Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=1>[N+](C1C=CC=CC=1)([O-])=O.[Cu]>[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:20][CH:19]=1
Reactant: Fc1ccc(S)cc1
Reactant: O=C(O)c1ccccc1I
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)c1ccccc1Sc1ccc(F)cc1
Temperature: 160 °C
Reaction time: 0.67 h

Procedure:
A mixture of 147 g of iodobenzoic acid, 45.5 g of potassium carbonate in 57 ml of nitrobenzene is maintained with stirring at 160° C. for 40 minutes. Thereafter, 46.5 g of additional potassium carbonate which is followed by the addition of 73.1 g of 4-fluorothiophenol, another 46.5 g of potassium carbonate and 0.35 g of copper powder. The reaction mixture is stirred in a 160° C. bath for 45 minutes. The resulting solid is collected and then cooled to 0° C. before being mixed with 100 ml of water and 220 ml of 6 N hydrochloric acid. The aqueous mixture is then diluted to 1 liter total volume before being stirred with 450 ml of chloroform. The resulting white solid is collected and washed successively with chloroform and water. The solid is dissolved in hot acetone and the acetone solution is successively filtered and cooled to provide a white crystalline product. The product is recrystallized from acetone and then converted to a salt with potassium carbonate. The salt is dissolved in water and the aqueous solution acidified with 1 N hydrochloric acid to provide 2-(4-fluorophenylthio)benzoic acid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH:6]([O:11][CH2:12][CH3:13])[C:7](=[CH2:10])[CH2:8][OH:9])[CH3:4].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1.CN(C)C=O>[CH2:12]([O:11][CH:6]([O:5][CH2:3][CH3:4])[C:7](=[CH2:10])[CH2:8][O:9][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13]
Reactant: C=C(CO)C(OCC)OCC
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: C=C(COCc1ccccc1)C(OCC)OCC
Reaction time: 2 h

Procedure:
3.0 g (62.4 mmol) of 50% sodium hydride dispersion in mineral oil are placed in 50 ml of tetrahydrofuran and 40 ml of dimethylformamide, a solution of 10.0 g (62.4 mmol) of 3-hydroxy-2-methylenepropionaldehyde-diethylacetal in 10 ml of tetrahydrofuran is slowly added dropwise at 0°, and the mixture is stirred at 0° for 2 hours. The mixture is diluted with 15 ml of tetrahydrofuran and 10 ml of dimethylformamide and stirred at room temperature for a further 2 hours. 7.2 ml (62.4 mmol) of benzyl chloride in 10 ml of dimethylformamide are then added at 0°, and the mixture is stirred at room temperature for 18 hours. Water is added to the reaction mixture, which is then extracted three times with ethyl acetate, and the organic phases are washed with saturated sodium chloride solution. The organic phases are combined, dried over Na2SO4, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride, yielding 3-benzyloxy-2-methylenepropionaldehyde-diethylacetal in the form of a pale yellowish liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]([O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])([CH3:13])[CH3:12].C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>C1(C)C(C)=CC=CC=1>[CH:11]([O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH:18][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])([CH3:13])[CH3:12]
Reactant: CC(C)Oc1cccc(N)c1
Reactant: Cc1ccccc1C(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccccc1C(=O)Nc1cccc(OC(C)C)c1
Reaction time: 3 h
Yield: 77.9 %

Procedure:
A 13.6 g (0.1 mol) portion of o-methylbenzoic acid, 15.1 g (0.1 mol) of m-isopropoxyaniline and 10.1 g (0.1 mol) of triethylamine were dissolved in 100 ml of xylene. A 5.1 g (0.033 mol) amount of phosphorus oxychloride was added dropwise to the prepared solution with stirring at 90° - 100° C. Stirring of the resulting solution was continued at 90° - 100° C for 3 hours. The reaction mixture was cooled and washed with water, and the product was dried over anhydrous sodium sulfate. The xylene was removed to obtain 20.9 g (77.9%) of white prismatic crystals having a melting point of 92°-94° C.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[C:7]([OH:8])=[CH:6][C:5]=1[OH:14])(=[O:3])[CH3:2].[OH-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19]>O.ClCCCl>[CH2:19]([C:6]1[C:7]([OH:8])=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=[C:4]([C:1](=[O:3])[CH3:2])[C:5]=1[OH:14])[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: CC(=O)c1cc(C(C)=O)c(O)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Product: C=CCc1c(O)c(C(C)=O)cc(C(C)=O)c1O
Temperature: 25 °C

