Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][NH:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl[CH2:15][C:16]([OH:18])=[O:17].Cl>>[O:11]=[C:6]1[N:7]([CH2:15][C:16]([OH:18])=[O:17])[CH:8]=[CH:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: O=c1[nH]ccc2ncccc12
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2ncccc2c1=O
Temperature: 100 °C

Procedure:
To 1,6-naphthyridin-5(6H)-one (0.625 g, 4.28 mmol) was added 5 M sodium hydroxide solution (1.7 mL) followed by chloroacetic acid (0.404 g, 4.28 mmol). The reaction mixture was heated at 100° C. for 2 h. After cooled down to ambient temperature and neutralized with 2 N hydrochloric acid (2.1 mL), the title compound was collected by filtration as a yellow solid. 1H NMR (DMSO-d6): δ 13.1 (s, 1H), 8.94 (dd, J=4.6, 1.8 Hz, 1H), 8.51 (dd, J=8.0, 1.6 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.52 (dd, J=8.0, 4.6 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H), 4.72 (s, 2H). LC/MS 205.2 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([N:56]2[CH:60]=[C:59]([CH2:61][OH:62])[N:58]=[CH:57]2)=[CH:52][CH:51]=1>O1CCOCC1.CN(C)C(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:49][C:50]2[CH:51]=[CH:52][C:53]([N:56]3[CH:60]=[C:59]([CH2:61][OH:62])[N:58]=[CH:57]3)=[CH:54][CH:55]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(-n2cnc(CO)c2)cc1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CO
Solvent: CC(=O)N(C)C
Product: Cc1cc(Cc2ccccc2)nc(Nc2ccc(-n3cnc(CO)c3)cc2)n1
Yield: 26.9 %

Procedure:
A mixture of 4-benzyl-2-chloro-6-methyl-pyrimidine (86 mg, 0.39 mmol), 1-(4-amino-phenyl)-1H-imidazol-4-yl]-methanol (75 mg, 0.39 mmol, Europ. J. Med. Chem. 19 (3), 285-7 (1984), CAS 94128-93-5) and potassium carbonate (1.10 g, 7.86 mmol) in dioxane (4 mL) and N,N-dimethylacetamide (1 mL) was degassed with nitrogen. Palladium(II) acetate (3.6 mg, 0.016 mmol) and 2-(dicyclohexylphosphino)biphenyl (12 mg, 0.031 mmol) were added and the reaction mixture was irradiated in a microwave oven at 200° C. for 25 minutes. [1-(4-Amino-phenyl)-1H-imidazol-4-yl]-methanol (43 mg, 0.19 mmol) was added and the reaction mixture was irradiated in a microwave oven at 200° C. for another 25 minutes. The reaction mixture was filtered; the filtrate was diluted with ethyl acetate, washed with water and brine, dried with magnesium sulfate and concentrated in vacuo. Purification by column chromatography on silica eluting with dichloromethane/methanol (14:1 v/v) afforded the title compound as a light yellow viscous oil (19 mg, 13%). MS ISP (m/e): 372.2 [(M+H)+].
Reaction SMILES: [I:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[CH:18]([Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19].O>CN(C=O)C>[I:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:18]([CH3:20])[CH3:19])[CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2cccc(I)c2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](Oc1ccc2cccc(I)c2c1)(C(C)C)C(C)C
Temperature: 40 °C

Procedure:
1-Iodo-7-hydroxynaphthalene, as described in Step A, (15.84 g, 58.65 mmol), imidazole (5.59 g, 82.11 mmol) and triisopropylsilyl chloride (17.6 mL, 82.11 mmol) were dissolved in DMF (40 mL) and heated to 40° C. for 18 hours. The reaction was poured into H2O and extracted with hexanes (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo, to yield the above-titled compound.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N1C=CN=C1.[C:18]([Si:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: N#Cc1nc2ccc(O)cc2s1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc2nc(C#N)sc2c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 112 %

