Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=O)=[N:4][C:5]([C:8]2[CH:13]=[C:12]([S:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=2[CH3:23])=[CH:6][N:7]=1.Cl.[CH3:33][O:34][NH2:35].C(O)C.C(N(CC)CC)C>O>[CH3:33][O:34][N:35]=[C:24]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]2[CH:13]=[C:12]([S:14]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=2[CH3:23])[N:4]=1)[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: CON
Reactant: Cc1ccc(S(=O)(=O)N2CCOCC2)cc1-c1cnc(N)c(C(=O)c2cccnc2)n1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CON=C(c1cccnc1)c1nc(-c2cc(S(=O)(=O)N3CCOCC3)ccc2C)cnc1N

Procedure:
{3-Amino-6-[2-methyl-5-(morpholine-4-sulfonyl)-phenyl]-pyrazin-2-yl}-pyridin-3-yl-methanone (Ex. 2) (0.05 g, 0.11 mmol), O-methylhydroxylamine hydrochloride (0.095 g, 1.14 mmol), ethanol (4 ml), water (1 ml) and triethylamine (0.07 g, 0.68 mmol) are heated at 120° C. in a microwave for 3.5 hours. The reaction mixture is purified by reverse phase column chromatography (C18, 0-100% MeCN in water −0.1% TFA) to yield the title compound. 1H NMR (400 MHz, DMSO-6) δ 8.56 (1H, dd), 8.48 (1H, d), 8.35 (1H, s), 7.75 (1H, dt), 7.70 (2H, bs), 7.55-7.53 (2H, m), 7.48-7.43 (2H, m), 4.01 (3H, s), 3.61 (4H, t), 2.76 (4H, t) 2.19 (3H, s); MS m/z 469 [M+H]+
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](O)=O)=[N:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:12]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)=[N:17][CH:18]=1)[CH2:11][CH2:10][CH3:9]
Reactant: Nc1ccccc1N
Reactant: CCCCc1ccc(C(=O)O)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCc1ccc(-c2nc3ccccc3[nH]2)nc1
Reaction time: 1.5 h

Procedure:
0.6 g. of o-phenylenediamine, 1 g. of fusaric acid and 10 g. of polyphosphoric acid were heated at 200°-250° C. under nitrogen gas current with stirring for 1.5 hours. The reaction mixture was diluted with 200 ml. of water and then neutralized with sodium carbonate. The resulting crystals were filtered off, dried and recrystallized from ethyl acetate. 1.2 g. of colorless needles of the product (86% of theory) was obtained. M.P. 138.0°-139.0° C.
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O>CO>[CH2:14]([CH:5]([C:4]([O:11][CH3:12])=[O:10])[C:6]([O:8][CH3:9])=[O:7])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCBr
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCC(C(=O)OC)C(=O)OC
Yield: 78.3 %

Procedure:
350.1 g of 30 percent sodium methylate solution in methanol were diluted with 550 ml of methanol under nitrogen and while stirring. 264.2 g of dimethyl malonate were added dropwise. After warming the suspension to 40° 321.0 g of 1-bromohexane were added dropwise. After stirring at 40° for 1 hour, under reflux for 2 hours, at 65°-69° for 2.5 hours and cooling the suspension to room temperature water was added and the mixture was stirred. The organic phase was separated. The aqueous phase was extracted with methylene chloride, the combined organic extracts were dried and filtered, the filter cake was washed with methylene chloride and the combined filtrates were concentrated. After distillation of the product there were obtained 329.3 g (78.3%) of dimethyl n-hexylmalonate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([NH:9][C:10](=[O:29])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:13]([C:25]([F:28])([F:27])[F:26])[CH:12]=2)[CH:3]=1.S([C:34]1[N:39]=[C:38]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH:37]=[CH:36][N:35]=1)(C)(=O)=O.[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)(Cl)Cl.CO.CN(C=O)C>[CH3:24][N:21]1[CH2:20][CH2:19][N:18]([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:4]3[CH:3]=[C:2]([NH:1][C:34]4[N:39]=[C:38]([C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)[CH:37]=[CH:36][N:35]=4)[C:7]([CH3:8])=[CH:6][N:5]=3)=[O:29])=[CH:12][C:13]=2[C:25]([F:28])([F:27])[F:26])[CH2:23][CH2:22]1
