Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:25][CH:26]=[CH2:27])[CH3:24])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:25]([N:23]([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[NH:8][CH2:9][CH2:10][CH2:11]2)[CH:26]=[CH2:27]
Reactant: C=CCN(C)CCCCOc1ccc2c(c1)CCCN2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCN(C)CCCCOc1ccc2c(c1)CCCN2
Temperature: 40 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
3.64 g (9.7 mmol) 6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester in 5 ml CH2Cl2 were treated with 3.5 ml TFA at 0° C., and the solution was stirred at 40° C. for 1 h. The solution was concentrated and the residue dissolved in a mixture of a saturated aqueous solution of NaHCO3 and ether. The inorganic phase was extracted with ether and the combined organic phases were washed with water and dried over Na2SO4 to yield 1.85 g (69%) Allyl-methyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-butyl]-amine, MS: 275 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]([O-:22])(=[S:21])[CH3:20].[K+].O.CC(OC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([S:21][C:19](=[O:22])[CH3:20])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Crude 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester was dissolved in 200 ml DMF, and potassium thioacetate (18.5 g, 162 mmol) was added. The mixture was stirred overnight under a nitrogen atmosphere at about 65° C. The reaction mixture solidified overnight, and after it was cooled to room temperature, 250 ml water and 250 ml TBME was added, and the mixture was stirred for 10 minutes. The layers were separated, and the aqueous layer was extracted with 200 ml TBME. The combined organic layers were washed with water (2×250 ml) and saturated aqueous NaCl solution (150 ml), dried over sodium sulfate, filtered, and evaporated to dryness (30.3 g, 94%) to give a dark-brown oil identified as the product by 1H-NMR, which was used without purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14](O)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:48][C:45]3[CH:46]=[CH:47][C:42]([O:41][CH3:40])=[CH:43][CH:44]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Reactant: COc1ccc(N)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (150 mg, 0.439 mmol), EDC (118 mg, 0.615 mmol), and HOBT (83 mg, 0.615 mmol) in DMF (3 mL) was added p-anisidine (54 mg, 0.44 mmol), and the reaction mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (191 mg) as a yellow solid. LC-MS (ES) m/z=447 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([NH:9][C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)=[S:8])C=C[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])(=O)=[O:16]>C(Cl)(Cl)Cl>[ClH:18].[O:16]1[CH:4]=[CH:3][CH:2]=[C:1]1[C:7]1[S:8][N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[N:9]=1
Reactant: S=C(Nc1ncc[nH]1)c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cl
Product: c1coc(-c2nc3nccn3s2)c1
Reaction time: 4 h

Procedure:
To a solution of 0.19 g. of 2-(2-furylthiocarbonylamino)-imidazole [(IV), R = 2-furyl] in 25 ml. of chloroform, at 20°-25°C, there is added dropwise 0.09 ml. of sulfuryl chloride in 5 ml. of chloroform. After four hours, the reaction mixture is chilled in ice, followed by filtration to yield 2-(2-furyl)-1,2,4-thiadiazolo-[2,3-a]-imidazole hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:25]2[CH:29]=[C:28]([CH2:30][CH2:31][OH:32])[N:27]=[N:26]2)[CH:22]=[CH:21][C:20]=1[CH3:33])=[O:18].[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1.CCOC(C)=O.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:25]2[CH:29]=[C:28]([CH2:30][CH2:31][O:32][S:41]([C:38]3[CH:39]=[CH:40][C:35]([CH3:34])=[CH:36][CH:37]=3)(=[O:43])=[O:42])[N:27]=[N:26]2)[CH:22]=[CH:21][C:20]=1[CH3:33])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCCc2cn(-c3ccc(C)c(C(=O)c4ccc(Nc5ccc(F)cc5F)cc4Cl)c3)nn2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of compound 128 (250 mg, 0.53 mmol) in dry pyridine (2.0 mL) was flushed with argon and cooled to 0° C. 4-Methyl-benzenesulfonyl chloride (102 mg, 0.53 mmol) was added and the reaction was allowed to come to RT overnight under stirring. The reaction mixture was poured into a mixture of EtOAc/water. The organic phase was washed with water, brine, filtered and concentrated in vacuo to give the crude product. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 25:75 to 50:50 as the eluent to afford the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)(=O)=O.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(#N)C>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)OCCCc1ccc(Br)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CCCc2ccc(Br)cc2)CC1
Temperature: 75 °C

