Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[C:14]([O:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[S:30](Cl)(=[O:32])=[O:31])=[O:20])([CH3:17])([CH3:16])[CH3:15]>ClCCCl.CN(C1C=CN=CC=1)C>[C:14]([O:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[S:30](=[O:32])(=[O:31])[NH:11][C:10]1[CH:12]=[CH:13][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:8][CH:9]=1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)n1c(S(=O)(=O)Cl)cc2ccccc21
Reactant: Nc1ccc(-c2ccncc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)n1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2)cc2ccccc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 49.1 %

Procedure:
To a solution of (4-pyridine-4-yl)aniline (CAS: 13296-04-3, 0.054 g) and 2-chlorosulfonyl-indole-1-carboxylic acid tert-butyl ester (0.120 g; cf. Shankar, Bandarpalle B.; Gilbert, Eric; Rizvi, Razia K.; Huang, Chunli; Kozlowski, Joseph A.; McCombie, Stuart; Shih, Neng-Yang. WO 2006002133) in 1,2-dichlorethane (5.0 ml) was added DMAP (0.047 g). The reaction mixture was stirred at 50° C. for 3 h and chromatographed on silica gel using dichloromethanelethyl acetate as eluent to obtain the desired compound (0.070 g) as a colorless powder. MS (ISP): 450.4 (M+H)+
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38].O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:38][CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[O:34][CH3:33])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1CN
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Solvent: O
Solvent: CCO
Product: COc1ccccc1CNc1ncnc2c1ncn2C1O[C@H](COC(=O)c2ccccc2)C(C)(OC(C)=O)[C@@]1(C)F
Yield: 33 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.2 g, 0.43 mmol) in ethanol (5 ml) was added 2-methoxybenzylamine (about 0.67 ml, 5.19 mmol) and refluxed for about 20 minutes. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compound (0.08 g) as a colorless gummy mass. Yield: 35%; 1H NMR (300 MHz, CDCl3): δ 8.51 (s, 1H), 8.06-7.96 (m, 3H), 7.58-7.33 (m, 5H), 6.94-6.88 (m, 2H), 6.54 (d, 1H, J=23.1 Hz), 6.27 (bs, 1H), 4.85-4.78 (m, 2H), 4.48-4.44 (m, 1H), 3.88 (s, 3H), 2.16 (s, 3H), 1.88 (d, 3H, J=2.4 Hz), 1.44 (d, 3H, J=23.1 Hz); Mass: [M+1]+ 564 (100%), [M+Na]+ 586 (60%); IR cm−: 3429, 2929, 2863, 2177, 1733, 1466, 1240, 1033, 713; HPLC: 93.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:22])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:26][C:27]#[N:28]>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:26][C:27]#[N:28])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2cccc(Cl)c2)C1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC#N)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (32.5 g, 0.1 mol) in MeCN (325 mL), NaH (12 g, 0.3 mol) was added at 0° C. The mixture was stirred for 1 hr at rt. The mixture was cooled to −40° C., then bromoacetonitrile (35.7 g, 0.3 mol) was added in portions. The mixture was stirred for 0.5 hr at −20° C. After the reaction was complete it was quenched with sat. NH4Cl. The mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4, concentrated. Crude (R)-tert-butyl 3-((R)-(3-chlorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylate was used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6]=[CH:7][C:8]3[C:9]([C:14](=[O:15])[C:4]=2[CH:3]=1)=[N:10][CH:11]=[CH:12][CH:13]=3.ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6]=[CH:7][C:8]3[C:9]([C:14](=[O:15])[C:4]=2[CH:3]=1)=[N+:10]([O-:26])[CH:11]=[CH:12][CH:13]=3
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=c1c2cc(Br)ccc2ccc2cccnc12
Solvent: ClC(Cl)Cl
Product: O=c1c2cc(Br)ccc2ccc2ccc[n+]([O-])c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.5 %

Procedure:
