Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:12])[N:3]=1.CN(C)C=O.[CH3:18][CH:19]([CH3:22])[CH2:20][NH2:21]>C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:21][CH2:20][CH:19]([CH3:22])[CH3:18])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: CC(C)CN
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(NCC(C)C)c([N+](=O)[O-])c(Cl)n1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2,4-Dichloro-6-methyl-3-nitropyridine (7.01 g), anhydrous dimethylformamide (70 ml), and triethylamine (4.72 ml) were combined and cooled to 0° C. 2-Methylpropylamine (3.36 ml) was added dropwise to the resulting mixture. The reaction was stalled at 75% completion, as determined by HPLC and TLC monitoring, after 16 hours. The dimethylfornamide was removed from the resulting reaction mixture under reduced pressure, and the resulting oil was dissolved in ethyl acetate. The ethyl acetate solution was washed with water, dried with magnesium sulfate, and the solvent was removed under reduced pressure. The resulting yellow oil was put through a column of silica using 90/10 hexane/ethyl acetate. After removing the solvent from the resulting eluted solution, the resulting yellow oil (5.0 g) was dried under high vacuum and used in the next step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17]CN3C(=O)N4C=CC=CC4=N3)[CH2:14][CH:15]=2)=[CH:2]1.[O:29]=[C:30]1[N:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]2=[N:32][N:31]1CCOS(C1C=CC(C)=CC=1)(=O)=O.N1CCC(C2C3C(=CC=CC=3)NC=2)CC1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:31]3[C:30](=[O:29])[N:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]4=[N:32]3)[CH2:12][CH2:11]2)=[CH:2]1
Reactant: O=c1n(CCCN2CC=C(c3c[nH]c4ccccc34)CC2)nc2ccccn12
Reactant: Cc1ccc(S(=O)(=O)OCCn2nc3ccccn3c2=O)cc1
Agent: c1ccc2c(C3CCNCC3)c[nH]c2c1
Product: O=c1n(CCN2CCC(c3c[nH]c4ccccc34)CC2)nc2ccccn12

Procedure:
2-{2-[4-(1H-Indol-3-yl)-piperidin-1-yl]-ethyl}-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one was prepared in a similar fashion to of 2-{2-[4-(1H-Indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl}-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (example 22) using of toluene-4-sulfonic acid 2-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2-yl)-ethyl ester and 3-Piperidin-4-yl-1H-indole. Yield: 70 mg of compound was obtained (39%). mp: 142° C.; M+:362.1; H-NMR: 8.14 (b, 1H, NH), 7.74 (m, 1H), 7.62 (m, 1H), 7.35(m, 1H), 7.08 (m, 5H), 6.94 (m, 1H), 6.45 (m, 1H), 4.23 (m, CH2), 3.13 (d, CH2), 2.93 (m, CH2), 2.82 (m, 1H) 2.28 (t, CH2), 2.04(m, CH2), 1.86(m, CH2).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4].[CH:9](N)([CH3:11])[CH3:10]>CN(C=O)C>[CH:9]([N:8]1[CH2:2][C:3](=[O:4])[NH:5][C:6]1=[O:7])([CH3:11])[CH3:10]
Reactant: NC(=O)NC(=O)CCl
Reactant: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)N1CC(=O)NC1=O
Temperature: 135 °C

Procedure:
(2-Chloroacetyl)-urea (0.68 g, 5.00 mmol) and isopropylamine (0.86 mL, 10.0 mmol) in DMF (10 mL) was stirred for 6 h at room temperature and then heated to 135° C. for 4 hours. DMF was removed under vacuum and the residue was purified by column chromatography (silica gel 230-400 mesh; eluting with hexane:dichloromethane:ethyl acetate 2.5:1.0:0.5) to give 1-isopropyl-imidazolidine-2,4-dione as a white solid. Yield: 0.20 g (28%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:12]([O:16][C:17](=[O:29])[NH:18][CH2:19][C:20]1[C:21]([O:27][CH3:28])=[N:22][CH:23]=[C:24]([NH2:26])[CH:25]=1)([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>C(Cl)Cl>[C:12]([O:16][C:17](=[O:29])[NH:18][CH2:19][C:20]1[C:21]([O:27][CH3:28])=[N:22][CH:23]=[C:24]([NH:26][S:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])[CH:25]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: COc1ncc(N)cc1CNC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ncc(NS(=O)(=O)c2cccnc2Cl)cc1CNC(=O)OC(C)(C)C
Yield: 95 %

