Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:27]4[C:22](=[C:23]([O:28][CH2:29][CH2:30][CH2:31][S:32](=[O:35])(=[O:34])[NH2:33])[CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])C.O[Li].O.O.CCO>C1COCC1>[S:32]([CH2:31][CH2:30][CH2:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:22]=1[CH:21]=[CH:20][N:19]2[C:17]1[CH:16]=[CH:15][N:14]=[C:13]([NH:12][CH:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[N:18]=1)(=[O:35])(=[O:34])[NH2:33]
Reactant: CCOC(=O)C1CCC(Nc2nccc(-n3ccc4c(OCCCS(N)(=O)=O)cccc43)n2)CC1
Agent: [Li]O
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)CCCOc1cccc2c1ccn2-c1ccnc(NC2CCC(C(=O)O)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
4-{4-[4-(3-Sulfamoyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexane-carboxylic acid ethyl ester (590 mg, 1.176 mmol) and LiOH.H2O (493.5 mg, 11.76 mmol) were combined in THF (2.5 mL), H2O (2.5 mL), and EtOH (2.0 mL) and allowed to stir overnight at RT. 10% HV1 solution was then added and the product precipitated. The organic solvents were removed in vacuo and the remaining suspension was filtered, washed with water and the yellow solid dried to yield 4-{4-[4-(3-sulfamoyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclo-hexanecarboxylic acid (Compound 220, 550 mg, 99%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[CH2:28]([CH2:30][NH2:31])[OH:29].C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([NH:31][CH2:30][CH2:28][OH:29])[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Reactant: NCCO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)NCCO)cc3)cc12

Procedure:
2-(1-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethylamino)ethanol (from Example 171) was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone and ethanol amine (commercially available) following the procedures described for Example 176. 1H NMR (Acetone-d6) of TFA Salt: δ 8.78 (d, 1H), 8.29 (d, 1H), 7.83 (s, 1H), 7.45 (m, 3H), 7.28 (m, 3H), 4.22 (m, 1H), 3.52 (m, 2H), 3.23 (t, 2H), 3.09 (t, 2H), 2.85 (m, 1H), 2.65 (m, 1H), 2.41 (s, 3H), 1.61 (d, 3H). LRMS [M+H]=401.2
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)[CH:3]=1.CO[CH2:21][CH2:22]OC.C(=O)([O-])[O-].[Na+].[Na+]>[OH-].[Na+]>[N:5]1[CH:22]=[CH:21][CH:2]=[C:3]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][CH:10]=3)[CH:3]=2)[CH:4]=1
Reactant: COCCOC
Reactant: Clc1cc(Oc2ccc3cccnc3c2)ncn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: c1cncc(-c2cc(Oc3ccc4cccnc4c3)ncn2)c1
Temperature: 200 °C

Procedure:
To a 5 mL, microwave vial containing 7-(6-chloro-pyrimidin-4-yloxy)-quinoline, (Example 102(a)), (0.30 g, 1.2 mmol) and ethylene glycol dimethyl ether (2 mL) was added 3-diethyl (3-pyridyl)borane (0.21 g, 1.5 mmol, Aldrich), 1 N sodium carbonate (1.8 mL), and palladium(0)-tetrakis-triphenylphosphine (0.14 g, 0.15 mmol, Strem Chemical). The vial was sealed and heated at 200° C. for 20 min in a microwave synthesizer, allowed to cool to room temperature, and the reaction mixture was diluted with 1 N sodium hydroxide (25 mL) and extracted with dichloromethane (2×50 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated onto silica gel. The crude material was purified by silica gel chromatography (gradient: 1-2% 2 N ammonia in methanol/dichloromethane) to obtain the title compound as an off-white solid. Mp: 155-158° C. MS (ESI, pos. ion.) mn/z: 301 (M+1).
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:16][C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:3]=1[N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:17]([Cl:16])=[O:19]
Reactant: Fc1cccc(Nc2ccccc2)c1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)N(c1ccccc1)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
2,3-Difluoro-N-phenylaniline (100 mg, 0.487 mmol) and triphosgene (159 mg, 0.536 mmol) were dissolved in CH2Cl2 (1 mL). The solution was cooled in an ice bath, and pyridine (79 μL, 0.975 mmol) was added slowly. Upon complete addition, the reaction was warmed to room temperature and stirred for 1 h. Then, it was cooled in an ice bath and quenched by the slow addition of H2O (1 mL). The reaction mixture was extracted with H2O (5 mL) and CH2Cl2 (5 mL). The aqueous layer was extracted again with CH2Cl2 (5 mL). The organic layers were combined and washed once with H2O (10 mL), dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography to yield the title compound as a light brown oil (114.7 mg).
Reaction SMILES: S([N:11]=[C:12]=[O:13])(C1C=CC(C)=CC=1)(=O)=O.[CH3:14][N:15]([CH:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1)[C:16]1[N:21]2[N:22]=[C:23]([NH2:25])[N:24]=[C:20]2[CH:19]=[C:18]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:17]=1.[CH2:39](N)[CH3:40]>CN(C=O)C.C1COCC1>[CH2:39]([NH:11][C:12]([NH:25][C:23]1[N:24]=[C:20]2[CH:19]=[C:18]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:17]=[C:16]([N:15]([CH3:14])[CH:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)[N:21]2[N:22]=1)=[O:13])[CH3:40]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCN
Reactant: CN1CCC(N(C)c2cc(-c3cccnc3)cc3nc(N)nn23)CC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(N(C)C3CCN(C)CC3)n2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
TosNCO (0.38 g, 1.93 mmol) was added to a solution of the product of Step 1 (0.26 g, 0.77 mmol) in DMF (2.5 mL). After stirring at room temperature for 24 h, ethylamine (3.5 mL of a 2 M solution in THF, 7 mmol) was added to the homogeneous solution, from which a solid precipitated immediately. The mixture was microwaved at 120° C. for 10 min. After cooling to 5° C. for 1 h, a precipitate was collected by filtration, washed with a small volume of MeOH and dried in vacuo at 60° C. to yield 1-ethyl-3-(5-[methyl-(1-methyl-piperidin-4-yl)-amino]-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-urea. MS m/z 409 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:10](CC([O-])=O)=[CH2:11].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH:10]([O:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)=[CH2:11]
Reactant: Oc1cc(F)cc(F)c1
Reactant: C=CCC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=COc1cc(F)cc(F)c1
Temperature: 100 °C
Yield: 70.3 %

