Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[H][H]>C(O)C.[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Agent: O=[Pt]
Solvent: CCO
Product: COc1ccc(N)c(F)c1

Procedure:
All of the product from Step A was placed in a Parr hydrogenation apparatus, and 0.35 g of platinum oxide in 200 mL of ethanol was added. This mixture was reacted with hydrogen until the theoretical amount of hydrogen was absorbed. The reaction was stopped, and the reaction mixture was filtered through Celite® filter aid. The solvent was then evaporated under reduced pressure, leaving 18.5 g of 2-fluoro-4-methoxyaniline as a solid residue.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][P:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([F:33])[CH:27]=1)([CH3:25])=[O:24].Cl.[OH-].[Na+]>COCCO.C(O)C>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([P:23]([CH3:22])([CH3:25])=[O:24])=[CH:27][C:28]=2[F:33])=[N:3][CH:4]=1
Reactant: CP(C)(=O)c1ccc(N)c(F)c1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: CCO
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc(P(C)(C)=O)cc2F)ncc1Cl
Temperature: 90 °C
Yield: 15.1 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (as prepared in Example 17: 0.040 g, 0.12 mmol) in 1 mL of 2-methoxyethanol was added 4-(dimethylphosphoryl)-2-fluoroaniline (0.023 g, 0.12 mmol) and 49 μL of 2.5 M HCl in ethanol. The mixture was heated in a sealed tube at 90° C. for 16 h. The mixture was basified with 1N NaOH solution, and extracted with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The crude residue was purified by prep-HPLC to afford the final compound (9.0 mg, 22% yield). MS/ES+: m/z=497.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[NH2:9][C:10]1[CH:11]=[C:12]([C:16]2[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[C:19](=[O:26])[NH:18][N:17]=2)[CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1.O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:9][C:10]1[CH:11]=[C:12]([C:16]2[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[C:19](=[O:26])[NH:18][N:17]=2)[CH:13]=[CH:14][CH:15]=1)=[O:7]
Reactant: Nc1cccc(-c2n[nH]c(=O)c3c2CCCC3)c1
Reactant: O=C(Cl)CCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCCCCl)Nc1cccc(-c2n[nH]c(=O)c3c2CCCC3)c1
Reaction time: 0.5 h

Procedure:
5-chloropentanoyl chloride (171 mg) was added dropwise to a mixed solution of the compound prepared in Example 1 (241 mg) and potassium carbonate (89.8 mg) in tetrahydrofuran (3.00 mL) and water (1.00 mL) in ice bath and the mixture was stirred for 30 minutes. Moreover, potassium carbonate (45.0 mg) and 5-chloropentanoyl chloride (85.5 mg) was added the reaction mixture, which was stirred for 30 minutes. 1N hydrochloric acid was added to the reaction mixture, which was adjusted to pH 2. Water was added thereto and the deposited crystal was collected by filtration. It was washed with water and hexane sequentially and dried under reduced pressure to give the compound of the present invention (347 mg) having the following physical data.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[CH2:5][N:6]([C:16](=[O:18])[CH3:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(CNc1ccccn1)OCC
Solvent: c1ccncc1
Product: CCOC(CN(C(C)=O)c1ccccn1)OCC
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A solution of 2-pyridylaminoacetaldehyde diethyl acetal (8.0 g.) in a mixture of acetic anhydride (30 ml.) and pyridine (30 ml.) was stirred for 4 hours at 80° C and allowed to stand for 12 hours at ambient temperature. The reaction mixture was post-treated according to a similar manner to that of Example 5 (a) (2) to give oil of N-acetyl-N-(2-pyridyl)aminoacetaldehyde diethyl acetal (6 g.).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[S:7][C:6]=1[NH2:18])=[O:4].[OH-].[Na+].O>CO>[NH2:18][C:6]1[S:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:9][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)sc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cc(C(=O)O)c(N)s2)cc1
Yield: 90.5 %

