.99 mmol) was stirred at 70° C. for 16 hr, concentrated, diluted in EtOAc/water, and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated. The crude material was purified by silica gel column chromatography (hexane/EtOAc 4:1) to afford the title compound (377 mg, 57% yield) as a yellow oil. TLC (hexane/EtOAc 4:1): Rf=0.26.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28](F)=[CH:27][CH:26]=2)[N:12]=[N:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32](OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.C1(CNC)CCCCC1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH3:32])[N:12]=[N:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(CNc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: CNCC1CCCCC1
Product: CN(CC1CCCCC1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Yield: 26 %

Procedure:
Prepared as described for 5,6-bis(benzyloxy)-N-[(4-fluorophenyl)methyl]pyridazin-3-amine (Intermediate 45) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 1-cyclohexyl-N-methylmethanamine in 26% yield.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.[CH:24]([C:26]1[S:27][CH:28]=[C:29](B(O)O)[CH:30]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O.C(Cl)Cl>[NH2:23][C:9]1[N:8]=[CH:7][C:6]2[C:2]([C:29]3[CH:30]=[C:26]([CH:24]=[O:25])[S:27][CH:28]=3)=[CH:3][O:4][C:5]=2[C:10]=1[O:11][C@@H:12]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=1[Cl:22])[CH3:13]
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: O=Cc1cc(B(O)O)cs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H](Oc1c(N)ncc2c(-c3csc(C=O)c3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 80 °C

Procedure:
3-Bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridin-6-ylamine (150.0 mg, 0.357 mmol), 2-formylthiophene-4-boronic acid (111 mg, 0.714 mmol), potassium carbonate (148 mg, 1.07 mmol), 1,4-dioxane (4.2 mL, 54 mmol), H2O (1.2 mL, 67 mmol) and (1,1′bis-(diphenylphosphino)ferrocene palladium dichloride (10 mg, 0.02 mmol) were mixed and heated at 80° C. overnight. The crude was worked up with DCM and H2O. Product was purified by prep-TLC in DCM/methanol system. MS (ES+): m/z 451.01/453.04 (100/73) [MH+]. HPLC: tR=0.93 min (HPLC-ACQUITY, Analytical). 1H NMR (400 MHz, DMSO-d6): δ 9.99 (d, J=1.3 Hz, 1H), 8.49 (s, 1H), 8.42-8.47 (m, 2H), 8.26 (s, 1H), 7.49-7.56 (m, 1H), 7.42-7.49 (m, 1H), 6.26 (q, J=6.7 Hz, 1H), 5.71 (s, 2H), 1.85 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([N:19]=[C:20]=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20]([NH:19][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:21])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CCCCCCCN=C=O
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCCNC(=O)Nc1ccc(F)cc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 65.7 %

Procedure:
4-fluoro-2-nitroaniline (1.56 g), heptyl isocyanate (1.41 g) and 4-dimethylaminopyridine (0.37 g) were stirred in toluene (5 ml) at 80°-90 C. for 5 hrs. This solution was diluted with ethyl acetate, washed with 1N hydrochloric acid, sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous MgSO4, and the solvent was distilled off. The resulted crystals were washed with hexane to give 1-(4-fluoro-2-nitrophenyl)-3-heptylurea (1.95 g, 66%).
Reaction SMILES: [CH:1]1([C:6]([OH:8])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.[CH:9]([N-]C(C)C)([CH3:11])[CH3:10].[Li+].C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.ICCC.Cl>O1CCCC1.O>[CH2:10]([C:1]1([C:6]([OH:8])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1)[CH2:9][CH3:11]
Reactant: O=C(O)C1CC=CC1
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CCCI
Product: CCCC1(C(=O)O)CC=CC1
Temperature: 25 °C
Yield: 77 %