Reactant: CS(=O)(=O)c1nccc(-c2cccnc2)n1
Reactant: Cc1cnc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cnc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a flask was added N-(4-amino-5-methylpyridin-2-yl)-4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)benzamide (7.1 g), 2-mesyl-4-(3-pyridyl)pyrimidine (5.0 g) and DMF (50 mL). After the solution was cooled to about 0° C., sodium hydride (60%, 1.5 g) was added in several portions and the reaction was stirred at the same temperature for 2 hours, then warmed up to room temperature for 1 hour. A mixture solvent of chloroform/methanol (30:1, 100 mL) was added and the PH value was adjusted to 7 using 10% citric acid. The aqueous phase was extracted, then the organic combined phase was washed with brine, dried, filtered, concentrated and Purified through column chromatography to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=O)[CH:10]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH3:25][O:26][NH2:27].N1C=CC=CC=1.Cl>C(O)C>[Cl:1][C:2]1[C:3]([C:9](=[N:27][O:26][CH3:25])[CH:10]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C(=O)c1ncc(Cl)cc1Cl)N1C(=O)c2ccccc2C1=O
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(c1ncc(Cl)cc1Cl)C(C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To 1.00 g of N-[2-(3,5-dichloropyridin-2-yl)-1-methyl-2-oxoethyl]phthalimide in 10 ml of ethanol, 2.39 g of methoxyamine hydrochloride and 3.40 g of pyridine were added and refluxed with heating for 18 hours with stirring. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 30 ml of 1N aqueous hydrochloric acid and extracted with ethyl acetate (40 ml×2). The resulting organic layers were combined, washed with 30 ml of 1N aqueous hydrochloric acid and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 0.81 g of the desired product as a colorless resinous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:5][N:4]=1.O=S(Cl)[Cl:29]>C(#N)C.O1CCOCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25][Cl:29])=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:5][N:4]=1
Reactant: COc1cc(Nc2ncnc3[nH]c(-c4ccc(CO)cc4)cc23)ccn1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(Nc2ncnc3[nH]c(-c4ccc(CCl)cc4)cc23)ccn1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
At 0° C., a suspension of 1.23 g (3.5 mMol) of {4-[4-(2-methoxy-pyridin-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol in 18 ml of acetonitrile, 18 ml of dioxane and 1.5 ml of SOCl2 is prepared at 0° C. and then stirred for 4.5 h at RT. The mixture is diluted with 0.2 l of EtOAc and 0.1 l of saturated NaHCO3-solution, stirred and the title compound off; MS-ES+: (M+H)+=366. More product can be obtained by extraction of the filtrate.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[C:5]([CH3:16])=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:3]=1.[C:22]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:31]=1)([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([C:26]1[CH:27]=[C:28]([C:2]2[N:6]([S:7]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)(=[O:9])=[O:8])[C:5]([CH3:16])=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:3]=2)[CH:29]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:31]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1cc(B(O)O)cc(C(C)(C)C)c1
