Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:33][CH2:32][C:27]3([O:31][CH2:30][CH2:29][O:28]3)[CH2:26][CH2:25]2)[N:9]=1)=[O:7])(C)(C)C.O[Li].O.CO.ClCCl>O1CCCC1.O>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:25][CH2:26][C:27]3([O:28][CH2:29][CH2:30][O:31]3)[CH2:32][CH2:33]2)=[N:11][C:12]=1[OH:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3ccccc3)CCC3(CC2)OCCO3)nc(O)c1OCc1ccccc1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1nc(CC2(c3ccccc3)CCC3(CC2)OCCO3)nc(O)c1OCc1ccccc1
Yield: 91.8 %

Procedure:
A mixture of 5-benzyloxy-6-hydroxy-2-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-ylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (269) (850 mg, 1.60 mmol), LiOH.H2O (670 mg, 15.96 mmol) in tetrahydrofuran-water (5:1, 48 mL) was refluxed for 20 h while silica thin layer chromatography was performed (methanol:dichloromethane=1:9, Rf=0.1). Tetrahydrofuran was removed from the reaction mixture in vacuo and the residue was diluted with water (25 mL), cooled in ice water, neutralized to about pH 7 with 1N aqueous HCl and extracted with ethyl acetate (2×50 mL). The combined organic parts were washed with brine (25 mL), dried and concentrated in vacuo to get pure 5-benzyloxy-6-hydroxy-2-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-ylmethyl)-pyrimidine-4-carboxylic acid (270) (700 mg, 92.05%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:27])=[C:5]([C@H:10]2[O:15][CH2:14][C@@H:13]3[CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19][N:12]3[CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>>[F:31][C:30]([F:33])([F:32])[C:28]([OH:34])=[O:29].[F:9][C:8]1[C:3]([C:1]#[N:2])=[C:4]([CH3:27])[C:5]([C@H:10]2[O:15][CH2:14][C@@H:13]3[CH2:16][NH:17][CH2:18][CH2:19][N:12]3[CH2:11]2)=[CH:6][CH:7]=1
Reactant: Cc1c([C@@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)ccc(F)c1C#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1c([C@@H]2CN3CCNC[C@H]3CO2)ccc(F)c1C#N

Procedure:
tert-Butyl (3R,9aS)-3-(3-cyano-4-fluoro-2-methylphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (1.73 g, 4.61 mmol) was treated with 10 mL TFA at RT for 1 h. The trifluoroacetic acid was then removed under reduced pressure to yield the title compound. LC-MS: M+1=276: 1H-NMR (600 MHz, DMSO) δ ppm 7.724 (dd, J=9.0, 6.2 Hz, 1H), 7.353 (t, J=8.85 Hz, 1H), 4.738 (d, J=10.3 Hz, 1H), 3.924 (d, J=11.10 Hz, 1H), 3.386 (t, J=11.65 Hz, 1H), 3.285 (d, J=12.3 Hz, 1H), 3.20 (d, J=11.8 Hz, 1H), 3.01 (b, 1H), 2.934 (d, J=111.6 Hz, 1H), 2.884 (d, J=11.0 Hz, 1H), 2.642 (b, 1H), 2.476 (s, 3H), 2.47 (b, 1H), 2.329-2.367 (m, 1H), 2.054-2.089 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:9]2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:29][CH:30]1[CH2:32][CH2:31]1.CN(C)C=O>O>[CH:30]1([CH2:29][N:20]2[CH2:19][CH2:18][N:17]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=3)[CH2:22][CH2:21]2)[CH2:32][CH2:31]1
Reactant: ClCC1CC1
Reactant: Fc1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-n2nc(N3CCN(CC4CC4)CC3)c3ccccc32)cc1

