Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.[N:4]1[C:11](Cl)=[N:10][C:8]([Cl:9])=[N:7][C:5]=1[Cl:6]>CCOCC.C1COCC1>[Cl:6][C:5]1[N:7]=[C:8]([Cl:9])[N:10]=[C:11]([CH3:1])[N:4]=1
Reactant: C[Mg]Br
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
Methylmagnesium bromide (9.00 mL of a 3.0 M solution in Et2O, 27.1 mmol, 1.00 equiv) was added dropwise over 1 h to a cooled (0° C.) solution of cyanuric chloride (5.00 g, 27.1 mmol, 1.00 equiv) in THF (270 mL). The reaction mixture was stirred at room temperature overnight and was then quenched with sat NH4Cl (aq). The aqueous layer was extracted 3 times using ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified using silica gel chromatography (0-40% CH2Cl2/hexanes) to afford 1.5 g (34%) of the title compound. MS (ES+): m/e 164.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:26][CH2:27][C@@H:28]1[CH2:32][C@@H:31]([OH:33])[CH2:30][N:29]1[C:34]([O:36][CH2:37][CH3:38])=[O:35].C(OCC)(=O)C>CN(C)C(=O)C>[CH2:37]([O:36][C:34]([N:29]1[CH2:30][C@H:31]([OH:33])[CH2:32][C@H:28]1[CH2:27][CH2:26][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)=[O:35])[CH3:38]
Reactant: CCOC(=O)N1C[C@H](O)C[C@H]1CCCl
Reactant: COc1cccc(CCc2cc(F)ccc2O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(F)cc1CCc1cccc(OC)c1
Temperature: 40 °C
Reaction time: 5 h
Yield: 76.5 %

Procedure:
399 mg of 4-fluoro-2-[2-(3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 4) were dissolved in 8 ml of N,N-dimethylacetamide, and then 363 mg of potassium t-butoxide and 718 mg of (2S,4R)-2-(2-chloroethyl)-1-ethoxycarbonyl-4-hydroxypyrrolidine were added, whilst ice-cooling, to the resulting solution. The resulting mixture was then stirred at 40° C. for 5 hours. At the end of this time, 50 ml of ethyl acetate were added, and the reaction mixture was washed with water and with a saturated aqueous solution of sodium chloride, in that order. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then concentrated by evaporation under reduced pressure. The resulting oily substance was purified by silica gel column chromatography, using a 3:7 by volume mixture of hexane and ethyl acetate as the eluent, to give 535 mg (yield 76%) of the title compound as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[NH:9])=[N:6][CH:7]=1.C([O:13][C:14](=O)[CH:15]([CH2:19][CH3:20])[C:16]([CH3:18])=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:10]=[C:14]([OH:13])[C:15]([CH2:19][CH3:20])=[C:16]([CH3:18])[N:9]=2)=[N:6][CH:7]=1
Reactant: N=C(N)c1ccc(N)cn1
Reactant: CCOC(=O)C(CC)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1c(C)nc(-c2ccc(N)cn2)nc1O
Reaction time: 24 h

Procedure:
To a solution of compound of example 12 (0.2 g, 1.47 mmol) in water (5 mL) and ethanol (2.5 mL) was added ethyl-2-ethylacetoacetate (0.379 g, 2.35 mmol) and sodium carbonate (0.280 g, 2.64 mmol) at room temperature and the reaction mixture was stirred for 24 hours. Ethanol was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: [Br-].[O:2]=[C:3]1[N:8]([CH3:9])[C:7](=[O:10])[N:6]([CH3:11])[CH2:5][NH+:4]1[CH3:12].[NH2:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.C(=O)(O)[O-].[Na+]>O>[O:2]=[C:3]1[N:8]([CH3:9])[C:7](=[O:10])[N:6]([CH3:11])[CH:5]([C:17]2[CH:18]=[CH:19][C:14]([NH2:13])=[CH:15][C:16]=2[OH:20])[N:4]1[CH3:12]
Reactant: CN1C[NH+](C)C(=O)N(C)C1=O
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CN1C(=O)N(C)C(c2ccc(N)cc2O)N(C)C1=O

