Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].I[C:14]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[C:16]([CH3:35])[N:15]=1.[NH2:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1>O.CN(C)C=O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:20][C:19]1[C:14]([C:41]2[CH:42]=[C:37]([NH2:36])[CH:38]=[CH:39][CH:40]=2)=[N:15][C:16]([CH3:35])=[CH:17][CH:18]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(N)c3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Toluene (1 ml), N,N-dimethylformamide (0.5 ml), and a saturated aqueous sodium hydrogencarbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (28 mg), and 3-aminophenylboronic acid (162 mg) under an argon atmosphere, and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The ethyl acetate layer was then washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (39 mg, yield 85%).
Reaction SMILES: [CH3:1][N:2]1[CH2:22][CH2:21][C:5](=[C:6]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH:14]=[CH:13][C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)[CH2:4][CH2:3]1.[H][H]>C(O)(=O)C.C(O)C.[Pt]=O>[CH:11]1[C:12]2[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:6](=[C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:22][CH2:21]3)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: CN1CCC(=C2c3ccccc3CCc3ccccc32)CC1
Yield: 94.2 %

Procedure:
Dissolved cyproheptadine (22.2 g, 0.077 mol) in 150 mL of glacial acetic acid and 20 mL of ethanol. Added platinum oxide catalyst (1.0 g), and hydrogenated on Paar shaker at 57 psi of hydrogen pressure for 5 hours. Filtered, and evaporated filtrate to give a solid. Recrystallized crude product from ether-pet ether to give 21.0 g (94% yield) of 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine as a white solid.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][C:9]([F:14])([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:4].[OH-].[Li+]>O1CCOCC1.O>[C:18]([O:17][C:15]([N:6]1[CH2:7][CH2:8][C:9]([F:14])([CH2:11][CH2:12][CH3:13])[CH2:10][CH:5]1[C:3]([OH:4])=[O:2])=[O:16])([CH3:19])([CH3:20])[CH3:21]
Reactant: CCCC1(F)CCN(C(=O)OC(C)(C)C)C(C(=O)OC)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCC1(F)CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 21c (m=2, P2=Boc, R9=n-propyl) (1.06 g, 3.47 mmol) in dioxane-water 6:1 (42 mL) was treated with 1.0 M aq. lithium hydroxide (5.3 mL, 5.3 mmol). The reaction mixture was stirred at room temperature overnight, then treated with additional 1.0 M aq. lithium hydroxide (1.5 mL) and the resulting reaction mixture was stirred 5 h. The reaction solvent was removed, the residue was taken up in ethyl acetate (500 mL), washed with 10% Citric acid and brine and dried over MgSO4. Concentration of organic solution to afford the desired product 4-fluoro-4-propyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 21d (m=2, P2=Boc, R9=n-propyl) (0.88 g, 87%) as a white solid.
Reaction SMILES: [OH:1][C:2]([CH3:12])([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[Cl:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>O1CCCC1>[CH3:11][C:2]([O:1][C:23](=[O:24])[CH2:22][CH2:21][Cl:20])([CH3:12])[C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(O)C(=O)c1ccccc1
Reactant: O=C(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(OC(=O)CCCl)C(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 72 h
Yield: 6.5 %

Procedure:
9.9 g (60 mmol) 2-hydroxy-2-methyl-1-phenyl-1-propanone (DAROCUR™ 1173) was dissolved in 60 ml tetrahydrofuran. 6.1 g (60 mmol) triethyl amine was added and the reaction mixture was cooled to −10° C. 7.6 g (60 mmol) 3-chloro-propionyl chloride was added while the temperature was kept below −5° C. The reaction was allowed to continue for 30 minutes at 0° C. and for 72 hours at 40° C. The precipitated salts were removed by filtration and the solvent was evaporated under reduced pressure. 3-chloro-propionic acid 1,1-dimethyl-2-oxo-2-phenylethyl ester was purified by preparative column chromatography on a Prochrom LC80 column, using n.-hexane/ethyl acetate 80/20 as eluent at a flow rate of 150 ml/min and Kromasil 60A 10 micron as silica. 1 g of 3-chloro-propionic acid 1,1-dimethyl-2-oxo-2-phenylethyl ester was isolated.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:12])([C:10]#[CH:11])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[N:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N+:14]=[N-:15].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.C([O-])(O)=O.[Na+]>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][N:13]1[CH:11]=[C:10]([C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)([OH:12])[CH3:9])[N:15]=[N:14]1)[CH3:21]
Reactant: C#CC(C)(O)c1cccc(Br)n1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)Cn1cc(C(C)(O)c2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(6-Bromopyridin-2-yl)but-3-yn-2-ol (300 mg, 1.33 mmol) and ethyl azidoacetate (0.82 mL, 1.46 mmol) were combined in t-BuOH (3.0 mL) and water (1.0 mL). CuSO4.5H2O (17 mg, 0.066 mmol) in water (1.0 mL) was added, followed by sodium ascorbate (53 mg, 0.27 mmol) in water (1.0 mL). The reaction was stirred at room temperature overnight, diluted with saturated NaHCO3, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Purification by flash chromatography (10-100% EtOAc/hexanes) afforded the title compound as a colorless oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].CN1CCCC1=[O:18].[NH2:19][CH2:20][CH2:21][O:22][CH:23](O)[CH3:24].C([O-])([O-])=O.[K+].[K+]>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][OH:18])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CC(O)OCCN
Reactant: CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1NCCOCCO
Temperature: 60 °C