Procedure:
A stirred mixture of 5.0 g of 1-(4-fluorophenyl)-3-(1-piperazinyl)-1H-indazole, 1.6 g of sodium bicarbonate, 1.7 g of chloromethylcyclopropane and 60 ml of dimethylformamide was heated at 85°-90° for 16 hours. Additional chloromethylcyclopropane (0.43 g) was added and the reaction mixture heated at 85°-90° for 8 hrs. The reaction mixture was then poured into water and the aqueous mixture extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to a solid. The solid was purified by flash chromatography on silica gel utilizing ethyl acetate/diethylamine (3%) as the eluent. Concentration of the appropriate fractions gave 3-[4-(cyclopropyl)methyl-1-piperazinyl]-1-(4-fluorophenyl)-1H-indazole as a solid. The solid was dissolved in anhydrous diethyl ether and treated with ethereal hydrogen chloride to give the hydrochloride salt. The salt was recrystallized from ethanol-diethyl ether (twice) to give 2.6 g (40%) of 3-[4-(cyclopropyl)methyl-1-piperazinyl] -1-(4-fluorophenyl)-1H-indazole hydrochloride, mp 213°-215°.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][N:8]2[CH3:9])[CH:4]=[CH:3][CH:2]=1.[Br-].[Na+].Br.Br([O-])(=O)=[O:17].[Na+].BrBr.Cl>[Zn].C(O)(=O)C>[CH3:9][N:8]1[C:10](=[O:17])[CH2:11][CH2:12][C@H:7]1[C:5]1[CH:4]=[CH:3][CH:2]=[N:1][CH:6]=1
Reactant: [O-][Br+2]([O-])[O-]
Reactant: CN1CCCC1c1cccnc1
Agent: Br
Agent: BrBr
Agent: Cl
Solvent: CC(=O)O
Product: CN1C(=O)CC[C@H]1c1cccnc1

Procedure:
The invention will be better understood by reference to the FIGURE which illustrates the invention by way of example. As shown in the FIGURE, nicotine together with an alkali metal bromide, e.g., sodium bromide or hydrogen bromide, and an alkali metal bromate, e.g., sodium bromate, was placed in an aqueous solution in a reactor and heated in the presence of an acid, e.g., hydrochloric and acetic acids. The red color produced in the reactor indicated the presence of elemental bromine. A red-orange precipitate of dibromocotinine hydrobromide perbromide was then separated and collected by suction filtration. This intermediate product was then kept in the same reactor or, if desired, isolated and placed in a second reactor. The intermediate product is mixed with an acid, e.g., acetic acid and hydrochloric acid, followed by the addition of zinc dust or granules. The zinc was removed by suction filtration and the resulting cotinine was extracted with an organic solvent, e.g., chloroform. Finally, the extract was concentrated by evaporation to produce cotinine as a brown, viscous liquid. Analysis by thin-layer chromatography (TLC) showed that the material collected was about 95% cotinine with norcotinine as a by-product with a trace of nicotine present.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH:11]2[O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]3[O:36][CH2:35][CH2:34][N:33]([CH2:37][CH2:38][CH2:39][O:40][CH3:41])[C:32]=3[CH:42]=2)=[CH:6][CH:5]=1)(O)=[O:2].[O:43]([C@@H:50]1[CH2:54][CH2:53][NH:52][CH2:51]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH3:41][O:40][CH2:39][CH2:38][CH2:37][N:33]1[C:32]2[CH:42]=[C:28]([CH2:27][O:26][CH:11]3[CH:10]([C:7]4[CH:6]=[CH:5][C:4]([C:1]([N:52]5[CH2:53][CH2:54][CH:50]([O:43][C:44]6[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=6)[CH2:51]5)=[O:2])=[CH:9][CH:8]=4)[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[O:17])[CH2:12]3)[CH:29]=[CH:30][C:31]=2[O:36][CH2:35][CH2:34]1
Reactant: c1ccc(O[C@@H]2CCNC2)cc1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(=O)O)cc3)cc21
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(=O)N4CCC(Oc5ccccc5)C4)cc3)cc21

