Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1([O:32][CH3:33])[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@@H:22]([CH2:24]CS([O-])(=O)=O)[O:21][C:20]3=[O:30])=[CH:15][CH:14]=2)[CH2:9][CH:8]1[F:31]>CN(C)C=O>[CH3:5][O:6][C:7]1([O:32][CH3:33])[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:23][C@@H:22]([CH2:24][N:1]=[N+:2]=[N-:3])[O:21][C:20]3=[O:30])=[CH:17][CH:18]=2)[CH2:9][CH:8]1[F:31]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@@H](CCS(=O)(=O)[O-])OC3=O)cc2)CC1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(OC)CCN(c2ccc(N3C[C@@H](CN=[N+]=[N-])OC3=O)cc2)CC1F
Temperature: 70 °C
Yield: 78 %

Procedure:
The mixture of sodium azide (88.5 mmol) and (R)-{3-[4-(4,4-dimethoxy-3-fluoropiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-methanesulfonate (29.6 mmol) in dimethylformamide (75 ml) was heated at 70° C. for 14 hours. The reaction mixture was poured on ice cold water, and the solid was filtered to afford title compound in 78% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[N:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[CH2:11][CH2:10]3)=[O:7])=[CH:4][CH:3]=1.[CH2:19]=O.[Cl-].[CH3:22][NH:23][CH3:24]>C1C=CC=CC=1>[CH3:22][N:23]([CH2:19][CH:11]1[CH2:10][N:9]2[C:13](=[CH:14][CH:15]=[C:8]2[C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][CH:17]=2)[C:12]1=[O:16])[CH3:24]
Reactant: O=C1CCn2c1ccc2C(=O)c1ccc(Cl)cc1
Reactant: CNC
Reactant: C=O
Agent: [Cl-]
Solvent: c1ccccc1
Product: CN(C)CC1Cn2c(C(=O)c3ccc(Cl)cc3)ccc2C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 113.1 %

Procedure:
A mixture of 10 g compound (3), paraformaldehyde 1.6 g and dimethylamine chloride 4 g in 400 ml benzene was refluxed with stirring for 10 hours. After cooling to room temperature, the mixture was filtered by suction, a solid was obtained. The solid obtained was recrystallized from absolute ethanol, and 13.8 g of (4) was obtained as a white powder, mp 182°-183° C., yield 84%.
Reaction SMILES: [ClH:1].Cl.N[C@@H](CC)[C@H](O)[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7].[NH2:15][C@@H:16]([CH2:19][CH2:20][CH3:21])[CH2:17][OH:18].[N+](CCCC)#[C-:23]>>[ClH:1].[ClH:1].[NH2:15][C@@H:16]([CH2:19][CH2:20][CH3:21])[C@H:17]([OH:18])[C:6]([NH:8][CH2:9][CH2:11][CH2:10][CH3:23])=[O:7]
Reactant: CCC[C@H](N)CO
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: [C-]#[N+]CCCC
Agent: Cl
Product: CCCCNC(=O)[C@@H](O)[C@@H](N)CCC

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide dihydrochloride, Representative Procedure A, using (S)-2-aminopentan-1-ol in the first step (A1), and 1-isocyanobutane in the third step (A3).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].FC(F)(F)S(O[CH2:25][C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])(=O)=O>CN(C)C=O>[F:34][C:26]([F:35])([C:27]([F:32])([F:33])[C:28]([F:29])([F:31])[F:30])[CH2:25][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(Cc1ccc(C(F)(F)F)cc1)CC(F)(F)C(F)(F)C(F)(F)F
Yield: 8.1 %

