Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Br)[CH3:2].[O-]CC.[Na+].[CH2:14]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[OH:29])[C:25](=[O:30])[CH2:24][CH2:23]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O>C(O)C>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][O:29][C:28]1[CH:27]=[C:26]2[C:22](=[CH:21][C:20]=1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:23][CH2:24][C:25]2=[O:30])[CH3:2]
Reactant: CCOC(=O)CCCBr
Reactant: CCCCCCc1cc2c(cc1O)C(=O)CC2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCc1cc2c(cc1OCCCC(=O)OCC)C(=O)CC2

Procedure:
3.6 ml of ethyl4-bromobutyrate dissolved in 15 ml of ethanol are added to a mixture of sodium ethoxide (1.6 g, 0.0233 mol) and 5-hexyl-6-hydroxyindan-1-one (4.5 g, 0.0194 mol) in 45 ml of ethanol. The reaction medium is heated for 5 hours at reflux. The mixture is poured into water and extracted with ether. The organic phase is dried (Na2SO4) and the solvents are evaporated off (5.9 g; 60%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH:13][C:14]2[NH:15][C:16]3[C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[O:12])[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:59]1[C:63]2[CH2:64][CH2:65][CH2:66][CH2:67][C:62]=2[N:61]=[C:60]1[NH2:68]>CN(C=O)C>[NH:59]1[C:63]2[CH2:64][CH2:65][CH2:66][CH2:67][C:62]=2[N:61]=[C:60]1[NH:68][C:23]([C:22]1[C:16]2[N:15]=[C:14]([NH:13][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:12])[NH:18][C:17]=2[CH:19]=[CH:20][CH:21]=1)=[O:25]
Reactant: O=C(Nc1nc2cccc(C(=O)O)c2[nH]1)c1cc2ccccc2cn1
Reactant: Nc1nc2c([nH]1)CCCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2c(C(=O)Nc3nc4c([nH]3)CCCC4)cccc2[nH]1)c1cc2ccccc2cn1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 13 %

Procedure:
To a solution of 70 mg (0.2 mmol) of 2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid in DMF (2 mL) was added 100 mg (0.26 mmol) of HBTU and DIEA (0.3 mL). The mixture was stirred for 5 min, then 100 mg (0.7 mmol) of (4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylamine was added. The resulting reaction mixture was heated at 80° C. for 1.5 h. After usual workup, the residue was purified by column chromatography eluting with DCM/EtOAc (v/v=11:1) to afford 12 mg (13%) of isoquinoline-3-carboxylic acid [4-(4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 452 (M+1)+.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][CH:7]=1>CN(C=O)C>[C:11]1([C:9]2[S:10][C:6]([CH2:5][C:1]#[N:2])=[CH:7][N:8]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [C-]#N
Reactant: BrCc1cnc(-c2ccccc2)s1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1cnc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 10 h
Yield: 73.2 %

