Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[O:23]=[C:14]1[N:13]([CH2:24][CH2:25][CH3:26])[C:12]2[N:11]=[C:10]([C:5]34[CH2:8][CH2:9][C:2]([O:1][S:35]([CH3:34])(=[O:37])=[O:36])([CH2:7][CH2:6]3)[CH2:3][CH2:4]4)[NH:18][C:17]=2[C:16](=[O:19])[N:15]1[CH2:20][CH2:21][CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(O)(CC3)CC4)nc2n(CCC)c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1c(=O)c2[nH]c(C34CCC(OS(C)(=O)=O)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a solution of 50 mg of 8-(4-Hydroxy bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (Example 13a) (0.14 mmol) in CH2Cl2 (5 ml) was added 20 μL of Et3N and the reaction mixture cooled in an ice bath. To this was added 20 μL of methanesulfonyl chloride (0.26 mmol) and the reaction mixture kept at 10° C. overnight. The reaction mixture was concentrated in vacuo and the residue taken up in EtOAc and washed 2× with dilute HCl (5 ml). The organic layer was dried over NaSO4 and conc'd. The residue was triturated in acetonitrile to afford 36 mg (59%) of pure white solid (MH+=439.4).
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]([OH:8])([CH3:7])[CH3:6].[C:9]([NH:22][C@H:23]([C:29](O)=[O:30])[CH2:24][CH2:25][C:26](=[O:28])[NH2:27])(=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O>[CH:5]([O:8][C:29](=[O:30])[C@H:23]([CH2:24][CH2:25][C:26](=[O:28])[NH2:27])[NH:22][C:9](=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([CH3:7])[CH3:6]
Reactant: CC(C)O
Reactant: CCCCCCCCCCCC(=O)N[C@@H](CCC(N)=O)C(=O)O
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(N)=O)C(=O)OC(C)C
Yield: 52.4 %

Procedure:
108 g of L-glutamine was dissolved in 343 g of water and 102 g of aqueous 27% sodium hydroxide solution, and cooled to 10° C. 138 g of acetone was added to it, and 152 g of lauroyl chloride and 108 g of aqueous 27% sodium hydroxide solution were dropwise added thereto. The acylation liquid was diluted with 300 g of water, then neutralized with 35 g of 75% sulfuric acid and filtered to obtain a white powdery substance, N-lauroyl-L-glutamine. 72.4 g of thionyl chloride was dropwise added to 424 g of isopropyl alcohol, then 100 g of N-lauroyl-L-glutamine was added thereto and reacted at room temperature for 8.5 hours. The reaction liquid was added to 2.0 L of water to precipitate the intended product, and this was taken out by filtration to obtain a crude product. This was recrystallized repeatedly three times with acetone to obtain 59.1 g of N-lauroyl-L-glutamine isopropyl ester.
Reaction SMILES: C(O[C:6]([C:8]1[N:13]=[C:12](Br)[C:11]2[CH:15]=[C:16]([S:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:17][C:10]=2[C:9]=1[OH:25])=[O:7])CCC.C([O:30][C:31]([C:33]1C(O)=C2C=C(SC3C=CC=CC=3)SC2=C(Br)[N:38]=1)=[O:32])CCC>>[OH:25][C:9]1[C:10]2[S:17][C:16]([S:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][C:11]=2[CH:12]=[N:13][C:8]=1[C:6]([NH:38][CH2:33][C:31]([OH:32])=[O:30])=[O:7]
Reactant: CCCCOC(=O)c1nc(Br)c2sc(Sc3ccccc3)cc2c1O
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Sc3ccccc3)sc2c1O
Product: O=C(O)CNC(=O)c1ncc2cc(Sc3ccccc3)sc2c1O

