Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:38])[CH2:10][N:11]([C:21](=[O:37])[CH2:22][N:23]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])CC1C=CC=CC=1)[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)C1C=CC=CC=1.[H][H].[ClH:41].CCOCC>C(O)C.[C].[Pd]>[ClH:41].[CH2:35]([O:34][C:32]([CH2:31][NH:23][CH2:22][C:21]([N:11]([CH:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20]1)[CH2:10][C:9]([OH:38])=[O:8])=[O:37])=[O:33])[CH3:36]
Reactant: [H][H]
Reactant: CCOC(=O)CN(CC(=O)N(CC(=O)OCc1ccccc1)C1Cc2ccccc2C1)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CNCC(=O)N(CC(=O)O)C1Cc2ccccc2C1

Procedure:
N-(N'-Ethoxycarbonylmethyl-N'-benzylglycyl)-N-(indan-2-yl)glycine benzyl ester (3 g) is dissolved in 100 ml of ethanol, and catalytic reduction is carried out at ordinary temperature and pressure using 5% palladium-carbon as catalyst. After absorption of 2 equivalents of hydrogen, the reaction mixture is filtered to remove the catalyst. The ethanol is distilled off under reduced pressure to give an oily substance. Addition of ethanolic hydrochloric acid with 100 ml of ether to the oily substance gives N-(N'-ethoxycarbonylmethylglycyl)-N-(indan-2-yl)glycine hydrochloride as colorless powder.
Reaction SMILES: O1CCCC1.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([N+:33]([O-])=O)[CH:31]=4)[NH:26][C:25](=[O:36])[CH:24]=3)[CH2:17][CH2:16]2)=[CH:7]1>CO>[NH2:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:36])[CH:24]=[C:23]2[CH2:22][CH2:21][N:18]1[CH2:17][CH2:16][CH:15]([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:6][CH:7]=2)[CH2:20][CH2:19]1
Reactant: O=c1cc(CCN2CCC(c3c[nH]c4ccccc34)CC2)c2cc([N+](=O)[O-])ccc2[nH]1
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2[nH]c(=O)cc(CCN3CCC(c4c[nH]c5ccccc45)CC3)c2c1
Temperature: 55 °C
Reaction time: 4 h
Yield: 77.3 %

Procedure:
Into a mixed solvent of tetrahydrofuran (800 ml) and methanol (200 ml) was dissolved 4-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-6-nitro-2(1H)-quinolinone (III-19) (6 g, 14.4 mmol) under heating. Paladium on carbon (2.5 g) was added thereto and the mixture was stirred under hydrogen atmosphere at 55 ° C. for 4 hours. The reaction mixture was filtered at the same temperature and the solvent was distilled off from the filtrate. The residue was dried and then recrystallized from a mixture of methanol, THF and water to give the desired product (III-20) (4.3 g) as pale yellow crystals (mp 214°-216 ° C. (methanol/tetrahydrofuran water)). Yield 77.3 %.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([OH:14])[CH:5]=[CH:4][C:3]1=2.Br[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1>>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Product: CC1(C)CCC(C)(C)c2cc(Oc3ccc(C=O)cc3)ccc21

Procedure:
In a manner similar to Example 1(a) above, by the reaction of 5.3 g (15 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol with 3.1 g (16.5 mmol) of 4-bromobenzaldehyde, 2.4 g of the expected aldehyde of melting point 75-6° C. were obtained after purification by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (50/50).
Reaction SMILES: [CH2:1]([NH:9][C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][N:18]3[C:22](=[O:32])[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:25]=[C:17]23)[CH:13]=[CH:12][N:11]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:33]C1C=CC=CC=1CCN>>[Cl:33][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][CH2:1][NH:9][C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][N:18]3[C:22](=[O:32])[CH:23]=[C:24]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:25]=[C:17]23)[CH:13]=[CH:12][N:11]=1
Reactant: O=c1cc(-c2ccccc2)cc2n1CCCN2c1ccnc(NCCc2ccccc2)n1
Reactant: NCCc1ccccc1Cl
Product: O=c1cc(-c2ccccc2)cc2n1CCCN2c1ccnc(NCCc2ccccc2Cl)n1

