Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=[O:35])[NH:7][C@H:8]([C:13](=[O:34])[NH:14][CH:15]1[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][N:18]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)(=[O:26])=[O:25])[CH2:17][CH:16]1[OH:33])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.Cl.O1CCOCC1.Cl.[O:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[CH:46]=[C:45]1C(O)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>>[OH:33][CH:16]1[CH:15]([NH:14][C:13]([C@@H:8]([NH:7][C:6]([C:45]2[O:44][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=3[CH:46]=2)=[O:35])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:34])[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][N:18]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)(=[O:25])=[O:26])[CH2:17]1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CC(C)(C)CN(S(=O)(=O)c2ccccn2)CC1O
Reactant: O=C(O)c1cc2ccccc2o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CC(C)(C)CN(S(=O)(=O)c2ccccn2)CC1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To {(S)-1-[3-Hydroxy-6,6-dimethyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-carbamic acid tert-butyl ester of Example 92h (0.22 g, 0.43 mmol) was added HCl/dioxane (4M, 20 ml, 80 mmol). The mixture was stirred at r.t. for 2 h before solvents and excess amount of HCl was removed on rotavapor. The resulting white solid was dissolved in 5 ml DMF. To the solution was added 2-benzofurancarboxylic acid (84 mg, 0.52 mmol), HBTU (0.2 g, 0.52 mmol) and NMM (0.2 g, 2 mmol). The mixture was stirred at r.t. overnight. DMF was then removed and the residue was redissolved in EtOAc (50 ml), washed with 10% NaHCO3 (50 ml×2) and brine (50 ml). Evaporation of the solvent gave crude product 0.26 g. Purification by column chromatograghy gave the title compound 0.15 g in 63% total yield; MS (M+H+): 556.8; 1H-NMR (400 MHz, CDCl3): •8.66-8.63(m, 1H), 7.94-7.11(m, 10H), 4.72(m, 1H), 4.01-2.98(m, 7H), 1.78-1.39(m, 5H), 1.02-0.85(m, 12H).
Reaction SMILES: [C:1]12([C:11]3[S:15][CH:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:13][N:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([S:24][CH2:25][CH2:26][C:27](Cl)=[O:28])(=O)C>>[C:1]12([C:11]3[S:15][CH:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:13]([C:27](=[O:28])[CH2:26][CH2:25][SH:24])[N:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCOC(=O)C1NN=C(C23CC4CC(CC(C4)C2)C3)S1
Reactant: CC(=O)SCCC(=O)Cl
Product: CCOC(=O)C1SC(C23CC4CC(CC(C4)C2)C3)=NN1C(=O)CCS

Procedure:
The crude product of step (c) was treated with 3-acetylthiopropanoyl chloride by the process of Example 3, step (b) to give the sub-title product as an oil.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][NH:5][C@@H:4]2[CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C@@H:3]12.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[Cl:24][CH2:25][C:26]([N:5]1[CH2:6][CH2:7][O:2][C@@H:3]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][C@@H:4]12)=[O:27]
Reactant: O=C(Cl)CCl
Reactant: c1ccc2c(c1)OCC[C@H]1NCCO[C@H]21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCO[C@@H]2c3ccccc3OCC[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.21 g of trans-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine hydrochloride, prepared according to the procedure of Example 2, and 1.65 ml of triethylamine in 25 ml of methylene chloride is treated dropwise with a solution of 0.70 ml of chloroacetyl chloride dissolved in 10 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature, washed with a dilute solution of hydrochloric acid, followed by a water wash, a wash of dilute sodium hydroxide solution and finally by a wash of a saturated solution of sodium chloride. The reaction mixture is dried over anhydrous magnesium sulfate and evaporated to dryness to obtain 1.44 g of trans-N-chloroacetyl-3,4,4a,5,6,11b-hexahydro-2H-[1]-benzoxepino[5,4-b]-1,4-oxazine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[C:12](Cl)(Cl)=[O:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:5]([O:7][C:12](=[O:13])[NH:11][C:3]=12)=[O:6]
Reactant: O=C(Cl)Cl
Reactant: Nc1c(Cl)cccc1C(=O)O
Solvent: Cc1ccccc1
Product: O=c1[nH]c2c(Cl)cccc2c(=O)o1
Temperature: -20 °C

