Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[N:6][CH:7]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[N:6][CH:7]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Nc1ccc(CCC(=O)O)nc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: O=C(O)CCc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cn1
Yield: 63.4 %

Procedure:
A solution of 3-(5-aminopyrid-2-yl)propionic acid (1.00 g) and 4-chlorobenzenesulphonyl chloride (1.27 g) in pyridine (15 ml) was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in dilute sodium hydroxide (30 ml) and extracted with chloroform (4×50 ml). The aqueous layer was acidified with dilute hydrochloric acid (pH 3) and extracted with ethyl acetate (4×100 ml). The ethyl acetate extracts were combined, dried over magnesium sulphate, the solvent was removed and the residue was recrystallised from acetonitrile to give the title compound (1.30 g). m.p. 144°-146° C.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@H:11]2[CH2:13][C@H:12]2[CH2:14]O)=[N:3]1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@H:11]2[CH2:13][C@H:12]2[CH2:14][N:51]2[C:47](=[O:57])[C:48]3[C:49](=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:50]2=[O:52])=[N:3]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cn1cc2c([C@H]3C[C@H]3CO)cccc2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cn1cc2c([C@H]3C[C@H]3CN3C(=O)c4ccccc4C3=O)cccc2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Under argon gas atmosphere, to a solution of cis-[2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methanol (130 mg, 0.643 mmol) in tetrahydrofuran (6.5 mL) were added a solution (40%, 0.351 mL, 0.771 mmol) of diethyl azodicarboxylate in toluene, triphenylphosphine (219 mg, 0.835 mmol) and phthalimide (123 mg, 0.836 mmol), and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added a solution (40%, 0.176 mL, 0.386 mmol) of diethyl azodicarboxylate in toluene, triphenylphosphine (110 mg, 0.419 mmol) and phthalimide (61.5 mg, 0.418 mmol) were added, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→50/50) to give the title compound as a crudely purified product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O.S(Cl)([Cl:21])=O>N1C=CC=CC=1.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH2:5][Cl:21])=[CH:7][CH:8]=[CH:9][C:10]=1[S:11][C:12]1[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: COc1c(CO)cccc1Sc1ccccc1C
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1c(CCl)cccc1Sc1ccccc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-methoxy-3-(o-tolylthio)benzyl alcohol (8.5 g), thionyl chloride (4.8 ml) and pyridine (3 drops) in benzene (80 ml) was stirred at room temperature and then at 80° C. for 10 minutes. The reaction mixture was treated in a similar manner to that of Example 21-(6) to give oily o-tolyl 2-methoxy-3-chloromethylphenyl thioether (8.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@H:10]([CH3:18])[NH:9]2)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@H:10]([CH3:18])[N:9]2[C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:28])=[CH:4][CH:3]=1
Reactant: C[C@H]1Cc2ccccc2[C@@H](c2ccc(Cl)cc2)N1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: C[C@H]1Cc2ccccc2[C@@H](c2ccc(Cl)cc2)N1C(=O)Nc1ccc(F)cc1
Reaction time: 4 h

Procedure:
To a solution of (1R,3S)-1-(4-chlorophenyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline (60 mg, 233 μmol) in CH2Cl2 (1.0 mL) at RT was added 1-fluoro-4-isocyanatobenzene (42 μL, 361 μmol). The reaction was stirred 4 h and directly purified by reverse phase HPLC to give (1R,3S)-1-(4-chlorophenyl)-N-(4-fluorophenyl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide as a light purple solid. MS (ESI pos. ion) m/z: 395 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1S(=O)(=O)N.NC1CCN(CC2C=CC(OCC=C)=CC=2)CC1.C(O)CCCC>>[O:7]=[C:6]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:12][CH:11]=2)[C:9](=[O:10])[NH:8]1
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)NC2=O
Agent: C=CCOc1ccc(CN2CCC(N)CC2)cc1
Solvent: CCCCCO
Product: O=C1NC(=O)c2ccccc21