Procedure:
The title compound was prepared from a mixture of 4-bromo-7-hydroxy-2-phenylsulfanyl-thieno[3,2-c]pyridine-6-carboxylic acid n-butyl ester and 7-bromo-4-hydroxy-2-phenylsulfanyl-thieno[2,3-c]pyridine-5-carboxylic acid n-butyl ester, example 17.b, under conditions analogous to experimental example 1.g. The products were purified by column chromatography eluting from silica gel with a gradient of 20-60% ethyl acetate in hexanes. Product A, (Lower Rf product); MS: (+) m/z 360.01 (M+1); Product B, (Higher Rf product); MS: (+) m/z 360.02 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Cl)[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[SH:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1.COC1C=C(C=CC=1OC)C(Cl)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][S:30][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Sc1ccncc1
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)c1cccc(CCl)c1
Agent: COc1ccc(C(=O)Cl)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Br)ccc1NC(=O)c1cccc(CSc2ccncc2)c1
Reaction time: 12 h
Yield: 67 %

Procedure:
Subsequently, methyl 5-bromo-2-[3-(chloromethyl)benzoyl]aminobenzoate (1.5 g) was dissolved in anhydrous methylene chloride. Triethylamine (2.0 ml) and 4-mercaptopyridine (compound B′) (880 mg) were added to the solution at room temperature, and the mixture was stirred at that temperature for 12 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, was dried over sodium sulfate, and was then concentrated. Diethyl ether was added to the residue for crystallization. The crystals were filtered through Kiriyama Rohto (21 mmφ) and were washed with diethyl ether to give methyl 5-bromo-2-(3-[(4-pyridylsulfanyl)methyl]benzoylamino)benzoate (1.20 g, yield 67%) as a useful intermediate.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH:10]1[C:19]2[C:14](=[C:15]([CH:20]([CH3:24])[C:21](O)=[O:22])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][N:11]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:21](=[O:22])[CH:20]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[CH:13]=[CH:12][N:11]=[CH:10]3)[CH3:24])=[CH:4][CH:3]=1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1ccc(Br)cc1
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(Br)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-bromobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 371, 369 (M+H)+; MS (ESI−) m/z 369, 367 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.57 (d, J 7.1, 3H), 4.23 (d, J 6.1, 2H), 4.63 (q, J 7.1, 1H), 7.14 (m, 2H), 7.47 (m, 2H), 7.76 (m, 1H), 7.98 (t, J 7.5, 1H), 8.17 (d, J 7.1, 1H), 8.43 (d, J 7.8, 1H), 8.69 (br s, 1H), 8.74 (d, J 6.8, 1H), 8.92 (t, J 5.8, 1H), 9.88 (s, 1H); Anal. Calcd for C19H17BrN2O+1.4HCl: C, 54.30; H, 4.41; N, 6.66. Found: C, 54.49; H, 4.28; N, 6.75.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=[O:20])=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:53]([N:55]1[N:59]=[N:58][C:57]([CH2:60][N:61]2[C:66]3[CH:67]=[C:68]([C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)[S:69][C:65]=3[C:64](=[O:76])[N:63]([CH:77]3[CH2:82][CH2:81][NH:80][CH2:79][CH2:78]3)[C:62]2=[O:83])=[N:56]1)[CH3:54].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[C:18]([C:19]([N:80]4[CH2:81][CH2:82][CH:77]([N:63]5[C:64](=[O:76])[C:65]6[S:69][C:68]([C:70]7[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=7)=[CH:67][C:66]=6[N:61]([CH2:60][C:57]6[N:58]=[N:59][N:55]([CH2:53][CH3:54])[N:56]=6)[C:62]5=[O:83])[CH2:78][CH2:79]4)=[O:20])[CH:22]=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)O)c1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nnn(CC)n5)c4=O)CC3)c1)=N[C@@H]1CCSC[C@H]21

Procedure:
In analogy to the procedure described for example 14 3-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (120 mg; compound C8) is reacted with HBTU (120 mg), 1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (132 mg; compound B39) and DIPEA (0.16 ml) in DCM (10 ml). After purification by flash column chromatography (silica gel, eluent: EtOAc) the title compound is obtained as a solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:11]2[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)#[N:2].C(O)C>[C].[Pd].O1CCCC1>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[C:11]2[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)#[N:2]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(C#CCCCC#N)cc23)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(CCCCCC#N)cc23)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 91.7 %