Procedure:
2 g of 2-fluoro-5-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.63 g of 2-aminoethoxyethanol and 2.14 g of K2CO3. The reaction medium was heated at 60° C. for 12 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The resulting medium was extracted with ethyl acetate and the organic phase was then concentrated under vacuum. 2.2 g of 2-[2-(4-nitro-2-methylphenylamino)ethoxy]ethanol (13) were obtained.
Reaction SMILES: C([Li])(CC)C.CN(CCN(C)C)C.Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[CH:19]1[N:25]([CH3:28])[CH2:26][CH2:27][C:18]21[CH3:29].[CH2:30]([N:32]([C:35](=[O:41])[C:36](OCC)=[O:37])[CH2:33][CH3:34])[CH3:31]>CCOCC>[CH2:30]([N:32]([CH2:33][CH3:34])[C:35](=[O:41])[C:36](=[O:37])[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[CH:19]1[N:25]([CH3:28])[CH2:26][CH2:27][C:18]21[CH3:29])[CH3:31]
Reactant: CCOC(=O)C(=O)N(CC)CC
Reactant: CN1CCC2(C)c3cc(Br)ccc3N(C)C12
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CCN(CC)C(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a stirred (-78° C.) solution of sec-butyllithium (1.3M in cyclohexane; 6.6 ml) and TMEDA (1.3 ml) in anhydrous ether (4.0 ml) was added via canula under a N2 atmosphere a solution of 5-bromo-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole (1.69 g), in anhydrous ether (4.0 ml). The solution was stirred at -78° C. for 2.5 hours and then added via canula, under N2, to a stirred (-78° C.) solution of N,N-diethylamino-oxo-acetic acid, ethyl ester (3.6 g) in diethyl ether (8.0 ml). The solution was stirred at -78° C. for 3 hours and gradually allowed to warm to room temperature over 2 hours. The mixture was quenched by the addition of an aqueous solution of saturated NH4Cl. The organic phase was separated and washed with two 50 ml portions of an aqueous solution of saturated NaHCO3, with brine, and dried (Na2SO 4). The crude residue was purified using preparative HPLC (silica gel, loading and eluting with 3% methanol in dichloromethane). The appropriate fractions were combined and concentrated to a foam which solidified upon trituration with hexane, to afford 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, diethyl amide.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([N:9]2[CH:14]=[CH:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:6]=[CH:7][CH:8]=1.[Si:19]([O:36][CH2:37][C@H:38](O)[CH3:39])([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[Si:19]([O:36][CH2:37][C@H:38]([N:11]1[C:12](=[O:15])[CH:13]=[CH:14][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)[C:10]1=[O:16])[CH3:39])([C:32]([CH3:33])([CH3:34])[CH3:35])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)c(=O)[nH]1
Reactant: C[C@@H](O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)n1c(=O)ccn(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a solution of 1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 98 or 99) (740.0 mg) in tetrahydrofuran (10.0 ml) was added (R)-1-(tert-butyldiphenylsilyloxy)propane-2-ol (1.82 g), triphenylphosphine (1.5 g) and diethyl azodicarboxylate (2.7 ml:2.2 M toluene solution) and the resulting mixture was stirred at room temperature for twelve hours. To the reaction mixture was added water (50 ml), and the resulting mixture was extracted with ethyl acetate (30 ml×2) and the organic layer was washed with water (20 ml) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-3-[1-(tert-butyldiphenylsilyloxy)propane-2-yl]-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (969.8 mg).
Reaction SMILES: C=O.[Cl:3][C:4]1[C:5]([F:33])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:31][CH3:32])=[C:18]([O:21][C@@H:22]4[CH2:27][CH2:26][NH:25][C@@H:24]([C:28]([NH2:30])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O.C(Cl)Cl>[Cl:3][C:4]1[C:5]([F:33])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:31][CH3:32])=[C:18]([O:21][C@@H:22]4[CH2:27][CH2:26][N:25]([CH3:34])[C@@H:24]([C:28]([NH2:30])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN[C@@H](C(N)=O)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C)[C@@H](C(N)=O)C1
Yield: 803.6 %

