Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:11][OH:12])=[CH:6][CH:5]=1.ClN1C(=O)CCC1=O.[Cl:22][C:23]1[CH:24]=[C:25]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:26]=[C:27]([Cl:29])[CH:28]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:31][C:30]([C:25]3[CH:26]=[C:27]([Cl:29])[CH:28]=[C:23]([Cl:22])[CH:24]=3)([C:32]([F:33])([F:35])[F:34])[O:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=NO)cc1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 68.7 %

Procedure:
In a solution of 2.70 g of 4-(hydroxyiminomethyl) benzoic acid methyl ester in 15 ml of N,N-dimethylformamide, 2.04 g of N-chlorosuccinic acid imide was added, and stirred at 40° C. for 40 minutes. Then, the reaction mixture was cooled to 0° C., 3.40 g of 3,5-dichloro-1-(1-trifluoromethylethenyl) benzene and 1.72 g of triethylamine were added, continued to stir at room temperature for 18 hours. After the completion of the reaction, the reaction mixture was poured into 100 ml of ice water, extracted with ethyl acetate (50 ml×2), the organic phase was washed with water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residual solid was subjected to purification with medium-pressure preparative liquid chromatography (Yamazen Corporation, medium pressure preparative system; YFLC-Wprep) that was eluted with ethyl acetate-hexane (1:1 to 1:3 gradient), and 4.05 g of the aimed product was obtained as white crystal.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]([CH3:22])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[C:17][C:18]([OH:21])([CH3:20])[CH3:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>N1C=CC=CC=1>[C:24]([O:21][C:18]([CH3:20])([CH3:19])[C:17]#[C:16][C:15]1[N:14]=[CH:13][N:12]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=3[C:8](=[O:23])[N:9]([CH3:22])[CH2:10][C:11]=12)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN1Cc2c(C#CC(C)(C)O)ncn2-c2cccc(Cl)c2C1=O
Solvent: c1ccncc1
Product: CN1Cc2c(C#CC(C)(C)OC(=O)C(C)(C)C)ncn2-c2cccc(Cl)c2C1=O
Reaction time: 24 h
Yield: 23.2 %

Procedure:
3.30 g (10 mmol) of 7-chloro-4,5-dihydro-3-(3-hydroxy -3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzo diazepin-6-one were dissolved in 20 ml of pyridine and treated at room temperature with 1.57 g (13 mmol) of pivaloyl chloride. The reaction mixture was stirred at 65° for 24 hours and then evaporated. The residue was taken up in methylene chloride, the solution was washed once with lN hydrochloric acid and twice with water, dried over magnesium sulfate and evaporated. By chromatography on silica gel while eluting with ethyl acetate and subsequent crystallization from ethyl acetate and hexane, there was obtained 0.96 g (23%) of 3-(7-chloro-5,6-dihydro-5-methyl -6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl)-1,1-dimethyl-2-propynyl pivalate of melting point 132-133°.
Reaction SMILES: CS[C:3](SC)=[C:4]([C:21]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:22])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C@@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)[C:8]=1[F:20])=[O:6].[C:31]1([NH2:38])[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH2:37]>C(O)C>[NH:37]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[NH:38][C:3]1=[C:4]([C:21]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:22])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C@@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)[C:8]=1[F:20])=[O:6]
Reactant: CSC(SC)=C(C(=O)c1cccnc1)C(=O)c1cccc([C@@H]2COC(C)(C)O2)c1F
Reactant: Nc1ccccc1N
Solvent: CCO
Product: CC1(C)OC[C@@H](c2cccc(C(=O)C(C(=O)c3cccnc3)=C3Nc4ccccc4N3)c2F)O1
Yield: 97 %

Procedure:
A 0.12 g portion of 2-[bis(methylsulfanyl)methylene]-1-[3-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-fluorophenyl]-3-pyridin-3-yl-propan-1,3-dione and 36 mg of 1,2-phenylenediamine were dissolved in 8 ml of ethanol and heated under reflux for 3 hours. After concentration of the reaction liquid, the thus formed residue was purified by a silica gel column chromatography to obtain 0.12 g (97%) of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-{3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-fluorophenyl}-3-pyridin-3-yl-propane-1,3-dione as a yellow solid from an ethyl acetate-hexane (3:1) eluate. FA: 460
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[CH:17][CH:16]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.4 %

