Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:97]=[CH:98][CH:99]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:76][CH2:75][N:74]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[CH2:73][CH2:72]5)=[C:67]([N+:84]([O-:86])=[O:85])[CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:97]=[CH:98][CH:99]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:76][CH2:75][N:74]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[CH2:73][CH2:72]5)=[C:67]([N+:84]([O-:86])=[O:85])[CH:66]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)c([N+](=O)[O-])c4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2[N+](=O)[O-])CC1
Yield: 111.5 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-nitrophenyl)piperazine-1-carboxylate (120 mg, 0.15 mmol) was hydrolyzed by lithium hydroxide (20 mg, 0.47 mmol) in THF/methanol/water (5/5/2 ml) to yield crude 100 mg of the titled compound after purification by preparative TLC (Silicagel-1000 micron) using ethyl acetate as eluent.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[CH:17][C:16]=2[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C.[Pd]>[Si:30]([O:29][C:16]1[CH:17]=[C:18]([O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:24])[CH3:23])[CH:19]=[CH:20][C:15]=1[C@H:12]1[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]1)([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](NCc3ccccc3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](N)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 18 h

Procedure:
To a flask was added trans-N-benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl) cyclohexyl]amine (500 mg, 0.95 mmol) and ethanol (20 ml). To the stirred solution was added palladium (10% w/w on activated carbon, 200 mg, 0.19 mmol) as a slurry in ethanol (5 ml). The reaction vessel was evacuated, then placed under hydrogen. The reaction mixture was stirred vigorously under an atmosphere of hydrogen for 18 hr, then filtered through a celite plug, washing with methanol (100 ml). The solvent was removed in vacuo affording the title compound (402 mg, 97%) as a colourless oil. δH(CDCl3) 0.01 (6H, s), 0.05 (6H, s), 0.78 (9H, s), 0.82 (9H, s), 1.08 (2H, m), 1.21 (2H, m), 1.62 (2H, m), 1.78 (2H, m), 2.59 (2H, m), 6.11 (1H, d), 6.22 (1H, dd), 6.78 (1H, d).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([F:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:28]([NH2:31])[CH2:29][CH3:30]>C(#N)C>[F:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:31][CH2:28][CH2:29][CH3:30])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: CCCN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCCNC[C@H]1COc2c(F)cc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [(2R)-5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.2 g, 0.5 mmol), propan-1-amine (1 ml) and ACN (3 ml) was heated under microwave radiation at 120° C. for 20 min. Purification on SCX-3 column (TEA/MeOH) and by flash chromatography (isooctane/EtOAc/MeOH). Yield: 0.12 g, 79%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 192° C. MS m/z (rel. intensity, 70 eV) 303 (M+, 2), 73 (5), 72 (bp), 70 (11), 69 (7), 63 (5). [α]=−64° (MeOH).
Reaction SMILES: [F:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[N:20][OH:21])=[CH:15][CH:14]=2)[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C1C(=O)N(Cl)C(=O)C1.[Cl:30][C:31]1[CH:36]=[C:35]([C:37](=[CH2:42])[C:38]([F:41])([F:40])[F:39])[CH:34]=[C:33]([Cl:43])[C:32]=1[Cl:44].C(=O)(O)[O-].[K+]>CCOC(C)=O.CN(C=O)C>[F:1][C:2]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH2:42][C:37]([C:35]4[CH:34]=[C:33]([Cl:43])[C:32]([Cl:44])=[C:31]([Cl:30])[CH:36]=4)([C:38]([F:41])([F:40])[F:39])[O:21][N:20]=3)=[CH:17][CH:18]=2)[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C=NO)cc2)C1
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a DMF (8 mL) solution of tert-butyl 3-fluoro-3-(4-((hydroxyimino)methyl)-phenyl)azetidine-1-carboxylate (Preparation 7, 486 mg, 1.65 mmol) was added NCS (232 mg, 1.65 mmol) in two portions over 10 minutes. The reaction was stirred at room temperature overnight. The reaction was diluted with EtOAc (8 mL) and 1,2,3-trichloro-5-(1,1,1-trifluoroprop-2-en-2-yl)benzene (546 mg, 1.98 mmol) was added, followed by potassium bicarbonate (248 mg, 2.48 mmol). The reaction was stirred at room temperature for 3 days. The reaction was concentrated under vacuum. The residue was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were dried and condensed. The crude material was adsorbed on silica and chromatographed on a 40 g silica column eluting with a gradient of 0%-40% EtOAc/hexanes over 20 minutes. Fractions containing the desired material were combined and concentrated to yield 526 mg of a white solid. 1H NMR (CDCl3) δ 7.74 (d, 2H), 7.67 (s, 2H), 7.56 (d, 2H), 4.39-4.51 (m, 2H), 4.24 (m 2H), 4.12 (d, 1H), 3.72 (d, 1H), 1.5 (s, 9H).
Reaction SMILES: ClCCCCO[C:7]1[C:12]2[C:13]([CH2:20][CH3:21])([CH2:18][CH3:19])[O:14][C:15](=[O:17])[NH:16][C:11]=2[CH:10]=[CH:9][CH:8]=1.[C:22]1([SH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([S:28][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:8]2[CH:9]=[CH:10][C:11]3[NH:16][C:15](=[O:17])[O:14][C:13]([CH2:18][CH3:19])([CH2:20][CH3:21])[C:12]=3[CH:7]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCC1(CC)OC(=O)Nc2cccc(OCCCCCl)c21
Reactant: Sc1ccccc1
Product: CCC1(CC)OC(=O)Nc2ccc(OCCCCSc3ccccc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy-4,4-diethyl-4H-3,1-benzoxazin-2-one and thiophenol.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][CH:12]=[O:13])[CH:2]=1.[C:14](O)(=[O:16])C.C(OC(=O)C)=O.C(OC(=O)C)(=O)C>C1COCC1.[Pt]=O.CO.C(O)=O>[CH:14]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][CH:12]=[O:13])[CH2:2]1)=[O:16]
Reactant: CC(=O)O
Reactant: O=CNc1cnc2ccccc2c1
Agent: O=[Pt]
Agent: CC(=O)OC=O
Solvent: O=CO
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: O=CNC1Cc2ccccc2N(C=O)C1
Reaction time: 0.25 h
Yield: 69 %

