Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:11])([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:39])=[C:19]([C:21]2([CH:36]([F:38])[F:37])[CH2:23][N:22]2[S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])[CH:20]=1>CN(C=O)C.C1COCC1>[C:6]([O:5][C:3](=[O:4])[C:2]([O:1][CH2:23][C:21]([C:19]1[CH:20]=[C:15]([Br:14])[CH:16]=[CH:17][C:18]=1[F:39])([NH:22][S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])[CH:36]([F:38])[F:37])([CH3:11])[CH3:10])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)C(C)(C)O
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CC1(c1cc(Br)ccc1F)C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)OCC(NS(=O)(=O)c1ccccc1[N+](=O)[O-])(c1cc(Br)ccc1F)C(F)F
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a solution of tert-butyl α-hydroxyisobutyrate (533 mg, 3.32 mmol) in 4.5 mL DMF and 0.75 mL THF was added portion wise (133 mg, 3.32 mmol) sodium hydride at room temperature. After the reaction mixture had been stirring for 15 minutes, a solution of 2-(5-bromo-2-fluoro-phenyl)-2-difluoromethyl-1-(2-nitro-benzenesulfonyl)-aziridine (1 g, 2.22 mmol) was added. The reaction mixture was stirred at rt for 150 minutes and quenched with aqueous NH4Cl solution. TBME was added, the layers were separated, washed with brine and TBME. The combined organic layers were dried over MgSO4.H2O and evaporated. The crude product was purified on a silica gel column by eluting with hexane/EtOAc 6/1->5/1 to give 1.10 g of the title compound as a pale yellow resin.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si](OCC)(OCC)OCC.[C:15]1(C=[CH:21][C:19](O)=[CH:18][CH:17]=1)[OH:16]>C1(C)C=CC=CC=1>[O:16]1[C:15]2[CH:17]=[CH:18][CH:19]=[CH:21][C:4]=2[CH:3]=[CH:2][NH:1]1
Reactant: Oc1ccc(O)cc1
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1
Yield: 65 %

Procedure:
This compound was prepared according to the method described previously using 3-aminopropyltriethoxysilane (22.1 g, 100 mmole), paraformaldehade (6.3 g, 210 mmole), hydroquinone (5.5 g, 50 mmole), and toluene (150 ml). The final product was a viscous liquid. The yield was 65% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:10]=[C:11]([CH3:13])[CH3:12])[C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][CH:11]([CH3:12])[CH3:13])[C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1
Reactant: CCc1ncc(Br)cc1N=C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1ncc(Br)cc1NC(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To solution of (5-bromo-2-ethyl-pyridin-3-yl)-isopropylidene-amine (Stage 162.1.2, 1.17 mmol) in dichloromethane (25 ml) was added AcOH (0.25 ml) and sodium triacetoxyborohydride (3.51 mmol). The reaction mixture was stirred for 4 h at rt. The RM was quenched with aqueous NaHCO3 and extracted with dichloromethane (2×). The combined organic layers were washed with saturated aqueous NaHCO3, with brine, dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and eluted (CH2Cl2/MeOH 0% to 3%). The fractions containing the product were purified by preparative HPLC. The fractions containing pure product were basified with NaHCO3, concentrated and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and evaporated to the title compound as an oil (HPLC: tR 2.40 min (Method A); M+H=243, 245 MS-ES).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:11]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:23][C:22]2[CH:24]=[CH:25][C:19]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:20][CH:21]=2)=[CH:5][CH:4]=1
Reactant: CCCCCCCCc1ccc(N)cc1
Reactant: COc1ccc(C=O)cc1
Product: CCCCCCCCc1ccc(NCc2ccc(OC)cc2)cc1
Yield: 99.1 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-methoxybenzaldehyde (1.0 g) and 4-octylaniline (1.4 g) as starting materials, [(4-methoxyphenyl)methyl](4-octylphenyl)amine (2.2 g) was obtained.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[S:10]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11]1>>[S:10]1[CH:14]=[CH:13][C:12]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=2)=[CH:11]1
Reactant: OB(O)c1ccsc1
Reactant: O=Cc1ccc(Br)nc1
Product: O=Cc1ccc(-c2ccsc2)nc1

