Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)=[CH:5][CH:4]=1.[NH2:21][C:22]1[CH:23]=[C:24]([S:29]([OH:32])(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1[NH2:28]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[N:21][C:22]3[C:27](=[CH:26][CH:25]=[C:24]([S:29]([OH:32])(=[O:30])=[O:31])[CH:23]=3)[N:28]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Reactant: Nc1ccc(S(=O)(=O)O)cc1N
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nc3ccc(S(=O)(=O)O)cc3nc2-c2ccc(OC)cc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 36.4 %

Procedure:
To a solution of 1,2-bis(4-methoxyphenyl)ethane-1,2-dione (200 mg, 0.74 mmol) in ethanol (3 mL) and water (3 mL) was added 3,4-diaminobenzene-1-sulfonic acid (116 mg, 0.62 mmol). The resulting solution was stirred overnight at 100° C. in an oil bath, and then quenched by the addition of water (60 mL), extracted with dichloromethane (3×20 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 2,3-bis(4-methoxyphenyl)quinoxaline-6-sulfonic acid (95.3 mg, 30.4%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:19])[NH:16]2)=[C:11]([C:20](=[O:23])[CH2:21]Cl)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].[OH-].[Na+].[Cl-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:19])[NH:16]2)=[C:11]([CH:20]2[CH2:21][O:23]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)c1cc(OCc2ccccc2)cc2[nH]c(=O)ccc12
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1ccc2c(C3CO3)cc(OCc3ccccc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6.0 g (18.3 mmol) 7-benzyloxy-5-(2-chloro-acetyl)-1H-quinolin-2-one are placed in 150 mL tetrahydrofuran and at 0 to 5° C. combined with 434 mg (819.9 mmol) lithium borohydride. The mixture is stirred for 30 minutes, then 43 mL of a 2.5 molar sodium hydroxide solution are added and the mixture is stirred for a further 4 hours with heating to ambient temperature. The mixture is combined with sodium chloride solution, filtered and extracted repeatedly with ethyl acetate/tetrahydrofuran (1:1). The solid filtered off and the organic phases are combined and freed from the solvent. The residue is suspended in methanol, suction filtered and dried. Yield 4.8 g (89%); mass spectroscopy: [M+H]+=294.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:22](COCC[Si](C)(C)C)[C:21]([O:31][C@H:32]3[C@H:36]4[O:37][CH2:38][C@@H:39]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C@H:35]4[O:34][CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:31][C@H:32]3[C@H:36]4[O:37][CH2:38][C@@H:39]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C@H:35]4[O:34][CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)C[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 2-[(3R,3aR,6R,6aS)-6-[6-chloro-5-(4-phenylphenyl)-1-(2-trimethylsilylethoxymethyl)-imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]acetate (34 mg, 0.052 mmol) in TFA (0.5 mL) and DCM (0.5 mL) was stirred at room temperature. After 1 hour, the reaction mixture was evaporated to an oil, dissolved in EtOH (1 mL) and purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-100% acetonitrile/water+0.05% TFA gradient followed by a 100% acetonitrile/water+0.05% TFA flush. The desired fractions were lyophilized to give the title compound as a solid. LC-MS: calculated for C28H26ClN3O5 519.16 observed m/e: 520.22 (M+H)+ (Rt 0.74/2 min); 1H NMR δ (ppm) (CD3OD): 7.87 (s, 1H), 7.75 (ABq, 4H), 7.71 (d, 2H), 7.48 (dd, 2H), 7.38 (dd, 1H), 5.57 (qt, 1H), 5.01 (t, 1H), 4.60 (t, 1H), 4.16 (q, 2H), 4.10 (dd, 1H), 4.00-4.06 (m, 2H), 3.53 (dd, 1H), 2.71 (dd, 1H), 2.59 (m, 1H), 2.51 (dd, 1H) and 1.27 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[C:16]([OH:17])=[C:15]([OH:18])[C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][C:10]=3[C:11](=[O:14])[CH2:12][CH2:13][C:4]=2[CH:3]=1.COB(OC)OC.