Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:9]2)=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][O:26][C:27]1[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29](=[O:30])[C:28]1[CH:33]=[CH:34][CH:35]=[CH:36][C:27]=1[O:26][CH2:25][CH2:24][N:20]1[CH2:19][CH2:18][CH:17]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:8]([CH2:7][C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=2)[CH2:22][CH2:21]1
Reactant: COC(=O)c1ccccc1OCCCl
Reactant: Clc1ccc(Cn2cc(C3CCNCC3)c3cccnc32)s1
Product: COC(=O)c1ccccc1OCCN1CCC(c2cn(Cc3ccc(Cl)s3)c3ncccc23)CC1
Yield: 33.2 %

Procedure:
This compound was prepared following the procedure described in example 4, part E starting with 2.8 g (6.5 mmol) of 1-(5-chloro-thiophen-2-ylmethyl)3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 1.5 g (7.2 mmol) of methyl 2-(2-chloroethoxy)benzoate. After standard work-up and purification, 1.1 g (33% yield) of 2-(2-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperidin-1-yl}ethoxy)benzoic acid methyl ester were obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[C:5]=1[O:13][CH3:14].[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18]Br.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[C:5]=1[O:13][CH3:14])[CH3:1]
Reactant: CNCc1ccc2c(c1OC)OCO2
Reactant: COC(CBr)OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1c(CN(C)CC(OC)OC)ccc2c1OCO2
Temperature: 25 °C
Yield: 92 %

Procedure:
0.98 g of N-methyl-(2-methoxy-3,4-methylenedioxybenzylamine obtained in Example 14, 0.93 g (1.1 equivalent) of bromoacetaldehyde dimethylacetal and 0.76 g (1.5 equivalent) of triethylamine as base were mixed in 7.3 ml of toluene and heated under reflux for 4 hours. On cooling the reaction mixture to room temperature, the deposited salts were filtered out and the toluene layer was analyzed to show that 1.302 g of the desired N-(2-methoxy-3,4-methylenedioxybenzyl)-N-methylaminoacetaldehyde dimethylacetal was obtained. Yield 92%. Because 0.25 g of excessive triethylamine was present in the toluene layer, a toluene solution of the desired N-(2-methoxy-3,4-methylenedioxybenzyl)-N-methylaminoacetaldehyde dimethylacetal was obtained by distilling off excessive triethylamine at atmospheric pressure.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 96.8 %

Procedure:
In a 500 mL three-opening flask, 2,2-diphenyl ethanol (17 g, 86 mmol) was dissolved in 170 mL dichloromethane. To the flask was added triethylamine (13.03 g, 129 mmol). The resulting mixture was stirred at 0° C. for half an hour. To the resulting mixture was slowly added MsCl (11.92 g, 104 mmol) dropwisely. The reaction was conducted at 25° C. After the completion of reaction monitored by TLC, the reaction solution was washed with water thrice. The organic phase was dried over anhydrous sodium sulfate and evaporated to remove the solvent to produce 2,2-diphenylethyl methanesulfonate (23 g) in a yield of 96.78%.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:21]3[O:20][C:19]([CH2:22][CH3:23])=[N:18][C:17]=3[C:16]([O:24][CH:25]([F:27])[F:26])=[CH:15][CH:14]=2)=[O:12])=CC=1)([O-])=O.[CH3:28][N:29]1[C:33]([NH2:34])=[CH:32][CH:31]=[N:30]1.C(OCC)C>CCCCCC>[CH3:28][N:29]1[C:33]([NH:34][C:11]([C:13]2[C:21]3[O:20][C:19]([CH2:22][CH3:23])=[N:18][C:17]=3[C:16]([O:24][CH:25]([F:26])[F:27])=[CH:15][CH:14]=2)=[O:12])=[CH:32][CH:31]=[N:30]1
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)Oc3ccc([N+](=O)[O-])cc3)c2o1
Reactant: Cn1nccc1N
Solvent: CCCCCC
Solvent: CCOCC
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Nc3ccnn3C)c2o1
Yield: 15.7 %

Procedure:
Starting from 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid 4-nitro-phenyl ester (100 mg) and 2-methyl-2H-pyrazole-3-ylamine (51 mg). Purification by column chromatography on silica eluting with ethyl acetate afforded, after trituration with a mixture of diethyl ether and hexane, the title compound as a pale yellow solid (14mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: N#Cc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(Nc2ccccc2[N+](=O)[O-])c1
Temperature: 135 °C
Reaction time: 16 h
Yield: 59.5 %