Procedure:
To a solution of ethyl 4-aminobenzoate (10 g) and 4-(dimethylamino)benzaldehyde (9.0 g) in methylene chloride (200 mL) is added sodium triacetoxyborohydride (18.9 g) and acetic acid (3.47 mL) under ice-cooling, and the mixture is stirred at room temperature for 2 days. To the reaction mixture is added a saturated sodium hydrogencarbonate solution and extracted with chloroform (×2). The extract is concentrated in vacuo and the residue is triturated in n-hexane/ethyl acetate to give ethyl 4-[4-(dimethylamino)benzylamino]benzoate (11.6 g, yield; 64%) as powder. MS (APCI) m/z; 299 [M+H]+
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20](/[C:23](=[CH:28]\[CH:29]=[CH:30]\[C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=1)/[C:24]([O:26][CH3:27])=[O:25])=[N+]=[N-]>C(OCC)C>[CH3:27][O:26][C:24]([C:23](=[CH:28][CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=1)[N:20]=[P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:25]
Reactant: COC(=O)/C(=C/C=C/c1ccc(C(C)C)cc1)N=[N+]=[N-]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: COC(=O)C(=CC=Cc1ccc(C(C)C)cc1)N=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Following General Procedure J, triphenylphosphine (1.4 g, 5.2 mmol), methyl (2Z,4E)-2-azido-5-(4-isopropylphenyl)penta-2,4-dienoate (Compound 111, 1.4 g, 5.2 mmol) in diethyl ether (50 ml) were reacted to produce the title compound as a yellow solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].CO.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[CH2:20][CH3:21])=[CH:15][CH:14]=1>O>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[N:2][OH:3])[CH2:20][CH3:21])=[CH:15][CH:14]=1
Reactant: CCC(=O)c1ccc(OC)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(=NO)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.7 %

Procedure:
Hydroxylamine hydrochloride (7.0 g, 100 mmol) and sodium acetate (8.2 g, 100 mmol) were added to 50 mL of methanol and the resulting white slurry was stirred at room temperature for 30 min. 1-(4-Methoxyphenyl)propan-1-one (15 g, 91.4 mmol) was added and the mixture was stirred at room temperature for 20 hours, and then refluxed for 20 hours. Water (50 mL) was added and the mixture was stirred for 10 min. The product was extracted with EtOAc and the organic layer was washed with saturated NaHCO3 solution and dried over MgSO4. The solvent was evaporated in vacuo to give 18.3 g of the title compound. MS: (+) m/z 180.39 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][CH2:8][CH2:9][C@H:10]([NH:19]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:11]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>CN(C)C=O>[C:1]([O:5][C:6](=[O:37])[NH:7][CH2:8][CH2:9][C@H:10]([NH2:19])[C:11]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)NCC[C@H](N)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
[(S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-morpholin-4-yl-4-oxobutyl]carbamic acid tert-butyl ester (172 mg, 0.338 mol) obtained in Step 1 above was dissolved in N,N-dimethylformamide (1.5 ml), and then piperidine (84 μl) was added thereto. After the solution was stirred at room temperature for 30 minutes, the solvent was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: dichloromethane:methanol=20:1) to yield ((S)-3-amino-4-morpholin-4-yl-4-oxobutyl)carbamic acid tert-butyl ester (95 mg) as a colorless oily material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:36])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:32])([CH3:31])[C:28](=[O:30])[CH3:29])=[CH:23][C:22]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1.[C:37](Cl)([Cl:39])=[O:38]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:36])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:37]([Cl:39])=[O:38])[C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:32])([CH3:31])[C:28](=[O:30])[CH3:29])=[CH:23][C:22]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)C(C)=O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C(C)=O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, 3-{4-[4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-phenyl}-3-methyl-butan-2-one was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:40])[CH2:20][NH:21][C:22](=[O:39])[NH:23][C:24]1[CH:25]=[C:26]([CH:36]=[CH:37][CH:38]=1)[C:27]([O:29]CC[Si](C)(C)C)=[O:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:9]1[C:19](=[O:40])[CH2:20][NH:21][C:22](=[O:39])[NH:23][C:24]1[CH:25]=[C:26]([CH:36]=[CH:37][CH:38]=1)[C:27]([OH:29])=[O:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCC[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 30.6 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 41, but starting from 1.3 g of 2-trimethylsilylethyl (2R,4R)-3-{3-[2-(4-tert-butoxycarbonyl-2-phenyl-3-thiazolidinyl)-2-oxoethyl]ureido}benzoate and 4.5 cm3 of a molar tetrabutylammonium fluoride solution. The crude product is purified by chromatography on silica [eluent: ethyl acetate/methanol (95/5 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. The solid residue is dissolved in 4.0 cm3 of 0.5N aqueous sodium hydroxide solution. The solution is filtered, and acidified with 2.1 cm3 of a 1N aqueous hydrochloric acid solution. The insoluble product is separated by filtration, washed with 2 times 5 cm3 of water and dried in air. 0.33 g of (2R,4R)-3-{3-[2-(4-tert-butoxycarbonyl-2-phenyl-3-thiazolidinyl)-2-oxoethyl]ureido}benzoic acid, melting at 134° C., is thus obtained. ([α]D20 =+85°±3° (C=0.40%; CHCl3)) [proton NMR (250 MHz, DMSO D6, δ in ppm), 2 rotamers at room temperature, peak coalescence at 120° C., characteristic chemical shifts at 120° C.: 7.3 to 7.7 (m, 8H, aromatic); 8.0 (bs, 1H, N--C6H4 --C in position 2). Infrared spectrum (KBr), characteristic bands in cm-1 : 3380, 2980, 2930, 2600, 1690, 1650, 1610, 1590, 1555, 1490, 1370, 1235, 1150, 760, 730, 700, 680].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[I-].C[N+]1C=CN([C:16](=[O:25])[N:17]([CH3:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)C=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:16](=[O:25])[N:17]([CH3:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6][CH:7]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: Oc1ccc(Cl)cn1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C(=O)Oc1ccc(Cl)cn1)c1ccccc1
Yield: 99 %

