Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH:9]([OH:13])[CH2:10][CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[C:1]([O:5][C:6]([NH:7][CH2:8][CH:9]([O:13][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10][CH2:11][O:12][S:23]([CH3:22])(=[O:25])=[O:24])=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(O)CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(CCOS(C)(=O)=O)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (2,4-Dihydroxy-butyl)-carbamic acid tert-butyl ester in dichloromethane (15 ml) was added triethylamine (1.96 ml). The reaction mixture was cooled to 0° C. and methanesulfonyl chloride (0.82 ml) was added drop wise. The mixture was stirred at 0° C. for 2 hours. The mixture was filtered and dichloromethane was added (200 ml). The mixture was washed with 0.2M hydrochloric acid (50 ml), water (30 ml) and 0.2M sodium carbonate (50 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated to give crude methanesulfonic acid 1-(tert-butoxycarbonylamino-methyl)-3-methanesulfonyloxy-propyl ester (1.24 g) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[C:10]([NH:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:9]=2)[CH2:4][CH2:3]1>C(OCC)(=O)C.ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[C:10]([NH:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(CO)c(NC3CCOCC3)c2)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(C=O)c(NC3CCOCC3)c2)CC1
Reaction time: 5 h
Yield: 50.3 %

Procedure:
85 mg (0.982 mmol) of manganese dioxide is added at room temperature to a solution of (4-(4-methylpiperazine-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)phenyl)methanol (100 mg, 0.327 mmol) in a mixture of ethyl acetate (10 ml) and dichloromethane (9 ml). The reaction mixture is placed in an ultrasonic bath for 5 hours. The reaction mixture is filtered, the solvents are evaporated and the crude product is purified by chromatography to yield 50.0 mg (yield-50.3%) of (4-(4-methylpiperazine-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzaldehyde in the form of a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][NH2:8].[CH3:9][NH:10][S:11]([C:14]1[CH:15]=[C:16]([C:24](Cl)=[O:25])[C:17]2[O:22][CH2:21][CH2:20][O:19][C:18]=2[CH:23]=1)(=[O:13])=[O:12].O>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][NH:8][C:24]([C:16]1[C:17]2[O:22][CH2:21][CH2:20][O:19][C:18]=2[CH:23]=[C:14]([S:11](=[O:13])(=[O:12])[NH:10][CH3:9])[CH:15]=1)=[O:25]
Reactant: CN1CCCC1CN
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Solvent: ClC(Cl)Cl
Solvent: O
Product: CNS(=O)(=O)c1cc2c(c(C(=O)NCC3CCCN3C)c1)OCCO2
Yield: 78.5 %

Procedure:
61 g of dextrorotatory 1-methyl-2-aminomethyl-pyrrolidine, 465 ccm of chloroform and, in portions, 155 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride, with the temperature being maintained at 5°-10° C., were introduced into a balloon flask provided with an agitator and a thermometer. After agitation of the mixture and the addition of 1,850 cm3 of water, chloroform was distilled and the remaining solution was filtered. The base was precipitated by the addition of 65 cm3 of 20% ammonia. The crystals formed were dried off, washed and dried. 154 g of dextrorotatory-N-(1-methyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 187°-188° C.; yield: 78.5%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]6[CH2:45][CH2:46][CH2:47][CH2:48][C:43]6=[N:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]6[CH2:45][CH2:46][CH2:47][CH2:48][C:43]6=[N:42][CH:41]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cnc5n4CCCC5)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cnc5n4CCCC5)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)methyl]thio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (460 mg) in dichloromethane (10 ml) was added a solution of 3-chloroperbenzoic acid (70%, 0.25 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., an aqueous solution of sodium thiosulfate was added to the mixture and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, and dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate:hexane 9:1→ethyl acetate), and was recrystallized from ethyl acetate-diisopropyl ether, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 405) (311.3 mg) as yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[N:7]=1.Br[C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([F:34])[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>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.O>[F:34][C:27]1[CH:26]=[C:25]([C:2]2[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[N:14]=[CH:13][CH:12]=3)[N:7]=2)[CH:33]=[CH:32][C:28]=1[C:29]([OH:31])=[O:30]
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: COc1ccc2c(OCCn3nc(Cl)ccc3=O)ccnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(OCCn3nc(-c4ccc(C(=O)O)c(F)c4)ccc3=O)ccnc2c1
Reaction time: 0.33 h
Yield: 65.1 %

