Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].CO>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(OCc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(OCc2ccccc2)c1

Procedure:
A mixture of methyl 3-benzyloxybenzoate (23.9 g; 0.099 mol), potassium hydroxide (8.42 g; 0.15 mol) and methanol (100 cm3) was stirred at room temperature until a small sample in water gave a clear solution (˜18 hrs). The solution was then evaporated to dryness and the colourless solid residue dissolved in water (100 cm3) and the resulting stirred solution was acidified slowly with 50% sulphuric acid (30 cm3). After stirring for ˜30 minutes, the crystalline precipitate was filtered, washed with water and dried in vacuo at 40° to give the title compound as a colourless powder.
Reaction SMILES: [CH2:1]([S:13]([N:16]1[CH2:21][CH2:20][CH2:19][S:18][C:17]1=[CH:22][N+:23]([O-:25])=[O:24])(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:26]N1C(=O)CCC1=O>>[CH2:1]([S:13]([N:16]1[CH2:21][CH2:20][CH2:19][S:18][C:17]1=[C:22]([Cl:26])[N+:23]([O-:25])=[O:24])(=[O:14])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCS(=O)(=O)N1CCCSC1=C[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Product: CCCCCCCCCCCCS(=O)(=O)N1CCCSC1=C(Cl)[N+](=O)[O-]

Procedure:
was prepared, as a yellow solid, m.p.: 76°-77° C., by treating (3A) with N-chlorosuccinimide according to the procedure described in Example 2.
Reaction SMILES: [Na].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)#[N:3].[C:11]([CH2:13][N:14]=[CH:15]OC)#[N:12]>CO>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:13]2[NH:14][CH:15]=[N:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:3]
Reactant: COC=NCC#N
Reactant: N#Cc1ccc(O)cc1
Agent: [Na]
Solvent: CO
Product: N#Cc1ccc(Oc2cnc[nH]2)cc1
Temperature: 127.5 °C

Procedure:
Sodium metal (1.10 g, 47.8 mmol) was dissolved in anhydrous methanol and 4-cyanophenol (5.70 g, 47.8 mmol) was added. The resultant solution was concentrated and dried under vacuum overnight. A mixture of this sodium salt and 4-cyanophenol (25 g, mp 110-113° C.) was heated to 125-130° C. and neat methyl N-(cyanomethyl)methanimidate (5.0 g, 51 mmol; Hosmane, R. S. et al, J. Org. Chem., 1212, 1984) was added dropwise over a period of 10 minutes under a slow stream of dry argon. The resultant mixture was stirred at 120° C. for 2 hours, cooled, and the reaction product partitioned between methylene chloride (500 mL) and aqueous sodium hydroxide (1 M, 500 mL). The aqueous layer was separated and extracted with methylene chloride (3×100 mL). The organic extracts were combined, washed with brine (100 mL), dried (K2CO3), and the solvent evaporated in vacuo. The residue was purified by chromatography (Silica gel, 3:7 acetone in CHCl3) to afford the title compound as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.CC(C)([O-])C.[K+].[CH3:19][NH:20][C:21]([C:23]1[CH:28]=[C:27](Cl)[CH:26]=[CH:25][N:24]=1)=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:19][NH:20][C:21]([C:23]1[CH:28]=[C:27]([O:12][C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[N:4][C:5]=3[CH:11]=2)[CH:26]=[CH:25][N:24]=1)=[O:22]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Nc1nnc2cc(O)ccc2n1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3nc(N)nnc3c2)ccn1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 55.1 %

