Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2([OH:22])[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[N:29]=[CH:28][C:27]2[CH:30]=[N:31][NH:32][C:26]=2[CH:25]=1.C([O-])([O-])=O.[K+].[K+].CNCCNC>O1CCOCC1.[Cu]I>[Cl:23][C:24]1[N:29]=[CH:28][C:27]2[CH:30]=[N:31][N:32]([C:2]3[N:7]=[C:6]([C:8]4([OH:22])[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]4)[CH:5]=[CH:4][CH:3]=3)[C:26]=2[CH:25]=1
Reactant: Clc1cc2[nH]ncc2cn1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(c2cccc(Br)n2)CC1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2cccc(-n3ncc4cnc(Cl)cc43)n2)CC1
Temperature: 100 °C
Yield: 63.9 %

Procedure:
To a mixture of tert-butyl 4-(6-bromopyridin-2-yl)-4-hydroxyazepane-1-carboxylate (792 mg, 2.4 mmol) and 6-chloro-1H-pyrazolo[4,3-c]pyridine (300 mg, 1.94 mmol) in 1,4-dioxane (20 mL) was added CuI (150 mg, 0.78 mmol), K2CO3 (1.08 g, 7.8 mmol), and N1,N2-dimethylethane-1,2-diamine (138 mg, 1.56 mmol). The mixture was heated at 100° C. for 3 hours, which was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude was purified by silica gel chromatography using petroleum ether/EtOAc (4/1) to afford tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-4-hydroxyazepane-1-carboxylate as a white solid (550 mg, 58%). MS (ESI) m/z: 444 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH3:16])[CH2:15][CH2:14][C:9]2(OCC[O:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C1COCC1.Cl.CCOC(C)=O>[CH3:16][C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8][C:9](=[O:10])[CH2:14][CH2:15]1
Reactant: CCOC(=O)C1(C)CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-Methyl-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (Compound 282G) was dissolved in THF (20 mL) and 3N aq. HCl (30 mL). The resulting mixture was stirred at rt overnight. The mixture was diluted with EtOAc (50 mL), washed with brine (20 mL), and dried over anhydrous sodium sulfate. 1H NMR (CDCl3): 1.28 (t, J=7.1 Hz, 3H), 1.29 (s, 3H), 1.63-1.70 (m, 2H), 2.30-2.74 (m, 6H), 3.94 (s, 4H), 4.19 (q, J=7.1 Hz, 2H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([Cl:17])=[C:14]([Cl:16])[Cl:15])[CH:8]=1>C(Cl)Cl>[Cl:17][C:13]([C:9]1[CH:8]=[C:7]([OH:6])[CH:12]=[CH:11][CH:10]=1)=[C:14]([Cl:15])[Cl:16]
Reactant: COc1cccc(C(Cl)=C(Cl)Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(C(Cl)=C(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 3.0 g (12.0 mmol) of boron tribromide in 10 mL of CH2Cl2 was magnetically stirred at 0° C. with an external ice-water bath, while a solution of 2.38 g (10.0 mmol) of the product of Step C in 20 mL CH2Cl2 was slowly added over a period of 1 h. At this point the reaction mixture was allowed to slowly warm to room temperature and stirring was continued for an additional 5 h. The reaction was again cooled to 0° C. and quenched by addition of 40 mL water. The organic layer was separated and then washed with 2 N NaOH. The aqueous extracts were acidified with 1 N HCl and extracted with ether. The organic extracts were combined, washed with brine, dried (MgSO4), filtered and evaporated in vacuo to afford the title compound which was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:45]/[O:46][CH3:47])/[C:8]([NH:10][CH:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([O:29]C(C4C=CC=CC=4)C4C=CC=CC=4)=[S:28])=[C:15]([C:18]4[S:19][C:20]5[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=5[N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[Na]>>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:45]/[O:46][CH3:47])/[C:8]([NH:10][CH:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([OH:29])=[S:28])=[C:15]([C:18]4[S:19][C:20]5[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=5[N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3nc4ccccc4s3)CS[C@H]12)c1nsc(N)n1
Agent: [Na]
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(O)=S)=C(c3nc4ccccc4s3)CS[C@H]12)c1nsc(N)n1
Yield: 55.5 %

Procedure:
Using 324 mg of diphenylmethyl 7-{(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido}-3-(benzothiazol-2-yl)thio-3-cephem-4-carboxylate, the reaction and purification process of Inventive Example 1 (d) was repeated to obtain 137 mg of the title compound as a sodium salt (yield, 64%).