Procedure:
To a 5 ml CEM microwave tube was added 6-chloro-2-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridazin-3(2H)-one (0.1 g, 0.3 mmol), 4-bromo-2-fluorobenzoic acid (0.08 g, 0.5 mmol), sodium carbonate (0.10 g, 0.9 mmol), dichlorobis(triphenylphosphine)-palladium(II) (30 mg, 0.05 mmol), and DMF (4 mL)-water (0.4 mL). The vial was sealed and placed in CEM microwave for 20 min at 130° C., with 100 Watts of power via Powermax. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried over MgSO4 and concentrated (toluene was added in order to removed most of DMF). The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-026, 12 g SiO2, isocratic 5% MeOH in DCM with 1% AcOH, Flow=30 mL/min). The peak at 30 min was collected to afford the desired product as white solid (85 mg). MS (ESI pos. ion) m/z (M+1): 436.2. Calc'd exact mass for C23H18FN3O5: 357.41. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.86 (s, 3 H) 4.70 (s, 4 H) 6.96-7.04 (m, 2 H) 7.13 (d, J=9.79 Hz, 1 H) 7.25-7.30 (m, 1 H) 7.69-7.73 (m, 1 H) 7.75 (s, 1 H) 7.86 (s, 1 H) 7.87-7.95 (m, 2 H) 8.12 (d, J=9.79 Hz, 1 H) 8.64 (d, J=5.26 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[O:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:13]([S:12][C:8]1[C:6]2[N:7]=[C:2]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccco4)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(SCc4ccco4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(furfuryl-thio)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 173°-175° C.) and piperazine.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]([C:17](=O)[CH2:18][CH3:19])[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([O-:3])=[O:2].[BH4-].[Na+].O.[NH3:24]>N.C(O)C.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[NH2:24][CH:17]([C:15]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([N+:1]([O-:3])=[O:2])[CH:16]=1)[CH2:18][CH3:19]
Reactant: CCC(=O)c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reactant: N
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC(N)c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reaction time: 6 h

Procedure:
Tert-butyl 2-nitro-4-propionylbenzoate (9.2 g) was suspended in 2N ammonia/ethanol solution (81 ml), then tetraisopropoxytitanium (18.7 ml) was added at room temperature and the mixture was stirred at that temperature for 6 hours. Next, sodium borohydride (1.8 g) was added to the mixture, and the resulting mixture was stirred at that temperature for 16 hours. Then 2.1N ammonia water (81 ml) and Celite (9g) were added to the reaction solution and the inspluble materials were filtered off and washed with water and ethyl acetate. The filtrate was concentrated in vacuo, then a 5N aqueous sodium hydroxide solution and ethyl acetate were added to the obtained residue. The separated organic layer was concentrated in vacuo, then the obtained residue was purified by silica gel column chromatography to obtain the title compound (7.6 g) as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[CH:22]=[C:21]([Cl:28])[CH:20]=2)[C:12]=1[F:29])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[CH:22]=[C:21]([Cl:28])[CH:20]=2)[C:12]=1[F:29])=[O:8]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C3CC3)c2)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(Cl)c(Oc2cc(Cl)cc(C3CC3)c2)c1F)c1[nH]cnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-chloro-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (94 mg, 0.161 mmol) in DCM (6 ml) was added TFA (3.0 ml) and the reaction mixture was stirred at rt for 1 hour. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-({4-chloro-3-[(3-chloro-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (45 mg, 0.099 mmol, 62% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.70 (s, 1H), 7.25-7.39 (m, 2H), 6.76 (s, 1H), 6.56 (s, 1H), 6.53 (s, 1H), 4.63 (s, 2H), 1.67-2.00 (m, 1H), 0.96 (dd, 2H), 0.63 (dd, 2H). LC-MS (ES+) m/z 454.02, [M+H].
Reaction SMILES: Br[CH2:2][C:3]([O:5]C)=[O:4].[CH2:7]([O:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][NH:21][C:20](=[O:24])[N:19]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:7]([O:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][N:21]([CH2:2][C:3]([OH:5])=[O:4])[C:20](=[O:24])[N:19]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Nc1cc[nH]c(=O)n1)OCc1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)Cn1ccc(NC(=O)OCc2ccccc2)nc1=O
Temperature: 0 °C

