Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([CH:14]2[CH2:23][CH2:22][C:17]3(OCC[O:18]3)[CH2:16][CH2:15]2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:27]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:23][CH2:22][C@H:17]([OH:18])[CH2:16][CH2:15]2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:30][CH:31]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 4′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (3.6 g) in tetrahydrofuran (40 mL) was added 3M hydrochloric acid (40 mL), and the mixture was stirred at 70° C. for 2 hr. The mixture was allowed to cool, and diluted with ethyl acetate, and the mixture was neutralized with 8M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (20 mL)-tetrahydrofuran (20 mL). Thereto was added sodium borohydride (0.26 g) at 0° C. After stirring for 1 hr, ethyl acetate and saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (2.9 g, 87%).
Reaction SMILES: C([NH:8][CH:9]([CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:23]3[CH:35]=[C:34]([CH3:36])[S:33][C:24]=3[NH:25][C:26]3[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=3[N:28]=2)[CH2:18][CH2:17]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OC(C)(C)C)=O.[ClH:37].C(O)C>>[ClH:37].[ClH:37].[ClH:37].[NH2:8][CH:9]([CH2:15][N:16]1[CH2:17][CH2:18][N:19]([C:22]2[C:23]3[CH:35]=[C:34]([CH3:36])[S:33][C:24]=3[NH:25][C:26]3[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=3[N:28]=2)[CH2:20][CH2:21]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(CN1CCN(C2=Nc3ccccc3Nc3sc(C)cc32)CC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(N)CN1CCN(C2=Nc3ccccc3Nc3sc(C)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(N-Boc)amino-3-[4-(2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-yl)-piperazin-1-yl]-propionic acid, ethyl ester, H, (50 mg, 0.096 mmole) and HCl/ethanol (1.25 M, 2 ml) was stirred overnight at room temperature. The solvent was evaporated, the residue was diluted with water and washed with diethylether. The aqueous solution was lyophilized. Yield of Compound 2—30 mg (60%).
Reaction SMILES: [O:1]1[CH2:10][CH:2]1[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C.O>[N:11]([CH2:10][CH:2]([OH:1])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: c1ccc(CC2CO2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC(O)Cc1ccccc1
Temperature: 90 °C

Procedure:
To the stirring solution of (2,3-epoxypropyl)benzene (1.0 g, 7.5 mmol) in 4 mL DMF was added a solution of sodium azide (0.97 g, 15 mmol) in 4 mL water. The solution was heated to 90° C. for 1 h. The solvent was removed under reduced pressure. The solid residue was partitioned between ethyl acetate and near saturated sodium chloride. The aqueous layer was washed three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and purified on 10 g of silica eluting with 0 to 50% ethyl acetate/hexanes to give a clear oil. NMR (CDCL3) d (1H, 1.97 ppm), m (2H, 2.73-2.82 ppm), m (1H, 3.22-3.30 ppm), dd (1H, 3.36 ppm), m (1H, 3.92-4.02 ppm), m (3H, 7.13-7.28 ppm), m (2H, 7.28-7.34 ppm).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:23]([O:27][C:28]([N:30]1[CH2:37][CH:36]([CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:35][C@H:31]1[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].[N:48]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=[C:50]([NH:58][C:59](=[O:78])[C@@H:60]2[CH2:64][C@@H:63]([NH:65][C:66](=[O:77])[C@H:67]([OH:76])[CH2:68][CH2:69][C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[CH2:62][NH:61]2)[CH:49]=1>ClCCl.C(Cl)(Cl)Cl.C(N(CC)CC)C>[N:48]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=[C:50]([NH:58][C:59](=[O:78])[C@@H:60]2[CH2:64][C@@H:63]([NH:65][C:66](=[O:77])[C@H:67]([OH:76])[CH2:68][CH2:69][C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)[CH2:62][N:61]2[C:32](=[O:33])[C@@H:31]2[CH2:35][CH:36]([CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][N:30]2[C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH:49]=1
