Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[CH2:28]([O:35][C:36]1[N:41]=[CH:40][C:39](Br)=[CH:38][N:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O>[CH2:28]([O:35][C:36]1[N:41]=[CH:40][C:39]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[CH:38][N:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C1COCCN1
Reactant: Brc1cnc(OCc2ccccc2)nc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(COc2ncc(N3CCOCC3)cn2)cc1
Temperature: 50 °C

Procedure:
Tris(dibenzylideneacetone)dipalladium (1.78 g), 2-(di-tert-butylphosphino)-biphenyl (2.32 g) and sodium tert-butoxide (4.49 g) were added to a solution of 2-benzyloxy-5-bromo-pyrimidine (10.3 g) and morpholine (4.1 ml) in toluene (180 ml) and the mixture was stirred under nitrogen atmosphere at 50° C. for an hour. The reaction mixture was cooled to room temperature. Water and ethyl acetate were added and the organic layer was separated, washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate and hexane to give the titled compound (9.12 g). MS (m/z): 272 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=[O:6].[Cl:15][C:16]([Cl:21])([Cl:20])C([O-])=O.[Na+].O>CN(C)C=O>[OH:6][CH:5]([C:4]1[CH:7]=[C:8]([O:13][CH3:14])[C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1])[C:16]([Cl:21])([Cl:20])[Cl:15]
Reactant: O=C([O-])C(Cl)(Cl)Cl
Reactant: COc1cc(OC)c(OC)cc1C=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c(C(O)C(Cl)(Cl)Cl)cc1OC
Temperature: 25 °C
Reaction time: 9 h
Yield: 86.3 %

Procedure:
In 1.2 l of dimethylformamide, 196 g of 2,4,5-trimethoxybenzaldehyde were dissolved, followed by the addition of 241 g of sodium trichloroacetate salt under ice cooling. The resulting mixture was stirred at room temperature for 9 hours. After the reaction, 2 l of water were added to the reaction mixture under ice cooling. The solid so precipitated was collected by filtration, followed by washing with water and diethyl ether, whereby 272 g of 1-(1-hydroxy-2,2,2-trichloroethyl)-2,4,5-trimethoxybenzene were obtained (yield: 86%).
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[H-].[Na+].CS(C)=O.C[O:13][C:14](=O)[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24](=[O:26])[CH3:25])=[C:17]([O:27][CH3:28])[CH:16]=1>O>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([C:14](=[O:13])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])[CH:16]=[C:17]([O:27][CH3:28])[C:18]=1[NH:23][C:24](=[O:26])[CH3:25]
Reactant: CS(C)(=O)=O
Reactant: COC(=O)c1cc(OC)c(NC(C)=O)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(C(=O)CS(C)(=O)=O)cc(OC)c1NC(C)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A suspension of 30.1 g. of dimethylsulfone and 11.5 g. of sodium hydride (50% dispersion in oil) in 80 ml. of dimethylsulfoxide was stirred at 50° C. for 3 hours with the exclusion of moisture. Then, 20.3 g. of 4-acetamido-3,5-dimethoxy-benzoic acid methyl ester were added and the mixture was stirred at room temperature for an additional 20 hours. Thereafter, the solution was diluted with 1 liter of water and extracted with three 1 liter portions of ethyl acetate. The ethyl acetate extracts were washed with two 300 ml. portions of water, combined, dried over magnesium sulfate and evaporated to dryness under vacuum. Recrystallization of the residue from ethyl acetate gave 2',6'-dimethoxy-4'-[(methylsulfonyl-acetyl)]-acetanilide having a melting point of 206°-207° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:32])([C:28]([CH3:31])([CH3:30])[CH3:29])[O:3][CH2:4][C@@H:5]1[C@@H:14]2[C@@H:8]([O:9][CH2:10][C:11]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH2:13]2)[CH2:7][C@H:6]1[O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1.C(=O)([O-])[O-].