Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:33]Br.O>O1CCCC1>[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:33][N:2]([CH3:1])[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CNC(=O)c1ccncc1-c1ccccc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1-c1cnccc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a solution of 226 mg (1 mmol) N-methyl-3-o-tolyl-isonicotinamide in 10 ml tetrahydrofuran were added dropwise 1.3 ml (1.3 mmol) 1M potassium hexamethyldisilazide solution in tetrahydrofuran at room temperature. The white suspension was stirred for 30 min at room temperature and 0.18 ml (1 mmol) 3,5-bis(trifluoromethyl)benzyl bromide were added at the same temperature. The light brown suspension was stirred for 1 h and water was added. The aqueous layer was separated and washed with ethyl acetate. The combined organic layers were washed twice with brine, dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 440 mg (97%) of the title compound as a light brown oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]([C:13]([CH3:17])=[C:14]([OH:16])[CH:15]=1)[C:5]([O:7][CH2:8][C:9]([Cl:12])([Cl:11])[Cl:10])=[O:6]>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[C:2]([O:1][C:2]1[C:3]([CH3:18])=[C:4]([C:13]([CH3:17])=[C:14]([O:16][C:5](=[O:6])[CH3:4])[CH:15]=1)[C:5]([O:7][CH2:8][C:9]([Cl:10])([Cl:11])[Cl:12])=[O:6])(=[O:1])[CH3:15]
Reactant: Cc1c(O)cc(O)c(C)c1C(=O)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc(OC(C)=O)c(C)c(C(=O)OCC(Cl)(Cl)Cl)c1C

Procedure:
A solution of 6.27 g of 2,2,2-trichloroethyl 3,5-dihydroxy-2,6-dimethylbenzoate in 15 ml of acetic anhydride and 0.3 ml of pyridine was heated under reflux for 3 hours. The solution was cooled and the solvent removed under reduced pressure. The residue was dissolved in 20 ml of ethyl acetate and crystallized by the addition of 120 ml of n-hexane to yield 2,2,2-trichloroethyl 3,5-diacetoxy-2,6-dimethylbenzoate as white crystals with mp 127°-128° C.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7]O.[C:9]1(=O)[CH:12]2[CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[CH:11]2[CH2:10]1>CO>[CH2:9]1[NH:7][CH2:10][CH:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13][CH:12]12
Reactant: O=C1CC2c3ccccc3CC12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1ccc2c(c1)CC1CNCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium acetate (1.45 g, 17.7 mmol) and hydroxylamine hydrochloride (0.68 g, 9.75 mmol) were added to a solution of 2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one (1.4 g, 8.86 mmol) in MeOH (18 mL), and stirred overnight at room temperature. The reaction solution was concentrated via rotary evaporation. The residue was dissolved in CH2Cl2 (100 mL), washed with H2O (50 mL), dried over MgSO4, and concentrated to give the subtitle compound, which was used without further purification. MS calculated for C11H11NO+H: 174, observed: 174.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:9][C:10]2[S:25][C:13]3[N:14]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:15](=[O:20])[N:16]([CH3:19])[C:17](=[O:18])[C:12]=3[C:11]=2[C:26]([N:28]2[CH2:32][CH:31]([O:33][Si](C(C)(C)C)(C)C)[CH2:30][O:29]2)=[O:27])[C:4](=[O:8])[S:5][C:6]=1[Cl:7].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[N:3]([CH2:9][C:10]2[S:25][C:13]3[N:14]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:15](=[O:20])[N:16]([CH3:19])[C:17](=[O:18])[C:12]=3[C:11]=2[C:26]([N:28]2[CH2:32][CH:31]([OH:33])[CH2:30][O:29]2)=[O:27])[C:4](=[O:8])[S:5][C:6]=1[Cl:7]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)N3CC(O[Si](C)(C)C(C)(C)C)CO3)c(Cn3c(Cl)c(Cl)sc3=O)sc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)N3CC(O)CO3)c(Cn3c(Cl)c(Cl)sc3=O)sc21