Procedure:
To a stirred solution of 2-amino-5-(4-methoxy-phenyl)-thiophene-3-carboxylic acid methyl ester (6.6 g, 26.6 mmol) in MeOH (200 mL) was added 6N NaOH (100 mL) and water (50 mL). The reaction was heated to reflux for 2 h or until starting material was gone by TLC or LCMS. The solution was concentrated under vacuum to about half of the original volume. The pH of the resultant cloudy mixture was adjusted to 3-5 by the careful addition of 6N HCl (˜150 mL) while stirring. The gummy red precipitate was filtered and dried. Purification was achieved by triturating in boiling hexanes. The product (6.0 g, 91%) was isolated in pure form by filtration after cooling to room temperature and drying in a vacuum oven overnight. 1H NMR (d6-DMSO δ 7.37, d, 2H, δ 7.11, s, 1H; δ 7.10, br s, 2H; δ 6.94, d, 2H), LC/MS (APCI, ES, M+H=250).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3](=O)[CH2:4][C:5](=O)[CH3:6].[NH2:11]/[C:12](/[CH3:18])=[CH:13]\[C:14]([O:16][CH3:17])=[O:15]>C(#N)C>[CH3:18][C:12]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:3]([C:2]([F:10])([F:9])[F:1])[CH:4]=[C:5]([CH3:6])[N:11]=1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: COC(=O)/C=C(/C)N
Solvent: CC#N
Product: COC(=O)c1c(C(F)(F)F)cc(C)nc1C

Procedure:
1,1,1-Trifluoro-2,4-pentanedione (25.01 g, 135.3 mmol) was dissolved in acetonitrile (230 mL). Methyl 3-aminocrotonate (15.57 g, 135.2 mmol) was added to the solution, followed by refluxing for 20 hours. The reaction mixture was allowed to stand for cooling, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (eluent: n-hexane/acetone=10/1), to thereby yield methyl 2,6-dimethyl-4-trifluoromethylpyridine-3-carboxylate as a yellow oil (22.30 g, 71%).
Reaction SMILES: [C:1]([CH2:3][C:4](=O)[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)#[N:2].[NH:20]1[C:24]([NH2:25])=[CH:23][CH:22]=[N:21]1>CC(O)=O>[NH2:2][C:1]1[N:20]2[N:21]=[CH:22][CH:23]=[C:24]2[N:25]=[C:4]([CH2:5][CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH:3]=1
Reactant: Nc1ccn[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)CC#N)CC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Cc2cc(N)n3nccc3n2)CC1

Procedure:
The crude tert-butyl 4-(3-cyano-2-oxopropyl)piperidine-1-carboxylate was then heated at 100° C. overnight with 1H-pyrazol-5-amine (1197 mg, 14.41 mmoL) in HOAc (25 mL). Concentration provided crude tert-butyl 4-((7-aminopyrazolo[1,5-a]pyrimidin-5-yl)methyl)piperidine-1-carboxylate.
Reaction SMILES: C([O:3][C:4]([C:6]1[C@@H:10]2[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][C@@H:9]2[O:8][N:7]=1)=O)C.[BH4-].[Na+].O>C(O)C>[C:17]([O:16][C:14]([N:12]1[CH2:13][C@H:9]2[C@H:10]([C:6]([CH2:4][OH:3])=[N:7][O:8]2)[CH2:11]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)C1=NO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@@H]2ON=C(CO)[C@@H]2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To ester 6 (1.50 g; 5.29 mmol) in ethanol (50 mL) at 0° C., was added sodium borohydride (1.57 g; 41.5 mmol) in several portions. The reaction mixture was stirred at 0° C. for 30 minutes and then at room temperature for 3 hours. The reaction mixture was carefully added to water (150 mL) and extracted with methylene chloride (3×100 mL). The combined organic layers were washed with several portions of water, brine, dried (MgSO4), filtered and evaporated to yield alcohol 7 as a white solid.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([CH:49]=[O:50])=[CH:45][C:41]=2[C:42](O)=[O:43])[CH:34]=[CH:35][C:36]=1[F:37]>CN(C)C=O>[F:30][C:31]1[CH:32]=[C:33]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([CH:49]=[O:50])=[CH:45][C:41]=2[C:42]([NH:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[O:43])[CH:34]=[CH:35][C:36]=1[F:37]
Reactant: Nc1cccnc1
Reactant: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)O)c1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C

