Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1([CH:8]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[C:9]2[N:13]=[CH:12][NH:11][N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O>ClCCl>[C:2]1(=[C:8]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[C:9]2[N:13]=[CH:12][NH:11][N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: N#Cc1ccc(C(c2nc[nH]n2)C2(O)CCCCC2)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(C(=C2CCCCC2)c2nc[nH]n2)cc1
Reaction time: 2 h
Yield: 21.4 %

Procedure:
7.24 g of crude 4-[1-hydroxycyclohex-1-yl-1-(1,2,4-triazolyl)methyl]benzonitrile is dissolved at 0° in 50 ml of dichloromethane and stirred for 1 hour at 0° with 22.7 ml of thionyl chloride. Then the mixture is concentrated to dryness under vacuum, dissolved in 50 ml of dichloromethane, stirred with 30 ml of triethylamine for 2 hours, diluted with water, extracted four times with ethyl acetate, washed with sodium chloride solution, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, yielding 1.45 g of 4-[1-cyclohexylidene-1-(1,2,4-triazolyl)methyl]benzonitrile as a free base, mp 92°-93°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([O:15]CC)=[O:14])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CCO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccn(-c2ccc(F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccn(-c2ccc(F)cc2)n1
Temperature: 50 °C
Yield: 51.3 %

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)pyrazole-3-carboxylate (0.92 g, 3.9 mmol, 1 eq) in 18 mL of EtOH/H2O (1.5:1) was added NaOH (0.47 g, 11.8 mmol, 3 eq). The reaction mixture was heated at 50° C. for 1 h then quenched with H2O and extracted with ethyl acetate. The combined organic layers were concentrated and purified by silica gel column chromatography (EtoAc:MeOH 3:1) to provide 1-(4-fluorophenyl)pyrazole-3-carboxylic acid (0.42 g, 2.0 mmol, 52%).
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:25]N)[CH:22]=[CH:23][CH:24]=1>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:22]([C:3]([S:4][C:5]3[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)=[C:2]([CH3:15])[NH:25]2)=[CH:23][CH:24]=1
Reactant: CC(=O)CSc1cccc(CC(=O)O)c1
Reactant: COc1cccc(NN)c1
Agent: Cl
Product: COc1ccc2c(Sc3cccc(CC(=O)O)c3)c(C)[nH]c2c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: [3-(2-oxo-propylsulfanyl)-phenyl]-acetic acid and 3-methoxyphenylhydrazine hydrochloride.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3][CH2:2]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>O1CCCC1>[C:12]([N:3]1[CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:1][CH2:2]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: C1CCC2(CC1)CCNCC2
Solvent: C1CCOC1
Product: CC(=O)N1CCC2(CCCCC2)CC1

