Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1Br.[Br-].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Fc1ccc(Br)c(F)c1
Reactant: C1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Fc1ccc(N2CCNCC2)c(F)c1
Temperature: 110 °C

Procedure:
1-(2,4-Difluorophenyl)piperazine is prepared from 2,4-difluorobromobenzene. To the bromide (8.0 g, 41.4 mmol), piperazine (21.4 g, 249 mmol), sodium t-butoxide (5.6 g, 58 mmol) and BINAP (1.55 g, 2.5 mmol) in toluene (20 ml), add Pd2(dba)3 (0.477 g, 0.83 mmol). Heat the mixture at 110° C. under N2 for 20 h. Allow to cool and extract with 1N HCl. Basify the extract with NaOH to pH=10, extract with CH2Cl2, dry and concentrate to obtain the title compound as a brown oil.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])[O:12][N:11]=2)=[CH:6][CH:5]=1.[OH:30][CH:31]1[CH2:36][NH:35][CH2:34][CH:33]([C:37]([OH:39])=[O:38])[CH2:32]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(O)C.CS(C)=O>[OH:30][CH:31]1[CH2:36][N:35]([CH2:3][CH:2]([OH:1])[C:4]2[CH:5]=[CH:6][C:7]([C:10]3[N:14]=[C:13]([C:15]4[O:19][N:18]=[C:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:16]=4[C:26]([F:27])([F:28])[F:29])[O:12][N:11]=3)=[CH:8][CH:9]=2)[CH2:34][CH:33]([C:37]([OH:39])=[O:38])[CH2:32]1
Reactant: O=C(O)C1CNCC(O)C1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Solvent: CS(C)=O
Product: O=C(O)C1CC(O)CN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a mixture of 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole, Preparation 28C (30 mg, 0.075 mmol) and 5-hydroxypiperidine-3-carboxylic acid (21.81 mg, 0.150 mmol) in 2-propanol (2 mL) and DMSO (2.000 mL) was added cesium carbonate (122 mg, 0.376 mmol). The reaction mixture was heated at 80° C. Next, 5-hydroxypiperidine-3-carboxylic acid (21.81 mg, 0.150 mmol) was added and the reaction was checked after 4 hr. Product peak was observed but starting material remained. The reaction mixture was heated overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the desired product was 5.6 mg, and its purity was 99%. 1H NMR (400 MHz, MeOD) δ ppm 8.21 (2H, d, J=7.78 Hz), 7.69 (4H, d, J=6.78 Hz), 7.53-7.65 (3H, m), 5.19 (1H, dt, J=10.10, 3.61 Hz), 4.16 (1H, br. s.), 3.08-3.26 (5H, m), 2.86-3.06 (2H, m), 1.87-2.06 (3H, m). MS (m+1)=545.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[N:13]=[CH:12][C:11]([C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=2)[CH2:3]1.[OH-].[Na+]>CCO>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1
Reactant: CCOC(=O)c1ccc(OC2CCN(C)C2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC(Oc2ccc(C(=O)O)cn2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 170 %

Procedure:
Ethyl 6-[(1-methylpyrrolidin-3-yl)oxy]pyridine-3-carboxylate (Intermediate 241, 0.089 g, 0.36 mmol) was dissolved in EtOH (2 mL), 2M aq. sodium hydroxide (0.53 mL, 1.07 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was concentrated under vacuum and the residue acidified to pH 6 by adding 2M hydrochloric acid. The mixture was then concentrated and dried under vacuum to afford the title compound as a cream solid (0.136 g), which was used directly in the next step without further purification. Method C HPLC-MS: MH+ requires m/z=223 Found: m/z=223, Rt=0.38 min (17% by ELS).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[I:10].C(=O)([O-])O.[Na+].Cl>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[I:10]
Reactant: COc1ccc(Cl)c(I)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(Cl)c(I)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-chloro-2-iodo-4-methoxybenzene (2.68 g, 10.0 mmol) in dichloromethane (20 ml) was dropped under ice cooling 0.91M boron tribromide in dichloromethane (13.0 ml, 12.0 mmol). The mixture was stirred for 1 hour under ice cooling and for a day at room temperature. To the reaction mixture was added an aqueous saturated sodium hydrogencarbonate solution. The mixture was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution and dried over sodium sulfate. The solvent was removed to give the subject compound as pale brown crystals (2.61 g, quantitatively).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[C:9]([CH3:15])[CH:10]=[CH:11][C:12]=2[CH3:14])[N:7]=[C:6](O)[CH:5]=1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:19]>C1(C)C=CC=CC=1>[Cl:19][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]2[C:8](=[C:9]([CH3:15])[CH:10]=[CH:11][C:12]=2[CH3:14])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(C)c2c(C(C)C)cc(O)nc12
Solvent: Cc1ccccc1
Product: Cc1ccc(C)c2c(C(C)C)cc(Cl)nc12
Yield: 71 %

