Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]\[CH:34]=O)=[CH:4][N:3]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][C:38]1=[O:43]>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([CH:32]=[CH:33][CH2:34][N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[C:38](=[O:43])[CH2:39]2)=[CH:4][N:3]=1
Reactant: CN1CCNCC1=O
Reactant: COc1cc(-c2csc3c(/C=C\C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: COc1cc(-c2csc3c(C=CCN4CCN(C)C(=O)C4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-(4-{4-amino-7-[(1Z)-3-oxoprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide, 1-methyl-piperazin-2-one (trifluoroacetic acid salt), and General Procedure B. 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (s, 1H), 7.99 (m, 1H), 7.97 (s, 1H), 7.70 (d, 1H), 7.60 (s, 1H), 7.58 (d, 1H), 7.33 (s, 1H), 7.31 (t, 1H), 7.19 (s, 1H), 7.11 (t, 1H), 7.07 (d, 1H), 6.71 (d, 1H), 6.22 (m, 1H), 5.65 (br, 2H), 4.02 (s, 3H), 3.89 (s, 3H); 3.30 (m, 4H), 3.03 (s, 2H), 2.81 (s, 3H), 2.72 (m, 2H); MS: (MH)+ 581.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([S:29]([NH:32][CH2:33][CH2:34][CH2:35][CH3:36])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.C(OCC)(=O)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][C:19](=[O:21])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([S:29](=[O:31])(=[O:30])[NH:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:24]=3)=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: CCCCNS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCNS(=O)(=O)c1cccc(NC(=O)COc2ncc(C(=O)Nc3ccc(F)cc3)cn2)c1
Yield: 27 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 3-amino-N-butyl-benzenesulfonamide (53 mg, 0.21 mmol) as the coupling partner. Chromatography (1:1 ethyl acetate:dichloromethane) through SiO2 yielded 23 mg (27%) of the titled compound. ESI-MS m/z 502 (MH+), 500 (M−H−).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH3:9][C:10]([CH3:15])([CH2:13]O)[CH2:11][OH:12].C(Cl)Cl.[OH-].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:9][C:10]1([CH3:15])[CH2:11][O:12][C:3]2([CH2:4][CH2:5][CH2:6][C:1](=[O:8])[CH2:2]2)[O:7][CH2:13]1
Reactant: CC(C)(CO)CO
Reactant: O=C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)COC2(CCCC(=O)C2)OC1
Temperature: 25 °C
Yield: 43.6 %

Procedure:
448.5 g 1,3-cyclohexanedione, 416 g 2,2-dimethyl-1,3-propanediol and 12 g p-toluenesulfonic acid were introduced into 3,000 ml methylene chloride and the mixture was heated under reflux for 24 hours using a water separator. When the reaction had ended the mixture was cooled to room temperature and 2,000 ml 32% sodium hydroxide solution were added. The phases were separated and the organic phase was washed first with sodium bicarbonate solution (44.4 g sodium bicarbonate solution/850 ml water) and then with 350 ml water. The organic phase was dried over sodium sulfate and the solvent was then evaporated in vacuo. 345 g (50% of theory) 3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-8-one were obtained in this way.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:13][CH2:12]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:7]([CH3:8])[CH2:9][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:17][CH2:18][CH2:19][O:20][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:15][CH2:16]1)=[O:21])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CC[C@H]1CC[C@H](CCCO)CC1)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC[C@H]1CC[C@H](CCCOS(C)(=O)=O)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.35 g (11.20 mmol) trans-{2-[4-(3-hydroxy-propyl)-cyclohexyl]-ethyl}-methyl-carbamic acid tert-butyl ester and 1.54 ml (13.4 mmol) of methanesulfonyl chloride in 35 ml dichloromethane was added under ice-cooling within 5 minutes a solution of 1.87 ml (13.4 mmol) triethylamine in 5 ml of dichloromethane. The reaction mixture was then stirred for 1 hour at room temperature. It was subsequently partitioned between ether, water and 1N hydrogen chloride solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure giving 4.06 g (96.1%) almost pure trans-methanesulfonic acid 3-{4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexyl}-propyl ester as colorless viscous oil, MS: 395 (MNH4+).
Reaction SMILES: [N:1]1[C:2](=O)[NH:3][CH:4]=[C:5]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12.O(Cl)[Cl:15].[P+3]>>[Cl:15][C:2]1[N:3]=[CH:4][C:5]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:1]=1
Reactant: ClOCl
Reactant: O=c1nc2c(c[nH]1)CCCCCC2
Agent: [P+3]
Product: Clc1ncc2c(n1)CCCCCC2