[K+].[K+].[CH:39](I)([CH3:41])[CH3:40].CC(OC)(C)C>CN(C=O)C.O>[CH3:32][Si:2]([CH3:1])([C:28]([CH3:29])([CH3:31])[CH3:30])[O:3][CH2:4][C@@H:5]1[C@@H:14]2[C@@H:8]([O:9][CH2:10][C:11]([CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:39]([CH3:41])[CH3:40])=[O:19])=[CH:12][CH2:13]2)[CH2:7][C@H:6]1[O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1
Reactant: CC(C)I
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]2CC=C(CCCC(=O)O)CO[C@H]2C[C@H]1OC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)OC(=O)CCCC1=CC[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC3CCCCO3)C[C@@H]2OC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
Under the argon atmosphere, the compound (15.4 mmol) produced in Example 7 was dissolved in DMF; potassium carbonate (5.31 g, 38.5 mmol) and isopropyl iodide (2.31 mL, 23.1 mmol) were added, followed by stirring at 60° C. for 3 hours. After cooling, MTBE and water were added, and extraction; washing with a saturated saline; drying with anhydrous sodium sulfate; and concentration were carried out. Purification by silica gel column chromatography (hexane:ethyl acetate=90:10→50:50) was carried out to obtain a titled compound (7.25 g) having the following physical property values.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([S:25](Cl)(=[O:27])=[O:26])=[C:20]([CH3:29])[CH:19]=1.Cl>ClCCl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH3:29])[C:21]([S:25]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:7][OH:8])(=[O:26])=[O:27])=[C:22]([CH3:24])[CH:23]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: OC[C@@H]1CCCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2CO)c(C)c1
Reaction time: 1.5 h
Yield: 20 %

Procedure:
(S)-Piperidin-2-ylmethanol (1.1 eq.) was dissolved in dichloromethane (4 ml/mmol) and cooled, and triethylamine (2.5 eq.) was added. A solution of 4-methoxy-2,6-dimethylbenzenesulfonyl chloride (1 eq.) in dichloromethane (2 ml/mmol) was added dropwise at 0° C., and then stirring was carried out for 90 min at room temperature. Hydrogen chloride solution (eq., 0.5 mol/l, 2 ml/mmol) was added, stirring was carried out for 15 min, and the phases were separated. The organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo. The crude product was used in the next stage without being purified further. Yield: 20%
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:23][C:24]=3[CH3:25])=[CH:14][CH:13]=2)=[CH:6][C:5]=1[CH2:32][C:33]([O:35]C)=[O:34])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:23][C:24]=3[CH3:25])=[CH:16][CH:17]=2)=[CH:6][C:5]=1[CH2:32][C:33]([OH:35])=[O:34])[CH3:2]
Reactant: CCOc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CC(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a mixture of methyl 2-[2-ethoxy-5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (0.56 g), tetrahydrofuran (2 mL) and methanol (2 mL) was added 1N aqueous sodium hydroxide solution (2.2 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals (0.45 g, 87%) of 2-[2-ethoxy-5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 122-123° C.