Procedure:
Synthesized using compound 43c (840 mg, 4.52 mmol) and thiophen-3-ylboronic acid (867 g, 6.77 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (8:2) as eluent. Orange solid. Yield: 556 mg, 65%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=7.45 (dd, J=5.0, 2.8 Hz, 1H), 7.72-7.80 (m, 2H), 8.11 (dd, J=2.8, 1.3 Hz, 1H), 8.19 (dd, J=8.2, 2.2 Hz, 1H), 9.06 (dd, J=2.2, 0.9 Hz, 1H), 10.11 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=120.3, 126.3, 126.4, 126.9, 129.6, 136.5, 141.1, 152.6, 158.0, 190.2; (ESI): m/z=190.27 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1.[Li+].[OH-].O.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 50 °C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
To a magnetically stirred solution of ethyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (18.44 g, 0.0466 mol) in THF (240 ml) was added LiOH (2.24 g, 0.0932 mol) and H2O (240 ml). The resulting mixture was stirred at 50° C. for 16 h to give a clear solution. After cooling to room temperature, HCl (1 N solution, 95 ml) and H2O (240 ml) were added to give a precipitate which was collected by filtration, washed with water and dried in vacuo to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid (16.83 g, 98% yield), mp 138–142° C. (decomposition); 1H-NMR (600 MHz, DMSO-d6) δ 7.08 (br d, J=8 Hz, 2H), 7.31–7.37 (m, 4H), 7.45 (d, J=8 Hz, 1H), 7.96 (s, 1H); 13C-NMR (150 MHz, DMSO-d6) δ 126.87, 127.85, 127.91, 128.47, 129.36, 129.66, 133.56, 133.99, 134.44, 134.49, 135.54, 135.99, 143.77, 163.67.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH2:7][CH:8]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:8]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:7][C:2]([CH3:23])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(C)(C)CC(CCCCO)CCCc1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)CC(CCCCOS(C)(=O)=O)CCCc1cccnc1
Reaction time: 1 h

Procedure:
To a solution of 1.28 g (4 mmol) of methyl 2,2-dimethyl-4-[3-(3-pyridyl)propyl]8-hydroxyoctanoate in 20 ml methylene chloride at 0° is added 0.9 ml (6.5 mmol) triethylamine followed by 0.4 ml (5.2 mmol) methylsulfonyl chloride. After 1 h, the reaction mixture is diluted with methylene chloride and washed with saturated sodium bicarbonate, water and brine. The organic phase is dried, filtered and evaporated to give methyl 8-methylsulfonyloxy-2,2-dimethyl-4-[3-(3-pyridyl)propyl]-octanoate as an oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.COC1C=CC(C[O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([C:36]3[CH:40]=[CH:39][O:38][N:37]=3)[CH2:23][C:24]([O:26][CH2:27][C:28]3C=CC(OC)=CC=3)=[O:25])=[CH:18][CH:17]=2)=CC=1>C(Cl)Cl>[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:36]2[CH:40]=[CH:39][O:38][N:37]=2)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=1
Reactant: COc1ccc(COC(=O)CC(c2ccc(OCc3ccc(OC)cc3)cc2)c2ccon2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC(c1ccc(O)cc1)c1ccon1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79 %

Procedure:
TFA (10 mL) was added to 40.4 (940 mg) in DCM (10 mL). The mixture was stirred at room temperature for 1.5 hours. TFA and DCM were removed under vacuum, and the residue was treated with EtOH (50 mL). The insoluble solid was removed by filtration. To the filtrate was added concentrated sulfuric acid (2 drops). The mixture was stirred at 80° C. overnight. After concentration, the crude product was purified by flash chromatography to give 40.5 (410 mg). MS ESI (pos.) m/e: 262 (M+H). 1HNMR (CDCl3) δ 8.29 (d, 1H), 7.12 (d, 2H), 6.76 (d, 2H), 6.10 (d, 1H), 4.56 (t, 1H), 4.10 (q, 2H), 3.27 (dd, 1H), 2.97 (dd, 1H), 1.19 (t, 3H). The racemic compound 40.5 was separated into two enantiomers 40.6 and 40.7 using chiral preparative AD-H column (8% IPA/92% hexanes). The stereochemistry of 40.6 and 40.7 was assigned arbitrarily.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([NH2:20])=[N:16][NH:17]2)=[CH:13][CH:12]=1>N1C=CC=CC=1>[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([NH:20][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])=[N:16][NH:17]2)=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2cc(Cl)ccc12)c1ccccc1
Temperature: 3 °C
Reaction time: 12 h

