Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([CH2:10]O)=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CN(C)C=O.S(Cl)([Cl:19])=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(Cl)(Cl)Cl>[C:1]([C:4]1[C:5]([CH2:10][Cl:19])=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)c1cccnc1CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cccnc1CCl
Reaction time: 1 h

Procedure:
A mixture of 3-acetyl-2-hydroxymethylpyridine(0.2 g) in dichloromethane(10 ml) was treated with catalytic amount of N,N-dimethylformamide. To the mixture was added dropwise a solution of thionyl chloride (1 ml) in dichloromethane (2 ml) at ca. 5° C. in an ice-water bath. The mixture was stirred for 1 hour under the same condition, and then at room temperature for 40 minutes. To the mixture was added carefully dropwise saturated sodium carbonate aqueous solution under stirring in an ice-water bath. The mixture was taken up with chloroform and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 3-acetyl-2-chloromethylpyridine (0.11 g) as a black oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.N(S([O-])(=O)=O)(S([O-])(=O)=[O:16])[O].[K+].[K+]>CO.OP([O-])(O)=O.[K+].O>[OH:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2](=[O:1])[CH:3]=[CH:4][C:5]2=[O:16]
Reactant: Oc1ccc2c(O)cccc2c1
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C1C=CC(=O)c2cc(O)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,6-Dihydroxynaphtalene from Aldrich (3.0 g, 18.7 mmol) was dissolved in a mixture of MeOH (150 mL), KH2PO4-solution (0.167 M, 150 mL) and water (200 mL), and Potassium nitrosodisulfonate (Fremy's salt) (12.0 g, 44.7 mmol) was added. The mixture was stirred at room temperature 2 h. The reaction mixture was put in refrigerator and then filtered. Yield 3.0 g. 1H NMR (400 MHz, CD3OD) δ 6.90 (d, 2 H), 7.12 (dd, 1 H), 7.34 (d, 1 H), 7.92 (d, 1 H).
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:3]([C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH:11]=1)[OH:10])[CH3:4].[CH2:18]=O.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>>[CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8]([CH2:18][N:22]([CH2:23][CH3:24])[CH2:20][CH3:21])=[C:9]([CH:11]=1)[OH:10])[CH3:4]
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Reactant: C=O
Reactant: CCNCC
Product: CCCCCC(C)C(C)c1cc(O)c(CN(CC)CC)c(O)c1

Procedure:
Using the procedure of Example 2, 5-(3-methyl-2-octyl) resorcinol is reacted with formaldehyde and diethylamine to obtain 5-(3-methyl-2-octyl)-2-diethylaminomethyl resorcinol.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8](=[N:10][OH:11])[CH3:9].[CH3:12][C:13]1[C:14]([C@H:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[N:20]2[CH2:32][C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35](F)[CH:34]=2)=[N:15][CH:16]=[CH:17][CH:18]=1>CN(C=O)C>[CH3:31][C:30]1[C:25]([C@H:21]2[CH2:22][CH2:23][CH2:24][C@@H:19]([C:14]3[C:13]([CH3:12])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:20]2[CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:37]#[N:38])=[C:39]([O:11][N:10]=[C:8]([CH3:9])[CH3:7])[CH:40]=2)=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)=NO
Reactant: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1Cc1ccc(C#N)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=NOc1cc(CN2[C@@H](c3ncccc3C)CCC[C@H]2c2ncccc2C)ccc1C#N
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a solution of potassium tert-butoxide (0.140 g, 1.25 mmol) in dry DMF (5 mL) was added acetone oxime (0.0877 g, 1.20 mmol), and the mixture was stirred for 30 min. A solution of 4-((2′R,6′S)-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-2-fluoro-benzonitrile (0.400 g, 1.00 mmol) in dry DMF (5 mL) was then added, and the mixture was stirred overnight. The solvent was then removed by evaporation under vacuum, and saturated aqueous NaHCO3 (10 mL) was added. The mixture was extracted with EtOAc (3×30 mL), and the extract was dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified on silica gel column (1000:25:1 CH2Cl2/CH3OH/NH4OH), affording 4-((2′R,6′S)-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-2-isopropylideneaminooxy-benzonitrile as a pale yellow solid (0.311 g, 69%). 1H NMR (CDCl3) δ 1.65-1.75 (m, 3H), 2.06 (s, 3H), 2.07 (s, 3H), 2.09-2.14 (m, 1H), 2.20-2.40 (m, 2H), 2.45 (s, 6H), 3.58 (s, 2H), 4.19 (s, 1H), 4.23 (s, 1H), 6.14 (d, 1H, J=7.8 Hz), 6.68 (s, 1H), 6.91-6.96 (m, 3H), 7.22 (d, 2H, J=7.2 Hz), 8.35 (d, 2H, J=3.9 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14]SC1=S)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20]CCN>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:15][CH2:14][CH2:20][CH2:19][CH2:18][NH2:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCCCN
Reactant: O=C(OCc1ccccc1)N1CCSC1=S
Solvent: ClCCl
Product: NCCCCCNC(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 63.1 %

