Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[C:7]([CH2:13]O)[CH:6]=1)[CH:2]=[CH2:3].CCN(CC)CC.C[S:23](Cl)(=O)=O.[S-2].[Na+].[Na+]>C(Cl)Cl.O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]2[CH2:11][S:23][CH2:13][C:7]=2[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(CO)c(CO)c1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOc1ccc2c(c1)CSC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
Crude diol from stage (i) (3.5 g, 18 mmol) was dissolved in DCM (60 mL) and treated with Et3N (10 mL, 72 mmol) and the solution was cooled to 0° C. Methanesulfonyl chloride (4.2 mL, 54 mmol) was added dropwise and the solution was stirred for 1 h being allowed to reach room temperature. The reaction was then quenched by the addition of water followed by 2M HCl (50 mL). The DCM layer was separated and the aqueous layer was re-extracted with DCM (50 mL). The combined organic fractions were washed with water (50 mL), dried (MgSO4) and concentrated to a volume of ca. 30 mL. Benzyltriethylammonium chloride (1 g) was added followed by a solution of sodium sulfide (5 g, 91 mmol) in water (50 mL). The mixture was stirred rapidly under a nitrogen atmosphere for 15 h. The organic layer was separated and the aqueous layer was re-extracted with DCM (50 mL). The combined organic layers were dried (MgSO4) and evaporated to a yellow oil. Flash chromatography afforded two fractions; the first was pure product and the second product contaminated with dimeric material. Trituration of the second fraction caused crystallisation of the dimeric material which was removed by filtration. The filtrate was combined with the first chromatography fraction to afford the desired product (800 mg, 23%); δH (CDCl3, 400 MHz) 4.16 (2H, s), 4.19 (2H, s), 4.48 (2H, m), 5.26 (1H, d), 5.37 (1H, d), 5.95-6.06 (1H, m), 6.74 (2H, m), 7.09 (1H, d).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:41]=[C:42]([CH2:44][O:45]C(=O)C)[CH:43]=1)[O:9][CH2:10][CH2:11][C:12]1([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([N:26]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)[C:27]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[O:28])[CH2:22][CH2:21]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:41]=[C:42]([CH2:44][OH:45])[CH:43]=1)[O:9][CH2:10][CH2:11][C:12]1([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([N:26]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)[C:27]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[O:28])[CH2:22][CH2:21]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(=O)OCc1cc(COC(C)=O)cc(OCCC2(CCN3CCC(N(C(=O)c4ccco4)c4ccc(C)cc4)CC3)CCCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCOc4cc(CO)cc(CO)c4)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a solution of N-[1-[2-[1-[2-[3,5-bis(acetoxymethyl)phenoxy]ethyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide (276 mg) dissolved in methanol (4 mL) was added potassium carbonate (11 mg). The solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the solution, and it was extracted with chloroform-ethanol (80:20). The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was then concentrated under reduced pressure to give the title compound (228 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:20][CH3:21])[C:15]([O:22][CH3:23])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[C:26](OC(=O)C)(=O)[CH3:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9]3[C:18]4[C:13]([N:12]=[CH:11][N:10]=3)=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[C:17]=4[N:19]=[C:26]2[CH3:27])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3)c2c(N)c1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2ncnc3c2c(c1OC)N=C(C)N3c1cccc(Cl)c1

Procedure:
A solution of N4-(3-chloro-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine (0.2 g, 0.60 mmol) (from Example 11, Step B supra) in acetic anhydride (3 mL) was heated at 150° C. for 2 hours. Aqueous NaOH solution was added to the reaction mixture to a pH 10–12. The solution was extracted with chloroform (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:1:0.05) as eluent to give the desired 3-(3-chloro-phenyl)-8,9-dimethoxy-2-methyl-3H-1,3,4,6-tetraaza-phenalene as a yellow solid. (Yield 90 mg, 42%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.C(N(CC)CC)C.C([NH:21][C:22](=[CH2:27])[C:23]([O:25][CH3:26])=[O:24])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[F:10][C:7]1[CH:6]=[C:3]2[C:2]([CH:27]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[N:21]=[CH:4]2)=[CH:9][CH:8]=1
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: O=Cc1cc(F)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2ccc(F)cc2cn1
Temperature: 110 °C
Yield: 39.8 %

