Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([NH:13][C:14]([O:16]C2C=CC=CC=2)=O)[CH:3]=1.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH2:34])(=[O:33])=[O:32])#[N:24]>>[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C:14]([NH:13][C:4]1[CH:3]=[C:2]([Cl:1])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:16])(=[O:33])=[O:32])#[N:24]
Reactant: N#Cc1ccccc1S(N)(=O)=O
Reactant: CCOC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Product: CCOC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccccc1C#N

Procedure:
As the starting substances, ethyl 4-chloro-2-phenoxycarbonylaminobenzoate and 2-cyanobenzenesulfonamide were used and the same method was applied as in Example 36 to obtain N-(2-cyanobenzenesulfonyl)-N'-(2-ethyloxycarbonyl-5-chlorophenyl)urea and further to obtain from 1.52 g (3.73 mmol) of N-(2-cyanobenzenesulfonyl)-N'-(2-carboxyl-5-chlorophenyl)urea 810 mg of the above-identified compound (yield 60.1%). Properties: colorless crystal, Melting point: 160°-161° C., PMR (δppm, DMSO-d6):3.71 (3H,s), 6.61 (1H,s), 6.90 (1H,s), 7.12 (1H,s), 7.23 (1H,d), 7.72 (1H,s), 7.86 (1H,d), 11.59 (1H,br).
Reaction SMILES: [P:1]([OH:5])(O)(O)=[O:2].[C:6]1([CH:12]([NH2:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOCC.CC(C)=O>C(O)C>[CH:12]([NH:19][P:1]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:2])[OH:5])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=P(O)(O)O
Reactant: O=Cc1ccccc1
Solvent: CCOCC
Solvent: CCO
Solvent: CC(C)=O
Product: O=P(O)(Cc1ccccc1)NC(c1ccccc1)c1ccccc1
Reaction time: 2.5 h

Procedure:
A mixture of 24.95 g (100 mmole) of diphenylmethylamine orthophosphate in 75 ml of anhydrous ethanol is boiled under reflux with stirring. 200 mmole of benzaldehyde in solution in 24 ml of ethanol is added drop by drop in 30 min. The reaction is followed by HPLC. After 2.5 hours, the reaction is returned to ambient temperature. An Et2O/Acetone mixture (75 ml) is added to the mixture. The white precipitate obtained is filtered, washed with water (2×60 ml) and acetone (2×60 ml) and dried. White solid, 20.2 g (60.1%).
Reaction SMILES: O.C(O)(=O)C.[CH:6]([S:9][C:10]1[CH:15]=[C:14]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[Cl:27])[CH:13]=[CH:12][C:11]=1[N+:28]([O-])=O)([CH3:8])[CH3:7].C(SC1C=C(C2C(C(F)(F)F)=NNC=2)C=CC=1C(OC)=O)CC>C1(C)C=CC=CC=1.[Fe]>[Cl:27][C:17]1[CH:18]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:20]=[C:21]([Cl:22])[C:16]=1[C:14]1[CH:13]=[CH:12][C:11]([NH2:28])=[C:10]([S:9][CH:6]([CH3:8])[CH3:7])[CH:15]=1
Reactant: CC(C)Sc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: CCCSc1cc(-c2c[nH]nc2C(F)(F)F)ccc1C(=O)OC
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Sc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1N
Temperature: 25 °C
Yield: 36 %

Procedure:
3.5 g (63.6 mmol) of iron powder, 10 m of water and 1 m of acetic acid were stirred in 20 ml toluene at 60° C. for 30 minutes, and 3.0 g (7.3 mmol) of [5-(2,6-dichloro-4-trifluoromethylphenyl)-2-nitrophenyl] isopropyl sulfide (the compound prepared in Example 8 (2)) in 10 ml toluene was added dropwise. The reaction was carried out with reflux and heating for another 3 hours, and then the reaction mixture was cooled to room temperature. The insolubles were filtered off, and the filtrate was separated with water and toluene. The toluene layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 1.0 g of 4-(2,6-dichloro-4-trifluoromethylphenyl)-2-isopropylthioaniline (yield 36.0%) as a pale yellow dough (nD20 1.5782).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7]([OH:18])(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>[Pd]>[CH2:7]([O:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:2][CH2:3][O:18][CH2:7][CH3:8]
Reactant: CCCCCCCCCC(=O)O
Reactant: OCC(O)CO
Agent: [Pd]
Product: CCCCCCCCCCOCC(O)CO
Product: CCOCC
Temperature: 120 °C
Yield: 46 %