Procedure:
A solution of 2-cyano-6-hydroxybenzothiazole (5.0 g, 28 mmol) in 100 ml of anhydrous DMF under inert atmosphere was treated with 2.9 g of imidazole (4.2 mmol) followed by t-butyldiphenylchlorosilane (9.34 g, 34 mmol). The reaction was stirred at room temperature for 3 h and then diluted with 200 ml of ethyl acetate and washed with water (4×400 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography, eluting with 5-10% ethyl acetate/hexanes to afford 13.0 g of the desired product containing ~10% silyl impurity in quantitative yield. The product was taken on without further purification. 1H NMR (CDCl3): δ 1.12 (s, 9H) ; 7.13-7.46 (m, 8H); 7.70-7.72 (m, 4H); 7.92-7.95 (d, 1H).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3](O)=O.[F:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:14]=[CH:13][C:10]=1C=O.N1CCCCC1.Cl>O.N1C=CC=CC=1>[F:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:14]=[CH:13][C:10]=1/[CH:3]=[CH:2]/[C:1]([OH:7])=[O:6]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(OCc2ccccn2)cc1F
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)/C=C/c1ccc(OCc2ccccn2)cc1F
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
To 1.8 g of malonic acid were added 18 mL of pyridine, 2.0 g of 2-fluoro-4-(2-pyridylmethoxy)benzaldehyde and 0.21 mL of piperidine. The mixture was stirred at 75° C. for 1.5 hours and further stirred at 95° C. for 1 hour. The reaction mixture was cooled with ice, water was added thereto, and 10% hydrochloric acid was added to adjust the pH to 4. The resulting precipitate was separated by filtration to give 2.0 g of the title compound (85% yield).
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH2:11][O:12]C(=O)C)[CH2:6][O:7]C(=O)C)(=O)C.[OH-].[Na+].[ClH:36]>CO>[ClH:36].[NH2:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH2:6][OH:7])[CH2:11][OH:12]
Reactant: CCCCCCCCCCCCCCCCCCC(COC(C)=O)(COC(C)=O)NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCC(N)(CO)CO

Procedure:
2-Acetamido-1,3-diacetoxy-2-octadecylpropane (1.00 g) was dissolved in 26 ml of methanol and 6.4 ml of a 1 N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 6 hours. The mixture was neutralized with a 1 N aqueous hydrochloric acid solution and concentrated under reduced pressure. The concentrate was washed with water and ethyl acetate:hexane=1:1 in order to give 639 mg of 2-amino-2-octadecyl-1,3-propanediol hydrochloride.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[NH2:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[C:16]([N:17]=[C:2]=[O:4])[CH:18]=[C:19]([CH3:21])[CH:20]=1
Reactant: Cc1cc(N)cc(Cl)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)cc(N=C=O)c1
Reaction time: 0.5 h

Procedure:
Triphosgene (17.01 g, 0.0573 mol) was dissolved in 200 ml of toluene in a 1 liter flask. 150 ml of a toluene solution of 3-chloro-5-methylaniline (21.9 g, 0.155 mol) and triethylamine (36.0 ml) was added dropwise thereto over 30 minutes at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[CH:9]=[CH:10][N:11]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:16])[C:13]=2[C:14]=1[OH:15])=[O:4].[C:25]([Cu])#[N:26].[NH4+].[OH-].Cl>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[CH:9]=[CH:10][N:11]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:16])[C:13]=2[C:14]=1[OH:15])=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(I)c2ccn(Cc3ccccc3)c(=O)c2c1O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1nc(C#N)c2ccn(Cc3ccccc3)c(=O)c2c1O
Temperature: 25 °C
Yield: 58.9 %

Procedure:
A mixture of 6-benzyl-4-hydroxy-1-iodo-5-oxo-5,6-dihydro-[2,6]naphthyridine-3-carboxylic acid methyl ester (180 mg, 0.41 mmol) and CuCN (74 mg, 0.83 mmol) in 5 mL of DMF was refluxed for 8 min. The reaction mixture was cooled to r.t. and poured into a stirring mixture of 1% NH4OH solution and CH2Cl2. 4 M HCl was then added with vigorous stirring until no more solid was present. The aqueous layer was extracted with additional CH2Cl2, and the combined organic layer was dried over MgSO4 and concentrated. The crude was chromatographed (0-15% CH2Cl2/EtOAc+1% AcOH) to give 81 mg of the title compound as a pale yellow solid. MS: (−) m/z 334.00 (M−1).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=O)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[N:4][C:3]=1[C:17]([F:20])([F:19])[F:18].P(Cl)(Cl)(Cl)(Cl)[Cl:22]>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[S:6][C:5]([N:7]=[C:8]([Cl:22])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[N:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: O=C(Nc1nc(C(F)(F)F)c(Cl)s1)c1cccc(Cl)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1nc(N=C(Cl)c2cccc(Cl)c2)sc1Cl

