Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][O:14][Si](C(C)(C)C)(C)C)[NH:8][N:7]=1)=[O:5])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][OH:14])[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(CCCO[Si](C)(C)C(C)(C)C)[nH]n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(CCCO)[nH]n1
Yield: 79.3 %

Procedure:
A solution of 5-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-1H-pyrazole-3-carboxylic acid ethyl ester (327 mg, 1.05 mmol) and tetrabutylammonium fluoride (288 mg, 1.10 mmol) in THF (50 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo. Flash chromatography (EtOAc to EtOAc:MeOH 19:1) provided the title alcohol (165 mg). 1H NMR (400 MHz, CDCl3) δ 6.58 (s, 1H), 4.35 (q, 2H), 3.71 (t, 2H), 2.84 (t, 2H), 1.91 (m, 2H), 1.36 (t, 3H); MS 199 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].[H-].[Na+].Cl[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1>C1COCC1>[CH3:9][C@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[N:13]=[C:14]([CH3:24])[S:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[O:11])[C@H:3]1[CH2:2][O:1][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CO)c(-c2ccc(F)cc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2COc2ccc(C(F)(F)F)cn2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of rac-cis-(2-(hydroxymethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone in THF was added NaH (4 eq) at 0° C. and stirred for 30 min at RT. 2-Chloro-5-(trifluoromethyl)pyridine (2 eq) was then added and solution refluxed for 2 h. The reaction was cooled and quenched with saturated NH4Cl and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 493.7 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCC1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCOCC3)c2n1

Procedure:
Prepared similarly to Intermediate 223 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(2-bromoethyl)tetrahydro-2H-pyran but conducting the alkylation over 1 hour at 60° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.CCN(CC)CC.[C:21](Cl)(=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C(Cl)Cl>[C:21]([NH-:2])(=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1
Reactant: CCCCCCCCCC(=O)Cl
Agent: Cl
Agent: NCCc1c[nH]c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCC([NH-])=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
These compounds were synthesized by a slightly modified reported procedure (2). Tryptamine hydrochloride salt (0.8 mmol) was dissolved in CH2Cl2 (10 mL) and cooled to 0° C. in an ice bath in a 100 mL round bottom flask. Et3N (3.2 mmol) was added dropwsie to the cold solution followed by addition of n-decanoyl chloride (1.6 mmol). The reaction mixture was stirred for 2 h at room temperature and quenched by addition of water (10 mL) and extracted with CH2Cl2 (3×10 mL). The organic layer was then dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with 100% hexanes and 20-30% EtOAc/hexanes to afford N-decanoylamide of tryptamine as an yellow solid (236 mg, 92%). Rf=0.5 (20% EtOAc/hexanes).
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[Br:38][C:39]1[CH:40]=[CH:41][C:42](I)=[C:43]([CH3:45])[CH:44]=1>C1COCC1.[Zn].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].O>[Br:38][C:39]1[CH:40]=[CH:41][C:42]([CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)=[C:43]([CH3:45])[CH:44]=1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: Cc1cc(Br)ccc1I
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: BrCCBr
Solvent: O
Product: Cc1cc(Br)ccc1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 65 °C
Reaction time: 0.05 h

Procedure:
To a vial with zinc dust (2.77 g, 42.4 mmol) in anhydrous THF (15 mL) under nitrogen was added 1,2-dibromoethane (0.24 mL, 2.83 mmol), then the suspension was stirred at 65° C. for 3 min. After cooling to ambient temperature, chloro(trimethyl)silane (0.36 mL, 2.83 mmol) was added and the mixture was stirred at room temperature for 30 min. Then, a solution of tert-butyl 3-iodoazetidine-1-carboxylate (8.00 g, 28.3 mmol) in THF (10 mL) was added and the mixture was stirred for 45 min. P(2-furyl)3 (1.31 g, 5.7 mmol) and tris(dibenzylidene acetone)dipalladium (0) (2.59 g, 2.83 mmol) were added to a separate vial, dissolved in THF (5 mL) and stirred under nitrogen at ambient temperature for 10 min, then the mixture and 5-bromo-2-iodotoluene (4.84 mL, 33.9 mmol) in THF (10 mL) were added to the organozine reagent solution. The mixture was then placed in a 65° C. oil bath for 2 h. The reaction mixture was allowed to cool to room temperature and then was poured into water. The mixture was extracted with EtOAc, and the organic layer was concentrated in vacuo. Purification by chromatography on silica gel (0 to 50% EtOAc in hexanes, then 50 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 271.8 [M-t-Bu+2H]+; 1H NMR (500 MHz, acetone-d6) δ 7.40-7.30 (m, 3 H),4.23 (br, 2 H),3.99 (m, 1 H),3.91 (m, 2 H),2.21 (s, 3 H),1.42 (s, 9 H).
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([C:24]1[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=1)O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C(#N)C>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:24]1[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CSc1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O
Product: CSc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
In a nitrogen stream, triethylsilane (1.23 mL, 7.72 mmol) and a boron trifluoride-diethyl ether complex (0.88 mL, 5.48 mmol) were added to a solution of (2-benzyloxy-phenyl)-(4-methylsulfanylphenyl)-methanol (2.13 g, 6.3 mmol) in acetonitrile (15 mL) at −40° C. and the mixture solution was stirred at the same temperature for 1.5 hours and further at 0° C. for 30 minutes, and then water was added thereto and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (1.9 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[C:4]([F:23])[CH:3]=1.[Sn].Cl.O>C(O)C>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:23])=[C:5]([C:11]2[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)[CH:6]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc([N+](=O)[O-])c(Cl)cc2F)c1=O
Agent: Cl
Agent: [Sn]
Solvent: CCO
Solvent: O
Product: Cn1c(C(F)(F)F)ccc(-c2cc(N)c(Cl)cc2F)c1=O
Reaction time: 1 h
Yield: 100.2 %

