Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[S-:10][C:11]#[N:12].[NH4+].N>CO>[Cl:1][C:2]1[CH:7]=[C:6]([S:10][C:11]#[N:12])[CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9]
Reactant: N#C[S-]
Reactant: Oc1c(Cl)cccc1Cl
Agent: N
Agent: [NH4+]
Solvent: CO
Product: N#CSc1cc(Cl)c(O)c(Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 14.8 %

Procedure:
2,6-Dichlorophenol (lOOg, 0.613 mole) and ammonium thiocyanate (102.73 g, 1.350 mole) were mixed in methanol and the solution cooled to 0° C. Chlorine gas was bubbled throught the reaction, maintaining the temperature below 10° C. The solution turned a pale yellow color. The reaction was stirred for a total of 3 hours until acidic, at which time ammonia gas was bubbled through and the solution stirred for an additional three hours at 0° to 10° C. The reaction was poured into iced distilled water, and filtered, yielding approximately 20 g of a yellow solid which was dried overnight in vacuo. The filtrate was extracted with ethyl acetate, the extracts dried over magnesium sulfate and solvent removed in vacuo to yield approximately 100 g of crude product. Following purification by silica chromatography, the material was taken up in 1 liter of toluene, charcoal added, filtered and recrystallized from hexane to yield 55.03 g of product as a yellow solid, m.p. about 94.5°-97° C. The structure was confirmed by NMR.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[CH:4]=1.[C:11]([NH:14][CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])[CH3:12].[I-].[K+].[O-]CC.[Na+]>O1CCOCC1.C(O)C.[Cl-].[Na+].O.O>[CH2:24]([O:23][C:21](=[O:22])[C:15]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[CH:4]=1)([NH:14][C:11](=[O:13])[CH3:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:25]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: N#Cc1cccc(CBr)c1
Agent: CC[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(Cc1cccc(C#N)c1)(NC(C)=O)C(=O)OCC
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a stirred solution of alpha-bromo-meta-tolunitrile (45.0 g, 0.24 mole), diethyl acetamidomalonate (48.0 g, 0.22 mole) and potassium iodide ((3.0 g, 0.018 mole) in dioxane (500 mL) was added 2.5M sodium ethoxide in ethanol (100 mL) dropwise under an argon atmosphere. After the addition was complete, the solution was refluxed for 6 hours. The reaction mixture was allowed to stand overnight at room temperature, then diluted with brine (250 mL) and water (250 mL), and extracted with ethyl acetate four times (1.0 L total). The combined extracts were washed with water (100 mL), 10% citric acid (100 mL), water (100 mL) and brine (2×50 mL), then dried over anhydrous magnesium sulfate and filtered; the solvent was removed under vacuum. The crude residue was recrystallized from ethyl acetate and diethyl ether in two crops to yield 43.51 g (60%) of the 3-cyanobenzyl-N-acetylaminomalonic acid diethyl ester as yellow crystals.
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH:7]2[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:39]=[N:38][C:20]5[N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:22]6[CH:27]=[N:26][C:25]([C:28]#[N:29])=[CH:24][C:23]=6[C:19]=5[CH:18]=4)=[CH:13][CH:12]=3)[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH:40]1[N:44]=[CH:43][N:42]([C:45](N2C=NC=C2)=[S:46])[CH:41]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:28]([C:25]1[N:26]=[CH:27][C:22]2[N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:36])[CH3:37])[C:20]3[N:38]=[CH:39][C:17]([C:14]4[CH:15]=[CH:16][C:11]([CH2:10][N:9]5[CH:7]6[CH2:6][CH2:5][CH:4]5[CH2:3][CH:2]([O:1][C:45]([N:42]5[CH:41]=[CH:40][N:44]=[CH:43]5)=[S:46])[CH2:8]6)=[CH:12][CH:13]=4)=[CH:18][C:19]=3[C:23]=2[CH:24]=1)#[N:29]
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(-c3ccc(CN4C5CCC4CC(O)C5)cc3)cnc21
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(-c3ccc(CN4C5CCC4CC(OC(=S)n4ccnc4)C5)cc3)cnc21
Yield: 96.6 %