Procedure:
A solution of 5-chloro-2-pyridol (0.39 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70)) yielding the title compound (0.78 g, 99% yield) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:12][C:11](=[O:13])[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[N:9][N:8]=1.S(Cl)(Cl)=O.O1CC[CH2:30][CH2:29]1.[O-]CC.[Na+]>O>[CH2:29]([O:13][C:11]1[N:12]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:8]=[N:9][C:10]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=1)[CH3:30]
Reactant: C1CCOC1
Reactant: O=c1[nH]c(-c2ccccn2)nnc1-c1ccc(C(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCOc1nc(-c2ccccn2)nnc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 3-(2-pyridyl)-6-(4-trifluoromethylphenyl)-1,2,4-triazin-5-one (10.00 g, 31.4 mmol) and thionyl chloride (100 ml) was heated under reflux for two hours. The mixture was allowed to cool to room temperature, and the solvent was distilled off. To the residue were added tetrahydrofuran (100 ml) and sodium ethoxide (10.69 g, 157 mmol, 15.0 eq.), and the mixture was heated under reflux for two hours. The mixture was allowed to cool to room temperature, and water (300 ml) was added to the reaction mixture. The mixture was extracted with methylene chloride (300 ml), and washed with water (200 ml), and then washed with 5% brine (200 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting solid was purified by flash silica gel column chromatography (ethyl acetate-hexane) to give the title compound (7.57 g, 70%) as pale yellow prisms.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:15])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH2:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][CH2:14][N:5]1[CH2:4][C@@H:3]([OH:15])[CH2:2][NH:1][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC[C@H](O)CN1CCc2ccccc2C1
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1ccccc1
Yield: 18.3 %

Procedure:
A solution of (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (200 mg, 0.97 mmol), benzoic acid (122.5 mg, 1.07 mmol), HATU (387.6 mg, 1.02 mmol) and TEA (196.1 mg, 1.94 mmol) in DCM (20 mL) was stirred at room temperature for 2 h until completion of the reaction. The reaction mixture was then diluted with water and extracted with DCM (20 ml×2). The combined organic layers were dried and concentrated with the residue purified by pre-HPLC and SFC separation to give the desired compound (55 mg, Yield 18%). 1H NMR (400 MHz, MeOD): 7.66 (d, J=8.0 Hz, 2H), 7.36-7.34 (m, 1H), 7.26 (d, J=7.6 Hz, 2H), 6.99-6.89 (m, 4H), 4.01-3.96 (m, 1H), 3.61 (s, 2H), 3.43-3.37 (m, 2H), 2.77-2.72 (m, 4H), 2.56-2.53 (m, 2H). LCMS (m/z): 311.1 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH2:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][NH:14][C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[C:18]([N:29]3[C:33](=[O:34])[CH:32]=[CH:31][C:30]3=[O:35])=[CH:17][N:16]=2)[CH:8]=[CH:7][C:6]=1[N+:36]([O-:38])=[O:37]>>[NH2:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][NH:14][C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[C:18]([N:29]3[C:33](=[O:34])[CH2:32][CH:31]([N:2]([CH3:3])[CH3:1])[C:30]3=[O:35])=[CH:17][N:16]=2)[CH:8]=[CH:7][C:6]=1[N+:36]([O-:38])=[O:37]
Reactant: CNC
Reactant: Nc1nc(NCCNc2ncc(N3C(=O)C=CC3=O)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Product: CN(C)C1CC(=O)N(c2cnc(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc2-c2ccc(Cl)cc2Cl)C1=O

Procedure:
A large excess of dimethylamine was added to clean fractions of 1-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)4-(2,4-dichlorophenyl)pyrimidin-5-yl]-3-pyrroline-2,5-dione concentrated in vacuo.
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([C:9]#[N:10])=O.C(=O)(O)O.[NH2:20][NH:21][C:22]([NH2:24])=[NH:23]>O>[C:22]([NH:21][N:20]=[C:7]([C:9]#[N:10])[C:6]1[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:5]=1[Cl:4])(=[NH:23])[NH2:24]
Reactant: N=C(N)NN
Reactant: N#CC(=O)c1cccc(Cl)c1Cl
Agent: O=C(O)O
Solvent: O
Solvent: CC#N
Product: N#CC(=NNC(=N)N)c1cccc(Cl)c1Cl
Reaction time: 0.5 h

