Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[N:8][CH:9]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[N:8][CH:9]=1
Reactant: O=C1CCCN1c1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCCC2=O)nc1
Yield: 109.4 %

Procedure:
A methanol (20 ml) solution containing 1-(5-nitropyridin-2-yl)pyrrolidin-2-one (31 mg) was prepared and subjected to a hydrogenation reaction (30° C.; 1 bar; flow rate: 1 ml/min; 10% Pd/C) using H-cube™. Then, the solvent was distilled away under reduced pressure, and a purple solid of 1-(5-aminopyridin-2-yl)pyrrolidin-2-one (29 mg) was thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:16]([NH:18][CH2:19][CH2:20][C:21]#[N:22])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C[Si]([N:68]=[N+:69]=[N-:70])(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3[N:18]([CH2:19][CH2:20][C:21]#[N:22])[N:70]=[N:69][N:68]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)NCCC#N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)c1nnnn1CCC#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
To a solution of (S)-tert-butyl 3-(3′-chlorobiphenyl-4-yl)-1-(2-cyanoethylamino)-1-oxopropan-2-ylcarbamate (1.07 g, 2.500 mmol) in THF (50 ml) at room temperature was added Ph3P (1.640 g, 6.25 mmol), and the mixture was stirred at room temperature for 10 minutes. Then, to the mixture at 0° C. was added DIAD (1.215 ml, 6.25 mmol) and 2 minutes later was slowly added trimethylsilyl azide (0.828 ml, 6.25 mmol). The resulting light yellow suspension was slowly warmed up to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, 25 to 50% EtOAc/Heptane) and gave the title compound: 423 mg (yield: 85%). LCMS (condition B): 453.2 (M+1); retention time=1.23 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][NH:6][C:7](=[O:12])[O:8][CH:9]([CH3:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+].[C:22]1(OB(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[Na+]>C(O)C.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.C1(C)C=CC=CC=1>[C:22]1([C:2]2[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=2)[CH2:5][NH:6][C:7](=[O:12])[O:8][CH:9]([CH3:11])[CH3:10])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)Oc1ccccc1
Reactant: CC(C)OC(=O)NCc1cccc(Br)c1
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: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)NCc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
1.20 g of isopropyl N-(3-bromobenzyl)carbamate, 0.47 g of sodium carbonate in aqueous solution (20 ml) and 0.10 g of tetrakis(triphenylphosphine)palladium (0) were added to toluene (40 ml) under a nitrogen atmosphere. The resulting solution was mixed with 0.54 g of phenylboric acid in ethanol (20 ml) at room temperature with stirring and refluxed under heating for 2 hours. After the reaction, the reaction solution was cooled to room temperature, poured into saturated aqueous sodium chloride and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 0.85 g of isopropyl N-(3-phenylbenzyl)carbamate as white crystals. m.p. 61-64° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CC([O-])(C)C.[Na+].O(CCCC)CCCC>>[CH2:10]([NH:16][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COc1ccc(Cl)cc1
Reactant: CCCCCCN
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: CCCCCCNc1ccc(OC)cc1
Temperature: 85 °C
Yield: 88.2 %

Procedure:
Following general procedure D, a mixture of 4-chloroanisole (1.23 mL, 10 mmol), hexylamine (1.83 mL, 14 mmol), NaOt-Bu (1.15 g, 12 mmol), 10 (4 mg, 0.05 mol %), 1 (2.5 mg, 0.05 mol %), and Bu2O (3 mL) was heated to 85° C. for 1 h. The crude product was purified via the Biotage SP4 (silica-packed 100 g; 0-50% EtOAc/hexanes) to provide the title compound as a yellow oil (1.828 g, 88%). 1H NMR (300 MHz, CDCl3) δ: 6.84 (d, J=9.0 Hz, 2H), 6.62 (d, J=9.0 Hz, 2H), 3.78 (s, 3H), 3.40 (s, 1H), 3.09 (t, J=7.0 Hz, 2H), 1.64 (pentet, J=7.5 Hz, 2H), 1.42 (m, 6H), 0.97 (t, J=7.0 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 152.2, 143.2, 115.1, 114.2, 56.0, 45.3, 32.0, 30.0, 27.2, 23.0, 14.4 ppm. IR (neat, cm−1): 3394, 2929, 2857, 2831, 1513, 1466, 1237, 1180, 1040, 819, 520.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:22]=1[NH2:23]>>[CH3:20][C:21]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:22]=1[NH:23][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][N:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1cc(C)c(N)cc1OC
Reactant: Clc1nccc(Nc2cc(-c3ccccc3)on2)n1
Product: COc1cc(C)c(Nc2nccc(Nc3cc(-c4ccccc4)on3)n2)cc1OC

