Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NN>C1(C)C=CC=CC=1>[C:1]1([C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1CCC[C@@H]1c1ccccc1
Agent: NN
Solvent: Cc1ccccc1
Product: N[C@@H]1CCC[C@@H]1c1ccccc1
Yield: 99.9 %

Procedure:
Scheme IB, step C: A 1000 mL three necked flask equipped with a mechanical stirrer, thermometer, addition funnel and a reflux condenser is charged with (+,−) cis-2-(2-phenyl-cyclopentyl)-isoindole-1,3-dione (27.34 g, 93.91 mmol) and toluene (400.0 mL). To this solution was added anhydrous hydrazine (29.48 mL, 939.09 mmol) dropwise over a period of 15 minutes. Stirred reaction at room temperature for 60 minutes then heated it at 90° C.-95° C. for 6.0 hours. Cooled reaction to room temperature, filtered precipitates, washed cake with toluene (50.0 mL) and concentrated filtrate to provide the title compound as an oil (mass=15.13 g);
Reaction SMILES: [CH3:1][C:2]([CH:6]([OH:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:3][CH2:4][CH3:5].[CH2:13](Br)[CH:14]=[CH2:15]>>[CH2:15]([O:12][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:2]([CH3:1])=[CH:3][CH2:4][CH3:5])[CH:14]=[CH2:13]
Reactant: CCC=C(C)C(O)CCCCC
Reactant: C=CCBr
Product: C=CCOC(CCCCC)C(C)=CCC
Yield: 55.9 %

Procedure:
10 g of 4-methyl-3-decen-5-ol are reacted with 12.1 g of allyl bromide analogously to Example 7. After the usual working-up, there are obtained 6.9 g of 5-allyloxy-4-methyl-3-decene, boiling point 51° C./0.03 Torr, nD20 =1.4447, odour: fatty, fruity, green, quince.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1[C:4](Cl)=[N:5][OH:6].[C:13]([C:15]1[CH:16]=[C:17]([NH:21][CH2:22][CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[CH:18]=[CH:19][CH:20]=1)#[CH:14].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1[C:4]1[CH:14]=[C:13]([C:15]2[CH:16]=[C:17]([NH:21][CH2:22][CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[CH:18]=[CH:19][CH:20]=2)[O:6][N:5]=1
Reactant: C#Cc1cccc(NCCP(=O)(OCC)OCC)c1
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCNc1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1)OCC
Temperature: 25 °C
Yield: 89.2 %

Procedure:
2,6-Dichloro-N-hydroxybenzimidoyl chloride (370 mg, 1.6 mmol) and diethyl 2-(3-ethynylphenylamino)ethylphosphonate (450 mg, 1.6 mmol) were dissolved in anhydrous tetrahydrofuran (40 mL) and triethylamine (0.30 mL, 1.6 mmol). The mixture was then heated at reflux for 5 h. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by flash column chromatography on silica gel, eluting with 98:2 methylene chloride:methanol to give diethyl 2-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenylamino)ethylphosphonate (670 mg) as a pale yellow oil. 1H NMR (CDCl3): 7.30 (m, 2H), 7.21 (m, 1H), 7.15 (m, 1H), 7.05 (m, 1H), 7.00 (m, 1H), 6.59 (m, 1H), 6.48 (s, 1H), 4.03 (m, 4H), 3.40 (m, 2H), 2.00 (m, 2H), 1.24 ppm (m, 6H). MW=469 confirmed by LC-MS, tr=14.80 min (Method Y) MH+=467-472.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH3:12][O:13][CH2:14][CH2:15][CH2:16][NH2:17]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:17][CH2:16][CH2:15][CH2:14][O:13][CH3:12])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: COCCCN
Solvent: CS(C)=O
Solvent: O
Product: COCCCNc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To a 100 mL round bottom flask containing 5-bromo-2-chloro-3-nitropyridine (5.12 g, 21.6 mmol) in DMSO (20.5 mL) was added 3-methoxypropylamine (4.40 mL, 43.1 mmol) dropwise. The reaction was heated to 60° C. and monitored with TLC and LC-MS. After 2.5 h, LC-MS showed that the reaction was complete. The mixture was cooled to rt then diluted with water. After extracting three times with EtOAc, the organic layers were combined then washed with brine and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated in vacuo to give a light yellow brown solid as 5-bromo-N-(3-methoxypropyl)-3-nitropyridin-2-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.62 (1H, br. s.), 8.54 (1H, d, J=2.3 Hz), 8.43 (1H, d, J=2.3 Hz), 3.69-3.78 (2H, m), 3.56 (2H, t, J=5.7 Hz), 3.40 (3H, s), 1.96 (2H, dt, J=12.2, 6.2 Hz).
Reaction SMILES: [CH2:1]1[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[S:4][S:3][CH2:2]1.O[N:14]1C(=O)CCC1=O.C(Cl)CCl>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]1[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH2:14])=[O:12])[S:4][S:3][CH2:2]1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)CCCC[C@@H]1CCSS1

