Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C2C(OC)=CC=C([C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)=[O:17])C=2F)C=CC=1.C(NC1C=CC(C(O)=O)=CC=1)(=O)C.O=S(Cl)[Cl:44]>C1COCC1.CN(C=O)C>[C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]([Cl:44])=[O:17])=[CH:19][CH:20]=1)(=[O:27])[CH3:26]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)c2ccc(NC(C)=O)cc2)c(F)c1-c1cccc(Cl)c1
Agent: CC(=O)Nc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Synthesis of N-[4-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-carbonyl)-phenyl]-acetamide (I-19, R1═CH3, R2═Cl, Y═F, R3=4-acetylaminophenyl): To a stirred suspension of 4-acetylaminobenzoic acid (Aldrich, 1.32 g, 5.58 mmol) in anhydrous THF (20 mL) was added SOCl2 (1.19 g, 10.04 mmol) and DMF (4 drops). The reaction mixture was stirred at room temperature for 3 h, concentrated under vacuum to afford 4-acetylaminobenzoyl chloride (I-18, R3=4-acetylaminophenyl) as a light yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([O:26][CH3:27])=[C:12]([NH:14][CH:15]3[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]3)[CH:13]=2)[CH:5]=[CH:4][N:3]=1.[CH3:28][NH2:29].CO>CN1C(=O)CCC1>[CH3:27][O:26][C:11]1[N:10]=[CH:9][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:29][CH3:28])[CH:7]=2)=[CH:13][C:12]=1[NH:14][CH:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1
Reactant: COc1ncc(-c2ccnc(F)c2)cc1NC1CN(C(=O)OC(C)(C)C)C1
Reactant: CN
Solvent: CO
Solvent: CN1CCCC1=O
Product: CNc1cc(-c2cnc(OC)c(NC3CN(C(=O)OC(C)(C)C)C3)c2)ccn1
Temperature: 140 °C
Yield: 80 %

Procedure:
To a solution of tert-butyl 3-((2′-fluoro-6-methoxy-[3,4′-bipyridin]-5-yl)amino)azetidine-1-carboxylate (530 mg, 1.42 mmol) in NMP (3 mL) was added CH3NH2/MeOH (5 mL). The reaction mixture was stirred while being heated at 140° C. in a microwave for 1 h. The mixture was cooled to rt, the solvent was removed and diluted with ethyl acetate (100 mL). The organic layer was washed with water (60 mL), brine (60 mL), dried over Na2SO4, filtered, concentrated in vacuo, and the residue was purified by flash chromatography to obtain 436 mg of tert-butyl 3-((6-methoxy-2′-(methylamino)-[3,4′-bipyridin]-5-yl)amino)azetidine-1-carboxylate as a yellow solid (80%): 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=5.3 Hz, 1H), 7.72 (d, J=2.1 Hz, 1H), 6.63 (dd, J=5.3, 1.5 Hz, 1H), 6.58 (s, 1H), 6.39 (d, J=1.7 Hz, 1H), 4.63 (d, J=6.7 Hz, 1H), 4.53 (d, J=6.5 Hz, 1H), 4.27 (dd, J=8.8, 7.1 Hz, 2H), 4.18 (ddt, J=9.4, 7.0, 3.4 Hz, 1H), 3.97 (s, 3H), 3.74 (dd, J=9.0, 4.6 Hz, 2H), 2.90 (d, J=4.2 Hz, 3H), 1.37 (s, 9H); MS (ES) m/z 386 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=O)[CH:17]=1.[CH2:25]=[C:26]([CH3:28])[CH3:27].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([O:14][CH3:13])=[O:24])[CH:17]=1)[CH2:25][C:26]2([CH3:28])[CH3:27])=[O:12])[CH3:2]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: C=C(C)C
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)OC)c1)N2
Temperature: 85 °C
Reaction time: 18 h
Yield: 35.1 %

