Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[C:6]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:7][C:8]([OH:10])=O.[C:15]([CH2:17][CH:18]1[CH2:21][CH:20](C(Cl)=O)[CH2:19]1)#[N:16]>CCCCCC.O1CCCC1.Cl>[C:15]([CH2:17][CH:18]1[CH2:21][CH:20]([C:8](=[O:10])[CH2:7][C:6]([O:12][CH2:13][CH3:14])=[O:11])[CH2:19]1)#[N:16]
Reactant: N#CCC1CC(C(=O)Cl)C1
Reactant: CCOC(=O)CC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C1CC(CC#N)C1
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyllithium in hexane (2.5M, 146 ml) was added dropwise to a mechanically stirred solution of ethyl hydrogen malonate (24.3 g, 0.18 ml) in dry tetrahydrofuran (210 ml) cooled to -60° C. under nitrogen atmosphere. After addition, the reaction mixture was stirred at -10° C. for 10 minutes then cooled to -60° C. and a solution of 3-cyanomethylcyclobutanecarbonyl chloride (17.0 g, 0.11 ml) in dry tetrahydrofuran (230 ml) added dropwise at such a rate to maintain temperature below -10° C. The reaction mixture was stirred overnight at room temperature, diluted with aqueous hydrochloric acid (2M, 180 ml) and extracted with diethyl ether (2×200 ml). The combined extracts were washed with a saturated solution of sodium bicarbonate (100 ml), water (100 ml) and brine solution (100 ml), dried, filtered and evaporated to a yellow oil (20.5 g). The crude product was purified by chromatography eluting with diethyl ether-hexane (1:1 and then 3:2) to give the title compound as an oil.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([NH2:24])[CH2:22][NH2:23]>>[N+:18]([C:16]1[CH:17]=[C:9]2[C:10]([C:11](=[O:13])[N:23]3[CH2:22][CH2:21][NH:24][C:1]32[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:15]=1)([O-:20])=[O:19]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Reactant: NCCN
Product: O=C1c2ccc([N+](=O)[O-])cc2C2(c3ccccc3)NCCN12

Procedure:
Condense 2-benzoyl-4-nitrobenzoic acid with ethylenediamine by the procedure of Example 1 to obtain 8-nitro-9b-phenyl-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one, m.p. 203° C.
Reaction SMILES: [C:1]1([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:17](=O)([O-:21])[O:18][CH2:19][CH3:20].[O-]CC.[Na+].[Na]>C(O)C>[C:1]1([CH:11]([C:17]([O:18][CH2:19][CH3:20])=[O:21])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)[O-]
Reactant: CCOC(=O)Cc1cccc2ccccc12
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1cccc2ccccc12
Temperature: 105 °C

Procedure:
A mixture of 103.9 g (485 mmol) of ethyl naphthalene-1-acetate and 430 ml of ethyl carbonate is stirred at 105° C., and a solution of sodium ethoxide (11 g (478 mmol) of sodium in 255 ml of absolute ethanol) is then added in such a way that the ethanol distils in the course of the introduction. The mixture is heated for a further 15 min. to distil the maximum amount of ethanol, the flask is rapidly cooled and the mixture is poured onto 300 g of crushed ice and 20 ml of concentrated hydrochloric acid. It is extracted with diethyl ether, the organic phase is dried over magnesium sulphate and filtered, and the solvent is evaporated under reduced pressure. An oil is obtained which crystallises in pentane in the cold. The crystals are separated by filtration, treated with vegetable charcoal in diethyl ether and filtered, the filtrate is evaporated and the residue is recrystallised in a 25:75 mixture of diethyl ether/pentane. 97 g (339 mmol) of crystals are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:19])[CH:12]=2)[N:7]=1.[NH2:24][C:25]1[S:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:29]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[C:14]([C:16](=[O:18])[NH:24][C:25]2[S:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:29]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:19])[CH:12]=2)[N:7]=1
Reactant: Cc1ccc2nc(OCc3ccccc3Cl)cc(C(=O)O)c2c1
Reactant: CCOC(=O)c1cnc(N)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(NC(=O)c2cc(OCc3ccccc3Cl)nc3ccc(C)cc23)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.4 %

