Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].[CH:3]([NH:5][C:6]1[N:11]=[C:10]([C:12](=O)[C:13]([O:15]CC)=[O:14])[CH:9]=[CH:8][CH:7]=1)=[O:4].Cl.[NH2:20]O>C(O)C>[CH:3]([NH:5][C:6]1[N:11]=[C:10]([C:12](=[N:20][OH:1])[C:13]([OH:15])=[O:14])[CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: [OH-]
Reactant: CCOC(=O)C(=O)c1cccc(NC=O)n1
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=CNc1cccc(C(=NO)C(=O)O)n1
Reaction time: 0.5 h

Procedure:
1N Sodium hydroxide (27.5 ml.) was added to a stirred solution of ethyl 2-(6-formamidopyridin-2-yl)glyoxylate (5.55 g.) in ethanol (100 ml.) at room temperature, and the solution was stirred at the same temperature for 30 minutes. To the solution was added hydroxylamine hydrochloride (1.9 g.) all at once, and the solution was stirred at room temperature for 2 hours. After removing ethanol from the resultant solution under reduced pressure, ethylacetate was added to the residue, and then the solution was adjusted to pH 7 with an aqueous solution of sodium bicarbonate. The aqueous layer was separated and adjusted to pH 2 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried to give 2-(6-formamidopyridin-2-yl)-2-hydroxyiminoacetic acid (3.6 g.), mp 190° to 192° C. (dec.).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[OH:12][C:13]1[C:14]([N+:25]([O-:27])=[O:26])=[C:15]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:16]([O:18][CH3:19])=[O:17]>CN(C)C=O>[CH:5]1([CH2:4][O:12][C:13]2[C:14]([N+:25]([O-:27])=[O:26])=[C:15]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:16]([O:18][CH3:19])=[O:17])[CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: COC(=O)c1ccc(OC)c(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(OCC2CC2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
(Bromomethyl)cyclopropane (136 g, 1.01 mol) and potassium carbonate (173 g, 1.25 mol) were added to a solution of methyl 3-hydroxy-4-methoxy-2-nitrobenzoate (190 g, 837 mmol) and dimethylformamide (1 L). The mixture was stirred at room temperature overnight and then quenched with water/ice (3 L). The resulting solids were collected by filtration, washed with water (500 mL×3), and then dried in an oven to give 220 g of methyl 3-(cyclopropylmethoxy)-4-methoxy-2-nitrobenzoate as a yellow solid. MS (ESI): 281.9.
Reaction SMILES: [F:1][C:2]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:3]=1[NH:4][C@H:5]([CH3:9])[C:6]([OH:8])=[O:7].Cl.[CH3:17]O>>[F:1][C:2]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:3]=1[NH:4][C@H:5]([CH3:9])[C:6]([O:8][CH3:17])=[O:7]
Reactant: CO
Reactant: C[C@@H](Nc1ccc(F)c(F)c1F)C(=O)O
Agent: Cl
Product: COC(=O)[C@@H](C)Nc1ccc(F)c(F)c1F

Procedure:
(2R)-2-(2,3,4-trifluoroanilino)propionic acid (1.1 g; 98% ee) was dissolved in methanol (10 ml) and hydrochloric acid (5 mol/l; 1 ml) was added thereto at room temperature. The liquid reaction mixture was heated under reflux for 6 hours and then the solvent was evaporated. To the obtained residue was added chloroform (10 ml). Next, the organic layer was washed with a saturated aqueous solution of sodium chloride and water and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography (ethyl acetate-normal hexane=1:4) to give the title compound (1.17 g) as an oily substance. The optical purity of the product was 99% ee. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 5.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+]>CN(C)C=O>[CH3:10][O:11][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: COc1cccnc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccnc1OC
Yield: 29 %

