Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH2:37]([NH:39][CH2:40][CH3:41])[CH3:38]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:39]([CH2:40][CH3:41])[CH2:37][CH3:38])=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CCNCC
Reactant: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CN(CC)CC)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-7-(methyl-propyl-amino)-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 29) (219 mg, 0.50 mmol) by reaction with thionylchloride in dichloro-methane and subsequent treatment of the corresponding chloride with diethylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (123 mg, 50%).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:6].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CC(=O)CC>C(=O)(O)[O-].[K+].C(Cl)Cl>[CH3:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:19][CH3:20])[CH:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:7]([C:5]([NH:4][CH2:3][CH2:2][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:6])[CH2:16][CH2:15]2
Reactant: C1CCNCC1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)N(C(=O)NCCCl)CC2
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(c1ccccc1)N(C(=O)NCCN1CCCCC1)CC2
Temperature: 65 °C

Procedure:
A mixture of 3.0 parts of the N-(2-chloroethyl)-6,7-dimethoxy-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxamide prepared in Example 8 and 4.3 parts of piperidine in approximately 40 parts of 2-butanone is heated at 65°C. for 20 hours. The reaction mixture is then stripped in vacuo and the residue taken up in dilute aqueous potassium bicarbonate solution and methylene chloride. The organic layer is dried and stripped in vacuo and the residue is crystallized from ether to afford 6,7-dimethoxy-1-phenyl-N-(2-piperidinoethyl)-3,4-dihydro-2(1H)-isoquinolinecarboxamide, melting at about 101°-102°C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([C:21]([F:24])([F:23])[F:22])([OH:20])[C:16]([F:19])([F:18])[F:17])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.[OH2:40]>CN(C=O)C>[F:1][C:2]([F:25])([F:26])[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([C:16]([F:17])([F:18])[F:19])([O:20][S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=2)(=[O:36])=[O:40])[C:21]([F:23])([F:22])[F:24])[CH:10]=1)([O:8][S:35]([C:32]1[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=1)(=[O:37])=[O:36])[C:4]([F:7])([F:6])[F:5]
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC(c1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1)(C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OC(c2cccc(C(OS(=O)(=O)c3ccc(C)cc3)(C(F)(F)F)C(F)(F)F)c2)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
4.1 g (10 mmol) of 1,3-bis-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)-benzene were dissolved in 20 ml of dry DMF, and 0.75 g (25 mmol) of sodium hydride (80% strength dispersion) was added. The clear solution formed was stirred for a further 30 minutes. 4.75 g (25 mmol) of toluene-4-sulfonyl chloride in 15 ml of DMF were added dropwise at 10° to 15° C. The mixture was stirred for 48 hours at room temperature and poured into water. The crystalline precipitate was filtered off, washed with water and dried. The residue was chromatographed over a silica gel column with methylene chloride. 3.5 g of 1,3-bis-[2,2,2-trifluoro-1-(toluene-4-sulfonyloxy)-1-trifluoromethylethyl]-benzene were obtained (colorless crystals, m.p.: 131° C.).
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6]([O:8][C:9]1([CH3:13])[CH2:12][CH2:11][CH2:10]1)=[O:7].CO.[OH-].[Na+].S(=O)(=O)(O)O>O>[CH3:13][C:9]1([O:8][C:6]([NH:5][C@H:4]([C:3]([OH:21])=[O:2])[CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:7])[CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC1(C)CCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(OC(=O)N[C@@H](Cc2ccccc2)C(=O)O)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 171 mg. (0.74 mM) of phenylalanine methyl ester hydrochloride in 10 ml. of chloroform is cooled to 0°C. and the pH adjusted to 8 by addition of triethylamine. 1-Methylcyclobutyl chloroformate 1.5 mM is added portion-wise at 0°C. and the pH of the reaction is maintained at 8 by addition of triethylamine. Upon completion of the addition, the reaction is stirred overnight at 20°-25°C. The reaction solution is washed successively with 10 ml. portions of a saturated sodium bicarbonate solution, 50% saturated solution of sodium chloride, 0.2 N sulfuric acid saturated with sodium sulfate, 50% saturated solution of sodium chloride (twice), and the chloroform solution is dried over sodium acetate. Removal of the chloroform affords N-(1-methylcyclobutyloxycarbonyl)-phenylalanine methyl ester. Saponification of the above ester is carried out by dissolving the residue in 10 ml. of methanol, water (10 ml.) is added and the pH is adjusted to 12 by addition of 2 N sodium hydroxide. After stirring overnight at 25°C., the pH is adjusted to 7 with 2 N sulfuric acid. The methanol is removed in vacuo and saturated sodium bicarbonate solution is added to the water solution. The aqueous bicarbonate solution is washed two times with ether and then the pH is adjusted to 3 by addition of concentrated hydrochloric acid. The acidified solution is extracted three times with ethyl acetate and the organic extracts combined, washed twice with sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo and trituration with pet ether affords N-(1-methylcyclobutyl-oxycarbonyl)-phenylalanine, which is isolated by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]Cl)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[F:36][C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1.O>CN1CCCC1=O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:40]4[CH2:39][CH:38]=[C:37]([F:36])[CH2:42][CH2:41]4)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: FC1=CCNCC1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)ccc21
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CC=C(F)CC3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of N-(4-chlorobenzyl)-6-(chloromethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation No. 35 (60 mg) in 1-methyl-2-pyrrolidinone (3 mL) is added N,N-diisopropylethylamine (0.075 mL) and 4-fluoro-1,2,3,6-tetrahydropyridine hydrochloride from Preparation No. 38 (119 mg). The reaction mixture is stirred at room temperature overnight and then heated at 60° C. for 4 hrs. The mixture is cooled to room temperature and poured into water to precipitate the product. The crude solid is adsorbed onto silica and purified by chromatography (eluent 100% CH2Cl2 (1 L), 0.25% MeOH in CH2Cl2 (1 L), 0.5% MeOH in CH2Cl2 (1 L), 0.75% MeOH in CH2Cl2 (1 L), 1% MeOH in CH2Cl2 (1 L), 1.25% MeOH in CH2Cl2 (1 L), 1.5% MeOH in CH2Cl2 (2 L)). Fractions homogenous by TLC are combined and concentrated to afford 32.2 mg (46%) of the desired product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[H-].[Na+].CN(C)C=O.Br[CH2:35][C:36]1[S:37][CH:38]=[CH:39][CH:40]=1>C(OCC)(=O)C>[CH3:1][C:2]1[N:3]([CH2:35][C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)[C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc(C)n(Cc2cccs2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.8 %

