Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CS(C)=O>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Yield: 84.6 %

Procedure:
A mixture of 19.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 30.1 g of anhydrous piperazine and 100 ml of dimethylsulphoxide is heated at 135° to 140° C. for 2 hours. The solvent is distilled off under a fine vacuum and the residue is suspended in H2O, filtered off with suction and washed with water. For further purification, the moist crude product is boiled up with 100 ml of water, filtered off with suction at room temperature, washed with H2O and dried to constant weight over CaCl2 at 100° C. in a vacuum drying cabinet. 19.6 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid of decomposition point 255° to 257° C. are obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH:14]([OH:16])[CH2:15][CH:9]1[CH2:10][C:11](=[O:17])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C(Cl)Cl>[CH2:1]([N:8]1[CH:13]2[CH:14]([O:16][Si:27]([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28])[CH2:15][CH:9]1[CH2:10][C:11](=[O:17])[CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC2CC(O)C(C1)N2Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CC2CC(=O)CC1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a mixture of 8-benzyl-6-hydroxy-8-azabicyclo[3.2.1]octan-3-one (prepared according to the procedure reported in Journal of Heterocyclic Chemistry 1992, 29(6), 1541-4; 46.2 g, 0.2 mol, 1.0 eq) and imidazole (16.3 g, 0.24 mol, 1.2 eq) in DCM (500 mL) was added TBSCl (33.1 g, 0.22 mol, 1.1 eq) in DCM (100 mL) slowly at room temperature in 10 min, then the mixture was stirred at room temperature for 2 h, washed with water (300 mL) and brine (300 mL), the organic layer was dried over Na2SO4 and concentrated to give 8-benzyl-6-[tert-butyl(dimethyl)silyl]oxy-8-azabicyclo[3.2.1]octan-3-one 86a as a colorless oil, 62 g, yield: 90%. MS: calc'd (MH+) 232, measured (MH+) 232.
Reaction SMILES: CCN(CC)CC.[C:8]([NH:11][CH:12](Br)[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(=[O:10])[CH3:9].[CH3:24][SH:25]>C1COCC1>[C:8]([NH:11][CH:12]([S:25][CH3:24])[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(=[O:10])[CH3:9]
Reactant: CC(=O)NC(Br)C(=O)NCc1ccccc1
Reactant: CS
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSC(NC(C)=O)C(=O)NCc1ccccc1
Reaction time: 0.5 h
Yield: 27 %

Procedure:
A cooled (-78° C.) solution or Et3N (4.85 g, 48.0 mmol) in THF (20 mL) was added to a cooled (-78° C.) solution of 2-acetamido-N-benzyl-2-bromoacetamide (prepared from 2-acetamido-N-benzyl-2-ethoxyacetamide (4.00 g, 16.0 mmol) and BBr3 (1M in CH2Cl2, 20.0 mL, 20.0 mmol)) in THF (275 mL). A cooled (-78° C.) solution of excess MeSH (5-6 equiv) in THF (55 mL) was then added. The reaction mixture was stirred at this temperature (30 min) and then at room temperature (1 h). The insoluble materials were filtered and the filtrate was evaporated to dryness in vacuo. The oily residue obtained was purified by flash column chromatography on SiO2 gel (2% MeOH/CHCl3) to give 1.10 g (27%) of the desired product as a yellow orange oil. The product was purified by a second flash column chromatography on SiO2 gel (2% MeOH/CHCl3) to give 0.72 g of the pure product as a white solid.
Reaction SMILES: C1C2C(=CC=CC=2)C=C(N)[N:2]=1.[CH2:12]([O:14][CH:15]([O:19][CH2:20][CH3:21])[C:16](=[NH:18])[O-])[CH3:13].Cl.C1(CN)C=CC=CC=1.CO[Na]>CO>[CH2:12]([O:14][CH:15]([O:19][CH2:20][CH3:21])[C:16]([NH2:2])=[NH:18])[CH3:13]
Reactant: CCOC(OCC)C(=N)[O-]
Reactant: Nc1cc2ccccc2cn1
Agent: CO[Na]
Agent: Cl
Solvent: NCc1ccccc1
Solvent: CO
Product: CCOC(OCC)C(=N)N
Temperature: 70 °C

