Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](/[CH:9]=[CH:10]\[N+:11]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[Si]([N:24]=[N+:25]=[N-])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:24]=[N:25][NH:11][CH:10]=2)[CH:6]=[CH:5][C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: COc1cc(/C=C\[N+](=O)[O-])ccc1-c1ccccn1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Product: COc1cc(-c2c[nH]nn2)ccc1-c1ccccn1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-{2-methoxy4-[(Z)-2-nitroethenyl]phenyl}pyridine (0.23 g, 0.89 mmol) and TMSN3 (0.18 mL, 1.34 mmol) in DMF (1 mL) was heated to slowly to 50° C. while TBAF (0.98 mL, 1.0 M in THF, 0.98 mol) was added dropwise over 20 min. The resulting reaction mixture was continued to stir at 50° C. for 30 min. The mixture was partitioned between sat. NaHCO3 (20 mL) and EtOAc (60 mL). The phases were separated and the aqueous layer was extracted with EtOAc (3×60 mL). The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified on silica gel (20:1 hexane-ethyl acetate) to afford a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)=[CH:17][CH:16]=2)[C:10](=[O:26])[CH2:9]1)=O)(C)(C)C.[ClH:27]>CO.C(OCC)(=O)C>[ClH:27].[ClH:27].[N:21]1([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]3=[O:26])=[CH:16][CH:17]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-n3ccnc3)cc2)C(=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CNCCN1Cc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(tert-butoxycarbonyl)-1-[4-(1H-imidazol-1-yl)benzyl]-2-piperazinone (1.5 g) in methanol (10 ml) was added 4N hydrochloric acid in ethyl acetate solution (50 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was powdered with ethyl acetate, filtered and dried to give hygroscopic colorless solid of the title compound (1.12 g).
Reaction SMILES: O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:11].[Mg+2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]([NH:30][C:31]([C@H:33]2[CH2:38][CH2:37][C@H:36]([NH:39][S:40]([C:43]3[CH:48]=[CH:47][C:46]([C:49]4[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=4)=[CH:45][CH:44]=3)(=[O:42])=[O:41])[CH2:35][CH2:34]2)=[O:32])[CH3:29])=[CH:24][CH:23]=1>CO.C(Cl)Cl>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]([NH:30][C:31]([C@H:33]2[CH2:34][CH2:35][C@H:36]([NH:39][S:40]([C:43]3[CH:44]=[CH:45][C:46]([C:49]4[CH:54]=[CH:53][N+:52]([O-:11])=[CH:51][CH:50]=4)=[CH:47][CH:48]=3)(=[O:41])=[O:42])[CH2:37][CH2:38]2)=[O:32])[CH3:29])=[CH:24][CH:23]=1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: C[C@@H](NC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(-c3ccncc3)cc2)CC1)c1ccc(F)cc1
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: C[C@@H](NC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(-c3cc[n+]([O-])cc3)cc2)CC1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Magnesium monoperoxyphthalate hexahydrate (66.8 mg, 0.135 mmol) was suspended in MeOH (0.5 ml) and cooled to 0° C. Trans-4-(4-pyridin-4-yl-benzenesulfonylamino)-cyclohexanecarboxylic acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide (Example 284, 50 mg, 0.097 mmol) in DCM (0.5 ml) was added dropwise and the reaction mixture was left to stir overnight at 23° C. LCMS indicated that the reaction was complete, and the mixture was concentrated in vacuo to a residue which was purified by reverse phase chromatography on prep-HPLC (150 mm, C8 luna, 15-20 min run, 10%-100% MeCN in water containing 0.1% TFA). Product containing fractions were lyophilized to yield the title compound (10 mg, 21%). MS MH+ 498.1
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[C:27](F)[CH:28]=3)[C:23](=[O:32])[C:22]([C:33]([OH:35])=[O:34])=[CH:21]2)[CH2:19][CH2:18]1>>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:11]2([CH2:12][CH2:13][N:14]([C:27]3[CH:28]=[C:29]4[C:24]([C:23](=[O:32])[C:22]([C:33]([OH:35])=[O:34])=[CH:21][N:20]4[CH:17]4[CH2:19][CH2:18]4)=[CH:25][C:26]=3[F:31])[CH2:15][CH2:16]2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CC12CCNCC2
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: CC(C)(C)OC(=O)NC1CC12CCN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)CC2
Yield: 96.3 %