Procedure:
To a stirred solution of 2-(2-chlorobenzyloxy)-4-carboxy-6-methylquinoline (Method 7; 0.350 g, 1.067 mmol) and ethyl 2-aminothiazole-5-carboxylate (0.184 g, 1.067 mmol) in dimethyl formamide (DMF, 6 ml) was added 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.307 g, 1.601 mmol) and 4-dimethylaminopyridine (0.391 g, 3.202 mmol). The reaction mixture was stirred overnight at room temperature, and then diluted with ethyl acetate (20 ml). The mixture was washed with water (20 ml), and the aqueous washings extracted with ethyl acetate (3×15 ml); the organic phases were combined and concentrated in vacuo. Flash chromatography on silica gel, eluting with a gradient of 2–20% ethyl acetate in iso-hexane, gave the title compound as a colourless solid (0.100 g, 19%). NMR: 1.30 (3H, t), 2.40 (3H, s), 4.30 (2H, q), 6.65 (2H, d), 7.20 (2H, m), 7.55 (2H, m), 7.65 (1H, m), 7.75 (1H, d), 7.95 (1H, s), 8.10 (2H, m), 8.15 (1H, s); m/z 482 (M+H)+, 480 (M−H)+,
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[C:13](=O)[C:12](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][S:10](=[O:23])(=[O:22])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][NH2:25]>CO>[C:1]1([CH:7]2[NH:25][N:24]=[C:13]3[C:12](=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][S:10](=[O:23])(=[O:22])[CH2:9][CH:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C(=Cc2ccccc2)CS(=O)(=O)CC1=Cc1ccccc1
Reactant: NN
Solvent: CO
Product: O=S1(=O)CC(=Cc2ccccc2)C2=NNC(c3ccccc3)C2C1
Yield: 90.1 %

Procedure:
A mixture of 5.0g of tetrahydro-3,5-bis-(phenylmethylene)-4H-thiopyran-4-one-1,1-dioxide and 600mg of anhydrous hydrazine in 300ml of methanol is heated at reflux temperature for 2 hours. The mixture is cooled in an ice bath, filtered, and the product is washed with fresh methanol. The filtrate and washings are concentrated to about 100ml and cooled in an ice bath, yielding an additional small amount of product. The combined yield is 4.7g of the title compound, melting point 202°-208°C, dec.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[N:12]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[CH:13]=[C:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:15]=2)=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[C:36]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[N:35]1.O>CN(C)C=O.O>[C:51]([O:50][C:49](=[O:55])[NH:48][C:36]1[C:37]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]3[N:12]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:22])=[O:23])[CH:13]=[C:14]([CH2:16][C:17]([CH3:18])([CH3:19])[CH3:20])[N:15]=3)=[O:10])=[CH:4][CH:3]=2)=[CH:38][N:34]([CH3:33])[N:35]=1)([CH3:54])([CH3:53])[CH3:52]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)n1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(-c2cn(C)nc2NC(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (23 mg, 0.03 mmol) was added to a degassed, ambient temperature solution of 2-[(4-bromophenyl)acetyl]-4-(2,2-dimethylpropyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Intermediate 7) (123 mg, 0.28 mmol), sodium carbonate (89 mg, 0.84 mmol) and tert-butyl [1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-3-yl]carbamate (90 mg, 0.28 mmol) in N,N-dimethylformamide/water (2:1) (7.5 mL). After stirring at 80° C. overnight, the reaction mixture was cooled, poured into water and extracted with diethyl ether. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-30% acetone/methylene chloride afforded tert-butyl[4-(4-{2-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylpropyl)-1H-imidazol-2-yl]-2-oxoethyl}phenyl)-1-methyl-1H-pyrazol-3-yl]carbamate.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH:13]([CH3:15])[CH3:14].[Br:17]Br.[O-]S([O-])=O.[Na+].[Na+]>[Fe].C(Cl)Cl>[CH3:1][CH:2]([CH3:16])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([Br:17])[CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: BrBr
Reactant: CC(C)COc1ccccc1OCC(C)C
Agent: [Fe]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)COc1ccc(Br)cc1OCC(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1,2-Bis(-2-methylpropyloxy)benzene (359.61 g, 1.62 mol) and 500 ml of CH2Cl2 were placed in the reaction vessel and admixed with a little iron powder. While cooling, bromine (266.88 g, 1.78 mol) (mixed with about 200 ml of CH2Cl2) was slowly added dropwise. The mixture was stirred for about 20 hours at room temperature. For the work-up, the mixture was stirred with aqueous Na2SO3 solution and the iron powder was subsequently filtered off. The organic phase was then shaken twice with NaHCO3 solution and subsequently washed with water until neutral. After drying, the organic phase was evaporated.
Reaction SMILES: [NH2:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[C:16]([S:18]Cl)=[O:17]>ClC1C=CC=CC=1>[O:17]=[C:16]1[NH:1][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[S:18]1
Reactant: O=C(Cl)SCl
Reactant: CCOC(=O)C=C(N)c1ccccc1
Solvent: Clc1ccccc1
Product: CCOC(=O)c1sc(=O)[nH]c1-c1ccccc1
Temperature: 110 °C
Yield: 55 %