Procedure:
1.0 g (2.8 mmol) of 3-(4-chloro-2-fluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone and 1.3 g (11 mmol) of tin were suspended in 30 ml of ethanol, and 5 ml of concentrated hydrochloric acid was added at room temperature, followed by stirring for 1 hour. After completion of the reaction, the reaction solution was poured into water and neutralized. Insoluble substances were filtered off, and the filtrate was extracted with ethyl acetate. After washing with water and a saturated sodium hydrogencarbonate aqueous solution, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. Then, the obtained crude crystals were washed with diisopropyl ether to obtain 0.90 g (yield: 98%) of the desired product. Melting point: 155-157° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:37])=[C:23]([O:25][C@@H:26]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[C:30]([F:35])[C:29]=4[Cl:36])[CH3:27])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:36][C:29]1[C:30]([F:35])=[CH:31][CH:32]=[C:33]([Cl:34])[C:28]=1[C@H:26]([O:25][C:23]1[C:22]([NH2:37])=[N:21][CH:20]=[C:19]([C:17]2[CH:16]=[N:15][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:18]=2)[CH:24]=1)[CH3:27]
Reactant: C[C@@H](Oc1cc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-c2cnn(C3CCNCC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of 4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (11.8 g, 21.45 mmol) in CH2Cl2 (59 mL, 0.2M) was added 4N HCl/Dioxane (21 mL). The solution was stirred overnight forming a solid. The solid was crushed thoroughly with a glass rod and sonicated to release starting material trapped in the solid. Additional 4N HCl/Dioxane (21 mL) was added and stirred for another 2 hours at room temperature in which LCMS showed no starting material. The suspension was filtered in a Buchner funnel lined with filter paper. The mother liquor was saved because it contained <5% of product. The solid was transferred to a 500 mL beaker and HPLC water was added until the solid dissolved completely. The pH was adjusted to 10 with the addition of solid Na2CO3. The water solution was extracted with CH2Cl2 (5×200 mL) or until LCMS showed no product in the aqueous layer. The CH2Cl2 solution was dried over Na2SO4 and concentrated. The crude product, re-dissolved in CH2Cl2 (10 mL) and MeOH (1 mL), was purified on a silica gel column eluting with CH2Cl2/MeoH/NEt3 system (Biotage 40+ Column: equilibrium 600 mL CH2Cl2 100% giving byproduct, segment 1: 1200 mL 10% MeOH/CH2Cl2 linear, segment 2: 2400 mL 10% MeOH/CH2Cl2 step, segment 3: 2400 mL 9% MeOH/1% NEt3/CH2Cl2). The desired fractions were collected to provide 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine (7.19 g, 75% combined yield, white solid). MS m/e 450 (M+1)+. 1H NMR (DMSO-d6, 400 MHz) δ 7.92 (s, 1H), 7.76 (s, 1H), 7.58 (m, 1H), 7.53 (s, 1H), 7.45 (m, 1H), 6.90 (s, 1H), 6.10 (m, 1H), 5.55 (bs, 2H), 4.14 (m, 1H), 3.05 (m, 2H), 2.58 (m, 2H), 1.94 (m, 2H), 1.80 (d, 3H), 1.76 (m, 2H).
Reaction SMILES: [CH2:1]([N:9]=[C:10]=[S:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:12]1[CH:16]=[C:15]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:14]=[CH:13]1.[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25]>C1(C)C=CC=CC=1.C(O)(C)C>[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25].[CH2:1]([NH:9][C:10]([N:20]1[CH2:19][CH2:18][CH:17]([C:15]2[N:14]=[CH:13][NH:12][CH:16]=2)[CH2:22][CH2:21]1)=[S:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1nc(C2CCNCC2)c[nH]1
Reactant: S=C=NCCc1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: S=C(NCCc1ccccc1)N1CCC(c2c[nH]cn2)CC1
Temperature: 80 °C

