Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[N:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])[O:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH3:29][O:30][C:31](=[O:37])[CH2:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[O:14][N:13]=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH2:5][CH2:4][C@@H:3]4[NH:2][S:33]([CH2:32][C:31]([O:30][CH3:29])=[O:37])(=[O:35])=[O:34])[N:16]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4N)no2)cc1C#N
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)N[C@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Prepared using General Procedure 16: To a stirred solution of (S)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 50 (0.36 g, 1.0 mmol) in DCM (5 mL) was added methyl-2-(chlorosulfonyl)acetate (112 mg, 0.6 mmol). After 0.5 h, the crude reaction was partitioned between DCM and saturated NaHCO3. The organic layer was dried over MgSO4, concentrated, and purified by column chromatography (EA/hexanes) to give 0.21 g (42%) of (S)-methyl 2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate 72. LCMS-ESI (m/z) calculated for C24H24N4O6S: 496.1; found 519.1 [M+Na]+, tR=3.71 min. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.1 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 8.13 (d, J=7.7 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 5.20-5.00 (m, 2H), 4.78 (hept, J=6.2 Hz, 1H), 4.16 (d, J=14.9 Hz, 1H), 4.08 (d, J=14.9 Hz, 1H), 3.82 (s, 3H), 3.51 (ddd, J=17.4, 8.9, 3.5 Hz, 1H), 3.28-3.11 (m, 1H), 2.71 (dtd, J=11.3, 8.1, 3.6 Hz, 1H), 2.16-2.02 (m, 1H), 1.46 (d, J=6.1 Hz, 6H). (R)-methyl 2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate was synthesized in an analogous fashion from (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([OH:29])[C:19]=2[C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[N:6]=1.[Cl:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33](S(C)(=O)=O)[N:32]=1.O>C1COCC1>[Cl:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[N:34]=[C:33]([O:29][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([O:13][C:7]3[N:6]=[C:5]([O:4][CH3:3])[CH:10]=[C:9]([O:11][CH3:12])[N:8]=3)[C:19]=2[C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])=[O:21])[N:32]=1
Reactant: COc1cc(OC)nc(Oc2cccc(O)c2C(=O)OCC[Si](C)(C)C)n1
Reactant: COc1cc(Cl)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)OCC[Si](C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (0.4 g, purity: 60%) was suspended in 50 ml of THF. To this suspension, trimethylsilylethyl 6-(4,6-dimethoxypyrimidin-2-yl)oxysalicylate (3.0 g) was added, and the mixture was stirred at room temperature for 30 minutes. To this mixture, 4-chloro-6-methoxy-2-methylsulfonylpyrimidine (1.8 g) was added, and the mixture was stirred at room temperature for further 12 hours. After completion of the reaction, water was added thereto, and the mixture was extracted with ethyl ether. The ethyl ether layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The crude extract thus obtained was purified by silica gel column chromatography to obtain the above identified compound as a slightly yellow liquid (4.0 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH2:20]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)[CH3:21]>>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:27][C:26]3[CH:28]=[CH:29][C:23]([O:22][CH2:20][CH3:21])=[CH:24][CH:25]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: CCOc1ccc(N)cc1
Reactant: COc1ccc(Nc2nc(Cl)ncc2F)cc1OC
Product: CCOc1ccc(Nc2ncc(F)c(Nc3ccc(OC)c(OC)c3)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine with 4-ethoxyaniline gave N4-(3,4-dimethoxyphenyl)-N2-(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.90 (bs, 1H), 7.37 (dd, 2H, J=2.4 and 6.3 Hz), 7.21 (d, 1H, J=2.4 Hz), 7.03 (dd, 1H, J=2.4 and 8.1 Hz), 6.86-6.80 (m, 4H), 6.65 (bs, 1H), 4.00 (q, 2H, J=7.2 Hz), 3.89 (s, 3H), 3.75 (s, 3H), 1.39 (t, 3H, J=6.9 Hz); 19F NMR (CDCl3): −47501; LCMS: ret. time: 22.69 min.; purity: 98%; MS (m/e): 385 (MH+).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:15]([OH:17])=O.[NH2:18][C@H:19]([C:24]([NH:26][C@H:27]([C:32]([NH:34][C@H:35]1[CH2:39][CH2:38][O:37][CH:36]1[O:40][CH3:41])=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22]>>[CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:15]([NH:18][C@H:19]([C:24]([NH:26][C@H:27]([C:32]([NH:34][C@H:35]1[CH2:39][CH2:38][O:37][CH:36]1[O:40][CH3:41])=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17]
