Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[CH3:7][C@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH3:14])[NH:9]1.Cl>C1(C)C=CC=CC=1>[CH3:7][C@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH3:14])[N:9]1[C:2]([O:4][CH2:5][Cl:6])=[O:3]
Reactant: O=C(Cl)OCCl
Reactant: C[C@@H]1CCC[C@H](C)N1
Agent: Cl
Solvent: Cc1ccccc1
Product: C[C@@H]1CCC[C@H](C)N1C(=O)OCCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution (24 ml) of 2.39 ml of chloromethyl chloroformate in toluene was added dropwise to 46 ml of a solution of 9.11 ml of cis-2,6-dimethylpiperidine in toluene under ice cooling over a period of 10 min, and the mixture was stirred at room temperature for 16 hr. 1 N hydrochloric acid (60 ml) was added thereto, followed by separation. The organic layer was washed with 60 ml of a 5% aqueous sodium hydrogencarbonate solution and 60 ml of 20% brine, was dried over anhydrous magnesium sulfate, and was filtered, and the solvent was removed by distillation under the reduced pressure to give 12.7 g of (cis-2,6-dimethylpiperidin-1-yl)carbonyloxymethyl chloride.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[Cl-].[Li+].C(N(CC)CC)C.CS([Cl:42])(=O)=O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:42][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CO)cc2)CC3)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To a mixture of N-[4-(hydroxymethyl)phenyl]-7-(4methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (2.20 g), lithium chloride (505 mg), triethylamine (1.67 ml), DMAP [4-dimethylaminopyridine] (catalytic amount) and dichloromethane (200 ml) was added methanesulfonyl chloride (645 μl), and the mixture was stirred at room temperature for 42 hours and concentrated under reduced pressure. To the residue was added 0.5N hydrochloric acid (200 ml), and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (973 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]3)[CH2:12][CH:11]2[OH:27])=[C:6]([F:28])[C:5]=1[F:29])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CC(O)C>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]3)[CH2:12][C:11]2=[O:27])=[C:6]([F:28])[C:5]=1[F:29])[CH3:2]
Reactant: CCCCCC1CCC(C2CCC(c3ccc(OCC)c(F)c3F)C(O)C2)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CC(C)O
Product: CCCCCC1CCC(C2CCC(c3ccc(OCC)c(F)c3F)C(=O)C2)CC1

Procedure:
46.7 g of 4-(4-ethoxy-2,3-difluorophenyl)-4′-pentylbicyclohexyl-3-ol were dissolved in 600 ml of dichloromethane, and 20 g of Celite were added. 28.0 g of pyridinium chlorochromate were added with stirring, and the mixture was stirred overnight at RT. After 10 ml of 2-propanol had been added, the mixture was stirred for 1 hour and then subjected to conventional work-up, giving 4-(4-ethoxy-2,3-difluorophenyl)-4′-pentylbicyclohexyl-3-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH2:61])=[N:58][C:57]=1[CH3:62])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:64](Cl)(=[O:67])[CH2:65][CH3:66]>>[CH3:1][O:2][C:3](=[O:63])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61][C:64](=[O:67])[CH2:65][CH3:66])=[N:58][C:57]=1[CH3:62])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1nc(C)c(S(=O)(=O)N2Cc3cc4c(cc3CC2C(=O)N[C@@H](Cc2ccc(-c3ccc(C#N)cc3)cc2)C(=O)OC)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)s1

