Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]=[C:9]([C:14]([CH3:16])=[O:15])[C:10]([O:12][CH3:13])=[O:11].[F:17][CH2:18]Br>CS(C)=O.CN(C)C=O>[F:17][CH2:18][O:7][N:8]=[C:9]([C:14]([CH3:16])=[O:15])[C:10]([O:12][CH3:13])=[O:11]
Reactant: FCBr
Reactant: COC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COC(=O)C(=NOCF)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.6 %

Procedure:
14.2 g of potassium carbonate was added to a solution of 14.5 g of methyl 2-hydroxyimino-acetoacetate in 50 ml of dimethylsulfoxide, and then 11.6 g of fluoro-bromomethane in 9 ml of N,N-dimethylformamide was added dropwise thereto. The mixture was stirred for 1 hour 30 minutes at room temperature, then poured into ice-water, and the resultant mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline, dried over Na2SO4 and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (120 g) with a mixture solvent of ethyl acetate and toluene (1/4 volume) as a eluent to give 4.7 g (27% yield) of methyl 2-fluoromethoxyiminoaceto-acetate (syn isomer).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[C:16](=[O:17])[C@H:15]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[NH:14][C:13]2=[O:25])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][C:60]1[S:61][CH:62]=[CH:63][N:64]=1>CN1CCCC1=O.O>[CH:1]1([CH2:7][C@H:8]([N:12]2[C:16](=[O:17])[C@H:15]([CH2:18][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[NH:14][C:13]2=[O:25])[C:9]([NH:59][C:60]2[S:61][CH:62]=[CH:63][N:64]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1C(=O)N[C@@H](CC2CCCCC2)C1=O
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1C(=O)N[C@@H](CC2CCCCC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A solution of (S,S)-3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidin-1-yl]propanoic acid [Step (iii); 25 mg, 0.071 mmol] in N-methylpyrrolidinone (1 mL) was treated with diisopropylethylamine (19 μL, 1.065 mmol) and HBTU (29.3 mg, 0.078 mmol). The reaction mixture was then treated with 2-aminothiazole (7.2 mg, 0.071 mmol) and stirred at ambient temperature overnight. The reaction mixture was then diluted with water (2 mL) and extracted with ethyl acetate (2×3 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The product was purified by using flash chromatography (Merck Silica gel 60, 230-400 mesh, 99/1 dichloromethane/methanol) to furnish (S,S)-3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidin-1-yl]-N-(thiazol-2-yl)propanamide (27 mg, 88%) as a white foam: EI-HRMS m/e calcd. for C22H32N4O3S (M+) 433.2273, found 433.2270.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].[CH3:11][C:12]1([CH3:20])[O:19][C:17](=[O:18])[CH2:16][C:14](=[O:15])[O:13]1.N1CCCC1C(O)=O.[CH3:29][S:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:40]=1[NH:39][CH:38]=[CH:37]2>C(#N)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([C:37]2[C:36]3[C:40](=[C:32]([CH2:31][S:30][CH3:29])[CH:33]=[CH:34][CH:35]=3)[NH:39][CH:38]=2)[CH:16]2[C:17](=[O:18])[O:19][C:12]([CH3:20])([CH3:11])[O:13][C:14]2=[O:15])=[CH:4][C:3]=1[F:10]
Reactant: CSCc1cccc2cc[nH]c12
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: O=C(O)C1CCCN1
Solvent: CC#N
Product: CSCc1cccc2c(C(c3ccc(Cl)c(F)c3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.34 g (8.46 mmol) of 4-chloro-3-fluorobenzaldehyde, 1.22 g (8.46 mmol) of Meldrum's acid and 0.05 g (0.42 mmol) of D,L-proline were added to a solution of 1.50 g (8.46 mmol) of the compound from Example 8A in 12 ml of acetonitrile. The reaction mixture was stirred at RT overnight. The precipitated solid was filtered off with suction, washed with acetonitrile and dried under high vacuum. 2.42 g (98% of theory) of the title compound were obtained.