Reactant: COC1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)c1ccc2c(c1)Nc1ccccc1O2
Product: COC1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)c1ccc2c(c1)Nc1ccccc1O2
Yield: 72 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of intermediate 1.1, starting with 10H-phenoxazine-2-carboxylic acid (J. Org. Chem. 1960, 25, 747-753) and L-leucyl-N1-[(3S)-2-methoxytetrahydrofuran-3-yl]-L-leucinamide (intermediate 1.6). The condensation product is purified by chromatography on a silica column (eluent: heptane/ethyl acetate: 3/7). A yellow solid is obtained with a yield of 72%. Melting point: 178-179° C.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH:30]([NH:33][CH:34]([CH3:36])[CH3:35])[CH2:31][CH3:32])[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:40](=O)[CH3:41].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[CH:30]([N:33]([CH2:40][CH3:41])[CH:34]([CH3:35])[CH3:36])[CH2:31][CH3:32])[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CC=O
Reactant: CCC(NC(C)C)c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CCC(c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C)N(CC)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[1-(isopropylamino)propyl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (28.5 mg, 0.0500 mmol) in dichloroethane (1 mL) was added acetaldehyde (2 mL) and NaBH(OAc)3 (excess). The reaction was stirred at room temperature for 16 hours, and then diluted with EtOAc (10 mL) and washed with water and brine (5 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification by PTLC (50% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2 {1-[ethyl(isopropyl)amino]propyl}-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.53 (50% EtOAc/hexanes). LCMS=599.3 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.90 (s, 1H), 7.81 (s, 2H), 7.56-7.49 (m, 3H), 5.78-5.74 (m, 1H), 5.02 (d, J=16.4 Hz, 1H), 4.74-4.71 (m, 1H), 4.07-4-04 (m, 1H), 3.90-3.87 (m, 1H), 2.89-2.85 (m, 1H), 2.62-2.52 (m, 2H), 2.00-1.96 (m, 1H), 1.79-1.72 (m, 1H), 1.26-0.69 (m, 15H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[C@@H:15]([CH3:14])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1Cc2ccccc2CN1
Product: C[C@H]1Cc2ccccc2CN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-Methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([CH2:14]C=C)[C:8]=1[OH:17].C(=O)(O)[O-].[Na+]>C(OO)(=O)C>[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([CH2:14][CH:1]2[O:4][CH2:2]2)[C:8]=1[OH:17]
Reactant: CC(=O)[O-]
Reactant: C=CCc1ccc(Cl)c(Cl)c1O
Agent: CC(=O)OO
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1c(CC2CO2)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A stirred solution of sodium acetate (1 g.) in 40% peracetic acid (25 ml.) is cooled to 15° C. then treated dropwise with 2,3-dichloro-6-allylphenol. The reaction mixture is stirred at 25° C. for 48 hours, poured into excess aqueous sodium bicarbonate, extracted into ether, washed with aqueous sodium bicarbonate, water, aqueous ferrous sulfate, water, brine and dried over magnesium sulfate. Evaporation of the ether leaves 2,3-dichloro-6-(2,3-epoxypropyl)phenol which is rearranged by heating at 110° C. for ten minutes then distilled to give 10.4 g. of 6,7-dichloro-2,3-dihydro-2-hydroxymethylbenzofuran which boils at 130°/0.1 mm.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH:9]([CH3:10])[CH2:8][N:7]([C:11](=[O:24])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)[CH2:6][CH2:5][NH:4]1.Cl[C:26]1[N:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:36])[CH:32]=2)[N:27]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:10][CH:9]1[CH:3]([CH3:2])[N:4]([C:26]2[N:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([F:36])[CH:32]=3)[N:27]=2)[CH2:5][CH2:6][N:7]([C:11](=[O:24])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)[CH2:8]1
Reactant: Fc1ccc2nc(Cl)ncc2c1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCNC(C)C(C)C2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCN(c3ncc4cc(F)ccc4n3)C(C)C(C)C2)c1
