Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:27])[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:28](C[Sn])=[N+:29]=[N-:30]>O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]4[NH:30][N:29]=[N:28][N:2]=4)[CH:4]=3)=[O:27])[CH2:14][CH2:15]2)=[CH:21][CH:22]=1
Reactant: [N-]=[N+]=NC[Sn]
Reactant: N#Cc1cccc(NC(=O)C(=O)N2CCC(Cc3ccc(F)cc3)CC2)c1
Solvent: O
Product: O=C(Nc1cccc(-c2nnn[nH]2)c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from N-(3-cyano-phenyl)-2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-2-oxo-acetamide (Example 14) and azidomethyltin (Aldrich) according to the method described in Example 71. Melting Point: 107-112° C. (water)
Reaction SMILES: [K].[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].[CH2:13](Cl)[CH:14]=[CH2:15]>O>[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]=[CH2:15]
Reactant: C=CCCl
Reactant: COCCOCCOCCO
Agent: [K]
Solvent: O
Product: C=CCOCCOCCOCCOC
Yield: 74 %

Procedure:
540 mls of dried peroxide free tetrahydrofuran and 21.5 g of potassium metal are charged into a 2000 ml three-neck flask equipped with mechanical stirrer and a dry nitrogen inlet. 88.4 ml of triethylene glycol monomethyl ether, available from Chemical Samples Co., is added to the mixture dropwise. After the potassium metal has completely reacted, 48.6 ml of allyl chloride is added dropwise to the mixture at such a rate in order to maintain a gentle reflux. After the reaction is complete, 500 mls of distilled water are added in order to dissolve the precipitated salt. The tetrahydrofuran layer is washed with salt water (270 g NaCl/1 liter water) in order to remove the excess alcohol. The resulting product in tetrahydrofuran is collected and the tetrahydrofuran is removed with a water aspirator. The product is distilled at reduced pressure. 75.5 g (74% yield) of triethylene glycol allyl methyl ether is obtained (b.p. 97° C.-100° C./2 mm). The analytical data is consistent with a product of the general formula:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH2:11][CH2:12][CH2:13][Cl:14]>>[Cl:14][CH2:13][CH2:12][CH2:11][O:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1ccc(O)cc1C
Reactant: ClCCCBr
Product: Cc1ccc(OCCCCl)cc1C

Procedure:
Prepared by Procedure U and Scheme AK using 3,4-dimethylphenol and 1-bromo-3-chloropropane.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]#[N:31])[CH:20]=1.N1C=CC=CC=1.CCCP(=O)=O>CC1CCCO1>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([NH:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]#[N:31])[CH:20]=1)=[O:6]
Reactant: Cc1cc(Cl)c(C(=O)O)cc1-c1ccccn1
Reactant: N#Cc1cc(N)n(-c2ccccc2)n1
Agent: CCCP(=O)=O
Solvent: CC1CCCO1
Solvent: c1ccncc1
Product: Cc1cc(Cl)c(C(=O)Nc2cc(C#N)nn2-c2ccccc2)cc1-c1ccccn1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
A mixture of 2-chloro-4-methyl-5-(pyridin-2-yl)benzoic acid (Preparation 25, 234 mg, 0.94 mmol), 5-amino-1-phenyl-1H-pyrazole-3-carbonitrile (Preparation 53, 191 mg, 1.04 mmol) and pyridine (0.23 mL, 2.83 mmol) in 2-methyl tetrahydrofuran (20 mL) was heated at reflux for 10 minutes. To this refluxing mixture was added propylphosphonic anhydride solution (2.8 mL, 50% w/w in EtOAc) and the reaction heated at reflux under an atmosphere of argon for 18 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and 2M aqueous sodium hydroxide solution (50 mL). The organic layer was washed with 2M aqueous sodium hydroxide solution (50 mL), saturated aqueous ammonium chloride solution (50 mL), water (50 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-20% EtOAc in DCM followed by trituration with diethylether to afford the title compound as a white solid (119 mg, 31%).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[C:7]([Cl:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:12][C:13]1[NH:17][N:16]=[C:15]([NH2:18])[CH:14]=1.CCN(C(C)C)C(C)C>CCO>[Cl:1][C:2]1[N:9]=[C:8]([NH:18][C:15]2[CH:14]=[C:13]([CH3:12])[NH:17][N:16]=2)[C:7]([Cl:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(N)n[nH]1
Reactant: N#Cc1cc(Cl)c(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)c(C#N)cc2Cl)n[nH]1
Temperature: 55 °C
Yield: 59.8 %

