Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:5]([C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:21])[C@@H:6]([O:11]C(=O)C1C=CC=CC=1)[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH3:4].C[O-].[Na+]>CO>[CH2:1]([C@@H:5]([C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])=[O:21])[C@@H:6]([OH:11])[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)[C@@H](OC(=O)c1ccccc1)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)[C@@H](O)C(=O)OC
Reaction time: 2 h

Procedure:
To methyl 3-(R)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-1-ylcarbonyl)-2-(R)-benzoyloxypropionate H-2 (8.7 mmol) in methanol (25 mL) at 0° C. was added sodium methoxide (catalytic; pH adjusted to 10) and the solution stirred for 2 h. Amberlite IR-120 resin (H+ form) was added, then the solution was filtered and concentrated to afford methyl 3-(R)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-1-yl-carbonyl)-2-(R)-hydroxypropionate H-3 (quant.).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.Br[CH2:20][C:21]1[C:22]([CH3:32])=[N+:23]([O-:31])[C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[CH:6]=[CH:5][N:4]3[C:15](=[O:18])[N:16]([CH2:20][C:21]4[C:22]([CH3:32])=[N+:23]([O-:31])[C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)[N:17]=[C:3]3[C:2]=2[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][CH:2]=2)=[CH:9][CH:10]=1
Reactant: Cc1c(CBr)ccc(C(F)(F)F)[n+]1[O-]
Reactant: O=c1[nH]nc2c(Br)c(-c3ccc(Cl)cc3)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)ccn3c2=O)ccc(C(F)(F)F)[n+]1[O-]

Procedure:
The title compound was also prepared from 8-bromo-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one by treatment with 3-(bromomethyl)-2-methyl-6-(trifluoromethyl)pyridine 1-oxide and potassium carbonate in N,N-dimethylformamide at 70° C., followed by treatment with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and aqueous potassium carbonate solution in toluene under (Ph3P)4Pd catalysis at 100° C.
Reaction SMILES: [CH:1]1([C:7](=[CH2:10])[CH:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:11]([Mg]Br)=[CH:12][CH2:13][CH3:14].BrCCC=C.[Mg]>CCOCC>[CH:1]1([C:7]([CH:8]([OH:9])[CH2:14][CH2:13][CH:12]=[CH2:11])=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C(C=O)C1CCCCC1
Reactant: CCC=C[Mg]Br
Agent: C=CCCBr
Agent: [Mg]
Solvent: CCOCC
Product: C=CCCC(O)C(=C)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
2-Cyclohexylprop-2-en-1-al (69 g, 0.5 mol) in 100 ml of ether was slowly added to but-1-enylmagnesium bromide prepared by slow addition of 4-bromo-but-1-ene (81.0 g, 0.6 mol) in 100 ml of ether at 0° C. to magnesium turnings (13.2 g, 0.55 mol) in 300 ml of ether. After the addition was complete, the reaction mixture was allowed to warm to room temperature (RT) and was stirred for additional 3 hours. After quenching with 2N HCl, the organic phase was separated, washed with H2O until neutral pH was achieved, dried (MgSO4), and the solvent was evaporated in vacuo. The crude product was distilled over a Vigreux column (0.15 Torr, 91° C.) yielding 85 g (88%) of pure product as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].Cl[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]([NH:33][CH3:34])=[O:32])[CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=2)[O:18][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]([NH:33][CH3:34])=[O:32])[CH:26]=2)=[CH:4][C:3]=1[C:20]([F:21])([F:22])[F:23]
Reactant: O=C(CCc1cccc(O)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2cccc(CCC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c2)ccn1
Temperature: 100 °C

Procedure:
A mixture of N-[4-chloro-3-(trifluoromethyl)phenyl]-3-(3-hydroxyphenyl)propanamide (585 mg, 1.70 mmol), 4-chloro-N-methylpyridine-2-carboxamide (318 mg, 1.87 mmol), and Cs2CO3 (7.76 g, 8.5 mmol) in DMF (3.4 mL) was heated at 100° C. overnight. The reaction mixture was concentrated and diluted with EtOAc. The organic solution was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, 0-30% EtOAc in hexanes) to give the product as a white solid. 1H NMR (400 MHz, CD3OD) δ: 8.62 (d, 1H), 8.26 (m, 1H), 7.89-7.96 (m, 1H), 7.71-7.74 (m, 1H), 7.63 (t, 1H), 7.41-7.47 (m, 1H), 7.28 (br s, 1H), 7.17-7.24 (m, 2H), 2.58 (t, 2H), 3.15 (s, 3H), and 2.93 (t, 2H). LCMS, AA: Rt=2.05 min, [MH+ 478.3].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1B1OC(C)(C)C(C)(C)O1.[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][C:22]=1[CH3:28].N#N.C([O-])([O-])=O.[Na+].[Na+].Cl>O1CCOCC1.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>[CH3:18][O:19][C:20]([C:21]1[CH:26]=[CH:25][C:24]([C:7]2[CH:6]=[CH:5][C:4]([OH:17])=[CH:3][C:2]=2[CH3:1])=[CH:23][C:22]=1[CH3:28])=[O:29]
Reactant: Cc1cc(O)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: N#N
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(O)cc2C)cc1C
Temperature: 90 °C
Yield: 75.4 %

