Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].BrCCBr.C(Cl)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1.[CH3:21][C:22]([CH3:24])=[O:23].S(=O)(=O)(O)O>O1CCCC1>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([C:22]([OH:23])([CH3:24])[CH3:21])[C:18]([OH:20])=[O:19])=[CH:15][CH:16]=1
Reactant: CC(C)=O
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: CC(C)Cl
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC(C)(O)C(C(=O)O)c1ccc(F)cc1
Yield: 109.6 %

Procedure:
24.3 g (1.00 mol) of magnesium shavings were suspended in 50 ml of tetrahydrofuran under argon and while stirring in a 1.5 l four-necked sulphonation flask fitted with a reflux condenser, mechanical stirrer, 500 ml dropping funnel, thermometer and a device for inert gasification. After the dropwise addition of 0.5 ml of 1,2-dibromoethane, a solution of 86.4 g (1.10 mol) of isopropyl chloride in 225 ml of tetrahydrofuran was added dropwise within 90 minutes, with the reaction temperature being held at about 30°. The resulting dark grey suspension was stirred at RT for a further 18 hours. Then, a solution of 73.0 g (0.473 mol) of p-fluorophenylacetic acid in 150 ml of tetrahydrofuran was added dropwise to the mixture within 90 minutes while maintaining the temperature at about 25° and thereafter the suspension was heated to 35-40° and stirred at this temperature for a further 1 hour. After cooling 30.0 g (0.516 mol) of acetone were added dropwise at about 25° within 30 minutes and subsequently the mixture was stirred at 35-40° for a further 1 hour. The reaction mixture was treated with 350 ml of 14.2% sulphuric acid while cooling with an ice bath at <30°. The aqueous phase was separated, extracted with 200 ml of tetrahydrofuran and the organic phases were combined and evaporated at 50° on a rotary evaporator. 110 g of crude 2-(p-fluorophenyl)-3-hydroxy-3-methylbutyric acid were obtained as a dark viscous oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([CH:10]1[CH2:12][CH2:11]1)=[O:9].[C:13]1([CH3:26])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[S:21]([O:24][NH2:25])(=[O:23])=[O:22].C1(C)C=C(C)C=C(C)C=1S(Cl)(=O)=O>ClCCl>[CH3:20][C:15]1[CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]([CH3:26])[C:14]=1[S:21]([O-:24])(=[O:23])=[O:22].[NH2:25][N+:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([CH:10]1[CH2:11][CH2:12]1)=[O:9]
Reactant: O=C(Nc1cnccn1)C1CC1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Agent: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: N[n+]1ccncc1NC(=O)C1CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1.0 g (6.13 mmol) of N-pyrazin-2-ylcyclopropanecarboxamide in 10 mL of dichloromethane at 0° C. was added a solution of 1.58 g (7.36 mmol) of O-mesitylenesulfonylhydroxylamine, prepared from mesitylenesulfonyl chloride using a procedure analogous to that described in the literature (Y. Tamura et al., J. Org. Chem., 38: 1239 (1973)). The reaction mixture was allowed to stir at ambient temperature for 1.5 h. The resultant thick yellow mixture was concentrated in vacuo to give the title compound as a yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([C:9]([O:11]C)=O)=[CH:7][C:6]([C:13]([O:15][CH3:16])=[O:14])=[N:5]1.C(N(C(C)C)CC)(C)C.[C:26]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][NH2:41])[CH2:35][CH2:34]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].[I-].[K+]>CC#N>[CH3:16][O:15][C:13]([C:6]1[CH:7]=[C:8]2[C:9](=[O:11])[N:41]([CH2:40][CH2:39][CH:36]3[CH2:35][CH2:34][N:33]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:38][CH2:37]3)[CH2:2][CH2:3][N:4]2[N:5]=1)=[O:14]
Reactant: COC(=O)c1cc(C(=O)OC)n(CCBr)n1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2n(n1)CCN(CCC1CCN(C(=O)OC(C)(C)C)CC1)C2=O