Procedure:
N-(5-Chloro-4-trifluoromethylthiazol-2-yl)-3-chlorobenzamide (15.5 g was mixed with phosphorous pentachloride (9.5 g) and phosphorous oxychloride (60 ml) and the mixture was refluxed for 12 hr. The excess phosphorous oxychloride was removed under reduced pressure and the residue was mixed with cold water then extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure then the residue was recrystallized from n-hexane to give N-(5-chloro-4-trifluoromethylthiazol-2-yl)-3-chlorobenzimidoyl chloride; as pale brown needles (11.0 g), m. p. 89-90° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:12]([N:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]1([CH3:10])[CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCBr
Reactant: CC1(C)CCCC(C)(C)N1
Product: CCCCCCCCN1C(C)(C)CCCC1(C)C

Procedure:
A mixture of 56.4 parts of 2,2,6,6-tetramethylpiperidine and 38.6 parts of 1-bromooctane was heated at 125°-30°C for 120 hours. The cooled reaction mixture was filtered to remove 2,2,6,6-tetramethylpiperidine hydrobromide formed during the reaction. Fractional distillation of the residue gave 1-n-octyl-2,2,6,6-tetramethylpiperidine having a boiling point of 168°C/17 mm of Hg.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:16][C:17]1[CH:29]=[C:28]([O:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])[CH:27]=[CH:26][C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([NH:16][C:17]1[CH:29]=[C:28]([O:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])[CH:27]=[CH:26][C:18]=1[C:19]([OH:21])=[O:20])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccc(Cl)cc2Cl)cc1NC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(Oc2ccc(Cl)cc2Cl)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.0 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(benzamido)-4-(2,4-dichlorophenoxy)benzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the obtained residue was purified with reversed-phase silica gel column chromatography [eluent; 80-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to obtain 8.7 mg of 2-(benzamido)-4-(2,4-dichlorophenoxy)benzoic acid as white solid.
Reaction SMILES: Cl.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](NC3C=CC(Cl)=CC=3F)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:29][CH3:30])C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[OH:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:29][CH3:30]
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2cncnc2cc1O
Yield: 130.6 %

Procedure:
A solution of 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (892 mg, 2 mmol) in TFA (10 ml) was refluxed for 50 minutes. After cooling, the mixture was poured onto ice. The precipitate was collected by filtration, dissolved in methanol (10 ml) and basified to pH11 with aqueous ammonia. After concentration by evaporation, the solid product was collected by filtration, washed with water then ether and dried under vacuum to give 4-4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline as a yellow solid (460 mg, 72%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[N:12]([C:27]([CH2:30][CH3:31])=[CH:28][CH:29]=3)[N:13]=[C:14]([CH2:25][OH:26])[C:15]=2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:7]=[N:8][CH:9]=1.[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CN(C=O)C>[N:32]1([C:38]([O:26][CH2:25][C:14]2[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:10]([C:6]3[CH:7]=[N:8][CH:9]=[C:4]([Br:3])[CH:5]=3)[C:11]3[N:12]([C:27]([CH2:30][CH3:31])=[CH:28][CH:29]=3)[N:13]=2)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCOC(=O)CCCCc1c(CO)nn2c(CC)ccc2c1-c1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCc1c(COC(=O)N2CCOCC2)nn2c(CC)ccc2c1-c1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
To a suspension of 60% NaH (695 mg) in DMF (3 mL) was added ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate 5 (200 mg) under ice-water cooling and the mixture was stirred at 0° C. for 0.5 hour. To this was added 4-morpholinecarbonyl chloride (659 mg) and the mixture was stirred at ambient temperature for 15 hours. The mixture was partitioned between AcOEt and water. The organic layer was separated, washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (20:1-1:1) to give [4-(5-bromo-3-pyridinyl)-3-(5-ethoxy-5-oxopentyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]methyl 4-morpholinecarboxylate as yellow oil (75 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][S:14]([N:17]3[CH2:22][C@H:21]([CH3:23])[NH:20][C@H:19]([CH3:24])[CH2:18]3)(=[O:16])=[O:15])[CH:10]=[CH:9][C:8]=2[NH:25][C:26]([C:28]2[N:29](COCC[Si](C)(C)C)[CH:30]=[C:31]([C:33]#[N:34])[N:32]=2)=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CCO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][S:14]([N:17]3[CH2:18][C@H:19]([CH3:24])[NH:20][C@H:21]([CH3:23])[CH2:22]3)(=[O:15])=[O:16])[CH:10]=[CH:9][C:8]=2[NH:25][C:26]([C:28]2[NH:29][CH:30]=[C:31]([C:33]#[N:34])[N:32]=2)=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[C@@H]1CN(S(=O)(=O)Cc2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)C[C@H](C)N1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(S(=O)(=O)Cc2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.9 %

