Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[S:10]([C:13]1[S:17][C:16]([NH:18][C:19]([N:21]([CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:20])=[N:15][CH:14]=1)(=[O:12])=[O:11])=[O:4].C1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.FC1C=C(C=CC=1F)N.C1(C=O)CCCC1.COC([C@@H]1CCCN1S(C1SC(N)=NC=1)(=O)=O)=O>>[CH:31]1([CH2:30][N:21]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)[C:19](=[O:20])[NH:18][C:16]2[S:17][C:13]([S:10]([N:6]3[CH2:7][CH2:8][CH2:9][C@H:5]3[C:3]([OH:4])=[O:2])(=[O:12])=[O:11])=[CH:14][N:15]=2)[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)s1
Agent: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc(N)s1
Agent: Nc1ccc(F)c(F)c1
Agent: O=C(O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)n1
Product: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)s1

Procedure:
The title compound was prepared via (S)-1-{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonyl}-pyrrolidine-2-carboxylic acid methyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3,4-difluoroaniline, cyclopentanecarbaldehyde and (S)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])=[CH:16][N+:17]([O-:19])=[O:18])=[CH:7][CH:6]=1)[CH3:3].[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH2:39][S:40][CH2:41][CH2:42][NH:43][C:44](SC)=[CH:45][N+:46]([O-:48])=[O:47]>C(OCC)(=O)C>[CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:44]([NH:43][CH2:42][CH2:41][S:40][CH2:39][C:35]2[O:34][CH:38]=[CH:37][CH:36]=2)=[CH:45][N+:46]([O-:48])=[O:47])=[CH:16][N+:17]([O-:19])=[O:18])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1ccco1
Reactant: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])NCCCCCCCCCCCCN)o1
Solvent: CCOC(C)=O
Product: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])NCCCCCCCCCCCCNC(=C[N+](=O)[O-])NCCSCc2ccco2)o1
Yield: 69.8 %

Procedure:
A mixture of N-[1-[[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]amino]-2-nitroethenyl]-1,12-dodecanediamine (0.8 g.) and N-2-[[(2-furanyl)methyl]thio]ethyl-1-(methylthio)-2-nitroethenamine (0.57 g.) in ethyl acetate (8 ml.) was evaporated and the residue heated at 98°-100° for 2 hours. The oily residue was dissolved in methanol (10 ml.) and evaporated to dryness (×2). The oily residue was triturated with ethyl acetate (30 ml.), the solid which separated was washed with ethyl acetate and dried to give the title compound (0.82 g.), m.p. 69°-72°
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:23]([C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=O)=O)[CH:12]=[C:13]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:33][CH:34]([OH:36])[CH3:35]>C1(C)C=CC=CC=1>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:23]3[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[C:33]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:34](=[O:36])[C:35]=3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:12]=[C:13]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(C(=O)c1cc(C#Cc2ccccc2)cc(C#Cc2ccccc2)c1)c1ccccc1
Reactant: CC(C)O
Solvent: Cc1ccccc1
Product: O=C1C(c2ccccc2)=C(c2ccccc2)C(c2cc(C#Cc3ccccc3)cc(C#Cc3ccccc3)c2)=C1c1ccccc1
Temperature: 2 °C
Reaction time: 0.7 h
Yield: 85.3 %