Procedure:
A stirred autoclave was charged, at room temperature, with 65.35 g (710 mmol) of glycerol, 3.01 g (17.5 mmol) of decanoic acid, 0.30 g (10 wt %) of AMBERLYST® (a polymer based catalyst) 35 resin and 0.39 g (1.0 mol %) of Pd/C at 5%. The autoclave was then pressurized at 50 bar of dihydrogen gas H2, and then it was heated at 120° C. for 16 h, stirring vigorously. After 16 h of reaction, the reaction mixture was brought back to room temperature. The catalyst was filtered on a MILLIPORE® filter (a membrane filter) (0.1 μm) and was rinsed with absolute ethanol. The solvents were evaporated and the organic products were extracted from the glycerol phase by extraction with CH2Cl2 (3×50 ml). The organic phase was washed with water (2×30 ml) and the CH2Cl2 was then evaporated at reduced pressure. The crude reaction product was purified on a flash silica column (eluent:cyclohexane/ethyl acetate=4:1˜1:1). 1-O-decanyl-glycerol ether was obtained at an isolated yield of 46%.
Reaction SMILES: C[Al](C)C.CO[C:7]([C:9]1[S:13][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)=[O:8].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH2:37][CH2:38][C:39]2[CH:40]=[C:41]([NH2:44])[NH:42][N:43]=2)[CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1>C1(C)C=CC=CC=1.CC(C)=O>[CH3:36][O:35][C:33]1[CH:32]=[C:31]([CH2:37][CH2:38][C:39]2[CH:40]=[C:41]([NH:44][C:7]([C:9]3[S:13][C:12]([N:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]4)=[CH:11][CH:10]=3)=[O:8])[NH:42][N:43]=2)[CH:30]=[C:29]([O:28][CH3:27])[CH:34]=1
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)s3)[nH]n2)cc(OC)c1
Temperature: 20 °C
Reaction time: 20 h
Yield: 50.2 %

Procedure:
2M Trimethylaluminium (1.250 ml, 2.50 mmol) in toluene, was added dropwise to a stirred solution of tert-butyl 4-(5-(methoxycarbonyl)thiophen-2-yl)piperazine-1-carboxylate (0.326 g, 1 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.247 g, 1.00 mmol) in toluene (7.14 ml) at 20° C. under nitrogen. The reaction mixture was stirred at 20° C. for 20 h. The temperature was increased to 60° C. and the reaction mixture was stirred for 20 h and then allowed to cool. The reaction mixture was diluted with acetone (10 ml) and quenched with damp solid sodium sulphite. The mixture was stirred for 30 mins, and then a solution of 10% methanol in DCM (10 mL) was added and the mixture stirred for a further 30 mins. The suspension was filtered and the solid washed with 10% methanol in DCM (20 mL); the combined filtrates were evaporated to give a yellow foam. The crude product was purified by silica column chromatography, eluting with a gradient of 1 to 10% 2M ammonia/methanol in DCM. Pure fractions were evaporated to dryness to afford the crude product. This was further purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford tert-butyl 4-[5-[[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]thiophen-2-yl]piperazine-1-carboxylate (0.272 g, 50.2%) as a white dry film.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[S:4]/[C:3]/1=[CH:12]\[C:13]([O:15][CH3:16])=[O:14].[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[S:4]/[C:3](=[CH:12]\[C:13]([O:15][CH3:16])=[O:14])/[C:2]1=[O:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)/C=C1\Sc2ccccc2NC1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C1\Sc2ccccc2N(Cc2ccccc2)C1=O
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Methyl (Z)-2-(3,4-dihydro-3-oxo-2H-1,4-benzothiazin-2-ylidene)acetate (940 mg) was dissolved in 8 ml of N,N-dimethylformamide, and the solution was added dropwise to a suspension of sodium hydride (60% in oil, 192 mg) in 2 ml of N,N-dimethylformamide. The mixture was stirred for 30 minutes. To the mixture was added dropwise a solution of 752 mg of benzyl bromide in 2 ml of N,N-dimethylformamide. The stirring was continued for an hour under ice-cooling, the reaction mixture was poured onto ice water, and extracted with ethyl acetate. Then, the ethyl acetate layer was washed with water. After the drying of the organic layer over anhydrous magnesium sulfate, the solvent was distilled off. The resulting oily matter was solidified in isopropyl etherhexane to give 1.04 g of methyl (Z)-2-(4-benzyl-3,4-dihydro-3-oxo-2H-1,4-benzothiazin-2-ylidene)acetate as yellow powder. The structural formula and physical data of this compound are shown in Table 14.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[Cl:9][C:10]1(C)[CH:15]=[CH:14][CH:13]=[CH:12][NH:11]1.[CH2:17]([O:19][C:20](=[O:24])OCC)[CH3:18].[NH4+].[Cl-]>C1COCC1>[Cl:9][C:10]1[CH:15]=[C:14]([CH2:2][C:20]([O:19][CH2:17][CH3:18])=[O:24])[CH:13]=[CH:12][N:11]=1
Reactant: CC1(Cl)C=CC=CN1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccnc(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
A solution of LDA (2.0 M in THF, 809 mL, 1.62 mol) was added dropwise over 3 hr to a stirred solution of 2-chloropicoline (43) (59.1 mL, 674 mmol) in THF (500 mL) at −78° C. The reaction mixture was stirred for a further 15 min and then diethylcarbonate (106 mL, 876 mmol) was added in a single portion. After 10 min the reaction mixture was allowed to warm to 0° C., was stirred at this temperature for 20 min and then a saturated aqueous solution of NH4Cl (800 mL) was added. The mixture was extracted with ether and the organic phase was washed with water, dried (MgSO4), and evaporated in vacuo to give a dark oil, (˜200 g) which was purified in three batches by flash column chromatography (SiO2, 330 g, 5-20% EtOAc in isohexane, gradient elution) to give the title compound (44) (72 g, 51%): m/z 200 (M+H)+ (ES+)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[NH2:31])[CH2:20][CH:19]2[OH:32])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7].CO[CH:35]1[CH2:39][CH2:38][CH:37](OC)O1>C(O)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[N:31]3[CH:35]=[CH:39][CH:38]=[CH:37]3)[CH2:20][CH:19]2[OH:32])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7]
Reactant: COC1CCC(OC)O1
Reactant: Nc1cc(F)ccc1N1CCC(NC(=O)C2(NC(=O)c3ccco3)CCCCC2)C(O)C1
Solvent: CC(=O)O
Product: O=C(NC1(C(=O)NC2CCN(c3ccc(F)cc3-n3cccc3)CC2O)CCCCC1)c1ccco1