Procedure:
KCN (154 mg, 2.36 mmol) was added to a solution of 5-(bromomethyl)-2-phenylthiazole (400 mg, 1.57 mmol) in dry DMF (10 mL). The resulting reaction mixture was stirred at room temperature for 10 h. The mixture was then quenched with water and the organic product was extracted with EtOAc. The combined extracts were washed with H2O and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 20% EtOAc in petroleum ether) to afford 2-(2-phenylthiazol-5-yl)acetonitrile (230 mg, yield 73%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.94-7.90 (m, 2H), 7.76 (s, 1H), 7.47-7.45 (m, 3H), 3.98 (d, J=1.1 Hz, 2H). MS (ESI) m/z: Calculated for C11H8N2S: 200.05. found: 201.2 (M+H)+.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:22](I)=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([F:24])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH:32](=[O:34])[CH3:33]>O1CCCC1>[C:1]12([CH2:11][O:12][C:13]3[C:22]([CH:32]([OH:34])[CH3:33])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([F:24])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC=O
Reactant: COC(=O)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(C)O)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: -40 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a mixture of methyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoate (1.25 g, 2.80 mmol) in anhydrous tetrahydrofuran (10 mL) was added isopropylmagnesium chloride lithium chloride complex (1.3 M solution in tetrahydrofuran, 3.2 mL, 4.20 mmol) at −40° C. The reaction mixture was stirred for 1 hour at −40° C., after which acetaldehyde (0.79 mL, 14.10 mmol) was added. The reaction mixture was allowed to warm to ambient temperature, stirred for 16 hours and then was quenched by addition of saturated ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (2×50 mL) and the combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo gave a residue which was purified by silica gel column chromatography using 0-35% ethyl acetate in hexanes as eluent to afford the title compound as an amorphous solid (0.76 g, 75%): 1H NMR (300 MHz, CDCl3) δ 7.96 (d, J=8.5 Hz, 1H), 6.58 (d, J=12.7 Hz, 1H), 5.16-5.06 (m, 1H), 3.88 (s, 3H), 3.55 (d, J=8.9 Hz, 1H), 3.52 (d, J=9.3 Hz, 1H), 2.27 (d, J=4.8 Hz, 1H), 2.08-1.98 (m, 3H), 1.83-1.61 (m, 12H), 1.49 (d, J=6.5 Hz, 3H); MS (ES+) m/z 345.2 (M−17).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH2:13])=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.[C:15](=N)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO.ClCCCl>[C:15](=[N:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[CH3:12])[C:2]([Cl:1])=[N:3][CH:4]=[CH:5]2)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc2c(Cl)nccc2cc1N
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: ClCCCl
Product: Cc1cc2c(Cl)nccc2cc1N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To a solution of 1-chloro-7-methyl-isoquinolin-6-ylamine (0.1 g, 0.52 mmol) in MeOH (5 mL) at 0° C. is bubbled HCl gas for 1 minute, then the solvent is removed in vacuo. The remaining white solid is diluted with 1,2 dichloroethane and benzophenone imine (0.15 mL, 0.89 mmol) is added. The resulting suspension is heated to reflux for 48 hours, then cooled to room temperature and concentrated to dryness. The crude material is diluted with CH2Cl2 and washed with saturated NaHCO3 solution and brine. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography using 10% EtOAc/hexanes as the eluent to afford the title compound (0.159 g, 0.45 mmol) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[C@@H:7]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:13][C@@H:14]([OH:17])[CH2:15]Cl)([CH3:4])([CH3:3])[CH3:2].[C-:37]#[N:38].[K+].C1OCCOCCOCCOCCOCCOC1>>[C:1]([O:5][C:6](=[O:36])[C@@H:7]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:13][C@@H:14]([OH:17])[CH2:15][C:37]#[N:38])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN(C[C@@H](O)CCl)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN(C[C@@H](O)CC#N)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Yield: 51.1 %

Procedure:
According to the method described for the preparation of 14a, 13b (3.23 g, 6.10 mmol) was reacted with KCN (3.96 g, 60.82 mmol) and 18-crown-6 (242 mg, 0.92 mmol) to obtain 14b (1.62 g, 51%) as a colorless oil: 1H NMR δ 1.20-1.84 (m, 6H), 1.44 (s, 9H), 1.45 (s, 9H), 2.55 (m, 2H), 3.20-3.50 (m, 4H), 3.92 (dd, 1H, J=8.2, 5.1), 4.07 (m, 1H), 5.13 (s, 2H), 7.26-7.41 (m, 5H); 13C NMR δ 24.1, 24.2, 28.3, 28.8, 32.4, 55.7, 67.1, 68.4, 80.4, 82.5, 118.9, 129.0, 129.2, 129.6, 138.0, 158.1, 173.7; HRMS m/z calcd for C27H42N3O7 520.3023, found 520.3048. Anal. calcd. for C27H41N3O7: C 62.41, H 7.95, N 8.09. Found: C 62.14, H 7.95, N 7.97. [α]22D−5.3 (c 1.15, CH3OH).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1[N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CO.Cl>C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(N1CCc2ccc(Cl)c(N3CCCC3c3ccccc3)c2CC1)C(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Clc1ccc2c(c1N1CCCC1c1ccccc1)CCNCC2
Yield: 82 %