Procedure:
To a solution of 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl trifluoromethanesulfonate (3.03 g, 6.13 mmol), copper iodide (176 mg, 0.920 mmol) and hex-5-ynenitrile (2.86 g, 30.7 mmol) in tetrahydrofuran (30 ml)-triethylamine (10 ml) was added dichlorobistriphenylphosphinepalladium (431 mg, 0.613 mmol), and the mixture was stirred under an argon atmosphere at 80° C. for 10 min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give black crystals. The crystals were recrystallized from ethyl acetate-n-hexane to give tert-butyl {[6-(5-cyanopent-1-yn-1-yl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.56 g, yield 84%) as white crystals. Subsequently, tert-butyl {[6-(5-cyanopent-1-yn-1-yl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.56 g, 5.17 mmol) and 10% palladium-carbon (550 mg) were suspended in a mixed solvent of ethanol (200 ml)-tetrahydrofuran (35 ml) and the mixture was stirred under a hydrogen atmosphere at room temperature for 3.5 hrs. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl {[6-(5-cyanopentyl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.37 g, yield 92%) as white crystals.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([N:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)O1.Br[C:35]1[CH:40]=[N:39][C:38]([Br:41])=[CH:37][N:36]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[Br:41][C:38]1[N:39]=[CH:40][C:35]([C:9]2[CH:10]=[CH:11][C:12]([N:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)=[N:36][CH:37]=1
Reactant: Brc1cnc(Br)cn1
Reactant: Cc1ccccc1N(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1cccc2ccccc12
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: C1COCCO1
Solvent: O
Product: Cc1ccccc1N(c1ccc(-c2cnc(Br)cn2)cc1)c1cccc2ccccc12
Temperature: 80 °C
Yield: 75 %

Procedure:
A mixture of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(o-tolyl)naphthalen-1-amine (Compound 22) (0.55 g, 1.26 mmol), 2,5-dibromopyrazine (0.77 g, 3.0 mmol), Pd(PPh3)4 (0.1 g, 0.09 mmol), K2CO3 (0.414 g, 3 mmol) in dioxane/water (40 mL/8 mL) was degassed and heated at 80° C. overnight. The resulting mixture was worked up with ethyl acetate/brine, dried over Na2SO4, loaded on silica gel and purified by flash column using eluents of hexanes/dichloromethane 9:1 to 3:2. After removal of solvents, a yellow solid (Compound 23) was obtained, 0.44 g in 75% yield.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C@H:16]3[C@H:21]([NH2:22])[CH2:20][CH2:19][CH2:18][O:17]3)[CH2:10]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:32]([C:35]1[CH:36]=[C:37]([N:41]=[C:42]=[O:43])[CH:38]=[CH:39][CH:40]=1)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([C:35]1[CH:36]=[C:37]([NH:41][C:42]([NH:22][C@@H:21]2[CH2:20][CH2:19][CH2:18][O:17][C@H:16]2[CH2:15][N:11]2[CH2:12][CH2:13][CH2:14][C@@H:9]([CH2:8][C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:24][CH:23]=3)[CH2:10]2)=[O:43])[CH:38]=[CH:39][CH:40]=1)(=[O:34])[CH3:33]
Reactant: N[C@@H]1CCCO[C@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1
Reactant: CC(=O)c1cccc(N=C=O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cccc(NC(=O)N[C@@H]2CCCO[C@H]2CN2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reaction time: 0.01 h
Yield: 64.9 %

Procedure:
To a solution of (2S,3R)-2-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-ylamine dihydrochloride (16 mg, 0.043 mmol—prepared according to Part I) and excess triethylamine (100 μL, 0.719 mmol) in methylene chloride (1 mL) was added 3-acetylphenyl isocyanate (6.9 mg, 0.043) dissolved in methylene chloride (1 mL). The resulting yellow solution was shaken vigorously for 20 sec, and allowed to stand at 23° C. for 10 min. The solution was then concentrated in vacuo, and the resulting residue was purified by flash chromatography (5% methanol in methylene chloride) to yield the desired urea (13 mg, 65%) as a pale yellow oil. MS (ESI), m+/z: (M+H)+=468.3.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:14]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:14])=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc2ccc(Br)cc21
Reaction time: 0.33 h
Yield: 90.4 %

