Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]([O:6]C(=O)[C@H](CCCNCOC=N)NC(OC(C)(C)C)=O)(C)(C)[CH3:3].[C:26]([O:30][C:31](=[O:47])[C@H:32]([CH2:41][CH2:42][CH2:43][NH:44][C:45]#[N:46])[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])([CH3:29])([CH3:28])[CH3:27].C(OC(=O)[C@H](CCCNC#N)N)(C)(C)C>>[ClH:1].[C:26]([O:30][C:31](=[O:47])[C@H:32]([CH2:41][CH2:42][CH2:43][NH:44][CH:45]=[N:46][O:6][CH2:2][CH3:3])[NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC#N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNCOC=N)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)[C@@H](N)CCCNC#N
Agent: Cl
Product: CCON=CNCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 75 %

Procedure:
By a method described above for the preparation of N2-(tert-butoxycarbonyl)-N5-(iminomethoxymethyl)-L-ornithine tert-butyl ester hydrochloride, 1.05 g (3.35 mmol) of N2-(tert-butoxycarbonyl)-N5-cyano-L-ornithine tert-butyl ester produced 0.95 g (75%) N2-(tert-butoxycarbonyl)-N5-(ethoxyiminomethyl)-L-ornithine tert-butyl ester hydrochloride (TLC, silica gel, methanol:dichloromethane/1:4, Rf=0.61) and 1.195 g (3.2 mmol) of N2-tert-butoxycarbonyl)-N5-cyano-L-ornithine tert-butyl ester produces 0.63 g (63%) N2-(tert-butoxycarbonyl)-N5-(iminoisopropoxymethyl)-L-ornithine tert-butyl ester hydrochloride (TLC, silica gel, methanol:dichloro methane/1:4, Rf=0.53). Mass Spectrum (CI) 360 (MH+, 100%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][C:7]1[NH:8][CH:9]=[C:10]([CH3:26])[C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[N:13]=1.[CH3:27]O>C=O.O>[CH2:1]([N:3]([CH2:27][C:9]1[NH:8][C:7]([CH3:6])=[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:13]=2)[C:10]=1[CH3:26])[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1c[nH]c(C)c1-c1ccnc(Nc2ccc(F)cc2)n1
Reactant: CO
Reactant: CCNCC
Agent: C=O
Solvent: O
Product: CCN(CC)Cc1[nH]c(C)c(-c2ccnc(Nc3ccc(F)cc3)n2)c1C

Procedure:
Diethylamine (40 μL, 0.31 mmol) was diluted with methanol (0.5 mL) and formaldehyde (30 μL of a 37% w/w aq solution, 0.37 mmol) was added. [4-(2,4-Dimethyl-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine (87 mg, 0.31 mmol) was added in small portions and the mixture was heated to reflux. After 1.5 h the mixture was diluted with H2O (10 mL). The resulting precipitate was filtered and triturated in 2 M aq HCl. The mixture was filtered and the filtrate was washed with 2 M aq NaOH. The filtrate was extracted with EtOAc (3×15 mL). The combined organic extracts were washed (brine), dried (MgSO4), filtered, and evaporated in vacuo. The crude product was purified by SiO2 chromatography (heptane/EtOAc gradient elution) to afford the title compound (36 mg) as an orange solid after recrystallisation from iPr2O. M.p. 71.9–74.2° C. MS: [M+H]+=367.7 (C21H26FN5 requires 367.5). 1H-NMR (CD3OD) δ: 1.10 (t, 6H, J=7.1 Hz, CH3), 2.19 (s, 3H, CH3), 2.41 (s, 3H, CH3), 2.58 (t, 4H, J=7.8 Hz, CH2), 3.56 (s, 2H, CH2), 6.78 (d, 1H, J=5.6 Hz, pyrimidinyl-H), 7.00 (t, 2H, J=8.5 Hz, Ph-H), 7.61–7.63 (m, 2H, Ph-H), 8.22 (d, 1H, J=5.4 Hz, pyrimidinyl-H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:20]#[N:21].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26].Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:20]#[N:21]
Reactant: COc1cc2cc3ncc(C#N)c(Cl)c3cc2cc1OC
Reactant: Nc1ccc(F)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2cc3ncc(C#N)c(Nc4ccc(F)c(Cl)c4)c3cc2cc1OC
Yield: 90.4 %

