Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)N.[CH:6]([C:8]1[CH:37]=[CH:36][CH:35]=[CH:34][C:9]=1[O:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:33])[CH2:18][NH:19][C:20]([C:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:24][N:23]=2)=[O:21])[CH2:13][CH2:12]1)=[O:7].Cl([O-])=[O:39].[Na+].O>CC(C)=O>[C:27]1([C:25]2[NH:24][N:23]=[C:22]([C:20]([NH:19][CH2:18][C:17]([N:14]3[CH2:15][CH2:16][CH:11]([O:10][C:9]4[CH:34]=[CH:35][CH:36]=[CH:37][C:8]=4[C:6]([OH:39])=[O:7])[CH2:12][CH2:13]3)=[O:33])=[O:21])[CH:26]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=Cc1ccccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reactant: [O-][Cl+][O-]
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2C(=O)O)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 0.03 h
Yield: 53.5 %

Procedure:
Sulphamic acid (34 mg, 0.3 mmol) was added to stirred a mixture of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-formyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide (50 mg, 0.1 mmol) in acetone (1 mL). After 2 minutes, sodium chlorite (36 mg, 0.4 mmol) was added and the resulting mixture was stirred at ambient temperature for 1 hour. Water was added and the solid obtained was isolated by filtration to afford 24 mg (53% yield) of 2-(1-{2-[(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-piperidin-4-yloxy)-benzoic acid. LC/MS [M+H]+: 449.17, 90.6%, 1H NMR (300 MHz, DMSO-d6): δ13.8 (b, 1H), 12.8 (b, 1H), 8.1 (m, 1H), 7.8 (m, 2H), 7.6 (m, 1H), 7.5 (m, 3H), 7.4 (m, 1H), 7.2 (m, 1H), 7.1 (m, 1H), 7.0 (m, 1H), 4.8 (m, 1H), 4.2 (m, 2H), 3.7 (m, 3H), 3.5 (m, 1H), 2.0 (m, 1H), 1.7 (m, 3H).
Reaction SMILES: [CH2:1]([C:3]1[S:17][C:6]2[S:7][CH2:8][CH2:9][CH:10]3[CH2:15][C:14](=[O:16])[NH:13][N:12]=[C:11]3[C:5]=2[CH:4]=1)[CH3:2].BrBr>C(O)(=O)C>[CH2:1]([C:3]1[S:17][C:6]2[S:7][CH2:8][CH2:9][C:10]3[C:11](=[N:12][NH:13][C:14](=[O:16])[CH:15]=3)[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(s1)SCCC1CC(=O)NN=C21
Agent: BrBr
Solvent: CC(=O)O
Product: CCc1cc2c(s1)SCCc1cc(=O)[nH]nc1-2
Reaction time: 0.25 h
Yield: 49 %

Procedure:
To a solution of 3.7 g of 9-ethyl-4,4a,5,6-tetrahydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one in 40 ml of acetic acid is added dropwise a solution of 2.3 g of bromine in 10 ml of acetic acid with stirring for 15 minutes at 45°-50° C. and the mixture is stirred for 30 minutes at the same temperature. Then, the mixture is poured into ice-cold water and the precipitated crystals are collected by filtration and washed with water. The resulting crude crystals are dissolved in chloroform, subjected to column chromatography on silica gel and eluted with a mixed solvent of chloroform and ethanol (100:0.5). The crystals obtained from the fraction are recrystallized from a mixed solvent of chloroform and ethanol to give 1.8 g of 9-ethyl-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as white crystals, melting at 256°-258° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1.[I:21]I.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CCCCCC.C1COCC1.O>[F:13][C:14]1[C:19]([I:21])=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1
Reactant: Cc1ccc(F)nc1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cnc(F)c(I)c1
Temperature: -18 °C
Reaction time: 0.33 h
Yield: 84.5 %

