Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]2[N:20]([CH3:21])[C:19](=[O:22])[CH2:18][N:17]=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:15]=2[CH:30]=1)=[O:9])(=O)C.C[O-].[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C.C(Cl)Cl>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:16]1[C:15]2[CH:30]=[C:11]([NH:10][C:8]([NH:7][CH2:6][CH2:5][OH:4])=[O:9])[CH:12]=[CH:13][C:14]=2[N:20]([CH3:21])[C:19](=[O:22])[CH2:18][N:17]=1
Reactant: CC(=O)OCCNC(=O)Nc1ccc2c(c1)C(c1ccccc1F)=NCC(=O)N2C
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1C(=O)CN=C(c2ccccc2F)c2cc(NC(=O)NCCO)ccc21

Procedure:
20 mg (0.048 mM) of 2-[3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]ureido]-ethyl acetate are dissolved in 2 ml of absolute methanol and stirred at 30°-40° C. for 1 hour with 13 mg of sodium methylate. The mixture is then buffered with a few drops of glacial acetic acid, diluted with methylene chloride, treated with 10% sodium bicarbonate solution and extracted several times with methylene chloride. The organic phases are combined, dried over sodium sulphate, filtered and concentrated. The residue is crystallised from acetone/ether. There is obtained 1-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxyethyl)urea which, according to the IR spectrum, is identical with a sample of this substance prepared in another manner (see Example 7).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[C:16]2[S:15][C:14](=[S:17])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.CI.[CH3:20]COC(C)=O>CN(C=O)C>[Br:7][C:8]1[C:16]2[S:15][C:14]([S:17][CH3:20])=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(C)=O
Reactant: S=c1[nH]c2cccc(Br)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1nc2cccc(Br)c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium carbonate (67 mg, 0.49 mmol) was added to a solution of 7-bromo-1,3-benzothiazole-2(3H)-thione (100 mg, 0.41 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 30 min. Methyl iodide (25 μL, 0.41 mmol) was added and the resulting mixture was stirred at room temperature for 30 min. EtOAc was added the separated organic fraction was washed with water and brine, dried over sodium sulfate, and concentrated. The title compound thus obtained was used without further purification. MS (ESI): 260.34, 262.32 [M+H]+; HPLC tR=1.54 min (HPLC: Anayltical—2 min).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)=[CH:3][CH:2]=1.[OH:26]O>>[N:1]1[CH:2]=[CH:3][C:4]([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:23])([CH3:24])[C:17]=3[CH:25]=2)=[O:26])=[CH:5][CH:6]=1
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccncc3)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccncc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-pyridylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[N+:19]([C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1F)([O-:21])=[O:20]>O.C(O)C>[N+:19]([C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[NH:11][CH2:10][CH2:9][C:8]1[C:12]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:13]=2)[NH:6][CH:7]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: Cc1ccc2[nH]cc(CCN)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2[nH]cc(CCNc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
1 mMole of 5-metyltryptamine was dissolved in 100 ml of water and the pH was adjusted to pH 8.3 with 2.5 moles of sodium bicarbonate (NaHCO3), A 1.5% solution of 2,4-dinitrofluorobenzene in 200 ml ethanol was added and the mixture was stirred during 2 hours at room temperature. The desired product precipitates out, it is washed and dried. The product is obtained in 85% yield, and TLC (chloroform, silica-gel plates, reveals one yellow spot (Rf=0.8) which is well resolved from the starting materials under the same conditions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[N:5]=[C:4](CO)[CH:3]=1.C(N(CC)CC)C.[CH:19]([Cl:22])(Cl)Cl.CS([Cl:27])(=O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][Cl:27])[N:5]=[C:4]([CH2:19][Cl:22])[CH:3]=1
Reactant: OCc1cc(Cl)cc(CO)n1
Reactant: CS(=O)(=O)Cl
Reactant: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClCc1cc(Cl)cc(CCl)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-chloro-2,6-bis(hydroxymethyl)pyridine (2.41 g, 13.93 mmol) and triethylamine (7.8 ml, 55.72 mmol) at 0° C. in 100 ml of anhydrous dichloromethane and 50 ml of anhydrous chloroform under an argon atmosphere was added methanesulfonyl chloride (3.2 ml, 41.79 mmol). The solution was stirred at 0° C. for 30 minutes, warmed to room temperature and stirred a further 36 hours. The reaction mixture was quenched with water (50 ml), the aqueous phase extracted with dichloromethane, dried (MgSO4) and concentrated in vacuo to afford a red-orange oil. The residual oil was passed through a short plug of silica gel using dichioromethane as eluent thus affording after concentration a pale yellow solid which was identified by 1H NMR as 4-chloro-2,6-bis-(chloromethyl)pyridine (1.9 g, 65%).
Reaction SMILES: [C:1]([NH:18][C:19]1[CH:20]=[C:21]([OH:36])[C:22]2[C:27]([C:28]=1[O:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].[Na+].[C:39]([C:41]1[C:42](=[O:69])[N:43]([CH3:68])[C:44]([OH:67])=[C:45]([N:48]=[N:49][C:50]2[CH:55]=[CH:54][C:53]([CH2:56]OS(C3C=CC=CC=3)(=O)=O)=[CH:52][CH:51]=2)[C:46]=1[CH3:47])#[N:40]>>[C:39]([C:41]1[C:42](=[O:69])[N:43]([CH3:68])[C:44]([OH:67])=[C:45]([N:48]=[N:49][C:50]2[CH:55]=[CH:54][C:53]([CH2:56][O:36][C:21]3[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:28]([O:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[C:19]([NH:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:20]=3)=[CH:52][CH:51]=2)[C:46]=1[CH3:47])#[N:40]
Reactant: Cc1c(N=Nc2ccc(COS(=O)(=O)c3ccccc3)cc2)c(O)n(C)c(=O)c1C#N
Reactant: CCCCCCCCCCCCCCCC(=O)Nc1cc(O)c2ccccc2c1OCOCCOC
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCC(=O)Nc1cc(OCc2ccc(N=Nc3c(C)c(C#N)c(=O)n(C)c3O)cc2)c2ccccc2c1OCOCCOC
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 70.6 %