Procedure:
A solution of 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.241 g, 1.03 mmol) and 4-bromo-2-methyl-benzoic acid methyl ester (0.236 g, 1.03 mmol) in 1,4-dioxane (20 mL) is evacuated and re-filled with N2 3 times. To this solution, Pd(PPh3)4 (0.010 g) and aqueous Na2CO3 (1.0 mL, 2.0 M) are added. The resulting mixture is heated at 90° C. for 24 hours under N2. The reaction mixture is cooled to room temperature, neutralized with HCl (1.0 M, 3.0 mL), and concentrated. The residue is extracted with ethyl acetate (30 mL×2) and the combined organic layers are dried over sodium sulfate and concentrated. The residue is purified via silica gel chromatography eluting with 25-30% ethyl acetate in hexanes to give the title compound (0.199 g, 75%). 1H NMR (400 MHz, CDCl3): δ 7.95-7.91 (d, 1H), 7.18 (s, 1H), 7.18 (d, 1H), 7.08 (d, 1H), 6.75 (d, 1H), 6.72 (d, 1H), 3.90 (s, 3H), 2.61 (s, 3H).
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH3:8][NH2:9].[OH-].[Na+]>>[CH3:8][NH:9][C@@H:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[OH:7]
Reactant: C1CCC2OC2C1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Product: CN[C@@H]1CCCC[C@H]1O
Reaction time: 1.5 h

Procedure:
Cyclohexene oxide (202 mL, 2 mol) was added dropwise to aqueous methyl amine (466 mL or 40% solution, 6 mol) over 70 minutes. After a further 90 minutes, the temperature of the reaction mixture was 48° C. and was reduced to 30° C. by cooling in a water bath. After a further 2 hours, the mixture had returned to room temperature. It was stirred overnight, and then refluxed for 3 h. The mixture was saturated with sodium hydroxide (cooled during addition), extracted several times with diethyl ether (total 500 mL), the diethyl ether layer dried over sodium sulphate overnight, and the diethyl ether removed on a rotary evaporator. The remaining diethyl ether and cyclohexene oxide were removed by partial vacuum distillation. Distillation under full vacuum yielded a colorless fraction boiling at 95° C., (±)-trans-2-(methylamino)cyclohexanol: 217 g (84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[CH:6][S:5][CH:4]=1.[CH2:10](O)[C@@H:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]CC>>[CH2:10]([CH:1]1[O:2][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:8][CH2:9]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COc1cscc1OC
Reactant: CCCCCCCC[C@H](O)CO
Product: CCCCCCCCC1COc2cscc2O1

Procedure:
Chiral 2-n-octyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine was synthesized by transetherification of 3,4-dimethoxythiophene with (S)-1,2-decanediol and purified to a purity of 99.24% as described in INVENTION EXAMPLE 1. It was characterized by GC-MS and 1H-NMR-spectroscopy, and exhibited a specific rotation of −88° at 25° C. and 436 nm in hexane.
Reaction SMILES: [OH:1][C@H:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C@@H:5]2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[ClH:22].[CH3:23]O>>[ClH:22].[CH3:23][O:1][C@H:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C@@H:5]2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CN1CCN2c3ccccc3[C@H](O)c3ccccc3[C@H]2C1
Reactant: CO
Agent: Cl
Product: CO[C@@H]1c2ccccc2[C@H]2CN(C)CCN2c2ccccc21
Reaction time: 1 h

