Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].C[O-].[Na+].[C:7]([O:13]C)(=O)[C:8]([O:10][CH3:11])=[O:9].P(=O)(O)(O)O>CO>[CH3:1][N:2]([CH3:3])[C:7](=[O:13])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(=O)OC
Reactant: CNC
Agent: C[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)N(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 1,000 mL reactor are added at 0° C., 360 g (4 mol) of dimethylamine (DMA) solution at 50% by weight in methanol and 43.2 g (0.2 mol) of sodium methylate at 25% by weight in methanol. To this mixture are added at 0.5° C. and within 1 hour, 472 g (4 mol) of dimethyl oxalate. The mixture is maintained with stirring and at 0° C. for 2 hours. The reaction medium is concentrated in vacuo (Pmax=200 mbar) for removing residual DMA and methanol and an 85% orthophosphoric acid solution (23 g 0.2 mol) is then added. The salts formed are filtered and then the filtrate is distilled in vacuo (Tbp=68-70° C., P<1 mbar) in order to recover the desired product (461 g).
Reaction SMILES: [CH3:1][N:2]([CH:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)[C:3]([C:5]1[S:6][C:7]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=NOC)[CH2:20][CH2:19]3)=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].[O:35]1CCOCC1.CC(C)=O>Cl>[CH3:1][N:2]([CH:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)[C:3]([C:5]1[S:6][C:7]([C:16]2[CH:17]=[C:21]3[C:22](=[CH:23][CH:24]=2)[C:18](=[O:35])[CH2:19][CH2:20]3)=[C:8]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[CH:9]=1)=[O:4]
Reactant: CON=C1CCc2cc(-c3sc(C(=O)N(C)C4CCN(C)CC4)cc3-c3ccncc3)ccc21
Reactant: C1COCCO1
Agent: Cl
Solvent: CC(C)=O
Product: CN1CCC(N(C)C(=O)c2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=O)s2)CC1
Yield: 67 %

Procedure:
The product of step 3 (476 mg 1 mmol) was dissolved in 5N hydrochloric acid (10 ml), dioxane (10 ml) and acetone (5 ml) and heated at 80° C. for 2 hours. The resulting solution was concentrated in vacuo and co-evaporated with ethanol (×3) to afford a crude solid. This was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate (×2), and the combined organic extracts were washed with water (×3), brine, dried and evaporated in vacuo to a crude solid. This was purified by column chromatography (1:9:40 0.880 ammonia:thanol:dichloromethane) to afford title product (300 mg, 67%); MS (AP+) m/e 446 [M+H]+
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1.C(Cl)(=O)C(Cl)=O.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1
Reactant: COCCc1nc2cnc3ccccc3c2n1CCCCC(=O)O
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Product: COCCc1nc2cnc3ccccc3c2n1CCCCC(=O)N1CCOCC1
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
5-[2-(2-Methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]pentanoic acid (5.5 g, 17 mmol) was treated according to a modification of the method described in Part F of Example 6. The reaction with oxalyl chloride (2.63 mL, 30.2 mmol) was carried out at ambient temperature and was complete in 30 minutes. The reaction with morpholine (4.40 mL, 50.4 mmol) was complete after 30 minutes. Following the work-up procedure, 6.5 g of 2-(2-methoxyethyl)-1-(5-morpholin-4-yl-5-oxopentyl)-1H-imidazo[4,5-c]quinoline were obtained.
Reaction SMILES: [O:1]1[C@H:8]([CH2:9][OH:10])[C@H:6]([OH:7])[C@H:4]([OH:5])[CH:3]=[CH:2]1.[C:11](OC=C)(=[O:13])[CH3:12]>O>[C:11]([O:10][CH2:9][C@H:8]1[O:1][CH:2]=[CH:3][C@@H:4]([OH:5])[C@H:6]1[OH:7])(=[O:13])[CH3:12]
Reactant: OC[C@H]1OC=C[C@@H](O)[C@H]1O
Reactant: C=COC(C)=O
Solvent: O
Product: CC(=O)OC[C@H]1OC=C[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1.0 g (6.85 mmol) of galactal is dissolved in about 1 ml of water, and 1-4 g of crushed molecular sieves, 25-75 ml of vinyl acetate and 800 mg of lipase from Candida cylindracea (Sigma) are added. The mixture is stirred at room temperature for about 45 min. Drying, filtration, concentration in vacuo and chromatography on silica gel (ethyl acetate/hexane 1:1) or crystallization (from ethyl acetate/hexane) yields 1.090 to 1.160 (85-90%) of the desired 6-O-acetylgalactal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:21](=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[C:6]([NH:8][C:9](=[O:20])[NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17](O)=[O:18])[N:15]=2)[CH:7]=1.[CH3:31][NH2:32].C1COCC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:21](=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[C:6]([NH:8][C:9](=[O:20])[NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:32][CH3:31])=[O:18])[N:15]=2)[CH:7]=1
Reactant: COc1ccccc1C(=O)c1ccc(F)cc1NC(=O)Nc1nc(CC(=O)O)cs1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)Cc1csc(NC(=O)Nc2cc(F)ccc2C(=O)c2ccccc2OC)n1
Yield: 65 %

