Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[NH2:18][C:19]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[F:39][C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1[C:30]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[C:19]([NH:18][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:8]=2[CH3:7])[CH:31]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(F)cc2F)cc1N
Reactant: Cc1cccc(C(=O)O)c1C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(C(=O)Nc2cc(-c3ccc(F)cc3F)ccc2C(=O)OC(C)(C)C)c1C
Reaction time: 1 h

Procedure:
1.7 mL of methylene chloride, 1.0 μL of N,N-dimethylformamide and 0.025 mL of oxalyl chloride were added to 41 mg of 2,3-dimethylbenzoic acid at room temperature sequentially and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 49 mg of tert-butyl 2-amino-4-(2,4-difluorophenyl)benzoate, 2.8 mL of methylene chloride and 0.36 mL of triethylamine and stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain tert-butyl 4-(2,4-difluorophenyl)-2-(2,3-dimethylbenzamido)benzoate.
Reaction SMILES: C1(CO[C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)CCC1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][OH:29].C(OC(C1NC2C(C=1)=C(O)C=CC=2)=O)C>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][O:29][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]2
Reactant: COc1ccccc1CCO
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Agent: CCOC(=O)c1cc2c(O)cccc2[nH]1
Product: COc1ccccc1CCOc1cccc2[nH]c(C(=O)O)cc12

Procedure:
4-[2-(2-Methoxy-phenyl)-ethoxy]-1H-indole-2-carboxylic acid (16j) is synthesized analogous to 16a from 2-(2-methoxy-phenyl)-ethanol and 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([NH2:10])(=[O:9])=[O:8])[CH:2]=1.C[Al](C)C.C.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH:24][C:25](=O)[O:26]C)[N:18]=1>C(Cl)Cl.C(O)(=O)C>[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH:24][C:25]([NH:10][S:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:9])=[O:8])=[O:26])[N:18]=1
Reactant: NS(=O)(=O)c1cccnc1
Reactant: COC(=O)Nc1nc(C)cc(C)n1
Agent: C
Agent: C[Al](C)C
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccnc2)n1
Reaction time: 66 h

Procedure:
To a slurry of 3-pyridinesulfonamide (1 m mole) in methylene chloride is added 2 m mole of trimethylaluminum. Following methane evolution, the reaction mixture becomes homogeneous, whereupon 1 m mole of methyl (4,6-dimethylpyrimidin-2-yl)carbamate is added, and stirring is continued for 66 hours. Aqueous acetic acid is added and the product is extracted into methylene chloride. The solvent is evaporated and the product is isolated by trituration on chromatography.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([C:17]2[CH:22]=[C:21]([C:23](=O)[C:24]#[CH:25])[CH:20]=[CH:19][C:18]=2[CH3:27])[C:5]([CH3:16])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]=[C:12]([CH3:15])[S:13][CH:14]=1.Cl.[OH:30][C:31]([CH3:36])([CH3:35])[C:32]([NH2:34])=[NH:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:3](=[O:28])[N:4]([C:17]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][N:34]=[C:32]([C:31]([OH:30])([CH3:36])[CH3:35])[N:33]=3)[CH:20]=[CH:19][C:18]=2[CH3:27])[C:5]([CH3:16])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]=[C:12]([CH3:15])[S:13][CH:14]=1
Reactant: CC(C)(O)C(=N)N
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3csc(C)n3)c(Br)c2=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc(COc2nc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ccc3C)c(=O)c2Br)cs1
Temperature: 75 °C
Yield: 39.5 %