To a solution of 2.15 grams (0.0075 mole) of 9-bromo-11-oxo-benzo[5,6]cyclohepta-[1,2-b]pyridine in 40 milliliters of chloroform was added 1.78 grams (0.0082 mole) of m-chloroperbenzoic acid and the resulting solution was stirred at room temperature for about 24 hours. At this time, an additional 0.9 gram of m-chloroperbenzoic acid oxidant was added and the stirring continued for 5 hours, after which time, yet another 0.45 gram of the oxidant was added and the stirring continued overnight at room temperature. The resulting mixture was washed twice with 10 percent aqueous sodium hydroxide and twice with water and dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate concentrated at reduced pressure to obtain a residue. The latter was triturated with acetonitrile to obtain 1.37 grams of 9-bromo-11-oxo-benzo[5,6]cyclohepta[1,2-b]pyridine N-oxide intermediate.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:30]=[CH:29][C:9]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21](N5CCOCC5)=[O:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[CH3:31][Mg]Cl.[Cl-].[NH4+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:30]=[CH:29][C:9]3[N:10]=[C:11]([N:13]4[CH2:14][CH2:15][CH:16]([O:19][CH2:20][C:21](=[O:22])[CH3:31])[CH2:17][CH2:18]4)[O:12][C:8]=3[CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=C(COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1)N1CCOCC1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6-(cyclopropylmethoxy)-2-{4-[2-(morpholin-4-yl)-2-oxoethoxy]piperidin-1-yl}-1,3-benzoxazole (2.10 g) in THF (17 mL) was added methylmagnesium chloride (3.0 M THF solution, 5.06 mL), and the mixture was stirred at room temperature for 3 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (1.31 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[C:11]([O:15][C:16]([N:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[CH2:20][C:21](=[O:26])[CH2:22]2)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(O)(=O)C>C1COCC1>[C:11]([O:15][C:16]([N:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[CH2:20][C:21]([OH:26])([C:2]1[O:1][CH:5]=[CH:4][N:3]=1)[CH2:22]2)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: c1cocn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ncco1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
Borane-THF complex (1M, 4.5 mL, 4.5 mmol) was added to a solution of oxazole (0.3 mL, 4.5 mmol) in THF (5 mL) and stirred for 1 hour under nitrogen before cooling to −78° C. n-Butyl lithium (2.5M, 1.8 mL, 4.5 mmol) was added and the reaction mixture stirred for a further 30 minutes. A solution of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.675 g, 3.0 mmol) in THF (5 mL) was added and the reaction mixture stirred for 30 minutes. 10% acetic acid in IMS (10 mL) was added and the reaction mixture warmed to room temperature and then further to 40° C. for 30 minutes. The solvent was removed by evaporation under vacuum, water and ethyl acetate were added to the residues, the organics extracted, dried over magnesium sulphate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica eluting with 25-60% ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.3 g) as a colourless oil. LCMS m/z 295.2 [M+H]+. R.T.=3.07 min (Analytical Method 3).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([Cl:24])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=O.Cl.[C:26]([O:30][NH2:31])([CH3:29])([CH3:28])[CH3:27].Cl>N1C=CC=CC=1>[C:26]([O:30][N:31]=[CH:12][CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1[C:14]([Cl:24])=[CH:15][C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:22])[Cl:23])=[CH:17][C:2]=1[Cl:1])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)ON
Reactant: O=CCOCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)ON=CCOCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.5 %

Procedure:
To a mixture of 0.42 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetaldehyde and 10 ml of pyridine was added 0.13 g of O-tert-butylhydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.45 g (yield, 92%) of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetaldehyde O-tert-butyloxime, nD25.2 1.5185.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][N:16]([CH3:34])[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][N:25]=3)=[C:19]([CH3:33])[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:43][C:44]([F:55])([F:54])[C:45]1[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Pt].[C]>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][N:16]([CH3:34])[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[N:25]=[CH:26][C:27]([NH:30][C:49](=[O:50])[C:48]4[CH:52]=[CH:53][C:45]([C:44]([F:43])([F:54])[F:55])=[CH:46][CH:47]=4)=[CH:28][CH:29]=3)=[C:19]([CH3:33])[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(N(C)CC(=O)N2CCN(Cc3ccccc3)CC2)ccc1Oc1ccc([N+](=O)[O-])cn1
