Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].N1C=CC=CC=1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25])([O-:20])=[O:19]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH:8][C:24]([C:23]1[CH:27]=[CH:28][CH:29]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=1)=[O:25])=[O:6]
Reactant: NNC(=O)c1cccc(Cl)c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NNC(=O)c1cccc([N+](=O)[O-])c1)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-chlorobenzohydrazide (1 equivalent) and pyridine (2 equivalents) in CH2Cl2 at 0° C. was added a CH2Cl2 solution of 3-nitrobenzoyl chloride (1 equivalents) and stirred at 0° C. for 1 h and then at room temperature for overnight. The resulting solution was concentrated and diluted with water, basified with NaHCO3, the solid was filtered, washed with water, dried and analyzed to obtain N′1-(3-chlorobenzoyl)-3-nitrobenzene-1-carbohydrazide. 1H NMR (DMSO-d6): δ 10.99 (s, 1H), 10.79 (s, 1H), 8.73 (bs, 1H), 8.43 (bdd, 1H, J=1.2 and 8.1 Hz), 8.33 (bdd, 1J, J=8.4 Hz), 7.95 (s, 1H), 7.87 (m, 2H), 7.67 (bdd, 1H, J=1.2 and 8.1 Hz), 7.57 (t, 1H, J=7.8 Hz); LCMS: purity: 85%; MS (m/e): 320 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][C:13]=2[CH2:19][N:20]2[CH2:24][CH2:23][O:22][C:21]2=[O:25])[CH:6]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)=[CH:14][C:13]=2[CH2:19][N:20]2[CH2:24][CH2:23][O:22][C:21]2=[O:25])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Reactant: OB(O)c1cccnc1
Product: COC(=O)Cc1cccc(Oc2ccc(-c3cccnc3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 7, Step 1, using the following starting materials: {3-[4-bromo-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester and 3-pyridineboronic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:28])[N:6]=[C:7]([C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([O:23]C(=O)C)=[C:18]([CH3:27])[CH:17]=1)[N:8]2[CH3:15].[OH-].[Na+]>C(O)C>[OH:23][C:19]1[C:20]([CH3:22])=[CH:21][C:16]([C:7]2[N:8]([CH3:15])[C:9]3[C:4]([C:5](=[O:28])[N:6]=2)=[C:3]([O:2][CH3:1])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=3)=[CH:17][C:18]=1[CH3:27]
Reactant: COc1cc(OC)c2c(=O)nc(-c3cc(C)c(OC(C)=O)c(C)c3)n(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)c2c(=O)nc(-c3cc(C)c(O)c(C)c3)n(C)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.9 %

Procedure:
A solution of 2,4-dimethoxy-6-methylamino-benzamide (0.28 g, 1.33 mmol) in pyridine (10 mL) was added to acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester (1.1 eq.) and stirred at room temperature for 14 h. The solvent was removed and the reaction mixture was acidified with 1 N HCl and extracted with ethyl acetate. The solvent was removed and the crude was purified by silica gel column chromatography (40 g) employing 1% methanol in dichloromethane to give acetic acid 4-(5,7-dimethoxy-1-methyl-4-oxo-1,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenyl ester (0.34 g, 67%). Acetic acid 4-(5,7-dimethoxy-1-methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenyl ester (0.34 g, 0.89 mmol) was dissolved in ethanol (5 mL), 5% aqueous NaOH solution (10 mL) was added dropwise and the mixture was stirred at room temperature for 1.5 h. The compound was extracted with ethyl acetate and washed with ether to give 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-1-methylquinazolin-4(1H)-one (0.13 g, 43%). Selected data: MS (ES) m/z: 340.17; MP 188.5-189.1° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](N)=[C:4]([Cl:13])[CH:3]=1.[ClH:14].N([O-])=O.[Na+]>O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:14])=[C:4]([Cl:13])[CH:3]=1
Reactant: Nc1c(Cl)cc(Br)c2ccccc12
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1cc(Br)c2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To an ice-cooled solution of 4-bromo-2-chloro-1-naphthylamine (25.7 g) in water (60 ml) and concd. hydrochloric acid (30 ml) was added a solution of sodium nitrite (8.4 g) in water (16 ml) at 0°-5° C. The diazonium solution was stirred at same temperature an hour. There was added to it an ice-cooled solution of cuprous chloride (11 g) in concd. hydrochloric acid (60 ml). After stirring at 0°-5° C for 2 hrs., the mixture was warmed to room temperature. The brown percipitate was collected, washed with cold water, dried, and crystallized from EtOH to give colorless crystals (14.7 g, 75 %) of mp 84°-86° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([N+:10]([O-])=O)[C:4]([CH2:13][CH2:14][CH3:15])=[N:3]1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:10][C:5]1[C:4]([CH2:13][CH2:14][CH3:15])=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: [H][H]
Reactant: CCCc1nn(C)c(C(N)=O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1nn(C)c(C(N)=O)c1N

