Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:5])#[N:2].CO/[CH:16]=[CH:17]/[C:18](=O)[CH3:19].N12CCN(CC1)CC2.C(OCC)(=O)C>COCCOCCO.O>[F:13][C:9]1[CH:8]=[C:7]([N:6]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:3]([C:1]#[N:2])[C:4]2=[O:5])[CH:12]=[CH:11][CH:10]=1
Reactant: CO/C=C/C(C)=O
Reactant: N#CCC(=O)Nc1cccc(F)c1
Agent: C1CN2CCN1CC2
Solvent: COCCOCCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)c(=O)n1-c1cccc(F)c1
Yield: 30.8 %

Procedure:
A solution (50 mL) of 2-cyano-N-(3-fluorophenyl)acetamide (6.60 g, 37.0 mmol), (3E)-4-methoxybut-3-en-2-one (5.60 g, 56.0 mmol) and 1,4-diazabicyclo[2.2.2]octane (6.20 g, 56.0 mmol) in 2-(2-methoxyethoxy)ethanol was stirred at 120° C. for 12 hr. The reaction solution was divided into two layers with ethyl acetate and water and subjected to extraction (3 times) with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (2.60 g, 31%) as a brown solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[CH2:8]([O:15][C:16]([NH:18][C:19](=[NH:22])OC)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH2:8]([O:15][C:16]([NH:18][C:19]([N:5]1[CH2:6][CH2:7][CH:3]([CH2:2][OH:1])[CH2:4]1)=[NH:22])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=N)NC(=O)OCc1ccccc1
Reactant: OCC1CCNC1
Solvent: Cc1ccccc1
Product: N=C(NC(=O)OCc1ccccc1)N1CCC(CO)C1
Temperature: 60 °C
Yield: 25.2 %

Procedure:
1.01 g (0.01 mole) (3RS)-3-hydroxymethyl pyrrolidine and 2.29 g (0.011 mole) N-benzyloxycarbonyl-O-methylisourea was dissolved (the amine not very soluble) in toluene and heated to 60° C. for three hours followed by stirring at room temperature over night. The mixture was evaporated and the 1H-NMR showed that the reaction was not completed. The mixture was therefore dissolved in 15 ml acetonitrile and heated to 60° C. for three hours followed by stirring at room temperature over night. The solvebt was evaporated and the mixture was dissolved in CH2Cl2, washed once with water, dried (Na2 SO4), filtered and evaporated. The crude product was purified by flash chromatography using CH2Cl2 /MeOH 95/5 as eluent to yield 0.70 g (25%) of the product.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:11])[C:6]=1[C:7](OC)=[O:8].Cl[C:13]1[N:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1>>[CH3:11][C:5]1[C:6]2[C:7](=[O:8])[N:18]3[CH:17]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14][C:13]3=[N:1][C:2]=2[S:3][CH:4]=1
Reactant: COC(=O)c1c(C)csc1N
Reactant: COC(=O)c1ccc(Cl)nc1
Product: COC(=O)c1ccc2nc3scc(C)c3c(=O)n2c1

Procedure:
A mixture of 11.27 g (0.066 mol) of 2-amino-4-methyl-3-thiophenecarboxylic acid, methyl ester (Chemische Berichte, Vol. 98, pages 3571-3577, 1965) and 11.3 g (0.066 mol) of 6-chloro-3-pyridinecarboxylic acid, methyl ester (Alfred Bader Chemical Company) is heated in a wax bath at 173°-190° C. for 220 minutes under nitrogen. The distillate is collected in a Dean-Stark trap attached to the reaction flask. The mixture is cooled, dissolved in hot methanol, cooled and 0.61 g of 3-methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid, methyl ester is collected; mp 208°-209° C. after recrystallization from dichloromethane-methanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Si](C)(C)C)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][N:10]=2)[N:7]=1.[I:22]CCI>C1COCC1.ClCCl>[Cl:1][C:2]1[C:3]([I:22])=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][N:10]=2)[N:7]=1
Reactant: C[Si](C)(C)c1cc2nnc(-c3ccccc3F)n2nc1Cl
Reactant: ICCI
Solvent: ClCCl
Solvent: C1CCOC1
Product: Fc1ccccc1-c1nnc2cc(I)c(Cl)nn12
Reaction time: 18 h
Yield: 60.6 %

