Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=O.[CH2:3]([SH:7])[CH2:4][CH2:5][CH3:6].CO.[OH-].[Na+]>O>[CH2:3]([S:7][S:7][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCS
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCSSCCCC
Reaction time: 1 h

Procedure:
This example illustrates the invention and shows that when the reaction liquid is circulated through a restricted area (aspirator) such that a more intimate contact with oxygen is made, the rate of reaction (rate of mercaptan conversion) is greatly increased. A 10-gallon glass-lined reactor, equipped with a Scott oxygen analyzer, reflux condenser, stirrer, thermocouple and circulating inlet tube as shown in FIG. 1 was charged with 38 pounds (0.42 pound moles) of n-butyl mercaptan, 17.2 pounds (0.432 pound moles) of methyl alcohol and 0.91 pounds (0.023 pound moles) of sodium hydroxide. The reactor was sealed and pressured with nitrogen to 220 psig. The stirrer was started and the liquid externally circulated at 1.5-2 gallons per minute using a Lawrence can pump by first passage through a heat exchanger and then being passed through an Ametex water jet exhauster (aspirator) having a 1.27 cm (0.50 in.) opening on the circulated side and a 0.635 cm (0.25 in.) opening on the suction side. The liquid was then returned to the vapor phase of the reactor. Oxygen was then added such that entry was made through the aspirator (see FIG. 1). The system was pressured to about 280 psig with the additional oxygen and the amount of oxygen present in the vapor phase of the reactor monitored by a Scott analyzer and maintained at about 20 mole percent. The reaction temperature immediately began to slowly rise such that after about 1 hour the temperature in the liquid phase of the reactor was about 60° C. (140° F.). The temperature was maintained between about 49° C.-60° C. (120° F.-140° F.) throughout the run. After 1 hour analysis indicated the reaction was 65 percent complete and after 2 hours the reaction was complete as determined by GLC. The product was separated and dried as previously described to give 33.3 pounds (88.6 mole percent yield) of essentially pure di-n-butyl disulfide. A comparison of the rates of reaction carried out by the closed system (Example I) and the circulating-intimate mixing system (Example II) is shown in Table I and FIG. 2. When another run employing the method described in Example II was carried out wherein the separated oil was distilled rather than air dried at 100° C.-120° C., the yield of di-n-butyl disulfide was increased giving 35 pounds (93.1 mole percent) of product.
Reaction SMILES: CS(O[CH2:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=2)[CH:8]=1)(=O)=O.[N:20]1([C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[C:28]#[N:29])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[F:17][C:16]([F:19])([F:18])[C:12]1[CH:13]=[C:14]2[S:15][C:7]([CH2:6][N:23]3[CH2:22][CH2:21][N:20]([C:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=4[C:28]#[N:29])[CH2:25][CH2:24]3)=[CH:8][C:9]2=[N:10][CH:11]=1
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: CS(=O)(=O)OCc1cc2ncc(C(F)(F)F)cc2s1
Product: N#Cc1ccccc1N1CCN(Cc2cc3ncc(C(F)(F)F)cc3s2)CC1

Procedure:
The solution from Example 25C (2 mL) and 2-(1-piperazinyl)benzonitrile (187 mg) were processed as described in Example 25D to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 2.81 (4H, t, J=4.8 Hz), 3.29 (4H, J=4.8 Hz), 4.00 (s, 2H), 7.03 (2H, m), 7.50 (2H, m), 7.59 (dd, 1H, J=7.5, 1.5 Hz), 8.39 (1H, m), 8.86 (1H, m). MS (DCI/NH3) m/z 403.1 (M+H)+. Anal. Calcd for C20H17N4F3S: C, 59.69; H, 4.26; N, 13.92. Found: C, 59.53; H, 4.12; N, 14.22.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH2:22][CH2:23][CH2:24][CH2:25][C:26](N(OC)C)=[O:27])[CH:11]=[C:12]3[C:17]=2[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]3[CH3:21])[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:33]1[S:34][CH:35]=[C:36]([Cl:38])[N:37]=1>>[Cl:38][C:36]1[N:37]=[C:33]([C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][N:10]2[C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[C:1]#[N:2])=[C:17]3[C:12]([N:13]([CH3:21])[C:14](=[O:20])[N:15]([CH3:19])[C:16]3=[O:18])=[CH:11]2)[S:34][CH:35]=1
Reactant: CON(C)C(=O)CCCCn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C
Reactant: Clc1csc(Br)n1
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCCCC(=O)c3nc(Cl)cs3)cc2n(C)c1=O

