Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1([C:9]([C:11]2[CH:36]=[CH:35][C:14]([O:15][C:16]3[N:21]=[CH:20][C:19]([NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)=[CH:13][CH:12]=2)=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH:37]([C:39]1[S:40][CH:41]=[CH:42][N:43]=1)=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[S:40]1[CH:41]=[CH:42][N:43]=[C:39]1[CH2:37][N:6]1[CH2:7][CH2:8][N:3]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[N:21]=[CH:20][C:19]([NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)=[CH:35][CH:36]=2)=[O:10])[CH2:4][CH2:5]1
Reactant: O=Cc1nccs1
Reactant: O=C(Nc1ccc(Oc2ccc(C(=O)N3CCNCC3)cc2)nc1)c1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Oc2ccc(C(=O)N3CCN(Cc4nccs4)CC3)cc2)nc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-{6-[4-(piperazine-1-carbonyl)phenoxy]pyridin-3-yl}-4-trifluoromethyl-benzamide dihydrochloride (400 mg, 0.74 mmol) in 1,2-dichloroethane (20 mL) were added 2-formylthiazole (125 mg, 1.10 mmol) and triethylamine (0.21 mL, 1.50 mmol). After the resulting solution was stirred at room temperature for 30 minutes, sodium triacetyloxy borohydride (312 mg, 1.47 mmol) was added under ice cooling. The reaction mixture was stirred at the same temperature for 30 minutes and at room temperature for 1 hour. Acetic acid (0.085 mL, 1.48 mmol) was added to the reaction mixture, and stirred at room temperature for 17 hours. The reaction mixture was poured into ice water, and extracted with chloroform. The chloroform layer was washed with a saturated sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. A significant part of the solvent was evaporated. The white precipitate was then filtered off and washed with ethyl acetate, to thereby yield 293 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH3:14][O:15][C:16](=[O:23])[C@@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18]>>[CH3:21][CH:20]([CH3:22])[CH2:19][C@@H:17]([NH:18][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)=[O:13])[C:16]([O:15][CH3:14])=[O:23]
Reactant: COC(=O)[C@H](N)CC(C)C
Reactant: Cc1ccc2[nH]c(C(=O)O)cc2c1
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1cc2cc(C)ccc2[nH]1
Yield: 50 %

Procedure:
Prepared in a similar manner to example 4 using 5-Methyl-1H-indole-2-carboxylic acid and D-leucine methyl ester. Yield: 50%. NMR (500 MHz, CDCl3): 0.98 (d, 3H, J=6.3 Hz), 1.00 (d, 3H, J=6.1 Hz), 2.44 (s, 3H), 3.784 (s, 3H), 4.87 (m, 1H), 6.56 (d, 1H, J=8.39 Hz), 6.85 (dd, 1H, J=1.94 Hz, J=0.68 Hz), 7.12 (dd, 1H, J=8.46 Hz, J=1.55 Hz), 7.31 (d, 1H, J=8.45 Hz), 7.42 (s, 1H). MS (MH+, 303).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([O:22]C)=[O:21])=[CH:13][C:12]=3[CH:24]=2)=[CH:4][CH:3]=1.Cl>COCCOC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([OH:22])=[O:21])=[CH:13][C:12]=3[CH:24]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(F)cc3)ccc2S(=O)(=O)CC1
Agent: Cl
Solvent: COCCOC
Product: O=C(O)C1=Cc2cc(-c3ccc(F)cc3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Yield: 93 %

Procedure:
To a solution of methyl 7-(4-fluorophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.55 g) in 1,2-dimethoxyethane (20 ml) was added 6N hydrochloric acid (10 ml), and the mixture was refluxed for 29 hours, cooled to room temperature, extracted with ethyl acetate, saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were collected by filtration. The crystals were washed with diisopropylether and hexane to give pale yellow crystals of 7-(4-fluorophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (490.7 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:17])=O>[OH-].[Na+]>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([Cl:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c(N)nc2ccccc2c1O
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1c(N)nc2ccccc2c1Cl
Temperature: 110 °C

