Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:18]=[C:19]([C:21]3[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=3)[S:20][C:13]=12.[NH4+].[Cl-]>CO.O.[Fe]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:18]=[C:19]([C:21]3[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=3)[S:20][C:13]=12
Reactant: Cn1cnc(-c2cc3nccc(Nc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Cn1cnc(-c2cc3nccc(Nc4ccc(N)cc4F)c3s2)c1
Temperature: 25 °C
Yield: 136.4 %

Procedure:
To a stirred suspension of nitro compound 338 (370 mg, 1.00 mmol) in a mixture of MeOH (20 mL) and water (10 mL) were added iron powder (280 mg, 5.01 mmol) and NH4Cl (107 mg, 2.00 mmol). The reaction mixture heated to reflux for 2 hrs, cooled down to room temperature, filtered through Celite, and rinsed with methanol. The filtrate was concentrated, diluted a bit with methanol, precipitated with AcOEt/hexanes to afford title compound 339 (463 mg, quantitative yield, ammonium salt) as a yellow solid. MS (m/z): 340.0 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH2:13]>>[CH2:2]([OH:1])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@H:7]([OH:8])[C:9]([C:11]([OH:13])=[O:12])=[O:10].[OH:12][CH2:11][C@@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: O
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 21 h

Procedure:
In the same manner as described in Example 3, the seed culture (200 ml) of the mixture of Gluconobacter suboxydans IFO 3255 and the strain DSM No. 4025 was inoculated into 3-L fermenter containing 8% D-sorbitol in the fermentation medium and the working volume was adjusted to 2 L with sterilized water. The fermentation was started under the same conditions as described in Example 3. Separately, a 500 ml medium bottle charged with 300 ml of feeding medium: 120 g of D-sorbitol, 10 g of yeast extract, 50 g of corn steep liquor, 0.172 g of KH2PO4, 1.72 g of urea (sterilized separately) and 2.5 g of antifoam, was prepared. During the fermentation, the above feeding medium was continuously fed to the fermenter at the rate of 15 ml/hr between the fermentation period of 12 and 18 hours, 60 ml/hr between that of 18 hours and 21 hours and 4.3 ml/hr between that of 21 hours and 28 hours by using a peristaltic pump. As a result, 224 g of 2-keto-L-gulonic acid was produced from 276 g of D-sorbitol at the conversion yield of 76.1 mol % in 51 hours fermentation.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[CH:6]1([P:12]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>O>[CH:25]1([P:12]([CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)[CH:13]2[CH2:14][CH2:15][CH:16]([C:19]3[CH:20]=[CH:21][C:22]([S:1]([OH:3])(=[O:5])=[O:2])=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=S(=O)(O)O
Reactant: c1ccc(C2CCC(P(C3CCCCC3)C3CCCCC3)CC2)cc1
Solvent: O
Product: O=S(=O)(O)c1ccc(C2CCC(P(C3CCCCC3)C3CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
Sulfuric acid (96 percent, 200 mL) is added slowly under nitrogen to dicyclohexyl(4-phenylcyclohexyl)phosphine (25 g; 70.2 mol), prepared above, at −70° C. The mixture is warmed to room temperature and stirred for 3 hrs. The reaction mixture is added carefully to 2 L of water purged with nitrogen and cooled to about +5° C. The water solution is extracted 4 times with methylene chloride (250 mL each, four times). The solid present initially in the water solution disappears during the course of extraction. Methylene chloride is evaporated, a white residue is dried in vacuum for 1 h to give 25.1 g (82%) of the product 4-[4-(dicyclohexylphosphino)cyclohexyl]benzenesulfonate in the acid form, Cy2PC6H10C6H4SO3H. 31P{1H} NMR (δ CD2Cl2, ppm): 13.07; 1H NMR (δ CD2Cl2, ppm): 1.2-2.2 (m, 31H, cyclohexyl), 2.60 (m, 1H, PhCH), 7.24 and 7.59 (dd, J=8.2 Hz, 4H, aromatic).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1.C(N(CC)CC)C>C(Cl)Cl.O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][CH:12]=2)[C:8]([NH:53][C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nccs1
Reactant: O=C(Cc1cccs1)Nc1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1cccs1)Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(2-thiophen-2-yl-acetylamino)-phenyl]-propionic acid (76.6 mg, 0.21 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (142.0 mg, 0.32 mmol) and 2-aminothiazole (32.1 mg, 0.32 mmol) in methylene chloride (1 mL) at 25° C. was treated with triethylamine (0.9 mL, 0.64 mmol). The reaction mixture was stirred at 25° C. for 16 h. This mixture was then poured into water (50 mL) and extracted with methylene chloride (2×25 mL). The combined organic extracts were washed with a 1N aqueous sodium hydroxide solution (1×25 mL), a 1N aqueous hydrochloric acid solution (1×25 mL), water (1×25 mL), and a saturated aqueous sodium chloride solution (3×25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-thiazol-2-yl-2-[4-(2-thiophen-2-yl-acetylamino)-phenyl]-propionamide (82.7 mg, 87.8%) as a tan solid: mp 220-221° C.; EI-HRMS m/e calcd for C23H25N3O2S2 (M+) 4391388, found 439.1379.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:18]2[C:26]([OH:27])=[C:25]([CH3:28])[C:24]([CH3:29])=[C:23]3[C:19]=2[CH2:20][CH2:21][CH2:22]3)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=[O:31].[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:18]2[C:26]([OH:27])=[C:25]([CH3:28])[C:24]([CH3:29])=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:31])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: O=[Cr](=O)([O-])Cl
Reactant: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(O)c(C)c(C)c2c1CCC2
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(O)c(C)c(C)c2c1CCC2=O
Reaction time: 23 h
Yield: 65.7 %

