Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=3)[CH:17]=[C:16]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:15]=2[CH3:30])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH3:29][O:28][C:26](=[O:27])[CH2:25][C:16]1[C:15]([CH3:30])=[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=2)[CH:17]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)OC(C)(C)C)CC2)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a yellow solution of (4-(7-fluoro-3-methoxycarbonylmethyl-2-methyl-naphthalen-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.48 mmol) in dichloromethane (10 mL) was added excess trifluoroacetic acid (1.1 g, 742 μL, 9.6 mmol) at room temperature under nitrogen. The resulting dark brown solution was stirred for 2 hours at room temperature under nitrogen. The solvent was removed under vacuum and the residue (˜270 mg) was purified by flash chromatography (40 g ISCO column, 0-100% ethyl acetate/hexanes then 20% MeOH/dichloromethane) to give (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt as a light yellow solid (110 mg, 53%). MS cald. for C19H23FNO2 [(M+H)+] 316, obsd. 316.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19]([OH:21])=O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25][NH2:26]>>[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25][NH:26][C:19]([C:12]1[C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:10][CH:11]=1)=[O:21]
Reactant: O=C(O)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Reactant: CC(C)(C)CCN
Product: CC(C)(C)CCNC(=O)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Yield: 50.7 %

Procedure:
In a manner similar to Reference Example 1 (c) 2-(3-chlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (50 mg) and 3,3-dimethylbutylamine (17 mg, ex Aldrich) afforded the title compound (32 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([Li])CCC.CN(C)CCN(C)C.Cl[CH2:25][C:26]1([CH2:30]Cl)[CH2:29][O:28][CH2:27]1>C1COCC1.O>[C:5]1([S:2]([CH:1]2[CH2:30][C:26]3([CH2:29][O:28][CH2:27]3)[CH2:25]2)(=[O:4])=[O:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)c1ccccc1
Reactant: ClCC1(CCl)COC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)C1CC2(COC2)C1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of methylsulfonylbenzene (2.00 g; 12.8 mmol) in dry THF (40 mL) under nitrogen at 0° C. was added butyl lithium (25.6 mmol; 2.5M solution on hexane). The mixture was stirred for 1 hour and then cooled to −20° C. Tetramethylethylenediamine (1.93 mL; 12.8 mmol) was added followed by a solution of 3,3-bis(chloromethyl)oxetane (1.98 g; 12.8 mmol) in dry THF (10 mL). The mixture was allowed to warm to 0° C. and then slowly allowed to reach 15° C. over 12 hours. Water (100 mL) was added and the mixture was extracted into ethyl acetate (4×50 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The material was purified on silica gel (Biotage system, utilizing two 120 g columns in series) eluting with hexane/ethyl acetate (2:1 to 1:2 gradient). The desired product was obtained as an off white solid (700 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14](N)=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2].N(OCCC(C)C)=O.[CH3:28][S:29]SC>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([S:29][CH3:28])=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(N)cc3c2n1
Reactant: CSSC
Agent: CC(C)CCON=O
Product: CCOC(=O)c1ncc2[nH]c3ccc(SC)cc3c2n1

Procedure:
400 mg of 8-amino-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester (Example 11) is heated in 4.8 ml of dimethyl disulfide under argon to 60° C. The mixture is then combined with 2.8 ml of isoamyl nitrite and heated for one hour to 80° C. After evaporation, the mixture is chromatographed over silica gel with methylene chloride/ethanol=10:1 as the eluent. Recrystallization of the corresponding fractions yields 130 mg of 8-methylthio-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester, mp 265°-266° C.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:17]=2[N:18]=[C:19]([C:21]2[O:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[O:25]1[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[C:28]([CH3:29])=[C:27]([CH3:30])[S:26][C:17]=3[N:18]=2)=[CH:22][CH:23]=[N:24]1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1C
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Cc1sc2nc(-c3ccno3)nc(NCCc3ccc4c(c3)OCCO4)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-ethylenedioxyphenethylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CC1C=CC(S(OCC2CC3C=C(Cl)C=C(OC)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:29]([CH2:32][CH:33]1[CH2:37][C:36]2[CH:38]=[C:39]([Cl:44])[CH:40]=[C:41]([O:42][CH3:43])[C:35]=2[O:34]1)=[N+]=[N-].[N-]=[N+]=[N-]>[Pt]>[Cl:44][C:39]1[CH:40]=[C:41]([O:42][CH3:43])[C:35]2[O:34][CH:33]([CH2:32][NH2:29])[CH2:37][C:36]=2[CH:38]=1
Reactant: COc1cc(Cl)cc2c1OC(CN=[N+]=[N-])C2
Agent: [Pt]
Agent: COc1cc(Cl)cc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Agent: [N-]=[N+]=[N-]
Product: COc1cc(Cl)cc2c1OC(CN)C2
Yield: 56 %

