Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22].CCCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:13]([C:19]([OH:18])=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:26]=[N:12]2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(SCc2ccccc2)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCCC
Product: CCOC(=O)c1cnc2cc(SCc3ccccc3)ccc2c1O
Temperature: 265 °C
Reaction time: 0.75 h
Yield: 71.3 %

Procedure:
A mixture of 7.40 g of 3-(benzylsulfanyl)aniline from Preparation No. 28 and 7.70 g of diethyl ethoxymethylene malonate is heated at 135° C. under a gentle flow of argon for 2 h, then diluted with 30 mL of diphenyl ether and heated to 260-270° C. After 45 min, the solution was added to 500 mL of stirred heptane. The resulting solid was filtered, washed well with hexane, and dried under vacuum to afford 8.32 g of the title compound.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]([S:16][CH3:17])=[S:15])[CH2:10][CH2:9]1)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:2][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]([S:16][CH3:17])=[S:15])[CH2:10][CH2:9]1
Reactant: CSC(=S)N1CCN(Cc2ccccc2[N+](=O)[O-])CC1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CSC(=S)N1CCN(Cc2ccccc2N)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
To a mixture of 4 ml of conc. hydrochloric acid and 4 ml of ethanol was added 622 mg (2.0 mmol.) of methyl 4-(2-nitrobenzyl)-1-piperazinecarbodithioate. The mixture was chilled with ice, and then to this chilled mixture was dropwise added under stirring a solution of 2.7 g (12 mmol.) of SnCl2.2H2O in 5 ml of ethanol for 15 min. After the addition was complete, the mixture was further stirred at room temperature for 2 hours. Ethanol was distilled off under reduced pressure, and to the residue were added 10 ml of water and 10 ml of ethyl acetate. The resulting mixture was made alkaline by addition of saturated aqueous sodium hydrogen carbonate solution. Precipitated insolubles were removed by filtration. The organic filtrate was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. The residue was crystallized from ether, and collected by filtration, yielding 436 mg of the desired compound as a white crystalline product, m.p. 110°-113.5° C., yield 77.6%.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3=[N:15][C:16]([CH3:20])=[CH:17][C:18]([CH3:19])=[C:13]3[N:12]=[C:11]2[CH2:21][CH3:22])=[CH:6][CH:5]=1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C=O)C>[CH2:21]([C:11]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:23]=[N+:24]=[N-:25])=[CH:5][CH:6]=2)[C:14]2=[N:15][C:16]([CH3:20])=[CH:17][C:18]([CH3:19])=[C:13]2[N:12]=1)[CH3:22]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN=[N+]=[N-])cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a stirred solution of 3-[4-(2-chloroethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (step 7, 2.8 g, 9.0 mmol) and KI (1.5 g, 9.0 mmol) in DMF (50 mL) was added sodium azide (1.2 g, 18.0 mmol), and then the resulting mixture was stirred overnight at 100° C. The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 2.35 g (85%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.41 (2H, d, J=8.4 Hz), 7.35 (2H, d, J=8.4 Hz), 6.90 (1H, s), 3.59 (2H, t, J=7.1 Hz), 2.99 (2H, t, J=7.1 Hz), 2.83 (2H, q, J=7.6 Hz), 2.65 (3H, s), 2.52 (3H, s), 1.27 (3H, t, J=7.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([O:12]P(N3CCOCC3)(N3CCOCC3)=O)[CH2:9][N:8]=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:33]=1.[CH3:34][O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([O:12][CH3:34])[CH2:9][N:8]=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:33]=1
Reactant: C[O-]
Reactant: O=P(OC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)(N1CCOCC1)N1CCOCC1
Agent: [Na+]
Solvent: CO
Product: COC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reaction time: 8 h

