Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[NH:13][C:12](=O)[C:11]=2[CH2:10][CH2:9]1.P(N)([NH2:32])(=O)OC1C=CC=CC=1.[OH-].[Na+]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([NH2:32])[C:11]=2[CH2:10][CH2:9]1
Reactant: NP(N)(=O)Oc1ccccc1
Reactant: Cc1ccccc1N1CCc2c1c1cccc(C)c1[nH]c2=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccccc1N1CCc2c(N)nc3c(C)cccc3c21
Temperature: 230 °C
Yield: 15.2 %

Procedure:
Impure 1-(2-methylphenyl)-4-oxo-6-methyl-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline (10.0 g) and phenyl phosphorodiamidate (12 g) were fused at 230° C. After 30 minutes the mixture was diluted with diphenyl ether (50 ml), further phenyl phosphorodiamidate (4 g) added, and heated for a further 30minutes at 230° C. Aqueous sodium hydroxide was added and the product extracted into dichloromethane. Chromatography (silica gel, 3% methanolic ammonia in dichloromethane) to remove unchanged starting material was followed by recrystallisation from ethanol to yield 1-(2-methylphenyl)-4-amino-6-methyl-2,3-dihydropyrrolo[3,2-c]quinoline (1.51 g), m.p. 173°-174°.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([O:13][CH3:14])=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH:15]([NH2:17])=O>>[CH3:14][O:13][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][C:10]=1[CH3:12])[NH:1][CH:15]=[N:17][C:4]2=[O:5]
Reactant: COC(=O)c1cc(OC)c(C)cc1N
Reactant: NC=O
Product: COc1cc2c(=O)nc[nH]c2cc1C
Temperature: 140 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
Methyl 2-amino-5-methoxy-4-methylbenzoate (510 mg) was suspended in formamide (5 ml), and the suspension was stirred at 140° C. overnight. The precipitated crystal was washed with ether to give 6-methoxy-7-methyl-1H-quinazolin-4-one (275 mg, yield 55%).
Reaction SMILES: [Br:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[CH3:9][C:10](=[CH2:12])[CH3:11].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>CCOCC>[Br:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([O:5][C:10]([CH3:12])([CH3:11])[CH3:9])=[O:4]
Reactant: CC(C)C(Br)C(=O)O
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)C(Br)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4.0 mm of (+)-2-bromo-3-methylbutyric acid is dissolved in a solvent consisting of 100 ml of ether, 100 ml of isobutylene, and 0.5 ml of sulfuric acid. The resulting solution is shaken for approximately 72 hours in an autoclave at room temperature. The solution is then neutralized with sodium bicarbonate, dried with magnesium sulfate, and then evaporated to yield (+)-t-butyl 2-bromo-3-methylbutyrate.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CI.[C:17](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([O:12][CH3:17])=[O:11])=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
A mixture of 5.80 g of p-nitrocinnamic acid, 10.4 g of methyl iodide, 10.4 g of anhydrous potassium carbonate and 200 ml of acetone was stirred at room temperature for 2 days. The resultant precipitate was filtered off, the filtrate was concentrated under reduced pressure and, after addition of water, the residue was extracted with ethyl acetate. The organic layer was washed with saturated solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3.30 g of methyl 4-nitrocinnamate.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH3:12].[B:13](OC)([O:16]C)[O:14]C.S(=O)(=O)(O)O>BrC1C=C(C)C=CC=1C.C1COCC1>[CH3:12][C:6]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=1[B:13]([OH:16])[OH:14]
Reactant: COB(OC)OC
Reactant: Cc1ccc(C)c(Br)c1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C)c(B(O)O)c1
Temperature: 25 °C

