Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N1CCC(N)CC1)=O)(C)(C)C.[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]([C:42]#[N:43])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-:44].[K+].[OH2:46]>>[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]([C:42]#[N:43])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]([C:42]([OH:46])=[O:44])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O
Reactant: [OH-]
Agent: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: N#Cc1ccc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)c2ccccc12
Agent: [K+]
Product: O=C(O)c1ccc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)c2ccccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4-Cyano-naphthalene-1-sulfonic acid (1-benzyl-piperidin-4-yl)-amide (33) was prepared according to the general procedure in Scheme 11, substituting 1-benzyl-piperidin-4-ylamine piperidin-4-ylamine for 4-amino-piperidine-1-carboxylic acid tert-butyl ester. To a solution of 4-cyano-naphthalene-1-sulfonic acid (1-benzyl-piperidin-4-yl)-amide 33 (3.0 g, 7.43 mmol) in H2O (70 mL) was added KOH (4.2 g, 75 mmol). After stirring at 100° C. overnight, the resultant mixture became a clear solution. The aqueous layer was washed with CH2Cl2 twice and acidified to pH 4 by adding hydrochloric acid. After filtration, the resultant solid was dried to give 1.8 g of crude 4-(1-benzyl-piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid 34 in 57% yield. LCMS showed m/z: 425 (M+H)+. This material was used without further purification.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[C:14]([CH2:15]O)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].O=S(Cl)[Cl:19]>C(Cl)Cl>[ClH:19].[Cl:19][CH2:15][C:14]1[C:9]([C:8]2[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][CH:7]=2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)n1nccc1-c1ncccc1CO
Solvent: ClCCl
Product: CC(C)n1nccc1-c1ncccc1CCl
Product: Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol) (440 mg, 2.02 mmol) in DCM (4 mL) was added SOCl2 (2 eq) at 0° C. The reaction mixture was stirred at RT for 15 mins and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (432 mg) as an off-white solid, which was used for next step without further purification. MS (ESI) m/z 236.5 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3]1.[NH:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1>C(O)(=O)CC>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:13]3[NH:9][C:10]([C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[C:10]4[N:9]=[C:13]([C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)=[C:10]5[NH:9][C:13](=[C:7]([C:5]6[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=6)[C:10]6[CH:11]=[CH:12][C:13]=2[N:9]=6)[CH:12]=[CH:11]5)[CH:12]=[CH:11]4)=[CH:11][CH:12]=3)[CH:4]=[N:3]1
Reactant: Cn1cc(C=O)cn1
Reactant: c1cc[nH]c1
Solvent: CCC(=O)O
Product: Cn1cc(-c2c3nc(c(-c4cnn(C)c4)c4ccc([nH]4)c(-c4cnn(C)c4)c4nc(c(-c5cnn(C)c5)c5ccc2[nH]5)C=C4)C=C3)cn1
Reaction time: 8 h
Yield: 17.6 %

Procedure:
To a refluxing solution of propionic acid (200 mL) and 1-methylpyrazole-4-carboxaldehyde (48, 0.92 g, 8.32 mmol), prepared according to literature procedure (Finar, I. L.; Lord, G. H. J. Chem. Soc. 1957, 3314-3315), was added pyrrole (0.63 mL, 8.32 mmol). The reaction was covered with foil and was heated under reflux for 3.5 h. Upon cooling the reaction mixture was exposed to air overnight. The propionic acid was then removed by vacuum distillation. The crude residue was dissolved in 5% MeOH/CH2Cl2, then adsorbed onto silica gel (5.3 g). Purification by column chromatography (5% MeOH/CH2Cl2) provided porphyrin 49 as a purple solid (231 mg, 17.5%): 1H NMR (300 MHz, DMSO-d6) δ −2.74 (s, 2 H), 4.28 (s, 12 H), 8.31 (s, 4 H), 8.67 (s, 4 H), 9.16 (s, 8 H).
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11].C(O)(=O)C.[F:16][C:17]([F:25])([F:24])[C:18](=O)[CH2:19][C:20](=O)[CH3:21]>COCCO>[CH3:21][C:20]1[N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[OH:3])[N:11]=[C:18]([C:17]([F:25])([F:24])[F:16])[CH:19]=1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: COc1ccccc1NN
Agent: Cl
Solvent: COCCO
Solvent: CC(=O)O
Product: Cc1cc(C(F)(F)F)nn1-c1ccccc1O