Procedure:
To a 100 ml round bottom flask was added 3,5-difluorophenol (3.85 g, 29.6 mmol), vinylacetate (5.1 g, 59.2 mmol), Na2CO3 (1.88 g, 17.8 mmol), chloro-1,5-cycooctadiene iridium (I) dimmer (199 mg, 0.296 mmol) and 10 ml toluene. The resulting reaction mixture was flushed with nitrogen and heated at 100° C. overnight. After cooling to room temperature, the reaction mixture was diluted with 60 ml hexane and washed with 60 ml water. The organics were dried over sodium sulfate, filtered through a pad of silica gel, rinsed with 60 ml hexane. The filtrates were concentrated to give 3.25 g desired product as colorless liquid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.Cl[C:24]1[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:16][C:14]1[CH:13]=[CH:12][C:11]([N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)=[C:10]([CH:15]=1)[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][C:24]1[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1)=[O:22]
Reactant: FC(F)(F)c1cnc(Cl)cn1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2N)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(C(F)(F)F)cn2)c1

Procedure:
A microwave vial was charged with N-[(1S,2S)-2-aminocyclopentyl]-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 7; 450 mg, 1.40 mmol), 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 306 mg, 1.68 mmol) and DIPEA (733 μl, 4.20 mmol) in dry DMSO (4.7 ml). The reaction was subjected to microwave irradiation at 140° C. for 2 hours and then partitioned between ethyl acetate and water, washed with water, brine and concentrated in vacuo. The crude product was then purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) to give a cream solid which was then recrystallised from a mixture of ethyl acetate and pentane to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[C:10]3[CH:30]=[CH:31][N:32]=[C:33]([O:34]C)[C:9]2=3)[CH2:4][CH2:3]1.Cl.N1C=CC=CC=1>C(#N)C.O>[CH3:1][C:2]1([CH3:36])[CH2:3][CH2:4][CH:5]([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]5)=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[C:10]3[CH:30]=[CH:31][N:32]=[C:33]([OH:34])[C:9]2=3)[CH2:6][CH2:7]1
Reactant: COc1nccc2c3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n(C3CCC(C)(C)CC3)c12
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)CCC(n2c3nc(Nc4ccc(N5CCNCC5)cn4)ncc3c3ccnc(O)c32)CC1
Temperature: 170 °C
Yield: 207.5 %

