Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]3[CH:22]=C[C:20]([N:23]4[CH2:27][CH2:26][C@H:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]4)=[CH:19][CH:18]=3)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.ClC1C=CC([N+]([O-])=O)=C[N:39]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:27][CH2:26][C@H:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])[CH2:24]4)=[N:39][CH:22]=3)=[O:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(c2ccc(NC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2)C1
Product: CC(C)(C)OC(=O)NC[C@H]1CCN(c2ccc(NC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cn2)C1

Procedure:
The synthetic sequence for preparing tert-butyl (R)-[1-(4-{[4-(4-chlorophenyl)piperidin-1-carbonyl]amino}phenyl)pyrrolidin-3-yl]methylcarbamate was carried out starting from 2-chloro-5-nitropyridine instead of 4-fluoronitrobenzene. This resulted in the product with the molecular weight of 514.07 (C27H36ClN5O3); MS (ESI): 514 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.N1C=CC=CC=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>CN(C=O)C>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][N:19]=[C:18]2[N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1])[CH2:7][CH2:8]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1cccc2c1NCC2
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCc4cccc(C)c43)c2cc1OC
Yield: 65 %

Procedure:
Utilizing a procedure analogous to that described in Example 24, this product was prepared in 65% yield from 7-methyl-indoline (1 eq.), pyridine (2 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in DMF. (M.P. 146°-147° C.; GC-MS: 321 (M+); anal. RP18-HPLC RT: 4.41 min.).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:16][C:17]1[CH:23]=[CH:22]C(N)=[CH:19][C:18]=1[O:24][CH3:25].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[Br:16][C:17]1[CH:23]=[CH:22][C:1]([NH:2][C:3]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:19][C:18]=1[O:24][CH3:25]
Reactant: CCOC(=O)C=C(NC)c1ccccc1
Reactant: COc1cc(N)ccc1Br
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)C=C(Nc1ccc(Br)c(OC)c1)c1ccccc1
Reaction time: 20 h
Yield: 93.7 %

Procedure:
To a solution of the product from Step 1 (31.3 g, 152 mmol) and 4-bromo-3-methoxyaniline (28 g, 139 mmol) in DCM (700 mL) was added PPTS (38.3 g, 152 mmol). The mixture was heated to reflux with stirring for 20 hours and cooled, and the solids removed by filtration and washed with DCM. The filtrate was concentrated and purified on silica (10% to 50% DCM/hexanes) to give the title compound (49 g). LRMS (M+H)+ Calcd.: 376.0; found 376.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]2)[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][C:2]2[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]3)[N:5]=[C:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=2)=[CH:26][CH:25]=1
Reactant: OCCN1CCN(c2cc(Cl)nc(-c3ccccc3)n2)CC1
Reactant: Sc1ccc(Cl)cc1
Product: OCCN1CCN(c2cc(Sc3ccc(Cl)cc3)nc(-c3ccccc3)n2)CC1
Temperature: 160 °C

Procedure:
A well blended mixture of 3.8 g. of 4-(4-chloro-2-phenylpyrimidin-6-yl)-1-piperazineethanol and 7.0 g. of p-chlorothiophenol is heated in an oil bath maintaining the temperature at 160°C. for 3 hours. After being cooled to room temperature, the reaction mixture is triturated with 60 ml. of 30°/o sodium hydroxide. The product is collected on a sintered glass funnel and washed with water repeatedly. Upon recrystallization from 65°/o ethanol, there is obtained 4-[4-(4-chlorophenylthio)-2-phenyl-6-pyrimidinyl]-1-piperazine ethanol, m.p. 118°-120°C.
Reaction SMILES: C([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][CH2:18][NH2:19])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.Cl[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=1.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[C:26]([C:25]1[CH:28]=[CH:29][C:22]([N:19]([CH2:13][CH2:14][CH2:16][CH2:17][CH2:18][CH2:31][CH3:32])[CH2:18][CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:20])[S:12][CH:13]=2)=[N:23][CH:24]=1)#[N:27]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCCN)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCCc1csc(SC(C)(C)C(=O)O)n1)c1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using 2-{[4-(3-aminopropyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester synthesized in Example 33 and 6-chloronicotinonitrile as starting materials and by operations similar to those of Example 265-1 and Example 265-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=50:1) to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[CH3:15][C:16]1[CH:17]=[C:18]([CH:28]([NH2:30])[CH3:29])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][C:24]([F:27])([F:26])[F:25]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:30]([CH:28]([C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[C:16]([CH3:15])[CH:17]=3)[CH3:29])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: Cc1cc(C(C)N)cnc1OCC(F)(F)F
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Yield: 62 %