Procedure:
A solution of 163 mg (0.266 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(cis-3,5-dimethyl-piperazine-1-sulfonylmethyl)-phenyl]-amide (as prepared in the previous step) in CH2Cl2 (15 mL) was treated with EtOH (300 μL) and TFA (4.5 mL), and stirred at RT for 4 h. Solvents were evaporated in vacuo, and the residue was purified by reverse phase high pressure liquid chromatography (RP-HPLC) (C18) with 10-80% CH3CN in 0.1% TFA/H2O over 30 min to afford 8.8 mg (7%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.31 (d, 1H, J=8.4 Hz), 8.04 (s, 1H), 7.39 (dd, 1H, J=8.4, 2.0 Hz), 7.33 (d, 1H, J=2.0 Hz), 5.91-5.87 (m, 1H), 4.47 (s, 2H), 3.87-3.79 (m, 2H), 3.31-3.25 (m, 2H), 2.76-2.67 (m, 2H), 2.36-2.27 (m, 4H), 1.94-1.79 (m, 4H), 1.29 (d, 6H, J=6.4 Hz). Mass spectrum (ESI, m/z): Calcd. for C24H30N6O3S, 483.2 (M+H). found 482.9.
Reaction SMILES: BrC1SC2C(=NC=CC=2Cl)C=1.[Br:12][C:13]1[S:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[O:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=2F)[CH:14]=1.[N+](C1C=CC(O)=CC=1)([O-])=O>>[Br:12][C:13]1[S:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[O:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Agent: Clc1ccnc2cc(Br)sc12
Agent: O=[N+]([O-])c1ccc(O)cc1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)cc1
Yield: 48 %

Procedure:
Starting from the compound 41 (scheme 8) and following the procedure described above for the synthesis of compound 42 (scheme 8) but replacing 2-fluoro-4-nitrophenol for 4-nitrophenol, title compound 197 was obtained in 48% yield. LRMS (M+1) 350.9 (100%). 352.9 (100%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[CH3:12][CH:13]([CH3:19])[CH2:14][CH:15]([NH2:18])[CH2:16][CH3:17]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:18][CH:15]([CH2:14][CH:13]([CH3:19])[CH3:12])[CH2:16][CH3:17])=[O:7]
Reactant: CCC(N)CC(C)C
Reactant: Cc1ccc(C(=O)O)cc1C
Product: CCC(CC(C)C)NC(=O)c1ccc(C)c(C)c1

Procedure:
Prepared in a similar manner to example 4 using 3,4-dimethylbenzoic acid and 5-methylhexan-3-amine (example 5a). 1H NMR (500 MHz, CDCl3): δ 0.94 (m, 9H); 1.38 (m, 2H); 1.46 (m, 1H); 1.65 (m, 2H); 2.29 (s, 3H); 2.30 (s, 3H); 4.18 (m, 1H); 5.70 (d, 1H); 7.17 (d, 1H); 7.46 (d, 1H); 7.55 (s, 1H). MS (248, M+H).
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][C:4]#[CH:5].Cl.[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>>[CH2:9]([N:11]([CH2:12][CH3:13])[C:1]([CH2:2][CH2:3][C:4]#[CH:5])=[O:7])[CH3:10]
Reactant: CCNCC
Reactant: C#CCCC(=O)O
Agent: Cl
Product: C#CCCC(=O)N(CC)CC
Yield: 94.7 %

