Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[N:10]=[C:11]([N:14]3[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]3)[S:12][CH:13]=2)=[O:8])[CH2:3][CH2:2]1.[C:23]([O-:26])(=[S:25])[CH3:24].[K+]>CN(C)C=O>[C:23]([S:25][CH:16]1[CH2:15][N:14]([C:11]2[S:12][CH:13]=[C:9]([C:7]([N:4]3[CH2:3][CH2:2][S:1][CH2:6][CH2:5]3)=[O:8])[N:10]=2)[CH2:17]1)(=[O:26])[CH3:24]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCSCC3)cs2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N3CCSCC3)cs2)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 61.7 %

Procedure:
To a solution of 1-(4-thiomorpholinocarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (709 g, 1.95 mmol) (obtained as described in Reference Example 25(3)) in dimethylformamide (20 ml) was added potassium thioacetate (1.34 g, 11.7 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) for 5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:n-hexane:methylene chloride (1:1:1) as the eluant to afford 3-acetylthio-1-(4-thiomorpholinocarbonyl-1,3-thiazol-2-yl)azetidine (413 mg, yield 64%) as a pale brown solid.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:30])[CH:11]=1)=[O:9].F[C:50](F)(F)C1C=C(C(N)C)C=CC=1>>[N:22]1([C:20]2[CH:19]=[CH:18][C:17]([NH:28][C:29]([C:31]3[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=3)[CH2:34][S:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:30])=[C:16]([C:12]3[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH:6]([C:5]4[CH:44]=[CH:45][CH:46]=[C:3]([C:2]([F:47])([F:1])[F:48])[CH:4]=4)[CH3:50])[CH:15]=[CH:14][N:13]=3)[CH:21]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(N)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Product: CC(NC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CSCCC(=O)O)c2)c1)c1cccc(C(F)(F)F)c1

Procedure:
This compound was prepared using the procedure used to prepare 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzylthio)propanoic acid 1.1, using 1-(3-(trifluoromethyl)phenyl)ethanamine in place of 3-(trifluoromethyl)benzylamine. 1H-NMR (300 MHz, CD3OD, ppm): δ 9.044-9.062 (d, J=5.4 Hz, 1H), 8.786-8.816 (d, J=9.0 Hz, 1H), 8.378 (s, 1H), 8.125-8.133 (d, J=2.4 Hz, 1H), 8.003 (s, 1H), 7.875-7.905 (m, 2H), 7.707-7.754 (m, 3H), 7.499-7.623 (m, 4H), 5.324-5.393 (m, 1H), 3.913 (s, 2H), 3.678-3.714 (m, 4H), 2.709-2.754 (m, 2H), 2.574-2.618 (m, 2H), 2.043-2.060 (m, 4H), 1.831-1.846 (m, 2H), 1.641-1.664 (d, J=6.9 Hz, 3H). MS (ES, m/z): 692 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:4]=1)#[N:2].[CH2:19]([NH2:22])[CH2:20][CH3:21].[OH-].[Na+]>>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:22][CH2:19][CH2:20][CH3:21])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:4]=1)#[N:2]
Reactant: CCCN
Reactant: N#Cc1nc(Cl)c(-c2cccc(Cl)c2)nc1C#N
Agent: [Na+]
Agent: [OH-]
Product: CCCNc1nc(C#N)c(C#N)nc1-c1cccc(Cl)c1
Yield: 78.4 %

Procedure:
2,3-Dicyano-5-chloro-6-(m-chlorophenyl)pyrazine (1.0 g; 0.0036 mole), 0.24 g (0.004 mole) of n-propylamine and 40 ml of a 0.1N aqueous solution of sodium hydroxide were worked up in the same way as in Example 17, and recrystallized from methanol to afford 0.84 g (yield 78%) of 2,3-dicyano-5-n-propylamino-6-(m-chlorophenyl)pyrazine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>O.ClC(Cl)Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=3[CH3:11])[CH2:20][CH2:21]2)=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)nnc(Cl)c1C
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cccc(N2CCN(c3nnc(Cl)c(C)c3C)CC2)c1C
Temperature: 190 °C
Yield: 30 %

Procedure:
A mixture of 3.9 parts of 3,6-dichloro-4,5-dimethylpyridazine, 4.2 parts of 1-(2,3-dimethylphenyl)piperazine and 2.94 parts of potassium carbonate was stirred and heated for 4 hours in an oil bath at 190° C. After cooling, the mixture was taken up in water and trichloromethane. The organic layer was separated, dried, filtered and evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 2 parts (30%) of 3-chloro-6-[4-(2,3-dimethylphenyl)-1-piperazinyl]-4,5-dimethylpyridazine; mp. 194.5° C. (compound 217).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.O=C1[N:15]2[CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH:14]2[CH2:13]O1.O>CN(C=O)C>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:13][C@@H:14]2[NH:15][CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:19]2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)OCC2C1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN[C@@H](COc2cccnc2)C1
Temperature: 120 °C
Yield: 41.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 4.50 g, 113 mmol) was added portionwise to a solution of 3-hydroxypyridine (13.2 g, 139 mmol) and tert-butyl tetrahydro-3-oxo-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate (3.37 g, 13.9 mmol) in DMF (100 mL). Upon complete addition, the reaction mixture was heated to 120° C. for 60 h. Upon cooling to rt, water (10 mL) was added and the reaction mixture was concentrated under reduced pressure. The material was dissolved in H2O (150 mL) and EtOAc (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organics were concentrated under reduced pressure. The material was dissolved in EtOAc (150 mL) and washed with 1 N NaOH (3×50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (0 to 5% MeOH in CH2Cl2 gradient) gave 1.7096 g (42%) of the desired product as a white solid. LC-MS: RT=3.81 min, [M+H]+=294.2.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>ClCCl>[C:27]([NH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2CCCc3ccccc32)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
To a solution of 1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline (0.5 g) in dichloromethane (20 ml) is added triethylamine (0.3 g), and thereto is added benzoyl chloride (0.28 g) under ice-cooling. The mixture is stirred at room temperature for 1 hour. To the reaction mixture is added water and extracted with dichloromethane. The extract is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1) and recrystallized from methanol to give 1-[4-(benzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (245 mg) as white powder, m.p. 202.5-203.5° C.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([NH:12][C:13]([C@@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]3)=[O:14])[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(N(CC)C(C)C)(C)C.[Cl:31][C:32]1[C:33](F)=[N:34][CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1>CS(C)=O>[C:1]1([C:7]2[N:11]=[C:10]([NH:12][C:13]([C@@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][N:16]3[C:33]3[C:32]([Cl:31])=[CH:37][C:36]([C:38]([F:41])([F:39])[F:40])=[CH:35][N:34]=3)=[O:14])[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1nc(-c2ccccc2)ns1)[C@@H]1CCCCN1
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1nc(-c2ccccc2)ns1)[C@@H]1CCCCN1c1ncc(C(F)(F)F)cc1Cl
Temperature: 100 °C

Procedure:
To a stirred solution of (S)-Piperidine-2-carboxylic acid (3-phenyl-1,2,4-thiadiazol-5-yl)-amide; hydrochloride (70 mg; 0.215 mmol) and N,N-diisopropylethylamine (0.037 mL; 0.215 mmol) in DMSO (1 mL) is added 3-chloro-2-fluoro-5-trifluoromethylpyridine (42.9 mg; 0.215 mmol). The reaction mixture is heated at 100° C. for 4 hours. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 468 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12]C(C)(C)C(C)(C)[O:9]2)=[CH:4][N:3]=1.[NH:17]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[OH:22][CH:19]1[CH2:20][CH2:21][N:17]([C:2]2[N:3]=[CH:4][C:5]([B:8]([OH:9])[OH:12])=[CH:6][CH:7]=2)[CH2:18]1
Reactant: OC1CCNC1
Reactant: CC1(C)OB(c2ccc(Cl)nc2)OC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: OB(O)c1ccc(N2CCC(O)C2)nc1
Temperature: 180 °C

Procedure:
To a solution of 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (239 mg, 1 mmol) in NMP (2 mL) was added pyrrolidin-3-ol (174 mg, 2 mmol) and DIPEA (500 uL, 3 mmol), then the mixture was sealed in a microwave tube and heated in microwave reactor at 180° C. for 1.5 hours. TLC and LC-Ms showed the reaction had completed and the desired compound was detected. The reaction mixture was poured into 30 mL of H2O, and extracted with n-BuOH, washed with water and brine, concentrated and purified on TLC(CH2Cl2:MeOH=10:1) to give a white solid. MS (m/z): 209 (M+H)+
Reaction SMILES: [CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9](OS(C(F)(F)F)(=O)=O)=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1.[CH3:21][C:22]([OH:26])([C:24]#[CH:25])[CH3:23].C(N(CC)CC)C>CN(C)C=O.[Cu]I>[CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:25]#[C:24][C:22]([OH:26])([CH3:23])[CH3:21])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: CSc1ncnc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1ncnc2cc(C#CC(C)(C)O)ccc12
Yield: 174.2 %

Procedure:
4-(Methylthio)-7-(trifluoromethanesulphonyloxy)quinazoline (592 mg, 1.82 mmol) in dimethylformamide (20 ml) was reacted with 2-methyl-3-butyn-2-ol (0.53 ml, 0.54 mmol) in the presence of bis dichloro(triphenylphosphine)palladium (64 mg, 0.091 mmol), copper (I) iodide (20 mg) and triethylamine (1.1 ml, 0.8 mmol), at 90° C. for 2.5 hours. The solvent was removed in vacuo, aqueous hydrochloric acid (2N) was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and the solvents were evaporated in vacuo. Purification by flash chromatography on silica gel, eluting with isohexane/ethyl acetate (55:45), yielded, 4-(methylthio)-7-(3-hydroxy-3-methylbut-1-ynyl)quinazoline (243 mg, 51% yield):
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[CH:9][CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:27][CH2:28][CH:29]([OH:31])[CH3:30]>C1(C)C=CC=CC=1>[CH3:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:27]([CH2:28][CH:29]([OH:31])[CH3:30])[C:5]=32)=[CH:10][CH:9]=1
Reactant: CC(O)CN
Reactant: Cc1ccc2c(c1)C(=O)C(CC=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)-c1c(ccn1CC(C)O)C2
Reaction time: 0.75 h
Yield: 43.6 %

Procedure:
A solution of 1.88 g of (RS)-2-(2-oxoethyl)-6-methyl-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 0.99 g (44%) of (RS)-1-(7-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][C@@H:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:24]1([CH:13]([O:12][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(OCc1ccccc1)[C@@H](O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC(C(=O)OCc2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 9 h

Procedure:
A CH2Cl2 (200 mL) solution of p-toluenesulfonyl chloride (8.65 g, 45.4 mmol) was added dropwise to a cooled (−5° C.) CH2Cl2 (200 mL) solution of (S)-benzyl 2-hydroxy-2-phenylacetate (10.0 g, 41.3 mmol), triethylamine (5.75 mL, 41.3 mmol) and 4-dimethylaminopyridine (0.504 g, 4.13 mmol), while maintaining the temperature between −5° C. and 0° C. The reaction was stirred at 0° C. for 9 hours, and then stored in a freezer (−25° C.) for 14 hours. It was allowed to thaw to ambient temperature and washed with water (200 mL), 1N HCl (100 mL) and brine (100 mL), dried (MgSO4), filtered, and concentrated in vacuo to provide benzyl 2-phenyl-2-(tosyloxy)acetate as a viscous oil which solidified upon standing (16.5 g). The chiral integrity of the product was not checked and that product was used for the next step without further purification. 1H NMR (DMSO-d6, δ=2.5, 500 MHz) δ 7.78 (d, J=8.6, 2H), 7.43-7.29 (m, 10H), 7.20 (m, 2H), 6.12 (s, 1H), 5.16 (d, J=12.5, 1H), 5.10 (d, J=12.5, 1H), 2.39 (s, 3H). RT=3.00 (Cond. 3); >90% homogeneity index;
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@@H:5]([OH:8])[CH2:6][OH:7])[CH3:2].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[CH3:13][C:12]([Si:9]([CH3:11])([CH3:10])[O:7][CH2:6][C@H:5]([OH:8])[CH2:4][O:3][CH2:1][CH3:2])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC[C@@H](O)CO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC[C@@H](O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2S)-3-ethoxy-1,2-propanediol (product from step (0.50 g) in DCM (30 mL) was added tert-butyldimethylsilyl chloride (0.88 g), triethylamine (0.43 mL) and 4-(dimethylamino)pyridine (31 mg) at 0° C. The solution was then warmed to ambient temperature and stirred for 16 h. The reaction mixture diluted with H2O and extracted with EtOAc. The organic layer was washed with brine and evaporated. Purification was by column chromatography on silica gel using EtOAc/isohexane (2:8) as eluent to give the subtitle compound as an oil. Yield: 0.69 g
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][CH2:20][OH:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.Cl[C:23]1[CH:33]=[C:27]2[N:28]([CH3:32])[CH2:29][CH2:30][CH2:31][N:26]2[C:25](=[O:34])[N:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=1)[CH2:19][CH2:20][O:21][C:23]1[CH:33]=[C:27]2[N:28]([CH3:32])[CH2:29][CH2:30][CH2:31][N:26]2[C:25](=[O:34])[N:24]=1
Reactant: OCCc1ccc(Oc2cccc(C(F)(F)F)c2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCCc1ccc(Oc3cccc(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 2-(3-fluoro-4-(3-(trifluoromethyl)phenoxy)phenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:21]([N:23]1[CH2:62][CH2:61][CH2:60][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([NH:32][C@H:33]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=1[Cl:45])=[O:40])=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[NH:63]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[C@H:64]([C:66](O)=[O:67])[CH3:65].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(Cl)(Cl)Cl.CO>[NH:63]([C:69]([O:71][C:72]([CH3:73])([CH3:75])[CH3:74])=[O:70])[C@H:64]([C:66]([NH:2][C@H:3]([C:21]([N:23]1[CH2:62][CH2:61][CH2:60][C@H:24]1[C:25]([NH:27][C@H:28]([C:30]([NH:32][C@H:33]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=1[Cl:45])=[O:40])=[O:31])[CH3:29])=[O:26])=[O:22])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:20])[NH:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[CH:18][CH:19]=1)(=[O:11])=[O:12])=[O:67])[CH3:65]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
At 0° C. the solution of 1490 mg (1.63 mmol) of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12) in 25 ml of anhydrous tetrahydrofuran was adjusted to pH 9, to which the pre-cold solution of 320 mg (169 mmol) of Boc-Ala-OH, 220 mg (1.63 mmol) of 1-hydroxybenzotriazole and 350 mg (1.70 mmol) of dicyclohexylcarbodiimide in 40 ml of anhydrous tetrahydrofuran was added. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 16 h and TLC (chloroform/methanol, 10:1) indicated complete disappearance of HCl.Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12). The resulted precipitates of N,N-dicyclohexylurea were filtrated and the filtrate was diluted with 100 ml of ethyl acetate. The solution obtained was washed successively with saturated NaCO3 in water (50 ml×3), saturated NaCl in water (50 ml×3) and KHSO4 in water (5%, 50 ml×3). The separated ethyl acetate layer was dried with anhydrous MgSO4, and then evaporated. The residue was purified on sinica gel chromatography (CHCl3/CH3OH, 30/1) to provide 1620 mg (94%) of the title compound as a glassy mass . Mp 96–98° C., FAB-MS (m/e) 1076.7[M+Na]+, 1093.4[M+K]+, 954.9[M-Boc]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]([F:13])([F:12])C(O)=O.CN(C=O)C.[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([OH:26])[CH:25]=1>O>[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([O:26][CH:8]([F:12])[F:13])[CH:25]=1
Reactant: Oc1cncc(Br)c1
Reactant: O=C(O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1cncc(Br)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Potassium carbonate (7.13 g) and chlorodifluoroacetic acid (1.75 ml) were added to a DMF solution (40 ml) of 3-bromo-5-hydroxypyridine (3.0 g). The temperature of the obtained mixture was heated to 100° C., and the mixture was then stirred for 24 hours. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with diethyl ether. The organic layer was successively washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over magnesium sulfate, followed by filtration. The solvent was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (n-hexane:diethyl ether), so as to obtain the title compound (670 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:39](Cl)([O:41][C:42](=[O:48])OC(Cl)(Cl)Cl)Cl.[CH3:50][C:51]1[CH:56]=[CH:55][C:54]([S:57][CH2:58][CH2:59]CO)=[CH:53][CH:52]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:42](=[O:48])[O:41][CH2:39][CH2:59][CH2:58][S:57][C:54]1[CH:55]=[CH:56][C:51]([CH3:50])=[CH:52][CH:53]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: Cc1ccc(SCCCO)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCCSc4ccc(C)cc4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Yield: 52.2 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (80 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (125 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-[(4-methylphenyl)sulfanyl]-1-propanol (66 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (68 mg, yield 49%).
Reaction SMILES: [CH:1]1([N:4]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:14]#[CH:15])[CH:8]=2)[CH3:5])[CH2:3][CH2:2]1.[CH2:16]([O:18][C:19](=[O:48])/[C:20](/C)=[CH:21]/[C:22]1[CH:27]=[CH:26][C:25](C#CC2C=C(C3CC3)C3OC4(CC4)C(C)=C(C)C=3C=2)=[CH:24][CH:23]=1)[CH3:17].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([O:18][C:19](=[O:48])/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][C:25]([C:15]#[C:14][C:9]2[CH:8]=[C:7]([CH2:6][N:4]([CH:1]3[CH2:3][CH2:2]3)[CH3:5])[CH:12]=[CH:11][C:10]=2[CH3:13])=[CH:24][CH:23]=1)[CH3:17]
Reactant: CCOC(=O)/C(C)=C/c1ccc(C#Cc2cc3c(c(C4CC4)c2)OC2(CC2)C(C)=C3C)cc1
Reactant: C#Cc1cc(CN(C)C2CC2)ccc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)/C=C/c1ccc(C#Cc2cc(CN(C)C3CC3)ccc2C)cc1

Procedure:
Following General Procedure B and using cyclopropyl-(3-ethynyl-4-methyl-benzyl)-methyl-amine (Intermediate 99, 0.095 g, 0.48 mmol), ethyl-4-iodo-cinnamate (Reagent 3, 0.144 g, 0.47 mmol), triethyl amine (13 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.071 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-20% ethyl acetate in hexane as the eluent, the title compound was obtained (0.14 g, 82%).