Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[NH:16][NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[N:21][C:19]=3[N:20]=2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:25]([Cl:33])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>>[ClH:33].[C:25]([N:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[N:21][C:19]=2[N:20]=[C:15]([N:12]2[CH2:11][CH2:10][N:9]([CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:14][CH2:13]2)[NH:16]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: c1ccc(CN2CCN(C3=Nc4ncccc4NN3)CC2)cc1
Agent: Cl
Product: O=C(c1cccnc1)N1NC(N2CCN(Cc3ccccc3)CC2)=Nc2ncccc21
Yield: 83 %

Procedure:
3-(N-Benzylpiperazino)-1,2-dihydro-pyrido[2,3-e]-as-triazine hydrochloride is reacted with nicotinoyl chloride as described in Example 6. The title compound, melting at 218°-219° C., is obtained with a yield of 83%.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]=[CH2:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[Cl:10][SiH:11]([Cl:13])[Cl:12].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.CCCCCCCCCCCCCCCCCCOC(CCSCCC(OCCCCCCCCCCCCCCCCCC)=O)=O>>[C:1]([O:6][CH2:7][CH2:8][CH2:9][Si:11]([Cl:13])([Cl:12])[Cl:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CCOC(=O)C(=C)C
Agent: CCCCCCCCCCCCCCCCCCOC(=O)CCSCCC(=O)OCCCCCCCCCCCCCCCCCC
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=C(C)C(=O)OCCC[Si](Cl)(Cl)Cl
Temperature: 150 °C

Procedure:
A methacryloxypropyl trichlorosilane was synthesized by a known method where allyl methacrylate and trichlorosilane were used as starting materials. 20 g of the obtained product and 5 mg of a styrenated phenothiazine (ANTAGE STDP-N, molecular weight was 407.6; the product of Kawaguchi Chemical Company, Ltd.) was sealed in a bottle with a threaded cap and heated in a 150° C. oil bath. The obtained product was not gelled and maintained flowability even 20 hours after the above-described treatment.
Reaction SMILES: [CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6]([C:12]([O:14]CC3C=CC=CC=3)=[O:13])/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10]>C(O)C.[Pd]>[CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6]([C:12]([OH:14])=[O:13])/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10]
Reactant: O=C(OCc1ccccc1)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21

Procedure:
Benzyl clavulanate (100 mgs) in ethanol (5 ml) was hydrogenated over 10% Pd/C (30 mgs) for 45 minutes at ambient temperature and atmospheric pressure. The catalyst was filtered, washed with ethanol and the combined filtrates were evaporated in vacuo to give clavulanic acid as an unstable, viscous oil (58 mgs). N.m.r. (C5D5N): 3.05(d,1,J=18Hz), 3.60(dd,1,J1 =18Hz, J2 =2.5Hz), 4.75(d,2,J=7.5Hz), 5.58(t,1,J=7.5Hz), 5.66 (S,1), 6.0δ(d,1,J=18Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.C(N(CC)CC)C.Cl[C:27](OC1C=CC=CC=1)=[O:28].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>O1CCCC1.CN(C)C=O>[CH3:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:27]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[O:28])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(N)c1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)N2CCOCC2)c1
Yield: 52.8 %

Procedure:
To a solution of 4-(2-methyl-4-nitrophenoxy)pyridin-2-ylamine (1.00 g, 4.08 mmol) in tetrahydrofuran (50 ml) was added triethylamine (1.14 ml, 8.16 mmol), and then phenyl chloroformate (0.768 ml) was added dropwise thereto while stirring in an ice bath, followed by stirring for 1 hr. Phenyl chloroformate (0.252 ml) was further added thereto while stirring in an ice bath, followed by stirring for 30 min. The reaction mixture was concentrated under a reduced pressure to give a residue, to which N,N-dimethylformamide (18.9 ml) and morpholine (1.42 ml) were added, followed by stirring at room temperature for 5 hrs. The reaction mixture was partitioned between ethyl acetate:tetrahydrofuran=1:1 (150 ml) and water (100 ml). The aqueous layer was extracted with ethyl acetate:tetrahydrofuran=1:1. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=2:1 to 1:1, then ethyl acetate). The crude fraction was concentrated to give a residue, which was purified again by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1, ethyl acetate, and then ethyl acetate:methanol=10:1) to provide the titled compound (772 mg, 52.8%) as a colorless solid.
Reaction SMILES: C(C1C=CC=CC=1[C:9]1[CH:34]=[CH:33][C:12]([CH2:13][C:14]23[C:22](=[O:23])[N:21]([C:24]4[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=4)[C:20](=[O:32])[N:19]2[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=1)=O.C1(P(=[CH:54][C:55]([O:57][CH3:58])=[O:56])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:59]1([CH3:65])[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>>[CH3:58][O:57][C:55]([CH:54]=[CH:65][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]23[C:22](=[O:23])[N:21]([C:24]4[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=4)[C:20](=[O:32])[N:19]2[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:33][CH:34]=1)=[O:56]
Reactant: Cc1ccccc1
Reactant: O=Cc1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)C=Cc1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1

