Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:18]([O:19]C)=[CH:17][C:6]2[C:7](=[O:16])[CH2:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=1.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[C:18]([OH:19])=[CH:17][C:6]2[C:7](=[O:16])[CH2:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)C(=O)Cc1ccccc1O2
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C1Cc2ccccc2Oc2cc(O)c(O)cc21
Temperature: 190 °C
Yield: 66.9 %

Procedure:
A mixture of 7,8-dimethoxy-10,11-dihydrodibenz[b,f]oxepin-10-one (5 mg) and pyridine hydrochloride (20 mg) was heated at 190° C. for two hours. Water was added to the reaction mixture followed by extracting with ethyl acetate. This was washed with water and dried over magnesium sulfate and the solvent was evaporated to give the title compound (Compound 13) (3 mg, 60%) as brown plates.
Reaction SMILES: C(OCC)(=O)C.N1C=CC=CC=1CC(O)=O.O.[CH2:18]1[CH:23]([C:24]([NH:26][CH:27]([C:34]([OH:36])=[O:35])[CH2:28][C:29]2[NH:33][CH:32]=[N:31][CH:30]=2)=[O:25])[NH:22][C:20](=[O:21])[CH2:19]1.[CH:37]1[CH:42]=[C:41]2[C:43]([CH2:46][CH:47]([NH2:57])[C:48]([NH:50][CH:51]([C:54]([OH:56])=O)[CH2:52][OH:53])=[O:49])=[CH:44][NH:45][C:40]2=[CH:39][CH:38]=1.[CH3:58][O:59][C:60]([C@@H:62]([NH2:71])[CH2:63][C:64]1[CH:69]=[CH:68][C:67]([OH:70])=[CH:66][CH:65]=1)=[O:61]>>[CH2:18]1[CH:23]([C:24]([NH:26][CH:27]([C:34]([OH:36])=[O:35])[CH2:28][C:29]2[NH:33][CH:32]=[N:31][CH:30]=2)=[O:25])[NH:22][C:20](=[O:21])[CH2:19]1.[NH2:57][C@H:47]([C:48]([NH:50][C@H:51]([C:54]([NH:71][C@H:62]([C:60]([O:59][CH3:58])=[O:61])[CH2:63][C:64]1[CH:65]=[CH:66][C:67]([OH:70])=[CH:68][CH:69]=1)=[O:56])[CH2:52][OH:53])=[O:49])[CH2:46][C:43]1[C:41]2[C:40](=[CH:39][CH:38]=[CH:37][CH:42]=2)[NH:45][CH:44]=1
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)NC(CO)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: O=C(O)Cc1ccccn1
Agent: O=C1CCC(C(=O)NC(Cc2cnc[nH]2)C(=O)O)N1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12

