Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:23])[C@@H:10]([CH2:21][NH2:22])[C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])(C)[CH3:15])[CH3:12])C1C=CC=CC=1>[Pd]>[NH2:22][CH2:21][C@@H:10]([C@H:11]([O:13][SiH:14]([C:17]([CH3:18])([CH3:20])[CH3:19])[CH3:15])[CH3:12])[C:9]([OH:23])=[O:8]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CN)C(=O)OCc1ccccc1
Agent: [Pd]
Product: C[C@@H](O[SiH](C)C(C)(C)C)[C@H](CN)C(=O)O

Procedure:
subjecting (2S, 3R)-2-aminomethyl-3- (tert-butyldimethylsilyloxy)butanoic acid benzyl ester to catalytic hydrogenation in the presence of the palladium catalyst under hydrogen atmosphere to give (2S, 3R)-2-aminomethyl-3-(tert-butylmethylsilyloxy)butanoic acid, and
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](=[O:8])[C:6]=1[Br:7].Cl.[NH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>O>[Br:7][C:6]1[C:5](=[O:8])[N:4]([CH3:9])[C:3](=[O:10])[C:2]=1[N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1
Reactant: O=C1CCNCC1
Reactant: CN1C(=O)C(Br)=C(Br)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN1C(=O)C(Br)=C(N2CCC(=O)CC2)C1=O
Yield: 93.4 %

Procedure:
To a stirred solution of 3,4-dibromo-1-methyl-1H-pyrrole-2,5-dione (100 mg, 0.373 mmol) in AcN (20 mL) was added piperidin-4-one hydrochloride (101 mg, 0.746 mmol) at room temperature followed by K2CO3 (102 mg, 7.46 mol). The reaction mixture was then refluxed for 2 h, diluted with water, extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via silica gel column chromatography eluting with 30% EtOAc in hexanes to afford 3-bromo-1-methyl-4-(4-oxopiperidin-1-yl)-1H-pyrrole-2,5-dione (100 mg, 99%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11](OCC)=[O:12])[N:8]([CH2:16][CH2:17][CH2:18][CH2:19][F:20])[C:5]2=[CH:6][N:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OC(=O)C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([CH2:11][OH:12])[N:8]([CH2:16][CH2:17][CH2:18][CH2:19][F:20])[C:5]2=[CH:6][N:7]=1
Reactant: CCOC(=O)c1cc2cc(Cl)ncc2n1CCCCF
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1cc2cc(Cl)ncc2n1CCCCF
Temperature: 0 °C
Reaction time: 2 h
Yield: 29.3 %

Procedure:
To a solution of ethyl 5-chloro-1-(4-fluorobutyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate 10-c (2.19 g, 7.3 mmoles) in THF (150 mL) was added lithium aluminium hydride (8.064 mL, 1.1 eq, 1M in THF) at −75° C. under a nitrogen atmosphere. The reaction was allowed to stir on the cooling bath for two hours while it was slowly warming up until 0° C. Then the mixture was cooled on an ice ethanol bath and carefully decomposed by adding 150 mL ethylacetate followed by 10 g of Na2SO4.10H2O. The mixture was stirred for one hour and then dried over MgSO4, filtered off and the filtrate was evaporated. The residue was purified over silica with dichloromethane/methanol 95/5 as eluent to give 550 mg (30% yield) of the targeted compound 10. m/z=257 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][C:13]([CH3:22])([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])/[C:8]([OH:10])=[O:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][S:30](Cl)(=[O:32])=[O:31].Cl>C(OCC)(=O)C.CN(C)C(=O)C>[CH3:29][S:30]([O:9][C:8](=[O:10])/[C:7](/[C:4]1[N:3]=[C:2]([NH2:1])[S:6][N:5]=1)=[N:11]\[O:12][C:13]([CH3:22])([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])(=[O:32])=[O:31]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)O)c1nsc(N)n1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)OS(C)(=O)=O)c1nsc(N)n1
Temperature: 3.5 °C
Yield: 96.7 %

