Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]([C:10]1[C:18]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[OH:23])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:24](C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1O)(=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[OH-].[Na+].C(Br)C1C=CC=CC=1>[C:2]([C:10]1[C:18]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(O)c1C(=O)c1ccccc1
Agent: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(OCc2ccccc2)c1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-benzoyl-3-hydroxy-5-sulfamylbenzoic acid hemihydrate (3.21 g) in 0.50 N NaOH (40.0 ml), benzyl bromide (1.2 ml) is added and the mixture is stirred at room temperature for 5 hours. The mixture is left in a refrigerator for about 16 hours, and the separated sodium 4-benzoyl-3-benzyloxy-5-sulfamylbenzoate is collected by filtration and washed with a small amount of ice-cold water. The salt is dissolved in 1 N sodium hydroxide (30 ml) and the solution is added to ice-cold 1 N acetic acid (35 ml). The resulting precipitate is collected by filtration and washed with water. After drying in vacuo in the presence of P2O5, 4-benzoyl-3-benzyloxy-5-sulfamylbenzoic acid is obtained. The material is identical (IR, analysis) with the material prepared as in Example 40.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=2)=[CH:6][CH:7]=1.O.[NH2:22][NH2:23]>C(O)C>[CH3:18][Si:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][O:14][CH2:13][N:11]1[CH:12]=[C:8]([C:5]2[N:4]=[N:3][C:2]([NH:22][NH2:23])=[CH:7][CH:6]=2)[CH:9]=[N:10]1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccc(Cl)nn2)cn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(-c2ccc(NN)nn2)cn1
Temperature: 50 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
To a suspension of 3-chloro-6-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-pyridazine (640 mg, 2.06 mmol) in ethanol (5 mL) was added hydrazine monohydrate (1.34 mL, 1.4 g, 28 mmol). The reaction mixture was stirred at 50° C. for 18 h, then cooled to room temperature. The precipitate was collected via filtration, washed with cold ethanol and dried in vacuo to provide title compound as a white solid (500 mg, 1.6 mmol, 79% yield): 1H NMR (DMSO-d6) δ 0.00 (9H, s), 0.89 (2H, t), 3.61 (2H, t), 4.34 (2H, bs), 5.48 (2H, s), 7.09 (1H, d), 7.69 (1H, d), 7.94 (1H, bs), 8.08 (1H, s), 8.44 (1H, s); MS (m/z) 307 [M+H+]+.
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH2:10][CH:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:7]=1)=[O:4].[C:21](OC(=O)CC)(=O)CC>O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[CH:9]([CH3:11])[CH2:10][C:6]([NH:5][C:3](=[O:4])[CH2:2][CH3:21])=[N:7]2)=[CH:13][CH:14]=1
Reactant: CCC(=O)OC(=O)CC
Reactant: CC1CC(NC(=O)C(F)(F)F)=NN1c1ccc(F)cc1
Solvent: O
Product: CCC(=O)NC1=NN(c2ccc(F)cc2)C(C)C1
Reaction time: 2 h