Procedure:
190.7 g of 90% 3-chloroanthranilic acid, corresponding to 171.6 g (1.0 mol) of 100% 3-chloroanthranilic acid, are initially introduced, in 1,820.0 g of toluene, into a four-necked flask having a stirrer, a thermometer and a reflux condenser cooled down to -20° C., and 300.0 g of phosgene are then metered in at room temperature over a period of about 3 h while stirring thoroughly. The reaction mixture is heated to 100° C. and a further 150.0 g of phosgene are passed in over a period of 2 h. After that, the mixture is stirred at 100° C. for a further 1 h, and subsequently blown free of phosgene at this temperature using nitrogen. After cooling to about 25° C., the crystals which have precipitated out are filtered off with suction, and the filter cake is washed with 2×50 ml of toluene and dried at 100° C. in vacuo. 188.3 g of 3-chloroisatoic anhydride, having a purity by GC of >99%, are obtained, corresponding to 95.2% of theory.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[F:34][C:35]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[CH:37][C:36]=1[N:50]1[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:34][C:35]1[CH:40]=[C:39]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[N:13][N:14]([CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=5)[CH:15]=4)=[CH:9][N:8]([S:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=4)(=[O:25])=[O:26])[C:5]3=[N:6][CH:7]=2)[CH:38]=[CH:37][C:36]=1[N:50]1[CH2:51][CH2:52][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:54][CH2:55]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Yield: 68.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (160 g, 0.304 mmol) was coupled with tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (intermediate 69) (216 mg, 0.530 mmol) using sodium carbonate (97 mg, 0.912 mmol) and Pd(PPh3)2Cl2 (11 mg, 0.015 mmol) in DME/water (5/2 mL). This afforded 150 mg (68.10% yield) after purification by column (Silica gel 60/120) using 25% ethyl acetate in hexane as eluent. MS: m/z=725.3 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=3)=[C:12]([F:13])[C:7]=2[N:6]([CH3:21])[C:5]1=[O:22].C(=O)([O-])[O-].[K+].[K+].Cl[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[C:38]#[N:39]>CS(C)=O>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=3)[O:20][C:32]3[C:33]([C:38]#[N:39])=[CH:34][N:35]=[CH:36][CH:37]=3)=[C:12]([F:13])[C:7]=2[N:6]([CH3:21])[C:5]1=[O:22]
Reactant: N#Cc1cnccc1Cl
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(O)c3)c(F)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(Oc4ccncc4C#N)c3)c(F)c21
Reaction time: 0.33 h

Procedure:
A solution of 1-(2,2-dimethylpropyl)-4-fluoro-5-(3-hydroxyphenyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (7-15, 55 mg, 0.17 mmol) in DMSO (1 ml) was charged with Potassium carbonate (46.3 mg, 0.34 mmol, 2.0 eq) and 4-Chloro-3-cyanopyridine (34.8 mg, 0.25 mmol, 1.5 eq). The mixture was irradiated in a microwave at 160 deg C. for 20 min, then purified via reverse-phase HPLC (Acetonitrile/Water gradient with 0.1% TFA present) providing 4-{3-[1-(2,2-dimethylpropyl)-4-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]phenoxy}nicotinonitrile (8-1) as a tan solid-oil. 1H NMR (400 MHz, CDCl3) δ 8.81 (bs, 1H), 7.60-7.53 (m, 2H), 7.35 (s, 1H), 7.27 (s, 1H), 7.17-7.14 (m, 1H), 7.11-7.07 (m, 1H), 6.91 (d, 2H, J=8.24 Hz), 3.69 (s, 2H), 3.66 (s, 3H), 1.10 (s, 9H). LRMS m/z: Calc'd for C25H23FN4O2(M+H) 431.4, found 431.5.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[F:20])[C:14]([OH:16])=O.Cl.[CH3:22][O:23][C:24](=[O:30])[C@H:25]([C@@H:27]([CH3:29])[OH:28])[NH2:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[CH3:22][O:23][C:24](=[O:30])[C@@H:25]([NH:26][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:19]([F:20])=[C:11]([Br:10])[CH:12]=1)[C@H:27]([OH:28])[CH3:29]
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: O=C(O)c1ccc(F)c(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](NC(=O)c1ccc(F)c(Br)c1)[C@@H](C)O
Temperature: 0 °C
Reaction time: 20 h
Yield: 99.9 %

