Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH2:19][CH2:18][N:17]3[S:24]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])(=[O:26])=[O:25])=[O:13])=[CH:7][CH:6]=1)C.[OH-].[Na+]>O1CCCC1.CO>[Cl:33][C:31]1[CH:30]=[CH:29][C:28]([O:34][CH3:35])=[C:27]([S:24]([N:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:36])=[O:3])=[CH:6][CH:7]=4)=[O:13])[CH:15]=3)[NH:20][CH2:19][CH2:18]2)(=[O:26])=[O:25])[CH:32]=1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCN3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCNc2ccc(C(=O)Nc3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-benzoic acid ethyl ester (30 mg, 0.06 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was treated with NaOH 2N (2 mL) and warmed until a clear solution was obtained. The mixture was stirred at room temperature 2 hours, the organic solvents were then partially removed. The aqueous slurry was acidified with HCl 1N (4 mL) and the resulting precipitate filtered, washing with water. 4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-benzoic acid was obtained as a white solid, 26 mg (91%), MS (ISP): m/e=499.9, 501.9 (M−H); δH (300 MHz; d6-DMSO) 12.67 (1H, s), 10.15 (1H, s), 7.91 (4H, s), 7.89 (1H, s), 7.81 (1H, s), 7.73 (1H, d), 7.63 (1H, d), 7.23 (1H, d), 6.88 (1H, bs), 6.66 (1H, d), 3.64 (2H, bs), 3.53 (3H, s), 2.99 (2H, bs).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=3)=[CH:11][CH:12]=2)[N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[N:4]=1.[C-:30]#[N:31].[Na+].CS(C)=O>O>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:5]1[C:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=3)=[CH:11][CH:12]=2)=[CH:7][C:3]([CH2:2][C:30]#[N:31])=[N:4]1
Reactant: [C-]#N
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(CBr)nn3-c3ccccc3Cl)s2)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(CC#N)nn3-c3ccccc3Cl)s2)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 54.3 %

Procedure:
A mixture of the 3-bromomethyl-1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-thiophen-2-yl]-1H-pyrazole (720 mg, 1.42 mmol), NaCN (250 mg, 5.1 mmol), and DMSO (10 mL) was stirred in a sealed vial at 100° C. for 5 h, diluted with water, and extracted with EtOAc. The combined extracts were washed with water, brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified by flash chromatography (0-80% EtOAc/hexanes) to give the title compound as a white solid (350 mg, 54%). 1HNMR (CDCl3): δ 8.03 (d, 1H), 7.84 (m, 1H), 7.72 (m, 1H), 7.58-7.44 (m, 5H), 7.22 (d, 1H), 6.79 (d, 1H), 6.73 (s, 1H), 3.87 (s, 2H), 3.09 (s, 3H). MS(ES): 454 [M+H]+.
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:10]>>[Cl:10][C:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=Cc1ccccc1
Reactant: Cl
Product: ON=C(Cl)c1ccccc1

Procedure:
60.5 g (0.5 mol) of benzaldoxime was suspended in 390 ml of 8N hydrochloric acid and chlorine gas was bubbled into the suspension while stirring and maintaining the reaction temperature at from 5° to 15° C. The oxime immediately showed a green color upon reaction with chlorine and, after allowing the reaction mixture to stand, pale yellow crystals of α-chlorobenzaldoxime precipitated. Filtration of the reaction mixture yielded 66 g of crystals having a melting point of 45°-47° C. Yield, about 84%.
Reaction SMILES: [Li]C(C)(C)C.CCCCC.Br[C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH:19]=2)[N:14]([Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:13]=1.[C:35](=[O:37])=[O:36]>C1COCC1>[C:31]([Si:28]([CH3:30])([CH3:29])[N:14]1[C:15]2=[N:16][CH:17]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH:19]=[C:20]2[C:12]([C:35]([OH:37])=[O:36])=[CH:13]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: O=C=O
Reactant: CC(C)(C)[Si](C)(C)n1cc(Br)c2cc(-c3cccc(F)c3)cnc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)[Si](C)(C)n1cc(C(=O)O)c2cc(-c3cccc(F)c3)cnc21
Yield: 76 %

