Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7]O)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.[NH:19]1[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([CH2:7][N:19]2[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:20]2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1
Reactant: Cc1oc(CO)cc1-c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2cc(-c3cccc(C(F)(F)F)c3)c(C)o2)c1
Reaction time: 1 h
Yield: 33.9 %

Procedure:
A solution of the compound (0.40 g) obtained in Example 128d, ethyl 1H-pyrazole-4-carboxylate (0.26 g) and triphenylphosphine (0.49 g) in tetrahydrofuran (5 mL) was cooled in an ice bath, diisopropyl azodicarboxylate (0.36 mL) was added, and the mixture was stirred at the same temperature for 1 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane/ethyl acetate) to give the title compound (0.20 g) as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[C:9]1S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.[OH-].[Na+]>CO.O[W](O)(=O)=O>[CH2:1]([N:8]1[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cnc(S)n1Cc1ccccc1
Agent: O=[W](=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: CO
Product: OCc1cncn1Cc1ccccc1
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 69 %

Procedure:
1-Benzyl-2-mercapto-5-hydroxymethylimidazole(2.2 g, 9.99 mmol) and tungstic acid(H2WO4, 25 mg, 1 mol %) were mixed in 11 ml of methanol. The mixture was warmed to 40° C. in a water bath and 30% hydrogen peroxide(3.75 g, 3.2 molar eq.) was added dropwise thereto for 5 minutes while stirring. The reaction mixture was warmed to 65° C. and refluxed, and stirred at the same temperature for 2.5 hours. Upon exhaustion of the starting material, the mixture was cooled in an ice bath and thereto was added 1 N sodium hydroxide solution(18 ml) to adjust pH of the mixture to 10. The resulting solid was further stirred for 15 minutes, filtered, washed twice with 15 ml of distilled water and 15 ml of isopropyl ether, respectively, and dried to give 1.3 g(Yield 69%, HPLC purity 96.7%) of the title compound as a white powder.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([NH:7][C@H:8]([C:16]([OH:18])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:3].[C:20](=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:3][C:2]([CH3:19])([O:4][C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:20])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 99.7 %

Procedure:
To a solution containing N-[(1,1-dimethylethoxy)carbonyl]phenylalanine (10 g, 37.7 mmole) in dimethylformamide (40 ml) is added solid sodium bicarbonate (4.75 g, 56.6 mmole) and iodometbane (16 g, 113 mmole). The mixture is heated at 40° under argon for 12 hours, the cooled and the reaction mixture partitioned between water (150 ml) and ether (250 ml). The organic layer is rinsed with 2% aqueous sodium bicarbonate (2×100 ml), 2% aqueous sodium bisulfite (100 ml), water (2×100 ml), and brine, dried over magnesium sulfate, and concentrated in vacuo to give 10.5 g of N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine, methyl ester as an oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:19]1[C:20]2[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[S:25][C:21]=2[N:22]=[CH:23][N:24]=1>O1CCCC1>[CH3:30][CH:28]([C:26]1[S:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([O:1][CH:2]3[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]3)[C:20]=2[CH:27]=1)[CH3:29]
Reactant: CC(C)c1cc2c(Cl)ncnc2s1
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc2c(OC3CCC(NC(=O)OC(C)(C)C)CC3)ncnc2s1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate (3.3 g, 15.33 mmol, 1.10 equiv) in tetrahydrofuran (20 mL). This was followed by the addition of sodium hydride (800 mg, 33.33 mmol, 2.36 equiv) in portions at 0-5° C. The resulting solution was stirred for 2.5 h at room temperature. To this was added a solution of commercially available 4-chloro-6-(propan-2-yl)thieno[2,3-d]pyrimidine (3.0 g, 14.10 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) at 5-10° C. The resulting solution was stirred overnight at room temperature. The reaction mixture was cooled to 5-10° C. with a water/ice bath. The reaction was then quenched by the addition of 100 mL of water. The resulting mixture was concentrated under vacuum. The solids were collected by filtration. This resulted in 4.8 g (87%) of tert-butyl N-(4-[[6-(propan-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy]cyclohexyl)carbamate as a yellow solid. MS: m/z 392 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=O)=[CH:14][CH:15]=2)[N:10]([CH:20]([CH3:22])[CH3:21])[N:9]=1.[CH3:23][C:24]1[N:28]=[C:27]([C@H:29]([NH2:31])[CH3:30])[O:26][N:25]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([NH:31][C@@H:29]([C:27]3[O:26][N:25]=[C:24]([CH3:23])[N:28]=3)[CH3:30])=[O:19])=[CH:14][CH:15]=2)[N:10]([CH:20]([CH3:22])[CH3:21])[N:9]=1
Reactant: CC(C)n1nc(-c2ccccc2Cl)c2ccc(C(=O)O)cc21
Reactant: Cc1noc([C@@H](C)N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1noc([C@@H](C)NC(=O)c2ccc3c(-c4ccccc4Cl)nn(C(C)C)c3c2)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
To a solution of 3-(2-chlorophenyl)-1-isopropyl-1H-indazole-6-carboxylic acid (13.3 mg, 42.0 μmol) in N,N-dimethylformamide (0.5 mL) were added hydrochloride salt of (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine (10.4 mg, 63.0 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16.2 mg, 85.0 μmol), 1-hydroxy-7-azabenzotriazole (2.9 mg, 21.0 μmol) and N-methylmorpholine (18.6 μL, 0.17 mmol). The mixture was heated to 50° C. and stirred for 30 min. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the bistrifluoroacetate salt of the title compound (12 mg): HRMS [M+1] found=424.1530; 1H NMR (500 MHz, CDCl3): δ 8.12 (s, 1H); 7.75 (d, J=8.4 Hz, 1H); 7.63-7.59 (m, 1H); 7.57-7.53 (m, 1H); 7.49 (d, J=8.4 Hz, 1H); 7.39 (dd, J=5.9, 3.5 Hz, 2H); 6.84 (d, J=7.7 Hz, 1H); 5.68-5.61 (m, 1H); 5.03-4.95 (m, 1H); 2.42 (s, 3H); 1.74 (d, J=7.0 Hz, 3H); 1.67 (d, J=6.6 Hz, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[N:5]=[C:4]([C:22]([O:24][CH3:25])=[O:23])[N:3]=1.Cl.[NH2:27][C@@H:28]([CH3:33])[C:29]([O:31][CH3:32])=[O:30].CCN(C(C)C)C(C)C>C(#N)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]([C:6]3[CH:7]=[C:2]([NH:27][C@@H:28]([CH3:33])[C:29]([O:31][CH3:32])=[O:30])[N:3]=[C:4]([C:22]([O:24][CH3:25])=[O:23])[N:5]=3)=[CH:9][CH:10]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)[C@H](C)N
Reactant: COC(=O)c1nc(Cl)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1nc(N[C@@H](C)C(=O)OC)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 80 °C
Yield: 56.5 %