Procedure:
The mixture of 10 g of 2-amino-3-cyano-4-hydroxyquinoline and 15 ml of phosphoryl chloride is heated under stirring at 110 ° C. The reaction mixture is cooled down, poured onto 100 ml of ice-water and neutralized with 60 ml of 10% sodium hydroxide solution. The resulting yellow precipitate is filtered off, washed with 50 ml of water. After drying 7.5 g of the title compound is obtained, mp.: 210° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:23][CH3:24])[C:14]([CH2:15][C:16]3([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1>FC(F)(F)C(O)=O.[Pt](=O)=O>[NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:23][CH3:24])[C:14]([CH2:15][C:16]3([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:10]2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCCCC1
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc2c(N)nc3c(c2c1CC1(O)CCCCC1)CCCC3
Reaction time: 16 h
Yield: 37 %

Procedure:
1-[(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]cyclohexanol (0.226 g, 0.70 mmol) and platinum(IV) oxide (0.107 g, 0.47 mmol) were slurried in trifluoroacetic acid (10 mL). The flask was degassed three times and charged to 50 psi hydrogen (3.45×105 Pa). After 16 hours, the catalyst was removed via filtration through a bed of CELITE filter agent, rinsing with methanol. The filtrate was concentrated. The oily residue was dissolved in 6N hydrochloric acid (3 mL). The acidic mixture was brought to pH 14 using 50% aqueous sodium hydroxide. The mixture was extracted with 10% methanol in dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The material was purified via automated flash chromatography eluting with a linear gradient of 2-20% CMA in chloroform. The resulting white solid was triturated in acetonitrile and then isolated by filtration to provide 0.085 g of 1-[(4-amino-2-ethyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]cyclohexanol as a white solid, m.p. 232-234° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=1)[CH3:2].[H-].[Na+].I[CH3:28]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:6]1[CH:11]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:9]=[C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=1)[CH3:28])[CH3:2]
Reactant: CCOC(=O)Cc1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (3-benzyloxy-5-trifluoromethyl-phenyl)-acetic acid ethyl ester (5.0 g, 14.8 mmol) in DMF (50 mL) at 0° C. under N2 was added sodium hydride (60% in mineral oil; 0.65 g, 16.3 mmol), and the mixture was stirred at room temperature for 15 minutes. Iodomethane (1 mL, 16.3 mmol) was added, and the reaction was monitored by analytical LCMS and tlc. After work-up with EtOAc and H2O, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[CH:3][N:2]=1.[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:4]4[CH:5]=[CH:6][N:1]=[N:2][CH:3]=4)=[O:15])[CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1ccnnc1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccnnc1)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Yield: 59.3 %

Procedure:
A solution of 2,2,2-trichloroethyl pyridazin-4-ylcarbamate (100 mg, 0.370 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (90.7 mg, 0.370 mmol), diisopropylethylamine (0.0645 ml, 0.370 mmol) and dimethylsulfoxide (2 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to obtain the desired product (80.4 mg, 59.1%) as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:18][NH:19][CH2:20][CH2:21][NH:22][CH3:23]>>[CH3:18][N:19]([C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1)[CH2:20][CH2:21][NH:22][CH3:23]
Reactant: Clc1nccnc1OCCOc1ccccc1
Reactant: CNCCNC
Product: CNCCN(C)c1nccnc1OCCOc1ccccc1

Procedure:
A mixture of 2-chloro-3-(2-phenoxyethoxy)pyrazine (50 mg, 0.20 mmol; from Example 1, Step 1) and N,N′-dimethylethylenediamine (0.2 mL, 1.9 mmol) was heated in a MicroWell 10 microwave reactor for 6 min at 100W. The reaction mixture was partitioned between water and EtOAc and applied to a hydromatrix column. The column was eluted with EtOAc and the elute was concentrated. The product was purified by Amberchrom CG-161m LC using CH3CN/H2O (gradient: CH3CN 0% to 100%). Yield 2 mg (4%). MS m/z 303 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[CH2:7][CH2:8][C:9]#[N:10])[CH3:2].[OH-:16].[Na+]>O>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[CH2:7][CH2:8][C:9]([NH2:10])=[O:16])[CH3:15]
Reactant: CCN(CC)c1cccc(CCC#N)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CCN(CC)c1cccc(CCC(N)=O)c1
Temperature: 60 °C