Procedure:
(S)-2-({(S)-7-(2-Amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (30 mg) treated with propionyl chloride according to General Procedure F to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(4-methyl-2-propionylamino-thiazole-5-sulfonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino-[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester (19 mg).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:3]=1[CH2:4]OS(C1C=CC(C)=CC=1)(=O)=O.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCOCC1>[F:1][C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:3]=1[CH2:4][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCc2cc([N+](=O)[O-])ccc2F)cc1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(F)c(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of toluene-4-sulfonic acid 2-fluoro-5-nitro-benzyl ester (compound of step B of example 29) (0.696 g, 2.31 mmoles) in 1,4-dioxane (20 mL) was added TEA (0.32 mL, 2.31 mmoles) and pyrrolidine (0.19 mL, 2.31 mmoles). The reaction mixture was stirred for 24 h at room temperature, concentrated and purified by TLC (petroleum ether/AcOEt/NH4OH//8/2/0.2). The expected compound was obtained as a yellow oil (0.399 g, 77% yield). MALDI-TOF: m/z 225.1 [M+H]+. 1H NMR (300 MHz, CDCl3) δ8.38; (dd, J=6.2 Hz and 2.9 Hz, 1H), 8.15; (ddd, 4-CH, J=8.9 Hz, 2.9 Hz and 4.4 Hz, 1H), 7.17; (dd, J=8.9 Hz and 8.9 Hz, 1H), 3.76; (s, 2H), 2.5-2.6; (m, 4H), 1.8-1.9; (m, 4H). 13C NMR (75 MHz, CDCl3) δ127.0; (CH, d, J=6.4 Hz), 124.5; (CH, d, J=10.1 Hz), 116.2; (CH, d, J=24.9 Hz), 54.1; (CH2), 52.2; (CH2), 23.5; (CH2).
Reaction SMILES: O=O.[O:3]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:5]([NH:7][CH3:8])=[O:6].CO.[H][H]>Cl.C(Cl)Cl>[OH:3][C@H:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:5]([NH:7][CH3:8])=[O:6]
Reactant: [H][H]
Reactant: CNC(=O)C(=O)C(C)(C)C
Agent: Cl
Agent: O=O
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)[C@H](O)C(C)(C)C
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
A catalyst solution was prepared in a glove box (O2 content<1 ppm) by dissolving 385 mg (0.5 mmol) of [Ru(OAc)2((R)-BIPHEMP)] in 40 ml of a 0.025 molar methanolic hydrochloric acid solution and 40 ml of methylene chloride, subsequently stirred at 20° C. for 1.5 hours and thereafter transferred into a pressure-tight catalyst supply vessel. A 2 l steel autoclave was charged with 71.6 g (0.5 mol) of 2-keto-3,3,N-trimethyl-butyramide and 310 ml of methanol and sealed. After replacement of the atmosphere with hydrogen the catalyst solution was allowed to flow from the catalyst supply vessel into the autoclave with slight over-pressure and the hydrogenation was carried out while stirring at 60° C. and at a pressure of 60 bar (6 MPa). After 20 hours the hydrogenation was interrupted and the reaction mixture was evaporated. From a solution of the residue in 250 ml of diisopropyl ether there firstly separated at room temperature 1.2 g of crystalline product with ee=3% and a melting point of 135-137° C. By adding 275 ml of cyclohexane and stirring the mixture in an ice bath for 3 hours there were isolated 43.9 g (60.5%) of (R)-2-hydroxy-3,3,N-trimethyl-butyramide; m.p. 69-71° C.; [α]=+61.0° (c=1, CHCl3), ee=98.7% (measured by GC on an OV-61/p-DiMe-β-CD chiral column).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:34][CH:35]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:19]2[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=2)[CH2:29][C:30]2[CH:35]=[N:34][C:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:32][CH:31]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Reactant: ClCc1ccc(-c2ccccc2)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(-c3ccccc3)nc2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (600 mg) synthesized in Example 265-1 and 5-(chloromethyl)-2-phenylpyridine (360 mg) synthesized in Reference Example 21 were dissolved in N,N-dimethylformamide (10 mL), potassium tert-butoxide (200 mg) was added thereto, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:2 to 2:1) to give the title compound (740 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:5]([CH3:9])[C:6]([OH:8])=O.COC(C1C=C(O)C2C(=CC=C(F)C=2)C=1)=O>>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH3:9])=[C:6]([OH:8])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[CH:10]=1)=[O:18]
Reactant: COC(=O)C(=Cc1ccc(F)cc1)C(C)C(=O)O
Agent: COC(=O)c1cc(O)c2cc(F)ccc2c1
Product: COC(=O)c1cc2ccc(F)cc2c(O)c1C

