Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[C@@H:17]3[CH2:30][C@@H:18]3[C:19]2=[O:29])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>O1CCCC1.CCOCC>[C:1]([O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[C@@H:17]3[CH2:30][C@@H:18]3[C@@H:19]2[OH:29])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]12CC[C@H](OC(=O)c3ccccc3)CC1=CC[C@H]1[C@@H]3[C@@H]4C[C@@H]4C(=O)[C@@]3(C)CC[C@@H]12
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](OC(=O)c5ccccc5)CC[C@@]43C)[C@@H]1[C@@H]1C[C@@H]1[C@@H]2O
Yield: 101.1 %

Procedure:
6.4 g of 3β-benzoyloxy-15β,16β-methylene-5-androsten-17-one was stirred in 64 ml of tetrahydrofuran with 6.4 g of lithium tri-tert.-butoxyaluminohydride for 1 hour at room temperature. The solution was then diluted with ether, washed with 2N sulfuric acid and water, dried, and evaporated, yielding as the residue 6.5 g of 3β-benzoyloxy-15β,16β-methylene-5-androsten-17β-ol, used without further purification in the subsequent stage.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:23]1CC[CH2:25][CH2:24]1>C(OC(=O)C)(=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:24](=[O:23])[CH3:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccccc2N)CC1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccccc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
After dissolving 400 mg of 1-(tert-butoxycarbonyl)-4-(2-aminophenoxymethyl)piperidine in 10 ml of tetrahydrofuran, 0.15 ml of acetic anhydride and 0.24 ml of triethylamine were added and the mixture was stirred overnight at room temperature. The reaction solution was filtered with silica gel and NH silica gel. The solvent was distilled off under reduced pressure to obtain the title compound (459 mg, 100% yield).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:30])=[C:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([OH:26])[C:18]=2[CH2:27][CH2:28][CH3:29])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].C(=O)(O)[O-].[Na+].[CH2:36](I)[CH3:37]>CN(C)C=O>[CH2:36]([O:22][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][C:17]([O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:4]2[CH:5]=[C:6]([CH3:9])[C:7]([OH:8])=[C:2]([OH:1])[C:3]=2[CH3:30])=[C:18]([CH2:27][CH2:28][CH3:29])[C:19]=1[OH:26])[CH3:37]
Reactant: CCI
Reactant: CCCc1c(OCCCCCCc2cc(C)c(O)c(O)c2C)ccc(C(=O)O)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCCc2cc(C)c(O)c(O)c2C)ccc(C(=O)OCC)c1O
Reaction time: 10 h
Yield: 67 %

Procedure:
A mixture of 0170 g (1.68 mmole) of 4-[6-(3,4-dihydroxy-2,5-dimethylphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid, 0.157 g (1.87 mmole) of sodium bicarbonate and 1.4 mL (16.8 mmole) of ethyl iodide in 10 mL of dimethylformamide was stirred at 50° for 10 hours. Workup as in Example 160 gave an oil which was purified by chromatography on 20 g of silica gel. Elution with 25% ethyl acetate-hexane gave the product which was recrystallized from hexane to give 0.50 g, mp 61°-64°, (67% yield) of 4-[6-(3,4-dihydroxy-2,5-dimethylphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid ethyl ester.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7](B(O)O)[CH:8]=1)=[O:2].[CH3:14][C:15]1[O:16][C:17]2[CH:23]=[CH:22][C:21](Br)=[CH:20][C:18]=2[N:19]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.C1(C)C=CC=CC=1>[CH3:13][O:12][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][C:7]=1[C:21]1[CH:22]=[CH:23][C:17]2[O:16][C:15]([CH3:14])=[N:19][C:18]=2[CH:20]=1
Reactant: COc1ccc(C=O)cc1B(O)O
Reactant: Cc1nc2cc(Br)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C=O)cc1-c1ccc2oc(C)nc2c1
Yield: 89.6 %

