Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2CCCCC2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2C(OC)=C[CH:26]=[CH:25][C:24]=2OC)CCCCC1.[C:39](=[O:42])([O-])[O-:40].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:26][C:25]1[C:39](=[O:42])[O:40][CH:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:17]=2)[C:24]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1=C(c2ccccc2)C(c2ccccc2)OC1=O
Yield: 40 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 5. The difference is that, the reactants are (R)-(−)-3-propyl-4-chloride-5-phenyl-2(5H)— furanone (22.9 mg, 0.097 mmol, 97% ee), phenylboronic acid (19.0 mg, 98%, 0.15 mmol), palladium acetate (1.1 mg, 0.005 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2.1 mg, 0.005 mmol), potassium carbonate (62.1 mg, 0.45 mmol) and 1 mL of anhydrous toluene. The reactants are reacted for 1 hours under 110° C., and 3-methyl-4,5-diphenyl-2(5H)-furanone is obtained. The yield is 40%, <16% ee, 11% the starting material is recycled.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)([OH:10])[CH3:9])=[CH:4][CH:3]=1.Cl[C:35](OC1C=CC([N+]([O-])=O)=CC=1)=[O:36].[NH2:47][CH2:48][C:49]([CH3:52])([OH:51])[CH3:50].C(N(CC)CC)C>O1CCCC1>[F:28][C:25]([F:26])([F:27])[C:24]([C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:14]2[CH2:13][CH2:12][CH:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:35]([NH:47][CH2:48][C:49]([OH:51])([CH3:52])[CH3:50])=[O:36])=[CH:3][CH:4]=3)([OH:10])[CH3:9])[CH2:16][CH2:15]2)=[CH:19][CH:20]=1)([OH:33])[C:29]([F:32])([F:30])[F:31]
Reactant: CC(O)(c1ccc(N)cc1)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(O)CN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(O)CNC(=O)Nc1ccc(C(C)(O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.4 %

Procedure:
2-(4-((4-(1-(4-Aminophenyl)-1-hydroxyethyl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.252 mmol, 120 mg) and 4-nitrophenyl chloroformate (0.252 mmol, 50.8 mg) were combined in tetrahydrofuran (2 mL) and the reaction stirred at room temperature for 1 hour. 1-Amino-2-methylpropan-2-ol (0.252 mmol, 22.45 mg) and triethylamine (0.756 mmol, 76 mg) were added and the mixture stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue purified by HPLC then treated with strong cation exchange column chromatography. The resulting product was purified by silica gel column chromatography (eluting with 2% to 15% methanol/dichloromethane) to afford the title compound (5 mg). MS (ESI) m/z 592.2 [M+H]+
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([NH2:22])=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:23](O)([C:25](F)(F)F)=O>C(OC)(OC)(OC)C>[CH3:23][C:25]1[N:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:22]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccc(OCc2ccccc2)nc1Nc1ccccc1
Agent: COC(C)(OC)OC
Product: Cc1nc2ccc(O)nc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(Benzyloxy)-N2-phenylpyridine-2,3-diamine (68 mg, 0.23 mmol) was dissolved in trimethyl orthoacetate (5.0 mL) and TFA (10 μL) was added. The mixture was stirred at room temperature for 2 h and concentrated in vacuo. The benzyl group of the residue was then removed as described in Example 1.11, Step B to give the title compound as a white solid (15 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.35 (s, 1H), 6.51 (d, J=8.6 Hz, 1H), 7.48-7.55 (m, 3H), 7.57-7.63 (m, 2H), 7.84 (d, J=8.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)=[C:4]([CH:8]=[C:9]([O:11][CH2:12][CH:13]=[C:14]([Cl:16])[Cl:15])[CH:10]=1)[C:5](O)=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:44][CH2:45][CH2:46][OH:47]>C1(C)C=CC=CC=1>[OH:47][CH2:46][CH2:45][NH:44][C:5](=[O:6])[C:4]1[CH:8]=[C:9]([O:11][CH2:12][CH:13]=[C:14]([Cl:16])[Cl:15])[CH:10]=[C:2]([Cl:1])[C:3]=1[O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][N:23]=1
Reactant: NCCO
Reactant: O=C(O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1OCCCOc1ccc(C(F)(F)F)cn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Product: O=C(NCCO)c1cc(OCC=C(Cl)Cl)cc(Cl)c1OCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C

