Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[CH3:14][O:15][C:16]1[CH:24]=[C:23]([NH2:25])[C:22]([Cl:26])=[CH:21][C:17]=1[C:18]([OH:20])=O.[CH:27]1([CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[CH:27]1([CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([NH:40][C:18](=[O:20])[C:17]3[CH:21]=[C:22]([Cl:26])[C:23]([NH2:25])=[CH:24][C:16]=3[O:15][CH3:14])[CH2:36][CH2:35]2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: NC1CCN(CC2CCCCC2)CC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCCCC2)CC1
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
Triethylamine (5.6 ml; 0.04 moles) and ethyl chloroformate (3.84 ml; 0.04 moles) were added successively to a stirred suspension of 2-methoxy-4-amino-5-chlorobenzoic acid (8 g; 0.04 moles) in anhydrous tetrahydrofuran (300 ml) whilst maintaining the temperature beween -5° and -10° C. After stirring at this temperature for 0.5 hours, a solution of 1-cyclohexylmethyl-4-aminopiperidine (7.85 g; 0.04 moles) in anhydrous tetrahydrofuran (50 ml) was added, the temperature was maintained at -5° to -10° C. for 1 hour and then allowed overnight to reach room temperature. The solvent of the mixture was removed in vacuo, the residue poured into water, extracted with chloroform and the organic layer washed with water. The chloroformic solution was dried (Na2SO4) and the solvent removed in vacuo to give a solid which was triturated with a mixture of methanol and diethyl ether. N-(1-Cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide (8 g) was thus obtained.
Reaction SMILES: [NH:1]([C:5]1[C:22](=[O:23])[CH:21]=[CH:20][C@@:19]2([CH3:24])[C:6]=1[CH:7]=[CH:8][C@@H:9]1[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]1[CH2:11][CH2:12][C:13]2=[O:25])[C:2]([CH3:4])=[O:3].[OH:26]O.[OH-].[Na+]>CO.C(Cl)Cl>[NH:1]([C:5]1[C:22](=[O:23])[C@@H:21]2[O:26][CH:20]2[C@@:19]2([CH3:24])[C:6]=1[CH:7]=[CH:8][C@@H:9]1[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]1[CH2:11][CH2:12][C:13]2=[O:25])[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)NC1=C2C=C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)C=CC1=O
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)NC1=C2C=C[C@H]3[C@@H]4CCC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)C2O[C@H]2C1=O
Temperature: 0 °C
Reaction time: 120 h
Yield: 80 %

Procedure:
To an ice cold solution of 4-acetamino-androsta-1,4,6-triene-3,17-dione (3.384 g, 10 mmol) in methanol (50 ml) and CH2Cl2 (25 ml) are added gradually 35% H2O2 (4.5 ml) and 2N NaOH (1 ml). The mixture was allowed to stand at 0°-5° C. for 5 days. Then ice water was added, the mixture concentrated under vacuum to a small volume and the precipitate filtered off. Thus almost pure title compound was obtained (1.99 g). From the mother liquor 1.020 g of starting product was recovered. Therefore the yield is about 80% considering the recovery.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.CS[N:16]1[CH2:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[S:18](=[O:27])(=[O:26])[NH:17]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][N:16]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[S:18](=[O:26])(=[O:27])[NH:17]2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1CCCCN
Reactant: CSN1Cc2ccccc2S(=O)(=O)N1
Product: Cc1cc(Br)cnc1CCCCNN1Cc2ccccc2S(=O)(=O)N1

Procedure:
4-(5-Bromo-3-methylpyrid-2-yl)-butylamine (0.73 g) and 3-methylthiobenzothiadiazine-1,1-dioxide (0.68 g) were fused at 130°-140° C. for 3 hours. The product was crystallised from acetonitrile to yield 3-[4-(5-bromo-3-methylpyrid-2-yl)-butylamino]benzothiadiazine-1,1-dioxide m.p. 187°-8° C.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=3[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:33][CH2:34][CH2:35][C:36](=[O:37])[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=3[C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(CCCI)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(C2CCCCC2)C2(CCNCC2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccccc1CN1CN(C2CCCCC2)C2(CCN(CCCC(=O)c3ccccc3)CC2)C1=O
Yield: 65.5 %