Procedure:
A solution of 4-isopropyl-5,8-dimethylquinolin-2-ol (1.30 g, 6.05 mmol), 700 L (1.2 eq) of POCl3 in toluene were reacted as outlined in Scheme 1 above to yield 1.00 g of 2-chloro-4-isopropyl-5,8-dimethylquinoline (71%). Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.34 (d, J=6.74 Hz, 6 H) 2.71 (s, 3 H) 2.87 (s, 3 H) 4.12 (quin, J=6.74 Hz, 1 H) 7.21 (d, J=7.33 Hz, 1 H) 7.32 (s, 1 H) 7.40 (d, J=7.33 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](C=O)[C:3]=1[O:10][CH3:11].[Na].FC(F)(F)C(OO)=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C(OCC)C>[Br:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([OH:16])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(Br)cccc1C=O
Reactant: O=C(OO)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: ClCCl
Product: COc1c(O)cccc1Br
Reaction time: 8 h

Procedure:
A solution of 0.037 g 2-bromo-6-formyl-anisole in 1 ml methylene chloride is treated with 0.54 sodium dibasic phosphate and 1.3 ml trifluoroperacetic acid, stirred overnight, treated with 10% aqueous sodium carbonate (5 ml) and 5 ml diethyl ether, stirred for 1.5 hours, and partitioned between water and ether. The ether portion is extracted with 1 N aqueous sodium hydroxide, the hydroxide extracts acidified and then extracted with ether. Concentration of the ether extracts affords 3-bromo-2-methoxyphenol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])=O)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]3[CH3:18])=[N:9][N:8]=2)[CH:7]=1
Reactant: C[C@H]1COCCN1C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1nnc2ccc(F)cn12
Temperature: 55 °C
Yield: 28.8 %

Procedure:
To an ice cold solution of Intermediate 139a (574 mg, 2.26 mmol) in THF (23.0 mL) was added sequentially triphenylphosphine (1.18 g, 4.52 mmol), triethylamine (1.26 mL, 9.04 mmol) and hexachloroethane (1.07 g, 4.52 mmol). The cooling bath was removed and the reaction was heated to 55° C. overnight. The reaction was cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was taken up in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH and eluted with 2M NH3 in MeOH. The residue was concentrated in vacuo and then re-submitted to the above reaction conditions overnight. The reaction was cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to give the title compound (154 mg, 29%). 1H NMR (300 MHz, CDCl3): 0.94 (3H, d, J=6.3 Hz), 3.13 (1H, dt, J=12.2, 3.1 Hz), 3.32 (1H, ddd, J=12.4, 9.5, 3.2 Hz), 3.49 (1H, dd, J=11.1, 8.6 Hz), 3.56-3.68 (1H, m), 3.84 (1H, ddd, J=12.1, 9.4, 2.7 Hz), 3.92-4.01 (2H, m), 7.16 (1H, ddd, J=9.9, 7.5, 2.3 Hz), 7.68 (1H, ddd, J=10.0, 4.8, 0.8 Hz), 7.85 (1H, m).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][CH:9]([C:11](=[O:13])[CH3:12])[CH3:10]>CCO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:12][C:11](=[O:13])[CH:9]([CH3:10])[CH3:8]
Reactant: CC(=O)C(C)C
Reactant: O=Cc1ccco1
Solvent: CCO
Product: CC(C)C(=O)C=Cc1ccco1