Procedure:
300 mg of 2-methoxyphenyl hydrazine hydrochloride was dissolved in 1.3 ml of 2-methoxyethanol, and 2.5 ml of acetic acid and 208 μl of 1,1,1-trifluoro-2,4-pentanedione were added and heated at reflux for 1 hour and 40 minutes. The solvent was distilled off under reduced pressure, and 50 ml of ethyl acetate was added, and the organic layer was washed with 50 ml of a saturated sodium bicarbonate solution and 50 ml of saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to yield 485.6 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:18]=3[N:19]=2)=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl>>[NH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([S:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][C:18]=3[N:19]=2)=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])cc(Cl)c1Sc1nc2cc(C(F)(F)F)ccc2s1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: CC(=O)c1cc(N)cc(Cl)c1Sc1nc2cc(C(F)(F)F)ccc2s1
Yield: 112.2 %

Procedure:
The title compound was prepared using the method of example 270, starting with 1-[3-chloro-5-nitro-2-(5-trifluoromethyl-benzothiazol-2-ylsulfanyl)-phenyl]-ethanone (259) (750 mg, 1,67 mmol), tin chloride dihydrate (Aldrich, 1.89 g, 8.37 mmol). Compound 271 (755 mg, 100%) was obtained as a yellowish solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15]>CCOCC>[CH3:1][N:2]1[C:6]([C:21](=[O:22])[C:20]2[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:25][CH:24]=2)=[C:5]([CH3:7])[CH:4]=[C:3]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)Cc1cc(C)cn1C
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCOCC
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc([N+](=O)[O-])cc2)n1C
Yield: 84.8 %

Procedure:
A solution of 7.24 g (0.04 mole) of ethyl 1,4-dimethylpyrrole-2-acetate and 11.1 g (0.06 mole) of p-nitrobenzoyl chloride in 30 ml of ether under argon is stirred at room temperature in the dark for two days. The precipitate is collected by filtration. Recrystallization from isopropanol gives 11.2 g (85% yield) of ethyl 1,4-dimethyl-5-(p-nitrobenzoyl)pyrrole-2-acetate as yellow crystals, m.p. 148°-149° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[C-:12]#[N:13].[K+].Cl>C(O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][C:12]#[N:13])=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.9 %

Procedure:
To a stirred suspension of 2.5 g (11.5 mmol) 2-bromo-1-(4-fluoro-phenyl)-ethanone (the preparation of which is described in example . . . ) in 40 ml ethanol was added a solution of 0.90 g (23 mmol) potassium cyanide in 9 ml water. The mixture was then stirred at RT for 2 h, then acidified to ph=5-6 with aqueous HCl 1M and then extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 6:1) afforded 0.11 g (6%) 3-(4-fluoro-phenyl)-3-oxo-propionitrile as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1.Cl.Cl.[F:13][C:14]([F:34])([F:33])[C:15]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1)([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([S:7]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:15]([OH:20])([C:14]([F:13])([F:34])[F:33])[C:16]([F:19])([F:17])[F:18])=[CH:26][CH:25]=3)[CH2:28][CH2:29]2)(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1cscc1Br
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1cscc1Br)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
To a 20 mL vial containing 4-bromothiophene-3-sulfonyl chloride (0.20 g, 0.77 mmol, ASDI, Newark, Del.) was added a solution of 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-yl)phenyl)-2-propanol dihydrochloride (0.31 g, 0.77 mmol, Example 91) and triethylamine (0.53 mL, 3.8 mmol) in CH2Cl2 (7 mL). The solution was stirred at room temperature for 16 h. To the vial was added saturated aqueous sodium bicarbonate (4 mL) and the solution was stirred for 15 min. The solution was transferred onto a phase separation cartridge (Radleys Discovery Technologies, Essex, UK) with the organic phase being collected and passed through a plug of Na2SO4. The resulting solution was concentrated and purified by Prep-HPLC (Instrumentation: MS—Waters SQ; UV—Waters 2487 or Waters PD, Waters, Milford, Mass. Solvents: A: Water w/0.1% NH4OH B: Acetonitrile w/0.1% NH4OH. Column: Phenomenex Gemini-NX C18 110 Å 5 μm 21×100. Flow Rate: 44 mL/min. 10 min Method, variable gradient over 8 min. Mass spectral data were acquired from 100-850 amu in electrospray positive mode) to afford 2-(4-(4-(4-bromothiophen-3-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (81 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.43 (br s, 1H), 8.08 (d, J=5.1 Hz, 1H), 7.47 (d, J=9.0 Hz, 2H), 7.37 (d, J=5.1 Hz, 1H), 7.02 (d, J=9.0 Hz, 2H), 3.31-3.35 (m, 4H), 3.26-3.29 (m, 4H). m/z (ESI, +ve ion) 552.8 (M+H)+. GK-GKRP IC50 (Binding)=0.816 μM.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]=O)[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8].[C:38](=O)([O-])[O-].[K+].[K+].CC(C)C(=O)C(P(=O)([O-])[O-])=[N+]=[N-]>CO.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[CH:38])[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(C=O)c2)c1F
Agent: CC(C)C(=O)C(=[N+]=[N-])P(=O)([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-cyano-5-formylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (90 mg, 0.160 mmol) and potassium carbonate (66.2 mg, 0.479 mmol) in Methanol (5 ml) was added dimethyl-1-diazo-2-oxopropylphosphonate (46.0 mg, 0.240 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethynylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (48 mg, 0.086 mmol, 54% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.87 (s, 1H), 7.54 (s, 1H), 7.31-7.45 (m, 2H), 7.25 (s, 1H), 7.20 (s, 1H), 5.57 (s, 3H), 4.59 (s, 2H), 3.75 (s, 1H), 3.47 (t, 2H), 0.80 (t, 2H), −0.07 (s, 9H).
Reaction SMILES: C([C:8]([NH2:12])([OH:11])[CH2:9][CH3:10])(OC(C)(C)C)=O.[OH:13][C:14]([CH:16]([C:18]1[CH:27]=[CH:26][C:21]([CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:20][CH:19]=1)[CH3:17])=[O:15].[ClH:28].C(OCC)(=O)C.C(OCC)C>ClCCl>[NH2:12][CH:8]([OH:11])[CH2:9][CH3:10].[ClH:28].[OH:15][C:14]([CH:16]([C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]([CH3:24])[CH3:25])=[CH:26][CH:27]=1)[CH3:17])=[O:13]
Reactant: CCC(N)(O)C(=O)OC(C)(C)C
Agent: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCC(N)O
Temperature: 25 °C