Procedure:
Treat (+/−)-7-chloro-3-(2,2,2-trifluoroacetyl)-6-(2-phenyl-pyrrolidin-1-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (prepared essentially as described in Preparation 38) (80 mg, 0.19 mmol) with basic methanol in a similar fashion to the isolated enantiomers of (+/−)-7-chloro-3-(2,2,2-trifluoroacetyl)-6-(2-phenyl-pyrrolidin-1-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine. Treat the resultant residue with excess 2 N HCl in diethyl ether to give the product as a white solid (57 mg, 82%).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)[CH:10]=2)[N:5]=[C:4]([S:25][CH3:26])[CH2:3]1>C1COCC1.CCO.[Li+].[OH-]>[CH3:1][C:2]1([CH3:27])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)[CH:10]=2)[N:5]=[C:4]([S:25][CH3:26])[CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(SC)=N3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CSC1=Nc2ccc(C#Cc3ccc(C(=O)O)cc3)cc2C(C)(C)C1

Procedure:
A solution of 0.100 g (0.30 mmol) of ethyl 4-[(4,4-dimethyl-2-methylthio-3,4-dihydro-6-quinolinyl)ethynyl]benzoate (Compound 9) in 2 ml of THF, 1 ml of EtOH and 2 ml of 1N LiOH was stirred at room temperature for 1 h, followed by aqueous work up to yield the title compound as a yellow solid.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[C:17]([F:20])([F:19])[F:18])=[C:12]([OH:22])[CH:11]=1>CO>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[N:7][OH:8])[C:17]([F:20])([F:19])[F:18])=[C:12]([OH:22])[CH:11]=1
Reactant: NO
Reactant: O=C(c1ccc(Br)cc1O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=C(c1ccc(Br)cc1O)C(F)(F)F
Temperature: 64 °C

Procedure:
To a round bottom flask were added sodium acetate (9.46 g, 115 mmol), hydroxylamine hydrochloride (7.09 g, 102 mmol) and MeOH (10 mL). To this mixture was added a solution consisting of 1-(4-bromo-2-hydroxy-phenyl)-2,2,2-trifluoro-ethanone (2.5 g, 9.3 mmol) and MeOH (62 mL). The reaction vessel was heated at 64° C. for 7 h before cooling to rt and pouring the reaction mixture into ice water (100 mL). The aqueous solution was then extracted with EtOAc (75 mL×2) and the organic layers dried (Na2SO4) and concentrated to yield the title compound as a mixture of the two possible oxime isomers (2.64 g, 100%).
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[CH:34])=[N:31][CH:32]=2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[C:34][C:2]3[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=3)=[N:31][CH:32]=2)=[CH:25][CH:26]=1
Reactant: FC(F)(F)c1cc(I)ccc1OCCN1CCCC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: FC(F)(F)c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
Prepared according to general working method I from 1-[2-(4-iodo-2-trifluoromethyl-phenoxy)-ethyl]-pyrrolidine (180 mg, 0.47 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (83 mg, 0.39 mmol).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]Br)(=[O:3])[CH3:2].CS(C)=O.[CH3:15][O:16][C:17]([CH:19]1[CH2:24][CH2:23][C:22]2[CH:25]=[C:26]([C:30](=[O:32])[CH3:31])[C:27]([OH:29])=[CH:28][C:21]=2[O:20]1)=[O:18].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:15][O:16][C:17]([CH:19]1[CH2:24][CH2:23][C:22]2[CH:25]=[C:26]([C:30](=[O:32])[CH3:31])[C:27]([O:29][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[CH:28][C:21]=2[O:20]1)=[O:18]
Reactant: COC(=O)C1CCc2cc(C(C)=O)c(O)cc2O1
Reactant: CC(=O)OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C1CCc2cc(C(C)=O)c(OCCCCCOC(C)=O)cc2O1
Temperature: 25 °C
Reaction time: 19 h
Yield: 105.1 %

