Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)C.[CH3:5][O:6][C:7]1[CH:44]=[CH:43][C:10]([CH2:11][N:12]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:13]2[N:18]=[CH:17][C:16]([C:19]3[C:20]4[CH2:33][CH2:32][NH:31][C:21]=4[N:22]=[C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:24]=3)=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[I:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]=[C:53]=[O:54])=[CH:48][CH:47]=1>CN(C1C=CN=CC=1)C.O>[I:45][C:46]1[CH:51]=[CH:50][C:49]([NH:52][C:53]([N:31]2[C:21]3[N:22]=[C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:24]=[C:19]([C:16]4[CH:15]=[N:14][C:13]([N:12]([CH2:11][C:10]5[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:44][CH:43]=5)[CH2:34][C:35]5[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=5)=[N:18][CH:17]=4)[C:20]=3[CH2:33][CH2:32]2)=[O:54])=[CH:48][CH:47]=1
Reactant: O=C=Nc1ccc(I)cc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC(Cl)Cl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3ccc(I)cc3)cn2)cc1
Temperature: 25 °C

Procedure:
To dichloroethane solution (2 ml) of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (108 mg), DMAP (2.4 mg) and 1-iodo-4-isocyanato-benzene (120 mg) were added, followed by refluxing for 3 hours. This was cooled to room temperature, followed by addition of water, and passed through Whatman tube, to obtain the desired compound as a crude product (70.2 mg, 45%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][C@@H:12]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=5)=[CH:21][CH:20]=4)[CH2:13][NH:14]3)=[CH:9][C:8]=2[CH2:7][N:6]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:4].[OH-].[Li+].Cl>C1COCC1.CO>[C:38]([O:37][C:35]([N:6]1[CH:5]([C:3]([OH:4])=[O:2])[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][C@@H:12]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=5)=[CH:21][CH:20]=4)[CH2:13][NH:14]3)=[CH:9][C:8]=2[CH2:7]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CN3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)NC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester 7-methyl ester (598 mg) was dissolved in THF-methanol (4:1). 2 N Lithium hydroxide (1 mL) was added and the resulting reaction mixture was stirred at room temperature for 4 hours. Excess 1N HCl was added and the mixture extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to afford the product in pure form (0.56 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:24])[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6].[OH-].[Li+].CO.ClCl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:24])[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6]
Reactant: CCOC(=O)CCC1CCCN1C(=O)c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Agent: ClCl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCCC2CCC(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 23 %

Procedure:
Prepared analogously to Example 19b from 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-4-[(2R/S)-2-(ethoxycarbonylethyl)pyrrolidin-1-ylcarbonyl]benzamide and lithium hydroxide in tetrahydrofuran. Yield: 23%; Rf value: 0.34 (Reversed phase RP 8: methanol/5% sodium chloride solution=6:4); C24H24C12N4O4 (503.384); mass spectrum: (M+H)+=503/505/507 (chlorine isotope).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[CH2:15]([NH:22][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)CC1
Reaction time: 72 h
Yield: 92.3 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-piperidone (10.0 g, 50.2 mmol), benzylamine (5.4 g, 50.2 mmol), and acetic acid (3.01 g, 50.2 mmol) in 200 mL of dry dichloromethane was added sodium triacetoxyborohydride (21.2 g, 100 mmol) under nitrogen. The mixture was stirred for three days, and then aqueous 1 N NaOH (200 mL) solution was added. After 1 h of stirring, the layers were separated, and the aqueous layer was extracted twice with dichloromethane (100 mL). The organic extracts were combined, washed twice with 1 N NaOH (100 mL), dried (Na2SO4), and concentrated to give 13.46 g of 4-benzylamino-1-(tert-butoxycarbonyl)piperidine as a cream-colored waxy solid. MS (ES), m/z 291 (MH+). 300 MHz 1H NMR (CDCl3) δ1.22-1.39 (br q, 2H), 1.45 (s, 9H), 1.86 (br d, J=11.3 Hz, 2H), 2.60-2.93 (m, 4H), 3.82 (s, 2H), 3.85-4.20 (br m, 2H), 7.19-7.37 (m, 5H).
Reaction SMILES: COP([CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[C:9](=[O:17])[O:8]1)(=O)OC.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.O>O1CCCC1>[CH:18](=[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[C:9](=[O:17])[O:8]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: COP(=O)(OC)C1OC(=O)c2ccc(Br)cc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1OC(=Cc2ccccc2)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 1C (4.6 g, 14.08 mmol) in anhydrous tetrahydrofuran (30 mL) was added benzaldehyde (0.71 mL, 7.4 mmol) and triethylamine (1.00 mL, 7.39 mmol). The reaction mixture was stirred at ambient temperature overnight. Water was added and the mixture stirred for 10 minutes. The precipitated solid was filtered and dried under vacuum to yield the title compound. MS (ESI) m/z 302 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][OH:12]>>[CH3:11][O:12][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CO
Reactant: BrCCCc1ccccc1
Product: COCCCc1ccccc1
Temperature: 0 °C

