Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:24](OCC)(=[O:30])[C:25](OCC)=[O:26]>CCOCC>[CH3:13][O:12][C:5]1[CH:4]=[C:3]2[C:2]([NH:1][C:24](=[O:30])[C:25](=[O:26])[N:14]2[CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COC(=O)c1cc(N)c(NCc2ccc(OC)cc2)cc1OC
Solvent: CCOCC
Product: COC(=O)c1cc2[nH]c(=O)c(=O)n(Cc3ccc(OC)cc3)c2cc1OC
Yield: 71 %

Procedure:
The solution of methyl 5-amino-2-methoxy-4-(4-methoxybenzylamino)benzoate (30 g, 94.83 mmol) in diethyl oxalate (100 mL) was stirred for 3 h at reflux and then cooled with a water/ice bath and diluted with ether (500 mL). The product was collected by filtration to afford methyl 7-methoxy-1-[(4-methoxyphenyl)methyl]-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate as a light yellow solid (25.0 g, 71%).
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([CH2:16][C@H:17]2[CH2:21][NH:20][C@H:19]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)=[O:23])[CH2:18]2)=[C:14]([CH3:41])[CH:13]=1>>[N:2]1([CH2:7][C:8]([N:20]2[CH2:21][C@H:17]([CH2:16][C:15]3[CH:39]=[CH:40][C:12]([F:11])=[CH:13][C:14]=3[CH3:41])[CH2:18][C@H:19]2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[O:23])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: Cc1cc(F)ccc1C[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: Cc1cc(F)ccc1C[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Yield: 41 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(4-fluoro-2-methylbenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 8, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(4-fluoro-2-methylbenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (127.6 mg, 41%). Major isomer 1H-NMR (400 MHz, CDCl3): δ 9.02 (s, 1H), 8.25 (s, 1H), 7.99 (s, 1H), 7.42-7.37 (m, 2H), 7.31-6.82 (m, 9H), 5.06 (d, 1H), 4.98 (d, 1H), 4.79 (d, 1H), 3.69 (t, 1H), 3.27 (t, 1H), 3.04-2.91 (m, 1H), 2.84 (dd, 1H), 2.70 (dd, 1H), 2.59 (dd, 1H), 2.33 (s, 3H), 1.76-1.67 (m, 1H). MS (EI) for C29H28F2N5O3 found 532 (MH+).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25](O)[CH3:26].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][O:17][C:16]([C@@H:11]1[CH2:12][S:13][CH2:14][CH2:15][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=1)(=[O:9])=[O:8])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Reactant: CC(O)c1cccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)OCCc2cccs2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
0.301 g (1 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.190 g (1.5 mmol) of (thiophen-2-yl)-ethanol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH2Cl2. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: ethyl acetate:cyclohexane=1:6) to obtain the product as a oil (0.28 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[C:4]=1[S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)Cl.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>C(N(CC)CC)C>[CH:26]1([C:29]([N:9]2[CH2:8][CH2:7][C:6]3[CH:12]=[C:13]([O:14][CH3:15])[C:3]([O:2][CH3:1])=[C:4]([S:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:5]=3[CH2:11][CH2:10]2)=[O:30])[CH2:28][CH2:27]1
Reactant: COc1cc2c(c(Sc3ccccc3)c1OC)CCNCC2
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(c(Sc3ccccc3)c1OC)CCN(C(=O)C1CC1)CC2

Procedure:
To a solution of 1.58 g. (0.005 mole) of 7,8-dimethoxy-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine in 25 ml. of methylene chloride and 1.0 g. of triethylamine is added dropwise 1.05 g. (0.010 mole) of cyclopropanecarboxylic acid chloride at 5° C. and the mixture is stirred at room temperature for 3 hours. The reaction mixture is filtered and the filtrate is washed with water, 5% potassium carbonate solution and then with water, dried and subsequently concentrated to give 3-cyclopropanecarbonyl-7,8-dimethoxy-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.[CH:15]12[O:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][NH:17][CH2:16]2.[OH-].[Na+]>O>[C:1]12([C:11]([N:17]3[CH2:16][CH:15]4[O:22][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C1CC2CNCC1O2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(N1CC2CCC(C1)O2)C12CC3CC(CC(C3)C1)C2
Temperature: 30 °C
Reaction time: 8 h