Procedure:
Using 0.50 g of (4-(trifluoromethyl)benzyl)malononitrile, 5 ml of N,N-dimethylformamide, 59 mg of sodium hydride (60% in oil), and 0.77 g of 2,2,3,3,4,4,4-heptafluorobutyl trifluoromethanesulfonate, and according to the process described in the Production Example 1, there was obtained 73 mg of 2-(2,2,3,3,4,4,4-heptafluorobutyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (77)).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.Cl[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12].[Cl:17][C:18]([Cl:27])([Cl:26])[C:19]([C:21]1[NH:22][CH:23]=[CH:24][CH:25]=1)=[O:20].[Cl-].[Al+3].[Cl-].[Cl-]>C[N+]([O-])=O.C(Cl)Cl.O>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:15]([NH:14][S:11]([C:23]2[NH:22][C:21]([C:19](=[O:20])[C:18]([Cl:27])([Cl:26])[Cl:17])=[CH:25][CH:24]=2)(=[O:13])=[O:12])=[O:16])[N:3]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccc(C(=O)C(Cl)(Cl)Cl)[nH]2)n1
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 2.59 g (0.021 mol) of 2-amino-4,6-dimethylpyrimidine in 60 ml dry CH3NO2 at -10° was added dropwise, via syringe, under nitrogen, 2.0 ml (0.023 mole) of chlorosulfonyl isocyanate at such a rate to maintain the temperature below 5°. The resulting clear solution was stirred 0.5 hour at -5°, then treated dropwise with a solution of 4.46 g (0.021 mole) of 2-trichloroacetyl-1H-pyrrole in 30 ml dry CH3NO2. Upon completion of the addition, 2.95 g (0.022 mole) of aluminum (III) chloride was added in one portion and the reaction mixture stirred 1.5 hour at ambient temperatures followed by 0.5 hour under reflux. The cool solution was poured into H2O, diluted with CH2Cl2 and the layers separated. A precipitate was present in the aqueous layer and was collected by filtration and washed well with water. The organic solution was washed with H2O, dried over MgSO4, evaporated and triturated with CH2Cl2 to afford a second crop of product. Total yield of product was 2.45 g of a tan solid, m.p. 215°-218°(d). The infrared spectrum of the product included absorptions at 3230 (NH), 1692 (C=O), 1340 and 1160 cm-1 (SO2).
Reaction SMILES: [F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3]O.CCN(C(C)C)C(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[C:34]([S:53][CH2:54][C@@H:55]([C:57]([OH:59])=[O:58])[NH2:56])([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][NH:56][C@@H:55]([CH2:54][S:53][C:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:57]([OH:59])=[O:58]
Reactant: N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: OCC(F)(F)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a −78° C. methylene chloride solution (75 mL) of 2,2,3,3,3-pentafluoropropan-1-ol (1.5 g, 10.0 mmol) and DIPEA (6.1 mL, 35.0 mmol) was added triflic anhydride (1.78 mL, 10.5 mmol). After 2.5 h, S-tritylcysteine was added all at once and the reaction mixture was stirred at 0° C. for 80 min. The reaction mixture was stirred at RT for 18 h and then concentrated on the rotovap. Ethyl acetate was added and the reaction mixture was washed with 1N HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (3 hexanes/1 ethyl acetate+1% acetic acid) to provide 2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-tritylsulfanylpropionic acid (3.29 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:42][C:43]1[CH:47]=[C:46]([CH3:48])[O:45][N:44]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:31]([NH:42][C:43]2[CH:47]=[C:46]([CH3:48])[O:45][N:44]=2)=[O:33])=[CH:18][CH:17]=1
Reactant: Cc1cc(N)no1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4cc(C)on4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (40 mg) was dissolved in chloroform (1.2 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (20 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 5 min. Next, 3-amino-5-methylisoxazole (15 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was concentrated, and the residue was then purified by chromatography (chloroform:acetone=2:1) to give the title compound (20.0 mg, yield 35.2%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].Cl[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[C:30]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:31]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Reactant: ClCc1cncc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cncc(-c4ccccc4)c3)cc2)nc1OCC
Temperature: 80 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (700 mg), 3-chloromethyl-5-phenylpyridine (500 mg), potassium carbonate (500 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[4-(5-phenyl-3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (720 mg, yield: 67%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:11])([CH2:9][CH3:10])[CH2:7][CH3:8].C1COCC1.N[C@H]([C:21]([OH:23])=[O:22])C[SeH].[Li]CCCC.Cl>O.C(OCC)(=O)C>[C:21]([C:5]1[O:1][C:2]([C:6]([OH:11])([CH2:9][CH3:10])[CH2:7][CH3:8])=[CH:3][CH:4]=1)([OH:23])=[O:22]
Reactant: CCC(O)(CC)c1ccco1
Reactant: N[C@@H](C[SeH])C(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)(CC)c1ccc(C(=O)O)o1
Temperature: -78 °C
Yield: 71.7 %