Reactant: O=C(N[C@H]1CN[C@H](C(=O)Nc2cnc3ccccc3c2)C1)[C@H](O)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCC1C[C@@H](C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
Triethylamine (21 μL), 1-hydroxybenzotriazole (9 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28 mg) were added to a solution of N-tert-butoxycarbonyl-4-[2-(tert-butoxycarbonylamino)ethyl]-L-Proline (48 mg) and trans-4-((R)-2-hydroxy-4-phenylbutyrylamino)-L-proline 3-quinolylamide (Compound D101 (H), 56 mg) in dichloromethane (3 mL) at 0° C. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with chloroform and washed with saturated sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by preparative silica gel thin layer chromatography (chloroform:methanol=12:1, v/v) to give the title compound (47 mg) as a colorless foam: 1H NMR (400 MHz, CDCl3) δ 1.40 (s, 9H), 1.48 (s, 9H), 1.71 (m, 2H), 1.99 (m, 1H), 2.13-2.51 (m, 6H), 2.75 (m, 2H), 3.16 (m, 2H), 3.63 (m, 1H), 3.73 (m, 1H), 3.87 (m, 1H), 3.90 (m, 1H), 4.38 (m, 1H), 4.53 (m, 1H), 4.80 (m, 1H), 4.82 (m, 1H), 5.50 (m, 1H), 7.15-7.64 (m, 9H), 7.68 (m, 1H), and 8.54 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[NH:7][CH3:8].C(O)(=O)C.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C.[Zn]>[Br:1][C:2]1[CH:9]=[C:6]([NH:7][CH3:8])[C:5]([NH2:10])=[CH:4][CH:3]=1
Reactant: CNc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CNc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-bromo-N-methyl-2-nitroaniline (1-1) (12.4 g, 53.7 mmol) in 1,4 Dioxane (100 mL) at 0° C. was added powdered zinc (17.6 g, 269 mmol), followed by dropwise addition of glacial acetic acid (15.0 mL, 262 mmol). The reaction mixture was then permitted to warm to room temperature, sonicated for a few minutes, then permitted to stir at room temperature overnight, then heated to 90° C. in a hot oil bath for four hours. The crude reaction mixture was then cooled to room temperature, then suspended in ethyl acetate, cooled to 0° C. and neutralized with 6N NaOH while stirring until slightly basic. Crude mixture was then filtered. Filtrate organics were separated, then washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated to give 4-bromo-N2-methylbenzene-1,2-diamine (1-2) as a black oil. MS (M)+: observed=200.9, calculated=201.06.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C@H:12]([CH2:16][CH3:17])[C:13]([OH:15])=[O:14])[CH2:7][CH2:6]2.[C:18]([O-])(O)=O.[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C@H:12]([CH2:16][CH3:17])[C:13]([O:15][CH3:18])=[O:14])[CH2:7][CH2:6]2
Reactant: CC[C@H](C(=O)O)[C@@H]1CCc2cc(OC)ccc21
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H](C(=O)OC)[C@@H]1CCc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
