Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][CH2:14][C@H:15]2[CH2:24][N:19]3[CH2:20][CH2:21][NH:22][CH2:23][C@@H:18]3[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.Cl>>[F:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C@H:15]2[CH2:24][N:19]3[CH2:20][CH2:21][N:22]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=4)[CH2:23][C@@H:18]3[CH2:17][CH2:16]2)=[CH:25][CH:26]=1
Reactant: Fc1ccc(OC[C@@H]2CC[C@H]3CNCCN3C2)cc1
Reactant: Brc1ccccn1
Agent: Cl
Product: Fc1ccc(OC[C@@H]2CC[C@H]3CN(c4ccccn4)CCN3C2)cc1

Procedure:
The title compound was synthesized according to Preparation 11 using 2-bromopyridine and (7R,9aS)-7-(4-fluorophenoxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H -pyrido[1,2-a]pyrazine (Preparation 8). mp (—HCl) 261-263° C. HRMS calcd for C20H24FN3O: 341.1903; found, 341.1928.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:5](Br)=[CH:4][C:3]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[Mg].Br[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1>O1CCCC1.C(OCC)(=O)C>[S:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:5]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[CH:4][C:3]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCOc1cc(Br)c(OCCCCCCCC)cc1Br
Reactant: Brc1cccs1
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCOc1cc(-c2cccs2)c(OCCCCCCCC)cc1-c1cccs1
Yield: 45 %

Procedure:
A solution of 1,4-dibromo-2,5-dioctyloxybezene (6.580 grams, 13.365 mmol) in 15 milliliters of anhydrous tetrahydrofuran (THF) was added slowly over a period of 20 minutes to a mechanically stirred suspension of magnesium turnings (0.975 gram, 40.095 mmol) in 5 milliliters of THF in a 250 milliliter round-bottomed flask under an inert argon atmosphere. The resultant mixture was stirred at 60° C. for 3.5 hours. Subsequently, the resulting mixture was added to a mixture of 2-bromothiophene (5.447 grams, 33.412 mmol) and [1,3-bis(diphenylphosphinoethane]dichloronickel (II) (0.350 gram, 0.663 mmol) in 45 milliliters of anhydrous THF in a 250 milliliter round-bottomed flask under an inert atmosphere, and refluxed for 24 hours. Thereafter, the reaction mixture was diluted with 200 milliliters of ethyl acetate, washed twice with water and then dried with anhydrous magnesium sulfate. A brown solid, obtained after evaporation of the solvent, was purified by column chromatography on silica gel and recrystallization yielding 1,4-bis(2-thienyl)-2,5-dioctyloxybenzene as a light yellow crystalline product in 45 percent yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1Br.C([Sn](CCCC)(CCCC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)CCC>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: Fc1cc(F)c(C(F)(F)F)cc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Fc1cc(F)c(C(F)(F)F)cc1-c1ccccn1

