Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[CH:3][C:2]1=[O:7].[CH:8]([Li])=[CH2:9]>>[CH:8]([CH:4]1[CH2:5][CH2:6][O:1][C:2](=[O:7])[CH2:3]1)=[CH2:9]
Reactant: [Li]C=C
Reactant: O=C1C=CCCO1
Product: C=CC1CCOC(=O)C1

Procedure:
5,6-Dihydro-2H-pyran-2-one is treated with vinyllithium in the presence of a cuprous salt to obtain 4-ethenyl-tetrahydro-2H-pyran-2-one which is reacted with 3-bromopyridine under conditions of a Heck condensation (J. Org. Chem. 43, 2952 (1978), e.g. in the presence of Pd(OAc)2 and tri-o-tolylphosphine) to obtain 4-[2-(3-pyridyl)-ethenyl]-tetrahydro-2H-pyran-2-one. The lactone is reduced to the corresponding lactol, e.g. with diisobutyl aluminum hydride, which is condensed under Wittig conditions with e.g. methyl (triphenylphosphoranylidene)-acetate to obtain methyl 7-hydroxy-5-[2-(3-pyridyl)-ethenyl]-hept- 2-enoate. The two double bonds are then saturated using e.g. hydrogen in the presence of palladium on charcoal catalyst to obtain methyl 7-hydroxy-5-[2-(3-pyridyl)-ethyl]-heptanoate. The alcohol is converted to a reactive intermediate, e.g. the mesylate derivative, treated with e.g. sodium cyanide to obtain the nitrile which is then reduced to the methyl ester of the amine of formula XII wherein Het represents 3-pyridyl, A and M represent 1,3-propylene and B represents 1,2-ethylene.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:11]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[N:10]=[C:9]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[S:8]1)=[N+]=[N-].Cl.CO>CO.[Pd]>[NH2:1][CH2:4][CH2:5][CH2:6][C:7]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:11]([C:12](=[O:17])[C:13]([CH3:16])([CH3:14])[CH3:15])[N:10]=[C:9]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[S:8]1
Reactant: CC(C)(C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN=[N+]=[N-])c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN)c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2,2-dimethylpropan-1-one (100 mg, 0.225 mmol) in MeOH (3 mL) was added 1N HCl/MeOH (1 mL) followed by 10% Pd/C (40 mg, wet, Degussa type). After stirring under a H2 balloon for 3 hours, the mixture was filtered and concentrated under reduced pressure to provide the product as a white foam. MS ESI (+) m/z 418 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.47 (m, 1H), 7.43 (d, 2H, J=7 Hz), 7.35 (t, 2H, J=7 Hz), 7.25 (m, 1H), 7.11 (m, 2H), 3.47 (m, 1H), 3.22 (m, 1H), 2.85 (m, 2H), 2.33 (m, 