Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]([C:10]1[O:16][C@H:15]2[N:12]([C:13](=[O:33])[C@@H:14]2[C@@H:17]([O:19]C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH3:18])[C:11]=1[C:34]([O:36]CC1C=CC([N+]([O-])=O)=CC=1)=[O:35])([CH3:9])[CH3:8])=[N+]=[N-].[H][H]>[Pd].C(OCC)(=O)C.O>[NH2:1][CH2:4][CH2:5][CH2:6][C:7]([C:10]1[O:16][C@H:15]2[N:12]([C:13](=[O:33])[C@@H:14]2[C@@H:17]([OH:19])[CH3:18])[C:11]=1[C:34]([OH:36])=[O:35])([CH3:8])[CH3:9]
Reactant: C[C@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(C(C)(C)CCCN=[N+]=[N-])O[C@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(C(C)(C)CCCN)O[C@H]12
Reaction time: 0.33 h
Yield: 74.7 %

Procedure:
In a 100 ml two necked flask fitted with a magnetic stirrer, a rubber septum and connected to a hydrogenation apparatus palladium on carbon catalyst (10%, 300 mg) in ethyl acetate (13 ml) and water (13 ml) was prehydrogenated for 20 min at 0° C. A solution of p-nitrobenzyl (5R,6R)-3-[4-azido-1,1-dimethylbutyl]-6-[(S)-1-p-nitrobenzyloxycarbonyloxyethyl]-7-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (280 mg, 0.44 mmol) in ethyl acetate (10 ml) was then added with a syringe at 0° C. with stirring. After 50 min of stirring at 0° C. hydrogen uptake came to an end (90 ml of hydrogen was consumed). The catalyst was removed by filtration, washed with a small portion of ethyl acetate and water and the chilled two phase mixture allowed to separate. The aqueous phase was washed twice with portions (3 ml) of cold ethyl acetate and water and the ethyl acetate phases were reextracted twice with portions (3 ml) of water. Residual ethyl acetate was removed from the combined water phases in vacuum and then in high vacuum at 0° C. and the volume was reduced to 13 ml in high vacuum. The solution was lyophilized at −25° C. for three days to give (5R,6R)-3-[4-amino-1,1-dimethylbutyl]-6-[(S)-1-hydroxyethyl]-7-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (YOB) as a colourless voluminous powder (98 mg, 75%)
Reaction SMILES: CS(O[CH2:6][C@@H:7]([C:9]1[C:10]([Cl:17])=[N:11][C:12]([Cl:16])=[N:13][C:14]=1Cl)[CH3:8])(=O)=O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>>[Cl:16][C:12]1[N:11]=[C:10]([Cl:17])[C:9]2[C@@H:7]([CH3:8])[CH2:6][N:27]([CH2:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[C:14]=2[N:13]=1
Reactant: C[C@@H](COS(C)(=O)=O)c1c(Cl)nc(Cl)nc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C[C@H](C)c3c(Cl)nc(Cl)nc32)cc1
Yield: 74 %

Procedure:
(R)-2,4-dichloro-7-(4-methoxybenzyl)-5-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was prepared from (R)-2-(2,4,6-trichloropyrimidin-5-yl)propyl methanesulfonate (60 mg, 0.188 mmol), (4-methoxyphenyl)methanamine (39 mg, 0.28 mmol) and triethyl amine (38 mg, 0.375 mmol), and isolated as a yellow (45 mg, yield 74%). 1H NMR (400 MHz, CDCl3) δ ppm 7.16-7.19 (d, 2H, J=8.8 Hz), 6.86-6.88 (d, 2H, J=8.4 Hz), 4.54 (s, 2H), 3.80 (s, 3H), 3.66-3.71 (t, 1H, J=6.0 Hz), 3.33-3.36 (m, 1H), 3.08-3.12 (dd, 1H, J=4.4 Hz, 10.0 Hz), 1.29-1.31 (d, 3H, J=6.8 Hz).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([F:31])=[C:26]([CH:30]=1)[C:27](O)=O>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([F:31])=[C:26]([C:27]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:30]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1cc(Cl)ccc1F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc(Cl)ccc3F)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 5-chloro-2-fluorobenzoic acid: MS (APCI) m/z 421 (M+1).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14].C(=O)(O)[O-].[Na+].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>ClCCl>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]([C:3]1[N:2]([NH:1][C:22](=[O:23])[O:24][CH2:25][CH3:26])[CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: Nn1cccc1C(=O)c1ccccc1Cl
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Nn1cccc1C(=O)c1ccccc1Cl
Yield: 120.2 %