Procedure:
3.2 g (19.73 mmol) of 3-amino-benzo[1,2,4]triazine-7-ol was dissolved in 80 mL of anhydrous dimethylformamide under argon atmosphere. 2.44 g (21.71 mmol, 1.1 equivalent) of solid potassium tert-butoxide was added to the solution. The resulting dark-red mixture was heated to about 100° C. and stirred at that temperature for 15 min. A solution of 3.7 g (21.71 mmol, 1.1 equivalent) of 4-chloro-pyridine-2-carboxylic acid methylamide in 10 mL of anhydrous dimethylformamide was added, followed by 3.28 g (23.68 mmol, 1.2 equivalent) of anhydrous K2CO3. The reaction mixture was heated at 140° C. for 30 hrs. The progress of the reaction was monitored by LC/MS. Then it was allowed to cool down to ambient temperature. The resulting dark-brown slurry was poured into 500 mL of water and 100 mL of ethyl acetate. The formed precipitate was collected by filtration, washed with 50 mL of water, 50 mL of methanol, 50 mL of diethyl ether and dried in vacuum to produce 3.22 g of the product as a dirty-yellow solid. The filtrate was extracted four times with 100 mL of ethyl acetate. The combined extracts were washed 3 times with 100 mL of water, then with brine and dried over anhydrous sodium sulfate. Solvent was removed in vacuum to yield additional 1.2 g of the product in a form of a yellow solid. Yield: 75% combined.
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([F:13])[C:5]=1[CH:6]=[O:7]>[Ag]=O.O>[F:3][C:4]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([F:13])[C:5]=1[C:6]([OH:1])=[O:7]
Reactant: Cc1cc(F)c(C=O)c(F)c1
Reactant: [OH-]
Agent: O=[Ag]
Agent: [Na+]
Solvent: O
Product: Cc1cc(F)c(C(=O)O)c(F)c1
Reaction time: 1 h
Yield: 52.8 %

Procedure:
Silver oxide (43.8 g, 0.189 mol) was placed in a flask along with water (200 mL) and sodium hydroxide (33.7 g, 0.842 mol). To it was added 2,6-difluoro-4-methylbenzaldehyde (29.23 g, 0.187 mol) in small portions over a 30 min period. After a vigorous exothermic reaction, the color of the reaction mixture changed from black to gray. The resulting thick suspension was stirred for 1 hr and then filtered through a Buchner funnel. The filtrate was acidified to pH 2 with concentrated HCl to give a suspension. The precipitate was collected by suction filtration, dissolved in ether, dried over anhydrous Na2SO4, filtered and concentrated to give white solid (17.0 g, 53%). 1H-NMR (500 MHz, d6-DMSO): δ13.7 (br.s, 1H), 7.02 (d, 2H, J=9.3 Hz), 2.32 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[CH:20]=[CH:21][C:22](O)=O>>[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1/[CH:20]=[CH:21]/[C:22]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccccc3F)nc2n(CCC)c1=O
Yield: 68.1 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.00 g (13.3 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.43 g (14.6 mmol) of 2-fluorocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 3.23 g (yield 68%) of Compound 42 as white needles.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:18]([F:17])[CH:19]=2)[N:3]=1
Reactant: Nc1cccc(F)c1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Fc1cccc(Nc2nc(Cl)nc3c2ncn3C2CCCC2)c1

Procedure:
2-Chloro-6-(3-fluorophenylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-fluoroaniline, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][S:9][CH:8]=2)=[N:4][N:3]=1.CC(N=NC(C#N)(C)C)(C#N)C.C([O-])(=O)C.[Na+].C1C(=O)N([Br:43])C(=O)C1>C(O)(=O)C.C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][Br:43])=[CH:14][CH:13]=3)=[CH:10][S:9][CH:8]=2)=[N:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2cscc2-c2nnc(C)o2)cc1
Agent: CC(=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nnc(-c2cscc2-c2ccc(CBr)cc2)o1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
5-Methyl-2-(4-(4-methylphenyl)-3-thienyl)-[1,3,4]oxadiazole (3.4 g, 13.3 mmol) was dissolved into carbontetrachloride (60 ml). AIBN (0.21 g), sodium acetate (0.52 g), NBS (2.6 g, 14.6 mmol) and glacial acetic acid (0.52 ml) were added. The reaction mixture was heated at reflux temperature for 8h and then allowed to cool to ambient temperature. The reaction mixture was filtered through silica gel and the filtrate was evaporated in vacuo. The oily residue was dried in vacuo over sodium hydroxide to give 2.6 g of crude 5-methyl-2-(4-(4-bromomethylphenyl)-3-thienyl)- [1,3,4]oxadiazole.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[N:8]=2)[CH2:3][CH2:2]1.[Cl:31]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:31][C:12]1[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:8][C:9]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)=[N:10][C:11]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: c1ccc(N2CCN(c3nc(N4CCOCC4)cc(N4CCOCC4)n3)CC2)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Clc1c(N2CCOCC2)nc(N2CCN(c3ccccc3)CC2)nc1N1CCOCC1
Yield: 43.7 %

