Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2]Br.[CH:4]1([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:16]=3)=[C:13]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:12]=[CH:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>C(O)C>[CH2:23]([N:22]1[C:17]2[CH:16]=[C:15]([C:14]3[N:10]([CH:4]4[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]4)[CH:11]=[N:12][C:13]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:20]=[CH:19][C:18]=2[N:21]=[C:2]1[NH2:1])[CH:24]([CH3:26])[CH3:25]
Reactant: N#CBr
Reactant: CC(C)CNc1cc(-c2c(-c3ccccc3)ncn2C2CCCCC2)ccc1N
Solvent: CCO
Product: CC(C)Cn1c(N)nc2ccc(-c3c(-c4ccccc4)ncn3C3CCCCC3)cc21
Temperature: 25 °C
Yield: 52 %

Procedure:
Add cyanogen bromide (101 mg, 0.96 mmol) to a solution of 1-(cyclohexyl)-4-phenyl-5-(3-(isobutylamino)-4-aminophenyl)-1H-imidazole (250 mg, 0.64 mmol) in 6 mL ethanol. Stir over night at room temperature. Add saturated aqueous sodium carbonate and extract well with 9:1 ethyl acetate:methanol. Combine the organic phases, dry over magnesium sulfate, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with a gradient of 5-8% methanol in dichloromethane to provide the title compound (52%).
Reaction SMILES: CN(C)[CH:3]=[C:4]([N:9]=[CH:10]N(C)C)[C:5]([O:7][CH3:8])=[O:6].[CH3:15][N:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1>C(O)(=O)C.C(O)(C(F)(F)F)=O>[CH3:15][N:16]1[C:20]2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[N:9]=[CH:10][C:19]=2[CH:18]=[CH:17]1
Reactant: Cn1cccc1
Reactant: COC(=O)C(=CN(C)C)N=CN(C)C
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2c(ccn2C)cn1
Temperature: 110 °C
Reaction time: 4 h
Yield: 37.6 %

Procedure:
In a 500 ml round bottom flask, methyl 3-(dimethylamino)-2-((dimethylamino)methyleneamino)acrylate (1A, 24 g, 120 mmol) was dissolved in acetic acid (60 ml) and TFA (20 ml). 1-Methyl-1H-pyrrole (10.56 ml, 119 mmol) was added. The mixture was stirred at room temperature for an hour and at 110° C. for 4 hours until completion of the reaction. Volatiles were then evaporated from the reaction mixture, the residue was cooled in an ice bath. Ice cold saturated K2CO3 solution (˜200 ml) was slowly added to it. The mixture was extracted with EtOAc (3×250 ml). Combined organic layers were then washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified on silica column using hexane-EtOAc (0-100%). Desired product methyl 1-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (1B, 8.5 g, 38%) was obtained as a thick brown oil.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.N1CCCCC1.[CH:15](=O)/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[C:18]1([CH:17]=[CH:16][CH:15]=[C:2]2[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]2=[O:8])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: O=C1CCCC(=O)C1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1CCCC(=O)C1=CC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 11.2 g (0.1 mol) of 1,3-cyclohexanedione in 110 mL of ethanol was stirred at room temperature while 1 mL of piperidine was added followed by the dropwise addition of 13 mL (0.103 mol) of trans-cinnamaldehyde over a 2 min period. The resulting mixture was stirred at room temperature for 2 hr and then in an ice-bath for 1 hr. The resulting yellow slurry was filtered with suction and the solid dried under high vacuum giving 13.9 g (61.5%) of the title dione. Recrystallization of a sample of this material from ethyl acetate gave yellow solid, mp 115.5°-118° C.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:44]1[CH:53]=[C:52]2[C:47]([C:48]([C:55]3[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][C:56]=3[O:65][CH3:66])=[N:49][C:50]([CH3:54])=[N:51]2)=[CH:46][CH:45]=1.CCN(C(C)C)C(C)C.[CH2:76]([SH:83])[C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:76]([S:83][C:44]1[CH:53]=[C:52]2[C:47]([C:48]([C:55]3[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][C:56]=3[O:65][CH3:66])=[N:49][C:50]([CH3:54])=[N:51]2)=[CH:46][CH:45]=1)[C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1
Reactant: COc1cc(C(F)(F)F)ccc1-c1nc(C)nc2cc(Br)ccc12
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(F)(F)F)ccc1-c1nc(C)nc2cc(SCc3ccccc3)ccc12
Reaction time: 1 h