Procedure:
To a solution of 20.0 g (0.105 mole) of ethyl β-amino-cinnamate in 40 ml. of chlorobenzene under ice cooling was added a solution of 11.6 g (0.112 mole) of chorocarbonylsulfenyl chloride in 10 ml. of chlorobenzene. The reaction mixture was heated at 110° C. for 2 hours, cooled to triturated with petroleum ether. The precipitate was heated with hot benzene, cooled and filtered to give 14.4 g (55%) of ethyl 2,3-dihydro-2-oxo-4-phenyl-5-thiazolecarboxylate as yellow needles. A mixture of 3.0 g (0.012 mole) of ethyl 2,3-dihydro-2-oxo-4-phenyl-5-thiazolecarboxylate and 14 ml. of phosphorus oxychloride was held at reflux for 24 hours and cooled. The reaction mixture was poured into ice water. The solid precipitate was extracted into ether. The ether solution was dried and concentrated under reduced pressure. The residue was recrystallized from hexane to give 2.2 g (68%) of ethyl 2-chloro-4-phenyl-5-thiazolecarboxylate, m.p. 56°-57° C.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=O.Cl.[NH2:20][OH:21]>N1C=CC=CC=1>[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4](=[N:20][OH:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12]
Reactant: NO
Reactant: O=C(c1ccccc1F)c1ccc(O)c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(c1ccccc1F)c1ccc(O)c(Cl)c1Cl

Procedure:
A solution of 31.8 g of 2,3-dichloro-4-hydroxy-2'-fluoro-benzophenone and 15.3 g of hydroxylamine hydrochloride in 150 ml of pyridine is refluxed for 64 hours. Thereafter, the pyridine is evaporated under vacuum and a 5% aqueous hydrochloric acid solution is added. The acidified solution is extracted with ethyl acetate and the combined extracts are dried before being concentrated to dryness. The resulting solid is recrystallized from an aqueous ethanol solution to yield the product 2,3-dichloro-4-hydroxy-2'-fluorobenzophenone oxime with a melting point of 168° to 175° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:16]3[N:15]4[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:14]4=[CH:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O:26][CH2:27][CH2:28]Br.[H-].[Na+]>>[CH3:25][O:26][CH2:27][CH2:28][N:22]1[CH2:21][CH2:20][CH2:19][N:15]2[C:16]3[CH:17]=[CH:18][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][C:12]=3[CH:13]=[C:14]2[C:23]1=[O:24]
Reactant: O=C1NCCCn2c1cc1cc(OCCCN3CCCC3)ccc12
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Product: COCCN1CCCn2c(cc3cc(OCCCN4CCCC4)ccc32)C1=O
Yield: 15 %

Procedure:
The title compound was synthesized in analogy to example 17, from 9-(3-pyrrolidin-1-yl-propoxy)-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (example 16), 2-bromoethyl methyl ether and sodium hydride, to give the desired product as a colorless oil (15%).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9](O)=[O:10]>>[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:10]
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccc(F)c(Cl)c1
Yield: 89 %