Procedure:
2-(2-{3-[5-Fluoro-2-(2-methoxy-benzoyl)-phenyl]-ureido}-thiazol-4-yl)-N-methyl-acetamide (144 mg, 65%) was prepared from (2-{3-[5-fluoro-2-(2-methoxy-benzoyl)-phenyl]-ureido}-thiazol-4-yl)-acetic acid (215 mg, 0.5 mmol) and 1N solution of methyl amine in THF (0.5 mL, 0.5 mmol) following the general procedure K.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:16])=[CH:4][C:3]=1[CH:17](SC)[C:18]([NH2:20])=[O:19]>[Ni].C(O)C.CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:16])=[CH:4][C:3]=1[CH2:17][C:18]([NH2:20])=[O:19]
Reactant: CSC(C(N)=O)c1cc(Cl)cc(C(=O)c2ccccc2)c1N
Agent: [Ni]
Solvent: CCO
Solvent: CN(C)C=O
Product: NC(=O)Cc1cc(Cl)cc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 21.34 g (0.0639 mole) of 2-amino-3-benzoyl-5-chloro-α-(methylthio)-phenylacetamide and excess Raney nickel in a mixture of 900 ml of absolute ethanol and 200 ml of dimethylformamide was stirred at room temperature for 45 min. The mixture was filtered through celite to remove the Raney nickel. The solvent was removed in vacuo to give a yellow solid which when recrystallized melted at 213.5°-215.0° C.(d).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[OH:32][C@@H:33]([CH2:37][CH3:38])[C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:32][C@@H:33]([CH2:37][CH3:38])[C:34]([N:22]1[CH2:23][CH2:24][N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:7]=2)[CH2:20][CH2:21]1)=[O:35]
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Reactant: CC[C@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg, 0.78 mmol) in CH2Cl2 (6 mL) was added triethylamine (217 μL, 1.56 mmol) followed by the addition of (S)-2-hydroxybutanoic acid (105 mg, 1.0 mmol) and HATU (380 mg, 1.00 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with H2O. The aqueous layer was extracted twice with CH2Cl2, dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2:hexanes gave (S)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-one (300 mg, 95%). LC/MS: m/z 407.5 (M+H)+ at 2.31 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) d 8.45 (m, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.70 (s, 1H), 7.39 (m, 2H), 6.95 (m, 2H), 4.92 (d, J=7.0 Hz, 1H), 4.28 (q, J=6.5 Hz, 1H), 3.89 (m, 8H), 2.52 (s, 3H), 1.67 (m, 1H), 1.51 (m, 1H), 0.91 (t, J=7.4 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].C([Li])CCC.[CH3:17][N:18]([CH3:29])[CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:29][N:18]([CH3:17])[CH2:19][CH2:20][C:21]([OH:22])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1ccccc1C
Reactant: CN(C)CCC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNC(=O)c1ccccc1CC(O)(CCN(C)C)c1ccccc1
Temperature: 5 °C