Procedure:
A solution of 1.63 g (0.01 mol) of phenethyl isothiocyanate in 60 ml of toluene and 1.51 g (0.01 mol) of 4-(4-imidazolyl)piperidine is heated to reflux for 1h 30 min. After cooling, the solution is evaporated under reduced pressure and the residual oil obtained is dissolved in 60 ml of isopropanol in the presence of 1.2 equivalents of oxalic acid. After 30 minutes of heating at 80° C., the white precipitate formed is drained, washed with ether and recrystallised in acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[CH:18][N:19]3[CH3:22])=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:23](Cl)(=[O:27])[C:24]([Cl:26])=[O:25]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:21]=[C:20]3[C:16]([C:17]([C:23](=[O:27])[C:24]([Cl:26])=[O:25])=[CH:18][N:19]3[CH3:22])=[CH:15][CH:14]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cn1ccc2ccc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)cc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: Cn1cc(C(=O)C(=O)Cl)c2ccc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)cc21
Temperature: 0 °C
Reaction time: 12 h

Procedure:
1.1 g 3,5-dichloro-N-(1-methyl-1H-indol-6-yl)phenylsulphonamide are dissolved in 15 ml diethyl ether, cooled to 0° C. and combined with 296 μl oxalyl chloride. Then the mixture is stirred for 2 hours at 0° C. and for 12 hours at ambient temp. The solvents are distilled off at 50° C. The crude product thus obtained is further reacted directly (XLVII).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]([S:57]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)(=[O:59])=[O:58])[CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]\[CH2:43]/[CH:44]=[CH:45]\[CH2:46]/[CH:47]=[CH:48]\[CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])(C)(C)C.O>C1COCC1>[C:60]1([S:57]([CH:36]([CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]\[CH2:43]/[CH:44]=[CH:45]\[CH2:46]/[CH:47]=[CH:48]\[CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][OH:24])(=[O:58])=[O:59])[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC(CCCCCCCCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC(CCCCCCCCCCCO)S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 65.6 %

