Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)C[C:5](=[O:34])[N:6]([CH2:9][C:10]1[CH:15]=[C:14]([C:16](=[O:22])[NH:17][O:18][CH2:19][CH2:20][OH:21])[C:13]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:12]([F:32])[C:11]=1[F:33])[O:7][CH3:8].[CH3:36][O-:37].[Na+]>CO.[Cl-].[NH4+]>[F:32][C:12]1[C:13]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:14]([CH:15]=[C:10]([CH2:9][N:6]([C:5](=[O:34])[CH2:36][OH:37])[O:7][CH3:8])[C:11]=1[F:33])[C:16]([NH:17][O:18][CH2:19][CH2:20][OH:21])=[O:22]
Reactant: C[O-]
Reactant: COC(=O)CC(=O)N(Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F)OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CON(Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F)C(=O)CO
Reaction time: 2 h
Yield: 44.5 %

Procedure:
To a solution of acetoxyacetic acid (13.9 mg, 0.12 mmol) in methylene chloride (1 ml) were added 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (18.9 mg, 0.12 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.5 mg, 0.12 mmol), and the mixture was stirred for 3 hours. This solution was added dropwise to a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-benzamide (50.0 mg, 0.10 mmol) obtained in Example 15 in THF (2 ml), and triethylamine (40.9 μl, 0.29 mmol) was added thereto. The mixture was stirred for 24 hours. The reaction mixture was diluted with ethyl acetate (45 ml), and washed with saturated aqueous ammonium chloride (20 ml), and then with saturated brine (2×20 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue was roughly purified by preparative TLC (CH2Cl2/MeOH (10:1)) to give {[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-benzyl]-methoxy-carbamoyl}acetic acid methyl ester (14.0 mg, containing impurities) as a colorless oil. To a solution of the resultant {[2,3-difluoro-4-(2-fluoro-4-iodo-phenylamino)-5-(2-hydroxy-ethoxycarbamoyl)-benzyl]-methoxy-carbamoyl}acetic acid methyl ester (14.0 mg, containing impurities) in methanol (1 ml) was added sodium methoxide (3.0 mg, 0.06 mmol), and the mixture was stirred for 2 hours. The reaction mixture was diluted with saturated ammonium chloride, and extracted with methylene chloride (30 ml and 15 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue was purified by preparative TLC (CH2Cl2/MeOH (10:1)) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-{[(2-hydroxy-acetyl)-methoxy-amino]-methyl}-N-(2-hydroxy-ethoxy)-benzamide (F-5, 5.8 mg, 12% for 2 steps) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2=[CH:8][C:9]3[C:14]([N:6]2[CH2:5][CH2:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=[CH:11][CH:10]=3.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22].CN(C)C(N(C)C)=N.Cl>C(#N)C.O>[CH2:18]([O:17][C:15]([C:3]1([CH2:22][CH2:21][C:20]([O:24][CH3:25])=[O:23])[CH2:4][CH2:5][N:6]2[C:14]3[C:9]([CH:8]=[C:7]2[C:2]1=[O:1])=[CH:10][CH:11]=[CH:12][CH:13]=3)=[O:16])[CH3:19]
Reactant: C=CC(=O)OC
Reactant: CCOC(=O)C1=C(O)c2cc3ccccc3n2CC1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1(CCC(=O)OC)CCn2c(cc3ccccc32)C1=O
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A mixture of 5 g of ethyl 6,7-dihydro-9-hydroxypyrido[1,2-a]indole-8-carboxylate. 1.85 g of methyl acrylate and 250 mg of 1,1,3,3-tetramethylguanidine was dissolved in 250 ml of acetonitrile and the solution was stirred overnight, poured into 500 ml of water containing 20 ml of 2M hydrochloric acid and extracted with diethyl ether. The ethereal extracts were washed with water, dried and concentrated. There were obtained 6.33 g of methyl 8-(ethoxycarbonyl)-6,7,8,9-tetrahydro-9-oxopyrido[1,2-a]indole-8-propionate.
Reaction SMILES: [CH2:1](Cl)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I-].[K+]>Cl>[C:9]1([NH:8][CH2:1][CH:2]2[CH2:3][CH2:4][CH2:5][O:6]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCC1CCCO1
Reactant: Nc1ccccc1
Agent: Cl
Agent: [I-]
Agent: [K+]
Product: c1ccc(NCC2CCCO2)cc1
Temperature: 130 °C
Yield: 4.3 %

