Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:5]1[CH2:10][C:9]([C:18]#[N:19])([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:20])(OC)=O.S(=O)(=O)(O)O>C(O)(=O)C>[C:18]([C:9]1([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:10][CH2:5][C:6](=[O:20])[CH2:7][CH2:8]1)#[N:19]
Reactant: COC(=O)C1CC(C#N)(c2ccc(F)cc2)CCC1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: N#CC1(c2ccc(F)cc2)CCC(=O)CC1
Yield: 67 %

Procedure:
A reaction mixture consisting of 33.9 gm. (0.123 mole) of 2-carbomethoxy-4-cyano-4-(p-fluorophenyl)cyclohexanone (prepared in Part B, above), 900 ml. glacial acetic acid, and 450 ml. 10% aqueous sulfuric acid is heated with stirring on a steam bath for twenty-four (24) hours. After allowing the reaction mixture to cool, it is diluted with 2000 ml. water and extracted thoroughly with benzene. The benzene extracts are combined and washed successively with water, with aqueous sodium bicarbonate, and finally with brine. The benzene is then removed by evaporation under reduced pressure, and the solid residue thus obtained is recrystallized from diethyl ether to afford 16.23 gm. (67% yield) of 4-cyano-4-(p-fluorophenyl)cyclohexanone having a melting point at 84° to 88° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8](=[O:15])[O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])[S:4][N:3]=1.O[C@H:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CN(C=O)C>[CH3:1][C:2]1[CH:6]=[C:5]([N:7]([C:8]([O:9][CH2:10][C:11]([Cl:12])([Cl:14])[Cl:13])=[O:15])[C@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:22][CH:23]([CH3:25])[CH3:24])[S:4][N:3]=1
Reactant: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)sn1
Reactant: COC(=O)[C@H](O)CC(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1cc(C)ns1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice cold solution of 2,2,2-trichloroethyl 3-methylisothiazol-5-ylcarbamate (20.6 g, 71.1 mmol), methyl (2R)-2-hydroxy-4-methylpentanoate (15.9 g, 109 mmol) and triphenylphosphine (28.9 g, 110 mmol) in DMF (260 mL) was slowly added over 15 min diisopropylazodicarboxylate (21.7 mL, 110 mmol). The resulting brown solution was stirred at room temperature for 30 min and then heated to 60° C. for 18 h. The reaction mixture was allowed to cool to room temperature and it was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified twice by flash chromatography using EtOAc in hexane to afford methyl N-(3-methylisothiazol-5-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]-L-leucinate as a yellow syrup.
Reaction SMILES: Br[C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.Cl.[Br:16][C:17]1[CH:18]=[C:19]([O:26][CH3:27])[CH:20]=[C:21]2[C:25]=1[NH:24][CH2:23][CH2:22]2>>[Br:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:26][CH3:27])=[CH:18][C:17]=3[Br:16])[CH2:22][CH2:23]2)[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=1
Reactant: CCC(CC)n1cc(Br)nc(Br)c1=O
Reactant: COc1cc(Br)c2c(c1)CCN2
Agent: Cl
Product: CCC(CC)n1cc(Br)nc(N2CCc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-(1-ethylpropyl)-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 133-135° C.; 1H NMR (300 MHz, CDCl3): δ 6.92 (d, J=2.6 Hz, 1 H), 6.81 (s, 1 H), 6.78 (d, J=2.2 Hz, 1 H), 4.81-4.78 (m, 1 H), 4.35 (t, J=7.7 Hz, 2 H), 3.78 (s, 3 H), 3.11 (t, J=7.7 Hz, 2 H), 1.87-1.73 (m, 2 H), 1.70-1.60 (m, 2 H), 0.89 (t, J=7.3 Hz, 6 H); HRMS (ESI) calcd for C18H22N3O2Br2 (M+H)+: 470.0079; found m/z 470.0084.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](O)[C:5]2[CH:11]=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14]>N1C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([SH:14])[C:5]2[CH:11]=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Nc1nc(O)c2cccnc2n1
Solvent: c1ccncc1
Product: Nc1nc(S)c2cccnc2n1