Procedure:
According to the procedure of example 1A, 1-tert-butoxycarbonylamino-6-azaspiro[2.5]octane (260.0 mg, 1.15 mmol ) and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (274 mg, 1.04 mmol) were reacted to generate the title product (472 mg, 1.00 mg, 97% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]2[O:19][CH2:18]2)[O:4][N:3]=1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>>[CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:19])[CH2:18][NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])[O:4][N:3]=1
Reactant: CC(C)(C)N
Reactant: Cc1cc(C=Cc2ccccc2OCC2CO2)on1
Product: Cc1cc(C=Cc2ccccc2OCC(O)CNC(C)(C)C)on1

Procedure:
This compound is obtained by the method described for Example 1 from 5.0 g (0.019 mole) of 3-methyl-5-[2-(2,3-epoxypropoxy)-styryl]-isoxazole and 1.56 g (0.2 mole) of tert.-butylamine. 3.1 g (48% of theory) of colorless crystals, melting point 83°-85° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][CH2:16][C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.O1CCOCC1>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([CH2:14][CH2:15][CH2:16][C:17]#[N:18])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: C1COCCO1
Product: N#CCCCN1CCC(c2ccccc2)CC1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A suspension of 4-phenylpiperidine (5.20 g, 32.2 mmol, 1.00 equiv), 4-bromobutyronitrile (4.81 mL, 48.4 mmol, 1.50 equiv), potassium carbonate (11.14 g, 80.6 mmol, 2.50 equiv), and potassium iodide (266 mg, 12.9 mmol, 0.4 equiv) in n-butanol (60 mL) and 1,4-dioxane (60 mL) was stirred at reflux under argon for 48 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by flash chromatography (SiO2, MeOH—EtOAc 1:19) to afford 3.95 g of 4-(4-phenylpiperidin-1-yl)butyronitrile (white solid, 53%), which was characterized spectroscopically.
Reaction SMILES: [OH:1][C@@:2]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:42]([NH:44][CH3:45])=[O:43])[CH:38]=2)[CH:33]=1)([C:8]1[N:9]=[CH:10][N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)[CH2:3][C:4](OC)=[O:5].O.Cl>C(OCC)(=O)C>[OH:1][C@@:2]([C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH:38]=[C:37]([C:42]([NH:44][CH3:45])=[O:43])[CH:36]=[CH:35]2)([C:8]1[N:9]=[CH:10][N:11]([C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)[CH2:3][CH2:4][OH:5]
Reactant: CNC(=O)c1ccc2cc([C@@](O)(CC(=O)OC)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc2cc([C@@](O)(CCO)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
0.188 g (0.314 mmol) of methyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate was added at 0˜5° C., and the mixture was stirred for 30 minutes. The mixture was stirred at room temperature for 4.5 hours. 7 mL of water was added dropwise at 35° C. or lower. 2.5 mL of 1N hydrochloric acid was added dropwise, followed by dilution with 10 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 2 mL of an aqueous saturated sodium bicarbonate solution and 2 mL of an aqueous saturated sodium chloride solution. After concentrated under reduced pressure, the concentration residue was loosened with 2 mL of IPE, crystals were filtered, and washed with 1 mL of IPE. Vacuum drying (40° C.) to a constant weight afforded 0.16 g of 6-[(1S)-1,3-dihydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide (yield 90%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=1)[CH3:2].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:8]=[C:9]([Cl:14])[CH:10]=[C:11]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([F:16])=[CH:18][CH:19]=2)[N:12]=1)[CH3:2]
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)CSc1nc(Cl)cc(Nc2ccc(F)cc2)n1
Yield: 30.3 %

Procedure:
A stirred mixture of 10.7 g of (4,6-dichloro-2-pyrimidinylthio)acetic acid ethyl ester, 4.4 g of p-fluoroaniline and 4.2 g of sodium carbonate was heated under reflux for 6 hr. and filtered. Water was added to the filtrate to the precipitation point. The precipitate was removed by filtration and recrystallized from 95% ethanol to afford 4.1 g of product; mp. 97°-102°C.
Reaction SMILES: N([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)=[N+]=[N-].[C:23]([NH:30][C@H:31]([C:53]([OH:55])=O)[CH2:32][S:33][C:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C[CH2:57][N:58]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CO.[Pd]>[C:23]([NH:30][C@H:31]([C:53]([C:5]1[C:4]([CH2:57][NH2:58])=[CH:9][CH:8]=[CH:7][C:6]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:11]=1)=[O:55])[CH2:32][S:33][C:34]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24]
Reactant: CC(C)(C)OC(=O)c1cccc(-c2cccc(N=[N+]=[N-])c2)c1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: [Pd]
Agent: On1nnc2ccccc21
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)c1c(CN)cccc1-c1cccc(C(=O)OC(C)(C)C)c1
Reaction time: 5 h
Yield: 44 %

