Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:25][CH:26]=1>CCCCCC.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:25]3[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=3)[NH2:20])[N:3]=2)[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1cccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)c1

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 3-aminophenylboronic acid pinacol ester with reaction time of 15 h. Column chromatography (hexane/ethyl acetate 1:1) gave the title compound as an colorless solid.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.[CH3:20][O:21]C1C(OC)=CC=CC=1C=O>>[C:11]1([C:10]#[C:9][CH:8]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([O:21][CH3:20])[C:5]=2[O:18][CH3:19])[OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(C=O)c1OC
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Product: COc1cccc(C(O)C#Cc2ccccc2)c1OC
Yield: 66 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2,3-dimethoxybenzaldehyde was reacted to give the title compound as a colourless oil (352 mg, 66%). LCMS (Method B): RT=4.09 min, [M+Na]+=291.
Reaction SMILES: [C:1]([C@:4]1([CH2:38][OH:39])[O:10][C@@:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)O)=[CH:14][CH:13]=2)([OH:9])[C@:7]([C:27](=[O:29])[CH3:28])([OH:26])[C@@:6]([C:31](=[O:33])[CH3:32])([OH:30])[C@@:5]1([C:35](=[O:37])[CH3:36])[OH:34])(=[O:3])[CH3:2].O=S(Cl)[Cl:42]>C(Cl)Cl>[C:1]([C@:4]1([CH2:38][OH:39])[O:10][C@@:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[Cl:42])=[CH:14][CH:13]=2)([OH:9])[C@:7]([C:27](=[O:29])[CH3:28])([OH:26])[C@@:6]([C:31](=[O:33])[CH3:32])([OH:30])[C@@:5]1([C:35](=[O:37])[CH3:36])[OH:34])(=[O:3])[CH3:2]
Reactant: CC(=O)[C@]1(O)[C@](O)(C(C)=O)[C@](CO)(C(C)=O)O[C@](O)(Oc2ccc(C(O)c3ccccn3)cc2)[C@@]1(O)C(C)=O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(=O)[C@]1(O)[C@](O)(C(C)=O)[C@](CO)(C(C)=O)O[C@](O)(Oc2ccc(C(Cl)c3ccccn3)cc2)[C@@]1(O)C(C)=O
Reaction time: 1 h

Procedure:
Tetraacetyl-(p-(pyridinylhydroxymethyl)phenoxy)-β-galactose (600 mg, 1.1 mmol) is dissolved in 15 ml of CH2Cl2. SOCl2 (143 mg, 88 μl, 1.2 mmol) is added dropwise and the solution is left stirring for 1 hour. The solvent is evaporated under vacuum. The product is obtained pure and quantitatively.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[C:5]([F:11])[CH:4]=1.[F:12][C:13]1[CH:14]=[C:15]([Mg]Br)[CH:16]=[CH:17][C:18]=1[O:19]C.II>O1CCCC1.[Pd](Cl)Cl>[F:11][C:5]1[CH:4]=[C:3]([C:15]2[CH:16]=[CH:17][C:18]([OH:19])=[C:13]([F:12])[CH:14]=2)[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: COc1ccc([Mg]Br)cc1F
Reactant: COc1ccc(Br)cc1F
Agent: Cl[Pd]Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Oc1ccc(-c2ccc(O)c(F)c2)cc1F
Reaction time: 1 h