Procedure:
2-Amino-4-hydroxypyrido[2,3-d]pyrimidine (8.1 gm) is heated to boiling for ten hours with phosphorus pentasulfide (25 gm) in pyridine (125 ml). After the solvent has been distilled off, the residue is triturated with water, made alkaline with sodium hydroxide solution, and purified with activated charcoal, and the filtrate is acidified with acetic acid. The yellow fine crystalline powder precipitate is washed with water and dried.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([C:11]2([OH:34])[CH2:17][CH:16]3[N:18]([CH:19]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[CH:13]([CH2:14][CH2:15]3)[CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)=[N+]=[N-]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:1][CH2:4][C:5]1[C:6]([C:11]2([OH:34])[CH2:12][CH:13]3[N:18]([CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])[CH:16]([CH2:15][CH2:14]3)[CH2:17]2)=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: [N-]=[N+]=NCc1cccnc1C1(O)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Product: NCc1cccnc1C1(O)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl

Procedure:
Follow the procedure of Step 6 of Example 15, using the product from Step 5 (69 mg) and Lindlar catalyst (7 mg) to produce the title compound. 1H NMR (CDCl3) 8.40 (d, 1H), 7.95 (d, 2H), 775 (d, 1H), 7.05-7.15 (m, 7H), 5.60 (s, 1H), 5.25 (b, s, 1H), 4.40 (s, 2H), 3.20 (s, br, 2H), 2.50 (dd, 2H), 2.3 (m, 4H), 1.75 (d, 2H).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:16]1([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: c1ccc(N2c3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
18.12 g of acridan (0.10 mol), 17.30 g of bromobenzene (0.11 mol), 14.40 g of sodium t-butoxide (0.15 mol), 1.12 g of Pd(OAc)2 (5 mmol), and 0.81 g of tri-t-butylphosphine (4 mmol) were taken up in 100 mL of dry toluene and this reaction mixture was allowed to stir under inert atmosphere. The exothermic reaction heated to reflux, then cooled to room temperature and was allowed to stir for 1 h. TLC analysis showed the reaction had gone to completion, so the reaction mixture was passed through a short plug of silica gel, which was subsequently washed with 1 L of CH2Cl2. The filtrate was concentrated to dryness and purified by column chromatography to afford 25.21 g of the N-phenylacridan (98.0%).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:15]([O:17][C:18]([C:20]1[C:21]([CH2:26][CH2:27][CH2:28][C:29]([OH:31])=O)=[CH:22][NH:23][C:24]=1[CH3:25])=[O:19])[CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:25][C:24]1[NH:23][C:22]2[C:29](=[O:31])[CH2:28][CH2:27][CH2:26][C:21]=2[C:20]=1[C:18]([O:17][CH2:15][CH3:16])=[O:19]
Reactant: CCOC(=O)c1c(CCCC(=O)O)c[nH]c1C
Agent: O=C([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: CCOC(=O)c1c(C)[nH]c2c1CCCC2=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
P2O5 7.1 g was added into polyphosphoric acid 142 g, then after the mixture was stirred for 30 minutes at 70° C., 4-(4-(ethoxycarbonyl)-5-methyl-1H-pyrrol-3-yl)butanoic acid (S2) 6.3 g (0.026 mol) was added and stirred for 48 hours. The mixture was poured into the ice water and adjusted pH to 8 with saturated sodium carbonate solution, then extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, then dried over anhydrous Na2SO4 and concentrated to saturated solutions in vacuo. The residue was colded to −5° C., then the white solid was collected by filtration and dried in vacuum to give 3.5 g (61%) ethyl 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylate (S3).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]([NH:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[F:24])[C:12](=O)[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:15]=[C:16]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=2[F:24])[O:25][C:12]=1[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(CCOCc1ccccc1)NC(=O)c1ccc(Br)cc1F
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1oc(-c2ccc(Br)cc2F)nc1CCOCc1ccccc1
Temperature: 25 °C

