Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1([C:17]([NH:19][C@H:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:21][CH2:22][OH:23])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl[C:32]1[N:37]=[CH:36][N:35]=[C:34]2[NH:38][N:39]=[CH:40][C:33]=12>C(O)CCC.CCOC(C)=O>[NH2:10][C:11]1([C:17]([NH:19][C@H:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:21][CH2:22][OH:23])=[O:18])[CH2:16][CH2:15][N:14]([C:32]2[N:37]=[CH:36][N:35]=[C:34]3[NH:38][N:39]=[CH:40][C:33]=23)[CH2:13][CH2:12]1
Reactant: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCNCC1
Reactant: Clc1ncnc2[nH]ncc12
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ncc23)CC1
Temperature: 60 °C
Reaction time: 6 h
Yield: 32.6 %

Procedure:
DIPEA (0.419 mL, 2.41 mmol) was added to (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamide (Intermediate 49) (250 mg, 0.80 mmol) and 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (124 mg, 0.80 mmol) in butan-1-ol (5 mL). The resulting solution was stirred at 60° C. for 6 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 6% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness and triturated with diethyl ether to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidine-4-carboxamide (112 mg, 32.5%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=[O:14].[H-].[Na+].Br[CH2:21][CH3:22].Cl>CN(C=O)C.CCO.[OH-].[Na+].O>[CH2:21]([NH:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=[O:14])[CH3:22]
Reactant: CCBr
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CCNc1c(C(=O)O)cnn1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
To a solution of ethyl 5-amino-1-phenyl-1H-pyrazole-4-carboxylate (10 g, 43 mmol) in DMF (100 mL) at 0° C. was slowly added sodium hydride (60% dispersion, 1.9 g, 47.6 mmol). After the evolution of gas had ceased, bromoethane (3.55 mL, 47.6 mmol) was added dropwise. The reaction was stirred at 0° C. for 2 hour, then gradually warmed to RT. Water was added to the reaction, resulting in the formation of a precipitate which was collected by filtration and used directly in the next step. The material thus obtained was dissolved in EtOH (50 mL) along with 3N NaOH (38 mL) and the solution was heated to reflux overnight. The reaction was cooled to 0° C. and the pH was slowly adjusted to between 3-4 using 1N HCl. The resulting white precipitate was collected by filtration and recrystallized from acetonitrile to afford 5-(ethylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid (6.6 g, 28.6 mmol). The compound had an HPLC retention time=2.32 min. CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.2% H3PO4; Solvent B=90% MeOH, 10% H2O, 0.2% H3PO4. LC/MS M+1=232.3. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.89 (t, J=7.2 Hz, 3H), 2.77 (m, 2H), 6.14 (br. s, 1H), 7.43 (m, 1H), 7.52 (m, 4H), 7.72 (s 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:14]([NH:22][C:23]1[CH:35]=[C:34]([CH:36]=[CH2:37])[CH:33]=[CH:32][C:24]=1[C:25]([O:27]C(C)(C)C)=[O:26])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:14]([NH:22][C:23]1[CH:35]=[C:34](/[CH:36]=[CH:37]/[C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:33]=[CH:32][C:24]=1[C:25]([OH:27])=[O:26])(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Reactant: Brc1cccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(/C=C/c2cccnc2)ccc1C(=O)O)c1ccccc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
