Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.NC(N)=[S:23].[OH-].[Na+]>>[CH3:20][C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:4]=[N:3][C:2]([SH:23])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=1
Reactant: NC(N)=S
Reactant: Cc1cccc(N2CCN(c3ccc(Cl)nn3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(N2CCN(c3ccc(S)nn3)CC2)c1
Temperature: 165 °C
Reaction time: 3 h
Yield: 22.7 %

Procedure:
A mixture of 5.8 parts of 3-chloro-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine and 3 parts of thiourea was stirred for 3 hours in an oil bath at 165° C. After cooling, there were added 150 parts of a sodium hydroxide solution 0.5N. The whole was stirred and refluxed for 15 minutes. It was filtered while hot and the filtrate was neutralized with acetic acid. The product was filtered off, washed with water and separated by column chromatography over silica gel using a mixture of trichloromethane and methanol (98.5:1.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of ethanol and tetrahydrofuran. The product was filtered off and dried, yielding 1.3 parts (22.7%) of 6-[4-(3-methylphenyl)-1-piperazinyl]-3-pyridazinethiol; mp. 174.2° C. (compound 273).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[O-:14][CH2:15][CH3:16].[Na+]>C(O)C>[CH2:15]([O:14][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[CH3:16]
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
To an equimolar amount of chloro-2,4-dinitrobenzene acid is added sodium ethoxide in ethanol to yield 2,4-dinitrophenyl ethyl ether. Next, to a weighed aliquot of poly(glycidol) containing 0.2 mole polymer in 300 ml of ethanol is added 0.2 mole 2,4-dinitrophenyl ethyl ether, and the reactants heated to reflux and maintained at reflux reaction conditions for 1 to 2 hours. The dry benzene is added and distillation initiated and continued until nearly all ethanol and water are azeotropically removed, to form the product identified as (I) where n is greater than 10. ##SPC17##
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1O)[OH:8])([CH3:4])([CH3:3])[CH3:2].BrCCBr.C(=O)([O-])[O-].[K+].[K+].[CH2:27](O)[CH2:28][OH:29]>O>[C:1]([C:5]1[C:6]2[O:29][CH:28]=[CH:27][O:8][C:7]=2[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Reactant: OCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: BrCCBr
Solvent: O
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC=CO2
Temperature: 120 °C

Procedure:
3,5-Di-tert-butylhydroquinone (3.33 g, 15 mmol) was combined with 1,2-dibromoethane (5.6 g), potassium carbonate (4.35 g) and ethylene glycol (25 mL). The mixture was heated in a 120° C. oil bath under an Ar atmosphere for 12 h. Water was added to the reaction mixture to quench the reaction and then the organic compound was extracted by CH2Cl2. The resulting solution was concentrated to afford a crude oil. The crude oil was then chromatographed (silica, hexane/ethyl acetate=20:1) mixture to afford the title compound (Rf=0.5, 5:1 hexane/ethyl acetate). 1H NMR (500 MHz, CDCl3): δ 7.03 (d, J=2 Hz, 1H), 6.93 (d, J=2 Hz, 1H), 4.34 (s, 4H), 1.53 (s, 9H), 1.43 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[CH:11](O)=[O:12].Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:11]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)=[O:12]
Reactant: O=CO
Reactant: Nc1ccc2c(c1)CCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=CNc1ccc2c(c1)CCC2
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of 5-aminoindane (7.53 g, 56.5 mmol) in DMF (100 mL) was added formic acid (2.2 mL, 58.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.94 g, 57 mmol) and diisopropylethylamine (19.7 mL, 0.11 mol). The resulting solution was stirred overnight and then partitioned between saturated aqueous citric acid (100 mL) and ethyl acetate (200 mL). The organic layer was separated and washed with aqueous sodium bicarbonate solution (100 mL) and water (3×100 mL), then concentrated under reduced pressure to give the formamide as a thick oily solid (8.5 g, 93%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([NH2:9])=[O:8])([O-:3])=[O:2].[CH2:13]=[O:14]>CN(C)C=O>[OH:14][CH2:13][NH:9][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][N:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: NC(=O)c1ccnc([N+](=O)[O-])c1
Reactant: C=O
Solvent: CN(C)C=O
Product: O=C(NCO)c1ccnc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
0.8 g. of 2-nitroisonicotinamide and 2 ml. of 37% formalin were stirred in 2 ml. of dimethylformamide at 110° C for 2 hours. After cooling, to this solution was added ice-water, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was evaporated yielding crystals. The crystals obtained were recrystallized from ethyl acetate to give 0.6 g. of pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11].[C:31](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([CH3:31])[CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: CC(Oc1cc(-c2cn(C3CCNCC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(Oc1cc(-c2cn(C3CCN(C)CC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h

