Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]12[CH:23]=[CH:22][CH:21]=[CH:20][CH:9]1[CH2:10][CH:11]2[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=O)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOCC>[NH2:1][CH2:4][CH2:5][CH2:6][O:7][C:8]12[CH:23]=[CH:22][CH:21]=[CH:20][CH:9]1[CH2:10][CH:11]2[CH2:12][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: [N-]=[N+]=NCCCOC12C=CC=CC1CC2C(=O)N1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCCCOC12C=CC=CC1CC2CN1CCCCC1

Procedure:
A solution of the azidobenzocyclobutenylamide compound of Step 2. above (3.2 g) in THF (20.4 ml) is added dropwise to a suspension of LAH (0.93 g) in anhydrous ether (122 ml) stirred under nitrogen maintained at ice bath temperatures. The reaction mixture is refluxed for 15 hours, cooled and quenched with water (0.93 ml), aqueous sodium hydroxide (15% solution, 0.93 ml) and water (2.79 ml) and filtered. The solid is washed with ether and the combined filtrate dried, filtered, evaporated in vacuo and chromatographed (silica gel: ethyl acetate/methanol). The pure fractions are combined and evaporated in vacuo yielding an oil, which is identified as the desired product by NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]2[NH:29][N:28]=[N:27][N:26]=2)[CH:22]=[CH:23][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH:20]=3)(=[O:16])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1cccc(-c2ccc(Cl)cc2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1cccc(-c2ccc(Cl)cc2)c1
Yield: 92 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with [3-(4-chlorophenyl)phenyl]sulfonyl chloride (15.8 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 92% yield (18.9 mg). MS (ESI+) calcd mass for C19H14ClN5O2S 411.055673, found 411.055743.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[O:31][C:32](=[O:34])[CH3:33])/[C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([OH:27])=[O:26])=[C:15](/[CH:18]=[CH:19]\[CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C([O-])([O-])=O.[Na+].[Na+].[C:41]([O:44][CH:45](Br)[CH3:46])(=[O:43])[CH3:42]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[O:31][C:32](=[O:34])[CH3:33])/[C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O:27][CH:45]([O:44][C:41](=[O:43])[CH3:42])[CH3:46])=[O:26])=[C:15](/[CH:18]=[CH:19]\[CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)OC/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC(C)=O)c3csc(N)n3)[C@H]2SC1
Reactant: CC(=O)OC(C)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OC/C=C\C1=C(C(=O)OC(C)OC(C)=O)N2C(=O)C(NC(=O)/C(=N\OC(C)=O)c3csc(N)n3)[C@H]2SC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a solution of the product of Example 68 (248 mg, 0.49 mmol) in 25 ml of dry DMF was added Na2CO3 (51 mg, 0.49 mmol) and 1-acetoxyethyl bromide (82 mg, 0.49 mmol) at -10° C. The mixture was stirred at 5° C. for 30 min and 82 mg (0.49 mmol) of 1-acetoxyethyl bromide was added to the suspension. After being stirred for 30 min more, the reaction mixture was diluted with AcOEt (50 ml), washed with water (30 ml×3) and brine, dried over MgSO4 and evaporated under diminished pressure. The crude product was purified by silica gel chromatography eluted with 3% MeOH in chloroform. Removal of the solvent from appropriate eluant followed by freeze-drying gave 157 mg (54%) of the title compound, mp 125° C. (dec). IR νmax (KBr) cm-1 3430, 3290, 1770, 1680. UV λmax (pH 7 phosphate buffer) nm (ε) 228 (21900), 287 (12700). 1H NMR (DMSO-d6) δ 1.51 (3H, d, J=6 Hz, 4-COOCHCH3), 2.02 (3H, s, AcO), 2.06 (3H, s, AcO), 2.22 (3H, s, AcO), 3.47 (2H, br.s, 2-H), 4.46 (1H, q, J=6 Hz, 4-COOCHCH3), 4.55 (2H, ABq, CH2OAc), 5.12 (1H, d, J=5 Hz, 6-H), 5.70 (1H, m, 3-CH=CH), 5.95 (1H, dd, J=5 & 7 Hz, 7-H), 6.25 (1H, d, J=12 Hz, 3-CH=CH), 6.92 (1H, s, thiazole).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[CH2:10]([Mg]Br)[CH2:11][CH3:12]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:6]([OH:7])[CH2:10][CH2:11][CH3:12])=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: CCC[Mg]Br
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(Cl)nc1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a −10° C. solution of 6-chloronicotinaldehyde (553 mg, 3.91 mmol) in 3.5 mL THF was added n-propylmagnesium bromide (2.34 mL of a 2.0 M solution in THF, 4.69 mmol). The solution was stirred at −10° C. for 10 min, and was then allowed to warm to room temperature. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The organic layer was concentrated. The crude residue was purified by silica gel chromatography to give 1-(6-chloropyridin-3-yl)butan-1-ol (400 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.24-8.31 (m, 1H), 7.61-7.67 (m, 1H), 7.25-7.30 (m, 1H), 4.68-4.74 (m, 1H), 2.05-2.26 (br s, 1H), 1.69-1.82 (m, 1H), 1.57-1.68 (m, 1H), 1.19-1.49 (m, 2H), 0.91 (t, J=7.43 Hz, 3H).
Reaction SMILES: IC.[CH3:3][N:4]1[C:8]2[CH:9]=[C:10]([C:13]3[CH:14]=[C:15]([NH:19][S:20]([CH:23]4[CH2:25][CH2:24]4)(=[O:22])=[O:21])[CH:16]=[N:17][CH:18]=3)[CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[O:26].[C:27](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:27][N:19]([C:15]1[CH:16]=[N:17][CH:18]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]3[O:6][C:5](=[O:26])[N:4]([CH3:3])[C:8]=3[CH:9]=2)[CH:14]=1)[S:20]([CH:23]1[CH2:25][CH2:24]1)(=[O:22])=[O:21]
Reactant: O=C([O-])[O-]
Reactant: Cn1c(=O)oc2ccc(-c3cncc(NS(=O)(=O)C4CC4)c3)cc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(c1cncc(-c2ccc3oc(=O)n(C)c3c2)c1)S(=O)(=O)C1CC1
Reaction time: 4 h

