Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[CH:26][C:25]([CH3:28])=[N:24]2)=[CH:19][C:18]=1O.N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[F:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH:27]=[CH:26][C:25]([CH3:28])=[N:24]2)=[CH:21][C:22]=1[O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccn(-c2ccc(F)c(O)c2)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccn(-c2ccc(F)c(OS(=O)(=O)C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
To an ice cooled solution of trifluoromethanesulfonic anhydride (0.29 mL, 1.72 mmol) in DCM (10 mL) was added 2-fluoro-5-(3-methylpyrazol-1-yl)phenol (which may be prepared as described in Description 68) (288 mg, 1.5 mmol) followed by pyridine (0.6 mL, 7.49 mmol). The reaction was stirred at 00° C. for 10 minutes, then allowed to warm to room temperature over 1 hour, then the reaction was stirred overnight at room temperature. Additional trifluoromethanesulfonic anhydride (0.29 mL, 1.72 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction was diluted with DCM (30 mL) and subsequently poured into an aqueous solution of citric acid (10% w/w, 50 mL), and the layers were separated. The aqueous was then re-extracted with DCM (30 mL). The combined organics were dried through a phase separator, and concentrated in vacuo. The residue was loaded onto a silica column (10 g, SNAP cartidge), which was eluted with a gradient of EtOAc:isohexane, 0% to 30%. Fractions containing desired product were combined and concentrated in vacuo, to give [2-fluoro-5-(3-methylpyrazol-1-yl)phenyl]trifluoromethanesulfonate (D69) (308 mg, 0.9024 mmol, 60.2% yield);
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)(=O)=O.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1>CN(C)P(N(C)C)(N(C)C)=O.O>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[O:8][CH2:7][CH2:6][NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)OCCOc1ccc2ccccc2c1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCOc2ccc3ccccc3c2)cc1

Procedure:
A mixture of 18.7 g of 2-(2-naphthyloxy)ethanol O-methanesulfonate and 23.6 g of ethyl p-aminobenzoate is heated in 300 ml of hexamethylphosphoramide at 110° C. for 16 hours. The mixture is cooled, diluted with water, and worked up as described in Example 3 to give the crystalline product. Recrystallization from ethanol gives crystals, mp 158°-162° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl.[O:46]1[CH:50]=[CH:49][N:48]=[C:47]1[CH2:51][NH2:52]>CC(O)C>[C:1]([C:5]1[N:10]=[C:9]([NH:52][CH2:51][C:47]2[O:46][CH:50]=[CH:49][N:48]=2)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2Cl)CN(C(=O)OC(C)(C)C)C1
Reactant: NCc1ncco1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2NCc2ncco2)CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 15 h
Yield: 85.2 %

Procedure:
To a solution of 1-tert-butyl 3-methyl (3R,5S)-5-{[(2-tert-butyl-4-chloropyrimidin-5-yl)carbonyl](isobutyl)amino}piperidine-1,3-dicarboxylate (0.55 g) and diisopropylethylamine (0.87 ml) in 2-propanol (5 ml) was added 2-oxazolylmethylamine hydrochloride (0.34 g), and the mixture was stirred at 80° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography, and the fraction eluted with hexane to ethyl acetate-hexane (1:2) was concentrated under reduced pressure to give the object compound (525 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([CH:16]=O)[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)[CH3:2].[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25]>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([CH:16]=[C:23]3[S:19][C:20](=[O:25])[NH:21][C:22]3=[O:24])[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1coc2ccc(C=O)cc12
Reactant: O=C1CSC(=O)N1
Product: CCOC(=O)CCc1coc2ccc(C=C3SC(=O)NC3=O)cc12

Procedure:
Following the general method as outlined in Example 1, starting from 3-(5-Formyl-benzofuran-3-yl)-propionic acid ethylester (intermediate 71) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][C:7]#[CH:8])[C:3]#[N:4].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:1][CH:2]([CH2:5][CH2:6][C:7]#[CH:8])[C:3]#[N:4])(=[O:19])=[O:18]
Reactant: C#CCCC(O)C#N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCC(C#N)OS(C)(=O)=O
Yield: 87.4 %