Procedure:
The mixture of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(4-fluoro-2-aminophenyl)piperidin-3-ol (3.0 g) obtained in Step 2 of Example 87 and 2,5-dimethoxytetrahydrofuran (0.96 ml) was refluxed in 80 ml of acetic acid for 1 hour. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with 70 ml of dichloromethane and washed with a saturated sodium bicarbonate and brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 1.8 g of the titled compound as white color.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([Cl:9])[CH:6]=[N:7][CH:8]=1.S(Cl)([Cl:12])=O>>[ClH:9].[Cl:9][C:5]1[CH:6]=[N:7][CH:8]=[C:3]([CH2:2][Cl:12])[CH:4]=1
Reactant: OCc1cncc(Cl)c1
Reactant: O=S(Cl)Cl
Product: Cl
Product: ClCc1cncc(Cl)c1

Procedure:
The title compound was prepared in accordance with the general method of example E from 5-(hydroxymethyl)-3-chloropyridine and thionylchloride.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][C@@H:10](O)[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P([N:27]=[N+:28]=[N-:29])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.O>[N:27]([C@H:10]1[CH2:11][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[CH:9]1)=[N+:28]=[N-:29]
Reactant: O[C@H]1C=C[C@H](c2ccccc2)C1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Solvent: O
Product: [N-]=[N+]=N[C@@H]1C=C[C@H](c2ccccc2)C1
Reaction time: 5 h

Procedure:
A solution of Example 48A (458 mg, 2.86 mmol) and toluene (4.6 mL) was cooled to <5° C. and diphenylphosphoryl azide (0.740 mL, 3.43 mmol) and DBU (0.603 mL, 4.00 mmol) were added. After 5 hours at room temperature, LCMS showed complete reaction. Water (20 mL) and toluene (50 mL) were added and organic layer was washed with water (20 mL), 2N HCl (20 mL), and brine (10 mL) sequentially. The organic layer was dried (Na2SO4), filtered, and concentrated, and crude title compound was used in the next step. MS (DCI) m/z 203 (M+NH4)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:14]=1[OH:26].O>CN(C)C=O>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:14]=1[O:26][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.7 %

Procedure:
A reaction vessel was charged with 10.6 g of 1,3-dibromopropane, 5.53 g of potassium carbonate and 100 ml of N,N-dimethylformamide, to which a solution of 30.5 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol dissolved in 40 ml of N,N-dimethylformamide was slowly added dropwise. After stirring at room temperature for 24 hours, the reaction mixture was poured into water, and extracted twice with 150 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 11.1 g of 3,5-dichloro-4-(3-bromopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (77% yield), nD24.0 1.5693.
Reaction SMILES: [CH2:1]=[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[O:3]1.C(N(CC)CC)C.[C-]#N.[K+]>C(#N)C.O>[CH:8]12[CH2:9][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:1][C:2]2=[O:3]
Reactant: C=C1OC(=O)C2CCC1C2
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CC(=O)C2CCC1C2
Yield: 74.2 %