Procedure:
1-Amino-2-(2-chlorobenzoyl)pyrrole (32 g, 0.145 mol) was combined with sodium bicarbonate (30.2 g, 0.36 mol) in 400 ml of dichloromethane. To this rapidly stirred mixture was added ethyl chloroformate (18.6 g, 0.172 mol) over 2 minutes and the resultant slurry heated under reflux for 2.5 hours. The reaction mixture was quenched with 300 ml of H2O, separated, washed with H2O, dried (MgSO4), filtered, and evaporated to give 51 g of an oil. This oil was purified by HPLC (silica, 10:1 DCM-ethyl acetate) to give after evaporation 32.8 g (77%) of crystals, m.p. 90°-92°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:24]1[S:31][C:27]2[S:28][CH:29]=[CH:30][C:26]=2[CH:25]=1)[C:20]([O:22][CH3:23])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:24]2[S:31][C:27]3[S:28][CH:29]=[CH:30][C:26]=3[CH:25]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C(N)c1cc2ccsc2s1
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cc2ccsc2s1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(thieno[2,3-b]thiophen-2-yl)acetate (from Example D4 above), the title compound was prepared as a solid. The product was purified by titruation from Et2O/hexanes.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH2:30][CH2:31][O:32][CH2:33][CH:34]=2)[N:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]3[CH2:30][CH2:31][O:32][CH2:33][CH:34]=3)[N:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Brc1cccc(C2=CCOCC2)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(C4=CCOCC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared by using the procedure listed in Example 1 with 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.24 g, 0.75 mmol) and 2-bromo-6-(3,6-dihydro-2H-pyran-4-yl)pyridine (0.18 g, 0.74 mmol) as the starting materials.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[C:10]([C:14]1[CH:15]=[C:16]([NH2:36])[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH:20]=2)[N:18]=1)([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](=[O:6])[NH:36][C:16]1[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si:26]([CH:27]([CH3:29])[CH3:28])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:31])[CH3:32])[CH:20]=2)[N:18]=[C:14]([C:10]([CH3:11])([CH3:13])[CH3:12])[CH:15]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)[Si](Oc1cccc(-n2nc(C(C)(C)C)cc2N)c1)(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
2,2,2-Trichloroethylchloroformate (1.09 mL, 7.92 mmol) was added to a solution of Intermediate 22a (1.53 g, 3.96 mmol) and DIPEA (2.75 mL, 15.8 mmol) in THF (40 mL) at 0° C. The reaction was stirred at RT for 3 h then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-50% EtOAc in cyclohexane, to give the title compound (2.22 g, 99%). LCMS (Method 4): Rt 5.55 min, m/z 560, 562 [MH+].
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]1[N:37]=[C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[S:39][CH:40]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[N:37]=[C:38]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[S:39][CH:40]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2csc(-c3ccccc3)n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 4-(chloromethyl)-2-phenyl-1,3-thiazole (0.71 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.20 g, 66%).
Reaction SMILES: [C:1]([O:4][CH2:5][C@:6]1([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][CH:9](OC(=O)C)[C@H:8]([O:15][C:16](=[O:18])[CH3:17])[C@@H:7]1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2].[NH:36]1[CH:44]=[C:42]([CH3:43])[C:40](=[O:41])[NH:39][C:37]1=[O:38].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>C(#N)C>[C:1]([O:4][CH2:5][C@:6]1([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][C@@H:9]([N:36]2[CH:44]=[C:42]([CH3:43])[C:40](=[O:41])[NH:39][C:37]2=[O:38])[C@H:8]([O:15][C:16](=[O:18])[CH3:17])[C@@H:7]1[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)(=[O:3])[CH3:2]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: CC(=O)OC[C@]1(COCc2ccccc2)OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CC(=O)OC[C@]1(COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
To a stirred solution of the anomeric mixture 33 (736 mg, 1.51 mmol) and thymine (381 mg, 3.03 mmol) in anhydrous acetonitrile (14.5 cm3) was added N,O-bis(trimethylsilyl)-acetamide (2.61 cm3, 10.6 mmol). The reaction mixture was stirred at reflux for 1 h, then cooled to 0° C. Trimethylsilyl triflate (0.47 cm3, 2.56 mmol) was added dropwise under stirring and the solution was stirred at 65° C. for 2 h. The reaction was quenched with a cold saturated aqueous solution of sodium hydrogen carbonate (15 cm3) and extraction was performed with dichloromethane (3×10 cm3). The combined organic phase was washed with saturated aqueous solutions of sodium hydrogencarbonate (2×10 cm3) and brine (2×10 cm3), and was dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (98:2, v/v) as eluent to give nucleoside 34 as a white solid material (639 mg, 76%). δH (CDCl3) 8.98 (1 H, br s, NH), 7.39-7.26 (11 H, m, Bn, 6-H), 6.22 (1 H, d, J 5.3, 1′-H), 5.42 (1 H, t, J 5.4, 2′-H), 4.63-4.43 (5H, m, 3′-H, Bn), 4.41 (1 H, d, J 12.2, 5′-Ha), 4.17 (1 H, d, J 12.1, 5′-Hb), 3.76 (1 H, d, J 10.2, 1″-Ha), 3.51 (1 H, d, J 10.4, 1″-Hb), 2.09 (3 H, s, COCH3), 2.03 (3 H, s, COCH3), 1.53 (3 H, d, J 0.9, CH3). δC (CDCl3) 170.8, 170.4 (C═O), 163.9 (C-4), 150.6 (C-2), 137.4 (C-6) 137.4, 136.1, 128.9, 128.8, 128.4, 128.2, 127.9 (Bn), 111.7 (C-5), 87.2, 87.2, 86.1 (C-1′, C-3′, C-4′), 77.6 (C-2′), 74.8, 73.9, 71.1, 63.8 (Bn, C-1″, C-5′), 20.9, 20.8 (COCH3), 12.0 (CH3). FAB-MS m/z 553 [M+H]+. Found: C, 62.7; H, 5.9; N, 4.7; C29H32N2O9 requires C, 63.0; H, 5.8; N, 5.1%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:36])[CH2:20][NH:21][C:22](=[O:35])[NH:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=1)[C:27]([O:29]CC)=[O:28]>CO>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:9]1[C:19](=[O:36])[CH2:20][NH:21][C:22](=[O:35])[NH:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=1)[C:27]([OH:29])=[O:28]
Reactant: CCOC(=O)c1cccc(NC(=O)NCC(=O)N2C(c3ccccc3)CCC2c2ccccc2O)c1
Solvent: CO
Product: O=C(NCC(=O)N1C(c2ccccc2)CCC1c1ccccc1O)Nc1cccc(C(=O)O)c1
Yield: 27.9 %