Procedure:
1-Adamantanecarbonyl chloride (19.87 grams, 0.1 mole, pulverized) (Aldrich Chemical Co., Inc., Milwaukee, Wisc.) was added to a mixture of 8-oxa-3-azabicyclo(3.2.1)octane hydrochloride (14.96 grams, 0.1 mole) and sodium hydroxide (10 grams) in 300 ml water. The reaction mixture was heated at 30° C. for 3 hours and then left overnight at room temperature. The product (22 grams) was filtered off, washed with water, and finally recrystallized from a blend of about 30% petroleum ether (boiling point 30°-60° C.) and 70% diethyl ether (v/v). The product had a melting point of 134°-136° C.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:12][C:13]1[C:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:20])=[C:17]([C:30]([F:33])([F:32])[F:31])[N:16]=[CH:15][CH:14]=1>>[F:1][CH:2]([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]1[N:21]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:19](=[O:20])[C:18]2[C:17]([C:30]([F:33])([F:31])[F:32])=[N:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: Nc1ccnc(C(F)(F)F)c1C(=O)NCCc1ccccc1
Reactant: O=Cc1ccccc1C(F)F
Product: O=c1c2c(C(F)(F)F)nccc2nc(-c2ccccc2C(F)F)n1CCc1ccccc1

Procedure:
Prepared analogous to Example 1 starting from 2-(difluoromethyl)benzaldehyde and 4-Amino-N-phenethyl-2-(trifluoromethyl)nicotinamide. 1H NMR (400 MHz, CDCl3) δ 8.88 (d, 1H), 7.77 (d, 1H), 7.72 (d, 1H), 7.69 (t, 1H), 7.61 (t, 1H), 7.19 (m, 4H), 6.89 (m, 2H), 6.77 (t, 1H), 4.28 (m, 1H), 3.78 (m, 1H), 2.95 (m, 2H). MS m/z 446.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[OH-:13].[Na+]>O1CCOCC1>[I:11][C:10]1[C:3]2[C:2](=[O:13])[NH:7][CH:6]=[N:5][C:4]=2[N:8]([CH3:12])[CH:9]=1
Reactant: [OH-]
Reactant: Cn1cc(I)c2c(Cl)ncnc21
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cc(I)c2c(=O)[nH]cnc21
Temperature: 100 °C

Procedure:
To a stirred solution of 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (19.0 g, 64.9 mmol) in 1,4-dioxane (481 ml) was added 2M sodium hydroxide (aq) solution (479 ml, 959 mmol). The solution was heated to 100° C. and heated for 4 h. The solution was cooled. The organic solvent was removed in vacuo. The aqueous was acidified to ca pH 4 using concentrated hydrochloric acid. The resulting suspension was filtered and dried under vacuum and flowing nitrogen to afford the title compound which was used without further purification (15.7 g, 88%). LCMS RT=0.65 min, M+H+=276.0. 1H NMR (500 MHz, d6-DMSO) 11.93 (br s, 1H), 7.90 (s, 1H), 3.68 (s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)CCC.C(O)(C(F)(F)F)=O>ClCCl>[CH2:12]([O:11][CH2:10][CH2:9][O:8][CH2:7][C:6]([OH:19])=[O:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCCOC(=O)COCCOCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a stirred solution of ester 9 (2.66 g, 10 mmol) in dichloromethane (91 ml) was added TFA (9 ml) reaction mixture was stirred at room temperature for 2 hrs and mixture was concentrated. Obtained residue was diluted in water and basified with a NaOH 1N solution. This aqueous layer was extracted with ether then acidified and extracted twice with EtOAc. Combined organic layers were dried over MgSO4, filtered and concentrated to give acid 10 (2 g, 95%) as an oil, used for next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1.C[Si](C)(C)[O-:15].[K+].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([CH3:11])[C:9]([NH2:10])=[O:15])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[O-]
Reactant: CC(C)(C#N)c1ccc(Br)cc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C(N)=O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
To a solution of 2-(4-bromophenyl)-2-methylpropanenitrile (3.29 g) in toluene (33 mL) was added potassium trimethylsilanolate (8.37 g) portionwise. After being stirred at reflux temperature for 5 h, the reaction mixture was cooled to room temperature. Water(17 mL) was added to the mixture dropwise. Filtration gave the product (3.28 g, 92%). 1HNMR (CDCl3) 400 MHz δ: 7.49 (d, J=8.7 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H), 5.52-4.93 (m, 2H), 1.57 (s, 6H).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].S=[C:7]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9][NH:8]1.C(OCC)C>CO>[OH:3][N:2]=[C:7]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9][NH:8]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCNC(=S)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCNC(=NO)CC1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A solution of hydroxylamine hydrochloride (2 eq.) in methanol was added to an equimolar methanolic solution of potassium hydroxide. Potassium chloride was filtered off and the filtrate was added to a solution of the above tert-butyl 5-thioxo-1,4-diazepane-1-carboxylate (1 eq.) in methanol. The mixture was stirred at 55° C. overnight, then cooled to room temperature and the solvent was removed under reduced pressure. The residue was taken in chloroform, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give, after trituration with ethyl ether, the title amidoxime. 1H NMR (300 MHz, CDCl3) δ 6.4-6.1 (bs, 1H), 5.8 (broad triplet, 1H), 3.6-3.5 (m, 4H), 3.35-3.22 (m, 2H), 2.5-2.4 (m, 2H), 1.45 (s, 9H); MS (ES) C10H19N3O3 requires 229. Found: 230 (M+H+).
Reaction SMILES: C(O[N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([OH:17])=O)C1C=CC=CC=1.O[N:19]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>C(Cl)Cl.C(N(CC)CC)C>[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([NH2:19])=[O:17]
Reactant: O=C(O)C1CCCCN1OCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)C1CCCCN1
Reaction time: 72 h
Yield: 89 %

