Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.O=P(Cl)(Cl)Cl.CN([CH:22]=[O:23])C.CC([O-])=O.[Na+].[OH-].[Na+]>ClC(Cl)C>[CH:22]([C:3]1[C:4]2[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1)=[O:23]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2[nH]cc(C=O)c12
Temperature: 50 °C

Procedure:
A solution of methyl indole-4-carboxylate (250 mg, 1.43 mmol) in dichloroethane (2 mL) was treated with a solution of POCl3-DMF (1.5 equivalent (eq)) at room temperature (rt). The orange solution was heated at 50° C. for 1 hour. The reaction solution was poured into ice-cold aqueous (aq.) NaOAc (1 g in 2 mL), the aqueous solution was adjusted to pH=8 with 1M NaOH, and extracted with EtOAc (10 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated to give methyl 3-formyl-indole-4-carboxylate as an oil, 271 mg (93%). 1H NMR (300 MHz, d6-DMSO) δ 3.68 (s, 3H), 7.16 (t, 1H, J=7.8 Hz), 7.40 (dd, 1H, J=7.8, 0.8 Hz), 7.56 (d, 1H, J=7.8, 0.8 Hz), 8.16 (d, 1H, J=3.2 Hz), 10.00 (s, 1H), 12.30 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].C[O-].[Na+].CO.[CH:16]1([CH:22]=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(OC)(OC)OC>[CH:16]1([CH:22]=[CH:1][C:2]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=2)=[O:3])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(=O)c1cccc(O)c1
Reactant: O=CC1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: O=C(C=CC1CCCCC1)c1cccc(O)c1
Reaction time: 0.67 h

Procedure:
A mixture of 3-hydroxyacetophenone on Wang resin (6.0 g, 5.52 mmol) was swelled in trimethyl orthoformate (60 mL) for 10 min. 25% NaOMe in MeOH (2.4 g, 11.0 mmol) was added and the mixture was stirred for 40 min. Cyclohexanecarboxaldehyde (1.9 g, 16.56 mmol) was added and stirring was continued for 40 min. The resin was filtered and washed with alternating MeOH and CH2Cl2 (×5) and dried under high vacuum overnight to give 6.62 g of 3-cyclohexyl-1-(3-hydroxyphenyl)-2-propen-1-one on Wang resin.
Reaction SMILES: [ClH:1].[OH:2][C@H:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](N)=[O:17])=[CH:11][CH:10]=1.S(=O)(=O)(O)O.[CH3:30][OH:31]>>[ClH:1].[OH:2][C@H:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:31][CH3:30])=[O:17])=[CH:11][CH:10]=1
Reactant: CO
Reactant: NC(=O)Cc1ccc(OCCNC[C@H](O)c2ccccc2)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(OCCNC[C@H](O)c2ccccc2)cc1

Procedure:
(R)-4-[2-(2-Hydroxy-2-phenylethylamino)ethoxy]phenylacetamide hydrochloride (0.45 g) was heated under reflux in methanol (20 ml) containing concentrated sulphuric acid (0.5 ml) for 18 hours. The mixture was cooled and the solvent evaporated under reduced pressure. The residue was dissolved in dichloromethane (30 ml) and washed successively with water (20 ml), 5% NaHCO3 solution (50 ml) and water (20 ml), dried over MgSO4 and then the solvent was removed under reduced pressure. The residue was dissolved in methyl acetate (20 ml) and treated with a solution of ether saturated with hydrogen chloride. The precipitated solid was crystallized from a mixture of methanol and methyl acetate to give (R)-methyl 4-[2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetate hydrochloride (0.25 g), m.p. 181°-183° C.; microanalysis: found, C, 62.6; H, 6.6; N, 3.8; Cl, 9.9%; required for C19H24ClNO4 : C, 62.4; H, 6.6; N, 3.8; Cl, 9.7%; [α]25D =-25.3° (c=0.99 in methanol).
Reaction SMILES: [Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[C:16](I)[C:15]([N:19]3[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1.[F:28][C:29]1[CH:30]=[N:31][NH:32][C:33]=1[Sn](CCCC)(CCCC)CCCC.CCOC(C)=O>CS(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[C:16]([C:33]3[NH:32][N:31]=[CH:30][C:29]=3[F:28])[C:15]([N:19]3[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1[nH]ncc1F
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC(CO)C2)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC(CO)C2)c(-c2[nH]ncc2F)c1
Temperature: 100 °C
Reaction time: 21 h

