Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C@@H:5]([NH:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH:6]([CH3:8])[CH3:7])[CH3:2].[NH2:26][CH2:27][C@@H:28]([C:30]1[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=1)[OH:29]>>[CH2:1]([O:3][C:4](=[O:25])[C@@H:5]([NH:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([NH:26][CH2:27][C@H:28]([OH:29])[C:30]3[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH:6]([CH3:8])[CH3:7])[CH3:2]
Reactant: CCOC(=O)[C@@H](NC(=O)c1ccc(N2CCC(=O)CC2)cc1)C(C)C
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CCOC(=O)[C@@H](NC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1)C(C)C

Procedure:
The title compound was prepared from 3-methyl-(2S)-2-[4-(4-oxo-piperidine-1-yl)-benzoylamino]-butyric acid ethyl ester (which was obtained in Example 163) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as an off-white solid; mp >85° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 0.92 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H), 1.17 (t, J=7.1 Hz, 3H), 1.20-1.40 (m, 2H), 1.75-1.95 (m, 2H), 2.05-2.20 (m, 1H), 2.55-2.90 (m, 5H), 2.90 (s, 3H), 3.70-3.85 (m, 2H), 4.00-4.20 (m, 2H), 4.22 (t, J=7.7 Hz, 1H), 4.48 (dd, J=8.0, 4.4 Hz, 1H), 6.80 (d, J=8.2 Hz, 1H), 6.95 (d, J=8.9 Hz, 2H), 6.98 (dd, J=8.2, 2.0 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.76 (d, J=8.9 Hz, 2H), 8.17 (d, J=7.9 Hz, 1H); MS (ES) m/z: 577.2 (MH+); HRMS Calcd. for C29H43N4O7S(MH+): 577.2690. Found: 577.2682.
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:1]([CH3:3])[CH3:2])=[CH:21][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@H](Cc1ccc(OC(C)C)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 98.8 %

Procedure:
Isopropyl iodide (680 uL, 6.8 mmol) was added to a mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate (1 g, 3 mmol) (Step 1) and potassium carbonate (940 mg, 6.8 mmol) in acetonitrile (20 mL). The reaction was heated at 60° C. overnight. The reaction was partitioned between water and ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product, (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-isopropoxyphenyl)propanoate (1 g, 90%) as a white solid. Analytical LCMS (M+H-Boc)+: m/z=237.9.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][S:10][C:4]=2[CH:3]1[NH:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.[N+:24]([O-])([OH:26])=[O:25].[K+].[Br-]>C(O)(=O)C>[OH:1][CH:2]1[CH2:7][O:6][C:5]2[CH:8]=[C:9]([N+:24]([O-:26])=[O:25])[S:10][C:4]=2[CH:3]1[NH:11][C:12](=[O:23])[C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=1
Reactant: O=C(NC1c2sccc2OCC1O)c1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C(NC1c2sc([N+](=O)[O-])cc2OCC1O)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared as described in Example 9 starting with 5,6-dihydro-6-hydroxy-7-(4-trifluoromethylbenzamido)-7H-thieno[3,2-b]pyran (1.5 g, 4.04 mmol) and 90% nitric acid (2.5 mL) in acetic acid (20 mL) to give a yellow solid, 0.165 g (10%): mp 219°-220° C.; IR (KBr): 3310, 1661, 1538 and 1504 cm-1 ; MS: m/z 417 (MH+); 1H NMR (DMSO-d6): δ1.26(s, 3H), 1.45(s, 3H), 3.92(m, 1H, simplifies to d, J=8.9 Hz, with D2O), 4.98(m, 1H, simplifies to d, J=8.9 Hz, with D2O), 5.99(d, 1H, exchanges with D2O), 7.74(s, 1H), 7.92(d, J=8.5 Hz, 2H), 8.12(d, J=8.5 Hz, 2H) and 9.30 (d, 1H, exchanges with D2O).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([I:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([I:12])[CH:6]=1)[CH2:11][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(I)cc(C(C)(C)C)c1
Reactant: C1COCCN1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(I)cc(CN2CCOCC2)c1
Temperature: 70 °C

