Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:34][C:33]2=[O:46])=[CH:28][C:27]=1[NH:47][CH3:48].[CH3:49][O:50][C:51]([CH:53]1[CH2:55][CH:54]1[C:56](O)=O)=[O:52].C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH2:39]([O:38][C:35]1[CH:36]=[CH:37][N:32]([C:29]2[CH:30]=[CH:31][C:26]3[N:25]=[C:56]([CH:54]4[CH2:55][CH:53]4[C:51]([O:50][CH3:49])=[O:52])[N:47]([CH3:48])[C:27]=3[CH:28]=2)[C:33](=[O:46])[CH:34]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CNc1cc(-n2ccc(OCc3ccccc3)cc2=O)ccc1N
Reactant: COC(=O)C1CC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)C1CC1c1nc2ccc(-n3ccc(OCc4ccccc4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
HATU (4.97, g) was added to a solution of 1-(4-amino-3-(methylamino)phenyl)-4-(benzyloxy)pyridin-2(1H)-one (3.5 g), (1RS,2SR)-2-(methoxycarbonyl)cyclopropanecarboxylic acid (1.884 g) and N,N-diisopropylethylamine (3.80 ml) in DMF (70 ml) at room temperature. The mixture was stirred at room temperature for 1 h. To the resulting mixture was added water, and the resulting precipitate was collected by filtration and washed with water and IPA. The obtained solid was dissolved in AcOH (35 ml). The mixture was stirred at 80° C. for 1 h. After evaporation of the mixture, the residue was diluted with saturated NaHCO3 solution and EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was washed with IPE to give the title compound (2.9 g) as a pink solid.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[O:22][CH2:23][C:24]([O:26]CC)=[O:25].[OH-].[Na+]>C1COCC1.CO>[CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[O:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](OCC(=O)O)CC[C@H]4[C@@H]3CC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To ethyl 4-methyl-5α-4-azaandrostan-3-on-17β-yloxyacetate (275 mg) in THF (10 ml) and MeOH (5 ml) under N2 was added 2N NaOH (3.0 ml). The mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The aqueous residue was extracted with CH2Cl2. The aqueous layer was then acidified with 3.0 N HCl (ca. 2.1 ml) to pH 2, and extracted with CH2Cl2. The organic layer was washed with brine and dried (Na2SO4). The solvent was removed, and the crude product recrystallized from CH2Cl2 /hexane to give the title compound. m.p. 180.5°-184° C.
Reaction SMILES: [CH:1]([O:4][P:5]([CH2:7][CH3:8])[OH:6])([CH3:3])[CH3:2].[C:9](#[N:12])[CH:10]=[CH2:11].C(O)(C)C.[Na]>>[C:9]([CH2:10][CH2:11][P:5]([CH2:7][CH3:8])(=[O:6])[O:4][CH:1]([CH3:3])[CH3:2])#[N:12]
Reactant: CCP(O)OC(C)C
Reactant: C=CC#N
Agent: [Na]
Solvent: CC(C)O
Product: CCP(=O)(CCC#N)OC(C)C
Reaction time: 1 h

Procedure:
To a solution of 262 g of ethyldichlorophosphine in 1200 ml of diethylether is added with stirring and cooling with ice at 5-10° a solution of 370 ml of isopropanol and 280 ml of triethylamine in 400 ml of diethylether. The reaction is exothermic. After stirring for 12 hours at 20° the white precipitate is filtered off and the filtrate is fractionally distilled. There is obtained ethylphosphonous acid-isopropylester as a colorless liquid, b.p. 80-85°/26 kPa. To 34 g of ethylphosphonous acid-isopropylester and 16.45 ml of acrylonitrile is added with stirring 40 ml of isopropanol containing 0.25 mol of sodium isopropylate. The reaction is exothermic. After 1 hour stirring at 20° the mixture is fractionated. There is obtained isopropyl 2-cyanoethyl(ethyl)phosphinate as a colorless oil, b.p. 102-104°/10 Pa.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.Cl.