Procedure:
0.2 g of 3-chloro-5-(3,3-dichloroprop-2-enyloxy)-2-[3-(5-trifluoromethylpyrid-2-yloxy)-propyloxy]benzoic acid and 0.065 g of carbonyldiimidazole were allowed to react at room temperature in 4 ml of anhydrous toluene for 1.5 hours. 0.027 g of 2-amino-ethanol was then added, and the mixture was stirred at room temperature for another hour. The reaction mixture was concentrated under reduced pressure and purified by column chromatography. Yield: 0.159 g (73%)
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]2[C:7]([NH:9][C:10](=[O:11])[C:3]=12)=[O:8].[NH3:12]>>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([NH2:12])=[O:8])[C:3]=1[C:10]([NH2:9])=[O:11]
Reactant: Nc1snc2c1C(=O)NC2=O
Reactant: N
Product: NC(=O)c1nsc(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A mixture of 10.1 parts of 5-aminoisothiazole-3,4-dicarboximide and 70 parts of concentrated aqueous ammonia solution is stirred for 2 hours at room temperature, and the colorless precipitate is then filtered off under suction, washed with water and dried to give 9.3 parts (83% of theory) of 5-aminoisothiazole-3,4-dicarboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH:9]([OH:11])=O.[C:12](=O)([O-])[O-:13]>C(O)C>[CH:12]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][CH:9]=[O:11])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: O=CO
Reactant: Nc1ccncc1N
Solvent: CCO
Product: O=CNc1ccncc1NC=O

Procedure:
A stirred mixture of 3,4-diaminopyridine (10.0 g, 0.092 mol) and formic acid (20 ml) was heated under reflux for 2.5 hours. The resulting mixture was cooled and the formic acid was evaporated off under reduced pressure to a yield a residue. The residue was dissolved in ethanol (300 ml) at 80° C. and the resulting solution was treated with calcuim carbonate (10 g) and neutralized by stirring under reflux for 1 hour. The hot mixture was filtered and the residue was washed with hot ethanol (3×300 ml). The filtrate and washings were combined and the ethanol was evaporated off under reduced pressure to yield 3,4-diformylaminopyridine as a colorless solid. The 3,4-diformylaminopyridine was heated at 200°-220° C. and 0.5 mm.Hg pressure in a Kugelrohr bulb-to-bulb distillation apparatus to yield a crude product as a distillate which solidified on cooling. The crude product was recrystallized from ethyl acetate to yield imidazo[4,5-c]pyridine as a colorless crystalline solid, having a melting point of 174°- 176° C. and the following physical characteristics:
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.CS(N)(=O)=O.[CH3:64][O:65][N:66]([CH3:72])[C:67](=[O:71])[C:68]([CH3:70])=[CH2:69].[OH2:73]>>[OH:73][C@@:68]([CH3:70])([CH2:69][OH:22])[C:67]([N:66]([O:65][CH3:64])[CH3:72])=[O:71]
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: O
Reactant: C=C(C)C(=O)N(C)OC
Agent: CS(N)(=O)=O
Product: CON(C)C(=O)[C@@](C)(O)CO
Temperature: 25 °C
Yield: 118 %

Procedure:
A round bottom flask was charged with 3BuOH (850 mL), water (850 mL), Ad-Mix-β (230 g, 166 mmol) and methanesulfonamide (15.8 g, 166 mmol). The mixture was stirred at ambient temperature until both phases were clear (about 5 minutes) and then cooled to 0° C., after which orange salts precipitated. N-methoxy-N-methylmethacrylamide (21.5 g, 166 mmol) was added and the heterogeneous slurry was stirred vigorously 0° C. for 2 hours and warmed to ambient temperature and stirred for 24 hours. The reaction was quenched by the slow, portionwise addition of sodium bisufite (223 g) and stirred for 1 hour. The reaction mixture was extracted with EtOAc (3×300 mL), dried over sodium sulfate, filtered and concentrated to afford (S)-2,3-dihydroxy-N-methoxy-N,2-dimethylpropanamide (32 g, 196 mmol, 118% yield) as a yellow oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:30])[N:12]([CH3:29])[CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])[N:10]=2)[CH2:3]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C(Cl)Cl>[CH3:31][S:32]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:30])[N:12]([CH3:29])[CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])[N:10]=2)[CH2:3]1)(=[O:34])=[O:33]
Reactant: CN(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.6 %