[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27].Cl>C(Cl)Cl.O1CCCC1.O.C(N(CC)CC)C>[OH:17][C:16]1[C:2]([O:1][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[CH:3][C:4]2[CH2:13][CH2:12][C:11](=[O:14])[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[C:5]=2[C:15]=1[OH:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCc2cc(O)c(O)c(O)c2C2=C1CCC2
Agent: COB(OC)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2cc3c(c(O)c2O)C2=C(CCC2)C(=O)CC3)cc1
Reaction time: 16 h
Yield: 97.6 %

Procedure:
30 g of 2,3,5,6-tetrahydro-8,9,10-trihydroxy-benz[e]azulen-4(1H)-one obtained in Example 1, 300 ml of tetrahydrofuran, 60 ml of triethylamine and 12.9 ml of trimethylborate were stirred for 90 minutes at 20° C.±2° C. 30 g of tosyl chloride were added and the mixture was stirred for 16 hours at 20° C.±2° C. and then over 10 minutes at 20° C.±2° C., the reaction medium was poured into a stirred mixture of 900 ml of demineralized water and 150 ml of concentrated hydrochloric acid. Then, 90 ml of tetrahydrofuran and 60 ml of methylene chloride were added and the solution was stirred for one hour at 20° C. Then, 150 ml of methylene chloride were introduced and the mixture was stirred for 15 minutes, followed by decanting and extracting twice with 75 ml of methylene chloride. The combined organic phases were washed 4 times with 150 ml of demineralized water and reextracted with 75 ml of methylene chloride. After concentration under a reduced pressure of 20 mbars until distillation no longer occurred at 50° C., 47.6 g of the expected product were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=[O:5].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=[O:5]
Reactant: C1=COCCC1
Reactant: Cc1cc(O)cc(O)c1C=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(OC2CCCCO2)cc(O)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
A light yellow suspension of 2,4-dihydroxy-6-methyl-benzaldehyde (4.90 g, 24.98 mmol) in DCM (400 mL) was treated with 3,4-dihydro-2H-pyran (3.5 mL, 38.61 mmol) followed by pyridinium-p-toluenesulfonate (0.20 g, 0.80 mmol). The suspension slowly cleared to a yellow solution. The solution was stirred at rt overnight then diluted with water and washed with saturated NaHCO3. The organic layer was dried (Na2SO4), filtered and concentrated to a yellow oil. The residue was purified by column chromatography (SiO2, EtOAc/hexanes; 1:9) to afford 2-hydroxy-6-methyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (4.60 g, 70%), as a light yellow liquid. 1H NMR (400 MHz, CDCl3) δ 12.33 (s, 1H), 10.09 (s, 1H), 6.45 (d, J=2 Hz, 1H), 6.08 (d, J=2 Hz, 1H), 5.49-5.40 (m, 1H), 3.90-3.80 (m, 1H), 3.65-3.60 (m, 1H), 2.52 (s, 3H), 2.10-1.40 (m, 6H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)Cl>[C:1]([N+:8]1([O-:21])[CH2:9][CH:10]=[CH:11][CH2:12]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC=CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[N+]1([O-])CC=CC1