Procedure:
To a 25-ml, round-bottom flask, was added 2,5,6-trichloronicotinonitrile (Method 44, 1 g, 4.8 mmol), 5-methyl-1H-pyrazol-3-amine (466 mg, 4.8 mmol), DIEA (1.1 ml, 6.3 mmol), and EtOH (5 ml) and set to heat at 55° C. for 16 hours. The resulting mixture was then purified by silica gel chromatography (Biotage Horizon System) using 25-75% EtOAc/hexanes to give 770 mg of the title compound. 1H NMR: 12.36 (s, 1H) 9.68 (s, 1H) 8.39 (s, 1H) 6.32 (s, 1H) 2.29 (s, 3H). MS: Calcd.: 268. Found: [M+H]+ 267/269.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=2)[C:5]([OH:19])=[C:4]([C:20]([OH:22])=[O:21])[N:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].S([O-])(OC)(=O)=O>CC(C)=O>[CH3:23][O:21][C:20]([C:4]1[N:3]=[C:2]([Br:1])[C:11]2[C:6]([C:5]=1[OH:19])=[CH:7][CH:8]=[C:9]([S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=2)=[O:22]
Reactant: O=C(O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Reactant: O=C([O-])[O-]
Agent: COS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Yield: 92.5 %

Procedure:
1-Bromo-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid (10.0 g), potassium carbonate (3.7 g) and methyl sulfate (3.4 g) were suspended in 500 ml acetone and stirred at reflux overnight. Reaction mixture was concentrated and residue partitioned between 1 N hydrochloric acid and ethyl acetate. Organic layer was dried over magnesium sulfate and filtered. Filtrate concentrated to give title compound (9.6 g). MS-(+)-ion M+1=389.9, 391.9.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[N:10]2)=[CH:4][CH:3]=1.CI.[C:34](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([N:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:34])=[CH:12][C:11]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[N:10]2)=[CH:30][CH:31]=1
Reactant: CCOC(=O)Nc1cc(-c2ccc(OC)cc2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)N(C)c1cc(-c2ccc(OC)cc2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Yield: 89.2 %

Procedure:
In N,N-dimethylformamide, 2-(4-chlorocinnamyl)-4-ethoxycarbonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one (100 mg) was stirred at 80° C. for 1 hour in the presence of methyl iodide and potassium carbonate. The procedures of Example 1 were then repeated likewise, whereby the title compound (92 mg, 89.2%) was obtained.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].NCCCNCC[CH2:20][N:21]([CH2:29][CH:30]1[CH2:35][CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[O:31]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[O:31]1[C:32]2[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=2[CH2:34][CH2:35][CH:30]1[CH2:29][N:21]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:20][CH2:11][CH2:12][N:8]1[CH2:9][CH2:6][CH2:7][NH:3][C:1]1=[O:2]
Reactant: NCCCNCCCN(Cc1ccccc1)CC1CCc2ccccc2O1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1NCCCN1CCCN(Cc1ccccc1)CC1CCc2ccccc2O1
Temperature: 25 °C
Reaction time: 17 h
Yield: 42 %

Procedure:
1,1′-Carbonylbis-1H-imidazole (0.02 mol) was added to a solution of (±)-N-(3-aminopropyl)-N′-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N′-(phenylmethyl)-1,3-propanediamine (0.0(2 mol) in THF (100 ml). The reaction solution was stirred for 17 hours at room temperature. The solvent was evaporated. Water was added to the residue and the mixture was extracted with toluene. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was crystallized from ethyl acetate (50 ml). The precipitate was filtered off and dried, yielding 3.3 g (42%) of (±)-1-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl](phenylmethyl)amino]propyl]-tetrahydro-2(1H)-pyrimidinone (comp. 13): mp. 94.7° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:11]1[C:12]([N+:17]([O-:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1>>[CH2:3]([N:2]([CH3:1])[C:11]1[C:12]([N+:17]([O-:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ncccc1Cl
Reactant: CNCc1ccccc1
Product: CN(Cc1ccccc1)c1cccnc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The mixture of N-methylbenzylamine (6.085 mL), TEA (13.19 μL) and 3-chloro-2-nitropyridine (5 g) was stirred at 60° C. under N2 overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-30% EtOAc in hexane) to give N-benzyl-N-methyl-2-nitropyridin-3-amine (2.6 g) as dark yellow oil.
Reaction SMILES: [C:1]1([CH-:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].[CH3:15][C:16]([CH3:22])=[C:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1>C1COCC1>[CH:17]1([C:16]([CH3:22])([CH3:15])[CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:21]=[CH:20][CH:19]=[CH:18]1
Reactant: c1ccc([CH-]c2ccccc2)cc1
Reactant: CC(C)=C1C=CC=C1
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C1C=CC=C1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium diphenylmethanide (5.72 g, 27.8 mmols) in about 50 mL of THF was slowly added to 6,6-dimethylfulvene (2.94 g, 27.8 mmols) in about 100 mL of THF at about 25 C. The reaction mixture was stirred at about 25° C. for about 16 hours. The solvent was removed under reduced pressure to give the desired product as a sticky, oily solid.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[NH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:7])=[CH:3][C:4]([NH:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:5]
Reactant: CC(C)=CC(=O)Cl
Reactant: COC(=O)c1ccccc1N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(=O)C=C(C)C
Reaction time: 0.5 h