Procedure:
A solution of lipoic acid (25.6 g, 124 mmol), N-hydroxysuccinimide (15.6 g, 136 mmol), and EDC (26.1 g, 136 mmol) in anhydrous CH2Cl2 (300 mL) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (500 mL) and washed with H2O (500 mL), saturated aqueous NaHCO3 (500 mL), saturated aqueous NaCl (500 mL) and dried (MgSO4). The drying agent was removed by filtration and the filtrate was concentrated to dryness giving the product as a yellow sold (35.4 g, 94%).
Reaction SMILES: O[CH:2]([C:30]1[S:31][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:33][CH:34]=1)[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:15]=[C:14]([CH2:16][CH:17]([C:19]3[S:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:23]=3)O)[CH:13]=[CH:12][N:11]=2)[CH:5]=1>C1(C)C=CC=CC=1>[CH2:35]([C:32]1[S:31][C:30]([CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][N:7]=[C:6]([C:10]3[CH:15]=[C:14]([CH:16]=[CH:17][C:19]4[S:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:23]=4)[CH:13]=[CH:12][N:11]=3)[CH:5]=2)=[CH:34][CH:33]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCc1ccc(C(O)Cc2ccnc(-c3cc(CC(O)c4ccc(CCCCCC)s4)ccn3)c2)s1
Solvent: Cc1ccccc1
Product: CCCCCCc1ccc(C=Cc2ccnc(-c3cc(C=Cc4ccc(CCCCCC)s4)ccn3)c2)s1
Reaction time: 4 h
Yield: 85.3 %

Procedure:
4,4′-bis[2-hydroxy-2-(5-hexyl-2-thienyl)ethyl]-2,2′-b ipyridine (1.5 g) was dissolved in 110 g of toluene containing pyridindium p-toluenesulfonate (0.2 g) and reflux was performed for 4 hours using a Dean-Starc device. The solvent was distilled off under reduced pressure, and a residue was dissolved in methylene chloride and washed with a saturated solution of sodium bicarbonate. An organic layer was washed with anhydrous magnesium sulfate and distilled to obtain 1.2 g of a yellow-colored product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)=[CH:5][CH:4]=1.[H-].[Li+].[CH2:23](Br)[CH:24]=[CH2:25]>>[CH2:25]([N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:7][C:6]1[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: COc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Agent: [H-]
Agent: [Li+]
Product: C=CCn1c(=Nc2ccc(OC)cc2)sc2ncccc2c1=O

Procedure:
The reaction procedure of Example 11 was followed except that 428 mg of 2-(4-methoxyanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 14 mg of lithium hydride and 0.13 ml of allyl bromide were used. As a result, 213 mg of 3-allyl-2-[(4-methoxyphenyl)imino]-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a low polarity substance, and 85 mg of 2-[N-allyl-N-(4-methoxyphenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a high polarity substance.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[CH2:1]([O:8][C@H:9]([C@H:15]([C@H:14]([C@@H:13]([CH2:32][O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[OH:12])[O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Reaction time: 8 h
Yield: 90.3 %