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O>[CH3:14][O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N-BOC-L-alanine (150 mmol) in DMF (250 mL) at 0° C., is added proline methyl ester.HCl (150 mmol), 1-hydroxybenzotriazole hydrate (22.2 g, 0.164 mmol), ethyl-3-(3-dimethylamino)propyl carbodiimide.HCl (31.4 g, 0.164 mmol) and 4-methylmorpholine (22.6 g, 0.224 mmol). The reaction mixture is stirred for 12 h while allowing the reaction to warm to room temperature. The reaction mixture is poured in water (750 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts are washed as follows: KHSO4 (0.25M, 2×50 mL), water (1×50 mL), saturated aqueous NaHCO3 (2×50 mL) and saturated NaCl (1×50 mL). The organic layer is dried over MgSO4, filtered and the solvent removed in vacuo to give title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[CH2:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7]>C1(C)C=CC=CC=1>[Br-:1].[Br:1][CH2:2][CH2:3][CH2:4][N+:8]([CH2:11][CH3:12])([CH2:9][CH3:10])[CH2:6][CH3:7]
Reactant: CCN(CC)CC
Reactant: BrCCCBr
Solvent: Cc1ccccc1
Product: CC[N+](CC)(CC)CCCBr
Product: [Br-]
Temperature: 100 °C
Yield: 33 %

Procedure:
1,3-Dibromopropane (20.0 g, 100 mmol) and triethylamine (5.06 g, 50 mmol) were mixed in dry toluene (50 ml). This solution was heated at 100° C. under nitrogen atmosphere for 4 h, during which time a thick white solid precipitated. The mixture was then cooled and the solid collected by filtration, washed with toluene and ether and dried under vacuum at 50° C. to give the titled compound 5.0 g (36%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][C@@H:26]([CH3:28])[N:25]([CH3:29])[CH2:24][C@@H:23]2[CH3:30])=[CH:18][CH:17]=1.BrC1C=C2C(=CC=1)[C:38](=[O:42])NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/[O:42][CH3:38].[CH3:30][CH:23]1[CH2:24][N:25]([CH3:29])[CH:26]([CH3:28])[CH2:27][N:22]1[C:19]1[CH:18]=[CH:17][C:16]([NH2:15])=[CH:21][CH:20]=1
Reactant: C[C@@H]1CN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2)[C@@H](C)CN1C
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Product: CC1CN(c2ccc(N)cc2)C(C)CN1C
Product: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione, 0.68 g (91.0% yield) of yellow solid is obtained from 0.45 g (0.46 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione and 4-(2,4,5-trimethyl-piperazin-1-yl)-phenylamine (0.38 g, 1.76 mmol): mp 184-185° C.; MS (ESI) m/z 469.1-471.1 (M+H)+1
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl-].[O:12]([C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[CH:22]=[N+:23]([CH3:25])[CH3:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O(C1C=C(C=CC=1)C=O)C1C=CC=CC=1.CNC>>[CH3:24][N:23]([CH3:25])[CH:22]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1])[C:21]1[CH:26]=[CH:27][CH:28]=[C:19]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:20]=1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: C[N+](C)=Cc1cccc(Oc2ccccc2)c1
Agent: CNC
Agent: O=Cc1cccc(Oc2ccccc2)c1
Agent: [Cl-]
Product: Cc1[nH]c2ccccc2c1C(c1cccc(Oc2ccccc2)c1)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-methyl-1H-indole and (3-phenoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3-phenoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH2:13]([NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([N:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:4]
Reactant: CCCCNCCCC
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)C(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2.0 g isatoic anhydride is dissolved in 50 ml methylene chloride/5 ml dimethylformamide and 1.87 g 4-dimethylaminopyridine and 1.98 g dibutylamine are added. The mixture is stirred at room temperature for 5 hours, then diluted with 250 ml of ethyl acetate. The organic solution is washed with 10% HCl and brine and dried over sodium sulfate followed by filtration and evaporation to obtain a residue. The residue is dissolved in 25 ml ethyl acetate, the solution filtered, concentrated and this residue purified by flash chromatography on silica gel in ethyl acetate/hexane, 2:3, to give 2-amino-N,N-dibutyl benzamide.
