Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([S:25][CH3:26])=[CH:9]2)=[N:6][CH:7]=1.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([S:25][CH3:26])=[CH:9]2)=[N:6][CH:7]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Product: CSc1cn(-c2ncc(-c3ccccc3Cl)cn2)c2cc(C(=O)N3CCOCC3)ccc12

Procedure:
Synthesized according to general procedure 1 from (1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indol-6-yl)(morpholino)methanone (1.0 g, 2.30 mmol, 1.0 eq) and (2-chlorophenyl)boronic acid (0.429 g, 2.77 mmol, 1.2 eq). Yield: 0.7 g (65% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]3[C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=[C:7]3[C:6]=2[CH:21]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH3:12])=[C:6]([C:7]2[N:8]([CH2:9][C:10](=[O:13])[N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:14]([C:17]([F:20])([F:18])[F:19])=[N:15][N:16]=2)[CH:21]=1
Reactant: C1COCCN1
Reactant: CN1C(=O)Cn2c(nnc2C(F)(F)F)-c2cc(Cl)ccc21
Product: CNc1ccc(Cl)cc1-c1nnc(C(F)(F)F)n1CC(=O)N1CCOCC1

Procedure:
4.8 g. (0.0152 mole) of 10-chloro-7-methyl-3-(trifluoromethyl)-5H-s-triazolo[4,3-d] [1,4] benzodiazepin- 6(7H)-one from example 1a are dissolved in 40 ml. of morpholine and the resulting solution is refluxed for 3 days. The morpholine is removed under vacuum, 3N aqueous NaOH is added, and the mixture is extracted with benzene. The benzene solution is dried over Na2SO4, decanted from drying agent, and the solvent removed under vacuum to yield a gum. This gum is chromatographed on silica gel plates with chloroform/ethyl acetate, 6:4. The largest band is isolated, extracted with chloroform, the chloroform is evaporated, and the residue is recrystallized from ethanol to yield 3-[5-chloro-2-(methylamino)phenyl]-4-[2-oxo-2-(4-morpholinyl)ethyl]-5-(trifluoromethyl)-1,2,4-triazole; m.p. 152°-153°.
Reaction SMILES: C([N:3](CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[C:21]([OH:23])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC)=O.N>O1CCCC1>[NH2:3][C:21]([C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20][N:15]1[C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])=[O:23]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(N)=O
Reaction time: 0.67 h

Procedure:
Triethylamine (14.46 ml) was added to a solution of (2S)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid (18.3 g) [see Preparation 1] in tetrahydrofuran (240 ml) at −20° C. under an atmosphere of nitrogen. Ethyl chloroformate (7.52 ml) was then added to the mixture and the resulting solution was stirred for 40 mins. at −10° C. and then 0.88 aqueous ammonia solution (32 ml) added. The reaction mixture was stirred for 10 mins. after which time the solvent was removed under reduced pressure and the residue diluted with ethyl acetate and water. The organic layer was separated and dried over magnesium sulphate and the solvent was removed under reduced pressure to afford tert-butyl (2S)-2-(aminocarbonyl)-1-piperidinecarboxylate (18.65 g) as a white solid. 1H-NMR (CDCl3) δ: 6.0 (1H, bs), 5.40 (1H, bs), 4.80 (1H, s), 4.00 (1H, m), 2.85 (1H, t), 2.30 (1H, d), 1.80-1.40 (14H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].Cl.[O-:15][C:16]#N.[K+]>O>[OH:13][CH2:12][CH2:11][CH2:10][N:9]1[C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[NH:1][C:16]1=[O:15]
Reactant: Cc1ccc(NCCCO)c(N)c1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1ccc2c(c1)[nH]c(=O)n2CCCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 31 %