Procedure:
A mixture of 3.0 g. of 3-amino-1-(p-fluorophenyl)-5-methyl-2-pyrazoline (prepared in Example 44) and 5.0 ml. of propionic anhydride is allowed to remain at room temperature for 2 hours. The reaction mixture is poured into water and the water is decanted. This step is repeated. The precipitate is treated with saturated sodium bicarbonate solution then is filtered. The solid is dissolved in dichloromethane. The solution is columnized and the desired product is recrystallized as described in Example 26 (A) to give 2.77 g. as colorless plates, m.p. 125°-126.5° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([CH:15]([CH2:20][CH2:21][CH2:22][CH3:23])[C:16]([O:18][CH3:19])=[O:17])[CH3:14].[CH2:24]=[O:25].[Cl-].[NH4+]>C1COCC1.CC(OC)(C)C>[CH2:13]([C:15]([CH2:24][OH:25])([CH2:20][CH2:21][CH2:22][CH3:23])[C:16]([O:18][CH3:19])=[O:17])[CH3:14]
Reactant: C=O
Reactant: CCCCC(CC)C(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCC(CC)(CO)C(=O)OC
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
47 ml (0.334 mol) of diisopropylamine are added dropwise at −20° C. to a solution of 118 ml (0.319 mol) of n-butyllithium (2.7 M in heptane) in 118 ml of THF, and the mixture is stirred at −20° C. for 30 min. Within approx. 15 min, 48 g (0.304 mol) of methyl 2-ethylhexanoate are added dropwise at −20° C., and the mixture is stirred at −20° C. for a further 30 min and subsequently admixed with 18 g (0.60 mol) of paraformaldehyde. After 30 min at −20° C., the mixture is stirred at 0° C. for 2 h. After addition of 100 ml of MTBE and 100 ml of saturated aqueous solution of ammonium chloride, the mixture is stirred at RT for 2 h. The organic phase is removed, the aqueous phase is re-extracted 1×with 100 ml of MTBE and the combined organic phases are concentrated on a rotary evaporator. The crude product (97% conversion based on methyl 2-ethylhexanoate) can be purified by distillation to obtain methyl 2-ethyl-2-hydroxymethylhexanoate (b.p.: 100° C., 6 mbar) in 91% yield with a purity of >99%.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[BH4-].[Na+].[CH2:9]([OH:21])[CH:10]([OH:20])[CH:11]([OH:19])[CH:12]([OH:18])[C:13]([C:15]([O-:17])=[O:16])=[O:14].[Na+]>CO>[CH2:9]([OH:21])[C@@H:10]([OH:20])[C@@H:11]([OH:19])[C@H:12]([OH:18])[C:13]([C:15]([OH:17])=[O:16])=[O:14]
Reactant: O=C([O-])C(=O)C(O)C(O)C(O)CO
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 10% aqueous solution of sodium 2,5-diketogluconate was adjusted to a pH of 6.1 by addition of sodium carbonate, methanol was added to give 50% by volume and the solution was cooled to between -15° C. and -25° C. One equivalent of sodium borohydride was added to the cooled solution which was stirred for six hours at -15° C. to -25° C. and at room temperature overnight. A mixture of sodium 2-ketogulonate and 2-ketogluconate was isolated by precipitation with methanol and filtration. Analysis of the methyl esters by liquid chromotography showed a 78:22 ratio of 2-ketogulonic acid to 2-ketogluconic acid in the product mixture.
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.[F:31][C:32]([F:37])([F:36])[CH2:33]NN>>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[CH:6]=[N:2][N:3]([CH2:33][C:32]([F:37])([F:36])[F:31])[C:4]=2[C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[CH:12][CH:11]=1
Reactant: NNCC(F)(F)F
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Product: FC(F)(F)Cn1ncc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting (2,2,2-trifluoro-ethyl)-hydrazine provided the title compound. MS: (M+H m/z=461.2).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[C:6]([CH3:21])[CH:5]=[C:4]([N+:22]([O-])=O)[N:3]=1.[NH4+].[Cl-].CO.C1COCC1>[Zn].CCOC(C)=O>[CH3:21][C:6]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[C:2]([CH3:1])[N:3]=[C:4]([NH2:22])[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])nc(C)c1Oc1ccnc(-c2cnn(C)c2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(N)nc(C)c1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 77.1 %

Procedure:
2,4-Dimethyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-nitropyridine (0.56 g, 1.8 mmol) and NH4Cl (2.76 g, 51.6 mmol) were combined in a solution of MeOH (8.6 mL) and THF (8.6 mL) and cooled to 0° C. Zinc powder (1.13 g, 17.2 mmol) was added portion-wise over 30 min and the reaction mixture was allowed to warm to RT and stirred vigorously for 12 h. EtOAc (100 mL) was added and the resultant suspension was filtered through a pad of diatomaceous earth. The filter cake was washed with EtOAc (3×10 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 4,6-dimethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (0.41 g, 81%) as a light red solid. MS (ESI) m/z: 296.1 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:10]2[C:11]3[C:12](=[N:24][NH:25][N:26]=2)[CH:13]=[C:14]([CH2:19][C:20]([NH:22][CH3:23])=[O:21])[C:15]=3[CH2:16][S:17][N:18]=1.Cl.[Cl:28][C:29]1[C:30]([CH2:38]Cl)=[N:31][CH:32]=[C:33]([CH3:37])[C:34]=1[O:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:8][C:9]1[C:10]2[C:11]3[C:12](=[N:24][N:25]([CH2:38][C:30]4[C:29]([Cl:28])=[C:34]([O:35][CH3:36])[C:33]([CH3:37])=[CH:32][N:31]=4)[N:26]=2)[CH:13]=[C:14]([CH2:19][C:20]([NH:22][CH3:23])=[O:21])[C:15]=3[CH2:16][S:17][N:18]=1
Reactant: COc1c(C)cnc(CCl)c1Cl
Reactant: CNC(=O)Cc1cc2n[nH]nc3c-2c1CSN=C3N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)Cc1cc2nn(Cc3ncc(C)c(OC)c3Cl)nc3c-2c1CSN=C3N
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 84.4 %