Procedure:
The reaction solution containing pyroglu-his azide, prepared as described in Example 22, is cooled to a temperature of -40°C., and to this is added a solution of 1.1 g. of trp-ser-tyr-OMe trifluoroacetate, as prepared in Example 4, 5, 6 and 7, in 4 ml. of degassed dimethylformamide. The pH of the resulting solution is adjusted to 8.0 by the addition of diisopropylethylamine, and the mixture is maintained at a temperature of -5°C. (with periodic adjustment of the pH to 8.0 by addition of diisopropylethylamine) for a period of 18 hours, at the end of which time the reaction to form the pentapeptide is substantially complete as shown by thin layer chromatography on silica gel G using the solvent system ethyl acetate-pyridine-acetic acid-water (10:5:1:3). The reaction solution is evaporated in vacuo; the residual material is dissolved in 50 ml. butanol; the butanol solution is washed with three 25 ml.-portions of water; the combined water washings are extracted with six 10 ml.-portions of butanol; and the combined butanol solutions are evaporated to a small volume. The crystalline material which precipitates is recovered by filtration, dried and further purified by chromatography on a silica gel column to give 0.5 g. of substantially pure pyroglu-his-trp-ser-tyr-OMe.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1.[F:22][C:23]([F:42])([F:41])[O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[CH:33][C:34]3[O:38][N:37]=[C:36]([OH:39])[C:35]=3[CH:40]=2)=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:62][N:63]1[CH:67]=[C:66]([CH2:68]O)[N:65]=[CH:64]1>C1COCC1>[CH3:62][N:63]1[CH:67]=[C:66]([CH2:68][O:39][C:36]2[C:35]3[CH:40]=[C:31]([C:28]4[CH:29]=[CH:30][C:25]([O:24][C:23]([F:22])([F:41])[F:42])=[CH:26][CH:27]=4)[CH:32]=[CH:33][C:34]=3[O:38][N:37]=2)[N:65]=[CH:64]1
Reactant: Oc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Reactant: Cn1cnc(CO)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cn1cnc(COc2noc3ccc(-c4ccc(OC(F)(F)F)cc4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
Diisopropylazodicarboxylate 40% solution in toluene (0.27 mL, 0.51 mmol) was added under stirring to a solution of 5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-ol (100 mg, 0.34 mmol), triphenylphosphine on resin (3 mmol/g) (330 mg, 1 mmol), and 1-methylimidazol-4-yl methanol (60 mg, 0.51 mmol) in THF. The reaction mixture was stirred at ambient temperature overnight. Volatiles were evaporated under vacuum and the residue was purified on 12 g silica gel with 0-20% methanol in dichloromethane and gave the title compound (40 mg, 0.103 mmol) as yellowish oil.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][CH2:22]Br.[OH-].[Na+].O>CS(C)=O>[C:15]([C:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][Br:21])#[N:16]
Reactant: BrCBr
Reactant: CCCCC(C#N)c1cccc(Oc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCC(C#N)(CBr)c1cccc(Oc2ccccc2)c1
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a solution of 10 g (0.038 mole) of 2-(3-phenoxyphenyl)hexanenitrile, 6.6 g (0.038 mole) of dibromomethane in 50 ml of dimethyl sulfoxide is added 3.2 g (0.04 mole) of 50% sodium hydroxide solution dropwise. The reaction mixture is stirred at 60° for one hour, poured into water and extracted with ether. The combined ether extracts are washed with water and dried over MgSO4. Solvent is evaporated to give 12 g of product.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][NH:16]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[H-].[Na+].I[CH3:24].Cl>C1COCC1.O>[F:20][C:2]([F:1])([F:19])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][N:16]3[CH3:24])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(-c2ccc3cc[nH]c3c2)cc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccc2ccc(-c3ccc(OC(F)(F)F)cc3)cc21
Reaction time: 0.5 h

Procedure:
To a solution of 6-(4-trifluoromethoxyphenyl)-1H-indole (0.853, 3.08 mmoles) in dry THF (10 mL) was added sodium hydride (60% dispersion on mineral oil, 0.47 g, 12.3 mmol), portionwise. The reaction mixture was stirred under nitrogen for 30 minutes and, then cooled in ice bath. A solution of iodomethane (0.38 mL, 6.1 mmole) in dry THF (10 mL) was added and the reaction mixture was stirred for 1 hour at room temperature. The mixture was then poured into excess water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography (Biotage apparatus) using 0.5% t-butyl methyl ether in hexane as an eluant. The title compound was obtained as a cream-colored solid that was vacuum dried at 66° C. (0.623 g, 70%). 1HNMR (300 MHz, DMSO-d6): δ7.85 (d, 2H, J=8.3 Hz), 7.75 (s, 1H), 7.65 (d, 1H, J=8.3 Hz), 7.45 (d, 2H, J=8.3 Hz), 7.3-7.4 (m, 2H), 6.45 (s, 1H), and 3.85 ppm (s, 3H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]2([OH:19])[CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.Cl.[O:21]=[S:22]1(=[O:30])[CH2:26][CH:25]([C:27]([NH2:29])=[O:28])[NH:24][CH2:23]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:24]3[CH:25]([C:27]([NH2:29])=[O:28])[CH2:26][S:22](=[O:30])(=[O:21])[CH2:23]3)=[O:14])[CH:9]=[CH:8][C:7]=2[C:15]2([OH:19])[CH2:18][CH2:17][CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2(O)CCC2)c(OCC2CC2)n1
Reactant: NC(=O)C1CS(=O)(=O)CN1
Agent: Cl
Product: NC(=O)C1CS(=O)(=O)CN1C(=O)c1ccc(C2(O)CCC2)c(OCC2CC2)n1
Yield: 9 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-(cyclopropylmethoxy)-5-(1-hydroxycyclobutyl)pyridine-2-carboxylic acid (CAN 1415899-53-4, 50 mg, 190 μmol) was reacted with 1,1-dioxo-1,3-thiazolidine-4-carboxamide hydrochloride (Example 127 d, 45.7 mg, 228 μmol) to give the title compound (7 mg, 8%) as colorless oil, MS (EI): m/e=410.5 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:39]1([C@H:45]([NH2:47])[CH3:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([C:5](=[O:7])[NH:47][C@@H:45]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:46])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Reactant: C[C@@H](N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc(C(=O)N[C@H](C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
A mixture of 3-bromo-5-(methoxycarbonyl)benzoic acid (0.60 g, 2.32 mmol) and HATU (1.06 g, 2.78 mmol) in DMF (15 mL) was stirred at room temperature for 10 min. Then (R)-1-phenylethanamine (0.28 g, 0.3 mL, 2.32 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with H2O (3 times) and brine, dried over sodium sulfate, and concentrated under vacuum to give the title compound (0.839 g, 99.9% yield): HPLC retention time: 2.17 min (method A). MS (ESI) (M+H)+ 362/364.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:15][C:16]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:17]=1[NH2:18]>>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][CH2:15][C:16]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:17]=3[NH2:18])=[N:3][C:4]=2[CH:10]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: Cc1ccc(N)c(CCl)c1
Agent: Cl
Product: COc1ccc2[nH]c(SCc3cc(C)ccc3N)nc2c1
Yield: 41.8 %