Procedure:
Compound 20 (0.75 g, 2.43 mmol) was dissolved in 30 mL of methanol. A catalytic amount of 5% palladium on barium sulfate (0.30 g) was added. The mixture was hydrogenated at 1 atm for 5 hr. The catalyst was removed by filtration and the methanol was evaporated. This residue was dissolved in 40 mL of methylene chloride. N-Boc-S-trityl cysteine (1.12 g, 2.43 mmol) was added at 0° C. followed by EDCI (1 eq) and HOBT (1 eq). The mixture was stirred for 24 hr. After workup and evaporation of solvents, the residue was purified by flash column chromatography (hexane:ethyl acetate=3.2:1) to give 21 (570 mg, 44%). m.p. 84-86° C. 1H NMR (CDCl3) δ 8.17 (s, 1H), 7.95 (d, 7.7 Hz, 1H), 7.70 (d, 7.7 Hz, 1H), 7.50-7.30 (m, 9H), 7.30-7.10 (m, 11H), 6.44 (br, 1H), 4.86 (br, 1H), 4.45 (d, 4.0 Hz, 2H, CH2Ph), 3.87 (br, 1H, Cys α H), 2.75 (dd, 7.2 and 12.8 Hz, 1H, CH2S), 2.55 (dd, 5.3 and 12.8 Hz, 1H, CH2S), 1.62 (s, 9H), 1.36 (s, 9H). Anal. (C45H48N2O5S) C, H, N, S.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:11](C#C)[CH2:10][C:9]([CH3:15])([CH3:14])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH2:17]([Li])[CH2:18]CC.[C:22](=[O:24])=[O:23].[Cl-].[NH4+]>C1COCC1>[CH3:16][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]([CH3:15])([CH3:14])[C:8]2[CH:7]=[C:6]([C:17]#[C:18][C:22]([OH:24])=[O:23])[CH:5]=[CH:4][C:3]1=2
Reactant: C#CC1CC(C)(C)c2ccccc2C1(C)C
Reactant: [Li]CCCC
Reactant: O=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C#CC(=O)O)ccc21

Procedure:
A solution of 4.1 g (19 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-6-ethynylnaphthalene in 75 ml of THF is introduced into a three-necked flask under a stream of nitrogen, 13.3 ml (21 mmol) of n-butyllithium (2.5M) are added dropwise at −78° C. and the mixture is allowed to return to room temperature. At −78° C., a stream of CO2 is introduced for 30 min and the mixture is allowed to return to room temperature. The reaction medium is poured into saturated ammonium chloride solution and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is triturated with hexane, filtered off and dried. 3.5 g (73%) of the expected propargylic acid, with a melting point of 175-7° C., are collected.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:34]([O:36][C:37](=[O:42])[C:38](Br)([CH3:40])[CH3:39])[CH3:35]>C1COCC1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH2:22][C:38]([C:37]([O:36][CH2:34][CH3:35])=[O:42])([CH3:40])[CH3:39])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)CC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc1
Reaction time: 0.5 h

Procedure:
To 4-(5-acetyl-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (1.36 g, 4.24 mmol) in THF (15 mL) at −78° C. was added 0.5M potassium bis(trimethylsilyl)amide in toluene (17 mL) and stirred for 30 min before adding 2-bromo-2-methyl-propionic acid ethyl ester (1.25 mL, 8.49 mmol) at −78° C. After overnight stirring at r.t., the reaction was quenched with 1N HCl, extracted with dichloromethane, washed with water/brine, dried over sodium sulfate, and concentrated. The product was purified using a Single Step column (7:3 hexanes:ethyl acetate) to obtain 0.458 g (25%); MS m/z 435 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:10](=O)[CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)N)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([N:40](CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:8]([C:10]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:40][N:6]=2)[CH:7]=1
Reactant: NN(C(=O)CCN1CCCC1)c1ccc(F)cn1
Reactant: CCN(CC)CC
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc2nnc(CCN3CCCC3)n2c1
Reaction time: 18 h
Yield: 73.2 %

