Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH2:21][C@@H:22]([C:25]1[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[CH2:23][OH:24].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH:21][C@@H:22]([C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)[CH2:23][OH:24])[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: COc1ccc([C@H](N)CO)cn1
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Cl)c2C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@@H](CO)Nc2ncnc3c2CN(c2ccc(Cl)cc2C#N)CC3)cn1

Procedure:
A reaction mixture of 5-chloro-2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (250 mg, 0.82 mmol) and (S)-2-amino-2-(6-methoxypyridin-3-yl)ethanol (110 mg, 0.68 mmol) in acetonitrile (3 mL) and N,N-diisopropylethylamine (240 μL, 1.4 mmol) was subjected to microwave irradiation at 180° C. for 4 h. The reaction mixture was concentrated and the residue was purified by silica gel column (0-15% MeOH/CH2Cl2) to yield a crude product which was recrystallized from MeOH to yield colorless crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][CH3:25])[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[NH2:17][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][N:24]([CH3:25])[C:33]([NH:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:34])[C:7]=2[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[N:10]=1
Reactant: O=C=Nc1ccccc1
Reactant: CNCCOCCn1c(CCOC)nc2c(N)nc3c(c21)CCCC3
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3c(c2n1CCOCCN(C)C(=O)Nc1ccccc1)CCCC3
Reaction time: 8 h
Yield: 16.9 %

Procedure:
2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (750 mg, 2.16 mmol) was dissolved in 30 mL of anhydrous CH2Cl2 and treated with phenyl isocyanate (239 μL, 2.20 mmol). After stirring under N2 overnight, the reaction mixture was concentrated under reduced pressure. Crystallization from EtOAc and CH2Cl2 gave 170 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methyl-N′-phenylurea as fluffy white crystals. m.p. 167.7-170.0° C.;
Reaction SMILES: N1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2C(=O)NC1=O.N1C=CC(=O)NC1=O.C[Si](C)(C)[CH2:22][CH2:23][O:24][CH2:25][Cl:26]>>[CH2:23]([O:24][CH2:25][Cl:26])[C:22]1[CH:8]=[CH:9][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c2c(c(=O)[nH]1)CCC2
Reactant: C[Si](C)(C)CCOCCl
Agent: O=c1cc[nH]c(=O)[nH]1
Product: ClCOCc1ccccc1

