Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:36])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([C:24]([NH:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)=[O:36])=[O:35])=[CH:26][CH:27]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: [H][H]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2cccc(OCc3ccccc3)c2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2cccc(O)c2)cc1
Reaction time: 12 h
Yield: 88 %

Procedure:
To a stirred solution of N-(3-benzyloxyphenyl)-2-[(4-tert-butylbenzoyl)amino]benzamide (0.58 g, 1.2 mmol) in tetrahydrofuran (50 mL) was added 10% palladium-on-carbon (0.29 g). The vessel was placed under vacuum and the atmosphere was replaced with hydrogen (1 atm). After 12 h, the balloon was removed and the mixture was filtered through diatomaceous earth and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium chloride solution, dried (magnesium sulfate), filtered, and concentrated In vacuo to give 0.41 g (88%) of the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH:14]([CH3:16])[CH3:15])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[CH2:21]([NH:23][CH2:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:22].N12CCCN=C1CCCCC2>C(#N)C>[CH2:21]([NH:23][CH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:20])[C:6]([C:17]([OH:19])=[O:18])=[CH:7][N:8]3[CH:14]([CH3:16])[CH3:15])=[CH:3][C:2]=2[F:1])[CH2:26]1)[CH3:22]
Reactant: CC(C)n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: CCNCC1CCNC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C(C)C)c3c2F)C1
Temperature: 25 °C
Yield: 73.7 %

Procedure:
A solution of 0.57 g (2.0 mmol) of 6,7,8-trifluoro-1,4-dihydro-1-(1-methylethyl)-4-oxo-3-quinolinecarboxylic acid, 0.32 ml (2.2 mmol) of 3-[(ethylamino)methyl]pyrrolidine, 0.30 ml (2.0 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 15 ml of acetonitrile was heated under reflux for one hour. After cooling to room temperature the mixture was filtered and the solid washed with acetonitrile and methanol to give 0.58 g of the title compound, mp 230°-231° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=[C:13]2[C:9]=1[C:10](=[O:25])[N:11]([CH3:24])[CH2:12]2)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)=[O:18])=[C:13]2[C:9]=1[C:10](=[O:25])[N:11]([CH3:24])[CH2:12]2
Reactant: CN1Cc2c(C(=O)N3CCCC3)ccc(NC(=O)OC(C)(C)C)c2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1Cc2c(C(=O)N3CCCC3)ccc(N)c2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl[2-methyl-3-oxo-7-(pyrrolidin-1-ylcarbonyl)-2,3-dihydro-1H-isoindol-4-yl]carbamate (Compound 116B) was added DCM (0.5 mL) and TFA (0.5 mL). The reaction mixture was stirred at room temperature for 30 minutes, after which it was concentrated to dryness an used without further purification. MS (ES+): m/z 260.30 (100) [MH+]; HPLC: tR=0.69 min (UPLC, Analytical).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:17][CH:16]([CH3:18])[NH:15][CH2:14][CH:13]2[CH3:19])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=1.C(N(C(C)C)CC)(C)C.CN(C=O)C>C(OCC)(=O)C>[Cl:27][C:26]1[C:21]([N:15]2[CH2:14][CH:13]([CH3:19])[N:12]([S:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])[CH2:17][CH:16]2[CH3:18])=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1CN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)C(C)CN1
Reactant: Clc1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1CN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)C(C)CN1c1ncccc1Cl
Yield: 2 %

Procedure:
1-(3,4-dichlorophenylsulfonyl)-2,5-dimethylpiperazine (1.04 g, 3.22 mmol), 2,3-dichloropyridine (476.5 mg. 3.22 mmol), diisopropylethylamine (1.4 mL, 8.05 mmol) and DMF (1.2 mL) were charged to a microwave vial and the mixture was irradiated at 200° C. for 1 hour. Reaction was complete as determined by TLC. The reaction mixture was diluted with ethyl acetate and washed with water. After solvent evaporation crude product was purified with flash column chromatography to yield 1-(3-chloropyridin-2-yl)-4-[(3,4-dichlorophenyl)sulfonyl]-2,5-dimethylpiperazine in 2% yield (27.1 mg) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:26][O:27][C:28](=[O:40])[C:29]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][C:32](Cl)=[N:31][CH:30]=1.N12CCN(CC1)CC2>C(N(CC)CC)C>[CH3:26][O:27][C:28](=[O:40])[C:29]1[C:34]([C:35]([F:36])([F:37])[F:38])=[CH:33][C:32]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:25])[C:10]([C:16]3[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)([OH:15])[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=2)=[N:31][CH:30]=1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Agent: C1CN2CCN1CC2
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3cc(C)c(=O)n(C)c3)C(F)(F)F)c(Cl)c2)cc1C(F)(F)F