Procedure:
In 600 ml of CH3OH was dissolved 20 g of Na, and 120 g of 3-bromopropylbenzene was added dropwise with heating under reflux. After aging under reflux for 6 hours, the reaction solution was poured into 2 liters of ice water, and the separated oil layer was extracted with benzene. The benzene was distilled off, after which the residue was distilled under reduced pressure to obtain 3-methoxypropylbenzene. The boiling point of this compound was 96°-98° C/15 mmHg.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[C:24]([F:33])[CH2:25][O:26]C1CCCCO1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(N=C=S)O[Sn](CCCC)(CCCC)N=C=S)CCC>CO>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[C:24]([F:33])[CH2:25][OH:26])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCCCCC=C(F)COC1CCCCO1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](CCCC)(N=C=S)O[Sn](CCCC)(CCCC)N=C=S
Solvent: CO
Product: CC(C)(C)[Si](OCCCCC=C(F)CO)(c1ccccc1)c1ccccc1
Yield: 88.9 %

Procedure:
The tetrahydropyranyl derivative prepared in 3C (2.26 g, 4.8 mmoles) was dissolved in methanol. Tetrabutyl-1,3-diisothiocyanatodistannoxane (30 mg) was added and the mixture was refluxed for 24 hrs. Methanol was evaporated under reduced pressure. The residue was dissolved in ether and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Flash chromatography on silicagel and elution with a 2:8 mixture of hexane and ethyl acetate afforded the alcohol as an oil (1.65 g, 92%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH2:7][CH:6]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K].O>CN(C)C=O>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9]([CH2:8][CH2:7][CH:6]=[C:5]2[CH2:4][CH2:3][CH2:2][N:21]2[C:17](=[O:27])[C:18]3[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:20]2=[O:22])=[CH:10][CH:11]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc2c(c1)C(CCCBr)=CCC2
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)C(CCCN1C(=O)c3ccccc3C1=O)=CCC2
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A mixture of 4-(3-bromopropyl)-1,2-dihydro-6-methoxynaphthalene (10 g, 35.6 mmol.) and potassium phthalimide (7.9 g, 42.7 mmol.) was stirred in N,N-dimethylformamide (50 ml) for one hour at 100° C. The reaction mixture was cooled to room temperature, to which was poured water, then the organic substance was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, which was dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue thus obtained was purified by means of a silica gel column chromatography (ethyl acetate:hexane=2:8) to afford the titled compound (11.8 g, yield 95%, oily).
Reaction SMILES: [Cl:1][C:2]1[C:3](C(O)=O)=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[C@H:15]1([NH2:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1.C1(C(N)C2CCCCC2)CCCCC1>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([NH:25][C@H:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)=[N:4][CH:3]=1
Reactant: CS(=O)(=O)c1ncc(Cl)c(C(=O)O)n1
Reactant: N[C@@H]1CCCc2ccccc21
Agent: NC(C1CCCCC1)C1CCCCC1
Solvent: CN1CCCC1=O
Product: Clc1cnc(N[C@@H]2CCCc3ccccc32)nc1
Yield: 11 %

