Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([C:8]#[CH:9])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].Br[C:11]1[C:16]([F:17])=[CH:15][C:14]([Br:18])=[CH:13][N:12]=1.C(N(CC)CC)C>C1COCC1.[Cu]I>[Br:18][C:14]1[CH:15]=[C:16]([F:17])[C:11]([C:9]#[C:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[N:12][CH:13]=1
Reactant: Fc1cc(Br)cnc1Br
Reactant: C#C[Si](C)(C)C(C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)C#Cc1ncc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere, 2.62 mL (13.811 mmol) of tert-butylethynyldimethylsilane was added to a solution of 3.20 g (12.56 mmol) of 2,5-dibromo-3-fluoropyridine, 5.22 mL of triethylamine (37.67 mmol), 59.8 mg (0.31 mmol) of CuI, and 220.3 mg (0.31 mmol) of bis(triphenylphosphane)palladium (II) chloride in 30 mL of absolute THF at 15° C. and the mixture was stirred for 2 hours at RT. 1 mL of tert-butylethynyldimethylsilane was added and the mixture was again stirred for 1 hour at RT. The reaction mixture was evaporated down in vacuo and the residue was taken up in EtOAc. The organic phase was washed with semisaturated aqueous sodium bicarbonate solution, 5% aqueous ammonia, and water, dried over magnesium sulfate, and evaporated down in vacuo. The crude product was purified by column chromatography (silica gel, PE/DCM 9:1). Yield: 1.62 g (41% of theoretical); C13H17BrFNSi (M=314.269); calc.: molpeak (M+H)+: 314/316 (Br); found: molpeak (M+H)+: 314/316 (Br); HPLC-MS: 7.85 minutes (method B).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Si:1]([O:8][CH:9]1[CH2:12][NH:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
A mixture of 295 (200 mg, 0.696 mol), DCM (1 mL) and TFA (1 mL) was stirred for 1 h at room temperature, concentrated under reduced pressure; NaOH (1 M, 15 mL) was added to the residue and the suspension was extracted with DCM, the extract was dried (anhydrous Na2SO4) and concentrated, to afford title compound 296 (90.4 mg, 69% yield) as a syrup. MS (m/z): 188.1 (M+1).
Reaction SMILES: [Cl:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[N:8]2)=[N:3]1.C1C(=O)N([I:18])C(=O)C1>>[Cl:1][N:2]1[C:10]([I:18])=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[N:8]2)=[N:3]1
Reactant: O=C1CCC(=O)N1I
Reactant: Cln1cc2ncccc2n1
Product: Cln1nc2cccnc2c1I

Procedure:
2-Heteroaryl pyrazolopyridines can be synthesized according to Scheme 1. 2-Chloro pyrazolopyridine 1 can be treated with NIS to yield 2-chloro-3-iodo pyrazolopyridine 2 which can be converted to 3-substituted 2-chloro pyrazolopyridine 3 under Suzuki conditions. Further Suzuki reaction of 3 with an appropriate heteroaryl boronate affords the desired 2-heteroaryl pyrazolopyridine 4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:28])[N:13]2[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27].[C:29]([N:36]1[CH2:41][CH2:40][NH:39][CH:38]([CH3:42])[CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][N:39]2[CH2:40][CH2:41][N:36]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:37][CH:38]2[CH3:42])[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:28])[N:13]2[C:20]1[C:21]([Cl:27])=[CH:22][CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=Cc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC1CN(C(=O)OC(C)(C)C)CCN1Cc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carbaldehyde (Intermediate AAA1, 208 mg, 0.48 mmol) and 1-BOC-3-methylpiperazine (96 mg, 0.48 mmol) in dichloroethane (5 mL) was stirred at rt for 30 min. To this was added sodium triacetoxyborohydride (150 mg, 0.67 mmol) followed by acetic acid (29 mg, 0.48 mmol). The resulting reaction mixture was stirred at rt for 20 h. The reaction was quenched with 2N NaOH solution (6 mL) followed by extraction with ethyl acetate (100 mL×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent and subsequent purification by flash chromatography using 25% acetone/hexane provided tert-butyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methyl}-3-methylpiperazine-1-carboxylate as a white solid. 1H NMR (CDCl3, 500 MHz): δ 0.98 (s, 3H), 1.46 (s, 9H), 2.06 (brs, 1H), 2.39 (brs, 1H), 2.60 (brs, 1H), 2.82 (brs, 1H), 3.05 (brs, 1H), 3.15 (m, 1H), 3.54 (brs, 2H), 3.82 (brs, 1H), 4.34 (abq, 2H, J=14.2 Hz), 5.15 (s, 1H), 6.16 (d, 1H, J=5.2 Hz), 6.88 (s, 1H), 7.20-7.60 (m, 7H). MS (API-ES+): 617 (M+H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:18])[CH:5]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH:7]([CH3:9])[CH3:8].C(N(CC)CC)C.[C:26](Cl)(=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29]>C(Cl)(Cl)Cl>[C:14]([O:13][C:11]([NH:10][CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH:4]([OH:18])[CH2:3][NH:2][C:26](=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:12])([CH3:16])([CH3:15])[CH3:17]
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C(O)CN
Reactant: CC(C)CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)CC(=O)NCC(O)C(CC(C)C)NC(=O)OC(C)(C)C

