Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:24]=[C:25]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:26]=[CH:27][CH:28]=1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1cccc(C(F)(F)F)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3-(trifluoromethyl)phenyl isocyanate (0.37 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a beige solid (0.30 g, 41% yield), mp=60–62° C.; MS (−) ESI m/z=366 (M−H)−; [α]D25=−22.0° (c=1, EtOH).
Reaction SMILES: C(C(CCCC)COC(=O)C[CH2:8][S:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]1[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[N:21][N:22]=[C:15]1[CH:14]=[CH:13]2)C.FC1[N:40]=[C:39]([C:41]2([C:47]#[N:48])[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH:38]=[CH:37][CH:36]=1.CC(C)([O-])C.[K+]>CN(C=O)C.CCOC(C)=O.O>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:20]1[N:16]2[C:17]3[C:12]([CH:13]=[CH:14][C:15]2=[N:22][N:21]=1)=[CH:11][C:10]([S:9][C:8]1[N:40]=[C:39]([C:41]2([C:47]#[N:48])[CH2:42][CH2:43][O:44][CH2:45][CH2:46]2)[CH:38]=[CH:37][CH:36]=1)=[CH:19][CH:18]=3
Reactant: N#CC1(c2cccc(F)n2)CCOCC1
Reactant: CCCCC(CC)COC(=O)CCSc1ccc2c(ccc3nnc(-c4ccccn4)n32)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CC1(c2cccc(Sc3ccc4c(ccc5nnc(-c6ccccn6)n54)c3)n2)CCOCC1
Temperature: 80 °C

Procedure:
5m (93 mg, 0.2 mmol) and 4-(6-Fluoro-pyridin-2-yl)-tetrahydro-pyran-4-carbonitrile (5n, 41 mg, 0.2 mmol) were dissolved in DMF (2 mL) and degassed with N2. Potassium tert-butoxide (22 mg, 0.2 mmol) was added, and the reaction was sealed and heated to 80° C. overnight. After cooling to room temperature, the mixture was diluted with EtOAc and water, and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to obtain the desired product, 5p.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]([CH3:13])=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].[CH3:16][C:17]1[NH:21][N:20]=[C:19]([NH2:22])[CH:18]=1>CC(O)=O>[CH3:15][O:14][C:11]1[C:12]([CH3:13])=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:7])[NH:2][C:1]([NH:22][C:19]1[CH:18]=[C:17]([CH3:16])[NH:21][N:20]=1)=[CH:3]2
Reactant: COc1ccc(C(=O)O)c(CC#N)c1C
Reactant: Cc1cc(N)n[nH]1
Solvent: CC(=O)O
Product: COc1ccc2c(=O)[nH]c(Nc3cc(C)[nH]n3)cc2c1C
Temperature: 130 °C

Procedure:
A 10˜20 mL process vial was charged with 500 mg 2-Cyanomethyl-4-methoxy-3-methyl-benzoic acid and 5-Methyl-1H-pyrazol-3-ylamine in 15 mL AcOH. The vial was heated at 130° C. for 30 min under microwave irradiation. Most of the solvent was removed under reduced pressure, and the residue was poured into ice-water. The solid was collected and washed with water.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([CH:14]2[CH2:23][CH2:22][C:17]3(OCC[O:18]3)[CH2:16][CH2:15]2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[C:28]([F:40])[CH:27]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:15][CH2:16][C@H:17]([OH:18])[CH2:22][CH2:23]2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[C:28]([F:40])[CH:27]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 4′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-fluorobiphenyl-2-carbonitrile (4.7 g) in tetrahydrofuran (40 mL) was added 3M hydrochloric acid (40 mL), and the mixture was stirred at 70° C. for 2 hr. The mixture was allowed to cool, and diluted with ethyl acetate, and the mixture was neutralized with 8M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (20 mL)-tetrahydrofuran (20 mL). Thereto was added sodium borohydride (0.26 g) at 0° C. After stirring for 1 hr, ethyl acetate and saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (3.3 g, 98%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:12][C:13]1[CH:25]=[CH:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][C:15]=2[CH:14]=1>C(OCC)(=O)C>[CH:14]1[C:15]2[CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]=2[CH:24]=[CH:25][C:13]=1[NH:12][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: Nc1ccc2c(c1)Cc1ccccc1-2
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(O)cc1Nc1ccc2c(c1)Cc1ccccc1-2
Temperature: 140 °C
Reaction time: 9 h