Procedure:
The title compound (2.12 g, 4.94 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (1.10 g, 5.20 mmol), tert-butyl(5-amino-2-methoxypyridin-3-yl)methylcarbamate (IntA34) (1.45 g, 5.72 mmol) and pyridine (1.26 mL, 15.6 mmol) in DCM (20 mL) at rt using the methods of (IntC1).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2>N1CCCCC1.C(O)C>[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13]
Reactant: Cc1c(Cl)ccc2c1CC(=O)N2
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(Cl)c(C)c21
Yield: 55 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (91 mg), 91 mg 5-chloro-4-methyl-2-oxindole and 2 drops piperidine in 2 mL of ethanol were heated at 90° C. for 4 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 95 mg of the title compound.
Reaction SMILES: [OH:1][C:2]([CH3:24])([CH3:23])[CH2:3][O:4][CH2:5][C:6]1[N:11]=[C:10]([NH:12]C(=O)OCC2C=CC=CC=2)[CH:9]=[CH:8][CH:7]=1.[H][H]>CO.[Pd]>[NH2:12][C:10]1[N:11]=[C:6]([CH2:5][O:4][CH2:3][C:2]([CH3:24])([OH:1])[CH3:23])[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CC(C)(O)COCc1cccc(NC(=O)OCc2ccccc2)n1
Agent: [Pd]
Solvent: CO
Product: CC(C)(O)COCc1cccc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl {6-[(2-hydroxy-2-methylpropoxy)methyl]pyridin-2-yl}carbamate (368 mg, 1.11 mmol) in methanol (11 mL) was added palladium on carbon (10% w/w, 119 mg, 1.11 mmol). A hydrogen balloon was fitted on top of the flask and the flask was evacuated and then backfilled with hydrogen. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through CELITE, and the CELITE was washed with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-12% methanol/DCM, linear gradient) to afford 1-[(6-aminopyridin-2-yl)methoxy]-2-methylpropan-2-ol. MS ESI calc'd. for C10H17N2O2 [M+H]+ 197. found 197. 1H NMR (500 MHz, CDCl3) δ 7.42 (t, J=7.8 Hz, 1H), 6.69 (d, J=7.3 Hz, 1H), 6.39 (d, J=8.2 Hz, 1H), 4.53 (s, 2H), 4.49 (s, 1H), 3.41 (s, 2H), 1.23 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O-:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1.[C:26]1([C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:33][CH2:34]O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH2:34][CH:33]=[C:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C(=O)[O-])C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Reactant: OCC=C(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC1=C(C(=O)OCC=C(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1

Procedure:
308 mg (0.85 mmol) of mono(2-cyanoethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, 348 mg (1.65 mmol) of 3,3-diphenyl-2-propene-1-ol, 260 mg (1.36 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 26 mg (0.21 mmol) of 4-dimethylaminopyridine were stirred together in 10 ml of dichloromethane at room temperature for one hour. Water was added to the reaction liquid. After the extraction with dichloromethane, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=2/1) to obtain the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH:10]([OH:16])[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]([C:28]([F:31])([F:30])[F:29])=[CH:19][C@@H:20]1[C@H:22]([C:23](Cl)=[O:24])[C:21]1([CH3:27])[CH3:26].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:17][C:18]([C:28]([F:29])([F:30])[F:31])=[CH:19][C@@H:20]1[C@H:22]([C:23]([O:16][CH:10]2[CH2:9][C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11]2)=[O:24])[C:21]1([CH3:27])[CH3:26]
Reactant: OC1Cc2cccc(-c3ccccc3)c2C1
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OC1Cc2cccc(-c3ccccc3)c2C1
Yield: 61.4 %

Procedure:
In the manner of Example 12A, the reaction of 1.5 g (0.007 mole) of (+)-4-phenyl-2-indanol (EE≥95%) and 1.77 g (0.007 mole) of (+)-cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride in the presence of 0.7 g (0.009 mole) of pyridine and 20 ml of toluene gave 1.87 g of (+)-4-phenyl-2-indanyl (+)-cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate as an oil, EE≥95% (alcohol moiety). The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=[C:6]([CH2:14][OH:15])[CH:5]=1)[CH3:2]>ClCCl.C(O)C.O=[Mn]=O>[CH2:1]([O:3][C:4]1[C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=[C:6]([CH:14]=[O:15])[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(CO)cc2oc(=O)[nH]c12
Agent: O=[Mn]=O
Solvent: CCO
Solvent: ClCCl
Product: CCOc1cc(C=O)cc2oc(=O)[nH]c12
Temperature: 40 °C
Yield: 77.5 %