Procedure:
To a solution of the resultant compound of Example 76 (1.0 mmol) and triethyl amine (2.0 mmol) in chloroform (10ml) cooled to 0° C. was added isovaleryl chloride (1.0 mmol) in CHCl3 (2ml). After 3h, the solution was washed sequentially with 10% citric acid, saturated NaHCO3, and brine. Drying and evaporating provided the desired compound.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1.C(N(CC)CC)C.[CH3:17][N:18]([CH3:23])[S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:17][N:18]([CH3:23])[S:19]([N:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1)(=[O:21])=[O:20]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: c1nc2c([nH]1)CCCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)n1cnc2c1CCCC2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 76.9 %

Procedure:
To solution of 4,5,6,7-tetrahydro-1H-benzoimidazole (1.9992 g, 16.4 mmol) and triethylamine (4.60 mL, 32.8 mmol) in CH2Cl2 (20 mL) at 0° C. was added dropwise a solution of dimethyl sulfamoyl chloride (1.76 mL, 16.4 mmol) in CH2Cl2 (10 mL). The reaction was warmed to room temperature and stirred for 3.5 hours. CH2Cl2 (80 mL) was added and the organic phase was washed with distilled water (1×80 mL). The aqueous washing was extracted with CH2Cl2 (2×40 mL), and the combined organic extracts were washed with brine (1×80 mL), dried (Na2SO4), and concentrated. Purification of the crude material by column chromatography on silica gel (2:1 hexanes-EtOAc) provided 2.89 g (77%) of 4,5,6,7-tetrahydro-benzoimidazole-1-sulfonic acid dimethylamide as a white solid. 1H NMR (CDCl3) δ 1.77-1.86 (m, 4H), 2.58-2.61 (m, 2H), 2.72 (t, 2H, J=6 Hz), 2.87 (s, 6H), 7.77 (s, 1H).
Reaction SMILES: [I:1]I.[F:3][C:4]([F:13])([F:12])[C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:10]1[CH:11]=[C:5]([C:4]([F:12])([F:13])[F:3])[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: II
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)cc1I
Yield: 60.6 %

