Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:12]=1[C:13]#[N:14].N1C=CC=CC=1.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[C:28]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:12]=1[C:13]#[N:14])(=[O:30])[CH3:29]
Reactant: N#Cc1c(OCCCCCCCCO)cccc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCCCCCCCOc1cccc([N+](=O)[O-])c1C#N
Temperature: 0 °C
Yield: 99.7 %

Procedure:
2-(8-hydroxyoctyloxy)-6-nitrobenzonitrile (804 μmol, 235 mg) (Example 274c) was dissolved in dry DCM (10 mL), cooled to 0° C., and treated successively with pyridine (3.216 mmol, 260 μL) and acetyl chloride (1.608 mmol, 114 μL). The reaction mixture was stirred and allowed to warm slowly to room temperature. When the reaction was complete, the volatiles were removed in vacuo and the crude product purified on silica gel (10% to 50% EtOAc in hexanes) to give the desired product (268 mg, 100%). MS 335 (MH+).
Reaction SMILES: [H-].[Na+].CC[O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:37]=O)[C:23]2[C:28]([C:29]=1[O:30]COC)=[C:27]([CH2:34][CH2:35][CH3:36])[CH:26]=[CH:25][CH:24]=2>CN(C)C=O.[Cl-].[Na+].O>[OH:30][C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[CH2:34][CH2:35][CH3:36])[C:22](/[CH:37]=[C:8](\[CH3:9])/[C:6]([OH:5])=[O:7])=[CH:21][C:20]=1[O:19][CH3:18]
Reactant: CCCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(O)c12
Temperature: 10 °C
Reaction time: 1 h
Yield: 115.7 %

Procedure:
45 g of 60% sodium hydride was suspended in 650 ml of N,N-dimethylformamide and cooled to 10° C. 355 g of triethyl 2-phosphonopropionate was added to the solution to make a clear solution. A solution of 270 g of 3-methoxy-4-methoxymethoxy-5-propyl-1-naphthalenecarbaldehyde in N,N-dimethylformamide (250 ml) was dropped in the solution and stirred at room temperature for 1 hour. The reaction mixture was poured into brine and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (8% ethyl acetate/hexane) to obtain 325.3 g of the titled compound as a pale yellow oil (containing a small amount of Z isomer).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]=O.[C:12]1([C:18]2[CH:19]=[C:20]([NH:23][C:24](=[O:30])[C@@H:25]([NH2:29])[CH2:26][CH2:27][CH3:28])[NH:21][N:22]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[C:12]1([C:18]2[CH:19]=[C:20]([NH:23][C:24](=[O:30])[C@@H:25]([NH:29][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH2:26][CH2:27][CH3:28])[NH:21][N:22]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCC[C@H](N)C(=O)Nc1cc(-c2ccccc2)n[nH]1
Reactant: O=CCc1cccc(F)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC[C@H](NCCc1cccc(F)c1F)C(=O)Nc1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-amino-5-phenyl pyrazole (31.2 mmol) was combined with (S)-2-tert-butoxycarbonylamino-pentanoic acid (37.5 mmol) and dissolved in 50 mL of anhydrous dichloromethane. Triethylamine (93.6 mmol) was added, followed by TBTU (37.5 mmol) and the reaction mixture was stirred at rt for 2 h. The solution was then diluted with 50 mL of fresh dichloromethane and extracted with 50 mL portions of aqueous saturated bicarbonate solution, water and then brine. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified through flash chromatography on silica gel. The purified product was then heated neat at 150° C. for 3 h. The reaction mixture (14.4 mmol) was then cooled to rt and dissolved in 40 mL of anhydrous 4.0 N HCl dioxane solution and stirred at rt for 3 h. The reactions were concentrated under reduced pressure and triturated with 20 mL of anhydrous Et2O. The solids were filtered and dried to give the desired amine, (S)-2-Amino-pentanoic acid (5-phenyl-2H-pyrazol-3-yl)-amide. 2-(2,3-Difluoro-phenyl)-acetaldehyde (0.2 mmol) was combined with (S)-2-Amino-pentanoic acid (5-phenyl-2H-pyrazol-3-yl)-amide (0.2 mmol) in 2 mL of anhydrous dichloromethane under N2. Sodium triacetoxyborohydride (0.3 mmol) and two drops of acetic acid were then added and the reaction was stirred at rt for 16 h. The crude solution was then concentrated under reduced pressure and purified through flash chromatography on silica gel to give 2-(S)-[2-(2,3-Difluoro-phenyl)-ethylamino]-pentanoic acid (5-phenyl-2H-pyrazol-3-yl)-amide, LC-MS 2.7 min, 398 [M+1].
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15](=[O:28])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=O)C.[Na+].[Cl-].[Mg+2].[Cl-]>CO>[CH3:1][O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:15](=[O:28])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
2 g of sodium 3-acetoxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate were dissolved in 20 ml of 50% v/v aqueous methanol, and 20 g of magnesium chloride were added to the resulting solution. The mixture was then stirred at 70° C. for 1 hour, after which it was treated as described in Example 2, to give 1.4 g of 3-methoxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylic acid, in the form of a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:42]1[N:43]=[C:44]([NH:47]C=O)[S:45][CH:46]=1)[C:12]([NH:14][CH:15]1[C:40](=[O:41])[N:17]2[C:18]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:19]([CH:22]=[CH2:23])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)(O)[O-].[Na+].C(OC(C)C)(C)C>CO.O>[NH2:47][C:44]1[S:45][CH:46]=[C:42]([C:11](=[N:10][O:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:12]([NH:14][CH:15]2[C:40](=[O:41])[N:17]3[C:18]([C:24]([O:26][CH:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:25])=[C:19]([CH:22]=[CH2:23])[CH2:20][S:21][C@H:16]23)=[O:13])[N:43]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CO
Solvent: O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.9 %