Procedure:
4,6-Diacetylresorcinol (19.4 g; 0.1 mole), sodium hydroxide (8.0 g; 0.2 mole) and allyl bromide (12.1 g; 9 ml; 0.1 mole) in water (160 ml) and 1,2-dichloroethane (150 ml) were stirred at reflux for 3 hours. The mixture was cooled to room temperature, the organic layer was separated and the aqueous layer was extracted with 1,2-dichloroethane (3×50 ml). The combined organic layers were dried (anhydrous sodium sulphate) and evaporated to give 2-allyl-4,6-diacetylresorcinol as a pink oil (9 g; 38%) which rapidly crystallised, m.p. 84°-86° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu]I>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: Brc1ccc2ccccc2c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2-c2ccc3ccccc3c2)CCN(C)C1

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.4 g, 4 mmol), 2-Bromonaphthalene (0.828 g, 4 mmol), K3PO4 (0.848 g, 4 mmol), CuI (38 mg, 0.2 mmol) and L-Proline (46 mg, 0.39 mmol) in dry DMF (6 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-naphthalen-2-yl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (50 mg). 1H NMR (HCl salt, CD3OD) d (ppm): 8.15 (d, 1H), 8.05-7.95 (m, 2H), 7.9 (s, 1H), 7.6 (m, 2H), 7.5 (d, 2H), 7.35 (s, 1H), 7.19 (d, 1H), 7.05 (d, 1H), 4.8 (d, 1H), 4.45 (d, 1H), 3.8-3.79 (m, 1H), 3.6-3.59 (m, 1H), 3.3-3.25 (m, 1H), 3.19 (s, 3H), 3.05-3.0 (m, 1H), 2.45 (s, 3H).
Reaction SMILES: ClC1C=CC(C([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=O)=CC=1C#N.[OH:25][C:26]1[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:27]=1[C:28]([OH:30])=O>>[OH:25][C:26]1[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:27]=1[C:28]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]1)=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Cl)c(C#N)c2)CC1
Reactant: O=C(O)c1cc(I)ccc1O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(I)ccc2O)CC1

Procedure:
Performed identical to tert-butyl 4-(4-chloro-3-cyanobenzoyl)piperazine-1-carboxylate in Example 1 except 2-hydroxy-5-iodobenzoic acid was used in place of 3-cyano-4-chlorobenzoic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc(C#Cc2csc(C)n2)cn1
Temperature: 80 °C

Procedure:
2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (1.0 mmol, 234 mg), 2-methoxyphenylboronic acid (2.0 mmol, 304 mg), dichlorobis(triphenylphosphine)palladium(II) (0.05 mmol, 35 mg), and potassium carbonate (3.5 mmol, 500 mg) were added to deoxygenated DME:water (1:1, 5 mL) at room temperature. The reaction was heated for 18 h at 80° C., then partitioned in a separatory funnel with EtOAc (100 mL) and water (30 mL). The organic layer was washed with one additional portion of water (20 mL) and the combined aqueous layers back extracted with EtOAc (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2, eluting with a 0% to 60% EtOAc gradient in hexanes, to afford the title compound as a pale yellow solid, which was dissolved in ether and precipitated as the hydrochloride salt with 1M HCl in ether. 1H-NMR (CD3OD, 500 MHz) δ 9.02 (s, 1H), 8.73 (d, 1H), 8.34 (d, 1H), 7.97 (s, 1H), 7.68-7.77 (m, 2H), 7.32 (d, 1H), 7.24 (dd, 1H), 3.99 (s, 3H), 2.77 (s, 3H). MS (ESI) 307.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH2:9][CH2:8][CH:7]=[C:6]([CH3:10])[CH2:5][CH2:4][CH:3]=1.CC1CCC(C)=CCCC=1.[IH:21]>>[CH3:10][C:6]12[CH:3]([I:21])[C:2]([CH3:1])([CH2:4][CH2:5]1)[CH2:9][CH2:8][CH2:7]2
Reactant: CC1=CCCC(C)=CCC1
Reactant: I
Agent: CC1=CCCC=C(C)CC1
Product: CC12CCCC(C)(CC1)C2I
Yield: 80.6 %

