Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=O)[CH:3]([NH:10][C:11]([CH:13]1[N:17]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:16][CH2:15][S:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1C(Cl)=NC(Cl)=NC=1Cl.O>CN(C=O)C>[C:24]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:25]=[CH:26][C:21]([S:18]([N:17]2[CH2:16][CH2:15][S:14][CH:13]2[C:11]([NH:10][CH:3]([C:2]#[N:1])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:12])(=[O:19])=[O:20])=[CH:22][CH:23]=1
Reactant: NC(=O)C(NC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(NC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Yield: 69.3 %

Procedure:
To a stirred solution of compound 1b, e.g., N-(2-amino-2-oxo-1-phenylethyl)-3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carboxamide (385 mg, 0.8 mmol) in DMF (1 mL) at RT was added cyanuric chloride (74 mg, 0.4 mmol) in one portion. After one night, the reaction was done. Water (3 mL) was added and a precipitate was formed. The aqueous phase was extracted with two portions of EtOAc (5 mL). Combined organic phases were washed with 5% aqueous sodium bicarbonate, with water, dried over MgSO4 and concentrated under reduced pressure. A light yellow solid was isolated and was purified by flash chromatography (Cyclohexane/EtOAc gradient form 8:2 to 1:1), affording product Ic, e.g., 3-(biphenyl-4-ylsulfonyl)-N-[cyano(phenyl)methyl]-1,3-thiazolidine-2-carboxamide (257 mg, 69% yield) in 100% purity by HPLC.
Reaction SMILES: [Na].Cl.[OH:3][N:4]1[C:8]2[CH:9]=[C:10]([CH2:13][OH:14])[CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH2:20](O)C>>[OH:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]2[N:6]=[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:4]([O:3][CH3:20])[C:8]=2[CH:9]=1
Reactant: CCO
Reactant: CCOC(=O)c1nc2ccc(CO)cc2n1O
Agent: Cl
Agent: [Na]
Product: CCOC(=O)c1nc2ccc(CO)cc2n1OC
Reaction time: 0.17 h
Yield: 50 %

Procedure:
(a-4) To a stirred soluiton of 0.92 parts of sodium in 32 parts of ethanol were added 5.46 parts of ethyl 1-hydroxy-6-(hydroxymethyl)-1H-benzimidazole-2-carboxylate monohydrochloride. The whole was stirred for 10 minutes and concentrated. 18 Parts of methylbenzene were added and the mixture was evaporated. 13.5 Parts of N,N-dimethylformamide and a solution of 2.84 parts of iodomethane in 4.5 parts of N,N-dimethylformamide were added. After stirring for 30 minutes, the reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and acetonitrile (80:20 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane (1:4 by volume). The product was filtered off and dried, yielding 2.5 parts (50%) of ethyl 6-(hydroxymethyl)-1-methoxy-1H-benzimidazole-2-carboxylate; mp. 110.1° C. (int. 32).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]1([N:25]2[C:29](=[S:30])[N:28]=[N:27][NH:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C@@H:38]1[CH2:40][C@H:39]1[CH2:41]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C@@H:38]1[CH2:40][C@H:39]1[CH2:41][S:30][C:29]1[N:25]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[N:26]=[N:27][N:28]=1
Reactant: S=c1nn[nH]n1-c1cccc2ccccc12
Reactant: OC[C@@H]1C[C@H]1c1ccccc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccccc1[C@@H]1C[C@H]1CSc1nnnn1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
DIAD (87 μL, 0.44 mmol) was added dropwise to a solution of 1,2-dihydro-1-(1-naphthalenyl)-5H-tetrazole-5-thione (84.0 mg, 0.37 mmol), trans-2-(2-chlorophenyl)cyclopropanemethanol (80.5 mg, 0.44 mmol), and PPh3 (116 mg, 0.44 mmol) in THF (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h then was concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2:(CH3)2CO, 95:5) to give the title compound (81 mg, 56% yield) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:28]=[CH:27][C:10]([C:11]([C:13](=[CH:19][NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:14](OCC)=[O:15])=[O:12])=[C:9](F)[CH:8]=2)=[CH:3][CH:2]=1.[H-].[Na+].[NH3:32]>O1CCOCC1>[C:21]1([N:20]2[C:27]3[C:10](=[CH:9][CH:8]=[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH:28]=3)[C:11](=[O:12])[C:13]([C:14]([NH2:32])=[O:15])=[CH:19]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(=CNc1ccccc1)C(=O)c1ccc(-c2ccncc2)cc1F
Reactant: N
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: NC(=O)c1cn(-c2ccccc2)c2cc(-c3ccncc3)ccc2c1=O