Procedure:
Treatment of (±)-(5-chloro-7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.10 g, 2.98 mmol) with sodium azide (1.5 g, 23.1 mmol) generally according to the procedure described for Intermediate 98 provided (±)-2-(azidomethyl)-5-chloro-7-methoxy-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.080 g, 5 wt. %) generally according to the procedure described for Example 1 afforded 0.415 g (56%) of (±)-1-(5-chloro-7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 195-198° C.; Anal. calcd. for C10H12ClNO2HCl: C, 48.02; H, 5.24; N, 5.6. Found: C, 46.41; H, 5.09; N, 5.31.
Reaction SMILES: C[O:2][C:3](=[O:21])/[C:4](/[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([Cl:20])[CH:11]=1)=[N:5]/[O:6][CH:7]([CH3:9])[CH3:8].[OH-].[Li+]>CO.C(Cl)(Cl)Cl>[Cl:20][C:12]1[CH:11]=[C:10](/[C:4](=[N:5]\[O:6][CH:7]([CH3:9])[CH3:8])/[C:3]([OH:21])=[O:2])[CH:15]=[CH:14][C:13]=1[S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: COC(=O)/C(=N/OC(C)C)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)O/N=C(/C(=O)O)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
This estimated 80% pure (E)-(3-chloro-4-methanesulfonyl-phenyl)-isopropoxyimino-acetic acid methyl ester (0.52 g, <1.5 mmol) was dissolved in methanol (14 mL) and cooled to 0° C. An aqueous solution of lithium hydroxide (2.0 N, 1.86 mL, 3.72 mmol) was added dropwise. After stirring 1.25 h, the reaction mixture was diluted with chloroform (175 mL) and washed with 0.2 M aqueous potassium bisulfate solution (50 mL). The aqueous phase was extracted with chloroform (75 mL) and the combined organic phases were dried over magnesium sulfate and evaporated in vacuo to afford (E)-(3-chloro-4-methanesulfonyl-phenyl)-isopropoxyimino-acetic acid (506 mg, quant.) as a slightly yellow paste that was used without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[O:6][CH2:7][CH:8]1[O:10][CH2:9]1.[C:17]1(=[O:23])[NH:21][C:20](=[O:22])[CH2:19][CH2:18]1>N1C=CC=CC=1>[CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[O:6][CH2:7][CH:8]([OH:10])[CH2:9][N:21]1[C:17](=[O:23])[CH2:18][CH2:19][C:20]1=[O:22]
Reactant: CNc1cc(OCC2CO2)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1
Solvent: c1ccncc1
Product: CNc1cc(OCC(O)CN2C(=O)CCC2=O)ccc1[N+](=O)[O-]

Procedure:
0.087 mol (19.5 g) of 1-(3'-methylamino-4'-nitrophenoxy)-2,3-epoxypropane is dissolved in 75 ml of absolute alcohol to which 6 drops of pyridine have been added. 0.10 mol (10.1 g) of succinimide is added and the mixture is then heated under reflux for 4 hours. The reaction mixture is filtered at the boil. On cooling of the filtrate, the expected product crystallises. After recrystallisation from alcohol and drying in vacuo, it melts at 152° C.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([CH2:12][CH2:13][C:4]2=[N:3][N:2]=1)=[CH:10][C:9]([C:14]1[CH:15]=[C:16]([C:20]2([C:23](OC)=[O:24])[CH2:22][CH2:21]2)[CH:17]=[N:18][CH:19]=1)=[CH:8][CH:7]=3.[C:27](=[N:30]O)([NH2:29])[CH3:28].[O-]CC.[Na+]>C(O)C>[CH3:28][C:27]1[N:30]=[C:23]([C:20]2([C:16]3[CH:15]=[C:14]([C:9]4[CH:10]=[C:11]5[C:6](=[CH:7][CH:8]=4)[N:5]4[CH:1]=[N:2][N:3]=[C:4]4[CH2:13][CH2:12]5)[CH:19]=[N:18][CH:17]=3)[CH2:21][CH2:22]2)[O:24][N:29]=1
Reactant: COC(=O)C1(c2cncc(-c3ccc4c(c3)CCc3nncn3-4)c2)CC1
Reactant: CC(N)=NO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1noc(C2(c3cncc(-c4ccc5c(c4)CCc4nncn4-5)c3)CC2)n1
Temperature: 150 °C

