Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:9]=1[O:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].O.O.Cl[Sn]Cl>CCO>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:9]=1[O:10][CH2:11][CH2:12][N:13]([CH3:14])[CH3:15]
Reactant: CN(C)CCOc1ccc([N+](=O)[O-])cc1-c1c(Br)cnn1C
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CN(C)CCOc1ccc(N)cc1-c1c(Br)cnn1C
Yield: 57.1 %

Procedure:
{2-[2-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-nitro-phenoxy]-ethyl}-dimethyl-amine (0.128 g, 0.35 mmol) was treated with SnCl2.2H2O (0.319 g, 1.39 mmol, 4.0 equiv.) in EtOH (20 mL), in a similar manner as described in Example 1.1, providing 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-dimethylamino-ethoxy)-phenylamine (0.067 g, 0.20 mmol, 56%) as an oil. LCMS m/z (%)=339 (M+H79Br, 78), 341 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 7.68 (dd, J=2.5, 8.9 Hz, 1H), 7.55 (s, 1H), 7.45-7.51 (m, 2H), 4.62-4.82 (m, 2H), 3.76 (s, 3H), 3.65-3.76 (m, 2H), 2.87 (s, 6H). The intermediate {2-[2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-nitro-phenoxy]-ethyl}-dimethyl-amine was prepared in the following manner:
Reaction SMILES: [C:1]([C:3]1[CH:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14](C(OC(C)(C)C)=O)[N:13]=[C:12]3[NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[C:7]([C:32]#[N:33])=[C:6]([CH3:34])[NH:5][C:4]=1[CH3:35])#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[C:7]([C:32]#[N:33])=[C:6]([CH3:34])[NH:5][C:4]=1[CH3:35])#[N:2]
Reactant: CCCS(=O)(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)Nc1n[nH]c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
57.8 mg (0.12 mmol) tert-butyl 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-3-[(propyl-sulfonyl)amino]-1H-indazole-1-carboxylate (Example 20A) were dissolved in dichloromethane (4 ml) and treated with 0.1 ml (1.28 mmol) trifluoroacetic acid. The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (acetonitrile/water gradient) to give 13 mg (29% of th.) of the title compound.
Reaction SMILES: [CH2:1]1[CH:14]2[C:5](C(OCC)=O)([C:6]3[C:11]([CH2:12][CH2:13]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4][CH:3]=[CH:2]1.[N-:20]=[C:21]=[O:22].[C:23]1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>>[N:20]([C:5]12[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]([CH3:23])[CH2:13][CH:14]1[CH2:1][CH:2]=[CH:3][CH2:4]2)=[C:21]=[O:22]
Reactant: CCOC(=O)C12CC=CCC1CCc1ccccc12
Reactant: [N-]=C=O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: CC1CC2CC=CCC2(N=C=O)c2ccccc21
Yield: 74 %

Procedure:
The unsaturated carboxylic acid (1.5 g, 6.2 mmol) derived from hydrolysis of the product from Example 29 was converted to the isocyanate with diphenylphosphorylazide (1.87 g, 6.8 mmol) according to the method used in Example 31. Purification by silica gel chromatography gave the title compound as a clear oil (1.1 g, 74%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10](NC2C=CC=CC=2N)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:24]([CH2:27][CH3:28])CC.[C:29](Cl)(Cl)=[O:30]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]1[N:24]1[C:27]2[CH:28]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8][C:29]1=[O:30])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccccc2N)C1
Reactant: O=C(Cl)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1n1c(=O)[nH]c2ccccc21
Reaction time: 2 h
Yield: 60 %

