Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8](=[O:10])[CH3:9])[C:5]([OH:7])=[O:6].[BrH:11].BrBr>C(Cl)Cl.C(O)(=O)C>[Br:11][CH2:9][C:8](=[O:10])[C:4](=[N:3][O:2][CH3:1])[C:5]([OH:7])=[O:6]
Reactant: Br
Reactant: CON=C(C(C)=O)C(=O)O
Agent: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: CON=C(C(=O)O)C(=O)CBr
Reaction time: 0.5 h

Procedure:
In 3 liters of methylene chloride was dissolved 460 g of the 2-methoxyimino-3-oxobutyric acid obtained by the procedure of Example 1. To the solution was added 46 ml of a 25% hydrogen bromide solution in acetic acid. To the resultant solution was added dropwise over 2 hours at 7° to 15° C. a solution of 372 g of bromine in 372 ml of methylene chloride. Nitrogen was then blown into the mixture violently at 7° to 8° C. for 30 minutes so as to eliminate the byproduct hydrogen bromide. Silica gel (Kieselgel 60, 70 to 230 mesh, manufactured by Merck; 80 g) and activated carbon (Shirasagi of larger grain A grade, manufactured by Takeda Chemical Industries; 30 g) were added to the supernatant obtained. The mixture was stirred at 10° to 15° C. for 30 minutes and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, the oily residue was dissolved in 685 ml of xylene, and the solution was allowed to stand at 5° C. for 15 hours. The resultant crystalline precipitate was collected by filtration, washed with 100 ml of a 1:1 (v/v) mixture of xylene and n-hexane and then with 200 ml of n-hexane, and dried under reduced pressure to give 434 g of 4-bromo-2-methoxyimino-3-oxobutyric acid. The filtrate (mother liquor) was concentrated under reduced pressure and the oily residue was crystallized by addition of 238 ml of a 100:15 (v/v) mixture of xylene and n-hexane to give 82.3 g of 4-bromo-2-methoxyimino-3-oxobutyric acid as a second crop.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Si]([O:12][CH:13]1[CH2:17][CH2:16][NH:15][CH:14]1[C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:26])=[CH:20][C:19]=1[F:33])(C(C)(C)C)(C)C>>[C:13]([O:12][CH:13]1[CH2:17][CH2:16][N:15]([C:25](=[O:26])[CH3:27])[CH:14]1[C:18]1[CH:23]=[C:22]([N+:1]([O-:4])=[O:2])[C:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:26])=[CH:20][C:19]=1[F:33])(=[O:12])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OC1CCNC1c1ccc(NC(=O)c2ccccn2)cc1F
Reactant: O=[N+]([O-])O
Product: CC(=O)OC1CCN(C(C)=O)C1c1cc([N+](=O)[O-])c(NC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
1 ml of fuming nitric acid was added to 57 mg of N-(4-(3-((t-butyl(dimethyl)silyl)oxy)pyrrolidin-2-yl)-3-fluorophenyl)pyridine-2-carboxamide, and the reaction liquid was stirred at room temperature for 40 minutes. The reaction liquid was poured into a mixed solution of ice-aqueous saturated sodium bicarbonate, extracted with chloroform, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=20/1) to obtain diastereomer A and diastereomer B of the entitled compound each as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:20])=[CH:4][C:5]([F:19])=[C:6]([CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[C:9]=1[N+:15]([O-:17])=[O:16].[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>>[NH2:14][C:10]1[C:9]([N+:15]([O-:17])=[O:16])=[C:8]([O:7][C:6]2[C:5]([F:19])=[CH:4][C:3]([F:20])=[C:2]([NH:1][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[C:24]([O:23][C:22]([F:21])([F:33])[F:34])[CH:25]=3)[CH:18]=2)[CH:13]=[CH:12][N:11]=1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: Nc1cc(Oc2ccnc(N)c2[N+](=O)[O-])c(F)cc1F
Product: Nc1nccc(Oc2cc(NC(=O)c3cccc(OC(F)(F)F)c3)c(F)cc2F)c1[N+](=O)[O-]
Yield: 88 %