Procedure:
To a solution of 4-ethoxy-6-hydroxymethyl-3H-benzooxazol-2-one (0.69 g, 3.30 mmol, 1.0 equiv) in a mixture of dichloromethane (40 mL) and ethanol (5 mL) was added activated MnO2 (1.15 g, 13.2 mmol, 4.0 equiv). The reaction mixture was heated to 40° C. for 2 h, filtered through Hyflo Super Cel and concentrated by evaporation under reduced pressure. The residue was purified by flash column chromatography on silica eluting with heptane/ethyl acetate (1:1) to yield 0.53 g (78% yield) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.43 (t, J=7.0 Hz, 3H), 4.23 (q, J=7.0 Hz, 2H), 7.38 (s, 1H), 7.42 (s, 1H), 9.87 (s, 1H), 12.28 (br s, 1H). 13C NMR (75 MHz, DMSO): δ 14.41, 64.63, 104.07, 109.32, 125.20, 131.05, 143.13, 143.88, 154.21, 191.11. MS (ISP): 208.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:8]#[N:9])[CH2:6][C:5](=[CH2:7])[CH2:4]1.C(Cl)Cl.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>>[CH3:20][S:21]([O:1][CH2:2][C:3]1([C:8]#[N:9])[CH2:6][C:5](=[CH2:7])[CH2:4]1)(=[O:23])=[O:22]
Reactant: C=C1CC(C#N)(CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C1CC(C#N)(COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-(hydroxymethyl)-3-methylenecyclobutanecarbonitrile (0.756 g, 0.00614 mol) in methylene chloride (20 mL, 0.3 mol) was added triethylamine (1.28 mL, 0.00921 mol) followed by methanesulfonyl chloride (0.594 mL, 0.00767 mol) at 0° C. The reaction was stirred at rt for 1 h, quenched with water, and extracted with dichloromethane. The combined organic layers were washed with water, brine, and then dried over magnesium sulfate and evaporated to dryness. The residue was used directly in next step.
Reaction SMILES: [CH:1]([C@:4]12[CH2:12][CH2:11][C:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C:9]=3[C:8]1=[CH:7][CH2:6][C:5]2=[O:23])([CH3:3])[CH3:2]>O1CCOCC1.[Ni].[H][H]>[CH:1]([C@:4]12[CH2:12][CH2:11][C:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C:9]=3[C@@H:8]1[CH2:7][CH2:6][C:5]2=[O:23])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCC1=C2CC[C@]2(C(C)C)C(=O)CC=C12
Reactant: [H][H]
Agent: [Ni]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CCC1=C2CC[C@]2(C(C)C)C(=O)CC[C@@H]12
Yield: 59.6 %

Procedure:
Shake 13β-isopropyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (2 g) in dioxan (50 cc) with a freshly prepared but moderately active Raney nickel catalyst (ca. 0.5 g) in hydrogen at atmospheric pressure. When, after several hours the theoretical amount of hydrogen for half-hydrogenation (160 cc) has been absorbed, filter off the nickel catalyst and remove the solvent by evaporation. Crystallize the residual gum from methanol to obtain the title product (1.2 g), m.p. 85°-100°C; ultraviolet absorption peak at 280 mμ (ε11,800).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH3:30])[CH:24]=[CH:23]2.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[C:25]([CH3:30])[CH:24]=[CH:23]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Cc1ccc2cc(N)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2cc(NS(=O)(=O)c3cccc(Cl)c3C)ccc2n1
Reaction time: 0.08 h
Yield: 67.5 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (149 mg, 0.664 mmol) in dichloromethane (4 mL) was added pyridine (130 μL, 1.58 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-amino-2-methylquinoline (100 mg, 0.632 mmol) was added. The resulting mixture was stirred for 90 min at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford an off-white solid (148 mg, 68%), single spot at Rf 0.64 (ethyl acetate). mp 178.1-178.4° C., HPLC purity 99+% (tR 2.27 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.93-7.89 (3H, m), 7.53 (1H, d, J=8.2 Hz), 7.44 (1H, d, J=2.5 Hz), 7.31-7.24 (2H, m), 7.18 (1H, t, J=8.1 Hz), 2.73 (3H, s), 2.69 (3H, s). LCMS: 345.17 (M−). FAB-MS (MH+, C17H15CIN2O2S): calcd 347.0621, found 347.0622.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=1)=[O:6].Br[CH:28]([C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=1)[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:32]([O:31][C:29]([CH:28]([C:39]1[CH:40]=[CH:41][C:42]([CH2:45][CH:46]([CH3:48])[CH3:47])=[CH:43][CH:44]=1)[O:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=1)=[O:6])=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2cccc(O)c2)c2ccccc21
Reactant: CC(C)Cc1ccc(C(Br)C(=O)OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCn1cc(C(=O)c2cccc(OC(C(=O)OCc3ccccc3)c3ccc(CC(C)C)cc3)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 165.9 %