Procedure:
A solution of 6-chloro-3-(2-fluorophenyl)-7-(trimethylsilyl)-1,2,4-triazolo[4,3-b]pyridazine (5.0 g, 15.6 mmol), prepared as in Example 25 Step c), and 1,2-diiodoethane (14 g, 50 mmol) in anhydrous THF (150 ml) was added via cannula to a stirred suspension of tris(dimethylamino)-sulfur (trimethylsilyl)difluoride (5.0 g, 18 mmol) in anhydrous THF (200 ml) at room temperature under nitrogen. After 18 h, the mixture was diluted with dichloromethane (400 ml) and washed sequentially with water (300 ml) and brine (200 ml). The organic layer was dried (Na2SO4), filtered and concentrated. Flash column chromatography on silica gel, eluting with 3% methanol-dichloromethane, gave crude 6-chloro-3-(2-fluorophenyl)-7-iodo-1,2,4-triazolo[4,3-b]pyridazine (3.54 g) as a dark brown solid. This was subjected to the conditions described in Example 27 Step b) to give 3-(2-fluorophenyl)-7-iodo-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine (1.32 g, 19% over two steps) as a yellow solid; 1H NMR (360 MHz, CDCl3) δ 3.97 (3H, s), 5.51 (2H, s), 7.28 (1H, dd, J=8 and 8 Hz), 7.37 (1H, dd, J=8 and 8 Hz), 7.56-7.64 (1H, m), 7.86 (1H, ddd, J=7, 7 and 1 Hz), 7.90 (1H, s), 8.68 (1H, s); MS (ES+) m/e 452 [MH]+.
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([C:14](=[O:28])[NH:15][C@H:16]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:17][CH3:18])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:50]2[C@H:51]([CH3:74])[C@H:52]3[C@@H:69]([C@H:70]([OH:72])[CH3:71])[C:68](=[O:73])[N:53]3[C:54]=2[C:55]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][C:62]([N+:65]([O-:67])=[O:66])=[CH:61][CH:60]=2)=[O:56])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[Si:21]([O:20][CH2:19][C@@H:16]([NH:15][C:14]([C:12]1[N:13]=[C:9]([N:7]2[CH2:8][CH:5]([S:4][C:50]3[C@H:51]([CH3:74])[C@@H:52]4[C@@H:69]([C@H:70]([OH:72])[CH3:71])[C:68](=[O:73])[N:53]4[C:54]=3[C:55]([O:57][CH2:58][C:59]3[CH:64]=[CH:63][C:62]([N+:65]([O-:67])=[O:66])=[CH:61][CH:60]=3)=[O:56])[CH2:6]2)[S:10][CH:11]=1)=[O:28])[CH2:17][CH3:18])([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:23])[CH3:22]
Reactant: CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(SC(C)=O)C2)n1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of 3-acetylthio-1-{4-[(1S)-1-(t-butyidimethylsilyloxymethyl)-propylcarbamoyl]-1,3-thiazol-2-yl}azetidine (610 mg, 1.37 mmol) (obtained as described in Reference Example 34) in dimethylformamide (30 ml) was added hydrazine acetate (152 mg, 1.65 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (814 mg, 1.37 mmol) in acetonitrile (40 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (955 μl, 5.48 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 10% aqueous sodium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane: ethyl acetate (1:2) and ethyl acetate as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[(1S)-1-(t-butyidimethylsilyloxymethyl)-propylcarbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (928 mg, yield 89%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:24]([O-])=O)=[C:6](/[CH:8]=[CH:9]/[C:10](=[O:23])[CH2:11][C:12](=[O:22])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:7]=1.[Sn](Cl)Cl>C(OCC)(=O)C.CO.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[NH2:24][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][C:6]=1/[CH:8]=[CH:9]/[C:10](=[O:23])[CH2:11][C:12](=[O:22])/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1
Reactant: O=C(/C=C/c1ccc(O)cc1)CC(=O)/C=C/c1cc(O)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1ccc(O)cc1/C=C/C(=O)CC(=O)/C=C/c1ccc(O)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 28.8 %

Procedure:
To a solution of (1E,6E)-1-(5-hydroxy-2-nitrophenyl)-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione (26 mg, 73 μmol, synthesized in Example 4) in 3.0 mL of ethyl acetate was added anhydrous tin(II) chloride (57 mg, 0.30 mmol) at room temperature. After being stirred at 60° C. for 1.5 h, the reaction mixture was cooled to room temperature, and was diluted with 10% methanol/chloroform and saturated NaHCO3 aqueous solution, successively. The mixture was shaken before filtration to remove inorganic salts. The organic layer after separation was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40 to 30/70) to obtain the title compound as a solid (6.8 mg, 37%) having the following characteristics.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=1)[C:28]([NH2:30])=[O:29].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([NH:22][C:23]4[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=4)[C:28]([NH2:30])=[O:29])=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: NC(=O)c1cncc(N)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)c1cncc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Temperature: 25 °C
Yield: 61.6 %

