Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:25])=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=3[CH3:24])[CH:12]=[CH:13]2)=[C:8]([CH:26]2[CH2:28][CH2:27]2)[CH:7]=1)=[O:5])C.[Li+].[OH-].Cl.C(OCC)(=O)C>C1COCC1.O>[CH:26]1([C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15](=[O:16])[N:14]3[C:9]=2[C:10]([CH3:25])=[C:11]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=2[CH3:24])[CH:12]=[CH:13]3)[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(O)cc3C)ccn2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(O)ccc1-c1ccn2c(=O)c(C(=O)O)cc(C3CC3)c2c1C
Temperature: 60 °C

Procedure:
A solution of 1-cyclopropyl-8-(4-hydroxy-methyl-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (60 mg, 0.159 mmol) in THF (6 mL) and water (2 mL) was treated with LiOH (27 mg, 0.642 mmol). The reaction was heated to 60° C. overnight and acidified with 1N HCl to pH 4. The precipitate was dissolved with ethyl acetate (50 mL) and washed with brine (2×20 mL). The organic phase was separated, dried, and concentrated. The precipitate was filtered to afford the title compound EXAMPLE 48 as yellow solid (21 mg, 38%). ESI-MS m/z: 350 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.38 (d, J=7.2 Hz, 1H), 8.30 (s, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.59-7.56 (m, 4H), 5.41 (t, 1H), 4.64 (d, J=5.7 Hz, 2H), 2.91 (s, 3H), 2.54-2.51 (m, 1H), 1.13-1.10 (m, 2H), 0.83-0.81 (m, 2H).
Reaction SMILES: [C:1]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1=[O:20])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>C1COCC1>[CH2:3]([C@@H:2]([C:1]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1=[O:20])=[O:7])[CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:4][CH2:5][CH3:6]
Reactant: COC(=O)CBr
Reactant: CCCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[C@H](CC(=O)OC)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of N-hexanoyl-4-(S)-benzyloxazolidin-2-one A-2 (7.3 mmol) in THF at −78° C. is added 1.0 M NaHMDS (8.8 mmol) and the reaction stirred at −78° C. for 1 hour. A solution of methyl bromoacetate (8.8 mmol) in THF is then added dropwise, and the resulting mixture is stirred at −78° C. for 1 hour and then at rt overnight. The reaction is quenched with NH4Cl, concentrated, then suspended in EtOAc and washed with 0.5 N HCl and brine, dried and purified by silica gel chromatography (EtOAc/hexanes) to afford the methyl 3-(R)-(n-butyl)-3-[4-(S)-benzyloxazolidin-2-one-3-ylcarbonyl)propionate (A-3).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:10]([Si:14]([CH3:17])([CH3:16])Cl)([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C.C(OCC)C>[Si:14]([O:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([I:1])[CH:3]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:17])[CH3:16]
Reactant: Cc1ccc(O)cc1I
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-iodo-4-methylphenol 1-1 (500 mg, 2.14 mmol), tert-butyldimethylchlorosilane (387 mg, 2.57 mmol) and imidazole (175 mg, 2.57 mmol) in 11 mL of DMF was stirred at rt for 16 h, and then diluted with diethylether, washed with water, brine, dried (MgSO4) and evaporated. The residue was subjected to MPLC on a 40 g column of SiO2 eluting with hexanes to provide 5-tert-butyldimethylsilyloxy-2-methylphenyliodide 1-2 as an oil. 1H NMR (300 MHz, DMSO-d6): δ 0.17 (s, 6H), 0.93 (s, 9H), 2.29 (s, 3H), 6.81 (dd, 1H, J=8, 2 Hz), 7.20 (d, 1H, J=8 Hz), 7.28 (d, 1H, J=2 Hz).
Reaction SMILES: COC1C=C2C(=CC=1OC)N=C[N:7]=C2SC1C=C(C=CC=1)N.[F:23][C:24]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=[O:41])OC2C=CC=CC=2)[O:29][N:28]=1)([CH3:26])[CH3:25].COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[F:23][C:24]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=[O:41])[NH2:7])[O:29][N:28]=1)([CH3:26])[CH3:25]
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: CC(C)(F)c1cc(NC(N)=O)on1
Temperature: 25 °C
Reaction time: 72 h
Yield: 118.7 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (200 mg, 0.639 mmol) was reacted with phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate from Example 42A (253 mg, 0.959 mmol) according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B, except the reaction mixture was stirred at room temperature for 72 h. Purification via trituration with methanol afforded 14346,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea as a colorless solid (142 mg, 46%). 1H NMR (300 MHz, DMSO-d6) δ 10.43 (brs, 1H), 9.13 (brs, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.57 (m, 1H), 7.46 (m, 1H), 7.30-7.35 (m, 3H), 6.16 (s, 1H), 3.99 (s, 6H), 1.67 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 484 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=O)[C:5]([NH:10][C:11](=[O:17])OC(C)(C)C)=[CH:4][CH:3]=1.[Cl-].[CH2:19]1[CH2:29][CH2:28]N2[C:22](=NCCC2)[CH2:21][CH2:20]1.[CH2:30]1COCC1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:10][C:11](=[O:17])[C:30]([C:22]1[CH:21]=[CH:20][CH:19]=[CH:29][CH:28]=1)=[CH:8]2
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1C=O
Reactant: C1CCC2=NCCCN2CC1
Reactant: C1CCOC1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2ccc(Cl)nc2cc1-c1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl (6-chloro-2-formylpyridin-3-yl)carbamate (1-4) (5 g, 19.5 mmol), phenylacethyl chloride (3.3 g, 21.4 mmol), and DBU (9.8 g, 39 mmol) in THF (215 mL) was stirred at room temperature for 2 days and at 100° C. for overnight. The mixture was diluted with CHCl3, washed with water and brine, dried (MgSO4), filtered, and the solvent was removed under reduced pressure. To the residue was added CHCl3, and the resulting solid was collected by filtration to give 6-chloro-3-phenyl-1,5-naphthyridin-2(1H)-one (7-1) as colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([OH:14])[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][OH:14])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCO
Reactant: FCc1cccc(Br)n1
Product: OCCC#Cc1cccc(CF)n1
Yield: 80.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(A), from 2-bromo-6-(fluoromethyl)pyridine (compound 190(E); 3.50 g, 18 mmol) and 3-butyn-1-ol (1.3 g, 18 mmol). The crude residue was purified over silicagel chromatography (prepacked 85 g silicagel column, DCM/MeOH: from 100/0 to 97/3 as eluent) to afford 2.60 g of 4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn-1-ol as an orange solid (Yield: 79%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl>CN(C=O)C>[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26][N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=[C:3]1[CH2:2][OH:1]
Reactant: C[Si](C)(C)CCOCCl
Reactant: OCc1nc2ccccc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(CO)nc2ccccc21
Temperature: 60 °C
Yield: 43.7 %