Reaction SMILES: [C:1]([O:9][C:10]12[O:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CCOCC.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:1]([O:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC12CCCCC1O2)c1ccccc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O[C@@H]1CCCCC1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 78 %

Procedure:
To a solution of (R)-(+)-binaphthol (7.9 mg, 0.0275 mmol) in CH2Cl2 (0.5 mL) was added a solution of Ti(OiPr)4 (3.8 uL, 3.6 mg, 0.0125 mmol) in CH2Cl2 (0.5 mL). Upon stirring at room temperature for 5-10 h, the reaction mixture was concentrated and dried using a vacuum pump (ca. 0.5 h). The catalyst was then dissolved in Et2O (1 mL) and cooled in an ice bath. To this solution was added a solution of racemic 1-benzoyloxy-1,2-epoxycyclohexane (0.109 g, 0.5 mmol) in Et2O (1 mL). After stirring at 0° C. for 1 h, the reaction mixture was quenched with saturated NaHCO3 solution (4 mL) and poured into a mixture of ether (20 mL) and saturated NaHCO3 solution (10 mL). The organic layer was washed with water and brine, dried (Na2SO4), and rapidly filtered through a plug of silica gel (ca. 10 g) (pre-treated with 5% Et3N in hexane and washed thoroughly with hexane to remove Et3N before use). The silica gel was further washed with Et2O (10 mL). The combined ether solutions were concentrated to give a residue. Upon drying under vacuum for 1 h, the mixture was dissolved in CH2Cl2 (4 mL) followed by addition of anhydrous p-TsOH (8.6 mg, 0.05 mmol). After stirring at room temperature for 20 min, the mixture was rapidly filtered through a plug of silica gel (ca. 10 g) (without Et3N treatment) followed by washing with ether (2×10 mL). The combined solutions were concentrated to give (R)-2-benzoyloxycyclohexanone as a white solid (0.0845 g, 78% yield, 93% ee).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[NH:10][C:11]([CH3:20])=[C:12]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[N:13]=1.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:23]=1[N+:31]([O-:33])=[O:32]>C1(C)C=CC=CC=1>[N+:28]([C:25]1[CH:24]=[C:23]([N+:31]([O-:33])=[O:32])[CH:22]=[CH:27][C:26]=1[N:10]1[C:11]([CH3:20])=[C:12]([C:14]([O:16][CH:17]([CH3:18])[CH3:19])=[O:15])[N:13]=[C:9]1[Br:8])([O-:30])=[O:29]
Reactant: Cc1[nH]c(Br)nc1C(=O)OC(C)C
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)OC(C)C)nc(Br)n1-c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
4.2 ml of triethylamine was added dropwise to 5 g (0.02 mol) of isopropyl 2-bromo-5-methyl-4-imidazolecarboxylate, 3.9 g of 1-fluoro-2,4-dinitrobenzene and 200 ml of toluene, and the mixture was refluxed for 16 hours. The toluene solution was then washed with water, dried and concentrated. The residue was stirred with diethyl ether and the solid obtained in this manner was isolated.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]2[C:13]([C:14](Br)=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2.[CH:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)=[CH2:29]>>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]2[C:13]([C:14]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([CH:28]=[CH2:29])[CH:35]=3)=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: Brc1c2ccccc2c(-c2ccccc2-c2ccccc2)c2ccccc12
Reactant: C=Cc1cccc(B(O)O)c1
Product: C=Cc1cccc(-c2c3ccccc3c(-c3ccccc3-c3ccccc3)c3ccccc23)c1
Yield: 63 %

Procedure:
A run was carried out as in Example 1 aside from using 9-biphenyl-2-yl-10-bromoanthracene and 3-vinylphenylboronic acid. There was obtained 9-biphenyl-2-yl-10-(3-vinylphenyl)anthracene in a yield of 63%. From this monomer, a polymer was prepared in a yield of 78% and had a weight average molecular weight of 21,000. An organic EL device was fabricated as in Example 1. This device produced blue light emission from tetraphenylbutadiene and showed a current efficiency of 4.0 cd/A upon constant current driving at 10 mA/cm2. The luminance half-life at 10 mA/cm2 was 580 hours.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH:4]=[N:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[CH3:14].[CH2:19]([N:23]([CH2:30][CH2:31][CH2:32][CH3:33])[S:24][N:25]([C:27](F)=[O:28])[CH3:26])[CH2:20][CH2:21][CH3:22].[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1(C)C=CC=CC=1>[CH2:19]([N:23]([CH2:30][CH2:31][CH2:32][CH3:33])[S:24][N:25]([CH3:26])[C:27](=[O:28])[O:13][C:9]1[CH:8]=[C:7]([CH3:14])[C:6]([N:5]=[CH:4][C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[OH:1])=[C:11]([CH3:12])[CH:10]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN(CCCC)SN(C)C(=O)F
