Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[C:1](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:19][CH3:20])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)/C=C/C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)/C=C/C(=O)c1ccccc1
Temperature: 62 °C
Reaction time: 3 h

Procedure:
A mixture of 7.75 g of trans-β-benzoylacrylic acid, 25.8 ml of ethanol and 1.63 g of sulfuric acid was stirred at 62° C. for 3 hours. A pressure was gradually reduced with the aspirator and ethanol was distilled away for 20 minutes. After a pressure was finally reduced to 20 mmHg, the resultant was stirred at 62° C. for 1.5 hours and then cooled, followed by the procedure as in Example 1 to give 8.18 g of ethyl trans-β-benzoylacrylate.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([Cl:7])[C:3]=1[Cl:8].[F:9][C:10]([F:24])([F:23])[S:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:13])=[O:12].CCOCC>C(=O)=O.CC(C)=O>[F:9][C:10]([F:24])([F:23])[S:11]([O-:14])(=[O:13])=[O:12].[CH2:15]([N+:5]1[S:6][C:2]([Cl:1])=[C:3]([Cl:8])[C:4]=1[Cl:7])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Clc1nsc(Cl)c1Cl
Reactant: CCCCCCCCOS(=O)(=O)C(F)(F)F
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CCOCC
Product: CCCCCCCC[n+]1sc(Cl)c(Cl)c1Cl
Product: O=S(=O)([O-])C(F)(F)F
Yield: 31 %

Procedure:
Trichloroisothiazole (6.6 g, 0.035 mol) and n-octyl trifluoromethane sulfonate (7.5 g, 0.0286 mol) were heated at 110° for 2 hrs. After cooling, 150 ml of ether was added and solution cooled in dry ice/acetone bath. The ether was decanted and the brown oil dried to yield 4.0 g (31%) of product. Spectral data (NMR & IR) were consistent with the assigned structure.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][CH2:16]O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>C1COCC1>[Br:38][CH2:16][C:15]#[C:14][C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCC#Cc1ccc(Oc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCC#Cc1ccc(Oc2ccccc2)cc1

Procedure:
A solution of 3-(4-Phenoxy-phenyl)-prop-2-yn-1-ol of Example 51 (415 mg, 1.85 mmol), triphenylphosphine (514 mg, 1.96 mmol), carbon tetrabromide (650 mg, 1.96 mmol) in THF (3 ml) was stirred at room temperature for 3 days. Evaporation of the solution, and chromatography of the residue gave the title compound as a brown oil:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[CH2:5]2.CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1.Cl.ClC1C=CN=CC=1>O1CCOCC1>[N:1]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][C:6](=[O:13])[CH2:5]3)[CH:16]=[CH:20][CH:19]=[CH:18]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc2c(c1)CC(=O)NC2=O
Agent: Cl
Agent: Clc1ccncc1
Solvent: C1COCCO1
Product: O=C1Cc2cc(-n3cccc3)ccc2C(=O)N1
Yield: 66.9 %

Procedure:
A mixture of 6-amino-4H-isoquinoline-1,3-dione (1 g, 5.68 mmol), 2,5-dimethoxytetrahydrofuran (0.736 mL, 5.68 mmol), 4-chloropyridine hydrochloride (0.417 g, 2.78 mmol) in dioxane (20 mL) is heated at 70° C. for 2 h [Ref: J. Heterocyclic Chem. 35, 1313, (1998)] After cooling, the solid is filtered, washed successively with water, ether and hexane to yield 0.86 g (67%) of the title compound as a light brown solid, mp 212-213° C.; HRMS (ESI) m/z calcd for C13H10N2O2 227.08151. found 227.08151 (M+H)+1. Analysis for C13H10N2O2 (0.5H2O): Calcd: C, 66.37; H, 4.71; N, 11.91. Found: C, 66.19; H, 4.56; N, 11.09.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15](=O)[C:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=O)[CH2:2][CH3:3].C([O-])(=O)C.[NH4+:29].[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.[OH-].[NH4+:40]>C(O)(=O)C.C(OCC)(=O)C>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]2[NH:29][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:15]([C:6]3[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][CH3:14])=[CH:10][C:5]=3[O:4][CH2:1][CH2:2][CH3:3])[N:40]=2)=[CH:33][CH:32]=1
Reactant: CCCOc1ccc(C(=O)C(=O)c2ccncc2)c(OCCC)c1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCOc1ccc(-c2nc(-c3ccc(Cl)cc3)[nH]c2-c2ccncc2)c(OCCC)c1
Temperature: 0 °C
Yield: 30 %