Procedure:
A mixture of 2-hydroxy-5-hexynenitrile (8.0 g, 73.3 mmol) and dry triethylamine (10.1 g, 0.1 mol) in 50 ml of dry CH2Cl2 was treated with a solution of methanesulfonyl chloride (10.3 g, 90 mmol) in 50 ml of CH2Cl2, at 0° C. for 11/2 h. The reaction mixture was diluted with CH2Cl2, washed twice with cold 1.0N H2SO4, twice with water, and dried over MgSO4. The filtered CH2Cl2 solution was concentrated at 40° C./30 mm to give 12 g of pale yellow liquid. Purification of this material on 220 g of silica gel and eluted with ether-petroleum ether (1:1 parts by volume) gave 8.7 g (56% by weight yield from pentynal) of 2-[(methylsulfonyl)]-5-hexynenitrile as a colorless liquid.
Reaction SMILES: [OH-].[Na+:2].[C:3]1([CH2:9][C:10](=[O:14])[C:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Na+].[CH3:16]I.Cl>CO>[O:14]=[C:10]([CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:16])[C:11]([O-:13])=[O:12].[Na+:2]
Reactant: O=C([O-])C(=O)Cc1ccccc1
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)C(=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 2N aqueous solution of sodium hydroxide (10 ml, 20 mmoles) and 30 ml of methanol were added to 3.92 g (20 mmoles) of sodium phenylpyruvate to form a solution. Then, 1.25 ml of methyl iodide was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with 150 ml of ether. The ether layer was dried over magnesium sulfate, and concentrated under reduced pressure to give a pale yellowish white oil. A 3N aqueous solution of sodium hydroxide (6.5 ml) was added, and the mixture was concentrated. Ether was added to the resulting semi-solid mixture, and the precipitated sodium 2-oxo-3-phenylbutanoate was isolated by filtration as a white solid (1.62 g, yield 85 %).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([OH:9])=O)[O:3]1.[CH3:10][NH:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)=[O:22])[CH2:17][CH2:16]1>>[CH3:10][N:11]([CH2:12][CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=2)=[O:22])[CH2:19][CH2:20]1)[C:7]([C:4]1[O:3][C:2](=[O:1])[NH:6][CH:5]=1)=[O:9]
Reactant: O=C(O)c1c[nH]c(=O)o1
Reactant: CNCCCN1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Product: CN(CCCN1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)c1c[nH]c(=O)o1

Procedure:
The title compound was prepared from 2-oxo-2,3-dihydrooxazole-5-carboxylic acid (Example 21 step 1) and 3,5-dichlorobenzyl 4-(3-(methylamino)propyl)piperazine-1-carboxylate (step 5) analogously to Example 15 step 3;
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:24])([CH3:23])[CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][C:3]([CH3:24])([CH3:23])[CH2:2][NH:1][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: O=C=Nc1ccccc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CN
Product: COCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CNC(=O)Nc1ccccc1

Procedure:
Using the general method of Example 145, 1-(3-amino-2,2-dimethylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.05 mmol) was reacted with phenyl isocyanate to provide 0.45 g of N-(3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropyl)-N′-phenylurea as a white powder, m.p. 125.0-130.0° C. Analysis: Calculated for C25H30N6O2. 0.40H2O: %C, 66.18; %H, 6.84; %N, 18.52; Found: %C, 66.05; %H, 6.61; %N, 18.64. %H2O calculated: 1.59; found: 1.53 (Karl Fisher);
Reaction SMILES: [ClH:1].C(O[C:5](=[NH:8])[CH2:6][F:7])C.[C:9]([NH:12][CH:13]([CH2:17][C:18]#[C:19][CH2:20][NH2:21])[C:14]([OH:16])=[O:15])(=[O:11])[CH3:10].C1CCN2C(=NCCC2)CC1>C(O)C>[ClH:1].[C:9]([NH:12][CH:13]([CH2:17][C:18]#[C:19][CH2:20][NH:21][C:5](=[NH:8])[CH2:6][F:7])[C:14]([OH:16])=[O:15])(=[O:11])[CH3:10]
Reactant: CC(=O)NC(CC#CCN)C(=O)O
Reactant: CCOC(=N)CF
Agent: Cl
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)NC(CC#CCNC(=N)CF)C(=O)O
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Ex-8h) 2.86 g of ethylfluoroacetimidate hydrochloride, 1 equivalent of 2-acetylamino-6-amino-4-hexynoic acid and 6.84 g of DBU are taken up in 200 mL absolute ethanol and stirred for 16 h at 20° C. under argon. Solvent is removed under vacuum and 100 mL water is added. This reaction mixture is filtered through acidic ion exchange column and the product is eluted with 10% pyridine/water. (±)-2-Acetylamino-6-(1-imino-2-fluoroethylamino)-hex-4-ynoic acid hydrochloride is obtained by removing the solvent under vacuum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]2)=[N:21][CH:22]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]>>[Cl:37][C:38]1[CH:43]=[C:42]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]3)=[N:21][CH:22]=2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Yield: 56.7 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-propionylquinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (46 mg, 0.091 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (37 mg, 0.137 mmol) to afford the desired product (32 mg, 60%) as an yellow solid: ESI MS m/z 619, [C33H35ClFN5O4+H]+
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH:11][C:12]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)=[O:13])[CH:5]=1>C(O)(=O)C>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH+:11]([O-:1])[C:12]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)=[O:13])[CH:5]=1
Reactant: Cc1cc(C)nc(NC(=O)c2cnccn2)c1
Reactant: OO
Solvent: CC(=O)O
Product: Cc1cc(C)nc([NH+]([O-])C(=O)c2cnccn2)c1
Temperature: 70 °C

