Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH2:32])[N:17]=[C:16](C3C=CN=CC=3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[F:39][C:40]([F:46])([F:45])[S:41](Cl)(=[O:43])=[O:42]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH:32][S:41]([C:40]([F:46])([F:45])[F:39])(=[O:43])=[O:42])[N:17]=[C:16]([C:7]3[CH:6]=[CH:5][CH:4]=[CH:9][N:8]=3)[N:15]=2)(=[O:11])=[O:12])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ccncc2)nc1OCCN
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ccccn2)nc1OCCNS(=O)(=O)C(F)(F)F

Procedure:
According to the procedure described in Example 4a) 100 mg 5-isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with trifluoromethanesulfonylchloride to give 83 mg 5-isopropyl-N-[6-(2-(trifluoromethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(2-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=5.02 min, [M+1]+=669.59, [M−1]−=667.68.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:14]([F:17])([F:16])[F:15])=[C:10]([CH2:12]O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:20])=O>>[Cl:20][CH2:12][C:10]1[N:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][C:9]=1[C:14]([F:17])([F:16])[F:15]
Reactant: O=S(Cl)Cl
Reactant: OCc1nc(-c2ccccc2)oc1C(F)(F)F
Product: FC(F)(F)c1oc(-c2ccccc2)nc1CCl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
359 mg (1.137 mmol, 76% purity) of the compound from Example 23A are initially charged in 0.63 ml (8.64 mmol) of thionyl chloride. The reaction mixture is stirred at RT for 48 h. After concentration on a rotary evaporator, the residue is taken up in 10 ml of ethyl acetate and washed once with 5 ml of sat. aqueous sodium bicarbonate solution. The organic phase is dried over magnesium sulfate. After filtration, the solvent is removed on a rotary evaporator. The residue is purified by column chromatography on silica gel 60 (mobile phase gradient: cyclohexane/ethyl acetate 400:1→60:1). This gives a light-brown solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:34][C:35]1[CH:65]=[CH:64][C:38]([CH:39]=[CH:40][CH2:41][N:42]2[C:47](=[O:48])[C:46]([CH2:49]OS(C)(=O)=O)=[CH:45][C:44]([C:55]3[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([F:63])[CH:56]=3)=[N:43]2)=[CH:37][CH:36]=1.CN1CCNCC1>>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([CH:39]=[CH:40][CH2:41][N:42]2[C:47](=[O:48])[C:46]([CH2:49][N:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[CH:45][C:44]([C:55]3[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([F:63])[CH:56]=3)=[N:43]2)=[CH:64][CH:65]=1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)cc1F
Agent: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)cc1F
Yield: 66.3 %

Procedure:
Following the procedure of Example 1 (10), 2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as pale brown neeldes (yield: 66.3%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2([CH3:32])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8]>CO.[OH-].[Pd+2].[OH-]>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2([CH3:32])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)=[CH:3][CH:2]=1
Reactant: COc1cc(-c2nnc3n2CCCC3(C)c2ccc(F)c(Cl)c2)ccc1-c1cnc(C)o1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2nnc3n2CCCC3(C)c2ccc(F)cc2)ccc1-c1cnc(C)o1
Reaction time: 120 h
Yield: 35.2 %

Procedure:
To a mixture of 8-(3-chloro-4-fluorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-8-methyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (80.0 mg) in methanol (1.8 mL) was added palladium hydroxide (8.0 mg), and the mixture was stirred for 5 days under a hydrogen stream. The catalyst was removed, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (26.0 mg).
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([OH:37])[C:5]=2[N:4]=1.Br[CH2:40][CH2:41][CH2:42][OH:43].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:38][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH2:40][CH2:41][CH2:42][OH:43])[C:5]=2[N:4]=1
Reactant: OCCCBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(O)cccc43)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OCCCO)cccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.6 %