1H), 1.92 (m, 1H), 1.48 (m, 2H), 1.39 (s, 9H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C)(C)[O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:35]2[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=2)=[CH:32][C:33]#[N:34])=[CH:27][C:26]=1[O:45][CH3:46])(C)(C)C.CCOCC>C1COCC1>[CH3:42][O:41][C:39]1[CH:40]=[C:35]([C:31]([C:28]2[CH:29]=[CH:30][C:25]([OH:24])=[C:26]([O:45][CH3:46])[CH:27]=2)=[CH:32][C:33]#[N:34])[CH:36]=[C:37]([O:43][CH3:44])[CH:38]=1
Reactant: COc1cc(OC)cc(C(=CC#N)c2ccc(O[Si](C)(C)C(C)(C)C)c(OC)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2ccc(O)c(OC)c2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
Tetrabutylammonium fluoride (1.0 M solution in THF, 5.55 ml, 5.55 mmol) was added at rt to a stirred solution of 3-[4-(tert-butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-3-(3,5-dimethoxy-phenyl)-acrylonitrile (1.97 g, 4.63 mmol) in THF (35 ml). The colorless clear solution immediately turned into brown/red wine color. The reaction should be done within one hour. Ice water (15 ml) was poured into the reddish solution, followed by addition of ether (80 ml). The mixture was washed with water (2×100 ml), dried over MgSO4, filtered and concentrated to a yellow oil, which was lyophilized to give 3-(3,5-dimethoxy-phenyl)-3-(4-hydroxy-3-methoxy-phenyl)-acrylonitrile as a white gummy solid (1.26 g, 88%): mp, 120-122° C.; 1HNMR (DMSO-d6) δ 9.68 (s, 1H, OH group of one isomer), 9.60 (s, 1H, OH group of the other isomer), 7.11-6.61 (m, 8H, Ar), 6.49-6.46 (m, 4H, Ar), 6.23 (s, 1H, double bond proton of one isomer), 6.11 (s, 1H, double bond proton of the other isomer), 3.78-3.74 (multiple singlets, 18H, 6OCH3), isomer ratio based on 1HNMR was 49%:51%; 13C NMR (CDCl3) δ 163.0, 162.9, 160.9, 160.8, 148.2, 147.7, 146.6, 146.3, 141.6, 139.2, 130.9, 128.9, 124.2, 122.9, 118.5, 118.2, 114.6, 114.5, 112.3, 110.6, 107.9, 107.2, 102.3, 102.2, 93.7, 93.1, 56.4, 56.2, 55.7, 55.6; Anal. Calcd. For C18H17NO4: C, 69.44; H, 5.50; N, 4.50. Found: C, 69.24; H, 5.38; N, 4.27.
Reaction SMILES: CC1C=CC([C:8](=O)[CH2:9][C:10](=[O:12])C)=CC=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:26])[CH:22]=[C:23]([CH3:25])[NH2:24])=[CH:17][CH:16]=1>>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([C:22]2[CH:8]=[CH:9][C:10](=[O:12])[NH:24][C:23]=2[CH3:25])=[O:26])=[CH:19][CH:20]=1
Reactant: CC(N)=CC(=O)c1ccc(C)cc1
Reactant: CC(=O)CC(=O)c1ccc(C)cc1
Product: Cc1ccc(C(=O)c2ccc(=O)[nH]c2C)cc1