Procedure:
EDC (0.79 g, 4.11 mmol), HOBT (0.84 g, 5.48 mmol), N-ethylmorpholine (0.87 ml, 6.84 mmol) and 3-pyridinamine (0.48 g, 5.13 mmol) were added to a solution of 2-{[(3,4-difluorophenyl)methyl]oxy}-5-formylbenzoic acid (may be prepared as described in Description 101; 1 g, 3.42 mmol) in N,N-dimethylformamide (25 ml), and the mixture was stirred at room temperature. The N,N-dimethylformamide was evaporated under reduced pressure and the residue was diluted with ethyl acetate (100 ml). The organic layer was washed with saturated sodium hydrogencarbonate (2×50 ml) and water (2×50 ml). The organic layer was dried (MgSO4), filtered and evaporated under reduced pressure to yield the title compound as a yellow solid. 1.19 g.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([C:19]([C:37]1[CH:42]=[CH:41][C:40](OS(C(F)(F)F)(=O)=O)=[C:39]([CH3:51])[CH:38]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([CH2:34][CH3:35])([OH:33])[CH2:31][CH3:32])=[C:24]([CH3:36])[CH:23]=1)[CH2:20][CH3:21])[CH3:18].O>CN(C)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>[CH2:17]([C:19]([C:37]1[CH:42]=[CH:41][C:40]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=2)=[C:39]([CH3:51])[CH:38]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([CH2:31][CH3:32])([OH:33])[CH2:34][CH3:35])=[C:24]([CH3:36])[CH:23]=1)[CH2:20][CH3:21])[CH3:18]
Reactant: Bc1cccc(C(=O)O)c1
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(OS(=O)(=O)C(F)(F)F)c(C)c2)cc1C)CC
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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cccc(C(=O)O)c3)c(C)c2)cc1C)CC
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 59.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (6.8 mg, 0.0059 mmol), 3-carboxyphenylborane acid (6.8 mg, 0.0195 mmol) and potassium carbonate (13.4 mg, 97.5 μmol) were added to a solution of trifluoromethanesulfonic acid 4-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl ester (Example 1-(6); 10 mg, 0.0195 mmol) in N,N-dimethylformamide (0.5 mL) at room temperature, and then the mixture was stirred at 80° C. for five minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (chloroform/methanol=8/3, saturated with water) to give the title compound (5.6 mg, 60%).
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH:11]=[CH:12][O:13][C:9]=2[CH:8]=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:15]([O:14][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]=[CH:11][C:10]=2[C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)c1c(O)ccc2occc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1c(OCc2ccccc2)ccc2occc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
4-tert-butyl-5-hydroxybenzofuran [J. Org. Chem., 53, 4135 (1988); 40 g, 0.21 mol], benzyl bromide (43 g, 0.25 mol) and potassium carbonate (28.8 g, 0.21 mol) were dissolved in N,N-dimethylformamide (200 ml) and the solution was stirred at room temperature for 24 h. After distilling off the N,N-dimethylformamide under vacuum, water was added to the residue and the mixture was subjected to extraction with ethyl acetate. The extracted layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 5-benzyloxy-4-tert-butylbenzofuran [49.1 g (yield, 83%)].
Reaction SMILES: II.Br[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[CH3:11].[N:12]1[C:19]([Cl:20])=[N:18][C:16](Cl)=[N:15][C:13]=1[Cl:14].Cl>C1COCC1.C1(C)C=CC=CC=1>[Cl:14][C:13]1[N:12]=[C:19]([Cl:20])[N:18]=[C:16]([C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=2[CH3:11])[N:15]=1
Reactant: Cc1ccc(Br)c(C)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: II
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc(Cl)nc(Cl)n2)c(C)c1
Yield: 79.8 %