Procedure:
Novel quinolones (see Examples 1, 2, 3, 4, 5, 6 and 7) of this invention may be prepared by a mild ring closure reaction of ethyl 2-[4-(4-pyridyl)-2-fluoro-benzoyl]-3-phenylamino-propenoate (Formula 3) with sodium hydride in dioxane followed by treatment of the propeonate with ammonia to afford the desired 1,4-dihydro-1-phenyl-7-(4-pyridyl)-4-oxo-3-quinolinecarboxamide (Formula 5) as shown in Scheme 1.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[C:15]([OH:17])=O)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[H-].[Na+].[O:20]1[CH:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=2[CH3:32])[CH2:21]1>CN(C=O)C>[CH3:32][C:26]1[C:27]([CH3:31])=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][CH2:23][CH:22]([OH:20])[CH2:21][N:1]1[C:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=2[N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[C:15]1=[O:17]
Reactant: O=C(O)C1CCCN1c1ncccc1[N+](=O)[O-]
Reactant: Cc1cccc(OCC2CO2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCC(O)CN2C(=O)C3CCCN3c3ncccc32)c1C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a stirred solution of the product of Example 1 (2.7 g., 0.015 mole) in 40 ml. of dry DMF was added 0.6 g. of sodium hydride (0.025 mole of 50% dispersion in mineral oil). After the evolution of gases subsided, 2.6 g. (0.015 mole) of 1,2-epoxy-3-[2,3-dimethylphenoxy]propane was added. The reaction mixture was stirred overnight and DMF was evaporated in vacuo and the residue was extracted with 200 ml. of diethyl ether. The ether layer was dried and concentrated in vacuo to 30 ml. TLC indicated the presence of two products, one of which is a major component (about 80%). The ether layer was cooled overnight and the separated solid was filtered and recrystallized from diethyl ether to afford 1.8 g. (51% yield) of the title compound m.p. 123°-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[CH2:4][NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8](Cl)[N:7]=1.[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][C@@H:30]([CH2:33][NH2:34])[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CC#N>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[CH2:4][NH:5][C:6]1[N:7]=[C:8]([NH:34][CH2:33][C@@H:30]2[CH2:31][CH2:32][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:29]2)[CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NCc1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@@H](CNc2ccc([N+](=O)[O-])c(NCc3c(Cl)cccc3Cl)n2)C1
Yield: 27.3 %

Procedure:
A mixture of 16 (100 mg, 0.34 mmol), (S)-tert-Butyl-3-(aminomethyl)pyrrolidine-1-carboxylate (0.4 g, 2.0 mmol), potassium carbonate (56.4 mg, 0.41 mmol) in 10 mL MeCN was stirred at reflux for 2 hours. The solvent was removed by vacuum and the residue was purified by silica gel chromatography (MeOH:DCM=1:10) giving 17 [46 mg, 27% yield].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C@H:12]([NH:27][C:28]([N:30]1[CH2:39][CH2:38][C:37]2[CH:36]=[N:35][C:34]([NH:40][CH:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[N:33][C:32]=2[CH2:31]1)=[O:29])[C@H:13]1[N:17](C(OC(C)(C)C)=O)[C:16]([CH3:26])([CH3:25])[CH2:15][CH2:14]1.Cl.CC(O)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:25][C:16]1([CH3:26])[NH:17][C@H:13]([C@H:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:9])[F:11])=[CH:7][C:2]=2[F:1])[NH:27][C:28]([N:30]2[CH2:39][CH2:38][C:37]3[CH:36]=[N:35][C:34]([NH:40][CH:41]4[CH2:42][CH2:43][O:44][CH2:45][CH2:46]4)=[N:33][C:32]=3[CH2:31]2)=[O:29])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](NC(=O)N2CCc3cnc(NC4CCOCC4)nc3C2)c2ccc(C(F)(F)F)cc2F)CCC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CC1(C)CC[C@@H]([C@@H](NC(=O)N2CCc3cnc(NC4CCOCC4)nc3C2)c2ccc(C(F)(F)F)cc2F)N1
Reaction time: 1 h

Procedure:
To a solution of 324 (0.380 g, 0.584 mmol) and DCM (5 mL). was added 6M HCl in IPA (0.973 mL, 5.84 mmol) and the reaction was stirred for 1 h and then poured into Na2CO3 and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (500:40 to 500:50) to afford 0.210 g (65.3%) of I-86: MS m/z (APCI-pos) M+1=551.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]#[N:20])[CH:14]=1.[Br:21]Br.C([O-])(=O)C.[K+].S([O-])(O)(=O)=O.[Na+]>>[Br:21][C:14]1[C:15]([C:19]#[N:20])=[N:16][N:17]([CH3:18])[C:13]=1[CH2:12][N:3]1[C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:11]
Reactant: BrBr
Reactant: Cn1nc(C#N)cc1CN1C(=O)c2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: Cn1nc(C#N)c(Br)c1CN1C(=O)c2ccccc2C1=O
Reaction time: 48 h