Procedure:
A mixture of N-(3-quinolyl)formamide (30.0 g, 0.175 tool), platinum oxide (2.0 g) and acetic acid (300 mL) was hydrogenated (50 lb. initial H2 pressure) until 2 equivalents of H2 were consumed (reaction time 3 hours). The mixture was filtered through celite and the acetic acid removed under reduced pressure. It was dissolved in ethyl acetate and washed with NaOH solution and water. Evaporation of the ethyl acetate gave 29.4 g of crude material. This was dissolved in 200 mL THF and acetic formic anhydride (prepared from formic acid (27.2 g, 0.59 tool) and acetic anhydride (53.5 g, 0.52 tool) was added at 0° C. After 15 minutes, the solution was allowed to was to room temperature, and after an additional 15 minutes, methanol (60 mL) was added. The solution was evaporated and the resulting oil was partitioned between ethyl acetate and 4N sodium hydroxide solution. The sodium hydroxide solution was repeatedly extracted with ethyl acetate. The combined ethyl acetate was evaporated, and the crude product was purified by chromatography on silica gel using 2.5% methanol:chloroform as eluant to give 22.55 g (69%) of product. An analytical staple was crystallized from medrol:ether (1:3); mp 125°-128° C. Anal. Calc'd for C11H12N2O2 : C, 64.69; H, 5.92; N, 13.72. Found: C, 64.60; H, 5.97; N, 13.66.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(C(C)C)CC)(C)C.Cl.[N:25]1([C:30]2[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=2)[CH:29]=[CH:28][N:27]=[CH:26]1>CN(C)C1C=CN=CC=1.ClCCl>[N:25]1([C:30]2[CH:31]=[CH:32][C:33]([C:34]([N:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH2:10][N:4]4[CH:3]=[CH:2][CH:1]=[C:5]4[CH2:6]3)=[O:35])=[CH:37][CH:38]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: O=C(Cl)c1ccc(-n2ccnc2)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(-n2ccnc2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine (0.75), diisopropylethylamine (1.20 g), and 4-dimethylaminopyridine (0.1 g) in dichloromethane (50 ml) was added 4-(imidazol-1-yl)benzoyl chloride hydrochloride (1.12 g). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered through a short column of hydrous sodium magnesium silicate, and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.57 g), m.p. 171-172° C.; MS, m/z: 354 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=[CH2:7]>CO.C(OCC)(=O)C.[C].[Pd]>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH2:6][CH3:7])[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: C=Cc1cc(OC)cc(OC)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1cc(OC)cc(OC)c1
Yield: 84.2 %