Procedure:
tert-Butyl 2-((1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.30 g, 0.585 mmol), 4-iodobutyrophenone (0.17 g, 0.585 mmol), and potassium carbonate (0.12 g, 0.878 mmol) in N,N-dimethylformamide (8 mL) were stirred at 65° C. for 2 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.22 g, 65%); MS for C35H47N3O4 m/z 574 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C@@H:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[CH2:10][N:9]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(N(CC)CC)C>ClCCl>[CH3:14][O:13][C@H:11]1[CH2:10][N:9]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:8]([CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12]1
Reactant: CS(=O)(=O)Cl
Reactant: CO[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@@H]1C[C@@H](COS(C)(=O)=O)N(C(=O)OCc2ccccc2)C1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.175 mL, 2.26 mmol, 1.2 equiv) was added to a solution of (2S,4R)-2-(hydroxymethyl)-4-methoxy-1-pyrrolidinecarboxylate (3-3, 0.500 g, 1.88 mmol, 1 equiv) and triethylamine (0.394 mL, 2.83 mmol, 1.50 equiv) in dichloromethane (30 mL) at 0° C. The resulting mixture was warmed to 23° C. and stirred for 1 h. The reaction mixture was partitioned between saturated sodium bicarbonate solution and dichloromethane (2×40 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100% hexane initially, grading to 100% EtOAc) to provide benzyl (2S,4R)-4-methoxy-2-{[(methylsulfonyloxy]methyl}-1-pyrrolidinecarboxylate (3-4) as a light yellow oil. 1H NMR (300 MHz, CDCl3) major rotamer: δ7.37-7.25 (br m, 5H), 5.17 (d, 1H, J=11.8 Hz), 5.10 (d, 1H, J=11.8 Hz), 4.65 (dd, 1H, J=8.3, 3.8 Hz), 4.24 (br m, 2H), 3.95 (m, 1H), 3.68 (br d, 1H, J=12.0 Hz), 3.45 (dd, 1H, J=12.0, 4.4 Hz), 3.30 (s, 3H), 2.88 (s, 3H), 2.39 (m, 1H), 2.12 (m, 1H).
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][NH:17][C:16](=S)[C@H:15]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14][CH2:13]1>CO>[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][NH:17][C:16](=[N:2][NH2:3])[C@H:15]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14][CH2:13]1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=NN
Reaction time: 0.5 h

Procedure:
Hydrazine monohydrate (2.23 mL, 46.0 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-thioxoazepan-3-ylcarbamate (546 mg, 1.53 mmol) in methanol (25 mL). After 30 min, the mixture was concentrated under reduced pressure. Saturated aqueous NaHCO3 was added and the mixture was extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=355 (M+1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[OH:9][C:10]1[C:19]2[C:14](=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=[C:17]([CH3:20])[CH:18]=2)[N:13]=[CH:12][C:11]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>ClCCCl>[Br:1][CH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=1)[N:13]=[CH:12][C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]2[OH:9]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cc(C)cc2c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCCl
Product: CCOC(=O)c1cnc2c([N+](=O)[O-])cc(CBr)cc2c1O