Procedure:
To a solution of 5-bromo-2-methyl-3-(2-methyl-5-propynoyl-phenyl)-6-(2-methyl-thiazol-4-ylmethoxy)-3H-pyrimidin-4-one of Step D (64 mg, 0.14 mmol) in acetonitrile (1 mL) was added 2-hydroxy-2-methylpropionamidine HCl (30 mg, 0.21 mmol) and potassium carbonate (60 mg, 0.42 mmol) and the slurry was heated at 75° C. for two hours and at ambient temperature for eighteen hours. The reaction was filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a white solid (30 mg, 39% yield). MS (M, M+2): 542, 544; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.64 (s, 6H), 2.16 (s, 3H), 2.21 (s, 3H), 2.76 (s, 3H), 5.59-5.67 (m, 2H), 7.26 (s, 1H), 7.54-7.58 (m, 2H), 7.92 (s, 1H), 8.14 (d, J=8.61, 1H), 8.78 (d, J=5.48, 1H).
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[Cl:15][C:16]1[C:21]2[C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[O:24][C:20]=2[C:19]([N:28]=[C:29]=[O:30])=[C:18]([Cl:31])[CH:17]=1>O1CCCC1.O>[Cl:15][C:16]1[C:21]2[C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[O:24][C:20]=2[C:19]([N:28]2[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:29]2=[O:30])=[C:18]([Cl:31])[CH:17]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CC1(C)Oc2c(N=C=O)c(Cl)cc(Cl)c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Oc2c(c(Cl)cc(Cl)c2-n2c(=O)cc(C(F)(F)F)[nH]c2=O)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (0.78 g, 0.019 mole) was placed in a flask, and the mineral oil was removed from it with two heptane washes. The sodium hydride was suspended in 40 mL of dry tetrahydrofuran, and this suspension was cooled to 0°-10° C. A solution of 2.96 g (0.0162 mole) of ethyl 3-amino-4,4,4-trifluorocrotonate in 5 mL of dry tetrahydrofuran was added dropwise to the suspension of sodium hydride. This mixture was then stirred at ambient temperature for 30 minutes. A solution of 4.40 g (0.0162 mole) of 4,6-dichloro-2,3-dihydro-2,2-dimethyl-benzofuran-3-on-7-yl isocyanate in 10 mL of dry tetrahydrofuran was added dropwise. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 30 minutes and then was heated at reflux for three hours. At the conclusion of this period the mixture was diluted with water, and the resulting mixture was extracted three times with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure, yielding 9.58 g of a gummy, pale yellow residue. This residue was triturated with methylene chloride, yielding 4.79 g of 3-(4,6-dichloro-2,3-dihydro-2,2-dimethylbenzofuran-3-on-7-yl)-6-trifluoromethyluracil as an off-white solid, m.p. 308°-320° C. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: C(O[CH2:9][C:10]1[C:11]([O:24]C)=[N:12][CH:13]=[CH:14][C:15]=1[C:16]([OH:23])([CH2:21][CH3:22])[CH2:17][C:18]([OH:20])=[O:19])C1C=CC=CC=1.C([O-])=O.[NH4+].C1(N=C=NC2CCCCC2)CCCCC1.[I-].[Na+].C[Si](Cl)(C)C>CO.C1COCC1.[Pd].O.C(#N)C>[CH2:21]([C:16]1([OH:23])[C:15]2[CH:14]=[CH:13][NH:12][C:11](=[O:24])[C:10]=2[CH2:9][O:19][C:18](=[O:20])[CH2:17]1)[CH3:22]
Reactant: CCC(O)(CC(=O)O)c1ccnc(OC)c1COCc1ccccc1
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: CCC1(O)CC(=O)OCc2c1cc[nH]c2=O
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 48.2 %

Procedure:
(−)-3-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-3-hydroxy-pentanoic acid (13.5 g; 39 mmol; Stage 80.b) is put in solution in 87 ml of methanol. This solution is poured under nitrogen onto 10% Palladium on damp carbon at 50% (27.7 g; 13 mmol). The reaction medium is agitated for 5 minutes, then it is poured into a solution of ammonium formate (11,5 g; 183 mmol) in 135 ml of methanol. The reaction medium is agitated for 30 minutes while allowing the temperature to rise, then it is heated at 40° C. for 30 minutes. The medium is then filtered on a bed of Clarcel followed by concentrating. 40 ml of toluene is poured in which is evaporated off; this operation is repeated in order to eliminate the methanol. The residue thus obtained is taken up in 45 ml of THF. Then a solution of dicyclohexylcarbodiimide (7.180 g; 34.5 mmol) in 20 ml of THF is then poured in. The reaction medium is heated to 50° C. for 1 hour. The mixture is taken to 20° C. then the dicyclohexylurea is filtered. The filtrate is concentrated to dryness. The residue is put in solution in 46 ml of acetonitrile, 6.0 g (40.5 mmol.) of sodium iodide then 5.13 ml (40.5 mmol) of trimethylsilyl chloride are added. The reaction medium is maintained under agitation at ambient temperature for 5 hours. Then 28 ml of acetonitrile and 5.6 ml of water are added. The precipitate obtained is filtered then taken up in 1 ml of water, and the pH is adjusted to 7.5 by the addition of a solution of ammonium hydroxide. The solid obtained is filtered and dried. M=4.2 g of final product is obtained with a yield of 34% and a (+) enantiomer/(−) enantiomer proportion of 88.4/11.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:6]=2[CH:19]=1.[Cl:20][CH2:21][C:22]([N:24]=[C:25]=[O:26])=[O:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:25]([NH:24][C:22](=[O:23])[CH2:21][Cl:20])=[O:26])[CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:6]=2[CH:19]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCCN2
Reactant: O=C=NC(=O)CCl
Solvent: ClCCl
Product: O=C(CCl)NC(=O)N1CCN=C(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of 8 parts of 7-chloro-5-(o-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine, 4.9 parts of chloroacetylisocyanate, and 200 parts by volume of methylene chloride is stirred under nitrogen atmosphere at ambient temperature for about one hour. The mixture is then filtered through a layer of activated magnesium silicate and the filtrate evaporated to dryness. The resultant yellow oil is dissolved in ether and the solvent removed by evaporation to give gummy residue which upon crystallization from ether affords 7-chloro-N-chloracetyl-5-(o-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-1-carboxamide, as a yellow solid melting at about 152°-156° C. This compound is represented by the following formula ##STR21##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[OH:9].C(=O)(O)[O-].[Na+].Cl[CH2:16][C:17](Cl)=[O:18]>C(#N)C.O.CCOC(C)=O>[Br:8][C:4]1[C:3]2[O:9][CH2:16][C:17](=[O:18])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Br)c1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: O=C1COc2c(Br)cccc2N1
Temperature: 0 °C
Yield: 94 %