Procedure:
A mixture of N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)azetidin-1-yl)-5-iodonicotinamide (Stage 92.1, 200 mg, 0.392 mmol), 4-fluoro-5-(tributylstannyl)-1H-pyrazole (147 mg, 0.392 mmol), Pd(PPh3)4 (22.67 mg, 0.02 mmol) in DMSO (2 mL) was stirred at 100° C. under argon atmosphere for 21 h. The RM was treated with EtOAc, washed with sat. aq. NaHCO3 and brine dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The residue was purified by flash chromatography on silica gel, dissolved in MeOH (3 mL), filtered through a SPE PL-Thiol cartridge (StratoSphere™, 500 mg 1.5 mmol), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was further purified by preparative SFC (Column Diol, from 21% to 26% in 6 min) to give the title product as a white solid. HPLC (Condition 7) tR=5.701 min, UPLC-MS (Condition 8) tR=0.95 min, m/z=468.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.58-2.73 (m, 1H) 3.43-3.51 (m, 2H) 3.51-3.60 (m, 2H) 3.75-3.85 (m, 2H) 4.68-4.77 (m, 1H) 7.30-7.38 (m, 3H) 7.83-7.91 (m, 2H) 7.99-8.07 (m, 1H) 8.73-8.83 (m, 1H) 10.21 (s, 1H) 12.92-13.18 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]O[Si](CC(C)C)(C)C.Cl[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].[Mg].ClC1CCC=C1>O1CCCC1.O>[CH3:26][C:25]([Si:22]([CH3:24])([CH3:23])[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:5]1[CH2:4][CH2:3][CH:2]=[CH:6]1)([CH3:28])[CH3:27]
Reactant: CC(C)C[Si](C)(C)OCCCCCCl
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCl
Agent: ClC1C=CCC1
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCC1C=CCC1
Temperature: 25 °C

Procedure:
All reactions are carried out under an inert atmosphere. The starting material, (5-chloro-1-pentyloxy)(2,2-dimethylethyl) dimethylsilane {[(5-chloropentyl)oxy](1,1-dimethylethyl)dimethylsilane} (534 g, 2.26 moles), diluted in tetrahydrofuran (500 ml), is added portionwise to a refluxing solution of tetrahydrofuran and granular magnesium (75 g). After the addition is complete the reaction is refluxed an additional 2 hours and the resultant Grignard salt is cooled to room temperature, cannulated into a three liter flask, and cooled to -20° C. A solution of Li2CuCl4 (6.4 mmoles) is added, followed by the dropwise addition of 3-chlorocyclopentene (219 g, 2.1 moles) cooled in a -20° C. dry ice/ethanol bath. After the addition is complete the mixture is warmed to room temperature. Water (500 ml) is added. The reaction mixture is extracted with hexane (3×400 ml). The organic layers are combined, washed with brine (2×500 ml) and dried over anhydrous sodium sulfate. The remaining solvent is removed under vacuum leaving a clear yellow oil. The crude product is fractionally distilled under reduced pressure leaving a clear, colorless oil (478 g, 1.78 moles), BP 96° C./0.3 mm.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[NH:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:3]([CH3:5])=[CH:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: C1CCNC1
Reactant: COC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C=C(C)C1CCCN1
Temperature: 140 °C
Yield: 99.5 %