Procedure:
To a solution of 3(R)-(2-Amino-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (52 mg, 0.18 mmol), Et3N (1.0 ml) in CH2Cl2 (1 ml) at 0° C. was added a solution of phosgene (20% in toluene, 0.1 ml). After stirring for 2 hr and evaporation of solvent, the residue was purified by chromatography (1%-2% MeOH in CH2Cl2) to give a colorless oil (34 mg, 60%). 1H-NMR (300 MHz, CDCl3) δ 7.80 (d, 1H), 4.20 (m, 3H), 3.50 (m, 1H), 2.75 (m, 1H), 2.65 (m, 1H), 2.10 (m, 1H), 1.90 (m, 1H), 1.70 (m, 1H), 1.50 (s, 9H) ppm; IR (film) 3067, 2975, 2935, 2858, 1745, 1692, 1612, 1487, 1423, 1383, 1347, 1266, 1246, 1158 cm−1; LRMS (calculated for C17H23N3O3—BOC)+ 217. found 217.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:11]([C:12]#[N:13])=[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:9][C:8]=2[C:20]([O:22]CC)=[O:21])=[CH:4][C:3]=1[F:27].O1CCCC1.CO.[OH-].[Na+].O>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:11]([C:12]#[N:13])=[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:9][C:8]=2[C:20]([OH:22])=[O:21])=[CH:4][C:3]=1[F:27]
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1Cc1ccc(Cl)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1Cc1ccc(Cl)c(F)c1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
To a solution of ethyl 3-(4-chloro-3-fluorobenzyl)-4-cyano-5-morpholin-4-ylthiophene-2-carboxylate in tetrahydrofuran (5.64 mL, 69.6 mmol) was added methanol (2.5 mL, 62 mmol) and 1 M sodium hydroxide in water (4.23 mL, 4.23 mmol) and the resulting suspension was stirred at room temp. The reaction was stirred for 16 hours at room temperature. Volatiles were then removed in vacuo, and the residue diluted with EtOAc (30 mL). Mixture was then transferred to a separatory funnel containing 1N HCl (5.0 mL) and water (10 mL), at which time the pH of aqueous layer was measured at ˜2.0. Layers were separated, and the aqueous layer was extracted 3×20 mL with EtOAc. Combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo. Resulting residue was adsorbed to celite, and the resulting solid was placed into a dryload cartridge and purified via column chromatography (gradient elution, 0-5% MeOH:CH2Cl2) to afford 3-(4-chloro-3-fluorobenzyl)-4-cyano-5-morpholin-4-ylthiophene-2-carboxylic acid (94) as a white solid (0.128 g, yield 66.3%). LCMS: (FA) ES+ 381, 383; 1H NMR (400 MHz, DMSO) δ 13.25 (s, 1H), 7.52 (dd, J=8.1, 8.1, 1H), 7.22 (dd, J=1.9, 10.5, 1H), 7.05 (dd, J=1.5, 8.3, 1H), 4.31 (s, 2H), 3.80-3.65 (dd, J=4.5, 5.2, 4H), 3.59-3.47 (dd, J=4.5, 5.2, 4H).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:28][OH:29]>CCCCCC.C(OCC)(=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:28][O:29][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: OCc1ccc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Clc1ccc(-c2cnc(OCc3ccc(Cl)c(Cl)c3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylthio-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (from Reference Example 3) was reacted with 3,4-dichlorobenzyl alcohol according to the procedures described in Example 1 to afford 2-(3,4-dichlorobenzyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine as the higher Rf product (95/5 hexane/ethyl acetate TLC). HPLC/MS: m/e=511 (M+); Rt=5.07 min; 1H-NMR 500 MHz (CDCl3): δ 5.47 (s, 2H), 7.04 (d, J=9 Hz, 2H), 7.21 (d, J=9 Hz,1H), 7.22-7.30 (m, 3H), 7.38 (m, 2H), 7.43 (d, J=9 Hz, 1H), 7.66 (d, J=2 Hz,1H), 8.61 (s, 1H). 2-(3,4-Dichlorobenzyloxy)-4-(2-chloro-4-thiomethyl-phenyl)-5-(4-chlorophenyl)pyrimidine was obtained as the lower Rf product which was the by-product of the thiomethyl anion displacement of the 4-chloro substituent on the 4-(2,4-dichlorophenyl) ring. HPLC/MS: m/e=523 (M+1); Rt=4.93 min; 1H-NMR 500 MHz (CDCl3): δ 2.52 (s, 3H), 5.48 (s, 2H), 7.0-7.10 (m, 1H), 7.15-7.21 (m, 2H), 7.24-7.30 (m, 3H), 7.40-7.60 (m, 3H), 7.68 (d, J=2 Hz,1H), 860 (s, 1H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].[CH3:32][N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:39][CH:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)=[O:27])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: CN1CCC(N)CC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NC3CCN(C)CC3)cn2)c1O