Procedure:
17.84 g of the product of Step A in solution in 100 ml of methylene chloride were added to 16.4 g of 1,5-diamino-pentane in solution in 85 ml of methylene chloride and after stirring for 3 hours and concentration to dryness, the residue was chromatographed (eluant: methanol-ammonia 99-1) to obtain 10.5 g of the expected product.
Reaction SMILES: C([O:8][CH2:9][C:10]1([C:34]([OH:36])=[O:35])[CH:15]2[CH2:16][CH:12]3[CH:13]([CH:14]2[C:17]2[NH:25][C:24]4[C:23](=[O:26])[N:22]([CH2:27][CH2:28][CH3:29])[C:21](=[O:30])[N:20]([CH2:31][CH2:32][CH3:33])[C:19]=4[N:18]=2)[CH:11]13)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[O:30]=[C:21]1[N:20]([CH2:31][CH2:32][CH3:33])[C:19]2[N:18]=[C:17]([CH:14]3[CH:13]4[CH:11]5[CH:12]4[CH2:16][CH:15]3[C:10]5([CH2:9][OH:8])[C:34]([OH:36])=[O:35])[NH:25][C:24]=2[C:23](=[O:26])[N:22]1[CH2:27][CH2:28][CH3:29]
Reactant: CCCn1c(=O)c2[nH]c(C3C4C5CC3C(COCc3ccccc3)(C(=O)O)C54)nc2n(CCC)c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCn1c(=O)c2[nH]c(C3C4C5CC3C(CO)(C(=O)O)C54)nc2n(CCC)c1=O

Procedure:
3-Benzyloxymethyl-5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-tricyclo[2.2.1.02,6]heptane-3-carboxylic acid (50 mg) was hydrogenated in ethyl acetate using Pd/C 5% under 1 atm of H2 overnight. The catalyst was filtered through silica eluting with 10% MeOH:CHCl3. Yield 31 mg. Mass (ES+ 403).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16]C)=[O:15])[CH:6]=[CH:5]2.O.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([OH:16])=[O:15])[CH:6]=[CH:5]2
Reactant: COC(=O)c1ccccc1-c1ccc2cc(C)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc2nc(-c3ccccc3C(=O)O)ccc2c1
Temperature: 60 °C

Procedure:
7.08 g (25.5 mmol) of methyl 2-(6-methylquinolin-2-yl)benzoate obtained in Example 5 was suspended in 75 ml of methanol and 35 ml of water in which 3.06 g (76.6 mmol) of sodium hydroxide was dissolved was added thereto. After heating at 60° C. for 3 hours, the reaction mixture was concentrated under reduced pressure and 200 ml of water was added to the residue. The resulting solution was acidified with 2N hydrochloric acid and the thus formed precipitate was collected by filtration. The precipitate was washed with water and dried to obtain 2-(6-methylquinolin-2-yl)benzoic acid. NMR (270 MHz, CD3OD):
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([CH3:11])[CH:3]=1.[Br:12]Br>C(O)(=O)C.O>[Br:12][C:3]1[C:4]([CH3:11])=[N:5][CH:6]=[C:7]([C:2]=1[OH:1])[C:8]([OH:10])=[O:9]
Reactant: BrBr
Reactant: Cc1cc(O)c(C(=O)O)cn1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ncc(C(=O)O)c(O)c1Br
Temperature: 60 °C
Reaction time: 5 h
Yield: 98.1 %