Procedure:
A 12-L three-neck, round-bottom flask equipped with a mechanical stirrer and a nitrogen bubbler, was charged with 375.0 g (1.79 moles) of 5-bromo-1-pentanyl acetate, 3.5 L of dimethyl sulfoxide, 407.0 g (1.63 moles) of rac-6-acetyl-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid methyl ester and 510.0 g of anhydrous granular potassium carbonate in finely powdered form. The mixture was stirred at room temperature under nitrogen for 19 hours, poured into an extractor containing 10 L of deionized water, and extracted with 2×4 L and 1×2 L=10 L of ethyl acetate. The organic layer was washed with 2×4 L=8 L of 1:1 deionized water-saturated brine, followed by 2 L of saturated brine, dried (anhydrous sodium sulfate), and filtered. The solvent was removed at 45°/70 mm and then under high vacuum to give 648.3 g of crude rac-6-acetyl-3,4-dihydro-7-[(5-acetoxypentyl)oxy]-2 H-1-benzopyran-2-carboxylic acid methyl ester. The crude product was dissolved in 2 L of anhydrous ether and the solution was poured into a 12 L three-neck flask equipped with a mechanical stirrer. The stirred solution was cooled in an ice-bath and 2 L of petroleum ether (35°-60°) was slowly added, which resulted in the formation of a precipitate heavy enough to stop the stirrer. The solid was broken with a spatula and stirring was continued in the ice-bath for 1 hour. The product was collected by filtration, washed with cold (3°) 1:1 ether-petroleum ether, and dried at room temperature under high vacuum to give 601.5 g (97.7% yield) of rac-6-acetyl-3,4-dihydro-7-[(5-acetoxypentyl)oxy]-2H-1-benzopyran-2-carboxylic acid methyl ester as a white powder, mp 37°-49° C. UV (EtOH): λ max, 312 (ε=7,200), 268 (ε=11,200), 230 (ε=16,900), and 216 (ε=19,000) nm; MS: m/z 378 (M+, 40).
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].Cl[CH2:6][C:7]1[CH:8]=[C:9]([CH:30]=[CH:31][N:32]=1)[C:10]([NH:12][C:13]1[O:14][C:15]2[C:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:20][CH:19]=[C:18]([O:28][CH3:29])[C:16]=2[N:17]=1)=[O:11].Cl>O1CCOCC1.CN(C)C=O>[CH3:1][O:2][CH2:6][C:7]1[CH:8]=[C:9]([CH:30]=[CH:31][N:32]=1)[C:10]([NH:12][C:13]1[O:14][C:15]2[C:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:20][CH:19]=[C:18]([O:28][CH3:29])[C:16]=2[N:17]=1)=[O:11]
Reactant: CO
Reactant: COc1ccc(C2CCOCC2)c2oc(NC(=O)c3ccnc(CCl)c3)nc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COCc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCOCC4)c3o2)ccn1
Temperature: 50 °C
Yield: 67.1 %

Procedure:
To a stirred solution of 0.05 ml (1.24 mmol) methanol in 5 ml dioxane and 1 ml N,N-dimethylformamide at room temperature was added 27 mg (0.62 mmol) sodium hydride (55% dispersion in mineral oil), and the mixture heated at 50° C. for 1 hour. 50 mg (0.12 mmol) 2-chloromethyl-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl]-isonicotinamide was then added, and the mixture heated at 50° C. for 20 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was acidified with 1 N aq. hydrochloric acid and then extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (dichloromethane) followed by trituration in ether afforded 32 mg (65%) 2-methoxymethyl-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl]-isonicotinamide as a white crystalline solid. ES-MS m/e (%): 398 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:22][CH:23]=[CH2:24])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:33])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([C:8]1([CH2:22][CH:23]2[CH2:24][O:33]2)[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@]1(C(=O)OC(C)(C)C)CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1CC(CC2CO2)(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.1 %

Procedure:
(3S)-3-Allyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (4.9 g, 14.9 mmol) was dissolved in methylene chloride, and mCPBA (10.3 g, 59.5 mmol) was added. The mixture was stirred at room temperature for 15 hours and then heated to reflux for three hours. The solvent was evaporated under reduced pressure, and then the residue was blended with a mixture of ethyl acetate and a saturated sodium thiosulfate solution. The organic layer was washed with saturated sodium bicarbonate water, dried over magnesium sulfate, and filtered, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=4:1→1:1) to give 4.33 g (84%) of the colorless oil title compound as a diastereomer mixture. The diastereomers were used for the next step without separation and purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[OH:24])[N:9]=[N:8][CH:7]=1)=[O:5])[CH3:2].[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28]Br>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:28][C:27]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:26]=2[F:25])[N:9]=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CCOC(=O)c1cnnc(C2=C(c3cc(Cl)ccc3O)CCC2)c1
Product: CCOC(=O)c1cnnc(C2=C(c3cc(Cl)ccc3OCc3ccc(F)cc3F)CCC2)c1