Procedure:
In a three-necked round bottom flask equipped with mechanical stirring and nitrogen inlet was placed methyl bromacetate (7.82 mL, 82.6 mmol) and a suspension of N4 -benzyloxycarbonyl-cytosine (9, 21 g, 82.6 mmol) and potassium carbonate (11.4 g, 82.6 mmol) in dry DMF (900 mL). The mixture was stirred vigorously overnight, filtered, and evaporated to dryness, in vacuo. Water (300 mL) and 4N hydrochloric acid (10 mL) were added, the mixture was stirred for 15 minutes at 0° C., filtered, and washed with water (2×75 mL). The isolated precipitate was treated with water (120 mL), 2N sodium hydroxide (60 mL), stirred for 30 minutes, filtered, cooled to 0° C., and 4N hydrochloric acid (35 mL) was added. The title compound was isolated by filtration, washed thoroughly with water, recrystallized from methanol (1000 mL) and washed thoroughly with ether. This afforded 7.70 g (31%) of pure title compound. The mother liquor from recrystallization was reduced to a volume of 200 mL and cooled to 0° C. This afforded an additional 2.30 g of a material that was pure by tlc but had a reddish color. M.p. 266°-274° C. Anal. for C14H13N3O5. Found(calc.); C: 55.41 (55.45); H: 4.23(4.32); N: 14.04(13.86). 1H-NMR (90 MHz; DMSO-d6): 8.02 ppm (d,J=7.32 Hz, 1H, H-6); 7.39 (s, 5H, Ph); 7.01 (d, J=7.32 Hz, 1H, H-5); 5.19 (s, 2H, PhCH2 --); 4.52 (s, 2H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2)(=[O:3])[CH3:2].[Se](=O)=[O:20]>O1CCOCC1.O>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH:18]=[O:20])[CH:14]=[CH:13]2)(=[O:3])[CH3:2]
Reactant: O=[Se]=O
Reactant: CC(=O)OCCOc1cccc2ccc(C)nc12
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OCCOc1cccc2ccc(C=O)nc12
Yield: 96.4 %

Procedure:
To a solution of 2-(2-methylquinolin-8-yloxy)ethyl acetate (0.29 g, 1.2 mmol) in dioxane (20 mL) and water (0.20 mL) was added selenium dioxide (0.16 g, 1.4 mmol) and the resultant mixture heated at reflux for 2 hours. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane. The filtrate was concentrated under reduced pressure and purified by normal phase chromatography on silica gel (10-20% ethyl acetate/hexanes) to afford the title compound (0.30 g, 99%).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[H-].[Na+].[CH:15](Br)=[CH:16][C:17](=[CH2:19])[CH3:18]>>[CH:15]([N:6]1[C:5](=[O:12])[O:4][C:2](=[O:3])[C:1]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:7]12)=[CH:16][C:17](=[CH2:18])[CH3:19]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: C=C(C)C=CBr
Agent: [H-]
Agent: [Na+]
Product: C=C(C)C=Cn1c(=O)oc(=O)c2ccccc21