Procedure:
2-iodo-4-(trifluoromethyl)aniline was prepared according to method D Step I with iodine (1.58 g; 6.21 mmol), silver sulphate (1.94 g; 6.21 mmol) and 4-(trifluoromethyl)aniline (0.8 mL; 6.21 mmol) in ethanol (40 mL). The crude residue was purified by flash chromatography on silica gel (eluent 2 to 40% ethyl acetate in heptane) to afford 1.08 g (61%) of 2-iodo-4-(trifluoromethyl)aniline as a red oil.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]1[C:28]2([CH2:33][CH2:32][CH:31](O)[CH2:30][CH2:29]2)[O:27][CH2:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:24]1[C:28]2([CH2:33][CH2:32][CH:31]([N:16]3[C:17]4=[N:18][CH:19]=[N:20][C:21]([NH2:23])=[C:22]4[C:14]([C:11]4[CH:12]=[CH:13][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:9][CH:10]=4)=[N:15]3)[CH2:30][CH2:29]2)[O:27][CH2:26][CH2:25]1
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: OC1CCC2(CC1)OCCO2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 15) (3.36 g, 11.1 mmol, 1,4-dioxaspiro[4.5]decan-8-ol (Intermediate M) (5.26 g, 33.3 mmol), Triphenylphosphine (5.81 g, 22.2 mmol) were suspended in 130 ml of tetrahydrofuran. The reaction mixture was cooled in an ice-water bath and diethyl azodicarboxylate (3.9 ml, 22.2 mmol) was added dropwise. 10 minutes later, the reaction mixture was allowed to warm up to room temperature. After stirring for 2 hours, solvent was removed and the residue was taking into ethyl acetate. The organic layer was washed, dried and evaporated. The crude product was purified via Biotage flash column chromatography using dichloromethane/ethyl acetate (from 50:50 to 10:90) as the mobile phase to yield 3.829 g of 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (CDCl3) 1.83 (m, 2H), 1.945 (m, 2H), 2.05 (m, 2H), 2.45 (m, 2H), 3.99 (s, 4H), 4.86 (m, 1H), 5.74 (bs, 2H), 7.09 (m, 2H), 7.15 (m, 3H), 7.39 (m, 2H), 7.66 (d, J=8.70 Hz, 2H), 8.37 (s, 1H); LC/MS (MH+32 444).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:16](OC)=[O:17])=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1)#[N:2].Cl.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C.CN(C=O)C>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:16]([NH:28][CH:25]3[CH2:27][CH2:26]3)=[O:17])=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(C#N)nncc3c2)c1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C#N)nncc2c1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To methyl 3-(1-cyanophthalazin-6-yl)-4-methylbenzoate (0.800 g, 2.6 mmol) was added 6N HCl (10.6 mL) and the reaction was heated in a microwave oven for 25 min at 120° C. The reaction was concentrated, dried in vacuo and DMF (5.3 mL) and cyclopropylamine (0.92 mL, 13 mmol) were added. HATU (2.0 g, 5.3 mmol) was added and the reaction mixture was stirred at RT for 1 h, then diluted with 75 mL ethyl acetate, partitioned with sodium bicarbonate (saturated, aqueous), and the organic layers were washed 2×20 mL with sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, concentrated in vacuo, and purified by HPLC to give the title compound. MS (ES+): 329(M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[NH:5][CH:6]=[N:7][C:8]=2[N:9]([CH2:13][CH2:14][CH3:15])[C:10](=[O:12])[N:11]=1.[H-].[Na+].Cl[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:21]([O:20][CH2:19][N:5]1[C:4]2[C:3]([S:2][CH3:1])=[N:11][C:10](=[O:12])[N:9]([CH2:13][CH2:14][CH3:15])[C:8]=2[N:7]=[CH:6]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCOCc1ccccc1
Reactant: CCCn1c(=O)nc(SC)c2[nH]cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(=O)nc(SC)c2c1ncn2COCc1ccccc1

Procedure:
After 224 mg (1.0 mmol) of Compound b obtained in Reference Example 2 was dissolved in 2 ml of N,N'-dimethylformamide, 48.0 mg (1.2 mmol) of 60% sodium hydride was added to the mixture under ice cooling. 15 minutes after, 209 μl (1.5 mmol) of benzyl chloromethyl ether was added to the mixture. The mixture was stirred for an hour, poured onto 10 ml of water, and extracted 3 times with 5 ml of chloroform. After washing with a saturated aqueous sodium chloride solution, the extracts were dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated with ether to give 223 mg (yield, 65%) of Compound f as a white powder.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[N:16]=[C:6]2[N:7]=[C:8]3[CH2:15][CH2:14][CH2:13][S:12][C:9]3=[C:10](Cl)[N:5]2[N:4]=1.CC(O)C.[NH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl.C(N(CC)CC)C>C(N(CC)CC)C>[CH3:1][N:2]([CH3:17])[C:3]1[N:16]=[C:6]2[N:7]=[C:8]3[CH2:15][CH2:14][CH2:13][S:12][C:9]3=[C:10]([NH:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:5]2[N:4]=1
Reactant: CN(C)c1nc2nc3c(c(Cl)n2n1)SCCC3
Reactant: NCCN1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CN(C)c1nc2nc3c(c(NCCN4CCOCC4)n2n1)SCCC3
Reaction time: 1 h

