Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][C:12](=[O:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])[C:5]([OH:7])=O.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[CH2:44]([O:46][C:47]([CH2:49][N:50]1[C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=2[NH:54][CH2:53][CH2:52][C:51]1=[O:61])=[O:48])[CH3:45].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][C:12](=[O:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])[C:5]([N:54]1[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2[N:50]([CH2:49][C:47]([O:46][CH2:44][CH3:45])=[O:48])[C:51](=[O:61])[CH2:52][CH2:53]1)=[O:7]
Reactant: Cc1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)O)cc1Cl
Reactant: CCOC(=O)CN1C(=O)CCNc2ccccc21
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1C(=O)CCN(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3C)c(Cl)c2)c2ccccc21
Temperature: 25 °C
Yield: 77.5 %

Procedure:
To a solution of 3-chloro-4-[2-(2-methylphenyl)benzoylamino]benzoic acid (309 mg), diphenyl chlorophosphate (251 mg), 1-ethoxycarbonylmethyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (210 mg) in tetrahydrofuran (15 ml) was added triethylamine (172 mg) at 0° C. The resulting mixture was allowed to warm to ambient temperature where it was maintained for 5 hours. The solvent was evaporated and diluted with ethyl acetate and washed with water, diluted hydrochloric acid, saturated sodium bicarbonate aqueous solution and brine. The organic layer was dried over magnesium sulfate and concentrated to give 5-{3-chloro-4-[2-(2-methylphenyl)benzoylamino]benzoyl}-1-ethoxycarbonylmethyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (390 mg) which was purified by recrystallization from a mixture of ethyl acetate and n-hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH:26]1[O:30][C:29](=[O:31])[N:28]([CH3:32])[CH2:27]1.[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35]>>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH:26]3[O:30][C:29](=[O:31])[N:28]([CH3:32])[CH2:27]3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CN1CC(CCCl)OC1=O
Reactant: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)C1CCNCC1
Agent: O=C(O)C(=O)O
Product: CN1CC(CCN2CCC(C(O)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)OC1=O

Procedure:
Following the procedure of Example 1, α,α-bis(4-chlorophenyl)-4-piperidinemethanol and 5-(2-chloroethyl)-3-methyl-2-oxazolidinone are reacted and the product thereof is reacted with oxalic acid to give the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=2[NH2:21])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:22]([C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>C(O)(C)C.[Pd]>[C:22]([C:26]1[CH:27]=[CH:28][C:29]([C:30]2[NH:20][C:16]3=[N:17][CH:18]=[CH:19][C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[C:15]3[N:21]=2)=[CH:32][CH:33]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc(N)c2N)CC1
Agent: [Pd]
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(-c2nc3c(N4CCNCC4)ccnc3[nH]2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 73.8 %

Procedure:
4-(2,3-Diamino-pyridin-4-yl)-piperazine-1-carboxylic acid t-butyl ester (6) (368 mg, 1.3 mmol) was dissolved in isopropanol (9 ml) with Pd/C 10% (100 mg) and para-t-butyl benzaldehyde (324 mg, 2 mmol). The mixture was heated to 80° C. for 18 hours. MS showed the disappearance of the diamine starting material. The solvent was filtered through CELITE to remove the palladium, and the solvent was removed under vacuum. The residue was dissolved in NMP (4 ml), TFA (12 ml) was added and the reaction mixture was allowed to stir under nitrogen for 12 hours. MS showed the formation of the title product, and the TFA was removed under vacuum. The crude product-NMP mixture was purified by HPLC Method E to yield the title product 7 (320 mg (74%), 0.96 mmol). 1H NMR (DMSO-d6): δ 13.35 (bs, 1H), 8.75 (bs, 1H), 8.11 (dd, J=7.3 Hz, 2.1 Hz, 2H), 8.01 (d, J=6.2 Hz, 1H), 7.55 (dd, J=7.3 Hz, 2.1 Hz, 2H), 6.60 (d, J=6.2 Hz, 1H), 4.14 (m, 4H), 3.26 (m, 4H), 1.33 (s, 9H). MS (ESI-POS): [M+H]+=336.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1
Reactant: Cc1cc2ccccc2s1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc2ccccc2s1

