Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:11](F)=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[C:5]([C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1.[OH-].[NH4+:22]>>[NH2:22][C:11]1[C:10]([C:8]([C:6]2[C:5]([C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=2)=[O:9])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: [NH4+]
Reactant: O=C(c1cccnc1F)c1nc(Cl)ccc1C(F)(F)F
Agent: [OH-]
Product: Nc1ncccc1C(=O)c1nc(Cl)ccc1C(F)(F)F
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A mixture of (6-chloro-3-(trifluoromethyl)pyridin-2-yl)(2-fluoropyridin-3-yl)methanone (2.27 g, 7.452 mmol) and a saturated aqueous solution of ammonium hydroxide (20 mL, 513.6 mmol) was heated to 70° C. for 18 hours. The mixture was cooled down to room temperature and the resulting solid was filtered, washed with water and dried under vacuum to give the title compound as a pale yellow solid (2.12 g, 94% yield).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[Si]([O:25][C@@H:26]([CH3:59])[CH2:27][CH2:28][CH2:29][C@H:30]([OH:58])/[CH:31]=[CH:32]/[C@H:33]1[C@H:37]([O:38]C2CCCCO2)[CH2:36][C@@H:35]([Cl:45])[C@@H:34]1[CH2:46][CH2:47][CH2:48][C:49]1[S:53][C:52]([C:54]([O:56][CH3:57])=[O:55])=[CH:51][CH:50]=1)(C(C)(C)C)(C)C>CO>[Cl:45][C@H:35]1[C@H:34]([CH2:46][CH2:47][CH2:48][C:49]2[S:53][C:52]([C:54]([O:56][CH3:57])=[O:55])=[CH:51][CH:50]=2)[C@@H:33](/[CH:32]=[CH:31]/[C@@H:30]([OH:58])[CH2:29][CH2:28][CH2:27][C@H:26]([OH:25])[CH3:59])[C@H:37]([OH:38])[CH2:36]1
Reactant: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/[C@@H](O)CCC[C@H](C)O[Si](C)(C)C(C)(C)C)[C@H](OC3CCCCO3)C[C@H]2Cl)s1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/[C@@H](O)CCC[C@@H](C)O)[C@H](O)C[C@H]2Cl)s1
Reaction time: 24 h
Yield: 96.8 %

Procedure:
Pyridinium p-toluenesulfonate (20.4 mg, 0.081 mmol) was added to a solution of the THP-ether 15 (52 mg, 0.081 mmol) in MeOH (3 mL) at 23° C. The reaction was stirred for 24 h and then concentrated in vacuo. The residue was diluted with EtOAc and washed with 1N HCl, saturated aqueous NaHCO3 and brine. The organic portion was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by FCC (silica gel, 19:1 EtOAc/MeOH) to afford 34.9 mg (97%) of triol 11.
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[N:4]=1.Cl.[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[CH:35][CH:34]=[C:33]([NH:39][CH:40]2[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]2)[N:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[CH:35][CH:34]=[C:33]([NH:39][CH:40]2[CH2:45][CH2:44][CH2:43][N:42]([C:3]3[N:8]4[N:9]=[C:10]([CH:12]5[CH2:13][CH2:14][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]5)[N:11]=[C:7]4[CH:6]=[C:5]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[F:28])[N:4]=3)[CH2:41]2)[N:32]=1
Reactant: N#Cc1ccc(NC2CCCNC2)nc1N
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(N4CCCC(Nc5ccc(C#N)c(N)n5)C4)n3n2)CC1
Temperature: 130 °C

Procedure:
80 mg (0.2 mmol) of 5-chloro-7-(2,4-difluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 53A), 69.1 mg (0.25 mmol) of 2-amino-6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 20A) and 0.213 ml (1.23 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 34 mg (28% of theory) of the product as a solid.
Reaction SMILES: [OH:1][C:2]1[C:19]2[C@@H:18]3[C@@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=[O:20])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([OH:21])[CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[S:23]([O:1][C:2]1[C:19]2[C@@H:18]3[C@@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=[O:20])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:21][S:23]([CH3:22])(=[O:25])=[O:24])[CH:3]=1)([CH3:22])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@]12CC[C@@H]3c4c(O)cc(O)cc4CC[C@@H]3[C@@H]1CCC2=O
Solvent: c1ccncc1
Product: C[C@]12CC[C@@H]3c4c(cc(OS(C)(=O)=O)cc4OS(C)(=O)=O)CC[C@@H]3[C@@H]1CCC2=O
Temperature: 0 °C