Procedure:
1.7 M solution of t-BuLi in pentane (24.8 mL, 42.2 mmol) was added dropwise over a period of 25 min to a stirred and cooled (−78° C.) solution of 9 (8.20 g, 20.3 mmol) in THF (93 in L) at such a rate that the temperature did not exceed −65° C. After the addition, the mixture was stirred for 1 h at −78° C. Dry gaseous CO2 was introduced to the flask over a period of 10 min (exothermic reaction, external dry ice bath). When the exothermic reaction subsided, cooling bath was removed, and the mixture was allowed to reach 0° C. The mixture was then separated between brine-AcOEt. The aqueous layer was extracted with AcOEt (2×). Combined organic solutions were dried dried (MgSO4), concentrated and purified by SGC with CH2Cl2:AcOEt as eluent in gradient (up to 12% AcOEt) to afford 10 (5.74 g, 76%) as tan solid. 1H NMR (400 MHz, CDCl3) δ 0.71 (s, 6H), 0.99 (s, 9H), 7.05-7.12 (m, 1H), 7.37-7.42 (m, 1H), 7.43-7.50 (m, 2H), 8.11 (s, 1H), 8.58 (d, J=2.3 Hz, 1H), 8.61 (d, J=2.3 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH:4]([CH2:5][CH:6]=[C:7]2[C:9]([O:11][CH3:12])=[O:10])[CH2:3]1.[CH2:13]([SH:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:13]([S:15][CH:6]1[CH2:5][CH:4]2[N:8]([C:2](=[O:1])[CH2:3]2)[CH:7]1[C:9]([O:11][CH3:12])=[O:10])[CH3:14]
Reactant: CCS
Reactant: COC(=O)C1=CCC2CC(=O)N12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSC1CC2CC(=O)N2C1C(=O)OC
Reaction time: 1 h

Procedure:
A stirred solution of methyl 7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (9) (0.050 g) in dry dimethylformamide (1 ml) at room temperature was treated with ethane thiol (0.10 ml) followed by powdered potassium carbonate (0.023 g). After a period of 1 hour, the excess thiol was blown off in a stream of argon and the residue concentrated at 30° under reduced pressure. The residual gum was dissolved in ethyl acetate, washed with brine and dried over sodium sulphate. The ethyl acetate solution was concentrated and the three diastereoisomers (10, 11 and 12 in order of increasing polarity) were separated by column chromatography on silica gel 60 (<230 mesh), eluting with 60°-80° petroleum ether/ethyl acetate 7:3.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[C:4]([CH3:10])[CH:3]=1.[C-:11]#[N:12].[K+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:11]#[N:12])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1CCl
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Product: Cc1cc(Cl)ccc1CC#N
Temperature: 100 °C
Yield: 70.4 %