Procedure:
Followed the same procedure described for the synthesis of 1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro -pyrido[1,2-a]pyrimidin-6-one, the sulfoxide (0.22 g, 0.6 mmol) was displaced with 2-(2-chlorophenyl)ethylamine (0.25 mL, 1.8 mmol) to give the title compound as a yellow solid. MS m/e 458 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[C:12]([OH:18])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].IC.[C:21]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[C:12]([O:18][CH3:21])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1oc2c(Cl)cc(Cl)c(O)c2c1C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1oc2c(Cl)cc(Cl)c(OC)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To 120 mg of 5,7-dichloro-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 1 mL of iodomethane, 200 mg of K2CO3 and 4 mL of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate solution was washed with brine. Removal of the solvent in vacuo gave 125 mg (99% yield) of 5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([N:26]([CH3:28])[CH3:27])[C:23]([F:29])=[CH:22][C:21]=1B(O)O>>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:21]2[CH:22]=[C:23]([F:29])[C:24]([N:26]([CH3:27])[CH3:28])=[CH:25][C:20]=2[Cl:19])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Reactant: CN(C)c1cc(Cl)c(B(O)O)cc1F
Product: CN(C)c1cc(Cl)c(-c2ccnc(OCc3ccccc3)c2[N+](=O)[O-])cc1F
Yield: 58.9 %

Procedure:
2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et. al. WO 99/01454) (800 mg, 3.02 mmol) and 2-chloro-4-dimethylamino-5-fluorophenylboronic acid (Example B) (854 mg, 3.93 mmol) were treated substantially as described in Part A of Example 19a to give 715 mg (59%) of 2-benzyloxy-4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridine: 1H NMR (400 MHz, CDCl3) δ ppm 8.27 (d, J=5.4 Hz, 1 H), 7.45–7.43 (m, 2H), 7.40–7.29 (m, 3H), 6.93 (d, J=5.4 Hz, 1 H), 6.89 (d, J=13.2 Hz, 1 H), 6.85 (d, J=8.0 Hz, 1 H), 5.53 (s, 2 H), 2.91 (d, J=1.2 Hz, 6 H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3Br)[CH2:5][C:4]=2[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>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(O)C>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: Nc1ncc2c(n1)CC(c1ccc(F)cc1Br)CC2=O
Reactant: OB(O)c1cccnc1
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: CCO
Product: Nc1ncc2c(n1)CC(c1ccc(F)cc1-c1cccnc1)CC2=O
Temperature: 150 °C

Procedure:
To a microwave vessel was added 2-amino-7-(2-bromo-4-fluoro-phenyl)-7,8-dihydro-6H-quinazolin-5-one (30 mg, 0.089 mmol), example 2/i stage 2, pyridine-3-boronic acid (22 mg, 0.11 mmol), potassium carbonate (51 mg, 0.22 mmol) and tetrakis(triphenylphosphine)palladium (9 mg, 5 mol %), in a 2:1 mixture of ethanol:toluene (1 ml) and the suspension thoroughly degassed. The reaction mixture was then heated in a CEM microwave at 300 W, 150° C. with a 5 min ramp time and a hold time of 30 min. On completion of the reaction the solution was filtered through celite and then the cake further washed with fresh methanol. The combined washings were evaporated to give a pale yellow residue which was triturated with fresh diethyl ether and the desired product removed by filtration as a pale yellow solid.
Reaction SMILES: C([Si]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH:16]2[CH2:18][CH2:17]2)=[CH:11][C:10]=1[CH3:19])(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>C1COCC1>[CH:16]1([C:12]2[CH:11]=[C:10]([CH3:19])[C:9]([OH:8])=[C:14]([CH3:15])[CH:13]=2)[CH2:18][CH2:17]1
Reactant: Cc1cc(C2CC2)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(C2CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a suspension of (4-bromo-2,6-dimethylphenoxy)tert-butyldimethylsilane (668 mg, 2.12 mmol) and tetrakis(triphenylphosphine)palladium (122 mg, 0.11 mmol) in THF (20 mL) was added cyclopropyl zinc chloride (28.0 mL, 11.2 mmol). The mixture was heated at 80° C. for 24 h and cooled to room temperature. The reaction was passed through a short pad of SiO2 to remove the catalyst and the solution was concentrated to oil. The resulting oil was diluted in EtOAc (100 mL), washed with brine (100 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=90:10) yielded 370 mg (63%) of tert-butyl(4-cyclopropyl-2,6-dimethylphenoxy)dimethylsilane. To tert-butyl(4-cyclopropyl-2,6-dimethylphenoxy)dimethylsilane (320 mg, 1.16 mmol) in THF (10 mL) was added a solution of tetrabutylammonium fluoride (5.0 mL, 1 M in THF, 5.0 mmol) and acetic acid (0.40 mL). The reaction was stirred at room temperature for 3 h and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=85:15) yielded 175 mg (93%) of 4-cyclopropyl-2,6-dimethylphenol as a light yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([OH:8])[N:5]2[N:9]=[C:10]([C:21]([F:24])([F:23])[F:22])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])=[C:4]2[N:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(O)C.C(OCC)(=O)C>[Cl:20][C:14]1[C:15]([Cl:19])=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][C:11]1[C:10]([C:21]([F:24])([F:23])[F:22])=[N:9][N:5]2[C:6]([OH:8])=[CH:7][C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:3][C:4]=12
Reactant: C1COCCN1
Reactant: Oc1cc(Cl)nc2c(Cc3cccc(Cl)c3Cl)c(C(F)(F)F)nn12
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1cc(N2CCOCC2)nc2c(Cc3cccc(Cl)c3Cl)c(C(F)(F)F)nn12