Procedure:
3,5-Dimethoxystyrene (8.29 g) is dissolved in a mixture of methanol (70 ml) and ethyl acetate (10 ml), and the mixture is subjected to catalytic hydrogenation with using 10% palladium-carbon (51.4% aqueous, 1.2 g) under atmospheric pressure. One hour thereafter, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; hexane/ethyl acetate) to give 1,3-dimethoxy-5-ethylbenzene (7.07 g).
Reaction SMILES: B(Cl)(Cl)Cl.C([NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[N:23]=[C:22]([NH:24][C:25]3[CH:29]=[C:28]([CH:30]4[CH2:32][CH2:31]4)[NH:27][N:26]=3)[C:21](/[CH:33]=[CH:34]/[CH2:35][OH:36])=[CH:20][N:19]=2)=[CH:16][CH:17]=1)(=[O:12])=[O:11])(C)(C)C>C(Cl)Cl>[CH:30]1([C:28]2[NH:27][N:26]=[C:25]([NH:24][C:22]3[C:21](/[CH:33]=[CH:34]/[CH2:35][OH:36])=[CH:20][N:19]=[C:18]([C:15]4[S:14][C:13]([S:10]([NH2:9])(=[O:12])=[O:11])=[CH:17][CH:16]=4)[N:23]=3)[CH:29]=2)[CH2:32][CH2:31]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(/C=C/CO)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2ncc(/C=C/CO)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Reaction time: 0.5 h
Yield: 11.9 %

Procedure:
BCl3 (1 M in CH2Cl2, 0.5 mL, 6.0 mmol, 20 eq) was added to a stirred solution of (E)-N-tert-butyl-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(3-hydroxyprop-1-enyl)pyrimidin-2-yl)thiophene-2-sulfonamide (Compound 214) (40 mg, 0.08 mmol) in CH2Cl2 (10 mL) at room temperature under nitrogen. The reaction mixture was stirred for 30 min and then quenched with aq. NaHCO3 in ice bath. The reaction mixture was extracted with ethyl acetate and washed with water, brine, dried and evaporated. The crude product was crystallized with THF/isopropyl to afford (E)-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(3-hydroxyprop-1-enyl)pyrimidin-2-yl)thiophene-2-sulfonamide (Compound 281) (4 mg, 11%). LC-MS (m/z)=419 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.73-0.77 (m, 2H), 0.95-1.00 (m, 2H), 1.90-1.96 (m, 1H), 4.16 (d, J=4.4 Hz, 2H), 6.37 (dt, J=15.6 Hz, 4.8 Hz, 1H), 6.45 (s, 1H), 6.88 (d, J=15.6 Hz, 1H), 7.57 (d, J=4.4 Hz, 1H), 7.76 (d, J=4.0 Hz, 1H), 7.78 (s, 2H), 8.43 (s, 1H), 9.27 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C[Si](Cl)(C)C.BrCCBr.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.Br/[C:39](/[C:47]1[N:52]=[C:51]([O:53][CH3:54])[C:50]([Cl:55])=[CH:49][CH:48]=1)=[CH:40]\[CH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>O1CCCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Cl:55][C:50]1[C:51]([O:53][CH3:54])=[N:52][C:47](/[C:39](/[CH2:2][C:3]2[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][CH:4]=2)=[CH:40]/[CH:41]2[CH2:42][CH2:43][O:44][CH2:45][CH2:46]2)=[CH:48][CH:49]=1
Reactant: COc1nc(/C(Br)=C/C2CCOCC2)ccc1Cl
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COc1nc(/C(=C/C2CCOCC2)Cc2ccc(S(C)(=O)=O)cc2)ccc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
1-(Bromomethyl)-4-(methylsulfonyl)benzene (110 mg), trimethylsilyl chloride (12.5 μL) and 1,2-dibromoethane (8.6 μL) were added to a solution of zinc powder (78 mg) in tetrahydrofuran (4 mL) in the presence of an argon gas, and the mixture was stirred at 80° C. for two hours. The reaction solution was returned to room temperature. A solution of tris(dibenzylideneacetone)dipalladium (45 mg), tri(2-furyl)phosphine (69 mg) and 6-[(Z)-1-bromo-2-(tetrahydro-2H-pyran-4-yl)ethenyl]-3-chloro-2-methoxypyridine (380 mg) in tetrahydrofuran (2 mL) was added and the mixture was stirred at 90° C. for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to give 3-chloro-2-methoxy-6-[(1E)-3-[4-(methylsulfonyl)phenyl]-1-(tetrahydro-2H-pyran-4-yl)prop-1-en-2-yl]pyridine as a yellow oil (110 mg).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C([O-])=O.[Br:52][C:53]1[CH:58]=[CH:57][C:56]([S:59](Cl)(=[O:61])=[O:60])=[CH:55][CH:54]=1>>[Br:52][C:53]1[CH:58]=[CH:57][C:56]([S:59]([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:16])(=[O:61])=[O:60])=[CH:55][CH:54]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 65 %

