Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH3:8].[C:10]1([C:16](Br)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][CH:3]([CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH3:8])[C:2]#[CH:1])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C#CC(O)C/C=C\CC
Product: C#CC(C/C=C\CC)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Treatment of 22 g. of cis-oct-5-en-1-yne-3-ol, prepared according to the procedure of J. Fried, C. H. Lin, J. C. Sih, F. Dalven, G. F. Cooper, J. Amer. Chem. Soc., 94, 4342 (1972), with 58 g. of triphenylmethyl bromide in 100 ml. of pyridine and purification on Florisil, all as described in Example 728 gives the title compound.
Reaction SMILES: NC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC#N)C=CC=1OC.[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([N+:48]([O-])=O)=[C:30]([C:32]([C:36]2[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([O:46][CH3:47])[CH:37]=2)=[CH:33][C:34]#[N:35])[CH:31]=1>[Pd]>[NH2:48][C:29]1[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][C:30]=1[C:32]([C:36]1[CH:37]=[C:38]([O:46][CH3:47])[C:39]([O:44][CH3:45])=[C:40]([O:42][CH3:43])[CH:41]=1)=[CH:33][C:34]#[N:35]
Reactant: COc1ccc([N+](=O)[O-])c(C(=CC#N)c2cc(OC)c(OC)c(OC)c2)c1
Agent: [Pd]
Agent: COc1ccc(C(=CC#N)c2ccc(OC)c(OC)c2)cc1N
Product: COc1ccc(N)c(C(=CC#N)c2cc(OC)c(OC)c(OC)c2)c1
Yield: 22 %

Procedure:
3-(2-Amino-5-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile was prepared analogously to 3-(3-amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile using 3-(5-methoxy-2-nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile (1.5 g, 4.0 mmol) and 10% Pd/C (0.2 g). The crude product was purified by flash chromatography (silica gel, CH2Cl2:EtOAc 85:15) to afford a single isomer of 3-(2-amino-5-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile (0.3 g, 25%) as a yellow solid: mp 132-134° C.; 1H NMR (CDCl3) δ 6.87-6.82 (dd, J=3, 8 Hz, 1H), 6.81 (s, 2H), 6.68 (d, J=2 Hz, 1H), 6.64 (d, J=8.8 Ha, 1H), 5.58 (s, 1H), 3.90 (s, 3H), 3.83 (s, 6H), 3.77 (s, 3H), 3.28 (b, 2H); 13C NMR (CDCl3) δ 161.09, 153.38, 152.40, 140.15, 138.26, 131.07, 125.44, 117.94, 117.84, 117.24, 115.55, 106.15, 96.46, 60.95, 55.79, 55.32; Anal Calcd for C19H20N2O4: C, 67.05; H, 5.92; N, 8.23. Found: C, 67.02; H, 6.02; N, 8.07.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[Cl:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][NH2:40]>CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:20]([NH:40][CH2:39][C:38]1[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=1[Cl:36])=[O:22])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: NCc1ccccc1Cl
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1Cl
Temperature: 25 °C

