Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CC(C)=O.O>[CH:2]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:16])=[O:17])=[O:1]
Reactant: N#Cc1ccc(C2OCCCO2)c(S(=O)(=O)c2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1ccc(C=O)c(S(=O)(=O)c2ccccc2)c1
Temperature: 160 °C
Reaction time: 0.1 h

Procedure:
In an Emrys microwave, 4-(1,3-dioxan-2-yl)-3-(phenylsulfonyl)benzonitrile (260 mg, 0.789 mmol) and pyridinium 4-toluenesulfonate (149 mg, 0.592 mmol; 0.75 eq.) in acetone/water (1:1, 3 ml) were heated with stirring at 160° C. for 6 min. The reaction mixture was then added to water (50 ml) and extracted with ethyl acetate (8×20 ml). The combined organic phases were subsequently washed with saturated sodium chlroide solution (2×30 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound was obtained as a solid (0.21 g, quant.).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[CH:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][O:27][CH:28]4[CH2:33][O:32][C:31]5=[N:34][C:35]([N+:37]([O-:39])=[O:38])=[CH:36][N:30]5[CH2:29]4)=[CH:22][CH:21]=3)=[C:16]([F:40])[CH:15]=2)[CH2:9]1)(C)(C)C.BrC1C=CC(N2C[C@@H](C(C)(C)O[SiH2]C(C)(C)C)OC2=O)=CC=1F>>[F:40][C:16]1[CH:15]=[C:14]([N:10]2[CH2:9][C@@H:8]([CH2:7][OH:6])[O:12][C:11]2=[O:13])[CH:19]=[CH:18][C:17]=1[C:20]1[CH:21]=[CH:22][C:23]([CH2:26][O:27][C@H:28]2[CH2:33][O:32][C:31]3=[N:34][C:35]([N+:37]([O-:39])=[O:38])=[CH:36][N:30]3[CH2:29]2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CN(c2ccc(-c3ccc(COC4COc5nc([N+](=O)[O-])cn5C4)cc3)c(F)c2)C(=O)O1
Agent: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CN(c2ccc(Br)c(F)c2)C(=O)O1
Product: O=C1O[C@H](CO)CN1c1ccc(-c2ccc(CO[C@H]3COc4nc([N+](=O)[O-])cn4C3)cc2)c(F)c1

Procedure:
5-(tert-Butyl-dimethyl-silanyloxymethyl)-3-[2-fluoro-4′-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)-biphenyl-4-yl]-oxazolidin-2-one. The title compound was prepared by following the same procedure as described in the preparation of Example 26, except 3-(4-bromo-3-fluoro-phenyl)-5(S)-(tert-butyl-dimethyl-silanyloxymethyl)-oxazolidin-2-one was used in place of N-[3-(3,5-difluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5(R)-ylmethyl]-acetamide. ESI MS m/z 599.6 (M+H+); 1H NMR (400 MHz, DMSO) δ 8.00 (s, 1H), 7.56 (dd, J=13.6, 2.4 Hz, 1H), 7.52-7.47 (m, 3H), 7.40-7.35 (m, 3H), 5.71 (s, 2H), 4.77-4.74 (m, 1H), 4.67-4.62 (m, 3H), 4.43 (d, J=11.6 Hz, 1H), 4.24-4.20 (m, 2H), 4.11 (t, J=9.2 Hz, 1H), 3.84 (dd, J=11.6, 2.4 Hz, 1H), 3.79 (dd, J=9.2, 5.2 Hz, 1H), 3.71 (dd, J=11.6, 2.8 Hz, 1H), 0.74 (s, 9H), 0.002 (s, 3H), 0.000 (s, 3H).
Reaction SMILES: C([O:8][NH:9][C:10](=[O:45])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:44])[C@@H:18]([NH:29][C:30](=[O:43])[CH2:31][CH2:32][CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][NH:9][C:10](=[O:45])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:44])[C@@H:18]([NH:29][C:30](=[O:43])[CH2:31][CH2:32][CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1
Reactant: O=C(CCCCCNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CCCc1c[nH]c2ccccc12)NOCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(CCCCCNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CCCc1c[nH]c2ccccc12)NO
Reaction time: 4 h
Yield: 410.4 %

