Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[CH2:8]([CH:10]1[O:12][CH2:11]1)Cl.[OH-].[Na+]>O>[CH2:1]([N:4]([CH2:5][CH:6]=[CH2:7])[CH2:8][CH:10]([OH:12])[CH2:11][N:4]([CH2:5][CH:6]=[CH2:7])[CH2:1][CH:2]=[CH2:3])[CH:2]=[CH2:3]
Reactant: ClCC1CO1
Reactant: C=CCNCC=C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCN(CC=C)CC(O)CN(CC=C)CC=C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
17.4 g (173.8 mmol) of diallylamine (from Aldrich) and 10.0 g of deionized water are stirred in a round-bottomed flask at 55° C. while 8.08 g (86.48 mmol) epichlorohydrin is added from an addition funnel. After 30 minutes the addition is complete. Then sodium hydroxide (10.0 g, 125 mmol, 50%) is added to the reaction mixture and it is stirred for an additional 3.5 hours, after which time the alkylation is complete as determined gas chromatography. The temperature is then cooled to 25° C. and the pH is made alkaline with caustic. The product is extracted from the reaction mixture with ether (three times, 25 ml). On removal of the ether a clear yellow liquid is obtained with a purity of 98.6% (GC and NMR).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]=[C:16]=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[NH2:18]/[C:19](/[CH3:27])=[C:20](/[CH3:26])\[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]([CH3:27])=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:26])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CCOC(=O)/C(C)=C(/C)N
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Product: CCOC(=O)C(C)=C(C)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
using isopropyl 2-chloro-4-fluoro-5-isocyanatobenzoate and ethyl 3-amino-2-methylcrotonate there is obtained isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-methylpropenyl]ureido}-benzoate, m.p. 145°-147° C.,
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][NH:15][C@H:14]([C:17]([NH:19][C:20]2([C:23]#[N:24])[CH2:22][CH2:21]2)=[O:18])[CH2:13]1)(=[O:11])=[O:10].[CH2:25]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:39][CH2:38][CH:37]2[C:40]([O-])=[O:41])[CH2:32][CH2:31]1)=[O:29])[CH3:26].[Li+]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:40]([CH:37]2[CH2:38][CH2:39][N:36]2[CH:33]2[CH2:32][CH2:31][N:30]([C:28]([O:27][CH2:25][CH3:26])=[O:29])[CH2:35][CH2:34]2)=[O:41])[C@H:14]([C:17](=[O:18])[NH:19][C:20]2([C:23]#[N:24])[CH2:22][CH2:21]2)[CH2:13]1)(=[O:10])=[O:11]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)CN2)CC1
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7A and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-2-(1-cyanocyclopropylcarbamoyl)pyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a white solid (58%). MS ISP (m/e): 610.3/612.2 (100/42) [(M+H)]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[O:16][CH2:15][C:14](=[O:17])[NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].N[CH2:19][CH:20]([C:22]1C=CC(OC)=C(OC2CCCC2)[CH:23]=1)O>>[CH:1]1([O:2][C:3]2[CH:4]=[C:5]([CH:11]3[O:16][CH2:15][C:14](=[O:17])[NH:13][CH2:12]3)[CH:6]=[CH:7][C:8]=2[O:9][CH3:10])[CH2:23][CH2:22][CH2:20][CH2:19]1
Reactant: COc1ccc(C(O)CN)cc1OC1CCCC1
Reactant: COc1ccc(C2CNC(=O)CO2)cc1OC
Product: COc1ccc(C2CNC(=O)CO2)cc1OC1CCCC1
Yield: 42.7 %