Reaction SMILES: [C:1](=[O:27])(ON1C(=O)CCC1=O)[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:18])[NH:16][CH3:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:28][NH:29][CH2:30][C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:35][CH:36]=1.C(N(CC)CC)C>ClCCl>[CH3:28][N:29]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:32]=1)[C:1](=[O:27])[O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15](=[O:18])[NH:16][CH3:17])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CNC(=O)c1ccc(-c2ccc(OC(=O)ON3C(=O)CCC3=O)cc2)cc1
Reactant: CNCc1cccc(-c2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc(-c2ccc(OC(=O)N(C)Cc3cccc(-c4ccccc4)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask was placed a solution of 4-[4-(methylcarbamoyl)phenyl]phenyl 2,5-dioxopyrrolidin-1-yl carbonate from Example 1 Step 4 (560 mg, 1.5 mmol, 1 equiv) in dichloromethane (40 mL), N-methyl (3-biphenyl)methylamine (301 mg, 1.5 mmol, 1 equiv) and triethylamine (153 mg, 1.5 mmol, 1 equiv). The resulting solution was stirred overnight at room temperature. The reaction mixture was washed with 2×20 mL of water and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The crude product (650 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-002(Agilent)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water and acetonitrile (10.0% acetonitrile up to 80.0% in 10 min, up to 100.0% in 1 min, down to 10.0% in 2 min); Detector, uv 220 & 254 nm. The title compound was obtained as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:30])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][C:21]([O:25][CH:26]([CH3:28])[CH3:27])=[C:22]([Cl:24])[CH:23]=3)[O:15][N:14]=2)=[CH:8][C:7]=1[CH3:29].[C:31](O)(=[O:34])[CH2:32][OH:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CC(=O)OCC>[Cl:24][C:22]1[CH:23]=[C:18]([C:16]2[O:15][N:14]=[C:13]([C:9]3[CH:10]=[C:11]([CH3:12])[C:6]([O:5][CH2:4][CH:3]([OH:30])[CH2:2][NH:1][C:32](=[O:33])[CH2:31][OH:34])=[C:7]([CH3:29])[CH:8]=3)[N:17]=2)[CH:19]=[N:20][C:21]=1[O:25][CH:26]([CH3:27])[CH3:28]
Reactant: O=C(O)CO
Reactant: Cc1cc(-c2noc(-c3cnc(OC(C)C)c(Cl)c3)n2)cc(C)c1OCC(O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(-c2noc(-c3cnc(OC(C)C)c(Cl)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.3 %

Procedure:
To a solution of (RS)-1-amino-3-{4-[5-(5-chloro-6-isopropoxy-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (313 mg, 0.6 mmol) in DCM (10 mL), glycolic acid (95 mg, 1.25 mmol) and Hünig's base (233 mg, 1.8 mmol) are added. The mixture is cooled to 0° C. and TBTU (236 mg, 0.74 mmol) is added. The mixture is stirred at 0° C. for 1 h, then at rt for 16 h before it is diluted with EA (250 mL), washed with 1N aq. NaOH solution (3×25 mL), 1N aq. KHSO4 (25 mL) and brine (25 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by prep. HPLC to give N—((RS)-3-{4-[5-(5-chloro-6-isopropoxy-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide (42 mg) as a white powder; LC-MS: tR=1.06 min; [M+1]+=491.48; 1H NMR (CD3OD) δ 1.45 (d, J=6.3 Hz, 6H), 2.38 (s, 6H), 3.47 (dd, J=13.6, 7.3 Hz, 1H), 3.66 (dd, J=13.6, 4.5 Hz, 1H), 3.87 (m, 2H), 4.04 (s, 2H), 4.14 (m, 1H), 5.52 (m, 1H), 7.78 (s, 2H), 8.43 (s, 1H), 8.85 (s, 1H)
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].F[P-](F)(F)(F)(F)F.Br[P+](N(C)C)(N(C)C)N(C)C.C(N(C(C)C)CC)(C)C.[NH2:74][C:75]1([C:78](O)=[O:79])[CH2:77][CH2:76]1>ClCCl>[NH2:74][C:75]1([C:78]([NH:41][C@H:40]([C:39]([N:38]([C@@H:33]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([N:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:6])[CH3:46])=[O:45])[CH:42]([CH3:44])[CH3:43])=[O:79])[CH2:77][CH2:76]1
