Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[CH3:12][Si:13]([CH3:22])([CH:20]=[CH2:21])[O:14][Si:15]([CH3:19])([CH3:18])[CH:16]=[CH2:17]>>[CH3:9][O:8][Si:5]([O:10][CH3:11])([O:6][CH3:7])[CH2:4][CH2:3][CH2:2][S:1][CH2:17][CH2:16][Si:15]([CH3:18])([CH3:19])[O:14][Si:13]([CH3:22])([CH3:12])[CH:20]=[CH2:21]
Reactant: CO[Si](CCCS)(OC)OC
Reactant: C=C[Si](C)(C)O[Si](C)(C)C=C
Product: C=C[Si](C)(C)O[Si](C)(C)CCSCCC[Si](OC)(OC)OC
Reaction time: 0.17 h

Procedure:
1-(7,7-dimethoxy-8-oxa-3-thia-7-silanonyl)-1,1,3,3-tetramethyl-3-vinyldisiloxane was prepared according to the following process. Two and one-half moles (490 grams) of gamma mercaptopropyltrimethoxy silane was added to a 1-liter flask. A portion of a total quantity of one mole (186 grams) of 1,1,3,3-tetramethyl-1,3-divinyldisiloxane was added to the flask, resulting in the immediate formation of a bluegreen color and generation of heat. The flask was placed in a hood and stirred. The exotherm was measured at 75° C, subsided to about 55° C. and remained there for 10 minutes. The remaining 1,1,3,3-tetramethyl-1,3-divinyldisiloxane was added with no further exotherm. Gas/liquid chromotography revealed consumption of substantially all of the 1,1,3,3-tetramethyl-1,3-divinyldisiloxane reagent and the presence of mono- and diadduct products. The reaction product was distilled through a Vigreaux column to yield 60 g of approximately 95% pure product having a boiling point of 157° C. at 3.0 mm Hg.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].[O:9](C(OC(C)(C)C)=O)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=O>O1CCCC1>[OH:4][CH2:3][C@@H:2]([NH:1][C:10](=[O:9])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C[C@H](N)CO
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
To a stirred solution of (S)-2-amino-4-methylpentan-1-ol (5 g, 42.7 mmol) in tetrahydrofuran (100 mL) at rt was added BOC2O (9.91 mL, 42.7 mmol) dropwise and the reaction was stirred at rt for 5 h. After the completion of reaction, solvent was removed under reduced pressure to yield (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (6.3 g, 29.0 mmol, 68% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 6.42 (d, J=8.8 Hz, 1H), 4.55 (m, 1H), 3.32 (m, 1H), 3.27 (m, 1H), 3.17 (m, 1H), 1.47 (m, 1H), 1.37 (s, 9H), 1.22 (m, 2H), 0.85 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][NH:10][C:11]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)=[O:12])=[C:4]([O:25][CH2:26][C:27]([O:29]C)=[O:28])[CH:3]=1.CCO.O.[Li+].[OH-]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][NH:10][C:11]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:17]=2)=[O:12])=[C:4]([O:25][CH2:26][C:27]([OH:29])=[O:28])[CH:3]=1
Reactant: COC(=O)COc1cc(N)nc(C)c1CNC(=O)c1cnn(Cc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1nc(N)cc(OCC(=O)O)c1CNC(=O)c1cnn(Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
Methyl 2-(6-amino-3-((1-benzyl-1H-pyrazole-4-carboxamido)methyl)-2-methylpyridin-4-yloxy)acetate (28 mg, 0.051 mmol) was dissolved in THF, EtOH, H2O 2:1:1 (5 ml), then LiOH (4.31 mg, 0.103 mmol) was added and the reaction mixture was stirred at rt over night. After adjusting the pH to 4, the reaction mixture was evaporated, co-evaporated with Toluene (4 times) then dried under HV to get the title compound which was used for the next step without further purification. HPLC/MS (Method B) Rtb=0.43 min, MS [M+H]+=396.3.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10](=[CH2:13])[CH2:11]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:26][O:27][C:28]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31]>C(Cl)(Cl)Cl.O>[Si:1]([O:8][CH2:9][C:10](=[CH2:13])[CH2:11][NH:31][CH2:30][C:29]1[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:28]=1[O:27][CH3:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: C=C(CO)CO[Si](C)(C)C(C)(C)C
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=C(CNCc1ccc(OC)cc1OC)CO[Si](C)(C)C(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of 2-(tert-butyldimethylsilanyloxymethyl)-2-propen-1-ol (1.58 g) in chloroform (16 ml) were sequentially added triethylamine (2.2 ml) and methanesulfonyl chloride (0.73 ml) at 0° C., and then the mixture was stirred for 2 hours. To this reaction solution were sequentially added triethylamine (1.2 ml) and 2,4-dimethoxybenzylamine (1.3 ml), and then the mixture was stirred at room temperature for 15 hours. To this reaction mixture was added water, and an organic layer was separated from the mixture, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to give the titled compound (1.14 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.[F-].[K+]>C1(C)C=CC=CC=1>[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)cc1
Reactant: Cc1ccccc1B(O)O
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccccc2C)cc1
Yield: 100.9 %