Procedure:
23.6 g (0.1 mol) of 2,4-dioxo-1,2,3,4-tetrahydro-1,3,5-trimethyl-s-triazinium bromide are dissolved in 50 ml of water and 10.9 g (0.1 mol) of m-aminophenol are added. After a few minutes, a clear solution has formed. 8 g of sodium bicarbonate are added to the solution. 25 g (89%) of 2,4-dioxo-hexahydro-1,3,5-trimethyl-6-[2-hydroxy-4-amino-phenyl]-s-triazine precipitate out as white crystals, which, after they have been dissolved in aqueous hydrochloric acid and the solution has been clarified with active charcoal and neutralised, melt at 240° C.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1.O>N1C=CC=CC=1>[C:1]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCC(=O)Nc1ccc(C(=O)O)cc1
Reaction time: 3 h
Yield: 86.2 %

Procedure:
n-Dodecanoyl chloride (8.74 g.; 40 mmoles) is added dropwise to a solution of p-aminobenzoic acid (40 mmoles) dissolved in pyridine (100 ml.). The mixture is stirred for 3 hours and poured into water (3 l.). The precipitate which forms is filtered and dried in vacuo to give N-(n-dodecanoyl)-p-aminobenzoic acid (11.01 g.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21].[NH2:23][CH:24]([CH2:28][CH3:29])[CH:25]([OH:27])[CH3:26]>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:23][CH:24]([CH2:28][CH3:29])[CH:25]([OH:27])[CH3:26])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21]
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(Cl)cc1C
Reactant: CCC(N)C(C)O
Solvent: CN1CCCC1=O
Product: CCC(Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC)C(C)O
Temperature: 130 °C

Procedure:
A mixture of 4-chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-nicotinic acid methyl ester (500 mg, 1.47 mmol) and 3-amino-pentan-2-ol (758 mg, 7.35 mmol) in 1-methyl-2-pyrrolidinone was heated in 130° C. oil bath for 24 hr. The mixture cooled to rt and quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give an oil. The oil was purified through silica gel column chromatography using 20% ethyl acetate in hexane as eluent to give the title compound as a white crystal, mp 133–135° C.
Reaction SMILES: OC[C:3]1[CH:4]=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6](=[O:16])[N:7]2[C:12]=1[C:11]1[S:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8]2.[C:23]([O:26][C:27](=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:26][CH2:27][SH:13]1[C:11]2[C:12]3[N:7]([CH2:8][CH2:9][C:10]=2[CH:15]=[CH:14]1)[C:6](=[O:16])[C:5]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH:4][CH:3]=3)(=[O:25])[CH3:24]
Reactant: O=c1c(-c2ccccc2)cc(CO)c2n1CCc1ccsc1-2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[SH]1C=CC2=C1c1ccc(-c3ccccc3)c(=O)n1CC2

Procedure:
A suspension of 1.55 g of 4,5-dihydro-10-(hydroxymethyl)-8-phenyl-7H-thieno[2.3-a]quinolizin-7-one in 6.7 ml of pyridine was treated with 3.35 ml of acetic anhydride while stirring, whereby a clear solution was obtained after about 15 minutes. After stirring overnight, the precipitated yellow crystals were removed by filtration under suction and washed with ether. The filtrate was evaporated in vacuo and the residue together with the above yellow crystals were recrystallized from methanol. There was obtained pure (4,5-dihydro-7-oxo-8-phenyl-thieno[2,3-a]-quinolizin-1-yl)methyl acetate of m.p. 145°-146°.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[C:20]1([CH:26]2[CH:33]3[CH2:34][CH:29]4[CH2:30][CH:31]([CH2:35][CH:27]2[CH:28]4[CH2:36][C:37](O)=[O:38])[CH2:32]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:20]1([CH:26]2[CH:33]3[CH2:34][CH:29]4[CH2:30][CH:31]([CH2:35][CH:27]2[CH:28]4[CH2:36][C:37]([N:12]2[CH2:13][CH:14]4[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]4)[CH2:11]2)=[O:38])[CH2:32]3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: O=C(O)CC1C2CC3CC(C2)C(c2ccccc2)C1C3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1C3CC4CC(C3)C(c3ccccc3)C1C4)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Triethylamine 1.00 ml was added in a methylene chloride 30 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 815 mg, and stirred at 0° C. for 30 min. 4-phenyl-2-adamantyl acetic acid 774 mg and WSC 1.65 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 16.5 hours. The reaction mixture was washed with 1N hydrochloric acid and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-(4-phenyl-2-adamantylacetyl)1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 30 ml solution of lithium aluminum hydride 229 mg and refluxed under heating for I hour. The reaction mixture was cooled, then added water and 2.5N sodium hydroxide thereto, and removed the insoluble material by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of flash column chromatography (Merck, silica gel 60: 230-400 mesh, chloroform) to obtain the product. Yield: 878 mg (Yield 78%)
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[C:6]=2[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=1.[CH3:28][O:29][CH2:30][CH2:31][NH:32][CH3:33]>CCN(C(C)C)C(C)C.O>[OH:18][C:14]1[CH:13]=[C:12]([C:11]2[C:6]3[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=[C:2]([N:32]([CH2:31][CH2:30][O:29][CH3:28])[CH3:33])[C:7]=3[N:8]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CNCCOC
Reactant: O=C(O)c1cc(Cl)c2nc(N3CCOCC3)nc(-c3cccc(O)c3)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCCN(C)c1cc(C(=O)O)nc2c(-c3cccc(O)c3)nc(N3CCOCC3)nc12

