Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C1COCC1.CO.O.NN>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH2:12])[CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC[C@H](c1ccc(Cl)c(Cl)c1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC[C@@H](N)c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 111 %

Procedure:
To a solution of 160 (2.05 g, 5.21 mmol) and THF:MeOH (1:1, 40 mL) at RT was added hydrazine monohydrate (1.31 mL, 26.1 mmol) and the reaction was heated to 50° C. and stirred for 24 h. THF (20 mL) was added and precipitated phthalimide was filtered and discarded. The filtrate was washed with brine, extracted with DCM and the organic phases combined, dried (Na2SO4), filtered and concentrated to afford 1.18 g (89%) of (R)-1-(3,4-dichloro phenyl)propan-1-amine (162) as a viscous yellow oil. The 19F NMR of the Mosher amide indicated an ee of 93% based on peaks at −69.28 and −69.31.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:39]([NH:44][NH2:45])(=[O:43])[CH2:40][CH2:41][CH3:42]>ClCCl.C(=O)([O-])O.[Na+]>[C:39]([NH:44][NH:45][C:13]([CH:10]1[CH2:9][CH2:8][N:7]([C:2]2[N:1]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:12][CH2:11]1)=[O:15])(=[O:43])[CH2:40][CH2:41][CH3:42]
Reactant: O=C(O)C1CCN(c2ncccn2)CC1
Reactant: CCCC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: CCCC(=O)NNC(=O)C1CCN(c2ncccn2)CC1
Reaction time: 18 h
Yield: 62 %

Procedure:
A mixture of 1-pyrimidin-2-yl-piperidine-4-carboxylic acid (3.0 g, 14.5 mmol)(see reference U.S. Pat. No. 4,826,843), 1-hydroxybenzotriazole hydrate (1.96 g, 14.5 mmol) and 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (2.78 g, 14.5 mmol) in dichloromethane (100 ml) was stirred for 10 minutes. Butyric acid hydrazide (1.78 g, 17.4 mmol) was added and the reaction mixture was stirred under a nitrogen atmosphere for 18 hours. The reaction mixture was diluted with dichloromethane (100 ml) and sodium hydrogen carbonate solution was added. The reaction mixture was concentrated under reduced pressure and the solid formed was isolated by filtration. The material obtained was dried under vacuum at 40° C. to give the title compound (2.62 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12)[NH2:5].Cl[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[C:22]([NH2:30])[N:21]=1.[OH-].[Na+].CO>O.Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[N:23]=[C:22]([NH2:30])[N:21]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12
Reactant: Nc1ccc(Cc2ccnc3[nH]ccc23)c(F)c1
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1nc(Nc2ccc(Cc3ccnc4[nH]ccc34)c(F)c2)cc(C(F)(F)F)n1

Procedure:
32 mg (0.11 mmol) of 3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)aniline and 26 mg (0.12 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are suspended in 5 ml of water and 0.07 ml of 2N hydrochloric acid. The reaction mixture is heated at reflux for 20 hours. After cooling, the mixture is made alkaline using dilute aqueous sodium hydroxide solution, a little methanol is added and the mixture is extracted with ethyl acetate. The extract is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2([C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[C:21]([CH3:28])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[C:21]([CH3:28])[CH:20]=1)[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)[CH:7]=1
Reactant: OB(O)c1cncnc1
Reactant: COc1c(C)cc(C2(c3ccnc(Br)c3)N=C(N)c3c(F)cccc32)cc1C
Product: COc1c(C)cc(C2(c3ccnc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc1C
Yield: 5 %

Procedure:
The title compound was synthesized as described in Example 33 in 5% yield starting from 1-(2-Bromopyridin-4-yl)-4-fluoro-1-(4-methoxy-3,5-dimethylphenyl)-1H-isoindol-3-amine (400 mg, 0.91 mmol) and pyrimidin-5-ylboronic acid (124 mg, 1.00 mmol).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:29])[C:16]3[C:21]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:20][N:19]([CH3:28])[C:17]=3[N:18]=2)=[C:9]([O:30][CH3:31])[CH:8]=1.Cl[CH2:33][CH2:34][N:35]=[C:36]=[O:37]>O>[CH:22]1([C:21]2[C:16]3[C:15](=[O:29])[NH:14][C:13]([C:10]4[CH:11]=[CH:12][C:7]([N:6]5[CH2:33][CH2:34][NH:35][C:36]5=[O:37])=[CH:8][C:9]=4[O:30][CH3:31])=[N:18][C:17]=3[N:19]([CH3:28])[N:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C=NCCCl
Reactant: COc1cc(N)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N2CCNC2=O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.9 %