Procedure:
Molecular sieves (0.5 g) followed by aqueous formaldehyde (1 ml) were added to a stirred solution of (2R,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxamide (9) (0.102 g, 0.23 mmol) in DCM-AcOH (10:1 ml) at room temperature. The reaction mixture was stirred for 1-2 minutes before solid sodium triacetoxyborohydride (0.10 g, 0.463 mmol) was added portionwise over 5 minutes. The reaction was essentially complete after all the sodium triacetoxyborohydride reducing agent had been added. DCM was added (20 ml) and the reaction was carefully neutralised with saturated aqueous NaHCO3(aq). The organic extract was washed with brine, dried (MgSO4) and concentrated to a yellow foam. The residue was purified by preparative LCMS (standard basic conditions) to give the title product as a white solid (0.85 g, 80%): 1H NMR Spectrum: (DMSO d6) 1.87-1.92 (m, 3H), 2.07-2.09 (m, 1H), 2.20 (s, 3H), 2.43-2.47 (m, 1H), 2.71-2.80 (m, 2H), 3.96 (s, 3H), 4.82 (m, 1H), 7.03 (s, 1H), 7.23 (s, 1H), 7.26-7.30 (m, 2H), 7.47-7.54 (m, 2H), 7.82 (s, 1H), 8.37 (s, 1H), 9.60 (s, 1H); Mass Spectrum: (M+H)+ 459.9.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([OH:7])=O.Cl.[Cl:9][C:10]1[CH:11]=[C:12]([OH:30])[CH:13]=[C:14]([NH:16][C:17]2[C:18]3[C:25]4[CH2:26][CH2:27][NH:28][CH2:29][C:24]=4[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:15]=1.[CH:31]12[CH2:38][CH:35]([CH2:36][CH2:37]1)[CH2:34][NH:33][CH2:32]2>>[CH:31]12[CH2:38][CH:35]([CH2:36][CH2:37]1)[CH2:34][N:33]([CH2:2]/[CH:3]=[CH:4]/[C:5]([N:28]1[CH2:27][CH2:26][C:25]3[C:18]4[C:17]([NH:16][C:14]5[CH:13]=[C:12]([OH:30])[CH:11]=[C:10]([Cl:9])[CH:15]=5)=[N:22][CH:21]=[N:20][C:19]=4[S:23][C:24]=3[CH2:29]1)=[O:7])[CH2:32]2
Reactant: C1CC2CNCC1C2
Reactant: O=C(O)/C=C/CBr
Reactant: Oc1cc(Cl)cc(Nc2ncnc3sc4c(c23)CCNC4)c1
Agent: Cl
Product: O=C(/C=C/CN1CC2CCC(C2)C1)N1CCc2c(sc3ncnc(Nc4cc(O)cc(Cl)c4)c23)C1

Procedure:
In analogy to Example 130, the title compound was prepared from (2E)-4-bromobut-2-enoic acid (84 mg, 0.41 mmol), 3-chloro-5-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol hydrochloride from Example 65A (100 mg, 0.27 mmol) and 3-azabicyclo[3.2.1]-octane (48 mg, 0.43 mmol) to yield 44 mg (32%).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[CH:18]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:25].[C:26](Cl)(=[O:28])[CH3:27]>>[C:26]([N:22]1[CH2:23][CH2:24][C@H:20]([O:19][C:17]2[CH:18]=[C:13]([C:9]3[CH:8]=[C:7]4[C:12](=[CH:11][CH:10]=3)[N:3]([CH3:2])[C:4](=[O:25])[CH2:5][CH2:6]4)[CH:14]=[N:15][CH:16]=2)[CH2:21]1)(=[O:28])[CH3:27]
Reactant: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CCNC4)c3)ccc21
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CC[C@H](Oc2cncc(-c3ccc4c(c3)CCC(=O)N4C)c2)C1