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-methylpiperidin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.71-1.85 (m, 2H) 1.92-2.14 (m, 2H) 2.38-2.47 (m, 3H) 2.70-2.89 (m, 3H) 3.06-3.18 (m, 2H) 3.24-3.40 (m, 1H) 3.49 (d, J=11.87 Hz, 1H) 3.98-4.24 (m, 1H) 7.67 (d, J=7.58 Hz, 1H) 7.71-7.87 (m, 2H) 8.21 (d, J=12.13 Hz, 1H) 8.35-8.59 (m, 2H) 8.72 (d, J=6.32 Hz, 1H) 8.88-8.98 (m, 1H) 9.46 (br. s., 1H) 12.72-13.42 (m, 1H). MS m/z [M+H]+ 417.2.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:11][SiH:12]([CH3:17])N[SiH](C)C>>[C:1]1([C:7]#[C:8][CH2:9][O:10][SiH:12]([CH3:17])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: OCC#CC1=CCCCC1
Reactant: C[SiH](C)N[SiH](C)C
Product: C[SiH](C)OCC#CC1=CCCCC1
Yield: 176 %

Procedure:
3-Cyclohexenylprop-2-yn-1-ol (2.509 g, 26.10 mmol) and 1,1,3,3-tetramethyldisilazane (1.527 g, 11.45 mmol) were used according to the method mentioned above to produce the title compound as a brown clear liquid (3.916 g, 20.15 mmol, 77.2%). The crude reaction mixture was analyzed by 1H NMR to confirm the product formation and used in KOtBu catalyzed transhydrosilylation reaction.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:53]1([S:58]([NH:61][C:62]([C@@:64]2([NH:69][C:70]([C@@H:72]3[CH2:83][C@:75]4([C:80]([CH3:82])([CH3:81])[C:76]54[CH2:79][CH2:78][CH2:77]5)[CH2:74][N:73]3[C:84](=[O:91])[C@@H:85]([NH2:90])[C:86]([CH3:89])([CH3:88])[CH3:87])=[O:71])[CH2:66][C@H:65]2[CH:67]=[CH2:68])=[O:63])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55][CH2:54]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:90][C@H:85]([C:84]([N:73]1[C@H:72]([C:70](=[O:71])[NH:69][C@:64]2([C:62]([NH:61][S:58]([N:53]3[CH2:54][CH2:55][CH2:56][CH2:57]3)(=[O:60])=[O:59])=[O:63])[CH2:66][C@H:65]2[CH:67]=[CH2:68])[CH2:83][C@:75]2([C:80]([CH3:82])([CH3:81])[C:76]32[CH2:79][CH2:78][CH2:77]3)[CH2:74]1)=[O:91])[C:86]([CH3:89])([CH3:88])[CH3:87])[C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1(C)CCCCC1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](N)C(C)(C)C)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C1(C)CCCCC1)C(C)(C)C)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Reaction time: 15 h