Procedure:
According to the same procedure as in Example 1(2) to (3), using 2-amino-1-(3-cyclopentyloxy-4-methoxyphenyl)ethanol instead of 2-amino-1-(3,4-dimethoxyphenyl)ethanol, the above-described compound (yield 42.7%) was obtained as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=O)[N:12]=2)=[CH:4][CH:3]=1.Br.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:22][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:3][CH:4]=2)=[N:12][C:11]=1[CH2:13][CH2:14][N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH3:21]
Reactant: BrCc1ccccn1
Reactant: Cc1oc(-c2ccc(O)cc2)nc1CC(=O)N1CCC[C@H]1C
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(OCc3ccccn3)cc2)nc1CCN1CCC[C@H]1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-1-(2-(R)-methyl-pyrrolidin-1-yl)-ethanone (See Example 56) (0.35 g, 1.2 mmol), 2-bromomethylpyridine hydrobromide (0.40 g, 1.6 mmol), and Cs2CO3 (1.4 g, 4.3 mmol) in DMF (5 mL) is stirred at room temperature overnight. The mixture is partitioned between EtOAc and water. The aqueous phase is extracted with EtOAc (2×), and the combined organic phase is washed with brine, dried (Na2SO4), and concentrated. The residue is purified by flash chromatography [40 g SiO2, elute 20% (10% 2 M NH3 in MeOH/90% CH2Cl2): 80% CH2Cl2 to 70% (10% 2 M NH3 in MeOH/90% CH2Cl2): 30% CH2Cl2] to yield the title compound. MS (m/e): 378.3 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]=1[F:15].C([Li])CCC.B(OC)(OC)[O:22]C.Cl>C(OCC)(=O)C.C1COCC1>[F:1][C:2]1([OH:22])[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]1[F:15]
Reactant: CCCCCCOc1cccc(F)c1F
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCOC1=CC=CC(O)(F)C1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
1,2-Difluoro-3-hexyloxybenzene (s-1) (17.8 g) and THF (500 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. n-Butyllithium (1.57M; n-hexane and cyclohexane solution; 58.0 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. Trimethyl borate (9.5 g) in a THF (50 ml) solution was added dropwise in the temperature range of −74° C. to −65° C., and the stirring was continued for 8 hours while the mixture was allowed to return to 25° C. The reaction mixture was poured into a vessel containing 1N-hydrochloric acid (100 ml) and ice-water (500 ml) and mixed with them. Ethyl acetate (300 ml) was added, and mixture was then allowed to stand until it had separated into organic and aqueous layers, and the extraction was carried out. The resulting organic layers were separated, and washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue and acetic acid (100 ml) were placed in a reaction vessel at room temperature under an atmosphere of nitrogen, and an aqueous solution of hydrogen peroxide (31%; 10.1 ml) was added dropwise in the temperature range of 25° C. to 30° C., and the stirring was continued for another 2 hours. The reaction mixture was poured into a vessel containing an aqueous solution of sodium hydrogen sulfite (100 ml) and ethyl acetate (300 ml) and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous layers, and the extraction was carried out. The resulting organic layers were separated, and washed successively with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 1,2-difluoro-3-hexyloxyphenol (s-20) (12.8 g). The yield based on the compound (s-1) was 66.6%.
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.Cl.[Cl:14][CH2:15][C:16]1[N:17]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:19][CH:20]=1>>[ClH:14].[C:21]1([C:18]2[S:19][CH:20]=[C:16]([CH2:15][O:1][NH2:2])[N:17]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cl
Product: NOCc1csc(-c2ccccc2)n1

Procedure:
Prepared by a similar procedure as described for preparation 12, starting from N-hydroxyphthalimide and 4-chloromethyl-2-phenyl-thiazole hydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][Br:23])[CH2:13][C:14]#[CH:15].C(N(CC)CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:16][CH2:12][CH2:13][C:14]#[C:15][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: C#CCCOCCCCCCBr
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1cccc(C#CCCOCCCCCCBr)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 90.7 %

