Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[OH-].[Na+].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1B(O)O.[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCCC1.O.O1CCOCC1.ClCCl.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]>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: Brc1ccncc1
Reactant: OB(O)c1c(F)cccc1F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Fc1cccc(F)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.8 %

Procedure:
A suspension of 4-bromopyridine hydrochloride (6.81 g, 35 mmol) in tetrahydrofuran (100 ml) was treated with sodium hydroxide (8.75 ml of a 4 N solution in water) and this mixture was stirred at ambient temperature for 5 min. 2,6-Difluorobenzeneboronic acid (6.36 g, 40 mmol) and potassium fluoride (6.71 g, 116 mmol) were added and this mixture was degassed with nitrogen for 10 min before adding tris(dibenzylideneacetone)dipalladium(0) (640 mg, 0.7 mmol) followed by tri-tert-butylphosphine (7 ml of a 0.2 M solution in 1,4-dioxane, 1.4 mmol). This mixture was stirred at ambient temperature for 15 min then heated at 50° C. for 30 min. The reaction mixture was diluted with dichloromethane then extracted with ice-cold 1 N sodium hydroxide solution (×2). The organics were dried over anhydrous magnesium sulphate, filtered and pre-adsorbed onto silica. Purification by chromatography (silica gel, 20–30% EtOAc/isohexane containing 0.5% methanol and 0.5% triethylamine) gave 4-(2,6-difluorophenyl)pyridine as a white solid (3.2 g, 48%): 1H NMR (360 MHz, CDCl3) δ 6.99–7.06 (2H, m), 7.32–7.39 (1H, m), 7.40–7.42 (2H, m), 8.71 (2H, d, J 6).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.CC(O)=O.C(O[C:39]1(O[Si](C)(C)C)[CH2:41][CH2:40]1)C.[BH3-]C#N.[Na+].[NH4+].[Cl-]>C(Cl)Cl.CO.C1COCC1>[CH:39]1([N:29]2[CH2:30][CH2:31][CH:26]([CH2:25][N:23]3[CH:24]=[C:20]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([S:11]([C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)(=[O:12])=[O:13])[CH:7]=4)[CH:21]=[N:22]3)[CH2:27][CH2:28]2)[CH2:41][CH2:40]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCNCC3)c2)c2ccc(F)cc21
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCN(C4CC4)CC3)c2)c2ccc(F)cc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
A mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole (Intermediate 21; 277 mg; 0.63 mmol), HOAc (121 mg; 2.01 mmol), (1-ethoxycyclopropoxy)trimethylsilane (220 mg; 1.26 mmol) and NaBH3CN (60 mg; 0.95 mmol) in DCM/MeOH/THF (10 ml/1 ml/15 ml) was stirred at 70° C. overnight. The reaction mixture was added saturated aqueous NH4Cl (20 mL), extracted with EtOAc (50 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by reverse phase flash chromatography to afford 137 mg (45%) of the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O>>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Brc1ccccn1
Product: Fc1ccccc1-c1ccccn1

Procedure:
2-Bromopyridine and 2-fluorobenzeneboronic acid were coupled using the procedure described in Example 43 to afford 2-(2-fluorophenyl)pyridine as a pale yellow oil which crystallised on standing: δH (400 MHz, CDCl3) 7.13-7.19 (1H, m), 7.24-7.28 (2H, m), 7.35-7.41 (1H, m), 7.73-7.81 (2H, m), 7.97 (1H, ddd, J 8, 8 and 2), 8.72-8.74 (1H, m); m/z (ES+) 174 (M++H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[F:44][C:45]([F:57])([F:56])[C:46]1[CH:51]=[CH:50][C:49]([CH2:52][C:53](O)=[O:54])=[CH:48][CH:47]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:53](=[O:54])[CH2:52][C:49]3[CH:48]=[CH:47][C:46]([C:45]([F:56])([F:44])[F:57])=[CH:51][CH:50]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1ccc(C(F)(F)F)cc1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 67.2 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 4-(trifluoromethyl)phenylacetic acid (0.6 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) then washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 4:6) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(4-trifluoromethyl-phenyl)-acetamide (0.7 g, 71%) as a white solid: mp 144-146° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=5.58 min. (97%); 1H NMR (DMSO-d6) δ 2.03-2.08 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.91 (m, 1H), 3.66 (s, 2H), 4.74 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.50-7.82 (m, 7H), 8.75 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.94, 30.90, 37.89, 41.75, 48.83, 121.93, 124.95 (125.01, 125.05, 125.10), 122.56 (126.16), 126.96 (127.15, 127.38), 129.94, 131.52, 133.26, 134.69, 138.95, 140.95, 166.88, 167.41, 169.78, 169.87, 172.73; Anal. Calcd. for C23H18N3O5F3: C, 58.35; H, 3.83; N, 8.88; F, 12.04. Found: C, 58.19; H, 3.53; N, 8.73; F, 12.07.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:14][C:15]#[N:16]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13](/[C:14](=[CH:7]/[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)/[C:15]#[N:16])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccccn1
Product: COc1ccc(/C(C#N)=C/c2ccccn2)cc1OC
Yield: 70.9 %

