Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]=[CH:5][C:4]1=[O:57])[CH3:2].C(O)(=O)C.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.7 %

Procedure:
A solution of 17-ethyl-1-hydroxy-12-[2'-(4"-azido-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-14,18-diene-2,3,10,16-tetraone (55 mg, Example 31), tetrakistriphenylphosphine palladium (10 mg), and acetic acid (10 μl) in 3 ml of dry toluene was stirred for 5 min at room temperature under nitrogen atmosphere. To this yellow solution was added tributyltin hydride (40 μl) and stirred an additional 45 min at room temperature. The brown colored reaction mixture was subjected to column chromatography on silica gel (eluted first with hexane and then with 50% ethyl acetate/hexane) to give 50 mg of the title compound (Mass and 1H NMR data were consistent with the proposed structure).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][P:11](=[O:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:21]>CCO.[Pd]>[ClH:21].[C:14]1([P:11]2(=[O:20])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=P1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=P1(c2ccccc2)CCNCC1
Reaction time: 60 h

Procedure:
1-Benzyl-4-phenyl-[1,4]azaphosphinane 4-oxide (14.2 g, 49.8 mmol) was dissolved in absolute EtOH (65 mL) and 1N HCl (50 mL). Palladium on carbon (10%, 2.0 g) was added and the mixture was hydrogenated on a Parr shaker at 50 psi for 60 hours. After filtration through Celite, the filtrate was rotovapped and the residue was triturated with ether to give 4-phenyl-[1,4]azaphosphinane 4-oxide hydrochloride, as an off-white solid (11.40 g, 99%). 1H NMR (400 MHz, DMSO-d6) δ 7.85 (m, 2H), 7.65 (m, 3H), 3.5 (m, 4H), 2.7 (m, 2H), 2.2 (broad t, 2H). 31P NMR (DMSO-d6); δ 24.0 (s).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:12]([NH2:21])[CH2:13][N:14]([CH2:18][CH2:19][NH2:20])[CH2:15][CH2:16][NH2:17].[K+].[Br-]>>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([CH:12]([NH2:21])[CH2:13][N:14]([CH2:18][CH:19]([NH2:20])[C:1](=[O:10])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH2:15][CH:16]([NH2:17])[C:1](=[O:10])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])=[O:10]
Reactant: NCCN(CCN)CCN
Reactant: COC(=O)c1ccccc1O
Agent: [Br-]
Agent: [K+]
Product: NC(CN(CC(N)C(=O)c1ccccc1O)CC(N)C(=O)c1ccccc1O)C(=O)c1ccccc1O
Temperature: 100 °C
Yield: 47 %

Procedure:
Methyl salicylate (78 mmol) was mixed with distilled TREN (17 mmol). The mixture was sealed and heated to 100° C. overnight. The thick resulting oil was purified on a silica column eluted with 0-4% MeOH in CH2Cl2, resulting in a white powder after removal of solvent. Overnight drying in vacuo gave a colorless glass. Yield: 47%. IR (KBr) 1543, 1590, 1636 cm31 1. 1H NMR(300 MHz, CD3OD, 25 C) 2.78 (t, 3J=6.2 Hz, 6H, CH2), 3.49 (t, 3J=6.2 Hz, 6H, CH2), 6.68 (t, 3J=7.2 Hz, 3H, ArH), 6.80 (d, 3J=7.4 Hz, 3H, ArH), 7.23 (t, 3J=5.8 Hz, 3H, ArH), 7.63 (d, 3J=6.4 Hz, 3H, ArH), 8.44 (t br, 3H, NH). 13C NMR (400 MHz, CD3OD, 25 C) 39.0 (CH2), 54.6 (CH2), 117.1 (Ar), 118.4 (Ar), 120.2 (Ar), 129.0 (Ar), 134.7 (Ar), 160.9 (ArCO), 170.9 (C═O). Anal. Calcd (Found) for C27H30N4O6: C, 64.02 (63.94); H, 5.97 (5.97); N, 11.06 (11.01).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>CCOCC>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][C:25](=[O:27])[CH3:26])[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1)(=[O:3])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)OC1Oc2ccc(OS(C)(=O)=O)cc2C1(C)C
Reaction time: 4 h

