Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[CH:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)=[O:27]>C1COCC1>[N+:35]([C:32]1[CH:33]=[CH:34][C:29]([O:28][C:26](=[O:27])[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([C:9]3[N:13]=[CH:12][N:11]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:16][CH:15]=4)[N:10]=3)=[CH:5][CH:4]=2)=[CH:30][CH:31]=1)([O-:37])=[O:36]
Reactant: CNc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CN(C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Yield: 60.7 %

Procedure:
A suspension of 4-[1-(4-trifluoroethyloxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenylamine (1.2 g, 3.7 mmol) in EtOH (4 mL) was treated with 1H-benzotriazole (0.48 g, 4.0 mmol) and formaldehyde (0.5 mL of 37% aqueous, 6 mmol), and the solution was heated to 40° C. for 10 min. Upon cooling, a solid formed, which was collected by filtration. There was obtained 1.33 g of the triazole adduct as a light yellow solid, mp 185-187° C. This material (1.2 g, 2.66 mmol) was dissolved in THF (20 mL) and treated with NaBH4 (0.11 g, 2.9 mmol). The solution was stirred at ambient temperature for 30 min, then heated to reflux for 1 h. After cooling, the solution was poured onto water (30 mL) and extracted with ether. Drying and concentration, followed by silica gel chromatography (75:25 Hexanes:EtOAc) furnished methyl-{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenyl}-amine (0.76 g, 86%) as a white solid, mp 121-123° C.; 1H NMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 8.02 (d, J=8.8 Hz, 2H), 7.78 (d, J=9.1 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 6.68 (d, J=8.8 Hz, 2H), 3.96 (s, 1H), 2.91 (s, 3H); EIMS m/z 499 (M+). A portion of this amine (0.11 g, 0.33 mmol) was dissolved in dry THF (2 mL) and treated with 4-nitrophenyl chloroformate (0.069 g, 0.34 mmol). The solid which formed over 10 min was collected by filtration and air-dried to give an off-white solid (0.10 g): mp 145-147° C.; 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.28 (d, J=8 Hz, 4H), 7.8 (d, J=8 Hz, 2H), 7.50-7.3 (m, 6H) 3.55 (s, 3H); EIMS m/z 499 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[O:23])=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([CH3:10])=[C:4]2[N:3]=1.[CH3:35][C:36](OC(C)=O)=[O:37]>N1C=CC=CC=1>[CH3:11][C:7]1[N:6]=[C:5]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])=[O:23])=[CH:17][CH:18]=3)[C:2]([NH:1][C:36](=[O:37])[CH3:35])=[N:3][C:4]2=[C:9]([CH3:10])[CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3c(N)nc4c(C)cc(C)nc43)cc2)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 5 %

Procedure:
2-amino-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine (73 mg) was treated with pyridine (1 ml) and Ac2O (0.2 ml) at room temperature for 3 hours. After evaporation in vacuo, the residue was purified by preparative TLC (hexane/acetone=1/1) to afford 4 mg (5%) of the title compounds.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:24][CH2:23][CH2:22]2)=[O:20])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:24][CH2:23][CH2:22]2)=[O:20])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)N2CCC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CNC1)N1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
Azetidine hydrochloride salt (515 mg, 5.50 mmol) was added to a solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.0 g, 4.97 mmol), HATU (2.09 g, 5.50 mmol) and DIPEA (2.18 mL, 12.52 mmol) in DMF (100 mL) and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give 3-(azetidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of 3-(azetidine-1-carbonyl)-azetidine-1-carboxylic acid tert-butyl ester in DCM (15 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a colourless oil (260 mg, 37%). 1H NMR (CD3OD, 400 MHz) δ 4.19-4.08 (m, 2 H); 4.07-3.92 (m, 2 H); 3.91-3.78 (m, 2 H); 3.72-3.52 (m, 3 H) and 2.36-2.21 (m, 2 H).
Reaction SMILES: [F:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.Cl>C(OCC)(=O)C>[F:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2ccccn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: FC1(c2ccccn2)CCNCC1
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4-fluoro-4-pyridin-2-ylpiperidine-1-carboxylate (0.075 g, 0.27 mmol.) in 10 mL of ethyl acetate was saturated with gaseous HCl. After 1 h, the reaction was concentrated in vacuo to provide 2-(4-fluoropiperidin-4-yl)pyridine that gave a mass ion (ES+) of 181.1 for [M+H]+
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCO[SiH](OCC)OCC
Reactant: C=Cc1ccccc1
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccccc1)(OCC)OCC
Temperature: 41 °C
Yield: 8.5 %