Procedure:
A solution of 5-formyl-2-methoxybenzeneboronic acid (1 g, 5.6 mmol), 2-methyl-5-bromobenzoxazole (1 g, 4.72 mmol) and K2CO3 (1.63 g, 11.8 mmol) in ethanol (20 mL) and toluene (40 mL) was degassed prior to addition of Pd(Ph3)4 (55 mg, 0.047 mmol). The mixture was refluxed for 20 hours then cooled and filtered through diatomaceous earth. The filtrate was concentrated in vacuo, extracted with ethyl acetate, washed with water and the organic layer dried over sodium sulphate. The crude was purified by column chromatography (heptane/ethyl acetate 7/3 to 6/4) to give 1.13 g of title compound.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([CH2:15][C:16]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[NH:33][N:32]=[N:31][N:30]=5)=[CH:25][CH:24]=4)[NH:20]C(=O)N[C:17]3=[O:22])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-:34].[Na+].Cl>>[NH2:20][C:16]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[CH:25][CH:24]=1)([CH2:15][CH:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:17]([OH:22])=[O:34]
Reactant: O=C1NC(=O)C(CC2c3ccccc3Oc3ccccc32)(c2ccc(-c3nnn[nH]3)cc2)N1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: NC(CC1c2ccccc2Oc2ccccc21)(C(=O)O)c1ccc(-c2nnn[nH]2)cc1

Procedure:
5-(9H-xanthen-9-ylmethyl)-5-[4-(1H-tetrazol-5-yl)phenyl]hydantoin (3.2 g, 7.6 mmol) was heated with aqueous sodium hydroxide (2M, 23 ml) at 130° C. for 2 days following the procedure described in Example 1 (vi). The reaction mixture was acidified with aqueous hydrochloric acid and the product isolated by filtration to give the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][C:31]([NH2:34])=[N:32][CH:33]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:9]1([CH3:13])[O:8][C:6]2[N:7]=[C:2]([C:28]3[CH:29]=[N:30][C:31]([NH2:34])=[N:32][CH:33]=3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]=2[O:11][CH2:10]1
Reactant: CC1(C)COc2c(nc(Cl)nc2N2CCOCC2)O1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC1(C)COc2c(nc(-c3cnc(N)nc3)nc2N2CCOCC2)O1
Temperature: 120 °C
Yield: 71.1 %

Procedure:
A mixture of 2-chloro-7,7-dimethyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (285 mg, 1.00 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (440 mg, 1.99 mmol), Pd(PPh3)2Cl2 (70 mg, 0.10 mmol) and sodium carbonate (3.3 mL, 3.3 mmol, 1M aqueous solution) in acetonitrile (7 mL) was degassed then heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture was diluted with methanol and DCM and absorbed onto diatomaceous earth. The resulting residue was purified by column chromatography (SiO2, gradient 0-4% methanol in DCM then SiO2, gradient 0-100% ethyl acetate in cyclohexane) affording 104 as a white solid (245 mg, 71%). LCMS: RT=3.28 min, [M+H]+=345. 1H NMR (400 MHz, DMSO): δ 8.90 (2H, s), 7.00 (2H, s), 3.97 (2H, s), 3.70 (8H, s), 1.35 (6H, s).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=2)[C:3]=1[N+:21]([O-])=O.C(N(CC)CC)C.C(O)=O>C(#N)C.[Pd]>[NH2:21][C:3]1[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=2)=[N:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1]
Reactant: Cc1c([N+](=O)[O-])cnc(Nc2ccc(CCO)cc2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c([N+](=O)[O-])cnc(Nc2ccc(CCO)cc2)c1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.3 %