Temperature: 130 °C

Procedure:
Compound 1-7 (75 mg, 0.21 mmol) was combined with 2-chloro-6-fluoroquinazoline 1-8 (39 mg, 0.21 mmol; see example 1-D), triethylamine (30 uL, 0.21 mmol), and potassium carbonate (296 mg, 2.1 mmol) in toluene (2 mL) and heated in a sealed tube to 130° C. overnight. The reaction was concentrated in vacuo and the residue purified by reverse phase preparative chromatography on a C-18 column (5 to 75% acetonitrile in water with 0.1% TFA buffer). The clean fractions were combined and made basic with 20% sodium carbonate solution. This was extracted with ethyl acetate two times and the combined organics washed with brine and dried with sodium sulfate. Concentration in vacuo gave the titled compound as a solid. Data for 1-9: LC/MS: m/z (M+Na)=460.2 found; 460.5 calculated.
Reaction SMILES: C([O:8][C:9]1([CH3:30])[CH2:18][CH2:17][C:16]2[NH:15][CH:14]=[C:13]3[C:19](=[O:29])[N:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[N:21]=[C:12]3[C:11]=2[CH2:10]1)C1C=CC=CC=1.[H][H]>CN(C=O)C.CCO.[Pd]>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:20]2[C:19](=[O:29])[C:13]3=[CH:14][NH:15][C:16]4[CH2:17][CH2:18][C:9]([OH:8])([CH3:30])[CH2:10][C:11]=4[C:12]3=[N:21]2)=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: CC1(OCc2ccccc2)CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC1(O)CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1

Procedure:
8-Benzyloxy-2-p-chlorophenyl-8-methyl-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one (4 g) is dissolved in 200 mL of a 1:1 mixture of DMF/EtOH and subjected to catalytic hydrogenation with 5% palladium on carbon (1 g) for 24 hours under 1 atm. of hydrogen. After the reaction is over, the catalyst is filtered off, the filtrate is evaporated, and the dried residue is triturated with EtOH to yield 2-p-chlorophenyl-8-hydroxy-8-methyl-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([O:19]CCCC)=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2O)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)O)nn1
Reaction time: 1.5 h
Yield: 73.8 %

Procedure:
A solution of butyl 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazine-3-carboxylate (reference example 11) (0.36 g, 1.0 mmol) in THF (4 ml) and methanol (4 ml) was treated with aqueous sodium hydroxide 1N (4 ml) and allowed to stand at ambient temperature for 1.5 hours. The reaction was evaporated to a small volume, diluted with water and acidified with acetic acid. After standing for 18 hours, the precipitate was filtered, washed with water and ether, and air dried to give the title compound as a white solid (0.26 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]#[CH:11])=[CH:4][N:3]=1.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]#[C:11][C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:22])([F:21])[F:12])=[CH:15][CH:16]=2)=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: C#Cc1cnc(N)c(C#N)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1nc(C#Cc2ccc(C(F)(F)F)cc2)cnc1N

Procedure:
A solution of 3.2 grams (0.022 mole) of 2-amino-3-cyano-5-ethynylpyrazine, 8.4 grams (0.031 mole) of 4-trifluoromethylphenyl iodide, 10.7 grams (0.077 mole) of triethylamine, 0.5 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride, and 0.5 gram (catalyst) of copper iodide in 100 mL of acetonitrile is stirred at ambient temperature for about 18 hours. After this time the reaction mixture is concentrated under reduced pressure to a residue. The residue is partitioned between ethyl acetate and aqueous 1N hydrochloric acid. The two-layered mixture is filtered to remove a solid. The aqueous layer and the organic layer are separated, and the aqueous layer is washed with ethyl acetate. The ethyl acetate wash is combined with the organic layer, and the combination is washed with an aqueous solution of 10% lithium chloride. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is triturated with methylene chloride and filtered. The filtrate is subjected to column chromatography on silica gel. Elution is accomplished using methanol/methylene chloride combinations. The product-containing fractions are combined and concentrated under reduced pressure, yielding 2-amino-3-cyano-5-[(4-trifluoromethylphenyl)ethynyl]pyrazine.
