Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH2:21]O)=[C:4]([O:23]C)[CH:3]=1.[I:25]I>C1([Si](C)(C)C)C=CC=CC=1.Cl>[F:1][C:2]1[CH:3]=[C:4]([OH:23])[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH2:21][I:25])=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9]
Reactant: II
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CO
Agent: C[Si](C)(C)c1ccccc1
Agent: Cl
Product: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2CI)c(O)cc1F
Temperature: 25 °C

Procedure:
A solution of [4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol (71.5 mg, 0.209 mmol) and iodine (610 mg, 2.40 mmol) in phenyltrimethylsilane (877 μL) was heated at 110° C. in a sealed tube overnight. The reaction was cooled to room temperature, diluted with 1N HCl (10 mL) and extracted with EtOAc (3×20 mL). The combined extracts were washed with 10% Na2S2O3 (20 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-20% EtOAc in hexanes gradient) to afford 4-fluoro-2′-(iodomethyl)-5-isopropyl-4′-(trifluoromethyl)biphenyl-2-ol. Rf=0.65 (20% EtOAc in hexanes). 1H NMR (500 MHz, CDCl3) δ 7.81 (s, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.69 (d, J=11.1 Hz, 1H), 4.82 (s, 1H), 4.41 (d, J=9.4 Hz, 1H), 4.23 (d, J=9.3 Hz, 1H), 3.27-3.19 (m, 1H), 1.27 (br s, 6H).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]#[N:23])[CH2:18][CH2:17]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][O-:25].[Na+]>CO>[CH3:24][O:25][C:22]([N:19]1[CH2:18][CH2:17][CH:16]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:21][CH2:20]1)=[NH:23]
Reactant: C[O-]
Reactant: N#CN1CCC(c2nn(-c3ccccc3)c3ccccc23)CC1
Agent: [Na+]
Solvent: CO
Product: COC(=N)N1CCC(c2nn(-c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
A mixture of 4-(1-phenyl-1H-indazol-3-yl)piperidine-1-carbonitrile of Example 73 (4.0 g, 0.013 moles) and sodium methoxide (3 ml of 25% sodium methoxide in methanol, 0.013 moles) in methanol (30 ml) was warmed to effect solution and then stirred at ambient temperature for 16 hours. The solvent was removed which left an oil (4.5 g). The oil was dissolved in ether, washed with H2O, and dried (MgSO4). Removal of the ether left an oil which began to crystallize upon standing. Crystallization was enhanced by triturating the oil with hexane which produced 3.5 g of product. The product was recrystallized twice from hexane yielding 2.31 g (52%) of 4-(1-phenyl-1H-indazol-3-yl)piperidine-1-carboximidic acid methyl ester, mp 80°-83° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[C:20]1([CH2:26][C:27]([OH:29])=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)(=O)C>O>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7](/[CH:10]=[C:26](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[C:27]([OH:29])=[O:28])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)Cc1ccccc1
Reactant: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCCCc1ncc(/C=C(/C(=O)O)c2ccccc2)n1Cc1ccccc1Cl
Temperature: 140 °C
Reaction time: 6 h
Yield: 18.1 %

Procedure:
A mixture of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde (554 mg, 2 mmol), phenylacetic acid (310 mg, 2.3 mmol), potassium carbonate (126 mg, 0.91 mmol), and acetic anhydride (1 mL) was heated gradually to 140° C. and held at this temperature for 6 hours. The cooled reaction was diluted with water and the oily solid was separated, triturated several times with ether, and the solid was crystallized several times from methanol/ethyl acetate to give 143 mg (18%) of the title compound; mp 210°-212° C. The NMR was consistent with the trans olefinic product.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([N:30]2[CH2:35][CH2:34][C@@:33]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)([CH2:36][CH2:37][OH:38])[O:32][C:31]2=[O:46])[CH3:29])=[CH:24][CH:23]=1.N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:38][CH2:37][CH2:36][C@@:33]1([C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)[O:32][C:31](=[O:46])[N:30]([C@H:28]([C:25]2[CH:26]=[CH:27][C:22]([C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[F:14])=[CH:23][CH:24]=2)[CH3:29])[CH2:35][CH2:34]1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)(c2ccc(F)cc2)OC1=O
Reaction time: 8 h
Yield: 51.3 %

