Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:11]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:15][CH2:14]1)[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCN1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C

Procedure:
To 4-fluro-1-nitrobenzene(1 eq) in N,N-dimethylformamide was added Ethyl piperazine (2 eq) and N,N-diisopropylethyl amine (2 eq) and heated at 80° C. for 16 h. Concentrated the resultant mixture and partitioned between ethyl acetate and water. The organic layer was then washed with brine and dried with sodium sulfate and concentrated. Passed through a plug of silica to yield 4-Ethyl-1-(4-nitrophenyl)piperazine. MS: MH+=235.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O-:18][C:19]#[N:20].[K+]>CO.O>[CH2:10]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:9][C:19](=[O:18])[NH2:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: NC(=O)ON(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred suspension of 10.70 g of N,N-dibenzylhydroxylamine in 25 ml of methanol is admixed dropwise with a solution of 4.53 ml conc. hydrochloric acid in 10 ml of water. A solution of 4.06 g of potassium cyanate in 15 ml of water is then added and the resulting suspension is stirred at room temperature for 3 hours. The crude product is removed by filtration and further purified by liquid chromatography to afford the title compound as a white solid; m.p. 127°-29° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]=[CH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][S:16]([CH3:19])(=[O:17])=[O:18])[CH2:10][CH2:9]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=CS(C)(=O)=O)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCS(C)(=O)=O)CC1
Temperature: 90 °C

Procedure:
Trans [4-(2-methanesulfonyl-vinyl)-cyclohexyl]-carbamic acid tert-butyl ester (1.00 g, 3.30 mmol) was dissolved in ethanol (15 mL, IMS grade) and 10% palladium on carbon (100 mg) was added, followed by ammonium formate (1.25 g, 19.8 mmol). The mixture was heated at 90° C. for 45 min, then cooled to room temperature. A further 100 mg palladium on carbon was added and the mixture was heated at 95° C. for 16 h. The mixture was cooled to room temperature then filtered and concentrated under vacuum. The residue was taken up in water and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine then dried (Na2SO4) and concentrated under vacuum to give 928 mg (92%) of trans [4-(2-methanesulfonyl-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester. LCMS (method Q, ESI): RT=3.35 min, m+H=204.1; NMR (400 MHz, CDCl3) δ: 4.36 (br s, 1H), 3.38 (br s, 1H), 3.01 (m, 2H), 2.89 (s, 3H), 2.07-1.98 (m, 2H), 1.82-1.72 (m, 4H), 1.44 (s, 9H), 1.36-1.08 (m, 5H).
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:13][C:14]1[C:22]([Cl:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(O)C.C(Cl)(Cl)(Cl)Cl>[Cl:13][C:14]1[C:22]([Cl:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: O=C(Cl)c1cc(F)c(F)c(Cl)c1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.3 %

Procedure:
Magnesium turnings (0.77 g) and carbon tetrachloride (0.4 ml) was added to absolute ethanol (5.3 ml). To the stirring suspension was added a solution of diethyl malonate (4.89 g) and absolute ethanol (8.5 ml) in toluene (21.3 ml) dropwise during 40 minutes at 20° to 40° C. The mixture was stirred at 50° to 60° C. for 2 hours, and then cooled in an acetone-dry ice bath. A solution of 2,3-dichloro-4,5-difluorobenzoyl chloride (6.00 g) in anhydrous toluene (7.1 ml) was added dropwise to the resulting solution at -18° to -13° C. during 10 minutes. The mixture was warmed gradually to room temperature during 2 hours and then mixed with ice water (17 ml) containing concentrated sulfuric acid (1.1 ml). The resulting organic layer was collected and the water layer was extracted with toluene. The combined organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated to give the title compound (9.68 g) as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:21]1([CH2:26][CH2:27][N:28]2[CH:32]=[C:31]([NH2:33])[CH:30]=[N:29]2)[CH2:25][CH2:24][CH2:23][CH2:22]1.C1(P(C2CCCCC2)C2(P(C3CCCCC3)C3CCCCC3)CC=CC=C2C2C=CC=CC=2)CCCCC1.Cl>O1CCOCC1>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:33][C:31]4[CH:30]=[N:29][N:28]([CH2:27][CH2:26][N:21]5[CH2:25][CH2:24][CH2:23][CH2:22]5)[CH:32]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17].[ClH:1].[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:33][C:31]4[CH:30]=[N:29][N:28]([CH2:27][CH2:26][N:21]5[CH2:25][CH2:24][CH2:23][CH2:22]5)[CH:32]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: Nc1cnn(CCN2CCCC2)c1
Agent: C1=CCC(P(C2CCCCC2)C2CCCCC2)(P(C2CCCCC2)C2CCCCC2)C(c2ccccc2)=C1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cnn(CCN5CCCC5)c4)nc23)cc1