Procedure:
The 2-chloro-3-methoxypyridine (2) (13 g, 90.6 mmol), from Step I, was stirred with 3-equivalents of sodium methoxide (14.7 g, 271.8 mmol) in dimethylformamide (100 mL) at 100° C. until completion of the reaction. The reaction mixture was then quenched with water and extracted with dichloromethane. The combined extracts were washed with water, concentrated and distilled (74° C.; 5 mm Hg) to give the product, 2,3-dimethoxypyridine (3), as a clear oil (7 g; 29% yield for two steps).
Reaction SMILES: [ClH:1].Cl.Cl.S1C(C2C=CN=C([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)N=2)=CC2C=CC=CC1=2.[Br:30][C:31]1[C:32]([C:38]2[S:42][C:41]3[C:43]([O:47][CH3:48])=[CH:44][CH:45]=[CH:46][C:40]=3[CH:39]=2)=[N:33][C:34]([Cl:37])=[N:35][CH:36]=1.NCCCN1CCN(C)CC1>>[ClH:37].[ClH:1].[ClH:37].[Br:30][C:31]1[C:32]([C:38]2[S:42][C:41]3[C:43]([O:47][CH3:48])=[CH:44][CH:45]=[CH:46][C:40]=3[CH:39]=2)=[N:33][C:34]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]2)=[N:35][CH:36]=1
Reactant: CN1CCN(CCCNc2nccc(-c3cc4ccccc4s3)n2)CC1
Reactant: COc1cccc2cc(-c3nc(Cl)ncc3Br)sc12
Agent: CN1CCN(CCCN)CC1
Agent: Cl
Product: COc1cccc2cc(-c3nc(NCCCN4CCN(C)CC4)ncc3Br)sc12

Procedure:
Using the method of [4-(benzo[b]thiophen-2-yl)-pyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine tri-hydrochloride, the title compound is prepared from 5-bromo-2-chloro-4-(7-methoxy-benzo[b]thiophen-2-yl)-pyrimidine and 1-(3-aminopropyl)-4-methylpiperazine and isolated as a yellow solid. ES+(m/z) 476 (79Br) and 478 (81Cl) [M+H].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](=O)[C:36]([F:39])([F:38])[F:37])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)(Cl)(Cl)[Cl:42]>>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]([Cl:42])[C:36]([F:39])([F:38])[F:37])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: FC(F)(F)C(Cl)=Nc1ccc(OCc2ccccc2)cc1

Procedure:
A mixture of resin-supported triphenylphosphine (3 mmol triphenylphosphine/g resin; 58.6 g) and N-(4-benzyloxy-phenyl)-2,2,2-trifluoro-acetamide (20.8 g) in carbon tetrachloride (800 ml) was heated to reflux under nitrogen for 18 h. The mixture was allowed to cool then filtered, washing the resin with dichloromethane (1 l) and ether (1 l). The organics were concentrated in vacuo to give the title compound as a yellow solid (20.7 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([CH2:11][Br:12])[CH:8]=[C:7]([CH2:13]Br)[CH:6]=1)[CH3:2].[O-:16][CH2:17][CH3:18].[K+]>C(O)C>[Br:12][CH2:11][C:9]1[CH:10]=[C:5]([CH:6]=[C:7]([CH2:13][O:16][CH2:17][CH3:18])[CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:15]
Reactant: CC[O-]
Reactant: CCOC(=O)c1cc(CBr)cc(CBr)c1
Agent: [K+]
Solvent: CCO
Product: CCOCc1cc(CBr)cc(C(=O)OCC)c1
Reaction time: 8 h