Procedure:
To solution of (4-adamantan-1-yl-phenoxy)-acetic acid (50 mg, 0.17 mmol), 5-amino nicotinamide (47.89 mg, 0.34 mmol) and DMAP (42.71 mg, 0.34 mmol) in DMF 5 ml was added PyBOP (181 mg, 0.34 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by preparative-TLC(CH2Cl2:MeOH=6:1) to afford 5-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-nicotinamide as a colorless solid (42.48 mg, 60% yield).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[CH:9][CH:8]=1.S(Cl)(Cl)=O.[F:21][C:22]([F:39])([F:38])[C:23]1[CH:24]=[C:25]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:26][NH:27][CH:28]1[CH2:30][CH2:29]1>ClCCl.CN(C)C=O>[F:21][C:22]([F:38])([F:39])[C:23]1[CH:24]=[C:25]([CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=1)[CH2:26][N:27]([CH:28]1[CH2:29][CH2:30]1)[C:13](=[O:15])[C:12]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:16])=[CH:8][CH:9]=[N:10][CH:11]=1
Reactant: FC(F)(F)c1cc(CNC2CC2)cc(C(F)(F)F)c1
Reactant: Cc1ccccc1-c1ccncc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1ccccc1-c1ccncc1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
A solution of 106 mg (0.5 mmol) 4-o-tolyl-nicotinic acid in 5 ml dichloromethane and 2 drops N,N-dimethylformamide was stirred with 0.1 ml (1.4 mmol) thionyl chloride for 1.5 h at room temperature. The solvent was removed and the residue was taken up in 5 ml dichloromethane and 0.3 ml triethylamine. After the addition of 155 mg (0.55 mmol) (3,5-bis-trifluoromethyl-benzyl)-cyclopropyl-amine the mixture was stirred at room temperature for 1 h and washed twice with water. The organic layer was dried (magnesium sulfate) and evaporated. The crude oil was subjected to column chromatography to give 140 mg (58%) of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8].[CH2:13]([N:15](CC)[CH2:16]C)C.CNC.CCO>C(Cl)Cl.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:15]([CH3:16])[CH3:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Agent: CNC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CN(C)S(=O)(=O)c1cnc(Cl)c(Br)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A cooled (0° C.) solution of 5-bromo-6-chloropyridine-3-sulfonyl chloride (2.00 g; 6.87 mmol) in DCM (20 mL) was treated first with triethylamine (1.06 ml; 7.56 mmol) then with a 5.6 M solution of dimethylamine in EtOH (1.35 ml; 7.56 mmol). The reaction was stirred at 0° C. for 1.5 hours then brine was added and the phases separated. The organic phase was washed with brine, dried on MgSO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc to give the title compound as a colorless oil.
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](B(O)O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O:3][C:4]([CH3:7])(C)C)=[O:2].N1C=CC=CC=1.[C:26]([C:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[NH:32][N:31]=1)([CH3:29])([CH3:28])[CH3:27].B(O)O>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:26]([C:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:32]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([C:1]([O:3][CH2:4][CH3:7])=[O:2])[CH:9]=[CH:10]3)[N:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(B(O)O)ccc21
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc2c(ccn2C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
Commercially available N-Boc-5-indoleboronic acid (0.30 g, 1.1 mmol) was dissolved in CH2Cl2 (20 mL) and pyridine (1 mL) with molecular sieves (activated 4 A) and stirred overnight at RT. Commercially available ethyl 3-t-butyl-1 H-pyrazole-5-carboxylate, Cu(OAc)2 and molecular sieves (4 A activated, powder) were added to the boronic acid solution and the whole stirred at RT open to the atmosphere for 2d. The reaction mixture was filtered through a pad of Celite®, concentrated and purified by column chromatography to yield ethyl 5-(3-t-butyl-5-(ethoxycarbonyl)-1H-pyrazol-1-yl)-1H-indole-1-carboxylate (0.18 g, 38% yield). LC-MS (EI) m/z: 412.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]12[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3]2=O.C[Li]>CCOCC>[CH3:1][C:2]12[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH:4]=[CH:3]2
Reactant: CC12CCC(CC1=O)C2(C)C
Agent: [Li]C
Solvent: CCOCC
Product: CC12C=CC(CC1)C2(C)C