Procedure:
Alternatively, Starting with 2-(4-fluoro-benzylidene)-3-methyl-succinic acid 1-methyl ester, using a method analogous to the one described above for 6-fluoro-4-hydroxy-naphthalene-2-carboxylic acid methyl ester, 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carboxylic acid methyl ester was obtained as a pale solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[C:15](Cl)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(OCC)(=O)C.CCCCCC>O1CCCC1.O>[O:8]=[C:5]1[CH2:6][CH2:7][N:2]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3][CH2:4]1
Reactant: O=C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 2.5 °C
Reaction time: 1.5 h

Procedure:
To a solution of piperidin-4-one hydrochloride (32 g, 0.23 mol) in tetrahydrofuran (320 ml, 10×) was added K2CO3 (64.2 g) dissolved in water (160 ml) at room temperature. The mixture was cooled to 0-5° C. and then Cbz chloride (50%) (74.28 ml, 1.1 eq.) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1-2 h. Progress of the reaction was monitored by TLC (30% ethyl acetate/hexane). Upon disappearance of the starting material the mixture was filtered and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×300 ml) and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica, 12% ethyl acetate/hexane). Yield: 40.7 g (74%)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH:11]([CH2:14][OH:15])[O:10][C:9]=2[CH:16]=1)(=[O:4])=[O:3].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:15][CH2:14][CH:11]2[O:10][C:9]3[CH:16]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[O:13][CH2:12]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CO)CO2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
A mixture of [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (0.9 g, 3.7 mmol), p-toluenesulfonyl chloride (1.0 g, 5.5 mmol), TEA (0.76 ml, 5.5 mmol) and 4-DMAP (0.4 g, 3.7 mmol) in DCM (20 ml) was stirred at room temperature for 1 h and 30 min. The solution was diluted with DCM and washed with HCl (1 N), water and brine. The organic phase was dried and concentrated to give the title compound (1.1 g). MS m/z (rel. intensity, 70 eV) 398 (M+, 51), 226 (bp), 225 (23), 213 (30), 91 (62).
Reaction SMILES: [CH:1]1([CH:4]2[CH2:9][N:8]3[N:10]=[C:11]([I:18])[C:12]([C:13]([O:15]CC)=[O:14])=[C:7]3[CH2:6][N:5]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O.C(Cl)Cl>[C:22]([O:21][C:19]([N:5]1[CH:4]([CH:1]2[CH2:2][CH2:3]2)[CH2:9][N:8]2[N:10]=[C:11]([I:18])[C:12]([C:13]([OH:15])=[O:14])=[C:7]2[CH2:6]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)c1c(I)nn2c1CN(C(=O)OC(C)(C)C)C(C1CC1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2c(C(=O)O)c(I)nn2CC1C1CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 93.9 %