Procedure:
To a vial containing the title compound from Example 71 Step D (75 mg, 0.217 mmol), acetamide oxime (32.1 mg, 0.433 mmol) and sodium ethoxide (73.7 mg, 1.083 mmol) was added ethanol (2.2 mL). The vial was capped tightly and heated to 150° C. for 15 minutes in the microwave. The reaction solution was then concentrated under reduced pressure. The resulting material was diluted with acetonitrile and then purified by HPLC (C18 column, 10 to 100% acetonitrile/water, both 0.1% v/v trifluoroacetic acid). Fractions containing product were combined, aqueous 1 N HCl solution was added, and the resulting solution concentrated to provide the title compound: LCMS m/z 370.97 [M+H]+; 1H NMR (500 MHz, CD3OD) δ 10.1 (s, 1H), 9.28 (s, 1H), 9.13 (s, 1H), 8.1-8.01 (m, 4H), 3.49-3.46 (m, 2H), 3.39-3.36 (m, 2H), 2.29 (s, 3H), 2.04-2.02 (m, 2H), 1.94-1.91 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>ClCCl>[CH:25]1([C:28]([N:15]2[CH2:16][CH2:17][N:12]([C:4]3[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:13][CH2:14]2)=[O:29])[CH2:27][CH2:26]1
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCNCC1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc([N+](=O)[O-])cc1N1CCN(C(=O)C2CC2)CC1
Reaction time: 12 h
Yield: 90 %

Procedure:
To a solution of 1-(2-methoxy-5-nitrophenyl)-piperazine (500 mg, 2.1 mmol) in dichloromethane (50 ml) at 0° C. under argon was added triethylamine (0.59 ml, 4.2 mmol) and cyclopropane carbonyl chloride (2.1 mmol). Stirring was continued for 12 hrs. The reaction mixture was concentrated in vacuo and partitioned between saturated aqueous NaHCO3 and dichloromethane. The organic layer was dried over sodium sulphate and concentrated in vacuo to give the title compound (D17) in 90% yield. Found MH+ 306.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[C:5]2=[CH:4][CH:3]=1.[CH3:33][O:34][CH:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH3:36].[H-].[Li+].IC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH3:33])[CH:11]3[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[C:5]2=[CH:4][CH:3]=1.[CH3:33][O:34][CH:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH3:36]
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: COC(C)[Si](C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C1N(C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 104 %

