Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([NH:12][CH:13]2[CH:18]3[CH:14]2[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17]3)=[N:10][CH:11]=1)=[O:5])[CH3:2].[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27].C(Cl)Cl>>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[CH:14]12[CH:13]([NH:12][C:9]3[N:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][N:10]=3)[CH:18]1[CH2:17][NH:16][CH2:15]2
Reactant: CCOC(=O)c1cnc(NC2C3CN(C(=O)OC(C)(C)C)CC32)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cnc(NC2C3CNCC32)nc1

Procedure:
A solution of tert-butyl 6-{[5-(ethoxycarbonyl)pyrimidin-2-yl]amino}-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.15 g) was allowed to stand in 20% TFA/DCM (10 ml) at r.t. for 1 h. The reaction mixture was concentrated to dryness giving the title product as the TFA salt (0.17 g). LCMS purity 76%, m/z 249 [M+H]+. The product was used in the next stage without purification.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OCC3C=CC=CC=3)=O)[CH2:8][C@@H:9]([O:10][S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C@H:5]2[O:4][CH2:3]1.[H][H]>[Pd].C(O)C>[CH3:18][C:17]1[CH:19]=[CH:20][C:14]([S:11]([O:10][C@@H:9]2[CH2:8][NH:7][C@@H:6]3[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]23)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OCc3ccccc3)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CN[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reaction time: 1.75 h
Yield: 89 %

Procedure:
Preparation of (3R,3aR,6R,6aS)— Benzyl 3-hydroxy-6-(tosyloxy)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (34b). Ethanol (1.5 mL) was added dropwise to a mixture of 10% palladium on charcoal (10 mg) and anti-(33b) (12.0 mg, 0.028 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 1.75 hours before filtering the mixture through celite in vacuo. The filter cake was washed with ethanol (7.5 mL) then the solvents removed in vacuo from the filtrate. The residue was azeotroped with toluene (2 mL) to obtain (3R,3aR,6R,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl 4-methylbenzenesulfonate (7.6 mg, 89%) as a pale yellow oil which was used without further purification. TLC (Rf=0.01, EtOAc:heptane 1:1), HPLC-MS 300.1 [M+H]+, 621.2 [2M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:36])=[C:4]([CH3:35])[C:5]2[N:6]([C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21]C(=O)OC(C)(C)C)[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.Cl.O1CCOCC1.[OH-].[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[C:3]([CH3:36])=[C:4]([CH3:35])[C:5]2[N:6]([C:8]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]4([NH2:21])[CH2:18][CH2:19][CH2:20]4)=[CH:15][CH:16]=3)[N:10]=2)[N:7]=1
Reactant: Cc1c(Cl)nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(Cl)nn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a mixture of the tert-butyl {1-[4-(6-chloro-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-32 (179 mg, 0.360 mmol, 1.0 eq) in DCM (2.29 mL) and MeOH (1.44 mL) was added a solution of 4 M hydrogen chloride in dioxane (1.78 mL, 7.12 mmol, 20.0 eq) and the mixture was stirred overnight at rt. The mixture was poured onto ice, made alkaline with aqueous sodium hydroxide (2 N) and extracted with DCM. The combined organic phases were washed with brine, dried and concentrated in vacuo. The crude mixture was purified via MPLC (Biotage Isolera; 10 g SNAP cartridge: DCM→DCM/ethanol 95/5) to give 64 mg (44% yield) of the title compound.
Reaction SMILES: [C:1]([C:9]1[N:10]=[C:11]([CH2:35][CH2:36][CH2:37][CH3:38])[N:12](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:13]=1[C:14]#[N:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C>[C:1]([C:9]1[N:10]=[C:11]([CH2:35][CH2:36][CH2:37][CH3:38])[NH:12][C:13]=1[C:14]#[N:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCc1nc(C(=O)c2ccccc2)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: CCCCc1nc(C(=O)c2ccccc2)c(C#N)[nH]1
Temperature: 60 °C
Reaction time: 5 h
Yield: 84.7 %