Procedure:
The title compound was prepared by the method described in Example 1 using 2-chloro-N4-(5-phenylisoxazol-3-yl)-4-pyrimidineamine and 2-methyl-4,5-dimethoxyaniline.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[C:4]([F:27])[CH:3]=1.[N+:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)([O-:30])=[O:29].C(=O)([O-])[O-].[K+].[K+].Cl>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.O1CCOCC1>[F:27][C:4]1[CH:3]=[C:2]([C:34]2[CH:35]=[CH:36][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CC(C)c1nn(Cc2ccc(Br)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nn(Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 40.7 %

Procedure:
To a 5 mL microwave tube was added N-{[2-[(4-bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 46(b), 1 g, 2.261 mmol), 4-nitrobenzenboronic acid (0.377 g, 2.261 mmol), potassium carbonate (0.938 g, 6.78 mmol), tetrakis(triphenylphosphine)palladium (0) (0.078 g, 0.068 mmol), 1,4-Dioxane (5 ml) and Water (1.667 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (10 ml) and acidified with 1N HCl to give a off-white precipitate that was collected by filtration. The mixture of products was purified by HPLC chromatography (ODS silica, gradient 10-100% acetonitrile/water (0.1% TFA)) to afford the title compound (450 mg, 0.920 mmol, 40.7% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 15.93 (s, 1H), 12.97 (br. s., 1H), 10.14 (t, J=5.68 Hz, 1H), 8.30 (td, J=9.16, 2.65, 2.34 Hz, 2H), 8.01 (td, J=9.16, 2.65, 2.34 Hz, 2H), 7.73 (dd, J=11.37, 1.77 Hz, 1H), 7.63 (dd, J=7.96, 1.89 Hz, 1H), 7.41 (t, J=7.96 Hz, 1H), 5.37 (s, 2H), 4.10 (d, J=5.56 Hz, 2H), 3.19 (sept, J=6.86 Hz, 1H), 1.19 (d, J=6.82 Hz, 6H). MS (ES+) m/e 485 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:16]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)(=[O:18])[CH3:17].C1COCC1>CCOC(C)=O>[C:16]([C:19]1[CH:24]=[CH:23][C:22]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:21][CH:20]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)CBr
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.3 %

Procedure:
Ethyl bromoacetate (1.70 g, 10.2 mmol), tris-(1-naphthylene)phosphine (379 mg, 0.93 mmol) and tribasic potassium phosphate (10.8 g, 51 mmol) were placed in a flask. The flask was evacuated and back-filled with argon. A solution of 4-acetylphenylboronic acid (2.0 g, 12.2 mmol) in anhyd THF (40 mL) was added to the flask. The reaction was stirred at rt for 16 h. The reaction was diluted with EtOAc, washed with water and brine, dried over MgSO4, filtered and evaporated to dryness. The residue was pre-adsorbed on to SiO2 and the product isolated via SiO2 chromatography to yield 616 mg (29%) of ethyl 4-acetyl-phenylacetate. MS 207.1 (M+H)+.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9]O)[CH2:5][CH2:4]1)=[CH2:2].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:35]I>C1(C)C=CC=CC=1>[I:35][CH2:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([CH:1]=[CH2:2])[CH2:4][CH2:5]1
Reactant: C=C[C@H]1CC[C@H](CO)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C[C@H]1CC[C@H](CI)CC1
Temperature: 5 °C