A suspension of the acid prepared in Example 21 (220.0 g, 0.94 mol), NaHCO3 (237.0 g, 2.82 mol), CH3l (200 g, 1.41 mol) in DMF (2.0 L) was stirred under argon at rt for 18 h. Adding additional CH3l (100 g, 0.71 mol) and stirring for an additional 24 h at rt caused completion of the reaction. The reaction mixture was poured into 4.0 L water, and extracted with EtOAc (2×2 L). The combined organic layers were sequentially washed with water (2×1 L), NaOH (1 L, 1 N aqueous solution), water (2×1 L), and brine (0.5 L). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (233 g, 99%) as a light yellow. 1H NMR (300 MHz, DMSO-d6) δ 6.90 (d, 1H), 6.78 (d, 1H), 6.66 (dd, 1H), 3.70 (s, 3H), 3.60 (s, 3H), 3.20 (m, 1H), 2.80 (m, 2H), 2.40 (m, 1H), 2.08 (m, 1H), 1.80 (m, 1H), 1.58 (m, 1H), 1.40 (m, 1H), 0.80 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5]O.C(N(CC)CC)C.CS([Cl:23])(=O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][Cl:23]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CO)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a solution of 3-fluoro-4-methoxybenzyl alcohol (1 g, 6.5 mmol) in dichloromethane (10 mL) were added under ice-cooling triethylamine (1.8 mL, 13 mmol) and methanesulfonyl chloride (0.60 mL, 7 mmol) and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an almost pure title compound (1.1 g, 100%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH3:21])=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH3:21])[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: CNc1ccc(OC)cc1
Reactant: Clc1ccnc2ccccc12
Product: COc1ccc(N(C)c2ccnc3ccccc23)cc1
Temperature: 140 °C
Yield: 74.2 %

Procedure:
A mixture of 4-chloroquinoline (50 mg, 0.31 mmol) and (4-methoxy-phenyl)-methyl amine (300 mg, 2.2 mmol) was heated in a sealed tube at 140° C. overnight. The crude product was purified by chromatography (20-40% ethyl acetate/hexanes) on silica gel to give the title compound (60 mg, 0.23 mmol, 74%). 1H NMR (CDCl3): 8.77 (d, 1H, J=5.1), 8.00-8.04 (m, 1H), 7.61-7.64 (m, 1H), 7.55 (ddd, 1H, J=1.5, 6.9, 8.4), 7.22 (ddd, 1H, J=1.5, 6.9, 8.1), 6.99 (d, 1H, J=4.8), 6.92 (m, 2H), 6.89 (m, 2H), 3.77 (s, 3H), 3.43 (s, 3H).
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]([OH:13])=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.C(=O)([O-])O.[Na+].O.[Br:20][CH:21]([CH2:25][CH2:26][CH2:27][Br:28])[C:22](Cl)=[O:23]>C(OCC)(=O)C>[Br:20][CH:21]([CH2:25][CH2:26][CH2:27][Br:28])[C:22]([NH:2][C:3]1[C:4]([OH:13])=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)=[O:23]
Reactant: Nc1cc2c(cc1O)CCCC2
Reactant: O=C(Cl)C(Br)CCCBr
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1cc2c(cc1O)CCCC2)C(Br)CCCBr
Reaction time: 0.5 h

Procedure:
To a mixture of 3-amino-5,6,7,8-tetrahydro-2-naphthol hydrobromide (1.70 g), sodium hydrogencarbonate (1.46 g), ethyl acetate (15 ml) and water (10 ml) was added under ice-cooling while stirring a solution of 2,5-dibromovaleryl chloride (1.94 g) in ethyl acetate (6 ml). The whole mixture was stirred for further 30 minutes. The ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layer was washed with an aqueous saline. solution, then dried (MgSO4), followed by distilling off the solvent to obtain 3-(2,5-dibromovaleryl)amino-5,6,7,8-tetrahydro-2-naphthol. This compound was dissolved in dimethylformamide (20 ml). To the solution was added powdery potassium carbonate (1.2 g), and the mixture was stirred at room temperature for 1.5 hour. To the resultant was added water, and precipitated crystals were collected by filtration, washed with water and dried, followed by recrystallization from ethyl acetate to obtain 1.53 g (67.8%) of 2-(3-bromopropyl)-6,7,8,9-tetrahydro-2H-naphtho [2,3 -b][1,4]oxazin-3(4H)-one as crystals, m.p. 139°-140° C. This compound was found to be identical with the product obtained in Reference Example 7.
