Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(O[C:35](=O)[N:36]([CH2:38][CH2:39][NH2:40])C)(C)(C)C.Cl>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[CH2:21][CH2:22]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH:40][CH2:39][CH2:38][NH:36][CH3:35])=[O:14])=[CH:4][CH:3]=1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: O=C(O)Cn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21
Agent: Cl
Product: CNCCNC(=O)Cn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of {6-chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetic acid (preparation described herein), with (commercially available) (2-amino-ethyl)-methyl-carbamic acid tert-butyl ester gave, after treatment with HCl and neutralisation, the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N+:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33])([O-:28])=[O:27]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:32]([C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([N+:26]([O-:28])=[O:27])[CH:30]=4)=[O:33])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc([N+](=O)[O-])c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 3-nitrobenzoyl chloride as starting compounds. The crude product is purified by column chromatography (silica gel and DCM/EA=1:1) and by crystallization from EA and diethyl ether to yield 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-{1-[(3-nitrophenyl)carbonyl]piperidin-4-yl}-2,4-dihydro-3H-pyrazol-3-one as the product.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([CH:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1)([C:17]#[N:18])[C:12](OCC)=[O:13])=O)(C)(C)C.[H-].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[C:17]([C:11]1([CH:19]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]2)[CH2:10][CH2:9][NH:8][C:12]1=[O:13])#[N:18]
Reactant: CCOC(=O)C(C#N)(CCNC(=O)OC(C)(C)C)C1CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C2(C#N)CCNC2=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
tert-Butyl 3-(4-((tert-butoxycarbonyl)amino)-2-cyano-1-ethoxy-1-oxobutan-2-yl)azetidine-1-carboxylate (7 g) obtained in Step B of Example 309 in tetrahydrofuran (80 mL) was added sodium hydride (60% in mineral oil, 816 mg) in an ice bath, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:21])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCc1ccccc1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)Cc1ccccc1)CC2

Procedure:
First 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane (60 g, 0.2 mol) is heated to 130° C. with N-methyl-benzylamine (65 g, 0.54 mol) for 1.5 hours. After cooling the mixture is distributed between water and methylene chloride. The organic phase is separated off, dried and evaporated. The residue is purified by chromatography on silica gel (eluant: methylene chloride/methanol=10:1). M.p. of the hydrochloride: 205°-208° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([O:24][CH3:25])=[C:13]([CH:23]=2)[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:6]=[CH:7][CH:8]=1.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH:2]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([O:24][CH3:25])=[C:13]([CH:23]=2)[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH:6]=[CH:7][CH:8]=1)=[O:1]
Reactant: COc1ccc(-c2cccc(CO)c2)cc1CNC(=O)OC(C)(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COc1ccc(-c2cccc(C=O)c2)cc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
747 mg of t-Butyl N-{5-[3-(hydroxymethyl)-phenyl]-2-methoxybenzyl}carbamate, 510 mg of N-methylmorpholin-N-oxide, 76 mg of tetrapropyl ammonium perruthenate and 1 g of 4A molecular sieve powder were dissolved in 1 g of dichloromethane, and the mixture was stirred at room temperature for 2hours. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by silica gel column, to give 566 mg of the title compound in the 3:1→1:1 hexane-ethyl acetate fraction.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3](OC)([O:19]C)[C:4]([NH:9][C:10](=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13])=[CH:5][C:6]2=[O:8].C(OCC)(=O)C>C(Cl)Cl>[O:1]1[CH:2]2[CH:7]1[C:6](=[O:8])[CH:5]=[C:4]([NH:9][C:10](=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13])[C:3]2=[O:19]
Reactant: COC1(OC)C(NC(=O)c2ccccc2O)=CC(=O)C2OC21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NC1=CC(=O)C2OC2C1=O)c1ccccc1O
Yield: 47.1 %

Procedure:
5,6-Epoxy-4,4-dimethoxy-3-salicyloylamino-2-cyclohexenone (1.0 g, 3.27 mmol) was dissolved in methylene chloride (25 ml), trifluoroboron diethyl ether complex (1 ml) was added thereto under ice cooling, and the mixture was stirred at the same temperature as described above for 30 minutes. Ethyl acetate (300 ml) was added to the reaction mixture and the reaction mixture was washed with water (200 ml). After drying it over Glauber's salt, the ethyl acetate layer was dried under vacuum to obtain brown solids, which were washed with methanol (5 ml) to obtain the titled compound (399 mg) as pale brown solids (yield: 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH3:8].[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19].CCN(C(C)C)C(C)C.N#N>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([O:9][CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH3:8]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1cc([N+](=O)[O-])ccc1OCC(C)O
Agent: N#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc([N+](=O)[O-])ccc1OCC(C)OCOCC[Si](C)(C)C
Yield: 156.8 %

