Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:7][N:8]=1)[NH2:2].[C:16]([O-])([O-])(OCC)[CH3:17]>CCCCCC>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:7]=[N:8][C:3]3[N:4]([C:16]([CH3:17])=[N:2][N:1]=3)[N:5]=2)=[CH:14][CH:13]=1
Reactant: NNc1ncc(-c2ccc(F)cc2)nn1
Reactant: CCOC(C)([O-])[O-]
Solvent: CCCCCC
Product: Cc1nnc2ncc(-c3ccc(F)cc3)nn12

Procedure:
A mixture of 3.09 g. of 3-hydrazino-6-(p-fluorophenyl)-1,2,4-triazine and 35 ml. of ethyl orthoacetate is refluxed for 4 hours, cooled, poured into hexane and the solid is collected, and washed with ethanol giving the desired product as a brown solid, m.p. 147°-150° C.
Reaction SMILES: [Br:1][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]Br.[CH2:17]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[CH2:18][CH3:19]>>[Br-:1].[Br-:1].[CH2:17]([N+:20]([CH2:24][CH2:25][CH3:26])([CH2:21][CH2:22][CH3:23])[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][N+:20]([CH2:24][CH2:25][CH3:26])([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:18][CH3:19])[CH2:18][CH3:19]
Reactant: CCCN(CCC)CCC
Reactant: BrCCCCCCCCCCCCCCBr
Product: CCC[N+](CCC)(CCC)CCCCCCCCCCCCCC[N+](CCC)(CCC)CCC
Product: [Br-]

Procedure:
3.56 g (10 mM) of -1,14-dibromotetradecane are added to 20 ml tripropylamine and held at 80/90° C. over night. The excess tertiary amine is evaporated under vacuum, and a minimal amount of ethanol is added to redissolve the derivative which is reprecipitated with ether. The derivative defined in the title is obtained by recrystallization in a isopropanol/iisopropylic ether mixture, M.P.=170° C.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH:48]([F:50])[F:49])=[CH:43][CH:42]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>CO>[F:50][CH:48]([F:49])[O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][CH2:39][C:28]2[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=2)=[CH:46][CH:45]=1
Reactant: FC(F)Oc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CO
Solvent: C1CCOC1
Product: O=c1[nH]nc(CCc2ccc(OC(F)F)cc2)cc1O

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-((4-(difluoromethoxy)phenyl)ethynyl)pyridazine (Intermediate 36) except that the solvent mixture used for the hydrogenation was made up of tetrahydrofuran and methanol and the final material was recrystallised from 2-propanol and heptanes.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][O:17][C:18](=[O:33])[CH2:19][C:20]1[C:29]([CH3:30])=[C:28](O)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:32])[CH:26]=2)[CH:21]=1.N1C=CC=CC=1.O>ClCCl>[CH3:16][O:17][C:18](=[O:33])[CH2:19][C:20]1[C:29]([CH3:30])=[C:28]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:32])[CH:26]=2)[CH:21]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(O)c1C
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Cc1cc2ccc(F)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
Trifluoromethanesulfonic anhydride (0.35 mL, 2.1 mmol) was added drop-wise to a 0° C. solution of (6-fluoro-4-hydroxy-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (400 mg, 1.61 mmol) and pyridine (0.195 mL, 2.42 mmol) in dichloromethane (12.0 mL). The reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was warmed to room temperature, and stirred for 4 hours. The reaction mixture was then cooled to 0° C. Water (150 mL) was added, and the mixture was extracted three times with 50 mL portions of dichloromethane. The combined organic layers were dried over Na2SO4, filtered, and evaporated to yield a yellow oil. A solution of this crude product in dichloromethane was evaporated over silica gel, and the resulting silica gel-supported product was subjected to flash chromatography (RediSep® Flash column, 230-400 mesh, 28% ethyl acetate in hexane) to give 514 mg (84%) of (6-fluoro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester as a white, crystalline solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.82 (dd, J=8.9, 5.6 Hz, 1 H), 7.73 (s, 1 H), 7.64 (d, J=10.0 Hz, 1 H), 7.27-7.35 (m, 1 H), 3.84 (s, 2 H), 3.73 (s, 3 H), 2.49 (s, 3 H). HRMS (ES+) cald. for C15H12F4O5S [(M+Na)+] 403.0234, obsd. 403.0233.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=2)[CH:8]=1.C(Cl)(=O)C(Cl)=O.[CH2:21]([N:28]1[C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([NH2:37])[C:31]=2[CH:30]=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:21]([N:28]1[C:36]2[C:31](=[C:32]([NH:37][C:12]([C:9]3[N:7]4[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]4=[N:11][CH:10]=3)=[O:14])[CH:33]=[CH:34][CH:35]=2)[CH:30]=[N:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Reactant: COc1ccc2ncc(C(=O)O)n2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2ncc(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)n2c1
Temperature: 25 °C
Yield: 24.5 %

