Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[Br:18][C:19](Br)([Br:23])C([O-])=O.[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCCl>[Br:18][C:19]1([Br:23])[C:2]2([CH2:3][C@@H:4]([C:14]([O:16][CH3:17])=[O:15])[N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8])[CH2:6]2)[CH2:1]1
Reactant: O=C([O-])C(Br)(Br)Br
Reactant: C=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)[C@@H]1CC2(CN1C(=O)OC(C)(C)C)CC2(Br)Br
Temperature: 70 °C
Yield: 88.4 %

Procedure:
To a mixture of (S)-1-tert-butyl 2-methyl 4-methylenepyrrolidine-1,2-dicarboxylate (6 g, 24.9 mmol) and tetrabutylammonium bromide (161 mg, 0.02 eq) in anhydrous 1,2-dichloroethane (60 mL, 10 volumes) was added sodium tribromoacetate (17.48 g, 2.2 eq). The mixture was degassed and filled with N2 gas. It was heated at 70° C. for 2.5 hrs before additional sodium tribromoacetate (2.4 g, 0.3 eq) was added. The mixture was heated at 70° C. for 40 min. After the completion of the reaction, it was allowed to cool to room temperature and evaporated. The residue was diluted with 30% hexanes in tert-butyl methyl ether (100 mL) and filtered through a pad of celite. The filtrate was washed with water and brine, dried (Na2SO4), filtered and evaporated to dryness. The residue was passed through a silica gel (5.5 wt. volumes) pad with 0-15% tert-butyl methyl ether in hexanes and concentrated to afford the title compound (9.09 g, 88%) as a yellow oil as a mixture of two regioisomers. 1H NMR (500 MHz, CDCl3): 4.63-4.44 (m, 1H), 3.92-3.86 (m, 1H), 3.79 and 3.74 (2 s, 3H), 3.53-3.42 (m, 1H), 2.83-2.35 (m, 1.5H), 1.91-1.70 (m, 2.5H), 1.48 and 1.43 (2 s, 9H). ESI MS m/z (M+H)+ 413.85.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:12][C:11]1[C:2]([OH:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Oc1cc2ccccc2nc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3O)c2cc1OC
Temperature: 135 °C
Reaction time: 5.5 h
Yield: 38.4 %

Procedure:
2,3-Dihydroxyquinoline (450 mg), 4-chloro-6,7-dimethoxyquinoline (575 mg), and 4-dimethylaminopyridine (472 mg) were suspended in o-dichlorobenzene (12 ml), and the mixture was stirred at 135° C. for 5.5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography using acetone-chloroform to give 3-(6,7-dimethoxy-quinolin-4-yloxy)-quinolin-2-ol (344 mg, yield 77%).
Reaction SMILES: [C:1]([NH:8][O:9][CH2:10][CH2:11][OH:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16].C(N(CC)CC)C>ClCCl>[Br:13][C:14]([CH3:19])([CH3:18])[C:15]([O:12][CH2:11][CH2:10][O:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])=[O:16]
Reactant: CC(C)(C)OC(=O)NOCCO
Reactant: CC(C)(Br)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NOCCOC(=O)C(C)(C)Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
A solution of N-Boc-2-(aminooxy)ethanol (14.5 g, 81.8 mmol) and the NHS ester of 2-bromoisobutyric acid (22.2 g, 84 mmol) in anhydrous dichloromethane (300 mL) was cooled in an ice bath. Anhydrous triethylamine (11.5 mL, 83 mmol, 1.01 eq.) and N,N-dimethylaminopyridine (1 g, 8.2 mmol, 10 mol %) were added. The ice bath was removed and the reaction was allowed to warm to room temperature and stirring was continued for 18 h. The reaction mixture was concentrated to dryness under reduced pressure giving a viscous oil, which was loaded onto a silica gel column (about 200 g SiO2). Gradient elution (100% hexanes→15% ethyl acetate in hexanes) afforded the product as a pale, clear oil (20.8 g, 78%). (Rf=0.74, ethyl acetate:hexanes (1:2)). 1H NMR (CDCl3, 300 MHz): δ 7.42 (s, 1H), 4.40 (apparent t, J=3.0 Hz, 2H), 4.05 (apparent t, J=3.0 Hz, 2H), 1.92 (s, 6H), 1.45 (s, 9H). 13C NMR (CDCl3, 300 MHz): δ 172.2, 156.9, 82.1, 74.0, 63.3, 55.8, 31.0, 28.4. EIMS m/z: 348, ([M+Na]+), 350 ([M+Na]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:6]2[CH:7]([C:9]#[N:10])[CH2:8][C:5]=2[CH:4]=1.N>[Ni].CO>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:6]2[CH:7]([CH2:9][NH2:10])[CH2:8][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)C(C#N)C2
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1cc2c(cc1OC)C(CN)C2