Procedure:
The title compound was prepared from 5-(5-(3-cyanophenyl)-1,3-dimethyl-2,4-dioxo-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)-N-methoxy-N-methylpentanamide and 2-bromo-4-chlorothiazole by a method similar to Example 13, step 3;
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([OH:17])[CH:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7]1)C.[OH-].[Na+].O>CCO>[OH:17][CH:5]([CH:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7]1)[C:4]([OH:18])=[O:3]
Reactant: CCOC(=O)C(O)C1Sc2ccccc2NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(O)C1Sc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of hydroxy-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetic acid ethyl ester (1.12mmol) in 5 mL of EtOH is added NaOH (1N) (2.24 mmol) and the mixture is stirred at room temperature for 1 hour. Water (20 ml) is added into the mixture followed by extraction (EtOAc, 3×10 mL). The aqueous layer is then treated with HCl (1N) (2.5 mL) and extracted with EtOAc (3×30 mL). The combined extracts are washed with brine and dried over MgSO4. After filtering off the drying agent, the solution is concentrated to provide the crude product hydroxy-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetic acid as a off white solid. Yield: 76%. MS: (ES+): 240 [M+1].
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.O=[C:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[C:27]#[N:28].[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:22]3[CH2:26][CH2:25][CH2:24][CH:23]3[C:27]#[N:28])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: N#CC1CCCC1=O
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3CCCC3C#N)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and rac-2-oxo-cyclopentanecarbonitrile using decaborane yielded a mixture of epimers of the title compound as a white foam. MS (ESI): m/z=372.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7](B(O)O)[N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26](Br)[CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>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>[C:14]([O:13][C:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[CH:6]=[C:7]1[C:26]1[CH:25]=[N:24][CH:23]=[C:22]([OH:21])[CH:27]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(Cl)cc21
Reactant: Oc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1c(-c2cncc(O)c2)cc2ccc(Cl)cc21
Temperature: 110 °C

Procedure:
A microwave flask is charged with 6-chloro-1-Boc-indole-2-boronic acid (1.91 g, 6.46 mmol), 3-hydroxy-5-bromopyridine (0.750 g, 4.31 mmol), potassium phosphate (1.83 g, 8.62 mmol) and DMF (15 mL). The flask is evacuated and filled with nitrogen thrice and Pd(PPh3)4 (0.250 g, 0.215 mmol) is added. The flask is evacuated and filled with nitrogen thrice again, and heated to 110° C. under microwave irradiation for 45 min. Pd(PPh3)4 (0.100 g, 0.086 mmol) is added and the vial is heated again to 110° C. under microwave irradiation for 45 min. The mixture is then diluted with ethyl acetate and washed with water thrice. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel flash chromatography (dichloromethane-methanol, 19:1) to afford 6-chloro-2-(5-hydroxy-pyridin-3-yl)-indole-1-carboxylic acid tert-butyl ester as a solid. MS (ESI) m/z 345.06 (M+H)+
Reaction SMILES: C([O:3][C:4]([C:6]1(C(OCC)=O)[C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[O:7]1)=[O:5])C.C(O)(=O)C.Cl>O>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:8](=[O:9])[O:7][C:6]=2[C:4]([OH:5])=[O:3])=[CH:23][CH:22]=1
Reactant: CCOC(=O)C1(C(=O)OCC)OC(=O)c2ccccc2C1(O)c1ccc(F)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1oc(=O)c2ccccc2c1-c1ccc(F)cc1
Yield: 97.4 %