Reaction SMILES: Br[CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH2:3]1.[CH3:15][C:16]([CH3:20])([CH3:19])[CH:17]=[O:18].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN1CCCC1=O>[CH3:15][C:16]([CH3:20])([C:17]([N:7]1[CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1)=[O:18])[CH2:19][N:25]1[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]1
Reactant: Clc1ccc(N2CCNC(Br)C2)cc1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)C=O
Solvent: CN1CCCC1=O
Product: CN1CCN(CC(C)(C)C(=O)N2CCN(c3ccc(Cl)cc3)CC2)CC1
Temperature: 200 °C
Reaction time: 0.33 h
Yield: 36.4 %

Procedure:
3-Bromo-1-(4-chlorophenyl)piperazine-2,2-dimethylpropan-1-one (0.87 g, 2.43 mmol) was dissolved in N-methylpyrrolidinone (3 mL). N-Methylpiperazine (0.54 mL, 4.85 mmol) was added and the reaction mixture was heated at 200° C. for 15 minutes in a Biotage Initiator microwave at normal absorption. The reaction mixture was purified by reverse phase column chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (100 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated ill vacuo, to give a pale brown oil which was recrystallised from heptane to give 1-{2,2-dimethyl-3-[4-(4-chlorophenyl)piperazin-1-yl]-3-oxopropyl}-4-methylpiperazine (335 mg, 36.4%) as a white solid.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:14]([N:21]1[CH2:11][C:5]2[C:4](=[C:9]([I:10])[CH:8]=[CH:7][CH:6]=2)[C:3]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(I)cccc1CBr
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2c(I)cccc2CN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (1.07 g, 3.0 mmol), benzylamine (0.34 mL, 3.1 mmol), and K2CO3 (0.83 g, 6 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-benzyl-7-iodo-2,3-dihydro-isoindol-1-one 0.586 g, 56%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.16 (s, 2H), 4.82 (s, 2H) 7.18-7.40 (m, 7H), 7.90 (d, 1H). GC-MS: m/z 349 (M)+.
Reaction SMILES: [H-].[Li+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[C:11]2=[O:19])=[CH:6][CH:5]=1.IC.[CH3:22]COC(C)=O>CN(C=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][C:12]([CH3:22])([C:15]([O:17][CH3:18])=[O:16])[C:11]2=[O:19])=[CH:8][CH:9]=1
Reactant: COC(=O)C1CCN(c2ccc(F)cc2)C1=O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1(C)CCN(c2ccc(F)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
LiH (13.8 mg, 1.737 mmol) was added to the solution of methyl 1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylate (0.206 g, 0.868 mmol) in DMF (5 mL) at 0° C. After 30 minutes stirring, iodomethane (0.16 mL, 2.61 mmol) was added to the reaction mixture at 0° C., and then the reaction was warmed to room temperature. The reaction mixture was stirred for 17 hours and heated at 40° C. for 3 hours. After cooling to room temperature, the mixture was treated with EtOAc, quenched with ice water, extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated to give the crude material that was purified by silica gel flash column chromatography (19:1=CH2Cl2:EtOAc) to afford 0.149 g (68%) of the desired product. LRMS (ESI pos) m/e 252.1 (M+1). 1H-NMR (400 MHz, CDCl3) δ 7.61 (m, 2H), 7.07 (m, 2H), 3.94 (m, 1H), 3.78 (m, 1H), 3.75 (s, 3H), 2.68 (m, 1H), 2.06 (m, 1H), 1.55 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −117.6.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=3[CH3:34])=[CH:25][C:20]=2[N:19]=[CH:18]1>C(O)(C)C.ClCCCl>[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=5)[N:5]=[CH:4][N:3]=4)=[CH:29][C:28]=3[CH3:34])=[CH:25][C:20]=2[N:19]=[CH:18]1
Reactant: COCCOc1ccc2ncnc(Cl)c2c1
Reactant: Cc1cc(N)ccc1Oc1ccc2ocnc2c1