Procedure:
1 g cis-10-hydroxy-2-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine is suspended in 25 ml methanol, after which 2 ml of a saturated solution of HCl in methanol is added and the mixture is boiled for about 1 hour with exclusion of moisture. The solution is evaporated to dryness under vacuum and the residue is crystallized from methanol. Yield 300 mg. Melting point of the HCl salt: 247°-251° C.; melting point free base 182°-184° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[CH3:20][NH:21][CH2:22][C@H:23]([OH:31])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1>>[C:8]1([C:5]2[N:6]=[CH:7][C:2]([N:21]([CH2:22][C@@H:23]([C:24]3[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=3)[OH:31])[CH3:20])=[N:3][C:4]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CNC[C@H](O)c1cccc(O)c1
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Product: CN(C[C@H](O)c1cccc(O)c1)c1cnc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
In the same manner as in the step 1 of Example 9, except that 2-chloro-5,6-diphenylpyrazine was used in place of 2-chloro-5,6-di-p-tolylpyrazine and L-phenylephrine was used in place of 4-(methylamino)-1-butanol, the desired compound was prepared as a pale brown amorphous.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)(=[O:16])=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33].Cl[Si](C)(C)C>CO>[CH3:1][N:2]([CH3:36])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)(=[O:16])=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:31][C:32]([CH3:34])([CH3:33])[CH3:35]
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)CC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Agent: C[Si](C)(C)Cl
Solvent: CO
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)CC3CCNCC3)ccc21
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
A mixture of tert-butyl 4-((1-(2-(dimethylamino)ethyl)-2-neopentyl-1H-benzo[d]imidazol-5-ylsulfonyl)methyl)piperidine-1-carboxylate (STEP B, 1.48 g, 2.84 mmol) and chlorotrimethylsilane (1.45 mL, 11.4 mmol) in methanol (5 mL) was stirred at 50° C. for 1.5 h. The reaction mixture was concentrated in vacuo, followed by addition of dichloromethane (100 ml). The resulting mixture was washed with sodium bicarbonate aqueous solution and brine and dried over sodium sulfate. The resulting solution was concentrated and the residue was purified by silica gel column chromatography (pre-treatment with triethylamine, dichloromethane-ethyl acetate=100:0 to 0:100) to give the title compound (1.18 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=C)[C:4]=1[C:5]([O:7][CH3:8])=[O:6].[O:15]=[O+][O-]>C(Cl)Cl>[CH:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([O:7][CH3:8])=[O:6])=[O:15]
Reactant: C=Cc1cccc(OC)c1C(=O)OC
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: COC(=O)c1c(C=O)cccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
Into a solution of methyl 2-methoxy-6-vinylbenzoate (22 g, 0.11 mol) in anhydrous DCM (400 mL) was bubbled O3 at −78° C. over a 30 minute period. Next, nitrogen gas was bubbled into the solution until it turned colorless. Dimethylsulfane (20 mL) was added dropwise and the resulting mixture was warmed to RT and stirred for 2 hours. The mixture was washed with water (30 mL) and the aqueous layer was extracted with DCM (3×100 mL). The organic layers were combined, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography eluting with a gradient of EtOAc (0-90%) and PE to give the title compound (11.8 g, 53.6%). 1H NMR (400 MHz, CDCl3) δ ppm 9.97 (s, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 3.98 (s, 3H), 3.90 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].BrBr.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCOCC1>[OH:16][C:10]1[CH:15]=[CH:14][C:13]([CH:7]2[NH:1][C:2](=[O:3])[NH:4][C:5]2=[O:6])=[CH:12][CH:11]=1
Reactant: Oc1ccccc1
Reactant: O=C1CNC(=O)N1
Agent: BrBr
Solvent: C1COCCO1
Product: O=C1NC(=O)C(c2ccc(O)cc2)N1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
4.0 g (40 mmol) of hydantoin, 10 ml of dioxane, and 2.0 ml (40 mmol) of bromine were mixed at room temperature. The reaction mixture was then vigorously stirred at a temperature of 100° C. for 30 minutes. The reaction mixture was then cooled to a temperature of 0° C. To the reaction mixture was then added 5.7 g (60 mmol) of phenol. The reaction mixture was then allowed to undergo reaction at a temperature of 0° C. for 12 hours. The resulting precipitate was recovered by filtration, washed with water, and then dried to obtain 5.53 g (yield: 72%) of 5-(p-hydroxy-phenyl)hydantoin. The crystal thus obtained exhibited a melting point of 263° to 265° C. The infrared spectrum, NMR spectrum and Rf value of silica gel thin layer chromatography of the crystal showed a complete conformance to that of a specimen synthesized by the method as disclosed in JP-B-55-22474.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[C:15]3[CH2:16][NH:17][CH2:18][CH2:19][C:14]=3[NH:13][C:12](=[O:20])[N:11]2[CH:21]=1>[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:20])[N:11]2[CH:21]=1
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CNCC2
Agent: [Pd]
Product: O=c1[nH]c2ccncc2c2nc(-c3ccccc3F)cn12
Temperature: 280 °C

