Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[C:6]=2[N:19]=1.IC.[CH3:22]N(C)C(=O)C.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:22])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[C:6]=2[N:19]=1
Reactant: CC1CCCC1N1CCC(=O)Nc2cnc(Cl)nc21
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC1CCCC1N1CCC(=O)N(C)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.14 g (0.0005 mole) of (rac)-2-chloro-9-(2-methyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-57), 0.047 mL (0.00075 mole) of iodomethane and 1 mL of N,N-dimethylacetamide at 0 degrees, was added 0.03 g (0.00075 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.130 g of (rac)-2-chloro-5-methyl-9-(2-methyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-57) as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].S(OC)(O[CH3:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+].N>CC(C)=O>[CH3:18][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1cc2ccccc2[nH]1
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc2ccccc2n1C
Reaction time: 2 h

Procedure:
A stirred suspension of methyl 1H-indole-2-carboxylate (5.0 g), dimethyl sulphate (9 ml) and potassium carbonate (10.4 g) in dry acetone (200 ml) was heated under reflux for 24 h. After cooling to room temperature 5% ammonia solution (50 ml) was added and the mixture stirred for 2 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane and water. The organic layer was dried and the solvent evaporated to give methyl 1-methyl-1H-indole-2-carboxylate (5.4 g) as a white solid; IR (CHBr3) max 1695 cm-1. The ester was treated with ethylenediamine and trimethylaluminium as described in Example 1(a). Purification via column chromatography on silica eluting with 5% v/v methanolic ammonia in dichloromethane gave 2-(2-imidazolin-2-yl)-1-methyl-1H-indole as a white solid. The hydrochloride salt was prepared as in Example 3 and that recrystallised from ethanol/diethyl ether; mp 290°-295° C. (decomp) (Literature mp 260°-280° C. (decomp) D. J. Hlasta, D. Luttinger, M. H. Perrone, M. J. Silbernagel, S. J. Ward and D. R. Haubrich, J. Med. Chem. 1967, 30, 1555).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[CH:22]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Br:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[CH2:27][C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11]
Reactant: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc(C2(Cc3cccc(Br)c3)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (40 mg, 0.15 mmol) (from Example 6b supra), 1-bromo-3-bromomethyl-benzene (43 mg, 0.17 mmol) (Aldrich), potassium iodide (29 mg, 0.17 mmol) and potassium carbonate (43 mg, 0.31 mmol) in acetone (2 mL) was heated at 60° C. for 16 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate and extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-3-(3-bromo-benzyl)-6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as a white solid. (Yield 28 mg, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:5]([CH2:7][CH2:8][C:9](O)=[O:10])=O.O.[NH2:18][NH2:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:7][CH2:8][C:9](=[O:10])[NH:18][N:19]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: NN
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1Cl
Solvent: O
Product: COc1ccc(C2=NNC(=O)CC2)cc1Cl
Yield: 84 %

Procedure:
This compound was prepared in 84% yield by reaction of 3-(3-chloro-4-methoxybenzoyl)propionic acid with hydrazine hydrate in ethanolic solution at reflux temperature for 5 hours. It had mp 194°-195° C after crystallisation from ethanol.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11]O>S(=O)(=O)(O)O>[CH3:11][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: CO
Reactant: O=C(O)c1ccc(I)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(I)cc1
Reaction time: 15 h

Procedure:
A solution of 4-iodobenzoic acid (5.0 g in a mixture of 50 mL methanol and 2.2 mL of conc. sulfuric acid) was heated to reflux on an oil bath. After 15 hours, the mixture was concentrated to half-volume in vacuo then poured into saturated sodium bicarbonate. This mixture was extracted with diethyl ether and the organic portion washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 95:5) gave the title compound (5.12 g).
Reaction SMILES: C(OC([N:11]([CH2:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14](O)=[O:15])=O)C1C=CC=CC=1.P(=O)(O)(O)O>C(OC(=O)C)(=O)C>[CH2:20]([NH:11][C@@H:12]1[C:17](=[O:19])[O:18][C:14](=[O:15])[CH2:13]1)[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)CCN(C(=O)OCc1ccccc1)[C@@H](CC(=O)O)C(=O)O
Agent: O=P(O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)CCN[C@H]1CC(=O)OC1=O
Temperature: 25 °C