Procedure:
Dimethylformamide (1 ml) was added to 2-(4-amino-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl)-N-methylacetamide trifluoroacetate (28 mg), 3-chloro-2-(chloromethyl)-4-methoxy-5-methylpyridine hydrochloride (36 mg), and potassium carbonate (69 mg). The resulting mixture was stirred at 60° C. for 2.5 hours. Thereafter, the insoluble matter was removed by filtration, and the solvent was then distilled away in a nitrogen stream. The resulting residue was dissolved in dimethyl sulfoxide (1 ml), and it was then purified by preparatory reverse-phase HPLC. The solvent was distilled away under reduced pressure, so as to obtain the title compound (27.0 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]([OH:13])=O)[C:7](=[O:20])[CH:6]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:48][C:49]1[CH:53]=[CH:52][N:51]([CH2:54][C:55]([CH3:58])([OH:57])[CH3:56])[N:50]=1>ClCCl>[Cl:1][C:2]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]([NH:48][C:49]2[CH:53]=[CH:52][N:51]([CH2:54][C:55]([OH:57])([CH3:56])[CH3:58])[N:50]=2)=[O:13])[C:7](=[O:20])[CH:6]=1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: COc1cccc(OC2=CC(=O)N([C@@H](CC3CCCC3)C(=O)O)C2)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cccc(OC2=CC(=O)N([C@@H](CC3CCCC3)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
A solution of (S)-2-[4-(2-chloro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclopentyl-propionic acid (200 mg, 0.53 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (90 mg, 0.58 mmol) and 1-hydroxybenzotriazole (75 mg, 0.55 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 94 mg, 0.61 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 10% methanol/dichloromethane) to afford (S)-2-[4-(2-chloro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (147 mg, 54%) as a light yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (br. s., 3H) 1.06 (br. s., 3H) 1.08-1.95 (m, 11H) 3.89 (br. s., 2H) 3.90 (s, 3H) 4.21 (d, J=18.4 Hz, 1H) 4.59 (d, J=18.4 Hz, 1H) 4.67 (s, 1H) 4.80 (s, 1H) 4.81-4.87 (m, 1H) 6.45 (d, J=2.1 Hz, 1H) 7.09 (d, J=8.2 Hz, 1H) 7.13 (d, J=8.5 Hz, 1H) 7.41 (t, J=8.5 Hz, 1H) 7.53 (d, J=2.1 Hz, 1H) 10.80 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:10]([C:12]3[C:16]4=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=[C:15]4[N:14]([CH3:25])[CH:13]=3)=[CH:11][C:4]=12.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1>>[CH3:24][O:23][C:18]1[N:17]=[C:16]2[C:12]([C:10]3[N:9]([S:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:5]4=[N:6][CH:7]=[CH:8][C:3]([CH2:2][NH:36][CH:37]5[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]5)=[C:4]4[CH:11]=3)=[CH:13][N:14]([CH3:25])[C:15]2=[CH:20][C:19]=1[O:21][CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CCl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CCN(C(=O)OC(C)(C)C)CC4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Yield: 40.6 %

Procedure:
The product is prepared by following the procedure described in example 52c, starting with 0.3 g of 3-[4-chloromethyl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridine and 0.253 g of 4-amino-1-Boc-piperidine instead of the N-Boc-ethylenediamine used in example 52c. 0.161 g of tert-butyl 4-{[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}piperidine-1-carboxylate is obtained with the following characteristics:
Reaction SMILES: [CH3:1]O.S(=O)(=O)(O)O.[CH2:8]([C@H:11]1[CH2:16][CH2:15][C@H:14]([C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)[CH2:9][CH3:10].O>C1(C)C=CC=CC=1>[CH3:1][O:24][C:23]([C@H:20]1[CH2:21][CH2:22][C@H:17]([C@H:14]2[CH2:15][CH2:16][C@H:11]([CH2:8][CH2:9][CH3:10])[CH2:12][CH2:13]2)[CH2:18][CH2:19]1)=[O:25]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)O)CC2)CC1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)OC)CC2)CC1