Procedure:
To a stirred solution of 4-amino-benzoic acid ethyl ester (12.9 g, 78.4 mmol) and 3-formyl-benzoic acid methyl ester (12.9 g, 78.4 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 85° C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(3-methoxycarbonyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (10.1 g, 35.0%) as a light yellow solid: MS (ESI) M+1=368.1.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8](O)=[O:9].[BH4-].[Na+].B(F)(F)F.CCOCC>COCCOC>[CH3:1][N:2]([CH3:15])[C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[CH2:8][OH:9]
Reactant: CN(C)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: CN(C)c1ccc([N+](=O)[O-])c(CO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 189 g of 5-dimethylamino-2-nitrobenzoic acid in 1.5 l of 1,2-dimethoxyethane was treated with 52 g of sodium borohydride and then dropwise at 10° with a solution of 225 ml of boron trifluoride etherate in 500 ml of 1,2-dimethoxyethane. The mixture was then stirred at room temperature for 1 hour, cautiously poured into ice/water and the crude product was filtered. Recrystallization from ethyl acetate/hexane gave pure 5-dimethylamino-2-nitrobenzyl alcohol, m.p. 138°-139°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH3:21])[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][C:29]([C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)([CH3:32])[C:30]#[N:31].O>CN(C)C(=O)C.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>[ClH:1].[CH3:21][N:18]1[C:19]([CH3:20])=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[C:2]([C:36]4[CH:37]=[CH:38][C:33]([C:29]([CH3:32])([CH3:28])[C:30]#[N:31])=[CH:34][CH:35]=4)=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:9][CH2:10]2)[CH:16]=[N:17]1
Reactant: Cc1c(CN2CCN(c3nccnc3Cl)CC2)cnn1C
Reactant: CC(C)(C#N)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c(CN2CCN(c3nccnc3-c3ccc(C(C)(C)C#N)cc3)CC2)cnn1C
Product: Cl
Temperature: 120 °C
Yield: 35 %

Procedure:
Dissolve 3′-chloro-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (307 mg, 1.0 mmol) in N,N-dimethylacetamide (4 mL). Add potassium carbonate (332 mg, 2.4 mmol), 2-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionitrile (300 mg, 1.2 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0050 g, 0.0058 mmol), then water (2 mL) and degas with nitrogen for 10 min. Heat at 120° C. for 20 hr., then purify by SCX-2® chromatography washing with methanol. Elute with 2 M ammonia in methanol and concentrate. Purify by low pH reverse phase HPLC, then form the free base by passing through an SCX-2® ion exchange cartridge washing with methanol then eluting with 2 M ammonia in methanol and concentrate. Dissolve the free base in acetonitrile and convert to the hydrochloride salt by adding 2 M aq HCl solution. Add water and lyophilize to give the title compound as a light yellow powder (158 mg, 35%). MS (ES): m/z=416 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])=[CH:8][C:7]=1[CH3:30].[Li+].[OH-]>C1COCC1.C(O)C>[CH3:30][C:7]1[CH:8]=[C:9]([NH:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:31])=[O:2]
Reactant: COC(=O)COc1ccc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A solution of (2-methyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid methyl ester (330 mg, 0.73 mmol) in THF (2.2 ml) and ethanol (2.2 ml) was treated at 0° C. with 1N LiOH (2.2 ml) and stirred for 1.25 h at RT. The reaction was extracted with aqueous 10% KHSO4/Et2O (3×). The organic phase was washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated. The product was crystallized from CH2Cl2/Et2O to give pure (2-methyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid, MS: 437.4 (MH)+, MP: 201-203° C., dec.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13][C:14]1[S:15][C:16]([C:21](=[O:23])[CH3:22])=[CH:17][C:18]=1[C:19]#[N:20].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[CH3:12][S:13]([C:14]1[S:15][C:16]([C:21](=[O:23])[CH3:22])=[CH:17][C:18]=1[C:19]#[N:20])=[O:9]
Reactant: CSc1sc(C(C)=O)cc1C#N
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc(C#N)c(S(C)=O)s1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
5.0 g of 83% m-chloroperbenzoic acid are gradually added while stirring at a temperature of 0°-5° C. in 45 minutes to a solution of 5.0 g of 2-methylthio-3-cyano-5-acetylthiophene in 500 ml of methylene chloride. After stirring for another 30 minutes at 5° C., a saturated solution of sodium bicarbonate in approximately 50 ml of water is added; the reaction mixture is then stirred for 60 minutes. The organic layer is separated, washed with water and dried. After distilling off the solvent, the desired product is obtained in a yield of 4.6 g; melting-point 150° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][C:24]=2[CH:32]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][C:24]=4[CH:32]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Reactant: COc1ccc(Nc2nc(Cl)ncc2F)cc1Cl
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc(OC)c(Cl)c4)n3)ccc2o1