Procedure:
To a solution of methyl (R)-7-(4-fluorophenyl)-7-(5-hydroxy-6,7-dimethylindan-4-yl)heptanoate (16.0 g, 40.2 mmol) in toluene (640 ml) was added a mixture of pyridinium chlorochromate (43.3 g, 0.20 ml) and Celite (52 g) at 0° C. under argon atmosphere, followed by stirring for 23 hours at the same temperature. Insolubles were filtered and washed with toluene. The filtrate and washes were combined and concentrated. The residue was subjected to a silica gel column chromatography to give methyl (R)-7-(4-fluorophenyl)-7-(5-hydroxy-6,7-dimethyl-l-oxoindan-4-yl)heptanoate (10.9 g). The compound obtained is the same as Compound No. 15. Likewise, Compound 29 was prepared. Physico-chemical properties and spectral data are shown in [Table 6].
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([CH3:46])[CH:41]=2)[CH:35]=1)=[O:33])(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]2[CH2:17][CH2:18]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([CH3:46])[CH:41]=2)[CH:35]=1)=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC2CC2)c(C(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC4CC4)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-5-cyclopropylmethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J29) (260 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (325 mg, 74%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[NH2:14][CH2:15][C:16]1([NH2:20])[CH2:19][O:18][CH2:17]1.[S:21]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][NH:24][CH2:23][CH2:22]1>>[NH2:20][C:16]1([CH2:15][NH:14][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=3)[N:3]=[C:2]([N:24]3[CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[S:21][CH2:22][CH2:23]3)[N:11]=2)[CH2:19][O:18][CH2:17]1
Reactant: Clc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: NCC1(N)COC1
Reactant: c1ccc2c(c1)CNCCS2
Product: NC1(CNc2nc(N3CCSc4ccccc4C3)nc3ccc(Cl)cc23)COC1

Procedure:
The title compound was prepared in analogy to Example 57-1 in Scheme 23 by using 2,4,6-trichloroquinazoline, 3-(aminomethyl)oxetan-3-amine and 2,3,4,5-tetrahydro-1,4-benzothiazepine. MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.18 (s, 1 H), 7.97 (s, 1 H), 7.70 (s, 1 H), 7.51-7.44 (m, 2 H), 7.27-7.21 (m, 2 H), 7.16-7.12 (t, J=7.2 Hz, 1 H), 4.93 (s, 2 H), 4.50-4.35 (m, 5 H), 3.97-3.80 (m, 2 H), 2.96-2.87 (m, 2 H), 2.69-2.67 (m, 1 H), 2.35-2.33 (m, 1 H), 2.10 (s, 2 H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].[C:33]([NH2:37])(=[O:36])[CH:34]=[CH2:35]>C1(C)C=CC=CC=1>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:35][CH2:34][C:33](=[O:36])[NH2:37])[CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Reactant: C=CC(N)=O
Solvent: Cc1ccccc1
Product: NC(=O)CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (150 mg), acrylamide (24 mg) in toluene (1.5 ml) was stirred at room temperature for 1 hour and then was refluxed for 5 hours. After additional acrylamide (24 mg) was added, the whole mixture was refluxed for 3 hours and evaporated under reduced pressure. The obtained residue was purified by column chromatography on a silica gel eluting with a mixture of ethyl acetate and methanol (10:1) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(2-carbamoylethyl)-2-(1H-indol-3-yl-methyl)piperazine (89 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=2.[C:18]1([CH2:24][CH2:25][C:26]2[C:30]3[CH:31]=[CH:32][C:33](O)=[C:34]([CH2:35][CH2:36][CH3:37])[C:29]=3[O:28][N:27]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([CH2:24][CH2:25][C:26]2[C:30]3[CH:31]=[CH:32][C:33]([O:1][CH2:2][CH2:3][C:4]4[NH:5][C:6]5[C:11]([CH:12]=4)=[CH:10][C:9]([CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=5)=[C:34]([CH2:35][CH2:36][CH3:37])[C:29]=3[O:28][N:27]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)Cc1ccc2[nH]c(CCO)cc2c1
Reactant: CCCc1c(O)ccc2c(CCc3ccccc3)noc12
Product: CCCc1c(OCCc2cc3cc(CC(=O)O)ccc3[nH]2)ccc2c(CCc3ccccc3)noc12

