Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:33]([C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)(=[O:35])=[O:34])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a solution of 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (3 g, 7.7 mmol) in pyridine (15 mL) was added pyridine-3-sulfonyl chloride (1.49 g, 8.4 mmol) dropwise to the mixture. The reaction was stirred at rt overnight. The reaction was washed with water (100 mL), and extracted with DCM (2×100 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:EtOAc 5:1) to afford the title compound of Step A (2.9 g, 71.5% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.55-10.60 (br, 1H), 8.82-8.86 (m, 1H), 8.72-8.76 (m, 1H), 8.30 (d, J=5.3 Hz, 1H), 8.07-8.13 (m, 1H), 7.51-7.52 (m, 1H), 7.39-7.47 (m, 1H), 7.27-7.40 (m, 2H), 6.47 (d, J=5.3 Hz, 1H) 3.47-3.57 (m, 4H), 3.67-3.75 (m, 4H). MS (ES+): 533 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([NH:12][CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C)[CH:5]=1.CI.[C:32](O)(=O)C>O1CCCC1.O>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([N:12]([CH:13]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:14][CH2:15][OH:16])[CH3:32])[CH:5]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)[Si](C)(C)OCCC(Nc1cc(Cl)ccc1C#N)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CN(c1cc(Cl)ccc1C#N)C(CCO)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of sodium hydride (60% dispersion, 270 mg, 6.75 mmol) in dry tetrahydrofuran (20 ml) under nitrogen and at 0° C. was added 4-chloro-2-[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-phenylpropyl]amino]benzonitrile (2.3 g, 5.74 mmol) in tetrahydrofuran (10 ml). The resulting yellow suspension was stirred at room temperature for 2 h, and then treated with methyl iodide (3.6 ml, 57.4 mmol). The resulting mixture was heated under reflux for 10 h, and then treated with acetic acid (10 ml) and water (2 ml). Heating and stirring were continued overnight. The mixture was concentrated under vacuum and the residue partitioned between water (50 ml) and ethyl acetate (100 ml). The organic extract was collected and dried over magnesium sulphate. After concentration of the extract the residue was purified on silica gel using 80% isohexane/diethyl ether as eluent. The title compound was isolated as a colourless oil (1 g, 58%).
Reaction SMILES: [NH2:1][C:2](=[S:19])[C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:20](OC(OCC)CBr)[CH3:21]>CC(C)=O.Cl.O1CCOCC1>[C:5]1([CH2:4][C@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[C:2]2[S:19][CH:20]=[CH:21][N:1]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(CBr)OCC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(N)=S
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.2 %