Procedure:
A suspension of 10.3 g of 4-benzoyl-2-butyl-5-cyano-1-tritylimidazole [prepared as described in step (i) above] in 80% v/v aqueous acetic acid was stirred at 60° C. for 5 hours. At the end of this time, the solution thus obtained was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent. The resulting oily product was dissolved in carbon tetrachloride and the solution was allowed to stand at room temperature, to precipitate crystals, which were collected by filtration to give 4.46 g of the title compound, melting at 121°-122° C.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:38])[CH:14]([N:23](C(OC(C)(C)C)=O)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:27]([O:26][C:24](=[O:25])[NH:23][CH:14]([CH2:15][N:16]1[CH2:17][CH2:18][C:19](=[O:22])[CH2:20][CH2:21]1)[C:13]([N:10]1[CH2:11][CH2:12][CH:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][CH2:9]1)=[O:38])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C(CN1CCC(O)CC1)C(=O)N1CCC(N2CCCCC2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CN1CCC(=O)CC1)C(=O)N1CCC(N2CCCCC2)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-[1,4′]bipiperidinyl-1′-yl-2-(di-tert-butoxycarbonylamino)-3-(4-hydroxy-piperidin-1-yl)-propan-1-one (200 mg, 0.37 mmol) in methylene chloride (4 mL) was added Dess-Martin periodinane (316 mg, 2 equiv) in two portions. After 1 h, the reaction was quenched by the addition of saturated sodium bicarbonate, and extracted into methylene chloride (3×). The combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated to give 187 mg (94%) which was used without purification. Mass spec.: 437.63 (MH)+.
Reaction SMILES: [C:1]([C:4]1[C:11]2[C:7]([N:8]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[CH:9]([C:12]([O:14]CC3C=CC=CC=3)=[O:13])[CH:10]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[H][H]>C(OCC)(=O)C.[Pd].[OH-].[Na+].O>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[CH2:22][N:8]1[CH:9]([C:12]([OH:14])=[O:13])[CH:10]=[C:11]2[C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=[C:7]12
Reactant: O=C(O)C1=CC=C2C1=CC(C(=O)OCc1ccccc1)N2Cc1ccc(Cl)c(Cl)c1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)C1=CC=C2C1=CC(C(=O)O)N2Cc1ccc(Cl)c(Cl)c1
Yield: 40.2 %

Procedure:
Benzyl 4-carboxy-1-(3,4-dichlorobenzyl)cyclopenta[b]pyrrole-2-carboxylate (0.1 g) was dissolved in ethyl acetate (5 mL). Palladium on carbon (5% Pd, 10 mg) was added and the reaction was exposed to an hydrogen atmosphere (1.1 atm) for 4 hours until reaction was complete. The hydrogen was evacuated and the resulting solution was filtered through Celite to remove catalyst. The reaction was concentrated in vacuo to afford the crude product, which was dissolved in a minimum of 2M NaOH, diluted with water (1 mL), and then precipitated by addition of dilute aqueous HCl. The solid was collected and dried to yield the title product as a pale cream solid (32 mg, 41%), NMR d(DMSO) 2.40 (4H, m), 3.70 (1H, t), 5.40 (2H, AB d), 6.68 (1H, s), 6.95 (1H, dd), 7.15 (1H, s), 7.58 (1H, d); M/z (−) 355, 353 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([OH:28])=O)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl.Cl.[CH3:36][N:37]1[CH:42]2[CH2:43][CH2:44][CH:38]1[CH2:39][CH:40]([CH2:45][C:46]1[CH:47]=[C:48]([C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([CH2:58][NH2:59])[CH:53]=3)[CH:49]=[CH:50][CH:51]=1)[CH2:41]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:31]=[CH:30][CH:29]=[C:25]([C:26]([NH:59][CH2:58][C:54]4[CH:53]=[C:52]([C:48]5[CH:49]=[CH:50][CH:51]=[C:46]([CH2:45][CH:40]6[CH2:39][CH:38]7[N:37]([CH3:36])[CH:42]([CH2:43][CH2:44]7)[CH2:41]6)[CH:47]=5)[CH:57]=[CH:56][CH:55]=4)=[O:28])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Reactant: CN1C2CCC1CC(Cc1cccc(-c3cccc(CN)c3)c1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CC4CC5CCC(C4)N5C)c3)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.2 %