Procedure:
4-Chloroanisole (74 mg, 0.52 mmol) reacted with 2-methylphenylboronic acid (102 mg, 0.75 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (87 mg, 1.50 mmol) in toluene at 80° C. to give the title compound (104 mg, 99%) as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 7.35-7.31 (m, 6H), 7.04 (d, 2H, J=8.8 Hz), 3.92 (s, 3H), 2.37 (s, 3H). 13C{1H}-NMR (125 MHz, CDCl3): δ 158.43, 141.47, 135.40, 134.28, 130.25, 130.19, 129.85, 126.91, 125.71, 113.41, 55.19, 20.52. GC/MS(EI): m/z 198 (M+).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:18]=[C:17]2[O:19][CH2:20][O:21][C:16]2=[CH:15][C:6]=1[CH:7](O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[S-:22][C:23]#[N:24].[NH4+]>C(O)(=O)C>[CH:1]([N:4]1[C:5]2[C:6](=[CH:15][C:16]3[O:21][CH2:20][O:19][C:17]=3[CH:18]=2)[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:24][C:23]1=[S:22])([CH3:3])[CH3:2]
Reactant: CC(C)Nc1cc2c(cc1C(O)c1ccccc1)OCO2
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CC(C)N1C(=S)NC(c2ccccc2)c2cc3c(cc21)OCO3

Procedure:
To a solution of 1 gram of 2-isopropylamino-4,5-methylenedioxybenzhydrol and 28 mls. glacial acetic acid is added 2 grams of ammonium thiocyanate. The resultant mixture is stirred at room temperature for 24 hours to solid precipitates and is removed by filtration. The filtrate is evaporated to dryness and the residual solid taken up in chloroform. This solution is washed with water, dried and evaporated to dryness. The resulting solid is recrystallized from ethyl acetate to yield 1-isopropyl-4-phenyl-6,7-methylenedioxy-3,4-dihydro-2[1H]-quinazolinthione m.p. 214°-218°C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[C:4]#[N:5].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2([CH2:25][C:26](O)=[O:27])[NH:24][CH:23]=[CH:22][S:21]2)[CH:15]=1>>[C:4]([C:3]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([O:10][CH3:11])=[CH:9][C:2]=1[NH:1][C:26](=[O:27])[CH2:25][C:20]1([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[NH:24][CH:23]=[CH:22][S:21]1)#[N:5]
Reactant: O=C(O)CC1(c2cccnc2)NC=CS1
Reactant: COc1cc(N)c(C#N)cc1OC
Product: COc1cc(C#N)c(NC(=O)CC2(c3cccnc3)NC=CS2)cc1OC

Procedure:
This compound was prepared according to the method described in Example 1c by employing 2-amino-4,5-dimethoxybenzonitrile (Aldrich) and 2-(3-pyridyl)-thiazole acetic acid (Example 2, Step b). Mp: 65-67° C. MS m/z: 381.1 (M+1). Calc'd for C19H16N4O3S: 380.09.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=[O:12])=[CH:8][C:6]=2[N:7]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:5]2[S:10][C:9]([CH2:11][OH:12])=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Yield: 94 %

