Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Si:8]([O:25][CH:26]([CH2:48][O:49]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:27][O:28][C:29](=[O:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[Si:8]([O:25][CH:26]([CH2:48][OH:49])[CH2:27][O:28][C:29](=[O:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])([C:21]([CH3:22])([CH3:24])[CH3:23])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(CO)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 3 h
Yield: 54 %

Procedure:
4 ml of trifluoroacetic acid is slowly dropped into a solution of 4 (4.65 mmol) in 50 ml of dichloromethane at room temperature. After 3 hours, this is washed with water and saturated sodium hydrogen carbonate solution. The combined organic phases are dried over MgSO4, filtrated and concentrated. The residue is purified on silica gel by flash chromatography using isohexane/ethyl acetate (7:1). Yield: 54% of a colorless oil.
Reaction SMILES: C([Li])CCC.N1CCOCC1.[O:12]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13]1.C([Li])(CC)C.[CH3:24][Si:25](Cl)([CH3:27])[CH3:26].Cl>CCCCCC.O1CCCC1.C1CCCCC1>[CH3:24][Si:25]([CH3:27])([CH3:26])[C:16]1[O:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=Cc1ccoc1
Agent: Cl
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CCCCCC
Solvent: C1COCCN1
Product: C[Si](C)(C)c1cc(C=O)co1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
n-Butyl lithium (a 2.5M solution in hexane; 28.8 ml, 72 mmol) was added to a solution of morpholine (6.28 ml, 72 mmol) in tetrahydrofuran (700 ml) at -78° under argon. After 20 minutes, 3-furaldehyde (7.0 g, 72 mmol) was added. After another 20 minutes, sec-butyl lithium (a 1.3M solution in cyclohexane; 55.4 ml, 72 mmol) was added dropwise and stirring continued at -78° for 7 hours before trimethylsilyl chloride (27 ml, 216 mmol) was added. Stirring was continued overnight (14 hours) while the cooling bath was allowed to attain room temperature. The solution was poured into ice cold 10% (v/v) hydrochloric acid (200 ml) and after stirring at 0° for 10 minutes, the layers were separated. The aqueous phase was extracted with diethyl ether. All the organic phases were combined, dried (magnesium sulfate) and evaporated to dryness to give a light brown oil, which was purified by flash chromatography on silica using 2% ethyl ether/hexane. Fractions with Rf of about 0.30 (silica, 10% ethyl ether/hexane) on evaporation gave the title aldehyde as a light yellow oil, b.p. 48°-50°/0.25 torr.
Reaction SMILES: [C:1]([C:3]([CH3:39])([CH3:38])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([CH:19]([CH:26]3[CH2:28][CH2:27]3)[CH2:20][C:21]([O:23]CC)=[O:22])[CH:16]=[CH:15][N:14]=2)[CH:8]=[CH:7][C:6]=1[C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1[F:37])#[N:2].[OH-].[Na+].Cl>C(O)C>[C:1]([C:3]([CH3:39])([CH3:38])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([CH:19]([CH:26]3[CH2:27][CH2:28]3)[CH2:20][C:21]([OH:23])=[O:22])[CH:16]=[CH:15][N:14]=2)[CH:8]=[CH:7][C:6]=1[C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1[F:37])#[N:2]
Reactant: CCOC(=O)CC(c1ccnc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C#N)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(F)c(-c2ccc(OCc3cc(C(CC(=O)O)C4CC4)ccn3)cc2CC(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
To a solution of ethyl 3-(2-(((2-(2-cyano-2-methylpropyl)-2′-fluoro-5′-methoxybiphenyl-4-yl)oxy)methyl)pyridin-4-yl)-3-cyclopropylpropanoate (234 mg) in ethanol (5.0 mL) was added 2N aqueous sodium hydroxide solution (0.44 mL), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (220 mg) as a white solid.