Procedure:
A stirred suspenson of 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxamide (EP-A-0463756; 237.7 g, 1.12 mol) and 5% palladium on charcoal (47.5 g) in ethyl acetate (2.02 1) was hydrogenated at 344.7 kPa (50 psi) and 50° C. for 4 hours, when the uptake of hydrogen was complete. The cool reaction mixture was filtered, then the filter pad washed with ethyl acetate, the combined filtrate and washings thus furnishing an ethyl acetate solution of the title compound (EP-A-0463756) which was of sufficient purity to use directly in the next stage of the reaction sequence.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=[C:11]3[N:10]=[CH:9]2)=[CH:4][CH:3]=1.[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.[H-].[Na+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[F:20][C:21]([F:31])([F:32])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:12]4=[N:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=[C:11]4[N:10]=[CH:9]3)=[CH:4][CH:3]=2)=[CH:25][CH:24]=1
Reactant: O=C(O)c1cnc2c(c1)ncn2-c1ccc(O)cc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cnc2c(c1)ncn2-c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(4-hydroxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (54 mg, 0.21 mmol), tetrabutylammonium iodide (8 mg, 0.021 mmol), 4-(trifluoromethoxy)benzyl bromide (0.13 mL, 0.84 mmol) and sodium hydride (50.4 mg, 1.26 mmol) in DMF (3 mL) was stirred at rt under nitrogen for 4 h. Then, water (3 mL) was added and the mixture washed with EtOAc (10 mL). The aqueous phase was acidified with 6N HCl(aq) and the resulting precipitate isolated by filtration. The EtOAc wash was concentrated in vacuo and the residue dissolved in MeOH and stirred with 6N NaOH(aq) for 2 h prior to acidification (2M HCl(aq) and filtration of product. The combined solids were dried in vacuo to give 3-{4-[(4-(trifluoromethoxy) benzyl)oxy]phenyl}-3H-imidazo[4,5-b]pyridine-6-carboxylic acid. 1H NMR (400 MHz, D6-DMSO) δ 5.26 (s, 2H), 7.26 (d, J=8.9 Hz, 2H), 7.42 (d, J=8.2 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H), 7.82 (d, J=8.9 Hz, 2H), 8.61 (d, J=1.6 Hz, 1H), 8.95 (s, 1H), 8.97 (d, J=1.6 Hz, 1H) and 13.2 (br.s, 1H); MS (ES+): m/z 430 [MH+].
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:10]([O:17][C:18]([NH:20][C:21]1[C:22](=[O:28])[NH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[CH2:10]([O:17][C:18]([NH:20][C:21]1[C:22](=[O:28])[N:23]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:24]([CH3:27])=[CH:25][CH:26]=1)=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
tert-Butyl bromoacetate (3.9 g, 20 mmol) was added to a stirred suspension of 3-benzyloxycarbonylamino-6-methyl-2-pyridinone (5.15 g, 20 mmol), as prepared in the preceding step, and Cs2CO3 (6.5 g, 20 mmol) in N,N-dimethylformamide (50 mL) and stirred at 40° C. overnight. The solid was removed by filtration and the filtrate concentrated under high vacuum. The residue was dissolved in ethyl acetate (150 mL), washed with water (2×50 mL), brine (50 mL), dried over Na2SO4 and concentrated in vacuo. After evaporating the solvent in vacuo, the residue was purified by flash column chromatography (25% ethyl acetate in hexane) to give the title compound as a white crystalline solid (4.2 g, 56%). 1H-NMR (300 MHz, CDCl3) δ7.95 (d, J=7.3 Hz, 1H), 7.76 (s, 1H), 7.37 (m, 5H), 6.09 (d, J=7.6 Hz, 1H), 5.19 (s, 2H), 4.75 (s, 2H), 2.32 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:36]=[C:37]([O:39][CH3:40])[CH:38]=1)[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:28][C:27]3[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: COc1cc(COCCCCCBr)cc(OC)c1
Agent: Cl
Product: COc1cc(COCCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc(OC)c1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 5-(3,5-dimethoxybenzyloxy)pentyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(5-(3,5-dimethoxybenzyloxy)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21]>>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:7]([C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]1[C:10]([OH:9])=[O:11])=[O:8]
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Reactant: COc1ccccc1OC
Product: COc1ccc(C(=O)[C@@H]2CCCC[C@H]2C(=O)O)cc1OC