Procedure:
Methyl acetoacetate (20 g, 172.23 mmol) was dissolved in 250 mL of toluene, and then pyrrolidine (43 ml, 516.70 mmol) and p-toluenesulfonic acid hydrate (about 100 mg) were added dropwise. After installing a Dean-Stark separator to the reactor, the reaction mixture was refluxed 140° C. for two days, and then solvent was removed by concentrating the resulting mixture under a reduced pressure, thereby to obtain the desired product (29 g, 99%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>C(O)C>[NH:12]([C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][N:3]=1)[NH2:13]
Reactant: Clc1nccc2ncnn12
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1nccc2ncnn12
Reaction time: 1.5 h

Procedure:
A solution of 155 mg (1 mmol) of 5-chloro[1,2,4]triazolo[1,5-c]pyrimidine [D. J. Brown and K. Shinozuka, Aust. J. Chem., 33, 1147 (1980)] in 6 mL of dry ethanol was added gradually to a vigorously stirred solution of 198 mg (204 mg, 4 mmol) of hydrazine monohydrate in 2 mL of dry ethanol. A white precipitate separated during the addition. After 1.5 h, the solid was collected on a filter. It was suspended in 2 mL of concentrated ammonium hydroxide and agitated for a few minutes. The solid was then collected on a filter and washed with some additional concentrated ammonium hydroxide, then with some ethanol, and finally with a large volume of diethyl ether. After drying, the title compound was obtained as a white solid, mp 245-246° C. (decomposition). LC-MS 151 (M+1).
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]2[CH:16]=[C:15]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[S:14][C:9]=2[N:10]=[C:11]([CH3:13])[N:12]=1)(=O)=O.CC#N.[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>O>[CH:17]1([C:15]2[S:14][C:9]3[N:10]=[C:11]([CH3:13])[N:12]=[C:7]([CH2:6][NH:31][CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[C:8]=3[CH:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC1CCCC1
Reactant: Cc1nc(COS(C)(=O)=O)c2cc(C3CCCCC3)sc2n1
Solvent: CC#N
Solvent: O
Product: Cc1nc(CNC2CCCC2)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of (6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl methanesulfonate (500 mg) and CH3CN (10 mL) was added cyclopentylamine (1.0 mL), followed by stirring at room temperature for 3 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by basic silica gel column (hexane/EtOAc) and silica gel column (hexane/EtOAc) to obtain N-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]cyclopentaneamine (326 mg).
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Li]CCCC.[C:25](Cl)(=[O:29])[O:26][CH2:27][CH3:28].Cl>C1COCC1.O>[S:1]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH:13]=[C:12]1[C:25]([O:26][CH2:27][CH3:28])=[O:29])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cnccc32)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cnccc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of compound 6-b (10 g, 367 mmol) in dry THF (150 mL) was cooled to −70° C. and n-BuLi (CAS 109-72-8) (2.5 M in hexane, 16.7 mL, 41.9 mmol) was added dropwise under N2. The mixture was stirred at −78° C. for 1 hour and then ethyl carbonochloridate (CAS 541-41-3) (fresh redistilled, 4.2 mL, 44 mmol) was added dropwise at −70° C. The mixture was warmed to 20° C. naturally and stirred at 20° C. for 1 hour. Then water (800 mL) was added. The mixture was acidified to pH=4 to 5 with a 1N HCl aqueous solution and extracted with ethyl acetate (400 mL×2). Then the pH of the aqueous layer was adjusted to pH=8 by addition of NaHCO3. The resulting mixture was extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated. The residue was washed with tert-butylmethyl ether. The solid was dried under high vacuum. The residue was purified by flash column chromatography, eluting with petroleum ether/ethyl acetate (3:2). After evaporation of the fractions, 6-c is obtained (6 g, 47%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=2)[N:8]([CH2:23][CH3:24])[C:7]1=[O:25])=O)C.[NH2:26][C:27]1[CH:28]=[C:29]([CH:39]=[CH:40][CH:41]=1)[C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31]>>[C:33]1([NH:32][C:30]([C:29]2[CH:28]=[C:27]([NH:26][C:4]([CH:6]3[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:15](=[O:22])[C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH:13]=4)[N:8]([CH2:23][CH3:24])[C:7]3=[O:25])=[O:3])[CH:41]=[CH:40][CH:39]=2)=[O:31])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)C1C(=O)N(CC)c2ccc(C(=O)c3ccccc3)cc21
Reactant: Nc1cccc(C(=O)Nc2ccccc2)c1
Product: CCN1C(=O)C(C(=O)Nc2cccc(C(=O)Nc3ccccc3)c2)c2cc(C(=O)c3ccccc3)ccc21