Procedure:
Magnesium turnings (13.3 g; 0.55 mol) are introduced into a baked-out, argon-blanketed apparatus, covered with about 30 ml of THF and a few crystals of iodine are added. Without stirring, a few drops of bromo-p-xylene (cf. Example A1 a)) were subsequently added to the solution. The Grignard reaction began very quickly and the remaining bromo-p-xylene (total amount: 92.59; about 70 ml; 0.5 mol) was subsequently added dropwise while stirring. The mixture was refluxed for 4 hours and then cooled. The Grignard solution was then transferred in a countercurrent of protective gas into a 500 ml dropping funnel and added dropwise to a solution of trimethyl borate (62.4 g; 67 ml; 0.6 mol) in 350 ml of THF while stirring at −70° C. (time: about 1 hour). A precipitate was formed during this addition. The reaction mixture was allowed to warm to RT overnight and was then introduced while stirring into a mixture of 700 g of ice and 20 ml of concentrated sulfuric acid. The organic phase was separated off, the aqueous phase was extracted three times with chloroform and the combined organic phases were evaporated. The crude product was recrystallized from chloroform/hexane. This gave a colorless microcrystalline powder: 47.71 g (64%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][CH2:20][C@@H:19]2[C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[CH:12][C:11]=1[F:32])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:24][C:22]1([CH3:25])[CH2:23][C@H:18]([O:17][C:13]2[C:14]([F:16])=[CH:15][C:10]([S:7]([NH:6][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][N:34]=3)(=[O:8])=[O:9])=[C:11]([F:32])[CH:12]=2)[C@@H:19]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)[CH2:20][CH2:21]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CC(C)(C)CC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC(C)(C)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 92.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-5,5-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (100 mg, 0.159 mmol) prepared in Example 72e, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (70 mg, 92%) as a colorless solid.
Reaction SMILES: [CH2:1]1[O:23][CH:4]([C:5]2[C:13]3[NH:12][C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[N:10][C:9]=3[CH:8]=[CH:7][CH:6]=2)[O:3][CH2:2]1.[H-].[Na+].[CH3:26]I.O>C1COCC1>[CH2:1]1[O:23][CH:4]([C:5]2[C:13]3[N:12]=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])[N:10]([CH3:26])[C:9]=3[CH:8]=[CH:7][CH:6]=2)[O:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1-c1nc2cccc(C3OCCO3)c2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(-c2ccccc2[N+](=O)[O-])nc2c(C3OCCO3)cccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2-(2-nitrophenyl)-benzimidazole-4-carboxaldehyde ethylene acetal 5 (4.53 g, 14.6 mmol) in dry THF (20 mL) was added to a stirring suspension of NaH (0.640 g, 60% dispersion in mineral oil, 16.0 mmol) in dry THF (50 mL) at 0° C. under N2. The mixture was then allowed to warm to room temperature for 1 hour resulting in an orange solution. Methyl iodide (4.58 mL, 72.8 mmol) was syringed into the above mixture at room temperature under N2. This mixture was stirred for 24 hours under N2 to give a yellow mixture. Water was added and the aqueous layer was extracted with CHCl3. The combined extracts were washed with brine and dried over Na2SO4. After rotary evaporation, the resulting residue was purified by column chromatography on silica gel using Et2O:CH2Cl2 (3:1) as the eluent to give the title compound. (3.53 g, 74%). 1H NMR (CDCl3): δ 3.58 (s, 3H), 4.02-4.19 (m, 4H), 6.55 (s, 1H), 7.33-7.41 (m, 1H), 7.52-7.56 (m, 1H), 7.62-7.75 (m, 4H), 8.19 (d, J=1.7, 7.9 Hz, 1H); HRMS: Calcd. for C17H15N3O4 325.1062, found 325.1050.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=[O:13])[NH:3]1.[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:3]1
Reactant: O=C(O)CC1NC(=O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)CC1NC(=O)c2ccccc21
Reaction time: 4 h

Procedure:
A solution of 2,3-dihydro-3-oxo-1H-isoindole-1-acetic acid (described by F. M. Rowe et al., cited above, 2.0 g) in ethanol (40 ml) containing p-toluene-sulfonic acid (0.10 g) is refluxed with stirring for 4.0 hr. Most of the ethanol is evaporated and the residue is dissolved in chloroform. The solution is washed with water, dried and evaporated. The residue (2.2 g) is crystallized from benzenehexane to give ethyl 1,3-dihydro-3-oxo-2H-isoindole-1-acetate, mp 116°-118° C.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][CH:7]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:6]1=[O:34])([OH:3])=[O:2].[C:35]([O:41][CH2:42]Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].C(N(CC)CC)C>CN(C)C=O>[C:35]([O:41][CH2:42][O:2][C:1]([CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:8][CH:7]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:6]1=[O:34])=[O:3])(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: O=C(O)CN1C(=O)C(NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOC(=O)CN1C(=O)C(NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21
Reaction time: 48 h