Procedure:
3,5-bis(phenylethynyl)benzil (65.6 grams, 0.16 mole) prepared in the manner of Example 1,1,3-diphenylacetone (37.8 grams, 0.18 mole), 2-propanol (583 milliliters) and toluene (218 milliliters), were added to a 2 liter glass four neck Morton reactor containing a magnetic stirring bar. The reactor was additionally outfitted with chilled (2° C.) condenser, a thermometer with thermostatically controlled heating mantle and a subsurface tube for sparging with nitrogen. Under a nitrogen atmosphere, an addition funnel was loaded with tetrabutylammonium hydroxide (1M in methanol) (5.46 milliliters) diluted into 2-propanol (97 milliliters) which had been sparged with nitrogen. This addition funnel was then attached to the reactor under dynamic nitrogen flow. Sparging and heating of the stirred slurry commenced, and after 42 minutes, once a reflux (80° C.) was achieved, a clear light yellow colored solution had formed. At this time, the sparge tube was move up out of the solution in the reactor to provide nitrogen overhead, then dropwise solution of the catalyst commenced, inducing the formation of a dark red color. After 92 minutes at reflux, 44 milliliters of the catalyst solution had been added and HPLC analysis indicated that full conversion of the 3,5-bis[phenylethynyl)benzil reactant had been achieved, with minimum formation of coproducts. After a cumulative 101 minutes at reflux, the heating mantle was removed from the reactor, additional 2-propanol was added (413 milliliters), then an ice bath was placed under the reactor and the stirred contents were maintained therein for the next 39 minutes until a temperature of 5° C. was achieved. The product was recovered via filtration through a coarse flitted glass funnel. The product cake on the funnel was washed with two portions (50 milliliters) of 2-propanol, giving a clear filtrate with the second wash. Drying in a vacuum oven to provided 79.66 grams (85.3 percent isolated yield) of 4-(3,5-bis(phenylethynyl)-phenyl)-2,3,5-triphenylcyclopentadienone (unsymmetrically substituted 3,5-AAB monomer) as a dark red purple colored crystalline product. HPLC analysis revealed the presence of the desired product at 100 area percent.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1([N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[C:12]1([N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(-n2cccc2)cc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: O=C(O)c1ccccc1C(=O)c1cccn1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2.96 g (0.02 mole) of phthalic anhydride and 5.72 g (0.04 mole) of N-phenylpyrrole in 50 ml of chlorobenzene, maintained at 0°-5° C. in an ice bath, 810 g (0.06 mole) of aluminum chloride was added in small portions. The reaction mixture was held at 0°-5° C. for approximately two hours. The reaction was allowed to warm to room temperature and then set aside overnight at ambient temperature. The reaction mixture was worked up in a manner similar to that described in part A of Example 15 to obtain 2-[(1-phenyl-2-pyrrolyl)carbonyl]benzoic acid (Formula IX: R°=R1 =R2 =R3 =H; R7 =C6H5) which melted over the range 159°-168° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:28]([NH:31][CH2:32][CH2:33][CH3:34])[CH2:29][CH3:30]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][N:31]([CH2:32][CH2:33][CH3:34])[CH2:28][CH2:29][CH3:30])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCCNCCC
Solvent: CC#N
Product: CCCN(CCC)C[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), N-propylpropan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 361 (M+, 0.2), 332 (6), 115 (9), 114 (bp), 86 (7), 72 (4).
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1.[NH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:11][C:7]1[CH:6]=[C:5]([NH:4][CH2:3][CH2:2][NH:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: Clc1cccc(NCCBr)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](NCCNc2cccc(Cl)c2)C1
Temperature: 70 °C
Reaction time: 48 h
Yield: 74.2 %

Procedure:
A mixture of 3-chloroaniline (50 g, 0.39 mol) and 1,2-dibromoethane (73 g, 0.39 mol) in MeCN (500 mL) was heated at 80° C. for 2 days. The reaction mixture was concentrated on rotavap and subjected to silica flash column chromatography using 0 to 30% EtOAc in PE to isolate N-(2-bromoethyl)-3-chloroaniline (397) (9.0 g, 10%) as a yellow solid. To a solution of N-(2-bromoethyl)-3-chloroaniline (397) (9.0 g, 38.46 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (7.74 g, 38.46 mmol) in THF (100 mL) was added DIEA (14.88 g, 115.38 mmol). The resulting mixture was stirred at 70° C. for 2 days. It was partitioned in EtOAc (50 mL) and water (50 mL). The layers were separated and the aqueous was extracted with EtOAC (50 mL×3). The combined organic layer was washed with brine, dried, concentrated and subjected to silica flash column chromatography using 0 to 5% MeOH in DCM to isolated (R)-tert-butyl 3-(2-(3-chlorophenylamino)ethylamino)piperidine-1-carboxylate (398) (10.1 g, 74.4%) as a white solid.
Reaction SMILES: [OH-:1].[K+].[CH2:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1C=CC=CC=1>[CH2:3]([O:1][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCc1ccccc1
Reactant: [OH-]
Agent: [K+]
Solvent: c1ccccc1
Product: c1ccc(COCc2ccccc2)cc1
Yield: 190.5 %