Procedure:
4-Hydroxy-6-methylnicotinic acid 19 (95.6 g, 0.625 mol) was dissolved in acetic acid (950 ml) and water (190 ml), and bromine (39 ml, 0.750 mol) was added over 15 minutes. After the solution was stirred at 60° C. for 5 hours, the solvent was distilled off under reduced pressure, methanol (200 ml) was added and, crystals were collected by filtration. The solution was distilled off under reduced pressure, methanol was added again to the residue, and crystals were collected by filtration. A total of 142.2 g (98%) of 5-bromo-4-hydroxy-6-methylnicotinic acid 20 was obtained as a colorless crystal.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[CH:20][C:19]([C:22]5[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:28]=[CH:29][N:30]=[CH:31][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:20][N:21]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:28]=[CH:29][N:30]=[CH:31][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1=C(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CCNC1
Agent: [Pd]
Solvent: CO
Product: c1cc2c3cnc(Nc4ccc(C5CCNCC5)cn4)nc3n(C3CCCC3)c2cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
To a solution of compound 412 (90 mg, 0.22 mmol) in methanol (5 mL) was added Pd/C (10% wt, dry basis) (50 mg). The reaction was stirred at room temperature with H2 ballon for 3 hours. Insolubles were removed by filtration. The filtrate was purified using prep-HPLC to give compound 413 as a yellow solid (30 mg, 33%). 1H NMR (500 MHz, DMSO-d6) δ ppm 10.98 (1 H, br. s.), 9.64 (1 H, s), 9.42 (1 H, s), 8.83 (1 H, dd, J=3.5, 1.1 Hz), 8.71 (1 H, d, J=6.1 Hz), 8.55-8.68 (2 H, m), 8.30 (1 H, d, J=2.7 Hz), 8.17 (1 H, d, J=8.6 Hz), 7.85 (1 H, dd, J=8.8, 2.4 Hz), 5.41 (1 H, dq, J=8.9, 8.8 Hz), 3.43 (2 H, dd, J=10.4, 2.3 Hz), 2.96 (3 H, tt, J=12.1, 3.7 Hz), 2.42 (2 H, m), 2.00-2.08 (4 H, m), 1.68-1.92 (2H, m); LCMS-ESI (POS), M/Z, M+1: Found 414.2, Calculated 414.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].Br[CH2:18][CH2:19][CH2:20][CH2:21]Br.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: BrCCCCBr
Reactant: CCOC(=O)c1oc2cccc(N)c2c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1oc2cccc(N3CCCC3)c2c1C
Temperature: 110 °C
Yield: 48 %

Procedure:
To 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (500 mg, 2.28 mmol, 1 eq., prepared according to Example 60, Step 1) were added toluene (3 mL), 1,4-dibromobutane(272 uL, 2.28 mmol, 1 eq.), and N,N-diisopropylethylamine (953 uL, 5.47 mmol, 2.4 eq.) under argon in a sealed tube and the mixture was heated at 110° C. for 16 hours. After work-up and flash column chromatography, 3-methyl-4-pyrrolidin-1-yl-benzofuran-2-carboxylic acid ethyl ester was obtained in 48% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (t, J=7.1 Hz, 3 H) 1.9 (m, 4 H) 2.7 (s, 3 H) 3.1 (m, 4 H) 4.3 (q, J=7.1 Hz, 2 H) 6.8 (dd, J=8.0, 0.6 Hz, 1 H) 7.2 (dd, J=8.3, 0.8 Hz, 1 H) 7.3 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20]2[N:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1>CCO.C1COCC1.[Ni]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[N:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: O=C1CCc2ccc(C=CCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C1CCc2ccc(CCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Yield: 85.1 %