Procedure:
Analogously to Example 255b, 0.207 g of benzyl 4-(4-carboxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 243b) and 0.0832 g of (R)-3-phenoxypyrrolidine are reacted. The title compound is obtained as a colourless oil. Rf=0.17 (EtOAc); Rt=5.33.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][C:5]1([CH3:33])[C@H:7](/[CH:8]=[C:9](/[F:13])\[C:10](=[O:12])[OH:11])[C@H:6]1[C:14]([O:16][C@H:17]([C:31]#[N:32])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:15]>C(Cl)Cl.C(O)(=O)C>[CH3:4][C:5]1([CH3:33])[C@H:7](/[CH:8]=[C:9](/[F:13])\[C:10](=[O:11])[O:12][CH3:3])[C@H:6]1[C:14]([O:16][C@H:17]([C:31]#[N:32])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:15]
Reactant: C=[N+]=[N-]
Reactant: CC1(C)[C@H](/C=C(/F)C(=O)O)[C@H]1C(=O)O[C@H](C#N)c1cccc(Oc2ccccc2)c1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)/C(F)=C\[C@@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A slight excess of diazomethane in methylene chloride solution was added at 5° to 10° C. to a solution of 860 mg of the product of Step A in 2 ml of methylene chloride and the mixture was stirred at 5° C. for 15 minutes and at room temperature for 30 minutes. A few drops of acetic acid were added to the mixture which was then evaporated to dryness to obtain 950 mg of an oil residue. The latter was chromatographed over silica gel and was eluted with an 85-15 hexane-ethyl acetate mixture to obtain 700 mg of (S)α-cyano-3-phenoxy-benzyl (1R, trans) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =-31°±2.5° (c=0.25% in chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C:8]2[N:13]=[C:12](I)[C:11]3[CH2:15][C:16]([CH3:19])([CH3:18])[CH2:17][C:10]=3[N:9]=2)[CH:7]=1.[CH3:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[NH2:28].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C:8]2[N:13]=[C:12]([NH:28][C:27]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[CH3:21])[C:11]3[CH2:15][C:16]([CH3:19])([CH3:18])[CH2:17][C:10]=3[N:9]=2)[CH:7]=1
Reactant: CC1(C)Cc2nc(-c3cc(Cl)ccc3F)nc(I)c2C1
Reactant: Cc1cnccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1CC(C)(C)C2
Temperature: 85 °C

Procedure:
To a solution of 2-(5-Chloro-2-fluoro-phenyl)-4-iodo-6,6-dimethyl-6,7-dihydro-5H-cyclopentapyrimidine (100 mg, 0.25 mmol), 3-Methyl-pyridin-4-ylamine (30 mg, 0.27 mmol), Pd(OAc)2 (3 mg, 12.42 μmol) and Rac-BINAP (12 mg, 18.63 μmol) in dry dioxane (3 mL) was added Cs2CO3 (121 mg, 0.37 mmol). The mixture was heated for 48 h at 85° C., cooled and evaporated. HPLC purification gave, after lyophilization, the desired product of formula (60) as the TFA salt, which was a white solid (6.4 mg). The same procedure was used to prepare compound of formula (61).
Reaction SMILES: [CH2:1]([N:8]1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]2=[O:45])[S:27][C:28]=1[C:29]([OH:31])=O.C(N)C1C=CC=CC=1>>[CH2:1]([NH:8][C:29]([C:28]1[S:27][C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]2=[O:45])=[N:25][C:24]=1[CH3:23])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(CCc3ccccc3)C2=O)sc1C(=O)O
Solvent: NCc1ccccc1
Product: Cc1nc(N2CCN(CCc3ccccc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 26 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-phenethylimidazolidin-1-yl)thiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a white powder in 26% yield: mp 156-157° C.; 1H NMR (300 MHz, CDCl3) δ 7.36-7.18 (m, 10H), 5.93 (s, 1H), 4.54 (d, J=5.7 Hz, 2H), 3.99 (t, J=7.8 Hz, 2H), 3.54 (t, J=7.2 Hz, 2H), 3.41 (t, J=7.8 Hz, 2H), 2.87 (t, J=7.2 Hz, 2H), 2.59 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.4, 157.3, 155.3, 153.0, 151.7, 138.2, 137.9, 128.7, 128.6, 127.8, 127.6, 126.7, 117.1, 45.3, 44.0, 42.7, 42.0, 34.0, 17.2; MS (ES+) m/z 421.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:18][NH2:19].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.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]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:19][CH2:18][C:17]3[CH:16]=[C:15]([F:14])[CH:22]=[C:21]([F:23])[CH:20]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: NCc1cc(F)cc(F)c1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(NCc3cc(F)cc(F)c3)ccc12
Yield: 4.8 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (50 mg, 0.193 mmol), 3,5-difluorobenzylamine (0.026 mL, 0.212 mmol), Pd2(dba)3 (6 mg, 0.0066 mmol), rac-BINAP (18 mg, 0.029 mmol) and NaOt-Bu (46 mg, 0.482 mmol) in DMA (3 mL) was heated at 80° C. for 1.5 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3,5-difluoro-benzylamino)-2H-phthalazin-1-one (3 mg) as a brown solid, 1H (400 MHz, CDCl3) δ: 4.41 (s, 2H), 6.67 (m, 1H), 6.83 (m, 3H), 6.96 (dd, 1H), 8.10 (d, 1H), 9.58 (s, 1H) ppm; m/z (M+1) 321.98.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[F:22])[NH2:18].C(N(CC)CC)C>C(OCC)C>[F:14][C:15]1[CH:16]=[C:17]([NH:18][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(Nc1ccc(F)c(F)c1)C12CC3CC(CC(C3)C1)C2