Procedure:
To a solution of N-(t-butoxycarbonyl)tryptophan (21.28 g, 70 mmol) in 140 ml of acetone was added triethylamine (9.76 ml, 7.08 g, 70 mmol) in a portionwise manner. The resulting mixture was stirred for about thirty-five minutes at room temperature and then stirred at 45° C. for 30 minutes under nitrogen. To the resulting mixture ethyl chloroformate (7.35 ml, 8.36 g, 77 mmol) was added with continued cooling and the reaction mixture was stirred for about one hour. Next, 2-chlorobenzylamine (9.30 ml, 10.9 g, 77 mmol) was added and the reaction mixture was then stirred until a white precipitate formed. The ice bath was removed and additional acetone was added. The reaction mixture was then stirred overnight.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:13][CH:12]=2)[C:8]([F:22])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:23][C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])[CH:27]=[CH:26][C:25]=1O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:13][CH:12]=2)[C:8]([F:22])=[CH:7][C:3]=1[C:4]([O:6][C:25]1[CH:26]=[CH:27][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])=[CH:29][C:24]=1[F:23])=[O:5]
Reactant: CCCCCc1ccc(-c2cc(F)c(C(=O)O)cc2F)cc1
Reactant: Oc1ccc(-c2ccccc2F)cc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCc1ccc(-c2cc(F)c(C(=O)Oc3ccc(-c4ccccc4F)cc3F)cc2F)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of 2,5-difluoro-4-(4-pentylphenyl)benzoic acid (28.40 mmol), 2-fluoro-4-(2-fluorophenyl)phenol (28.40 mmol), and dichloromethane (100 ml), 4-dimetylaminopyridine (34.10 mmol) is added dropwise. Then, a solution of 1,3-dicyclohexylcarbodiimide (34.10 mmol) in dichloromethane (100 ml) is added dropwise. After the addition is completed, the reaction mixture is stirred for 17 hrs at room temperature. Solid formed is filtered off, and a saturated aqueous solution of sodium chloride is added dropwise to the reaction mixture. The organic layer is washed with in the order of 3N-hydrochloric acid (300 ml), water, a saturated aqueous solution of sodium hydrogen carbonate (300 ml), and dried over anhydrous magnesium sulfate. The dichloromethane solution is concentrated under reduced pressure, purified by silica-gel chromatography, and further recrystallized to give the titled compound.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=O)[NH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[N:11][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[N:42]1([CH2:47][CH2:48][O:49][CH2:50][CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl>[C:1]1([C:7]2[C:15]3[C:14]([N:54]4[CH2:55][CH2:56][CH:51]([CH2:50][O:49][CH2:48][CH2:47][N:42]5[CH2:46][CH2:45][CH2:44][CH2:43]5)[CH2:52][CH2:53]4)=[N:13][C:12]([C:17]([F:20])([F:19])[F:18])=[N:11][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c(C(F)(F)F)nc2scc(-c3ccccc3)c12
Reactant: C1CCN(CCOCC2CCNCC2)C1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: FC(F)(F)c1nc(N2CCC(COCCN3CCCC3)CC2)c2c(-c3ccccc3)csc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
5-Phenyl-2-(trifluoromethyl)thieno[2,3-d]pyrimidin-4-one (0.20 g, 0.67 mmol) was stirred in dichloromethane (5 mL) at 0° C. Pyridine (0.11 mL, 1.3 mmol) was added, followed by trifluoromethanesulfonic anhydride (0.14 mL, 0.81 mmol) and stirring continued for 30 mins and the mixture allowed to warm to room temperature. 4-(2-Pyrrolidin-1-ylethoxymethyl)piperidine (0.29 g, 1.3 mmol) was added and the reaction stirred for 1 hour at room temperature. The reaction mixture was diluted with DCM (20 mL), washed with water (20 mL), dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by flash chromatography, eluting with a gradient of petroleum ether to 50/50 petroleum ether/ethyl acetate to afford 5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]-2-(trifluoromethyl)thieno[2,3-d]pyrimidine (0.16 g). LCMS: purity 98%, RT=4.28 min, M+1=491.2
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10](Br)[CH2:9]1)=O)(C)(C)C.[C:16]([NH2:24])(=[S:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[C:17]1([C:16]2[S:23][C:10]3[CH2:9][NH:8][CH2:13][CH2:12][C:11]=3[N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Solvent: CN(C)C=O
Product: c1ccc(-c2nc3c(s2)CNCC3)cc1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
A solution of 1-tert-butoxycarbonyl-3-bromopiperidin-4-one (8 g) and thiobenzamide (3.4 g) in DMF was heated at 70 ° C. for 16 h, then cooled to room temperature. The solvent was evaporated in vacuo and the residue dissolved in water (100 ml) and washed with ether (100 ml), then basified with sodium hydroxide and extracted into ethyl acetate (3×100 ml). The solvent was dried (MgSO4) and evaporated to give the title compound as cream solid (2.81 g, 53% based on thiobenzamide used).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[NH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:14]=[CH:15][N:16]3[C:21]=2[C:20]([NH:22][C:23]2[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=2)[N:28]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[N:27]=[CH:26]4)=[N:19][CH:18]=[N:17]3)[CH2:8][CH2:7]1>CO>[F:39][C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)[CH2:32][N:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][C:20]3[C:21]4=[C:13]([CH2:12][N:9]5[CH2:8][CH2:7][CH:6]([NH:5][CH2:3][CH2:2][C:1]#[N:4])[CH2:11][CH2:10]5)[CH:14]=[CH:15][N:16]4[N:17]=[CH:18][N:19]=3)=[CH:31][CH:30]=2)[CH:26]=[N:27]1
Reactant: C=CC#N
Reactant: NC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Solvent: CO
Product: N#CCCNC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Yield: 76 %