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:16]=[C:17]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[O:26])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=2)C2C=CC=CC=2)C=CC=CC=1.Cl.CCOC(C)=O>C1COCC1>[NH2:14][C:15]1[CH:16]=[C:17]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:26])[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1
Reactant: CN1CCC(C(=O)c2cc(N=C(c3ccccc3)c3ccccc3)cc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCC(C(=O)c2cc(N)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
Dissolve (3-(diphenylmethyleneamino)-5-(trifluoromethyl)phenyl)(1-methylpiperidin-4-yl)methanone (210 mg, 0.47 mmol) in THF (2 mL) in an ice-bath, add hydrochloric acid (4N, 0.5 mL), then stir it at room temperature for one hour. TLC (PE:EtOAc=1:1) shows the reaction is complete. Partition the mixture between EtOAc and water. Collect the aqueous layer, adjust pH=9 with sodium hydroxide solution, extract with ethyl acetate three times, combine the organic layers, dry over anhydrous sodium sulfate, concentrate to yield the crude product (78 mg, 59%). MS: (M+1): 287.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:16])[CH2:12]CC#N)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:17]([OH:20])(=[O:19])[CH3:18]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:16])[CH2:12][CH2:18][C:17]([OH:20])=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(=O)O
Reactant: COc1ccc(C(=O)CCC#N)cc1OC
Agent: Cl
Product: COc1ccc(C(=O)CCC(=O)O)cc1OC
Temperature: 25 °C

Procedure:
A stirred solution of 4-(3',4'-dimethoxyphenyl)-4-oxobutyronitrile (111) (2.26 g, 0.01 mol) in acetic acid (15 ml) and hydrochloric acid (12N, 40 ml) was heated at reflux for 1.5 hours and cooled to room temperature. The solvent was removed under reduced pressure to give a brown solid. Recrystallization from water gave 112 as light tan crystals (1.57 g, 66%). 1H NMR (CDCl3) 2.80 (t, J=7.5 Hz, 2H), 3.30 (t, J=7.5 Hz, 2H), 3.94 (s, 3H), 3.96 (s, 3H), 6.89 (d, 1H, J=9 Hz), 7.55 (d, 1H, J=1 Hz) and 7.64 (dd, 1H, 1 and 9 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([O:12][C:13](=[O:18])[CH2:14][C:15](=[NH:17])[NH2:16])[CH3:11]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[CH3:1])[C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:18])=[C:15]([NH2:16])[NH:17][C:15]=1[NH2:16])=[O:18])[CH3:11]
Reactant: CCOC(=O)CC(=N)N
Reactant: Cc1ccccc1C=O
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccccc1C
Yield: 67 %

Procedure:
Upon boiling a solution of 6.0 g 2-methylbenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for two hours, 2,6-diamino-4-(2-methylphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 158°C (ethanol) is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([CH3:34])=[CH:28]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([CH3:34])=[CH:28]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCN1CCCCC1
Temperature: 85 °C
Yield: 54.8 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (100 mg, 0.29 mmol), 5-hydroxy-2-methylindole (53 mg, 0.36 mmol), (prepared as described for the starting material in Example 48), and potassium carbonate (62 mg, 0.44 mmol) in DMF (2 ml) was heated at 85° C. for 3 hours, followed by heating at 95° C. for 2 hours. After cooling, ice/water (15 ml) was added and the precipitate was collected by filtration and dried under vacuum. The solid was purified by column chromatography eluting with methylene chloride/methanol (95/5) followed by methylene chloride/methanol/3M ammonia in methanol (95/3/2) to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline (71 mg, 54%).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:12]([CH2:23][C:24]([OH:26])=[O:25])([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:11][CH2:10]2.[CH3:27]O>>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:12]([CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH2:18][C:19]([F:20])([F:21])[F:22])[CH2:11][CH2:10]2
Reactant: CO
Reactant: O=C(O)CC1(CC(F)(F)F)CCc2cc(O)ccc2C1=O
Agent: O=S(=O)(O)O
Product: COC(=O)CC1(CC(F)(F)F)CCc2cc(O)ccc2C1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