Procedure:
Using the procedures in Example 1, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)indole-5-acetate and 3-(2-phenyl)ethyl-7-(n-propyl)-6-hydroxybenz[4,5]isoxazole as a slightly tan solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=[O:11])[CH:2]=1.[C:16](Cl)(=O)C(Cl)=O>C(Cl)Cl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([O:12][CH3:16])=[O:11])[CH:2]=1
Reactant: O=C(O)c1cccc(-c2cccnc2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 98.5 %

Procedure:
To a suspension of 3-(pyridin-3-yl)benzoic acid (0.8 g, 4 mmol) and N,N-dimethylformide (2 drops) in anhydrous methylene chloride (30 mL) was added oxalyl chloride (0.42 mL, 4.8 mmol) dropwise at 0° C. under argon. The mixture was stirred at RT for 3.5 hr and then concentrated. The yellow solid obtained was dissolved in anhydrous methanol (20 mL) at 0° C. After stirring at RT for 30 min, the mixture was concentrated. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, brine, and dried over anhydrous sodium sulfate. Concentration gave 0.84 g (99% yield) of methyl 3-(pyridin-3-yl)benzoate as a yellow solid. (M+H)+=214.16.
Reaction SMILES: F[C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:17][C:16]([C:18]([OH:20])=O)=[C:15]([CH3:21])[CH:14]=3)[CH:9]=[N:8]2)=CC=1.C1(CCN2C(=O)N(C3SC(C(O)=O)=C(C)C=3)C=N2)CC1.[NH2:44][CH2:45][C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1>>[CH:22]1([CH2:5][CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:17][C:16]([C:18]([NH:44][CH2:45][C:46]4[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=4)=[O:20])=[C:15]([CH3:21])[CH:14]=3)[CH:9]=[N:8]2)[CH2:23][CH2:2]1
Reactant: NCc1cccnc1
Reactant: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Agent: Cc1cc(-n2cnn(CCC3CC3)c2=O)sc1C(=O)O
Product: Cc1cc(-n2cnn(CCC3CC3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 87 %

Procedure:
Following the procedure as described in Example 31, making variations as required to replace 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid with 5-(1-(2-cyclopropylethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid to react with 3-(aminomethyl)-pyridine, the title compound was obtained as a colorless solid in 87% yield: mp 148-150° C.; 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.52 (s, 1H), 7.74 (s, 1 H), 7.69 (d, J=7.7 Hz, 1H), 7.27 (s, 1H), 6.87 (s, 1H), 6.44 (t, J=5.7 Hz, 1H), 4.60 (d, J=5.7 Hz, 2H), 3.91 (t, J=7.0 Hz, 2H), 2.50 (s, 3H), 1.70-1.61 (m, 2H), 0.75-0.60 (m, 1 H), 0.47-0.39 (m, 2H), 0.06-−0.02 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.6, 150.5, 149.2, 149.0, 140.8, 135.6, 134.7, 131.6, 125.0, 123.7, 119.9, 46.0, 41.4, 33.4, 16.0, 8.1, 4.0: MS (ES+) m/z 384.4 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[NH2:26][C@H](C(O)=O)C.CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1>>[C:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH2:26])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: C[C@H](N)C(=O)O
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(C)(C)OC(=O)N1CCC(N)C1