Procedure:
To a stirred solution of 3-(4-bromophenyl)propyl methanesulfonate (4.2 g, 14.33 mmol) in acetonitrile (33.2 ml) was added tert-butyl piperazine-1-carboxylate (3.47 g, 18.62 mmol) and triethylamine (2.60 ml, 18.62 mmol). Reaction mixture heated to 75° C. overnight. The reaction mixture was evaporated to dryness and redissolved in EtOAc (40 mL), and washed with 2:8 saturated brine:water (45 mL). The aqueous was extracted with EtOAc (2×25 mL), organics combined and washed with 2:8 saturated brine:water (2×45 mL) and saturated brine (25 mL). The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography using Isco Companion, 50 g silica column, elution gradient 30 to 50% EtOAc in dichloromethane. Pure fractions were evaporated to dryness to afford the sub-title compound as a yellow oil. Yield: 2.4 g
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2I)[N:3]=1.[NH2:13][C:14]1[C:22]2[O:21][C:20]([CH3:24])([CH3:23])[CH2:19][C:18]=2[CH:17]=[CH:16][CH:15]=1.[O:25]=[S:26]1(=[O:33])[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1>>[CH3:23][C:20]1([CH3:24])[CH2:19][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:13][C:2]3[CH:11]=[CH:10][C:9]4[C:8]([NH:32][CH:29]5[CH2:30][CH2:31][S:26](=[O:33])(=[O:25])[CH2:27][CH2:28]5)=[CH:7][CH:6]=[CH:5][C:4]=4[N:3]=3)[C:22]=2[O:21]1
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: NC1CCS(=O)(=O)CC1
Reactant: CC1(C)Cc2cccc(N)c2O1
Product: CC1(C)Cc2cccc(Nc3ccc4c(NC5CCS(=O)(=O)CC5)cccc4n3)c2O1

Procedure:
The title compound, MS: m/e=438.3 (M+H+), was prepared in accordance with the general method of example 3 from 2-chloro-5-iodo-quinoline (CAS 455955-26-7), 7-amino-2,3-dihydro-2,2-dimethylbenzofuran (CAS 68298-46-4) and 1,1-dioxo-tetrahydro-2H-thiopyran-4-amine.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[Br:25][CH:26]([CH3:30])[C:27](Br)=[O:28].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[Br:25][CH:26]([CH3:30])[C:27]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:28]
Reactant: CC(Br)C(=O)Br
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(Br)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 0.17 h
Yield: 47.3 %

Procedure:
To a solution of (4S)-4-benzyloxazolidin-2-one (0.164 g; 0.927 mmol) in dry tetrahydrofuran (3.8 ml), a 1.62 N solution of n-butyl lithium in hexane (0.571 ml; 0.927 mmol) was added at 0° C., and then 2-bromopropionyl bromide (0.106 ml; 1.01 mmol) was added at the same temperature. After 10 minutes, an aqueous solution of saturated sodium hydrogen carbonate (1 ml) was added to decompose the excess reaction agent. The reaction mixture was diluted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, the resulting solid was purified by silica gel chromatography (hexane:dichloromethane=2:3-0:1) to give a less polar (4S)-3-(2'-bromopropionyl)-4-benzyloxazolidin-2-one (0.137 g, yield, 47%) and a (4S)-3-(2'-bromopropionyl)-4-benzyloxazolidin-2-one (0.145 g, yield, 50%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4].S(Cl)([Cl:11])=O.C(OCC)C.O.[CH2:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[ClH:11].[NH2:1][C@@H:2]([CH2:6][CH:7]=[CH2:8])[C:3]([O:5][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:4]
Reactant: C=CC[C@H](N)C(=O)O
Reactant: OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: C=CC[C@H](N)C(=O)OCc1ccccc1
Product: Cl
Yield: 68 %

