Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[C:8]([CH3:27])=[N:9][O:10][C:11]=2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2C(OCC2C=CC=CC=2)=O)=[CH:4][CH:3]=1.I[Si](C)(C)C>ClCCl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[C:8]([CH3:27])=[N:9][O:10][C:11]=2[C@H:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)=[CH:4][CH:3]=1
Reactant: Cc1noc([C@H]2CCCN2C(=O)OCc2ccccc2)c1Cc1ccc(Cl)cc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: Cc1noc([C@H]2CCCN2)c1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
To a solution of (R)-benzyl 2-(4-(4-chlorobenzyl)-3-methylisoxazol-5-yl)pyrrolidine-1-carboxylate (220 mg, 0.54 mmol) in dichloromethane (20 mL) at 0° C. was added iodotrimethylsilane (110 μL, 0.8 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 3 h, concentrated in vacuo and diluted with ether (30 mL). The organic layer was extracted with 1M HCl (2×50 mL). The aqueous layer was basified with 6 M NaOH and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford (R)-4-(4-chlorobenzyl)-3-methyl-5-(pyrrolidin-2-yl)isoxazole (110 mg, 74%). LCMS: calculated: 276, found (MH+): 277.
Reaction SMILES: [CH3:1][CH:2]([S:4]Cl)[CH3:3].[O:6]1[CH2:10][CH2:9][NH:8][C:7]1=[O:11].CN(C)CC1C=CC=CC=1>ClC1C=CC=CC=1.CN(C)C=O>[CH3:1][CH:2]([S:4][N:8]1[CH2:9][CH2:10][O:6][C:7]1=[O:11])[CH3:3]
Reactant: O=C1NCCO1
Reactant: CC(C)SCl
Agent: CN(C)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: Clc1ccccc1
Product: CC(C)SN1CCOC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
A solution of 0.6 mol of 2-propylsulphenyl chloride in 200 ml of chlorobenzene was added dropwise at 0° to 10° C. to 52.2 g (0.6 mol) of oxazolidin-2-one and 85 g (0.62 mol) of dimethylbenzylamine in 200 ml of chlorobenzene and 50 ml of dimethylformamide. After stirring for 1.5 hours at room temperature, the mother liquor was filtered from precipitated amine hydrochloride, washed with water and dried over sodium sulphate and the solvent was subsequently removed in vacuo at 40° C. 58 g of 3-(2-propylthio)oxazolidin-2-one were obtained as a brown oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:20][C:21]1[C:30]([CH2:31][CH2:32][CH3:33])=[C:29]2[C:24]([CH2:25][CH2:26][CH:27]([C:34]([O:36][CH3:37])=[O:35])[O:28]2)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:38](C1NC=CN=1)(=[O:40])[CH3:39].S([O-])(O)(=O)=O.[K+]>O1CCCC1>[C:38]([C:27]1([C:34]([O:36][CH3:37])=[O:35])[CH2:26][CH2:25][C:24]2[C:29](=[C:30]([CH2:31][CH2:32][CH3:33])[C:21]([O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:22][CH:23]=2)[O:28]1)(=[O:40])[CH3:39]
Reactant: CCCc1c(OCc2ccccc2)ccc2c1OC(C(=O)OC)CC2
Reactant: CC(=O)c1ncc[nH]1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCc1c(OCc2ccccc2)ccc2c1OC(C(C)=O)(C(=O)OC)CC2
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
A 100 ml 3 neck roundbottom flask was fitted with a magnetic stirring bar, dropping funnel, serum cap, and gas inlet tube, flushed with argon and flame dried. 1.11 g or 1.54 ml (11 mmole) of diisopropylamine and 30 ml dry tetrahydrofuran were added. After cooling to -20° C., 6.43 ml of 1.71M n-butyl lithium (11 mmole) was added dropwise via syringe. The solution was stirred 15 minutes at -10° C. and then cooled to -70° C. 3.40 g (10 mmole) of the product of Example 22 in 20 ml tetrahydrofuran at -70° C. was added dropwise over a period of half hour. After stirring one additional hour at -70° C., 1.27 g (11.5 mmole) of acetylimidazole in 10 ml tetrahydrofuran was added and the reaction mixture allowed to warm slowly to -10° C. 0.5M potassium hydrogen sulfate solution was added until the pH reached 2.0, the layers were separated and 100 ml ethyl acetate was added. The organic layer was washed with 0.5M potassium hydrogen carbonate, twice with water and then dried with anhydrous magnesium sulfate. After filtration, the ethyl acetate was removed by rotary evaporation and the residual oil purified by high pressure liquid chromatography (10% ethyl acetate-hexane) to give 2.42 g (63%) of the title compound as an oil. Calc: C, 72.22; H, 6.85; Found: C, 72.43; H, 6.86.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:9]([CH:11]([CH2:14][CH3:15])[CH2:12]O)[CH3:10]>C([O-])(=O)C([O-])=O.[Sn+4].C([O-])(=O)C([O-])=O.O>[C:1]([O:8][CH2:12][CH:11]([CH2:14][CH3:15])[CH2:9][CH3:10])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCC(CC)CO
Reactant: CCCCCC(=O)O
Agent: O=C([O-])C(=O)[O-]
Agent: [Sn+4]
Solvent: O
Product: CCCCCC(=O)OCC(CC)CC
Temperature: 10 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
580.8 g (5 mol) of caproic acid, 613.1 g (6 mol) of 2-ethylbutanol and 0.34 g of tin oxalate (“Fascat 2001”) were heated to 160° C. under N2, during which water separation was observed. Once water separation had subsided, the mixture was heated to 210° C. in 10° C. steps. This temperature was then held for 3 h. Then, firstly the excess alcohol was removed by distillation and then the product was distilled at 13-31 mbar and 114-124° C. The product (879.9 g) was obtained as a clear liquid with an acid number of 0.26 and an OH number of 2.17.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=O)[CH2:8]2.C(O)C.C1(C)C=CC(S([CH2:24][N+:25]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+]>COCCOC>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:24]#[N:25])[CH2:8]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: N#CC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 77.1 %