Reaction SMILES: [H-].[Na+].COP([CH2:9][C:10](=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)(=O)OC.[CH3:20][O:21][C:22](=[O:38])[CH2:23][O:24][CH2:25][C:26]#[C:27][CH2:28][N:29]1[C:34](=[O:35])[CH2:33][CH2:32][CH2:31][C@@H:30]1[CH:36]=O>C1COCC1>[CH3:20][O:21][C:22](=[O:38])[CH2:23][O:24][CH2:25][C:26]#[C:27][CH2:28][N:29]1[C:34](=[O:35])[CH2:33][CH2:32][CH2:31][C@@H:30]1/[CH:36]=[CH:9]/[C:10](=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1
Reactant: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1C=O
Reactant: COP(=O)(CC(=O)Cc1cccc(Cl)c1)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
Sodium hydride (60% dispersion in oil, 15 mg, 0.39 mmol) was added to a solution of [3-(3-chlorophenyl)-2-oxopropyl]-phosphonic acid dimethyl ester (97 mg, 0.35 mmol) in THF (1.5 mL) at 0° C. After 1 h at 0° C., a solution of [4-((R)-2-formyl-6-oxo-piperidin-1-yl)-but-2-ynyloxy]-acetic acid methyl ester (0.37 mmol, crude) in THF (1.5 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with aqueous acetic acid (50%, 15 mL) and extracted with EtOAc (3×15 mL). The combined organic phase was washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (20%→30% EtOAc/CH2Cl2, gradient) afforded 100 mg (68%) of the title compound.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][CH3:28])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][CH3:28])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OCC)ccn1
Solvent: CN(C)C=O
Solvent: CO
Product: CCOc1ccnc(N(CCCCCCC(=O)NO)c2ccccn2)c1
Reaction time: 17 h
Yield: 75 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (16 mg, 0.045 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 17 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:3 to 100:8) to furnish IV as a colourless oil (12 mg, 75%).
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[Br-].[CH3:15][O:16][C:17]([C:19]1[CH:44]=[CH:43][C:22]([CH2:23][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:21][C:20]=1[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:18].C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+]>C(Cl)Cl>[N:1]1([CH2:6]/[C:7](/[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:23]/[C:22]2[CH:43]=[CH:44][C:19]([C:17]([O:16][CH3:15])=[O:18])=[C:20]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:21]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccccc1
Reactant: O=C(Cn1ccnc1)c1nccs1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Solvent: ClCCl
Product: COC(=O)c1ccc(/C=C(/Cn2ccnc2)c2nccs2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72 %

Procedure:
To a mixture of 2-(imidazol-1-yl)-1-(thiazol-2-yl)ethanone (1.66 g; 8.5 mmol), 4-methyloxycarbonyl-3-phenyl-benzyl-triphenylphosphonium bromide (see Example 7, compound a), step E), (7.3 g; 12.8 mmol) and 18-crown-6 (0.1 g; 0.37 mmol) in methylene chloride (60 ml) was added at −50° C., under argon atmosphere, potassium tert-butoxide (1.56 g; 12.8 mmol). After 20 min at −50° C., the mixture was stirred at room temperature for 4 hours. The solvent was evaporated to dryness and the residue purified on HP20SS resin eluting with a gradient of 0-60% CH3CN/(NH4)2CO3 buffer (2 g/l pH 6.8) to give methyl 4-[(Z)-3-(imidazol-1-yl)-2-(thiazol-2-yl)-prop-1-enyl]-2-phenyl-benzoate (1.1 g; 72%).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:43]=[CH:44][CH:45]=1)[C:20]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:42])=[C:27]([NH:29][C:30](=[O:41])[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)[CH:28]=1)=[O:21])=[O:14])(C)(C)C>C(Cl)Cl>[C:13]([CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:43]=[CH:44][CH:45]=1)[C:20]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:42])=[C:27]([NH:29][C:30](=[O:41])[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)[CH:28]=1)=[O:21])([OH:14])=[O:12]