Procedure:
To a solution of 24.5 mg. (0.5 mmoles) of 7-chloro-2-di-(morpholino)phosphinyloxy-5-phenyl-3H-1,4-benzodiazepine in 5 ml. of methanol at room temperature was added 82 mg. (1.5 mmoles) of sodium methoxide. The mixture was left at room temperature overnight. Methanol was evaporated and the residue was slurried with ether. Insoluble salts were removed by filtration. The clear ether solution was evaporated. Crystallization of the residue from petroleum ether yielded a final product having a m.p. of 94°-97°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10](O)[N:9]=2)=[CH:4][CH:3]=1.C(#N)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:36][NH:37][S:38]([CH3:41])(=[O:40])=[O:39]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([N:37]([CH3:36])[S:38]([CH3:41])(=[O:40])=[O:39])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CNS(C)(=O)=O
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(O)nc1C(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CC#N
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
In a 1000 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 50.0 g (172 mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 20.8 g (189 mmol.) of sodium t-pentoxide, and 344 mL of acetonitrile, and the resulting mixture was stirred at 0-10° C. for 30 minutes. To the mixture was slowly added 36.1 g (189 mmol.) of p-toluenesulfonyl chloride, and the reaction was carried out at for 5 hours at room temperature. Subsequently, the reaction mixture was cooled to a temperature of 0-10° C. To the cooled reaction mixture were added 28.2 g (258 mmol.) of N-methylmethanesulfonamide and 26.5 g (241 mmol.) of sodium t-pentoxide. The mixture was kept at 0-10° C. for one hour and then heated to 75-82° C. for 2 hours under refluxing, to carry out a reaction. After the reaction was complete, the mixture was cooled to room temperature. To the cooled mixture was added 344 mL of water. The aqueous mixture was cooled to 0-10° C. and stirred for one hour, precipitating a crystalline product. The crystalline product was collected by filtration and dried, to obtain 45.3 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesul-fonylamino)pyrimidine as a pale yellow crystalline product. The yield was 68% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH:9]=[C:8](OC)[CH:7]=[N:6]1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:8]1[CH:7]=[N:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:10](=[O:11])[CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCn1ncc(OC)cc1=O
Product: COCCn1ncc(Cl)cc1=O

Procedure:
The title compound, light yellow oil, was prepared in accordance with the general method of example 23c by treatment of 2-(2-methoxy-ethyl)-5-methoxy-2H-pyridazin-3-one with phosphorus oxychloride.
Reaction SMILES: CN([CH:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[CH:27][CH:26]=2)[CH2:16][CH2:15][CH2:14]1)CCCOC1CCCCO1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C(O)C>[CH3:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:32]([NH:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([N:17]2[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:13][CH2:14][CH2:15][CH2:16]2)=[O:41])=[CH:26][CH:27]=1)=[O:40]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CCCOC3CCCCO3)c3ccccc32)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Temperature: 60 °C
Yield: 68.3 %

Procedure:
To a solution of 5-(N-methyl-N-[3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propyl]amino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g) in ethanol (10 ml) is added pyridinium p-toluenesulfonate (0.03 g) and the mixture is heated at 60° C. overnight. After the mixture is refluxed for more 2 hours, water and pyridinium p-toluenesulfonate (0.03 g) are added thereto. The mixture is refluxed for 4 hours. The reaction solution is concentrated and to the resulting residue is added dichloromethane. The mixture is basified with aqueous sodium hydrogen carbonate solution and extracted three times with dichloromethane. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30 :1) to give 5-IN-methyl-N-(3-hydroxypropyl)amino]-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.26 g) as colorless amorphous.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH:15][C:16]1[C:21](I)=[C:20]([CH3:23])[N:19]=[C:18]([NH2:24])[N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:25]([O:29][CH2:30][CH3:31])(=[O:28])[CH:26]=[CH2:27]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:30]([O:29][C:25](=[O:28])/[CH:26]=[CH:27]/[C:21]1[C:16]([NH:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:17][C:18]([NH2:24])=[N:19][C:20]=1[CH3:23])[CH3:31]
Reactant: C=CC(=O)OCC
Reactant: Cc1nc(N)nc(NCc2ccccc2)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1c(C)nc(N)nc1NCc1ccccc1
Temperature: 95 °C
Reaction time: 24 h
Yield: 28 %

Procedure:
Triethylamine (7.60 mL, 54.5 mmol) was added to a suspension of N4-benzyl-5-iodo-6-methylpyrimidine-2,4-diamine (3.14 g, 10.9 mmol), ethyl acrylate (3.55 mL, 32.7 mmol) and Pd(PPh3)4 (629 mg, 0.545 mmol) in anhydrous DMF (20 mL). The reaction was heated to 95° C. under nitrogen. After 24 h, the reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was poured into a 10% solution of LiCl and washed with ethyl acetate (100 mL). The organic phase was separated and washed with brine, separated and dried over Na2SO4. The filtrate was concentrated in vacuo and purified on SiO2 (3:2 methylene chloride:ethyl acetate) to afford (E)-ethyl-3-(2-amino-4-(benzylamino)-6-methylpyrimidin-5-yl)acrylate (0.954 g, 28% yield) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[NH3:10]>C(O)(C)C>[Cl:8][C:7]1[N:6]=[CH:5][N:4]=[C:3]([NH2:10])[C:2]=1[NH2:1]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: N
Solvent: CC(C)O
Product: Nc1ncnc(Cl)c1N
Temperature: 130 °C