Procedure:
6-Methoxyimidazo[1,2-a]pyridine-3-carboxylic acid (29.5 mg, 0.154 mmol) was taken up in DCM. Oxalyl chloride (1.1 equivalents) was added followed by a drop of DMF. The reaction was stirred at ambient temperature until bubbling ceased, and then 1-benzyl-1H-indazol-4-amine (34.3 mg, 0.154 mmol) was added followed by DIEA (1.2 equivalents). The reaction was stirred at ambient temperature overnight. The reaction was concentrated, triturated with ether and purified by Preparative TLC (1 mm) eluting with 10% MeOH/DCM to give 15 mg (25%) of the desired product. MS (ES+APCI) m/z=398.3 (M+H).
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](I)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[C:27]([CH:35]1[CH2:40][CH2:39][N:38]([C:41](=[O:43])[CH3:42])[CH2:37][CH2:36]1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:27]([OH:34])([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:35]3[CH2:40][CH2:39][N:38]([C:41](=[O:43])[CH3:42])[CH2:37][CH2:36]3)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(=O)N1CCC(C(=O)c2ccccc2)CC1
Reactant: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(-n2cncn2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1nc2ccc(C(O)(c3ccccc3)C3CCN(C(C)=O)CC3)cc2c(Cl)c1Cc1ccc(-n2cncn2)cc1
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
A solution of isopropylmagnesium chloride-lithium chloride complex in tetrahydrofuran (1.3 M, 0.73 mL, 0.94 mmol) was added dropwise to an ice-water cooled, stirring solution of 3-(4-(1H-1,2,4-triazol-1-yl)benzyl)-4-chloro-6-iodo-2-methoxyquinoline (300 mg, 0.63 mmol, Intermediate 20: step c) in dry tetrahydrofuran (6 mL). After 10 minutes, a solution of 1-(4-benzoylpiperidin-1-yl)ethanone (218 mg, 0.94 mmol, Intermediate 18) in tetrahydrofuran (5 mL) was added dropwise. After 30 minutes, the flask was warmed to 23° C. After 1 hour, the flask was warmed to 55° C. After 30 minutes, the flask was allowed to cool to 23° C. Water (20 mL), saturated aqueous sodium chloride solution (20 mL), and ethyl acetate (100 mL) were added. The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. Silica gel (5 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash column chromatography purification. Elution with dichloromethane initially, grading to 5% methanol-dichloromethane provided the title compound which was further purified by RP-HPLC eluting initially with 5% acetonitrile-water (containing 0.05% trifluoroacetic acid), grading to 95% acetonitrile-water (containing 0.05% trifluoroacetic acid) to provide the title compound as a white solid after partitioning the purified material between dichloromethane-saturated aqueous sodium bicarbonate solution, separating the layers, drying the organic layer with sodium sulfate, filtering the dried solution, and concentrating the filtrate to dryness. 1H NMR (500 MHz, CDCl3) δ ppm 8.47 (s, 1H), 8.32-8.25 (m, 1H), 8.06 (s, 1H), 7.80-7.72 (m, 1H), 7.72-7.62 (m, 1H), 7.57-7.48 (m, 4H), 7.44-7.38 (m, 2H), 7.37-7.29 (m, 2H), 7.26-7.18 (m, 1H), 4.75-4.63 (m, 1H), 4.34 (s, 2H), 4.05 (s, 3H), 3.90-3.75 (m, 1H), 3.17-2.99 (m, 1H), 2.76 (t, J=11.8 Hz, 1H), 2.66-2.49 (m, 1H), 2.28 (s, 1H, rotamer), 2.27 (s, 1H, rotamer), 2.05 (s, 3H, rotamer), 2.04 (s, 3H, rotamer), 1.75-1.62 (m, 1H), 1.55-1.28 (m, 3H); MS (ESI): mass calcd. for C33H32ClN5O3, 581.2. m/z found, 582.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[C:9]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]([CH:7]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)s1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Cc1ccc(C)s1)C(=O)OCC