Procedure:
2,4-Difluoro-5-(trifluoromethyl)bromobenzene (2.0 g, 7.7 mmol), 2-tributylstannylpyridine, and Bis(triphenylphosphine)palladium(II)chloride (0.16 g, 0.23 mmol) were added to 50 mL. xylenes and the mixture was heated to reflux for 16 hours. The reaction mixture was filtered through a silica gel plug and then purified with column chromatography to give 2-(2,4-difluoro-5-trifluoromethylphenyl)pyridine (1.4 g, 5.4 mmol). The product was confirmed by Mass Spectroscopy and 1H NMR.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[NH:6][C:7]3[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[O:21]1[CH2:23][CH:22]1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:23][CH:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[OH:21])[C:7]3[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CN1CCc2[nH]c3cc(C(F)(F)F)ccc3c2C1
Reactant: c1cc(C2CO2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3ccc(C(F)(F)F)cc3n2CC(O)c2ccncc2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g, 3.937 mmol) in DMF (5 mL) was added NaH (472 mg, 11.81 mmol) in portions at 0° C. After stirring the reaction mixture at 0° C. for 15 min, a solution of 4-(oxiran-2-yl)pyridine (714 mg, 5.90 mmol) in DMF (1 mL) was dropwise added into the reaction mixture at the same temperature and stirring was continued at RT overnight. The progress of reaction was monitored by TLC, LCMS and NMR. After consumption of starting material, ice water was added into the reaction mixture and the product was extracted with EtOAc (3×50 mL). The organic layer was washed with water (5×50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography to yield 2-(2-methyl-7-(trifluoromethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.54 (d, 2H), 7.5 (s, 1H), 7.37 (d, 1H), 7.3 (d, 1H), 7.18 (d, 2H), 4.78 (m, 1H), 4.17 (m, 2H), 3.5 (m, 2H), 2.8 (m, 1H), 2.7 (m, 2H), 2.63 (m, 1H), 2.4 (s, 3H). Separation by chiral HPLC provides enantiomers 65a and 65b.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:6](=[O:24])[N:5]([CH3:25])[C:4]=2[N:3]=1.[Cl:26][C:27]1[CH:28]=[C:29]([OH:38])[CH:30]=[C:31]([O:33][C:34]([F:37])([F:36])[F:35])[CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]=[C:31]([O:33][C:34]([F:35])([F:36])[F:37])[CH:32]=1)[O:38][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:6](=[O:24])[N:5]([CH3:25])[C:4]=2[N:3]=1
Reactant: Oc1cc(Cl)cc(OC(F)(F)F)c1
Reactant: Cn1c(=O)n(CCCO)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCO)c(=O)c2c1nc(Oc1cc(Cl)cc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a solution of the 8-bromo-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)— dione (50 mg, 0.116 mmol, intermediate 63) in DMF (2 mL) was added 3-chloro-5-(trifluoromethoxy)phenol (29.82 mg, 0.140 mmol) followed by potassium carbonate (24.24 mg, 0.175 mmol). The reaction was stirred at 85° C. for 2 h. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product, which was purified by preparative HPLC to give 8-(3-chloro-5-(trifluoromethoxy)phenoxy)-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (35 mg, 53.5% yield) as white solid. 1H-NMR (CD3OD) δ 7.458-7.435(m,3H), 7.381-7.365(m,3H), 7.361(s,1H), 5.507(s,2H), 4.138-4.102(t,2H), 3.640-3.608(t,2H), 3.448(s,3H), 1.905-1.871(m,2H). LCMS retention time 3.325 min; LCMS MH+ 559.
Reaction SMILES: [N+:1]([CH:4]([C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:5])([O-])=O.Cl.[N:20]#[C:21][NH2:22]>[Pd]>[CH3:5][C:4]1[NH:1][C:21]([NH2:22])=[N:20][C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#CN
Reactant: CC(C(=O)CCCCCc1ccccc1)[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Product: Cc1[nH]c(N)nc1CCCCCc1ccccc1

Procedure:
2-Nitro-8-phenyloctan-3-one (0.025 g, 0.10 mmol) reacted with concentrated HCl (0.50 mmol) and palladium, 5 wt. % on activated carbon (0.043 g, 0.020 mmol) under H2, then reacted with cyanamide (0.021 g, 0.50 mmol) according to the general procedure. Purification by column chromatography gave 0.010 g (41%) over two steps as a yellow oil: 1H NMR (300 MHz, CD3OD) δ 7.22 (m, 2H), 7.14 (m, 3H), 2.59 (t, J=7.5 Hz, 2H), 2.42 (t, J=6.9 Hz, 2H), 2.01 (s, 3H) 1.60 (m, 4H), 1.31 (m, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 146.2, 142.5, 128.3, 128.1, 125.5, 121.9, 117.5, 35.5, 31.1, 28.6, 28.1, 22.9, 7.5 ppm; IR νmax (cm−1) 3169, 2929, 2857, 1680, 1453, 1020, 749, 700; HRMS (FAB) calcd for C15H21N3 (MH+) 244.1808, found 244.1814.
Reaction SMILES: CN(C)NC(C1SC2C(=NC=CC=2O[C:16]2[CH:21]=[CH:20][C:19]([N:22]([C:29]3C=CC=CC=3OC)[C:23](=[O:28])[CH2:24][C:25](N)=[O:26])=[CH:18][C:17]=2F)C=1)=O.[NH2:39][C:40]1[CH:62]=[CH:61][C:43]([O:44][C:45]2[CH:50]=[CH:49][N:48]=[C:47]3[CH:51]=[C:52]([C:54]([N:56]([CH3:60])[N:57]([CH3:59])[CH3:58])=[O:55])[S:53][C:46]=23)=[C:42]([F:63])[CH:41]=1>>[F:63][C:42]1[CH:41]=[C:40]([NH:39][C:25](=[O:26])[CH2:24][C:23]([N:22]([CH3:29])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:21][CH:20]=2)=[O:28])[CH:62]=[CH:61][C:43]=1[O:44][C:45]1[CH:50]=[CH:49][N:48]=[C:47]2[CH:51]=[C:52]([C:54]([N:56]([CH3:60])[N:57]([CH3:58])[CH3:59])=[O:55])[S:53][C:46]=12
Reactant: CN(C)N(C)C(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: COc1ccccc1N(C(=O)CC(N)=O)c1ccc(Oc2ccnc3cc(C(=O)NN(C)C)sc23)c(F)c1
Product: CN(C(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)N(C)N(C)C)sc23)c(F)c1)c1ccccc1
Yield: 43 %