Procedure:
N-Bromosuccinimide (3.52 g) is added to a solution of ethyl 4-hydroxy-6-methyl-8-nitro-3-quinolinecarboxylate (2.76 g) in 1,2 dichloroethane (250 mL). The refluxing solution is irradiated with a sun lamp (625 watt) for 20 min. The crude ethyl 6-bromomethyl-4-hydroxy-8-nitro-3-quinolinecarboxylate thus formed is reacted with morpholine (5 mL). After evaporation, the product is partitioned between ethyl acetate and water. Evaporation of the ethyl acetate gives a solid, which is dissolved in chloroform and is chromatographed on silica gel with 1% methanol/chloroform as the initial eluant. Elution of the column with 10% methanol/chloroform gives the title compound, which is crystallized from methanol. Physical characteristics: M.p. 214-216° C. 1H NMR (CDCl3) δ1.41, 2.50, 3.68, 3.74, 4.42, 8.69, 8.73, 8.78, 11.6. Anal. Found: C, 56.30; H, 5.32; N, 11.56.
Reaction SMILES: C1(S([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=2)[N:25]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[N:24]=[CH:23]4)=[N:16][CH:15]=[N:14]3)=O)C=CC=CC=1.[NH:37]1[CH2:43][CH:42]([OH:44])[CH2:41][NH:40][CH2:39][CH2:38]1>CS(C)=O.C(Cl)Cl>[F:36][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][N:25]1[C:26]2[C:22](=[CH:21][C:20]([NH:19][C:17]3[C:18]4=[C:10]([CH2:9][N:37]5[CH2:43][CH:42]([OH:44])[CH2:41][NH:40][CH2:39][CH2:38]5)[CH:11]=[CH:12][N:13]4[N:14]=[CH:15][N:16]=3)=[CH:28][CH:27]=2)[CH:23]=[N:24]1
Reactant: O=S(Cc1ccn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)c1ccccc1
Reactant: OC1CNCCNC1
Solvent: ClCCl
Solvent: CS(C)=O
Product: OC1CNCCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)C1
Temperature: 140 °C
Yield: 62.2 %

Procedure:
A mixture of (5-benzenesulfinylmethyl-pyrrolo[2,1-f][1,2,4]triazin-4-yl)-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (397 mg, 0.8 mmole) and [1,4]diazepan-6-ol (417 mg, 4.5 equiv, Saari et al., J. Org. Chem., 1971, 36, 1711) in dry DMSO (1.5 mL) in a sealed tube was heated at 140° C. for 11 hr. This was diluted with DCM (150 ml), washed with water and dried (Na2SO4). Removal of the solvent followed by radial chromatography (4 mm silica gel plate; gradient elution with DCM containing 0 to 3% of a 2N NH3 solution in MeOH) gave the title compound as a solid (242 mg, 62%), MS: 487 (M+H)+; HPLC Ret Time: 0.96 min (Xterra S7 3.0×50 mm S7 C18 column, 2 min gradient, 5 ml/min). The racemic material could be separated on a Chiralpak AD 4.6×250 mm column, eluting with 0.05% diethylamine in EtOH for 25 min with a flow rate of 0.7 mL/min) The S and R enantiomers had retention times of 16.20 and 18.90 min respectively. The R enantiomer was synthesized as outlined below.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29]Br)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:31]#[N:32].[Na+].[I-].[Na+].O>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][C:31]#[N:32])[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: [C-]#N
Reactant: Nc1ncnn2c(CCCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCc1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Temperature: 25 °C
Yield: 67.4 %