Procedure:
To a solution of 1-(2-methoxy-4-nitrophenoxy)propan-2-ol (1.537 g, 6.76 mmol) in DCM (20 mL) was added SEM-Cl (2.4 mL, 13.5 mmol) followed by DIPEA (4.7 mL, 27.1 mmol) dropwise under N2. The mixture was stirred O.N. at RT., diluted with DCM (20 mL), washed with 1N HCl, brine, dried (Na2SO4), and evaporated under reduced pressure to obtain a yellow oil (3.79 g) which was purified by flash chromatography (40 g silica, 0% to 100% EtOAc-Hexanes) to yield. Example 6A (2.03 g, 5.68 mmol, 84% yield) as a yellow oil.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:4]([OH:8])[C:5]([OH:7])=[O:6].[CH3:13]O>>[ClH:1].[NH2:2][C@@H:3]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:4]([OH:8])[C:5]([O:7][CH3:13])=[O:6]
Reactant: CO
Reactant: CC(C)C[C@H](N)C(O)C(=O)O
Agent: Cl
Product: COC(=O)C(O)[C@@H](N)CC(C)C
Reaction time: 8 h

Procedure:
Hydrogen chloride was passed into a solution 110 mg of (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoic acid in 10 ml of methanol under ice-cooling, and the mixture was stirred overnight. The reaction mixture was evaporated to dryness under reduced pressure to obtain 150 mg of methyl (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride as a white powder.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CO)cc1OC1CCCC1

Procedure:
To a solution of 48.70 g (220 mmoles) of 3-cyclopentyloxy-4-methoxybenzaldehyde in 250 ml of methanol was added portionwise 8.57 g (220 mmoles) of 97% sodium borohydride within 10 min at 15-22° C. under cooling. After a further 20 min the methanol was removed in vacuo and the residue taken up in 10 ml of water and 300 ml of ether. The ether phase was evaporated to dryness: 48.5 g (99.2%) of liquid benzyl alcohol.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([CH:21]3[CH2:25][CH2:24][CH2:23][N:22]3[CH3:26])[CH:18]=[N:19][CH:20]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].[Cs+]>CO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[C:17]([CH:21]3[CH2:25][CH2:24][CH2:23][N:22]3[CH3:26])[CH:18]=[N:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: CN1CCCC1c1cncc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: CN1CCCC1c1cncc(-c2ccc(O)cc2)c1
Yield: 92.5 %

Procedure:
The above-described pyridine derivative (750 mg, 2.04 mmol) was dissolved in methanol (40 mL) and cesium fluoride (620 mg, 4.08 mmol) was added. The stirred mixture was heated at reflux for 18 h under inert atmosphere. After cooling the solvent was removed in vacuo and the resulting oil was dissolved in ethyl acetate (50 mL). This was washed with water (20 mL), brine (20 mL), dried (MgSO4) and concentrated. The crude material was chromatographed on "flash" silica gel with ethyl acetate:hexane (1:2 ) to 10% methanol:ethyl acetate as eluant to afford 5-(4-hydroxyphenyl)-3-(1-methyl-2-pyrrolidinyl)pyridine 480 mg, 93% as a colorless foam, 1H NMR (CDCl3, 300 MHz): δ 8.66 (d, J=2 Hz, 1H), 8.43 (d, J=2 Hz, 1H), 7.90 (s, 1H), 7.32 (d, J=9 Hz, 2H), 6.81 (d, J=9 Hz, 2H), 3.33 (t, J=8 Hz, 1H), 3.22 (t, J=8 Hz, 1H), 2.41 (m, 1H), 2.28 (s, 3H), 2.10 (m, 2H), 1.93 (m, 2H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].S(Cl)([Cl:16])=O>C(Cl)Cl.CN(C=O)C>[N:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: O=S(Cl)Cl
Reactant: [N-]=[N+]=NCc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=NCc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of p-azidomethylbenzoic acid (1.063 g, 6.00 mmol) in CH2Cl2 (60 ml) at room temperature were added dropwise thionyl chloride (1 ml, excess) and DMF (5 drops). The mixture was stirred at room temperature for 2.5 h and evaporated, yielding 1.13 g of title compound as a light yellow oil: 1Hmr (CDCl3) δ: 4.48 (2H, s, --CH2N3), 7.38-7.52-8.07-8.22 ppm (4H, A2 'B2 ', aromatic Hs); ir (neat) νmax : 2090 (--N3) and 1750 cm-1 (br. --COCl). This material was used in the next step without further purification.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.[CH3:9][CH:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCCCCC.O>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:10]([CH3:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:1][CH:2]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCCCCC(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: CCCCCC(C)Oc1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 60.4 %