Procedure:
To a 4 ml tetrahydrofuran solution of 150 mg (0.425 mmol) of the compound obtained in Example 44, 71 μl (0.829 mmol) of 2-chloroethyl isocyanate was added, and the mixture was stirred at room temperature for 20 hours. Then, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. To the residue, 4 ml of ethanol and 2 ml of a 1M aqueous solution of sodium hydroxide were added, and the mixture was stirred at room temperature for 15 hours. Then, the reaction mixture was neutralized with a 1M aqueous solution of hydrochloric acid, and extracted with chloroform. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=1/1) to obtain 95 mg (53%) of the captioned compound.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]2[CH:6]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][C:21]([OH:23])=[O:22])[C:12]=3[CH3:24])[NH:7][S:8](=[O:10])(=[O:9])[C:4]=2[CH:3]=1.Cl[CH2:28][C:29]1[C:30]([CH3:35])=[N:31][O:32][C:33]=1[CH3:34]>>[CH3:35][C:30]1[C:29]([CH2:28][N:7]2[CH:6]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][C:21]([OH:23])=[O:22])[C:12]=3[CH3:24])[C:5]3[CH:25]=[CH:26][C:2]([F:1])=[CH:3][C:4]=3[S:8]2(=[O:10])=[O:9])=[C:33]([CH3:34])[O:32][N:31]=1
Reactant: Cc1c(C2NS(=O)(=O)c3cc(F)ccc32)c2ccccc2n1CC(=O)O
Reactant: Cc1noc(C)c1CCl
Product: Cc1noc(C)c1CN1C(c2c(C)n(CC(=O)O)c3ccccc23)c2ccc(F)cc2S1(=O)=O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 13, step e) and chloromethyl-3,5-dimethyl-isoxazole. 1H NMR (DMSO-d6) δ 13.1 (bs, 1H), 7-99 (dd, J=2.4, 7.5 Hz, 1H), 7.47 (dt, J=2.1, 8.8 Hz, 1H), 7.14-6.74 (m, 4H), 5.93 (s, 1H), 5.01 (s, 2H), 4.02 (d, J=15 Hz, 1H), 3.98 (d, 1H, J=15 Hz, 1H), 2.40 (s, 3H), 2.04 (s, 3H), 1.71 (s, 3H); MS: ESI (negative): 482 (M−H).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[CH:21][C:20]=3[CH2:34][CH2:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[CH:21][C:20]=3[CH2:34][CH2:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)cc2CCCC(C)(C)C)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(C(CC(=O)O)C4CC4)c3)c(CCCC(C)(C)C)c2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((3-(4,4-dimethylpentyl)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)oxy)methyl)phenyl)propanoate (385 mg) in ethanol (3.0 mL) was added 1N aqueous sodium hydroxide solution (3.0 mL), and the reaction mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract 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 column chromatography (ethyl acetate/hexane) to give the title compound (320 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:21]([CH3:22])=[CH:20][C:8](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)=[CH:7][C:6]=1[CH3:23].C1CCC(N=C=NC2CCCCC2)CC1.[C:39]1([SH:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH3:23])=[CH:7][C:8](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14](=[O:16])[S:45][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:20][C:21]=1[CH3:22]
Reactant: Sc1ccccc1
Reactant: COCOc1c(C)cc(/C=C/c2cccc(C(=O)O)c2)cc1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCOc1c(C)cc(/C=C/c2cccc(C(=O)Sc3ccccc3)c2)cc1C
Reaction time: 18 h