Procedure:
Method H was used with 4-(5-amino-2,4-difluorophenoxy)-3-nitropyridin-2-amine and 3-(trifluoromethoxy)benzoyl chloride to afford the title compound as a yellow solid (0.33 g, 88%). 1H NMR δ (DMSO): 6.09 (d, 1H, Hpy,5, J=5.5 Hz), 7.26 (bs, 2H, NH2), 7.7 (m, 3H, Harom), 7.90 (s, 1H, Harom,2′), 8.0 (d, 1H, Harom), 8.06 (d, 1H, Hpy,6, J=5.5 Hz), 10.4 (bs, 1H, NHamide). 19F NMR δ (DMSO): −56.78 (s, 1F, CF3), −118.54 (s, 1F, aromF), −129.58 (s, 1F, aromF).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([N+:24]([O-])=O)=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]>[Pd].C(O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([NH2:24])=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cc(OC)c(OCCCN2CCOCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OC)c(OCCCN2CCOCC2)cc1N
Reaction time: 18 h
Yield: 100.4 %

Procedure:
A suspension of ethyl 3-methoxy-4-(3-morpholinopropoxy)-6-nitrobenzoate (132.2 g, 359 mmol) and 10% palladium on carbon (3.0 g) in a mixture of ethanol (200 ml) and ethyl acetate (2000 ml) was stirred under an atmosphere of hydrogen for 18 hours. Removal of the catalyst by filtration, followed by solvent evaporation in vacuo yielded ethyl 3-methoxy-4-(3-morpholinopropoxy)-6-aminobenzoate (122 g, 100% yield) as a brown oil:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])[CH:7]=[CH:6][C:5]=1[I:15])[CH3:2].[H-].[Na+].I[CH3:19]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:14])([CH3:13])[CH2:11][O:12][CH3:19])[CH:7]=[CH:6][C:5]=1[I:15])[CH3:2]
Reactant: CCOc1cc(C(C)(C)CO)ccc1I
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc(C(C)(C)COC)ccc1I
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
To a solution of 2-ethoxy-4-(2-hydroxy-1,1-dimethylethyl)iodobenzene (1.0 g, 3.123 mmol, example 4) in tetrahydrofuran cooled to 0° C. was added sodium hydride (150 mg, 6.246 mmol, 60% in mineral oil). Iodomethane (0.58 mL, 9.369 mmol) was added after 15 min. The icebath was then removed and the reaction mixture was stirred at room temperature for 12 h. Saturated solution of ammonium chloride was added and the mixture was partitioned between ethyl acetate (20 mL) and water (5 mL). The product was extracted with ethyl acetate (2×). The organic layers were washed with water (1×), brine (1×), dried over anhydrous sodium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of 0-60% ethyl acetate in hexanes) gave 2-ethoxy-4-(2-methoxy-1,1-dimethylethyl)iodobenzene (891 mg, 85% yield) as clear oil.
Reaction SMILES: N12CCCN=C1CCCCC2.[Si:12]([O:19][CH2:20][C@H:21]1[O:27][C@H:25]([CH3:26])[CH:24]=[CH:23][C@@H:22]1[OH:28])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Cl:29][C:30]([Cl:34])([Cl:33])[C:31]#[N:32]>ClCCl>[Si:12]([O:19][CH2:20][C@H:21]1[O:27][C@H:25]([CH3:26])[CH:24]=[CH:23][C@@H:22]1[O:28][C:31](=[NH:32])[C:30]([Cl:34])([Cl:33])[Cl:29])([C:15]([CH3:17])([CH3:18])[CH3:16])([CH3:14])[CH3:13]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: C[C@@H]1C=C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H]1C=C[C@H](OC(=N)C(Cl)(Cl)Cl)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (1.00 ml, 6.83 mmol) was added to a dichloromethane (22 ml) solution of the compound (6.83 mmol) obtained in Step 2 above combined with trichloroacetonitrile (0.82 ml, 8.20 mmol) under ice cooling and the resulting mixture was stirred at room temperature for 1 hour. The solvent in the reaction mixture was evaporated under reduced pressure and the residue was dissolved in chloroform and added dropwise into n-hexane:ethyl acetate [4:1 (v/v)] mixed solvent. The resulting insoluble matter was removed by filtration through celite and the solvent in the filtrate was evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=99:1→10:1 (v/v)] to give 2.1 g (77%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:14]([C@@H:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH3:16])[C:13](=[O:24])[C:12]3[CH:25]=[C:26](I)[CH:27]=[CH:28][C:11]=3[NH:10][C:9]2=[O:30])=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:14]([C@@H:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH3:16])[C:13](=[O:24])[C:12]3[CH:25]=[C:26]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH3:31])[CH:27]=[CH:28][C:11]=3[NH:10][C:9]2=[O:30])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: C[C@H](c1ccc(Cl)cc1)N1C(=O)c2cc(I)ccc2NC(=O)[C@@H]1c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1ccc2c(c1)C(=O)N([C@H](C)c1ccc(Cl)cc1)[C@@H](c1ccc(Cl)cc1)C(=O)N2
Temperature: 25 °C
Yield: 81.1 %