Reactant: NC1(C(=O)O)CC1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)[P+](Br)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C1(N)CC1)C(C)C
Reaction time: 2 h
Yield: 40.5 %

Procedure:
To a solution of #50 (100 mg, 0.15 mmol, 1 eq.), bromotris(dimethylamino)phosphonium hexafluorophosphate (Brop, 70 mg, 0.18 mmol, 1.2 eq.) and diisopropylethylamine (0.08 mL, 0.45 mmol, 3 eq.) in dichloromethane (15 mL, 0.01 M) at 0° C. was added 1-aminocyclopropanecarboxylic acid (18 mg, 0.18 mmol, 1.2 eq.). After 2 hours, the mixture was quenched with water and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) to give #51 (45 mg, 34%). Rf 0.5 (10% methanol in dichloromethane). LC-MS (Protocol L): m/z 741.44 [M+H+]; 1H NMR (300 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.64 (br d, J=8 Hz) and 8.88 (br d, J=8 Hz), total 1H], [8.16 (br d, J=9 Hz) and 8.22 (br d, J=10 Hz), total 1H], [7.77 (d, J=3.5 Hz) and 7.79 (d, J=3.5 Hz), total 1H], [7.63 (d, J=3.5 Hz) and 7.65 (d, J=3 Hz), total 1H], 7.10-7.32 (m, 5H), 5.33-5.60 (m, 1H), 3.16, 3.20, 3.21 and 3.26 (4 s, total 6H), 2.93 and 3.02 (2 br s, total 3H), [1.05 (d, J=6.3 Hz) and 1.10 (d, J=6.3 Hz), total 3H].
Reaction SMILES: [Cl:1][C:2]([Cl:17])=[CH:3][C:4]1[S:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.S([O-])(O[O-])(=O)=[O:19].[K+].[K+]>CO.O.C(O)(C)C>[Cl:17][C:2]([Cl:1])=[CH:3][C:4]1[S:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:16])=[O:19])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=S(=O)([O-])O[O-]
Reactant: CSc1ccc(-c2ccc(C=C(Cl)Cl)s2)cc1
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Solvent: CO
Product: CS(=O)c1ccc(-c2ccc(C=C(Cl)Cl)s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 126.1 %

Procedure:
To a stirred solution of 2-(2,2-dichloroethenyl)-5-(4-methylthiophenyl)thiophene (1.2 g, 0.0040 mole) in methanol (50 mL) was added a solution of potassium peroxymonosulfate (1.2 g, 0.0020 mole) in water (50 mL). After stirring for one hour at room temperature, an additional 0.3 g of potassium peroxymonosulfate was added, and a second addition of 0.3 g was made after an additional hour. After a total of about four hours of stirring at room temperature the mixture was extracted, first with diethyl ether, followed by methylene chloride. The extracts were combined and dried over anhydrous magnesium sulfate. The dried extract was filtered, and the filtrate was evaporated under reduced pressure leaving a solid residue. This residue was dissolved in isopropyl alcohol (15 mL), and a solution of potassium peroxymonosulfate (0.5 g) dissolved in about 5 mL of water was added. The resultant mixture was heated on a steam bath for approximately one hour. The mixture was diluted with 400 mL of water and cooled to 0° C. for one hour. A solid formed and was collected by filtration. The filter cake was dissolved in methylene chloride, and the solution was dried over anhydrous magnesium sulfate. The dried solution was filtered, and the filtrate was evaporated under reduced pressure, leaving a solid residue. This residue was purified by column chromatography on silica gel, eluting first with petroleum ether, followed by ethyl acetate, to yield 0.8 g of 2-(2,2-dichloroethenyl)-5-(4-methylsulfinylphenyl)thiophene as a solid (mp 124°-126° C.) .