Procedure:
Crude 5,6,7,8,9,10-Hexahydrocycloocta[d]pyrimidin-2(3H)-one was heated in phosphorus (III) oxychloride (50 mL) for 1.75 h. The solvent was removed under vacuum and the residue was treated with ice water and 1M aqueous potassium carbonate solution, the aqueous layer was extracted with a mixture of diethyl ether and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 2-chloro-5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidine as a yellow solid, 1.5 g; 1H NMR (CDCl3, 300 MHz) 8.18 (s, 1H), 2.82 (m, 2H), 2.66 (m, 2H), 1.74 (m, 2H), 1.61 (m, 2H), 1.34 (m, 4H) ppm; 13C NMR (CDCl3, 75 MHz) 173.25, 158.66 (2C), 132.74, 34.28, 32.03, 30.20, 28.57, 26.02, 25.90; MS (ES) 197/199 (M+H).
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH3:8])[C:5]2[CH:9]=[C:10]([Br:17])[C:11]([Br:16])=[C:12]([N+:13]([O-:15])=[O:14])[C:4]=2[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:24]>CCO>[Br:16][C:11]1[C:10]([Br:17])=[CH:9][C:5]2[N:6]([CH2:7][CH3:8])[C:2]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][C:19]3=[O:24])=[N:3][C:4]=2[C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: O=C1CNCCN1
Reactant: CCn1c(Br)nc2c([N+](=O)[O-])c(Br)c(Br)cc21
Solvent: CCO
Product: CCn1c(N2CCNCC2=O)nc2c([N+](=O)[O-])c(Br)c(Br)cc21
Temperature: 170 °C
Yield: 95.7 %

Procedure:
2,5,6-tribromo-1-ethyl-4-nitro-1H-1,3-benzodiazole (100 mg, 0.23 mmol) and 2-piperazinone (117 mg, 1.17 mmol) were dissolved in EtOH (3.0 ml). The resulting mixture was stirred at temperature 170° C. under microwave conditions until the reaction was complete (20 min) by LC/MS. The mixture was allowed to cool to RT and concentrated in-vacuo. The product was filtered off, washed with EtOH and dried to afford-(5,6-dibromo-1-ethyl-4-nitro-1H-1,3-benzodiazol-2-yl)piperazin-2-one (97 mg, 0.22 mmol); m/z 462.9; rt 3.1 min.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:19]=[N:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:16]([CH3:26])[N:15]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[CH3:26][C:16]1[N:15]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)[CH3:13])[CH:19]=[N:18][C:17]=1[O:20][CH2:21][C:22]([F:25])([F:24])[F:23]
Reactant: O=COc1ccccc1
Reactant: Cc1nc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Product: Cc1nc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1OCC(F)(F)F
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (130 mg, pale brown solid) from 4-chloro-2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.39 mmol, Intermediate-72, single enantiomer) and phenyl formate (95 mg, 0.78 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14].Cl>CCOCC.O1CCCC1>[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C@H:12]([CH:16]([CH3:18])[CH3:17])[CH2:13][OH:14]
Reactant: CC(C)C(C(=O)O)c1ccco1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)[C@H](CO)c1ccco1
Yield: 74.9 %

Procedure:
10.5 g (0.277 mol) of lithium aluminium hydride were suspended in 100 ml of absolute ether and treated while stirring within 10 minutes with 100 ml of absolute tetrahydrofuran. To this stirred suspension was added dropwise within 6-8 hours, while heating to reflux, 46.7 g (0.277 mol) of (+) 2-(2-furyl)-3-methylbutyric acid in 100 ml of absolute tetrahydrofuran. The reaction mixture was cooled and treated slowly with a 3N hydrochloric acid solution. The organic phase was separated, washed with water, dried and evaporated under reduced pressure. The remaining oil was distilled in a high vacuum, to obtain 32 g (75%) of (R)-(+)-2-(2-furyl)-3-methyl-1-butanol as a colorless liquid of 96% purity, boiling point 58°/39 Pa, [α]D20 =+2.5° (c=1%, ethanol).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]=[CH:18]2)=O)(C)(C)C.[ClH:23].CO>>[ClH:23].[CH:18]1[C:19]2[C:14](=[C:13]([NH:12][CH2:11][CH2:10][CH2:9][NH2:8])[CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:16][N:17]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1cccc2cnccc12
Agent: Cl
Solvent: CO
Product: NCCCNc1cccc2cnccc12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 28 (301 mg) and 10% hydrogen chloride/methanol solution (5 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (264 mg) as light yellow powdery solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][C:15](=[CH:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH3:26])[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]>[Pd].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH3:26])[CH2:20]3)[CH2:16][CH2:17]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN1CCCC(C=C2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Agent: [Pd]
Solvent: CCO
Product: CCN1CCCC(CC2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Reaction time: 4 h
Yield: 62.2 %