Procedure:
A stirred solution of 3,5-bis[bromomethyl]benzoic acid ethyl ester (3g) in ethanol (100 ml) was treated with potassium ethoxide (0.75 g) and stirred overnight. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated and the residue purified by chromatography eluting with 10% ethyl acetate in isohexane. Yield 1.3 g.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([OH:14])[C@H:6]([OH:13])[C@H:7]([OH:12])[C@@H:8]([OH:11])[CH:9]=O)=[N+]=[N-].B(F)(F)F.[CH3:19]COCC.CCOC(C)=O.CCCCCC>C(O)C1C=CC=CC=1>[CH3:19][O:11][C@@H:8]1[C@H:7]([OH:12])[C@@H:6]([OH:13])[C@H:5]([OH:14])[CH2:4][NH:1][CH2:9]1
Reactant: CCOCC
Reactant: [N-]=[N+]=NC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C=O
Agent: FB(F)F
Solvent: CCCCCC
Solvent: OCc1ccccc1
Solvent: CCOC(C)=O
Product: CO[C@H]1CNC[C@@H](O)[C@H](O)[C@H]1O
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
A suspension of 6-azido-6-deoxy-D-galactose 14 (1.63 g, 7.9 mmol) obtained as describe above in benzyl alcohol (5 mL) was heated to 80° C. and BF3.OEt2 (984 μL, 8 mmol) was added dropwise. After 20 minutes the suspension became transparent. The solution was allowed to cool down. The reaction mixture was passed through a SiO2 column. Benzyl alcohol came out first using EtOAc:Hexane 1:5, then benzyl 6-azido-6-deoxy-D-galactopyranoside was separated from the furanose byproduct with EtOAc as eluent (1.21 g, 75%, α/β 60:40): 1H-NMR (CD3OD, δ, ppm, α-anomer only): 7.4-7.6 (5H, Benzyl group); 5.3 (H1, overlapped by HDO signal); 4.98 and 4.78 (2H, AB system, J=12 Hz, CH2—OBn); 4.18 (1H, dd, J=4.2 Hz, 8.7 Hz, H5); 4.0 (3H, overlapped, H2, H3, H4); 3.75 (1H, dd, J=13 Hz, 8.7 Hz, H6); 3.49 (1H, dd, J=13 Hz, 4.2 Hz, H6′). 13C-NMR (CD3OD, δ, ppm, α-anomer only): 139.76, 131.64, 130.31, 100.28, 72.54, 72.36, 72.10, 71.36, 70.89, 53.62.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][NH:8][CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:25][C:26]([NH:28][C@H:29]([C:37](O)=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C)C=O.C(P(=O)(OCC)OCC)#N>C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][N:8]([C:37](=[O:38])[C@H:29]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[NH:28][C:26]([O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27])[CH2:9][CH:10]([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(CNCC(=O)OC(C)(C)C)OCC
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(CN(CC(=O)OC(C)(C)C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
A mixture of 11.0 g of N-(2,2-diethoxyethyl)glycine t-butyl ester, 13.3 g of N-benzyloxycarbonyl-L-phenylalanine and 50 ml of dimethylformamide was cooled to 0° C., and there were added dropwise 9.4 g of diethyl cyanophosphonate, then 5.9 g of triethylamine. The mixture was stirred for one hour at the same temperature, then for 5 hours at room temperature. The reaction mixture was diluted with ethyl acetate, which was poured into ice-water. The ethyl acetate layer was dried over anhydrous magnesium sulfate, then concentrated under reduced pressure to give a crude product. The crude product was purified by means of chromatography on silica gel using an eluent (n-hexane:ethyl acetate=9:1) to afford 20.0 g of the title compound as a colorless oily product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12>C(O)(=O)C>[Br:8][C:6]1[CH:7]=[C:2]([N:1]2[C:12](=[O:13])[C:11]3[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]2=[O:14])[CH:3]=[N:4][CH:5]=1
Reactant: Nc1cncc(Br)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1cncc(Br)c1
Temperature: 25 °C

Procedure:
A flask is charged with 3-amino-5-bromo pyridine (1.00 g, 5.78 mmol), phthalic anhydride (0.856 g, 5.78 mmol) and acetic acid (20 mL). The reaction is refluxed overnight. The reaction is then cooled to room temperature and concentrated in vacuo. The crude is dissolved in ethyl acetate and washed with water once. The organic layer is dried over sodium sulfate and concentrated in vacuo to afford 2-(5-bromo-pyridin-3-yl)-isoindole-1,3-dione. MS (ESI) m/z 305.1 (M+H)+
Reaction SMILES: [C:1]1([C:7]2(O[CH:11]2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][NH2:20]>C(O)C>[CH3:9][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[NH:20][N:19]=1
Reactant: NN
Reactant: CC(=O)C1(c2ccccc2)OC1c1ccncc1
Solvent: CCO
Product: Cc1n[nH]c(-c2ccncc2)c1-c1ccccc1

Procedure:
A solution of 3-phenyl-4-(4-pyridyl)-3,4-epoxy-2-butanone (step 2) (350 mg, 1.46 mmol) and anhydrous hydrazine (0.7 ml, 20 mmol) in ethanol (3 ml) was heated at reflux for 4 hours. The reaction was cooled, and the solvent was evaporated to dryness. The resulting residue was purified by chromatography (silica gel, 1:1 acetone/hexane) to give the desired product as a crystalline solid, which was recrystallized from ethyl acetate and hexane to give pure 4-(3-methyl-4-phenyl-1H-pyrazol-5-yl)pyridine (145 mg, 42%): m. p. 164-165° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:16])=[C:10]2[O:14][CH:13](O)[CH2:12][C:11]=12)=[O:5])[CH3:2].C(OC(C1C=CC(Cl)=C2OC(OC)CC=12)=O)C.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:16])=[C:10]2[O:14][CH:13]=[CH:12][C:11]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(Cl)c2c1CC(O)O2
Agent: CCOC(=O)c1ccc(Cl)c2c1CC(OC)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(Cl)c2occc12
Reaction time: 5 h