Procedure:
In a manner similar to the method described in example 24c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.3 g, 0.5 mmol) prepared in example 55b was reacted with LiH (0.17 g, 21.4 mmol) (Aldrich) and iodomethane (4 g, 28.2 mmol) in N,N-dimethyl-formamide (40 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-methyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white solid (Yield: 0.16 g, 51.6%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:12]1[CH:13]=[C:14]([CH2:31][NH:32][CH3:33])[CH:15]=[CH:16][C:17]=1[Sn:18]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].C1C(=O)N(O[C:44]([CH2:46][CH2:47][N:48]2[C:53](=[O:54])[CH:52]=[CH:51][C:49]2=[O:50])=[O:45])C(=O)C1>C(#N)C>[O:54]=[C:53]1[CH:52]=[CH:51][C:49](=[O:50])[N:48]1[CH2:47][CH2:46][C:44]([N:32]([CH2:31][C:14]1[CH:15]=[CH:16][C:17]([Sn:18]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:19][CH2:20][CH2:21][CH3:22])=[C:12]([C:3]([O:8][CH2:9][O:10][CH3:11])([C:4]([F:5])([F:6])[F:7])[C:2]([F:1])([F:34])[F:35])[CH:13]=1)[CH3:33])=[O:45]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CNC)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Reactant: O=C(CCN1C(=O)C=CC1=O)ON1C(=O)CCC1=O
Solvent: CC#N
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(CN(C)C(=O)CCN2C(=O)C=CC2=O)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
Compound 14 (86 mg, 138 μmol) was dissolved in anhydrous acetonitrile (2 mL) and 3-(Maleimido)propionic acid N-hydroxysuccinimide ester (44 mg, 166 mmol) was added. The mixture was stirred overnight at room temperature, the solvent removed under reduced pressure and the residue purified over silica gel using chloroform/methanol (98/2) as eluant to give 86 mg (111 μmol, 81% yield) of a colorless oil.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CS(C)=O.C1([O:14][C:15](=O)[NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[C:33]4[C:28](=[CH:29][C:30]([O:37][CH3:38])=[C:31]([C:34](=[O:36])[NH2:35])[CH:32]=4)[N:27]=[CH:26][CH:25]=3)=[CH:19][C:18]=2[C:39]([F:42])([F:41])[F:40])C=CC=CC=1.O>C(OCC)(=O)C>[C:34]([C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:37][CH3:38])[N:27]=[CH:26][CH:25]=[C:24]2[O:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:15]([NH:3][CH2:1][CH3:2])=[O:14])=[C:18]([C:39]([F:41])([F:40])[F:42])[CH:19]=1)(=[O:36])[NH2:35]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(C(F)(F)F)c3)c2cc1C(N)=O
Reactant: CCN
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(N)=O)cc23)cc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
Ethylamine 2N tetrahydrofuran solution (0.10 ml) was added to dimethylsulfoxide (0.5 ml), and then (4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-trifluoromethylphenyl)carbamic acid phenyl ester (25 mg) was dissolved therein and the mixture was stirred for 10 minutes. Water and ethyl acetate were added to the reaction solution, and the precipitated crystals were filtered out to obtain the title compound (5.0 mg).
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].N1C(C)=CC(C)=CC=1C.[OH:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]1[CH2:28][S:27][C:26](=[O:29])[NH:25]1)=[O:23]>C(#N)C>[N+:7]([O:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]1[CH2:28][S:27][C:26](=[O:29])[NH:25]1)=[O:23])([O-:8])=[O:6]
Reactant: O=C1N[C@H](C(=O)NCCO)CS1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: Cc1cc(C)nc(C)c1
Product: O=C1N[C@H](C(=O)NCCO[N+](=O)[O-])CS1
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
0.44 g of nitronium tetrafluoroborate and a solution of 0.41 g of 2,4,6-collidine in 20 ml of acetonitrile were added at a temperature of from -10° C. to 0° C. to 30 ml of acetonitrile, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, 0.50 g of (4R)-N-(2-hydroxyethyl)-2-oxothiazolidine-4-carboxamide was added to the mixture, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was then freed from the solvent by distillation under reduced pressure. The residue was mixed with ethyl acetate and insoluble materials were filtered off. The filtrate was concentrated by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent. The pale yellow crystals thus obtained were recrystallized from ethyl acetate, to give 86 mg of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]([CH3:20])[C:7](=CN)[C:6]2=[O:23].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]([CH3:20])[CH2:7][C:6]2=[O:23]
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CN)C1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)CC1C
Reaction time: 72 h