Procedure:
Step B To a solution of 4-chloro-2-methylbenzyl chloride (5.2 g, 30 mmol) in ethanol (40 mL) was added an aqueous solution (30 mL) of KCN (5 g, 77 mmol) at room temperature. The reaction mixture was then heated at 100° C. for 2 h. The mixture was cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:10, then 1:4) to give 4-chloro-2-methylbenzyl cyanide as a yellow oil (3.5 g, 66%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:41][OH:42]>O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:41][OH:42])=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
Intermediate (16b) (7.7 g, 17.2 mmol) was dissolved in pyridine (40 mL, 500 mmol). Hydroxylamine hydrochloride (3.6 g, 51.5 mmol) was added, followed by the addition of water (20 mL, 1 mol). The mixture was stirred at room temperature overnight. Water (50 ml) was added and the mixture was stirred for 20 minutes. The precipitant was filtered off and dried to yield intermediate (16c) (7.8 g). MS m/z: [M+H+] calcd for C26H28FN3O4, 466.2. found 466.4. 1H-NMR (CDCl3): 9.78 (1H, s), 7.81 (1H, d), 7.48 (2H, m), 7.26 (1H, s), 7.0 (4H, m), 6.20 (1H, d), 5.53 (1H, d), 5.50 (2H, s), 4.55 (2H, q), 1.43 (3H, t), 1.25 (9H, s).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:30])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:22])[C:14]([C:18]([NH:20][OH:21])=[NH:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:38]([C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=1[O:49][CH:50]([CH3:52])[CH3:51])[C:43](Cl)=O)#[N:39]>O1CCOCC1>[CH2:1]([O:5][C:6](=[O:30])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:22])[C:14]([C:18]3[N:19]=[C:43]([C:42]4[CH:46]=[CH:47][C:48]([O:49][CH:50]([CH3:52])[CH3:51])=[C:40]([C:38]#[N:39])[CH:41]=4)[O:21][N:20]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1C#N
Reactant: CCCCOC(=O)CC1c2ccc(C(=N)NO)c(C)c2CCN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCOC(=O)CC1c2ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c(C)c2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 11.1 %

Procedure:
To a solution of 1,1-dimethylethyl 1-[2-(butyloxy)-2-oxoethyl]-6-[(hydroxyamino)(imino)methyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 19; 264 mg, 0.629 mmol) in dioxane (4 ml) was added triethylamine (0.263 ml, 1.89 mmol) followed by dropwise addition of 3-cyano-4-[(1-methylethyl)oxy]benzoyl chloride (preparation described in WO 2008128951; 169 mg, 0.755 mmol) in dioxane (2 ml). The resulting mixture was stirred at room temperature for 90 min, then heated at 100° C. for 24 h. The mixture was cooled to room temperature and most of the solvent removed in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The layers were separated, and the aqueous layer further extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography, eluting with 5-25% ethyl acetate in cyclohexane, gave the title compound as a pale yellow oil (41 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[CH3:10].[OH:11]O>C(O)=O.O>[Cl:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([C:8]([OH:11])=[O:9])=[CH:6][N:7]=1
Reactant: Cc1cc(C=O)cnc1Cl
Reactant: OO
Solvent: O
Solvent: O=CO
Product: Cc1cc(C(=O)O)cnc1Cl
Temperature: 0 °C
Reaction time: 15 h

Procedure:
A solution of 6-chloro-3-formyl-5-methyl-pyridine (10 g, 64 mmol) in formic acid (200 mL) is cooled at 0° C. and an aq. 50% wt solution of H2O2 in water (9.6 mL, 360 mmol) is added at this temperature. The mixture is stirred at 0° C. for 15 h, carefully diluted with water (200 mL) and extracted with DCM (8×100 mL). The combined org. extracts are washed with 1M aq. HCl (100 mL) (check for remaining peroxide), dried (MgSO4), filtered and evaporated. The residue is dried to give 6-chloro-5-methyl-nicotinic acid (9.56 g); LC-MS: tR=0.72 min, [M+1]+=172.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH2:19][CH3:20])=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reaction time: 16 h

