Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([O:18]CCCC)=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOC(=O)[C@H]1CC[C@@H](CNC(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.9 %

Procedure:
To a solution of crude butyl cis-4-{[(tert-butoxycarbonyl)amino]methyl}cyclohexanecarboxylate (28.4 g, approximately 79.3 mmol) in methanol (200 ml) was added dropwise over five minutes 2N sodium hydroxide solution (400 mmol). The mixture was stirred 18 hours at ambient temperature under nitrogen. The mixture was concentrated under reduced pressure to remove methanol. To the aqueous residue was added methyl orange (1 mg) and 3N hydrochloric acid was added to adjust the mixture to pH 4. The mixture was extracted with ethyl acetate (3×200 ml). The extract was washed with water (100 ml), and brine (100 ml), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give cis-4-{[(tert-butoxycarbonyl)amino]methyl}cyclohexanecarboxylic acid (18.76 g, 92%) as an off-white solid. MS: 258.3 (M+1).
Reaction SMILES: C([O:6][C@@H:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][Cl:9])(=O)CCC.Cl>>[Cl:9][CH2:8][C@H:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:6]
Reactant: CCCC(=O)O[C@H](CCl)c1ccccc1
Agent: Cl
Product: O[C@H](CCl)c1ccccc1
Yield: 23 %

Procedure:
Sixteen grammes of enzyme (produced by Amano pharmaceutical Co. Ltd., Lipase "Amano CES"), 7.9g (0.05mol) of (R,S)-2-chloro-1-phenylethanol and 17.8g (0.059mol) of tributyrin were charged into three-necked flask and reacted with stirring for 16days at 35° C. After the reaction was stopped, the enzyme was removed by filtration, the filtrate was concentrated by distillation under reduced pressure, and the desired compounds were isolated by column chromatography. As the result, 4.0g of (R)-2-chloro-1-phenylethanol (yield: 50%, 58% ee) and (S)-2-chloro-1-phenylethyl butyrate were obtained. The obtained (S)-2-chloro-1-phenylethyl butyrate was hydrolyzed in an acidic solution of hydro chloric acid, and (S)-2-chloro-1-phenylethanol (yield: 23%, >99% ee) was obtained. Optical purity of the obtained compounds was determined by HPLC of optical resolution.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([C:22]([O-])=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.C(NCC)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[CH2:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CCCCNC(=O)OCc1ccccc1)C(=O)[O-]
Agent: C=O
Solvent: CCNCC
Solvent: CCOC(C)=O
Product: C=C(CCCCNC(=O)OCc1ccccc1)C(=O)OCC
Temperature: 0 °C
Yield: 61.4 %

Procedure:
The monoethyl 2-(4-benzyloxycarbonylaminobutyl)malonate (3.03 g) obtained in the above step (d) was cooled to 0° C. and added with 36% formaldehyde solution (3 ml) and then with diethylamine (3 ml), and then the mixture was stirred at room temperature for 19.5 hours. Ethyl acetate was added to the reaction system to extract the organic substances, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (150 g, hexzane:acetone=5:1) to obtain ethyl 2-(4-benzyloxycarbonylaminobutyl)acrylate (1.69 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)[N:4]=1.N1(C2C=C[C:25]([CH:26]=[O:27])=CC=2)C=CC=N1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[CH:25][CH:26]=[O:27])=[CH:11][CH:10]=2)[N:4]=1
Reactant: COc1ccnc(-c2ccc(C=O)cc2)n1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: COc1ccnc(-c2ccc(C=CC=O)cc2)n1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-methoxy-2-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 13) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 241 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]#[C:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.FC(F)(F)C(O)=O.N>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]#[C:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(C#Cc3ccccc3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C#Cc5ccccc5)c34)n(-c3ccccc3)c(=O)c12
Yield: 144.2 %

Procedure:
(S)-5-Methyl-3-phenyl-2-(1-((5-(phenylethynyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (9 mg, 0.01 mmol) was treated with trifluoroacetic acid (180 μl, 2.34 mmol) and a solution of ammonia (7N in methanol, 180 μl, 1.26 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 100% n-hexane-ethyl acetate) to obtain 7 mg (98% yield) of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[N:10][O:11][C:7]=2[C:6]([OH:20])=[C:5]([C:21](OCC)=[O:22])[N:4]=1)#[N:2].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].Cl>C(=O)(O)[O-].[Na+]>[C:1]([C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[N:10][O:11][C:7]=2[C:6]([OH:20])=[C:5]([C:21]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:22])[N:4]=1)#[N:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(-c3ccc(OC)cc3)noc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Product: COc1ccc(-c2noc3c(O)c(C(=O)NCC(=O)O)nc(C#N)c23)cc1
Temperature: 25 °C
Yield: 71.6 %

