Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:29][CH3:30])=[C:18]([O:21]CC4C=CC=CC=4)[CH:19]=3)[C:14]([OH:31])=[C:13]([C:32]([O:34][CH3:35])=[O:33])[C:12]=2[C:36]([O:38][CH3:39])=[O:37])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>O1CCCC1.CO.[H][H].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:29][CH3:30])=[C:18]([OH:21])[CH:19]=3)[C:14]([OH:31])=[C:13]([C:32]([O:34][CH3:35])=[O:33])[C:12]=2[C:36]([O:38][CH3:39])=[O:37])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1c(C(=O)OC)c(-c2ccc(OC)c(OC)c2)c2cc(OCc3ccccc3)c(OC)cc2c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(C(=O)OC)c(-c2ccc(OC)c(OC)c2)c2cc(O)c(OC)cc2c1O
Yield: 90.3 %

Procedure:
2 g of 1-(3,4-dimethoxyphenyl)-2,3-bis(methoxycarbonyl)-4-hydroxy-6-methoxy-7-benzyloxynaphthalene obtained in Example 6 are dissolved in a mixture of 200 ml of tetrahydrofuran and 50 ml of methanol. The solution is stirred in the presence of 2 g of 10% palladium-charcoal in hydrogen atmosphere at 40 psi for 2 hours. After the reaction, the catalyst is removed by filtration, and the filtrate is evaporated to dryness under reduced pressure. The resultant crude crystals are triturated with methanol, whereby 1.5 g of 1-(3,4-dimethoxyphenyl)-2,3-bis(methoxycarbonyl)-4-hydroxy-6-methoxy-7-hydroxynaphthalene is obtained.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][CH2:2][C@H:3]2[N:8]([C:9]([C:11]3[N:12]=[C:13]([CH3:23])[S:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@H:6]3[C@@H:4]2[CH2:5]3)=[O:30])=[CH:27][CH:26]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1ccc(Cl)cc1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc(Cl)cc2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Chloro-benzoic acid.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH2:20]O.CS(Cl)(=O)=O.[CH2:36]([N:38](CC)CC)C>ClCCl>[C:26]([O:25][C:23](=[O:24])[NH:22][CH:4]1[C:3](=[O:2])[N:38]([CH3:36])[CH2:20][C:7]2[CH:8]=[C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:6]=2[CH2:5]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CCN(CC)CC
Reactant: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1CO)NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CN1Cc2cc(OCc3ccccc3)ccc2CC(NC(=O)OC(C)(C)C)C1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2-acetoxymethyl-4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (1.85 g, 4.0 mmol) in methanol (40 mL) was added potassium carbonate (560 mg, 4.0 mmol) at room temperature and stirred for 1 h. The reaction mixture was diluted with dichloromethane (150 mL), washed with 1.0 M aqueous hydrogen chloride and dried (Na2SO4) to give the pure 3-(4-benzyloxy-2-hydroxymethyl-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester in almost quantitative yield. To the alcohol (800 mg, 1.93 mmol) in dichloromethane (50 mL) was added methanesulfonyl chloride (0.18 mL, 2.3 mmol) followed by triethylamine (0.38 mL, 2.70 mmol) at 0° C. and then brought to room temperature. After 1 h, the reaction mixture was washed with aqueous sodium hydrogencarbonate, dried (Na2SO4). The solvent was removed, dissolved the crude product in anhydrous THF (20 mL) followed by addition of 2.0 M solution of methylamine in THF (10 mL) in a sealed tube. The sealed tube was heated at 80° C. for a period of 12 h and then removed the solvent. The crude product was purified by flash chromatography using 30% ethyl acetate in hexane to give (8-benzyloxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-carbamic acid tert-butyl ester in 39% overall yield. 1H NMR (500 MHz, CDCl3): in δ 7.40-7.31 (m, 5 H), 7.01-7.00 (m, 1 H), 6.83-6.82 (m, 1 H), 6.66 (s, 1 H), 5.91-5.90 (m, 1 H), 5.13-5.01 (m, 4 H), 3.50-3.46 (m, 1 H), 3.03 (s, 3 H), 2.85-2.78 (m, 1 H), 1.45 (s, 9 H).