Procedure:
In a similar manner to the procedures described in Reference Example 3, reactions were carried out using 6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-dione, instead of pyrimidine-2,4-dione, and using 2-(trimethylsilyl)ethoxymethyl chloride, instead of benzyloxymethyl chloride, to give the title compound (yield 71%) as a pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:16])[CH2:11][CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([CH3:17])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:28]1[CH:33]([CH:34]=[O:35])[CH2:32][CH2:31][O:30][CH2:29]1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:17])[C:5]([C:9]2[C:10](=[O:16])[CH:11]([CH:34]([OH:35])[CH:33]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:6]([CH3:8])[CH:7]=1
Reactant: O=CC1CCOCC1
Reactant: COC1=C(c2c(C)cc(Br)cc2C)C(=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1=C(c2c(C)cc(Br)cc2C)C(=O)C(C(O)C2CCOCC2)C1
Temperature: -75 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-bromo-2,6-dimethylphenyl)-3-methoxycyclopent-2-enone (7.5 g, 26.0 mmol) in anhydrous tetrahydrofuran (70 ml) under a nitrogen atmosphere is added lithium bis(trimethylsilyl)amide (44.6 ml, 31.0 mmol, 0.7M in tetrahydrofuran) dropwise at −75°C. After stirring for 40 minutes at this temperature a second solution of tetrahydropyranyl-4-carboxaldehyde (5.90 g, 52.0 mmol) in tetrahydrofuran (70 ml) is added over 20 minutes, and the resulting solution is stirred at −75°C. for 2 hours. After warming to room temperature the mixture is stirred for a further 2 hours, then is quenched with ice cold water (100 ml) and extracted with ethyl acetate (3×150 ml). Organics are combined, dried over sodium sulphate, filtered and the filtrate is concentrated in vacuo to afford 2-(4-bromo-2,6-dimethylphenyl)-5-[hydroxy(tetrahydropyran-4-yl)methyl]-3-methoxycyclopent-2-enone. This material is used directly in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[H-].[Na+].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15]>CN(C=O)C.C(OCC)(=O)C>[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:7]2[C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[N:4]=[C:3]2[CH2:2][OH:1])=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: OCc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cn2c(CO)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
To a solution of 3 g of 2-hydroxymethylbenzimidazole in 20 mL of dried DMF at 0° was added portionwise 1 g of NaH (50% oil dispersion). After stirring at room temperature for 15 minutes, 4.3 g of p-nitrobenzyl bromide was added. The reaction mixture was stirred for 16 hours and then diluted with ethyl acetate and washed with water. The organic layers were dried and evaporated. Recrystallization from acetonitrile afforded 3.5 g of a brownish solid; m.p. 162.5-165°.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH2:17][N:18]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[N:7]=1.[Br:35]Br>C(O)(=O)C.O>[ClH:1].[NH2:2][C:3]1[S:4][C:5]([Br:35])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([CH2:17][N:18]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[O:16])=[CH:12][CH:13]=2)[N:7]=1
Reactant: Nc1nc(-c2ccc(NC(=O)CN(C(=O)c3ccc(F)cc3)c3ccc(F)cc3)cc2)cs1
Reactant: BrBr
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(-c2ccc(NC(=O)CN(C(=O)c3ccc(F)cc3)c3ccc(F)cc3)cc2)c(Br)s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N-{[4-(2-aminothiazol-4-yl)phenylcarbamoyl]methyl}-4-fluoro-N-(4-fluorophenyl)benzamide monohydrochloride (200 mg) was dissolved in a mixed solvent of acetic acid (10 ml) and water (5 ml), mixed with bromine (20 μl) under ice-cooling and then stirred at room temperature for 5 minutes. The reaction solution was concentrated under a reduced pressure, and the residue was dissolved in ethyl acetate (30 ml)-saturated sodium bicarbonate aqueous solution (20 ml). The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated under a reduced pressure. The residue was dissolved in ethyl acetate (5 ml) and mixed with 4 M hydrogen chloride in ethyl acetate solution (0.15 ml), and the thus precipitated solid was collected by filtration, dried and then recrystallized from methanol-ether, thereby obtaining 184 mg of N-{[4-(2-amino-5-bromothiazol-4-yl)phenylcarbamoyl]methyl}-4-fluoro-N-(4-fluorophenyl)benzamide monohydrochloride (colorless powder).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][C@@H:12]([CH:20]([CH3:22])[CH3:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].Cl[C:24]([O:26][CH3:27])=[O:25]>C1COCC1>[CH3:27][O:26][C:24]([NH:11][C@@H:12]([CH:20]([CH3:22])[CH3:21])[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[O:25]
Reactant: COC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
DIEA (137.5 mL, 0.766 mol) was added to a suspension of (S)-tert-butyl 2-amino-3-methylbutanoate hydrochloride (75.0 g, 0.357 mol) in THF (900 mL), and the mixture was cooled to 0° C. (ice/water bath). Methyl chloroformate (29.0 mL, 0.375 mol) was added dropwise over 45 min, the cooling bath was removed and the heterogeneous mixture was stirred at ambient temperature for 3 h. The solvent was removed under diminished pressure and the residue partitioned between EtOAc and water (1 L each). The organic layer was washed with H2O (1 L) and brine (1 L), dried (MgSO4), filtered and concentrated under diminished pressure. The crude material was passed through a plug of silica gel (1 kg), eluting with hexanes (4 L) and 15:85 EtOAc/hexanes (4 L) to afford (S)-tert-butyl 2-(methoxycarbonylamino)-3-methylbutanoate as a clear oil (82.0 g, 99% yield). 1H NMR (500 MHz, DMSO-d6, δ=2.5 ppm) 7.34 (d, J=8.6, 1 H), 3.77 (dd, J=8.6, 6.1, 1 H), 3.53 (s, 3 H), 1.94-2.05 (m, 1 H), 1.39 (s, 9 H), 0.83-0.92 (m, 6 H). 13C-NMR (126 MHz, DMSO-d6, δ=39.2 ppm) 170.92, 156.84, 80.38, 60.00, 51.34, 29.76, 27.62, 18.92, 17.95. LC/MS: [M+Na]+254.17.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)O)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:19][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1
Reactant: CN1CCC(C(O)c2ccc(F)cc2)CC1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN1CCC(C(Cl)c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-fluorophenyl 1-methylpiperidin-4-yl methanol 1.2 g (4.98 mmol) in toluene (5 ml) was added thionyl chloride (0.44 ml) dropwise. The resulting mixture was stirred at room temperature over night. The mixture was then made alkaline with NaOH solution and extracted with ethyl acetate (3×40). The combined organic solution was dried and concentrated to give 1.1 g of desired product.
Reaction SMILES: [CH2:1]([C:9]1[CH:24]=[CH:23][C:12]([CH:13]=[N:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CC(O)=O>C1COCC1.CCOCC>[CH2:1]([C:9]1[CH:24]=[CH:23][C:12]([CH2:13][NH:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(C=NNC(=O)OC(C)(C)C)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCCCCc1ccc(CNNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.6 %