Procedure:
p-Bromophenol (295.52 grams (“g”), 1500.00 millimole) is dissolved in anhydrous dimethyl formamide (“DMF”) (500 milliliters) in a 2000 milliliter (“mL”) 3-necked flask equipped with mechanical stirrer and condenser, under an argon atmosphere. To this solution, (1-methyl) hexylbromide (322.38 grams, 1800.00 millimoles), sodium iodide (33.57 g, 225.00 mmol) and anhydrous potassium carbonate (621.95 g, 4500.00 mmol) are added. The resulting suspension is heated to 100° C. and stirred at that temperature for 72 hours. After cooling to room temperature, water (1000 mL) and n-hexane (300 mL) are added. The aqueous layer is separated and extracted with n-hexane (3×100 mL). The combined organic layers are washed with diluted sodium chloride solution (2×100 mL) and dried (MgSO4). The solvent is removed by rotary evaporation under reduced pressure and the residue is filtered using a SiO2 layer (10×10 cm) and n-hexane as eluent. After removal of solvent by rotary evaporation and in vacuo a colorless liquid (245.54 g, 60%) is obtained.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1.[OH-].[Na+].S(OC)(O[CH3:27])(=O)=O>O>[CH3:27][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(O)c1ccc(-c2ccccc2S)cc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C(O)c1ccc(-c2ccccc2SC)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 3.85 g. of ethyl 2'-mercapto-4-biphenylylglycolate is 40 ml. of water containing 0.65 g. of sodium hydroxide is added 2 ml. of dimethyl sulfate with stirring. The reaction mixture is gradually warmed to 40°C and stirred for 2 hours. The mixture is cooled and extracted with ether which is washed with water, dried and evaporated in vacuo. The residue is distilled to obtain ethyl 2'-methylthio-4-biphenylylglycolate.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[S:12][C:11]([NH:14][C:15]([NH:17][CH2:18][CH3:19])=[O:16])=[N:10][C:9]=2[CH:8]=[C:7]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=1)=O.O.[NH2:27][NH2:28]>CO.O>[CH2:18]([NH:17][C:15]([NH:14][C:11]1[S:12][C:13]2[C:5]([C:3]([NH:27][NH2:28])=[O:2])=[CH:6][C:7]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:8][C:9]=2[N:10]=1)=[O:16])[CH3:19]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)OC)c2s1
Reactant: NN
Solvent: CO
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)NN)c2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
A suspension of 2-(3-Ethyl-ureido)-5-pyridin-3-yl-benzothiazole-7-carboxylic acid methyl ester (319 mg, 0.895 mmol) in methanol (10 ml) was treated with hydrazine hydrate (2 ml) and stirred at ambient temperature for 16 h. HPLC indicated that the reaction mixture still contained a considerable amount of starter so a further 1 ml of hydrazine hydrate was added and the stirring continued for a further 24 h. The resultant mixture was diluted with water (50 ml) and the solid collected by filtration. This was washed with water (25 ml) followed by ethanol (25 ml) and dried in vacuo to give 1-Ethyl-3-(7-hydrazinocarbonyl-5-pyridin-3-yl-benzothiazol-2-yl)-urea as an off-white solid (312 mg, 98%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(=O)([O-])[O-].[Na+].[Na+].[C:19](Cl)(=[O:21])[CH3:20].Cl>CC(C)=O>[OH:12][C:3]1[C:2]([NH:1][C:19](=[O:21])[CH3:20])=[CH:11][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: CC(=O)Cl
Reactant: Nc1cc2ccccc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)Nc1cc2ccccc2cc1O
Temperature: 0 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
An acetone solution (60 ml) of 3-amino-2-naphthol (5.0 g, 31.4 mmol) was added to an aqueous solution (20 ml) of sodium carbonate (4.77 g, 34.5 mmol). The mixture was cooled in an ice-water bath, and then acetyl chloride (2.27 ml, 32.0 mmol) was added to the mixture dropwise over 5 minutes. The resulting mixture was stirred at 0° C. for 4 hours and then allowed to stand at room temperature overnight. 2N Hydrochloric acid was added to the reaction mixture to adjust its pH to 3. The generated insoluble matter was separated, washed with water, and then dried, giving a white powder of N-(3-hydroxynaphthalen-2-yl)acetamide (4.9 g, yield: 78%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:27])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[C:13]([CH3:26])[CH:12]=1>ClCCl>[CH3:8][O:9][C:10](=[O:27])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[C:13]([CH3:26])[CH:12]=1
Reactant: COC(=O)c1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (20 ml) was added to a solution of 4-tert-butoxycarbonylmethoxy-3-methyl-benzoic acid methyl ester from Example E41.1 (3.8 g, 13.6 mmol) in di-chloromethane (40 ml) and the mixture was stirred for 1 h at room temperature. Volatiles were removed in vacuo and azeotroped with dichloromethane to yield the title compound (3.04 g, 100%).
Reaction SMILES: [O:1]1[C@H:3]2[CH:4]=[C:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[NH2:30][CH2:31][CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1.C(O)CCC>COC(C)(C)C>[OH:1][C@:2]12[CH2:26][C@@H:25]([OH:27])[CH2:24][CH2:23][C@:22]1([CH3:28])[C@@H:21]1[C:5]([C@H:6]3[C@:18]([CH3:29])([CH2:19][CH2:20]1)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]3)=[CH:4][C@H:3]2[NH:30][CH2:31][CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1
Reactant: NCCc1c[nH]cn1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Solvent: COC(C)(C)C
Solvent: CCCCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C[C@@H](NCCc4c[nH]cn4)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 18 %