Procedure:
The title compound is prepared in 62% yield (135 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (154 mg, 0.57 mmol, Amine-37, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH2:24][O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]([CH2:32][CH2:33][CH2:34][CH3:35])=[N:20][C:14]=3[CH:15]=[N+:16]([O-])[C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C([N:40]=C=O)=O.C[O-].[Na+]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH2:24][O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]([CH2:32][CH2:33][CH2:34][CH3:35])=[N:20][C:14]=3[C:15]([NH2:40])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CCCCc1nc2c[n+]([O-])c3cc(OCc4ccccc4)ccc3c2n1CCOc1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: CCCCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCOc1ccccc1
Reaction time: 2 h
Yield: 64.3 %

Procedure:
A modification of the general method described in Part C of Example 3 was used to treat 7-benzyloxy-2-butyl-5-oxido-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline (1.0 g, 2.1 mmol). An analysis by TLC indicated that the reaction with trichloroacetyl isocyanate (1.35 mL, 11.3 mmol) was incomplete after two hours, and additional trichloroacetyl isocyanate (1 mL) was added and stirred for one hour. Following the reaction with sodium methoxide, a tan precipitate formed, and the mixture was stirred over two days. The precipitate was isolated by filtration, recrystallized from ethanol, isolated by filtration, washed with hexanes, and dried overnight in a vacuum oven to provide 0.63 g of 7-benzyloxy-2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white, crystalline solid, mp 188.0-189.0° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][CH:5]=[CH:6][N:7]=1.N1C=CN=C1.[Si:13](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[Si:13]([O:1][CH2:2][C:3]1[NH:4][CH:5]=[CH:6][N:7]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ncc[nH]1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1ncc[nH]1)(c1ccccc1)c1ccccc1
Yield: 82 %

Procedure:
A solution of 2-hydroxymethylimidazole (1.96 g ; 0.02 mole), imidazole (3.4 g; 0.05 mole), tert-butyldiphenylsilyl chloride (6.6 g; 0.024 mole) in DMF (20 ml) was stirred under an argon atmosphere for 16 hours. The mixture was extracted with ethyl acetate and purified by flash column chromatography eluting with a gradient 50-70% ethyl acetate/petroleum ether to give 2-(tert-butyldiphenylsilyloxymethyl)imidazole as a solid.
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[Br:20]Br.S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>O>[Br:20][CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19])[C:11]([OH:13])=[O:12]
Reactant: O=C(O)CCCCCN1C(=O)c2ccccc2C1=O
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)C(Br)CCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
Combine 6-phthalimidohexanoic acid (12.7 g, 48 mmol) and dry red phosphorous (1.95 g, 63 mmol). Cool in an ice bath and add bromine (12.7 mL, 246 mmol) dropwise. Warm to room temperature and then heat to 80° C. After 3 hours, cool the reaction mixture to ambient temperature, pour into water (300 mL) containing sodium bisulfite, and neutralize using solid sodium bicarbonate and extract with diethyl ether (about 150 mL). Acidify the aqueous layer with concentrated hydrochloric acid to give a solid. Collect the solid by filtration and dry to give the title compound (15 g, 91.5% yield, 73.2% for both steps).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=[C:7]2[C:3]=1[N:4]([CH2:19][C:20]([N:22]([CH2:29][CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21])[C:5](=[O:18])[N:6]2[CH3:17].[CH3:31][O-:32].[Na+]>CO.CN1CCN(C)C1=O>[CH2:29]([N:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](=[O:21])[CH2:19][N:4]1[C:3]2[C:7](=[N:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:2]=2[O:32][CH3:31])[N:6]([CH3:17])[C:5]1=[O:18])[CH3:30]
Reactant: CCN(C(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)nc(Cl)c21)c1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: CO
Product: CCN(C(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)nc(OC)c21)c1ccccc1

