Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8]2)=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:13]1([CH:9]2[NH:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:19]=[CH:20][C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22]([F:33])([F:32])[F:21])=[CH:3][CH:4]=3)[CH2:8]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccc(CN2CCNC(c3ccccc3)C2)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCNC(c3ccccc3)C2)cc1
Temperature: 120 °C
Yield: 41.4 %

Procedure:
100 mg of 1-(4-Bromo-benzyl)-3-phenyl-piperazine was combined with 136 mg of 2-(Trifluoromethyl)phenyl boronic acid, 17 mg of tetrakis(triphenylphosphine)palladium(0), 1.01 mL of 2M sodium carbonate solution, 2.7 mL toluene and 1.4 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography eluting in a 0-20% methylene chloride/methanol gradient. The product fractions were pooled and concentrated to afford 49.5 mg of product. ES MS (+) m/z 397
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:15]1([S:21]([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]([CH:13]=[O:14])=[C:4]2[Cl:3])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1c(Cl)n(S(=O)(=O)c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.5 %

Procedure:
The title compound is prepared in accordance with the procedure of O. Olton et al., Tetrahedron, 54 (1998), 13915-13928 as follows. Sodium hydroxide is added to a stirred solution of 2-chloro-1H-indole-3-carboxaldehyde (239 mg, 1.33 mmol) in ethanol (10 mL). After 2 hr, the solvent is removed and the solid residue is dissolved in acetone and treated with benzenesulfonyl chloride (0.25 mL, 1.96 mmol). Soon a solid precipitated. After stirring for 1.5 hr at room temperature, the reaction mixture is heated to reflux for 1.5 hr. After cooling, water is added and the reaction is extracted with dichloromethane. The combined dichloromethane layer is washed with brine, dried over sodium sulfate and concentrated to an oil that is purified by chromatography eluting with heptane-0 to 10% ethyl acetate. Product containing fractions are combined and concentrated to afford 1-benzenesulfonyl-2-chloro-1H-indole-3-carboxaldehyde (70 mg, 17% yield) as a yellow solid. MS 320 (M+H); NMR 10.09 (1H, s); 8.26 (1H, d, J=9 Hz); 8.15 (3H, m); 7.85 (3H, m); 7.56 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[C:11]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]([CH3:17])=[CH:13][C:14]=2[CH3:16])[NH:9][CH2:8]1)=[O:4].I[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].CCOC(C)=O>CN(C=O)C>[CH2:26]([N:9]1[C:10]2[C:15](=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=2[NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[CH:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH2:8]1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: COC(=O)CCC1CNc2c(NC(=O)C(C)(C)C)c(C)cc(C)c21
Reactant: CCCCCCCCI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCN1CC(CCC(=O)OC)c2c(C)cc(C)c(NC(=O)C(C)(C)C)c21
Temperature: 40 °C
Reaction time: 10 h
Yield: 82.2 %