Procedure:
Iodomethane (55.4 mg, 0.39 mmol) was added dropwise to a suspension of N-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-3-yl)cyclopropanesulfonamide (104 mg, 0.3 mmol), potassium carbonate (207 mg, 1.5 mmol) in DMF (1.5 mL) at room temperature. The resulting mixture was stirred at this temperature for 4 h. The mixture was diluted with ethyl acetate (50 mL) and washed with water (2×50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with NaHCO3 solution and dried over anhydrous Na2SO4. After filteration and concentration, the residue was treated with ether then filterated to pale solid (30 mg). ESI-MS m/z: 3601 [M+1]+, Retention time 1.15 min; 1HNMR (MeOD, 400.342 MHz) δ 0.96-1.03 (m, 4H), 2.65-2.72 (m, 1H), 3.47 (s, 3H), 7.38 (d, J=8 Hz, 1H), 747 (dd J=8, 2 Hz, 1H), 7.52 (s, 1H), 8.18 (t J=2 Hz, 1H), 8.64 (d, J=2 Hz, 1H), 8.76 (s, 1H).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:15][C:10]=2[N:9]=[CH:8]1.[I:22]N1C(=O)CCC1=O>CCCCCC.C1COCC1>[I:22][C:8]1[N:7]([CH3:6])[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:15][C:10]=2[N:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cn1cnc2cc(CN3CCCC3)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1c(I)nc2cc(CN3CCCC3)ccc21
Reaction time: 0.17 h

Procedure:
0.80 mL (1.28 mmol) 1.6 M n-butyllithium solution in hexane are added to a solution, cooled to −75° C., of 250 mg (1.16 mmol) 1-methyl-5-pyrrolidin-1-ylmethyl-1H-benzimidazole in 8 mL THF. The reaction mixture is stirred for 10 min at this temperature and then 288 mg (1.28 mmol) N-iodosuccinimide in 5 mL THF are added. The cooling bath is removed and the reaction stirred for 1 h at RT. 12 mL 0.1 M HCl are added and the aqueous phase is extracted with EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (gradient: DCM to DCM/MeOH/NH3 9:1:0.1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:22][NH2:23])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(CC(=O)c2ccc(Cl)cc2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(CC(=NN)c2ccc(Cl)cc2)cc1
Yield: 96 %