Procedure:
5-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazole-3-carbonitrile (1.57 g, 5.90 mmol) was brominated using a modified version of the method described in Part F of Examples 1-4. In the reaction, 1.4 equivalents of bromine were used instead of 1.1 equivalents. After the reaction was stirred for two days, additional potassium acetate (1.31 g) and bromine (0.211 mL) were added, and the reaction was stirred for five more days. After the addition of sodium hydrogensulfate, most of the acetic acid was removed under reduced pressure, and 2 M aqueous sodium carbonate was added. A solid formed and was isolated by filtration, washed with water, and dried on the vacuum filter funnel to provide 1.85 g of 4-bromo-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-methyl-1H-pyrazole-3-carbonitrile as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:17]=[N:18][N:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:20]=1)=[O:10])(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH2:7][CH:8]([CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:17]=[N:18][N:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:20]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCC[C@H]1c1nnn(Cc2ccccc2)n1)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(C(=O)N1CCC[C@H]1c1nnn(Cc2ccccc2)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound E in DCM (4 mL) is added TFA (4 mL) at 0° C. The solution is stirred at room temperature for 1 hr and dried under vacuum. The crude oil is used directly in the next step without further purification. M+H+=369.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:14]2[CH:19]=[C:18]([C:20]3[C:25]4[O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:24]=4[CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:15]=2[OH:33])=[CH:3][CH:2]=1.C(Cl)Cl.C(N(CC)CC)C.[C:44](Cl)(=[O:47])[CH:45]=[CH2:46]>O>[C:44]([O:33][C:15]1[CH:16]=[CH:17][C:18]([C:20]2[C:25]3[O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:19][C:14]=1[C:4]1[C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=[CH:2][CH:3]=1)(=[O:47])[CH:45]=[CH2:46]
Reactant: Oc1ccc(-c2cccc3c2oc2ccccc23)cc1-c1cccc2c1oc1ccccc12
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)Oc1ccc(-c2cccc3c2oc2ccccc23)cc1-c1cccc2c1oc1ccccc12
Reaction time: 0.5 h
Yield: 79 %

Procedure:
1.89 g of the thus obtained 2,4-bis(4-dibenzofuranyl)phenol is placed in a round bottom flask; 20 mL of methylene chloride is added to form a transparent solution; after ice cooling the flask, 0.54 g of triethylamine is added; 0.48 g of acryloyl chloride is then added dropwise; after adding the whole, the temperature is returned to room temperature; and the mixture is stirred for 30 minutes. 10 mL of water is added; the mixture is vigorously stirred; an aqueous layer is then removed; the aqueous layer is washed with methylene chloride and gathered with the original methylene chloride solution; and the mixture is dried upon application of magnesium sulfate. The resulting mixture is concentrated by filtration with a filter paper; and the concentrate is separated by a silica gel column (eluate: hexane/ethyl acetate=90/10 (volume ratio)) to concentrate a component having an Rf of 0.20, thereby obtaining 1.69 g (yield: 79%) of the foregoing white solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 5.66 (dd=1.2 & 10.8 Hz, 1H), 5.98 (dd=10.8 & 17.2 Hz, 1H), 6.28 (dd=1.2 & 17.2 Hz, 1H), 7.34 to 7.38 (m, 2H), 7.41 to 7.46 (m, 4H), 7.51 to 7.61 (m, 4H), 7.66 to 7.68 (m, 1H), 7.95 to 7.98 (m, 4H), 7.99 to 8.00 (m, 1H), 8.05 to 8.06 (m, 1H)
Reaction SMILES: O.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1C1C=C2C(=CC=1)NN=C2C(NCC1CCN(CC2OC=C(C(O)=O)N=2)CC1)=O.Br[C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][N:43]=[C:42]2[C:48]([NH:50][CH2:51][CH:52]1[CH2:57][CH2:56][N:55]([CH2:58][C:59]2[O:63][C:62]([C:64]([O:66]CC)=[O:65])=[CH:61][CH:60]=2)[CH2:54][CH2:53]1)=[O:49].FC1C(F)=CC=CC=1B(O)O>>[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][N:43]=[C:42]2[C:48]([NH:50][CH2:51][CH:52]1[CH2:53][CH2:54][N:55]([CH2:58][C:59]2[O:63][C:62]([C:64]([OH:66])=[O:65])=[CH:61][CH:60]=2)[CH2:56][CH2:57]1)=[O:49]
Reactant: CCOC(=O)c1ccc(CN2CCC(CNC(=O)c3n[nH]c4ccc(Br)cc34)CC2)o1
Reactant: O=C(O)c1coc(CN2CCC(CNC(=O)c3n[nH]c4ccc(-c5cccc(F)c5F)cc34)CC2)n1
Agent: OB(O)c1cccc(F)c1F
Solvent: O
Product: O=C(O)c1ccc(CN2CCC(CNC(=O)c3n[nH]c4ccc(-c5cccc(F)c5F)cc34)CC2)o1
Reaction time: 0.25 h