Procedure:
To 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (1.5 g,) in ethanol (30 mL) was added sodium borohydride (1 g). After 4 hours the reaction mixture was quenched with brine and the resulting solid was collected by filtration and air dried to yield (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol (1.42 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[C:13]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:14]=1[N+:22]([O-])=O)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[C:13]1[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:22]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1-c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(N)c1-c1c(N)cccc1N
Reaction time: 6 h
Yield: 88 %

Procedure:
Under the protection of nitrogen gas, the 2,2′,6,6′-tetranitrobiphenyl (1.00 g, 3 mmol) and 100 mg 10% Pd/C were added into a 100 mL hydrogenation flask. Subsequently, 20 mL of methanol is added, and the resultant mixture was bubbled with nitrogen gas. The hydrogenation flask was placed in an autoclave, and was added 10 atm of hydrogen gas. After 6 hours, the reaction is completed. The resultant was filtered to remove Pd/C, and was rotary evaporated to remove the methanol. The residue was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, filtered, and votary evaporated, to afford the product in a yield of 88%.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][CH3:18])[C:6]=1[C:7]([O:9]C)=[O:8])[CH2:2][CH3:3].[OH-].[K+]>C(O)C>[CH2:16]([O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[C:6]=1[C:7]([OH:9])=[O:8])[CH2:17][CH3:18]
Reactant: CCCOc1cccc(OCCC)c1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1cccc(OCCC)c1C(=O)O

Procedure:
Methyl 2,6-dihydroxybenzoate was reacted with n-propyl iodide in the presence of sodium hydride to provide methyl 2,6-di-n-propoxybenzoate. The ester thus formed was saponified by reaction with 40% aqueous potassium hydroxide in ethanol to afford 2,6-di-n-propoxybenzoic acid. A 20 g portion of the acid was then reacted with 30 g of thionyl chloride in 100 ml of benzene at reflux for five hours. Removal of the solvent by evaporation under reduced pressure and purification of the product by distillation provided 4.88 g of 2,6-di-n-propoxybenzoyl chloride. B.P. 135°-140° C. at 0.2 torr.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:36]([Cl:37])=[CH:35][C:29]([C:30]([O:32]CC)=[O:31])=[CH:28][N:27]=2)[CH2:22][CH:21]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]([CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:36]([Cl:37])=[CH:35][C:29]([C:30]([OH:32])=[O:31])=[CH:28][N:27]=2)[CH2:22][CH:21]1[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cnc(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc(OC)c3)C(c3ccccc3)C2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc([C@@H](C)N(CC2CCN(c3ncc(C(=O)O)cc3Cl)CC2c2ccccc2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 131 mg of ethyl 6-[4-({(tert-butoxycarbonyl)[(1R)-1-(3-methoxyphenyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-5-chloronicotinate were added 2.0 mL of THF, 1.0 mL of methanol, and 1.0 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 2 days. It was neutralized by addition of 1.1 mL of 1 M hydrochloric acid, and then extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and dried to obtain 143 mg of a colorless foamy substance of 6-[4-({(tert-butoxycarbonyl)[(1R)-1-(3-methoxyphenyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-5-chloronicotinic acid as a crude product. ESI+: 580
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27][O:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>>[ClH:1].[C:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:13](=[O:14])[CH:12]([NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])[CH2:27][O:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)([OH:25])=[O:24]
Reactant: COC(=O)CCCCCCCNC(=O)C(COc1cccnc1)NS(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(O)CCCCCCCNC(=O)C(COc1cccnc1)NS(=O)(=O)c1ccc(Cl)cc1
Yield: 197.4 %