Procedure:
A mixture of 13.6 g (0.1 mol) of 1,5-dimethyl-1,5-cyclooctadiene and 1,6-dimethyl-1,5-cyclooctadiene, ratio 80/20, was boiled under reflux while stirring for two hours with 100 ml 55% hydrogen iodide in the presence of 2 g AMBERLYST A15 ion-exchange resin. The reaction product was extracted with pentane after cooling. The pentane layer was washed with water and an aqueous sodium bicarbonate solution. Residual free iodine present in the solution was washed away with a diluted sodium thiosulfate solution. The resulting pentane solution was dried over anhydrous sodium sulfate and pentane was flashed off. Fractional distillation under reduced pressure gave 17 g of 1,5-dimethyl-8-iodobicyclo[3,2,1]octane (b.p. 106° C./7 mm Hg). Yield 80.6% calculated on the amount of 1,5-dimethyl-1,5-cyclooctadiene added to the reaction. The purity of the product according to gas-liquid chromatography was more than 95%. The product appeared to be sensitive to day-light.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[OH:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].Br[CH2:23][CH2:24][CH2:25][OH:26]>CN(C)C=O.C(OCC)(=O)C>[OH:26][CH2:25][CH2:24][CH2:23][O:10][N:11]1[C:12](=[O:21])[C:13]2[C:14](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:16]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCCCBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1OCCCO
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 64.3 %

Procedure:
Diisopropylethylamine (43 mL, 246 mmol) was added to a stirring solution of N-hydroxyphthalimide (20.6 g, 123 mmol) in dimethylformamide (95 mL). After 5 minutes, 3-bromopropanol (11.5 mL, 127 mmol) was added and the reaction mixture was heated to 80° C. for 18 h. The cooled solution was diluted with ethyl acetate (700 mL) and was washed with water (4×500 mL) and saturated brine (2×500 mL), dried over sodium sulfate and concentrated to an oil that solidified on standing to afford 2-(3-hydroxy-propoxy)-isoindole-1,3-dione (17.5 g, 65% yield) as a tan-colored solid: 1H NMR (400 MHz, CDCl3) δ 7.81 (m, 2H), 7.74 (m, 2H), 4.36 (t, 2H, J=5.6 Hz), 3.92 (t, 2H, J=5.9 Hz), 1.98 (quintet, 2H, J=5.9 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][CH2:24][O:25][CH2:26][CH2:27][OH:28].[Na+].[I-]>CC#N.CCOC(C)=O>[OH:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: OCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1ccc(OCCOCCO)cc1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
To a suspension of 4-hydroxybenzophenone (4.0 g, 19.8 mmol) in CH3CN (30 mL) was added K2CO3 (8.20 g, 59.3 mmol). The mixture was refluxed under nitrogen for 1 h. Cooled to room temperature, 2-(2-chloroethoxy)ethanol (4.3 mL, 39.6 mmol) was added, followed by addition of NaI (3.00 g, 19.8 mmol). The reaction mixture was refluxed under nitrogen overnight. The mixture was cooled to room temperature and EtOAc (50 mL) was added. The precipitated white solid was filtered and washed with EtOAc (50 mL). The filtrate was transferred to a separatory funnel and washed with 1 N NaOH, water, brine and dried over Na2SO4. Concentration yielded a yellow oil which was further purified by chromatography on a silica gel column eluted with a gradient from hexanes to 70% EtOAc:hexanes to give 7 as colorless crystals (4.96 g, 88%). mp 31-32° C. 1H NMR (400 MHz, CDCl3): δ 3.65-3.75 (m, 2H), 3.75-3.80 (m, 2H), 3.90-3.95 (m, 2H), 4.20-4.25 (m, 2H), 6.99 (d, J=8.8 Hz, 2H), 7.45-7.50 (m, 2H), 7.55-7.60 (m, 1H), 7.70-7.80 (m, 2H), 7.83 (d, J=8.8 Hz, 2H). LRMS (ESI): m/z 287 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Br)[CH3:2].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([SH:18])[CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][S:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[CH:13]=1)[CH3:2]
Reactant: COc1cccc(S)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(CSc1cccc(OC)c1)OCC
Reaction time: 16 h
Yield: 97.2 %