Procedure:
Under a nitrogen atmosphere, (trans-4-vinyl cyclohexyl) methanol (7) (12.0 g), imidazole (7.6 g), and triphenylphosphine (Ph3P) (29.2 g) were put in toluene (200 ml) and stirred at 5° C. Iodine (27.2 g) was divided into 10 parts and added thereto in the temperature range of 5 to 10° C., and then stirred for another 3 hours . Completion of the reaction was confirmed by means of gas chromatographic analysis. The deposit was removed from the reaction mixture obtained by filtration, and the solvent was distilled off from the filtrate under reduced pressure. The residue obtained was purified with a fractional operation by means of column chromatography using heptane as the eluent and silica gel as the stationary phase powder, and dried, giving 15.2 g of 1-iodomethyl-trans-4-vinylcyclohexane (8). The yield based on the compound (7) was 71.0%.
Reaction SMILES: [CH2:1]1[CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=2[O:2]1>CC(C)=O>[CH2:1]1[CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:3](=[O:2])[CH3:4])=[CH:4][C:3]=2[O:2]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Solvent: CC(C)=O
Product: CC(=O)C=Cc1ccc2c(c1)OCCO2

Procedure:
(i)(b) 1-(3,4-Ethylenedioxyphenyl)but-1-en-3-one was prepared from 3,4-ethylenedioxybenzaldehyde and acetone following essentially the same procedure as that described in Example 1 part (i). The product was obtained as a crystalline solid, mp 80° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]#[N:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:20]1(Br)[CH2:23][CH2:22][CH2:21]1>CN(C=O)C>[CH:20]1([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[C:7]([C:12]#[N:13])=[CH:8]2)[CH2:23][CH2:22][CH2:21]1
Reactant: BrC1CCC1
Reactant: COc1ccc2c(C#N)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc2c(C#N)cn(C3CCC3)c2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To 6-methoxy-1H-indole-3-carbonitrile (98.2 g, 0.57 mol) was added cesium carbonate (430 g, 1.32 mol), DMF (165 mL) and cyclobutylbromide (96%, 67.5 mL, 0.69 mol). The mixture was heated to 90° C. and stirred overnight. The mixture was cooled to 37° C. and poured into ice water (500 mL), washing in with water. After stirring for 1 hour the precipitate was collected on a filter and dried under a stream of nitrogen to give 1-cyclobutyl-6-methoxy-1H-indole-3-carbonitrile as a tan solid (124.1 g, 96%).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]([O:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])=[O:7])([O-])=O>C(O)(=O)C.C1COCC1.[Pd]>[C:6]([O:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])(=[O:7])[C:5]1[C:4](=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:1]
Reactant: O=C(OCN1C(=O)c2ccccc2C1=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1ccccc1C(=O)OCN1C(=O)c2ccccc2C1=O