Procedure:
Ethyl 4-cyano-7-hydroxy-3-(4-methoxyphenyl)isoxazolo[4,5-c]pyridine-6-carboxylate (86 mg, 0.254 mmol) and glycine (381 mg, 5.07 mmol) were added to sodium methoxide solution (7.6 mL, 3.80 mmol, 0.5 M in MeOH) and the mixture was refluxed for 3 days. The mixture was cooled to room temperature and 0.25 M hydrochloric acid was added until pH was 3. The precipitate was isolated by filtration and dried under vacuum to give 75 mg of crude solid. The solid was dissolved in 200 mL of saturated sodium bicarbonate solution and washed with EtOAc. The aqueous layer was acidified to pH 3 with concentrated hydrochloric acid and the precipitate was collected by filtration. The solid was dried under vacuum to afford 67 mg of the title compound. MS: (−) m/z 367.34 (M−1).
Reaction SMILES: [F:1][C:2]([F:17])([C:6]1([OH:16])[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[C:3]([OH:5])=O.CCN(CC)CC.ClC(OCC)=O.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:48]=[CH:49][C:50]=1[O:51][CH3:52])[O:36][CH2:37][C:38]1[O:42][C:41]([C@@H:43]2[CH2:47][CH2:46][CH2:45][NH:44]2)=[N:40][CH:39]=1>C1COCC1.O>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:48]=[CH:49][C:50]=1[O:51][CH3:52])[O:36][CH2:37][C:38]1[O:42][C:41]([C@@H:43]2[CH2:47][CH2:46][CH2:45][N:44]2[C:3](=[O:5])[C:2]([F:1])([F:17])[C:6]2([OH:16])[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7]2)=[N:40][CH:39]=1
Reactant: COc1ccc(OCc2cnc([C@@H]3CCCN3)o2)cc1OC
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)O)C1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(OCc2cnc([C@@H]3CCCN3C(=O)C(F)(F)C3(O)CC(C)(C)CC(C)(C)C3)o2)cc1OC
Yield: 78.6 %

Procedure:
To a solution of 2,2-difluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexyl)acetic acid (0.075 g) and Et3N (0.038 ml) in THF (1 ml), ethyl chloroformate (0.028 g) was added over an ice bath, followed by stirring at the same temperature for an hour. To the reaction mixture, a solution of (S)-5-((3,4-dimethoxyphenoxy)methyl)-2-(pyrrolidin-2-yl)oxazole (0.075 g) in THF (1 ml) was added over an ice bath, followed by stirring at room temperature for 15 hours. After adding water and performing extraction with AcOEt, the organic layer was washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by silica gel chromatography (AcOEt/hexane) to give the titled compound (0.104 g, colorless amorphous.)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][C@H:33]([CH3:35])[O:32][C@H:31]([CH3:36])[CH2:30]5)=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].CO.Cl>O.O1CCCC1>[CH3:35][C@H:33]1[O:32][C@@H:31]([CH3:36])[CH2:30][N:29]([C:26]2[CH:25]=[CH:24][C:23]([N:20]3[CH2:19][CH2:18][N:17]([C:14]4[CH:15]=[CH:16][C:11]([C:8]5[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=5)=[CH:12][CH:13]=4)[CH2:22][CH2:21]3)=[CH:28][CH:27]=2)[CH2:34]1
Reactant: COC(=O)c1ccc(-c2ccc(N3CCN(c4ccc(N5C[C@@H](C)O[C@@H](C)C5)cc4)CC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@@H]1CN(c2ccc(N3CCN(c4ccc(-c5ccc(C(=O)O)cc5)cc4)CC3)cc2)C[C@H](C)O1
Temperature: 25 °C
Yield: 102.4 %