Procedure:
A mixture of 6-[4-(2-formylphenyl)benzyl]-8-(3,5-dichloro-phenyl)-1,8-diazabicyclo[4.3.0]nonane-7,9-dione (0.205 g) and methyl (triphenylphosphoranylidene)acetate (0.223 g) in toluene (5 mL) was refluxed for 8 hours. The mixture was evaporated and the residue was purified by chromatography (Silica gel: EtOAc/hexane: 1/4 to 1/3, Chromatotron) to afford the titled compound (0.229 g). MS (m/z) 571(M++Na).
Reaction SMILES: C[C:2]1C=C(C2OC=NC=2)C=[C:16](C)[C:3]=1[O:4][CH2:5][CH2:6]CCCC1ON=C(C)C=1.C[C:27]1[CH:28]=[C:29]([CH:32]=[C:33](C)[C:34]=1OCCCCCC1ON=C(C)C=1)C=[O:31].S(C[N+]#[C-])(C1C=CC(C)=CC=1)(=O)=O>>[C:5]([O:4][CH:3]([CH3:16])[CH3:2])(=[O:31])[CH3:6].[CH3:29][CH2:28][CH2:27][CH2:34][CH2:33][CH3:32]
Reactant: Cc1cc(CCCCCOc2c(C)cc(C=O)cc2C)on1
Reactant: Cc1cc(CCCCCOc2c(C)cc(-c3cnco3)cc2C)on1
Agent: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Product: CC(=O)OC(C)C
Product: CCCCCC
Yield: 69 %

Procedure:
5-{5-[2,6-Dimethyl-4-(5-oxazolyl)phenoxy]pentyl}-3-methylisoxazole [I; Het=4-(5-oxazolyl), R=CH3, R1 =2-CH3, R2 =6-CH3, R3 =H, X=O, Y=(CH2)5 ] was prepared from 3,5-dimethyl-4-[5-(3-methyl-5-isoxazolyl)pentyloxy]benzaldehyde and tosylmethyl isocyanide according to the procedure of Example 96(b), and was obtained in 69% yield as a pale yellow powder, m.p. 56°-58° C. (from isopropyl acetate-hexane).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[O:24])[C@H:4]([CH:25]([OH:28])[CH2:26][CH3:27])[CH2:3]1.[CH3:29][C:30]([CH3:32])=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>CO>[OH:28][CH:25]([C@@H:4]1[CH2:3][C@H:2]([N:1]([CH:30]([CH3:32])[CH3:29])[CH3:33])[CH2:7][CH2:6][C@@H:5]1[N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:9]1=[O:24])[CH2:26][CH3:27]
Reactant: CC(C)=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCC(O)[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CCC(O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reaction time: 0.17 h