Procedure:
N-[3-(2-Methoxycarbonylethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide (1.0 g) was dissolved in DMF (10 ml) and 1-iodooctane (1.44 g) and K2 CO3 (830 g) were added, which was followed by stirring at 40° C. for 10 hr. AcOEt (100 ml) was added, and after washing with water, the mixture was dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene/AcOEt=20/1−5/1) to give 1.1 g of the title compound.
Reaction SMILES: [C:1]([C:6]1[CH:40]=[C:39]([C:41]([CH2:44][CH3:45])([CH3:43])[CH3:42])[CH:38]=[CH:37][C:7]=1[O:8][CH:9]([CH2:35][CH3:36])[C:10]([NH:12][C:13]1[CH:14]=[C:15]([CH:32]=[CH:33][CH:34]=1)[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:22]2[C:23]([C:30]=1[OH:31])=[CH:24][CH:25]=[CH:26][C:27](=[O:29])[N:28]=2)=[O:17])=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].S(Cl)([Cl:49])(=O)=O.C(OCC)(=O)C.[Cl-].[Na+]>C(Cl)Cl>[Cl:49][C:21]1[C:22]2[C:23](=[CH:24][CH:25]=[CH:26][C:27](=[O:29])[N:28]=2)[C:30]([OH:31])=[C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:32]=[CH:33][CH:34]=[C:13]([NH:12][C:10](=[O:11])[CH:9]([O:8][C:7]3[CH:37]=[CH:38][C:39]([C:41]([CH2:44][CH3:45])([CH3:42])[CH3:43])=[CH:40][C:6]=3[C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])[CH2:35][CH3:36])[CH:14]=2)[CH:20]=1
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cccc(C(=O)Nc2ccc3nc(=O)cccc3c2O)c1
Reactant: O=S(=O)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cccc(C(=O)Nc2cc(Cl)c3nc(=O)cccc3c2O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 30 ml of methylene chloride was dispersed 6 g of the 7-{3-[2-(2,4-di-t-amylphenoxy)butanoylamino]benzoylamino}-6-hydroxybenzazepin-2-one prepared in (6) above, and 0.84 ml of sulfuryl chloride was added drop-wise to the dispersion at room temperature. After stirring at room temperature for 2 hours, ethyl acetate and a saturated aqueous solution of sodium chloride were added thereto to effect extraction. The extract was concentrated under reduced pressure, and the residue was dispersed in 30 ml of acetonitrile and 15 ml of ethyl acetate. The dispersion was heat-refluxed, followed by cooling. The precipitated crystals were collected by filtration and dried to obtain 5.8 g of the desired coupler having a melting point of 234° to 236° C.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3](=O)[C:4]([O:6][CH3:7])=[O:5].[N+:11]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])([O-:13])=[O:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]([F:10])([F:9])[CH:3]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(=O)C(F)(F)F
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(Nc1cccc([N+](=O)[O-])c1)C(F)(F)F
Reaction time: 0.33 h
Yield: 43.9 %

Procedure:
To a solution of methyl trifluoropyruvate (500 mg) and 3-nitroaniline (442 mg) in methylene chloride (32 mL), titanium tetrachloride (350 μL) was added at room temperature, and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture, sodium triacetoxyborohydride (1.35 g) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture, water and methylene chloride were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 20% hexane in ethyl acetate) to obtain methyl 3,3,3-trifluoro-2-((3-nitrophenyl)amino)propanoate (C13, 391 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].O>CN(C)C=O>[C:18]1(=[O:28])[N:22]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13])[C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12
Reactant: COC(=O)C(C)(C)CCCCCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CCCCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 103 %

Procedure:
12.3 g of methyl 11-bromo-2,2-dimethylundecanoate in solution in 70 cm3 of N,N-dimethylformamide are added to 8.2 g of potassium phthalimide in 70 cm3 of N,N-dimethylformamide and the mixture is heated for 3 hours at a temperature in the region of 80° C. The solution is cooled to a temperature in the region of 20° C. and then poured into 1400 cm3 of distilled water. Acidification is carried out to a pH in the region of 2 using 4N hydrochloric acid and extraction is then carried out with a total of 1000 cm3 of ethyl acetate. The organic phase is washed with a total of 450 cm3 of distilled water, dried over magnesium sulphate, and then concentrated under reduced pressure (13.5 Pa) at a temperature in the region of 60° C. 15.4 g of methyl 11-phthalimido-2,2-dimethylundecanoate are thus obtained in the form of a pale yellow viscous oil [Rf =0.38; silica thin layer chromatography; eluent: cyclohexane/ethyl acetate 8/2 (by volume)].
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:43][NH:44][CH3:45]>>[CH3:43][N:44]([CH3:45])[C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)=[O:37]
Reactant: CNC
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: COc1cc(C(=O)N(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with dimethylamine to give (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-dimethylcarbamoyl-2-methoxy-phenyl)-amide. MS (ES+) m/z calcd. for C33H35Cl2F2N4O3: [(M+H)+]: 643. found: 643.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([N:13]([OH:26])[C:14](=[O:25])[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)=[O:4].[H-].[Na+].[CH2:29](Br)[C:30]#[CH:31]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([N:13]([O:26][CH2:31][C:30]#[CH:29])[C:14](=[O:25])[CH2:15][C:16]2[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])[CH2:6][CH2:7][N:8]([O:11][CH3:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(N(O)C(=O)Cc2c(C)cc(C)cc2C)CCN(OC)CC1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCON(C(=O)Cc1c(C)cc(C)cc1C)C1(C(=O)OC)CCN(OC)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-{hydroxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-1-methoxy-piperidine-4-carboxylic acid methyl ester (compound P3ii.3 obtained in analogy to preparation example 11, step 4) (500 mg, 1.37 mmol) in tetrahydrofuran (3 ml) at 0° C. was added sodium hydride (66 mg, 55% w/w dispersion in mineral oil, 1.51 mmol) in 2 portions. The reaction mixture was stirred at 0° C. for one hour, treated with propargyl bromide (202 mg, 1.65 mmol) dropwise, and further stirred at room temperature overnight. The reaction mixture was evaporated, diluted with ethyl acetate and filtered to remove salts. The filtrate was washed twice with brine, dried over sodium sulfate and concentrated. The oily residue was purified by chromatography on silica gel (ethyl acetate/hexane 1:2). Yield: 321 mg of 1-methoxy-4-{prop-2-ynyloxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylic acid methyl ester (compound P3ii.4) as a colorless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:6]([CH2:12]Cl)=[N:7]2.O.[SH:24][C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[NH:27][CH:28]=[N:29]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:6]([CH2:12][S:24][C:25]1[N:33]=[CH:32][N:31]=[C:30]3[C:26]=1[N:27]=[CH:28][NH:29]3)=[N:7]2
Reactant: COc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1-n1c(CSc2ncnc3[nH]cnc23)nc2cccc(Cl)c2c1=O
Yield: 75.5 %