Procedure:
A mechanically stirred mixture of 104 g (0.78 mole) of (R,S)-2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane, 500 ml of benzene, 86 g (1.53 mole) of powdered potassium hydroxide and 175 ml (1.52 mole) of benzyl chloride was refluxed for 17 hours while separating the condensed waterlayer (14 ml of water separated). After cooling the mixture was washed with water, 1M sodium hydrogen carbonate and brine respectively, dried with magnesium sulphate, filtered and evaporated to give 287 g of crude benzyl ether. This was stirred with a mixture of 300 ml of methanol, 100 ml of water and 20 ml of 36% hydrochloric acid for 1,5 hours. Next the mixture was neutralized with about 10 g of sodium hydroxide in water and concentrated in vacuum. The residue was extracted with diethyl ether and the extract was dried with magnesium sulphate, filtered and evaporated to give 163 g of residue. This was purified over silica to give 118 g of (R,S)-3 -benzyloxy-propane-1,2-diol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=3)[CH2:30][CH2:31]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 86 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(4-nitrophenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 86%). 1H NMR (300 MHz, CDCl3): δ 2.46 (s, 3H), 3.52-3.58 (m, 4H), 3.82 (s, 3H), 4.09-4.13 (m, 4H), 6.85 (d, J=9.2 Hz, 2H), 7.03-7.15 (m, 1H), 7.41 (m, 1H), 7.52-7.58 (m, 2H), 8.16 (d, J=9.2 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N:9]2[CH:13]=[N:12][N:11]=[CH:10]2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([C:21](=O)[CH3:22])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N:9]2[CH:13]=[N:12][N:11]=[CH:10]2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([CH:21]([NH2:30])[CH3:22])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c(C)c(-n2cnnc2)c1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1-n1cnnc1
Temperature: 65 °C

Procedure:
A mixture of 1-[4-chloro-3′-fluoro-5-methyl-6-(4H-1,2,4-triazol-4-yl)biphenyl-2-yl]ethanone (44 mg, 0.13 mmol), ammonium acetate (103 mg, 1.33 mmol) and sodium cyanoborohydride (17 mg, 0.27 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65° C. overnight in a sealed tube. The mixture was then cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (15 mg, 34%). LCMS calculated for C17H17ClFN4 (M+H)+: m/z=331.1. found: 331.1.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:8][O:7][CH2:6]1)=[O:4].Cl>O1CCOCC1>[CH3:32][C:24]1[CH:23]=[C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([S:11]([NH:10][CH:9]3[CH2:8][O:7][CH2:6][CH:5]3[C:3]([OH:4])=[O:2])(=[O:12])=[O:13])=[CH:15][CH:16]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1
Reactant: COC(=O)C1COCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(COc2ccc(S(=O)(=O)NC3COCC3C(=O)O)cc2)c2ccccc2n1
Temperature: 60 °C

Procedure:
To a solution of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic acid methyl ester (0.9 g, 1.97 mmol) in 1,4-dioxane (4 mL) was added concentrated HCl (4 mL). The reaction was heated to 60° C. for 19 h. The solvent was removed in vacuo to provide 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic acid as a crude solid (0.6 g, 69%). MS: 443 (M+H)+
Reaction SMILES: C([O:3]CC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:12]1[CH:13]=[C:14]([C:28]([F:31])([F:30])[F:29])[CH:15]=[C:16]([NH:18][C:19]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25](O)=O)[CH:17]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:29][C:28]([F:31])([F:30])[C:14]1[CH:15]=[C:16]([NH:18][CH:19]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][CH:21]=2)[OH:3])[CH:17]=[CH:12][CH:13]=1
Reactant: O=C(O)c1cccnc1Nc1cccc(C(F)(F)F)c1
Reactant: CCOCC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(Nc1cccc(C(F)(F)F)c1)c1cccnc1
Yield: 85 %