Procedure:
A solution of N-benzyloxycarbonyl-N-neohexyl-L-aspartic acid, in acetic anhydride with a catalytic amount of phosphoric acid, is heated at reflux for 0.5 to 5 hours, is cooled to room temperature, and is concentrated under reduced pressure, with heating. The residual material is dissolved in water, then neutralized with aqueous sodium hydroxide. The resulting precipitate is collected by vacuum filtration, and is recrystallized to provide substantially pure N-neohexyl-L-aspartic anhydride.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1([C:13]([OH:15])=[O:14])C(O)=O.S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[C:13]([O:15][CH2:21][CH3:22])=[O:14]
Reactant: O=C(O)C1(C(=O)O)Cc2ccccc2C1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1Cc2ccccc2C1

Procedure:
11.7 g of 2,2-indandicarboxylic acid was heated at 200° C. for 30 minutes. After liberation of bubbles ceased, the reaction product was cooled and dissolved in 150 ml of ethanol. 4 ml of concentrated sulfuric acid was added to the solution and the mixture was heated under reflux for 4 hours. The reaction mixture was concentrated in vacuo and the residue was neutralized by addition of sodium carbonate. The mixture was extracted with chloroform. The extract was washed with water and dried and then concentrated in vacuo to give 9.4 g of ethyl 2-indancarboxylate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:14]([CH3:15])=[C:13]([CH3:16])[S:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>CN(C=O)C>[Br:17][C:11]1[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=1[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:9]
Reactant: Cc1scc(C(=O)c2ccc(Cl)cc2)c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1sc(Br)c(C(=O)c2ccc(Cl)cc2)c1C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a solution of (4-chlorophenyl)(4,5-dimethylthiophen-3-yl)methanone (1.99 g, 7.94 mmol) in DMF (15 mL) was added N-bromosuccinimide (1.55 g, 8.71 mmol) in one portion. After 2 h, the reaction mixture was partitioned between water and MTBE. The aqueous layer was extracted with MTBE and the combined organic layer was washed with 1% sodium thiosulfate, water, dried over Na2SO4 and concentrated to give light yellow solids. The resultant solids was purified on Biotage system (gradient elution 1% EtOAc:99% Hexanes to 4% EtOAc:96% Hexanes) to give the titled compound as yellow solids (2.40 g, 7.28 mmol, 92% yield). LC/MS m/z 329 [(M (35Cl, 79Br)+H]+ and m/z 331 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30].[Cu](C#N)[C:32]#[N:33].O>CN1CCCC1=O>[C:32]([C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30])#[N:33]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Reactant: N#C[Cu]C#N
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3)c(=O)c1C#N)C2(C)C
Temperature: 110 °C
Reaction time: 24 h
Yield: 4.9 %

Procedure:
2-[5-Bromo-6-oxo-4{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide (100 mg, 0.21 mmol) in N-methylpyrrolidone (2.5 mL) was mixed with copper cyanide (100 mg, 1.05 mmol) at room temperature and stirred at 110° C. for 24 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate and chloroform. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to give the desired product (4.3 mg, 5% yield).
Reaction SMILES: [CH3:1][Si:2]1([CH3:7])[CH2:6][CH:5]=[CH:4][CH2:3]1.[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH3:41][C:42]1[CH:43]=[CH:44][C:45]([S:48]([NH:51]Cl)(=[O:50])=[O:49])=[CH:46][CH:47]=1>C(#N)C>[CH3:1][Si:2]1([CH3:7])[CH2:6][CH:5]2[CH:4]([N:51]2[S:48]([C:45]2[CH:46]=[CH:47][C:42]([CH3:41])=[CH:43][CH:44]=2)(=[O:49])=[O:50])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)NCl)cc1
Reactant: C[Si]1(C)CC=CC1
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N2C3C[Si](C)(C)CC32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethyl-2,5-dihydro-1H-silole (3.0 g, 26.7 mmol) in acetonitrile (50 mL) was added phenyltrimethylammonium tribromide (1.0 g, 2.67 mmol) and chloramine-T (6.69 g, 29.4 mmol). After stirring at rt overnight the reaction mixture was filtered though a pad of Celite and concentrated under vacuum. Purification by silica gel chromatography (20% EtOAc/hexanes) afforded the desired product.
Reaction SMILES: [Br:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21].O>CN(C=O)C>[CH2:19]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:11][CH2:10][CH:2]=[CH2:3])[C:2]([Br:1])=[C:3]([O:12][CH2:6][CH:5]=[CH2:4])[CH:4]=1)[CH:20]=[CH2:21]
Reactant: C=CCBr
Reactant: O=C(O)c1cc(O)c(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)c1cc(OCC=C)c(Br)c(OCC=C)c1
Reaction time: 15 h
Yield: 194.8 %