Procedure:
Introduce 4,5-dimethoxy-1-cyano-benzocyclobutane (6 kg), methanol (30 liters), Raney nickel (0.6 liters) and ammonia (7.32 kg) into a hydrogenator. After having purged with nitrogen and then with hydrogen, hydrogenate at 60° C. and at 30 bar until the theoretical amount of hydrogen has been absorbed. After returning to 20° C., filter off the catalyst, rinsing it with methanol, and then evaporate off the solvent. The title compound is obtained in the form of an oil, in a quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:25]([O:29][C:30](=[O:36])[N:31]([CH2:33][CH2:34][NH2:35])[CH3:32])([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[C:25]([O:29][C:30](=[O:36])[N:31]([CH2:33][CH2:34][NH:35][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:12])[CH3:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: Nc1nc(N)c(C(=O)O)nc1Cl
Reactant: CN(CCN)C(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN(CCNC(=O)c1nc(Cl)c(N)nc1N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid (3.85 g, 20.5 mmol) in DMF (90 mL) is treated with CDI (6.64 g, 41 mmol) and stirred at RT for 1 h. To this mixture is added N-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (5.0 g, 28.6 mmol) and stirring continues at RT for 72 h. The solvent is removed in vacuo and the residue is partitioned between EtOAc (100 mL) and water (60 mL). The organic portion is separated, dried (MgSO4) and concentrated in vacuo. The resulting yellow residue is washed with diethyl ether to afford the title compound which is used in the next step without further purification. [M+H]+ 345.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:14])[N:4]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Br>CC(N(C)C)=O.O>[Br:1][C:2]1[C:3](=[O:14])[N:4]([CH2:10][CH:11]2[CH2:12][CH2:13]2)[C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:24][C:23]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:22]=1[F:21]
Reactant: Cc1cc(O)c(Br)c(=O)n1CC1CC1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1CC1CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 3-bromo-1-(cyclopropylmethyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.276 g, 1.07 mmol) and K2CO3 (0.148 g, 1.07 mmol) in DMA (4 mL) was added 2,4-difluorobenzyl bromide (0.14 ml, 1.07 mmol). The mixture stirred at room temperature for 1.5 hours. The reaction mixture was diluted in water and extracted with ethyl acetate. The organic extracts were dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (ethyl acetate/hexane 1:1 v/v). The appropriate fractions were combined, and concentrated. 1H-NMR (CD3OD, 400 MHz) δ 7.60 (q, 1H), 7.04 (m, 2H), 6.42 (s, 1H), 5.26 (s, 2H), 4.06 (s, 1H), 4.04 (s, 1H), 2.50 (s, 3H), 0.53 (m, 2H), 0.43 (m, 2H); ES-HRMS m/z 384.0392 (M+H calculated for C17H17N2OBrF2 requires 384.0405).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[OH:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([O:13][CH2:2][C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])=[CH:15][CH:16]=1)#[N:19]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(COc2ccc(C#N)cc2)c1