Procedure:
A mixture of 40 parts of 3-diethylamino-hydrocinnamonitrile (A), 34 parts by volume of 66° Be sulfuric acid and 6 parts of water was heated at 100°-105° C. for one hour. The reaction mixture was then left to cool to about 60° C., then poured onto 500 parts of ice. It was neutralized by addition of about 160 parts by volume of a 35° Be solution of sodium hydroxide, while assuring that the temperature of the mixture did not exceed 20° C. After filtering and washing with water, 3-diethylamino-hydrocinnamamide was obtained of the formula: ##STR18## which melted at 59° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>CN(C1C=CN=CC=1)C>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[S:20]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:22])=[O:21]
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1ccc(Cl)cc1Cl
Yield: 103.4 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.69 mmol), 2,4-dichlorobenzenesulfonyl chloride (200 mg, 0.83 mmol) and DMAP (cat.) gave the title compound (252 mg, 100%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [O-]CC.[Na+].[C:5]([NH:8][C:9](=[O:32])[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11]1[S:12][C:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:14][C:15]=1[C:16](OCC)=[O:17])(=O)C.IC>C(O)C>[CH3:5][N:8]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:12][C:11]=2[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:9]1=[O:32]
Reactant: CCOC(=O)c1cc(Cc2ccccc2)sc1N(CC(C)C)C(=O)NC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Cc3ccccc3)sc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.8 %

Procedure:
Sodium ethoxide (1.96 g) was added to a solution of N′-acetyl-N-(2-methylpropyl)-N-[3-ethoxycarbonyl-5-(phenylmethyl)-2-thienyl]urea (2.90 g) in ethanol (40 ml) under nitrogen. The mixture was stirred for 20 hours then iodomethane (1.80 ml) was added. The mixture was heated to reflux for 3 hours and then allowed to cool to room temperature and evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate twice. The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography eluting with diethyl ether:isohexane (1:1) to give an oil which was recrystallised from diethyl ether/isohexane to give the title compound (1.70 g).
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([S:10]([N:13]2[CH:26]([CH3:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)(=[O:12])=[O:11])=[CH:5][C:4]=1[CH3:28].C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH3:9][C:8]1[CH:7]=[C:6]([S:10]([N:13]2[CH:26]([CH3:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)(=[O:12])=[O:11])[CH:5]=[C:4]([CH3:28])[C:3]=1[OH:2]
Reactant: COc1c(C)cc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C)cc1C
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C)cc(C)c1O
Yield: 81.9 %

Procedure:
The title compound was prepared from 5-[(4-methoxy-3,5-dimethylphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (1.0 g, 2.54 mmol), cyclohexene (0.64 mL, 6.36 mmol) and 1.0 M boron tribromide in dichloromethane (15.3 mL, 15.3 mmol) according to the procedure and in the same manner as described in Example 1, step b. The crude product was purified by flash column chromatography on silica gel, eluting with dichloromethane to yield 2,6-dimethyl-4-[(6-methylphenanthridin-5(6H)-yl)sulfonyl]phenol (0.79 g, 2.08 mmol, 82%) as a white solid, m.p. 211-213° C.;
Reaction SMILES: Br.Br[CH2:3][CH2:4][C:5]1[C:10](=[O:11])[N:9]2[C:12]([CH3:15])=[CH:13][S:14][C:8]2=[N:7][C:6]=1[CH3:16].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:20][CH:19]=1.C[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.CC(C)CC(=O)C>[F:37][C:34]1[CH:35]=[CH:36][C:31]([C:24]([C:21]2[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=2)=[C:25]2[CH2:30][CH2:29][N:28]([CH2:3][CH2:4][C:5]3[C:10](=[O:11])[N:9]4[C:12]([CH3:15])=[CH:13][S:14][C:8]4=[N:7][C:6]=3[CH3:16])[CH2:27][CH2:26]2)=[CH:32][CH:33]=1
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Reactant: Cc1nc2scc(C)n2c(=O)c1CCBr
Agent: Br
Agent: C[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Cc1nc2scc(C)n2c(=O)c1CCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 72.8 %