Procedure:
To a solution of benzyl (S)-1-((1S,2R,4R)-4-amino-2-(1-hydroxypropyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (0.86 mmol) in MeOH (5 mL) was added acetone (0.6 mL), and the mixture was stirred for 10 minutes. Then sodium triacetoxyborohydride (544 mg, 2.58 mmol) was added, and the mixture was stirred for 4 h at rt. At the end of the stirring 37% aq. HCHO (0.4 mL) was added, and the mixture was stirred for 30 min at rt. Finally additional sodium triacetoxyborohydride (181 mg, 0.86 mmol) was added, and the mixture was stirred for 18 h at rt. The reaction was quenched by addition of sat. Na2CO3, and the product was extracted with EtOAc (3×). The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue via flash chromatography on silica gel with elution by 1:9:90 cNH4OH-MeOH—CH2Cl2 afforded the desired benzyl (S)-1-((1S,2R,4R)-2-(1-hydroxypropyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (267 mg) as an oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[C:11]3=[O:20])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.O=C(Cl)[O:23][C:24](Cl)(Cl)Cl.[CH2:29]([NH:33][CH3:34])[CH:30]([CH3:32])[CH3:31]>>[CH2:29]([N:33]([CH3:34])[C:24]([N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:15][CH2:16]1)=[O:23])[CH:30]([CH3:32])[CH3:31]
Reactant: CNCC(C)C
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C1N(c2ccc(C3CC3)cc2)CCC12CCNCC2
Product: CC(C)CN(C)C(=O)N1CCC2(CC1)CCN(c1ccc(C3CC3)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-Cyclopropyl-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and isobutyl-methyl-amine. MS (ESI): 384.3 (MH+).
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH:12]2[CH2:17][CH2:16][CH2:15][S:14][CH2:13]2)[CH2:7][C:6]1=[O:18])(=O)[CH2:2][CH3:3].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][CH2:28][O:29][NH2:30])=[CH:22][CH:21]=1>CO>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]=[CH:27][CH2:28][O:29][N:30]=[C:1]([C:5]2[C:10](=[O:11])[CH2:9][CH:8]([CH:12]3[CH2:17][CH2:16][CH2:15][S:14][CH2:13]3)[CH2:7][C:6]=2[OH:18])[CH2:2][CH3:3])=[CH:24][CH:25]=1
Reactant: NOCC=Cc1ccc(Br)cc1
Reactant: CCC(=O)C1C(=O)CC(C2CCCSC2)CC1=O
Solvent: CO
Product: CCC(=NOCC=Cc1ccc(Br)cc1)C1=C(O)CC(C2CCCSC2)CC1=O
Yield: 68.4 %

Procedure:
3.0 g (0.011 mol) of 2-propionyl-5-(3-tetrahydrothiopyranyl)-cyclohexane-1,3-dion and 3.0 g (0.013 mol) of 3-(4-bromophenyl)-prop-2-enyloxiamine in 100 ml of methanol were stirred at 20° C. for 16 hours. The precipitated reaction product was isolated at 0° C. washed with ice-cold methanol and petroleum ether and dried. Yield 68.4%; m.p.: 97°-99° C.
Reaction SMILES: [Zn:1].[Br:2]CCBr.Cl[Si](C)(C)C.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C1COCC1.BrCC(OC(C)(C)C)=O>[Br-:2].[C:16]([O:15][C:13](=[O:14])[CH2:12][Zn+:1])([CH3:19])([CH3:18])[CH3:17]
Reactant: [Zn]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: BrCCBr
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[Zn+]
Product: [Br-]
Temperature: 70 °C
Reaction time: 0.02 h

Procedure:
To a solution of zinc dust (809 mg) in dry THF (10 mL) at rt was added 1,2-dibromoethane (0.10 mL; 0.2 eq.). The reaction mixture was stirred at 70° C. for 1 min and cooled down to rt. This procedure was repeated 3 times. Chlorotrimethylsilane (0.06 mL; 0.08 eq.) was added and the resulting suspension was stirred at rt for 15 min. It was then heated to 65° C. and a few drops of tert-butyl bromoacetate were added. A solution of tert-butyl bromoacetate (1.99 g) in dry THF (2.0 mL) was then added at such a rate that reflux was maintained. Upon completion of the addition, the reaction mixture was refluxed for an additional 20 min and allowed to cool down to rt. The zinc was allowed to settle and the supernatant was used further.
Reaction SMILES: [Si:1]([N:8]1[CH:11]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][C:9]1=[O:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:33][C:34]1[O:35][C:36]([CH:40]=[O:41])=[C:37]([CH3:39])[N:38]=1.N1CCC1=O>C(Cl)Cl>[Si:1]([N:8]1[CH:11]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:10]([CH:40]([C:36]2[O:35][C:34]([CH3:33])=[N:38][C:37]=2[CH3:39])[OH:41])[C:9]1=[O:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nc(C)c(C=O)o1
Agent: O=C1CCN1
Solvent: ClCCl
Product: Cc1nc(C)c(C(O)C2C(=O)N([Si](C)(C)C(C)(C)C)C2SC(c2ccccc2)(c2ccccc2)c2ccccc2)o1