Procedure:
(Method J15F) 6-[3-(1H-Indol-3-yl)-2-(4-1H-indol-3-yl-butyrylamino)-propionylamino]-hexanoic acid benzyloxy-amide (19/97) (1.654 g, 0.274 mmol) was dissolved in ethanol (20 ml), 10% Pd/C (50 mg) was added and the reaction mixture was hydrogenated at room temperature for 4 hours. The catalyst was filtered off, the solvent was evaporated and the residue was chromatographed on silica gel with acetonitrile-acetic acid (60:1) and acetonitrile-acetic acid-water (30:1:1) as eluent to give the title product (0.582 g, 41%) as white powder. M.p. 94-96° C.1H NMR (DMSO-d6, HMDSO), δ: 1.06-1.55 (m, 6H); 1.68-1.97 (m, 4H); 2.04-2.27 (m, 2H); 2.42-2.67 (m, 2H overlapped with DMSO) 2.80-3.15 (m, 4H); 4.44-4.57 (m, 1H); 6.87-7.17 (m, 6H); 7.31 (d, 2H, J=7.6 Hz); 7.44 (d, 1H, J=7.6 Hz); 7.58 (d, 1H, J=7.6 Hz); 7.80-8.03 (m, 2H); 8.67 (s, 1H); 10.33 (s, 1H); 10.72 (s, 1H); 10.76 ppm (s, 1H). HPLC analysis on Symmetry C8 column: impurities 2.5% (column size 3.9×150 mm; mobile phase acetonitrile−0.1M phosphate buffer (pH 2.5), 35:65; detector UV 220 nm; sample concentration 0.5 mg/ml, flow rate 1.0 ml/min). Anal. Calcd for C29H35N5O4: C, 67.29; H, 6.82; N, 13.53. Found: C, 67.06; H, 6.86; N, 13.66.
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:11]=[C:10]3[CH2:12][CH2:13][O:14][C:9]3=[CH:8][C:6]=2[N:7]=1.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH2:20]>COCCOC>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH:20][C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:11]=[C:10]3[CH2:12][CH2:13][O:14][C:9]3=[CH:8][C:6]=2[N:7]=1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCO3
Reactant: CN(C)CCN
Solvent: COCCOC
Product: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCO3
Yield: 87.2 %

Procedure:
A solution of chloride 206 (100 mg, 0.45 mmol) and N1,N1-dimethylethane-1,2-diamine (0.2 mL, 1.8 mmol) in DME (10 mL) was stirred at reflux temperature for 1 h, the solvent evaporated and the residue purified by chromatography, eluting with a gradient (5-8%) of MeOH/DCM to give the 1-oxide 207 (108 mg, 88%) as a yellow solid, mp 163-165° C.; 1H NMR δ 8.09 (t, J=1.4 Hz, 1H, H-9), 6.79 (s, 1H, H-5), 5.83 (br s, 1H, NH), 4.72 (t, J=8.3 Hz, 2H, H-7), 3.52-3.56 (m, 2H, CH2N), 3.31 (dt, J=8.3, 1.4 Hz, 2H, H-8), 2.57 (t, J=8.3 Hz, 2H, CH2N), 2.29 [s, 6H, N(CH3)2]; 13C NMR δ 166.5, 159.3, 151.8, 129.3, 126.4, 116.6, 102.0, 72.9, 57.6, 45.0 (2), 38.6, 28.6. HRMS (FAB+) calcd for C13H18N5O2 (MH+) m/z 276.1461, found 276.1461.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:24]2[C:19](=[C:20]([CH3:32])[C:21]3[NH:27][C:26]4[CH:28]=[CH:29][N:30]=[CH:31][C:25]=4[C:22]=3[CH:23]=2)[CH:18]=[CH:17][N:16]=1)[CH3:9]>C1(C)C=CC=CC=1>[CH2:8]([N:10]([CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:24]2[C:19](=[C:20]([CH3:32])[C:21]3[NH:27][C:26]4[CH:28]=[CH:29][N:30]=[CH:31][C:25]=4[C:22]=3[CH:23]=2)[CH:18]=[CH:17][N:16]=1)[C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH3:9]
Reactant: O=C1CCC(=O)O1
Reactant: CCNCCCNc1nccc2c(C)c3[nH]c4ccncc4c3cc12
Solvent: Cc1ccccc1
Product: CCN(CCCNc1nccc2c(C)c3[nH]c4ccncc4c3cc12)C(=O)CCC(=O)O