Procedure:
Prepared as in Example 1, Step A, from 5-benzoyl-1-ethyl-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid ethyl ester (U.S. Pat. No. 4,686,224) and 3-amino-N-phenyl-benzamide. Purified by trituration in ethyl acetate/hexanes. mp 129-135° C.
Reaction SMILES: [O:1]([C@H:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([O:22][C@@H:23]1[C@H:27]([O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:26]([CH2:37][O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:25][C@H:24]1[N:47]1[CH:55]=[N:54][C:53]2[C:48]1=[N:49][C:50]([Cl:57])=[N:51][C:52]=2Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>O1CCOCC1>[C:14]([O:22][C@@H:23]1[C@H:27]([O:28][C:29](=[O:36])[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C@@H:26]([CH2:37][O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:25][C@H:24]1[N:47]1[C:48]2[N:49]=[C:50]([Cl:57])[N:51]=[C:52]([NH:13][C@@H:9]3[CH2:10][CH2:11][CH2:12][C@@H:8]3[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:53]=2[N:54]=[CH:55]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@@H]1CCC[C@@H]1Oc1ccccc1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCC[C@@H]4Oc4ccccc4)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reaction time: 50 h
Yield: 94.7 %

Procedure:
cis-2-Phenoxycyclopentylamine (0.75 g, 4.23 mmol) was combined with 9-(2,3,5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.95 g, 4.7 mmol) and triethylamine (0.64 g, 6.3 mmol) in dioxan (30 ml) and stirred for 50 h. The reaction mixture was filtered, evaporated and the residue dissolved in ethyl acetate and washed with water (2×50 ml). The organic phase was dried (MgSO4), evaporated and the residue coevaporated to give cis-2',3',5'-tri-O-benzoyl-2-chloro- N-(2-phenoxycyclopentyl)adenosine (3.1 g, 90%) as an amorphous foam, which was deprotected using saturated methanolic ammonia (50 ml). After 70 h at room temperature the reaction mixture was evaporated and the residue purified by flash chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (19:1). The title cis-2-chloro- N-(2-phenoxycyclopentyl)adenosine (0.925 g, 53%) was obtained as an amorphous foam (a 1:1 mixture of diastereoisomers), 1H NMR (DMSO-d6)δ 1.58-2.15 (6H, 3m, --CH2CH2CH2 --), 3.51-3.60 (1 H, m, H-5'a), 3.62-3.71 (1H, m, H-5'b), 3.95 (1H, br q, H-4'), 4.12 (1H, br q, H-3'), 4.46-4.62 (2H, m, H-2' and --CH), 4.82-4.89 (1H, m, --CH), 5.07 (1H, br t, 5'-OH), 5.22, 5.49 (2H, 2d, 2'- and 3'-OH), 5.83 (1H, d, H-1'), 6.80-6.91 (3H, m, Ar--H), 7.15-7.24 (2H, t, Ar--H), 7.99, 8.22 (1H, d & m, N--H), 8.41, 8.45 (1 H, 2s, H-8).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:20]3[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=3)=[N:9][C:10]3[CH:11]=[CH:12][N:13]4[CH:19]=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:28]C(C)(CC(C)C)C(O)=O>CN(C=O)C>[C:1]1([C:7]2[C:8]([C:20]3[CH:27]=[CH:26][C:23]([CH2:24][NH2:28])=[CH:22][CH:21]=3)=[N:9][C:10]3[CH:11]=[CH:12][N:13]4[CH:19]=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)CC(C)(N)C(=O)O
Reactant: O=Cc1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Solvent: CN(C)C=O
Product: NCc1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Temperature: 150 °C

