Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(P(N(C)C)(N(C)C)=O)C.C([C:39]([O:41][CH3:42])=[O:40])#N>C1COCC1>[CH3:42][O:41][C:39]([CH:23]1[CH2:24][CH:19]([CH2:18][CH2:17][O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:20][CH2:21][C:22]1=[O:25])=[O:40]
Reactant: O=C1CCC(CCOCc2ccccc2)CC1
Reactant: COC(=O)C#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C1CC(CCOCc2ccccc2)CCC1=O
Temperature: 0 °C

Procedure:
A solution of LDA (33 ml, 1.5 M in Et2O) in THF (50 mL) at −78° C. was treated with 4-(2-benzyloxy-ethyl)-cyclohexanone (9.5 g, 40.2 mmol). The mixture was warmed to 0° C. over 30 m before re-cooling to −78° C. and adding HMPA (7 mL). Methyl cyanoformate (4.1 mL, 85 mmol) was added and the mixture was stirred for 15 m before aqueous quench and work-up. The product was purified by chromatography on SiO2 with 10% EtOAc:Hx. 5-(2-Benzyloxy-ethyl)-2-oxo-cyclohexanecarboxylic acid methyl ester was isolated, 5.8 g (49%) and reduced with an equivalent of NaBH4 in MeOH at −10° C. to provide the alcohol (Intermediate R2). Intermediate R2 was purified by chromatography on SiO2 with 30 to 50% EtOAC:Hx. (˜90% yield).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:43])[NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:39]=[CH:38][C:24]([CH2:25][N:26]([CH2:34][CH2:35][O:36][CH3:37])C(=O)OC(C)(C)C)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)[CH2:3][CH2:2]1.Cl.O1CCOCC1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:39]=[CH:38][C:24]([CH2:25][NH:26][CH2:34][CH2:35][O:36][CH3:37])=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)=[O:43])[CH2:3][CH2:2]1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
To a solution of 112 (560 mg, 0.923 mmol) in DCM (10 mL) was added 4.0M HCl in dioxane (0.923 mL, 3.69 mmol) and the reaction mixture was stirred at RT for 2 hours. The mixture was diluted with saturated NaHCO3 solution and the layers were separated. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. The resultant solid was triturated with Et2O to afford title compound 113 (350 mg, 75% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.69 (s, 1H), 8.48 (d, J=5.48 Hz, 1H), 8.00 (s, 1H), 7.82 (d, J=8.41 Hz, 1H), 7.70 (m, 1H), 7.44 (d, J=8.22 Hz, 1H), 7.36 (t, J=9.19 Hz, 1H), 7.19 (m, 1H), 6.56 (m, 2H), 3.75 (s, 2H), 3.39 (t, J=5.67 Hz, 2H), 3.22 (s, 3H), 2.64 (t, J=5.67 Hz, 2H), 2.53 (m, 1H), 0.63 (m, 2H), 0.41 (m, 2H). MS (m/z)=507.5 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][O:7][C:8]([C:10]1C(C2C=CC=C([N+]([O-])=O)C=2)C(C(OC(C)C)=O)=C(C)[NH:14][C:15]=1[CH3:16])=[O:9].C(O)C>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][O:7][C:8](=[O:9])/[CH:10]=[C:15](\[NH2:14])/[CH3:16]
Reactant: COc1ccc(COC(=O)C2=C(C)NC(C)=C(C(=O)OC(C)C)C2c2cccc([N+](=O)[O-])c2)cc1OC
Solvent: CCO
Solvent: CC(C)O
Product: COc1ccc(COC(=O)/C=C(/C)N)cc1OC
Yield: 77 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid isopropyl ester and 75 mmols of β-aminocrotonic acid 3,4-dimethoxybenzyl ester in 120 ml of isopropanol gave 2,6-dimethyl-3-isopropoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 3,4-dimethoxybenzyl ester of melting point 154° C (from ethanol).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[F:15][C:16]1[CH:17]=[C:18]([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>ClCCl>[F:38][C:34]1[CH:33]=[C:32]([C:22]2([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=3)[CH:30]3[CH:26]([CH2:27][N:28]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[N:2]([CH3:1])[CH3:13])[CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:37]=[CH:36][CH:35]=1
Reactant: O=C1CCC(c2cccc(F)c2)(c2cccc(F)c2)C2CNCC12
Reactant: CN(C)c1ccccc1CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccccc1CC(=O)N1CC2C(=O)CCC(c3cccc(F)c3)(c3cccc(F)c3)C2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.4 %

