Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[C:4]([CH:9]=[N:10]O)=[N:5][CH:6]=[CH:7][CH:8]=1)C.[Cl:12]NC(=O)CCC(N)=O>CN(C=O)C>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:3][C:4]=1[C:9]([Cl:12])=[NH:10]
Reactant: CCc1cccnc1C=NO
Reactant: NC(=O)CCC(=O)NCl
Solvent: CN(C)C=O
Product: N=C(Cl)c1ccccn1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a mixture of ethyl 2-pyridin-aldoxime (15 gm) and N-chlorosuccinamide (25 gm) in DMF (30 ml) was stirred at 30° C. over a period of 2 h. The reaction mixture was quenched with ice-cold water (150 ml). The suspension was filtered and the wet cake washed with small quantity of water to provide pure title compound in 7 gm quantity (55%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH2:22][OH:23].[CH2:24](N(S(F)(F)F)CC)C.CO>O1CCCC1>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH2:22][O:23][CH3:24]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2CO
Reactant: CCN(CC)S(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2COC
Reaction time: 4 h

Procedure:
65 mg of the compound (177) obtained in Example 54 was suspended in 5 ml of tetrahydrofuran, and 270 μl of diethylaminosulfurtrifluoride was added to the solution. The solution was stirred for 4 hours, and 1 ml of methanol was added to the solution. The deposited solid matter was filtered off and washed with ether to obtain 34 mg of the subject compound (180).
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[NH:11][CH:12]=[CH:13][CH:14]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[CH2:8]([C:10]1[NH:11][CH:12]=[CH:13][CH:14]=1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)c1ccc[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc(CCc2ccc[nH]2)cc1

Procedure:
A solution of 6.00 g (0.032 mole) of the 2-phenylacetylpyrrole (III) in 200 ml of anhydrous tetrahydrofuran was added to a suspension of 600 g (0.153 mole) of lithium aluminum hydride in dry tetrahydrofuran. The mixture was stirred at reflux temperature for 48 h. The mixture was cooled to 0°, ethyl acetate was cautiously added to destroy the excess hydride and then saturated aqueous sodium sulfate was added. The organic phase was decanted, dried over sodium sulfate and evaporated in vacuo. The residue was subjected to column chromatography on neutral alumina (Fluka, Act II). 4.800 g (88%) of 2-[phenethyl]pyrrole (IV) was eluted with hexane-ethyl acetate and crystallized, m.p. 40°-42° (hexane). (Step 2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:28][CH2:27][N:26]([CH3:30])[CH3:25])[C:12]3[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3cc(C)c(C)cc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3cc(C)c(C)cc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 90.7 %

Procedure:
A mixture of 4.4 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-7,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 2.12 g of 2-(dimethylamino)ethyl chloride hydrochloride, 4.06 g of potassium carbonate and 200 ml of acetone is refluxed for 20 hours. After the reaction is completed, insoluble materials are removed by filtration and then washed with ethanol. The filtrate and the washing are combined and then evaporated to remove solvent. The residue is dissolved in ethyl acetate, and the solution is washed with water, dried and then evaporated to remove solvent. The residue is recrystallized from a mixture of ethyl acetate and n-hexane. 4.85 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-7,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10](I)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[CH2:17]([Sn](CCCC)(CCCC)C=C)[CH2:18]CC>C1(C)C=CC=CC=1.CN(C)C=O.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:17]=[CH2:18])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCCCc1nc(=O)c2cc(I)ccc2[nH]1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=Cc1ccc2[nH]c(CCCC)nc(=O)c2c1
Yield: 53.3 %