0.030 mL of 3-bromopyridine, 0.10 g of cesium carbonate, 15 mg of tetrabutylammonium bromide and 24 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) were added to 1.0 mL of toluene solution containing 50 mg of tert-butyl 2-(benzamido)-4-vinylbenzoate at room temperature and stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, 24 mg of polymer supported bis(acetato)triphenylphosphine palladium(11) was added and stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. 10 mL of trifluoroacetic acid was added to the obtained residue and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the obtained residue was purified with reversed-phase silica gel column chromatography [eluent; 40-90% acetonitrile/0.1% trifluoroacetic acid aqueous solution]. Ethyl acetate and water were added to the obtained purified substance and pH was adjusted to pH 6.0 with a saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with water, and the solvent was evaporated under reduced pressure to obtain 2.3 mg of 2-(benzamido)-4-((E)-2-(pyridin-3-yl)vinyl)benzoic acid as white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:25]=O)=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].Cl.[NH2:28][OH:29].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH:25]=[N:28][OH:29])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: NO
Reactant: COC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)NC(C=NO)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of dimethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (3.6 g), hydroxylamine hydrochloride (764 mg) and sodium acetate (1.06 g) in acetic acid (20 ml) was stirred at room temperature for 45 minutes to form dimethyl 2-methyl-4-(2-nitrophenyl)-6-hydroxyliminomethyl-1,4-dihydropyridine-3,5-dicarboxylate. To the reaction mixture was added acetic anhydride (3.37 g) and the mixture was stirred at room temperature for 15 minutes and then heated at 100° C. for 3 hours with stirring. After removal of the acetic acid, the residue was adjusted to pH 7.5 with an aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed twice with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The resultant oil (3.80 g) was chromatographed on a column of silica-gel (110 g) and eluted with a mixture of benzene and ethyl acetate (9:1, v/v) to give crystals (2.05 g), which were recrystallized from a mixture of ethyl acetate (12 ml) and n-hexane (6 ml) to give yellow granules of dimethyl 2-methyl-4-(2-nitrophenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate (1.19 g), mp 170.5° to 171.5° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([CH:34]=[O:35])[CH2:22][C:23](=[N:29][NH:30][C:31]([NH2:33])=[O:32])[O:24]C(C)(C)C)=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12].C(Cl)Cl.C(O)(C(F)(F)F)=O.CCOCC>C1(OC)C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([CH:34]=[O:35])[CH2:22][C:23](=[N:29][NH:30][C:31]([NH2:33])=[O:32])[OH:24])=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12]
Reactant: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Solvent: CCOCC
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)N[C@H](C=O)CC(O)=NNC(N)=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
(3S)-3-[(1-Methylindole-2-carbonyl)valinyl]amino-4-oxobutanoic acid, t-butyl ester semicarbazone (170 mg, 0.36 mmol) was dissolved in anisole (0.2 mL) and methylene chloride (2 mL) and the resulting solution was treated with TFA (1 mL). The resulting solution was stirred for 3.5 hours under a nitrogen atmosphere at room temperature. The reaction mixture was concentrated in vacuo and chased with methylene chloride to give a purple foam. Trituration of the foam with ether afforded the title product as a solid purple powder (133 mg, 89%).
Reaction SMILES: [N:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[N:3][C:2]=1[S:14][CH2:15][C:16]([OH:18])=O.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:49][CH2:50][CH:51]1[CH2:55][CH2:54][N:53]([CH2:56][C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([Cl:64])[CH:58]=2)[CH2:52]1>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:64][C:59]1[CH:58]=[C:57]([CH:62]=[CH:61][C:60]=1[Cl:63])[CH2:56][N:53]1[CH2:54][CH2:55][CH:51]([CH2:50][NH:49][C:16](=[O:18])[CH2:15][S:14][C:2]2[N:3]=[N:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:12][C:13]=3[N:1]=2)[CH2:52]1
Reactant: NCC1CCN(Cc2ccc(Cl)c(Cl)c2)C1
Reactant: O=C(O)CSc1nnc2c(n1)[nH]c1ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CSc1nnc2c(n1)[nH]c1ccccc12)NCC1CCN(Cc2ccc(Cl)c(Cl)c2)C1
Reaction time: 14 h