Procedure:
The titled compound was prepared according to General Method 2 by reacting 2-furaldehyde (117 mmol), 2-methyl-butan-3-one (117 mmol), anhydrous Ba(OH)2 (2.2 g) and EtOH (200 mL) to afford the desire compound.
Reaction SMILES: Cl[S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:13][C:14]([F:24])([F:23])[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.N1C=CC=CC=1.Cl>ClC(Cl)C>[CH:9]([C:8]1[CH:11]=[CH:12][C:5]([S:2]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:14]([F:13])([F:23])[F:24])=[CH:17][CH:18]=2)(=[O:4])=[O:3])=[CH:6][CH:7]=1)=[O:10]
Reactant: O=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: O=Cc1ccc(S(=O)(=O)Nc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.3 %

Procedure:
to a mixture of 610 mg of 4-chlorosulfonylbenzaldehyde (3 mmoles) and 460 mg of 4-trifluoromethoxyaniline (3 mmoles) in 2 ml of dichloroethane is added 2 ml of pyridine (25 mmoles). The reaction mixture is stirred at room temperature for 5 hours and then poured into 100 ml of 10% HCl solution. The mixture is extracted twice with 30 ml of DCM. The combined organic extracts are washed with 30 ml of water, 30 ml of a saturated solution of sodium bicarbonate and brine, and the solution is dried over MgSO4 and concentrated. The crude product is purified on silica gel using DCM/AcOEt 90/10 as eluent. 0.48 g of 4-formyl-N-(4-trifluoromethoxy-phenyl)-benzenesulfonamide is isolated as a white solid (yield=47%). Analytical LC/MS method A:([M+H]+): 346, RT: 5.53 min (gradient 5 to 85% acetonitrile in 7 min).
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[C:14]2[C:10](=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[O:12][N:13]=2)[CH:9]=[CH:8][CH:7]=1.O>CS(C)=O>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:11]1[O:12][N:13]=[C:14]2[C:6]([CH2:5][C:1]#[N:2])=[CH:7][CH:8]=[CH:9][C:10]=12
Reactant: [C-]#N
Reactant: Clc1ccc(-c2onc3c(CBr)cccc23)c(Cl)c1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1cccc2c(-c3ccc(Cl)cc3Cl)onc12
Reaction time: 8 h
Yield: 33 %

Procedure:
To a slurry of 1.8 g (0.028 mole) of potassium cyanide in 80 ml of dimethylsulfoxide at 60° C. was added 9.7 g (0.027 mole) of 7-(bromomethyl)-3-(2,4-dichlorophenyl)-2,1-benzisoxazole. The mixture was heated at 50°-60° C. for 3 hr, poured into 1 liter of water and let stand overnight. The resulting solid was collected by filtration, washed with water and dried to give 7.6 g of crude tan solid. The solid was chromatographed on 160 g of silica gel to give 2.7 g of solid. The solid was recrystallized from carbon tetrachloride (charcoal) and then from acetonitrile to yield 0.7 g (8%) of crystals, m.p. 147°-148° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:6]1[O:7][C:8]1[C:9]([N+:14]([O-])=O)=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2]>C1COCC1.[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:6]1[O:7][C:8]1[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 98 %

Procedure:
1.45 g of palladium-on-charcoal at 10% is added to a solution of 14.5 g (35.4 mM) of 2-nitro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside in 290 ml of THF. The mixture is stirred under a hydrogen atmosphere at ambient temperature for 15 hours and then filtered. The filtrate is concentrated under reduced pressure. The expected product is obtained in the form of a beige solid with a yield of 98%.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:25])[O:21][CH2:22][CH2:23]Cl)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CN(C)C=O>[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][O:21][C:20]2=[O:25])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(NCCCN1CCN(Cc2ccccc2)CC1)OCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OCCN1CCCN1CCN(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Sodium hydride(60% in oil, 0.5 g/12.5 mmol) was added to a solution of 2-chloroethyl 3-(4-benzyl-1-piperazinyl)propylcarbamate in dimethylformamide(20 ml) and stirred for 1 day at 80° C. The solvent was removed in vacuo and the residue was diluted with dichloromethane (50 ml) and water (50 ml). The aqueous layer was extracted with dichloromethane (50 ml). The combined extracts were washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH2 gel/dichloromethane) to give a colorless oil (1.40 g/54%).
Reaction SMILES: Cl[N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1.[CH3:16][N:17]([CH3:22])[CH2:18][CH2:19][CH2:20][NH2:21].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH3:16][N:17]([CH3:22])[CH2:18][CH2:19][CH2:20][NH:21][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1
Reactant: CN(C)CCCN
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(Cl)S1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CN(C)CCCNN1NC=C(c2ncc([N+](=O)[O-])n2C)S1
Temperature: 25 °C