Procedure:
A solution of 4-nitrophenyl chloroformate (133 mg, 0.66 mmol) in dichloromethane (1 mL) was added to a solution of (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (100 mg, 0.22 mmol) and pyridine (608 mg, 7.7 mmol) in dichloromethane (2.8 mL). The mixture was stirred at it overnight. The reaction was quenched with 1 N HCl (7 mL), and the mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with brine, dried and concentrated to give 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl 4-nitrophenyl carbonate (70 mg, crude), which was used for the next step without purification.
Reaction SMILES: [NH:1]1[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[CH:3]=[CH:2]1)[CH:10]=[N:9][CH:8]=[CH:7]3.[CH2:14]1[O:17][C@@H:15]1[CH3:16]>>[N:1]1([CH2:14][C@H:15]([OH:17])[CH3:16])[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[CH:3]=[CH:2]1)[CH:10]=[N:9][CH:8]=[CH:7]3
Reactant: C[C@@H]1CO1
Reactant: c1cc2c(ccc3cc[nH]c32)cn1
Product: C[C@@H](O)Cn1ccc2ccc3cnccc3c21

Procedure:
(R)-1-(1H-Pyrrolo[2,3-f]isoquinolin-1-yl)-2-propanol was prepared according to the method described in Example 1 using 1H-pyrrolo[2,3-f]isoquinoline (Farmaco, 1989, 44(12), 1141-55) and (R)-propylene oxide to give 0.77 g (71%) of the product as a white solid. A recrystallised sample [cyclohexane-ethanol (4:1)] gave mp 169-170° C.; Found: C, 74.09; H, 6.28; N, 12.27%. C14H14N2O requires C, 74.31; H, 6.24; N, 12.37%.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]([C:14]([O:16]CC)=O)=[CH:7]2.[CH3:19][N:20]1C2C(=CC=CC=2)C=C1C(OCC)=O>>[CH3:19][NH:20][C:14]([C:8]1[N:9]([CH3:13])[C:10]2[C:6]([CH:7]=1)=[CH:5][C:4]([F:3])=[CH:12][CH:11]=2)=[O:16]
Reactant: CCOC(=O)c1cc2ccccc2n1C
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1C
Agent: [Na+]
Agent: [OH-]
Product: CNC(=O)c1cc2cc(F)ccc2n1C
Yield: 68 %

Procedure:
According to the procedure of Preparation 1 (b), except substituting ethyl 5-fluoro-1-methyl-1H-indole-2-carboxylate for the ethyl 1-methyl-1H-indole-2-carboxy late, the title compound (2.1 g, 68%) was prepared as a white solid: MS (ES) m/e 207 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]2[CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([O-])=O>CN(C=O)C.[Pd]>[NH2:1][C:4]1[S:8][C:7]2[CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1
Reactant: O=C1CCCc2sc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1cc2c(s1)CCCC2=O

Procedure:
2-Nitro-6,7-dihydrobenzo[b]thiophen-4(5H)-one (3.6 g, 18.2 mmol) was dissolved in DMF (50 mL) and stirred under an atmosphere of hydrogen (300 psi) for 18 hr with 10% palladium on carbon. The mixture was filtered through celite and used directly in the next step as a solution in DMF.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O.Cl[C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH:17]=[O:18].[CH3:26][S:27]([C:30]1[N:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>O>[CH3:26][S:27]([C:30]1[N:35]=[CH:34][C:33]([O:36][C:15]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=2[CH:17]=[O:18])=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CS(=O)(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2C=O)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Cesium carbonate (10 g) was added to an N-methylpyrrolidinone (70 ml) solution of 2-chloro-5-nitrobenzaldehyde (5.0 g) and 6-(methylsulfonyl)-3-pyridinol (5 g) obtained in Reference Example 2, and stirred at room temperature for 3 hours. Water was added, then the formed crystal was collected by filtration to obtain the entitled compound as a pale brown solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.[OH:12][C:13]1[CH:34]=[CH:33][C:16]([CH2:17][O:18]/[N:19]=[C:20](/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)\[CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.CCCCCC.O>[N:4]1[C:3]([CH2:2][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][O:18]/[N:19]=[C:20](/[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)\[CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:33][CH:34]=2)=[CH:11][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: ClCc1cn2ccccc2n1
Reactant: COC(=O)CC/C(=N\OCc1ccc(O)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)CC/C(=N\OCc1ccc(OCc2cn3ccccc3n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 45.4 %

Procedure:
A mixture of 2-chloromethylimidazo[1,2-a]pyridine (293 mg), methyl E-4-(4-hydroxybenzyloxyimino)-4-phenylbutyrate (500 mg), potassium carbonate (442 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 17 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain methyl E-4-[4-(imidazo[1,2-a]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyrate (321 mg, yield 45%) as a colorless oil from an ethyl acetate-hexane (3:2, v/v)-eluted fraction.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:34])=[O:4])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)CCCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 0.1 %