Procedure:
A mixture of 4 g. (0.026 m.) of 2-methylbenzothiophene, 4.7 g. (0.027 m.) of N-bromosuccinimide, a catalytic amount of benzoyl peroxide and 250 ml. of carbon tetrachloride was stirred under irradiation for 30 minutes. The cooled and filtered mixture was evaporated to give an oily 2-bromomethylbenzothiophene.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][C:6](=[O:8])[CH2:5][C:4]([CH3:10])([CH3:9])[P:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=1[CH:29]([CH3:31])[CH3:30].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:45](O)[CH2:46][OH:47]>>[CH3:32][C:2]1([CH3:1])[P:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[C:22]([CH:23]([CH3:24])[CH3:25])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=2[CH:29]([CH3:31])[CH3:30])[C:4]([CH3:9])([CH3:10])[CH2:5][C:6]2([O:47][CH2:46][CH2:45][O:8]2)[CH2:7]1
Reactant: OCCO
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC(=O)CC2(C)C)c(C(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC3(CC2(C)C)OCCO3)c(C(C)C)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A flask was charged with 3.75 g of 2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinan-4-one (8.32 mmol, 1.0 equiv) and 0.16 g of p-toluenesulfonic acid monohydrate (0.84 mmol, 0.1 equiv). The atmosphere was purged with nitrogen and the flask was charged with 80 mL of nitrogen-sparged toluene. To this solution was added 4.6 mL of ethylene glycol (83 mmol, 10 equiv). The reaction flask was equipped with a Dean-Stark trap and warmed to an internal temperature of 110° C. for 2 h under nitrogen atmosphere. The distilled toluene was collected in the Dean-Stark trap. The reaction mixture was cooled to room temperature under nitrogen gas. The reaction was quenched with 1.6 mL of aqueous 10 wt % sodium carbonate solution and partitioned between 65 mL of heptane and 35 mL of water. The organic solution was washed twice with 20 mL portions of water, concentrated in vacuo with gentle heating and the residue was chased once with heptane. The concentrate was dissolved in 35 g of methanol. Seed crystals were added to induce crystallization, the solvent was removed in vacuo and 16 mL of methanol was added to the crystalline solid. The mixture was stirred overnight at room temperature and the crystalline product was isolated by filtration, washed with methanol and dried in vacuo at 50° C. to give 3.5 g of 7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropylbiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane (96 area % by HPLC, 82% yield).
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1.[CH2:9]=[CH:10]CCCC>CO.[Ru]>[CH3:9][CH2:10][CH2:1][CH2:8][CH:7]=[CH:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: C=CCCCC
Reactant: C1=CCCC=CCC1
Agent: [Ru]
Solvent: CO
Product: CCCCC=CCCCC
Yield: 20 %

Procedure:
In contrast to the “classical” ruthenium metathesis catalysts mentioned above, which react only with highly-strained olefins, alkylidenes 6 and 7 of Example 6 also promote the ROMP of less-strained monomers such as 1,5-cyclooctadiene, and are active in the metathesis of acyclic olefins in protic solvents. For example, 6 will dimerize 1-hexene in methanol to give 5-decene in 20% yield (Equation 3). In these systems, separation of catalyst from product is facilitated through addition of water to the reaction mixture. Olefins collected from the resulting two-phase system contain very low levels of detectable ruthenium.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].CN(C=O)C.C(Cl)Cl.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>N1C=CC=CC=1>[CH2:24]([O:23][C:21]([NH:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:22])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1nccn1N
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nn1ccnc1C(=O)OCC
Temperature: 12.5 °C
Reaction time: 1.5 h