Procedure:
A stirred mixture of 3,3-bis(ethoxycarbonyl)-4-(4-fluorophenyl)-4-hydroxy-3,4-dihydroisocoumarin (3.85 g), glacial acetic acid (40 ml) and concentrated hydrochloric acid (40 ml) was heated at reflux for 2 hours. The mixture was then cooled and poured onto a mixture of ice and water (200 ml), and the resulting solid was filtered off and washed with water, to give 4-(4-fluorophenyl)isocoumarin-3-carboxylic acid (2.65 g) in the form of a white powder, m.p.218°-220° C. [Elemental analysis: C,67.4; H,3.41; F,6.73%; calculated: C,67.6; H,3.19; F,6.68%].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)[N:5]([C:7]([C:9]1([CH2:14][CH2:15][O:16][CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8])[CH3:6].[Cl-].[NH4+].CO>[Zn].O>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1)[N:5]([CH3:6])[C:7]([C:9]1([CH2:14][CH2:15][O:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13]1)=[O:8]
Reactant: COCCC1(C(=O)N(C)[C@@H](Cc2ccc([N+](=O)[O-])cc2)C(=O)OC)CCCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COCCC1(C(=O)N(C)[C@@H](Cc2ccc(N)cc2)C(=O)OC)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a mixture of N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-N-methyl-4-nitro-L-phenylalanine methyl ester (1.35 mmol, 530 mg), zinc dust (˜325 mesh, 13.5 mmol, 0.88 g, 10 equiv.) and ammonium chloride (20.2 mmol, 1.08 g, 15 equiv.) was added methanol (10 mL) and water (5 mL) at room temperature. After addition of water, the reaction was exothermic. The suspension was stirred for 2 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting material, the reaction mixture was filtered through a pad of celite and the filter cake was washed with methanol (50 mL) and water (40 mL). The mixture was concentrated and extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine solution (30 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent afforded 490 mg (100%) of a yellow oil. HR MS (C20H30N2O4): Obs. mass,362.2202. Calcd. mass, 362.2206 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[O:13].C(CN)O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[C:17]1[NH:11][C:12](=[O:13])[NH:14][C:15]1=[O:16]
Reactant: COc1cccc(C=O)c1
Reactant: O=C1CNC(=O)N1
Solvent: NCCO
Solvent: O
Product: COc1cccc(C=C2NC(=O)NC2=O)c1
Yield: 79.9 %

Procedure:
A mixture of m-methoxybenzaldehyde (2.00 g., 14.7 mmoles) and hydantoin (1.47 g.) in water (12 ml) was heated to 70°; monoethanolamine (1.35 g., 1.5 molar ratio) was then added and the mixture was heated in an oil bath at 90°-92° for 4 hours with magnetic stirring. Isolation in the usual manner gave the title compound as a beige solid (2.56 g.), m.p. 229°-231° .
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:32][CH:31]=1)[C:9](=[O:29])[NH:10][C@H:11]([C:19]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([I:28])=[CH:27][C:21]=2[N:20]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(C)(C)C.Cl.O1CCOCC1>C(#N)C.O1CCOCC1>[NH2:7][C@H:8]([C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:34][CH:35]=1)[C:9]([NH:10][C@H:11]([C:19]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([I:28])=[CH:27][C:21]=2[N:20]=1)[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:29]
Reactant: CC(C)(C)OCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)c2nc3cc(I)ccc3[nH]2)cc1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: CC(C)(C)OCCOc1ccc([C@@H](N)C(=O)N[C@@H](Cc2ccccc2)c2nc3cc(I)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of {(R)-[4-(2-tert-butoxy-ethoxy)-phenyl]-[(S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethylcarbamoyl]-methyl}-carbamic acid tert-butyl ester (260 mg, 0.36 mmol) in 6:1 v/v acetonitrile/p-dioxane (14 mL) at 0° C. under an atmosphere of nitrogen was added 4.0 M hydrogen chloride in p-dioxane (420 μL, 1.68 mmol) and the resulting solution stirred at room temperature for 1 hour. Additional 4.0 M hydrogen chloride (420 μL, 1.68 mmol) was added and stirring continued for 30 minutes. The solvent was removed in vacuo and the residue was basified with saturated aqueous sodium hydrogen carbonate solution. The aqueous mixture was extracted with ethyl acetate (2×25 mL), washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give (R)-2-amino-2-[4-(2-tert-butoxy-ethoxy)-phenyl]-N-[(S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethyl]-acetamide which was used in the subsequent step without further purification (210 mg, 94%).
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(OCC)(=O)C>CN(C)C=O>[Si:15]([O:14][CH2:13][CH2:12][CH2:11][O:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
Ethyl hydroxyacetate (600 mg, 5.76 mmol) was dissolved in N,N-dimethylformamide (6 mL), sodium hydride (55%; 277 mg, 0.447 mmol) was added under ice cooling, and then the mixture was stirred at room temperature for 30 minutes. (3-Bromopropoxy)(tert-butyl)dimethylsilane (1.46 mL, 6.34 mmol) was added, and the mixture was stirred at room temperature for 6.5 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with water (×3) and saturated sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1, v/v) to give the title compound (842 mg; yield, 53%) as a colorless oily substance.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].C(N=[C:22]=[O:23])CCC.C(Cl)(Cl)=O>>[N:1]([S:2]([C:5]1[CH:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3])=[C:22]=[O:23]
Reactant: COC(=O)c1ccc(SC)cc1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: O=C(Cl)Cl
Product: COC(=O)c1ccc(SC)cc1S(=O)(=O)N=C=O
Temperature: 25 °C
Yield: 111.4 %