Procedure:
Aqueous 0.5 M NaOH (13.2 mL, 6.6 mmol) was added to a stirring solution of 15b (1.41 g, 3.3 mol) in 25 mL of THF. The reaction mixture was stirred for 3 days at room temperature, and then the solvent was removed by rotary evaporation. The purification was carried out by flash column chromatography (gradient 10% EtOAc in hexanes to 100% EtOAc) to obtain 1.28 g (93%) of a pale yellow oil 16b. 1H-NMR (400 MHz, CDCl3, δH ppm): 7.43 (6H, m, p-Ar), 7.28 (6H, m, m-Ar), 7.21 (3H, m, o-Ar), 3.03 (2H, t, 3JH—H=6.6 Hz, HO—CH2), 2.33 (2H, t, 3JH—H=7.5 Hz, CH2CO2), 1.56-1.66 (4H, m, 2CH2), 1.20-1.40 (8H, m, 4CH2). 13C-NMR (100 MHz, CDCl3, δH ppm): 180.26, 144.46, 128.63, 127.64, 126.74, 86.22, 63.55, 34.04, 29.95, 29.24, 29.13, 28.96, 26.15, 24.60. HRMS (EI): m/z calcd 416.2351 (C28H32O3), found 416.2360 [M]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH3:12])[N:8]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])=[O:23])=[CH:15][CH:14]=3)[C:7]=2[CH:35]=1)#[N:2].[OH-:36].[K+]>CC(O)(C)C>[CH2:11]([C:9]1[N:8]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[O:23])=[CH:15][CH:14]=2)[C:7]2[CH:35]=[C:3]([C:1]([NH2:2])=[O:36])[CH:4]=[CH:5][C:6]=2[N:10]=1)[CH3:12]
Reactant: [OH-]
Reactant: CCc1nc2ccc(C#N)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCc1nc2ccc(C(N)=O)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 62.9 %