Procedure:
A solution of 2-hydroxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (5 parts) in ether (85 parts) was treated with triethylamine (2.2 parts) and acetic anhydride (2.3 parts) at 10°C and allowed to stand for 4 hours. The solution was then diluted with light petroleum (80 parts) and filtered. The filtrate was evaporated to give an oil which solidified. This was recrystallised from a mixture of chloroform and petroleum to give 2-acetoxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (2.5 parts), melting point 84°-85°C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH:15](OCC)=[O:16]>>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][CH:15]=[O:16])[CH2:3]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC=O
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Product: CC(C)(C)OC(=O)N1CCCC(NC=O)C1

Procedure:
The title compound of Example 4 (10.1 g, 50.5 mmol) was dissolved in ethyl formate (50 mL) and the solution was refluxed overnight when TLC (solvent system A) showed the reaction to be complete. The solvent was evaporated in vacuo and the residue was dried under high vacuum to give the product (11.5 g, quantitative) as a colorless oil: 1H-NMR (CDCl3) ∂8.16. (s, 1H), 6.03 (20%), 5.77 (80%) (br s, 1H), 4.06 (m, 1H), 3.22-3.58 (complex m, 4H), 1.20-1.89 (complex m, 4H), 1.46 (s, 9H). CIMS (MH+ calcd for C11H20N2O3): 229. Found (MH+): 229; HRMS (M+ calcd for C11H20N2O3): 228. 1474. Found (M+): 228. 1469.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[S:3]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[C:10]([CH:17]([OH:20])[CH2:18][OH:19])[CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:5])=[O:4].N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].O>CN(C=O)C>[F:22][C:2]([F:1])([F:21])[S:3]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[C:10]([CH:17]([OH:20])[CH2:18][O:19][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:5])=[O:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=S(=O)(Oc1ccc2cccc(C(O)CO)c2n1)C(F)(F)F
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(O)c1cccc2ccc(OS(=O)(=O)C(F)(F)F)nc12
Yield: 87.3 %

Procedure:
A solution of 12 g (35 mmol) of 2-trifluoromethanesulfonyloxy-8-(1,2-dihydroxyethyl)quinoline, of 5.33 g (78.3 mmol) of imidazole and of 5.63 g of tert-butyldimethylsilyl chloride in 280 ml of DMF is stirred at ambient temperature for 16 h. 800 ml of water are added and extraction is carried out with ethyl acetate (3×250 ml). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by silica chromatographic column (eluent: cyclohexane/ethyl acetate 8/2) to provide 13.8 g of 2-trifluoromethanesulfonyloxy-8-(1-hydroxy-2-tert-butyldimethylsilyloxyethyl)quinoline in the form of a yellow oil. (Yield: 91%)
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][C:24]([C:26]4[N:30]=[CH:29][N:28](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:27]=4)=[O:25])[CH:17]=3)=[O:13])=[N:6][C:5]=2[S:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][C:24]([C:26]4[N:30]=[CH:29][NH:28][N:27]=4)=[O:25])[CH:17]=3)=[O:13])=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: Cc1csc2nc(C(=O)NCc3cccc(CNC(=O)c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3)[nH]c(=O)c12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1csc2nc(C(=O)NCc3cccc(CNC(=O)c4nc[nH]n4)c3)[nH]c(=O)c12
Yield: 99.9 %

Procedure:
A solution of 5-methyl-4-oxo-N-({3-[({[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]carbonyl}amino)methyl]phenyl}methyl)-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxamide (565.0 mg, 0.849 mmol), triethylsilane (0.142 mL, 0.891 mmol) and trifluoroacetic acid (3 mL) in dichloromethane (10 mL) was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from IPE. The obtained powder was suspended in ethanol, and the suspension was stirred under heating for 2 hr to give the title compound as a white powder (359 mg, 99%).
Reaction SMILES: C1(S([CH2:10][C:11](=[CH2:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)=O)C=CC=CC=1.[SnH:18]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22].CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[CH2:27]([Sn:18]([CH2:10][C:11](=[CH2:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:28][CH2:29][CH3:30]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C=C(CS(=O)(=O)c1ccccc1)C(=O)OCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: C=C(C[Sn](CCCC)(CCCC)CCCC)C(=O)OCC