Procedure:
Prepared according to Procedure C using Intermediate 21 (250 mg, 0.746 mmol), 6-mercaptopurine monohydrate (140 mg, 0.821 mmol), K2CO3 (113 mg, 0.821 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 254 mg of an off-white solid (76%), mp 237.0° C. (dec; discolors at 154.6° C.). 1H NMR (DMSO-d6) δ: 13.53 (br s, 1H); 8.52 (s, 1H); 8.45 (s, 1H); 7.78 (t, J=7.9 Hz, 1H); 7.64 (d, J=8.0 Hz, 1H); 7.59 (d, J=7.7 Hz, 1H); 7.48 (d, J=7.3 Hz, 1H); 7.42 (t, J=7.7 Hz, 1H); 7.15 (d, J=8.2 Hz, 1H); 7.03 (t, J=7.5 Hz, 1H); 4.45 (s, 2H); 3.76 (s, 3H). 13C NMR (DMSO-d6) ppm: 158.9, 157.1, 154.8, 154.7, 151.5, 149.6, 143.6, 135.1, 133.2, 131.3, 130.4, 130.0, 127.0, 124.8, 121.2, 117.8, 112.7, 56.1, 32.0. MS (ES): m/z 451.0 (M+). Anal. calcd. for C21H15ClN6O2S.0.15C2H6O.0.05KCl: C, 55.43; H, 3.47; Cl, 8.07; N, 18.21; S, 6.95. Found: C, 55.49; H, 3.68; Cl, 7.95; N, 17.82; S, 6.82.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[CH3:11][C:12]([CH3:14])=[O:13].C[O-].[Na+]>C1COCC1>[N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:3](=[O:4])[CH2:11][C:12](=[O:13])[CH3:14])[CH:6]=1
Reactant: CC(C)=O
Reactant: COC(=O)c1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.4 %