Procedure:
Prepared from trans-cyclohexane-1,2-dicarboxylic anhydride and 1,2-dimethoxybenzene as described for compound A M.p. 202°-205° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[CH2:10]([N:17]1[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(O)cc(=O)o1
Solvent: O
Product: Cc1cc(O)cc(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-hydroxy-6-methyl-2-pyrone (0.2 mol, 25.2 g) and benzylamine (0.2 mol, 21.4 g) were added to water (800 mL) and heated to reflux with stirring for 2 hours. After cooling to room temperature, a light brown solid was collected by filtration. (33.4 g, 77%): 1H NMR (DMSO-d6/300 MHz) δ: 10.5 (s, 1H), 7.4-7.1 (m, 5H), 5.8-5.6 (m, 2H), 5.2 (s, 2H), 5.1 (s, 2H), 2.2 (s, 3H). ES HRMS m/z 216.100 (M+H, C12H13NO2 requires 216.102).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([C:8]([I:17])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:10]=1[I:11])[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH3:23][NH:24][CH3:25].[OH-].[Na+]>O>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([C:8]([I:17])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:10]=1[I:11])[C:5]([N:24]([CH3:25])[CH3:23])=[O:7]
Reactant: CC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: CNC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: CC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)N(C)C)c1I

Procedure:
The acid chloride (16.23 g.) prepared from 3-amino-5-(N-methylacetamido)-2,4,6-triiodobenzoic acid and thionyl chloride was interacted with 60 ml. of dimethylamine (40% in water), 20 ml. of 35% aqueous sodium hydroxide and 30 ml. of water. The product was isolated and recrystallized from isopropyl alcohol to give 3-amino-2,4,6-triiodo-5-(N-methylacetamido)-N,N-dimethylbenzamide as a pale yellow solid, m.p. 235°-240° C.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:2]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.CCCCCC.S(Cl)([Cl:33])=O>>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:2]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([Cl:33])=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Solvent: CCCCCC
Product: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1

Procedure:
A mixture of 1.39 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]benzoic acid in 2.0 ml of thionyl chloride is heated on a steam bath for 1 hour. Cold hexane is added and the crystalline solid collected and dried to give 1.34 g of the desired product, m.p. 118°-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C1([O:25][C:26]([C:28]2[N:29]([CH3:37])[C:30]([CH2:33][N:34]([CH3:36])[CH3:35])=[N:31][CH:32]=2)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:26]([C:28]3[N:29]([CH3:37])[C:30]([CH2:33][N:34]([CH3:35])[CH3:36])=[N:31][CH:32]=3)=[O:25])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: CN(C)Cc1ncc(C(=O)Oc2ccccc2)n1C
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3cnc(CN(C)C)n3C)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 2-dimethylaminomethyl-3-methyl-3H-imidazole-4-carboxylic acid phenyl ester, the title compound was obtained as off-white solid (49% yield). MS: m/e=431(M+H+), mp 229-231° C.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[CH3:11][OH:12]>>[CH3:11][O:12][C:3]([OH:4])([C:5]([F:8])([F:7])[F:6])[C:2]([F:10])([F:9])[F:1]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: CO
Product: COC(O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.6 %