Procedure:
A solution of 1 g. of 1,3-dihydroxy-8α-estra-1,3,5(10)-trien-17-one (prepared from compound of Example 9 by saponification) in 14 ml. of pyridine is combined at 0° C. with 1.9 ml. of methanesulfonic acid chloride and agitated for 3 days at 0°-10° C. The mixture is then introduced into ice water (acidified with HCl), filtered off, and the residue dissolved in methylene chloride. After chromatography on SiO2, 800 mg. of 1,3-bis(mesyloxy)-8α-estra-1,3,5(10)-trien-17-one is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[CH2:17][CH2:16]2)[N:3]=1.I[CH2:31][CH:32]1[CH2:35][CH2:34][CH2:33]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([O:12][CH2:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:10]=2)[N:5]=[C:4]([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[O:23])[CH2:17][CH2:16]2)[N:3]=1
Reactant: ICC1CCC1
Reactant: COc1cc2nc(N3CCCN(C(=O)N4CCOCC4)CC3)nc(N)c2cc1O
Product: COc1cc2nc(N3CCCN(C(=O)N4CCOCC4)CC3)nc(N)c2cc1OCC1CCC1

Procedure:
The title compound was prepared from 4-amino-6-hydroxy-7-methoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinazoline and iodomethyl cyclobutane [Bailey et al J Org Chem, 60, 297-300 (1995)] following a similar procedure to that described in Example 2(b), and was obtained as a solid (14%). Rf 0.40 (0.880 aqueous ammonia:methanol:dichloromethane 1:7:92, v/v). MS m/z 471 (MH)+. Found: C, 59.35; H, 7.12; N, 17.44; C24H34N6O4 0.15CH2Cl2 0.15 H2O, requires C, 59.6 H, 7.18; N, 17.28%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([C:10]([CH3:21])([CH3:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:3]=1.[Mg].II.[C:25](=[O:27])=[O:26].Cl>C1COCC1>[CH3:20][C:10]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[C:25]([OH:27])=[O:26])([CH3:21])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCC(C)(C)c1cc(Br)ccc1OC
Reactant: O=C=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCC(C)(C)c1cc(C(=O)O)ccc1OC
Temperature: -40 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
The 4-bromo-2-(1,1-dimethyldecyl) anisole (15.72 g, 44.2 mmoles) obtained in Example 11(a), above, is dissolved in THF (50 ml). This solution is slowly added to magnesium (1.18 g, 48.7 mmoles) and an iodine crystal, while being maintained at reflux by heating. Once the addition is complete, the reaction mixture is maintained at reflux for 30 minutes and then cooled to -40° C. 300 ml of THF are added and a stream of CO2 is passed therethrough for 2 hours. The reaction mixture is then poured into a solution of HCl (4N, 300 ml) and the product is extracted with ether (3×300 ml). The organic phase is washed with water until neutral, dried on MgSO4, and the solvents are evaporated. The residue is pulverized in isooctane to produce 7.25 g (51%. yield) of 3-(1,1-dimethyldecyl)-4-methoxy benzoic acid which melts at 112° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[NH:16][N:15]=NN=2)[CH:3]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[O:20][C:19]([CH2:18][Cl:17])=[N:15][N:16]=2)[CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: Cn1ncc2c(-c3nnn[nH]3)cc(Br)cc21
Solvent: ClC(Cl)Cl
Product: Cn1ncc2c(-c3nnc(CCl)o3)cc(Br)cc21
Temperature: 110 °C
Reaction time: 46 h
Yield: 74.4 %