Procedure:
Diisopropylamine (92 mL) was added to THF (1.2 L), and the mixture was cooled to −18° C. in a nitrogen atmosphere. A 2.69 M solution of n-butyllithium in hexane (224 mL) was added dropwise to the solution. After completion of the dropwise addition, the mixture was warmed to −5° C. with stirring over 20 minutes. The reaction mixture was cooled to −73° C. A solution of 2-fluoro-5-methylpyridine (61 g) in THF (240 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at −75° C. for 3.5 hours. A solution of iodine (139 g) in THF (24 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at −75° C. for one hour and 55 minutes. After completion of the reaction, water (220 mL) was added to the reaction mixture at the same temperature. The mixture was stirred at the same temperature for five minutes. The reaction mixture was returned to room temperature, and water (1.2 L) was then added. A solution of sodium thiosulfate pentahydrate (136 g) in water (300 mL), and water (300 mL) were added to the mixture, followed by stirring for 10 minutes. The mixture was extracted with MTBE (1.2 L). The organic layer was washed with brine (500 mL). The combined aqueous layers were extracted with MTBE (1 L). The combined organic layers were dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. n-heptane was added to the residue, followed by cooling. The precipitated solid was collected by filtration. The residue was washed with n-heptane. The filtrate was cooled, and the precipitated solid was collected by filtration. This operation was repeated five times to give the title compound (109.69 g).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([OH:27])=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[C:8]([S:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[OH:37]O.Cl>C(O)(=O)C.O.CCOC(C)=O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:18]([C:25]([OH:27])=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)[C:8]([S:28]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)=[O:37])=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(SCc2ccc(Cl)cc2)n1Cc1ccc(OC(C(=O)O)c2ccccc2)cc1
Reactant: OO
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCCc1nnc(S(=O)Cc2ccc(Cl)cc2)n1Cc1ccc(OC(C(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
To a stirred solution of 60 mg (0.11 mmol) of 3-butyl-4-[[4-[1-carboxy-1-phenylmethoxy]phenyl]methyl]-5-(4-chlorobenzylthio) -4H-1,2,4-triazole from (Example 5) in 0.75 ml of glacial acetic acid was added gradually 0.75 ml of 30% hydrogen peroxide in H2O. The solution became turbid during the addition but largely clarified within a few minutes. After adding an additional 4 drops of acetic acid, the mixture was stirred at room temperature in a stoppered flask for 16 hours. It was then diluted with 50 ml of EtOAc and shaken with 50 ml of dilute HCl (pH 2.5). The aqueous phase was extracted with an additional 3 portions of EtOAc. The combined EtOAc fractions were washed once with dilute HCl (pH 2), then dried (MgSO4), filtered, and concentrated. Trituration of the residue with Et2O gave a gum. Upon decantation of the Et2O and drying in vacuo, 31 mg (51%) of the title compound was obtained as a stiff foam, mp 76°-78° C. dec.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:41]([NH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:42][CH2:43][CH2:44][CH3:45]>>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][CH:13]([C:14]([N:46]([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: CCCCCNCCCCC
Product: CCCCCN(CCCCC)C(=O)C(Cc1ccc(OCC(=O)O)c(C(=O)O)c1)NC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 53.1 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (100 mg, 0.18 mmol) and dipentylamine (46 mg, 0.29 mmol) according to Method C with HPLC purification to give the title compound (64 mg). 1H-NMR (400 MHz, CD3OD) δ 0.90 (m, 6H) 1.14-1.53 (m, 21H) 2.65-2.82 (m, 1H) 2.86-3.38 (m, 7H) 4.30 (m, 1H) 4.80 (d, 2H) 4.94 (m, 1H) 7.02 (m, 1H) 7.21 (m, 5H) 7.35-7.35 (dd, 1H) 7.76 (dd, 1H); HRMS m/z 669.3634 (calc. of monoisotopic mass for C36H51N3O9 gives 669.3625); mp 87-90° C.
Reaction SMILES: [C:1]([C:3]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10]C(=O)OC(C)(C)C)#[N:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:18]=[CH:19][CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:3]=1[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)NCCCCOc1cccc([N+](=O)[O-])c1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1c(OCCCCN)cccc1[N+](=O)[O-]
Yield: 148.4 %

Procedure:
A solution of tert-butyl 4-(2-cyano-3-nitrophenoxy)butylcarbamate (Example 234e) (671 mg, 2 mmol) in DCM/TFA (1:1, 20 mL) was stirred at room temperature for 2 hrs. The solvent was removed under vacuum to give the title compound (698 mg, 100%). MS 236 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][C:5]=1[NH2:12].[I:14]I>CCO.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([I:14])[C:7]([CH2:10][CH3:11])=[CH:6][C:5]=1[NH2:12]
Reactant: II
Reactant: CCc1ccc(C(=O)OC)c(N)c1
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CCc1cc(N)c(C(=O)OC)cc1I
Yield: 72.8 %