Procedure:
Into 1.82 g of dry methanol was introduced 18.86 g of hexafluoroacetone, and the mixture was stirred at room temperature. After 6 hours, the reaction mixture was distilled under a reduced pressure, to obtain 11.2 g of hexafluoroacetone methylhemiacetal as an intermediate fluorinated hemiacetal. Next, in 50 mL of THF was dissolved 11.2 g of hexafluoroacetone methylhemiacetal, and the mixture was cooled to −78° C. To the solution was added dropwise 35.5 mL of a n-butyllithium solution in hexane (concentration: 1.6 mol/L). After stirring for one hour, 5.14 g of acryloyl chloride was added dropwise thereto. After stirring for 4 hours under ice cooling, precipitated lithium chloride was filtered off and the filtrate was concentrated in vacuo. To the residue was added 200 mL of ether, and the ethereal layer was sequentially washed with a saline solution and water. The ethereal layer was dried over anhydrous magnesium sulfate. After evaporation of ether under a reduced pressure, the residue was distilled under a reduced pressure to obtain 3.06 g of the desired acrylate 3 (yield: 21%, colorless liquid).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:61][C:62]1[CH:63]=[CH:64][C:65]([O:72][CH3:73])=[C:66]([CH2:68][C:69](O)=[O:70])[CH:67]=1>CN(C)C(=O)C>[F:61][C:62]1[CH:63]=[CH:64][C:65]([O:72][CH3:73])=[C:66]([CH2:68][C:69]([NH:1][C:2]2[CH:3]=[CH:4][N:5]([CH3:27])[C:6]3[C:7]=2[CH:8]=[CH:9][C:10]2[N:19]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH2:18][CH:17]=[C:12]4[NH:13][C:14](=[O:16])[C:15]=3[C:11]=24)=[O:70])[CH:67]=1
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Reactant: COc1ccc(F)cc1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1ccc(F)cc1CC(=O)NC1=c2ccc3c4c([nH]c(=O)c-4c2N(C)C=C1)=CCN3c1ccc(F)cc1
Yield: 91 %

Procedure:
A stock solution of Example 23e and N,N-diisopropylethylamine (0.09 M and 0.25 M in N,N-dimethylacetamide, respectively, 450 μL, 0.2 mmol Example 23e and 0.6 mmol N,N-diisopropylethylamine), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.14 M in N,N-dimethylacetamide, 450 μL, 0.3 mmol), and 2-(5-fluoro-2-methoxyphenyl)acetic acid (0.40 M in N,N-dimethylacetamide, 125 μL, 0.24 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL min−1 (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified using reverse phase HPLC(C8, acetonitrile/water (0.1% TFA), 5-100%) to give 0.0243 g (91%) of the title compound as the TFA salt. 1H NMR (400 MHz, DMSO-d6/D2O) δ 10.28 (s, 1H), 8.12 (d, J=2.44 Hz, 1H), 7.65 (s, 1H), 7.42 (dd, J=8.54, 2.44 Hz, 1H), 7.20 (d, J=8.54 Hz, 1H), 7.11 (m, 2H), 7.04 (s, 1H), 7.01 (m, 1H), 6.83 (m, 2H), 6.48 (m, 2H), 5.02 (d, J=15.56 Hz, 1H), 4.18 (d, J=15.87 Hz, 1H), 4.04 (s, 3H), 3.79 (s, 3H), 3.70 (s, 2H). MS (APCI+) m/z 527.1 (M+H)+.
Reaction SMILES: N1C=CN=C1.C(O[C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([C:20]3[CH:25]=[CH:24][C:23](OC)=[CH:22][CH:21]=3)[CH2:16][O:17]2)=[CH:12][CH:11]=1)(=O)C>C(O)C>[O:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][CH:19]=2)[CH:14]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16]1
Reactant: COc1ccc(C2=Cc3ccc(OC(C)=O)cc3OC2)cc1
Agent: c1c[nH]cn1
Solvent: CCO
Product: C1=C(c2ccccc2)COc2ccccc21
Reaction time: 8 h

Procedure:
Imidazole (0.18 g) was added to a suspension of 7-acetoxy-4′-methoxyisoflav-3-ene (0.06 g, 0.02 mmol) in absolute ethanol (5.0 ml) and the mixture was refluxed for 45 minutes under argon. The solution was concentrated under reduced pressure and the product was precipitated by addition of distilled water (10 ml). The mixture was left overnight in the fridge and filtered to yield isoflav-3-ene. The crude product was recrystallised from methanol/benzene to yield 7-hydroxy-4′-methoxyisoflav-3-ene (0.034 g, 66%). 1H NMR (CDCl3+d6-DMSO): δ 3.74 (s, 3H, OCH3), 4.99 (s, 2H, H2), 6.21 (d, 1H, J 2.3 Hz, H8), 6.29 (dd, 1H, J 2.3 Hz, 8.3 Hz, H6), 6.67 (bs, 1H, H4), 6.85 (d, 1H, J 8.3 Hz, H5), 6.86 (d, 2H, J 8.7 Hz, ArH), 7.33 (d, 2H, J 8.7 Hz, ArH).
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[F:21])=[CH:12][N:11]([CH3:22])[C:9]=2[N:10]=1)[CH2:2][CH3:3].[H-].[Na+].I[CH3:31]>CN(C)C=O>[CH2:25]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:31])=[CH:16][C:15]=3[F:21])=[CH:12][N:11]([CH3:22])[C:9]=2[N:10]=1)[CH2:26][CH3:27]
Reactant: CI
Reactant: CCCN(CCC)c1nc2c(c(-c3ccc(O)cc3F)cn2C)c(=O)n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCC)c1nc2c(c(-c3ccc(OC)cc3F)cn2C)c(=O)n1C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of 2-(dipropylamino)-5-(2-fluoro-4-hydroxyphenyl)-3,7-dimethyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (30 mg, 0.0805 mmol) in N,N-dimethylformamide (0.5 ml) were added sodium hydride (66% dispersion in oil; 3.2 mg, 0.0886 mmol) and iodomethane (0.006 ml, 0.0886 ml) at 0° C., and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was diluted with ice-cold water and extracted with ethyl acetate (×1). The organic layer was washed with water (×1) and brine (×1), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 20% hexane/ethyl acetate mixture. The desired fractions were concentrated in vacuo to give 23 mg (74%) of the title compound as an oil.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:13])[CH2:9]1)C1C=CC=CC=1>CCO.[Pd]>[CH3:13][C:10]1([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC1(NC(=O)OC(C)(C)C)CCNC1
Reaction time: 3 h
Yield: 73.6 %