Procedure:
Bromoacetaldehyde diethyl acetal (16.5 ml, 0.11 mol) was added dropwise to a mixture of m-methoxybenzenethiol (15.0 ml, 0.12 mol) and K2CO3 (16.6 g, 0.12 mol) in acetone (150 ml) at room temperature. The reaction mixture was stirred for 16 hours and then filtered. The solid was washed with acetone, and the combined filtrate and washes were concentrated in vacuo. The residue was diluted with H2O and extracted with Et2O. The Et2O extracts were washed with 0.5M KOH, H2O, and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 27.4 g of 1-[(2,2-diethoxy)ethylthio]-3-methoxybenzene as a dark yellow oil. 'H NMR, δ: (CDCl3): 1.18 (6H, t, --OCH2CH3); 3.13 (2H, d, --SCH--); 3.43--3.73 (4H, m, --OCH2CH3); 3.77 (3H, s, -- OCH3); 4.67 (1H, t, --SCH2CH--); 6.60-7.27 (4H, m, aromatics).
Reaction SMILES: C([O:8][C:9]([C:11]1[C:12]([C:18]2[CH:23]=[C:22]([C:24](=[O:33])[NH:25][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:21]=[CH:20][C:19]=2[CH2:34][C:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44]#[N:45])=[CH:41][CH:42]=3)[N:37]([CH2:46][CH3:47])[CH:36]=2)=[CH:13][CH:14]=[C:15]([CH3:17])[CH:16]=1)=[O:10])C1C=CC=CC=1.[NH2:48]CC1C=NC=CC=1>>[C:44]([C:40]1[CH:39]=[C:38]2[C:43]([C:35]([CH2:34][C:19]3[CH:20]=[CH:21][C:22]([C:24](=[O:33])[NH:25][CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:23][C:18]=3[C:12]3[C:11]([C:9]([OH:8])=[O:10])=[CH:16][C:15]([CH3:17])=[CH:14][CH:13]=3)=[CH:36][N:37]2[CH2:46][CH3:47])=[CH:42][CH:41]=1)(=[NH:45])[NH2:48]
Reactant: NCc1cccnc1
Reactant: CCn1cc(Cc2ccc(C(=O)NCc3cccnc3)cc2-c2ccc(C)cc2C(=O)OCc2ccccc2)c2ccc(C#N)cc21
Product: CCn1cc(Cc2ccc(C(=O)NCc3cccnc3)cc2-c2ccc(C)cc2C(=O)O)c2ccc(C(=N)N)cc21
Yield: 88 %