Procedure:
A 5.0 liter reactor was charged with N,N-dimethylacetamide (1.4 L). Solid (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)acetic acid (250 g, 1 eq., prepared according to the method disclosed in U.S. Pat. No. 7,129,232) was added to the reactor at ambient temperature and the mixture was stirred until the solid was dissolved. The solution was cooled to about 4° C. (target: 2-5° C.) and stirred for another 10-15 minutes. Potassium carbonate (106.7 g, 184.9 mmol, 1.1 eq.) was added to the reactor in one portion. Methanesulfonyl chloride (118.0 mL, 2.2 eq.) was added to the reactor at a rate of about 5 mL/min while maintaining the batch temperature <10° C. The reaction was stirred for 1-2 hours at about 6° C., then cooled to about 0-5° C. Ethyl acetate (2.5 L, 10 volumes) was added to the reactor while maintaining a temperature of about 0-5° C. 1.6% HCl (aq) (1.35 L) was added to the reactor, maintaining a temperature of about 10-15° C. The biphasic mixture was agitated and the layers were then separated. The organic layer was washed with sodium chloride solution, dried with sodium sulfate and concentrated under reduced pressure to obtain crude material. The crude material was dissolved in ethyl acetate (150 mL) and filtered over silica gel. The filtrate was concentrated under reduced pressure to yield the title compound (299 g, 96.7%) as a colorless solid. Exact Mass: 408.08. HRMS: 409.0846 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])#[N:21]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([C:20]#[N:21])[CH:23]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: N#Cc1cccc(C(=O)Cl)c1
Product: N#Cc1cccc(C(=O)NCCCCn2cnc3c(N)nc4ccccc4c32)c1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 3-cyanobenzoyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-cyanobenzamide as a white crystalline solid, m.p. 200.0-201.0° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 8.68 (t, J=5.7 Hz, 1H), 8.22 (s, 1H), 8.17 (t, J=1.8 Hz, 1H), 8.10-7.97 (m, 3H), 7.69-7.60 (m, 2H), 7.42 (dt, J=7.5, 1.2 Hz, 1H), 7.20 (dt, J=7.5, 1.5 Hz, 1H), 6.62 (s, 2H), 4.63 (t, J=6.9 Hz, 2H), 3.32 (m, 2H), 1.91 (quintet, J=7.5 Hz, 2H), 1.59 (quintet, J=7.5 Hz, 2H); IR (KBr) 3455, 3295, 3072, 2941, 2231, 1638, 1581, 1527, 1479, 1396, 1312, 1251, 1205 cm−1; MS (EI) m/e 384.1699 (384.1699 calcd for C22H20N6O).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:12][CH:11]([N:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]([F:26])[CH:17]=2)[CH3:14])[CH:10]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:9]1)=[O:7].[C-:35]#[N:36].[K+]>CN(C=O)C>[C:35]([CH2:2][CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:12][CH:11]([N:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[C:18]([F:26])[CH:17]=2)[CH3:14])[CH:10]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:9]1)=[O:7])#[N:36]
Reactant: [C-]#N
Reactant: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(C(=O)OCCCCl)CC1c1ccc(Cl)c(Cl)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(C(=O)OCCCC#N)CC1c1ccc(Cl)c(Cl)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a stirred solution of (3SR,4RS)-3-(3,4-dichloro-phenyl)-4-[(3-fluoro-4-trifluoromethyl-benzyl)-methyl-amino]-pyrrolidine-1-carboxylic acid 3-chloro-propyl ester (XVI-1) (40 mg, 0.068 mmol) in DMF (2 ml) was added potassium cyanide (5.0 mg, 0.077 mmol) and 18 crown 6-ether (18 mg, 0.068 mmol). The reaction mixture was stirred at 40° C. overnight, concentrated under vacuo. The product was purified by preparation HPLC to yield 18 mg (45%) of the title product as a colorless oil. ES-MS m/e: 532.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:16][C:15]3[C:14]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]5[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=5)=[C:20]([CH3:32])[CH:19]=4)=[N:13][CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH3:33][O:34][CH2:35][C:36](O)=[O:37].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.ClCCl.C(N(CC)CC)C>[CH3:33][O:34][CH2:35][C:36]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:16][C:15]3[C:14]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]5[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=5)=[C:20]([CH3:32])[CH:19]=4)=[N:13][CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1)=[O:37]
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4cc(-c5ccc(N)cc5)[nH]c34)cc2C)cn1
Reactant: COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COCC(=O)Nc1ccc(-c2cc3ncnc(Nc4ccc(Oc5ccc(C)nc5)c(C)c4)c3[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine (40 mg), methoxyacetic acid (0.0145 mL) and 1-hydroxybenzotriazole monohydrate (38 mg) in N,N-dimethylformamide (1.9 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54 mg) and triethylamine (0.079 mL) at room temperature. After stirring overnight at room temperature, the reaction mixture was diluted with dichloromethane (10 mL). The residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→ethyl acetate:methanol=85:15) and crystallized from diisopropyl ether to give the title compound (24 mg).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=O)[CH:23]=[CH:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=4[O:33][CH3:34])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li].[H-]>>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6](=[C:16]3[CH2:17][CH2:18][N:19]([CH2:22][CH:23]=[CH:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=4[O:33][CH3:34])[CH2:20][CH2:21]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc(C=CC(=O)N2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)c(OC)c1
Agent: [H-]
Agent: [Li]
Product: COc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)c(OC)c1
Yield: 12.3 %