Procedure:
A mixture of 4′-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]-1,1′-biphenyl-4-carboxylic acid methyl ester (3.70 g) and 1.0 mol/l sodium hydroxide solution (30 ml) in a mixed solvent of methanol (75 ml) and tetrahydrofuran (185 ml) was refluxed for 15.5 hours. After cooling to ambient temperature, the reaction mixture was poured into cold water, and the mixture was adjusted to pH 2 with 1.0 mol/l hydrochloric acid. The resulting precipitates were filtered, washed with water and diisopropyl ether and dried to give 4′-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]-1,1′-biphenyl-4-carboxylic acid (3.68 g).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=2)=[C:7]([Br:24])[CH:6]=1.[C:26]1([CH3:35])[CH:31]=[CH:30][CH:29]=[C:28]([C:32](Cl)=[O:33])[CH:27]=1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:24][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:2])=[O:25])[CH:10]=[C:9]([Br:11])[C:8]=1[O:12][C:13]1[CH:14]=[C:15]([CH:21]([CH3:22])[CH3:23])[C:16]([O:19][CH2:20][CH2:6][C:5]([CH3:10])=[CH2:4])=[CH:17][C:18]=1[C:32](=[O:33])[C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH3:35])[CH:27]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(OC)c(C(C)C)c2)c(Br)c1
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: C=C(C)CCOc1cc(C(=O)c2cccc(C)c2)c(Oc2c(Br)cc(CC(=O)O)cc2Br)cc1C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
TiCl4 (25.2 mL, 229 mmol) was added dropwise to a solution of 3,5-dibromo-4-(3-isopropyl-4 -methoxyphenoxy)phenylacetic acid methyl ester (31.0 g, 65.6 mmol) and m-toluoyl-chloride (35.4 g, 229 mmol) in CH2Cl2 (310 mL) at 0° C. The mixture was stirred at room temperature for 3 d, cooled to 0 C, and quenched with ice (300 g). The layers were separated and the aqueous phase was extracted with EtOAc (3×100 mL). The combined organic phases were washed with NaHCO3 (aq., sat, 3×100 mL), concentrated and purified by chromatography on silica gel to give 18.5 9 (49%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[CH3:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][O:19][NH2:20]>>[CH3:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][O:19]/[N:20]=[C:10](/[C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=1)\[CH3:11]
Reactant: COc1ccc(C(C)=O)cc1O
Reactant: Cc1cccc(CON)c1
Agent: Cl
Product: COc1ccc(/C(C)=N/OCc2cccc(C)c2)cc1O
Yield: 90.8 %

Procedure:
Acetophenone 12 (50 mg, 0.301 mmol) was condensed with O-(3-methylbenzyl)hydroxylamine hydrochloride (28) (57 mg, 0.328 mmol) according to the general procedure II-B defined above. After being heated for 15 h the reaction mixture was cooled and the solvent removed under reduced pressure. The ensuing residue was dissolved in CH2Cl2 (15 mL), washed with H2O (2×10 mL) then dried (MgSO4), filtered and concentrated under reduced pressure. The oil thus obtained was subjected to flash chromatography (1:19 v/v ethyl acetate/hexane elution) to afford the title compound CP30264 (78 mg, 91%) as a pale-orange oil, Rf 0.6 in 1:1 v/v ethyl acetate/hexane.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:28][CH3:29].O>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:28][CH3:29])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: CCI
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.5 %

Procedure:
To a stirred solution of 1.0 g (0.0033 mole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20) in 10 mL of dimethylformamide was added 3.23 g (0.0099 mole) of cesium carbonate followed by 0.8 mL (0.0099 mole) of iodoethane. The mixture was stirred at room temperature for 18 hours, then water was added. After 15 minutes, the mixture was extracted with ethyl acetate. The organic layer was washed with water, 5% aqueous sodium metabisulfite solution and then brine. The aqueous layers were reextracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexanes-dichloromethane to give 0.90 g of 2-chloro-9-cyclopentyl-5-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-138) as white crystals.
Reaction SMILES: [C:1]([C:4]([C:18]([O:20][CH3:21])=[O:19])([CH2:13][C:14]#[C:15][CH2:16][CH3:17])[CH:5]([CH:11]=O)[CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]>C1C=CC=CC=1.C(O)(=O)C.N1CCCCC1>[CH3:21][O:20][C:18]([C:4]1([CH2:13][C:14]#[C:15][CH2:16][CH3:17])[C:1](=[O:3])[CH:2]=[CH:11][CH:5]1[CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:19]
Reactant: CCC#CCC(C(C)=O)(C(=O)OC)C(C=O)CC(=O)OC
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CCC#CCC1(C(=O)OC)C(=O)C=CC1CC(=O)OC