Procedure:
3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-2-aminopyridine (451 mg, 1 mmol) in the above mentioned Example 2 was added to N,N-dimethyl formamide (10 mL), potassium carbonate (276 mg, 2 mmol) and iodomethane (425.7 mg, 3 mmol) were added, and the reaction was performed overnight at room temperature. The resultant mixture was washed with water for several times, dried over anhydrous sodium sulfate, filtered, the filtrate was rotatedly concentrated to dryness to yield a solid, which was purified via silica gel column chromatography (dichloromethane/methanol=10:1) to yield the target product as white solid powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl.N1C=CC=CC=1>>[O:17]1[CH2:16][CH:15]1[CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: COC(=O)Cc1ccc(O)cc1
Solvent: c1ccncc1
Product: COC(=O)Cc1ccc(OCC2CO2)cc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 33.7 %

Procedure:
A mixture of methyl 4-hydroxyphenylacetate (4.98 g, 0.030 mol), epichlorohydrin (23.5 ml, 0.30 mol) and pyridine (121 μl, 1.5 mmol) was stirred at 85° C. for 2 hours. The reaction mixture was cooled and excess epichlorohydrin was distilled off (rotavapor). The residue was taken up in ethyl acetate, washed with brine and dried (Na2SO4). The solution was filtered and concentrated. The dark residue was chromatographed (silica, hexane/ethyl acetate 7:3) to give 2.25 g (34%) of a colourless oil. 1H (300 MHz) and 13C NMR (75 MHz) spectra were in accordance with the structure.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH2:15][C:16]2([C:33]([NH:35][OH:36])=[O:34])[CH2:21][CH2:20][N:19]([C:22]([C:24]3([CH3:32])[CH2:29][O:28]C(C)(C)[O:26][CH2:25]3)=[O:23])[CH2:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].Cl>C1COCC1.CCOC(C)=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH2:15][C:16]2([C:33]([NH:35][OH:36])=[O:34])[CH2:17][CH2:18][N:19]([C:22](=[O:23])[C:24]([CH2:25][OH:26])([CH3:32])[CH2:29][OH:28])[CH2:20][CH2:21]2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)NO)CCN(C(=O)C3(C)COC(C)(C)OC3)CC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)NO)CCN(C(=O)C(C)(CO)CO)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 694.2 %