Procedure:
In analogy to Example 163, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with methyl-6-chloro-4-(trifluoromethyl)-nicotinate in the presence of triethylamine and 1,4-diazabicyclo[2.2.2]octane to give the title compound as an off-white solid. MS (m/e)=579.3 [M+H+].
Reaction SMILES: C1C=CC=CC=1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:17])([CH3:16])[C:13]([O-])=[O:14].CC(C[AlH]CC(C)C)C.O>CCCCCC.C(OCC)C>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][OH:14]
Reactant: CC(C)(CCCCBr)C(=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: CC(C)(CO)CCCCBr
Reaction time: 8 h
Yield: 82.1 %

Procedure:
In a 1-L 3-neck round-bottomed flask fitted with condenser, dropping funnel pressure equalizer and magnetic stirrer were placed dry benzene (300 ml) and 6-bromo-2,2-dimethylhexanoate (40 g, 0.159 mol) under argon. To this solution, DIBAL (400 ml as a 1M solution in hexane) was added over 45 min at room temperature, via a syringe. During the addition, the temperature rose to ca. 50° C., and when the exothermic reaction ceased, the mixture was heated to 50˜60° C. for an additional 4 hrs. The reaction mixture was allowed to reach room temperature and stir overnight. The resulting mixture was treated with water (ca. 50 ml) under vigorous stirring, while cooling in an ice-bath. Diethyl ether (200 ml) was added to facilitate the stirring. The ice bath was removed when no more evolution of gas occurred. The reaction product, as a white sludge, was filtered through a fritted glass funnel and the filtrate was evaporated under vacuum. CHCl3 (ca. 300 ml) was added to the resulting residue and the resulting solution was washed with saturated aqueous NHCl4 (200 ml) and brine (200 ml), then dried (MgSO4). The solvent was evaporated under vacuum, to provide 27.30 g (82.2% yield) of the above-titled compound: 1H NMR CDCl3, δ (ppm): 3.38 (t, J=7.4 Hz, 2H), 3.50-3.40 (brs, 1H, OH), 3.22 (d, J=5.6 Hz, 2H), 1.85 (qv, J=7.4 Hz, 2H), 1.50-1.35 (m, 2H), 1.30-1.20 (m, 2H), 0.85 (s, 6H). 13C NMR CDCl3, δ (ppm): 71.4, 37.5, 34.9; 33.9, 33.4, 23.7, 22.4.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:16][CH2:17][C@@H:18]1[O:22][C@H:21]([N:23]2[CH:30]=[C:29]([F:31])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[C@H:20]([OH:32])[CH2:19]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)C>N1C=CC=CC=1>[C:1]([O:32][C@@H:20]1[CH2:19][C@H:18]([CH2:17][O:16][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:22][C@@H:21]1[N:23]1[CH:30]=[C:29]([F:31])[C:27](=[O:28])[NH:26][C:24]1=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(OC[C@H]1C[C@@H](O)[C@@H](n2cc(F)c(=O)[nH]c2=O)O1)c1ccccc1
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1C[C@H](COC(=O)c2ccccc2)O[C@@H]1n1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 96 %