Procedure:
To a solution of 3-hydroxy-1-(4-{N-methyl-N-[2-(p-nitrobenzyloxycarbonylamino)-ethyl]carbamoyl}-1,3-thiazol-2-yl)azetidine (428.2 mg, 1.01 mmol) (obtained as described in Reference Example 58(4)) in methylene chloride (21.4 ml) were added methanesulfonyl chloride (0.25 ml, 3.23 mmol) and triethylamine (0.45 ml, 3.23 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 6 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (15:1) as the eluant to afford 3-methanesulfonyloxy-1-(4-{N-methyl-N-[2-(p-nitrobenzyloxycarbonylamino)-ethyl]carbamoyl}-1,3-thiazol-2-yl)azetidine (480.1 mg, yield 93%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6](/[CH:7]=[N:8]/[C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][O:12][C:13]3=[O:18])=[CH:5][CH:4]=1.[CH3:23][N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH:29]=O.[O-:31][CH2:32][CH3:33].[Na+].C(O)C>C(OCC)(=O)CC>[CH3:23][N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH:29]1[C:11](=[O:12])[C:10]2[C:14]([C:13]([O:31][CH2:32][CH3:33])=[O:18])=[CH:15][CH:16]=[CH:17][C:9]=2[NH:8][CH:7]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:20][CH:19]=1
Reactant: Cn1ccnc1C=O
Reactant: O=C1OCc2c(/N=C/c3ccc(C(F)(F)F)cc3)cccc21
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(C(F)(F)F)cc1)N2
Temperature: 0 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
A mixture of (E)-4-(4-(trifluoromethyl)benzylideneamino)isobenzofuran-1(3H)-one (1 g, 3.28 mmol) and N-methyl-2-imidazolecarbaldehyde (400 mg, 3.61 mmol) in ethyl propionate (40 mL) was cooled to 0° C. Then a solution of sodium ethoxide in ethanol (sodium (31 mg, 13.1 mmol) in ethanol (10 mL)) was added dropwise. After the addition, the mixture was stirred at room temperature for 2 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=1:1) to give the title compound (150 mg, yield 8%). LC-MS (ESI) m/z: 444 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]([OH:15])=[O:14].[CH2:16]1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COc1ccc2[nH]cc(CC(=O)O)c2c1
Reactant: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)Cc1c[nH]c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A reaction mixture containing 2-(5-methoxy-1H-indol-3-yl)acetic acid (0.5 g, 2.44 mmol) and BOP-Cl (0.62 g, 2.44 mmol) in 7 mL of anhydrous CH2Cl2 was treated with triethyl amine (0.49 g, 4.87 mmol) and allowed to stir at ambient temperature for 5 min. The mixture was then combined with anhydrous methanol (0.34 mL) and continuously stirred overnight at room temperature. Following dilution with dichloromethane (30 mL), the organic solution was washed with water (2×15 mL), dried over Na2SO4, and filtered (using a commercial phase separator syringe with attached drying cartridge). The organic filtrate was collected and concentrated in vacuo and the crude ester was purified by flash chromatography on silica gel (ethyl acetate/hexane gradient) to afford the title compound as viscous yellow oil, which permanently crystallized upon storage at −20° C. (453 mg, 85%). C12H13NO3, Mr=219.24; 1H NMR (400 MHz, DMSO-d6) d: 3.60 (s, 3H), 3.70 (s, 2H), 3.74 (s, 3H), 6.72 (dd, J=2.4/8.8 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 7.19 (d, J=2.4 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 10.77 (s, 1H); LCMS (ESI) tR: 1.95 min (>99%, UV254), m/z: 220.1 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([CH:17]=[O:18])=[C:11]([CH3:19])[C:10]=1[CH:20]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]CC1C=CC=CC=1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:43]>O1CCOCC1.[Ag]=O>[CH2:1]([CH:25]([CH2:24][CH2:23][CH2:22][CH2:21][CH:20]([C:10]1[C:11]([CH3:19])=[C:12]([C:17]([OH:43])=[O:18])[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[C:26]([OH:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C)c(OCc2ccccc2)c(C(CCCCCC(=O)OCc2ccccc2)c2ccc(F)cc2)c(C)c1C=O
Reactant: O
Agent: O=[Ag]
Solvent: C1COCCO1
Product: Cc1c(C)c(C(=O)O)c(C)c(C(CCCCC(Cc2ccccc2)C(=O)O)c2ccc(F)cc2)c1OCc1ccccc1
Reaction time: 288 h