Procedure:
To a cold solution of 5-amino-4,6-dichloropyrimidine (2.0 g, 12.2 mmol) in isopropanol (20 ml) was added liquid ammonia (5 ml), and the mixture was transfered into a sealed tube. The tube was heated at 130° C. for 3 hours and then cooled to room temperature. The product precipitated out was filtered and dried in vacuo. Yield 2.0 g (quantitative).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(Oc2ccc(Cl)cn2)cc1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ccc(Cl)cn2)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(5-chloro-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(#N)C.[CH:18]1(/[CH:21]=[CH:22]/[C:23]#[N:24])[CH2:20][CH2:19]1.N12CCCN=C1CCCCC2>>[CH:18]1([CH:21]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:22][C:23]#[N:24])[CH2:20][CH2:19]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#C/C=C/C1CC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OB(c2cnn(C(CC#N)C3CC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.0 g, 0.0515 mol) in acetonitrile (129 mL, 2.46 mol) was added (E)-3-cyclopropylacrylonitrile (5.75 g, 0.0617 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (3.85 mL, 0.0258 mol). The resulting mixture was stirred at room temperature overnight, and evaporated to dryness. The mixture was purified on silica gel, eluting with 0 to 80% EtOAc in hexanes, to give the desired product as racemic mixture (10.8 g, 73.0%). LCMS (M+H) 288.4.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[N:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[OH:18])=O.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:13][C:11]1[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]2[O:18][C:4]([C:3]3[CH:19]=[CH:20][N:21]=[CH:22][C:2]=3[Cl:1])=[N:6][C:7]=2[CH:12]=1
Reactant: O=C(Nc1cc(Cl)c(C(F)(F)F)cc1O)c1ccncc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: FC(F)(F)c1cc2oc(-c3ccncc3Cl)nc2cc1Cl
Reaction time: 1.5 h
Yield: 58.2 %

Procedure:
To a mixture of 0.67 g of 3-chloro-N-[5-chloro-2-hydroxy-4-(trifluoromethyl)phenyl]isonicotinamide, 7 ml of tetrahydrofuran and 0.55 g of triphenylphosphine, 0.91 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred for 1.5 hours. To the mixture, 0.14 g of triphenylphosphine and 0.23 g of 40% toluene solution of diethyl azodicarboxylate were added and stirred for further one hour. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the resultant crystals were washed with isopropanol and hexane to give 0.37 g of 5-chloro-2-(3-chloropyridin-4-yl)-6-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 79”).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH:10]([N:12]([CH2:17][CH2:18][O:19][CH3:20])[S:13]([CH3:16])(=[O:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:21])[CH:8]=2)[O:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([O:31][CH2:32][CH2:33][CH2:34]Br)[CH3:30]>CCCCCCC.CC(=O)OCC>[CH2:29]([O:31][CH2:32][CH2:33][CH2:34][O:21][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:22])([CH3:1])[CH2:11][CH:10]2[N:12]([CH2:17][CH2:18][O:19][CH3:20])[S:13]([CH3:16])(=[O:15])=[O:14])[CH3:30]
Reactant: CCOCCCBr
Reactant: COCCN(C1CC(C)(C)Oc2ccc(O)cc21)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOCCCOc1ccc2c(c1)C(N(CCOC)S(C)(=O)=O)CC(C)(C)O2

Procedure:
0.5 g (1.5 mmol) of N-[2,2-dimethyl-6-hydroxychroman-4-yl]-N-(2-methoxyethyl)methanesulfonamide (Example 16b) was reacted with potassium carbonate and 3-ethoxy-1-bromopropane analogously to Example 1g. After column chromatography on silica gel using n-heptane/EA (5:1), 0.35 g of oily product was obtained.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([OH:17])=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:18][C:19]1[C:20]([CH3:26])=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[CH3:26])=[CH:13][C:12]([OH:17])=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2ccc(O)cc2c1Cl
Reactant: Cc1cc(O)ccc1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2ccc(O)cc2c1Nc1ccc(O)cc1C
Yield: 24.1 %

Procedure:
3-Butyryl-4-chloro-6-hydroxyquinoline (4.0 g) and 4-amino-m-cresol (2.0 g) were heated together under reflux in 1,4-dioxan (60 ml) for 2 hours. The solvent was evaporated and the residue was dissolved in chloroform and washed successively with 2M HCl, sodium hydrogen carbonate solution (×2) and brine. The organic solution was dried, filtered and evaporated to a brown oil. A quantity of solid material that appeared insoluble in chloroform was combined with the oil and the mixture was chromatographed (silica gel, 2-4% methanol in chloroform) to give 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-6-hydroxyquinoline (1.3 g, 24%) as orange crystals, m.p. 242°-244°.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=[O:2].[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH3:12])=[O:6])=[O:2]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1C=O
Temperature: 25 °C