Procedure:
Flaky metallic magnesium (2.43 g) was added to 50 ml of dry tetrahydrofuran, and while the mixture was heated, a solution of 20.5 g of 4-bromo-2-fluoroanisole in 100 ml of dry tetrahydrofuran was added dropwise little by little in a stream of nitrogen to prepare a tetrahydrofuran solution of 3-fluoro-4-methoxy-phenyl magnesium bromide. Then, 18.0 g of 4-bromo-2-fluoroanisole was added to 100 ml of dry tetrahydrofuran containing 0.05 g of iodine and 0.1 g of palladium chloride. The mixture was maintained at 40° to 50° C. in a stream of nitrogen, and the above-prepared tetrahydrofuran solution of 3-fluoro-4-methoxyphenyl magnesium bromide was added dropwise gradually. The addition was completely in about 1 hour, and thereafter, the mixture was reacted for 5 hours at the refluxing temperature of tetrahydrofuran. After the reaction, the reaction mixture was after-treated in a customary manner to give 38.2 g of a crude product. The desired product was isolated from the crude product by silica gel column chromatography using ethyl acetate/hexane as an eluent. Thus, 15.0 g of 3,3'-difluoro-4,4'-dimethoxybiphenyl was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[NH:16][C:17](=[O:33])[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][O:14][C:12]1[CH:11]=[CH:10][C:9]2[NH:16][C:17](=[O:33])[CH2:18][C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:21]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: COc1ccc(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)c(NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)N=C(c1cccc(-c3cccnc3)c1)CC(=O)N2

Procedure:
The title compound was prepared from {5-methoxy-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M51) (229 mg, 0.50 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (159 mg).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=[O:8].C(N(CC)CC)C.[CH3:17][O:18][C:19](Cl)=[O:20]>CN(C=O)C>[CH3:17][O:18][C:19]([N:2]([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=[O:8])=[O:20]
Reactant: COC(=O)Cl
Reactant: CNCCOCC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)N(C)CCOCC(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.4 %

Procedure:
[2-(Methylamino)ethoxy]acetic acid (Bull. Soc. Chim.; 1956, 1210) (130 mg, 0.98 mmol) was mixed with triethylamine (0.56 mL, 4 mmol) in dry DMF (2 mL). Methylchloroformate (185 mg, 1.95 mmol) was added and the mixture was stirred at room temperature for 20 minutes, then quenched with water. Aqueous HCl (2M) was added to adjust the pH to ˜2. Product was extracted with ethyl acetate, the organic phase was dried over magnesium sulfate and concentrated under reduced pressure to give the crude product as an oil (100 mg), which was used without further purification.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1(=[O:15])[O:10][C:8](=[O:9])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([OH:21])=[CH:19][C:18]=1[OH:24]>[N+](C1C=CC=CC=1)([O-])=O>[C:8]([C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[C:5](=[O:15])[C:22]1[CH:23]=[C:17]([Cl:16])[C:18]([OH:24])=[CH:19][C:20]=1[OH:21])([OH:10])=[O:9]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Oc1ccc(Cl)c(O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)c1ccccc1C(=O)c1cc(Cl)c(O)cc1O
Reaction time: 8 h

Procedure:
AlCl3 (40.0 g, 300 mmol) was added to a solution of phthalic anhydride (20.0 g, 135 mmol) and 4-chlororesorcinol (18.8 g, 130 mmol) in 225 ml nitrobenzene and purged with N2. After stirring overnight, the solution was poured into a vigorously stirred biphasic solution of 750 ml hexanes and 1.0 L 0.5 M aqueous HCl. The solution was allowed to stir for 2 h and the light tan precipitate that formed was filtered and washed with 200 ml aqueous 0.1 M HCl and 300 ml hexanes. The crude product was crystallized from hot MeOH/H2O (12.1 g, 32%). 1H NMR (CD3OD) δ 6.48 (1 H, s), 6.95 (1 H, s), 7.39 (1 H, dd, J=7.2 1.5), 7.62-7.52 (2 H, m), 8.12 (1 H, dd, J=1.2, 7.8).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Product: O=[N+]([O-])c1ccc2ncnc(Nc3cccc(Br)c3)c2c1

