Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)(O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:28])CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)([F:28])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(c2cc(F)cc(F)c2)CCN(Cc2ccccc2)C1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Fc1cc(F)cc(C2(F)CCN(Cc3ccccc3)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To a cooled (0° C.) solution of 1-benzyl-3-(3,5-difluorophenyl)pyrrolidin-3-ol (1.9 g, 6.6 mmol) in dichloromethane (20 mL) was added dropwise diethylaminosulphurtrifluoride (1.05 mL, 7.26 mmol) dissolved in dichloromethane (5 mL) and the mixture was stirred at ambient temperature for 1 h. Additional diethylaminosulphurtrifluoride (0.1 mL, 0.69 mmol) was added and stirring was continued 0.5 h. Aqueous sodium carbonate (10%, 50 mL) was added and the phases separated. The aqueous phase was extracted with dichloromethane (50 mL) and the pooled organic phase was dried (MgSO4) and evaporated. Purification by flash column chromatography gave the title compound (0.65 g). MS m/z (rel. intensity, 70 eV) 291 (M+, 44), 200 (17), 133 (51), 132 (45), 91 (bp).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:27])([CH3:26])[CH2:5][C:6]1[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][C:11]([O:16][CH3:17])=[CH:10][CH:9]=2.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:7]2[C:8]3[C:13](=[CH:12][C:11]([O:16][CH3:17])=[CH:10][CH:9]=3)[C:14]([CH3:15])=[C:6]2[CH2:5][C:4]([CH3:27])([CH3:26])[CH2:3][OH:2])=[CH:20][CH:21]=1
Reactant: COC(=O)C(C)(C)Cc1c(C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(C)c(CC(C)(C)CO)n2Cc1ccc(Cl)cc1
Temperature: -78 °C

Procedure:
700 mg of 3-[1-(4-chlorobenzyl)-3-methyl-5-methoxyindol-2-yl]-2,2-dimethyl propanoic acid methy ester was dissolved in 20 ml dry tetrahydrofuran. The reaction was cooled to -78° C. and 2 equivalents di-isobutyl aluminium hydride (DIBAL) in THF was added. The reaction was allowed to warm to room temperature and quenched with NH4Cl (aq.). Ethyl acetate was added (75 ml) and the organic phase separated, dried and evaporated. The product was isolated by column chromatography.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:33])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Br-:46].[Li+]>O1CCCC1>[Br:46][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:33])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=1
Reactant: [Br-]
Reactant: CCCCCCCCCCCCCCOc1cccc(CC(=O)Nc2ccccc2CO)c1
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCOc1cccc(CC(=O)Nc2ccccc2CBr)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.1 %

Procedure:
To a solution of 4 g of N-[2-(hydroxymethyl)phenyl]-3-(tetradecyloxy)benzeneacetamide in 75 ml of tetrahydrofuran is added 1.19 g of triethylamine and 1.34 g of methanesulfonyl chloride, followed by stirring at room temperature for 1.5 hours. Added 7.66 g of lithium bromide with stirring continued for an additional 2.5 hours. The solvent is evaporated and the residue partitioned between chloroform and saturated sodium bicarbonate. The organic layer is dried and evaporated to a residue which is crystallized from hexane to give 2.6 g of the desired product as a white solid, m.p. 103°-106° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CC(N(C)C)=O>[Cl:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Solvent: CC(=O)N(C)C
Product: O=C(O)c1nc(N2CCOCC2)ccc1Cl
Temperature: 80 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
3,6 Dichloropyridine-2-carboxylic acid (0.55 g, 2.86 mmol), morpholine (1.37 g, 15.7 mmol) and N,N dimethylacetamide (1.37 mL) were combined and stirred for 24 h at 80° C. An additional volume of morpholine (1.39 g, 15.7 mmol) was added and heating continued for 40 hours more. After cooling the DMA was removed in the presence of toluene. The residue was dissolved in water and extracted with ether to remove excess morpholine. The aqueous was acidified to pH=2 and the product extracted into ether. Crystallization from water gave a white solid, 369 mg (53% yield). 1H NMR (CD3OD): δ 3.52 (t, 4H), 3.78 (t, 4H), 6.97 (d,1H), 7.65 (d, 1H). LC-MS, M+H: 243.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N+:23]([O-])=O)[CH:17]=4)[NH:12][C:11]=3[CH:10]=[CH:9][C:8]=2[C:6]1=[O:7].[H][H]>CO.[C].[Pd]>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([NH2:23])[CH:17]=4)[NH:12][C:11]=3[CH:10]=[CH:9][C:8]=2[C:6]1=[O:7]
Reactant: CN(C)CCN1C(=O)c2ccc3[nH]c4ccc([N+](=O)[O-])cc4c3c2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)CCN1C(=O)c2ccc3[nH]c4ccc(N)cc4c3c2C1=O
Reaction time: 0.17 h
Yield: 54.7 %