Procedure:
A mixture of 5.6 parts of 6-(2-bromoethyl)-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one monohydrobromide, 3.5 parts of 4-[bis(4-fluorophenyl)methylene]piperidine, 1 part of a sodium methoxide solution 30%, 8 parts of sodium carbonate and 240 parts of 4-methyl-2-pentanone was stirred and refluxed for 20 hours using a water-separator. The reaction mixture was filtered while hot and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 4.3 parts (72.8%) of 6-[2-[4-[bis(4-fluorophenyl)methylene]-1-piperidinyl]-ethyl]-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one; mp. 183.8° C. (compound 112).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:17][CH:16]2[N:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]([CH2:14][CH2:15]2)[CH:12]=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[CH2:17][CH:16]2[N:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]([CH2:14][CH2:15]2)[CH2:12]1
Reactant: CCOC(=O)N1C2C=C(c3ccc4ccccc4c3)CC1CC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)N1C2CCC1CC(c1ccc3ccccc3c1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
A mixture of 4.0 gm (13.0 mMol) 3-(naphth-2-yl)-8-ethoxycarbonyl-8-azabicyclo[3.2.1]oct-2-ene, 0.5 gm 10% palladium on carbon and 8.22 gm (130 mMol) ammonium formate in 100 mL ethanol was stirred at room temperature for 16 hours and then at reflux for 1.5 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography. Fractions containing product were combined and concentrated under reduced pressure to provide 2.83 gm (70.4%) of 3-(naphth-2-yl)-8-ethoxycarbonyl-8-azabicyclo-[3.2.1]octane.
Reaction SMILES: [C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:43][C:44]1[CH:49]=[CH:48][C:47](Br)=[CH:46][N:45]=1>>[NH2:43][C:44]1[N:45]=[CH:46][C:47]([C:33]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:31]([CH:32]=2)[CH2:30][N:15]([C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH:12]2[CH2:13][CH2:14][CH:9]([N:8]([CH3:42])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:5])[CH3:6])[CH2:10][CH2:11]2)=[CH:48][CH:49]=1
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: Nc1ccc(Br)cn1
Product: COc1ccc(-c2ccc(N)nc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 9 (1.10 g, 1.76 mmol) is coupled to 2-amino-5-bromopyridine (365 mg, 2.11 mmol) using Method A to give the title compound.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]([F:27])([F:26])[C:11]1[N:16]=[C:15]([N:17]2[CH2:21][C@@H:20]3[C:22](=[O:25])[CH2:23][CH2:24][C@@H:19]3[CH2:18]2)[CH:14]=[CH:13][CH:12]=1>O1CCCC1>[C:1]1([C@:22]2([OH:25])[C@@H:20]3[C@@H:19]([CH2:18][N:17]([C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:10]([F:26])([F:9])[F:27])[N:16]=4)[CH2:21]3)[CH2:24][CH2:23]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@H]12
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O[C@]1(c2ccccc2)CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Temperature: -10 °C