Procedure:
The synthesis method shall be explained concretely, and in order, below. 4,6-dimorpholino-2-(4-phenylpiperazin-1-yl)pyrimidine (300 mg, 0.73 mmol) was dissolved in chloroform solution (5 ml), benzoyl peroxide (0.3 mg, 0.0014 mmol) and N-chlorosuccinimide (117 mg, 0.87 mmol) was added, and refluxed under heating for 1 hour. Water was added, and extraction was done with dichloromethane. After washing the organic layer with saturated saline, drying was done with MgSO4, and the solvent was distilled away under reduced pressure. Purification was done by silica gel chromatography (hexane:ethyl acetate=4:1), and 142 mg of 5-chloro-4,6-dimorpholino-2-(4-phenylpiperazin-1-yl)pyrimidine was obtained (yield 46%). The melting point measurement result, the MS measurement result, and the NMR data for the obtained Compound 130 are shown below.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[C:11]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:12][C:13]([CH3:24])=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[C:11]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[CH:12][C:13]([CH3:24])=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(N2CCOCC2)c(C#Cc2cccc(N)c2)cc1NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N2CCOCC2)c(CCc2cccc(N)c2)cc1NC(=O)OC(C)(C)C
Yield: 102.1 %

Procedure:
tert-Butyl {5-[(3-aminophenyl)ethynyl]-2-methyl-4-morpholin-4-ylphenyl}carbamate (62 mg, 0.15 mmol) was stirred in methanol (2 mL) and 10% palladium on carbon (50 mg). The mixture was stirred under a balloon pressure of hydrogen gas for 3 hours. The mixture was filtered through celite and evaporated to give the desired compound (63 mg, 100%). LCMS for C24H34N3O3 (M+H)+: m/z=412.1.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)=O.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1
Reactant: O=C(O)[C@H]1CC[C@H](C(=O)c2ccccc2Cl)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CCC(Cc2ccccc2Cl)CC1
Yield: 42 %

Procedure:
Trans-4-(2-chlorobenzoyl)cyclohexane-1-carboxylic acid (300 mg; 1.12 mmol) and triethylsilane (654 mg; 5.62 mmol) was carried out using Method G in 4 mL of trifluoroacetic acid. Title compound was obtained as a white solid. (118 mg; 42% yield).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH2:11]1[O:13][CH:12]1[CH2:14][OH:15].C(N(CC)CC)C>O1CCCC1>[C:2](=[O:3])([O:15][CH2:14][CH:12]1[O:13][CH2:11]1)[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: OCC1CO1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCC1CO1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A three-necked round bottom flask, equipped with a reflux condenser, an addition funnel, and a nitrogen gas inlet is charged with 25.00 g (0.160 mole) of phenyl chloroformate and 70 g of THF. The reactor was placed in a 0° C. bath and purged with nitrogen. After 30 minutes, a solution of 13.00 g (0.175 mole) glycidol, 19.50 g (0.193 mole) triethylamine, and 75 g of anhydrous tetrahydrofuran (THF) was added drop wise over the course of one hour, after which the reaction was allowed to warm to room temperature and allowed to stir overnight under a nitrogen atmosphere. The contents of the reactor were discharged, filtered, and evaporated to dryness to afford 29.51 g of crude product, which was purified by flash chromatography using silica gel and eluted with a 1:1 solution of iso-propyl acetate and hexane. See FIG. 10.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[N:11]=[N:10]2)=[C:4]([F:19])[CH:3]=1.[H-].[Na+].F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[N:11]=[N:10]2)=[C:4]([F:19])[CH:3]=1
Reactant: O=c1n(CCCF)nnn1-c1cc(O)c(Cl)cc1F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1n(CCCF)nnn1-c1cc(Oc2ccc([N+](=O)[O-])cc2)c(Cl)cc1F
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
A solution of 9.3 g (0.032 mole) of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one in approximately 30 ml of N,N-dimethylformamide was added to a stirred mixture of 1.5 g (0.030 mole) of sodium hydride (50% suspension in oil) in 100 ml of N,N-dimethylformamide. The mixture was stirred for 15 minutes and 4.50 g (0.0304 mole) of 4-fluoronitrobenzene was added. This mixture was stirred at room temperature for approximately 18 hours then was heated at 80° C. for five hours. The mixture was cooled, poured into ice water and was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to leave a solid residue. This residue was purified by recrystallization from n-heptane to yield 8.1 g of 1-[4-chloro-2-fluoro-5-(4-nitrophenoxy)phenyl]-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one, m.p. 109°-110° C.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][C:25](O)=[O:26])=[C:17]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:16]=2)=[CH:11][N:10]=1)=O)(C)(C)C.[CH3:34][S:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])=[O:36]>>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][C:25]([N:41]3[CH2:42][CH2:43][N:38]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:39][CH2:40]3)=[O:26])=[C:17]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:16]=2)=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CC(=O)O)c3n2)cn1
Reactant: CS(=O)(=O)N1CCNCC1
Product: CS(=O)(=O)N1CCN(C(=O)Cn2cnc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc32)CC1