Procedure:
To a solution of 2-amino-4-ethyl-benzoic acid methyl ester (500 mg, 2.79 mmol) in EtOH (2 mL) were added Ag2SO4 (868.15 mg, 2.79 mmol) and I2 (708.1 mg, 2.79 mmol) and the resultant mixture was stirred at r.t. for 3 h. The reaction mixture was filtered and the solvent was removed in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with 1M Na2S2O3 and sat. aq NaHCO3. The solvent was removed in vacuo and the orange oil was purified by flash chromatography (silica gel, hexanes→4:1 hexanes:EtOAc) to provide the title compound (620 mg, 73%) as an orange solid. ESI-MS: m/z 306.2 [M+H]+, rt 6.03 min
Reaction SMILES: Cl[C:2]1[N:7]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:11]([Cl:21])=[CH:10][C:9]=2[F:22])[C:6](=[O:23])[CH:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:3]=1.[CH3:28][C:29](=[N:31][OH:32])[CH3:30].C(=O)([O-])[O-].[K+].[K+].O1CCCC1>[Cl-].[Na+].O>[Cl:21][C:11]1[C:12]([O:14][C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:13][C:8]([N:7]2[C:6](=[O:23])[CH:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:3]=[C:2]2[O:32][N:31]=[C:29]([CH3:30])[CH3:28])=[C:9]([F:22])[CH:10]=1
Reactant: O=c1cc(C(F)(F)F)nc(Cl)n1-c1cc(Oc2ncccn2)c(Cl)cc1F
Reactant: CC(C)=NO
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=NOc1nc(C(F)(F)F)cc(=O)n1-c1cc(Oc2ncccn2)c(Cl)cc1F
Yield: 93.3 %

Procedure:
A mixture of 2-chloro-3-[4-chloro-2-fluoro-5-(2-pyrimidinyloxy)phenyl]-6-trifluoromethyl-4(3H)-pyrimidinone(1.52 g, 0.0036 mol), acetone oxime(0.26 g, 0.0036 mol), potassium carbonate(0.50 g, 0.0036 mol) and tetrahydrofuran(15 ml) was heated under reflux for 5 hours. The reaction mixture was poured into brine, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel(50% ethyl acetate/hexane) to give compound II-11 (1.54 g, yield 93.3%) as a white amorphous solid, m.p 70-80° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=O)[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.O.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>CO>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[CH2:21]([N:28]1[CH2:33][CH2:32][N:31]([C:12]([CH2:11][CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2](=[O:1])[N:3]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:14])[CH2:30][CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(O)CC1c2ccccc2C(=O)N1c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Product: O=C(CC1c2ccccc2C(=O)N1c1ccccc1)N1CCN(Cc2ccccc2)CC1
Yield: 83.5 %

Procedure:
An oily product (4.3 g), which was prepared from 2.67 g of 3-oxo-2-phenylisoindoline-1-acetic acid and 1.94 g of 1-benzylpiperazine in the same manner as Example 3, was dissolved in 4 ml of methanol, and to this solution a solution of 1.5 g of oxalic acid dihydrate in 6 ml of methanol was added, and the crystals precipitated were collected by filtration. Yield, 4.90 g; m.p., 207°-210° C. (recrystallization from methanol).
Reaction SMILES: [Br:1][C:2]([CH2:4]Br)=[CH2:3].[C:6]1([CH2:12][CH:13]=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>[Zn].C1(C)C=CC=CC=1>[Br:1][C:2]([CH2:4][CH:13]([OH:14])[CH2:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:3]
Reactant: C=C(Br)CBr
Reactant: O=CCc1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Product: C=C(Br)CC(O)Cc1ccccc1

Procedure:
49.93 Grams of 2,3-dibromo-1-propene were added dropwise to a mixture of 20.00 g of phenylacetaldehyde, 40 g of toluene, 60 g of 0.01% hydrochloric acid and 16.33 g of zinc powder at 30° C., and the mixture was allowed to react at the same temperature for 3 hours. After the reaction was completed, zinc-derived insolubles were filtered off, and the resultant filtrate was separated. The organic phase was washed with a 7% sodium carbonate aqueous solution, and the toluene was distilled off under reduced pressure. The resultant oily substance was purified by silica gel column chromatography to give 24.01 g of 2-bromo-5-phenyl-1-penten-4-ol; nD25 =1.536, FI-MS m/e 240(M+), 242(M+2+).
Reaction SMILES: C([C@H]1COC(C)(C)N1C(=O)CC1C=CN(C2C=CC(C3C=CC=CC=3)=CC=2)C=1)C1C=CC=CC=1.C(O[CH:39]([C:56]1[O:60][C:59]([C:61]2[CH:66]=[CH:65][C:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[CH:63][CH:62]=2)=[CH:58][CH:57]=1)[C:40]([N:42]1[C@@H:46]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:45][O:44][C:43]1([CH3:55])[CH3:54])=[O:41])(=O)C>>[CH2:47]([C@H:46]1[CH2:45][O:44][C:43]([CH3:55])([CH3:54])[N:42]1[C:40](=[O:41])[CH2:39][C:56]1[O:60][C:59]([C:61]2[CH:62]=[CH:63][C:64]([C:67]3[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=3)=[CH:65][CH:66]=2)=[CH:58][CH:57]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CC(=O)OC(C(=O)N1[C@@H](Cc2ccccc2)COC1(C)C)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Agent: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)Cc1ccn(-c2ccc(-c3ccccc3)cc2)c1
Product: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)Cc1ccc(-c2ccc(-c3ccccc3)cc2)o1
Yield: 42 %