Procedure:
A mixture of 3-bromo-benzenesulfonamide (625 g), 6-bromohexyl but-3-ynyl ether (850.1 g), bis(triphenylphosphine)palladium (II) chloride (62.5 g), triphenylphosphine (18.1 g) and triethylamine (536.3 g) in tetrahydrofuran (6250 ml) was stirred under an atmosphere of nitrogen for 20 mins. Copper (I) iodide (12.5 g) was then added to give a dark red/brown mixture that was heated to 50° C. for 23 h. The reaction mixture was then cooled to room temperature and filtered through a short silica pad (1000 g). The pad was washed with additional tetrahydrofuran (15.6 L) and the resulting solution then concentrated under reduced pressure to give crude product (1382 g) as a viscous oil. This was purified by chromatography (7 kg silica) eluting with 5:1 petroleum ether:ethyl acetate followed by 2:1 petroleum ether:ethyl acetate to give the title compound (932.9 g) as an oil, LC RT=5.69 min, δ (DMSO-d6) 7.79 (1H, s), 7.76 (1H, d, J 7.6 Hz), 7.56 (2H, m), 7.42 (2H, m), 3.55 (2H, t, J 6.6 Hz), 3.49 (2H, t, J 6.6 Hz), 3.42 (2H, t, J 6.6 Hz), 2.68 (2H, t, J 6.6 Hz), 1.76 (2H, m), 1.50 (2H, m), 1.35 (4H, m).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.[C:11]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][C:22](Cl)=[O:23])[CH2:16][CH2:15]1)(=[O:13])[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[C:11]([N:14]1[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][C:22]([C:9]2[CH:8]=[CH:7][C:6]3[S:1][CH2:2][CH2:3][CH2:4][C:5]=3[CH:10]=2)=[O:23])[CH2:18][CH2:19]1)(=[O:13])[CH3:12]
Reactant: CC(=O)N1CCC(CCC(=O)Cl)CC1
Reactant: c1ccc2c(c1)CCCS2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)N1CCC(CCC(=O)c2ccc3c(c2)CCCS3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a mixture of 3,4-dihydro-2H-1-benzothiopyran (1.5 g) and 3-(1-acetylpiperidin-4-yl)propionyl chloride (2.18 g) in 1,2-dichloroethane (20ml) was added aluminum chloride (3.2 g) portionwise at 10°-15° C. The mixture was stirred at room temperature for 2 hours then refluxed for additional 2 hours, and poured into icewater. The mixture was extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate) to obtain 2.7 g of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10]([NH:17][CH2:18][CH2:19][CH2:20]O)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:13]([O:12][C:10](=[O:11])[NH:17][CH2:18][CH2:19][CH2:20][O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: Oc1cc(F)ccc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCOc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The solution of 2.50 g of 2,5-difluorophenol, 3-(Boc-amino)-1-propanol, 7.26 g of triphenylphosphine and tetrahydrofuran (30 ml) is cooled to 0° C. and admixed dropwise with 5.65 ml of diisopropyl azodicarboxylate. The reaction mixture is stirred at room temperature for a further 2 hours and subsequently concentrated by evaporation. The title compound is obtained as a yellowish solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.34 (1:2 EtOAc-heptane); Rt=4.69.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].CC1(C)C(C)(C)OB([C:30]2[N:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>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.COCCOC>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])=[N:31][CH:32]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(Br)c1
Reactant: CC1(C)OB(c2cnc(N)cn2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1cnc(-c2cccc(C(=O)Nc3ccc(OC(F)(F)F)cc3)c2)cn1

Procedure:
3-Bromo-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 3.1, 50 mg, 0.139 mmol), 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-amine (0.180 mmol), 2 M Na2CO3 (0.104 mL, 0.208 mmol), (Ph3P)4Pd (8 mg, 6.94 μmol), water (0.8 mL) and DME (2.4 mL) were added to a vial, which was sealed and subjected to MW irradiation at 150° C. for 10 min. The RM was filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL) and the cartridge was washed with MeOH (10 mL). The combined filtrates were evaporated to dryness under reduced pressure and the crude product was purified by preparative HPLC to afford the title compound. UPLC-MS (Condition 6) tR=1.84 min, m/z=375.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]([OH:20])([C:22]([F:24])([F:23])[F:21])[C:16]([F:18])([F:19])[F:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C(=O)C(F)(F)F)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(Br)cc(C(O)(C(F)(F)F)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl 3-bromo-5-(trifluoroacetyl)benzoate (1.0 g, 2.8 mmol) was dissolved in THF (28 mL) and trifluoromethyltrimethylsilane (2.0 g, 14.1 mmol) added. The mixture was cooled to 0° C. and TBAF (0.07 g, 0.28 mmol) was added dropwise. After stirring for 15 minute additional TBAF (0.74 g, 2.8 mmol) was added. The mixture was stirred for an additional 15 minutes, allowed to warm to rt and then quenched with 1N HCl, diluted with EtOAc and the layers separated. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give title compound which was used directly step C.
Reaction SMILES: [N:1]12[CH2:14][CH2:13][N:7]([CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2.[CH2:15]1[O:18][CH:16]1[CH3:17]>>[OH:18][CH:16]([CH3:15])[CH2:17][N:10]1[CH2:9][CH2:8][N:7]2[CH2:13][CH2:14][N:1]([CH2:2][CH2:3][N:4]([CH2:15][CH:16]([OH:18])[CH3:17])[CH2:5][CH2:6]2)[CH2:12][CH2:11]1
Reactant: CC1CO1
Reactant: C1CN2CCNCCN(CCN1)CC2
Product: CC(O)CN1CCN2CCN(CC1)CCN(CC(C)O)CC2