Procedure:
This compound was prepared from ethyl α-(benzenesulphonylmethyl)acrylate, n-Bu3SnH and AIBN in benzene at 80° C. for 1.5 h according to the procedure described in Journal of the Chemical Society, Chemical Communications, 1986, 1339-1340. 1H NMR (CDCl3) δ 0.85-1.65 (30H, m, 3× CH2CH2CH2CH3, OCH2CH3), 2.00 (2H, s, allylic CH2Sn), 4.15 (2H, q, OCH2CH3, J 7.5 Hz), 5.25 (1H, s, olefinic proton), 5.75 (1H, s, olefinic proton).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1[NH:7][C:6]2[CH:8]=[C:9]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])=[O:17])[CH:10]=[C:11]([C:12]([OH:14])=O)[C:5]=2[N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[Cl:62][C:63]1[CH:64]=[C:65]([CH:67]=[CH:68][C:69]=1[CH3:70])[NH2:66]>CN(C=O)C.C(OCC)(=O)C>[Cl:62][C:63]1[CH:64]=[C:65]([NH:66][C:12]([C:11]2[C:5]3[N:4]=[C:3]([N:2]([CH3:28])[CH3:1])[NH:7][C:6]=3[CH:8]=[C:9]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:25])([F:26])[F:27])=[O:17])[CH:10]=2)=[O:14])[CH:67]=[CH:68][C:69]=1[CH3:70]
Reactant: Cc1ccc(N)cc1Cl
Reactant: CN(C)c1nc2c(C(=O)O)cc(NC(=O)c3ccccc3C(F)(F)F)cc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2cc(NC(=O)c3ccccc3C(F)(F)F)cc3[nH]c(N(C)C)nc23)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxylic acid (50 mg) and HATU (82 mg) in DMF (1 mL), were added N,N-diisopropylethylamine (88 μL) and 3-chloro-4-methylaniline (26 μL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on column chromatography to obtain N-(3-chloro-4-methylphenyl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (65 mg) as white powder. This was suspended in MeOH (1.5 mL), 2N hydrogen chloride/MeOH (1 Eq) was added, and it was stirred and concentrated. The residue was triturated in diethyl ether, and the precipitate was collected by filtration and dried to obtain the titled compound (40 mg) as white powder.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12](Cl)=[CH:11][C:10]([NH:14][CH3:15])=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]=1.O.[H][H]>[Ni].C(N(CC)CC)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[CH:12]=[CH:11][C:10]([NH:14][CH3:15])=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]=1
Reactant: [H][H]
Reactant: CNc1cc(Cl)[n+](C)nc1-c1ccccc1
Agent: [Ni]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCN(CC)CC
Product: CNc1cc[n+](C)nc1-c1ccccc1

Procedure:
15 parts of 1-methyl-3-phenyl-4-methylamino-6-chloropyridazinium perchlorate, 100 parts of water, 5 parts of triethylamine and about 2 parts of Raney nickel are treated at room temperature in a shaking apparatus with hydrogen at atmospheric pressure. After twenty-four hours the reaction mixture is suction filtered, the residue is boiled with 200 parts of methanol and filtered and the filtrate is concentrated and cooled. 10.3 parts (76.6% of theory) of 1-methyl-3-phenyl-4-methylaminopyridazinium perchlorate is obtained; C12H14O4N3Cl, melting point 155° to 157° C.
Reaction SMILES: ClC(OCC)=O.[C:7]([O:11][C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].[NH:19]([C:21]1[N:22]=[N:23][C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:25]([CH3:27])[N:26]=1)[NH2:20]>C(Cl)Cl>[C:7]([O:11][C:12]([NH:14][CH2:15][C:16]([NH:20][NH:19][C:21]1[N:22]=[N:23][C:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:25]([CH3:27])[N:26]=1)=[O:18])=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cc1nc(NN)nnc1-c1ccccc1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: Cc1nc(NNC(=O)CNC(=O)OC(C)(C)C)nnc1-c1ccccc1
Yield: 75.8 %