Procedure:
Subject 2.29 g. of adamantane carboxylic acid chloride (11.5 mmoles) 1.29 g. of (10 mmoles) 3,4-difluoro-aniline and 4.0 ml. of triethylamine to the process of Example 11. Crystallize the residue obtained thereby from ethyl ether to yield the title product, m.p. 168.5°-170°C.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[C:11]3[C:15]([CH:16]=[C:17](B4OC(C)(C)CC(C)(C)O4)[CH:18]=2)=[N:14][N:13](C2CCCCO2)[CH:12]=3)=[O:8])[N:6]=1.Br[C:36]1[CH:37]=[CH:38][C:39]([Cl:47])=[C:40]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>CO.Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:47][C:39]1[CH:38]=[CH:37][C:36]([C:17]2[CH:16]=[C:15]3[C:11]([CH:12]=[N:13][NH:14]3)=[C:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[O:8])[CH:18]=2)=[CH:41][C:40]=1[NH:42][S:43]([CH3:46])(=[O:45])=[O:44]
Reactant: CS(=O)(=O)Nc1cc(Br)ccc1Cl
Reactant: Cc1nc(C(=O)Nc2cc(B3OC(C)(C)CC(C)(C)O3)cc3nn(C4CCCCO4)cc23)cs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc(C(=O)Nc2cc(-c3ccc(Cl)c(NS(C)(=O)=O)c3)cc3[nH]ncc23)cs1
Temperature: 140 °C
Reaction time: 2 h
Yield: 36.1 %

Procedure:
2-Methyl-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1,3-thiazole-4-carboxamide (55 mg), N-(5-bromo-2-chlorophenyl)methanesulfonamide (39 mg), sodium carbonate (48 mg) and Pd(dppf)Cl2 (8.3 mg) were weighed to a microwave vial. 1,4-Dioxane (0.5 ml) and water (0.5 ml) were added and the reaction was heated under microwave irradiation at 140° C. for 20 min. The reaction was passed through a 1 g silica SPE cartridge preconditioned with MeOH, washing with MeOH, the evaporated to dryness. The residue was dissolved in DMSO:MeOH (1:1, v/v, 1 ml) and purified by MDAP (method E). The residue obtained was dissolved in MeOH and a couple of drops of 2M HCl (aq) were added. The reaction was stirred for 2 h and evaporated to dryness to give the title compound (19 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([S:21]([CH3:23])=[O:22])=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH2:18][CH2:19][CH3:20])[CH3:17])[CH:11]=[CH:10]2)(=O)=O.[S:26]1[C:30](B(O)O)=[CH:29][C:28]2[CH:34]=[CH:35][CH:36]=[CH:37][C:27]1=2.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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>[S:26]1[C:30]([C:7]2[C:8]([S:21]([CH3:23])=[O:22])=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH:16]([CH2:18][CH2:19][CH3:20])[CH3:17])[CH:11]=[CH:10]3)=[CH:29][C:28]2[CH:34]=[CH:35][CH:36]=[CH:37][C:27]1=2
Reactant: CCCC(C)n1ccc2c(S(C)=O)c(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: OB(O)c1cc2ccccc2s1
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: Cc1ccccc1
Product: CCCC(C)n1ccc2c(S(C)=O)c(-c3cc4ccccc4s3)ccc21
Temperature: 90 °C
Yield: 68 %