Procedure:
Methyl alcohol (200 ml) and conc. sulfuric acid (15 ml) were added to trans-4-(trans-4'-propylcyclohexyl)cyclohexanecarboxylic acid (68.2 g, 0.27 mol) and the mixture was heated under reflux for 4 hours, followed by cooling, adding water (200 ml) and toluene (100 ml), transferring the resulting mixture to a separating funnel, three times washing the toluene layer with water (each time 100 ml), distilling off toluene, adding ethyl alcohol (40 ml) to the residue, recrystallizing, filtering off and drying to obtain the objective trans-4-(trans-4'-propylcyclohexyl)cyclohexanecarboxylic acid methyl ester (65 g) (yield: 90.2%).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[N:9]([C@@H:10]2[O:22][C@H:21]([CH2:23][O:24]C(=O)C)[C@@H:16]([O:17]C(=O)C)[C@H:11]2[O:12]C(=O)C)[CH:8]=[N:7][C:6]=1[C:28]([NH2:30])=[O:29].N>CO>[C:4]([C:5]1[N:9]([C@@H:10]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:16]([OH:17])[C@H:11]2[OH:12])[CH:8]=[N:7][C:6]=1[C:28]([NH2:30])=[O:29])#[CH:3]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(N)=O)c2C#C[Si](C)(C)C)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: C#Cc1c(C(N)=O)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 8 h
Yield: 87.1 %

Procedure:
400 mg of the glutinous substance obtained in (1) was added to a solvent mixture of aqueous ammonia and methanol and, after the mixture was left to stand overnight, the solvent was evaporated. The residue obtained was adsorbed onto a silica gel column (2.3×13 cm), eluted with a 5-10% ethanol-chloroform solvent mixture and crystallized from ethanol to obtain 200 mg of white crystals (yield: 87.1%).
Reaction SMILES: Cl.[NH2:2]O.[CH2:4]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][C@@H:12]1[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[OH-].[Na+].C(O)C>[CH2:4]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][C@@H:12]1[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:2])=[CH:26][CH:25]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1ccc([C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc([C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)cc1
Reaction time: 2 h
Yield: 64.1 %

Procedure:
Hydroxylamine hydrochloride (0.5 g, 7.75 mmol) was added to a solution of 4-((2S)-1,4-dibenzylpiperazin-2-yl)benzaldehyde (2.2 g, 5.94 mmol) in 1N aqueous sodium hydroxide (10 ml) and ethanol (10 ml) at room temperature and stirred for 2 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in acetic acid (10 ml) and was stirred at 80° C. for 6 hours. The solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous sodium bicarbonate and chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 5-10% methanol in chloroform to furnish 4-((2S)-1,4-dibenzylpiperazin-2-yl)benzonitrile (1.4 g, 64%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:10][CH2:11][OH:12])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:40]([O:42][C:43](=[O:56])[CH:44]([O:53][CH2:54][CH3:55])[CH2:45][C:46]1[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=1)[CH3:41].CCOC(/N=N/C(OCC)=O)=O>>[CH2:40]([O:42][C:43](=[O:56])[CH:44]([O:53][CH2:54][CH3:55])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:12][CH2:11][CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:48][CH:47]=1)[CH3:41]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: COc1ccc(C(=CCO)c2ccc(OC)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCC=C(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1)OCC
Yield: 22.9 %

Procedure:
Reaction of 3,3-bis(4-methoxy-phenyl)-prop-2-en-1-ol (216 mg, 0.8 mmol), triphenylphosphine (240 mg, 0.9 mmol), 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (240 mg, 1.0 mmol) and diethylazodicarboxylate (0.11 mL, 0.9 mmol) in an identical manner to Example 1 gave the title compound (90 mg).
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ClC1C(C([N:57]2[CH2:62][CH2:61][C:60]([C:83]3[CH:88]=[CH:87][CH:86]=[C:85](F)[CH:84]=3)([CH2:63][CH2:64][N:65]3[CH:70]4[CH2:71][CH2:72][CH:66]3[CH2:67][CH:68]([N:73]3[C:77]5[CH:78]=[CH:79][CH:80]=[CH:81][C:76]=5[N:75]=[C:74]3[CH3:82])[CH2:69]4)[CH2:59][CH2:58]2)=O)=C(Cl)C=CC=1S(NC)(=O)=O>>[F:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[C:5]([C:12]([N:57]2[CH2:58][CH2:59][C:60]([CH2:63][CH2:64][N:65]3[CH:66]4[CH2:72][CH2:71][CH:70]3[CH2:69][CH:68]([N:73]3[C:77]5[CH:78]=[CH:79][CH:80]=[CH:81][C:76]=5[N:75]=[C:74]3[CH3:82])[CH2:67]4)([C:83]3[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=3)[CH2:61][CH2:62]2)=[O:14])=[CH:4][CH:3]=1
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3cccc(F)c3)CC2)c1Cl
Reactant: O=C(O)c1ccc(F)c2[nH]c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccc(F)c3[nH]c(=O)oc23)CC1
Yield: 17 %