Reaction SMILES: [Br:1][C:2]1[O:3][C:4](C=O)=[CH:5][CH:6]=1.C1COCC1.Cl.[NH2:15][N:16]1[CH2:20][CH2:19][NH:18][C:17]1=[O:21].[OH-].[Na+]>O>[Br:1][C:2]1[O:3][C:4](=[N:15][N:16]2[CH2:20][CH2:19][NH:18][C:17]2=[O:21])[CH2:5][CH:6]=1
Reactant: O=Cc1ccc(Br)o1
Reactant: NN1CCNC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1NCCN1N=C1CC=C(Br)O1
Reaction time: 8 h

Procedure:
33.5 pts. by wt. of 2-bromofuran-5-aldehyde, dissolved in 100 pts. by vol. of THF, are added to a solution of 1-amino-2-oxo-imidazolidine hydrochloride in 350 pts. by vol. of water, which has been adjusted to pH 5 with sodium hydroxide solution, and the mixture is stirred overnight. The precipitate is filtered off, washed with water and recrystallised from methanol. 30.0 pts. by wt. of 1-(5-bromofurylideneamino)-2-oxo-imidazolidine of dec. pt. 153°-158° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([CH2:20][CH2:21][OH:22])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:13]([CH3:15])[CH3:14])[C:8](=[O:12])[N:9]([CH3:11])[N:10]=1.CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:19]=[C:18]([CH2:20][C:21]([OH:26])=[O:22])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:13]([CH3:15])[CH3:14])[C:8](=[O:12])[N:9]([CH3:11])[N:10]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(CCO)cc2Cl)nn(C)c1=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC(C)c1cc(Oc2c(Cl)cc(CC(=O)O)cc2Cl)nn(C)c1=O
Temperature: 11 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
A solution of 6-[2,6-dichloro-4-(2-hydroxy-ethyl)-phenoxy]-4-isopropyl-2-methyl-pyridazin-3-one (36) (330 mg, 0.92 mmol) in acetone (5 mL) was treated with Jones Reagent (0.51 mL of a 2.7M solution) slowly dropwise at 10° C. The resulting red reaction mixture was stirred at 11° C. for 30 min. The reaction mixture was then concentrated under vacuum. The resulting residue was diluted with ethyl acetate (25 mL) and water (20 mL) and was treated with sodium bisulfite (100 mg). The resulting mixture was shaken and turned from red to green. The aqueous layer was separated and was re-extracted with ethyl acetate (25 mL). The organic layers were combined and washed with a saturated aqueous sodium chloride solution. The organic layer was separated, dried with sodium sulfate, filtered, and concentrated under vacuum. The resulting solid was recrystallized from ethyl acetate and dried under vacuum overnight to afford [3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-acetic acid (37) (70 mg, 19%) as a white solid; EI(+)-HRMS) m/z calcd for C16H16Cl2N2O4 (M+H)+ 371.0560, found 371.0561. Molecular Weight=371.2229; Exact Mass=370.0487
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]([CH3:65])([CH2:63][CH3:64])[CH2:9][C:10]1[N:11]=[C:12]([CH2:34][CH:35]([N:49]([CH3:62])S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)=[CH:38][CH:37]=2)[N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1.C1(S)C=CC=CC=1>CN(C)C=O>[CH3:7][C:8]([CH3:65])([CH2:63][CH3:64])[CH2:9][C:10]1[N:11]=[C:12]([CH2:34][CH:35]([C:36]2[CH:37]=[CH:38][C:39]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)=[CH:40][CH:41]=2)[NH:49][CH3:62])[N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:14]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(c2ccc(-c3ccc(F)cn3)cc2)N(C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)n1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(NC)c2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (1.1 g, 7.7 mmol) was added to an ambient temperature solution of N-{2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}-N-methyl-4-nitrobenzenesulfonamide (2.5 g, 3.1 mmol) and benzenethiol (0.64 mL, 6.2 mmol) in N,N-dimethylformamide (20 mL). After stirring at 50° C. for 3 h, then at 70° C. for a further 3 h, the reaction mixture was cooled and partitioned between diethyl ether and saturated aqueous sodium bicarbonate. The organic phase was dried (magnesium sulfate) and concentrated. Chromatography over silica eluting with 0-100% ethyl acetate (containing 5% 2 M ammonia in methanol)/hexane afforded 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]-N-methylethanamine.