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)#[N:7].C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:1][CH2:2][CH2:3][CH2:4][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]#[N:7])=[CH:9][CH:10]=1
Reactant: BrCCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OCCCBr)cc1
Yield: 69 %

Procedure:
1,3-Dibromopropane (1.02 L, 10 mol) was added to a stirred suspension of p-cyanophenol (238 g, 2 mol), K2CO3 (276.4 g, 2 mol) in MeCN (2.7 L). The reaction mixture was refluxed for 4 h, filtered and concentrated. The residue was recrystallised from iso-propyl ether to give the sub-title compound in a 69% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.I[CH2:27][CH3:28]>O1CCCC1>[CH2:27]([N:16]1[C:17]2[C:12](=[N:11][CH:10]=[C:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:18]=2)[C:13]([OH:25])=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]1=[O:19])[CH3:28]
Reactant: CCI
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC)c1=O
Yield: 98.1 %

Procedure:
In a manner similar to that described in example 316 step 1, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (160 mg, 0.468 mmol), lithium (bis-trimethylsilyl)amide (0.94 mL of a 1 M solution in tetrahydrofuran, 0.940 mmol), and iodoethane (0.22 mL, 2.81 mmol) was prepared ethyl 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (170 mg, 95% yield) as a yellow oil. The product was carried on without further purification. 1H NMR (CDCl3) δ 8.37 (s, 1 H), 7.34 (s, 1 H), 7.10-7.05 (m, 2 H), 6.95-6.91 (m, 2 H), 4.39 (m, 2 H), 4.11 (m, 2 H), 4.06 (s, 2 H), 1.35 (m, 3 H), 1.15 (m, 3 H); MS m/z 393 (M+23).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[N:10]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:19]([CH2:22][C:23](=[O:25])[CH3:24])(=[O:21])[CH3:20]>C(O)(=O)C.Cl.O.C(O)C>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][N:10]=[C:22]([C:23](=[O:25])[CH3:24])[C:19](=[O:21])[CH3:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: O=N[O-]
Reactant: CC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(NN=C(C(C)=O)C(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
To a solution of 4-methoxyaniline (1000 mg, 8.13 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrochloride solution, sodium nitrite (673 mg, 9.76 mmol) in 4 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (2000 mg, 24.39 mmol) and acetylacetone (1057 mg, 10.57 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give 3-[(4-methoxyphenyl)hydrazono]pentane-2,4-dione (950 mg, 50%).
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=[O:23])[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](=[N:35]O)[NH2:34])=[CH:28][CH:27]=1>>[CH:1]1([C:6]([N:8]2[CH2:9][CH:10]([C:22]3[O:23][N:35]=[C:33]([CH2:32][C:29]4[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=4)[N:34]=3)[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:13]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Reactant: NC(Cc1ccc(F)cc1)=NO
Product: CCc1ccc(C2CC(c3nc(Cc4ccc(F)cc4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 37 mg (0.22 mmol, 1.1 eq.) of 2-(4-fluorophenyl)-N′-hydroxyethanimidamide were reacted according to the General Method 1. Yield: 22 mg (24% of theory)
Reaction SMILES: FC(F)(F)C(O)=O.N1([C:13]23[O:28][N:27]=[C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:14]2[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18]3)CCCC1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:28]1[C:13]2[CH2:18][CH2:17][NH:16][CH2:15][C:14]=2[C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:27]1
Reactant: CCOC(=O)C1=NOC2(N3CCCC3)CCN(C(=O)OC(C)(C)C)CC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1noc2c1CNCC2
Temperature: 0 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
Trifluoroacetic acid (6.67 ml, 89.9 mmol) was added at 0° C. to a solution of 5-tert-butyl 3-ethyl 7a-(pyrrolidin-1-yl)-3a,4,7,7a-tetrahydroisoxazolo[4,5-c]pyridine-3,5(6H)-dicarboxylate (5.5 g, 14.98 mmol) in DCM (100 ml), and the mixture was stirred for 16 hours under reflux. Cooling to 0° C. was then carried out and NaHCO3 solution was added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the crude product was carried out by column chromatography (silica gel, 16% methanol in ethyl acetate). Yield: 62% [Alternatively, ethyl 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-carboxylate A-06 can be synthesised as described in WO2006105945.]