Procedure:
A mixture of compound 331 (90 mg, 153 μmol) and pyridine hydrochloride (177 mg, 1.53 mmol) was heated at 170° C. (oil bath) for 4 h. After cooling to room temperature, the mixture was subjected to reverse phase preparative HPLC (acetonitrile/water containing 0.1% TFA each, 40 min from 10 to 50%). Lyophilization provided compound 334 (150 mg) as a yellow solid (TFA salt). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.66 (1 H, br. s.), 9.30 (1 H, s), 8.80 (2 H, br. s.), 8.05 (1 H, d, J=2.7 Hz), 7.92 (1 H, d, J=8.6 Hz), 7.75 (1 H, br. s.), 7.28 (1 H, t, J=5.7 Hz), 7.06 (1 H, d, J=6.3 Hz), 3.33-3.43 (4 H, m), 3.29 (5 H, d, J=1.6 Hz), 2.71-2.94 (2 H, m), 1.47-1.70 (4 H, m), 1.31-1.45 (2 H, m), 1.16 (3 H, s), 0.99 (3 H, s). LCMS-ESI (POS), M/Z, M+1: Found 473.2.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:51]2[N:52]=[C:53]([NH:56]C(OC(C)(C)C)=O)[S:54][CH:55]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]3[CH2:41][N:42](C(OC(C)(C)C)=O)[CH2:43][C:38]3=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:56][C:53]1[S:54][CH:55]=[C:51](/[C:22](=[N:21]/[O:20][C:17]2([C:15]([OH:16])=[O:14])[CH2:18][CH2:19]2)/[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:32])=[O:33])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]3[CH2:41][NH:42][CH2:43][C:38]3=[N:37]2)=[O:24])[N:52]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2nc3c(n2)CN(C(=O)OC(C)(C)C)C3)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: Nc1nc(/C(=N/OC2(C(=O)O)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2nc3c(n2)CNC3)cs1
Yield: 61.3 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)-cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((5-(tert-butoxycarbonyl)-5,6-dihydropyrrolo[3,4-d][1,2,3]triazol-2(4H)-yl)methyl)-4-oxoazetidine-1-sulfonic acid (20 mg, 0.022 mmol), anisole (5 μl, 0.046 mmol), DCM (300 μL) and TFA (51 μL, 0.66 mmol). The crude residue was purified by reverse phase prep HPLC (XSELECT CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (7.3 mg, 60%) as a white powder. LCMS: Rt=0.37 min, m/z=542.1 (M+1) Method 2m_acidic_polar; 1H NMR (500 MHz, D2O) δ 7.18 (s, 1H), 5.51 (d, J=5.3 Hz, 1H), 5.01-4.92 (m, 2H), 4.87 (d, J=6.0 Hz, 1H), 4.61-4.35 (m, 4H), 1.42-1.32 (m, 2H), 1.32-1.23 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:30])[CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[N:9]=[C:8]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:7]=1.C([O-])(=O)C.[K+].[N:36]#[C:37]Br.Cl>O.CO>[NH2:36][C:37]1[O:30][CH:3]([CH2:4][NH:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[N:9]=[C:8]([N:17]3[CH2:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]3)[CH:7]=2)[CH2:2][N:1]=1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(O)CN)c2c1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3CN=C(N)O3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.4 %

Procedure:
A mixture of 1-amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-2-ol (80 mg, 0.18 mmol, prepared in analogy to Example 9-7) and potassium acetate (89 mg, 0.91 mmol) in a mixture solution of methanol and water (7 ml, V/V=6/1) was added cyanogen bromide (89 mg, 0.84 mmol) at 0° C. After being stirred at room temperature for 3 hours, the mixture was stirred further with concentrated hydrochloric acid (3 mL) for 1 hour, and then concentrated in vacuo. The residue was dissolved in a saturated aqueous solution of sodium bicarbonate (10 mL) and extracted with dichloromethane (15 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column (10% methanol in dichloromethane) to afford 32 mg of the desired product as a white solid. MS obsd. (ESI+) [(M+H)+] 452, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-7.87 (m, J=4.6 Hz, 2 H), 7.72 (s, 1 H), 7.65-7.62 (t, J=3.7 Hz, 1 H), 7.49-7.45 (t, J=3.9 Hz, 1 H), 7.32 (d, J=2.1 Hz, 1 H), 7.23 (d, J=2.1 Hz, 1 H), 6.85 (t, J=2.6 Hz, 1 H), 6.46 (brs, 2 H), 6.10 (s, 1 H), 5.10 (s, 2 H), 4.82-4.77 (m, J=4.8 Hz, 1 H), 4.49 (brs, 2 H), 3.75 (m, 1 H), 3.63 (s, 2 H), 3.52 (m, 3 H), 2.35 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:3]=1.Br[C:28]1[S:32][C:31]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:30][CH:29]=1>>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([C:28]3[S:32][C:31]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:30][CH:29]=3)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(B(O)O)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3ccc(S(N)(=O)=O)s3)c2)n1

Procedure:
The title compound was prepared from 3-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-benzeneboronic acid (example G.9) (0.40 g, 1.1 mmol) and commercially available 5-bromo-thiophene-2-sulfonic acid amide (0.478 g, 2.4 mmol) according to the general procedure VI. Obtained as a white solid (0.180 g, 42%). MS (ISP) 475.2 [(M+H)+]; mp 215° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=2)[CH2:9][O:10][CH2:11][C:12]#[C:13][CH2:14][OH:15])=[CH:2]1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=2)[CH2:9][O:10][CH2:11]/[CH:12]=[CH:13]/[CH2:14][OH:15])=[CH:2]1
Reactant: OCC#CCOCc1cccc(-c2ccsc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC/C=C/COCc1cccc(-c2ccsc2)c1
Reaction time: 2 h
Yield: 57.9 %