Procedure:
A solution of 1-(2,4-di-n-propyloxyphenyl)-2-(4-pyridyl)ethane-1,2-dione from Step D (61 mg, 0.19 mmol), ammonium acetate (144 mg, 1.87 mmol) and 4-chlorobenzaldehyde (33 mg, 0.23 mmol) in acetic acid (1.5 mL) was heated to 100° C. for 3.5 h. After cooling to 0° C., the ice (4g), ethyl acetate (2 mL) and a concentrated solution of ammonium hydroxide was added until the pH was 10. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic extracts were successively washed with water and saturated salt solution and dried over anhydrous sodium sulfate. The mixture was filtered and the solvent removed by rotoevaporation. The residue was purified by flash column chromatography on silica gel eluted with 0-3% methanol in methylene chloride to yield the title compound as a cream-colored solid (25 mg, 30% yield), mass spectrum (CI) m/e=448 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])[CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>C(=O)([O-])[O-].[Ag+2].C1C=CC=CC=1>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][C:2]2[N:7]=[C:6]([N:8]3[C:12](=[O:13])[C:11]4[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=4[C:9]3=[O:18])[CH:5]=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cccc(O)n1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: O=C1C2=C(CCCC2)C(=O)N1c1cccc(OCc2ccc(Cl)cc2)n1
Reaction time: 72 h

Procedure:
A mixture of N-(6-hydroxy-2-pyridyl)-3,4,5,6-tetrahydrophthalimide (3.9 g), silver carbonate (2.2 g), p-chlorobenzyl chloride (2.6 g) and benzene (75 ml) is stirred, in the dark, at 45° for about 72 hours. Then, the reaction is cooled and filtered. The filtrate is washed with 10% sodium bicarbonate and water, dried and stripped to give N-[6-(4-chlorobenzyloxy)-2-pyridyl]-3,4,5,6-tetrahydrophthalimide.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]([N+:15]([O-:17])=[O:16])=[C:11]([CH3:18])[N:10]([CH3:19])[C:9]1=[O:20])(=[O:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O.C([O-])(=O)C.[Na+]>CC(O)=O.CC(=O)OCC.O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]([N+:15]([O-:17])=[O:16])=[C:11](/[CH:18]=[CH:25]/[C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([Cl:21])[CH:23]=2)[N:10]([CH3:19])[C:9]1=[O:20])(=[O:3])[CH3:2]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(=O)OCCCn1c(=O)c([N+](=O)[O-])c(C)n(C)c1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCCCn1c(=O)c([N+](=O)[O-])c(/C=C/c2cccc(Cl)c2)n(C)c1=O
Temperature: 150 °C
Yield: 16.3 %

Procedure:
To a solution of 3-(3,4-dimethyl-5-nitro-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)propyl acetate (300 mg, 1.05 mmol) in HOAc (0.7 mL) was added 3-chlorobenzaldehyde (221 mg, 1.58 mmol) and sodium acetate (431 mg, 5.26 mmol). The reaction was heated at 150° C. for 7 h, cooled to RT then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography PE/EA (5:1 to 2:1) to give (E)-3-(4-(3-chlorostyryl)-3-methyl-5-nitro-2,6-dioxo-2,3-dihydropyrimidin-1 (6H)-yl)propyl acetate (70 mg, 16.4% yield) as a brown oil. LCMS: MH+ 408 and TR=1.560 min.
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]=[C:7]1[CH3:20].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1ccccc1
Yield: 48.8 %

Procedure:
Using the general method of Example 232, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (0.50 g, 1.9 mmol) was reacted with benzenesulfonyl chloride (0.24 mL, 1.9 mmol) to provide 0.38 g of N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide as brown granules, m.p. 215.4-216.0° C. Analysis: Calculated for C21H23N5O2S: %C, 61.59; %H, 5.66; %N, 17.10; Found %C, 61.24; %H, 5.65; %N, 16.95.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.CN1CCCC1=O.[CH3:18][CH:19]1[N:24]([CH2:25][CH2:26][CH2:27][NH2:28])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C>O>[CH3:18][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][CH2:27][NH:28][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC1CCCCN1CCCN
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC1CCCCN1CCCNc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Yield: 75.1 %