Procedure:
A mixture of tetrahydrofurfuryl chloride (100 g, 0.829 mol), aniline (2.09 g, 2.25 mol) and potassium iodide (1.0 g) was heated at 130° C. under nitrogen for 36 hours and cooled to room temperature. A 3N hydrochloric acid solution (400 mL) was added and the solution was washed several times with isopropyl ether and made basic with a 50% sodium hydroxide solution. The product was extracted three times into isopropyl ether, washed twice with water and once with a saturated sodium chloride solution, dried (sodium sulfate), filtered and evaporated to a liquid that was added to water (3L) and extracted into three portions of isopropyl ether. The combined extracts were washed twice with water and once with a saturated sodium chloride solution, dried (magnesium sulfate), treated with charcoal, filtered and evaporated under reduced pressure to a liquid (91.4 g). A 6.0 g portion was dissolved in isopropanol and a solution of oxalic acid (3.1 g) in isopropanol was added. The resulting solid was collected by filtration and rinsed with isopropyl ether to give 6.3 g of solid. A 1.5 g portion was recrystallized from isopropanol/isopropyl ether/light pet ether to give a solid that was removed by filtration. A second crop of crystals was obtained from the filtrate, dried under high vacuum at 60° C. to give 0.31 g, mp 149°-156° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=2)=[C:13]([F:18])[CH:12]=1
Reactant: Cc1cc(Br)cc(C)n1
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccc(Br)cc2F)cc(C)n1
Temperature: 150 °C
Yield: 80 %

Procedure:
A mixture of 4-bromo-2,6-dimethyl-pyridine (1 g, 5.4 mmol), 4-bromo-2-fluoro-phenol (0.59 g, 5.4 mmol), and potassium carbonate (0.89 g, 6.4 mmol) in xylenes (2 ml) was heated at 150° C. (oil bath temperature) in a sealed tube for 48 hours. After cooling to room temperature the mixture was diluted with EtOAc and filtered through a diatomaceous earth pad. The filtrate was evaporated till dryness and the crude product thus obtained was purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 10% as eluent). The desired fractions were collected and evaporated vacuo to yield intermediate 19 (1.28 g, 80%).
Reaction SMILES: Cl[C:2]([C@:4]12[CH2:39][CH2:38][C@@H:37]([CH:40]([CH3:42])[CH3:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C@@H:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)=[O:3].[NH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1>ClCCCl.CN(C1C=CN=CC=1)C.O>[CH:40]([C@H:37]1[C@@H:5]2[C@@H:6]3[C@@:19]([CH3:22])([CH2:20][CH2:21][C@@:4]2([C:2](=[O:3])[NH:43][CH2:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)[CH2:39][CH2:38]1)[C@@:18]1([CH3:23])[C@@H:9]([C@:10]2([CH3:36])[C@@H:15]([CH2:16][CH2:17]1)[C:14]([CH3:25])([CH3:24])[C@@H:13]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)[CH2:12][CH2:11]2)[CH2:8][CH2:7]3)([CH3:42])[CH3:41]
Reactant: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)Cl)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Reactant: NCCc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)NCCc6ccccn6)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 70 %

Procedure:
To a flask containing methyl 4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-(chlorocarbonyl)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (77 mg, 0.13 mmol) in DCE (2 mL) was added Hunig'sBase (0.068 mL, 0.390 mmol), DMAP (1 mg, 8.19 μmol), and 2-(2-Aminoethyl)pyridine (0.031 mL, 0.260 mmol). The mixture was stirred for 2.5 hours at rt. The reaction was diluted with 5 mL of water and was extracted with dichloromethane (3×5 mL). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by Biotage flash chromatography using a 0-75% ethyl acetate in hexanes gradient. The fractions containing the expected product were combined and concentrated. The expected product, methyl 4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3a-(2-(pyridin-2-yl)ethylcarbamoyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.062 g, 0.091 mmol, 70.0% yield), was isolated as a white foam. LCMS: m/e 679.7 (M−H)−, 3.09 min (method 3).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@@H:13]([CH3:41])[CH2:14][N:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]2[CH:32]=[CH:31][N:30]3[N:33]=[CH:34][C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:29]3[N:28]=2)[C:16]1=[O:40].NN>CO.C1COCC1>[NH2:3][CH2:12][C@@H:13]([CH3:41])[CH2:14][N:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]2[CH:32]=[CH:31][N:30]3[N:33]=[CH:34][C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:29]3[N:28]=2)[C:16]1=[O:40]
Reactant: COC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cn(C[C@H](C)CN4C(=O)c5ccccc5C4=O)c3=O)nc12
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cn(C[C@H](C)CN)c3=O)nc12
Temperature: 50 °C
Reaction time: 14 h
Yield: 77 %