Procedure:
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (1.85 g, 4.16 mmol) was hydrogenated using Ra—Ni (1 g) in EtOH/THF (50 mL) for 1.4 h. The reaction was filtered and concentrated to give a solid. Recrystallization from hot CH3CN gave the title compound as a white solid (1.58 g, 3.54 mmol, 85%). MS: APCI: M+1: 447.1 (Exact Mass: 446.16).
Reaction SMILES: [OH:1][C:2]1[CH:9](C(OC)=O)[CH:8]2[CH2:14][CH:4]([CH:5](C(OC)=O)[C:6]([OH:19])=[C:7]2C(OC)=O)[C:3]=1C(OC)=O.Cl.O.C(O)(=O)C>CC(C)=O>[CH:4]12[CH2:14][CH:8]([CH2:7][C:6](=[O:19])[CH2:5]1)[CH2:9][C:2](=[O:1])[CH2:3]2
Reactant: COC(=O)C1=C(O)C(C(=O)OC)C2CC1C(C(=O)OC)C(O)=C2C(=O)OC
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC2CC(=O)CC(C1)C2
Temperature: 130 °C
Yield: 85.4 %

Procedure:
A suspension of tetramethyl 3,7-dihydroxybicyclo[3.3.1]nona-2,6-diene-2,4,6,8-tetracarboxylate (19.2 g, 50 mmol) in an aqueous solution of 10 M HCl (50 mL), water (50 mL) and glacial acetic acid (100 mL) was heated at 130° C. for 6 h. After cooling at room temperature, the reaction mixture was poured onto crushed ice (200 mL) and extracted with DCM (4×200 mL). The combined organic layers were washed with an aqueous saturated solution of NaHCO3. The organic layer was dried over MgSO4, and concentrated under reduced pressure to give an orange solid. This crude product was dissolved in acetone and the salts which precipitated were filtered. Concentration of the filtrate and washing with Et2O afford the desired diketone (1) as a white solid (6.5 g, 85%).
Reaction SMILES: [CH2:1](/C(/C)=C/CN1CCOCC1)C.[CH2:13]([OH:18])[C:14]#[C:15][CH2:16][CH3:17].COCCO[AlH2-]OCCOC.[Na+].[I:31]I>C1COCC1.C1(C)C=CC=CC=1.CCOCC>[CH3:1][CH:14]([CH:15]=[CH:16][CH3:17])[CH2:13][OH:18].[I:31][C:15]([CH2:16][CH3:17])=[CH:14][CH2:13][OH:18]
Reactant: CCC#CCO
Reactant: II
Reactant: CC/C(C)=C/CN1CCOCC1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC=CC(C)CO
Product: CCC(I)=CCO

Procedure:
Preparation of (E)-N-(3-Ethyl-3-methyl-2-propenyl)-morpholine (17): 2-Methyl-3-penten-1-ol was prepared using a modification of the procedure outlined by Corey and coworkers (Corey et al. (1973)Tetrahedron Lett. 18:1611). To a solution of 2-pentyn-1-ol (2.5 mL, 27 mmol) in THF (100 mL) was added Red-Al (8.1 mL of a 3.5 M solution in toluene, 28 mmol). The resulting solution was warmed to reflux for 3.5 h and then cooled to −78° C., before a solution of iodine (20.5 g, 81.0 mmol) in THF (50 mL) was added dropwise by syringe. The resulting solution was then allowed to warn to rt before Et2O (200 mL) was added, and the reaction mixture washed with 5% Na2SO4 (3×200 mL), dried (Na2SO4), and concentrated to afford 3-iodo-2-penten-1-ol as a crude product that was used without further purification. To a solution of copper(I)iodide (20.1 g, 0.11 mol) and methyl lithium (162 mL of a 1.3 M solution in Et2O, 0.21 mol) in Et2O (60 mL) at 0° C. was added a solution of the crude 3-iodo-2-penten-1-ol. The reaction mixture was stirred at 0° C. for 62 h and then washed with sat. aq. NH4Cl (3×200 mL), dried (Na2SO4), and concentrated to provide 2-methyl-3-penten-1-ol in 91% yield (2.1 g, 21 mmol) as a pure oil by 1H NMR analysis. Spectroscopic data of this material were in complete agreement with reported literature values. Normant et al. (1973) Tetrahedron Lett. 26:2407.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>[Pd]>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2N)n1
Reactant: Brc1cccnc1
Agent: [Pd]
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2)n1