Procedure:
Acetic anhydride (0.88 mL, 9.28 mmol) was added under argon to a solution of 15 (2.50 g, 7.14 mmol) in dry pyridine (50 mL) and the resulting mixture was stirred at room temperature for 22 h. Then, ethanol was added and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (0-2%) in methylene chloride] to give pure 16 (2.69 g, 96%) as a white foam; mp=68-70° C. (foam); UV (ethanol): λmax=239 nm (ε=15000) 267 nm (ε=8800), λmin=248 nm (ε=5600); 1H NMR (DMSO-d6): δ ppm 11.9 (br s, 1H, NH), 8.1-7.5 (m, 6H, C6H5CO and H-6), 6.10 (d, 1H, H-1′, J1′-2′=4.3 Hz), 5.4 (m, 1H, H-2′), 4.6-4.4 (m, 3H, H-4′, H-5′ and H-5″), 2.6 (m, 1H, H-3′), 2.03 (m, 1H, H-3″), 1.86 (s, 3H, CH3CO); MS (matrix GT): FAB>0 m/z 785 (2M+H)+, 393 (M+H)+, 263 (S)+, 131 (BH2)+, 105 (C6H5CO)+; 43 (CH3CO)+; FAB<0 m/z 391 (M−H)−, 129 (B)−, 121 (C6H5CO2)−, 59 (CH3CO2)−; [α]D20=−81 (c, 0.95 DMSO).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][CH2:10][CH2:11][Cl:12].CO>C1COCC1>[Cl:12][CH2:11][CH2:10][CH2:9][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: ClCCCBr
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: ClCCCn1ccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
Anhydrous THF (25 mL) was cooled in an ice bath. After NaH (1.40 g, 35 mmol, 60%) was added to the THF in one portion, the mixture was stirred at rt for 30 min and cooled in an ice bath. Then a solution of 1H-imidazole (2.00 g, 30 mmol) in anhydrous THF (6 mL) was added dropwise. The reaction mixture was then warmed to rt and stirred at rt for 1.5 h. To the mixture was added 1-bromo-3-chloropropane (4.60 g, 30 mmol) dropwise, and stirred at rt overnight. To the resulting mixture was added MeOH (5 mL) in one portion. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=30:1) to give the title compound as pale yellow oil (3.10 g, 73%).
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:3][CH2:4]O.[C:22]1([OH:29])[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1.B(F)(F)F.CCOCC.O>O1CCOCC1>[CH3:1][C:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:3][CH2:4][C:27]1[CH:26]=[CH:25][C:24]([OH:28])=[CH:23][C:22]=1[OH:29]
Reactant: Oc1cccc(O)c1
Reactant: CC(=CCO)CCCC(C)CCCC(C)CCCC(C)C
Agent: FB(F)F
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(=CCc1ccc(O)cc1O)CCCC(C)CCCC(C)CCCC(C)C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
3,7,11,15-Tetramethyl-2-hexadecen-1-ol(14.8 g; 50 mmole) in 15 ml of dioxane was dropwise added to 11.0 g (100 mmole) of 1,3-benzenediol and 4.3 g (30 mmole) of boron trifluoride ethyl etherate in 30 ml of diozane at room temperature over one hour. After stirring the reaction solution at that temperature overnight, the solution was poured into 75 ml of water and was extracted with isopropyl ether (100 ml). The extract was washed with 200 ml of water (3 times) and 200 ml of saturated aqueous solution of sodium chloride (3 times) followed by drying it over anhydrous magnesium sulfate, distilling off the solvent and subjecting the resulting residue to silica gel column chromatography to thereby obtain 2.80 g of the title compound from the fractions eluted with hexane-ethyl acetate (3:1). Yield=14%.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:11]=[C:10]([CH3:12])[NH:9][N:8]=2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>>[Br:13][C:11]1[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:8][NH:9][C:10]=1[CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(-c2ccc(Cl)s2)n[nH]1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: Cc1[nH]nc(-c2ccc(Cl)s2)c1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
3-(5-chloro-2-thienyl)-5-methyl-1H-pyrazole (111 mmol) was dissolved in 200 mL dry 1V, N-dim ethyl formamide and cooled to 0° C. under nitrogen atmosphere. N-Bromosuccinimide (118 mmol) was added in small portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The solution was poured into a mixture of saturated aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution (1:1) at room temperature. The precipitate was filtered, washed thoroughly with water, dissolved in ethyl acetate, dried over MgSO4, filtered and evaporated to afford 19.5 g of 4-bromo-3-(5-chloro-2-thienyl)-5-methyl-1H-pyrazole (64% yield) that was used without further purification.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:21][C:22]1[CH:23]=[C:24]([CH2:34][C:35](O)=[O:36])[CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])[CH2:19][CH3:20]>>[CH2:18]([O:21][C:22]1[CH:23]=[C:24]([CH2:34][C:35]([NH:17][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:14][CH2:15][CH3:16])=[O:36])[CH:25]=[CH:26][C:27]=1[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])[CH2:19][CH3:20]
Reactant: CCCC(N)c1ccccc1N1CCCCC1
Reactant: CCCOC(=O)c1ccc(CC(=O)O)cc1OCCC
Product: CCCOC(=O)c1ccc(CC(=O)NC(CCC)c2ccccc2N2CCCCC2)cc1OCCC