Procedure:
first using 1-(4-methylphenyl)-1,3-butanedione to prepare 3-(4-methylphenyl)-1-methyl-3-oxo-1-propenamine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:12](O)([CH2:15][CH3:16])([CH3:14])[CH3:13].[OH-].[Na+]>FC(F)(F)C(O)=O>[C:12]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[CH:7][C:8]=1[OH:11])([CH2:15][CH3:16])([CH3:14])[CH3:13]
Reactant: CCC(C)(C)O
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)(C)c1cc(C(C)(C)C)ccc1O
Yield: 40 %

Procedure:
4-t-butylphenol (73 g, 0.49 mole) is dissolved in 200 ml anhydrous trifluoroacetic acid (TFA). T-amyl alcohol (47 g, 0.53 mole) is added with stirring. The mixture is stoppered and stirred for 19 hours at ambient (~22° C.) temperature. The solution is then diluted into 400 ml of 1M NaOH, and the resulting upper organic layer is isolated in a separatory funnel. The crude product is dried over anhydrous magnesium sulfate. The product, 2-t-amyl-4-t-butylphenol, is purified by eluting 35 g of the mixture with 60:40 hexanes:dichloromethane (v/v) in a 5×20 cm silica column and eluted with 300 to 700 ml of solvent and collected in aliquots of 50 ml. Aliquots showing a single spot by Thin Layer Chromatography (TLC) (on silica eluted with 60:40 hexanes:dichloromethane v/v)) are combined and rotoevaporated to a thick syrup, typically giving a 40% yield.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:47]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH:48]=[CH2:49]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[N+:22]([C:11]1[CH:10]=[C:9]([CH:49]=[CH:48][CH2:47][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:21]=[CH:20][C:12]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: C=CCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(C=CCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
19 mg of palladium acetate (II) was added to 5 mL of toluene solution containing 0.50 g of tert-butyl 4-bromo-2-nitrobenzoate, 50 mg of tri(o-tolyl)phosphine, 0.44 mL of allylbenzene and 0.46 mL of triethylamine, and the resulting mixture was heated to reflux under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, 20 mg of palladium acetate (II) was added and the resulting mixture was heated to reflux for 7 hours. After the reaction mixture was cooled to room temperature, Insoluble were removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=30:1] to obtain 0.31 g of tert-butyl 2-nitro-4-(3-phenyl-1-propenyl)benzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[N:10]=[N:9]2)=[CH:5][CH:4]=1.[H-].[Na+].C[O:21][C:22](=O)[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1>C1COCC1>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C:22](=[O:21])[CH2:14][C:13]([C:11]2[N:10]=[N:9][N:8]([CH2:7][C:6]3[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:12]=2)=[O:15])=[CH:25][CH:26]=1
Reactant: COC(=O)Cc1ccc(F)cc1
Reactant: COc1ccc(Cn2cc(C(C)=O)nn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(C(=O)CC(=O)Cc3ccc(F)cc3)nn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a solution of 1-[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]ethanone (1.0 g, 4.30 mmol) in anhydrous THF (25 mL) was added NaH (0.38 g, 9.5 mmol) at 0° C. The mixture was stirred at RT for 1 hour, and (4-fluoro-phenyl)-acetic acid methyl ester (1.67 g, 10.0 mmol) was added at 0° C. and the mixture was refluxed overnight. The reaction mixture was evaporated and the residue was purified via column chromatography (silica gel, EtOAc/Petroleum ether 1:5) to yield the title compound (0.6 g, 38.0%) as a colorless oil.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:10]1[O:14][N:13]=[C:12]([CH2:15][NH2:16])[N:11]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH:16][CH2:15][C:12]2[N:11]=[C:10]([C:2]3[O:1][C:9]4[CH:8]=[CH:7][N:6]=[CH:5][C:4]=4[CH:3]=3)[O:14][N:13]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCc1noc(-c2cc3cnccc3o2)n1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NCc2noc(-c3cc4cnccc4o3)n2)CC1
Reaction time: 72 h

Procedure:
A solution of C-(5-furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-yl)methylamine (Preparation 14, 350 mg, 1.62 mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (322 mg, 1.62 mmol) in anhydrous CH2Cl2 (5 mL) was stirred for 10 min. Na(AcO)3BH (412 mg, 1.94 mmol) was added, then the mixture was stirred for 3 d. Standard aqueous work-up, followed by column chromatography (EtOAc-IH, 1:1) gave the title compound: m/z (ES+)=400.0 [M+H]+.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1[CH:19]=[C:20]([O:24][CH2:25][C@@H:26]2[CH2:29][CH2:28][N:27]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:21]=[N:22][CH:23]=1)(C1C=CC(C)=CC=1)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-:54]>C1COCC1>[F:54][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1[CH:19]=[C:20]([O:24][CH2:25][C@@H:26]2[CH2:29][CH2:28][N:27]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:21]=[N:22][CH:23]=1
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OCCCCC#Cc2cncc(OC[C@@H]3CCN3C(=O)OC(C)(C)C)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(C#CCCCCF)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 100 %

