Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[N:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:30]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][N:24]=3)=[O:31])=[C:16]2[N:15]=1
Reactant: O=C(O)c1cnccn1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12)c1cnccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
To a mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol), pyrazine-2-carboxylic acid (12 mg, 0.095 mmol), and HATU (36 mg, 0.095 mmol) was added 0.6 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.041 mL, 0.24 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for 10 minutes. The reaction mixture was diluted with EtOAc (15 mL), washed with water and brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 65% acetonitrile/water to yield the final product as a yellowish solid (31 mg, 93% yield). MS (apci) m/z=422.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:2]2[CH:3]=[C:4]([C:8]3[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:11]=[C:10]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)[CH:29]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-c3cccc(Br)c3)n2)cc1
Reactant: OB(O)c1cccnc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-c3cccc(-c4cccnc4)c3)n2)cc1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (example E.20) (0.525 g, 1.0 mmol) and commercially available 3-pyridineboronic acid (0.16 g, 1.3 mmol) according to the general procedure VI. Obtained as a white solid (0.083 g, 19%). MS (ISP) 445.2 [(M+H)+]; mp 164-166° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:6]=2[CH:5]=[CH:4]1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O1CCCC1>[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([N:3]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:13])[C:6]=3[CH:5]=[CH:4]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(OCc1ccccc1)c1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(=O)OCc4ccccc4)cccc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a suspension of sodium hydride (133 mg) in tetrahydrofuran (5.0 ml) was added dropwise a solution of benzyl indole-4-carboxylate (580 mg) in tetrahydrofuran (5.0 ml) at 0° C. and the mixture was stirred at 0° C. for 1 hour. 4-Toluenesulfonyl chloride (440 mg) was added to the mixture and the solution was stirred at ambient temperature for 1 hour. The reaction was quenched with 1 N hydrochloric acid and then the aqueous solution was extracted with ethyl acetate. Drying, filtering and removal of solvents afforded a crude product. The crude product was purified by column chromatography (eluent; n-hexane:ethyl acetate=15:1) to give benzyl 1-(4-toluenesulfonyl)indole-4-carboxylate (560 mg) as a colorless syrup.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C@@H:10]2[N:5]([C:6](=[O:12])[CH2:7][CH2:8][CH2:9]2)[C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:3]1.N1C=CN=C1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26].O.C(=O)(O)[O-].[Na+]>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[Si:28]([O:1][C@H:2]1[CH2:11][C@@H:10]2[N:5]([C:6](=[O:12])[CH2:7][CH2:8][CH2:9]2)[C@H:4]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:3]1)([C:25]([CH3:27])([CH3:26])[CH3:24])([CH3:30])[CH3:29]
Reactant: O=C1CCC[C@@H]2CC(O)C[C@@H](c3ccccc3)N12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H]2CCCC(=O)N2[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
A solution of (6S*,9aR*)-8-hydroxy-6-phenyloctahydroquinolizin-4-one (96.4 mg) in DMF (5.0 mL) was cooled to 0° C. Imidazole (80.3 mg), TBSCl (88.9 mg), and DMAP (4.8 mg) were sequentially added to the reaction solution, which was then stirred at room temperature overnight. Saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 77 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH2:17][CH3:18])=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20].[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=1[Cl:36])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.N1C=CC=CC=1>C(O)(C)C>[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:16][CH2:17][CH3:18])=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:19]#[N:20])=[CH:31][C:30]=1[Cl:36])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1NC(C)=O
Reactant: Nc1ccc(OCc2ccccc2)c(Cl)c1
Agent: Cl
Solvent: CC(C)O
Solvent: c1ccncc1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccc4)c(Cl)c3)c2cc1NC(C)=O

Procedure:
A mixture of 4.17 g (0.0149 moles) of the N-(4-chloro-3-cyano-7-ethoxy-6-quinolinyl)acetamide, 4.04 g (0.0173 moles) of 4-benzyloxy-3-chloro-phenylamine (example 5), and 2.0 g (0.017 moles) of pyridine hydrochloride in 85 ml of isopropanol was stirred and refluxed in an oil bath for 30 minutes. The reaction was cooled in an ice bath, and the solid was collected by filtration and washed with isopropanol, and then with ether yielding 7.26 g of crude product as the hydrochloride salt. This material was purified by chromatography of the free base on silica gel by elution with 1:39 methanol-methylene chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:14]=[N:13]2)[CH2:10][OH:11])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[C:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:14]=[N:13]2)[CH:10]=[O:11])=[CH:4][CH:3]=1
Reactant: OCC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1nnnc1-c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1nnnc1-c1ccccc1
Reaction time: 24 h