Procedure:
Following the procedure described above for compound 236 (step 4, example 95, scheme 63) but replacing amine 239 with 7-(4-amino-2-fluorophenoxy)-N,N′,N′-trimethylthieno[3,2-b]pyridine-2-carbohydrazide (244), title compound 241 was obtained in 43% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.45 (s, 1H), 8.45 (d, J=5.4 Hz, 1H), 7.79 (d, J=13.3 Hz, 1H), 7.67 (s, 1H), 7.62-7.31 (m, 7H), 6.62 (d, J=5.4 Hz, 1H), 3.40 (s, 9H), 3.23 (s, 2H), 3.21 (s, 3H). MS (m/z): (M+1) 536.2 (100%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH2:11]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:15]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCCNCCCC
Reactant: O=C(O)c1cccc(Br)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCN(CCCC)C(=O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
To a solution of 6-bromopicolinic acid (Aldrich, 404 mg, 2.00 mmol) in DMF (3.0 mL) were added dibutylamine (Aldrich, 258 mg, 2.00 mmol), HATU (760 mg, 2.00 mmol) and DIEA (1.1 mL, 6.00 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched by adding sat. aq. NH4Cl solution. The mixture was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography, gradient from 0 to 20% EtOAc/DCM to give a light brown oil (450 mg, 72%). 1H NMR (CDCl3) δ 7.67-7.57 (m, 2H), 7.51 (dd, J=7.5, 1.3 Hz, 1H), 3.53-3.42 (m, 2H), 3.36-3.27 (m, 2H), 1.72-1.56 (m, 4H), 1.46-1.33 (m, 2H), 1.27-1.15 (m, 2H), 0.97 (t, J=7.4 Hz, 3H), 0.85 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 313.2 (M+H)+.
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.[Si:6]([O:13][CH2:14][CH2:15][NH2:16])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]>CO>[Si:6]([O:13][CH2:14][CH2:15][NH:16][CH:3]1[CH2:2][O:1][CH2:4]1)([C:9]([CH3:11])([CH3:12])[CH3:10])([CH3:8])[CH3:7]
Reactant: O=C1COC1
Reactant: CC(C)(C)[Si](C)(C)OCCN
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCNC1COC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 249.3 %

Procedure:
To a stirred solution of oxetan-3-one (1 g, 13.87 mmol) in methanol (40 mL) was added 2-(tert-butyl-dimethylsilanyloxy)-ethylamine (2.7 mg, 15.27 mmol). The mixture was stirred for 30 min at room temperature after cooling, Na(CN)BH3 was added portion-wise, followed by stirring at room temperature for 2 h. The reaction mixture was quenched with water, extracted with dichloromethane (3×30 mL). The organic part was concentrated, dried and purified by Combi-Flash column (eluted at 20-50% ethyl acetate in hexane) to get [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-oxetan-3-yl-amine (8 g) (1.5 g, 46.71%) as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[F:15][C:16]1[CH:17]=[C:18]([CH:28]([NH:30][C:31]([C:33]2[N:34]=[C:35](Cl)[O:36][CH:37]=2)=[O:32])[CH3:29])[CH:19]=[C:20]([F:27])[C:21]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:27][C:20]1[CH:19]=[C:18]([CH:28]([NH:30][C:31]([C:33]2[N:34]=[C:35]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=3)[O:36][CH:37]=2)=[O:32])[CH3:29])[CH:17]=[C:16]([F:15])[C:21]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: OB(O)c1ccc(F)c(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2ccc(F)c(C(F)(F)F)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 7.6 %