Solvent: ClCCCl
Solvent: CC(C)O
Product: COCCOc1ccc2ncnc(Nc3ccc(Oc4ccc5ocnc5c4)c(C)c3)c2c1
Temperature: 80 °C
Yield: 27.2 %

Procedure:
To a solution of 4-chloro-6-(2-methoxyethoxy)quinazoline (0.199 g, 0.83 mmol) and 4-(benzo[d]oxazol-5-yloxy)-3-methylbenzenamine (0.200 g, 0.83 mmol) in isopropanol (2 mL) and DCE (2 mL). After heating to 80° C. for 12 hours, the mixture was concentrated under reduced pressure. The residue was partitioned between saturated NaHCO3 and EtOAc. The aqueous phase was extracted 2× with EtOAc, the combined organic phase was washed with brine, dried (Na2SO4), filtered and condensed. The residue was chromatographed to provide the product (0.100 g, 27%) as off-white solids. MS APCI (+) m/z 443 (M+1) detected; 1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.76 (s, 1H), 8.50 (s, 1H), 7.96 (s, 1H), 7.75 (m, 4H), 7.52 (dd, 1H), 7.26 (m, 1H), 7.10 (m, 1H), 6.97 (d, 1H), 4.30 (m, 2H), 3.76 (m, 2H), 3.36 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[C:8]([CH3:22])[CH:7]=1)=[O:5].[CH2:24]([Mg]Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:22][C:8]1[CH:7]=[C:6]([C:4](=[O:5])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:11]=[CH:10][C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=1
Reactant: CON(C)C(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(C)c1
Reactant: CCCCCC[Mg]Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(C)c1
Yield: 82.6 %

Procedure:
Dissolve 2-methyl-4′-trifluoromethyl-biphenyl-4-carboxylic acid methoxy-methyl-amide (0.58 g, 1.8 mmol) in tetrahydro-furan (10 mL). Add hexyl magnesium bromide (2.0M ethyl ether, 2.69 mL, 5.39 mmol) at 0° C. under inert atmosphere and stir 1.5 hours. Quench reaction with saturated solution of ammonium chloride, dilute with ethyl acetate. Wash organic phase with water then saturated sodium chloride solution. Dry organic fraction with Na2SO4, filter and concentrate under reduced pressure. Purify on silica gel chromatography (0-30% Ethyl acetate/hexanes gradient) to provide 0.518 g of title compound (83%).
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9]([CH3:11])=[CH:8][C:6]=2[N:7]=1.[CH:13]1[C:18]2[CH2:19][NH:20][CH2:21][CH2:22][S:23](=[O:24])[C:17]=2[CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:24]=[S:23]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:18]=2[CH2:19][N:20]([C:2]2[NH:3][C:4](=[O:12])[C:5]3[S:10][C:9]([CH3:11])=[CH:8][C:6]=3[N:7]=2)[CH2:21][CH2:22]1
Reactant: O=S1CCNCc2ccccc21
Reactant: Cc1cc2nc(Cl)[nH]c(=O)c2s1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)[nH]c(=O)c2s1
Yield: 81.1 %

Procedure:
2-Chloro-6-methylthieno[3,2-d]pyrimidin-4(3H)-one (3.01 g, 15 mmol) was dissolved in toluene (50 mL), followed by addition of 6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene-5-oxide (3.39 g, 18.7 mmol), triethylamine (6 mL, 43 mmol). Then the solution was heated to reflux overnight. The suspension was filtrated and the solid was washed by methanol to afford 4.2 g of 2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylthieno[3,2-d]pyrimidin-4(3H)-one (yield was 81.1%) as a slight brown solid. MS obsd. (ESI+) [(M+H)+] 346.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]2[N:16]([CH:17]=1)[C:15]([CH2:18]O)=[CH:14][S:13]2)([O-:3])=[O:2].[CH2:20]([N:22](CC)[CH2:23][CH3:24])[CH3:21].CS(Cl)(=O)=O.N1CCCC1>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]2[N:16]([CH:17]=1)[C:15]([CH2:18][N:22]1[CH2:23][CH2:24][CH2:21][CH2:20]1)=[CH:14][S:13]2)([O-:3])=[O:2]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccccc1-c1cn2c(CO)csc2n1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: O=[N+]([O-])c1ccccc1-c1cn2c(CN3CCCC3)csc2n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