Procedure:
2-Pyridinecarboxaldehyde (2.14 g) was condensed with 3,4-dimethoxybenzyl cyanide (3.54 g) through Method A (production step 2), to thereby yield the target product (yield: 3.77 g, 71%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:21][N:22]1[C:26]([CH2:27][CH:28]([C:30]2[S:31][CH:32]=[CH:33][N:34]=2)O)=[CH:25][N:24]=[CH:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]([O:18][CH:28]([C:30]3[S:31][CH:32]=[CH:33][N:34]=3)[CH2:27][C:26]3[N:22]([CH3:21])[CH:23]=[N:24][CH:25]=3)=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(O)ccc1CCc1ccc(F)cc1
Reactant: Cn1cncc1CC(O)c1nccs1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC(Cc2cncn2C)c2nccs2)ccc1CCc1ccc(F)cc1
Temperature: 25 °C
Yield: 66.6 %

Procedure:
A mixture of methyl 2-(4-fluorophenethyl)-5-hydroxybenzoate (1.83 g, 6.7 mmol), 2-(1-methylimidazol-5-yl)-1-(thiazol-2-yl)ethanol (1.40 g, 6.68 mmol) and triphenylphosphine (2.10 g, 8.0 mmol) in tetrahydrofuran (25 ml) was stirred at ambient temperature under a nitrogen atmosphere. DEAD (1.39 g, 1.25 ml 8.0 mmol) was added dropwise to the solution. (The reaction was maintained at ambient temperature ±2° C.). The orange solution was then stirred at ambient temperature under a nitrogen atmosphere for 16 hours. The tetrahydrofiran solution was evaporated to dryness to give an oil. Purification by flash column chromatography eluting with ethyl acetate, ethyl acetate/methanol (9:1 and 4:1) gave methyl 2-(4-fluorophenethyl)-5-[2-(1-methylimidazol-5-yl)-1-(thiazol-2-yl)ethoxy]benzoate (2.07 g, 67%) as a clear oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1.[H][H]>[Pd].C(O)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=1
Reactant: COC(=O)Cc1ccc(C#CCCO)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)Cc1ccc(CCCCO)cc1
Yield: 99.3 %

Procedure:
A solution of methyl 4-(4-hydroxybutyn-1-yl)phenylacetate (178 mg, 0.82 mmole) and 10% palladium on carbon (30 mg) in ethanol (2 mL) were stirred under a balloon of hydrogen for 3 days at room temperature. The mixture was filtered and the filtrate concentrated in vacuo to give the title compound (181 mg) as an oil. NMR (CDCl3): δ 1.52 (s, 1H); 1.64 (m, 2H); 1.71 (m, 2H); 2.65 (t, 2H); 3.61 (s, 2H); 3.68 (t, 2H); 3.71 (s, 3H); 7.15 (d, 2H); 7.21 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]>C1COCC1.C(O)C.[Ni]>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1cc(F)cc([N+](=O)[O-])c1N
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: NC(=O)c1cc(F)cc(N)c1N
Reaction time: 5 h

Procedure:
To a solution of EXAMPLE 45C (11.2 g) in a mixture of THF (50 mL) and ethanol (50 mL) was added Raney nickel (50% in water, 11.0 g). The mixture was stirred under hydrogen (60 psi) for 5 hours. Solid material was filtered off and the filtrate was concentrated.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:16]([N:18]2[CH:22]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:21][CH:20]=[N:19]2)=[O:17])[CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1>[CH:1]1([CH2:6][C@@H:7]([C:16]([N:18]2[CH:22]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:21][CH:20]=[N:19]2)=[O:17])[CH2:8][C:9]([OH:11])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)N1CCOCC1
Reaction time: 4 h
Yield: 100 %

Procedure:
To 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-[5-(4-morpholinylcarbonyl)-4,5-dihydro-1H-pyrazol-1-yl]-4-oxobutanoate (244 mg, 0.58 mmol) in 1,4-dioxane (5.0 mL) was added 4.0 M hydrochloric acid in 1,4-dioxane (7.25 mL, 29.0 mmol) at room temperature. The resulting reaction mixture was stirred for 4 hours. The solvent was then removed by reduced pressure to afford the crude product (3R)-3-(cyclopentylmethyl)-4-[5-(4-morpholinylcarbonyl)-4,5-dihydro-1H-pyrazol-1-yl]-4-oxobutanoic acid (212 mg, 0.58 mmol, 100% yield), which was used directly in the next step. MS: 366 ([M+H]+).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH:3]([OH:5])[CH3:4].[C:7](O)(=[O:11])/[CH:8]=[CH:9]/[CH3:10]>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:4][CH:3]([O:5][C:7](=[O:11])[CH:8]=[CH:9][CH3:10])[CH:2]([CH3:6])[CH3:1]
Reactant: CC(C)C(C)O
Reactant: C/C=C/C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=CC(=O)OC(C)C(C)C
Yield: 52.4 %