Procedure:
A 1-round-bottom flask was charged with 6-bromo-1H-indole (14.88 g, 76 mmol) and THF (150 ml) to give a dark maroon solution. The flask was put under a N2 sweep, and sodium hydride (60 wt %) (3.64 g, 91 mmol) was added in several portions over 15 min. The resulting mixture was stirred for 20 min, then iodomethane (5.94 ml, 95 mmol) was added via syringe. Within a few minutes, an exotherm was observed. After stirring for 20 min, the mixture was concentrated in vacuo, and the residue was taken up in saturated aq. sodium bicarbonate solution and extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (0 to 40% EtOAc/Heptane) to afford 6-bromo-1-methyl-1H-indole (14.44 g, 68.7 mmol, 91% yield) as a lightly colored oil. 1H NMR (400 MHz, CDCl3) δ=7.51-7.46 (m, 2 H), 7.24-7.19 (m, 1 H), 7.03 (d, J=3.1 Hz, 1 H), 6.47 (dd, J=0.9, 3.1 Hz, 1 H), 3.77 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18]([OH:20])=[O:19])[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21]N(C)CCN(C)C.C([Li])(C)(C)C.IC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18]([OH:20])=[O:19])[CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)O)c2C1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CI
Product: CC1c2c(cccc2C(=O)O)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid (2.25 g) and tetramethylethylenediamine (1.347 mL) in tetrahydrofuran (40 mL) was added dropwise t-butyllithium (1.6M, 15.21 mL) at −78° C. The mixture was stirred at −78° C. for 40 minutes. To the resulting mixture was added iodomethane (5.07 mL) dropwise and the mixture was stirred at −78° C. for 3 hours, followed by stirring at room temperature overnight. The reaction mixture was quenched with saturated ammonium chloride. The reaction mixture was extracted with ethyl acetate (150 mL), and the organic layer was washed with brine (40 mL×3), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flask chromotography (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=O.[Br:19][C:20]1[CH:21]=[N:22][C:23]([NH2:26])=[N:24][CH:25]=1.O>CN(C=O)C>[Br:19][C:20]1[CH:21]=[N:22][C:23]2[N:24]([C:2]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:3]([C:5]3[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=3)[N:26]=2)[CH:25]=1
Reactant: Nc1ncc(Br)cn1
Reactant: O=Cc1ccc(C(=O)C(Br)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(-c2nc3ncc(Br)cn3c2-c2ccccc2)cc1
Temperature: 90 °C