Procedure:
A mixture of 5-(6-tosyloxy-1-hexynyl)-3-(1-tert-butoxycarbonyl -2(S)-azetidinylmethoxy)pyridine (35 mg, 68 μmol) in 1 mL of 1.0 M solution of TBAF in THF was stirred at room temperature for 10 h. The reaction mixture concentrated. The residue was purified by chromatography with hexane-EtOAc (3:1) to give a viscous oil (25 mg, 100%), [α]D−40.6 (c 1.4, CHCl3). 1H NMR (CDCl3) δ 8.24 (s, 2H), 7.24 (m, 1H), 4.52 (dt, 2H, J=47.3, 6.0 Hz), 4.56-4.47 (m, 1H), 4.38-4.26 (m, 1H), 4.12 (dd, 1H, J=10.2, 2.7 Hz), 3.89 (t, 2H, J=7.8 Hz), 2.50 (t, 2H, J=6.9 Hz), 2.42-2.21 (m, 2H), 2.04-1.69 (m, 4H), 1.42 (s, 9H); 13C NMR (CDCl3) δ 156.13, 154.40, 144.85, 137.26, 123.22, 121.05, 92.94, 83.54 (d, J=164.7 Hz), 79.74, 77.69, 68.69, 60.00, 53.62, 47.09, 29.53 (d, J=20.2 Hz), 28.38, 24.31 (d, J=5.0 Hz), 19.03; 19F NMR (CDCl3, CFCl3) δ 135.4 (tt, J=47.3, 24.4 Hz).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)(Cl)Cl>[C:14]1([C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][Cl:5])=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)CCCCCCl
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CCCCCCl)c1ccccc1
Reaction time: 0.25 h
Yield: 34.6 %

Procedure:
Aluminum chloride (16 g, 0.12 mol) is suspended in carbon tetrachloride (80 ml) and 6-chlorohexanoyl chloride (20 g, 0.12 mol) is added dropwise to the suspension with ice-cooling. After completion of addition, the mixture is stirred for 15 minutes and benzene (7.8 g, 0.1 mol) is added dropwise to the mixture with ice-cooling. After stirring with ice-cooling for 1 hour, the mixture is poured into ice-hydrochloric acid and extracted with carbon tetrachloride. The carbon tetrachloride extract is washed with water, saturated aqueous sodium bicarbonate, water and then saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The dried solution is distilled to obtain 5-chloropentyl phenyl ketone (7.3 g), b.p. 143°-150° C./0.5 mmHg.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.Br[C:17]1[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([Cl:23])[CH:22]=1>>[CH3:13][C:7]1([CH3:14])[O:8][CH2:9][C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][C:2]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([F:24])[CH:18]=3)=[CH:15][C:6]1=2
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Product: CC1(C)OCC(=O)Nc2ccc(-c3cc(F)cc(Cl)c3)cc21

Procedure:
Prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-bromo-5-chloro-1-fluorobenzene generally according to the coupling procedure described in examples 82 and 1. 1H NMR (DMSO-d6): δ 10.01 (s, 1H), 7.61-7.65 (m, 4H), 7.36-7.39 (m, 1H), 7.18 (d, J=8.54 Hz, 1H), 4.26 (s, 2H), 1.62 (s, 6H); MS (ESI) m/z 320/322 ([M+H]+); MS (ESI) m/z 318/320 ([M−H]−). Anal. calcd for C17H15ClFNO2: C: 63.86; H: 4.73; N: 4.38 Found: C: 62.53; H: 4.55; N: 3.50.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.[NH2:23][NH:24][C:25](=O)[CH2:26][NH:27][CH3:28].C[O-].[Na+]>CO>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[N:6]=[C:25]([CH2:26][NH:27][CH3:28])[NH:24][N:23]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: CNCC(=O)NN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNCc1nc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)n[nH]1
Reaction time: 24 h
Yield: 11 %

Procedure:
A suspension of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (0.300 g, 0.94 mmol) and N-amino-2-(methylamino)acetamide (0.290 g, 2.81 mmol) in 4 mL of anhydrous methanol was prepared. An excess of a commercial solution of sodium methoxide in methanol (0.643 mL, 4.37 M) was added. After an hour, the temperature was raised to reflux and was maintained for 48 hours although no further conversion was observed after 24 hours. The reaction was then quenched with water, the pH adjusted to neutral and the crude product extracted with ethyl acetate. The title compound was purified by preparative HPLC (0.034 g, 11% yield): 1H NMR (CD3OD) δ 8.71 (s, 1H), 8.11–8.03 (m, 3H), 7.69 (d, 1H), 7.3 (t, 2H), 3.95 (s, 2H), 2.49 (s, 3H); ES-MS (m/z) 323 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:17][C@@H:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]([NH:21][CH3:22])=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([NH:17][C@@H:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)c1cccc(-c2cccc(Cl)c2)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and (2S)-2-amino-N,3,3-trimethyl-butanamide (CAN 89226-12-0) as starting materials, MS (EI): m/e=360.0 [M+H]+.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([CH2:7][C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:3][CH:2]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)=O)=O)=[CH:22][CH:21]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C(O)C>[C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([C:7]2[C:8](=[O:17])[C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[C:26]=2[C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[CH:25][CH:24]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(CC(=O)Cc2ccc(C)cc2)cc1
Reactant: Cc1ccc(C(=O)C(=O)c2ccc(C)cc2)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C2=C(c3ccc(C)cc3)C(c3ccc(C)cc3)=C(c3ccc(C)cc3)C2=O)cc1
Reaction time: 0.42 h