Procedure:
A solution of 75 mg of succinic anhydride (0.75 mM) and 250 mg (0.75 mM) of N-ethyl-N′-(6-methyl-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-g]isoquinolin-10-yl)propane-1,3-diamine in 80 ml of dry toluene was brought to reflux for 4 h. The precipitate obtained after cooling was dried and recrystallized with acetone. 240 mg (65.6%) was obtained in the form of solid (F˜150°). Centesimal analysis for C24H27N5O3+3H2O; Calc.: C, 59.12; H, 6.82; N, 14.37; Exp.; C, 59.14; H, 6.88; N, 14.17. NMR and MS in agreement.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=1)(=O)=O.[N-:16]=[N+:17]=[N-:18].[Na+]>O>[N:16]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1ccc(C#N)c(F)c1
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(CN=[N+]=[N-])cc1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice cooled solution of 4-cyano-3-fluorobenzyl methanesulfonate (1.8 g, 7.9 mmol; see step (iii) above) was added sodium azide (0.80 g, 0.012 mol). The mixture was stirred overnight and then poured into 200 mL of water and extracted three times with diethyl ether. The combined ethereal phase was washed five times with water, dried (Na2SO4) and evaporated. The crude colourless oil could be used without further purification. Yield: 1.2 g (87%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][OH:22]>CC(C)=O.O>[C:1]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][OH:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(c1ccccc1)N1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzoyl chloride (18.5 ml) and an aqueous (50 ml) solution of sodium carbonate (17.0 g) were added dropwise to a solution of (S)-2-pyrrolidinemethanol (12.0 g) in a mixture of acetone (70 ml) and water (14 ml). After addition, the reaction mixture was stirred for 30 mins at room temperature. The reaction mixture was filtered. Water was added to the filtrate. The mixture was extracted with methylene chloride. The extract was washed, dried and evaporated. The residue was purified by column chromatography on silica-gel (hexane-EtOAc) to give the title compound (24.1 g) having the following physical data:
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([I:14])=[C:8]([CH2:10][C:11](O)=[O:12])[CH:9]=1.S(Cl)([Cl:17])=O>CCO.O.C(Cl)Cl.CN(C=O)C>[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([I:14])=[C:8]([CH2:10][C:11]([Cl:17])=[O:12])[CH:9]=1
Reactant: Cc1ccc(I)c(CC(=O)O)c1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1ccc(I)c(CC(=O)Cl)c1
Temperature: 25 °C

Procedure:
The nitrile (94.5 g, 0.37 mol) is dissolved in EtOH (350 ml) and treated with NaOH (29.4 g, 0.74 mol) which has been dissolved in water (200 ml). The reaction is heated to reflux temperature for 14 hours. After cooling to room temperature, ethanol is removed on a rotovap and 6N HCl added until the pH=1. The solid 5-methyl-2-iodophenylacetic acid is filtered off and washed with water (2×500 ml). After drying over P2O5 in a vacuum dessicator, the solid 5-methyl-2-iodophenyl acetic acid (mp 112-114°, 83 g, 0.30 mol) is dissolved in CH2Cl2 (450 ml) that contains several drops of DMF. To the solution thionyl chloride (32 ml, 0.450 mol) is added and the reaction heated to reflux temperature overnight. After cooling to room temperature, the reaction mixture is diluted with additional CH2Cl2 (500 ml) and washed with water (2×250 ml), saturated NaHCO3 (250 ml) and brine (250 ml). The solution is dried (MgSO4) and concentrated on a rotovap to give 5-methyl-2-iodophenylacetyl chloride as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[C:13]([F:16])=[C:12]([C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[N:11]=[C:10]2[O:24][CH3:25])=[C:4]([F:26])[CH:3]=1.[C:27](Cl)(=[O:31])/[CH:28]=[CH:29]/[CH3:30].[H-].[Na+]>CN(C)C=O>[C:27]([O:8][C:7]1[CH:6]=[C:5]([N:9]2[C:14](=[O:15])[C:13]([F:16])=[C:12]([C:17]([F:22])([F:23])[C:18]([F:19])([F:21])[F:20])[N:11]=[C:10]2[O:24][CH3:25])[C:4]([F:26])=[CH:3][C:2]=1[Cl:1])(=[O:31])/[CH:28]=[CH:29]/[CH3:30]
Reactant: COc1nc(C(F)(F)C(F)(F)F)c(F)c(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: C/C=C/C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C/C=C/C(=O)Oc1cc(-n2c(OC)nc(C(F)(F)C(F)(F)F)c(F)c2=O)c(F)cc1Cl