Procedure:
Reagents: Isatoic anhydride (6.13 mmols, 1 g); Sodium hydride (9.2 mmols, 0.23 g); Isoprenyl bromide (12 mmols, 1.9 g). Yield: 0.95 g (67%), white solid, m.p.=119° C.-120° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7]4=[C:8]([C:17](=[O:21])[NH:18][C:19](=[S:20])[N:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3.FC(F)(F)C1C=CC2SC3C4=C(C(=O)NC(=[O:43])N4C=2C=1)C=CC=3>>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:16]=[CH:15][C:14]2[S:13](=[O:43])[C:12]3[C:7]4=[C:8]([C:17](=[O:21])[NH:18][C:19](=[S:20])[N:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3
Reactant: O=c1[nH]c(=O)n2c3c(cccc13)Sc1ccc(C(F)(F)F)cc1-2
Reactant: O=c1[nH]c(=S)n2c3c(cccc13)Sc1ccc(C(F)(F)F)cc1-2
Product: O=c1[nH]c(=S)n2c3c(cccc13)S(=O)c1ccc(C(F)(F)F)cc1-2

Procedure:
When an equivalent amount of 10-trifluoromethyl-1H-pyrimido[5,4,3-kl]phenothiazine-3-one-1(2H)-thione is substituted in the procedure of Example 6 for 10-trifluoromethyl-1H-pyrimido[5,4,3-kl]phenothiazine-1,3(2H)-dione, the title compound is obtained.
Reaction SMILES: [Mg].ClC1C=CC(C=CC)=CC=1.II.Cl[C:15]1[CH:23]=[CH:22][C:18]([C:19]([CH3:21])=[CH2:20])=[CH:17][CH:16]=1.Cl[Si:25]([CH3:28])([CH3:27])[CH3:26]>C1COCC1.O>[CH3:26][Si:25]([CH3:28])([CH3:27])[C:15]1[CH:23]=[CH:22][C:18]([C:19]([CH3:21])=[CH2:20])=[CH:17][CH:16]=1
Reactant: C=C(C)c1ccc(Cl)cc1
Reactant: C[Si](C)(C)Cl
Agent: CC=Cc1ccc(Cl)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)c1ccc([Si](C)(C)C)cc1
Temperature: 40 °C

Procedure:
Placing 2 g (83 mmol) of dry magnesium into a 250 mL flask equipped with a condenser, a dropping funnel and a magnetic stirrer, the reaction was carried out in a nitrogen atmosphere. The magnesium was initially activated by adding 1 mL of p-chloro-methylstyrene (Aldrich, Germany) with 0.5 g iodine in 5 mL THF at 50° C. for a period of 30 minutes. Into the mixture a solution of 11 g (72 mmol) of p-chloro-α-methylstyrene in 50 mL THF was dropped over a period of 12 hours under reflux. The reaction mixture was cooled to 40° C., then 7.8 g (72 mmol) of chlorotrimethylsilane (Fluka, Japan) in 30 mL of THF were added dropwise and reacted for 24 hours. After the reaction was completed, a large amount of water was added and the reaction mixture was extracted with ether. The ether layer was dried over magnesium sulfate, and distilled under reduced pressure, bp 66°-67° C./2 mmHg. Yield, 56%. The colorless liquid crude product was purified by column chromatography, which was performed on silica gel using n-hexane as an eluent. The product was identified by IR and 1H-NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[C:26]([S:28]([CH3:30])=[O:29])[N:27]=2)[C:21](OC)=[O:22])[CH2:14][CH2:13]1)=[O:10].[OH-].[Li+].Cl.Cl.[CH3:35][O:36][NH2:37]>C1COCC1>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[C:26]([S:28]([CH3:30])=[O:29])[N:27]=2)[C:21]([NH:37][O:36][CH3:35])=[O:22])[CH2:16][CH2:17]1)=[O:10]
Reactant: COC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(S(C)=O)c1
Reactant: CON
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(S(C)=O)c1
Reaction time: 0.75 h