Procedure:
To a solution of the product of step e) (180 mg) in THF (5 ml) under a nitrogen atmosphere, was added glacial acetic acid (0.10 ml) follwed by 1 N tetrabutylammonium fluoride solution in THF (0.5 ml). After 16 h at ambient temperature the mixture was neutralised with sat sodium bicarbonate solution and extracted into ethyl acetate. The organics were washed with water, and dried over magnesium sulphate. Concentration in vacuo gave a white solid that was purified by reverse phase HPLC to give the title compound as a white solid (100 mg). δ 1HDMSO 0.92 (6H,d), 2.18 (1H,non), 3.20 (3H,s), 3.43-4.11 (6H,m), 4.60-4.76 (1H,m), 5.04-5.11 (2H,m), 5.51 (1H,s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C@@H:13](O)[CH2:14][C@H:15]([CH2:19][O:20]CC2C=CC=CC=2)[CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([CH:29]([CH3:31])[CH3:30])[C@@H:9]1[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:46][OH:47]>[Pd]>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C@@H:13]([CH2:46][OH:47])[CH2:14][C@H:15]([CH2:19][OH:20])[CH:16]([CH3:17])[CH3:18])[CH2:11][C@@H:10]([CH:29]([CH3:31])[CH3:30])[C@@H:9]1[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H]([C@@H](O)C[C@H](COCc3ccccc3)C(C)C)N2C(=O)OC(C)(C)C)ccc1OC
Reactant: CO
Agent: [Pd]
Product: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H]([C@@H](CO)C[C@H](CO)C(C)C)N2C(=O)OC(C)(C)C)ccc1OC

Procedure:
A solution of 0.48 g of 8 in 1.5 mL of methanol is treated with 0.1 g of 10% palladium on charcoal. The suspension is stirred under an atmosphere of hydrogen until the uptake is stable. The suspension is filtered and the solid washed with 5 mL of methanol in two portions. Removal of the solvent in vacuum provides alcohol 9 as an oil. A negative [a]d (e.g. −34.1, −34.6) is found at c=1, CHCl3.
Reaction SMILES: [F:1][C:2]1[CH:21]=[N:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[OH:17])=O.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:21]=[N:20][CH:19]=[CH:18][C:3]=1[C:4]1[O:17][C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[N:6]=1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccncc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 50 °C
Yield: 96 %

Procedure:
To a mixture of 0.51 g of 3-fluoro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, 5 ml of tetrahydrofuran and 0.53 g of triphenylphosphine, 0.89 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred while heating at 50° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.46 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 25”).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].[Li]CCCC.[CH2:16]([CH:18]1[CH:22]([C:23]2[N:27]3[C:28]4[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:29]=4[N:30]=[CH:31][C:26]3=[N:25][N:24]=2)[CH2:21][C:20](=[O:43])[CH2:19]1)[CH3:17]>C1COCC1>[CH2:16]([CH:18]1[CH:22]([C:23]2[N:27]3[C:28]4[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[C:29]=4[N:30]=[CH:31][C:26]3=[N:25][N:24]=2)[CH2:21][C:20]([CH2:1][S:2]([N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)(=[O:4])=[O:3])([OH:43])[CH2:19]1)[CH3:17]
Reactant: CCC1CC(=O)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Reactant: CS(=O)(=O)N1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC1CC(O)(CS(=O)(=O)N2CCOCC2)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.4 %

Procedure:
To a solution of 4-(methylsulfonyl)morpholine (0.217 g, 1.314 mmol, Preparation #41) in THF (4 mL) at about 0° C. was added n-BuLi (2.5 M in hexanes, 0.53 mL, 1.3 mmol). The reaction mixture was stirred at about 0° C. for about 1 h. The resulting solution was added dropwise to a solution of 3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone (0.350 g, 0.876 mmol, Example #35 Step G) in THF (4 mL) at about 0° C. The reaction mixture was maintained at about 4° C. in a refrigerator for about 48 h. The reaction mixture was partitioned between water (5 mL) and DCM (5 mL) The layers were separated and the aqueous solution was extracted with DCM (2×5 mL). The combined organic extracts were concd under reduced pressure. The product was purified by silica gel chromatography eluting with a gradient of 0-2% MeOH/DCM, then by RP-HPLC (Table 1, Method 1) to give 3-ethyl-1-(morpholinosulfonylmethyl)-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (0.17 g, 34%) as a yellow oil: LC/MS (Table 1, Method b) Rt=2.32 & 2.42 min; MS m/z: 565 (M+H)+.
Reaction SMILES: CC(OC(=O)[NH:7][CH2:8][CH2:9][C@@H:10]([O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:24]#[N:25])[C:11]1[S:12][CH:13]=[CH:14][N:15]=1)(C)C.Cl>O1CCOCC1>[ClH:23].[NH2:7][CH2:8][CH2:9][C@@H:10]([O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:24]#[N:25])[C:11]1[S:12][CH:13]=[CH:14][N:15]=1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](Oc1cc(Cl)ccc1C#N)c1nccs1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(Cl)cc1O[C@H](CCN)c1nccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 178.3 %