Procedure:
Dissolve 1-tert-butyl-3-iodo-5-methyl-benzene (1 g, 3.6 mmol, prepared according to Chem. Soc. Perkin Trans. I, 1987, page 859-866) in carbon tetrachloride (20 mL) under nitrogen. Add NBS (0.71 g, 1.1 equiv.) followed by AIBN (0.06 g, 0.1 equiv.) and heat overnight at 70° C. Filter in the morning, washing with hexanes. Concentrate filtrate and use crude. Dissolve this residue in THF (10 mL) under nitrogen and cool to 0° C. Add morpholine (0.64 mL, 2 equiv.) dropwise via syringe and stir 5 minutes with cooling. Remove ice bath and let warm to room temperature. After one hour concentrate to dryness and purify the residue on silica gel (Hexanes→4:1 Hexanes Ethyl Acetate) to give product (0.785 g, 60% over 2 steps). MS (ES), m/z 360.1 (M+1).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)(O)[CH2:15][C:9]=2[CH:8]=[CH:7][C:6]=1[O:29][CH3:30])([CH3:3])[CH3:2]>C(O)(=O)C.O>[CH:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[CH:15][C:9]=2[CH:8]=[CH:7][C:6]=1[O:29][CH3:30])([CH3:3])[CH3:2]
Reactant: COc1cc(C2(O)CCCc3c(ccc(OC)c3OC(C)C)C2)cc(OC)c1OC
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C2=Cc3ccc(OC)c(OC(C)C)c3CCC2)cc(OC)c1OC
Yield: 95.1 %

Procedure:
A mixture of the SM (40) (1.1 g, 2.64 mmol) in 30 mL of acetic acid and 100 mL of water, taken in a 250 mL round bottom flask were refluxed for 12 h. The reaction mixture was cooled and extracted with dichloromethane (3×25 mL) and the combined organic phases were dried over magnesium sulfate. The solvent evaporated and the crude product was purified by flash column chromatography (10:90 ethylacetate:hexanes), to afford 1 g (95%) of 4-Isopropoxy-3-methoxy-8-(3,4,5-trimethoxy-phenyl)-6,7-dihydro-5H-benzocycloheptene as white crystals. Rf:56 (60:40, Hex:EA)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[NH:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)=[O:21])=[O:10])=[N:6][CH:7]=1.Cl.[OH:31][NH2:32].CCN(CC)CC>CCO>[NH2:29][C:28](=[N:32][OH:31])[C:25]1[CH:24]=[CH:23][C:22]([C:20]([NH:19][C:12]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=2[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])=[O:21])=[CH:27][CH:26]=1
Reactant: COc1ccc(NC(=O)c2ccc(C#N)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2ccc(C(N)=NO)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a suspension of compound N-(5-chloro(2-pyridyl)){2-[(4-cyanophenyl)carbonylamino]-5-methoxyphenyl}carboxamide (150 mg) in EtOH (10 mL) was added hydroxyamine hydrochloride (80 mg) and Et3N (200 μL). The mixture was stirred at 60° C. overnight and the reaction was complete. The solvent was evaporated and the crude material was purified by RP-HPLC to give the title compound. MS found for C21H18ClN5O4 (M+H)+: 440.1.
Reaction SMILES: O1CCCC1.[O:6]([C:13]1[CH:14]=[C:15]([CH2:19][C:20](Cl)=[N:21][OH:22])[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:24]([C:26]1[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[O:6]([C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH2:19][C:20]1[CH:25]=[C:24]([C:26]2[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=2)[O:22][N:21]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ON=C(Cl)Cc1cccc(Oc2ccccc2)c1
Reactant: C#Cc1ccc(N)nc1N
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3cccc(Oc4ccccc4)c3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 28.7 %