Procedure:
A solution of 7 ml of 3-azaspiro[5.5]undecane and 9.7 ml of acetic anhydride in 19.5 ml of tetrahydrofuran was refluxed for 3 hours. The volatiles were evaporated to a yellow oil which was distilled in a Kugelrohr still giving a yellow oil, BP 90°-100° C./200-atm. The distillate was purified by chromatography on silica gel using 1:1 ethyl acetate:hexanes giving 7.89 g of the desired product as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([OH:18])=[C:7]3[C:15](=[O:16])[NH:14][NH:13][C:12](=[O:17])[C:8]3=[N:9][C:10]=2[CH:11]=1.[C:19](Cl)(=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([OH:18])=[C:7]3[C:15]([O:16][C:19](=[O:28])[CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:14][NH:13][C:12](=[O:17])[C:8]3=[N:9][C:10]=2[CH:11]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: O=c1[nH][nH]c(=O)c2c(O)c3ccc(Cl)cc3nc12
Solvent: c1ccncc1
Solvent: O
Product: O=C(CCc1ccccc1)Oc1n[nH]c(=O)c2nc3cc(Cl)ccc3c(O)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-chloro-2,3-dihydro-10-hydroxypyridazino[4,5-b]quinoline-1,4-dione (0.60 g, 2.3 mM), as prepared in Example 2, and hydrocinnamoyl chloride (1.15 g, 6.84 mM) in pyridine (9 mL) was refluxed for 1 hr. Upon cooling to room temperature, the solution solidified. After 2 hr at room temperature, the mixture was diluted with water (60 mL) and the solids broken up with a glass rod to provide a free-flowing aqueous suspension which was stirred for 1 hr. The solids were collected, washed with water (10 mL), and resuspended in 50% aqueous methanol (60 mL). After stirring for 15 minutes, this suspension was filtered and the collected solids were washed with 50% aqueous methanol (10 mL) and then sucked dry under a stream of nitrogen to provide a tan solid. This material was dried for 2.5 days in vacuo (50 mTorr) at 100° C. and then was recrystallized from dimethylsulfoxide/methanol. The title compound was obtained (0.40 g, 44%), after drying 24 hr in vacuo (50 mTorr) at 100° C., as an off-white powder, mp >300° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH:29]1[CH2:32][C:31]([C:38]([O:40][CH2:41][CH3:42])=[O:39])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:30]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:29]3[CH2:30][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:32]3)[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][CH:10]=3)[C:22]=12
Reactant: CCOC(=O)C1(C(=O)OCC)CC(OS(C)(=O)=O)C1
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Yield: 28571.4 %

Procedure:
A solution of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.129 g, 0.00042 mmol) in N,N-dimethylformamide (5 mL) was reacted with diethyl 3-[(methylsulfonyl)oxy]-1,1-cyclobutanedicarboxylate (0.150 g, 0.00051 mmol) and cesium carbonate (0.166 g, 0.00051 mmol) at 70° C. for five days. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (2×10 mL) and brine (10 mL). The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica using dichloromethane/methanol (98:2). The solvent was removed in vacuo to give diethyl 3-[4-amino-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1,1-cyclobutanedicarboxylate (0.060 g, 0.00012 mol) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](O)([CH3:13])[O:11][C:10](=O)[C:9]=2[C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[N:23][NH:22][C:10](=[O:11])[C:9]=2[C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC1(O)OC(=O)C(c2ccsc2)=C1c1ccc(Cl)cc1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: Cc1n[nH]c(=O)c(-c2ccsc2)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 40 %

Procedure:
A mixture of 3.77 g of 4-(4-chlorophenyl)-5-hydroxy-5-methyl-3-(3-thienyl)-2(5H)-furanone, 0.73 g of hydrazine monohydrate and 30 ml of 1-butanol was heated under reflux for 0.5 hours. The reaction mixture was cooled to 0° C. The deposited solid was collected by filtration. The solid was washed with a mixed solvent of hexane and t-butyl methyl ether, and dried under reduced pressure, to obtain 1.49 g of 5-(4-chlorophenyl)-6-methyl-4-(3-thienyl)-2H-pyridazin-3-one.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:26].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:26]
Reactant: O=C1c2c(ccc(F)c2Cl)-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3ccc(F)c2Cl)no1
Yield: 83.6 %

Procedure:
0.88 g (2.5 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one was stirred at room temperature overnight with 0.5 g (6.8 mmol) of diethylamine and 10 ml of N,N-dimethylformamide. After evaporating the reaction mixture the residue was dissolved in methylene chloride and the solution was washed with water. By drying the organic phase over magnesium sulfate and evaporating the solvent there was obtained 0.9 g (95%) of (S)-8-chloro-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[C:3](=[N:4][O:5][N+:6]=2[O-:10])[CH:2]=1.[CH:11](=O)[CH3:12]>C(N(CC)CC)C>[CH:9]1[CH:8]=[C:7]2[N:6]([O-:10])[CH:11]=[CH:12][N+:4](=[O:5])[C:3]2=[CH:2][CH:1]=1
Reactant: [O-][n+]1onc2ccccc21
Reactant: CC=O
Solvent: CCN(CC)CC
Product: O=[n+]1ccn([O-])c2ccccc21
Reaction time: 24 h