Procedure:
A mixture of 7-chloro-2-hydroxy-2,3-dihydro-benzofuran-4-carboxylic acid ethyl ester and 7-chloro-2-methoxy-2,3-dihydro-benzofuran-4-carboxylic acid ethyl ester (3.36 g, see above) in toluene (20 mL) is added dropwise to a solution of PTSA (0.69 mmol) in toluene (14 mL) which is heated to reflux. Heating is continued for 5 h, an additional portion of PTSA (0.69 mmol) is added and the mixture is again heated to reflux for 150 min. The solvents are removed in vacuo and the residue is purified by FC (gradient: heptane to heptane/EtOAc 95/5) to give the desired product.
Reaction SMILES: CC1CN(C(=O)C(F)(F)F)CCC2N=C(O)C=CC1=2.O=P(Cl)(Cl)Cl.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[CH:35]([CH3:36])[CH2:34][N:33](C(=O)C(F)(F)F)[CH2:32][CH2:31][C:30]=2[N:43]=1.C([O-])([O-])=O.[K+].[K+]>CO.CN(C=O)C>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[CH:35]([CH3:36])[CH2:34][NH:33][CH2:32][CH2:31][C:30]=2[N:43]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2nc(Cl)ccc21
Agent: CC1CN(C(=O)C(F)(F)F)CCc2nc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: CC1CNCCc2nc(Cl)ccc21
Temperature: 100 °C
Yield: 22.3 %

Procedure:
A mixture of 5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (100 mg, 365 μmol), DMF (50 μl) and POCl3 (5 ml) was heated at 100° C. for 3 h. The reaction mixture was concentrated in vacuo and purified by column chromatography rendering 101 mg (94%) of 2-chloro-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. MS (ESI) m/z 293.2/295.2. A mixture of 2-chloro-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (40.0 mg, 137 μmol), K2CO3 (80.0 mg) and MeOH (5 ml) was heated for 2 h at 70° C. The reaction mixture was concentrated in vacuo and purified by column chromatography furnishing 6.0 mg (22%) of 2-chloro-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ. 1H-NMR (CDCl3) δ 7.48 (d, 1H), 7.91 (d, 1H), 3.58 (s, 3H), 3.55-3.20 (m, 5H), 2.93 (dd, 1H), 2.73 (dd, 1H), 1.43 (d, 3H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:14]O)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.C1(C)C=CC(S([Cl:32])(=O)=O)=CC=1.CCOC(C)=O>C(Cl)Cl>[Cl:32][CH2:14][C:6]1[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(CO)cc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(CCl)cc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 52.8 %

Procedure:
Dissolve [3-nitro-5-(trifluoromethyl)phenyl]methanol (1.1 g, 5.18 mmol) and triethylamine (1.62 mL) in DCM (20 mL), cool to 0° C., add slowly p-toluenesulfonyl chloride (1.1 g, 6.02 mmol). After the addition, stir the reaction at room temperature for 15 hrs. TLC (EtOAc:PE=1:15) shows the reaction is complete. Concentrate under reduced pressure to get the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:15) affords the title compound (655 mg, 55%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH3:1][S:2]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: OCCCCOCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (1 mL, 13.3 mmol) was added to a cooled (0° C.) solution of 4-(benzyloxy)butan-1-ol (2 g, 11.1 mmol) and triethylamine (1.9 mL, 13.3 mmol) in DCM (20 mL) and it was stirred at 0° C. for 1 h. HCl (1M) was added to the reaction mixture and the aqueous layer was extracted with DCM (2×). The organics were combined, dried over sodium sulfate, and evaporated to dryness to afford 4-(benzyloxy)butyl methanesulfonate as a yellow oil. LCMS [M+1]+ 259.5.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31][CH:32](P(=O)(OCC)OCC)[C:33]3=[O:35])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(O)C>O1CCCC1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31]/[C:32](=[CH:8]\[C:7]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:5]([O:4][CH3:3])[CH:6]=4)/[C:33]3=[O:35])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3ccc(Cl)cc3)N2C1=O
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4ccc(Cl)cc4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 78.9 %