Procedure:
N-benzyloxypiperidine-2-carboxylic acid (2.0 g), 1-hydroxybenzotriazole (1.6 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.3 g) were dissolved in methylene chloride (20 mL). Concentrated aqueous ammonia (3 mL) and triethylamine (2 mL) were added to the resultant solution at room temperature, followed by stirring for 3 days. The reaction mixture was partitioned between water and methylene chloride. The organic layer was dried over magnesium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. 10% Palladium-carbon (1 g, 50% wet) was added to the residue in methanol (30 mL), and the resultant mixture was stirred in a hydrogen atmosphere for 20 hours. The catalyst was removed by filtration. The solvent was evaporated under reduced pressure, and the thus-obtained oily product was dried, to thereby give the title compound as a solid (970 mg, quantitative amount).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]=[C:16](O)[C:17]4[S:22][CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:16]1[C:17]2[S:22][CH2:21][CH2:20][C:18]=2[N:19]=[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)[N:15]=1
Reactant: Oc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1SCC2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(N2CCN(c3nc(Cl)c4c(n3)CCS4)CC2)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
1.25 g (3.05 mmol) of 2-[4-(4-chlorophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (II) is placed in 4.50 mL of phosphorus oxychloride, then stirred for 4 hours at 120° C. Then excess phosphorus oxychloride is distilled off, the residue is combined with water. The precipitate formed is suction filtered, washed with plenty of water, and dried, then stirred with methanol. 0.960 g of product III (85%) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.[CH3:21][O:22][CH2:23][C:24]([NH:26][NH2:27])=O>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:24]([CH2:23][O:22][CH3:21])=[N:26][N:27]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: COCC(=O)NN
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Solvent: CCCCO
Product: COCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, a solution of 1,3-dihydro-7-chloro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol was heated to reflux with methoxyacetic acid hydrazide to give 8-chloro-1-(methoxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[OH-].[Na+].O.[Br:14][CH2:15][CH2:16]Br>>[Br:14][CH2:15][CH2:16][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: BrCCBr
Reactant: O=[N+]([O-])c1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccccc1OCCBr
Temperature: 107 °C
Yield: 63 %