Procedure:
1-t-Butyldimethylsilyl-4-tritylthioazetidin-2-one (1) (1.99 g, 4.34 mmol) was reacted with 2,4-dimethyloxazole-5-carboxaldehyde (45) (520 mg, 4.16 mmol) using the method described in preparation 1(a) to give after work-up two fractions which were partially separable by chromatography. The less polar fraction (290 mg) contained a 4:1 mixture of a trans (isomer A) and a cis isomer (isomer B) of the title azetidinone (46); νmax (CH2Cl2) 3600-3300, 1745 cm-1 ; δ(CDCl3) 0.13 (4.8H, s), 0.35 (0.6H, s), 0.38 (0.6H, s), 0.89 (7.2H, s), 0.98 (1.8H, s) 1.59 (0.8H, d, J5.6 Hz), 1.95 (0.6H, s), 1.99 (2.4H, s), 2.35 (2.4H, s), 2.36 (0.6H, s), 2.90 (0.2H, d, J5.3 Hz), 3.53 ( 0.2H, dd, J1.5, 4.6 Hz), 3.67 (0.8H, dd, J1.7, 3.2 Hz), 3.76 (0.2H, bd, J 4.7 Hz), 4.13 (0.8H, dd, J3.2, 5.6 Hz), 4.43 (0.8H d, J1.7 Hz), 4.79 (0.2H, d, J4.7 Hz), 7.15-7.56 (15H m). (Found [MH]+ 585). The more polar fraction (610 mg) contained a trans isomer (isomer C) of the title azetidinone (46); νmax (CH2Cl2) 3600-3300, 1740 cm-1 ; δ(CDCl3), -0.02 (3H, s). 0.09 (3H, s), 0.87 (9H, s), 1.81 (3H, s), 2.31 (3H, s), 2.56 (1H, d, J9.8 Hz), 3.79 (1H, dd, J1.9, 7.2 Hz), 4.04 (1H, d, J1.9 Hz), 4.09 (1H, dd, J7.3, 6 Hz), 7.12-7.53 (15H, m). (Found [MH]+ 585).
Reaction SMILES: C(C([C:6]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N:9][NH:10]2)C)(=O)N.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[ClH:15].[NH2:9][CH:8]([C:6]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[N:9][NH:10]2)[CH2:7][CH3:6]
Reactant: CC(C(N)=O)c1c(Cl)ccc2[nH]nc(-c3ccccc3)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC(N)c1c(Cl)ccc2[nH]nc(-c3ccccc3)c12
Product: Cl
Yield: 74.4 %

Procedure:
By the procedure similar to that described in Example 27, 1-carbamoylethyl-3-phenyl-5-chloroindazole (m.p. 156°-157° C) (5.0 g) was treated with the use of lithium aluminum hydride (1.5 g) to obtain 2.0 g of 1-aminopropyl-3-phenyl-5-chloroindazole hydrochloride having a melting point between 163°-164° C after recrystallization from ethanol-ether.
Reaction SMILES: OS(O)(=O)=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([OH:17])=[O:16])=[N:7]1.[CH3:18]O>>[CH3:18][O:16][C:15]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][N:7]=1)=[O:17]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1n[nH]c2ccccc12
Yield: 61 %

Procedure:
Concentrated H2SO4 (1 mL) was added to a solution of indazole-3-carboxylic acid (2.0 g, 12 mmol) in MeOH (40 mL). The reaction mixture was heated at reflux for 3 h, the MeOH was removed under reduced pressure and the residue was partitioned between diethyl ether (100 mL) and H2O (100 mL). Saturated sodium hydrogen carbonate solution was added (100 mL) and the diethyl ether layer was separated. The aqueous layer was further extracted with 2×200 mL of diethyl ether. The combined extracts were dried (MgSO4) and solvent removed under reduced pressure and the solid was recrystallised from cyclohexane/ethyl acetate to afford the title compound (1.29 g, 61%). Mp 158–159° C., lit 168–169° C. v.Auwers, Dereser Chem. Ber. 1919, 52, 1343.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].ClC1C=CC=C(Cl)C=1NC1C=CC=CC=1C(=O)C(OC)=O>>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([OH:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Agent: COC(=O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Product: CCOC(=O)C(O)c1ccccc1Nc1c(Cl)cccc1Cl
Yield: 94.1 %