Procedure:
6-Bromo-1-methyl-4-(1H-tetrazol-5-yl)-1H-indazole (604.6 mg, 2.166 mmol) was dissolved in chloroform (20 ml). Chloroacetyl chloride (0.520 ml, 6.49 mmol) was added and the mixture stirred at 110° C. for 46 h. Further chloroacetyl chloride (0.174 ml, 2.166 mmol) was added and the reaction continued stirred at 110° C. for 26 h. The reaction mixture was cooled and the solvent removed in vacuo. The resultant white solid was washed with DCM, the solvent removed under vacuum and the solid dried under high vacuum for 18 h to give the title compound as a white solid (528 mg).
Reaction SMILES: [CH2:1]([N:5]([CH3:17])[C:6](=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][CH2:14]O)[CH2:2][CH2:3][CH3:4].C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:19][CH2:14][C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH3:17])=[O:16]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCN(C)C(=O)CCCCCC#CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCN(C)C(=O)CCCCCC#CCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To a solution of 1.65 g of the product of Step B in 16.5 ml of methylene chloride cooled to -5° C. there were added 2.85 g of carbon tetrabromide and 2.25 g of triphenylphosphine. The reaction solution was stirred for 30 minutes at 0° C. and chromatographed on silica (eluant: methylene chloride-ethyl acetate 90-10) to obtain 1.82 g of the desired product.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:22])=[C:4]([CH:9]=[C:10](B2OC(C)(C)C(C)(C)O2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[N:31]1([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][C:10]3[C:11]([CH3:12])=[C:2]([F:1])[C:3]([OH:22])=[C:4]([CH:9]=3)[C:5]([O:7][CH3:8])=[O:6])=[CH:26][CH:27]=2)[CH:35]=[CH:34][CH:33]=[N:32]1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(F)c1O
Reactant: ClCc1ccc(-n2cccn2)cc1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)c(F)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 14.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.40 g) was added to a mixture of methyl 3-fluoro-2-hydroxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.13 g), 1-(4-(chloromethyl)phenyl)-1H-pyrazole (1.32 g), sodium carbonate (1.46 g), DME (30.0 mL) and water (10.0 mL) under argon atmosphere, and the mixture was stirred overnight at 80° C. The reaction mixture was allowed to be cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.33 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:12]1[S:16][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[N:19]=2)=[C:14]([C:26]([NH2:28])=[O:27])[CH:13]=1.[O:29]1[C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][NH:31][C:30]1=[O:39]>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[S:16][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:36]3[CH2:35][CH2:34][C:33]4([O:29][C:30](=[O:39])[NH:31][CH2:32]4)[CH2:38][CH2:37]3)[N:19]=2)=[C:14]([C:26]([NH2:28])=[O:27])[CH:13]=1
Reactant: O=C1NCC2(CCNCC2)O1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C=O)n3)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CN4CCC5(CC4)CNC(=O)O5)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to Example 106 Step 2 using 5-(2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl)-2-((6-formyl-2-pyridinyl)amino)-3-thiophenecarboxamide (19.5 mg, 0.05 mmol) and 1-oxa-3,8-diaza-spiro[4.5]decan-2-one (7.6 mg, 0.05 mmol) as the starting materials.
Reaction SMILES: [CH3:1][C:2]1[NH:20][C:5]2=[N:6][C:7]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=1.Br[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[CH3:1][C:2]1[N:20]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:5]2=[N:6][C:7]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=1
Reactant: BrCc1cccc2ccccc12
Reactant: COC(=O)c1cc(N2CCOCC2)nc2[nH]c(C)nc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)nc2c1nc(C)n2Cc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 5 h
Yield: 68.7 %

Procedure:
A mixture of methyl 2-methyl-5-morpholino-3H-imidazo[4,5-b]pyridine-7-carboxylate (138 mg, 0.5 mmol), 1-(bromomethyl)naphthalene (166 mg, 0.75 mmol) and Na2CO3 (138 mg, 1 mmol) in DMF (10 mL) was stirred at 80° C. for 5 h. It was cooled to room temperature and poured into water (50 mL). It was extracted with EA (100 mL×2). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with 100% EA to afford the desired product as a black solid (143 mg, 69%); LC/MS: MS (ES+) m/e 417 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.42 (s, 3H), 3.42 (t, J=4.5 Hz, 4H), 3.67 (t, J=4.5 Hz, 4H), 3.93 (s, 3H), 5.92 (s, 2H), 6.70 (d, J=7.2 Hz, 1H), 7.09 (s, 1H), 7.39 (t, J=7.5 Hz, 1H), 7.57-7.65 (m, 2H), 7.87 (d, J=9.0 Hz, 1H), 7.90 (d, J=9.0 Hz, 1H), 8.34 (d, J=7.2 Hz, 1H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])[O:19][CH2:20][C:21]([NH:23][NH2:24])=[O:22])([CH3:15])[CH3:14]>O1CCCC1.C(OCC)(=O)C>[CH3:15][C:13]([C:16]1[CH:17]=[C:18]([CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])[O:19][CH2:20][C:21]1[O:22][C:1](=[O:2])[NH:24][N:23]=1)([CH3:12])[CH3:14]
Reactant: CC(C)(C)c1cc(OCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(OCc2n[nH]c(=O)o2)cc(C(C)(C)C)c1O
Reaction time: 0.5 h