Procedure:
A solution of (S)-tert-Butoxycarbonylamino-(1-methyl-cyclohexyl)-acetic acid (0.217 g; 0.80 mmol) (prepared according to Tetrahedron Let. 2007, 48, 6343-6347) and HATU (0.38 g; 1.00 mmol) in DCM (10 mL) was stirred for 20 min at ambient temperature. After addition of DIPEA (0.698 mL; 4.00 mmol) and (5R,8S)-7-((S)-2-Amino-3,3-dimethyl-butyryl)-10,10-dimethyl-7-aza-dispiro[3.0.4.1]decane-8-carboxylic acid [(1R,2S)-1-(pyrrolidine-1-sulfonylaminocarbonyl)-2-vinyl-cyclopropyl]-amide (0.400 g; 0.67 mmol) in DCM (10 mL) the reaction mixture was stirred for 15 h, the solvent was removed in vacuo and the residue was purified by preparative HPLC (method L) to yield the title compound. LC-MS (method E): Rt=2.91 min; M/z=818 [M+H], HPLC (method A3) Rt=7.18 min
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[OH-].[NH4+:12].O>C1COCC1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:12])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1ccc(I)cc1
Reaction time: 3 h
Yield: 97 %

Procedure:
Crude 4-iodobenzoyl chloride (11.4 g, 42.7 mmol) in THF (75 mL), prepared above, was treated with ammonium hydroxide (5 mL) followed by water (40 mL) at ambient temperature. The reaction mixture was stirred for 3 hours and then partitioned between EtOAc (50 mL) and brine (50 mL). The phases were separated and the organic phase was washed with 10% aqueous NaHCO3 solution (30 mL) and brine (30 mL), dried over Na2SO4, and filtered. The filtrate volume was reduced until a white solid precipitated from solution. The white solid was collected by filtration and washed with diethyl ether to provide the desired product (10.2 g, 41.4 mmol, 97%).
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][CH:22]([C:26](O)=[O:27])[C:23](O)=[O:24]>>[OH:27][C:26]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:23](=[O:24])[C:22]=1[S:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH3:14]
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: Cc1ccccc1SC(C(=O)O)C(=O)O
Product: Cc1ccccc1Sc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(2-methylphenyl)thio]propanedioic acid (1.43 g, 5.07 mmol). m.p. 210-211° C.; 1H NMR (400 MHz, DMSO-d6) δ2.47 (s, 3H), 6.82 (s, 1H), 6.86 (d, 1H), 7.04 (m, 2H), 7.17 (d, 1H), 7.56 (m, 3H), 7.86 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12]CC)=O.[H-].[Na+].[CH3:17]I.CN.O.[CH3:22][N:23](C=O)C>C1COCC1.O>[CH3:22][NH:23][C:10]([C:2]1[N:1]([CH3:17])[C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: CI
Reactant: CN(C)C=O
Agent: CN
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
To a stirred solution of ethyl indole-2-carboxylate (25.0 g, 132.1 mmole) in dry DMF (100 mL) at 5° C. was added 60% NaH (6.9 g, 171.7 mmole). After 10 min, methyl iodide (56.2 g, 396.3 mmole) was added and the reaction slurry was allowed to warm RT and stirred for 12 hr. The reaction contents were poured into H2O (200 mL) and extracted with EtOAc (2×150 mL). The combined organic phases were washed sequentially with H2O and brine, then were dried over Na2SO4. Concentration under reduced pressure gave a yellow oil. This oil was suspended in a 40% methylamine/H2O solution (100 mL) containing THF (50 mL) and stirred vigorously at RT for 24 hr. The reaction solution was concentrated under vacuum to remove the THF and then poured into H2O (400 mL). The precipitate was filtered, washed with H2O and dried under vacuum at RT to afford the title compound (23.3 g, 94%) as a white solid: MS (ES) m/e 189 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Si:8]([O:15][C@H:16]1[CH2:20][N:19](C(OC(C)(C)C)=O)[CH:18]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])[CH2:17]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C(Cl)[Cl:37]>>[ClH:37].[Si:8]([O:15][C@H:16]1[CH2:20][NH:19][CH:18]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])[CH2:17]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC1c1cc(F)ccc1F
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)O[C@H]1CNC(c2cc(F)ccc2F)C1
Product: Cl
Reaction time: 2 h