Procedure:
To a solution of methyl 5-((R)-2-(1-((S)-3-(1,3-dioxoisoindolin-2-yl)-2-methylpropyl)-5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (110 mg, 0.197 mmol) in MeOH/THF (3 mL/3 mL) was added hydrazine (31.6 mg, 0.985 mmol). The reaction was stirred for 14 hours at 50° C. After cooling, the reaction mixture was concentrated and the resulting residue was diluted with EtOAc (20 mL) and washed with saturated aqueous NaHCO3 (5 mL), water (2×5 mL) and brine (5 mL). The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography, eluting with EtOAc/MeOH/NH4OH 10:1:0.1 to give the desired product (65 mg, 77% yield). MS (apci) m/z=429.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][CH:8]2[CH2:24][N:12]3[CH2:13][CH2:14][N:15]([C:17]4[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=4)[CH2:16][CH:11]3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][CH:8]2[CH2:24][N:12]3[CH2:13][CH2:14][N:15]([C:17]4[N:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH2:16][CH:11]3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Fc1ccc(OCC2CCC3CN(c4ccc(Cl)nn4)CCN3C2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Fc1ccc(OCC2CCC3CN(c4cccnn4)CCN3C2)cc1

Procedure:
A mixture of 0.150 g (0.363 mmol) of (7RS,9aSR)-7-(4-fluorophenoxy)methyl-2-(6-chloropyridazin-3-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Example 32). 0.10 mL (0.72 mmol) of triethylamine, and 20 mg of 10% Pd/C in 10 mL of ethanol were shaken under 50 psi of hydrogen for 18 h. The mixture was filtered through Celite and the filtrate was evaporated. The residue was dissolved in chloroform, washed with water, dried (magenesium sulfate), filtered and evaporated. mp (.HCl) 246–250° C. HRMS calcd for C19H23FN4O: 342.1851, found: 342.1826.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1>>[CH2:1]([N:8]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[CH:12][C:11]=1[Br:20])[C:24]([CH:21]1[CH2:23][CH2:22]1)=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(Br)c(CNCc2ccccc2)c1
Reactant: O=C(Cl)C1CC1
Product: O=C(C1CC1)N(Cc1ccccc1)Cc1cc(C(F)(F)F)ccc1Br

Procedure:
Benzyl-(2-bromo-5-trifluoromethyl-benzyl)-amine and cyclopropanecarbonyl chloride were reacted as described in Example 11, Step 2 to provide cyclopropanecarboxylic acid benzyl-(2-bromo-5-trifluoromethyl-benzyl)-amide.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:10][C:9](=[O:23])[C:7]=2[N:8]=1.C[O-].[Na+].[C:27](O)(=[O:29])C>CO>[CH3:27][O:29][C:3]1[N:4]=[N:5][C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:10][C:9](=[O:23])[C:7]=2[N:8]=1
Reactant: CCCOc1ccccc1-c1nc2nnc(SC)nc2c(=O)[nH]1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCOc1ccccc1-c1nc2nnc(OC)nc2c(=O)[nH]1

Procedure:
A stirred mixture of 5,6-dihydro-3-methylthio-5-oxo-7-(2-propoxyphenyl)pyrimido[5,4-e][1,2,4]triazine (0.80 g) and sodium methoxide (prepared from sodium, 0.28 g and methanol) in methanol (50 ml) was heated under reflux for 1.5 hours. The cooled reaction mixture was neutralized by th e addition of glacial acetic acid (0.7 ml) to afford a yellow precipitate (0.63 g) which was recrystallized from methanol to afford the title compound, 0.47 g, m.p. 221-222° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:53]=[CH:52][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][OH:51])[CH2:45][CH2:44]2)=[O:41])=[CH:38][C:37]=1[O:54][CH3:55]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:53]=[CH:52][C:39]([C:40]([NH:42][CH:43]5[CH2:44][CH2:45][N:46]([CH2:49][CH2:50][OH:51])[CH2:47][CH2:48]5)=[O:41])=[CH:38][C:37]=4[O:54][CH3:55])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)NC2CCN(CCO)CC2)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(CCO)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Yield: 20 %