Procedure:
The same procedures as in the Step 3 of Example 6 were repeated except that 3.38 g of ethyl 2-(2,6-dichloroanilino)-phenylglyoxylate were employed instead of 3.24 g of methyl 2-(2,6-dichloroanilino)phenylglyoxylate, thereby yielding 3.2 g of ethyl 2-(2,6-dichloroanilino)phenylglycolate. m.p. 154°-155.5° C. Yield: 93% of theoretical amount
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[CH:9]=2)[N:4]=1.O.[SH:26][C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[NH:29][CH:30]=[N:31]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[CH:9]=2)[N:4]=[C:3]1[CH2:2][S:26][C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[N:29]=[CH:30][NH:31]2
Reactant: O=c1c2cc3ccccc3cc2nc(CCl)n1-c1ccccc1Cl
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cc3ccccc3cc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 48.3 %

Procedure:
Prepared according to Procedure C using Intermediate 2n (200 mg, 0.563 mmol), 6-mercaptopurine monohydrate (105 mg, 0.619 mmol), K2CO3 (86 mg, 0.619 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 128 mg of a dark yellow solid (48%), mp 247.8-254.4° C. (decomposes). 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.90 (s, 1H); 8.50 (s, 1H); 8.46 (s, 1H); 8.34 (s, 1H); 8.27 (d, J=8.2 Hz, 1H); 8.16 (d, J=8.2 Hz, 1H); 7.81 (dd, J=1.6, 7.3 Hz, 1H); 7.70 (t, J=7.5 Hz, 1H); 7.61-7.74 (m, 2H); 7.49 (t, J=7.5 Hz, 1H); 7.44-7.53 (m, 1H); 4.44-4.56 (m, 2H). 13C NMR (DMSO-d6) ppm: 161.3, 151.6, 151.5, 143.9, 142.2, 136.7, 134.4, 132.5, 131.8, 131.6, 130.5, 129.7, 129.3, 128.8, 128.6, 128.3, 128.3, 127.1, 125.2, 119.5, 32.4. MS (ES): m/z 471.0 (M+). Anal. calcd. for C24H15ClN6OS.0.2C2H6O.0.05KCl: C, 60.57; H, 3.37; Cl, 7.69; N, 17.37; S, 6.63. Found: C, 60.24; H, 3.46; Cl, 7.50; N, 17.34; S, 6.69.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[S:9]1[C:13](B(O)O)=[CH:12][C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]1=2.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1>>[S:9]1[C:13]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:24][CH2:23]3)[N:7]=2)=[CH:12][C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]1=2
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Clc1ccnc(Cl)n1
Product: c1ccc(CN2CCC(Nc3nccc(-c4cc5ccccc5s4)n3)CC2)cc1

Procedure:
The title compound was prepared analogous to Method A, starting from 2,4-dichloro-pyrimidine, benzo[b]thiophen-2-boronic acid and 4-amino-1-benzyl-piperidine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1.[Cl:12][CH2:13][CH2:14][N:15]=[C:16]=[O:17].C(N(CC)CC)C>C(C(C)=O)C>[Cl:12][CH2:13][CH2:14][NH:15][C:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1)=[O:17]
Reactant: O=C=NCCCl
Reactant: O=c1oc2ccc(O)cc2s1
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCCCl)Oc1ccc2oc(=O)sc2c1
Reaction time: 0.33 h