Procedure:
3-Bromoaniline is coupled with 4-chloro-6-nitroquinazoline, to produce 4-[(3-bromophenyl)amino]-6-nitroquinazoline, which is reduced thereafter to the corresponding 6-aminoquinazoline. The 4-[(3-bromophenyl)amino]-6-aminoquinazoline is then reacted with bistributyltin, using tetrakis(triphenylphosphine)palladium in THF solution as the reaction catalyst, as is described hereinbelow (see, iodine-124 labeled Compound 5). The stanylated quinazoline is then reacted with bromine-76 or bromine-77, in the presence of an oxidizing agent, to produce bromine-76 labeled or bromine-77 labeled 4-[(3-bromophenyl)amino]-6-aminoquinazoline, which is farther reacted with acryloyl chloride as described, to yield the final bromine-76 labeled or bromine-77 labeled product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:34])([CH3:33])[CH2:14][O:15][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[C:10](=[O:35])[C@@H:9]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[O:8][C@H:7]([C:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH:45]=[CH:44][CH:43]=3)[C:6]=2[CH:52]=1.C(=O)(O)[O-].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:33])([CH3:34])[CH2:14][OH:15])[C:10](=[O:35])[C@@H:9]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[O:8][C@H:7]([C:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH:45]=[CH:44][CH:43]=3)[C:6]=2[CH:52]=1
Reactant: CCOC(=O)C[C@H]1O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc2N(CC(C)(C)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C[C@H]1O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc2N(CC(C)(C)CO)C1=O
Reaction time: 18 h
Yield: 80.5 %

Procedure:
Ethyl trans-7-chloro-5-(1-naphthyl)-1-(3-tert-butyldiphenylsilyloxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate (8.52 g, 11.62 mmol) was dissolved in acetonitrile (200 ml). A solution of HF in water (50%, 50 ml) was added at room temperature. Stirring for 18 hours was followed by hydrolysis with saturated sodium bicarbonate and repeated extraction of the aqueous layer with dichloromethane. The combined organic layers were dried with MgSO4. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (dichloromethane/methanol 99:1) to give the title compound (4.64 g, 81%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[CH:22]1([CH2:25][O:26][C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[CH:30]=O)[CH2:24][CH2:23]1.[O-]CC.[Na+]>C(O)C>[CH:22]1([CH2:25][O:26][C:27]2[CH:28]=[C:29](/[CH:30]=[CH:1]/[C:2]3[N:3]=[C:4]4[S:21][CH:20]=[CH:19][N:5]4[C:6](=[O:18])[C:7]=3[C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=3)[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[CH2:23][CH2:24]1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(C=O)cc1OCC1CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(C(F)(F)F)cc2)cc1OCC1CC1
Yield: 42.9 %

Procedure:
The title compound was synthesized by condensation of Intermediate 5 (400 mg, 1.350 mmol) with 3-cyclopropylmethoxy-4-methoxybenzaldehyde (417 mg, 2.025 mmol) in presence of sodium ethoxide (183 mg, 2.701 mmol) in ethanol (20 ml) according to the procedure described in Example 24 to give 289 mg of the desired product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.23-0.30 (m, 2H), 0.50-0.58 (m, 2H), 1.12-1.18 (m, 1H), 3.72-3.80 (m, 5H), 6.60 (d, J=15.6 Hz, 1H) 6.94-7.00 (m, 3H), 7.48-7.53 (m, 1H), 7.58-7.64 (m, 2H), 7.78-7.84 (m, 3H), 7.98-8.05 (m, 1H); ESI-MS (m/z) 499.12 (M+H)+.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:16]=2[N:17]=[C:18]([C:20]2[O:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[O:24]1[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:16]=3[N:17]=2)=[CH:21][CH:22]=[N:23]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccno3)nc(NCCc3ccc4c(c3)OCO4)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-methylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][CH2:14][CH:15]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)[CH2:16][CH3:17])[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl>C(O)C>[NH2:8][C@@H:12]([CH2:13][CH2:14][CH:15]([C:18]1[CH:19]=[C:20]([F:25])[CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:16][CH3:17])[CH2:11][OH:10]
Reactant: CCC(CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1cc(F)cc(F)c1
Agent: Cl
Solvent: CCO
Product: CCC(CC[C@H](N)CO)c1cc(F)cc(F)c1
Reaction time: 16 h
Yield: 85.1 %