Procedure:
5 g of Compound [1-f] was dissolved in 30 ml of dried diglime and to the solution was added 0.48 g of a 50% oily sodium hydride. Then, 4.4 g of Compound [2-b] was added and the mixture was stirred at 80° C. for 1.5 hours. By subjecting the same treatment as described in Step [1-i], 5.5 g of Compound [2-c] was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][C:14](=[O:29])[C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CO.C1COCC1.[BH4-].[Na+]>O>[OH:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][CH:14]([OH:29])[C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:25])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C#CC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.9 g (7.4 mmol) of methyl 2-hydroxy-4-[3-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate and 100 ml of a methanol/THF (50/50) mixture were introduced into a round-bottomed flask and 140 mg (3.7 mmol) of sodium borohydride were added in small amounts. The reaction mixture was stirred at room temperature for 2 hours, poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (50/50). After evaporation of the solvents, 1.6 g (55%) of the expected compound, with a melting point of 92°-93° C., was recovered.
Reaction SMILES: C(OC([N:8]1[C:12]2([CH2:16][CH2:15][CH2:14][CH:13]2[C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)[C:11](=[O:24])[N:10]([C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)[C:9]1=[S:33])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.O>>[Br:23][C:20]1[CH:19]=[CH:18][C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][C:12]32[NH:8][C:9](=[S:33])[N:10]([C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)[C:11]3=[O:24])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1C(=S)N(c2cc(Cl)cc(Cl)c2)C(=O)C12CCCC2c1ccc(Br)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=S)NC12CCCC2c1ccc(Br)cc1
Yield: 60.4 %

Procedure:
6-(4-Bromophenyl)-3-(3,5-dichlorophenyl)-4-oxo-2-thioxo-1,3-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (42 mg, 74 μmol) (Preparation 10) was added to a TFA/DCM/H2O (1/1/0.1) solution (1 ml) at RT. After 30 min the reaction mixture was concentrated to give a beige solid which was washed with pentane to yield 6-(4-Bromophenyl)-3-(3,5-dichlorophenyl)-2-thioxo-1,3-diazaspiro[4.4]nonan-4-one (21 mg, beige solid). 1H NMR (CDCl3): 8.39 (1H, s), 7.51 (2H, d, J=8.4 Hz), 7.35 (1H, m), 7.19 (2H, d, J=8.4 Hz), 6.44 (2H, m), 3.36 (1 H, dd, J1=12.9 Hz, J2=6.1 Hz), 2.45-2.65 (2H, m), 1.8-2.25 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:10]([O:16][CH2:17][CH3:18])=[CH:9][C:3]=1[C:4](OCC)=[O:5].Cl.[CH:20](N)=[NH:21]>C(N)=O>[CH2:17]([O:16][C:10]1[CH:9]=[C:3]2[C:2](=[CH:12][C:11]=1[O:13][CH2:14][CH3:15])[N:1]=[CH:20][NH:21][C:4]2=[O:5])[CH3:18]
Reactant: CCOC(=O)c1cc(OCC)c(OCC)cc1N
Reactant: N=CN
Agent: Cl
Solvent: NC=O
Product: CCOc1cc2nc[nH]c(=O)c2cc1OCC
Temperature: 140 °C
Yield: 72.7 %