Procedure:
A mixture of ethyl 4-[3-(3-hydroxybenzoyl)indol-1yl]butyrate (984 mg), benzyl 2-bromo-2-[4-isobutylphenyl)acetate (362 mg) and diisopropylethylamine (362 mg) in dichloromethane (10 ml) was stirred at 25° C. for 20 hours, and then refluxed for 70 hours. The mixture was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (20 g) eluting with a mixture of ethyl acetate and hexane (1:4) to give ethyl 4-[3-[3-[(benzyloxycarbonyl)(4isobutylphenyl)methoxy]benzoyl]indol-1-yl]butyrate (1.05 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH3:14].[Br:15][C:16]1[CH:17]=[C:18]([C:28](O)=O)[N:19]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>C(#N)C>[Br:15][C:16]1[CH:17]=[C:18]([C:28]2[O:12][C:11](=[O:13])[C:10]3[C:2](=[C:3]([CH3:14])[CH:4]=[C:5]4[CH:6]=[N:7][NH:8][C:9]4=3)[N:1]=2)[N:19]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1
Reactant: Cc1cc2cn[nH]c2c(C(=O)O)c1N
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 700 mg (3.66 mmol) of 6-amino-5-methyl-1H-indazole-7-carboxylic acid in 26 mL of anhydrous acetonitrile is added 1.11 g (3.66 mmol) of 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid followed by 1.3 mL (16.2 mmol) of pyridine. The mixture is stirred at ambient temperature during 30 minutes. Then the suspension is cooled to 0° C. and 1.0 mL (12.9 mmol) of methanesulfonyl chloride is added drop wise. The mixture is stirred at ambient temperature for 16 hours. Then the solvent is evaporated and the residue is triturated with a minimum of cold water. The precipitate, which is formed is filtrated, washed with cold water and dried. The pale yellowish product obtained (1.6 g) is engaged in the next step; LC/MS:459/461 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C:25](=[O:44])[C:26]([CH3:43])([C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1)[CH3:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:44])[C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:16]2[CH:17]=[CH:18][C:13]([C:12]3[O:11][N:10]=[C:9]([CH3:20])[C:8]=3[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])=[CH:14][CH:15]=2)=[CH:30][CH:29]=1)([CH3:43])[CH3:27])[CH3:23]
Reactant: CCOC(=O)C(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Product: CCOC(=O)C(C)(C)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)(C)C)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid tert-butyl ester and 2-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid ethyl ester.
Reaction SMILES: P(=O)(O)(O)O.O.[CH2:7]([N:14]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:15]1[CH2:19][C@H:18]([C:20]([O-:22])=[O:21])[C@H:17]([CH3:23])[CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1([C@H](N)C)C=CC=CC=1>CC(OC)(C)C>[CH2:24]([N:14]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C@@H:15]1[CH2:19][C@H:18]([C:20]([OH:22])=[O:21])[C@H:17]([CH3:23])[CH2:16]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C[C@@H]1C[C@H](N(Cc2ccccc2)Cc2ccccc2)C[C@@H]1C(=O)[O-]
Agent: C[C@@H](N)c1ccccc1
Agent: O=P(O)(O)O
Solvent: O
Solvent: COC(C)(C)C
Product: C[C@@H]1C[C@H](N(Cc2ccccc2)Cc2ccccc2)C[C@@H]1C(=O)O
Yield: 99.2 %