Procedure:
A solution of 3-2 (14.0 g, 48.0 mmol), diisopropylethyl amine (25 ml, 144 mmol), Boc-4-aminoethylpiperidine (12.0 g, 52.6 mmol), and potassium iodide (2.39 g, 0.3 mmol) in 250 ml CH3CN was refluxed under N2 for 4.5 h then cooled, filtered and evaporated at reduced pressure. The resulting yellow residue was chromatographed on silica gel using EtOAc as eluent to give 3-3 as an off-white crystalline solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH3:8])[CH2:3]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].O>ClCCl.CS(Cl)(=O)=O>[CH3:8][N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([O:1][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCCC(O)C1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCCC(OS(C)(=O)=O)C1
Reaction time: 2 h
Yield: 325.1 %

Procedure:
To a solution of 3-hydroxy-N-methyl piperidine (2 cm3, 17.4 mmol) in dichloromethane (40 cm3) was added triethylamine (3.6 cm3, 26.05 mmol) and then methanesulfonyl chloride (1.5 cm3, 19:1 mmol). The reaction was then stirred for 3 h before a further aliquot (0.2 equiv., 3.47 mmol) of methanesulfonyl chloride was added. Stirring was continued for another 2 h at room temperature before the reaction was treated with water (60 cm3) and extracted into dichloromethane (40 cm3). The organic layer was washed with saturated aqueous sodium chloride solution (60 cm3) and dried over sodium sulfate before being evaporated under reduced pressure to afford (A) (2.18 g, 11.28 mmol, 65%).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[C:16](B(O)O)[CH:17]=[N:18][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:24]1[CH:25]=[C:26]([C:30]2[N:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:33]3[CH:41]=[CH:42][CH:43]=[CH:44][C:32]=3[N:31]=2)[CH:27]=[N:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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:35]1([N:34]2[C:33]3[CH:41]=[CH:42][CH:43]=[CH:44][C:32]=3[N:31]=[C:30]2[C:26]2[CH:25]=[C:24]([C:16]3[CH:17]=[N:18][CH:19]=[C:14]([N:12]4[C:13]5[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=5[C:6]5[C:11]4=[CH:10][CH:9]=[CH:8][CH:7]=5)[CH:15]=3)[CH:29]=[N:28][CH:27]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: OB(O)c1cncc(-n2c3ccccc3c3ccccc32)c1
Reactant: Brc1cncc(-c2nc3ccccc3n2-c2ccccc2)c1
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: C1COCCO1
Solvent: O
Product: c1ccc(-n2c(-c3cncc(-c4cncc(-n5c6ccccc6c6ccccc65)c4)c3)nc3ccccc32)cc1
Temperature: 90 °C
Yield: 49 %

Procedure:
A mixture of (5-(9H-carbazol-9-yl)pyridin-3-yl)boronic acid (2C) (0.90 g, 3.1 mmol), 2-(5-bromopyridin-3-yl)-1-phenyl-1H-benzo[d]imidazole (1F) (0.856 g, 3.1 mmol), Pd(PPh3)4 (0.18 g, 0.155 mmol) and potassium carbonate (1.07 g, 7.8 mmol) in dioxane/water (20 mL/5 mL) was degassed and heated at about 90° C. overnight under argon atmosphere. The whole was poured into ethyl acetate (100 mL), then washed with brine (50 mL). The organic phase was collected and dried over Na2SO4, absorbed on silica gel, then purified by flash column (dichloromethane/methanol 40:1) to give a light yellow solid (0.78 g), which was purified again by flash column (silica gel, dichloromethane/methanol 50:1) followed by recrystallization in dichloromethane/methanol to give HTH-2, a light yellow solid (0.60 g, 38% yield).
Reaction SMILES: CN(C)[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9](CN)=[CH:8][CH:7]=1.C1(O)C=CC=CC=1.C([Cl:25])CO.O(CCO)C1C=CC=CC=1.S(Cl)(Cl)=O>>[O:5]([CH2:4][CH2:3][Cl:25])[C:6]1[CH:13]=[CH:12][CH:9]=[CH:8][CH:7]=1
Reactant: OCCCl
Reactant: CN(C)CCOc1ccc(CN)cc1
Solvent: Oc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: OCCOc1ccccc1
Product: ClCCOc1ccccc1