Procedure:
A solution of 3-[4-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-ylmethyl)-phenyl]-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (155 mg, 0.29 mmol), DMAP (5 mg, catalytic) and N,N′-thiocarbonyldiimidazole (455 mg, 8.76 mmol) in DCM (10 mL) was heated under reflux for 12 h. The cooled reaction mixture was purified by flash chromatography (silica, 50 g column, Biotage, 0-5% MeOH in DCM) to afford the title compound as a white solid (182 mg, 97%). 1H NMR (CDCl3, 300 MHz): 9.28-9.25 (m, 1H), 9.04 (dd, J=7.0, 2.2 Hz, 1H), 8.69-8.66 (m, 1H), 8.51 (d, J=1.0 Hz, 1H), 8.47-8.39 (m, 1H), 7.81-7.61 (m, 5H), 7.15-7.10 (m, 1H), 6.12 (s, 2H), 4.35 (s, 2H), 3.76-3.61 (m, 4H), 2.32-2.17 (m, 4H), 2.13-1.93 (m, 5H), 1.08-0.96 (m, 2H), 0.00 (s, LCMS (Method B): RT=3.13 min, M+H+=650.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(N(CC)CC)C.[Cl:24][C:25]([Cl:30])([Cl:29])[C:26](Cl)=[O:27].O>O1CCCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:2]([NH:1][C:26](=[O:27])[C:25]([Cl:30])([Cl:29])[Cl:24])=[C:3]([CH:12]=1)[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
To a solution of 23.2 g (100 mmol) of 2-amino-5-chlorobenzophenone and 11 g (110 mmol) of triethylamine in 200 mL of tetrahydrofuran was added dropwise 20 g (110 mmol) of trichloroacetyl chloride at temperature of 5° C. to 15° C. After being stirred for 3 hours at ambient temperature, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer separated was washed with water and then with brine, dried on anhydrous sodium sulfate and concentrated in vacuo. The resulting crude crystals were recrystallized from ethanol to give 33.8 g (89.9 mmol) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:13]([NH2:15])[CH3:14])[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[N:16]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=1.[BH4-].[Na+].Cl.[OH-].[Na+]>CO.O>[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:15][CH:13]([C:9]2([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:12][CH2:11][CH2:10]2)[CH3:14])=[CH:18][CH:17]=1
Reactant: COc1ccc(C2(C(C)N)CCC2)cc1
Reactant: O=Cc1ccncc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C2(C(C)NCc3ccncc3)CCC2)cc1
Reaction time: 16 h

Procedure:
1-[1-(4-Methoxyphenyl)cyclobutyl]ethylamine (2.8 g) was heated to 120° C. and 4-pyridinecarboxaldehyde (2.1 g) was added and the mixture was heated at 120°-200° C. for 2 hours. The mixture was allowed to cool and diluted with methanol. Sodium borohydride (1.75 g) was added and the resulting mixture heated under reflux for 21/2 hours. After standing at room temperature for 16 hours the mixture was poured into water, treated with 5N hydrochloric acid and then basified with 5N aqueous sodium hydroxide solution. The product was extracted into ether and the ether extracts were washed with water, dried and evaporated to dryness to give a red oil. The oil was purified by distillation and the distillate dissolved in ether and treated with a solution of excess maleic acid in ether to give a white solid and a sticky yellow gum. Recrystallisation of the white solid from propan-2-ol and ether gave N-(4-pyridylmethyl)-1-[1-(4-methoxyphenyl)cyclobutyl]-ethylamine (1.25) maleate as a pale yellow solid (m.p. 110°-113° C.).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18]1(C)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(B(O)O)C=CC=CC=1>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.O>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][CH2:13]1
Reactant: Cc1ccccc1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2I)CC1
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: OB(O)c1ccccc1
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2-c2ccccc2)CC1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(2-iodo-4-nitrophenyl)-4-methylpiperazine (Preparation Example 241) (406 mg), toluene (3 mL) and water (3 mL), sodium carbonate (496 mg), phenylboronic acid (157 mg) and tetrakis(triphenylphosphine)palladium (68 mg) were added in an argon atmosphere and stirred overnight at 110° C. The reaction liquid was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform/methanol) to give 1-methyl-4-(5-nitrobiphenyl-2-yl)piperazine (348 mg) as a yellow brown oil.
Reaction SMILES: C(Br)CBr.Br[C:6]([CH3:8])=[CH2:7].[CH:9](=[O:15])[CH2:10][CH2:11][C:12]#[C:13][CH3:14].[Cl-].[NH4+]>O1CCCC1>[CH3:8][C:6]([CH:9]([OH:15])[CH2:10][CH2:11][C:12]#[C:13][CH3:14])=[CH2:7]
Reactant: C=C(C)Br
Reactant: CC#CCCC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: C=C(C)C(O)CCC#CC
Temperature: 25 °C
Yield: 85 %

