Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7](I)[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O>>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH3:12])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(I)ccnc1Cl
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1ccnc(Cl)c1C(=O)O
Yield: 89.6 %

Procedure:
In a similar manner to Reference Example 5,2-chloro-4-iodonicotinic acid (compound of Reference Example 1; 5.67 g) was reacted with 2-methylphenylboronic acid (3.00 g) to obtain 2-chloro-4-(2-methylphenyl)nicotinic acid (4.44 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH:8]([OH:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:21]([O-])(=[O:23])[CH3:22].[Na+]>C(OC(=O)C)(=O)C>[C:21]([O:13][CH:8]([C:9]([CH3:11])([CH3:12])[CH3:10])[CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][CH:19]=1)[N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)(=[O:23])[CH3:22]
Reactant: CC(C)(C)C(O)C(Oc1ccc(Cl)cc1)n1ccnc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC(C(Oc1ccc(Cl)cc1)n1ccnc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 730.7 %

Procedure:
8.0 g (0.027 mol) of 1-(4-chlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butan-2-ol are heated in 40 ml of acetic anhydride with 0.15 g of sodium acetate for 10 hours at 100° C. The solution is then cooled and stirred into 400 ml of ice water, the temperature being kept at 20°-25° C. The mixture is left to stand overnight. A smeary crystalline mass precipitates out and is taken up in chloroform. The chloroform solution is washed several times with water and sodium bicarbonate solution, dried over sodium sulphate and concentrated in vacuo by distilling off the solvent. The crystalline residue is boiled up in petroleum ether and the product is filtered off cold and dried. 4.5 g (49% of theory) of 2-acetoxy-1-(4-chlorophenoxy)-1-imidazol-1-yl-3,3-dimethyl-butane are obtained as a mixture of isomers with a melting point of 81°-91° C.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.N1C=CN=C1.[Si:12](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.O>[C:25]([Si:12]([O:6][CH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC1CC=CC1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](OC1CC=CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of cyclopent-3-enol (500 mg, 6.0 mmol) in CH2Cl2 (30 mL) at 0° C. was added imidazole (1.06 g, 15.6 mmol) and TBDPS-Cl (2.1 g, 7.8 mmol). The reaction was gradually warmed to room temperature and stirred for 16 hours. The reaction was then diluted with water (40 mL) and extracted using EtOAc (100 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification of the residue on a silica gel column with 0 to 5% EtOAc/Hexanes afforded tert-butyl(cyclopent-3-en-1-yloxy)diphenylsilane, which was then dissolved in CH2Cl2 (30 mL). 70% m-CPBA (830 mg, 6.9 mmol) was added at 0° C. The reaction was gradually warmed to room temperature while stirring for 16 hours. The reaction was then diluted with a saturated aqueous solution of NaHCO3 (40 mL) and extracted using CH2Cl2 (100 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification of the residue on a silica gel column with 0 to 20% EtOAc/Hexanes afforded (6-oxabicyclo[3.1.0]hexan-3-yloxy)(tert-butyl)diphenylsilane.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].CCN(C(C)C)C(C)C>C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCNCC(=O)OCc1ccccc1
Yield: 66.8 %