Procedure:
To a stirred solution of 2-hydroxymethylbenzimidazole (31.94, 0.216 mol) in dry DMF (450 mL) was added N,N-diisopropylethylamine (90 mL, 0.52 mol) followed by 2-(trimethylsily)ethoxymethyl chloride (75% in pentane, 55 g, 0.25 mol) and the mixture heated to 60° C. for 2 h. The mixture was cooled to room temperature, concentrated under reduced pressure and partitioned between EtOAc (400 mL) and distilled water (700 mL). The phases were separated and the aqueous layer extracted with EtOAc (2×200 mL). The combined organic extracts were washed with brine (1×400 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. Purification of the crude oil by column chromatography on silica gel (4% MeOH/CH2Cl2) afforded the desired 1-(2-trimethylsilylethoxymethyl)-2-hydroxymethylbenzimidazole (26.28 g, 44%) as a yellow oil. 1H NMR (CDCl3) δ −0.04 (s, 9H), 0.89 (t, 2H, J=9 Hz), 1.75 (br s, 1H), 3.55 (t, 2H, J=9 Hz), 4.94 (s, 2H), 5.58 (s, 2H), 7.26-7.30 (m, 2H), 7.43-7.45 (m, 1H), 7.70-7.72 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:23]([F:24])=[CH:22][C:5]2[NH:6][C:7]([NH:9][CH:10]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]3)=[N:8][C:4]=2[CH:3]=1.Cl[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:1][C:2]1[C:23]([F:24])=[CH:22][C:5]2[N:6]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:7]([NH:9][CH:10]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: CCOC(=O)N1CCCC(Nc2nc3cc(F)c(F)cc3[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCCC(Nc2nc3cc(F)c(F)cc3n2Cc2ccc(F)cc2)CC1
Temperature: 80 °C
Yield: 40.6 %

Procedure:
A mixture of 11 parts of ethyl 4-[[5,6-difluoro-1H-benzimidazol-2-yl]-amino]hexahydro-1H-azepine-1-carboxylate, 7.2 parts of 1-(chloromethyl)-4-fluorobenzene, 3.2 parts of sodium carbonate and 90 parts of N,N-dimethylformamide was stirred and heated for 24 hours at 80° C. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 6 parts (40.6%) of ethyl 4-[[5,6-difluoro-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]hexahydro-1H-azepine-1-carboxylate as a residue; (compound 35).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]([CH3:17])([O:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:10])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26]>C(OCC)C>[C:25](=[O:26])([O:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][C:9]([CH3:17])([O:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:10]
Reactant: CCCCOC(=O)Cl
Reactant: CC(CCO)CCCC(C)(C)OOC(C)(C)C
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCOC(=O)OCCC(C)CCCC(C)(C)OOC(C)(C)C

