Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][O:9][CH2:10][CH2:11][N:6]2[N:5]=1)([O-])=O>[Pd].C(O)C>[N:5]1[N:6]2[C:7]([CH2:8][O:9][CH2:10][CH2:11]2)=[CH:12][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1cc2n(n1)CCOC2
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2n(n1)CCOC2
Reaction time: 2 h
Yield: 73 %

Procedure:
A 500-mL Parr hydrogenation bottle was purged with nitrogen and charged with 110a (1.01 g, 5.92 mmol), 10% palladium on carbon (50% wet, 125 mg dry weight) and ethanol (50 mL). The bottle was evacuated, charged with hydrogen gas to a pressure of 25 psi and shaken for 2 h on a Parr hydrogenation apparatus. The hydrogen was then evacuated and nitrogen charged to the bottle. The catalyst was removed by filtration through a pad of Celite 521 and the filtrate concentrated under reduced pressure. The resulting residue was purified by column chromatography using 400 cc of silica gel and eluting with 3% methanol in methylene chloride. The fractions containing 110b were collected to afford, after concentrating under reduced pressure, a 73% yield (601 mg) of 110b as a yellow solid: mp 74-76° C. 1H NMR (300 MHz, CDCl3) d 5.37 (s, 1H), 4.72 (s, 2H), 4.07 (t, 2H, J=5.1 Hz), 3.98 (t, 2H, J=5.1 Hz), 3.57 (br s, 2H); MS (ESI+) m/z 140.4 (M+H).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Br:13][C:14]1[CH:19]=[C:18]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([Br:37])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:17]=[C:16]([Br:38])[C:15]=1[OH:39].O[C@H:41]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:42]([O:44][CH3:45])=[O:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC.C1C=CC=CC=1>[Br:38][C:16]1[CH:17]=[C:18]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([Br:37])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:19]=[C:14]([Br:13])[C:15]=1[O:39][C@@H:41]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:42]([O:44][CH3:45])=[O:43]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reactant: COC(=O)[C@H](O)Cc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: COC(=O)[C@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Temperature: 80 °C
Yield: 96.3 %

Procedure:
Diethylazodicarboxylate (0.839 mL, 5.50 mmol) was added dropwise to a stirred, room temperature suspension of 2,6-dibromo-4-(6-bromo-benzo [b]naphtho[2,3-d]thiophen-11-yl)-phenol (2.00 g, 3.55 mmol), (R)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.96 g, 5.50 mmol), triphenylphosphine (1.40 g, 5.50 mmol) and benzene (15 mL) under a dry nitrogen atmosphere. Dissolution occurred and the solution was heated in an 80° C. oil bath for 19 h. Upon cooling to room temperature, the reaction mixture was diluted with ether and silica gel (60 mL) was added. The reaction mixture was concentrated and the silica adsorbate was flash chromatographed (95:5 petroleum ether:ethyl acetate) to provide the title compound as a white solid (2.48 g, 94 %): mp 140-143° C.: [a]D25=-56.87° (10.02 mg/mL CHCl3); NMR (CDCl3); δ8.36 (ddd, J=8, 1, 1 Hz, 1 H), 7.83 (ddd, J=8, 1, 1 Hz, 1 H), 7.68 (ddd, J=8, 7, 1 Hz, 1 H), 7.60 (dd, J=5, 2 Hz, 2 H), 7.60-7.49 (m, 2 H), 7.46-7.27 (m, 6 H), 7.18 (ddd, J=8, 7, 1 Hz, 1 H), 6.74 (ddd, J=8, 1, 1 Hz, 1 H), 5.26 (dd, J =8, 6 Hz, 1 H), 3.76 (s, 3 H), 3.59 (dd, J=8, 5 Hz, 2 H); MS (FAB+): [M+], 3 bromine isotope pattern, 722 (31%), 724 (94%) 726 (100%) 728 (40%); Anal. Calc. for C32H21Br3O3S: C, 52.99, H, 2.99, N, 0.00. Found: C, 52.99, H, 2.85, N, 0.03.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[C:19]([O:23][C:24]([N:26]([C:34]1[N:39]=[C:38]2[N:40]([CH2:46][C:47]3[C:52]([CH3:53])=[C:51]([O:54][CH3:55])[C:50]([CH3:56])=[CH:49][N:48]=3)[N:41]=[C:42]([CH2:43][CH2:44][OH:45])[C:37]2=[C:36]([Cl:57])[N:35]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:45][CH2:44][CH2:43][C:42]2[C:37]3[C:38](=[N:39][C:34]([N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:25])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[N:35][C:36]=3[Cl:57])[N:40]([CH2:46][C:47]3[C:52]([CH3:53])=[C:51]([O:54][CH3:55])[C:50]([CH3:56])=[CH:49][N:48]=3)[N:41]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1c(C)cnc(Cn2nc(CCO)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)cnc(Cn2nc(CCOS(=O)(=O)c3ccc(C)cc3)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Reaction time: 12 h
Yield: 91 %