Procedure:
To a suspension of methyl 4-chloro-6-(4-(4-fluorophenoxy)phenyl)pyrimidine-2-carboxylate (0.719 g, 2.00 mmol) in acetonitrile (10 mL) was added (S)-methyl 2-aminopropanoate hydrochloride (0.310 g, 2.22 mmol) and iPr2NEt (0.77 mL, 4.4 mmol). The mixture was heated at 50° C. for 2 h than 80° C. for 6 days. The mixture was evaporated in vacuo and the residue chromatographed over silica gel with 20-60% EtOAc/hexanes. The product fractions were evaporated in vacuo to give (S)-methyl 4-(4-(4-fluorophenoxy)phenyl)-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-2-carboxylate as a pale tan oil (0.479 g, 1.13 mmol, 56% yield). LC/MS: m/z=426.2 [M+H]+.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:13]([O:15][P:16]([CH2:21][C:22]([OH:24])=O)([O:18][CH2:19][CH3:20])=[O:17])[CH3:14].[C:25]([C:27]1[CH:28]=[C:29]([NH:34][C:35]2[C:36]3[CH:44]=[C:43]([NH2:45])[N:42]=[CH:41][C:37]=3[N:38]=[CH:39][N:40]=2)[CH:30]=[CH:31][C:32]=1[F:33])#[CH:26].C1COCC1>O.ClCCl.CO.CC(N(C)C)=O>[C:25]([C:27]1[CH:28]=[C:29]([NH:34][C:35]2[C:36]3[CH:44]=[C:43]([NH:45][C:22](=[O:24])[CH2:21][P:16](=[O:17])([O:15][CH2:13][CH3:14])[O:18][CH2:19][CH3:20])[N:42]=[CH:41][C:37]=3[N:38]=[CH:39][N:40]=2)[CH:30]=[CH:31][C:32]=1[F:33])#[CH:26]
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: C#Cc1cc(Nc2ncnc3cnc(N)cc23)ccc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: C#Cc1cc(Nc2ncnc3cnc(NC(=O)CP(=O)(OCC)OCC)cc23)ccc1F
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
To a stirred mixture of CDI (2.01 g, 12.4 mmol) and dry THE (9 mL), at room temperature and under a nitrogen atmosphere, was added a solution of 2-(diethoxyphosphoryl)acetic acid (2.18 g, 11.1 mmol) in THE (7 mL). After addition the reaction mixture was stirred further at 40° C. (bath) for 15 min (whence evolution of gases ceased). A mixture of compound 226 (1.24 g, 4.44 mmol) in a mixed solvents of dry THF (5 mL) and DMA (6 mL) was added and stirred further at 40° C. The reaction was monitored by TLC (dichloromethane-MeOH=30:1). After stirred for 22 h, it was poured into water (200 mL) and the residue washed down with MeOH. Petroleum ether (300 mL) was added and stirred at room temperature for 1 h. Petroleum ether layer was decanted. It was repeated once more with petroleum ether (150 mL). The solid was collected by suction filtration; washed with water (5×20 mL) and dried to give diethyl 2-(4-(3-ethynyl-4-fluorophenylamino)pyrido[3,4-d]-pyrimidin-6-ylamino)-2-oxoethylphosphonate (235) (1.85 g, 91%); mp 103-106° C.; 1H NMR δ [(CD3)2SO]: 10.84 (s, 1H), 10.33 (s, 1H), 9.01 (s, 1H), 8.86 (s, 1H), 8.61 (s, 1H), 8.01 (dd, J=6.4, 2.7 Hz, 1H), 7.92-7.83 (m, 1H), 7.35 (t, J=9.1 Hz, 1H), 4.51 (s, 1H), 4.17-4.03 (m, 4H), 3.32 (d, partially obscured by water peak, 2H), 1.26 (t, J=7.0 Hz, 6H). Anal. Calcd for C21H21FN3O4P.MeOH: C, 53.99; H, 5.15; N, 14.31%. Found C, 54.21; H, 4.94; N, 14.43%.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:3]=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[C:26]=1[S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[S:1]1[CH:5]=[C:4]([N:6]([S:33]([C:26]2[C:27]([F:32])=[CH:28][C:29]([F:31])=[CH:30][C:25]=2[F:24])(=[O:35])=[O:34])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)Nc1cscn1
Reactant: O=S(=O)(Cl)c1c(F)cc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1c(F)cc(F)cc1F
Yield: 77.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 86a by using tert-butyl 1,3-thiazol-4-ylcarbamate (Synthesis, 2010, 3152-3162; 1.00 g, 4.99 mmol), lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 5.99 mL, 5.99 mmol), 2,4,6-trifluorobenzenesulfonyl chloride (1.38 g, 5.99 mmol) and THF (15 mL), to yield the title compound (1.53 g, 78%) as a pale yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[CH:18][C:19]=2[CH3:20])=[CH:10][CH:9]=1)[NH2:6].[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:26]=1[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[CH:18][C:19]=2[CH3:20])=[CH:12][CH:13]=1)[NH:6][C:27]([C:26]1[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:25]=1[Cl:24])=[O:28]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)ccn(C)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2c(C)ccn(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Reaction time: 72 h
Yield: 26.5 %