Procedure:
To a solution of 2-amino-6-bromophenol (1 g, 5.32 mmol) in acetonitrile (10 mL) and water (10 mL) was added sodium bicarbonate (1.028 g, 12.23 mmol). The mixture was cooled to 0° C. and chloroacetyl chloride (0.554 mL, 6.91 mmol) was added dropwise. The reaction was refluxed overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water, dried over anhydrous MgSO4, filtered, and concentrated to afford the title compound (1.14 g, 94% yield) as a dark brown solid. 1H NMR (400 MHz, CDCl3) δ 8.22 (br. s, 1H), 7.23 (dd, J=8.0, 1.4 Hz, 1H), 6.86 (t, J=8.0 Hz, 1H), 6.76 (dd, J=7.9, 1.3 Hz, 1H), 4.74 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:2].[Br:13]Br>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:12])[CH:5]([Br:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)Cc1ccccn1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
16.52 g (100 mmol) of 2-pyridylacetic acid ethyl ester is dissolved in 50 ml of carbon tetrachloride. It is cooled to 0° C. and 15.98 g (100 mmol) of bromine, dissolved in 15 ml of carbon tetrachloride, is then instilled in it within 30 minutes. Then, it is allowed to react for one more hour at 25° C. The bromine coloring fades away. It is concentrated by evaporation in a vacuum and obtains the hydrobromide of the title compound. The free compound is obtained by extraction of ether from the aqueous solution after adding sodium bicarbonate.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:16][CH2:15][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOc1cc(C)ccc1C(=O)OC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COCOc1cc(CBr)ccc1C(=O)OC
Yield: 101.9 %

Procedure:
To a solution of methyl 2-methoxymethoxy-4-methylbenzoate (9.41 g, 0.0448 mol) in 150 mL of carbon tetrachloride was added N-bromosuccinimide (7.97 g, 0.0448 mol) and benzoyl peroxide (0.45 g, 0.002 mol). The reaction mixture was refluxed for 18 hours. The solid was filtered and the filtrate was concentrated in vacuo to give 13.2 g of an oil. The product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane to give 10.2 g (79%) of product as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:13]=[CH:14][CH:15]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([CH2:25][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:13]=[CH:14][CH:15]=1
Reactant: C1CCNC1
Reactant: O=Cc1ccc2c(c1)ncn2-c1cccc(COCc2ccccn2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(COCc2cccc(-n3cnc4cc(CN5CCCC5)ccc43)c2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
A solution of compound 12a (80 mg, 0.15 mmol) and pyrrolidine (0.013 mL) in dichloromethane (10 mL) was stirred for 30 min at RT, then sodium triacetoxyboro-hydride (100 mg) was added to the reaction mixture at 0° C. The mixture was stirred for 12 hours at RT. The reaction mixture was quenched with water and the product was extracted with CH2Cl2 (3×40 mL). The combined organic layers were dried over anhydrous Na2SO4, the solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel using a 3:7 mixture of ethyl acetate and pet-ether as the eluent to afford compound 13a (40 mg, 68%) as a solid. Mp 192-194° C.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][C:8]2[C:3]3=[C:4]([C:11]4[C:20]([C:2]=13)=[CH:19][C:18]1[CH:17]=[C:16]([CH2:21][OH:22])[CH:15]=[CH:14][C:13]=1[N:12]=4)[CH:5]=[CH:6][CH:7]=2.[Mn]([O-])([O-])(=O)=O.[Ba+2].C(Cl)Cl>CCOC(C)=O.C1COCC1>[CH:1]1[CH:10]=[CH:9][C:8]2[C:3]3=[C:4]([C:11]4[C:20]([C:2]=13)=[CH:19][C:18]1[CH:17]=[C:16]([CH:21]=[O:22])[CH:15]=[CH:14][C:13]=1[N:12]=4)[CH:5]=[CH:6][CH:7]=2
Reactant: OCc1ccc2nc3c(cc2c1)-c1cccc2cccc-3c12
Agent: O=[Mn](=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1ccc2nc3c(cc2c1)-c1cccc2cccc-3c12
Yield: 71.7 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser, N2 inlet line with bubbler was aded acenaphtho[1,2-b]quinoline-10-methanol (14A, 2.25 g, 8 mmol), barium manganate (Aldrich, 4.0 g, 16 mmol) and dry CH2Cl2 (1 L). The mixture was refluxed for 24 h, filtered and the resulting dark yellow solution filtered and the solvent removed by rotary evaporation to give a dark green solid. This material was dissolved in a mixture of EtOAc (700 mL) and THF (200 mL) and passed through a small plug of SiO2 using EtOAc as the eluting solvent. The appropriate fractions were combined and the solvent removed by rotary evaporation to give a 71.7% yield of acenaphtho[1,2-b]quinoline-10-carbaldehyde, mp 245°-246°, (C,H,N).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.Br[CH:11]([Cl:14])[CH2:12][CH3:13].[OH-].[K+]>C(O)C>[Cl:14][CH2:11][CH2:12][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1
Reactant: CCC(Cl)Br
Reactant: OCc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OCc1ccc(OCCCCl)cc1