Procedure:
A mixture of 0.60 g (1.1 mmol) of tert-butyl 4-[4-[2-(difluoromethyl)-4-hydroxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperazine-1-carboxylate (Example 5), 0.47 g (3.3 mmol) of 3-bromo-1-propanol, and 0.80 g (5.5 mmol) of powdered K2CO3 in 20 mL dry DMF was stirred at room temperature for 8 hrs. Dilution with water, filtration, and dry gave 0.66 g (99% yield) of tert-butyl 4-[4-[2-(difluoromethyl)-4-(3-hydroxypropoxy)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate: 1H NMR (CDCl3) δ 7.94 (dd, J=8.4. 0.7 Hz, 1H), 7.49 (t, JHF=53.4 Hz, 1H), 7.34 (t, J=8.1 Hz, 1H), 6.92 (dd, J=8.0, 0.6 Hz, 1H), 4.47 (t, J=5.9 Hz, 2H), 3.98 (t, J=5.4 Hz, 2H), 3.87 (m, 8H), 3.79 (m, 4H), 3.54 (m, 4H), 3.30 (m, exchangeable with D2O, 1H), 2.14 (pentet, J=5.8 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[H-].[Na+].[CH:29]1([CH2:32]Br)[CH2:31][CH2:30]1>CN(C)C=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:26][CH2:32][CH:29]2[CH2:31][CH2:30]2)[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: BrCC1CC1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(OCC1CC1)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.8 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (120.0 mg, 0.292 mmol) in N,N-dimethylformamide (1.5 mL) was added sodium hydride (23.4 mg, 0.584 mmol) at 0° C. After 20 min, to the mixture was added cyclopropylmethyl bromide (0.14 mL, 1.46 mmol). The reaction mixture was stirred at room temperature for 1 day. The mixture was quenched with water and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-30% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from n-hexane to give the title compound as a colorless powder (123.0 mg, 0.265 mmol, 91%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[NH:7][C:6](=[O:11])[C:5]=1[CH2:12][NH:13][C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH3:26])[C:17]=1[CH3:33])=[O:15].C([O-])([O-])=O.[K+].[K+].CC#N.CN(C=O)C.Br[CH2:49][CH2:50][F:51]>>[F:51][CH2:50][CH2:49][N:30]1[CH2:29][CH2:28][CH:27]([CH:25]([N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]([C:14]([NH:13][CH2:12][C:5]3[C:6](=[O:11])[NH:7][C:8]([CH3:10])=[CH:9][C:4]=3[O:3][CH3:2])=[O:15])=[C:17]2[CH3:33])[CH3:26])[CH2:32][CH2:31]1
Reactant: FCCBr
Reactant: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCNCC2)c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCN(CCF)CC2)c2ccccc12
Temperature: 82 °C
Reaction time: 4 h

Procedure:
A 25 mL vial was charged with a magnetic stir bar, (R or S)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(piperidin-4-yl)ethyl)-1H-indole-3-carboxamide hydrochloride (Compound 326) (0.062 g, 0.131 mmol), K2CO3 (0.072 g, 0.524 mmol), MeCN (0.655 ml, 0.131 mmol), DMF (0.262 ml, 0.131 mmol) and 1-bromo-2-fluoroethane (0.020 ml, 0.262 mmol). The reaction was capped and heated to 82° C. with stirring for 4 h. The reaction was allowed to cool to rt, filtered, and the filtrate was pre-absorbed onto silica gel (12 g). The material was purified via SiO2 chromatography (25 g) using DCM/MeOH/Et3N (85:15:0.5) as eluent to afford the title compound as an off white solid (30 mg, 0.059 mmol, 45.1% yield).). LCMS 483 (M+1)+; 1H NMR (DMSO-d6, 400 MHz) δ 11.59 (s, 1H), 7.75-7.68 (m, 2H), 7.60 (d, 1H) 7.09-7.03 (m, 2H), 6.15 (s, 1H) 4.53-4.51 (m, 1H), 4.42-4.39 (m, 1H), 4.32 (d, 2H), 4.24-4.2 (m, 1H), 3.84 (s, 3H), 2.98 (br. d., 1H), 2.70-2.49 (m, 4H), 2.60 (s, 3H), 2.20 (s, 3H), 2.01 (dt, 1H), 1.92-1.90 (m, 1H), 1.75-1.71 (m, 1H), 1.54 (d, 3H), 1.38-1.36 (m, 1H), 1.02-0.98 (m, 1H), 0.7-0.66 (br. d., 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-])=O)[CH:8]=[C:9]([CH3:15])[C:10]=1[O:11][CH2:12][C:13]#[N:14])(=[O:4])[CH2:2][CH3:3]>C(O)(=O)C.[Fe]>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([CH3:15])[C:10]=1[O:11][CH2:12][C:13]#[N:14])[NH2:16])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)c1cc([N+](=O)[O-])cc(C)c1OCC#N
Agent: [Fe]
Solvent: CC(=O)O
Product: CCC(=O)c1cc(N)cc(C)c1OCC#N
Reaction time: 4 h
Yield: 89 %