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 0.8 g of ethyl (2RS,5SR)-3-{3-{2-[2-(2-hydroxyphenyl)-5-phenyl-1-pyrrolidinyl]-2-oxoethyl}ureido}benzoate in solution in 15 cm3 of methanol and 0.27 g of potassium hydroxide in solution in 3 cm3 of water, and after treatment and recrystallization in diisopropyl ether, 0.21 g of (2RS,5SR)-3-{3-{2-[2-(2-hydroxyphenyl)-5-phenyl-1-pyrrolidinyl]-2-oxoethyl}ureido}benzoic acid, melting at about 160° C., is obtained [proton NMR (200 MHz, DMSO D6, δ in ppm), 1.8 to 2.5 (2m, 4H, CH2 --CH2); 3.3 and 4 (ABX, 2H, CH2N); 5.2 (m, 2H, 2 CHN); 6.7 to 7.4 (m, 13H, aromatic); 6.8 (bt 9(s) 9.8(bs) 12.8(vbs) (4H exchangeable, 1 OH, 1 CO2H and 2NH)], [Infrared spectrum (KBr), characteristic bands in cm-1 3400, 3070, 2980, 1695, 1630, 1560, 1490, 1460, 760, 700, 685].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.[CH:9]1([NH2:13])[CH2:12][CH2:11][CH2:10]1.CC(C)([O-])C.[Na+]>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].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>[CH:9]1([NH:13][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: Fc1cccc(I)c1
Reactant: NC1CCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Fc1cccc(NC2CCC2)c1
Temperature: 120 °C
Yield: 71.2 %