Procedure:
0.20 g (0.84 mmol) of 5-chloro-2-(methylsulfonyl)pyrimidine-4-carboxylic acid, 0.15 g (1.01 mmol) of (1R)-1,2,3,4-tetrahydronaphthalene-1-amine and 0.33 g (1.69 mmol) of dicyclohexylmethylamine in 1.5 ml of N-methylpyrrolidone are heated in a closed cuvette in the microwave at 150° C. for 30 minutes (Biotage Initiator, http://www.biotage.com/DynPage.aspx?id=22001). The crude mixture obtained in this manner is applied to silica gel and purified by column chromatography using the mobile phase heptane/ethyl acetate. Concentration gives initially 0.024 g of 5-chloro-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrimidine-2-amine (solid) and then 0.08 g of 2-(methylsulfonyl)-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrimidine-5-amine (wax-like, yield 31% at a purity of 95%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)([OH:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:16][CH2:17][C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=3)([OH:21])[CH2:19][CH2:20]2)=[CH:13][CH:14]=1
Reactant: OC1(c2ccc(C(F)(F)F)cc2)CCN(c2ccc(OCc3ccccc3)cc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1ccc(N2CCC(O)(c3ccc(C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.6 %

Procedure:
1-(4-Benzyloxyphenyl)-4-(4-trifluoromethylphenyl)piperidin-4-ol (2 g) was dissolved in ethanol (20 ml) and ethyl acetate (20 ml). 20% palladium hydroxide on carbon (0.2 g) was added to the mixture and stirred at room temperature under a hydrogen atmosphere for 1.5 hours. The mixture was filtered through Celite to remove the catalyst, and the filtrate was concentrated under reduced pressure. The residue was washed with an ether-hexane mixed solvent to afford the title compound as a pale pink powder (1.43 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][N:22]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:21][N:22]1[CH2:28][CH2:27][CH2:26][N:25]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=2)[CH2:24][CH2:23]1
Reactant: CC(C)Oc1cc(Br)ccc1[N+](=O)[O-]
Reactant: CN1CCCNCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)Oc1cc(N2CCCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
A mixture of 250 mg of 4-bromo-1-nitro-2-(propan-2-yloxy)benzene, 1.13 g of caesium carbonate, 197 mg of N-methylhomopiperazine, 47.5 mg of tris(dibenzylideneacetone)dipalladium(0) and 50 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene in 5 ml of 1,4-dioxane is microwave-heated in a sealed tube, at 150° C. for 30 min, and then 200° C. for 10 min. The mixture is diluted with ethyl acetate and filtered on Clarcel. The Clarcel is washed with ethyl acetate and the organic phase is washed with water. The organic phase is dried over anhydrous magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The residue is purified on 12 g of silica, elution being carried out with 0-5% methanol in dichloromethane, so as to obtain 110 mg of 4-(4-methyl-1,4-diazepan-1-yl)-2-(propan-2-yloxy)nitrobenzene in the form of an orangey-coloured oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]1([CH2:14][CH:15]([N:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[N:20][CH2:19]2)[CH2:16][NH2:17])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][CH:15]([N:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[N:20][CH2:19]1)[CH2:14][CH:11]1[CH2:13][CH2:12]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(CC1CC1)N1C=CC(C(F)(F)F)=NC1
Product: O=C(NCC(CC1CC1)N1C=CC(C(F)(F)F)=NC1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS (MH+): m/z=384.1, tR (minutes, Method D)=0.76
Reaction SMILES: [N+:1]([O-])([O-:3])=[O:2].[K+].[CH2:6]([O:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])[CH3:7]>S(=O)(=O)(O)O>[N+:18]([C:16]1[C:15]([N+:1]([O-:3])=[O:2])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:8][CH2:6][CH3:7])[CH:17]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1C(=O)O
Reaction time: 3 h
Yield: 87.9 %