Procedure:
To (S)-4-[3-(3,5-difluoro-phenyl)-pentyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.5 g) was added under an argon atmosphere 5.5 M HCl solution in ethanol (2 ml). The mixture was stirred for 16 h. The mixture was concentrated. The residue was dissolved in dichloromethane and an excess of ammonia in methanol and some silica gel was added. The solvents were evaporated and the crude product was purified by column chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: dichloromethane/methanol=90:10) to give (S)-2-amino-5-(3,5-difluoro-phenyl)-heptan-1-ol (0.27 g) as a colourless liquid. MS (ISP): 244.3 ([M+H]+).
Reaction SMILES: Cl[C:2]1C=CC(C#N)=CN=1.[NH2:10][C:11]1[N:16]=[C:15]([NH:17][CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[NH:28][CH:29]=[CH:30][N:31]=3)=[C:23]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[Cl:39])[N:22]=2)[CH:14]=[CH:13][C:12]=1[N+]([O-])=O>>[Cl:39][C:33]1[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:32]=1[C:23]1[N:22]=[C:21]([NH:20][CH2:19][CH2:18][NH:17][C:15]2[N:16]=[CH:2][C:12]([C:11]#[N:10])=[CH:13][CH:14]=2)[CH:26]=[CH:25][C:24]=1[C:27]1[NH:31][CH:30]=[CH:29][N:28]=1
Reactant: Nc1nc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: N#Cc1ccc(Cl)nc1
Product: N#Cc1ccc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
6-[(2-{[6-(2,4-dichlorophenyl)-5-imidazolyl-2-pyridyl]amino}ethyl)amino]-pyridine-3-carbonitrile was prepared from 2-chloropyridine-5-carbonitrile using the general method for {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[6-(2,4-dichlorophenyl)-5-imidazolyl(2-pyridyl)]amine.
Reaction SMILES: [CH3:1][NH2:2].C(O)C.C(Cl)CCl.[CH3:10][S:11][C:12](SC)=[CH:13][N+:14]([O-:16])=[O:15]>C(Cl)CCl>[CH3:1][NH:2][CH:12]([S:11][CH3:10])[CH2:13][N+:14]([O-:16])=[O:15]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CN
Solvent: ClCCCl
Solvent: CCO
Product: CNC(C[N+](=O)[O-])SC

Procedure:
A solution of methylamine in ethanol/ethylenedichloride (112.5 ml of 33% ethanolic methylamine in 0.8 liters of ethylene dichloride; 0.94 mole) was added over 51/2 hr at 70° to a stirred solution of 1,1-bismethylthio-2-nitroethene (99.0 g, 0.6 mole) in ethylene dichloride (1.5 liters). The solution was heated to boiling and 0.7 liters of solvent were distilled off. The cooled solution was washed with 2N hydrochloric acid (0.25 liters), then with brine (0.25 liters). The solvent was removed and the residue crystallised from isopropyl acetate (0.5 liters), treating the hot solution with charcoal (10.0 g). The product (35.0 g) formed yellow prisms, m.p. 114°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:19][CH:18]3[CH:14]([CH2:15][NH:16][CH2:17]3)[CH2:13]1)[N:6]=[CH:5]2.[F:20][C:21]1[C:22]([C:30]2[N:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25]>>[F:20][C:21]1[C:22]([C:30]2[N:31]=[CH:32][CH:33]=[CH:34][N:35]=2)=[C:23]([C:24]([N:16]2[CH2:17][CH:18]3[CH:14]([CH2:13][N:12]([C:7]4[N:6]=[CH:5][C:4]5[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=5)[N:8]=4)[CH2:19]3)[CH2:15]2)=[O:25])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1cccc(F)c1-c1ncccn1
Reactant: Fc1ccc2nc(N3CC4CNCC4C3)ncc2c1
Product: O=C(c1cccc(F)c1-c1ncccn1)N1CC2CN(c3ncc4cc(F)ccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 43 and 3-fluoro-2-(pyrimidin-2-yl)benzoic acid. MS (ESI): mass calculated for C25H20F2N6O, 458.17; m/z found 459.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.98 (d, J=8.1, 1H), 8.82-8.74 (m, 2H), 7.61 (dt, J=12.7, 6.4, 1H), 7.53-7.41 (m, 2H), 7.31 (td, J=8.0, 2.7, 1H), 7.25-7.18 (m, 2H), 7.15 (t, J=4.9, 1H), 4.00-3.88 (m, 1H), 3.89-3.69 (m, 3H), 3.68-3.52 (m, 3H), 3.36 (dd, J=10.9, 4.6, 1H), 3.14-2.97 (m, 2H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]2[CH:18]=[C:17]([CH2:19][CH2:20][CH:21]=O)[O:16][N:15]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:37]=[CH:36][CH:35]=[CH:34][C:26]=1[CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][N:31]3[CH2:30][CH2:29][N:28]([CH2:27][C:26]4[CH:34]=[CH:35][CH:36]=[CH:37][C:25]=4[C:24]([F:38])([F:39])[F:23])[CH2:33][CH2:32]3)[O:16][N:15]=2)[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccccc1CN1CCNCC1
Reactant: O=CCCc1cc(-c2cccc(Oc3ccccc3)c2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1ccccc1CN1CCN(CCCc2cc(-c3cccc(Oc4ccccc4)c3)no2)CC1
Yield: 93.9 %