Procedure:
A mixture of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 2-(bromomethyl)thiophene (4.5 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.74 g, 58%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[CH:10]=O)=[N:6][CH:7]=1.[CH2:12]1[CH2:17][C@H:16]([C:18](O)=O)[NH:15][CH2:14][CH2:13]1.[CH3:21][N:22]1[C:26](=[O:27])C=[CH:24][C:23]1=[O:28]>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[CH:10]2[N:15]3[CH:16]([CH2:17][CH2:12][CH2:13][CH2:14]3)[CH:18]3[C:26](=[O:27])[N:22]([CH3:21])[C:23](=[O:28])[CH:24]23)=[N:6][CH:7]=1
Reactant: O=C/C=C/c1ccc(Br)cn1
Reactant: CN1C(=O)C=CC1=O
Reactant: O=C(O)[C@H]1CCCCN1
Solvent: CC#N
Product: CN1C(=O)C2C(C1=O)C1CCCCN1C2/C=C/c1ccc(Br)cn1

Procedure:
A mixture of 820 mg of (E)-3-(5-bromopyridin-2-yl)propenal, 500 mg of D-pipecolinic acid, 430 mg of N-methylmaleinimide and 20 ml of MeCN is boiled at reflux for 2 h. The solvents are removed and the residue is purified by column chromatography (silica gel, ethyl acetate:DCM=3:1). Using this method, 3 pure fractions are obtained.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4]N1C=CC=C1.ClCC#N.Cl.[Cl:19][CH2:20][C:21]([C:23]1[N:24]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2F)[CH:25]=[CH:26][CH:27]=1)=[O:22]>CCOCC>[F:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][CH2:21][C:23]1[NH:24][CH:25]=[CH:26][CH:27]=1.[Cl:19][CH2:20][C:21]([C:23]1[N:24]([CH2:28][CH2:29][C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:2]=2[F:1])[CH:25]=[CH:26][CH:27]=1)=[O:22]
Reactant: Fc1ccccc1Cn1cccc1
Reactant: O=C(CCl)c1cccn1Cc1ccccc1F
Agent: Cl
Agent: N#CCCl
Solvent: CCOCC
Product: Fc1ccccc1CCc1ccc[nH]1
Product: O=C(CCl)c1cccn1CCc1ccccc1F
Reaction time: 1 h

