Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([S:7]([CH2:10][CH2:11][C:12]([NH:14][NH:15][C:16]([N:18]1[CH2:24][C:23]2[CH:25]=[CH:26][C:27]([O:29]C)=[CH:28][C:22]=2[O:21][C:20]2[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:19]1=2)=[O:17])=[O:13])(=[O:9])=[O:8])[CH3:6]>C(Cl)Cl>[CH2:5]([S:7]([CH2:10][CH2:11][C:12]([NH:14][NH:15][C:16]([N:18]1[CH2:24][C:23]2[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:22]=2[O:21][C:20]2[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:19]1=2)=[O:17])=[O:13])(=[O:8])=[O:9])[CH3:6]
Reactant: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2ccc(OC)cc2Oc2ccc(Cl)cc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2ccc(O)cc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.9 %

Procedure:
To a stirred solution of boron tribromide (I.0M in 7.3 mL of methylene chloride) at approximately 5° C. (ice water bath) under nitrogen was added dropwise 1.09 g of 8-chloro-3-methoxydibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide, prepared as described above in Example 7, in 5 mL of methylene chloride. The ice bath was removed and the reaction stirred at room temperature for 3 hours. The reaction was carefully quenched by the addition of 10 mL of 1N HCl, and poured into 150 mL of ethyl acetate. The solution was washed with 150 mL of 1N HCl and brine, dried over magnesium sulfate, and evaporated in vacuo to a greenish residue. This was treated with 10 mL of ethanol (3A), and the resulting solid was collected by filtration. Recrystallization from ethanol (3A) yielded 0.58 g (54.9%) pure product as a white solid.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][CH:9]=1>[Zn].C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:14][CH2:13][CH2:12][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:17][CH:16]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(CCC=O)cc1
Agent: [Zn]
Solvent: ClCCl
Product: COc1ccc(CCC=C(Br)Br)cc1
Reaction time: 2 h

Procedure:
A solution of 39.2 g. of zinc dust, 157 g. of triphenylphosphene and 200 g. of carbon tetrabromide in 500 ml. methylene chloride is stirred at room temperature for 25 hours. To the resultant solution is added 50 g. of 4-methoxyhydrocinnamaldehyde and stirring is continued for an additional 2 hours. The solution is diluted with 2 l. of pentane and the precipitate is filtered. The precipitate is stirred with 100 ml. methylene chloride, diluted with 400 ml. pentane, and again filtered. The organic solutions are combined and evaporated to yield 1,1-dibromo-4-(4-methoxyphenyl)-1-butene as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH:8]=[CH:9][CH2:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:3][C:4](OC)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(=O)C>CCOCC>[CH3:1][C:2]([CH:8]=[CH:9][CH2:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:3][CH2:4][OH:5]
Reactant: COC(=O)C=C(C)C=CCC(C)CCC=C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)=CCCC(C)CC=CC(C)=CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2 g. of methyl 3,7,11-trimethyldodeca-2,4,10-trienoate and 20 ml. of dry ether, at -78°, is added slowly about 0.4 g. of lithium aluminum hydride in dry ether. The mixture is allowed to stand about 1 hour after addition is complete and then allowed to warm up to room temperature. Then 2.5 ml. of acetic acid is added. The mixture is then washed with ice water and the organic phase separated, which is dried over magnesium sulfate and evaporated to yield 3,7,11-trimethyldodeca-2,4,10-trien-1-ol.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH2:17][C:16](=[O:18])[NH:15][C:14]3[CH:19]=[C:20]([Cl:26])[C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:13]=3[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=O.[NH2:27][C:28]([NH2:30])=[S:29]>C1COCC1.CCOC(C)=O>[NH2:30][C:28]1[S:29][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([C:11]3[CH2:17][C:16](=[O:18])[NH:15][C:14]4[CH:19]=[C:20]([Cl:26])[C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:13]=4[N:12]=3)[CH:8]=[CH:9][CH:10]=2)[N:27]=1
Reactant: NC(N)=S
Reactant: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(C(=O)CBr)c1)=N2
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3csc(N)n3)c1)=N2
Temperature: 60 °C
Yield: 20.2 %