Procedure:
To a stirred solution of 2-{4-[(4-methyl-3,5-dinitro-2-pyridinyl)amino]phenyl}ethanol (step 1, 4.2 g, 13.1 mmol), triethylamine (9.6 mL, 68.9 mmol), 10% Pd-C (624 mg, 0.59 mmol) in acetonitrile (14 mL) was added dropwise a solution of formic acid (2.3 mL, 61.0 mmol) in acetonitrile (6.2 mL) at 0° C. over a period of 30 min. After stirring at room temperature for 5 h, the mixture was filtered through a pad of Celite, and the filtrate was concentrated. The residue was dissolved in dichloromethane (100 mL). The solution was washed with 1N aqueous NaOH (50 mL), brine (50 mL), dried (MgSO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 1:1 to 1:2) afforded 2.2 g (60%) of the title compound as red crystals: 1H-NMR (CDCl3) δ 8.42 (1H, s), 7.42 (2H, d, J=8.4 Hz), 7.21 (2H, d, J=8.4 Hz), 6.7 (1H, br s), 3.85 (2H, t, J=6.4 Hz), 2.86 (2H, t, J=6.6 Hz), 2.47 (3H, s).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[OH-].[Na+].OO.CC[O:17]CC>C1COCC1>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH2:3][OH:17])=[CH:5][CH:6]=1
Reactant: C=CCc1ccc(Br)cc1
Reactant: CCOCC
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
BH3 (1M in THF, 412 mL, 412 mmol) is added to a sol. of 1-allyl-4-bromo-benzene (204 g, 1.03 mmol) in THF (1.00 L) under nitrogen at 0° C. The mixture is stirred overnight while warming up to rt. Aq. NaOH (2.5M, 1.65 L, 4.12 mol) is added, and the mixture is cooled to 0° C. H2O2 (35%, 480 mL, 5.15 mol) is dropped carefully, and the mixture is stirred for 3 h. Et2O is added, and the phases are separated. The org. layer is washed with water (1×), and brine (1×). The org. layer is dried over MgSO4, filtered, and the solvents are removed under reduced pressure. Purification by FC (Et2O/petroleum ether 1:1→Et2O) yields the title compound (97.4 g, 44%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]([C:19]([CH3:23])([CH3:22])[C:20]#[N:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][C:10]([C:19]([CH3:23])([CH3:22])[CH2:20][NH2:21])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C#N)c1cc(-c2ccccc2)n(Cc2ccccc2)n1
Agent: B
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(CN)c1cc(-c2ccccc2)n(Cc2ccccc2)n1
Temperature: 60 °C
Yield: 102.3 %

Procedure:
2-(1-Benzyl-5-phenyl-1H-pyrazol-3-yl)-2-methylpropanenitrile (50 mg, 0.16 mmol) was dissolved in THF (1.6 mL). Borane-tetrahydrofuran (0.8 mL, 1 M solution) was added and the reaction was heated to 60° C. for 3 h. Minimal water was added to quench the reaction. Ethyl acetate was added followed by sodium sulfate and the solids were removed by filtration. The filtrate was concentrated under reduced pressure to yield 2-(1-benzyl-5-phenyl-1H-pyrazol-3-yl)-2-methylpropan-1-amine (50 mg, crude), which was carried through without further purification. MS (ESI) m/z: Calculated for C20H23N3: 305.19. found: 306.2 (M+H)+.
Reaction SMILES: C(Cl)Cl.[F:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:16])[C:14]=1[F:15])[N:11]([NH:17][CH3:18])[CH:10]=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]2=[O:24].[C:25]([O:29][C:30]([C:32](=[CH2:40])[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:31])([CH3:28])([CH3:27])[CH3:26].O>C(OCC)(=O)C.[Ti](Cl)(Cl)(Cl)Cl>[F:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:16])[C:14]=1[F:15])[N:11]([N:17]([CH3:18])[CH2:40][CH:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:10]=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]2=[O:24]
Reactant: C=C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cn(NC)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(N(C)CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2c(F)c(F)c(F)cc2c1=O
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
Methylene chloride (10 ml) solution of ethyl 6,7,8-trifluoro-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.0 g) and tert-butyl 2-tert-butoxycarbonylacrylate (1.52 g) was cooled in an ice bath in nitrogen atmosphere, and titanium tetrachloride (632.4 mg) was dropwise added thereto. After 30 minutes, this was diluted with ethyl acetate (100 ml) and then with water (100 ml). The organic layer was separated out, washed with water (2×50 ml), dried over magnesium sulfate and concentrated under reduced pressure to obtain an yellow syrup product. The syrup product was subjected to column chromatography with silica gel and eluted with a mixed solvent of methylene chloride/ethyl acetate (10/1) to obtain ethyl 6,7,8-trifluoro-1-[N-methyl-N-{2,2-bis(tert-butoxycarbonyl)ethyl}amino]-1,4-dihydro-4-oxoquinoline-3-carboxylate (988 mg), as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]I.[CH3:17][O:18][CH2:19][CH2:20][NH:21][CH3:22].C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][N:21]([CH2:20][CH2:19][O:18][CH3:17])[CH3:22]
Reactant: CNCCOC
Reactant: COC(=O)[C@H](CCI)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COCCN(C)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 70 °C
Reaction time: 16 h
Yield: 492.8 %