Procedure:
A mixture of 1-carboxymethyl-1,3-dihydro-3-(2-indolecarbonylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one (85 mg, 0.20 mmol), pivaloyloxymethylchloride (32 μl, 0.22 mmol) and triethylamine (28 μl, 0.20 mmol) was combined in 2 ml of dry dimethylformamide and allowed to stand at room temperature for 48 hours. Solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. Extractive work-up gave 100 mg of crude Product which was chromatographed on silica gel (CH3OH-CHCl3, 3:97 v/v elution) to give a white solid after trituration with ether: m.p. 225°-226° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][O:7][CH2:8]2)([O-])=O.[H][H]>[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][O:7][CH2:8]2
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc2c1COC2
Agent: [Pd]
Product: Nc1cccc2c1COC2

Procedure:
Nitration of the 1,3-dihydro-iso-benzofuran derivatives of Formula 17 provides the 1,3-dihydro-4-nitro-iso-benzofuran compounds of Formula 18. The nitro compounds of Formula 18 are reduced with hydrogen on a suitable catalyst, such as palladium, to give the 1,3-dihydro-4-amino-iso-benzofuran compounds of Formula 19.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH:13]=1)C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH:13]=1
Reactant: COC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(C(=O)N(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1ccc([N+](=O)[O-])c(C(=O)N(C)C)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 80.3 %

Procedure:
The 2-(3-dimethylcarbamoyl-4-nitrophenyl)malonic acid tert-butyl ester methyl ester (1.22 g) obtained in Example 2b) was dissolved in dichloromethane (10 mL), and the solution was cooled to 0° C. After addition of trifluoroacetic acid (10 mL), the mixture was stirred at room temperature for 6 hours, and concentrated, followed by azeotropic distillation with toluene. The residue was purified by column chromatography on silica gel with ethyl acetate:hexane=3:1 to give the title compound (712 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>C1COCC1>[C:21]([O:24][CH2:25][C:26](=[O:27])[NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11])(=[O:23])[CH3:22]
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CC(=O)OCC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 75 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added (chlorocarbonyl)methyl acetate (0.55 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.56 g (75%) of product as an off-white solid: mp 234-236° C.; 1H NMR (DMSO-d6) , 11.15 (s, 1H), 10.06 (s, 1H), 8.55 (d, J=8.3 Hz, 1H), 7.87 (t, J=8.0 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 5.17 (dd, J=5.0 and 12.4 Hz, 1H), 4.78 (s, 2H), 2.99-2.85 (m, 1H), 2.65-2.52 (m, 2H), 2.22 (s, 2H), 2.11-2.07 (m, 1H); 13C NMR (DMSO-d6) δ 172.70, 169.69, 169.50, 167.99, 166.57, 136.40, 135.59, 131.35, 125.34, 118.72, 116.96, 62.60, 48.98, 30.90, 21.91, 20.41; Anal. Calcd. For C17H15N3O7: C, 54.69; H, 4.05; N, 11.26. Found: C, 54.43; H, 4.05; N, 10.97.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23].C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[CH:34]=[CH2:35].O>CN(C)C=O>[C:19]([C:4]1[C:3]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:2]([NH:1][CH2:35][CH:34]=[CH2:33])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: C=CCBr
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCNc1c(C(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoroacetylpyrazole (1 g) in anhydrous N,N-dimethylformamide (4 ml) at room temperature was added potassium carbonate (0.7 g), then allyl bromide (165 μl). The mixture was stirred at room temperature for 40 minutes. Water (50 ml) was then added, and the mixture was extracted with ether (50 ml, ×2). The combined organic layers were washed with water (50 ml), dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (50 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a very pale yellow/white solid, m.p 115-116° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[N:11]=[C:12]([O:22][CH:23]3[CH2:40][CH:39]4[N:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]5[C:36]([C:42](O)=[O:43])([NH:37][C:38]4=[O:41])[CH2:35]5)[CH2:24]3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=3)[N:9]=1)([CH3:3])[CH3:2].ClC1N=C(OC2CC3N(C(=O)N(C)CCCCC=CC4C(C([NH:82][S:83]([CH:86]5[CH2:88][CH2:87]5)(=[O:85])=[O:84])=O)(NC3=O)C4)C2)C2C(C=1)=CC(OC)=CC=2>>[CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[N:11]=[C:12]([O:22][CH:23]3[CH2:40][CH:39]4[N:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]5[C:36]([C:42]([NH:82][S:83]([CH:86]6[CH2:88][CH2:87]6)(=[O:85])=[O:84])=[O:43])([NH:37][C:38]4=[O:41])[CH2:35]5)[CH2:24]3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=3)[N:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3csc(NC(C)C)n3)cc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3csc(NC(C)C)n3)cc2c1