Procedure:
A mixture of 0.112 g (0.34 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.097 g (0.51 mmole) of toluenesulfonic acid monohydrate, 0.10 g (0.34 mmole) of 4-amino-N-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-3-methoxy-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 170 degrees in a microwave reactor for 2 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was by preparative thin layer chromatography, eluting with dichloromethane-methanol (90:10) to give 0.040 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-3-methoxy-benzamide (I-267).
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].CCN=C=NCCCN(C)C.Cl.[CH3:21][O:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][O:28][CH3:29]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:21][O:22][CH2:23][CH2:24][N:25]([CH2:26][CH2:27][O:28][CH3:29])[C:1](=[O:8])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: C#CCCCC(=O)O
Reactant: COCCNCCOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C#CCCCC(=O)N(CCOC)CCOC
Temperature: 25 °C

Procedure:
To a solution of hex-5-ynoic acid (7.11 g, 63.4 mmol), EDC.HCl (14.0 g, 72.9 mmol) and DMAP (387 mg, 3.17 mmol) in DCM (600 mL) at 0° C. was added bis(2-methoxyethyl)amine (9.3 mL, 63 mmol). The resulting mixture was warmed to RT for 20 hr and was then washed with hydrochloric acid (1 M, 2×500 mL) and water (500 mL). The organic layer was dried and evaporated in vacuo to afford the title compound, Intermediate B, as a yellow oil (16 g, 97%): 1H NMR (400 MHz, CDCl3) δ: 1.88 (3H, m), 2.26 (2H, m), 2.49 (2H, m), 3.32 (6H, s), 3.51 (4H, m), 3.55 (4H, m)
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH:25]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([N:30]3[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]3)[CH:25]=2)[C:11]=1[CH3:12]
Reactant: CC1(C)OB(c2ccnc(N3CCNCC3)c2)OC1(C)C
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccnc(N3CCNCC3)c2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.5 g, 2.0 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (0.641 g, 2.22 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.0 mmol) in toluene (4.0 mL) at 100° C. for 23 h to give 4-chloro-5,7-difluoro-3-methyl-2-(2-(piperazin-1-yl)pyridin-4-yl)quinoline as a yellow solid. Mass Spectrum (ESI) m/e=375.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([Cl:18])=[CH:13][CH:14]=3)[N:9]([CH2:19][C:20]([O:22]CC)=[O:21])[C:8]2=[O:25])=[C:4]([F:28])[CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([Cl:18])=[CH:13][CH:14]=3)[N:9]([CH2:19][C:20]([OH:22])=[O:21])[C:8]2=[O:25])=[C:4]([F:28])[CH:3]=1
Reactant: CCOC(=O)Cn1c(=O)n(Cc2ccc(Br)cc2F)c(=O)c2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1c(=O)n(Cc2ccc(Br)cc2F)c(=O)c2ccc(Cl)cc21
Yield: 84.6 %

Procedure:
A mixture of ethyl 2-[3-(4-bromo-2-fluorobenzyl)-7-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl]acetate (249 g) and 1N aqueous sodium hydroxide (795 ml) in methanol (1.6 l) was refluxed for 30 minutes with stirring. The solvent was evaporated and the residue was dissolved in hot water (5 l). The aqueous solution was poured into ice-cold 0.5N hydrochloric acid (3 l). The precipitates were collected by filtration and recrystallized from a mixture of ethanol (6 l) and water (3 l) to give 2-[3-(4-bromo-2-fluorobenzyl)-7-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl]acetic acid (198 g).
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1(C)C=CC=CC=1.[N+]([O-])([O-])=O.[Ag+:36]>O>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Ag+:36]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of 54.4 g of behenic acid dissolved into 1200 ml of toluene were added 2400 ml of water, and the mixture liquid was homogenized by a high-speed homogenizer. To this solution, with stirring, were added dropwise spending about 30 minutes 400 ml of an aqueous ammoniacal silver nitrate solution containing 27.7 g of silver nitrate, with keeping the temperature of the reaction liquid at 60° C. The stirring was further continued for another 30 minutes. The resulting crystals were filtrated, washed with water, washed with methanol, and then dried under reduced pressure, whereby 65.0 g of silver behenate were obtained.
Reaction SMILES: F[C:2]1[N:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([O:17][CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][N:20]2[CH3:24])[CH:8]=1)=[O:5].C(O)(C(F)(F)F)=O.[NH2:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]2[C:38]=1[CH2:39][NH:40][C:41]2=[O:46].Cl.[OH-].[Na+]>C(O)(C)(C)C>[CH3:24][N:20]1[CH2:21][CH2:22][CH2:23][C@@H:19]1[CH2:18][O:17][C:9]1[CH:8]=[C:7]([NH:6][C:4]([C:3]2[C:2]([NH:36][C:37]3[CH:45]=[CH:44][CH:43]=[C:42]4[C:38]=3[CH2:39][NH:40][C:41]4=[O:46])=[N:28][CH:27]=[CH:26][CH:25]=2)=[O:5])[CH:12]=[CH:11][C:10]=1[C:13]([F:16])([F:15])[F:14]
Reactant: Nc1cccc2c1CNC2=O
Reactant: CN1CCCC1COc1cc(NC(=O)c2cccnc2F)ccc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)(C)O
Product: CN1CCC[C@@H]1COc1cc(NC(=O)c2cccnc2Nc2cccc3c2CNC3=O)ccc1C(F)(F)F
Temperature: 150 °C

