Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:34][C:35]1[CH:36]=[C:37]([OH:46])[C:38]([CH3:45])=[C:39]([CH:44]=1)[C:40]([O:42][CH3:43])=[O:41].[CH2:47]([NH:54][C:55]([C@H:57]1[CH2:62][CH2:61][C@@H:60](O)[CH2:59][CH2:58]1)=[O:56])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C1COCC1>[CH2:47]([NH:54][C:55]([C@H:57]1[CH2:62][CH2:61][C@H:60]([O:46][C:37]2[C:38]([CH3:45])=[C:39]([CH:44]=[C:35]([Cl:34])[CH:36]=2)[C:40]([O:42][CH3:43])=[O:41])[CH2:59][CH2:58]1)=[O:56])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: COC(=O)c1cc(Cl)cc(O)c1C
Reactant: O=C(NCc1ccccc1)[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)cc(O[C@H]2CC[C@H](C(=O)NCc3ccccc3)CC2)c1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a cooled (0° C. ice bath) solution of triphenylphosphine (392 mg, 1.495 mmol) in THF (10 mL) was added DIAD (0.291 mL, 1.495 mmol). The reaction was stirred for 15 minutes (became a suspension). To this suspension with stirring was added a solution of methyl 5-chloro-3-hydroxy-2-methylbenzoate (250 mg, 1.246 mmol) and (cis)-N -benzyl-4-hydroxycyclohexanecarboxamide (350 mg, 1.500 mmol) in THF (5 mL) in one portion. The reaction was allowed to warm to room temperature and stirred overnight, at which time the reaction was concentrated in vacuo. The residue was purified by silica gel chromatography (Analogix, SF25-60 g, 10 to 60% EtOAc in hexanes). The resulting solid was triturated with 10% methanol in water, filtered, washed with water, and dried under vacuum to give methyl 3-(((trans)-4-(benzylcarbamoyl)cyclohexyl)oxy)-5-chloro-2-methylbenzoate (180 mg, 0.433 mmol, 34.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.33 (t, J=5.94 Hz, 1H), 7.38 (d, J=2.02 Hz, 1H), 7.27-7.35 (m, 3H), 7.16-7.27 (m, 3H), 4.37-4.49 (m, 1H), 4.27 (d, J=5.81Hz, 2H), 3.82 (s, 3H), 2.25 (s, 3H), 1.97-2.16 (m, 3H), 1.75-1.89 (m, 2H), 1.53-1.69 (m, 2H), 1.30-1.47 (m, 2H). MS(ES) [M+H]+ 259.0 (weak).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH:5]([N:16]2[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)=[O:22])[CH2:17]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cc1ccc(C2(O)CCC(=O)CC2)cn1
Product: Cc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(6-methyl-pyridin-3-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[OH:17][CH2:16][C:15]1[C:9]2[O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][C:10]=2[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)c1cccc2cc(-c3ccccc3)oc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc2cc(-c3ccccc3)oc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
2-Phenylbenzofuran-7-carboxylic acid (40 g) is dissolved in tetrahydrofuran (300 ml) and the solution is added dropwise to a suspension of lithium aluminum hydride (19.12 g) in tetrahydrofuran (130 ml) under ice-cooling. After the mixture is stirred at 70° C. for 2 hours, water is added to the mixture to decompose excess lithium aluminum hydride and its complex. Insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure to remove solvent. The residue is dissolved in ethyl acetate, and the solution is washed with water, dried and concentrated under reduced pressure to remove solvent. The residue is recrystallized from a mixture of ethyl acetate and n-hexane, whereby 7-hydroxymethyl-2-phenylbenzofuran (34.4 g) is obtained. Yield: 91%.
Reaction SMILES: [OH:1][C@H:2]([CH2:48][OH:49])[CH2:3][CH2:4][NH:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([C:35]2[CH2:36][CH2:37]N(CC3C=CC=CC=3)[CH2:39][CH:40]=2)([CH3:34])[CH3:33])[NH:9]1)=[O:7].C(OCC)(=[O:52])C>O=[Pt]=O>[OH:1][C@H:2]([CH2:48][OH:49])[CH2:3][CH2:4][NH:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:33])([CH:35]2[CH2:40][CH2:39][O:52][CH2:37][CH2:36]2)[CH3:34])[NH:9]1)=[O:7]
Reactant: CC(C)(CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C1=CCN(Cc2ccccc2)CC1
Reactant: CCOC(C)=O
Agent: O=[Pt]=O
Product: CC(C)(CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C1CCOCC1