Procedure:
N,N'-Carbonyldiimidazole (0.59 g) is added to a solution, cooled to +4° C., of (2-dimethylaminophenyl)acetic acid (0.65 g) in dry dichloromethane (20 cc). The mixture is stirred for 90 minutes at 25° C. and a solution of 7,7-bis(3-fluorophenyl)perhydro-4-isoindolone hydrochloride (1.3 g) and triethylamine (1.02 cc) in dry dichloromethane (25 cc) is then added dropwise. The reaction mixture is stirred for 16 hours at 25° C. and washed with water (2×250 cc) and with saturated sodium chloride solution (250 cc). The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 2.3 cm, height 23 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (55:45) and collecting 15-cc fractions. Fractions 6 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is solidified with isopropyl ether to give (3aRS,7aRS)-7,7-bis(3-fluorophenyl)-2-[(2-dimethylaminophenyl)acetyl]perhydro-4-isoindolone (0.6 g), the hydrochloride of which is prepared by dissolution in ethyl acetate (1 cc) and the addition of a 3N solution of hydrochloric acid in isopropyl ether. The precipitate is drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-Bis(3-fluorophenyl)-2-[(2-dimethylaminophenyl)acetyl]perhydro-4-isoindolone hydrochloride (0.48 g) is obtained in the form of a white solid.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8]CC)=[O:7].[N:17]1([C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][N:29]([CH2:34][C:35](NC[C@@H](NS(C4C=CC=CC=4)(=O)=O)C(O)=O)=[O:36])[C:30]3=[O:33])=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[N:17]1([C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][N:29]([CH2:34][C:35]([NH:3][C@H:4]([C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)[CH2:5][C:6]([OH:8])=[O:7])=[O:36])[C:30]3=[O:33])=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)C[C@H](N)c1cccnc1
Reactant: O=C(CN1CCc2ccc(N3CCNCC3)cc2C1=O)NC[C@@H](NS(=O)(=O)c1ccccc1)C(=O)O
Agent: Cl
Product: O=C(O)C[C@H](NC(=O)CN1CCc2ccc(N3CCNCC3)cc2C1=O)c1cccnc1

Procedure:
Following the procedure described for 1-7, but substituting 2(R)-(phenylsulfonylamino)-β-alanine for ethyl 3-amino-3(S)-(3-pyridyl)propionate dihydrochloride, the title compound was prepared. 1H NMR (CD3OD): δ 1.50 (9H, s), 3.00 (2H, m), 3.18 (2H, m), 3.3-3.7 (10H, m), 4.09 (1H, dd), 4.23 (2H, m), 7.2 (2H, m), 7.5-7.6 (4H, m), 7.85 (2H, m), 8.22 (1H, m). ##STR43## N-{[7-(Piperazin-1-yl)-3,4-dihydro-1(1H) -isoquinolinone-2-yl]acetyl}-2(R)-(phenylsulfonylamino)-β-alanine (1-22)
Reaction SMILES: [C:1]([CH:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]=2[CH2:6][CH2:5][CH2:4]1)#[N:2].[OH2:18]>>[C:1]([CH:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]=2[CH2:6][CH2:5][CH2:4]1)(=[O:18])[NH2:2]
Reactant: O
Reactant: CCOC(=O)c1cccc2c1CCCC2C#N
Product: CCOC(=O)c1cccc2c1CCCC2C(N)=O

Procedure:
To 500 g. of polyphosphoric acid is added 22.4 g. of ethyl 1-cyano-1,2,3,4-tetrahydro-5-naphthoate and the mixture is stirred at 90°-100°C for 2 hours. Then, 1 l. of water is added, followed by cooling. The resultant crystals are collected by filtration, washed with water and recrystallized from ethanol. The procedure gives ethyl 1-carbamoyl-1,2,3,4-tetrahydro-5-naphthoate, melting point: 159.5°-161.5°C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][O:11][CH2:12][C:13]([OH:15])=[O:14].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:10][O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: NOCC(=O)O
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CON=Cc1ccc(Cl)cc1