Sulfuric acid (2 mL) was added to a solution of 1E (8.5 g, 28.1 mmol) in methanol (80 mL), and the mixture was stirred at 80° C. for 3 h. Methanol was removed from reaction mixture under reduced pressure, and the residue was diluted with ethyl acetate and extracted with saturated NaHCO3 solution and brine solution. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the title compound (8.5 g, 91%) as a syrup. 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 7.77 (d, J=8.6 Hz, 1H), 6.75 (dd, J1=8.7 Hz, J2=2.4 Hz, 1H), 6.65 (s, 1H), 3.57 (s, 3H), 3.05-2.78 (m, 4H), 2.73-2.55 (m, 2H), 2.32 (m, 1H), 2.09 (m, 1H). ESI-MS m/z: 317 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:7][C:8]=1[C:9](O)=[O:10])([CH3:3])[CH3:2].[CH3:22][O:23][C:24](=[O:35])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=1[CH3:34].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:22][O:23][C:24](=[O:35])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:9]([C:8]2[S:7][C:6]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=3)=[N:5][C:4]=2[CH:1]([CH3:3])[CH3:2])=[O:10])=[CH:29][C:28]=1[CH3:34]
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)O
Reactant: COC(=O)CCc1ccc(N)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCc1ccc(NC(=O)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a mixture of 4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid (0.11 g, 0.35 mmol), 3-(4-Amino-2-methyl-phenyl)-propionic acid methyl ester (0.07 g, 0.35 mmol), and DMAP (0.01 g, 0.082 mmol) in CH2Cl2 (5 mL) is added EDCI (0.08 g, 0.42 mmol). After stirring for 2 h at RT, the mixture is concentrated. The residue is redissolved in EtOAc, and the organics are washed with 1N HCl (1×), 2N NaOH (2×), water, and brine, and dried with MgSO4. The crude material is purified by flash chromatography to yield the title compound (0.12 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][CH2:21][OH:22])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[N:10]=[N:11][C:12]([Cl:18])=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1.CC(C)=[O:25].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:25])=[O:22])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[N:10]=[N:11][C:12]([Cl:18])=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1
Reactant: CC(C)=O
Reactant: CC(C)c1cc(Oc2c(Cl)cc(CCO)cc2Cl)nnc1Cl
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC(C)c1cc(Oc2c(Cl)cc(CC(=O)O)cc2Cl)nnc1Cl
Temperature: -1.5 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of 2-[3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-ethanol (17) (8.4 g, 23.2 mmol) in acetone (270 mL) was treated with Jones Reagent (34.8 mL of a 2.7 M solution, prepared via standard method) slowly dropwise at −4° C. The resulting red reaction mixture was stirred for 1 h at −3 to 0° C. The red reaction mixture was quenched with isopropanol. The resulting green suspension was filtered through celite and the celite was washed well with ethyl acetate (600 mL). The filtrate was washed with water (600 mL) and a saturated aqueous sodium chloride solution (300 mL). The organic layer was separated, dried with magnesium sulfate, filtered, and concentrated. The resulting solid was dried under vacuum overnight to afford [3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-acetic acid (18) (8.3 g, 95%) as a white solid; LRMS for C15H15Cl3N2O3 (M+) m/z=377. Molecular Weight=377.6574; Exact Mass=376.0148
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:26])([CH3:25])[CH2:9]2)=[O:5])[CH3:2].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[C:10]([CH3:26])([CH3:25])[CH2:9]2)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(Br)cc(OC)c1)N2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(OC)cc(N3CCOCC3)c1)N2
Temperature: 120 °C
Yield: 35.3 %

Procedure:
A mixture of 2-(3-bromo-5-methoxy-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.85 g, 2.0 mmol), morpholine (1.77 g, 20 mmol), copper (I) iodide (0.23 g, 1.2 mmol), N,N-dimethylglycine hydrochloride (0.22 g, 1.6 mmol) and potassium carbonate (0.83 g, 6.0 mmol) in DMSO (5 mL) was heated for 4 hours at 120° C. After cooling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(20% ethyl acetate/hexanes) to afford 3,3-dimethyl-2-(3-methoxy-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.30 g, 36%) as a white solid: LC/MS m/e calcd for C25H32N2O4 (M+H)+: 425.5, observed: 425.3.