Procedure:
0.7 of magnesium(scraped shape) and 100 mg of a chip of iodine were added to 5 ml of anhydrous diethyl ether. 10 ml of anhydrous diethyl ether solution of 5.6 g of p-bromochlorobenzene was dropwise added thereto under nitrogen stream at a rate that was just fast enough to maintain a gentle reflux. This solution was stirred at room temperature for 20 minutes to react them, a solution of 4.8 g of p-tert-butylphenyl acetonitrile in 5 ml of anhydrous diethyl ether was dropwise added thereto at a rate that was just fast enough to maintain a gentle reflux. The solution was further stirred for 30 minutes to react them. After completion of the reaction, a mixture solution of 10 g of ice and 130 ml of 6N-hydrochloric acid was added thereto and a reaction product was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The redisue was purified by silica gel column chromatography (developing solvent: ethyl acetate/n-hexane=1/9) to obtain 1.3 g of 4'-chloro-2-(4-tert-butylphenyl)acetophenone. (2) 1.3 g of (4.5 mmol) of 4'-chloro-2-(4-tert-butylphenyl)acetophenone was dissolved in 15 ml of ethanol, and 0.2 g (4.5 mmol) of hydrazine monohydrate was added thereto. The mixture was refluxed under heating for three hours. After completion of the reaction, ethanol was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 1.3 g of [4'-chloro-2-(4-tert-butylphenyl)acetophenone]hydrazone as a yellow oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:14][NH:15][O:16][CH3:17].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:17][O:16][N:15]([CH3:14])[C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CNOC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a suspension of N-(tert-butoxycarbonyl)glycine (4.0 g, 23 mmol), N,O-dimethylhydroxylamine hydrochloride (3.0 g, 31 mmol) and N,N-dimethylpyridin-4-amine (300 mg, 2.5 mmol) in dry CH2Cl2 (100 mL) was added N-(3-dimethylaminopropyl)-W-ethylcarbodiimide hydrochloride (5.2 g, 27 mmol) followed by triethylamine (5.4 mL, 39 mmol) at 0° C. The mixture was stirred at that temperature 30 minutes and then at room temperature over 3 days. The suspension was washed with aqueous HCl (1 M, 2×40 mL) followed by a saturated aqueous solution of NaHCO3 (2×40 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to yield tert-butyl {2-[methoxy(methyl)amino]-2-oxoethyl}carbamate as a white solid (4.5 g, yield 90%). 1H-NMR (400 MHz, CDCl3): δ 1.45 (s, 9H), 3.20 (s, 3H), 3.71 (s, 3H), 4.08 (br s, 2H), 5.26 (br s, 2H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:30]=[C:31]([F:42])[C:32]([N+:39]([O-])=O)=[C:33]([CH:38]=3)[C:34]([O:36][CH3:37])=[O:35])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:22])[NH:20][CH3:21])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.CO>C1COCC1.[Pd]>[NH2:39][C:32]1[C:31]([F:42])=[CH:30][C:29]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19](=[O:22])[NH:20][CH3:21])=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c([N+](=O)[O-])c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 78.1 %

Procedure:
A suspension of methyl 5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluoro-2-nitrobenzoate (810 mg, 1.351 mmol) and Pd/C (10% wt, 144 mg, 0.135 mmol) was stirred under hydrogen (1 atm) in THF (10.0 mL) and MeOH (5.0 mL) overnight. The mixture was filtered through 45 um disc and washed with EtOAc. The filtrate was concentrated and purified by silica gel chromatography (0-50% EtOAc in hexanes) to give methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluorobenzoate (601 mg, 78% yield) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.81-1.11 (m, 3H), 2.14-2.26 (m, 1H), 2.91-3.03 (m, 3H), 3.19 (s, 3H), 3.86 (s, 3H), 5.80 (d, J=4.5 Hz, 1H), 5.88 (br. s., 2H), 7.15-7.25 (m, 2H), 7.40 (dd, J=12.1, 2.5 Hz, 1H), 7.44 (s, 1H), 7.70 (s, 1H), 7.80 (dd, J=2.4, 1.5 Hz, 1H), 7.84-7.94 (m, 2H). LCMS (m/z, ES+)=570.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([CH:19]=[O:20])[CH3:18])[CH2:8][C@@H:7]([O:28][CH2:29][O:30][CH3:31])[CH2:6]1.COC(O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C=O)C)C[C@@H](OC(OC)=O)C1)=O>>[CH3:1][O:2][CH2:3][O:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([CH3:18])[CH2:19][OH:20])[CH2:8][C@@H:7]([O:28][CH2:29][O:30][CH3:31])[CH2:6]1
Reactant: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OCOC)C1
Agent: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OCOC)C1
Yield: 98.5 %