Procedure:
In 30 ml of methanol was dissolved 60 mg of N-(2-dimethylaminoethyl)-6-nitrocarbazole-3,4-dicarboximide. Thereto was added 30 mg of 5% palladium-carbon. The mixture was subjected to catalytic reduction in a hydrogen atmosphere at room temperature at atmospheric pressure for 5 hours. Thereto was added Celite, and the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was mixed with diethyl ether, and the mixture was stirred for 10 minutes. The resulting crystals were collected by filtration and dried to obtain 30 mg (yield: 55%) of N-(2-dimethylaminoethyl)-6-aminocarbazole-3,4-dicarboximide as orange crystals.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:4]=[C:5]([C:16]2([OH:22])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1.[H-].[Na+].[CH3:27]I>O1CCCC1>[CH3:27][O:22][C:16]1([C:5]2[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:13])[CH3:14])[CH:7]=[C:3]([C:2]([F:1])([F:23])[F:24])[N:4]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1C1(O)CCOCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)CCOCC1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
Into a 250-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-(4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)tetrahydro-2H-pyran-4-ol (compound 216.3, 2 g, 5.46 mmol) in tetrahydrofuran (100 mL). This was followed by the addition of sodium hydride (262 mg, 6.55 mmol, 60%) at −70° C. and stirred for 30 min. To this was added MeI (930 mg, 6.55 mmol). The resulting solution was stirred for 1 h at room temperature, then carefully quenched with 10 mL of water. The resulting mixture was diluted with 50 mL of brine. The aqueous phase was extracted with 2×50 mL of ethyl acetate. The combined organic layers were washed with 1×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:3) as eluent to furnish 1.6 g (77%) of the title compound as light brown oil.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[CH3:25][NH2:26]>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:6]2[C:7]3[CH2:8][CH2:9][N:26]([CH3:25])[C:2]=3[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:5]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Reactant: CN
Product: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3C)c1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and methylamine, the desired compound was obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:10]=[N:9][C:8]=2[C:19]([F:22])([F:21])[F:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([F:32])[CH:31]=1)[CH2:27]Br.C(N(C(C)C)CC)(C)C>C(#N)C>[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([F:32])[CH:31]=1)[CH2:27][N:16]1[CH2:15][CH2:14][N:13]([C:11]2[N:10]=[N:9][C:8]([C:19]([F:22])([F:21])[F:20])=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:12]=2)[CH2:18][CH2:17]1
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: FC(F)(F)c1nnc(N2CCNCC2)cc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Fc1cc(F)cc(CN2CCN(c3cc(-c4ccccc4)c(C(F)(F)F)nn3)CC2)c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 53.2 %