Procedure:
1,7,7-Trimethylbicyclo[2.2.1]heptan-2-one (1-camphor) was converted into its 4-toluenesulfonylhydrazone, which was then reacted with methyllithium in ether, to give the title compound. The method used was that described by Shapiro and Duncan, Organic Synthesis, Vol 51, pp 67-69, for the conversion of racemic camphor into racemic 1,7,7-trimethylbicyclo[2.2.1]hept-2-ene.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:17][C:3]1[CH:4]=[C:5]2[C:10]([C:9]([CH:12]([CH3:13])[CH3:14])=[CH:8][CH2:7][C:6]2([CH3:15])[CH3:16])=[CH:11][C:2]=1[Br:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)C1=CCC(C)(C)c2cc(O)c(Br)cc21
Reactant: BrCc1ccccc1
Product: CC(C)C1=CCC(C)(C)c2cc(OCc3ccccc3)c(Br)cc21
Yield: 100 %

Procedure:
Following General Procedure O, 3-bromo-5-isopropyl-8,8-dimethyl-7,8-dihydronaphthalen-2-ol (Compound 97, 0.29 g, 0.98 mmol) was reacted with benzylbromide to afford 0.38 g (100%) of the title compound as a yellow oil.
Reaction SMILES: [N:1]1([C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:17]([OH:19])=[O:18])=[CH:13][C:14]=3[C:15]=2[CH3:16])[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)C.[ClH:23]>[Pd].C(O)(=O)C>[ClH:23].[N:1]1([CH:6]2[CH:15]([CH3:16])[C:14]3[CH:13]=[C:12]([C:17]([OH:19])=[O:18])[CH:11]=[CH:10][C:9]=3[CH2:8][CH2:7]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC1=C(n2ccnc2)CCc2ccc(C(=O)O)cc21
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CC1c2cc(C(=O)O)ccc2CCC1n1ccnc1
Reaction time: 8 h

Procedure:
A mixture of 5,6-dihydro-7(1H-imidazol-1-yl)-8-methyl-2-naphthalenecarboxylic acid (1.5 g), 10% palladium on activated carbon (0.65 g), ethanol 95% (100 ml), glacial acetic acid (30 ml) and concentrated hydrochloric acid (10 ml) is hydrogenated for 8 hours at room temperature in a Parr-Burgess low pressure apparatus at an initial pressure of 50 psi. At the end of this time the theoretical amount of hydrogen has been absorbed. The catalyst is filtered off, washed with 95% ethanol, and the solution is evaporated under reduced pressure. The solid residue is crystallized from 95% ethanol-ethyl ether mixture, giving 1.4 g of 5,6,7,8-tetrahydro-7-(1H-imidazol-1-yl)-8-methyl-2-naphthalenecarboxylic acid hydrochloride.
Reaction SMILES: [Br-].[CH2:2]([N+:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([O-])(=O)C.[NH4+:25].O>C(O)(=O)C>[C:5]1([C:3]2[N:25]=[C:20]3[CH2:19][C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH2:12][N:11]3[CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [NH4+]
Reactant: O=C(C[n+]1ccc2ccccc2c1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Br-]
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(-c2cn3c(n2)Cc2ccccc2C3)cc1

Procedure:
A solution of 2-phenacylisoquinolinium bromide prepared as above (13.1 g) and ammonium acetate (28 g) in glacial acetic acid (36 ml) was heated under reflux for 2 hours. The cooled reaction mixture was poured, with stirring, into water (600 ml). The resultant solid was filtered off and washed well with water. The solid was dissolved in methanol (20 ml), and added dropwise, with stirring, to a solution of sodium hydroxide (1.6 g) in water (100 ml). A further 300 ml of water was added to the suspension, and the granulated solid filtered off, washed well with water, dried, and crystallised from methanol. Yield 2.1 g (21%) m.p. 195°-197°. (Found C 82.8; H 6.0; N 11.4, Required C 82.9; H 5.7; N 11.4).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]([OH:13])[CH2:11][CH3:12])=[CH:4][C:3]=1[O:14][CH3:15]>C(Cl)Cl.O=[Mn]=O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: CCC(O)c1cc(OC)c(Br)c(OC)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCC(=O)c1cc(OC)c(Br)c(OC)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 100.9 %