Procedure:
Reaction of 4-chloro-5-sulfamoylphthalimide (4.54 g., 0.0174 mole) and 4-amino-1-[4-(2-propenyloxy)benzyl]piperidine (4.29 g., 0.0174 mole) in 100 ml. of n-pentanol at reflux temperature for 24 hrs. according to the procedure of Example 1(a) afforded crude 1,3-dioxoisoindole product. Purification was carried out by treating with methanol-decolorizing charcoal followed by trituration with ether to afford 4.8 g. (57%) of the 1,3-dioxoisoindole used without further purification below.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[C@H:5]1[S:22][CH2:21][C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9].[SH:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1>C(#N)C.[Cl-].[Zn+2].[Cl-]>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[CH2:21][S:22][C@H:5]1[S:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1)(=[O:10])[CH3:9]
Reactant: N#Cc1ccc(S)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](OC(=N)C(Cl)(Cl)Cl)SC[C@H]1OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc(C#N)cc2)SC[C@H]1OC(C)=O
Yield: 23 %

Procedure:
A suspension of 192 mg (0.44.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl trichloroacetimidate, 71 mg (0.52.10-3 mol) of 4-mercaptobenzonitrile, 20 mg (0.15.10-3 mol) of zinc chloride and a 400 pm sieve in 2 ml of acetonitrile is stirred for 4 h under an inert atmosphere. The reaction mixture is then filtered on Celite® in ethyl acetate and subsequently washed with a 1N solution of sodium hydroxide, water and finally a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure. After precipitation in ether, 42 mg (yield: 23%) of the expected product are obtained.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:23](=[O:26])[CH2:24][CH3:25]>C1COCC1.CS(C)=O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:23]1([CH2:24][CH3:25])[CH2:4][O:26]1
Reactant: CCC(=O)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCC1(c2ccc(Oc3ccc(Cl)cc3)cc2Cl)CO1
Temperature: 5 °C
Reaction time: 1 h
Yield: 107.5 %

Procedure:
To a solution of sodium hydride (35.72 g, 1.49 mol) in THF (1 L) and dry DMSO (2 L) was added under argon drop wise at 5° C. a solution of trimethylsulfonium iodide (290.5 g, 1.42 mol) in dry DMSO (2 L). The mixture was stirred 1 hour at 5° C. followed by a dropwise addition of 1-[2-chloro-4-(4-chlorophenoxy)phenyl]propan-1-one (199.0 g, 0.65 mol) in DMSO (500 mL). The resulting mixture was then warmed to room temperature overnight and quenched with an aqueous solution of ammonium chloride and iced water, and then extracted with MTBE. The organic solvents were washed with water, dried and evaporated to give 2-[2-chloro-4-(4-chlorophenoxy)phenyl]-2-ethyl-oxirane as a yellowish solid (216.0 g, 97%). 1H-NMR (CDCl3; 400 MHz) • • (ppm)=0.9 (t, 3H); 1.75 (m, 1H); 2.10 (m, 1H); 2.80 (d, 1H); 3.05 (d, 1H); 6.85 (d, 1H); 6.95 (m, 3H); 7.30 (d, 2H); 7.40 (d, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[CH:11]=[C:10]3[O:13][CH2:14][O:15][C:9]3=[CH:8][C:7]=2[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].OS(O)(=O)=O.[N+:25]([O-])([O-:27])=[O:26].[K+]>O>[CH2:1]([N:3]1[C:12]2[CH:11]=[C:10]3[O:13][CH2:14][O:15][C:9]3=[C:8]([N+:25]([O-:27])=[O:26])[C:7]=2[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3c(cc21)OCO3
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2c([N+](=O)[O-])c3c(cc21)OCO3
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
5-Ethyl-8-oxo-5,8-dihydro-[1,3]dioxolo[4,5-g]quinoline-7-carboxylic acid (50 g, 191 mmol) was dissolved in H2SO4 (112 ml, 2105 mmol) with stirring. The thick solution was cooled to 0° C. and potassium nitrate (21.29 g, 211 mmol) was added in small portions. The temperature of the reaction mixture was maintained below 10° C. by use of an iced water bath. After the addition, the mixture was kept under 10° C. for 1 h, and then was allowed to warm up to r.t. and stirred for overnight. It was poured into iced water (2 L). The yellow precipitates were collected by filtration, washed with water and ethanol, and dried in vacuo to afford 5-ethyl-9-nitro-8-oxo-5,8-dihydro-[1,3]dioxolo[4,5-g]quinoline-7-carboxylic acid (61 g, 187 mmol, 98% yield) as a light brown solid. LCMS: (M+H)+: 307.4.
Reaction SMILES: C([NH:4][C:5]1[C:6]([Br:17])=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH:9]([CH2:15][CH3:16])[CH2:8]2)(=O)C.C[O-].[Na+].[CH:21]([C:23]([CH2:25][CH3:26])=[O:24])=[CH2:22]>CO>[NH2:4][C:5]1[C:6]([Br:17])=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[C:9]([CH2:15][CH3:16])([CH2:22][CH2:21][C:23](=[O:24])[CH2:25][CH3:26])[CH2:8]2
Reactant: C=CC(=O)CC
Reactant: CCC1Cc2c(ccc(NC(C)=O)c2Br)C1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(=O)CCC1(CC)Cc2c(ccc(N)c2Br)C1=O
Temperature: 60 °C
Yield: 102 %