Procedure:
3-(2-Furanyl)pentan-3-ol (3.0 g, 19 mmol) is added to THF (20 mL) under a nitrogen atmosphere. The solution is stirred and cooled to −78° C. Sec-BuLi (1.3 M in cyclohexane, 31 mL, 41 mmol) is added dropwise maintaining the temperature below −55° C. After complete addition, the ice bath is removed and the solution slowly warmed to room temperature where it is stirred for 18 hours. The mixture is cooled to 48° C. and CO2 gas is bubbled through the solution. A thick yellow past results and the temperature is increased to −10° C. Water (50 mL) is added and the solution is stirred at room temperature for 30 minutes. Ethyl acetate is added followed by water and the ph is adjusted to 1 with 1 N HCl. The organic layer is separated and the water layer was discarded. The organic layer is added to 1N NaOH solution and extracted. The pH of the water layer is adjusted to 1 with 1N HCl followed by addition of EtOAc. The organic layer is separated, dried over sodium sulfate, filtered, and evaporated under vacuum to give 2.7 grams of an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[C:24]([F:31])[CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:29])[NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[C:24]([F:31])[CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C(=O)O)c(F)c3)c2CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 3-tert-butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.1 g, 2.36 mmol) in DMF (7 mL), add tert-butylamine (12.05 g, 165.2 mmol), EDC (1.81 g, 9.44 mmol) and HOBt (1.44 g, 10.62 mmol) and stir in a sealed tube at 70° C. overnight. Dilute with EtOAc, wash with water, dry over anhydrous MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give 3-tert-butoxycarbonyl-6-(4-tert-butylcarbamoyl-3-fluorobenzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a clear oil. MS (APCI+) m/z: 421 (M+H)+. Use a method similar to the General Procedure 1-4 to give the title compound as a white powder. MS (APCI+) m/z: 421 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7]O.S(Cl)([Cl:15])=O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7][Cl:15]
Reactant: Cc1ccc([N+](=O)[O-])c(CO)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1ccc([N+](=O)[O-])c(CCl)c1
Reaction time: 18 h

Procedure:
The above reaction product obtained in step (a) is mixed with 600 ml of benzene and 60 ml of thionyl chloride, and left to stand for 18 hours at room temperature. The reaction solution is concentrated and subsequently partitioned between benzene and ice-water. After the organic phase is washed, dried and evaporated, the heading compound remains as an orange, semi-crystalline crude product, which is used in step (c) without further purification.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)C(C)C)(C)C.C[C:21]1[CH:25]=[CH:24][O:23][C:22]=1[CH2:26][C:27]([NH:29][C:30]1[N:35]=[CH:34][C:33]([C:36](Cl)=[O:37])=[CH:32][CH:31]=1)=[O:28]>C(Cl)Cl.O>[S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([C:36]([C:33]3[CH:32]=[CH:31][C:30]([NH:29][C:27]([C:26]4[CH:25]=[CH:24][O:23][C:22]=4[CH3:21])=[O:28])=[N:35][CH:34]=3)=[O:37])[C:4]=2[CH:3]=[CH:2]1
Reactant: c1cc2c(s1)CCCCN2
Reactant: Cc1ccoc1CC(=O)Nc1ccc(C(=O)Cl)cn1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1occc1C(=O)Nc1ccc(C(=O)N2CCCCc3sccc32)cn1