Procedure:
In a manner similar to the method described in Examples 118a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide prepared in Example 127e (0.28 g, 0.45 mmol) was treated with PtO2 and H2 in ethyl acetate to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-methyl-2-(tetrahydro-pyran-4-yl)-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a off white solid (0.15 g, 54%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2O)c1
Reactant: CCCCCCCCBr
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(CCCC(=O)OC)cc1-c1cc(CCCC(=O)OC)ccc1O
Yield: 91.4 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl and 0.895 ml (5.181 mmol) of octyl bromide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 5 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolve din chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 15 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 100/1) to obtain 236 mg (0.4738 mmol, 91%) of 2-octyloxy-2'-hydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 0.87 (3H, t, CH3), 1.0-2.2 (16H, m, 8CH2), 2.36 (4H, t, 2CH2), 2.65 (4H, t, 2CH2), 3.66 (6H, s, 2CH3), 4.01 (2H, t, CH2), 6.61 (1H, s, OH), 6.8-7.3 (6H, m, arom-H) MS (FAB): 497 (M-H)-
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][C:4]=1[OH:11].[C:12]([O:15]C(=O)C)(=[O:14])[CH3:13]>>[C:12]([OH:15])(=[O:14])/[CH:13]=[CH:9]/[C:7]1[CH:6]=[CH:5][C:4]([OH:11])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(=O)OC(C)=O
Product: COc1cc(/C=C/C(=O)O)ccc1O

Procedure:
Vaniline is reacted according to Perkin's reaction with acetic anhydride to form ferulic acid which is then decarbonized by heating to prepare 3-methoxy-4-hydroxystyrene. This compound is then acetylated with acetic anhydride, polymerized and then hydrolyzed to obtain 3-methoxy-4-hydroxystyrene polymer. ##STR4## wherein n stands for a positive number corresponding to the number of monomeric units in the polymer.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:8]([N:10]2[CH:14]([C:15](O)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1.[CH3:50][CH:51]([C:53]1[N:58]=[C:57]([NH2:59])[CH:56]=[CH:55][CH:54]=1)C>C(#N)C>[CH:1]1([CH2:6][C@@H:7]([C:8]([N:10]2[CH:14]([C:15]([NH:59][C:57]3[CH:56]=[CH:55][CH:54]=[C:53]([CH2:51][CH3:50])[N:58]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)O
Reactant: CC(C)c1cccc(N)n1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCc1cccc(NC(=O)C2CC=NN2C(=O)[C@@H](CC(=O)OC(C)(C)C)CC2CCCC2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of 1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (352 mg, 1.0 mmol) in acetonitrile (10 mL) at 0° C. was added 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (656 mg, 2.0 mmol) and N-methylmorpholine (0.29 mL, 2.6 mmol). The reaction was stirred for 2 hours at 0° C., and then 6-(1-methylethyl)-2-pyridinamine (177 mg, 1.30 mmol) was added to the reaction. The mixture was allowed to warm to room temperature and was stirred for 3 hours. The solvent was removed under reduced pressure, and then water (5 mL) and DCM (15 mL) were added. The phases were separated. The aqueous phase was extracted twice with DCM (15 mL), and the combined organics were dried over sodium sulfate and concentrated. The resulting residue was purified by Combiflash silica gel chromatography (0-100% EtOAc in hex) to give 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-(5-{[(6-ethyl-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoate (368 mg, 0.81 mmol, 81% yield) as a yellow oil. MS: 457 ([M+H]+).
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3].[NH2:14][C:15]1[CH:20]=[C:19]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:17][C:16]=1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]>C(Cl)Cl>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[CH:13][C:4]([C:2]([NH:14][C:15]2[CH:20]=[C:19]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[CH:18]=[CH:17][C:16]=2[NH:26][C:27]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:33])=[O:3])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Methyl 4-(chlorocarbonyl)benzoate (0.75 g, 3.79 mmol) and anhydrous DCM (0.25 M) was treated with tert-butyl 2-amino-4-thien-2-ylphenylcarbamate (1.0 g, 3.44 mmol). The resulting solution was stirred at ambient temperature for 14 hours. The reaction mixture was quenched with a solution of aqueous NaOH (1M) and partitioned between ethyl acetate and water. The organic layer was washed with water, saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue was carried on without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4]([C:14]#[N:15])=[CH:3]1.[N-:16]=[N+:17]=[N-:18].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[C:8]1([C:6]2[O:5][C:4]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)=[CH:3][C:2](=[O:1])[CH:7]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(=O)cc(-c2ccccc2)o1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccccc2)oc(-c2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-oxo-6-phenyl-4H-pyran-2-carbonitrile (1.10 g), sodium azide (0.45 g) and ammonium chloride (0.37 g) in dry dimethylformamide (10 ml) was stirred at room temperature for 2 hours. A precipitate formed. Dilute hydrochloric acid (1 M, 20 ml) was added and the resulting white solid was filtered off. Recrystallisation from acetic acid yielded the title product as white crystals (251°-254° C. with decomposition).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[C:6]([NH:9][CH:10]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)[C:11]([NH:13][CH2:14][C:15](=O)[CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][CH3:19])=O)(=[O:8])[CH3:7]>C1(C)C(C)=CC=CC=1>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH:10]([NH:9][C:6](=[O:8])[CH3:7])[C:11]2[NH:13][CH:14]=[C:15]([CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][CH3:19])[N:5]=2)=[CH:25][CH:26]=1
Reactant: CCC(C)(C)CC(=O)CNC(=O)C(Cc1ccc(Br)cc1)NC(C)=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: CCC(C)(C)Cc1c[nH]c(C(Cc2ccc(Br)cc2)NC(C)=O)n1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
Ammonium acetate (1.17 g, 79 mmol) was added to an ambient temperature solution of 2-(acetylamino)-3-(4-bromophenyl)-N-(4,4-dimethyl-2-oxohexyl)propanamide (650 mg, 1.58 mmol) in xylene (10 mL). After stirring at 15° C. for 1 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate and methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded N-{2-(4-bromophenyl)-1-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]ethyl}acetamide.
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[C:13]1(=[O:19])[NH:17][C:16](=[O:18])[CH2:15][CH2:14]1>CCOCC>[O:7]([C:8]([N:17]1[C:13](=[O:19])[CH2:14][CH2:15][C:16]1=[O:18])=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C1CCC(=O)N1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C1CCC(=O)N1C(=O)Oc1ccccc1
Reaction time: 1 h