Procedure:
To a mixture of #13 (5.65 g, 20.2 mmol, 1 eq.) in acetone (101 mL, 0.2 M) was added bromoacetaldehyde diethyl acetal (8.76 mL, 58.2 mmol, 2.89 eq.) and 2 drops of 4 M hydrochloric acid in dioxane. The mixture was degassed with nitrogen three times before being heated to reflux. After 2 hours, the reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude orange oil was diluted with ethyl acetate before being concentrated in vacuo onto silica and purified by silica gel chromatography (Gradient: 0% to 35% ethyl acetate in heptane) and then by reverse phase chromatography (Method A) to give #14 (625 mg, 10%); HPLC (Protocol E): m/z 304.5 [M+H+], 248.9 [(M−2-methylprop-1-ene)+H+], retention time=7.416 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, major rotamer: δ 7.75 (d, J=3.3 Hz, 1H), 7.75 (br d, J=8.6 Hz, 1H), 7.61 (br d, J=3.1 Hz, 1H), 7.25-7.30 (m, 5H), 4.99 (ddd, J=10.5, 8.9, 4.5 Hz, 1H), 3.29-3.36 (m, 1H, assumed; partially obscured by water signal), 2.98 (dd, J=13.8, 10.6 Hz, 1H), 1.31 (s, 9H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[N:7]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[CH3:23])[C:6]=2[CH:5]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:3]=1.[Li]CCCC.[B:35](OC)([O:38]C)[O:36]C.B(O)O.OP([O-])([O-])=O.[K+].[K+]>C1COCC1.C(OCC)(=O)C.C(Cl)(Cl)Cl>[Cl:22][C:18]1[C:17]([CH3:23])=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][N:7]1[C:6]2[CH:5]=[C:4]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:3]=[C:2]([B:35]([OH:38])[OH:36])[C:10]=2[N:9]=[C:8]1[C:11]([F:12])([F:14])[F:13]
Reactant: Cc1c(Cl)cccc1Cn1c(C(F)(F)F)nc2c(Br)cc(N3CCOCC3)cc21
Reactant: COB(OC)OC
Agent: O=P([O-])([O-])O
Agent: OBO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)cccc1Cn1c(C(F)(F)F)nc2c(B(O)O)cc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
To a solution of 4-(4-bromo-1-(3-chloro-2-methylbenzyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)morpholine (1.38 g, 2.82 mmol) in THF (55 mL) stirring at −78° C. under nitrogen was slowly added 2.5M BuLi (2.259 mL, 5.65 mmol) via syringe. Immediately after the addition of n-BuLi, trimethyl borate (1.262 mL, 11.29 mmol) was added via syringe and then the dry ice bath was removed and the reaction was allowed to warm to room temperature. After stirring at RT for 60 minutes the mixture was quenched with MeOH and the entire reaction mixture was concentrated in vacuo to leave 2.1 g of crude reaction products—containing both the desired boronic acid and the des-bromo analog by LCMS with the desired boronic acid as the major product. The crude material was combined with crude material from a second reaction. The entire mixture was purified on silica gel that had been pre-treated with 3 column volumes of 0.5M ammonium acetate in methanol prior to being washed and equilibrated with chloroform. The column was eluted sequentially with chloroform/hexane (1:1, 300 mL) followed by chloroform (500 mL), then (a 2N solution of ammonia in methanol)/chloroform (5:95, 2 L). The fractions corresponding to product were combined and concentrated in vacuo to provide partially purified desired product that was free of the des-bromo analog by HPLC. The material was subsequently purified by preparative chiral phase HPLC. The product fractions were concentrated to provide an oil. Next added 200 ml CHCl3 and 200 ml of aqueous 0.5 M K2HPO4 (pH 3.4) and mixed. Separated the two phases, and re-extracted the aqueous phase with 2×100 ml CHCl3. Washed CHCl3 layer with H2O, then dried the CHCl3 layer over Na2SO4, filtered and concentrated to leave a beige glassy solid. The solid was chased with ethyl acetate (2×50 ml), and then dried @ 50° C. under high vacuum (4.5 hr.) to give desired product (250 mg). MS (ES+) m/e: 453.1, 454.1 [M+H]+; C18 HPLC 99.5%; 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.51 (s, 3H) 3.05-3.22 (m, 4H) 3.70-3.93 (m, 4H) 5.67 (s, 2H) 6.19 (d, J=8.08 Hz, 1H) 6.84 (br. s., 1H) 7.02 (t, J=8.08 Hz, 1H) 7.19-7.30 (m, 1H) 7.34 (d, J=8.34 Hz, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.[Br:18][C:19]1[C:24]([CH:25]=[CH:26][C:27](O)=[O:28])=[CH:23][CH:22]=[C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:20]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CN1C(=O)CCC1>C1COCC1>[Br:18][C:19]1[C:24]([CH:25]=[CH:26][C:27]([NH:2][CH2:3][C:4]2[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=2)=[O:28])=[CH:23][CH:22]=[C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:20]=1
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(C=CC(=O)O)c(Br)n1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(C)(C)C)nc2Br)cc(F)c1NS(C)(=O)=O
Yield: 55.9 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (41.2 mg, 0.148 mmol) was reacted with 3-(2-bromo-6-tert-butyl-pyridin-3-yl)-acrylic acid (1.0 eq, 42 mg), DMTMM (1.0 eq, 41 mg) and NMP (1.2 eq, 20 μl) in THF to give the title compound (42 mg, 55.8%) after purification by column chromatography (Hex/EtOAc=3/2).
Reaction SMILES: [NH2:1][C:2]1[N:12]=[C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9](Cl)[N:4]2[N:3]=1.[SH-:13].[Na+]>O>[NH2:1][C:2]1[N:12]=[C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([SH:13])[N:4]2[N:3]=1
Reactant: [SH-]
Reactant: Cc1cc(Cl)n2nc(N)nc2n1
Agent: [Na+]
Solvent: O
Product: Cc1cc(S)n2nc(N)nc2n1
Yield: 74.3 %

Procedure:
The product obtained in Step 1 (15 g) was added all at once at room temperature to a solution of 12 g of sodium hydrosulfide in 300 ml of water with stirring under a nitrogen stream. The mixture was stirred at room temperature for one hour, the insoluble matters were removed by filtration, the pH was adjusted to 1.0 with concentrated hydrochloric acid, and the formed crystals were collected by filtration and washed twice with 20 ml water, affording 11 g of the objective compound as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:21])[N:8](C)C(C)[N:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.[Cl-].[NH4+]>>[NH:10]([C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[C:7]([NH2:8])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc2c(c1)N(c1ccccc1)C(C)N(C)C2=O
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc(C(N)=O)c(Nc2ccccc2)c1

