Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1([CH3:22])[CH2:12][C:11](=O)[C:10]2[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH2:18][CH2:19][CH3:20])[C:9]=2[O:8]1)[CH3:2].B.B(F)(F)F.CCOCC>O1CCCC1>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1([CH3:22])[CH2:12][CH2:11][C:10]2[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH2:18][CH2:19][CH3:20])[C:9]=2[O:8]1)[CH3:2]
Reactant: CCCc1c(O)ccc2c1OC(C)(CCC(=O)OCC)CC2=O
Agent: B
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCc1c(O)ccc2c1OC(C)(CCC(=O)OCC)CC2
Yield: 79.3 %

Procedure:
Using the procedure of Example 2, 257 mg of racemic-3,4-dihydro-7-hydroxy-2-methyl-4-oxo-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester was reduced with borane.tetrahydrofuran and boron trifluoride etherate. There was obtained 195 mg of racemic-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester as a pale yellow oil, after chromatographic purification on silica gel.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:27][C:28]1[N:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]#[N:31].Cl.C(OCC)(=O)C>C(OCC)C>[ClH:27].[C:30]([C:29]1[C:28]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=2)=[N:35][CH:34]=[CH:33][CH:32]=1)#[N:31]
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Reactant: N#Cc1cccnc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncccc1C#N

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2-chloronicotinonitrile as starting materials and by operations similar to those of Example 303-3 and 303-4 was dissolved in diethyl ether, and reacted with 4 mol/L hydrochloric acid-ethyl acetate to give the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]3[O:15][C:14](=[O:16])[NH:13][C:12]=3[CH:17]=2)[CH2:7][CH2:6]1)=[O:4].O[Li].O>CO.O>[O:16]=[C:14]1[NH:13][C:12]2[CH:17]=[C:8]([C:5]3([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]3)[CH:9]=[CH:10][C:11]=2[O:15]1
Reactant: COC(=O)C1(c2ccc3oc(=O)[nH]c3c2)CC1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)C1(c2ccc3oc(=O)[nH]c3c2)CC1
Temperature: 50 °C
Reaction time: 20 h
Yield: 84.5 %

Procedure:
To a solution of 1-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-cyclopropanecarboxylic acid methyl ester (1.9 g, 8.1 mmol) in MeOH (20 mL) and water (2 mL) was added LiOH.H2O (1.7 g, 41 mmol) in portions at room temperature. The reaction mixture was stirred for 20 hours at 50° C. MeOH was removed by evaporation under vacuum before water (100 mL) and EtOAc (50 mL) were added. The aqueous layer was separated, acidified with HCl (3 mol/L) and extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)cyclopropanecarboxylic acid (1.5 g, 84%). 1H NMR (DMSO, 400 MHz) δ 12.32 (brs, 1 H), 11.59 (brs, 1 H), 7.16 (d, J=8.4 Hz, 1 H), 7.00 (d, J=8.0 Hz, 1 H), 1.44-1.41 (m, 2 H), 1.13-1.10 (m, 2 H). MS (ESI) m/e (M+H+) 218.1.
Reaction SMILES: COC1C=C([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([O:31][CH3:32])[CH:20]=2)=S)C=CC=1N1C=C(C)N=C1.[Cl:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([NH:40]N)=[O:39])=[CH:36][CH:35]=1>CO.[Hg]=O>[Cl:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]2[O:39][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]4)=[C:21]([O:31][CH3:32])[CH:20]=3)=[N:15][N:40]=2)=[CH:36][CH:35]=1
Reactant: COc1cc(NC(=S)Nc2ccc(-n3cnc(C)c3)c(OC)c2)ccc1-n1cnc(C)c1
Reactant: NNC(=O)c1ccc(Cl)cc1
Agent: O=[Hg]
Solvent: CO
Product: COc1cc(Nc2nnc(-c3ccc(Cl)cc3)o2)ccc1-n1cnc(C)c1
Yield: 8.1 %