Procedure:
To 50 millimolses of phenylchloroformate in 25 ml of ether are added 16.7 ml of a 3M potassium hydroxide solution containing 50 millimoles of predissolved succinimide. The system is then stirred for about 1 hour, additional ether added and then restirred for about 1 hour. The insolubles formed are removed by filtering. Thereafter, the crude product is recrystallized from butanol saturated with water to give the desired product, melting point 132° - 133.5°C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]=3[OH:29])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:24]([C:25]([F:27])([F:28])[F:26])=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]=3[O:29][C:31]3[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1c(-c2ccc(OCc3ccccc3)cc2)c(C(F)(F)F)cc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2c(-c3ccc(OCc4ccccc4)cc3)c(C(F)(F)F)cc3ccccc23)cc1
Yield: 71 %

Procedure:
2-{4-[(Phenylmethyl)oxy]phenyl}-3-(trifluoromethyl)-1-naphthalenol (186) (0.25 g, 0.64 mmol) and 4-fluorobenzaldehyde was heated with Cs2CO3 in DMSO at 100° C. for 5 h using microwave synthesizer to give 0.23 g (71%) of the title compound (187) as a light brown viscous oil. 1H NMR (400 MHz, CDCl3): δ 5.01 (s, 2H), 6.67 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.6 Hz, 2H), 7.06 (d, J=8.4 Hz, 2H), 7.30-7.44 (m, 5H), 7.57-7.68 (m, 4H), 7.88 (d, J=8.3 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 8.25 (s, 1H), 9.82 (s, 1H). LCMS (ESI): m/z 521 (M+Na)+.
Reaction SMILES: [CH:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[CH:8][C:7]=2[C:19]([O:21]C)=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+:24]>C1COCC1.CO>[CH:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[CH:8][C:7]=2[C:19]([O-:21])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5]1.[Na+:24]
Reactant: COC(=O)c1cc(-c2cncc(C)c2)cnc1C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cncc(-c2cnc(C3CCCC3)c(C(=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 6-cyclopentyl-5′-methyl-3,3′-bipyridine-5-carboxylate (6-2, 0.060 g, 0.020 mmol, 1.0 equiv) in THF/methanol (1.7 mL/0.3 mL) was added 10 N sodium hydroxide (0.10 mL, 1.0 mmol, 5.0 equiv) and the system was stirred for 18 h at ambient temperature. The reaction mixture was concentrated and azeotroped with ethyl acetate (2×10 mL) and toluene (3×10 mL) to afford the desired product (6-3) as a white solid. ESI+MS [M+H]+ C17H18N2O2 calc'd 283.1, found 283.0.
Reaction SMILES: C1(C(=[N:14][C:15]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH:16]2[CH3:18])C2C=CC=CC=2)C=CC=CC=1.[ClH:24]>CCOCC>[ClH:24].[NH2:14][C:15]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH:16]1[CH3:18]
Reactant: CCOC(=O)C1(N=C(c2ccccc2)c2ccccc2)CC1C