Procedure:
To a suspension of 4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride salt (68 mg, 0.2 mmol), 2-chloro-6-methylbenzoic acid (45 mg, 0.25 mmol) and HBTU (95 mg, 0.25 mmol) in DMF (1.5 mL) was added DIEA (174 μL, 1.0 mmol) at room temperature. The resulting solution was stirred for 72 h, the mixture was poured into water (25 mL) and was extracted with ethyl acetate (2×15 mL). The combined ethyl acetate extracts were washed successively with 0.5 N HCl (25 mL), saturated NaHCO3 solution (25 mL), brine solution (25 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product, which was purified by silica gel chromatography using a Biotage (40 s) column to afford 24 mg (27% yield) of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C25H25ClN2O4 (M+Na) 475.1395, found 475.1400.
Reaction SMILES: C([O:8][C:9](=[O:39])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH2:20][CH2:19][CH2:18][C:17]=2[C:21]2[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:11]=1)C1C=CC=CC=1>C(O)C.[OH-].[Na+].O>[CH3:30][S:27]([C:25]1[CH:24]=[CH:23][C:22]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:21]([C:17]2[CH2:18][CH2:19][CH2:20][C:16]=2[C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=2)[C:9]([OH:39])=[O:8])[CH:26]=1)(=[O:28])=[O:29]
Reactant: CS(=O)(=O)c1ccc(OCc2ccccc2)c(C2=C(c3cccc(C(=O)OCc4ccccc4)c3)CCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(OCc2ccccc2)c(C2=C(c3cccc(C(=O)O)c3)CCC2)c1