Procedure:
2-(2-(2-(tert-butoxycarbonylamino)pyrimidin-5-yl)-6-morpholino-9H-purin-9-yl)acetic acid (35 mg) was reacted with 1-(methylsulfonyl)piperazine via General Procedure E followed by Boc deprotection via General Procedure D and purified via reverse phase HPLC to give 9 mg 123 as a white solid. MS (Q1) 503.2 (M)+.
Reaction SMILES: [CH2:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][CH:6]([CH2:8][NH:9][CH:10]([CH3:12])[CH3:11])[O:5][C:4]1=[O:13])[CH3:2].[CH:20](O)=O.C=O>C(O)C.O>[CH2:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][CH:6]([CH2:8][N:9]([CH3:20])[CH:10]([CH3:12])[CH3:11])[O:5][C:4]1=[O:13])[CH3:2]
Reactant: CCC1(c2ccccc2)CC(CNC(C)C)OC1=O
Reactant: O=CO
Agent: C=O
Solvent: CCO
Solvent: O
Product: CCC1(c2ccccc2)CC(CN(C)C(C)C)OC1=O
Yield: 73 %

Procedure:
A solution containing 1.3 g of 3-ethyldihydro-5-[[(1-methylethyl)amino]methyl]-3-phenyl-2(3H)-furanone, 1.3 g of 90% formic acid, and 1.1 g of 37% formaldehyde in 15 ml of ethanol was refluxed 2.5 hrs. The solution was cooled and then diluted with water and washed with diethyl ether. The aqueous layer was made basic with dilute sodium hydroxide and extracted with diethyl ether. The ether extract was washed with saturated sodium chloride solution, dried over anhydrous potassium carbonate, and concentrated in vacuo to an oil. The oil was dried at 40°/1 mm to yield 1.0 g of the title compound, having the following elemental analysis:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]1[S:16][C:15]([C:17]([OH:19])=O)=[CH:14][CH:13]=1.C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[NH2:43]>O1CCCC1.O>[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[NH:43][C:17]([C:15]1[S:16][C:12]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[N:8]=[CH:7][N:6]=2)=[CH:13][CH:14]=1)=[O:19]
Reactant: O=C(O)c1ccc(-c2ncnc3ccc(Br)cc23)s1
Reactant: Nc1ccc(F)cc1F
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1F)c1ccc(-c2ncnc3ccc(Br)cc23)s1
Reaction time: 1 h
Yield: 42.8 %

Procedure:
300 mg of 5-(6-bromoquinazolin-4-yl)thiophen-2-carboxylic acid (compound in Production Example 382) was dissolved in 4 mL tetrahydrofuran, then 0.37 mL triethylamine and 0.14 mL isobutyl chlorocarbonate were added thereto under ice-cooling, and the mixture was stirred for 1 hour under nitrogen atmosphere. This mixture was added to a solution of 1.15 g 2,4-difluorophenylamine in 10 mL tetrahydrofuran and stirred at room temperature for 1 hour. Further, the reaction mixture was stirred at 70° C. for 3 hours, then water was added thereto, the reaction mixture was extracted with ethyl acetate, and the solvent was evaporated. The residue was washed with ether to give 171 mg of the title compound as pale yellow crystals.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:21]1([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[NH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].O1CCOCC1>[C:21]1([C:27](=[N:28][C:2]2[N:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(Br)cn2)CC1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(N=C(c3ccccc3)c3ccccc3)cn2)CC1
Temperature: 115 °C
Yield: 75.2 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 189b (3.3 g, 9.6 mmol), diphenylmethanimine (1.74 g, 9.6 mmol), palladium diacetate (440 mg, 0.48 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (598 mg, 0.96 mmol), Cs2CO3 (6.2 g, 19.2 mmol), and 1,4-dioxane (80 mL). After three cycles of vacuum/argon flush, the mixture was heated at 115° C. for 64 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 5:1 petroleum ether/ethyl acetate to afford 189c as a yellow solid (3.2 g, 75%). MS: [M+H]+ 444.2.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[CH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.C[O-].[Na+]>CO>[CH3:17][N:18]1[CH2:23][CH2:22][C:21]([C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[C:8]([S:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:9]=3)[NH:13][CH:12]=2)=[CH:20][CH2:19]1
Reactant: CN1CCC(=O)CC1
Reactant: c1ccc(Sc2ccc3[nH]ccc3c2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(Sc4ccccc4)cc23)CC1