Procedure:
A solution of mercury-(II)-oxide (97 mg, 0.45 mmol) in 5 ml of methanol was treated with 1,3-bis-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (200 mg, 0.45 mmol) and 4-chloro-benzhydrazide (76 mg, 0.45 mmol). The resulting mixture was refluxed for 3 hours, concentrated and triturated with ethyl acetate. Filtering of the suspension and chromatography on silica gel using ethyl acetate as eluent gave the title compound as a brownish solid (14 mg, 8%).
Reaction SMILES: FC1C=C(C[C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C2N(C3C=CC(OC)=CC=3)C=CN=2)C=C(F)C=1.[C:41]1([CH2:47][C@@H:48]([C:50]2[O:54][N:53]=[C:52]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[N:51]=2)[NH2:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[F:61][C:62]1[CH:63]=[C:64]2[C:68](=[CH:69][CH:70]=1)[NH:67][CH:66]=[C:65]2[CH2:71][C:72](O)=[O:73]>>[F:61][C:62]1[CH:63]=[C:64]2[C:68](=[CH:69][CH:70]=1)[NH:67][CH:66]=[C:65]2[CH2:71][C:72]([NH:49][C@H:48]([C:50]1[O:54][N:53]=[C:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[N:51]=1)[CH2:47][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:73]
Reactant: O=C(O)Cc1c[nH]c2ccc(F)cc12
Reactant: N[C@@H](Cc1ccccc1)c1nc(-c2ccccc2)no1
Agent: COc1ccc(-n2ccnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Product: O=C(Cc1c[nH]c2ccc(F)cc12)N[C@@H](Cc1ccccc1)c1nc(-c2ccccc2)no1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5F of Example 5 utilizing 18A and 2-(5-fluoro-1H-indol-3-yl)acetic acid. 1H NMR (400 MHz, DMSO) δ 10.92 (s, 1H), 8.90 (d, J=8.0 Hz, 1H), 7.94 (m, 2H), 7.68-7.39 (m, 3H), 7.37-7.06 (m, 8H), 6.85 (td, J=9.2, 2.5 Hz, 1H), 5.34 (dd, J=13.8, 9.2 Hz, 1H), 3.46-3.20 (m, 4H); MS (m/z) 441.1 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[C:13]3([CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][CH2:23][CH2:24][Br:25])[CH2:16][CH2:15][S:14]3(=[O:27])=[O:26])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Br-:25].[C:1]1([CH2:7][CH:8]2[C:13]3([CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][CH2:23][CH2:24][N+:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:16][CH2:15][S:14]3(=[O:27])=[O:26])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CC2(CCCCC2Cc2ccccc2)S(=O)(=O)CCN1CCCCBr
Reactant: c1ccncc1
Product: O=C1CC2(CCCCC2Cc2ccccc2)S(=O)(=O)CCN1CCCC[n+]1ccccc1
Product: [Br-]

Procedure:
1-Phenylmethyl-10-(4-bromobutyl)-11-oxo-7-thia-10-azaspiro[5.6]dodecane 7,7-dioxide (0.34 g) in pyridine (5 ml) was refluxed for thirty minutes. Then pyridine was evaporated in vacuo to give 1-phenylmethyl-10-{4-(1-pyridinio)butyl}-11-oxo-7-thia-10-azaspiro[5.6]dodecane 7,7-dioxide bromide (0.42 g).
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20]C)=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.OO.CC(C)=[O:28].Cl>C(O)=O.CO>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:15][CH2:16][C@:17]2([OH:28])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:20]
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Reactant: CC(C)=O
Agent: Cl
Agent: OO
Solvent: O=CO
Solvent: CO
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Reaction time: 20 h
Yield: 80 %

Procedure:
Thebaine (67 g, 0.215 mol) was dissolved in formic acid (98-100%, 120 g) and hydrogen peroxide (30% in water, 24.5 g, 0.216 mol) added at 0° C. The mixture was pumped continuously at 2 ml/min through a 30 ml continuous flow reactor at 80° C. (15 min residence time). An analytical control after the continuous reactor showed less than 1% Thebaine remaining. The continuous stream was added directly to acetone, containing 32% HCl, whereupon the 14-Hydroxycodeinone HCl was precipitated and isolated in 80% yield. The 14-Hydroxycodeinone HCl was then dissolved in MeOH and HCOOH (4:1 w/w) and hydrogenated at 80° C. under 15 bar H2 pressure. The hydrogenation was stirred for 20 h. After the hydrogenation, the catalyst was filtered off and the crude mixture was either basified with NaOH to obtain the low impurity Oxycodone base, or treated with HCl in 2-Propanol to give the Oxycodone HCl. The 14-Hydroxycodeinone content of the base was 48 ppm.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([O:13][C:14](=[O:21])[CH2:15][C@@H:16]([NH2:20])[CH2:17][CH2:18][CH3:19])[CH3:12].C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[CH2:11]([O:13][C:14](=[O:21])[CH2:15][C@@H:16]([NH:20][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH2:17][CH2:18][CH3:19])[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCC[C@H](N)CC(=O)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCC[C@@H](CC(=O)OCC)Nc1ccccc1[N+](=O)[O-]
Yield: 81 %