Procedure:
Lithium hydroxide (355 mg) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (875 mg) and diethyl [(3S,8aR)-3-(4-chlorophenyl)-5-oxooctahydroindolizin-6-yl]phosphonate (2.5 g) in tetrahydrofuran (8 mL)-ethanol (30 mL), and the reaction solution was stirred under shading at room temperature for five hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 1.43 g of the title compound as a colorless solid. The property values of the compound are as follows.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([NH2:13])[CH2:12][CH2:11]1.[NH:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:16](O)=[O:17]>ClCCl>[C:22]([O:21][C:19](=[O:20])[NH:14][CH2:15][C:16](=[O:17])[NH:13][CH:10]1[CH2:12][CH2:11]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NC1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)NC1CC1
Reaction time: 17 h
Yield: 26.4 %

Procedure:
—TBTU (5.1 g, 16.5 mmol), DIPEA (2.9 ml, 16.5 mmol) and cyclopropylamine (2.2 ml, 33 mmol) were added to a solution of BOC-Gly-OH (2.63 g, 15 mmol) in dry dichloromethane (10 ml). After 17 h stirring, the reaction mixture was concentrated under reduced pressure and water was added to the residue. The product was extracted into ethyl acetate. The combined organic phases were washed with an aqueous solution of 2M hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, brine, dried over sodium sulfate and concentrated under reduced pressure to give 2-cyclopropylcarbamoylmethyl-carbamic acid tert-butyl ester (847 mg). The product was used in the following step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH:55]([C:57]2[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=2)[OH:56])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][CH:55]([C:57]2[CH:58]=[CH:59][C:60]([F:63])=[CH:61][CH:62]=2)[OH:56])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCC(O)c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CC(O)c2ccc(F)cc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.5 %

Procedure:
To a solution of 80 mg (0.5 mmol) of 1H-indole-7-carboxylic acid and 159 mg of TBTU (0.5 mmol) in 6 ml DMF, were added 0.43 ml (2.48 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 150 mg (0.5 mmol) of [rac]-(4-tert-butyl-benzyl)-[2-(4-fluoro-phenyl)-2-hydroxy-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 60 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; heptane/EtOAc 2:1) to give 150 mg (66%) of an white solid. MS (ISP) 445.4 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:53])[CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([O:43][Si](C(C)(C)C)(C)C)[C:39]([CH3:42])([CH3:41])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][C:20]=2[CH3:52])[N:16]=[N:15][CH:14]=1)[CH3:9]>ClCCl>[CH2:8]([O:10][C:11](=[O:53])[CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH2:26][CH3:27])([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([OH:43])[C:39]([CH3:40])([CH3:41])[CH3:42])=[C:32]([CH3:51])[CH:31]=3)[CH2:28][CH3:29])=[CH:21][C:20]=2[CH3:52])[N:16]=[N:15][CH:14]=1)[CH3:9]
Reactant: CCOC(=O)Cc1cnnc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cc1cnnc(-c2ccc(C(CC)(CC)c3ccc(CCC(O)C(C)(C)C)c(C)c3)cc2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
Trifluoroacetic acid (0.063 mL) was added to a solution of {6-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]pyridazin-4-yl}acetic acid ethyl ester (Example 183-(3); 9.0 mg, 0.014 mmol) in dichloromethane (0.36 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 7 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1) to give the title compound (6.5 mg, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([N:11]=[N+:12]=[N-:13])[CH2:6]1)=[O:4].[H-].[Na+].[CH3:16]N(C=O)C>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C@H:8]([O:10][CH3:16])[C@@H:7]([N:11]=[N+:12]=[N-:13])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])[C@@H](O)C1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1C[C@H](N=[N+]=[N-])[C@@H](OC)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred, cooled (0° C.) solution of (1R,3S,4S)-3-azido-4-hydroxy-cyclopentanecarboxylic acid methyl ester (300 mg; CAS 213742-85-9) in DMF (5 ml) under an argon atmosphere was added NaH (78 mg; 55% dispersion in mineral oil). The ice bath was removed and stirring at r.t. was continued for 1 h. The mixture was cooled again and methyl iodide (0.3 ml) was added in one portion. The mixture (slowly warming up to r.t.) was then stirred for 18 h. More methyl iodide (0.3 ml) was added and the mixture (orange slurry) was stirred at r.t. for another 7 h. More methyl iodide (0.3 ml) was added and stirring was continued for another 17 h. The mixture was diluted with EtOAc and washed with H2O (10 ml). The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 65:35) to give (3S,4S)-3-azido-4-methoxy-cyclopentanecarboxylic acid methyl ester (215 mg, epimeric mixture) as light yellow oil. MS: 200.3 ([M+H]+).