Procedure:
Using cyclopropylamine and 3-chloro-4-fluorobenzoic acid in the general procedure for coupling of amines to carboxylic acids, the title compound was obtained (89% yield) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ=8.56 (d, J=3.5 Hz, 1 H), 8.03 (dd, J=7.3, 2.3 Hz, 1 H), 7.85 (ddd, J=8.6, 4.8, 2.3 Hz, 1 H), 7.52 (t, J=9.0 Hz, 1 H), 2.83 (tq, J=7.4, 3.9 Hz, 1 H), 0.66-0.75 (m, 2 H), 0.53-0.61 ppm (m, 2 H). ESI-MS: m/z 214.0 (M+H)1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (290 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) according to the general procedure M. Obtained as a white foam (430 mg, 82%).
Reaction SMILES: CON(C)[C:4]([C@H:6]1[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[N:7]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:5].OS([O-])(=O)=O.[K+]>C1COCC1>[CH:4]([C@H:6]1[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[N:7]1[C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])=[O:5]
Reactant: CON(C)C(=O)[C@H]1COC(C)(C)N1C(=O)OCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](C=O)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of LiALH4 (1 M, 20 mL, 20 mmol) was added dropwise to a cold (−15° C.) solution of (R)-benzyl 4-(methoxy(methyl)carbamoyl)-2,2-dimethyloxazolidine-3-carboxylate (12.2 g, 37.9 mmol) in THF (75 mL). The mixture was stirred for 30 min keeping the temperature below 0° C. A saturated solution of KHSO4 (100 mL) was added slowly to the mixture and it was warmed to room temperature. The mixture was filtered and the solvent was removed to dryness. (R)-benzyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate was obtained as a clear oil (9.161 g, 92% yield) after purification by column chromatography (SiO2, using a mixture of hexane/EtOAc).
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]2[CH:13]=[C:12]([CH3:14])[C:11](=[O:15])[N:10]([CH3:16])[C:9]=2[N:17]([C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])C(=O)OC(C)(C)C)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:32][C:26]1[CH:27]=[C:28]([I:31])[CH:29]=[CH:30][C:25]=1[NH:17][C:9]1[N:10]([CH3:16])[C:11](=[O:15])[C:12]([CH3:14])=[CH:13][C:8]=1[NH:7][S:4]([CH:1]1[CH2:2][CH2:3]1)(=[O:6])=[O:5]
Reactant: Cc1cc(NS(=O)(=O)C2CC2)c(N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)n(C)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NS(=O)(=O)C2CC2)c(Nc2ccc(I)cc2F)n(C)c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 49.9 %

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 3-(cyclopropanesulfonamido)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-2-yl(2-fluoro-4-iodophenyl)carbamate (120 mg, 0.21 mmol) in 20% mixture of TFA in DCM (10 mL). The reaction mixture was stirred at room temperature for 14 hours and the solvents were removed under reduced pressure. The crude material was purified by flash chromatography (Biotage system) using a gradient of EtOAc (0-50%) in hexane to afford the title product as a white solid (50 mg, 50%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])#[CH:19]>C(#N)C.O1CCOCC1.[Cu]I>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:3][C:2]=1[C:19]#[C:18][Si:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(NC2CCN(C)CC2)cc1I
Agent: [Cu]I
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1ccc(NC2CCN(C)CC2)cc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Into a flask maintained under argon atmosphere N-(3-iodo-4-methoxyphenyl)-1-methylpiperidin-4-amine (180 mg, 0.52 mmol), CuI (9.9 mg, 0.052 mmol) and Pd(Ph3P)Cl2 (36.5 mg, 0.052 mmol) were added and dissolved in acetonitrile (5 mL) and dioxane (5 mL). The solution was degassed and backfilled with argon for three times. TEA (0.725 mL, 526 mg, 5.2 mmol) and (ethynyl)trimethylsilane (0.147 mL, 0.102 mg, 1.04 mmol) were added with a syringe and the solution was stirred at room temperature for 75 min. The volatiles were evaporated and the residue was taken up with EtOAc (30 mL), washed with water (3×5 mL), dried over sodium sulfate and the solvent was removed under vacuum.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.N[CH2:8][C@@H:9]1CC[CH2:11][N:10]1CC>>[N:1]1([CH2:8][CH2:9][NH:10][CH3:11])[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]1
Reactant: C1=CCNCC1
Reactant: CCN1CCC[C@H]1CN
Product: CNCCN1CC=CCC1