Procedure:
The title product 72 was prepared from 17-[3-(2-isopropylaminothiazol-4-yl)-6-methoxyisoquinolin-1-yloxy]-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo-[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (71) following the same procedures described for the preparation of N-[17-(3-chloro-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl]-(cyclopropyl)sulfonamide (43, Example 11): m/z=752 (M+H)+. 1H NMR (CDCl3): 0.93-1.03 (m, 1H), 1.05-1.15 (m, 1H), 1.18-1.28 (m, 3H), 1.32 (d, J=6.6 Hz, 3H), 1.34 (d, J=6.6 Hz, 3H), 1.36-1.67 (m, 4H), 1.93-2.07 (m, 2H), 2.22-2.36 (m, 1H), 2.45-2.65 (m, 3H), 2.85 (s, 3H), 2.91-3.00 (m, 1H), 3.05-3.17 (m, 1H), 3.64-3.80 (m, 3H), 3.89 (s, 3H), 4.08 (dd, J=3.8 Hz, J=10.9 Hz, 1H), 4.78 (t, J=8.1 Hz, 1H), 5.15 (t, J=10.4 Hz, 1H), 5.21-5.36 (broad s, 1H), 5.73 (dd, J=8.1 Hz, J=18.4 Hz, 1H), 5.94-6.02 (m, 1H), 6.92-6.99 (broad s, 1H), 7.00-7.07 (m, 2H), 7.22 (s, 1H), 7.74 (s, 1H), 7.95 (d, J=8.6 Hz, 1H), 10.54-10.99 (broad s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:29][CH2:28][CH2:27][CH2:26][CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: OCCCCc1ccccc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCCCCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, 4-phenyl-1-butanol and DBU in DME. ES-MS m/e (%): 357 (M+Na+, 20), 335 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[N:16]=[C:15]([CH3:17])[N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2C1CCCCO1.[NH:24]1[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([NH2:33])[C:27]=2[CH:26]=[N:25]1.Cl>C(O)C.C([O-])(O)=O.[Na+]>[CH3:17][C:15]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][NH:12]2)=[C:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[NH:33][C:28]2[C:27]3[CH:26]=[N:25][NH:24][C:32]=3[CH:31]=[CH:30][CH:29]=2)[N:16]=1
Reactant: Nc1cccc2[nH]ncc12
Reactant: Cc1nc(-c2cnccc2Cl)c2ncn(C3CCCCO3)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(-c2cnccc2Nc2cccc3[nH]ncc23)c2nc[nH]c2n1
Temperature: 160 °C
Yield: 67.2 %

Procedure:
A glass microwave reaction vessel was charged with 6-(4-chloropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (33 mg, 0.100 mmol) and 1H-indazol-4-amine (26.6 mg, 0.200 mmol, Bionet Research, Cornwall, UK) in Ethanol (1 mL) and a drop of 5 N HCl. The reaction mixture was stirred and heated in a Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 160° C. for 30 min. The reaction mixture was diluted with saturated NaHCO3 (5 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with saturated NaCl (3 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give a yellow solid. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column, eluting with 10% MeOH/CH2Cl2 to provide N-(3-(2-methyl-9H-purin-6-yl)pyridin-4-yl)-1H-indazol-4-amine (23 mg, 67% yield) as yellow solid. 1H NMR (300 MHz, d6-DMSO) δ 13.27 (s, 1H); 12.54 (s, 1H); 10.22 (s, 1H); 8.64 (s, 1H); 8.30 (d, J=5.85 Hz, 1H); 8.16 (s, 1H); 7.30-7.43 (m, 3H); 7.18 (d, J=6.87 Hz, 1H); 2.82 (s, 3H). m/z (ESI, +ve ion) 343 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][N:14]=1>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:15][N:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)nc1
Reactant: OB(O)c1cc(F)ccc1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)c1ccc(-c2cc(F)ccc2F)nc1
Temperature: 90 °C
Yield: 39.6 %