Procedure:
219 c) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-amine was synthesized from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1.5-a]pyridine (0.150 g, 0.487 mmol) and 1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-ylamine (0.105 g, 0.585 mmol) with 2,2-bis-dicyclohexylphosphanyl-biphenyl (0.048 g, 0.088 mmol) as the ligand in a manner analogous to Example 2d. The isolated pure product was treated with 2N hydrogen chloride in dioxane. [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-amine hydrochloride was isolated as a light green solid (70 mg, 30%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][CH:11]=1>CO.[Ni]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc3ccccc3o2)cc1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(C2Cc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.1 %

Procedure:
To a solution of tert-butyl 4-(benzofuran-2-yl)benzoate (0.3 g, 1.0 mmol) in methanol (20 mL) was added raney nickel (0.20 g). The reaction mixture was stirred at room temperature for 2 hours under hydrogen (4 atm). After the reaction, the mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/petroleum ether=1:20) to give pure product tert-butyl 4-(2,3-dihydrobenzofuran-2-yl)benzoate as a white solid (0.03 g, 10%).
Reaction SMILES: [C:1]1([CH3:33])[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:20]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:21][C:22]([O:24]CC)=[O:23])[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1>C(O)C>[C:1]1([CH3:33])[CH:2]=[CH:3][C:4]([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:20]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:21][C:22]([OH:24])=[O:23])[CH:17]=3)[CH2:12]2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C=C(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(C)cc1)C2
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)NC2Cc3ccc(C(=CC(=O)O)c4cccnc4)cc3C2)cc1

Procedure:
4.2 g of ethyl 3-(2-(4-toluenesulphonylamino)indan-5-yl)-3-(3-pyridyl)-prop-2-enoate are refluxed for 30 minutes in 40 ml of ethanol and 1.5 ml of 15N sodium hydroxide solution. Then the cooled solution is washed 3 times with 50 ml of methylene chloride and then acidified. The precipitate formed is washed, dried and then recrystallised from n-butanol.
Reaction SMILES: FC1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:37][CH:36](O)[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([OH:39])[CH:34]=3)[O:29]2)=[CH:24][CH:23]=1)([O-:21])=[O:20]>>[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:37][CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[C:33]([OH:39])[CH:34]=3)[O:29]2)=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(C2CC(O)c3cc(O)ccc3O2)cc1
Agent: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Product: O=[N+]([O-])c1ccc(C2CCc3cc(O)ccc3O2)cc1