Procedure:
The title compound (370 mg, 95%) was prepared from 4-pentynoic acid (250 mg, 2.55 mmol) and diethylamine hydrochloride (310 mg, 2.83 mmol) by the procedure similar to that described in Example 51(1).
Reaction SMILES: CI.[C:3](#N)C.[I:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:24])[NH:14][CH:15]([C:20]([NH:22][CH3:23])=[O:21])[C:16]([O:18][CH3:19])=[O:17])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[I:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:24])[NH:14][C:15]([CH3:3])([C:20]([NH:22][CH3:23])=[O:21])[C:16]([O:18][CH3:19])=[O:17])=[CH:9][CH:8]=1
Reactant: CNC(=O)C(NC(=O)c1ccc(I)cc1)C(=O)OC
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)C(C)(NC(=O)c1ccc(I)cc1)C(=O)OC
Yield: 82 %

Procedure:
Methyl iodide (0.35 mL) was added to an acetonitrile (40 mL)-DMF (16 mL) suspension of 1-iodo-4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl]carbamoyl}benzene (1.5 g) as obtained in Example 15-(1) and potassium carbonate (0.81 g), and the mixture was stirred for 4 days at room temperature under closed conditions. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the desiccant was filtered out, whereafter the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with hexane/ethyl acetate=45/55→14/86) to obtain 1-iodo-4-{[1-methoxy-2-methyl-3-(methylamino)-1,3-dioxopropan-2-yl]carbamoyl}benzene (colorless oil) (1.3 g, 82%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[N:22]3[C:17]([C:18]([NH2:23])=[N:19][CH:20]=[N:21]3)=[C:16](Br)[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([N:32]1[CH:40]=[C:39]2[C:34]([CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=[CH:38]2)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[N:22]3[C:17]([C:18]([NH2:23])=[N:19][CH:20]=[N:21]3)=[C:16]([C:36]3[CH:37]=[CH:38][C:39]4[C:34]([CH:35]=3)=[N:33][N:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:40]=4)[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cc(Br)c3c(N)ncnn23)C1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 110 °C
Yield: 46.2 %

Procedure:
To a stirred solution 3-(4-Amino-5-bromo-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.49 g, 1.24 mmol), Intermediate C (0.62 g, 1.86 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.37 g, 0.32 mmol) in degassed DMF (8 mL) was added aqueous Na2CO3 (2M, 2.00 mL). The resulting mixture was heated at 110° C. for 3 h and then cooled to rt. The reaction mixture was diluted with EtOAc and filtered through a Celite® pad. The organic layer was separated and concentrated in vacuo. The residue was purified by silica-gel column using a gradient of 50% to 100% EtOAc in hexanes to afford 0.30 g (46%) of the product. LC-MS [M+H]+=524.1, RT=3.19 min.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[N:14]=1.C([O-])([O-])=O.[K+].[K+].O>C(OC(O)C)C>[NH2:12][C:13]1[N:14]=[C:15]([NH:19][C:2]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C(O)c1ccc(Cl)cc1Br
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1cccc(Nc2cc(Cl)ccc2C(=O)O)n1
Temperature: 130 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
A mixture of 2-bromo-4-chlorobenzoic acid (5 g), 2,6-diaminopyridine (6.95 g), K2CO3 (3.18 g), Cu powder (0.13 g) and Cu(I) oxide (0.15 g) in ethoxyethanol (10 mL) was heated at 130° C. for 2 h, until the reaction was complete (as confirmed by tlc). The mixture was cooled to RT, and water (70 mL) and activated carbon was added, and the mixture stirred for 3 h. The product was then filtered, and HCl (4 M) was added until pH 7 was reached. The resulting brown precipitate was filtered and dried in an oven (50° C., pressure=30 mbar) overnight to provide 2-(6-amino-pyridin-2-ylamino)-4-chlorobenzoic acid (2.4 g).