Procedure:
FR 2549828 discloses a multistage process for preparing 4-[2-(dimethylamino)ethoxy]benzylamine starting from phenol. Reaction of phenol with ethylenechlorohydrin initially delivers 2-phenoxyethanol which is reacted with thionyl chloride to give 2-phenoxyethyl chloride. After distilling this intermediate, it is reacted with acetamide and paraformaldehyde and then treated with mineral acid to give N-(2-chloroethoxybenzyl)acetamide. Reaction with dimethylamine then leads to N-[2-(dimethylamino)-ethoxy]acetamide, from which the desired product is released by acid hydrolysis. The process disclosed which has 6 separate process steps and an overall yield of 50% based on the phenol used is uneconomic.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH2:13][CH3:14])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Br:16])=[C:7]([Br:15])[CH:8]=2)[N:3]=1.Br[CH2:18][C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(COC)OC>[Br-:15].[NH2:1][C:2]1[C:11]([O:12][CH2:13][CH3:14])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Br:16])=[C:7]([Br:15])[CH:8]=2)[N+:3]=1[CH2:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:25]
Reactant: CCOc1nc2cc(Br)c(Br)cc2nc1N
Reactant: CCOC(=O)C(=O)CBr
Solvent: COCCOC
Product: CCOC(=O)C(=O)C[n+]1c(N)c(OCC)nc2cc(Br)c(Br)cc21
Product: [Br-]
Yield: 113 %

Procedure:
A solution of 0.68 g of the product of Step A in 25 ml of dimethoxyethane and 0.5 g of ethyl bromopyruvate was stirred for 5 days at room temperature and the mixture was filtered to obtain 0.6 g of 2-amino-6,7-dibromo-1-carbethoxycarbonylmethyl-3-ethoxy-quinoxalinium bromide as a white crystalline solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=2)[CH:3]=1.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]3[S:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=3)[CH:3]=2)[CH2:25][CH2:24]1
Reactant: OCCN1CCNCC1
Reactant: CCOC(=O)c1cnc(Nc2cc(Br)nc(C)n2)s1
Product: CCOC(=O)c1cnc(Nc2cc(N3CCN(CCO)CC3)nc(C)n2)s1
Yield: 80.6 %

Procedure:
Prepared from ethyl 2-(6-bromo-2-methylpyrimidin-4-ylamino)thiazole-5-formate and Compound 3: ethyl 2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-formate was yielded (yield: 80.6%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH:23][C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[C:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:28]3[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:40]N(C)C=O.[H-].[Na+].CI>>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([N:23]([CH3:40])[C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[C:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:28]3[CH3:33])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: Cn1c(-c2ccccc2)nc2c(N[C@@H]3C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C3)ncnc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(c1ncnc2c1nc(-c1ccccc1)n2C)[C@@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reaction time: 0.5 h