Procedure:
2-(4-Nitrophenyl)chroman-6-ol was prepared as described for 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 2-(4-nitrophenyl)chroman-4,6-diol. 1H NMR (400 MHz, d6-DMSO) δ: 8.84 (s, 1H), 8.26 (d, 2H, J 6.9 Hz), 7.71 (d, 2H, J 6.9 Hz), 6.69 (d, 1H, J 8.6 Hz), 6.53 (dd, 1H, J 8.6, 2.8 Hz), 6.50 (d, 1H, J 2.8 Hz), 5.19 (dd, 1H, J 9.9, 2.2 Hz), 2.87-2.91 (m, 1H), 2.61-2.66 (m, 1H), 2.16-2.21 (m, 1H), 1.89-1.93 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:26][CH2:27][C:28](Cl)=[O:29]>O>[Cl:26][CH2:27][C:28]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:2]=1[CH3:1])=[O:29]
Reactant: COc1ccc(C)c(NCC=O)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(C)c(N(CC=O)C(=O)CCl)c1
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-methyl-5-methoxyanilino)-acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0° C. and α-chloroacetyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2-methyl-5-methoxyanilino)acetaldehyde.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[NH2:13][C:14]1([C:17]([OH:19])=[O:18])[CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].C(C1CCCCC1=O)(=O)C>CN(C=O)C.[Cu]I.C(N(CC)CC)C.O>[CH3:9][NH:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([NH:13][C:14]2([C:17]([OH:19])=[O:18])[CH2:16][CH2:15]2)=[CH:3][C:4]=1[F:12])=[O:7]
Reactant: NC1(C(=O)O)CC1
Reactant: CNC(=O)c1ccc(Br)cc1F
Agent: [Cu]I
Agent: CC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CNC(=O)c1ccc(NC2(C(=O)O)CC2)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
To a stirred solution of 4-bromo-2-fluoro-N-methylbenzamide (6.4 g, 27.5 mmol), 1-aminocyclopropanecarboxylic acid (4.29 g, 42.4 mmol), CuI (1.047 g, 5.5 mmol), K2CO3 (9.50 g, 68.0 mmol), in DMF (64 mL) was added H2O (6.4 mL), triethylamine (0.164 mL, 1.1 mmol) followed by 2-acetyl cyclohexanone (0.717 g, 5.10 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction was monitored by TLC and LCMS. H2O was added, and the aqueous layer was washed with ethyl acetate. The aqueous layer was acidified with 1M citric acid solution (pH˜4) and extracted with ethyl acetate. The organic extracts were dried over anhydrous Na2SO4, concentrated under reduced pressure and crystallized with DCM to afford 3.01 g of the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Br:7][C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:14]=1)[NH2:11].N1C=CC=CC=1.Cl>C(Cl)Cl>[Br:7][C:8]1[CH:9]=[C:10]([NH:11][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:14]=1
Reactant: Nc1cc(Br)cc(Oc2ccc(F)cc2F)c1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cc(Br)cc(Oc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.6 %

Procedure:
Ethylsulfonyl chloride (15 uL, 0.16 mmol) was added dropwise to a stirred solution of 3-bromo-5-(2,4-difluorophenoxy)aniline (48 mg, 0.16 mmol) and pyridine (40 uL, 0.48 mmol) in DCM (320 uL) at 0° C. under nitrogen. After the mixture was allowed to warm to rt and stir for 12 h, it was treated with 1N HCl (1 mL) and extracted with DCM (3×5 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The crude solid was purified by silica gel column chromatography using a gradient of EtOAc (5 to 60%) in hexanes to afford the title compound (60 mg, 95%) as a tan solid. LCMS (M+H)+=393.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:18][CH2:17][C:16]([OH:15])([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-(4-chlorophenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 83% overall yield. FDMS m/e=401 (M+ of free base). α[D]589 =-14.17 (c=0.45, methanol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O.[I-].[K+]>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)([O-:3])=[O:2]
Reactant: ClCc1cccc(-c2ccccc2)n1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(OCc2cccc(-c3ccccc3)n2)c1