Procedure:
A solution of tert-butyl 1-benzyl-3-methylpyrrolidin-3-ylcarbamate (1.17 g, 4.0 mmol) in EtOH (40 mL) was added to 10% Pd on C and shaken under 45 psi of H2 for 3 h. The mixture was filtered through Celite and concentrated to afford tert-butyl 3-methylpyrrolidin-3-ylcarbamate (0.59 g, 73%). LC-MS Method 1 tR=0.72 min, m/z=201.
Reaction SMILES: C(O)C.[O:4]=[C:5]1[CH:11]([N:12]2C(=O)C3=CC=CC=C3C2=O)[CH2:10][CH2:9][C:8]2[CH:23]=[CH:24][CH:25]=[CH:26][C:7]=2[N:6]1[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].O.NN>>[NH2:12][CH:11]1[CH2:10][CH2:9][C:8]2[CH:23]=[CH:24][CH:25]=[CH:26][C:7]=2[N:6]([CH2:27][C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[C:5]1=[O:4]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CCc2ccccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)C(N)CCc2ccccc21
Yield: 86.9 %

Procedure:
To 100 mol of ethanol is added 10 g of tert-butyl 2-oxo-3-phthalimido-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate, and 5 g of hydrazine hydrate is added to the mixture, followed by refluxing for 2 hours. The reaction mixture is concentrated under reduced pressure, and 300 ml of water is added to the residue, followed by extraction with 200 ml of ethyl acetate. The extract is washed with 1N aqueous sodium hydroxide and water, successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystals, which separate out, are treated with a mixture of ether and petroleum ether and collected by filtration to give 6 g of tert-butyl 3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate as colorless prisms. m.p. 121°-122° C.
Reaction SMILES: Br[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([N+:23]([O-:25])=[O:24])[C:7]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)[O:4][C:3]=1[CH:26]([CH3:28])[CH3:27].[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[C:11](=[O:12])[C:10]3[C:5](=[C:6]([N+:23]([O-:25])=[O:24])[C:7]([NH:13][CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)=[CH:8][CH:9]=3)[O:4][C:3]=2[CH:26]([CH3:27])[CH3:28])=[CH:32][CH:31]=1
Reactant: COc1ccc(CNc2ccc3c(=O)c(Br)c(C(C)C)oc3c2[N+](=O)[O-])cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CNc2ccc3c(=O)c(-c4ccc(Cl)cc4)c(C(C)C)oc3c2[N+](=O)[O-])cc1
Temperature: 100 °C

Procedure:
3-Bromo-2-isopropyl-7-(4-methoxybenzylamino)-8-nitro-chromen-4-one (105 mg, 0.235 mmol), 4-chlorophenylboronic acid (73 mg, 0.47 mmol) and tetrakis(triphenylphosphine) palladium (0) (28 mg, 0.024 mmol) are dissolved in absolute ethanol (3 ml) in a 5 ml capacity microwave tube. Aqueous sodium carbonate solution (2M, 0.35 ml, 0.7 mmol) is added, and the mixture is heated at 100° C. under microwave irradiation for 10 min. The mixture is poured into water (10 ml) and extracted with ethyl acetate (3×30 ml). The ethyl acetate extracts are combined, washed with saturated brine (30 ml), dried (MgSO4), filtered and evaporated to give a green solid. This is triturated with n-pentane and filtered to give a pale yellow powder.