Reactant: Cc1cc(O)cc(C)c1N=Cc1ccccc1O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCN(CCCC)SN(C)C(=O)Oc1cc(C)c(N=Cc2ccccc2O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a manner identical to that described in Example II, Part A, 4-(2-hydroxybenzylideneamino)-3,5-dimethylphenol was prepared. To a 1 liter round bottom flask equipped with a magnetic stirrer was added 9.65 grams (0.040 moles) of 4-(2-hydroxybenzylideneamino)-3,5-dimethylphenol, 10.65 grams (0.045 moles) of N-(di-n-butylaminosulfenyl)-N-fluorocarbonyl-N-methylamine, 400 milliliters of toluene, 100 milliliters of 0.4 molar sodium hydroxide and 10 drops of tricaprylmethylammonium chloride solution. The resulting reaction mixture was stirred continuously for 2 hours at room temperature forming an organic layer. After the stirring period, the organic layer was separated, washed twice with water and twice with a saturated brine solution, dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown oil. Purification of the dark brown oil by column chromatography yielded 2.80 grams (0.0061 moles) of 4-(2-hydroxybenzylideneamino)-3,5-dimethylphenyl N-(dibutylaminosulfenyl)-N-methylcarbamate in the form of an amber oil having the following structural formula: ##STR26##
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([OH:10])(=[S:9])[CH3:8].[CH2:11]([O:14][C:15]([N:17]1[CH2:21][C@H:20](OS(C)(=O)=O)[CH2:19][C@H:18]1[CH2:27][CH2:28][N:29]=[N+:30]=[N-:31])=[O:16])[CH:12]=[CH2:13].O>CN(C)C=O.C(OCC)(=O)C>[C:7]([S:9][C@@H:20]1[CH2:21][N:17]([C:15]([O:14][CH2:11][CH:12]=[CH2:13])=[O:16])[C@H:18]([CH2:27][CH2:28][N:29]=[N+:30]=[N-:31])[CH2:19]1)(=[O:10])[CH3:8]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCN=[N+]=[N-]
Reactant: CC(O)=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CCN=[N+]=[N-]
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a suspension of potassium t-butoxide (6.99 g) in dimethylformamide (150 ml) was added thioacetic acid (4.45 ml) under ice-cooling. After stirring for 15 minutes, a solution of (2R,4R)-1-allyloxycarbonyl-2-(2-azidoethyl)-4-methanesulfonyloxypyrrolidine (15.3 g) in dimethylformamide (20 ml) was added to the mixture under ice-cooling. The mixture was warmed to 80° C. and stirred for 4 hours, then cooled to ambient temperature and poured into water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with sat. sodium bicarbonate, water (twice) and brine, dried over magnesium sulfate, and evaporated under reduced pressure to give (2R,4S)-4-acetylthio-1-allyloxycarbonyl-2-(2-azidoethyl) pyrrolidine (14.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([N+:27]([O-:29])=[O:28])=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][CH:3]=1.[OH:30]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([N+:27]([O-:29])=[O:28])=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:30])=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCSc3ccc(Cl)cc3)cc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCS(=O)c3ccc(Cl)cc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-chlorophenylmercapto)-butoxy]-7-nitro-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=2)=[CH:30][CH:29]=1>CN(C)C=O>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:36][CH:35]=2)=[CH:32][CH:33]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: COc1ccc(C2=CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C2=CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 19.4 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1 -dioxide (6.74 g), triethylamine (3.4 cc) and 4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (4.5 g ) in dimethylformamide (70 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 12 hours at this temperature. After purification by flash-chromatography on silica gel, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (60 cc), 2{3-[4-(4-methoxyphenyl)-1,2,3,6-tetrahydro -1-pyridyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (2 g) is obtained, m.p. 178° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:4]2[N:3]=1.