Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:18]([O:17][C:15]([CH:14]1[CH2:13][CH:12]=[CH:11][CH2:10][N:9]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)(=[O:26])=[O:27])[CH:8]1[C:6]([OH:7])=[O:5])=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)OCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)OCc3ccccc3)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(4-Methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2,3-dicarboxylic acid 3-benzyl ester 2-tert-butyl ester (1.6 g, 3.2 mmol) was dissolved in anhydrous methylene chloride (16 mL) and treated with trifluoroacetic acid (4 mL). The solution was stirred at ambient temperature for 3 hrs and then the solvents were removed in vacuo. The residue was coevaporated with toluene two times and then purified by column chromatography (silica) to yield 1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2,3-dicarboxylic acid 3-benzyl ester; MS: (M+H)+ 446.
Reaction SMILES: [O:1]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH2:4][N:5]([S:7]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[CH3:17])(=[O:9])=[O:8])[CH3:6])[CH2:2]1.[C:24]([O-:27])(=[O:26])[CH3:25].[Na+]>C(O)(=O)C>[C:24]([O:27][CH2:2][C:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([OH:1])[CH2:4][N:5]([S:7]([C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[CH3:17])(=[O:8])=[O:9])[CH3:6])(=[O:26])[CH3:25]
Reactant: CC(=O)[O-]
Reactant: Cc1ccc(C)c(S(=O)(=O)N(C)CC2(c3ccccc3)CO2)c1
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCC(O)(CN(C)S(=O)(=O)c1cc(C)ccc1C)c1ccccc1
Reaction time: 48 h
Yield: 57.5 %

Procedure:
A mixture of 5.30 g of 1,2-epoxy-2-phenyl-3-[N-(2,5-dimethylphenylsulfonyl)-N-methylamino]propane which had been prepared in accordance with Reference Examples 4 to 8, 3.30 g of anhydrous sodium acetate and 50 ml of acetic acid was stirred at 100° to 110° C. for 2 days. After evaporation, the residue was dissolved in 150 ml of benzene, washed subsequently with water, a saturated aqueous sodium bicarbonate and saturated brine, and then dried over anhydrous magnesium sulfate. After evaporation, the residue was purified by silica gel column chromatography (developing solvent: n-hexane-ethyl acetate (5:1)) to obtain 3.60 g of the titled compound.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>O1CCCC1>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:7][C:8]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])=[O:23])=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(Cl)cc1N
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1ccc(Cl)cc1NC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Pyridine (0.144 mole) is given to a solution of 2-amino-4-chlorobenzonitrile (0,131 mole) in 100 ml tetrahydrofuran (THF) and a solution of 4-bromobenzoylchloride (31,6 g, 0,144 mole) in 50 ml THF is added under nitrogen. After addition of 100 ml THF, the mixture is stirred for 6 h at room temperature (rt). The crude reaction is then customary worked up for solution reactions affording 4-bromo-N-(5-chloro-2-cyano-phenyl)-benzamide as a solid; m.p. 151-152°.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29].CS(C)=O>O>[CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]2[S:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(C=O)cc1
Reactant: Nc1ccccc1S
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(-c2nc3ccccc3s2)cc1
Yield: 45.6 %

Procedure:
A solution of 4-dodecyloxybenzaldehyde (37.12 g, 0.128 mol), 2-aminobenzenethiol (16 g, 0.128 mol) and dimethylsulfoxide acid (200 cm3) was heated under reflux for 24 hours. The cooled solution was added to water and extracted into dichloromethane (3×50 cm3). The combined organic layers were dried (MgSO4), filtered and the filtrate evaporated down under reduced pressure. The solid residue was recrystallised from ethanol to give 23.1 g (45.7%) of the desired product.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=1.[Br:15]N1C(C)(C)C(=O)N(Br)C1=O>C(O)(=O)C>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:8]=[C:7]([Br:15])[CH:6]=[C:5]([C:9]([F:10])([F:11])[F:12])[CH:4]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: FC(F)(F)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 35 °C