Procedure:
TFA (0.27 mL, 0.414 g, 3.63 mmol) was added to a solution of (4R)-tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2-(2,5-difluorophenyl)pyrrolidine-1-carboxylate (0.5 g, 1.21 mmol) in DCM (10 mL) at 0° C. and stirring was continued at 28° C. for 2 hr. Reaction mixture was concentrated under reduced pressure to afford (4R)-4-((tert-butyldimethylsilyl)oxy)-2-(2,5-difluorophenyl)pyrrolidine hydrochloride (Int-57).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[N:11]2[CH3:20])=[CH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]([O:31]C(C)(C)C)=[O:30]>CN(C=O)C.CCOC(C)=O>[CH3:20][N:11]1[C:12](=[O:19])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]1[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:28][C:29]([OH:31])=[O:30])[CH:2]=1
Reactant: CN1C(=O)c2ccccc2C1c1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)c2ccccc2C1c1cn(CC(=O)O)c2ccccc12
Temperature: 100 °C

Procedure:
The product from example 20, step b) (450 mg, 1.72 mmol) was dissolved in DMF and treated with K2CO3 (284 mg, 2.06 mmol) followed by t-butyl bromoacetate (255 μL, 1.72 mmol). The reaction was heated to 100° C. for 5 h. The reaction was cooled, diluted with EtOAc, washed 3 times with water, and concentrated. The crude product was treated with TFA (neat) at room temperature for 45 minutes. The reaction was then concentrated to dryness and purified by preparative LCMS to give the title compound. 1H NMR (CD3OD) δ 7.74-7.78 (m, 1H), 7.43 (t, J=3.7 Hz, 1H), 7.41 (t, J=3.6 Hz, 1H), 7.36 (s, 1H), 7.28-7.31 (m, 1H), 7.20 (d, J=8.1 Hz, 1H), 6.96 (t, J=7.2 Hz, 1H), 6.67 (t, J=7.2 Hz, 1H), 6.48 (d, J=7.8 Hz, 1H), 4.62 (s, 2H), 2.78 (s, 3H); MS: ESI (negative): 319 (M−H).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]5[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([C:37]#[N:38])[CH:3]=1.[CH:39]1(B(O)O)[CH2:41][CH2:40]1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC.C(OCC)(=O)C.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>[C:37]([C:4]1[CH:3]=[C:2]([CH:39]2[CH2:41][CH2:40]2)[C:10]2[O:9][C:8]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]5[N:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][N:26]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=1)#[N:38]
Reactant: OB(O)C1CC1
Reactant: N#Cc1cc(Br)c2oc(-c3ccc(C(=O)NCC4CCN(c5nccc(C(F)(F)F)n5)CC4)cc3)nc2c1
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: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(C2CC2)c2oc(-c3ccc(C(=O)NCC4CCN(c5nccc(C(F)(F)F)n5)CC4)cc3)nc2c1
Reaction time: 96 h