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-5-fluoro-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone and crotonoyl chloride with sodium hydride in dimethylformamide there is obtained {2-chloro-4-fluoro-5-[5-fluoro-2 -methoxy-6-oxo-4-pentafluoroethyl-1(6H) -pyrimidinyl]-phenyl} crotonate, 1H-NMR (CDCl3, 400 MHz): 7.42 ppm (d,1H), 7.28 ppm (m,1H), 7.20 ppm (d,1H), 6.08 ppm (m,1H), 3.98 (s,3H), 2.01 ppm (q,3H);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](OC)=[O:9])=[N:6][CH:7]=1.[BH4-].[Na+].O.CCOC(C)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(Cl)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: OCc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a stirring solution of methyl 5-chloropicolinate (1 g, 5.8 mmol) in methanol at room temperature under argon was added sodium borohydride (440 mg, 11.57 mmol). The reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was concentrated under vacuum to obtain a gum. Water (15 mL) and EtOAc (30 mL) were added and the layers were separated. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to obtain 840 mg of the title compound as colorless gum. HPLC/MS: retention time=0.755 min, [M+H]+=144.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>C(#N)C>[CH2:19]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9])[CH:18]=[CH2:17]
Reactant: CC(=O)c1ccccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1ccccc1C(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 25 g quantity of 1-(2-hydroxyphenyl)ethanone and 76 g of potassium carbonate were suspended in 500 ml of acetonitrile, and 31 ml of allyl bromide was added. The mixture was stirred at room temperature for 48 hours. The reaction mixture was filtered to remove insolubles, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give 34 g of pale yellow oily 1-(2-allyloxyphenyl)ethanone.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1.[CH3:22][O:23][CH2:24][CH2:25][NH2:26].C(NC(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:18])[NH:26][CH2:25][CH2:24][O:23][CH3:22])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1
Reactant: COCCN
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(Cl)ncn1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCCNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(6-chloropyrimidine-4-carboxamido)-3-methylbenzene-1-sulfonyl chloride (Intermediate 30, 400 mg; 1.15 mmol) in THF (20 ml) was treated with 2-methoxyethanamine (125 mL; 1.4 mmol) and diisopropylamine (0.4 ml; 2.9 mmol). After stirring at RT for 18 hours the solvent was removed in vacuo and the residue redissolved in DCM and washed with water. The organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc. The title product was obtained as a white solid.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:48][C:49]1[CH:54]=[CH:53]C=[CH:51][C:50]=1O)[C:6]([NH:8][CH:9]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:30](=[O:33])[NH:31][CH3:32])[CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[CH2:14][CH:13]1[CH2:34][CH2:35][O:36]C(=O)C)=[O:11])=[O:7])(=[O:3])[CH3:2].[O:56]([CH3:58])[Na]>CO>[C:1]([NH:4][CH:5]([CH2:48][C:49]1[CH:54]=[CH:53][C:58]([OH:56])=[CH:51][CH:50]=1)[C:6]([NH:8][CH:9]([CH2:40][C:41]1[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH:18]([CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:30]([NH:31][CH3:32])=[O:33])[CH2:14][CH:13]1[CH2:34][CH2:35][OH:36])=[O:11])=[O:7])(=[O:3])[CH3:2]
Reactant: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)C(Cc2ccccc2O)NC(C)=O)C(CCOC(C)=O)C1
Reactant: CO[Na]
Solvent: CO
Product: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)C(Cc2ccc(O)cc2)NC(C)=O)C(CCO)C1
Reaction time: 8 h