Procedure:
Triethylamine (0.048 mL), p-toluenesulfonyl chloride (43 mg) and 4-dimethylaminopyridine (0.7 mg) were added to a mixture composed of di-tert-butyl{4-chloro-3-(2-hydroxyethyl)-1-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}imidodicarbonate of 8) above (64 mg) and dehydrated dichloromethane (1 mL) under cooling in an ice bath. The ice bath was removed and the mixture was stirred for 12 hours. The reaction mixture was diluted with ethyl acetate and sequentially washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (74 mg, 91%) as an amorphous substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:12]=2[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:26]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:26][CH2:18][C:14]1[C:12]2[N:13]=[C:9]([N:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[S:10][C:11]=2[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccc2sc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2c(CBr)cccc2s1
Temperature: 80 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a solution of 2-(bis(tert-butoxycarbonyl)amino)-4-methylbenzothiazole (1.09 g, 3.00 mmol) in carbon tetrachloride (15 ml) were added N-bromosuccinimide (694 mg, 3.90 mmol) and 2,2′-azobis(isobutyronitrile) (99 mg, 0.20 mmol) and the mixture was stirred under nitrogen atmosphere at 80° C. for 2 hr. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The crude residue was subjected to column chromatography (eluent: n-hexane:chloroform=60:40 to 50:50) to obtain the title compound (1.26 g, 95%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].[CH:8]([CH2:10][CH2:11][C:12]([O:14]CCC)=O)=O.[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26]>>[C:25]([NH:1][CH2:2][CH2:3][N:4]1[C:12](=[O:14])[CH2:11][CH2:10][CH:8]=[N:7][CH2:6][CH2:5]1)(=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18]
Reactant: NCCNCCN
Reactant: CCCCCCCC(=O)O
Reactant: CCCOC(=O)CCC=O
Product: CCCCCCCC(=O)NCCN1CCN=CCCC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 103.1 g (1 mole) of diethylenetriamine and 144.2 g (1 mole) of propyl 3-formylpropionate. At 140° to 145° C., 18 g of water and 60 g of propyl alcohol were distilled off. Then, after adding 144.2 g (1 mole) of octylic acid, the reaction was allowed to proceed at 150° to 155° C. to distil off 18 g of water, obtaining 4-octamidoethyl-2,3,6,7-tetrahydro-1,4-diazocin-5-one.
Reaction SMILES: CC1CNC(C2C=CN=C(NC(=O)C3C=CC=CC=3)C=2)=N1.[C:22]1([CH:28]2[CH2:32][NH:31][C:30]([C:33]3[CH:38]=[CH:37][N:36]=[C:35]([NH:39][C:40](=[O:47])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH:34]=3)=[N:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([C:28]2[N:29]=[C:30]([C:33]3[CH:38]=[CH:37][N:36]=[C:35]([NH:39][C:40](=[O:47])[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:34]=3)[NH:31][CH:32]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(Nc1cc(C2=NC(c3ccccc3)CN2)ccn1)c1ccccc1
Agent: CC1CNC(c2ccnc(NC(=O)c3ccccc3)c2)=N1
Product: O=C(Nc1cc(-c2nc(-c3ccccc3)c[nH]2)ccn1)c1ccccc1
Yield: 13 %