Procedure:
To a solution of 4-Bromo-3,5-dihydroxybenzoic acid (20.43 g, 87.5 mmol, 1.0 equiv) in DMF (120 mL) at room temperature was added solid K2CO3 (60.5 g, 438 mmol, 5 equiv). To the suspension was added allylbromide (31 ml, 358 mmol, 4.1 equiv) dropwise over 25 minutes. After 15 hours, water (150 mL) was added and the slurry was poured into water (300 mL). The precipitate was separated by filtration, washed with water, and dissolved in ether. The solution was washed with brine, dried over MgSO4, filtered, and concentrated to afford 16 as a white powder (30.1 g, 97%). Rf=0.52 (15% EtOAc/hexane); FTIR (neat, cm−1) 3088, 2900, 1717, 1649, 1582, 1424, 986; 1H NMR (400 MHz, CDCl3) δ, 7.24 (s, 2H), 6.12-5.98 (m, 3H), 5.51 (dd, J=17.6, 1.6 Hz, 2H), 5.40 (dd, J=17.2, 1.2 Hz, 1H), 5.32 (dd, J=10.2, 1.2 Hz, 2H), 5.30 (dd, J=8.4, 1.6 Hz, 1H), 4.81 (d, J=6.0 Hz, 2H), 4.66 (d, J=3.4 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ132.2, 132.0, 129.9, 118.4, 117.9, 107.9, 106.9, 69.9, 65.7; MS EI+ calculated for C16H17BrO4 (M−H+): 351, found: 351.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[C:11](I)[S:12][C:3]=12.[CH3:14][N:15]([CH3:25])[C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.O>COCCOC.C(=O)(O)[O-].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[C:11]([C:19]3[CH:20]=[CH:21][C:16]([N:15]([CH3:25])[CH3:14])=[CH:17][CH:18]=3)[S:12][C:3]=12
Reactant: N#Cc1cnc2cc(I)sc2c1Cl
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN(C)c1ccc(-c2cc3ncc(C#N)c(Cl)c3s2)cc1
Yield: 59.6 %

Procedure:
A mixture of 7-chloro-2-iodothieno[3,2-b]pyridine-6-carbonitrile (321 mg, 1.0 mmol), 4-(dimethylamino)phenylboronic acid (248 mg, 1.5 mmol) and 58 mgs of tetrakis(triphenylphosphine)palladium(0) in 13 mL of ethylene glycol dimethyl ether and 11 mL of aqueous saturated sodium bicarbonate is heated at reflux for 6 hours. 4-(dimethylamino)phenylboronic acid (105 mg) and tetrakis(triphenylphosphine)palladium(0) (29 mg) are added and the reaction mixture is heated at reflux for 6 hours. The mixture is treated with water and extracted into dichloromethane and the organic phase is washed with brine and dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of dichloromethane to 2% ethyl acetate in dichloromethane to provide 187 mg (60%) of 7-chloro-2-[4-(dimethylamino)phenyl]thieno[3,2-b]pyridine-6-carbonitrile as an orange solid, mp 270-272° C.; 1H NMR (CDCl3) δ 3.07 (s, 6H), 6.73 (d, J=5 Hz, 2H), 7.58 (s, 1H), 7.63 (d, J=5 Hz, 2H), 8.74 (s, 1H); HRMS found: 314.05127.
Reaction SMILES: [C:1]([C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7][C:8]1[CH:9]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11](=[O:18])[N:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2)([O:3][CH2:4][CH3:5])=[O:2].[BH3-]C#N.[Na+].O>C(O)C>[C:24]([CH:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:7][C:8]1[CH:9]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11](=[O:18])[N:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2)([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(=Cc1cc(C(=O)OCC)c(=O)n2ccccc12)C(=O)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(CC(C(=O)OCC)C(=O)OCC)c2ccccn2c1=O
Reaction time: 1 h
Yield: 36.4 %