Procedure:
To a solution of (E)-3-[4-(methoxymethoxy)-3,5-dimethylstyryl]benzoic acid (0.1 g, 0.320 mmol) in DCM (5 mL) were added DCC (72.6 mg, 0.352 mmol), DMAP (7.9 mg, 0.064 mmol), and benzenethiol (65.7 μL, 0.640 mmol) at room temperature. The reaction mixture was stirred overnight (about 18 hours) and filtered through Celite. The filtrate was washed with 10% citric acid, brine, and dried with Na2SO4. The solution was filtered and concentrated. The compound was purified by column chromatography (9:1 Hexane:EtOAc) to afford (E)-S-phenyl 3-(4-(methoxymethoxy)-3,5-dimethylstyryl)benzothioate in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[O:35][CH3:36]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[C:27]([O:35][CH3:36])[CH:28]=2)[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:13])([F:14])[F:12]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: COc1cc(B(O)O)ccc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COc1cc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
In analogy to Example 151, step 8, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 151, step 7) was reacted with 4-fluoro-3-methoxyphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as an off-white solid. MS (m/e)=486.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[C:5]([F:10])=[CH:4][C:3]=1[CH:11]([CH3:26])[C:12]([C:18]1[CH:19]=[CH:20][C:21](=[O:25])[N:22]([CH3:24])[CH:23]=1)([OH:17])[C:13]([F:16])([F:15])[F:14].B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([F:10])=[CH:4][C:3]=1[CH:11]([CH3:26])[C:12]([C:18]1[CH:19]=[CH:20][C:21](=[O:25])[N:22]([CH3:24])[CH:23]=1)([OH:17])[C:13]([F:16])([F:15])[F:14]
Reactant: COc1cc(Cl)c(C(C)C(O)(c2ccc(=O)n(C)c2)C(F)(F)F)cc1F
Agent: BrB(Br)Br
Product: CC(c1cc(F)c(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 147, step 5, 5-[2-(2-chloro-5-fluoro-4-methoxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one was reacted with BBr3 to give the title compound as a light yellow foam. MS (m/e)=380.3 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][C:18]3([CH3:28])[CH3:27])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:29]([O:32][CH2:33][C:34]1[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][C:37]([F:49])=[CH:36][C:35]=1[N:50]1[CH2:62][CH2:61][N:53]2[C:54]3[CH2:55][CH2:56][CH2:57][CH2:58][C:59]=3[CH:60]=[C:52]2[C:51]1=[O:63])(=[O:31])[CH3:30].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:29]([O:32][CH2:33][C:34]1[C:35]([N:50]2[CH2:62][CH2:61][N:53]3[C:54]4[CH2:55][CH2:56][CH2:57][CH2:58][C:59]=4[CH:60]=[C:52]3[C:51]2=[O:63])=[CH:36][C:37]([F:49])=[CH:38][C:39]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:24][O:25][CH2:26]4)[CH2:19][C:18]3([CH3:27])[CH3:28])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:31])[CH3:30]
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C4COC4)CC3(C)C)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4(C)C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 90 °C
Yield: 29.6 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 125e (190 mg, 1.0 eq., 0.42 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 115m (405 mg, 2.0 eq., 0.84 mmol), PdCl2(dppf) (33 mg, 0.10 eq., 0.040 mmol), K3PO4 (178 mg, 2.0 eq., 0.84 mmol), sodium acetate (69 mg, 2.0 eq., 0.84 mmol), acetonitrile (20 mL), and water (0.1 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/ethanol to afford 125f (90 mg, 29%) as yellow solid. MS: [M+H]+ 724.3.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[O:18]=[C:19]1[C@@H:22]([NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:21][N:20]1[S:34]([O-:37])(=[O:36])=[O:35].[OH:38][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]2[C:48]=1[N:47]=[CH:46][CH:45]=[CH:44]2.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>ClC(Cl)C>[OH:38][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]2[C:48]=1[NH+:47]=[CH:46][CH:45]=[CH:44]2.[O:18]=[C:19]1[C@@H:22]([NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:21][N:20]1[S:34]([O-:37])(=[O:35])=[O:36]
Reactant: Oc1cccc2cccnc12
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(N[C@H]1CN(S(=O)(=O)[O-])C1=O)OCc1ccccc1
Solvent: CC(Cl)Cl
Product: Oc1cccc2ccc[nH+]c12

Procedure:
To a stirred solution of 3.58 g of (3S)-2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinesulfonic acid, tetrabutylammonium salt and 960 mg of 8-hydroxyquinoline in 10 ml of dichloroethane was added 1.53 g of camphorsulfonic acid. An additional 5 ml of dichloroethane was added and the mixture was stirred to effect solution and a seed crystal of the desired product was added to initiate precipitation. After ca. 5 minutes, 15 ml of ethyl acetate was added slowly. After an additional 30 minutes, the solid was isolated by filtration, washed with 1:1 dichloromethane/ethyl acetate and dried in vacuo to afford 1.98 g of the title compound as a fine, light yellow powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].O[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:23][C:22]([F:25])([F:24])[C:19]1[CH:20]=[CH:21][C:16]([O:1][CH2:2][CH2:3][N:4]2[C:8](=[O:9])[C:7]3=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]3[C:5]2=[O:14])=[CH:17][CH:18]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCOc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
A mixture of N-(2-hydroxyethyl)phthalimide (3.59 g, 18.75 mmol), 4-hydroxybenzotrifluoride (3.04 g, 18.75 mmol), diethyl azodicarboxylate (4.37 ml, 28.13 mmol) and triphenylphosphine (7.38 g, 28.13 mmol) in THF (50 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=5/1) to afford N-[2-(4-trifluoromethylphenoxy)ethyl]phthalimide (4.05 g, yield 69%) as a colorless crystalline powder.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([CH2:12][Cl:13])=[N:9]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.P(Cl)(Cl)([Cl:25])=O>COCCOC>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:25])=[N:7][C:8]([CH2:12][Cl:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(CCl)nc2cc(Br)ccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: COCCOC
Solvent: Cc1cccc(C)n1
Product: ClCc1nc(Cl)c2ccc(Br)cc2n1
Temperature: 25 °C