Procedure:
Following the procedure of Example 11, a mixture of 149.4 mg (0.50 mmol) of 4-chloro-7,8-dimethoxybenzo[g]quinoline-3-carbonitrile, 87.3 mg (0.60 mmol) of 3-chloro-4-fluoroaniline and 57.8 mg (0.50 mmol) of pyridine hydrochloride in 7.0 mL of 2-ethoxyethanol is heated at 100–110° C. for 1.0 hour to yield 184.4 mg (83.0%) of the product as a yellow solid, mp>280° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].Cl[C:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:15]=[N:14][C:13]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]>O1CCCC1.O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:12]1[N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[N:15]=[N:14][C:13]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: Nc1ccccc1S
Reactant: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1Sc1ccccc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
Under the argon atmosphere, to an ice-cooled solution of 2-aminobenzenethiol (0.20 ml, 1.87 mmole) in tetrahydrofuran (15 ml) was added 60% sodium hydride (76 mg, 1.90 mmole), and the mixture was stirred at room temperature for 30 minutes. Ethyl 5-chloro-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate (499 mg, 1.69 mmole) was then added, and the mixture was stirred under ice-cooling for 30 minutes and at room temperature for further 3 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, and washed with water and a saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=3:1-1:4) to give ethyl 5-(2-aminophenylthio)-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate (594 mg, 91.4%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl.[CH3:21][NH:22][CH3:23].C(N(CC)CC)C>O1CCOCC1.C(OCC)(=O)C>[CH3:21][N:22]([CH3:23])[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: CNC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1N(C)C
Yield: 59.5 %

Procedure:
A mixture of 4-chloro-3-ethoxycarbonyl-8-nitroquinoline (199 mg), dimethylamine hydrochloride (63.6 mg) and triethylamine (78.9 mg) in dioxane was refluxed for 3 hours. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate:n-hexane, 1:2, v/v) to give 4-dimethylamino-3-ethoxycarbonyl-8-nitroquinoline (122 mg).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[CH:23]=[CH:24][C:25](=[O:28])[NH:26][N:27]=1.N1NC(=O)C=CC=1>>[CH3:21][C:22]1[CH:23]=[CH:24][C:25](=[O:28])[N:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:10][C@H:11]([N:13]5[CH2:14][CH2:18][CH2:15][CH2:16][CH2:17]5)[CH2:12]4)[S:8][C:4]=3[CH:3]=2)[N:27]=1
Reactant: Cc1ccc(=O)[nH]n1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: O=c1cccn[nH]1
Product: Cc1ccc(=O)n(-c2ccc3nc([C@H]4C[C@H](N5CCCCC5)C4)sc3c2)n1

Procedure:
The title compound was prepared according to the procedure described in Example 22, substituting the product of Example 44A for the product of Example 1E and substituting 6-methyl-3(2H)-pyridazinone for 3(2H)-pyridazinone. 1H NMR (400 MHz, CDCl3) δ ppm 8.12 (d, J=2.15 Hz, 1H) 8.01 (d, J=8.90 Hz, 1H) 7.67 (dd, J=8.90, 2.15 Hz, 1H) 7.16 (d, J=9.51 Hz, 1H) 7.00 (d, J=9.51 Hz, 1H) 3.52-3.64 (m, 1H) 2.72-2.86 (m, 1H) 2.53-2.73 (m, 2H) 2.40 (s, 3H) 2.24-2.38 (m, 4H) 1.65-1.75 (m, 2H) 1.54-1.65 (m, 4H) 1.46 (d, J=4.91 Hz, 2H). MS: (M+H)+=381.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1.[C:32]([O:36][C:37](=[O:42])[NH:38][CH2:39][CH:40]=O)([CH3:35])([CH3:34])[CH3:33].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:32]([O:36][C:37](=[O:42])[NH:38][CH2:39][CH2:40][N:3]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCNC3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCN(CCNC(=O)OC(C)(C)C)C3)ccc21
Yield: 58.5 %

Procedure:
[2-(3-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]amino}-pyrrolidin-1-yl)-ethyl]-carbamic acid tert-butyl ester (56 mg) was prepared by following General Procedure P starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid pyrrolidin-3-ylamide dihydrochloride (84 mg), (2-oxo-ethyl)-carbamic acid tert-butyl ester (40 mg), and Na(OAc)3BH (65 mg) in DCM (2 mL).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]([CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:9][CH2:10]P(OCC)(=O)OCC.[CH3:25][CH:26]([CH:29]([O:32][CH3:33])[O:30][CH3:31])[CH:27]=O.O>O1CCCC1.CCOCC>[CH3:25][CH:26]([CH:27]=[CH:10][CH:9]=[C:8]([CH3:7])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH:29]([O:32][CH3:33])[O:30][CH3:31]
Reactant: COC(OC)C(C)C=O
Reactant: CCOP(=O)(CC=C(C)CCC=C(C)C)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(OC)C(C)C=CC=C(C)CCC=C(C)C
Temperature: -27.5 °C
Yield: 65.7 %