Procedure:
To a solution of (2S)-2-amino-4-pentenoic acid 17 (225 mg, 1.96 mmol) in benzyl alcohol (5 mL) was added thionyl chloride (2 mL) and the resulting mixture was allowed to stir for 16 h before addition of diethyl ether (30 mL) and extraction with water (3×30 mL). The aqueous layer was concentrated, diluted with 2M sodium bicarbonate (20 mL), and extracted with DCM (3×30 mL). The combined organic fractions were dried and acidified with 1M HCl/diethyl ether (2 mL) and evaporated. The crude product dissolved in a minimal volume of MeOH and precipitated with diethyl ether to yield the title compound (322 mg, 1.34 mmol, 68%) as a white solid. [α]D20 −40.6 (c. 0.1, H2O). Mp 186-191° C. 1H NMR (D2O, 300 MHz): δ 7.28 (m, 5H, ArH); 5.51 (m, 1H, H4); 5.11 (m, 4H, H5 and ArCH2); 4.08 (t, J=5.4 Hz, 1H, H2); 2.55 (m, 2H, H3). Mass Spectrum (CI, +ve) m/z 205 (25%) [MH+]. HRMS calcd for C12H16NO2 206.1181, found 206.1169.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][N:11]=[C:10]([CH2:19][N:20]2[N:24]=[N:23][C:22]([C:25]([F:28])([F:27])[F:26])=[N:21]2)[N:9]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[C:10]([CH2:19][N:20]2[N:24]=[N:23][C:22]([C:25]([F:26])([F:27])[F:28])=[N:21]2)[N:9]=1
Reactant: CCOC(=O)c1cnc(Cn2nnc(C(F)(F)F)n2)nc1-c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc(Cn2nnc(C(F)(F)F)n2)nc1-c1ccccc1Cl
Temperature: 25 °C

Procedure:
1.74 g (4.21 mmol) of ethyl 4-(2-chlorophenyl)-2-{[5-(trifluoromethyl)-2H-tetrazol-2-yl]methyl}pyrimidine-5-carboxylate were dissolved in 12 ml of ethanol and 45% strength aqueous sodium hydroxide solution (5.05 mmol) was added dropwise at 0° C. The reaction was stirred for a further hour and warmed to RT. The ethanol was then removed under reduced pressure, and ice-water (10 ml) was added to the residue. The aqueous phase was extracted with ethyl acetate. The organic phase was discarded. Then the aqueous phase was adjusted to a pH of 3 using hydrochloric acid, and again extracted with ethyl acetate (3×20 ml). The combined organic phases were dried over sodium sulphate. (logP: 2.50; MH+: 385; 1H-NMR (400 MHz, DMSO, ppm): 6.59 (s, 2H), 7.48 (m, 4H), 9.27 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([O:10][CH3:11])[C:5]([O:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.[C:16](=[O:19])([O-])[O-:17].[K+].[K+].[I-].[Na+].[CH2:24](O)[CH3:25]>>[CH:8]([C:7]1[C:6]([O:10][CH3:11])=[C:5]([O:12][CH2:13][CH2:14][CH3:15])[CH:4]=[CH:3][C:2]=1[O:1][CH2:7][CH2:2][CH2:3][CH2:4][C:16]([O:17][CH2:24][CH3:25])=[O:19])=[O:9]
Reactant: CCO
Reactant: CCCOc1ccc(O)c(C=O)c1OC
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Product: CCCOc1ccc(OCCCCC(=O)OCC)c(C=O)c1OC
Reaction time: 16 h

Procedure:
6-Hydroxy-2-methoxy-3-n-propoxybenzaldehyde (5.25 g, 0.025 M), ethyl 5-brown pentanoate (3.96 ml, 0.025 M), anhydrous potassium carbonate (3.71 g). sodium iodide (0.15 g) and 95% ethanol (50 ml) were refluxed with stirring for 16 hr. The cooled reaction mixture was filtered and the solid washed well with ethanol. The filtrate was evaporated to dryness and the residue partitioned between ether and water. The organic layer was separated and washed with 2 N sodium hydroxide solution, water, dried (sodium sulphate) and evaporated to give ethyl 5-(2-formyl-3-methoxy-4-n-propoxyphenoxy)pentanoate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])=[O:7])=[CH:4][CH:3]=1.[CH2:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1Cl)[C:27](N)=O)[CH3:23].COC1C=C2C(=CC=1)[NH:41][C:40](C)=C2CCN.C1(CC(O)=O)C=CC=CC=1>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])=[O:7])=[CH:4][CH:3]=1.[CH2:22]([C:24]1[CH:25]=[C:26]([CH2:27][CH2:40][NH-:41])[CH:30]=[CH:31][CH:32]=1)[CH3:23]
Reactant: CCc1cc(C(N)=O)ccc1Cl
Reactant: COc1ccc2[nH]c(C)c(CCN)c2c1
Agent: COc1ccc2c(c1)cc(C)n2C(=O)c1ccc(Cl)cc1
Agent: O=C(O)Cc1ccccc1
Product: CCc1cccc(CC[NH-])c1