Procedure:
A mixture of 4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxamide (0.106 g, 0.2 mmol) and 2 mL of 1N HCl in 2 mL of THF was stirred at room temperature for 4 h. The reaction was diluted with EtOAc, washed with H2O, saturated NaHCO3, brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with ether to provide 0.67 g (71%) of the desired product as an off white solid. Electrospray Mass Spec: 483.2 (M+H)+
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:26][CH2:27][CH3:28])=[C:11]([C:13]2[NH:14][C:15](=[O:25])[C:16]3[CH:21]=[N:20][N:19]([CH2:22][CH2:23][CH3:24])[C:17]=3[N:18]=2)[CH:12]=1.[C:29](=[O:31])=[O:30].[Cl-].[NH4+]>C1COCC1>[CH2:27]([O:26][C:10]1[CH:9]=[CH:8][C:7]([C:29]([OH:31])=[O:30])=[CH:12][C:11]=1[C:13]1[NH:14][C:15](=[O:25])[C:16]2[CH:21]=[N:20][N:19]([CH2:22][CH2:23][CH3:24])[C:17]=2[N:18]=1)[CH3:28]
Reactant: CCCn1ncc2c(=O)[nH]c(-c3cc(Br)ccc3OCC)nc21
Reactant: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCn1ncc2c(=O)[nH]c(-c3cc(C(=O)O)ccc3OCC)nc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
n-Butyllithium (2.5 M solution in hexane, 2.0 ml, 0.005 mol) was added dropwise to a stirred solution of 6-(5-bromo-2-ethoxyphenyl)-1-n-propyl-1,5-dihydro-4H-pyrazolo[3, 4-d]pyrimidin-4-one (0.755 g, 0.002 mol) in dry THF (20 ml) at −78° C. under a dry nitrogen atmosphere. The bright yellow solution was stirred for 1 hour at −78° C., then excess crushed solid carbon dioxide was added and the resulting solution was allowed to warm to room temperature. Saturated aqueous ammonium chloride solution (3 ml) was then added and the solvents removed by evaporation under vacuum. The residue was partitioned between saturated aqueous sodium carbonate solution (30 ml) and dichloromethane (30 ml), the organic phase was removed and the aqueous phase extracted with further dichloromethane (3×30 ml). The aqueous phase was then acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate (5×40 ml). The combined ethyl acetate extracts were dried (Na2SO4) and the solvent removed by evaporation under vacuum to give a white solid. Crystallisation from ethyl acetate-methanol gave the title compound as a white powder (0.130 g, 19%), m.p. 277-279° C. Found: C,59.64; H,5.19; N,16.39. C17H18N4O4 requires C,59.64; H,5.23; N,16.37%.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][OH:20])[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=2)[CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1>>[CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][O:20][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:16])([F:17])[F:15])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(O)cc1
Reactant: N#Cc1ccc(N(CCO)CC2CC2)cc1C(F)(F)F
Product: COc1ccc(OCCN(CC2CC2)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(cyclopropylmethyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-methoxyphenol: MS (APCI) m/z 391 (M+1).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[N:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][C:25]=1[NH:39][C:40]([C:42]1[N:43]([CH3:51])[C:44]2[C:49]([CH:50]=1)=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[N:3]=[C:2]([C:28]3[CH:27]=[CH:26][C:25]([NH:39][C:40]([C:42]4[N:43]([CH3:51])[C:44]5[C:49]([CH:50]=4)=[CH:48][CH:47]=[CH:46][CH:45]=5)=[O:41])=[C:24]([O:23][CH3:22])[CH:29]=3)[C:10]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CN1CCN(CCCn2nc(I)c3c(N)ncnc32)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn(CCCN3CCN(C)CC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 30 %

Procedure:
A solution of 3-iodo-1-[3-(4-methylpiperazino)propyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.188 g, 0.469 mmol) in ethylene glycol dimethyl ether (16 mL) was treated with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (0.209 g, 0.516 mmol), tetrakis(triphenylphosphine)palladium (0.033 g, 0.028 mmol), and a solution of sodium carbonate (0.119 g, 1.13 mmol) in water (8 mL). The reaction mixture was stirred for 4.5 h at 80° C. The organic solvent was removed under reduced pressure and ethyl acetate (200 mL) was added. The layers were partitioned and the aqueous layer was extracted with ethyl acetate (400 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a step-wise gradient of 20% methanol in dichloromethane to 50% methanol in dichloromethane. The column afforded 0.078 g (30%) of pure N2-(4-{4-amino-1-[3-(4-methylpiperazino)propyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.442 (s, 1H), 8.258 (s, 1H), 8.122-8.1076 (d, 1H, J=8.16 Hz), 7.719-7.6991 (d, 1H, J=7.96 Hz), 7.6005-7.5793 (d, 1H, J=8.48 Hz), 7.349-7.294 (m, 4H), 7.172-7.135 (t, 1H), 4.405-4.371 (m, 2H), 4.04 (s, 3H), 3.958 (s, 3H), 3.291 (m, 2H), 2.5 (m, 3H), 2.45-2.337 (m, 5H), 2.30-2.10 (m, 3H), 2.022-2.005 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.05 min (100%), MH+ 554.3.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[NH:22]C(=O)C(C)(C)C)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCCCO.Cl>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[NH2:22])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C1(O)CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCCCO
Product: Nc1ccc(Cl)cc1C1=CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Yield: 47.2 %