Procedure:
A solution of 2 mmol of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine, 5 mmol of N,N-diisopropylethylamine and 2.2 mmol of 6-[(3-methyl-2-furanylacetyl)amino]pyridine-3-carbonyl chloride in 10 ml of CH2Cl2 is stirred at room temperature for 16 hours. The mixture is diluted with 50 ml of CH2Cl2 and 25 ml of water and the organic layer separated. The organic layer is washed with H2O, 1N NaHCO3, brine and dried (Na2SO4). The solvent is removed and the residue is chromatographed on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[Cl:11][C:12]1[CH:13]=[C:14]([C@@H:18]2[C@@H:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:22]([CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[C:21](=[O:36])[C@:20]([CH2:38][C:39]#[N:40])([CH3:37])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1>CS(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([C@@H:18]2[C@@H:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:22]([CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[C:21](=[O:36])[C@:20]([CH2:38][C:39](=[N:2][OH:3])[NH2:40])([CH3:37])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC#N)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCC(CC)N1C(=O)[C@@](C)(CC(N)=NO)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 75 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 1.49 g (20.6 mmol) of hydroxylamine hydrochloride in DMSO (10 mL) was added 2.88 mL (20.6 mmol) of triethylamine. The slurry was stirred for 5 min and then filtered twice through cotton, rinsing with THF, to remove the solids. The filtrate was partially concentrated under reduced pressure to remove THF, and then was added to a flask containing 915 mg (2.06 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetonitrile (Example 82, Step B). The resulting yellow solution was heated at 75° C. for 22 h, and then was partitioned between water and EtOAc. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (1 to 7% MeOH/DCM, gradient elution) provided the title compound as a white solid.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[CH2:16][C@@H:15]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][N:13]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=O)=O)=CC=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.[K].O.C(OCC)(=O)C>CN(C)C=O>[C:25]([O:24][C:22]([N:13]1[CH2:14][C@H:15]([O:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:16][C@H:12]1[CH2:11][N:34]1[C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]2[C:30]1=[O:40])=[O:23])([CH3:26])([CH3:27])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OC(C)(C)C)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 70 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
To a solution of (2S,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol p-toluenesulfonate (20.78 g) in dimethylformamide (200 ml), potassium phthalimide (9.61 g) is added. The mixture is stirred at 70° C. for 3 hours. The reaction mixture is poured into a mixture of water and ethyl acetate. The organic layer is taken, successively washed with dilute aqueous sodium hydroxide and water, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by 5% wet silica gel column chromatography to give (2S,4R)-1-t-butoxycarbonyl-2-phthalimidomethyl-4-methanesulfonyloxypyrrolidine (11.17 g). Yield: 60%. Colorless foam. NMR δ(CDCl3) ppm: 1.33, 1.42(2×s, 9H), 2.0 to 2.55(m, 2H), 3.02(s, 3H), 3.4 to 4.6(m, 5H), 5.15 to 5.3(m, 1H), 7.6 to 7.95(m, 4H). IR ν (CHCl3) cm-1 : 1775, 1716, 1693.
Reaction SMILES: CS(C)=O.C(OC([NH:12][CH:13]1[C:17]2([CH2:19][CH2:18]2)[CH2:16][NH:15][CH2:14]1)=O)(C)(C)C.C(N(CC)CC)C.[NH2:27][C:28]1[CH:29]=[C:30]([N:36]2[C:45]3[C:40](=[CH:41][C:42]([F:47])=[C:43]([Cl:46])[N:44]=3)[C:39](=[O:48])[C:38]([C:49]([OH:51])=[O:50])=[CH:37]2)[C:31]([F:35])=[CH:32][C:33]=1[F:34]>C(OCC)C>[ClH:46].[NH2:27][C:28]1[CH:29]=[C:30]([N:36]2[C:45]3[C:40](=[CH:41][C:42]([F:47])=[C:43]([N:15]4[CH2:14][CH:13]([NH2:12])[C:17]5([CH2:18][CH2:19]5)[CH2:16]4)[N:44]=3)[C:39](=[O:48])[C:38]([C:49]([OH:51])=[O:50])=[CH:37]2)[C:31]([F:35])=[CH:32][C:33]=1[F:34]
Reactant: CC(C)(C)OC(=O)NC1CNCC12CC2
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)c(F)cc1F
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cl
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C5(CC5)C4)nc32)c(F)cc1F
Temperature: 80 °C
Yield: 46 %