Procedure:
To a solution of 1-fluoro-2-nitrobenzene (500 mg, 3.5 mmol) in DMF (150 mL) were added (S)-3-Amino-hexanoic acid ethyl ester (600 mg, 3.8 mmol) and diisopropyl ethylamine (0.65 mL, 3.8 mmol). The solution was heated to 90 C for 16 hours. The solution was cooled down and was water (300 mL) was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4. The mixture was filtered and the filtrate was concentrated. The residue was purified by CombiFlash with 5% EtOAc in Hexane as the eluent to afford the desirable product (S)-3-(2-Nitro-phenylamino)-hexanoic acid ethyl ester (795 mg, 80%) as a colorless oil.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=[CH:20][CH:19]=1.O=[C:25]1[CH2:30][CH2:29][CH:28]([C:31]([O:33]CC)=[O:32])[CH2:27][CH2:26]1>C(O)C>[CH2:19]([CH:26]1[C:25]2[NH:16][C:13]3[C:12](=[CH:11][C:10]([O:9][CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)=[CH:15][CH:14]=3)[C:30]=2[CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27]1)[CH3:20]
Reactant: c1ccncc1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cl
Solvent: CCO
Product: CCC1CC(C(=O)O)Cc2c1[nH]c1ccc(OCc3ccccc3)cc21
Temperature: 50 °C
Yield: 82.3 %

Procedure:
To a suspension of 3.242 gm (12.93 mMol) 4-benzyloxy-phenylhydrazine hydrochloride in 80 mL ethanol were added 1.05 mL (12.93 mMol) pyridine. The resulting mixture was heated to 50° C. for about 20 minutes and then 1.87 mL (11.75 mMol) ethyl 4-oxocyclohexanecarboxylate were added. The resulting mixture was stirred at reflux for 18 hours. The reaction mixture was then concentrated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic phase was separated, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 35% ethyl acetate in hexane. Fractions containing product were combined and concentrated under reduced pressure to give 3.38 gm (83%) of the desired compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][S:12][C:13]2[C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:3][CH:2]=1.[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN(C)C=O>[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:19]([C:18]2[C:13]([S:12][CH2:11][C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=[CH:2][CH:3]=3)=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:21])=[CH:25][CH:24]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)c1cccnc1SCc1ccnc2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)c1cccnc1SCc1ccnc2ccccc12
Yield: 75 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetrauroniumhexafluorophosphate (140 mg, 0.38 mmol) was added to a solution of 2-(quinolin-4-ylmethylthio)pyridine-3-carboxylic acid (Reference Compound No. 7-1.91 mg, 0.31 mmol), 4-chloroaniline (52 mg, 0.40 mmol) and N,N-diisopropylethylamine (0.13 mL, 0.74 mmol) in anhydrous N,N-dimethylformamide (2.0 mL) at room temperature, and the mixture was stirred for 24 hours. Ethyl acetate (50 mL) was added thereto, and the whole was washed with saturated aqueous sodium hydrogencarbonate solution (50 mL, twice) and brine (50 mL), The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the precipitated solid was filtered off and washed with a mixture of diethyl ether and ethyl acetate (1:1). The resulting solid was dried at 50° C. under reduced pressure to give 93 mg of the target compound as a reddish-brown solid (Yield: 75%)
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13]([CH:16]=O)[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH2:27]([NH2:31])[CH2:28][CH2:29][NH2:30].[BH4-].[Na+]>C1COCC1.CO>[NH2:30][CH2:29][CH2:28][CH2:27][NH:31][CH2:16][C:13]1[C:14]([F:15])=[C:2]([F:1])[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=1)[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: NCCCN
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: NCCCNCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F

Procedure:
3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide obtained in Step F of Example 1 was reacted with propane-1,3-diamine in THF. The thus-obtained imine was reduced with sodium borohydride in methanol to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18]([NH2:21])[CH2:19][NH2:20]>>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([NH:20][CH2:19][CH2:18][NH2:21])[CH:7]=1
Reactant: NCCN
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(NCCN)ncc1[N+](=O)[O-]