Procedure:
To a solution of methylpyridine-3-carboxylate (20.0 g, 146 mmol) in THF (200 mL) was added acetone (50 mL, 681.0 mmol). Sodium methoxide (32.7 mL of 25% w/w, 146.0 mmol) was added dropwsie at rt under N2. The mixture was stirred at rt for 72 hours, quenched with sat. NH4Cl, acidifed with 1 N HCl to pH-5. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by column chromatography (0-10% EtOAc-Hex) to provide 1-(3-pyridyl)butane-1,3-dione (7 g) as a light yellow crystalline solid. 1H NMR (400 MHz, CDCl3) δ 15.98 (s, 1H), 9.19-8.99 (m, 1H), 8.74 (dd, J=4.8, 1.7 Hz, 1H), 8.34-8.04 (m, 1H), 7.41 (ddd, J=8.0, 4.8, 0.8 Hz, 1H), 6.20 (s, 1H), 2.24 (s, 3H). ESI-MS m/z calc. 163.06, found 164.3 (M+1)+; Retention time: 0.32 minutes (3 min run).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[SH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.C[O-].[Na+]>CO.O>[N:22]1[CH:23]=[CH:24][C:19]([S:18][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[CH:20][CH:21]=1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: Sc1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1CCc2cc(OCCCCSc3ccncc3)ccc2N1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3.0 gm of 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril were added to a solution of 1.3 gm of 4-mercapto-pyridine and 2.3 gm of a 30% sodium methylate solution in 15 ml of methanol, and the mixture was stirred for 14 hours at room temperature. Subsequently, the reaction solution was diluted with 20 ml of water and the resulting precipitate was recrystallized from ethanol.
Reaction SMILES: [CH:1]([Si:4]([O:11][C:12](=[O:36])[N:13]([CH2:19][CH2:20][C:21]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([F:35])[CH:28]=2)[CH:24]=[N:23][CH:22]=1)[C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH:37]([Si:40]([CH:58]([CH3:60])[CH3:59])([CH:55]([CH3:57])[CH3:56])[O:41][C:42]1[CH:51]=[C:50]2[C:45]([CH:46]=[CH:47][CH:48]=[C:49]2[C:52](O)=[O:53])=[CH:44][CH:43]=1)([CH3:39])[CH3:38].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH:1]([Si:4]([O:11][C:12](=[O:36])[N:13]([CH2:19][CH2:20][C:21]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([F:35])[CH:28]=2)[CH:24]=[N:23][CH:22]=1)[C@H:14]1[CH2:18][CH2:17][N:16]([C:52]([C:49]2[C:50]3[C:45](=[CH:44][CH:43]=[C:42]([O:41][Si:40]([CH:55]([CH3:57])[CH3:56])([CH:58]([CH3:60])[CH3:59])[CH:37]([CH3:38])[CH3:39])[CH:51]=3)[CH:46]=[CH:47][CH:48]=2)=[O:53])[CH2:15]1)([CH:5]([CH3:6])[CH3:7])[CH:8]([CH3:9])[CH3:10])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](OC(=O)N(CCc1cncn1Cc1ccc(C#N)c(F)c1)[C@H]1CCNC1)(C(C)C)C(C)C
Reactant: CC(C)[Si](Oc1ccc2cccc(C(=O)O)c2c1)(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](OC(=O)N(CCc1cncn1Cc1ccc(C#N)c(F)c1)[C@H]1CCN(C(=O)c2cccc3ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(S)-N-{2-[1-(4-Cyano-3-fluorobenzyl)-1H-imidazol-5-yl]ethyl}-N-(pyrrolidin-3-yl)carbamic acid triisopropylsilyl ester, as described above in Step H, (242 mg, 0.471 mmol), 7-(triisopropylsilyloxy)-1-naphthlenecarboxylic acid, as described in Example 54, Step C, (162 mg, 0.471 mmol), PYBOP (245 mg, 0.471 mmol), and triethylamine (0.085 mL, 0.612 mmol) were combined in CH2Cl2 (4 mL). The reaction mixture was stirred at ambient temperature for 4 hours, then poured into 10% aqueous citric acid and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo, to yield the above-titled compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:30])[CH2:10][C:11]1([C:24]2[S:25][C:26](Br)=[CH:27][CH:28]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13][CH2:12]1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:30])[CH2:10][C:11]1([C:24]2[S:25][C:26]([C:36]3[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=3)=[CH:27][CH:28]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13][CH2:12]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CS(=O)(=O)N1CCC(CC(=O)NOC2CCCCO2)(c2ccc(Br)s2)S(=O)(=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(C3(CC(=O)NOC4CCCCO4)CCN(S(C)(=O)=O)CCS3(=O)=O)s2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
A mixture of N-(2-tetrahydropyranyloxy)-2-[7-(5-bromo-2-thienyl)-4-methanesulfonyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (200 mg), 4-methoxyphenylboronic acid (83.6 mg) and tetrakis(triphenylphosphine)palladium(0) (21.2 mg) in a mixture of 1,2-dimethoxyethane (2 ml) and aqueous 2M sodium carbonate (0.75 ml) was stirred for 2 hours at 80° C. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. The obtained residue was purified with silica gel column chromatography (eluent; 0.5-3% methanol in chloroform) to give N-(2-tetrahydropyranyloxy)-2-[7-(5-(4-methoxyphenyl)-2-thienyl)-4-methanesulfonyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (130 mg) as an amorphous powder.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:7][CH:6]=1.[NH2:23][CH:24]([CH:31]=[CH2:32])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[NH2:2][N:3]=[CH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([N:15]([CH2:4][C:5]2[CH:14]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:16](=[O:22])[CH2:17][CH2:18][C:19]([NH:23][CH:24]([CH:31]=[CH2:32])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:21])=[CH:7][CH:6]=1
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)O)c2ccccc12
Reactant: C=CC(N)CC(=O)OCC
Agent: Cl
Product: C=CC(CC(=O)OCC)NC(=O)CCC(=O)N(Cc1ccccc1)c1ccc(C=NN)c2ccccc12