Procedure:
The procedure described in Example 115 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(7-methoxycarbonylheptyl)-3-(pyridin-3-yloxy)propanamide (16.5 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(7-carboxyheptyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride (17.0 mg).
Reaction SMILES: C([O-])(O)=O.[Na+].[N:6]1([NH2:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>ClCCl>[CH2:20]([O:19][C:17](=[O:18])[NH:15][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: Nn1ccc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Nn1ccc2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of NaHCO3 (50 g) in 100 ml dichloromethane (DCM) was added a solution of 1H-indol-1-amine (36 g) in 200 ml DCM. After cooling to 0° C. with an ice bath, a solution of ethyl chloroformate (29 ml) in 50 ml DCM was added over a period of thirty minutes. After stirring at ambient temperature for three hours, the mixture was filtered, and the filtrate washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to an oil which was eluted on a silica gel column with DCM, via HPLC to give N-(1H-indol-1-yl) carbamic acid ethyl ester, 33.6 g (61%) as an oil. To a cold solution of N-(1H-indol-1-yl) carbamic acid ethyl ester (15 g) in 100 ml tetrahydrofuran, was added potassium t-butoxide (9 g) and the mixture stirred at 5° C. for one hour. To this was added 1-bromopropane (7.3 ml) and the mixture stirred at ambient temperature for five hours. The mixture was poured into 300 ml iced-water, stirred for five minutes, then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated, NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to give N-(1H-indol-1-yl)-N-propylcarbamic acid ethyl ester as an oil, 16.5 g (91%). To a solution of N-(1H-indol-1-yl)-N-propylcarbamic acid ethyl ester (16.5 g) in 35 ml ethylene glycol, was added a solution of NaOH (10 g) in 30 ml water. After stirring at 120° C. for four hours, the mixture was poured into 300 ml ice water, stirred for five minutes, then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to give N-(1H-indol-1-yl)-N-propylamine, 9.0 g (78%) as an oil.
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:50]1[CH:55]=[C:54]([O:56][C@H:57]([CH2:67][O:68][CH2:69][CH3:70])[CH2:58][O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])[N:53]=[C:52]([S:71][CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([F:79])[C:74]=2[F:80])[N:51]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:80][C:74]1[C:75]([F:79])=[CH:76][CH:77]=[CH:78][C:73]=1[CH2:72][S:71][C:52]1[N:51]=[C:50]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:55]=[C:54]([O:56][C@H:57]([CH2:67][O:68][CH2:69][CH3:70])[CH2:58][O:59][Si:60]([C:63]([CH3:64])([CH3:65])[CH3:66])([CH3:61])[CH3:62])[N:53]=1
Reactant: CCOC[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: NS(=O)(=O)N1CCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of azetidine-1-sulfonamide (prepared according to patent WO 2004/011443, 0.29 g), tris(dibenzylideneacetone)dipalladium (0) (0.13 g), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (93 mg), cesium carbonate (0.68 g), 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-(ethoxymethyl)ethoxy]-pyrimidine (the product of step iv) (0.70 g) and dioxane (15 mL). Purification was by column chromatography on silica gel using EtOAc/isohexane (3:7) 70:30 as eluent, to give the title compound as a white solid.
Reaction SMILES: N1C=CN=C1.[CH2:6]([Si:8](Cl)([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7].[Br:14][C:15]1[S:19][C:18]([C:20]2[CH:44]=[CH:43][C:23]([CH2:24][CH:25]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[S:38][C:39]([Br:42])=[CH:40][CH:41]=4)=[CH:33][CH:32]=3)[C:26]([CH3:29])([OH:28])[CH3:27])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1.[Cl-].[NH4+]>CN(C)C=O>[Br:42][C:39]1[S:38][C:37]([C:34]2[CH:33]=[CH:32][C:31]([CH2:30][CH:25]([CH2:24][C:23]3[CH:43]=[CH:44][C:20]([C:18]4[S:19][C:15]([Br:14])=[CH:16][CH:17]=4)=[CH:21][CH:22]=3)[C:26]([O:28][Si:8]([CH2:11][CH3:12])([CH2:9][CH3:10])[CH2:6][CH3:7])([CH3:27])[CH3:29])=[CH:36][CH:35]=2)=[CH:41][CH:40]=1
Reactant: CC(C)(O)C(Cc1ccc(-c2ccc(Br)s2)cc1)Cc1ccc(-c2ccc(Br)s2)cc1
Reactant: CC[Si](Cl)(CC)CC
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC(C)(C)C(Cc1ccc(-c2ccc(Br)s2)cc1)Cc1ccc(-c2ccc(Br)s2)cc1
Yield: 97.5 %