Procedure:
A 215 g (1.71 moles) sample of 5-methyl-2-thiophenecarboxaldehyde, 258 ml (1.71 moles) diethyl malonate, 25 ml piperidine, 0.52 g benzoic acid, and 1.5 L toluene were placed into a round bottom flask and heated to reflux for four hr. with azeotropic removal of water. The reaction was cooled and water was added. The toluene layer was washed with sodium bicarbonate solution. 3N hydrochloric acid, water, brine and dried (MgSO4). The solvent was evaporated in vacuo. The residue was washed with methylcyclohexane. The washings were collected, the solvent removed in vacuo and the residue was recrystallized from methylcyclohexane. The solid materials were combined to give 299.86 g of diethyl 2-[(5-methyl-2-thienyl)methylene]propanedioate, mp 53°-56° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([CH3:12])=[N:4]1)[CH3:2].[I:13]N1C(=O)CCC1=O.CCOC(C)=O>CN(C=O)C.O>[CH2:1]([N:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([I:13])[C:5]([CH3:12])=[N:4]1)[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCn1nc(C)cc1C(=O)OC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1nc(C)c(I)c1C(=O)OC
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a flask, methyl 1-ethyl-3-methylpyrazol-5-ylcarboxylate (1.00 g, 0.006 mol, Ref. CN1626520A) was dissolved in 10 mL of DMF and N-iodosuccinimide (1.47 g, 0.007 mol) was added in batches. After reacting for 8 h at r.t., the mixture was diluted with 50 mL of water, and then extracted with 50 mL of ethyl acetate. The organic layer was washed with 50 mL of saturated aqueous sodium bicarbonate solution and 50 mL of saturated brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. Column chromatography (EtOAc:P.E.=1:10 as eluent) gave 0.82 g of the title compound as a yellow oil (yield 47%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:17]([CH:20]=[CH2:21])=[CH:16][C:10]=1[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.[OH-:31].[Na+].OO>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:31])=[CH:16][C:10]=1[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(OCc2ccccc2)c(C(=O)N(C)C)c1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1cc(CCO)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 14.5 h

Procedure:
To a stirred solution of 2-benzyloxy-N,N-dimethyl-5-vinylbenzamide (560 mg) in tetrahydrofuran (5 ml) was added dropwise a solution of 9-borabicyclo[3.3.1]nonane (255 mg) in tetrahydrofuran (8 ml) at −20° C. under an argon atmosphere, and the mixture was stirred for 14.5 hours at room temperature. To the stirred reaction mixture were added 2N aqueous sodium hydroxide solution (3.0 ml) and 30% aqueous hydrogen peroxide solution (2.4 ml) under ice-cooling, and the resulting mixture was stirred for 5 hours at room temperature. To the reaction mixture was added water, and the resulting mixture was extracted with dichloromethane. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent:hexane/diethyl ether/dichloromethane=1/2/2 and methanol/diethyl ether/dichloromethane=1/10/10) gave 2-benzyloxy-5-(2-hydroxyethyl)-N,N-dimethylbenzamide (300 mg).
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C[Al](C)C.[O:10]1[CH:14]=[C:13]([C:15]([O:17]C)=O)[N:12]=[CH:11]1.Cl.C(Cl)Cl>ClC(Cl)C>[O:10]1[CH:14]=[C:13]([C:15]([N:4]([CH3:5])[O:3][CH3:2])=[O:17])[N:12]=[CH:11]1
Reactant: CNOC
Reactant: COC(=O)c1cocn1
Agent: C[Al](C)C
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1cocn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81.1 %