Procedure:
To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube maintained under a nitrogen atmosphere there is added at room temperature 40.0 g. (0.28 mole) of o-methyl-N-methyl benzamide and 250 ml. of anhydrous tetrahydrofuran. The reaction flask is immersed in an ice bath and cooled to an internal temperature of 5° C. Stirring is initiated and 360 ml. of 1.6 M. n-butyllithium (0.616 mole) in hexane is added dropwise for about 1 hour maintaining the temperature below 8° C. The resulting red dilithio salt (compound VIII) is stirred at 5° C. for 1 additional hour and the reaction flask is then immersed in a dry-ice acetone bath and cooled to an internal temperature of -30° C. To the cold reaction mixture a solution of 49.7 g. (0.28 mole) 3-dimethylaminopropiophenone in 140 ml. anhydrous tetrahydrofuran is added dropwise in ca. 45 minutes maintaining the temperature between -30° and -20° C. The resulting reaction mixture is stirred at -25° C. for 1 hour, allowed to warm to -10° C. in ca. 1 hour, and then treated with 200 ml. of saturated aqueous ammonium chloride while maintaining the temperature below 0° C. The resulting solid in filtered, washed thoroughly with water and recrystallized from methylene chloride-ether (1:1) to give 2-(β-[2-dimethylaminoethyl]-β-hydroxyphenethyl)-N-methylbenzamide; m.p. 139.5° to 140.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][CH:11]([C:12](OCC)=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][CH:11]([CH2:12][OH:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reaction time: 0.33 h
Yield: 95.9 %

Procedure:
To a solution of 516 mg of ethyl N-t-butoxycarbonyl-isonipecotate in 30 ml of tetrahydrofuran, 200 mg of lithium-aluminum hydride was added under cooling with ice, followed by 20 minutes' stirring at the same temperature. Sodium sulfate decahydrate was added to the reaction liquid, stirred for 30 minutes and filtered with Celite. Distilling the solvent off under reduced pressure, 414 mg of the title compound was obtained.
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][CH2:9][C@H:10]([OH:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][C:26]1[CH:31]=[C:30](Cl)[N:29]=[C:28]([S:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[F:42])[N:27]=1.[H-].[Na+]>C1COCC1>[Cl:25][C:26]1[CH:31]=[C:30]([O:12][C@H:10]([CH3:11])[CH2:9][O:8][C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:29]=[C:28]([S:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[F:42])[N:27]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: C[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iii) using (2R)-1-(triphenylmethoxy)-2-propanol (1.35 g) and 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step (ii) (1 g) in THF (15 mL) and 60% sodium hydride (0.18 g) to give the subtitle compound as a pale yellow oil. Yield: 1.8 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:5]([CH3:13])[CH:4]=1.[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:5]([CH3:13])[CH:4]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(NC(C)=O)c(C)c1
Solvent: CC(=O)O
Product: COc1cc(C)c(NC(C)=O)cc1[N+](=O)[O-]
Yield: 53 %

Procedure:
34 g (0.19 mol) of N-(4-methoxy-2-methylphenyl)acetamide were added in small portions to a mixture of 40 ml of glacial acetic acid and 70 ml of fuming nitric acid at −10 to −15° C. These portions were such that the temperature did not rise above −10° C. The reaction mixture was then poured onto ice. The resulting precipitate was filtered off with suction and washed with water, ethanol and diethyl ether. 22.5 g (53%) of the desired product were obtained.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]#[N:20])[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1.CCO>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]#[N:20])[CH:18]=[C:13]3[C:12]([C:24]3[CH:25]=[CH:26][O:22][CH:23]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccccc1
Reactant: OB(O)c1ccoc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#Cc1cnc2c(c1)c(-c1ccoc1)cn2S(=O)(=O)c1ccccc1
Yield: 72 %