Procedure:
About 2 min after dissolving 3-[3-(3-phenoxyphenyl)isoxazol-5-yl]propanal (10 mg, 0.03 mmol) and 1-[2-(trifluoromethyl)benzyl]piperazine (7.1, 0.03 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (22 mg, 0.10 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 4 hr and followed the same processes as in Example 1 to obtain 14.7 mg (82.7%) of the target compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:7][C:8]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1Cl)=[CH:17][CH:16]=[C:15]([Cl:21])[CH:14]=2)=[O:9])[CH3:6].O>CN(C)C=O>[CH2:5]([O:7][C:8]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[N:1]=[N+:2]=[N-:3])=[CH:17][CH:16]=[C:15]([Cl:21])[CH:14]=2)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1cnc2cc(Cl)ccc2c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2cc(Cl)ccc2c1N=[N+]=[N-]
Reaction time: 18 h

Procedure:
Sodium azide (0.62 g; 0.009 M) was suspended in a solution of ethyl-4,7-dichloroquinoline-3-carboxylate E. F. Elslager, et al., J. Med. Pharm, Chem, 5, 550 (1962) (1.75 g; 0.006 M) in dry dimethyl formamide (20 ml) and this mixture stirred at ambient temperatures. After 18 hr. the mixture was poured into reapidly stirred water (200 ml), the resultant precipitate filtered off, dried at the pump and then recrystallised from ethanol (8 ml/g), 1.27 g (71%), m.p. 94.5° C., (Found: C, 51.7; H, 3.4; N, 20.2; Cl, 12.9% C12H9N4O2Cl requires C, 52.0; H, 3.3; N, 20.2; Cl, 12.8%); max (KBr) 2140, 1722, 1390, 1372, 1274, 1239, 1199 and 1058 cm-1, (CDCl3) 1.48 (t) and 4.55 (m) (CH3CH2), 7.59 (m), 8.11 (d), 8.32 (d) and 9.29 (s) (aromatic H's) m/e 276 (M+, 14%), 248 (9%), 218 (22%), 154 (29% 152 (100%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([CH:14]([CH3:16])[CH3:15])[C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH:14]([C:5]1[C:6]([O:12][CH3:13])=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[N:11]=[CH:10]2)([CH3:16])[CH3:15]
Reactant: Nc1ccccc1
Reactant: COc1ccc2cnc(Cl)nc2c1C(C)C
Solvent: CC#N
Product: COc1ccc2cnc(Nc3ccccc3)nc2c1C(C)C
Temperature: 80 °C
Yield: 77.1 %