Procedure:
200 mg Of styrene, 320 mg of triethoxysilane, and 370 mg of toluene were placed in a glass reaction tube and 0.004 ml of ethyl acetate was added. Next, 0.01 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.4 Wt. %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 41° C. When the tube contents were analyzed by GC-MS following cooling, the conversion rate of styrene was 13.5%, phenethyltriethoxysilane was produced at a yield of 8.5%, and the yield of (α-methylbenzyl) triethoxysilane was 13.6%.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH:15]=[CH2:16])[C:9]=2[C:8](=[O:17])[NH:7][C:6]1=[O:18])[CH2:2][CH2:3][CH3:4].C1C(=O)N([Cl:26])C(=O)C1>CN(C=O)C>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:26])[N:10]([CH2:14][CH:15]=[CH2:16])[C:9]=2[C:8](=[O:17])[NH:7][C:6]1=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCC
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Temperature: 25 °C
Reaction time: 22 h
Yield: 63.9 %

Procedure:
To a solution of 3-butyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (3.34 g, 13.4 mmol) in anhydrous DMF (19 ml) was added NCS (1.97 g, 14.8 mmol) and left to stir at rt under nitrogen for 22 hours. The mixture was concentrated in vacuo to give a yellow solid which was filtered and washed with methanol. The filtrate was concentrated and the process repeated. On the final wash the filtrate was purified by SPE (Si, 20 g) cartridge eluting with 1:1; EtOAc:cyclohexane. The combined solids were dried under vacuum to afford the title compound (2.42 g, 64%); m/z 283.3[MH+]
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23]>C(O)(C)C.[Ni]>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH2:1][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: NCCCCCCCCCCCCN
Reactant: O=Cc1ccccc1O
Agent: [Ni]
Solvent: CC(C)O
Product: Oc1ccccc1CNCCCCCCCCCCCCNCc1ccccc1O