Procedure:
500 mg (2.18 mmol) of methyl 3-bromomethylbenzoate, 437 mg (2.40 mmol) of 4-hydroxybenzonitrile and 600 mg of potassium carbonate were stirred in dimethylformamide at room temperature for 1.5 hours. The reaction mixture was filtered through Celite, then treated by an ordinary method and purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10])#[N:2].[N+:11]([O-])([OH:13])=[O:12].O>C(O)(=O)C>[C:1]([C:3]1[CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10])#[N:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C#N)c1O
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])cc(C#N)c1O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a heated (45° C.), stirred solution of 2-cyano-6-methylphenol (5 g) in glacial acetic acid (32 mL) was added a solution of fuming nitric acid (3.2 mL) in acetic acid (12 mL). After 1 h at elevated temperature (45° C.), the reaction mixture was cooled (to 0° C.), water added and partitioned between DEE/water. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated in vacuo to afford a solid. Recrystallization from DEE afforded the title compound as yellow crystals (3.6 g).
Reaction SMILES: CO.[S-2:3].[CH3:4][Na].Cl[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][N:8]=1>O>[CH3:4][S:3][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][N:8]=1
Reactant: C[Na]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: [S-2]
Solvent: O
Solvent: CO
Product: CSc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 92.3 %

Procedure:
The methanol solution of methyl sodium sulfide (6 g, 86 mmol) was added portionwise at 0° C. into the methanol solution of 2-chloro-5-nitropyridine (2 g, 13 mmol). Then, the reaction mixture was heated to room temperature and stirred for 14 hours. The reaction mixture was poured into 20 mL water, and extracted with ethyl acetate 20 mL for three times. The organic phases were combined, dried with anhydrous sodium sulfate, filtered and concentrated. The residual was recrystallized in diethyl ether to yield yellow solid 2-(methylthio)-5-nitropyridine (2 g, 12 mmol). 1H-NMR (300 MHz, CDCl3): δ 2.64 (3H, s), 7.28-7.32 (1H, m), 9.24 (1H, dd), 9.26 (1H, d); LC-MS m/z: 171 [M++1]; purity (HPLC)>95%.
Reaction SMILES: C(OC([N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:9][CH2:10][C:11]1[NH:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.Br[CH2:41][CH2:42][O:43][CH3:44]>C(OCC)(=O)C>[CH3:44][O:43][CH2:42][CH2:41][N:15]1[C:11]([CH2:10][CH2:9][NH:8][C:22](=[O:23])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[N:12][C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:14]1
Reactant: CC(C)(C)OC(=O)N(CCc1nc(-c2ccccc2)n[nH]1)C(=O)OC(C)(C)C
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCn1nc(-c2ccccc2)nc1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 140.2 %

Procedure:
5-[2-Bis(tert-butoxycarbonyl)aminoethyl]-3-phenyl-[1,2,4]triazole (96 mg, 247 μmol; example 22, step 1) and potassium carbonate (85.4 mg, 618 μmol) were combined with DMF (1 mL) and the mixture was stirred for 30 min at RT. 1-Bromo-2-methoxyethane (34.3 mg, 23.2 μL, 247 μmol) was added and the mixture was stirred at 60° C. for 16 h. The reaction mixture was cooled down to RT, a second portion of 1-bromo-2-methoxyethane (34.3 mg, 23.2 μL, 247 μmol) and potassium carbonate (34.2 mg, 247 μmol) were added and the mixture was stirred at 60° C. for another 4 h. The reaction mixture was poured into ethyl acetate (25 mL) and the organic phase was washed with water (3×10 mL) and brine (1×15 mL). The aqueous layers were back-extracted with ethyl acetate (1×25 mL). The organic layers were dried over MgSO4 and concentrated in vacuo to give 120 mg crude product. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as colorless oil (29 mg, 83.7 μmol, 33.9%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:12])[C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].[NH2:13][C:14]1[CH:15]=[C:16]([C@:21]2([CH2:32][F:33])[CH2:26][C@@H:25]([C:27]([F:30])([F:29])[F:28])[O:24][C:23]([NH2:31])=[N:22]2)[C:17]([F:20])=[N:18][CH:19]=1>>[NH2:31][C:23]1[O:24][C@H:25]([C:27]([F:28])([F:30])[F:29])[CH2:26][C@:21]([C:16]2[CH:15]=[C:14]([NH:13][C:9](=[O:11])[C:6]3[C:5]([CH3:12])=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH:19]=[N:18][C:17]=2[F:20])([CH2:32][F:33])[N:22]=1
Reactant: Cc1cc(C#N)cnc1C(=O)O
Reactant: NC1=N[C@](CF)(c2cc(N)cnc2F)C[C@@H](C(F)(F)F)O1
Product: Cc1cc(C#N)cnc1C(=O)Nc1cnc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1