Procedure:
17.0 g (0.70 mol) of iodine-activated magnesium turnings in 25 ml of anhydrous THF are heated briefly to 60° C. Then 154.9 g (0.70 mol) of 4-bromo-m-xylene (in c. 90% purity) and 155 ml of THF are added dropwise over 30 min and the mixture is heated for 2 hours to reflux. After cooling, the Grignard solution is added over 1.5 hours to a mixture of 43.0 g (0.233 mol) of cyanuric chloride and 150 ml of THF, while keeping the temperature of the mixture in the range from 0° to 10° C. The mixture is then diluted with 210 ml of toluene, the resultant suspension is poured into 220 g of 12% aqueous HCl, the organic phase is separated, washed with a total amount of 280 g of water and concentrated. The resultant material is recrystallised from 2-butanol, giving the title compound with a melting point of 135.5°-137° C. in a yield of 79.8%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:32])=[C:13]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C:16]2=[O:31])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]=[O:34].[OH-].[Na+]>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:32])=[C:13]([C:15]2([CH2:33][OH:34])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C:16]2=[O:31])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(c2cc(OCc3ccccc3)ccc2O)c2ccccc2N1Cc1ccc(Cl)s1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1N(Cc2ccc(Cl)s2)c2ccccc2C1(CO)c1cc(OCc2ccccc2)ccc1O
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a mixture of 3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chlorothiophen-2-yl)methyl]-1,3-dihydro-2H-indol-2-one (2.80 g, 6.07 mmol), para-formaldehyde (0.73 g, 24.3 mmol) in tetrahydrofuran (10.0 mL) was added an aqueous solution of sodium hydroxide (0.97 g, 24.3 mmol) in water (10.0 mL) at 0° C. The reaction solution was stirred for 2 h, then quenched by the addition of 10% aqueous hydrochloric acid solution (30.0 mL). The reaction mixture was extracted with ethyl acetate (3×50 mL). The combined organic solution was washed with saturated ammonium chloride (3×50 mL), brine (50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was triturated with diethyl ether, filtered and dried to afford 3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chlorothiphen-2-yl)methyl]-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (2.71 g, 91%) as a colourless solid: MS (ES+) m/z 494.2 (M+1), 492.3 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:24]2[S:25][CH:26]=[C:27]([CH3:29])[N:28]=2)=[CH:11][N:10]=1)(C)(C)C.[ClH:31]>C(Cl)Cl.O1CCOCC1>[ClH:31].[NH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:24]2[S:25][CH:26]=[C:27]([CH3:29])[N:28]=2)=[CH:11][N:10]=1
Reactant: COc1cc2c(Nc3nc(C)cs3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc2c(Nc3nc(C)cs3)cnc(CN)c2cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
[6,7-Dimethoxy-4-(4-methyl-thiazol-2-ylamino)-isoquinolin-1-ylmethyl]carbamic acid tert-butyl ester (11.6 mg, 0.0269 mmol) in CH2Cl2 (0.6 mL) was added a 4.0 M HCl solution in dioxane (0.40 mL) at room temp. After the reaction mixture was stirred at room temperature for 5.0 h, the suspension was filtered. The yellow solid was further dried in vacuo to give (1-aminomethyl-6,7-dimethoxy-isoquinolin-4-yl)-(4-methyl-thiazol-2-yl)amine hydrochloride salt (7.4 mg; 75%). 1H-NMR (D2O): δ, 8.33 (s, 1H), 7.26 (s, 1H), 7.15 (s, 1H), 6.34 (s, 1H), 4.70 (s, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 2.05 (s, 3H); MS: calculated for C16H19N4O2S (M−Cl) 331.0; found: 331.0.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[CH:3]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12](B(CC)CC)[CH:11]=1>N1C=CC=CC=1>[I:9][C:4]1[CH:3]=[C:2]([C:12]2[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([I:8])[CH:5]=1
Reactant: CCB(CC)c1cccnc1
Reactant: Ic1cc(I)cc(I)c1
Solvent: c1ccncc1
Product: Ic1cc(I)cc(-c2cccnc2)c1

Procedure:
The pyridine was prepared as above from 1,3,5-triiodobenzene and 3-pyridyldiethylborane. ##STR97##
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][CH2:14][O:15][C:16]([CH3:18])=[O:17].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]=[CH:34][N+:35]([O-:37])=[O:36])[CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:14]([O:15][C:16](=[O:17])[CH2:18][CH:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:28]=1)[CH2:34][N+:35]([O-:37])=[O:36])[CH3:13]
Reactant: O=[N+]([O-])C=Cc1cccc(OCc2ccccc2)c1
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC(C[N+](=O)[O-])c1cccc(OCc2ccccc2)c1
Temperature: -78 °C

Procedure:
To a dry round bottom flask was added 2.7 mL of diisopropylamine and 20 mL THF. The mixture was cooled to −78° C. with stirring. A solution of n-BuLi (11.4 mL, 1.6 M) was added dropwise and the resulting solution was stirred for 20 min. EtOAc (1.5 mL) was added slowly to quench and the mixture was stirred for an additional 20 min. 1-Benzyloxy-3-(2-nitrovinyl)benzene (3.4 g, 13 mmol) in 50 mL THF was then added and the solution was stirred for 2 h. The mixture was warmed to r.t., quenched with sat. NH4Cl solution (50 mL), extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 3.2 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:8])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[N+:14]([O-])([OH:16])=[O:15].C1C=CC=CC=1>CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([F:8])[CH:5]=[CH:6][C:7]=1[N+:14]([O-:16])=[O:15]
Reactant: Fc1cccc(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(F)cc1Cl
Reaction time: 13 h
Yield: 15.7 %