Procedure:
According to the procedure described in Example 6A Step 4, a mixture of ethyl 2-amino-4,5-diethoxybenzoate (2.53 g, 10 mmol) and formamidine hydrochloride (0.966 g, 12 mmol) in formamide (10 mL) was heated at 140° C. for 5 hours, to afford 6,7-diethoxyquinazolin-4(3H)-one as a white solid (1.702 g, 73%). 1H NMR (300 MHz, CDCl3) δ 10.49 (br, 1H), 7.98 (s, 1H), 7.60 (s, 1H), 7.14 (s, 1H), 4.24 (m, 4H), 1.54 (m, 6H); LC-MS (ESI) m/z 235 (M+H)+.
Reaction SMILES: O[CH:2]1[CH:7]([CH2:8][CH2:9][O:10][CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][N:4]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:3]1.C(N(CC)CC)C.[C:39](Cl)(=[O:42])[CH2:40][CH3:41].O>C(Cl)Cl>[C:39]([C@H:2]1[C@H:7]([CH2:8][CH2:9][O:10][CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5][N:4]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH2:3]1)(=[O:42])[CH2:40][CH3:41]
Reactant: OC1CN(Cc2ccc(F)cc2)CCC1CCOC(c1ccccc1)c1ccccc1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCC(=O)[C@@H]1CN(Cc2ccc(F)cc2)CC[C@H]1CCOC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 61 mg 3-hydroxy-4-[2-(diphenylmethoxy)ethyl]-1-[(4-fluorophenyl)methyl]piperidine (0.15 mmol) and 21 mg triethylamine (0.23 mmol, 1.5 equiv) in 2 mL CH2Cl2 cooled in an ice bath was added dropwise 18 mg propionyl chloride (0.19 mmol, 1.3 equiv) and the reaction was allowed to warm to RT. After 1 hr, the same quantities of triethylamine and propionyl chloride were added. After 1 hr, H2O was added and the organic layer was separated, dried (MgSO4) and evaporated. The remaining residue was chromatographed (SiO2; CH2Cl2/MeOH) to yield the title compound as the free base (53 mg, 77%). 1H NMR (CdCl3 ∂ 1.1 (3H, t, J=8.1 Hz), 1.26-1.95 (7H, m), 2.26 (2H, q, J=7.2 and 7.5 Hz), 2.71 (1H, d, J=11.7 Hz), 3.02 (1H, d, J=10.5 Hz), 3.41-3.52 (4H, m), 4.67 (1H, t, J=9.6 Hz), 5.31 (1H, s), 6.98 (2H, t, J=9.3 Hz), 7.2-7.4 (12H, m). This was then reacted in a mixture of 2 mL 50% EtOH/Et2O with oxalic acid dihydrate (15.4 mg, 1.1 equiv) to furnish the title compound. mp ° C. Elemental analysis calculated for C32H36NO7F·0.5 H2O: C, 67.43; H, 6.41; N, 2.46. Found: C, 67.34; H, 6.43; N, 2.44.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])=[O:6]
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(NC(=O)c2cccc(Cl)c2)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of 15.1 gm (86 mmol) of 3-chlorobenzoyl chloride in 70 mL of dichloromethane was added 10.0 gm (66 mmol) of methyl 3-aminobenzoate. Triethylamine (9.38 gm, 13 mL, 93 mmol) was then added slowly to the mixture. After the addition was complete, the solution was warmed to 45° C. and stirred overnight. Ice was added to the solution to quench excess benzoyl chloride. After one hour, the layers were separated. The organic fraction was washed with 5% aqueous hydrochloride acid, saturated sodium bicarbonate, and finally with saturated sodium chloride solution. The dichloromethane solution was dried over magnesium sulfate. The drying agent was filtered off, and the solvent was removed by rotoevaporation to give the desired methyl 3-(3-chlorobenzamido)benzoate. 1H NMR (CDCl3): δ3.91 (s, 3H), 7.61 (d of t, 1H), 7.78 (d of t, 1H, 7.87 (d of t, 1H), 8.40 (d of d, 1H), and 8.94 ppm (br s, 1H). MS m/z: 290.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[NH:4][CH2:3]1.[CH:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24]>ClCCCl>[CH:23]([NH:26][C:27]([N:4]1[CH2:3][C:2]([CH3:22])([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=1)=[O:28])([CH3:25])[CH3:24]
Reactant: CC1(C)CNC(c2ccc(C(F)(F)F)cc2)c2ccccc21
Reactant: CC(C)N=C=O
Solvent: ClCCCl
Product: CC(C)NC(=O)N1CC(C)(C)c2ccccc2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 25-mL round-bottomed flask was charged with 4,4-dimethyl-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (366 mg, 1.2 mmol), iso-propyl isocyanate (141 μL, 1.4 mmol), DCE (5 mL) and stirred at RT for 1 h. Then the solvent was removed under vacuum and the product was purified by recrystallization from a mixture of ether/hexane. MS (ESI, positive ion) m/z: 391 (M+H).
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:8]1(=[O:13])[O:12][CH2:11][CH2:10][O:9]1>>[CH2:1]([NH:7][C:8](=[O:13])[O:9][CH2:10][CH2:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN
Reactant: O=C1OCCO1
Product: CCCCCCNC(=O)OCCO
Temperature: 70 °C
Reaction time: 5 h