Procedure:
To a solution of 2-adamantanone (6.24 g, 41.50 mmol) in anhydrous 1,2-dimethoxyethane (150 mL) was added anhydrous ethanol (3.6 mL, 61.00 mmol) and p-toluenesulfonylmethyl isocyanide (10.0 g, 51.50 mmol) at 0° C. Potassium tert-butoxide (7.03 g, 62.70 mmol) was added in portions over 35 minutes under nitrogen atmosphere. The reaction mixture was stirred for 3.5 hours at ambient temperature. The mixture was filtered through a pad of diatomaceous earth that was washed with ethyl acetate (200 mL). The filtrate was washed with brine (2×200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to dryness. The residue was purified by column chromatography with a gradient of 0-10% ethyl acetate in hexanes to afford the title compound (5.16 g, 77% yield) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 2.88 (s, 1H), 2.15-2.11 (m, 4H), 1.92-1.85 (m, 4H), 1.75-1.70 (m, 6H); MS (ES−) m/z 162.2 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2Cl)[CH3:2].[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOCC>[CH2:1]([C:3]1[CH2:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: CCC1=Cc2cccc(Cl)c2C1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: CCC1=Cc2cccc(-c3ccccc3)c2C1
Yield: 80 %

Procedure:
A 5 L flask was equipped as in Example 3. 178 g 2-ethyl-7-chloroindene (1 mol), 1 L ether and 10.8 g Ni(dpp) (0.02 mol, 2 mol%) added, followed by 355 mL of 3.1M phenylmagnesium bromide in ether (1.1 mol, 10% excess). After quenching and work-up by the method described in Example 3, 176 g 2-ethyl-7-phenylindene (0.8 mol) was obtained by vacuum distillation at 140° C. in 80% yield.
Reaction SMILES: [C:1](=[S:3])=S.[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[N:14]=[C:13]2[CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)=[CH:7][CH:6]=1.[C:35]1([CH2:41][N:42]2[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[N:44]=[C:43]2[CH2:51][CH:52]2[CH2:57][CH2:56][N:55]([CH2:58][CH2:59][NH2:60])[CH2:54][CH2:53]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[N:14]=[C:13]2[CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][CH2:27]2)=[CH:7][CH:6]=1.[N:60]([CH2:59][CH2:58][N:55]1[CH2:56][CH2:57][CH:52]([CH2:51][C:43]2[N:42]([CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[N:44]=2)[CH2:53][CH2:54]1)=[C:1]=[S:3]
Reactant: NCCN1CCC(Cc2nc3ccccc3n2Cc2ccccc2)CC1
Reactant: S=C=S
Agent: Cc1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3cccnc32)cc1
Solvent: C1CCOC1
Product: S=C=NCCN1CCC(Cc2nc3ccccc3n2Cc2ccccc2)CC1
Yield: 89 %