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([O:13]CC)=[O:12])[CH2:7][CH2:8][CH2:9][CH3:10])=[O:4].[OH-].[K+]>O.C1COCC1>[NH:1]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=[O:12])[CH2:7][CH2:8][CH2:9][CH3:10])=[O:4]
Reactant: CCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Boc-Gly-Nleu-OEt (28.8 g, 0.094 mol.) was dissolved in a mixture of 150 ml H2O and 150 ml THF. KOH (11.9 g, 0.18 mol.) dissolved in 50 ml H2O was added while stirring the solution. After one hour, The THF was removed under reduced pressure. The aqueous solution was chilled to 0° C. and acidified to about pH=2 by addition of concentrated HCl (swirling the solution vigorously at the same time). The product was extracted from the aqueous layer by ethyl acetate 3×100 ml. The organic layers were combined, washed by brine and dried by Na2SO4. The ethyl acetate was removed under reduced pressure to get the crude product. Column chromatography (elution solvents: E/H, 1:1. This solvent system was used to remove the impurities and the pure product was washed out from the column by a mixture of methanol and ethyl acetate) was carried out to obtain the pure product (white oil, 20 g, 74%). TLC Rf=0.2 (developing solvents: E/H, 3:1). FAB-MS, observed (M+H)+=289. 1H-NMR (360 MHz, DMSO-d6) d 6.72 (m, Gly-NH), 6.62 (m, Gly-NH), 4.03 (s, Nleu-α), 3.87 (s, Nleu-α), 3.78 (d, Gly-α), 3.68 (d, Gly-α), 3.06 (m, Nleu-β), 1.82 (m, 1H, Nleu-γ), 1.32 (s, 9H, Boc-CH3), 0.85 (d, Nleu-δ), 0.76 (d, Nleu-δ).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O.C(OCC)C>[CH3:3][O:4][C:5](=[O:6])[CH:7]=[C:24]1[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:22][CH2:23]1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
60% sodium hydride in mineral oil (7.92 g, 198.02 mmoles) was washed with hexanes then suspended in N,N-dimethylformamide (220.00 mL). The mixture was cooled to 0° C. Trimethyl phosphonoacetate (29.0 mL, 189.82 mmoles) was added drop-wise to the reaction. The mixture was held at 0° C. with stirring on and held for 20 min. A solution of N-tert-butoxycarbonyl-4-piperidone (30.41 g, 152.62 mmoles) in 80 mL N,N-dimethylformamide was added to the mixture drop-wise. Reaction was stirred at room temperature for 3 hours. Mixture was diluted with diethyl ether (650 mL). Mixture was washed once with water. Aqueous layer was back extracted once with diethyl ether. Organic layers were combined. The mixture was washed 4 times with water and the aqueous phase was discarded. The mixture was washed with brine and the aqueous phase was discarded. The material was dried over MgSO4, filtered, and concentrated to dryness. Title compound was obtained as white solid in 92% yield. 1H NMR (300 MHz, CDCl3): δ=5.68 (s, 1H), 3.66 (s, 3H), 3.40-3.51 (m, 4H), 2.90 (t, J=5.49, 2H), 2.25 (t, J=5.49, 2H), 1.44 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([SH:21])=[S:20])[CH2:15][CH2:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[Na+].[CH3:24]I>CO.[Cl-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]2[CH2:14][CH2:15][N:16]([C:19]([S:21][CH3:24])=[S:20])[CH2:17][CH2:18]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CI
Reactant: COc1cc(N2CCN(C(=S)S)CC2)cc(OC)c1OC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(N2CCN(C(=S)SC)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
In a nitrogen atmosphere, 1.5 g (4.6 mmol.) of 4-(3,4,5-trimethoxyphenyl)-1-piperazinecarbodithioic acid was suspended in methanol. After addition of 0.2 g of granular sodium hydroxide, the suspension was stirred at room temperature for one hour. The reaction mixture was chilled in a mixture of ice and sodium chloride. To the reaction mixture was dropwise added a solution of 0.29 ml of methyl iodide in 3.7 ml of methanol. After the addition was complete, the mixture was stirred at room temperature for 1 hour. Precipitated crystals were collected by filtration to give 0.8 g of the desired compound as a gray-brown powder, m.p. 135°-137° C. (decomp.), yield 50.8%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH2:12])[NH:8][C:7](=[O:13])[CH2:6][C:5]2([CH3:15])[CH3:14].[C:16](OC(=O)C)(=O)[CH3:17].Cl>C(O)C>[CH3:16][C:17]1[NH:1][C:2]2=[CH:3][C:4]3[C:5]([CH3:15])([CH3:14])[CH2:6][C:7](=[O:13])[NH:8][C:9]=3[CH:10]=[C:11]2[N:12]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Agent: Cl