Procedure:
A solution of 40 g of 1-(o-fluorobenzyl)pyrrole and 17.2 g of chloroacetonitrile in 200 ml of anhydrous ether at a temperature between 0° and -5° C. is saturated with hydrogen chloride gas and then the solution is stirred until a heavy white cake forms. This cake is broken up and permitted to sit for one hour at ambient temperature. The white solid is filtered, washed with ether and dried and then hydrolyzed in water and extracted with ether. Concentration of the ether extracts leaves white crystals, mp 76°-78° C., of 2-chloroacetyl-1-(o-fluorobenzyl)pyrrole. The analagous treatment of o-fluorophenethylpyrrole produces 2-chloroacetyl-1-(o-fluorophenethyl)pyrrole.
Reaction SMILES: ClC([O:4][C:5]([Cl:8])(Cl)Cl)=O.[CH3:9][O:10][C:11]1[CH:22]=[CH:21][C:14]([CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:9][O:10][C:11]1[CH:22]=[CH:21][C:14]([CH2:15][N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:5]([Cl:8])=[O:4])=[CH:13][CH:12]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COCCNCc1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(Cc1ccc(OC)cc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.51 g (0.31 ml, 2.56 mmol) of trichloromethyl chloroformate (“diphosgene”) are dissolved in 15 ml of dichloromethane, and 1.00 g (5.12 mmol) of 4-methoxybenzyl(2-methoxyethyl)amine and 0.78 g (7.68 mmol) of triethylamine are slowly added. After stirring at room temperature overnight, the mixture is poured into ice-water and extracted three times with dichloromethane, and the organic phase is dried over magnesium sulfate and concentrated to dryness in a rotary evaporator. The crude product is employed without workup directly in the next stage.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH:16]=[C:15](OS(C(F)(F)F)(=O)=O)[N:14]([C@H:25]([C:27]2[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=2)[CH3:26])[N:13]=1.[CH3:38][O:39][C:40]1[CH:41]=[C:42]2[C:47](=[CH:48][CH:49]=1)[CH:46]=[C:45](B(O)O)[CH:44]=[CH:43]2.C(N(CC)CC)C.N#N>COCCOC.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH:16]=[C:15]([C:45]2[CH:44]=[CH:43][C:42]3[C:47](=[CH:48][CH:49]=[C:40]([O:39][CH3:38])[CH:41]=3)[CH:46]=2)[N:14]([C@H:25]([C:27]2[CH:28]=[CH:29][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:36][CH:37]=2)[CH3:26])[N:13]=1
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Reactant: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(C(F)(F)F)ccc3F)cc2OS(=O)(=O)C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(C(F)(F)F)ccc3F)cc2-c2ccc3cc(OC)ccc3c2)cc1
Temperature: 100 °C

Procedure:
Ethyl 4-[(1S)-1-(3-[2-fluoro-5-(trifluoromethyl)phenyl]-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazol-1-yl)ethyl]benzoate (1.05 g, 1.90 mmol), 6-methoxy-2-naphthylboronic acid (0.43 g, 2.1 mmol), and triethylamine (0.53 ml, 3.8 mmol) were dissolved in DME (20 ml). After deoxygenation (vacuum-N2 cycles) Pd(PPh3)4 (85 mg, 4% mol) was added. The mixture was deoxygenated again and heated in microwave reactor to 100° C. for 15 min. The reaction mixture was filtered through a Celite pad, concentrated and purified by flash column chromatography (SiO2, 5-20% ethyl acetate in hexane gradient) to give ethyl 4-{(1S)-1-[3-[2-fluoro-5-(trifluoromethyl)phenyl]-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoate as colorless gel. NMR (500 MHz, CDCl3) δ: 1.38 (t, J=7.1 Hz, 3H); 1.99 (d, J=7.1 Hz, 3H); 3.96 (s, 3H); 4.37 (q, J=7.1 Hz, 2H); 5.64 (q, J=7.1 Hz, 1H); 6.87 (d, JF-H=4.2 Hz, 1H); 7.17 (d, J=2.5 Hz, 1H); 7.20 (dd, J=2.5 Hz, 8.9 Hz, 1H); 7.25 (t, J=9.5 Hz, 1H); 7.30 (d, J=8.4 Hz, 2H); 7.32 (dd, J=1.5 Hz, 8.4 Hz, 1H); 7.56 (m, 1H); 7.66 (d, J=1.5 Hz, 1H); 7.68 (d, J=8.9 Hz, 1H); 7.77 (d, J=8.4 Hz, 1H); 8.00 (d, J=8.4 Hz, 2H); 8.48 (dd, J=2.7 Hz, 6.8 Hz, 1H). MS C32H26F4N2O3 Cald: 562.19; Obsd (M+1): 563.33.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH3:27][C:28]1[CH:29]=[C:30]([OH:37])[CH:31]=[CH:32][C:33]=1[N+:34]([O-:36])=[O:35]>C(C(C)=O)C(C)C>[CH3:27][C:28]1[CH:29]=[C:30]([CH:31]=[CH:32][C:33]=1[N+:34]([O-:36])=[O:35])[O:37][C:7]1[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)c1c(Oc2ccc([N+](=O)[O-])c(C)c2)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 95.2 %

