Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCCCCC.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1>[C:4]1([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][C:17]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 42 %

Procedure:
0.56 g (6 mmol) of 4-bromotriphenylamine, 0.35 g (0.6 mmol) of bis(dibenzylideneacetone)palladium(0), and 0.58 g (6 mmol) of sodium-tert-butoxide were put into a 100 mL three neck flask, and 5 mL of toluene was added thereto. After nitrogen was substituted for the content of the flask, 0.56 g (6 mmol) of aniline and 0.37 mL (1.8 mmol) of a hexane solution (10 wt %) of tri-tert-butylphosphine were added. This mixture was stirred for 5 hours at 80° C. to be reacted. After the reaction, the reaction was completed by adding a saturated saline solution to the reaction mixture, and an aqueous layer was extracted by approximately 100 mL of ethyl acetate to be separated from an organic layer. The organic layer was dried with magnesium sulfate and filtered. A solid that was obtained by concentrating the filtrate was purified by silica column chromatography, whereby 0.24 g of a light yellow powder solid of DPA that is an object was obtained in the yield of 42% (Synthesis Scheme (i-2)). For the column purification, a mixed solvent of ethyl acetate:hexane=1:20 was used as a developing solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([OH:21])=[CH:13][CH:12]=1.CC(C)([O-])C.[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([O:21][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([NH2:10])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(O)c2ccccc12
Reactant: Fc1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1ccc(Oc2ccnc(Cl)c2)c2ccccc12
Temperature: 25 °C
Yield: 98.4 %

Procedure:
To a stirred solution of 2-chloro-4-fluoropyridine (1.26 g, 9.58 mmol) and 4-amino-1-naphthol hydrochloride (750 mg, 3.83 mmol) in NMP (40 mL) at −20° C. was added potassium tert-butoxide (1.29 g, 11.50 mmol) and the reaction mixture then warmed to RT for 2.5 hr. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL and 2×80 mL) and the combined organic extracts were washed with brine (150 mL), dried and evaporated in vacuo. The crude product was subjected to SCX capture and release and the volatiles were removed in vacuo to give 4-(2-chloropyridin-4-yloxy)naphthalen-1-amine as a brown solid (1.02 g, 92%): m/z 271 (M+H)+ (ES+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>S(Cl)(Cl)=O>[CH2:8]([O:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][Br:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)CCCBr
Reactant: OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCCBr)OCc1ccccc1
Temperature: -50 °C
Reaction time: 4 h

Procedure:
4-bromobutyric acid (10.6 g, 60 mmole) was dissolved in thionyl chloride (20 mml), and the reaction was kept for 4 hr. The solution was evaporated and coevaporated with toluene several times. The residue was redissolved in dichloromethane (120 ml), and then benzyl alcohol (4.14 ml, 40 mmole) was added. The solution was cooled down to −50° C. and triethylamine (10 ml, 72 mmole) was added. The reaction mixture was slowly warmed to room temperature. After 3 hr, the reaction mixture was poured into sodium bicarbonate aqueous solution and the organic phase was washed with water and dried, giving the titled product, 6.8 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.[C:30]([N:33]1[CH2:40][CH:39]([OH:41])[CH2:38][C@H:34]1[C:35](O)=[O:36])(=[O:32])[CH3:31].CN1CCOCC1.ClC(OC)=O.O=C1N=CC=CC1C(O)=O>ClCCl.C(O)(=O)C.C(O)(C)C>[C:30]([N:33]1[CH2:40][CH:39]([OH:41])[CH2:38][C@H:34]1[C:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)=[O:36])(=[O:32])[CH3:31]
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: CC(=O)N1CC(O)C[C@H]1C(=O)O
Agent: COC(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: O=C(O)C1C=CC=NC1=O
Solvent: CN1CCOCC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)N1CC(O)C[C@H]1C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
A suspension of 40.0 g (0.173 mol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 72.1 ml (0.517 mol) of triethylamine, and 2800 ml of dichloromethane is stirred at room temperature and 67.8 ml (0.52 mol) of chlorotrimethylsilane is added. The mixture is stirred at room temperature until the solid is almost completely dissolved. A suspension of 63 g (0.362 mol) of N-acetyl-4-hydroxy-L-proline in 650 ml of dichloromethane is cooled to -10° to -15° and 41 ml (0.363 mol) of N-methylmorpholine is added followed by 28.3 ml (0.363 mol) of methyl chloroformate. The reaction is stirred at -15° to -10° for 25 minutes. The reaction temperature is then lowered below -20° and the oxonicotinic acid solution is added in aliquots keeping the temperature below -5°. When the addition is complete, the reaction is stirred in an ice bath overnight, allowing the bath to come to room temperature. The reaction is treated with 30 ml of isopropanol and 30 ml of glacial acetic acid and the resulting mixture is stirred for 10 min at room temperature. The reaction is concentrated and filtered to give 50.1 g of 6-[4-(N-acetyl-4-hydroxy-L-prolylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid [α]D23 -60.5° (cl, pH 7).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[C:4]([NH2:16])[CH:3]=1.[CH3:17][C:18]([CH3:20])=O.[BH4-].S(=O)(=O)(O)O>O>[CH:18]([NH:16][C:4]1[CH:3]=[C:2]([CH3:1])[CH:15]=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])([CH3:20])[CH3:17]
Reactant: Cc1ccc(C(=O)c2ccccc2)c(N)c1
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: O
Product: Cc1ccc(C(=O)c2ccccc2)c(NC(C)C)c1
Reaction time: 1 h