Procedure:
A suspension of 4-(9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzaldehyde (4-2, 0.80 g, 2.3 mmol) and 2-amino-2,4-dimethylpentanoic acid (3-7, 0.340 g, 2.3 mmol) in DMF (10 mL) was heated at 150° C. for 30 min. The reaction mixture cooled and the solvent was removed in vacuo. The crude residue was dissolved in 3N HCl (8 mL) and was heated at 100° C. for 30 min. The mixture was cooled and purified via reverse phase HPLC (5-65% acetonitrile/water over 15 min) to give, upon evaporation of the solvents, the title compound as a yellow solid. 1H-NMR (CD3OD) δ 9.60 (s, 1H), 8.98 (s, 1H), 8.73 (d, 1H), 7.75 (d, 1H), 7.60 (d, 2H), 7.46 (d, 2H), 7.39-7.36 (m, 5H), 4.15 (s, 2H).
Reaction SMILES: [Mg].II.Cl[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10].[Cl:11][C:12]1[C:13]([F:33])=[C:14]([CH:30]=[CH:31][CH:32]=1)[C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16]>C1COCC1>[Cl:11][C:12]1[C:13]([F:33])=[C:14]([C@:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:18]2)([OH:16])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10])[CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2F)C1
Reactant: COCCCCCl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
A flame dried 250 mL three-necked flask was charged with magnesium turnings (7.02 g, 0.293 mol), a small crystal of iodine and THF (30 mL). The flask was evacuated and refilled with N2. A solution of 1-chloro-4-methoxybutane (28.69 g, 0.234 mol) in THF (120 mL) was added dropwise slowly to the mixture. The reaction mixture was stirred under reflux for 2.5 h and most of magnesium was consumed. The resulting Grignard reagent was used as follows To another 100 mL three-necked flask was added (R)-tert-butyl 3-(3-chloro-2-fluorobenzoyl)piperidine-1-carboxylate (10 g, 0.0293 mol) and THF (100 mL). The flask was evacuated and refilled with N2. The mixture was cooled with dry ice-acetone bath and the Grignard reagent (250 mL) was added. The reaction mixture was allowed to warm slowly to rt while stirring overnight. The mixture was quenched with satd aq NH4Cl (50 mL), extracted with EtOAc (3×), and the combined organic layers were dried over Na2SO4. Evaporation of the solvent gave the crude product. The LC-MS analysis of the crude product indicated the presence of two isomers (95:5). Flash column chromatography, eluting with 10% EtOAc/PE afforded (R)-tert-butyl 3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (9.4 g, 75% yield). 1H NMR (400 MHz, DMSO): 0.68 (m, 1H), 1.50-1.01 (m, 7H), 1.37 (s, 9H), 1.75 (m, 2H), 2.01 (m, 1H), 3.11 (s, 3H), 3.17 (m, 2H), 3.85 (m, 1H), 7.2 (t, 1H), 7.45 (m, 2H). MS (E/Z): 430 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:6]2[CH2:7][CH2:8][CH:3]1[CH:4]1[C:12](=[O:13])[O:11][C:9](=[O:10])[CH:5]12.[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:9]([C@@H:5]2[C@H:6]3[C:2]([CH3:1])([CH3:14])[C@H:3]([CH2:8][CH2:7]3)[C@@H:4]2[C:12]([OH:11])=[O:13])=[O:10])=[CH:18][CH:17]=1
Reactant: CC1(C)C2CCC1C1C(=O)OC(=O)C12
Reactant: Nc1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Product: CC1(C)[C@@H]2CC[C@H]1[C@@H](C(=O)Nc1ccc(Br)cc1)[C@H]2C(=O)O