Procedure:
To a mixture of potassium nitrate (4.80 g, 47.4 mmol) in concentrated sulphuric acid (20 mL) was added portion-wise at 0° C. 2-ethoxy-4-nitrobenzoic acid (4.00 g, 19.0 mmol). The mixture was stirred at 0° C.-r.t. for 3 h, then poured onto ice (120 mL) and stirred for a further 1 h. The precipitate formed was collected by filtration, washing with water, and dried through azeotrope with toluene to give the title compound (4.28 g) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.95 (s, 1H), 4.35 (q, 2H), 1.35 (t, 3H).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=4)(O)[C:20]4[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=4)[CH:17]=3)[N:12]([CH3:34])[C:11](=[O:35])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH:42]1([NH2:45])[CH2:44][CH2:43]1>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=4)([NH:45][CH:42]4[CH2:44][CH2:43]4)[C:20]4[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=4)[CH:17]=3)[N:12]([CH3:34])[C:11](=[O:35])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: NC1CC1
Reactant: Cn1cncc1C(O)(c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C)c1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cncc1C(NC1CC1)(c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.1 %

Procedure:
For the formation of the correspondent chloride, the same procedure was used as that in example 2, except that 4-(3-chloro-phenyl)-6-[(5-chloro-pyridin-2-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-1H-quinolin-2-one (55 mg, 0.112 mmol) was used in the place of 4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1H-quinolin-2-one. The obtained chloride was dissolved in DMF (8 ml). To this solution were added potassium carbonate (K2CO3) and cyclopropylamine (0.049 ml, 0.786 mmol). The reaction mixture was stirred at ambient temperature for 15 hours after which time it was partitioned between CHCl3 and water. The organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to give the crude product. It was chromatographed on silica gel with MeOH—CHCl3—NH4OH (2:98:0.2 to 5:95:0.5) as eluents to afford the title compound as a white solid (19 mg, 0.036 mmol, 32% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC1C=C(N=C=S)C=C(Cl)C=1C#N.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH:34]=O.[BH4-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[C:31]([C:30]([F:29])([F:39])[F:40])[CH:32]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: N#Cc1c(Cl)cc(N=C=S)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: FC(F)(F)c1cccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)c1
Reaction time: 8 h
Yield: 46 %

Procedure:
To a stirred solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (80 mg, 0.33 mmol) in 5 mL methanol, was added 3-(trifluoromethyl)benzaldehyde (114 mg, 0.66 mmol). The reaction mixture was stirred overnight, after which, sodium borohydride (24.8 mg, 0.656 mmol) was added and the mixture was for stirred for 10 min. The reaction was diluted the water (20 mL) and extracted with EtOAc (3×10 mL). The organic layers were combined and dried with sodium sulfate. The solvent was removed and the residue was chromatographed on a combiflash machine (6% methanol/methylene chloride) to give 61 mg (46%) of the desired product. MS +m/z: 401.9 (M+H)+
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[C:7]([NH2:9])[C:6]([NH2:10])=[CH:5][CH:4]=1.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:15](=[O:16])C1.ClCCl>CC#N>[F:12][C:2]([F:1])([F:11])[C:3]1[N:8]=[C:7]2[NH:9][C:15](=[O:16])[NH:10][C:6]2=[CH:5][CH:4]=1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: Nc1ccc(C(F)(F)F)nc1N
Solvent: ClCCl
Solvent: CC#N
Product: O=c1[nH]c2ccc(C(F)(F)F)nc2[nH]1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
A mixture of the pyridine-2,3-diamine (160 mg, 0.9 mmol) from step (b) above and N,N′-disuccinimidyl carbonate (250 mg, 0.9 mmol, Aldrich) in MeCN (5 mL) was stirred at room temperature for 13 h. Another batch of N,N′-disuccinimidyl carbonate (125 mg, 0.5 mmol, Aldrich) was added and the reaction mixture was heated at 75° C. for 90 min. The reaction mixture was cooled to room temperature and dichloromethane (20 mL) was added. The precipitate was filtered and dried under vacuo to give the title compound, which was used in the next step without additional purification. MS (ESI, pos. ion) m/z: 204 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br)=[CH:5][CH:4]=1.[IH:16]>C(O)(=O)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][I:16])=[CH:5][CH:4]=1
Reactant: I
Reactant: COc1ccc(CCCCCCBr)cc1
Solvent: CC(=O)O
Product: Oc1ccc(CCCCCCI)cc1