Reactant: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(OCC(=O)OC(C)(C)C)c3)ccc2C)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(OCC(=O)O)c3)ccc2C)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a stirred solution of N-[5-(3-tert-butoxycarbonylmethoxybenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide (0.455 g) in methylene chloride (5 ml) and the mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated and the residue was azeotroped with toluene. The resultant solid was dried under vacuum at 60° C. There was thus obtained the title compound (0.375 g), m.p. 206-207° C.; NMR Spectrum: (DMSOd6) 2.18 (s, 3H), 3.83 (s, 6H). 4.74 (s, 2H), 7.06 (d, 1H), 7.11 (m, 1H), 7.23 (d, 1H), 7.43 (t, 1H), 7.48 (d, 1H), 7.55 (br m, 1H), 7.63 (m, 1H), 7.8 (d, 1H), 9.75 (br s, 1H), 10.17 (br s, 1H); Mass Spectrum: M+H+ 465.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])[CH2:8]1.C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(OCC)C>[C:34]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])[CH2:8]1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCCCN1c1ccccc1CCN1CCC(C2CCCCN2)C1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)N1CCCCC1C1CCN(CCc2ccccc2N2CCCCC2=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To a solution of 1-(2-{2-[3-(piperidin-2-yl)pyrrolidin-1-yl]ethyl}phenyl)piperidin-2-one a12-1 (25 mg, 0.070 mmol, 1 eq) in diethylether (2 ml) at 0° C. are added triethylamine and acetic anhydride (7 μl, 0.077 mmol, 1.1 eq). The mixture is stirred for 1 hour at room temperature. The solvent is removed under vacuum. The residue obtained is purified by basic reverse phase chromatography (gradient: acetonitrile/H2O/ammonium formate from 5% to 95% of acetonitrile in 8 minutes) to afford 14.5 mg of 1-(2-{2-[3-(1-acetylpiperidin-2-yl)pyrrolidin-1-yl]ethyl}phenyl)piperidin-2-one 72 as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])C(=O)OC(C)(C)C.[ClH:16]>C(OCC)(=O)C>[ClH:16].[CH3:1][NH:2][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CN(CCS(C)(=O)=O)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a mixture of tert-butyl N-methyl-N-[2-(methylsulfonyl)ethyl]carbamate (0.81 g) and ethyl acetate (10 mL) was added dropwise a 4N hydrochloric acid.ethyl acetate solution (2 mL) with stirring under ice-cooling. After stirring at room temperature overnight, the precipitated crystals were collected by filtration and washed with ethyl acetate to give N-methyl-N-[2-(methylsulfonyl)ethyl]amine hydrochloride as crystals (0.38 g, yield 64%). Recrystallization from ethanol gave colorless prism crystals. melting point: 259–260° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[CH2:18]([O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])[C:19]#[CH:20].C(N(CC)CC)C>O1CCCC1.[Cu]I.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>[OH:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:18][C:19]#[C:20][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(OCc1ccccc1)c1cccc(I)c1
Reactant: C#CCOCCOCCOCCOCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)c1cccc(C#CCOCCOCCOCCOCCO)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of benzyl 3-iodobenzoate (25.68 g, 66.19 mmol, 1.00 equiv) in tetrahydrofuran (300 mL), 2-(2-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)ethoxy)ethanol (15.36 g, 66.21 mmol, 1.00 equiv), copper(I) iodide (1.26 g, 6.63 mmol, 0.10 equiv), Pd(PPh3)2Cl2 (4.65 g, 6.62 mmol, 0.10 equiv), triethylamine (13.4 g, 132.67 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether/ethyl acetate (1:1). This resulted in 20 g (68%) of benzyl 3-(3-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)prop-1-ynyl)benzoate as a brown oil.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=O)[C:4]1=[O:14])[CH3:2].[N+:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[C-:16]>>[CH2:1]([N:3]1[C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:16]=[N:15][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]2[C:4]1=[O:14])[CH3:2]
Reactant: CCn1c(=O)c(=O)[nH]c2cccnc21
Reactant: [C-]#[N+]CC(=O)OCC
Product: CCOC(=O)c1ncn2c1c(=O)n(CC)c1ncccc12

Procedure:
Ethyl 5-et hyl-4,5-dihydro-4-oxo-imidazo(1,5-a)pyrido(2,3-e)-pyrazine-3-carboxylate was prepared from 4-ethyl-1,2,3,4-tetrahydro-2,3-dioxo-pyrido(2,3-e)pyrazine and ethyl isocyanoacetate. M.p. 215.5°-216.8° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:37])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:28]([CH:30]2[CH2:35][CH:34]3[CH2:36][CH:31]2[CH2:32][CH2:33]3)[CH:29]=1)=O)C.[CH2:38]([NH2:40])[CH3:39]>CO>[CH2:38]([NH:40][C:4]([C:6]1[C:7](=[O:37])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:28]([CH:30]2[CH2:35][CH:34]3[CH2:36][CH:31]2[CH2:32][CH2:33]3)[CH:29]=1)=[O:3])[CH3:39]
Reactant: CCN
Reactant: CCOC(=O)c1cn(C2CC3CCC2C3)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Solvent: CO
Product: CCNC(=O)c1cn(C2CC3CCC2C3)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
8-Bicyclo[2.2.1]hept-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (5.7 mg, 0.11 mmol) was dissolved in MeOH (1 mL) and ethylamine (1 mL of 1.0 M solution in THF, 1.0 mmol) was added and the reaction mixture was heated at 80° C. After 16 h, the solution was cooled to rt and purified by preparative HPLC (C-18 column, 32 mL/min 5-100% MeCN/H2O gradient over 15 min) and lyophilized to provide 3.7 of 8-bicyclo[2.2.1]hept-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide. 1H NMR (TFA salt) (400 MHz, CDCl3) δ (ppm): 9.62 (s, 1H), 9.26 (s, 1H), 8.90 (s, 1H), 7.54 (d, 2H, J=8.8 Hz), 6.89 (d, 2H, J=8.9 Hz), 4.85-4.88 (m, 1H), 3.26-3.64 (m, 9H), 2.91-2.94 (m, 2H), 2.82 (s, 3H), 2.55 (s, 1H), 2.44 (s, 1H), 2.03 (br s, 8H), 1.59-1.61 (m, 4H), 1.35-1.41 (m, 2H), 1.19 (t, 1H, J=7.3 Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. for C28H35N7O2: 501.29, Found: 502.3 (M+H).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[Cl:19])[NH:15][N:14]=[CH:13]2.[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:54])[C@H:29]([NH:33][C:34]([C:36]2[C:44]3[C:39](=[N:40][CH:41]=[C:42](I)[N:43]=3)[N:38]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:37]=2)=[O:35])[CH:30]2[CH2:32][CH2:31]2)[CH2:24][CH2:23]1)#[N:21].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.C1(C)C=CC=CC=1>[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:54])[C@H:29]([NH:33][C:34]([C:36]2[C:44]3[C:39](=[N:40][CH:41]=[C:42]([N:15]4[C:16]5[C:12](=[CH:11][C:10]([Cl:9])=[C:18]([Cl:19])[CH:17]=5)[CH:13]=[N:14]4)[N:43]=3)[N:38]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:52])([CH3:51])[CH3:53])[CH:37]=2)=[O:35])[CH:30]2[CH2:31][CH2:32]2)[CH2:24][CH2:23]1)#[N:21]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(I)cnc21
Reactant: Clc1cc2cn[nH]c2cc1Cl
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(-n3ncc4cc(Cl)c(Cl)cc43)cnc21
Temperature: 110 °C
Yield: 97.6 %

Procedure:
In a 5 mL microwave vial were placed copper(I) iodide (6 mg, 0.033 mmol), K3PO4 (146 mg, 0.69 mmol), 5,6-dichloro-1H-indazole (74 mg, 0.39 mmol), 2-iodo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (200 mg, 0.33 mmol), toluene (1.2 mL), and trans-N,N′-dimethylcyclohexane-1,2-diamine (9 mg, 0.066 mmol). The vial was purged with a stream of nitrogen then sealed and heated in an oil bath at 110° C. for 48 h. The reaction mixture was cooled to room temperature and diluted with EtOAc then filtered over a Buchner funnel, rinsing with EtOAc. The filtrate was concentrated and the resultant residue was purified by silica gel chromatography with 0% to 2% MeOH/CH2Cl2 (0.5% NH4OH) to afford 215 mg (98%) of 2-(5,6-dichloro-indazol-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a light yellow foam.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:12][N:11]([C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[S:17][C:16]=2[NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[O:14])[CH2:10]1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O>[NH2:7][CH2:8][CH:9]1[CH2:10][N:11]([C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[S:17][C:16]=2[NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[O:14])[CH2:12]1