Procedure:
To the liquid mixture of 3-fluoro-4-nitrobenzoic acid 9.71 g and ethanol 35 mL, conc. sulfuric acid 1.6 mL was added, followed by 16 hours' heating under reflux. After distilling the solvent off, water and tert-butyl methyl ether were added to the residue. The organic layer was extracted, washed with water and dried over magnesium sulfate. Distilling the solvent off, 7.40 g of the title compound was obtained.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6]1)(C)C.I[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.[F-].[Cs+]>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:5]1[CH:9]=[CH:8][C:7]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)=[CH:6]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Reactant: COC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc[nH]c2)cc1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of 1-(triisopropylsilyl)pyrrole-3-boronic acid (prepared according to the method of Alvarez, A.; Guzman, A.; Ruiz, A.; Velarde, E., J. Org. Chem. 1992, 57, 1653-1656) (6.12 g, 22.9 mmol) in anhydrous dimethoxyethane (76 mL) is added methyl 4-iodobenzoate (96.61 g, 25.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.484 g, 0.69 mmol) and cesium fluoride (6.96 g, 45.8 mmol). The mixture is heated at reflux under a nitrogen atmosphere for 17 h. The reaction mixture is cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (4×25 mL). The extract is washed with water, dried over MgSO4 and concentrated to give the crude product. The product is purified by silica gel chromatography (5-15% ethyl acetate/hexane) to give 2.69 g of methyl 4-(1H-pyrrol-3-yl)-benzoate as a white solid (58% yield). 1H NMR (300 MHz, DMSO-d6): δ 3.83 (s, 3H), 6.53 (m, 1H), 6.83 (m, 1H), 7.35 (m, 1H), 7.66 (d, 2H, J=8.4 Hz), 7.86 (d, 2H, J=8.4 Hz), 11.11 (br s, 1H).
Reaction SMILES: C(N(CC)CC)C.[S:8](Cl)([CH3:11])(=[O:10])=[O:9].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:35][CH2:34][C:29]4([CH2:32][CH:31]([OH:33])[CH2:30]4)[CH2:28][CH2:27]3)=[N:24][CH:25]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:11][S:8]([O:33][CH:31]1[CH2:30][C:29]2([CH2:34][CH2:35][N:26]([C:23]3[CH:22]=[CH:21][C:20]([C:17]4[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=4)=[CH:25][N:24]=3)[CH2:27][CH2:28]2)[CH2:32]1)(=[O:10])=[O:9]
Reactant: OC1CC2(CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CC2(CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)C1
Yield: 99.7 %

Procedure:
The process is performed according to the procedure described in Example 6 (step 6.2.). 3.25 mL (23.34 mmol) of triethylamine and then 0.91 mL (11.67 mmol) of mesyl chloride are added to a solution of 2.43 g (7.78 mmol) of 7-[5-(4-fluorophenyl)pyridin-2-yl]-7-azaspiro[3.5]nonan-2-ol, obtained in step 10.2., in 25 mL of dichloromethane. 3.03 g of product are obtained in the form of a yellow oil, which is used without further purification in the following step.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:28][CH3:29])[C:10]1=[O:30])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH2:28]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([F:20])=[C:14]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:13]=2)[C:18](=[O:19])[N:9]([OH:8])[C:10]1=[O:30])[CH3:29]
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCN(C)CC3)cc21
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Product: CCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCN(C)CC3)cc21
Yield: 94 %

Procedure:
Five percent Pd/BaSO4 (110 mg) was added to a solution of 3-benzyloxy-1-ethyl-6-fluoro-7-(4-methylpiperazin-1-yl)-1H-quinazoline-2,4-dione (Example H, 0.14 g, 0.33 mmol) in 50 mL of THF. The mixture was shaken under 50 PSI of hydrogen for 60 hours, filtered, and concentrated to afford 0.1 g of the title compound as a solid, mp 132-134° C.
Reaction SMILES: Cl.Cl.[N:3]1([C:10]2[CH:11]=[C:12]([CH2:20][CH3:21])[CH:13]=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[CH2:23][C:24]1[N:25]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:27][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH2:20]([C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([N:3]3[CH2:9][CH2:8][CH2:7][N:6]([CH2:23][C:24]4[N:25]=[C:26]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[S:27][CH:28]=4)[CH2:5][CH2:4]3)[CH:11]=1)[N:18]=[CH:17][CH:16]=[CH:15]2)[CH3:21]
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: CCc1cc(N2CCCNCC2)c2ncccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc(N2CCCN(Cc3csc(-c4ccccc4)n3)CC2)c2ncccc2c1
Temperature: 60 °C
Yield: 51.3 %