Procedure:
Examples 1-19 as recorded in the following Table I represent trials in which the amount of 4-methyl-2-aminobenzophenone (a compound III in amount of 21.1 grs. or 0.1 mol) is held constant and the amount of other reaction system components including acetone (the compound III), borohydride (sodium borohydride), acid (sulfuric acid) and water are varied. In these examples, the reaction system is maintained at 20°-25° C. throughout the reaction and the rate of addition of the borohydride is controlled accordingly, such addition requiring in most cases about 60 minutes, after which the reaction system is stirred for an additional 60 minutes, followed by filtering. The filtrate is concentrated and the residue dissolved in about 88 mls. of heptane and the resulting solution extracted first with 20 mls. of 4N. ammonium hydroxide solution, then three times each with 10 mls. of 2N. sulfuric acid, and then washed with 10 mls. of 0.5N sulfuric acid. The heptane is distilled off to obtain the desired 2-(N-isopropylamino)-4-methylbenzophenone which boils at 180° -185° C./5 mm Hg.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9].Cl[C:18]1[N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([N:10]1[CH2:11][CH2:12][CH:13]([O:16][C:18]2[N:23]3[CH:24]=[CH:25][N:26]=[C:22]3[CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:15]1)=[O:9]
Reactant: Clc1cccc2nccn12
Reactant: O=C(c1cccs1)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cccs1)N1CCC(Oc2cccc3nccn23)CC1
Yield: 4.6 %

Procedure:
To a suspension of 60% sodium hydride in oil (0.40 g, 10 mmoles) in dimethylformamide (30 ml) was added 1-(2-thienylcarbonyl)-4-hydroxypiperidine (2.11 g, 10 mmoles) with stirring under ice-cooling and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added 5-chloroimidazo[1,2-a]pyridine (1.53 g, 10 mmoles) with stirring under ice-cooling, followed by stirring at room temperature for 7 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate and dried. After the solvent was distilled off, the residue was purified with column chromatography [eluent: ethyl acetate/hexane (1:1)→ethyl acetate/hexane (2:1)→ethyl acetate/ethanol (50:1)] to obtain 0.15 g of the desired product (4.6%, pale yellow oily product).
Reaction SMILES: C([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[CH3:18])(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CCSC)N.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:51][O:52][C:53](=[O:76])[C@H:54]([CH2:72][CH2:73][S:74][CH3:75])[N:55](C(=O)C1C=CC(N)=CC=1)[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57]>CCN(CC)CC>[CH3:51][O:52][C:53](=[O:76])[C@H:54]([CH2:72][CH2:73][S:74][CH3:75])[N:55]([C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([NH2:8])=[C:10]([CH3:18])[CH:11]=1)[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57]
Reactant: Cc1cc(C(=O)O)ccc1NC(=O)OC(C)(C)C
Reactant: COC(=O)[C@H](CCSC)N(C(=O)OC(C)(C)C)C(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)[C@@H](N)CCSC
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCSC)N(C(=O)OC(C)(C)C)C(=O)c1ccc(N)c(C)c1
Yield: 85.7 %