Reaction SMILES: [F:1][C:2]1([F:20])[C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:10]([O:12]C)=[O:11])=[CH:4][C:3]1=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:1][C:2]1([F:20])[C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:10]([OH:12])=[O:11])=[CH:4][C:3]1=[CH2:19]
Reactant: C=C1C=C(Oc2cc(C(=O)OC)ccc2OC)C1(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C=C1C=C(Oc2cc(C(=O)O)ccc2OC)C1(F)F
Temperature: 65 °C

Procedure:
A solution of methyl 3-(4,4-difluoro-3-methylenecyclobut-1-enyloxy)-4-methoxybenzoate (1.39 g) in methanol (22 mL) is treated with a solution of potassium carbonate (0.83 g) in water (8 mL) and the solution is heated at 60-70° C. for 8 hours, cooled and evaporated. The residue is dissolved in water (30 mL), extracted with diethyl ether (50 mL) and acidified to pH 4 by treatment with glacial acetic acid. The precipitated solid is extracted with ethyl acetate (2×75 mL). The combined organic extracts are dried over magnesium sulfate and concentrated, to give 3-(4,4-difluoro-3-methylene-cyclobut-1-enyloxy)-4-methoxybenzoic acid, in the form of a white solid, m.p. 163-165° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[CH3:21][C:22]1[N:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[N:23][C:22]([CH3:21])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: Cc1cnc(C(=O)O)cn1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Product: Cc1cnc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OC(C)(C)C3(F)F)c2)cn1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-methyl-pyrazine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=408.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.C([Li])CCC.[O:14]=[C:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:15]2([OH:14])[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:18]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Brc1cnc(I)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(O)(c2ncc(Br)cn2)C1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
A solution of 5-bromo-2-iodopyrimidine (2 g, 7.02 mmol) in anhydrous toluene (25 mL) was cooled to −78° C. with stirring under nitrogen, forming a thick paste. n-Butyllithium (2.5M solution in hexanes, 2.83 mL) was then added dropwise over 10 minutes. The reaction mixture was stirred at −78° C. for 30 minutes, then solid tert-butyl 3-oxoazetidine-1-carboxylate (1.33 g, 7.74 mmol) was added portionwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL) and further diluted with water (20 mL). The crude material was extracted into ethyl acetate (2×30 mL). The combined organic phases were dried over sodium sulphate, filtered and concentrated under vacuum. The resulting brown oil (2.66 g) was loaded onto a 50 g KP-silica cartridge, and eluted from a 0-90% ethyl acetate in heptane gradient using a Biotage isolera 4, to afford the title compound (1.083 g, 46%) as a yellow solid. δH (500 MHz, CDCl3) 8.84 (s, 2H), 4.91 (s, 1H), 4.35 (d, J 9.0 Hz, 2H), 4.22 (d, J 9.1 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[C:13]([C:21]#[N:22])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N=C=NC(C)C)(C)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH2:29][C:25]4[S:24][CH:28]=[CH:27][CH:26]=4)=[CH:17][CH:18]=3)[C:13]([C:21]#[N:22])=[CH:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: OCc1cccs1