Procedure:
Phthalimidomethyl o-nitrobenzoate (10 g) dissolved in a mixture of 60 ml acetic acid and 150 ml THF was hydrogenated with 10% palladium on charcoal catalyst (0.5 g) in a Parr shaker apparatus for 1 hour. The solution was filtered and the filtrate concentrated in vacuo. The crystalline product precipirated and was filtered off yielding 7.0 g, m.p. 160°-162° C.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([I:18])[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>O1CCCC1>[CH:6]1([CH2:5][CH:4]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([I:18])[CH:13]=[N:12]2)[C:3]([OH:19])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)n1ncc(I)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)n1ncc(I)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (Intermediate 73, Step 2, 1.78 g, 4.73 mmol) in tetrahydrofuran (13 mL, 0.36M) was treated with a 4N aqueous sodium hydroxide solution (1.3 mL, 5.2 mmol) and stirred at 25° C. overnight. After this time, the reaction was concentrated in vacuo and the residue was diluted with water (50 mL) and was then acidified with a 1N aqueous hydrochloric acid solution. The precipitate was filtered and concentrated in vacuo to afford 3-cyclopentyl-2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-propionic acid (1.45 g, 85%) as an off-white solid; ES+-HRMS m/e calcd for C12H15N2O3I [M+H+] 363.0200, found 363.0197. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.18 (m, 2H), 1.36-1.75 (m, 7H), 1.88-2.02 (m, 1H), 2.17 (ddd, J=13.9, 10.8, 5.1 Hz, 1H), 5.30 (dd, J=10.8, 4.3 Hz, 1H), 7.65 (d, J=1.9 Hz, 1H), 8.23 (d, J=1.9 Hz, 1H), 13.10 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:36])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:35])/[C:14](/[C:25]2[CH:30]=[CH:29][C:28]([O:31]COC)=[CH:27][CH:26]=2)=[C:15](/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)\[CH2:16][CH2:17][CH3:18])=[CH:8][CH:7]=1.Cl.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O.O>[CH3:36][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:35])/[C:14](/[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[C:15](/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)\[CH2:16][CH2:17][CH3:18])=[CH:10][CH:11]=1
Reactant: CCC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(OCOC)cc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CCC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 5a (45 mg, 0.0921 mmol) in MeOH (1 ml) was added 3N HCl in AcOEt (0.5 ml) under ice cooling, and the mixture was stirred at room temperature for 1 h. A solution of NaHCO3 (139 mg) in H2O was poured into the reaction mixture under ice cooling, and the whole was extracted with AcOEt and a little MeOH. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. The residue was crystallized with Et2O to give 6a (83%). 6a: colorless powder; 1H-NMR (CD3OD) δ 0.87 (3H, t, J=7.4 Hz), 1.38 (2H, m), 2.46 (6H, s), 2.59 (2H, m), 2.91 (2H, t, J=5.1 Hz), 4.14 (2H, t, J=5.1 Hz), 6.51 (2H, d, J=8.6 Hz), 6.92-6.96 (4H, m), 7.10-7.24 (5H, m), 7.53 (2H, d, J=8.8 Hz). HRMS calcd for C28H33N2O3 [M+H]+: 445.2491. Found: 445.2510.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:7]=1)C.CO.[NH3:26]>>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([C:8]2[CH:7]=[C:6]([CH2:5][C:4]([NH2:26])=[O:3])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[CH:9]=2)[CH2:17][CH2:18]1
Reactant: N
Reactant: CCOC(=O)Cc1cc(N2CCN(C)CC2)cc2c1CCCC2
Solvent: CO
Product: CN1CCN(c2cc3c(c(CC(N)=O)c2)CCCC3)CC1
Reaction time: 48 h