Procedure:
According to the procedure described in Example 13 for the preparation of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(biphenyl-4-yl-1H-pyrrol-3-yl)-ethanone, 2-acetoxy-1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(2-biphenyl-4-yl-furan-5-yl)-ethanone was hydrogenolyzed to provide in 42% yield 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(2-biphenyl-4-yl-furan-5-yl)-ethanone as an amorphous solid.
Reaction SMILES: [C:1]([NH:4][CH:5](C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].[H-].[Na+].[C:18]1([C:24](Cl)(Cl)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[I-].[K+]>CN1CCCC1=O.O.C1(C)C=CC=CC=1>[C:1]([NH:4][CH:5]([CH:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: ClC(Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)NC(C(=O)O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution (1.25 M) of diethyl acetamidomalonate (6.79 g, 31.25 mmol) in N-methyl-2-pyrrolidone (25 mL) was added 60% sodium hydride (1.25 g, 31.25 mmol), and the mixture was stirred at room temperature for 1 hr. Diphenylmethylene chloride (4.45 mL, 25.0 mmol) and potassium iodide (4.15 g, 25 mmol) were added, and the mixture was stirred at 50° C. for 7 hrs. After completion of the reaction, toluene (75 mL) and water (31.5 mL) were added to the reaction mixture, and the mixture was partitioned. The organic layer was washed twice with water (31.5 mL) and concentrated. Ethanol (31.5 mL) and 2M aqueous sodium hydroxide solution (37.5 mL) were added to the concentrated solution, and the mixture was stirred at 80° C. for 11 hrs and allowed to cool to 25° C. Toluene (9 mL) was added and the mixture was partitioned. The aqueous layer was concentrated to a half volume and adjusted to pH 1.1 with concentrated hydrochloric acid, which resulted in the precipitation of white crystals. The crystals were collected by filtration and dried under vacuum to give the title compound (5.0 g).
Reaction SMILES: [CH3:1][CH:2]([C@@H:14]1[C@:31]2([CH3:32])[C@H:17]([C:18]3[C@H:28]([CH2:29][CH2:30]2)[C@:26]2([CH3:27])[C:21]([CH2:22][C@@H:23]([O:37][CH2:38][O:39][CH3:40])[CH2:24][C@@H:25]2[O:33][CH2:34][O:35][CH3:36])=[CH:20][CH:19]=3)[CH2:16][CH2:15]1)[CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5].C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[O:61]1[CH:63]([C:64]([CH3:73])([O:66][CH:67]2[CH2:72][CH2:71][CH2:70][CH2:69][O:68]2)[CH3:65])[CH2:62]1.[Cl-].[NH4+]>O1CCCC1.C(OCC)C.CCCCCC>[CH3:36][O:35][CH2:34][O:33][C@@H:25]1[C@@:26]2([CH3:27])[C:21](=[CH:20][CH:19]=[C:18]3[C@@H:28]2[CH2:29][CH2:30][C@@:31]2([CH3:32])[C@H:17]3[CH2:16][CH2:15][C@@H:14]2[C@H:2]([CH3:1])[CH:3]([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:62][CH:63]([OH:61])[C:64]([O:66][CH:67]2[CH2:72][CH2:71][CH2:70][CH2:69][O:68]2)([CH3:73])[CH3:65])[CH2:22][C@@H:23]([O:37][CH2:38][O:39][CH3:40])[CH2:24]1
Reactant: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CS(=O)(=O)c5ccc(C)cc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OCOC)C1
Reactant: CC(C)(OC1CCCCO1)C1CO1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)C(CC(O)C(C)(C)OC5CCCCO5)S(=O)(=O)c5ccc(C)cc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OCOC)C1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
In 2 ml of tetrahydrofuran was dissolved 43 mg of 20-methyl-1α,3β-bis(methoxymethoxy)-21-p-tolylsulfonylpregna-5,7-diene and the solution was cooled in a dry ice-acetone bath under argon atmosphere. To the solution was added 0.35 ml of a lithium diisopropylamide solution prepared from 2 ml of a 1.5N hexane solution of butyllithium and 0.5 ml of diisopropylamine in 10 ml of tetrahydrofuran. The mixture was stirred at -30° C. for 30 minutes and then again cooled in a dry ice-acetone bath. A solution of 100 mg of 1,2-epoxy-3-methyl-3-(2-tetrahydropyranyloxy)butane in 1 ml of tetrahydrofuran was added and the resulting mixture was stirred at -20° C. for 7 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was allowed to warm to ambient temperature. Diethyl ether was added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layer was combined, washed in sequence with an aqueous solution of sodium hydrogen carbonate and an aqueous solution of sodium chloride, then dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 38 mg of 1α,3β-bis-(methoxymethoxy)-22-p-tolylsulfonyl-25-(2 -tetrahydropyranyloxy)cholesta-5,7-dien-24-ol.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=[N:34][O:35][CH3:36])[CH2:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O>[CH3:36][O:35][N:34]=[C:24]1[CH2:23][CH2:22][CH2:21][C:20]2[N:19]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:8]4([NH2:7])[CH2:9][CH2:10][CH2:11]4)=[CH:13][CH:14]=3)[C:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:26][C:25]1=2
Reactant: CON=C1CCCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Solvent: O=C(O)C(F)(F)F
Product: CON=C1CCCc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Reaction time: 0.01 h
Yield: 91.5 %