Procedure:
A mixture of 4-phenyl-6-piperazin-1-yl-3-trifluoromethyl-pyridazine (E1) (0.050 g, 0.16 mmol), 3,5-difluorobenzyl bromide (0.031 ml, 0.24 mmol) and diisopropylethylamine (0.056 ml, 0.32 mmol) in acetonitrile (2 ml) was stirred at 100° C. for 10 min., under microwave irradiation. The solvent was evaporated in vacuo and then, dichloromethane and ammonium chloride (10% aqueous solution) were added. The mixture was filtered through a diatomaceous earth cartridge. The solvent was then evaporated in vacuo and the residue was purified by CC-TLC (centrifugal circular thin-layer chromatography) on a chromatotron (a preparative, centrifugally accelerated, radial, thin-layer chromatograph). The crude product was crystallised from diethyl ether/heptane to yield E3 (0.037 g, 52%) as a solid. C22H19F5N4 requires 434. Found 435 (MH+).
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[NH:9])[CH3:3].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[N:18]=[C:19]=[O:20].C(OCC)(=O)C>C1C=CC=CC=1>[CH3:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH3:10])[C:12]=1[NH:18][C:19]([N:9]=[C:5]1[CH2:6][CH2:7][CH2:8][N:4]1[CH2:2][CH3:3])=[O:20]
Reactant: CCN1CCCC1=N
Reactant: Cc1cccc(C)c1N=C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCN1CCCC1=NC(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The hydrochloride of 1-ethyl-2-iminopyrrolidine (7.43 g.; 0.05 mole) is converted to free base (5.6 g.; 0.05 mole) in benzene in the usual manner. Then 7.35 g. (0.05 mole) of 2,6-dimethylphenylisocyanate, dissolved in anhydrous benzene, is added. The reaction mixture is stirred at room temperature for 13/4 hours and then the solvent is evaporated to dryness in vacuo to give an oily residue. Trituration with ethyl acetate and cooling produces a solid product, 1-(2,6-dimethylphenyl)-3-(1-ethyl-2-pyrrolidylidene)urea, m.p. = 120°-122° C. Recrystallization from acetone gives the pure product, m.p. - 121°-123° C.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[Br:14]Br>CCOCC>[Br:14][CH:9]1[CH2:8][CH2:7][O:6][C:5]2[CH:12]=[CH:13][C:2]([F:1])=[CH:3][C:4]=2[C:10]1=[O:11]
Reactant: O=C1CCCOc2ccc(F)cc21
Reactant: BrBr
Solvent: CCOCC
Product: O=C1c2cc(F)ccc2OCCC1Br
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Dissolved 7-fluoro-3,4-dihydrobenzo[b]oxepin-5(2H)-one (1.58 g, 8.77 mmol) in 80 mL ether and added bromine (0.497 mL, 9.65 mmol) and allowed the reaction mixture to stir at room temperature 20 hours. Reaction was complete by LCMS. Concentrated the reaction in vacuo and purified by flash chromatography (0 to 30% ethyl acetate/heptanes). Concentrated in vacuo and NMR indicated 4-bromo-7-fluoro-3,4-dihydrobenzo[b]oxepin-5(2H)-one.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.Cl.N1C=CC=CC=1>O>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][C:6]3[C:5]([CH2:20][C:21]([F:24])([F:22])[F:23])=[CH:4][C:3]([OH:2])=[CH:19][C:7]=3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc(CC(F)(F)F)c3o2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc(-c2cc3cc(O)cc(CC(F)(F)F)c3o2)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
A mixture of 140 (50 mg, 0.15 mmol) and Pyridine HCl (3 g) was heated to 200° C. After 1 hr, the reaction was cooled, diluted with water and extracted with EtOAc. The EtOAc was dried over MgSO4, concentrated to give a solid which was triturated with CH2Cl2 and filtered to give 141 (30 mg, 65%): Mp=210–213° C.; 1H NMR (DMSO-d6) δ 9.86 (s, 1 H), 9.28 (s, 1 H), 7.71 (d, 2 H, J=8.8 Hz), 7.05 (s, 1 H), 6.89–6.86 (m, 3 H), 6.69 (d, 1 H), 2.0 Hz), 3.91–3.84 (m, 2 H); MS 307 [M−H]−
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH2:14][CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:17][CH2:16]1>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][CH2:14][CH:15]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:17][CH2:16]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1COc2ccccc2C1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.2 %

Procedure:
6.29 g (33 mmol) of p-toluenesulphonyl chloride are added while stirring at room temperature to a solution of 5.35 g (30 mmol) of 3-(2-hydroxyethyl)chroman in 30 ml of absolute pyridine, the slightly exothermic reaction being maintained at room temperature by means of an ice bath. After stirring for a further three hours at room temperature, the reaction mixture is poured onto ice-water. The crystals formed are filtered off with suction, washed with water and dried in vacuo. 5.9 g (59.2%) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman, which melts at 91°-93°, are obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:14][C:13]([NH2:15])=[N:12][C:11]2[C:7]=1[N:8]=[CH:9][N:10]=2.[OH-].[K+].S(O[CH2:23][C@H:24]([CH3:33])[NH:25]C(OCCCC)=O)(=O)(=O)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CS(C)=O.O>[NH2:25][C@@H:24]([CH3:33])[CH2:23][N:10]1[CH:9]=[N:8][C:7]2[C:11]1=[N:12][C:13]([NH2:15])=[N:14][C:6]=2[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)N[C@@H](C)COS(C)(=O)=O
Reactant: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](N)Cn1cnc2c(-c3ccco3)nc(N)nc21
Reaction time: 0.17 h
Yield: 51.9 %