Procedure:
This product was prepared as described in Example 31: 7.0 g (0.022 mol) of product of Example 19, 3.31 g (0.024 mol) of K2CO3, 3.33 g (0.022 mol) of 3-methyl-4-nitrophenol in 75 ml of methyl isobutyl ketone were reacted affording 9.18 g of an oil. Purification by HPLC using 5% ethyl acetate/cyclohexane as eluting solvent gave 5.31 g (55.1%) of product as a yellow solid; mp 55°-57° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O1[CH2:16][CH2:15][CH2:14][CH2:13]1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28]>C(N(CC)CC)C>[CH:13]1[C:26]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:27]([N:1]([S:27]([C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=1)(=[O:29])=[O:28])[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:29])=[O:28]
Reactant: C1CCOC1
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(N(S(=O)(=O)c2ccc3ccccc3c2)S(=O)(=O)c2ccc3ccccc3c2)c1
Reaction time: 0.17 h
Yield: 140.5 %

Procedure:
To 1.0 g of methyl 3-aminobenzoate (6) (6.62 mmol) in 10 mL of tetrahydrofuran containing 2 mL (14.4 mmol) of triethylamine was added 1.58 g (6.96 mmol) of 2-napthalenesulfonyl chloride. After 10 min, 100 mg of N,N-dimethylaminopyridine was added. After 15 min, another 600 mg of 2-napthalenesulfonyl chloride was added. After stirring for 30 min, the reaction mixture was quenched with 2N HCl and then extracted into ether. The ethereal phase was washed sequentially with water and saturated NaHCO3, then dried (MgSO4), concentrated, and triturated with ether/petroleum ether to give 2.6 g of the title compound as a colorless powder: 1H-NMR (CDCl3, 200 MHz) δ8.46 (s, 2H), 8.13 (d, 1H, J=7.8 Hz), 7.92-8.04 m, 8H), 7.59-7.75 (m, 5H), 7.42 (t, 1H, J=8 Hz), 7.22 (d, 1H, J=7.6 Hz), 3.80 (s, 3H).
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[H][H].[CH2:16]([N:23]1[C:28]2[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=2[C:26](=O)[O:25]C1=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CC(N(C)C)=O>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:23]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:28]2[C:27]([C:26]=1[OH:25])=[CH:32][C:31]([CH3:33])=[CH:30][CH:29]=2)=[O:4])[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: [H][H]
Reactant: Cc1ccc2c(c1)c(=O)oc(=O)n2Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2cc(C)ccc2n(Cc2ccccc2)c1=O
Temperature: 90 °C
Yield: 97.2 %

Procedure:
Neat diethyl malonate (19.07 mL, 125 mmol) was added slowly to a suspension of sodium hydride (60% in mineral oil, 5.52 g, 138 mmol) in dimethylacetamide under N2 atmosphere. The mixture was stirred at room temperature until the evolution of hydrogen gas ceased, then heated to 90° C. for 30 min and cooled to room temperature. A solution of Compound 12 (36.8 g, 138 mmol) in dimethylacetamide was added slowly and the mixture was heated overnight at 110° C. The mixture was cooled to room temperature, poured into ice water, and acidified by cold 10% HCl. The solids formed were filtered, washed several times by water, and dried at room temperature under vacuum to yield 41 g (97%) of white solids. M.P. 113° C. 1H NMR (DMSO-d6): δ 1.31 (t, J=7.5 Hz, 3H), 2.33 (s, 3H), 4.35 (q, J=7.5 Hz, 2H), 5.43 (s, 2H), 7.15–7.30 (m, 6H), 7.43 (dd, J=1.6, 8.7 Hz, 1H), 7.85 (d, J=1.5 Hz, 1H). EIMS m/z 338 (M+1), 360 (M+23). Anal. (C20H19NO4) C, H, N.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:8][CH2:9][CH3:10])[CH2:3][CH:4]([OH:7])[C:5]#[CH:6].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>P(Cl)(Cl)(Cl)=O>[CH3:1][C:2]([CH3:11])([CH2:8][CH2:9][CH3:10])[CH2:3][CH:4]([O:7][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1)[C:5]#[CH:6]
Reactant: C#CC(O)CC(C)(C)CCC
Reactant: C1=COCCC1
Solvent: O=P(Cl)(Cl)Cl
Product: C#CC(CC(C)(C)CCC)OC1CCCCO1

