Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:36](=[O:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:36](=[O:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
7-[[4-[(1-t-Butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile obtained in Reference Example 2 (200 mg) was dissolved in 2 ml of dichloromethane, 299 mg of ethyl chloroglyoxylate and 266 mg of triethylamine were added to the solution, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate was added to the reaction solution. The mixture was washed with 10% citric acid aqueous solution and saturated sodium bicarbonate aqueous solution in that order, dried over anhydrous sodium sulfate, and then evaporated. The resulting residue was purified by silica gel column chromatography using hexane:ethyl acetate (8:2) as the eluent to give 241 mg of ethyl N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]oxamate.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29]([N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC=CC=1C>[C:24]([O:28][C:29]([N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]([C:20]2[CH:21]=[CH:22][C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH2:12][CH2:13]3)=[CH:18][CH:19]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCNc2ccccc21
Reactant: O=C(OCc1ccccc1)N1CCN(c2ccc(Br)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)cc2)c2ccccc21
Temperature: 150 °C
Yield: 78.7 %

Procedure:
8.43 g of 4-(4-bromophenyl)piperazine-1-carboxylic acid benzyl ester are placed in a 500 ml three-necked flask under a nitrogen atmosphere. 170 ml of anhydrous o-xylene, 5.01 g of 3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester and then 3.08 g of sodium tert-butoxide are added, followed by 0.48 g of palladium acetate, and then the addition is completed with 0.53 ml of tri(tert-butyl)phosphine. The reaction mixture is heated at 150° C. for 18 h. Heating is halted and the mixture is brought back to ambient temperature. The o-xylene is evaporated and the mixture is taken up in ethyl acetate before filtering it through celite. The organic phase is washed with water and then with a saturated aqueous sodium chloride solution. The aqueous phase is extracted with ethyl acetate. The organic phases are combined and then dried over sodium sulphate, filtered through a sintered glass filter and concentrated under vacuum. 8.9 g of 4-[4-(4-(Benzyloxycarbonyl)piperazin-1-yl)phenyl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are obtained after purification on a silica column, elution being carried out with a gradient of heptane/ethyl acetate solvent varying from 95/5 to 60/40).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:16][S:17][S:18][CH2:19][C@@H:20]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C:21]([OH:23])=[O:22])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.O>CN(C=O)C>[CH2:41]([O:14][C:13](=[O:15])[C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:16][S:17][S:18][CH2:19][C@@H:20]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[C:21]([O:23][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: BrCc1ccccc1
Reactant: O=C(N[C@H](CSSC[C@@H](NC(=O)OCc1ccccc1)C(=O)O)C(=O)O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N[C@H](CSSC[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of (2S)-2-{[(benzyloxy)carbonyl]amino}-3-{[(2S)-2-{[(benzyloxy)carbonyl]amino}-2-carboxyethyl]disulfanyl}propanoic acid LXVI (5.6 g; 11 mmol) and anhydrous potassium carbonate (6.08 g; 44.0 mmol) in DMF (50 mL) cooled to 0° C. was added benzyl bromide (7.8 mL; 66.0 mmol). The mixture was stirred overnight at r.t. Water (150 mL) was added, and solution was extracted once with DCM (40 mL). The solvent was evaporated under reduced pressure and the residue was dissolved in diethyl ether (60 mL). The ether was washed with 10% aq Na2S2O3 until all the DMF was removed and once with water. The organic phase was dried over anhydrous MgSO4, evaporated and the residue purified on a silica gel column (100% CHCl3→200:3 CHCl3:MeOH). Benzyl (2S)-3-{[(2S)-3-(benzyloxy)-2-{[(benzyloxy)carbonyl]amino}-3-oxopropyl]disulfanyl}-2-{[(benzyloxy)carbonyl]amino}propanoate LXVII was obtained as a light-green viscous oil (5.9 g; 8.56 mmol; 77.8% yield). 1H NMR (CDCl3) 3.04-3.18 (m, 4H), 4.62-4.76 (m, 2H), 5.12 (s, 2H), 5.17 (s, 2H), 5.62-5.76 (m, 2H), 7.28-7.40 (m, 20H); ESIMS found for C36H36N2O8S2 m/z 689.5 (M+H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:35][C:36]1[CH:41]=[C:40]([CH3:42])[N:39]2[N:43]=[CH:44][C:45](C(Cl)=O)=[C:38]2[N:37]=1.O>C1COCC1.CCOC(C)=O>[CH3:35][C:36]1[CH:41]=[C:40]([CH3:42])[N:39]2[N:43]=[CH:44][C:45]([C:4](=[O:3])[CH2:5][C:6]3[N:10]4[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]4=[N:8][C:7]=3[C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[C:38]2[N:37]=1
Reactant: CCOC(=O)Cc1c(-c2ccc(OC)cc2)nc2ccc(C)cn12