Procedure:
A solution of the 6-(2-furyl)-1H-purine-2-amine (0.1 g, 0.5 mmol) in DMSO was treated with freshly ground KOH (112 mg, 2 mmol), shaken for 10 min, treated with N-butoxycarbonyl-L-alaninol mesylate (316 mg, 3 mmol), shaken at 40° C. for a further 17 h, treated with di-tert-butyl dicarbonate (655 mg, 3 mmol), shaken for a further 30 min, diluted with H2O, extracted with EtOAc and the extracts dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; (EtOAc)]. The resulting gelatinous solid was dissolved in MeOH (3 mL), treated with HCl solution (4-M in dioxan, 0.5 mL), stirred for 17 h, diluted with Et2O and filtered to give the title compound (67 mg, 45%) as a yellow solid.
Reaction SMILES: CCOCC.[OH:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:10]=[CH:11][CH:12]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[CH2:27]([O:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:10]=[CH:11][CH:12]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCc2ccccc2)c1
Temperature: 70 °C

Procedure:
Instead of a Mitsunobu reaction, the ether was formed by alkylation as described. A suspension of phenol 58 (1 g, 3.5 mmol), benzyl bromide (0.3 mL, 3.5 mmol), cesium carbonate (1.158 g, 3.5 mmol) in NMP (3.5 mL) was heated at 70° C. for 24 h. The reaction mixture was quenched by the addition of water, extracted with DCM, washed with water, and dried over anhy. Na2SO4. Filtration and concentration under reduced pressure gave the crude product, which was purified by flash chromatography (hexane-ethyl acetate (0-30%) gradients) to give 2-(3-(3-(benzyloxy)phenyl)propyl) isoindoline-1,3-dione as a white solid. Yield (0.708 g, 55%): 1H NMR (400 MHz, DMSO-d6) δ 7.81-7.84 (m, 2H), 7.69-7.72 (m, 2H), 7.30-7.44 (m, 5H), 7.13-7.18 (m, 1H), 6.83-6.85 (m, 1H), 6.80 (d, J=7.6 Hz, 1H), 6.74 (dd, J=7.8, 2.0, 1H), 5.03 (s, 2H), 3.74 (t, J=7.2 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 2.0-2.08 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6](=[O:8])[CH3:7].[H-].[Na+].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>CN(C=O)C>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:1][CH2:2][C@@H:3]2[CH2:5][C@H:4]2[C:6](=[O:8])[CH3:7])=[CH:15][CH:14]=1
Reactant: CC(=O)[C@@H]1C[C@H]1CO
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COC[C@@H]2C[C@H]2C(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 58.3 %

Procedure:
To a solution of trans-1-[2-(hydroxymethyl)cyclopropyl]ethanone (3.4 g, 30 mmol) (prepared as disclosed in Cossy, J.; Blanchard, N.; Meyer, C. Eur. J. Org. Chem. 2001, 339) in anhydrous DMF (60 mL) was added sodium hydride (60 percent dispersion in oil, 1.4 g, 36 mmol) in portions under N2 at 0° C. After the addition was complete, the mixture was stirred for 25 minutes and 4-methoxybenzyl chloride (5.2 g, 33 mmol) was added in one portion. The reaction was then allowed to warm to approximately 25° C. and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride solution (30 mL) followed by dilution with water and was extracted with ether (4×50 mL). The combined organic layer was then washed with half-saturated brine and dried over Na2SO4. After filtration and concentration, the residue was purified on silica gel (20 percent acetone/hexane) to give 4.1 g of product as a colorless oil in 58 percent yield.
Reaction SMILES: [OH-].[Na+].O.[CH2:4]([O:11][C@H:12]([C@@H:14]([N:17]1[C:21](=[O:22])[N:20]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:35]4[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=4)[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[CH:19]=[N:18]1)[CH2:15][CH3:16])[CH3:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CC1C=CC(S(O[CH2:53][C@H:54]2[CH2:58][C@:57]([CH2:67][N:68]3[CH:72]=[N:71][CH:70]=[N:69]3)([C:59]3[CH:64]=[CH:63][C:62]([F:65])=[CH:61][C:60]=3[F:66])[O:56][CH2:55]2)(=O)=O)=CC=1>CS(C)=O>[N:68]1([CH2:67][C@@:57]2([C:59]3[CH:64]=[CH:63][C:62]([F:65])=[CH:61][C:60]=3[F:66])[O:56][CH2:55][C@@H:54]([CH2:53][O:41][C:38]3[CH:39]=[CH:40][C:35]([N:32]4[CH2:31][CH2:30][N:29]([C:26]5[CH:27]=[CH:28][C:23]([N:20]6[C:21](=[O:22])[N:17]([C@H:14]([CH2:15][CH3:16])[C@@H:12]([O:11][CH2:4][C:5]7[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=7)[CH3:13])[N:18]=[CH:19]6)=[CH:24][CH:25]=5)[CH2:34][CH2:33]4)=[CH:36][CH:37]=3)[CH2:58]2)[CH:72]=[N:71][CH:70]=[N:69]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO[C@@](Cn3cncn3)(c3ccc(F)cc3F)C2)cc1
Reactant: CC[C@@H]([C@H](C)OCc1ccccc1)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC[C@H]([C@H](C)OCc1ccccc1)n1ncn(-c2ccc(N3CCN(c4ccc(OC[C@@H]5CO[C@@](Cn6cncn6)(c6ccc(F)cc6F)C5)cc4)CC3)cc2)c1=O
Temperature: 52.5 °C
Reaction time: 0.75 h