Procedure:
A suspension of N-[2-(1-benzyl-4-hydroxy-piperidin-4-yl)-4-chloro-phenyl]-2,2-dimethyl-propionamide (6.00 g) in n-BuOH (50 ml) and 6N HCl (120 ml) was heated to reflux temperature for 5 days. The solution was then poured into ice water, made acidic with cone. HCl and extracted with ethyl acetate. The water layer was made basic and extracted three times with CH2Cl2, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (hexane:ethyl acetate:triethyl amine 49:49:2) to afford 2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-4-chloro-phenylamine (2.11 g; viscous oil; Retention Time HPLC 1.81 min; MS (ES+) 299 (M+H)) and 4-(2-amino-5-chloro-phenyl)-1-benzyl-piperidin-4-ol (2.11 g; viscous oil; Retention Time HPLC 1.58 min; MS (ES+) 317 (M+H−).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:11]1[C:12]([N+:17]([O-:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1>>[CH2:3]([N:2]([CH3:1])[C:11]1[C:12]([N+:17]([O-:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1ccccc1
Reactant: O=[N+]([O-])c1ncccc1Cl
Product: CN(Cc1ccccc1)c1cccnc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The mixture of N-methylbenzylamine (6.085 mL), TEA (13.19 μL) and 3-chloro-2-nitropyridine (5 g) was stirred at 60° C. under N2 overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-30% EtOAc in hexane) to give N-benzyl-N-methyl-2-nitropyridin-3-amine (2.6 g) as dark yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[CH3:18])[CH:3]=1.OB(O)[C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1>C(O)C>[CH3:18][C:10]1[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:9]=1[NH:8][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[N:7]=[CH:6][N:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1cc(Cl)ncn1
Reactant: OB(O)c1cncnc1
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])cc1Nc1cc(-c2cncnc2)ncn1
Yield: 21.1 %

Procedure:
3.28 g of 2-[(6-chloro)pyrimidin-4-ylamino]-1-methyl-4-nitrobenzene (Reference Example 20 (step 1)) were dissolved with heating in 130 ml of anhydrous ethanol. 1.69 g of dihydroxy(5-pyrimidinyl)borane was added, and then deaeration was performed, followed by purging with argon. 5.82 g of potassium carbonate and 2.15 g of tetrakis(triphenylphosphine)palladium (0) were added in turn, and then the mixture was heated at reflux for 7.5 hours. The reaction solution was mixed with water, followed by extraction with ethyl acetate twice, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was crystallized by adding chloroform-methanol to obtain 808 mg of the objective compound as ocherous crystals.
Reaction SMILES: [N:1](=[C:3]([C:7](=[O:9])[CH3:8])[C:4](=O)[CH3:5])O.C[NH:11][CH:12](C(O)=O)[CH2:13][CH2:14][CH3:15]>C(#N)C>[C:7]([C:3]1[NH:1][C:12]([CH2:13][CH2:14][CH3:15])=[N:11][C:4]=1[CH3:5])(=[O:9])[CH3:8]
Reactant: CC(=O)C(=NO)C(C)=O
Reactant: CCCC(NC)C(=O)O
Solvent: CC#N
Product: CCCc1nc(C)c(C(C)=O)[nH]1
Yield: 51.6 %