Procedure:
2,3,4,6-Tetra-O-benzyl-D-galactopyranose (107 g) was dissolved in ethanol (0.6 L) and, whilst stiffing at 0° C., sodium borohydride (31 g) was added. After stiffing overnight TLC analysis indicated completion of the reaction. The ethanol solution was partitioned between water (3 L) and ether (1.5 L). The organic phase was dried (Na2SO4), filtered and concentrated. The resulting oil was purified by flash chromatography (gradient elution using 20→50% ethyl acetate/petroleum ether) and then crystallised from a mixture of ethyl acetate/petroleum ether to give 2,3,4,6-tetra-O-benzyl-D-galactitol (97 g, 91%) as a white solid. 1H NMR (CDCl3): δ 2.4 (1H, bs), 3.35 (1H, bs), 3.55 (2H, m), 3.8 (3H, m), 3.9 (2H, m), 4.1 (1H, m), 4.4-4.8 (8H, m, OCH2Ph), 7.2-7.4 (20H, m, ArH). Mass spectrum: m/z 543 (M+H)+565 (M+Na)+.
Reaction SMILES: C1(O)C=CC=CC=1.C1(S)C=CC=CC=1.C[O:16][C:17]1[CH:22]=[C:21]([C:23]2[CH:24]=[N:25][NH:26][CH:27]=2)[CH:20]=[CH:19][C:18]=1[C:28]1[N:29]=[N:30][C:31]([O:34][CH:35]2[CH2:40][C:39]([CH3:42])([CH3:41])[NH:38][C:37]([CH3:44])([CH3:43])[CH2:36]2)=[CH:32][CH:33]=1.C([O-])([O-])=O.[K+].[K+].[ClH:51].O1CCOCC1>CN1C(=O)CCC1>[ClH:51].[NH:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[CH:19][C:18]([C:28]3[N:29]=[N:30][C:31]([O:34][CH:35]4[CH2:40][C:39]([CH3:42])([CH3:41])[NH:38][C:37]([CH3:44])([CH3:43])[CH2:36]4)=[CH:32][CH:33]=3)=[C:17]([OH:16])[CH:22]=2)[CH:24]=[N:25]1
Reactant: COc1cc(-c2cn[nH]c2)ccc1-c1ccc(OC2CC(C)(C)NC(C)(C)C2)nn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Solvent: CN1CCCC1=O
Solvent: Oc1ccccc1
Solvent: C1COCCO1
Product: CC1(C)CC(Oc2ccc(-c3ccc(-c4cn[nH]c4)cc3O)nn2)CC(C)(C)N1
Reaction time: 18 h
Yield: 9 %