Procedure:
A solution of (3S)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-7-iodo-1,4-benzodiazepine-2,5-dione (120 mg, 0.22 mmol), tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol), 2-methylbenzene boronic acid (35 mg, 0.26 mmol) and sodium carbonate (220 μL, 2M in H2O) in ethanol (300 μL) and toluene (5 mL) was heated under argon, at 90° C., for 10 h. After the mixture was cooled at room temperature, the solvent was evaporated in vacuo. The residue was partitioned between AcOEt (20 mL) and water (15 mL), dried (Na2SO4) and evaporated. Chromatography on silica (AcOEt/hexanes/CH2Cl2, 1:6:3) afforded the title compound (92 mg, 68%) as a colorless powder: 1H NMR (400 MHz, CDCl3) δ 1.78 (d, J=7.2 Hz, 3H, CH3), 1.99 (s, 3H, CH3), 5.29 (s, 1H, CH), 6.51 (q, J=7.2 Hz, 1H, CH), 6.64–6.67 (m, 2H, ArH, 6.71 (d, J=8.4 Hz, 1H, ArH), 6.93 (d, J=8.4 Hz, 2H, ArH), 7.05–7.11 (m, 1H, ArH), 7.15 (dd, J=8.0 Hz, J=2.0 Hz, 1H, ArH), 7.20–7.26 (m, 3H, ArH), 7.35 (d, J=8.4 Hz, 2H, ArH), 7.56 (d, J=8.4 Hz, 2H, ArH), 7.61 (d, J=2.0 Hz, 1H, ArH), 7.91 (br s, 1H, NH). Mass spectrum (LCMS, ESI pos.): Calcd for C30H24Cl2N2O2: 514.0; found: 515.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH:9]([CH3:12])[CH2:10][OH:11])[CH:6]=[CH:7][N:8]=1)[CH2:2][CH3:3].[CH2:13]([O:15][C:16](=[O:22])[CH2:17][C:18]([CH2:20]Cl)=[O:19])[CH3:14].Cl>O1CCCC1>[CH2:1]([C:4]1[N:5]([CH:9]([CH3:12])[CH2:10][O:11][CH2:20][C:18](=[O:19])[CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:22])[CH:6]=[CH:7][N:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1nccn1C(C)CO
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1nccn1C(C)COCC(=O)CC(=O)OCC
Reaction time: 4 h
Yield: 40.2 %