Procedure:
To 2-nitrophenol (25.0 g, 0.180 mol) in sodium hydroxide (14.4 g, 359 mmol) and Water (6.0 mL, 330 mmol) in a 500 mL flask at 107° C. with a reflux condenser was added 1,2-dibromoethane (61.9 mL, 719 mmol), and the flask was heated at 107° C. for three days (FIG. 18). Then, the product was extracted twice with 100 mL DCM, washed with 2M NaOH and brine, dried with sodium sulfate, and concentrated. Silica gel chromatography eluting with hexanes and ethyl acetate provided the bromide 82 in 63% yield. 1H NMR (500 MHz, CDCl3) δ 7.83 (dd, J=8.4, 1.6 Hz, 1H), 7.53 (td, J=8.1, 1.6 Hz, 1H), 7.12-7.01 (m, 2H), 4.45-4.34 (m, 2H), 3.67 (t, J=6.5 Hz, 2H), according to: WO 2002076926
Reaction SMILES: C([Li])CCC.C([Sn]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)(CCCC)CCCC)CCC.[CH3:34][Si:35]([CH3:44])([CH3:43])[C:36]1[O:40][CH:39]=[C:38]([CH:41]=[O:42])[CH:37]=1>CCCCCC.O1CCCC1>[OH:42][CH:41]([C:38]1[CH:37]=[C:36]([Si:35]([CH3:44])([CH3:43])[CH3:34])[O:40][CH:39]=1)[CH2:19][O:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: CCCC[Sn](CCCC)(CCCC)COCCCc1ccc2ccccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)c1cc(C(O)COCCCc2ccc3ccccc3c2)co1
Reaction time: 0.08 h

Procedure:
n-Butyl lithium (a 1.6M solution in hexane; 0.56 ml, 0.94 mmol) was added dropwise to a solution of (2-naphthyl)propyl tributylstannylmethyl ether (437 mg, 0.89 mmol), prepared as in Example 3, in tetrahydrofuran (5 ml) at -78° under argon. After 5 minutes, a solution of 5-trimethylsilyl-3-furaldehyde (150 mg, 0.89 mmol) in tetrahydrofuran (1 ml) was added. Stirring was continued at -78° for 2 hours and at room temperature for 1 hour. The mixture was quenched with water and extracted with ethyl ether. Evaporation of the dried (magnesium sulphate) extracts gave an oil, which was flash chromatographed on silica using 30% ethyl ether/hexane. The title alcohol was obtained as a colorless oil.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.Br[CH2:11][C:12]1[CH:27]=[CH:26][C:15]([C:16]([N:18]([CH3:25])[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])=[CH:14][CH:13]=1>CN(C)C(=O)C>[CH:19]1([N:18]([CH3:25])[C:16](=[O:17])[C:15]2[CH:26]=[CH:27][C:12]([CH2:11][N:1]3[CH:9]=[C:8]4[C:4](=[N:5][CH:6]=[N:7]4)[N:3]=[CH:2]3)=[CH:13][CH:14]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: c1ncc2[nH]cnc2n1
Reactant: CN(C(=O)c1ccc(CBr)cc1)C1CCCCC1
Solvent: CC(=O)N(C)C
Product: CN(C(=O)c1ccc(Cn2cnc3ncnc-3c2)cc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 7 h
Yield: 35.5 %