Procedure:
2.17 g of 3-fluoro-4-nitrophenol and 5 g of 2-aminofluorene were mixed and stirred for 9 hours at 140° C. The raw mixture was taken up in ethyl acetate and water and washed with 1N aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed three times with 2N aqueous hydrochloric acid and once with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was chromatographed on silica gel.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH2:12][C@@H:11]([N:23]2[C:27]3[N:28]=[CH:29][N:30]=[C:31]([NH:32][C@@H:33]4[C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH2:35][CH2:34]4)[C:26]=3[CH:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.C(O)(=O)C>O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:10][C@H:11]([N:23]2[C:27]3[N:28]=[CH:29][N:30]=[C:31]([NH:32][C@@H:33]4[C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH2:35][CH2:34]4)[C:26]=3[CH:25]=[CH:24]2)[CH2:12][C@H:13]1[CH2:14][OH:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@H]1CO
Temperature: 40 °C

Procedure:
7-[(1R,3S,4S)-3-[tert-butyl(dimethyl)silyl]oxy-4-([tert-butyl(dimethyl)silyl]-oxymethyl)cyclopentyl]-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.66 g, 0.00280 mol) was dissolved in a mixture of tetrahydrofuran (6.6 mL), water (6.6 mL, 0.36 mol), and acetic acid (19 mL, 0.34 mol). The solution was then heated to 40° C. overnight. The mixture was then cooled and evaporated, azeotroped with toluene (2×50 mL) and the residue was purified by silica gel chromatography eluting with 0 to 100% ethyl acetate in dichloromethane to yield the product as a white solid, 1.05 g (74%). LC/MS: Rt=1.68 min, ES+ 479 (AA standard).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])(C)(C)C.[ClH:28].O1CCOCC1>>[ClH:28].[NH2:7][C@@H:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1Cc2ccccc2C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C(=O)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[(1S)-Benzyl-2-(1,3-dihydro-isoindol-2-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (88 mg) was dissolved in cold 4N HCl-dioxane (1.5 mL), stirred 2 h at 25° C., and the mixture concentrated. The residue was triturated with ether and dried (65 mg, 91%). TSPMS 267 (MH+, 100%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[C:13]([C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:34])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:18]=[CH:19][CH:20]=1)#[N:14].C(N(CC)CC)C>C(#N)C>[C:13]([C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:34])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=3)(=[O:31])=[O:32])=[CH:26][CH:25]=2)[CH:18]=[CH:19][CH:20]=1)#[N:14]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)Cl)cc2)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3cccc(C(F)(F)F)c3)cc2)c1
Reaction time: 72 h
Yield: 97.3 %