Solvent: CCO
Product: Cc1nc2cc3c(cc2[nH]1)C(C)(C)CC(=O)N3

Procedure:
3.1 g. 6,7-diamino-4,4-dimethyl-1,2,3,4-tetrahydro- quinolin-2-one and 2.8 ml. acetic anhydride were stirred in 50 ml. ethanol for 30 minutes at ambient temperature. 20 ml. concentrated hydrochloric acid were then added thereto and the reaction mixture refluxed for 18 hours. The solvent was removed in a vacuum and the residue was dissolved in water, rendered alkaline with ammonia, filtered off with suction and washed with water. After recrystallisation from ethyl acetate, there were obtained 2.4 g. of the title compound; m.p. 290 294° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[C:3]=1[F:10].CC(C)([O-])C.[K+].[Cl:17][C:18]1[CH:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>CC(N(C)C)=O>[Cl:17][C:18]1[CH:23]=[C:22]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([F:10])[C:4]=2[F:9])[CH:21]=[CH:20][N:19]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1ccc(O)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
4-amino-2,3-difluorophenol (6 g, 41.4 mmol) and potassium tert-butoxide (4.9 g, 43.5 mmol) were suspended in DMAc (200 mL) and stirred at RT for 30 min under Ar atmosphere. 2,4-Dichloropyridine (6.1 g, 41.4 mmol) was added, and the resulting mixture was heated at 70° C. for 8 h. The reaction mixture was filtered, concentrated in vacuo and purified by silica gel chromatography to afford 4-(2-chloro-pyridin-4-yloxy)-2,3-difluoro-phenylamine (7 g, 66% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.27 (d, J=6.0 Hz, 1 H), 7.05 (s, 1 H), 6.95 (m, 1 H), 6.92 (m, 1 H), 6.62 (m, 1 H), 5.60 (s, 2 H); MS (ESI) m/z: 257.1[M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=1.O1CCOCC1.[H][H].[ClH:22]>CO.[Pd]>[ClH:22].[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH2:12])[CH:6]=1
Reactant: [H][H]
Reactant: COC(=O)Cc1cccc(C#N)c1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)Cc1cccc(CN)c1

Procedure:
To a solution of (3-cyano-phenyl)-acetic acid methyl ester (18.06 g, 103 mmol) in MeOH (150 mL) and 4M HCl in dioxane (30.0 mL, 120 mmol) was added 10% palladium on carbon (2 g). The mixture was placed on a Parr shaker and was hydrogenated at 50 psi hydrogen for 24 h. The catalyst was removed via filtration through Celite® and the organic solution was concentrated in vacuo. The resulting solid was stirred in EtOAc and filtered to provide the title compound as a white solid (20.42 g). 1H NMR (400 MHz, CD3OD) δ 7.42-7.32 (m, 4H), 4.09 (s, 2H), 3.69 (s, 2H), 3.67 (s, 3H); MS 180 (M+1). mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]([F:45])([F:44])[F:43])=[CH:32][C:31]=2[C:46](=O)/[CH:47]=[CH:48]/N(C)C)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.[NH:53]([CH:55]1[CH2:58][N:57]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:56]1)[NH2:54].C(=O)([O-])O.[Na+]>C(O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:9])=[O:10])[C:5]([F:28])=[CH:4][C:3]=1[O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]([F:43])([F:44])[F:45])=[CH:32][C:31]=1[C:46]1[N:53]([CH:55]2[CH2:56][N:57]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:58]2)[N:54]=[CH:48][CH:47]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccccc4C(F)(F)F)cc3C(=O)/C=C/N(C)C)cc2F)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CC(NN)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccccc4C(F)(F)F)cc3-c3ccnn3C3CN(C(=O)OC(C)(C)C)C3)cc2F)c(OC)c1
Temperature: 70 °C
Yield: 266.6 %

Procedure:
(5-Chloro-N-(2,4-dimethoxybenzyl)-4-({3-[(2E)-3-(dimethylamino)prop-2-enoyl]-2′-(trifluoromethyl)biphenyl-4-yl}oxy)-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 44, 563 mg, 0.724 mmol) in ethanol (10 mL) was slowly added a solution of tert-butyl 3-hydrazinoazetidine-1-carboxylate (Preparation 36, 603 mg, 3.22 mmol) in ethanol (10 mL) and acetic acid (0.25 mL) at 0° C. under nitrogen. The reaction was heated to 70° C. for 3 hours and then cooled to room temperature. The reaction mixture was neutralised to pH7 with saturated aqueous sodium hydrogen carbonate solution (2.0 mL) and concentrated in vacuo to afford a yellow oil. The oil was partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous layer was then extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×100 mL) dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil (1.74 g). The oil was partially purified by silica gel column chromatography (0%-10% methanol in dichloromethane gradient elution) to afford the title compound as a solid (228 mg) of 52% purity via LCMS. The compound was used without further purification in the next step.