Procedure:
0.69 cm3 of benzoyl chloride is added to 1 g of 6-chloro-1H-indazole-3-amine in 15 cm3 of pyridine, cooled to about 3° C. The reaction medium is allowed to return to about 19° C. over 12 hours and is then evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 25 cm3 of ethyl acetate and 25 cm3 of distilled water. The organic phase is washed with 25 cm3 of distilled water and 25 cm3 of saturated aqueous sodium chloride solution. The resulting solution is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4 cm), eluting with a dichloromethane/methanol mixture (99/1 by volume) and collecting 15 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 990 mg of N-[6-chloro-1H-indazol-3-yl]benzenamide are obtained in the form of a white solid melting at 188° C.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([NH:16]C(=O)C)=[N:13][C:12]=2[CH3:20])=[CH:7][CH:6]=1.[OH-].[Na+]>O.C(O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:15][C:14]([NH2:16])=[N:13][C:12]=2[CH3:20])=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2sc(NC(C)=O)nc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2sc(N)nc2C)cc1

Procedure:
A solution of concentrated hydrochloric acid HCl (20 ml) in water (30 ml) is added to N-[5-(4-Methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 28a) (2 g, 7.63 mmol) in ethanol. After 5 hours at reflux, the reaction is poured into water (600 ml) and the pH is adjusted to 9/10 with 2.5 M NaOH. The aqueous layer is then extracted with ethyl acetate (3×200 ml). The combined organic layers are dried over MgSO4, filtered and concentrated to afford 5-(4-Methoxy-phenyl)-4-methyl-thiazol-2-ylamine.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.C1N2CC[N:26](CC2)[CH2:25]1>C(#N)C>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[N:3]=[C:2]([C:25]#[N:26])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1
Reactant: Cc1ccc(Cn2cnc3c(-c4ccco4)nc(Cl)nc32)cc1
Reactant: C1CN2CCN1CC2
Solvent: CC#N
Product: Cc1ccc(Cn2cnc3c(-c4ccco4)nc(C#N)nc32)cc1
Reaction time: 48 h
Yield: 57.3 %

Procedure:
A solution of 2-chloro-6-(2-furyl)-9-(4-methylbenzyl)-9H-purine (0.10 g, 0.31 mmol) and Et4NCN (0.10 g, 0.62 mmol) in acetonitrile (10 mL) was treated with DABCO (0.07 g, 0.62 mmol), stirred for 48 h, concentrated in vacuo, dissolved in chloroform (50 mL), washed with water (2×30 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (56 mg, 57%) as a pale green solid.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:12]O>>[CH3:12][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[OH:11]
Reactant: Oc1cccc2ccccc12
Reactant: CO
Product: Cc1ccc2ccccc2c1O

Procedure:
α-Naphthol is methylated using methanol to form 2-methyl-1-naphthol over a catalyst bed of alumina. The reaction provides high selectivity to 2-methyl-1-naphthol. Alumina catalysts derived from alumina alkoxide hydrolysis are preferred.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2=[N:12][CH:13]=[N:14][C:15]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)=[C:10]2[CH:9]=[N:8]1.[ClH:32]>O1CCOCC1>[ClH:32].[NH:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([NH:16][C:15]2[N:14]=[CH:13][N:12]=[C:11]3[NH:7][N:8]=[CH:9][C:10]=23)[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncnc3c2cnn3COCC[Si](C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: c1nc(N[C@@H]2CCCNC2)c2cn[nH]c2n1
Reaction time: 0.5 h

