Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: II.[CH3:3][O:4][C:5]1[C:13]2[O:12][CH:11]([CH2:14][CH:15]=[CH2:16])[C:10](=O)[C:9]=2[CH:8]=[CH:7][CH:6]=1.Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(O)(=O)C>C1COCC1.[Zn]>[CH3:3][O:4][C:5]1[C:13]2[O:12][C:11]([CH2:14][CH:15]=[CH2:16])=[C:10]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: C=CCC1Oc2c(OC)cccc2C1=O
Reactant: COC(=O)CBr
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CCc1oc2c(OC)cccc2c1CC(=O)OC
Temperature: 0 °C
Yield: 67 %

Procedure:
THF (10 ml) was added to zinc powder (5.92 g) and then a catalytic amount of iodine was added. While vigorously stirring the resulting solution, a small amount of a solution of 7-methoxy-3-oxo-2-(2-propenyl)-2,3-dihydrobenzofuran (6.16 g) and methyl bromoacetate (8.9 ml) in THF (90 ml) was added at room temperature. After confirming generation of heat, the reaction solution was cooled to 0° C. and the remainder of the solution was added dropwise for 15 minutes. The reaction solution was stirred at 0° C. for 3 hours, cooled to room temperature and was stirred for another 2.5 hours. Acetic acid (5.5 ml) was added to the reaction solution and the resultant was filtered through Celite. After removing the solvent under reduced pressure, the residue was dissolved in toluene (100 ml) and p-toluenesulfonic acid (536 mg) was added thereto, followed by stirring the resulting mixture at room temperature for 2 hours. The reaction solution was poured into water (150 ml) and the resultant was extracted twice with ethyl acetate (50 ml). After combining the organic layers, the resultant was washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, and dried over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=3/1) using a silica gel to obtain the desired compound (5.23 g, yield: 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5](Cl)[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][N:8]=2)[N:3]=1.[CH3:17][N:18]([CH2:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)[CH3:19]>>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:25][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:18]([CH3:19])[CH3:17])=[CH:27][CH:26]=1
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CS(=O)(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CN(C)Cc1ccc(Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)cc1
Yield: 72.4 %

Procedure:
Following general procedure I, 2,8-dichloro-7-(methylsulfonyl)-1,5-naphthyridine (150 mg, 0.53 mmol) was acted with 4-[(dimethylamino)methyl]aniline (120 mg, 0.80 mmol) to afford the desired product (150 mg, 80%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.05 (s, 1H), 8.95 (s, 1H), 8.18 (d, J=8.8 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.34-7.27 (m, 2H), 7.12-7.04 (m, 2H), 3.49 (s, 2H), 3.17 (s, 3H), 2.30 (s, 6H); ESI MS m/z 391 [M+H]+
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C@H:20]1[NH:24][C:23](=[O:25])[CH2:22][CH2:21]1>CN(C=O)C>[CH3:10][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([CH3:11])[C:2]=1[O:1][CH2:19][C@@H:20]1[CH2:21][CH2:22][C:23](=[O:25])[NH:24]1)[CH:6]=[O:7]
Reactant: O=C1CC[C@@H](CBr)N1
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C=O)cc(C)c1OC[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.6 %

Procedure:
To a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (2.65 g, 17.7 mmol) in DMF (100 mL) was added K2CO3 (3.66 g, 26.6 mmol). The mixture was stirred at room temperature under nitrogen for 30 minutes. Then, a solution of (S)-5-(bromomethyl)pyrrolidin-2-one (3.15 g, 17.7 mmol) in DMF (100 mL) was added, and the mixture heated at reflux for 16 hours. The mixture was then concentrated, ethyl acetate (250 mL) added, and the organic phase washed sequentially with water (2×150 mL), and brine (200 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with 100% ethyl acetate to 10% MeOH/ethyl acetate, followed by a second chromatography, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH, to afford (S)-3,5-dimethyl-4-((5-oxopyrrolidin-2-yl)methoxy)benzaldehyde as a white solid (0.200 g, 5%).