Procedure:
To a 500 mL three-neck reaction flask protected from atmospheric moisture by nitrogen gas throughout the course of the reaction a solution of 2.4 g potassium t-butoxide (0.11 mol) in 60 mL of anhydrous tetrahydrofuran was added with an external cold bath to maintain the internal temperature of approximately −30 to −25° C. Then diethyl 3,7-dimethyl-2,6-octadiene-phosphonate (3B) (0.10 mol) was added dropwise over 30 min under mechanical stirring and the reaction mixture was subsequently stirred in the cold for 60 min to ensure the formation of carbanion thoroughly. Then 13.2 g of 2-methyl-3,3-dimethoxy-1-propanal (4A) (0.10 mol) was added dropwise at −30˜25° C. over 1 h and the reaction mixture was subsequently stirred for 30 min at this temperature until the reaction completed according to GC. Followed by the addition of 50 mL water and 100 mL ether and stirring for 10 min, after stratification, the organic layer was washed with 5% aqueous sodium chloride (3×25 mL), then dried over anhydrous magnesium sulfate and subsequently filtered. Removal of the volatile organic solvents in vacuo, the residue subsequently was fractional distillated to afford 17.9 g of (5-E and 5-Z)-2,6,10-trimethyl-1,1-dimethoxy-3,5,9-undecatriene (2C) of 99-103° C./1 mmHg, as a colorless liquid with GC content of 92.5% (total content of cis and trans) and the yield of 65.7%. There are 2 peaks according to GC and GC-MS. ascertained is the same with that of Example II
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH3:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH3:17])[CH2:16][CH2:15][N:14]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Reactant: Clc1ccc(Cl)nc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2ccc(Cl)cn2)CC1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester (0.5 g, 2.02 mmol, Example 30B) in dioxane (5.0 mL) at room temperature was added 2,5-dichloro-pyridine (0.4 g, 2.79 mmol) and diisopropylethyl amine (0.2 mL, 1.1 mmol). The reaction mixture was stirred at 80° C. for 48 hours, concentrated under reduced pressure and purified by flash chromatography with 10% to 40% ethyl acetate in hexane to provide (5′-chloro-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamic acid benzyl ester. MS (CI) m/z 360 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.01(d, 1H), 7.49 (dd, 1H), 7.36-7.27 (m, 5H), 7.26 (m, 1H), 6.78 (d, 1H), 5.04 (s, 2H), 3.82 (m, 2H), 3.21 (m, 2H), 2.15 (m, 2H), 1.58 (m, 2H), 1.35 (s, 3H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[C:8]2=[O:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:33]([O:35][P:36]([O:40]CC)[O:37][CH2:38][CH3:39])[CH3:34]>C1(C)C(C)=CC=CC=1>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][P:36]([O:37][CH2:38][CH3:39])(=[O:40])[O:35][CH2:33][CH3:34])[C:8]2=[O:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOP(OCC)OCC
Reactant: O=c1n(CCCCCCCBr)c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Solvent: Cc1ccccc1C
Product: CCOP(=O)(CCCCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O)OCC
Yield: 75.2 %

Procedure:
A solution of 1,4,5-triphenyl-3-(7-bromoheptyl)-imidazol-2-one (1.0 g) and triethylphosphite (1.66 g) in xylene (5 ml) was heated at reflux temperature for 40 hours. The solution was evaporated to an oil and chromatographed on silica gel (ethyl acetate/ethanol)The resulting oil was taken up in diethyl ether, filtered and evaporated to give diethyl 7-(3,4,5-triphenyl-2-oxo-2,3-dihydroimidazol-1-yl)heptanephosphonate as a clear oil (0.84 g, 75%).
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]4[CH:29]=3)=[CH:12][CH:13]=2)[N:8]([CH3:30])[S:7]1(=[O:32])=[O:31].C(Cl)Cl.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[F:33][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][NH:20][CH2:19][CH:18]4[CH:29]=3)=[CH:12][CH:13]=2)[N:8]([CH3:30])[S:7]1(=[O:32])=[O:31]
Reactant: CN1c2nc(C3=CC4CN(C(=O)OC(C)(C)C)CC4C3)ccc2N(CC2CC2(F)F)S1(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1c2nc(C3=CC4CNCC4C3)ccc2N(CC2CC2(F)F)S1(=O)=O
Reaction time: 1 h