Procedure:
A mixture of Example 9 (0.1 g, 0.25 mmol) and N-(2-methoxyethyl)methyl amine (34 mg, 0.38 mmol) in DIEA (1 mL) and water (0.5 mL) was stirred at 170° C. for 2 hours. The two phases were separated and the aqueous layer concentrated in vacuo. Purification by column chromatography (increasing amount of MeOH in DCM) followed by washing with Et2O afforded the title compound as a yellow solid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(N(CC)CC)C.[C:16](Cl)(=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(Cl)Cl>[CH2:17]([C:16]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC(=O)Cl
Reactant: Nc1ccccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCc1nc2ccccc2[nH]1
Yield: 46.6 %

Procedure:
To a solution of 0-phenylenediamine (2.2 g) and triethylamine (2.0 g) in methylene chloride (20 ml) was added dropwise caproyl chloride (2.3 g) with stirring under ice-cooling. The mixture was stirred for 3 hours at room temperature, washed with a saturated aqueous sodium bicarbonate and water, then dried. The solvent was evaporated. To the residue was added 3N-HCl, and the mixture was heated for 1.5 hour under reflux. The reaction mixture was made basic with 6N NaOH. Then precipitating crystals were recrystallized from ethyl acetate-hexane to give colorless needles (1.5 g, 47%), m.p. 161°-162° C.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([NH2:15])[NH:13][N:14]=2)=[CH:6][CH:5]=1.[CH3:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:24][CH2:25][C:26](O)=[O:27]>>[F:16][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]([NH:15][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][N:19]3[CH2:20][CH2:21][CH2:22][C@@H:18]3[CH3:17])[NH:13][N:14]=2)=[CH:8][CH:9]=1
Reactant: C[C@H]1CCCN1CCCC(=O)O
Reactant: Nc1cc(-c2ccc(OC(F)F)cc2)n[nH]1
Product: C[C@H]1CCCN1CCCC(=O)Nc1cc(-c2ccc(OC(F)F)cc2)n[nH]1

Procedure:
Prepared following the general synthetic method for the one-pot synthesis of ω-amino-alkanoic acid (1H-pyrazol-3-yl-5-aryl)-amides, starting from 5-(4-Difluoromethoxy-phenyl)-2H-pyrazol-3-ylamine (112.5 mg, 0.5 mmol, 1.0 eq) and 4-((S)-2-Methyl-pyrrolidin-1-yl)-butyric acid (155.0 mg, 0.8 mmol, 1.5 eq).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[Na+].[I-:13].O>CN(C=O)C>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([I:13])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Reactant: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)cnc1I
Temperature: 97.5 °C