Procedure:
Acrylonitrile (0.2 mL, 30 equiv.) was added to a solution of [5-(4-amino-piperidin-1-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (47 mg, 0.1 mmole) in MeOH (3 mL) at RT. Removal the solvent followed by radial chromatography (1 mm silica gel plate, gradient elution with DCM containing 0 to 2% MeOH) afforded 40 mg (76%) of the title compound as a solid. MS: 524 (M+H)+; HPLC Ret Time: 0.99 min (Xterra 3.0×50 mm S7 C18 column, 2 min gradient, 5 mL/min).
Reaction SMILES: C1(S([CH:10]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[CH2:11][C@H:12]2[O:17][C@@H:16]([O:18]C)[CH2:15][C@H:14]([O:20]CC3C=CC=CC=3)[CH2:13]2)(=O)=O)C=CC=CC=1.P(O)([O-])([O-])=O.[Na+].[Na+].O>CO.[Na].[Hg]>[Cl:35][C:29]1[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:28]=1[CH2:10][CH2:11][C@@H:12]1[O:17][C:16](=[O:18])[CH2:15][C@H:14]([OH:20])[CH2:13]1
Reactant: CO[C@H]1C[C@H](OCc2ccccc2)C[C@@H](CC(c2ccc(Cl)cc2Cl)S(=O)(=O)c2ccccc2)O1
Agent: O=P([O-])([O-])O
Agent: [Hg]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1C[C@H](O)C[C@H](CCc2ccc(Cl)cc2Cl)O1
Yield: 125.8 %

Procedure:
To a mixture of 1-(2,4-dichlorophenyl)-2-(4(R)-benzyloxy-2(R)-methoxy-3,4,5,6-tetrahydro-2H-pyran-6(S)-yl)ethyl phenyl sulfone (0.06 g, 0.11 mmole) and anhydrous disodium phosphate (0.065 g, 0.45 mmoles) in dry methanol (5 ml) was added pulverized 5% sodium amalgam (0.2 g). The mixture was stirred at room temperature for twenty hours, during which time an additional 0.4 g of 5% sodium amalgam was added in three portions. The reaction mixture was poured into water and extracted with ether. The ether solution was dried (MgSO4), filtered, and the solvent evaporated in vacuo to give the title compound as a colorless viscous oil (0.04 g); 'H NMR (CDCl3) δ 1.53 (1H, ddd), 1.58-1.88 (4H, m), 2.06 (1H, m), 2.70 (1H, ddd), 2.95 (1H, ddd), 3.42 (3H, s), 3.76 (1H, p), 4.16 (1H, d), 4.52 (1H, d), 4.65 (1H, d), 4.78 (1H, dd), 7.13-7.40 (8H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][OH:24])=[C:9]2[CH3:25])=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([O:24][CH2:23][C:10]2[CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=3)[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]=2[CH3:25])=[CH:29][CH:28]=1
Reactant: Cc1c(CO)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(COc2ccc(Cl)cc2)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 7.4 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole-3-methanol (Example 21) (300 mg, 0.83 mmol), 4-chlorophenol (107 mg, 0.83 mmol), and triphenylphosphine (219 mg, 0.83 mmol) in THF (20 ml), diethyl azodicarboxylate (132 μl, 0.83 mmol) was added. The mixture was stirred at room temperature for 48 hours. The solvent was removed under reduced pressure and the crude (830 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 1/1) to give 3-[(4-chlorophenoxy)methyl]-1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (29 mg, 7%): mp (DSC) 145° C. Anal Calc'd. for C25H21NSClFO3 ·0.25 H2O: C, 63.29; H, 4.57; N, 2.95. Found: C, 63.46; H, 4.57; N, 2.81.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[C@@H:5](/[CH:15]=[CH:16]/[C:17](=[O:25])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][S:3]1.C1(C)C=CC=CC=1.[B]1OC2C(=CC=CC=2)O1>C(Cl)Cl>[OH:25][CH:17]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)/[CH:16]=[CH:15]/[C@H:5]1[CH2:4][S:3][C:2](=[O:1])[N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14]
Reactant: N#CCCCCCCN1C(=O)SC[C@@H]1/C=C/C(=O)Cc1ccccc1
Agent: [B]1Oc2ccccc2O1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: N#CCCCCCCN1C(=O)SC[C@@H]1/C=C/C(O)Cc1ccccc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of 4-3 (0.15 g, 0.4 mmol) in 8 mL CH2Cl2 was added 1M (R)-CBS in toluene (0.45 mL, 0.45 mmol) and cooled to −40° C. to which a solution of catechol borane (0.13 mL, 1.2 mmol) in CH2Cl2 (1 mL) was added dropwise. The solution was stirred at −40° C. for one hour and allowed to warm up to −20° C. during the following two hours. The reaction mixture was quenched at −20° C. with 1 N HCl and was stirred for 4 hours at room temperature. The phases were separated and the organic phase was sequentially washed with 1N HCl, H2O, 1 N NaOH, brine and dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by flash chromatography using 40–50% ethyl acetate/hexanes to yield 125 mg of 4-4 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.37–7.21 (m, 5H), 5.84 (dd, 1H), 5.65 (dd, 1H), 4.46 (q, 1H), 4.22 (q, 1H), 3.86–3.35 (m, 2H), 2.97 (dd, 1H), 2.88 (m, 2H), 2.80 (m, 1H), 2.36 (t, 2H), 1.70–1.27 (m, 8H); MS (+ESI): m/z 359.0 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][C:12](O)=O.S(Cl)(Cl)=O.[CH:25]([NH:28][CH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26].[H-].[Al+3].[Li+].[H-].[H-].[H-]>ClCCl.CCOCC>[CH:25]([N:28]([CH2:12][CH2:11][CH:10]([C:4]1[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26]
Reactant: COc1ccc(C)cc1C(CC(=O)O)c1ccccc1
Reactant: CC(C)NC(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(C)cc1C(CCN(C(C)C)C(C)C)c1ccccc1
Reaction time: 2 h