Procedure:
A mixture of 6-chloro-N-ethyl-8,9-dihydro-9-methyl-8-oxo-2-phenyl-N-phenyl-7H-purin-7-acetamide (0.6 g) obtained in Example 45, a 28% solution of sodium methoxide in methanol (0.3 g), methanol (20 ml) and 1,3-dimethyl-2-imidazolidinone (5 ml) is refluxed for four hours. The reaction mixture is concentrated under reduced pressure, and to the residue are added water and chloroform. The chloroform layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from ethanol to give the desired compound (0.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[N:8]=[CH:7][C:6]([C:15]#[N:16])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]([Cl:32])[CH:19]=1.C(N(C(C)C)CC)(C)C.[Cl:42][CH2:43][CH2:44][CH2:45][CH:46]=[CH:47][C:48](Cl)=[O:49]>O1CCCC1>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH2:13][CH3:14])=[C:2]([NH:1][C:48](=[O:49])[CH:47]=[CH:46][CH2:45][CH2:44][CH2:43][Cl:42])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:15]#[N:16])=[CH:19][C:20]=1[Cl:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccc4)c(Cl)c3)c2cc1N
Reactant: O=C(Cl)C=CCCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccc4)c(Cl)c3)c2cc1NC(=O)C=CCCCCl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 6-amino-4-[4-(benzyloxy)-3-chloroanilino]-7-ethoxy-3-quinolinecarbonitrile (0.89 g, 2.0 mmol) and diisopropylethylamine (0.47 ml, 2.7 mmol) in 16 ml of tetrahydrofuran at 0° C. was added a freshly-prepared solution of 6-chloro-2-hexenoyl chloride in 4 ml of tetrahydrofuran during 30 s. The mixture was then stirred at 25° C. for 2.5 h and partitioned between ethyl acetate and water. The organic layer was washed with water, dried and concentrated. The residue was chromatographed on silica gel with methylene chloride-ethyl acetate to give 0.83 g of amber solid; mass spectrum (electrospray, m/e) 574.8 (M+H)+.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[O:13]=[CH:14][C@@H:15]([C@H:17]([C@H:19]([C@@H:21]([CH2:23][OH:24])[OH:22])[OH:20])[OH:18])O.[OH:25][CH2:26][C:27]([C@H:29]([C@@H:31]([C@@H:33]([CH2:35][OH:36])[OH:34])[OH:32])[OH:30])=[O:28]>>[OH:1][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([O:8][C@@H:23]2[O:24][C@H:15]([CH2:14][OH:13])[C@H:17]([OH:18])[C@H:19]([OH:20])[C@H:21]2[OH:22])[C@H:5]([OH:6])[C@H:3]1[OH:4].[OH:25][CH2:26][C:27]([C@H:29]([C@@H:31]([C@@H:33]([CH2:35][OH:36])[OH:34])[OH:32])[OH:30])=[O:28]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O