Procedure:
Magnesium (14.4g, 0.6g atom) was dried in a 250ml flask fitted with reflux condenser, mechanical stirrer and addition funnel. After initiation of reaction under dry N2 with about one ml ethylene dibromide in 70ml tetrahydrofuran, 36.0g (0.30 mole) 2-bromopropene was added dropwise at such a rate as to maintain reflux without external heating. The Grignard solution was then stirred until it cooled to room temperature (30 minutes-1 hour). It was then cooled further to -15° in ice-salt, and the total crude 4-hexynal from part (c) above was added dropwise over 15 minutes. The reaction mixture was stirred for 2 hours at room temperature, saturated ammonium chloride solution was added and the product was extracted with ether. There was obtained 23.50g of (2-methyloct-1-en-6-yn-3-ol (85%, based on 4-methyl hexynoate) as a pale yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:17]([NH:19][C@H:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:21][OH:22])=[O:18])[C@@H:14]([CH3:16])[OH:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.FC([C:31]([OH:33])=[O:32])(F)F.C(Cl)Cl>C(N(CC)CC)C>[NH:12]([C:31]([O:33][C:4]([CH3:9])([CH3:5])[CH3:3])=[O:32])[C@H:13]([C:17]([NH:1][C@H:2]([C:10]([NH:12][C@H:13]([C:17]([NH:19][C@H:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:21][OH:22])=[O:18])[C@@H:14]([CH3:16])[OH:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:18])[C@@H:14]([CH3:16])[OH:15]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1ccccc1)[C@@H](C)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O)[C@@H](C)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Phe-Thr-Ser-OMe.TFA, 6.4 g., and BOC-Thr-HSE, 4.6 g., is suspended in 100 ml. of methylene chloride. The reaction mixture is adjusted to a pH of 7 by the addition of triethylamine. After stirring the reaction mixture for 11/2 hours at 25° C., the crude product is isolated by filtration. The crude product is partially dissolved in 50 ml. methanol and precipitated by the addition of 450 ml. of ether. The partially purified product is isolated by filtration and this precipation process is repeated four times to give substantially pure BOC-Thr-Phe-Thr-Ser-OMe, 6.04 g.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19](Cl)[N:18]=[CH:17][N:16]=1.C(N(CC)CC)C>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:3][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:19]2[N:18]=[CH:17][N:16]=[C:15]([Cl:14])[C:20]=2[N+:21]([O-:23])=[O:22])[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)c2[N+](=O)[O-])CC1

Procedure:
A solution of 1-[1,1-dimethylethoxycarbonyl]piperazine (1.88 g) in dichloromethane (30 ml) is added drop by drop over 1.5 hr to a solution of 4,6-dichloro-5-nitropyrimidine (1.94 g) and triethylamine (1.32 g) in dichloromethane (170 ml) at -78°. After stirring an additional hr at -78°, the reaction is diluted with aqueous sodium bicarbonate (10%). The phases are separated, the organic phase is concentrated to a liquid which solidified on standing at 20°-25°. The solid is dissolved in chloroform and flash chromatographed on silica gel eluting with methanol/chloroform (1/99), pooling and concentrating the appropriate fractions gives the title compound, Anal. Calc for C13H18 N5ClO4 ; MW=343.77: C,45.42; H,5.28; N,20.37; Cl,10.31. Found: C,45.52; H,5.40; N,20.34; Cl,10.36.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])O.[Na+]>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.C1(C)C=CC=CC=1.O.C(O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:4]2[CH:3]=[C:2]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=3)[CH:14]=[CH:13][C:5]=2[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:17][CH:18]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2cccc(F)c2)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To toluene 2.1 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.10 g were added ethanol 0.6 mL, water 0.3 mL, 3-fluorophenylboronic acid 46 mg, sodium hydrogen carbonate 69 mg and tetrakis(triphenylphosphine)palladium(0) 16 mg at room temperature, and it was heated and refluxed for 2 hours. After the reaction mixture was cooled to room temperature, tetrakis(triphenylphosphine)palladium(0) 16 mg were added, and it was heated and refluxed for 2 hours. After the reaction mixture was cooled to room temperature, toluene and saturated sodium hydrogen carbonate aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-(4-fluoroanilino)-4-(3-fluorophenyl)benzoate.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[O:13])=[CH:21][CH:20]=1
Reactant: O=Cc1cccc(O)c1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2cccc(C=O)c2)cc1
Reaction time: 27.5 h
Yield: 18.5 %