Procedure:
The title compound was synthesized using procedures analogous to those described in Method H Step 2 (Example 66) above, but using 5-cyano-3-methylpicolinic acid and (4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (12k, as described in Example 138, method S). MS m/z=455.1 [M+H]+. Calculated for C19H15F5N6O2: 454.4
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH3:11])[N:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13].O>C(O)C>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([NH:15][CH2:14][CH2:12][OH:13])[N:4]([CH3:11])[N:3]=1
Reactant: Cn1nc(Br)c([N+](=O)[O-])c1Br
Reactant: NCCO
Solvent: O
Solvent: CCO
Product: Cn1nc(Br)c([N+](=O)[O-])c1NCCO
Temperature: 5 °C
Yield: 81 %

Procedure:
3 g (10.5 mmoles) of 3,5-dibromo-1-methyl-4-nitropyrazole are heated in a solution of 30 ml ethanolamine in 30 ml ethanol for 15 hours at boiling temperature. The reaction mixture is then poured on 200 ml water, the separated product is filtered, washed with water (20 ml) and vacuum dried. Additional product crystallizes from the filtrate when cooled (5° C.). 2.25 g (81 percent of theory) of 3-bromo-5-(2'-hydroxyethyl)amino-1-methyl-4-nitropyrazole are obtained in the form of yellow crystals with a melting point of 150° C.
Reaction SMILES: [CH3:1][C:2]1([C:15](=[O:27])[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23](=[O:26])(=[O:25])[NH2:24])[CH:18]=2)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.Cl>CO>[CH3:1][C:2]1([C:15]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23](=[O:26])(=[O:25])[NH2:24])[CH:18]=2)=[O:27])[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)Nc2cccc(S(N)(=O)=O)c2)CC1
Agent: Cl
Solvent: CO
Product: CC1(C(=O)Nc2cccc(S(N)(=O)=O)c2)CCNCC1