Procedure:
After 2.5 hours in reaction, 0.625 g of N-Boc-3-pyrrolidinone, 0.91 g of D-glucose, 1.8 g of L-alanine, and 3.3 mg of pyridoxal phosphate were added. Further, after five hours in reaction, 0.625 g of N-Boc-3-pyrrolidinone, 0.91 g of D-glucose, and 3.3 mg of pyridoxal phosphate were added. Furthermore, after nine hours in reaction, 0.25 g of N-Boc-3-pyrrolidinone, 0.36 g of D-glucose, 19 mg of NAD+, and 3.3 mg of pyridoxal phosphate were added. During the reaction, the reaction liquid was sampled. From the sample, N-Boc-3-aminopyrrolidine was extracted by the addition of ethyl acetate after basifying the sample with 6 N aqueous solution of sodium hydroxide. The amount of N-Boc-3-aminopyrrolidine produced was measured by analyzing N-Boc-3-aminopyrrolidine under the following GC conditions. Further, by the law of the art, N-Boc-3-aminopyrrolidine thus obtained was acted on by 3,5-dinitrobenzyl chloride to form a dinitrobenzyl derivative. After that, the dinitrobenzyl derivative was analyzed under the following HPLC conditions, whereby the optical purity thereof was measured. In the result, the amount of N-Boc-3-aminopyrrolidine produced after 23 hours in reaction was 2.14 g. The absolute configuration of N-Boc-3-aminopyrrolidine was (S), and the optical purity was 99.4% e.e.
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH:10][C:11]1[O:12][CH2:13][C:14]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=2[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]1([S:25](Cl)(=[O:27])=[O:26])[CH2:24][CH2:23]1>>[O:1]([CH2:8][CH2:9][NH:10][C:11]1[O:12][CH2:13][C:14]2[CH:20]=[C:19]([NH:21][S:25]([CH:22]3[CH2:24][CH2:23]3)(=[O:27])=[O:26])[CH:18]=[CH:17][C:15]=2[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2
Product: O=S(=O)(Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2)C1CC1
Yield: 72.3 %

Procedure:
Prepared from the above described N2-(2-phenoxy-ethyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (155 mg, 0.50 mmol, HPLC 0.691 min) and cyclopropanesulfonyl chloride (77 mg, 0.55 mmol) according to the procedure described for Example 27. Obtained the title compound as an off-white foam (140 mg, 73%, HPLC 1.261 min), MS (ISP) m/e=388.3 [(M+H)+].
Reaction SMILES: C1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12](O)=O)[CH:9]=CC=2OC(F)(F)F)CC1.[Cl:20][C:21]1[N:26]=[C:25]([C:27]([OH:29])=O)[CH:24]=[CH:23][C:22]=1[O:30][CH2:31][CH:32]1[CH2:34][CH2:33]1.CC1(C)COCN1>>[Cl:20][C:21]1[N:26]=[C:25]([C:27]([N:11]2[C:10]([CH3:12])([CH3:9])[CH2:4][O:5][CH2:6]2)=[O:29])[CH:24]=[CH:23][C:22]=1[O:30][CH2:31][CH:32]1[CH2:34][CH2:33]1
Reactant: O=C(O)c1ccc(OC(F)(F)F)c(OCC2CC2)n1
Reactant: O=C(O)c1ccc(OCC2CC2)c(Cl)n1
Agent: CC1(C)COCN1
Product: CC1(C)COCN1C(=O)c1ccc(OCC2CC2)c(Cl)n1

Procedure:
The title compound was synthesized in analogy to Example 47 b, using the mixture of 6-cyclopropylmethoxy-5-trifluoromethoxy-pyridine-2-carboxylic acid and 6-chloro-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 47 a, 50 mg, 180 μmol) and 4,4-dimethyl-oxazolidine (CAN 51200-87-4; 28.4 μl (75%), 198 μmol) as starting materials and isolated (13 mg, 23%) as colorless oil; LC-MS (UV peak area, ESI) 100%, 311.1158 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2S(C1C=CC(C)=CC=1)(=O)=O.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1[S:30](Cl)(=[O:32])=[O:31]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:30]([C:24]1[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=1[O:22][CH3:21])(=[O:32])=[O:31]
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)cccc32)cc1
Product: COc1ccc(C)cc1S(=O)(=O)n1ccc2c(Br)cccc21