Procedure:
6 Grams of 2-formylbenzoic acid and 6 g of potassium carbonate were added to 30 ml of dimethylformamide, then 6 g of methyl iodide were added dropwise thereto at room temperature with stirring. The reaction mixture was continuously stirred at room temperature overnight, then was concentrated. The residue obtained was extracted with chloroform, and the chloroform layer was washed with water, and was dried with anhydrous magnesium sulfate, then concentrated. The residue obtained was purified by distillation under reduced pressure to yield 3 g of methyl 2-formylbenzoate. Boiling point: 95° C. (at 0.5 mm-Hg).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:30]([OH:32])=O)[CH2:19][C:20]3[CH:29]=[CH:28][C:23]4[O:24][CH2:25][CH2:26][O:27][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH3:66][N:67]1[CH2:72][CH2:71][N:70]([CH:73]2[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]2)[CH2:69][CH2:68]1>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]4[O:24][CH2:25][CH2:26][O:27][C:22]=4[CH:21]=3)[C:30]([N:76]3[CH2:75][CH2:74][CH:73]([N:70]4[CH2:69][CH2:68][N:67]([CH3:66])[CH2:72][CH2:71]4)[CH2:78][CH2:77]3)=[O:32])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1
Reactant: O=C(O)[C@@H](Cc1ccc2c(c1)OCCO2)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reactant: CN1CCN(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(C2CCN(C(=O)[C@@H](Cc3ccc4c(c3)OCCO4)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
A solution of 35 mg (0.07 mmol) (R)-1-carboxy-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 25 mg (0.08 mmol) TBTU, 11 μL (0.08 mmol) triethylamine and 14 mg (0.08 mmol) 1-methyl-4-piperidin-4-yl-piperazine in 1 mL DMF was stirred overnight at RT. The reaction mixture was purified by HPLC, the fractions containing the product were combined and lyophilised.
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)=O)=[C:8](C)[C:7](OC)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[K+].O.N1C=CC=C[CH:27]=1>>[OH:3][C:1]1[C:4]2[C:9](=[CH:8][C:7]([CH3:27])=[CH:6][CH:5]=2)[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[CH:2]=1
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2cccc(C)n2)c1C
Reactant: c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(O)cc(-c3cccc(C)n3)nc2c1
Temperature: 150 °C
Yield: 95 %

Procedure:
To a solution of 6-methylpyridine-2-carboxylic acid (6-acetyl-3-methoxy-2-methyl-phenyl)-amide (96) in pyridine (15 mL) was added 2.5 equivalent of freshly grounded KOH along with water (200 μL). The mixture was heated by microwave irradiation at 150° C. for 30 min, then 80-85% of the pyridine was evaporated under reduced pressure. The residue was poured on ice and neutralized with acetic acid. The precipitate was filtered off, then dried to give the title compound (1.8 g, 95%): m/z=299 (M+H)+.
Reaction SMILES: N[C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([CH3:11])[N:3]=1.N([O-])=[O:13].[Na+]>S(=O)(=O)(O)O.O>[OH:13][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([CH3:11])[N:3]=1
Reactant: O=N[O-]
Reactant: Cc1cc(N)nc(C)c1C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(O)nc(C)c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.3 %

Procedure:
To a stirred solution of 6-amino-2,4-dimethylnicotinonitrile (Sato, K.; et al. Bull. Chem. Soc. Jpn., 1969, 42, 2319., 22.4 g, 152 mmol) in 5% aqueous sulfuric acid (600 mL) was added dropwise a solution of sodium nitrite (25.2 g, 365 mmol) in water (100 mL) at 0° C., and the mixture was stirred at room temperature for 16 h. The resulting precipitate was collected by filtration to afford 10.2 g (45%) of the title compound: 1H-NMR (DMSO-d6) δ 12.27 (1H, br.s), 6.17 (1H, s), 2.38 (3H, s), 2.20 (3H, s).
Reaction SMILES: [CH2:1]([C:9]1[NH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(OC)(O[CH3:21])(=O)=O>C(O)=O>[CH3:21][N:10]1[C:11]([N+:14]([O-:16])=[O:15])=[CH:12][N:13]=[C:9]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: COS(=O)(=O)OC
Reactant: CCCCCCCCc1ncc([N+](=O)[O-])[nH]1
Solvent: O=CO
Product: CCCCCCCCc1ncc([N+](=O)[O-])n1C
Yield: 66 %

Procedure:
225 parts of 2-octyl-5-nitroimidazole is boiled under reflux with 500 parts of formic acid and 126 parts of dimethyl sulfate for 4 hours, the formic acid is distilled off in vacuo and 500 parts of water is added to the residue. The unreacted 2-octyl-5-nitroimidazole (72 parts) is separated and the aqueous phase is adjusted with aqueous ammonia solution to pH 10 so that the 1-methyl-2-octyl-5-nitroimidazole separates as an oily substance. The crude product is dissolved in ether and saturated with hydrogen chloride while cooling. 123 parts of 1-methyl-2-octyl-5-nitroimidazole having a melting point of 141° C. is obtained and this is equivalent to a yield of 66% of theory based on the 2-octyl-5-nitroimidazole reacted.