Procedure:
To a stirring solution of N-[1-(2-benzyloxy-ethyl)-2-oxo-propyl]-4-bromo-2-fluoro-benzamide (1.0 mmol) (See Intermediate 36) in dimethylformamide (0.25M), slowly add phosphorus oxychloride (3.0 mmol) and heat to 90° C. for 2.5 hours. After this time, remove the heat and carefully add water (same amount as DMF) and allow the reaction to cool to room temperature before extracting with ether. Wash organics with water and brine. Dry the organics with sodium sulfate, filter and concentrate in vacuo. Purify via radial chromatography eluting with ethyl acetate and hexane. MS (m/e) (79Br/81Br): 390.2/392.2 (M+1)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([C:26]1[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:28]=[N:27][C:26]([CH2:24][CH3:25])=[C:31]([N+:32]([O-:34])=[O:33])[CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CCc1ncc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1[N+](=O)[O-]

Procedure:
The title compound was synthesized in a similar manner as described for for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-ethyl-3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (stage 208.1.2) to give the title compound as a yellow foam. (HPLC: tR 2.72 min (Method A); M+H=444 MS-ES).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:26].C(O[C:41]([N:43]([CH:45]1[CH2:49][CH2:48][NH:47][CH2:46]1)C)=O)(C)(C)C>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:47]3[CH2:48][CH2:49][CH:45]([NH:43][CH3:41])[CH2:46]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:26]
Reactant: O=C1c2c(-c3ccccc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Product: CNC1CCN(c2cc(-c3ccccc3)c3c(n2)OCCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)C1
Yield: 50.1 %

Procedure:
In a similar manner to Example 11, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (40.0 mg) was reacted with 3-(N-(t-butoxycarbonyl)-N-methylamino)pyrrolidine (38.9 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-9-[3-(methylamino)pyrrolidine-1-yl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (22.5 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:22])[N:9]2[CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[CH:23]1([NH:29][C:30]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:31]=2[C:32](O)=[O:33])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.Cl.C(N=C=NCCCN(C)C)C.CN(C1C=CC=CN=1)C>C(N(CC)CC)C.C(Cl)Cl>[Si:15]([O:14][CH2:13][CH2:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:37]([C:39]([F:41])([F:42])[F:40])=[CH:38][C:30]=3[NH:29][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH:11]=2)[CH2:6][CH2:7][C:8]1=[O:22])([C:18]([CH3:19])([CH3:21])[CH3:20])([CH3:16])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OCCN1C(=O)CCc2ccc(N)cc21
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1NC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCN1C(=O)CCc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3NC3CCCCC3)cc21

Procedure:
A methylene chloride solution of 7-amino-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,4-dihydroquinolin-2(1H)-one, 2-(cyclohexylamino)-4-(trifluoromethyl)benzoic acid, 1-ethyl-3-[3-(N,N-dimethylamino)propyl]carbodiimide hydrochloride, dimethylaminopyridine and triethylamine was allowed to undergo the reaction at room temperature. By post-treating the reaction liquid, N-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl]-2-(cyclohexylamino)-4-(trifluoromethyl)benzamide was obtained.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]=[O:21])=[CH:15][CH:14]=1>O.CO>[F:12][C:13]1[CH:18]=[CH:17][C:16](/[C:19](=[CH:6]/[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[Cl:3])/[CH:20]=[O:21])=[CH:15][CH:14]=1
Reactant: O=CCc1ccc(F)cc1
Reactant: O=Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C/C(=C\c1ccccc1Cl)c1ccc(F)cc1
Temperature: 10 °C
Reaction time: 10 h