Procedure:
Solid (9H-1,3,4,9-tetraazafluoren-2-ylsulfanyl)acetic acid (390 mg, 1.5 mmol, 1.2 equiv.) was added to a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (360 mg, 1.9 mmol, 1.5 equiv.), 1-hydroxybenzotriazole hydrate (260 mg, 1.9 mmol, 1.5 equiv.) and triethylamine (0.65 mL, 4.6 mmol, 3.7 equiv.) in chloroform (10 mL). 3-(RS)-Aminomethyl-1-(3,4-dichlorobenzyl)pyrrolidine (320 mg, 1.2 mmol) was added and the suspension was made homogeneous upon addition of dimethylformamide (5 mL). The brown solution was stirred for 14 h, then concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1 M sodium hydroxide. The organic phase was concentrated to dryness and the residue purified by chromatography (5→10% methanol in CHCl3) to provide N-[1-(3,4-dichlorobenzyl)-pyrrolidin-3-(RS)-ylmethyl]-2-(9H-1,3,4,9-tetraazafluoren-2-ylsulfanyl)acetamide as a pale yellow solid. The solid was dissolved into 4 M HCl in dioxane (1 mL) and the mixture concentrated under vacuum to afford pure product as its hydrochloride salt (250 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[CH2:10][C:11]1([CH2:27][CH3:28])[CH2:16][CH2:15][N:14]([C:17]2[S:18][C:19]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:13][CH2:12]1.O.[OH-].[Na+]>O1CCCC1>[Cl:26][C:24]1[CH:23]=[CH:22][C:20]2[N:21]=[C:17]([N:14]3[CH2:15][CH2:16][C:11]([CH2:10][CH2:9][OH:8])([CH2:27][CH3:28])[CH2:12][CH2:13]3)[S:18][C:19]=2[CH:25]=1
Reactant: CCC1(CC(=O)OC)CCN(c2nc3ccc(Cl)cc3s2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC1(CCO)CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
Lithium aluminium hydride (202 mg) was suspended in tetrahydrofuran (10 mL). A solution of [1-(6-chlorobenzothiazole-2-yl)-4-ethyl piperidine-4-yl]acetic acid methyl ester (940 mg) in tetrahydrofuran (10 mL) was added thereto at 0° C. After stirring at 0° C. for 1 hour, to the reaction solution were sequentially added water (0.2 mL), 10% sodium hydroxide (0.2 mL) and water (0.6 mL). The insoluble material was filtrated and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (790 mg). Yield: 91%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:11]=3[C:10]2=[O:25])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(C(C)C)CC)(C)C.Cl.[NH2:36][OH:37]>C(O)C>[OH:37][N:36]=[C:1]([NH2:2])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:11]=3[C:10]2=[O:25])[CH:4]=1
Reactant: NO
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C#N)c1)C2=O
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(N)=NO)c1)C2=O
Yield: 96 %

Procedure:
(S)-5-(3-Cyanophenyl)-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (2.00 g, 5.69 mmol) obtained in Step 1 of Example 71 was suspended in ethanol (30 mL), and the mixture was refluxed for 5 hours after adding diisopropylethylamine (1.90 mL, 10.9 mmol) and hydroxylamine hydrochloride (761 mg, 10.9 mmol). After concentrating the mixture under reduced pressure, water was added to the resulting residue, and the precipitated white solid was filtered off to give (S)—N′-hydroxy-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzamidine (2.10 g, 96%).
Reaction SMILES: Cl[S:2]([NH:5][C:6](=[O:9])[O:7][CH3:8])(=[O:4])=[O:3].[Cl:10][C:11]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([Cl:22])[C:12]=1[NH2:13].C(N(CC)CC)C.O>C(Cl)Cl>[Cl:10][C:11]1[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:15]=[C:14]([Cl:22])[C:12]=1[NH:13][S:2]([NH:5][C:6](=[O:9])[O:7][CH3:8])(=[O:4])=[O:3]
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: COC(=O)NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)NS(=O)(=O)Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: -20 °C
Reaction time: 12 h