Procedure:
A mixture of benzhydryl 7-[2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (19.0 g) and conc. hydrochloric acid (11.6 g) in methanol (380 ml) was stirred at ambient temperature for 15 minutes. After addition of water (200 ml), the reaction mixture was neutralized with sodium bicarbonate, followed by removing the methanol under reduced pressure. The resultant aqueous solution was extracted three times with ethyl acetate, and the combined extract was washed with water and an aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. Removal of the solvent gave an oil, which was pulverized with diisopropyl ether to obtain benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (15.3 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]=[CH:13][N:14]([CH3:16])[CH3:15])(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+].CC([N-]C(C)C)C.CN([CH:28]=[O:29])C.CC(O)=O>C1COCC1.C(NC(C)C)(C)C.[Li]CCCC.O>[F:8][C:6]1[CH:5]=[C:4]([S:9]([N:12]=[CH:13][N:14]([CH3:16])[CH3:15])(=[O:10])=[O:11])[CH:3]=[C:2]([F:1])[C:7]=1[CH:28]=[O:29]
Reactant: CN(C)C=O
Reactant: CN(C)C=NS(=O)(=O)c1cc(F)cc(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CN(C)C=NS(=O)(=O)c1cc(F)c(C=O)c(F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To a solution of diisopropylamine (231 mL, 1.63 mmol, 2.1 eq) in THF (1 L) was slowly added BuLi (2.5M in Hex, 653 mL, 1.63 mmol, 2.1 eq) at 0° C. The solution was cooled to −78° C., and then a solution of N′-(3,5-difluorophenylsulfonyl)-N,N-dimethylformimidamide (193 g, 777 mmol) in THF (1 L) was added dropwise to the stirred LDA solution over 1 h at −78° C. and allowed to stir another 2 h at same temperature. To the reaction mixture was added anhyd DMF (72 mL, 932 mmol, 1.2 eq) and, 30 minutes later, was added AcOH (50 mL) and water. The reaction mixture was extracted with EtOAc (500 mL×3). The combined extracts were washed with brine (1 L), dried over MgSO4 and concentrated in vacuo to give N′-(3,5-difluoro-4-formylphenylsulfonyl)-N,N-dimethylformimidamide (171 g), which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1([CH:35]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:39]1([CH:35]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:36]([NH:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[O:37])[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)C(c3ccccc3)c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and diphenylacetyl chloride: ESMS m/e: 574.3 (M+H)+.
Reaction SMILES: C1C=CC2N([OH:10])N=NC=2C=1.[CH2:11]1[CH2:16][CH2:15][CH:14]([N:17]=[C:18]=[N:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:13][CH2:12]1>CN(C=O)C.C(OCC)(=O)C>[CH:20]1([NH:19][C:18]([NH:17][CH:14]2[CH2:13][CH2:12][CH2:11][CH2:16][CH2:15]2)=[O:10])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 8 h