Procedure:
A solution of 10 ml of glacial acetic acid and 0.7 ml of aqueous hydrogen peroxide solution (35%) are added, with stirring, to 1 g of compound obtained in Example 21. The reaction medium is heated at 70° C. for 7 h and then concentrated under reduced pressure and at low temperature.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: C1CCNC1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1

Procedure:
A mixture of 163.8 mg (0.7 mmol) 2-Chloro-5-methanesulfonyl-benzoic acid in 2 ml pyrrolidine was heated for 16 h to 100° C. After evaporation of all volatiles the residue was taken up in 2 ml methanol/formic acid 3/1 and subjected to reversed phase HPLC purification eluting with an acetonitrile/water gradient to yield after evaporation of the product fractions 143.4 mg (77%) of the title compound. MS (m/e): 268.1 (MH−, 100%).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.[C:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36]O)[CH2:31][CH2:30]1)(=[O:28])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][O:24][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:10]4[C:2]([F:1])=[C:3]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([CH3:25])=[CH:4]5)=[N:13][CH:14]=[N:15]3)=[CH:20][C:19]=2[O:22][CH3:23])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCN(CCO)CC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCN1CCN(C(C)=O)CC1
Reaction time: 1.5 h
Yield: 17.3 %

Procedure:
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazoline (300 mg, 0.88 mmol), (prepared as described for the starting material in Example 7), 2-(4-acetylpiperazin-1-yl)ethanol (183 mg, 1.06 mmol) and triphenylphosphine (278 mg, 1.06 mmol) were stirred together in dichloromethane (10 ml) and the mixture cooled in an ice/water bath. Diisopropyl azodicarboxylate (2091, 1.06 mmol) was added and the mixture stirred for 1.5 hours. A further one mole equivalent of 2-(4-acetylpiperazin-1-yl)ethanol (172 mg, 1 mmol), triphenylphosphine (262 mg, 1 mmol) and diisopropyl azodicarboxylate (197 μl, 1 mmol) were added and the mixture stirred for a further 1 hour. The volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give a crude solid that was further purified by preparative HPLC to give 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (75 mg, 17%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22]O)=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:24])[F:25])=[CH:20][CH:19]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: OCCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cc(F)ccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)ccc1OCCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.79 g (10.5 mmol) of methyl 5-fluorosalicylate, 20 g (10.5 mmol) of 2-(4-trifluoromethyl-phenyl)ethanol and 2.76 g (10.5 mmol) of triphenylphosphine are introduced into 50 ml of THF and, at 0° C., a solution of 1.83 g (10.5 mmol) of DEAD in 10 ml of THF is added dropwise. The mixture is stirred at RT overnight and the volatile components are then removed in vacuo. The resulting crude product is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:1). 2.09 g (58% of theory) of the title compound are obtained.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[CH:8]1([NH:11][C:12]([C:14]2[C:22]3[CH:21]=[C:20]([C:23]4[C:28]([Cl:29])=[CH:27][N:26]=[C:25]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]5[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]5)[N:24]=4)[S:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)=[O:13])[CH2:10][CH2:9]1>CN(C=O)C.C(OCC)(=O)C>[Cl:29][C:28]1[C:23]([C:20]2[S:19][C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:12](=[O:13])[NH:11][CH:8]4[CH2:9][CH2:10]4)[C:22]=3[CH:21]=2)=[N:24][C:25]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]2[CH2:35][CH2:36][N:37]([C:6]([NH2:5])=[O:7])[CH2:38][CH2:39]2)=[N:26][CH:27]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3Cl)cc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)N1CCC(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reaction time: 2 h
Yield: 76.2 %