Procedure:
To a solution of 5-chloro-3-[(2,3-dichlorophenyl)methyl]-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-ol (79 mg, 0.2 mmol) in ethanol (2 mL) was added morpholine (87 mg, 0.99 mmol) in a microwave reaction vessel. It was sealed and irradiated (microwave) at 150° C. for three hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with 5% HCl solution (5 mL). Organic layer was dried, filtered, and concentrated. The crude product was purified by reverse-phase HPLC to provide the titled compound. (28 mg, 31%); LC/MS: MS (ES+) m/e 447 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 3.35 (br. s., 4H) 3.65-3.75 (m, 4H) 4.19 (s, 2H) 5.22 (s, 1H) 6.84 (s, 1H) 7.25 (t, J=7.96 Hz, 1H) 7.52 (s, 1H) 11.28 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[Li]CCCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C>C1COCC1>[CH3:9][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:15]([OH:20])[OH:16]
Reactant: CSc1ccccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccccc1B(O)O
Reaction time: 0.42 h
Yield: 84.9 %

Procedure:
2-Bromothioanisole (29.0 g, 143 mmol) was dissolved in dry THF (400 mL) and cooled to -75° C. n-BuLi (62.0 mL, 2.5 M in hexane, 155 mmol) was added over 50 minutes. After stirring 25 minutes, triisopropyl borate (46 mL, 199 mmol) was added over 35 minutes. The cold bath was removed and the reaction was stirred at room temp for 16 hours. The resulting solution was cooled in an ice bathours, and 6 M HCl (100 mL) was added. This mixture was stirred at room temp 5 hours and concentrated to about half of the original volume. The concentrated solution was partitioned between Et2O and water. The organic layer was extracted with 2 M NaOH, which was subsequently reacidified with 6 M HCl and extracted several times back into Et2O. These Et2O washes were dried over Na2SO4, filtered, and evaporated to yield a beige solid (20.4 g, 85%). 1H NMR (CDCl3): δ8.01 (dd, 1H, J=7.3, J'=1.4), 7.53 (dd, 1H, J=7.7, J'=1.1), 7.43 (td, 1H, J=7.3, J'=1.8), 7.34 (td, 1H, J=7.3, J'=1.5), 6.22 (s, 2H) , 2.50 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:21]=[CH:20][C:12]2[N:13]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[N:14]=[N:15][C:11]=2[C:10]=1[C:22]([F:25])([F:24])[F:23])C1C=CC=CC=1>CO.C(OCC)(=O)C>[CH:17]1([CH2:16][N:13]2[C:12]3[CH:20]=[CH:21][C:9]([OH:8])=[C:10]([C:22]([F:24])([F:25])[F:23])[C:11]=3[N:15]=[N:14]2)[CH2:19][CH2:18]1
Reactant: FC(F)(F)c1c(OCc2ccccc2)ccc2c1nnn2CC1CC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1ccc2c(nnn2CC2CC2)c1C(F)(F)F
Reaction time: 1.5 h