Procedure:
To a solution of 1-(4-bromo-3,5-dimethoxyphenyl)propan-1-ol (5.4 g, 19.6 mmol) in anhydrous CH2Cl2 (75 mL) was added MnO2 (17 g, 196 mmol). After the mixture was placed under a drying tube and stirred at room temperature for 22 hrs, it was filtered through a pad of Celite and silica gel and rinsed with EtOAc. Concentration of the filtrate in vacuo gave 1-(4-bromo-3,5-dimethoxyphenyl)propan-1-one as a white solid (5.4 g, 100% yield). The product was used without further purification.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][C:18](O)=[O:19])=[CH:8]1.O.[OH-].[Na+]>C1COCC1>[OH:19][CH2:18][CH2:17][CH2:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][CH:8]=1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1c[nH]c2ccccc12
Temperature: 0 °C
Yield: 40.5 %

Procedure:
To a stirred suspension of LiAlH4 (4.02 g) in THF (200 mL) at 0° C. and under N atmosphere was added dropwise a THF solution (100 mL) containing indole-3-propanoic acid (20.0 g). After the addition was complete, the reaction was heated at reflux for 16 h, after which time the mixture was cooled to 0° C. and water (4 mL) added, followed by 15% NaOH (4 mL), and finally additional water (12 mL). The reaction was filtered and the THF filtrate extracted with 5% NaOH (4 mL), and finally additional water (12 mL). The reaction was filtered and the THF filtrate extracted with 5% NaHCO3 followed by a sat. NaCl solution. The organic phase was dried with anhydrous K2CO3, filtered, and concentrated under reduced pressure to yield 3-(3-hydroxypropyl)indole (VI; 7.5 g; 41%).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].CS(O[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([Br:18])[CH:17]=1)(=O)=O>CN(C)C=O>[Br:18][C:16]1[CH:15]=[N:14][CH:13]=[C:12]([CH2:11][S:5][CH2:3][CH3:4])[CH:17]=1
Reactant: CCS
Reactant: CS(=O)(=O)OCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) solution of sodium hydride (60% dispersion in mineral oil, 0.094 g, 2.35 mmol) in N,N-dimethylformamide (9.4 mL) was added ethanethiol (0.140 mL, 1.88 mmol). The reaction was warmed to room temperature and stirred for 30 minutes. It was then cooled to 0° C., and a solution of the title compound from Example 62 Step A (0.250 g, 0.939 mmol) in N,N-dimethylformamide (1 mL) added. The resulting solution stirred at room temperature until the reaction was complete. The reaction was then quenched with water and extracted with ethyl acetate. The combined organic extracts were washed with water and saturated aqueous sodium chloride solution, dried, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (0-60% ethyl acetate in hexanes) provided the title compound: LCMS m/z 233.91 [M+2+H]+; 1H NMR (500 MHz, CDCl3) δ 8.50 (s, 1H), 8.39 (s, 1H), 7.79 (s, 1H), 3.62 (s, 2H), 2.39 (q, J=7.4, 2H), 1.19 (t, J=7.4, 3H).
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH2:6][N:5]([C@H:15]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:16]([O:18]CC2C=CC=CC=2)=[O:17])[CH2:4]1)=O.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:35][CH:34]=1.Cl>>[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:39][CH2:40][CH2:41][CH:42]2[CH2:43][CH2:44][N:45]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=4)[CH2:6][N:5]([C@H:15]([CH2:26][CH:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)[C:16]([OH:18])=[O:17])[CH2:4]3)[CH2:46][CH2:47]2)=[CH:37][CH:38]=1
Reactant: Fc1ccc(CCCC2CCNCC2)cc1
Reactant: O=C[C@H]1CN([C@H](CC2CCCC2)C(=O)OCc2ccccc2)C[C@@H]1c1cccc(F)c1
Agent: Cl
Product: O=C(O)[C@@H](CC1CCCC1)N1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2cccc(F)c2)C1
Yield: 102.7 %

Procedure:
The title compound was prepared from 20 mg (0.047 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-cyclopentylpropanoic acid, benzyl ester (from EXAMPLE 20, Step K) and 13 mg of 4-(3-(4-fluorophenyl)propyl)piperidine.HCl (from EXAMPLE 96, Step B) using a procedure analogous to that described in EXAMPLE 1, Step J to provide 26 mg (89%) of the title compound: RF: 0.20 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 1.01-1.83 (m, 22H), 2.21-2.88 (m, 10H), 3.12-3.19 (m, 2H), 3.37 (m, 1H), 5.16 (ABq, J=12.1 Hz, 2H), 6.83-7.39 (m, 13H).