Procedure:
tert-butyl(1-(4-(5-(methoxyimino)-3-phenyl-5,6,7,8-tetrahydroquinolin-2-yl)phenyl)cyclobutyl)carbamate (44 mg, 0.088 mmol) was dissolved in TFA (1 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (32 mg, 73% yield). 1H-NMR (500 MHz, CD3OD) δ 8.35 (1H, s), 7.48 (2H, d), 7.43 (2H, d), 7.30 (3H, t), 7.18-7.23 (2H, m), 4.02 (3H, s), 3.05 (2H, t), 2.85 (2H, t), 2.73-2.81 (2H, m), 2.54-2.63 (2H, m), 2.19-2.30 (1H, m), 2.03 (2H, p), 1.91-2.03 (1H, m). LCMS (Method A) RT=4.57 min, M+H+=398.10.
Reaction SMILES: [CH:1]1(/[CH:4]=[N:5]/[S:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])[CH2:3][CH2:2]1.[F:12][CH:13]([F:23])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Na+].[Cl-]>C1COCC1>[CH:1]1([CH:4]([NH:5][S:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])[C:13]([F:12])([F:23])[S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH2:2][CH2:3]1
Reactant: CC(C)(C)S(=O)/N=C/C1CC1
Reactant: O=S(=O)(c1ccccc1)C(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC(C1CC1)C(F)(F)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-[(1E)-cyclopropylmethylene]-2-methylpropane-2-sulfinamide (1.0 g, 5.8 mmol) and [(difluoromethyl)sulfonyl]benzene (1.1 g, 5.8 mmol) in THF (60 mL) was added dropwise NaHMDS (2 M, 4 mL, 8.2 mmol) at −78° C. The reaction mixture was stirred at this temperature for 2 h. A saturated NaCl solution (60 mL) was added to the reaction mixture to quench the reaction at −78° C. After warmed to room temperature, the mixture was extracted with EtOAc. The combined organic phases were dried, concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 7.80 (d, 2H); 7.60 (t, 1H); 7.48 (d, 2H); 3.48 (d, 1H); 1.06-1.10 (m, 1H); 1.05 (s, 9H); 0.45-0.75 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]([F:24])([F:23])[S:14]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)=[O:15]>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([S:14]([C:13]([F:24])([F:12])[F:23])=[O:15])=[CH:17][CH:18]=1)=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: Nc1ccc(S(=O)C(F)(F)F)cc1
Product: O=C(Nc1ccc(S(=O)C(F)(F)F)cc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 169.2 using 5-bromo-6-chloro-nicotinic acid and 4-(trifluoromethylsulfinyl)aniline To afford an off-white crystalline solid. HPLC (Condition 4) tR=5.59 min, UPLC-MS (Condition 3) tR=1.10 min, m/z=425 [M−H]−.