Procedure:
To a stirred and cooled solution of 54 parts of 3-[(2-amino-4-methylphenyl)amino]-1-propanol in 30 parts of hydrochloric acid solution 10% and 200 parts of water is added dropwise a solution of 28 parts of potassium cyanate in 50 parts of water at a temperature below 10° C. Upon completion, stirring is continued first for 1 hour at room temperature and further for 24 hours at reflux temperature. After cooling to room temperature, the product is extracted with trichloromethane. The extract is washed with a hydrochloric acid solution 5%, dried, filtered and evaporated. The residue is cyrstallized from 4methyl-2-pentanone, yielding 19.5 parts (31%) of 1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one; mp. 114.1° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:27][O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.CO.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>[CH3:27][O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34]([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]4[CH:17]=[C:16]([N:18]5[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]5)[N:15]=[C:14]([NH2:25])[N:13]=4)[CH2:9]3)=[CH:4][CH:3]=2)[CH:33]=[N:32]1
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
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: O
Solvent: CO
Solvent: C1COCCO1
Product: COCCn1cc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)cn1
Temperature: 90 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.1 mg, 0.036 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in 1,4-dioxane (0.2 mL) and water (0.1 mL) was stirred at 90° C. for 2 h. After cooling, it was diluted with methanol, and purified with RP-HPLC (pH=10). to afford the desired product (4.7 mg). LCMS (M+H)+: m/z=463.3.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[S:27](Cl)(=[O:29])=[O:28])[CH:20]=[CH:19][CH:18]=1>C1COCC1>[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[S:27]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)(=[O:29])=[O:28])[CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NS(=O)(=O)c2cccc3cccnc23)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
To a solution of 4-aminobenzoic acid (10 g, 73 mmol) in 100 mL of anhydrous THF was added pyridine (1.15 g, 146 mmol), and quinoline-8-sulfonyl chloride (20 g, 88 mmol) at 0° C. The resulting mixture was stirred at 70° C. overnight. After filtration, the residue was washed with EtOH and 14 g of title compound was obtained as pure product.
Reaction SMILES: FC1C=CC(S(N)(=O)=O)=CC=1[N+]([O-])=O.[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20].F[C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][C:24]=1[S:33]([C:36]([F:39])([F:38])[F:37])(=[O:35])=[O:34]>>[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH:20][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][C:24]=1[S:33]([C:36]([F:37])([F:39])[F:38])(=[O:35])=[O:34]
Reactant: CN(C)CCCN
Reactant: NS(=O)(=O)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Agent: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Product: CN(C)CCCNc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F

Procedure:
The title compound was prepared by following the procedure described in Example 10C, replacing Example 10B and 4-fluoro-3-nitrobenzenesulfonamide with N′,N′-dimethylpropane-1,3-diamine and 4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide, respectively.
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8]([C:10]3[CH2:16][CH:15]4[NH:17][CH:12]([CH2:13][CH2:14]4)[CH:11]=3)=[CH:9][C:5]=2[CH:4]=1.O.N.[Cl:22]CCl>>[ClH:22].[CH:12]12[NH:17][CH:15]([CH2:14][CH2:13]1)[CH2:16][C:10]([C:8]1[S:7][C:6]3[CH:18]=[CH:19][C:3]([OH:2])=[CH:4][C:5]=3[CH:9]=1)=[CH:11]2
Reactant: COc1ccc2sc(C3=CC4CCC(C3)N4)cc2c1
Reactant: ClCCl
Agent: N
Solvent: O
Product: Cl
Product: Oc1ccc2sc(C3=CC4CCC(C3)N4)cc2c1
Reaction time: 15 h

