Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[CH3:33][N:34]([CH3:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([N:34]([CH3:44])[CH3:33])[CH:40]=2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(I)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CN(C)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2csc3c(-c4cccc(N(C)C)c4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 0.42 h
Yield: 20.3 %

Procedure:
A mixture of 1-Methyl-1H-indole-2-carboxylic acid [4-(4-amino-7-iodo-thieno[3,2-c]pyridin-3-yl)-2-methoxy-phenyl]-amide (0.100 g, 0.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was reacted with 3-(dimethylamino)phenylboronic acid (0.045 g, 0.27 mmol), sodium carbonate (0.06 g, 0.54 mmol) and tetrakis triphenylphosphine palladium (0) (0.017 g, 0.01 mmol) at reflux for two hours. The solvent was removed in vacuo and the residue was purified by preparative RP-HPLC (Hypersil-HS 100 A, C18, 8 μm, 100 Å, 25 cm; 5% acetonitrile—0.1M ammonium acetate 5–100% acetonitrile—0.1M ammonium acetate over 25 min, 21 ml/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyophilized to provide the title compound (20 mg) as an off-white powder. 1H NMR (DMSO-d6, 400 MHz) δ 9.52 (s, 1H), 8.01 (t, 1H), 7.94 (s, 1H), 7.72 (d, 1H), 7.58 (m, 2H), 7.34 (m, 3H), 7.23 (s, 1H), 7.16 (t, 1H), 7.10 (d, 1H), 6.97 (s, 1H), 6.95 (d, 1H), 6.79 (d, 1H), 5.56 (bs, 2H), 4.04 (s, 3H), 3.92 (s, 3H), 2.97 (s, 6H); LCMS (Conditions b), Rt=6.22 min, MS m/e: 548 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([OH:15])=[O:14])[CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N+]=[N-])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[CH:22]([O:14][C:13](=[O:15])[CH:9]([CH2:10][CH2:11][OH:12])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC(CCO)C(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CCO)C(=O)OC(c1ccccc1)c1ccccc1
Yield: 81.5 %

Procedure:
6 g of the obtained N-t-butoxycarbonyl DL-homoserine was dissolved in 100 ml of methylene chloride, and 50 ml of a methylene chloride solution containing 6 g of diphenyldiazomethane was added dropwise thereto over an hour. After completion of the reaction, the reaction mixture was concentrated to a small volume, and petroleum ether was added thereto. The formed crystals were filtered off to obtain 8.6 g of N-t-butoxycarbonyl DL-homoserine benzhydryl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH3:31][C:32]([CH3:36])=[CH:33][CH2:34]Br.O>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:34][CH:33]=[C:32]([CH3:36])[CH3:31])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CC(C)=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)=CCN(C(=O)OC(C)(C)C)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 21.9 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-4-(4-tert-butyloxycarbonylaminophenyloxy)piperidine (0.9 g) in acetone (20 ml) were added solid potassium hydroxide (0.13 g) and 3-methyl-2-butenyl bromide (0.34 g) and the mixture was heated under reflux overnight. Water was added to the reaction mixture and the mixture was extracted with methylene chloride (50 ml×3). The combined organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=4/1 (v/v)) to obtain 1-tert-butyloxycarbonyl-4-[4[N-tert-butyloxycarbonyl-N-(3-methyl-2-butenyl)amino]-phenyloxy]piperidine (0.23 g) as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11][S:12]2)=[CH:7][C:6]=1[O:23][CH3:24])=[O:4].C(=O)([O-])[O-].[K+].[K+]>>[C:19]([O:18][C:16]([NH:15][CH:9]1[C:8]2[C:13](=[CH:14][C:5]([C:3]([OH:4])=[O:2])=[C:6]([O:23][CH3:24])[CH:7]=2)[S:12][CH2:11][CH2:10]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1cc2c(cc1OC)C(NC(=O)OC(C)(C)C)CCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc2c(cc1C(=O)O)SCCC2NC(=O)OC(C)(C)C
Yield: 94 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 6 using 4-(tert-butoxycarbonylamino)-6-methoxythiochromane-7-carboxylic acid methyl ester (800 mg) and potassium carbonate (627 mg), the objective 4-(tert-butoxycarbonylamino)-6-methoxythiochromane-7-carboxylic acid (722 mg) was obtained as colorless crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[NH2:14])([CH3:3])[CH3:2].[C:15](Cl)(Cl)=[O:16]>>[N:14]([C:5]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([O:10][CH3:11])=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])=[C:15]=[O:16]
Reactant: COc1cc(N)c(C(C)C)cc1OC
Reactant: O=C(Cl)Cl
Product: COc1cc(N=C=O)c(C(C)C)cc1OC