Procedure:
To a stirred solution of 4.2 g (0.03 mol) of 3-nitrophenol in 150 ml of acetone is added 7.5 (0.05 mol) of 2-chloromethyl-6-phenylpyridine hydrochloride3, 10 g (0.03 mol) of cesium carbonate and 0.5 g of potassium iodide, and the slurry is heated to reflux for 20 hours. The hot mixture is filtered, and the filtrate is concentrated in vacuo to obtain an oil (9.3 g). The crude product is recrystallized from ethyl acetate/pentane to give a first crop (4.5 g, 49%) of crystals, m.p. 77°-80° C. and a second crop (1.7 g, 19%) of crystals, m.p. 77°-81° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([O:14]CC)=[O:13])=[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[N:4]2[N:3]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[N:4]2[N:3]=1
Reactant: CCOC(=O)c1c(C)nn2c(C)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn2c(C)cccc2c1C(=O)O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To 1.00 g (4.6 mmol) of ethyl 2,7-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate prepared in accordance with the procedure disclosed in "YAKUGAKU ZASSHI", 91(11), 1154-1157 (1971), 5 ml of 3N aq. NaOH solution and 2 ml of ethanol were added, followed by stirring at 100° C. for 8 hours. After the reaction, the solvents were distilled off, and the residue was dissolved in water and then washed with benzene. The aqueous layer was made acidic with concentrated hydrochloric acid. Crystals precipitated were collected by filtration and then washed with water. Yield: 0.85 g (4.5 mmol) (97%).
Reaction SMILES: [CH3:1][N:2]([CH:14](Cl)[C:15]([Cl:18])([Cl:17])[Cl:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:4].[S-:20][C:21]#[N:22].[NH4+]>C(COC)OC>[CH3:1][N:2]([CH:14]([N:22]=[C:21]=[S:20])[C:15]([Cl:18])([Cl:17])[Cl:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:4]
Reactant: CN(C(=O)Nc1ccc(Cl)c(Cl)c1)C(Cl)C(Cl)(Cl)Cl
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: COCCOC
Product: CN(C(=O)Nc1ccc(Cl)c(Cl)c1)C(N=C=S)C(Cl)(Cl)Cl
Reaction time: 2 h

Procedure:
1-methyl-1-(1,2,2,2-tetrachloroethyl)-3-(3,4-dichlorophenyl) urea (7.7 g, 0.02 mol) was dissolved in 200 ml dimethoxyethane, followed by addition of 1.5 g (0.02 mol) of ammonium thiocyanate. The mixture was stirred for 2 hours, filtered and stripped of solvent. Ether was added to the residue, which was again filtered to remove a small amount of solid. The remaining solvent was then removed, leaving a dark oil which solidified upon standing. This material had a melting point of 142°-146° C. The infrared spectrum of the material showed a broad absorption band at 4.9 micron (for the --N=C=S group). Elemental analysis showed: %Cl, calc., 43.6, found 36.7; %S, calc. 7.9, found 6.3.
Reaction SMILES: C(NCC)C.[C:6]([OH:12])(=[O:11])[CH2:7][CH2:8][C:9]#[CH:10].[I:13][C:14]1[S:15][CH:16]=[C:17](I)[CH:18]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[I:13][C:14]1[S:15][C:16]([C:10]#[C:9][CH2:8][CH2:7][C:6]([OH:12])=[O:11])=[CH:17][CH:18]=1
Reactant: C#CCCC(=O)O
Reactant: Ic1csc(I)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: O=C(O)CCC#Cc1ccc(I)s1
Reaction time: 8 h