Procedure:
3-(5-Methoxy-benzo[b]thiophen-2-yl)-8-aza-bicyclo[3.2.1]oct-2-ene (0.30 g, 1.105 mmol) was solved in dichloromethane (25 ml) and was cooled on an ice-bath. Borontribromide (1 M, 2.21 ml, 2.21 mmol) was added dropwise under cooling, followed by stirring for 15 hours at room-temperature. Water (40 ml) was added and the mixture was made alkaline by adding aqueous ammonia. The product was filtered and was recrystallised with ethanol (25 ml, 96%) and HCl in ethanol (0.5 ml, 3 M). Yield 0.15 g (46%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)=[N:8][CH:7]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:56][C@@H:57]([CH2:71][C:72]1[CH:77]=[C:76]([F:78])[CH:75]=[C:74]([F:79])[CH:73]=1)[C@H:58]([OH:70])[CH2:59][NH:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([CH2:68][CH3:69])[CH:63]=1>C(Cl)Cl.CN(C=O)C>[F:78][C:76]1[CH:77]=[C:72]([CH:73]=[C:74]([F:79])[CH:75]=1)[CH2:71][C@H:57]([NH:56][C:14]([C:13]1[CH:12]=[C:11]([C:9]2[O:10][C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:20])=[CH:7][N:8]=2)[CH:19]=[CH:18][CH:17]=1)=[O:16])[C@H:58]([OH:70])[CH2:59][NH:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([CH2:68][CH3:69])[CH:63]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: COC(=O)CCc1cnc(-c2cccc(C(=O)O)c2)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(-c3ncc(CCC(=O)OC)o3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[5-(3-Methoxy-3-oxopropyl)-1,3-oxazol-2-yl]benzoic acid (285 mg, 1.0 mmol) is dissolved in methylene chloride (5 mL) and DMF (5 mL), and diisopropylethylamine (695 μL, 4.0 mmol), HATU (472 g, 1.2 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method of EXAMPLE SP-272 (448 mg, 1.1 mmol) are added. The reaction stirred at room temperature 1 h. The reaction is partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/chloroform) provides the title compound. ESI MS m/z 591.9 [M+H]+.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:23]=[C:22]3[C:17]([C:18]([OH:33])=[C:19]([C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:20](=[O:25])[N:21]3[CH3:24])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=[O:7])(C)(C)C.OC1C2C(=CC(C3C=CC(C(OC(C)(C)C)=O)=CC=3)=CC=2)N(C)C(=O)C=1C(=O)CCC=O.OOS([O-])=O.[K+].O>CN(C=O)C>[C:29]([CH2:28][CH2:27][C:26]([C:19]1[C:20](=[O:25])[N:21]([CH3:24])[C:22]2[C:17]([C:18]=1[OH:33])=[CH:16][CH:15]=[C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:6]([OH:7])=[O:5])=[CH:13][CH:12]=1)[CH:23]=2)=[O:32])([OH:31])=[O:30]
Reactant: Cn1c(=O)c(C(=O)CCC(=O)O)c(O)c2ccc(-c3ccc(C(=O)OC(C)(C)C)cc3)cc21
Agent: Cn1c(=O)c(C(=O)CCC=O)c(O)c2ccc(-c3ccc(C(=O)OC(C)(C)C)cc3)cc21
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c(C(=O)CCC(=O)O)c(O)c2ccc(-c3ccc(C(=O)O)cc3)cc21
Reaction time: 1 h