Procedure:
Following the procedure as described in Example 10, making variations as required to replace N-(4-(4-methyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl)benzamide with N-(4-(4-phenyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl)benzamide, N-(4-(4-phenyl-1H-imidazol-2-yl)pyridin-2-yl)benzamide was obtained as a colorless solid in 13% yield: mp 265-267° C.; 1H NMR (300 MHz, DMSO-d6) δ 13.14 (br s, 1H), 10.88 (br s, 1H), 8.81 (s, 1H), 8.47 (d, J=5.2 Hz, 1H), 8.10-8.05 (m, 2H), 7.93-7.88 (m, 2H), 7.72 (dd, J=5.2, 1.5 Hz, 1H), 7.65-7.36 (m, 6H), 7.28-7.21 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 165.9, 152.8, 148.5, 143.6, 141.9, 139.1, 134.1, 134.0, 131.9, 128.5, 128.4, 127.9, 126.5, 124.5, 115.8, 115.2, 110.0; MS (ES+) m/z 341.3 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([O:23]C)=[O:22])=[CH:14][C:13]=3[CH:25]=2)[CH:2]=1.[C:26](=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH3:26][CH:17]1[CH2:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14][C:13]2[CH:25]=[C:9]([O:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:10]=[CH:11][C:12]=2[S:18]1(=[O:20])=[O:19]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1=Cc2cc(OCc3cccnc3)ccc2S(=O)(=O)CC1
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1CC(C(=O)O)=Cc2cc(OCc3cccnc3)ccc2S1(=O)=O
Temperature: 60 °C
Reaction time: 19 h
Yield: 75.8 %

Procedure:
Into a suspension of methyl 7-(3-pyridylmethoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (650 mg) in THF/methanol (6/3 ml) was added at room temperature an aqueous solution (1.4 ml) of potassium carbonate (415 mg), and the resulting mixture was stirred at 60° C. for 19 hours. Into this reaction mixture was added further an aqueous solution (0.7 ml) of potassium carbonate (207 mg), and the resulting mixture was stirred further at 60° C. for 3 days. After cooling to room temperature, 1 N hydrochloric acid was added to the reaction mixture until the pH was adjusted to 7-8, and the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain methyl 7-(3-pyridylmethoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (493 mg) as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.CS(O)(=O)=O.[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[NH2:21]>O1CCOCC1>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)[CH:22]=[C:23]([CH3:25])[CH:24]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: Cc1cc(N)cc(Br)c1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Product: Cc1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Yield: 68.9 %

Procedure:
2-Chloro-4-(trifluoromethyl)pyrimidine (182 g, 995 mmol) and methanesulfonic acid (97.5 g, 1.02 mol) were added sequentially to a solution of 3-bromo-5-methylaniline (162.5 g, 874 mmol) in 1,4-dioxane (2 L). The resulting solution was heated to reflux overnight then cooled and concentrated under reduced pressure. The residue was diluted with water (2 L), adjusted to pH 7-8 with aqueous sodium bicarbonate solution and extracted with EtOAc (2×2 L). The organic layers were combined, washed with water (2×2 L), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford N-(3-bromo-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine (200 g, 602 mmol, 69%) as a light yellow solid. MS ESI calcd. For C11H8BrF3N4 [M+H]+ 332, 334.0. found 332, 334. 1H NMR (400 MHz, CDCl3): δ 8.68 (d, J=4.9 Hz, 1H), 7.79 (s, 1H), 7.30 (s, 2H), 7.10-7.06 (m, 2H), 2.36 (s, 3H). Synthetic Reference: PCT Int. Appl., 2011075517; PCT Int. Appl., 2011075515.
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][O:4][C:5]1[N:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]=1[C:7](O)=[O:8].S(Cl)([Cl:20])=O>CN(C=O)C.C(Cl)Cl>[F:1][CH:2]([F:17])[CH2:3][O:4][C:5]1[N:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]=1[C:7]([Cl:20])=[O:8]
Reactant: O=C(O)c1cc([N+](=O)[O-])cnc1OCC(F)F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc([N+](=O)[O-])cnc1OCC(F)F