Procedure:
The title compound (1.95 g) was prepared by the method of Example 1 using 2.81 g of 2-mercapto-5-methoxybenzimidazole instead of 2-mercaptobenzimidazole and 3.00 g of 2-(chloromethyl)-4-methylaniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline. Analysis. Calc'd. for C16H17N3OS: C, 64.19; H, 5.72; N, 14.04; S, 10.71. Found: C, 63.71; H, 5.80; N, 13.86; S, 10.60.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:6]=1.[C:15](OC1C(Cl)=CC(Cl)=CC=1Cl)(=[O:29])[CH2:16][C:17](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:18].ClC1C=CC=CC=1>CCCCCC>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][C:15]([OH:29])=[CH:16][C:17](=[O:18])[N:6]2[N:5]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(CC(=O)Oc1c(Cl)cc(Cl)cc1Cl)Oc1c(Cl)cc(Cl)cc1Cl
Reactant: Nc1nnc(SCc2ccccc2)s1
Solvent: Clc1ccccc1
Solvent: CCCCCC
Product: O=c1cc(O)nc2sc(SCc3ccccc3)nn12
Reaction time: 0.33 h
Yield: 97.9 %

Procedure:
A mixture of 44.7 g of 2-amino-5-benzylthio-1,3,4-thiadiazole, 98.1 g of bis(2,4,6-trichlorophenyl) malonate and 140 ml of chlorobenzene was heated to 130°-140° C. and stirred for 20 minutes. After cooling, hexane was added to the mixture, and the formed precipitate was separated by filtration. The solid was washed with hexane and thus 57.1 g of 2-benzylthio-7-hydroxy-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 98%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([NH2:14])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)[CH3:2].C(O)(=O)C.CO[CH:25]1[CH2:29][CH2:28][CH:27](OC)O1>CCCCCCC>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([N:14]2[CH:25]=[CH:29][CH:28]=[CH:27]2)=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)[CH3:2]
Reactant: COC1CCC(OC)O1
Reactant: CCOC(=O)c1cc(OCC)c(N)c(OCC)c1
Solvent: CCCCCCC
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(OCC)c(-n2cccc2)c(OCC)c1
Yield: 82 %