Procedure:
To round-bottom flask was added 2,5-difluoro phenylboronic acid (306 mg, 1.94 mmol), palladium tetrakis(triphenylphosphine) (22.4 mg, 0.0194 mmol)) and tert-butyl 6-bromonicotinate (500 mg, 1.94 mmol) and the mixture was evacuated 3× with N2. The solids were dissolved in 25 mL of DMF, followed by addition of 2.9 mL of 2 M cesium carbonate. The resulting mixture was heated to ˜90° C. The mixture was cooled to rt and then poured into a sep. funnel, followed by addition of EtOAc and water (1×200 mL). The layers were separated and the organic extract washed with brine (1×200 mL), dried MgSO4, filtered and concentrated to afford an orange oil. The crude mixture was purified by chromatography (silica, 10% EtOAc:Heptane) to afford the desired product (224 mg, 40%). 1H NMR (400 MHz, DMSO-d6) □ ppm 9.07-9.19 (1H, m), 8.36 (1H, dd, J=8.2, 2.2 Hz), 7.99 (1H, dd, J=8.3, 1.8 Hz), 7.75-7.86 (1H, m), 7.36-7.52 (1H, m), 7.36-7.52 (2H, m), 1.59 (9H, s). LC/MS (M+H)=292.1 observed, 292.11 expected.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[C:12]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)=[C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:10](=[O:28])[N:9]([CH2:29][C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[O:38][CH3:39])[C:8]=3[C:6]=2[CH:7]=1.[C:40]1(B(O)O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[C:40]1([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[C:12]([C:15]5[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=5)=[C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:10](=[O:28])[N:9]([CH2:29][C:30]5[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=5[O:38][CH3:39])[C:8]=4[C:6]=3[CH:7]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)c2oc3ccc(Br)cc3c2n(Cc2cc(OC)ccc2OC)c1=O
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)c2oc3ccc(-c4ccccc4)cc3c2n(Cc2cc(OC)ccc2OC)c1=O

Procedure:
Ethyl 8-bromo-1-(2,5-dimethoxybenzyl)-4-(4-methoxyphenyl)-1,2-dihydro-2-oxobenzofuro[3,2-b]pyridine-3-carboxylate is reacted analogously to Example 3 with phenylboronic acid to give ethyl 8-phenyl-1-(2,5-dimethoxybenzyl)-4-(4-methoxyphenyl)-1,2-dihydro-2-oxobenzofuro[3,2-b]pyridine-3-carboxylate, m.p. 216°. By ester hydrolysis thereof the 8-phenyl-1-(2,5-dimethoxybenzyl)-4-(4-methoxyphenyl)-1,2-dihydro-2-oxobenzofuro[3,2-b]pyridine-3-carboxylic acid is obtained, m.p. 270°.
Reaction SMILES: [C:1]([OH:6])(=[S:5])[CH:2](C)O.[F:7][C:8]([F:15])([F:14])[C:9](=[CH2:13])[C:10]([OH:12])=[O:11]>>[C:1]([S:5][CH2:13][CH:9]([C:8]([F:15])([F:14])[F:7])[C:10]([OH:12])=[O:11])(=[O:6])[CH3:2]
Reactant: CC(O)C(O)=S
Reactant: C=C(C(=O)O)C(F)(F)F
Product: CC(=O)SCC(C(=O)O)C(F)(F)F

Procedure:
A mixture of thiolactic acid (50 g.) and 2-(trifluoromethyl)acrylic acid [M. W. Buxton, et al., J. Chem. Soc., 366 (1954)] (66 g.) is heated on the steam bath for one hour and then stored at room temperature for eighteen hours. The reaction mixture is distilled in vacuo to give 3-acetylthio-2-trifluoromethylpropanoic acid.