Procedure:
A solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (80 mg, 0.173 mmol), sodium cyanide (17 mg, 0.35 mmol, 2.0 eq.), and sodium iodide (2.6 mg, 0.017 mmol, 0.1 eq.) in anhydrous DMF (1.7 mL) was stirred at 100° C. for 16 h. The reaction mixture was cooled to rt and poured into water. The aqueous layer was extracted with 3×25 mL of EtOAc and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified via preparative HPLC. The product containing fractions were collected, and the TFA from the eluent was removed via filtration through an acidic resin followed by washing with acetonitrile. The product was then eluted with 2M NH3 in MeOH. The filtrate was concentrated and the residue was crystallized from DCM-ether to provide the title compound (47.5 mg, 67%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8.54 (s, 1H), 7.91 (s, 1H), 7.80 (d, 1H), 7.59 (s, 1H), 7.36 to 7.30 (m, 5H), 7.15 (dd, 1H), 6.65 (s, 1H), 5.65 (s, 2H), 3.00 (t, 2H), 2.59 (t, 2H), 2.04 to 1.96 (m, 2H); ES-MS m/z 408.3 [M+H]+, RT (min) 2.95.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[I:16]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[NH2:1][C:2]1[C:11]([I:16])=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(C(F)(F)F)cc(I)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
A solution of methyl 2-amino-5-(trifluoromethyl)benzoate (0.59 g, 2.7 mmoles) in trifluoroacetic acid (5 ml) was treated with N-iodosuccinimide (0.68 g, 3.0 mmoles) and stirred at ambient temperature for 18 h. The mixture was evaporated to dryness and the residue treated with water (25 ml) and basified with potassium carbonate then extracted with dichloromethane (25 ml). The organic phase was then washed with 10% sodium metabisulphite solution (25 ml), separated and dried over sodium sulphate, filtered and evaporated to dryness. The residue was chromatographed on silica gel eluting with an ethyl acetate/isohexane gradient. This gave the title compound 2 as a white solid (0.633 g, 68%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][NH:17][C:18](=[O:22])[C:19]([OH:21])=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C.[NH2:43][CH2:44][C:45]1[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=1>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][NH:17][C:18]([C:19]([NH:43][CH2:44][C:45]3[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=3)=[O:21])=[O:22])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCc1ccncc1
Reactant: COc1ccc(CCNC(=O)C(=O)O)cc1OC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Product: COc1ccc(CCNC(=O)C(=O)NCc2ccncc2)cc1OC1CCCC1

Procedure:
Using a solution of N-[2-(3-cyclopentyloxy-4-methoxyphenyl)ethyl]oxamic acid (284 mg, 0.92 mmol), EDAC (220 mg, 1.16 mmol) and dimethylaminopyridine (140, 1.25 mmol) and 4-aminomethyl pyridine in an analogous method to that of Example 12 above provided the title compound yielding (126 mg, 34%): m.p. 129°-131° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5](C)[N:6]=1.[Li+].CC([N-]C(C)C)C.Cl[CH2:20][C:21]1[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23][O:24][C:25]=1[CH3:26]>C1COCC1>[CH3:26][C:25]1[O:24][N:23]=[C:22]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]=1[CH2:20][CH2:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[CH:5][N:6]=1
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: Cc1onc(-c2ccccc2)c1CCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1CCc1ncc(C(=O)O)s1
Temperature: 25 °C
Yield: 63 %

Procedure:
To a stirred solution of 2,4-dimethyl-thiazole-5-carboxylic acid (250 mg, 1.59 mmol) in THF (16 mL) at −78° C. and under argon was added LDA (1.6 mL of a 2M solution in THF, 3.2 mmol) dropwise. After 1.5 h a solution of 4-chloromethyl-5-methyl-3-phenyl-isoxazole (330 mg, 1.59 mmol) in THF (4 mL) was added dropwise. After 1 h the reaction mixture was quenched with HCl (1N, 10 mL) then warmed to room temperature and extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) gave the title compound (315 mg, 60%) as a light yellow gum. MS: m/e=329.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:27])[C:5](=[N:10][NH:11][C:12]1[C:25]([F:26])=[CH:24][C:15]2[O:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[O:19][C:14]=2[CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:28]OC(OC)N(C)C>>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[N:10][N:11]([C:12]2[C:25]([F:26])=[CH:24][C:15]3[O:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[O:19][C:14]=3[CH:13]=2)[CH:28]=1
Reactant: COC(OC)N(C)C
Reactant: COCC(=O)C(=NNc1cc2c(cc1F)OC(F)(F)C(F)(F)O2)C(=O)OC
Product: COC(=O)c1nn(-c2cc3c(cc2F)OC(F)(F)C(F)(F)O3)cc(OC)c1=O
Yield: 37 %

Procedure:
A mixture of methyl 4-methoxy-3-oxo-2-[(2,2,3,3,7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)hydrazono]butanoate (6.84 g, 17.2 mmol) in N,N-dimethylformamide dimethyl acetal (68 mL) was heated to reflux for 2.5 h. The mixture was concentrated in vacuo, diluted with brine, extracted with EtOAc, dried over MgSO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100 and EtOAc/MeOH=100/0 to 70/30) and on basic silica gel (hexane/EtOAc=80/20 to 0/100 and EtOAc/MeOH=100/0 to 70/30) to yield the title compound (2.58 g, 37% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.79 (3H, s), 3.83 (3H, s), 8.01 (1H, d, J=10.2 Hz), 8.16 (1H, d, J=7.2 Hz), 8.58 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>[OH-].[Na+]>[Cl:1][C:2]1[N:3]=[N:4][C:5]([O:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc(Oc2ccccc2)nn1
Temperature: 25 °C