Procedure:
Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 3-n-Propoxy-4-n-propoxycarbonyl-phenylacetic acid.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2([CH3:22])[CH2:17][CH2:16][C:15]3[C:10](=[C:11]([CH3:21])[C:12]([CH3:20])=[C:13]([OH:19])[C:14]=3[CH3:18])[O:9]2)=[O:7])[CH2:3][CH2:2]1.[O:23]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[CH:1]1([CH2:4][NH:5][C:6](=[O:7])[C:8]([OH:23])([CH3:22])[CH2:17][CH2:16][C:15]2[C:10](=[O:9])[C:11]([CH3:21])=[C:12]([CH3:20])[C:13](=[O:19])[C:14]=2[CH3:18])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCC1CC1)O2
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCC2CC2)=C(C)C1=O
Yield: 88.4 %

Procedure:
Oxidation as described in protocol B, using 76.7 mg (0.253 mmol) of N-(cyclopropylmethyl)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide and 435 mg CAN (0.794 mmol) yielded 71.4 mg of N-(cyclopropylmethyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow powder.
Reaction SMILES: [P:1]([O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]3[O:32][CH2:31][O:30][C:27]=3[CH:28]=2)[N:23]=[C:22]([C:33]2[C:34]3[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=3[O:36][CH:37]=2)[CH:21]=1)([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2]>CO.[Pd]>[P:1]([OH:11])([OH:3])([O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]3[O:32][CH2:31][O:30][C:27]=3[CH:28]=2)[N:23]=[C:22]([C:33]2[C:34]3[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=3[O:36][CH:37]=2)[CH:21]=1)=[O:2]
Reactant: O=P(OCc1ccccc1)(OCc1ccccc1)Oc1cc(-c2coc3ccccc23)nc2cc3c(cc12)OCO3
Agent: [Pd]
Solvent: CO
Product: O=P(O)(O)Oc1cc(-c2coc3ccccc23)nc2cc3c(cc12)OCO3
Yield: 46.3 %

Procedure:
A suspension of 157 (80.1 mg, 0.14 mmol) in anhydrous MeOH (40 mL) was hydrogenated in the presence of 10% Pd/C (40.0 mg) at 25° C. for 15 min. The catalyst and precipitate were collected and dissolved in 10% NaHCO3 solution and then filtered. The filtrate was acidified with dil aq HCl and the precipitate was then collected and washed with acetone to give 158. Obtained as white solid; yield: 46.3%; ESI-MS (Positive mode): m/z 386 [M+H]+, 408 [M+Na]+; ESI-MS (Negative mode): m/z 384 [M−H]−; 1H-NMR (D2O+NaOD, 500 MHz): δ 6.12 (2H, s), 7.32 (1H, s), 7.42 (2H, m), 7.56 (1H, s), 7.63 (1H, d, J=8.0 Hz), 7.78 (1H, s), 8.29 (1H, d, J=7.0 Hz), 8.40 (1H, s).
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([OH:9])(=O)C.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:18]=[C:19]([NH:22][CH:23]=[NH:24])[NH:20][N:21]=1.C(OC(=O)OCC)C>C(O)C>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:18]=[C:19]2[N:22]=[CH:23][NH:24][C:6](=[O:9])[N:20]2[N:21]=1
Reactant: CC(=O)O
Reactant: N=CNc1cc(-c2ccccc2Cl)n[nH]1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(=O)OCC
Solvent: CCO
Product: O=c1[nH]cnc2cc(-c3ccccc3Cl)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
To an ethanolic solution of sodium ethoxide, generated by portionwise addition of sodium metal (4.2 g, 185 mmol) to stirred ethanol (250 ml), was added N-[5-(2-chlorophenyl)-2H-pyrazol-3-yl]-formamidine, acetate salt (I-3A-9b; 5.2 g, 18.5 mmol) in one portion. Diethylcarbonate (17.8 ml, 148 mmol) was added, dropwise, and the mixture was heated at reflux for 2 hours. After cooling to room temperature, the reaction was concentrated, in vacuo, and then extracted with ethyl acetate from water after adjusting to pH 7 with 3 M aqueous HCL. The combined organic layers were washed with water and then brine, dried (MgSO4), filtered, and then concentrated, in vacuo, to one-third volume at which time a precipitate began to form. After stirring overnight, the product was collected by vacuum filtration and then dried, in vacuo, to afford I-3A-9c as a solid (2.61 g, 57%). A second crop of the intermediate was collected from the filtrate after standing an additional 24 hours (600 mg, 19%): +ESI MS (M+1) 247.1; 1H NMR (400 MHz, CD3OD) δ 7.97 (s, 1H), 7.86-7.82 (m, 1H), 7.55-7.51 (m, 1H), 7.45-7.39 (m, 2H), 6.92 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][S:8][CH2:7]1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC#N>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10](=[O:11])[CH2:9][S:8][CH2:7]2)[CH2:22][CH2:21]1
Reactant: O=C1CSCN1CCCCBr
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCCN2CSCC2=O)CC1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
A suspension of 3-(4-bromobutyl)-4-thiazolidinone (3.0 g), 1-(2-methoxyphenyl)piperazine (2.43 g), anhydrous K2CO3 (3 g) and NaI (200 mg) in 100 ml of anhydrous CH3CN was heated to reflux under N2. After 18 hours the mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo, and the residue taken up and chromatographed (silica, EtOAc eluent) to provide 3.49 g of product as a white solid, mp 80-81° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:12]/[CH2:13][CH2:14]O)=[CH:3][N:2]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[Cl:18][CH2:14][CH2:13]/[CH:12]=[CH:11]/[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=[N:2][CH:3]=1
Reactant: OCC/C=C/c1cncc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCC/C=C/c1cncc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3.3 g of (E)-4-(4-isoquinolinyl)-3-buten-1-ol in 15 mL of dry chloroform was added to a cold solution of 1.8 mL of thionyl chloride in 5 mL of dry chloroform. After 15 minutes, the cooling bath was removed and the reaction was stirred at room temperature for 1 hour and then at reflux for 3 hours. The cooled mixture was washed with NaHCO3 solution and with brine, then was dried (Na2SO4) and evaporated. The residue was purified by chromatography over silica gel (ethyl acetate-toluene; 3:17) to yield 2.2 g of (E)-4-(4-chloro-1-butenyl)isoquinoline as an oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].OS(O)(=O)=O.C([O:13][C:14]1[CH:23]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[C:21]([Cl:28])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])(=O)C>>[N+:1]([C:23]1[C:22]([NH:24][C:25](=[O:27])[CH3:26])=[C:21]([Cl:28])[CH:20]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:14]=1[OH:13])([O-:4])=[O:2]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC(C)=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c([N+](=O)[O-])c1O
Temperature: -10 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 90 ml concentrated HNO3 and 10 ml concentrated H2SO4 cooled to -10° C. is added portionwise over 5 minutes 10.9 g (38.2 mmol) methyl 2-acetoxy-4-acetylamino-5-chlorobenzoate. The mixture is stirred another 5 minutes and poured into ice water (400 ml). The ppt. which forms is filtered, washed (H2O) and dried to obtain methyl 3-nitro-4-acetylamino-5-chlorosalicylate; m.p. 166°-69° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:25]([O:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][C:29]=1[O:43][CH3:44])[CH3:26]>>[CH2:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]5[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:30][C:29]=1[O:43][CH3:44])[CH3:26]
Reactant: CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Reactant: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1
Product: CCOc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(CC)nc2C)c(=O)n4C)cc1OC