Procedure:
Intermediate 1a (400 mg) was dissolved in THF (20 mL) and cooled in an ice/water bath. Triphenylphosphine (643 mg, 2.45 mmol) was added followed by triethylamine (682 μL, 4.90 mmol) and hexachloroethane (581 mg, 2.45 mmol). The reaction mixture was stirred for 18 h and then loaded onto an SCX-2 cartridge, which was washed with MeOH then eluted with 2M NH3 in MeOH. The resulting residue was purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to give the title compound (292 mg, 1.16 mmol, 52%). 1H NMR (400 MHz, CDCl3): 1.80-1.87 (4H, m), 2.60-2.68 (4H, m), 3.00-3.10 (2H, t, J 7.3), 3.24-3.34 (2H, t, J 7.3), 7.13-7.21 (1H, ddd, J 9.9, 7.6, 2.3), 7.70-7.77 (1H, dd, J 9.8, 4.5), 8.00-8.04 (1H, m).
Reaction SMILES: BrBr.[F:3][C:4]1[CH:5]=[C:6]([CH3:11])[C:7](=[CH:9][CH:10]=1)[NH2:8].C([Br:19])C1C=CC=CC=1>>[F:3][C:4]1[CH:5]=[C:6]([CH3:11])[C:7](=[CH:9][CH:10]=1)[NH:8][Br:19]
Reactant: BrCc1ccccc1
Reactant: Cc1cc(F)ccc1N
Agent: BrBr
Product: Cc1cc(F)ccc1NBr

Procedure:
Bromine (0.5 mole) is added over 1 hour to stirred 4-fluoro-2-toluidine (0.5 mole) at 100° C. illuminated with a high wattage lamp. The crude benzyl bromide is used as prepared.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[NH:21][C:12]3[N:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][NH2:20])=[O:18])[C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([O-])([O-])(OCC)[CH3:23]>>[CH3:22][C:23]1[O:18][C:17]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:21][C:9]([CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:10][C:11]=23)=[N:19][N:20]=1
Reactant: CCOC(C)([O-])[O-]
Reactant: NNC(=O)c1ccnc2[nH]c(CCc3ccccc3)cc12
Product: Cc1nnc(-c2ccnc3[nH]c(CCc4ccccc4)cc23)o1
Temperature: 140 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 2-(2-phenylethyl)-1H-pyrrolo[2,3-b]pyridine-4-carbohydrazide (104 mg, 0.371 mmol) and ethyl orthoacetate (5 mL) was stirred at 120° C. for 1 hr and at 140° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-0/1) and basic silica gel column chromatography (hexane/ethyl acetate=4/1-0/1), and recrystallized from hexane/ethyl acetate to give the title compound (85 mg, yield 75%) as pale-yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:14]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:6][CH:5]=1)([O-])=O.C1CCCCC=1>CO.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:14]=2[C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)=[CH:6][CH:5]=1
Reactant: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1CCCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CO
Product: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1CCCc1ccc(N)cc1
Yield: 103 %

Procedure:
45 mg of 5-[3-(4-nitrophenyl)propyl]-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole was dissolved in 6 ml of methanol, followed by the addition of 2 ml of cyclohexene. Then, 45 mg of 10% palladium-carbon was added thereto, followed by heating under reflux for 2 hours. After the reaction mixture was filtered, the filtrated was concentrated to obtain 43 mg of the title compound quantitatively as a colorless amorphous substance.
Reaction SMILES: [S:1]1(=[O:9])(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH:14]=O.[NH2:20][C:21]1[CH:25]=[CH:24][NH:23][N:22]=1>C(O)C>[Br:10][C:11]1[CH:12]=[C:13]([CH:14]2[N:22]3[N:23]=[CH:24][CH:25]=[C:21]3[NH:20][C:3]3[CH2:4][CH2:5][CH2:6][S:1](=[O:9])(=[O:8])[C:2]2=3)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: O=C1CCCS(=O)(=O)C1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: Nc1cc[nH]n1
Solvent: CCO
Product: O=S1(=O)CCCC2=C1C(c1ccc(F)c(Br)c1)n1nccc1N2
Temperature: 25 °C