Procedure:
(I9C): In 10 lit, round bottom flask charged ethyl 1-amino-1H-imidazole-2-carboxylate (70 g, 451 mmol) along with DMF and DCM (1200 ml) was added and cooled to 10-15° C. Then pyridine was added (35 ml) at single lot. Followed by slow addition of ethyl chloroformate (30 ml) and stirred at same temperature for 1.5 hrs. After 1.5 hrs additional pyridine (25 ml) and ethyl chloroformate (20 ml) was added. The reaction mixture was stirred for additional 30 minutes. The reaction mixture was concentrated under high vacuum and the crude residue was diluted with ethyl acetate and given saturated aqueous citric acid (250 ml) washing. The organic layer was separated. The citric acid layer was extracted with EtOAc (3×500 ml). All organic layers combined and washed with brine (2×150 ml), dried with sodium sulphate and concentrated to get the syrupy gel. The syrupy gel was triturated with ether-hexane mixture to give 65 g of ethyl 1-((ethoxycarbonyl)amino)-1H-imidazole-2-carboxylate as pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]([NH2:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl.O>[C:23]([NH:15][CH:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([O:25][CH2:26][CH3:27])=[O:24]
Reactant: Cc1ccsc1C(N)Cc1ccccc1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)NC(Cc1ccccc1)c1sccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred two-phase mixture of 10 g (0.047 mol) of α-(3-methyl-2-thienyl)benzeneethanamine and 7.4 g (0.07 mol) of sodium carbonate in 150 ml of dichloromethane and 200 ml of water at 0° C. was added dropwise 7.6g (0.07 mol) of ethyl chloroformate. The resulting mixture was allowed to warm to ambient temperature and stirred vigorously overnight. The layers were separated, aqueous phase extracted with CH2Cl2 (2×50 ml), organic layers were combined and washed with 1N aqueous hydrochloric acid, brine, and dried. The crude N-carbethoxy-α-(3-methyl-2-thienyl)benzeneethanamine thus obtained was purified by silica gel chromatography to give 13.3 g of a pale yellow oil. A solution of 7.5 g (0.026 mol) of the oil in tetrahydrofuran (50 mL) was added dropwise to a stirred solution of 22 ml (0.075 mol) of a 3.4M solution of sodium bis (2-methoxyethoxy)aluminum hydride in toluene (Red-AL) dissolved in 150 ml of tetrahydrofuran at ambient temperature. The mixture was stirred overnight and quenched by dropwise addition of isopropanol until bubbling had ceased followed by dropwise addition of water until a white precipitate formed. After stirring for 30 minutes longer, the clear yellow solution was decanted and concentrated to dryness giving the crude product as an oil. The oil was dissolved in 50 ml of isopropanol, chilled to 0° C., and made acidic with hydrochlorinated isopropanol. The resulting white solid was collected by filtration and freeze-dried from water to give 1.8 g of white solid product (mp 214°-216° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[CH3:19][C:20]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22].C(O)(=O)C.[OH-].[Na+]>CN(C=O)C.O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]([NH2:18])=[O:17])=[C:2]2[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:26]([CH3:27])[C:20]=1[CH3:19]
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Reactant: Cc1cccc(N)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncc(C(N)=O)c(Nc3cccc(C)c3C)c2cc1OC
Temperature: 100 °C
Yield: 80.4 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g, 0.17 mmol), 2,3-dimethylaniline (20 μl, 0.22 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100° C. for 3.5 h. After cooling the reaction mixture was diluted with water (15 ml) and made alkaline with 1 M NaOH. The precipitate was collected by filtration, rinsed with water and dried to give the title compound (48 mg, 79%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[CH2:17])[C:11]2=[O:18])=[C:6](/[CH:19]=[CH:20]/[CH3:21])[CH:5]=1)([O-:3])=[O:2].C12BC(CCC1)CCC2.[OH-:31].[Na+].OO>O1CCCC1>[OH:31][CH2:17][CH2:16][C:12]1[C:11](=[O:18])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2/[CH:19]=[CH:20]/[CH3:21])[CH:15]=[CH:14][CH:13]=1
Reactant: [OH-]
Reactant: C=Cc1cccn(-c2ccc([N+](=O)[O-])cc2/C=C/C)c1=O
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: C/C=C/c1cc([N+](=O)[O-])ccc1-n1cccc(CCO)c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
452 g (1.60 mmol) of the compound from Example 45A are dissolved in 1.7 ml of anhydrous tetrahydrofuran and cooled to 0° C. 488 mg (176 mmol) of 9-bora-bicyclo[3.3.1]nonane (0.5 M solution in tetrahydrofuran) are added slowly, and the mixture is stirred at room temperature for 2 h. The mixture is then again cooled to 0° C., and 8 ml of 1N aqueous sodium hydroxide solution are added slowly. After the addition has ended, 1.6 ml of 30% strength hydrogen peroxide solution are added dropwise at this temperature. The mixture is stirred at 0° C. for 30 min and then washed with 1.3 ml of 40% strength sodium bisulphite solution to destroy the peroxides and diluted with 500 ml of ethyl acetate. The organic phase is removed and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and, after filtration, concentrated to dryness under reduced pressure. The product is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate=2:1). This gives 514 mg (100% of theory) of the desired product.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=2)[CH:7]=1)(=[O:4])=[O:3].[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]=[C:27]3[S:23][C:24](=[O:29])[NH:25][C:26]3=[O:28])=[CH:19][CH:20]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1cccc(CCOc2ccc(C=O)cc2)c1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)Oc1cccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)c1
Yield: 51.7 %