Procedure:
A solution of 4-hydroxy benzyl alcohol CAS No. [623-05-2] (10 g, 80.5 mmol) in ethanol (70 mL) was treated with 1, 3 bromochloro propane (16.0 g , 100 mmol) and potassium hydroxide (5.0 g, 89 mmol) was refluxed for 2 hours. The solution was cooled and filtered and then the filtrate concentrated. The concentrate was taken up in ether and washed with water, brine and dried over magnesium sulfate. The material was chromatographed on silica gel using ethyl acetate/hexanes (3:7) to yield 11.6 g of the product as a white solid: Mp=65° C.; 1H NMR (DMSO) 7.21 (d, 2H, J=8.8 Hz), 6.88 (d, 2H, J=8.8 Hz), 5.03 (t, 1H, J=5.7 Hz), 4.40 (d, 2H, J=5.5 Hz), 4.05 (t, 2H, J=6.1 Hz), 3.77 (t, 2H, J=6.4 Hz); MS eI m/z 200.
Reaction SMILES: [CH:1](=[N:8][N:9]1[CH:13]2[CH2:14][C:15](=[O:17])[CH2:16][CH:12]2[N:11]([CH2:18][CH2:19][CH3:20])[C:10]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH:1](=[N:8][N:9]1[CH:13]2[CH2:14][CH:15]([OH:17])[CH2:16][CH:12]2[N:11]([CH2:18][CH2:19][CH3:20])[C:10]1=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCN1C(=O)N(N=Cc2ccccc2)C2CC(=O)CC21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCN1C(=O)N(N=Cc2ccccc2)C2CC(O)CC21
Yield: 35.5 %

Procedure:
The compound of step (e) (21 g) was dissolved in methanol (100 ml) and the solution cooled to 0° C. while sodium borohydride (1.5 g) was added portionwise over 15 minutes. When addition was complete, the solvent was removed in vacuo, water (100 ml) and chloroform (100 ml) added and the organic phase separated. After drying over anhy. sodium sulphate, filtration and concentration in vacuo gave the crude product as a brown gum (21 g). This was purified by column chromatography (silica, 10:1 diethyl ether:methanol) to give the desired product as fine white needles (7.5 g), mp 150.3°-150.8° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]3[CH:12]=[C:11]2I)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Sn](CCCC)(CCCC)[C:27]1[CH2:31][CH2:30][CH2:29][CH:28]=1)CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3[C:13](=[C:18]([O:19][CH3:20])[CH:17]=[CH:16][N:15]=3)[CH:12]=[C:11]2[C:27]2[CH2:31][CH2:30][CH2:29][CH:28]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccnc2c1cc(I)n2S(=O)(=O)c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccnc2c1cc(C1=CCCC1)n2S(=O)(=O)c1ccccc1
Temperature: 90 °C
Yield: 64.9 %