Procedure:
To a solution of the product of Step A (0.13 g; 0.391 mmol) in anhydrous THF (1 ml) and glacial AcOH (0.6 ml) NaBH3CN (0.06 g; 0.95 mmol) was added at −0° C. (ice bath). The resulting mixture was stirred overnight at room temperature then diluted to 15 ml with Et2O. This was washed with 5% NaHCO3 H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure to give the title compound (0.01 g; 16%) as a colourless syrup, which was used in the next step without further purification. 1H-NMR (CDCl3) 7.23 (d, 2H, J=8 Hz); 7.12 (d, 3H, J=8 Hz); 6.0 (s, 1H); 4.1 (broad s, 2H); 3.94 (s, 2H); 2.57 (t, 3H, J=7.9 Hz); 1.56 (m, 2H); 1.45 (s, 9H); 1.26 (m, 10H); 0.86 (t, 3H, J=7 Hz).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[S:8][CH2:9][C:10](=O)[C:11]=1[C:12]#[N:13].[CH2:15](N(CC)CC)C.Cl>ClCCl.ClCCl.CO>[C:12]([C:11]1[C:10]([CH3:15])=[CH:9][S:8][C:7]=1[NH:6][C:2](=[O:3])[O:4][CH3:5])#[N:13]
Reactant: CCN(CC)CC
Reactant: N#CC1=C(N)SCC1=O
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Nc1scc(C)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 166.4 %

Procedure:
Methyl chloroformate (55 g, 0.58 mol) was added to a stirred solution of 2-amino-4-oxo-4,5-dihydrothiophene-3-carbonitrile (68 g, 0.49 mol) and triethylamine (147 g, 1.45 mol) in dichloromethane (1000 ml) at 0° C. After the addition, the mixture was warmed to 25° C. and stirred overnight. The reaction was treated with dichloromethane-methanol (20:1, 2000 mL) and 2N hydrochloric acid (1500 mL). The resulting mixture was filtered and the resulting solid was further extracted with dichloromethane-methanol (20:1, 1500 mL×3). The combined organic extracts were dried over sodium sulfate and concentrated to give a brown solid. The solid was washed with tert-butyl methyl ether (1500 mL) and dried under vacuum to give crude methyl 3-cyano-4-methylthiophen-2-ylcarbamate (160 g) as a brown solid, which was used in next step without purification.
Reaction SMILES: [CH:1](O)(C)C.[Na].[CH:6]1[CH2:10]C=[CH:8][CH:7]=1.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)[CH3:12]>O.CO>[CH3:1][C:12]1[CH:8]=[CH:7][C:6](=[CH2:10])[C:11]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)O
Reactant: C1=CCC=C1
Reactant: CC(=O)c1ccccc1
Agent: [Na]
Solvent: CO
Solvent: O
Product: C=C1C=CC(C)=C1c1ccccc1

Procedure:
To a two-liter 3-necked flask are charged isopropyl alcohol (1000 ml), methanol (300 ml) and sodium (10 g). Freshly distilled cyclopentadiene (180 g) and acetophenone (261 g) are mixed and slowly added, with stirring, to the solution in the flask. The reaction is run at room temperature. After 11/2 hours, the addition is complete. The reaction mixture is mixed with water and the organic layer extracted into hexane. The hexane extract is washed with water and stripped. The crude methyl phenyl-fulvene is distilled (80°-85° C./0.1 mm) and the distillate is a ruby-red liquid.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[NH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[C:12]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25]OS(C)(=O)=O)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:12]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][N:11]1[C:4]2[C:3]([S:2][CH3:1])=[N:8][CH:7]=[N:6][C:5]=2[CH:9]=[N:10]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)OCCOCCOC(=O)c1ccccc1
Reactant: CSc1ncnc2cn[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncnc2cnn(CCOCCOC(=O)c3ccccc3)c12
Temperature: 60 °C
Reaction time: 4 h
Yield: 33.1 %

Procedure:
A mixture of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (747 mg), 2-{2-[(methylsulfonyl)oxy]ethoxy}ethyl benzoate (1.43 g), potassium carbonate (931 mg) and N,N-dimethylformamide (12 mL) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water (30 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The organic layers were combined, washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→20:80), and further purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=90:10→40:60) to give the title compound (533 mg).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH2:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccc(Br)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cccc(Br)n1
Temperature: 70 °C
Yield: 87.8 %