Procedure:
In 1 ml of dichloromethane, 636 mg (1.75 mmol) of the Boc-aminopropanol-ibuprofen obtained above was dissolved, and 4 ml of 4 M hydrochloric acid/ethyl acetate was added thereto under ice-cooling, followed by stirring under ice-cooling for 10 minutes and at room temperature for 3 hours. After confirming disappearance of Boc-aminopropanol-ibuprofen by TLC, diethyl ether was added thereto, followed by decantation three times. Thereafter, the residue was dried under reduced pressure to give the titled substance at a yield of 406 mg (77%). The structure was identified by 1H-NMR (CDCl3).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([N:25]=[C:26]=[S:27])[CH3:24]>>[CH2:23]([NH:25][C:26]([NH:19][NH:18][C:16](=[S:17])[NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[S:27])[CH3:24]
Reactant: CCN=C=S
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Product: CCNC(=S)NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1

Procedure:
The above compound is prepared by a method analogous to that of Example 5 from N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-hydrazine carbothioamide and ethylisothiocyanate. The analytical values are summarized in Table I.
Reaction SMILES: [CH2:1]1[CH:7](O)[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[OH:16][NH:17][C:18]([NH2:20])=[O:19].ClC(Cl)(Cl)C(O)=O>O>[OH:16][N:17]([CH:7]1[CH2:1][CH2:2][O:3][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[NH:6]1)[C:18]([NH2:20])=[O:19]
Reactant: NC(=O)NO
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: O
Product: NC(=O)N(O)C1CCOP(=O)(N(CCCl)CCCl)N1
Reaction time: 20 h

Procedure:
16 g (58 mmol) of 4-hydroxycyclophosphamide and 5.2 g (68 mmol) of hydroxyurea were dissolved in 160 ml of water, acidified with trichloracetic acid (pH 3-4) and left to stand for 20 hours at 0° C. in a refrigerator. The crystal sludge was then drawn off by suction, washed with water, dried over P2O5 under high vacuum and recrystallized from methanol/chloroform.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][N:7]=1.[C:9]([O-])([O-])=O.[K+].[K+].CI>C(#N)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH3:9])[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1ccc(Cl)n[nH]1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CI
Product: Cn1nc(Cl)ccc1=O
Temperature: 25 °C

Procedure:
To a solution 6-chloropyridazin-3(2H)-one (130 mg, 1.0 mmol) in acetonitrile (3.0 mL) was added K2CO3 (437 mg, 3.16 mmol), CH3I (299 mg, 2.11 mmol), the reaction mixture was stirred at reflux for 2 h. The mixture was cooled to ambient temperature, diluted with EtOAc (20 mL), washed with sodium bicarbonate (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified with silica gel column (Petroleum ether:ethyl acetate=4:1) to obtained product: LC/MS m/z=145 (M+H)+.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:11]1)=[O:7])(C)(C)C.[CH2:21]([N:24]=[C:25]=[O:26])[CH2:22][CH3:23].[NH2:27][C:28]1[C:36]([Cl:37])=[CH:35][C:31](C(O)=O)=[C:30]([O:38][CH3:39])[CH:29]=1>>[NH2:27][C:28]1[C:36]([Cl:37])=[CH:35][C:31]([C:6]([NH:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:25]([NH:24][CH2:21][CH2:22][CH3:23])=[O:26])[CH2:11]2)=[O:7])=[C:30]([O:38][CH3:39])[CH:29]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCN(CCCCCN)C1
Reactant: CCCN=C=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: CCCNC(=O)NCCCCCN1CC[C@@H](CNC(=O)c2cc(Cl)c(N)cc2OC)C1