Procedure:
A mixture of 2-chloro-7-methoxy-8-(2-propyl)quinazoline (100 mg, 0.42 mmol) and aniline (120 mg, 1.29 mmol) in acetonitrile (3 mL), was heated at 80° C. for 18 hours in a sealed tube. The solvent was removed under reduced pressure, to the residue 5% sodium carbonate solution was added. The product was extracted with ethyl acetate (3×25 mL). The combined organic extract was washed with brine, dried (Na2SO4), and concentrated. The product was purified on a column of silica gel to give the title compound as an off-white solid (95 mg, 76.3%), mp 172–173° C.; 1H NMR (CDCl3): δ 1.46 (d, 6H, 2×CH3), 3.97 (s, 3H, OCH3), 4.33 (m, 1H, CH), 7.0–7.1 (m, 2H, Ar-H), 7.38 (t, 2H, Ar-H, 7.58 (d, 1H, Ar-H), 7.85 m, 2H, Ar-H), 8.93 (s, 1H, Ar-H); MS m/z C18H19N3O 294.21 (M++1); Analysis: Calcd.; C, 73.7; H, 6.53; N, 14.32. Found: C, 73.8; H, 6.83; N, 14.59.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:27][C:24]=1[CH:25]=O.C[O-].[Li+]>CN(C=O)C.CO>[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:27][C:24]=1/[CH:25]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: COc1cc(OC)c(N2CCCC2)cc1C=O
Reactant: CC(=O)c1ccc(S(=O)(=O)NCc2ccccn2)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(OC)c(N2CCCC2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)NCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.9 %

Procedure:
A solution 4-acetyl-N-pyridin-2-ylmethyl-benzenesulfonamide (Ex-53A, 617 mg, 2.13 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde (Ex-38B, 500 mg, 2.13 mmol) in DMF (9.3 mL) and MeOH (4.0 mL) was treated with lithium methoxide (162 mg, 4.26 mmol) and stirred for 20 h at room temperature under nitrogen. The reaction mixture was quenched with water (20 mL) and extracted ethyl acetate (3×50 mL). The organic phase was brined, dried over sodium sulfate, and concentrated to a red solid. Crystallization from hot ethanol (25 mL) and water (50 mL) gave the title compound as a red solid (626 mg, 58%), mp 112–116° C. 1H-NMR (300 MHz, DMSO-d6) 8.40 (m, 3H), 8.19 (d, 2H, J=9.0 Hz), 8.05 (d, 1H, J=15.9 Hz), 7.89 (d, 2H, J=9.0 Hz), 7.62 (m, 2H), 7.25 (dd, 1H, J=4.5, 5.7 Hz), 7.17 (s, 1H), 6.67 (s, 1H), 4.05 (d, 2H, J=5.7 Hz), 3.86 (s, 3H), 3.85 (s, 3H), 3.16 (br s, 4H), 1.82 (br s, 4H). HRMS (ESI) Calcd. for C27H29N3O5S: 508.1906 [(M+H)+]; Found: 508.1902.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][NH2:7])=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[CH2:24][C:25](Cl)=[O:26]>O1CCCC1>[CH2:1]([O:3][C:4]([NH:6][NH:7][C:25](=[O:26])[CH2:24][C:17]1[C:16]([CH3:15])=[CH:21][C:20]([CH3:22])=[CH:19][C:18]=1[CH3:23])=[O:5])[CH3:2]
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Reactant: CCOC(=O)NN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)NNC(=O)Cc1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of hydrazinecarboxylic acid ethyl ester (ethyl carbazate, 32.8 g, 314.9 mmol) and triethylamine (44.1 ml, 32.0 g, 316.4 mmol) in tetrahydrofuran (1000 ml) at 0° C. was added (2,4,6-trimethyl-phenyl)-acetyl chloride (62.0 g, 315.2 mmol) dropwise. The thick suspension was stirred at room temperature for one hour and the solvent evaporated. The residue was suspended in a mixture of t-butyl methyl ether (500 ml) and water (500 ml), stirred, filtered and the solid washed with small portions of water and t-butyl methyl ether. The solid was dried in vacuo over phosphorus pentoxide at 40° C. Yield: 78.4 g of N′-[2-(2,4,6-trimethyl-phenyl)-acetyl]-hydrazinecarboxylic acid ethyl ester as a white solid, mp 184-186° C.