Procedure:
To a deaerated solution of 4-(methylsulfinyl)-1-(pentan-2-yl)-1H-indol-5-yltrifluoromethanesulfonate 17) (0.40 g, 1.0 mmol) and benzo[b]thiophen-2-ylboronic acid (18) (0.35 g, 2.0 mmol), and Pd(PPh3)4 (60 mg, 0.05 mmol) in toluene (10 mL) was added aqueous K2CO3 (2M, 6.0 mL). The mixture was heated at 90° C. for 4 h. Toluene (20 mL) was added and the organic phase was washed with water (20 mL) and then concentrated to dryness in vacuo. The residual was purified by silica gel column chromatography (2:1 hexanes/ethyl acetate) to give 5-(benzo[b]thiophen-2-yl)-4-(methylsulfinyl)-1-(pentan-2-yl)-1H-indole (19) (0.26 g, 68%) as a yellow oil. 1H NMR (500 MHz, CD2Cl2): δ 7.88 (d, J=8.0, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.40 (m, 4H), 7.35 (d, J=3.5, 1H), 7.2 9s, 1H), 4.62 (m, 1H), 3.00 (d, 3H), 1.88 (m, 2H), 1.57 (m, 3H), 1.24 (m, 2H), 0.93 (m, 3H). Mass (ESI, M+H): 382.7. See also Im, G-Y. J., et al., J. Am. Chem. Soc., 132:17933 (2010).
Reaction SMILES: BrC1C=CC(C(C)CO)=CC=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:25])([CH3:24])[C:20](OC)=[O:21])=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([CH3:25])([CH3:24])[CH2:20][OH:21])=[CH:17][CH:18]=1
Reactant: COC(=O)C(C)(C)c1ccc(Br)cc1
Agent: CC(CO)c1ccc(Br)cc1
Product: CC(C)(CO)c1ccc(Br)cc1
Yield: 100.8 %

Procedure:
According to the procedure for the preparation of 73B, methyl 2-(4-bromophenyl)-2-methylpropanoate (2.15 g, 8.36 mmol) afforded 1.93 g of 74A as a colorless oil. MS (ESI) m/z 211.1 (M-OH)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1.I[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:24][C:23]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][C:4]([O:3][C:2]([F:1])([F:15])[F:16])=[CH:5][CH:6]=2)[C:11]1=[O:14]
Reactant: O=C1NCCc2ccc(OC(F)(F)F)cc21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccc(OC(F)(F)F)cc2C1=O
Yield: 5.4 %

Procedure:
Using analogous conditions as described for the preparation of Example 1A above, 7-(trifluoromethoxy)-3,4-dihydroisoquinolin-1(2H)-one (I-51d: 160 mg, 0.6896 mmol) was reacted with 3-iodo-4-methyl-pyridine (151 mg, 0.6896 mmol), 1,4-dioxane (20 mL), copper iodide (13.1 mg, 0.0689 mmol), trans-N,N′-dimethyl-cyclohexyl-1, 2-diamine (29.3 mg, 0.2068 mmol) and potassium phosphate (365 mg, 1.724 mmol) to afford the crude product. Purification by column chromatography on silica gel (40% ethylacetate in hexane), followed by preparative HPLC afforded 12 mg of the product (5.4% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[C:8]([NH2:10])[CH:9]=1)([O-:3])=[O:2].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[NH2:10][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:24])[CH2:15][CH2:16]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])ccc1N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1cc([N+](=O)[O-])ccc1N1CCN(C(=O)c2ccccc2)CC1
Yield: 85.9 %