Procedure:
0.48 g of the resulting alcohol compound was dissolved in 5 ml of tetarahydrofuran, and under a nitrogen atmosphere, a tetrahydrofuran solution (5 ml) of 78 mg of lithium aluminum hydride was added. The mixture was stirred under ice cooling for 2 hours, and then at room temperature for 1 hour. Ethyl acetate and water were added, and the organic layer separated was worked up in a customary manner. The product was purified by silica gel column chromatography [hexane / ethyl acetate=4/1] to give 0.28 g of the captioned compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:23])[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][C:47](=[O:50])[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].[Cl-].[NH4+]>C1COCC1>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][C:47]([C:2]2[CH:25]=[CH:24][C:5]([O:6][C:7]3[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:23])[C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)=[CH:9][CH:8]=3)=[CH:4][CH:3]=2)([OH:50])[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: O=C(Nc1ccc(Oc2ccc(Br)cc2)cc1)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cc3)cc2)CC1
Reaction time: 0.33 h
Yield: 36.5 %

Procedure:
To a solution of N-[4-(4-bromophenoxy)phenyl]-3,4-dichlorobenzamide (4.94 g, 11.3 mmol) in THF (100 mL) was stirred at −85° C., and added a solution of 2.46 M n-butyl lithium hexane (9.65 mL, 23.7 mmol) dropwise over 10 minutes. Upon stirring for 20 minutes at the same temperature, crystals were precipitated. To this reaction solution was added a solution of 1-(t-butoxycarbonyl)-4-piperidone (2.48 g, 12.4 mmol) in THF (20 mL). The temperature of the solution was raised over 3 hours to −40° C., and then aqueous saturated ammonium chloride was added to the solution. The resulting reaction solution was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was then evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:3 to 1:1), to yield 2.30 g of a white powder. These crystals were washed with ether, to thereby yield 1.80 g of the title compound.
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5].Br[CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[C:9]([O:10][CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5]
Reactant: BrCCOC1CCCCO1
Reactant: O=Cc1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c(F)ccc(OCCOC2CCCCO2)c1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.2 %

Procedure:
To 2,6-difluoro-3-hydroxy-benzaldehyde (540, 0.150 g, 0.95 mmol) in N,N-dimethylformamide (8.0 mL) were added 2-(2-bromo-ethoxy)-tetrahydro-pyran (0.218 g, 1.04 mmol) and potassium carbonate (0.52 g, 3.8 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 72 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound as colorless oil (541, 180 mg, 66%).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6]O)[C@@H:3]([OH:4])[CH2:2]1.N1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:43]I>O1CCOCC1.CO>[I:43][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CI)O2)c(=O)[nH]c1=O
Temperature: 21 °C
Reaction time: 7 h
Yield: 57.3 %

Procedure:
To a suspension of thymidine (0.968 g, 4.0 mM) in dioxane (20 mL) containing pyridine (0.65 mL, 8.0 mM) was added triphenylphosphine (1.57 g, 6.0 mM) and iodine (1.52 g, 6.0 mM). After stirring the mixture for 7 hours at 21° C., methanol (1.0 mL) was added, followed by removal of the solvent by evaporation. A solution of the residue in ethyl acetate (150 mL) was extracted successively with water (30 mL), 10% aqueous sodium thiosulfate solution (30 mL), and brine (30 mL). The ethyl acetate phase was concentrated in vacuo to a sirup which was taken up in hot ethanol (50 mL) and filtered. The filtrate was concentrated to a volume of 15 mL. On cooling, 5'-deoxy-5'-iodothymidine crystallized out. The crystals were filtered, rinsed with ethyl acetate, and dried, affording 5'-deoxy-5'-iodothymidine (0.806 g), a compound according to Formula 2.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:28]4[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=4)=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:24])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: OB(O)c1ccncc1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccncc1
Yield: 8.2 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with pyridine-4-boronic acid (available from Combi-Blocks Inc.; 49 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2-pyridin-4-yl-benzoic acid (7 mg, 8%). 1H NMR (300 MHz, DMSO-d6), δ 13.35 (br s, 1H), 8.69 (d, J=6.0 Hz, 2H), 8.50 (s, 1H), 8.48 (d, J=1.7 Hz, 1H), 8.34 (d, J=1.9 Hz, 1H), 8.30 (dd, J=7.9, 1.9 Hz, 1H), 8.10 (dd, J=8.5, 2.1 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.54 (d, J=5.8 Hz, 2H).