Procedure:
To a solution of 4-amino-3,5-diethoxy-benzoic acid ethyl ester (3.0 g, 11.84 mmol, 1.0 equiv; prepared as described in I. Kompis and A. Wick Helv. Chim. Acta 1977, 60, 3025-3034) in heptane (10 mL) and conc. acetic acid (0.2 mL) was added 2,5-dimethoxy-tetrahydro-furan (1.88 g, 14.21 mmol, 1.2 equiv). After heating to reflux for 5 h, a Dean-Stark apparatus was attached and the reaction mixture heated for an additional time period of 5 h. Filtration of the crude reaction mixture and crystallization at 0° C. from heptane provided 2.94 g (82%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.15 (t, J=7.0 Hz, 6H), 1.27 (t, J=7.1 Hz, 3H), 3.98 (q, J=7.0 Hz, 4H), 4.28 (q, J=7.1 Hz, 2H), 6.07-6.08 (m, 2H), 6.73-6.74 (m, 2H), 7.22 (s, 2H). 13C NMR (75 MHz, DMSO): δ 14.11, 14.35, 61.06, 64.57, 106.87, 107.64, 122.61, 123.33, 129.29, 153.75, 165.06. MS (ISP): 303.4 [M+H]+.
Reaction SMILES: I[CH2:2]CI.[Cl:5][C:6](=[CH2:23])[CH2:7][C:8]1([CH3:22])[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:9]1=[O:21].ICI.[OH-].[Na+].Cl>C1COCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH:10]2[C:9]3([O:21][CH2:2]3)[C:8]([CH:7]=[C:6]([Cl:5])[CH3:23])([CH3:22])[CH2:12][CH2:11]2)=[CH:15][CH:16]=1
Reactant: C=C(Cl)CC1(C)CCC(Cc2ccc(Cl)cc2)C1=O
Reactant: ICCI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ICI
Product: CC(Cl)=CC1(C)CCC(Cc2ccc(Cl)cc2)C12CO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon atmosphere, anhydrous THF (9 ml) was combined with Sm (1.01 g, 6.71 mmol), and then, at room temperature, 1,2-diiodoethane (1.05 g, 3.73 mmol) was added. The reaction solution was stirred for 1 hour at room temperature, and then cooled to −7 degrees C. to −2 degrees C., and 2-(2-chloro-2-propenyl)-5-(4-chlorobenzyl)-2-methylcyclopentanone (Compound (V), (Ra)Xana=CH3, (Rb)Xbnb=CH2CCl═CH2, Ym=4-Cl) dissolved in diiodomethane (0.90 g, 0.00168×2.0 mol) and THF (5 ml) was added, and stirred for 1.5 hours at the same temperature. To this, a 2N aqueous solution of NaOH (8 ml) was added, and stirring was conducted for 1 hour while cooling with ice. A 2N aqueous solution of hydrochloric acid (8 ml) was added, and then extraction with hexane (100 ml×2) was conducted. The organic layer was washed with water (50 ml) and saturated brine (30 ml), and then dried over anhydrous sodium sulfate and concentrated to obtain a crude intended substance (0.44 g), which was used in the next reaction as it was.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[C:24](O)(=[O:28])[CH:25]([CH3:27])[CH3:26]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH:17][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Reactant: CC(C)C(=O)O
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)C(C)C)c2c1N

Procedure:
Prepared as in Example Da from ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example Db) and isobutyric acid as a white solid (58%). MS 388 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH2:18][C@@H:19]([OH:21])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:24]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25].[Na+].[I-]>C1COCC1.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH2:18][C@@H:19]([O:21][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](O)Cn1ncc2ccc(OCc3ccccc3)cc21
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc(OCc3ccccc3)cc21)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a mixture of (S)-1-(6-benzyloxyindazol-1-yl)-propan-2-ol (2.03 g, 7.20 mmol) in anhydrous THF/DMF (100 mL/35 mL) under nitrogen was added sodium hydride (60% in mineral oil, 0.40 g, 10.0 mmol). After 30 min tert-butyl-chloro-dimethyl-silane (1.52 g, 110 mmol) and a catalytic amount of NaI were added and the mixture was stirred overnight at ambient temperature. Additional NaH (5 mmol) and tert-butyl-chloro-dimethyl-silane (5 mmol) were added to the reaction mixture, which was stirred for 6 h. The reaction mixture was evaporated to a residue that was mixed with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2×200 mL). Purification by chromatography (silica, EtOAc/hexane) gave an oil (2.81 g, 99%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=1.[H-].[Na+].[CH2:20]([O:22][CH2:23][CH2:24]Br)[CH3:21]>CN(C=O)C>[CH3:13][C:10]1([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]2[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=[C:2]([O:1][CH2:21][CH2:20][O:22][CH2:23][CH3:24])[C:11]1=2
Reactant: CCOCCBr
Reactant: CC1(C)CCC(C)(C)c2c(O)cc(C=O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCOc1cc(C=O)cc2c1C(C)(C)CCC2(C)C
Reaction time: 1 h
Yield: 86 %

Procedure:
36 g (156 mmol) of 4-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde are dissolved in 400 mL of anhydrous DMF. 6.5 g (163 mmol) of 60% sodium hydride are added portionwise and the reaction medium is stirred for 1 hour. 25 g (163 mmol) of 2-ethoxyethyl bromide are added portionwise and the medium is stirred at room temperature for 2 hours and then hydrolysed and extracted with ethyl ether. The organic phase is washed with 1N sodium hydroxide solution, and then three times with water. The residue obtained is purified by chromatography (eluent:heptane). A yellow oil is obtained (m=40.7 g; yield=86%).
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[OH-].[Na+].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].Cl>CC(C)=O.O>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:1][CH:2]([CH2:3][CH2:4][S:5][CH3:6])[C:7]([OH:9])=[O:8])=[O:16]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CSCCC(N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CSCCC(NC(=O)c1ccccc1F)C(=O)O

