Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=2)[CH2:30][CH2:29]1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1.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>[CH:23]1([NH:22][C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)=[CH:40][CH:39]=3)[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: OB(O)c1ccc(CN2CCOCC2)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(NC3CCCC3)c2C)c(=O)[nH]1
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: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc(NC3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 5-bromo-3-(cyclopentylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.), (4-(morpholinomethyl)phenyl)boronic acid (1.2 equiv.) and Pd (PPh3)4 (0.1 equiv.) in 1,4-dioxane (4 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 solution (3.6 equiv.) was added to it and argon was purged again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford 5-(cyclopentylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide which was further purified using preparative HPLC which gave the TFA salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[N:17]=[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=12.[O:29]=[C:30]([OH:41])[C@@H:31]([C@H:33]([C@@H:35]([C@@H:37]([CH2:39][OH:40])[OH:38])[OH:36])[OH:34])[OH:32].O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=12.[O:29]=[C:30]([O-:41])[C@@H:31]([C@H:33]([C@@H:35]([C@@H:37]([CH2:39][OH:40])[OH:38])[OH:36])[OH:34])[OH:32]
Reactant: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: COc1cc(NS(C)(=O)=O)ccc1Nc1c2ccccc2nc2ccccc12
Solvent: CCO
Solvent: O
Product: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 16 h

Procedure:
A solution of 3.93 gm of m-AMSA and 5.15 gm of D-gluconic acid-water solution (38% w/w) in 305 ml of specially denatured 3A anhydrous ethanol at 70°-80° C. is filtered with suction. The filtrate is cooled to 30°-35° C. and 100 ml of anhydrous diethyl ether is added with stirring. After chilling to 0°-5° C. with stirring, the mixture is stored about 16 hours at 5° C. The product is collected, washed with specially denatured 3A anhydrous ethanol and anhydrous diethyl ether (3:1) at 5° C., then with several portions of anhydrous ether and dried under reduced pressure at 50°-55° C. to give 3.95 gm of m-AMSA D-gluconate. The salt obtained by this process retains a small amount (about 1% of ethanol).
Reaction SMILES: C1([CH:7]([O:14][C:15]([C@@H:17]2[N:21]3[C:22](=[O:35])[C@@H:23]([NH:24][C:25](=[O:34])[CH2:26][O:27]C4C=CC=CC=4)[C@H:20]3[S@@:19](=O)[C:18]2([CH3:38])[CH3:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)C=CC=CC=1.[C:39](Br)(=O)[CH3:40]>N1C=CC=CC=1>[C:8]1([CH:7]([O:14][C:15]([C:17]2[N:21]3[C:22](=[O:35])[C@@H:23]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:40]4[CH:39]=[CH:37][CH:18]=[CH:17][CH:15]=4)[C@H:20]3[S:19][CH2:37][C:18]=2[CH3:38])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC1(C)[C@H](C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2[S@]1=O
Reactant: CC(=O)Br
Solvent: c1ccncc1
Product: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 25 °C

Procedure:
(1S,3S,5R,6R) 2,2-Dimethyl-6-phenoxyacetamidopenam-3-carboxylic acid-1-oxide diphenylmethyl ester (55.06 gms, 100.00 mmoles) was dissolved in sieve-dried, peroxide-free dioxane (550 mls) at 25° C. with good agitation. To this solution, in order, were added pyridine (24.21 mls, 23.73 gms, 300.00 mmmoles), acetyl bromide (1.48 mls, 2.46 gms, 20.00 mmoles) and methylsilyl triisocyanate (89% pure, 21.30 mls, 25.34 gms, 133.33 mmoles). The slurry was heated to reflux (ca 100° C.) for 4 hours. The reaction mixture was then cooled to 25° C. and filtered, with the clear yellow filtrate being concentrated in vacuo at 50° C. to a highly viscous oil. The oil was dissolved in hot 2-propanol (~80° C., 3000 mls), filtered, and allowed to cool to 25° C. The slurry was cooled to 0°-5° C. for 2 hours, filtered, and washed with 2-propanol (0°-5° C., 400 mls), and oven-dried at 45° C. to constant weight. Yield: 38.6 gms, 75% of white crystalline title compound. The 80 MHz H' NMR spectrum was clean and consistent for the desired structure.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)N)=[CH:5][CH:4]=1.C(O[CH:21](OCC)[CH2:22][CH2:23][CH2:24][NH:25][CH3:26])C>C(O)C.O>[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[N:9]([CH2:11][CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:21]=[C:22]2[CH2:23][CH2:24][NH:25][CH3:26]
Reactant: NN(CCC1CCCC1)c1ccc(Cl)cc1
Reactant: CCOC(CCCNC)OCC
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNCCc1cn(CCC2CCCC2)c2ccc(Cl)cc12
Temperature: 60 °C
Yield: 56.7 %