Reactant: CC(C)(C)OC(=O)NCC1CN(C(=O)c2c(Nc3ccc(I)cc3F)sc3ncccc23)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: NCC1CN(C(=O)c2c(Nc3ccc(I)cc3F)sc3ncccc23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Example 28 (65 mg, 0.11 mmol) in DCM (7 mL) was treated with trifluoroacetic acid (3 mL) and stirred for 1 h at r.t. The reaction mixture was concentrated in vacuo to give a yellow gum, which was dissolved in water (25 mL) and basified to pH 10 with sodium carbonate. The aqueous solution was extracted with 5% methanol in DCM (4×25 mL), and the extracts combined, then dried (Na2SO4), filtered and concentrated in vacuo. The crude product was subjected to column chromatography (SiO2, 4:1 DCM/methanol) to give the title compound as a gummy solid, which was triturated from ether to give a cream-coloured powder (34 mg, 63%). δH (DMSO-d6) 8.31 (1H, m), 7.93 (1H, m), 7.72 (1H, dd, J 1.5, 10.5 Hz), 7.55 (1H, m), 7.37 (1H, dd, J 4.6, 8.1 Hz), 7.29-7.24 (1H, m), 4.88 (2H, br s), 4.03-3.97 (2H, m), 3.71-3.67 (2H, m), 2.65 (1H, m), 2.70-2.68 (2H, m). LCMS RT 2.93 minutes, (ES−) 481 (M−H)−, (ES+) 483 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:24]([O:26]CC)=[O:25])=[C:5]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:43])=[O:42])=[CH:10][CH:9]=2)[C:5]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:6]1[C:24]([OH:26])=[O:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1C(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=C(O)c1c(-c2ccccc2)c2cc(NS(=O)(=O)c3ccccc3)ccc2n1C(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-benzhydryl-3-phenyl-1H-indole-2-carboxylate and phenylsulfonyl chloride followed the procedure of Example 1 Step 3 as a pale yellow solid: 1H NMR (DMSO-d6) δ 6.68 (d, J=9.0 Hz, 1H, 6.78 (dd, J=9.2, 2.2 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H, 7.13 (d, J=7.1 Hz, 4H, 7.25-7.30 (m, 2H, 7.30-7.40 (m, 7H, 7.40-7.55 (m, 4H, 7.58-7.68 (m, 3H, 7.84 (s, 1H, 9.93 (s, 1H, 13.19 (br s, 1H; MS (ESI) m/z 557 [M-H]−; HRMS calcd for C34H27N2O4S: 559.1689; found (ESI+): 559.1686; Anal. calcd for C34H26N2O4S.0.6H2O: C, 71.71; H, 4.81; N, 4.92. Found: C, 71.51; H, 4.77; N, 5.11.
Reaction SMILES: CN1CCOCC1.Cl.Cl.[CH3:10][N:11]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:15]2=[CH:16][CH:17]=[C:18]([C:19]([F:22])([F:21])[F:20])[N:14]2[CH2:13][CH2:12]1.[OH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][C:31]=1[O:39][CH3:40].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:26]2[CH2:27][CH2:28][C:23]3([N:11]([CH3:10])[CH2:12][CH2:13][N:14]4[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:16]=[C:15]34)[CH2:24][CH2:25]2)=[O:35])=[CH:32][C:31]=1[O:39][CH3:40]
Reactant: CN1CCn2c(C(F)(F)F)ccc2C12CCNCC2
Reactant: COc1cc(C(=O)O)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)c2ccc(C(F)(F)F)n2CCN3C)ccc1O
Temperature: 60 °C
Yield: 56.4 %

Procedure:
4-Methyl morpholine (1.59 mL, 14.4 mmol) was added to a mixture of 2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]dihydrochloride (1.00 g, 2.89 mmol), 4-hydroxy-3-methoxy-benzoic acid (486 mg, 2.89 mmol), EDCI (831 mg, 4.33 mmol), HOBt (585 mg, 4.33 mmol) and DMF (10 mL) at room temperature. The mixture was heated at 60° C. overnight before it was cooled to room temperature and partitioned between ethyl acetate and 1N HCl. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was subjected to column chromatography (0-100% ethyl acetate/hexanes) to give (4-hydroxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone (690 mg, 58%). ESI-MS m/z calc. 423.2, found 424.1 (M+1)+; Retention time: 1.16 minutes (3 min run). 1H NMR (400 MHz, CD3CN) δ 7.04 (d, J=1.8 Hz, 1H), 6.94 (dd, J=8.1, 1.9 Hz, 1H), 6.87 (d, J=8.1 Hz, 1H), 6.82 (s, 1H), 6.62-6.56 (m, 1H), 6.05 (d, J =3.9 Hz, 1H), 4.35 (s, 1H), 4.00 (t, J=6.0 Hz, 2H), 3.89 (s, 3H), 3.64 (s, 2H), 3.36 (t, J=6.0 Hz, 2H), 3.29 (s, 1H), 2.36 (s, 3H), 2.16-2.04 (m, 2H), 1.81 (dd, J=17.1, 7.3 Hz, 2H).26-7.21 (m, 2H), 7.14 (t, J=8.1 Hz, 1H), 2.78 (d, J=1.4 Hz, 2H), 1.24 (d, J=0.8 Hz, 6H).