Procedure:
A solution of 3-{2-[5-methylsulfonyl-(benzyloxy)-phenyl]-cyclopent-1-enyl}-benzoic acid benzyl ester (30 mg, 0.059 mmol) in ethanol (5 ml) and 2M sodium hydroxide (1 ml) was left at room temperature for 20 hours then diluted with water, washed with ether and the aqueous phase separated, acidified with 2M hydrochloric acid and extracted with ether. The organic extract was dried (MgSO4), evaporated to dryness and the residue triturated with iso-hexane to yield the title compound as a white solid. (14 mg, 57%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[OH:26])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C.O>[CH2:11]([N:18]1[CH2:19][CH2:20][CH:21]([CH2:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])=[O:26])[CH2:22][CH2:23]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC(CC1CCN(Cc2ccccc2)CC1)c1ccccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=C(CC1CCN(Cc2ccccc2)CC1)c1ccccc1Cl
Temperature: -78 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
After dissolving 1.30 ml of oxalyl chloride in 30 ml of dichloromethane, the solution was cooled to −78° C., and a solution of 1.22 ml of dimethylsulfoxide in dichloromethane (5 ml) was added dropwise while stirring. The mixture was stirred for 3 minutes, and then a solution of 2-(1-benzylpiperidin-4-yl)-1-(2-chlorophenyl)ethanol in dichloromethane (10 ml) was added dropwise. After stirring for 30 minutes, 8.01 ml of triethylamine was added, the temperature was raised to room temperature and stirring was continued for 3 hours. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (1.78 g, 47% yield, 2 steps).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[NH2:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)=[O:6].[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O>CO>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:5]([C:4]2[CH:15]=[CH:16][C:17]3[N:18]=[C:19]([C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH3:22])[NH:1][C:2]=3[CH:3]=2)=[O:6])[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccccc1C=O
Reactant: Nc1ccc(C(=O)Nc2cccc(Cl)c2)cc1N
Solvent: CO
Product: Cc1ccccc1-c1nc2ccc(C(=O)Nc3cccc(Cl)c3)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,4-diamino-N-(3-chloro-phenyl)-benzamide (0.1 mL in 0.2 M DMSO solution), 2-methyl benzaldehyde (0.1 mL in 0.2 M toluene solution) and FeCl3 (0.05 mL in 0.02M THF solution) was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give 2-o-tolyl-3H-benzoimidazole-5-carboxylic acid (3-chloro-phenyl)-amide as white powder: MS (m/z) 362 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=O.[CH2:12]([O:14][C:15](=[O:21])[CH2:16][C:17]([CH2:19][Cl:20])=[O:18])[CH3:13].N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1.C(OCC)(=O)C.O>[CH2:12]([O:14][C:15](=[O:21])[C:16](=[CH:4][C:3]1[C:2]([CH3:1])=[CH:9][C:8]([CH3:10])=[CH:7][C:6]=1[CH3:11])[C:17](=[O:18])[CH2:19][Cl:20])[CH3:13]
Reactant: Cc1cc(C)c(C=O)c(C)c1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1c(C)cc(C)cc1C)C(=O)CCl
Reaction time: 6 h
Yield: 39 %

Procedure:
90 g of 2,4,6-trimethylbenzaldehyde, 150 g of 4-chloroacetoacetic acid ethyl ester, 2.6 ml of piperidine and 7 ml of glacial acetic acid were dissolved in 60 ml of benzene and the solution was boiled for 6 hours using a water separator. 200 ml of ethyl acetate were added to the cooled solution, the solution was extracted in each case once with saturated sodium bicarbonate solution, water and 1 M citric acid solution and the extract was dried over magnesium sulphate and evaporated. The crude product was subjected to incipient distillation under a high vacuum in order to free it from excess 4-chloroacetoacetic acid ethyl ester. After chromatography of the product on Silica gel 60 (Merck, 70-230 mesh), 21 g of the E-isomer could be crystallized with isopropanol and 3:1 Z/E mixture remained as the mother liquor in the form of an oil. Total yield: 39%. E-isomer: melting point 85°.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:32])[N:11]([CH2:15][C:16](=[O:31])[N:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[OH:8][C:9]1[C:10](=[O:32])[N:11]([CH2:15][C:16](=[O:31])[N:17]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=C(Cn1cccc(OCc2ccccc2)c1=O)N(Cc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(Cn1cccc(O)c1=O)N(Cc1ccccc1)c1ccccc1
Yield: 22 %