Procedure:
The procedure for Intermediate 3 was followed using (2-methoxy-5-methylphenyl)sulfonyl chloride. Yield 1.4 g (72%). MS (ESI+) for C16H14BrNO3S m/z 382 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(O[CH:20](N(C)C)[N:21]([CH3:23])[CH3:22])(C)(C)C>CN(C=O)C>[CH3:20][N:21]([CH3:23])/[CH:22]=[CH:1]/[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1/C=C/N(C)C
Temperature: 143 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To Intermediate 3A (11.35 g, 58.2 mmol) in DMF (15 ml) was added 1-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (39.6 ml, 192 mmol). The mixture was heated at 143° C. for 3.0 h. DMF was removed by vacuum distillation at 70° C. to leave a semi solid. The semi-solid was triturated with EtOAc/hexanes (1:4) and stored at 4° C. overnight. The precipitate was collected by filtration to give Intermediate 3B (10.2 g, 40.8 mmol, 70.1% yield) as a dark solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.21 (d, J=2.20 Hz, 1H) 7.87 (d, J=8.79 Hz, 1H) 7.66 (dd, J=8.79, 2.20 Hz, 1H) 7.02 (d, J=13.19 Hz, 1H) 6.12 (d, J=13.74 Hz, 1H) 3.91 (s, 3H) 2.94 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)=[CH:9][C@H:8]([NH2:18])[CH2:7][N:6]1[CH3:19].[C:20]([N:27]1[CH:31]=[CH:30]N=[CH:28]1)(N1C=CN=C1)=[S:21].[CH2:32](NCC)C>>[Br:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)=[CH:9][C@H:8]([NH:18][C:20](=[S:21])[N:27]([CH2:31][CH3:30])[CH2:28][CH3:32])[CH2:7][N:6]1[CH3:19]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCNCC
Reactant: CN1C[C@@H](N)C=C2c3cccc4[nH]c(Br)c(c34)C[C@H]21
Product: CCN(CC)C(=S)N[C@H]1C=C2c3cccc4[nH]c(Br)c(c34)C[C@H]2N(C)C1

Procedure:
By reaction of 656 mg of 2-bromo-9,10-didehydro-6-methylergoline-8α-amine (1.5 mmol) with 1,1'-thiocarbonyldiimidazole and diethylamine, as described in Example 11, 535 mg of 3-(2-bromo-9,10-didehydro-6-methyl-8α-ergolinyl)-1,1-diethylthiourea is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[N:16]=[N:17][S:18][C:19]=2[CH2:20][O:21][Si](C(C)C)(C(C)C)C(C)C)[CH:5]=[CH:6][C:7]=1[F:8].CO.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[N:16]=[N:17][S:18][C:19]=2[CH2:20][OH:21])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)[Si](OCc1snnc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=c1onc(-c2nnsc2CO)n1-c1ccc(F)c(Cl)c1
Temperature: 70 °C
Yield: 87.9 %

Procedure:
Into a round bottom flask was added 4-(3-chloro-4-fluorophenyl)-3-(5-[(triisopropylsilyl)-oxy]methyl-1,2,3-thiadiazol-4-yl)-1,2,4-oxadiazol-5(4H)-one (89 mg, 0.18 mmol), anhydrous MeOH (1.5 mL), and hydrogen chloride in 1,4-dioxane (1.5 mL, 4.0 M). The reaction was heated to 70° C. for 2.5 h. The reaction was concentrated in vacuo and the crude purified by flash chromatography to give the desired product (52 mg, 86%). MF=C11H6ClFN4O3S; LCMS calculated for C11H7ClFN4O3S (M+H)+: m/z=329.0.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH3:11])[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=1.[CH3:16][N:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(O)(=O)/C=C/C(O)=O>>[CH2:10]([O:9][CH2:8][CH2:7][N:6]1[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=[C:2]1[N:20]1[CH2:21][CH2:22][CH2:23][N:17]([CH3:16])[CH2:18][CH2:19]1)[CH3:11]
Reactant: CN1CCCNCC1
Reactant: CCOCCn1c(Cl)nc2ccccc21
Agent: O=C(O)/C=C/C(=O)O
Product: CCOCCn1c(N2CCCN(C)CC2)nc2ccccc21

Procedure:
In the same manner as described in Example 1 using 2-chloro-1-[2-(ethoxy)ethyl]benzimidazole (3.00 g), N-methylhomopiperazine (3.10 g) and fumaric acid (2.63 g), ther are obtained crude crystals, which are recrystallized from ethyl acetate-ethanol to give 1-[2-(ethoxy)ethyl]-2-(4-methyl-1-homopiperazinyl)benzimidazole.difumarate (3.78 g) as colorless needles, m.p. 141°-143° C.