Procedure:
A mixture of 3-fluoroiodobenzene (1.0 g, 4.5 mmol), cyclobutylamine (320 μL, 3.8 mmol), Pd2(dba)3 (34 mg, 38 μmol), XantPhos (54 mg, 94 μmol), and sodium tert-butoxide (541 mg, 5.6 mmol) in toluene (10 mL) was degassed with nitrogen then heated at 120° C. for 30 minutes in a microwave reactor. Saturated aqueous NaHCO3 was added and then extracted with EtOAc, washed with brine, dried with Na2SO4, concentrated and purified by silica gel column chromatography (0-50% DCM in cyclohexane) to give cyclobutyl-(3-fluoro-phenyl)-amine (447 mg, 71%). LCMS (m/z, Method A) ES+ 166[M+1]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]([NH:11][C:12]2[C:13]3[C:20]([CH3:21])=[C:19]([C:22]([O:24]C)=[O:23])[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].[OH-].[Na+]>CO>[CH:1]([O:4][C:5]1[C:10]([NH:11][C:12]2[C:13]3[C:20]([CH3:21])=[C:19]([C:22]([OH:24])=[O:23])[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1sc2ncnc(Nc3cccnc3OC(C)C)c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC(C)C)c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Methyl 4-(2-isopropoxypyridin-3-ylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (2.04 g) was dissolved in methanol (24.0 ml), NaOH (2M; 6.0 ml) was added and the mixture was stirred at 60° C. for 1 h. Then the reaction was cooled and washed with dichloromethane. The aqueous layer was acidified to pH 5 with conc. HCl and the precipitate was filtered and washed with water.
Reaction SMILES: [C:1]([C:3]1([CH3:12])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5](=O)[CH2:4]1)#[N:2].O=C1CC(C)(C)CC(C)=C1.C#N>CO>[C:1]([C:3]1([CH3:12])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: CC1(C)CC(=O)CC(C)(C#N)C1
Agent: C#N
Solvent: CC1=CC(=O)CC(C)(C)C1
Solvent: CO
Product: CC1(C)CCCC(C)(C#N)C1
Yield: 70 %

Procedure:
West German Patent No. 1,240,854 discloses a method for synthesizing 3-cyano-3,5,5-trimethyl cyclohexanone by causing isophorone to react with hydrogen cyanide in the presence of an alkali metal salt as a catalyst with methanol used as a dispersant for the catalyst. When this method was replicated, however, it was found that the reaction produced 3-cyano-3,5,5-trimethyl cyclohexane only in a low yield of about 70% and entailed by-production of a large amount of polymer of hydrogen cyanide. Thus, this method is problematic as a commercial process.
Reaction SMILES: [F:1][B-](F)(F)F.[CH2:6]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([N+]#N)=[CH:21][CH:20]=[C:19]([N:25]([C:29](=[O:31])[CH3:30])[CH:26]3[CH2:28][CH2:27]3)[N:18]=2)[CH2:13][CH2:12]1)=[O:10])[CH3:7]>C1(C)C=CC=CC=1>[C:29]([N:25]([CH:26]1[CH2:28][CH2:27]1)[C:19]1[N:18]=[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH2:12][CH2:13]2)[C:22]([F:1])=[CH:21][CH:20]=1)(=[O:31])[CH3:30]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)N1CCN(c2nc(N(C(C)=O)C3CC3)ccc2[N+]#N)CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(c2nc(N(C(C)=O)C3CC3)ccc2F)CC1
Yield: 39.1 %

Procedure:
To 800 mL of refluxing toluene was added in portions, as a solid, 46.2 g (0.1 mole) of 2-[4-(ethoxycarbonyl)-1-piperazinyl]-6 -(acetylcyclopropylamino)-3-pyridinediazonium tetrafluoroborate. After the addition was complete, the reaction was refluxed for ten minutes and the toluene was decanted from the insoluble precipitate. The toluene was evaporated in vacuo and the residue was partitioned between chloroform and water. The chloroform layer was washed with 5% aqueous sodium bicarbonate, water, dried over magnesium sulfate and evaporated in vacuo to give 13.7 g of the title compound, as a viscous oil. An additional 10.2 g could be obtained by partitioning the original toluene insoluble material in chloroform and water. The organic layer was washed with 5% aqueous sodium bicarbonate, dried over magnesium sulfate, evaporated in vacuo and the residue was chromatographed on silica gel eluting with chloroform/ethyl acetate (6:4). This fraction was also a viscous oil which did not crystallize upon standing. Both fractions were of sufficient purity to be used as is in the ensuing steps.
Reaction SMILES: C1(C(N[C@H:9]([C:17]([NH:19][C@H:20]([C:25]([NH:27][C@@H:28]([CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH:29]([P:31]([O:35][CH3:36])([O:33][CH3:34])=[O:32])[OH:30])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)CCCC1.C(O)(=O)CCC1C=CC=CC=1.O.OC1C2N=NNC=2C=CC=1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:18]=[C:17]([NH:19][C@H:20]([C:25]([NH:27][C@@H:28]([CH2:37][CH:38]1[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1)[C@@H:29]([P:31]([O:35][CH3:36])([O:33][CH3:34])=[O:32])[OH:30])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COP(=O)(OC)C(O)[C@H](CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CCc1ccccc1
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COP(=O)(OC)[C@@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 64 h
Yield: 33.1 %