Procedure:
Following GENERAL METHOD 3-1 for phenol deprotection using thiophenol, 3-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine (0.58 mg, 1.41 mmol) was treated with thiophenol (0.15 mg, 1.36 mmol) and K2CO3 (0.23 mg, 1.64 mmol) in NMP (9 mL) for 15 min at 190° C. After purification (0.1% trifluoroacetic acid as modifier), desired fractions were free based by catch and release using SiliaBond Propylsulfonic Acid® (5 g, MeOH as eluent and a 2 N ammonia solution in MeOH to release the material). The solvent was evaporated under reduced pressure. The resulting beige solid was dissolved in CH3CN/H2O/MeOH (6/1/6 mL) and SiliaMetS® DMT (2.7 g, 1.4 mmol) was added and the mixture was shaken 18 h. The mixture was then filtered through a small celite plug and the filtrate was purified by catch and release using SiliaBond Propylsulfonic Acid® (5 g, MeOH as eluent and a 2 N ammonia solution in MeOH to release the material). The solvent was concentrated in vacuo and the resulting solid was suspended in CH3CN/H2O (4/1 mL). 4 N HCl in 1,4-dioxane (4 equivalents) was added and solvent was concentrated in vacuo to afford a yellow solid (59 mg, 9%). LCMS RT=0.51 min (LCMS method Q); [M+H]: 394.2225; 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J=12.0 Hz, 1H), 8.49 (d, J=9.5 Hz, 1H), 8.36 (d, J=12.0 Hz, 1H), 8.16 (s, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.47 (d, J=9.5 Hz, 1H), 7.21-7.28 (m, 2H), 5.63-5.87 (m, 1H), 2.34 (dd, J=13.0, 4.0 Hz, 2H), 1.81 (dd, J=13.0, 10.5 Hz, 2H), 1.53 (s, 6H), 1.50 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:27]([C:28]#[C:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=[CH:24][C:19]=3[C:20]([O:22][CH3:23])=[O:21])[CH:8]=2)[N:3]=1>C(O)C.CCOC(C)=O.[Pd]>[NH2:1][C:2]1[C:11]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:27]([CH2:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=[CH:24][C:19]=3[C:20]([O:22][CH3:23])=[O:21])[CH:8]=2)[N:3]=1
Reactant: COC(=O)c1cccc(C#CC(C)(C)C)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1cccc(CCC(C)(C)C)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(2-amino-3-morpholinoquinolin-6-yl)-3-(3,3-dimethylbut-1-ynyl)benzoate (655 mg, 1.477 mmol) in ethanol (30 mL) and EtOAc (5 mL) was added palladium on activated carbon (10% wt., 400 mg). The reaction mixture was evacuated and backfilled with nitrogen gas. The reaction mixture was evacuated and backfilled with hydrogen gas. The reaction mixture was allowed to stir overnight at RT. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated. Ethanol (10 mL) and palladium on activated carbon (10% wt., 500 mg) were added. The reaction mixture was evacuated and backfilled with hydrogen and allowed to stir overnight at RT. The reaction mixture was filtered through a pad of celite. The solvent was removed under reduced pressure and methyl 2-(2-amino-3-morpholinoquinolin-6-yl)-3-(3,3-dimethylbutyl)benzoate was obtained as a yellow-tan residue and used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:16])=[C:13]([CH3:23])[NH:12][C:11]([CH3:24])=[C:10]1[C:25]([O:27]CCC#N)=[O:26].[OH-].[Na+]>COCCOC>[CH:18]1([O:17][C:15]([C:14]2[CH:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:10]([C:25]([OH:27])=[O:26])=[C:11]([CH3:24])[NH:12][C:13]=2[CH3:23])=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC1=C(C(=O)OCCC#N)C(c2c(F)cccc2Cl)C(C(=O)OC2CCCC2)=C(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CC1=C(C(=O)O)C(c2c(F)cccc2Cl)C(C(=O)OC2CCCC2)=C(C)N1

Procedure:
98 g (0.22 mol) of 2-cyanoethyl cyclopentyl 4-(2-chloro-6-fluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate are dissolved in 400 ml of 1,2-dimethoxyethane and the solution is stirred with 400 ml of 1 N sodium hydroxide solution at room temperature overnight.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:10]([O:12][C:13](=[O:29])[CH2:14][C@H:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27]Br)=[CH:21][CH:22]=2)[CH2:17][CH2:16]1)[CH3:11].[NH4+].[Cl-]>CN(C=O)C>[NH:1]([CH2:27][CH2:26][CH2:25][O:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[C@H:15]([CH2:14][C:13]([O:12][CH2:10][CH3:11])=[O:29])[CH2:16][CH2:17]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCBr)ccc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3ccccc3)ccc21
Reaction time: 0.33 h
Yield: 8.5 %