Procedure:
A solution of 1.4 g (8.74 mmole) of N-(t-butoxycarbonyl)ethylenediamine (prepared in Example 2, Step A above), 1.35 mL (8.74 mmole) of benzyl 2-bromoacetate, and 1.53 mL (8.74 mmole) of DIEA in 18 mL of acetonitrile was stirred for 18 hr at room temperature. The mixture was then concentrated in vacuo and the residue purified by flash chromatography on 130 g of silica eluting with 2 L of 75:25 hexanes: ethyl acetate then 1 L of 100:4 methylene chloride:methanol to give 1.8 g (67%) of an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[OH:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[C:13]1[CH:17]=[CH:16][S:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccsc1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CO)c1ccsc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (±)-2-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)acetic acid in THF at 0° C. was added BH3-THF dropwise. The solution was allowed to warm to room temperature and stirred for an additional 2 hours. The solution was cooled to 0° C., quenched with AcOH (10%)/MeOH and evaporated. Column chromatography (SiO2, EtOAc) gave pure tert-butyl 2-hydroxy-1-(thiophen-3-yl)ethylcarbamate (E1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:23])=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[S:24]1[CH:28]=[CH:27][N:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:23])=[C:18]([NH:19][S:29]([C:25]3[S:24][CH:28]=[CH:27][N:26]=3)(=[O:31])=[O:30])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)c1nccs1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3nccs3)c2F)c(-c2ccnc(Cl)n2)s1
Yield: 30 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-isopropylthiazol-4-yl)-2-fluoroaniline (2.5 g, 7.2 mmol) and thiazole-2-sulfonyl chloride (1.45 g, 7.88 mmol) the title compound of Step A was obtained (1.05 g, 30.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.01 (br. s., 2H), 8.58 (d, J=5.2 Hz, 1H), 8.09 (d, J=3.2 Hz, 1H), 8.01 (d, J=2.8 Hz, 1H), 7.49-7.40 (m, 1H), 7.31-7.25 (m, 1H), 6.88 (d, J=5.6 Hz, 1H), 3.35-3.30 (m, 1H), 1.36 (d, J=6.8 Hz, 6H). MS (ES+): 496 [M+H]+.
Reaction SMILES: [N:1]([CH:4]([O:15][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)[CH2:5][CH2:6][CH2:7][NH:8]C(=O)C(F)(F)F)=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:8][CH2:7][CH2:6][CH2:5][CH:4]([N:1]=[N+:2]=[N-:3])[O:15][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(COC(CCCNC(=O)C(F)(F)F)N=[N+]=[N-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(COC(CCCN)N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4-[(1-azido-4-trifluoroacetamidobutoxy)methyl]benzoate (0.4 g; 1.1 mmol) in MeOH (4.6 mL) was added a solution of potassium carbonate (0.4 g; 2.9 mmol) in water (2.4 mL) and stirred at room temperature for 4 h. The mixture was diluted with water and extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtrated and evaporated. The residue was purified by column chromatography (MeCN+5% MeOH) to provide methyl 4-[(4-amino-1-azidobutoxy)methyl]benzoate in 0.19 g yield (65%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][OH:20])[C:12](=[O:21])[N:11]([CH3:22])[C:10]=3[N:9]=[C:8]2[CH2:23][C:24]([OH:26])=[O:25])=[CH:4][CH:3]=1.[CH2:29](O)[CH3:30]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][OH:20])[C:12](=[O:21])[N:11]([CH3:22])[C:10]=3[N:9]=[C:8]2[CH2:23][C:24]([O:26][CH2:29][CH3:30])=[O:25])=[CH:27][CH:28]=1
Reactant: CCO
Reactant: Cn1c(=O)n(CCCO)c(=O)c2c1nc(CC(=O)O)n2Cc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1nc2c(c(=O)n(CCCO)c(=O)n2C)n1Cc1ccc(Cl)cc1
Yield: 40 %

Procedure:
Step 3 Crude 2-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)acetic acid (0.14 g, 0.36 mmol) was dissolved in ethanol (5 mL) and concentrated sulfuric acid (1 drop). The reaction was heated at reflux for 1 h. The reaction was cooled, evaporated under reduced pressure to remove the ethanol then diluted with water (50 mL) and extracted with ethyl acetate (3×40 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to a light golden oil. The oil was purified using a 12 g silica gel flash column and eluted with 20% ethyl acetate/hexanes to give ethyl 2-(7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)acetate (0.062, 40% yield) as a light tan solid. LCMS retention time=2.804 min and 99% purity, LCMS MH+ 435. 1H NMR (CDCl3) δ 7.21 (dd, 4H, J=8 Hz and 84 Hz), 5.57 (s, 2H), 4.11-4.23 (m, 4H), 3.77 (s, 2H), 3.59 (s, 3H), 3.50-3.56 (m, 2H), 3.32-3.39 (m, 1H), 1.86-1.94 (m, 2H), 1.25 (t, 3H, J=8 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:21](CC)CC)C.C(OC(Cl)=O)C(C)C.N>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16](=[O:18])[NH2:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(=O)O)CC1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OCC(N)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-carboxymethoxypiperidine-1-carboxylic acid tert-butyl ester (Preparation 1, 14.13 g, 54.7 mmol) and triethylamine (7.68 ml, 65.6 mmol) in anhydrous THF (250 ml) was cooled to 0° C. and isobutylchloroformate (8.51 ml, 65.6 mmol) introduced dropwise. After stirring at 0° C. for 30 min, the reaction mixture was cooled to −20° C. and added rapidly via cannula to a solution of 0.7M ammonia in anhydrous CH2Cl2 (250 ml, 180 mmol) at −70° C. The reaction was allowed to warm to rt and stirred for 1 h. The mixture was diluted with CH2Cl2 (250 ml) and washed with saturated aqueous NaHCO3 (200 ml), 0.5M HCl (200 ml) and brine (200 ml) then dried (MgSO4). The solvent was evaporated and the residue purified by flash chromatography IH-THF 3:7) to afford the title compound: δH (CDCl3) 1.49 (9H, s), 1.53-1.60 (2H, m), 1.85-1.92 (2H, m), 3.11 (2H, m), 3.58 (1H, m), 3.76-3.83 (2H, m), 3.98 (2H, s), 6.19 (1H, bs), 6.56 (1H, bs).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].C[C:14]([N:16](C)C)=O.C(OCC)(=O)C>CO>[CH:5]([C:4]1[CH:3]=[C:2]([C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=1)[C:14]#[N:16])=[O:6]
Reactant: COc1cc(C=O)cc(Br)c1O
Reactant: CC(=O)N(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(C=O)cc(C#N)c1O