Procedure:
2-(2-propylimidazol-1-yl)propan-1-ol (from Preparation 1 above) (5.4 g) was added and the suspension was sonicated until there was no further gas evolution. Ethyl-4-chloroacetoacetate (4.83 g) in tetrahydrofuran (10 ml) was added over 5 minutes with sonication and sonication continued at 25°-35° C. for a further 4 hours. The suspension was poured into 2N hydrochloric acid (30 ml) and the tetrahydrofuran removed under reduced pressure. The aqueous solution was washed with toluene (30 ml) and then neutralised with potassium carbonate. The aqueous solution was extracted with dichloromethane (3×100 ml), the combined organic extracts dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was chromatographed over silica eluting with a mixture of methanol and ethyl acetate (1:9) yielding the title compound as a pale red oil 3.5 g (40%).
Reaction SMILES: [C:1]1([S:7]([OH:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Ca+2].[Cl-].[CH3:13][O:14][C:15]1[CH:16]=[C:17](C=[CH:27][C:28]=1[O:29][CH3:30])[CH2:18][CH:19]1[CH2:23][CH2:22][CH:21](OC)[O:20]1>C(Cl)Cl>[C:1]1([S:7]([CH:21]2[CH2:22][CH2:23][CH:19]([C:18]3[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[C:28]([O:29][CH3:30])[CH:27]=3)[O:20]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(O)c1ccccc1
Reactant: COc1ccc(CC2CCC(OC)O2)cc1OC
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C2CCC(S(=O)(=O)c3ccccc3)O2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.2 %

Procedure:
To a solution of benzenesulphinic acid (8.68 g, 0.061M) in DCM (120 ml) containing a suspension of powdered calcium chloride (1.0 g) at room temperature was added a solution of 2-(3,4,dimethoxybenzyl)-5-methoxytetrahydrofuran (7.0 g, 0.029M) in DCM (80 ml). The mixture was stirred at room temperature for 4 h, quenched by washing with water (2×50 ml), dried over anhydrous sodium sulphate, filtered and evaporated. Column chromatography (flash silica gel; 3:2 hexane/ethyl acetate) provided the product (Rf 0.3) as a clear oil which was crystalized from ethyl acetate/hexane to give 2-benzenesulphonyl-5-(3,4-dimethoxyphenyl)tetrahydrofuran (3.5 g, 35%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[O:11][CH2:12][C:13](=[O:20])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:6][CH2:5]1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.N1CCCCC1>C(O)C>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:12]2[O:11][C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[CH2:9][CH2:8]3)=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]2=[O:20])=[CH:22]1
Reactant: CCOC(=O)C1=C(N2CCN(CCO)CC2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(N2CCN(CCO)CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 10.1 %