Procedure:
Prepared from a mixture of 4-fluoro-2-oxo-2,3-dihydro-1,3-benzoxazole-7-carboxylic acid (9.8 mg, 0.05 mmol, 1 equiv), endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride (25 mg, 0.05 mmol, 1 equiv), DIEA (36 μL, 0.2 mmol, 4 equiv) and HATU (19 mg, 0.05 mmol, 1 equiv) following the general procedure for 2,4-dichloro-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-N-methylbenzenesulfonamide (example 880). The crude product was purified by prep HPLC (HPLC Method C) to provide 4-fluoro-7-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl-1-piperidinyl)carbonyl]-1,3-benzoxazol-2(3H)-one as a white solid (5 mg, 17% yield).
Reaction SMILES: C([Zn][CH2:4][CH3:5])C.[CH2:6]([O:8][C:9]([C:11]1[S:12][C:13](SC)=[C:14]([C:23]#[N:24])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=1)=[O:10])[CH3:7]>C1COCC1.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:6]([O:8][C:9]([C:11]1[S:12][C:13]([CH2:4][CH3:5])=[C:14]([C:23]#[N:24])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=1)=[O:10])[CH3:7]
Reactant: CC[Zn]CC
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(I)cc1
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(CC)c(C#N)c1-c1ccc(I)cc1
Temperature: 60 °C
Yield: 60 %

Procedure:
Add dropwise diethylzinc (1.0M in hexanes, 7 ml, 6.99 mmol, 3 eq) to a mechanically stirring suspension of 4-cyano-3-(4-iodo-phenyl)-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester (1 gr, 2.33 mmol) and 1,3-bis-(diphenylphosphino)propane nickel (II) chloride (24 mg, 0.0466 mmol, 0.02 eq) in dry THF (12 ml) and heat the resulting mixture 60° C. for 30 min. Cool the reaction to room temperature and remove solvents in vacuo. Purify the solid by chromatography on silica gel (eluting with 10-80% Ethyl acetate/hexane) to provide the title compound in 60% yield: Mass spectrum (EI+): m/z 412 (M++1); 1H NMR (CDCl3, 200 MHz): δ 7.72 (d, 2H, J=8.5); 7.05 (d, 2H, J=8.5); 4.14 (q, 2H, J=7.2); 3.01 (q, 2H, J=7.2); 1.36 (t, 3H, J=7.5); 1.17 (t, 3H, J=7.2).
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].C1(C)C=CC=CC=1.Cl>[Cl-].C[N+](C)(C)CCCCCCCCCCCCCCCC.CC(C)=O>[O:8]=[C:7]1[O:9][C@H:3]([C@H:2]([CH2:1][OH:13])[OH:12])[C:4]([OH:10])=[C:5]1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 2-keto-L-gulonic acid (250 g, content: 89.6%, water: 8.6%) and trimethylcetylammonium chloride (0.275 g) was stirred in a mixed solvent of toluene (960 ml) and acetone (24 ml), and 35% conc. hydrochloric acid (30.0 g) was added. This mixture was stirred at 60° C. for 1 hour, a solution of hydrogen chloride gas (30.0 g) in acetone (116 g) was added, and the mixture was stirred at the same temperature for 5 hours. Then, about 1200 g of the solvent was distilled away under reduced pressure while continuously introducing toluene (850 ml). The residue was filtered to give crude crystals of L-ascorbic acid. The crude crystals were dissolved in water. Quantitative analysis of the solution by HPLC showed that the solution contained L-ascorbic acid (190.0 g, yield: 93.5%) and 2-keto-L-gulonic acid (2.7 g, residual ratio: 1.2%).