Procedure:
5-Benzyloxy-1-(cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazole (5.04 g, 14.5 mmol) was dissolved in 1:1 mixture of methanol/ethyl acetate (40 mL), sparged under nitrogen, treated with Pearlman's catalyst (2 g, 0.2 wt equiv) and then sparged under hydrogen (1 atm). After stirring vigorously for 90 minutes, the mixture was filtered through a pad of Celite, which was washed with methanol (500 mL) and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C[O-].[Na+].CO.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[CH2:24][CH2:25][C:26](Cl)=[N:27]O>O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[CH2:24][CH2:25][C:26]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:1]([CH:2]([CH3:4])[CH3:3])[O:5][N:27]=1
Reactant: COC(=O)CC(=O)C(C)C
Reactant: ON=C(Cl)CCc1c(Cl)cccc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(CCc2c(Cl)cccc2Cl)noc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
A solution of methyl isobutyrylacetate (0.662 g, 5.8 mmol) in tetrahydrofuran (1.16 mL) was stirred at 0° C. as 0.5 N sodium methoxide in methanol solution (11.6 mL, 5.8 mmol) was added. A solution of 3-(2,6-dichlorophenyl)-N-hydroxypropanimidoyl chloride (1.04 g, 4.82 mmol) in tetrahydrofuran (3.8 mL) was added and the solution was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated and the residue triturated with water and filtered to yield a white solid which was dried in a 45° C. oven with P2O5 under reduced pressure to yield the title compound (0.926 g, 56%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([O:13][Si](C(C)(C)C)(C)C)[C:5]=1[CH2:21]Br.[CH3:24][NH2:25].CO.Cl>C1COCC1>[OH:13][C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]2[C:5]=1[CH2:21][N:25]([CH3:24])[C:3]2=[O:2]
Reactant: COC(=O)c1c([N+](=O)[O-])ccc(O[Si](C)(C)C(C)(C)C)c1CBr
Reactant: CN
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CN1Cc2c(O)ccc([N+](=O)[O-])c2C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
At room temperature, a solution of 2-bromomethyl-3-(tert-butyl-dimethyl-silanyloxy)-6-nitro-benzoic acid methyl ester (12.6 g, 25.1 mmol) in 60 mL of THF is added 2M solution of methylamine in THF (37.7 mL, 75.3 mmol) at 0° C. and then the reaction mixture is stirred for 6 hours at the room temperature. Methanol and 1M Hydrochloric acid solution are added to the reaction mixture. The mixture is evaporated in vacuo and the precipitate is collected to give 4-hydroxy-2-methyl-7-nitro-2,3-dihydro-isoindol-1-one (2.1 g) as yellow solid in 40% yields for 3 steps.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[CH:4][C:3]1=[O:8].[Br:9]Br.C(N(CC)CC)C>CO>[CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([Br:9])[C:3]1=[O:8]
Reactant: CN1C(=O)C=CC1=O
Reactant: BrBr
Solvent: CCN(CC)CC
Solvent: CO
Product: CN1C(=O)C=C(Br)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
To N-methyl maleimide (0.5 g, 4.5 mmol) in methanol (22.5 mL) was added bromine (0.52 mL, 10 mmol) dropwise. The reaction mixture was stirred at room temperature for 24 hours. Solvent was removed in vacuo and the reaction mass was dissolved in tetrahydrofuran (20 mL) and triethylamine (0.8 mL, 5.85 mmol) added, then stirred for 24 hours at room temperature. The material was purified by flash chromatography on silica gel (petroleum ether: ethyl acetate, 7:3) to afford a pale white powder (0.761 g, 4.0 mmol) in 89% yield.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[S+](C)(C)=O.[F:13][C:14]1[CH:15]=[C:16]([CH2:38][N:39]2[CH2:42][CH:41]([C:43]([O:45][CH3:46])=[O:44])[CH2:40]2)[CH:17]=[CH:18][C:19]=1[C:20]1[S:21][C:22]2[C:27]([N:28]=1)=[CH:26][CH:25]=[C:24]([C:29]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[CH2:30])[N:23]=2>CS(C)=O.C1COCC1>[F:13][C:14]1[CH:15]=[C:16]([CH2:38][N:39]2[CH2:40][CH:41]([C:43]([O:45][CH3:46])=[O:44])[CH2:42]2)[CH:17]=[CH:18][C:19]=1[C:20]1[S:21][C:22]2[C:27]([N:28]=1)=[CH:26][CH:25]=[C:24]([C:29]1([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[CH2:1][CH2:30]1)[N:23]=2
Reactant: CC(C)(C)[O-]
Reactant: C=C(c1ccc(F)cc1)c1ccc2nc(-c3ccc(CN4CC(C(=O)OC)C4)cc3F)sc2n1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccc(F)cc6)CC5)nc4s3)c(F)c2)C1
Reaction time: 0.5 h