Procedure:
A solution of 12.5 ml of 3-methylbut-2-enoyl chloride in 110 ml of toluene is added dropwise at room temperature to a solution of 13.4 ml of methyl 2-aminobenzoate and 21.8 ml of triethylamine in 110 ml of toluene. After 30 minutes, the reaction mixture is diluted with toluene, washed with 1N HCl (2×), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.34 (1:10 EtOAc-heptane); Rt=4.78.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1.O>CN(C)C=O>[CH2:20]([O:19][C:17]([C:16]1[CH:22]=[CH:23][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[CH:14][CH:15]=1)=[O:18])[CH3:21]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1ccc(OCCCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCCn2ccnc2)cc1
Temperature: 100 °C

Procedure:
Sodium hydride (0.6 g, 50% suspension in mineral oil) was added cautiously to a stirred and cooled solution of imidazole (0.79 g) in dry N,N-dimethylformamide (50 ml). After the initial vigorous reaction had subsided the mixture was heated to 100° C. for 10 minutes and then stirred at room temperature for a further 1 hour. Ethyl 4-(3-chloropropoxy)benzoate (2.8 g) was added over 2 minutes and the resulting mixture was heated on a steam bath for 6 hours and then cooled. Water (1 ml) was added to decompose any unreacted sodium hydride and the solution was evaporated and the residue was chromatographed on silica gel. Elution with chloroform gave mineral oil and small amounts of impurity. Elution with chloroform/methanol (20:1) gave the pure 1-[3-(4-ethoxycarbonylphenoxy)propyl]imidazole as an oil on evaporation of the solvent.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[C:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=[O:27])[CH3:26]>>[C:25]([N:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:3]=[CH:4][C:5]([C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:6]([CH3:8])[N:7]=2)[C:29]1=[O:33])(=[O:27])[CH3:26]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3C)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(C)n2)C1=O
Yield: 87.4 %

Procedure:
Using (6-bromo-2-methylpyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (655 mg) described in Preparation Example 247 and 1-acetylimidazolidin-2-one (259 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (642 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH3:19])=[C:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])=[O:10])[O:8][C:4]=2[CH:3]=1.[OH:22][CH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:9]([C:7]1[O:8][C:4]2[CH:3]=[C:2]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:23][OH:22])[CH:29]=3)[CH:21]=[CH:20][C:5]=2[C:6]=1[CH3:19])=[O:10]
Reactant: OCc1cccc(B(O)O)c1
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(Br)ccc12
Product: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(-c3cccc(CO)c3)ccc12

Procedure:
(2,4-Dichloro-phenyl)-[6-(3-hydroxymethyl-phenyl)-3-methyl-benzofuran-2-yl]-methanone was prepared via a Suzuki coupling of (6-Bromo-3-methyl-benzofuran-2-yl) (2,4-dichloro-phenyl)-methanone and 3-(Hydroxymethyl)phenylboronic acid as described in method 1 step 5. 1H-NMR (CDCl3) δ 7.62 (d, J=8 Hz 1H), 7.57-7.53 (m, 1H), 7.48 (dd, J=9 Hz, J=2 Hz, 1H), 7.46-7.44 (m, 2H), 7.40 (d, J=2 Hz, 1H), 7.37-7.33 (m, 2H), 7.30-7.26 (m, 2H), 4.68 (s, 2H), 2.51 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[N:14][CH:15]=1)=[O:8].[N:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=[C:19]=[O:20]>C1C=CC=CC=1>[CH3:17][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19]([NH:18][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)=[O:20])=[CH:16][C:6]=1[C:7](=[O:8])[NH:9][C:10]1[CH:15]=[N:14][CH:13]=[N:12][CH:11]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1C(=O)Nc1cncnc1
Solvent: c1ccccc1
Product: Cc1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)cc1C(=O)Nc1cncnc1
Temperature: 75 °C

