Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([N:51]=[S:52]([CH3:58])([N:54]([CH2:56][CH3:57])[CH3:55])=[O:53])=[CH:47][CH:46]=1>>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:43])[CH3:42])[C:5]4=[N:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([C:45]6[CH:46]=[CH:47][C:48]([N:51]=[S:52]([CH3:58])([N:54]([CH2:56][CH3:57])[CH3:55])=[O:53])=[CH:49][CH:50]=6)=[CH:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Reactant: CCN(C)S(C)(=O)=Nc1ccc(Br)cc1
Product: CCN(C)S(C)(=O)=Nc1ccc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)cc1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N′-(4-bromophenyl)-N-ethyl-N-methyl-methanesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3). LC (method 1): tR=1.16 min; Mass spectrum (ESI+): m/z=714 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][CH:4]([OH:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1C.[BH4-].[Na+].[CH3:18][OH:19]>>[F:1][C:2]([F:15])([F:14])[CH2:3][C@H:4]([OH:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:19][CH3:18]
Reactant: Cc1ccccc1CC(O)CC(F)(F)F
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccccc1C[C@@H](O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4,4,4-trifluoro-1-(2-methoxyphenyl)butan-2-one (6 g, 25.8 mmol, synthesized as in example 52, step 1) in MeOH (100 ml) was added NaBH4 (1.47 g, 38.7 mmol) at 0° C. and stirred for 1 h at RT. Then the reaction mixture was quenched with MeOH and concentrated under reduced pressure to afford crude compound. The title compound was purified by separation methods A, E and H. Yield (1.7 g). The enantiomer showed up at tr=12.8 min with Chiralpak 1A (4.6×250 mm) 5μ, hexane:2-PrOH:TFA (90:10:0.1), 1 ml/min.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[C:8]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:35]([C:37]1[N:38]=[CH:39][N:40](C(OC(C)(C)C)=O)[CH:41]=1)=[CH2:36]>CN(C=O)C>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:8]2[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2](/[CH:36]=[CH:35]/[C:37]4[N:38]=[CH:39][NH:40][CH:41]=4)=[CH:3][CH:4]=3)=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:10][C:9]=2[CH:20]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(Br)cc2)cc1
Reactant: C=Cc1cn(C(=O)OC(C)(C)C)cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/c3c[nH]cn3)cc2)cc1
Temperature: 150 °C
Yield: 79.6 %

Procedure:
To a microwave vial, 3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (50 mg, 0.113 mmol) was dissolved in DMF (2 mL) and triethyl amine (0.474 mL, 3.40 mmol). To the solution was added tert-butyl 4-vinyl-1H-imidazole-1-carboxylate (66.0 mg, 0.340 mmol) and Pd(PPh3)2C12 (7.95 mg, 0.011 mmol). The system was flushed with nitrogen and heated at 150° C. for 1 h under microwave radiation. The mixture was cooled to room temperature and diluted with DCM and sat. NH4Cl. The organic layer was collected (phase separator) and concentrated onto silica gel and the material was purified by column chromatography (SiO2, 0-30% DCM/MeOH) to afford (E)-4-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1H-imidazole (41 mg, 0.090 mmol, 80% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.78 (d, J=1.52 Hz, 1H), 7.51-7.62 (m, 2H), 7.46-7.51 (m, 1H), 7.39 (d, J=9.09 Hz, 2H), 7.32 (d, J=2.53 Hz, 1H), 7.15 (d, J=9.09 Hz, 1H), 7.08 (d, J=16.67 Hz, 1H), 6.76-6.95 (m, 6H), 3.77 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: C1COCC1.CC(C)([O-])C.[K+].[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH2:16][OH:17].Cl[C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[N:22][N:21]=1>O>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:18][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[N:22][N:21]=1
Reactant: Clc1nnnn1-c1ccccc1
Reactant: OCCCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCCCOc1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