Reactant: Cc1cc(C)n2ncc(C(=O)Cl)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2nc3ccc(C)cn3c2CC(=O)c2cnn3c(C)cc(C)nc23)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 20.3 %

Procedure:
To a magnetically stirred solution of [2-(4-methoxy-phenyl)-6-methyl-imidazo[1,2-a]pyridin-3-yl]-acetic acid ethyl ester 13c (0.075 g, 0.231 mmol) in THF (3.0 mL) at −78° C. under Ar atmosphere was added potassium bis(trimethylsilyl)amide (KHMDS) (0.508 mL, 0.5M, 0.254 mmol). The reaction mixture was stirred for 15 min at −78° C., then a THF solution of 5,7-dimethyl-pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (0.053 g, 0.254 mmol) was added. After an additional 60 min at −78° C., water (20 mL) was added, and the reaction mixture was warmed to room temperature. Water was added, and the aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, dried (MgSO4), and concentrated in vacuo to the crude alkylated product. The crude adduct was dissolved in acetic acid (HOAc) (1 mL) and 12 N HCl (1 mL). The reaction mixture refluxed for 2 h. The mixture was cooled to room temperature and treated with aq Na2CO3 solution until basic. The aqueous solution was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water (20 mL), dried (MgSO4), and concentrated in vacuo to the crude product. The pure product was obtained by column chromatography over silica gel,(40:60 EtOAc/hexane, then 100% EtOAc as eluent), which gave the title compound (0.02 g, 20%) as an off white solid. 1H NMR (400 MHz, CDCl3) 2.28 (s, 3H), 2.62 (s, 3H), 2.82 (s, 3H), 3.81 (s, 3H), 4.98 (s, 2H), 6.80 (s, 1H), 6.91 (d, J=8.4 Hz, 2H), 7.02 (d, J=9.1 Hz, 1H), 7.54 (d, J=9.1 Hz, 1H), 7.68 (d, J=9.0 Hz, 2H), 7.76 (s, 1H), 8.62 (s, 1H). Mass spectrum m/e 426 (M+).
Reaction SMILES: ClC([O:4][C:5]([Cl:8])(Cl)Cl)=O.[CH3:9][O:10][C:11]1[CH:22]=[CH:21][C:14]([CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:9][O:10][C:11]1[CH:22]=[CH:21][C:14]([CH2:15][N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:5]([Cl:8])=[O:4])=[CH:13][CH:12]=1
Reactant: COCCNCc1ccc(OC)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(Cc1ccc(OC)cc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.51 g (0.31 ml, 2.56 mmol) of trichloromethyl chloroformate (“diphosgene”) are dissolved in 15 ml of dichloromethane, and 1.00 g (5.12 mmol) of 4-methoxybenzyl(2-methoxyethyl)amine and 0.78 g (7.68 mmol) of triethylamine are slowly added. After stirring at room temperature overnight, the mixture is poured into ice-water and extracted three times with dichloromethane, and the organic phase is dried over magnesium sulfate and concentrated to dryness in a rotary evaporator. The crude product is employed without workup directly in the next stage.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.CCCCCC.[CH3:12][N:13]([CH3:27])[C:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.C(Br)C=C>C1COCC1>[CH2:3]([CH:18]1[CH2:19][C:14]([N:13]([CH3:27])[CH3:12])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15][CH2:16][C:17]1=[O:20])[CH:2]=[CH2:1]
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: [Li]CCCC
Solvent: C=CCBr
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCC1CC(c2ccccc2)(N(C)C)CCC1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine (2.1 ml, 15 mmol) was provided in dry THF (30 ml) in argon and mixed with a solution of butyl lithium in hexane (2.5M, 6 ml, 15 mmol) at −30° C. (bath temperature). The reaction mixture was cooled to −78° C. After this temperature was reached, 4-(dimethyl-amino)-4-phenylcyclohexanone (2.17 g, 10 mmol), dissolved in dry THF (20 ml), was added in drops within 15 min. The batch was left for 30 min at −78° C. Then, allyl bromide (2.6 ml, 30 mmol), dissolved in dry THF (20 ml), was added in drops within 1 min. The reaction mixture was stirred for 10 min at −78° C., then the cooling was removed. After room temperature was reached, the batch was stirred for a further 18 h. For work up the batch was carefully mixed with water (1 ml), then saturated NH4Cl solution (40 ml) was added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3×20 ml). The combined organic phases were washed with saturated NH4Cl solution (2×40 ml). The organic phases were then mixed with 1N HCl (30 ml) and thoroughly shaken out. The acid aqueous phase was separated and the organic phase was washed with water (2×20 ml). The combined aqueous phases were washed with ethyl acetate (1×30 ml). The aqueous solution was then placed on 2 N NaOH (70 ml). An oil separated out of the alkaline solution. The formed mixture was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried over Na2SO4 and then concentrated to low volume. The more non-polar diastereoisomer of the ketone was isolated from the residue (2 g) with a yield of 540 g (22%) by means of chromatographic purification [silica gel 60 (50 g); cyclohexane/ethyl acetate 1:10 (700 ml)]. The more polar diastereoisomer was obtained with a yield of 470 mg (19%).