Procedure:
The compound (3) (500 mg) obtained above is dissolved in 200 ml of benzene containing 1 ml of acetic acid and 1 ml of piperidine, and the solution is refluxed for 6 hours. On completion of the reaction, the solvent is removed and the residue dissolved in ethyl acetate. The solution is washed with 10% hydrochloric acid and an aqueous solution of sodium bicarbonate and then dried. The product is concentrated, and the residue purified by a silica gel column, giving 5-methoxycarbonyl-4-methoxycarbonylmethyl-5-(2-pentynyl)-2-cyclopentenone (compound (1-a), R1 =R2 =CH3) in a yield of 81%, b.p. 110°-115° C./0.15 mm Hg.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH2:4][CH2:3]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:17]([CH3:16])(=[O:19])=[O:18])[CH2:8]2)[CH2:6][CH2:7]1
Reactant: CN1CCC2(CC1)CNc1ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCC2(CC1)CN(S(C)(=O)=O)c1ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
Dissolve 1,2-dihydro-1'-methyl-spiro[3H-indole-3,4'-piperidine] (3.0 g, 14.8 mmoles) in dry CH2Cl2 (25 ml) and cool under N2 in an ice bath. Add, dropwise, methane sulfonyl chloride (1.5 ml, 19.3 mmoles), followed by ethyl diisopropyl amine (5.0 ml, 28.7 mmoles). Warm to room temperature and stir overnight. Dilute the solution to 100 ml with CH2Cl2. Wash the solution with saturated aqueous NaHCO3 (4×25 ml), then with water. Dry solution with anhydrous Na2SO4, then remove the solvent using reduced pressure. Purify the resulting reaction mixture by flash chromatography (SiO2) using 5% MeOH(NH3)/EtOAc as eluent. Yield: 3.37 g (81%) of the title compound.
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][CH2:6][C:5](=[O:8])[C:4]([I:9])=[CH:3]1.[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1([F:10])[CH2:7][CH2:6][C:5]2([O:13][CH2:12][CH2:11][O:8]2)[C:4]([I:9])=[CH:3]1
Reactant: OCCO
Reactant: O=C1CCC(F)(F)C=C1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: FC1(F)C=C(I)C2(CC1)OCCO2

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 67a by using the 4,4-difluoro-2-iodocyclohex-2-en-1-one (1.46 g, 5.66 mmol) prepared in Example 88c, ethylene glycol (750 mg, 12.1 mmol), p-toluenesulfonic acid hydrate (60 mg, 0.31 mmol) and benzene (30 mL), to yield a mixture of the title compound and a by-product.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N-].C(=O)([O-])[O-].[K+].[K+]>CCOCC>[CH2:24]([O:23][C:21]([CH:20]1[C:14](=[O:17])[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15]1)=[O:22])[CH3:25]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)CCC1=O
Temperature: 25 °C

Procedure:
To 1.0 g (4.28 mmol) 4-oxo-piperidine-1-carboxylic acid benzyl ester in 5 mL anhydrous ether maintained between −25° C. and −30° C. were added, over 20 minutes, solutions of 0.7 mL (5.56 mmol) BF3Et2O in 1.5 mL anhydrous ether, followed by 0.67 mL (6.42 mmol) ethyl diazoacetate in 1.5 mL anhydrous ether, and the reaction was maintained between −25° C. and −30° C. for 1 hour. The mixture was allowed to warm up to room temperature, 10 mL 30% potassium carbonate solution was added and the mixture extracted with EtOAc (3×15 mL), the organic layers were combined and dried with MgSO4. After filtration and evaporation of the solvent the product was purified by flash column chromatography (silica, hexane/EtOAc 9:1 to 8:2).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.S(Cl)([Cl:16])=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(Br)cc1[N+](=O)[O-]