Procedure:
1-Isocyanato-2-isopropyl-4,5-dimethoxy-benzene was prepared by reaction of 2-isopropyl-4,5-dimethoxy-phenylamine with phosgene following the procedure of step 2 of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N+](=[CH2:26])=[N-]>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]([CH3:21])([C:17]([F:18])([F:19])[F:20])[C:14]([O:16][CH3:26])=[O:15])=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: CC(Oc1ccc(-c2ccc(Cl)cc2)cc1)(C(=O)O)C(F)(F)F
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)C(C)(Oc1ccc(-c2ccc(Cl)cc2)cc1)C(F)(F)F

Procedure:
A solution of (±)-2-[4-(4-chlorophenyl)phenoxy]-3,3,3-trifluoro-2-methylpropionic acid (3.0 g.) in ether (100 ml.) is treated with an excess of ethereal diazomethane at 0° C. The solvent is evaporated and the residue recrystallised from methanol to give (±)-methyl 2-[4-(4-chlorophenyl)phenoxy]-3,3,3-trifluoro-2-methylpropionate, m.p. 87°-88° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:27])[CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([OH:26])[CH:19]=2)[O:16][CH:17]=1)[CH3:2].Cl[CH:29]([F:31])[F:30]>>[F:30][CH:29]([F:31])[O:26][C:20]1[CH:19]=[C:18]([C:15]2[O:16][CH:17]=[C:13]([CH2:12][CH2:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH2:1][CH3:2])=[O:27])[N:14]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(O)c2)n1
Reactant: FC(F)Cl
Product: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(OC(F)F)c2)n1

Procedure:
Using the compound obtained in Example 101 and chlorodifluoromethane, white powdery 3-[2-(3-difluoromethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one was obtained following the procedure of Example 4.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(#N)C>[CH2:18]([O:11][C:5]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Yield: 103.2 %

Procedure:
To 2-nitro-5-fluorophenol (6.28 g) in acetonitrile (50 ml) was added potassium carbonate (5.6 g) and benzyl bromide (7.2 g). The mixture was stirred at reflux for 2 hrs, added to water and extracted with diethyl ether. The organic layer was washed with brine, dried and evaporated to dryness to give 2-(benzyloxy)-4-fluoro-nitrobenzene (10.2 g) as a solid. nmr (deuterochloroform): 5.2d (s), 2H; 6.7d, (m), 1H; 6.8d (q), 1H; 7.4d (m), 5H; 8.0d, (q), 1H;
Reaction SMILES: N1C=CN=C1.C(N(CC)CC)C.[CH:13]([OH:15])=O.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:34]=[C:33]([NH:35][C:36]3[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([O:46][CH3:47])[CH:37]=3)[C:32]3=[C:48]([CH3:52])[N:49]=[C:50]([CH3:51])[N:31]3[N:30]=2)=[CH:25][CH:24]=1>ClCCl>[CH3:52][C:48]1[N:49]=[C:50]([CH3:51])[N:31]2[C:32]=1[C:33]([NH:35][C:36]1[CH:37]=[C:38]([O:46][CH3:47])[C:39]([O:44][CH3:45])=[C:40]([O:42][CH3:43])[CH:41]=1)=[N:34][C:29]([C:26]1[CH:25]=[CH:24][C:23]([NH:22][CH:13]=[O:15])=[CH:28][CH:27]=1)=[N:30]2
Reactant: O=CO
Reactant: COc1cc(Nc2nc(-c3ccc(N)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Agent: O=C(Cl)C(=O)Cl
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Nc2nc(-c3ccc(NC=O)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
16 mg (0.24 mmol) of imidazole, 48 mg (0.48 mmol) of triethylamine and 11 mg (0.24 mmol) of formic acid are introduced into 4 ml dichloromethane under argon, cooled to 0° C. and treated dropwise with a solution of 30 mg (0.24 mmol) of oxalyl dichloride in dichloromethane. The mixture is allowed to warm to 20° C. and subsequently 100 mg (0.24 mmol) of N-[2-(4-aminophenyl)-5,7-dimethyl-imidazo[5,1-f][1,2,4]triazin-4-yl]-N-(3,4,5-trimethoxyphenyl)amine from example 3 are added thereto. It is stirred overnight and then washed with aqueous sodium hydrogencarbonate solution. The organic phase is dried and purified by flash chromatography (dichloromethane/methanol 100:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH3:17][S:18]([CH2:21][C:22](=O)[CH3:23])(=[O:20])=[O:19].[Na]>CC(O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:22]([CH3:23])[C:21]([S:18]([CH3:17])(=[O:20])=[O:19])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)CS(C)(=O)=O
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Agent: [Na]
Solvent: CC(C)O
Product: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1S(C)(=O)=O
Yield: 34 %