Procedure:
Tetrabutylammonium fluoride (1 M solution in THF, 0.764 mL, 0.764 mmol) was added drop wise to a stirred solution of tert-butyldiphenyl((17Z,20Z,23Z,26Z)-12-(phenylsulfonyl)dotriaconta-17,20,23,26-tetra-enyloxy)silane (0.16 g, 0.191 mmol) in dry THF (2 mL) and stirring was continued for 1 h. Upon completion of reaction as judged y TLC, water (3 mL) was added and the reaction mixture was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude was purified by silica gel column chromatography using 30% ethyl acetate/hexane to afford the title product as a clear oil (0.075 g, 66%). 1H NMR (CDCl3): δ7.88 (d, 2H, J=7.2 Hz), 7.57 (m, 3H), 5.38 (m, 8H), 3.65 (br s, 2H), 2.81 (m, 7H), 2.05 (m, 4H), 1.81 (m, 2H), 1.37-1.20 (m, 30H), 1.04 (t, 3H, J=6.9 Hz). m/z (APCI) 599.45 (M++1).
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[CH3:14]>O1CCCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:2][CH3:1])(=[O:12])=[O:11])=[CH:6][C:5]=1[CH3:14]
Reactant: CN
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Br
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
Methylamine (2.0 M in tetrahydrofuran, 46.37 mL, 92.75 mmol) was added to a stirred solution of 4-bromo-3-methyl-benzenesulfonyl chloride (5.0 g, 19 mmol) in tetrahydrofuran at 0° C., and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (50 mL), washed with 2.0 N aqueous HCl (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 4-bromo-3-methyl-N-methyl-benzenesulfonamide (4.2 g, 85.7%) as a white solid. MS cald. for C8H10BrNO2S [M+] 264.1, obsd. 263.9.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]=O)=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]2[NH:11][CH2:10][CH2:9][N:4]3[C:3]([CH2:1][CH3:2])=[N:7][C:6]([I:8])=[C:5]23)=[CH:15][CH:14]=1
Reactant: O=CCCc1ccc(Br)cc1
Reactant: CCc1nc(I)cn1CCN
Product: CCc1nc(I)c2n1CCNC2CCc1ccc(Br)cc1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (26.610 mmol) and 3-(4-bromo-phenyl)-propionaldehyde (6.350 g; 29.803 mmol) afforded 8-[2-(4-bromo-phenyl)-ethyl]-3-ethyl-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.74 min.; [M+H]+=460.01 g/mol.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][CH:9]([F:48])[O:10][CH2:11][C@@H:12]([O:14][C:15]1[CH:16]=[C:17]([CH:33]=[C:34]([O:36][C:37]2[CH:42]=[N:41][C:40]([C:43](=[O:47])[N:44]([CH3:46])[CH3:45])=[CH:39][N:38]=2)[CH:35]=1)[C:18]([NH:20][C:21]1[CH:25]=[CH:24][N:23](C(OC(C)(C)C)=O)[N:22]=1)=[O:19])[CH3:13]>C(Cl)Cl>[F:48][CH:9]([F:8])[O:10][CH2:11][C@@H:12]([O:14][C:15]1[CH:35]=[C:34]([CH:33]=[C:17]([C:18](=[O:19])[NH:20][C:21]2[CH:25]=[CH:24][NH:23][N:22]=2)[CH:16]=1)[O:36][C:37]1[N:38]=[CH:39][C:40]([C:43]([N:44]([CH3:46])[CH3:45])=[O:47])=[N:41][CH:42]=1)[CH3:13]
Reactant: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(C(=O)Nc2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl 3-[[3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-benzoyl]amino]pyrazole-1-carboxylate (150 mg, 0.26 mmol) in DCM (16 mL) and stirred at RT for 2 hours. The solvent was removed in vacuo, DCM (20 mL) added and the mixture washed with water (20 mL), saturated sodium bicarbonate solution (20 mL), brine (20 mL), dried (MgSO4) and reduced in vacuo to give the desired compound (94 mg).
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=1)[C:3](O)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:14][CH:13]([CH3:15])[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH:2]([CH3:1])[CH2:3][OH:4])=[CH:11][CH:10]=1
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)Cc1ccc(C(C)CO)cc1

Procedure:
The title compound was prepared by the procedure of Preparation 2 in quantitative yield from α-methyl-4-(2-methylpropyl)benzeneacetic acid which is Ibuprofen® and lithium aluminum hydride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH3:33]B(O)O.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.O.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH3:33])=[CH:10][CH:9]=2)=[O:4]
Reactant: CB(O)O
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
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: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2ccccc2)c2cc(C)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Temperature: 100 °C
Reaction time: 12 h
Yield: 76.8 %

Procedure:
A mixture of 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg), methylboronic acid (180 mg), tetrakis(triphenylphosphine)palladium(0) (70 mg), potassium carbonate (250 mg), toluene (6 ml) and THF (4 ml) was stirred at 100° C. for 12 hrs. under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The solvent was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=2:1) and recrystallized (ethyl acetate-hexane) to give the title compound (200 mg).
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][N:15]2[C:18]([Sn](CCCC)(CCCC)CCCC)=[CH:19][N:20]=[C:14]2[N:13]=1)([O:4][Si:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7])[CH3:3].[Cl:34][C:35]1[N:40]=[C:39](Cl)[CH:38]=[CH:37][N:36]=1>>[Cl:34][C:35]1[N:40]=[C:39]([C:18]2[N:15]3[CH:16]=[CH:17][C:12]([C:2]([CH3:1])([O:4][Si:5]([CH2:10][CH3:11])([CH2:6][CH3:7])[CH2:8][CH3:9])[CH3:3])=[N:13][C:14]3=[N:20][CH:19]=2)[CH:38]=[CH:37][N:36]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(C)(C)O[Si](CC)(CC)CC)ccn12
Reactant: Clc1ccnc(Cl)n1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1

Procedure:
7-(1-Methyl-1-triethylsilanyloxyethyl)-3-tributylstannyl-imidazo[1,2-α]pyrimidine was reacted with 2,4-dichloropyrimidine by the method of Example 5 to afford 3-(2-chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine as a white solid: δH (400 MHz, CDCl3) 0.70 (6H, q, J 8.0), 1.00 (9H, t, J 8.0), 1.69 (6H, s), 7.57 (1H, d, J 5.5), 7.67 (1H, d, J 7.0), 8.53 (2H, m), 10.07 (1H, d, J 7.0); m/z (ES+) 403 (M++H).