Procedure:
2 g of para-fluoronitrobenzene were added to a solution of 20 ml of N-methyl-pyrrolidinone, 1.65 g of 1-(3-aminopropyl)-2-pipecoline and 1.72 g of triethylamine. The reaction medium was heated at 60° C. for 8 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 2.2 g of N-[3-(2-methyl-piperidin-1-yl)propyl]-4-nitro-1-aminobenzene (17) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[O:10])=[C:4]([N+:33]([O-])=O)[CH:3]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl.CO.O>[NH2:33][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:10]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)cc4[N+](=O)[O-])cc3)c2cc1OC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)cc4N)cc3)c2cc1OC
Temperature: 60 °C
Reaction time: 0.62 h
Yield: 22.2 %

Procedure:
N-(4-Chloro-2-nitrophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea (158 mg) was dissolved in chloroform/methanol/water (10 ml/70 ml/5 ml), sodium thiosulfate (1.01 g) was added, and the admixture was stirred at 60° C. for 37 minutes. The reaction mixture was extracted 2 times with chloroform, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 33 mg of the title compound (yield: 22%).
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH2:3][C:4]#[CH:5].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.N1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:1][CH:2]([O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1)[CH2:3][C:4]#[CH:5]
Reactant: C#CCC(C)O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#CCC(C)OC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(+/−)-4-Pentyn-2-ol (5.58 ml, 59.4 mmol) and 3,4-dihydro-2H-pyran (8.08 ml, 89 mmol) were dissolved in DCM (100 ml). 4-Toluenesulfonic acid pyridine salt (1.494 g, 5.94 mmol) was added and the resulting mixture was stirred for 4 h at RT with CaCl2-tube. The mixture was concentrated. 50 ml of diethyl ether was added, extracted with brine and dried with MgSO, filtered and evaporated. The product was used in the subsequent steps without further purifications. LC-MS: [M+1]=169.23.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH2:18])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH3:5].[OH:21][C@@H:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23](O)=[O:24]>>[CH3:1][O:2][C:3](=[O:20])[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH:18][C:23](=[O:24])[CH:22]([OH:21])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:5])[CH3:6]
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1
Reactant: CC(C)(C)[C@H](O)C(=O)O
Product: CCCC(NC(=O)C(O)C(C)(C)C)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1

Procedure:
2-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-2-methyl-propionic acid methyl ester was coupled with (S)-2-hydroxy-3,3-dimethyl-butyric acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 19.1, 26.1, 26.2, 26.3, 35.3, 35.5, 52.6, 53.3, 61.1, 79.6, 106.1, 131.9, 137.5, 169.6, 172.7, 173.1; MS 397.23 m/z (M+1).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=1)=[O:14].I[C:31]1[S:35][CH:34]=[C:33]([C:36]#[N:37])[CH:32]=1>>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:16]=[CH:17][C:18]([C:31]2[S:35][CH:34]=[C:33]([C:36]#[N:37])[CH:32]=2)=[CH:19][CH:20]=1)=[O:14]
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: N#Cc1csc(I)c1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2cc(C#N)cs2)cc1
Yield: 30 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure A using [2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (351 mg, 0.88 mmol) and 5-Iodo-thiophene-3-carbonitrile (CAS 18800-02-7) (165 mg, 0.88 mmol) to give 100 mg (30% yield). MS (ES+) 380.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:23][Mg]Br.[Cl-].[NH4+]>CCOCC>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]([OH:22])([CH3:23])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(C(=O)CCCCC#C[Si](C)(C)C)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1cc(OC)cc(C(C)(O)CCCCC#C[Si](C)(C)C)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
[7-(3,5-Dimethoxyphenyl)-7-oxo-1-heptynyl]trimethylsilane (1 equiv.) was dissolved in anhydrous ether (0.5 M), the solution was cooled in an ice-bath under argon and methylmagnesium bromide (2 equiv., 3M solution in diethyl ether) was added dropwise. The light gray solution was allowed to warm to room temperature and stirred for an additional hour. The reaction mixture was poured into saturated ammonium chloride solution, the organic phase was separated and the aqueous phase was extracted with diethyl ether. The combined organic extracts were dried and ether removed to afford pure [7-(3,5-dimethoxyphenyl)-7-hydroxy-1-octynyl]trimethylsilane as a viscous oil after passing through a short silica gel column, in 95% yield.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][C:18]1[CH:32]=[CH:31][C:21]([C:22]([NH:24][C:25]([CH3:30])([CH3:29])[C:26]([OH:28])=O)=[O:23])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[N:55]1([C:61]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=2[C:69]([F:72])([F:71])[F:70])=[O:62])[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>CN(C=O)C.O>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:24][C:25]([CH3:30])([CH3:29])[C:26](=[O:28])[N:58]2[CH2:59][CH2:60][N:55]([C:61](=[O:62])[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=3[C:69]([F:72])([F:70])[F:71])[CH2:56][CH2:57]2)=[O:23])=[CH:31][CH:32]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(NC(=O)c1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)c1ccc(OCc2ccccc2)cc1)C(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 50.2 %