Procedure:
From 1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (1.1.4) and propylene oxide.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:20](=[O:25])[C:21]([O:23][CH3:24])=[O:22]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH:7][C:20](=[O:25])[C:21]([O:23][CH3:24])=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(=O)Cl
Reactant: CC(C)(C)c1ccccc1N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)C(=O)Nc1ccccc1C(C)(C)C
Temperature: -30 °C
Yield: 92.9 %

Procedure:
A 3-L, 3-necked round-bottomed flask, equipped with a mechanic stirrer and a thermal probe (under nitrogen) was charged with 2-tert-Butylaniline (109 g, 114 mL, 732 mmoles), triethylamine (81.4 g, 112 mL, 804 mmoles, 1.1 equiv.) and toluene (600 mL). The resulting mixture was stirred at a moderate speed at −30° C. An additon funnel was charged with Methyl chlorooxoacetate (100 g, 816 mmoles, 1.11 equiv.) with toluene (200 mL), and the mixture added to the reaction mixture at such a rate that the internal batch temperature is less than −20° C. After addition, the reaction was warmed to room temperature for an hour, quenched with water, then partitioned between EtOAc/water. The aqueous phase was extracted with EtOAc (200 mL), and the combined organic layers were washed successively with KHSO4 (200 mL), NaHCO3 (sat'd) (200 mL) and brine (200 mL), then dried the organic over MgSO4. The organic phase was concentrated by rotary evaporation, yielding the title compound as a pale yellow solid [Methyl 2-(2-tert-Butylphenylamino)-2-oxoacetate, 160 g, 93.1%]. MP 61.7–63.6° C. IR (KBr) 3409, 2954, 1736, 1724, 1530, 1299, 1166, 766 cm−1; 1H NMR (300 MHz, CDCl3): δ(ppm): 9.20 (br, 1H), 7.97 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.43 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.31–7.16 (m, 2H), 4.00 (s, 3H), 1.47(s, 9H). The product thus obtained can be used directly for the subsequent reaction.
Reaction SMILES: Cl[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)=[O:4].Cl.[CH3:17][NH:18][CH3:19].C([O-])([O-])=O.[K+].[K+].O>CC#N>[CH3:17][N:18]([CH3:19])[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(=O)Nc1ccc(C(=O)C(C)Cl)cc1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)C(C)N(C)C)cc1
Yield: 89.3 %

Procedure:
A mixture of N-[4-(2-chloro-1-oxopropyl)phenyl]acetamide (0.19 mol), N-methylmethanamine hydrochloride (1:1)(0.38 mol) and K2CO3 (78.8 g) in CH3CN (1400 ml) was stirred and refluxed for 12 hours. The mixture was cooled, poured into water and extracted with CH2Cl2. The organic layer was dried, filtered and the solvent was evaporated, yielding 39.77 g (89%) of (±)-N-[4-[2-(dimethylamino)-1-oxopropyl]phenyl]-acetamide (interm. 9).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:2]1.[C:22]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C@@H:32]2[CH2:34][O:33]2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C@@H:32]([OH:33])[CH2:34][N:1]2[CH2:6][CH2:5][CH2:4][C:3]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:2]2)=[CH:28][CH:27]=1)([CH3:23])([CH3:24])[CH3:25]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCCNC1)O2
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Product: CC(C)(C)c1ccc(OC[C@@H](O)CN2CCCC3(CSC4=C(O3)c3ccccc3C(=O)C4=O)C2)cc1