Procedure:
To 2 ml of dimethylsulfoxide were added 173 mg of 7-tert-butyloxycarbonylamino-5-azaspiro[2.4]heptane B form and 164 mg of triethylamine. With heating and stirring at 80° C., 200 mg of 1-(3-amino-4,6-difluorophenyl)-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid was added to the solution, which was stirred at the temperature overnight. After the reaction solution was allowed to cool down, diethyl ether was added thereto. The diethyl ether layer was concentrated in vacua. The residue was combined with chloroform, washed with water, and dried over magnesium sulfate. The solvent was distilled off. Diethyl ether was added to the residue whereupon the solid was collected by filtration. To the solid were added 30 ml of chloroform and 5 ml of 4N hydrochloric acid/dioxane. After stirring at room temperature for 2 hours, the reaction solution was concentrated in vacua. Diethyl ether was added to the residue whereupon the solid was collected by filtration and washed with diethyl ether to give 120 mg of the title compound.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:14]=[C:15]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:16][O:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH:25]=1)[C:23]#[N:24]>C(#N)C>[C:23]([C:22]1[CH:21]=[N+:20]([O-:9])[CH:19]=[C:18]([O:17][CH2:16][C:15]2[CH:26]=[C:27]([F:29])[CH:28]=[C:13]([F:12])[CH:14]=2)[CH:25]=1)#[N:24]
Reactant: N#Cc1cncc(OCc2cc(F)cc(F)c2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC#N
Product: N#Cc1cc(OCc2cc(F)cc(F)c2)c[n+]([O-])c1
Reaction time: 20 h
Yield: 75.1 %

Procedure:
224 mg of m-CPBA is added at 0° C. to a solution in acetonitrile of 250 mg of 5-(3,5-difluorobenzyloxy)nicotinonitrile. The reaction medium is stirred for 20 hours while a precipitate is formed progressivelt. this solid is then filtered and washed to yield 200 mg (75%) of 3-cyano-5-(3,5-difluorobenzyloxyl)pyridine 1-oxide in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])/[C:5](=[N:13]\[OH:14])/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[C:21](OC(=O)C)(=[O:23])[CH3:22].C([O-])(O)=O.[Na+]>CCOCC>[C:21]([O:14]/[N:13]=[C:5](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])\[C:4]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:2]([Cl:1])[C:3]=1[OH:20])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(/C(=N\O)c2ccccc2F)c(O)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc(/C(=N\OC(C)=O)c2ccccc2F)c(O)c1Cl

Procedure:
E-3-chloro-2'-fluoro-2-hydroxy4-methoxybenzophenone oxime (18.1 g) is warmed at 60° C. for 30 minutes with 9 ml of acetic anhydride. The reaction mixture is distributed between ether and 10% NaHCO3 and washed with 10% NaHCO3 until the washes remained basic. Drying, evaporation and trituration with hexane gives E-3-chloro-2'-fluoro-2-hydroxy-4-methoxybenzophenone O-acetyl oxime, mp 125°-128° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].C(=O)(O)[O-].[Na+].Br[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([CH3:32])[CH3:31]>C(#N)C>[CH2:1]([N:3]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([CH3:32])[CH3:31])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=1)[OH:8])[CH3:2]
Reactant: CC(C)(F)CCCCBr
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN(CCCCC(C)(C)F)CCCC(O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
According to Procedure B (Example 17, Step IV), a stirred mixture of N-[4-[4-(ethylamino)-1-hydroxybutyl]phenyl]methanesulfonamide (Example 7, Step II) and sodium bicarbonate in acetonitrile was allowed to react with 1-bromo-5-fluoro-5-methylhexane (Step III) to give the titled product, a compound of Formula I'. The high resolution mass spectrum had M+ at m/z 402. Theory for C20H35FN2O3S: 402.2352; measured: 402.2350.