Procedure:
To a tetrahydrofuran (10.0 mL) solution of (3-phenoxy-phenyl)-acetohydroximoyl chloride (133 mg, 0.508 mmol) described in Manufacturing Example 64-1-3 and 3-ethynyl-pyridine-2,6-diamine (30.0 mg, 0.254 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (94.1 μL, 0.675 mmol) at room temperature, which was stirred for 14 hours at room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=3:1) to obtain the title compound (26.1 mg, 80.6%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][CH:4]=1.[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1>C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:11]([O:10][C:9]([NH:8][CH2:7][C:6]1[CH:16]=[CH:17][C:3]([CH2:2][NH:1][C:18](=[O:24])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:4][CH:5]=1)=[O:15])([CH3:12])([CH3:13])[CH3:14]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)CCC(=O)O)cc1
Temperature: 36 °C
Yield: 73.4 %

Procedure:
A mixture of the above compound (27) (2.0 g, 8.5 mmol) and succinic anhydride (0.85 g, 8.5 mmol) in DCM (50 mL) were stirred at 36° C. for several hours. The product was diluted with 5% citric acid and extracted with DCM (3×50 mL). The combined extracts were washed with brine and dried over MgSO4 to give 2.1 g (28) (72%) of the desired compound. MS (ESI−) m/z 335.23 (M−H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:43])[C@@H:30]([CH3:42])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:41])([CH3:40])[C@@H:35]([OH:39])[C@@H:36]([OH:38])[CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[N+:53]([C:56]1[CH:61]=[CH:60][C:59]([S:62](Cl)(=[O:64])=[O:63])=[CH:58][CH:57]=1)([O-:55])=[O:54].O>ClCCl>[CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:43])[C@@H:30]([CH3:42])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:41])([CH3:40])[C@@H:35]([OH:39])[C@@H:36]([O:38][S:62]([C:59]5[CH:58]=[CH:57][C:56]([N+:53]([O-:55])=[O:54])=[CH:61][CH:60]=5)(=[O:63])=[O:64])[CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)[C@@H](O)C[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)[C@@H](OS(=O)(=O)c3ccc([N+](=O)[O-])cc3)C[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Reaction time: 6 h
Yield: 69.7 %

Procedure:
To a solution of Compound (48a) (200 mg, 0.34 mmol) in 15 ml of dichloromethane were added 83 mg (0.68 mmol) of dimethylaminopyridine and 112 mg (0.51 mmol) of p-nitrobenzenesulfonyl chloride under ice-cooling, and the mixture stirred for 6 hours at the same temperature. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed sequentially with 1N HCl, water, an aqueous saturated sodium hydrogen carbonate solution, and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by a column chromatography (Merck, Lobar column, size B; toluene:ethyl acetate=4:1) to give 184 mg (70%) of Compound (48f).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([NH:11][C@@H:12]2[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13]2)=[C:4]([F:19])[CH:3]=1.[CH3:20][S:21]([C:24]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[NH:26][N:25]=1)(=[O:23])=[O:22].CS([C:37]1[C:45]2C(=CC=CC=2)NN=1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]2[N:11]([C@@H:12]3[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13]3)[C:37]([CH2:45][N:26]3[C:27]4=[CH:28][N:29]=[CH:30][CH:31]=[C:32]4[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[N:25]3)=[N:8][C:6]=2[CH:7]=1
Reactant: CS(=O)(=O)c1n[nH]c2ccccc12
Reactant: O=[N+]([O-])c1cc(Cl)cc(F)c1N[C@@H]1CCS(=O)(=O)C1
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)cc(F)c3n2[C@@H]2CCS(=O)(=O)C2)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 2-1 by using (4-chloro-2-fluoro-6-nitrophenyl)-((R)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-amine and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine instead of (4-chloro-2-nitro-phenyl)-((R)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-amine and 3-methanesulfonyl-1H-indazole.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9]O)=[N:7][CH:8]=1.[Br:13]P(Br)Br.O>C(Cl)Cl>[Br:13][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][N:7]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(C(F)(F)F)cn1
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)c1ccc(CBr)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [5-(trifluoromethyl)pyridin-2-yl]methanol (5.0 g, 28.24 mmol) in DCM (50 ml) was added tribromophosphane (0.58 g, 3.50 mmol) at 0° C. The reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction was then poured into water (50 ml) and the organics were extracted with DCM (2×50 ml), washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:10](=[O:11])[O:9][CH2:8]2)([O:3]C)=[O:2].C[O-].[Na+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.Cl>CO.O>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][CH2:8][C:7]1[CH:6]=[C:5]([C:1]([OH:3])=[O:2])[CH:14]=[CH:13][C:12]=1[C:10]([OH:9])=[O:11]
Reactant: COC(=O)c1ccc2c(c1)COC2=O
Reactant: O=Cc1ccccc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C(=O)O)c(CCc2ccccc2F)c1