Procedure:
To glacial acetic acid (22.0 mL), cooled to 15° C. in a 1 L 3-n RB flask (equipped with mechanical stirrer, thermocouple, and addition funnel), was added concentrated (96%) sulfuric acid (142 mL) in one portion. An exothermic heat of solution raised the temperature to 35° C. After cooling to 25° C., 1,3-bis(trifluoromethyl)benzene (107 g, 500 mmol) was added. With the acid mixture rapidly stirring, 1,3-dibromo-5,5-dimethylhydantoin (77.25 g; 270 mmol) was added over 2 min to give a multiple phase mixture (solid and two liquid). An exothermic reaction occured that raised the internal temperature to ˜40° C. (jacket cooling at 15° C.). After the reaction temperature began to drop (after 5 min) the reaction mixture was maintained at 45° C. for 4.5 hr.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7]1>CN(C)C=O>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:14][C:9]=2[O:8][CH2:7]1
Reactant: c1ccc2c(c1)OCO2
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 16.3 %

Procedure:
To a solution of 4.25 g of anhydrous N,N-dimethylformamide at 0° C. under nitrogen was added 7.84 g of sulfuryl chloride, whereupon a solid formed. After stirring for 15 minutes, 6.45 g of 1,3-benzodioxole was added, and the mixture heated at 100° C. for 2 hours. The reaction was cooled, poured into ice water, extracted with methylene chloride, dried over magnesium sulfate, filtered and concentrated to give 7.32 g of crude material as a black oil. This was chromatographed on silica gel using 20% methylene chloride/hexane to afford 1.9 g of (1,3-benzodioxol-5-yl)sulfonyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1)[CH3:2].S(Cl)(Cl)=O.[CH2:16](OC1C=CC(CO)=CC=1)[CH2:17]CC>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1)[CH2:2][CH2:16][CH3:17]
Reactant: CCOc1ccc(CCl)cc1
Reactant: CCCCOc1ccc(CO)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCOc1ccc(CCl)cc1

Procedure:
Was synthesized following the same general procedure as that for the preparation of 4-ethoxybenzyl chloride; thionyl chloride (7.42 g, 69.2 mmol), 4-butoxybenzyl alcohol (9.45 g, 52.4 mmol), CH2Cl2 (145 mL).
Reaction SMILES: CN(C)[CH2:3][CH2:4]CN=C=NCC.C(O)C.[C:15]([CH:17]([C:30]1[CH:31]=[N:32][CH:33]=[C:34]([Br:36])[CH:35]=1)[CH:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[CH2:19][C:20]([OH:22])=[O:21])#[N:16]>CN(C)C1C=CN=CC=1.ClCCl>[C:15]([CH:17]([C:30]1[CH:31]=[N:32][CH:33]=[C:34]([Br:36])[CH:35]=1)[CH:18]([C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1)[CH2:19][C:20]([O:22][CH2:3][CH3:4])=[O:21])#[N:16]
Reactant: CCN=C=NCCCN(C)C
Reactant: N#CC(c1cncc(Br)c1)C(CC(=O)O)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(Cl)cc1)C(C#N)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under protective gas (Ar), 0.121 g (0.632 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC), a spatula tip of 4-dimethylaminopyridine (DMAP) and 0.061 g (1.317 mmol) of ethanol were added to 0.200 g (0.527 mmol) of 4-cyano-4-(5-bromopyridin-3-yl)-3-(4-chlorophenyl)butanoic acid (Example A4) in 4 ml of dichloromethane, and the mixture was stirred at 25° C. for 8 h. The solvent was removed under reduced pressure and the residue was taken up in dichloromethane and washed twice with in each case 15 ml of water. The combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure. Chromatography of the residue on silica gel (gradient: starting with ethyl acetate/heptane=5:95 over the course of 20 minutes increased to ethyl acetate/heptane=20:80) gave 0.143 g (67% of theory) of the title compound (erythro:threo=58:42). 1H-NMR in CDCl3 see Table 2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:34]#[N:35])([NH:14][C:15]([O:17][C@@H:18]([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[C:34]([C:11]1([NH:14][C:15]([O:17][C@@H:18]([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])=[O:16])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)#[N:35].[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)O[C@@H](CC2CCCCC2)C(=O)N2CCOCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(NC(=O)O[C@@H](CC2CCCCC2)C(=O)N2CCOCC2)CCNCC1
Reaction time: 1 h