Procedure:
The title compound, was prepared in accordance with the general method of example 4, step 2 using 2-amino-4-methylthiazole instead of 2-chloro-4-aminopyridine to yield 6-Methyl-2-(4-methyl-thiazol-2-ylcarbamoyl)-pyridin-3-yl]-carbamic acid tert-butyl ester as a light yellow solid. MS (ISP): m/e=349.0 (M+H+). Boc-deprotection as described in example 4 step 3 yielded 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide as an off-white solid, MS (ISP): m/e=249.4 (M+H+). Palladium catalysed arylation with 3-Bromopyridine as described in example 4 step 4 yielded the final product as a yellow solid, MS (ISP): m/e=326.0 (M+H+).
Reaction SMILES: [N:1]([CH:4]([CH2:13][CH2:14][CH3:15])[CH:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7])=[N+]=[N-]>[Pd].CO>[NH2:1][CH:4]([CH2:13][CH2:14][CH3:15])[CH:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:10][CH2:11]1)=[O:7]
Reactant: CCCC(N=[N+]=[N-])C(O)C(=O)NC1CC1
Agent: [Pd]
Solvent: CO
Product: CCCC(N)C(O)C(=O)NC1CC1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
Compound 40 (15.1 g, 71.3 mmol), Pd/C (1.5 g, 5 wt %, 50% wet) and MeOH (150 mL) was charged to a pressure vessel then purged with nitrogen gas for 5 min. The vessel was sealed, pressurized to 1 bar with nitrogen gas then released three times. The same was repeated with hydrogen gas. After the third purge with hydrogen the vessel was charged with 3 hydrogen at a pressure of 3 bars. The reaction was agitated and a temperature of 25±5° C. was maintained for 14 hours after which time the reaction mixture was filtered through a pad of Celite 545 and the solvent removed to provide crude compound 41 (8.48 g) as a yellow solid. To this material was added acetonitrile (ACN; 150 mL) and the reaction heated to reflux at which time all of the solids dissolved. The mixture was then cooled to 25±5° C. and the white needles formed were collected, washed with cold ACN and dried to provide purified compound 41. 1H NMR (500 MHz, d6-DMSO): 8.05 (br s, 3H), 4.20 (d, J=3.2, 1 H), 3.42-3.34 (m, 1H), 2.71-2.65 (m, 1H), 1.51-1.20 (m, 4H), 1.17 (d, J=6.5 Hz, 1H), 0.83 (t, J=7.6 Hz, 3H), 0.64-0.60 (m, 2H), 0.54-0.49 (m, 2H).
Reaction SMILES: [C:1](#[N:5])/[CH:2]=[CH:3]/[CH3:4].O1CCCC1.[O:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:22]([N+:32]([O-:34])=[O:33])[CH:21]=2)[C:18]#[N:19])[CH2:13][CH2:12]1.[OH-].[K+]>O.CO>[O:29]1[CH2:30][CH2:31][N:26]([C:23]2[CH:24]=[CH:25][C:20]([C:17]([C:18]#[N:19])([N:14]3[CH2:15][CH2:16][O:11][CH2:12][CH2:13]3)[CH:3]([CH3:4])[CH2:2][C:1]#[N:5])=[CH:21][C:22]=2[N+:32]([O-:34])=[O:33])[CH2:27][CH2:28]1
Reactant: C/C=C/C#N
Reactant: N#CC(c1ccc(N2CCOCC2)c([N+](=O)[O-])c1)N1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(CC#N)C(C#N)(c1ccc(N2CCOCC2)c([N+](=O)[O-])c1)N1CCOCC1
Reaction time: 6 h