Procedure:
To a stirred mixture of 2-bromo-5-chloro-3-nitro-pyridine (2.5 g, 10.5 mmol) in anhydrous DMF (20 mL) was added NaI (12.0 g, 80 mmol) was added in one portion and the resulting mixture was heated at 95-100° C. for 2 days. The reaction mixture was cooled to room temperature and poured into water. It was then extracted with EtOAc and the combined extracts were washed with aqueous 10% Na2S2O3. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide 5-Chloro-2-iodo-3-nitro-pyridine. Mass spectrum m/z: 285.2 (M+H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH2:12][P:13]([O:17]Cl)([O:15]Cl)=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].[CH:21]([NH2:24])([CH3:23])[CH3:22]>CCOCC>[F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH2:12][P:13]([O:17][NH:24][CH:21]([CH3:23])[CH3:22])([O:15][NH:24][CH:21]([CH3:23])[CH3:22])=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4]
Reactant: CC(C)N
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)CN(CP(=O)(ONC(C)C)ONC(C)C)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (6.6 g, 0.02 mole) in 200 ml. of ether was added dropwise with good stirring isopropylamine (4.9 g, 0.08 mole) in 70 ml. of ether. The reaction temperature was controlled by cold water bath. The reaction was stirred at room temperature overnight, then was filtered and the filtrate concentrated in vacuo. The residue was taken up in ether, washed with water, dried, concentrated in vacuo, extracted into hot petroleum ether and concentrated to give ethyl N-trifluoroacetyl-N-(bis(isopropylamino)phosphonomethyl)-glycinate as a light yellow oil-gum, ND =1.4495.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].Cl.[NH2:12][CH2:13][C:14]([NH2:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][CH2:13][C:14]([NH2:16])=[O:15])=[C:6]([C:7]#[N:8])[CH:9]=1
Reactant: N#Cc1cc(Br)ccc1F
Reactant: NCC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(Br)ccc1NCC(N)=O
Temperature: 100 °C
Yield: 77.3 %

Procedure:
16.3 g (81.5 mmol) 5-bromo-2-fluorobenzonitrile, 9.2 g (83.1 mmol) glycinamide hydrochloride and 23.6 g (170.8 mmol) K2CO3 were suspended in 40 ml DMSO and heated at 100° C. for 3 h. Having cooled down to room temperature, the solvent was concentrated and water was added. The resulting precipitate was sucked off and washed with water. 16.0 g (77%) 2-(4-bromo-2-cyano-phenylamino)acetamide was obtained. ESI-MS [m/z]: 254, 256 [M+H]+
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1.C(N(C(C)C)CC)(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[CH3:32][S:33]([O:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: OCCn1c(Cn2nnc3ccccc32)nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCn1c(Cn2nnc3ccccc32)nc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
1-[1-(2-Hydroxylethyl)-1-H-benzimidazol-2-ylmethyl)-1H-benzotriazole (300 mg, 1.02 mmol) was suspended in anhydrous methylene chloride and cooled to 0° C. with an ice bath. Diisopropylethylamine (0.36 ml, 2.05 mmol) and methanesulfonyl chloride (0.16 mL, 2.05 mmol) were slowly added. The reaction was stirred at 0° C. for 1 hour during which the solution became clear. The solvent was stripped under vacuum, and the residue was purified by flash chromatography (EtOAc) to give 221 mg (58%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17](Br)=[CH:18][C:19]=1[N:20]([CH:30]([CH3:32])[CH3:31])[C:21]([CH:23]1[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22])=[O:14].C1(C)C=CC=CC=1.CO.C([O-])([O-])=O.[Na+].[Na+]>C1(C)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>[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:18][C:19]=1[N:20]([CH:30]([CH3:32])[CH3:31])[C:21]([CH:23]1[CH2:24][CH2:25][CH:26]([CH3:29])[CH2:27][CH2:28]1)=[O:22])=[O:14]
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)C1CCC(C)CC1)C(C)C
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: CO
Product: COC(=O)c1sc(-c2cccc(F)c2)cc1N(C(=O)C1CCC(C)CC1)C(C)C
Temperature: 70 °C
Yield: 99.8 %