Procedure:
To a stirred and cooled (-10° C.) mixture of 20.8 parts of carbon disulfide, 9 parts of N,N-methanetetraylbis[cyclohexanamine] and 135 parts of tetrahydrofuran was added dropwise a solution of 15 parts of 4-[[1-(phenylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidineethanamine in tetrahyrofuran at a temperature below -10° C. The reaction mixture was allowed to reach room temperature and the solvent was evaporated. The residue was crystallized from acetonitrile. The precipitate was filtered off and the filtrate was evaporated, yielding 15 parts (89%) of 2-[[1-(2-isothiocyanatoethyl)-4-piperidinyl]methyl]-1-(phenylmethyl)-1H-benzimidazole (385).
Reaction SMILES: CC([N:5]([C@@H:9]1[CH2:14][C@@H:13]([CH3:15])[CH2:12][N:11]([C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([F:30])[CH:23]=3)[N:19]=[C:18]([NH2:31])[N:17]=2)[CH2:10]1)C(=O)[O-])(C)C.[ClH:32]>O1CCOCC1>[ClH:32].[NH2:31][C:18]1[N:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([F:30])[CH:23]=2)[CH:21]=[C:16]([N:11]2[CH2:12][C@H:13]([CH3:15])[CH2:14][C@@H:9]([NH2:5])[CH2:10]2)[N:17]=1
Reactant: C[C@@H]1C[C@@H](N(C(=O)[O-])C(C)(C)C)CN(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H](N)CN(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1,1-dimethylethyl{(3R,5R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-5-methyl-3-piperidinyl}carbamate (127 mg, 0.298 mmol) in 1,4-dioxane (4 mL) was added 4M HCl in 1,4-dioxane (0.074 mL, 0.298 mmol), and the reaction was allowed to stir at room temperature for 3 hours. The reaction was concentrated to afford the bis HCl salt of the title compound (164 mg) as an off-white solid. LC-MS (ES) m/z=327 [M+H]+.
Reaction SMILES: [ClH:1].C1(C)C=CC=C[C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14]N.Cl.O.[NH:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.Cl>CCO>[ClH:1].[CH3:3][C:8]1[C:9]2[NH:14][C:22]3[CH2:21][CH2:20][NH:19][CH2:24][C:23]=3[C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccccc1-c1ccccc1NN
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cccc2c3c([nH]c12)CCNC3
Temperature: 25 °C
Yield: 89 %

Procedure:
o-Tolylphenylhydrazine hydrogen chloride (25 g, 158.6 mmol) and 4-piperidone monohydrate hydrogen chloride (24.4 g, 158.6 mmol) were suspended in EtOH (310 mL). Concentrated aqueous HCl (26 g, 317 mmol) was then added. The mixture was refluxed for 3 h, and then the reaction was cooled to rt. The ppt was filtered and washed with cold EtOH. The white solid was air-dried for 18 h. 6-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (36.6 g, 141.2 mmol, 89%) was isolated and a white powder. 1H NMR (CD3OD, 300 MHz) δ 7.22–7.25 (1H, m), 6.89–6.96 (2H, m), 4.40 (2H, m), 3.60 (2H, t, 6.2 Hz), 3.16 (2H, t, 6.2 Hz), 2.45 (3H, s) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])=[CH:4][CH:3]=1.Br[CH:30]([CH3:39])[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=O>C(#N)C>[CH3:39][C:30]1[N:7]2[CH:6]=[C:5]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])[CH:4]=[CH:3][C:2]2=[N:1][C:31]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Nc1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1
Reactant: CC(Br)C(=O)c1ccccc1
Solvent: CC#N
Product: Cc1c(-c2ccccc2)nc2ccc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cn12
Temperature: 80 °C
Reaction time: 24 h
Yield: 37.5 %