Procedure:
8.5 G. of 5-carbomethoxyphthalide and 2.43 g. of sodium methoxide were refluxed for 15 minutes in 250 ml of methanol, and then 5.55 g. of o-fluorobenzaldehyde was added. The mixture was refluxed for 20 hours and then poured into water and acidified with dilute hydrochloric acid. The solution was extracted with ethyl acetate and the extract washed, dried and evaporated. The residue was refluxed for 48 hours in 75 ml of acetic acid and 45 ml of 57% aqueous hydriodic acid containing 7.5 g. of red phosphorus. The mixture was poured into water and filtered. The residue was dissolved in ethanol and the solution filtered and evaporated to afford 2-(o-fluorophenethyl)benzene-1,4-dicarboxylic acid which was cyclized according to the method described in Example I, A to obtain 2-carboxy-9-fluoro-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene having a m.p. of 248.5° to 249.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][N:3]=1.N12CCN(CC1)CC2.[N:21]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]1.O>CN(C)C=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([C:26]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:27])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][N:3]=1
Reactant: Cn1c(=O)[nH]c2cnc(Cl)nc21
Reactant: O=C(Cl)N1CCCC1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C(=O)N2CCCC2)c2cnc(Cl)nc21
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-9-methyl-7,9-dihydro-8H-purine-8-one <the compound of Reference Example 1> (3.0 g) in N,N-dimethylformamide (50 ml) were added 1,4-diazabicyclo[2.2.2]octane (5.5 g) and 1-pyrrolidine carbonyl chloride (2.7 ml) and the mixture was stirred for 1 hour. The reaction mixture was poured into cold water and the crystals precipitated were collected by filtration to give the title compound 3.0 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40])([O-:32])=[O:31]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH2:12][N:11]([S:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[N+:30]([O-:32])=[O:31])(=[O:40])=[O:41])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc2c(c1)CNCC2c1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2c(c1)CN(S(=O)(=O)c1ccccc1[N+](=O)[O-])CC2c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To an ice-cold solution of 4-(3,4-dichlorophenyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline (2.65 g, 8.6 mmol) and N,N-diisopropylethylamine (1.8 mL, 10.3 mmol) in dichloromethane (80 mL) was slowly added a solution of 2-nitrobenzene-1-sulfonyl chloride (2.1 g, 9.5 mmol) in dichloromethane (10 mL). The mixture was stirred for 2 hours and then quenched with water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (hexanes to ethyl acetate) to give 4-(3,4-dichlorophenyl)-7-methoxy-2-(2-nitrophenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (3.39 g, 80%) as a yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.80 (dd, J=8, 1.3 Hz, 1H), 7.67-7.63 (m, 1H), 7.58 (dd, J=7.9, 1.2 Hz, 1H), 7.54-7.50 (m, 1H), 7.15 (d, J=8.3 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.87 (dd, J=8.3, 2 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 6.75 (d, J=2.6 Hz, 1H), 6.73 (s, 1H), 4.77 (d, J=16.0 Hz, 1H), 4.56 (d, J=16.0 Hz, 1H), 4.18 (dd, J=4.9, 4.9 Hz, 1H), 3.82 (dd, J=13.2, 4.5 Hz, 1H), 3.81 (s, 3H), 3.63 (dd, J=13.1, 5.5 Hz, 1H).
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:4]=2[CH2:3]1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:4]=3[CH2:3][CH:2]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[C:8]=2[CH:9]=1
Reactant: Cc1ccc2c(c1)Sc1ccc(F)cc1C(Cl)C2
Reactant: CN1CCNCC1
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)Sc1ccc(F)cc1C(N1CCN(C)CC1)C2