Procedure:
A solution of 5-(acetylamino)-4-bromo-2-ethyl-1-indanone (1.0 g, 3.39 mmol) in MeOH (5.1 mL) was treated with 0.5M NaOMe in MeOH (3.4 mL, 1.7 mmol) and ethyl vinyl ketone (0.506 mL, 5.08 mmol). The mixture was stirred and heated at 60° C. for 4.5 hours, then evaporated under vacuum. The residue was partitioned between EtOAc (75 mL), brine (50 mL), and water (10 mL). The organic portion was dried over MgSO4, filtered, and evaporated under vacuum. The residue was added to a short column of silica gel (30 mL) which was washed with CH2Cl2 (150 mL) and eluted with EtOAc (150 mL). The EtOAc eluant was evaporated under vacuum to provide crude 5-amino-4-bromo-2-ethyl-2-(3-oxopentyl)-1-indanone (1.17 g) as an oil.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[S:31](Cl)(=[O:33])=[O:32].CCN(CC)CC>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[S:31]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)(=[O:32])=[O:33]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(Cl)c1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24 %

Procedure:
A mixture of 37.7 mg (0.12 mmol) 2-(4-Trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, 29.7 mg (example 251, step A), 0.132 mmol), 2-chloro-6-methylbenzene-1-sulfonyl chloride and 36.4 mg (0.36 mmol) NEt3 in 2 mL DCM was stirred for 16 h at room temperature. The mixture was evaporated to dryness and the residue was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 14.7 mg (24%) of the title compound. MS (ESI): 503.4 (MH+).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.O.[C:6]([NH:10][S:11]([C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(OCC)(=O)C>[CH:1]1([NH:4][S:20]([C:16]2[CH:15]=[C:14]([S:11]([NH:10][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=2)(=[O:22])=[O:21])[CH2:3][CH2:2]1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: NC1CC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)NS(=O)(=O)c1cccc(S(=O)(=O)NC2CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5 ml of cyclopropylamine and 10 ml of water was added to a solution of 1 gram (3.9 mmole) of 3-tert-butylsulfamoyl-benzenesulfonyl chloride in ethyl acetate. The mixture was stirred at room temperature for 2 hours. The ethyl acetate layer was separated, dried over magnesium sulfate and concentrated in vacuo to an oil which crystallized from isopropyl ether to give 839 mg of the titled compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[C:8](=[O:14])[C:9]([CH3:13])([CH3:12])[CH2:10][F:11])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:8]([OH:14])[C:9]([CH3:12])([CH3:13])[CH2:10][F:11])=[CH:20][CH:21]=1
Reactant: CC(C)(CF)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(CF)C(O)C(Oc1ccc(Cl)cc1)n1cncn1
Reaction time: 1 h
Yield: 72.4 %