Procedure:
A mixture of 8-[1,4]-diazepan-1-yl-6-ethylquinoline dihydrochloride (0.32 g, 1 mmol, 1 equiv), 4-chloromethyl-2-phenylthiazole (0.21 g, 1 equiv) and Cs2CO3 (1.63 g, 5 equiv) in 5 mL of DMF was heated at 60° C. for 3 hours and then cooled to room temperature. EtOAc (˜70 mL) was added and the mixture washed with saturated aqueous NaHCO3 (70 mL) and brine (70 mL), dried over magnesium sulfate and concentrated. The residue was purified by silica gel flash column chromatography using 5% to 40% EtOAc in hexanes. Silica gel chromatography was repeated using 5% to 10% MeOH in EtOAc to afford the title compound as a light tan solid (0.22 g). 1H NMR (400 MHz, CD3OD) δ 8.65 (dd, 1H, J=1.8 and 4 Hz), 8.04 (dd. 1H, J=1.5 and 8.4 Hz), 7.91 (m, 1H), 7.90 (d, 1H, J=2.2 Hz), 7.41 (m, 3H), 7.36 (s, 1H), 7.31 (dd, 1H, J=4 and 8 Hz), 7.11 (s, 1H), 6.98 (s, 1H), 3.89 (s, 2H), 3.69 (m, 2H), 3.57 (t, 2H, J=5.87 Hz), 3.11 (m, 2H), 2.92 (t, 2H, J=5.3 Hz), 2.72 (q, 2H, J=7.0 Hz), 2.10 (m, 2H), 1.28 (t, 3H, J=7.0 Hz). MS (ES) m/z 429.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([O:17]C)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.O.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(NC(=O)OC(C)(C)C)cn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)O
Reaction time: 8 h
Yield: 80.6 %

Procedure:
Methyl 4-(tert-butoxycarbonylamino)-1-methyl-1H-pyrrole-2-carboxylate (Eldon E. Baird and Peter B. Dervan, J. Am. Chem. Soc. 1996, 118, 6141-6146) (5.0 g, 19.67 mmol) in 120 ml of 1:1 THF/H2O was added 8 g of NaOH in 30 ml of water. The mixture was stirred overnight, concentrated, diluted with water, extracted with EtAc/Hexane (1:1). The aqueous solution was adjusted to pH 4.0 with 20% H3PO4 and extracted with EtAc (4×60 ml). The organic solutions were combined, dried over MgSO4, filtered, evaporated and crystallized with ethanol/EtAc/Hexane to afford 3.81 g (81%) of the title product. 1H NMR (CD3OD) 12.79 (s, 1H), 10.48 (br, 1H), 7.51 (s, 1H), 6.99 (s, 1H), 3.78 (s, 3H), 1.49 (s, 9H); 13C NMR 158.47, 153.82, 123.64, 121.56, 109.58, 79.52, 37.06, 28.42; MS m/z− 239.2 (M−H).
Reaction SMILES: F[C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=O.O.[NH2:22][NH2:23]>CCO>[F:13][C:9]1[CH:8]=[C:7]([NH:6][C:4]2[C:3]3[C:2](=[CH:17][CH:16]=[C:15]([N+:18]([O-:20])=[O:19])[CH:14]=3)[NH:23][N:22]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Nc1cccc(F)c1)c1cc([N+](=O)[O-])ccc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]nc(Nc3cccc(F)c3)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
2-Fluoro-N-(3-fluoro-phenyl)-5-nitro-benzamide (1.1 μg, 4 mmol) was suspended in EtOH (25 mL) and the mixture heated to ˜60° C. To the resulting solution was added hydrazine monohydrate (1.06 mL, 20 mmol). The mixture was heated at reflux for 5 minutes and a yellow solid was precipitated out. The mixture was allowed to cool to room temperature then the solid was filtered off. The solid was dissolved in phosphorous oxychloride (40 mL) and the mixture heated at 90° C. for 1.5 hr then allowed to cool to room temperature and stirred for overnight. The reaction mixture was concentrated and partitioned between EtOAc and saturated sodium bicarbonate. The organic phase was dried over MgSO4 and concentrated to afford the title compound as a red solid (0.7 g, 64%). MS (ESI) m/z=273 [M+H]+. 1H NMR (400 MHz, d6-DMSO) δ 12.84 (s, 1H), 9.69 (s, 1H), 9.22 (d, J=2.0 Hz, 1H), 8.19 (dd, J=9.2 and 2.0 Hz, 1H), 7.77 (m, 1H), 7.54 (d, J=9.2 Hz, 1H), 7.37 (m, 2H), 6.69 (m, 1H)
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[C:5](=[O:18])[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1.O.O.Cl[Sn]Cl>C(O)C.O.N>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][N:6]2[C:5](=[O:18])[C:4]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:3]=[C:2]2[CH3:1])=[CH:14][CH:13]=1
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CCc1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: N
Solvent: CCO
Solvent: O
Product: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CCc1ccc(N)cc1
Temperature: 50 °C
Yield: 97.4 %