Procedure:
4-Fluoro-3-trifluoromethylphenylboronic acid (54.1 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (5 mg, 8%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH2:10][CH2:9]1)=[O:6].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:11]1([C:8]2([N:7]3[CH2:2][CH2:3][CH2:4][C:5]3=[O:6])[CH2:10][CH2:9]2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=C(CCCBr)NC1(n2ccnc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCCN1C1(n2ccnc2)CC1
Temperature: 25 °C

Procedure:
In a 50 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, the crude 4-bromo-N-(l-imidazol-1-yl-cyclopropyl)-butyramide a18 (2.76 g), K2CO3 (1.26 g, 9.1 mmol) and KI (0.0075 g) in DMF (25 ml) are heated 3 h at 60° C., 17 h at 80° C., cooled down to room temperature and concentrated in vacuo. The reaction mixture is diluted with CH2Cl2, filtered and concentrated in vacuo to give the crude pyrrolidone (1.7 g). The residue is purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 95/4.5/05 (v/v/v)) to give, after treatment with HCl in ether (1 eq) and recrystallization in MeCN, 1-[l-(1H-imidazol-1-yl)cyclopropyl]pyrrolidin-2-one 23 (0.033 g, 7.5%) as an hydrochloride.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:34][C:21]3=[N:22][CH:23]=[C:24]([CH2:26][CH:27]4[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[O:28]4)[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:34][C:21]3=[N:22][CH:23]=[C:24]([CH2:26][CH:27]4[CH2:31][O:30][C:29]([CH3:32])([CH3:33])[O:28]4)[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OCC(Cc2cnc3[nH]c(C(=CC4CCCC4)c4ccc(S(C)(=O)=O)cc4)cc3c2)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)OCC(Cc2cnc3[nH]c(C(CC4CCCC4)c4ccc(S(C)(=O)=O)cc4)cc3c2)O1
Temperature: 25 °C
Yield: 86.1 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (310 mg, 0.65 mmol) and 10% palladium on activated carbon (100 mg) in methanol (250 mL) was heated at 50° C. under 50 bar of hydrogen in a steel bomb pressure for 8 h. The mixture was cooled to room temperature. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (270 mg, 86.8%) as a white solid: LC/MS m/e calcd for C27H34N2O4S [M+H]+ 483.65, observed 483.3.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[C:5](O)=[O:6].C(Cl)[Cl:17].C(Cl)(=O)C(Cl)=O>CN(C=O)C>[Br:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[C:5]([Cl:17])=[O:6]
Reactant: ClCCl
Reactant: O=C(O)C(CCBr)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)C(CCBr)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
Dissolve the product of Step 2 (8.1 g, 25.96 mmoles) in 20 ml. of dry CH2Cl2. Add oxalyl chloride (8.1 g, 62.3 mmoles), followed by 50 μl of dry DMF and heat the solution to reflux for 3 h. Cool the solution to room temperature and remove the solvent and excess reagent using reduced pressure. Yield: 8.2 g (IR: 1785 cm- 1).
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6](=[O:21])[CH2:7][CH2:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[NH:13][CH:12]=1)=[O:10].Cl[C:25]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:28]=[C:27]([N:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40][CH2:39][CH2:38]2)[N:26]=1>>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:25]1[N:26]=[C:27]([N:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:40][CH2:39][CH2:38]3)[N:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:30]=1)[CH:12]=[C:11]2[C:9](=[O:10])[CH2:8][CH2:7][C:6]([OH:5])=[O:21]
Reactant: Clc1nc(-c2ccccc2)nc(N2CCCc3ccccc32)n1
Reactant: C[Si](C)(C)CCOC(=O)CCC(=O)c1c[nH]c2ccc(Cl)cc12
Product: O=C(O)CCC(=O)c1cn(-c2nc(-c3ccccc3)nc(N3CCCc4ccccc43)n2)c2ccc(Cl)cc12