Procedure:
The title compound was prepared in the manner of Example 1 substituting 4-[[4-(aminoiminomethyl)naphthyl]amino]-4-oxobutanoic acid hydrochloride for 4-[[4-(aminoiminomethyl)-3-phenyl]amino]-4-oxobutanoic acid hydrochloride and using ethyl 3-amino-4-pentenoate. The product was purified by reverse phase HPLC using the conditions of Example 1 to afford the title compound. The product was verified by 13C NMR (CD3 OD) δ13.2, 30.5, 31.3, 39.0, 48.5, 60.4, 114.6, 120.3, 123.1, 123.9, 124.8, 126.6, 127.0, 128.0, 128.1, 130.3, 136.8, 137.4, 167.6, 171.0, 172.6, 173.0; Chemical Ionization Mass Spectrometry (MH+)=411
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([C:13]#[N:14])=[CH:5][CH:4]=1.[C:15]([O-])(O)=[O:16].[Na+].C(Cl)(Cl)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[N:2]([C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([C:13]#[N:14])=[CH:5][CH:4]=1)=[C:15]=[O:16]
Reactant: O=C([O-])O
Reactant: N#Cc1ccc(N)c2c1CCCC2
Agent: Cl
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: N#Cc1ccc(N=C=O)c2c1CCCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a stirring suspension of compound 2D (0.10 g, 0.48 mmol) and NaHCO3 (0.404 g, 4.80 mmol) in CH2Cl2 (4 mL) cooled to 0° C. was rapidly added a solution of phosgene (20%) in toluene (0.95 mL, 4.32 mmol). After addition, the mixture was stirred at rt for 2 h, then filtered to remove the solid. The filtrate was concentrated under reduced pressure, the resulting solid residue dried under vacuum for 1 h to afford compound 2E (95 mg) as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[C:18](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:18][O:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1sc(C(=O)OC)c([N+](=O)[O-])c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1sc(C(=O)OC)c([N+](=O)[O-])c1OC
Yield: 43.6 %

Procedure:
To a solution of methyl 4-hydroxy-5-(methoxycarbonyl)-3-nitrothiophene-2-carboxylate (650 mg, 2.5 mmol) in acetone (20 mL) was added potassium carbonate (0.68 g, 5 mmol) at it Dimethyl sulfate (0.36 mL, 3.73 mmol) was added to the above reaction mixture slowly with stirring and a catalytic amount of KI was added. The mixture was refluxed for 4 h and the cooled reaction mixture was filtered and the solids were washed with acetone. Acetone was removed under reduced pressure and the residue was chromatographed over silica gel column using hexane-ethyl acetate (90:10) as eluents to give the product as a pale yellow color solid (0.3 g, 45%), mp 80-82° C. 1H NMR (400 MHz, CDCl3): δ 4.08 (3H, s), 3.94 (3H, s), 3.92 (3H, s).