Procedure:
A mixture consisting of 3.8 gm., 0.0155 mole of 2-(2-chloro-5-thiadiazolyl)-1-methyl-5-nitroimidazole, prepared as in Example 16 2.5 gm., 0.029 mole of 3-dimethylaminopropylamine, 2.1 gm. 0.025 mole, of sodium bicarbonate and 100 ml. of benzene is refluxed for 22 hours. The reaction mixture is cooled to room temperature, washed with aqueous sodium bicarbonate and sodium chloride solutions. Cooling to 5° C. gives a crystalline precipitate which is collected and recrystallized from benzene to give the pure compound melting at 153°-154° C. More product is obtained from the mother liquors to give an overall yield of 3.0 gm.
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]1
Reactant: Cc1c(CCl)cccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(CN2CCN(C)CC2)cccc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 16 h

Procedure:
2-Methyl-3-nitrobenzylchloride (1.0 g, 5.4 mmol) was dissolved in 30 ml of THF, and to this was added 1-methyl-piperazine (0.65 g, 6.5 mmol) and sodium bicarbonate (2.26 g, 26.9 mmol). The reaction mixture was stirred at 65° C. for 16 hours. The mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with saturated NH4Cl, H2O, brine and dried over MgSO4. Solvent evaporation afforded 1-(2-methyl-3-nitrobenzyl)-4-methylpiperazine.
Reaction SMILES: C(N1C(=O)CCC1=O)(=O)C.C[Si](C)(C)N1C(=O)CCC1=O.C[Si](C)(C)[O:24][C:25]([CH:27]([N:31]1[CH:34]([S:35][N:36]2[C:40](=[O:41])[CH2:39][CH2:38][C:37]2=[O:42])[CH:33]([NH:43][C:44](=[O:52])[CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:32]1=[O:53])[C:28]([CH3:30])=[CH2:29])=[O:26].C>C1C=CC=CC=1>[C:25]([CH:27]([N:31]1[CH:34]([S:35][N:36]2[C:37](=[O:42])[CH2:38][CH2:39][C:40]2=[O:41])[CH:33]([NH:43][C:44](=[O:52])[CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:32]1=[O:53])[C:28]([CH3:30])=[CH2:29])([OH:26])=[O:24]
Reactant: C=C(C)C(C(=O)O[Si](C)(C)C)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)CCC1=O
Agent: CC(=O)N1C(=O)CCC1=O
Agent: C[Si](C)(C)N1C(=O)CCC1=O
Solvent: c1ccccc1
Product: C=C(C)C(C(=O)O)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)CCC1=O
Temperature: 25 °C

Procedure:
A mixture of 5.3 g of benzylpenicillin-S-sulphoxide, 50 g of N-acetylsuccinimide, 12.5 ml of N-trimethylsilylsuccinimide and 35 ml of benzene was refluxed for 16 hours. The reaction mixture (containing 1-(1-trimethylsilyloxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one) was then allowed to cool to room temperature, diluted with benzene (200 ml), treated with decolourizing charcoal, and evaporated to dryness. The residue was purified by column chromatography on silica gel using 5% acetic acid in ethyl acetate as eluent. The fractions containing the major component of the original residue were combined, evaporated to dryness and the residue triturated with diethyl ether. The precipitate was chromatographed a second time to obtain 1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one in a pure state. The structure was confirmed by PMR and IR spectroscopy.
Reaction SMILES: [CH3:1][C@:2]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][C:5](=[O:7])[N:4]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:3]1.P(OCC)(OCC)[O:24]CC.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[OH:24][CH:6]1[C:5](=[O:7])[N:4]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:3][C@@:2]1([CH3:1])[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17]
Reactant: C[C@H](c1ccccc1)N1C[C@@](C)(C(=O)OC(C)(C)C)CC1=O
Reactant: CCOP(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@@](C)(C(=O)OC(C)(C)C)C(O)C1=O
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a solution of tert-butyl(3S)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (10.0 g, 33.0 mmol) and triethyl phosphite (6.78 mL, 39.6 mmol) in anhydrous tetrahydrofuran (165 mL), lithium bistrimethylsilylamide (46.1 mL, 46.1 mmol, 1.0M solution in tetrahydrofuran) was added at −5° C., and the mixture was stirred at the same temperature for 30 minutes. After bubbling oxygen gas into the reaction mixture for 2 hours, saturated aqueous solution of ammonium chloride (150 mL) was added to the mixture in an ice bath, and the mixture was concentrated under reduced pressure. Water (100 mL) was added to the residue and the mixture was extracted with ethyl acetate (200 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (200 mL), and dried with anhydrous sodium sulfate. After removing the solvent by distillation under reduced pressure, the residue was purified by silica gel column chromatography (hexane ethyl acetate=1:1→1:4) to obtain 9.61 g (91.3%) of the title compound as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18](F)=[C:19]([O:22][CH2:23]C)[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:26]#[N:27].[O:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[CH2:34][OH:35]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:35][CH2:34][CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][O:28]3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:27]=[CH:26][C:13]=1[C:14]#[N:15]
Reactant: OCC1CCCCO1
Reactant: CCOc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Product: COc1cc(Nc2c(C#N)cnc3cc(OCC4CCCCO4)c(OC)cc23)c(Cl)cc1Cl