Procedure:
A mixture of iodide 37 (2.00 g, 4.89 mmol), furan-3-boronic acid (820 mg, 7.33 mmol), PdCl2(PPh3)2 (343 mg, 0.49 mmol), LiCl (622 mg, 14.7 mmol), 1.0 M aqueous Na2CO3 (12.2 mL, 12.2 mmol), EtOH (23 mL) and toluene (23 mL) were refluxed for 50 min. After cooling the layers were separated, brine was added to the aqueous layer and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (MgSO4) and concentrated. The resulting solid was purified by silicagel chromatography using 30% ethyl acetate in hexane (gradient elution) to give 38 as an orange solid (1.23 g, 72%);
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=[O:11].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46](O)[CH2:45]2>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([O:12][C@@H:46]1[CH:47]2[CH2:50][CH2:51][N:44]([CH2:49][CH2:48]2)[CH2:45]1)=[O:11]
Reactant: O=C(O)C(c1ccc(F)cc1F)N1CCCCC1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1ccc(F)cc1F)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
2-(2,4-Difluorophenyl)-2-(piperidin-1-yl)acetic acid (304 mg, 1.19 mmol), DCC (491 mg, 2.38 mmol), and HOBT (365 mg, 2.38 mmol) were dissolved in dry THF (12 ml). (R)-quinuclidin-3-ol (454 mg, 3.57 mmol) was added and the mixture was stirred at room temperature for 16 hours. THF was evaporated and the residue was taken up with EtOAc and washed with sat. NaHCO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=9/1+0.1% NH4OH) to obtain the title product as colorless oil (280 mg, 64.5% yield).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH:5]([CH3:14])[CH2:6][CH2:7][CH2:8][C:9]([S:12][CH3:13])([CH3:11])[CH3:10].Cl>O1CCCC1>[CH3:13][S:12][C:9]([CH3:10])([CH3:11])[CH2:8][CH2:7][CH2:6][CH:5]([CH3:14])[CH2:4][CH:3]=[O:2]
Reactant: COC(CC(C)CCCC(C)(C)SC)OC
Agent: Cl
Solvent: C1CCOC1
Product: CSC(C)(C)CCCC(C)CC=O

Procedure:
A mixture of 5 g. of 1,1-dimethoxy-7-methylthio-3,7-dimethyloctane, 50 ml. of aqueous tetrahydrofuran (1:1) and 10 ml. of 3N hydrochloric acid is stirred at room temperature until hydrolysis is completed as followed by thin layer chromatography to give crude 7-metylthio-3,7-dimethyloctan-1-al which is worked up by extraction with ether and purified by chromatography.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14])[CH:7]=[O:8].[BH4-].[Na+].[OH-].[Na+]>C(O)C>[F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14])[CH2:7][OH:8]
Reactant: O=Cc1ccc(OC(F)F)c(OC(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1ccc(OC(F)F)c(OC(F)F)c1

Procedure:
3,4-Bisdifluoromethoxybenzaldehyde (26.2 g, 110 mmol) in absolute ethanol (150 mL) was treated with sodium borohydride (8.32 g, 220 mmol) under an argon atmosphere at room temperature for 0.5 h. Ten percent aqueous sodium hydroxide (130 mL) was added, the ethanol was removed in vacuo, the mixture was partitioned between ether and water and was extracted twice with ether. The organic extract was dried (magnesium sulfate) and evaporated to a pale yellow oil (26.4 g, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[CH3:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.[K+].[Br-]>>[CH3:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[NH:2])=[CH:12][CH:11]=1
Reactant: Cc1ccc(N)cc1
Reactant: N#Cc1ccncc1
Agent: [Br-]
Agent: [K+]
Product: Cc1ccc(NC(=N)c2ccncc2)cc1
Yield: 72.5 %