Procedure:
A sealed tube was charged with 2-bromo-5-fluorobenzaldehyde (300 mg, 1.47 mmol), dry dimethylformamide (1.5 ml), triethylamine (0.7 ml, 5.02 mmol), methyl 2-acetamidoacrylate (273 mg, 1.91 mmol), tris-o-tolyl-phosphine (89 mg, 0.29 mmol) and palladium acetate (33 mg, 0.14 mmol). The solution was degassed with Argon for 10 min. and then warmed at 110° C. for 4.5 hours. The mixture was cooled to room temperature and poured onto an aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography over silica gel (gradient cyclohexane/dichloromethane: 0-80%) to yield methyl 7-fluoro-isoquinoline-3-carboxylate (120 mg, 39%) as beige solid.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)=O.[NH:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.C(N(CC)CC)C>C(#N)C>[C:27]([O:26][C:25]([NH:24][CH:21]1[CH2:20][CH2:19][N:18]([CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:23][CH2:22]1)=[O:31])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(NCCBr)OCc1ccccc1
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(CCNC(=O)OCc2ccccc2)CC1
Yield: 77.5 %

Procedure:
Into a solution of 2-bromoethylamine hydrobromide (5.0 g) and potassium carbonate (5.06 g) in THF/water (20/5 ml) was added at 0° C. benzyl chloroformate (4.16 g), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to obtain benzyl 2-bromoethylcarbamate (7.32 g). A solution of benzyl 2-bromoethylcarbamate (7.23 g), tert-butyl 4-piperidinyl-carbamate formic acid salt (4.63 g) and triethylamine (8 ml) in acetonitrile (30 ml) was heated at reflux for 24 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to purification using column chromatography (ethyl acetate/hexane) to obtain benzyl 2-[4-(tert-butoxycarbonylamino)piperidin-1-yl]ethylcarbamate (5.5 g) as colorless crystals.
Reaction SMILES: [OH:1][C@H:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:21][C:22]1[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[C:24]([CH:30]2[CH2:32][O:31]2)[N:23]=1>>[OH:31][CH:30]([C:24]1[N:23]=[C:22]([CH3:21])[C:27]([C:28]#[N:29])=[CH:26][CH:25]=1)[CH2:32][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][C@H:2]([OH:1])[C:10]2[C:11]([CH3:20])=[C:12]3[C:13](=[CH:18][CH:19]=2)[C:14](=[O:17])[O:15][CH2:16]3)[CH2:5][CH2:6]1
Reactant: Cc1c([C@@H](O)CN2CCNCC2)ccc2c1COC2=O
Reactant: Cc1nc(C2CO2)ccc1C#N
Product: Cc1nc(C(O)CN2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC2)ccc1C#N

Procedure:
6-[1-Hydroxy-2-[4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-2-methyl-pyridine-3-carbonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 58 starting from 5-[(1R)-1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1 (3H)-one and 2-methyl-6-(oxiran-2-yl)pyridine-3-carbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](Cl)=[O:6].[NH2:13][C:14]([CH3:30])([CH2:17][N:18]1[CH:26]=[C:25]2[C:20]([C:21]([Cl:29])=[C:22]([Cl:28])[CH:23]=[C:24]2[Cl:27])=[N:19]1)[C:15]#[N:16]>C1COCC1>[C:15]([C:14]([NH:13][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([F:1])[CH:3]=1)([CH3:30])[CH2:17][N:18]1[CH:26]=[C:25]2[C:20]([C:21]([Cl:29])=[C:22]([Cl:28])[CH:23]=[C:24]2[Cl:27])=[N:19]1)#[N:16]
Reactant: COc1ccc(C(=O)Cl)cc1F
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NC(C)(C#N)Cn2cc3c(Cl)cc(Cl)c(Cl)c3n2)cc1F

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 3-fluoro-4-methoxybenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (6.6 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=455, RT=0.69 min.
Reaction SMILES: F[C:2]1[CH:3]=C[C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)=[N:6][CH:7]=1.BrC1C=CC(F)=C[N:19]=1>>[N:6]1[CH:7]=[CH:2][CH:3]=[N:19][C:5]=1[N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[N:10]=[CH:9]1
Reactant: Fc1ccc(Br)nc1
Reactant: Fc1ccc(-n2cnc3cnccc32)nc1
Product: c1cnc(-n2cnc3cnccc32)nc1