Procedure:
A mixture of 1-fluoro-2-nitrobenzene (2.00 g, 14.2 mmol), 3-aminobenzonitrile (3.35 g, 28.3 mmol) and potassium carbonate (5.88 g, 42.5 mmol) in DMF (30 mL) was stirred at 135° C. for 16 h under a nitrogen atmosphere. After cooling to RT, the reaction mixture was partitioned between DCM and water. The aqueous phase was extracted with DCM (×3) and the combined organic fractions dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 25-100% DCM in cyclohexane) then loaded onto an SCX-2 cartridge and washed with DCM to afford 3-(2-nitrophenylamino)benzonitrile as a bright orange foam (2.02 g, 60%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[C:32]3[C:28]([C:29]([NH:42][C:43](=[O:47])[CH2:44][CH2:45][CH3:46])=[N:30][N:31]3COCC[Si](C)(C)C)=[CH:27][CH:26]=2)[CH:20]=1.C(OCC)(=O)C>O1CCCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[C:32]3[C:28]([C:29]([NH:42][C:43](=[O:47])[CH2:44][CH2:45][CH3:46])=[N:30][NH:31]3)=[CH:27][CH:26]=2)[CH:20]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3cccnc3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3cccnc3)ccc12
Temperature: 66 °C

Procedure:
13.3 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 900 mg of N-[6-(3-pyridyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 20 cm3 of tetrahydrofuran. The reaction medium is heated at about 66° C. for 21 hours. The heating is then stopped and 100 cm3 of ethyl acetate are added. This mixture is washed with 50 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 2×50 cm3 of distilled water and 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2 cm), eluting with ethyl acetate and collecting 25 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 50° C.), 380 mg of N-[6-(3-pyridyl)-1H-indazol-3-yl]butanamide are thus obtained in the form of a white product melting at 205° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:19][NH2:20].C(N(CC)CC)C>C(Cl)Cl>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:19][NH:20][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: COc1ccc(CN)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(SC)nc1NCc1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
In DCM (50 mL) were dissolved ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1.5 g, 6.46 mmol), 3-fluoro-4-methoxybenzylamine (1.0 g, 6.45 mmol) and triethylamine (1.3 g, 12.9 mmol). The reaction mixture was stirred at ambient temperature for 30 min, and washed with water. The organic phase was dried over sodium sulfate and concentrated to give ethyl 4-((3-fluoro-4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-carboxylate as a yellow oil (2.2 g, yield: 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=1[F:25]>CN(C=O)C.CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[F:25]
Reactant: COc1cc2ncnc(Nc3ccc([N+](=O)[O-])cc3F)c2cc1OC
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc2ncnc(Nc3ccc(N)cc3F)c2cc1OC
Reaction time: 3 h
Yield: 64.9 %