Procedure:
Diisopropylethylamine (6.8 mL, 39.0 mmol) was added to a stirred solution of 3-bromo-4-fluorobenzoic acid 1 (2.152 g, 9.83 mmol), L-threonine methyl ester hydrochloride (1.968 g, 11.6 mmol), EDCI (2.218 g, 11.6 mmol) and HOBt (1.410 g, 10.4 mmol) in anhydrous DMF (60 mL) at 0° C. under N2. The solution was stirred at 0° C. for 1 h and at room temperature for 20 h. The solution was diluted with EtOAc (300 mL) and washed with 1.0 M HCl (2×80 mL), saturated NaHCO3 (2×80 mL), H2O (4×80 mL), dried over MgSO4, filtered and concentrated in vacuo to give a colorless syrup which solidified on standing to afford 3.280 g (100%) of (2S,3R)-2-(3-bromo-4-fluoro-benzoylamino)-3-hydroxy-butyric acid methyl ester 2 as a white solid, mp 73-74° C. MS (ES+) m/z 333.9 (C12H13BrFNO4+H requires 334.00).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.OCC([C@H]([C@@H]([C@@H](CO)O)O)O)=O.C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[C@@H]1(O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)[C@H]1O.O=C[C@@H]([C@@H]([C@H]([C@H](C)O)O)O)O.C(O)[C@H]1O[C@H](OC[C@H]2O[C@H](O[C@]3(CO)O[C@H](CO)[C@@H](O)[C@@H]3O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@H]1O>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O
Agent: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)CO

Procedure:
D-xylose +; D-glucose +; D-fructose +; sucrose +; inositol +; L-rhamnose +; raffinose +; D-mannite +
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-])=O)=[C:4]([F:12])[C:3]=1[CH3:13]>[Pd].C(O)(=O)C>[F:12][C:4]1[C:3]([CH3:13])=[C:2]([F:1])[C:7]([F:8])=[CH:6][C:5]=1[NH2:9]
Reactant: Cc1c(F)c(F)cc([N+](=O)[O-])c1F
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1c(F)c(N)cc(F)c1F
Yield: 77.5 %

Procedure:
To acetic acid (350 ml) are added 5% Pd-C (3.5 g) and 2,3,6-trifluoro-5-nitrotoluene (35 g) and the mixture is subjected to catalytic reduction at room temperature under atomospheric pressure. 5% Pd-C is filtered off and the acetic acid is distilled off under reduced pressure. The residue is poured into ice-water, neutralized, extracted with dichloromethane, and the extract is washed with water and dried. The solvent is distilled off under reduced pressure and the obtained residue is distilled under reduced pressure to give 2,4,5-trifluoro-3-methylaniline (22.86 g), as yellow crystals, b.p. 85° C./20 mmHg.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:13]3[C:25]([CH:26]4[CH2:28][CH2:27]4)=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([F:29])[CH:14]=3)[CH2:7][CH2:6]2)[O:4]CC1.FC(F)(F)C(O)=O>O1CCCC1.O.C(OCC)(=O)C>[CH:26]1([C:25]2[C:13]([O:12][CH2:11][CH:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)=[CH:14][C:15]([F:29])=[C:16]([CH:24]=2)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2CCC3(CC2)OCCO3)cc1F
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2CCC(=O)CC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
To a mixture of tert-butyl 4-(1,4-dioxaspiro[4.5]decan-8-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate (3.16 g, 7.77 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was added trifluoroacetic acid (2.7 mL) and the reaction mixture was stirred for 16 hours at ambient temperature. After diluting the reaction mixture with ethyl acetate (200 mL), the organic phase was washed with 1 N sodium hydroxide solution (2×15 mL), brine (15 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave a residue which was purified by silica gel column chromatography using 0-40% ethyl acetate in hexanes as eluent to afford the title compound as a colorless oil (2.70 g, 96%): 1H NMR (300 MHz, CDCl3) δ 7.37 (d, J=8.4 Hz, 1H), 6.50 (d, J=12.5 Hz, 1H), 3.90 (d, J=6.0 Hz, 2H), 2.53-2.15 (m, 8H), 2.03-1.92 (m, 1H), 1.73-1.59 (m, 1H), 1.55 (s, 9H), 0.92-0.83 (m, 2H), 0.65-0.58 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].[CH2:12]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13][CH2:12][C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]2=3)=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1F
Reactant: c1ccc2c(c1)CCc1ccccc1C2
Product: COc1cc(C=C2c3ccccc3CCc3ccccc32)ccc1F
Yield: 49 %