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CN(C=O)C>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:3]2[CH2:2][CH2:1][C@@H:10]3[C@H:5]([CH2:6][CH2:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=43)[CH2:4]2)=[CH:24][CH:23]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: c1ccc2c(c1)CC[C@@H]1CNCC[C@@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(CN2CC[C@H]3c4ccccc4CC[C@@H]3C2)cc1
Yield: 32.7 %

Procedure:
Following the procedure of Example 3, step 4, 0.202 g (1.08 mmol) of crude trans-1,2,3,4,4a,5,6,10b-octahydro benz[f]isoquinoline in 10 ml of anhydrous DMF was reacted with 0.164 g (1.19 mmol) of anhydrous potassium carbonate and 0.183 g (1.14 mmol) of 4-chlorobenzyl chloride. Chromatography on flash silica, eluting with 30% ethyl acetate/petroleum ether, gave 0.110 g (33%) of the title product as a white solid. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent the title product hydrochloride was obtained as a white solid, m.p. 257°-259° C. NMR δ(D2O/CD3CN) 1.51 (1H, m), 1.65 (1H, m), 1.78-1.82 (2H, m), 2.59-2.67 (2H, m), 2.80-2.89 (3H, m), 3.13 (1H, t of d), 3.41 (1H, m), 3.60 (1H, m), 4.29 (2H, d, J=3.7 Hz), 7.14-7.20 (3H, m), 7.25-7.28 (1H, m), 7.52 (4H, m). m/z (CI+, NH3) 312 (M+H)+, 186 (M-CH2C6H4Cl) +, 125. Analysis calcd. for C20H23Cl2N: C, 68.97; H, 6.66; N, 4.02%. Found: C, 68.59; H, 6.63; N, 3.98%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[C:25](=O)[CH:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=2)[CH2:23][CH2:22][CH2:21]1>C(O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH:24]2[C:23]3[N:18]=[C:16]([NH:15][C:5]4[CH:6]=[CH:7][C:8]([N:9]5[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[S:17][C:22]=3[CH2:21][CH2:20][CH2:25]2)=[CH:28][C:29]=1[C:34]([F:35])([F:36])[F:37]
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: O=C1C(Br)CCCC1c1ccc(Cl)c(C(F)(F)F)c1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccc(Cl)c(C(F)(F)F)c2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 28.3 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (39 mg, 0.15 mmol) and of crude 6-bromo-2-(4-chloro-3-trifluoromethyl-phenyl)-cyclohexanone (53 mg, 0.16 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound (22 mg, 29%) as a yellow gum. MS ISP (m/e): 518.8/520.9 (100/36) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.62 (s, 1H), 7.56 (s, 1H), 7.41 (d, 2H), 7.30 (s, 1H), 7.10 (d, 1H), 6.83-6.89 (m, 2H), 6.67 (d, 1H), 4.05 (m, 1H), 3.55 (s, 3H), 2.75 (m, 2H), 2.29 (s, 3H), 2.22 (m, 1H), 1.78-2.05 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][CH2:13][C:14]1[NH:15][CH2:16][CH2:17][N:18]=1.[Mn]([O-])(=O)(=O)=O.[K+].CO>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][CH2:13][C:14]1[NH:18][CH:17]=[CH:16][N:15]=1
Reactant: O=[N+]([O-])c1ccc(CCCC2=NCCN2)c(F)c1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CCCc2ncc[nH]2)c(F)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68.2 %

Procedure:
Compound 121 (888 mg, 3.53 mmol) was first dissolved in acetonitrile (100 mL), with potassium permanganate (1.12 g, 7.07 mmol) and alumina (4.9 g) added into the solution in batch. After stirring the resulting mixture at room temperature for 40 min, CH3OH (1 mL) was added to reduce excess oxidant. The mixture was then filtered and the solid material was washed with DCM:CH3OH=10:1. The filtrate was evaporated to dryness to give the compound 122 (600 mg, 68%) as a light yellow oil. The crude product was used directly for the next step without purification. 1H NMR (400 MHz, CDCl3) δ7.94-7.99 (m, 1H), 7.85-7.91 (m, 1H), 7.35-7.41 (m, 1H), 6.96 (br s, 2H), 2.75-2.85 (m, 4H), 2.06-2.19 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([CH:24]=1)[C:7]([NH:9][CH2:10][CH:11]([OH:23])[CH2:12][N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)=[O:8].[O:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH2:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:21][CH2:22][N:13]1[CH2:12][CH:11]([OH:23])[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:24]=[C:2]([NH:1][CH:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)[CH:3]=[CH:4][C:5]=1[F:25]
Reactant: Nc1ccc(F)c(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cc(NC2CCOCC2)ccc1F
Temperature: 17 °C
Reaction time: 4 h
Yield: 26.3 %

Procedure:
A solution of 5-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-fluorobenzamide (372 mg, 1.08 mmol), dihydro-2H-pyran-4(3H)-one (108 mg, 1.08 mmol) and AcOH (0.05 mL) in MeOH (20 mL) was stirred at 17° C. for 2 h. Then NaBH3CN (109 mg, 1.63 mmol) was added and the resulting solution was stirred at 17° C. for 4 h. The solution was concentrated and the residue was purified by column chromatography to afford the title product (121.5 mg, Yield 17.5%). 1H NMR (CD3OD, 400 MHz): δ 7.16-7.07 (m, 3H), 7.03 (dd, J=2.9, 5.9 Hz, 2H), 6.95 (dd, J=8.9, 10.7 Hz, 1H), 6.79 (td, J=3.6, 8.8 Hz, 1H), 4.11 (quin, J=6.0 Hz, 1H), 3.98 (d, J=11.5 Hz, 2H), 3.80-3.69 (m, 2H), 3.64-3.40 (m, 5H), 2.98-2.81 (m, 4H), 2.72-2.60 (m, 2H), 1.99 (d, J=12.8 Hz, 2H), 1.56-1.39 (m, 2H). LCMS (m/z): 428.2 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].[H-].[Na+].Cl[CH2:13][CH2:14][N:15]([CH2:17][CH2:18]Cl)[CH3:16]>CS(C)=O.Cl>[CH3:16][N:15]1[CH2:17][CH2:18][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)([C:8]#[N:9])[CH2:13][CH2:14]1
Reactant: N#CCc1ccccn1
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1CCC(C#N)(c2ccccn2)CC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
A solution of 2-pyridyl acetonitrile (1.0 g, 8.54 mmol) in DMSO (8 mL) was treated with sodium hydride (1.195 g, 29.88 mmol) portionwise. The resulting brown suspension was stirred at 23° C. for 30 minutes. 2-Chloro-N-(2-chloroethyl)-N-methylethanamine (1.81 g, 9.39 mmol) was then slowly added over 5 minutes, then the suspension was heated at 65° C. overnight. The reaction was then diluted with 1N hydrochloric acid and washed with ethyl acetate (2×). The aqueous phase was basified with 1N sodium hydroxide and extracted with ethyl acetate (3×). The combined extracts were washed with water (5×) and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. This was purified on Biotage silica gel column (1% to 10% (methanol+1% ammonia) in dichloromethane) to give the desired product as an oil (0.583 g, 34%). 1H NMR (400 MHz, CDCl3) δ ppm: 2.14-2.25 (2H, m), 2.30-2.38 (2H, m), 2.40 (3H, s), 2.51 (td, J=12.25 and 2.27 Hz), 2.99 (2H, d, J=12.13 Hz), 7.25-7.36 (1H, m), 7.56 (1H, d, J=8.08 Hz), 7.75 (1H, td, J=7.71 and 1.77 Hz), 8.64 (1H, d, J=4.80 Hz). LC/MS (M+H)+: 202. HPLC ret. time (Condition E): 1.025 