Procedure:
3-Propionyl-4-cyanomethoxy-5-methylnitrobenzene (X =CH3 ; ##STR16## R1 =-CH2C≡N) (4.96 g) in acetic acid (60 ml) was dropwise added to an aqueous solution (300 ml) containing acetic acid (15 ml) and iron (20 g). The resulting mixture was kept at 40° C. for 4 hours with vigorous stirring. The solid was removed by filtration, and the filtrate was extracted with dichloromethane. The extract was washed with an aqueous solution of potassium carbonate and water, dried over magnesium sulfate and concentrated under reduced pressure to give 3-propionyl-4-cyanomethoxy-5-methylaniline (3.88 g) in a yield of 88.8%. NMR δ (CDCl3): 1.18 (t, 3H), 2.30 (s, H), 2.85 (q, 2H), 4.61 (s, 2H), 6.68 (s, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@@H:14]([N:16]([CH:24]=[O:25])[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH3:15])[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH3:70][NH:71][C:72](=[O:79])[C@@H:73]([NH2:78])[C:74]([CH3:77])([CH3:76])[CH3:75]>CN(C=O)C>[CH3:75][C:74]([CH3:77])([CH3:76])[C@H:73]([NH:78][C:11](=[O:13])[C@H:10]([CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@@H:14]([N:16]([CH:24]=[O:25])[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[CH3:15])[C:72](=[O:79])[NH:71][CH3:70]
Reactant: C[C@@H]([C@@H](CCCc1ccccc1)C(=O)O)N(C=O)OC1CCCCO1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)[C@@H](NC(=O)[C@H](CCCc1ccccc1)[C@H](C)N(C=O)OC1CCCCO1)C(C)(C)C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a solution of (2R,3S)-2-(3-phenyl-1-propyl)-3-(formyl-2-tetrahydropyranyloxyamino)buta noic acid (5.5 g, 15.76 mmol) in DMF (20 mL) is added BOP reagent (7.66 g, 17.34 mmol), HOBt (2.34 g, 17.34 mmol), and NMM (4.78 g, 47.28 mmol). After 30 min, addition of (2S)-2-Amino-3,3-dimethylbutanoic acid methylamide (3.4 g, 23.64) occurs and the resulting solution is stirred at 25.degree. C. for 20 h. The reaction mixture is poured into ethyl acetate/hexanes (1:1, 200 mL) and washed sequentially with 1 M hydrochloric acid, 1 M aqueous sodium carbonate, and saturated aqueous sodium chloride. The organic layer is dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 2:1 ethyl acetate-hexane) to provide (2R,3S)-3-(Formyl-2-tetrahydropyranyloxyamino)-2-(3-phenyl-1-propyl)butanoic acid [(1S)-2,2-dimethyl-1-(methylcarbamoyl)-1-propyl]amide as a white solid (2.7 g, 36% yield).
Reaction SMILES: Cl[C:2]1[N:30]=[CH:29][C:5]2[N:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]5[CH2:28][CH2:27][CH2:26]5)[CH2:21][CH2:20]4)=[CH:14][CH:13]=3)[N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH:25]1([N:22]2[CH2:21][CH2:20][CH:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]([C:7]4[N:8]([CH3:11])[C:9](=[O:10])[C:4]5[CH:3]=[CH:2][N:30]=[CH:29][C:5]=5[N:6]=4)=[CH:13][CH:14]=3)[CH2:24][CH2:23]2)[CH2:26][CH2:27][CH2:28]1
Reactant: [H][H]
Reactant: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2cnc(Cl)cc2c1=O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2cnccc2c1=O
Yield: 14.9 %

Procedure:
6-Chloro-2-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-3-methylpyrido[3,4-d]pyrimidin-4(3H)-one (40.8 mg, 0.096 mmol) produced in Example 30 and triethylamine (77 μL, 0.48 mmol) were dissolved in ethyl acetate (0.5 mL), and 10% palladium-carbon (10 mg) was added thereto and stirred in a hydrogen atmosphere at room temperature for 1 hour. The reaction solution was filtered through Celite, then the Celite was washed with ethyl acetate, and the mother liquid was concentrated. The residue was purified through silica gel thin-layer chromatography (chloroform/methanol=9/1) to obtain the entitled compound (5.6 mg, 15%) as a pale yellow solid. The resulting compound was recrystallized from ethanol-water to give a colorless solid (m.p. 147.0-148.0° C.).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([NH:12][C:13]([C:15]2[CH:45]=[CH:44][C:18]3[N:19]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[C:20]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[C:27]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:26]=[N:25]5)=[N:21][C:17]=3[CH:16]=2)=[O:14])[C:9]([OH:11])=[O:10])CCCC[CH2:2]1.N(C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H](C(O)=O)CC1[N:53]=[CH:52][NH:51]C=1>>[CH:38]1([N:19]2[C:18]3[CH:44]=[CH:45][C:15]([C:13]([NH:12][CH:8]([CH2:7][C:1]4[N:51]=[CH:52][NH:53][CH:2]=4)[C:9]([OH:11])=[O:10])=[O:14])=[CH:16][C:17]=3[N:21]=[C:20]2[C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=[N:25]3)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(NC(CC1CCCCC1)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Product: O=C(NC(Cc1c[nH]cn1)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Yield: 51 %