Procedure:
0.05 g (0.13 mmol) of N-[6-aminopyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide prepared according to the protocol described in step 4.2, 0.056 g (0.26 mmol) of 2-bromo-1-phenylpropan-1-one and 4 mL of acetonitrile are introduced into a 10 mL screw-topped tube equipped with a magnetic bar. The top is then screwed on and the tube is heated at 80° C. with stirring for 24 hours. After this time and cooling to room temperature, the precipitate obtained is filtered off and rinsed successively with 2 mL of acetonitrile and 2 mL of isopropyl ether. The solid obtained is dried under reduced pressure. 0.024 g of the expected product is thus obtained.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH:19]([CH3:21])[N:18]([C:22]3[S:23][C:24]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:25]=4[N:26]=3)[CH:17]([CH3:35])[CH2:16]2)[CH:6]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:36])=[O:2])=[CH:6][C:7]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH:19]([CH3:21])[N:18]([C:22]2[S:23][C:24]3[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][C:25]=3[N:26]=2)[CH:17]([CH3:35])[CH2:16]1
Reactant: COC(=O)Cc1ccc(Cl)c(OCCN2CC(C)N(c3nc4ccc(C(F)(F)F)cc4s3)C(C)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1CN(CCOc2cc(CC(=O)O)ccc2Cl)CC(C)N1c1nc2ccc(C(F)(F)F)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
A mixture of [4-chloro-3-[2-[3,5-dimethyl-4-(6-trifluoromethyl benzothiazole-2-yl)piperazine-1-yl]ethoxy]phenyl]acetic acid methyl ester (178 mg), 2N aqueous sodium hydroxide (0.66 mL), tetrahydrofuran (2 mL) and methanol (2 mL) was stirred at room temperature for 2 hours. The mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (83 mg). Yield: 48%.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20]>O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:19]([O:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[O:20])[CH2:3][CH2:2]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2c(c1)NCCO2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1 g of 3,4-dihydro-2H-1,4-benzoxazine, 1.03 ml of triethylamine, 27 ml of tetrahydrofuran and then 1.5 g of para-nitrophenyl chloroformate are introduced into a 100 ml round-bottomed flask. The reaction mixture is stirred at ambient temperature for three hours and then filtered. The solvent is evaporated under reduced pressure and the residue is taken up in dichloromethane and washed with a 2N aqueous hydrochloric acid solution and then twice with water. The organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure to result in 2.1 g of 4-nitrophenyl 2,3-dihydro-4H-1,4-benzoxazine-4-carboxylate.
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[C:7]([C:17]([O:19][CH2:20]C)=[O:18])[CH:6]=1)(=O)C.[OH-].[Na+].Cl.OS(O)(=O)=O>O.C(O)C.CO>[OH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:6]=1
Reactant: CCOC(=O)c1cc(OC(C)=O)c2cc(OC)ccc2c1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(O)c2cc(OC)ccc2c1
Yield: 67.5 %

Procedure:
A solution of ethyl 4-acetoxy6-methoxy-2-naphthoate (3.0 g, 10.4 mmol) and sodium hydroxide (2.5 g, 62.5 mmol) in water (60 cm3) and ethanol (15 cm3) was maintained at 80-90° C. for 3 hours. The cooled solution was poured into water (400 cm3) and cautiously acidified with c. HCl. The resulting suspension was extracted with EtOAc (5×75 cm3). The combined extracts were dried (Na2SO4) and evaporated to give a pale brown solid. This solid was dissolved in methanol (50 cm3) containing c. H2SO4 (˜1 cm3) and was refluxed for 4 hours. The cooled mixture was diluted with water (500 cm3) and extracted with EtOAc (4×50 cm3). The combined extracts were washed with aq. sat. NaHCO3 (2×100 cm3) and water (100 cm3). Removal of the dried (Na2SO4) EtOAc gave a pale brown solid which was recrystallised from EtOAc/hexane to afford methyl 4-hydroxy-6-methoxy-2-naphthoate (yield=1.63 g, theoretical yield=2.41 g, 68%, m.p.=193-195° C. (uncorrected)).
Reaction SMILES: [O:1]1[CH2:6]C[CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=3[F:32])[CH:14]=2)=[N:11][CH:12]=1.O1CCOC1C1C=CC(C2SC3C(=NC=CC=3Cl)C=2)=NC=1>>[O:1]1[CH2:6][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=3[F:32])[CH:14]=2)=[N:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Agent: Clc1ccnc2cc(-c3ccc(C4OCCO4)cn3)sc12
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1
Yield: 72 %

Procedure:
Following the procedure described above for the synthesis of compound 30 (Scheme 8) but substituting compound 29 for compound 36, title compound 37 was obtained in 72% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.68 (d, J=1.8 Hz, 1H), 8.64 (d, J=5.5 Hz, 1H), 8.49 (dd, J=10.4, 2.5 Hz, 1H), 8.47 (s, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.23-8.21 (m, 1H), 8.00 (dd, J=8.2, 2.0 Hz, 1H), 7.73 (t, J=8.5 Hz, 1H), 6.99 (d, J=5.5 Hz, 1H), 5.89 (s, 1H), 4.12-4.06 (m, 2H), 4.04-3.98 (m, 2H). MS (m/z): 440.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH3:21])[C:12]3[CH:32]=[CH:33][C:34]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:35][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:44](=[O:46])[CH3:45])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH3:21])[C:12]3[CH:32]=[CH:33][C:34]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:35][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2Sc3cc(OCc4ccccc4)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(OCc4ccccc4)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2OC(C)=O)cc1