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a stirred solution of N-Boc-3-pyrroline (1.69 g, 10 mmol) in CH2Cl2 (20 mL) was added m-chloroperbenzoic acid (MCPBA) (˜85%, 5.2 g) in CH2Cl2 (20 mL) dropwise, and stirring was continued at room temperature overnight. The solution was extracted with saturated aqueous NaHCO3, saturated aqueous Na2SO3 and saturated aqueous NaHCO3 successively. The organic layer was dried over Na2SO4 and filtered. The solvent was evaporated and the residue was purified by flash chromatography (20% ethyl acetate in hexane) to give the product as an oil (1.54 g, 82%): 1H NMR (300 MHz, CDCl3) δ 3.77 (dd, J=22, 13 Hz, 2H), 3.66 (m, 2H), 3.31 (dd, J=13, 3 Hz, 2H), 1.44 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>CC(C)=O>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:9]=[CH:10]2
Reactant: BrCCCCBr
Reactant: Oc1ccc2c(ccn2-c2ccc(F)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(-n2ccc3cc(OCCCCBr)ccc32)cc1
Temperature: 55 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
To 230 mg (1 mmol) 1-(4-Fluoro-phenyl)-1H-indol-5-ol in 4 ml acetone were added 280 mg (2 mmol) powdered K2CO3 and 0.24 ml (2 mmol) 1,4-dibromobutane. The suspension was stirred at 55° C. for 5 h, cooled to RT and concentrated. The crude product was extracted with water and ether, the combined organic phases were washed and dried with Na2SO4. Purification by column chromatography on silica gel with hexane/EtOAc 9:1 yielded 320 mg (88%) 5-(4-Bromo-butoxy)-1-(4-fluoro-phenyl)-1H-indole as light yellow solid, 59-61° C., MS: 361 (M, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:34]=[N:33][C:32]([CH:35]=[CH2:36])=[CH:31][N:30]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:28][C:29]2[CH:34]=[N:33][C:32]([CH:35]=[CH2:36])=[CH:31][N:30]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: C=Cc1cnc(N)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 470 mg, 1.42 mmol) in methylene chloride (7 mL) was cooled to 0° C. and then was treated with a 2.0M solution of oxalyl chloride in methylene chloride (817 μL, 1.63 mmol) and N,N-dimethylformamide (1 mL). The reaction mixture was stirred at 0° C. for 30 min, concentrated in vacuo, and azeotroped with methylene chloride (3×2 mL). The resulting oil was then dissolved in tetrahydrofuran (10 mL) at 25° C. and then treated dropwise with a solution of 2-amino-5-vinylpyrazine (207 mg, 1.71 mmol) and 2,6-lutidine (198 μL, 1.71 mmol) in tetrahydrofuran (8 mL) via an addition funnel. The resulting cloudy solution was then stirred 25° C. overnight for 16 h. After this time, the reaction was diluted with water (10 mL) and then extracted with methylene chloride (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35 to 20/80 hexanes/ethyl acetate) afforded the 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-vinyl-pyrazin-2-yl)-propionamide (472 mg, 77%) as a light yellow solid: (ES)+-HRMS m/e calcd for C21H24ClN3O3S (M+H)+ 434.1300, found 434.1301.
Reaction SMILES: [CH3:1][C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH2:3][C:4](=[O:20])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[O:17])[O:15][N:14]=[C:13]([CH3:18])[C:12]=2[CH:19]=1)=[O:6].[CH3:28][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[OH:20][C:4]([CH3:28])([CH2:3][C:2]([CH3:1])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH3:21])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[O:17])[O:15][N:14]=[C:13]([CH3:18])[C:12]=2[CH:19]=1)=[O:6]
Reactant: Cc1noc(=O)c2ccc(NC(=O)C(=O)CC(C)(C)c3ccccc3)cc12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1noc(=O)c2ccc(NC(=O)C(C)(O)CC(C)(C)c3ccccc3)cc12
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