Procedure:
Intermediate 5 was prepared in a manner analogous to Intermediate 1, substituting 2-bromopyrimidine for 2-bromo-5-fluoropyridine. MS (ESI): mass calculated for C10H7N5, 198.07. m/z found 199.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1(/[CH:17]=[CH:18]/[C:19](/[CH2:26][CH2:27][CH3:28])=[CH:20]\[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]([CH3:15])([CH3:14])[CH2:12][C:5]2(OC(C)C(C)[O:6]2)[CH:4]=[C:3]1[CH3:16].O>CC(C)=O.Cl>[OH:1][C:2]1(/[CH:17]=[CH:18]/[C:19](/[CH2:26][CH2:27][CH3:28])=[CH:20]\[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]([CH3:15])([CH3:14])[CH2:12][C:5](=[O:6])[CH:4]=[C:3]1[CH3:16]
Reactant: CCCC(=C/C(=O)OCC)/C=C/C1(O)C(C)=CC2(CC1(C)C)OC(C)C(C)O2
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCCC(=C/C(=O)OCC)/C=C/C1(O)C(C)=CC(=O)CC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl (2Z)-3-[(E)-2-(8-hydroxy-2,3,7,9,9-pentamethyl-1,4-dioxaspiro[4.5]-dec-6-en-8-yl)vinyl]hex-2-enoate (180 mg, 0.46 mmol) was dissolved in acetone (5 ml) under argon in a round-bottom flask, and 3 drops of conc. hydrochloric acid were added. The resulting reaction solution was stirred at room temperature for 30 minutes, and water was then added. After removing acetone under reduced pressure, the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By final column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), ethyl (2Z)-3-[(E)-2-(1-hydroxy-2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl)vinyl]hex-2-enoate (114 mg, 74% of theory) was obtained in the form of a colorless oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.77 (d, 1H), 6.15 (d, 1H), 6.05 (s, 1H), 5.93 (s, 1H), 4.19 (q, 2H), 2.96 (br. s, 1H, OH), 2.47 (d, 1H), 2.31 (d, 1H), 2.24 (t, 2H), 1.92 (s, 3H), 1.58 (m, 2H), 1.27 (t, 3H), 1.24 (s, 3H), 1.12 (s, 3H), 0.92 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:28])[C:9](=[O:27])[C:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:3]=1.[H-].[Na+].C1(S(Cl)(=O)=O)C=CC=CC=1.O>CN(C)C=O>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:18]=[C:13]([C:10]([CH3:12])([CH3:11])[C:9]([N:8]([C:5]2[CH:6]=[N:7][C:2]([N:1]=[CH:5][N:8]([CH3:28])[CH3:9])=[CH:3][C:4]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH3:28])=[O:27])[CH:14]=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=1
Reactant: Cc1ccccc1-c1cc(N)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1cc(N=CN(C)C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of 100 mg (0.2 mmol) N-(6-amino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide (Example 73) in 4 ml N,N-dimethylformamide was added at 0° C. 11 mg (0.252 mmol) sodium hydride as a 60% dispersion in oil and the mixture was stirred for 30 min without cooling. Then 28 il (0.218 mmol) benzenesulfonyl chloride were added at 0° C. and the solution was stirred over night at room temperature. The reaction mixture was added to water and extracted with ethyl acetate (3×10 ml). The combined extracts were washed with water (3×20 ml), brine (20 ml), dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 51 mg (46%) of the title compound as a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH:28]4[CH2:30][O:29]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN1CCCC1=O>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH:28]([OH:29])[CH2:30][NH:38][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC4CO4)cc3)cc2)CC1
Reactant: NCc1ccccc1
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(O)CNCc4ccccc4)cc3)cc2)CC1
Temperature: 85 °C