Procedure:
3-(2-Methoxy-5-methylphenyl)-3-phenylpropionic acid (12.8 g, 0.05 mol) (J. D. Simpson & H. Stehphen, J. Chem. Soc. 1956 1382) and thionyl chloride (50 ml) are heated on a water bath for 3 h. The excess of thionyl chloride is distilled off under reduced pressure. The remaining crude 3-(2-methoxy-5-methylphenyl)3-phenylpropionyl chloride is dissolved in 50 ml of dichloromethane and added dropwise to a stirred solution of diisopropylamine (20.2 g, 0.20 mol) in 200 ml of dichloromethane at about 0° C. The solution is left for 2 h, the solvent is distilled off and the remaining material is treated with water. The solid product consisting of N,N-diisopropyl-3-(2-methoxy-5-methylphenyl)-3-phenylpropionamide is filtered off, dried and added in small portions to a stirred suspension of lithium aluminium hydride (6.0 g, 0.16 mol) in dry ether (700 ml). The mixture is refluxed for 2 days. Excess of hydride is destroyed by the careful addition of water, the ether layer is separated and dried with anhydrous sodium sulfate. After filtration the solution is added to a solution of excess fumaric acid in ether. The precipitated salt is collected and crystallized from 2-propanol. The hydrogen fumarate melts at 176° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][C:21]([O:23]C(C)(C)C)=O)=[CH:14][CH:13]=1.ClC(OCC)=O.Cl[CH:35](F)[F:36]>C(O)(=O)C.O1CCCC1>[F:36]/[CH:35]=[C:20](\[CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=1)/[CH2:21][OH:23]
Reactant: CC(C)(C)OC(=O)CCCc1ccc(F)cc1
Reactant: FC(F)Cl
Agent: CCOC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OC/C(=C/F)CCc1ccc(F)cc1
Reaction time: 0.25 h

Procedure:
Cool a tetrahydrofuran solution of sodium bis(trimethylsilyl)amide (545 kg, 2M, 877 mol) to -10° C. Slowly add, t-butyl 4-(p-fluorophenyl)butyrate (84.1 kg, 80% by weight in toluene, 353 mol). After 15 minutes, slowly add ethyl chloroformate (38.6 kg, 356 mol) at such a rate that the reaction temperature is maintained at or below -5° C. After 20 minutes, warm the reaction mixture to 40° C.-45° C. Seal the reaction vessel and add chlorodifluoromethane (38.15 kg, 445 mol) to the head space. After 1 hour, cool to 15° C.-20° C. and vent the reaction vessel. Add a solution of acetic acid (421 kg, 20% in water) and stir. After 30 minutes, separate the aqueous layer and evaporate the organic layer in vacuo to obtain a residue. Add toluene (45 kg) and evaporate in vacuo until the internal temperature of the reaction vessel is 55° C. to obtain the title compound as a toluene solution.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([S:19][C:20]3[S:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:28][CH3:29])C1C=CC=CC=1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:29][O:28][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[N:16]=[CH:15][CH:14]=[C:13]2[S:19][C:20]1[S:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COc1cc2c(Sc3ccc([N+](=O)[O-])s3)ccnc2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: COc1cc2c(Sc3ccc([N+](=O)[O-])s3)ccnc2cc1O
Yield: 85.7 %