Procedure:
tert-Butyl 5-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-3,3a,4,6a-tetrahydrocyclopenta[c]-pyrrole-2(1H)-carboxylate (24-1, 1.7 g, 3.4 mmol) was added to a mixture of DCM (28 mL) and TFA (7 mL) and stirred for 60 min. Following this duration, the contents were cautiously added to a mixture of saturated NaHCO3 (50 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous layer was back-extracted with ethyl acetate (2×30 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give an orange semi-solid. The material was carried forward without further purification.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH2:22]([O:24][C:25](=[O:37])[CH:26]=[CH:27][C:28]1[CH:36]=[CH:35][C:31]2[CH:32]=[CH:33][O:34][C:30]=2[CH:29]=1)[CH3:23].[NH4+].[Cl-]>C1COCC1>[CH2:22]([O:24][C:25](=[O:37])[CH2:26][C@@H:27]([C:28]1[CH:36]=[CH:35][C:31]2[CH:32]=[CH:33][O:34][C:30]=2[CH:29]=1)[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:16])[CH3:23]
Reactant: C[C@@H](NCc1ccccc1)c1ccccc1
Reactant: CCOC(=O)C=Cc1ccc2ccoc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H](c1ccc2ccoc2c1)N(Cc1ccccc1)[C@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of N-benzyl-α-(R)-methylbenzylamine (1.32 g, 6.30 mmol) in THF (25 mL) at 0° C. was treated with n-BuLi (2.52 mL of a 2.5M soln in hexanes). The resulting solution was stirred at 0° C. for 30 min and then cooled to -78° C. A solution of acrylate 3-4 (0.681 g, 3.15 mmol) in THF (5 mL) was added. After stirring for 15 min at -78° C., satd. aq. NH4Cl soln (5 mL) was added and the cold bath removed. The mixture was warmed to room temperature, and extracted with Et2O (2×40 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (10% ethyl acetate/hexanes) to give the β-aminoester 3-5 as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([C:9]([OH:11])=O)[CH2:3][C@@H:4]([C:6]([OH:8])=O)[NH2:5].[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[NH2:23]C(N)=O.C(OC(=O)C)(=O)C>N1C=CC=CC=1.C(O)C>[CH3:1][CH:2]1[C:9](=[O:11])[NH:23][C:6](=[O:8])[CH:4]([N:5]2[C:15](=[O:16])[C:14]3[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12]2=[O:17])[CH2:3]1
Reactant: NC(N)=O
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C[C@H](N)C(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: CC1CC(N2C(=O)c3ccccc3C2=O)C(=O)NC1=O
Reaction time: 1 h
Yield: 130.5 %

Procedure:
2.00 g (11 mmoles) 4-methylglutamic acid and 1.95 g (13 mmoles) phthalic anhydride were heated for 6 hours under reflux in 15 ml of dry pyridine. After removing the solvent by distillation, the residue was heated to boiling for 1 hour in 10 ml acetic anhydride. The solid which precipitated on cooling was filtered off under suction and the filtrate was concentrated. After treating the filtrate with ether, the precipitate which formed was filtered off under suction and the purified precipitates were recrystallised from absolute toluene. 2.00 g (7 mmoles) of the crystalline material and 0.23 g (3.8 mmoles) urea were well mixed and were fused on an oil bath at about 200° C. for 30 minutes. The solidified melt was heated briefly to boiling, with 4 ml acetic anhydride and 6 ml ethanol in succession. The precipitated solid was filtered off under suction and recrystallised from DMF/water. 1.35 g (67% theoretical) 2-(5-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dihydro-2H-isoindole-1,3-dione (1) were obtained, with a melting point of 270 to 272° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)[CH3:2].C(O[C:17]1[CH:22]=[CH:21]C(CC(OC2CCCCO2)=O)=[CH:19][CH:18]=1)C>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]([OH:13])=[O:12])[CH2:21][CH2:22][CH2:17][CH2:18][CH2:19]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(CC(=O)OC2CCCCO2)cc1
Reactant: CCOc1ccc(CC(=O)O)cc1
Product: CCOc1ccc(C2(C(=O)O)CCCCC2)cc1
Yield: 40 %