Procedure:
A solution of compound of step e) (394 mg, 1.2 mmol) in methanol/NH3 (4 molar) is transferred into an autoclave and kept at 120° C. for 48 hours. After cooling the reaction is concentrated and the crude residue is purified on silica gel (methylene chloride/methanol 90/105) affording the pure title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:20][C:21]3[CH:22]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:24]=[CH:25][CH:26]=3)=[C:7]([CH3:19])[N:8]2[C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=2)=[CH:4][CH:3]=1.[CH:31]1([S:34]([NH2:37])(=[O:36])=[O:35])[CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:20][C:21]3[CH:22]=[C:23]([CH2:27][C:28]([NH:37][S:34]([CH:31]4[CH2:33][CH2:32]4)(=[O:36])=[O:35])=[O:29])[CH:24]=[CH:25][CH:26]=3)=[C:7]([CH3:19])[N:8]2[C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: CCCn1cc(-n2c(C)c(Sc3cccc(CC(=O)O)c3)c3ccc(Cl)cc32)cn1
Reactant: NS(=O)(=O)C1CC1
Product: CCCn1cc(-n2c(C)c(Sc3cccc(CC(=O)NS(=O)(=O)C4CC4)c3)c3ccc(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in the synthesis of Example 117 using the following starting materials: {3-[6-Chloro-1-(1-propyl-1H-pyrazol-4-yl)-2-methyl-1H-indol-3-ylsulfanyl]-phenyl}-acetic acid and cyclopropanesulfonamide.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][C:20]3([NH:27][CH2:26][CH2:25][N:24]4[C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=[C:23]34)[CH2:19][CH2:18]2)=[O:16])=[CH:11][C:10]=1[O:35][CH3:36])([CH3:7])[CH3:6]>N1C=CC=CC=1>[CH:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:18][CH2:19][C:20]3([N:27]([C:1](=[O:3])[CH3:2])[CH2:26][CH2:25][N:24]4[C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=[C:23]34)[CH2:21][CH2:22]2)=[O:16])=[CH:11][C:10]=1[O:35][CH3:36])([CH3:7])[CH3:6]
Reactant: COc1cc(C(=O)N2CCC3(CC2)NCCn2c(C(F)(F)F)ccc23)ccc1OC(C)C
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(C(=O)N2CCC3(CC2)c2ccc(C(F)(F)F)n2CCN3C(C)=O)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
Acetyl chloride (158 μL, 2.22 mmol) was added drop-wise to a mixture of (4-isopropoxy-3-methoxy-phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone (100 mg, 0.222 mmol) and pyridine (1 mL) at room temperature. The mixture was allowed to stir for 16 h at room temperature before it was partitioned between ethyl acetate and 1N HCl. The layers were separated and the organic layer was washed with 1N HCl, water, and then brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was taken up in DMF and was purified by preparatory-HPLC (10-99% ACN/water with ammonium formate modifier) to give 1-[1′-(4-isopropoxy-3-methoxy-benzoyl)-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-2-yl]ethanone (60 mg, 53%) as a white solid. ESI-MS m/z calc. 493.2, found 494.7 (M+1)+; Retention time: 1.70 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.06 (d, J=1.8 Hz, 1H), 7.05-6.98 (m, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.55 (d, J=3.3 Hz, 1H), 6.15 (d, J=3.9 Hz, 1H), 4.57 (d, J=6.1 Hz, 1H), 4.19-4.10 (m, 2H), 3.88 (m, s, 5H), 3.79 (s, 2H), 3.70-3.52 (m, J=31.5 Hz, 2H), 3.11 (s, 2H), 2.24 (s, 3H), 1.92-1.75 (m, 2H), 1.38 (d, J=6.1 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:31][C:32]1[CH:41]=[CH:40][C:35]2[O:36][CH2:37][CH2:38][O:39][C:34]=2[CH:33]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([C:27](O)=[O:28])=[CH:19][C:18]2=[O:30])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56].N12CCCN=C1CCCCC2>O1CCCC1>[O:36]1[C:35]2[CH:40]=[CH:41][C:32]([CH2:31][N:8]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20]([C:27]([NH:58][S:55]([CH3:54])(=[O:57])=[O:56])=[O:28])=[CH:19][C:18]4=[O:30])[CH2:11][CH2:10]3)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:33][C:34]=2[O:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(C(=O)O)c3ccccc32)CC1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(C(=O)NS(C)(=O)=O)c3ccccc32)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To 5 mL of tetrahydrofuran suspension containing 0.10 g of 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, 58 mg of 1,1′-carbonyldiimidazole was added, and stirred at 50° C. for 1 hour. The reaction mixture was cooled to the room temperature, then 84 mg of methanesulfonamide and 0.13 mL of 1,8-diazabicylo[5.4.0] undec-7-ene were added, and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, water was added, and adjusted to pH 4 with 1 mol/L hydrochloric acid. The resulting solid was filtered to afford 0.10 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-(((methylsulfonyl)amino)carbonyl)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([N:7]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.N12CCCN=C1CCC[CH2:27][CH2:26]2.C(Br)C>C1C=CC=CC=1>[C:1]1([CH3:24])[CH:2]=[CH:3][C:4]([N:7]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:26][CH3:27])=[O:13])=[CH:15][CH:16]=2)=[CH:5][CH:6]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C(=O)O)cc2)cc1
Solvent: c1ccccc1
Solvent: CCBr
Product: CCOC(=O)c1ccc(N(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Yield: 75.5 %

Procedure:
4-(Di-p-tolylamino)benzoic acid (69.7 g, 0.22 mol) dissolved in benzene (500 mL), was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (38 mL, 0.25 mol), followed by the addition of ethyl bromide (33 mL, 0.44 mol). The reaction was filtered to remove salts, washed with saturated ammonium chloride until neutral (1.5 L), washed with water, washed with brine, and dried over magnesium sulfate. The solvent was removed at 40° C. and the residual crystalline solid was washed with cold ethanol to give ethyl 4-(di-p-tolylamino)benzoate (57.4 g, 76% yield).