Procedure:
To a suspension of 5.40 g (0.02 mole) of 2-(dimethylamino)-5-chloro-7,8-dihydro-9H-thiopyrano[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidine in 20 ml of 2-propanol 2,125 g (0.021 mole) of triethylamine and 2.73 g (0.021 mole) of 2-aminoethylmorpholine are successively added, and the reaction mixture is boiled for one hour. Upon cooling triethylamine hydrochloride gets separated, which is filtered and washed with 2-propanol. The filtrate is evaporated to dryness in vacuo and the residue is dissolved in chloroform. The solution thus obtained is extracted twice with water, dried over anhydrous Na2SO4 and evaporated in vacuo. The oily product is suspended in ethyl acetate, the crystalline product thus obtained is filtered off and washed with ethyl acetate.
Reaction SMILES: [C:1]1([C:7]([NH2:10])([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]=O.[BH4-].[Na+]>C1C=CC=CC=1.CO>[CH3:11][NH:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:9])[CH3:8]
Reactant: C=O
Reactant: CC(C)(N)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CNC(C)(C)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-phenylpropan-2-amine (1 eq.) in benzene (0.25 M) was added formaldehyde (37% w/w aqueous solution, 2 eq.). The vessel attached a Dean-Stark apparatus and heated at 80° C. for 36 h. The reaction mixture was cooled to RT, dried with Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the crude imine. This was then taken up in methanol (1.4 M) and added sodium borohydride (10 eq.). The resulting mixture was stirred at RT for 2 h and then quenched with 1 N aq. HCl. The volatiles were removed in vacuo and the pH of the resulting residue was carefully brought up to ˜12 with 1 N aq. NaOH. The mixture was then extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO2, 2:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][OH:23]>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:23][CH2:22][C:18]3[S:17][CH:21]=[CH:20][CH:19]=3)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: OCc1cccs1
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3cccs3)c21
Yield: 20.6 %

Procedure:
The title compound (cis/trans=20/80) was prepared as a grayish white powder in 20.6% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=20/80) and 2-thiophenemethanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][S:14][C:15]1[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[CH:17][C:16]=1[N+:24]([O-])=O)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>[Zn].CO.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][S:14][C:15]1[C:16]([NH2:24])=[CH:17][CH:18]=[CH:19][C:20]=1[NH2:21])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSc1c([N+](=O)[O-])cccc1[N+](=O)[O-])C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CSc1c(N)cccc1N)C(=O)O
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of (R)-2-tert-butoxycarbonylamino-3-(2,6-dinitro-phenylsulfanyl)-propionic acid (1.7 g, 4.4 mmol) in 3:1 v/v MeOH/H2O (80 mL) containing NH4Cl (7.0 g, 130 mmol) was added Zn dust (5.7 g, 87.2 mmol) and the resulting mixture was stirred for 1 h. The mixture was filtered through a pad of Celite, the filtrate volume was reduced in vacuuo and acidified to pH 4 with 1.0 M HCl. The mixture was extracted with EtOAc, the combined extracts washed with H2O, brine, dried over Na2SO4, filtered and concentrated to give (R)-2-tert-butoxycarbonylamino-3-(2,6-diamino-phenylsulfanyl)-propionic acid (1.0 g) which was used without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[C:3]=1[NH2:18].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1.O>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([C:14]([F:15])([F:16])[F:17])[C:3]=1[NH:18][C:27](=[O:28])[CH2:26][C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=1
Reactant: Nc1c(Br)cc(N2CCOCC2)cc1C(F)(F)F
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: CC#N
Solvent: O
Product: O=C(Cc1ccc(F)cc1)Nc1c(Br)cc(N2CCOCC2)cc1C(F)(F)F
Temperature: 150 °C
Yield: 9 %

Procedure:
2-Bromo-4-morpholin-4-yl-6-trifluoromethyl-phenylamine (0.236 g) and 4-fluorophenylacetyl chloride (0.105 mL) were dissolved in acetonitrile (5 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. Water (25 mL) was added and the product was extracted with ethyl acetate (3×25 mL). The organic phases were washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 0.027 g (9%) of the title compound as an off-white solid. LC-MS (m/z) 462 (MH+); tR=2.84, (UV, ELSD) 96%, 100%. 1H NMR (500 MHz, DMSO-d6): 3.23 (m, 4H), 3.62 (s, 2H), 3.72 (m, 4H), 7.14 (dd, 2H), 7.19 (d, 1H), 7.35 (dd, 2H), 7.46 (d, 1H), 9.78 (s, 1H).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17][CH3:18])[CH:14]=2)[C:9]1=[O:19])[CH:5]=CC>CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17][CH3:18])[CH:14]=2)[C:9]1=[O:19]
Reactant: CC=CCC1Cc2cc(OC)ccc2C1=O
Reactant: O=[O+][O-]
Solvent: CO
Product: COc1ccc2c(c1)CC(CC=O)C2=O
Reaction time: 1.42 h
Yield: 110.5 %