Procedure:
7-(Benzyloxy)-6-methoxy-4-[(5-nitro-2-thienyl)sulfanyl]quinoline (4.0 g), trifluoroacetic acid (40 ml) and thioanisole (4 ml) were stirred together at 65° C. for 2 hours. The mixture was returned to room temperature, the solvent was distilled off under reduced pressure, 80 ml of methanol was added to the residue, and then sodium bicarnobate water was added until the foaming subsided. The precipitated solid was filtered out to obtain 2.7 g of a yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccc(C)cc2)cc1
Agent: Cl
Product: Cc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1
Yield: 97.1 %

Procedure:
In a manner similar to Example 4, Step (b), 4-(4′-methyl-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester (1.21 g, 0.0043 mol) was refluxed in 6 M aqueous hydrochloric acid to give 1.12 g of 4-(4′-methyl-biphenyl-4-yl)-4-oxo-butyric acid as an off-white solid; mp 183-186° C.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.Cl.[NH2:52][CH2:53][CH2:54][CH2:55][C:56]1([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[N:58]([CH3:65])[C:57]1=[O:66]>CN(C=O)C>[CH3:17][CH:16]([CH3:18])[CH2:15][C@H:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[C:12](=[O:14])[NH:52][CH2:53][CH2:54][CH2:55][C:56]1([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[N:58]([CH3:65])[C:57]1=[O:66]
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: CN1C(=O)C(CCCN)(c2ccccc2)c2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)NCCCC1(c2ccccc2)C(=O)N(C)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.39 g, 1.5 mmol, Example 1, Step B) was dissolved in dry DMF (5 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N-methylmorpholine (0.66 mL, 6.0 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.60 g, 1.6 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; then a solution of 3-(3-amino-propyl)-1-methyl-3-phenyl-1,3-dihydro-indol-2-one monohydrochloride monohydrate (0.49 g, 1.5 mmol) in dry DMF (7 mL) was added. After additional 20 minutes stirring at 0° C., the ice-water bath was removed and the reaction mixture was stirred and allowed to warm up to ambient temperature for 15 minutes. The reaction mixture was poured into 50 mL of EtOAc, the resulting mixture was successively washed with 3% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution, brine, and was dried over Na2SO4. The solution was concentrated in vacuo affording a white solid. Recrystallization from EtOAc-hexanes afforded 0.56 g (72%) of the pure titled compound as a white powder: mp 181-182° C. APCI-MS m/z 519.1 (MH+).
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:27])[CH2:6][O:7][C:8]([CH3:26])([CH3:25])[C:9]#[C:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:16]=1[CH3:17]>O1CCOCC1.O>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[CH:14]=[CH:15][C:16]([CH3:17])=[C:11]([C:10]#[C:9][C:8]([CH3:26])([CH3:25])[O:7][CH2:6][C:5]([OH:27])=[O:4])[CH:12]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)COC(C)(C)C#Cc1cc(-c2ccc(Cl)cc2)ccc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C#CC(C)(C)OCC(=O)O
Temperature: 20 °C
Reaction time: 4 h
Yield: 69.8 %

Procedure:
Potassium hydroxide (1.105 g, 19.7 mmol) is added to a solution of [3-(4′-chloro-4-methyl-biphenyl-3-yl)-1,1-dimethylprop-2-ynyloxy]acetic acid methyl ester (6.7 g, 18.8 mmol) in dioxane (20 ml) and water (20 ml). After stirring for four hours at 20° C., the reaction mixture is extracted twice with dichloromethane. The aqueous layer is acidified at 0° C. to pH 2-3 using 1N aqueous hydrochloric acid and extracted twice with ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue is stirred in hexane and filtered to afford [3-(4′-chloro-4-methylbiphenyl-3-yl)-1,1-dimethylprop-2-ynyloxy]acetic acid (4.50 g) as a white solid (m.p. 125° C.).