Procedure:
In analogy to the procedure described in example 76, 1-methyl-6-[5-((S)-pyrrolidin-3-yloxy)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 60) has been reacted with acetyl chloride to give the title compound as a colorless solid. MS: 366.4 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][C:14]([O:16]CC)=[O:15])=[N:10][C:9]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].Cl>C(O)C>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][C:14]([OH:16])=[O:15])=[N:10][C:9]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)Cc1nc(-c2cccc(C)c2)c(-c2ccnc(N)c2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(-c2nc(CC(=O)O)sc2-c2ccnc(N)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a suspension of ethyl [5-(2-amino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]acetate (7.00 g, 19.8 mmol) in ethanol (40 mL) was added 1N aqueous sodium hydroxide solution (40 mL), and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was neutralized with 2N hydrochloric acid (20 mL) and the resulting solid was collected by filtration. The crude product was washed with water and dried to give the title compound (6.10 g, yield 95%).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][O:18][C:19]4[CH:40]=[CH:39][C:22]([C:23]([NH:25][C@H:26]([C:34]([O:36]CC)=[O:35])[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:24])=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][O:18][C:19]4[CH:40]=[CH:39][C:22]([C:23]([NH:25][C@H:26]([C:34]([OH:36])=[O:35])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:24])=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(OCc2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc3ccc(COc4ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc4)cc3c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
Diethyl N-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoyl)-L-glutamate (0.18 g, 0.33 mmol) was suspended in ethanol (2 ml) and 0.25N NaOH (8 ml) and stirred 1.5 hours at room temperature with intermittent periods of sonication. Additional ethanol (4 ml) and warming were required to obtain a homogeneous solution. The solution was stirred 3 hours at room temperature and then adjusted to pH 3 with 1N HCl. The resulting suspension was filtered, and the white solid washed with water and dried under high vacuum to give N-(4-((1,2-dihydro-3-methyl-oxobenzo[f]quinazolin-9-yl)methoxy)benzoyl)-L-glutamic acid (0.158 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.87-2.16 (m, 2H, glu CH2), 2.35 (t, J=7 Hz, 2H, glu CH2), 2.44 (s, 3H, CH3), 4.33-4.43 (m, 1H, glu CH), 5.43 (s, 2H, CH2O), 7.16 (d, J=9 Hz, 2H, Ar), 7.64 (d, J=9 Hz, 1H, Ar), 7.74 (dd, J=8,2 Hz, 1H, Ar), 7.88 (d, J=9 Hz, 2H, Ar), 8.08 (d, J=8 Hz, 1H, Ar), 8.26 (d, J=9 Hz, 1H, Ar), 8.47 (d, J=8 Hz, 1H, glu NH), 9.94 (s, 1H, Ar), 12.36 (br s, 2H, CO2H's ), 12.59 (s, 1H, N2H). Anal. Calculated for C26H23N3O7.1/4H2O: C, 63.22; H, 4.79; N, 8.51. Found: C, 63.23; H, 4.80; N, 8.48.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[C:15]=1[OH:16])=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH2:18](Br)[CH:19]=[CH2:20].O.C(=O)([O-])[O-].[K+].[K+].[CH3:29][C:30]([CH3:32])=O>ClCCl>[CH2:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[C:15]=1[O:16][CH2:32][CH:30]=[CH2:29])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:19]=[CH2:20]
Reactant: C=CCBr
Reactant: CC(C)=O
Reactant: O=c1c2ccccc2oc2c(O)c(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: C=CCOc1ccc2c(=O)c3ccccc3oc2c1OCC=C
Temperature: 25 °C
Yield: 95 %

Procedure:
A stirred solution of 3,4-dihydroxyxanthen-9-one (290 mg, 1.27 mmol), allyl bromide (800 μL, 9.20 mmol), potassium carbonate hydrate (1.28 g, 7.77 mmol) and acetone (15.0 mL) was refluxed for 2.5 h. The solution was cooled to room temperature and dichloromethane was added. The mixture was filtered and the filtrate was rotary evaporated to yield 372 mg (95%) of the title compound as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 8.33 (dd, J1=7.84 Hz, J2=1.79, 1H), 8.07 (d, J=8.79 Hz, 1H), 7.72 (ddd, J1=8.10 Hz, J2=7.01, J3=1.65, 1H), 7.56 (dd, J1=8.51 Hz, J2=0.55, 1H), 7.38 (ddd, J1=7.76 Hz, J2=7.07, J3=1.03, 1H), 7.00 (d, J=9.06 Hz, 1H), 6.15 (m, 2H), 5.48 (m, 1H), 5.38 (m, 2H), 5.25 (m, 1H), 4.74 (m, 4H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][NH:20][C:21]([C@@H:23]3[CH2:26][CH2:25][N:24]3C(OC(C)(C)C)=O)=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1>ClCCl>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][NH:20][C:21]([C@@H:23]3[CH2:26][CH2:25][NH:24]3)=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nccc2cc(CNC(=O)[C@@H]3CCN3)ccc12
Yield: 121.7 %