Procedure:
A mixture of 2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (110 mg) and palladium black (150 mg) was placed in a sublimator and evacuated (1 mm Hg). The temperature was slowly raised to 280° C. The desired product sublimed from the mixture and was collected after the apparatus had been cooled back down to room temperature. In this manner 2-(2-Fluorophenyl)-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 1), m.p. 315-320° C. was obtained as tan crystals.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([N:12]1[C:16]2[N:17]=[C:18]([Cl:21])[N:19]=[CH:20][C:15]=2[C:14](I)=[CH:13]1)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([CH:35]=1)[C:29](N(OC)C)=[O:30]>>[Br:23][C:24]1[CH:35]=[C:28]([C:29]([C:14]2[C:15]3[CH:20]=[N:19][C:18]([Cl:21])=[N:17][C:16]=3[N:12]([CH:10]([CH3:11])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:13]=2)=[O:30])[CH:27]=[N:26][CH:25]=1
Reactant: CON(C)C(=O)c1cncc(Br)c1
Reactant: CC(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cnc(Cl)nc21
Product: CC(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(Br)c2)c2cnc(Cl)nc21

Procedure:
The title compound was prepared according to the method described for Preparation 28 using 7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 55, enantiomer 2) and 5-bromo-N-methoxy-N-methylnicotinamide to afford the title compound as a yellow solid in 30% yield, 1.4 g. 1H NMR (400 MHz, DMSO-D6) δ: −0.14 (s, 6H), 0.61 (s, 9H), 1.52 (d, 3H), 3.91-3.96 (m, 2H), 5.00 (m, 1H), 8.37 (s, 1H), 8.58 (s, 1H), 8.95 (s, 1H), 9.00 (s, 1H), 9.33 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9][CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[O:21]=[C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:22])[N:12]1[CH2:11][CH2:10][CH2:9][N:8]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]1[C:2]([NH:1][C:29](=[O:36])[CH:30]2[CH:31]=[CH:32][CH2:33][CH2:34][CH2:35]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccnc1N(CCCN1C(=O)c2ccccc2C1=O)c1ccccc1
Product: O=C(Nc1cccnc1N(CCCN1C(=O)c2ccccc2C1=O)c1ccccc1)C1C=CCCC1