Procedure:
To 40 g (0.31 moles) of 3-oximino-2,4-pentanedione dissolved in 297 ml of acetonitrile was added 40.64 g (0.31 moles) of methyl d,1-norvaline. The reaction mixture was refluxed 21.2 h under nitrogen, cooled, then concentrated in vacuo. The resulting oil was dissolved in 50 ml of ethanol and 140 ml of 10% aqueous sodium hydroxide. After 4 h of reflux, the cooled mixture was extracted with ethyl acetate (900 ml total) and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded 0.16 moles (51% yield) of 5-acetyl-4-methyl-2-propylimidazole.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Br:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(F)cc1Br
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(F)cc4Br)nccc3c2)cc1

Procedure:
To a microwave vial charged with 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.053 g, 0.119 mmol) was added (2-bromo-4-fluorophenyl)boronic acid (Combi-Blocks, San Diego, Calif.) (0.042 g, 0.190 mmol), potassium carbonate (0.082 g, 0.594 mmol), dioxane (0.594 ml) and water (0.198 ml). The mixture was purged with argon prior to the addition of Pd(PPh3)4 (0.014 g, 0.012 mmol). The vessel was sealed and irradiated at 100° C. for 30 mins affording fairly clean conversion to desired product. The organic phase was decanted, the aqueous rinsed with EtOAc and the EtOAc decanted. The combined organics were dried under reduced pressure and purified with a 25 g HP silicycle column ramping EtOAc in heptane (0-45%, then isocratic at 45%) to provide product as an off-white foam 1-(2-bromo-4-fluorophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate KKK) (54 mg, 0.092 mmol, 78% yield) with minor impurities according to LC/MS and NMR (˜20% impurity). m/z (ESI) 582.2/584.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]=C)=[CH:10][CH:9]=1)[C:4]([F:7])([F:6])[F:5].CC([OH:22])(C)C>O1CCOCC1.O.O=[Os](=O)(=O)=O>[F:1][C:2]([F:17])([F:16])[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:22])=[CH:10][CH:9]=1)[C:4]([F:7])([F:6])[F:5]
Reactant: C=Cc1ccc(C(C(F)(F)F)C(F)(F)F)cc1
Reactant: CC(C)(C)O
Agent: O=[Os](=O)(=O)=O
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccc(C(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
1-(2,2,2-Trifluoro-1-trifluoromethyl-ethyl)-4-vinyl-benzene (80 mg, 0.3 mmol) was dissolved in dioxane (6 ml) and water (5 ml). NaIO4 (181 mg, 0.84 mmol) and OsO4 (0.18 ml of a 2.5 % t-BuOH solution) were added. The mixture was allowed to stir at room temperature for 2 h, and then it was partitioned between ethyl acetate and brine. The ethyl acetate was washed with three additional times with brine, dried over MgSO4, and the solvent was removed under vacuum to give the title product (47 mg (61%), 0.18 mmol). 1H NMR (CDCl3): δ=10.08 (s, 1H), 8.04 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.3 Hz, 2H), 5.82 (m, 1H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][C:12]([O:14]CC)=O.[NH2:17][NH2:18]>C(O)C>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][C:12]([NH:17][NH2:18])=[O:14]
Reactant: NN
Reactant: CCOC(=O)CN1CCc2ccccc2C1
Solvent: CCO
Product: NNC(=O)CN1CCc2ccccc2C1
Yield: 99.9 %

Procedure:
A solution of 90 (2.0 g, 9.12 mmol) and hydrazine (5.1 g, 91 mmol) in ethanol (30 mL) was heated at reflux overnight. The mixture was concentrated under reduced pressure to give 91 (1.87 g ˜100%) which was used without further purification.