Procedure:
Following the procedure used to prepare Example 15, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-fluoro-3-quinolinecarbonitrile (250 mg, 0.64 mmol) and tetrahydropyran-2-methanol provides 177 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-(tetrahydro-2H-pyran-2-ylmethoxy)-3-quinolinecarbonitrile, mp 193-196° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH:9]([NH:13]C(OC(C)(C)C)=O)[CH2:8]2)=[CH:4][CH:3]=1.[ClH:23].CCOCC>CO>[ClH:1].[ClH:23].[NH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][CH:21]=2)[CH2:8]1
Reactant: CC(C)(C)OC(=O)NC1CCCN(Cc2ccc(Cl)cc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NC1CCCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a methanol (25 mL) solution of 1-(4-chlorobenzyl)-3-[(tert-butoxycarbonyl)amino]piperidine (2.55 g, 7.85 mmol), was added 1M HCl-Et2O (50 mL). The resulting reaction mixture was stirred at 25° C. for 15 hours, and the solvent was removed under reduced pressure to afford 3-amino 1-(4-chlorobenzyl)piperidine dihydrochloride as an amorphous solid (2.49 g, quantitative). The purity was determined by RPLC/MS (>95%). ESI/MS m/e 225.2 (M++H, C12H18ClN2).
Reaction SMILES: [CH3:1][CH:2]1[CH2:13][C:12]2[C:4](=[CH:5][C:6]3[CH2:7][CH2:8][CH2:9][C:10]=3[CH:11]=2)[C:3]1=[O:14].[Cl-].[Cl-].[Cl-].[Al+3].[Br:19]Br>C(Cl)(Cl)Cl>[Br:19][C:11]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[C:12]=1[CH2:13][CH:2]([CH3:1])[C:3]2=[O:14]
Reactant: CC1Cc2cc3c(cc2C1=O)CCC3
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC1Cc2c(cc3c(c2Br)CCC3)C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 120.2 %

Procedure:
31 g (162 mmol) of 2-methyl-3,5,6,7-tetrahydro-s-indacen-1(2H)-one (1a) were added to a suspension of 50 g (0.37 mol) of anhydrous aluminum trichloride in 200 ml of chloroform while stirring vigorously at 0° C. After stirring for one hour, a solution of 8 ml (160 mmol) of bromine in 20 ml of chloroform was added dropwise to the mixture at 0° C. and the mixture was subsequently stirred overnight. The reaction mixture was poured into 500 g of an ice/water mixture. The organic phase was separated off, washed with 5% strength sodium hydrogencarbonate solution and water and subsequently dried over magnesium sulfate. Filtration and removal of the solvent under reduced pressure gave 51 g of a red oil. GC-MS analysis indicated that the oil contained 84% of the desired compound (1b) and 14% of a dibromide by-product. The mixture was separated by column chromatography on silica gel using methylene chloride as eluant. This gave 18.7 g (44% yield) of the compound (1b).