72 mg of 6-(4-methyl4-phenyl-2-oxo-valeroylamino)-4-methyl-2,3-benzoxazin-1-one in 4 ml of tetrahydrofuran is mixed with 3 ml of methylmagnesium bromide (3 mol) at 0° C. After 30 minutes, ammonium chloride solution is added, the organic phase is separated, dried and concentrated by evaporation. After chromatography on silica gel (hexane/ethyl acetate 1:1), 39 mg of 6-(2-hydroxy-2,4-dimethyl4-phenyl-valeroylamino)-4-methyl-2,3-benzoxazin-1-one, melting point 173-175° C., is obtained.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:11][C:9](=[O:10])[C:8]([CH2:12][C:13]3[C:22](=[O:23])[O:21][C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:14]=3O)=[C:7](O)[C:5]=2[CH:6]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl.C(N(CC)CC)C>[CH2:12]([C:8]1[C:9](=[O:10])[O:11][C:4]2[C:3]([C:7]=1[S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)(=[O:34])=[O:33])=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:13]1[C:22](=[O:23])[O:21][C:20]2[C:15]([C:14]=1[S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)(=[O:34])=[O:33])=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1oc2ccccc2c(O)c1Cc1c(O)c2ccccc2oc1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)c2c(Cc3c(S(=O)(=O)c4ccc(C)cc4)c4ccccc4oc3=O)c(=O)oc3ccccc23)cc1

Procedure:
To a solution of dicumarol (10 mmol) and p-toluenesulfonyl chloride (1.0 eq.) in dichloromethane (20 ml), triethylamine was added at room temperature under air atmosphere. After the reaction was complete, as monitored by TLC, the reaction mixture was evaporated and the residue was purified by flash chromatography (silica gel) to afford the product, 3,3′-methylenebis[4-tosylcoumarin].
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:23]1[C:40]2[C:41]3[C:26]([C:27]4[CH:28]=[CH:29][CH:30]=[C:31]5[C:42]=4[C:35]([C:36]=3[CH:37]=[CH:38][CH:39]=2)=[C:34]2[CH:43]=[CH:44][CH:45]=[CH:46][C:33]2=[CH:32]5)=[CH:25][CH:24]=1>O.[Cu]>[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([N:7]([C:23]2[C:40]3[C:41]4[C:26]([C:27]5[CH:28]=[CH:29][CH:30]=[C:31]6[C:42]=5[C:35]([C:36]=4[CH:37]=[CH:38][CH:39]=3)=[C:34]3[CH:43]=[CH:44][CH:45]=[CH:46][C:33]3=[CH:32]6)=[CH:25][CH:24]=2)[C:4]2[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=2)=[CH:9][CH:10]=1
Reactant: Brc1ccc2c3cccc4cc5ccccc5c(c5cccc1c25)c43
Reactant: Cc1ccc(Nc2ccc(C)cc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc3c4cccc5cc6ccccc6c(c6cccc2c36)c54)cc1

Procedure:
Then, di-p-tolylamine, potassium carbonate, and copper power were added to the thus obtained bromobenzo[a]perylene. This mixture stood still for reaction at 200 degrees centigrade for thirty hours. After reactant solution was diluted with water, reactant was extracted by chloroform. Thereafter, the reactant was refined in a conventional manner to thereby obtain di-p-tolylaminobenzo [a] perylene.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][C@H:8]2[NH:18][C:19](=[O:21])[CH3:20])[C:3]1=[O:22].O([C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=2)[N+:33]([O-:44])=[CH:32][N:31]=1)C1C=CC=CC=1.C(N(CC)C(C)C)(C)C>CC(O)C>[C:19]([NH:18][C@@H:8]1[CH2:9][C@H:10]([NH:13][C:14]([CH3:17])([CH3:15])[CH3:16])[CH2:11][CH2:12][C@@H:7]1[N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:43])([F:41])[F:42])[CH:38]=3)[N+:33]([O-:44])=[CH:32][N:31]=2)[C:3]1=[O:22])(=[O:21])[CH3:20]
Reactant: CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: [O-][n+]1cnc(Oc2ccccc2)c2cc(C(F)(F)F)ccc21
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](Nc2nc[n+]([O-])c3ccc(C(F)(F)F)cc23)C1=O
Temperature: 120 °C
Yield: 120 %

Procedure:
To a solution of N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexyl)acetamide (50 mg, 0.161 mmol, prepared as described above) and 4-phenoxy-6-(trifluoromethyl)quinazoline 1-oxide (99 mg, 0.161 mmol; see Example 5, Alternative Preparation, Step 2) in i-PrOH (2 ml) was added N,N-diisopropylethylamine (0.056 ml, 0.322 mmol). The vessel was sealed under argon atmosphere and heated in a microwave for 1 hr at 120° C. LC/MS found: (M+H)+=523.3 as the major product peak. The reaction was repeated on the same scale in a separate vessel. The two reactions were combined and evaporated to give an oily residue, which was purified by automated flash chromatography (40 g silica gel) with elution by 8:92 (10% cNH4OH in MeOH). The fractions containing the desired product were pooled and concentrated in vacuo. The residue was crystallized from CH2Cl2 and hexane. The two crops were combined and dried under vacuum to afford 4-((S)-1-((1S,2R,4R)-2-acetamido-4-(tert-butylamino)cyclohexyl)-2-oxopyrrolidin-3-ylamino)-6-(trifluoromethyl)quinazoline 1-oxide (101 mg). Analysis by 1H-NMR showed that this material contained ˜0.6 molar equivalents of CH2Cl2. LC/MS found: [M+H]+=523.30. 1H-NMR (400 MHz, CD3OD), δ ppm: 9.00 (s, 1H), 8.80 (s, 1H), 8.61 (d, J=9.0 Hz, 1H), 8.32 (dd, J=9.0, 1.6 Hz, 1H), 5.28 (t, J=8.3 Hz, 1H), 4.57 (brs, 1H), 4.02 (brd, 1H), 3.65-3.51 (m, 2H), 3.24 (brs, 1H), 2.59-2.51 (m, 1H), 2.34-2.20 (m, 1H), 2.04 (s, 3H), 2.04 (m, 1H), 1.89 (brs, 3H), 1.74 (brs, 2H), 1.20 (s, 9H).
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[Cl:9][C:10]1[C:11]([C:23]#[N:24])=[N:12][CH:13]=[C:14]([Cl:22])[C:15]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19]>C(O)C>[Cl:9][C:10]1[C:11]([C:23]([NH2:24])=[O:2])=[N:12][CH:13]=[C:14]([Cl:22])[C:15]=1[O:16][CH2:17][C:18]([F:21])([F:19])[F:20]
Reactant: N#Cc1ncc(Cl)c(OCC(F)(F)F)c1Cl
Reactant: O=C([O-])O
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ncc(Cl)c(OCC(F)(F)F)c1Cl
Reaction time: 2 h
Yield: 100 %

Procedure:
To 5 ml of ethanol were added 0.41 g of sodium bicarbonate and 0.34 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.6 g of 3,5-dichloro-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonitrile was added at room temperature, and the mixture was stirred for 2 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was washed with hexane three times to obtain 0.64 g of 3,5-dichloro-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide=oxime.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-])=O.Cl>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: CCOC(=O)/C=C/c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCc1ccc(N)cc1
Reaction time: 16 h
Yield: 86.2 %

Procedure:
A 500 mL Parr hydrogenation vessel was charged with 12.36 g (55.9 mmol) of (E)-3-(4-nitrophenyl)-2-propenoic acid, ethyl ester, 100 mL of absolute ethanol, 15 mL of concentrated hydrochloric acid and 0.75 g of 10% palladium-on-activated charcoal. The slurry was purged with nitrogen and then agitated under an initial pressure of 44.5 psi of hydrogen gas. After 16 h, 18.5 psi had been consumed. The flask was evacuated, purged again with nitrogen and the contents filtered through Celite and evaporated. The residue was dissolved in water and adjusted to pH 9 with solid sodium carbonate. The resulting mixture was extracted thrice with dichloromethane and the combined organic extracts dried over Na2SO4, filtered and evaporated to provide 9.31 g, 86% of title compound as a yellow oil, sufficiently pure for use in subsequent reactions.