Procedure:
500 ml of anhydrous ethyl ether are run gently onto 26 g of lithium aluminum hydride, and 100 g of niflumic acid, dissolved in 250 ml of anhydrous tetrahydrofuran, are then added dropwise. The mixture is then brought to reflux for 3 hours. After cooling, it is hydrolyzed with 150 ml of ethyl acetate and 100 ml of saturated sodium sulfate solution. After filtration, the filtrate is concentrated to obtain the expected compound in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][CH:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]([CH3:17])[CH:8]2[CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC1CCC(NCc2ccc(Cl)cc2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(Cc1ccc(Cl)cc1)C1CCC(O)CC1

Procedure:
7.2 g (30 mMol) of 4-[N-(4-chloro-benzyl)-amino]-cyclohexanol are dissolved in 30 ml of dimethyl-formamide, and after the addition of 2.2 g (16 mMol) of potassium carbonate, 4.26 g (30 mMol) of methyliodide are added dropwise. When the slightly exothermic reaction has ended, the mixture is concentrated by evaporation, mixed with water and extracted with chloroform. The concentrated extracts are chromatographed on silica gel to purify them (eluant; methylene chloride/methanol=20/1).
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][C@H:11]([N:14](C)[C:15](=O)OC(C)(C)C)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:15][NH:14][C@H:11]1[CH2:12][CH2:13][N:9]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH2:10]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(C(=O)c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H]1CCN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of compound 4c (0.12 g, 0.394 mmol) in CH2Cl2 (3 mL) was added trifluoroacetic acid (1 mL) at room temperature. The mixture was stirred at room temperature for 5 h. The solvent was removed by evaporation. Ether (10 mL) was added to the residue. The crude product was collected by filtration, washed with ether, and dried under vacuum. MS m/z (M+H+) 205.2.
Reaction SMILES: [C:1]([O:25][CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[N:29]([OH:34])[C:28]([CH3:36])([CH3:35])[CH2:27]1)(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([OH:21])[C:15]([CH3:23])([CH3:22])[CH2:14]1)=[O:11].[C:37]1([C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([CH3:45])[CH3:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:1]([O:25][CH:26]1[CH2:27][C:28]([CH3:36])([CH3:35])[N:29]([O:34][CH2:45][C:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH3:44])[C:30]([CH3:33])([CH3:32])[CH2:31]1)(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH:13]1[CH2:14][C:15]([CH3:22])([CH3:23])[N:16]([O:21][CH2:44][C:43]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:45])[C:17]([CH3:19])([CH3:20])[CH2:18]1)=[O:11]
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Reactant: CC(C)(c1ccccc1)c1ccccc1
Product: CC(CON1C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OCC(C)(c3ccccc3)c3ccccc3)C(C)(C)C2)CC1(C)C)(c1ccccc1)c1ccccc1

Procedure:
Bis(1-oxyl-2,2,6,6-tetramethylpiperidin-4-y) sebacate and 2,2-diphenylpropane are reacted following a procedure similar to that of Example 6.
Reaction SMILES: C([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20](O)=[O:21])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[NH2:26][CH2:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[CH:35]1[CH2:38][CH2:37][N:36]1[C:39]([O:41][CH2:42][C:43]([Cl:46])([Cl:45])[Cl:44])=[O:40].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:34][C:32]1[CH:31]=[CH:30][C:29]([CH:35]2[CH2:38][CH2:37][N:36]2[C:39]([O:41][CH2:42][C:43]([Cl:45])([Cl:46])[Cl:44])=[O:40])=[C:28]([CH2:27][NH:26][C:20](=[O:21])[C@@H:19]2[CH2:23][CH2:24][CH2:25][NH:18]2)[CH:33]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: NCc1cc(Cl)ccc1C1CCN1C(=O)OCC(Cl)(Cl)Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCc1cc(Cl)ccc1C1CCN1C(=O)OCC(Cl)(Cl)Cl)[C@@H]1CCCN1
Reaction time: 0.5 h
Yield: 19 %