Procedure:
Treatment of 23.1 g. (0.150 mole) of 5,5-dimethyl-1-octyn-3-ol (Example 998) with 126 g. of dihydropyran and 1 drop of phosphorus oxychloride as described in Example 995 gives the title compound.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:16])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=1)([CH3:3])[CH3:2].Cl.[NH2:18][OH:19].N1C=CC=CC=1>CO>[CH:1]([O:4][C:5](=[O:16])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[N:18][OH:19])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)OC(=O)COc1cccc(C=O)c1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)OC(=O)COc1cccc(C=NO)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.4 %

Procedure:
A solution of (3-formyl phenoxy)acetic acid isopropyl ester (3.7 g, 17 mmol) in methanol (55 mL) was stirred under nitrogen as hydroxylamine hydrochloride (1.2 g, 17 mmol) and pyridine (6 mL, 74 mmol) were added. The reaction was stirred for 15 h at room temperature. The volatiles were removed in vacuo and the residue was diluted with ethyl acetate. The resulting solution was washed with 1N HCl, and the resulting aqueous solution was washed with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (4.13 g, 100%) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (d, 6H) 4.67-4.72 (m, 2H) 5.15-5.34 (m, 1H) 7.01-7.07 (m, 1H) 7.33-7.36-7.43 (m, 2H) 8.17 (s, 1H). LRMS m/z calcd. for C12H15NO4([M+H]+): 237.1. Found: 238.1.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:19](SC)=[N:18][C:13]=3[CH:14]=[N:15][C:16]=2[CH:17]=1.[S:34](=[O:37])(O)[O-:35].[Na+].[C:39](O)(=O)C>O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[C:19]([S:34]([CH3:39])(=[O:37])=[O:35])=[N:18][C:13]=3[CH:14]=[N:15][C:16]=2[CH:17]=1
Reactant: CC(=O)O
Reactant: CSc1nc2cnc3cc(Br)ccc3c2n1CCCNC(=O)OC(C)(C)C
Reactant: O=S([O-])O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)NCCCn1c(S(C)(=O)=O)nc2cnc3cc(Br)ccc3c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of potassium permanganate (1.9 g, 12 mmol) in deionized water (90 mL) was added to a solution of tert-butyl 3-(7-bromo-2-(methylthio)-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate (2.7 g, 6 mmol) in glacial acetic acid (35 mL), and the reaction was stirred at room temperature overnight. The reaction was diluted with water and treated with sodium bisulfite. The aqueous layer was separated and extracted three times with chloroform. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 2.3 g of tert-butyl 3-(7-bromo-2-(methylsulfonyl)-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate.
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].Cl[C:6]1[C:7](=[O:24])[N:8]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[N:9]=[CH:10][C:11]=1Cl.[OH2:25]>CN(C)C=O>[OH:25][C:6]1[C:7](=[O:24])[N:8]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[N:9]=[CH:10][C:11]=1[N+:1]([O-:3])=[O:2]
Reactant: O
Reactant: O=N[O-]
Reactant: O=c1c(Cl)c(Cl)cnn1Cc1cccc2ccccc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c(O)c([N+](=O)[O-])cnn1Cc1cccc2ccccc12
Temperature: 85 °C
Reaction time: 24 h

Procedure:
A solution of 11.04 g (160 mmol) of sodium nitrite in 40 ml of water was added to a solution of 12 g (39.3 mmol) of 4,5-dichloro-2-naphthalen-1-ylmethyl-2H-pyridazin-3-one in 120 ml of dimethylformamide and the mixture was stirred for 24 hours at 85° C.