Procedure:
(2-Amino-5-bromo-phenyl)-phenyl-methanone (10 g, 36 mmol), methanesulfonylacetone (7.4 g, 54 mmol) and sodium tetrachloroaureate(III) dihydrate (720 mg, 1.8 mmol) were heated at reflux in 2-propanol (100 mL) for 4.5 days. The resulting suspension was evaporated to dryness and the residue extracted with dichloromethane (2×), 1 N NaOH (2×), which removes excess of methanesulfonylacetone, and sat. NaCl (1×). The crude product was purified twice by chromatography in dichloromethane and then crystallized from dichloromethane/heptane by evaporation of dichloromethane. One obtained 4.6 g (33%) of beige crystals. MS: m/z=375/377 (M).
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=2)[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:5][C:4]=1[S:24][CH3:25])#[N:2].[Cl:26][S:27](O)(=[O:29])=[O:28]>CO>[C:1]([C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=2)[C:6]([C:18]2[CH:19]=[CH:20][C:21]([S:27]([Cl:26])(=[O:29])=[O:28])=[CH:22][CH:23]=2)=[N:5][C:4]=1[S:24][CH3:25])#[N:2]
Reactant: O=S(=O)(O)Cl
Reactant: CSc1nc(-c2ccccc2)n(-c2ccc(C)c(C)c2)c(=O)c1C#N
Solvent: CO
Product: CSc1nc(-c2ccc(S(=O)(=O)Cl)cc2)n(-c2ccc(C)c(C)c2)c(=O)c1C#N
Yield: 13 %

Procedure:
A solution of 5-cyano-1-(3,4-dimethylphenyl)-4-(methylthio)-2-phenyl-6-oxo-1,6-dihydropyrimidine (3 g, 8.6 mmol) (obtained according to example 57) in chlorosulfonic acid (50.37 g, 432 mmol) was stirred at 0° C. for 2 hr and at ambient temperature for 24 hr and then poured onto ice and extracted with chloroform. The collected chloroform layer was dried over anhydrous Na2SO4 and concentrated in vacuo to yield crude compound, which was further purified by column chromatography using chloroform:methanol mixture as eluent to yield title compound (0.5 g, yield 13%). 1H-NMR (CDCl3):δ 2.37 (s, 3H), 2.65 (s, 3H), 2.68 (s, 3H), 7.26-7.55 (m, 7H). MS m/z:446.1 (M+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH2:14][S:13][CH:12]3[N:9]([C:10](=[O:23])[CH:11]3[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]=2[C:24]([O:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:5][N:6]=1.Cl[C:41]([C:43]1[S:44][CH:45]=[CH:46][CH:47]=1)=[O:42]>C(N(CC)CC)C>[CH:27]([O:26][C:24]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[C:4]1[S:3][C:2]([NH:1][C:41]([C:43]3[S:44][CH:45]=[CH:46][CH:47]=3)=[O:42])=[N:6][CH:5]=1)[CH:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]2=[O:23])=[O:25])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(N)s3)CSC12
Reactant: O=C(Cl)c1cccs1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(NC(=O)c4cccs4)s3)CSC12
Yield: 85.9 %