Procedure:
A mixture of the alkenes N-(3,4-dichlorophenyl)-4-[(1-ethylpiperidin-3-yl)methyl]-3,6-dihydropyridine-1(2H)-carboxamide and N-(3,4-dichlorophenyl)-4-[(1-ethylpiperidin-3-yl)methylene]piperidine-1-carboxamide (3:1) (40 mg) and 10% palladium on charcoal (30 mg) in ethanol (5 mL) was evacuated and purged with hydrogen. The mixture was left under an atmosphere of hydrogen for 4 hrs and then filtered through celite. The celite pad was washed with ethanol and the filtrate evaporated. The residue was purified using reverse phase HPLC eluting with a mixture of 5-95% acetonitrile in water and then by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in dichloromethane to give the title compound as a white solid (25 mg, 62%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]>[Cl-].[Cl-].[Cl-].[Ti+3]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(N2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: [Ti+3]
Agent: [Cl-]
Product: CCc1ccc(N2CCN(Cc3ccc(N)cc3)CC2)cc1

Procedure:
In the manner given in Example 1B, 1-(p-ethylphenyl)-4-(p-nitrobenzyl)piperazine is reduced with aqueous titanium trichloride to give 1-(p-ethylphenyl)-4-[(4-aminophenyl)methyl]piperazine.
Reaction SMILES: [C:1]1([C:7]2[C:12](B(O)O)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:22][C:23]1[C:27]([C:28]2[CH:29]=[C:30](C3C(C)=CC=C4C=3C=CC=N4)[C:31]3[NH:35][C:34](=[O:36])[NH:33][C:32]=3[CH:37]=2)=[C:26]([CH3:49])[O:25][N:24]=1>>[CH3:22][C:23]1[C:27]([C:28]2[CH:29]=[C:30]([C:12]3[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[N:8][CH:9]=[CH:10][CH:11]=3)[C:31]3[NH:35][C:34](=[O:36])[NH:33][C:32]=3[CH:37]=2)=[C:26]([CH3:49])[O:25][N:24]=1
Reactant: OB(O)c1cccnc1-c1ccccc1
Reactant: Cc1ccc2ncccc2c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1noc(C)c1-c1cc(-c2cccnc2-c2ccccc2)c2[nH]c(=O)[nH]c2c1

Procedure:
6-(3,5-dimethylisoxazol-4-yl)-4-(2-phenylpyridin-3-yl)-1H-benzo[d]imidazol-2(3H)-one was synthesized using 2-phenylpyridin-3-ylboronic acid and Cs2CO3 in a similar fashion as 6-(3,5-dimethylisoxazol-4-yl)-4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one (Example 2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][CH:3]=1.C(OCC)(=O)C>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:20])[CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(CCCC(=O)N1CCOCC1)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(CCC[C@H](O)c1ccc(F)cc1)N1CCOCC1

Procedure:
As per the present invention, the ketoreductase enzyme is dissolved in buffer and to this a solution of 1-(4-Fluoro-phenyl)-5-morpholin-4-yl-pentane-1,5-dione in an alcohol solvent such as methanol is added at a temperature of 20-40° C. for 15-40 hours and monitored by HPLC. To this immiscible organic solvent such as ethyl acetate is added and (S)-5-(4-Fluoro-phenyl)-5-hydroxy-1morpholin-4-yl-pentan-1-one is isolated from organic phase.
Reaction SMILES: [CH2:1]1[CH2:7][S:4](=[O:6])(=[O:5])[O:3][CH2:2]1.[CH3:8][C:9]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C1(C)C=CC=CC=1>[CH3:8][C:9]1([NH:15][CH2:2][CH2:1][CH2:7][S:4]([OH:3])(=[O:6])=[O:5])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=S1(=O)CCCO1
Reactant: CC1(N)CCCCC1
Solvent: Cc1ccccc1
Product: CC1(NCCCS(=O)(=O)O)CCCCC1
Temperature: 25 °C