Procedure:
18 (280 mg, 0.7 mmol) was suspended in 150 mL of EtOH. 10% (w/w, 38 mg) of 10% Pd/C catalyst was added to the hydrogenation flask (500 mL Pyrex® Parr reaction bottle tested to 120 psi, max. working pressure of 60 psi). The hydrogen pressure was set to 35 psi with agitation, and the process went on for 19 h. The catalyst was removed by vacuum filtration and separated from the product by dissolving the white precipitate in 100 mL hot CH2Cl2. An additional batch of product was isolated by cooling the EtOH filtrate to 0° C. for 2 h. The clear solution was concentrated by rotary evaporation to yield a white solid. The solid was washed with MeOH to remove residual DCU. Yield: 22%. 1H NMR (d6-DMSO, 400 MHz, 25° C.): δ 4.34 (d, J=6.0 Hz, 2H, —CH2—), 4.63 (s, 2H, —CH2—), 6.08 (t, J=7.2 Hz, 1H, Ar—H), 6.69 (d, J=7.2 Hz, 1H, Ar—H), 7.10 (d, J=6.4 Hz, 1H, Ar—H), 7.44 (m, 5H, Bz-H), 7.64 (m, 4H, Phenyl-H), 8.70 (t, J=5.6 Hz, 1H, —NH—), 9.02 (s, 1H, —OH). APCI-MS: m/z 334.9 [M+H]+. Anal. Calcd for C20H18N2O3: C, 71.84; H, 5.43; N, 8.38. Found: C, 71.49; H, 5.78; N, 8.52.
Reaction SMILES: [CH:1]1([C:4](Cl)=O)[CH2:3][CH2:2]1.Cl.[CH3:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:10]=1[O:11][CH2:12][C@H:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH:1]1([CH2:4][N:15]2[CH2:16][CH2:17][CH2:18][C@H:13]([CH2:12][O:11][C:10]3[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:9]=3[CH3:8])[CH2:14]2)[CH2:3][CH2:2]1
Reactant: Cc1cccc(C)c1OC[C@H]1CCCNC1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1OC[C@H]1CCCN(CC2CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopropylcarbonyl chloride (1.7 mL, 18 mmol) was added dropwise during 15 minutes to an ice cold mixture containing (S)-3-(2,6-dimethylphenoxymethyl)piperidine hydrochloride (4.4 g, 17 mmol), aqueous sodium bicarbonate (75 mL), and ethyl acetate (100 mL). After the addition was complete, the reaction was stirred at room temperature for 1 hour, and the resulting ethyl acetate layer was separated and concentrated. The residue was dissolved in dry tetrahydrofuran (125 mL) under a dry nitrogen atmosphere and a 1M solution of lithium aluminum hydride in tetrahydrofuran (18.9 mL) was added dropwise. When the addition was complete, the reaction mixture was heated to reflux for 2 hours, then cooled to room temperature. Solid sodium sulfate decahydrate (10 g) was slowly added with stirring and the mixture was filtered. The filtrate was concentrated and chromatographed on silica gel, eluting with acetone/hexanes (1:3) to give (S)-1 -cyclopropylmethyl-3-(2,6-dimethylphenoxymethyl)piperidine as an oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O)[CH2:2][CH3:3].[F:13][C:14]1[CH:25]=[C:24]2[C:17]([NH:18][CH:19]=[C:20]2[CH2:21][CH2:22][NH2:23])=[CH:16][CH:15]=1.[BH4-].[Na+]>CO.COCCOCCOC>[F:13][C:14]1[CH:25]=[C:24]2[C:17](=[CH:16][CH:15]=1)[NH:18][CH:19]=[C:20]2[CH2:21][CH2:22][NH:23][CH2:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:6]=1
Reactant: NCCc1c[nH]c2ccc(F)cc12
Reactant: CCCOc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOCCOC
Product: CCCOc1cccc(CNCCc2c[nH]c3ccc(F)cc23)c1

Procedure:
Combine 3-propoxybenzaldehyde (29.6 mg; 0.18 mmol) and 5-fluorotryptamine (14.2 mg; 0.080 mmol) in methanol (2 mL). Add a solution of sodium borohydride in diglyme (1 ml of a 0.5 M solution; 0.50 mmol)and agitate. After 63 h at room temperature concentrate in a stream of nitrogen. Dissolve the residue in methanol and add to a 1 gm SCX column previously rinsed with 5% acetic acid in methanol. Elute the product from the SCX column with 1 M ammonia in methanol to give the title compound: MS (ES+): m/e (M+1); HPLC (10–90% water/acetonitrile over 10 min, Tr=4.08 min.