Procedure:
A mixture of (S)-2-tert-butoxycarbonylamino-4-iodobutyric acid methyl ester (0.200 g, 0.58 mmol), (2-methoxyethyl)-methylamine (0.062 g, 0.70 mmol), and triethylamine (0.41 mL, 2.9 mmol) in dioxane (1 mL) was stirred at 70° C. for 16 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and dissolved in dichloromethane (20 mL). The solution was washed with water (3×10 mL), brine (10 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure. The tan oil was chromatographed eluting with ether to provide 0.87 g of pale yellow oil (49% yield).
Reaction SMILES: [C:1]([CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=2)[C:13](=O)[C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[N:16][CH:15]=2)[CH2:8][CH2:7]1)[CH3:5])#[N:2].B.C1COCC1.Cl>C1COCC1>[NH2:2][CH2:1][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[C:22]2[CH:23]=[CH:24][C:25]([S:28][CH3:29])=[CH:26][CH:27]=2)[CH2:8][CH2:7]1)[CH3:5]
Reactant: CSc1ccc(N(C(=O)c2cnccc2C)C2CCN([C@H](C)CC#N)CC2)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CSc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCN)CC2)cc1
Yield: 72.8 %

Procedure:
The above amide (276 mg, 0.70 mmol) in THF (10 mL) was reduced with BH3-THF (1.0M in THF, 4.2 mL, 4.2 mmol) at reflux and treated with 6N HCl (8 mL) to afford [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methyl-pyridin-3-ylmethyl)-(4-methylsulfanyl-phenyl)-amine as a clear oil (203 mg, 70%) after basic work-up and purification.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[C@@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([OH:21])[C@H:15]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH2:29][C:30]4[S:31][C:32]([C:35]5[O:36][CH:37]=[CH:38][CH:39]=5)=[CH:33][N:34]=4)[CH:23]=3)[O:14]2)(=O)=O)=CC=1.[I-:40].[Na+].O>CC(=O)CC>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C@H:15]2[C@H:16]([OH:21])[C@@H:17]([OH:20])[C@H:18]([OH:19])[C@@H:13]([CH2:12][I:40])[O:14]2)=[CH:23][C:24]=1[CH2:29][C:30]1[S:31][C:32]([C:35]2[O:36][CH:37]=[CH:38][CH:39]=2)=[CH:33][N:34]=1
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](c3ccc(Cl)c(Cc4ncc(-c5ccco5)s4)c3)[C@H](O)[C@@H](O)[C@@H]2O)cc1
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: O[C@@H]1[C@@H](O)[C@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)O[C@H](CI)[C@H]1O
Yield: 48.3 %

Procedure:
The solution of toluenesulfonate 90 (100 mg, 0.17 mmol) and sodium iodide (38 mg 0.25 mmol) in 2-butanone (1.7 mL) was stirred at 80° C. for 2 h. H2O was added to the reaction mixture and then extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by prep HPLC (C18) to afford the titled compound 95 (45 mg, 48%) as a solid. MH+547
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[NH2:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH2:24][C:23]([CH3:26])([CH3:25])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:27]#[N:28])[CH:21]=3)[NH:16]2)[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1>ClCCl>[C:27]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]([C:11]1[CH:10]=[C:9]([NH:8][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])[CH:14]=[CH:13][CH:12]=1)[CH2:24][C:23]2([CH3:26])[CH3:25])#[N:28]
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)Nc1cccc(C2CC(C)(C)c3cc(C#N)ccc3N2)c1
Reaction time: 168 h
Yield: 46.8 %