Procedure:
4.2 g of 4-chlorobenzaldehyde and 3.3 g of hemihydrochloride of amino-oxyacetic acid were dissolved in 50 ml of 90% ethanol. The solution was mixed with 7.4 g of sodium acetate and then refluxed for 20 minutes. The reaction mixture was subsequently concentrated by evaporation in a vacuum. After an excess of 2 N sodium hydroxide had been added, the residue was twice extracted with ether, after which the remaining aqueous solution was acidified with 2 N hydrochloric acid and again extracted twice with ether. The latter ethereal solution was washed twice with water, then dried over anhydrous sodium sulfate and subsequently concentrated by evaporation. The residue was crystallized from a mixture of ether and petroleum ether, them from highly dilute ethanol and ultrimately twice from a mixture of benzene and petroleum ether. The substance obtained melted at 121° C.-123° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:14](O)(=O)[CH:15]([CH3:17])[CH3:16]>>[CH:15]([C:14]1[N:12]([CH3:13])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)([CH3:17])[CH3:16]
Reactant: CC(C)C(=O)O
Reactant: CNc1c(N)cnc2ccccc12
Product: CC(C)c1nc2cnc3ccccc3c2n1C

Procedure:
Using the method of Example 147, 3-amino-4(methylamino)quinoline (the hydrochloride salt of which having been obtained in Exmple 27) was reacted with isobutyric acid to provide 2-isopropyl-1-methyl-1H-imidazo[4,5-c]quinoline. The crude product was dissolved in ethyl acetate and an excess of concentrated hydrochloric acid was added. The precipitate was separated by filtration and recrystallized from ethanol to provide 2-isopropyl-1-methyl-1H-imidazo[4,5-c]quinoline hydrochloride, m.p. 260°-263° C. This salt was suspended in water and the mixture was basified (pH 8-10) with 50% aqueous sodium hydroxide. The solid was separated by filtration, washed with water and recrystallized from hexane to provide the free base as the hydrate, m.p. 76°-81° C. Analysis: Calculated for C14H15N3.0.25H2O: %C, 73.2; %H, 6.8; %N, 18.3; Found: %C, 73.0 %H, 7.0; %N, 18.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25](CC3C=CC(OC)=CC=3)[N:24]=[C:23]4[CH3:38])[CH2:10][CH2:9]2)=[N:6][CH:7]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[C:23]4[CH3:38])[CH2:10][CH2:9]2)=[N:4][CH:3]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(NCC[C@@H]4C[C@@H]4C4CCN(c5ncc(Cl)cn5)CC4)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2ccc(NCC[C@@H]3C[C@@H]3C3CCN(c4ncc(Cl)cn4)CC3)cc12
Temperature: 75 °C
Reaction time: 4.5 h

Procedure:
N-(2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl)-1-(4-methoxybenzyl)-3-methyl-1H-indazol-5-amine (22 mg, 0.041 mmol) from step 3 of this example was dissolved in TFA (200 uL) and stirred at 75° C. for 4.5 hours. The volatiles were removed in vacuum. The residue was then dissolved in MeOH, and the volatiles removed in vacuum. The residue was then dissolved in DCM, and the volatiles removed in vacuum. The product was purified by chromatography on KPNH2™ SiO2 (Biotage) eluting with 5% acetone:DCM to give the titled compound. LRMS calc: 410.20; obs: 411.05 (M+1). Compounds reported in Table 8 are prepared by a general procedure analogous to that described in step 3, Example 48 above.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH2:10])[S:8][CH:9]=1)=[O:4].[C:11]([NH:18][C@H:19]([C:27](O)=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:27](=[O:28])[C@@H:19]([NH:18][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(N)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.8 %