Procedure:
To a solution of aniline (273 mg, 2.93 mmol) in DMF (4 mL) under argon was added sodium hydride (117 mg, 2.93 mmol, 60% dispersion in mineral oil), and the mixture was stirred under argon for 20 min. A solution of ethyl [(1S)5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 45, 500 mg, 1.47 mmol) in DMF (4 mL) was added and the reaction mixture was stirred for 24 h at rt. A saturated aqueous NH4Cl solution was added, and the solvents were evaporated under vacuum. The residue was suspended in EtOAc and filtered through a small silica gel plug. The filtrate was concentrated under reduced pressure and then purified by silica gel chromatography (5-10% EtOAc in hex) to give the title compound (44 mg, 9%) as an oil containing minor impurities. 1H NMR (400 MHz, CDCl3): δ 7.11-6.92 (m, 3H), 6.68-6.48 (m, 5H), 4.12-3.93 (m, 4H), 3.50-3.37 (br, 1H), 3.22 (t, 2H), 2.85-2.68 (m, 2H), 2.62 (dd, 1H), 2.38-2.23 (m, 2H), 2.04-1.96 (m, 2H), 1.72-1.60 (m, 1H), 1.08 (t, 3H).
Reaction SMILES: S1(CCCC1)(=O)=O.[F:8][C@@H:9]1[CH2:13][NH:12][CH2:11][C@H:10]1[NH:14][C:15](=[O:22])[CH2:16][CH2:17]S(C)(=O)=O.F[C:24]1[N:32]=[C:31]2[C:27]([N:28]=[CH:29][N:30]2[CH3:33])=[C:26]([NH:34][C:35]2[C:36]([O:41][CH3:42])=[N:37][N:38]([CH3:40])[CH:39]=2)[N:25]=1.C(N(CC)C(C)C)(C)C.[OH-].[K+]>O>[F:8][C@@H:9]1[CH2:13][N:12]([C:24]2[N:32]=[C:31]3[C:27]([N:28]=[CH:29][N:30]3[CH3:33])=[C:26]([NH:34][C:35]3[C:36]([O:41][CH3:42])=[N:37][N:38]([CH3:40])[CH:39]=3)[N:25]=2)[CH2:11][C@H:10]1[NH:14][C:15](=[O:22])[CH:16]=[CH2:17]
Reactant: CS(=O)(=O)CCC(=O)N[C@@H]1CNC[C@H]1F
Reactant: COc1nn(C)cc1Nc1nc(F)nc2c1ncn2C
Agent: [K+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: C=CC(=O)N[C@@H]1CN(c2nc(Nc3cn(C)nc3OC)c3ncn(C)c3n2)C[C@H]1F
Temperature: 40 °C
Reaction time: 12 h
Yield: 58.9 %

Procedure:
To a 200 L Hastelloy reactor heated to 40° C. was added sulfolane (22.4 L) and N-((3R,4R)-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide (4.03 kg, 16.9 mol, 1.05 eq) and stirred the resulting mixture until all solids were dissolved. To this solution was added 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-amine (4.47 kg, 16.1 mol, 1.00 eq) and N,N-diisopropylethylamine (8.50 L, 48.7 mol, 3.0 eq) and the mixture heated at 115° C. for 16 hr. The reaction mixture was cooled to 30° C., and a solution of potassium hydroxide (2.26 kg, 40.3 mol, 2.5 eq) in water (44.7 L) was added. After stirring for 4 hr, the reaction mixture was cooled to 20° C., water (44.7 L) was added and the resulting mixture granulated for 12 hr. The crude product was isolated on a Nutsche filter and washed with water (27 L) and then dried under nitrogen on the filter. The reactor was cleaned and then charged with water (35.8 L) and acetone (53.6 L). The crude product cake was charged back into the reactor and heated to 60° C. until all of the solids had dissolved. The batch was then cooled to 40° C. and then transferred into a speck free 100 L reactor via an in-line 10 μm filter. The 200 L reactor, line and filter were rinsed with acetone (5 L) and sent into the 100 L reactor. The batch was concentrated with the jacket temperature set at 70° C. under partial vacuum until the acetone content reduced to 5 wt %, as determined by gas chromatography head space. The batch was then cooled to 20° C. and granulated for 4 hr. The product was filtered, washed with water (18 L) and dried in a vacuum oven at 55° C. for 8 hr. The title compound (3.942 kg, 9.49 mol, 59%) was isolated as a white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (d, J=6.5 Hz, 1 H) 7.97 (s, 1 H) 7.82 (s, 1 H) 7.78 (s, 1 H) 6.23 (dd, J=10.0, 17.0 Hz, 1 H) 6.14 (dd, J=2.8, 17.0 Hz, 1 H) 5.62 (dd, J=2.8, 10.0 Hz, 1 H) 5.12 (d, J=51.0 Hz, 1 H) 4.46 (td, J=6.0, 11.9 Hz, 1 H) 3.88-3.6 (m, 4 H) 3.82 (s, 3 H) 3.71 (s, 3 H) 3.62 (s, 3 H). m/z (APCI+) for C18H23FN9O2 416.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15]([O:17]C)=[O:16])[CH2:12][CH2:11][N:10]1[C:19]([O:21][CH3:22])=[O:20].C(#N)C.[Br-].[Li+].CCN(CC)CC>CC(OC)(C)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][CH2:11][N:10]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccc(F)cc2F)C1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC#N
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccc(F)cc1F