Procedure:
A suspension of 2-(6-Bromo-pyridin-2-ylmethyl)-isoindole-1,3-dione (4000 mg, 12.61 mmol) in ethanol (60 mL) was heated at 70° C. until complete dissolution was observed. Hydrazine hydrate (3156 mg, 63.06 mmol) was then added and the resulting mixture was heated at 70° C. for 5 h. The resulting solution was cooled to 0° C. and filtered. The filtrate was concentrated in vacuo and the crude residue was purified by column chromatography with a gradient of 0 to 30% methanol/dichloromethane to give C-(6-Bromo-pyridin-2-yl)-methylamine as a yellow solid (2070 mg, 79%). MS ES (MH+ 187.1, RT=1.11 min).
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25][C:24]=4[CH:31]=3)[N:13]=2)=[CH:7][CH:6]=1)(C)(C)C.[Li+].[OH-:33]>>[C:28]([C:26]1[O:27][C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:14]3[N:13]=[C:12]([NH:11][C:8]4[CH:9]=[CH:10][CH:5]=[C:6]([OH:33])[CH:7]=4)[C:17]([F:18])=[CH:16][N:15]=3)=[CH:31][C:24]=2[CH:25]=1)([OH:30])=[O:29]
Reactant: [OH-]
Reactant: CC(C)(C)c1ccc(Nc2nc(Nc3ccc4c(c3)CC(C(=O)O)O4)ncc2F)cc1
Agent: [Li+]
Product: O=C(O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2o1

Procedure:
In a manner similar to the preparation of N4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine, 5-fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-4-pyrimidinediamine upon LiOH treatment gave N2-(2-carboxybenzofuran-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.97 (bd, 2H), 7.60-7.44 (m, 4H), 7.20-7.05 (m, 3H), 6.69 (bd, 1H); 19F NMR (CD3OD): −21844; LCMS: ret. time: 16.77 min.; purity: 100%; MS (m/e): 381 (MH+).
Reaction SMILES: COCCO[CH2:6][O:7][CH:8]([C:10]1[CH:11]=[C:12]([S:16]([NH2:19])(=[S:18])=[O:17])[S:13][C:14]=1[CH3:15])[CH3:9].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>CO>[CH3:6][O:7][CH:8]([C:10]1[CH:11]=[C:12]([S:16]([NH2:19])(=[S:18])=[O:17])[S:13][C:14]=1[CH3:15])[CH3:9]
Reactant: COCCOCOC(C)c1cc(S(N)(=O)=S)sc1C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(C)c1cc(S(N)(=O)=S)sc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-[1-(methoxyethoxymethoxy)ethyl]-5-methylthiothiophene-2-sulfonamide (6.8 g, 0.02 mol) in methanol (25 ml) was added dropwise 50% (by volume) cold sulfuric acid (50 ml) over a 10 minute period. The solution was stirred for an additional 1/2 hour at room temperature and the mixture was basified with NaHCO3 with cooling. The gum which separated was extracted into ethyl acetate. The aqueous layer was concentrated to dryness in vacuo and the solid residue was extracted with hot ethyl acetate. The ethyl acetate extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give an amber liquid which was purified by chromatography on silica gel (100 g) using ethyl acetate (40%)/hexane (60%). There was recovered 1.9 g (36%) of white solid, m.p. 86-94° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][OH:28])[CH:25]=2)[CH:20]=[C:19]1[C:29]1[CH:34]=[C:33]([C:35]2[CH:40]=[C:39]([CH3:41])[C:38]([OH:42])=[C:37]([CH3:43])[CH:36]=2)[N:32]=[N:31][C:30]=1[O:44][CH3:45])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH:27]=[O:28])[CH:25]=2)[CH:20]=[C:19]1[C:29]1[CH:34]=[C:33]([C:35]2[CH:36]=[C:37]([CH3:43])[C:38]([OH:42])=[C:39]([CH3:41])[CH:40]=2)[N:32]=[N:31][C:30]=1[O:44][CH3:45])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1cc2ccc(CO)cc2n1C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1cc2ccc(C=O)cc2n1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A dry flask is charged with 0.399 mL oxalyl chloride and 69 mL dichloromethane. After cooling to −78° C. 0.304 mL DMSO is added dropwise. After stirring for 15 minutes at this temperature, 2.04 g (6-hydroxymethyl-2-[6-(4-hydroxy-3,5-dimethyl-phenyl)-3-methoxy-pyridazin-4-yl]-indole-1-carboxylic acid tert-butyl ester in 46 mL dichloromethane are slowly added by syringe. After stirring for 60 minutes at −78° C. 2.98 mL triethylamine is added. The reaction mixture is stirred for 60 minutes at −78° C., allowed to warm to 0° C. and quenched by addition of sat. aq. NH4Cl-solution. The reaction mixture is diluted with dichloromethane, washed with sat. aq. NH4Cl-solution and brine, dried (MgSO4) and concentrated in vacuo. 1.96 g (97%) crude 6-formyl-2-[6-(4-hydroxy-3,5-dimethyl-phenyl)-3-methoxy-pyridazin-4-yl]-indole-1-carboxylic acid tert-butyl ester are obtained.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:13]=[CH:12][C:7]2[O:8][CH:9]=[CH:10][O:11][C:6]=2[CH:5]=1)=[O:3].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42][CH:43]([C:47](O)=[O:48])[C:44](O)=[O:45])([CH3:35])[CH3:34]>C(Cl)Cl>[O:8]1[C:7]2[CH:12]=[CH:13][C:4]([C:2]3[O:3][C:44](=[O:45])[C:43]([S:42][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[CH:33]([CH3:34])[CH3:35])=[C:47]([OH:48])[CH:1]=3)=[CH:5][C:6]=2[O:11][CH2:10][CH2:9]1
Reactant: CC(=O)c1ccc2c(c1)OC=CO2
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc3c(c2)OCCO3)oc1=O