Procedure:
To a solution of ethyl 2-[4-(2-hydroxyethyl)piperazinyl]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.35 g, 1.2 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.18 g, 1.2 mmol) in ethanol (6.0 mL), piperidine (0.12 mL, 1.4 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.050 g, y. 10%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17]([O:19]CCCC)=O)[O:14][C:13]3=[O:24])=[CH:11][C:6]=2[S:5][C:4]1=[O:25])[CH3:2].[CH3:26][NH2:27]>CO.CCOCC>[CH3:26][NH:27][C:17]([C@@H:15]1[O:14][C:13](=[O:24])[N:12]([C:10]2[CH:9]=[CH:8][C:7]3[N:3]([CH2:1][CH3:2])[C:4](=[O:25])[S:5][C:6]=3[CH:11]=2)[CH2:16]1)=[O:19]
Reactant: CN
Reactant: CCCCOC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3CC)C(=O)O1
Solvent: CCOCC
Solvent: CO
Product: CCn1c(=O)sc2cc(N3C[C@H](C(=O)NC)OC3=O)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The butyl(5R)-3-(2,3-dihydro-3-ethyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 30, Step 3, 300 mg, 0.823 mmol) is treated with 2N methylamine in MeOH (8.2 mL), and the mixture is stirred at ambient temperature for 1 h. The resulting slurry is diluted with Et2O (10 mL) and filtered to give the title compound, mp 227-229° C.; MS (ESI+) for C14H15N3O4S m/z 322 (M+H)+; [α]25D−43 (c 0.93, DMSO).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:14](OS(C)(=O)=O)[CH2:13][CH2:12][CH:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:25]([CH:14]1[CH2:13][CH2:12][CH:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH:9]1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C1CCC(OS(C)(=O)=O)C(NC(=O)OC(C)(C)C)C1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(N=[N+]=[N-])C(NC(=O)OC(C)(C)C)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
To a solution of Racemate-ethyl 3-(tert-butoxycarbonylamino)-4-(methylsulfonyloxy)cyclohexanecarboxylate (11.0 g, 30 mmol) in dimethyl sulfoxide (110 mL) was added sodium azide (20 g, 300 mmol), and the mixture was stirred at 90° C. overnight under N2. The solution was cooled to ˜30° C., dissolved in ethyl acetate (˜500 mL), washed with water (500 mL×5) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=4:1˜2:1) to thereby give the title compound (4.1 g, 44%) as an colorless oil. MS (ES+) C14H24N4O4 requires: 312, found: 213 [M+H−100]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[CH:22]=1.[C:23]([O-])([O-])(OCC)[CH3:24].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:23]([CH3:24])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[CH:22]=1
Reactant: COc1ccc(C2=NCC(NN)=Nc3ccc(Cl)cc32)cc1
Reactant: CCOC(C)([O-])[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C2=NCc3nnc(C)n3-c3ccc(Cl)cc32)cc1
Reaction time: 0.25 h

Procedure:
To a mixture of 2.1 parts of 7-chloro-2-hydrazino-5-(p-methoxyphenyl)-3H-1,4-benzodiazepine, prepared in Example 2, 4.33 parts of ethyl orthoacetate and 60 parts by volume of ethanol is added dropwise 0.75 part by volume of concentrated sulfuric acid. The mixture is stirred for about 15 minutes. After completion of the reaction, the reaaction mixture is neutralized with a saturated aqueous solution of sodium bicarbonate, whereby 8-chloro-1-methyl-6-(p-methoxyphenyl)-4H-s-triazolo [4,3-a] [1,4] benzodiazepine is yielded as crystals. Recrystallization from a mixture of methanol and chloroform yields colorless needles melting at 268° C to 269° C.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[O:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=2)[CH2:9][CH2:8]1.Br[C:24]1[CH:25]=[C:26]([C:31]2[N:32]=[N:33][N:34]([CH:36]([CH3:38])[CH3:37])[CH:35]=2)[C:27]([NH2:30])=[N:28][CH:29]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:36]([N:34]1[CH:35]=[C:31]([C:26]2[C:27]([NH2:30])=[N:28][CH:29]=[C:24]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][N:10]4[CH2:11][CH2:12][O:7][CH2:8][CH2:9]4)[CH:15]=3)[CH:25]=2)[N:32]=[N:33]1)([CH3:38])[CH3:37]
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Reactant: OB(O)c1cccc(CN2CCOCC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2cc(-c3cccc(CN4CCOCC4)c3)cnc2N)nn1
Temperature: 120 °C
Yield: 58.5 %

Procedure:
Cs2CO3 (858 mg, 2.64 mmol) was added to a solution of (3-(morpholinomethyl)phenyl)boronic acid (250 mg, 0.88 mmol) and 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (215 mg, 0.97 mmol) in dioxane: water (8 mL: 4 mL) degassed the reaction mixture for 10 min with nitrogen. Then added Pd(PPh3)4 (50 mg, 0.044 mmol), degassed the reaction mixture for additional 10 min with nitrogen, the reaction mixture was heated to 120° C. in microwave for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). Combined organic layers was dried over Na2SO4 and concentrated under reduced pressure. Crude product was purified by silica (100-200 mesh) column eluted with 80-90% ethyl acetate in pet-ether to afford 195 mg (Yield: 58.13%) of the title compound as a pale yellow solid. Product was converted to its HCl salt by using HCl in ether (2M) to afford 202 mg as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].CC(=CC)C.Cl([O-])=[O:24].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[CH2:1]([O:3][C:4]([C:5]([CH3:7])([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]([OH:24])=[O:16])[CH3:6])=[O:17])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C=O)c1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)C(C)(C)Oc1cccc(C(=O)O)c1
Reaction time: 2 h
Yield: 89.7 %