Procedure:
To a solution of 7.9 g (0.03 mole) of 3,7-dimethyl-7(t-butylperoxy)octyl alcohol and 2.4 g (0.03 mole) of pyridine in diethyl ether cooled at 10°±1° C was added a solution of 4.09 (0.03 mole) of n-butyl chloroformate in diethyl ether. The reaction temperature was maintained at 15°±1° C during the addition.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:3].[N:24]([CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[N+:25]=[N-:26]>CN(C)C=O.CO.[Cu]I>[CH3:3][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[N:26]=[N:25][N:24]([CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:37])[CH:18]=3)[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:1]
Reactant: C#Cc1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Reactant: CC(C)(C)OC(=O)NCCCN=[N+]=[N-]
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)N1c2ccc(-c3cn(CCCNC(=O)OC(C)(C)C)nn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 126 %

Procedure:
To a solution of 1-methylethyl[(2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 58) (250 mg, 0.795 mmol) in a mixture of N,N-dimethylformamide (DMF) (4.5 mL) and methanol (0.500 mL) were successively added 1,1-dimethylethyl (3-azidopropyl)carbamate (for a preparation, see Intermediate 74) (318 mg, 1.590 mmol) and copper(I) iodide (7.57 mg, 0.040 mmol). The resulting mixture was stirred at 100° C. under microwave irradiation for 2 h, and then cooled to room temperature and partitioned between EtOAc and brine. The two layers were separated and the aqueous phase was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over a Na2SO4 cartridge and concentrated in vacuo. Purification of the residue by SP4 column using a 10 G silica cartridge (gradient: 2 to 10% MeOH in DCM) gave 1-methylethyl((2S,4R)-1-acetyl-6-{1-[3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl]-1H-1,2,3-triazol-4-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (514 mg, 0.999 mmol, 126%) as a viscous yellow oil which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[H-].[Na+].[CH3:22][CH:23]1[CH:27]([CH3:28])OS(=O)(=O)[N:24]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>CN(C=O)C>[C:34]([O:33][C:31]([NH:24][CH:23]([CH3:22])[CH:27]([N:1]1[C:5]2=[N:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:28])=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2n1
Reactant: CC1OS(=O)(=O)N(C(=O)OC(C)(C)C)C1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)C(C)NC(=O)OC(C)(C)C)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 106.5 %

Procedure:
To a solution of diethyl 1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (Intermediate D, 3.40 g, 13.0 mmol) in DMF (15 mL) cooled to 0° C. is added 60% sodium hydride in mineral oil (570 mg, 14.3 mmol). The mixture is stirred at 0° C. for 20 min after which a solution of tert-butyl 4,5-dimethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (5.35 g, 14.3 mmol) in DMF (10 mL) is added. The mixture is stirred at 0° C. for 30 min after which the reaction was allowed to warm and stir at ambient temperature overnight. The reaction is quenched with H2O and was stirred for 15 min. The mixture is extracted with ethyl acetate and the combined organic phases are washed with brine, and are dried (Na2SO4). The solvent is removed in vacuo and the crude material is purified via flash column chromatography using a gradient elution of 0-20% ethyl acetate/heptane to afford the title compound as a colorless oil (6.00 g, quantitative). LCMS: 434.83 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH:20]2[CH3:25]>>[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][N:19]([C:11]([C:9]1[CH:10]=[C:5]3[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]3[N:8]=1)=[O:13])[CH:20]2[CH3:25]
Reactant: CC1NCCc2c(Br)cccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2cccc(Br)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].[CH3:15][Sn:16](Cl)([CH3:18])[CH3:17]>C(OCC)C>[CH3:15][Sn:16]([CH3:18])([CH3:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14]
Reactant: C[Sn](C)(C)Cl
Reactant: COc1ccccc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccccc1[Sn](C)(C)C
Temperature: 25 °C
Yield: 76.6 %

Procedure:
To a stirring solution of n-BuLi (2.6 mL, 2.5M in hexane, 6.42 mmol) in diethyl ether (2.5 mL) at −78C. was added 2-bromoanisole (1.0 g, 5.35 mmol) in diethyl ether (2mL) dropwise. After stirring for 1h at −78C., trimethyltin chloride (6.4 mL, 1.0M in THF, 6.42 mmol) was added dropwise. The mixture was allowed to stir an additional 2h while slowly warming to room temperature. The mixture was then washed with saturated aqueous NaHCO3. The aqueous layer was extracted with diethyl ether (1×50 mL) and the organic layers were combined, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (silica gel, hexane) to yield the title compound as a colorless oil (1.11 g, 76%), 1HNMR (400 MHz, CDCl3) δ 7.47 (d, 1H), 7.40 (t, 1H), 7.05 (t, 1H), 6.90 (d, 1H), 3.36 (s, 3H), 0.34 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:4]=1[CH:13]=[CH:14]C.BrN1[C:21](=[O:22])CCC1=O>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:4]=1[CH:13]([CH3:14])[CH:21]=[O:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC=Cc1cc(OC)c(OC)cc1OC
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Solvent: O
Product: COc1cc(OC)c(C(C)C=O)cc1OC
Yield: 43 %