Reaction SMILES: Cl[CH:2]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]1[O:4][C:5]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:6]=2[C:7]=1[CH3:8].[NH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl.[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C=O>[CH:14]1([CH:2]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[C:3]2[O:4][C:5]3[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:6]=3[C:7]=2[CH3:8])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1c(C(Cl)C2CCCCC2)oc2cc(F)ccc12
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2cc(F)ccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a mixture of 2-[chloro(cyclohexyl)methyl]-6-fluoro-3-methyl-1-benzofuran (945 mg) synthesized above, methyl 4-aminobenzoate (508 mg), sodium iodide (1.01 g) and N,N-dimethylformamide (10 mL) was added sodium carbonate (712 mg), and the mixture was stirred at 80° C. overnight. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give a yellow solid. To a mixture of the obtained solid, tetrahydrofuran (20 mL) and ethanol (20 mL) was added 1N aqueous sodium hydroxide solution (10.0 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (40 mL), and 1N hydrochloric acid (10.0 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (722 mg, 56%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]([CH3:13])[CH3:12])[CH2:9][OH:10])=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].[O:21]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:11]([CH3:13])[CH3:12])[CH2:9][O:10][CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:29]=2)=[CH:6][CH:7]=1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(CO)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)C(COCc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
2.0 g of 2-(4-chlorophenyl)-3-methylbutanol in 10 ml of a 20% mixture of dimethylformamide and toluene was added over a 5 minute period to sodium hydride (0.8 g, 50% in oil) in 20 ml of toluene at 110°-120° C, and the mixture was stirred for 15 minutes. 3.0 g of 3-phenoxybenzyl bromide in 15 ml of toluene was then added over a 15 minute period and the mixture was gently refluxed for 2 hours, then was cooled and 10 ml of mineral spirits was added. The mixture was poured into ice/hydrochloric acid, extracted with ether, washed with sodium bicarbonate solution and dried (MgSO4). The solvent was removed to give an orange oil, which was chromatographed on silica gel using 1:1 methylene dichloride:hexane as eluent to give 1.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][OH:13])[CH:10]=2)[N:5]=[C:4]([N:14]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17](=O)(=O)[CH2:16][CH2:15]2)[CH:3]=1.ClC1C2C(=CC=C(C(OC)=O)C=2)N=C(N2CC3C=CC=CC=3SCC2)C=1.[BH4-].[Na+]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][OH:13])[CH:10]=2)[N:5]=[C:4]([N:14]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17][CH2:16][CH2:15]2)[CH:3]=1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(CO)ccc3n2)Cc2ccccc21
Agent: COC(=O)c1ccc2nc(N3CCSc4ccccc4C3)cc(Cl)c2c1
Agent: [BH4-]
Agent: [Na+]
Product: OCc1ccc2nc(N3CCSc4ccccc4C3)cc(Cl)c2c1

Procedure:
The title compound was prepared in analogy to 4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinoline-6-methanol in Example 3-23 in Scheme 5 by using methyl 4-chloro-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine in Example 1-1 in Scheme 4 by using methyl 2,4-dichloro quinoline-6-carboxylate and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and sodium borohydride.