Procedure:
A solution of 2-amino-thiazole-4-carboxylic acid methyl ester (2.4 g, 15.17 mmol), (S)—N-Boc-phenylalanine (4.518 g, 16.69 mmol), 1-hydroxybenzotriazole (2.255 g, 16.69 mmol) and 1,3-diisopropylcarbodiimide (2.127 g, 16.69 mmol) in a mixture of dichloromethane (50 mL) and N,N-dimethylformamide (25 mL) were stirred at ambient temperature for 24 hours. The mixture was diluted with dichloromethane, washed with water, brine and dried with magnesium sulfate. Evaporation of the solvents and chromatography of the residue over silica gel using a gradient between 0 and 25% ethyl acetate in dichloromethane gave 2-((S)-2-tert-butoxycarbonylamino-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (4.97 g, 81%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][C@H:19]([F:22])[CH2:18]1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29].C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([F:24])[CH:26]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][C@H:19]([F:22])[CH2:18]1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1CC[C@H](F)C1
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCN1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39.6 %

Procedure:
A mixture of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-((S)-3-fluoro-pyrrolidin-1-yl)-ethoxy]-phenylamine (76 mg, 0.2 mmol), 3-fluorobenzoyl chloride (32 mg, 0.22 mmol), triethylamine (0.3 mL) in THF (2 mL) was stirred at r.t. for 20 min. The solvent was concentrated in vacuo and the crude was purified by HPLC to give the title compound (40 mg, 40%) as a yellow solid as TFA salt. 1H NMR (DMSO-d6, 400 MHz) δ 1.98-2.10 (m, 2H), 2.90-3.45 (m, 6H), 3.68 (s, 3H), 4.28-4.30 (m, 1H), 4.39-4.42 (m, 1H), 5.28-5.42 (m, 1H), 7.28-7.31 (m, 1H), 7.44-7.49 (m, 1H), 7.57-7.63 (m, 1H), 7.67 (d, 1H), 7.73-7.82 (m, 3H), 7.94 (dd, 1H), 10.4 (s, 2H). Exact mass calculated for C23H23BrF2N4O2 504.1. found 505.5/507.5 (MH+).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:37]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)(=[O:39])[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:43]2[CH:44]=[CH:45][C:40]([C:37](=[O:39])[CH3:38])=[CH:41][CH:42]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 88.5 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.5 g, 0.96 mmol), 4-acetylphenylboronic acid (394 mg, 2.4 mmol) and dichlorobis(triphenylphosphine)palladium (II) (67 mg, 0.1 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 1.2 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (200 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 30% ethyl acetate/hexanes) afforded 1-{4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-ethanone (400 mg, 89%) as a white solid: LC/MS m/e calcd for C28H26N2O3S [M+H]+ 471.60, observed 471.0.
Reaction SMILES: [CH2:1]1[CH2:19][O:18][O:17][C:4]([O:15][CH3:16])([CH:5]=[CH:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][CH:8]=2)[O:3][O:2]1.C.[H][H]>CO>[CH2:19]1[CH2:1][O:2][O:3][C:4]([O:15][CH3:16])([CH2:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]=[O:14])=[CH:11][CH:12]=2)[O:17][O:18]1
Reactant: COC1(C=Cc2ccc(C=O)cc2)OOCCOO1
Reactant: [H][H]
Solvent: CO
Product: COC1(CCc2ccc(C=O)cc2)OOCCOO1
Yield: 88.1 %

Procedure:
A solution of methyl 4-formylcinnamate ethylenedioxy acetal (15.24 g, 0.065 mole, from example 32) in methanol (200 ml) was hydrogenated over 10% palladinised charcoal (0.5 g) until 1 equivalent of hydrogen was absorbed. The filtered solution was then evaporated to give 15.36 g (100%) of an oil, νmax (film), 1730, 1610 cm-1, δ(CDCl3) 2.54 (2H, m, ArCH2), 2.91 (2H, m, CH2CO2), 3.63 (3H, s, ester CH3), 4.00 (4H, m, OCH2CH2O), 5.72 (1H, s, OCHO), 7.25 (4H, ABq, J 10 Hz, Δν19.5 Hz).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]([OH:8])[C@@H:6]([CH3:9])[CH2:5][N:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[C:28]([NH:29]C(=O)OCC3C=CC=CC=3)=[CH:27][C:26]3[C:21](=[CH:22][C:23]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][C:41]4=[O:46])=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:3]1.[H][H]>[Pd].CO>[NH2:29][C:28]1[C:19]([C:17]([NH:16][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:10]=2[N:4]2[CH2:5][C@H:6]([CH3:9])[C@@H:7]([OH:8])[C@H:2]([NH2:1])[CH2:3]2)=[O:18])=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([N:40]1[CH2:45][CH2:44][O:43][CH2:42][C:41]1=[O:46])[CH:22]=2
Reactant: [H][H]
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4=O)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](N)[C@@H]1O
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4=O)ccc3cc2N)C[C@@H](N)[C@@H]1O