Procedure:
(6,7-Dimethoxy-quinazolin-4-yl)-(2-fluoro-4-nitro-phenyl)-amine (673 mg, 1.95 mmol) was dissolved in a combination of DMF (20 ml) and MeOH (20 ml), to which was added 10% Pd/C (227 mg). The mixture was shaken under an atmosphere of H2 on a Parr hydrogenator at 40 psi for 3 hrs. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo. The resulting residue was triturated in EtOAc/Et2O. The resulting solids were filtered, washed with Et2O, and dried under vacuum to give N1-(6,7-dimethoxy-quinazolin-4-yl)-2-fluoro-benzene-1,4-diamine (398 mg, 65%) which was used in the next reaction without further purification. 1H-NMR (400 MHz, DMSO): 10.80 (br s, 1H), 10.30 (br s, 1H), 8.63 (s, 1H), 8.15 (s, 1H), 7.33 (s, 1H), 7.15 (m, 1H), 6.45 (m, 1H), 3.96 (s, 6H). LC/MS Calcd for [M+H]+ 315.1. found 315.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH3:22])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1
Reactant: CI
Reactant: Cc1nnc2c(NC(=O)OC(C)(C)C)cc(Cl)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc2c(N(C)C(=O)OC(C)(C)C)cc(Cl)nn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To a stirred solution of tert-butyl (6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl)carbamate (Step 112.4) (202 mg, 0.712 mmol) in DMF (4 mL) under Ar was added NaH (34.2 mg, 0.854 mmol) and the resulting mixture was stirred at RT for 30 min. MeI (0.053 mL, 0.854 mmol) was added to the mixture and stirred for further 30 min. The reaction was quenched with a saturated aq. NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with a saturated aq. NaHCO3 solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/EtOAc 25-40%) to afford the title product (208 mg, 0.699 mmol, 98% yield) as white solid. tR: 4.45 min (HPLC 1); tR: 1.00 min (LC-MS 2); ESI-MS: 298 [M+H]+ (LC-MS 2); Rf=0.45 (hexane/EtOAc 1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][CH3:11])[N:3]=1.[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>CCN(CC)CC>[C:12]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][CH3:11])[N:3]=1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CCNc1nc(N)cc(Cl)n1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCNc1nc(Cl)cc(NC(=O)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the pyrimidine 6-2 (3.76 g, 21.8 mmol), pivaloyl chloride (10.7 mL, 87 mmol), Et3N (15.2 mL, 109 mmol) and TBF (80 mL) was stirred at room temperature for 24 hours. A further 3 mL of pivaloyl chloride and 4 mL of Et3N was added and the mixture stirred for another 24 hours. The solution was poured into saturated Na2CO3, extracted twice with EtOAc, washed with brine, dried (MgSO4) and filtered through a pad of silica gel. Removal of the solvent afforded an orange solid. Trituration with ether/hexane (˜20: 1) and filtration provided the title compound 6-3 as a white solid.
Reaction SMILES: Br.[Br:2]/[C:3](/[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18]C)[N:12]=1)=[CH:4]\[C@@H:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.O>O1CCOCC1>[Br:2]/[C:3](/[C:11]1[NH:12][C:13](=[O:18])[C:14]([Cl:17])=[CH:15][CH:16]=1)=[CH:4]\[C@H:5]1[CH2:6][CH2:7][C:8](=[O:10])[NH:9]1
Reactant: COc1nc(/C(Br)=C/[C@H]2CCC(=O)N2)ccc1Cl
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: O=C1CC[C@H](/C=C(\Br)c2ccc(Cl)c(=O)[nH]2)N1
Temperature: 65 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
48% hydrobromic acid (2 mL) was added to a solution of (5R)-5-[(Z)-2-bromo-2-(5-chloro-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one (115 mg) in 1,4-dioxane (3 mL), and the mixture was stirred at 65° C. for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0→4:1) to give the title compound as a colorless powder (40 mg, 37%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:17])[C:8]([CH3:9])=[CH:7][CH2:6][CH:5]1[CH:10]([CH2:13][C:14]([CH3:16])=[CH2:15])[CH:11]=[O:12]>C(O)C>[CH3:3][C:4]1([CH3:17])[C:8]([CH3:9])=[CH:7][CH2:6][CH:5]1[CH:10]([CH2:13][C:14]([CH3:16])=[CH2:15])[CH2:11][OH:12]
Reactant: C=C(C)CC(C=O)C1CC=C(C)C1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C=C(C)CC(CO)C1CC=C(C)C1(C)C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 63.7 %

Procedure:
A 500 ml 3 neck flask was charged with 250 ml of ethanol and 6.0 g of sodium borohydride (0.16 mole). To the flask maintained at 0° C. in an ice bath was added dropwise 74.6 g of the aldehyde from example 1 at a purity of 84.3% (0.30 mole) in 100 ml of ethanol. The batch was stirred 45 minutes at 0° C. The reaction was now quenched by the addition of 50 ml of 25% hydrochloric acid at 0°-5° C. The mixture was poured onto 300 ml of brine and extracted with 3×100 ml of hexane. The hexane was washed with 2×250 ml of brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The batch was distilled through a 10 cm vigreaux column to afford 48 g of purified product (58% yield). BP 78° C./0.25 mmHg; 1H-NMR (300 MHz), δ 0.91 (3H, s), 1.09 (3H, s), 1.60 (3H, s), 1.77 (3H, s), 1.85-2.30 (71-1, m), 3.66 (2H, m), 4.80 (2H, s), 5.24 (1H, s); 13C-NMR (75 MHz), δ 12.90, 20.20, 22.76, 27.36, 34.07, 39.57, 40.61, 47.53, 50.32, 64.52, 112.63, 122.26, 146.38, 149.32; IR (Neat), 3370, 2960, 2940, 1650, 1040 cm-1 ; MS (m/e), 208 (M+), 95 (Base).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([O:18]C)=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1.CCN(CC)CC.[C:40](OC(=O)C)(=[O:42])[CH3:41]>ClCCl>[C:40]([NH:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[C:16]([OH:18])=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(CN)cc2c(=O)n1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc2c(-c3ccc(C)c(C)c3)c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c2c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 78.9 %