Procedure:
To a solution of 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (0.045 g, 0.1 mmol) in DMSO (0.5 mL) was added 1-{3′-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)methyl]-3-biphenylyl}methanamine dihydrochloride (0.047 g, 0.12 mmol), HBTU (0.054 g, 0.15 mmol), and TEA (0.042 mL, 0.3 mmol) and the reaction was stirred at room temperature for 16 h. The reaction mixture was purified using a Gilson HPLC (with 0.1% TFA), concentrated, basified with amino cartridge to afford 0.0409 g (52%) of the title compound. LC-MS m/z 754 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=[O:10])=[C:4]([N+:12]([O-])=O)[CH:3]=1.C(OCC)(=O)C>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][C:9](=[O:10])[NH:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1Cc2ccc(Br)cc2N1
Temperature: 100 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
Iron (40.0 g, 700 mmol) was added slowly to a stirred solution of 2-(4-bromo-2-nitrophenyl)acetic acid (preparation 1b, 46.6 g, 200 mmol) in acetic acid (390 mL) at 75° C., and then mixture was stirred for 1 hour at 100° C. Then the mixture was cooled and ethyl acetate was added. The mixture was filtered through Celite® and the solvent evaporated. The crude product was washed with 0.1M aqueous hydrochloric acid, water, diethyl ether and dried to give the title compound (22.0 g, 58%) as a solid.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[Na+].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29].Cl>O.C(OCC)(=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:2]2[CH2:6][CH2:5][CH2:4][C@H:3]2[C:7]([O:9][CH3:10])=[O:8])(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
At 0° C., a solution of 0.647 g (3.9 mmol) of methyl (S)-pyrrolidine-2-carboxylate hydrochloride in 6 ml of water was added to 0.83 g of sodium carbonate (7.8 mmol, 2 eq), followed portionwise by 1.0 g (3.9 mmol) of 4-chloro-3-nitrobenzenesulfonyl chloride. The medium was stirred at 0° C. for 4 hours. The reaction medium was diluted with ethyl acetate and brought to pH 5-6 with 2 N HCl. After extraction, the aqueous phase was basified with sodium bicarbonate and extracted twice with ethyl acetate. The organic phases were combined, washed with a saturated sodium chloride solution, dried over magnesium sulfate and evaporated. 1.22 g (90%) of product were obtained. Yield=90%.
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:15][CH3:16])([O:13][CH3:14])[CH2:11][Br:12])[CH:5]=1.[C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH3:19].[Li]>>[C:22]([O:21][C:18](=[O:20])[CH2:19][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:13][CH3:14])([O:15][CH3:16])[CH2:11][Br:12])[CH:5]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(C(CBr)(OC)OC)c1
Agent: [Li]
Product: COC(CBr)(OC)c1cccc(C(=O)CC(=O)OC(C)(C)C)c1

Procedure:
3-(2-Bromo-1,1-dimethoxy-ethyl)-benzoic acid methyl ester (3.9 g) was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give 3-oxo-3-[3-(2-bromo-1,1-dimethoxy-ethyl)-phenyl]-propionic acid tert-butyl ester (2.8 g) as a yellow oil.
Reaction SMILES: [K].CC(O)(C)C.[CH2:7]([N:14]([CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=O)[CH2:15][CH2:16][CH2:17]C(OCC)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C1(C)C(C)=CC=CC=1>[CH2:7]([N:14]1[CH2:15][CH2:16][CH2:17][C:26](=[O:28])[CH2:25][CH2:24][CH2:23]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CCCN(CCCC(=O)OCC)Cc1ccccc1
Agent: Cl
Agent: [K]
Solvent: Cc1ccccc1C
Solvent: CC(C)(C)O
Product: O=C1CCCN(Cc2ccccc2)CCC1

Procedure:
To a stirred boiling slurry made from potassium (1.28 g, 32.8 mmol) and t-BuOH (2.43 g, 32.8 mmol) in xylene (182.5 mL) under N2 was added diethyl 4,4′-(benzylazanediyl)dibutanoate (5 g, 14.9 mmol) over 5 hours in xylene (37.25 mL). The mixture was stirred and heated at reflux for 1 hour. After being cooled, the reaction mixture was neuturalized with 6N HCl (100 mL) and then was extracted with 6N HCl (3×50 mL). The combined acid solutions were filtered and the filtrate was heated under reflux for 1 hour. After cooling, the mixture was basified with concentrated KOH solution to pH 10 with cooling and extracted with dichloromethane. The combined organics were dried over Na2SO4 and concentrated to give a residue. Another 17 batches were done in parallel. The combined residue from 18 batches was purified together by column (P.E./EtOAc 5:1) to give 1-benzylazocan-5-one. 1H NMR (CDCl3, 400 MHz) δ 7.30-7.33 (m, 2H), 7.21-7.25 (m, 3H), 3.56 (s, 2H), 2.55 (t, J=6.0, 4H), 2.24 (t, J=6.4 Hz, 4H), 1.86-1.91 (m, 4H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10](=O)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:13][C:14]([S:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>C1COCC1.[Cl-].[Na+].O>[Si:1]([O:8][CH2:9]/[C:10](=[N:19]/[S:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])/[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)S(N)=O
Reactant: CC(=O)CO[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C/C(CO[Si](C)(C)C(C)(C)C)=N\S(=O)C(C)(C)C
Temperature: 70 °C
Yield: 65.2 %