Procedure:
3-Trifluoromethylbenzylamine (0.52 g, 1 eq.) was added to a solution of 4-[3-(3-cyanophenyl)-ureido]-benzenesulfonyl chloride (1 g, 1 eq.) and triethylamine (1.05 ml, 1.6 eq.) in acetonitrile (10 ml) under inert atmosphere. The mixture was stirred for 3 d, concentrated in vacuo and water was added. The resulting precipitate was filtered off and dried in vacuo to yield 1.37 g (97%) of 4-[3-(3-cyanophenyl)-ureido]-N-(3-trifluoromethylbenzyl)-benzenesulfonamide.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[NH:6][C:7](=[O:41])[C:8]2[S:13][C:12](=[O:14])[N:11]([C@@H:15]3[O:29][C@H:28]([CH2:30][O:31]C(C4C=CC(C)=CC=4)=O)[C@@H:17]([O:18]C(C4C=CC(C)=CC=4)=O)[CH2:16]3)[C:9]=2[N:10]=1>CO>[NH2:4][C:5]1[NH:6][C:7](=[O:41])[C:8]2[S:13][C:12](=[O:14])[N:11]([C@@H:15]3[O:29][C@H:28]([CH2:30][OH:31])[C@@H:17]([OH:18])[CH2:16]3)[C:9]=2[N:10]=1
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3c(=O)sc4c(=O)[nH]c(N)nc43)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nc2c(sc(=O)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium methoxide (120 mg, 2.2 mmol) was added to a solution of 5-Amino-3-(2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythropentofuranosyl)thiazolo[4,5-d]pyrimidin-2,7-dione (35; 0.465g, 0.87 mmol) in anhydrous methanol (100 mL) and the resulting solution stirred at room temperature for 8 hours. The solution was neutralized with Dowex 50W-X8 (H+ form) resin, filtered, and evaporated to dryness and the residue treated with anhydrous ether (35 mL). After trituration, the suspension was decanted to give a dry powder which was crystallized (charcoal treatment, Norit A) from ethanol. After filtering off the initial precipitate, 110 mg (42%) of the β isomer could be recovered by fractional crystallization using ethanol. mp>170° C. (scinters), UV 1H NMR (Me2SO-d6) σ4.68 (t, 1, J=5.7 Hz, C3 'OH, exchanged with D2O), 5.20 (d, 1, J=3.9 Hz, C5 'OH, exchanged with D2O), 6.24 (t, 1, J=7.2 Hz C1 'H), 6.94 (bs, 2, NH2, exchanged with D2O), 11.23 (bs, 1, N6H, exchanged with D2O); Anal. Calcd. for C10H12N4O5S: C, 40.00; H, 4.03; N, 18.66; S, 10.68; Found: C, 40.27; H, 3.92; N, 18.75; S, 10.42.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][C:12]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([C:23](OC)=[O:24])=[CH:17]2.Cl>C1(C)C=CC=CC=1.C1COCC1>[Br:11][C:12]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([CH2:23][OH:24])=[CH:17]2
Reactant: COC(=O)c1ccc2c(Br)cc(F)cc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1ccc2c(Br)cc(F)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
1.0 M diisobutylaluminium hydride in toluene (11.5 mL) was slowly added to a solution of 30 (1.3 g, 4.6 mmol) in THF (15 mL) at −78° C. After the addition was completed, the mixture was allowed to warm to room temperature and continuously stirred for 18 h. The mixture was poured in to HCl aqueous solution (0.5 N, 50 mL) and extracted in ethyl acetate (2×100 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated rotary evaporation, and purified by column chromatography to give (5-bromo-7-fluoronaphthalen-2-yl)methanol (31) (98%). 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J=8.8 Hz, 1H), 7.77 (s, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.45 (d, J=11.4 Hz, 1H), 4.90 (s, 2H). GC-MS (ES) for C11H8BrFO [M+1]+ 255.
Reaction SMILES: C(O)=O.C(N(CC)CC)C.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C:30](=[O:33])[CH2:31][Cl:32])[C:22]2[O:27][CH2:26][C:25](=[O:28])[NH:24][C:23]=2[CH:29]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([C@@H:30]([OH:33])[CH2:31][Cl:32])[C:22]2[O:27][CH2:26][C:25](=[O:28])[NH:24][C:23]=2[CH:29]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1COc2c(cc(OCc3ccccc3)cc2C(=O)CCl)N1
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1COc2c(cc(OCc3ccccc3)cc2[C@@H](O)CCl)N1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
The method is carried out analogously to a process described in the literature (Org. Lett. 2002, 4, 4373-4376). 8 mL of a mixture of formic acid and triethylamine (molar ratio=5:2) are added dropwise at −15° C. to 13.15 g (39.6 mmol) 6-benzyloxy-8-(2-chloro-acetyl)-4H-benzo[1,4]oxazin-3-one and 25.5 mg (0.04 mmol) Cp*RhCl[(S,S)-TsDPEN] (Cp*=pentamethylcyclopentadienyl and TsDPEN=(1S,2S)—N-p-toluenesulfonyl-1,2-diphenylethylenediamine) in 40 mL dimethylformamide. The mixture is stirred for 5 hours at this temperature, then 25 mg catalyst are added and the mixture is stirred overnight at −15° C. The reaction mixture is combined with ice water and filtered. The filter residue is dissolved in dichloromethane, dried with sodium sulfate and freed from the solvent. The residue is chromatographed (dichloromethane/methanol gradient) and the product recrystallized from diethyl ether/diisopropylether. Yield: 10.08 g (76%); Rf value=0.28 (dichloromethane:methanol=50:1 on silica gel).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]#[C:8][C:9]1[C:10]([C:19]([O:21][CH3:22])=[O:20])=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10]([C:19]([O:21][CH3:22])=[O:20])=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=1)=[O:4]
Reactant: COC(=O)CCC#Cc1cnc(C(=O)OC)cc1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCc1cnc(C(=O)OC)cc1C(=O)OC
Reaction time: 4 h