Procedure:
A mixture of benzofuroxan (2.5 g.), acetaldehyde (2.5 ml.) and triethylamine (20 ml.) is allowed to stand at room temperature for 24 hours. The solid material which precipitates is filtered and dried to give product, M.P. 223°-224° C. dec. (MIC against P. vulgaris is 12.5 mcg./ml.).
Reaction SMILES: O[CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[CH:3]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:11]>C(O)C.[Pd]>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:2][CH:3]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:11]
Reactant: COc1cccc(C(O)C2CCCCCCC2=O)c1
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(CC2CCCCCCC2=O)c1
Reaction time: 10 h
Yield: 42.6 %

Procedure:
A mixture of 2-{hydroxy-(3-methoxyphenyl)methyl}cyclooctanone (6.0 g) and 10% Pd/C (2 g) in ethanol (120 ml) was stirred under H2 for 10 hours. The catalyst was filtered off and filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 2-(3-methoxybenzyl)cyclooctanone (2.4 g). MS (m/z): 247 (M+ +1) IR (Neat): 1700 cm-1NMR (CDCl3, δ): 1.0-2.4 (12H, m), 2.4-2.6 (1H, m), 2.8-3.0 (2H, m), 3.77 (3H, s), 6.6-6.8 (3H, m), 7.17 (1H, t, J=8 Hz)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[F:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]=[C:46]=[O:47])=[CH:41][CH:40]=1>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:46](=[O:47])[NH:45][C:42]4[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=4)[CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCNC3)n2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCN(C(=O)Nc4ccc(F)cc4)C3)n2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.1 %

Procedure:
To a mixture of 2-(3-acetamidophenylamino)-4-(piperidin-3-ylmethylamino)pyrimidine-5-carboxamide (40 mg, 0.104 mmol) and DIEA (0.100 mL, 0.575 mmol) in CH2Cl2 (2 mL), 4-fluorophenyl isocyanate (0.023 mL, 0.205 mmol) was added. The mixture was stirred at room temperature for 4 h. It was then purified by HPLC to give the titled compound (32 mg). MS 521.5 (M+H); UV 204.1, 243.1 nm.
Reaction SMILES: [C:1](/[CH:3]=[C:4](\[O-])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:2].[Na+].Cl.[NH:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH2:14]>C(Cl)(Cl)Cl.C(OCC)C>[NH2:2][C:1]1[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[N:14]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)/C([O-])=C/C#N
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)c1cc(N)nn1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.5 %

Procedure:
To a suspension of sodium (Z)-1-cyano-3-ethoxy-3-oxoprop-1-en-2-olate (1.44 g, 8.78 mmol) in CHCl3 (80 mL) was added HCl (5 mL) in ethyl ether. t-butyl hydrazinecarboxylate (1.16 g, 8.78 mmol) was added, the mixture was stirred for 24 h at rt, the precipitate was removed by filtration, and the filtrate was concentrated to give 1-tert-butyl 5-ethyl 3-amino-1H-pyrazole-1,5-dicarboxylate (1.2 g, 37%), which was purified by preparative TLC. 1H NMR: δ 1.34 (m, 3H), 1.66 (s, 9H), 4.36 (m, 2H), 5.84 (s, 1H),
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]1[CH3:26])=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CC1CCCCN1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCCCC2C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-methylpiperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.58 minutes; C23H24Cl2N4O2 (459.38); mass spectrum: (M−H)−=458/460/462 (chlorine isotope).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:5]=1)([O-])=O.CO.[H][H]>[Ni].C1COCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:8][CH:9]=1
Reactant: O=C(C=Cc1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(CCC(=O)c2ccccc2)cc1