Procedure:
Dimethyl 2-(2,4-difluorophenyl)piperidine-1,4-dicarboxylate (2.38 g, 7.60 mmol) was dissolved into acetonitrile (35 mL) and water (0.700 mL), then lithium bromide (5.28 g, 60.77 mmol) was added. Et3N (4.24 mL, 30.39 mmol) was added and the resulting yellow suspension was heated under reflux for 2 h. Water (50 mL) and MTBE (150 mL) were added. The phases were separated and the organic layer was extracted with water (2 times). The pooled water layers were acidified to pH 1 with 3.8 M HCl and extracted with MTBE (2 times). The combined organic layer was dried over Na2SO4, filtered and evaporated yielding 2-(2,4-difluorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (2.27, quant.) as a slightly yellow semi-solid. MS m/z 300 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:22]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:22]=[C:21]([O:20][CH3:19])[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1cc(OC)cc(B2OC(C)(C)C(C)(C)O2)c1
Product: CCCNC(=O)c1nnc2c(-c3cc(OC)cc(OC)c3)cccc2c1N
Yield: 91 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 2-(3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-(1,3,2)-dioxaborolane (256 mg, 0.97 mmol) were reacted to afford the title compound (110 mg, 93.9% yield) as an off-white solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:23])([F:22])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)=[CH:7][CH:6]=1.Br[CH2:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32]C(C)(C)C)=[O:31])=[CH:28][CH:27]=1.Cl.O1CCOCC1>CN(C)C=O.CC#N.O>[O:21]=[C:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:4]([F:3])([F:22])[F:23])=[CH:10][CH:9]=3)[CH:12]=2)[N:17]1[CH2:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: O=C1CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(CN2C(=O)CCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)cc1
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
To a mixture of 95% dry sodium hydride (12 mg, 0.50 mmol) in anhydrous N,N-dimethylformamide (4 mL) at room temperature was added a solution of 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one (78 mg, 0.30 mmol) (PT-010 made as in Example 1B, above) in anhydrous N,N-dimethylformamide (1 mL). The reaction mixture was stirred for 30 minutes under an atmosphere of dry N2, followed by addition of a solution of tert-butyl 4-(bromomethyl)benzoate (271 mg, 1.00 mmol) in N,N-dimethylformamide (1.0 mL). The reaction mixture was stirred at room temperature until the majority of the starting material was converted (checked by LCMS), then it was quenched by addition of methanol (5 mL). The reaction mixture was concentrated under reduced pressure, anhydrous toluene (10 mL) was added, and the solvent removed under reduced pressure. To this crude product (tert-butyl 4-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoate) was added 4N hydrochloric acid in 1,4-dioxane (10 mL, 40 mmol). The reaction mixture was stirred at room temperature for 4 hours, and the solvent removed under reduced pressure. A second portion of 4N hydrochloric acid in 1,4-dioxane (10 mL, 40 mmol) was added with stirring at room temperature for another 13 hours, the solvent removed under reduced pressure. The crude reaction product was subjected to reverse phase HPLC with a gradient of MeCN/H2O (2% to 98%) to afford 4-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoic acid (70 mg, 0.16 mmol, 53%) (PT-088). LCMS mz 488.0 (M+H), 510.0 (M+Na), anal HPLC >98% in purity. 1H NMR (400 MHz; DMSO-d6) δ 7.90 (d, J=8.2 Hz, 2H); 7.86 (d, J=8.2 Hz, 2H); 7.78 (d, J=8.2 Hz, 2H); 7.68 (d, J=2.1 Hz, 1H); 7.53 (dd, J=8.3 and 2.1 Hz, 1H); 7.38 (d, J=8.2 Hz, 2H); 7.00 (d, J=8.6 Hz, 1H); 5.27 (s, 2H); 3.08 (m, 2H), 2.79 (m, 2H).