Procedure:
A mixture of 4-(7-bromo-5-cyano-1,3-benzoxazol-2-yl)-N-({1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methyl)benzamide (EXAMPLE 113, Step A) (59 mg, 0.10 mmol), cyclopropylboronic acid (86 mg, 1.0 mmol), potassium carbonate (138 mg, 1.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) in dimethoxyethane (7 ml)/water (0.7 ml) was heated to reflux and stirred at this temperature for 4 d. The mixture was diluted with ethyl acetate, filtered, and concentrated. The residue was purified by flash column chromatography to afford the title compound. Mass spectrum (ESI) 547.2 (M+1). 1H NMR (500 MHz, DMSO-d6) δ: 8.77 (t, J=5.5 Hz, 1H), 8.65 (d, J=4.8 Hz, 1H), 8.31 (d, J=8.2 Hz, 2H), 8.18 (s, 1H), 8.08 (d, J=8.3 Hz, 2H), 7.56 (s, 1H) 6.96 (d, J=4.8 Hz, 1H), 5.74 (s, 1H), 4.65 (br d, J=12.6 Hz, 2H), 3.22 (t, J=6.2 Hz, 2H), 2.95 (t, J=12.4 Hz, 2H), 2.40 (m, 1H), 1.93 (m, 1H), 1.81 (br d, J=11.9 Hz, 2H), 1.15 (m, 5H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]#[CH:24])[O:17]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:35])([F:34])[F:33].C(N(CC)CC)C>O1CCCC1.[Cu]I>[CH:1]1([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]#[C:24][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])[O:17]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#C[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)ncnc32)[C@H](O)[C@@H]1O
Reactant: FC(F)(F)c1ccccc1I
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O[C@@H]1[C@H](O)[C@@H](C#Cc2ccccc2C(F)(F)F)O[C@H]1n1cnc2c(NC3CCCC3)ncnc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (4S,2R,3R,5R)-2-[6-(cyclopentylamino)purin-9-yl]-5-ethynyloxolane-3,4-diol (40 mg, 0.12 mmol) in tetrahydrofuran (4 mL) under nitrogen was added catalytic amounts (3 mg) of (4S,2R,3R,5R)-2-[6-(cyclopentylamino)purin-9-yl]-5-ethynyloxolane-3,4-diol (II) and copper (I) iodide, followed by 1-iodo-2-trifluoromethylbenzene (0.042 mL). Triethylamine (0.4 mL) was then added, and the mixture was stirred for 15 minutes at room temperature. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC, eluting with methanol:methylene chloride (6.5:1), to yield (4S,2R,3R,5R)-2-[6-(cyclopentylamino)purin-9-yl]-5-{2-[2-(trifluoromethyl)phenyl]ethynyl}-oxolane-3,4-diol, a compound of Formula I.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=1.CN([CH:28]=[O:29])C.Cl>O1CCCC1.O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[C:18]=1[CH:28]=[O:29]
Reactant: CN(C)C=O
Reactant: Fc1ccc(Br)cc1F
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1c(Br)ccc(F)c1F
Yield: 56.2 %

Procedure:
A solution of 152 mmol of 2,2,6,6-tetramethylpiperidine and 152 mmol of n-butyllithium (1.6 M solution in n-hexane) in 280 ml of dry tetrahydrofuran is admixed with 145 mmol of 1-bromo-3,4-difluorobenzene at −75° C. This temperature is maintained for 4 hours, and then 174 mmol of DMF are added dropwise. The reaction mixture is then slowly thawed, hydrolyzed with water at −20° C., acidified using hydrochloric acid and extracted with tert-butyl methyl ether. The combined organic extracts are washed with saturated sodium chloride solution and dried using sodium sulfate. The solvent is removed under reduced pressure, and the raw product is purified by chromatography over silica gel (eluent: dichloromethane/n-heptane 1:1) and recrystallization from n-heptane, yielding 18 g (56%) of 2-bromo-5,6-difluorobenzaldehyde in the form of slightly yellow crystals.—M.p.: 40-43.5° C.—1H-NMR (400 MHz, CDCl3/TMS): δ=10.31 (dd, 4J(HF)=2 Hz, 5J(HF)=1.5 Hz, 1 H, CHO), 7.45 (ddd, 3J(HH)=9 Hz, 4J(HF)=4 Hz, 5J(HF)=2 Hz, 1 H, Har), 7.28 (ddd, 3J(HH)=9 Hz, 3J(HF)=9 Hz, 4J(HF)=8 Hz, 1 H, Har).—19F-NMR (376.5 MHz, 1H broad-band decoupled, CDCl3/CFCl3): δ=−136.4 (d, 3J=19.2 Hz), −139.2 (d, 3J=19.2 Hz).