[6-(2-Nitro-phenyl)-imidazo[2,1-b]thiazol-3-yl]-methanol (110 mg, 0.4 mmol) in CH2Cl2 (5 ml) with triethylamine (56 ul, 1 eq) was cooled to 0° C. Methylsulfonyl chloride (31 ul, 1 eq) was added dropwise, stirred at 0° C. for 10 min, warmed to room temperature, and stirred for 15 min. The reaction was quenched by the addition of brine, and the mesylate was extracted with CH2Cl2, dried over Na2SO4 and concentrated. The residue was dissolved in acetonitrile (3 ml), and added triethylamine (31 ul, 1 eq), followed by pyrrolidine (66 ul, 2 eq). The reaction mixture was stirred for 2 hours, concentrated and chased with pentane. Column chromatography in CH2Cl2 (0 to 4% MeOH gradient) gave 6-(2-Nitro-phenyl)-3-pyrrolidin-1-ylmethyl-imidazo[2,1-b]thiazole. This material was dissolved in methanol (16 ml) and a solution of sodium hydrogen sulfide (112 mg, 5 eq) in water (4 ml) was added. The reaction mixture was refluxed for 2 days with additional charges of NaHS (2×112 mg). The reaction was concentrated to remove the methanol, and the aqueous solution was extracted with CH2Cl2 (3×40 ml). The organic layer was dried over Na2SO4, and concentrated to obtain the product as a yellow film, 109 mg. (MS, M++H=299.1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[F:33][C:34]([F:41])([F:40])[C:35]1[CH:39]=[CH:38][NH:37][N:36]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:37]2[CH:38]=[CH:39][C:35]([C:34]([F:41])([F:40])[F:33])=[N:36]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Reactant: FC(F)(F)c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(c1ccc(-n2ccc(C(F)(F)F)n2)cc1Cl)N1Cc2cccn2Cc2ccccc21

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.8 g), 60% sodium hydride in oil (0.25 g, degreased with hexane), 3-trifluoromethylpyrazole (0.61 g) and dimethylformamide (25 ml), the title compound was obtained as an amorphous solid, MS, m/z: 457.2 (M+H)+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.C1(C)C=CC=CC=1.[CH3:13][O:14][C:15]1[C:35]([O:36][CH3:37])=[C:34]([O:38][CH3:39])[CH:33]=[C:32]([CH3:40])[C:16]=1[C:17]([C:19]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][N+:22]([O-])=[CH:21][C:20]=1[O:30][CH3:31])=[O:18]>CN(C)C=O>[CH3:13][O:14][C:15]1[C:35]([O:36][CH3:37])=[C:34]([O:38][CH3:39])[CH:33]=[C:32]([CH3:40])[C:16]=1[C:17]([C:19]1[C:20]([O:30][CH3:31])=[CH:21][N:22]=[C:23]([Cl:3])[C:24]=1[C:25]([F:28])([F:27])[F:26])=[O:18]
Reactant: COc1cc(C)c(C(=O)c2c(OC)c[n+]([O-])cc2C(F)(F)F)c(OC)c1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(OC)cnc(Cl)c2C(F)(F)F)c(OC)c1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
1.8 ml (19 mmol) of phosphorus oxychloride was added at 0° C. to 4 ml of toluene and 8 ml of dimethylformamide, followed by stirring for 10 minutes, and then 4.0 g (10 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-methoxy-5-trifluoromethylpyridine-N-oxide was added, followed by stirring for 20 minutes. After stirring at room temperature for 2 hours, the reaction solution was charged into ice water to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and then the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 3.57 g (yield: 85%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-2-chloro-3-trifluoromethyl-5-methoxypyridine (melting point 117 to 119° C.).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[Br:13])[CH:2]=[CH2:3].[CH2:15]([CH2:19][C:20](=O)[CH3:21])[C:16]([CH3:18])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(OCC)(=O)C>[CH2:1]([NH:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:20]([CH3:21])=[CH:19][CH:15]=[C:16]2[CH3:18])=[CH:8][C:7]=1[Br:13])[CH:2]=[CH2:3]