Procedure:
The reaction of ethyl chloroformate (2.441 g) with N-t-butoxycarbonylglycine (3.938 g) in methylene chloride under ice cooling gave a solution comprising the mixed acid anhydride, which was reacted with 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3.015 g) in a similar manner to that of Example 17-(1) to give 3-[2-(N-t-butoxycarbonylglycyl)hydrazino]-5-methyl-6-phenyl-1,2,4-triazine (4.068 g). The purification was conducted with column chromatography on silica gel (80 g) using a mixture of methylene chloride and methanol (30:1) as an eluent.
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: O=C(Cl)c1cc(-c2ccccc2)nc2ccccc12
Reactant: Nc1nnc(-c2ccco2)o1
Solvent: CO
Solvent: c1ccncc1
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: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:35]1[CH2:34][CH2:33][N:32]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=3)[CH2:37][CH2:36]1)=[O:19])=[N:5]2
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Product: COc1cc(N2CCN(C(=O)Nc3nc4cc(F)ccc4nc3OC)CC2)cc(OC)c1OC
Yield: 76 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,4,5-trimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 76%). 1H NMR (200 MHz, CDCl3): δ 3.22 (s, 4H), 3.79-3.85 (m, 12H), 4.13 (s, 4H), 6.19 (s, 2H), 7.20-7.34 (m, 1H), 7.35-7.36 (m, 1H), 7.44 (s, 1H), 7.67-7.70 (m, 1H).
Reaction SMILES: O1CCCCC1[O:7][C@@H:8]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:24]2[C:23](=[O:29])[CH2:22][C@@:21]2([CH3:30])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[C:18](=[O:20])[CH3:19])[CH2:9]1.[C:31](=[O:38])([O:35][CH2:36][CH3:37])OCC.[OH-].[Na+]>C(O)C>[CH2:36]([O:35][C:31]([CH2:19][C:18](=[O:20])[C@@H:17]1[C@:21]2([CH3:30])[C@H:14]([C@H:13]3[C@H:24]([C:23](=[O:29])[CH2:22]2)[C@:25]2([CH3:28])[C@H:10]([CH2:9][C@H:8]([OH:7])[CH2:27][CH2:26]2)[CH2:11][CH2:12]3)[CH2:15][CH2:16]1)=[O:38])[CH3:37]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC5CCCCO5)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
3α-(Tetrahydropyran-2ξ- yloxy)-5α-pregnane-11,20-dione (0.9 g) in boiling diethyl carbonate (12 ml) under nitrogen was treated with 1 drop of ethanol and then sodium hydroxide (0.17 g). The mixture was refluxed for 20 minutes, then cooled and the excess sodium hydride was destroyed with ethanol. The reaction mixture was partitioned between water and ether. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue (1.0 g) was purified by preparative t.l.c. to give the ester (0.59 g) This ester in ethanol (5 ml) was treated with 2N hydrochloric acid (0.5 ml) and after ca 6 hours the reaction mixture was partitioned between water and ether. The organic layer was washed with water, dried (MgS04) and evaporated. The residue (0.6 g) was subjected to preparative t.l.c. (ethyl acetate/petrol 1:2). The more polar fraction (0.29 g) gave after crystallisation from ispropyl ether the title compound (0.08 g), m.p. 120-121°, [α]D + 120.5°, λmax. 249 nm. (ε 4,250).
Reaction SMILES: [C:1]([CH2:3][C:4](N)=O)#[N:2].F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:19][C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>C1COCC1.C(O)C>[C:1]([CH2:3][C:4]1[N:29]([C@H:30]2[CH2:31][CH2:32][C@H:33]([CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:43])[CH3:42])[CH2:34][CH2:35]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:19]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Reactant: N#CCC(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](n2c(CC#N)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-Cyanoacetamide (120 mg, 1.5 mmol) and triethyloxonium tetrafluoroborate (270 mg, 1.4 mmol) in THF (1.1 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue dissolved in ethanol (0.5 mL) and added to a suspension of tert-butyl ({trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methyl)carbamate (150 mg, 0.40 mmol) in ethanol (1.7 mL). The mixture was stirred at 85° C. for 2 h. The solid was filtered and the filtrate was concentrated and purified on flash chromatography (0-10% methanol/dichloromethane) to give the desired product (0.12 g, 71%). LCMS calculated for C22H28N5O2S (M+H)+: m/z=426.2. Found: 426.0.
Reaction SMILES: CC1C=CC(S(O[CH2:12][N:13]2[CH:18]=[N:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)=[N:15][C:14]2=[O:32])(=O)=O)=CC=1.N12CCCN=C1CCCCC2.[NH:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=[N:45]1>ClCCl>[N:44]1[N:45]([CH2:12][N:13]2[CH:18]=[N:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)=[N:15][C:14]2=[O:32])[CH:46]=[C:47]2[C:52]=1[CH:51]=[CH:50][CH:49]=[CH:48]2
Reactant: Cc1ccc(S(=O)(=O)OCn2cnc(N3CCN(c4ccc(F)cc4)CC3)nc2=O)cc1
Reactant: c1ccc2[nH]ncc2c1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)ncn1Cn1cc2ccccc2n1
Yield: 5.8 %