Procedure:
To a solution of [(3R)-3-(5-chloro-2-cyanophenoxy)-3-(2-thiazolyl)propyl]-carbamic acid 1,1-dimethylethyl ester (140 mg, 0.36 mmol) in dry dioxan (3 ml) was added 4M HCl in dioxan (1 ml) and the mixture was stirred at room temperature for 16 h. The precipitate was collected, washed with ethyl acetate and vacuum dried to leave 106 mg of a white solid (90%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH2:31][CH2:32][CH3:33])(=[O:30])=[O:29])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2].[S:43]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44]1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:45]3[CH:46]=[CH:47][S:43][CH:44]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH2:32][CH3:33])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2]
Reactant: CCCS(=O)(=O)c1cc(Br)cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)c1
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCCS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)cc(-c2ccsc2)c1
Yield: 72.9 %

Procedure:
A similar procedure as described in Example 41, step 1 was used, starting from 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-bromo-5-(propane-1-sulfonyl)-phenoxy)-hexyl]-phenoxy]-butyric acid ethyl ester (208 mg, 0.31 mmol), 3-thiopheneboronic acid (81.2 mg, 0.62 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (34 mg, 0.047 mmol), and cesium carbonate (205 mg, 0.62 mmol) to afford 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-(propane-1-sulfonyl)-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy]-butyric acid ethyl ester (152 mg, 73%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C36H48O8S2 (M+Na)+ 695.2683, found 695.2680.
Reaction SMILES: Cl.CN(C)C.[S:6](Cl)([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH3:17][O:18][CH2:19][C@H:20]([OH:22])[CH3:21].C(N(CC)CC)C.CN(C)CCCN.Cl>O.C1(C)C=CC=CC=1>[CH3:13][C:12]1[CH:14]=[CH:15][C:9]([S:6]([O:22][C@H:20]([CH3:21])[CH2:19][O:18][CH3:17])(=[O:8])=[O:7])=[CH:10][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC[C@@H](C)O
Agent: CN(C)C
Agent: CN(C)CCCN
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC[C@@H](C)OS(=O)(=O)c1ccc(C)cc1
Temperature: -5 °C
Reaction time: 4.5 h

Procedure:
To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added trimethylamine hydrochloride (0.1 eq), tosyl chloride (1.3 eq) and toluene (5 vols) under a nitrogen atmosphere and the reaction mixture agitated to form an oily slurry. The slurry was cooled to −5° C., then (2R)-1-methoxypropan-2-ol (1.0 eq) was added drop-wise over 30 minutes. Toluene (2.5 vols) was added as a line wash followed by triethylamine (1.5 eq), which was added drop-wise via addition funnel over 30 minutes maintaining the reaction temperature <8° C. Further toluene (2.5 vols) was added as a line wash and the reaction mixture held at −5° C. to 5° C. for 4.5 hours. N,N-dimethyl-1,3-propane-diamine, (0.3 eq) was added over 10 minutes at −5° C. The reaction mixture was agitated at −5° C. to 5° C. for 30 minutes, then 2N hydrochloric acid (0.55 eq) and 70 ml water were added. The reaction mixture was agitated for 30 minutes at 22° C. and the aqueous layer was separated off and discarded. The mixture was washed twice more with water (10 vols each wash) then the toluene layer was distilled to an oil on the rotary evaporator. Toluene (20 vols) was added to the oil and the solution evaporated to an oil to give the title compound as a dry light brown oil. Yield corrected for assay 93-97%. 1H NMR δ (400 MHz CDCl3): 7.78-7.75 (d, 2H), 7.45-7.43 (d, 2H), 4.66-4.62 (m, 1H), 3.35-3.26 (m, 2H), 3.16 (s, 3H), 2.4 (s, 3H), 1.13-1.11 (d, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]3[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=3[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([CH3:37])[CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]4[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=4[F:26])(=[O:13])=[O:14])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[C:30]([CH3:37])[CH:29]=1
Reactant: Cc1cc(Cl)ccc1B(O)O
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Temperature: 50 °C
Yield: 39.3 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-chloroisoquinoline-6-sulfonate (see EXAMPLE 73, Step 1, 518.97 mg, 1.267 mmol), (4-chloro-2-methylphenyl)boronic acid (324 mg, 1.900 mmol), potassium carbonate (525 mg, 3.80 mmol), and Pd(PPh3)4 (146 mg, 0.127 mmol). The flask was flushed with Ar (g), then 1,4-dioxane (4750 μl) and water (1583 μl) were added. The flask was sealed and heated in a 50° C. heating bath overnight. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 0-30% EtOAc/Heptane) to give perfluorophenyl 1-(4-chloro-2-methylphenyl)isoquinoline-6-sulfonate (249 mg, 0.498 mmol, 39.3% yield) as a clear oil. m/z (ESI) 500.0 (M+H)+.
Reaction SMILES: [CH:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([N+]([O-])=O)[CH:18]=[CH:17][N:16]=1>>[Cl:14][C:15]1[CH:20]=[C:19]([O:11][CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH:18]=[CH:17][N:16]=1
Reactant: OC1CCCc2ccccc21
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(OC2CCCc3ccccc32)ccn1
Yield: 98.8 %