Procedure:
55 g (0.176 mol) of 1-(4-chlorophenoxy)-4-fluoro-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one (Example 1) were dissolved in 250 ml of methanol, and 3 g (0.08 mol) of sodium borohydride were added in portions. The reaction solution was subsequently stirred for 1 hour and then adjusted to a pH value of 3 with concentrated hydrochloric acid. After distilling off the solvent in vacuo, water was added to the residue and the mixture was extracted by shaking with methylene chloride. The combined organic phases were dried over sodium sulphate and concentrated in vacuo. The residue was crystallized with petroleum ether. 40 g (72% of theory) of 1-(4-chlorophenoxy)-4-fluoro-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol of melting point 103°-112° C. were obtained.
Reaction SMILES: N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O.[CH3:17][C:18](=[CH2:22])[CH:19](O)[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:42][C:43]1[CH:44]=[N:45][NH:46][CH:47]=1>C1COCC1.FC(F)(F)C(O)=O.ClCCl>[Br:42][C:43]1[CH:44]=[N:45][N:46]([CH:19]([C:18]([CH3:17])=[CH2:22])[CH3:20])[CH:47]=1
Reactant: C=C(C)C(C)O
Reactant: Brc1cn[nH]c1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C(C)C(C)n1cc(Br)cn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(E)-Di-tert-butyl diazene-1,2-dicarboxylate (940 mg, 4.08 mmol) was added slowly to a stirred solution of 3-methylbut-3-en-2-ol (293 mg, 3.40 mmol), triphenylphosphine (1.07 g, 4.08 mmol), and 4-bromo-1H-pyrazole (500 mg, 3.40 mmol) in THF (10 mL) at 0° C. The reaction was stirred for 10 min at 0° C. and then allowed to warm to RT for 1 hour. The reaction was quenched into water and the product was extracted with ethyl acetate (2×20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford an oil. The oil was dissolved in 20% trifluoroacetic acid in dichloromethane (5 mL) and stirred for 20 minutes. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate, washed with 10% aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude residue. The crude residue was purified by column chromatography on silica (20-100% ethyl acetate/hexanes) to afford 4-bromo-1-(3-methylbut-3-en-2-yl)-1H-pyrazole. MS ESI calcd. for C8H12BrN2 [M+H]+ 215 and 217. found 215 and 217.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([N:19]=[N+]=[N-])[C:15]([O:17][CH3:18])=[O:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10])[NH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13]2
Reactant: COC(=O)C(=Cc1cc(OC)c(OC)c(OC)c1)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: COC(=O)c1cc2cc(OC)c(OC)c(OC)c2[nH]1

Procedure:
Xylene (15 mL) was placed in a three-necked flask and stirred under reflux, and a xylene solution (30 mL) of methyl 3-(3,4,5-trimethoxyphenyl)-2-azidopropenoate (1.2 g) was added dropwise over 3 hours. The reaction mixture was refluxed for 1 hour and concentrated under reduced pressure. Water was added to the residue to conduct extraction with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:3) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[N:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[NH:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[C:29]([NH:1][C:2]1[CH:3]=[C:4]([C:8](=[N:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[NH:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: N#CNC(=NCCc1ccccc1Cl)c1cncc(N)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CNC(=NCCc1ccccc1Cl)c1cncc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.3 %