Procedure:
5-((3S)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)pentylamine (1.50 g) as starting compound was reacted and treated in the same manner as in Example 34 using n-propyl isocyanate (0.49 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.61 g) to give 4-amino-5-chloro-2-methoxy-N-((3S)-1-(5-(3-n-propylureido)pentyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)cc1F
Temperature: 25 °C

Procedure:
15.4 g of 2-fluoro-4-methylbenzoic acid was dissolved in 200 mL of methanol, and 10.0 mL of concentrated sulfuric acid was added thereto, followed by heating with reflux overnight. The reaction liquid was cooled to room temperature and then concentrated to about 50 mL, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 to 90:10) to obtain 15.2 g of methyl 2-fluoro-4-methylbenzoate.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:3]1.[CH:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CCCCCCC.C(Cl)Cl>[C:22]([C:4]1[CH:5]=[C:6]([C:7]([F:8])([F:9])[F:10])[N:2]([CH3:1])[N:3]=1)#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C(F)(F)F)n(C)n2)cc1
Reactant: C#CCCCCC
Solvent: ClCCl
Solvent: CCCCCCC
Product: CCCCCC#Cc1cc(C(F)(F)F)n(C)n1

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 7:3; yield (100 mg, 82%); 1H NMR δ (CDCl3): 6.63 (s, 1H), 3.95 (s, 3H), 2.38 (t, J=7.34 Hz, 2H), 1.64-1.56 (m, 2H), 1.46-1.28 (m, 4H), 0.90 (t, J=7.36 Hz, 3H); LCMS m/z: 244.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH2:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[N:16]1[S:20][N:19]=[C:18]2[C:21]([S:25]([NH:28][C:29]3[CH:37]=[C:36]([Cl:38])[C:35]([Cl:39])=[CH:34][C:30]=3[C:31](O)=[O:32])(=[O:27])=[O:26])=[CH:22][CH:23]=[CH:24][C:17]=12>>[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH:14][C:31](=[O:32])[C:30]1[CH:34]=[C:35]([Cl:39])[C:36]([Cl:38])=[CH:37][C:29]=1[NH:28][S:25]([C:21]1[C:18]2=[N:19][S:20][N:16]=[C:17]2[CH:24]=[CH:23][CH:22]=1)(=[O:27])=[O:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)cc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Cl)cc1)NC(=O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3-(4-chloro-phenyl)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (S)-2-amino-3-(4-chloro-phenyl)-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled to 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acid as in EXAMPLE 1, Part C, to afford the title compound. HPLC: RT=11.61 min. MS (ESI−): mass calcd. for C23H17Cl3N4O5S2, 597.97; m/z found, 597/599 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.20 (s, 1H), 8.36 (d, J=6.3, 1H), 8.23 (d, J=8.7, 1H), 7.87 (s, 1H), 7.74-7.71 (m, 1H), 7.27-7.25 (m, 3H), 6.98 (d, J=8.3, 2H), 6.38 (d, J=7.3, 1H), 4.96-4.92 (m, 1H), 3.82 (s, 3H), 3.23-3.14 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=4)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH3:37][C@H:38]1[CH2:43][NH:42][CH2:41][C@@H:40]([CH3:44])[NH:39]1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([C:32]([N:42]5[CH2:41][C@H:40]([CH3:44])[NH:39][C@H:38]([CH3:37])[CH2:43]5)=[O:34])=[CH:35][CH:36]=4)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=C(O)c1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CN(C(=O)c2ccc(Cn3ccc4ncnc(Nc5ccc(OCc6cccc(F)c6)c(Cl)c5)c43)cc2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.5 %

Procedure:
To a solution of 4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoic acid (120 mg) in N,N-dimethylformamide (2.4 mL) were added cis-2,6-dimethylpiperazine (95 mg) and 1H-1,2,3-benzotriazol-1-ol (65 mg), and the mixture was stirred at room temperature for 15 min. N-[3-(Dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (92 mg) and triethylamine (0.2 mL) were added, and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL×3). The organic layer was washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:ethyl acetate/methanol=10/0→9/1). The object fraction was concentrated under reduced pressure. Chloroform/diisopropyl ether (3/7) was added to the residue and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (85 mg) as white powder crystals.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][N:25]([CH2:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH3:26].[OH-].[Na+]>CN(C=O)C.CO>[CH3:26][N:25]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([NH:32]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:33][CH:34]=1)[CH3:24]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: COc1cccc(C(Cl)=C2C(=O)N(C(C)=O)c3ccccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccccc32)c1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(3-methoxyphenyl)-methylidene)-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.