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(O)ccc32)cc1
Agent: CC(C)N=C=NC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(OCc4cccs4)ccc32)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-(5-hydroxy-3-cyanoindol-1-yl)benzoic acid ethyl ester and thiophene-2-methanol (0.057 g) and triphenylphosphine (0.012 g) in tetrahydrofuran (2.5 mL) was added diisopropylcarbodiimide (40% toluene solution, 0.18 mL) at room temperature, and this mixture was stirred for 3 hours. This reaction mixture was concentrated under reduced pressure. This residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/3) to give the title compound (0.10 g).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH2:5][CH2:6]2)=O.[C:10]([CH2:12]C(O)=O)#[N:11].[OH-].[NH4+].CN(C)C=O>C1C=CC=CC=1>[C:10]([CH2:12][CH:1]=[C:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH2:5][CH2:6]2)#[N:11]
Reactant: O=CC1CC2CCC1C2
Reactant: N#CCC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: N#CCC=C1CC2CCC1C2
Yield: 78.7 %

Procedure:
A stirred solution of 95 g (0.77 mol) of 2-formylbicyclo[2.2.1]heptane, 65 g (0.76 mol) of cyanoacetic acid, 2 ml of ammonium hydroxide (58%), 132 ml of dimethylformamide, and 170 ml benzene was heated to reflux and the water removed with a Dean-Stark trap. The reaction was allowed to continue until the evaluation of carbon dioxide ceased (approx. 24 hrs.). Upon completion, the reaction was cooled and the solvent removed under reduced pressure. The residual oil was distilled under vacuum to give 88 g (79% yield) of 2-(2-cyanoethylidene)-bicyclo[2.2.1]heptane: b.p. 72-80° C/1 mm; ir 2960, 2870, 2260, 1685, 1450, 1420, 1305, 920; nmr 1.15-2.8 (10H, m), 2.96 (2H, m) 4.9-5.4 (1H, m); ms 147.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[C@@H:15]([CH3:16])[N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][CH2:12][N:11]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].O.CO>[C:24]([O:23][C:21]([N:11]1[CH2:12][CH2:13][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[C@H:15]([CH3:16])[C@@H:10]1[CH2:9][OH:8])=[O:22])([CH3:26])([CH3:27])[CH3:25]
Reactant: C[C@@H]1[C@H](COCc2ccccc2)N(C(=O)OC(C)(C)C)CCN1S(C)(=O)=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: C[C@@H]1[C@H](CO)N(C(=O)OC(C)(C)C)CCN1S(C)(=O)=O
Yield: 92.3 %

Procedure:
10% Palladium on activated carbon (1.5 g) was suspended in H2O (10 ml) and the suspension was added to a solution of (2R,3R)-2-benzyloxymethyl-1-tert-butoxycarbonyl-4-methanesulfonyl-3-methyl-piperazine (2.1 g) and ammonium formate (3.3 g) in MeOH (25 ml). The mixture was refluxed for 1.5 hours. Ammonium formate (3.4 g) in H2O (10 ml) and MeOH (10 ml) were added to the reaction mixture, and the mixture was refluxed for 1.5 hours. 10% Palladium on activated carbon (1.5 g) in H2O (10 ml) and ammonium formate (3.4 g) were added to the reaction mixture and the mixture was refluxed for 2.5 hours. The catalyst was removed by filtration through a celite pad and the pad was washed with MeOH. The combined filtrate and washings were concentrated in vacuo. The residue was partitioned between AcOEt and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give 1.5 g of (2R,3R)-1-tert-butoxycarbonyl-2-hydroxymethyl-4-methane-sulfonyl-3-methylpiperazine as a solid.