Procedure:
3-Cyclopentenecarboxylic acid (7.5 g, 66.9 mmole) in dry tetrahydrofuran (15 ml) was added dropwise under nitrogen to a stirred solution of lithium diisopropylamide prepared from diisopropylamine (19.7 ml, 0.14 mole) and 2.5M n-butyl lithium in hexane (56.2 ml, 0.14 mole) in dry tetrahydrofuran (150 ml) at -60° C. The resulting suspension was allowed to warm to room temperature and then stirred for a further hour, by which time a clear solution was obtained. Iodopropane (7.18 ml, 73.6 mmole) was added dropwise at -60° C., and the mixture was once again allowed to warm to room temperature and then stirred overnight. The solution was cooled to 15° C., water (10 ml) was added followed by 2N hydrochloric acid to pH 3. The organic layer was separated and the aqueous phased extracted twice with methylene chloride. The combined organic extracts were washed with saturated salt solution, dried (MgSO4) and evaporated under vacuum to give a crude product which was chromatographed on silica gel (200 g), eluting with a mixture of ethyl acetate and hexane to give 1-propyl-3-cyclopentene-carboxylic acid (7.96 g, 77%) as a hygroscopic solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[NH:24][C:23](=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=C2N=C(CCC3NC(=O)CCCC3)NC2=NC=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:52]([N:54]1[CH2:59][CH2:58][N:57]([S:60](C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)(=[O:62])=[O:61])[CH2:56][CH2:55]1)[CH3:53]>>[CH2:52]([N:54]1[CH2:59][CH2:58][N:57]([S:60]([C:4]2[CH:3]=[CH:2][C:1]([C:7]3[CH:8]=[C:9]4[N:15]=[C:14]([CH2:16][CH2:17][CH:18]5[NH:24][C:23](=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19]5)[NH:13][C:10]4=[N:11][CH:12]=3)=[CH:6][CH:5]=2)(=[O:61])=[O:62])[CH2:56][CH2:55]1)[CH3:53]
Reactant: O=C1CCCCC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)N1
Reactant: CCN1CCN(S(=O)(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: O=C1CCCCC(CCc2nc3cc(Br)cnc3[nH]2)N1
Agent: [Na+]
Product: CCN1CCN(S(=O)(=O)c2ccc(-c3cnc4[nH]c(CCC5CCCCC(=O)N5)nc4c3)cc2)CC1

Procedure:
The title compound is analogously synthesized as described for 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one (compound B1) from 300 mg of 7-[2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one (compound C1), 2.67 ml of aqueous sodium carbonate solution (strength 2.0 M), 510 mg 1-ethyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonyl]-piperazine (compound C4), and 131 mg of trans-dichloro-bis(tricyclohexyl-phosphine)-palladium(II) at 110° C. for 18 hours. After aqueous work-up using 200 ml of dichloromethane and 75 ml of water, purification by chromatography on flash silica gel (eluent gradient dichloromethane/5-50 vol. % ethanol) yields 175 mg of the title compound as a waxy solid. ESI-MS: 511.3 (MH+). TLC: Rf=0.30 (dichloromethane/ethanol 8:1 parts by volume).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.F>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:9]([F:11])([F:10])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(C(F)(F)F)C(F)(F)F)cc1
Agent: F
Solvent: c1ccccc1
Product: Cc1ccc(C(c2ccccc2)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 64 h

Procedure:
1290 g of 2-(4-methylphenyl)hexafluoropropan and 780 g of benzene were placed in a 5-liter steel autoclave and 1500 g of anhydrous hydrogen fluoride was pumped into the sealed autoclave. The reaction mixture was heated at 170°-175° C. with stirring for 64 hours. After completion of the reaction, hydrogen fluoride gas was allowed to escape at 80° C., and the liquid product was then washed twice with water, dried over calcium chloride, and fractionally distilled. Boiling point 135°-136° C./1.4 mbar. Yield: 1424 g (89.5%).
Reaction SMILES: NC1C=C(C2SC3C=CC=CC=3N=2)C([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=CC=1.[N:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=2)=[CH:30][CH:29]=1)=[N+]=[N-]>>[NH2:25][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=2)=[CH:30][C:29]=1[O:11][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:8]
Reactant: [N-]=[N+]=Nc1ccc(-c2nc3ccccc3s2)cc1
Reactant: Nc1ccc(OS(=O)(=O)C(F)(F)F)c(-c2nc3ccccc3s2)c1
Product: Nc1ccc(-c2nc3ccccc3s2)cc1OS(=O)(=O)C(F)(F)F
Yield: 12 %