Procedure:
Shown in scheme O is the synthesis of intermediates compounds O-1 containing isoquinolin-3-amine. In a 250 ml of three-neck round bottom flask equipped with magnetic stir bar was charged the 2,2-diethoxyacetimidate (O-3) (6.7 g, 41.6 mmol) and MeOH (20 ml) then the phenyl methanamine hydrochloride (0.5 eq., 20.8 mmol) and MeONa (1 eq., 20.8 mmol) were added. The mixture was heated to 70° C. for 1 hr. The solution appeared dark. After the reaction finished, the MeOH solvent was removed by vacuum and the residue was dissolved in CH2Cl2 (100 ml). The organic phase washed with water (3×50 mL), then brine (1×30 mL). The organic layer was dried over magnesium sulfate, and filtered and the solvent reduced under vacuum. The product was purified by a silica gel column with 100% EA to give about 40.0% of desired product of 2,2-diethoxyacetamidine (O-2). The 2,2-diethoxyacetamidine (O-2) was dissolved in 6 ml of concentrated H2SO4 (99.9%) and the reaction was stirred at 40° C. for 72 hours. The solution was neutralized by 1M NaOH aqueous to PH 7.0. The crude was purified by silica gel column with 50:50 (petroleum ether: EA) to give final product O-1; yield from 13% to 70% depending on the substitution of phenyl methane amidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:4]=1[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:8]=1[C:9](O)=[O:10])=[O:6]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[C:4]2[C:5](=[O:6])[C:7]3[C:8](=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][CH:15]=3)[C:9](=[O:10])[C:18]=2[C:19]([O:22][CH3:23])=[CH:20][CH:21]=1
Reactant: COc1ccc(OC)c(C(=O)c2cccc(OC)c2C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COc1cccc2c1C(=O)c1c(OC)ccc(OC)c1C2=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-(2',5'-Dimethoxybenzoyl)-6-methoxybenzoic acid (I) (3 g, 0.01 mole) was added in portions to stirred concentrated sulfuric acid (20 ml). After addition the mixture was heated on steam bath with constant stirring for 20 minutes, cooled to room temperature and poured onto crushed ice (400 g) and extracted with chloroform (3 × 100 ml). The organic extract was washed with 2% aqueous sodium hydroxide solution (10 × 100 ml) and water (100 ml), then dried over anhydrous sodium sulfate and the solvent stripped off under reduced pressure to yield 1,4,5-trimethoxyanthraquinone (II), as a brownish yellow solid (2.7 g, 90% yield). Recrystallization from ethanol gave yellow crystals, m.p. 201°-203° C; IR (CDCl3), 5.92μ; NMR (CDCl3) δ, 7.88-7.20 (m, 5H), 3.94 (s, 3H), 3.92 (d, 6H). Calcd: C, 68.46; H, 4-70. Found: C, 68.33; H, 4.82.
Reaction SMILES: [CH2:1]([SH:5])[CH:2]([SH:4])[CH3:3].[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]=O>C1CCCCC1>[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]1[S:4][CH:2]([CH3:3])[CH2:1][S:5]1
Reactant: CC(S)CS
Reactant: O=Cc1ccco1
Solvent: C1CCCCC1
Product: CC1CSC(c2ccco2)S1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Into a 100 ml reaction flask equipped with reflux condenser, thermometer and magnetic stirring bar and hot plate with magnetic stirring apparatus is placed 0.5 grams paratoluenesulfonic acid, 5 ml cyclohexane and 5.4 grams (0.05 moles) of 1,2-propanedithiol. Over a period of 25 minutes with stirring is added 4.8 grams (0.05 moles) of 2-furaldehyde. The reaction mass is then heated to reflux and refluxed for a period of 8 hours while removing water of reaction. At the end of the refluxing period, the reaction mass is cooled to room temperature and transferred to a separatory funnel. The reaction mass is washed with one 50 ml portion of aqueous saturated sodium chloride, and dried over anhydrous sodium sulfate. The reaction mass is then filtered and the filtrate is distilled on a Microvigreux column yielding the following three fractions:
Reaction SMILES: [C:1]1(=[O:12])[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:13]C1CC(C(C)C)CCC1=O>>[Br:13][CH:2]1[CH2:3][CH2:4][CH2:5][C:6]2([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)[C:1]1=[O:12]
Reactant: CC(C)C1CCC(=O)C(Br)C1
Reactant: O=C1CCCCC12CCCCC2
Product: O=C1C(Br)CCCC12CCCCC2