Procedure:
m-Chlorofluorobenzene (240 g. 1.85 moles) is added to a mixture of sulfuric acid (185 g. 1.85 moles) and nitric acid (166 g., 1.85 moles) at -5° C. in 3.5 hours, stirred 13 hours, then benzene (200 ml.) and hexane (200 ml.) are added. The extract is washed with water (1×300 ml.), sodium carbonate solution (1×300 ml.), and water (1×300 ml.), dried and the solvents removed. The residue is distilled to give 138 g. of mixed isomers. The 4-nitro isomer crystallizes and is filtered off to give 3-chloro-4-nitrofluorobenzene (51 g. 16.7%) m.p. 36°-38° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[Br:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br>>[Br:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][N:9]1[C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:11]=2[C:12](=[O:13])[N:7]([OH:6])[C:8]1=[O:21]
Reactant: BrCc1cccc(Br)c1
Reactant: COc1ccc(COn2c(=O)[nH]c3c(oc4ccccc43)c2=O)c(OC)c1
Product: O=c1c2oc3ccccc3c2n(Cc2cccc(Br)c2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-dimethoxy-benzyloxy)-1H-benzo[4,5]furo[3,2-d]pyrimidine-2,4-dione was alkylated with 3-bromobenzyl bromide and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 5.55 (s, 2H); 7.25-7.40 (m, 3H); 7.42-7.52 (m, 1H); 7.57-7.63 (m, 2H); 7.76-7.85 (m, 2H); Ret. time=2.64 min., m/z=386.0.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([Mg])=[CH:14][CH:13]=1>C1COCC1>[Cl:3][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[N:1]=1
Reactant: COc1ccc([Mg])cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(Cl)nc(Cl)n2)cc1
Temperature: 7.5 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
A 1-litre reactor is charged under nitrogen with cyanuric chloride (36.9 g, 0.2 mol) and then with 50 ml of THF. The suspension is cooled to 5-10° C. With stirring, at a temperature of less than 10° C., a 0.5M solution of para-methoxyphenylmagnesium in THF (400 ml, 0.2 mol) is run in under inert gas over 45 minutes. The reaction mixture is left to stand overnight. The solvent is evaporated on a rotary evaporator. The residue is poured into acidified water. Following extraction with dichloromethane, the organic phase is washed with water and dried over sodium sulphate. The solvent is evaporated. The crude solid obtained is triturated with isopropanol and then filtered. The solid is dissolved in hot toluene. Addition of the same volume of heptane precipitates the product. The precipitate is cooled, isolated by filtration and dried. This gives 31.7 g (yield: 62%) of 2,4-dichloro-6-(4-methoxyphenyl)[1,3,5]triazine in the form of a beige powder (m.p. 133-136° C.), which is used as it is in the following step.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1.[B:20](OC)([O:23]C)[O:21]C.Cl>O1CCCC1.C(OCC)C>[F:18][C:13]([F:19])([C:10]1[CH:11]=[CH:12][C:7]([B:20]([OH:23])[OH:21])=[CH:8][CH:9]=1)[C:14]([F:17])([F:16])[F:15]
Reactant: FC(F)(F)C(F)(F)c1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(C(F)(F)C(F)(F)F)cc1
Reaction time: 0.33 h
Yield: 71.2 %

Procedure:
A 1.5 M solution of n-butyllithium in tetrahydrofuran (0.57 mL) was added to a solution of 1-bromo-4-pentafluoroethylbenzene (180 mg, 0.65 mmol) in diethyl ether (1.0 mL) at −78° C., and the mixture was stirred for 20 minutes. Thereafter, trimethyl borate (101 mg, 3.28 mmol) was added and the mixture was stirred at −78° C. for 10 minutes and at room temperature for 30 minutes. 6 N aqueous hydrochloric acid (200 μL) was added to the reaction mixture, and the reaction was terminated. The mixture was then purified by silica gel column chromatography to give 4-pentafluoroethylphenylboronic acid as a white solid (111 mg, 71%).