Procedure:
23.13 g (0.11 mol) of 1,3-bis(p-tolyl)-2-propanone and 26.2 g (0.11 mol) of 4,4′-dimethylbenzil were dissolved in 75 ml of hot ethanol (abs.). 53 ml of a methanolic benzyltrimethylammonium hydroxide solution (0.11 mol Triton B, 35% Fluka) were slowly added dropwise at 80° C. with stirring (caution: the reaction batch froths vigorously) and refluxing was effected for 25 minutes. The crude product was filtered off after three hours, then washed with cold ethanol and recrystallized from toluene (violet red, yield: 46.2 g (95%); m.p.: 244-245° C., literature: 250.4-251.4° C. [15]; elemental analysis for C33H38O: found: C, 89.8%, H, 6.6%. calculated: C, 89.96%, H, 6.41%, MS-El [m/z (rel. intensity): M+440 (100), 412 (47), 206 (98), 191 (16), 189 (10)). The IR spectrum of 1,2,3,4-tetra(p-tolyl)cyclopenta-1,3-dien-5-one is shown in FIG. 10.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[CH2:14]([NH:21][C:6]1[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCc2ccccc2)c1C
Temperature: 55 °C
Yield: 45.7 %

Procedure:
2,4-Dichloro-5,6-Dimethyl-3-nitro-pyridine (2 g, 9 mmol) was dissolved in acetonitrile (100 mL) and benzylamine (1.0 mL, 9.5 mmol). Potassium carbonate (1.3 g, 9.5 mmol) was added in one portion, and the whole was heated at 55° C. for 16 h. The reaction mixture was diluted with EtOAc and washed with 50 mL water. The aqueous was re-extracted with EtOAc, the organics were combined and then dried over MgSO4 and evaporated to a dark red residue. This residue was purified by column chromatography on silica gel using 8:1 pentane:EtOAc as eluant to afford the title compound as a bright orange solid (1.2 g, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28]Cl)[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1.[NH2:31][C:32]1[NH:33][CH:34]=[CH:35][N:36]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][N:33]3[CH:34]=[CH:35][N:36]=[C:32]3[NH2:31])[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CCl)c1Cl
Reactant: Nc1ncc[nH]1
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(Cn2ccnc2N)c1Cl

Procedure:
In a manner similar to Paragraph A above, N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(2.0 g, 4.0 mmol) was reacted with 2-aminoimidazole (1.3 g, 16 mmol) to give N-(5-chloropyridin-2-yl)-2-[((4-((2-aminoimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide, which was purified by HPLC on a C18 Vydac column with acetonitrile in water gradient with 0.1% trifluoroacetic acid to afford N-(5-chloropyridin-2-yl)-2-[((4-((2-aminoimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide, trifluoroacetic acid salt, as a white solid; NMR (DMSO-d6/TFA) 10.9 (s, 1), 10.4 (s, 1), 8.3 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.8 (br, 1), 7.6 (s, 1), 4 (d, 1), 7.3 (d, 1), 6.9 (dt, 1), 5.0 (s, 2), 4.8 (s, 3) ppm.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([C:23]([O:25][CH3:26])=[O:24])[C:16](=[CH:21][CH:22]=2)[C:17]([O:19][CH3:20])=[O:18])[CH:6]=[CH:7][C:8]=1[OH:9])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>CC(=O)CC>[CH3:37][C:36]([CH3:39])([CH3:38])[C:35](=[O:40])[CH2:34][O:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([C:23]([O:25][CH3:26])=[O:24])[C:16](=[CH:21][CH:22]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:4][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cc(CCCc2ccc(C(=O)OC)c(C(=O)OC)c2)ccc1O
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCc1cc(CCCc2ccc(C(=O)OC)c(C(=O)OC)c2)ccc1OCC(=O)C(C)(C)C