Procedure:
28% aqueous HCl (0.3 mL, 2.26 mmol) was added to a solution of N-(4-Chloro-phenyl)-N-(2-cyclopentyl-ethyl)-hydrazine (0.54 g, 2.26 mmol) in ethanol (2.5 mL) and water (1 mL) under a nitrogen atmosphere. The reaction was heated to 60° C. (oil bath temperature) and 4,4-diethoxy-N-methylbutan-1-amine (0.32 g, 1.84 mmol) was added. The reaction was heated to reflux and 28% aqueous HCl (0.15 mL, 1.13 mmol) was added. The reaction was heated at reflux for 2.5 h. The reaction was cooled to 60° C. and then more 4,4-diethoxy-N-methylbutan-1-amine (0.32 g, 1.84 mmol) was added. The reaction was heated to reflux and then more 28% aqueous HCl (0.15 mL, 1.13 mmol) was added. The reaction was heated to reflux for a further 3.5 h. The reaction was cooled and concentrated under reduced pressure. The red brown residue was subjected to column chromatography (silica gel, eluent: EtOAc followed by EtOAc:EtOH:NH4OH 90:10:1) to give the product (0.318 g, 46%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[N:4]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1ccc(-c2nn(C3CCCCO3)c3ccc(C#N)cc23)cc1
Yield: 76.8 %

Procedure:
A flask was charged with 300 mg (0.98 mmol) of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile, 223 mg (1.47 mmol, 1.50 equiv.) of 4-methoxyphenylboronic acid, 80.3 mg (0.098 mmol, 0.100 equiv.) of [1,1′-bis (diphenylphosphino)-ferrocene}dichloropalladiuin (II) complex with dichloromethane (Aldrich), 1.04 g (4.90 mmol, 4.98 equiv.) of powdered potassium phosphate (K3PO4), and 4.90 mL of anhydrous 1,2-dimethoxyethane (DME). The mixture was refluxed under nitrogen for 19 h. The mixture was diluted with CH2Cl2, washed with 2× sat. aq. NaHCO3, and dried (Na2SO4). The crude material was purified by silica gel chromatography using 20-30% EtOAc in hexanes affording the title compound (251 mg, 77% yield): ES-MS (m/z) 334 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[CH:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CCC(O)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 91.9 %

Procedure:
Into a reactor were introduced 2.80 g (11.3 mmol) of the 1,1-bis(4-fluorophenyl)propanol, 60 mL of toluene, and 14 mg of p-toluenesulfonic acid monohydrate under a nitrogen atmosphere. Azeotropic dehydration was conducted for 1 hour with toluene refluxing. After being cooled, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, subsequently dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 2.39 g (92%) of the target compound as white crystals.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:3]=1.C(N(C(C)C)C(C)C)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH2:8][O:9][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:12][CH:11]=2)[N:3]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.60 g (9.7 mmol) of [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (example 1M]) were dissolved in 50 ml MeCl2 and cooled down to 0° C. 2.55 ml=1.93 g (14.6 mmol) of N-ethyl diisopropylamine was added, followed by 0.85 ml=1.25 g (10.7 mmol) of methane sulfonylchloride, drop by drop. After stirring for 30 min. at ambient temperature, the reaction mixture was poured into crashed ice and extracted twice with MeCl2. The combined organic phases were washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. This gave 3.44 g of crude title compound as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([S:12][CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[NH:11][C:6]2=[CH:5][CH:4]=1.[O-:24]O.C1(C(C)C)C=CC=CC=1>CN(C=O)C>[CH3:23][C:17]1[C:18]([O:21][CH3:22])=[C:19]([CH3:20])[C:14]([CH2:13][S@@:12]([C:10]2[NH:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:8][C:7]=3[N:9]=2)=[O:24])=[N:15][CH:16]=1
Reactant: [O-]O
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2n1
Solvent: CN(C)C=O
Solvent: CC(C)c1ccccc1
Product: COc1ccc2[nH]c([S@@](=O)Cc3ncc(C)c(OC)c3C)nc2n1
Temperature: 20 °C