Procedure:
Analogously to Example P3, 2.76 g (20 mmol) of 4-methylene-3-oxabicyclo[3.2.1]octan-2-one are stirred for 15 hours at room temperature in the presence of 2.23 g (22 mmol) of triethylamine and 0.13 g (2 mmol) of potassium cyanide in 10 ml of acetonitrile. The mixture is heated at 55° for a further 30 minutes and then taken up in water and the neutral components are removed at pH 10 using ethyl acetate. The aqueous phase, acidified to pH 2, is extracted with ethyl acetate, dried over sodium sulfate and concentrated by evaporation, yielding 2.05 g (74.3%0) of pure bicyclo[3.2.1]octane-2,4-dione having a melting point of 129-130° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH2:7])[CH3:6])[CH3:2].[C:11]1([CH:21]=O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH:7][CH2:21][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:6])[CH3:2]
Reactant: O=Cc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(OCC)[C@H](C)NCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a solution of (S)-1,1-diethoxypropan-2-amine (Compound XVIII-1) (682 mg, 3.55 mmol) in tetrahydrofuran (2 ml) was added 1-naphthaldehyde (554 mg, 3.55 mmol) and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was diluted with tetrahydrofuran (3 ml) and sodium triacetoxyborohydride (829 mg, 3.91 mmol) was added and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with saturated aqueous sodium bicarbonate (50 ml) twice, water (50 ml) twice and brine (50 ml) twice. The organic layer was dried over magnesium sulfate and filtered and the filtrate was concentrated in vacuo to obtain the title compound (685 mg, 67.1%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2C1CCCCO1.CC1C(OC2C=CC=C([N+]([O-])=O)C=2)=CC=C2C=1C=NN2C1CCCCO1.[Cl:44][C:45]1[CH:46]=[C:47]([N+:52]([O-:54])=[O:53])[CH:48]=[CH:49][C:50]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(N(CC)CC)C.O>[Cl:44][C:45]1[CH:46]=[C:47]([N+:52]([O-:54])=[O:53])[CH:48]=[CH:49][C:50]=1[O:11][C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][N:5]=[CH:4]2
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: Cc1c(O)ccc2c1cnn2C1CCCCO1
Agent: Cc1c(Oc2cccc([N+](=O)[O-])c2)ccc2c1cnn2C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccc([N+](=O)[O-])cc2Cl)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 85.6 %

Procedure:
Under nitrogen, the 4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-ol (150 mg, 0.646 mmol) obtained in Example 734, (a) and 3-chloro-4-fluoronitrobenzene (125 mg, 0.710 mmol) were dissolved in N,N-dimethylformamide (2 ml), followed by adding thereto potassium carbonate (134 mg, 0.969 mmol), and the resulting mixture was stirred at 70° C. for 1.5 hours. After the reaction solution was cooled to room temperature, water was added thereto, followed by extraction with toluene/ethyl acetate=1/3. The extract layer was washed with water and then a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the resulting concentration residue was suspended in methanol (10 ml), followed by adding thereto a 4N-hydrochloric acid/1,4-dioxane solution (5 ml), and the resulting mixture was stirred at room temperature for 14 hours. (The residue was once dissolved and then gave a white suspension again). The resulting mixture was made basic by adding triethylamine slowly under ice-cooling, and the solvent was distilled off under reduced pressure. Then, water was added to the residue, followed by extraction with ethyl acetate. The extract layer was washed with a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1, 2/1) to obtain 5-(2-chloro-4-nitrophenoxy)-4-methyl-1H-indazole (168 mg, yield 86%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1[NH:16][N:17]=[CH:18][C:13]=1[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[H-].[Na+].[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]Cl>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1=[N:16][N:17]([CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])[CH:18]=[C:13]1[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCc1cn[nH]c1-2
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc2c(n1)-c1c(nc3ccccc3c1N)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 11-amino-4,5-dihydro-1H-pyrazolo[3,4-a]acridine (8.0 g) in dry DMF (240 ml) was slowly added NaH (60%)(1.69 g). The reaction was stirred at room temperature for one hour, 2-dimethylaminoethylchloride (4.64 g) was added and stirring was continued for two hours. An additional 4.64 g of 2-dimethylaminoethylchloride was added and the reaction was stirred at room temperature overnight.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[O:14]1[CH2:17][C:16]([CH2:20][NH2:21])([CH2:18][NH2:19])[CH2:15]1.[S:22]1(=[O:34])(=[O:33])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][NH:25][CH2:24][CH2:23]1>>[NH2:19][CH2:18][C:16]1([CH2:20][NH:21][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=3)[N:3]=[C:2]([N:25]3[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[S:22](=[O:34])(=[O:33])[CH2:23][CH2:24]3)[N:11]=2)[CH2:17][O:14][CH2:15]1
Reactant: Clc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: O=S1(=O)CCNCc2ccccc21
Reactant: NCC1(CN)COC1
Product: NCC1(CNc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccc(Cl)cc23)COC1