Procedure:
To a stirred solution of Intermediate 348E (0.85 g, 1.843 mmol) in ethanol (2 mL) and water (1 mL) was added NaOH (0.369 g, 9.21 mmol) and the resulting solution was stirred at RT for 10 h. The reaction mixture was diluted with DCM (10 mL) and washed successively with an aqueous solution of 1N HCl, water and brine. The organic layer was then dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to afford the Intermediate 348F as an off-white solid (0.75 g, 94%). MS(ES): m/z=434 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 12.6 (br. s., 1H), 5.11 (d, J=18.89 Hz, 1H), 4.45 (d, J=18.51 Hz, 1H), 4.16-4.25 (m, 2H), 3.82 (br. s., 1H), 1.43 (s, 9H), 0.82-0.96 (m, 1H), 0.47 (d, J=7.93 Hz, 2H), 0.35 (dd, J=6.80, 4.91 Hz, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[C@H:39]([CH3:40])[CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:41])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:42]2[CH:43]=[N:44][N:45]([CH2:47][CH2:48][OH:49])[CH:46]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:59][S:60](Cl)(=[O:62])=[O:61]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[C@H:35]([CH3:41])[CH2:36][CH2:37][CH2:38][C@@H:39]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:42]2[CH:43]=[N:44][N:45]([CH2:47][CH2:48][O:49][S:60]([CH3:59])(=[O:62])=[O:61])[CH:46]=2)[N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCO)c4)c4ccccc43)cn12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reaction time: 1 h

Procedure:
To an ice-bath cooled solution of Intermediate 124b (174 mg, 0.26 mmol) in DCM (3 mL) was added DIPEA (182 μL, 1.0 mmol) followed by methanesulfonyl chloride (41 μL, 0.52 mmol). The reaction mixture was stirred for 1 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.47 min, m/z 746 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[N:13]=[C:14]([CH3:17])[S:15][CH:16]=2)[CH:7]=[C:6]([F:18])[C:3]=1[CH2:4][OH:5].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32](Cl)=[O:33])[C@H:28]([CH2:35][CH3:36])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[N:13]=[C:14]([CH3:17])[S:15][CH:16]=2)[CH:7]=[C:6]([F:18])[C:3]=1[CH2:4][O:5][C:32]([N:29]1[CH2:30][CH2:31][N:26]([C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH2:27][C@H:28]1[CH2:35][CH3:36])=[O:33]
Reactant: Cc1nc(COc2cc(F)c(CO)c(Cl)c2)cs1
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)cc(OCc2csc(C)n2)cc1Cl
Yield: 75 %

Procedure:
This compound was prepared from 2-chloro-6-fluoro-4-(2-methyl-thiazol-4-ylmethoxy)-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (582 mg; 75%); MS (ISP): 528.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([O:25]C(=O)C2C=CC=CC=2)[CH:6]=[C:7]([CH2:23][CH3:24])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[CH3:2].[OH-].[K+].Cl>CO.O>[CH2:23]([C:7]1[CH:6]=[C:5]([OH:25])[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[CH3:24]
Reactant: CCOC(COCCCCOc1c(CC)cc(OC(=O)c2ccccc2)cc1CC)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(COCCCCOc1c(CC)cc(O)cc1CC)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.5 %

Procedure:
To a solution of 31.0 g of 3,5-diethyl-1-benzoyloxy-4-(4-(2,2-diethoxyethoxy)butyloxy)benzene dissolved in 100 ml of methanol was added a solution of 5.1 g of potassium hydroxide dissolved in 25 g of water. After stirring at room temperature for 1 hour, the reaction mixture was acidified by the addition of diluted hydrochloric acid, and concentrated. The residue was poured into water, and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.60 g (yield, 94%) of 3,5-diethyl-4-(4-(2,2-diethoxyethoxy)butyloxy)phenol, nD25.0 1.4890.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:53]1[C:57]2[CH:58]=[CH:59][C:60]([C:62]3[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=3)=[CH:61][C:56]=2[CH2:55][CH2:54]1>CN(C=O)C>[O:53]1[C:57]2[CH:58]=[CH:59][C:60]([C:62]3[CH:63]=[C:64]([NH:68][C:24]([C:19]4[C:20](=[O:23])[O:21][C:22]5[C:17]([CH:18]=4)=[CH:16][CH:15]=[CH:14][C:13]=5[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:65]=[CH:66][CH:67]=3)=[CH:61][C:56]=2[CH2:55][CH2:54]1
Reactant: Nc1cccc(-c2ccc3c(c2)CCO3)c1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc3c(c2)CCO3)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 79.5 %