Procedure:
A mixture of 3.75 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-benzyloxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 23 ml of acetic anhydride and 8 ml of pyridine is treated in the same manner as described in Example 1-(2). 4.18 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-benzyloxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]2[O:23][CH:22]2[C:24]([O-:26])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:28]>CC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C@@H:21]2[O:23][C@H:22]2[C:24]([NH2:28])=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])C1OC1c1ccccc1CCCCCCCCc1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Product: NC(=O)[C@@H]1O[C@H]1c1ccccc1CCCCCCCCc1ccccc1
Temperature: 25 °C
Yield: 86 %

Procedure:
The ester of Example 5c (2R-trans)-(2-napththalenyl) 3-[2-(8-phenyloctyl)phenyl]oxiranecarboxylate (462 g, 1 mol) was dissolved in acetone (5 L) and ammonium hydroxide (1 L). After stirring briefly at room temperature the reaction mixture was heated to reflux for 20 minutes, recooled to room temperature and concentrated to 1/3 of the original volume on the rotary evaporator. The solution was diluted with toluene (10 L) and washed with 10% aq. NaOH (3×5 L), water (1×5 L) and brine (1×5 L). The toluene solution was further evaporated to a volume of 2.5 L and n-hexane (7.5 L) was added. Upon cooling in the refrigerator (~12 h), the solid was collected and dried to yield the titled oxiranecarboxamide (302 g, 86%). Mp 81°-82° C.; [α]D +13.2° (c 1, CH2Cl2, 25° C.), [α] 546 +16.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:20])[C:15]=2[Br:19])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>CN(C=O)C.C(OCC)(=O)C>[CH3:33][O:32][C:30](=[O:31])[CH2:29][O:20][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])[CH:10]=2)[C:15]=1[Br:19]
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(Br)c(O)ccc2c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc2cc(CNC(=O)OC(C)(C)C)ccc2c1Br
Reaction time: 8 h
Yield: 95.8 %

Procedure:
A mixture of (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-carbamic acid tert-butyl ester (0.89 g, 2.5 mmol), prepared in the previous step, potassium carbonate (1.7 g, 12.5 mmol), and methyl bromoacetate (1.26 mL, 2.75 mmol) in 10 mL of DMF was stirred under nitrogen for 18 h (overnight). The reaction was diluted with ethyl acetate and extracted three times with water. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give [1-bromo-6-(tert-butoxycarbonylamino-methyl)-naphthalen-2-yloxy]-acetic acid methyl ester (1.016 g, 96%) as an off white solid, mp 96-100° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[NH:8][NH2:9].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:19]>CN(C=O)C>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18](=[O:19])[CH2:17][NH:9][NH:8][C:7]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CNNC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Potassium carbonate (3 equivalents) was added to a solution of tert-butyl carbazate (500 mg, 3.8 mmol) in DMF at 0° C. After 10 minutes, 2-bromo-1-(4-methoxyphenyl)ethanone (1 equivalent) was added and the reaction stirred at 0° C. for 1 hour. After this time, the reaction was worked-up to give crude tert-butyl 2-[2-(4-methoxyphenyl)-2-oxoethyl]hydrazinecarboxylate. The material was carried through without purification. ESI-MI m/z [M+Na]+ 303.2.
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24][CH:25]([C:29](O)=[O:30])[C:26](O)=[O:27])([CH2:16][CH3:17])[CH3:15]>>[CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24][C:25]1[C:26](=[O:27])[O:9][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:29]=1[OH:30])([CH2:16][CH3:17])[CH3:15]
Reactant: CCC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Product: CCC(C)c1ccccc1Sc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.0 g, 6.17 mmol) and diethyl ester of [(2-sec-butylphenyl)thio]propanedioic acid (1.0 g, 3.09 mmol). m.p. 170-171° C.; 1H NMR (400 MHz, DMSO-d6) δ0.86(t, 3H), 1.22 (d, 3H), 1.57 (m, 1H), 1.67 (m, 1H), 3.22 (m, 1H), 6.89 (s, 1H), 6.97 (d, 1H), 7.06 (t, 1H), 7.13 (t, 1H), 7.22 (d, 1H), 7.56 (m, 3H), 7.86 (m, 2H).