Procedure:
N-hexylamine (8.8 g, 100 mmole) and ethylene carbonate (10.12 g, 100 mmole) was mixed into a solution, and the solution is then further heated to 70° C. After reacting for 5 hours, the product was purified by vacuum distillation (128-130° C./0.05 mmHg) to form 2-hydroxyethyl N-hexyl-carbamate (compound I), 15.1 g (yield: 80%), which is an achromatic oily liquid. 2-hydroxyethyl N-hexyl-carbamate (compound I, 4.73 g, 25 mmole), benzaldehyde dimethylacetal (3.79 g, 25 mmole), and a catalyst of p-toulenesulfonic acid (0.05g) are mixed. Thus, the mixed solution was gradually heated to 160° C. and then reacted for 2 hours. Methanol formed in the period is then removed. Thereafter, the mixed solution was processed by vacuum distillation (0.01 mmHg) and heated to 200° C. A thermally decomposable polymer (A) (poly(N,O)acetal, PA) 5.5 g (yield: 65%) was obtained after 2 hours, which is a highly viscous oily constituent with orange-red color. Referring to the reaction formula below, the synthesis procedure of the thermally decomposable polymer (A) is shown below:
Reaction SMILES: [CH:1]1([CH:6]([CH3:12])[CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:13][Li].O>C(OCC)C>[CH:1]1([CH:6]([CH3:12])[CH2:7][CH2:8][C:9](=[O:11])[CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(CCC(=O)O)C1CCCC1
Reactant: [Li]C
Solvent: CCOCC
Solvent: O
Product: CC(=O)CCC(C)C1CCCC1
Temperature: 5 °C
Reaction time: 3.5 h
Yield: 53.5 %

Procedure:
4-Cyclopentylpentanoic acid (3.4 g; 20 mmol; prepared in example 6) in diethyl ether (90 ml) was added at 0° C. to 1.6 M diethyl ether solution of methyllithium (25 ml; 40 mmol), and diluted with the same solvent (75 ml). After 3.5 hours stirring at 5° C., water (100 ml) was added, and the separated organic layer was washed with brine (3×400 ml), dried (MgSO4), concentrated in vacuo, and bulb-to-bulb distilled (125° C./0.2 torr) to give 1.8 g (53.5% yield) of 5-cyclopentylhexan-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].Cl>CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:9][CH:10]3[CH2:16][CH:14]([CH2:13][CH:12]([CH2:11]3)[CH2:17]1)[CH2:15]2)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CN2CCNCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Chloro-5-(4-[{1,1-dimethylethyl}oxycarbonyl]-piperazin-1-yl)methyl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide, (Example 8c, 0.080 g) was dissolved in methanol (3 ml), 4N HCl in dioxane (1 ml) was added and the mixture stirred at room temperature for 1.5 h. The solvent was removed under vacuum and the resulting solid was triturated with ether to afford the title compound as a white powder (0.062 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[O:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=1[C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1Oc1ccccc1
Reactant: N#Cc1cccnc1Cl
Product: N#Cc1cccnc1-c1ccccc1Oc1ccccc1
Yield: 50 %