Procedure:
To a bright yellow suspension of ethyl 1-(2,2-dicarboethoxyvinyl)-4-oxo-4H-quinolizine-3-carboxylate (12) (750 mg, 1.94 mmol) in 5 ml ethanol was added NaBH3CN (68 mg, 1.08 mmol). The reaction mixture turned red and all solid material dissolved. Stirring was continued for 1 h, and the reaction mixture was poured into 50 ml of water. Ethanol was added to the aqueous suspension until a clear solution was obtained, which was extracted three times with 100 ml dichloromethane. The organic solvent was evaporated and the crude product was purified by flash chromatography to give ethyl 1-(2,2-dicarboethoxyethyl)-4-oxo-4H-quinolizine-3-carboxylate (13) as a bright yellow solid (275 mg, 36%). M.p. 105-108° C. 1H NMR (δ, CDCl3): 1.22 (t, J=7 Hz, 6H), 1.41 (t, J=7 Hz, 3H), 3.41 (d, J=7 Hz, 2H), 3.65 (t, J=7 Hz, 1H), 4.10-4.25 (m, 4H), 4.41 (q, J=7 Hz, 2H), 7.23 (m, 1H), 7.70 (m, 1H), 7.84 (d, J=8 Hz, 1H), 8.33 (s, 1H), 9.50 (d, J=7 Hz, 1H). MS: m/z 389.1466; required for C20H23NO7: 389.1475.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9][CH:10]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[C:11]([C:8]1[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cnc(C(=O)c2ccccc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(C(=O)c2ccccc2)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
2-Benzoyl-pyrimidine-5-carboxylic acid methyl ester (420 mg, 1.73 mmol) is dissolved in THF (5 mL), and a solution of LiOH (46 mg, 1.91 mmol) in water (5 mL) is added in one portion at 0° C. The mixture is stirred at 0° C. for 60 min. THF is evaporated in vacuo, and the residue is diluted with water (5 mL) and washed with ether (10 mL). The aqueous layer is acidified with 2 N aqueous HCl to pH ˜3. The resulting precipitate is collected by filtration, washed with water three times, and dried in vacuum oven overnight to afford 2-benzoyl-pyrimidine-5-carboxylic acid (260 mg, 66%). MS: 229 (M+H); 1H NMR (300 MHz, DMSO): δ 7.60 (m, 3H), 7.73 (m, 1H), 7.85 (m, 2H), 9.4 (s, 1H).
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1)(=O)=O.[N:17]1(C2C=CC(C=O)=CC=2)[CH:21]=[N:20][CH:19]=[N:18]1>>[N:17]1([C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=2)[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: CS(=O)(=O)Oc1ccc(/C=C/C(=O)O)cc1
Reactant: O=Cc1ccc(-n2cncn2)cc1
Product: O=C(O)/C=C/c1ccc(-n2cncn2)cc1

Procedure:
1.9 g of (E)-3-(4-(1,2,4-triazol-1-yl)phenyl)acrylic acid were prepared as described for (E)-3-(4-(methanesulfonyloxy)phenyl)acrylic acid, using 4-(1,2,4-triazol-1-yl)benzaldehyde instead of methanesulfonic acid 4-formylphenyl ester.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=1.[Mn]([O-])(=O)(=O)=[O:23].[K+]>O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([OH:23])[C:17]3[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3=[N:14][CH2:13][CH2:12][N:11]23)=[CH:8][CH:9]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Clc1ccc(C2NCCNCc3ccccc32)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: OC1(c2ccc(Cl)cc2)c2ccccc2C2=NCCN21

Procedure:
Two grams of 1-(p-chlorophenyl)-1,2,3,4,5,6-hexahydro-2,5-benzodiazocine dihydrochloride are dissolved in 50 ml. of water. A solution of 1 g. of potassium permanganate in 50 ml. of water is added dropwise over a period of one-half hour. The mixture is filtered to remove inorganic salts and the filtrate is made basic with sodium carbonate solution. The precipitated solid is separated and washed with water. On recrystallization from ethanol there is obtained 5-(4-chlorophenyl)-2,3-dihydro-5H-imidazo [2,1-a]isoindol-5-ol which has the same physical characteristics as the identical compound of Example X.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:23][C:24]1[O:25][CH:26]=[CH:27][CH:28]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[N:14]([CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3cc(F)ccc23)CC1
Reactant: BrCc1ccco1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3ccco3)c3cc(F)ccc23)CC1
Reaction time: 15 h
Yield: 100 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 0.3 g (1.0 mmol) of 4-(6-fluoro-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 2.7 mL (1.6 mmol) of a freshly prepared 0.61 M solution of 2-bromomethylfuran in ethyl ether. After standard work-up, 0.38 g (100% of yield) of 4-(6-fluoro-1-furan-2-ylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: C([CH:3]([C:26]([OH:28])=[O:27])[N:4]([C:16](OCC1C=CC=CC=1)=O)[CH2:5][P:6]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:8][CH2:9][CH2:10][CH3:11])=[S:7])C.Br.[CH3:30]COCC>C(O)(=O)C>[CH2:16]([N:4]([CH2:5][P:6]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:8][CH2:9][CH2:10][CH3:11])=[S:7])[CH2:3][C:26]([OH:28])=[O:27])[CH3:30]
Reactant: CCCCP(=S)(CCCC)CN(C(=O)OCc1ccccc1)C(CC)C(=O)O
Reactant: CCOCC
Agent: Br
Solvent: CC(=O)O
Product: CCCCP(=S)(CCCC)CN(CC)CC(=O)O