Procedure:
A mixture of 1-benzenesulfonyl-2-iodo-4-methoxy-1H-pyrrolo[2,3-b]pyridine (1.1 g, 2.65 mmol), tributyl-cyclopent-1-enyl-stannane (1.9 g, 5.31 mmol), and bis(triphenylphosphine)palladium(II) chloride (93 mg) in DMF (10 mL) was heated in a sealed tube to 90° C. for seven hours. The mixture was washed with hexanes (2×10 mL) and the DMF phase was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient elution of 10-35% EtOAc/hexanes) to give 0.61 g of 1-benzenesulfonyl-2-cyclopent-1-enyl-4-methoxy-7-azaindole as a yellow solid; MS (m/z) 355 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][NH:10][C:9]1([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.OS([O-])(=O)=O.[K+].CCOCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][N:10]([C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:25])[C:9]1([CH3:15])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)NCC(=O)N1Cc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)N(Cc2ccccc2)C(=O)CN1C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
A cold (0° C.) solution of 3-benzyl-2,2-dimethylimidazolidin-4 -one (2.28 g, 11.16 mmol) in CH2Cl2 (25 mL) was treated with benzylchloroformate (0.96 mL, 6.70 mmol), a solution of 4-dimethylaminopyridine (1.71 g, 13.95 mmol) in CH2Cl2 (10 mL), and again with benzylchloroformate (0.96 mL, 6.70 mmol). The solution was stirred for 30 min and poured into aqueous 10% KHSO4 solution. The layers were separated, and the organic was washed twice with water and once with brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford an orange oil. The oil was treated with Et2O causing a precipitate which was filtered to afford the product as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 10H), 5.14 (s, 2H), 4.54 (s, 2H), 4.11 (s, 6H), 1.56 (s, 6H); ES MS (M+1)=339.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]Cl>CN(C=O)C>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[N:9]1
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCn1ncc2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Yield: 64 %

Procedure:
A mixture of 6-nitroindazole (2 g, 12 mmol) and potassium carbonate (5.1 g 37 mmol) in DMF (40 mL) for 30 minutes, followed by the addition of 2-(dimethylamino)ethylchloride hydrochloride (2.65 g 18.4 mmol) was added. The mixture was heated to 60° C. for 6 hours, cooled to room temperature, filtered through a plug of silica gel, which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound (1.8 g, 64% yield). 1H NMR (300 MHz, DMSO-d6) ppm 2.16 (s, 6H), 2.73 (t, J=6.44, 2H), 4.66 (t, J=6.44, 2H), 7.94 (m, 1H), 8.00 (m, 1H), 8.31 (m, 1H), 8.79 (m, 1H); MS (DCI/NH3) m/z 235 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O.C1(P(=[CH:32][C:33](=[O:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1/[CH:6]=[CH:32]/[C:33](=[O:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: O=Cc1ccccc1OC(F)F
Reactant: CCOC(=O)C(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C(=O)/C=C/c1ccccc1OC(F)F
Temperature: 100 °C
Yield: 109 %

Procedure:
A suspension of 2-(difluoromethoxy)benzaldehyde (295 g, 1714 mmol) and ethyl (triphenylphosphoranylidene)pyruvate (279.1 g, 742 mmol) was heated at 100° C. The dark red aldehyde immediately decolorized, and a yellow suspension was obtained, which slowly changed to a dark brown solution. 2-(Difluoromethoxy)benzaldehyde (52.5 g, 305 mmol) was added to the reaction mixture. Residual aldehyde was separated from the reaction mixture by distillation. The resulting mixture was stirred in heptane (500 mL) and diethyl ether (500 mL). The brown solid precipitate was filtered off, and washed with a 1:1 mixture of heptane and diethyl ether (3×250 mL). The filtrate was concentrated, yielding a brown oil (218.5 g). Purification by flash column chromatography (1.5 kg silica, 2-20% EtOAc in heptane, 125 mL/minute) gave the title compound (91 g) as a yellow oil. δH (CDCl3, 300 MHz) 1.42 (t, J 7.1 Hz, 3H), 4.40 (q, J 7.1 Hz, 2H), 6.59 (t, J 72.9 Hz, 1H), 7.20 (dd, J 7.3, 1.0 Hz, 1H), 7.28 (br t, J 7.6 Hz, 1H), 7.38 (d, J 16.3 Hz, 1H), 7.46 (dt, J 7.8, 1.7 Hz, 1H), 7.75 (dt, J 7.8, 1.6 Hz, 1H), 8.13 (d, J 16.3 Hz, 1H). MS [ES+] m/z 271 [M+H]+.