Procedure:
A solution of 68 g. (0.25 mole) of 6-(4-methoxyphenyl)hexyl bromide in 500 ml. of glacial acetic acid was treated with 200 ml. of 50% aqueous hydriodic acid. The reaction was boiled at reflux for 5 hours. During the reflux period the condenser was removed briefly from time to time to allow methyl iodide to escape. The reaction was evaporated to dryness in vacuo. The residue was partitioned between water and ether. The organic phase was washed with water, then with dilute sodium thiosulfate until the iodine color was gone. The clear organic solution was evaporated in vacuo in a warm water bath to give a clear oil, 70 g. (92%) of 6-(4-hydroxyphenyl)hexyl iodide, which crystallized slowly after several days at room temperature.
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:24])([CH3:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:13]=[CH:12][C:11]=1Br)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:26]([O:28][C:29]([N:31]1[CH:36]=[CH:35][C:34](=[O:37])[CH2:33][CH2:32]1)=[O:30])[CH3:27].[Cl-].[NH4+]>O1CCCC1.CCOCC>[CH2:26]([O:28][C:29]([N:31]1[CH2:32][CH2:33][C:34](=[O:37])[CH2:35][CH:36]1[C:11]1[CH:12]=[CH:13][C:14]([C:16]([CH3:24])([CH3:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:15][C:10]=1[O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:30])[CH3:27]
Reactant: CCCCCCC(C)(C)c1ccc(Br)c(OCc2ccccc2)c1
Reactant: CCOC(=O)N1C=CC(=O)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1ccc(C2CC(=O)CCN2C(=O)OCC)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
To 3.45 (0.142 mole) of magnesium is added a solution of 27.6 g (0.071 mole) of 2-benzyloxy-1-bromo-4-(1,1-dimethylheptyl)benzene in 71 ml of tetrahydrofuran, at such a rate that gentle reflux occurs. The Grignard solution is allowed to cool to 25° C. over 30 minutes, diluted with 71 ml of ether, the mixture cooled to -12° C. and 2.13 g (0.0112 mole) cuprous iodide is added followed by addition of 8.00 g (0.0473 mole) of N-ethoxycarbonyl-2,3-dihydro-4(1H)-pyridinone in 47 ml of ether over 20 minutes. The reaction is stirred 30 minutes longer at -12° C. and then added to 2 liters ether and 600 ml saturated ammonium chloride. The organic extract is washed with three 600 ml portions of saturated ammonium chloride, dried over magnesium sulfate and evaporated to an oil. This crude product is purified via column chromatography on 2 kg of silica gel eluting in 500 ml fractions with 50% ether-hexane to yield (fractions 17-24) 16.0 g (71%) of the title compound as an oil.
Reaction SMILES: C1C[O:4][CH2:3]C1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:30]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[CH:29][N:28]=[N:27][C:26]=2[NH:38][NH2:39])=[CH:21][CH:20]=1>O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:30]2[CH:29]=[N:28][N:27]3[C:3](=[O:4])[NH:39][N:38]=[C:26]3[C:25]=2[C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][CH:23]=2)=[CH:32][CH:33]=1
Reactant: NNc1nncc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Reactant: C1CCOC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Product: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a THF (20 mL) solution of carbonyldiimidazole (CDI), (1.7 g, 10.5 mmol) was added 1-(4,5-bis(4-chlorophenyl)pyridazin-3-yl)hydrazine (0.7 g, 2.1 mmol). The resultant brown solution was stirred at RT for 15 min. After this time, the reaction solution was poured into water (50 mL). The resultant pale colored solid was collected by filtration. Water was used to rinse the solid thoroughly to afford 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (0.75 g, 100%). MS (M+H)=357; 1H NMR (DMSO-d6, 500 MHz): δ 12.86 (1H, s), 8.37 (1H, s), 7.42-7.48 (4H, m), 7.35 (2H, d, J=10.0 Hz), 7.27 (2H, d, J=10.0 Hz).