Procedure:
N-BOC-4-amino-3-methylbenzoic acid (2.00 g, 7.96 mmol) was reacted with methionine methyl ester hydrochloride (1.75 g, 8.76 mmol), EDCI (1.68 g, 8.76 mmol), HOBT (1.18 g, 8.76 mmol) and Et3N (1.4 ml) in dry CH2C12 (31.8 ml) according to the procedure described for N-BOC-4-aminobenzoyl methionine methyl ester in Example 1. The crude material was recrystallized from ethyl acetate and hexanes to yield 2.61 g (85.7%) of pure product. mp 163°-165° C.; 1H NMR (CDCl3) 1.54 (9 H,s), 2.06-2.18 (4 H, m), 2.23-2.34 (4 H, m), 2.59 (2 H, t, J=6.8 Hz), 3.80 (3 H, s), 4.92 (1 H, m), 6.45 (1 H, s), 6.88 (1 H, d, J=7.5 Hz), 7.63 (1 H, d, J=8.6 Hz), 7.66 (1 H, s), 8.05 (1 H, d, J=8.6); 13C NMR (CDCl3) 15.47, 17.61, 28.22, 30.03, 31.55, 51.93, 52.57, 81.04, 118.73, 125.62, 127.66, 129.54, 139.89, 152.34, 166.58, 172.66.
Reaction SMILES: O.NN.[F:4][C:5]1[C:10]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[C:7]([N+:18]([O-])=O)[C:6]=1[NH2:21]>C(O)C>[F:4][C:5]1[C:10]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[C:7]([NH2:18])[C:6]=1[NH2:21]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: CN1CCN(c2ccc(N)c(N)c2F)CC1
Temperature: 25 °C

Procedure:
Hydrazine monohydrate (0.13 mL, 2.7 mmol) was added to a solution of phthalimide 1 (134 mg, 0.39 mmol) in ethanol (4 mL). The reaction was maintained overnight at rt and then was filtered through Celite. The filter cake was rinse with EtOAc (3×) and the organic portions were combined and concentrated to give diamine 2 which was carried forward without further purification: LCMS m/z 215.1 (MH+), tR=1.77 min.
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].[CH2:26]([N:33]1[CH2:38][CH2:37][CH2:36][C:35](=O)[CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]1[CH2:38][CH2:37][CH2:36][C:35](=[CH:6][CH2:5][CH2:4][C:2]#[N:3])[CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: N#CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: N#CCCC=C1CCCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
77.3 g (188.3 mmol) 3-cyanopropyl triphenylphosphonium bromide are suspended in 300 ml tolueneand added to 22.0 g (191.9 mmol) potassium-tert-butylate. The mixture is cooled to ca. 0° C. under moisture exclusion and a solution of 34.6 g (182.8 mmol) 1-benzyl-3-piperidone in 50 ml tolueneare added dropwise under cooling. The batch is left to stand overnight at ca. 0° C., subsequently diluted with 200 ml tolueneand washed twice, each with 100 ml water. The organic phase is extracted with 150 ml half-concentrated hydrochloric acid. Subsequently, the aqueous phase is made basic with 200 ml 10% sodium hydroxide solution and extracted twice, each with 250 ml toluol. The solvent is removed under vacuum and the residue is chromatographically purified over silica gel with CHCl3/CH3OH (97/3). After drawing off the solvent, a light brown oil remains which is further processed without additional purification. Yield: 47.4 g (90%).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].P(=O)(O)(O)O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[CH:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26]>[OH-].[Na+].C(=C1CCCC1=O)CCCC>[OH:27][CH:22]([CH:2]1[CH2:3][CH2:4][CH2:5][C:1]1=[O:6])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C1CCCC1
Reactant: CCCCC=O
Agent: CCCCC=C1CCCC1=O
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Product: CCCCC(O)C1CCCC1=O
Temperature: 15 °C
Yield: 84.5 %