Procedure:
A solution of Pd2(dba)3 (0.046 g, 0.050 mmol), Xantphos (0.058 g, 0.100 mmol), 7-bromo-4-(2-methoxy-4-(trifluoromethyl)phenyl)-2-methylquinazoline (0.797 g, 2.007 mmol), and n,n-diisopropylethylamine (1.051 ml, 6.02 mmol) in 10 mL dioxane was heated to 60° C. and was treated with benzyl mercaptan (0.237 ml, 2.007 mmol). After stirring for one hour, LC/MS showed mostly product, so the reaction mixture was concentrated. This material was carried on to step 3 without purification. (M+H)+=441.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17](=[O:19])[CH3:18])=[C:11]([N+:20]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>C1(C)C=CC=CC=1.O.CCOC(C)=O.[Fe]>[NH2:20][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([O:15][CH3:16])=[CH:13][C:12]=1[C:17](=[O:19])[CH3:18]
Reactant: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1
Temperature: 103 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A suspension of 1-(4-Benzyloxy-5-methoxy-2-nitrophenyl)ethanone (36.00 g, 120 mmol), iron powder (26.80 g, 480 mmol) and HCOONH4 (31.53 g, 500 mmol) in a mixture of toluene/water (500 mL/500 mL) was stirred at 103° C. overnight. The mixture was cooled to room temperature, diluted with EtOAc (500 mL), stirred at room temperature for 3 hours, and filtered through a celite pad. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (32.1 g, 99%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:44](Cl)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:44]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:18][CH2:19]1)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Reactant: O=C(Cl)c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)n1nc(C(=O)NCCN2CCC(NC(=O)c3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) and triethylamine (0.15 mL, 1.05 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added dropwise benzoyl chloride (0.116 mL, 1 mmol) and the resulting mixture was stirred 18 h at room temperature and filtered and the filtrate was evaporated to 0.498 g oil. Crystallization as the oxalate salt from ethyl acetate/methanol provided 0.265 g colorless crystals. Mp 130° C. Mass spectrum, m+ =433. Anal (C27H33N5O6) theory C, 61.94; H, 6.35; N, 13.38; found C, 61.73; H, 6.35; N, 13.33.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:13][OH:14]>N1C=CC=CC=1>[C:1]([O:14][CH2:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])(=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCOC(=O)CO
Solvent: c1ccncc1
Product: CCOC(=O)COC(=O)CCc1ccccc1

Procedure:
33.7 g (0.2 mole) of hydrocinnamoyl chloride was added to a stirred solution of 18 g (0.2 mole) of ethyl glycolate in 20 ml of pyridine. The precipitated pyridine hydrochloride was filtered, washed with benzene, and discarded. The benzene solution of carboethoxymethyl hydrocinnamate was water washed, dried over sodium sulfate, and the solvent stripped off using a rotary evaporator. The yield of product was essentially quantitative. Its structure was established by infrared and nuclear magnetic resonance spectroscopy. It had n30D 1.4900 and d304 1.0919.
Reaction SMILES: CI.[C:3]([O-:6])([O-])=O.[K+].[K+].[Br:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13](O)=[C:12]([Cl:18])[CH:11]=1.C(OCC)(=O)C>CN(C=O)C>[Br:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:6][CH3:3])=[C:12]([Cl:18])[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1c(Cl)cc(Br)cc1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(Cl)cc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 73.9 %