Procedure:
Nα-tert-butoxycarbonyl-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine was deprotected at the α position by treatment with TFA/CH2Cl2 as described in the procedure outlined in example 24 and the resulting trifluoroacetate salt was alkylated with 4-bromobenzenesulfonyl chloride as described in example 2, affording the title compound in 65% yield.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[C:35]=2[Cl:44])[CH2:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=1)(C)(C)C.C(Cl)[Cl:47].FC(F)(F)C(O)=O>CCOCC.Cl>[ClH:44].[ClH:47].[Cl:44][C:35]1[C:36]([C:40]([F:41])([F:42])[F:43])=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][N:18]([CH2:19][CH:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:17][CH2:16][CH2:15][O:14][C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][CH:11]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)Nc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Nc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1

Procedure:
(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-carbamic acid tert-butyl ester, (0.51 g, 0.8 mmol) was stirred overnight at room temperature in a mixture methylene chloride (5 mL) and trifluoroacetic acid (0.5 mL). The solvents were removed in vacuo to yield the crude amine as an oil. The oil was diluted with ether, and 1 N HCl in Et2O was added to precipitate the HCl salt of the product. The title compound was isolated as a cream yellow powder, 0.53 g (100%). MS (ESI) 539 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.[CH3:31][CH:32]1[NH:36][C:35](=[O:37])[CH2:34][CH2:33]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:36]4[CH:32]([CH3:31])[CH2:33][CH2:34][C:35]4=[O:37])=[CH:3][C:4]=3[N:24]3[CH2:28][CH2:27][CH2:26][S:25]3(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Reactant: CC1CCC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 74.2 %