Procedure:
DIEA (0.014 mL, 0.078 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.020 g, 0.071 mmol) and HATU (0.030 g, 0.078 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2,3-dihydro-benzofuran-5-yl)-phenylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.026 g of product in 76% yield: LCMS (ESI) m/z 484 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9]1[NH:27][C:12]2=[N:13][C:14]([O:21][CH:22]3[CH2:26][CH2:25][O:24][CH2:23]3)=[C:15]([C:17]([O:19]C)=[O:18])[CH:16]=[C:11]2[N:10]=1.[OH-].[Na+]>C(O)C>[Cl:28][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[NH:27][C:12]2=[N:13][C:14]([O:21][CH:22]3[CH2:26][CH2:25][O:24][CH2:23]3)=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=[C:11]2[N:10]=1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)[nH]c2nc1OC1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2nc(Nc3c(Cl)cncc3Cl)[nH]c2nc1OC1CCOC1

Procedure:
Prepared analogously to example 174e from the product obtained in (790e) using 2 N NaOH (aq) in ethanol.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH3:10][CH:11](C(C)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].COC1C=C2C(C(C)=C(C(OCC)=O)N2)=CC=1>>[CH3:1][S:2][C:3]1[CH:4]=[C:5]2[C:7]([CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6]2)=[CH:8][CH:9]=1
Reactant: CSc1cccc(N)c1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: CCOC(=O)c1[nH]c2cc(OC)ccc2c1C
Product: CCOC(=O)c1cc2ccc(SC)cc2[nH]1

Procedure:
Starting from 3-(methylthio)aniline and ethyl 2-methylacetoacetate, th title compound was prepared by following the published procedure for ethyl 6-methoxy-3-methyl-1H-2-indolecarboxylate (T. Gan et al, J. Org. Chem. 1997, 62, 9298–9304).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].Cl.[N:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1.[Cl-].[OH-].[Na+]>C1C=CC=CC=1>[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:1]2([CH2:19][C:16]3[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][C:2]2=[O:11])=[CH:15][CH:14]=1
Reactant: ClCc1ccncc1
Reactant: O=C1CCc2ccccc2C1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C1C=Cc2ccccc2C1(Cc1ccncc1)Cc1ccncc1

Procedure:
To a stirred mixture of 2-tetralone (4.4 g, 0.03 mol), 4-picolylchloride hydrochloride (10.82 g, 0.066 mol), and benzyltriethylanmonium chloride (1.4 g, 0.006 mol) in 80 ml of benzene was added 1N sodium hydroxide (178 ml, 0.178 mol) dropwise during a period of 1 h. at room temperature. Stirring was continued for another hour. Additional benzene (80 ml ) was added, the organic layer was separated, and dried over sodium sulfate. The inorganic salts were filtered off, and to the filtrate was added 5 g of Florisil (a magnesium silicate adsorbent). The mixture was stirred for 30 min., the solids were filtered off, and the benzene was removed by rotary evaporation. The oily residue was dissolved in the minimum amount of ethanolic HCl (5 ml), and a small amount of acetone was added, whereupon the dihydrochloride salt crystallized out of solution. This salt was collected (1.57 g), redissolved in water, and made basic with potassium carbonate. The solids obtained were air dried (900 mg), and recrystallized from cyclohexane to give 1,1-bis(4-pyridinylmethyl)-2(1H)-naphthalenone as a white solid, 460 mg, m.p. 111°-112° NMR (200 MHz, CDCl3) δ 1.9 (m, 4H); 3.30 (d, 4H); 6.55 (d, 4H); 6.95 (d, 1H); 7.15 (t, 7.45 (t, 1H); 7.66 (d, 1H); 8.30 (d, 4H). IR (nujol) 1709 cm-1. Analysis. Calcd. for C22H20N2O: C, 80.46; H, 6.14; N, 8.53. Found: C, 80.12; H, 6.25; N, 8.61.