Procedure:
Ethyl N-carbobenzoxy-N-(dibutylthiophosphinylmethyl)-glycine (2 g., 0.0046 mole) was reacted with 36% hydrogen bromide (10 ml) in glacial acetic acid at 0° C. Ether was added and the oily precipitate was isolated by decanting the ether layer. The oil was washed with ether twice, then suspended in benzene and treated with propylene oxide. The solution was concentrated in vacuo to yield ethyl N-(dibutylthiophosphinylmethyl)glycine as an amber oil, ND22 =1.4820.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][O:6][CH:5]([CH2:8][OH:9])[CH2:4][O:3]1.[OH-].[K+].[Mn]([O-])(=O)(=O)=[O:14].[K+]>O>[CH3:1][C:2]1([CH3:10])[CH2:7][O:6][CH:5]([C:8]([OH:14])=[O:9])[CH2:4][O:3]1
Reactant: CC1(C)COC(CO)CO1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1(C)COC(C(=O)O)CO1
Temperature: 5 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of (5,5-dimethyl-[1,4]dioxan-2-yl)-methanol (657 mg, 4.5 mmol) in 1 M potassium hydroxide solution (6.7 mL, 6.7 mmol) was stirred at 5° C. A solution of potassium permanganate (1.42 g, 9 mmol) in water (10 mL) was added dropwise maintaining the internal temperature below 10° C. The reaction mixture was stirred at 5° C. for 1 h and then at room temperature for 18 h. The reaction mixture was filtered through Celite and the filter pad was washed with water and methanol and the filtrate was evaporated. The residue was acidified to pH 2 with hydrochloric acid (2 M) and the mixture was extracted with ethyl acetate and chloroform. The organic extracts were combined and washed with a small volume of brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford crude 5,5-dimethyl-[1,4]dioxane-2-carboxylic acid (694 mg, 4.5 mmol) as a waxy solid. LCMS (m/z) 159.1 [M−H], Tr=0.88 min. A solution of 5,5-dimethyl-[1,4]dioxane-2-carboxylic acid (750 mg, 4.7 mmol), oxalyl chloride (600 mg, 0.4 mL, 4.7 mmol) and N,N-dimethylformamide (2 drops) in dichloromethane (15 mL) was stirred at room temperature under nitrogen for 2 h. A solution of benzyl alcohol (508 mg, 0.5 mL, 4.7 mmol) in dichloromethane (2 mL) was added and the reaction mixture was stirred at room temperature for 20 h. Additional benzyl alcohol (0.5 mL, 4.7 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated and the residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 9:1 to 1:1 to afford the title compound (870 mg, 74%) as an oil. 1H NMR (300 MHz, CDCl3) δ 1.19 (s, 3H), 1.32 (s, 3H), 3.43 (d, J=11.4 Hz, 1H), 3.72 (d, J=11.4 Hz, 1H), 3.88-3.92 (m, 2H), 4.21 (dd, J=8.2, 4.7 Hz, 1H), 5.24 (s, 2H), 7.34-7.39 (m, 5H). LCMS (m/z) 273.1 [M+Na], Tr=2.41 min.
Reaction SMILES: CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:12]1[O:20][C:19]2[CH:18]=[CH:17][C:16]([CH:21]([CH2:25][CH2:26][CH2:27][CH2:28]C)[C:22](O)=[O:23])=[CH:15][C:14]=2[O:13]1>O>[CH2:12]1[O:20][C:19]2[CH:18]=[CH:17][C:16]([CH:21]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:22][OH:23])=[CH:15][C:14]=2[O:13]1
Reactant: CCCCCC(C(=O)O)c1ccc2c(c1)OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCCCC(CO)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To 40 ml of ether suspension containing 1.74 g (46 mmol) of lithium aluminum hydride, was added dropwise under cooling with ice 40 ml of ether solution containing 10.9 g (46 mmol) of (-)-2-(3,4-methylenedioxyphenyl)-heptanoic acid obtained in Reference Example 2. After 2-hour reflux, the reaction mixture was cooled to room temperature and was treated with water under cooling with ice to obtain 10.2 g of oily 2-(3,4-methylenedioxyphenyl)hexyl alcohol.