Procedure:
Following General Procedure A, Compound 3 (0.047 g, 0.24 mmol) and 4-bromoaniline (0.041 g, 0.24 mmol) in chloroform (4 mL) were converted into the title compound, which was isolated as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([O:17][CH3:18])[C:10]([OH:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[C:19](OCC)(=O)C.CCCCCC>CO>[CH3:19][O:13][C:12](=[O:14])[C:11]1[CH:15]=[C:7]([Br:6])[CH:8]=[C:9]([O:17][CH3:18])[C:10]=1[OH:16]
Reactant: COc1cc(Br)cc(C(=O)O)c1O
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1cc(Br)cc(OC)c1O

Procedure:
To prepare this compound, initially 1.0 mL of 98% concentrated sulfuric acid was added to a solution of 5-bromo-2-hydroxy-3-methoxy-benzoic acid, (compound 6) (1.0 g, 4.0 mmol) in 50 ml of methanol. The reaction mixture was refluxed overnight until thin layer chromatography using 20% ethyl acetate and 80% hexane as the mobile phase indicated that the reaction was complete. After evaporating the methanol, the residue was dissolved in 60 mL of ethyl acetate and washed with a saturated NaHCO3 aqueous solution and then brine. After drying with anhydrous sodium sulfate, the solution was concentrated, and the crude product was purified on a silica gel column to isolate the intermediate, 5-bromo-2-hydroxy-3-methoxy-benzoic acid methyl ester. The yield of this intermediate was 94%. The 1H-NMR spectrum (300 MHz, CDCl3) of the purified product was: 3.88 (s 3H), 3.95 (s, 3H), 7.09 (d, 1H), 7.55 (t, 1H), 10.96 (d, 1H).
Reaction SMILES: [Na+].[NH2:2][C:3]1[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([S:9]([O-:12])(=[O:11])=[O:10])[CH:8]=1.C([O-])(O)=O.[Na+].Cl[C:21]([O:23][CH2:24][CH:25]1[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22]>O1CCOCC1.O>[CH:36]1[C:37]2[CH:25]([CH2:24][O:23][C:21]([NH:2][C:3]3[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([S:9]([OH:12])(=[O:10])=[O:11])[CH:8]=3)=[O:22])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]=2[CH:33]=[CH:34][CH:35]=1
Reactant: Cc1cc(C)c(S(=O)(=O)[O-])cc1N
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)O)cc1NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-amino-2,4-dimethylbenzenesulfonic acid sodium salt (3.0 g, 13.4 mmol) in dioxane (37 mL) and water (37 ml) was added NaHCO3 (2.5 g, 29.6 mmol) and 9-fluoreneylmethyl chloroformate. The mixture was then stirred at room temperature overnight and then quenched with 1N HCl and extracted with EtOAc. The organic layers were concentrated in vacuo. Purification by silica gel chromatography (0-10% MeOH/DCM) resulted in the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11](CC(C)C)[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([C:27]([NH2:29])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl.CN(C)C=O>O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[NH:11][C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)=[CH:17][C:16]([C:27]#[N:29])=[CH:15][CH:14]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c3ccc(C(N)=O)cc23)cc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)[nH]c(=O)c3ccc(C#N)cc23)cc1
Yield: 102.7 %

Procedure:
A solution of 3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide (Example 3 (4)) (0.37 g, 0.8 mmol) and cyanuric chloride (0.44 g, 2.4 mmol) in N,N-dimethylformamide (10 mmol) was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was, purified by silica gel column chromatography to give tert-butyl[6-cyano-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.32 g, 91.4%) as crystals.