Procedure:
A solution of sodium hydroxide (9.2 g) and water (10 ml) was cooled to 25-35° C. and added dimethyl sulfoxide (350 ml), followed by 1-((2S,3S)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one (50 gms) compound of formula-20 at 25-35° C. The reaction mixture was stirred for 45 minutes at the same temperature. ((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluoro phenyl)tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate (50 μms) compound of formula-10 was added to the above reaction mixture and heated to 45-60° C. The reaction mixture was stirred for 6 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with water and neutralized with hydrochloric acid. The reaction mixture was stirred for 1 hour at 25-35° C. Filtered the solid and washed with water. Dried the solid to get the title compound. Yield: 79 g
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][CH2:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:12]=2)[C@H:7]([NH:19][C:20](=[O:25])[O:21][CH:22]([CH3:24])[CH3:23])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2].[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:14]([C:27](=[O:29])[CH3:28])[CH2:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:12]=2)[C@H:7]([NH:19][C:20](=[O:25])[O:21][CH:22]([CH3:23])[CH3:24])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)CNc1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Product: CC(=O)CN(C(C)=O)c1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
1-Methylethyl {(2S,4R)-1-acetyl-2-methyl-6-[(2-oxopropyl)amino]-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (for a preparation see Intermediate 111) (200 mg, 0.553 mmol) was dissolved in acetic anhydride (1044 μl, 11.07 mmol) and the resulting mixture was stirred at room temperature under nitrogen for 1 h then partitioned between water (2 mL) and DCM (5 mL). The layers were separated and the organic phase washed with water, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 10 to 100% AcOEt in hexanes) gave 1-methylethyl {(2S,4R)-1-acetyl-6-[acetyl(2-oxopropyl)amino]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (130 mg, 0.274 mmol, 49%) as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>C(Cl)Cl>[CH3:22][C:3]1[C:2]([NH:1][C:26]([CH:23]2[CH2:25][CH2:24]2)=[O:27])=[N:11][C:10]2[C:5]([N:4]=1)=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]1[NH:20][C:19]2[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=2[CH:13]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(=O)C1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.6 %

Procedure:
To a stirred mixture of 2-(3-amino-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (445a, 79 mg, 0.269 mmol) and TEA (0.18 mL, 1.34 mmol) in DCM (3 mL) was added cyclopropane carbonyl chloride (0.037 mL, 0.404 mmol). After the addition, the mixture was stirred at RT 24 h, concentrated, and purified on a silica gel column (0-10% MeOH/DCM) to give the title compound (55 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.47 (1H, br. s.), 10.52 (1H, br. s.), 8.05 (1H, d, J=7.6 Hz), 7.64 (1H, d, J=8.0 Hz), 7.54 (1H, t, J=7.8 Hz), 7.03 (1H, d, J=2.0 Hz), 6.93 (1H, br. s.), 3.43 (2H, td, J=6.7, 2.3 Hz), 2.89 (2H, t, J=6.8 Hz), 2.74 (3H, s), 2.21 (1H, br. s.), 0.95-1.04 (2H, m), 0.90 (2H, d, J=7.2 Hz). m/z (ESI, +ve) 362 (M+H)+.