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([S:12](Cl)(=[O:14])=[O:13])=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[NH2:22]>N1C=CC=CC=1>[F:17][C:18]([F:30])([F:31])[C:19]1[CH:20]=[C:21]([NH:22][S:12]([C:8]2[C:9]([CH3:11])=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=2[CH3:16])(=[O:14])=[O:13])[CH:23]=[C:24]([C:26]([F:27])([F:29])[F:28])[CH:25]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cc(C(C)(C)C)cc(C)c1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1cc(C(C)(C)C)cc(C)c1S(=O)(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 23 %

Procedure:
4-Tert-butyl-2,6-dimethyl-benzenesulfonyl chloride (0.100 g, 0.383 mmol) was added to a solution of 3,5-bis(trifluoromethyl)aniline (0.089 g, 0.387 mmol) in dry pyridine (1 mL). The reaction was capped and stirred at room temperature for 1 day then stirred at 30° C. for 1 day. The reaction was then concentrated under vacuum. To this was added diethyl ether (60 mL) and the mixture was washed with 0.1 N HCl (3×20 mL) followed by 0.1 N NaOH (2×20 mL) then saturated NaCl (2×20 mL). After drying the organic layer over MgSO4, the solution was filtered and concentrated under vacuum. The crude compound was triturated with hexanes (2×10 mL) to afford the title compound (0.040 g, 23% yield). LCMS (M+Na) 476.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]=[CH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1)(=[O:7])=[O:6].[Cl:18][C:19]1[CH:28]=[CH:27][C:22]([CH:23]=[CH:24][CH:25]=O)=[CH:21][CH:20]=1.[Na].C(OCC)(=O)C>CO>[Cl:18][C:19]1[CH:28]=[CH:27][C:22]([CH:23]=[CH:24][CH2:25][NH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]2[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:14]=3[CH:15]=[CH:16][CH:17]=2)(=[O:7])=[O:6])=[CH:21][CH:20]=1
Reactant: O=CC=Cc1ccc(Cl)cc1
Reactant: NCCNS(=O)(=O)c1cccc2cnccc12
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=S(=O)(NCCNCC=Cc1ccc(Cl)cc1)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
2.01 g of N-(2-aminoethyl]-5-isoquinolinesulfonamide was dissolved in 30 ml of methanol, to the solution was added 1.60 g of p-chlorocinnamaldehyde, and the mixture was stirred for one hour at a room temperature. After an addition of 350 mg of sodium tetrahydrideborate in portions with ice cooling, the mixture was stirred for 30 minutes. After an addition of ethyl acetate, the reaction mixture was sequentially washed three times with water, and then twice with a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. The mixture was filtered and evaporated to remove the solvent under a reduced pressure. A residue was purified using a silica gel column (silica gel 80 g, eluant: 5% methanol in chloroform), and resulting crystals were washed with benzene/hexane (1:1), to obtain 2.30 g of the title compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12](O)=[O:13])[CH:8]=[C:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.C([O-])=O.[NH4+].F[P-](F)(F)(F)(F)F.[N:33]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([NH2:33])=[O:13])[CH:8]=[C:7]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)c2cccc(F)c2n1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2cccc(F)c2n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 9 %

Procedure:
8-Fluoro-4-(4-fluorophenyl)quinoline-2-carboxylic acid (7-4, 100.0 mg, 0.351 mmol), ammonium formate (88.0 mg, 1.40 mmol), BOP (202.0 mg, 0.456 mmol), and triethylamine (0.147 ml, 1.052 mmol) were dissolved into DMF (1.0 mL), and the resulting mixture was stirred at 60° C. for 5 hours. The mixture was cooled and diluted with Methylene Chloride, washed with water, brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier) to afford 8-Fluoro-4-(4-fluorophenyl)quinoline-2-carboxamide (7-5, 9.00 mg, 9.0%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 8.209 (s, 1H); 8.138 (br s, 1H); 8.658 (d, J=8.62 Hz, 1H); 7.379-7.493 (m, 4H); 7.145-7.214 (m, 2H); 6.004 (br s, 1H). LRMS m/z (M+H) 285.1 found, 285.1 required.