Procedure:
4-(7-(4-(tert-Butoxycarbonyl)phenyl)-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-4-oxobutanoic acid. tert-Butyl 4-(4-hydroxy-1-methyl-2-oxo-3-(4-oxobutanoyl)-1,2-dihydroquinolin-7-yl)benzoate (130 mg, 299 μmol) was dissolved in DMF (1493 μl). Oxone (184 mg, 299 μmol) was added to the mixture at room temperature, and the resulting mixture was stirred for 1 hour. Water was added to precipitate the product from solution. The mixture was filtered, washed with water and ether, and dried in a vacuum oven to give the title compound as an off-white solid.
Reaction SMILES: O=[CH:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1.[CH3:24][N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH2:34]>CC#N.C(Cl)Cl.CC(O)=O>[CH3:24][N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CC=O)c2)c1
Reactant: Cn1c(N)nc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCNc3nc4ccccc4n3C)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-(1-(2-oxoethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide (157 mg, 0.45 mmol) in MeCN (1 mL) and DCM (0.8 mL) was added 1-methyl-1H-benzo[d]imidazol-2-amine (66 mg, 0.45 mmol) followed by STAB (190 mg, 0.90 mmol) and 1 drop of AcOH. After stirring at rt for 18 h, the reaction mixture was filtered and directly purified by prep. HPLC. LC-MS conditions D: tR=0.77 min, [M+H]+=442.3.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)=[CH:12][CH:11]=1>>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=3)=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: Cc1cccc(-c2ccc(Cl)nc2)n1
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2ccc(-c3cccc(C)n3)cn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 1-ethyl-piperazine and 6′-chloro-6-methyl-[2,3′]bipyridinyl.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=1[C:5](Cl)=[O:6].[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([N+:38]([O-:40])=[O:39])=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=1[C:5]([NH:27][C:28]1[CH:29]=[CH:30][C:31]([N+:38]([O-:40])=[O:39])=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1)=[O:6]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-Methoxy-6-pentadecyl-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Methoxy-N-(4-nitro-3-trifluoromethyl-phenyl)-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: Cl.N1CC=[C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH2:20][CH2:21][N:22]([S:28]([NH:31][C:32]2[S:36][N:35]=[CH:34][N:33]=2)(=[O:30])=[O:29])[CH2:23]3)CC1.C[CH2:38][N:39]([CH:43]([CH3:45])C)[CH:40]([CH3:42])C.I[CH3:47]>C1COCC1>[OH-:29].[S:36]1[C:32]([NH:31][S:28]([N:22]2[CH2:21][CH2:20][C:19]3[C:24](=[CH:25][CH:26]=[CH:27][C:18]=3[C:9]3[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]=3[C:5]3[CH2:45][CH2:43][N+:39]([CH3:38])([CH3:47])[CH2:40][CH:42]=3)[CH2:23]2)(=[O:30])=[O:29])=[N:33][CH:34]=[N:35]1
Reactant: CI
Reactant: CCN(C(C)C)C(C)C
Reactant: O=S(=O)(Nc1ncns1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2C2=CCNCC2)C1
Agent: Cl
Solvent: C1CCOC1
Product: C[N+]1(C)CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3c2CCN(S(=O)(=O)Nc2ncns2)C3)CC1
Product: [OH-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
A solution of 5-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide hydrochloride (Example 6, 0.213 g, 0.382 mmol) and DIPEA (0.333 ml, 1.908 mmol) in 4 mL THF was treated with iodomethane (0.036 ml, 0.573 mmol) and was allowed to stir at room temperature overnight. The reaction mixture was concentrated. Purification of the resulting residue by reverse phase column chromatography [RediSep Gold C-18 50 g, 5 to 60% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] then by normal phase silica gel column chromatography [(0 to 100% EtOAc/MeOH), Interchim (San Pedro, Calif.) 15 micron MeOH stable column] gave 4-(2-(2-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-1,2,3,4-tetrahydro isoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-1,1-dimethyl-1,2,3,6-tetrahydropyridin-1-ium hydroxide (0.026 g, 0.047 mmol). [M+H]+=550.0 1H NMR (400 MHz, Acetone-d6) δ ppm: 7.71-7.79 (m, 3H), 7.48 (d, J=7.9 Hz, 1H), 7.14-7.22 (m, 1H), 7.06 (d, J=7.7 Hz, 2H), 5.75 (br. s., 1H), 4.15-4.45 (m, 4H), 3.67-3.84 (m, 2H), 3.55-3.65 (m, 1H), 3.23 (s, 3H), 3.18 (s, 3H), 3.09 (ddd, J=13.0, 9.6, 4.5 Hz, 1H), 2.64-2.75 (m, 1H), 2.51-2.61 (m, 2H), 2.32 (m, J=16.4, 4.4 Hz, 1H)
Reaction SMILES: Br[Zn][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[C:12]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([C:22]#[N:23])[C:16]=2[CH:15]=[CH:14][N:13]=1>C1COCC1.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>[C:22]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[CH:15]=[CH:14][N:13]=[C:12]2[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:23]
Reactant: CCOC(=O)CCC[Zn]Br
Reactant: N#Cc1cccc2c(Br)nccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCc1nccc2c(C#N)cccc12