Procedure:
To a solution of compound (R)-tert-butyl 3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (1 g, 2.22 mmol) in dioxane (10 mL) at 0° C., a solution of HCl in dioxane (10 mL) was added until the pH was acidic at 0° C. and stirred for 30 min, at the same temperature. The reaction mixture was concentrated to give a residue that was triturated with ether to give (R)—N-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride as a free flowing solid. Then the compound was dissolved in MeOH, and to the reaction mixture was added a carbonate polymer support resin until the mixture turns basic (Checked by pH paper). The reaction mixture was filtered and the filtrate was concentrated in vacuo to yield the titled compound (350 mg, 72%). 1H NMR (400 MHz, DMSO-d6): δ 13.1 (bs, 1H), 8.28 (s, 1H), 8.23 (s, 1H), 4.46 (bs, 2H), 3.36-3.34 (m, 2H), 3.16-3.08 (m, 1H), 2.99-2.86 (m, 2H), 2.50 (bs, 1H), 1.97-1.81 (m, 2H), 1.68-1.58 (m, 2H). LC-MS: m/z [M+1]=219.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[N:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[C:1]1([N:7]2[CH:11]=[N:10][C:9]([C:12]([Cl:17])=[O:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ncn(-c2ccccc2)n1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ncn(-c2ccccc2)n1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a mixture of 2.00 g (10.5 mmol) 1-phenyl-1H-[1,2,4]-triazole-3-carboxylic acid in 20 mL DCM was added 10.0 mL (137 mmol) thionyl chloride and 1 drop of DMF. The reaction mixture was stirred at 40° C. for 1 h. The solvent was removed by distillation. Yield: 2.20 g (100%); ESI-MS: m/z=204 (M+H)+ (methyl ester); Rt(HPLC): 1.04 min (method 8) (methyl ester)
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[C@H:15]1[CH2:19][C@@:18]2([CH2:24][CH2:23][CH2:22][NH:21][C@H:20]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O.O>[ClH:1].[CH2:37]([N:21]1[CH2:22][CH2:23][CH2:24][C@:18]2([O:17][CH2:16][C@@H:15]([C:5]3[CH:6]=[C:7]([O:10][C:11]([F:14])([F:12])[F:13])[CH:8]=[CH:9][C:4]=3[O:3][CH3:2])[CH2:19]2)[C@@H:20]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COc1ccc(OC(F)(F)F)cc1[C@@H]1CO[C@]2(CCCN[C@H]2c2ccccc2)C1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(OC(F)(F)F)cc1[C@@H]1CO[C@]2(CCCN(Cc3ccccc3)[C@H]2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3R,5R,6S)-3-(2-Methoxy-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxa-7-aza-spiro[4,5]decane hydrochloride (Example 165, 100 mg, 0.2 mmol) and potassium carbonate (38 mg) were dissolved in dimethyl formamide (0.5 mL). Benzyl bromide (0.3 mL) was added and the mixture was stirred at room temperature overnight, then at 60° C. for 3 h. The mixture was cooled, diluted with water (10 mL) and extracted into ether (3×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (5 mL) and ethereal hydrogen chloride (1 M, 1 mL) was added. The solid was collected and dried in vacuo to give the title compound as a crystalline solid (19 mg). 1H NMR (360 MHz, d6 -DMSO) δ 1.75 (3H, m), 2.01 (2H, m), 2.22 (2H, m), 2.96 (1H, m) 3.63 (3H, s), 3.67 (1H, m), 3.92 (1H, m), 4.01 (1H, m), 4.41 (1H, d, J 9.74 Hz), 6.92 (1H, d, J 8.9 Hz), 7.05 (1H, s), 7.13 (1H, d, J 8.65 Hz), 7.31 (2H, d, J 6.53 Hz), 7.42 (3H, m), 7.60 (4H, m), and 7.91 (1H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:64])[CH:7]([NH:13][C:14](=[O:63])[CH2:15][CH2:16][CH:17]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[NH:18][C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([CH2:27][NH:28][C:29](=[O:55])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:23][CH2:22]1)=[O:20])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:78]1[C:83](=[O:84])[CH2:82][CH2:81][C:79]1=[O:80])=[N+](C)C)C.CCN(C(C)C)C(C)C>C1COCC1>[O:80]=[C:79]1[CH2:81][CH2:82][C:83](=[O:84])[N:78]1[O:11][C:10](=[O:12])[CH2:9][CH2:8][CH:7]([NH:13][C:14](=[O:63])[CH2:15][CH2:16][CH:17]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[NH:18][C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([CH2:27][NH:28][C:29](=[O:55])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])[CH2:23][CH2:22]1)=[O:20])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:64]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NCC1CCC(C(=O)NC(CCC(=O)NC(CCC(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NCC1CCC(C(=O)NC(CCC(=O)NC(CCC(=O)ON2C(=O)CCC2=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Yield: 86.4 %