Procedure:
To a solution of N-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]-9-methyl-8-phenyl-9H-purin-6-amine (200 mg, 0.0004 mol) in N,N-dimethylformamide (10 mL, 0.1 mol) was added sodium hydride (0.112 g, 0.00280 mol). The mixture was stirred for 30 minutes and to this was added methyl iodide (0.05 mL, 0.0008 mol) and the mixture was stirred overnight. The reaction was quenched by addition of saturated aqueous NH4Cl, and the mixture was extracted with ethyl acetate, washed with water, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 10% MeOH/DCM) to obtain 200 mg (100%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([Si](C)(C)[O:24][CH2:25][CH2:26][C:27]1[O:28][C:29]([CH2:32][CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:30][CH:31]=1)(C)C>C1COCC1>[OH:24][CH2:25][CH2:26][C:27]1[O:28][C:29]([CH2:32][CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(CCOCc2ccccc2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCCc1ccc(CCOCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
Tetrabutylammonium fluoride (1.0M in THF, 3.06 mL, 3.06 mmol) was added to the solution of compound 255D (1.1 g, 3.06 mmol) in 10 mL of THF at 0° C. The reaction mixture was stirred at rt for 10 minutes, quenched by sat. NH4Cl and extracted with ether (3×). The combined extracts were dried over Na2SO4. Purification by flash chromatography on silica gel eluting with 10% EtOAc/90% CH2Cl2 gave 750 mg (3.05 mmol, 99.6%) of compound 255E as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[Br:5][C:6]1[C:7]([OH:16])=[CH:8][C:9]([OH:15])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH2:1]([O:12][C:11](=[O:13])[C:10]1[CH:14]=[C:6]([Br:5])[C:7]([O:16][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]=1[O:15][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:4]=[CH:10][CH:14]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(Br)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(OCc1ccccc1)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a 10 L jacketed vessel, fitted with a flange lid containing stirrer, thermometer and dropping funnel, was charged acetone (2.5 L) followed by 5-bromo-2,4-dihydroxybenzoic acid (100 g, 0.43 mol) and potassium carbonate (356 g, 2.58 mol). To the stirring mixture at ambient was added benzyl bromide (185 mL, 1.55 mol) at a rate of ˜20 ml/min. The mixture was heated at 60° C. for 18 h and then taken to 45° C. Water (1.5 L) was added and the mixture stirred for 30 min. The mixture was extracted with EtOAc (2×1 L) and the combined organic portions reduced in vacuo. To the residue was added Et2O (200 mL) and petroleum ether (1 L), the mixture stirred for 30 mm and the solid formed collected by filtration and dried in vacuo to give the title compound (197.2 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][C@@H:20]3[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:21]3[O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:12]=[CH:11]2)=[CH:4][CH:3]=1.[C:55](=O)([O-])[O-].[Cs+].[Cs+].CI>CC(C)=O>[CH3:55][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][C@@H:20]3[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:34])[CH3:35])[C@H:21]3[O:22][C:23](=[O:28])[C:24]([CH3:26])([CH3:27])[CH3:25])[CH:12]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2cccc3ccn(CCc4ccc(O)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: [Cs+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(CCn2ccc3cccc(O[C@@H]4O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]4OC(=O)C(C)(C)C)c32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
A mixture of 1-[2-(4-hydroxyphenyl)ethyl]-7-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indole (50 mg), cesium carbonate (43 mg) and methyl iodide (0.008 mL) in acetone (2 mL) was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent: n-hexane/ethyl acetate=5/1) to give 1-[2-(4-methoxyphenyl)ethyl]-7-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indole (51 mg). This material was dissolved in methanol (1 mL). To the solution were added water (0.1 mL) and lithium hydroxide monohydrate (13 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on silica gel (eluent: methylene chloride/methanol=8/1) to give the title compound (19 mg).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](OC)[CH:8]=2)[N:3]=1.[CH3:16][NH:17][CH3:18].O1CCOC[CH2:20]1>>[CH3:16][N:17]([CH3:18])[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:20])[CH:8]=2)[N:3]=1
Reactant: CNC
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: C1COCCO1
Product: Cc1ccc2nc(N(C)C)c(C=O)cc2c1
Temperature: 160 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
To a stirred solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde (1.0 g, 4.86 mmol) in dioxane (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added dimethylamine (40% in water, 6.1 mL, 48.6 mmol) and the reaction mixture was stirred for 45 min at 160° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum and the resulting yellow oil was taken back in CH2Cl2 (30 mL). The organic layer was washed with water (3×20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated under vacuum to give 2-(dimethylamino)-6-methylquinoline-3-carbaldehyde RBO 35148 as a yellow oil (988 mg, 95% yield).
Reaction SMILES: [C:1]([C:4]1[C:14]([O:15]CC2C=CC=CC=2)=[CH:13][CH:12]=[C:11]([O:23][C:24]2[C:32]([CH3:33])=[CH:31][C:30]([N+:34]([O-:36])=[O:35])=[C:29]3[C:25]=2[CH2:26][CH2:27][CH2:28]3)[C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.O.CSC>[C:1]([C:4]1[C:14]([OH:15])=[CH:13][CH:12]=[C:11]([O:23][C:24]2[C:32]([CH3:33])=[CH:31][C:30]([N+:34]([O-:36])=[O:35])=[C:29]3[C:25]=2[CH2:26][CH2:27][CH2:28]3)[C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1c(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)ccc(OCc2ccccc2)c1C(C)=O
Solvent: CSC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)ccc(O)c1C(C)=O
Reaction time: 8 h
Yield: 84.7 %