Procedure:
Bromo[4-(ethyloxy)-4-oxobutyl]zinc (0.5 M in THF, 26 ml) was added dropwise to a solution of 1-bromo-5-isoquinolinecarbonitrile (D38; 1 g) and tetrakis(triphenylphosphine)palladium(0) (20 mg) in THF (5 ml). The resulting solution was heated to reflux for 3 hours. The solvent was evaporated in vacuo and the residue was dissolved in DCM (50 ml). The organic solution was washed with 0.5 M aq. NaOH (15 ml), followed by washing with water and brine. The organic phase was dried over anhydrous sodium sulphate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give the title compound (0.65 g). δH (CDCl3, 400 MHz): 1.28 (3H, t), 2.20 (2H, m), 2.50 (2H, m), 3.41 (2H, m), 4.16 (2H, q), 7.71 (1H, dd), 7.93 (1H, d), 8.12 (1H, dd), 8.54 (1H, d), 8.63 (1H, d). MS (ES): C16H16N2O2 requires 268. found 269.1 (M+H+).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4](=[O:7])([O-])[O-:5].[K+].[K+].[CH3:10][C:11]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([NH:28][C:29]3[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=3)[CH:25]=[C:24]([CH3:39])[CH:23]=2)=[CH:18][N:17]=1)([CH3:14])[C:12]#[N:13]>C(O)C.CS(C)=O>[OH:3]/[N:2]=[C:12](\[NH2:13])/[C:11]([CH3:10])([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([NH:28][C:29]3[N:34]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:32]=[CH:31][N:30]=3)[CH:25]=[C:24]([CH3:39])[CH:23]=2)=[CH:18][N:17]=1)[CH3:14].[C:4]([OH:5])([C:35]([F:38])([F:37])[F:36])=[O:7]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(NC(C)(C)C#N)nc2)c1
Reactant: O=C([O-])[O-]
Reactant: NO
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(NC(C)(C)/C(N)=N/O)nc2)c1
Product: O=C(O)C(F)(F)F
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Hydroxylamine hydrochloride (101 mg, 1.46 mmol) and potassium carbonate (201 mg, 1.46 mmol) were added to a mixture of 2-methyl-2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}propanenitrile (100 mg, 0.242 mmol) in ethanol (404 μL). The reaction stirred at 85° C. overnight. The reaction mixture was diluted with DMSO, filtered, and purified by reverse phase HPLC (5-95% acetonitrile in water+0.5% TFA) to yield (1Z)—N′-hydroxy-2-methyl-2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}propanimidamide as a bis-TFA salt. MS APCI calc'd for C21H23F3N7O [M+H]+ 446. found 446.
Reaction SMILES: F[C:2]1[C:7](F)=[C:6](I)C=C[C:3]=1[C:10]1C=[CH:14][C:13](C2C=CC(CCC)=CC=2)=[CH:12][C:11]=1F.OCC(C)(CO)C.O.CC(C)=O>CC(O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:6][CH2:7][CH2:2][CH2:3][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCc1ccc(-c2ccc(-c3ccc(I)c(F)c3F)c(F)c2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(CO)CO
Solvent: CC(C)O
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCC
Yield: 65 %

Procedure:
A solution of (0.1 mmol) of 10, (0.12 mmol) of 12, 14 mg (0.13 mmol) of neopentyl glycol, 95 mg (0.3 mmol) of Ba(OH)2.8 H2O, 80 μl (6.08 mmol, 5 mol %) of a 76 mM acetone solution of Pd(OAc)2 in 2 ml of 95% i—PrOH is stirred at 80° C. for 12 hours. The solvent is subsequently removed under reduced pressure. 2 ml of 2 M HCl are added to the residue, and the mixture is extracted with dichloromethane (3×2 ml). The combined organic phases are dried over MgSO4 and filtered through SiO2. The solvent is removed under reduced pressure, and the residue is purified by recrystallisation twice from nonane (yield: 65%).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Reactant: Fc1ccc(Br)cc1
Product: O=C(c1ccc(F)cc1)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12e and 1-bromo-4-fluorobenzene
Reaction SMILES: Cl[C:2](=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:10]=[CH2:11].CCN(C(C)C)C(C)C.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:9]([N:12]([C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)[C:2](=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH:10]=[CH2:11]
Reactant: COC(=O)CC(=O)Cl
Reactant: C=CCNc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=CCN(C(=O)CC(=O)OC)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
Methyl 3-chloro-3-oxopropanoate (9.4 ml, 87 mmol) was added into a solution of N-allyl-4-fluorobenzenamine (12 g, 79 mmol), DIEA (15 ml, 87 mmol) and DMAP (0.97 mg, 7.9 mmol) in CH2Cl2 (200 mL) at 0° C. under nitrogen. The reaction was stirred at 0° C. for 1 hour. The reaction mixture was poured into ice and water, extracted with CH2Cl2, washed with saturated aqueous NaHCO3 and brine. The organic layer was dried with Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (50% EtOAc in hexane) to afford the product (18.3 g, 92% yield) as brown oil.