Procedure:
Following procedures essentially as described in Example 28 and using 4-fluoro-3-methoxybenzaldehyde (1.59 g, 10.3 mmol), dibenzosuberane (1.94 g, 10 mmol, provides 1.66 g of title compound in 49% yield as a light tan oil that slowly crystallized. HPLC shows 93% purity.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20](=[O:29])[C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=3)=[CH:10]2)[CH:5]=[CH:4][CH:3]=1.Cl.C(O)(=[O:33])C>>[CH3:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[CH3:27])[C:20]([C:11]1[C:12](=[O:19])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]([CH2:8][C:6]2[NH:7][C:2](=[O:33])[CH:3]=[CH:4][CH:5]=2)[CH:10]=1)=[O:29]
Reactant: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1C
Reactant: CC(=O)O
Agent: Cl
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(=O)[nH]3)c3ccccc3c2=O)cc1C

Procedure:
182 mg (0.41 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one in a solution of 3 mL acetic acid and 3 mL concentrated aqueous hydrochloric acid was heated in a sealed tube at 150° C. for 24 h. Purification on reverse-phase HPLC and free-basing gave 95 mg of a white solid: LC-MSD, m/z for C24H20N2O3 [M+H]+=385.1; HPLC retention time: 0.4 min.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[C:4]1/[C:5]2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=2[O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/1=2.[N+:23]([C:26]1[CH:34]=[CH:33][C:29]2[N:30]=[CH:31][NH:32][C:28]=2[CH:27]=1)([O-:25])=[O:24]>>[N+:23]([C:26]1[CH:34]=[CH:33][C:29]2[N:30]=[CH:31][N:32]([CH2:2]/[CH:3]=[C:4]3/[C:5]4[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=4[O:7][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/3=4)[C:28]=2[CH:27]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Reactant: COC(=O)c1ccc2c(c1)/C(=C/CCl)c1ccccc1CO2
Product: COC(=O)c1ccc2c(c1)/C(=C/Cn1cnc3ccc([N+](=O)[O-])cc31)c1ccccc1CO2

Procedure:
Compound h, 2.0 g, and 5.2 g of 5-nitrobenzimidazole were treated in a manner similar to Example 23 to give a 1:1 mixture of Compounds E-55a and E-56a. The mixture was separated and purified by silica gel column chromatography (eluting solvent, hexane:ethyl acetate:triethylamine=10:10:1) to give 1.1 g of methyl (E)-11-[2-(5-nitro-1-benzimidazolyl)ethylidene]-6,11-dihydiodibenz[b,e]oxepin-2-carboxylate (Compound E-55a) and 0.7 g of methyl (E)-11-[2-(6-nitro-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound E-56a).
Reaction SMILES: C(C1OC[C@H](C(C)(C)C)N=1)(C1OC[C@H](C(C)(C)C)N=1)(C)C.[Cl:22][C:23]([F:25])=[CH2:24].[N+](=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N-]>CCCCCCC.FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O>[Cl:22][C:23]1([F:25])[CH2:24][CH:28]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: C=C(F)Cl
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu+2]
Agent: CC(C)(C1=N[C@@H](C(C)(C)C)CO1)C1=N[C@@H](C(C)(C)C)CO1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCCCCCC
Product: CCOC(=O)C1CC1(F)Cl
Temperature: 30 °C
Reaction time: 1 h

Procedure:
n-Heptane (38.3 g), 2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] (162 mg, 0.55 mmol), and copper (II) trifluoromethanesulfonate (180 mg, 0.50 mmol) were added in in an autoclave, and then 1-chloro-1-fluoroethylene (40 g, 0.50 mol) was charged under elevated pressure. After the mixed solution was warmed to 30° C., a mixed solution containing 95% of ethyl diazoacetate (6.0 g, 50 mmol) and n-heptane (25 g) was charged under elevated pressure over five hours. n-Heptane (20 ml) was further charged under elevated pressure and stirring was continued at the same temperature for 1 hour, and then the internal pressure was released to obtain a solution of ethyl 2-chloro-2-fluorocyclopropanecarboxylate in n-heptane (90.0 g). The content of the ethyl 2-chloro-2-fluorocyclopropanecarboxylate was 3.73% (yield based on ethyl diazoacetate: 40.3%), and the ratio of cis-isomer/trans-isomer was 64.0/36.0. The optical purity of the cis-isomer was 98% e.e. (1S,2R), and the optical purity of the trans-isomer was 86% e.e. (1S,2S).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][OH:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18]([NH:21][C:22]1[C:27](Cl)=[N:26][C:25]([Cl:29])=[CH:24][N:23]=1)(=[O:20])=[O:19]>>[NH2:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][O:9][C:27]2[C:22]([NH:21][S:18]([C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=3[Cl:10])(=[O:20])=[O:19])=[N:23][CH:24]=[C:25]([Cl:29])[N:26]=2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Reactant: NCc1ccc(CO)o1
Product: NCc1ccc(COc2nc(Cl)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)o1