Procedure:
A solution in DMF (6 volumes) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]imidazo[4,5-b]pyridine (100 mg, 0.303 mmol) is added under stirring at 20° C., immediately followed by cumene hydroperoxide (80%, 65 μL, 0.352 mmol)
Reaction SMILES: Cl[Si](Cl)(Cl)Cl.[N-:6]=[N+:7]=[N-:8].[Na+].[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=O)[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:26]=1)[C:19]([CH3:42])([CH3:41])[CH2:18]2)=[O:14])[CH3:11]>C(#N)C>[CH2:10]([O:12][C:13]([C:15]1[CH:24]=[C:23]2[C:22](=[CH:17][CH:16]=1)[NH:21][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]3[C:32]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:8][N:7]=[N:6]3)[CH:26]=1)[C:19]([CH3:18])([CH3:42])[CH2:41]2)=[O:14])[CH3:11]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)Cc3ccccc3)c1)N2
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-n3nnnc3Cc3ccccc3)c1)N2
Temperature: 25 °C
Yield: 57.6 %

Procedure:
To a stirred solution of tetrachlorosilane (6.0 mL, 52 mmol), sodium azide (5.1 g, 78.1 mmol) in dry acetonitrile (20 mL) was added 3,3-dimethyl-2-(3-phenylacetylamino-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2.3 g, 5.2 mmol) at room temperature. Then the mixture solution was stirred at room temperature for over night. LC/MS showed that reaction finished completely. The reaction mixture was poured into ice-cold saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (40% ethyl acetate/hexanes) afforded 2-[3-(5-benzyl-tetrazol-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.4 g, 58.3%) as a white solid: LC/MS m/e calcd for C28H29N5O2 (M+H)+: 468.58, observed: 468.1.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: COc1ccc(C(=O)Cl)cc1C#N
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)N2CSc3ccccc32)cc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (1.89 g) and 37% formalin (1.25 mL) in the same manner as in Example 1 was dissolved in chloroform (20 mL), and triethylamine (2.08 mL) and 3-cyano-4-methoxybenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 2 hours. The organic solvent was distilled off under reduced pressure and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (e).
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:35])=[CH:20][C:12]=1[O:13][CH:14]([CH2:18][CH3:19])[C:15](Cl)=[O:16])([O-:10])=[O:9]>C(Cl)Cl>[CH2:1]([NH:7][C:15](=[O:16])[CH:14]([O:13][C:12]1[CH:20]=[C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:35])[CH:22]=[CH:23][C:11]=1[N+:8]([O-:10])=[O:9])[CH2:18][CH3:19])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Reactant: NCc1ccco1
Solvent: ClCCl
Product: CCC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)NCc1ccco1
Temperature: -15 °C

Procedure:
Furfurylamine (0.015 mole) triethylamine (5 ml) and methylene chloride (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to about -15° C. and a solution of 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]butyryl chloride (0.01 mole) in methylene chloride (50 ml) is added dropwise with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature with continued stirring. After this time the mixture is transferred to a separatory funnel and is washed with water and dilute aqueous sodium bicarbonate. The washed solution is then dried, filtered and stripped of solvent leaving a residue. This residue is then purified by subjecting it to elution chromatography using mixtures of ethyl acetate and hexane with increasing concentrations of ethyl acetate as the eluant. The desired fractions determined by IR spectroscopy are then stripped of solvent to yield the desired product N-furfuryl-2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]butyramide.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].[O-:11][C:12]#[N:13].[K+]>C(O)(=O)C.O>[F:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH:4][C:12]([NH2:13])=[O:11]
Reactant: COc1ccc(F)c(N)c1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(F)c(NC(N)=O)c1
Temperature: 19 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a stirred solution of 2-fluoro-5-methoxyaniline (35.15 g, 249 mmol) in acetic acid (99 mL) and water (177 mL) at 35° C. was added potassium cyanate (40 g, 0.49 mol) in water (170 mL) over 20 minutes under N2. The mixture was stirred at 40° C. for 20 min and at 18 to 20° C. for 2 h, and then quenched into water (500 mL). The crude product was filtered, washed with water (1.2 L), heptane (50 mL) and slurred in a mixture of tert-butylmethylether (100 mL) and ethyl acetate (5 mL) for 5 minutes at ambient temperature. The product was filtered, washed with tert-butylmethylether (30 mL) and dried in vacuo at 40° C. to give N-(2-Fluoro-5-methoxyphenyl)urea (31.75 g, 69%) as a light-brown solid.
Reaction SMILES: [C:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12]([NH2:15])(=[O:14])=[O:13])[CH2:5][CH2:4][CH2:3][CH:2]=1.C(N=[C:21]=[O:22])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>>[C:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12]([N:15]=[C:21]=[O:22])(=[O:13])=[O:14])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCCCN=C=O
Reactant: NS(=O)(=O)c1ccccc1C1=CCCC1
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: O=C=NS(=O)(=O)c1ccccc1C1=CCCC1