Procedure:
2-[3-[(3-Amino-2-pyridinyl)phenylamino]propyl]-1H-isoindole-1,3-(2H)-dione is reacted with benzoyl chloride to prepare the title compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:11][CH:10]=2)O1.C([O:30][C:31](=[O:42])[C:32]1[CH:37]=[CH:36][C:35](I)=[C:34]([O:39][CH2:40][CH3:41])[CH:33]=1)C.COCCOC.C(O)C.C([O-])([O-])=O.[Na+].[Na+].O.[OH-].[Na+].Cl.CCCCCCC.CCCCCCC.CC(C)=O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:40]([O:39][C:34]1[CH:33]=[C:32]([C:31]([OH:42])=[O:30])[CH:37]=[CH:36][C:35]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[S:16][CH:17]=[CH:18][C:19]=2[NH:20][S:21]([CH:24]([CH3:25])[CH3:26])(=[O:22])=[O:23])=[CH:13][CH:14]=1)[CH3:41]
Reactant: CCOC(=O)c1ccc(I)c(OCC)c1
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: COCCOC
Solvent: O
Solvent: CCCCCCC
Product: CCOc1cc(C(=O)O)ccc1-c1ccc(-c2sccc2NS(=O)(=O)C(C)C)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
Mix propane-2-sulfonic acid {2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) -phenyl]-thiophen-3-yl}-amide (1.00 equiv; 441.02 mmoles; 196.60 g), 3-ethoxy-4-iodo -benzoic acid ethyl ester (1.00 equiv; 441.47 mmoles; 141.27 g), DME (15.15 moles; 1.57 L; 1.37 kg), PdCl2(dppf) (2.42 mmoles; 1.97 g), and ethanol (13.57 moles; 790.00 mL; 625.13 g) under a N2 atmosphere. Then add Na2CO3 2M in water (1.89 equiv; 833.06 mmoles; 416.53 mL; 504.00 g) and heat the reaction mixture to reflux until HPLC monitoring indicates reaction completion. Cool reaction mixture to RT then add water (109.13 moles; 1.97 L). Separate the organic layer, filter through diatomaceous earth, then concentrate organic layer under reduced pressure. Add ethanol (2.36 L), and remove solvent under reduced pressure. Add 3-Mercaptopropyl-functionalized Silica Gel (50.00 g), and heat to 60° C. for 30 minutes. Cool to RT then filter over diatomaceous earth. Rinse cake with ethanol, then combine ethanol washes and filtrate. Add 14% Sodium Hydroxide (4.89 moles; 1.27 L; 1.43 kg) and heat the reaction mixture at 55° C. until monitoring by HPLC indicates the end of the reaction. Cool to RT then add 7N HCl to the reaction mixture. Stir the resulting precipitate overnight. Filter the reaction mixture and wash cake with EtOH/Water (40/60-v/v) (180.78 g), EtOH (155.49 g), and n-heptane (262 g). Redissolve cake in acetone (2.18 kg) and add activated charcoal (46 g). Heat the reaction mixture at 50° C. for 30 minutes. Cool to RT, filter over diatomaceous earth (765.59 mmoles; 200.00 g), and concentrate under reduced pressure. Cool to RT, then add n-Heptane (7.73 moles; 1.13 L; 775. 00 g) and stir for 1 h. Fltere and wash cake with n-heptane/acetone 60/40 (2.58 moles; 354.79 mL) and dry under reduced pressure to yield 124 g of the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Mg]Cl)CCC.[CH3:14][O:15][C:16]([C:18]1[S:19][CH:20]=[CH:21][C:22]=1[N:23]([C:31]([C@H:33]1[CH2:38][CH2:37][C@H:36]([CH3:39])[CH2:35][CH2:34]1)=[O:32])[CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:17].[I:40]I>C1COCC1>[CH3:14][O:15][C:16]([C:18]1[S:19][C:20]([I:40])=[CH:21][C:22]=1[N:23]([C:31]([C@H:33]1[CH2:34][CH2:35][C@H:36]([CH3:39])[CH2:37][CH2:38]1)=[O:32])[CH:24]1[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]1)=[O:17]
Reactant: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C)CC1
Reactant: II
Agent: CCCC[Mg]Cl
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1sc(I)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C)CC1
Reaction time: 24 h

Procedure:
To a stirred solution of diisopropyl amine (0.3 mL, 2.14 mmol) in THF (10 mL) was added n-BuMgCl (2.0 M in ether, 1.0 mL, 2.0 mmol), stirred for 24 h. To the resultant solution was added drop wise a solution of 3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino]-thiophene-2-carboxylic acid methyl ester (0.189 g, 0.5 mmol) in THF (2.0 mL), stirred for 1 h at room temperature. It was then added a solution of Iodine (1.28 g, 5.0 mmol) in THF (2.0 mL), stirred for 1 h. Reaction mixture was then quenched with 10% aq Na2S2O3 solution, extracted with EtOAc, washed with brine, dried, and concentrated. Purification of the residue on small plug of silica gel bond elute using DCM/CHCl3/MeOH/Et3N (200:90:16:1) as eluent gave 5-iodo-3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino]-thiophene-2-carboxylic acid methyl ester (0.250 g, quantitative). NMR 1H (CDCl3, 400 MHz): 7.05 (s, 1H), 4.68-4.55 (m, 1H), 3.83 (s, 3H), 2.95-2.8 (m, 2H), 2.26 (s, 3H), 2.2-1.1 (m, 14H), 0.819 (d, J=6.3, 3H), 0.75-0.6 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:17]=[C:16]([O:32][CH2:33][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:39])C.[OH-].[Na+].Cl>C(O)C>[CH:34]1([CH2:33][O:32][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:40])=[O:3])=[C:8]([CH3:39])[CH:9]=3)[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=3)[CH:17]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(OCC3CCCC3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(OCC3CCCC3)c2)ccc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
{4-[3-Cyclopentylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (120 mg; 0.202 mmol) was dissolved in ethanol (50 mL), and aqueous 1 N sodium hydroxide (2 mL) was added. The reaction mixture was stirred for 30 min, acidified with 1 N aqueous hydrochloric acid and extracted with dichloromethane. The organic phase was dried and evaporated to dryness. Yield: 100 mg. HPLC-MS: m/z: 551.5 (M+H)+; Rt: 2.69 min.