Procedure:
A 12.5% solution of phosgene in toluene (2.4 mL, 2.7 mmol) is added dropwise to a -78° C. of [3,5-bis(1,1-dimethylethyl)-4-hydroxyphenoxy]-acetic acid hydrazide (0.40 g, 1.36 mmol) in tetrahydrofuran (25 mL). The reaction mixture is stirred for 30 minutes, diluted with ethyl acetate, and washed three times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a pale yellow oil which is crystallized from ethyl acetate/hexane yielding 0.34 g (79%) of 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenoxy]methyl-1,3,4-oxadiazol-2(3H)-one; mp 138.0°-140.0° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:29]=[C:30]([S:34][C:35]2[CH:36]=[CH:37][C:38]3[N:39]([CH:41]=[C:42]([NH:44][C:45]([CH:47]4[CH2:49][CH2:48]4)=[O:46])[N:43]=3)[N:40]=2)[CH:31]=[CH:32][CH:33]=1>CN(C)C(=O)C.O1CCCC1>[CH:47]1([C:45]([NH:44][C:42]2[N:43]=[C:38]3[CH:37]=[CH:36][C:35]([S:34][C:30]4[CH:29]=[C:28]([NH:27][C:13]([C:4]5[CH:3]=[C:2]([CH3:1])[N:6]([C:7]6[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=6)[N:5]=5)=[O:15])[CH:33]=[CH:32][CH:31]=4)=[N:40][N:39]3[CH:41]=2)=[O:46])[CH2:48][CH2:49]1
Reactant: Nc1cccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cc1cc(C(=O)O)nn1-c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(Sc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)nn1-c1ccccc1
Yield: 49.9 %

Procedure:
Using 5-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid (196 mg, 0.97 mmol), tetrahydrofuran (2.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (80 μL, 0.92 mmol), N-{6-[(3-aminophenyl)thio]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide (200 mg, 0.61 mmol) and N,N-dimethylacetamide (4.0 mL), and in the same manner as in Example 255, the title compound (155 mg, 49%) was obtained as a white powder.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:10]=1[CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH:22]1([C:10]2[CH:11]=[C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=[CH:14][C:9]=2[OH:8])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CCOC(=O)C=Cc1ccc(OCc2ccccc2)c(C2CCCC2)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(O)c(C2CCCC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.5 %

Procedure:
A flask containing 10% Pd/C (120 mg) was evacuated and then purged under a N2 atmosphere. To this was added a solution of ethyl 3-(4-benzyloxy-3-cyclopentyl-phenyl)prop-2-enoate (1.2 g, 3.42 mmol) in ethanol (15 mL). The reaction was stirred under H2 atmosphere for 12 h at room temperature. The catalyst was filtered off and the solvent was removed under reduced pressure. Purification by silica gel chromatography (0-30% ethyl acetate/hexanes) afforded ethyl 3-(3-cyclopentyl-4-hydroxy-phenyl)propanoate (857 mg, 96% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 9.01 (s, 1H), 6.93 (d, J=2.1 Hz, 1H), 6.79 (dd, J=2.2, 8.1 Hz, 1H), 6.65 (d, J=8.1 Hz, 1H), 4.02 (q, J=7.1 Hz, 2H), 3.21-3.12 (m, 1H), 2.71 (t, J=7.5 Hz, 2H), 2.53-2.50 (m, obscured by DMSO peak, 2H), 1.92-1.85 (m, 2H), 1.78-1.68 (m, 2H), 1.66-1.55 (m, 2H), 1.54-1.45 (m, 2H), 1.15 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([C@H:15]3[C@H:19]([NH:20][C@@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:22])[CH2:18]S[CH2:16]3)=[O:14])[CH2:8]2)=[CH:4][CH:3]=1.CC(C)=O.O.[S:36]([O-:41])(O[O-])(=O)=[O:37].[K+].[K+]>CO>[O:37]=[S:36]1(=[O:41])[CH2:18][C@@H:19]([NH:20][C@@H:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:22])[C@H:15]([C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@@H:7]([CH2:6][C:5]3[CH:29]=[CH:30][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:8]2)=[O:14])[CH2:16]1
Reactant: O=S(=O)([O-])O[O-]
Reactant: C[C@@H](N[C@@H]1CSC[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: C[C@@H](N[C@@H]1CS(=O)(=O)C[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 72.1 %