Procedure:
5-({4-[({[5-(2,3-Difluorophenyl)-1H-indazol-3-yl]carbonyl}amino)methyl]piperidin-1-yl}methyl)furan-2-carboxylic acid 19 was prepared, according to the procedure described for compound 12, from compound 15 and (2,3-difluorophenyl)boronic acid and using the following preparative HPLC parameters for the purification: channel A=CH3CN+0.1% formic acid; channel B=H2O+0.1% formic acid: flow=40 ml/min; gradient=15%-50% of eluent A in 15 minutes. Yield: 32 mg, 11%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Li+].[Li+].[Br:18][CH2:19][C:20](Br)=[O:21]>O1CCOCC1>[Br:18][CH2:19][C:20]([N:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[CH3:1])=[O:21]
Reactant: O=C(Br)CBr
Reactant: CNc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CN(C(=O)CBr)c1ccc([N+](=O)[O-])cc1
Reaction time: 18 h

Procedure:
23.5 g (0.15 mol) of N-methyl-4-nitroaniline are dissolved in 400 ml of dioxane and combined with 22.2 g (0.3 mol) of lithium carbonate. Then 32.2 g (0.18 mol) of bromoacetylbromide are added dropwise in such a way that the internal temperature does not exceed 33° C. After 18 hours' stirring the reaction solution is evaporated down to 100 ml, combined with 500 ml of water and stirred for 1 hour. The precipitate formed is suction filtered, washed with water and dried. The crude product is stirred in 400 ml of ethyl acetate at 40° C. Then the insoluble matter is filtered off, the solution is evaporated down and the solid residue is triturated with ether.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][C:3]=1[CH:16]([CH3:18])[CH3:17].C([Li])(C)(C)C.CN([CH:27]=[O:28])C>CCCCC.O>[C:10]([Si:7]([CH3:9])([CH3:8])[O:6][C:5]1[CH:14]=[CH:15][C:2]([CH:27]=[O:28])=[C:3]([CH:16]([CH3:18])[CH3:17])[CH:4]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)c1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: O
Product: CC(C)c1cc(O[Si](C)(C)C(C)(C)C)ccc1C=O
Temperature: 25 °C
Yield: 55.1 %

Procedure:
A solution of (4-bromo-3-isopropyl-phenoxy)-tert-butyl-dimethyl-silane (Intermediate 145, 1.03 g, 3.13 mmols) in 25 mL E2O was cooled to −78° C. and treated with tert-butyllithium (401.0 mg, 6.26 mmols; 3.7 mL of a 1.7M solution in pentane). After 30 minutes the reaction was quenched with DMF (913.0 mg, 12.5 mmols) and warmed to room temperature. The solution was diluted with H2O, extracted with Et2O and the combined organic layers washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. Column chromatography (2% EtOAc-hexanes) afforded 480.0 mg (55%) of the title compound as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[N:9]([CH3:16])[CH2:8]2)=[O:4].[O:17]([CH2:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].[BH4-].[K+]>O.C(O)C>[OH:4][CH:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[N:9]([CH3:16])[CH2:8]2)[CH2:2][N:28]1[CH2:29][CH2:30][CH:25]([CH2:24][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:26][CH2:27]1
Reactant: CN1Cc2cc(C(=O)CCl)ccc2NC1=O
Reactant: c1ccc(OCC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CN1Cc2cc(C(O)CN3CCC(COc4ccccc4)CC3)ccc2NC1=O
Yield: 102.8 %