Procedure:
Heat a mixture of 7-bromo-2-chloromethyl-3H-quinazolin-4-one (5 g, 18.2 mmol), 2,6-lutidine (5 g), and phosphorus oxychloride (5 mL) in 1,2-dimethoxyethane (500 mL) at 80° C. for 16 hours. Cool the mixture to room temperature and fully evaporate the mixture, then dilute with ether and wash with water. Dry the solvent (Na2SO4) and evaporate the ether to obtain 7-bromo-4-chloro-2-chloromethylquinazoline (3.5 g) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]3([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=1)[C:8]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:7]2.O.[NH2:37][NH2:38]>O1CCOCC1.C(OCC)(=O)C>[NH:37]([C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]3([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=1)[C:8]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:7]2)[NH2:38]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(Cl)nccc4cc3-c3ccccc3)cc2)CCC1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(NN)nccc4cc3-c3ccccc3)cc2)CCC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl {1-[4-(8-chloro-3-phenyl-1,7-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (7-4) (288 mg, 0.593 mmol) in 1,4-dioxane (4 mL) was added hydrazine monohydrate (286 mL, 5.93 mmol). The mixture was stirred at 100° C. for 1 h. The mixture was cooled to room temperature, suspended in ethyl acetate, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl{1-[4-(8-hydrazino-3-phenyl-1,7-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (7-5) as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([CH2:9][CH3:10])[CH:3]=1.C([Li])CCC.CN(C)[CH:18]=[O:19].Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:18]=[O:19])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: CN(C)C=O
Reactant: CCc1cc(Br)ccc1I
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(Br)ccc1C=O
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a solution of 4-bromo-2-ethyl-1-iodobenzene (75 g, 0.24 mol) in tetrahydrofuran (375 ml) at −75° C. is added n-butyl lithium (1.6 M in hexanes, 196 ml, 0.31 mol) dropwise, maintaining the temperature of the reaction mixture below −70° C. When the addition is complete the mixture is stirred at −75° C. for an additional 30 minutes and then N,N-dimethylformamide (70.7 g, 0.97 mol) is added dropwise. After the addition is complete the reaction is stirred at −75° C. for 2 hours, then allowed to warm to room temperature for 2 hours. The mixture is cooled in an ice bath and acidified with 0.5 N aqueous hydrochloric acid. The mixture is extracted with ethyl acetate (3×500 ml) and the organic fractions are combined, washed with brine, and dried over anhydrous sodium sulphate. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2-ethylbenzaldehyde (48 g) as an oil.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11](=O)[CH2:12]Br)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].C(O)C.CCOCC.[C:23]([NH:26][C:27]([NH2:29])=[S:28])(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:1]([NH:4][CH:5]([C:11]1[N:29]=[C:27]([NH:26][C:23](=[O:25])[CH3:24])[S:28][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)CBr
Reactant: CC(=O)NC(N)=S
Solvent: c1ccncc1
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(NC(C)=O)c1csc(NC(C)=O)n1

Procedure:
To a solution of 34.6 g. of ethyl α-acetamido-β-oxo-γ-bromobutyrate in a mixture of 50 ml. of ethanol and 20 ml. of ether are added 18.9 g. of N-acetylthiourea and 15 ml. of pyridine. The mixture is heated under reflux for 4 hours, and condensed under reduced pressure. The condensate is extracted with ethyl acetate and the extract is washed with 5% aq. NaHCO3, then with water, and dried. The oily substance which is obtained from the extract by removal of the solvent is purified by silica gel chromatography to give ethyl α-acetamido-2-acetamidothiazol-4-ylacetate. 4.46 g. Melting point: 148.9°-150° C.
Reaction SMILES: [CH:1]1([C:5]2[C:14]([C:15]3[NH:16][C:17]([CH2:20][CH3:21])=[CH:18][N:19]=3)=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].CO.Cl>O>[CH:1]1([C:5]2[C:14]([C:15]3[NH:16][C:17]([CH2:20][CH3:21])=[CH:18][N:19]=3)=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCc1cnc(-c2cc(C(=O)OC)c(C)cc2C2CCC2)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1cnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Temperature: 60 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
A mixture of methyl 4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoate (compound 245.2, 200 mg, 0.600 mmol, 1.00 equiv, 90%) and sodium hydroxide (107 mg, 2.68 mmol, 4.00 equiv) in a solvent mixture of methanol and water (4/2 mL) was stirred for 3 h at 60° C. After cooling to ambient temperature, the pH was adjusted to 3-4 with hydrogen chloride (aq., 6 M). The resulting mixture was concentrated in vacuo to yield 150 mg of a white solid.