Procedure:
tert-Butyl 4-methyl-4-(3-sulfamoylphenylcarbamoyl)piperidine-1-carboxylate from step A (39 mg, 0.098 mmol) was treated with HCl (4.0 N in dioxane, 98 μL, 0.39 mmol) in methanol (1.0 mL) at 50° C. for 45 minutes. The mixture was concentrated to give the title compound as the hydrochloride salt in quantitative yield. MS (ES+) [M+H]+=298.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[SH:23].C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1>CN(C)C=O.O>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([S:23][C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=2)=[CH:9][C:6]=1[C:7]#[N:8])([O-:12])=[O:11]
Reactant: Sc1ccc2ccccc2c1
Reactant: N#Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N#Cc1cc(Sc2ccc3ccccc3c2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A stirred solution of 10.0 grams (0.055 mole) of 5-chloro-2-nitrobenzonitrile and 8.8 grams (0.055 mole) of 2-naphthalenethiol in 80 mL of N,N-dimethylformamide was cooled to 0° C., and 7.6 grams (0.055 mole) of potassium carbonate was added. Upon completion of addition, the reaction mixture was stirred at 0° C. for 1 hour. Thin layer chromatographic (TLC) analysis of the reaction mixture after this time indicated that the reaction had not gone to completion. The reaction mixture was then allowed to warm to ambient temperature, where it was stirred for about 18 hours. The reaction mixture was stirred with 80 mL of pyridine and then was diluted with water until a solid precipitate formed. The solid was collected by filtration and was washed in turn with an aqueous solution of 10% pyridine, water, an aqueous solution of 1% hydrochloric acid, and finally with water. The solid was then dissolved in ethyl acetate and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residual solid. The solid was subjected to column chromatography on silica gel. Elution was accomplished with 10% ethyl acetate in heptane. The product-containing fractions were combined and concentrated under reduced pressure, yielding 13.5 grams of 2-nitro-5-(naphth-2-ylthio)benzonitrile. A small sample was recrystallized from ethyl acetate/hexane, mp 139°-140° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][OH:26])=[CH:23][CH:22]=1>>[OH:26][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([O:20][CH2:19][CH2:18][CH2:17][N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:9][CH2:8]3)[CH2:3][CH2:2]2)=[CH:22][CH:23]=1
Reactant: OCc1ccc(OCCCBr)cc1
Reactant: c1ccc2c(c1)CCN2C1CCNCC1
Product: OCc1ccc(OCCCN2CCC(N3CCc4ccccc43)CC2)cc1
Yield: 88.6 %

Procedure:
1-(4-Piperidyl)indoline (263 mg) and 4-(3-bromopropoxy)benzyl alcohol (389 mg) were treated as in Example 2 to give the title compound (422 mg) as a pale orange amorphous solid (yield: 92%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[N:6]=[CH:5][N:4]=1.C(N(CCC)CCC)CC.N1C=CC=CC=1.[CH2:30]([CH:32]([CH2:36][CH3:37])[C:33](Cl)=[O:34])[CH3:31]>C(OCC)(=O)C>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:33](=[O:34])[CH:32]([CH2:36][CH3:37])[CH2:30][CH3:31])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: CCC(CC)C(=O)Cl
Reactant: Nc1ccc2ncnc(N)c2c1
Agent: CCCN(CCC)CCC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC(CC)C(=O)Nc1ccc2ncnc(N)c2c1
Reaction time: 3 h
Yield: 46.4 %

Procedure:
To a mixture of 4,6-diaminoquinazoline hydrochloride (1.97 g), tripropylamine (2.60 g) and dry pyridine (20 ml) in an ice-bath was added dropwise during 10 minutes 2-ethylbutyryl chloride (1.75 g). The mixture was stirred for 3 hours at the same temperature. Crushed ice was added to the reaction mixture. The mixture was stirred for 5 minutes and concentrated under reduced pressure. After the addition of water (50 ml), sodium hydrogen carbonate (3.36 g) was added in small portions to the residue to give precipitates which were separated by filtration, washed with water and dried. The crude crystals were dissolved in a mixture of chloroform and methanol under heating. After insoluble materials were removed by filtration, the filtrate was concentrated under reduced pressure to give a residue, which was suspended in ethyl acetate. After stirring under heating, the suspension was filtered to give crystalline 4-amino-6-(2-ethylbutyramido)quinazoline (1.20 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:31]([NH:44][C:45]3[CH:46]=[C:47]4[C:52](=[CH:53][CH:54]=3)[C:51]([N:55]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[N:50][CH:49]=[CH:48]4)[C:32]3[CH:37]=[C:36]([CH2:38][CH3:39])[CH:35]=[C:34]([O:40][CH2:41][CH3:42])[C:33]=3[F:43])[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(O)=O>[C:1]1([C:7]2[N:8]=[C:9]([CH:31]([NH:44][C:45]3[CH:46]=[C:47]4[C:52](=[CH:53][CH:54]=3)[C:51]([N:55]([C:56]([O:58][C:59]([CH3:60])([CH3:61])[CH3:62])=[O:57])[C:63]([O:65][C:66]([CH3:67])([CH3:68])[CH3:69])=[O:64])=[N:50][CH:49]=[CH:48]4)[C:32]3[CH:37]=[C:36]([CH2:38][CH3:39])[CH:35]=[C:34]([O:40][CH2:41][CH3:42])[C:33]=3[F:43])[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOc1cc(CC)cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Solvent: CC(=O)O
Product: CCOc1cc(CC)cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(-c3ccccc3)c[nH]2)c1F
Yield: 94.5 %