[C:23]1([NH2:30])[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>C(O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[N:4]3[N:3]=[C:2]([NH:29][C:26]4[CH:27]=[CH:28][C:23]([NH2:30])=[CH:24][CH:25]=4)[C:11]4[C:6]([C:5]3=[N:12][N:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[CH:16][CH:17]=1
Reactant: Nc1ccc(N)cc1
Reactant: COc1ccc(-c2nnc3c4ccccc4c(Cl)nn23)cc1
Solvent: CCO
Product: COc1ccc(-c2nnc3c4ccccc4c(Nc4ccc(N)cc4)nn23)cc1
Yield: 84.5 %

Procedure:
1.0 g 6-chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine (compound B1) and 2.7 g p-phenylene-diamine are stirred at 170° C. for 5 h. The reaction mixture is diluted with 6 ml ethanol and the precipitate is filtered with suction. The solid is recrystallized from N,N-dimethylformamide to yield 1.04 g of the title compound (m.p.: 295° C.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[CH:2].I[C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[CH:21][CH:22]=1.C(N(CC)C(C)C)(C)C>C1COCC1.O.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.[Cu]I>[C:26]([O:25][C:24]([NH:23][C:19]1[CH:18]=[C:17]([C:2]#[C:1][C:3]2[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])[CH:22]=[CH:21][CH:20]=1)=[O:30])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)Nc1cccc(I)c1
Reactant: C#Cc1cc(C(=O)OC)cc([N+](=O)[O-])c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc(C#Cc2cccc(NC(=O)OC(C)(C)C)c2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
A solution of methyl 3-ethynyl-5-nitrobenzoate (1.45 g, 7.08 mmol), tert-butyl (3-iodophenyl)carbamate (2.26 g, 7.08 mmol) in THF (28 mL) was treated with bis(triphenylphosphine)palladium(II) chloride (248 mg, 0.354 mmol), copper(I) iodide (108 mg, 0.566 mmol) and N,N-diisopropylethylamine (2.47 mL, 14.2 mmol) and stirred at 25° C. overnight. The reaction was diluted with water and extracted with ethyl acetate three times. The combined organic solutions were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.85 g, 66%). LCMS for C21H20N2O6Na (M+Na)+: m/z=419.3.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[O:14]=[C:4]1[CH:3]([CH2:2][O:1][C:30](=[O:31])[NH:29][C:26]2[CH:27]=[CH:28][C:23]([Br:22])=[CH:24][CH:25]=2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]1=2
Reactant: O=C1c2ccccc2SCCC1CO
Reactant: O=C=Nc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Br)cc1)OCC1CCSc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxymethyl-3,4-dihydro-2H-benzo[b]thiepin-5-one (224 mg, 1.08 mmol) in 14 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.16 ml, 1.18 mmol) and 4-bromophenyl isocyanate (0.423 g, 2.15 mmol). The mixture was stirred at room temperature for 2 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 tert-butyl methyl ether/cyclohexane). The product was obtained in a yield of 250 mg (57%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].ClC1C=CC=C(C(OO)=[O:34])C=1>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:22]([F:25])([F:24])[F:23])=[O:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Reaction time: 48 h
Yield: 57.8 %

Procedure:
A stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (10.0 g) in dichloromethane (100 ml) was treated with m-chloroperbenzoic acid (4.5 g). After stirring overnight additional m-chloroperbenzoic acid (1.6 g) was added in 2 portions, and left for 2 days. The reaction product was diluted with ethyl acetate (30 ml) and then washed in turn with sodium sulphite solution (50 ml), sodium carbonate solution (50 ml) and with water (50 ml). After drying over magnesium sulphate, this was filtered and evaporated in vacuo. Purification by chromatography on silica eluting with dichloromethane gave 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulphinylpyrazole as a white solid (6.0 g), m.p. 200.5°-201° C.