Procedure:
A solution of 8.0 parts of crotononitrile in 20 parts by volume of tetrahydrofuran is added to a stirred mixture of 16.5 parts of α-morpholino-α(4-morpholino-3-nitrophenyl)-acetonitrile in 150 parts by volume of tetrahydrofuran and 1.5 parts of potassium hydroxide in 5 parts by volume of methanol at room temperature under an atmosphere of nitrogen. The reaction mixture is stirred for a further 6 hours, diluted with 500 parts by volume of water and extracted with 4×250 parts by volume of ethyl acetate. The combined organic extracts are dried over magnesium sulphate and concentrated under vacuum. The resulting crude product is triturated with a mixture of 50 parts by volume of ethyl acetate and hexane. The solid product is collected, washed with ethyl acetate and dried at 80° under vacuum to give 4-(4-morpholino-3-nitrophenyl)-4-(cyano)-4-(morpholino)-3-methylbutyronitrile having melting point 175°-177° C.
Reaction SMILES: [F:1][C:2]1[C:3]([O:33]C)=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]([NH:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]3[C:15]=1[CH:16]=[N:17][C:18]([CH3:25])=[N:19]3)[C:7]([C:27]([F:30])([F:29])[F:28])([OH:26])[CH2:6][C:5]2([CH3:32])[CH3:31].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[CH:8]([NH:13][C:14]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]4[C:15]=3[CH:16]=[N:17][C:18]([CH3:25])=[N:19]4)[C:7]([C:27]([F:28])([F:29])[F:30])([OH:26])[CH2:6][C:5]([CH3:31])([CH3:32])[C:4]=2[C:3]=1[OH:33]
Reactant: COc1c(F)c(C)cc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1ccc(F)c2nc(C)ncc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ncc2c(NC3c4cc(C)c(F)c(O)c4C(C)(C)CC3(O)C(F)(F)F)ccc(F)c2n1
Temperature: 2.5 °C
Yield: 61.5 %

Procedure:
111.2 mg (0.231 mmol) of (rac.) 6-fluoro-1-[(8-fluoro-2-methylquinazolin-5-yl)-amino]-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is mixed at 0° C. with 3.2 ml of a 1 molar solution of boron tribromide in dichloromethane, and it is stirred for one and one-half hours at 0 to 5° C. At 0° C., the now carefully saturated sodium bicarbonate solution is added in drops. After 10 minutes of vigorous stirring at room temperature, the batch is extracted three times with ethyl acetate. The organic phases are dried, and the residue is chromatographed on a Flashmaster after the solvent is spun off. 66.4 mg (61.5%) of the desired compound is isolated.
Reaction SMILES: [H-].[Na+].FC(F)(F)[C:5]([NH:7][S:8]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=O.C[N:23]([CH3:26])[CH:24]=[O:25]>>[C:11]1([C@H:26]2[CH2:5][N:7]([S:8]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH2:15][CH2:14]4)(=[O:10])=[O:9])[C:24](=[O:25])[NH:23]2)[CH:12]=[CH:13][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C)C=O
Reactant: O=C(NS(=O)(=O)c1ccc2c(c1)CCN2)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: O=C1N[C@@H](c2ccccc2)CN1S(=O)(=O)c1ccc2c(c1)CCN2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
Sodium hydride (60% oily, 475 mg, 11.88 mmol) was suspended in 15 m of dimethylformamide and cooled down to 0° C. To the suspension was added N-trifluoroacetyl-indoline-5-sulfonamide (0.832 g, 2.97 mmol) prepared in Preparation 7 in several portions, and then the mixture was stirred at 0° C. for 10 min. Then, (S)-2-N-phenoxycarbonylamino-2-phenylethylmethane-sulfonate (1.0 g, 2.97 mmol) prepared in Preparation 6 was added thereto. The reaction mixture was stirred at 0° C. for 3 hours and further stirred at room temperature for 1 hour. After confirming the completion of reaction by TLC, the reaction mixture was poured into 30 m of ice. The resulting precipitate was collected and dried to afford 0.72 g of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:10]2)(=[O:3])[CH3:2].[CH2:22](Br)[C:23]#[CH:24]>>[C:1]([N:4]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[CH2:10]2)[CH2:24][C:23]#[CH:22])(=[O:3])[CH3:2]
Reactant: CCCN(CCC)C1CCc2c(cccc2NC(C)=O)C1
Reactant: C#CCBr
Product: C#CCN(C(C)=O)c1cccc2c1CCC(N(CCC)CCC)C2

Procedure:
Starting from 2.88 g (0.010 mol) of 5-acetylamino-2-di-n-propylamino-tetraline (Example 4.3.4) and 1.43 g (0.012 mol) of propargylbromide the title compound is obtained analogously to Example 4.7.1 in the form of a non-crystallising, extremely viscous oil in a yield of 2.33 g (71.4% of theory) and with an Rf value of 0.66 (solvent mixture as specified in 4.7.1).