Procedure:
To a solution of 3.2 g (8.2 mmoles) of 3,3-bis(4-fluorophenyl)-2-(5-phenyl-1H-tetrazol-1-yl)-2-propenol in 200 mL of dry methylene chloride at room temperature was added 1.9 g (8.8 mmoles) of pulverized pyridinium chlorochromate in a single portion. The oxidation was allowed to proceed at room temperature for 24 hours. The crude reaction suspension was diluted with 200 mL of hexanes and the resulting dark brownish suspension was filtered through a bed (1 cm thick) of fine silica gel. The pale filtrate was collected and evaporated under reduced pressure to give the desired product. The solid was recrystallized from an ethyl acetate-hexanes mixture to yield 2.9 g (91.1%) of the title compound; m.p.=193.0-194.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[CH3:16])=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:51])[CH2:32][C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)[CH3:29]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:28]([O:30][C:31](=[O:51])[CH2:32][C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH:18]=4)[CH3:16])=[CH:6][CH:7]=3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)[CH3:29]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)c1cc(-c2ccccc2)no1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)c4cc(-c5ccccc5)no4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(3-phenyl-isoxazol-5-yl)-ethyl]-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester. Additionally, (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@@H:12]([C:24]([OH:26])=[O:25])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([O-])=O.[Cl-].[NH4+]>[Zn].CO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@@H:12]([C:24]([OH:26])=[O:25])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: O=C(N[C@@H](CSc1ccccc1[N+](=O)[O-])C(=O)O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1ccccc1SC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 5 l 3-neck flask fitted with a mechanical stirrer and condenser is charged with 62.1 g of S-(o-nitrophenyl)-N-carbobenzyloxy-L-cysteine, 17.6 g of ammonium chloride and 3 l of methanol. To this mixture is added 150 g of zinc dust. The reaction is heated for 4 hr at reflux and then stirred overnight at room temperature. The reaction is filtered through celite and the solids are further washed with 300 ml of boiling methanol. The methanol fractions are combined and concentrated. The residue is dissolved in 1200 ml of 1N hydrochloric acid and filtered through celite. The acidic solution is cooled to 0° C. and the pH is adjusted to 5 with saturated sodium acetate. The resulting white precipitate is collected and dried at 80° C. in vacuo to give S-(o-aminophenyl)-N-carbobenzyloxy-L-cysteine; m.p. 161°-162° C.; [α]D =-50° ((c=1.0, absolute ethanol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:10][NH:11][C:12](=[O:26])[C@H:13]([NH:15]C(=O)OCC1C=CC=CC=1)[CH3:14])=[O:7])([CH3:4])(C)C.Cl>O1CCOCC1>[CH2:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:10][NH:11][C:12](=[O:26])[C@@H:13]([CH3:14])[NH2:15])[C:4]1[CH:29]=[CH:28][CH:27]=[CH:9][CH:10]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)NC[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](N)C(=O)NC[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 114.1 %

Procedure:
Benzyl [(1R)-2-({(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}amino)-1-methyl-2-oxoethyl]carbamate (335 mg, 0.74 mmol) was dissolved in 5 mL dioxane and hydrogen chloride (4M solution in dioxane, 5 mL, 20 mmol) added and the mixture stirred at room temperature for 16 h. The mixture was evaporated under reduced pressure and the residue purified by flash column chromatography eluting with a 9:1 mixture of dichloromethane in methanol to give 150 mg (63%) of the title compound as a waxy white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[CH3:28])[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:31][OH:32].C([O-])(O)=O.[Na+]>>[CH3:1][N:2]([CH3:29])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[CH3:28])[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:31][OH:32])=[CH:5][CH:4]=1
Reactant: NO
Reactant: Cc1[nH]c2ccccc2c1C(CC(=O)c1ccncc1)c1ccc(N(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1[nH]c2ccccc2c1C(CC(=NO)c1ccncc1)c1ccc(N(C)C)cc1