Reaction SMILES: Cl[C:2]1(Cl)[C:9](=[O:10])[CH2:8][CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([O:18][CH3:19])[CH2:16][CH3:17]>[Zn].C(O)(=O)C>[CH3:19][O:18][CH:15]([CH2:16][CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH:6]1[CH2:5][CH2:4][CH:3]2[CH:7]1[CH2:8][C:9](=[O:10])[CH2:2]2
Reactant: CCC(CCCCC1CCC2C1CC(=O)C2(Cl)Cl)OC
Agent: [Zn]
Solvent: CC(=O)O
Product: CCC(CCCCC1CCC2CC(=O)CC12)OC

Procedure:
6,6-Dichloro-2-(5-methoxyhept-1-yl)bicyclo[3.3.0]octan-7-one {1,1-dichlorohexahydro-4-(5-methoxyheptyl)-2(1H)-pentalenone} (45.9 g) is added to a 100 ml, round-bottomed flask fitted with a condenser. Powdered zinc metal (92 g) and glacial acetic acid (312 ml) are added to the flask and the solution allowed to reflux for an hour. The solution is filtered to remove the zinc and zinc chloride, formed in the reaction. The product is washed with an aqueous sodium bicarbonate solution and extracted three times with ether. The ether extracts are combined and dried over anhydrous sodium sulfate. The resulting yellow oil is chromatographed on silica gel and eluted with 4:1 hexane:ether. The fractions are combined, and gave 2-(5-methoxyhept-1-yl)bicyclo[3.3.0]octan-7-one {hexahydro-4-(5-methoxyheptyl)-2(1H)-pentalenone} as a clear, colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH2:34])=[CH:28][CH:27]=1>>[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH:34][C:14]2[N:13]=[C:12]3[N:11]([CH3:23])[C:10](=[O:24])[N:9]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[CH2:18][C:17]3=[CH:16][N:15]=2)=[CH:28][CH:27]=1
Reactant: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Reactant: NCCc1ccc(N)cc1
Product: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(NCCc3ccc(N)cc3)nc21
Temperature: 70 °C
Yield: 2.6 %

Procedure:
A mixture of 100 mg (0.26 mmol) of 3-(2,6-dichlorophenyl)-3,4-dihydro-7-methanesulfonyl-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 140 mg (1 mmol) of 2-(4-aminophenyl)ethylamine was heated at 70° C. for 20 minutes. The product was purified by flash column chromatography using 5% methanol in dichloromethane for the elution. Product-containing fractions were combined and evaporated. The residue was recrystallized from ethyl acetate and 3 mg (3%) of 7-[2-(4-aminophenyl)ethylamino]-3-(2,6-dichlorophenyl)-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one were isolated as a yellow solid of melting point 174-175° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@H:5]1[CH2:9][O:8]C(C2C=CC=CC=2)=[N:6]1)[CH3:2].[ClH:16]>>[ClH:16].[NH2:6][C@@H:5]([CH2:4][O:3][CH2:1][CH3:2])[CH2:9][OH:8]
Reactant: CCOC[C@H]1COC(c2ccccc2)=N1
Agent: Cl
Product: CCOC[C@H](N)CO
Temperature: 25 °C
Yield: 62 %

Procedure:
(S)-4-(ethoxymethyl)-2-phenyl-4,5-dihydrooxazole (909 mg, 4.43 mmol) was dissolved in 25 ml 4.0 M hydrochloric acid. The resulting solution was refluxed for 20 hours. After cooling to ambient temperature the mixture was filtered to remove the benzoic acid. The filtrate was extracted with ether, and the ether layer discarded. The aqueous layer was concentrated to afford (R)-2-amino-3-ethoxypropan-1-ol hydrochloride (425 mg, 62%) as a low-melting reddish solid.