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and 5-amino-2-(methoxycarbonyl)benzofuran were reacted to produce N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.34 (bs, 2H), 8.10-8.07 (m, 2H), 7.78 (t, 1H, J=2.7 Hz), 7.66-7.53 (m, 4H), 7.12 (d, 1H, J=9.3 Hz), 3.87 (s, 3H), 3.85 (s, 3H); LCMS: purity: 99%; MS (m/e): 443(MH+).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][OH:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.N>C(Cl)Cl.O>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([O:13][CH2:12][CH2:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Agent: N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCC23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-adamantaneethanol (3.06 g, 16.9 mmol) and triethylamine (2.8 mL, 20.1 mmol) in methylen chloride (30 mL) was added at 0° C. a suspension of 4-methylbenzene-1-sulfonyl chloride (3.88 g, 20.3 mmol) in methylen chloride (40 mL). The reaction mixture was stirred at room temperature overnight. Then, ice and a solution of ammonia 50% in water were added into the reaction mixture. The mixture was extracted with pentane and the organic layer was washed with water and brine. The solvent was removed under reduced pressure and the title compound was obtained as an oil (5.4 g, 90%). MS (M+): 335.
Reaction SMILES: OC[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].FC(F)(F)[C:19](=N[Si](C)(C)C)[O:20][Si](C)(C)C.[CH3:32][O:33][C:34]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:44]=1[NH:43][CH:42]=[C:41]2[C:45](=[O:49])[C:46](Cl)=[O:47])=[O:35].N1C=CC=CC=1>C(#N)C>[C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:46](=[O:47])[C:45]([C:41]2[C:40]3[C:44](=[C:36]([C:34]([O:33][CH3:32])=[O:35])[CH:37]=[CH:38][CH:39]=3)[NH:43][CH:42]=2)=[O:49])[CH:12]([CH2:19][OH:20])[CH2:13]1)(=[O:7])[C:5]1[CH:4]=[CH:3][CH:16]=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)N=C(O[Si](C)(C)C)C(F)(F)F
Reactant: COC(=O)c1cccc2c(C(=O)C(=O)Cl)c[nH]c12
Reactant: O=C(c1cccc(CO)c1)N1CCNCC1
Solvent: c1ccncc1
Solvent: CC#N
Product: COC(=O)c1cccc2c(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3CO)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-hydroxylmethyl-benzoylpiperazine XLIX (8.0 mg, 0.036 mmol) in acetonitrile (5 ml) was added BSTFA (8.1 mg, 0.036 mmol). After stirring for 30 minutes at room temperature, (7-methoxycarbonyl-indol-3-yl)-oxoacetyl chloride (8.1 mg, 0.036 mmol) and pyridine (0.5 ml) were added. The reaction was stirred for another 2 hours at room temperature. Concentration under vaccum provided a residue, which was then purified by Shimazu HPLC purification system to give 2 mg of N-(benzoyl)-3-hydroxylmethyl-N′-[(7-methoxycarbonyl-indol-3-yl)-oxoacetyl]-piperazine (Example 98).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:18]=3[CH3:26])[C:13](=[O:27])[N:12]([C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][C:29]=3[CH3:37])[C:11]2=[O:38])=[C:6]([CH3:39])[CH:5]=1)([O-])=O.Cl.O>C1COCC1.[Pd]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([N:14]2[C:15](=[O:16])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][C:6]=3[CH3:39])[C:11](=[O:38])[N:12]([C:28]3[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=3[CH3:37])[C:13]2=[O:27])=[C:18]([CH3:26])[CH:19]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1-n1c(=O)n(-c2ccc([N+](=O)[O-])cc2C)c(=O)n(-c2ccc([N+](=O)[O-])cc2C)c1=O
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(N)ccc1-n1c(=O)n(-c2ccc(N)cc2C)c(=O)n(-c2ccc(N)cc2C)c1=O
Yield: 79.2 %