Procedure:
The title compound was prepared in analogy to Example 56-1 in Scheme 23 by using 2,4,6-trichloroquinazoline, oxetane-3,3-diyldimethanamine and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide. MS obsd. (ESI+) [(M+H)+] 474, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (d, J=6.82 Hz, 1 H), 7.94 (d, J=2.53 Hz, 1 H), 7.88 (d, J=7.07 Hz, 1 H), 7.66-7.59 (m, 1 H), 7.52-7.42 (m, 2 H), 7.42-7.36 (m, 1 H), 5.21 (brs, 2 H), 4.69-4.56 (m, 5 H), 4.51 (d, J=6.32 Hz, 2 H), 4.05 (brs, 2 H), 3.52 (t, J=5.05 Hz, 2 H), 3.04 (s, 2 H).
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:30])[C@@H:19]([NH2:29])[CH2:20][C:21]2[CH:26]=[C:25](F)[CH:24]=[C:23](F)[CH:22]=2)[CH2:6]1)[CH:2]=[CH2:3].[CH2:31]([C@H:35]1[CH2:39][CH2:38][N:37]([C@@H:40]([CH2:44][CH:45]=[CH2:46])[C:41](O)=[O:42])[C:36]1=[O:47])[CH:32]([CH3:34])[CH3:33].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:30])[C@@H:19]([NH:29][C:41](=[O:42])[C@@H:40]([N:37]2[CH2:38][CH2:39][C@H:35]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:36]2=[O:47])[CH2:44][CH:45]=[CH2:46])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c2cc(OC)ccc21
Reactant: C=CC[C@@H](C(=O)O)N1CC[C@H](CC(C)C)C1=O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC=C)N2CC[C@H](CC(C)C)C2=O)c2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.3 %

Procedure:
Step O (1): (2R,3S)-1-((1S,3R)-3-(Allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-(3,5-difluorophenyl)butan-2-ol (20 mg, 52.3 μmol) from step E (2), (S)-2-((S)-3-isobutyl-2-oxopyrrolidin-1-yl)pent-4-enoic acid (12.5 mg, 52.3 μmol) from step M (5), EDC (10 mg, 52.3 μmol), HOBt (7.1 mg, 52.3 μmol), DIEA (46.7 μL, 262 μmol) were mixed in 1 mL of DMF. The mixture was stirred at RT for 24 h. Purified with reverse phase Prep-HPLC to give 28.2 mg of (S)—N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-2-((S)-3-isobutyl-2-oxopyrrolidin-1-yl)pent-4-enamide as the TFA salt: LC-MS (M+H)+=603.3 HRMS (M+H)+=604.3755 1H NMR (500 MHz, CDCl3) 8 ppm 0.80-0.96 (m, 6H) 1.08 (dd, J=10.53, 8.70 Hz, 1H) 1.23-1.38 (m, 1H) 1.54-1.66 (m, 2H) 1.96-2.06 (m, 1H) 2.26-2.45 (m, 3H) 2.51-2.77 (m, 3H) 2.85-2.95 (m, 1H) 3.03-3.16 (m, 2H) 3.28 (d, J=11.90 Hz, 1H) 3.76-3.84 (m, 3H) 3.92 (d, J=1.83 Hz, 1H) 4.03-4.12 (m, 2H) 4.20-4.29 (m, 1H) 4.46 (dd, J=10.22, 5.34 Hz, 1H) 4.73 (d, J=6.41 Hz, 1H) 4.78-4.87 (m, 1H) 4.95-5.07 (m, 2H) 5.21 (d, J=10.38 Hz, 1H) 5.30 (dd, J=17.40, 1.53 Hz, 1H) 5.54 (dd, J=14.80, 7.78 Hz, 1H) 5.84-5.98 (m, 1H) 6.71 (s, 1H) 6.95 (dd, J=8.24, 2.14 Hz, 1H) 7.11-7.28 (m, 6H) 7.34 (d, J=8.24 Hz, 1H).