Procedure:
A solution of tetrahydrothiopyran-3-one-1,1-dioxide (0.74 g, 5 mmol), 3-bromo-4-fluorobenzaldehyde (1.01 g, 5 mmol), and 3-aminopyrazole (0.41 g, 5 mmol) in ethanol (5 mL) was heated at reflux for 24 hours. After the reaction mixture was allowed to cool to ambient temperature, the solid that precipitated was filtered off, washed with ethanol, and dried to provide the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[N:10][C:11]([C:13]4[CH:18]=[CH:17]N=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[C:28]1(B(O)O)C=CC=CC=1>>[CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[N:10][C:11]([C:13]4[CH:14]=[CH:15][CH:28]=[CH:17][CH:18]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccccc1
Reactant: C[C@@H](Oc1nc(-c2ccncc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Product: C[C@@H](Oc1nc(-c2ccccc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Yield: 33.3 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of (R)-4-((R)-1-((3-cyclopropyl-6-(pyridin-4-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:, using instead phenylboronic acid (100.0 mg, 0.82 mmol) as a starting material to afford 32.6 mg (33.3%) of (R)-4-((R)-1-((3-cyclopropyl-6-phenyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl) pyrrolidin-2-one:. 1H NMR (300 MHz, DMSO-d6) δ 8.295 (s, 1H), 8.09 (dd, J=1.8, 5.4 Hz, 2H), 7.801 (s, 1H), 7.57 (s, 1H), 7.45 (t, J=7.2 Hz, 2H), 7.375-7.346 (m, 1H), 5.61-5.74 (m, 1H), 3.73-3.68 (m, 1H), 3.42 (t, J=9.3 Hz, 1H), 3.22 (dd J=6.3, 6.3 Hz, 1H), 2.87-2.82 (m, 1H), 2.34 (d, 9 Hz, 2H), 1.43 (d, J=6.6 Hz, 3H), 1.15-1.03 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd for C21H22N4O2: 362.17; found 363.09.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)(=[O:4])=[O:3].[NH2:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19]>CS(C)=O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCC(O)CO
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(NCC(O)CO)c([N+](=O)[O-])c1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
A mixture of 4-chloro-3-nitrophenyl methyl sulfone (5 g, 21 mmole) and 3-amino-1,2-propanediol (4.25 g, 47 mmole) in DMSO (15 ml) was stirred at 23° C. for 30 min. and poured into crushed ice. The resulting yellow crystal was collected by filtration and washed with ice-cold water to give the compound (21) (5.2 g, 95%) (m.p. 133° C.).
Reaction SMILES: C1C2C(CC=CC=2)CCC1=O.C1C2C(=CC=CC=2)CCC1.[CH3:22][C:23]1([CH3:47])[CH2:32][CH2:31][C:30](=[O:33])[C:29]2[CH:28]=[C:27](/[CH:34]=[CH:35]/[C:36]3[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=3)[CH:26]=[CH:25][C:24]1=2.Br[CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51]>[Zn]>[CH3:47][C:23]1([CH3:22])[CH2:32][CH2:31][C:30]([OH:33])([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[C:29]2[CH:28]=[C:27](/[CH:34]=[CH:35]/[C:36]3[CH:37]=[CH:38][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:45][CH:46]=3)[CH:26]=[CH:25][C:24]1=2
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(=O)CCC3(C)C)cc1
Agent: O=C1CCC2CC=CC=C2C1
Agent: [Zn]
Solvent: c1ccc2c(c1)CCCC2
Product: CCOC(=O)CC1(O)CCC(C)(C)c2ccc(/C=C/c3ccc(C(=O)OCC)cc3)cc21

Procedure:
Reaction Scheme 5 discloses another example for the preparation of compounds within the scope of Formula 3. In this example the substituent is introduced to replace the oxo function of tetrahydronaphthalene-2-one after the Z--Y(R2)--A--B group has already been coupled to the tetrahydronaphthalene nucleus. Thus, ethyl (E)-4-[2-(5,6-dihydro-5,5-dimethyl-naphthalen-8(7H)-one-2-yl)ethenyl]benzoate (Compound A2) is reacted with ethyl bromoacetate in the presence of zinc metal in a Reformatsky reaction to provide (±) ethyl (E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy-8-(carbethoxymethyl)naphthalen-2-yl)ethenyl]benzoate (Compound A32). Compound A32 is itself within the scope of the present invention, within the scope of Formula 1. Compound A32 is dehydrated, as shown in the example by treatment with (methoxycarbonylsulfamoyl)triethylammonium hydroxide (Burgess reagent) to yield a mixture of ethyl (E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(carbethoxymethyl)naphthalen-2-yl)ethenyl]benzoate (Compound A33a), and ethyl (E)-4-[2-(5,6-dihydro-5,5-dimethyl-8(7H)-anti (carbethoxymethylidenyl)-naphthalen-2-yl)ethenyl]benzoate (Compound A33b). Compound A33a is within the scope of Formula 6, and Compound A33b is within the scope of Formula 3. ##STR20##