Procedure:
4-Bromo-2-nitrobenzoic acid piperidine amide. A suspension of 4-bromo-2-nitrobenzoic acid (0.60 g, 2.44 mmol) in thionyl chloride (8 mL) was heated to reflux for 2 h. The reaction mixture became homogeneous. The mixture was cooled and concentrated in vacuo to give 4-bromo-2-nitrobenzoyl chloride as a white solid, which was used immediately in the following reaction. 1H NMR (400 MHz, CDCl3): 8.20 (d, J=1.9 Hz, 1H), 7.92 (dd, J=8.2, 1.9 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H). To a solution of 4-bromo-2-nitrobenzoyl chloride (2.44 mmol) in DCM (15 mL) at ambient temperature was added piperidine (1.2 mL, 12.2 mmol). The reaction mixture was stirred for 3 h then poured into water and extracted with DCM (2×). The combined organic extracts were washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc) to afford the title amide as a white solid (0.52 g, 76%). MS (ESI): m/z 313 [M+H]+. 1H NMR (400 MHz, CDCl3): (rotameric broadening) 8.33 (d, J=1.9 Hz, 1H), 7.82 (dd, J=8.1, 1.9 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H), 3.82–3.65 (bm, 2H), 3.16 (t, J=5.6 Hz, 2H), 1.90–1.35 (bm, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[N:10]=[C:11]([C:30]2[O:34][N:33]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH2:41][Cl:42])=[CH:37][CH:36]=3)[CH:31]=2)[C:12]([N:15](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:13][CH:14]=1>ClCCl>[Br:8][C:9]1[N:10]=[C:11]([C:30]2[O:34][N:33]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH2:41][Cl:42])=[CH:37][CH:36]=3)[CH:31]=2)[C:12]([NH2:15])=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccc(CCl)cc2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(Br)nc1-c1cc(-c2ccc(CCl)cc2)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Trifluoroacetic Acid (2.500 mL) was added to a solution of tert-butyl N-[5-bromo-3-[3-[4-(chloromethyl)phenyl]isoxazol-5-yl]pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (500 mg, 0.8836 mmol) in dichloromethane (20.00 mL) and the mixture was stirred at ambient temperature for 10 minutes. The reaction mixture was concentrated in vacuo to give 5-bromo-3-[3-[4-(chloromethyl)phenyl]isoxazol-5-yl]pyrazin-2-amine (323.1 mg, assumed 100% yield) which was used as such in next step. LC/MS m/z 365.4 [M−H]− Step 2: 5-bromo-3-[3-[4-(chloromethyl)phenyl]isoxazol-5-yl]pyrazin-2-amine was dissolved in ethanol, methanamine in ethanol (2.495 g, 3.300 mL, 26.51 mmol) was added and the mixture was stirred at 70° C. in a microwave. The reaction mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. Combined organic extract was dried (MgSO4) and concentrated in vacuo yielding 5-bromo-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine as an oil that was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[O:18]=[C:19]1[C:28]2[C:23]3[C:24](=[CH:29][CH:30]=[CH:31][C:22]=3[C:21](=[O:32])[N:20]1[CH2:33][CH2:34][NH2:35])[CH:25]=[CH:26][CH:27]=2>>[O:18]=[C:19]1[C:28]2[C:23]3[C:24](=[CH:29][CH:30]=[CH:31][C:22]=3[C:21](=[O:32])[N:20]1[CH2:33][CH2:34][NH:35][C:9](=[O:11])[CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH:25]=[CH:26][CH:27]=2
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCN1C(=O)c2cccc3cccc(c23)C1=O
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCN1C(=O)c2cccc3cccc(c23)C1=O

Procedure:
Batch size: 7.5 g (50.4 mmol) 3-(3-pyridyl)-acrylic acid, 17.4 g (137.4 mmol) oxalyl chloride and 11.0 g (45.8 mmol) 2-(1,3-dioxo-1H, 3H-benzo[de]isoquinolin-2-yl)-ethylamine.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[CH:20]=[CH2:21])[C:14](Cl)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:22][C:23]1[CH:34]=[CH:33][C:26]([C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])=[CH:25][CH:24]=1>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[CH:20]=[CH2:21])[C:14]([O:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])=[CH:33][CH:34]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C=CCOC(=O)c1ccc(O)cc1
Reactant: C=Cc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Product: C=CCOC(=O)c1ccc(OC(=O)c2ccc(C=C)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Yield: 70.3 %

Procedure:
In a manner analogous to Example 9(e) by reacting 1.35 g (4.5 mmoles) of 3-(1-adamantyl)-4-vinylbenzoyl chloride with 800 mg (4.5 mmoles) of allyl 4-hydroxybenzoate, 1.4 g (70% yield) of the expected ester in the form of a colorless oil are obtained.