Procedure:
To a suspension of 5-amino-2-methyl-N-(pyrimidin-5-yl)benzamide 26 (0.068 g, 0.30 mmol) in benzene (5 mL) was added 1-isocyanato-3-(trifluoromethyl)benzene (0.046 mL, 0.33 mmol). The reaction was heated at 75° C. for 2 hours, producing a solid precipitate. The mixture was concentrated and chromatographed on silica gel with 94/6 CH2Cl2/MeOH to afford 1-(4-methyl-3-(pyrimidin-5-ylcarbamoyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea 27 as a white solid. MS m/z: found 416 [MH+], calc. for C20H16F3N5O2=415.13.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[C:21]1([CH3:30])[CH:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[CH:23][CH:22]=1>>[NH2:19][C:13]1[N:12]=[C:11]([NH2:20])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([C:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:30])=[CH:22][CH:23]=3)=[O:28])[CH2:2][CH2:3]2)[N:14]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Product: Cc1ccc(C(=O)N2CCC(COc3cccc4nc(N)nc(N)c34)CC2)cc1
Yield: 64 %

Procedure:
The amidation of 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) was carried out using p-toluoyl chloride (57 mg; 0.37 mmol) via Method AA to yield 93 mg. (64% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.35 (t, J=8.0 Hz, 1H), 7.25 (m, 4H), 7.2 (br s, 2H), 6.77 (d, J=8.0 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 5.94 (br s, 2H), 4.53 (br s, 1H), 4.03 (d, J=6.0 Hz, 2H), 3.67 (br s, 1H), 3.07 (br s, 1H), 2.844 (br s, 1H), 2.34 (s, 3H), 2.18 (m, 1H), 1.82 (m, 2H), 1.29 (m, 2H). MS m/z (ESI) 392 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[C:12]([CH2:24][CH:25]([CH3:27])[CH3:26])=[N+:13]([O-:23])[C:14]([O:21][CH3:22])=[C:15]([C:17]([O:19]C)=[O:18])[N:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.O>[CH2:3]([O:10][C:11]1[N:16]=[C:15]([C:17]([OH:19])=[O:18])[C:14]([O:21][CH3:22])=[N+:13]([O-:23])[C:12]=1[CH2:24][CH:25]([CH3:27])[CH3:26])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1nc(OCc2ccccc2)c(CC(C)C)[n+]([O-])c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(C(=O)O)nc(OCc2ccccc2)c(CC(C)C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 14 h
Yield: 91 %

Procedure:
4.1 Milliliters of 1N sodium hydroxide was added to a solution of 0.71 g of 3-benzyloxy-2-isobutyl-6-methoxy-5-methoxycarbonylpyrazine 1-oxide dissolved in 15 ml of methanol, then the mixture was stirred for 14 hours at room temperature. The reaction mixture was diluted with water, and then extracted with dichloromethane. The aqueous layer was made acidic with 6.0 ml of 1N hydrochloric acid with ice cooling, then extracted with ethyl acetate. The extract was washed with an aqueous solution saturated with NaCl twice and dried over magnesium sulfate. The solvent was removed by evaporation to obtain 0.62 g of 6-benzyloxy-5-isobutyl-3-methoxypyrazine-2-carboxylic acid 4-oxide (Compound B-22).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[CH2:10]([N:13]1[C:22](=[O:23])[C:21]2[NH:20][C:19]([C:24]3[N:28]([CH3:29])[N:27]=[C:26]([O:30][CH2:31][C:32](O)=[O:33])[CH:25]=3)=[N:18][C:17]=2[N:16]([CH2:35][CH2:36][CH3:37])[C:14]1=[O:15])[CH2:11][CH3:12]>>[CH3:37][CH2:36][CH2:35][N:16]1[C:14](=[O:15])[N:13]([CH2:10][CH2:11][CH3:12])[C:22](=[O:23])[C:21]2[C:17]1=[N:18][C:19]([N:20]=2)=[C:24]1[N:28]([CH3:29])[NH:27][C:26]([O:30][CH2:31][C:32]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([CH3:1])[CH:3]=2)=[O:33])=[CH:25]1
Reactant: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CCC)c1=O
Reactant: Cc1ccc(N)cc1C
Product: CCCn1c(=O)c2c(n(CCC)c1=O)=NC(=C1C=C(OCC(=O)Nc3ccc(C)c(C)c3)NN1C)N=2