Reactant: CCOC(=O)c1cc(Br)n(S(=O)(=O)N2CCCCC2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n(S(=O)(=O)N2CCCCC2)c1C
Temperature: 100 °C
Yield: 61.4 %

Procedure:
A mixture of compound 4b (2.1 g, 5.0 mmol), (3,5-di-tert-butylphenyl)boronic acid (1.9 g, 8.1 mmol), Na2CO3 (1.9 g, 17.9 mmol) and Pd(PPh3)4 (100 mg) in dioxane (50 mL) and H2O (15 mL) was heated to 100° C. for 1 h, evaporated and dissolved in EA. The mixture was washed with water (4×80 mL) and brine, dried with Na2SO4, concentrated and purified by CC to afford compound 4c (1.5 g, 61%) as a right red oil.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6](C(OCC3C=CC=CC=3)=O)[CH2:5][CH2:4]2)[CH2:2]1.[NH3:19]>>[NH2:19][CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CO2
Reactant: N
Product: NCC1(O)CCNCC1

Procedure:
The synthesis of 1-oxa-4,9-diaza-spiro[5.5]undecan-3-ones is described in Scheme 8A (see R. D. Clark, J. M. Caroon, D. B. Repke, A. M. Strosberg, S. M. Bitter, M. D. Okada, A. D. Michel, R. L. Whiting, J. Med. Chem. 1983, 26, 855). N-protected 4-methylenepiperidine epoxides like benzyl 1-oxa-6-aza-spiro[2.5]octane-6-carboxylate are opened by heating with a methanolic solution of ammonia to give the corresponding 4-aminomethyl-4-hydroxypiperidine. The spiro-bicyclic nucleus is formed by the following condensation with chloroacetyl chloride. After removal of the benzyloxycarbonyl group with HBr in acetic acid the spiropiperidine is acylated with 4-cyanobenzoyl chloride. The subsequent steps of alkylation with ω-halogenoalkanoates, formation of the amidine, and cleavage of the ester are carried out as described in the previous Schemes.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[CH3:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:30]2[CH2:31][CH2:32][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:28][CH2:29]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Reactant: Cc1cccc(N2CCNCC2)c1
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2cccc(C)c2)CC1
Yield: 91 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(3-methylphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 91%). 1H NMR (300 MHz, CDCl3): δ 2.33 (s, 3H), 2.46 (s, 3H), 3.21-3.28 (m, 4H), 3.72-3.86 (m, 4H), 4.13 (s, 3H), 6.74-6.78 (m, 4H), 7.00-8.01 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C(N(CC)C(C)C)(C)C.[CH3:40][NH:41][CH2:42][CH2:43][N:44]([CH3:46])[CH3:45]>CN(C)C=O.O>[CH3:45][N:44]([CH3:46])[CH2:43][CH2:42][N:41]([CH3:40])[C:14](=[O:16])[CH2:13][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:18])[CH3:17]
Reactant: CNCCN(C)C
Reactant: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCN(C)C(=O)CC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