Procedure:
Ethyl 2-acetyl-3-benzyloxy-6-(5-methyl-7-nitroindan-4-yloxy)benzoate (314 mg) was dissolved in trifluoroacetic acid/water/dimethylsulfide (95/5/10) (3 mL). The mixture was stood overnight at room temperature and evaporated under reduced pressure to dryness. Adding water, the residue was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1−3/1) to give the title compound (217 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][CH2:13][NH2:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26](Cl)=[O:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].O.CCOC(C)=O>C1COCC1>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26]([NH:14][CH2:13][CH2:12][S:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(SCCN)cc1OC
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CC(=O)NCCSc2ccc(OC)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.2 %

Procedure:
To a cold (0° C.) solution of 2-(3,4-dimethoxy-phenylsulfanyl)-ethylamine (3.97 g, 18.6 mmol) in anhydrous THF (49 ml), were added TEA (3.11 ml, 18.6 mmol) and portionwise 3,4-dimethoxyphenylacetylchloride (4.0 g, 18.6 mmol). The resulting mixture was stirred at RT for 20 h under nitrogen. The mixture was combined with H2O and extracted three times with CH2Cl2. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude solid. Flash chromatography (AcOEt) gave the title product (7.08 g, 97%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:17][CH2:16][C:15]3[NH:18][N:19]=[C:20]([NH:21][C:22](=[O:43])[C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[CH:25][C:24]=4[NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[C:14]=3[CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:55]([O:57][CH2:58][CH3:59])=[O:56]>C1COCC1.O>[CH2:58]([O:57][C:55]([N:18]1[C:15]2[CH2:16][CH2:17][N:12]([S:9]([C:4]3[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:11])=[O:10])[CH2:13][C:14]=2[C:20]([NH:21][C:22](=[O:43])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[CH:25][C:24]=2[NH:36][CH:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[N:19]1)=[O:56])[CH3:59]
Reactant: CCOC(=O)Cl
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4c3CN(S(=O)(=O)c3cc(F)cc(F)c3)CC4)c(NC3CCOCC3)c2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCN(C)CC3)cc2NC2CCOCC2)c2c1CCN(S(=O)(=O)c1cc(F)cc(F)c1)C2
Reaction time: 0.08 h
Yield: 85.7 %

Procedure:
To a solution of N-[5-(3,5-difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide (1.38 g, 2.24 mmol) in anhydrous THF (150 mL), cooled to −40° C., under argon, was added lithium bis(trimethylsilyl)amide 1.0 M in THF (2.35 mL, 2.35 mmol). The mixture was stirred for 5 min. then ethyl chloroformate (0.225 mL, 2.35 mmol) was added. The reaction was stirred at −40° C. for 1 h, then was poured in water and extracted with ethyl acetate. The organic phase was washed with water, brine and dried with sodium sulfate. After filtration and evaporation the crude was triturated with ether to give the title compound as white solid (1.32 g, 86%).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].S(Cl)(Cl)=O.[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[C:12]1([O:6][C:1](=[O:7])[CH2:2][CH2:3][CH:4]=[CH2:5])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: C=CCCC(=O)O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: C=CCCC(=O)Oc1ccccc1
Temperature: 22 °C
Reaction time: 12 h
Yield: 29.2 %

Procedure:
A 250-mL round-bottom flask equipped with a stir bar was charged with 4-pentenoic acid (5.10 mL, 50.0 mmol) and CH2Cl2 (40 mL), followed by thionyl chloride (4.00 mL, 55.0 mmol). The mixture was allowed to stir for 30 min, at which point phenol (9.45 g, 100 mmol) was added as a solution in CH2Cl2 (10 mL). The mixture was allowed to cool to 0° C. (ice-bath), and triethylamine (28 mL, 200 mmol) was added dropwise by a syringe over 5 min (N.B., strong exotherm). The resulting solution was allowed to stir for 12 h at 22° C. The reaction was quenched by addition of a saturated aqueous solution of NaHCO3 (100 mL). The organic layer was separated, and the aqueous layer washed with CH2Cl2 (5×50 mL). The combined organic layers were washed with water (1×50 mL), brine (1×50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography (95:5 hexanes:EtOAc) to deliver a colorless oil. The oil was distilled from CaH2 under reduced pressure (1.0 torr) to afford phenyl(4-pentenoate) (2.58 g, 14.6 mmol, 29.0% yield) as a colorless oil. Spectral data matched those in the literature.