Reaction SMILES: [C:1]([NH:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])(=O)[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][CH3:16].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([NH:18][CH:19]([CH2:20][OH:21])[CH2:22][OH: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][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)NC(CO)CO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNC(CO)CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.0 g. of the resulted 2-(hexadecanoylamino)propane-1,3-diol were transferred to a three necks round bottom flask equipped with a dropping funnel, a cooling bath, and a magnetic stirrer, under an air stream. The compound was dissolved in 200 ml dry THF and the solution wasp cooled to 0° C. 1.2 g of LiAlH4 were added in small portions with strong stirring during 1 hour and then the mixture was left to react for another 2 hours at 0° C. The cooling bath was removed and the reaction was left to stir overnight. The next day, 2 ml of ethyl acetate followed by 10 ml of methanol and 10 ml of HCl 1N, were added very slowly and the solution was evaporated to approximately 20 ml. The mixture was transferred to a separatory funnel and 100 ml water, 100 ml dichloromethane and 50 ml methanol were added. Following shaking, the lower phase was collected and the upper, acidic-aqueous-methanolic phase was extracted twice with 50 ml CH2Cl2:MeOH, 3:1. The combined organic phases were washed with 100 ml HCl 0.1 N and then with 100 ml H2O, dried for 2 hours over MgSO4, filtered and evaporated to dryness. The resulted product was crystallized from ethanol:H2O. Yield: 0.5 g.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([O:17][CH2:18][C:19]([NH2:21])=[O:20])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:27].C1COCC1>ClCCl>[O-:27][N+:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:6]2[N:5]([O:17][CH2:18][C:19]([NH2:21])=[O:20])[C:4]([CH2:1][CH2:2][CH3:3])=[N:16][C:7]=2[CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1nc2cnc3ccccc3c2n1OCC(N)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1OCC(N)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-[(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]acetamide (2.7 g, 9.5 mmol) in dichloromethane (100 mL) was cooled to approximately 0° C., and 3-chloroperoxybenzoic acid (3.2 g of approximately 77% pure material, 14 mmol) was added. The reaction was stirred for ten minutes at 0° C. and for one hour at room temperature. An analysis by LC/MS indicated that no reaction had occurred; the starting material was very insoluble. THF (40 mL) was added, and the reaction was stirred for 23 hours. An analysis by LC/MS indicated the presence of starting material, and dichloromethane (500 mL) was added. The reaction was stirred for seven hours, was allowed to stand for three days, and then was concentrated under reduced pressure to provide 2-[(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]acetamide.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>COCCO>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH:16]=[C:15]2[CH2:14][CH2:13][CH2:12][OH:11]
Reactant: NNc1ccc(Br)cc1
Reactant: C1=COCCC1
Agent: Cl
Solvent: COCCO
Product: OCCCc1c[nH]c2ccc(Br)cc12
Yield: 68.8 %

Procedure:
A modification of a procedure reported by Grandberg (Chem. Abstr. 1973, 79,918895) was used. Thus, to a suspension of 4-bromophenylhydrazine hydrochloride (56.0 g, 0.25 mol) in 200 mL of 2-methoxyethanol was added 3,4-dihydro-2H-pyran (25.5 mL, 0.28 mol) over ca. 5 min and the resulting mixture was heated to reflux under Ar for 3.5 h. The cooled reaction mixture was evaporated and the residual oil was poured into 500 mL of cold water. The aqueous mixture was extracted with ether (2×250 mL) and the ethereal extract was washed with H2O (250 mL), 1N HCl (2×250 mL) and brine (250 mL). The organic phase was then dried (Na2SO4) and evaporated to give a dark orange-brown oil. This oil was purified on a 10×15 cm SiO2 pad (elution with CH2Cl2 then CH2Cl2 -ethyl acetate, 1:1) to give the title compound (43.7 g, 69%) as a viscous orange-brown oil: IR (neat) 3570, 3430, 3300 (br), 1460 cm-1 ; 1H NMR (CDCl3, 200 MHz) δ 0.11 (br s, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.30-7.18 (m, 2H), 6.97 (s, 1H), 3.72 (t, J=6.4 Hz, 2H), 2.80 (t, J=7.5 Hz, 2H), 2.03-1.89 (m, 2H), 1.68 (br s, 1H).