Procedure:
Compound 197 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,3′-piperidine]-5,6-dione, (2S)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=90-92° C., 400 MHz 1H NMR (CDCl3) δ: 8.04-8.02 (d, J=7.43 Hz, 1H), 7.75-7.73 (d, J=7.82 Hz, 1H), 7.63-7.58 (m, 1H), 7.48-7.44 (m, 1H), 7.31-7.21 (m, 2H), 6.83-6.80 (m, 1H), 4.13-4.07 (m, 1H), 3.15-2.96 (m, 3H), 2.82 (s, 1H), 2.65-2.50 (m, 5H), 2.04-1.73 (m, 4H), 1.29 (s, 9H); LCMS: 508 [M+H].
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Br.[C:21]([NH:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][NH:30][CH2:29]2)(=[O:23])[CH3:22].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:21]([NH:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][N:30]([C:11]1[CH:12]=[C:13]3[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:15])[CH2:29]2)(=[O:23])[CH3:22]
Reactant: CC(=O)NCc1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: Br
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)NCc1ccc2c(c1)CN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Yield: 74.2 %

Procedure:
398 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 490 mg of 5-acetamidomethylisoindoline hydrobromide, 795 mg of DBU, and 3 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 485 mg of 7-(5-acetamidomethyl-2-isoindolinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[N:24]([O:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:23]([CH3:37])([CH3:36])[CH2:22]2)[N:5]=[C:4]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH:51]2[CH2:56][C:55]([CH3:58])([CH3:57])[N:54]([O:59][CH:60]3[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)[C:53]([CH3:67])([CH3:66])[CH2:52]2)[N:3]=1.[CH2:68]([CH2:70][NH2:71])[OH:69]>>[OH:69][CH2:68][CH2:70][NH:71][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[N:24]([O:29][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[C:23]([CH3:37])([CH3:36])[CH2:22]2)[N:5]=[C:4]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH:51]2[CH2:56][C:55]([CH3:57])([CH3:58])[N:54]([O:59][CH:60]3[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65]3)[C:53]([CH3:67])([CH3:66])[CH2:52]2)[N:3]=1
Reactant: CC1(C)CC(CCCCCCCCCCCCNc2nc(Cl)nc(NCCCCCCCCCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Reactant: NCCO
Product: CC1(C)CC(CCCCCCCCCCCCNc2nc(NCCO)nc(NCCCCCCCCCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[N-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)dodecylamino]-1,3,5-triazine with ethanolamine according to the procedure of Example 1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[C:19]3[O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:18]=3[CH:17]=[CH:16][CH:15]=2)[C@@H:10]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH2:9]1)=O)(C)(C)C.[ClH:41]>>[ClH:41].[C:32]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][C:29]([CH2:28][O:27][C@@H:10]2[C@@H:11]([C:14]3[C:19]4[O:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=5[C:18]=4[CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2cccc3c2oc2ccccc23)[C@@H](OCc2ccc(-c3ccccc3)cc2)C1
Agent: Cl
Product: c1ccc(-c2ccc(CO[C@H]3CNCC[C@@H]3c3cccc4c3oc3ccccc34)cc2)cc1

Procedure:
A mixture of (3R*,4R*)-3-(biphenyl-4-ylmethoxy)-4-dibenzofuran-4-yl-piperidine-1-carboxylic acid t-butyl ester (prepared analogously as described in Example 1; 218 mg, 0.41 mmol) and HCl (5M in 2-propanol, 2 mL, 10 mmol) is stirred for 1 h at RT. The solvent is removed in vacuo, the residue triturated with hot MeOH and the suspension filtered. The filter cake is washed with MeOH and ether and dried at 60° C. in vacuo to afford (3R*,4R*)-3-(biphenyl-4-ylmethoxy)-4-dibenzofuran-4-yl-piperidine hydrochloride: MS 434.6 [M+H]+; Rf 0.23 (DCM/MeOH 9:1).