Procedure:
10 mL Trifluoroacetic acid was added to a solution of 2,4 g of N-(1-amino-isoquinolin-6-ylmethyl)-1-tert.butoxycarbonyl-azetidin-2(S)-carboxamide in 5.0 mL dichloromethane. The solvent was removed i.vac to give 2.1 g of the title compound as trifluoroacetate salt. MS: 371.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[NH:10][C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[CH:6]=1>C(O)C>[NH:2]([C:5]1[NH:10][C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[CH:6]=1)[NH2:3]
Reactant: NN
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Solvent: CCO
Solvent: O
Product: Cn1c(=O)cc(NN)[nH]c1=O
Temperature: 75 °C

Procedure:
Hydrazine hydrate (12.7 ml) was added to a suspension 6-chloro-3-methyl-2,4(1H,3H)-pyrimidinedione (10 g) in ethanol (190 ml). The mixture was heated at 75° C. for 40 hours, cooled to room temperature. The yellow solid precipitated was filtered and dried give the subtitle compound (8.5 g). Mass: 156.76 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:8]=3[CH:9]3[CH:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.[CH3:24][C:25]1([CH3:39])[C@@H:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:30][P:28]([OH:38])(=[O:29])[O:27][CH2:26]1.C(Cl)Cl.C(O)C>CC(=O)CC>[OH:38][P:28]1(=[O:29])[O:30][C@@H:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:25]([CH3:24])([CH3:39])[CH2:26][O:27]1.[Br:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:8]=3[C@H:9]3[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: NC1CCCN2c3cc(Br)c(F)cc3Oc3cccc(F)c3C12
Reactant: CC1(C)COP(=O)(O)O[C@@H]1c1ccccc1
Solvent: CCC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: CC1(C)COP(=O)(O)O[C@H]1c1ccccc1
Product: N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3cccc(F)c3[C@@H]12
Yield: 27 %

Procedure:
Preparation analogous to Example 5, step i, from 2.2 g, (5.77 mmol) of (±)-(cis)-(7-bromo-8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine, 0.7 g, (2.88 mmol) of (+)-phencyphos, CH2Cl2 (100 mL), ethanol (5 mL) and 2-butanone (50 mL). Recrystallization gave the title compound (0.8 g, 27%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12]CC[C@H:9]1[C:13](O)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]([F:37])([F:36])[C:18]1[CH:19]=[C:20]([S:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.F[C:39](F)(F)[C:40]1[CH:41]=[C:42](S(N2C[C@H]3[C@H](N)CC[C@H]3C2)(=O)=O)[CH:43]=[CH:44][CH:45]=1>>[F:37][C:17]([F:16])([F:36])[C:18]1[CH:19]=[C:20]([S:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH:35][C:13]([C@@H:9]4[CH2:39][C:40]5[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH2:12][N:8]4[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:14])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)(=[O:25])=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21

Procedure:
The title compound was prepared by substituting (S)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid for (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid and (3aR,4S,6aS)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Step D of Example 252 for (3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 266: 1H NMR (500 MHz, pyridine-d5, temperature 90° C.) δ ppm 8.26-8.27 (bs, 1H), 8.08-8.10 (m, 1H), 7.81-7.84 (m, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.29-7.36 (m, 1H), 7.12-7.14 (m, 2H), 7.08-7.11 (m, 2H), 4.83-5.02 (m, 1H), 4.78 (d, J=15.6 Hz, 1H), 4.67 (d, J=15.6 Hz, 1H), 3.90-3.97 (m, 1H), 3.52 (dd, J=10.1, 3.3 Hz, 1H), 3.30 (dd, J=15.3, 4.8 Hz, 1H), 3.14 (dd, J=9.9, 7.8 Hz, 1H), 3.11 (dd, J=15.4, 6.3 Hz, 1H), 3.04-3.08 (m, 2H), 2.45-2.53 (m, 1H), 2.38-2.45 (m, 1H), 1.64-1.75 (m, 2H), 1.50 (s, 9H), 1.35-1.46 (m, 1H), 1.15-1.25 (m, 1H); MS (ESI+) m/z 594 (M+H)+, 611 (M+NH4)+.