Procedure:
Methyl iodide (467 μL, 8.12 mmol) and K2CO3 (2.24 g, 16.24 mmol) were added to a solution of 4-bromo-2,6-dichlorophenol (982 mg, 4.06 mmol) in DMF (10 mL) and stirred at rt under Ar for 40 min. Upon completion, ethyl acetate was added and the reaction was washed with 1% HCl (2×20 mL), brine (1×), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (hexane) to afford 4-bromo-2,6-dichloroanisole (768 mg, 74%) as a white solid. See, for example, Li, J.; et al. J. Med. Chem. 1996, 39, 1846–1856, which is incorporated by reference in its entirety. 1H NMR (DMSO-d6, 400 MHz) δ 7.75 (s, 2H), 3.81 (s, 3H). 13C NMR (DMSO-d6, 100 MHz) δ 151.3, 131.5, 129.6, 116.5, 60.6. HREIMS calculated for C7H5BrCl2O (M+) 253.8905, found 253.8901.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[C:31]1([S:37][CH:38]([C:42](O)=[O:43])[C:39](O)=[O:40])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:11][C:39](=[O:40])[C:38]([S:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:42]([OH:43])[CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)c1cc(C)cc(C)c1
Reactant: O=C(O)C(Sc1ccccc1)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2cc(O)c(Sc3ccccc3)c(=O)o2)c1

Procedure:
The title compound was prepared by Method A using 3',5'-dimethylacetophenone (1.43 g, 9.70 mmol), trimethylsilyl triflate (2.24 mL, 11.64 mmol), triethylamine (2.70 mL, 19.40 mmol), methylene chloride (24 mL), and diethyl ester of (phenylthio)-propanedioic acid (1.00 g, 7.46 mmol). m.p. 210°-211° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.35 (s, 6H), 6.83 (s, 1H), 7.12 (m, 3H), 7.21 (s, 1H), 7.27 (t, 2H), 7.46 (s, 2H).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:13][CH2:12]2)[CH:3]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:42]>>[Cl:42][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH:11]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:13][CH2:12]2)[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)C1CCC(c2cc(O)n3nccc3n2)CN1C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C1CCC(c2cc(Cl)n3nccc3n2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Di-tert-butyl 5-(7-hydroxypyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1,2-dicarboxylate (16.7 mmol, 7.0 g), N,N′-diisopropylethylamine (51.9 mmol, 9.0 ml) and POCl3 (80 mL) were mixed and stirred at room temperature for 18 hours. The solution is concentrated in vacuo and cooled to 0° C. in an ice bath. The reaction is then quenched with sat. NaHCO3(aq) and extracted with DCM (100 mL×3). The combined organics are dried with Na2SO4 and the solvent removed in vacuo. LC-MS: 437 [M+H]. The resulting oil was used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH-].[Na+:9].C(O)(=[O:13])C=C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].OO.[Na]>>[C:1]([O-:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:13])=[O:5].[Na+:9].[Na+:9]
Reactant: O=C1C=CC(=O)O1
Reactant: C=CC(=O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: OO
Agent: [NH4+]
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
An aqueous sodium maleate solution was prepared by neutralizing maleic anhydride with an aqueous sodium hydroxide solution in a four-necked flask. The aqueous solution polymerization of the solution and an aqueous acrylic acid solution was effected in the presence of ammonium persulfate and hydrogen peroxide at 100° C. for 5 h. The resulting product was neutralized with an aqueous sodium hydroxide solution to obtain a dyeability-improving agent comprising sodium salt of the copolymer.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C>C(OC(=O)C)C.C(O)C>[CH3:12][O:5][C:4](=[O:6])[C:3]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: Nc1cccc(F)c1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1c(N)cccc1F
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Dissolve 2-Amino-6-fluoro-benzoic acid (3.00 g, 19.3 mmol) in ethylacetate (59 mL) and ethanol (59 mL) and add (trimethylsilyl) diazomethane (19.3 mL, 38.68 mmol, 2M in hexane) at room temperature and stir the solution for 1 h 30 min. Remove the solvent under reduced pressure to afford the title compound (3.26 g, quantitative). MS (ES+): 170 (M+H).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36])[CH2:4][NH:5][C:6](=[O:28])[CH2:7][N:8]1[C:12](=[O:13])[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:10]([C:22]2[S:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[N:9]1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>>[Cl:27][C:24]1[S:23][C:22]([C:10]2[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:12](=[O:13])[N:8]([CH2:7][C:6]([NH:5][CH2:4][CH:3]([NH:2][S:40]([CH3:39])(=[O:42])=[O:41])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]([F:36])([F:37])[F:38])=[O:28])[N:9]=2)=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC(CNC(=O)Cn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O)c1ccccc1C(F)(F)F
Agent: Cl
Product: CS(=O)(=O)NC(CNC(=O)Cn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O)c1ccccc1C(F)(F)F