Procedure:
The bromination of spiro[5.5]undecan-1-one takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:19]2[NH:23][C:22]([C:24]3[CH:29]=[C:28]([CH:30]=[O:31])[CH:27]=[CH:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:32][Mg]Br>O1CCCC1.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:19]2[NH:23][C:22]([C:24]3[CH:29]=[C:28]([CH:30]([OH:31])[CH3:32])[CH:27]=[CH:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3cc(C=O)ccn3)[nH]2)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)c1ccnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 2-(5-{1-[4-(methylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-4-carbaldehyde (210 mg) in tetrahydrofuran (5 mL) was added methylmagnesium bromide (3M diethyl ether solution, 0.5 mL) at 0° C., and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (165 mg, yield 76%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate. MS: 455 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[N:18]=[C:17](S(C)(=O)=O)[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:35]#[N:36].[Na+]>CS(C)=O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[N:18]=[C:17]([C:35]#[N:36])[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cc(-c3cccc(C(F)(F)F)c3)nc(S(C)(=O)=O)n2)CC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(c2cc(-c3cccc(C(F)(F)F)c3)nc(C#N)n2)CC1
Yield: 83.7 %

Procedure:
4-[2-Methanesulfonyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (139 mg) and sodium cyanide (22 mg) were heated to 45° C. in dimethylsulphoxide for four hours. The reaction mixture was diluted with dichloromethane (50 ml) and washed with water (3×30 ml). Organics were separated, dried over sodium sulphate and solvent was evaporated to yield product 4-[2-cyano-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (104 mg). The above product was then dissolved in dichloromethane (1 ml) and cooled to 0° C. Trifluoroacetic acid (200 μL) was added and the mixture stirred for ten minutes. Solvent was evaporated under reduced pressure to yield crude product. Purification by preparative HPLC yielded product 4-[1,4]diazepan-1-yl-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile trifluoroacetic acid salt (52 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH2:15](Cl)[CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: COc1ccccc1N1CCN(CCCO)CC1
Temperature: 0 °C
Reaction time: 10 h
Yield: 76.8 %

Procedure:
46 g of 1-(2-methoxyphenyl)-piperazin and 24.5 g of trimethylene chlorohydrine are dissolved in 200 ml of ethanol, and 25 g of potassium carbonate are added to the solution. The mixture is refluxed for 30 hours, thereafter it is cooled to 0° C, diluted with 50 ml of ethyl ether, filtered, and the filtrate is evaporated. The residue is dissolved in 100 ml of 50° C benzene, the solution is cooled to 0° C, and allowed to stand for 10 hours. The separated crystals are filtered off and dried. 46 g (77%) of 3-[4-(2-methoxyphenyl)-piperazine-1-yl]-1-hydroxy-propane are obtained; m.p.: 92°-93° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])[CH3:2].CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH:15]=[CH:19][CH:18]=[CH:17]1)[CH3:2]
Reactant: CCOC(=O)c1ccccc1N
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccccc1-n1cccc1
Reaction time: 2 h

Procedure:
To a stirred solution of 2-amino benzoic acid ethyl ester (20 g; 121 mmol) in acetic acid (35 mL) was added 2,5-dimethoxytetrahydrofuran (19 g; 174 mmol). The reaction mixture was stirred for two hours at reflux. After evaporation of the solvent, the crude product was purified by flash column chromatography (methylene chloride) to give compound 2-pyrrol-1-yl-benzoic acid ethyl ester as a yellow oil. Rf=0.63 (methylene chloride); (22.2 g; 103 mmol; 85%)
Reaction SMILES: C([S:4][CH:5]([CH3:12])[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])(=O)C.CN(C)C=O.[C:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])#[N:19]>CC(=O)OCC>[NH2:19][C:18]1[S:4][CH:5]([CH3:12])[C:6]([OH:11])([C:7]([F:10])([F:9])[F:8])[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)SC(C)C(=O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(N)SC(C)C1(O)C(F)(F)F
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask, was placed 3-(acetylsulfanyl)-1,1,1-trifluorobutan-2-one (5.8 g, 28.97 mmol, 1.00 equiv), N,N-dimethylformamide (10 mL). This was followed by the addition of TEA (3 g, 29.65 mmol, 1.02 equiv) and ethyl 2-cyanoacetate (3.27 g, 28.91 mmol, 1.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at 25° C. Then it was diluted with 20 mL of EA. The organic phase was separated and washed with 3×20 mL of H2O. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (30/70). The collected fractions were combined and concentrated under vacuum. This resulted in 6.5 g (79%) of ethyl 2-amino-4-hydroxy-5-methyl-4-(trifluoromethyl)-4,5-dihydrothiophene-3-carboxylate as a dark red liquid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[C:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])#[CH:18]>C(O)C>[C:17]([C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:23]=[CH:24][CH:25]=1)#[CH:18]
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: C#Cc1cccc(N)c1
Solvent: CCO
Product: C#Cc1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Yield: 67.2 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 ml ethanol, and 3.82 g (32.6 mmol) 3-ethynylaniline was heated to reflux under N2. Removed heat at 3.5 hours and added a solution of saturated sodium bicarbonate until basic. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane and collected solids. Washed with water and dried in vacuo. Dissolved in ethyl acetate, stirred with Darco, filtered, stripped solvent and dried in vacuo, giving 4.544 g of yellow solid: mass spectrum (electrospray m/e): M+H=315.1.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=O)[NH:10][CH:11]=[N:12]2)=[C:7]([O:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:6]=1)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:34])=O>ClCCCl>[C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:34])=[N:10][CH:11]=[N:12]2)=[C:7]([O:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(OC2CCOCC2)c2c(=O)[nH]cnc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Oc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Temperature: 80 °C