Procedure:
A solution of 5-nitro-2-(piperazin-1-yl)benzenamine (2.4 g, 10.7 mmol), benzoyl chloride (1.2 ml, 12.8 mmol) and triethylamine (6.0 ml, 42.7 mmol) in 40 ml DCM was stirred at 0° C. for 2 hours. The mixture was washed with water (2×10 ml) and dried over anhydrous sodium sulfate before removing the solvents. (4-(2-Amino-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (3.0 g, 86%) was obtained by flash column chromatograph (40% ethyl acetate in hexanes). A solution of (4-(2-amino-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (0.3 g, 0.9 mmol), acetyl chloride (0.065 ml, 0.9 mmol) and sodium hydroxide (0.037 g, 0.9 mmol) in 20 ml THF was stirred at 0° C. for 2 hours. The mixture was concentrated. N-(2-(4-benzoylpiperazin-1-yl)-5-nitrophenyl)acetamide (0.11 g, 32%) was obtained by flash column chromatograph (65% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.29 (s, 3H), 3.00 (s, br, 4H), 3.84 (s, br, 4H), 7.23 (d, J=8.8 Hz, 1H), 7.47-7.51 (m, 5H), 8.00 (dd, J=8.6, 2.6 Hz, 1H), 8.16 (s, br, 1H), 9.24 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 25.3, 52.3, 116.0, 119.9, 120.8, 127.6, 129.2, 130.7, 135.6, 171.2.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[N:13][N:12]([OH:15])[C:11]=3[CH:16]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].[CH2:19](O)C>>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[N:13][N:12]([O:15][CH3:19])[C:11]=3[CH:16]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: On1nnc2ccc(Cn3ccnc3)cc21
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: COn1nnc2ccc(Cn3ccnc3)cc21
Yield: 65.4 %

Procedure:
To a stirred suspension of 4.7 parts of 6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-ol in 60 parts of ethanol were added 22.5 parts of a sodium hydroxide solution 1N. The whole was stirred till a clear solution was obtained. The mixture was evaporated to dry. The residue was dissolved in 18 parts of N,N-dimethylformamide. To the thus obtained solution was added at once a solution of 3.2 parts of iodomethane in 9 parts of N,N-dimethylformamide. After stirring for 30 minutes at room temperature, the whole was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was recrystallized from 8 parts of 4-methyl-2-pentanone. The product was filtered off and dried, yielding 3.3 parts (65.4%) of 6-(1H-imidazol-1-ylmethyl)-1-methoxy-1H-benzotriazole; mp. 132.4° C. (compound 229).
Reaction SMILES: CC([S@]([NH:7][C@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)C.[ClH:21].CC(S(OC)=O)(C)C>CO.O1CCOCC1>[ClH:21].[F:18][C:17]([F:19])([F:20])[C:14]1[CH:15]=[C:16]2[C:11]([CH2:10][CH2:9][C@H:8]2[NH2:7])=[CH:12][CH:13]=1
Reactant: CC(C)(C)[S@@](=O)N[C@@H]1CCc2ccc(C(F)(F)F)cc21
Agent: COS(=O)C(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@H]1CCc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29 %

Procedure:
Intermediate 15B (370 mg, 1.21 mmol) was stirred in MeOH (5 mL) at rt. 4N HCl in dioxane (2 mL) was added. The resulting mixture was stirred at rt for 20 min. The solvents were evaporated and CH2Cl2 (3×) was added and evaporated. The resulting white solids were vacuum dried for 1 h to give Intermediate 15 (84 mg, 0.35 mmol, 29% yield) and methyl 2-methylpropane-2-sulfinate. The HCl salt was used directly in the next step. 1H NMR (400 MHz, MeOD) δ ppm 7.57 (1 H, d, J=7.8 Hz), 7.47 (1 H, d, J=7.6 Hz), 7.25 (1 H, t, J=7.8 Hz), 4.88 (1 H, dd, J=7.8, 4.8 Hz), 3.09-3.23 (1 H, m), 2.90-3.08 (1 H, m), 2.64 (1 H, dddd, J=14.1, 8.5, 8.3, 5.7 Hz), 2.01-2.23 (1 H, m, J=14.1, 8.7, 5.3, 5.3 Hz).