Procedure:
A mixture of 12.28 g of 2-butyl-6-iodo-4(1H)-quinazolinone 0.866 g of tetrakis (triphenylphosphine)palladium, 0.015 g of 2,6-di-t-butyl-4-methylphenol in 75 ml of toluene and 20 ml of N,N-dimethylformamide is treated with 13.06 g of tri-n-butyl vinyltin followed by heating at reflux for 4 hours. The reaction mixture is cooled and concentrated in vacuo. The residue is diluted with hexanes and filtered. The filter cake is washed with hexanes and the remaining tacky solid dissolved in 100 ml of chloroform-methanol (8:2) and purified by chromato- graphy on silica gel with 1:3 ethyl acetate-hexanes to afford 4.55 g of the desired product as a yellow solid. CI MASS SPEC 229(MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16].[C:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][C:21]=1[O:30][CH2:31][CH3:32])#[N:19]>C1COCC1.C1COCC1.CN(C=O)C>[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([S:26]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[C:21]([O:30][CH2:31][CH3:32])[CH:22]=2)(=[O:28])=[O:27])[C:8]=1[CH3:16]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOc1cc(S(=O)(=O)n2c(C)c(CC(=O)OC)c3cccnc32)ccc1C#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred, ice-cooled (0° C.) suspension of sodium hydride (26.3 mg of a 60% dispersion in mineral oil, 0.686 mmol) in dry THF (10 ml) under an inert atmosphere of Argon is added dropwise (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((0.1 g, 0.49 mmol) in THF/DMF (4 ml of a 3:1 mixture). The reaction mixture is stirred at 0° C. for 1 hour and then treated with 4-cyano-3-ethoxy-benzenesulfonyl chloride (168 mg, 0.686 mmol) in dry THF (1 ml). Stirring continued at 0° C. for 10 minutes and at room temperature for 10 minutes and then the reaction mixture is poured onto water (50 ml). The mixture is extracted with ethyl acetate (2×50 ml) and the organic portions are combined, washed brine (50 ml), dried (MgS04) and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with iso-hexane/ethyl acetate (0%-20% ethyl acetate) to yield the titled product. (MH+414).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[CH:15]([NH2:18])([CH3:17])[CH3:16].N1C=CC=CC=1.[Si](Cl)(Cl)(Cl)Cl>O>[CH3:16][CH:15]([NH:18][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([S:2][CH3:1])=[CH:4][C:5]=1[N+:12]([O-:14])=[O:13])[CH3:17]
Reactant: CC(C)N
Reactant: CSc1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: Cl[Si](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CSc1ccc(C(=O)NC(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
A solution of 4-methylthio-2-nitrobenzoic acid (3.07 g, 0.01439 mol) [Lit. Ref. DE 2421541], isopropylamine (1.47 ml, 0.01728 mol) and pyridine (100 ml) was cooled in an ice bath. Silicon tetrachloride (2.01 ml, 0.01728 mol) was added dropwise under nitrogen over 15 mins. After stirring at room temperature for 2 hr the solution was refluxed for 7 hr, then allowed to cool to room temperature. The solution was added to water and concentrated in vacuo. The precipitate was dissolved in dichloromethane and washed twice with 1N hydrochloric acid (150 ml), dried and concentrated in vacuo to afford 2.82 g of amorphous yellow solid. δ(1H NMR, CDCl3, ppm): 1.10 (6H, d), 2.50 (3H, s), 4.2 (1H, m), 5.50 (1H, s), 7.35 (2H, m), 7.75 (1H, s).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.CCCCCC.[B:32](OC(C)C)([O:37]C(C)C)[O:33]C(C)C.Cl>O1CCCC1>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([C:9]2[C:10]3[C:15]([C:2]([B:32]([OH:37])[OH:33])=[C:3]4[C:8]=2[CH:7]=[CH:6][CH:5]=[CH:4]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:21][CH:20]=1)([CH3:24])([CH3:25])[CH3:23]
Reactant: CC(C)(C)c1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2c3ccccc3c(B(O)O)c3ccccc23)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
15.4 g of the above-mentioned 9-bromo-10-(4-tert-butylphenyl) anthracene was dissolved in 380 ml of tetrahydrofuran to drop 30 ml of n-butylithium (1.6 M-hexane solution) thereto under nitrogen atmosphere at a temperature of 0° C. The solution was stirred at a temperature of 0° C. for 30 minutes and thereafter cooled to a temperature of −80° C. to drop 18.2 ml of triisopropyl borate thereto. The solution was heated up to room temperature by standing at room temperature and thereafter stirred at room temperature for 3 hours. 400 ml of 10%-hydrochloric acid was dropped thereto and further stirred at room temperature for 2 hours to thereafter extract 300 ml of diethyl ether therefrom. The organic layer was washed in 100 ml of 5%-sodium carbonate aqueous solution, washed in 100 ml of water, then dried by magnesium sulfate and thereafter concentrated by evaporation. The organic layer was purified by silica gel column chromatography (developing solvent was in the order of dichloromethane/hexane=1/1, dichloromethane and dichloromethane/methanol=50/1) and vacuum dried to thereafter obtain 6.78 g of 9-(4-tert-butylphenyl)-10-anthraceneboronic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[F:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.5 %

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (10 g, 53.7 mmol) in dichloromethane (300 mL), add triethyl amine (15.1 mL, 107.4 mmol) and 2-fluorobenzoyl chloride (6.4 mL, 53.7 mmol). Stir the mixture at room temperature overnight. Then add water (200 mL) and separate the organic layer, dry over sodium sulfate, filter and evaporate solvent under reduced pressure to give 17.3 g of 4-(2-fluoro-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester. ES+ (m/z) 309[M+H].
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=1.[OH-].[K+].Cl>CS(C)=O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Oc1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 0 °C
Yield: 35.6 %

Procedure:
40 ml of dimethyl sulfoxide, 4.2 g of hydroquinone, 5.0 g of 2-chloro-5-trifluoromethylpyridine and 2.3 g of potassium hydroxide were reacted at 150° C. for 2 hours with stirring in a nitrogen atmosphere. After the reaction product was allowed to cool, the product was added to a suitable amount of ice-water, neutralized with 30% concentrated hydrochloric acid, and extracted with methylene chloride. The extract was washed with water and dried over anhydrous sodium sulfate. 2.5 g of 2-(4-hydroxyphenoxy)-5-trifluoromethylpyridine (m.p. 82°-84° C.) was obtained by distilling off the methylene chloride.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Na].Br[CH:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=[O:14]>>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C@H:12]([C:13]([OH:15])=[O:14])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)C(Br)C(=O)O
Reactant: Nc1ccc(Cl)cc1F
Agent: [Na]
Product: CC(C)[C@H](Nc1ccc(Cl)cc1F)C(=O)O

Procedure:
Following the procedure of Example 6, 2-fluoro-4-chloroaniline is reacted with m-phenoxy-α-cyanobenzyl α-bromoisovalerate to give the m-phenoxy-α-cyanobenzyl ester of N-(2-fluoro-4-chlorophenyl)valine, MS m/e 452 (M+). Alternatively 2-fluoro-4-chloroaniline is reacted with the sodium salt of α-bromoisovaleric acid to give N-(2-fluoro-4-chlorophenyl)valine, which is then esterified using m-phenoxy-α-cyanobenzyl bromide or mesylate.
Reaction SMILES: [OH:1][C:2]([CH3:38])([CH3:37])[CH2:3][C@@:4]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[N:23][C:22]([C:25]4([C:28]([OH:30])=O)[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:39][NH:40][CH3:41]>>[CH3:39][N:40]([CH3:41])[C:28]([C:25]1([C:22]2[N:23]=[N:24][C:19]([C:16]3[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:37])[CH3:38])([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:14][CH:15]=3)=[CH:20][CH:21]=2)[CH2:27][CH2:26]1)=[O:30]
Reactant: C[C@@H](c1ccc(-c2ccc(C3(C(=O)O)CC3)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CNC
Product: C[C@@H](c1ccc(-c2ccc(C3(C(=O)N(C)C)CC3)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 21 %

Procedure:
The title compound was prepared from 1-[6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridazin-3-yl]-cyclopropanecarboxylic acid and dimethylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Step 2 for Intermediate 5. Yield: 21% of theory; LC (method 1): tR=1.79 min; Mass spectrum (ESI+): m/z=543 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:11]([CH2:12][CH3:13])[C:10]([C:14](=[N:17][OH:18])[C:15]#[N:16])=[N:9][C:4]=2[C:5]([Cl:8])=[N:6][CH:7]=1.C([N:21](CC)CC)C.NO>O1CCOCC1.CO>[Br:1][C:2]1[C:3]2[N:11]([CH2:12][CH3:13])[C:10]([C:14]3[C:15]([NH2:21])=[N:16][O:18][N:17]=3)=[N:9][C:4]=2[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CCn1c(C(C#N)=NO)nc2c(Cl)ncc(Br)c21
Reactant: CCN(CC)CC
Agent: NO
Solvent: CO
Solvent: C1COCCO1
Product: CCn1c(-c2nonc2N)nc2c(Cl)ncc(Br)c21
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a mixture of (7-bromo-4-chloro-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)hydroxyimino-acetonitrile (V, 545 g, 1.45 mol) in dioxane (5 L) was added triethylamine (1 L) and hydroxylamine (143 g, 55% in water). The reaction was heated at reflux for 6 h. After cooling the reaction to ambient temperature, the mixture was filtered and the filtrate concentrated under reduced pressure to give a brown solid. The solid was suspended in methanol (1 L) and the suspension was stirred at 65° C. for 0.5 h. The solid was collected by filtration and dried to give 321 g (70% yield) of the desired compound (VI). This was used in the next step without further purification. MS (ES+) m/z 343 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:4]3[C:5](=[CH:13][N:14]([C@@H:16]4[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@@:17]4([CH3:25])[OH:18])[N:15]=2)[CH:6]=[CH:7][C:8]=3[C:9](=[O:12])[NH:10][N:11]=1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].N1C=CN=C1>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:4]3[C:5](=[CH:13][N:14]([C@@H:16]4[O:22][C@H:21]([CH2:23][O:24][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@@H:19]([OH:20])[C@@:17]4([CH3:25])[OH:18])[N:15]=2)[CH:6]=[CH:7][C:8]=3[C:9](=[O:12])[NH:10][N:11]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2ccc3c(=O)[nH]nc(N)c(n1)c23
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc3ccc4c(=O)[nH]nc(N)c(n2)c34)[C@](C)(O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
A mixture of 4-amino-2-(2-C-methyl-β-D-ribofuranosyl)-2,6-dihydro-7H-2,3,5,6-tetraazabenzo[cd]azulene-7-one (65 mg, 0.19 mmol) in DMF, tert-butyldimethylsilyl chloride (70 mg, 0.45 mmol) and imidazole (61 mg, 0.90 mmol) was stirred overnight at room temperature and then concentrated in vacuo. The oily residue was dissolved in CH2Cl2 (20 mL), washed with aq. HCl (0.1 N), sat. aq. NaHCO3, water, brine and dried (Na2SO4). The evaporated residue was purified on silica gel with hexanes/EtOAc (1/1)+0.5% Et3N and EtOAc+0.5% Et3N to yield the target compound 16.1 as colorless oil (38 mg, 44%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)(Cl)Cl.O>[OH:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][CH2:10]1
Reactant: OCC1CCNCC1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)N1CCC(CO)CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
168.3 g (1.22 mol) of potassium carbonate are added to a solution of 61.6 g (406 mmol) of 4-piperidinemethanol hydrochloride in a mixture of 406 ml of chloroform and 406 ml of water, followed by 42.55 ml (440 mmol) of ethyl chloroformate dissolved in 160 ml of chloroform. The mixture is stirred for 3 h at 20° C., the organic phase is separated off, the aqueous phase is extracted with dichloromethane, the organic phases are combined to form a single phase, washed with water and dried over magnesium sulphate, and the solvents are evaporated off under reduced pressure. 76 g of an oil is obtained, this being used without further treatment in the following stage.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:13])=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[CH3:21][C:22]1[C:23](Cl)=[N:24][C:25]([Cl:29])=[N:26][C:27]=1[CH3:28]>CN(C)C=O>[CH3:21][C:22]1[C:23]([N:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][C:9]([OH:12])=[C:8]([OH:13])[CH:7]=3)[CH:2]2[CH3:1])=[N:24][C:25]([Cl:29])=[N:26][C:27]=1[CH3:28]
Reactant: Cc1nc(Cl)nc(Cl)c1C
Reactant: CC1NCCc2cc(O)c(O)cc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)nc(N2CCc3cc(O)c(O)cc3C2C)c1C
Yield: 75.9 %

Procedure:
After 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline(1.6 g, 4.98 mmol) and triethylamine(0.7 ml, 4.98 mmol) were added to a suspension of 5,6-dimethyl-2,4-dichloropyrimidine(0.8 g, 4.53 mmol) in dimethylformamide, 1.1 g of the titled compound was obtained in accordance with the same procedure as in Step 1 of Example 35. (Yield: 76%)
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH:19]2[CH3:24])[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:26]1[N:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=1>CN1CCCC1=O>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:26]3[N:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=3)[CH2:20][CH:19]2[CH3:24])[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CC1CNCCC1N(C(=O)c1ccc(-c2cnco2)cc1)C1CC1
Reactant: CCc1cnc(Cl)nc1
Solvent: CN1CCCC1=O
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)C(C)C2)nc1

Procedure:
The title compound is prepared from N-cyclopropyl-N-(3-methyl-piperidin-4-yl)-4-oxazol-5-yl-benzamide and 2-chloro-5-ethyl-pyrimidine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 3): tR=1.83 min; Mass spectrum (ESI+): m/z=432 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[N:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:41])([F:40])[O:29][C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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>[C:1]([O:5][C:6](=[O:26])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[N:24]=[CH:23][C:22]([C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]([F:27])([F:40])[F:41])=[CH:35][CH:34]=3)=[CH:21][N:20]=2)[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ncc(Br)cn2)cs1
Reactant: OB(O)Oc1ccc(OC(F)(F)F)cc1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cs1
Yield: 85 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(5-bromopyrimidin-2-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (600 mg) synthesized in Example 110-1 and 4-trifluoromethoxyphenylboric acid (400 mg) were dissolved in dioxane (6 mL) and aqueous sodium carbonate solution (2 mol/L, 3 mL), tetrakis(triphenylphosphine)palladium (75 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1) to give the title compound (600 mg) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14](Cl)[C:5]2=[N:4][CH:3]=1)=[CH:11][C:10]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:9][CH:8]=3.[NH2:21][CH2:22][CH2:23][CH2:24][OH:25]>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([NH:21][CH2:22][CH2:23][CH2:24][OH:25])[C:5]2=[N:4][CH:3]=1)=[CH:11][C:10]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:9][CH:8]=3
Reactant: FC(F)(F)Oc1ccc2c(c1)nc(Cl)c1ncc(Br)n12
Reactant: NCCCO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: OCCCNc1nc2cc(OC(F)(F)F)ccc2n2c(Br)cnc12
Yield: 87.6 %

Procedure:
To a stirred solution of 1-bromo-4-chloro-7-trifluoromethoxy-imidazo[1,2-a]quinoxaline (6.5 g, 17.7 mmol, 1 eq) in dioxane (87 mL) is added 3-aminopropan-1-ol (3.4 mL; 44.3 mmol; 2.5 eq). The resulting solution is then heated at reflux for 16 hours until completion of the reaction. The mixture is diluted with ethyl acetate (100 mL) and washed with a 1M aqueous solution of sodium hydroxide (50 mL). The organic layer is separated, dried over sodium sulphate and concentrated in vacuo to afford a beige solid. This powder is washed with diethyl ether to afford after filtration the title compound (6.3 g; 15.5 mmol; 87%) with a 99% HPLC purity.