Procedure:
The reaction mixture was subjected to purification by the column chromatography using active charcoal. Thus, the column was loaded with the oligosaccharide and elution of the adsorbed oligosaccharide was conducted by successively increasing the concentration of ethyl alcohol eluant. The eluate fraction obtained with 15% ethyl alcohol as the eluant was concentrated by evaporation and subjected to desalting and decoloration using active charcoal and an ion exchange resin followed by freeze-drying to give 2.7 g of the transglycosidation product B having a purity of 98%. A portion of this transglycosidation product B was taken and subjected to the fractionating high-performance liquid chromatography to give a chromatogram having a single peak as is shown in FIG. 3. Hydrolysis of the transglycosidation product B indicated that it was composed of glucose, galactose and fructose. The enzymolytic hydrolysis of the same with the β-fructofuranosidase gave lactose and fructose in equal molar amounts. FIG. 4 shows a 13C-NMR spectrum of the transglycosidation product B.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])/[C:7](=[CH:12]\[C:13]([O:15][CH2:16][CH3:17])=[O:14])/O[C:5]2=[O:18].[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>C(O)(=O)C>[CH3:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[CH3:1])[C:5](=[O:18])[N:24]([C:23]1[CH:25]=[CH:26][C:20]([F:19])=[CH:21][CH:22]=1)/[C:7]/2=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)/C=C1/OC(=O)c2cc(C)c(C)cc21
Reactant: Nc1ccc(F)cc1
Solvent: CC(=O)O
Product: CCOC(=O)/C=C1\c2cc(C)c(C)cc2C(=O)N1c1ccc(F)cc1
Yield: 87.3 %

Procedure:
Ethyl (E)-5,6-dimethyl-3-oxo-1,3-dihydroisobenzofuran-1-ylideneacetate (0.20 g, 0.81 mmol) and 4-fluoroaniline (0.10 g, 0.89 mmol) were stirred with heating in acetic acid at 110° C. for 7 hrs. The reaction solution was concentrated under reduced pressure, and methanol was added to the residue. The resulting crystals were collected by filtration, and dried to give 0.24 g of 5,6-dimethyl-3-[(E)-2-ethoxy-2-oxoethylidene]-2-(4-fluoro-phenyl)isoindolin-1-one [IUPAC name: ethyl 2-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylidene]acetate].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=3[F:24])[C:17]([O:19]C)=O)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH2:38][NH2:39])[CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:17](=[O:19])[NH:39][CH2:38][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)[CH:21]=[CH:22][C:23]=3[F:24])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: COC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Reactant: CN1CCN(c2ccccc2CN)CC1
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccccc2CNC(=O)c2ccc(F)c(NC(=O)c3cnc4cc(Br)ccn34)c2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Methyl 3-(7-bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-fluorobenzoate (Intermediate 1A)(1.08 g, 2.75 mmol), TBD (0.383 g, 2.75 mmol) and (2-(4-methylpiperazin-1-yl)phenyl)methanamine (0.565 g, 2.75 mmol) in toluene (35 ml) were heated to 80° C. for 6 hrs. A further portion of TBD (0.06 g, 0.431 mmol) and (2-(4-methylpiperazin-1-yl)phenyl)methanamine (0.100 g, 0.487 mmol) were added and the mixture was heated at 80° C. overnight. TBD (0.06 g, 0.431 mmol) was added and heating continued at 110° C. overnight. Toluene was removed in vacuo and the resulting solid was partitioned between aqueous sodium bicarbonate solution and EtOAc. The organic portion was washed with sodium bicarbonate solution (2×50 ml) and concentrated in vacuo. The resulting oil was dissolved in MeOH and purified by chromatography on silica eluting with 0-10% MeOH in DCM. The fractions were combined and the solvent removed in vacuo. The resulting solid was recrystallised from EtOAc (50 ml) to afford the title compound;
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N+:32]=3[O-:37])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[CH2:42]([OH:45])[CH2:43][OH:44]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:44][CH2:43][CH2:42][OH:45])[N:18]=[C:17]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N+:32]=3[O-:37])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2cccc[n+]2[O-])nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: OCCO
Solvent: CC(=O)O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2cccc[n+]2[O-])nc1OCCO
Temperature: 80 °C

Procedure:
216 mg of 2-[4-(4-tert-butyl-phenylsulphonylamino)-6-chloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine 1-oxide were added to a solution of 46 mg of Na in pure ethylene glycol and the solution which slowly resulted was heated at 80° C. overnight. The solution was poured into aqueous acetic acid, the precipitate was extracted with ethyl acetate, triturated with ether and filtered off under suction. There was obtained 2-[4-(4-tert-butyl-phenylsulphonylamino)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine 1-oxide as an amorphous mass which was dried in a high vacuum at 40° C. MS: (M+H)+ =567.4.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:23])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:23])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Yield: 95.5 %