Procedure:
Following the procedure of Example 2, starting from 3-(2-amino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (4.5 g), triethylamine (1.23 cc) and 2-chlorocarbonyl-thiophene (1.4 g), 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-[2-(thien-2-yl-carbonylamino)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (4.62 g) is obtained, in the form of a cream-coloured powder, after purification over Merck silica gel (0.06-0.2 mm).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)[CH:5]=[CH:6][N:7]=1.Cl.[C:24](=N)(OCC)[CH3:25]>CO>[CH3:24][C:25]1[NH:15][C:12]2[CH:13]=[CH:14][C:9]([CH:8]([N:4]3[CH:5]=[CH:6][N:7]=[C:3]3[S:2][CH3:1])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][C:11]=2[N:16]=1
Reactant: CSc1nccn1C(c1ccccc1)c1ccc(N)c(N)c1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CO
Product: CSc1nccn1C(c1ccccc1)c1ccc2[nH]c(C)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
(a-6) A mixture of 5.6 parts of (+)-4-[[2-(methylthio)-1H-imidazol-1-yl]-phenylmethyl]-1,2-benzendiamine, 2.8 parts of ethyl ethanimidate hydrochloride and 60 parts of methanol was stirred first overnight at room temperature and then for 2 hours at reflux temperature. After cooling, the reaction mixture was evaporated. The residue was treated with alkaline water and the product was extracted three times with dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 3.2 parts (79.3%) of (+)-2-methyl-5-[[2-(methylthio)-1H-imidazol-1-yl]phenylmethyl]-1H-benzimidazole as a residue (int. 144).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[F:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26](O)=[O:27])[CH:22]=[CH:23][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:26](=[O:27])[CH2:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([F:18])[CH:20]=2)[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(O)Cc1cccc(F)c1
Product: O=C(Cc1cccc(F)c1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 49.9 %

Procedure:
Example 3 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and (3-fluorophenyl)acetic acid (0.031 g) to give the title compound (0.041 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([C:48]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:49])=[CH:44][C:43]=1[CH3:56]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][C:45]([C:48]([N:50]6[CH2:55][CH2:54][O:53][CH2:52][CH2:51]6)=[O:49])=[CH:44][C:43]=5[CH3:56])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: Cc1cc(C(=O)N2CCOCC2)ccc1Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCOCC4)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (4-bromo-3-methyl-phenyl)-morpholin-4-yl-methanone (159 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-phenyl]-morpholin-4-yl-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-137) as a brown powder (58 mg, 62%).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([C:17](Cl)=[O:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[NH2:26][C:27]1[O:28][C:29]([C:32]2[O:33][CH:34]=[CH:35][CH:36]=2)=[N:30][N:31]=1>CO>[O:33]1[CH:34]=[CH:35][CH:36]=[C:32]1[C:29]1[O:28][C:27]([NH:26][C:17]([C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:16]=2)=[O:18])=[N:31][N:30]=1
Reactant: Nc1nnc(-c2ccco2)o1
Reactant: O=C(Cl)c1cc(-c2ccccc2)nc2ccccc12
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1nnc(-c2ccco2)o1)c1cc(-c2ccccc2)nc2ccccc12
Temperature: 60 °C
Reaction time: 6 h
Yield: 43.1 %

Procedure:
2-phenyl-4-quinolinecarbonyl chloride (2.00 g, 7.47 mmol) was added in small portions to a pyridine (40 mL) solution of commercially available 2-amino-5-(2-furyl)-1,3,4-oxadiazole (1.69 g, 11.2 mmol), and the mixture was heated with stirring at 60° C. for 6 hours. To the reaction solution, methanol was added, and the solvent was distilled off. The obtained residue was triturated by the addition of water. The deposited crystal was collected by filtration, washed with methanol and then with ethyl acetate, and then recrystallized from DMF-methanol to obtain the title compound (1.23 g, 3.22 mmol) as a light brown powder (yield: 43%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2].[H-].[Na+].[CH3:17][O:18][CH2:19]Cl>CN(C=O)C>[CH3:17][O:18][CH2:19][O:14][C:5]1[CH:6]=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COCCl
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(C(F)(F)F)ccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of 2-nitro-5-trifluoromethylphenol (400 mg) in DMF (4.0 ml), sodium hydride (77 mg) was added at 0° C. in a stream of argon. The mixture was stirred for 30 minutes. After stirring, methoxymethyl chloride (147 μl) was added dropwise thereto. The mixture was stirred for 20 minutes. The reaction mixture was quenched by iced water and extracted with ethyl acetate. The layer containing ethyl acetate was washed, dried over and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt=20:1) to give the title compound (353 mg) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=[O:27]>>[NH2:1][C:2]1[C:11]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([O:22][CH3:21])[CH:24]=3)[CH:15]=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Reactant: COc1cccc(C(=O)O)c1
Product: COC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3cccc(OC)c3)c2)c1