Procedure:
4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(2,4-dimethoxycinnamoyl)piperidine was reduced with lithium alminium hydride. Yield 12.3%
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][O:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:11][N:12]([CH3:14])[CH:13]=[CH:2][C:1]([C:4]1[CH:8]=[CH:7][O:6][CH:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccoc1
Product: CN(C)C=CC(=O)c1ccoc1

Procedure:
As in Example 1, Part A, 0.01 mol of 3-acetylfuran can be reacted with 0.02 mol of N,N-dimethylformamide dimethylacetal to produce 3-dimethylamino-1-(3-furyl)-2-propen-1-one.
Reaction SMILES: O[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([CH3:25])=[C:19]([CH:24]=3)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=2[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=1.S(Cl)([Cl:32])=O>C1(C)C=CC=CC=1>[Cl:32][CH2:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([CH3:25])=[C:19]([CH:24]=3)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=2[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc(-c2nc(COc3ccc(CO)cc3OC)c(C)o2)ccc1C
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)ccc1C
Yield: 97.2 %

Procedure:
To a mixture of methyl 5-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methylbenzoate (1.16 g) and toluene (50 mL) was added thionyl chloride (0.38 g), and the mixture was heated under reflux for 1 hr. The reaction mixture was concentrated and ethyl acetate was added to the residue. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 5-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methylbenzoate (1.18 g, yield 98%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 139-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][N:15](CC4C=CC(OC)=CC=4)[C:14]3=[O:37])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=4)[CH2:16][NH:15][C:14]3=[O:37])=[CH:11][CH:12]=2)=[CH:38][CH:39]=1
Reactant: COc1ccc(CN2C[C@H](c3cccc(C(F)(F)F)c3)N(c3ccc(Oc4ccc(Cl)cc4)cc3)C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 91.2 %

Procedure:
(S)-3-[4-(4-chloro-phenoxy)-phenyl]-1-(4-methoxy-benzyl)-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-one (2.1 g, 3.8 mmol) is treated with TFA (15 mL) at room temperature for 14 h. The excess of TFA is removed under vacuum and the residue is treated with saturated NaHCO3 aqueous solution (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layer is washed with brine and dried (MgSO4). After removing the drying agent, the solution is concentrated and purified by flash column chromatography (silica gel, EtOAc/hexane 0%˜70%) to provide the desired product (S)-1-[4-(4-chloro-phenoxy)-phenyl]-5-(3-trifluoromethyl-phenyl)-imidazolidin-2-one as white crystals (1.5 g, 91%). 1H NMR (CDCl3, 400 MHz) δ 7.45˜7.58 (m, 4H), 7.29 (d, 2H), 7.23 (d, 2H), 6.87 (m, 4H), 5.34 (dd, 1H), 4.82 (br, 1H), 4.01 (t, 1H), 3.35 (dd, 1H); HPLC-MS calculated for C22H16ClF3N2O2 (M+H+) 433.1, found 433.1.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:15][C:14]=3[CH2:31][CH3:32])=[N:8][CH2:7]1)C.CO.[OH-].[K+]>O1CCCC1>[CH2:31]([C:14]1[CH:15]=[C:16]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=2)[CH:17]=[C:18]2[C:13]=1[NH:12][C:11]([C:9]1[S:10][CH:6]([CH2:5][C:4]([OH:33])=[O:3])[CH2:7][N:8]=1)=[CH:19]2)[CH3:32]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(CC)c3[nH]2)S1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.4 %

Procedure:
To a solution of ethyl[2-(7-ethyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetate (3.0 g), methanol (15 mL), and tetrahydrofuran (30 mL) was added an aqueous solution (10 mL) of potassium hydroxide (1.1 g), and the mixture was stirred at room temperature for 15 hr. The reaction solution was concentrated, acidified with aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained pale-yellow crystals were washed with ethyl acetate-hexane to give the title compound (2.5 g, yield 88%) as pale-yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)=[CH:16][C:15](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[C:40]([O:44][CH2:45][CH2:46][CH2:47][CH3:48])(=[O:43])[CH:41]=[CH2:42].C(=O)([O-])O.[Na+].O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)=[CH:16][C:15](/[CH:42]=[CH:41]/[C:40]([O:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:43])=[CH:14][CH:13]=2)=[O:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)OCCCC
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c3ccc(OS(=O)(=O)C(F)(F)F)cc23)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)/C=C/c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Temperature: 100 °C
Yield: 41 %