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C1(N)CC1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottomed flask was charged with racemic (1S,2R)-ethyl 1-((diphenylmethylene)amino)-2-methylcyclopropanecarboxylate and a stir bar. Et2O (50 mL, 0.5 M) was added, and the mixture was cooled to 0° C. for the addition of 1 N HCl (9 mL, 1.2 equiv). The solution was warmed to room temperature and stirred overnight. The mixture was separated, and the organic layer was washed twice with water before being dried with Na2SO4 and concentrated. Lyophilization yielded racemic (1S,2R)-ethyl 1-amino-2-methylcyclopropanecarboxylate hydrochloride as a colorless oil that solidified upon sitting (yield not determined). LRMS (M+H)+: 144 m/z.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([S:17](C)(=O)=O)[CH2:14][C@H:13]2[C:21](=S)[OH:22])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].P([O-])([O-])(O)=O.[Na+].[Na+].C(N(CC)CC)C>C(Cl)Cl.O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]3[CH2:14][C@H:13]2[C:21](=[O:22])[S:17]3)=[O:11])=[CH:24][CH:25]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)[C@@H]1C[C@@H](C(O)=S)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1S[C@H]2C[C@@H]1N(C(=O)OCc1ccc([N+](=O)[O-])cc1)C2

Procedure:
For example, (2S,4R)-1-p-nitrobenzyloxycarbonyl -4-methanesulfonyl-2-pyrrolidinethiocarboxylic acid is allowed to react with disodium hydrogenphosphate or triethylamine in methylene chloride or tetrahydrofuran, thereby to give (1S,4S)-5-p-nitrobenzyloxycarbonyl-2-thia-5-azabicyclo[2.2.1]heptan-3-one.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[C:39]1(B(O)O)[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]=1>>[NH2:30][C:29]1[S:28][C:27]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Reactant: OB(O)C1=CCCCC1
Product: Cn1ncc(NC(=O)c2nc(C3CCCCC3)sc2N)c1N1CCC(CN)CC1
Yield: 51 %

Procedure:
Following the procedure for Example 281, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and cyclohex-1-ene-1-boronic acid gave 282 (44 mg, 51% over three steps). 1H NMR (400 MHz, d4-MeOD) δ 7.45 (s, 1H), 3.71 (s, 3H), 3.21-3.08 (m, 4H), 2.85-2.76 (m, 1H), 2.64 (d, J=6.6 Hz, 2H), 2.09 (d, J=12.1 Hz, 2H), 1.90-1.81 (m, 4H), 1.76 (d, J=13.0 Hz, 1H), 1.59-1.25 (m, 8H). LCMS (ES+) m/z 418 (M+1)
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[CH:39]=[CH:38][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:40][CH3:41].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>CC(C)CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:19][CH2:18]3)[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:39]=[CH:38][C:26]([C:27]([NH:29][CH:30]5[CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH2:35]5)=[O:28])=[CH:25][C:24]=4[O:40][CH3:41])=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCN1CCC(NC(=O)c2ccc(N)c(OC)c2)CC1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CC(C)CC(C)O
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC3(CC3)C(=O)N4C)c(OC)c2)CC1
Yield: 49.2 %

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 100 mg, 0.33 mmol), 4-amino-N-(1-ethyl-4-piperidyl)-3-methoxy-benzamide (Intermediate 190; 91 mg, 0.33 mmol) and p-toluenesulphonic acid monohydrate (156 mg, 0.81 mmol) were heated at 140° C. in 4-methyl-2-pentanol (4 mL) for 2 hours. The reaction mixture was loaded onto to an SCX-3 cartridge (10 g) pre-wet with methanol, then washed with methanol and eluted with 2% 7N ammonia/methanol. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (89 mg, 50%).