Procedure:
To a solution of 5-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide (100 mg, 0.33 mmol) in DMF (3 ml) were added triethylamine (101 mg, 1 mmol) and benzoyl chloride (94 mg, 0.67 mmol), and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was neutralized by adding ice and a saturated aqueous sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (Wako Gel C-200, 30 g; eluted with chloroform:methanol=200:1) to give the title compound (38 mg, 0.09 mmol, yield 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([OH:14])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:16][CH:17]1[CH2:19][O:18]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([O:14][CH2:16][CH:17]3[CH2:19][O:18]3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Oc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(-n2ccc(OCC3CO3)n2)cc1Cl
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 1-(3,4-dichlorophenyl)-1H-pyrazol-3-ol (0.2 g, 0.87 mmol; compound prepared in the same way as Example 1, Scheme 1-step 1B), 2-(chloromethyl)oxirane (0.1 g, 1.05 mmol), potassium carbonate (0.36 g, 2.62 mmol) and sodium iodide (0.13 g, 0.87 mmol) in dimethylformamide (6 ml) was warmed, with stirring, to 100° C. for 4 hrs. The solvent was evaporated to dryness in vacuo and residue partitioned between water and dichlorometane. The combined organic phases were dried over sodium sulphate, filtered and evaporated in vacuo to yield 0.24 g of 1-(3,4-dichlorophenyl)-3-(oxiran-2-ylmethoxy)-1H-pyrazole as a dark oil, used without further purification in next step of synthesis.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH3:13])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCCCC1.[Br:20]N1C(=O)CCC1=O>C(OC(=O)C)C>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][Br:20])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(=O)OC(C)(C)C)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(CBr)s1
Yield: 98.6 %

Procedure:
To 5-Methyl-thiophene-2-carboxylic acid tert-butyl ester (10.8 g, 54.5 mmol) was added cyclohexan (100 mL) and N-bromosuccinimide (9.7 g, 54.5 mmol) and was heated at reflux overnight. The suspension was to added ethylacetate (200 mL) and the organic solution was washed with water (4×100 mL). The solvent was removed in vacuo to yield 14.9 g of 5-bromomethylthiophene-2-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([F:13])[CH:6]=[C:7]([F:12])[CH:8]=2)[N:3]=1.[N:14]1[N:15]=[CH:16][N:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=12.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[N:14]1[N:15]=[C:16]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([F:13])[CH:6]=[C:7]([F:12])[CH:8]=3)[N:3]=2)[N:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=12
Reactant: c1ccn2cnnc2c1
Reactant: Fc1cc(F)c2nc(Cl)ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Fc1cc(F)c2nc(-c3nnc4ccccn34)ccc2c1
Yield: 59.5 %

Procedure:
2-Chloro-6,8-difluoroquinoline (0.025 g, 0.125 mmol) was combined with [1,2,4]triazolo[4,3-a]pyridine (0.016 g, 0.14 mmol), micronized Cs2CO3 (0.082 g, 0.25 mmol), and PdCl2(PPh3)2 (0.0088 g, 0.013 mmol), and the solids were slurried in dioxane (1.25 mL). The reaction was degassed with argon (bubbled through the solution) then heated to reflux for 20 hours. The crude reaction mixture was chromatographed without workup on SiO2 eluting with a gradient of 6% NH4OH in MeOH/ethyl acetate to provide the desired product as an orange solid (21 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1F
Reactant: Oc1cccc(Cl)c1
Product: COC(=O)c1cc(Cl)ccc1Oc1cccc(Cl)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 5-chloro-2-fluorobenzoate and 3-chlorophenol: 1H-NMR (CDCl3) δ 7.92 (1H, d, J=2.8 Hz), 7.46 (1H, dd, J=8.8, 2.8 Hz), 7.25–6.80 (5H, m), 3.81 (3H, s).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([F:28])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[N:12]=1.[CH3:29][C:30]([OH:34])([CH:32]=[CH2:33])[CH3:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:28][C:4]1[CH:5]=[C:6]2[C:10](=[C:2](/[CH:33]=[CH:32]/[C:30]([CH3:31])([OH:34])[CH3:29])[CH:3]=1)[NH:9][CH:8]=[C:7]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]2[CH2:19][C:20]([CH3:27])([CH3:26])[NH:21][C:22]([CH3:25])([CH3:24])[CH2:23]2)[N:12]=1
Reactant: CC1(C)CC(Nc2nccc(-c3c[nH]c4c(Cl)cc(F)cc34)n2)CC(C)(C)N1
Reactant: C=CC(C)(C)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(C)(O)/C=C/c1cc(F)cc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)c[nH]c12

Procedure:
The title compound was prepared by the general Heck procedure described in Example 256, using the SEM-protected intermediate of Example 254 and 2-methyl-but-3-en-2-ol, followed by TBAF deprotection of the SEM group.