Procedure:
A solution of methyl 2-(aminosulfonyl)-4-(methylthio)benzoate (5.23 g, 20.0 mmol), n-butyl isocyanate (2.25 mL, 20.0 mmol), and 1,4-diaza[2.2.2]bicyclooctane (0.09 g, 0.8 mmol) in mixed xylenes (50 mL) was heated at reflux for 10 minutes. Phosgene was then added at such a rate that the internal temperature stayed at 133° C. or above. When consumption of phosgene ceased, the solution was cooled to room temperature and then filtered under nitrogen. Rotary evaporation gave methyl 2-(isocyanatosulfonyl)-4-(methylthio)benzoate as a yellow oil (6.4 g). This was used immediately without further purification or characterization.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([C:31]([OH:33])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3([C:31]([OH:33])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[CH:12][CH:11]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Reactant: C[C@@H]1CCCN1CCc1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)O)CCCC3)cc2)cc1
Temperature: 150 °C

Procedure:
A mixture of (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (300 mg, 1.113 mmol), 1-(4-chlorophenyl)cyclopentanecarboxylic acid (300 mg, 1.335 mmol), Na2CO3 (472 mg, 4.45 mmol), and dichlorobis(p-dimethylaminophenyldi-tert-butylphosphine)palladium (7.88 mg, 0.011 mmol) in 1,4-dioxane (6 mL) and H2O (1.2 mL) was heated under microwave irradiation at 150° C. for 10 min. The mixture was concentrated. The residue was purified by HPLC to give the title compound. LCMS m/z=378.3 [M+H]+.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:1]([N:5]([C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)NNC(=O)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1cccs1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
N'-t-butyl-N-(2-thiophenecarbonyl)hydrazine (1 g) was dissolved in 10 ml toluene and treated with 50% aqueous sodium hydroxide (1.0 g) and water (2 ml) followed by benzoylchloride (0.8 g). After stirring for 14 hours at room temperature, the solid product, N'-t-butyl-N-(2-thiophenecarbonyl)-N'-benzoylhydrazine, was removed by filtration and washed with water. m.p. >190° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1B(O)O.C1(C)C=CC=CC=1.[CH2:17]([O:21][C:22]([C:24]1[N:25]=[C:26](Br)[C:27]2[C:32]([C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:23])[CH2:18][CH2:19][CH3:20].C([O-])([O-])=O.[Na+].[Na+]>CCO.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>[CH2:17]([O:21][C:22]([C:24]1[N:25]=[C:26]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:27]2[C:32]([C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:23])[CH2:18][CH2:19][CH3:20]
Reactant: OB(O)c1ccccn1
Reactant: CCCCOC(=O)c1nc(Br)c2ccccc2c1OCc1ccccc1
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: CCO
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1nc(-c2ccccn2)c2ccccc2c1OCc1ccccc1
Reaction time: 24 h