Procedure:
Propane-2-sulfonyl chloride (231 mg, 1.62 mmol) was added dropwise to a mixture of 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (150 mg, 0.54 mmol) and pyridine (342 mg, 4.32 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir for 7 days. The reaction mixture was washed by water, dried over magnesium sulfate. Filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to afford propane-2-sulfonic acid [3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide as off-white solid (97 mg, yield: 46.8%). MS (ESI+APCI) M+1=384.2.
Reaction SMILES: [C:1]1([N:7]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.[C:24](O)(=[O:26])C>>[C:1]1([N:7]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH:24]=[O:26])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: c1ccc(CN(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1ccc(N(Cc2ccccc2)c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
N,N-diphenylbenzylamine (935 mg, 3.60 mmol) was suspended in acetic acid (20 mL), and hexamethylenetriamine (1.12 g, 7.96 mmol) was added thereto, followed by stirring at 90° C. for 12 hours. The reaction liquid was cooled to room temperature, a 6 mol/L sodium hydroxide aqueous solution and water were added thereto, and then the product was extracted with chloroform. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=20/1→10/1), to obtain 4-(N-phenylbenzylamino)benzaldehyde (742 mg, 72%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:21](COCC[Si](C)(C)C)[C:20]3[CH:30]=[CH:31][CH:32]=[CH:33][C:19]=3[N:18]=2)[C:5](=[O:16])[N:6](COCC[Si](C)(C)C)[N:7]=1.[CH3:34][S:35][C:36]1[N:41]=[C:40]([Sn](CCCC)(CCCC)CCCC)[CH:39]=[CH:38][N:37]=1.[F-].[K+]>[Cl-].C([N+](CC)(CC)CC)C.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:21]1[C:20]2[CH:30]=[CH:31][CH:32]=[CH:33][C:19]=2[N:18]=[C:17]1[C:4]1[C:5](=[O:16])[NH:6][N:7]=[C:2]([C:38]2[CH:39]=[CH:40][N:41]=[C:36]([S:35][CH3:34])[N:37]=2)[CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Reactant: C[Si](C)(C)CCOCn1nc(Cl)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CSc1nccc(-c2cc(-c3nc4ccccc4[nH]3)c(=O)[nH]n2)n1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
The compound is prepared in analogy to example 15. A Stille coupling is carried out instead of the Suzuki coupling. This entails dissolving 6-chloro-4-[1-(2-trimethylsilanylethoxymethyl)-1H-benzimidazol-2-yl]-2-(2-trimethylsilanylethoxy-methyl)-2H-pyridazin-3-one, 2-methylsulfanyl-4-tributylstannylpyrimidine, tetra-ethylammonium chloride and bis(triphenylphosphine)palladium(II) chloride in DMF under argon and heating at 80° C. for 6 hours. After cooling to room temperature, 30% aqueous potassium fluoride solution is added, and the mixture is stirred for 30 minutes. Extraction with ethyl acetate and drying on a drying column afford after purification on SiO2 4-[1-(2-trimethylsilanylethoxymethyl)-1H-benzimidazol-2-yl]-6-(2-methyisulfanylpyrimidin-4-yl)-2-(2-trimethylsilanylethoxymethyl)-2H-pyridazin-3-one which is reacted further in analogy to example 15.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:26](=[O:29])[NH:27][CH3:28])[CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:10][CH:9]1[CH2:30][CH2:31][OH:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:26](=[O:29])[NH:27][CH3:28])[CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:10][CH:9]1[CH2:30][CH2:31][O:32][C:33](=[O:35])[CH3:34])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)OC(C)(C)C)C(CCO)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)OC(C)(C)C)C(CCOC(C)=O)C1

Procedure:
A solution of 2-(2-hydroxyethyl)-4-(1-methylcarbamoyl-2-naphthalen-2-ylethyl)piperazine-1-carboxylic acid tert-butyl ester, 60, (4.4 g, 10 mmol), acetic anhydride (13 mL), pyridine (1 mL) and N,N-dimethylaminopyridine (0.25 g) in dichloromethane (50 mL) is stirred for 1.5 hours. The solution is then extracted with water and 1N HCl. The organic phase is dried, concentrated in vacuo, and the resulting crude product purified over silica gel (EtOAc/hexane 1:3 then 1:1) to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[F:23][C:24]([F:33])([F:32])[C:25]1[O:29][N:28]=[C:27]([CH2:30][NH2:31])[CH:26]=1>>[F:33][C:24]([F:23])([F:32])[C:25]1[O:29][N:28]=[C:27]([CH2:30][NH:31][C:20]([C:10]2[N:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:9]=2)=[O:22])[CH:26]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Reactant: NCc1cc(C(F)(F)F)on1
Product: O=C(NCc1cc(C(F)(F)F)on1)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1

Procedure:
The title compound was synthesized in analogy to Example 41 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid (example M) and 5-trifluoromethyl-isoxazol-3-methanamine (example BF) as starting materials; LC-MS (UV peak area/ESI), 94.3%, 481.3 (M+H)+.
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[C:14]([F:25])([F:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C:14]([F:25])([F:24])[CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(F)(F)CCCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(F)(F)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and using 5-(4-bromo-phenyl)-4-(1,1-difluoro-4-phenyl-butyl)-3-methyl-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.