Reactant: C=CCNC(=O)c1ccc(N)cc1Br
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCNC(=O)c1ccc(-n2c(C)ccc2C)cc1Br

Procedure:
11 g of 4-amino-2-bromobenzoic acid-allylamide, 5.2 ml of acetonylacetone and 200 mg of 4-toluenesulfonic acid are refluxed for 1.5 hours with a water separator. Then, the solution is diluted with ethyl acetate, washed with 1N hydrochloric acid and then with potassium carbonate solution, dried (Na2SO4) and concentrated by evaporation. The residue is crystallized with hexane. 13.4 g of N-allyl-2-bromo-4-(2,5-dimethylpyrrol-1-yl)-benzamide, melting point 136-138° C., is obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[CH2:8]([N:10](CC)CC)C.C([N:17]([CH2:27][CH:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]([F:39])[F:38])=[C:32]([O:40][CH:41]2[CH2:45][CH2:44][O:43][CH2:42]2)[CH:31]=1)[CH3:29])[C:18](=[NH:26])OC1C=CC=CC=1)#N>CN(C)C1C=CN=CC=1.O1CCOCC1>[C:8]([N:26]=[C:18]([NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])[NH:17][CH2:27][CH:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]([F:38])[F:39])=[C:32]([O:40][CH:41]2[CH2:45][CH2:44][O:43][CH2:42]2)[CH:31]=1)[CH3:29])#[N:10]
Reactant: COC(CN)OC
Reactant: CCN(CC)CC
Reactant: CC(CN(C#N)C(=N)Oc1ccccc1)c1ccc(OC(F)F)c(OC2CCOC2)c1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Product: COC(CNC(=NC#N)NCC(C)c1ccc(OC(F)F)c(OC2CCOC2)c1)OC
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of 2,2-dimethoxyethanamine (0.0129 mol), N,N-diethylethanamine (0.023 mol) and N,N-dimethyl-4-pyridinamine (0.0059 mol) in 1,4-dioxane (30 ml) was added to a solution of intermediate 11 (0.0117 mol) in 1,4-dioxane (10 ml), stirred at RT. The reaction mixture was stirred and refluxed overnight. The solvent was evaporated and the residue was washed with water and 1 N NaOH, then extracted with CH2Cl2. The separated organic layer was dried, filtered, and the solvent was evaporated. The residue was purified by open column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 96/4). The pure fractions were collected and the solvent was evaporated, yielding 4.97 g (95%) of (±)-N"-cyano-N-[2-[4-(difluoromethoxy)-3-[(tetrahydro-3-furanyl)oxy]phenyl]propyl]-N'-(2,2-dimethoxyethyl)guanidine (intermediate 12).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C1N2CCN(CC2)C1.[O:25]1[CH2:30][CH2:29][N:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1>CN(C)P(=O)(N(C)C)N(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:15]=[N:14][C:13]([O:16][C:31]([N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[O:32])=[CH:12][CH:11]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Reactant: O=C(Cl)N1CCOCC1
Agent: C1CN2CCN1CC2
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1c(Cl)cc(-c2ccc(OC(=O)N3CCOCC3)nn2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
1.27 g of 6-(3,5-dichloro-4-methylphenyl)-3-pyridazone and 1.12 g of triethylenediamine were dissolved in 25 ml of hexamethylphosphoric triamide, and then 1.5 g of morpholinocarbonyl chloride were added dropwise thereto. When the addition was complete, the mixture was stirred at room temperature for 1 hour and then poured into about 200 g of ice-water. The precipitate thus produced was collected by filtration, washed with water and dried, giving 1.75 g (94%) of the desired Compound No. 10. The melting point and spectroscopic data of this product agreed completely with those of the product obtained in Example 2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH3:17][N:18]1[CH2:23][CH2:22][C:21]2=[C:24]([CH:27]=O)[NH:25][CH:26]=[C:20]2[C:19]1=[O:29]>N1CCCCC1.C(O)C>[CH3:17][N:18]1[CH2:23][CH2:22][C:21]2=[C:24]([CH:27]=[C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[CH:15][C:7]=4[CH:4]4[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]4)[NH:11][C:10]3=[O:16])[NH:25][CH:26]=[C:20]2[C:19]1=[O:29]