Procedure:
The procedure of Example 1 was repeated except that 93 mg of 1α,3β-bis(methoxymethoxy)pregna-5,7-diene-20-carbaldehyde was used in lieu of 100 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carbaldehyde to give 92 mg of 1α,3β-bis(methoxymethoxy)-20-methylpregna-5,7-dien-21-ol.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][S:6][C:5]([SH:8])=[N:4]1.[CH:9](N(C(C)C)CC)(C)C.CI>CO>[OH:1][CH2:2][C@@H:3]1[CH2:7][S:6][C:5]([S:8][CH3:9])=[N:4]1
Reactant: CCN(C(C)C)C(C)C
Reactant: OC[C@@H]1CSC(S)=N1
Solvent: CO
Solvent: CI
Product: CSC1=N[C@H](CO)CS1
Yield: 59 %

Procedure:
To a mixture solution of 4.88 g of 4(R)-hydroxymethyl-2-mercapto-1,3-thiazoline [Compound (5)] and 22.8 ml of diisopropylethylamine in 65 ml of dry methanol was added 14.00 g of methyl iodide under refluxing condition, and the reaction mixture was refluxed for 1 hour. After removal of the solvent under reduced pressure, the resulting residue was dissolved in ethyl acetate and the organic layer was washed with saturated sodium bicarbonate solution, water and saturated saline solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform-acetone) to give 3.14 g (59%) of 4(R)-hydroxymethyl-2-methylthio-1,3-thiazoline [Compound (6)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[S:27]([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([CH:46]=O)=[CH:38]1)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28].N1CCCCC1>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])/[C:8](=[CH:46]/[C:39]3[C:40]4[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:37]([S:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=4)(=[O:29])=[O:28])[CH:38]=3)/[O:9][C:5]=2[C:4]=1[CH2:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccccc32)cc1
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1cn(S(=O)(=O)c3ccc(C)cc3)c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
A solution of tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.488 g, 1.35 mmol) obtained in Example A40, Step 1 in methanol (5 mL) was added with 1-tosyl-1H-indole-3-carboxaldehyde (0.404 g, 1.35 mmol) obtained in Example A33, Step 1 and piperidine (0.0115 g, 0.135 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then added with methanol (2 mL), and the precipitated solid was suspended in methanol and thereby washed. The reaction mixture was filtered to obtain tert-butyl (Z)-4-({6-methoxy-3-oxo-2-[(1-tosyl-1H-indol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.485 g, 55%).
Reaction SMILES: Cl.O1CCOCC1.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[N:16](C(OC(C)(C)C)=O)[NH:17]C(OC(C)(C)C)=O>CC(O)C>[ClH:15].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][NH2:17]
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1c(Cl)cccc1Br
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: NNc1c(Cl)cccc1Br
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 162.1 %

Procedure:
4M Hydrogen chloride in dioxane (28.2 mL, 112.64 mmol) was added to di-tert-butyl 1-(2-bromo-6-chlorophenyl)hydrazine-1,2-dicarboxylate (Intermediate AH1) (9.5 g, 22.53 mmol) in iPrOH (30 mL) at ambient temperature. The resulting solution was heated to 60° C. and stirred for 20 minutes. The reaction mixture was allowed to cool to ambient temperature. A solid was filtered off, and dried under vacuum to afford the product (4.71 g). 1H NMR (400 MHz, DMSO) d 6.97 (1H, s), 7.06 (1H, t), 7.41 (1H, dd), 7.52 (1H, dd), 9.83 (3H, s). m/z M.+=220; GC-MS tR=10.419 min.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]2)[N:5]=[N:4]1)[CH3:2].[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1.C(N(CC)CC)C.CC1C=CC=CC=1.[OH2:48]>>[C:17]([OH:19])(=[O:18])[C:14]([OH:32])=[O:48].[CH:28]1([C:31]([N:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:14]2([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][N:6]3[C:7](=[O:8])[N:3]([CH2:1][CH3:2])[N:4]=[N:5]3)[CH2:16][CH2:15]2)=[O:32])[CH2:30][CH2:29]1
Reactant: CCn1nnn(CCN2CCC(Nc3ccccc3)(C(=O)OC)CC2)c1=O
Reactant: O
Reactant: O=C(Cl)C1CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCn1nnn(CCN2CCC(C(=O)OC)(N(C(=O)C3CC3)c3ccccc3)CC2)c1=O
Product: O=C(O)C(=O)O
Yield: 17.5 %