Agent: [Pt]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(N(C)CC(=O)N2CCN(Cc3ccccc3)CC2)ccc1Oc1ccc(NC(=O)c2ccc(C(F)(F)F)cc2)cn1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a suspension of 1-(4-benzylpiperazin-1-yl)-2-{methyl[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}ethanone (2.85 g, 6.0 mmol) in ethyl acetate (30 mL) was added 5% platinum-carbon (0.30 g) under a nitrogen atmosphere, and the resulting solution was stirred for 3 hours at 40° C. under a hydrogen atmosphere. The platinum-carbon was separated off with Celite, and the filtrate was concentrated. The residue was dissolved in THF (30 mL), and to this solution was added triethylamine (1.26 mL, 9.1 mmol) under ice cooling. To the resulting solution was then added dropwise 4-(trifluoromethyl)benzoyl chloride (1.16 mL, 7.8 mmol). This reaction solution was stirred overnight, then a saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1). The resulting product was then recrystallized from a mixed solvent consisting of diisopropyl ether-acetone, to thereby yield 1.37 g of the title compound.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)([OH:19])N.[Na]>C(O)(=O)C.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:10]([OH:19])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: NS(=O)(=O)O
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)O)cc1OC1CCCC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (66 g) and sulfamic acid (39.6 g) in glacial acetic acid (500 mL) is treated dropwise during 1 hour with a solution of sodium chicrite (35 g) in water (150 mL). The mixture is stirred at 20° C. during 1 hour and then it is treated with water (500 mL) dropwise during 30 minutes. The resulting solid is filtered, washed with water and dried, to give 3-cyclopentyloxy-4-methoxybenzoic acid (60.9 g) in the form of white crystals [Elemental analysis: C,65.8; H,6.7%; calculated: C,66.1; H,6.8%].
Reaction SMILES: C(O[C:4]1[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]([N:15]([CH:22]([CH3:24])[CH3:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=2[N:5]=1)C.[C:29]([NH:37][NH2:38])(=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC(O)=O.C(Cl)Cl>[CH:22]([N:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:13](=[O:14])[CH2:12][N:8]1[C:9](=[O:11])[CH2:10][C:4]2[N:5]([C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:37][N:38]=2)[C:6]2[CH:28]=[CH:27][CH:26]=[CH:25][C:7]1=2)([CH3:24])[CH3:23]
Reactant: CCOC1=Nc2ccccc2N(CC(=O)N(c2ccccc2)C(C)C)C(=O)C1
Reactant: NNC(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(4-ethoxy-2-oxo-2,3-dihydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide (Preparation 5(B) (71.14 g, 0.187 mol) in 1.04 L of AcOH was added benzoic acid hydrazide (27.28 g, 0.196 mol) in one portion. The reaction was heated to 80° C. and was stirred for 4 hours. The reaction was cooled to room temperature and the AcOH was removed in vacuo to give an off-white solid. The solid was dissolved in 1 L of methylene chloride. The organic solution was washed with 1 L of saturated NaHCO3 solution followed by brine and was dried over Na2SO4. The methylene chloride solution was diluted with an equal volume of methyl tert-butyl ether and the resulting solution was concentrated in vacuo to low volume causing a white solid to precipitate. The precipitate was collected on a sintered glass funnel and was rinsed with methyl tert-butyl ether. The solid was dried in vacuo to give 81.41 g of N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-phenyl-acetamide as a white solid. 1H NMR (CD2Cl2) δ 7.57-7.35 (m, 10H), 7.27 (br s, 1H), 7.21 (br s, 1H), 7.10 (t, 1H), 6.87 (d, 1H), 4.89 (m, 1H), 4.19-3.99 (m, 3H), 3.53 (d, 1H), 1.03 (m, 6H); MS 452.3 (M+1), 450.5 (M−1).