To a solution of 3-(benzyloxycarbonylamino)-3-methylbutanoic acid (described in international publication number WO 2008/083347 A1) (5.74 g, 22.9 mmol) in N,N-dimethylformamide (150 ml) was added N,N-carbonyldiimidazole (4.45 g, 27.4 mmol). The reaction mixture was stirred for 1 hour at room temperature. N,N-diisoproylethylamine (11.2 ml, 68.8 mmol) and N,N,N-trimethylethylenediamine (3.6 ml, 27.8 mmol) were added was added to the reaction mixture. The mixture was stirred for an additional 18 hours at room temperature. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic layer was washed two more times with water and dried over sodium sulfate. The dried organic layer was filtered and concentrated in vacuo. The crude product was purified on silica gel column chromatography (0 to 10% methanol in dichloromethane) to give 2.08 g (27% yield) of benzyl 4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methyl-4-oxobutan-2-ylcarbamate. 1H NMR (CDCl3) δ 7.34-7.26 (m, 5 H), 6.14 (s, 1 H), 5.04 (s, 2 H), 3.47 (t, J=5.3 Hz, 2 H), 3.02 (s, 3 H), 2.60 (s, 2 H), 2.59 (t, J=5.3 Hz, 2 H), 2.24 (s, 6 H), 1.46 (s, 6 H); MS (ESI+) calculated for C18H30N3O3: 335.23, Found: 336.2 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[N:11][CH:10]=2)[CH:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl.[Cl-].[Na+].O.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[N:12]1[CH:13]=[CH:14][C:9]([C:4]2[CH:3]=[C:2]([C:20]3[CH:21]=[CH:22][C:17]([C:16]([F:27])([F:26])[F:15])=[CH:18][CH:19]=3)[CH:7]=[CH:6][C:5]=2[OH:8])=[CH:10][N:11]=1
Reactant: Oc1ccc(Cl)cc1-c1ccnnc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1-c1ccnnc1
Temperature: 100 °C
Yield: 40.9 %

Procedure:
To a solution of 4-chloro-2-pyridazin-4-ylphenol (Preparation 7, 1.5 g, 7.26 mmol) and 4-trifluoromethylbenzene boronic acid (3.45 g, 18.1 mmol) in 1,4-dioxane (20 mL) was added a solution of potassium carbonate (2.0 g, 14.5 mmol) in water (4 mL). The reaction mixture was degassed, then bis(tri-t-butylphosphine) palladium (0) (371 mg, 0.726 mmol) added and the reaction mixture heated to 100° C. for 18 hours. The mixture was diluted with a 2M aqueous solution of hydrogen chloride and brine, then extracted with ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0%-100% ethyl acetate in dichloromethane gradient elution) to afford the title compound as a solid (940 mg, 41%).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]([CH3:28])=[C:15]3[CH3:29])=[CH:8][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[CH2:21]([N:17]1[C:18]2[C:14](=[CH:13][C:12]([C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])=[CH:11][CH:10]=3)=[CH:20][CH:19]=2)[C:15]([CH3:29])=[C:16]1[CH3:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)COc1ccc(-c2ccc3c(c2)c(C)c(C)n3Cc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C)n(Cc2ccccc2)c2ccc(-c3ccc(OCC(=O)O)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 4. Thus, [4-(1-benzyl-2,3-dimethyl-1H-indol-5-yl)-phenoxy]-acetic acid methyl ester (0.230 g, 0.576 mmol) was reacted with 1N KOH (1.2 ml) in THF/MeOH (6 ml/4 ml) to give the product (0.139 g, 0.361 mmol, 63%) as an off-white solid, mp 203-206° C. 1H NMR (DMSO-d6) δ 2.24 (s, 3H), 2.27 (s, 3H), 4.68 (s, 2H), 5.38 (s, 2H), 6.95-6.99 (m, 4H), 7.20 (t, J=7.2 Hz, 1H), 7.25-7.29 (m, 3H), 7.37 (d, J=8.6 Hz, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.62 (s, 1H), 13.00 (broad s, 1H); IR (solid) 3030, 2910, 1740, 1710, 1605, 1520, 1480, and 1240 cm−1; [ESI(−)], m/z 384 (M−H)—; Anal. Calcd. for C25H23NO3: C, 77.90; H, 6.01; N, 3.63; Found: C, 77.87; H, 5.99; N, 3.64.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].Br[CH2:10][C:11]#[N:12].CCN(CC)CC>C1COCC1>[OH:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[CH2:10][C:11]#[N:12]
Reactant: OCC1CCCCN1
Reactant: N#CCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CCN1CCCCC1CO