Procedure:
5,6α-epoxicholest-7-en-3β-ol (8.9 g, 22.1 mmol, 1 eq) and histamine (4.9 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-[2-(1H-imidazol-4-yl)-ethylamino]-cholest-7-en-3β-ol) as a white solid (7.2 g, 64%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 18% yield.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.[Si:22]([O:29][C@H:30]([CH3:60])[C@@H:31]([NH:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[C:49]([C:55]([F:58])([F:57])[F:56])[C:48]=1[CH3:59])[C:32]([NH:34][NH:35][C:36](=O)[C:37]1[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=1)=[O:33])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(Cl)Cl>[Si:22]([O:29][C@H:30]([CH3:60])[C@@H:31]([NH:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[C:49]([C:55]([F:58])([F:56])[F:57])[C:48]=1[CH3:59])[C:32]1[O:33][C:36]([C:37]2[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=2)=[N:35][N:34]=1)([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:23])[CH3:24]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Yield: 83.6 %

Procedure:
Triphenylphosphine (590 mg, 2.25 mmol) was dissolved in 25 mL of DCM followed by addition of I2 (571 mg, 2.25 mmol) and TEA (456 mg, 4.50 mmol) at 0° C. N′-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(4-cyano-2-methyl-3-(trifluoromethyl)phenylamino)butanoyl)-4-cyanobenzohydrazide (630 mg, 1.13 mind) in 25 mL DCM was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stirred. The temperature was allowed to rise to room temperature and stirred for additional 10 min. The reaction was quenched with 50 mL saturated sodium thiosulfate and extract with EtOAc. The crude mixture was chromatographed to give the product (510 mg, 84%) 1H NMR (400 MHz, acetone-d6, δ in ppm): 8.23 (d, J=9 Hz, 2H), 8.04 (d, J=9 Hz, 2H), 7.67 (d, J=9 Hz, 1H), 7.27 (d, J=9 Hz, 1H), 5.94 (d, J=9 Hz, 1H), 5.19 (m, 1H), 4.74 (m, 1H), 2.39 (m, 3H), 1.48 (d, J=6 Hz, 3H), 0.81 (s, 9H), 0.12 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)(=O)=O.[I-:20].[Na+]>CC(C)=O>[I:20][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)N1CCCC(COS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(CI)C1
Temperature: 58 °C
Yield: 90.9 %

Procedure:
t-Butyl 3-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (Preparation 68, 609.22 g, 2.08 mol, 1 eq) was dissolved in acetone (3 L), and the reaction mixture was flushed with nitrogen. Sodium iodide (619.84 g, 4.16 mol, 2 eq) was added, and the reaction was stirred at reflux (58° C.) under nitrogen. The reaction mixture was cooled to room temperature, filtered, and the solvent removed under vacuum. The residue was re-dissolved in diethyl ether (1.5 L), and this solution was washed with water (500 mL), saturated sodium bicarbonate (400 mL), 5% sodium thiosulfate (400 mL), and brine (400 mL). The solution was dried over sodium sulfate, and the solvent removed under vacuum to afford title compound as a yellow oil (616 g, 1.89 mol, 91%).