Procedure:
To a solution acetic acid 2-[1-{2-[2-acetylamino-3-(hydroxyphenyl)propionylamino]-3-(4-fluorophenyl)propionyl}-4-(1-methylcarbamoyl-2-naphthalen-2-ylethyl)piperazin-2-yl]ethyl ester, 65, (7.5 g, 10 mmol) in methanol (50 mL) is added freshly prepared NaOCH3 (0.55 g, 10.1 mmol) and the solution stirred overnight. The solution is concentrated in vacuo, the resulting residue partitioned between dichloromethane and water, the organic layer is dried and concentrated in vacuo to afford the desired product.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:19](=[O:32])[C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)=[C:14]([CH:18]=1)[C:15](O)=[O:16])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:34]1C2C=CC=CC=2N=N1.O>CN(C)C=O>[CH2:1]([O:9][C:10]1[CH:18]=[C:14]2[C:13]([C:19]([OH:32])([C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)[NH:34][C:15]2=[O:16])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: COc1cc(C(=O)c2ccc(OC(=O)c3ccccc3)cc2C(=O)O)cc(OC)c1OC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C2(O)NC(=O)c3cc(OCc4ccccc4)ccc32)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A mixture of 5-benzoyloxy-2-(3,4,5-trimethoxybenzoyl)benzoic acid 50 mg, 14.8M aqueous ammonia 50 μl, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimido hydrochloride 68 mg and 1-hydroxybenzotriazole 15.9 mg is dissolved under ice cooling in N,N-dimethylformamide 2 ml and the mixture is stirred overnight at room temperature. To the reaction mixture is added water. The mixture is extracted with ethyl acetate and the extract is washed with water and dried, followed by removal of the solvent. The residue is purified with silica gel chromatography (solvent: chloroform:ethyl acetate=1:1) and left to be crystallized. The crystals are triturated with diisopropyl ether-ethyl acetate to give 6-benzyloxy-3-hydroxy-3-(3,4,5-trimethoxyphenyl)-2,3-dihydroisoindol-1-one 46.7 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[OH-].[K+].Br[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>[Cu].CN1C(=O)N(C)CC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:21]2[C:22]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][CH:20]=2)=[C:4]([CH3:9])[CH:3]=1
Reactant: Brc1cccc2ccccc12
Reactant: Cc1cc(Cl)ccc1O
Agent: [Cu]
Agent: [K+]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: Cc1cc(Cl)ccc1Oc1cccc2ccccc12
Temperature: 150 °C
Reaction time: 3 h
Yield: 10.6 %

Procedure:
4-Chloro-2-methylphenol (10 g) and powdery KOH (4.6 g) were mixed together and then heated at 150° C. for 1 hour. After cooling down to 100° C., DMI (50 ml) was added to the resulting mixture for dissolving the mixture. Subsequently, 1-bromonaphthalene (14.5 g) and copper powder (350 mg) were added to the resulting solution, which was then heated under stirring at 130° C. for 3 hours. After leaving the solution to stand at room temperature, 1N NaOH was added to the solution, and then, the product was extracted with ether. The ether layer was washed with 1N NaOH, washed twice with water, and washed once in saturated sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ether=99:1) to give the title compound (2 g; 11%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]#[N:16].Cl.Cl[CH2:19][C:20]1[N:21]=[CH:22][S:23][CH:24]=1>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:12])([F:13])[F:14])[N:7]([CH2:19][C:20]3[N:21]=[CH:22][S:23][CH:24]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]#[N:16]
Reactant: N#Cc1ccc2[nH]c(C(F)(F)F)nc2c1Cl
Reactant: ClCc1cscn1
Agent: Cl
Product: N#Cc1ccc2c(nc(C(F)(F)F)n2Cc2cscn2)c1Cl