Reaction SMILES: [N:1]1([CH2:7][C:8](=[CH2:12])[C:9]([OH:11])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][C:33]([C:39]#[N:40])=[C:32]2[NH:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[C:44]([Cl:49])[CH:43]=1.C(=O)(O)[O-].[Na+]>C1COCC1.N1C=CC=CC=1>[Cl:49][C:44]1[CH:43]=[C:42]([NH:41][C:32]2[C:31]3[C:36](=[CH:37][CH:38]=[C:29]([NH:28][C:9](=[O:11])[C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH2:12])[CH:30]=3)[N:35]=[CH:34][C:33]=2[C:39]#[N:40])[CH:47]=[CH:46][C:45]=1[F:48]
Reactant: C=C(CN1CCOCC1)C(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(Cl)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=C(CN1CCOCC1)C(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 9.3 %

Procedure:
Partially dissolved 1.37 g (8.00 mmol) 2-morpholin-4-ylmethyl-2-propenoic acid in 50 ml THF and chilled to 0° C. under N2. Added 1.06 ml (9.6 mmol) N-methylmorpholine and 833 μl (6.4 mmol) isobutyl chloroformate. Stirred at 0° C. for 1 hour and added a solution of 1.00 g (3.20 mmol) 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-3-quinolinecarbonitrile in 5 ml pyridine. Stirred overnight at 25° C. Poured onto a mixture of ice and saturated sodium bicarbonate, extracted with ethyl acetate, dried organic layer with brine and sodium sulfate, and stripped solvent to a small volume. Loaded onto a column of silica gel, eluted with 1% methanol/ethyl acetate, stripped solvent from desired fractions and dried under vacuum, giving 139 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=465.8, 468.0.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=1)=[O:6].[C:21]1([C:27]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[OH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>C1(C)C(C)=CC=CC=1>[ClH:1].[OH:28][C:27]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)=[O:6])[CH2:31][CH2:30]1
Reactant: CCOC(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Agent: Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Reaction time: 2 h
Yield: 70.5 %

Procedure:
Dissolve 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid, ethyl ester (15.0 g, 49.53 mmol) and α,α-diphenyl-4-piperidinemethanol (29.66 g, 106.4 mmol) in xylene (60 mL). Reflux for 5.5 hours, cool in an ice bath, filter and wash with cold xylenes (25 mL). Filter the filtrate though silica gel (20 g) and wash the gel with xylenes (40 mL). Add xylene (60 mL) and concentrated hydrochloric acid (6.45 g, 65.6 mmol) with stirring. Add additional xylenes (40 mL) and stir for 2 hour. Filter, wash with xylene (50 mL), vacuum dry and slurry with a mixture of ethanol (60 mL) and hexane (120 mL) at 70-72° C. for 30 minutes. Filter, wash with 3:1 v/v solution of n-heptane/ethanol (30 mL) and dry to give the title compound as a light white solid (19.7 g, 70%); mp 206-208° C.