Procedure:
Part E. 2′-(6-cyano-1-ethyl-1H-indol-3-ylmethyl)-4-methyl-5′-[(pyridin-3-ylmethyl)-carbamoyl]-biphenyl-2-carboxylic acid benzyl ester: The compound of Part D was coupled with 3-aminomethylpyrdine using the procedure described for Example 15, Part G to provide the amide in 88% yield. 1H NMR (500 MHz, CDCl3) δ ppm 1.38 (t, J=7.42 Hz, 3H) 2.41 (s, 3H) 3.79 (s, 2H) 4.04 (q, J=7.15 Hz, 2H) 4.60 (m, 2H) 4.94 (m, 2H) 6.29 (t, J=5.50 Hz, 1H) 6.67 (s, 1H) 6.97 (d, J=7.70 Hz, 1H) 7.03 (m, 2H) 7.16 (d, J=8.25 Hz, 1H) 7.24 (m, 7H) 7.44 (s, 1H) 7.56 (s, 1H) 7.67 (t, J=8.52 Hz, 2H) 7.82 (s, 1H) 8.53 (s, 1H) 8.57 (s, 1H). LC/MS m/z 619.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:14])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.[CH2:15]([C:22]1[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH:14][C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]3)=[C:2]([F:1])[CH:3]=2)[N:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Clc1nccc(Cc2ccccc2)n1
Reactant: Cc1cn(-c2ccc(N)cc2F)cn1
Product: Cc1cn(-c2ccc(Nc3nccc(Cc4ccccc4)n3)cc2F)cn1

Procedure:
The title compound was prepared from 3-fluoro-4-(4-methyl-imidazol-1-yl)-phenylamine (94 mg, 0.49 mmol) and 4-benzyl-2-chloro-pyrimidine (100 mg, 0.49 mmol) in analogous manner to the procedure described in example 1e). Obtained as a pale-yellow solid (50 mg, 29%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH3:19])[CH2:14][CH2:13]2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:20][C:21]1[N:22]=[C:23]([C:28]([OH:30])=O)[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([N:18]([CH3:19])[CH:15]2[CH2:16][CH2:17][N:12]([C:4]3[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=3)[CH2:13][CH2:14]2)=[O:30])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1sc(N2CCC(NC)CC2)nc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCOC(=O)c1sc(N2CCC(N(C)C(=O)c3nc(Cl)c(CC)[nH]3)CC2)nc1C
Yield: 92.4 %

Procedure:
The same operation as in Example (217c) was performed using ethyl 4-methyl-2-[4-(methylamino)piperidin-1-yl]-1,3-thiazole-5-carboxylate obtained in Example (240b) (254 mg, 0.90 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (156 mg, 0.90 mmol), WSC hydrochloride (515 mg, 2.69 mmol), 1-hydroxybenzotriazole (121 mg, 0.90 mmol) and N-methylmorpholine (0.20 mL, 1.79 mmol), to obtain 366 mg of the title compound as a white solid (93%).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)C.[CH2:15]([NH2:27])[CH2:16][C:17]1[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=1.C(N(CC)CC)C>C(OCC)(=O)C.O>[CH3:21][O:20][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][NH:27][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[CH:26]=[CH:25][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(Cl)C1CCCCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1ccc(CCNC(=O)C2CCCCC2)cc1OC
Reaction time: 0.25 h

Procedure:
Dissolve 2.0 g. of cyclohexane carboxylic acid chloride in 10 ml. of ethyl ether and add to a previously prepared solution of 2.0 g. of homoveratrylamine in a mixture of 20 ml. of ethyl ether and 5.0 ml. of triethylamine. Stir the mixture for 15 minutes, then add 20 ml. of water and 25 ml. of ethyl acetate. Separate the layers and extract the aqueous layers several times with ethyl acetate. Combine the organic phases and wash with 2N hydrochloric acid, saturated sodium bicarbonate solution and water. Dry the organic layer over anhydrous sodium sulfate, filter and evaporate to a residue. Crystallize the residue from ethyl acetate to obtain the product of this step, m.p. 110°-111°C.
Reaction SMILES: [Cl:1][C:2]1[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]([Cl:19])[C:3]=1[NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:21]([S:23]Cl)=[O:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]([Cl:19])[C:3]=1[NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]1[O:8][C:21](=[O:22])[S:23][N:9]=1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(N)=O)c1Cl
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Product: Cc1ccc(Cl)c(Nc2ccccc2-c2nsc(=O)o2)c1Cl
Reaction time: 1 h