Procedure:
5-hydroxy-1,3-benzoxathiol-2-one (14.0 grams) was mixed with 2-chloroethyl isocyanate (8.79 grams) in 170 milliliters of methyl ethyl ketone in the presence of 0.84 gram of triethylamine. The resulting mixture was heated at reflux temperature with stirring for 6 hours and 20 minutes. The solvent was then removed by evaporation in vacuo. The residue was recrystallized from carbon tetrachloride (containing a small amount of ethyl acetate). A subsequent recrystallization from toluene gave the purified product, 5-[(2-chloroethyl)carbamoyloxy]-1,3-benzoxathiol-2-one, as a white crystal line solid with a melting point of 105.5°-107.5° C. Elemental analysis calculated for C10H8ClNO4S (percent): carbon--43.88; hydrogen--2.95; nitrogen--5.12. Found: carbon--43.7; hydrogen--3.13; nitrogen--5.37.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1.C(N(CC)CC)C.[F:40][C:41]([F:56])([F:55])[C:42]1[CH:43]=[C:44]([CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1)[C:45](Cl)=[O:46]>ClCCl>[F:40][C:41]([F:55])([F:56])[C:42]1[CH:43]=[C:44]([CH:48]=[C:49]([C:51]([F:54])([F:52])[F:53])[CH:50]=1)[C:45]([N:24]1[CH2:25][CH2:26][N:27]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:28][CH:23]1[CH2:22][C:21]1[CH:29]=[CH:30][C:31]([CH3:32])=[C:19]([O:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH3:12])[CH:20]=1)=[O:46]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COCCOCOc1cc(CC2CNCCN2)ccc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOCOc1cc(CC2CN(C(=O)OCc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of benzyloxycarbonyl chloride (0.75 g) in dichloromethane (1 ml) was added dropwise over 5 minutes to an ice-cooled solution of 2-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]piperazine (1.27 g) obtained by above procedure and triethylamine (2.2 ml) in dichloromethane (10 ml) below 5° C. After the mixture was stirred for 30 minutes at the same temperature, a solution of 3,5-bis(trifluoromethyl)-benzoyl chloride (0.93 ml) in dichloromethane (1.0 ml) was added dropwise to the mixture over 10 minutes below 5° C. After being stirred for 30 minutes at the same temperature, the reaction mixture was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using mixed solvents of toluene and ethyl acetate (5:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give 1-[3,5-bis(trifluoromethyl)benzoyl]-4-(benzyloxycarbonyl)-2-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]piperazine (1.61 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:15]#[N:16])[C:10](OCC)=O.[OH2:17].[NH2:18][NH2:19]>C(O)C.C(O)(=O)C>[NH2:16][C:15]1[NH:19][NH:18][C:10](=[O:17])[C:9]=1[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O
Reactant: CCOC(=O)C(C#N)Cc1ccccc1Cl
Reactant: NN
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1[nH][nH]c(=O)c1Cc1ccccc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-(2-chlorophenyl)-2-cyanopropanoate (2.37 g, 10 mmol) in ethanol (20 mL) and acetic acid (20 mL) under nitrogen was added hydrazine monohydrate (2.5 g, 49.9 mmol). The reaction mixture was heated and stirred at 100° C. overnight. Reaction mixture was concentrated. Oily residue was dissolved with ethyl acetate (60 mL) and 5% HCl solution (15 mL). Two layers were separated. Organic layer was washed with brine (15 mL), dried and concentrated to give product. It was used in next step without purification. (1.98 g, 89%); LC/MS: MS (ES+) m/e 224 (MH+)
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH:5][CH:6]=[CH:7][CH3:8])[CH3:2].[C:9]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:12])[CH:10]=[O:11].C1(C=CC(O)=CC=1)O>C(Cl)Cl>[CH2:14]([O:13][C:9]([CH:10]1[CH:7]([CH3:8])[CH:6]=[CH:5][CH:4]([O:3][CH2:1][CH3:2])[O:11]1)=[O:12])[CH2:15][CH2:16][CH3:17]
Reactant: CC=CC=COCC
Reactant: CCCCOC(=O)C=O
Agent: Oc1ccc(O)cc1
Solvent: ClCCl
Product: CCCCOC(=O)C1OC(OCC)C=CC1C

Procedure:
Following the procedure of Example 12, a solution of 26.7 g. (0.226 mol) of 1-ethoxy-1,3-pentadiene (purity, 95%), 32.5 g. (0.25 mol) of butyl glyoxylate and 0.250 g. of hydroquinone in 250 ml. of methylene chloride was refluxed for 48 hours to give 28.0 g. of a mixture of 1-ethoxy-1,3-pentadiene and butyl glyoxylate and 20.32 g. of distilled 2H-pyran butyl ester (b1.0 =100°-110°) as an oil. Yield based on 1-ethoxy-1,3-pentadiene, 34%.