Procedure:
A mixture of 23.1 g of 3-bromo-4-hydroxy-5-methoxy benzaldehyde, 9.3 g of cuprous cyanide and 140 ml of dimethyl acetamide (DMA) was refluxed for 2 hours with stirring. After cooling, the mixture was poured over ice and extract&d with an ethyl acetate--methanol mixture (90-10). The organic phase was washed and dried and the solvents were eliminated to obtain 18 g of crude product, which was used as is for the following step. It melted at 180° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[C:7]([C:16]([OH:18])=O)=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2>C(Cl)Cl>[OH:5][C:6]1[C:7]([C:16]([Cl:3])=[O:18])=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccc2cccnc2c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
Thionyl chloride (906 mg, 7.61 mmol) was added drop wise to a cold solution of 8-hydroxyquinoline-7-carboxylic acid (1.2 g, 6.34 mmol) in dry DCM (18 mL). The reaction mixture was allowed to warm to RT and was then stirred under nitrogen for 4 h. The reaction mixture was then concentrated to dryness affording the title compound (1.3 g, 6.26 mmol) that was used in the next steps without any further purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:10].[CH3:11][NH2:12]>>[Cl:10][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:2]=1[NH:12][CH3:11])[C:8]#[N:9]
Reactant: N#Cc1cncc(Cl)c1Cl
Reactant: CN
Product: CNc1c(Cl)cncc1C#N
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
4,5-Dichloronicotinonitrile (500 mg, 2.89 mmol) was suspended in 41% aqueous methylamine solution (5 mL). The resultant mixture was heated, with stirring, up to 60° C. over ca. 30 min. The mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with water, followed by brine then dried (MgSO4) and evaporated to provide the title compound (340 mg, 70%) as a white solid. 1H NMR (CDCl3) 8.39 (1H, s), 8.29 (1H, s), 5.50 (1H, s, br), 3.43 (3H, d, J=5.5 Hz).
Reaction SMILES: C(Cl)Cl.ClC(Cl)(Cl)C(=N)O[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:18][C@@H:19]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:20][C:21]([O:23][CH3:24])=[O:22].FC(F)(F)S(O)(=O)=O>C1CCCCC1>[CH2:8]([O:18][C@@H:19]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCC[C@H](O)CC(=O)OC
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CCCC[C@@H](CC(=O)OC)OCc1ccccc1
Temperature: 22.5 °C
Yield: 84.5 %

Procedure:
In a 2 flask were charged 275 ml of methylene chloride, 550 ml of cyclohexane, 140 g of benzyl trichloroacetoimidate, and 75 g of methyl (S)-3-hydroxyheptanoate (compound (37), R1 =ethyl), and 6 ml of trifluoromethanesulfonic acid was added thereto over 5 minutes while maintaining at 20 to 25° C., followed by allowing the mixture to react at 35 to 40° C. for 5 hours. The by-produced salt was removed by filtration, and the filtrate was washed with a sodium hydrogencarbonate aqueous solution. The solvent was removed by distillation under reduced pressure, and the residue was distilled under reduced pressure to obtain 99.0 g (78.7%) of the titled compound (b.p.: 105-108° C./0.1 mmHg).
Reaction SMILES: [Na].[CH3:2][CH:3]([CH3:10])[CH2:4][C:5](=[O:9])[C:6]([OH:8])=[O:7].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[CH3:2][CH:3]([CH3:10])[CH2:4][C:5](=[O:9])[C:6]([O:8][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7]
Reactant: BrCc1ccccc1
Reactant: CC(C)CC(=O)C(=O)O
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)CC(=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 92 %