Procedure:
ε-N-2ClZ-L-lysyl-L-aspartyl-β-benzyl ester-L-valyl-L-tyrosyl-O-benzyl ether-benzyl ester-3-thioamide (2 mmol) was dissolved in dry DMF (0.5 ml) at 0° C. under N2 and α-N-Boc-N-tosyl-L-arginine (2 mmol) was added to the solution with stirring. HOBt (2 mmol) and DCC (2 mmol) were added slowly at 0° C. and stirring was allowed to continue overnight. The mixture was diluted with 8 volumes of ethyl acetate and the N,N'-dicyclohexylurea so formed was filtered away from the solution. The filtrate was transferred to a separating funnel and washed successively with 5% aqueous sodium bicarbonate, 5% aqueous citric acid, and saturated brine. The organic phase was collected and dried over MgSO4, filtered, and concentrated in vacuo. The residue was purification by flash chromotography using 9:1 chloroform-methanol as an eluant to afford the α-N-Boc-N-tosyl-L-arginyl-ε-N-2ClZ-L-lysyl-L-aspartyl-β-benzyl ester-L-valyl-L-tyrosyl-O-benzyl ether-benzyl ester-4-thioamide in good yield (78%). The following physical characteristics were recorded for the compound: Melting point 105°-107° C.; IR (CHCl3) 1756, 1%90 cm-1UV (CHCl3) lambdamax 271. Elemental composition (C71H84Cl3N9O14S2): Theoretical: C, 58.13; H, 5.65; N, 8.34; S, 4.79. Found: C, 58.54; H, 5.81; N, 8.65; S, 4.40.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:26][C:27]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])([C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)[CH3:28].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:28][C:27]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])([C:29]1[CH:30]=[CH:31][C:32]([C:2]2[N:6]3[C:7]4[CH:19]=[CH:18][CH:17]=[N:16][C:8]=4[NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:5]3=[N:4][C:3]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:33][CH:34]=1)[CH3:26]
Reactant: Brc1c(-c2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2c(-c3ccccc3)nc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 80.2 %

Procedure:
A suspension of 3-bromo-2-phenyl-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepine (50 mg) and tert-butyl {1-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamate (93 mg) and potassium phosphate (82 mg) and PdCl2(dppf)CH2Cl2 (11 mg) in dioxane (2.5 mL) and H2O (0.25 mL) was degassed for 5 min then stirred at 80° C. for 18 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (0-50% ethyl acetate in hexanes) gave the product (56 mg, 80%). 1HNMR (DMSO-d6) 400 MHz δ: 8.54 (s, 1H), 8.09-8.00 (m, 1H), 7.95 (dd, 1H, J=7.8, 1.4 Hz), 7.55-7.48 (m, 2H), 7.38-7.32 (m, 3H), 7.31-7.19 (m, 5H), 7.17-7.07 (m, 3H), 6.91-6.77 (m, 1H), 6.70-6.59 (m, 1H), 1.50 (br s, 6H), 1.41-1.05 (m, 9H). LCMS: 544 [M+H].
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])=[CH:18][C:17]=1[F:30].O>CN(C)C(=O)C>[C:20]([C:19]1[CH:28]=[CH:29][C:16]([NH:15][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[C:17]([F:30])[CH:18]=1)(=[O:21])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1F
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2ccccc2)cc1F)C(F)(F)F
Temperature: -12.5 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (4.51 g) in N,N-dimethylacetamide (60 mL) at -20° C. was added thionyl chloride (3.39 g) and the mixture was allowed to stir at -10 to -15° C. for 1 hour. 4-Amino-3-fluorobenzophenone (4.00 g) was added in one portion and the reaction mixture was stirred at room temperature overnight. The mixture was poured into water and the aqueous solution was decanted. The remaining oily precipitate was dissolved in dichloromethane, dried, and evaporated to yield a tan solid. Recrystallization from dichloromethane and hexanes yielded the title compound as a white solid (5.43 g); mp 138-139° C.; MS: m/z=356(M+1); NMR: 1.62 (s,3), 7.56-7.64 (m,4), 7.70 (d,1, J=6.5), 7.75 (d,2, J=8.0), 7.82 (s,1), 8.01 (t,1, J=7.9), 9.39 (s,1). Analysis for C17H13F4NO3 : Calculated: C, 57.47; H, 3.69; N, 3.94; Found: C, 57.51; H, 3.60; N, 3.93.
Reaction SMILES: [C:1](N[C@H](C(O)=O)CS)(=O)[CH3:2].O.O.O.O.O.O.O.O.O.O.B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].C1([SeH-](C2C=CC=CC=2)=[Se])C=CC=CC=1.[O:63]1[CH:69]2[CH:64]1[C:65](=[O:74])[CH:66]1[CH:68]2[C:67]1([F:73])[C:70]([O-:72])=[O:71]>O.C(O)C.O.O1CCCC1>[F:73][C:67]1([C:70]([O:72][CH2:1][CH3:2])=[O:71])[CH:66]2[CH:68]1[CH:69]([OH:63])[CH2:64][C:65]2=[O:74]
Reactant: O=C1C2OC2C2C1C2(F)C(=O)[O-]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Agent: [Se]=[SeH-](c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C1(F)C2C(=O)CC(O)C21
Temperature: 38 °C
Reaction time: 12 h