Procedure:
To a suspension of methoxy-methylamine hydrochloride (2.3 g, 23.6 mmol) in 30 ml of dichloroethane at 0° C. was added dropwise 11.8 ml (23.6 mmol) of trimethylaluminum. The mixture was stirred at 0° C. for 20 min, methyl 4-oxazolecarboxylate (1 g, 7.9 mmol) in 20 ml of dichloroethane was added in one portion. The mixture was poured into an ice-cold solution of 0.5N HCl/methylene chloride (2:1) and stirred for 10 min. The aqueous layer was extracted with methylene chloride (2×50 ml), and the combined organic layer was washed with saturated ammonium chloride solution, dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by chromatography on silica (methylene chloride/ethyl acetate/methanol 6:3:1) to afford 1.0 g (81.9%) of 4-oxazolyl-N-methyl-N-methoxy-carboxamide.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([O:27][CH3:28])[CH:18]=2)=[C:11]([N+:29]([O-])=O)[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>O=[Pt]=O.CCO>[NH2:29][C:11]1[CH:10]=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:14]=[CH:13][C:12]=1[NH:15][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([O:27][CH3:28])[CH:18]=1
Reactant: COC(=O)c1ccc(CNc2ccc(O[Si](C)(C)C(C)(C)C)cc2[N+](=O)[O-])cc1OC
Agent: O=[Pt]=O
Solvent: CCO
Product: COC(=O)c1ccc(CNc2ccc(O[Si](C)(C)C(C)(C)C)cc2N)cc1OC
Reaction time: 1.5 h
Yield: 99.5 %

Procedure:
To the above nitro compound (Example 1, Part C; 0.5 g, 1.11 mmol) was added PtO2 (Adam's) catalyst (0.025 g) and EtOH (absolute, 40 mL). The mixture was rapidly stirred under a hydrogen atmosphere (balloon) for 1.5 h and then the catalyst removed by filtering over a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure, yielding 460 mg (99%) of the desired product.
Reaction SMILES: C(C[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[C:8]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)#N.[OH-:23].[Na+].[CH2:25]([OH:28])[CH2:26]O>O>[C:25]([CH2:26][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[C:8]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)([OH:28])=[O:23]
Reactant: OCCO
Reactant: [OH-]
Reactant: Cc1c(-c2cccnc2)n(CCCCC#N)c2ccccc12
Agent: [Na+]
Solvent: O
Product: Cc1c(-c2cccnc2)n(CCCCC(=O)O)c2ccccc12

Procedure:
1-(4-Cyanobutyl)-3-methyl-2-(3-pyridyl)-indole (578 mg) is heated at 185° for 0.5 hour with 450 mg of powdered NaOH and 5 ml of ethylene glycol; there is obtained, after pouring the reaction solution into 50 ml water, washing with ether, and adjusting the pH to 6 with 2 N HCl, an oily solid which crystallizes to give 1-(4-carboxybutyl)-3-methyl-2-(3-pyridyl)indole of Example 5 (m.p. 127°-129°).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[F:18][C:19]([F:39])([F:38])[CH2:20][O:21][CH2:22][CH2:23][O:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:27][CH:26]=1>>[F:39][C:19]([F:18])([F:38])[CH2:20][O:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([O:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:2][C:3]([NH:5][C@@H:6]3[CH2:11][O:10][C:9]4=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]4[CH2:7]3)=[O:4])[CH2:32][CH2:31]2)=[CH:36][CH:37]=1
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Reactant: FC(F)(F)COCCOc1ccc(OC2CCNCC2)cc1
Product: O=C(CN1CCC(Oc2ccc(OCCOCC(F)(F)F)cc2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 27.6 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(4-(2-(2,2,2-trifluoroethoxy)ethoxy)phenoxy)piperidine (319 mg, 1.0 mmol) as crude materials, 75 mg title compound was generated and yield was 27%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][O:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH2:35]([O:37][CH:38]1[CH2:41][NH:40][CH2:39]1)[CH3:36].C(Cl)(Cl)Cl>CN(C=O)C>[O:18]1[CH2:19][CH2:20][O:21][CH2:22][CH:17]1[C:16]1[C:10]2[S:9][C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:40]4[CH2:41][CH:38]([O:37][CH2:35][CH3:36])[CH2:39]4)[CH:3]=3)=[N:12][C:11]=2[C:13]([O:23][CH3:24])=[CH:14][CH:15]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CCOC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC1CN(c2cc(C(=O)Nc3nc4c(OC)ccc(C5COCCO5)c4s3)ccn2)C1