Procedure:
This compound was prepared in a similar way to the compound of Example XIV from 2-(4-azidophenyl)benzothiazole. The yield was 12%, (Found: M+ 374. C14H9F3N2O3S2 requires MW 374).
Reaction SMILES: CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[OH:28].[CH3:29][S:30]([CH3:32])=O.N#N.[OH-].[NH4+].[F:37][C:38]([F:53])([S:49]([O-:52])(=[O:51])=[O:50])[C:39]([F:48])([F:47])[C:40]([F:46])([F:45])[C:41]([F:44])([F:43])[F:42].[K+]>O>[F:53][C:38]([F:37])([S:49]([O-:52])(=[O:51])=[O:50])[C:39]([F:47])([F:48])[C:40]([F:46])([F:45])[C:41]([F:44])([F:43])[F:42].[CH3:29][S+:30]([CH3:32])[C:25]1[CH:24]=[C:23]([CH3:27])[C:22]([OH:28])=[C:21]([CH3:20])[CH:26]=1
Reactant: CS(C)=O
Reactant: Cc1cccc(C)c1O
Agent: CS(=O)(=O)O
Agent: N#N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: Cc1cc([S+](C)C)cc(C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8 ml of Eaton's Reagent (from Aldrich, 7.7 wt. % of P2O5 in methanesulfonic acid) through an addition funnel to a mixture of 2.44 g (0.02 mol) of 2,6-dimethylphenol and 1.56 g (0.02 mol) of dimethylsulfoxide in a 50-mL 3-necked round bottom flask equipped with a thermometer, N2 inlet and magnetic stirrer. The rate of the addition was adjusted so that the temperature of the mixture did not rise above 60° C. during addition. After the exotherm had subsided, the reaction mixture was stirred at room temperature for 2 hours and then poured into 40 mL of distilled water. The solution was neutralized to pH=7 by adding ammonium hydroxide solution. The resulting solution was stirred at room temperature for half an hour and then filtered through a filter paper to remove the brown oily side products. The filtrate was added dropwise to a solution of 6.76 g (0.02 mol) of potassium perfluorobutanesulfonate (KPFBuS) in 70 mL water while stirring. The mixture was further stirred overnight. The white precipitate was collected by suction filtration and washed with water and ether three times. The crude product was redissolved in 15-20 mL of ethyl acetate. To this solution, 200-300 mg of aluminum oxide (activated, basic) was added. The mixture was rolled on a roller overnight and then filtered through Celite. The filtrate was precipitated into 100 mL ether while stirring. The white precipitate was collected and further washed with ether three times. Final yield: 2.2 g (23%).
Reaction SMILES: Cl.C([N:6]1[C:15](=[O:16])[C:14]2[C:17](O[SiH3])=[C:18]([NH2:21])[C:19](C)=[C:12]3[C:13]=2[C:8](=[CH:9][C:10]([NH2:25])=[C:11]3C)[C:7]1=[O:26])(C)(C)C.C([OH:29])C>>[NH2:25][C:10]1[CH:11]=[C:12]2[CH:19]=[C:18]([NH2:21])[CH:17]=[C:14]3[C:13]2=[C:8]([CH:9]=1)[C:7](=[O:26])[N:6]([OH:29])[C:15]3=[O:16]
Reactant: CCO
Reactant: Cc1c(N)cc2c3c(c(O[SiH3])c(N)c(C)c13)C(=O)N(C(C)(C)C)C2=O
Agent: Cl
Product: Nc1cc2c3c(cc(N)cc3c1)C(=O)N(O)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1% HCl in ethanol (100 mL) was added to 2-tert-butyldimethyl-silyloxy-5,8-diamino-benzo[de]isoquinoline-1,3-dione (0.4 g, 1.0 mmol, from Example I1) with stirring at room temperature. After 1 hour, the solids formed were filtered, washed with ether, and dried to give 0.2 g of the title compound, mp 329-336° C.;
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[CH:5]2.[NH2:16][C@H:17]([CH3:20])[CH2:18][OH:19].C(N(CC)CC)C.CO>>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:16]([C@H:17]([CH3:20])[CH2:18][OH:19])[CH:6]=[CH:5]2
Reactant: C[C@@H](N)CO
Reactant: O=c1occc2c([N+](=O)[O-])c(Cl)ccc12
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@H](CO)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Reaction time: 0.5 h