Procedure:
Synthesized as described in Example 197B from 4-chloro-2-(trifluoromethyl)-1H-benzimidazole-5-carbonitrile and 4-(chloromethyl)-1,3-thiazole hydrochloride: MS (ESI) m/z 343 (M+1).
Reaction SMILES: [F:1][CH:2](P(=O)(C1C=CC=CC=1)C1C=CC=CC=1)[F:3].C([N-]C(C)C)(C)C.[Li+].[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][C:33]1[CH:50]=[CH:49][C:48]2[C:47]3[CH2:46][CH2:45][C@@:43]4([CH3:44])[C@@H:39]([CH2:40][CH2:41][C:42]4=O)[C:38]=3[CH2:37][CH2:36][C:35]=2[CH:34]=1>O1CCCC1.C(OCC)(=O)C.O>[F:1][C:2]([F:3])=[C:42]1[CH2:41][CH2:40][C@H:39]2[C:38]3[CH2:37][CH2:36][C:49]4[CH:50]=[C:33]([O:32][CH:27]5[CH2:28][CH2:29][CH2:30][CH2:31][O:26]5)[CH:34]=[CH:35][C:48]=4[C:47]=3[CH2:46][CH2:45][C@:43]12[CH3:44]
Reactant: O=P(c1ccccc1)(c1ccccc1)C(F)F
Reactant: C[C@]12CCC3=C(CCc4cc(OC5CCCCO5)ccc43)[C@@H]1CCC2=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12CCC3=C(CCc4cc(OC5CCCCO5)ccc43)[C@@H]1CCC2=C(F)F
Reaction time: 1 h
Yield: 60.8 %

Procedure:
A solution of 2.7 g of difluoromethyldiphenylphosphine oxide in 85 ml of tetrahydrofuran is slowly mixed with 5.3 ml of 2 M lithium diisopropylamide solution at a bath temperature of -50° C., and it is stirred for 1 hour. Then, a solution of 1.5 g of 3-tetrahydropyranyloxy-estra-1,3,5(10),8-tetraen-17-one in 42 ml of tetrahydrofuran is slowly added, stirred for 15 minutes, slowly heated at a bath temperature of from -50° C. to 100° C. and refluxed for 2.5 hours. For working-up, it is diluted with ethyl acetate and water, washed with water, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 1.0 g of 17-difluoromethylene-3-tetrahydropyranyloxy-estra-1,3,5(10),8-tetraene is obtained as colorless crystals with a melting point of 124-125° C., [α]D22 =+2.0° (c =0.525% in pyridine).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[O:12]C(=O)[NH:10]2)=[CH:4][C:3]=1[O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25].[OH-].[Na+]>C(O)C>[NH2:10][CH:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:22][C:23]([F:27])([F:28])[CH:24]([F:25])[F:26])[CH:4]=1)[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[OH:12]
Reactant: O=C1NC(Cc2ccc(Cl)c(OC(F)(F)C(F)F)c2)C(c2ccc(F)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1ccc(Cl)c(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Yield: 87.7 %

Procedure:
To a solution of (4RS,5SR)-4-((4-chloro-3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-5-(4-fluorophenyl)-1,3-oxazolidin-2-one (1.42 g, 3.37 mmol) in ethanol (20 ml) was added 8N aqueous sodium hydroxide solution (2.1 ml, 16.9 mmol), and the mixture was heated under reflux for 3 hrs. The reaction solution was concentrated, diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS,2SR)-2-amino-3-(4-chloro-3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-1-propanol (1.17 g, 88%).
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1C(=O)N([Br:25])C(=O)C1.O>C(Cl)(Cl)Cl.CC(O)=O>[Br:25][C:14]1[S:15][CH:16]=[CH:17][C:13]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCCCCCCCCCc1ccsc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a solution of 3-dodecylthiophene (5.00 g, 19.8 mmol) in CHCl3/HOAc (1:1) (Vt=20.0 mL) at 0° C. was added NBS (3.52 g, 19.8 mmol) in portions over a period of 45 minutes. The reaction mixture was stirred for 1 hour at 0° C., and overnight at room temperature. The reaction mixture was poured into water (50.0 mL) and extracted with chloroform (3×50.0 mL). The combined organic phases were washed with water (50.0 mL), NaOH solution, and dried over MgSO4. After filtration through Celite, the chloroform was removed in vacuo, and the product was obtained as a colorless oil (6.05 g, 93% yield). 1H NMR (CDCl3): δ 0.84-1.54 (m, 23H), 2.53 (t, 2H), 6.76 (d, 1H, J=4.5 Hz), 7.15 (d, 1H, J=4.5 Hz).