Procedure:
Following the procedure for 7-methoxy-2,3-dimethyl-1-phenyl-2,3-dihydroquinazolin-4(1H)-one (Step B), using ammonium chloride in place of methylamine hydrochloride, 2-anilino-4-methoxybenzamide was obtained.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH:20]([C:22]3[N:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[S:25][CH:26]=3)[O:19][C:18]([OH:40])([C:31]3N=C(C(F)(F)F)S[CH:35]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].C(CO[C:47]1[CH:52]=CC(CC(NCC(O)C2N=C(C(F)(F)F)SC=2)C)=[CH:49][CH:48]=1)(OC)=O.FC(F)(F)C1SC=C(C(=O)CBr)N=1.C(=O)([O-])O.[K+]>CC(C)=O>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH:20]([C:22]3[N:23]=[C:24]([C:27]([F:29])([F:28])[F:30])[S:25][CH:26]=3)[O:19][C:18]([OH:40])([C:31]3[CH:49]=[CH:48][CH:47]=[CH:52][CH:35]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)N2CC(c3csc(C(F)(F)F)n3)OC(O)(c3csc(C(F)(F)F)n3)C2)cc1
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Agent: O=C(CBr)c1csc(C(F)(F)F)n1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CC(C)N2CC(c3csc(C(F)(F)F)n3)OC(O)(c3ccccc3)C2)cc1

Procedure:
N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2,6-bis(2-trifluoromethyl-thiazol-4-yl)morpholine from N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine (pair of diastereomers A) with 2-trifluoromethyl-4-bromoacetyl-thiazole and potassium hydrogen carbonate in acetone.
Reaction SMILES: [ClH:1].[CH:2]1([CH2:7][CH:8]([C:19]2[NH:28][C:22]3=[N:23][CH:24]=[C:25](N)[CH:26]=[C:21]3[CH:20]=2)[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.N([O-])=O.[Na+].[OH-].[Na+]>Cl.O.[Cu]Cl>[Cl:1][C:25]1[CH:26]=[C:21]2[CH:20]=[C:19]([CH:8]([C:9]3[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=3)[CH2:7][CH:2]3[CH2:6][CH2:5][CH2:4][CH2:3]3)[NH:28][C:22]2=[N:23][CH:24]=1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(N)cnc3[nH]2)cc1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(Cl)cnc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
To a solution of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-ylamine hydrochloride (prepared as in Example 107, 327 mg, 0.78 mmol) in concentrated hydrochloric acid (5 mL) at 0° C. was added a solution of sodium nitrite (270 mg, 3.9 mmol) in water (3 mL) dropwise. After stirring for 10 min at 0° C., a solution of copper (I) chloride (232 mg, 2.34 mmol) in concentrated hydrochloric acid (3 mL) was added. After stirring for another 10 min at 60° C., the mixture was adjusted to pH 8 with a 20% aqueous sodium hydroxide solution, extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 5-chloro-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (94 mg, 30%): LC/MS m/e calcd for C21H23ClN2O2S [M+H]+ 403.95, observed 403.3; 1H NMR (400 MHz, CD3OD) δ ppm 1.22 (m, 2H), 1.49 (m, 2H), 1.60-1.88 (m, 5H, H), 2.11 (m, 1H), 2.26 (m, 1H), 3.08 (s, 3H), 4.30 (t, J=7.9 Hz, 1H), 6.37 (s, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.88 (s, 1H), 7.89 (d, J=8.4 Hz, 2H), 8.05 (br, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:33]=[C:34]([O:36][CH3:37])[CH:35]=1)[NH2:32]>>[CH3:37][O:36][C:34]1[CH:33]=[C:31]([NH:32][CH:23]2[CH2:22][CH2:21][N:20]([CH2:19][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)[CH:18]=3)[CH2:25][CH2:24]2)[CH:30]=[C:29]([O:28][CH3:27])[CH:35]=1
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Reactant: COc1cc(N)cc(OC)c1
Product: COc1cc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc(OC)c1

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl-4-piperidone (1.40 g) and 3,5-dimethoxyaniline (722 mg) were treated in the same manner as described in Preparation Example 37 to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[F:17])[C:5]1=[O:18])[CH3:3].Cl[CH2:20][C:21]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:22]=1[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>>[F:17][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:10]=1[N:6]1[C:7](=[O:9])[CH2:8][N:4]([CH:2]([CH3:1])[CH3:3])[C:5]1=[O:18])[O:16][CH2:20][C:21]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:22]=1[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26]
Reactant: CC(C)N1CC(=O)N(c2ccc(O)cc2F)C1=O
Reactant: COC(=O)C(C)Oc1cc(Cl)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)C(C)Oc1cc(Cl)ccc1COc1ccc(N2C(=O)CN(C(C)C)C2=O)c(F)c1
Yield: 90.5 %

Procedure:
By the method of Example 1, Step I, 0.60 g (0.0024 mole) of 1-(1-methylethyl)-3-(2-fluoro-4-hydroxyphenyl)imidazolidin-2,4-dione, 1.24 g (0.0048 mole) of methyl 2-(2-chloromethyl-5-chlorophenoxy)propionate (Example 2, Step E), and 0.5 g (0.0036 mole) of potassium carbonate were reacted in 25 mL of 2-utanone. After purification, 1.04 g of methyl 2-[2-[3-fluoro-4[1-(1-methylethyl)imidazolidin-2,4-dion-3-yl]phenoxymethyl]-5-chloro-phenoxy]propionate was isolated as a yellow oil. The NMR and IR spectra were consistent with the proposed structure. NMR: 1.24 (d, 6H, JHH=8 Hz); 1.64 (d, 3H, JHH=8 Hz); 3.68 (s, 3H); 3.96 (s, 1H); 4.44 (septet, 1H, JHH=8.0 Hz); 5.04 (q, 1H, JHH=8.0 Hz); 5.24 (s, 2H); 6.80-7.34 (m, 5H).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH3:18])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(Cl)Cl.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=2)[C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)C2CCCCC2)sc2cccnc12
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(c2sc3cccnc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 84 h
Yield: 62.4 %

Procedure:
To a mixture of cyclohexyl(3-methylthieno[3,2-b]pyridin-2-yl)methanone (1.38 g) synthesized above, methyl 4-aminobenzoate (884 mg), triethylamine (5.94 mL) and methylene chloride (30 mL) was added titanium (IV) chloride (700 μL) at 0° C., and the mixture was stirred at room temperature for 3.5 days under argon atmosphere. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (30 mL) of the obtained oil in tetrahydrofuran were added acetic acid (607 μL) and sodium cyanoborohydride (666 mg), and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-50% ethyl acetate/hexane) to give the title object compound (1.31 g, 62%) as a brown solid.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH2:23][CH2:24]NC(OC(C)(C)C)=O)[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S(CC2C(C(OCC)=O)=C(O)C(C3C=COC=3)=CC=2)(=O)=O)C=CC=CC=1.ICC>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH2:23][CH3:24])[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCNC(=O)OC(C)(C)C
Agent: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Solvent: CCI
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 10, starting from ethyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 36) and iodoethane.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[C:31]([O:35][C:36](=[O:45])[CH2:37][CH2:38][N:39]1[CH:43]=[CH:42][C:41]([NH2:44])=[N:40]1)([CH3:34])([CH3:33])[CH3:32].N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[C:31]([O:35][C:36](=[O:45])[CH2:37][CH2:38][N:39]1[CH:43]=[CH:42][C:41]([NH:44][C:8](=[O:9])[C@@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:22])([F:21])[F:23])[C:12]2=[O:24])[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:40]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)CCn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3c(cccc3C(F)(F)F)C2=O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 1, 100 mg, 0.29 mmol,) in methylene chloride (4 mL) and N,N-dimethylformamide (4 drops) was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 150 μL, 0.30 mmol) and stirred for 15 min at room temperature. After this time, the reaction mixture was then concentrated in vacuo and the resulting residue was dissolved in methylene chloride (4 mL) and then added dropwise to a separate reaction flask containing a mixture of 3-(3-amino-pyrazol-1-yl)-propionic acid tert-butyl ester (prepared as in US 20080021032, Example 8, 92 mg, 0.44 mmol) and 2,6-lutidine (100 μL, 0.87 mmol) in methylene chloride (3 mL) at room temperature. The resulting reaction mixture was the stirred room temperature for 2 h. The reaction mixture was quenched by the addition of methanol and then diluted with methylene chloride and then washed with a 1 N aqueous hydrochloric acid solution. The organic layer was then dried over sodium sulfate, filtered and the filtrate was then concentrated in vacuo with silica gel (2.0 g). The silica gel with absorbed material was placed in a SIM and purified via Biotage flash column chromatography (40 S silica gel column, 25% ethyl acetate/hexanes) to afford 3-{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-propionic acid tert-butyl ester (145 mg, 94%) as a white foam: HR-ES(+) m/e calcd for C27H33N4O4F3 [M+H]+ 535.2527, observed 535.2526; 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.01 (dd, J=7.67, 12.79 Hz, 2H), 7.71-7.82 (m, 1H), 7.56 (d, J=2.13 Hz, 1H), 6.39 (d, J=2.13 Hz, 1H), 4.96-5.14 (m, 2H), 4.71 (d, J=18.33 Hz, 1H), 4.19 (t, J=6.50 Hz, 2H), 2.72 (t, J=6.61 Hz, 2H), 0.77-2.09 (m, 20H).