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH:13]([OH:15])[CH:12]([N:16]3[CH2:21][CH2:20][CH:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[CH2:18][CH2:17]3)[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:30][C:31](OC(C)=O)=[O:32]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:14][CH:13]([OH:15])[CH:12]([N:16]3[CH2:17][CH2:18][CH:19]([N:22]([C:23]4[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=4)[C:31](=[O:32])[CH3:30])[CH2:20][CH2:21]3)[CH2:11]2)=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(Cl)cc1)N1CC(O)C(N2CCC(Nc3ccc(Cl)cc3)CC2)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N(c1ccc(Cl)cc1)C1CCN(C2CN(C(=O)c3ccc(Cl)cc3)CC2O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting materials (4-Chloro-phenyl)-{3-[4-(4-chloro-phenylamino)-piperidin-1-yl]-4-hydroxy-pyrrolidin-1-yl}-methanone (48 mg, 0.11 mmol) and Ac2O (16 uL, 0.17 mmol) were added in pyridine (0.5 mL) and stirred at room temperature overnight. The reaction mixture was concentrated down to dryness. The resulting crude residue was purified by column chromatography on silica (Methanol\CH2Cl2: 0%-6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:10])=[C:6](N)[C:7]=1[Cl:8].C(N=C=S)(C)C.[CH:17]1([N:23]=[C:24]=[N:25]C2CCCCC2)[CH2:22]CCC[CH2:18]1>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:10][C:24]([NH:23][CH:17]([CH3:22])[CH3:18])=[N:25][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Cl)c(Cl)c1N
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)N=C=S
Solvent: c1ccncc1
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Yield: 55.4 %

Procedure:
5,6-Dichloro-1,2-phenylenediamine (0.61 g, 3.4 mmol), isopropyl isothiocyanate (0.39 g, 3.8 mmol), dicyclohexyl carbodiimide (1.06 g, 5.14 mmol) and pyridine (10 L) were used according to general procedure I. The product was recrystallized from acetonitrile to afford a tan solid (0.46 g, 60%); m.p. 218-220° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:20](=[O:23])[CH2:21][Cl:22])=[C:13]3[C:18]=2[NH:17][C:16](=[O:19])[CH:15]=[CH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1.C1COCC1>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C@@H:20]([OH:23])[CH2:21][Cl:22])=[C:13]3[C:18]=2[NH:17][C:16](=[O:19])[CH:15]=[CH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCl)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=c1ccc2c([C@@H](O)CCl)ccc(OCc3ccccc3)c2[nH]1
Temperature: 1 °C

Procedure:
A dry 3 L, 4-necked flask equipped with a mechanical stirrer, thermometer, addition funnel and refluxing condenser is charged with 50 g 8-(phenylmethoxy)-5-(α-chloroacetyl)-(1H)-quinolin-2-one and 600 mL dry THF under N2. Then 15 mL of a 1 molar solution of (R)-tetrahydro-1-methyl-3,3-diphenyl-(1H,3H)-pyrrolo[1,2-c][1,3,2]-oxazaborole in toluene is added. The mixture is cooled to an internal temperature of 0-2° C. and while maintaining an internal temperature of 0-2° C., 153 mL of a 1 molar solution of BH3 in THF is added over 1-2 hours. The reaction is stirred for another hour at an internal temperature of 0-2° C. and then quenched by addition of 65 mL methanol. The resulting solution is warmed to 25° C. and concentrated to a volume of 250 mL (50° C./200 mbar). To this concentrate is added a mixture of 713 mL water and 37 g HCl 37%. During the addition 8-(phenylmethoxy)-5-((R)-2-chloro-1-hydroxy-ethyl)-(1-H)-quinolin-2-one precipitates as a nearly colourless precipitation. The resulting suspension is stirred for 30 minutes at 25° C., filtrated and washed with 220 mL water in several portions. Drying in a vacuum drier at 50° C. for 12 hours results in 47.41 g of 8-(phenylmethoxy)-5-((R)-2-chloro-1-hydroxy-ethyl)-(1H)-quinolin-2-one as a slightly yellowish powder.