Procedure:
A solution of 1,3-propanesultone (5.00 g, 40 mmol) in toluene (10 mL) was added dropwise to a the crude solution of 1-methyl-1-cyclohexylamine in MTBK (total volume 30 mL). The mixture was heated to reflux for 18 hours then cooled to room temperature. The solid was collected by suction filtration, rinsed with acetone (2×8 mL). The solid was dried overnight at 45° C. in the vacuum oven. The title compound was obtained as a fine white solid (9.22 g). However, the proton NMR and the ES-MS were not clean. The solid was suspended in methanol (45 mL) and the suspension was warmed to reflux. Water (12 mL) was added dropwise until a clear yellow solution was obtained. The mixture was slowly cool to room temperature with stirring. The solid was collected by suction-filtration, rinsed with methanol (2×5 mL). Another crop was collected from the filtrate. Both crops were dried overnight at 45° C. in the vacuum oven. The title compound was obtained as a fine white solid (6.82 g, 29.0 mmol, 66% overall yield). Both crops were identical and were mixed for submitting the compound. 1H NMR (500 MHz, D2O) δ 1.04-1.11 (m, 1H), 1.19 (s, 3H), 1.31 (q, J=12.2 Hz, 2H), 1.40 (qt, J=12.2 Hz, 2H), 1.46-1.62 (m, 2H), 1.63 (br d, J=11.7 Hz, 2H), 1.94 (q, J=7.3 Hz, 2H), 2.86 (t, J=7.1 Hz, 2H), 3.03 (t, J=7.6 Hz, 2H); 13C NMR (125 MHz, D2O) δ 19.1, 21.5, 22.0, 24.6, 34.1, 39.1, 48.2, 60.2; ES-MS 236 (M+H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1>C(O)=O>[CH:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: CCOC(=O)Cc1csc(=N)[nH]1
Solvent: O=CO
Product: CCOC(=O)Cc1csc(NC=O)n1
Reaction time: 1 h

Procedure:
To acetic anhydride (384 ml.) was added dropwise formic acid (169.2 ml.) over 15 to 20 minutes under cooling below 35° C., and the mixture was stirred for 1 hour at 55° to 60° C. To the mixture was added ethyl 2-(2-aminothiazol-4-yl)acetate, which can be represented as ethyl 2-(2-imino-2,3-dihydrothiazol-4-yl)acetate, (506 g.) over 15 to 20 minutes under ice-cooling and stirring, and then the mixture was stirred for 1 hour at room temperature. After the reaction, the solvents were distilled off. To the residue was added diisopropyl ether (2500 ml.), and the mixture was stirred for 1 hour at room temperature. The precipitates were collected by filtration, washed with diisopropyl ether and then dried to give ethyl 2-(2-formylaminothiazol-4-yl)acetate, which can be represented as ethyl 2-(2-formylimino-2,3-dihydrothiazol-4-yl)acetate, (451.6 g.), mp 125° to 126° C. The remaining filtrate was concentrated, and the residue was washed with diisopropyl ether (500 ml.) and then dried to give further the same object compound (78.5 g.).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13])[CH:7]=[CH:8][C:9]=1[OH:10].N[C@H](C(O)=O)C.B(O)(O)O.[C:27]([O:31][C:32](N=[N+]=[N-])=[O:33])([CH3:30])([CH3:29])[CH3:28]>O>[C:27]([O:31][C:32]([NH:13][C@H:12]([C:14]([OH:16])=[O:15])[CH2:11][C:6]1[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([OH:3])[CH:5]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: C[C@H](N)C(=O)O
Agent: OB(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-N aqueous sodium hydroxide is added in an argon atmosphere to a mixture of 100 g of 3-(3,4-dihydroxyphenyl)-L-alanine, 200 g of borax and 1000 ml of water, up to pH 9.5 (pH meter). A boric acid complex forms, in which the hydroxyl groups on the phenyl ring of the alanine derivative are esterified with boric acid. Half of the crude tertbutoxycarbonyl azide prepared from 120 g of tertbutoxycarbonyl hydrazide is then added in one portion, and the mixture is stirred at room temperature for 6 hours, the pH being held between 9.3 and 9.8 by the occasional addition of 2-N aqueous sodium hydroxide. The remaining tertbutoxycarbonyl azide is subsequently added and the mixture is stirred for a further 14 hours. After 14 hours, the pH falls to 8.5. It is then brought to pH 9.5 with 2-N aqueous sodium hydroxide, and the mixture is stirred for a further 2 hours. The mixture is then extracted twice with 300 ml of diethyl ether each time. The aqueous phase is brought to pH 2.5 with 10% aqueous citric acid solution, saturated with sodium chloride, and extracted twice with 300 ml of ethyl acetate each time. The combined organic extracts are washed 10 times with 500 ml of water each time, dried over sodium sulphate and then concentrated under vacuum. The glassy residue crystallizes on digesting with cyclohexane. After two recrystallizations from ethyl acetate/cyclohexane, there is obtained 100 g of N-(tertbutoxycarbonyl)-3-(3,4-dihydroxyphenyl)-L-alanine of melting point 148°C.; [α]D25 = +16.4° (c = 1%, methanol)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]=[C:26]=[O:27])[CH:20]=1>>[Br:18][C:19]1[CH:20]=[C:21]([NH:25][C:26]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:27])[CH:22]=[CH:23][CH:24]=1
Reactant: O=C=Nc1cccc(Br)c1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1cccc(Br)c1