Procedure:
Then, the aqueous layer and the distilled fraction of (a) were introduced into a 500-mL four-necked flask and then 51.1 g cyclopentanone (1.34 mol including a re-used cyclopentanone) and 0.87 g (0.0105 mol) 48% NaOH, including NaOH for converting phosphoric acid contained in the aqueous layer to trisodium phosphate, were added thereto. The mixture was cooled to 15° C. under stirring, and 50.0 g (0.58 mol) valeraldehyde was added dropwise at the same temperature over 5 hours. Thereafter, the mixture was stirred at the same temperature for 2 hours. After the reaction was finished, the mixture was neutralized with 0.84 g (0.009 mol) 105% condensed phosphoric acid and separated into two phases at 40° C. The pH of the aqueous layer was 5.5. The resulting organic layer was 171.2 g, and the aqueous layer was 4.33 g. The organic layer was analyzed in the same manner as in Example 1. The result indicated that the reaction mixture contained 83.5 g (0.490 mol) 2-(1-hydroxy-n-pentyl)cyclopentanone (yield 84.6%) and 2.28 g (0.015 mol) 2-pentylidene cyclopentanone. 61.7 g cyclopentanone and 8.5 g water could be recovered by distillation from the organic layer. The phosphoric acid contained in the aqueous layer, as determined by titration with NaOH for converting it into trisodium phosphate, was 0.028 mol.
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[K+].[C:9]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10]1.S(=O)(=O)(O)O.C[Si].C(OCCOCCO)C>[OH-].[Na+].C(=C1CCCC1=O)CCCC.O>[OH:6][CH:1]([CH:10]1[CH2:11][CH2:12][CH2:13][C:9]1=[O:14])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC=O
Reactant: O=C1CCCC1
Agent: CCCCC=C1CCCC1=O
Agent: C[Si]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCCOCCO
Product: CCCCC(O)C1CCCC1=O
Temperature: 0 °C
Yield: 87.4 %

Procedure:
Valeraldehyde having an acid value of 3.4 mg-KOH/g was used as the starting material. 117.6 g (1.4 mol) cyclopentanone, 125.2 g water and 2.8 g (0.033 mol) 48% NaOH were introduced into a 500-mL four-necked flask, then the mixture was cooled to 0° C. under stirring, and 72.4 g (0.84 mol) valeraldehyde was added dropwise at the same temperature over 4 hours. Thereafter, the mixture was stirred at the same temperature for 4 hours. After the reaction was finished, the mixture was neutralized with 17.4 g of 10% sulfuric acid and the organic layer was analyzed by gas chromatography. In this analysis, a methyl silicon column was used and diethylene glycol monoethyl ether (carbitol) was added as the standard. The result indicated that the reaction mixture contained 124.4 g (0.73 mol) 2-(1-hydroxy-n-pentyl)cyclopentanone (yield 87.4%) and 2.5 g (0.016 mol) 2-pentylidene cyclopentanone.
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[K+].[C:9]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10]1.P(=O)(O)(O)O>[OH-].[Na+].C(=C1CCCC1=O)CCCC.C1(=O)CCCC1.O>[OH:6][CH:1]([CH:10]1[CH2:11][CH2:12][CH2:13][C:9]1=[O:14])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C1CCCC1
Reactant: CCCCC=O
Agent: CCCCC=C1CCCC1=O
Agent: O=P(O)(O)O
Agent: [K+]
Solvent: O
Product: CCCCC(O)C1CCCC1=O
Temperature: 15 °C
Yield: 87.2 %