Procedure:
To 2-chloro-4-methyl-5-nitro-pyridine (250 mg, 1.45 mmol) was added potassium carbonate (320 mg, 2.32 mmol) followed by ethylenediamine (4.2 g, 70 mmol). The mixture turned hot and was filtered after cooling through kieselguhr. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica, gradient of 1 to 10% methanol containing 7N ammonia in DCM) to yield 205 mg (1.04 mmol, 72%) MS(ESI) m/z=197.1 [M+1]+.
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:5]=[C:6]([CH:23]=[C:24]([O:26][CH3:27])[N:25]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[C:12](F)[CH:11]=1)=[O:8])#[N:3].C(OC(N1CCO[C@@H](C2C=CC(N)=C([F:48])C=2)C1)=O)(C)(C)C>>[ClH:1].[C:2]([C:4]1[CH:5]=[C:6]([CH:23]=[C:24]([O:26][CH3:27])[N:25]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[CH:12][C:11]=1[F:48])=[O:8])#[N:3]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(F)c2)C1
Reactant: COc1cc(C(=O)Nc2ccc([C@H]3CNCCO3)c(F)c2)cc(C#N)n1
Agent: Cl
Product: COc1cc(C(=O)Nc2ccc([C@H]3CNCCO3)cc2F)cc(C#N)n1

Procedure:
In analogy to example 83, step a) using 2-Cyano-6-methoxy-isonicotinic acid (described in example 107) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (described in example 1 h) instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9]Cl.[Na+].[I-:12]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][I:12]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Clc1ccc(CI)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Dichloro-1-(chloromethyl)benzene (0.8 mmoles) in acetone (2 mL) was treated with NaI (0.48 g) and stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue extracted with DMF to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][N:17]=[C:16]4[C:19]5[C:24]([CH2:25][CH2:26][C:15]=34)=[CH:23][C:22]([CH2:27][OH:28])=[CH:21][CH:20]=5)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:28][CH2:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[C:16]1=[N:17][O:18][C:14]([CH:11]3[CH2:12][CH2:13][CH:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[C:15]1[CH2:26][CH2:25]2)(=[O:39])=[O:38]
Reactant: OCc1ccc2c(c1)CCc1c-2noc1C1CCC(c2ccc(Cl)cc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc2c(c1)CCc1c-2noc1C1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of the (3-(4-(4-chlorophenyl)cyclohexyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methanol (Preparation 27D, 0.046 g, 0.118 mmol) in dichloromethane (2.0 mL) at room temperature was added triethylamine (0.049 mL, 0.354 mmol) followed by methanesulfonyl chloride (0.014 mL, 0.177 mmol). The reaction mixture was stirred for 1 h at room temperature, concentrated under reduced pressure to yield (3-(4-(4-chlorophenyl)cyclohexyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl methanesulfonate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>C(Cl)Cl.O>[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:31][CH2:30][N:29]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:3]=2)[CH2:28]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 16 h
Yield: 76.1 %