Procedure:
Under a nitrogen atmosphere, 23.2 g of N-acetyl-L-cystein, 54.3 g of sodium tetraborate decahydrate and 0.7 g of diphenyldiselenide were suspended in 450 ml of a water-ethanol (1:1) mixture solution which had been deaerated. 9.5 g of (1RS,3RS,4RS,5SR,6RS)ethyl (3,4-epoxy-6-fluoro-2-oxobicyclo [3.1.0]hexane-6-carboxylate dissolved into 225 ml of tetrahydrofuran was added thereto, and this was stirred at room temperature for one day, at 38° C. for 12 hours, and at 85° C. for 5 hours. After the reaction solution was cooled down to room temperature, it was poured into water and extracted three times with diethyl ether. The obtained organic layers were consolidated and dried over anhydrous sodium sulfate. After filtering off the desiccant, concentration of the filtrate was carried out under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=3:1 to 1:1), yielding 3.9 g of (1RS,4SR,5SR,6RS)ethyl 6-fluoro-4-hydroxy-2-oxobicyclo[3.1.0]hexane-6-carboxylate. The proton NMR and mass spectrograph data are shown below.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[C:14]3[CH:13]=[CH:12][C:11]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:10][C:9]=3[NH:8][N:7]=2)=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35].O>CN(C)C=O>[CH:1]1([C:4]([C:6]2[C:14]3[CH:13]=[CH:12][C:11]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:10][C:9]=3[N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[N:7]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2)C1CC1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(C(=O)C2CC2)c2c1CC(c1ccccc1)(c1ccccc1)C=C2
Temperature: 20 °C
Yield: 70.9 %

Procedure:
A solution of 2.55 g of cyclopropyl(6,6-diphenyl-6,7-dihydro-1H-indazol-3-yl)methanone in 40 cm3 of dimethylformamide is added dropwise at a temperature in the region of 5° C. to a suspension, cooled to this same temperature, of 0.39 g of sodium hydride (at 60% in oil) in 20 cm3 of dimethylformamide. After stirring the mixture at this same temperature for about one and a half hours, a solution of 1.87 g of (2-chloromethoxyethyl)trimethylsilane in 20 cm3 of dimethylformamide is added dropwise without exceeding a temperature of 10° C. After warming to a temperature in the region of 20° C., the mixture is stirred for 2 hours at this same temperature. 20 cm3 of water are then added and the mixture is concentrated under reduced pressure (13 kPa). The residue is taken up in 80 cm3 of water and extracted three times with 60 cm3 of dichloromethane. The combined organic phases are dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. After flash chromatography on a column of silica [eluent: dichloromethane/methanol (99/1 by volume)], 2.5 g of cyclopropyl(6,6-diphenyl-1-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazol-3-yl)methanone are thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=2)[N:5]=[C:4]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)[N:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(O)CCC>[CH3:17][S:14]([C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[N:3]=[C:4]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[N:5]=2)[CH:13]=[CH:12][CH:11]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)c1cccc(-c2cc(Cl)nc(Nc3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: C1COCCN1
Solvent: CCCCO
Product: CS(=O)(=O)c1cccc(-c2cc(N3CCOCC3)nc(Nc3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
[4-Chloro-6-(3-methanesulfonyl-phenyl)-pyrimidin-2-yl]-(4-trifluoromethoxy-phenyl)-amine (0.14 g, 0.3 mmol) was reacted with morpholine (0.09 mL) in a solvent n-butanol (7 mL) at reflux temperature for 12 hours. Solid was filtered and dried to afford the desired compound.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1([F:25])[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1.IC>C1COCC1>[F:13][C:14]1([F:25])[CH2:15][CH2:16][C:17]([CH3:1])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: [Li]CCCC
Reactant: CCOC(=O)C1CCC(F)(F)CC1
Solvent: C1CCOC1
Solvent: CI
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(C)CCC(F)(F)CC1
Temperature: -78 °C
Yield: 107.6 %