Reaction SMILES: [C:1]12([C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=3)[CH2:6][O:5]1)[CH2:4][CH2:3][CH2:2]2.C(#N)C.Cl[C:18]1[N:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][N:19]=1.Cl>C(OCC)(=O)C.[Fe]>[C:1]12([C:12]3[CH:11]=[C:10]([O:13][C:18]4[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][N:19]=4)[CH:9]=[CH:8][C:7]=3[CH2:6][O:5]1)[CH2:4][CH2:3][CH2:2]2
Reactant: Oc1ccc2c(c1)C1(CCC1)OC2
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Agent: [Fe]
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1cnc(Oc2ccc3c(c2)C2(CCC2)OC3)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
To a solution of spiro[1H-isobenzofuran-3,1′-cyclobutane]-5-ol (Intermediate 24, 50 mg, 0.28 mmol) in dry acetonitrile (4 mL) dipotassium carbonate (58.8 mg, 0.43 mmol) and then 2-chloro-5-nitro-pyrimidine (43.0 mg, 0.27 mmol) were added and the reaction mixture was stirred for 4 hours at room temperature. The reaction was diluted with ethyl acetate (20 ml) and washed with an aqueous saturated solution of ammonium chloride (2×10 ml). The organic layer was dried (Na2SO4), filtered and evaporated. The residue was dissolved in ethanol (5 mL)/water (1 mL). Iron (95.0 mg, 1.7 mmol) and an aqueous 6M solution of hydrogen chloride (0.05 ml, 0.3 mmol) were added and the reaction mixture was stirred at 50° C. for 3 hours. The catalyst was filtered off and the solution was diluted with an aqueous saturated solution of NaHCO3 (10 ml) and extracted with ethyl acetate (2×15 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a SNAP 10 g as column and cyclohexane/ethyl acetate from 60:40 to 0:100 as eluent affording the title compound (24 mg) as a light yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)[CH:6]=[CH:5][N:4]=1>Cl>[F:18][C:15]([F:16])([F:17])[C:12]1[CH:13]=[CH:14][C:9]([C:7]2[CH:6]=[CH:5][NH:4][C:3](=[O:2])[CH:8]=2)=[N:10][CH:11]=1
Reactant: COc1cc(-c2ccc(C(F)(F)F)cn2)ccn1
Agent: Cl
Product: O=c1cc(-c2ccc(C(F)(F)F)cn2)cc[nH]1
Yield: 91.2 %

Procedure:
2′-Methoxy-5-(trifluoromethyl)-2,4′-bipyridine (337 mg, 1.32 mmol) was stirred in χoνχεντρατεδ hydrochloric acid (20 mL) at 120° C. for 18 h and then concentrated. The residue was adjusted to pH 8 with 6 N NaOH, and the solids were filtered off, washed with water and dried under vacuum to provide the title compound (289 mg, 89%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H) 9.10 (s, 1H), 8.35 (dd, J=8.4, 2.1 Hz, 1H), 8.25 (d, J=8.3 Hz, 1H), 7.53 (d, J=6.8, 1H), 7.09 (d, J=1.3 Hz, 1H), 6.90 (dd, J=6.8, 1.6 Hz, 1H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37](OC)=[O:38])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH2:27][N:28]([C:31]2[CH:32]=[CH:33][C:34]([CH2:37][OH:38])=[CH:35][CH:36]=2)[CH2:29][CH2:30]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(CO)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
Diisobutylaluminium hydride in toluene (1.5M, 15 ml, 22.5 mmol) was added dropwise to a solution of 1-(tert-butoxycarbonyl)-4-(4-methoxycarbonylphenyl)piperazine (2.90 g, 9.05 mmol) in THF (116 ml) at 0° C. The mixture was stirred at 0° C. for 2 hours then allowed to warm to room temperature. The solution was recooled to -4° C. and the reaction quenched by the addition of methanol (6 ml), water (3 ml) and finally 2M sodium hydroxide (3 ml). The mixture was allowed to warm to room temperature, the precipitated aluminium salts collected under suction and washed with dichloromethane. The filtrate was concentrated in vacuo and the residue purified by flash chromatography, eluting with dichloromethane/ethyl acetate, to give the title compound (2.30 g, 74%); δH (CDCl8) 1.48 (9H, s, C(CH3)8), 1.60 (1H, v br, CH2OH), 3.13 (4H, m, 2×piperazinyl CH2), 3.58 (4H, m, 2×piperazinyl CH2), 4.61 (2H, s, CH2OH), 6.92 (2H, m, ArH), and 7.29 (2H, m, ArH).