Procedure:
Prepared by general procedure F(iii) but using 6-{2-[5-chloro-2-(hydroxy)phenyl]cyclopent-1-enyl}-pyridazine-4-carboxylic acid ethyl ester instead of 6-{2-[5-methyl-2-(hydroxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylic acid ethyl ester and 2,4-difluorobenzyl bromide instead of 4-fluorobenzyl bromide.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(CC)CC)C.[CH3:30][C:31]1[N:32]=[C:33]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[S:34][C:35]=1[C:36](Cl)=[O:37]>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:36]([C:35]3[S:34][C:33]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[N:32][C:31]=3[CH3:30])=[O:37])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccccc2)sc1C(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.45 g, 4.5 mmol) in CH3CN (25 ml), were added triethyl amine (1.56 mL, 11.22 mmol) and 4-methyl-2-phenyl-1,3-thiazole-5-carbonyl-chloride (1.07 g, 4.5 mmol). The mixture was stirred at room temperature overnight. The resulting suspension was filtered, and the solid was rinsed with CH3CN (20 mL), water (2×20 mL) and EtOAc (20 mL) to afford 4-methyl-2-phenyl-thiazole-5-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a white solid (1.45 g, 66%): mp, 277-279° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient from 10/90 (CH3CN/H2O) to 95/5(CH3CN/H2O) in 10 minutes: tR=6.96 min. (99%); 1H NMR (DMSO-d6): δ 2.08-2.10 (m, 1H), 2.55-2.59 (m, 2H), 2.66 (s, 3H), 2.86-2.98 (m, 1H), 4.91 (d, J=5.6 Hz, 2H), 5.18 (dd, J=6, 12 Hz, 1H), 7.53-7.98 (m, 8H), 8.91 (t, J=5.6 Hz, 1H), 11.16 (s, 1H). 13C NMR (DMSO-d6) δ: 17.20, 30.92, 38.56, 48.87, 121.98, 125.65, 126.65, 126.25, 127.18, 129.37, 130.95, 131.57, 132.36, 133.15, 134.85, 138.83, 155.65, 161.37, 166.14, 166.93, 167.51, 169.82, 172.75. Anal Calcd for C25H20N4O5S: C, 61.47; H, 4.13; N, 11.47; S: 6.56. Found: C, 61.44; H, 4.04; N, 11.63; S: 6.49.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:23])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11].Cl[C:25]1[O:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[NH:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:23])[S:15][C:16]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:11]
Reactant: Cc1nc(C(=O)N2CCCC(C)C2CN)c(-c2ccccc2)s1
Reactant: Clc1nc2ccccc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CNc2nc3ccccc3o2)c(-c2ccccc2)s1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of (2-(aminomethyl)-3-methylpiperidin-1-yl)(2-methyl-5-phenylthiazol-4-yl)methanone, 2-chlorobenzoxazole, and DIPEA in CH2Cl2 was stirred at 60° C. overnight. The reaction mixture was concentrated in vacuo to leave a near colorless solid. This solid was triturated with Et2O/hexanes to leave the title compound as a colorless solid homogeneous by HPLC analysis. MS (ESI) 447.03 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:21]([O:23][C:24]([C:26]1[C:27](=[O:49])[C:28]2[CH:33]=[N:32][C:31](S(C)(=O)=O)=[N:30][C:29]=2[N:38]([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[CH2:45][CH2:44][CH2:43]3)[CH:39]=1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C:26]1[C:27](=[O:49])[C:28]2[CH:33]=[N:32][C:31]([NH:20][C:17]3[CH:16]=[CH:15][C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:19][CH:18]=3)=[N:30][C:29]=2[N:38]([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[CH2:45][CH2:44][CH2:43]3)[CH:39]=1)=[O:25])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(N4CCNCC4)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (52 mg, 0.19 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 70 mg, 0.17 mmol). A yellow solid was obtained (75 mg, 86%) after a preparative HPLC (32 mL min 5-100% MeCN/H2O gradient over 10 min) purification. The Boc group was removed by treatment with TFA in CH2Cl2 (1:1 v/v) to give the title compound. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.25 (s, 1H), 8.45 (s, 1H), 7.61 (br, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.21 (s, 1H), 7.14 (br, 2H), 7.10 (d, J=7.9 Hz, 1H), 6.57 (br, 2H), 4.30 (q, J=7.1 Hz, 2H), 3.02-2.90 (m, 12H), 2.15 (m, 2H), 1.30 (t, J=7.1 Hz, 3H).