Procedure:
1,3,5-tris-(4-nitro-2-methyl-phenyl)-[1,3,5]triazinane-2,4,6-trione (2.86 g, 5.4 mmol) was dissolved in THF (70 ml). HCl (4.5 ml, 6M), water (18 ml) and Pd/C (0.6 g, 10%) was added. The reaction vessel was evacuated and filled with argon in three cycles before hydrogenated on a Parr hydrogenation apparatus (60 psi). After 2 hours the excess hydrogen was evacuated with a membrane pump and the Pd/C (10%) was filtered off. The clear reaction solution was concentrated until no more THF remained and the pH adjusted to 7 with NaHCO3 (˜3.7 g). The aqueous phase was extracted with ethyl acetate (3×100 ml) and the combined organic phases were dried with MgSO4, filtered and concentrated to give a brown powder. The crude product was recrystallized from methanol to give the product as an off-white powder (1.9 g, 80%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]([CH3:17])([CH3:16])[C:5]=2[C:4]=1[OH:18])=[O:2].[OH-].[K+].S(OC)(O[CH3:25])(=O)=O.Cl>C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9]([CH3:14])([CH3:15])[CH2:8][CH2:7][C:6]([CH3:17])([CH3:16])[C:5]=2[C:4]=1[O:18][CH3:25])=[O:2]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(C=O)c(O)c2c1C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1c(C=O)cc(C)c2c1C(C)(C)CCC2(C)C
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 81.3 %

Procedure:
Methylation. 2-Formyl-1-hydroxy-4,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (42 g, 0.17 mol) was stirred with toluene (656 mL), and potassium hydroxide 85% (16.8 g, 0.255 mol) was added in one portion. The mixture was heated to 40° C., dimethyl sulfate (32.13 g, 0.255 mol) added at 40°-45° C. during 0.5 h, and the heating continued at 50° C. for an additional 1.5 h. The mixture was cooled to 20° C., neutralized with 5% HCl solution, then washed with water (20 mL), and finally washed with brine (25 mL). The solvent was removed by distillation and the residue distilled to give 2-formyl-1-methoxy-4,5,5,8,8- pentamethyl-5,6,7,8-tetrahydronaphthalene (36 g), bp 140°-142° C./1.5 mm, GLC purity 95%. Crystallization from hexane gave 28 g material, GLC purity 99%. 1H-NMR (CDCl3) δ10.23 (2 H, s), 7.41 (1H, s), 3.89 (3H, s), 2.52 (3H, s), 1.63 (4H, s), 1.42 (6H, s), 1.40 (6H, s). 13C-NMR (CDCl3) δ189.9 (1C, d), 162.3 (1C, s), 153.1 (1C, s), 139.9 (1C, s), 132.7 (1C, s), 131.3 (1C, d), 126.5 (1C, s), 66.0 (1C, q), 39.4 (1C, t), 38.2 (1C, t), 36.4 (1C, s), 35.6 (1C, s), 30.0 (2C, q), 28.9 (2C, q), 23.7 (1C, q). IR (KBr) 1683, 1235 cm-1, MS (m/e) 260.3 (M+, 46.3), 245.2 (100.0), 175 (38.5), 128 (31.1).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[N:67]1([C:73]2[CH:80]=[CH:79][C:76]([CH:77]=O)=[CH:75][CH:74]=2)[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:77]([C:76]3[CH:75]=[CH:74][C:73]([N:67]4[CH2:72][CH2:71][O:70][CH2:69][CH2:68]4)=[CH:80][CH:79]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Reaction time: 6 h
Yield: 36.7 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.051 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.15 mmol, 0.15 mL) and 4-morpholin-4-yl-benzaldehyde (1.1 eq, 0.056 mmol, 11 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (10 mg, 37%) as an off-white solid; δH (500 MHz, DMSO-d6) 2.61 (s, br, 4H, piperazine N(CH2)2), 3.24 (t, J=4.9 Hz, 4H, morpholine N(CH2)2), 3.62 (s, 2H, CH2), 3.64 (t, J=4.7 Hz, 4H, piperazine N(CH2)2), 3.76 (t, J=4.7 Hz, 4H, morpholine O(CH2)2), 7.06 (d, J=9.0 Hz, 2H, phenyl H-3 & H-5), 7.39 (dd, J=7.7, 4.8 Hz, 1H, pyridine H-5), 7.79 (dt, J=7.7, 1.7 Hz, 1H, pyridine H-4), 8.04 (d, J=9.0 Hz, 2H, phenyl H-2 & H-6), 8.17 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.8, 1.6 Hz, 1H, pyridine H-6), 8.56 (d, J=1.5 Hz, 1H, pyridine H-2), 13.22 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[C:18]([CH3:26])([CH2:22][C:23]([OH:25])=[O:24])[O:19][CH2:20][CH2:21][C:12]2=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[C:18]([CH3:26])([CH2:22][C:23]([OH:25])=[O:24])[O:19][CH2:20][CH2:21][C:12]2=1
Reactant: [H][H]
Reactant: CC1(CC(=O)O)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Agent: [Pd]
Solvent: CCO
Product: CC1(CC(=O)O)OCCc2c1[nH]c1ccc(O)cc21