Procedure:
A solution of 2.5 g of 2-(1-cyclopentenyl)benzenesulfonamide in 20 ml of xylenes was contacted with 1.4 g of n-butylisocyanate and a trace amount (ca. 20 mg) of DABCO then heated to reflux of 139°. Liquified phosgene (1.2 ml) was then added thereby reducing the temperature and reflux continued until the boiling point of the mixture stopped rising towards the original 139° (ca. 15 min. required), which indicated a complete reaction. The solution was then evaporated under reduced pressure to yield an oil. The infrared spectrum exhibited the characteristic 2220 cm-1 band indicating the presence of the title compound which was used directly.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]2[O:16][C:17]([CH2:20][OH:21])=[CH:18][CH:19]=2)[C:3]=1[N:22]=O.[H][H]>C(O)C.[Pd]>[NH2:22][C:3]1[C:4]([C:15]2[O:16][C:17]([CH2:20][OH:21])=[CH:18][CH:19]=2)=[N:5][N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[C:2]=1[NH2:1]
Reactant: [H][H]
Reactant: Nc1c(N=O)c(-c2ccc(CO)o2)nn1Cc1ccccc1F
Agent: [Pd]
Solvent: CCO
Product: Nc1c(-c2ccc(CO)o2)nn(Cc2ccccc2F)c1N

Procedure:
The compound from Example 5A (8 g) is dissolved in ethanol, treated with 0.5 g of 5% strength palladium on carbon and hydrogenated for 15 minutes in a Parr apparatus at a hydrogen pressure of 2 bar. The solution is filtered off with suction through kieselguhr and used for the next batch (Rf=0.21, T1E1, SiO2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]2=[O:24].[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[CH:11][CH:10]=3)[C:5](=[O:24])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7]2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(C#C[Si](C)(C)C)cc2c1=O
Reaction time: 1 h
Yield: 43.7 %

Procedure:
Compound D (450 mg, 1.15 mmol), trimethylsilylacetylene (179 μL, 1.27 mmol), PdCl2(PPh3)2 (40.5 mg, 0.058 mmol), CuI (22 mg, 0.12 mmol), triethylamine (321 μL, 2.31 mmol) and DMF (5.8 mL) were added to a microwave vial. The vial was capped and place in a microwave reactor at 150° C. for one hour. The reaction was washed with water and brine and extracted with EtOAc (2×). The organics were combined, dried (MgSO4), and concentrated to dryness. Purification by flash chromatography on silica gel afforded 205 mg (44%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.24 (d, J=1.84 Hz, 1H), 7.76-7.73 (m, 2H), 7.68 (dd, J=8.8 Hz, 1H), 7.52 (t, J=8.64, 8.72 Hz, 2H), 6.93 (d, J=8.8 Hz, 1H), 4.22 (q, J=7.08 Hz, 2H), 1.25 (t, J=7.12, 7.04 Hz, 3H), 0.24 (s, 9H); ES-MS [M+1]+: 408.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].[CH3:25][O:26][CH2:27]Cl>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][CH2:25][O:26][CH3:27])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: O=Cc1cc(O)ccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(OCc2ccccc2)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
To a mixture of 2-benzyloxy-5-hydroxybenzaldehyde (16.68 g) and N,N-dimethylformamide (100 mL) was added sodium hydride (60%, oil, 3.07 g) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Chloromethyl methyl ether (11.8 g) was dropwise added to the reaction mixture. The reaction mixture was further stirred at room temperature for 3 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-benzyloxy-5-methoxymethoxybenzaldehyde as a colorless oil (10.32 g, 52%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1>CN1CCCC1=O>[NH:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=[C:2]1[NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: CN1CCCC1=O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1

Procedure:
A solution of 2-chlorobenzimidazole (1 g) and ethyl 4-amino-1-piperidinecarboxylate (2 g) in 1-methyl-2-pyrrolidinone was heated at 130° C. for 24 h. The mixture was partitioned between water and ethyl acetate, the organic layer washed with water, dried and evaporated under reduced pressure. Purification was by chromatography eluting with 1% triethylamine/5% methanol in dichloromethane. Yield 0.630 g as a solid.