Procedure:
A sample of the title compound of Example 6 (125 mg, 0.254 mmol) is dissolved in DCM (1 mL) and TFA (1 mL). The reaction is allowed to stir for 1 hour and the volatiles are removed by rotary evaporation to afford pure (S)-4-cyano-4-(1-cyclohexylmethyl-2-morpholin-4-yl-2-oxo-ethoxycarbonylamino)-piperidine in quantitative yield as TFA salt. The corresponding free amine is prepared by addition of 1M NaOH and extraction into DCM followed by drying and rotary evaporation of the organic layer. HPLC-MS calculated for C20H32N4O4 (M+H+) 393.2, found 393.3.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([CH2:22][O:23][C:24](=[O:27])[CH2:25]Cl)[C:3]=1[F:28].Cl.[CH3:30][NH:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([CH2:22][O:23][C:24](=[O:27])[CH2:25][N:31]([CH3:32])[CH3:30])[C:3]=1[F:28]
Reactant: Nc1ccc(-c2cc(=O)c3c(N)c(F)c(COC(=O)CCl)c(F)c3o2)cc1F
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
1.50 g (3.63 mmol) of Compound 159 obtained in EXAMPLE 159 was dissolved in 30 mL of dimethylformamide, 1.48 g (18.2 mmol) of dimethylamine hydrochloride and 2.50 g (18.2 mmol) of potassium carbonate were added, and the mixture was stirred at 50° C. for 30 minutes. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane, to give 1.18 g of Compound 161 (yield: 77%). This compound was dissolved in ethyl acetate, 3 mL of a 1N hydrochloric acid/2-propanol solution was added, and the precipitated crystals were collected by filtration, to give a hydrochloride of Compound 161.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)[O:17][C:16](=O)[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:19])[O:11]1>C(O)C>[CH2:1]([N:8]1[CH2:15][CH2:14][CH:13]([C:12]([OH:19])=[O:11])[C:16]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: O=C(O)C1CCN(Cc2ccccc2)C1=O
Yield: 79.4 %

Procedure:
A mixture of benzylamine (0.962 mL; 8.82 mmol) and 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.5 g; 2.94 mmol) in ethanol (3 mL) was irradiated in a microwave oven for 3 minutes at 100° C. and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 30 to 100% ethyl acetate in heptane with 5% acetic acid) to afford 0.512 g (79%) of 1-benzyl-2-oxopyrrolidine-3-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([F:13])[CH:7]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([F:13])[CH:7]=1)=[O:16]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccc(C)c(F)c1
Product: COC(=O)c1nc(C)sc1-c1ccc(C)c(F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-fluoro-4-methyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=1.00 min; [M+H]+=266.0.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:57][N:56]4[C:58]([CH3:62])([CH3:61])[CH2:59][CH2:60][C@@H:55]4[CH2:54]3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]>CO.O1CCCC1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:29][N:30]=[N:31][N:32]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:57][N:56]4[C:58]([CH3:61])([CH3:62])[CH2:59][CH2:60][C@@H:55]4[CH2:54]3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc([C@@H]3C[C@H]4CCC(C)(C)N4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1nc2ccc([C@@H]3C[C@H]4CCC(C)(C)N4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 86.1 %