Procedure:
3-Methyl-butan-2-ol (180 g), crotonic acid (165 g), toluene (200 mL), and PTSA (8 g) were charged into to a 2-L reaction flask fitted with a Bidwell-Sterling trap. The reaction mixture was heated to reflux. Water was collected and removed via the Bidwell-Sterling trap. The reaction mixture was aged at reflux for about 13-15 hours till GC analysis showed completion of the reaction. The resulting reaction mixture was washed sequentially with brine, sodium carbonate (Na2CO3), and brine, and further purified by fractional distillation to provide but-2-enoic acid 1,2-dimethyl-propyl ester (157 g) with a boiling point of 53° C. at 0.77 mmHg.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][C@@H:37]4[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:39][CH2:38]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)cc1F
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c12) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless foam.
Reaction SMILES: [CH2:1]([N:8]1[CH2:22][CH2:21][CH2:20][C@H:9]1[C:10](OCC1C=CC=CC=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:22][CH2:21][CH2:20][CH:9]1[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A solution (0.06M) of benzyl 1-benzylprolinate in THF was cooled in an ice bath and treated with LiAlH4 (3 eq). The resulting mixture was stirred at RT for 3 h, before being quenched by the addition of H2O. The resulting mixture was stirred at RT for 30 min and then filtered through a pad of Solka-Floc and the filtrate concentrated in vacuo. The crude was purified by FC (PE/EtOAc 6:4+1% NEt3) to afford the title compound as an off-white solid (62%). 1H NMR (400 MHz, CDCl3) 1.66-1.81 (m, 2H), 1.82-1.97 (m, 2H), 2.25-2.34 (m, 1H), 2.40-2.53 (m, 1H), 2.71-2.77 (m, 1H), 2.94-3.01 (m, 1H), 3.34-3.39 (m, 1H), 3.40-3.45 (m, 1H), 3.63-3.68 (m, 1H), 3.95-3.99 (m, 1H), 7.26-7.30 (m, 5H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[O:35][CH3:36].O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)=[CH:28][C:27]=1[O:35][CH3:36]
Reactant: COc1cc(B(O)O)ccc1Cl
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(-c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3cc(C)nn23)ccc1Cl
Temperature: 110 °C
Yield: 40.4 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 80 mg, 0.232 mmol), 4-chloro-3-methoxyphenylboronic acid (56.2 mg, 0.302 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (16 mg, 22 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.774 mL of 1,4-dioxane and 0.387 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (65-70% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (42.3 mg, 40%). 1H NMR (DMSO-d6) δ: 11.15 (s, 1H), 7.95 (d, J=8.6 Hz, 2H), 7.91 (s, 1H), 7.78 (d, J=1.8 Hz, 1H), 7.59-7.65 (m, 1H), 7.50-7.59 (m, 3H), 6.34 (s, 1H), 3.88 (s, 3H), 2.34 (s, 3H), 1.39 (s, 6H); ESI-MS: m/z 451.1 (M+H)+.
Reaction SMILES: N([O-])=O.[Na+].[CH2:5]([C:7]1[CH:12]=[CH:11][C:10](N)=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])[CH3:6].[ClH:17].NC(N)=O>O>[Cl:17][C:10]1[CH:11]=[CH:12][C:7]([CH2:5][CH3:6])=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=1
Reactant: CCc1ccc(N)cc1[N+](=O)[O-]
Reactant: Cl
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
A solution of sodium nitrite (0.11 g, 1.32 mmol) in water (1 mL) was added, dropwise, at 0° C., to a suspension of 4-ethyl-3-nitro-phenylamine (80%, 0.25 g, 1.20 mmol) in a mixture of concentrated hydrochloric acid (2 mL) and water (4 mL). The reaction mixture was stirred at 0° C. for 5 minutes and then urea (15 mg, 0.24 mmol) was added. The resulting mixture was stirred for 10 minutes and then was poured into a suspension of cuprous chloride (0.18 g, 1.8 mmol) in a mixture of concentrated hydrochloric acid (1.5 mL) and water (0.6 mL) at 80° C. The reaction mixture was stirred at 80° C. for 2 hours and then was extracted with ethyl acetate. The organic extracts were washed with an aqueous solution of sodium hydroxide (1 M) and water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 200 mg (90% yield) of 4-chloro-1-ethyl-2-nitro-benzene as an oil.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29](=[O:45])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37]C(OC(C)(C)C)=O)[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:46]=[CH:47][CH:48]=[CH:49][C:4]=2[NH:3]1>Cl>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@@H:18]([C:29](=[O:45])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:46]=[CH:47][CH:48]=[CH:49][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)NCCCCCCNC(=O)OC(C)(C)C)cc(C)c1O
Agent: Cl
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)NCCCCCCN)cc(C)c1O