Procedure:
The general procedure described for Compound 242 was used with Fmoc-His Wang resin (250 mg, 0.4 mmol/g), producing 30 mg of the title compound (51% yield). MS: 584.24 (M−H+) HPLC Procedure A, retention time=11.16 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][O:13][CH2:14][CH2:15]Br>CS(C)=O>[CH3:12][O:13][CH2:14][CH2:15][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: COCCBr
Reactant: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: COCCOc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To 8-hydroxyquinoline (9.47 g, 0.065 mol) in dimethyl sulfoxide (50 ml) was added 2 -methoxyethyl bromide (8.96 g, 0.065 mol). The mixture was stirred at room temperature for two hours, and turned a dark red. The solvent was removed under vacuum, and the residue dissolved in water. The aqueous solution was extracted several times with ethyl acetate, and the ethyl acetate solution was then washed well with water, dried, and the solvent removed; the residual oil weighed 7.45 g. This was purified on a silica gel column, eluted with heptane:ethyl acetate, with increasing proportions of the latter. There was isolated 8-methoxyethoxyquinoline (7.11 g) as a light blue oil. NMR: (CDCl3) δ 3.51 (s, 3, OMe), 4.01 (tr, 2, CH2), 4.48 (tr, 2, CH2), 7.20 (m, 1, beta-pyridine-H), 7.45 (m, 3, Ar), 8.15 (dd, 1, gamma-pyridine-H), 8.98 (dd, 1, alpha-pyridine-H). Anal. Calcd. for C12H13NO2 : C, 70.92; H, 6.45; N, 6.89. Found: C, 70.80; H, 6.49; N, 6.90.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N+:3]=1[O-:12].[SH-:13].[Na+].[S-2].[Na+].[Na+].Cl.S>O>[SH:13][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N+:3]=1[O-:12]
Reactant: [SH-]
Reactant: [O-][n+]1c(Cl)ccc2ccccc21
Agent: Cl
Agent: S
Agent: [Na+]
Solvent: O
Product: [O-][n+]1c(S)ccc2ccccc21
Temperature: 45 °C
Yield: 63.2 %

Procedure:
30.5 g of 2-chloro-quinoline-N-oxide and 850 ml of water were added to a 2-liter flask equipped with a stirrer, condenser, thermometer and dropping funnel. The mixture was heated with stirring to 45°C. 5.8 g of sodium hydrosulfide (50% assay) and 41.7 g of sodium sulfide (32.5% assay) in 155 ml of water were added to the dropping funnel and added dropwise over 2 hours, to the contents of the flask while heating at 65°C for 45 minutes. The reaction mixture which was completely in solution was cooled to room temperature. A solution of 70 g of concentrated hydrochloric acid in 70 ml of water was placed in a dropping funnel and added dropwise to the reaction mixture with stirring. Hydrogen sulfide evolved from the reaction mixture was collected in a 20% NaOH trap. After 1 hour sufficient hydrochloric acid solution was added to bring the pH of the reaction mixture to 1.0. The copious precipitate deposited from the reaction mixture was filtered on a sintered glass funnel, washed with 700 ml of water and dried overnight under vacuum. The product weighed 19.0 g (63.2% yield), had a melting point of 65°-67°C. and was identified by infrared spectroscopy to be 2-mercapto-quinoline-N-oxide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([C:8]1[CH:13]=[CH:12][C:11](Cl)=[C:10](Cl)[CH:9]=1)[CH2:5][CH:6]=[O:7].COC(=O)CC1C=CC([F:27])=CC=1.COC(OC)CBr.Cl>>[CH3:1][O:2][C:3](=[O:16])[CH:4]([C:8]1[CH:13]=[CH:12][C:11]([F:27])=[CH:10][CH:9]=1)[CH2:5][CH:6]=[O:7]
Reactant: COC(=O)Cc1ccc(F)cc1
Reactant: COC(=O)C(CC=O)c1ccc(Cl)c(Cl)c1
Agent: COC(CBr)OC
Agent: Cl
Product: COC(=O)C(CC=O)c1ccc(F)cc1