Procedure:
A mixture of 6-benzyloxy-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (5.3 g., 0.015 mole), prepared as described in Example 25, in 250 ml. of anhydrous ethanol, and 1.1 g. of 10% palladium on carbon is stirred at room temperature under a hydrogen atmosphere until no more hydrogen is being taken up by the reaction mixture. The catalyst is removed by filtration through diatomaceous earth (Celite) and the filtrate concentrated. The residue is recrystallized from ethanol-benzene to afford the title compound, m.p. 170°- 171° C.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[CH2:10]([Li])CCC.[CH:15]([S:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:17])[CH3:16].CI.Cl>O1CCCC1>[CH:15]([S:18][C:19]([CH3:10])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C(C)SC(C)C
Reactant: [Li]CCCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)(C)SC(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1,1,1,3,3,3-hexamethyldisilazane (10.4 mL, 48 mmol) in tetrahydrofuran is cooled to 0° C., treated with a 2.04 M solution of n-butyllithium in tetrahydrofuran (22.6 mL, 46 mmol), stirred at 0° C. for 30 minutes, treated dropwise with ethyl 2-(isopropylthio)propionate (7.6 g, 42 mmol), stirred at 0° C. for 1 hour, treated with methyl iodide, stirred at room temperature for 22 hours, and poured into an ice-water mixture (100 g) containing 10 mL of 6 N hydrochloric acid. The resultant aqueous mixture is extracted with ether. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a brown liquid. Vacuum distillation of the brown liquid gives the title product as a liquid (6.8 g) which is identified by NMR spectral analysis.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:11]([OH:12])[CH:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH3:21])[N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:22]#[N:23])[CH:8]=2)[O:3]1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[CH3:1][C:2]1([CH3:24])[C:11]([O:12][C:25](=[O:27])[CH3:26])=[C:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH3:21])[N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:22]#[N:23])[CH:8]=2)[O:3]1
Reactant: Cn1nc(NC2c3cc(C#N)ccc3OC(C)(C)C2O)ccc1=O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1=C(Nc2ccc(=O)n(C)n2)c2cc(C#N)ccc2OC1(C)C

Procedure:
2.0 g of 2,2-dimethyl-4-(1-methyl-1,6-dihydro-6-oxo-3-pyridazinyl-amino)-6-cyano-3-chromanol are boiled in 20 ml of acetic anhydride for 2 hours. Customary working-up gives 2,2-dimethyl-3-acetoxy-4-(1-methyl-1,6-dihydro-6-oxo-3-pyridazinyl-amino)-6-cyano-3-chromene, m.p. 110°-112°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:19])[CH2:17][CH3:18].C(O)C(CC)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:19][C@@H:16]([CH2:17][CH3:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: CCC(C)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)CO
Solvent: CN(C)C=O
Product: CC[C@H](C)CCCCCOc1ccc(C#N)cc1

Procedure:
Add 5.75 g of 4-cyanophenol 10 g of 1 brom-6-methyl octane synthesized of available active amyl alcohol, 6.67 g of anhydrous potassium carbonate, 30 ml of N,N-dimethyl formamide into 100 ml four-mouth flask under nitrogen atmosphere, allow to react for 8 hours at 110° C. After the reaction, filter the insoluble matter, then extract ether. The organic layer is then washed with 5% NaOH, water and saturated salt water, then dried and evaporated to remove the ether. Then when the obtained oily matter is refined, 11.4 g of optical (s)-4-(6-methyloctyloxy)benzonitrile is obtained.