Procedure:
A mixture of 3 g (12.6 mmoles) 6-chloroacetyl-3methyl-3,4-dihydro-1H-quinazolin-2-one, 2.4 g 4-(phenoxymethyl)piperidine, 1.7 g sodium carbonate, 70 ml ethanol and 15 ml water is heated under reflux for 2 h. The mixture is cooled, 6 g potassium borohydride are added slowly, and the mixture is allowed to return to ambient temperature while stirring. 125 ml water are added, the mixture is stirred for 1 h, then the solid is filtered off, washed with water, and recrystallized from ethanol. 5.1 g of compound are finally isolated.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:28])=[CH:4][C:5]2[O:15][CH2:14][C:13]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[C:16]3[CH2:21][CH2:20][N:19](C(OCC)=O)[CH2:18][CH2:17]3)[C:6]=2[CH:27]=1.[NH4+].[OH-]>Cl>[Br:1][C:2]1[C:3]([Cl:28])=[CH:4][C:5]2[O:15][CH2:14][C:13]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[C:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[C:6]=2[CH:27]=1
Reactant: CCOC(=O)N1CCC(=C2c3cc(Br)c(Cl)cc3OCc3cccnc32)CC1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Clc1cc2c(cc1Br)C(=C1CCNCC1)c1ncccc1CO2
Temperature: 0 °C
Yield: 93 %

Procedure:
A solution of ethyl 4-(9-bromo-8-chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-1 1-ylidene)-1-piperidine-carboxylate (0.6 g, 1.29 mmol) in conc. HCl (5 ml) was stirred at 80° C. overnight. The reaction mixture was cooled to 0° C., basified with conc. NH4OH, and extracted with methylene chloride (2×100 ml). The organic layer was separated, washed with water (20 ml), dried (MgSO4), filtered and evaporated, yielding an oil which was chromatographed on silica gel and eluted with 10%methanol/ethylacetate containing 2% conc. NH4OH. The product, 4-(9-bromo-8-chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-ylidene)-piperidine (470 mg., 93% yield) was obtained as a white solid, m.p. 198-199° C.; MS (CI, M+H)=391; anal.: found: C, 55.32; H, 4.15; N, 7.12; C18H16BrClN2O requires: C, 55.19; H, 4.31; N, 7.15.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[C:10]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[C:12]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC>C(O)(=O)C.[Zn]>[CH2:16]([O:15][C:13](=[O:14])[C:12]1[CH:23]=[C:24]([NH2:26])[CH:25]=[C:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:29])[CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(OCc1ccccc1)c1cc(C(=O)OCc2ccccc2)cc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOCC
Product: Nc1cc(C(=O)OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.8 %

Procedure:
In acetic acid (15 mL) was stirred 5-nitroisophthalic acid dibenzyl ester (1.3 g, 3.3 mmol). To this was added in parts zinc dust (1.75 g, 26.6 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was filtered free of insoluble material and the acetic acid solution evaporated at reduced pressure. This residue was dissolved in ethyl acetate (120 mL) and washed successively with saturated sodium bicarbonate solution (50 mL), water (50 mL), and brine (50 mL). The organic phase was dried over magnesium sulfate and evaporated in vacuo to give a solid. The solid was stirred into ether (75 mL) and brought to reflux. The solution allowed to recrystallize to give 260 mg (22%) of a white solid. MS: M+1=362.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][C:10]=1[O:11][C:12]1[N:17]=[C:16]([NH:18][CH2:19][C:20]([O:22]CC)=O)[C:15]([N+:25]([O-])=O)=[C:14]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH:30]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>[Zn].O1CCCC1>[CH2:1]([O:8][C:9]1[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][C:10]=1[O:11][C:12]1[NH:17][C:16]2[C:15](=[C:14]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH:30]=3)[N:13]=1)[NH:25][C:20](=[O:22])[CH2:19][N:18]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CNc1nc(Oc2cc(C#N)ccc2OCc2ccccc2)nc(Oc2cccc(C(=O)N(C)C)c2)c1[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cccc(OC2=C3NC(=O)CN=C3NC(Oc3cc(C#N)ccc3OCc3ccccc3)=N2)c1
Temperature: 70 °C
Yield: 139.8 %

Procedure:
2-(2-Benzyloxy-5-cyanophenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-(dimethylaminocarbonyl)phenoxy)pyrimidine (1.1 g, 1.80 mmol), a compound of formula (H), and granular zinc (0.5 g) were mixed with tetrahydrofuran (50 mL) and 10% aqueous HCl (10 mL). The reaction mixture was heated for 30 minutes at 70° C. The volatiles were evaporated. Saturated aqueous NaHCO3 was added and the solution extracted with ethyl acetate (300 mL). The organic layer was dried (Na2SO4) and evaporated to afford 1.35 g of 2-(2-benzyloxy-5-cyanophenoxy)-4-(3-(dimethylaminocarbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone, a compound of formula (J).