Procedure:
Using the method of Example 3, Step A, 1,2,3,4-tetrahydronaphthalen-1-ol (935 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to provide 2-chloro-4-(1,2,3,4-tetrahydronaphthalen-1-yloxy)pyridine (1.62 g, 99% yield) as an oil. 1H NMR (CDCl3) δ 8.21 (d, 1H), 7.17-7.30 (m, 4H), 6.95 (s, 1H), 6.83 (d, 1H), 5.46 (t, 1H), 2.89 (ddd, 1H), 2.80 (ddd, 1H), 2.17 (m, 1H), 2.06 (m, 1H), 1.97 (m, 1H), 1.84 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C@@H:13]([O:24][CH2:25][O:26][CH3:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:7][C:6]=1[N+:28]([O-])=O)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C@@H:13]([O:24][CH2:25][O:26][CH3:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:7][C:6]=1[NH2:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COCO[C@H](C=Cc1ccc(C(C)(C)C)c([N+](=O)[O-])c1)CCCCC1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: COCO[C@@H](CCCCC1CCCCC1)CCc1ccc(C(C)(C)C)c(N)c1
Yield: 56.5 %

Procedure:
A solution of 2.2 g (5.27 mmol) of (S)-2-t-butyl-5-(3-methoxymethyloxy-7-cyclohexyl-1-heptenyl)-1-nitrobenzene [prepared as described in step (iii) above] in 40 ml of ethanol was vigorously stirred in a stream of hydrogen for 6 hours in the presence of 1.5 g of 10% w/w palladium-on-charcoal. The catalyst was then filtered off and washed with ethanol. The filtrate and the washings were combined, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 9:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.16 g (yield 57%) of the title aniline derivative as an oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=3)[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C@@H:20]([C:23]1[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH2:21][OH:22].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:30][O:29][C:26]1[N:25]=[CH:24][C:23]([C@H:20]([NH:19][C:2]2[C:3]3[CH2:11][N:10]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=4)[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:21][OH:22])=[CH:28][CH:27]=1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)nc1
Reactant: COc1ccc([C@H](N)CO)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc([C@@H](CO)Nc2ncnc3c2CN(c2ccc(C)cn2)CC3)cn1

Procedure:
A reaction mixture of 4-chloro-5,6,7,8-tetrahydro-6-(5-methylpyridin-2-yl)pyrido[4,3-d]pyrimidine (55 mg, 0.21 mmol) and (S)-2-amino-2-(6-methoxypyridin-3-yl)ethanol (35 mg, 0.21 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (73 μL, 0.42 mmol) was subjected to microwave irradiation at 180° C. for 2 h. The reaction mixture was concentrated and purified by semi-prep HPLC (100×20.2 mm, C18 column; 25-50% CH3CN-water [10 mM Et2NH]) to give a light yellow solid.
Reaction SMILES: C=O.[CH3:3][NH:4][C:5]([NH:7][C:8]1[CH:12]=[C:11]([C:13]([CH2:16][O:17][CH3:18])([CH3:15])[CH3:14])[O:10][N:9]=1)=[O:6].CN.[CH3:21][N:22]([CH3:25])[CH:23]=O>O>[CH3:3][N:4]1[CH2:23][N:22]([CH3:25])[CH2:21][N:7]([C:8]2[CH:12]=[C:11]([C:13]([CH2:16][O:17][CH3:18])([CH3:14])[CH3:15])[O:10][N:9]=2)[C:5]1=[O:6]
Reactant: CNC(=O)Nc1cc(C(C)(C)COC)on1
Reactant: CN(C)C=O
Agent: C=O
Agent: CN
Solvent: O
Product: COCC(C)(C)c1cc(N2CN(C)CN(C)C2=O)no1
Reaction time: 0.5 h