Procedure:
5.31 g (16.6 mmole) 3-[2-(4-formylphenoxy)ethyl]phenyl methanesulfonate, 2.13 g (18.2 mmole) 2,4-thiazolidinedione, 0.5 ml piperidine and 0.5 ml acetic acid in 300 ml toluene were refluxed with water separation in a Dean-Stark apparatus for 4 hours. The solvent was evaporated, acetic acid was added and the mixture was heated. The formed precipitate was filtered off and washed with diethyl ether to give 3.6 g (yield 51%) of 5-(4-[2-(3-methanesulfonyloxyphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:12][C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: ClCc1nc(-c2ccccc2)no1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2nc(-c3ccccc3)no2)cc1
Yield: 92 %

Procedure:
4-Nitrophenol (0.36 g, 2.56 mmole), 5-(chloromethyl)-3-phenyl-1,2,4-oxadiazole (0.5 g, 2.56 mmole) and anhydrous K2CO3 (0.39 g, 2.82 mmole) were dissolved in anhydrous acetone (20 mL) and heated to reflux for 12 h. Reaction mixture was cooled and the solvent removed under vacuum. The crude solid formed was collected by filtration, washed with water and dried under vacuum to provide 5-[(4-nitrophenoxy)methyl]-3-phenyl-1,2,4-oxadiazole (0.70 g, 92%). 1H NMR (CDCl3): δ 8.25 (d, 2H, J=8.8 Hz), 8.08 (dd, 2H, J=8.2 Hz), 7.52-7.49 (m, 3H), 7.13 (d, 2H, J=8.8 Hz), 5.45 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10](=O)[CH3:11])[CH:3]=1.[H-].[Na+].Cl.[CH2:16]([O:23][CH2:24][CH2:25][N:26](C)[CH2:27]CCl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:23][CH2:24][CH2:25][N:26]([CH2:11][CH2:10][NH:9][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1)[CH3:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(CCCl)CCOCc1ccccc1
Reactant: CC(=O)Nc1cc(C)cc(C)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(NCCN(C)CCOCc2ccccc2)c1
Temperature: 25 °C