Procedure:
5-Phenylthioindole (0.50 g, 2.22 mmol), 1-methylpiperid-4-one (0.292 g, 0.32 mL, 2.58 mmol) and sodium methoxide (0.139 g) were heated at reflux in MeOH (25 mL) for 20 hr. After cooling and work-up, 3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-phenylthioindole was obtained as a pale yellow solid, 0.399 g, (56%). This free base (0.20 g) was treated with fumaric acid (0.11 g, 0.94 mmol) in MeOH/Et2O to give: 3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-phenylthioindole fumarate, 0.124 g (46%), m.p. 225°-28° C.
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[Cl:9][C:10]1[C:11]([F:22])=[C:12]([CH:19]=[CH:20][CH:21]=1)[CH2:13][C:14]1[NH:18][CH:17]=[N:16][CH:15]=1.C([O-])(O)=O.[Na+].C1C=CC(OC(Cl)=[S:36])=CC=1>C1COCC1.O>[Cl:9][C:10]1[C:11]([F:22])=[C:12]([CH:19]=[CH:20][CH:21]=1)[CH2:13][C:14]1[NH:18][C:17](=[S:36])[NH:16][CH:15]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: Fc1c(Cl)cccc1Cc1cnc[nH]1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1c(Cl)cccc1Cc1c[nH]c(=S)[nH]1
Reaction time: 3 h

Procedure:
A solution of 5-(3-chloro-2-fluoro-benzyl)-1H-imidazole fumaric acid salt (Intermediate B3) (0.24 mmol) in THF (3 mL) and water (3 mL) was treated with NaHCO3 (0.12 g) at rt for 10 m. Phenyl chlorothionoformate (0.11 mL, 0.6 mmol) was added and stirring was continued for 3 h. The mixture was diluted with water (10 mL) and extracted with ether (3×15 mL). The organic portions were combined, dried over MgSO4, filtered and freed of solvent. The residue was dissolved in MeOH (5 mL) and treated with NEt3 (0.3 mL) for 16 h. The solvent was removed under vacuum and the product was washed on a glass frit with CH2Cl2 to give a white solid, 4-(3-chloro-2-fluoro-benzyl)-1,3-dihydro-imidazole-2-thione (Compound 2).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12](O)([CH3:14])[CH3:13].C1CCC(N=C=NC2CCCCC2)CC1.C(O)(=O)C>N1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)O
Reactant: O=C(O)CCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CC(C)OC(=O)CCc1ccccc1
Yield: 94 %

Procedure:
To a mixture of 3-phenylpropionic acid (15.0 g) and isopropanol (6.61 g) in pyridine (30 ml) perchloric acid (0.150 g) and DCC (24.8 g) are added. After stirring at room temperature for 24 h acetic acid (10 ml) is added, and the reaction mixture is worked-up as described in Example 1 to give a 94% yield of isopropyl 3-phenylpropionate (b. p., see Example 2).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)Cl>[Br:19][CH2:8][C:7]1[C:2]([F:1])=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc(F)c(CBr)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 14.9 %

Procedure:
2-Fluoro-3-methyl-5-nitro-pyridine (445 mg, 2.85 mmol) was dissolved in 20 mL DCM. NBS (1.01 g, 5.7 mmol, 2 eq.) was added. The reaction was stirred at room temperature for 2 days. HPLC showed 20% conversion. The reaction was concentrated down and purified (silica gel, 0-80% EtOAc/hexane) to give light yellow oil (100 mg, 15%). 1H NMR (300 MHz, CD3OD): δ 8.39 (m, 2H), 7.61 (m, 1H), 4.86 (s, 2H).