Procedure:
To a solution of potassium tert-butoxide (0.080 g, 0.71 mmol) and trimethylsulfoxonium iodide (0.16 g, 0.71 mmol) in 2 mL DMSO was added slowly dropwise a solution of methyl 1-((3-fluoro-4-(5-(1-(4-fluorophenyl)vinyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylate (0.170 g, 0.36 mmol) in 2 mL THF, with 1 mL rinse. The solution became colored. After 30 min, the reaction mixture was quenched with sat'd aq. NH4Cl and EtOAc. The organic layer was washed with water, then brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The material was treated with DCM and adsorbed onto 1.5 g silica gel and passed through a Redi-Sep® pre-packed silica gel column (12 g) using 0-100% EtOAc/hexane. The product-containing fractions were concentrated to afford methyl 1-((3-fluoro-4-(5-(1-(4-fluorophenyl)-cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylate as a yellow solid. MS (ESI) m/z: calculated: 491.2; Observed: 492.1 (M++1).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[C:26](OC(=O)C)(=[O:28])[CH3:27].C(N(CC)CC)C>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:26](=[O:28])[CH3:27])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: CC(=O)OC(C)=O
Agent: CS(=O)(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.75 g, 2.0 mmol) and acetic anhydride (0.19 mL, 2.0 mmol) in acetonitrile (20 mL), was added triethylamine (0.56 mL, 4.0 mmol) at room temperature under nitrogen. After 1 h, the solids were isolated by filtration. The crude product was triturated in water (20 mL) for 1.0 h, then isolated by filtration and dried in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-acetamide as a white solid (0.47 g, 75% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 3.28 min (96.26%); mp: 183-185° C.; 1H NMR (DMSO-d6) δ 1.89 (s, 3H, CH3), 1.93-2.07 (m, 1H, CHH), 2.26-2.48 (m, 1H, CHH), 2.54-2.70 (m, 1H, CHH), 2.77-3.04 (m, 1H, CHH), 4.22-4.51 (m, 4H, CH2, CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 7.39 (d, J=7.9 Hz, 1H, Ar), 7.47 (s, 1H, Ar), 7.68 (d, J=7.9 Hz, 1H, Ar), 8.45 (t, J=5.8 Hz, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 22.56, 31.21, 42.14, 47.10, 51.59, 122.08, 122.90, 127.05, 130.32, 142.36, 143.95, 167.93, 169.25, 171.00, 172.86; LCMS: MH=316; Anal Calcd for C16H17N3O4: C, 60.94; H, 5.43; N, 13.33. Found: C, 60.61; H, 5.31; N, 13.30.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][F:11])[C:5]([CH:8]=C)=[N:6][CH:7]=1.I([O-])(=O)(=O)=[O:13].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][F:11])[C:5]([CH:8]=[O:13])=[N:6][CH:7]=1
Reactant: C=Cc1ncc(Cl)cc1CF
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ncc(Cl)cc1CF
Reaction time: 0.08 h
Yield: 83.4 %

Procedure:
To a solution of 5-chloro-3-(fluoromethyl)-2-vinylpyridine (65 mg, 0.38 mmol) in THF (2.3 mL) and water (3.5 mL) was added a solution of osmium tetroxide (2.5 wt % in 2-methyl-2-propanol, 80 μl, 0.038 mmol, Aldrich). After 5 min, sodium meta-periodate (122 mg, 0.568 mmol, Aldrich) was added in one portion and the reaction mixture was allowed to stir for 1 h. The reaction mixture was partitioned between brine and EtOAc. The organic phase was separated and dried over MgSO4. The filtrate was absorbed onto a plug of silica gel and purified by chromatography, eluting with a gradient of 5% to 45% EtOAc in hexane, to provide the title compound as grey solid (55 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([S:9][CH:10]1[N:13]([CH:14](Cl)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C:12](=[O:29])[CH2:11]1)=[O:8].[C:30]1([P:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1C(C)=CC=CC=1C>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([S:9][CH:10]1[N:13]([C:14](=[P:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C:12](=[O:29])[CH2:11]1)=[O:8]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COCCOCC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: COCCOCC(=O)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 50 h
Yield: 43.2 %

Procedure:
A mixture of p-nitrobenzyl 2-[4-(2-methoxyethoxyacetylthio)-2-oxo-1-azetidinyl]-2-chloroacetate (761 mg.), triphenylphosphine (524 mg.; 2.00 mmoles) and 2.6-lutidine (0.235 ml.; 214 mg.; 2.00 mmoles) in tetrahydrofuran (7 ml.) was stirred under N2 atmosphere at room temperature for 50 hours. After filtration of the precipitate, the filtrate was evaporated to yield 1.39 g. of a crude oil. This oil was purified by column chromatography (SiO2 ; 30 g.; eluant-ethyl acetate) yielding title product (494 mg.; 0.736 mmole; yield 42.3% based on starting ester) as a brownish oil.