Procedure:
To a stirred solution of purine (300 mg, 2.5 mmol) in N,N-dimethylacetamide (30 mL) was added 4-bromomethyl-N-methyl-N-cyclohexyl benzamide (852 mg, 2.75 mmol). After stirring at 80° C. for 7 hr, the reaction was stirred at room temperature for 16 hr. The solvent was removed under reduced pressure and the residue (510 mg) chromatographed (silica gel, CH2Cl2 /MeOH/90/10) to give 9 (310 mg, 35%); m.p. 229°-30° C. Anal calcd. for C20H23N5O: C, 68.71; H, 6.61; N, 20.05. Found: C, 68.24; H, 6.79; N, 19.77.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[S:34](Cl)(=[O:36])=[O:35].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[S:34]([N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:15]1=[O:23])(=[O:35])=[O:36]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=c1n(C2CCNCC2)c2ccccc2n1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of 4-(2-oxo-2,3-dihydrobenzimidazol-1-yl)piperidine-1-carboxylic acid t-butyl ester (64 mg, 0.2 mmol) in CH2Cl2 at room temperature is treated with 2-naphthylsulfonyl chloride (50 mg, 0.2 mmol) followed by diisopropylethylamine (174 uL, 1.0 mmol) and 4-dimethylaminopyridine (24 mg, 0.2 mmol), stirred at 60° C. for 16 h and concentrated in vacuo. The resultant residue is dissolved in THF, treated with HCl in dioxane (4 N) (1 mL), stirred for 4 h and concentrated in vacuo. This residue is dissolved in a mixture of DMSO, methanol and water and purified by Gilson1 preparative HPLC to give the title product, 24 mg, [M+H] 408, retention time (RT) 1.89 minutes. 1Gilson Preparative HPLC conditions: Gilson Preparative HPLC system; YMC Pro C18, 20 mm×50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02% TFA/water; Solvent B: 0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mL/min; Detection: 254 nm DAD.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[CH3:30][C:31]([CH3:33])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCCl>[F:29][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:23]4[CH2:24][CH2:25][N:26]([CH:31]([CH3:33])[CH3:30])[CH2:27][CH:28]=4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: CC(C)=O
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3=CCNCC3)ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)N1CC=C(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To a stirred solution of 6-chloro-2-(1,2,3,6-tetrahydro-pyridin-4-yl)-quinoline-5-carboxylic acid (4,4-difluorocyclohexylmethyl)-amide (150.00 mg, 0.33 mmol, 1.00 eq) in 1,2-dichloroethane (5.00 mL, 33.33 V) was added acetone (0.05 mL, 0.66 mmol, 2.00 eq) and glacial acetic acid (0.04 mL, 0.66 mmol, 2.00 eq), then the reaction mixture was stirred at RT for 1 h and then cooled to 0° C. Sodium cyanoborohydride (43.54 mg, 0.66 mmol, 2.00 eq) was added and stirred at RT for 16 h. The solvent was removed and the crude product was purified by flash column chromatography using to afford 6-chloro-2-(1-isopropyl-1,2,3,6-tetrahydro-pyridin-4-yl)-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexyl methyl)-amide (100.00 mg, 0.21 mmol, 62.5%, pale yellow solid). 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.83 (t, J=6.03 Hz, 1H), 8.00-7.96 (m, 3H), 7.76 (d, J=9.02 Hz, 1H), 6.91 (s, 1H), 3.27 (t, J=6.12 Hz, 4H), 2.70-2.65 (m, 4H), 2.04-2.02 (m, 2H), 1.86-1.74 (m, 5H), 1.33-1.17 (m, 2H), 1.05 (br s, 6H). m/z: 462.3 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>C(Cl)Cl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([N:9]2[CH2:10][CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:38])=[CH:32][CH:31]=1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: CC(C)(C)CC1CN(C(=O)Nc2ccc(Cl)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol) and 1-chloro-4-isocyanato-benzene (Aldrich, 45.0 mg, 0.30 mmol) in CH2Cl2 (2 mL) was stirred at rt for 1 h. The reaction mixture was then concentrated and purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid (4-chloro-phenyl)-amide (35.9 mg, 59.3%) as a white amorphous. HRMS (ES+) m/z Calcd for C29H26Cl2F2N3O+H [(M+H)+]: 576.1183, found: 576.1183.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7]CO[CH2:4][C@@H:3]1[N:8]1[CH2:16][C:15]2[C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12]([CH2:21][C:22]3[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[CH:11][C:10]=2[C:9]1=[O:30].N[C@@H]1[C@@H](O)CC[O:34][CH2:33]1>>[CH3:29][O:28][C:25]1[N:24]=[CH:23][C:22]([CH2:21][C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]3[CH2:16][N:8]([C@@H:3]4[C@@H:2]([OH:1])[CH2:7][O:34][CH2:33][CH2:4]4)[C:9](=[O:30])[C:10]=3[CH:11]=2)=[CH:27][CH:26]=1
Reactant: N[C@H]1COCC[C@@H]1O
Reactant: COc1ccc(Cc2cc3c(c4ccccc24)CN([C@H]2COCC[C@@H]2O)C3=O)cn1
Product: COc1ccc(Cc2cc3c(c4ccccc24)CN([C@H]2CCOC[C@@H]2O)C3=O)cn1

Procedure:
1,5-Anhydro-2,3-dideoxy-3-{5-[(6-methoxypyridin-3-yl)methyl]-3-oxo-1,3-dihydro-2H-benzo[e]isoindol-2-yl}-L-threo-pentitol was prepared employing the procedures described for the construction of 2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-5-[(6-methoxypyridin-3-yl)methyl]-1,2-dihydro-3H-benzo[e]isoindol-3-one in Example 11, substituting (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol for (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol.