Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH:20]([F:22])[F:21])[CH:17]=2)[C:12]([CH2:23][C:24]2[C:29]([Cl:30])=[CH:28][N:27]=[CH:26][C:25]=2[Cl:31])=[N:11][N:10]=1>CN(C=O)C>[Cl:31][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:30])[C:24]=1[CH2:23][C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:19][CH:20]([F:21])[F:22])=[CH:15][CH:14]=2)[C:9]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[N:10][N:11]=1
Reactant: c1nc[nH]n1
Reactant: FC(F)Oc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(-n3cncn3)c2c1
Temperature: 25 °C
Yield: 56.2 %

Procedure:
A solution under N2 of 1,2,4-triazole (2.4 g, 34.8 mmoles) in DMF (100 ml) was added with NaH (1.05 g, 26.1 mmoles). The mixture was stirred at room temperature up to clarity, then added with 4-chloro-1(3,5-dichloro-pyridin-4-ylmethyl)-6-difluoromethoxy-phthalazine (6.8 g, 17.4 mmoles), prepared as described in example 99. The mixture was heated at 100° C. for 5 hours, extracted three times with CH2Cl2. The organic phase was anhydrified and dried to give a solid which was flash chromatographed (eluent: ethyl acetate/petrolatum 7:3 to 100% of ethyl acetate) to give 4.14 g of the title compound (yield: 28%). m.p.: 220-224° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[S:9]1[CH:13]=[C:12]([CH2:14][OH:15])[N:11]=[CH:10]1>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([O:15][CH2:14][C:12]2[N:11]=[CH:10][S:9][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: OCc1cscn1
Product: Clc1ccc(OCc2cscn2)nn1

Procedure:
3,6-Dichloropyridazine (1.0 g, 6.712 mmol) was reacted analogously to example 4a with thiazol-4-ylmethanol (578 mg, 6.712 mmol). Yield: 775 mg (51%), M+H+: 228.0,
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]([CH3:15])[CH2:7][C:6]2=[O:16].N1C=CC=CC=1.Cl[C:24]([O:26][CH3:27])=[O:25]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([C:24]([O:26][CH3:27])=[O:25])[CH:8]([CH3:15])[CH2:7][C:6]2=[O:16]
Reactant: COC(=O)Cl
Reactant: COc1cc2c(cc1OC)C(=O)CC(C)N2
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N1c2cc(OC)c(OC)cc2C(=O)CC1C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 1.2 g. (5.45 mmol) of the quinoline product of Example 4, 792 mg. (10.7 mmol) of dry pyridine and 5.5 ml. of methylene chloride was stirred and cooled by an ice-water bath while 758 mg. (8.02 mmol) of methyl chloroformate in 1 ml. of methylene chloride was added over a 10 min. period at a rate to maintain a 10°-15° C. temperature. The ice bath was removed and the reaction allowed to stir at room temperature for 45 min. then poured onto 25 ml. of saturated sodium bicarbonate solution. The methylene chloride layer was separated and washed with 25 ml. saturated sodium bicarbonate solution and saturated sodium chloride solution, then dried over magnesium sulfate, and gravity filtered and evaporated to a yellow solid. The solid was triturated with 5 ml. anhydrous ether, filtered, and washed with minimum ether, then air dried to 1.1 g. of a yellow solid, m.p. 156°-158°. This material was dissolved in 10 ml. of hot ethyl acetate, treated with 50 mg. Darco G60, filtered and crystallized by the addition of hexane to give 727 mg. of an off-white solid, m.p. 159°-160° after drying in vacuum at 100° C (1 mm) for 24 hrs.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2Cl)(=O)C.[N:16]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[S:18][C:17]=1[NH2:25]>>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:25][C:17]1[S:18][C:19]2[C:24]([N:16]=1)=[CH:23][CH:22]=[CH:21][N:20]=2
Reactant: Nc1nc2cccnc2s1
Reactant: CC(=O)Oc1ccc2ncnc(Cl)c2c1
Product: Oc1ccc2ncnc(Nc3nc4cccnc4s3)c2c1

Procedure:
The compound of Example 38 was manufactured using 6-acetoxy-4-chloro-quinazoline and thiazolo[5,4-b]pyridin-2-yl-amine by the same method as in Example 1 for the manufacture of 6-iodoquinazolin-4-yl)-thiazolo[5,4-b]pyridin-2-yl-amine, by a similar method thereto or by a combination of such a method with a conventional method.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].Cl.[C:14](=N)(OC)[CH3:15]>CO>[C:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:12][C:14]([CH3:15])=[N:1][C:2]=2[CH:7]=1)([CH3:9])([CH3:11])[CH3:10]
Reactant: COC(C)=N
Reactant: CC(C)(C)c1ccc(O)c(N)c1
Agent: Cl
Solvent: CO
Product: Cc1nc2cc(C(C)(C)C)ccc2o1
Yield: 24 %

Procedure:
In a 100 ml round bottom flask was placed 7.25 g (0.044 mol) of 2-Amino-4-tert-butylphenol, (Aldrich Cat #193282) with 6.0 g (0.055 mol) of Methyl acetimidate hydrochloride (Aldrich Cat #254940) with 50 ml of MeOH. This was refluxed for 4 hours. Then the MeOH was removed under vacuum. This was separated between 50 ml of ether and 50 ml of water. The ether was separated, dried, and removed under vacuum. Then 50 ml of hexanes was added to the resulting solid. Remaining 2-Amino-4-tert-butylphenol was insoluble in hexanes and was removed by filtration. The remaining oil was chromatographed using 2% MeOH/CH2Cl2 to provide 5-tert-butyl-2-methylbenzoxazole (Yield=2 g, 24%).
Reaction SMILES: C[O:2][C:3]([CH2:5][NH:6][C:7]1[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([N:17]([CH3:29])[CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[CH3:28])=[O:16])=[CH:9][CH:8]=1)=O.[CH3:30][NH2:31]>CO>[CH3:29][N:17]([CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][C:20]=1[CH3:28])[C:15](=[O:16])/[CH:14]=[CH:13]/[C:10]1[CH:11]=[N:12][C:7]([NH:6][CH2:5][C:3]([NH:31][CH3:30])=[O:2])=[CH:8][CH:9]=1
Reactant: COC(=O)CNc1ccc(/C=C/C(=O)N(C)Cc2c(C)[nH]c3ccccc23)cn1
Reactant: CN
Solvent: CO
Product: CNC(=O)CNc1ccc(/C=C/C(=O)N(C)Cc2c(C)[nH]c3ccccc23)cn1
Reaction time: 72 h
Yield: 100 %

Procedure:
To (E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide (0.7 g, 1.8 mmole) was added a solution of 2.0 M methylamine in MeOH (50 mL). After stirring for 72 h the reaction was concentrated to dryness. The residue was triturated with Et2O, filtered, and dried under vacuum to give the title compound (0.703 g, 100%) as an off-white solid: MS (ES) m/e 392.2 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([B:12]([OH:14])[OH:13])=[CH:8][CH:7]=1.O[C:16]([C:19](O)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(OCC)C>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:14][C:19]([CH3:21])([CH3:20])[C:16]([CH3:18])([CH3:17])[O:13]2)=[CH:8][CH:7]=1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OB(O)c1ccc(OCCCBr)cc1
Solvent: CCOCC
Product: CC1(C)OB(c2ccc(OCCCBr)cc2)OC1(C)C
Reaction time: 18 h
Yield: 112.8 %

Procedure:
To a solution of 4-(3-bromopropoxy)phenylboronic acid (1.0 g, 3.9 mmol) in diethyl ether (40 mL) was added pinacol (1.4 g, 12 mmol) and the reaction mixture was stirred for 18 h and concentrated to afford the desired product (1.5 g, crude) as a light brown oil which carried onto the next step without further purification: ESI MS m/z 247 [C15H22BBrO3−94]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NCc1ccccn1

Procedure:
A mixture of 5.0 g 2-(aminomethyl)pyridine, 5.02 ml acetic anhydride, 0.847 g 4-dimethylaminopyridine and 35 ml of pyridine is heated at reflux temperature for 23.5 hours. The cooled solution is poured into water and extracted with methylene chloride. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:5% methyl alcohol/ethyl acetate) to give 3.3 g of desired product as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C@@H:12]2[C@H:16]3[O:17]C(C)(C)[O:19][CH2:20][C@H:15]3[O:14][C@@H:13]2[O:23][CH3:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)(=O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C@@H:12]2[C@@H:16]([OH:17])[C@@H:15]([CH2:20][OH:19])[O:14][C@@H:13]2[O:23][CH3:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CO[C@H]1O[C@@H]2COC(C)(C)O[C@@H]2[C@H]1OS(=O)(=O)c1ccc(C)cc1
Solvent: O
Solvent: CC(=O)O
Product: CO[C@H]1O[C@H](CO)[C@H](O)[C@H]1OS(=O)(=O)c1ccc(C)cc1
Temperature: 50 °C

Procedure:
Compound 35.4 (32.18 g, 89.9 mmol) was dissolved in 400 mL of a 3:1 mixture of acetic acid and water. The mixture was heated to 50° C. for 2 h and the solvent was removed under reduced pressure. The residue was subjected to a column chromatography eluting with EtOAc to give compound 35.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl.[N:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47]Cl)[CH:42]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:47][C:43]4[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])=[O:24]
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1O
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1OCc1cccnc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)-oxy]phenyl}-N′-(2,4-difluorophenyl)urea (55 mg), potassium carbonate (31 mg), and 3-picolyl chloride hydrochloride (22 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 80° C. for one hr. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 30 mg (yield 48%) of the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C@H:10]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].C(O)C>[Pd].O>[F:27][C:25]([F:26])([F:28])[C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=1)[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)=[O:29]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(Cc2ccccc2)C[C@H]1Cc1ccc(F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 92.1 %

Procedure:
A mixture of (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-fluorobenzyl)piperazine (7.92 g), ammonium formate (2.38 g) and 10% palladium charcoal (0.79 g) in a mixed solvent of ethanol (80 ml) and water (8 ml) was stirred for 1.5 hours at 60° C. under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through Celite® pad. The filtrate was concentrated under reduced pressure and the residue was dissolved into ethyl acetate. The solution was washed with water and brine successively, dried over magnesium sulfate, and evaporated under reduced pressure to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-fluorobenzyl)piperazine (6.04 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([N:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17](=[O:28])/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7]I.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[CH3:1][O:2][C:3](=[O:29])[CH:4]([N:9]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:17](=[O:28])/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH2:7][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: C1CCNCC1
Reactant: COC(=O)C(CCCI)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC(=O)C(CCCN1CCCCC1)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 842.4 %

Procedure:
A solution of 0.111 g (0.20 mmol) of 2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-5-iodo-pentanoic acid methyl ester in 1 ml of DMA was treated at 0° C. with 0.021 ml (0.21 mmol) of piperidine and stirred 30 min at 0° C. and 1 h at RT. 0.065 g (0.20 mmol) of cesium carbonate was added at 0° C. and stirring was continued for 2 h. After additional 3 h at RT, the reaction was extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, aqueous 10% NaCl, dried over Na2SO4 evaporated and precipitated with CH2Cl2/n-pentane to yield 0.86 g (84%) of the title compound as a white foam. MS: 510.3 (MH+, 2Cl).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:16])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:16][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH:1][S:22]([C:18]3[S:17][CH:21]=[CH:20][CH:19]=3)(=[O:24])=[O:23])[CH:3]=1)[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCOC(=O)c1cc2cc(C)cc(N)c2[nH]1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(C)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.8 %

Procedure:
To a mixed solution of ethyl 7-amino-5-methyl-1H-indole-2-carboxylate (0.60 g) and pyridine (10 mL) was added 2-thiophenesulfonyl chloride (0.66 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=3:7-5:5), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (910 mg, yield 91%) as colorless needle crystals. melting point 168-169° C.
Reaction SMILES: [CH:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C@H:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:6]([NH:21]C(=O)OC(C)(C)C)[C:5]1=[O:29])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[NH2:21][C@@H:6]1[C:5](=[O:29])[N:4]([CH:1]([CH3:3])[CH3:2])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C@@H:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](c2ccccc2)Oc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1C(=O)[C@@H](N)[C@@H](c2ccccc2)Oc2ccccc21
Yield: 98.6 %

Procedure:
tert-Butyl [(2R,3S)-5-isopropyl-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]carbamate (69a) (80 mg, 0.202 mmol) was dissolved in 5:1 (v/v) dichloromethane:trifluoroacetic acid (3 mL) and kept at ambient temperature for 30 min. The solution was evaporated and the residue was dissolved in ethyl acetate and extracted with saturated aqueous sodium bicarbonate. The organic solution was dried and evaporated to afford the title compound (59 mg, 99%) as a white solid. MS APCI, m/z=297 (M+1). LC/MS: 1.79 min
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:41](O)(=[S:43])[CH3:42]>C1COCC1>[C:41]([O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=1)(=[S:43])[CH3:42]
Reactant: OCc1cccc(Cl)c1
Reactant: CC(O)=S
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=S)OCc1cccc(Cl)c1
Reaction time: 0.17 h

Procedure:
To a solution of 1 mmol 3-chlorobenzyl alcohol and 1 mmol triphenylphosphine in 5 mL THF at 0° C., 1 mmol diethylazodicarboxylate is added. After stirring for 10 minutes, 1 mmol thioacetic acid is added. The reaction is stirred for 3 hours, concentrated and purified by flash chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][CH:5]=1)[CH3:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CN(C)C=O>[CH2:1]([O:3][C:4]1[N:9]=[C:8](/[CH:10]=[CH:16]/[N:17]([CH3:19])[CH3:18])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc([N+](=O)[O-])c(C)n1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc([N+](=O)[O-])c(/C=C/N(C)C)n1
Temperature: 25 °C

Procedure:
To a stirred solution of the compound prepared in Example 421 (1.88 g) in N,N-dimethylformamide (25 mL) was added N,N-dimethylformamide dimethylacetal (1.61 mL) at room temperature. The resulting purple solution was placed in an oil bath and heating was started to 140° C. The mixture was heated for 30 minutes, cooled to room temperature, the solvent evaporated in vacuo, coevaporated from methanol and dried further under high vacuum for 2 hours. This material was triturated in 1:1 hexane-ether and collected by filtration to afford the title compound as red solids (2.2 g) with the following physical data.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([NH2:28])[CH2:26][CH:25]3[CH2:27][CH:22]2[CH2:23][CH2:24]3)=[CH:17][CH:16]=1>CN(C=O)C>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2([N:28]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)[CH2:26][CH:25]3[CH2:27][CH:22]2[CH2:23][CH2:24]3)=[CH:19][CH:20]=1
Reactant: BrCCCCCBr
Reactant: NC1(c2ccc(F)cc2)CC2CCC1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(C2(N3CCCCC3)CC3CCC2C3)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
Anhydrous potassium carbonate (0.94 g, 6.8 mmol) and 1,5-dibromopentane (0.47 ml, 3.4 mmol) were added to a crude base of (±) 2-(4-fluoro-phenyl)-bicyclo[2.2.1]hept-2-ylamine (compound 2; Table 1) (0.70 g, 3.4 mmol) in dry DMF (30 ml). The mixture was heated to 50° C. and incubated for 8 hours. The mixture was then stirred overnight at room temperature and subsequently quenched with water. The resultant mixture was extracted with chloroform (3×20 ml). The chloroform extracts were combined and the chloroform was removed using a rotary evaporator. The remaining residue was extracted with ether (2×25 ml), and the ethereal extract was washed with water (2×20 ml) and dried over anhydrous sodium sulfate. A pale yellow oil was obtained after removing the ether. Purification by TLC with a mobile phase of chloroform and diethyl ether (9:1) resulted in a colorless crystalline compound (0.65 g, 70% yield, m.p. 58-59° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:32]([O:35][CH2:36][C:37](Cl)=[O:38])(=[O:34])[CH3:33]>O1CCCC1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:37]([CH2:36][O:35][C:32](=[O:34])[CH3:33])=[O:38])=[CH:7][CH:6]=2)[C:9](=[O:10])[NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 22.9 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (prepared in Example 3, 105 mg, 0.33 mmol) in tetrahydrofuran (10 mL) was treated with N,N-diisopropylethylamine (0.068 mL, 0.40 mmol) and acetoxy acetyl chloride (0.03 mL, 0.33 mmol). The reaction mixture was stirred at 25° C. for 5 h. At this time, the reaction was concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 50/50 heptane/ethyl acetate) afforded acetic acid {4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-phenylcarbamoyl}-methyl ester (31.4 mg, 22.7%) as a white solid: mp 90-95° C.; EI-HRMS m/e calcd for C21H25N3O4S (M+) 415.1565, found 415.1567.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[N:15]=[N:14][C:13]([C:16]4[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[CH:1]1([N:4]2[CH2:5][CH2:6][N:7]([C:10]3[N:15]=[N:14][C:13]([C:16]4[CH:17]=[C:18]([NH:22][C:30](=[O:32])[CH3:31])[CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[CH2:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: Nc1cccc(-c2ccc(N3CCN(C4CC4)CC3)nn2)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cccc(-c2ccc(N3CCN(C4CC4)CC3)nn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[6-(4-cyclopropyl-piperazin-1-yl)-pyridazin-3-yl]-phenylamine (400 mg, 1.36 mmol) in CH2Cl2 (25 mL) was added triethylamine (275 mg, 2.72 mmol). Then acetyl chloride (171 mg, 2.18 mmol) was added dropwise and the resulting mixture was stirred overnight at rt. The reaction was quenched with water (15 mL) and the phases were separated. The organic phase was washed with brine, dried (Na2SO4) and concentrated to give a crude product, which was recrystallized from MeOH. This afforded 201 mg (48%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[CH:8][CH:9]=1)[C:6](Br)(Br)[CH2:5]2.S(=O)(=O)(O)[OH:13]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:13])[CH2:5]2
Reactant: O=S(=O)(O)O
Reactant: Brc1ccc2c(c1)CC2(Br)Br
Solvent: O
Product: O=C1Cc2cc(Br)ccc21
Temperature: 75 °C
Reaction time: 108 h

Procedure:
To a suspension of 3-bromo-7,7-dibromo-bicyclo[4.2.0]octa-1,3,5-triene (2) (186.2 g, 0.546 mol, theoretical) in H2O (1000 ml) was added sulfuric acid (97%, 50 ml) at 15° C. The resulting mixture was stirred at 75° C. for 4.5 days.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[C:3]#[C:4][CH2:5][CH2:6][CH2:7][OH:8].[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:11][S:12]([O:8][CH2:7][CH2:6][CH2:5][C:4]#[C:3][C:2]([CH3:10])([CH3:9])[CH3:1])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)C#CCCCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C#CCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
100 mg of the resulting alcohol compound was dissolved in 1 ml of ethyl acetate, and 60 μl of methanesulfonyl chloride and 200 μl of triethylamine were added. The mixture was stirred at room temperature for 1 hour, and then the precipitate of triethylamine hydrochloride was removed by filtration. The filtrate was diluted with ethyl acetate, and washed succesively with a saturated aqueous solution of sodium bicarbonate, 1N hydrochloric acid and a saturated aqueous slution of sodium chloride, then worked up in a customary manner to give 150 mg of the captioned compound as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.O[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]>>[O:26]=[C:17]1[C:18]2[C:19](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:21])[N:16]1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: CC(C)(C)OC(=O)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Yield: 72 %

Procedure:
Reaction of tert-butyl 4-hydroxypiperidine-1-carboxylate with N-hydroxyphthalimide following the procedure described for the preparation of Reference Example 9 gave tert-butyl 4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]piperidine-1-carboxylate (3.0 g, 72%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 1.46 (9H, s), 1.82-1.85 (2H, m), 1.92-1.96 (2H, m), 3.20-3.25 (2H, m), 3.86-3.90 (2H, m), 4.41-4.44 (1H, m), 7.74-7.78 (2H, m), 7.82-7.86 (2H, m).