Procedure:
30.0 g of a bisazomethine prepared from 2 mols of salicylaldehyde and 1 mol of 1,12-diaminododecane and having a melting point of 72°-73° C. are hydrogenated for 2 hours in 300 ml of isopropanol in an autoclave in the presence of 3 g of Raney nickel at 90°-100° C. and under a pressure of 60 atmospheres
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[CH:12]=[CH2:13])=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+]>CCOC(C)=O.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:14])[CH:12]=[CH2:13])=[CH:8][CH:9]=1
Reactant: C=CC(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC(=O)Nc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of N-(4-nitrophenyl)-acrylamide (Step 1) (0.203 g, 1.06 mmol), Iron powder (0.354 g, 6.34 mmol), FeSO4 (0.587 g, 2.11 mmol), Celite® (0.2 g) and water (6 mL) was heated to reflux with stirring for 3 h. The reaction mixture was cooled to RT and the solution was made basic to pH 13-14 by the addition of 2 N NaOH. The reaction mixture was diluted with EtOAc and water. The solution was filtered to remove the solids and solids washed with EtOAc. The aqueous layer was extracted three times with EtOAc (25 mL) and the combined organics were dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography using EtOAc as the solvent to give N-(4-aminophenyl)-acrylamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([F:25])[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[NH:39][N:38]=[CH:37]3)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:34]5[CH:35]=[C:36]6[C:40](=[CH:41][CH:42]=5)[NH:39][N:38]=[CH:37]6)=[CH:3][C:4]=4[F:25])[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4[nH]ncc4c3)cc2F)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
A solution of 4-(4-bromo-2-fluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.244 mmol) in dioxane (1.5 mL) was treated with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (0.269 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (10 mg), and 2M aq potassium carbonate (0.733 mmol). The reaction mixture was purged with nitrogen, sealed, and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH˜4 using 1N aq HCl and was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (10-50% acetonitrile/water+0.1% NH4OH) to afford the title compound as a beige solid (32%). MS(ES)+ m/e 447.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:20][CH2:19][C:14]4([O:18][CH2:17][CH2:16][O:15]4)[CH2:13][CH2:12]3)[N:9]=[CH:10][C:5]2=[C:4]([N:21]2[CH2:27][CH:26]3[O:28][CH:23]([CH2:24][CH2:25]3)[CH2:22]2)[N:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]3[C:43](=[CH:44][CH:45]=2)[NH:42][CH:41]=[CH:40]3)O1.C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O>CC#N.O.C(O)C.C1(C)C=CC=CC=1>[O:18]1[C:14]2([CH2:19][CH2:20][CH:11]([N:8]3[C:6]4=[N:7][C:2]([C:37]5[CH:38]=[C:39]6[C:43](=[CH:44][CH:45]=5)[NH:42][CH:41]=[CH:40]6)=[N:3][C:4]([N:21]5[CH2:27][CH:26]6[O:28][CH:23]([CH2:24][CH2:25]6)[CH2:22]5)=[C:5]4[CH:10]=[N:9]3)[CH2:12][CH2:13]2)[O:15][CH2:16][CH2:17]1
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cnn(C3CCC4(CC3)OCCO4)c2n1
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1cc2cc(-c3nc(N4CC5CCC(C4)O5)c4cnn(C5CCC6(CC5)OCCO6)c4n3)ccc2[nH]1
Yield: 25 %

Procedure:
6-Chloro-1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (0.20 g, 0.493 mmol) is treated with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (0.119 g, 0.74 mmol), aq. Na2CO3 (0.52 mL, 2M), and tetrakis triphenylphosphine palladium (20 mg) in 1:1 toluene:ethanol. The reaction mixture is heated in a microwave at 120 C for 60 min. Aq. workup followed by RP HPLC (H2O, CH3CN, TFA) gives the title compound as a white solid (60 mg). MS m/s=487.2 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:34])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH2:35][C@@H:36]([C:44]([OH:46])=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4](=[O:34])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:35][C@@H:36]([C:44]([OH:46])=[O:45])[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:24])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)N[C@H](Cc2ccccc2)C(=O)O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.2 %

Procedure:
To a solution of p-nitrophenyl 10-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoate (4.73 g, 10 mmol) and D-phenylalanine (1.65 g, 10 mmol) in N,N-dimethylformamide (30 ml), was added triethylamine (1.4 ml, 10 mmol). The mixture was stirred at room temperature for 2 days, whereupon the insoluble matter almost disappeared. The solvent was distilled off under reduced pressure and the residue was chromatographed on a column of silica gel (100 g). The column was washed well with chloroform and elution with chloroform-methanol-acetic acid (18:2:1, v/v) gave 10-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoyl-D-phenylalanine (2.56 g), melting at 96°-98° C., after washing up in the usual way.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH2:6][C:5]2=[O:13].C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>>[O:16]=[C:17]1[C:10]2=[CH:11][C:2]([F:1])=[CH:3][C:4]3=[C:9]2[N:8]([CH:7]([CH3:12])[CH2:6][C:5]3=[O:13])[CH:24]=[C:18]1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CC1CC(=O)c2cc(F)ccc2N1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cn2c3c(cc(F)cc3c1=O)C(=O)CC2C
Temperature: 60 °C