Procedure:
To a dichloromethane solution of {4-[4-(4-fluorophenyl)piperazin-1-yl]-2-oxo-1,3,5-triazin-1(2H)-yl}methyl 4-methylbenzenesulfonate (165 mg, 0.36 mmol) synthesized in Reference Synthesis Example 4, 1,8-diazabicyclo[5.4.0]undeca-7-ene (65 μL, 0.44 mmol) and 1H-indazole (43 mg, 0.40 mmol) were added at room temperature and the resultant mixture was stirred at room temperature for 30 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (8.5 mg, yield: 5.2%).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[F:14])[N:5]=[N:4][C:3]=1[C:15]([O:17]CC)=[O:16].Cl.N(OCCC(C)C)=O>CCO.CCOC(C)=O>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[F:14])[N:5]=[N:4][C:3]=1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1nnn(-c2cccc(Cl)c2F)c1Cl
Agent: CC(C)CCON=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)c1nnn(-c2cccc(Cl)c2F)c1Cl
Reaction time: 48 h

Procedure:
Ethyl 5-chloro-1-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate: (Can. J. Chem., 37:118-119 (1959)). To a solution of Intermediate 27A (1.1 g, 3.86 mmol) in EtOH (30 mL) at 0° C. was passed HCl gas until all of the solid dissolved. To the solution was added isoamyl nitrite (0.520 mL, 3.86 mmol) in one portion and the resulting solution was kept at 0-5° C. for 48 h. The reaction mixture was diluted in EtOAc and washed with aq NaHCO3 and brine. The organic layer was concentrated and purified by reverse phase HPLC to yield the desired product. MS(ESI) m/z: 304.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[NH:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1.C(OCC)(=O)C>C(O)(=O)C>[Br:8][C:7]1[C:2]2[N:1]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[NH:11][C:3]=2[C:4]([O:9][CH3:10])=[CH:5][CH:6]=1
Reactant: COc1ccc(Br)c(N)c1NC(=O)c1ccc(C(C)C)cc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(Br)c2nc(-c3ccc(C(C)C)cc3)[nH]c12
Yield: 81.7 %

Procedure:
A solution of 1.44 g (3.97 mmol) N-(2-amino-3-bromo-6-methoxy-phenyl)-4-isopropyl-benzamide in 25 ml glacial acetic acid is stirred at 100° C. for 3 h. The reaction mixture is cooled to room temperature 200 ml ethyl acetate is added. The solution is washed with 4N NaOH (2×) and with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=2:1) to afford 1.12 g of the title compound as slightly reddish solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][C:12]([N+:18]([O-])=O)=[CH:11][C:10]=1[C:21]([F:24])([F:23])[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.[Ni]>[NH2:15][C:14]1[C:9]([S:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([C:21]([F:22])([F:23])[F:24])[CH:11]=[C:12]([NH2:18])[CH:13]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(SCc2ccccc2)c(C(F)(F)F)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(N)c(SCc2ccccc2)c(C(F)(F)F)c1

Procedure:
3 g of 2-benzylthio-3,5-dinitrobenzotrifluoride in 30 ml of tetrahydrofuran are hydrogenated in a glass hydrogenation apparatus for 22 hours at room temperature, using a total of 3 g of Raney nickel. For working up, the catalyst is removed by filtration and washed with tetrahydrofuran, the filtrate is evaporated, and the residue is directly processed as crude product (brownish liquid).