Procedure:
1-[4′-(3-Methyl-4-oxiranylmethyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.160 g, 0.40 mmol) was dissolved in N-methylpyrrolidone (5 mL) then benzylamine (0.130 mL, 1.2 mmol) was added. The reaction was heated to 85° C. overnight then cooled and submitted to standard aqueous workup to yield the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=3)[CH:12]=2)=[CH:7][CH:6]=1.[C:28]([OH:33])(=O)[C:29]([CH3:31])=[CH2:30]>>[CH3:30][C:29](=[CH2:31])[C:28]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[C:15]([O:17][C:28](=[O:33])[C:29]([CH3:31])=[CH2:30])[CH:14]=[C:13]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:31])=[CH2:30])=[CH:20][CH:19]=3)[CH:12]=2)=[CH:9][CH:10]=1)=[O:33]
Reactant: C=C(C)C(=O)O
Reactant: OCCCc1ccc(-c2cc(O)cc(-c3ccc(CCCO)cc3)c2)cc1
Product: C=C(C)C(=O)OCCCc1ccc(-c2cc(OC(=O)C(=C)C)cc(-c3ccc(CCCOC(=O)C(=C)C)cc3)c2)cc1

Procedure:
In analogy to step 2 of example 1, 4,4″-bis-(3-hydroxy-propyl)-[1,1′;3′,1″]terphenyl-5′-ol and methacrylic acid are reacted to give 2-methyl-acrylic acid-4,4″-bis-[3-(2-methyl-acryloyloxy)-propyl]-[1,1′;3′,1″]terphenyl-5′-yl ester as colourless oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:18]([CH2:20][C:21]([O:23][CH:24]1[CH2:29][CH2:28][CH:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25]1)=[O:22])#[N:19].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[C:14]([C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]=1[OH:13])[CH:8]=[C:20]([C:18]#[N:19])[C:21]([O:23][CH:24]1[CH2:29][CH2:28][CH:27]([C:30]([CH3:31])([CH3:32])[CH3:33])[CH2:26][CH2:25]1)=[O:22])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)C1CCC(OC(=O)CC#N)CC1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C=C(C#N)C(=O)OC2CCC(C(C)(C)C)CC2)cc(C(C)(C)C)c1O

Procedure:
5.4 g of 3,5-di-tertiary-butyl-4-hydroxybenzaldehyde were dissolved in 50 ml of toluene. 5.9 g of 4-tertiary-butylcyclohexyl cyanoacetate, 0.1 g of piperidine and 0.25 g of acetic acid were added. 0.4 g of water was removed azeotropically under reflux. The mixture was washed, dried and concentrated.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH:13]=[N:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][CH2:6]1)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O>[CH2:16]([O:15][N:14]=[CH:13][C:5]1([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][CH2:6]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)C1(C=NOCc2ccccc2)CCC(C)(C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCC(C=NOCc2ccccc2)(C(=O)O)CC1
Temperature: 60 °C

Procedure:
A mixture of 1-(benzyloxyimino-methyl)-4,4-dimethyl-cyclohexanecarboxylic acid methyl ester (1.83 g, 6.04 mmol) and lithium hydroxide monohydrate (2.53 g, 60.4 mmol) in THF (60 mL) and water (30 mL) was heated at 60° C. for 18 h. The reaction mixture was acidified to pH 5 with 3N aqueous HCl and was extracted with dichloromethane (50 mL×6). The combined organic layers were dried (MgSO4) and were evaporated in vacuo to yield the title compound as a pale yellow oil. (1.47 g, 84%). MH+290.
Reaction SMILES: [Br:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14]CC)=[O:13])[NH:6]2.[OH-].[K+].[CH2:19](O)C>O>[Br:1][C:2]1[C:10]([O:11][CH3:19])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[NH:6]2
Reactant: CCO
Reactant: CCOC(=O)c1cc2c(Br)c(O)ccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2[nH]c(C(=O)O)cc2c1Br
Temperature: 50 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Ethyl 4-bromo-5-hydroxyindole-2-carboxylate (1.49 g, 5 mmol.), (Jnl. Org. Chem. 1984, 49, 4761), was dissolved in ethanol (10 ml) and water (3.5 ml). Potassium hydroxide (840 mg) was added and the mixture stirred at 50° C. under an atmosphere of nitrogen for 1 hour then cooled to ambient temperature. The solvent was evaporated and the residue redissolved in water (25 ml). 2M Aqueous hydrochloric acid was added until the reaction mixture was at pH4, giving a precipitate which was filtered off, washed with water and dried under vacuum to give 4-bromo-5-methoxyindole-2-carboxylic acid (1.30, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH:9]=[CH:8][CH2:7][C@H:6]1[C:11]([OH:13])=O)=[O:4].S(Cl)(Cl)=O.[CH:18]1C=CC=CC=1>>[C:11]([C@@H:6]1[CH2:7][CH:8]=[CH:9][CH2:10][C@@H:5]1[C:3]([O:2][CH3:1])=[O:4])(=[O:13])[CH3:18]
Reactant: c1ccccc1
Reactant: COC(=O)[C@H]1CC=CC[C@H]1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CC=CC[C@H]1C(C)=O
Temperature: -5 °C
Reaction time: 1 h