Procedure:
The procedure employed for preparation of Compound 9e was repeated except as follows. In the treatment of Compound 7, phenylacetic acid was used instead of 4-chlorobenzoic acid, so the resultant was 8i instead of 8e.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][OH:13])[CH:5]=O.[NH2:14][C:15]1[CH:30]=[CH:29][CH:28]=[CH:27][C:16]=1[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)=[O:18]>C(O)C>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([N:19]2[C:17](=[O:18])[C:16]3[C:15](=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:14]=[C:5]2[C:4]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][OH:13])=[C:2]([CH3:1])[CH:3]=2)=[CH:21][CH:22]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Br)cc1
Reactant: Cc1cc(C=O)ccc1OCCO
Solvent: CCO
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Br)cc2)ccc1OCCO
Temperature: 25 °C

Procedure:
To a solution of 3-methyl-4-hydroxyethoxy-benzaldehyde (0.38 g, 2.10 mmol) and 2-amino-N-(4-bromophenyl)benzamide (0.60 g, 2.10 mmol) in anhydrous ethanol (15 mL) was added anhydrous CuCl2 (0.85 g, 6.30 mmol). The reaction mixture was heated at reflux for 18 hours and then cooled to room temperature. Organic solvents were removed under reduced pressure, and the resulting residue was diluted with dichloromethane, washed with water, then brine, and dried over anhydrous magnesium sulfate. The solvent was removed under vacuum and the residual solid was purified by column chromatography (silica gel 230-400 mesh; 25-50% ethyl acetate in hexanes as eluent) to afford the title compound as a white solid. Yield: 0.21 g (22%). MP 92.0-93.0° C. 1H-NMR (400 MHz, CDCl3): δ 8.32 (d, J=8.4 Hz, 1H), 7.81 (dd, J=4.8 and 1.2 Hz, 2H), 7.45-7.54 (m, 3H), 7.23 (m, 1H), 7.00 (m, 3H), 6.63 (d, J=8.4 Hz and 1H), 4.05 (t, J=4.4 Hz, 2H), 3.97 (t, J=4.4 Hz, 2H), 2.15 (s, 3H). MS (ES+) m/z: 453.39, 451.37.
Reaction SMILES: [C:1](OC([NH:8][C:9]1[C:10]([F:34])=[C:11]([N:16]2[C:25]3[C:20](=[CH:21][C:22]([F:27])=[C:23]([Cl:26])[N:24]=3)[C:19](=[O:28])[C:18]([C:29]([O:31]CC)=[O:30])=[CH:17]2)[CH:12]=[CH:13][C:14]=1[F:15])=O)(C)([CH3:3])[CH3:2].Cl.[C:36]([OH:39])(=O)[CH3:37].[CH:40](Cl)(Cl)Cl>O>[CH:1]([O:39][CH:36]([CH3:37])[CH3:40])([CH3:3])[CH3:2].[NH2:8][C:9]1[C:10]([F:34])=[C:11]([N:16]2[C:25]3[C:20](=[CH:21][C:22]([F:27])=[C:23]([Cl:26])[N:24]=3)[C:19](=[O:28])[C:18]([C:29]([OH:31])=[O:30])=[CH:17]2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CC(=O)O
Reactant: ClC(Cl)Cl
Reactant: CCOC(=O)c1cn(-c2ccc(F)c(NC(=O)OC(C)(C)C)c2F)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: O
Product: CC(C)OC(C)C
Product: Nc1c(F)ccc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)c1F

Procedure:
Ethyl 1-(3-t-butoxycarbonylamino-2,4-difluorophenyl)-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (500 mg) was added to 8 ml of a mixture of 3N hydrochloric acid and acetic acid, which was stirred and heated at reflux for 3.5 hours. After 16 ml of distilled water was added, the reaction solution was heated at reflux for 10 minutes, then allowed to cool down, and combined with 80 ml of chloroform and 10 ml of distilled water. The solution was separated, the chloroform layer was concentrated in vacua. The precipitate was dispersed in ethanol, collected by filtration, and washed with ethanol and then with diisopropyl ether to give 295 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1.[CH2:25]([O:27][C:28](OCC)(OCC)OCC)[CH3:26].[OH-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]2[N:16]=[C:28]([O:27][CH2:25][CH3:26])[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:12]=2[CH:11]=1
Reactant: COC(=O)CCCCCOc1ccc(N)c(Nc2ccccc2)c1
Reactant: CCOC(OCC)(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOc1nc2ccc(OCCCCCC(=O)OC)cc2n1-c1ccccc1