Procedure:
A solution of n-butyl lithium (1.250 mL, 2.000 mmol) was added to a cold (−78° C.) solution of diisopropylamine (0.283 mL, 2.000 mmol) in THF under nitrogen and the mixture was stirred at −78° C. 1 h. A solution of ethyl 4,4-difluorocyclohexanecarboxylate (192 mg, 1 mmol) in THF (1 mL) was added at −78° C. The reaction mixture was stirred at −78° C. for 1 h and then gradually warm to −20° C. over 2 h. Then neat iodomethane (0.138 mL, 2.200 mmol) was added at −78° C. and the mixture was allowed to warm to rt and stirred at rt overnight. The reaction was quenched with satd. NH4Cl and extracted with EtOAc and the organic phase was washed with water, brine, dried (Na2SO4). Evaporation of the solvent afforded ethyl 4,4-difluoro-1-methylcyclohexanecarboxylate (222 mg) as a light brown oil which was dissolved in EtOH and was added a solution of KOH (112 mg, 2.000 mmol) in water (2.00 mL). The reaction mixture was heated to reflux overnight, then cooled and acidified and extracted with EtOAc to afford Cap-5 as a light brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 2.26-2.17 (m, 2H), 2.07-1.95 (m, 2H), 1.94-1.83 (m, 2H), 1.63-1.54 (m, 2H), 1.31 (s, 3H).
Reaction SMILES: C(=[N:14][CH:15]([C:17]1[C:18]([Cl:33])=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:21]=[CH:20]2)[CH3:16])(C1C=CC=CC=1)C1C=CC=CC=1.Cl.NO>CO>[NH2:14][CH:15]([C:17]1[C:18]([Cl:33])=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:21]=[CH:20]2)[CH3:16]
Reactant: CC(N=C(c1ccccc1)c1ccccc1)c1ccc2c(ccn2C(=O)OC(C)(C)C)c1Cl
Agent: Cl
Agent: NO
Solvent: CO
Product: CC(N)c1ccc2c(ccn2C(=O)OC(C)(C)C)c1Cl
Temperature: 40 °C
Reaction time: 16 h
Yield: 51.2 %

Procedure:
To a stirred solution of 324 (880.0 mg, 1.92 mmol) in anhydrous MeOH (20 mL) was added hydroxylamine hydrochloride (532.9 mg, 7.70 mmol), and the reaction mixture was stirred at 40° C. under N2 for 16 h. Volatile solvents were removed in vacuo, and the residue was diluted with EtOAc. The organic layer was washed with sat'd. aq. NaHCO3, water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/heptane gradient (20 to 100% EtOAc), followed a MeOH/EtOAc (+1% TEA) gradient (0 to 80% MeOH) to afford 290 mg (51.3%) of tert-butyl 5-(1-aminoethyl)-4-chloro-1H-indole-1-carboxylate (326) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J=8.7 Hz, 1H), 7.73 (d, J=3.7 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H), 6.71 (d, J=3.7 Hz, 1H), 4.49 (d, J=6.6 Hz, 1H), 2.36-1.90 (m, 2H), 1.63 (s, 9H), 1.26 (d, J=6.6 Hz, 3H).