Procedure:
To a solution of 6-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (Example 85, 162 mg, 0.33 mmol) in 2-methyl-2-propanol (10 mL) was added powdered KOH (66 mg, 1.0 mmol). The resulting mixture was heated at reflux temperature for 3 h. After removal of solvent, the reaction mixture was partitioned between dichloromethane (50 mL) and phosphate buffer (50 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (50 mL). The combined organic phases were washed with brine (50 mL), dried (Na2SO4), and concentrated. The residual solids were recrystallized from ethyl acetate to afford 105 mg (63%) of the title compound as white solids: 1H-NMR (CDCl3) δ: 7.79 (2H, d, J=8.4 Hz), 7.75 (1H, d, J=8.8 Hz), 7.71–7.63 (2H, m), 7.35–7.25 (4H, m), 7.16 (2H, d, J=8.4 Hz), 6.75 (2H, br.s), 6.55 (1H, br.s), 3.54 (2H, t, J=6.4 Hz), 2.88 (2H, t, J=6.4 Hz), 2.79 (2H, q, J=7.5 Hz), 2.40 (3H, s), 1.34 (3H, t, J=7.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:24]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCCCCBr
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCOc1ccc(Br)cc1C=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
5-Bromosalicylaldehyde (1.51 g, 7.5 mm) was dissolved in dry DMF and treated with sodium hydride (0.4 g, 8.3 mm, 50% dispersion). After stirring for 20 minutes, a solution of 1-bromo-undecane in DMF was added dropwise. The reaction was heated to 50°-65° C. overnight with stirring. The reaction was then poured into ice water, the pH was adjusted to 8.0 with K2CO3 and the mixture was extracted with diethylether. The organic extracts were washed with water, dried over MgSO4 and filtered. The solvent was evaporated to yield an oil which solidifies upon standing.
Reaction SMILES: [CH2:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1)[CH2:2][CH:3]=C.[BH4-].[Na+].C[OH:19]>C(Cl)Cl>[C:10]1([C:7]2[CH:6]=[C:5]([CH2:1][CH2:2][CH2:3][OH:19])[NH:9][N:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CCCc1cc(-c2ccccc2)n[nH]1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: OCCCc1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(But-3-enyl)-3-phenyl-1H-pyrazole (5.4 g, 27.2 mmol) was dissolved in MeOH (40 mL) and DCM (10 mL). The reaction was cooled on a dry-ice/acetone bath and ozone was bubbled through the solution for 2 h. The reaction was transferred into an ice bath and NaBH4 (1.546 g, 40.9 mmol) was added slowly portion-wise (bubbling was observed). Upon complete addition, the reaction was removed from the ice bath and stirred at room temperature for 1 h. Excess solvent was evaporated and the reaction was extracted (100 mL each of H2O and EtOAc). The aqueous layer was extracted again with EtOAc (100 mL). The combined organic layer was dried, concentrated, and the residue was purified by column chromatography to yield the title compound (3.0 g) as a white solid. LCMS m/z=203.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.72-1.82 (m, 2H), 2.54-2.69 (m, 2H), 3.46 (q, J=6.11 Hz, 2H), 4.40-4.54 (m, 1H), 6.45 (s, 1H), 7.21-7.45 (m, 3H), 7.66-7.79 (m, J=7.45 Hz, 2H), 12.53 (s, 1H).
Reaction SMILES: C(OC(N1CCN([CH2:14][CH2:15][NH:16][C@:17]23[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:18]2[C@@H:19]2[C@@:32]([CH3:35])([CH2:33][CH2:34]3)[C@@:31]3([CH3:36])[C@@H:22]([C@:23]4([CH3:48])[C@@H:28]([CH2:29][CH2:30]3)[C:27]([CH3:38])([CH3:37])[C:26]([C:39]3[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=3)=[CH:25][CH2:24]4)[CH2:21][CH2:20]2)CC1)=O)(C)(C)C.[CH3:55][S:56]([CH:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)(=[O:58])=[O:57]>>[CH3:35][C@:32]12[C@@:31]3([CH3:36])[C@@H:22]([C@:23]4([CH3:48])[C@@H:28]([CH2:29][CH2:30]3)[C:27]([CH3:37])([CH3:38])[C:26]([C:39]3[CH:40]=[CH:41][C:42]([C:43]([OH:45])=[O:44])=[CH:46][CH:47]=3)=[CH:25][CH2:24]4)[CH2:21][CH2:20][C@@H:19]1[C@H:18]1[C@H:49]([C:52]([CH3:54])=[CH2:53])[CH2:50][CH2:51][C@:17]1([NH:16][CH2:15][CH2:14][N:62]1[CH2:63][CH2:64][CH:59]([S:56]([CH3:55])(=[O:58])=[O:57])[CH2:60][CH2:61]1)[CH2:34][CH2:33]2
Reactant: CS(=O)(=O)C1CCNCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)OC(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 4-(methylsulfonyl)piperidine as the alkylating reagent in Step 3. The product was isolated as a white solid (200 mg, 84%). LCMS: m/e 719.58 (M+H)+, 2.31 min (method 11). 1H NMR (500 MHz, Acetic) δ 8.04 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.37 (d, J=4.6 Hz, 1H), 4.87 (s, 1H), 4.75 (s, 1H), 3.76-3.70 (m, 2H), 3.68-3.54 (m, 4H), 3.48-3.29 (m, 1H), 3.18-3.03 (m, 2H), 3.02 (s, 3H), 2.84 (td, J=11.8, 4.7 Hz, 1H), 2.46-1.03 (m, 26H), 1.77 (s, 3H), 1.22 (s, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([C@H:10]1[C:18]2[C:13](=[CH:14][C:15]([F:32])=[C:16]([O:19][CH2:20][CH2:21][NH:22][S:23]([C:26]3[N:27]=[CH:28][N:29]([CH3:31])[CH:30]=3)(=[O:25])=[O:24])[CH:17]=2)[CH2:12][C@H:11]1[N:33]1[CH2:36][C:35]([OH:38])([CH3:37])[CH2:34]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CI.[Cl-].[NH4+].[C:43](OCC)(=O)C>O1CCCC1>[CH2:3]([CH:10]1[C:18]2[C:13](=[CH:14][C:15]([F:32])=[C:16]([O:19][CH2:20][CH2:21][N:22]([CH3:43])[S:23]([C:26]3[N:27]=[CH:28][N:29]([CH3:31])[CH:30]=3)(=[O:25])=[O:24])[CH:17]=2)[CH2:12][CH:11]1[N:33]1[CH2:34][C:35]([OH:38])([CH3:37])[CH2:36]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: Cn1cnc(S(=O)(=O)NCCOc2cc3c(cc2F)C[C@@H](N2CC(C)(O)C2)[C@H]3Cc2ccccc2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(CCOc1cc2c(cc1F)CC(N1CC(C)(O)C1)C2Cc1ccccc1)S(=O)(=O)c1cn(C)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C. sodium hydride (0.589 mg, 0.022 mmol) was added to a solution of cis-N-(2-(3-benzyl-6-fluoro-2-(3-hydroxy-3-methylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide (9.1 mg, 0.018 mmol; see example 206) in dry tetrahydrofuran (1 ml). The obtained suspension was stirred for 30 min at 0° C. and 1 h at room temperature. After dropwise addition of methyl iodide (1.216 μl, 0.019 mmol) the reaction mixture was stirred for 5 h and poured on a mixture of sat. ammonium chloride/ethyl acetate. The organic layer was separated and the aqueous layer washed twice with ethyl acetate. The combined organic layers were washed with sat. ammonium chloride, water and brine, dried over magnesium sulfate, filtered and evaporated to obtain the crude product as a pale yellow oil, that was purified on 1.5×5 cm SiO2-column using 5% methanol in dichloromethane to afford N-(2-(3-benzyl-6-fluoro-2-(3-hydroxy-3-methylazetidin-1-yl)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-N,1-dimethyl-1H-imidazole-4-sulfonamide as clear oil. m=3.1 mg (33%)
Reaction SMILES: [OH:1][C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH2:15][C:16]([CH3:18])=[CH2:17])[CH2:3][CH2:4][N:5]([C:10]([CH3:14])([C:12]#[CH:13])[CH3:11])[C:6](=[O:9])[O:7][CH3:8].[N:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[N+:26]=[N-:27].O=C1O[C@H]([C@H](CO)O)C(O)=C1O>O.CC(O)(C)C.[O-]S([O-])(=O)=O.[Cu+2].O>[OH:1][C:2]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH2:15][C:16]([CH3:18])=[CH2:17])[CH2:3][CH2:4][N:5]([C:10]([C:12]1[N:27]=[N:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:13]=1)([CH3:14])[CH3:11])[C:6](=[O:9])[O:7][CH3:8]
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: C#CC(C)(C)N(CCC(O)(CC(=C)C)c1ccccc1)C(=O)OC
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: C=C(C)CC(O)(CCN(C(=O)OC)C(C)(C)c1cn(-c2ccccc2)nn1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 44 %