Procedure:
Phenylmagnesium bromide in tetrahydrofuran (0.266 mL, 0.266 mmol) was added to (3aR,6aS)-2-[6-(trifluoromethyl)pyridin-2-yl]hexahydrocyclopenta[c]pyrrol-4(1H)-one (60 mg, 0.222 mmol) from Example 32 in tetrahydrofuran (1 mL) at −40° C., and the reaction mixture was allowed to warm to −10° C. in 20 minutes. The reaction was quenched with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The combined organic washes were purified by silica gel chromatography using 0-40% ethyl acetate/hexane as eluent to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.78 (dt, J=8.2, 1.6, 2H), 7.45 (t, J=7.7, 3H), 7.37-7.27 (m, 1H), 6.90 (d, J=7.2, 1H), 6.70 (d, J=0.5, 1H), 6.46 (d, J=8.6, 1H), 4.02-3.94 (m, 1H), 3.92-3.82 (m, 1H), 3.62-3.42 (m, 2H), 3.07 (td, J=9.3, 2.8, 1H), 3.02-2.92 (m, 1H), 2.38-2.22 (m, 2H), 2.17-1.98 (m, 2H); MS (ESI+) m/z 349 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[C:9](Cl)(Cl)=[O:10]>C(#N)C.N1C=CC=CC=1>[N-:7]=[C:9]=[O:10].[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3]
Reactant: O=C(Cl)Cl
Agent: CCOC(=O)CN
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: [N-]=C=O

Procedure:
Alternatively, glycine ethyl ester hydrochloride (35.7 g, 0.256 mole) was suspended in dry acetonitrile (300 ml) containing phosgene (50.7 g, 0.512 mole) and the reaction mixture was refluxed. A few drops of dry pyridine was added after 1 hr. of refluxing. Unreacted glycine ethyl ester hydrochloride was filtered off and dry toluene (300 ml) was added then acetonitrile was distilled off. The toluene solution was refluxed for 1 hr. to obtain glycine ethyl ester isocyanate (IR 2250 cm-1). This isocyanate was reacted, without further purification, with anhydrous methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:17]C)[CH:5]=[C:6]([C:8]2([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH:11]=[CH:10][CH2:9]2)[CH:7]=1.B(Br)(Br)Br.C[Si](C=[N+]=[N-])(C)C.CCCCCC>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[C:6]([C:8]2([C:13]([O:15][CH3:16])=[O:14])[CH2:9][CH:10]=[CH:11][CH2:12]2)[CH:7]=1
Reactant: COC(=O)C1(c2cc(F)cc(OC)c2)CC=CC1
Agent: BrB(Br)Br
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: ClCCl
Product: COC(=O)C1(c2cc(O)cc(F)c2)CC=CC1
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a stirred solution of methyl 1-(5-fluoro-3-methoxyphenyl)cyclopent-3-ene-1-carboxylate (495 mg, 2.0 mmol) in dry dichloromethane (10 ml) was added a 1.0M solution of boron tribromide in dichloromethane (10 ml, 10 mmol) at -78° C. and the mixture stirred for 1 hr at the same temperature. The reaction mixture was quenched by the addition of water (20 ml) and the resulted mixture acidified with 1.0N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated under reduced pressure. The residue was dissolved in a mixture of methanol (5 ml) and toluene (15 ml) and a 2.0M solution of trimethylsilyldiazomethane in hexane (2 ml, 4 mmol) was added at ambient temperature with stirring. After 0.5 hr, the reaction mixture was partitioned between ethyl acetate and water, the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried with MgSO4 and concentrated in vacuo. The resultant oil was purified by column chromatography (SiO2, 150 g; hexane/ethyl acetate (4/1)) to afford 407 mg (87%) of methyl 1-(5-fluoro-3-hydroxyphenyl)cyclopent-3-ene-1-carboxylate white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([C:10]#[C:11][Si](C)(C)C)[CH:9]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+]>CO.C(OCC)(=O)C>[C:10]([C:8]1[CH:7]=[N:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1)#[CH:11]
Reactant: C[Si](C)(C)C#Cc1cncc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cncc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a solution of 3-nitro-5-((trimethylsilyl)ethynyl)pyridine (4.90 mmol) in MeOH (15 mL) was added K2CO3 (67 mg, 0.49 mmol). The mixture was stirred at rt for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and chromatographed (hexane/ethyl acetate) to afford the desired product (540 mg, 74% over two steps) as a light brown solid: 1H NMR (300 MHz, CDCl3) δ 9.39-9.38 (m, 1H), 8.99-8.98 (m, 1H), 8.56-8.54 (m, 1H), 3.40 (s, 1H).