Procedure:
The title A compound of Example 5 (622.2 mg, 1.5 mmol) was added to a solution of hydrocinnamic acid (225.3 mg, 1.5 mmol) in acetonitrile (7.5 mL) and cooled to 0° C. Hydroxybenzotriazole hydrate (229.5 mg, 1.5 mmol), N,N-diisopropylethylamine (287 μl, 1.65 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added sequentially. After 64 hours at 0° C., additional N,N-diisopropylethylamine (52 μl, 0.3 mmol) was added and the reaction was allowed to proceed for 24 hours at 25° C. The reaction mixture was then concentrated and stirred with pH 4.01 buffer solution for 10 minutes. The resulting precipitate was filtered, washed sequentially with pH 4.01 buffer (3×50 mL) and water (3×50 mL), and dried in vacuo yielding 476.9 mg of crude product. Purification by flash chromatography afforded 253.6 mg of product, which was crystallized from hexane/ethyl acetate yielding 230.6 mg of the title compound, m.p. 157° C., [α]D =-74.6° (c=0.50, CH3OH).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.[CH3:26][O:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:31]3[CH2:32][CH2:33][CH:28]([O:27][CH3:26])[CH2:29][CH2:30]3)=[O:21])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: COC1CCNCC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: COC1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)CC1

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 4-methoxypiperidine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 1.14-1.32 (m, 3H) 1.63-1.93 (m, 5H) 1.96-2.10 (m, 2H) 2.44 (s, 3H) 3.22 (t, J=6.3 Hz, 2H) 7.67 (d, J=7.6 Hz, 1H) 7.74 (s, 1H) 7.81 (br. s., 1H) 8.25 (br. s., 1H) 8.43 (br. s., 1H) 8.57 (br. s., 1H) 8.78 (br. s., 1H) 8.91-8.94 (m, 1H) 13.25 (br. s., 1H). MS m/z [M+H]+ 418.4.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[CH:20]=[C:19]([C@:24]3([CH3:30])[CH2:28][O:27]C(=O)[NH:25]3)[CH:18]=[CH:17]4)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].C(O)C.O>>[NH2:25][C@@:24]([C:19]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([O:13][C@H:10]3[CH2:9][CH2:8][C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:12][CH2:11]3)[CH:15]=2)[CH:20]=1)([CH3:30])[CH2:28][OH:27]
Reactant: C[C@@]1(c2ccc3cc(O[C@H]4CC[C@@H](c5ccccc5)CC4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@](N)(CO)c1ccc2cc(O[C@H]3CC[C@@H](c4ccccc4)CC3)ccc2c1
Yield: 41.3 %

Procedure:
The mixture of (R)-4-(6-(cis-4-phenyl-cyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (160 mg, 0.00040 mol) and lithium hydroxide (100 mg, 0.0044 mol) in ethanol (4 mL, 0.08 mol) and water (0.9 mL, 0.05 mol) was heated to reflux overnight. LCMS showed reaction complete. The solvent was removed under vacuum and the residue was partitioned between water and CH2Cl2. The aqueous layer was extensively is extracted with CH2Cl2. The combined organic phase was dried over Na2SO4. The concentrated residue was taken up into DCM and subjected to chromatographic purification with CH2Cl2/MeOH (10:90 to 80:20) to give the product. A final purification on Gilson HPLC 0.1% TFA-ACN/H2O to gave the product as a white solid (62.0 mg, 41% yield). LCMS 359.33 ([M−NH2]+, 100%). 1H NMR (400 MHz, CD3OD) δ ppm 1.71 (brd, J=13.1 Hz, 2H), 1.78 (s, 3H), 1.83 (brd, J=14.7 Hz, 2H), 1.98 (dd, J=13.7, 11.1 Hz, 2H), 2.24 (d, J=12.6 Hz, 2H), 2.67 (dd, J=11.6, 11.5 Hz, 1H), 3.82 (d, J=11.7 Hz, 1H), 3.92 (d, J=11.7 Hz, 1H), 4.84 (brs, 1H), 7.16 (m, 1H), 7.27-7.32 (m, 6H), 7.52 (d, J=8.7 Hz, 1H), 7.85 (m, 3H).