Procedure:
To 75ml of diethylamine was added with stirring 3.76g of 4-pentynoic acid, 22g of 2,4-diiodothiophene, and 300mg of tetrakis(triphenylphosphine)palladium(o). The slurry was degassed with argon and 960mg of CuI was added. The slurry was maintained under argon and allowed to stir overnight, producing a dark brown solution. Thereafter, the solvent was removed under reduced pressure and 100ml of 10% HCl was added to the residue. The residue was filtered and then extracted 3x with ethyl acetate. The combined extracts were washed 1x with water, dried over anhydrous MgSO4, filtered, and stripped. The resulting residue was flash chromatographed on a column of silica gel. Elution with a mixture of 30/70/2 parts ethyl acetate/hexane/acetic acid produced 3.5 g of the titled product as a yellow solid.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][C:11]([NH:13][C@H:14]1[CH2:18][N:17](C(OC(C)(C)C)=O)[C@H:16]([C:26]([N:28]2[CH2:33][CH2:32][CH:31]([O:34][C:35]3[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=3[Cl:42])[CH2:30][CH2:29]2)=[O:27])[CH2:15]1)=[O:12])=O)(C)(C)C>O1CCOCC1>[ClH:42].[ClH:1].[NH2:9][CH2:10][C:11]([NH:13][C@H:14]1[CH2:18][NH:17][C@H:16]([C:26]([N:28]2[CH2:33][CH2:32][CH:31]([O:34][C:35]3[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=3[Cl:42])[CH2:30][CH2:29]2)=[O:27])[CH2:15]1)=[O:12]
Reactant: Cc1ccc(Cl)c(OC2CCN(C(=O)[C@@H]3C[C@@H](NC(=O)CNC(=O)OC(C)(C)C)CN3C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(Cl)c(OC2CCN(C(=O)[C@@H]3C[C@@H](NC(=O)CN)CN3)CC2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 4 N hydrochloric acid in 1,4-dioxane (8 mL) was added to a solution of 1-[trans-4-(N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-prolyl]-4-(2-chloro-5-methylphenoxy)piperidine (C, 280 mg) in 1,4-dioxane (8 mL) at room temperature. After stirring at room temperature for 20 min, the reaction mixture was evaporated in vacuo. The residue was washed with ether to give the titled compound (142 mg) as a white powder: 1H NMR (400 MHz, D2O) δ 1.90-2.01 (4H), 2.32 (s, 3H), 2.43 (m, 1H), 2.61 (br s, 1H), 3.49 (br t, 2H), 3.67 (br s, 1H), 3.79 (m, 4H), 3.85 (s, 2H), 4.58 (br s, 1H), 5.02 (m, 1H), 6.91 (d, J=8.0 Hz, 1H), 7.09 (s, 1H), and 7.35 (d, J=8.0 Hz, 1H); mass spectrum (EI+) m/e 394 (M).
Reaction SMILES: Br[CH2:2][C@@H:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[N:13]=2)[N:8]=[CH:7][CH:6]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:16][O:15][C:12]1[N:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[C@@H:3]1[CH2:2][O:4]1
Reactant: COc1ccc2nccc([C@@H](O)CBr)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc2nccc([C@@H]3CO3)c2n1
Yield: 91.3 %

Procedure:
(R)-2-Bromo-1-(6-methoxy-[1,5]-naphthyridin-4-yl)ethanol (4.8 g, 0.017 mol) in methanol (20 ml) was stirred with potassium carbonate (2.6 g, 0.019 mol) for 1 hour, then evaporated and chromatographed on silica gel (ethyl acetate-hexane-dichloromethane) to give a solid (3.14 g, 92%), (91% ee by chiral HPLC).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH2:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36])(OCC)=O>O.C(#N)C>[C:27]1(=[O:36])[N:14]([CH:12]([CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:13])[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]12
Reactant: COc1ccc(CC(C)N)cc1OC
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(CC(C)N2C(=O)c3ccccc3C2=O)cc1OC
Reaction time: 0.67 h
Yield: 53.2 %

Procedure:
To a stirred solution of 3-(3,4-dimethoxyphenyl)-2-aminopropane (1.95 grams, 10.0 mmol) and sodium carbonate (1.06 grams, 10.0 mmol) in 50 milliliters of water was added N-carbethoxyphthalimide (2.19 grams, 10.0 mmol). After 10 minutes the reaction mixture was diluted with 40 milliliters of acetonitrile and the mixture stirred for 40 minutes The reaction solution was partially concentrated in vacuo to remove the acetonitrile. The resulting mixture of an oil and aqueous layer was extracted with methylene chloride (25 milliliters). The organic extract was dried over sodium sulfate and concentrated in vacuo to afford a crude product which was purified by flash chromatography to afford 1.73 grams (53%) of product as a thick oil which slowly solidified to a white wax: 1H NMR (dmso-d6, 250 MHz) δ7.7 (m, 4 H, Ar), 6.7 (m, 3 H, Ar), 4.63 (m, 1 H, CH), 3.79 (s, 3 H, OMe), 3.73 (s, 3 H, OMe), 3.28 (dd, 1 H, J =13.8, 9.8 Hz), 3.03 (dd, J=13.8, 6.5 Hz, 1 H), 1.54 (d, J=6.9 Hz, 3 H); 13C NMR (dmso-d6) δ168.4, 148.6, 147.4, 133.7, 131.8, 130.9, 122.9, 120.9, 111.1, 55.7, 55.6, 48.6, 39.3, 18.3. Anal. Calcd for C19H19NO2. Theoretical C, 70.14; H, 5.89; N, 4.30. Found C, 70.08; H, 5.83; N, 4.30.