Procedure:
Triethylamine (7.1 ml, 51 mmol) was added dropwise at room temperature to a suspension of 3-hydroxybenzaldehyde (1.72 g, 14.1 mmol), 4-methoxyphenylboronic acid (3.16 g, 20.8 mmol), molecular sieves 4A powder (1.95 g) and copper (II) acetate (2.96 g, 16.3 mmol) in methylene chloride (100 ml), and the mixture was stirred for 27.5 hrs. The reaction mixture was diluted with ethyl acetate (200 ml), and the insoluble materials were filtered off and washed with ethyl acetate. The filtrate and washings were combined, washed with 10% hydrochloric acid and brine in turn and dried. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=7) to give 3-[(4-methoxy)phenoxy]benzaldehyde (596 mg, 19%) as a pale brown oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:8])[NH:6][N:7]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:16]([CH3:27])[C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=[O:18]>CN(C=O)C>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:17](=[O:18])[CH:16]([O:8][C:5]1[NH:6][N:7]=[C:3]([CH2:1][CH3:2])[CH:4]=1)[CH3:27]
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Reactant: CCc1cc(O)[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1cc(OC(C)C(=O)c2ccc(Cl)cc2Cl)[nH]n1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-ethyl-2H-pyrazol-3-ol (4.40 g, 39.2 mmol) in DMF (40 ml) is added cesium carbonate (13.42 g, 41.2 mmol) and the reaction mixture is heated to 50° C. After 5 minutes, 2-bromo-1-(2,4-dichloro-phenyl)-propan-1-one (Intermediate AA) (11.62 g, 41.2 mmol) in DMF (60 ml) is added slowly (addition time 10 minutes, initially yellow) and the reaction is stirred for a further 45 minutes giving a tan solution which is allowed to cool to RT. The reaction mixture is partitioned between EtOAc (150 ml) and 1N Na2CO3 (400 ml) and extracted with EtOAc (4×75 ml). The combined organic extracts are washed with H2O (1×200 ml) and brine (250 ml), dried (Na2SO4), filtered and concentrated in vacuo to yield a brown oil. The residue is pre-absorbed (dissolved in dichloromethane) onto silica gel and purified via Flashmaster (SiO2 340 g Snap cartridge column) eluting with 4:1 iso-hexane/EtOAc to 2:1 iso-hexane/EtOAc to yield the title compound as a pale yellow solid MS: m/z 313.12 [M+H]+
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15](Cl)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(OCC)(=O)C>[CH2:18]([O:17][C:15]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
A solution of tert-butyl 4-aminopiperidine-1-carboxylate (1.2 g, 6 mmol) in dichloromethane (20 mL) was cooled to 0° C. Carbobenzoxy chloride (1.03 mL, 7.2 mmol) and diisopropylethylamine (3.15 mL, 18 mmol) were added at the same temperature, and the solution was stirred at 0° C. for one hour. The reaction solution was neutralized with saturated aqueous potassium carbonate solution, diluted with ethyl acetate, washed with brine, and dried over magnesium sulfate. Thereafter, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=3/1) to obtain 1.5 g of the title compound as a yellow oily substance (75%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=O.Cl.[NH2:18][OH:19].N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[N:18][OH:19]
Reactant: COc1ccc(C(=O)c2sccc2Br)cc1
Reactant: NO
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C(=NO)c2sccc2Br)cc1
Temperature: 0 °C
Yield: 95.1 %

Procedure:
Stir a solution of (3-bromothiophen-2-yl)-(4-methoxyphenyl)methanone (19.65 g, 0.066 mol), hydroxylamine hydrochloride (6.89 g, 0.099 mol), and pyridine (30 mL) at 85° C. under nitrogen for five hours. Pour the reaction mixture into a mixture of water (120 mL) and toluene (180 mL), and chill to 0° C. Add concentrated hydrochloric acid (approximately 30 mL) dropwise with cooling to adjust to pH 1-2. Filter the mixture and wash the solid with toluene and water. Separate the phases and extract the acidic aqueous phase with toluene. Wash the combined toluene phases twice with water, dry (Na2SO4), filter and evaporate. Combine the residue from the toluene extracts with the previously obtained solid filter cake, and triturate the mixture with petroleum ether. Filter the mixture and dry in vacuo at 60° C. to give the title compound as a white solid (19.6 g, 95% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:8]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[S:7][C:6]=2[CH:24]=1.[Li]CCCC.C(O[B:34]1[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]1)(C)C.O>C1COCC1>[C:20]1([CH3:23])[CH:21]=[CH:22][C:17]([C:8]2[S:7][C:6]3[CH:5]=[C:4]([B:34]4[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]4)[CH:3]=[CH:2][C:24]=3[C:9]=2[C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:18][CH:19]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(-c2sc3cc(Br)ccc3c2-c2ccc(C)cc2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2sc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2-c2ccc(C)cc2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
Under argon atmosphere, in a 500 ml round-bottomed flask, 5 g (12.75 mmol) of 6-bromo-2,3-di-p-tolyl-benzo[b]thiophene was dissolved in 150 ml of THF, and 6.12 ml (15.31 mmol) of n-BuLi 2.5M (hexane) was added thereto at −78° C. The resulting solution was stirred at −78° C. for 2 hours. Then 3.4 ml (16.58 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added thereto and stirred at room temperature for one hour. The reaction was ended by adding 50 ml of water. Then an organic layer was extracted with brine and methylene chloride. The extracted organic layer was dried with anhydride magnesium sulfate, filtered and removed of solvent. The organic layer was purified through chromatography (silica, hexane), and 4.8 g (yield 79%) of white solid product was obtained by increasing the polarity of the developing solvent.