Procedure:
A solution of intermediate 448.4 (780 mg, 0.844 mmol) in 90% aq. AcOH was stirred at rt for 3.5 h, then concentrated. The residue was dissolved in EtOAc. The solution was washed with sat. NaHCO3, H2O and brine. The organic phase was dried (Na2SO4), then concentrated. The crude product was purified by flash chromatography (0 to 80% EtOAc/hexanes gradient) to afford 544 mg of intermediate 448.5 as a white solid. LCMS (2 min. gradient) RT=1.82 min, 682.56 (M+H)+.
Reaction SMILES: Cl.[C:2]1([CH:8]2[C:17]3[C:12](=[C:13](Cl)[CH:14]=[CH:15][CH:16]=3)[C:11](C(=O)C)([NH2:19])[N:10]([CH3:23])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([NH2:26])[CH3:25].[CH2:27]([OH:29])[CH3:28]>>[CH2:24]([NH:26][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]([NH:19][C:27](=[O:29])[CH3:28])[N:10]([CH3:23])[CH2:9][CH:8]2[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:25]
Reactant: CCN
Reactant: CCO
Reactant: CC(=O)C1(N)c2c(Cl)cccc2C(c2ccccc2)CN1C
Agent: Cl
Product: CCNc1cccc2c1C(NC(C)=O)N(C)CC2c1ccccc1

Procedure:
A mixture of 5.3 g (0.015 mole) of 4-phenyl-8-chloro-acetyl-amino-2-methyl-1,2,3,4-tetrahydro-isoquinoline-hydrochloride, 15 ml (10.4 g, 0.23 mole) of ethyl amine and 50 ml of ethanol is reacted in a bomb tube at 60° C. for 5 hours. The reaction mixture is evaporated, the residual oil (7.1 g) is triturated with 50 ml of water, the mixture is made alkaline by adding 30 ml of a 30% aqueous sodium hydroxide solution under stirring and cooling. The mixture is extracted ten times with 100 ml of ether each. The ether solution is dried over anhydrous sodium sulfate and evaporated. The residual oil is rubbed with petrolether. Thus 4.3 g (0.0133 mole) of crude 8-ethylamino-acetylamino-4-phenyl-2-methyl-1,2,3,4-tetrahydro-isoquinoline are obtained in the form of a yellowish-white powder.
Reaction SMILES: C(OO)(=[O:3])C.C([O-])(=O)C.[Na+].[CH3:11][C:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH3:19])([CH3:18])[C:13]=1[CH:20]([OH:24])[CH:21]=[CH:22][CH3:23].C(Cl)Cl>O>[CH3:11][C:12]12[O:3][C:13]1([CH:20]([OH:24])/[CH:21]=[CH:22]/[CH3:23])[C:14]([CH3:18])([CH3:19])[CH2:15][CH2:16][CH2:17]2
Reactant: CC(=O)OO
Reactant: CC=CC(O)C1=C(C)CCCC1(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C/C=C/C(O)C12OC1(C)CCCC2(C)C

Procedure:
21 g. of 40 % peracetic acid and 0.6 g. of sodium acetate were added under nitrogen to a suspension of 2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]-1-cyclohexene (19.4 g.) and 12 g. of sodium acetate in 35 ml. of CH2Cl2 at 20°. The reaction mixture was left 2 more hours with stirring and it was then poured into 250 ml. of water.