Procedure:
To a solution of Pyridin-2-ylboronic acid (323 mg, 2.5 mmol) in EtOH (2.5 ml) was added subsequently toluene (15 ml), 4-Benzyloxy-1-bromo-isoquinoline-3-carboxylic acid butyl ester (1.035 mg, 2.5 mmol, see example D-86a), Pd(PPh3)4 (292 mg, 0.25 mmol), and aq. 2 M Na2CO3 solution (2.5 ml, 5 mmol). The mixture was then refluxed with stirring under N2 protection for 24 h. Subsequently, the mixture was concentrated in vacuo. To the residue was added water (15 ml) and the mixture was extracted with EtOAc (30 ml). The organic phase was dried over MgSO4 and evaporated in vacuo. Purification of the residue by flash column chromatography on silica gel using CH2Cl2 MeOH=98 2 as the eluent gave a dark oil that was further purified by flash column chromatography on silica gel using CH2Cl2 MeOH=99 1 as the eluent and subsequently by preparative TLC using CH2Cl2 MeOH=98 2 as the eluent (had to be repeated several times) to give the title compound as a yellow oil (19 mg); MS-(+)-ion M+1=413.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]2[C:14]([C:15]3[N:16]=[CH:17][S:18][C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[Cl:27])=[CH:13][C:12](Br)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].CC1(C)C(C)(C)OB([C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)O1>C(COC)OC.O>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]2[C:14]([C:15]3[N:16]=[CH:17][S:18][C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[Cl:27])=[CH:13][C:12]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CNc2ncc(Br)cc2-c2ncsc2-c2cccc(Cl)c2Cl)cc1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(CNc2ncc(-c3cccnc3)cc2-c2ncsc2-c2cccc(Cl)c2Cl)cc1
Temperature: 120 °C

Procedure:
A solution of N-(4-methoxybenzyl)-5-bromo-3-(5-(2,3-dichlorophenyl)thiazol-4-yl)pyridin-2-amine (50 mg, 0.116 mmol) in dimethoxyethane (0.5 mL) and water (0.5 mL) was degassed with nitrogen while adding NaHCO3 (30 mg, 0.347 mmol), and palladium tetrakis triphenylphosphine (13 mg, 0.012 mmol). 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (28 mg, 174 mmol)was added under nitrogen and the mixture was heated to 120° C. overnight. The reaction mixture was concentrated and taken up in ethyl acetate, filtered through silica with ethyl acetate eluant, and the filtrate concentrated to provide N-(4-methoxybenzyl)-3-(5-(2,3-dichlorophenyl)thiazol-4-yl)-5-(pyridin-3-yl)pyridin-2-amine, which was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=2)[N:23]=1)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2[CH:44]=[CH:45][CH:46]=[N:47]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:17])[NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:32]=[CH:31][C:27]([C:28](=[O:29])[NH:47][CH:46]3[CH2:44][CH2:45]3)=[CH:26][N:25]=2)[N:23]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)nc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-{2-[((S)-1-Benzyloxycarbonyl-pyrrolidine-2-carbonyl)-amino]-thiazol-4-yl}-nicotinic acid (0.18 g, crude), HATU (0.07 g, 0.18 mmol)), and DIEA (0.1 mL, 0.77 mmol) in DMF (5 mL) was stirred at room temperature for 30 min. then cyclopropylamine (0.030 ml, 0.4 mmol) was added and the reaction mixture was stirred at room temperature overnight. Purification by reverse phase HPLC furnished the desired product. 1HNMR (DMSO-d6) δ(ppm) 12.58-12.57 (d, 1H), 9.03 (s, 1H), 8.72-8.71 (d, 1H), 8.34-8.31 (m, 1H), 8.07-8.00 (m,2H), 7.44-7.38 (m, 2H), 7.22-7.12 (m, 2H), 5.17-4.95 (m, 2H), 4.61-4.55 (m, 1H), 3.59-3.52, (m, 2H), 2.95-2.90 (m,1H), 2.34-2.32 (m, 1H), 2.04-1.92 (m, 3H), 0.80-0.78 (m,4H); MS: 492.1 (M+H+).