Procedure:
Methyl chlorosulfonylcarbamate (27.90 g, 0.16 mol) was dissolved in CH2Cl2 (100 mL) and cooled to −20° C. To the solution of methyl chlorosulfonylcarbamate, was dropwisely added 2,6-dichloro-4-(trifluoromethyl)aniline (2.50 g, 10.7 mmol) and triethylamine (2.53 g, 32.1 mmol) in CH2Cl2 (70 mL) and agitated for 12 hr at room temperature. The reaction mixture was added with water (100 mL) for extraction to obtain the organic layer. The resultant was dried over MgSO4, concentrated under reduced pressure, and purified by column chromatography (hexane:ethyl acetate=7:3), giving the compound of interest (2.11 g, 6%, yellow solid). 1H NMR (300 MHz, CDCl3): δ 7.57 (s, 2H), 3.84 (s, 3H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:34][CH2:35]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: COc1cc(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)nc(C)nc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f59) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][N:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][CH:18]([NH:33][C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[O:44])[CH:38]=2)=[O:35])[C:17]1=[O:50])=[O:14])(C)(C)C.C(Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:49][S:46]([NH:45][C:43]([C:39]1[CH:38]=[C:37]([NH:36][C:34](=[O:35])[NH:33][CH:18]2[C:17](=[O:50])[N:16]([CH2:15][C:13]([OH:14])=[O:12])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:19]2)[CH:42]=[CH:41][CH:40]=1)=[O:44])(=[O:47])=[O:48]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(NC(=O)Nc2cccc(C(=O)NS(C)(=O)=O)c2)CN(c2ccccc2)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cccc(NC(=O)NC2CN(c3ccccc3)c3ccccc3N(CC(=O)O)C2=O)c1
Yield: 62.2 %

Procedure:
Trifluoroacetic acid (0.32 ml) was added to a solution of 1-(1-tert-butoxycarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-methylsulfonylaminocarbonylphenyl)urea (400 mg) obtained from example 16 in anhydrous 1,2-dichloroethane (10 ml), the mixture was refluxed for 5 hours. Methylene chloride (30 ml) and saturated aqueous sodium bicarbonate were added to the reaction mixture and separated into organic layer and aqueous layer, the aqueous layer was adjusted to pH 2 with 1N hydrochloric acid, and extracted with ethyl acetate. The extraction was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Isopropyl ether was added to the residue for trituration and filtrated, to thereby obtain 226 mg of the title compound as a yellow solid (Yield: 64.0%).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:12]([CH2:13][CH2:14]Cl)=[C:11](Cl)[C:10]2[C:5](=[C:6]([O:17][CH3:18])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([CH3:28])[CH:22]=1>CC(O)C>[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([N:25]2[C:11]3[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([O:17][CH3:18])[C:5]=4[N:4]=[C:3]([CH3:2])[C:12]=3[CH2:13][CH2:14]2)=[C:23]([CH3:28])[CH:22]=1
Reactant: COc1cccc2c(Cl)c(CCCl)c(C)nc12
Reactant: COc1ccc(N)c(C)c1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(N2CCc3c(C)nc4c(OC)cccc4c32)c(C)c1
Yield: 18.9 %

Procedure:
A mixture of 2-methyl-3-(2-chloroethyl)-4-chloro-8-methoxyquinoline hydrochloride (15.33 g, 50 mmol), 4-methoxy-2-methylaniline (9.0 ml. 70 mmol) and 2-propanol (200 ml) was heated at reflux for 2 days, then evaporated. The crude product was triturated with ether then recrystallised twice from aqueous ethanol to give the title compound (3.16g), m.p. 163°-167°.
Reaction SMILES: C(OC(O)[CH2:5][C:6]([F:9])([F:8])[F:7])C.[CH3:11][C@@H:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:13]1([C@H:12]([N:19]=[CH:5][C:6]([F:7])([F:8])[F:9])[CH3:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(O)CC(F)(F)F
Reactant: C[C@@H](N)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C[C@@H](N=CC(F)(F)F)c1ccccc1
Reaction time: 3 h

Procedure:
To solution of (trifluoromethyl)acetaldehyde ethyl hemiacetal (1.2 equiv.) in toluene is added (R)-(+)-α-methylbenzylamine (1 equiv.) and catalytic amount of p-toluenesulfonic acid. The solution is heated at reflux under a Dean-Stark apparatus. After 3 hr, the reaction flask is fitted with a short-path condenser and the reaction contents were fractionally distilled to give the title compound as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:30])[CH2:14][O:15][C:16]1[CH:17]=[C:18]([C:26]([O:28][CH3:29])=[O:27])[C:19](=[CH:24][CH:25]=1)[C:20]([O:22][CH3:23])=[O:21].C1C=CC=CC=1.[BH4-].[Na+]>CO>[CH3:29][O:28][C:26]([C:18]1[CH:17]=[C:16]([CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])[O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4])[CH3:30])=[O:27]
Reactant: COC(=O)c1ccc(OCC(C)=O)cc1C(=O)OC
Reactant: NCC(O)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1C(=O)OC