Procedure:
By using 1,2,3,6-tetrahydropyridine (960.2 mg) as a starting material, the title compound (855 mg) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: [CH3:1][N:2]([Si](C)(C)C)[C:3](=[O:6])[CH:4]=[CH2:5].[C:11](Cl)(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH3:1][N:2]([C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:3](=[O:6])[CH:4]=[CH2:5]
Reactant: C=CC(=O)N(C)[Si](C)(C)C
Reactant: CCCCCCCC(=O)Cl
Product: C=CC(=O)N(C)C(=O)CCCCCCC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To 4.1 g (0.0252 mole) of N-methyl-N-trimethylsilylacrylamide was added dropwise 3.66 g of octanoyl chloride at 0° C. After the addition was completed, the mixture was allowed to stir for 45 minutes at room temperature. Complete conversion was indicated by IR after 2 hours and 45 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:23]=1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1.C([O-])(=O)C.[K+].CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:24][C:25]1[C:30]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]5[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=5)[N:14]=[C:7]4[C:6]=3[CH:23]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(-c3cccnc3F)ccc1OCC2
Temperature: 105 °C
Yield: 80.3 %

Procedure:
10-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 187 (0.057 g, 0.15 mmol), 2-fluoropyridin-3-ylboronic acid (0.026 g, 0.183 mmol), potassium acetate (0.059 g, 0.609 mmol), and tetrakis(triphenylphosphine)palladium(0) (8.8 mg, 0.007 mmol), DMF (6 mL) and water (0.6 mL) were mixed. Nitrogen was bubbled through the reaction mixture for 5 minutes. The reaction mixture was allowed to stir and heat at 105° C. for 24 hours before cooling, diluting with EtOAc, and filtering through a pad of celite. The filtrate was concentrated under reduced pressure and diluted with EtOAc. The solution was washed sequentially with water, and brine, before drying over MgSO4 and concentrating under reduced pressure. The crude material was dissolved in DMF and purified by reverse phase HPLC to provide 10-(2-fluoropyridin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (47 mg, 80%). MS (ESI(+)): m/z 391.1 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.C(O[CH:20](N(C)C)[N:21]([CH3:23])[CH3:22])(C)(C)C>>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]=[CH:20][N:21]([CH3:23])[CH3:22])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COc1ccc2nc(Cl)cc(C)c2c1
Product: COc1ccc2nc(Cl)cc(C=CN(C)C)c2c1
Temperature: 120 °C
Yield: 92.6 %

Procedure:
2-Chloro-6-methoxy-4-methylquinoline (25 g, 0.12 mol) and tert-butoxybis(dimethylamino)methane (Bredereck's reagent) (30 g, 0.17 mol) was stirred under heating at 120° C. for 1.5 hours. After cooling the reaction mixture, the precipitated crystals were washed with diisopropyl ether to obtain the title compound (29.2 g, 92%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[S:15][CH:14]=[N:13][CH:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([NH:25][CH2:26][C@@H:27]3[C@H:32]([CH3:33])[CH2:31][CH2:30][CH2:29][NH:28]3)=[N:22][C:21]=2[CH:34]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([NH:25][CH2:26][C@@H:27]3[C@H:32]([CH3:33])[CH2:31][CH2:30][CH2:29][N:28]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:11]3[S:15][CH:14]=[N:13][CH:12]=3)=[O:9])=[N:22][C:21]=2[CH:34]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Reactant: Cc1ccc(-c2cncs2)c(C(=O)O)c1
Product: Cc1ccc(-c2cncs2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(thiazol-5-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 481 [M+1]+.
Reaction SMILES: [C:1]([NH:5][C:6](=[S:23])[NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])([O:3][CH3:4])=[O:2].[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[C:1]([NH:5][C:6](=[S:23])[NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH:22][C:31]([NH:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:32])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1N
Reactant: O=C=Nc1ccccc1
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1NC(=O)Nc1ccccc1
Reaction time: 8 h
Yield: 65 %

Procedure:
To a suspension of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (3.0 g.) in acetone (100 ml.) is added phenyl isocyanate (1.08 g.). The reaction mixture is refluxed for 11/2 hours and then allowed to stand at room temperature overnight. The precipitate is collected, washed with ether and dried to afford 2.65 g. (65% yield) of 3-(3-carbomethoxythioureido)-4-(3-phenylureido)benzophenone as a white solid, m.p. 212° C., dec.