Procedure:
A suspension of tert-butyl[2-isobutyl-4-(4-methylphenyl)-1-oxo-6-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinyl]methylcarbamate (Example 182 (1)) (1.42 g, 2.5 mmol), butyl acrylate (0.54 ml, 3.8 mmol), sodium hydrogencarbonate (0.32 g, 3.81 mmol), tetrabutylammonium chloride (83 mg, 0.3 mmol) and palladium acetate (67 mg, 0.3 mmol) in N,N-dimethylformamide (30 ml) was stirred with heating at 100° C. under an argon atmosphere for 20 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give butyl (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenate (0.56 g, 40.3%) as an amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[NH2:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[NH:17][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([O:19][CH3:18])[CH:21]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2[nH]nc(C)c2N)cc1OC
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)Nc2c(C)n[nH]c2-c2ccc(OC)c(OC)c2)c1

Procedure:
The preparation took place in analogy with Example 15a), starting with 300 mg of 5-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrazol-4-ylamine (44) and 242 mg of 3-methoxybenzoyl chloride. The following was obtained: 53 C20H21N3O4 (367.41) MS (ESI) 368 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:27][CH3:28])([CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH2:30]([O:37][NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:30]([O:37][NH:38][C:14](=[O:15])[CH2:13][C:12]([S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:10])=[O:11])([CH2:27][CH3:28])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCC(CCCCc1ccccc1)(CC(=O)O)S(=O)(=O)c1ccc(OC)cc1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(CCCCc1ccccc1)(CC(=O)NOCc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.8 %

Procedure:
To a solution of 0.4 g (0.99 mmol) of 3-(4-methoxyphenylsulfonyl)-3-ethyl-7-phenylheptanoic acid in 50 mL of methylene chloride is added 0.47 g (2.96 mmol, 3 eq) of O-benzyl-hydroxylamine hydrochloride, 0.13 g (0.247 mmol) of HOBT, 0.54 mL (4.94 mmol, 5 eq) of n-Methylmorpholine (NMM), and 0.25 g (1.28 mmol, 1.3 eq) of EDCl. After stirring for 18 hours at 25° C. the reaction is partitioned between methylene chloride and 1 N HCl. The organic layer is dried over anhydrous Na2SO4 then concentrated in vacuo. Purification by flash silica gel chromatography afforded 0.463 g (92%) of N-benzyloxy-3-(4-methoxyphenylsulfonyl)-3-ethyl-7-phenylheptanamide in the form of a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[H-].[Na+].I[CH2:32][CH3:33].CO>CN(C=O)C.O>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][CH:19]([CH2:22][OH:23])[CH2:20][O:21][CH2:32][CH3:33])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CO)CO
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CCOCC(CO)NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 750 mg (1.92 mmol) of 8-[(2,6-difluorobenzyl)oxy]-N-(1,3-dihydroxy-propan-2-yl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide were initially charged in 19 ml of DMF, 52 mg (2.11 mmol) of sodium hydride (95%) were added and the mixture was stirred at 0° C. for 30 min. A solution of 239 mg (1.53 mmol) of iodoethane in 2 ml of DMF was then slowly added dropwise at 0° C., and the mixture was stirred at RT overnight. At room temperature, another 9.4 mg (0.38 mmol) of sodium hydride (95%) were added, the mixture was stirred for 30 min and another 59.8 mg (0.38 mmol) of iodoethane were then added dropwise, and the mixture was stirred at room temperature overnight. A little methanol was added and the reaction mixture was poured into 20 ml of water and extracted twice with ethyl acetate. The combined organic phases were washed with aqueous saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was purified by silica gel chromatography (mobile phase dichloromethane:methanol=40:1, 20:1). This gave 280 mg of the target compound (33% of theory, purity 96%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[F:12][C:13]1[CH:34]=[CH:33][C:16]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][C:23]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:24][CH:25]=3)[CH:20]=[C:19]2[CH:31]=[O:32])=[CH:15][CH:14]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[F:12][C:13]1[CH:34]=[CH:33][C:16]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][C:23]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:24][CH:25]=3)[CH:20]=[C:19]2[CH:31]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[OH:32])=[CH:15][CH:14]=1
Reactant: Brc1nccs1
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(C=O)n2Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc2c(c1)cc(C(O)c1nccs1)n2Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
To a mixture of 2-bromothiazole (123 mg) and tetrahydrofuran (3.5 ml), 1.61 M n-butyl lithium solution in hexane (0.51 ml) was added at −78° C. and the mixture was stirred for 30 minutes, followed by addition of a solution of 1-(4-fluorobenzyl)-5-methanesulfonylindole-2-carbaldehyde (50 mg) obtained in Example 27 (4) in tetrahydrofuran (3.5 ml) at the same temperature, and the mixture was stirred as such for 30 minutes. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, extracted with chloroform, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel preparative thin-layer chromatography (hexane:ethyl acetate=1:1) to obtain 18 mg of the desired product as a yellow oil.