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 3.73 g of dimethyl 4-(2-oxopropoxy)phthalate (prepared as described in Preparation 54), 70 ml of benzene, 60 ml of absolute methanol and 1.32 g of sodium borohydride, the title compound was obtained having an Rf=0.29 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([S:15]([NH2:18])(=[O:17])=[O:16])[O:12][C:13]=2[CH3:14])=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:36])[CH2:33][CH2:34][CH3:35]>ClCCl.CN(C)C1C=CN=CC=1>[C:32]([NH:18][S:15]([C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:4]2[CH:3]=[CH:2][C:1]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:6][CH:5]=2)[CH:10]=1)(=[O:17])=[O:16])(=[O:36])[CH2:33][CH2:34][CH3:35]
Reactant: CCCC(=O)Cl
Reactant: Cc1oc(S(N)(=O)=O)cc1COc1ccc(-c2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)NS(=O)(=O)c1cc(COc2ccc(-c3ccccc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
To a stirred solution of 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid amide (45) (50 mg, 0.146 mmoles) in dichloromethane (5.0 ml) was added triethylamine (26 μl, 0.189 mmoles), dimethyl-pyridin-4-yl-amine (1 mg) and butyryl chloride (19 μl, 0.184 mmoles). After stirring for 16 hours at room temperature the reaction mixture was concentrated in-vacuo, and the residue was purified by HPLC to give compound 61 as an off-white solid (48 mg). LC/MS System C: Rt=3.82 mins, m/z (ES−)=412 (M−H) for C22H23NO5S).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]=[N:8][C:7]([O:19][CH3:20])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:21]=1.CI.O.[CH2:25](OCC)C>CN(C)C=O.[H-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:25])[C:10](=[O:12])[CH:9]=[N:8][C:7]([O:19][CH3:20])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:21]=1
Reactant: CCOCC
Reactant: COC1(c2ccccc2)N=CC(=O)Nc2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC1(c2ccccc2)N=CC(=O)N(C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7-chloro-5-methoxy-5-phenyl-1,5-dihydro-2H-1,4-benzodiazepin-2-one (600 mg) in dry dimethylformamide (2 ml), sodium hydride (50% suspension in a mineral oil; 106 mg) is added under ice-cooling, and the resultant mixture is stirred at room temperature for 10 minutes. Methyl iodide (740 mg) is added to the mixture, which is stirred at room temperature for 5 minutes. The reaction mixtute is poured into icy water and shaken with diethyl ether. The organic layer is washed with water, dried over sodium sulfate, and evaporated to remove the solvent. The residue is crystallized from isopropyl ether to give 7-chloro-5-methoxy-1-methyl-5-phenyl-1,5-dihydro-2H-1,4-benzodiazepin-2-one (381 mg) as colorless prisms melting at 146.5 to 147° C.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:19])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C:6]1=[O:18].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(#N)C.C(OCC)(=O)C>[Cl:1][CH2:2][C:3](=[O:19])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:7][C:6]1=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(O)CCl)C(=O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)CCl)C(=O)C1
Reaction time: 3 h
Yield: 18.3 %

Procedure:
In a 125 ml round-bottom flask equipped with a magnetic stirrer tert-butyl 4-(3-chloro-2-hydroxypropyl)-3-oxopiperazine-1-carboxylate (3.30 g, 11.3 mmol) was dissolved in acetonitrile (10 ml) and Dess-Martin periodinane (5.26 g, 12.4 mmol) was added. After agitating for 3 hours the mixture was diluted with ethyl acetate (100 ml) and washed with sodium bicarbonate and brine, dried and evaporated. Purified by column chromatography and eluting with 3% MeOH/CH2Cl2 to give the title compound (0.600 g, 18.31% yield).