Procedure:
A solution of 0.320 g of Cis-2-butyl-6-(hexahydro-6,6-dimethylpyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone in 5.0 ml of methanol and 1.0 ml of tetrahydrofuran is heated at reflux for 18 hours. The volatiles are evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 99:1 to 9:1 chloroform-methanol to give 0.194 g of the desired product as a solid. FAB MASS SPEC 576 (M+H).
Reaction SMILES: C(SC1C=C(O)C(=O)NC=1)C1C=CC=CC=1.[CH3:17][O:18][C:19]1[CH:40]=[CH:39][C:22]([CH2:23][S:24][C:25]2[CH:26]=[C:27]([O:35]COC)[C:28](=[O:34])[N:29](COC)[CH:30]=2)=[CH:21][CH:20]=1>>[OH:35][C:27]1[C:28](=[O:34])[NH:29][CH:30]=[C:25]([S:24][CH2:23][C:22]2[CH:39]=[CH:40][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[CH:26]=1
Reactant: COCOc1cc(SCc2ccc(OC)cc2)cn(COC)c1=O
Agent: O=c1[nH]cc(SCc2ccccc2)cc1O
Product: COc1ccc(CSc2c[nH]c(=O)c(O)c2)cc1

Procedure:
Prepared as described for 5-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (Example 12) from 5-[(4-methoxybenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 26).
Reaction SMILES: CC(O[C:6]([NH:8][C@@H:9]([CH2:12][CH2:13][CH2:14][CH3:15])CO)=[O:7])(C)C.CC(OC([NH:23][C@@H:24]([CH3:27])[CH2:25][OH:26])=O)(C)C>>[CH:9]1([NH:8][C:6](=[O:7])[CH:25]([OH:26])[C@@H:24]([NH2:23])[CH3:27])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CCCC[C@@H](CO)NC(=O)OC(C)(C)C
Product: C[C@H](N)C(O)C(=O)NC1CCCC1
Yield: 45 %

Procedure:
The same reaction procedure as in Reference Example 12 was repeated except that (S)-2-[N-(2-methyl-2-propyloxycarbonyl)amino]hexanol used in Reference Example 12 was replaced by 14.33 g of (S)-2-[N-(2-methyl-2-propyloxycarbonyl) amino]propanol, whereby 6.95 g of the captioned (2RS,3S)-N-cyclopentyl-3-amino-2-hydroxybutanamide was obtained in a yield of 45%. 1H-NMR (CDCl3, δ): 1.05 (3/2H, d, J=7 Hz), 1.15 (3/2H, d, J=7 Hz), 1.35-1.50 (2H, m), 1.55-1.76 (4H, m), 1.90-2.10 (2H, m), 3.31-3.41 (1/2H, m), 3.48-3.52 (1/2H, m), 3.74 (1/2H, d, J=3 Hz), 3.87 (1/2H, d, J=5 Hz), 4.13-4.29 (1H, m), 7.18 (1/2H, d, J=8 Hz), 7.25 (1/2H, d, J=8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:32])[C:5]([CH3:31])=[C:6]([CH2:12][C:13]2[C:14]([O:27]C(=O)C)=[C:15]([CH:24]=[CH:25][CH:26]=2)[C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:32])[C:5]([CH3:31])=[C:6]([CH2:12][C:13]2[C:14]([OH:27])=[C:15]([CH:24]=[CH:25][CH:26]=2)[C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)N3CCOCC3)c2OC(C)=O)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)N3CCOCC3)c2O)=C(C)C1=O
Yield: 48 %

Procedure:
N-[3-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]morpholine (0.050 g, 0.113 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.022 g, 0.0542 mmol, 48%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10](Br)=[C:9]([CH3:14])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.CO.[Pd]>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:14])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1Br
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cccc(C(=O)OC(C)(C)C)c1
Yield: 97 %

Procedure:
4-Bromo-3-methyl-benzoic acid tert-butyl ester (0.39 g, 1.438 mmol) was hydrogenated over 10% Pd—C (0.5 g) under H2 (50 psi) in EtOAc—MeOH (4:1, 20 mL) for 5 h. After filtration through Celite, filtrate was evaporated to dryness. Yield: 97%. MS (ESI) 193.28 (M+H+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>>[CH2:30]([S:32]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1)(=[O:34])=[O:33])[CH3:31]
Reactant: CCS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCNC3)cnc21
Product: CCS(=O)(=O)N1CC[C@@H](Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
((R)-1-Ethanesulfonyl-pyrrolidin-3-yl)-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine was prepared from (R)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and ethanesulfonyl chloride, following the general synthetic procedures described in the above Examples.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][C:11]([C:19]4[CH:20]=[N:21][CH:22]=[N:23][CH:24]=4)=[CH:12][CH:13]=3)[C:8]3([CH2:28][O:27][C:26]([NH2:29])=[N:25]3)[C:7]=2[CH:6]=1)[CH2:2][CH3:3].C(=O)=O>CO>[CH2:1]([O:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][C:11]([C:19]4[CH:20]=[N:21][CH:22]=[N:23][CH:24]=4)=[CH:12][CH:13]=3)[C@:8]3([CH2:28][O:27][C:26]([NH2:29])=[N:25]3)[C:7]=2[CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc2c(c1)C1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Agent: O=C=O
Solvent: CO
Product: CCCOc1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Yield: 32.5 %