Procedure:
A mixture of benzyl [2-[({4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(3-oxomorpholin-4-yl)quinolin-3-yl]carbamate (0.0068 g, 0.011 mmol) in of 3.0 mL of MeOH was hydrogenated in the presence of 8 mg of 10% Pd on carbon under a balloon of hydrogen at room temperature for 1 h. The mixture was filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C25H30N7O4 [M+H]+: m/z=492.2. found: 492.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]#[N:12])[N:7]([CH3:13])[C:6](=[O:14])[CH2:5]2.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[CH:16]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[CH3:13][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:17]3[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=3)=[C:10]([C:11]#[N:12])[CH:9]=2)[CH2:5][C:6]1=[O:14]
Reactant: CN1C(=O)Cc2cc(Br)c(C#N)cc21
Reactant: OB(O)c1cccnc1
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: ClCCl
Solvent: COCCOC
Product: CN1C(=O)Cc2cc(-c3cccnc3)c(C#N)cc21
Temperature: 100 °C

Procedure:
To 5-bromo-1-methyl-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile (58 mg, 0.23 mmol) was added 3-pyridine boronic acid (CAS#1692-25-7, 28 mg, 0.23 mmol), 1,2-dimethoxyethane (2.0 mL) and 2 M aqueous sodium carbonate (0.230 mL, 0.46 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.09 mmol/g loading, (105 mg, 0.009 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 100° C. for 1.75 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 6%) to afford 1-methyl-2-oxo-5-pyridin-3-yl-2,3-dihydro-1H-indole-6-carbonitrile; HRMS: (ESI) m/z 248.0838 (M−H)−; 1H NMR (400 MHz, CDCl3) δ ppm 3.30 (s, 2H), 3.68 (s, 2H), 7.19 (s, 1H), 7.42 (s, 1H), 7.49-7.58 (m, 1H), 8.02 (d, J=7.6 Hz, 1H), 8.72 (dd, J=4.8, 1.1 Hz, 1H), 8.77 (d, J=1.8 Hz, 1H).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=O)[CH3:8])[CH3:3].[CH3:12][O:13][C:14](=[O:27])/[C:15](/[CH3:26])=[C:16](\P(OCC)(OCC)=O)/[CH3:17].[Na]>C1C=CC=CC=1.CO>[CH3:12][O:13][C:14](=[O:27])[C:15]([CH3:26])=[CH:16][CH:17]=[CH:10][CH2:9][CH:7]([CH3:8])[CH2:6][CH2:5][CH:4]=[C:2]([CH3:3])[CH3:1]
Reactant: CC(C)=CCCC(C)CC=O
Reactant: CCOP(=O)(OCC)/C(C)=C(/C)C(=O)OC
Agent: [Na]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(C)=CC=CCC(C)CCC=C(C)C
Temperature: 60 °C
Reaction time: 5 h

Procedure:
24 g of citronellal and 40 g of diethylphosphono-α-methylcrotonic acid methyl ester are dissolved in 100 ml of absolute benzene. To this solution there is added dropwise 4 g of sodium in 50 ml of absolute methanol. The mixture is stirred for 5 hours at 60°C., poured on to ice-water and extracted with diethyl ether. The ethereal solution is washed with water, then with aqueous sodium bicarbonate solution and once again with water, dried over sodium sulphate, filtered and concentrated on a rotary evaporator. After chromatography on a 30-fold amount of Kieselgel, using hexane/diethyl ether (9:1 parts by volume) as the eluant, there is obtained 2,7,11-trimethyl-2,4,10-dodecatrienoic acid methyl ester; boiling point 95°C/0.001 mmHg.