Procedure:
The title compound was prepared by Method A using 1,4-benzodioxin-6-yl methyl ketone (2 g, 11.22 mmol), trimethylsilyl triflate (2.5 g, 11.22 mmol), triethylamine (2.27 g, 22.44 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (1.73 g, 5.61 mmol). m.p. 246-248° C.; 1H NMR (400 MHz, DMSO-d6) δ1.25 (d, 6H), 3.4 (m, 1H), 4.32 (m, 4H), 6.72 (s, 1H), 6.89 (d, 1H), 7.01 (d, 1H), 7.06 (t, 1H), 7.11 (t, 1H), 7.26 (d,1H), 7.31 (d, 1H), 7.35 (dd, 1H).
Reaction SMILES: N1C=CC=CC=1.[C:7]([C:11]1[C:12](=[O:22])[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:15](=O)[CH:16]=1)([CH3:10])([CH3:9])[CH3:8].[NH2:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[C:7]([C:11]1[C:12](=[O:22])[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:15](=[N:23][C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)[CH:16]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Reactant: Nc1cnccn1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C1=CC(=Nc2cnccn2)C=C(C(C)(C)C)C1=O
Temperature: 25 °C
Yield: 46.4 %

Procedure:
A 97.1 ml quantity of pyridine was dissolved in 944 ml of dichloroethane, and 32.9 ml of titanium tetrachloride was added thereto. The resulting mixture was refluxed with heating for 15 minutes. To the mixture were then added 132.2 g of 2,6-di-tert-butyl-1,4-benzoquinone and 57.1 g of aminopyrazine, and the mixture was refluxed with heating for 42 hours. The reaction mixture was cooled to room temperature and filtered through a Celite pad and the insoluble materials were washed there with dichloromethane. The filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent: diethyl ether-hexane=3:7), giving 82.8 g of Compound 1a.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH3:6][CH2:7]N(C(C)C)C(C)C.[CH2:15]1[CH2:19][O:18][CH2:17][CH2:16]1>>[O:18]=[C:19]1[CH2:15][CH2:16][CH2:17][CH2:7][CH:6]1[S:1]([NH2:2])(=[O:4])=[O:3]
Reactant: NS(=O)(=O)Cl
Reactant: C1CCOC1
Reactant: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)C1CCCCC1=O
Temperature: -60 °C
Reaction time: 2 h

Procedure:
Thereafter, the mixture was cooled to −60° C. and sulfamoyl chloride (11.85 g) in anhydrous THF (100 ml) was added dropwise (temperature increase from −60° C. to about −40° C.). The mixture was then cooled to −60° C. Then a solution of Hünig's base (13.3 g) in anhydrous THF (50 ml) was added gradually. The mixture was warmed up to room temperature and stirred for 2 hours. An unstirrable oil was the result. The THF was decanted off, and the oily residue was dissolved in methanol and filtered through silica gel. Subsequently, the methanol was removed under reduced pressure. The residue was dissolved completely in boiling 1:1 ethyl acetate/n-heptane (40 ml). After cooling to room temperature, the solution was cooled to 5° C. in a refrigerator. The precipitate was subsequently filtered off with suction using a frit. This gave the product (5.3 g) with a molecular weight of 177.2 g/mol (C6H11NO3S), MS (EST): m/e=178 (M+H+).