Procedure:
10.6 g. of 10-chloro-8-fluoro-10,11-dihydro-3-methyldibenzo[b,f]thiepin, 200 ml. of chloroform and 11.4 g. of N-methylpiperazine are heated at reflux for 30 hours. The mixture is evaporated under reduced pressure. The resulting residue is worked up via the neutral portion in essentially the same manner as described in Example 1, and there is obtained 1-{8-fluoro-10,11-dihydro-3-methyl-dibenzo[b,f]thiepin-10-yl}-4-methylpiperazine, having a melting point of 117°-121°C. By treatment with methanesulfonic acid, there is obtained the dimethanesulfonate having a melting point of 176°-178°C. (from methanol/ether).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])=[O:11].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.O.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>[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Oc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2ccc(O)cn2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 19.6 %

Procedure:
A mixture of 6-bromo-3-pyridinol (1.28 g, 7.35 mmol), [4-(methylsulfonyl)phenyl]boronic acid (1.47 g, 7.35 mmol), and 2M Na2CO3 (5 mL) in DMF (15 mL) was treated with PdCl2(PPh3)2 (0.52 g, 0.74 mmol) and the mixture was heated at 50° C. overnight. The reaction was treated with additional catalyst (PdCl2(PPh3)2, 0.26 g, 0.37 mmol) and was heated at 50° C. overnight, then was heated at 90° C. overnight. The reaction was allowed to cool to room temperature and was diluted with EtOAc and water and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated. The resulting residue was treated with MeOH and cooled in an ice bath. The resulting precipitate was collected, washed with cold MeOH and air-dried and the filtrates were combined and set aside. The resulting tan solid was dissolved in 10% MeOH/CH2Cl2 and loaded onto a 220 g silica column, which was eluted with 1 to 5% MeOH/CH2Cl2 over 30 min, followed by 5% MeOH/CH2Cl2 for 30 min to provide 6-[4-(methylsulfonyl)phenyl]-3-pyridinol (0.36 g, 20%) as a tan solid. The mother liquors from the MeOH trituration step were concentrated and purified by chromatography 1 to 5% MeOH/CH2Cl2 over 20 min to provide additional product (0.24 g, 33% overall yield) as a tan solid.
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].[F:18][C:19]1[C:24](F)=[CH:23][CH:22]=[C:21]([N+:26]([O-:28])=[O:27])[C:20]=1[O:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([O:38][CH3:39])[CH:37]=1)[C:33]#[N:34].Cl>C1COCC1>[CH3:13][C:12]([O:11][C:1](=[O:10])[CH:2]([C:24]1[CH:23]=[CH:22][C:21]([N+:26]([O-:28])=[O:27])=[C:20]([O:29][C:30]2[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[C:32]([C:33]#[N:34])[CH:31]=2)[C:19]=1[F:18])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])([CH3:15])[CH3:14]
Reactant: COc1cc(C#N)cc(Oc2c([N+](=O)[O-])ccc(F)c2F)c1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C#N)cc(Oc2c([N+](=O)[O-])ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
Di-tert-butyl malonate (11.22 g, 51.9 mmol) was added dropwise. to a 0° C. solution of NaH (5.09 g, 127 mmol) in THF (150 ml). The reaction mixture was allowed to warm to RT, stirred for an additional 30 mins, and cooled to 0° C. A solution of 3-[(2,3-difluoro-6-nitrophenyl)oxy]-5-(methyloxy)benzonitrile (14.44 g, 47.2 mmol) in THF (50 mL) was added slowly and the reaction mixture was stirred at RT overnight. Dilute HCl was carefully added and the solution was extracted with EtOAc (3×100 mL). The organic layer was dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography (0-35% EtOAc/hexanes) to afford the title compound (22.9 g, 97%) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.88 (dd, J=8.79, 1.46 Hz, 1H) 7.62 (dd, J=8.65, 6.46 Hz, 1H) 6.92 (s, 1H) 6.68-6.79 (m, 2 H) 4.81 (s, 1H) 3.83 (s, 3H) 1.49 (s, 16H).