Procedure:
To the mixture of 3-fluorobenzeneboronic acid (25.0 mg, 0.180 mmol) and 5-Bromo-3-[isopropyl-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (24 mg, 0.060 mmol) in 5:1 mixture of toluene/MeOH (1.0 mL) was added a solution of Pd(PPh3)4 (7.0 mg, 0.006 mmol, 10 mol %) in toluene (0.5 mL) followed by aqueous 2M Na2CO3 solution (0.06 mL, 0.120 mmol). The resultant reaction mixture was heated at 70° C. for 18 h, cooled to room temperature, filtered off through MgSO4 and washed with EtOAc. Evaporation of the solvent and purification of the residue over preparative TLC using ethyl acetate/hexane (20:80) as an eluent furnished (25.0 mg, 99% yield) of 5-(3-Fluoro-phenyl)-3-[isopropyl-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:3]=1N.N([O-])=[O:12].[Na+].O>OS(O)(=O)=O>[CH3:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:12]
Reactant: COc1cccc(N)c1C
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cccc(O)c1C
Temperature: 40 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
To a solution of 2-methyl-3-(methyloxy)aniline (Intermediate 58, 1.31 g) in H2SO4 (6 M, 100 mL) was added portionwise NaNO2 (794 mg, 11 mmol) at 0° C. The mixture was stirred for another 2 hours at 40° C. and water (100 mL) was added. The resulting mixture was extracted with ethyl acetate (3 times 100 mL) and the combined ethyl acetate phases were dried and evaporated. The residue was purified by silica gel column chromatography (PE:EtOAc=5:1) to afford the title compound as a solid (569 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]([CH3:15])[CH2:10][C:9]2=O)=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:26]2)=CC=1.CN(C)P(N(C)C)(N(C)C)=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]([CH3:15])[CH2:10][C:9]2=[S:26])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1CC(=O)N(c2ccc(F)cc2)C(=O)C1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CC1CC(=O)N(c2ccc(F)cc2)C(=S)C1
Temperature: 100 °C
Reaction time: 30 h
Yield: 57.5 %

Procedure:
A mixture of 1.02 g (4.68 mmol) of N-(4'-fluorophenyl)-3-methylglutarimide (Compound 66), 0.88 g (2.2 mmol) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (known as Lawesson's Reagent), and 6 ml of hexamethylphosphoramide in a 50 ml round-bottomed flask was warmed to 95°-100° C. for 21 hours. An additional 1.05 g (2.5 mmol) of Lawesson's Reagent were added and heating to 100° C. was continued for an additional 30 hours. The mixture was allowed to cool to room temperature and water (50 ml) was added. The mixture was extracted with ether (4×50 ml). The organic portions were combined, dried over MgSO4 and the solvent was removed in vacuo. The resulting 2 g of orange oil were purified via flash chromatography (silica gel, 1:1 hexanes/methylene chloride) to yield 300 mg (28% yield) of yellow oil which solidified to a solid: m.p. 84.5°-87.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9](O)[CH2:10][CH3:11])=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O>ClCCl>[Cl:15][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:8][CH:7]=1)[CH2:10][CH3:11]
Reactant: CCC(O)c1ccc(OC)nc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCC(Cl)c1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a stirred solution of 1-(6-methoxypyridin-3-yl)propan-1-ol (1.67 g, 9.99 mmol) in dichloromethane (30 mL) at 0° C. was added thionyl chloride (2.46 g, 1.5 mL, 20.68 mmol). The cooling bath was removed, and the mixture was allowed to warm to room temperature. After 1 h, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution. The phases were separated, and the organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated to provide 1.50 g (81%) of 5-(1-chloropropyl)-2-methoxypyridine as a yellow oil.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH2:17])=[CH:12][C:11]=1[OH:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([C:24]1[CH:36]=[C:35]([C:37]([CH2:40][CH3:41])([CH3:39])[CH3:38])[CH:34]=[CH:33][C:25]=1[O:26][CH:27]([CH2:31][CH3:32])[C:28](Cl)=[O:29])([CH2:22][CH3:23])([CH3:21])[CH3:20].N1C=CC=CC=1>C(OCC)(=O)C>[C:1]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:28](=[O:29])[CH:27]([O:26][C:25]2[CH:33]=[CH:34][C:35]([C:37]([CH2:40][CH3:41])([CH3:39])[CH3:38])=[CH:36][C:24]=2[C:19]([CH2:22][CH3:23])([CH3:21])[CH3:20])[CH2:31][CH3:32])=[CH:12][C:11]=1[OH:18])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(O)c(NC(=O)c2ccccc2)cc1Cl
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cc(O)c(NC(=O)c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 100 of ethyl acetate was dissolved 15 g (57×10-3 mole) of 2-benzamido-4-chloro-5-aminophenol, and then 21 g of 2-(2,4-di-t-amylphenoxy)butanoic acid chloride and 5 g of pyridine were added thereto and the mixture was stirred at room temperature for 3 hours. After the reaction, a solvent was distilled off, and the residue was separated and purified through column chromatography and recrystallized from n-hexane to obtain the title compound. Yield: 14.1 g, FD-Mass: 564, melting point: 190° to 191° C.