Procedure:
The title compound was obtained in a manner analogous to that for 1-Phenylcyclohexanecarboxylic acid (1/3) starting with (4-ethoxyphenyl)acetic acid (4b), via tetrahydro-2H-pyran-2-yl 2-(4-ethoxyphenyl)acetate (5b). The crude product 1/5 was chromatographed on silica gel with toluene-ethyl acetate-acetic acid (9:1:0.1) as eluent to give 1-(4-ethoxyphenyl)cyclohexanecarboxylic acid (1/5) in 40% yield. 1H NMR (CDCl3, HMDSO) δ: 1H NMR (CDCl3, HMDSO) δ: 1.17-2.08 (8H, m); 1.34 (3H, t, J=7.0 Hz); 2.26-2.63 (2H, m); 4.02 (2H, q, J=7.0 Hz); 6.88 (2H, d, J=8.8 Hz); 7.36 (2H, d, J=8.8 Hz); 10.09 (1H, br s).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH2:10][OH:11].Cl.C([O-])(O)=O.[Na+]>O>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[C:6](=[N:10]\[OH:11])/[NH2:7])=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N/C(=N/O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
To a solution of 4-fluorobenzonitrile (1.21 g, 10 mmol) and NH2OH.HCl (0.83 g, 12 mmol) in H2O (5 mL) was added NaHCO3 in portions. The reaction mixture was stirred at room temperature overnight. The mixture was then diluted with H2O (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the desired product (1.2 g). MS (ESI): 155 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][O:9][CH2:8][C:7]2=C.C[OH:14].C(Cl)Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][O:9][CH2:8][C:7]2=[O:14]
Reactant: C=C1COCc2c(F)cccc21
Reactant: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1COCc2c(F)cccc21
Temperature: -78 °C

Procedure:
8-Fluoro-4-methylene-3,4-dihydro-1H-isochromene (400 mg) was dissolved in a solution of 1:1 MeOH/DCM (50 mL) and 1 mL of pyridine added. The mixture was chilled to −78° C. and ozone was bubbled through the mixture for 40 min. The reaction monitored by TLC. The mixture was purged with nitrogen at −78° C. for 10 min and then treated with PPh3. After concentration, the resulting residue was purified by preparative TLC to offer 300 mg of the title compound.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.[F:51][C@@H]1CCNC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][C@@H:24]([F:51])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: F[C@@H]1CCNC1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2CC[C@@H](F)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-3-fluoropyrrolidine hydrochloride and isolated as light-yellow gum (9.8 mg, 54%). MS (m/e): 389.4 (MH+).
Reaction SMILES: [C@@H:1]1([C:7]([OH:9])=[O:8])[O:3][C@@H:2]1[C:4]([OH:6])=[O:5].[OH-:10].[Mg+2:11].[OH-]>>[C:7]([C@@H:1]([C@H:2]([C:4]([O-:6])=[O:5])[OH:10])[OH:3])([O-:9])=[O:8].[Mg+2:11]
Reactant: [OH-]
Reactant: O=C(O)[C@H]1O[C@H]1C(=O)O
Agent: [Mg+2]
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 35 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
In 100 ml of an aqueous solution containing 1.0 g of cis-epoxysuccinic acid and 0.44 g of magnesium hydroxide and adjusted to pH value of 8.0, a 0.5 g portion of clean microbic cells of Acetobacter curtus No. 4 (FERM-P No. 2879) obtained by following the procedure of Example 3 was added and shaken at 35° C for 5 hours. In the reaction mixture, there was formed magnesium L(+)-tartrate. The amount of the salt thus produced was 1.19 g and the yield was 91 percent. By treating this product with a column packed with Amberlite IR 120 (H+ type cation-exchange resin) similarly to Example 3, there was obtained L(+)-tartaric acid. This L(+)-tartaric acid was found to have an optical purity of 100 percent.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS([O-])=O.[Na+].[CH3:14][NH2:15].[C-:16]#[N:17].[K+]>>[CH3:14][NH:15][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:16]#[N:17]
Reactant: O=Cc1ccccc1
Reactant: CN
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Product: CNC(C#N)c1ccccc1
Temperature: 25 °C

Procedure:
Benzaldehyde (11 mmol) is added, with stirring, to a solution of NaHSO3 (12 mmol in 4 ml of water). When a white precipitate has formed, 28 ml of an aqueous 25% methylamine solution are added dropwise, and then 12 mmol of potassium cyanide are added at 0° C. The reaction mixture is stirred at room temperature until the reaction is complete. After conventional treatment, the title product is obtained in pure form.