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.[C:18](=[O:21])([O-])[O-].[Na+].[Na+].[CH3:24][N:25]([CH3:28])[CH:26]=[O:27]>>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:4][CH2:5][C:6]4[C:26](=[O:27])[N:25]5[CH2:28][CH2:16][CH2:17][CH:3]([O:21][CH3:18])[C:24]5=[N:8][C:7]=4[CH3:10])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Product: COC1CCCn2c1nc(C)c(CCN1CCC(c3noc4cc(F)ccc34)CC1)c2=O
Reaction time: 6 h
Yield: 36 %

Procedure:
A mixture of intermediate (13) (0.012 mol), 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole monohydrochloride (0.010 mol) and sodium carbonate (0.025 mol) in N,N-dimethylformamide (50 ml) was stirred for 6 hours at 80°-90° C. The reaction mixture was filtered and the filtrate was evaporated. Water was added to the residue and this mixture was extracted with dichloromethane. The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from acetonitrile/2,2'-oxybispropane. The crystals were filtered off and dried, yielding 1.6 g (36%) of (±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-methoxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 130.8° C. (comp. 7).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH:12]1(O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: OC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(Cc1ccc(O)cc1)OC1CCCCC1

Procedure:
A mixture of 4-hydroxyphenylacetic acid (7.6 g, 0.05 mol), cyclohexyl alcohol (6 g, 0.06 mol), p-toluenesulfonic acid (1 g, 0.006 mol) and benzene (300 mL) was refluxed with continuous water separation for 8 hours. The mixture was cooled and washed, first with aqueous 5% Na2CO3 solution, then twice with water, then was dried over anhydrous MgSO4. Evaporation of the solvent in vacuo gave cyclohexyl 4-hydroxyphenylacetate.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.Cl[C:14]1[C:19]([CH2:20][C:21]([OH:23])=O)=[CH:18][CH:17]=[CH:16][N:15]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.[Cl:31]CCl>C1COCC1>[Cl:31][C:16]1[N:15]=[CH:14][C:19]([CH2:20][C:21]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[O:23])=[CH:18][CH:17]=1
Reactant: Nc1ccccn1
Reactant: O=C(O)Cc1cccnc1Cl
Reactant: ClCCl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)nc1)Nc1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Under an inert atmosphere, 6.23 g (38.5 mmol) of N,N-carbonyldiimidazole are added to a suspension of 6 g (35 mmol) of 2-chloropyridylacetic acid in anhydrous THF (90 ml) at room temperature. The reaction mixture is stirred at this temperature for 2 hours, 5.43 g (57.7 mmol) of 2-aminopyridine are then added and the mixture is refluxed for 2 hours. 200 ml of dichloromethane are added to the reaction mixture, cooled to room temperature, and the organic phase thus obtained is washed with saturated ammonium chloride solution and then with aqueous sodium hydroxide solution (1N), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/ethyl acetate, from 0% to 70% ethyl acetate). 5.6 g of compound are obtained in the form of a white powder. Yield 65%. Melting point: 130° C. MH+: 248.1 (tr: 5.45 min., condition 1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[C:15]([O:21][C@H:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](Cl)=[O:24])(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].CN(C)C1C=CC=CC=1.Cl>ClCCl>[C:15]([O:21][C@H:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:14])[C:10]([F:13])([F:11])[F:12])=[O:24])(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Reactant: CC(C)(C)C(=O)O[C@@H](C(=O)Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: CC(C)(C)C(=O)O[C@@H](C(=O)Nc1ccc(Cl)cc1C(=O)C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (2, 5.0 g, 22.4 mmol) was dissolved in dichloromethane (50 mL) and (R)-2-chloro-2-oxo-1-phenylethyl pivalate (8.54 g, 33.5 mmol) was added. To this mixture N,N-dimethylaniline (2.8 mL, 22.4 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with dichloromethane (50 mL), treated with 1N HCl, washed with brine and the organic layer was separated and evaporated to give (R)-2-(4-chloro-2-(2,2,2-trifluoroacetyl)-phenylamino)-2-oxo-1-phenylethyl pivalate (12) as an brown oil.