Procedure:
To 24.5 g (0.149 mole) of N-(4,6-dimethyl-2-pyridyl)acetamide dissolved in 350 ml of dimethylformamide is added sodium hydride in mineral oil (50%) (7.2 g., 0.15 mole) in two portions with stirring, at room temperature. When reaction ceases, N-(2-benzyloxyethyl)-N-(2-chloroethyl)methylamine hydrochloride (24.5 g., 0.149 mole) is added in 2 portions. After bubbling ceases, the mixture is stirred at 50°-55° for 45 minutes and than heated on a steam bath for two hours. The mixture is cooled and concentrated under vacuum after 25 ml of acetic acid is added. The residue is taken up in dilute hydrochloric acid and extracted with hexane. The aqueous is made alkaline with 10 N sodium hydroxide and extracted with ether, then methylene chloride. The combined organic extracts are backwashed with brine, dried (sodium sulfate) and vacuum concentrated. The residue is distilled, the fraction boiling at 205°-215°/0.5 mm collected and this then refluxed in 5 N sodium hydroxide until hydrolysis is complete. On cooling, the mixture is extracted with toluene and then with methylene chloride. The combined organic extracts are washed with brine, dried and vacuum concentrated to obtain the product as an oil, weight 35 g.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[C:34]([CH:35]=O)=[C:33]([NH:37]C(=O)OC(C)(C)C)[CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C.O>[Cl:28][C:29]1[N:30]=[CH:31][CH:32]=[C:33]2[C:34]=1[CH:35]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]3([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:17][CH2:18][CH2:19]3)=[CH:12][CH:11]=1)=[N:37]2
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)Cc3ccccc3)cc2)CCC1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(Cl)c4cc3-c3ccccc3)cc2)CCC1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a round bottom flask was added tert-butyl {1-[4-(phenylacetyl)phenyl]cyclobutyl}carbamate (1-3) (2.7 g, 6.1 mmol), tert-butyl (2-chloro-3-formylpyridin-4-yl)carbamate (1-4) (1.6 g, 6.1 mmol), potassium carbonate (5.0 g, 6.0 mmol), and DMF (20 mL). The reaction mixture was heated to 80° C. while stirring in a hot oil bath under an atmosphere of nitrogen for 15 hours. Then the reaction mixture was warmed to 120° C. for 1 hour. The reaction mixture was permitted to cool to room temperature, added water, suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (5-50% EtOAc/5% DCM/Hexane) to give tert-butyl {1-[4-(5-chloro-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-5) as an off-white solid. HRMS (M+H)+: observed=486.1954, calculated=486.1943.
Reaction SMILES: CS(C)=O.[C:5]([C:9]1[C:10](=[O:34])[CH2:11][CH:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:20]=3[CH:33]=2)[CH2:13][C:14]=1[OH:15])(=O)[CH2:6][CH3:7].Cl.[CH2:36]([O:38][NH2:39])[CH3:37].C([O-])(=O)C.[Na+]>Cl.CCOCC>[CH2:36]([O:38][N:39]=[C:5]([C:9]1[C:10](=[O:34])[CH2:11][CH:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:20]=3[CH:33]=2)[CH2:13][C:14]=1[OH:15])[CH2:6][CH3:7])[CH3:37]
Reactant: CCC(=O)C1=C(O)CC(c2ccc3c(c2)N(Cc2ccccc2)C(=O)CO3)CC1=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCON=C(CC)C1=C(O)CC(c2ccc3c(c2)N(Cc2ccccc2)C(=O)CO3)CC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 10 mL of methyl sulfoxide were added in sequence 1.4 g (3.5 mmol) of 2-propionyl-3-hydroxy-5-(N-benzyl-3-oxo-(2H)-1,4-benzoxazin-6-yl)cyclohex-2-en-1-one, 0.42 g (4.4 mmol) of ethoxyamine hydrochloride and 0.37 g (4.5 mmol) of anhydrous sodium acetate. The resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with 50 mL of 0.5N HCl and extracted twice with 30 mL portions of ethyl acetate. The extracts were combined, dried over MgSO4 and filtered. Evaporation off of the solvent gave an oily residue. The residue was dissolved in 50 mL of ether, washed with water, then an aqueous NaCl solution, dried over MgSO4 and filtered. Evaporation off of the solvent gave a light amber glass which crystallized upon standing. The crude solid product was triturated in ether and the above-named product was isolated by filtration as a tan solid in a yield of 0.90 g (58 percent of theoretical). The product melted at 108°-110° C.; 1H NMR (CDCl3): d1.05-1.41 (m, 6H, both --CH2CH3 's), 2.42-3.45 (m, 7H), 4.12 (q, J=7 Hz, 2H, --OCH2CH3), 4.72 (2, 2H, --OCH2C=O), 5.20 (s, 2H, --CH2Ph), 6.75-7.08 (m, 3H, aromatic H's), 7.30 (s, 5H, --CH2Ph) ca. 14.7 (broad s, 1H, enol H); (Compound 7).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([O:11][CH3:12])[CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O>O.S(OC)(OC)(=O)=O>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([O:11][CH3:12])[C:5]=1[O:10][CH3:19]
Reactant: COc1cc(Br)cc(OC)c1O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(Br)cc(OC)c1OC
Temperature: 10 °C
Yield: 78.8 %

Procedure:
A mixture of 74 g (0.32 mol) of 4-bromo-2,6-dimethoxy-phenol 17 and 32 g (0.8 mol) of NaOH in 850 ml of H2O was cooled to 10° C. and 45 ml (0.48 mmol) of dimethyl sulfate was added. The mixture was refluxed for 3 h and an equal amount of dimethyl sulfate (total 0.96 mol) was then added. The mixture was refluxed for another 3 h. Upon cooling overnight, the gray product solidified and was filtered off and dissolved in 1.2 l of ether. The ether solution was filtered to remove insoluble impurity and washed sequentially with 5% NaOH solution (200 ml), water (2×200 mL), and brine (200 mL). The ether phase was dried over Na2SO4 to give a off-white solid, which was recrystallized in hexane (300 ml) to give 62.3 g (79%) of 18.