Procedure:
305 mg of dimethyl 5-(4-methoxycarbonyl-1-butinyl)-pyridine-2,4-dicarboxylate (from Example 9) are dissolved in 30 ml of methanol and, after addition of the palladium catalyst (10% strength on charcoal) are hydrogenated. The reaction has ended after 4 hours (thin layer control). The catalyst is filtered off and the solution is evaporated in vacuo. The colorless oil is chromatographed on silica gel.
Reaction SMILES: S(=O)(O)[O-].[Na+].[CH2:6]([O:8][N:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)[CH3:7].[C-:16]#[N:17].[K+]>O>[CH2:6]([O:8][N:9]1[CH2:14][CH2:13][C:12]([OH:15])([C:16]#[N:17])[CH2:11][CH2:10]1)[CH3:7]
Reactant: [C-]#N
Reactant: CCON1CCC(=O)CC1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CCON1CCC(O)(C#N)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium bisulfite (10.7 g, 103 mmol) in 10 ml of water was cooled in an ice bath. Then, 1-ethoxy-piperidin-4-one (12.3 g, 86 mmol, prepared according to J. Org. Chem. 1961, 26, 1867-74) was added dropwise. After the addition, the mixture was stirred for another 30 min. A solution of potassium cyanide (8.4 g, 129 mmol) in 10 ml of water was added slowly, the reaction mixture was warmed up to room temperature and left stirring for 24 hours. The mixture was thoroughly extracted with ethyl acetate (4×30 ml) and the combined organic layers were washed twice with brine (2×30 ml) and dried over sodium sulfate. After filtration and concentration under vacuum, the residue was purified by column chromatography on silica gel. Yield: 13.2 g of 1-ethoxy-4-hydroxy-piperidine-4-carbonitrile (title compound P4.9) as a light yellow oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].O.C([O:11][C:12]1[C:17]([CH3:18])=[C:16]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:15][C:14](=[O:28])[C:13]=1[CH3:29])(=O)C>CO>[CH2:21]([O:20][CH2:19][C:16]1[O:15][C:14](=[O:28])[C:13]([CH3:29])=[C:12]([OH:11])[C:17]=1[CH3:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)Oc1c(C)c(COCc2ccccc2)oc(=O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1c(COCc2ccccc2)oc(=O)c(C)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
K2CO3 (3.0 g) and water (10 ml) were added to a solution of 4-acetyloxy-6-(benzyloxy)methyl-3,5-dimethyl-2H-pyran-2-one (6.08 g) in MeOH (100 ml), and after stirring at room temperature overnight, the reaction solution was celite filtered and the mother liquor was concentrated under reduced pressure. Water was added to the residue, extraction was performed with AcOEt, and the organic layer was dried with Na2SO4 and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=5/1→1/1) to obtain 6-(benzyloxy)methyl-3,5-dimethyl-4-hydroxy-2H-pyran-2-one.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[C:11]3[C:15]([CH:16]=[C:17](B4OC(C)(C)CC(C)(C)O4)[CH:18]=2)=[N:14][N:13](C2CCCCO2)[CH:12]=3)=[O:8])[N:6]=1.Br[C:36]1[CH:37]=[C:38]([NH:43][S:44]([CH:47]2[CH2:49][CH2:48]2)(=[O:46])=[O:45])[C:39]([OH:42])=[N:40][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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]>[CH:47]1([S:44]([NH:43][C:38]2[CH:37]=[C:36]([C:17]3[CH:16]=[C:15]4[C:11]([CH:12]=[N:13][NH:14]4)=[C:10]([NH:9][C:7]([C:5]4[N:6]=[C:2]([CH3:1])[S:3][CH:4]=4)=[O:8])[CH:18]=3)[CH:41]=[N:40][C:39]=2[OH:42])(=[O:45])=[O:46])[CH2:49][CH2:48]1
Reactant: O=S(=O)(Nc1cc(Br)cnc1O)C1CC1
Reactant: Cc1nc(C(=O)Nc2cc(B3OC(C)(C)CC(C)(C)O3)cc3nn(C4CCCCO4)cc23)cs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(C(=O)Nc2cc(-c3cnc(O)c(NS(=O)(=O)C4CC4)c3)cc3[nH]ncc23)cs1
Temperature: 140 °C
Yield: 41 %