Procedure:
Using [4-bromo-2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (247 mg) described in Preparation Example 166 and 5-methylpyrrolidin-2-one (50 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (190 mg) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[C:12]([O:17]CC3C=CC=CC=3)=[N:13][CH:14]=[CH:15][CH:16]=2)=O)=[CH:5][CH:4]=1)[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:11]2[C:12]([OH:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)c2cccnc2OCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCc1ccc(Cc2cccnc2O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
The above 2-benzyloxy-3-pyridyl 4-ethylphenyl ketone (1.69 g) was dissolved in ethanol (15 ml), and thereto was added sodium borohydride (403 mg), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The mixture was washed with water and successively with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give crude 2-benzyloxy-3-pyridyl-4-ethylphenylmethanol as colorless oil, which was used in the subsequent step without further purification. (3) The above 2-benzyloxy-3-pyridyl-4-ethylphenylmethanol was dissolved in methanol (10 ml), and thereto were added concentrated hydrochloric acid (1.0 ml) and 10% palladium-carbon (500 mg). The mixture was stirred at room temperature for 15 hours under hydrogen atmosphere under normal pressure. Insoluble materials were filtered off, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with water and successively with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0-97:3) to give the desired 3-(4-ethylphenylmethyl)-2-hydroxypyridine (307 mg) as a pale brown solid. APCI-Mass m/Z 214 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:7]([S:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[C:11]([O:17][CH3:18])[CH:10]=3)=[CH:6][C:5](=[O:19])[CH:4]=1.[Cl:20]Cl.CO>C(O)(=O)C>[Cl:20][C:6]1[C:5](=[O:19])[CH:4]=[C:3]([O:2][CH3:1])[C:16]2[C:7]=1[S:8][C:9]1[C:14](=[CH:13][CH:12]=[C:11]([O:17][CH3:18])[CH:10]=1)[N:15]=2
Reactant: COc1ccc2nc3c(OC)cc(=O)cc-3sc2c1
Reactant: ClCl
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc2nc3c(OC)cc(=O)c(Cl)c-3sc2c1
Reaction time: 0.25 h

Procedure:
To a suspension of 1,7-dimethoxy-3H-phenothiazin-3-one (800 mg) in acetic acid (24 ml) was added a 1.15M solution of Cl2 in acetic acid (3.1 ml). After 15 minutes, methanol was added and the mixture was filtered, washed with ether and air dried to afford a mixture of the two title compounds (700 mg), which were separated on a silica gel column (EtOAc:CH2Cl2, 1:9), affording 4-chloro-1,7-dimethoxy-3H-phenothiazin-3-one, m.p. 278°-280° C. (dec.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1.[OH-].[K+].CCO.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCO>[CH2:21]([C:11]1[C:12](=[O:15])[NH:13][N:14]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:10]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(C2=NNC(=O)CC2)cc1
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2cc(Cc3ccccc3)c(=O)[nH]n2)cc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
6-(4-methoxy-phenyl)-4,5-dihydro-2H-pyridazin-3-one (1.65 g, 7.5 mmol) in 15 mL of EtOH was heated to 80° C. as 20 mL of 4% of KOH/EtOH solution was added dropwise. After 5 min., benzaldehyde (1.0 eq. 0.76 mL) was added and the mixture stirred at 80° C. for 2 h. The reaction was cooled to rt., poured into ice-H2O (75 mL) and the resulting solid was collected and crystallized from EtOH to give 1.67 g (76%) of intermediate 4-benzyl-6-(4-methoxy-phenyl)-2H-pyridazin-3-one: MS m/z 293 (M+H). This intermediate was used to prepare examples 45 and example 46.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C:11]#[CH:12])=[C:4]([N+:13]([O-])=O)[CH:3]=1>[Fe].O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C:11]#[CH:12])=[C:4]([NH2:13])[CH:3]=1
Reactant: C#CCCOc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: C#CCCOc1ccc(Br)cc1N
Yield: 89.3 %

Procedure:
4-Bromo-1-but-3-ynyloxy-2-nitro-benzene (82% pure, 4.22 g, 12.5 mmol) was heated in a mixture of IMS (Industrial Methylated Spirits, 40 mL) and glacial acetic acid (2 mL) at approx. 50° C. until a solution was formed. Iron powder (5.05 g, 89.8 mmol) and iron (III) chloride hexahydrate (0.56 g, 1.56 mmol) were added and the mixture was heated under reflux for 18 h. The cooled mixture was filtered through Celite®, and washed through with ethyl acetate. The filtrate was washed with water, followed by brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 10 to 20% ethyl acetate in cyclohexane) to give 5-Bromo-2-but-3-ynyloxy-phenylamine as an orange oil (2.68 g, 89%). LCMS: RT=4.10 min, M+H+=240/242.