Procedure:
A mixture of 2-(2,2-difluoroethyl)oxy-5-nitro-nicotinic acid (310 mg, 1.25 mmol), 2.0 mL thionyl chloride, 5.0 mL DCM and one drop of DMF was refluxed for 4 h and concentrated i.vac. The corresponding acid chloride was directly used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=1)[C:10]([NH:23][C:24]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25]1)=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C1(N)CC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1cccc(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(NC(=O)C(NC(=O)OC(C)(C)C)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 500 mg (1.57 mmol) of [(tert-butoxycarbonyl)amino][3-(trifluoromethyl)-phenyl]acetic acid, 243 mg (1.88 mmol) of ethyl 1-aminocyclopropanecarboxylate, 450 mg (2.35 mmol) of EDC and 317 mg (2.35 mmol) of HOBt in 10 ml of DMF was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate and washed twice with 1N hydrochloric acid and once with a saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulphate and then freed from the solvent on a rotary evaporator. The residue was dried under high vacuum. This gave 650 mg (96% of theory) of the title compound.
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.[CH3:18][CH:19]([CH:23]1[CH2:28][CH2:27][CH2:26][C:25](=O)[CH2:24]1)[C:20]([OH:22])=[O:21].[C:30](O)(=O)[CH3:31]>O>[CH2:30]([O:22][C:20](=[O:21])[CH:19]([CH3:18])[CH:23]1[CH2:28][CH2:27][C:26]2[C:14]3[C:13](=[CH: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]=3)[NH:16][C:25]=2[CH2:24]1)[CH3:31]
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: CC(C(=O)O)C1CCCC(=O)C1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: CCOC(=O)C(C)C1CCc2c([nH]c3ccc(OCc4ccccc4)cc23)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture containing 4-benzyloxyphenylhydrazine hydrochloride (37.0 g, 0.148 mol), a-methyl-3-oxocyclohexane acetic acid (40.0 g, 0.235 mol), glacial acetic acid (650 mL) and H2O (100 mL) is stirred at room temperature under a nitrogen atmosphere for 2.5 hours. The mixture is then refluxed for 20 minutes, cooled and poured into 200 mL of ice/H2O. The precipitate is filtered to give 80 g of red colored crude product.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:19](O)=[O:20])[CH:11]=2)[N:6]=1)([CH3:3])[CH3:2].CN1C2C=CC(C(Cl)=O)=CC=2OC1=O.Br[CH2:37][C:38]1[CH:53]=[CH:52][C:41]([O:42][C:43]2[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[C:45]([Cl:51])[CH:44]=2)=[CH:40][C:39]=1[Cl:54]>[Zn]>[Cl:51][C:45]1[CH:44]=[C:43]([O:42][C:41]2[CH:52]=[CH:53][C:38]([CH2:37][C:19]([C:10]3[CH:11]=[C:12]4[C:7](=[CH:8][CH:9]=3)[N:6]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:14]=[C:13]4[C:15]([F:16])([F:17])[F:18])=[O:20])=[C:39]([Cl:54])[CH:40]=2)[CH:50]=[CH:49][C:46]=1[C:47]#[N:48]
Reactant: N#Cc1ccc(Oc2ccc(CBr)c(Cl)c2)cc1Cl
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc(C(=O)O)ccc2n1
Agent: Cn1c(=O)oc2cc(C(=O)Cl)ccc21
Agent: [Zn]
Product: CC(C)Oc1cc(C(F)(F)F)c2cc(C(=O)Cc3ccc(Oc4ccc(C#N)c(Cl)c4)cc3Cl)ccc2n1