Procedure:
3,6-Dichloropyridazine (Aldrich, 4.47 g, 30 mmol) in NaOH (10%, 20 mL) was treated with phenol (Aldrich, 1.88 g, 20 mmol) at 100° C. for 15 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (2×50 mL). The extracts were combined and concentrated under reduced pressure. The title compound was purified by chromatography (SiO2, Hexanes: ethyl acetate=80: 20, Rf. 0.5) as a solid (3.8 g, yield, 92%). 1H NMR (CDCl3, 300 MHz) δ 7.11–7.29 (m, 3H), 7.38–7.55 (m, 4H) ppm. MS (DCl/NH3) m/z 207 (M+H)+, 209 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C=C(Br)C(F)(F)F
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 25.0 g of 3,5-dichlorophenyl boronic acid in 200 mL of tetrahydrofuran and 100 mL of water, 27.5 g of 2-bromo-3,3,3-trifluoropropene, 38.0 g of potassium carbonate and 1.84 g of dichlorobis(triphenylphosphine) palladium (II) were added, and the resultant reaction mixture was stirred while heating the mixture to reflux for 3 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature and 500 mL of ice water was added to the reaction mixture, followed by extracting the reaction mixture with ethyl acetate (500 mL×1). Subsequently, the organic phase was washed with water and was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with hexane to obtain 25.7 g of the objective substance as a colorless oily substance.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.Cl[CH2:32][C:33](=[O:40])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].Cl>O1CCCC1.C(O)(C)C>[CH2:38]([O:37][C:35]([CH2:34][C:33]([CH2:32][O:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:10][CH2:11]1)=[O:40])=[O:36])[CH3:39]
Reactant: OCCN1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOC(=O)CC(=O)COCCN1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.9 g of Sodium hydride was added to 15 ml of dry tetrahydrofuran stirring at room temperature under nitrogen. A solution of 1-(2-hydroxyethyl)-4-triphenylmethylpiperazine in 5 ml of dry tetrahydrofuran was added dropwise and then stirred a further 1 hour after the addition was complete. Finally, a solution of 1.8 g of ethyl 4-chloroacetoacetate in 5 ml of dry tetrahydrofuran was added over 1 hour and the mixture stirred at room temperature for 18 hours. 5 Drops of isopropanol were added to the mixture which was then poured onto 100 g of ice and carefully neutralised with concentrated hydrochloric acid. After extraction with ethyl acetate, the residual oil was dissolved in acetonitrile, washed three times with petroleum ether (40°-60°) and evaporated to give 2.6 g of 1-[2-(ethoxycarbonylacetylmethoxy)ethyl]-4-triphenylmethylpiperazine as an orange-red oil, used directly.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:12][C@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1O>>[CH3:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Reactant: C[C@H]1CCCC[C@H]1O
Product: CCOC(=O)/C(=N\O[C@@H]1CCCC[C@H]1C)C(C)=O

Procedure:
Ethvl (Z)-2-hydroxyimino-3-oxobutyrate (1.59 g) was alkylated with cis-2-methylcyclohexan-1-ol (1.71 g) as described in Example 4, method 3. The pure title compound was otained as a pale yellow oil (0.506 g). (Found: M+, 256.1552. C13H21NO4 requires M 256.1549); νmax (film) 1745, 1695 and 1595 cm-1 ; δH (CDCl3) 1.02 (3H, d, J 6 Hz), 1.35 (3H, t, J 7 Hz), ca 1.2-2.3 (9H, m), 2.40 (3H, s), 3.95 (1H, m) and 4.42 (2H, q, J 7 Hz).