Procedure:
A stirred mixture of 12 g (0.067 mole) of 6-fluoro-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline from example 4 and 14.8 g (0.070 mole) of diethyl ethoxymethylenemalonate was heated gradually to 160° to 180° C. while removing the ethanol generated by distillation. After 0.5 hour the mixture was cooled to 60° C., and 30 g of polyphosphoric acid was added. This mixture was heated gradually to 150° to 160° C. and maintained at 155° to 160° C. for 5 to 10 minutes. Following cooling, water was added, and the mixture was kneaded to produce an orange powder which was separated by filtration. Recrystallization from a mixture of 500 ml of 95% ethanol and 100 ml of glacial acetic acid gave a yellow product, ethyl 6,7-dihydro-1,7-dioxo-9-fluoro-5-methyl-1H,5H-benzo[ij]quinolizine-2-carboxylate, m.p. 262°-265° C.
Reaction SMILES: [CH:1]([S:5][C:6]1[N:10]=[CH:9][NH:8][N:7]=1)([CH2:3][CH3:4])[CH3:2].[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15](Cl)=[O:16])[CH:12]=[CH2:13].O1CCCC1.C(N(CC)CC)C>CCOCC>[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:5][CH:1]([CH2:3][CH3:4])[CH3:2])=[N:7]1)=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CCC(C)Sc1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(SC(C)CC)n1

Procedure:
A mixture of 7.9 g. 3-sec.butylthio-1,2,4-triazole, 8.0 g. diallylcarbamoyl chloride, 100 ml. dry tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 24 hours. The reaction mixture was worked up as described in Example 1, using ether in place of methylene dichloride, to produce an oil which was distilled under reduced pressure to give 1-diallylcarbamoyl-3-sec.butylthio-1,2,4-triazole, b.p. 121° - 123°C./0.1 mm. (96% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: C(N1[C@@:13]2([CH2:17][CH2:16][C@@H:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14]2)[O:12]C[C@H]1C)(=O)C1C=CC=CC=1>CC#N>[CH2:19]([O:18][C@@H:15]1[CH2:16][CH2:17][C:13](=[O:12])[CH2:14]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@@H]1CO[C@]2(CC[C@@H](OCc3ccccc3)C2)N1C(=O)c1ccccc1
Solvent: CC#N
Product: O=C1CC[C@@H](OCc2ccccc2)C1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
(3R, 5S, 7R)-4-Benzoyl-7-benzyloxy-3-methyl-1-oxa-4-azaspiro[4.4]nonane (250 mg, 0.7 mmol) were dissolved in 5 ml of CH3CN. IR 120[H+] (washed 2× with ethanol and 1× with H2O) was added to a pH of 5-6, The mixture was stirred at room temperature until starting material was no longer detectable. The reaction mixture was filtered and the filtrate was concentrated on a rotary evaporator. After column chromatography, (R)-3-benzyloxycyclopentanone (81 mg, 0.4 mmol) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:13][C:12](=[CH:14][O:15]C)[CH2:11]3)[NH:7][C:6]=2[CH:17]=1.Cl.[CH3:19]C#N>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:13][CH:12]([CH:14]=[O:15])[CH2:11]3)[N:7]([CH3:19])[C:6]=2[CH:17]=1
Reactant: CC#N
Reactant: COC=C1CC(c2nc3ccc(Br)cc3[nH]2)C1
Agent: Cl
Product: Cn1c(C2CC(C=O)C2)nc2ccc(Br)cc21
Reaction time: 16 h