Procedure:
200 mg of 6-(3-phenylamino-4-aminophenyl)oxyhexanoic acid methyl ester was mixed with 0.19 ml of tetraethylorthocarbonate and 40 μl of acetic acid, and the mixture was heated for 4 hours to 80° C. After cooling, it was mixed with 1N sodium hydroxide solution, extracted three times with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 124 mg was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15](O)[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1.C1(N)CCCCC1>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1
Reactant: O=C(O)CCC(O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Solvent: NC1CCCCC1
Solvent: O
Product: O=C(O)CCCc1ccc(-c2ccc(Cl)cc2Cl)cc1

Procedure:
Prepared analogous to Example 9 from 4-(2',4'-dichloro-4-biphenylyl)-4-hydroxy-butyric acid. Melting point of the cyclohexylamine salt: 154°-155° C. (from water).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[O:3]1.C1(C)C=CC(S(C[N+]#[C-])(=O)=O)=CC=1.[C:25]([OH:29])(C)(C)C.CC(C)([O-:33])C.[K+]>C(COC)OC.C(OCC)C>[CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([C:25]([OH:29])=[O:33])[CH2:5][C:4]([CH3:10])([CH3:9])[O:3]1
Reactant: CC(C)(C)O
Reactant: CC1(C)CC(=O)CC(C)(C)O1
Reactant: CC(C)(C)[O-]
Agent: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Solvent: COCCOC
Solvent: CCOCC
Product: CC1(C)CC(C(=O)O)CC(C)(C)O1
Temperature: 35 °C
Yield: 79.7 %

Procedure:
To a solution of 2,2,6,6-tetramethyl-tetrahydro-pyran-4-one (3.00 g, 19.20 mmol), p-toluenesulfonylmethyl isocyanide (4.90 g, 24.96 mmol), and t-butanol (3.06 mL, 32.64 mmol) in 75 mL dimethoxyethane at 0° C. was added potassium t-butoxide (5.38 g, 48.01 mmol) at such a rate that the temperature did not increase above 10° C. After addition was complete the mixture was allow to attain RT and then heated at 35° C. overnight. The mixture was then cooled to RT and 50 mL of diethyl ether was added and the mixture was filtered. The filtrate was concentrated and redissolved in 50 mL of diethyl ether and filtered to remove the ppt. The filtrate was again concentrated and then dissolved in 50 mL of 2.25 M KOH and refluxed overnight. The mixture was cooled and washed with 2×50 mL of DCM. The pH of the aqueous layer was then adjusted to 2 with conc HCl and the product extracted with EtOAc (2×50 mL). The organic phase was dried over Na2SO4, filtered and concentrated to give 2.85 g (80%) of the title compound as an off-white solid which was used without further purification.
Reaction SMILES: II.[CH2:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][N:12]1[CH2:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH2:14][CH2:13]1.Cl>CCOCC.C(Cl)C1C=CC=CC=1.O>[CH2:3]([CH:15]1[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH:16]1[C:18]([O:20][CH3:21])=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C1=CCCN(C)C1
Reactant: ClCc1ccccc1
Agent: Cl
Agent: II
Solvent: CCOCC
Solvent: O
Product: COC(=O)C1CN(C)CCC1Cc1ccccc1
Temperature: -15 °C

Procedure:
To a solution of 480 mg of Mg in 2 mL of dry ether was added a little bit of I2 and several drops of benzyl chloride (about 0.5 mL) of the solution of 2.3 mL (20 mmol) of benzyl chloride in 10 mL of ether. The mixture was gentle stirred, as soon as the reaction sets in, the reminder of benzyl chloride in ether was added at the rate that the reaction went vigorously by cooling the flask with water. Then the resulting solution was stirred at gentle reflux for fifteen minutes after, all the benzyl chloride has been added. Another 5 mL of dry ether was added to the Grignard reagent solution and it was cooled to −15° C., the arecoline (1.5 g) in 20 mL of dry ether was added dropwise to it. The resulting mixture was stirred at −15° C. for another 0.5 hour. The mixture was cooled to about −40° C. and treated slowly with 10% HCl (22 mL). The aqueous layer was separated, extracted with ether (20 mL), and then basified with saturated sodium bicarbonate solution when cooled in an ice bath. The mixture was extracted with ether and the combined organic extracts were washed with brine, dried and concentrated under reduced pressure. Flash chromatography afforded a mixture of cis isomer 76 and trans isomer 77 (500 mg, 21%).