Procedure:
In analogy to the procedure described for the synthesis of 2-(3,4-Dichloro-phenyl)-4-oxo-butyric acid methyl ester (example 2, step 1) the title compounds was prepared from 4-fluoro-phenyl-acetic acid methyl ester (commercially available), and bromoacetaldehyde dimethylacetal and subsequent treatment with HCl aq. MS (m/e): 209.3 (MH−).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:4]=1.C1C(=O)N([I:27])C(=O)C1>>[I:27][C:6]1[C:7]([NH2:9])=[N:8][C:3]([S:2][CH3:1])=[N:4][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CSc1nc(N)cc(-c2cccc(C(F)(F)F)c2)n1
Product: CSc1nc(N)c(I)c(-c2cccc(C(F)(F)F)c2)n1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 2.0 g (7.0 mmol) 2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-ylamine and 1.6 g (7.0 mmol) NIS. Yield after precipitation: 1.9 g (66%).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.CC1C=CC(S(O[CH2:23][CH2:24][C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH3:30])(=O)=O)=CC=1>>[CH3:9][O:8][C:7]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH2:23][CH2:24][C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: COc1ccc(C=O)cc1O
Reactant: CCCCC#CCCOS(=O)(=O)c1ccc(C)cc1
Product: CCCCC#CCCOc1cc(C=O)ccc1OC
Yield: 33.9 %

Procedure:
Isovanillin (0.90 g, 5.9 mmol) was alkylated with oct-3-ynyl 4-methylbenzenesulfonate (2.5 g, 8.9 mmol) according to Procedure 2. The crude product was recrystallised from purified by flash chromatography with 10% EtOAc/petrol as eluent to give 4-methoxy-3-(oct-3-ynyloxy)benzaldehyde (0.52 g, 34%) as a colourless crystalline solid; mp 42-43° C.; δH (400 MHz, CDCl3) 0.90 (t, J=7.2 Hz, 3H, CH3), 1.37-1.49 (m, 4H, CH3CH2CH2), 2.16 (tt, J=7.2, 2.4 Hz, 2H, CH2), 2.72 (tt, J=7.2, 2.4 Hz, 2H, CH2CH2O), 3.95 (s, 3H, OCH3), 4.17 (t, J=7.2 Hz, 2H, OCH2), 6.98 (d, J5,6=8.0 Hz, 1H, H5), 7.44 (d, J2,6=2.0 Hz, 1H, H2), 7.47 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 9.85 (s, 1H, CHO); δC (100 MHz, CDCl3) 13.6, 18.4, 19.7, 21.9, 30.9, 56.2, 67.6, 75.1, 82.5, 110.8, 111.0, 126.9, 130.1, 148.6, 154.9, 190.8; vmax 1019, 1132, 1262, 1508, 1585, 1684, 2932 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:23]#[C:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:9]=1[N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@H:11]1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:4].[Li+].[CH3:30][CH:31]([N-]C(C)C)[CH3:32].ICC=C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:23]#[C:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:9]=1[N:10]1[CH:11]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:13][C@@H:14]([CH2:32][CH:31]=[CH2:30])[C:15]1=[O:16])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)CCC[C@H]1C1CCCCC1
Reactant: CC(C)[N-]C(C)C
Agent: C=CCI
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H]1CCC(C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)OC)C1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-((S)-2-cyclohexyl-6-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (200 mg, 0.5 mmol, 1.0 equiv) in THF (2.0 mL) was added LDA (2.0 M in THF, 0.3 mL, 0.6 mmol, 1.2 equiv) at −78° C. and the resulting solution was stirred at −78° C. for 10 minutes. To the solution was then added 3-iodo-propene (250 mg, 1.5 mmol, 3.0 equiv) and the reaction mixture was stirred at room temperature for 15 minutes. The reaction was quenched by addition of water. The mixture was extracted with EtOAc. The organic layer was washed with sat. NaHCO3 aq. solution and brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography, Heptane/DCM (contained 3% EtOAc) to give 60 mg of less polar diastereomer and 100 mg of more polar diastereomer. MS: 442 [M+H+].