Procedure:
Methyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-6-(methylsulfinyl)isonicotinate (Example 334; 200 mg, 0.422 mmol) was dissolved in anhydrous THF (5 ml) and treated with 2 N lithium hydroxide (10 ml) with stirring for 45 minutes. The mixture was cooled in an ice bath and acidified with 1 N HCl. The aqueous solution was extracted with EtOAc. The organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo to give the acid derivative as a brown solid (LCMS showed a peak of 459). This acid (95 mg, 0.207 mmol) was treated with methoxyamine hydrochloride (17.3 mg, 0.207 mmol) in a manner analogous to Example 8 to afford the title compound. (30 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][CH2:9][NH:10][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NCCc1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCc1cccc(F)c1)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 250-mL, round-bottomed flask containing a solution of 2-(3-fluorophenyl)ethanamine (1.3 mL, 9.6 mmol) and diisopropylethylamine (1.7 mL, 9.6 mmol) in dichloromethane (32 mL) was cooled to 0° C. and treated dropwise with 4-(trifluoromethyl)benzoyl chloride (2.0 mL, 9.6 mmol) over 5 min. The ice-bath was removed after 2 h and the reaction mixture was stirred overnight. The precipitate formed was collected by filtration. The filtrate was diluted with dichloromethane (100 mL) and transferred to a separatory funnel and extracted with water (35 mL). The dichloromethane layer was separated and formation of precipitate was observed which was collected by filtration. The filtrate was concentrated to yield more solid and the combined solids were dried under vacuum to yield N-(3-fluorophenethyl)-4-(trifluoromethyl)benzamide as a white solid. MS (ESI pos. ion) m/z: 312 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:20])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3)c1)=N2

Procedure:
Compound 4 was prepared from {5-dimethylamino-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (M1) (306 mg, 0.56 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (162 mg). MS (ISP) 425.4 [(M+H)+]; mp 204° C.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][N:5]1[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][NH:8][C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]1=2.O.[OH-].[Li+]>CO.O>[C:17]1([CH2:16][CH2:15][C:14]([NH:13][C@@H:10]2[C:11](=[O:12])[N:5]([CH2:4][C:3]([OH:28])=[O:2])[C:6]3[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=3[NH:8][CH2:9]2)=[O:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)CCc2ccccc2)CNc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CN1C(=O)[C@@H](NC(=O)CCc2ccccc2)CNc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
(3(S)-(3-Phenylpropionylamino)-2-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)acetic acid methyl ester (104a) was dissolved in 90% methanol. Lithium hydroxide hydrate was added to the reaction and the reaction was stirred at room temperature for 4 h. The reaction was evaporated in vacuo to give a white solid. This was dissolved in 20 ml of water and acidified to pH 5 and extracted with ethyl acetate to afford 304 mg (88%) of the title compound as a white solid. 1H NMR (CDCl3) δ7.5-6.9 (11H, m), 4.92-4.8 (1H, m), 4.7-4.58 (1H, d), 4.38-4.25 (1H, d), 3.88-3.78 (1H, m), 3.45-3.25 (1H, m), 3.05-2.85 (2H, m), 2.55-2.45 (2H, m). 4-Oxo-3(S)-{2-[2-oxo-3(S)-(3-phenylpropionylamino)-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-ylacetylamino}butyric acid (106a). N-[1-(2-Benzyloxy5-oxotetrahydrofuran-3-ylcarbamoyl-methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-3-phenylpropionamide was prepared from 105a by the procedure used to prepare compound H (stepA) to afford 390 mg (93%) of the product as diastereomers. 1H NMR (CD3OD) δ7.58-7.22 (14H, m), 5.78-5.73 (0.5 H, d), 5.64 (0.5 H, s), 5.0-4.72 (4H, m), 4.54-4.42 (2H, m), 3.82-3.76 (0.5 H, m), 3.68-3.62 (o.5 H, m), 3.28-3.21 (0.5H, m), 3.19-3.12 (0.5H, m), 3.07-2.98 (2H, m), 2.78-2.48 (4H, m).