Procedure:
Imidazole (245 mg, 3.6 mmol), triethylsilyl chloride (1.2 mL, 7.2 mmol) and N,N-dimethylformamide (10 mL) were added at 0° C. to 3-(4-(5-bromothiophen-2-yl)benzyl)-4-(4-(5-bromothiophen-2-yl)phenyl)-2-methylbutan-2-ol (1.15 g, 2.0 mmol). Following stirring of the resulting mixed liquid at room temperature for 12 hours, a saturated aqueous solution of ammonium chloride was added to halt the reaction. The organic layer was separated from the mixed liquid, and the water layer was extracted with ether. The resulting organic layer was washed with a saturated aqueous solution of sodium chloride, and dried using anhydrous magnesium sulfate. Following filtering of the organic layer, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane), yielding the title compound (7b) (1.35 g, 1.95 mmol) as a colorless solid in a yield of 98%.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:16]=[C:17]1[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18]1[CH2:34][C:35](O)=[O:36].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:10]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9][C:35](=[O:36])[CH2:34][N:18]2[CH2:19][CH2:20][C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]2=[O:16])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: NCC(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,2-diphenylethanamine (0.20 g, 1.00 mmol) in dichloromethane (20 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.61 mg, 0.005 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:1) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.01 (t, J=5.6 Hz, 1H), 7.26-7.32 (m, 16H), 7.15-7.27 (m, 4H), 4.19 (t, J=7.9 Hz, 1H), 3.81 (s, 2H), 3.74 (dd, J=7.9, 5.6 Hz, 2H), 3.15 (t, J=6.4 Hz, 2H), 2.65 (t, J=6.4 Hz, 2H); MS (DCI+) m/z 475 (M+H)+, 492 (M+NH4)+.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.Cl[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:13][N:12]=1>CC(P(C1C=CC=CC=1)C1C=CC=CC=1)C.C1C=CC(PC2C=CC=CC=2)=CC=1.[Cl-].[Ni].O1CCCC1>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)=[CH:13][N:12]=2)=[CH:4][CH:5]=1
Reactant: Clc1ccc(COC2CCCCO2)cn1
Reactant: Fc1ccc(Br)cc1
Agent: [Ni]
Agent: CC(C)P(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Fc1ccc(-c2ccc(COC3CCCCO3)cn2)cc1
Temperature: 3 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
A grignard reagent solution prepared from 1.53 g of magnesium, 10.5 g of 1-bromo-4-fluorobenzene and 70 ml of tetrahydrofuran was added dropwise at 3°-7° C. within 45 minutes to a mixture of 16.9 g of crude 2-chloro-5-[(tetrahydro-2-pyranyloxy)methyl]pyridine, 60 ml of tetrahydrofuran and 0.62 g of 1,3-bis(diphenylphosphino)-propanenickel-(II) chloride. The dark reaction mixture was stirred at 3° C. for a further 1 hr. and at room temperature for 2 hrs. and then extracted with 200 ml of diethyl ether and 120 ml of 0.5N ammonium chloride solution. The organic phase was washed neutral with water, dried over sodium sulphate, filtered and concentrated. Chromatographic purification of the residue on 230 g of silica gel with hexane/ethyl acetate (vol. 9:1) yielded 13.4 g of 2-(4-fluorophenyl)-5-[(tetra-hydro-2-pyranyloxy)methyl]pyridine as a yellowish oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[N:3]=1.[F:21][CH:22]([F:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].O>C(#N)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>[F:21][CH:22]([F:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[N:3]=1
Reactant: CC1(C)OB(c2ccccc2C(F)F)OC1(C)C
Reactant: CC(C)COC(=O)N1CCN(c2nccc(Cl)n2)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: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)COC(=O)N1CCN(c2nccc(-c3ccccc3C(F)F)n2)CC1
Temperature: 120 °C

Procedure:
To a solution of the isobutyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate 8a and 2-(2-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 11a (1.2 eq) in acetonitrile was added Pd(PPh3)4 (0.10 eq), K2CO3 (2 eq) and water. The vial was sealed and heated by microwave irradiation at 120° C. for 15 minutes. The solvent was evaporated and the residue was dissolved in DMF and purified by reverse phase HPLC (using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 24. m/z 391.1 (M+1), r.t: 3.59 (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).