Procedure:
A mixture of 2-methyl-3-[2-(4-nitro-phenyl)-ethyl]-5,5-diphenyl-3,5-dihydro-imidazol-4-one (205 mg, 0.5 mmol) and SnCl2.2H2O (591 mg, 2.6 mmol) in 10 mL ethanol is heated to 50° C. for 5 hours. The reaction mixture is cooled to room temperature, diluted with water and aqueous ammonia is added to reach pH 8-9. The mixture is filtered, the filtrate evaporated and the residue purified by flash chromatography. ISCO Companion CombiFlash, 12 g silica gel, methylene chloride/ethanol to yield 3-[2-(4-amino-phenyl)-ethyl]-2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one (180 mg, 85%). LC/MS at 254 nm; [M+H] 370; Rt 2.424 min.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[N+:2]=[N-:3].[NH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].C([O-])([O-])=O.[Na+].[Na+].C(O)C>O>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[N+:2]=[N-:3]
Reactant: NCCC(=O)O
Reactant: [N-]=[N+]=Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=Nc1ccc(NCCC(=O)O)c([N+](=O)[O-])c1
Temperature: 55 °C

Procedure:
4-azido-1-fluoro-2-nitro-benzene (90 mg) is mixed with an aqueous solution (0.5 ml) containing 3-aminopropionic acid (53 mg) and Na2CO3 (106 mg). Following addition of 2 ml of ethanol and 0.5 ml of water, the solution is heated for 24 h at 55° C. After removal of the unreacted materials by several ether extractions, the product (3-(N-(4-azido-2-nitrophenyl)-amino)propionic acid) is obtained by ether extraction of the acidified (pH 2.0) aqueous phase.
Reaction SMILES: O.[NH2:2][NH2:3].[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[CH:11][CH:12]=O)[CH:5]=1>CC(O)(C)C>[N:2]1[NH:3][CH:10]([C:6]2[CH:5]=[N:4][CH:9]=[CH:8][CH:7]=2)[CH2:11][CH:12]=1
Reactant: O=CC=Cc1cccnc1
Reactant: NN
Solvent: O
Solvent: CC(C)(C)O
Product: C1=NNC(c2cccnc2)C1

Procedure:
Under N2 atmosphere, hydrazine hydrate (3.65 mL, 2 equiv.) was added to a solution of 3-(3-pyridyl)acrolein (5.0 g) in t-BuOH (25 mL). The mixture was refluxed for 3 days, followed by evaporation under reduced pressure. The residue was taken up in DCM and washed with 5% aqueous NaHCO3. The organic phase was dried over Na2SO4 and evaporated under reduced pressure. This gave 5.0 g of a red oil, containing 74% of the anticipated product and 26% of the hydrazone intermediate that failed to undergo ring-closure. This material was used in subsequent steps without further purification. Characteristic pyrazoline signals in 1H NMR (400 MHz, CDCl3): δ 2.63-2.75 (m, 1H), 3.13-3.25 (m, 1H) 4.72-4.82 (m, 1H), 6.85 (br s, 1H).