Procedure:
The method follows that of S3 using 2-piperidinemethanol (26.50 g, 0.230 mol), BrCH2CN (30.35 g, 0.253 mol), Et3N (35.27 mL, 0.253 mol) and dry THF (150 mL). The crude product was purified by flash chromatography using ether/CH3OH (19:1) as eluent. The title-compound was crystallised from ether yielding cream-coloured crystals (31.46 g, 89%). δH(250 MHz; CDCl3); 1.2-1.85 (m, 6H, NCH2CH2CH2, CH2CH2CH2CH and CH2CH2CH), 2.05 (s (broad), 6H, OH), 2.4 (m, 1H, NCH2CH2), 2.55 (3×d, 1H. 1×NCH2CH2), 2.95 (m, 1H, NCHCH2), 3.45 (d, 1H, J=17 Hz, 1×NCH2CN), 3.5 (2×d, 1H, J=3 Hz and 12 Hz, 1×CHCH2OH), 3.76 (2×d, 1H, J=3 Hz and 12 Hz, CHCH2OH) and 4.05 (d, 1H, J=17 Hz, 1×NCH2CN); δC (62.9 MHz; CDCl3); 23.71, 25.25, 28.69, 43.43, 54.04, 60.73, 64.46 and 115.05 (CN); FAB MS, m/z(M+H)+ 155; IR υmax/cm−1; 3400 (OH, m broad), 2350 and 2240 (CN) and 1650.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([NH:9][C:10]([NH:12][C:4]2=[CH:3][CH:2]=1)=[O:11])=[O:8].[CH:13]([CH:15]=[CH2:16])=[O:14]>CO.C(OCC)(=O)C.O>[O:11]=[C:10]1[N:9]([CH2:16][CH2:15][CH:13]=[O:14])[C:7](=[O:8])[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[NH:12]1
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Reactant: C=CC=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=CCCn1c(=O)[nH]c2ccccc2c1=O
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 59.4 %

Procedure:
Benzoylene urea (4.0 9, 24.7 mmol), Triton B (40 wt % in methanol) (11.0 mL, 24.7 mmol), water (80 mL) and methanol (400 mL) were combined at ambient temperature and stirred vigorously for 15 minutes. (until all the solids had gone into solution). To this colorless solution, acrolein (1.7 mL, 24.7 mmol) in methanol (20 mL) was added dropwise over 5 minutes. to give a yellow solution. The reaction was then heated to 55° C. and stirred for 2 hours. and then at room temperature for approximately 16 hours. The yellow solution was concentrated to give a yellow oil which was taken up in ethyl acetate (25 mL) and water (50 mL). The aqueous layer was extracted again with ethyl acetate (25 mL). The organic layers were combined, washed with 1N HCl (20 mL), water (20 mL), saturated sodium bicarbonate solution (20 mL) and brine (20 mL), the organic layer was dried over magnesium sulfate and concentrated to give 3-[2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]propionaldehyde as a yellow foam (3.2 g, 59%) which was used without further purification. The NMR data showed a purity of ˜70%. NMR CDCl3 δ9.85 (s, 1H), 8.10-8.06 (m, 1H), 7.63-7.57 (m, 1H), 7.24-7.19 (m, 1H), 7.13-7.07 (m, 1H), 4.44-4.40 (m, 2H), 2.85 (dt, 2H, J1,2=2 Hz, J1,3=7 Hz); MS=219 (p+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:31][C:32]4[CH:37]=[C:36](Cl)[N:35]=[CH:34][N:33]=4)=[CH:28][CH:29]=3)[CH:24]=[CH:23][N:22]=2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[C:45]([NH2:48])(=[O:47])[CH3:46].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:31][C:32]4[CH:37]=[C:36]([NH:48][C:45](=[O:47])[CH3:46])[N:35]=[CH:34][N:33]=4)=[CH:28][CH:29]=3)[CH:24]=[CH:23][N:22]=2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(N)=O
Reactant: COc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)c2nccc3cc(Oc4cc(Cl)ncn4)ccc23)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)c2nccc3cc(Oc4cc(NC(C)=O)ncn4)ccc23)cc1
Temperature: 70 °C

Procedure:
150.0 mg (0.28 mMol) 6-(6-Chloro-pyrimidin-4-yloxy)-isoquinoline-1-carboxylic acid [5-tert-butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-amide is dissolved in 5 ml dioxane. After addition of 131 mg Cs2CO3 (>99%, Fluka 20959; 0.40 mMol), 25 mg (0.43 mMol) acetamide, 20 mg Xantphos (Aldrich 52, 646-0; 0.034 mMol) and 10.5 mg Pd2(dba)3 (Aldrich 32, 877-4; 0.011 mMol) the reaction mixture is heated to 70° C. for 20 h. It is cooled to rt again and worked up by addition of H2O and EtOAc. The phases are separated and the aq. layer is repeatedly extracted with EtOAc. Combined organic extracts are washed with brine, dried and concentrated. The residual crude product is purified by flash chromatography (combi-flash: 40 g column, hexanes/EtOAc; gradient 0-50% EtOAc) to give the title compound as a yellow solid: MS: [M+1]+=553; 1H MNR (CDCl3): δ ppm 10.70 (s, 1H), 9.43 (d, 1H), 8.44 (s, 1H), 8.38 (d, 1H), 8.15 (bs, HN), 7.84 (s, 1H), 7.74 (d, 1H), 7.63 (s, 1H), 7.52-7.48 (m, 3H), 7.05 (d, 2H), 6.87 (s, 1H), 5.29 (s, 1H), 3.88 (s, 3H), 2.25 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@H:13]([NH2:20])[CH2:12]1.O.[OH-].[Na+].Cl[C:25]([O:27][CH3:28])=[O:26]>ClCCCl.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[CH3:28][O:27][C:25](=[O:26])[NH:20][C@H:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)[CH2:12]1
Reactant: N[C@@H]1C[C@@H](c2c[nH]c3ccc(Cl)cc23)c2ccccc21
Reactant: COC(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: COC(=O)N[C@@H]1C[C@@H](c2c[nH]c3ccc(Cl)cc23)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.73 g (1R,3R)-3-(5-chloro-1H-indol-3-yl)-indan-1-ylamine was suspended in 200 mL 1,2-dichloro-ethane, 100 mL water and 0.5 mL 9N NaOH. 0.25 mL Methyl chloroformate (1.2 equiv) and 50 mg Bu4NBr were added. The reaction mixture was stirred 30 minutes at room temperature. The organic phase was dried over MgSO4 and concentrated in vacuo to give 0.6 g [(1R,3R)-3-(5-chloro-1H-indol-3-yl)-indan-1-yl]-carbamic acid methyl ester. 0.6 g [(1R,3R)-3-(5-Chloro-1H-indol-3-yl)-indan-1-yl]-carbamic acid methyl ester was obtained after aqueous work up. [(1R,3R)-3-(5-Chloro-1H-indol-3-yl)-indan-1-yl]-carbamic acid methyl ester was dissolved in 250 mL dry THF and 0.6 g LiAlH4 was added. The reaction mixture was refluxed for 2 hours. The reaction was quenched with 2 mL water, filtered and concentrated in vacuo to give an oil. The oil was dissolved in ethyl acetate and 350 mg [(1R,3R)-3-(5-chloro-1H-indol-3-yl)-indan-1-yl]-methyl-amine precipitated on standing at room temperature over night.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][N+:8]([O-:10])=[O:9].[C:16]1([CH:23]=CC(O)=[CH:19][CH:18]=1)O.C=CC=C>C1(C)C=CC=CC=1>[CH3:15][O:14][C:13]1[CH:12]=[CH:11][C:5]([C@@H:6]2[CH2:19][CH:18]=[CH:16][CH2:23][C@H:7]2[N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: Oc1ccc(O)cc1
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1OC
Agent: C=CC=C
Solvent: Cc1ccccc1
Product: COc1ccc([C@@H]2CC=CC[C@H]2[N+](=O)[O-])cc1OC
Temperature: 160 °C
Reaction time: 144 h

Procedure:
50.0 g of 3,4-dimethoxy-nitrostyrene (compound J1), and 1.0 g (9.1 mmol) of hydroquinone are suspened in 200 ml of abs. toluene and treated at −70° C. with 55.0 g (1.02 mol) of liquid 1,3-butadiene. The mixture is stirred at 160° C. for 6 days in an autoclave and then cooled. Some of the solvent is removed on a rotary evaporator, and the resulting precipitate is filtered off with suction and recrystallized in ethanol. M.p.: 113.5-115.5° C.