Procedure:
To a solution benzyl 7-(2-benzyloxy-5-formyl-3,4,6-trimethylphenyl)-7-(4-fluorophenyl)heptanoate (2.3 g) in dioxane (20 ml) and water (2 ml) was added silver oxide (II) (4.5 g) and the mixture was stirred for 12 days. Insoluble materials were filtered off and washed with ethyl acetate. The washing was combined with the filtrate and the mixture was concentrated. Ethyl acetate was added and the mixture was washed with water and saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to obtain benzyl 7-(2-benzyloxy-5-carboxy-3,4,6-trimethylphenyl)-7-(4fluorophenyl)heptanoic acid (1.5 g) (Compound 68). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>ClCCl>[CH2:23]([O:22][C:20]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)/[C:6](=[CH:12]/[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)/[C:7]1=[O:11])=[O:21])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C(=O)/C(=C\C2CCCCC2)c2ccc(Cl)cc21
Yield: 95.1 %

Procedure:
In a manner similar to the method described in example 4b, E/Z-6-chloro-3-cyclohexylmethylene-1,3-dihydro-indol-2-one (2.71 g, 10.4 mmol) was reacted with ethyl chloroformate (1.47 mL, 15.6 mmol) and triethylamine (2.89 mL, 20.7 mmol) in dichloromethane to give E/Z-6-chloro-3-cyclohexylmethylene-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester as a brown solid (Yield 3.3 g, 95%).
Reaction SMILES: [CH3:1][C:2]([N+:10]([O-:12])=[O:11])([CH3:9])[CH2:3][CH2:4][C:5](OC)=[O:6].[BH4-].[Na+].[H][H].Cl>CC(=O)OCC.O.C(O)C>[CH3:1][C:2]([N+:10]([O-:12])=[O:11])([CH3:9])[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: COC(=O)CCC(C)(C)[N+](=O)[O-]
Reactant: [H][H]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(CCCO)[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
Methyl 4-methyl-4-nitropentanoate (15.5 g, 96.1 mmol) was added to a 1 L round bottomed flask, dissolved into denatured ethanol (300 ml) and cooled in an ice bath for 15 min. Sodium borohydride (7.27 g, 2 equiv, 190 mmol) was added in one portion. Hydrogen was liberated and slowly subsided. The reaction was stirred at 0° C. for 1 h then placed into a 70° C. water bath for 3 h. Water (150 ml) was poured into the flask and 6 N HCl (25 mL) was added dropwise to adjust the pH˜3 while cooled in an ice bath. The ethanol was removed under reduced pressure to give a suspension. Water (150 mL) and EA (300 mL) were added to the flask and the mixture poured into a separatory funnel. The layers were separated and the organic layer was washed with brine (100 mL), dried over anhydrous MgSO4, filtered and concentrated on a rotovap to give a pale yellow oil (12.0 g, 85.1%). 1H NMR (CDCl3, 400 MHz): ±1.5 (m, 2H), 1.61 (s, 6H), 1.95-2.05 (m, 2H), 3.65 (t, 2H). LRMS (ESI+) for C6H13NO3 (147.1); Found: 148 (MH+).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:18]=[C:19]3[C:27]4[C:26]([Cl:28])=[N:25][CH:24]=[N:23][C:22]=4[NH:21][C:20]3=[O:29])=[C:15]([CH3:17])[CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:30]([N:37]1[C:45]2[C:40](=[CH:41][C:42]([NH2:46])=[CH:43][CH:44]=2)[CH:39]=[CH:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[ClH:28].[N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:18]=[C:19]3[C:27]4[C:26]([NH:46][C:42]5[CH:41]=[C:40]6[C:45](=[CH:44][CH:43]=5)[N:37]([CH2:30][C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:38]=[CH:39]6)=[N:25][CH:24]=[N:23][C:22]=4[NH:21][C:20]3=[O:29])=[C:15]([CH3:17])[CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(Cl)c21
Reactant: Nc1ccc2c(ccn2Cc2ccccc2)c1
Product: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc4c(ccn4Cc4ccccc4)c3)c21
Product: Cl
Yield: 8 %