Reaction SMILES: C([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]([C:25]([OH:27])=O)=[C:17]2[CH2:28][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[C:30](=[O:31])[C:16]=12)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:40][C:41]1[S:42][CH:43]=[CH:44][N:45]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[S:42]1[CH:43]=[CH:44][N:45]=[C:41]1[NH:40][C:25]([C:18]1[C:19]2[CH:20]=[CH:21][CH:22]=[N:23][C:24]=2[C:15]([OH:14])=[C:16]2[C:30](=[O:31])[N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:28][C:17]=12)=[O:27]
Reactant: Nc1nccs1
Reactant: O=C(O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nccs1)c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 59.6 %

Procedure:
9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid 213 (0.02 g, 0.0386 mmol) was dissolved in 0.3 mL of dimethylformamide. To this was added 2-aminothiazole (0.0077 mL, 0.0772 mmol), diisopropylethylamine (0.027 mL, 0.1544 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.03 g, 0.0772 mmol) and stirred at room temperature. After 15 hours, starting material was consumed. Purified by reverse phase HPLC (0.1% TFA, H2O/ACN) to give 7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid thiazol-2-ylamide 319 (0.01 g, 0.023 mmol, 60%.) 1H NMR (CDCl3) δ 9.02 (dd, 1H), 8.61 (d, 1H), 7.65 (dd, 1H), 7.55 (d, 1H), 7.38 (dd, 2H), 7.21 (d, 1H), 7.07 (dd, 2H), 4.78 (s, 2H), 4.67 (s, 2H.) MS: 435 (M+1).
Reaction SMILES: [CH:1]1([C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([NH:21][C:12]([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:11]=2)=[O:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(O)c1cccc(C2CCCC2)n1
Reactant: NN1CCCCC1
Product: O=C(NN1CCCCC1)c1cccc(C2CCCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopentyl-pyridine-2-carboxylic acid and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (EI): m/e=274.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8].[NH2:24][C:25]1[CH:54]=[CH:53][C:28]([CH2:29][CH2:30][CH2:31][CH2:32][PH:33](=[O:52])[O:34][CH2:35][CH2:36][CH2:37][N:38]2[CH:42]=[C:41]([B:43]3[O:47][C:46]([CH3:49])([CH3:48])[C:45]([CH3:51])([CH3:50])[O:44]3)[CH:40]=[N:39]2)=[CH:27][C:26]=1[O:55][CH3:56].C(O)(C(F)(F)F)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:24][C:25]3[CH:54]=[CH:53][C:28]([CH2:29][CH2:30][CH2:31][CH2:32][PH:33](=[O:52])[O:34][CH2:35][CH2:36][CH2:37][N:38]4[CH:42]=[C:41]([B:43]5[O:47][C:46]([CH3:49])([CH3:48])[C:45]([CH3:50])([CH3:51])[O:44]5)[CH:40]=[N:39]4)=[CH:27][C:26]=3[O:55][CH3:56])[N:14]=2)=[C:6]([C:7](=[O:8])[NH:9][CH3:10])[CH:11]=1
Reactant: CNC(=O)c1cc(Br)ccc1Nc1nc(Cl)ncc1C(F)(F)F
Reactant: COc1cc(CCCC[PH](=O)OCCCn2cc(B3OC(C)(C)C(C)(C)O3)cn2)ccc1N
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(Br)ccc1Nc1nc(Nc2ccc(CCCC[PH](=O)OCCCn3cc(B4OC(C)(C)C(C)(C)O4)cn3)cc2OC)ncc1C(F)(F)F
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 5-bromo-2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 66B, 150.5 mg, 0.3674 mmol) and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propyl (4-amino-3-methoxybenzyl)propylphosphinate (Compound 66C, 175.4 mg, 0.3674 mmol) in TFE (5.0 mL) was charged with TFA (0.0602 mL). The reaction mixture was stirred at 50° C. for 24 hours. The reaction mixture was concentrated under reduced pressure to a light yellow oil and purified on a Teledyne ISCO Combiflash® Rf system using DCM/MeOH (100:0→90:10) as eluent to afford the racemic title compound as 0.245 g of a white solid (78%). MS (ESI): m/z 850.91/852.88 [M+H]+. UPLC: tR=1.52 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[C:11]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)([OH:12])[CH2:10][CH2:9][CH2:8][C:3]21OCC[O:4]2.Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[OH:12][C:11]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:10][CH2:9][CH2:8][C:3](=[O:4])[C:2]1([CH3:36])[CH3:1]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCCC4(OCCO4)C3(C)C)s2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCCC(=O)C3(C)C)s2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To a stirred solution of the product of Step 1(600 mg, 1.15 mmol) in THF (4 mL) was added HCl (6 M, 3.84 mL, 23.1 mmol). The reaction mixture was allowed to stir at room temperature for 30 min, neutralized with aqueous saturated sodium bicarbonate, and extracted with dichloromethane (3×). The combined organics were dried (sodium sulfate), filtered, concentrated, and purified by flash chromatography on silica to afford 3-hydroxy-2,2-dimethyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanone (534 mg, 1.12 mmol) as a yellow foam. MS ESI: [M+H]+ m/z 477.1.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1.[C:12]([O:16][C:17](=[O:27])[NH:18][CH:19]1[CH2:26][CH2:25][CH2:24][C:21]2([O:23][CH2:22]2)[CH2:20]1)([CH3:15])([CH3:14])[CH3:13]>CN(C=O)C>[N:3]1([CH2:22][C:21]2([OH:23])[CH2:24][CH2:25][CH2:26][C@@H:19]([NH:18][C:17](=[O:27])[O:16][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:20]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: CC(C)(C)OC(=O)NC1CCCC2(CO2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC(O)(Cn2ncc3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (1.1 mmol) was added to a vial containing indazole (2.2 mmol) in DMF (1 ml). The mixture was stirred at rt for 15 mins, then added tert-butyl-1-oxaspiro[2.5]octaN-5-ylcarbamate (0.22 mmol). The reaction was stirred at 60° C. overnight. Upon completion, the mixture was quenched by water (3 mL). The mixture was extracted using dichloromethane (3×5 mL). The extracts were combined and dried using anhydrous sodium sulfate. The product was purified using HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CN(C)C=O.O>[CH3:24][C:23]([CH3:26])([O:22][C:20]([CH2:19][NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1)=[O:21])[CH3:25]
Reactant: Nc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.6 %

Procedure:
To a solution of 2-aminonaphthalene (985 mg, 6.8 mmol) in N,N-dimethylformamide (DMF) (50 mL) was added potassium carbonate (1.806 g, 13.6 mmol) and tert-butyl bromoacetate (1.4 mL, 9.9 mmol). The resulting reaction mixture was stirred at ambient temperature. After 24 hours, the reaction mixture was diluted with water (200 mL), then extracted by ethyl acetate (150 mL). The organic layer was separated and washed with water (3×100 mL), then dried over sodium sulfate. The solvent was evaporated in vacuo to afford a product as ann yellow oil. Purification of product by flash column on silica gel afforded 2-((1,1-dimethylethoxycarbonyl)methyl)aminonaphthalene (1.2 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18][OH:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20](N1C=CN=C1)([N:22]1C=CN=C1)=[O:21].N.O>C1COCC1>[C:20]([O:19][CH2:18][C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])(=[O:21])[NH2:22]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1F
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](COC(N)=O)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
In a 250 mL flask equipped with magnetic stirrer, N-(t-butyloxycarbonyl)-o-fluorophenylalaninol (0.096 mole, 2.15 g) was dissolved in 200 ml of THF and was added with 1,1'-carbonyldiimidazole (0.010 mol, 1.62 g) at 0° C. The reaction mixture was stirred at room temperature for 2 hours, followed by the injection of ammonia at 0° C. for 30 min. Following elevating to room temperature, water was added to terminate the reaction. The organic layer was extracted 3 times with dichloromethane, dried over magnesium sulfate and distilled in vacuo, to give a solid. This was recrystalized in a solution mixture of n-hexane and diethyl ether, to produce 1.93 g of O-carbamoyl-N-(t-butyloxycarbonyl)-o-fluorophenylalaninol: Yield 75%.