Procedure:
2-Methyl-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1,3-thiazole-4-carboxamide (27.5 mg) was dissolved in 1,4-dioxane (0.5 ml) and N-(5-bromo-2-hydroxy-3-pyridinyl)cyclopropanesulfonamide (40 mg) was added. Sodium carbonate (48 mg) and Pd(dppf)Cl2 (8.3 mg) were weighed before further 1,4-dioxane (0.5 ml) and water (1 ml) were added. The reaction was heated under microwave irradiation at 140° C. for 20 min. The reaction was added to a silica SPE cartridge that was eluted with MeOH. The MeOH was evaporated to dryness and the residue was dissolved in DMSO:MeOH (1.6 ml, 1:1, v/v) and purified by MDAP (method F) to give the title compound (11 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH:25]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26]1.O>C(Cl)Cl>[CH:25]1([C:29]([NH:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[O:30])[CH2:28][CH2:27][CH2:26]1
Reactant: Nc1ccccc1N1CCc2ccccc21
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1N1CCc2ccccc21)C1CCC1
Temperature: 25 °C

Procedure:
A slurry of 1-(2-aminophenyl)indoline hydrochloride (41.44 g) in CH2Cl2 (400 ml) under N2 at 0° C. is treated dropwise with a solution of triethylamine (2.2 equivalents) in CH2Cl2 (80 ml) and then with a solution of cyclobutylcarbonyl chloride (20 g) in CH2Cl2 (50 ml). After warming to room temperature, the product is poured into water (300 ml). The organic layer is washed with 4 N HCl, 2.5 N NaOH, water, dried (Na2SO4), filtered, and concentrated to yield 1-[2-(cyclobutylcarbonyl)aminophenyl]indoline, m.p. 81°-83.5° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-].[CH3:5][CH:6]([CH3:8])[O-].CC(C)[O-].[Al+3].C(O)CCCCCO.[CH:22]([OH:25])([CH3:24])C>>[CH2:22]([OH:25])[CH2:24][CH2:1][CH2:2][CH2:4][CH:6]([CH3:8])[CH3:5]
Reactant: CC(C)O
Reactant: CC(C)[O-]
Agent: OCCCCCCO
Agent: [Al+3]
Product: CC(C)CCCCCO
Temperature: 125 °C

Procedure:
With the apparatus of Example 1, 174.2 grams aluminum tri-isopropoxide was charged, followed by 94.4 grams of isooctyl acohol and 108.4 grams of hexylene glycol. The mixture was heated with agitation to 90° C. where isopropyl alcohol began distilling off. A high boiling petroleum solvent was added and the material was heated to 125° C. where vacuum was applied to remove the remaining isopropyl alcohol. The material was cooled and adjusted to a final active solids content of 48% by addition of more petroleum solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH:12]([C:14]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[CH:32])[CH:26]=4)(=[O:24])=[O:23])([F:21])[C:15]4[O:16][C:17]([CH3:20])=[N:18][N:19]=4)[CH2:13][C:5]=3[C:4]=2[CH:3]=1>CO.[Pd]>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH:12]([C:14]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH3:32])[CH:26]=4)(=[O:23])=[O:24])([F:21])[C:15]4[O:16][C:17]([CH3:20])=[N:18][N:19]=4)[CH2:13][C:5]=3[C:4]=2[CH:3]=1
Reactant: C#Cc1cccc(S(=O)(=O)C(F)(c2nnc(C)o2)C2Cc3[nH]c4ccc(Cl)cc4c3C2)c1
Agent: [Pd]
Solvent: CO
Product: CCc1cccc(S(=O)(=O)C(F)(c2nnc(C)o2)C2Cc3[nH]c4ccc(Cl)cc4c3C2)c1
Reaction time: 5 h

Procedure:
A solution of 22 mg (0.05 mmol) (RS, SR)-7-chloro-2-[(3-ethynyl-benzenesulfonyl)-fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)-methyl]-1,2,3,4-tetrahydro-cyclopenta[b]indole in 0.5 mL of methanol was treated with 1 mg of palladium on activated charcoal (10%) and stirred intensely under H2 (atmospheric pressure) during 5 hrs. Filtration and evaporation of the solvent gave 21 mg (92%) of (RS, SR) 7-chloro-2-[(3-ethyl-benzenesulfonyl)-fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)-methyl]-1,2,3,4-tetrahydro-cyclopenta[b]indole, as a yellow solid, MS: 475 (MH+)