Procedure:
To a solution of 2-[4-tert-butoxycarbonyl-4-({4-[(19-tert-butoxycarbonylnonadecanoylamino)methyl]-cyclohexanecarbonyl}amino)butyrylamino]pentanedioic acid 1-tert-butyl ester (4.6 g) in THF (150 ml) was added TSTU (1.68 g). DIPEA (0.97 ml) was added. After stirring over night the mixture was concentrated in vacuo. The residue was crystallized from acetonitrile to afford the title compound as a solid (4.4 g, 87%)
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[C:11]2[OH:16])(=[O:4])=[O:3].C(O)C.[N:20]([O-])=[O:21].[Na+]>O.[Cl-].[Zn+2].[Cl-]>[N:20]([C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[CH:13][CH:14]=[CH:15][C:6]=2[NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:11]=1[OH:16])=[O:21]
Reactant: O=N[O-]
Reactant: CS(=O)(=O)Nc1cccc2c(O)cccc12
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Nc1cccc2c(O)c(N=O)ccc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture comprising 119 g of 5-methanesulfonylamino-1-naphthol, 100 g of zinc chloride and 500 ml of ethanol was heated at 50° C., and then a solution of 35 g of sodium nitrite as dissolved in 70 ml of water was added dropwise thereto at 50° to 65° C. After being heated and stirred at 60° to 65° C. for 2 hours, the resulting solution was cooled with water to room temperature, and reddish brown crystals formed were taken out by filtration and washed with ethanol. The crystals were added to 200 ml of concentrated hydrochloric acid and stirred for 1 hour at room temperature, and then 200 ml of water was added thereto. Yellowish brown crystals (2-nitroso-5-methanesulfonylamino-1-naphthol) formed were taken out by filtration, washed with water and dried. Yield: 90 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:11]([CH3:24])=[CH:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Se](=O)=[O:28]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:11]([CH2:24][OH:28])=[CH:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[Se]=O
Reactant: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(-c3ccccc3)cc21
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1c2ccc(-c3ccccc3)cc2C(CO)=CC1(C)C
Yield: 23.1 %

Procedure:
A solution of N-tert-butyloxycarbonyl-1,2-dihydro-2,2,4-trimethyl-6-phenyl quinoline (structure 10, where R1=phenyl) (310 mg, 0.888 mmol) and selenium dioxide (345 mg, 3.11 mmol) in 17 mL of dioxane was heated to reflux for 3 h. The reaction mixture was quenched with 1:1 NaS2O3 (10%)/Na2HCO3 (10%), extracted with dichloromethane, dried (MgSO4), and the organic phase was concentrated ill vacuo. Purification by flash chromatography (silica gel, hexane/ethyl acetate, 4:1) gave 212 mg of the intermediate aldehyde along with 75 mg of the desired alcohol of structure 11, where R1=phenyl. The aldehyde was treated with sodium borohydride in 25 mL of methanol at 0° C. After 1 h at 0° C., the reaction mixture was quenched with water, extracted with ethyl acetate and concentrated in vacuo to give an oil that was purified by flash chromatography (silica gel, hexane/ethyl acetate, 4:1) providing structure 11, where R1=phenyl (240 mg, 84%). 1H NMR (acetone d6) 7.68 (d, J=9, 2H), 7.61 (d, J=1.8, 1H), 7.47 (dd, J=6.2, 1.8, 1H), 7.41 (d, J=6.4, 2H), 5.80 (s, 1H), 4.51 (d, J=6.8, 2H), 4.12 (t, J=6.8, 1H), 1.52 (br s, 15H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:14]([CH2:15][S:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH3:24])[CH:18]=2)[C@H:13]([OH:25])[C@@H:12]2[C@H:10]1[C@H:11]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:40][S:41](Cl)(=[O:43])=[O:42]>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:14]([CH2:15][S:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH3:24])[CH:18]=2)[C@H:13]([O:25][S:41]([CH3:40])(=[O:43])=[O:42])[C@@H:12]2[C@H:10]1[C@H:11]2[C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(SC[C@@H]2[C@H](O)[C@H]3[C@H](C(=O)OC(C)(C)C)[C@H]3[C@]2(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1cc(SC[C@@H]2[C@H](OS(C)(=O)=O)[C@H]3[C@H](C(=O)OC(C)(C)C)[C@H]3[C@]2(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1F
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
Di-tert-butyl (1S,2R,3S,4R,5R,6R)-2-(tert-butoxycarbonylamino)-3-[(4-fluoro-3-methyl-phenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (4.6 g, 8.10 mmol) in pyridine (60 mL) is cooled to 0° C. To this mixture is added methanesulfonyl chloride (1.88 ml, 24.31 mmol). The mixture is warmed to 40° C. and stirred for 1 hour, and cooled to ambient temperature and allowed to stir for 18 hours. The mixture is concentrated under reduced pressure to give a residue. The residue is partitioned between ethyl acetate and 1N aqueous HCl (2×50 mL). The organic layer is separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (5.2 g, 8.05 mmol, 99.4% yield): MS (m/z): 643.6 (M−H).