Procedure:
A solution of 55 mg (0.08 mmol) (R)-1-(6-tert-butoxycarbonylamino-hexylcarbamoyl)-2-(4-hydroxy-3,5-dimethyl-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1.8) in 1 mL of 1M HCl was stirred overnight at RT. The reaction solution was lyophilised and the residue was purified by HPLC. The fractions containing the product were combined and again lyophilised.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([NH2:7])=[O:6].[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O>>[Cl:12][CH2:13][C:14]1[N:7]=[C:5]([C:4]2[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[CH:3]=2)[O:6][CH:16]=1
Reactant: Cc1cc(C)cc(C(N)=O)c1
Reactant: O=C(CCl)CCl
Product: Cc1cc(C)cc(-c2nc(CCl)co2)c1
Yield: 52 %

Procedure:
In substantially the same manner as in Reference Example 31, 3,5-dimethylbenzamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(3,5-dimethylphenyl)oxazole. The yield was 52%. Recrystallization from isopropyl ether gave colorless needles, mp 76-77° C.
Reaction SMILES: N1C=CC=CC=1P([CH2:14][P:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)C1C=CC=CC=1.ClCCl>ClCCCl>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[P:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:14][CH2:14][P:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(P(CP(c2ccccc2)c2ccccn2)c2ccccn2)cc1
Solvent: ClCCCl
Solvent: ClCCl
Product: c1ccc(P(CCP(c2ccccc2)c2ccccn2)c2ccccn2)cc1

Procedure:
An amount of 1,2-bis[(2-pyridyl)(phenyl)phosphino]ethane was prepared substantially in the same way as the diphosphine of Example 2, except that, instead of dichloromethane, 1,2-dichloroethane was employed.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]3([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:26](Cl)(=O)C(Cl)=O.CO.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[CH3:26][O:22][C:21]([C:15]1([CH2:14][S:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:25][CH:24]=3)=[CH:12][CH:11]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:23]
Reactant: O=C(O)C1(CSc2ccc(Oc3ccc(Cl)cc3)cc2)CCOCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(CSc2ccc(Oc3ccc(Cl)cc3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-[4-(4-chlorophenoxy)phenylthiomethyl]tetrahydropyran-4-carboxylic acid (580 mg, 1.53 mmol) and N,N-dimethylformamide catalyst (22 μL) in methylene chloride (15 mL) at 0° C. was added oxalyl chloride (0.33 mL, 3.83 mmol) dropwise over 10 minutes. The mixture was warmed to room temperature over 1 hour, the partial slurry stirred an additional 12 hours, and concentrated in vacuo until the theoretical mass of the acid chloride was obtained. The residue was suspended intetrahydrofuran (7.5 mL), and methanol (0.19 mL, 4.59 mmol), followed by triethylamine (0.64 mL, 4.59 mmol) was added. The mixture was heated to reflux for 14 hours, concentrated, and the resulting residue partitioned between methylene chloride (150 mL) and 1M aqueous hydrochloric acid (50 mL). The aqueous layer was back extracted with additional portions of methylene chloride (2×30 mL), the combined extracts dried over magnesium sulfate, and concentrated to afford crude 4-[4-(4-chlorophenoxy)phenylthiomethyl]-tetrahydropyran-4-carboxylic acid methyl ester, which was taken directly into the next reaction without further purification. 1HNMR (CDCl3) δ 1.62. (m, 2H), 2.15 (dm, J=13.6 Hz, 2H), 3.13 (s, 2H), 3.47 (td, J=11.9, 2.4 Hz, 2H), 3.59 (s, 3H), 3.81 (dt, J=12.0, 4.1 Hz, 2H), 6.92 (d, J=8.9 Hz, 2H), 7.29 (d, J=8.8 Hz, 2H), 7.36 (d, J=8.8 Hz, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])(C)(C)C.CC1(C)O[C:29](=[O:31])[CH:28]=[C:27]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:16]1([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:27]([C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)[CH2:28][C:29](=[O:31])[NH:22][C:9]=3[CH:10]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2ccncc2)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2ccncc2)=Nc2ccc(C#Cc3ccccc3)cc2N1

Procedure:
Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G2) and 2,2-dimethyl-6-pyridin-4-yl-[1,3]dioxin-4-one (Example J9) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a brown solid (50 mg).