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 39 mg, 0.100 mmol) and 2-(4-ethoxy-3-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Stage 29.1.1, 34 mg, 0.123 mmol) to give the title compound as a white solid. (HPLC: tR 2.88 min (Method A); M+H=458 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.92 (s, 1H), 8.16 (s, 1H), 8.07-8.02 (m, 1H), 7.94-7.88 (m, 1H), 7.51-7.47 (m, 1H), 7.06-6.96 (m, 3H), 4.20-4.12 (m, 2H), 4.06-3.98 (m, 2H), 3.85 (s, 3H), 3.57 (s, 3H), 1.97 (s, 3H), 1.42-1.29 (m, 6H))
Reaction SMILES: BrC1C(Cl)=[N:4]C=C(C)C=1.OCC1CC1.ClC1C=CC(B(O)O)=CC=1.[NH2:25][CH2:26][C@H:27]1[CH2:32][CH2:31][CH2:30]C[C@H:28]1[OH:33]>>[C:28]([NH2:4])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:25][CH:26]=1
Reactant: NC[C@H]1CCCC[C@H]1O
Reactant: Cc1cnc(Cl)c(Br)c1
Agent: OB(O)c1ccc(Cl)cc1
Agent: OCC1CC1
Product: NC(=O)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 2, using 3-bromo-2-chloro-5-methyl-pyridine, hydroxymethylcyclopropane, [4-chloro-phenyl]-boronic acid and cis-2-aminomethyl-1-cyclohexanol as starting materials to yield racemic cis-5-(4-chloro-phenyl)-6-cyclopropylmethoxy-N-2-hydroxy-cyclohexylmethyl)-nicotinamide. Separation with heptane/ethanol on ChiralpakAD® yielded the (−)-enantiomer, MS (ISP) 415.2 (M+H)+, αD20: −17.8° in MeOH.