Procedure:
Arylation of 4-(5-chloro-1H-indol-3-yl)-4-oxo-butyric acid 2-trimethylsilanyl-ethyl ester with 1-(4-chloro-6-phenyl-[1,3,5]-triazin-2-yl)-1,2,3,4-tetrahydro-quinoline and subsequent hydrolysis as outlined previously yielded the titled compound. Rf 0.34 (5% methanol in dichloromethane); 1H NMR (THF-d8, 300 MHz) δ 9.21 (1H, s, ArH), 8.72 (1H, m, ArH), 8.59 (2H, d, J=7 Hz, ArH), 8.39 (1H, d, J=2 Hz, ArH), 7.95 (1H, d, J=8 Hz, ArH), 7.62-7.51 (3H, m, ArH), 7.35-7.15 (4H, m, ArH), 4.32 (2H, t, J=6 Hz, CH2), 3.30 (2H, t, J=7 Hz, CH2), 2.88 (2H, t, J=6 Hz, CH2), 2.72 (2H, t, J=7 Hz, CH2), 2.13 (2H, m, CH2); ESI-LCMS e/z calculated for C30H24ClN5O3 537.157, found 538 (M+H)+, 560 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(O)C.Cl[CH:13]([CH:19]=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][N:8]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: Nc1cc(Br)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(Br)ccn12
Temperature: 60 °C

Procedure:
4-bromopyridin-2-amine (10.0 g, 0.06 mol) was mixed with ethanol (50 mL) in a reaction flask, under an atmosphere of dry nitrogen. A solution of ethyl 2-chloro-3-oxopropanoate (5% in benzene; 222 mL; Commercial solution from Toronto Research Chemicals Inc.) was added. The mixture was heated to 60° C. under nitrogen for 5 hours. After allowing the mixture to cool the solvent was removed under vacuum to give a brown solid. The solid was mixed with ethyl acetate (500 mL) and sodium bicarbonate solution (200 mL) and stirred to dissolve. The phases were separated and the bicarbonate solution was extracted further with ethyl acetate (100 mL). The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated under vacuum to give a solid. The crude material was dissolved in ethyl acetate and passed through a short column of silica, eluting with ethyl acetate to give ethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate as a pale yellow solid (15 g).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[C:12]([O:15][C@@H:16]1[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:19][S:18][C@@H:17]1Br)(=[O:14])[CH3:13]>[O-2].[Zn+2]>[C:12]([O:15][C@@H:16]1[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:19][S:18][C@H:17]1[S:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][CH:7]=1)(=[O:14])[CH3:13]
Reactant: FC(F)(F)c1ccc(S)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Agent: [O-2]
Agent: [Zn+2]
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc(C(F)(F)F)cc2)SC[C@H]1OC(C)=O
Yield: 48 %

Procedure:
If the procedure described in Preparation IV is followed starting from 5.6 g (32.10-3 mol) of 4-trifluoromethylbenzenethiol, 12.3 g (35.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 2.55 g (32.10-3 mol) of zinc oxide (ZnO), 7.4 g (yield: 48%) of the expected product are obtained after precipitation in ether.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][NH2:15])=[CH:11][CH:10]=1>CO>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][NH:15][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])=[CH:11][CH:10]=1
Reactant: C=CC(=O)OC
Reactant: COc1ccc(CCN)cc1
Solvent: CO
Product: COC(=O)CCNCCc1ccc(OC)cc1
Yield: 97.9 %

Procedure:
A mixture of methyl acrylate (6.0 g, 69.7 mmol) and p-methoxyphenethyl amine (10.5 g, 69.7 mmol) in anhydrous methanol (88 mL) was refluxed for 3 days and then was concentrated to give methyl 3-[(4-methoxyphenethyl)amino]-propionate (16.2 g). To a solution of methyl 3-[(4-methoxyphenethyl)amino]-propionate (3.0 g, 12.6 mmol) in anhydrous methylene chloride (35 mL) was added 3-nitrobenzenesulfonyl chloride (2.8 g, 12.6 mmol), followed by triethylamine (2.6 g, 25.3 mmol). After stirring for 18 h at room temperature, the mixture was quenched with 1 N HCl solution (150 mL) and extracted with methylene chloride (100 mL). Combined organic layers was washed successively with 1 N HCl solution (100 mL) and brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel flash chromatography (2.5/1 to 2/1: hexanes/EtOAc) to provide methyl 3-[(4-methoxyphenethyl)-(4-cyanobenzenesulfonyl)-amino]-propionate (3.28 g, 7.8 mmol).