Procedure:
The title compound (8% yield) was prepared from 5-(4-chloro-6-oxo-6,7-dihydro-pyrrolo[2,3-d]pyrimidin-5-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide and 1-benzyl-1H-indol-5-ylamine according to the procedure described for Example 12. 1H NMR (360 MHz, DMSO-d6) δ 13.44 (br s, 1H, NH), 11.79 (br s, 1H, NH), 10.97 (br s, 1H, HCl), 9.28 (br s, 1H), 8.85 (br s, 1H, CONHCH2), 8.25 (s, 1H, H-vinyl), 7.1-7.5 (m, 10H), 6.89 (br s, 1H), 6.43 (s, 1H), 5.40 (s, 2H), 3.96 (m, 2H, CH2), 3.84 (m, 2H, CH2), 3.68 (m, 2H, CH2), 3.52 (m, 2H, CH2), 3.29 (m, 2H, CH2), 3.12 (m, 2H, CH2), 2.53 (s, 3H, CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: OCc1ccccn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCc4ccccn4)cc3C)c2cc1OC
Yield: 105.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-pyridylmethanol (25 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (75 mg, yield 94%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[C:13]([CH:15]=[N:16][OH:17])[N:12]=[C:11]([CH3:18])[N:10]=1)=[O:8].[CH3:23][N:24]1[CH:29]=[C:28]([CH:30]=[CH2:31])[CH:27]=[CH:26][C:25]1=[O:32].Cl[O-].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[C:13]([C:15]2[CH2:31][CH:30]([C:28]3[CH:27]=[CH:26][C:25](=[O:32])[N:24]([CH3:23])[CH:29]=3)[O:17][N:16]=2)[N:12]=[C:11]([CH3:18])[N:10]=1)=[O:8]
Reactant: Cc1nc(C=NO)cc(C(=O)NCc2ccc(F)c(F)c2)n1
Reactant: C=Cc1ccc(=O)n(C)c1
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: ClCCl
Product: Cc1nc(C(=O)NCc2ccc(F)c(F)c2)cc(C2=NOC(c3ccc(=O)n(C)c3)C2)n1
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
To a solution of N-(3,4-difluorobenzyl)-6-((hydroxyimino)methyl)-2-methylpyrimidine-4-carboxamide (13.60 g, 44.4 mmol, Preparation #A.1.2) and 1-methyl-5-vinylpyridin-2(1H)-one (6 g, 44.4 mmol, Preparation #F.1.13) in DCM (150 mL) was added 9% aqueous sodium hypochlorite solution (80 mL, 1296 mmol, Avra labs) drop wise at 10-15° C. for about 30 min. Reaction mixture was allowed to stir for another 15-30 min, diluted the reaction mixture with water (100 mL) and the product extracted with DCM (2×100 mL). The combined organic layers was dried over sodiumsulphate and evaporated to dryness. The resulting crude material was purified by silica gel column chromatography by eluting with 2% methanol in DCM. Relevant fractions containing product were combined and evaporated under reduced pressure to afford N-(3,4-difluorobenzyl)-2-methyl-6-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide 3 g (15.38%) as pale yellow solid; 1H NMR (400 MHz, DMSO): δ 9.606-9.574 (m, 1H), 8.179 (s, 1H), 7.872-7.866 (d, J=2.4 Hz, 1H), 7.527-7.497 (dd, J=9.6 Hz, 1H), 7.421-7.353 (m, 2H), 7.205-7.173 (m, 1H), 6.436-6.412 (d, J=9.6 Hz, 1H), 5.688-5.637 (m, 1H), 4.504-4.488 (d, J=6.4 Hz, 2H), 3.836-3.764 (m, 1H), 3.463-3.440 (m, 1H), 3.425 (s, 3H), 2.767 (s, 3H); MS m/z: 440.2 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=O)[CH2:3][CH2:2]1.CC(C)C(=O)[CH2:14][C:15]#[N:16]>>[O:9]=[C:7]([CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[CH2:14][C:15]#[N:16]
Reactant: CC(C)C(=O)CC#N
Reactant: COC(=O)C1CCOCC1
Product: N#CCC(=O)C1CCOCC1
Yield: 24 %

Procedure:
Prepared from methyl tetrahydropyran-4-carboxylate (3 g, 20.80 mmol) according to the method described for 4-methyl-3-oxopentanenitrile in Example 122A Step 1, to afford 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanenitrile as a yellow oil (760 mg, 24%) which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 3.96-4.05 (m, 2H), 3.52 (s, 1H), 3.42-3.50 (m, 2H), 2.82 and 2.59 (2×m, 1H), 1.67-1.90 (m, 4H).