Procedure:
Using 3,4-dimethylaniline and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36), according to the method described in Example 36.
Reaction SMILES: [F:1][CH:2]([F:10])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11]Cl>FC(F)(F)C1C=CC=C(C(F)(F)F)C=1.[Cl-].[K+]>[Cl:11][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][CH:2]([F:10])[F:1]
Reactant: ClCl
Reactant: FC(F)Oc1ccccc1
Agent: FC(F)(F)c1cccc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [K+]
Product: FC(F)Oc1ccccc1Cl

Procedure:
0.5 g of potassium chloride and 10 g of difluoromethoxybenzene in 100 ml of 1,3-bistrifluoromethylbenzene were introduced as the initial charge, and chlorine was then introduced at 100° C. with UV irradiation. In the course of an hour, another 20 g of difluoromethoxybenzene were metered in. After chlorine uptake was complete, the reaction mixture was purged with nitrogen and subsequently distilled. 35.5 g of chlorodifluoromethoxybenzene were isolated (boiling point 144° C., refractive index nD20 1.4479).
Reaction SMILES: Cl.[OH:2][C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)C(C)C)(C)C.[F:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1F>C(#N)C>[F:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1[N:5]1[CH2:6][CH2:7][C@@H:3]([OH:2])[CH2:4]1
Reactant: O[C@@H]1CCNC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CC[C@@H](O)C2)c(F)c1
Yield: 95.6 %

Procedure:
(3R)-3-Hydroxypyrrolidine hydrochloride (20 g, 0.163 M) was suspended by stirring in acetonitrile (200 ml) under nitrogen at 50°, and treated with N,N-diisopropylethylarnine (52.5 g, 0.41 M) and 3,4-difluoronitrobenzene (25.9 g, 0.153 M). The mixture was heated at 90° for 17 hours, then the solvent evaporated. The residue was dissolved in dichloromethane (500 ml) and washed with 5% aqueous sodium dihydrogen phosphate (300 ml), which caused partial precipitation. The precipitate was filtered, washed, and the combined aqueous layers re-extracted with dichloromethane (200 ml). The organic layers were evaporated, and the residue combined with the previously filtered material, and dried by azeotroping with toluene to give the desired product (35 g), of sufficient quality for use without purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1)[CH3:2].[ClH:18].[Cl:19][CH2:20][CH2:21][N:22]1[CH2:28][CH:27]2[CH2:29][CH2:30][CH:24]([CH2:25][CH2:26]2)[CH2:23]1>>[ClH:19].[ClH:18].[CH:27]12[CH2:29][CH2:30][CH:24]([CH2:25][CH2:26]1)[CH2:23][N:22]([CH2:21][CH2:20][N:12]1[CH2:13][CH2:14][C:9]3[C:6]4[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=4[O:16][C:15](=[O:17])[C:10]=3[CH2:11]1)[CH2:28]2
Reactant: ClCCN1CC2CCC(CC2)C1
Reactant: CCc1ccc2c3c(c(=O)oc2c1)CNCC3
Agent: Cl
Product: CCc1ccc2c3c(c(=O)oc2c1)CN(CCN1CC2CCC(CC2)C1)CC3
Yield: 68 %

Procedure:
Prepared by the method described for Example 1 from 8-ethyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (5.5 g, 0.024 moles) and 3-(2-chloroethyl)-3-azabicyclo(3.2.2)nonane hydrochloride (5.5 g, 0.025 moles). Recrystallization from ethanol gave the product (7.4 g), mp 295°-300° C.
Reaction SMILES: [F:1][CH2:2][C:3]([NH:5][C:6]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[CH3:18])=[O:9])=O.B(F)(F)F.CCOCC>C(O)(=O)C>[F:1][CH2:2][C:3]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[CH3:18])[C:8](=[O:9])[C:7]2[C:6](=[CH:22][CH:21]=[C:20]([N+:23]([O-:25])=[O:24])[CH:19]=2)[N:5]=1
Reactant: Cc1cc(F)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1cc(F)ccc1-n1c(CF)nc2ccc([N+](=O)[O-])cc2c1=O
Yield: 79.1 %

Procedure:
4.0 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2-methyl-4-fluoraniline, 3.5 g of boron trifluoride etherate and 30 ml of acetic acid are treated in the same manner as described in Example 1-(2), whereby 3.0 g of 2-fluoromethyl-3-(2-methyl-4-fluorophenyl)-6-nitro-4(3H)-quinazolinone are obtained as colorless prisms.