Procedure:
[(S)-3-(4-fluorobenzyl)-piperidin-1-yl]-[(3R,4S)-4-[(R)-1-phenyl-ethylamino]-tetrahydro-thiophen-3-yl]-methanone (1.02 g, 2.39 mmol) was dissolved in methanol (10 mL) and acetone (10 mL) and stirred on ice. Water (10 mL) was added, and the resulting heterogeneous mixture was treated with potassium peroxymonosulfate (Oxone®, 3.67 g, 5.98 mmol). After 5 min the cooling bath was removed and the mixture was stirred at room temperature. After 20.5 h , the mixture was concentrated and diluted with water. The pH was adjusted to ca. 11 with 1N sodium hydroxide, and the mixture was extracted with ethyl acetate. The combined extracts were dried (Na2SO4) and concentrated, and the residue was purified by flash column chromatography (2.5% 2-propanol/chloroform) to provide the product as a glass (790 mg, 72%). 1H NMR (300 mHz, CDCl3) δ7.31 (m, 5H), 7.11 (m, 2H), 7.06 (m, 2H), 4.50 (m, 1H), 4.0-3.7 (m, 3H), 3.5-2.9 (m, 5H), 2.7-2.5 (m, 4H), 1.9-1.6 (m, 4H), 1.43 (m, 1H), 1.33 (m, 3H), 1.20 (m, 1H), ESI MS: (M+H)+=459.3.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Br)[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:23]([OH:26])[C:24]#[CH:25]>[Cu]I.C(NCC)C>[C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([C:25]#[C:24][CH2:23][OH:26])[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C#CCO
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ncc1Cl
Agent: [Cu]I
Solvent: CCNCC
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C#CCO)ncc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.5 %

Procedure:
A mixture of N-(1-adamantylmethyl)-2-bromo-5-chloroisonicotinamide (Example 1(ii)) (0.96 g), propargyl alcohol (0.16 g), copper (I) iodide, bis-triphenylphosphine palladium is dichloride (0.035 g) and diethylamine (10 ml) was stirred together at room temperature for 20 hours. The mixture was concentrated and the residue partitioned between ethyl acetate and 1M aqueous hydrochloric acid solution (2×25 ml) and the mixture was extracted into ethyl acetate (3×25 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate:iso-hexane (1:4 to 1:1) and then ethyl acetate to afford the sub-titled compound (0.48 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH3:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.[CH3:16][CH:17]([CH3:22])[CH2:18][CH2:19]CO>>[CH3:16][CH:17]([CH3:22])[CH2:18][CH2:19][CH2:1][O:2][C:3](=[O:15])[C@H:4]([CH3:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1
Reactant: COC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1
Reactant: CC(C)CCCO
Product: CC(C)CCCOC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following transesterification General Procedure AB above and using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above) and 4-methylpentanol (Aldrich), the title compound was prepared as an oil. The reaction was monitored by silica gel tlc (Rf=0.70 in 25% EtOAc/hexanes). Purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([Cl:35])[CH:34]=1)[C:5]([N:7]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([F:20])[CH:11]=1)=[O:6].[CH2:36](B(O)O)[CH3:37].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:7]([CH2:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[C:12]([F:20])[CH:11]=2)[C:5](=[O:6])[C:4]2[CH:3]=[C:2]([CH2:36][CH3:37])[CH:34]=[C:33]([Cl:35])[CH:32]=2)=[CH:23][CH:24]=1)([CH3:30])([CH3:29])[CH3:31]
Reactant: CCB(O)O
Reactant: CC(C)(C)c1ccc(CN(CCc2cc(F)cc(C(F)(F)F)c2)C(=O)c2cc(Cl)cc(Br)c2)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc(Cl)cc(C(=O)N(CCc2cc(F)cc(C(F)(F)F)c2)Cc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
285 mg of 3-bromo-N-(4-tert-butyl-benzyl)-5-chloro-N-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-benzamide (0.6 mmol, Example B177), 44 mg of ethylboronic acid (1.75 mmol), 371 mg of tri-potassium phosphate (0.05 mmol), 14 mg of tricyclohexylphosphine and 6 mg of palladium acetate were suspended in 2.3 ml toluene and 0.1 ml water and stirred at 100° C. for 3.5 h under nitrogen. The reaction mixture was then cooled down to RT, diluted with 4 ml water and extracted twice with ethylacetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered off and concentrated under vacuo. The resulting residue was purified by flash column chromatography (Heptane/AcOEt:95/5) to yield 192 mg of a yellow solid. MS (ISP) 520.3 (M+H)+.