Procedure:
Prepared in 50% yield from 2-chloro-3-cyanopyridine and 2-phenoxyphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 273.0 (M+H)+; 1H NMR (CDCl3) δ 6.94 (d, J=7.1 Hz, 1H), 7.06-7.11 (m, 3H), 7.20-7.44 (m, 5H), 7.54 (dd, J=7.5, 1.7 Hz, 1H), 8.00 (dd, J=8.1, 2.0 Hz, 1H), 8.86 (dd, J=5.1, 1.7 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:16]([Cl:21])(Cl)(Cl)(Cl)[Cl:17].Cl.C(O)=[O:24]>C(Cl)(Cl)(Cl)Cl>[Cl:17][P:16]([Cl:21])([NH:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:15][CH:14]=1)=[O:24]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: NC(=O)c1ccc(-c2ccccc2)cc1
Reactant: O=CO
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(NP(=O)(Cl)Cl)c1ccc(-c2ccccc2)cc1

Procedure:
A mixture of 23.5 g (0.12 mole) of 4-phenylbenzamide, 24.8 g (0.12 mole) of phosphorus pentachloride and 250 ml of AR carbon tetrachloride was heated at 70° until the HCl gas evolution nearly stops. It was chilled to 30° and 5.7 g (0.12 mole) of 97% formic acid added dropwise. The precipitate was collected, washed with AR carbon tetrachloride and air-dried to give 3.1 g, m.p. 123°-124°.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].[CH2:11](Br)[CH:12]=[CH2:13].C([O-])([O-])=O.[K+].[K+].CC(C)=O>O>[CH3:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][CH:12]=[CH2:11])=[CH:6][CH:5]=1)=[CH2:3]
Reactant: C=C(C)c1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1ccc(C(=C)C)cc1
Yield: 63 %

Procedure:
A 10 g-portion of p-isopropenylphenol, 1.0 equivalent allyl bromide, 1.0 equivalent K2CO3, and 20 ml acetone were mixed and refluxed overnight. The reaction mixture was poured into 60 ml water and extracted with two portions of ether. The combined ether layers were washed with two portions of 10% aqueous NaOH, two portions of saturated aqueous NaCl and dried over K2CO3. Removal of solvent followed by distillation under reduced pressure gave a 63% yield of 1-(1-methylethenyl)-4-(2-propenyloxy)benzene, mp 22°-23° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]([CH2:16][CH2:17][O:18][C:19]([F:22])([F:21])[F:20])[C:5]2=[N:6][CH:7]=1.[CH3:23][CH:24]([SH:26])[CH3:25]>>[CH3:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:9]1[N:8]([CH2:16][CH2:17][O:18][C:19]([F:22])([F:21])[F:20])[C:5]2=[N:6][CH:7]=[C:2]([S:26][CH:24]([CH3:25])[CH3:23])[CH:3]=[C:4]2[N:10]=1
Reactant: CC(C)S
Reactant: CC(C)(C)Cc1nc2cc(Br)cnc2n1CCOC(F)(F)F
Product: CC(C)Sc1cnc2c(c1)nc(CC(C)(C)C)n2CCOC(F)(F)F

Procedure:
The title compound was prepared according to the procedure described in Step E of Example 32 from 6-bromo-2-(2,2-dimethylpropyl)-3-[2-(trifluoromethoxy)ethyl]-3H-imidazo[4,5-b]pyridine (Step D of Example 49) and 2-propanethiol (TCI Tokyo Kasei Kogyo Co., Ltd.).
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1.BrC1C=CC(C(O)=O)=CC=1.ONC(=O)CCC(N)=O.[NH:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:42][N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1>O1CCCC1>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]([N:37]2[CH2:41][CH2:40][CH2:39][C@H:38]2[CH2:42][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[O:17])=[CH:15][CH:14]=1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(Br)cc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: NC(=O)CCC(=O)NO
Agent: O=C(O)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CN1CCCC1
Yield: 93 %

Procedure:
To a stirring solution of 4-bromobenzoic acid-2,5-dioxo-pyrrolidin-1-yl ester (3.5 g, 11.7 mmol), [which can be prepared from 4-bromobenzoic acid and N-hydroxy succinamide by the method of C. Mitsos, Chem Pharm Bull 48(2), 211-214 (2000), or purchased from Ambinter, CAS# 80586-82-9], in tetrahydrofuran (0.15 M), add (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine and heat to reflux for 4 h. After this time, remove the heat and wash the reaction with water while extracting with 10% isopropanol/dichloromethane. Dry the organic portion with sodium sulfate, filter and concentrate in vacuo. Purify the resulting residue on a silica column eluting with 2 M ammonia in methanol and dichloromethane to give (4-bromo-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-yl)methanone (93% yield with 80% purity). MS (m/e): 337.1 (M+1).