Procedure:
0.15 g (0.5 mM) of 4-[bromo(phenyl)acetyl]benzaldehyde and 2.0 equivalents of 5-bromopyrimidin-2-amine are dissolved in 6 ml DMF. The reaction mixture is heated at 90° C. overnight. The reaction mixture is cooled and water is added. It is then extracted with ethyl acetate. The organic layer is dried and concentrated. The crude product is purified by column chromatography to obtain the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]3[CH:17]=[C:18]([CH:22]([NH2:24])[CH3:23])[CH:19]=[CH:20][CH:21]=3)[CH:11]=2)=[CH:4][CH:3]=1.[F:25][C:26]([F:34])([F:33])[CH2:27][NH:28][S:29](Cl)(=[O:31])=[O:30].CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]3[CH:17]=[C:18]([CH:22]([NH:24][S:29]([NH:28][CH2:27][C:26]([F:34])([F:33])[F:25])(=[O:31])=[O:30])[CH3:23])[CH:19]=[CH:20][CH:21]=3)[CH:11]=2)=[CH:6][CH:7]=1
Reactant: CC(N)c1cccc(-c2cc(CCc3ccc(F)cc3)n(C)n2)c1
Reactant: O=S(=O)(Cl)NCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NS(=O)(=O)NCC(F)(F)F)c1cccc(-c2cc(CCc3ccc(F)cc3)n(C)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
This amine was dissolved in CH2Cl2 (5 mL) and treated with 2,2,2-trifluoroethylsulfamoyl chloride (91 mg, 0.45 mmol) and Et3N (63 μL, 0.45 mmol) and stirred at RT for 30 min. The solvent was evaporated under reduced pressure and the residue purified by silica chromatography eluting with 2% MeOH/CH2Cl2 to yield the title sulfamide as a colourless gum (18 mg, 23% over 2 steps). 1H NMR (CDCl3, 500 MHz) δ 7.80-7.76 (1H, s), 7.65 (1H, d, J=7.8 Hz), 7.38 (1H, t, J=7.8 Hz), 7.23 (1H, d, J=7.8 Hz), 7.18-7.10 (2H, m), 6.98 (2H, t, J=8.7 Hz), 6.35 (1H, s), 4.66-4.56 (2H, m), 4.38-4.28 (1H, m), 3.69 (3H, s), 3.53-3.42 (1H, m), 3.42-3.30 (1H, m), 3.02-2.84 (4H, m), 1.62-1.52 (3H, m). MS (ES+) C22H24F4N4O2S requires: 484, found: 485 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[F:28][C:29]1[C:34](B(O)O)=[CH:33][C:32]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([S:45][CH3:46])=[CH:41][CH:40]=2)=[CH:31][N:30]=1.C([O-])(=O)C.[K+]>CCO.O>[F:28][C:29]1[C:34]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:3]=2)=[CH:33][C:32]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([S:45][CH3:46])=[CH:41][CH:40]=2)=[CH:31][N:30]=1
Reactant: CSc1ccc(Cc2cnc(F)c(B(O)O)c2)cc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cc4ccc(SC)cc4)cnc3F)n2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79.5 %

Procedure:
4-Chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (2.37 g, 6.15 mmol), 2-fluoro-5-(4-(methylthio)benzyl)pyridin-3-ylboronic acid (1.89 g, 6.83 mmol), Am-Phos (224 mg, 0.316 mmol), and potassium acetate (2.72 g, 27.7 mmol) were suspended in EtOH (30 mL) and water (7.5 mL). Nitrogen was bubbled through the suspension for about 20 seconds, and then the flask was fitted with a reflux condenser and put in a preheated oil bath (80° C.-88° C.) and the reaction was stirred under nitrogen for 2 hours and 45 minutes. Then, the reaction was cooled to room temperature, treated with water (90 mL) and extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated. The residue was washed with hexanes, but the hexanes rinsings still contained product. So, these rinsings were combined with the residue and concentrated. The material was purified on a silica gel filter (600 mL fritted filter funnel with about 3 inches of silica gel; 5:1 DCM/hexanes to DCM to 40:1 DCM/MeOH to 30:1 DCM/MeOH) to give 4-(2-fluoro-5-(4-(methylthio)benzyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (2.843 g). 1H NMR (CDCl3, 400 MHz) δ 8.32 (dd, J=9.00 Hz, 2.35 Hz, 1H), 8.14 (dd, J=1.56 Hz, 1H), 7.24-7.18 (m, 6H), 7.13-7.09 (m, 2H), 6.90-6.83 (m, 4H), 4.81 (s, 2H), 4.78 (s, 2H), 3.99 (s, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 2.53 (s, 3H), 2.46 (s, 3H). m/z (ESI, pos. ion) 582 (M+H)+.
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>CN(C)C1C=CN=CC=1.ClCCl>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])=[CH:27][CH:28]=1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1ccc(C(F)(F)F)cc1)C2=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (20 mL) was added a solution of 4-(trifluoromethyl)phenyl isocyanate (0.41 g, 2.2 mmole) in dry dichloromethane (3 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. The resulting mixture was concentrated on a rotary evaporator and then partitioned between dichloromethane and 2N aqueous HCl. The organic layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (15% ethyl acetate/hexane) to yield the title compound as a yellow solid (0.67 g, 91% yield), mp=78–81° C.; MS (−) ESI m/z=366 (M−H)−; [α]-D (25)=+24.2° (c=1, EtOH).