Reaction SMILES: C(OC(=O)C)C.[ClH:7].[F:8][C:9]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[C:15]2[C:10]=1[C:11](=[O:47])[C:12]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)=[CH:13][N:14]2[CH2:23][CH2:24][NH:25][C:26]([C@@H:28]([NH:31]C(=O)OC(C)(C)C)[CH2:29][OH:30])=[O:27]>C(O)C>[ClH:7].[NH2:31][C@@H:28]([CH2:29][OH:30])[C:26]([NH:25][CH2:24][CH2:23][N:14]1[C:15]2[C:10](=[C:9]([F:8])[CH:18]=[CH:17][C:16]=2[O:19][CH2:20][CH2:21][CH3:22])[C:11](=[O:47])[C:12]([C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)=[CH:13]1)=[O:27]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCNC(=O)[C@H](CO)NC(=O)OC(C)(C)C)c12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCNC(=O)[C@@H](N)CO)c12
Temperature: 25 °C
Reaction time: 14 h
Yield: 50 %

Procedure:
A 4N hydrogen chloride ethyl acetate solution (5 ml) was added to an ethanol solution (5 ml) of tert-butyl ((S)-1-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylcarbamoyl}-2-hydroxyethyl)carbamate (330 mg, 0.6 mmol) and stirred at room temperature for 14 hours. The resulting mixture was concentrated under reduced pressure. Water was added to the residue, which was then washed with ethyl acetate. A 2N aqueous sodium hydroxide solution (6 ml) was added to the water layer to adjust its pH to 11, followed by extraction with dichloromethane. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=20:1→15:1). The purified product was concentrated under reduced pressure, the residue was dissolved in ethanol (3 ml) and ethyl acetate (3 ml), and a 4N hydrogen chloride ethylacetate solution (0.1 ml) was then added thereto. The mixture was stirred and concentrated to dryness under reduced pressure, and recrystallized from ethyl acetate, giving a white powder of (S)-2-amino-N-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethyl}-3-hydroxypropionamide hydrochloride (145 mg, yield: 50%).
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:32]=[CH:31][C:24]([C:25]([O:27]CC=C)=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[OH:33])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:31][CH:32]=5)=[CH:18]4)=[CH:13][C:12]=3[O:33][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CCOC(=O)CCCCCBr
Reactant: C=CCOC(=O)c1ccc(-c2ccc3cc(O)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Product: CCOC(=O)CCCCCOc1cc2ccc(-c3ccc(C(=O)O)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Yield: 58.5 %

Procedure:
Following the procedure of Example 12(a), but reacting 3 g (6.8 mmol) of allyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 2.3 g (10.2 mmol) of ethyl 6-bromohexanoate, 2.15 g (55%) of the expected compound were obtained, which compound had a melting point of 116°-7° C.
Reaction SMILES: S(Cl)(Cl)=O.Cl.[C:6]1([NH:12][C@@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:22]O>>[C:6]1([NH:12][C@@H:13]2[CH2:14][CH2:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CO
Reactant: O=C(O)[C@H]1CC[C@@H](Nc2ccccc2)CC1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CC[C@@H](Nc2ccccc2)CC1

Procedure:
Thionyl chloride (0.65 g, 5.47 mmol) was added to a stirred solution of cis-4-(phenylamino)cyclohexanecarboxylic acid hydrochloride (600 mg, 2.74 mmol) in MeOH (10 ml) at room temperature and heated at reflux for 5 h. The reaction mixture was concentrated under reduced pressure. The crude product was basified with saturated sodium bicarbonate solution and extracted with DCM (2×25 ml). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude compound which was purified by column chromatography over neutral alumina by eluting in 10% ethyl acetate in petroleum ether to afford 500 mg of cis-methyl 4-(phenylamino)cyclohexanecarboxylate (78%) as colorless oily liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[N:38]1([CH2:44][CH2:45][NH2:46])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:46][CH2:45][CH2:44][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: NCCN1CCCCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NCCN3CCCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 2-piperidin-1-yl-ethylamine according to conditions described in general procedure C. Mp: 88-89° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.31-1.39 (m, 6 H), 1.58-1.61 (m, 6 H), 1.99-2.27 (m, 6 H), 2.90-3.24 (m, 2 H), 3.23-3.29 (m, 4 H), 6.20-6.31 (bd, 1 H), 6.90-6.98 (m, 2 H), 7.15 (d, J=8.8 Hz, 1 H), 7.37 (d, J=8.0 Hz, 1 H), 7.43 (s, 1 H), 7.50-7.62 (m, 3 H), 7.78-7.80 (m, 1 H), 7.96 (d, J=8.0 Hz, 1 H), 8.20 (s 1 H), 10.40 (s, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20](=[O:23])[CH2:21][CH3:22].Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[C:21](\[CH3:22])/[C:20](=[O:23])[CH3:19])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Reactant: CCC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(/C=C(\C)C(C)=O)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of commercially available 3-benzyloxy-4-methoxybenzaldehyde (34 g, 0.14 mol, 1 eq) and 2-butanone (50 mL, 0.56 mol, 4 eq) in dry THF (50 mL) was cooled to −4° C. Hydrogen chloride gas was passed through the well-stirred solution for several minutes, and the reaction mixture was capped and stored at −4° C. for 16 h. The mixture was poured into a well stirred solution of ice-cold saturated sodium bicarbonate (NaHCO3) (about 2 L). If necessary, the pH was adjusted to >7 with sat. NaHCO3, and the mixture was extracted with EtOAc (3×300 mL).