Procedure:
An ice cold solution of methyl 2-(7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-(tert-butoxy)acetate (25 mg, 0.057 mmol) in dichloromethane (DCM) (549 μl) was treated with Et3N (15.96 μl, 0.115 mmol) and acetic anhydride (8.11 μl, 0.086 mmol), and then stirred for 3 hours. The mixture was quenched with sat. NaHCO3, extracted with DCM, washed with brine, dried with Na2SO4, filtered, and concentrated. The residue was hydrolyzed in a manner similar to that described in Example 165 Step C and purified by reverse phase HPLC to afford 2-(7-(acetamidomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-(tert-butoxy)acetic acid (21.6 mg, 0.045 mmol, 85% yield) as an off-white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm, 8.37 (s, 1 H), 7.47 (t, J=7.3 Hz, 1 H), 7.39-7.29 (m, 1 H), 7.24 (d, J=7.2 Hz, 1 H), 7.13 (dd, J=8.4, 12.6 Hz, 1 H), 7.09-6.98 (m, 1 H), 6.11 (br. s., 1 H), 5.34 (s, 1 H), 4.63-4.45 (m, 2 H), 3.69 (s, 3 H), 2.36 (s, 3 H), 2.31 (s, 3 H), 2.05 (s, 3 H), 1.10-0.96 (m, 9 H); LCMS (m/z) ES+=465 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:18]([Cl:27])=[CH:17][N:16]=1)([CH3:4])([CH3:3])[CH3:2].[N:29]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)=[C:30]=[O:31].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:30](=[O:31])[NH:29][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:41])[F:40])[CH:33]=3)[CH2:23][CH2:22]2)[C:18]([Cl:27])=[CH:17][N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1Nc1ncc(Cl)c(N2CCNCC2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1Nc1ncc(Cl)c(N2CCN(C(=O)Nc3cccc(C(F)(F)F)c3)CC2)n1
Temperature: 23 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a solution of tert-butyl(2-((5-chloro-4-(piperazin-1-yl)pyrimidin-2-yl)amino)phenyl)carbamate (28 mg, 0.068 mmol) in DCM (0.7 mL) was added 1-isocyanato-3-(trifluoromethyl)benzene (0.011 mL, 0.082 mmol) and triethylamine (0.015 mL, 0.1 mmol) and the mixture was stirred at 23° C. for 16 h. reaction. The crude reaction mixture was loaded onto silica gel and purified using 0-50% EtOAc/Hexanes gradient to give the title compound (25 mg, 62%). MS (ES+) C27H29ClF3N7O3 requires: 591. found: 592 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14][CH2:15][CH3:16])[CH:8]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:32]1([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:39][C:40]([CH3:56])=[C:41]([CH2:43][CH2:44]OS(C3C=CC(C)=CC=3)(=O)=O)[N:42]=2)[CH:33]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:44][CH2:43][C:41]2[N:42]=[C:38]([C:34]3[CH:33]=[C:32]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[CH:37]=[CH:36][CH:35]=3)[O:39][C:40]=2[CH3:56])=[C:9]([CH2:14][CH2:15][CH3:16])[CH:8]=1)[CH3:2]
Reactant: CCCc1cc(CC(C)(Oc2ccccc2)C(=O)OCC)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(CC(C)(Oc2ccccc2)C(=O)OCC)ccc1OCCc1nc(-c2cccc(-c3ccccc3)c2)oc1C
Temperature: 55 °C
Yield: 52.2 %