Procedure:
A mixture of 2,4,5 trimethoxy phenyl propene (1 mmol), N-bromosuccinimide (1.2 mmol), water (14 ml), cetyltrimethyl ammonium bromide (0.3 mmol) were taken in a 100 ml round bottom flask fitted with a condenser. The flask was shaken well and placed inside the monomode microwave oven and irradiated (220 W, 200° C.) for 12 minutes in parts. After completion of reaction, the reaction mixture was worked up as in example-1 to provide the corresponding 2-(2,4,5 trimethoxy phenyl)propionaldehyde (43% yield) whose spectral data matched with that mentioned in example-1.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O-:11])=O)=[CH:7][CH:6]=1)(=O)C.[Na+].[NH2:15][C@@H:16]1[CH2:25][CH2:24][C:23]2[C:18](=[C:19]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:20]=[CH:21][CH:22]=2)[CH2:17]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:32][N:29]1[CH2:30][CH2:31][N:26]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH2:17][C@H:16]([NH:15][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:13][CH:12]=2)[CH2:25][CH2:24]3)[CH2:27][CH2:28]1
Reactant: CC(=O)Oc1ccc(C(=O)[O-])cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(O)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of sodium 4-acetoxybenzoate (1.0 g, 5.4 mmol) in thionyl chloride (15 mL) was heated at reflux for 1 h (the mixture became homogeneous). The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (150 mg, 0.77 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (180 mg, 0.73 mmol) and triethylamine (150 μL, 1.1 mmol) in methylene chloride (20 mL) . After the addition the reaction was allowed to stir at ambient temperature for 15 min and was then washed with diluted aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in 99.5% ethanol (15 mL) and concentrated hydrochloric acid (5 mL) was added. After 17 h, the pH was adjusted to 8 and the solvent evaporated in vacuo. The residue was partitioned between water and chloroform. The organic phase was separated, dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 70 mg (26%) of the title compound as an oil: [α]21D −17° (c 0.50, chloroform); EIMS (70 eV) m/z (relative intensity) 365 (24, M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)C1CCN(Cc2c[nH]c3c(-c4noc(-c5ccc(OC(C)C)c(Cl)c5)n4)cccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CN5CCC(C(=O)O)CC5)c[nH]c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a solution of ethyl 1-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-4-piperidinecarboxylate (D74) (280 mg) in tetrahydrofuran (10 mL) and methanol (10 mL) stirred at 20° C. was added a solution of sodium hydroxide (54 mg) in water (10 mL) in one charge. The reaction mixture was stirred at 20° C. for 8 hours. The reaction mixture was concentrated and then H2SO4 (0.1 M) solution was added dropwise until no further white precipitate was formed. The solid was filtered and dried to afford 1-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-4-piperidinecarboxylic acid (E48) (98 mg). δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 1.61-3.02 (9H, m), 3.95 (2H, s), 4.87-4.93 (1H, m), 7.26 (1H, t), 7.45-7.47 (2H, m), 7.96 (1H, s), 7.96 (1H, s), 8.21 (1H, dd), 8.37 (1H, d), 11.07 (1H, s). MS (ES): C26H27ClN4O4 requires 494; found 495.2 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=2)[S:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19](OC)=[O:20].[H-].[Na+].O>CN(C=O)C>[OH:20][CH:19]=[C:11]([S:10][C:9]1[CH:16]=[CH:17][CH:18]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC=O
Reactant: COC(=O)CSc1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(=CO)Sc1cccc(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 15.4 %

Procedure:
Methyl (3-phenylthiophenoxy)acetate (6.60 g) and methyl formate (30.78 g) were dissolved in DMF (30 ml) and added dropwise at 0° C. to sodium hydride (0.83 g, 50% dispersion in oil) in DMF. The reaction mixture was stirred at 0° C. for 45 minutes and then left at room temperature under nitrogen over the weekend. The reaction mixture was then poured into water (300 ml) and washed with diethyl ether (3×150 ml). The aqueous phase was adjusted to pH 7 with hydrochloric acid and then extracted with diethyl ether (3×100 ml). The combined organic extracts were washed successively with water (3×100 ml) and brine (2×75 ml) and then dried. Filtration and evaporation of the solvent under reduced pressure gave methyl 3-hydroxy-2-(3'-phenylthiophenoxy)propenoate (1.13 g) which was used without further purification.