Procedure:
A mixture of 7-acetoxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (3.04 g), diisopropylethylamine (4.34 ml), phosphoryl chloride (1.02 ml) and 1,2-dichloroethane (60 ml) was stirred and heated to 80° C. for 2 hours. The mixture was evaporated to give 7-acetoxy-4-chloro-5-tetrahydropyran-4-yloxyquinazoline which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:7]([CH2:8][O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][N:5]([CH2:27][C@@H:28]2[C@H:31]([NH:32][C:33](=[O:42])[O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30](=[O:43])[N:29]2[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[O:53][CH3:54])[N:4]=1.[N+:55]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[S:64](Cl)(=[O:66])=[O:65])([O-:57])=[O:56]>C(Cl)Cl>[Si:10]([O:9][CH2:8][C:7]1[C:3]([CH2:2][NH:1][S:64]([C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=2[N+:55]([O-:57])=[O:56])(=[O:65])=[O:66])=[N:4][N:5]([CH2:27][C@@H:28]2[C@H:31]([NH:32][C:33](=[O:42])[O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30](=[O:43])[N:29]2[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[O:53][CH3:54])[N:6]=1)([C:23]([CH3:24])([CH3:25])[CH3:26])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2nc(CN)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n2)c(OC)c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2nc(CNS(=O)(=O)c3ccccc3[N+](=O)[O-])c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 2.2 h
Yield: 86.5 %

Procedure:
To a solution of benzyl ((2R,3S)-2-((4-(aminomethyl)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2H-1,2,3-triazol-2-yl)methyl)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-3-yl)carbamate (234 mg, 0.312 mmol) in DCM (3.1 mL) at 0° C. was added 2-nitrobenzene-1-sulfonyl chloride (77.2 mg, 0.338 mmol) followed by TEA (87 μL, 0.62 mmol). After 2.2 h of stirring at rt, it was diluted with DCM and washed with KHSO4 (2%, aq). The aqueous layer was extracted with DCM (3×) and the combined organic layers were washed with brine, dried over Na2SO4 and concd in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-Heptane, 0-60%), affording the title compound (252 mg, 87%) as an off-white solid. Rt=1.24 min, m/z=934.4 (M+1) Method 2m_acidic.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][C:11]2[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[C:13]([OH:22])[CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:24]>O1CCOCC1>[NH2:24][C:6]1[C:7]([C:8]([O:10][C:11]2[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[C:13]([OH:22])[CH:12]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: N
Reactant: CS(=O)(=O)Nc1cc(O)cc(OC(=O)c2c(Cl)ncnc2Cl)c1
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cc(O)cc(OC(=O)c2c(N)ncnc2Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
3-Hydroxy-5-(methylsulfonamido)phenyl 4,6-dichloropyrimidine-5-carboxylate (110 mg, 0.29 mmol) was dissolved in dioxane (5 ml) and cooled in an ice bath. Ammonia (0.86 ml, 7N in MeOH) was dropwise added and the mixture was stirred at 0° C. and overnight at room temperature. After dilution with ethyl acetate, this organic phase was successively washed with water and brine, dried over magnesium sulphate, filtered and the solvents evaporated under reduced pressure, to yield an oil as a residue (148 mg, 49% purity, 70% yield) which was used in the next synthetic step without further purification.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:24]([S:28](Cl)(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:28]([CH2:24][CH2:25][CH2:26][CH3:27])(=[O:30])=[O:29])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1
Reactant: CCCCS(=O)(=O)Cl
Product: CCCCS(=O)(=O)Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1
Yield: 62.7 %

Procedure:
Following procedures essentially as described in Example 90, 4-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine (100 mg, 0.336 mmol) and 1-butanesulfonyl chloride (158 mg, 1.01 mmol) affords 88 mg (63%) of the title compound as a yellow oil. MS (ES) 440 (M+Na), 416 (H); HPLC shows 98% purity.