Procedure:
1-(tert-butyldimethylsilyloxy)propan-2-one (188 mg, 1.0 mmol) and Ti(OEt)4 (0.52 mL, 2.5 mmol) were dissolved in THF (5 mL). Then 2-methylpropane-2-sulfinamide (121 mg, 1.0 mmol) was added to the mixture under nitrogen atmosphere. The mixture was heated to 70° C. for 2 h. The mixture was poured into brine and filtered through a plug of Celite. The organic layer was concentrated and purified by silica gel chromatography using PE/EA (5/1) to give product the title compound (190 mg, 65%). EDI-MS (M+1): 292. 1H NMR (300 MHz, CDCl3) δ 4.152 (s, 2H), 2.248 (s, 3H), 1.156 (s, 9H), 0.839 (s, 9H), 0.001 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[F:55][C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][CH:65]=1)[CH2:62][NH:61][CH2:60][CH2:59]2>ClCCl.O>[F:55][C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][CH:65]=1)[CH2:62][N:61]([C:19](=[O:20])[CH2:18][O:17][CH:14]1[CH2:13][CH2:12][CH:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:22]([F:23])([F:25])[F:24])[CH:6]=3)[CH2:16][CH2:15]1)[CH2:60][CH2:59]2
Reactant: Fc1ccc2c(c1)CCNC2
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCc2cc(F)ccc2C1
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
To a solution of 2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]acetic acid (144 mg, 0.40 mmol) in dichloromethane (15 ml) was added EDAC.HCl (114 mg, 0.59 mmol), HOBt (80 mg, 0.59 mmol) and triethylamine (120 mg, 1.19 mmol) with stirring for 30 minutes. Then 6-fluoro-1,2,3,4-tetrahydroisoquinoline (60 mg, 0.40 mmol) was added to the reaction mixture and the contents were stirred overnight at room temperature. The reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (3×80 ml). The organic fractions were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to give a residue, which was purified by silica gel column chromatography using 5% ethyl acetate in dichloromethane to afford 1-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]ethan-1-one as a yellow solid (93.8 mg, 48%); (ES, m/z): [M+H]+ 496.00; 1H NMR (300 MHz, CDCl3): δ 8.01 (d, J=9.0 Hz, 1H), 7.09 (m, 1H), 6.95-6.82 (m, 3H), 6.65 (d, J=9.0 Hz, 1H), 4.69 (m, 2H), 4.28 (s, 2H), 3.84-3.70 (m, 2H), 3.48-3.33 (m, 2H), 2.93-2.83 (m, 2H), 2.16-2.13 (m, 4H), 1.52-1.40 (m, 2H), 1.34-1.16 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:28]3[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=3)[S:8][C:7]=2[CH:36]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:17][CH:18]=3)=[O:12])=[C:9]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[S:8][C:7]=2[CH:36]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCOC(=O)C(C)(C)C)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: CC(C)(C)C(=O)OCOc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Yield: 69 %