Procedure:
2-Fluoro-N-[3-(1-methyl-pyrrolidin-2-ylmethoxy)-4-trifluoromethyl-phenyl]-nicotinamide (402 mg, 1.0116 mmol) was dissolved in tert-butanol (1 mL). To this mix was added TFA (115 mg, 1.0116 mmol) and 4-amino-2,3-dihydro-isoindol-1-one (450 mg, 3.035 mmol). The mix was heated for 6 h at 150° C., allowing the solvent to boil off. The reaction was cooled to RT, dissolved into 1N aqueous HCl, basified to pH 10 with solid NaOH, extracted twice with EtOAc, and dried over Na2SO4. The product precipitated out of solution along with a minor by-product. The EtOAc was filtered off. The crude product was dissolved in MeOH and filtered. The MeOH solution was concentrated down and eluted on silica gel column to yield the titled compound as a light yellow solid. MS: C27H26F3N5O3—525.528; M+H 526.1
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]=[C:21]([C@:26]2([CH3:32])[CH2:30][O:29]C(=O)[NH:27]2)[CH:20]=[CH:19]3)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.O.[OH-].[Li+]>>[NH2:27][C@@:26]([C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([S:15][C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[CH:17]=2)[CH:22]=1)([CH3:32])[CH2:30][OH:29]
Reactant: C[C@@]1(c2ccc3cc(Sc4cccc(OCc5ccccc5)c4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@](N)(CO)c1ccc2cc(Sc3cccc(OCc4ccccc4)c3)ccc2c1
Yield: 92.1 %

Procedure:
(R)-4-(6-(3-(benzyloxy)phenylthio)naphthalen-2-yl)-4-methyloxazolidin-2-one (30.0 mg, 0.0000679 mol) was dissolved in ethanol (2 mL, 0.03 mol) and water (0.8 mL, 0.05 mol) then lithium hydroxide (17 mg, 0.00072 mol) was added and was heated to reflux overnight. LCMS shows no SM and a new peak at 1.51 399.17 ([M−NH2]+, 100). After concentration, the residue was taken up into methylene chloride and water. The aqueous layer was extracted with methylene chloride and concentrated. Column chromatography with MeOH/methylene chloride gave (R)-2-amino-2-(6-(3-(benzyloxy)phenylthio)naphthalen-2-yl)propan-1-ol as a white solid (26.0 mg, 92%). LCMS 1.51 399.17 ([M−NH2]+, 100%). 1H NMR (400 MHz, MeOD) δ=7.95 (br. s., 1H), 7.89-7.76 (m, 3H), 7.64 (d, J=8.6 Hz, 1H), 7.43-7.20 (m, 7H), 6.98-6.87 (m, 3H), 5.00 (br. s., 2H), 3.84-3.77 (m, 1H), 3.77-3.69 (m, 1H), 1.60 (s., 3H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][CH:9]=[O:10].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1
Reactant: OCCO
Reactant: O=CCC1CC2C=CC1C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=CC2CC1CC2CC1OCCO1
Yield: 95 %

Procedure:
40.0 g of (5-norbornen-2-yl)acetoaldehyde, 23.0 g of ethylene glycol, 120 ml of toluene and 200 mg of p-toluenesulfonic acid were mixed and heated under reflux for one hour while the water formed was removed through an H tube. The reaction mixture was allowed to cool down and poured into 50 ml of saturated sodium bicarbonate water. The resulting mixture separated into two layers. The organic layer was washed with water and saturated sodium chloride water, dried over anhydrous sodium sulfate, and concentrated in vacuum. It was further purified by vacuum distillation, obtaining 50.3 g of 2-(5-norbornen-2-yl)methyl-1,3-dioxolane (boiling point 63° C./200 Pa, yield 95%).