Procedure:
In a manner similar to that described in Example 1, methyl 6-amino-5-((3-aminophenyl)ethynyl)nicotinate and 3-methoxybenzoic acid are converted to the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([N:12]=[C:13]=[S:14])[CH2:4][CH2:3]1.C(O)C.[CH2:18]([NH2:20])[CH3:19]>C(Cl)Cl>[CH2:18]([NH:20][C:13]([NH:12][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[CH2:3][CH2:4]1)=[S:14])[CH3:19]
Reactant: O=C1CCC(N=C=S)c2ccccc21
Reactant: CCN
Solvent: CCO
Solvent: ClCCl
Product: CCNC(=S)NC1CCC(=O)c2ccccc21
Reaction time: 18 h

Procedure:
To a solution of 1,2,3,4-tetrahydro-4-oxo-1-naphthyl isothiocyanate (5.0 g.) in methylene chloride (100 ml.), ethylamine is added via ethanol )15 ml.) saturated with ethylamine. After stirring for 18 hours, the mixture is heated at reflux for 2 hours, cooled and evaporated to dryness in vacuo. The residue is triturated with water and the title compound collected and dried; m.p. 134° C. to 138° C.
Reaction SMILES: [F:1][C:2]([F:17])([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)[C:3](OCC)=[O:4].[NH3:18]>>[F:1][C:2]([F:17])([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)[C:3]([NH2:18])=[O:4]
Reactant: CCOC(=O)C(F)(F)c1cccc([N+](=O)[O-])c1
Reactant: N
Product: NC(=O)C(F)(F)c1cccc([N+](=O)[O-])c1
Temperature: 75 °C

Procedure:
A solution of ethyl 2,2-difluoro-2-(3-nitrophenyl)acetate (0.701 g, 2.86 mmol) in Methanolic ammonia (7M, 20.0 ml) was taken in sealed tube. Resulting mixture was heated at 75° C. for 3 hrs. The reaction mixture was concentrated under vacuum and cold water was added to obtain the precipitate. Solid was filtered to obtain 2,2-difluoro-2-(3-nitrophenyl)acetamide (0.515 g).
Reaction SMILES: [NH2:1][N:2]1[C:6]([S:7][CH3:8])=[N:5][NH:4][C:3]1=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20](S(C)(=O)=O)[N:19]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>[NH2:1][N:2]1[C:6]([S:7][CH3:8])=[N:5][N:4]([C:20]2[N:21]=[C:22]([O:24][CH3:25])[CH:23]=[C:18]([O:17][CH3:16])[N:19]=2)[C:3]1=[O:9]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CSc1n[nH]c(=O)n1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OC)nc(-n2nc(SC)n(N)c2=O)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
A mixture of 3.0 g (0.02 mol) of 4-amino-5-methylthio-2,4-dihydro-3H-1,2,4-triazol-3-one and 200 ml of acetone is refluxed for 4 hours after 0.1 g of p-toluenesulphonic acid has been added. The mixture is concentrated, the residue is taken up in 100 ml of acetonitrile, and the reaction mixture is refluxed for 12 hours after 8.3 g (0.06 mol) of potassium carbonate and 4.4 g (0.02 mol) of 4,6-dimethoxy-2-methylsulphonyl-pyrimidine have been added. The cooled mixture is filtered, the filtrate is concentrated, the residue is taken up in 100 ml of ethanol/water (vol. 1:1) and stirred for 3 hours at 60° C. after 2 ml of concentrated hydrochloric acid have been added. The mixture is concentrated, the residue is stirred with saturated sodium hydrogen carbonate solution, and the crystalline product is isolated by filtering off with suction. 4.9 g (86% of theory) of 4-amino-5-methylthio-2 -(4,6-dimethoxy-pyrimidin-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one of melting point 198° C. are obtained.