Procedure:
[6-Methoxy-2-(4-Methoxyphenyl)benzo[b]thiophen-3-yl][4-(Trimethylacetoxymethoxy)phenyl]methanone (760 mg, 1.5 mmol) was converted to the title compound by the procedure of Example 3 using 300 mg (4.5 mmol) of ethanethiol and 600 mg (4.5 mmol) of aluminum chloride.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.N([O-])=O.[Na+].[ClH:18]>C(O)(=O)C.O>[Cl:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1
Reactant: Nc1ccccc1Sc1ncc[nH]1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccccc1Sc1ncc[nH]1
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of 5.6 g (29.3 mmoles) of the product from Example 32 in 50 ml of 3N hydrochloric acid and 50 ml of glacial acetic acid (cooled in an ice bath), was added dropwise over 20 minutes, a solution of 2.0 g (29.3 mmoles) of sodium nitrite in 8 ml of water. After stirring for 10 minutes, the mixture was added to a cold solution of 8.7 g (80 mmoles) cuprous chloride in 80 ml of 6N hydrochloric acid. After stirring at room temperature for 5 hours, the mixture was concentrated and the residue made alkaline with ammonium hydroxide. The product was extracted with dichloromethane which was washed with saturated sodium chloride, dried and concentrated. The residue was dissolved in hot dichloromethane and filtered through silica gel using dichloromethane/ethyl acetate (1:1 by volume) as the eluent. The fractions containing the product were concentrated to give 4.9 g (79%) of the product which was crystallized from dichloromethane to give colorless rods, mp 138°-141° C.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].Cl.O[C:10]1[C:11](C)=[C:12]([CH:16]=[CH:17]C=1)[C:13]([OH:15])=[O:14]>O.[OH-].[Na+]>[C:5]([O:4][C:1]1[C:16]([CH3:17])=[C:12]([CH:11]=[CH:10][CH:2]=1)[C:13]([OH:15])=[O:14])(=[O:7])[CH3:6]
Reactant: Cc1c(O)cccc1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1cccc(C(=O)O)c1C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a flat-flanged vessel, 80.0 g of 3-hydroxy-2-methylbenzoic acid (purity 97.78%) are dissolved in 320.0 g of water and 120.0 g of sodium hydroxide solution (w=30%), which results in a pH of 6.9. The clear solution is cooled to 0° C. and adjusted to pH=9 by metering in sodium hydroxide solution (w=30%). Acetic anhydride and sodium hydroxide solution are now simultaneously metered in at 0-5° C. in such a way that the pH remains within the range of 8.8-9.2. 112.6 g of acetic anhydride and 172.25 g of sodium hydroxide solution (w=30%) are metered in within 2.5 h. Afterwards, the mixture is stirred for a further 1.5 h. A second flat-flanged vessel is charged with 150.0 g of water and cooled to 0° C. The reaction mixture of the first vessel and hydrochloric acid (w=37%) are simultaneously metered in at a maximum of 5° C. in such a way that a pH of 3.8-4.2 is maintained. The product precipitates out as a white precipitate. The pH is adjusted to 1 by metering in hydrochloric acid (w=37%). The product is filtered off with suction and washed with 500.0 g of water. The precipitate is dried in a vacuum drying cabinet at 60° C. for 16 h. 172.6 g of 3-acetoxy-2-methylbenzoic acid (purity 99.9%) are obtained. This corresponds to 99.28% of theory.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:26](OCC)=[O:27]>O1CCCC1>[C:24]([C:23]([CH2:22][CH2:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:26][OH:27])#[N:25]
Reactant: CCOC=O
Reactant: N#CCCCCCc1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#CC(=CO)CCCCc1ccccc1
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
A stirred solution of 2.2 mL (0.016 mole) of diisopropylamine in 200 mL of tetrahydrofuran was cooled to -80° C., and 6.4 mL (0.016 mole) of n-butyllithium (2.5 Molar in hexanes) was added dropwise during a 15 minute period. Upon completion of addition, the reaction mixture was stirred for an additional 15 minutes. While still maintaining the reaction mixture temperature at -80° C. to -75° C., a solution of 2.5 grams (0.016 mole) of 6-phenylhexanenitrile in 50 mL of tetrahydrofuran was added dropwise during a 30 minute period. Upon completion of addition, the reaction mixture was stirred at -80° C. for an additional 30 minutes. After this time, a solution of 1.3 mL (0.016 mole) of ethyl formate in 50 mL of tetrahydrofuran was added dropwise during a ten minute period. Upon completion of addition, the reaction mixture was stirred for two hours at -80° C. to -70° C. The reaction was quenched with 100 mL of water, and the mixture was acidified with 6N hydrochloric acid. The mixture was extracted with two 150 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography using silica gel. Elution was accomplished using 1% to 3% methanol in methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure, yielding 2.7 grams of 2-cyano-6-phenyl-1-hexen-1-ol. The NMR spectrum was consistent with the proposed structure.