Procedure:
A microwave vial was charged with 6-chloro-5-nitro-1H-isochromen-1-one (80.0 mg, 0.000355 mol), (2R)-2-aminopropan-1-ol (29 mg, 0.00039 mol), triethylamine (0.15 mL, 0.0011 mol) and methanol (4 mL, 0.1 mol) and subjected to microwaves at 100° C. for 30 minutes. The reaction went to completion with 10% of cyclized product in addition to the required product. The solvent was removed and the residue purified by flash chromatography to obtain the product as a light yellow solid. MS m/z=283.2 (M+H). 1H NMR (400 MHz; DMSO-d6) δ 8.43 (d, J=8.86 Hz, 1H), 7.80 (d, J=8.86 Hz, 1H), 7.75 (d, J=7.98 Hz, 1H), 6.36 (d, J=7.09 Hz, 1H), 5.03-4.86 (m, 2H), 3.63-3.52 (m, 2H), 1.30 (d, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].CC(C)([O-])C.[K+].Br[C:16]1[CH:17]=[CH:18][C:19]2[S:23][CH:22]=[CH:21][C:20]=2[CH:24]=1.Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[S:23]1[C:19]2[CH:18]=[CH:17][C:16]([CH:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:24][C:20]=2[CH:21]=[CH:22]1
Reactant: CCOC(=O)CC#N
Reactant: Brc1ccc2sccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)c1ccc2sccc2c1
Yield: 46.3 %

Procedure:
To toluene (3 mL) solution of 0.21 g of ethyl cyanoacetate were added 0.41 g of potassium tert-butoxide, 0.30 g of 5-bromobenzothiophene and 0.02 g of tetrakis(triphenylphosphine)palladium(0), which was then refluxed for 7.5 hours. To the reaction mixture was added water, and the pH was adjusted to 2 with hydrochloric acid. Thereto was added ethyl acetate, and insoluble matter was filtered off. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to provide 0.16 g of ethyl 2-(1-benzothiophen-5-yl)-2-cyanoacetate as pale yellow solid form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:26][C:27](O)=[O:28])[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:27](=[O:28])[CH2:26][C:18]2[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Product: COc1ccc(CCNC(=O)Cc2cc(OC)c(OC)c(OC)c2)cc1OC