Procedure:
A mixture of 3-(4-nitro-phenyl)-1-phenyl-prop-2-en-1-one (24.9 g, 98.3 mmol), Raney nickel (7.0 g), MeOH (100 mL), and THF (400 mL) was shaken in a hydrogen atmosphere of 51 psi at 20° C. for 18.5 hours. The catalyst was filtered, and the filtrate was concentrated. The residue was recrystallized from 95% EtOH, to give the title compound, m.p. 76-78° C. 1H NMR (CDCl3) δ 2.98 (t, 2 H), 3.25 (t, 2 H), 3.62 (bs, 2 H), 6.65 (d, 2 H), 7.05 (d, 2 H), 7.40-7.61 (m, 3 H), 7.96 (d, 2 H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH:28]([F:30])[F:29])=[CH:22][C:21]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH:28]([F:30])[F:29])=[CH:22][C:21]=4[O:31][CH2:32][CH:33]4[CH2:34][CH2:35]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:38])[CH3:37]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3cc(F)c(OC(F)F)cc3OCC3CC3)ncnc12
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)c(OC(F)F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-cyclopropylmethoxy-4-(1,1-difluoro-methoxy)-5-fluoro-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A189) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C.ClCCl>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)CCO2
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)CCO2
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of 25.5 g (0.212 mol) of 2,3-dihydrobenzofuran in 175 mL of acetic acid was added about one quarter of 4.5 mL (0.227 mol) of 70% aqueous nitric acid dropwise. The reaction was monitored by TLC (EtOAc-hexanes, 15:85). The mixture was warmed to 70° C. where the reaction began. The remainder of the nitric acid was then added while maintaining the reaction at 70° C. After 30 minutes, the reaction was cooled and poured into 1.5 L of ice water. The black solid was collected by filtration washing with water. The solid was partitioned between 500 mL of saturated aqueous sodium bicarbonate and 150 mL of EtOAc. The aqueous layer was separated and extracted with three 150 mL portions of EtOAc. The combined organic layers were washed with three 100 mL portions of saturated aqueous sodium bicarbonate, 100 mL of saturated aqueous ammonium chloride, 100 mL of brine, dried over magnesium sulfate, filtered, and concentrated to afford a red oil/solid. The mixture was dissolved in dichloromethane and passed through a pad of silica gel, eluting with dichloromethane, and concentrated. The resulting red mixture was triturated with ether-hexanes (1:1) and filtered to afford 10.5 g (29%) of 5-nitro-2,3-dihydrobenzofuran as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[N:6]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1O
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(Cn2cc(Cl)cc([N+](=O)[O-])c2=O)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
The title compound was prepared in analogy to the procedure described for example 1 but using 5-chloro-3-nitropyridin-2-ol and 4-methoxybenzyl chloride. The reaction was stirred for 1 h at 80° C. The residue was purified by silica gel column chromatography (CH2Cl2/EtOAc, 8:2). tR: 0.91 min (LC-MS 4); ESI-MS: 295.2 [M+H]+ (LC-MS 4); Rf=0.59 (hexane/EtOAc, 1:1).
Reaction SMILES: [C:1]1([CH:7]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:8][CH2:9][N:10]([CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)[C:11]([NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=3)[N:18]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Cl:58])C(=O)C1>CN(C=O)C>[Cl:58][C:16]1[S:15][C:14]([NH:13][C:11](=[O:12])[N:10]([CH2:30][CH2:31][CH:32]2[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:39])[CH2:36][CH2:37]2)[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[N:18][C:17]=1[C:19]1[CH:20]=[CH:21][C:22]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:23][CH:24]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CCN(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2nc(-c3ccc(NS(C)(=O)=O)cc3)cs2)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCN(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2nc(-c3ccc(NS(C)(=O)=O)cc3)c(Cl)s2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 4-(2-(1-(3,3-diphenylpropyl)-3-(4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)ureido)ethyl)piperidine-1-carboxylate (0.35 g, 0.49 mmol) in DMF (10 ml) was added NCS (0.065 g, 0.49 mmol). The resulting mixture was stirred overnight at room temperature. After this time the mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and sat. aq. NaHCO3. The organic layer was washed with water and brine, dried over MgSO4 and concentrated under reduced pressure to give the crude product as a thick yellow oil. This crude product was purified by combi-flash (10-50% EtOAc/hexane). To give tert-butyl 4-(2-(3-(5-chloro-4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(3,3-diphenylpropyl)ureido)ethyl)piperidine-1-carboxylate 50 as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].[Cl:12]N1C(=O)CCC1=O>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4](=[N:5][OH:6])[Cl:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccc(Br)cc1F
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccc(Br)cc1F
Yield: 81.4 %