Procedure:
To a clear solution of D,L-methionine (10 g, 67.02 mmol) and NaOH (4.0 g, 100.53 mmol) in acetone (100 ml)/ H2O (100 ml) was added 2-fluorobenzoyl chloride dropwise with stirring between each addition. Basicity was maintained by adding 2N NaOH when necessary. After addition was completed, the reaction mixture was acidified to pH 2 with 6N HCl and extracted into EtOAc. The organic layer was dried with Na2SO4, filtered, and concentrated to give provide 2-(2-fluorobenzoylamino)-4-methylsulfanyl-butyric acid (intermediate XIIa, 13.6 g) as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70](=[O:72])[CH3:71])=[CH:66][CH:65]=1>>[C:70]([C:67]1[CH:68]=[CH:69][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)(=[O:72])[CH3:71]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(=O)c1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(NC(=O)C2NC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)cc1
Yield: 37.2 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.2 g, 0.36 mmol), was reacted with diisopropylethylamine (0.18 g, 1.4 mmol), diphenylphosphinic chloride (0.17 g, 0.71 mmol), then reacted with 1-(4-aminophenyl)ethanone (Aldrich) (0.058 g, 0.43 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-acetyl-phenyl)-amide as a yellow solid (Yield 0.078 g, 38%).
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[OH:10])=[N+:2]=[N-:3].[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([O:10][C@@H:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]1[N:1]=[N+:2]=[N-:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: [N-]=[N+]=NC1CCCCC1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@@H]1CCCC[C@H]1OCc1ccccc1
Reaction time: 0.17 h
Yield: 85.3 %

Procedure:
To a solution of 2-azidocyclohexylalcohol (1 g, 7.1 mmol) in THF (10 mL), sodium hydride (284 mg, 7.1 mmol) was added. After 10 minutes, benzyl bromide (0.84 mL, 7.1 mmol) was added. The reaction mixture was partitioned between ethyl acetate and NaHCO3 (aq.). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure and chromatography of the resulting liquid on silica gel (hexane: ethyl acetate; 10:1) gave product (1.4 g, 85%). EI-MS m/z 232 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:18]([OH:20])=O)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.[CH3:41][NH:42][O:43][CH3:44]>C1COCC1>[CH3:44][O:43][N:42]([CH3:41])[C:18]([C:9]1[O:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:11][C:10]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:20]
Reactant: CNOC
Reactant: O=C(O)c1oc(-c2ccccc2)nc1-c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON(C)C(=O)c1oc(-c2ccccc2)nc1-c1ccccc1
Temperature: 50 °C
Yield: 74.7 %

Procedure:
A solution of the above-prepared 2,4-diphenyl-oxazole-5-carboxylic acid (427 mg, 1.61 mmole, 1.0 eq) in dry THF was treated with carbonyldiimidazole (340 mg, 2.09 mmole, 1.3 eq) and the mixture heated at 50° C. for 3 hours. Triethylamine (360 uL, 2.58 mmole, 1.6 eq) and N,O-dimethylhydroxylamine-HCl (236 mg, 2.42 mmole, 1.5 eq) were added and the mixture heated at 50° C. for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with 5% KHSO4 and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to a brown oil. The crude oil was chromatographed on silica gel eluting with (7:3) hexanes-ether to give 371 mg (75%) of the title compound as a brown crystalline solid. 1H NMR (CDCl3) δ 3.35 (s, 3H), 3.8 (s, 3H), 7.3-7.6 (m, 6H), 7.95 (dd, 2H), 8.15 (dd, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH:12]=[CH2:13].[CH3:14]COC(C)=O>CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH:12]1[CH2:14][CH2:13]1
Reactant: C=Cc1c(Br)ccc2c1COC2=O
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: O=C1OCc2c1ccc(Br)c2C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) mixture of 5-bromo-4-vinyl-2-benzofuran-1(3H)-one (2.2 g, 9.21 mol) and Pd(OAc)2 (100 mg) in EtOAc (50 mL) was added a solution of CH2N2 in ether (100 mL) slowly. The resulting mixture was stirred at room temperature overnight, then quenched with acetic acid, filtered and the filtrate washed with water and brine, dried and concentrated to provide the title compound.