Procedure:
prepared by reaction of 3,4-dimethoxyphenylethylamine and 3,4,5-trimethoxyphenylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([C:22](O)=[O:23])[CH:19]=[C:18]([Cl:25])[CH:17]=4)[CH2:14][C:13](=[O:26])[NH:12][CH:11]3[C:27](=[CH2:30])[CH2:28][CH3:29])[C:5]2=[CH:4][CH:3]=1.N1C(F)=NC(F)=NC=1[F:34].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([C:22]([F:34])=[O:23])[CH:19]=[C:18]([Cl:25])[CH:17]=4)[CH2:14][C:13](=[O:26])[NH:12][CH:11]3[C:27](=[CH2:30])[CH2:28][CH3:29])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(CC)C1NC(=O)CC(c2cc(Cl)cc(C(=O)O)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(CC)C1NC(=O)CC(c2cc(Cl)cc(C(=O)F)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To the solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-5-hydroxycarbonyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.43 mmol) prepared in example 93 in dichloromethane (20 mL) at 0° C. was added cyanuric fluoride (48 mg, 0.35 mmol) (Alfa) and pyridine (37 mg, 0.48 mmol). After the mixture was stirred at 0° C. for 2 h, the mixture was partitioned between H2O and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over MgSO4, concentrated to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-5-fluorocarbonyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow gum and used for the next step without further purification (Yield: 0.2 g, 100%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C1C(=O)N(Cl)C(=O)C1.[NH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31](=[O:40])[N:32]([CH3:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31](=[O:40])[N:32]([CH3:39])[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:28][CH:29]=2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(S(=O)[O-])cc1
Reactant: CN(C(=O)Oc1ccc(CCN)cc1)c1ccccc1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1ccc(S(=O)(=O)NCCc2ccc(OC(=O)N(C)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (4-bromo-phenyl)-dimethylamine (4.02 g, 20 mmol) in THF (25 mL) was added dropwise 1.57 M solution in hexanes n-BuLi (11.5 mL, 18 mmol) over a 5-min period at −78° C. The mixture was stirred at −78° C. for 15 min. Then gaseous sulphur dioxide (ca. 5 g) was added causing an immediate precipitation. The mixture was allowed to warm to room temperature and stirred for 1 h. The precipitated lithium sulfinate was isolated by filtration under N2 (g), washed with THF (20 mL) and dried in vacuo providing 2.99 g (87%) of lithium; 4-dimethylamino-benzenesulfinate as a bluegreen solid. This lithium sulfinate (65 mg, 0.34 mmol) was suspended in CH2Cl2 (1 mL) and stirred with NCS (45 mg, 0.34 mmol) for 10 min at rt. A solution of N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.26 mmol) in CH2Cl2 (1.5 mL) was added together with DIPEA (0.90 mmol). The mixture was stirred at rt for 16 h and quenched with HOAc (2 mL) and water (2 mL). Extraction with CH2Cl2 and drying of the combined organic extracts gave the crude product which was purified by preparative HPLC (Gilson). This gave 37 mg (31%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([CH:8]([CH:12]([OH:19])[C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O-:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([CH:8]([CH:12]([OH:19])[C:13](=[O:18])[C:14]([CH3:15])([CH3:17])[CH3:16])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)C(O)C(Cc1ccccc1)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C(=O)C(O)C(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 300 mg (1.07 mmol) of the less polar (2R,3R or S)-2-benzyl-3-hydroxy-5,5-dimethyl-4-oxo-hexanoate and 1.07 ml of 1N sodium hydroxide solution in 10 ml of methanol is stirred at room temperature for 3 hours. Thereafter, the reaction mixture is neutralized with 1.07 ml of 1N hydrochloric acid and evaporated under reduced pressure. The residue is triturated with ethyl acetate and the insoluble solid is separated. After evaporation of the ethyl acetate phase there are obtained 180 mg of (2R,3R or S)-2-benzyl-3-hydroxy-5,5-dimethyl-4-oxohexanoic acid as a colourless solid, MS: 231 (M-CH3 -H2O)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[CH:4][CH:5]([NH2:9])[C:6]([OH:8])=[O:7].[OH-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S>O>[CH2:12]([O:7][C:6](=[O:8])[CH:5]([NH2:9])[CH:4]=[CH:3][CH2:2][OH:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: NC(C=CCO)C(=O)O
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(C=CCO)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Dissolve 5-hydroxy-2-amino-3-pentenoic acid (13.1 g, 0.1 mol) in 1N sodium hydroxide (200 mL, 0.2 mol). Add a solution of CuSO4.5H2O (12.5 g, 0.05 mol) in water (50 mL). Stir the mixture until solution is complete. Treat with benzyl bromide (17.1 g, 0.1 mol) and stir at room temperature until reaction is complete. Suction filter, wash the residue with 1:3.5 methanol-water and dry at 60° C. to give the copper complex. Suspend the copper complex in water, treat with excess hydrogen sulfide, heat to boiling, then cool to room temperature. Mix with 1N sodium hydroxide and filter. Stir the filtrate with a slight excess of 1N hydrochloric acid and filter. Wash the residue with water and dry to give O-benzyl-5-hydroxy-2-amino-3-pentenoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1.CC[O:20]CC>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10]2=[O:20])=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2ccc3ccccc32)cc1
Reactant: CCOCC
Product: COc1ccc(N2C(=O)Cc3ccccc32)cc1

Procedure:
Omitting the final chromatography, but triturating the crude product three times with ether, 1-(4-methoxyphenyl)indole (18.1 g, 81 mmoles) was converted to title product, 12.0 g, m.p. 115°-117° C., pnmr/CDCl3 /TMS/delta: 3.65 (s, 2H), 3.8 (s, 3H), 6.6-7.4 (m, 8H).