Procedure:
To a solution of tert-butyl (2S)-2-[(2-{[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate 271 (0.37 g, 0.74 mml) in methanol (25 mL) was added 5% Pd/C (0.40 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl (2S)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate 272 (0.29 g, 96%) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15](Cl)=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[NH:21][CH3:22].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[N:21]([CH3:22])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:16]
Reactant: O=C(Cl)c1cc2c(s1)-c1cc(F)ccc1OC2
Reactant: CNc1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C(=O)c1cc2c(s1)-c1cc(F)ccc1OC2)c1ccccc1Cl
Temperature: 25 °C
Yield: 28 %

Procedure:
To a reaction vial charged with 8-fluoro-4H-thieno[3,2-c]chromene-2-carbonyl chloride (0.05 g, 0.2 mmol) and 2-chloro-N-methylaniline (0.034 g, 0.24 mmol) was added a catalytic amount of DMAP. Pyridine in methylene chloride (1.2 M, 0.66 mL) was added and the reaction was stirred at room temperature with LC/MS monitor. The reaction was complete in a couple hours. After aqueous work up, the reaction was concentrated in vacuo, taken into DMF at 100 mg/ml and purified by preparative RP-HPLC to give 165bp. Yield=28% of theoretical. MS: (ESI+)=374.8
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:12]([CH3:14])[CH3:13].Br[CH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][CH:25]=1>CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])=[CH:26][CH:25]=1)[C:6](=[O:11])[C:5]2([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:12]([CH3:14])[CH3:13]
Reactant: CN(C)C1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN(C)C1(c2ccccc2Cl)C(=O)N(Cc2ccc(C(=O)OC(C)(C)C)cc2)c2ccc(Cl)cc21

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 89 from 1.5 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-dimethylaminoindol-2-one and 1.40 g of tert-butyl 4-bromomethylbenzoate. Chromatography on silica using a gradient of an AcOEt/hexane mixture (from 10/90; v/v to 20/80; v/v) as the eluent gives the expected product. m=1.5 g.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH3:12][O:13][C@@H:14]1[CH2:17][C@H:16]([NH2:18])[CH2:15]1.CCN(C(C)C)C(C)C>CC#N.[Pd]>[F:8][C:6]1[CH:7]=[C:2]([NH:18][C@H:16]2[CH2:17][C@@H:14]([O:13][CH3:12])[CH2:15]2)[C:3]([NH2:9])=[CH:4][CH:5]=1
Reactant: CO[C@H]1C[C@@H](N)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CO[C@H]1C[C@@H](Nc2cc(F)ccc2N)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 134.7 %

Procedure:
To a solution of 2,4-difluoro-1-nitrobenzene (0.18 mL, 1.6 mmol) in CH3CN (3 mL) were added cis-3-methoxycyclobutylamine (0.17 g, 1.6 mmol) and DIPEA (0.28 mL, 1.6 mmol). The reaction mixture was stirred at RT for 18 h then concentrated in vacuo. The resulting residue was carried to the next step without any further purification (0.39 g, quantitative). To a solution of the product thus obtained (1.6 mmol) in EtOAc (15 mL) was added Pd/C (350 mg) and the reaction mixture stirred at RT for 18 h under a hydrogen atmosphere. The suspension was filtered through a pad of Celite® and the filtrate concentrated in vacuo to afford the title compound as a dark oil (0.453 g, quantitative). 1H NMR (CDCl3, 300 MHz): δ 6.67-6.06 (1H, m), 6.35-6.17 (2H, m), 3.75-3.63 (1H, m), 3.61-3.25 (3H, br s), 3.22 (3H, s), 3.12-2.93 (1H, m), 2.90-2.78 (2H, m), 1.85-1.60 (2H, m).