Procedure:
Example 12 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-bromo-3-isocyanatobenzene (17.0 μl) to give the title compound (0.03 g). LC-MS (System A): Rt 2.50 mins, Mass Spectrum m/z 472 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]1([C:15]#[C:16][C:17]2[CH:31]=[CH:30][C:20]([C:21]([C:23]3[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=3)=[O:22])=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.CC(N(C)C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:26]2[CH:27]=[CH:28][C:23]([C:21]([C:20]3[CH:30]=[CH:31][C:17]([C:16]#[C:15][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:18][CH:19]=3)=[O:22])=[CH:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2ccc(C(=O)c3ccc(C#Cc4ccccc4)cc3)cc2)cc1
Temperature: 150 °C
Yield: 85 %

Procedure:
In a 250 mL flask equipped with nitrogen inlet, overhead stirring assembly, Dean-Stark trap, and reflux condenser were placed 4-aminophenol (5.46 g, 0.05 mol), 4-phenylethynyl-4'-fluorobenzophenone (15.02 g, 0.05 mol), potassium carbonate (7.6 g, 0.055 mol), toluene (20 mL), and DMAc (45 mL). The mixture was heated to 150° C. for 2 h, then cooled to room temperature. The reaction mixture was poured into water and the resulting light yellow powder was collected by filtration. Recrystallization from toluene afforded the desired product in 85% yield: m.p. 151°-153° C. IR (KBr); 3382 and 3314 cm-1 (NH2); 3049, 1599, and 1509 cm-1 (aromatic C--H); 2217 cm-1 (C=C); and 1645 cm-1 (C=O): Mass Spec. m/e (relative intensity): M+, 389.4 (100); FW=389.44 g/mol.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][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.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:38]([O:42][C:43]([NH:45][CH:46]1[CH2:51][CH2:50][CH2:49][CH:48]([C:52]([OH:54])=O)[CH2:47]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>ClCCl.C(OCC)(=O)C>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:52]([CH:48]1[CH2:49][CH2:50][CH2:51][CH:46]([NH:45][C:43]([O:42][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:44])[CH2:47]1)=[O:54])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NC1CCCC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCCC(C(=O)N(Cc2ccccc2)Cc2ccccc2)C1
Reaction time: 8 h
Yield: 91.4 %

Procedure:
A solution of dibenzylamine (0.448 g, 2.27 mmol) in dichloromethane (3 ml), 1-hydroxybenztriazole (0.337 g, 2.49 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (0.477 g, 2.49 mmol) were added to a solution of 3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid (0.502 g, 2.06 mmol) in dichloromethane (7 ml) and stirred overnight. The resulting solution was diluted with ethyl acetate and washed with a 5%-aqueous potassium hydrogensulfate solution (twice), a saturated aqueous sodium hydrogencarbonate solution (twice) and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by a silica gel chromatography (eluent: chloroform/ethyl acetate=20/1) to obtain tert-butyl 3-[(dibenzylamino)carbonyl]cyclohexanecarbamate (0.796 g, 91%).