Procedure:
Analogously to the procedure of Example 68, 35 mg (52 μmol) of the compound of Example 61A were reacted with methanesulphonyl chloride. This gave 14 mg (41% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15].[C@@H]1(N)CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[C:4]([F:9])[CH:3]=1
Reactant: Fc1cc(Cl)ccc1I
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1CCCN1c1ccc(Cl)cc1F
Yield: 108.4 %

Procedure:
A 100 mL sealed tube was charged with 4-chloro-2-fluoro-1-iodobenzene (0.498 ml, 3.90 mmol), pyrrolidin-2-one (0.598 ml, 7.80 mmol), (1R,2R)-cyclohexane-1,2-diamine (0.0703 ml, 0.585 mmol), potassium phosphate (1.66 g, 7.80 mmol), copper (1) iodide (0.0223 g, 0.117 mmol), and 1,4-dioxane (4.00 ml, 46.8 mmol), then flushed with argon, sealed, and placed in a 110° C. oil bath for 17 hours. The reaction mixture was filtered through a pad of silica gel, eluting with EtOAc and DCM, then the filtrate was concentrated to yield a brown oil This was purified by column chromatography using a 40 g ISCO column, eluting with a gradient of 3-5% MeOH/DCM over 30 minutes to give 1-(4-chloro-2-fluorophenyl)pyrrolidin-2-one (0.903 g, 108% yield) as a yellow solid.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:5]=1.[CH3:15][C:16]1[CH:17]=[C:18]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:29]=[C:28]([C:36](O)=O)[N:27]=2)[CH:19]=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23]>>[CH3:15][C:16]1[CH:17]=[C:18]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[N:29]=[C:28]([C:36]3[O:1][N:2]=[C:3]([C:4]4[CH:5]=[C:6]([S:10]([NH2:11])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=4)[N:14]=3)[N:27]=2)[CH:19]=[CH:20][C:21]=1[C:22]([F:23])([F:24])[F:25]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(C(=O)O)n2)ccc1C(F)(F)F
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3nc(-c4cccc(S(N)(=O)=O)c4)no3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (0.14 g, 0.65 mmol) and 4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.9) (0.175 g, 0.5 mmol) according to the general procedure V. Obtained as a white solid (0.15 g, 57%). MS (ISN) 528.3 [(M−H)−]; mp 223.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[C:5]([C:8](OC)=[O:9])=[N:6][CH:7]=1.Cl.[CH3:27][O:28][NH2:29].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C(=O)([O-])O.[Na+]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[C:5]([C:8]([NH:29][O:28][CH3:27])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1ncc(Cl)nc1Nc1ccc(N2CCN(C)CC2)cc1
Reactant: CON
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CONC(=O)c1ncc(Cl)nc1Nc1ccc(N2CCN(C)CC2)cc1
Reaction time: 0.33 h
Yield: 100.8 %