Procedure:
In analogy to Example 49, step 1, 2-isopropoxy-4-trifluoromethyl-quinoline-6-carboxylic acid was converted to the acid chloride and subsequently reacted with 4-(4-bromomethyl-3-chloro-phenoxy)-2-chloro-benzonitrile in the presence of zinc and tetrakis(triphenyl-phosphine)palladium(0) to give the title compound as a yellow oil. MS (m/e, ISP neg. ion)=557.0 [M−H+].
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([CH:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)C(Cl)=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[N:35]1[S:36][N:37]=[C:38]2[C:43]([NH2:44])=[CH:42][CH:41]=[CH:40][C:39]=12>>[N:35]1[S:36][N:37]=[C:38]2[C:43]([NH:44][C:16]([C@@H:9]3[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]3[C:6](=[O:7])[CH:25]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:18])=[CH:42][CH:41]=[CH:40][C:39]=12
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1cccc2nsnc12
Product: CON=C1C[C@@H](C(=O)Nc2cccc3nsnc23)N(C(=O)C(c2ccccc2)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and 2,1,3-benzothiadiazol-4-amine the title compound was obtained in 69% purity by LC/MS. MS(ESI+): mz=486.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]=1[CH3:21].Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=1>>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([N:18]2[CH2:19][CH2:20][N:15]([C:5]3[C:4]([CH3:21])=[C:3]([O:2][CH3:1])[C:11]4[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=4[C:6]=3[CH3:14])[CH2:16][CH2:17]2)=[CH:24][CH:25]=1)[CH3:31]
Reactant: CCOc1ccc(Br)cc1
Reactant: COc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Product: CCOc1ccc(N2CCN(c3c(C)c4c(c(OC)c3C)OC(C)(C)C4)CC2)cc1
Yield: 21.7 %

Procedure:
By using 1-(7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (400 mg, 1.38 mmol) synthesized in Reference example 96 and 1-bromo-4-ethoxybenzene (416 mg, 2.07 mmol), the reaction was carried out in the same manner as Reference example 59 to synthesize the title compound 123 mg (yield 22%). That is, sodium t-butoxide (398 mg, 4.14 mmol) was added to a mixture of toluene (30 mL) containing 1-(7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (400 mg, 1.38 mmol), 1-bromo-4-ethoxybenzene (416 mg, 2.07 mmol), palladium acetate (15 mg, 0.069 mmol) and BINAP (129 mg, 0.207 mmol), and the mixture was stirred under argon atmosphere and under heated reflux for 12 hours. After cooled to room temperature, saturated saline was added to the reaction solution, and extraction was performed using ethyl acetate. The organic layer was dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane-ethyl acetate 100:0-80:20). Crystallization was performed using ethyl acetate-hexane to give 123 mg of the title compound as a colorless crystal (yield: 22%). Melting point was 152 to 154° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C(O)=O.[N:29]12[CH2:37][CH2:36][CH:33]([CH2:34][CH2:35]1)[NH:32][CH2:31][CH2:30]2>C(#N)C.O>[N:29]12[CH2:37][CH2:36][CH:33]([CH2:34][CH2:35]1)[N:32]([C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])[CH:7]=1)[CH2:31][CH2:30]2
Reactant: CNS(=O)(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CN2CCC(CC2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CNS(=O)(=O)c1cc(N2CCN3CCC2CC3)ccc1[N+](=O)[O-]
Temperature: 96 °C
Yield: 80.6 %