Procedure:
A mixture of 570 mg. of l-ethyl 6,7-dimethoxy-3-aminomethylene-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-1-carboxylate, 1.78 ml. of 1N sodium hydroxide and 3 ml. of ethanol was heated under reflux for 24 hours and then stored at 25° C. for 3 days. The solvent was removed by evaporation in vacuo, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water and then it was concentrated to give 540 mg. of an oil. The oil was chromatographed using 30 g. of silica gel, and using 6:4 benzene-ethyl acetate as solvent, giving 6 fractions. Fractions 1 and 2 were combined and recrystallized from ethyl acetate-hexane to give 49 mg. of the title product, m.p. 92°-93° C. Fractions 3-6 were combined to give 152 mg. of 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline. This latter material was dissolved in 3 ml. of methylene chloride, and 3 ml. of pyridine followed by 0.5 ml. of ethyl chloroformate was added. After 20 minutes, the reaction mixture was diluted with an excess of methylene chloride and water. The organic phase was separated and washed successively with dilute hydrochloric acid, saturated sodium bicarbonate and brine. The methylene chloride solution was then dried, and evaporated in vacuo to give an oil. The oil was recrystallized from ethyl acetate-hexane to give 95 mg. of the title compound, m.p. 92°-93° C.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)CCCN2)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)Cc1ccc2c(c1)CCCN2
Temperature: 20 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a solution of #214 (750 mg, 2.25 mmol, 1 eq.) in dichloromethane (20 mL) was added dropwise trifluoracetic acid (2 mL) at 0° C. and then the solution was stirred at 20° C. overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in water (20 mL). The solution was basified with sodium carbonate and extracted with ethyl acetate/tetrahydrofuran (30 mL×3). The organic phase was dried over sodium sulfate and concentrated in vacuo to afford #215 (450 mg, 85%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 6.70 (d, 2H), 6.40 (m, 1H), 3.73 (s, 3H), 3.67 (m, 1H), 3.30 (m, 2H), 2.96 (m, 1H), 2.75 (m, 3H), 1.96 (m, 2H), 1.50 (br, 2H), 1.26 (br, 1H), HPLC (Protocol Y): m/z 235.14 [M+H+] retention time=4.35 minutes (purity >96%). Chiral HPLC retention time: 5.71 min (purity=98%). (Column: Chiralcel OJ-H, 150×4.6 mm, 5 μm; Mobile phase: ethanol (0.05% diethylamine) in CO2 from 5% to 40% over 15 minutes; Flow rate: 2.5 mL/minute.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=[O:6])=[CH2:3].C(O)C.[H][H]>O1CCCC1>[CH3:3][C@@H:2]([CH2:4][C:5]([OH:7])=[O:6])[C:1]([OH:9])=[O:8]
Reactant: [H][H]
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](CC(=O)O)C(=O)O

Procedure:
A solution of an itaconic acid (40.9 mg, 0.314 mmol) dissolved in tetrahydrofuran (THF) (0.3 mL) and ethanol (EtOH) (0.3 mL) is added to an autoclave in which the catalyst obtained in Preparation Example 7 was added. After replacing the atmosphere to hydrogen gas, it was stirred for 18 hours at reaction temperature of 50° C. under 3 atm pressure of hydrogen. After the reaction, it was cooled down to be room temperature, and the catalyst was filtered in the atmosphere to recover thereof and washed with THF (1 mL) three times. The solvent was concentrated from the filtrate, and the desired (S)-2-methylsuccinic acid was obtained. The yield thereof measured by NMR was >99%, and the optical purity thereof was >90% ee.
Reaction SMILES: C(SCS(C(C)C)=O)(C)C.[O:11]1CCC[CH2:12]1.[H-].[Na+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:23]Br>C(Cl)Cl>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:23][CH:12]=[O:11])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(CBr)cc1OC
Reactant: C1CCOC1
Agent: CC(C)SCS(=O)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CC=O)cc1OC
Reaction time: 1 h
Yield: 35 %

Procedure:
1.80 g of isopropyl isopropylthiomethyl sulfoxide was dissolved in 15 ml. of tetrahydrofuran, and under cooling with ice, 240 mg of sodium hydride was added, and the solution was stirred for one hour. 2.31 g of 3,4-dimethoxybenzyl bromide was added, and the mixture was stirred for 20 hours at room temperature, and for 3 hours at 35°C. 100 ml. of methylene chloride was added. After separating the insoluble water by filtration, the filtrate was concentrated at reduced pressure. The residue was dissolved in 20 ml. of tetrahydrofuran, and with the addition of 10 drops of concentrated sulfuric acid, the solution was stirred for 10 hours at 50°C. 500 mg of sodium bicarbonate was added, and the mixture was stirred for 30 minutes at room temperature. Then, the insoluble matter was separated by filtration. The filtrate was concentrated at reduced pressure, and the residue was subjected to column chromatography to give 631 mg of (3,4-dimethoxyphenyl)acetaldehyde in a yield of 35%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16](OC)=[O:17])=[CH:15][C:10]=2[N:9]=[CH:8]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][OH:17])=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: COC(=O)c1ccc2c(c1)ncn2C1CCCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc2c(c1)ncn2C1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
A solution of 22 (2.5 g, 9.61 mmol) in anhydrous THF (10 mL) was added dropwise to a mixture of LiAlH4 (0.55 g, 14.42 mmol) in anhydrous THF (20 mL) at 0° C. under nitrogen. The reaction mixture was stirred for 30 min at 0° C. then treated sequentially with water (2 mL) and 10% NaOH (1.8 mL). The resulting mixture was extracted with ether (2×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford 2.24 g (95%) of (1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methanol (24) as yellow oil: MS (ESI) m/z=233.2 [M+1]+.