Procedure:
2′-Propoxy-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (40 mg) was subjected to chromatography using 15:85:0.2 MeOH:CO2:DEA at 80 ml/min on a 20×250 mm, 5 μm ChiralPak AS-H column and 100-bar system pressure. The first peak (RT=3.5 min) provided (R)-2′-propoxy-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (13.0 mg, >99% ee), and the second peak (RT=4.3 min) provided (S)-2′-propoxy-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (12.8 mg, >99% ee).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:4]=1[CH2:5][NH:6][C:7](=[O:15])[CH2:8][CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11].[C:24](C1CC(=O)NC1=O)([O:26][CH2:27][CH:28]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25]>C(Cl)(Cl)Cl.CO.C(O)(=O)C>[NH:11]([C:24]([O:26][CH2:27][CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[C:40]1=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:25])[C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][CH2:8][C:7](=[O:15])[NH:6][CH2:5][C:4]1[C:3]([O:2][CH3:1])=[CH:19][C:18]([O:20][CH3:21])=[CH:17][C:16]=1[O:22][CH3:23]
Reactant: COc1cc(OC)c(CNC(=O)CC[C@H](N)C(=O)O)c(OC)c1
Reactant: O=C1CC(C(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(OC)c(CNC(=O)CC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(OC)c1

Procedure:
N'(2,4,6-trimethoxybenzyl)-L-glutamine (0.97 g, 3 mmol) was reacted with Fmoc-succinimide as described in Step 3 of Example 1 to give 1.23 g (78%), thin layer chromatography 1 spot Rf 0.35 chloroform/methanol/acetic acid (90:5:5).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:8]=[O:9])[O:6][CH:7]=1.[C:12]([Mg]Br)#[CH:13].C(=O)(O)[O-].[Na+]>O1CCCC1>[F:11][C:2]([F:10])([F:1])[C:3]1[CH:4]=[C:5]([CH:8]([OH:9])[C:12]#[CH:13])[O:6][CH:7]=1
Reactant: C#C[Mg]Br
Reactant: O=Cc1cc(C(F)(F)F)co1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(O)c1cc(C(F)(F)F)co1

Procedure:
1.8 g of the product of Stage F were cooled to 0°/+5° C. in 20 ml of tetrahydrofuran and 24 ml of ethynylmagnesium bromide were added over 30 minutes. The mixture was allowed to return to room temperature and was then poured into a saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The extract was dried and the solvent was evaporated to obtain 0.8 g of the expected product after chromatography on silica (eluent: methylene chloride).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:13][C:14]1[C:21]([F:22])=[C:20]([C:23]([F:26])([F:25])[F:24])[C:19]([F:27])=[C:18]([F:28])[C:15]=1[CH2:16]Br>CN(C=O)C>[CH3:12][O:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:16][C:15]2[C:18]([F:28])=[C:19]([F:27])[C:20]([C:23]([F:24])([F:26])[F:25])=[C:21]([F:22])[C:14]=2[F:13])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COc1ccc(N)cc1C(=O)O
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Solvent: CN(C)C=O
Product: COc1ccc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)cc1C(=O)O
Yield: 29.7 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 5-amino-2-methoxy-benzoic acid (2.10 g, 12.7 mmole), DMF (50 ml), TEA (6 ml), and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (2.00 ml, 14.0 mmole), 1.50 g (31.5% yield) of 2-methoxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid was obtained as a yellow solid: