Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=C(C2C=CC=CC=2)C(C2C=CC=CC=2)=[N:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([C:49]([C:51]([C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([O:59][CH3:60])[CH:54]=2)=O)=O)[CH:46]=[CH:47][CH:48]=1>>[CH3:41][O:42][C:43]1[CH:44]=[C:45]([C:49]2[C:51]([C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([O:59][CH3:60])[CH:54]=3)=[N:22][C:21]3[C:26](=[CH:27][CH:28]=[C:19]([C:8]4[N:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[C:11]5[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=5[N:9]=4)[CH:20]=3)[N:25]=2)[CH:46]=[CH:47][CH:48]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)c(-c4ccccc4)nc3c1)n2C1CCCCC1
Reactant: COc1cccc(C(=O)C(=O)c2cccc(OC)c2)c1
Product: COc1cccc(-c2nc3ccc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)cc3nc2-c2cccc(OC)c2)c1

Procedure:
Prepared as described for Compound 406 using 3,3′-dimethoxybenzil in place of benzil.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:19][F:20])[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]2[CH:14]=[C:15](I)[CH:16]=[CH:17][C:5]=2[O:4]1.[F:21][C:22]([F:27])([F:26])C([O-])=O.[K+].C1(C)C=CC=CC=1>CN(C)C=O>[F:1][CH2:2][C:3]1([CH2:19][F:20])[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]2[CH:14]=[C:15]([C:22]([F:27])([F:26])[F:21])[CH:16]=[CH:17][C:5]=2[O:4]1
Reactant: O=C([O-])C(F)(F)F
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(I)cc21
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Temperature: 150 °C
Reaction time: 5.5 h
Yield: 59.8 %

Procedure:
A mixture of 1.00 g of ethyl 2,2-bisfluoromethyl-6-iodo-2H-1-benzopyran-4-carboxylate, 0.84 g of potassium trifluoroacetate, 1.18 g of cuprous iodide, 4 ml of toluene and 10 ml of N,N-dimethylformamide was heated with stirring at 150° C. for 5.5 hours in a nitrogen gas atmosphere while removing toluene. The reaction mixture was added to a mixed solution of 2N hydrochloric acid and ethyl acetate, and an insoluble material was separated by filtration using celite. The organic layer was separated from the filtrate, and the aqueous layer was extracted with ethyl acetate. The resulting organic layers were combined, washed with a brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (an eluting solvent, ethyl acetate:hexane =10:1) to obtain 0.51 g of ethyl 2,2-bisfluoromethyl-6-trifluoromethyl-2H-1-benzopyran-4-carboxylate as an oily substance.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:35])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[CH:18]([C:36]([O:38]CC)=[O:37])[CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[OH-].[Na+]>C(O)C.O1CCCC1.O>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:35])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[CH:18]([C:36]([OH:38])=[O:37])[CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1ccc(-c2ccncc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.6 %

Procedure:
In a mixed solvent of ethanol (1 ml), tetrahydrofuran (1 ml) and water (1 ml), 4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonyl-1-[4-(pyridin-4-yl)benzoyl]piperazine hydrochloride (152 mg) obtained in Example 2 was dissolved under ice cooling, followed by the dropwise addition of a 1N aqueous solution of sodium hydroxide. The reaction mixture was stirred at room temperature for 90 minutes. After concentration under reduced pressure, 1N hydrochloric acid was added to the reaction mixture to make it weakly acidic. The colorless solid so precipitated was collected by filtration, followed by drying, whereby the title compound (62 mg, 42%) was obtained as a colorless solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)=[O:5].Br[CH:14]([CH3:16])[CH3:15].O>CN(C=O)C>[CH:14]([O:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH3:3])=[CH:7][CH:8]=1)([CH3:16])[CH3:15]
Reactant: CC(C)Br
Reactant: CC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
Sodium hydride (1.32 g, 33 mmol, 60% suspension in mineral oil) was suspended in anhydrous DMF (20 mL). A solution of 4-hydroxy acetophenone (4.08 g, 30 mmol) in anhydrous DMF (20 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 30 min. A solution of 2-bromopropane (4.61 g, 37.5 mmol) in anhydrous DMF (10 mL) was added slowly. The reaction mixture was stirred at room temperature overnight. Water (100 mL) was added. The mixture was extracted with ethyl acetate (2×100 mL). The organic layer was washed with water (3×50 mL) and brine (50 mL). Dried over anhydrous Na2SO4. Removal of solvent gave 1-(4-isopropoxy phenyl)ethanone as a pale yellow solid (3.52 g, 66%). To a stirred solution of 2-methoxy-5-pyrrolidin-1-ylmethyl nicotinic acid methyl ester (0.5 g, 2.0 mmol) and 1-(4-isopropoxy phenyl)ethanone in anhydrous DMF (10 mL), sodium hydride (96 mg, 2.4 mmol, 60% suspension in mineral oil) was added in small portions under nitrogen. The reaction mixture was stirred overnight at room temperature. Reaction mixture was stirred at 80° C. for 1 hours. Water (30 mL) was added. The mixture was extracted with chloroform (150 mL). The organic layer was washed with water (30 mL) and brine (30 mL). Dried over anhydrous Na2SO4. Removal of solvent gave brown solid (0.66 g) which was used in next step without further purification. The above solid (0.626 g, 1.58 mmol) and pyridine hydrochloride (1.18 g, 15.8 mmol) were mixed together and stirred at 190° C. for 20 min. Cooled to room temperature. Water (10 mL) was added, neutralized to pH ˜9. The mixture was extracted with chloroform (2×100 mL). The organic layer was washed with brine (50 mL) and dried (Na2SO4). Removal of the solvent gave 2-(4-isopropoxy phenyl)-6-pyrrolidin-1-ylmethyl pyrano[2,3-b]pyridine-one (0.237 g, 41%) as yellow solid. To a solution of the above compound in anhydrous CH2Cl2 (10 mL) was added 1.0 M solution of hydrogen chloride in ether dropwise. The reaction mixture was stirred for 10 min. The solvent was removed under reduced pressure. The residue was washed with hexane and ether. Purified by triturating with 10% methanol in ether to give 2-(4-isopropoxyphenyl)-6-(pyrrolidin-1-ylmethyl)-4H-pyrano[2,3-b]pyridin-4-one hydrochloride (0.20 g, 83%) as yellow solid. MS (ES) m/z: 264 (M); MP 261-263° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([F:29])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>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].C(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=2[F:11])=[C:22]([F:29])[CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1ccc(F)c(-c2ccc(OCc3ccccc3)cc2F)n1
Yield: 28 %

Procedure:
Method 1 was followed using 6-bromo-5-fluoropicolinic acid (1.0 equiv.) and 4-(benzyloxy)-2-fluorophenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.15 equiv.) to give 6-(4-(benzyloxy)-2-fluorophenyl)-5-fluoropicolinic acid in 28% yield. LC/MS=342.1 (M+H), Rt=1.05 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[CH3:23][CH:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>ClCCl.C(=O)(O)[O-].[Na+]>[CH2:26]([NH:27][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[CH2:25][CH:24]([CH3:28])[CH3:23]
Reactant: CC(C)CCN
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
4-Nitrobenzene-1-sulfonyl chloride (1.5 g, 6.57 mmol) was dissolved in dichloromethane (30 ml) and cooled to 0° C. followed by addition of diisopropylethylamine (2.293 ml, 13.13 mmol). 3-Methylbutan-1-amine (0.926 ml, 7.88 mmol) was dissolved in 5 ml dichloromethane and added via syringe. After the addition, the mixture was allowed to warm to room temperature for 3 hours. The solution was diluted with aqueous sodium bicarbonate and extracted twice with dichloromethane. The organics were combined, dried over magnesium sulfate, filtered and concentrated. Chromatography provided the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][C:10]1=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=[C:30]=[O:31])[CH:24]=1>C(Cl)Cl>[C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][CH2:13][NH:12][CH:11]([C:30](=[O:31])[NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH3:32])[CH:24]=2)[C:10]1=[O:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)CN1C(=O)CNCCCc2ccccc21
Solvent: ClCCl
Product: Cc1cccc(NC(=O)C2NCCCc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)c1

Procedure:
A solution of 1-tert-butyloxycarbonylmethyl-2-oxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine (438 mg, 1.44 mmol) and m-tolylisocyanate (0.2 ml, 1.6 mmol) in DCM (4 ml) was stirred at room temperature for 90 minutes. Evaporation of the solvent gave the crude product which was purified by flash chromatography on silica gel with ethyl acetate-hexane (1:2) as eluant. (550 mg, 87%)
Reaction SMILES: [S:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O)[C:2]#[N:3].S(=O)(=O)(O)[OH:18]>C(O)(=O)C>[F:14][C:13]([F:16])([F:15])[C:9]1[CH:8]=[C:7]([C:5]2[NH:3][C:2](=[O:18])[S:1][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(O)O
Reactant: N#CSCC(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2cccc(C(F)(F)F)c2)cs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 26.42 g (107.74 mmole) of 2-thiocyanato-1-(3-trifluoromethyl-phenyl)-ethanone, 11 mL of 50% aqueous sulfuric acid and 55 mL of acetic acid was heated at reflux for 1 hour. The mixture was cooled, poured into 500 mL of ice water mixture and stirred for 30 minutes. The solid was collected by filtration, washing with water to give 24 g of 4-(3-trifluoromethyl-phenyl)-3H-thiazol-2-one as a light orange-brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]([O:32][CH3:33])=[O:31])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.O>C(OCC)(=O)C.O=[Pt]=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:22][CH2:23]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]([O:32][CH3:33])=[O:31])[CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CC=C(c4ccccn4)CC3)nc2c1
Agent: O=[Pt]=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC(c4ccccn4)CC3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(4-(pyridin-2-yl)-5,6-dihydropyridin-1(2H)-yl)quinoxaline-6-carboxylate (150 mg, 0.34 mmol) in ethyl acetate (30 ml) was added PtO2 (38 mg) and the reaction mixture was stirred at room temperature for 2 hours under an atmosphere of H2(g). The reaction mixture was added to water (100 ml), extracted with dichloromethane (3×30 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 2-(4-fluorophenyl)-3-[4-(pyridin-2-yl)piperidin-1-yl]quinoxaline-6-carboxylate as a yellow solid (84 mg, 56%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][CH:14]1[C:20](=[O:21])[NH:19][C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:15]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:33][C:34]([N:36]([CH:43]([CH3:45])[CH3:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35].C1([C@H](OC(N[C@H]2C(=O)NC3C=CC=CC=3C(C3C=CC=CC=3)=N2)=O)C)C=CC=CC=1>CN(C=O)C.O>[CH:43]([N:36]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:34](=[O:35])[CH2:33][N:19]1[C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:15][CH:14]([NH:13][C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:12])[C:20]1=[O:21])([CH3:45])[CH3:44]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: CC(C)N(C(=O)CBr)c1ccccc1
Agent: C[C@@H](OC(=O)N[C@@H]1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(C(=O)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21)c1ccccc1
Reaction time: 1 h
Yield: 101 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 428 mg, 10.7 mmol) is added to a suspension of 3-[(benzyloxycarbonyl)amino]-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (3.924 g, 10.19 mmol), prepared as in Intermediate 6, in anhydrous DMF under nitrogen at 0°-5° C. After stirring for 1 hr., 2-Bromo-N-isopropyl-N-phenyl-acetamide (2.739 g, 10.70 mmol), prepared as in Intermediate 3, in anhydrous DMF (5 mL) is added and the mixture is allowed to stir at ambient temperature overnight. The reaction is added via pipette to water (200 mL) with vigorous agitation. The resulting slurry is diluted with water (50 mL) and then cooled to 0°-5° C. with a ice-water bath. After stirring for 30 min., the cold slurry is filtered, washed with water and then dried overnight under high vacuum to provide the title compound as a white solid (5.765 g, 10.29 mmol) of sufficient purity for the next step. 1H NMR (300 MHz, CDCl3) δ=1.09 (d, J=6.8 Hz, 6H); 3.92 (d, J=16.5 Hz, 1H); 4.28 (d, J=16.5 Hz, 1H); 4.97-5.08 (m, 1H); 5.08-5.19 (m, 2H); 5.39 (d, J=8.2 Hz, 1H); 6.70 (d, J=8.1 Hz, 1H); 7.11-7.62 (m, 19H). MS (FAB): [M+H]+ =561
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=[C:7](Cl)[N:6]=1)=[O:4].[CH:16]1(B(O)O)[CH2:18][CH2:17]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=[C:7]([CH:16]2[CH2:18][CH2:17]2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(Cl)nc1C(=O)OC
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(C2CC2)nc1C(=O)OC

Procedure:
To a solution of 6-chloro-pyridine-2,3-dicarboxylic acid dimethyl ester (D80, 16.8 g, 73.4 mmol) in toluene (340 ml) and water (34 ml) was added cyclopropylboronic acid (7.56 g, 88.1 mmol), K3PO4.H2O (58.6 g, 220.2 mmol) and tricyclohexylphosphine (2.06 g, 7.34 mmol) under N2 atmosphere, followed by addition of palladium diacetate (0.84 g, 3.67 mmol). After stirred at reflux for 4 hours, the mixture was filtered and partitioned between ethyl acetate and water. The combined extracts were washed with brine, dried over magnesium sulphate, filtered and evaporated. The resulting solid was purified by column chromatography on silica gel (12.5% ethyl acetate in petroleum ether) to give D81 (12.6 g) as a yellow solid.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[OH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].N1C=CN=C1>C(Cl)Cl>[Si:5]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)CCCCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)CCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
A solution of tert-butylchlorodimethylsilane (27.1 g, 179.79 mmol) in DCM (50 mL) was added dropwise to a stirred solution of methyl 5-hydroxypentanoate (CAS no. 14273-92-8, Huckstep, M.; Taylor, R. J. K.; Caton, M. P. L. Synthesis 1982, 10, 881) (19.8 g, 149.82 mmol) and 1H-imidazole (15.30 g, 224.73 mmol) in DCM (200 mL) at 5° C., over a period of 10 minutes under nitrogen. The resulting suspension was stirred at ambient temperature for 6 hours. The reaction mixture was diluted with DCM (250 mL), and washed sequentially with water (2×200 mL) and saturated brine (200 mL). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with 10 to 50% ethyl acetate in isohexane to afford the product (19.3 g, 52%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)C(OC(C)(C)C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.C(=O)=O>CO>[C:1]([O:5][C:6]([NH:8][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnccn1
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cnccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
Di-(t-butoxycarbonyl)aminopyrazine (2.1 g, 7.1 mM) in methanol (50 ml) under nitrogen, was treated with aqueous sodium hydroxide (2.5 M, 2.84 ml, 7.1 mM), and stirred at ambient temperature for 2 hours. The mixture was neutralised by the addition of water (25 ml) and solid carbon dioxide, then methanol evaporated. The residual aqueous solution was extracted with dichloromethane (2×20 ml), the extracts washed with brine (20 ml) and evaporated. The resulting solid was triturated with isohexane (50 ml) to give the title product as a white solid (1.03 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]([CH3:15])[C:12]([OH:14])=[O:13].Cl.[CH3:17]O>>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]([CH3:15])[C:12]([O:14][CH3:17])=[O:13]
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1F
Reactant: CO
Agent: Cl
Product: COC(=O)C(C)c1ccc([N+](=O)[O-])cc1F
Yield: 93 %

Procedure:
Compound (5) obtained above was esterified by adding a catalytic amount of concentrated hydrochloric acid in methanol to give compound (6) of interest as a clear yellow oil at a yield of 93%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][CH:26]=3)[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].[Si]([O:47][CH2:48][CH2:49][N:50]1[CH:54]=[CH:53][C:52](B(O)O)=[N:51]1)(C(C)(C)C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[OH:47][CH2:48][CH2:49][N:50]1[CH:54]=[CH:53][C:52]([C:2]2[CH:3]=[CH:4][C:5]([NH:13][C:14]3[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:18][N:17]=[C:16]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([CH2:29][P:30](=[O:37])([O:31][CH2:32][CH3:33])[O:34][CH2:35][CH3:36])=[CH:38][CH:39]=4)[N:15]=3)=[C:6]3[C:10]=2[CH2:9][N:8]([CH3:11])[C:7]3=[O:12])=[N:51]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(B(O)O)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4ccn(CCO)n4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared according to the procedure for Compound 97A diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate (30.0 mg, 0.0477 mmol) and [1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-pyrazol-3-yl]boronic acid (Compound 142A, 46.7 mg, 0.173 mmol). The afforded intermediate, diethyl (4-{[4-({7-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-pyrazol-3-yl]-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate, was purified using an ISCO Combiflash system (eluting with 0-100% EtOAc:CH2Cl2). The product thus obtained was dissolved in CH2Cl2 (2 mL), treated with 4.0 M of HCl in dioxane (0.5 mL) and stirred at rt for 2 h. The solid was filtered off and rinsed with a mixture of CH2Cl2/heptane, giving the title material as an off-white solid, 24.6 mg (77%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.89 (s, 1H), 10.03 (br s, 1H), 8.89 (br s, 1H), 8.49 (s, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.81 (d, J=2.3 Hz, 1H), 7.57 (br s, 2H), 7.30 (br d, J=6.6 Hz, 2H), 6.93 (br s, 1H), 4.72 (s, 2H), 4.21 (t, J=5.6 Hz, 2H), 3.97 (quin, J=7.4 Hz, 4H), 3.81 (t, J=5.7 Hz, 2H), 3.25 (d, J=21.5 Hz, 2H), 3.13 (s, 3H), 1.16 (t, J=7.1 Hz, 6H). MS (ES+): m/z 660.22 (100) [MH+]. HPLC: tR=2.72 min (ZQ3, nonpolar—5 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17]Cl)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:19]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(OCC)C>[C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][O:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(CCl)ccc21
Reactant: OC1CCCCC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)n1ccc2cc(COC3CCCCC3)ccc21
Temperature: 35 °C
Yield: 28 %

Procedure:
A mixture of 5-chloromethyl-indole-1-carboxylic acid tert-butyl ester (0.41 g, 1.55 mmol, 1.0 eq.), cyclohexanol (0.82 mL, 5.0 eq.) and Ag2O (1.80 g, 5.0 eq.) in diethyl ether (5 mL) was stirred at 35° C. over weekend. After cooling to room temperature, the reaction mixture was filtered through celite washing with ether. The filtrate was concentrated and the residue was purified by chromatography (3% EtOAc/hexanes) to give N-Boc-5-cyclohexyloxymethylindole (160 mg, 28%) as colorless oil. 1HNMR confirmed the compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[C:10]([S:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22](O)=[O:23])=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[C:10]([S:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([NH:33][CH2:32][CH2:31][N:30]([CH3:34])[CH3:29])=[O:23])=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: Cc1c(Sc2cccc(C(=O)O)c2)c2ccc(Br)cc2n1Cc1ccccc1
Product: Cc1c(Sc2cccc(C(=O)NCCN(C)C)c2)c2ccc(Br)cc2n1Cc1ccccc1

Procedure:
Prepared according to the procedure described in Example 89, Step 1 using the following starting materials: 3-(1-benzyl-6-bromo-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid and N,N-dimethylethylenediamine.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[OH:11])[CH2:6][CH2:5]1)(=O)C.[OH-].[K+]>C(O)C.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([CH:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)[OH:11])=[CH:19][CH:20]=1
Reactant: CC(=O)N1CCC(C(O)(c2ccccc2)c2ccc(F)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OC(c1ccccc1)(c1ccc(F)cc1)C1CCNCC1
Temperature: 0 °C
Yield: 24.5 %

Procedure:
A mixture of 16.3 g (0.05 mole) of 1-acetyl-α-(4-fluorophenyl)-α-phenyl-4-piperidinemethanol and 5.6 g (0.1 mole) of potassium hydroxide in 150 ml of 95% ethanol and 20 ml of water was heated at reflux for 18 h. The mixture was poured into 1.5 L of ice-water and a solid precipitated. The solid was collected by filtration and dried. The gummy solid was dissolved in ethyl ether, filtered, and the filtrate slowly evaporated to 50 ml. The resulting solid was collected by filtration and recrystallized from 2-propanol/isopropyl ether to yield 3.5 g (25%) of white solid, mp 144.5°-146° C.