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[N:15]([C@H:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3].[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[NH:18]1[CH2:19][CH2:20][CH2:21][C@H:16]([N:15]2[C:7]3=[C:8]4[S:14][CH:13]=[CH:12][C:9]4=[N:10][CH:11]=[C:6]3[N:5]=[C:4]2[C@H:2]([OH:1])[CH3:3])[CH2:17]1
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (3S)-3-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}piperidine-1-carboxylate (0.25 g, 0.62 mmol) in methylene chloride (3.5 mL) was added 4.0 M hydrogen chloride in 1,4-dioxane (1.2 mL, 5.0 mmol). A precipitate immediately formed. The reaction was stirred at room temperature for 2 h. The solvents were evaporated and the solids dried in vacuo to give 0.21 g of the product as the HCl salt. LCMS calculated for C15H19N4OS (M+H)+: m/z=303.1. Found: 303.0.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([C:13]1[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=1)[CH2:8]2.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(=O)(O)[O-].[Na+].O>CS(C)=O>[CH3:25][O:24][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:26][CH3:27])[N:14]=[C:13]([N:7]1[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[CH:12][C:3]=3[CH2:2][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH2:8]1)[NH:22][C:21]2=[O:23]
Reactant: C1COCCN1
Reactant: COc1cc2nc(N3CCc4c(CBr)cccc4C3)[nH]c(=O)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nc(N3CCc4c(CN5CCOCC5)cccc4C3)[nH]c(=O)c2cc1OC
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(5-bromomethyl-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxy-3H-quinazolin-4-one 23a (54 mg, 0.12 mmol), morpholine (12 mg, 0.13 mmol) and sodium bicarbonate (16 mg, 0.18 mmol) in dimethyl sulfoxide (0.5 mL) was heated to 80° C. with stirring for 18 h. After cooling to room temperature, water (2 mL) was added and the precipitated product was separated by filtration, rinsed with water and dried. 6,7-Dimethoxy-2-(5-morpholin-4-ylmethyl-3,4-dihydro-1H-isoquinolin-2-yl)-3H-quinazolin-4-one 701 was purified by flash chromatography eluting with 2% methanol in dichloromethane containing 0.2% of ammonium hydroxide. The product was converted to the hydrochloric acid salt. Yield 15 mg, mp. 227.9-229.6° C., [M+H]+=437.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:8][CH:7]([C:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]3=[C:11]([C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][C:25]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[N:26]4)=[CH:21][CH:20]=3)[N:10]=2)[CH2:6]1)=[N+]=[N-]>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:1][CH2:4][C@@H:5]1[CH2:6][C@H:7]([C:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]3=[C:11]([C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][C:25]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[N:26]4)=[CH:21][CH:20]=3)[N:10]=2)[CH2:8]1
Reactant: [N-]=[N+]=NCC1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)C1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: NC[C@H]1C[C@@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn32)C1
Reaction time: 16 h

Procedure:
3-[3-(Azidomethyl)cyclobutyl]-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-amine (0.81 mmol, 360 mg) was dissolved in hot ethanol (15 mL) and charged with Lindlar catalyst (0.14 mmol, 362 mg). The reaction mixture was purged with N2, evacuated and filled with H2. The reaction mixture was stirred under H2 for 16 h. The suspension was filtered through celite and the solvent was removed under reduced pressure. Part of the crude material (200 mg out of 300 mg) was purified by silica gel flush chromatography (Jones Flashmaster, 5 g/70 mL cartridge) eluting with 3% MeOH (7 N NH3) in DCM. The final compound was recrystallized from EtOAc and hexane to generate the desired product as a light yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.42-8.41 (m, 1H), 8.27 (dd, J=8.0 Hz, 0.4 Hz, 1H), 8.21-8.19 (m, 2H), 7.95-7.92 (m, 3H), 7.57-7.48 (m, 3H), 7.19 (d, J=4.0 Hz, 1H), 7.11 (d, J=4.0 Hz, 1H), 5.20 (b, 2H), 3.73-3.69 (m, 1H), 2.81 (d, J=7.2 Hz, 2H), 2.66-2.62 (m, 2H), 2.58-2.48 (m, 1H), 2.36-2.30 (m, 2H); MS (ES+): m/z 421.13 (40) [MH+]; HPLC: tR=1.69 min (OpenLynx, polar—5 min).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1F)[N:13]([CH3:18])[C:12](=[O:19])[N:11]([OH:20])[C:10]2=[O:21].C(N(CC)CC)C>C(#N)C>[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[N:13]([CH3:18])[C:12](=[O:19])[N:11]([OH:20])[C:10]2=[O:21]
Reactant: Cn1c(=O)n(O)c(=O)c2cc(F)c(F)cc21
Reactant: C1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1c(=O)n(O)c(=O)c2cc(F)c(N3CCCC3)cc21
Yield: 38 %

Procedure:
Pyrrolidine (0.07 mL, 0.8 mmol) was added to a solution of 6,7-difluoro-3-hydroxy-1-methyl-1H-quinazoline-2,4-dione (Example L, 0.15 g, 0.66 mmol) and triethylamine (1.2 mL, 8.6 mmol) in 30 mL of acetonitrile. The solution was warmed to reflux for 18 hours, cooled, and filtered to give a solid. The solid was triturated with chloroform, filtered, and dried to give 0.07 g of the title compound as a solid, mp>250° C.