Procedure:
Reactor (0.5 L) was charged under nitrogen with acetonitrile (200 ml) and polyphosphoric acid (220 g), and the mixture was stirred for 0.5 hour to obtain an emulsion. Solid 2,3-dichlorobenzoyl cyanide (41 g, 0.2 mole; assay 97.5%) was added to the emulsion. Aminoguanidine bicarbonate (41 g, 0.3 mole; assay 99.0%) was added to the mixture in 5 equal portions during 2 hours at 30-40° C. The reaction mixture was stirred at 50° C. during 22 hours. Water (40 ml) was then added to the reaction mixture to obtain a clear homogeneous mixture. The mixture was dropped to water at slow stirring for 0.5 hour, and the precipitate was collected by filtration to give wet phosphate salt of 2,3-dichlorobenzoyl cyanide amidinohydrazone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[S:30][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:28][C:27]=1[CH3:37])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:38](P(=O)(OCC)OCC)[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42].CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[S:30][C:29]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[N:28][C:27]=1[CH3:37])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:38]/[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1sc(-c2ccccc2)nc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2sc(-c3ccccc3)nc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 59.4 %

Procedure:
To a mixture of 3-({3-methoxy-4-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.60 g), tetraethyl methylenediphosphonate (0.37 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.060 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({3-methoxy-4-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.45 g, yield 58%) from a fraction eluted with ethyl acetate-hexane (5:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 113-114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:21])[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:5]=[CH:6][CH:7]=1.C[O:23][C:24](=[O:47])[C@H:25]([C@@H:44]([CH3:46])O)[NH:26]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([O:21][C@H:44]([CH3:46])[C@@H:25]([C:24]([OH:47])=[O:23])[NH2:26])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]3[C:20]2=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Reactant: OC1(c2cccc(Cl)c2)c2ccccc2-c2ccccc21
Product: C[C@@H](OC1(c2cccc(Cl)c2)c2ccccc2-c2ccccc21)[C@H](N)C(=O)O

Procedure:
from 9-(3-chlorophenyl)-9H-fluoren-9-ol (Example 3e) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[S:36](Cl)(=[O:38])=[O:37])[CH:29]=[CH:28][CH:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:36]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:35]=4[N:26]=[CH:27][CH:28]=[CH:29]5)(=[O:37])=[O:38])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc5cccnc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and quinoline-8-sulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=23)=[O:11])[C:6]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])=[N:5]1.C(N(CC)C(C)C)(C)C.[CH:39]1([C:42](Cl)=[O:43])[CH2:41][CH2:40]1>ClCCl>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH3:29])=[C:21]([C:6]2[C:7]([NH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[N:17][C:16]=34)=[O:11])=[CH:8][N:4]([CH2:3][CH2:2][NH:1][C:42]([CH:39]3[CH2:41][CH2:40]3)=[O:43])[N:5]=2)[CH:26]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(Cl)cc1-c1nn(CCN)cc1NC(=O)c1cnn2cccnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cl)cc1-c1nn(CCNC(=O)C2CC2)cc1NC(=O)c1cnn2cccnc12
Reaction time: 1 h
Yield: 47.1 %

Procedure:
To a solution of N-(1-(2-aminoethyl)-3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.030 g, 0.073 mmol, 1 equiv) and N,N-diisopropylethylamine (51 μL, 0.29 mmol, 4.0 equiv) in dichloromethane (1 mL) was added dropwise cyclopropanecarbonyl chloride (0.020 mL, 0.22 mmol, 3.0 equiv) at 24° C. After 1 h, the reaction mixture was concentrated in vacuo. Purification by preparative HPLC provided product (16.5 mg, 47% yield). 1H NMR (400 MHz, DMSO-d6), δ: 9.69 (s, 1H), 9.33 (dd, J=7.0, 1.6 Hz, 1H), 8.78 (dd, J=4.1, 1.5 Hz, 1H), 8.66 (s, 1H), 8.28 (s, 1H), 8.22 (t, J=5.5 Hz, 1H), 7.50 (dd, J=8.8, 2.8 Hz, 1H), 7.44 (d, J=2.7 Hz, 1H), 7.27-7.31 (m, 2H), 4.22 (t, J=6.1 Hz, 2H), 3.85 (s, 3H), 3.52 (q, J=6.0 Hz, 2H), 1.55 (m, 1H), 0.62-0.71 (m, 4H). LCMS (ESI): M+H=480.2.