Procedure:
A mixture of 4-(3-bromoacetyl-phenyl)-8-chloro-7-dimethylamino-1,3-dihydro-benzo[b][1,4]diazepin-2-one (0.73 g) (Example 193a) and thiourea (0.13 g) in THF (10 mL) was heated to 60° C. for 15 min. The mixture was diluted with AcOEt and washed with sat. NaHCO3 solution and with brine. The organic layer was dried and evaporated and the residue was stirred with CH2Cl2 to give the title compound (0.14 g) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[C:15]([C:29]([O:31]C)=[O:30])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)=[CH:17][CH:18]=2)=[CH:11][C:10]([C:33]([F:36])([F:35])[F:34])=[N:9]1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[C:15]([C:29]([OH:31])=[O:30])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)=[CH:17][CH:18]=2)=[CH:11][C:10]([C:33]([F:36])([F:34])[F:35])=[N:9]1
Reactant: COC(=O)c1cc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)ccc1-c1cccc(S(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)cc2C(=O)O)c1
Yield: 77.5 %

Procedure:
A solution of methyl 4-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3′-(methylsulfonyl)biphenyl-2-carboxylate (1.37 g, 2.6 mmol) and NaOH (1 g, 25 mmol) in MeOH—H2O (2:1, 16 mL) was refluxed for 2 h. After cooling, solid was removed and the filtrate was acidified with formic acid. Solid was collected by filtration and washed with water and dried under high vacuum to afford 4-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3′-(methylsulfonyl)biphenyl-2-carboxylic acid (1.05 g). MS(ES): 521 [M+H]+.
Reaction SMILES: [Cl:1][CH:2]([Cl:21])[C:3]([NH:5][C@H:6]([CH2:19][F:20])[C@H:7]([OH:18])[C:8]1[CH:13]=[CH:12][C:11]([Sn](C)(C)C)=[CH:10][CH:9]=1)=[O:4].Br[C:23]1[S:27][C:26]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[N:25][CH:24]=1>>[Cl:1][CH:2]([Cl:21])[C:3]([NH:5][C@H:6]([CH2:19][F:20])[C@@H:7]([C:8]1[CH:13]=[CH:12][C:11]([C:23]2[S:27][C:26]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[N:25][CH:24]=2)=[CH:10][CH:9]=1)[OH:18])=[O:4]
Reactant: CC(C)(C)OC(=O)NCc1ncc(Br)s1
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Product: CC(C)(C)OC(=O)NCc1ncc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1

Procedure:
Following the general procedure of Example 2—Step 1 and making non-critical variations but using 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethyl-stannyl)phenyl)propan-2-yl)acetamide and tert-butyl ((5-bromothiazol-2-yl)methyl)carbamate as starting materials title compound is obtained (346 mg): 1HNMR (400 MHz, DMSO-d6) 1.41 (s, 9H), 4.19-4.22 (m, 1H), 4.26-4.30 (m, 0.5H), 4.36-4.42 (m, 2.5H), 4.54-4.58 (m, 0.5H), 4.66-4.70 (m, 0.5H), 4.86 (t, J=3.4 Hz, 1H), 5.98 (d, J=4.16 Hz, 1H), 6.50 (s, 1H), 7.39 (d, J=8.2 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H), 7.77-7.82 (m, 1H), 8.05 (s, 1H), 8.60 (d, J=8.8 Hz, 1H) m/z (CI) 492 [M+H].
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[Br-].[Na+].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Cl>O1CCCC1.O>[F:22][C:23]1[CH:24]=[C:25]([CH2:26][CH2:14][C:13]2[C:8]([C:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Fc1cccc(CCl)c1
Reactant: Cc1cccnc1C(=O)NC(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NC(=O)c1ncccc1CCc1cccc(F)c1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran (125 mL), and N-(1,1-dimethylethyl)-3-methyl-2-pyridine carboxamide (1 equivalent), are charged and cooled to -40° C. under nitrogen. Two equivalents of n-butyllithium are then added over 40 minutes. When half the n-butyllithium is added the mixture turns purple. Sodium bromide (1.3 g) is added and 3-fluoro-benzyl chloride (1.05 equivalents) is added dropwise (1:1 solution in tetrahydrofuran) over 40-50 minutes while the temperature is maintained at -40° C. After 30 minutes at -40° C., the mixture is diluted with water (250 mL) and the organic phase separated. This phase is dried over sodium sulphate and the solvent removed yielding an oil from which solid product, 3-[2-( 3-fluoro-phenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridine carboxamide, may crystallize.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[N:3]1.[NH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:15])=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[N:3]1
Reactant: Cn1nnc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NN1CCOCC1
Product: Cn1nnc(-c2ccccc2)c1COc1ccc(C(=O)NN2CCOCC2)cn1
Yield: 84 %

Procedure:
As described for example 2b, 6-(3-methyl-5-phenyl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (155 mg, 0.5 mmol) was converted, using N-aminomorpholine instead of 4-aminotetrahydropyran, to the title compound (165 mg, 84%) which was obtained as a white solid. MS: m/e=395.2 [M+H]+.
Reaction SMILES: [S:1]([Cl:5])(=[O:4])(=[O:3])[OH:2].[F:6][C:7]([F:13])=[CH:8][C:9]([F:12])([F:11])[F:10]>>[C:9]([CH2:8][C:7]([O:3][S:1]([Cl:5])(=[O:2])=[O:4])([F:13])[F:6])([F:12])([F:11])[F:10]
Reactant: FC(F)=CC(F)(F)F
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)OC(F)(F)CC(F)(F)F
Reaction time: 24 h
Yield: 72.7 %

Procedure:
A 250 mL Hastelloy shaker tube was loaded with 60 g (0.51 mole) chlorosulfuric acid (HOSO2Cl), cooled in liquid nitrogen, evacuated and loaded with 60 g (0.45 mole) of 1,1,3,3,3-pentafluoropropene. The reaction vessel was allowed to warm and kept on a shaker at 20° C. at autogenous pressure for 24 hours. After 24 hours, the pressure tube was unloaded, and the reaction mixture quenched by ice and the organic layer washed with 5% sodium bicarbonate, water and dried under MgSO4. After distillation, 81.3 g of CF3CH2CF2OSO2Cl was obtained containing 6% of CF3CH2CF2OSO2F.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[N:3]=1.[CH2:13]([N:16]=[C:17]=[S:18])[CH2:14][CH3:15]>C(#N)C>[CH2:13]([NH:16][C:17](=[S:18])[NH:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[N:12])[N:3]=1)[CH2:14][CH3:15]
Reactant: CCCN=C=S
Reactant: N#CCCCCn1ccc(N)n1
Solvent: CC#N
Product: CCCNC(=S)Nc1ccn(CCCCC#N)n1

Procedure:
A solution of 5-(3-aminopyrazol-1-yl)valeronitrile (1.0 g.) in acetonitrile (10 ml.) was treated with n-propylisothiocyanate (0.74 g.) and the solution heated under reflux on the steam bath for 6 hours. Evaporation of the solvent gave a brown gum which on trituration with ether/EtOH gave 5-(3-[3-propylthioureido]pyrazol-1-yl)valeronitrile as a white solid (1.01 g.).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[N:8]([CH2:17][O:18][CH3:19])[C:7]=2[CH:20]=1.S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+].[C-:30]#[N:31].[Na+]>ClCCl>[CH3:19][O:18][CH2:17][N:8]1[C:7]2[CH:20]=[C:3]([CH2:2][C:30]#[N:31])[CH:4]=[CH:5][C:6]=2[C:15]2[NH:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]1=[O:16]
Reactant: COCn1c(=O)c2c(c3ccc(CO)cc31)NCCC2
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COCn1c(=O)c2c(c3ccc(CC#N)cc31)NCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
8-(hydroxymethyl)-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-5-(6H)-one (100 mg, 0.36 mmol) prepared in step 5 of Example 41 was dissolved in dichloromethane (10 ml), added dropwise with thionylchloride (66 μl, 0.91 mmol) at 0° C. The resulting mixture was stirred at room temperature for 4 hours and poured into saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was then dissolved in N,N-dimethylformamide (5 ml) and sodium cyanide (55 mg, 1.09 mmol) was added. The resulting mixture was stirred at room temperature overnight and poured into ice water. The mixture was extracted with chloroform and the organic layer was washed with brine. The solution was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was then purified by flash column chromatography (chloroform:methanol=30:1) to obtain the title compound (70 mg, yield: 69%, white solid).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH:7]=[O:8])[C:5]=1[OH:12])[CH3:2].[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[C:5]([O:12][CH3:13])=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOc1cccc(C=O)c1O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CCOc1cccc(C=O)c1OC
Temperature: 60 °C
Reaction time: 5 h
Yield: 101.4 %

Procedure:
To a suspension of 3-ethoxysalicylaldehyde (1.00 g, 6.02 mmol) and potassium carbonate (3.33 g, 24.1 mmol) in N,N-dimethylformamide (10 mL) was added dimethyl sulfate (0.91 g, 7.22 mmol), and the mixture was stirred at 60° C. for 5 hours. The reaction mixture was diluted with ethyl acetate, filtered, and the filtrate was washed with water, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=7:3) to give the title compound (1.10 g, yield 99%) as an oily matter.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.[CH3:11][O:12][CH2:13][CH2:14]Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH2:14][CH2:13][O:12][CH3:11])[CH:7]=1
Reactant: COCCBr
Reactant: OCc1ccc(Cl)cc1O
Product: COCCOc1cc(Cl)ccc1CO

Procedure:
The title compound was prepared from 5-chloro-2-(hydroxymethyl)phenol (PREPARATION 7) and 2-methoxyethylbromide according to the procedure for the preparation of Example 111, part A. 1H NMR (400 MHz, CDCl3): δ 3.24 (3H, s), 3.73-3.75 (2H, m), 4.16-4.18 (2H, m), 4.62 (2H, s), 6.87 (1H, d, J=1.6 Hz), 6.93 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.18 (1H, d, J=8.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[Cl:17].Br[C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].COCCOC>[Cl:17][C:3]1[CH:4]=[C:5]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Brc1cnccn1
Reactant: CC1(C)OB(c2ccc(N)c(Cl)c2)OC1(C)C
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1ccc(-c2cnccn2)cc1Cl
Temperature: 75 °C
Yield: 43.7 %

Procedure:
To a mixture of 4-amino-3-chlorophenylboronic acid pinacol ester (0.110 g, 0.434 mmol), 2-bromopyrazine (0.090 g, 0.56 mmol), 1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) DCM complex (24 mg, 0.029 mmol) was added anhydrous DME (3.0 mL) followed by 2M aqueous sodium carbonate (0.53 mL, 1.06 mmol). The microwave vial was heated at 75° C. for 40 minutes under microwave irradiation. Further catalyst (0.012 g) was added and the vial was heated at 90° C. for 25 minutes under microwave irradiation. Further 2-bromopyrazine (0.060 g), catalyst (12 mg) and 2M aqueous sodium carbonate (0.25 mL) were added and the reaction mixture was heated at 90° C. for an additional 30 minutes under microwave irradiation. The reaction was partitioned between ethyl acetate (60 mL) and a saturated aqueous NaHCO3 solution (15 mL). The organic layer was washed with a saturated aqueous NaHCO3 solution (2×15 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified using preparative TLC eluting with 7% ethyl acetate in CH2Cl2. The product band was recovered and stirred with 2% MeOH in ethyl acetate/CH2Cl2 (v/v; 1:10) (20 mL). The silica was removed by filtration, washed with ethyl acetate/CH2Cl2 (v/v; 1:5) (2×5 mL) and acetone (3×4 mL) to give the title compound as an off-white solid (0.039 g, 44%). 1H-NMR (500 MHz, DMSO-d6) 5.86 (s, 2H), 6.89 (d, J=8.5, 1H), 7.85 (dd, J=2.1, 8.5 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H), 8.44 (d, J=2.5 Hz, 1H), 8.57 (dd, J=1.6, 2.5 Hz, 1H), 9.12 (d, J=1.5 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=2)[CH:3]=1.CCOC(C1(C(OCC)=O)NC(=O)CC1C1C=CC=CC=1)=O.[Cl:40][C:41]1[CH:47]=[CH:46][CH:45]=[C:44]([CH3:48])[C:42]=1[NH2:43].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([C:15]([NH:43][C:42]3[C:44]([CH3:48])=[CH:45][CH:46]=[CH:47][C:41]=3[Cl:40])=[O:17])=[CH:13][N:14]=2)[CH:3]=1
Reactant: Cc1cccc(Cl)c1N
Reactant: Cc1nc(Br)cc(Nc2ncc(C(=O)O)s2)n1
Agent: CCOC(=O)C1(C(=O)OCC)NC(=O)CC1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(Br)cc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1
Temperature: 0 °C
Yield: 77.5 %

Procedure:
Under nitrogen atmosphere, 2-(6-bromo-2-methylpyrimidin-4-ylamino)thiazole-5-formic acid (Compound 12) (15.8 g, 0.05 mol), PDCP (9.0 mL, 0.06 mol) and 2-chloro-6-methylaniline (Compound 8)) (7.4 mL, 0.06 mol) were added into methylene dichloride (650 mL) by stirring and cooling, and then triethylamine (20.4 mL, 0.15 mol) was added by droplets at 0° C. When finish adding, it reacted by stirring at room temperature overnight. Saturated sodium bicarbonate aqueous solution was added and stirred for 15 mins and then filtrated. The cake was taken up and added in DMSO (80 mL) and heated to 60° C.-70° C. when stirring. After dissolving, the mixture of water and ethanol (1:1, 320 mL) was added in thermal insulation. Crystals precipitated by stirring and then cooled down to 0° C. to grow the grain for 1 h. After air pump filtration the cake was rinsed by water and then by the mixture of water and ethanol (1:1), and dried by air pump. With phosphorus pentoxide as an auxiliary desiccant, the cake was dried by vacuum (−0.095 MPa) at about 50° C. to give Compound 14 (17.0 g, yield: 77.5%).
Reaction SMILES: O[CH:2]([NH:7][C:8](=[O:20])[C:9]1[C:10](=[CH:12][CH:13]=[C:14]([C:16]([O:18]C)=[O:17])[CH:15]=1)[NH2:11])[C:3]([Cl:6])([Cl:5])[Cl:4]>S(=O)(=O)(O)O>[O:20]=[C:8]1[C:9]2[C:10](=[CH:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[CH:15]=2)[NH:11][CH:2]([C:3]([Cl:6])([Cl:5])[Cl:4])[NH:7]1
Reactant: COC(=O)c1ccc(N)c(C(=O)NC(O)C(Cl)(Cl)Cl)c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc2c(c1)C(=O)NC(C(Cl)(Cl)Cl)N2

Procedure:
N-(1-hydroxy-2,2,2-trichloroethyl)-5-methoxycarbonylanthranilamide (5 g.) and concentrated sulphuric acid (100 ml.) were heated together on a steam bath for 15 minutes, cooled, and poured onto a minimum quantity of ice. The precipitate thus formed was filtered off, dried and dissolved in hot ethanol (300 ml.). The ethanol solution was concentrated to 20 ml. and the solid produced was filtered off and discarded. The filtrate was further concentrated to 10 ml. and the product thus obtained was filtered off, dried and crystallised from glacial acetic acid/water, 1:1, to give 1,2-dihydro-4-oxo-2-trichloromethylquinazoline-6-carboxylic acid, m.p. > 280° C.
Reaction SMILES: [OH:1][C@H:2]([C@H:9]([CH3:16])[C:10]([O:12]C(C)C)=[O:11])[C:3]([O:5]C(C)C)=[O:4].[OH-].[K+]>C1COCC1.O>[OH:1][C@H:2]([C@H:9]([CH3:16])[C:10]([OH:12])=[O:11])[C:3]([OH:5])=[O:4]
Reactant: CC(C)OC(=O)[C@@H](C)[C@@H](O)C(=O)OC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](C(=O)O)[C@@H](O)C(=O)O
Temperature: 0 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
Diisopropyl (2R,3S)-2-hydroxy-3-methylsuccinate (9.75 g; 42.0 mmol; 1.00 eq.) was taken in THF (146 mL), cooled to 0° C. and was treated with KOH (14.1 g, 152 mmol) in water (49 mL). The resulting mixture was stirred at RT for 48 h. THF was removed and the residue was taken in water. The aqueous layer was washed with ether (100 mL) and was acidified with an aqueous solution of HCl (1.5 N), then was extracted with EtOAc (continuous extraction during 20 hours). The organic phase was dried over Na2SO4 and then concentrated to give the title product (mixture of diastereoisomers) as a pale yellow oil (2.49 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:16]([C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2)#[CH:17].C(N(CC)CC)C.N1C=CC=CC=1>[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:10][O:9][C:7]([C:6]1[CH:11]=[C:2]([C:17]#[C:16][C:18]23[CH2:27][CH:22]4[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]4)[CH2:19]2)[CH2:25]3)[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=1)=[O:8]
Reactant: C#CC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COC(=O)c1cc(C#CC23CC4CC(CC(C4)C2)C3)cc(C(=O)OC)c1
Reaction time: 1 h
Yield: 86 %

Procedure:
In a 1 L four-neck flask provided with a thermometer, a Dimroth condenser, a nitrogen inlet pipe and an agitator, 125 g of dimethyl 5-bromoisophthalate (0.458 mol), 1.1 g of triphenyl phosphine (0.00419 mol), 0.275 g of copper iodide (0.00144 mol) and 64.26 g of the obtained 1-ethynyladamantane (0.401 mol) were charged and nitrogen was passed into the flask. Then, 375 mL of dehydrated triethylamine and 200 mL of dehydrated pyridine were added therein and the mixture was agitated and dissolved. After nitrogen was passed into the flask for one hour, 0.3 g of dichlorobis (triphenyl phosphine) palladium (0.000427 mol) was quickly added and the mixture was heated and refluxed in an oil bath. Then, triethylamine and pyridine was removed under reduced pressure to obtain a brown viscous solution. The solution was added to 500 mL of water and filtered to separate a solid. The solid was washed with 500 mL of water, 500 mL of 5 mol/L hydrochloric acid and 500 mL of water each two times and dried under pressure at 50° C., thus obtaining 121.5 g of 1-(3,5-bis(methoxycarbonyl)phenyl)-2-(1-adamantyl)ethyne (the yield was 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:24]([O-])=O.C(N(CC)C(C)C)(C)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:36]([NH:24][C:3]1[CH:4]=[C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)[CH:6]=[CH:7][C:2]=1[F:1])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c([N+](=O)[O-])c1)N2
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)c3ccccc3)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
To a solution of methyl 2-(4-fluoro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (105 mg, 0.32 mmol) in dichloromethane (5 mL) was added N,N-diisopropylethylamine (83 mg, 0.64 mmol) followed by benzoyl chloride (49 mg, 0.35 mmol) at 0° C. under nitrogen. The reaction mixture was then stirred at room temperature for 16 hours. The solvent was removed and the residue was purified by preparative Thin layer chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to afford methyl 2-(3-benzamido-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate 130 mg (94%) as a pale yellow solid. MS (ESI+APCI) M+1=433.