10 ml of THF solution containing 225 mg of potassium t-butoxide was added with 0.6 g of 1,5-pentanediol and 0.36 g of 5-chloro-1-phenyl-tetrazole and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with water and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 0.4 g of the title compound (yield: 81%).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28]O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:44]=[N+:45]=[N-:46])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>O1CCCC1>[N:44]([CH2:28][C:26]1[N:27]=[C:23]([N:21]2[CH2:22][CH:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:20]2)[S:24][CH:25]=1)=[N+:45]=[N-:46]
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CO)cs2)C1)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC1CN(c2nc(CN=[N+]=[N-])cs2)C1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-hydroxymethyl-1,3-thiazol-2-yl)azetidine (1.02 g, 2.39 mmol) (obtained as described in Reference Example 2(2)) in tetrahydrofuran (50 ml) were added diphenylphosphoryl azide (0.8 ml, 3.71 mmol), triphenylphosphine (950 mg, 3.62 mmol) and 40% diethylazodicarboxylate in toluene solution (1.32 g, 3.59 mmol) in an ice bath under an atmosphere of nitrogen. The mixture was stirred in an ice bath for 2 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (8:1) as the eluant to afford 1-(4-azidomethyl-1,3-thiazol-2-yl)-3-t-butyldiphenylsilyloxyazetidine (1.06 g, yield 99%) as colorless syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CC=CC=1.[Cl:22][C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:23]([Cl:22])=[O:25])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc(Nc2ccccc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(N(C(=O)Cl)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a cooled solution of 3-methoxy-N-phenylaniline (100.0 mg, 0.502 mmol) and pyridine (0.102 mL, 1.267 mmol) in DCM (500 mL) was added triphosgene (120.0 mg, 0.406 mmol). The solution was allowed to warm up to room temperature and stirred overnight. The organic solvent was evaporated. The residue was dissolved in ethyl acetate, washed with water, brine, dried over MgSO4 and concentrated to provide the title compound (105.0 mg). LCMS m/z=261.9 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.79 (s, 3H), 6.90-7.31 (m, 3H), 7.32-7.52 (m, 4H), 7.52-7.70 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](OCC)([O:9]CC)[CH3:8])=[N:4][CH:3]=1.FC(F)(F)C(O)=O.O>ClCCl>[Br:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[N:4][CH:3]=1
Reactant: CCOC(C)(OCC)c1ncc(Br)s1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)c1ncc(Br)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
To a solution of the product of Step 2 (981 mg, 3.50 mmol) in dichloromethane (4 mL) at room temperature, under nitrogen, were added trifluoroacetic acid (6.204 mL, 81 mmol) and water (208 μL, 11.55 mmol). The mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and was washed with 5% aqueous sodium bicarbonate (3×) and brine, dried (sodium sulfate) and concentrated to give 1-(5-bromo-1,3-thiazol-2-yl)ethanone (654 mg, 3.17 mmol, 91% yield) as a yellow solid that was used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C([O-])(=O)C.[Na+]>CO.[Pd]>[N:8]1([C:7]2[CH:6]=[CH:5][N:4]=[N:3][CH:2]=2)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: Clc1cc(N2CCNCC2)c(Cl)nn1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: c1cc(N2CCNCC2)cnn1

Procedure:
9.3 g 3,6-dichloro-4-piperazin-1-yl-pyridazine (cf. 10.2) and 6.5 g sodium acetate are suspended in 100 ml of methanol and hydrogenated with 1 g Pd/C 10% at ambient temperature. The catalyst is suction filtered and the filtrate is evaporated to dryness. The product is extracted with chloroform, washed with sodium hydroxide solution and precipitated as the hydrochloride with an ethereal HCl solution. 8.6 g (V-4) are obtained. M.p.>300° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]#[C:5][CH2:6][O:7][Si:8]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[P:25](OCC)([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:28]([O:27][P:25]([CH2:2][CH2:3][C:4]#[C:5][CH2:6][O:7][Si:8]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:26])[O:30][CH2:31][CH3:32])[CH3:29]
Reactant: CCOP(=O)(OCC)OCC
Reactant: CC(C)(C)[Si](OCC#CCCBr)(c1ccccc1)c1ccccc1
Product: CCOP(=O)(CCC#CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCC
Yield: 98 %

Procedure:
A mixture of compound 6 (3.24 g, 80.7 mmol) and triethyl phosphate (40 mL) was refluxed under nitrogen atmosphere for overnight. After evaporation, the residue was purified with 50% EtOAc in hexanes by silica gel column chromatography to give 3.26 g of product 7 (7.90 mmol, 98% yield); 1H NMR (CDCl3) δ 7.77˜7.64 (m, 4H), 7.46˜7.32 (m, 6H), 4.29 (t, J=1.9 Hz, 2H), 4.16˜4.02 (m, 4H), 2.50˜2.34 (m, 2H), 1.96˜1.82 (m, 2H), 1.31 (t, J=7.1 Hz, 6H), 1.04 (s, 9H); 31P NMR (CDCl3) δ 30.43.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[C:5]2[C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.[H][H]>CO.[Pd].ClCCl>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=3)[CH:8]=[C:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]=2)=[CH:18][CH:19]=1)(=[O:24])=[O:25]
Reactant: [H][H]
Reactant: Cc1ccc2cc(CC(=O)O)cc(C(=O)c3ccc(S(C)(=O)=O)cc3)c2c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc2cc(CC(=O)O)cc(Cc3ccc(S(C)(=O)=O)cc3)c2c1
Yield: 21.4 %

Procedure:
A solution of [6-methyl-4-(4-methanesulfonyl-benzoyl)-naphthalen-2-yl]-acetic acid (example 2-28) (70 mg, 0.183 mmol) in methanol (8 mL) was hydrogenated using a H-cube hydrogenation reactor with a flow rate of 1 mL/min and a 10% palladium on carbon catalyst cartridge at 30° C. under 10 bar hydrogen pressure. After the reaction was complete (monitored by TLC, 4% methanol in dichloromethane), the solvent was evaporated in vacuo. Reverse-phase preparative HPLC (using a Waters® Delta-Prep™ 3000 with a Varian Pursuit® C-18 column [10 μm, 20×150 mm]) gave [4-(4-methanesulfonyl-benzyl)-6-methyl-naphthalen-2-yl]-acetic acid (14.4 mg, 21%) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm: 7.83 (d, J=8.4 Hz, 2 H), 7.74 (d, J=8.7 Hz, 1 H), 7.66 (s, 1H), 7.60 (s, 1 H), 7.38 (d, J=8.4 Hz, 2 H), 7.32 (d, J=8.7 Hz, 1 H), 7.22 (s, 1 H), 4.48 (s, 2 H), 3.78 (s, 2 H), 3.02 (s, 3 H), 2.46 (s, 3 H); HRMS cald. for O21H20O4S (ESI+) [(M+Na)+] 391.0974, obsd. 391.0976.
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:17]([C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1)(=[O:19])[CH3:18]>>[C:17]([C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH:16][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]3[N:4]([CH3:7])[N:5]=[CH:6][C:2]=3[F:1])[CH:9]=2)=[O:28])[CH:23]=[CH:24][CH:25]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)c1cccc(N=C=O)c1
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Product: COc1ccc(NC(=O)Nc2cccc(C(C)=O)c2)cc1-c1c(F)cnn1C
Yield: 53 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3-acetylphenylisocyanate, in a similar manner as described in Example 1.68. An additional purification by flash chromatography (SiO2, Hexanes/EtOAc gradient elution) was necessary, providing 36 mg (53% yield) of Compound 88: LCMS m/z (%)=383 (M+H, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.31 (s, 1H), 8.17 (s, 1H), 8.13 (s, 1H), 7.79 (dd, J1=9.0 Hz, J2=2.2 Hz, 1H), 7.63 (d, J1=15.5 Hz, J2=8.3 Hz, J3=2.7 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.41 (m, 3H), 7.14 (d, J=9.2 Hz, 1H), 3.84 (s, 3H), 3.65 (s, 3H), 2.56 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −177.39 (d, JH,F=4.1 Hz, 1F).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:17][NH:18][CH:19]([CH3:35])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[NH:31][CH2:32][CH2:33][N:34]=3)=[CH:24][CH:23]=2)[OH:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OC(=O)C)C.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:17][NH:18][CH:19]([CH3:35])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[NH:34][CH2:33][CH2:32][N:31]=3)=[CH:24][CH:23]=2)[OH:16])=[CH:11][CH:10]=1
Reactant: CC(COc1ccc(OCC2=NCCN2)cc1)NCC(O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(COc1ccc(OCC2=NCCN2)cc1)NCC(O)c1ccc(O)cc1

Procedure:
A solution of 4-benzyloxy-α-[[[2-[4-((4,5-dihydro-1H-2-imidazolyl)methyloxy)phenoxy]-1-methylethyl]amino]methyl]benzenemethanol (1.5 g) in ethylacetate (80 ml) was hydrogenated at atmospheric pressure in the presence of 10% palladium on carbon. The reaction mixture was filtered and evaporated to a foam which was purified by column chromatography on alumina. Elution with methanol-chloroform (8:92) gave 4-hydroxy-α [[[2-[4-((4,5-dihydro-1H-2-imidazolyl)-methyloxy)phenoxy]-1-methylethyl]amino]methyl]benzene-methanol m.pt. 160°-180° C. (ethyl acetate), as a 40:60 mixture of diastereoisomers.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:13][CH:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:15].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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.C(OCC)(=O)C>[CH3:13][CH:14]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=2)[CH:7]=[O:8])[CH2:18][CH2:17]1)[CH3:15]
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)N1CCNCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])c(C=O)c2)CC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 10 %

Procedure:
To 5-chloro-2-nitrobenzaldehyde (10.0 g, 54.0 mmol, Aldrich) in dioxane (300 mL) was added 1-(1-methylethyl)piperazine (13.8 g, 108.0 mmol, Aldrich), XANTPHOS (3.1 g, 5.4 mmol, Aldrich), and Cs2CO3 (35.2 g, 108.0 mmol, Aldrich). The mixture was bubbled with N2 for 15 min prior to the addition of Pd2(dba)3 (2.5 g, 2.7 mmol, Aldrich). The reaction was stirred at 100° C. for 5 h. Ethyl acetate (150 mL) was used to dilute the reaction mixture, followed by the addition of water (100 mL). After partitioning, extraction with Ethyl acetate (2×75 mL), drying (Na2SO4), concentration, and silica gel chromatography afforded 5-[4-(1-methylethyl)-1-piperazinyl]-2-nitrobenzaldehyde (1.5 g, 10% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.08 (d, J=6.6 Hz, 6 H), 2.62-2.69 (m, 4 H), 2.70-2.79 (m, 1 H), 3.46-3.51 (m, 4 H), 6.93 (dd, J=9.2, 2.9 Hz, 1 H), 7.13 (d, J=2.9 Hz, 1 H), 8.09-8.12 (m, 1 H), 10.53 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])=[CH:15][CH:16]=1
Reactant: Cc1ccc(C(O)c2ccccc2O)cc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1ccc(Cc2ccccc2O)cc1
Reaction time: 40 h

Procedure:
To a solution of crude Part A 4-methyl-2′-hydroxybenzhydrol (9.7 g containing no more than 40 mmol) in 175 mL of MeOH was added 0.59 g of 10% Pd/C and 1.75 mL of TFA. The suspension was stirred for 40 hr under 1 atmos. H2, filtered through celite and concentrated to yield 8.6 of crude 2-(4′-methylbenzyl)phenol as an oil.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1C(P(C)C)P(C)C.CC(C)([O-])C.[Na+].N#N.F[C:29]1[CH:30]=[C:31](CNS(C)(=O)=O)[C:32]([NH:45][C@H:46]([C:48]2[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=2)[CH3:47])=[N:33][C:34]=1NC1C=C(OC(C)C)NN=1.[NH2:61][C:62]1[CH:66]=[C:65]([CH:67]2[CH2:69][CH2:68]2)[N:64]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[N:63]=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:67]1([C:65]2[N:64]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[N:63]=[C:62]([NH:61][C:34]3[CH:29]=[CH:30][CH:31]=[C:32]([NH:45][C@H:46]([C:48]4[CH:49]=[CH:50][C:51]([F:54])=[CH:52][CH:53]=4)[CH3:47])[N:33]=3)[CH:66]=2)[CH2:69][CH2:68]1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(CNS(C)(=O)=O)cc2F)n[nH]1
Reactant: CC(C)(C)OC(=O)n1nc(N)cc1C1CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CP(C)C(c1ccccc1-c1ccccc1)P(C)C
Solvent: Cc1ccccc1
Product: C[C@H](Nc1cccc(Nc2cc(C3CC3)n(C(=O)OC(C)(C)C)n2)n1)c1ccc(F)cc1
Temperature: 110 °C
Yield: 36.3 %

Procedure:
To a 25 ml round bottom flask was added Pd2(dba)3 (84 mg, 0.092 mmol), (biphenyl-2-ylmethylene)bis(dimethylphosphine) (55 mg, 0.184 mmol) and sodium tert-butoxide (132 mg, 1.38 mmol). The flask was sealed and refilled with N2. To the mixture was added a solution of 6-chloro-N-[(1S)-1-(4-fluorophenyl)ethyl]pyridin-2-amine (Method 20; 230 mg, 0.92 mmol) and tert-butyl 3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate (223 mg, 1.0 mmol) in toluene (4 ml). The reaction mixture was heated at 110° C. overnight. Solvent was removed and EtOAc was added and the mixture was washed with brine and was concentrated. Flash chromatography (15-40% EtOAc in hexanes) gave the title compound (146 mg, 36%). 1H NMR (CDCl3) δ 0.80-1.00 (m, 4H), 1.60 (m, 3H), 1.65 (s, 9H), 1.95 (m, 1H), 4.71 (m, 1H), 4.75 (m, 1H), 5.75 (m, 1H), 6.09 (m, 1H), 6.21 (s, 1H), 7.00 (m, 2H), 7.23 (m, 2H), 7.30 (m, 1H), 9.40 (s, 1H).