Procedure:
Valeraldehyde having an acid value of 1.0 mg-KOH/g was used as the starting material. 112.3 g (1.34 mol) cyclopentanone, 50.0 g water and 0.24 g (0.0029 mol) 48% NaOH were introduced into a 500-mL four-necked flask, then the mixture was cooled to 15° C. under stirring, and 50.0 g (0.58 mol) valeraldehyde was added dropwise at the same temperature over 5 hours. Thereafter, the mixture was stirred at the same temperature for 2 hours. After the reaction was finished, the mixture was neutralized with 0.23 g (0.0025 mol) 105% condensed phosphoric acid and separated into two layers at 40° C. The resulting organic layer was 170.4 g, and the aqueous layer was 42.4 g. The pH of the aqueous layer was 5.5. The organic layer was analyzed in the same manner as in Example 1. The result indicated that the reaction mixture contained 86.0 g (0.505 mol) 2-(1-hydroxy-n-pentyl)cyclopentanone (yield 87.2%), 2.29 g (0.015 mol) 2-pentylidene cyclopentanone and 1.9 g (0.011 mol; content 1.1%) cyclopentanone dimer, and the aqueous layer contained 2.8 g cyclopentanone. 58.3 g cyclopentanone and 8 g water could be recovered by distillation from the organic layer. The phosphoric acid contained in the aqueous layer, as determined by titration with NaOH for converting it into trisodium phosphate, was 0.0062 mol.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C.O1CCOCC1>C(Cl)Cl.CCOCC>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([N:17]2[CH2:18][CH2:19][N:14]([CH:10]3[CH:11]([OH:13])[CH2:12][NH:8][CH2:9]3)[CH2:15][CH2:16]2)=[O:28])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C(N2CCN(C(=O)c3ccc(Cl)cc3)CC2)C1
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)N1CCN(C2CNCC2O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
3-[4-(4-Chloro-benzoyl)-piperazin-1-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in CH2Cl2. 4M HCL/dioxane (150 mL) was added. The mixture was stirred at RT for 4 h. White precipitate was formed. The mixture was diluted with ether, filtered. The white solid was washed with ether and dried to give desired product (99% yield). 1H-NMR (300 MHz, DMSO, HCl salt): δ 3.0-4.0 (m, 12 H), 4.85 (m, 2 H), 7.25 (d, 2 H), 7.54 (d, 2 H) Retention Time (LC method: formic acid polar): 1.01 min. MS (M+H+): 310
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C:13]([C:16]1[O:20][N:19]=[C:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[N:32]=[C:33]4[N:37]([CH:38]=3)[C:36]3[CH:39]=[CH:40][C:41]([O:43][CH2:44][CH2:45][N:46]5[CH2:51][CH2:50][O:49][CH2:48][CH2:47]5)=[CH:42][C:35]=3[S:34]4)=[CH:27][CH:26]=2)=[O:23])[CH:17]=1)([CH3:15])[CH3:14].C(N(CC)CC)C>ClCCl>[CH3:15][C:13]([C:16]1[O:20][N:19]=[C:18]([NH:21][C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[N:32]=[C:33]4[N:37]([CH:38]=3)[C:36]3[CH:39]=[CH:40][C:41]([O:43][CH2:44][CH2:45][N:46]5[CH2:47][CH2:48][O:49][CH2:50][CH2:51]5)=[CH:42][C:35]=3[S:34]4)=[CH:29][CH:30]=2)=[O:23])[CH:17]=1)([CH3:14])[CH:12]=[O:11]
Reactant: CC(C)(CO)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C=O)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Alternatively, 1-[5-(1,1-dimethyl-2-oxo-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-4a) is prepared in the following manner. To a stirred mixture of dimethyl sulfoxide (1 equivalent) in anhydrous dichloromethane at −78° C. under an argon atmosphere is added dropwise oxalyl chloride (0.5 equivalents). After stirring for a further 20 to 40 min, compound 1-[5-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-1) (0.3 equivalents) is added and the mixture is stirred at −78° C. Triethylamine (1-2 equivalents) is added, and the mixture is allowed to warm to rt, then the mixture is filtered through Celite and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford 1-[5-(1,1-dimethyl-2-oxo-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-4a).
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[C:5](Cl)(=[O:9])[C:6]([Cl:8])=[O:7]>>[CH:1]([O:4][C:5](=[O:9])[C:6]([Cl:8])=[O:7])([CH3:3])[CH3:2]
Reactant: CC(C)O
Reactant: O=C(Cl)C(=O)Cl
Product: CC(C)OC(=O)C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isopropanol (158 μL, 2.1 mmol, 1.0 eq.) was added dropwise over 5 minutes to oxalyl chloride (350 μL, 4.14 mmol, 2.0 eq.) at 0° C., and the resulting mixture was stirred at room temperature for 2 hours. The excess oxalyl chloride was removed by rotary evaporation (40° C., 50 mmHg) and used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH2:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:20]4=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]4[CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[CH:4][CH2:3]1>C1COCC1.CO.CC(O)=O.[Pt](=O)=O>[CH3:1][C:2]1([CH3:27])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[C:20]4=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]4[CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CC1(C)CC=C(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)CC1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)CCC(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.9 %

Procedure:
Platinum(IV) oxide (40 mg) was added to a solution of 9-{4-[(4,4-dimethylcyclohex-1-en-1-yl)oxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (340 mg) in THF (dry) (30 mL), MeOH (30 mL) and AcOH (10 mL). The mixture was stirred at room temperature under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc, to remove catalytic poison). Platinum(IV) oxide (40 mg) was added and the mixture was stirred at 50° C. under hydrogen for 6 hr. Platinum(IV) oxide was added and the mixture was stirred 50° C. under hydrogen for 12 hr. The insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo with silica-gel. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo. The residue was crystallized from EtOAc/hexane. This was dissolved in THF, silica-gel was added to the solution and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc). The residue was crystallized from THF-EtOAc/IPE to give the title compound (37.6 mg) as colorless crystals.