Procedure:
4.2 g of sodium hydroxide in 30 ml of water are added to a solution of 35 g of 2-chlorobenzaldehyde in 300 ml of methanol. The reaction mixture is cooled to 10° C. and 36 g of 4-fluorophenylacetaldehyde are rapidly added, during which the solution warms to 30°-40° C. The reaction solution is stirred at 40° C. for 10 hours and then cooled, and the crystals which separate out are filtered off with suction.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[C:6]([N:10]=[N:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])([CH3:9])([CH3:8])[CH3:7].O>CO.CCCCC>[C:6]([N:10]=[N:11][C:12]([CH3:14])([CH3:13])[C:15](=[N:2][OH:3])[NH2:16])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)N=NC(C)(C)C#N
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC
Solvent: O
Solvent: CO
Product: CC(C)(C)N=NC(C)(C)C(N)=NO
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.1 %

Procedure:
To a mixture of 8.35 grams (0.12 moles) of hydroxylamine hydrochloride and 9.6 grams (0.12 moles) of 50% NaOH in 110 ml of 90% aqueous methanol in a 250 ml round bottom flask equipped with a magnetic stirrer and condenser was added 15.3 grams (0.1 moles) of 2-t-butylazo-2-cyanopropane (from Example I). The mixture was stirred for 72 hours at room temperature, poured into 400 ml of water and extracted with 100 ml of methylene chloride, the organic layer separated, dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated under reduced pressure leaving a soft solid. The residue was slurried in 100 ml of pentane to remove any unreacted 2-t-butylazo-2-cyanopropane, filtered and the filter cake air dried. The yield was 12.5 grams (67% yield) of a white solid having a melting point of 105°-109°C (dec.). The infrared spectrum of the product was in agreement with the structure of the desired amidoxime.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:27])([CH3:26])[C@@H:14]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:15]([OH:17])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2].[C:28]1([CH2:34][O:35][CH2:36][C:37]([O:39][CH:40](Cl)[CH3:41])=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:27])([CH3:26])[C@@H:14]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:15]([O:17][CH2:41][CH2:40][O:39][C:37](=[O:38])[CH2:36][O:35][CH2:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(Cl)OC(=O)COCc1ccccc1
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](OCc1ccccc1)C(=O)O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](OCc1ccccc1)C(=O)OCCOC(=O)COCc1ccccc1
Yield: 8.4 %

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (17) (0.8 g, 2.0 mmol) dissolved in 12 mL of anhydrous toluene was reacted with 1.4 g (6.0 mmol) of 1-chloroethyl 2-(phenylmethoxy)acetate (25) in the presence of 1.1 g (4.0 mmol) of silver carbonate (Ag2CO3). After work-up and further purification by mass-guided preparative HPLC, 0.1 g (8.4% yield) of the title compound (45a) was obtained as a colorless, viscous oil. MS (ESI) m/z 594.15 (M+H)+, 616.20 (M+Na)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:16]3[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24]CC)=[O:23])=[CH:18][CH:17]=3)[N:14]=[C:13]([C:29]([F:32])([F:31])[F:30])[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+]>O1CCCC1.C(O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:16]3[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)[N:14]=[C:13]([C:29]([F:32])([F:30])[F:31])[CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CCOC(=O)COc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(OCC(=O)O)cc2)cc1
Yield: 68.8 %

Procedure:
A mixture of ethyl 4-{5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1-pyrazolyl}phenoxyacetate (1.7 g), 10% sodium hydroxide (10 ml) in tetrahydrofuran (10 ml) and ethanol (40 ml) was refluxed for 3 hours. The solvent was evaporated, and the residue was dissolved in water and acidified with hydrochloric acid. The precipitates were filtered and recrystallized from a mixture of tetrahydrofuran, ethanol, and isopropyl ether to give 4-{5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1-pyrazolyl}phenoxyacetic acid (1.1 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(P(CCCC)CCCC)CCC.[CH:23]1([C:26]2[CH:27]=[CH:28][C:29]([CH:42]([C:44]3[CH:49]=[CH:48][C:47]([S:50]([CH:53]4[CH2:55][CH2:54]4)(=[O:52])=[O:51])=[CH:46][CH:45]=3)O)=[N:30][C:31]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH:23]1([C:26]2[C:31]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)=[N:30][C:29]([CH:42]([C:44]3[CH:45]=[CH:46][C:47]([S:50]([CH:53]4[CH2:54][CH2:55]4)(=[O:52])=[O:51])=[CH:48][CH:49]=3)[O:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1
Reactant: Oc1ccc(F)cc1F
Reactant: COc1ccc(COc2nc(C(O)c3ccc(S(=O)(=O)C4CC4)cc3)ccc2C2CC2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(COc2nc(C(Oc3ccc(F)cc3F)c3ccc(S(=O)(=O)C4CC4)cc3)ccc2C2CC2)cc1
Temperature: 86 °C
Yield: 77.1 %