Reaction SMILES: [C:1](#[N:16])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl.[NH2:18][OH:19].[OH-].[Na+]>C(O)C>[NH2:16][C:1]1[CH:2]=[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[O:19][N:18]=1
Reactant: NO
Reactant: CCCCCCCCCCCCC#CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCc1cc(N)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
A solution of 2 -pentadecynenitrile (2.9 g, 13.2 mmol) in ethanol (60 mL) was added to a stirred solution of hydroxylamine hydrochloride (1.1 g, 15.8 mmol) in 1.0 N NaOH (29.1 mL, 29.1 mmol). The resulting mixture was stirred for 16 hours (25° C.). The resulting slurry was filtered and the crystals were washed with cold water and dried in a vacuum oven at 40° C. (24 hours) to yield 2.4 g (71.9%) of 3-amino-5-dodecyl-isoxazole as white platelets; m.p. 79.5°-81° C.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:8])[CH2:6][SH:7])(=[O:3])[CH3:2].[C:9]1([CH2:15][C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5](=[O:8])[CH2:6][S:7][C:16](=[O:17])[CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(=O)NC(=O)CS
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)NC(=O)CSC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 0.10 mole of N-acetyl-2-mercapto acetamide in 150 ml. of chloroform is added 0.1 mole of phenyl acetylchloride followed by 0.1 mole of triethylamine. The reaction mixture is stirred at ambient temperature for 1 hour and then concentrated to dryness. Chromatograph of the residue on 500 g. of silica gel eluting with ethylacetate in hexane (25-75%) gives N-acetyl-2-(phenylacetylthio) acetamide.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([OH:20])=O)[N:3]=1.[CH3:21][NH:22][C:23](=[O:30])[C@H:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[NH2:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:10][C:5]2=[C:4]([C:18](=[O:20])[NH:25][C@@H:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([NH:22][CH3:21])=[O:30])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Br)nc(C(=O)O)c2C1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CNC(=O)[C@@H](NC(=O)c1nc(Br)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
Acid Intermediate 1I (0.62 g, 1.79 mmol) was dissolved in DMF and L-tert-Leucine methylamide (0.31 g, 2.14 mmol) was added followed by DIEA (0.94 mL, 5.37 mmol). The resulting mixture was stirred for 20 minutes, HBTU (0.75 g, 1.97 mmol) was added in one portion and the mixture was stirred overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, then brine, and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by normal phase chromatography, eluting with a 0-10% methanol/DCM gradient to provide product Intermediate 1J as an off-white solid (0.68 g, 80%).
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:10](OCC)(=[O:15])[CH2:11][C:12]([CH3:14])=O.S(=O)(=O)(O)O.O.C([O-])(=O)C.[Na+]>>[OH:2][C:1]1[CH:9]=[C:7]([OH:8])[CH:6]=[C:4]2[C:3]=1[C:12]([CH3:14])=[CH:11][C:10](=[O:15])[O:5]2
Reactant: Oc1cc(O)cc(O)c1
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(=O)oc2cc(O)cc(O)c12
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 2.77 g (22 mmol) of phloroglucinol and 2.6 g (20 mmol) of ethyl acetoacetate were melted together, the mixture was cooled, and 40 ml of a mixture of sulfuric acid/water (75% w/w) was added rapidly to the semi-solid mass. The mixture was stirred for 24 h, during which time a semi-solid mass formed. It was poured into a mixture of ice/water (300 ml) containing 5 g of sodium acetate and the precipitate was recovered by suction filtration.