Procedure:
25 g of (1R, 2S)-2-methoxycarbonylcyclohex-4-ene-1-carboxylic acid and 40 ml of thionyl chloride were dissolved in 200 ml of dry benzene, and the mixture was refluxed for two hours. The solvent was distilled off under a reduced pressure, and to the residue was added ml of dried tetrahydrofuran. Further, 1.29 g of copper (I) iodide was added to the solution, which was cooled to -5° C, 182 ml of tetrahydrofuran solution of methylmagnesium bromide (0.82M) was added dropwise to the solution over a period of 1.5 hours. The solution was further stirred for one hour at the same temperature, and then 1N-hydrochloric acid was added. After the organic layer was separated, the water layer was extracted with ether. The organic layer was successively washed with 5% sodium thiosulfate solution, saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane=15:85) to be purified, and thus 18.27 g of the titled compound was obtained.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-])=O)=[C:14]([CH3:19])[N:13]=[C:12]([NH:20][C@H:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH2:22][OH:23])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-]>[Zn].CO.C1COCC1>[NH2:16][C:15]1[C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)=[N:11][C:12]([NH:20][C@H:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:22][OH:23])=[N:13][C:14]=1[CH3:19]
Reactant: Cc1nc(N[C@@H](CO)c2ccc(F)cc2)nc(Nc2cc(C3CC3)[nH]n2)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(N[C@@H](CO)c2ccc(F)cc2)nc(Nc2cc(C3CC3)[nH]n2)c1N
Reaction time: 3 h

Procedure:
To a suspension of (R)-2-[4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6-methyl-5-nitropyrimidin-2-ylamino]-2-(4-fluorophenyl)ethanol (Method 1, 1.0 g, 2.4 mmol) and zinc dust (0.79 g, 12.0 mmol) in the mixture of MeOH:THF (1:1, 70 ml) was slowly added saturated NH4Cl solution (10 ml). After 3 hours, the reaction was treated with saturated aqueous NH4OAc solution (40 ml), and the resulting mixture was stirred for 30 minutes. The reaction was then filtered through a plug of celite with EtOAc (100 ml). The resulting aqueous layer was extracted with EtOAc (2×100 ml), dried, filtered, and concentrated to give (0.8 g, 90%). MS: Calcd.: 383; Found: [M+H]+ 384.
Reaction SMILES: CC1(C)CO[C:5]2([C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N:14]([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=3)[N:7]([CH2:27][C:28]([O:30]C)=[O:29])[C:6]2=[O:32])[O:4]C1.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(OCC)(=O)C.CCCCCC>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[O:24]1[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][N:14]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH2:27][C:28]([OH:30])=[O:29])[C:6](=[O:32])[C:5]3=[O:4])[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:22][CH2:23]1
Reactant: COC(=O)CN1C(=O)C2(OCC(C)(C)CO2)c2cc(N(CCN3CCOCC3)S(C)(=O)=O)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CS(=O)(=O)N(CCN1CCOCC1)c1ccc2c(c1)C(=O)C(=O)N2CC(=O)O
Temperature: 80 °C
Yield: 69 %

Procedure:
A mixture of methyl 2-(5,5-dimethyl-5′-(N-(2-morpholinoethyl)-methylsulfonamido)-2′-oxospiro[[1,3]dioxane-2,3′-indoline]-1′-yl)acetate (0.450 g, 0.880 mmol) and TFA (0.678 ml, 8.80 mmol) in dioxane/water 1/1 (15 ml) was heated at 80° C. for 24 hours. Additional TFA (1.356 ml, 17.6 mmol) was added over 5 days with stirring at the same temperature. The volatiles were removed under vacuum, and the crude was triturated with diethyl ether. The insoluble was collected by filtration and dried under vacuum affording 2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-2,3-dioxoindolin-1-yl)acetic acid 2,2,2-trifluoroacetic acid salt (0.319 g, 0.607 mmol, 69.0% yield, MS/ESI+ 412.0 [MH]+).