Procedure:
16 ml of a 36% aqueous formaldehyde solution was added dropwise to a stirred solution of 4.1 g of 2D in 75 ml of dimethylformamide. The temperature of the mixture rose from 22° C. to 27° C. The mixture was stirred for 30 minutes, then 8 ml of a 40% solution of methylamine in water was added, drop-by-drop. The temperature of the mixture rose from 27° C. to 36° C. The mixture was refluxed for 3 hours, then the solvent was evaporated under reduced pressure. The residue was mixed with cold water, and the resulting mixture was extracted with ether. The solvent was evaporated from the extract, and the residue was crystallized when hexane was added, to give 2, as a white solid, m.p.: 49°-50° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)[CH3:2].C(O[C:17]1[CH:22]=[CH:21]C(CC(OC2CCCCO2)=O)=[CH:19][CH:18]=1)C>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]([OH:13])=[O:12])[CH2:21][CH2:22][CH2:17][CH2:18][CH2:19]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(CC(=O)O)cc1
Reactant: CCOc1ccc(CC(=O)OC2CCCCO2)cc1
Product: CCOc1ccc(C2(C(=O)O)CCCCC2)cc1
Yield: 40 %

Procedure:
The title compound was obtained in a manner analogous to that for 1-Phenylcyclohexanecarboxylic acid (1/3) starting with (4-ethoxyphenyl)acetic acid (4b), via tetrahydro-2H-pyran-2-yl 2-(4-ethoxyphenyl)acetate (5b). The crude product 1/5 was chromatographed on silica gel with toluene-ethyl acetate-acetic acid (9:1:0.1) as eluent to give 1-(4-ethoxyphenyl)cyclohexanecarboxylic acid (1/5) in 40% yield. 1H NMR (CDCl3, HMDSO) δ: 1H NMR (CDCl3, HMDSO) δ: 1.17-2.08 (8H, m); 1.34 (3H, t, J=7.0 Hz); 2.26-2.63 (2H, m); 4.02 (2H, q, J=7.0 Hz); 6.88 (2H, d, J=8.8 Hz); 7.36 (2H, d, J=8.8 Hz); 10.09 (1H, br s).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].FC1C=CC(C2(C3C=CC(F)=CC=3)CCN(CC(O)=O)C2=O)=CC=1.O[NH:48]/[C:49](/[C:52]1[CH:57]=[N:56][CH:55]=[CH:54][N:53]=1)=[N:50]\[H].ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[C:13]1([C:6]2([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:5][CH2:4][N:3]([CH2:19][C:20]3[O:21][N:50]=[C:49]([C:52]4[CH:57]=[N:56][CH:55]=[CH:54][N:53]=4)[N:48]=3)[C:2]2=[O:1])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(\NO)c1cnccn1
Agent: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: O=C1N(Cc2nc(-c3cnccn3)no2)CCC1(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)—N-hydroxypyrazine-2-carboximidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.15 (d, J=1.4, 1H), 8.87 (dt, J=2.0, 2.5, 2H), 7.40-7.21 (m, 10H), 5.01 (s, 2H), 3.54 (t, J=6.5, 2H), 2.84 (t, J=6.5, 2H); MS (DCI) m/z 398.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[F:12].C(NC(C)C)(C)C.[Li].CN(C)[CH:23]=[O:24].C(O)(=O)C>O1CCCC1>[F:12][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[C:5]([O:8][CH:9]([CH3:10])[CH3:11])[C:4]=1[CH:23]=[O:24]
Reactant: CC(C)Oc1ccc(F)c(F)c1
Reactant: CN(C)C=O
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(F)c(F)c1C=O
Yield: 89.8 %

Procedure:
In a manner similar to the method described in example 52a, 1,2-difluoro-4-isopropoxy-benzene (5.77 g, 33.5 mmol) prepared in example 62a was reacted with lithium diisopropyl amine (20.5 mL, 1.8 M in THF, 36.9 mmol), N,N-dimethyl-formamide (3.11 mL, 40.2 mmol) and quenched with acetic acid (8.0 g, 134 mmol) in tetrahydrofuran to give 2,3-difluoro-6-isopropoxy-benzaldehyde as a white crystal (Yield: 6.02 g, 89.9%).