Procedure:
A mixture of 5.7 parts of methyl 1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-4-(phenylamino)-4-piperidinecarboxylate, 1.9 parts of cyclopropanecarbonyl chloride, 2.7 parts of N,N-diethylethanamine and 68 parts of methylbenzene is stirred and refluxed overnight. The reaction mixture is cooled, 100 parts of water are added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and treated with 1 part of ethanedioic acid. The formed ethanedioate salt is filtered off and crystallized from a mixture of 2-propanone and 2,2'-oxybispropane, yielding 1.5 parts (17.5%) of methyl 4-[(cyclopropylcarbonyl)phenylamino]-1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-4-piperidinecarboxylate ethanedioate (2:3); mp. 181.5° C.
Reaction SMILES: [N:1]1([C@:4]23[CH2:30][CH2:29][C@@H:28]([C:31]([CH3:33])=[CH2:32])[C@@H:5]2[C@@H:6]2[C@@:19]([CH3:22])([CH2:20][CH2:21]3)[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:27])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:25])([CH3:24])[C:13](=[O:26])[CH2:12][CH2:11]4)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([N:41]([S:49]([C:52]([F:55])([F:54])[F:53])(=[O:51])=[O:50])S(C(F)(F)F)(=O)=O)=[N:39][CH:40]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[F:53][C:52]([F:55])([F:54])[S:49]([O:26][C:13]1[C:14]([CH3:24])([CH3:25])[C@H:15]2[C@:10]([CH3:27])([CH2:11][CH:12]=1)[C@@H:9]1[C@:18]([CH3:23])([C@@:19]3([CH3:22])[C@H:6]([CH2:7][CH2:8]1)[C@H:5]1[C@H:28]([C:31]([CH3:33])=[CH2:32])[CH2:29][CH2:30][C@:4]1([NH:1][CH2:2][CH2:3][N:41]([C:38]1[CH:37]=[CH:36][C:35]([Cl:34])=[CH:40][N:39]=1)[S:49]([C:52]([F:53])([F:54])[F:55])(=[O:50])=[O:51])[CH2:21][CH2:20]3)[CH2:17][CH2:16]2)(=[O:51])=[O:50]
Reactant: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=S(=O)(N(c1ccc(Cl)cn1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN(c3ccc(Cl)cn3)S(=O)(=O)C(F)(F)F)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: -78 °C

Procedure:
(1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)octadecahydro-1H-cyclopenta[a]chrysen-9(5bH)-one (353 mg, 0.781 mmol) was mixed with N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (338 mg, 0.860 mmol) in THF (2 mL) under nitrogen. The solution was stirred at −78° C. under nitrogen. A 0.5 M stock solution of potassium bis(trimethylsilyl)amide (1.875 mL, 0.938 mmol) was added, and the mixture was stirred at −78° C. for an hour. The desired product was purified by silica gel chromatography eluted with mixture of ethyl acetate and hexanes (230 mg, 35%). MS: m/e 844.3/846.3 (M+H)+, 6.47 min (method 15). 1H NMR (400 MHz, CHLOROFORM-d) δ (key fingerprint signals) 8.45 (d, J=2.0 Hz, 1H), 7.76 (dd, J=8.7, 2.6 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 5.57 (d, J=6.5 Hz, 1H), 4.80-4.57 (m, 3H), 3.71-3.65 (m, 1H), 2.80-2.73 (m, 1H), 2.73-2.49 (m, 2H), 2.45-2.29 (m, 1H), 2.26-2.12 (m, 2H), 2.08-1.94 (m, 2H), 1.93-1.80 (m, 2H), 1.80-1.72 (m, 3H), 1.71-1.65 (m, 6H). 19F NMR (376 MHz, CHLOROFORM-d) δ −74.84 (s), −74.85 (s).