Procedure:
The title compound was prepared from 4-cyanopyridine (9.72 g, 93 mmol) and 4-methylaniline (10 g, 93 mmol) by following the procedure described in preparation 10 (14.3 g, yield 72.5%, mp 120-123° C., purity 98.75% by HPLC). 1H-NMR (CDCl3):δ 2.33 (s, 3H), 5.06 (bs, 2H, D2O exchangeable), 6.84-6.86 (d, 2H), 7.16-7.18 (d, 2H), 7.71-7.72 (d, 2H), 8.66-8.67 (d, 2H). IR (KBr) cm−1: 3437, 3138, 1644. MS m/z:212.1 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:9]([CH2:25][CH2:26][CH3:27])[C:8]2=[O:28])=[CH:4][CH:3]=1.[CH2:31]([O:33][C:34](=[O:47])[C:35]([O:45][CH3:46])([CH3:44])[CH2:36][C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1)[CH3:32].C([O-])([O-])=O.[K+].[K+]>CCO.O>[CH2:31]([O:33][C:34](=[O:47])[C:35]([O:45][CH3:46])([CH3:44])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:14][CH2:13][CH2:12][C:10]2[N:9]([CH2:25][CH2:26][CH3:27])[C:8](=[O:28])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:30][CH:29]=3)[CH:11]=2)=[CH:39][CH:38]=1)[CH3:32]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)OC
Reactant: CCCn1c(CCOS(=O)(=O)c2ccc(C)cc2)cn(Cc2ccc(C)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCn1c(CCOc2ccc(CC(C)(OC)C(=O)OCC)cc2)cn(Cc2ccc(C)cc2)c1=O
Temperature: 75 °C
Yield: 43.1 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethyl ester (0.079 g, 0.184 mmol), 3-(4-hydroxy-phenyl)-2-methoxy-2-methyl-propionic acid ethyl ester (0.038 g, 0.169 mmol) and K2CO3 (0.047 g, 0.340 mmol) in EtOH (8 mL) was heated at 75° C. under N2 for 16 h. The reaction mixture was cooled to room temperature and quenched with aqueous 1 N HCl (1 mL). The solvent was removed in vacuo to give a residue that was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using a 2:1 hexanes:acetone to afford 0.036 g (44%) 2-methoxy-2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:20]([CH3:21])[CH:19]=[CH:18][C:5]2=[N:6][C:7]=1[C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9].[CH3:22][C:23]1[C:27](B2OC(C)(C)C(C)(C)O2)=[C:26]([CH3:37])[O:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:22][C:23]1[C:27]([C:2]2[CH:3]=[C:4]3[N:20]([CH3:21])[CH:19]=[CH:18][C:5]3=[N:6][C:7]=2[C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[C:26]([CH3:37])[O:25][N:24]=1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccn(C)c2cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1noc(C)c1-c1cc2c(ccn2C)nc1[C@H](C)NC(=O)OC(C)(C)C

Procedure:
A solution of (S)-tert-butyl (1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)carbamate (100 mg, 0.282 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (126 mg, 0.565 mmol) and PdCl2(dppf)-CH2Cl2 adduct (11 mg, 0.014 mmol) in dioxane (1.0 mL) and 3 M aqueous potassium carbonate (1.01 mL, 3.02 mmol) were heated at 120° C. for 1 hour in a microwave reactor. The mixture was diluted with EtOAc (50 mL), washed with saturated aqueous ammonium chloride (50 mL) and brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified on a silica gel column (24 g) eluting with a 0-50% EtOAc gradient in hexanes to give the title compound as a clear, colorless oil (107 mg, 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27-1.35 (m, 9 H), 2.05 (d, J=12.6 Hz, 3 H), 2.20-2.28 (m, 3 H), 3.77-3.85 (m, 3 H), 4.52-4.68 (m, 1H), 6.59 (d, J=3.0 Hz, 1 H), 6.81-6.90 (m, 1 H), 7.68 (d, J=3.3 Hz, 1 H), 7.71 (d, J=8.8 Hz, 1 H); ESI-MS m/z [M+H]+ calc'd for C20H26N4O3, 371; found 371.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:5][CH2:4]1.C(O)(=O)C.C(N(C(C)C)C(C)C)C.[CH2:29]([O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[CH3:40])[CH:35]=O)[CH3:30].C([BH3-])#N.[Na+]>C(O)C>[CH2:29]([O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[CH3:40])[CH2:35][N:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:5][CH2:4]1)[CH3:30]
Reactant: CCOc1cc(C=O)ccc1C
Reactant: c1cncc(NC2CCNCC2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(CN2CCC(Nc3cccnc3)CC2)ccc1C
Temperature: 55 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
To a solution of piperidin-4-yl-pyridin-3-yl-amine dihydrochloride (37.5 mg, 0.15 mmol, 1.0 equiv; intermediate A1) in ethanol (1 mL), acetic acid (72.1 mg, 1.2 mmol, 8.0 equiv) and N-ethyl diisopropylamine (77.6 mg, 0.6 mmol, 4.0 equiv) was added 3-ethoxy-4-methyl-benzaldehyde (29.6 mg, 0.18 mmol, 1.2 equiv; intermediate B21, vide infra) and the mixture stirred at 55° C. After 1 h, sodium cyanoborohydride (47.1 mg, 0.75 mmol, 5.0 equiv), dissolved in ethanol (0.5 mL), was added and the mixture stirred at 55° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 11.3 mg (23%) of the title compound. MS (ISP): 326.3 [M+H]+.