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:18](OC(=O)C)(=[O:20])[CH3:19]>S(=O)(=O)(O)O>[N+:12]([C:10]1[CH:11]=[C:6]([CH:7]=[C:8]([N+:15]([O-:17])=[O:16])[CH:9]=1)[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:18](=[O:20])[CH3:19])([O-:14])=[O:13]
Reactant: CCCCNc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CCCCN(C(C)=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
A stirred suspension of N-n-butyl-3,5-dinitroaniline (5.5 g.) in acetic anhydride (20 ml.) was treated with a few drops of concentrated sulphuric acid and then heated on the steam bath for 3 hours. The cooled reaction mixture was added to ice-water (400 ml.) and the product was extracted with ethyl acetate (3 × 100 ml.). The combined organic extract was washed with 2N aqueous sodium bicarbonate solution, dried with anhydrous magnesium sulphate, and the solvent removed in vacuo, to give 3',5'-dinitro-N-n-butylacetanilide (2.8 g.), in the form of an amber syrup, ν1670 cm-1.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[CH:24]([NH2:28])([CH2:26][CH3:27])[CH3:25]>CN1C(=O)CCC1.CCOC(C)=O>[CH:24]([NH:28][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1)([CH2:26][CH3:27])[CH3:25]
Reactant: CCC(C)N
Reactant: Clc1ccc2ncc(Cc3ccc4ncccc4c3)n2n1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCC(C)Nc1ccc2ncc(Cc3ccc4ncccc4c3)n2n1
Temperature: 180 °C
Reaction time: 29 h

Procedure:
6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-quinoline (Example 14, 70 mg, 0.237 mmol), KF (70 mg, 1.187 mmol) and sec-butylamine (484 μL, 4.75 mmol) were suspended in NMP (1 mL). The RM was stirred at 180° C. for 29 h. The mixture was diluted with EtOAc and washed with 1 M Na2CO3 (×1) and water (×2). The aqueous was further extracted with EtOAc (2×). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (Flashmaster) and then crystallized in Et2O to afford the title compound as a beige solid (tR 4.28 min (conditions 4), MH+ 332.3, 1H-NMR in DMSO-d6: 8.83 (m, 1H); 8.25 (m, 1H); 7.92 (d, 1H); 7.83 (m, 1H); 7.70 (m, 1H); 7.61 (d, 1H); 7.48 (dd, 1H); 7.32 (s, 1H); 6.66 (d, 1H); 6.56 (d, 1H); 4.34 (s, 2H); 3.70 (m, 1H); 1.46 (m, 2H); 1.07 (d, 3H); 0.80 (t, 3H)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH3:12])=[CH:5]2.OO.[O-:15]S([O-])=O.[Na+].[Na+].[I-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N+:8]([O-:15])=[CH:7][C:6]([CH3:12])=[CH:5]2
Reactant: Cc1cnc2ccc(F)cc2c1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc2cc(F)ccc2[n+]([O-])c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
6-Fluoro-3-methyl-quinoline (Intermediate 28) (48.0 mg, 0.298 mmol) was dissolved in acetic acid (1 mL) and 30% aqueous H2O2 (0.040 mL, 0.396 mmol) was added. This was stirred at 80° C. for 16 h before cooling. A few mLs of a 10% aq. solution of Na2SO3 was added followed by a spatula tip of sodium iodide. This was stirred for 10 min before partitioning between ethyl acetate and sat. NaHCO3. The separated aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (methanol/ethyl acetate) gave 6-fluoro-3-methyl-quinoline 1-oxide (29.4 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.72 (dd, J=9.4, 5.3 Hz, 1H) 8.38 (s, 1H) 7.36-7.50 (m, 3H) 2.46 (s, 3H); MS (M+1): 178.1.