Procedure:
2,4-Difluorophenol (219 mg), tributylphosphine (340 mg) and N,N,N′,N′-tetramethylazodicarboxyamide (289 mg) were sequentially added to a solution of {5-cyclopropyl-6-[(4-methoxybenzyl)oxy]pyridin-2-yl}[4-(cyclopropylsulfonyl)phenyl]methanol (390 mg) in tetrahydrofuran (12 mL). After replacement with nitrogen, the mixture was stirred under reflux at an external temperature of 86° C. for six hours, returned to room temperature and stirred overnight. The reaction solution was poured into water and a potassium carbonate solution was added, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=92:8→34:66) to give 3-cyclopropyl-6-{[4-(cyclopropylsulfonyl)phenyl](2,4-difluorophenoxy)methyl}-2-[(4-methoxybenzyl)oxy]pyridine as a yellow gum (373 mg, 77%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:26])[C:15]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:26])[C:15](=[O:16])[NH:17][CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(=O)NCCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C(=O)NCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using 2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-hydroxy-N-phenethyl-acetamide and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1.[BrH:14]>O.S>[Br:14][C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Br
Reactant: Nc1cccnc1CO
Agent: O=N[O-]
Agent: S
Agent: [Na+]
Solvent: O
Product: OCc1ncccc1Br

Procedure:
A solution sodium nitrite (2.28 g) in water (10 ml) was added dropwise to a stirred mixture of 3-amino-2-hydroxymethylpyridine (4.8 g) in aqueous hydrobromic acid (48%, 10 ml) and water (5 ml) at 0.5° C. This solution of the diazonium salt was added to a hot solution of cuprous bromide (2.5 g) in 60% hydromic acid and following cessation of nitrogen evolution the mixture was heated on the steam bath for 0.5 hours, diluted with water and saturated with hydrogen sulphide. Filtration, concentration to low bulk and extraction with chloroform yielded 3-bromo-2-hydroxymethylpyridine (4.8 g). This was dissolved in aqueous hydrobromic acid (48%, 50 ml), cysteamine hydrochloride (3.22 g) added and the solution obtained was heated under reflux for 6 hours. Concentration, followed by recrystalliation from aqueous ethanol afforded 2-((2-aminoethyl)thiomethyl)-3-bromopyridine dihydrobromide (6.1 g), m.p. 252°-254°.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2].[Br:17][C:18]1[CH:19]=[CH:20][C:21](F)=[C:22]([CH:25]=1)[CH:23]=[O:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH2:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[C:22]([CH:23]=[O:24])[CH:25]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOCCNCCCC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCN(CCCC(=O)OC(C)(C)C)c1ccc(Br)cc1C=O
Temperature: 90 °C
Reaction time: 60 h
Yield: 25.6 %

Procedure:
In DMF (43.9 ml) was dissolved tert-butyl 4-[(2-ethoxyethyl)amino]butyrate (5.5 g). To the solution was added 5-bromo-2-fluorobenzaldehyde (4.4 g), followed by addition of potassium carbonate (3.6 g). The mixture was stirred at 90° C. for 60 hours and cooled to room temperature. The reaction solution was added to water, the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=6/1→5/1) to give tert-butyl 4-(4-bromo(2-ethoxyethyl)-2-formylanilino]butyrate (2.3 g).