Procedure:
In analogy to example 1, step 2, from 3-(4-dimethylamino-phenyl)-3-(2-methyl-1H-indol-3-yl)-1-pyridin-4-yl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (8.8:1) as a yellow foam, MS (ESI+): m/z=399.3 ([M+H]+).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.Cl.[Br:20][C:21]1[C:29]([F:30])=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[C:23]([NH:31]N)[CH:22]=1>C(O)(=O)C>[Br:20][C:21]1[C:29]([F:30])=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[C:23]2[C:22]=1[C:7]1[CH2:6][CH2:5][CH:4]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][C:2]=1[NH:31]2
Reactant: CCOC(=O)C(C(=O)OCC)C1CCCC(=O)C1
Reactant: NNc1cc(Br)c(F)cc1C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(C(=O)OCC)C1CCc2c([nH]c3c(C(=O)O)cc(F)c(Br)c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
A solution of diethyl 2-(3-oxocyclohexyl)malonate (15.26 g, 59.5 mmol) and 4-bromo-5-fluoro-2-hydrazinylbenzoic acid hydrochloride [Intermediate 24B] (17.0 g, 59.5 mmol) in acetic acid (120 mL) was heated at reflux for 2 h, then was stirred overnight at room temperature. The precipitate which formed was collected by filtration to provide a white solid. The filtrate was concentrated and purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexanes (gradient from 0-100%). The resulting oily product was crystallized from a mixture of EtOAc, ether and hexanes to provide additional solid, which was combined with the first solid to provide 5-bromo-2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid as a white solid (10.5 g, 49% yield). Mass spectrum m/z 470, 472 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:40]=[CH:39][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH:22]=4)[CH:17]3[C:35]([O:37]C)=[O:36])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:27][CH2:28][N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH:22]=4)[CH:17]3[C:35]([OH:37])=[O:36])(=[O:14])=[O:15])=[CH:9][CH:8]=2)=[CH:39][CH:40]=1
Reactant: COC(=O)C1c2ccc(OCCN3CCOCC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1c2ccc(OCCN3CCOCC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 1 h
Yield: 75 %

Procedure:
86 mg (0.15 mmol) of methyl 2-[4-(4-fluorophenoxy)benzenesulfonyl]-6-(2-morpholin-4-ylethoxy)-1,2,3,4-tetrahydroisoquinoline-1-carboxylate are heated in 15 ml of 6 N HCl to 70° C. After one hour, the mixture is allowed to cool to room temperature and neutralized with 5 N NaOH. The aqueous solution is extracted with ethyl acetate, and the organic phase is dried with MgSO4 and concentrated, allowing the carboxylic acid to be isolated in a yield of 75%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:11])=[CH:4][C:3]=1[Cl:20].Br[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C.O>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:16][CH2:15]2)=[O:11])=[CH:4][C:3]=1[Cl:20]
Reactant: COc1nc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: BrCC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(N)c(Cl)cc1C(=O)NCC1CCN(CC2CCCCC2)CC1
Temperature: 90 °C
Reaction time: 10 h
Yield: 65.8 %

Procedure:
A mixture of 6-amino-5-chloro-2-(methyloxy)-N-(4-piperidinylmethyl)-3-pyridinecarboxamide (step 1, 150 mg, 0.50 mmol), (bromomethyl)cyclohexane (107 mg, 0.60 mmol), and triethylamine (140 μl, 1.00 mmol) in N,N-dimethylformamide (5 ml) was stirred at 90° C. for 10 h. After cooling to room temperature, the mixture was poured into water (50 ml) and the aqueous layer was extracted with ethyl acetate/toluene (2:1, 80 ml×2). The combined organic layer was washed with brine (100 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with 25% ammonia/methanol/dichloromethane (0.1:1:20) to give 130 mg (65%) of the title compound as a yellow amorphous solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:28]4[C:23]([C:24]([NH2:29])=[N:25][CH:26]=[N:27]4)=[C:22]([C:30]4[CH:31]=[CH:32][C:33]5[C:37]([CH:38]=4)=[N:36][N:35]([CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH:34]=5)[CH:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C>Cl.O1CCOCC1>[CH2:39]([N:35]1[CH:34]=[C:33]2[C:37]([CH:38]=[C:30]([C:22]3[CH:21]=[C:20]([C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:15]=4)[N:28]4[C:23]=3[C:24]([NH2:29])=[N:25][CH:26]=[N:27]4)[CH:31]=[CH:32]2)=[N:36]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1ncnn2c(-c3cccc(C4CCNCC4)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 4 h