Procedure:
In a fashion similar to that for preparation 14, 2-Fluoro-4-bromo-benzaldehyde oxime (2.77 g, 12.7 mmol), N-chlorosuccinimide (1.76 g, 13.2 mmol), and DMF (25 ml) gave 2-fluoro-4-bromo-benzoyl chloride oxime (2.61 g, 81%) after filtration through a plug of silica gel eluting with hexanes/Et2O.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[Cl:26])[CH:11]=[CH:10][C:9]=1Br)[CH3:6])[CH3:2].[CH3:29][N:30](C)C=O>>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[Cl:26])[CH:11]=[CH:10][C:9]=1[C:29]#[N:30])[CH3:6])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(C)Oc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1Br
Product: CCOC(=O)C(C)Oc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1C#N

Procedure:
A 15 g of ethyl-α-[2-bromo-5-(2,6-dichloro-4-trifluoromethyl phenoxy) phenoxy]propionate produced in Example 7 was dissolved in 25 ml of dimethylformamide. A 3 g of cuprous cyanide was added to the solution and the reaction was conducted under reflux condition for 4 hours with stirring the mixture.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CCO.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br>>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][N:16]2[CH2:31][C:30]1[CH:33]=[CH:34][CH:35]=[C:28]([F:27])[CH:29]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCOc1cccc2[nH]ccc12)C(=O)OC(C)(C)C
Reactant: Fc1cccc(CBr)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(CCOc1cccc2c1ccn2Cc1cccc(F)c1)C(=O)OC(C)(C)C

Procedure:
[2-(1H-Indol-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester was treated NaOH/EtOH followed by addition of 3-fluorobenzylbromide as described above in Step 1 of Example 5 to afford {2-[1-(3-fluoro-benzyl)-1H-indol-4-yloxy]-ethyl}-methyl-carbamic acid tert-butyl ester. MS: 299 (M−Boc+H)+.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].C(OCC)(=O)C.[Cl:15][C:16]([Cl:23])([Cl:22])[CH2:17][O:18][C:19](Cl)=[O:20]>N1C=CC=CC=1>[Cl:15][C:16]([Cl:23])([Cl:22])[CH2:17][O:18][C:19]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])=[O:20]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(OCC(Cl)(Cl)Cl)ON1C(=O)CCC1=O

Procedure:
Dissolve 5.75 gm. of N-hydroxysuccinimide in 200 ml. ethyl acetate and 4 gm. of pyridine; cool the resultant solution to 0° C. To this solution add 10.6 gm. 2,2,2-trichloroethylchloroformate dropwise over a period of 1.5 hours. Filter the resultant mixture and evaporate the filtrate to dryness. Wash the thereby formed needles with hexane to obtain N-(2,2,2-trichloroethoxycarbonyloxy) succinimide, mp. 98°-101° C; νmax (CHCl3) 1825, 1790, 1750, 1185, 826 cm.-1, δ(CDCl3) 2.85 (4H,s,--CO (CH2)2CO--) and 4.90 ppm. (2H,s,--COOCH2CCl3).