Procedure:
To a solution of a mixture of methyl 5-chloro-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxylate (Preparation Example 193) (20 mg) and THF (2 mL), O-methylhydroxylamine hydrochloride (14 mg) was added. To the reaction liquid, lithium hexamethyldisilazide (0.39 mL, 1M THF solution) was added under ice cooling and stirred for 20 minutes. The reaction liquid was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate, and then the organic layer was washed with saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 5-chloro-N-methoxy-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (21 mg) as a yellow powder.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+].[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][C@@H:24]1[CH2:46][CH2:45][C@@:44]2([CH3:47])[C@H:26]([CH2:27][CH2:28][C@@H:29]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:48])[C@H:30]3[CH2:31][CH2:32][C@@H:33]2[C@H:34]([CH3:39])[CH2:35][CH2:36][CH2:37][OH:38])[CH2:25]1>ClCCl>[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][C@@H:24]1[CH2:46][CH2:45][C@@:44]2([CH3:47])[C@H:26]([CH2:27][CH2:28][C@@H:29]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:48])[C@H:30]3[CH2:31][CH2:32][C@@H:33]2[C@H:34]([CH3:39])[CH2:35][CH2:36][CH:37]=[O:38])[CH2:25]1
Reactant: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](CCC=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 80.5 %

Procedure:
A suspension comprising a mixture of 221 mg of pyridinium chlorochromate (C5H5N+HCrO3Cl-) and 8.3 mg of sodium acetate in 1 ml of dichloromethane was prepared. To the suspension, a solution of 221 mg of 3α-(2-tetrahydropyranyloxy)-24-hydroxy-5β-cholane in 4 ml of dichloromethane was added at one time in an argon stream under stirring. After stirring for 3 hours, the supernatant of the reaction mixture was separated by decantation, and the precipitate was washed with dichloromethane three times. The supernatant was combined with the washings, passed through a short column with silica gel (4 g). The eluate with dichloromethane was concentrated under vacuum. 3α-(2-Tetrahydropyranyloxy)-24-oxo-5β-cholane (177 mg) was obtained as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])=[O:22])[C:16]=1[CH3:32].Cl.C(N=C=NCCCN(C)C)C.O[C:46]1[C:54]2[N:53]=N[NH:51][C:50]=2[CH:49]=[CH:48][CH:47]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:51][C:50]2[CH:49]=[CH:48][CH:47]=[CH:46][C:54]=2[NH2:53])=[O:30])=[O:22])[C:16]=1[CH3:32]
Reactant: Oc1cccc2[nH]nnc12
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCC(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.9 %

Procedure:
6-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-hexanoic acid (441 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (430 mg, 81% yield) as a red solid. 1H NMR (DMSO-d6)δ1.38 (m, 2H, CH2), 1.54 (m, 2H, CH2), 1.62 (m, 2H, CH2), 2.30 (s, 3H, pyrrole-CH3), 2.32 (t, J=8.0 Hz, 2H, CH2CO), 2.41 (s, 3H, pyrrole-CH3), 3.22 (m, 2H, NCH2), 4.82 (s, 2H, benzene-NH2), 6.51 (t, J=8.0 Hz, 1H, Ar—H), 6.69 (d, J=8.0 Hz, 1H, Ar—H), 6.87 (m, 2H, Ar—H), 7.14 (d, J=8.0 Hz, 1H, Ar—H), 7.20 (m, 1H, Ar—H), 7.65 (t, J=4.0 Hz, 1H, CONH), 8.33 (dd, J=4.0 and 8.0 Hz, 1H, Ar—H), 8.63 (s, 1H, vinyl-H), 9.11 (s, 1H, benzene-NH), 10.73 (s, 1H, indolinone-NH), 11.82 (s, 1H, pyrrole-NH). LC-MS (m/z) 532 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClCCl.[OH-].[Na+].[CH3:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[NH2:1][C:2]1[C:7]([O:8][CH2:14][C:15]2[CH:22]=[CH:21][C:18]([CH3:19])=[CH:17][CH:16]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: Nc1ncccc1O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(COc2cccnc2N)cc1
Reaction time: 16 h

Procedure:
A mixture of 2-amino-3-hydroxypyridine (2.7 g, 0.024 mol), dichloromethane (40 ml) and 40% aqueous sodium hydroxide solution (40 ml) was stirred for 5 rains, then 4methylbenzyl bromide (4.51 g, 0.024 mol) and Adogen 464 (3 ml) were added and stirring was continued for 16 hours. The mixture was diluted with water and extracted with dichloromethane (×2), and the combined organic layers dried, evaporated, and triturated with ether. Yield 2.92 g (56%), m.p. 123° 125 ° C.