Procedure:
Prepared by the method of Example 31 using (5-aminomethyl-2-furanyl)methanol (0.2 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.3 g). Purified by silica gel chromatography eluting with methanol/dichloromethane mixtures.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.[CH2:19]=O>C(O)=O>[CH3:19][NH:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]3)[O:8][C:4]=2[CH:3]=1
Reactant: C=O
Reactant: CN1CCN(c2nc3cc(Cl)c(N)cc3o2)CC1
Solvent: O=CO
Product: CNc1cc2oc(N3CCN(C)CC3)nc2cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 50 mg portion of 6-amino-5-chloro-2-(4-methyl-1-piperazinyl)benzoxazole was dissolved in 5 ml of formic acid, and the solution was mixed with 3 ml of formaldehyde and stirred at room temperature for 3 hours. The solvent was concentrated under a reduced pressure, and the resulting oily matter was mixed with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate, and then the solvent was evaporated under a reduced pressure. Thereafter, the thus obtained mixture was purified by a silica gel column chromatography (chloroform:methanol=20:1) to obtain the title compound (28 mg) in light yellow color.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH2:10][C:9]2=[O:22])=[CH:4][CH:3]=1.C(Cl)Cl.S(Cl)(Cl)(=O)=[O:27].C(=O)([O-])O.[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]([C:14]3[CH:15]=[CH:16][C:17]([S:20]([CH3:21])=[O:27])=[CH:18][CH:19]=3)[CH2:12][CH2:11][CH2:10][C:9]2=[O:22])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CSc1ccc(C2CCCC(=O)N2c2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CS(=O)c1ccc(C2CCCC(=O)N2c2ccc(Cl)cc2)cc1
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a stirred mixture of 7.7 g of 1-(4-chlorophenyl)-6-(4-methylthiophenyl)-2-piperidone, 80 ml of methylene chloride, 3 g of silica gel, and 2.2 g of water was added 3.44 g of sulfuryl chloride at 15° to 25° C., and the mixture was stirred at 15° to 25° C. for 2 hours. The reaction mixture was poured into a cold aqueous sodium hydrogen carbonate solution. The methylene chloride solution was washed with a saturated aqueous sodium chloride solution, dried, and concentrated. The residue was purified by silica gel column chromatography (solvent; ethyl acetate:ethanol=10:1) and recrystallization from ethyl acetate to give 7.69 g of 1-(4-chlorophenyl)-6-(4-methylsulfinylphenyl)-2-piperidone as colorless prisms.
Reaction SMILES: [C:1]([C:4]1[C:5]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14][C:6]=2[CH:7]=[C:8]2[C:13]=1[NH:12][CH2:11][CH2:10][CH2:9]2)([CH3:3])=[CH2:2]>CO.[Pd]>[CH:1]([C:4]1[C:5]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:15][CH2:14][C:6]=2[CH:7]=[C:8]2[C:13]=1[NH:12][CH2:11][CH2:10][CH2:9]2)([CH3:3])[CH3:2]
Reactant: C=C(C)c1c2c(cc3c1NCCC3)CCN(C(=O)OC(C)(C)C)CC2
Agent: [Pd]
Solvent: CO
Product: CC(C)c1c2c(cc3c1NCCC3)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 76 %

Procedure:
To a solution of 670 mg of t-butyl 11-isopropenyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 10 ml of MeOH was added 200 mg of palladium on carbon, followed by stirring at room temperature for 3.5 hours at normal pressure under a hydrogen atmosphere. Further, after stirring overnight at 4.5 atm under a hydrogen atmosphere, the reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 512 mg of t-butyl 11-isopropyl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:21].[CH2:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH3:23]>O1CCOCC1>[C:12]([C:11]1[C:2]([N:27]2[CH2:28][CH2:29][N:24]([CH2:22][CH3:23])[CH2:25][CH2:26]2)=[C:3]([F:21])[CH:4]=[C:5]2[C:10]=1[N:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6]2=[O:20])#[N:13]
Reactant: CCN1CCNCC1
Reactant: N#Cc1c(Cl)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: C1COCCO1
Product: CCN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2C#N)CC1

Procedure:
0.5 g of the product from Example 1 and 0.55 g of N-ethylpiperazine are boiled in 8 ml of dioxane for 3 hours. The mixture is then concentrated in vacuo. The residue is taken up in water and rendered neutral. The mixture is extracted with methylene chloride and the organic phase is separated off, dried over sodium sulphate and concentrated. 0.5 g of the title compound of melting point >300° C. remains.