Procedure:
Trimethylsilyl isocyanate (26 mg, 0.22 mmol) is added to a stirred suspension of 2-[5-chloro-2-(3-piperidin-4-yl-propylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (50 mg, 0.11 mmol) in DMF (1 mL) and stirred for 2 hours. The mixture is diluted with ethyl acetate (1 mL) then filtered to give the title compound as a yellow solid (43 mg). ES+(m/z) 513 (35Cl) and 515 (37Cl) [M+H].
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]([NH:15]C(=O)OC(C)(C)C)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:24].O1CCOCC1>C(Cl)Cl>[ClH:24].[NH2:15][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCN(Cc2ccccc2)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@H]1CCCCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
To a solution of (S)-tert-butyl 1-benzyl-2-oxoazepan-3-ylcarbamate (340 mg, 1.07 mmol) in DCM (5 mL) was added solution of 4 M HCl in dioxane (0.243 mL, 0.971 mmol) at rt under argon. The reaction was allowed to stir at rt for 5 hr. The reaction mixture was concentrated and dried under vacuum to give (S)-3-amino-1-benzylazepan-2-one hydrochloride (210 mg, 0.962 mmol, 99% yield) as a white solid. Anal. Calcd. for C13H18N2O m/z 218.3. found: 219.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([C:12]2[NH:13][C:14](=[O:27])[C:15]3[C:16](=[C:18]([CH2:25][CH3:26])[N:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=3)[N:17]=2)=[CH:10][C:9](I)=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31].C(#N)C>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:11]([C:12]2[NH:13][C:14](=[O:27])[C:15]3[C:16](=[C:18]([CH2:25][CH3:26])[N:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=3)[N:17]=2)=[CH:10][C:9]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ncc(I)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCOc1ncc(C#C[Si](C)(C)C)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Reaction time: 2 h
Yield: 92.4 %

Procedure:
The title compound from Example 1 (127 mg, 0.25 mmol) was suspended in triethylamine (2 mL) and trimethylsilylacetylene (38 mg, 0.39 mmol) and acetonitrile (2 mL to try and solubilise reactants). Pd(PPh3)2Cl2 (5 mg, 0.006 mmol) and cuprous iodide (1.2 mg, 0.006 mmol) were added and the reaction mixture stirred. After 1 h a further portion of trimethylsilylacetylene (19 mg, 0.19 mmol) was added and stirring continued for 2 h. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organics were washed with brine, dried (MgSO4) and concentrated to give a brown foam. Purification by flash column chromatography (gradient elution from 100% dichloromethane to 99% dichloromethane/methanol) gave the title compound as a light brown solid (108 mg).
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:27][CH2:28][CH2:29][CH3:30])[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[C:17]=2[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1>>[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:27][CH2:28][CH2:29][CH3:30])[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[C:17]=2[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCCN=C=O
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Product: CCCCNC(=O)NCCCCn1c(CCCC)nc2c(N)nc3cccnc3c21
Yield: 65.8 %

Procedure:
Using the general method of Example 47, butyl isocyanate (54 μL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmole) to provide 0.13 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]- N′-butylurea as a white solid. Analysis: Calculated for C22H33N7O: %C, 64.21; %H, 8.08; %N, 23.82; Found: %C, 64.05; %H, 7.97; %N, 24.00.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].[H-].[Na+].Cl[C:8]1[N:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11]>CN(C=O)C>[Cl:17][C:15]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[C:8]([O:4][CH2:1][CH2:2][CH3:3])[N:16]=1
Reactant: CCCO
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1nc(Cl)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a solution of propan-1-ol (2.94 mL, 39.26 mmol) in DMF (15 mL) at 0° C. was added sodium hydride (95% in mineral oil, 0.94 g, 39.26 mmol) in portions and stirred for 1 h at room temperature. This mixture was slowly added to a solution of 2,6-dichloro-nicotinamide (5.0 g, 26.17 mmol) in DMF (25 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. DMF was removed under reduced pressure, and the resulting mixture was diluted with EtOAc (60 mL), washed with water (2×20 mL) and brine (2×10 mL) solution, dried over anhydrous Na2SO4, filtered, and concentrated to give yellow oil. Purification was accomplished by flash chromatography on silica gel using 5-60% EtOAc/hexanes gradient elution to yield the title compound (3.8 g, 68%) as a transparent oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.46 (d, J=8.2 Hz, 1H), 7.69 (br. s., 1H), 7.06 (d, J=8.2 Hz, 1H), 5.86 (br. s., 1H), 4.48 (t, J=6.6 Hz, 2H), 1.99-1.79 (m, 2H), 1.07 (t, J=7.4 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(Cl)Cl.CO>[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[N:3]=[N:4][C:5]([CH2:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]([CH3:9])[C:7]=2[CH3:8])=[CH:21][CH:20]=1
Reactant: Cc1c(Cl)nnc(Cc2ccncc2)c1C
Reactant: COc1ccc(N)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(Nc2nnc(Cc3ccncc3)c(C)c2C)cc1

Procedure:
The compound is prepared from 0.070 g 3-chloro-4,5-dimethyl-6-(pyridin-4-yl)methylpyridazine and 0.129 g para-methoxyaniline in the manner described in Example 82A. Title compound is obtained after FC in CH2Cl2/Methanol 19/1. 1H-NMR (250 MHz, CDCl3): δ=8.45 (d, 2H); 7.45 (d, 2H); 7.10 (d, 2H); 6.85 (d, 2H); 6.05 (s, wide, 1H); 4.25 (s, 2H); 3.80 (s, 3H); 2.30 (s, 3H); 2.15 (s, 3H); 2.10 (s, 3H). ES-MS 321 (M+H).