Procedure:
To 2-(4-chloro-7-methyl-quinazolin-2-yl)-phenol (300 mg, 1.1 mmol) in 1.8 mL of CH2Cl2 at 0° C. was added (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (246 mg, 1.32 mmol) in 1.8 mL of CH2Cl2, followed by triethylamine (184 μL, 1.32 mmol). The reaction mixture was stirred from 0° C. to room temperature over 16 h. The reaction mixture was diluted with 10 mL of CH2Cl2 and 10 mL of water, and the organic layer was separated and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified via silica gel chromatography using 10-100% EtOAc in hexanes to give of (S)-{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (352 mg, 70%). LC/MS: m/z 421 (M+H)+ at 2.84 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: F[C:2](F)(F)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[F:13][C:14](S(O)(=O)=O)([F:16])[F:15].[K+].[Br-].[CH:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:2]1([C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:14]([F:16])([F:15])[F:13])[CH:7]=[CH:6][CH:5]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: c1ccccc1
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: [Br-]
Agent: [K+]
Product: FC(F)(F)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 10.0 g (0.057 mol) trifluoroacetophenone, 100 ml of benzene, and 5 ml of trifluoromethyl sulfonic acid was stirred for 48 hours at room temperature. The product was worked up as in Example 6 to give a white crystalline mass. Thin-layer and high-pressure liquid chromatography indicated the product was a complex mixture of many components. The thin-layer chromatogram under ultraviolet light indicated the presence of many intensely white and blue fluorescent components. The product mixture was column-chromatographed on silica gel, the material then eluted with pentane, collected, and twice rechromatographed to give 6.2 g (35%), of the white crystalline triphenyl compound: m.p. 158°-159° C.; IR (KBr) 1600 and 1590 (Ar), 1150 (C-F), 760 and 695 cm-1 (monosubstituted phenyl); NMR δ 7.18 (broad singlet); mass spectrum m/e, 312 (parent ion), 243 (P-69), 165 (P-147), 120 (P-192). Analytical: calculated for C20H15F3 ; C, 76.92; H, 4.81; F, 18.2%. Found: C, 76.77; H, 4.84; F, 17.9%.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=[O:8])=CC=1.[C:12]([NH:15][C:16]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:14])[CH3:13].Cl.[C:30]([N:38]1[CH2:43][CH2:42][CH2:41][C:40]([C:60]2[CH:65]=[CH:64][C:63]([Cl:66])=[C:62]([Cl:67])[CH:61]=2)([CH2:44][CH2:45][CH2:46]N2CCC(C(N3CCCC3)=O)CC2)[CH2:39]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.O>[OH2:8].[OH2:14].[ClH:66].[C:12]([NH:15][C:16]1([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:17][CH2:18][N:19]([CH2:46][CH2:45][CH2:44][C:40]2([C:60]3[CH:65]=[CH:64][C:63]([Cl:66])=[C:62]([Cl:67])[CH:61]=3)[CH2:41][CH2:42][CH2:43][N:38]([C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:39]2)[CH2:20][CH2:21]1)(=[O:14])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(c1ccccc1)N1CCCC(CCCN2CCC(C(=O)N3CCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Reactant: CC(=O)NC1(Cc2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)NC1(Cc2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Temperature: 90 °C
Yield: 132.7 %

Procedure:
A mixture of 0.44 g of 4-(acetylamino)-4-benzylpiperidine p-toluene-sulfonate, 0.50 g of the compound obtained in step B of EXAMPLE 1 and 0.53 g of K2CO3 in 5 ml of DMF is heated at 90° C. for 2 hours. The reaction mixture is poured into water and extracted with AcOEt, the organic phase is washed with 2 N NaOH and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a gradient of a DCM/MeOH mixture (99/1; v/v to 93/7; v/v) as the eluent. The product obtained is dissolved in DCM and acidified by the addition of ethereal hydrogen chloride and the precipitate formed is filtered off to give 0.38 g of the expected product, m.p=158° C. (dec.).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].O.[NH2:16][NH2:17]>CO>[C:8]1([S:5]([CH2:4][C:3]([NH:16][NH2:17])=[O:2])(=[O:7])=[O:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CS(=O)(=O)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)CS(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a stirred solution of 5.0 g (0.023 mol) of benzenesulfonyl-acetic acid methyl ester in 10 mL of MeOH at RT, 3.50 g (0.070 mol, 3 eq) of hydrazine hydrate were added. After one hour, the solvent and the excess of hydrazine were removed under reduced pressure, yielding 4.90 g (quantitative) of benzenesulfonyl-acetic acid hydrazide as a colorless oil, MS: 232 (MNH4+).
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[C:55]([C:58]1[CH:59]=[C:60]([C:69]([CH3:72])([CH3:71])[CH3:70])[C:61]2[O:66][CH2:65][C:64](=[O:67])[NH:63][C:62]=2[CH:68]=1)(=[O:57])[CH3:56].C(Cl)Cl.CO>C(Cl)(Cl)Cl>[Br:1][CH2:56][C:55]([C:58]1[CH:59]=[C:60]([C:69]([CH3:72])([CH3:71])[CH3:70])[C:61]2[O:66][CH2:65][C:64](=[O:67])[NH:63][C:62]=2[CH:68]=1)=[O:57]
Reactant: [Br-]
Reactant: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCC(=O)N2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)c1cc(C(=O)CBr)cc2c1OCC(=O)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
Tetra-n-butylammonium tribromide (64 mg, 0.13 mmol) was added to a solution of the 6-acetyl-8-(tert-butyl)-3,4-dihydro-2H-1,4-benzoxazin-3-one (30 mg, 0.12 mmol) in a methylene chloride (0.4 ml)-methanol (0.1 ml) mixed solvent under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 hours. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel chromatography (Wakogel-C200,1 g) to yield the title compound (36 mg, 91% yield) as light yellow needle-like crystals from the chloroform fraction.