Procedure:
800 mg (2.2 mmol) of dimethyl 4-[3-(3-ethyl-4-hydroxyphenyl)propyl}phthalate are dissolved in 40 ml of 2-butanone. 340 mg (2.5 mmol) of potassium carbonate and 330 μl (2.5 mmol) of 1-bromopinacolone are added. The reaction medium is heated under reflux for 8 hours, and is then filtered on celite. The residue obtained is purified by chromatography on a silica column (eluent ethyl acetate 20/heptane 80). A colorless oil is obtained (m=920 mg; y=90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][NH2:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:12]([C:16]1[C:17]([C:28](Cl)=[O:29])=[N:18][C:19]2[C:24]([C:25]=1[OH:26])=[CH:23][CH:22]=[C:21]([Cl:27])[CH:20]=2)(OC)=[O:13]>O1CCCC1.O.Cl>[Cl:27][C:21]1[CH:22]=[CH:23][C:24]2[C:25](=[O:26])[C:16]3[C:12]([OH:13])=[N:11][N:10]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=4)[C:28](=[O:29])[C:17]=3[NH:18][C:19]=2[CH:20]=1
Reactant: COc1ccc(NN)cc1Cl
Reactant: COC(=O)c1c(C(=O)Cl)nc2cc(Cl)ccc2c1O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a solution of 3-chloro-4-methoxyphenylhydrazine (4.26 g, 24.7 mM) in 35b.) in tetrahydrofuran (200 mL) was added a solution of 3-carbomethoxy-7-chloro-4-hydroxyquinoline-2-carbonyl chloride (3.54 g, 11.8 mM, as prepared in Example 35b.) in tetrahydrofuran (100 mL) at 0° C. The resulting yellow suspension was stirred at 0° C. for 30 minutes and diluted with water (200 mL) to give a yellow solution. This solution was further diluted with hydrochloric acid (600 mL, 1N) to give a tan suspension which was stirred for 1 hour. The suspension was filtered (the filtrate was saved) and the collected solids were washed with water and then ether to give the title compound (2.30 g, 45%) as a tan powder, MS(CI): 436 (M+H), which was used above in the synthesis described for 7-chloro-3-(3-chloro-4-methoxyphenyl)-1-hydroxy-3,4,5,10-tetrahydropyridazino[4,5-b]quinoline-4,10-dione. 1H NMR 12.69 (s, 1H, exchangeable), 10.72 (s, 1H, exchangeable), 8.14 (d, J=8.50 Hz, 1H), 8.00 (br s, 1H, exchangeable), 7.76 (s, 1H), 7.48 (d, J=8.50 Hz, 1H), 7.05 (d, J=8.80 Hz, 1H), 6.98 (d, J=2.28 Hz, 1H), 6.85 (dd, J=2.28, 8.80 Hz, 1H), 3.78 (s, 3H), 3.70 (s, 3H). After sitting for five days, further precipitation occurred in the above saved acidic filtrate. The solids were collected to provide material (1.80 g) consisting of a mixture of the title compound (60%), 7-chloro-2-(3-chloro-4-methoxyphenyl)-1-hydroxy-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione (35%) and 7-chloro-3-(3-chloro-4-methoxyphenyl)-1-hydroxy-3,4,5,10-tetrahydropyridazino[4,5-b]quinoline-4,10-dione (5%).