Procedure:
To a 90° C. solution of 2-(2,6-dichloro-3-methylanilino)benzamide (2.300 g, 7.79 mmols) [prepared according to Juby, J. Med. Chem., 11, 111 (1968)] in 40 mL of toluene is added chlorocarbonylsulfenyl chloride (1.300 mL, 15.38 mmols). Heating is continued at 90° C. for 1 hour. The solution is concentrated in vacuo and purified by flash chromatography, eluting with 10:1 hexane:diethyl ether providing 280 mg (10%) of 5-[2-[(2,6-dichloro-3-methylphenyl]amino]phenyl]-1,3,4-oxathiazol-2-one as a white solid; mp 135°-137° C.
Reaction SMILES: C([O:3][C:4]([C@@:6]12[CH2:24][C@H:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14](=[O:33])[N:13]1[C@@H:9]([CH2:10][C@@H:11]([O:34][C:35]3[C:44]4[C:39](=[CH:40][C:41]([O:45][CH3:46])=[CH:42][CH:43]=4)[N:38]=[C:37]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH:36]=3)[CH2:12]1)[C:8](=[O:53])[NH:7]2)=[O:5])C.[Li+].[OH-]>C1COCC1.O.CO>[C:29]([O:28][C:26]([NH:25][C@@H:15]1[C:14](=[O:33])[N:13]2[C@@H:9]([CH2:10][C@@H:11]([O:34][C:35]3[C:44]4[C:39](=[CH:40][C:41]([O:45][CH3:46])=[CH:42][CH:43]=4)[N:38]=[C:37]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH:36]=3)[CH2:12]2)[C:8](=[O:53])[NH:7][C@@:6]2([C:4]([OH:5])=[O:3])[C@@H:23]([CH2:24]2)[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)C[C@H]1C(=O)N2
Agent: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)O)C[C@H]5/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)cc(-c3ccccc3)nc2c1
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)O)C[C@H]5C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N4C3)cc(-c3ccccc3)nc2c1

Procedure:
Following an analogous experimental and purification procedure to Step 1i, (1S,4R,6S,14S,18R)-7-cis-14-tert-butoxycarbonylamino-18-(7-methoxy-2-phenylquinolin-4-yloxy)-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid ethyl ester (225 mg, 0.309 mmol) was reacted with 78 mg (2.0 mmol) of LiOH in 20.8 mL of 12.4:6.6:1.8 of THF/H2O/MeOH to afford (1S,4R,6S,14S,18R)-7-cis-14-tert-butoxycarbonylamino-18-(7-methoxy-2-phenylquinol-in-4-yloxy)-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene-4-carboxylic acid (178 mg, 82%): 1H NMR (500 MHz, CD3OD) δ 1.12-1.54 (m, 8H), 1.19 (s, 9H), 1.59 (dd, J=8.4, 5.0 Hz, 1H), 1.64 (dd, J=9.8, 4.9 Hz, 1H), 1.75-1.82 (m, 1H), 1.87-1.94 (m, 1H), 2.31 (q, J=9 Hz, 1H), 2.52-2.57 (m, 1H), 2.69 (dd, J=14, 7.5 Hz, 1H), 3.92 (s, 3H), 4.01 (dd, J=11.6, 3.2 Hz, 1H), 4.19 (dd, J=10.4, 2.4 Hz, 1H), 4.65 (t, J=8 Hz, 1H), 4.75 (d, J=11.6 Hz, 1H), 5.33 (t, J=9.6 Hz, 1H), 5.55-5.60 (m, 2H), 7.08 (dd, J=9.2, 2.1 Hz, 1H), 7.25 (s, 1H), 7.37 (d, J=2 Hz, 1H), 7.51-7.57 (m, 3H), 8.02-8.05 (m, 2H), 8.15 (d, J=9.2 Hz, 1H). LC-MS (Method E-retention time: 1.61), MS m/z 699 (M++1). HRMS m/z (M+H)+ calcd for C39H47N4O8: 699.3394, found 699.3395. Step 9j: Preparation of Compound 9, Example 9 (1S,4R,6S,14S,18R)-7-cis-[4-Cyclopropanesulfonylamino-carbonyl-18-(7-methoxy-2-phenylquinolin-4-yloxy)-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-en-14-yl]carbamic acid tert-butyl ester