Procedure:
A solution of 3-(4-hydroxy-3-propylphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (266 mg, 1.0 mmol) in DMF (10 mL) was treated with cesium carbonate (407 mg, 1.25 mmol) and toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethyl ester (520 mg, 1.20 mmol) (see Ex. 2, Part F) and then heated at 55° C. for 18 h. After cooling to ambient temperature, the mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and then the organic phases were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (100 mL SiO2, hexanes to 30% ethyl acetatelhexanes) to provide the desired product (315 mg, 60%) as a clear, colorless oil: 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.68–7.63 (m, 3H), 7.51 (t, J=7.6 Hz, 1H), 7.46 (t, J=8.0 Hz, 2H), 7.38 (t, J=7.2 Hz, 1H), 7.25–7.21 (m, 2H), 7.04–6.96 (m, 3H), 6.85–6.69 (m, 3H), 4.26 (t, J=6.4 Hz, 2H), 4.21 (q, J=6.8 Hz, 2H), 3.26 (A of AB, J=13.6 Hz, 1H), 3.09 (B of AB, J=13.6 Hz, 1H), 3.01 (t, J=6.4 Hz, 2H), 2.54 (t, J=7.6 Hz, 2H), 2.41 (s, 3H), 1.54 (sextet, J=7.6 Hz, 2H), 1.41 (s, 3H), 1.23 (t, J=6.8 Hz, 3H), 0.91 (t, J=7.2 Hz, 3H); MS (EI) 604.3 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:15])=[CH:6][C:7]([OH:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[C:1]([C:4]1[C:5]([O:15][CH2:1][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:13]=2)=[CH:6][C:7]([O:14][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)c(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C(C)=O)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 142.8 %

Procedure:
Methyl 5-acetyl-2,4-dihydroxybenzoate (2.62 g, 12.48 mmol) was dissolved in acetonitrile (40 ml), anhydrous potassium carbonate (4.93 g, 35.7 mmol) was added and the stirred mixture was treated with benzyl bromide (5.09 g, 29.75 mmol) and held at reflux for 3 hours. Upon cooling the solvent was removed in vacuo and the mixture partitioned between water and dichloromethane. The organic layer was separated and the solvent removed in vacuo to afford methyl 5-acetyl-2,4-bis-benzyloxybenzoate (3.48 g, 71%) as a colourless solid which was dried at 50° C. in a vacuum oven and used without further purification. 1H NMR (DMSO-d6) 8.21 (1H, s), 7.55 (4H, m), 7.43 (4H, m), 7.37 (2H, m), 7.04 (1H, s), 5.38 (4H, s), 3.79 (3H, s), 2.48 (3H, s). MS: [M+H]+ 391.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=1.[O:32]([C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45]O)[CH2:41][CH2:40]1)=[O:38])[C:33]([CH3:36])([CH3:35])[CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:33]([O:32][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][O:13][C:14]2[CH:15]=[C:16]([O:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
Diethyl azodicarboxylate (349 mg, 2.0 mmol) was added to a solution of 2-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (600 mg, 2.0 mmol), as prepared in the preceding step, N-tert-butoxylcarbonyl-4-piperidinemethanol (430 mg, 2.0 mmol), as prepared in step (b), and triphenylphosphine (525 mg, 2.0 mmol) in tetrahydrofuran (15 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 3 h. The reaction mixture was quenched with water (50 mL) and was extracted with ethyl acetate (3×50 mL). The organic phase was washed with saturated NaHCO3 (2×50 mL), brine (2×50 mL) and dried over Na2SO4. The solvent removed in vacuo and the residue was purified by flash column chromatography (2:1 ethyl acetate/hexane) to give the title compound as a colorless syrup (895 mg, 90%). 1H-NMR (300 MHz, CDCl3) δ 1.24 (m, 2 H), 1.47 (s, 9 H), 1.76 (d, 2 H, J=6.6 Hz), 1.89 (m, 1 H), 2.24 (s, 3 H), 2.72 (t, 2 H, J=2.4 Hz), 3.68 (d, 2 H, J=3.2 Hz), 4.13 (m, 2 H), 6.47 (t, 1 H, J=2.2 Hz), 6.52 (d, 1 H, J=0.7 Hz), 6.58 (d, 1 H, J=0.8 Hz), 7.38 (dd, 1 H, J=0.6, 0.8 Hz), 7.61 (m, 2 H), and 7.97 (dd, 1 H, J=0.8, 4.0 Hz).