Procedure:
To a solution of 5-fluoro-N-methyl-2-nitrobenzenesulfonamide (Intermediate 16A) (1.0 g, 4.27 mmol) in acetonitrile (10 mL) was added potassium carbonate (1.77 g, 12.81 mmol) followed by 1,4-diazabicyclo[3.2.2]nonane 2,2,2-trifluoroacetate (1.17 g, 4.27 mmol). The resulting suspension was heated to reflux at 96° C. overnight. The reaction mixture was diluted in water (50 mL) and split between two 20 g SCX cartridges. Purification by SCX and evaporation to dryness afforded 5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-methyl-2-nitrobenzenesulfonamide (1.17 g, 3.44 mmol).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:25][CH2:26][CH:27]1[CH2:29][CH2:28]1>>[CH:27]1([CH2:26][NH:25][C:3](=[O:24])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])=[N:6][CH:5]=2)[CH2:29][CH2:28]1
Reactant: NCC1CC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nc1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NCC2CC2)cn1
Yield: 85 %

Procedure:
As described for example 272, 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (97.6 mg, 0.3 mmol) was converted, using aminomethylcyclopropane instead of 4-aminotetrahydropyran, to the title compound (93 mg, 85%) which was obtained as an off white solid. MS: m/e=365.4 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=3[OH:25])[C:9]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[C:28]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=3[OH:25])[C:9]2=[O:27])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1cc(O)c(C2(O)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: Cc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4,5-dimethylphenyl)-1,3-dihydro-2H-indol-2-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, 1-(diphenylmethyl)-3-(2-hydroxy-4,5-dimethylphenyl)-1,3-dihydro-2H-indol-2-one was obtained (93%): 1H NMR (300 MHz, CDCl3) δ7.34-7.27 (m, 11H), 7.06-7.02 (m, 3H), 6.76 (s, 1H), 6.72 (s, 1H), 6.55-6.50 (m, 1H), 5.05 (s, 1H), 2.17 (s, 3H), 2.12 (s, 3H); MS (ES+) m/z 420.2 (M+1).
Reaction SMILES: COC(=O)[CH:4]([CH:13]1[CH2:16][N:15]([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH3:18])[CH2:14]1)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1.[CH3:27][Li].CC[O:31][CH2:32][CH3:33]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([CH:17]([N:15]2[CH2:14][C:13](=[C:4]([C:5]3[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=3)[C:32]([CH3:33])([OH:31])[CH3:27])[CH2:16]2)[CH3:18])=[CH:20][CH:21]=1
Reactant: CCOCC
Reactant: [Li]C
Reactant: COC(=O)C(c1cc(F)cc(F)c1)C1CN(C(C)c2ccc(Cl)cc2)C1
Product: CC(c1ccc(Cl)cc1)N1CC(=C(c2cc(F)cc(F)c2)C(C)(C)O)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 0.02 mg (0.53 mmol) of methyl{1-[1-(4-chlorophenyl)ethyl]azetidin-3-yl}(3,5-difluorophenyl)acetate in 2 mL ether was cooled to −78° C. under nitrogen. To this was added 0.8 mL of a 1.6M solution of methyllithium in ether and the solution was stirred at −78° C. After 1 h, the solution was quenched by addition of 1 mL water and the mixture was partitioned between 10 mL ether and 2 mL water. The aqueous layer was washed two times with 10 mL ethyl acetate and the combined organic extracts were dried over Na2SO4 and concentrated. The residue was purified by reverse phase chromatography (Waters Xterra C18, 19 mm×10 mm) using a gradient of CH3CN—H2O-Et3N (20:80:0.1 to 60:40:0.1). Homogenous fractions were pooled and concentrated to afford the title compound. 1NMR(CDCl3) δ 1.23 (s, 3H), 1.35 (s, 3H), 1.36 (s, 3H), 6.64-6.74 (m, 3H), 7.24-7.32 (m, 4H); Mass Spectrum: m/e=378 (M+1 35Cl) and 380 (M+1 35Cl).