Procedure:
N-Fmoc-L-proline (0.249 g, 0.739 mmol) was added to a stirred mixture of 2,2,2-trichloroethyl 2-[2-(aminomethyl)-4-chlorophenyl]azetidine-1-carboxylate (0.275 g, 0.739 mmol), EDC (0.213 g, 1.11 mmol) and HOAT (50 mg, 0.37 mmol) in DMF (2 mL). After 16 h the reaction mixture was partitioned between ethyl acetate and dilute HCl solution. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated in vacuo to a foam. This material was dissolved in DMF (2 mL) and piperidine (0.5 mL) and stirred for 30 min. The solution was poured into water (50 mL) and the precipitated solids were removed by filtration, washing with water (5×10 mL, which was collected and set aside) and methanol. The methanol was evaporated in vacuo and the residue was purified by flash column chromatography on silica (eluting with ethyl acetate followed by chloroform/methanol/ammonium hydroxide, 90:9:1) to give 2,2,2-trichloroethyl 2-{4-chloro-2-[(L-prolylamino)methyl]phenyl}azetidine-1-carboxylate (66 mg) as a gum. The milky aqueous washings were extracted into ethyl acetate (adding brine to dispel the emulsion) and the organic layer was washed with water and brine, dried (Na2SO4) and evaporated in vacuo to give more of the desired compound (0.206 g) as a gum: MS 468.5 (M+1) with an isotope distribution consistent with four chlorines.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[C:15]=2[O:14]1
Reactant: COc1ccccc1-c1cccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: CN
Product: CNCC1Cc2cccc(-c3ccccc3OC)c2O1

Procedure:
The title compound was prepared (0.250 g, 76%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.501 g, 1.22 mmol) and methylamine (4.56 g, 150.0 mmol). mp 157-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:17][CH2:16][CH2:15][C@H:14]3[N:9]2[C:10](=[O:18])[CH2:11][CH:12]=[CH:13]3)=[CH:4][CH:3]=1.[H][H]>CO.[Pt]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:17][CH2:16][CH2:15][C@H:14]3[N:9]2[C:10](=[O:18])[CH2:11][CH2:12][CH2:13]3)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C1CC=C[C@H]2CCC[C@@H](c3ccc(Cl)cc3)N12
Agent: O=[Pt]
Solvent: CO
Product: O=C1CCC[C@H]2CCC[C@@H](c3ccc(Cl)cc3)N12
Yield: 79.8 %

Procedure:
Platinum oxide (95 mg) was added to a solution of (6S,9aR)-6-(4-chlorophenyl)-3,6,7,8,9,9a-hexahydroquinolizin-4-one (1.09 g) in methanol (50 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for one hour. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 877 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:36][CH:35]=1)[C:11](=[O:32])[CH2:12][N:13]([CH3:31])[C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[C:1]([NH:9][CH:10]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:36][CH:35]=1)[CH:11]([OH:32])[CH2:12][N:13]([CH3:31])[C:14]([N:16]1[CH2:30][CH2:29][CH2:28][C@H:17]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC(=O)C(Cc1ccc(OCc2ccccc2)cc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: CN(CC(O)C(Cc1ccc(OCc2ccccc2)cc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1

Procedure:
The ester product from part (b) is treated with sodium borohydride according to the procedure of Example 1(f) to yield (±)-1-[[[3-(benzoylamino)-2-hydroxy-4-[4-(phenylmethoxy)phenyl]butyl]methylamino]carbonyl]-L-proline, phenylmethyl ester.