Procedure:
Ozone (3 g ozone/hour) was conducted while stirring for 85 minutes through a solution, cooled to -70°, of 19.2 g of (RS)-2-(2-buten-1-yl)-5-methoxy-1-indanone in 600 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen and then 9.1 ml of dimethyl sulfide were added to the cold solution. The solution came to room temperature overnight and was evaporated in a vacuum. The residue was chromatographed (dichloromethane) over a column with oxalic acid solution adsorbed on silica gel (600 g silica gel; 100 ml 10% oxalic acid solution). 14.1 g (78%) of (RS)-2-(2-oxoethyl)-5-methoxy-1-indanone were obtained as a yellow oil.
Reaction SMILES: [OH:1][C:2]([CH3:14])([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].C1CCN2C(=NCCC2)CC1.[C:26](Cl)(=[O:28])[CH3:27].Cl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:13][C:2]([O:1][C:26](=[O:28])[CH3:27])([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: CSc1ccc(C(=O)C(C)(C)O)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CSc1ccc(C(=O)C(C)(C)OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.1 %

Procedure:
To a 0° C. solution of 2-hydroxy-2-methyl-1-(4-(methylthio)phenyl)propan-1-one (150 g, example 1, Step 2), DBU (217 g) and DMAP (7 g) in dichloromethane (850 mL) was added acetyl chloride (112.2 g) dropwise and the mixture was stirred for 6 h. at 25° C. More DBU (32.5 g) was added and the mixture was stirred an additional 16 h. The reaction mixture was poured over 2N HCl (800 mL) and the organic layer was separated, washed with a saturated solution of NaHCO3, dried over MgSO4, filtered and the solvent was evaporated under vacuum. The residue was swished in Et2O, then 25% ethyl acetate in hexane, then filtered and dried giving 74 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[O:7][C:8]3[C:13]([C:14](=[O:16])[CH:15]=2)=[CH:12][CH:11]=[CH:10][C:9]=3[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1.Cl[CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:20]([O:19][C:17]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[O:7][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=3)=[CH:23][CH:22]=1)=[CH:15][C:14]2=[O:16])=[O:18])[CH3:21]
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCOC(=O)c1cccc2c(=O)cc(-c3ccc(O)cc3)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccc2c(=O)cc(-c3ccc(OCc4ccc5ccccc5n4)cc3)oc12
Temperature: 100 °C
Yield: 64 %

Procedure:
4'-Hydroxy-8-ethoxycarbonylflavone (1 eq.) and 2-chloromethylquinoline (1.1 eq.) were dissolved in DMF, followed by the addition of potassium carbonate (1.2 eq.). The resulting mixture was stirred at 100° C. and, subsequent to the completion of the reaction, was charged into water. The water layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from DMF-ethanol, whereby the title compound represented by the following formula was obtained (yield: 64%). ##STR21##
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][C:19]=2[NH:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)=[O:14])[CH:7]=1)#[N:2].C(N=C(OCC(F)(F)F)NC1C=CC=C(NC(C2SC=CC=2NCC2C3C(=CC=CC=3)N=CC=2)=O)C=1)#[N:40]>>[NH2:40][C:4]([NH:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][C:19]=2[NH:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1)=[N:3][C:1]#[N:2]
Reactant: N#CN=C(Nc1cccc(NC(=O)c2sccc2NCc2ccnc3ccccc23)c1)Oc1ccccc1
Reactant: N#CN=C(Nc1cccc(NC(=O)c2sccc2NCc2ccnc3ccccc23)c1)OCC(F)(F)F
Product: N#CN=C(N)Nc1cccc(NC(=O)c2sccc2NCc2ccnc3ccccc23)c1

Procedure:
The following analogues were prepared using phenyl N′-cyano-N-{3-[({3-[(quinolin-4-ylmethyl)amino]thien-2-yl}carbonyl)amino]phenyl}imidocarbamate (EXAMPLE 1) or 2,2,2-Trifluoroethyl N′-Cyano-N-{3-[({3-[(quinolin-4-ylmethyl)amino]thien-2-yl}carbonyl)amino]phenyl}imidocarbamate (EXAMPLE 2) and the appropriate amine, according to the procedure described above for EXAMPLE 3.