Procedure:
To a stirred solution of methyl 3-hydroxy-5-methyl-3-phenylhex-5-enyl(2-methylbut-3-yn-2-yl)carbamate (26 mg, 0.081 mmol) and azidobenzene (29 mg, 0.24 mmol) in H2O (1 mL) and t-BuOH (1 mL) was added ascorbic acid (3.2 mg, 0.016 mmol)followed by CuSO4.H2O (0.5 mg, 0.002 mmol). The mixture was stirred at rt for 2 d. Additional azidobenzene (29 mg, 0.24 mmol), ascorbic acid (3.2 mg, 0.016 mmol) and CuSO4.5H2O (0.5 mg, 0.002 mmol) were added. The mixture was stirred for 4 h at rt and purified by prep HPLC to afford methyl 3-hydroxy-5-methyl-3-phenylhex-5-enyl(2-(1-phenyl-1H-1,2,3-triazol-4-yl)propan-2-yl)carbamate (16 mg, 44%) as an oil. LC-MS Method 1 tR=2.00 min, m/z=449.
Reaction SMILES: [C:1]([O:4][C:5](=O)C)(=O)[CH3:2].[NH2:8][C:9]1[S:17][C:16]2[CH2:15][CH2:14][N:13]([CH2:18][CH3:19])[CH2:12][C:11]=2[C:10]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(OCC)(OCC)OCC>[CH2:1]([O:4][CH:5]=[N:8][C:9]1[S:17][C:16]2[CH2:15][CH2:14][N:13]([CH2:18][CH3:19])[CH2:12][C:11]=2[C:10]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:2]
Reactant: CCOC(=O)c1c(N)sc2c1CN(CC)CC2
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCOC=Nc1sc2c(c1C(=O)OCC)CN(CC)CC2
Yield: 94 %

Procedure:
0.5 ml of acetic anhydride was added to 3.8 g (14.9 mmol) of 2-amino-3-carboethoxy-5-ethyl-4,5,6,7-tetrahydrothieno-[3,2-c]pyridine in 40 ml of triethyl orthoformate, and the mixture was boiled under nitrogen and at reflux for 1 h. After the mixture had been decanted off from the insoluble black coating on the flask walls, it was then evaporated right down at 80° C. on a rotary evaporator. 3.5 g (94%) of crude product were isolated as a dark oil which is sufficiently pure for further reaction.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=2)=[CH:20][CH:19]=1.[ClH:33].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:33].[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:24]([C:21]5[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=5)=[N:25][CH:26]=4)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)nc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(F)cc4)nc3)cn12

Procedure:
Operations similar to those of Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 6-(4-fluorophenyl)nicotinic acid. The resulting solid was dissolved in ethyl acetate, followed by addition of 4N hydrochloric acid-ethyl acetate solution and concentration under reduced pressure. The title compound was obtained as white solid.