Procedure:
With reference to reaction Scheme 2, a slurry of 25 g (0.164 mol) of the sodium salt of 4-methyl-2-oxopentanoic acid, sodium salt in anhydrous N,N-dimethylformamide (50 ml) containing 19.6 ml (0.164 mol) of benzyl bromide was agitated at room temperature for 4 days. The solvent was removed in vacuo. The residue was dissolved in 250 ml of hexane and washed with water (3×50 ml) and brine (50 ml). After drying over anhydrous magnesium sulfate, the solution was filtered and concentrated in vacuo to give 33.2 g (92% yield) of benzyl 4-methyl-2-oxopentanoate (1a) as a viscous, colorless oil. TLC: Rf 0.70 (ethyl acetate-hexane 1:4); 1H NMR(CDCl3) δ 0.94(d, 6H), 2.18(m, 1H), 2.71(d, 2H), 5.26(s, 2H), 7.37(m, 5H); 13C NMR (CDCl3) δ 22.5, 24.2, 48.1, 67.9, 128.7, 128.8, 128.9, 134.7, 161.3, 194.0.
Reaction SMILES: [S:1]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)([O:4][CH2:5][C@H:6]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C@H:7]([CH3:16])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])=[O:2].C1C(=O)N([Br:39])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[S:1]([C:25]1[CH:26]=[CH:27][C:28]([CH3:29])=[CH:30][CH:31]=1)([O:4][CH2:5][C@H:6]([O:17][Si:18]([C:21]([CH3:23])([CH3:24])[CH3:22])([CH3:19])[CH3:20])[C@H:7]([CH3:16])[CH2:8][CH:9]([Br:39])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:2])=[O:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)CCc2ccccc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OC[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)CC(Br)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.8 %

Procedure:
To a 5 L 3-neck round-bottom flask equipped with a mechanical stirrer, reflux condenser and nitrogen inlet was added CCl4 (1680 mL), tosylate 19 (140 g, 0.30 mol), NBS (65 g, 0.365 mol) and AIBN (16.5 g, 0.10 mol). The mixture was degassed by evacuation under full vacuum with stirring, and backfilling with nitrogen (3×). The reaction mixture was then heated to reflux, whereupon the color became dark brown. After 15 min at vigorous reflux, the reaction mixture became light yellow, and chromatographic analysis indicated the reaction was complete. After cooling to room temperature, the reaction was filtered, and the filtrate was concentrated to dryness. The residue was redissolved in hexanes, filtered again, and concentrated to dryness to afford the title compound (170.3 g) as an amber oil.
Reaction SMILES: C([O:8][C:9]1[C:35]([O:36][CH3:37])=[CH:34][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:11]=2[CH:10]=1)[N:18]=[CH:17][C:16]([C:21]#[N:22])=[C:15]3[NH:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([F:32])=[CH:26][C:25]=1[Cl:33])C1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.[Pd]>[Cl:33][C:25]1[CH:26]=[C:27]([F:32])[C:28]([O:30][CH3:31])=[CH:29][C:24]=1[NH:23][C:15]1[C:14]2[C:19](=[CH:20][C:11]3[CH:10]=[C:9]([OH:8])[C:35]([O:36][CH3:37])=[CH:34][C:12]=3[CH:13]=2)[N:18]=[CH:17][C:16]=1[C:21]#[N:22]
Reactant: COc1cc(Nc2c(C#N)cnc3cc4cc(OCc5ccccc5)c(OC)cc4cc23)c(Cl)cc1F
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2cc3c(Nc4cc(OC)c(F)cc4Cl)c(C#N)cnc3cc2cc1O
Reaction time: 15 h
Yield: 95.7 %

Procedure:
A mixture of 8-(benzyloxy)-4-[(2-chloro-4-fluoro-5-methoxyphenyl)amino]-7-methoxybenzo[g]quinoline-3-carbonitrile (1.88 g, 3.70 mmol) and 280 mg of 15% Pd on carbon in a mixture of 50 mL of methylene chloride and 70 mL of N,N-dimethylformamide is hydrogenated at 50–40 psi for 15 hours. The mixture is filtered through Celite and concentrated in vacuo to a small volume. The yellow solid is collected by filtration to provide 1.50 g (95%) of 4-[(2-chloro-4-fluoro-5-methoxyphenyl)amino]-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile, mp 239–242° C. dec.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([Cl:29])=[CH:24][N:23]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[Cl:21][C:22]1[N:27]=[C:26]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][CH:3]=2)[C:25]([Cl:29])=[CH:24][N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Nc3nc(Cl)ncc3Cl)cc2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A mixture of (5)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (100 mg, 0.36 mmol), 2,4,5-trichloropyrimidine (66 mg, 0.36 mmol) and diisopropylethylamine (70 mg, 0.54 mmol) was dissolved in 2-propanol (1.5 ml) and stirred at 80° C. overnight. For work-up most of the solvent was evaporated, then aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The aqueous phase was re-extracted with ethyl acetate twice. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (20 g silica gel, 10 to 30% ethyl acetate in heptane) to yield a white solid (141 mg, 92%). MS (ISP): 425.1 ([{35Cl}M+H]+), 427.1 ([{37Cl}M+H]+).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[CH:23](=O)[C:24]1[O:28][CH:27]=[CH:26][CH:25]=1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:23][C:24]4[O:28][CH:27]=[CH:26][CH:25]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccco1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4ccco4)c23)c1

Procedure:
Analogously to Example 32, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 144 mg (1.5 mmol) of furfural to form 4-(3-chloro-phenylamino)-3-[(fur-2-yl)-methyleneamino]-1H-pyrazolo[3,4-d]-pyrimidine. Reduction of the above intermediate in 15 ml of DMEU with 8 ml (8 mmol) of DIBAL-H and analogous working-up yield 4-(3-chloro-phenylamino-3-[(fur-2-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100) 8.4; MS (M)+=340.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:10].Cl[C:25]1[N:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[N:26]=1>CN(C=O)C.CCOC(C)=O>[CH3:32][C:27]1[CH:28]=[C:29]([CH3:31])[N:30]=[C:25]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=4[N:19]4[N:20]=[CH:21][CH:22]=[N:23]4)=[O:10])[CH2:3]3)[CH2:6]2)[N:26]=1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(-n2nccn2)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CC3CN(c4nc(C)cc(C)n4)CC3C2)c(-n2nccn2)c1
Temperature: 120 °C
Yield: 104.3 %

Procedure:
To (hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (185 mg, 0.4 mmol) in DMF (2.2 mL) was added 2-chloro-4,6-dimethylpyrimidine (61 mg, 0.4 mmol). The flask was heated to 120° C. for 18 h. The flask was allowed to cool to rt, diluted with EtOAc and washed with H2O. The aq was back-extracted with EtOAc (1×). The combined organics were washed with brine and dried (Na2SO4) to give an oil. Purification via silica gel (15-75% EtOAc in hexanes) gave 175 mg (97%) of the title compound. MS (ESI) mass calcd. C22H25N7O2, 419.49; m/z found 420.2 [M+H]+. 1H NMR (CDCl3): 7.73 (s, 2H), 7.49 (d, J=7.8 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 6.95 (dd, J=8.5, 2.5 Hz, 1H), 6.29 (s, 1H), 3.93-3.80 (m, 5H), 3.72-3.63 (m, 2H), 3.58 (dd, J=11.6, 5.2 Hz, 1H), 3.46 (dd, J=11.6, 4.3 Hz, 1H), 3.39-3.28 (m, 1H), 3.05-2.84 (m, 3H), 2.33 (s, 6H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].C(N(CC)CC)C.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[O:9]([C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1)[Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: C=Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
The concentrated 4-vinylphenol solution above and 10 mL (7.3 g, 0,072 mol) of triethylamine (TEA) were transferred to a 1 L 3 neck round-bottomed flask fitted with a mechanical stirrer, pressure-equalized addition funnel, reflux condenser, and argon inlet tube. A solution of 75 g (0.5 mol) Of t-butyldimethylchlorosilane and 75 mL (55 9, 0.54 mol) of dry TEA in 50 mL of methylene chloride was added through the addition funnel over 45 minutes. The reaction mixture turned pink and remained clear for quite some time. Considerable heat was evolved, particularly in the early stages of the addition, necessitating cooling the mixture in ice occasionally. The mixture was stirred at room temperature for 10 hrs., being stored in the freezer if necessary to complete the following day.