Procedure:
To a solution of 6-bromo-2-(3-(methoxymethylidene)cyclobutyl)-1H-benzimidazole (850 mg) in CH3CN (20 ml) was added 2 M HCl (4.2 ml), and the resulting mixture was stirred at same temperature for 16 h. The reaction mixture was then quenched with saturated NaHCO3 solution, and extracted with DCM. The extract was washed with brine, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (hexane/EtOAc) to afford two isomers of the title compound (Less polar isomer: 200 mg, polar isomer: 300 mg) as yellow sticky solids.
Reaction SMILES: [CH3:1][C:2]1[NH:12][C:5]2=[N+:6]([O-])[CH:7]=[CH:8][C:9]([CH3:10])=[C:4]2[N:3]=1.P(Cl)(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[Cl:15][C:7]1[N:6]=[C:5]2[NH:12][C:2]([CH3:1])=[N:3][C:4]2=[C:9]([CH3:10])[CH:8]=1
Reactant: Cc1nc2c(C)cc[n+]([O-])c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(C)cc(Cl)nc2[nH]1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2,7-dimethyl-3H-imidazo[4,5-b]pyridine-4-oxide (4.45 g), chloroform (4.5 ml) and phosphorus oxychloride (25.4 ml) was stirred at 80° C. for 3 hr and concentrated to dryness under reduced pressure. The residue was poured into ice (75 g) and neutralized with aqueous ammonia under ice-cooling. After stirring at room temperature for 30 min, the precipitated solid was collected by filtration and washed with water to give 5-chloro-2,7-dimethyl-3H-imidazo[4,5-b]pyridine as a gray powder (3.66 g).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[CH3:16][NH:17][C:18]1[CH2:22][S:21][C:20](=[O:23])[N:19]=1.CC(C)([O-])C.[K+]>C(O)C>[CH3:16][NH:17][C:18]1=[N:19][C:20](=[O:23])[S:21]/[C:22]/1=[CH:1]\[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CNC1=NC(=O)SC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CNC1=NC(=O)S/C1=C\C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
tert-Butyl 4-formylpiperidine-1-carboxylate (1.61 g) and 4-(methylamino)-1,3-thiazol-2(5H)-one (1.18 g) were suspended in ethanol (10 mL), potassium tert-butoxide (1.02 g) was added, and the mixture was stirred at 80° C. for 8 hr. The reaction mixture was concentrated, saturated aqueous ammonium chloride solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.27 g).
Reaction SMILES: P([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12]P(O)(O)=O)[O:9][C@@H:8]([N:17]2[CH:24]=[C:23]([OH:25])[C:21]([NH2:22])=[N:20][C:18]2=[O:19])[CH2:7]1)(O)(O)=O.BrBr.[C@@H]1(N2C=CC(N)=NC2=O)O[C@H](CO)[C@@H](O)C1>O>[OH:25][C:23]1[C:21]([NH2:22])=[N:20][C:18](=[O:19])[N:17]([CH:24]=1)[C@@H:8]1[O:9][C@H:10]([CH2:11][OH:12])[C@@H:6]([OH:5])[CH2:7]1
Reactant: Nc1nc(=O)n([C@H]2C[C@H](OP(=O)(O)O)[C@@H](COP(=O)(O)O)O2)cc1O
Agent: BrBr
Agent: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Solvent: O
Product: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1O
Reaction time: 2 h

Procedure:
5-Hydroxydeoxycytidine is synthesized in a similar manner to the published procedure of Eaton et al. (Biochim. Biophys. Acta 319:281-287, 1973) for 5-hydroxydeoxycytidine-3',5'-diphosphate. Bromine is added to a cooled (0° C.) solution of 2'-deoxycytidine (available from Sigma Chemical Company) in water until the yellow color persists. The excess bromine is quenched with cyclohexene and 2,4,6-collidine is added. After 2 hours, the reaction mixture is washed with ether and evaporated to dryness under vacuum. The crude 5-hydroxydeoxycytidine is then purified by reversed-phase HPLC on an Ultrasphere C18 column (Phenomenex) using a linear gradient of 0%-20% B in A (solvent A: 0.1 M NH4OAc, solvent B: 50% CH3CN in 0.1 M NH4OAc).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([Cl:40])[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:35]([Cl:40])[CH:34]=1
Reactant: ICCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)c(Cl)c1
Yield: 59 %

Procedure:
A mixture of 5.6 g of 1-(6-iodohexyl)-2,3-bis(phenylmethoxy)benzene, 2.1 g of 3-chloro-4-hydroxybenzoic acid methyl ester and 5.0 g of potassium carbonate in 50 mL of acetone was stirred at reflux for 20 hours. Workup as in Example 16, chromatography on 100 g of silica gel using 15% ethyl acetate-hexane and crystallization from ethyl acetate-hexane gave 3.7 g (59% yield), mp 68°-69°, 3-chloro-4-[6-[2,3-bis (phenylmethoxy)phenyl]hexyloxy]benzoic acid methyl ester.