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: CN1CCc2c(c[nH]c2C=O)C1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CN1CCc2c(c[nH]c2C=C2C(=O)Nc3cccc(C4CCNCC4)c32)C1=O
Temperature: 25 °C
Reaction time: 168 h
Yield: 57.1 %

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one (58.4 mg, 0.27 mmol), 5-methyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (48 mg, 0.27 mmol) and piperidine (1 drop) in ethanol (1 mL) was stirred at room temperature for 7 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 58 mg (57%) of the title compound as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([C:8]2[CH2:13][CH2:12][C:11]([CH2:16][CH:17]3[CH2:19][CH2:18]3)([C:14]#[N:15])[CH2:10][CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.O1CCCC1.B>O1CCCC1.CO.ClCCl>[CH:1]1([CH2:4][S:5]([CH:8]2[CH2:13][CH2:12][C:11]([CH2:14][NH2:15])([CH2:16][CH:17]3[CH2:18][CH2:19]3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: N#CC1(CC2CC2)CC=C(S(=O)(=O)CC2CC2)CC1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.1 %

Procedure:
A cooled (0° C.) soution of 4-cyclopropylmethanesulfonyl-1-cyclopropylmethylcyclohex-3-enecarbonitrile (3.5 g, 12.4 mmol) in tetrahydrofuran (10 ml) was treated with borane tetrahydrofuran complex (1M in tetrahydrofuran, 62 ml) dropwise over 20 min. On complete addition the mixture was allowed to warm to ambient temperature and stirred for 4 hours. The solution was cooled to 0° C. and quenched by the slow addition onto cooled (0° C.) methanol (30 ml). On complete addition concentrated hydrochloric acid (3.5 ml) was added and the mixture was allowed to warm to ambient temperature and stirred for 1 hour. The solvent was evaporated and the residue azeotroped with toluene to give a white solid. The solid was dissolved in methanol:dichloromethane (1:1) and purified using an SCX cartridge. The product was washed with methanol then eluted with 2M ammonia in methanol and evaporated to give the desired product as a colourless oil (2.87 g, 81%). 1H NMR δ (ppm)(d6-DMSO): 3.21 (2H, s), 3.05-2.98 (3H, m), 2.62 (2H, s), 1.88-1.84 (2H, m), 1.80-1.74 (2H, m), 1.60-1.53 (2H, m), 1.28-1.22 (2H, m), 1.15 (2H, d, J=6.7 Hz), 1.10-1.02 (1H, m), 0.64-0.62 (3H, m), 0.43-0.36 (4H, m), 0.13-0.06 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([NH:20][NH2:21])[CH2:10][N:9]=1.[C:22](OCC)(OCC)(OCC)[CH2:23][CH3:24]>C1(C)C(C)=CC=CC=1>[CH2:23]([C:24]1[N:12]2[C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=3[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:9][CH2:10][C:11]2=[N:20][N:21]=1)[CH3:22]
Reactant: CCOC(CC)(OCC)OCC
Reactant: NNC1=Nc2ccc(I)cc2C(c2ccccc2F)=NC1
Solvent: Cc1ccccc1C
Product: CCc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2
Yield: 97 %

Procedure:
A mixture of 1 g of 5-(2-fluorophenyl)-7-iodo-2-hydrazino-7-iodo-3H-1,4-benzodiazepine (see example 3), 5 ml of triethyl orthopropionate and 10 ml of xylene was heated to reflux for 1 hour. The solvents were partially distilled over and the residue was diluted with hexane. The precipitated crystals were collected and recrystallized from methanol/ethyl acetate to leave 1.05 g (97%) of 1-ethyl-6-(2-fluorophenyl)-8-iodo-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine with m.p. 209°-211° C.