Procedure:
The product from step 4 was dissolved in 5 mL of 4M HCl in dioxane and the mixture was stirred for 4 h. Ethyl acetate (10 mL) was added into the resulting mixture and washed with 2M Na2CO2 (2 mL). The resulting organic solution was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC. (CH2Cl2/MeOH). δ 1H NMR (CD2Cl2) 1.60 (m, 1H), 1.80 (m, 2H), 2.80 (m, 3H), 4.10-4.30 (m, 3H), 5.60 (s, 2H), 5.80 (br, 2H), 7.00 (s, 1H), 7.10-7.50 (m, 9H), 7.80 (m, 2H), 7.90 (m, 2H), 7.95 (s, 1H), 8.10 (s, 1H); LC-MS [M+H]+=500.2, RT=2.39 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1>[Pt]>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][CH:4]([C:14]([F:17])([F:15])[F:16])[CH2:3][CH2:2]2
Reactant: COc1ccc2nc(C(F)(F)F)cc(Cl)c2c1
Agent: [Pt]
Product: COc1ccc2c(c1)CCC(C(F)(F)F)N2

Procedure:
4-Chloro-6-methoxy-2-trifluoromethylquinoline was reduced with platinum on carbon to give 6-methoxy-2-trifluoromethyltetrahydroquinoline.
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[O:16])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[C:24]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=3)[OH:16])[CH2:12][CH2:13]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccc(O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Oc1ccc(C(O)CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
In 50 ml of methanol was dissolved 3.0 g (7.8 mmol) of 2-(4-diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl)ethanone, to which 3.0 g (79 mmol) of sodium borohydride was added slowly under ice-cooled conditions. The reaction mixture was then stirred overnight at room temperature, and methanol was removed under reduced pressure. Thereafter, 100 ml of ether was added to the residue, and the solution was washed successively with water and saturated saline and dried over anhydrous sodium sulfate. The resultant ether solution was concentrated, and the residue was purified by silica gel column chromatography (silica gel 90 g; chloroform:methanol=100:1) to give 2.4 g of 2-(4-diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl)ethanol (yield: 79%) which, upon recrystallization from a mixed solvent of ethyl acetate and n-hexane, gave white crystals.
Reaction SMILES: Cl[CH:2]([CH2:8][C:9]([Cl:12])([F:11])[F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CC1C=CC=C(C)N=1.[H][H]>O1CCCC1.[Pd]>[Cl:12][C:9]([F:10])([F:11])[CH2:8][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Cl)CC(F)(F)Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)CCC(F)(F)Cl
Yield: 75 %

Procedure:
22.1 g of ethyl 2,4-dichloro-4,4-difluorobutyrate are dissolved in 100 ml of absolute tetrahydrofuran. 10.7 g of 2,6-dimethylpyridine and 2.0 g of 5% palladium/carbon catalyst are added and then gaseous hydrogen is passed in under atmospheric pressure until the hydrogen uptake is 100% of theory. The catalyst is removed by filtration and the tetrahydrofuran is removed by distillation and then the remaining oil is poured onto water, and the organic phase is separated off, dried with sodium sulfate, filtered and distilled under atmospheric pressure. 14.0 g of ethyl 4-chloro-4,4-difluorobutyrate are obtained in the form of a colourless oil of boiling point 154°-156° C.
Reaction SMILES: N#N.[F:3][C:4]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[N:14]2)[S:10][CH:11]=1)([F:6])[CH3:5].[NH4+].[Cl-]>CCO.O.[Fe]>[F:3][C:4]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]2)[S:10][CH:11]=1)([F:6])[CH3:5]
Reactant: CC(F)(F)c1csc(Cn2ccc([N+](=O)[O-])n2)n1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(F)(F)c1csc(Cn2ccc(N)n2)n1
Temperature: 75 °C
Reaction time: 2.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-(1,1-difluoro-ethyl)-2-(3-nitro-pyrazol-1-ylmethyl)-thiazole (95 mg, 0.35 mmol), iron powder (59 mg, 1.04 mmol) and NH4Cl (94 mg, 1.73 mmol) in a mixture of EtOH (3.0 mL) and water (1.5 mL) was stirred at 75° C. for 2.5 h. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (10 mL) was added followed by 1N NaOH (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a brown oil. TLC: rf (19:1 CH2Cl2-MeOH)=0.2. LC-MS-conditions 02: tR=0.7 min.