Procedure:
Phosphoric acid (11.40 mL, 196 mmol) was added to a flask containing water (500 mL). The solution was stirred for about 5 min. (1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylate•(R)-1-phenylethanamine (83 g, 187 mmol) was added to the solution in small portions. MTBE (500 mL) was added and the contents were mixed well, dissolving the solid. The phases were settled and separated. The aqueous layer was back extracted with MTBE (150 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford (1S,2R,4S)-4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid (60 g, 99%) as an oil: HPLC (Table 1, Method x) Rt=4.57 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11](OCC)(=[O:15])[C:12]([CH3:14])=O>O1CCCC1>[CH3:14][C:12]1[C:11](=[O:15])[NH:9][C:5]2[C:4]([N:10]=1)=[CH:3][C:2]([CH3:1])=[C:7]([CH3:8])[CH:6]=2
Reactant: Cc1cc(N)c(N)cc1C
Reactant: CCOC(=O)C(C)=O
Solvent: C1CCOC1
Product: Cc1cc2nc(C)c(=O)[nH]c2cc1C
Temperature: 25 °C

Procedure:
4,5-Dimethyl-o-phenylenediamine (10.0 g., 0.073 mol.) was dissolved in tetrahydrofuran (200 ml.) and ethyl pyruvate (12.75 g., 0.11 mol.) added. The reaction mixture was stirred at room temperature for eighteen hours, during which time a white solid precipitated was collected by filtration (13.35 g.). Recrystallization from methanol-chloroform gave fine white needles. (12.65 g., m.p. 306-308°, 92%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:19][CH:20]=[O:21])[CH:6](O)[C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:17])[CH3:16])[CH2:11][CH2:10]1)=[CH2:8])[CH3:2].S(Br)([Br:25])=O.O>ClCCCl>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:19][CH:20]=[O:21])[CH:6]=[C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:17])[CH3:16])[CH2:11][CH2:10]1)[CH2:8][Br:25])[CH3:2]
Reactant: O=S(Br)Br
Reactant: C=C(C1CCN(C(C)=O)CC1)C(O)C(NC=O)C(=O)OCC
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)C(C=C(CBr)C1CCN(C(C)=O)CC1)NC=O
Reaction time: 0.25 h

Procedure:
3.3 g (10.5 mmol) of 4-(1-acetylpiperidin-4-yl)-2-formylamino-3-hydroxy-pent-4-enoic acid ethyl ester are dissolved in 25 ml of 1,2-dichloroethane, and 0.98 ml (12.6 mmol) of thionyl bromide are added dropwise at room temperature. After 11/2 hours, 20 ml of water are added and the mixture is stirred vigorously for 15 minutes. The organic phase is separated off, washed in succession with water, N-potassium hydrogen carbonate solution and again with water, dried over sodium sulfate, filtered and concentrated by evaporation. 4-(1-acetylpiperidin-4-yl)-5-bromo-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a reddish-brown oil.
Reaction SMILES: [C:1]([C:3](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:18]=[C:19]3[C:25]([C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:24][N:23](COCC[Si](C)(C)C)[C:20]3=[N:21][CH:22]=2)=[CH:12][CH:11]=1)[C:4]([NH:6][CH2:7][CH3:8])=[O:5])#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3](=[CH:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[N:18]=[C:19]3[C:25]([C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:24][NH:23][C:20]3=[N:21][CH:22]=2)=[CH:14][CH:15]=1)[C:4]([NH:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCNC(=O)C(C#N)=Cc1ccc(Nc2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)C(C#N)=Cc1ccc(Nc2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 20 ml vial 2-cyano-3-[4-[[7-(2,2-dimethylpropanoyl)-5-(2-trimethylsilylethoxy-methyl)-pyrrolo[2,3-b]pyrazin-2-yl]amino]phenyl]-N-ethyl-prop-2-enamide (37 mg, 0.07 mmol was dissolved in DCM (3 ml) and TFA (2.63 ml, 18.88 mmol) was added. The reaction mixture was stirred at room temperature for 3 hr. The solvent was evaporated, the residue was neutralized with NaHCO3 to pH 7-8 and the aq. layer was extracted with EtOAc. The solvent was evaporated and the residue was dissolved in methanol (5 ml). HCl (4 drops) and water, were added and the reaction mixture was stirred at RT overnight. The reaction was neutralized with NaHCO3 to pH 7-8. The product was precipitated, filtrated and washed by water to yield 20 mg 2-cyano-3-[4-[[7-(2,2-dimethylpropanoyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]amino]phenyl]-N-ethyl-prop-2-enamide as dark red brown solid.