Procedure:
3.33 g (14.1 mmol) of 2-(3-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 55A])] was dissolved in 60 ml of tert.-butanol; 7.5 ml (70.5 mmol) of 2-methyl-2-butene was added, followed by a solution of 4.14 g (36.6 mmol) of sodium chlorite and 3.30 g (21.1 mmol) of sodium dihydrogen phosphate in 35 ml of water. After 2 hours, the reaction mixture was poured into crashed ice/EtOAc and extracted twice with EtOAc; the organic phases were washed with water, dried (MgSO4) and evaporated. The crude product was purified by recrystallisation from EtOAc/heptane to give 3.19 g of the title compound as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:8][C:7](=O)[CH:6]=[C:5]([CH3:10])[N:4]=1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:7]1[CH:6]=[C:5]([CH3:10])[N:4]=[C:3]([O:2][CH3:1])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1nc(C)cc(=O)[nH]1
Product: COc1nc(C)cc(Cl)n1
Yield: 2.3 %

Procedure:
2-Methoxy-6-methylpyrimidin-4(3H)-one (12 g, 85.71 mmol, 1 eq) was heated for 30-40 min at 100° C. in POCl3 (85 ml). The reaction mixture was then concentrated and diluted with ice-water (100 ml). The aqueous phase was rendered alkaline (pH˜9) with NaHCO3 and extracted with ethyl acetate (2×200 ml). The combined organic phases were washed with saturated sodium chloride solution (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 2% ethyl acetate/hexane). The desired product was in the form of a light-yellow solid. Yield: 2.3% (300 mg, 1.8987 mmol) after 2 stages
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)=O)=[CH:11][CH:10]=1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[C:12]1(=[C:15]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)[C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=2)[CH2:11][CH2:10][CH2:9][CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc(C(=O)c2ccc(O)cc2)cc1
Reactant: O=C1CCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
To a 3-necked round-bottomed flask were added zinc powder (0.40 g, 6.12 mmoL) and anhydrous THF (15 mL). To the stirred suspension was slowly added by syringe TiCl4 (0.32 mL, 0.55 g, 2.9 mmoL) at RT under a nitrogen atmosphere. The reaction mixture was heated at reflux for 2 h. A solution of cyclohexanone (0.24 mL, 0.227 g, 2.3 mmoL) and methyl 4-[(4-hydroxyphenyl)carbonyl]benzoate (24) (0.20 g, 0.78 mmoL) in anhydrous THF (5 mL) was added to the reaction mixture. The reaction mixture was heated a reflux for 2 h. The oil bath was removed and the reaction mixture was allowed to cool at RT. To the reaction mixture was added H2O (5 mL) followed by 10% K2CO3 (5 mL). The quenched reaction mixture was filtered through a pad of Celite with the aid of H2O and EtOAc. The filtrate was transferred to a separatory funnel and the layers were separated. The organic phase was dried (MgSO4), filtered, and the filtrate was concentrated to give the crude product as a yellow oil. The crude product was purified by flash chromatography on silica gel with a CH2Cl2:MeOH gradient (100:0 to 95:5) to give 0.176 g (70%) of compound 156 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.53 (m, 6H), 2.10 (m, 2H), 2.17 (m, 2H), 3.80 (s, 3H), 6.66 (d, J=8.3 Hz, 2H), 6.84 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.1 Hz, 2H), 7.86 (d, J=7.8 Hz, 2H), 9.34 (s, 1H).