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 3-ethoxy-azetidine hydrochloride in DMF. [α]D20=+44.3° (c=0.57, CHCl3), ES-MS m/e (%): 471 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[CH:3]=1.[C:20](Cl)(=O)C(Cl)=O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8](=[O:11])[C:9]([CH3:20])=[CH:10][N:12]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[CH:6][CH:7]=1
Reactant: CCC(=O)c1ccc(F)cc1Nc1ccccc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O
Temperature: 0 °C
Yield: 37.8 %

Procedure:
In a 250 mL round bottom flask, 1-[4-fluoro-2-(2-fluoro-phenylamino)-phenyl]-propan-1-one (3.05 g, 11.7 mmol) was added to DMF (4.3 mL) at 0° C. Oxalyl chloride (8.18 mL, 96.7 mmol) was added slowly and the reaction mixture stirred at 0° C. The mixture was then warmed up to room temperature and stirred for 1.5 hr. The mixture was concentrated to dryness and the crude redissolved in toluene (80 mL). The reaction mixture was heated at 115° C. for 24 hr. The mixture was concentrated to dryness and triturated from methanol to afford 7-fluoro-1-(2-fluoro-phenyl)-3-methyl-1H-quinolin-4-one (1.20 g, 37.8%) as a white solid.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C/[C:10](/[C:16]([O-:18])=[O:17])=[C:11](\C)/[C:12]([O-:14])=O.[CH2:19](N(CC)CC)C>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C(#N)C>[O:14]=[C:12]1[CH:11]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:4]1
Reactant: CCN(CC)CC
Reactant: C/C(C(=O)[O-])=C(\C)C(=O)[O-]
Reactant: Nc1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: COC(=O)c1cc(=O)[nH]c2ccccc12
Temperature: 25 °C

Procedure:
In a heavy-walled PYREX tube was placed 2-iodoaniline (2.84 g, 13 mmol), dimethylmaleate (2.44 g, 17 mmol), triethylamine (1.4 mL, 10 mmol), palladium diacetate (31 mg, 0.14 mmol) and 6 mL acetonitrile. The tube was flushed with nitrogen and sealed. The sealed tube was heated at 100° for 3.5 h then cooled to r.t. The tube was opened and the resulting solids filtered and washed with acetonitrile. The solids were dissolved in chloroform and the solvent removed under vacuum to provide a solid.
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH3:3].Br[CH2:19][CH2:20][CH2:21][OH:22].C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[C:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:16][CH2:17]2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH3:3]
Reactant: OCCCBr
Reactant: CC(=O)Nc1cccc(C2CCNCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(C2CCN(CCCO)CC2)c1
Yield: 83.5 %

Procedure:
5.3 g (20.8 mmol) of 4-(3-acetylaminophenyl)piperidine hydrochloride was dissolved in 50 ml of N,N-dimethylformamide, and then 3.8 g (27.0 mmol) of 3-bromo-1-propanol and 8.6 g (62 mmol) of K2CO3 were added to the resulting solution, followed by treating the mixture at 60° C. for 5 hours. The reaction mixture was combined with 150 ml of water and extracted with ethylacetate (100 ml×5), and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (10% methanol/CH2Cl2) to obtain 4.8 g (yield 85%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].CS(C)=O.[H-].[Na+].S(OCC1CCC=CC1)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=O)=O>O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:22][CH:21]1[CH2:23][CH2:24][CH2:18][CH:19]=[CH:20]1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OCC2CC=CCC2)cc1
Reactant: CCCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCOCCOCC1C=CCCC1
Reaction time: 8 h

Procedure:
A 500 niL round bottom flask equipped with a mechanical stirrer was charged with 16.7g (0.15 mol) 2-butoxyethanol, and 150 mL of DMSO. Sodium hydride (4.22 g, 95% in purity; 0.167 mol) was slowly added to above mixture in an ice bath over 20 min. After the above mixture was reacted at room temperature for 3 hrs, 39.9 g (0.15 mol) of 3-cyclohexene-1-methanol tosylate was slowly added to the above mixture over 20 min. The reaction was carried at room temperature overnight, then 80° C. for 3 hrs. The reaction mixture was added to water (150 mL), and then extracted with chloroform (3×150 mL), washed with water (2×100 mL), dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.