Procedure:
DIPEA (284 mg, 0.19 mL, 1.62 mmol) was added to a stirred solution of 2-(4-benzyloxy-benzoylamino)-2-methyl-propionic acid (170 mg, 0.54 mmol) in DMF (2 mL). HOBT (88 mg, 0.65 mmol) and EDCI (125 mg, 0.65 mmol) were then added at room temperature. After 2 minutes, piperazin-1-yl-(2-trifluoromethyl-phenyl)-methanone hydrochloride salt (192 mg, 0.65 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated out to afford 150 mg (50% yield) of 4-benzyloxy-N-{1,1-dimethyl-2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 93.29%. 1H NMR (DMSO-d6): δ 8.4 (bs, 1H), 7.6-7.8 (m, 5H), 7.4 (m, 6H), 7.0-7.1 (d, 2H), 5.2 (m, 2H), 3.5 (m, 5H), 3.0 (m, 3H), 1.4 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]([F:37])([F:36])[C:18]1[CH:19]=[C:20]([S:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.F[C:39](F)(F)C1C=C(S(N2C[C@H]3[C@H](N)CC[C@H]3C2)(=O)=O)C=CC=1>>[CH3:12][N:8]([C@@H:9]([CH2:10][CH2:11][CH3:39])[C:13](=[O:15])[NH:35][C@@H:32]1[C@@H:30]2[C@@H:29]([CH2:28][N:27]([S:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:36])[F:37])[CH:19]=3)(=[O:25])=[O:26])[CH2:31]2)[CH2:34][CH2:33]1)[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CCC[C@@H](C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21)N(C)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-norvaline for (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid and (3aR,4S,6aS)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Step D of Example 252 for (3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 266: 1H NMR (500 MHz, pyridine-d5, temperature 90° C.) δ ppm 8.30-8.31 (bs, 1H), 8.14 (d, J=7.9 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.64 (t, J=7.8 Hz, 1H), 7.49 (d, J=5.6 Hz, 1H), 4.72-4.73 (m, 1H), 4.04-4.11 (m, 1H), 3.67 (dd, J=10.1, 3.3 Hz, 1H), 3.26 (dd, J=10.1, 7.7 Hz, 1H), 3.10-3.13 (m, 2H), 2.93 (s, 3H), 2.46-2.59 (m, 2H), 1.86-2.01 (m, 2H), 1.71-1.84 (m, 2H), 1.46-1.58 (m, 1H), 1.45 (s, 9H), 1.29-1.36 (m, 2H), 1.22-1.30 (m, 1H), 0.86 (t, J=7.3 Hz, 3H); MS (ESI+) m/z 548 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)[NH:9]2)=[CH:5][CH:4]=1.[CH:18]([C:20]1[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][CH:21]=1)=[O:19].C1CCN2C(=NCCC2)CC1>ClCCl>[OH:19][CH:18]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:9][C:8]=1[C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1)[C:20]1[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cccc(C=O)n1
Reactant: COc1ccc2cc(-c3cncnc3)[nH]c2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)c1cccc(C(O)c2c(-c3cncnc3)[nH]c3cc(OC)ccc23)n1
Temperature: 30 °C
Reaction time: 76 h
Yield: 61.4 %

Procedure:
To a suspension of 6-methoxy-2-pyrimidin-5-yl-1H-indole (779 mg) and methyl 6-formylpyridine-2-carboxylate (628 mg) in dichloromethane (17.3 mL) was added 1,8-diazabicyclo[5,4,0]-7-undecene (0.052 mL), and the mixture was stirred at 30° C. for 76 hours. The reaction mixture was purified by aminopropylated silica gel column chromatography (eluting solvent: methanol-ethyl acetate) to obtain the title compound (829 mg). 1H-NMR (DMSO-d6) δ ppm: 3.75 (3H, s), 3.82 (3H, s), 5.99 (1H, d, J=3.5 Hz), 6.16 (1H, d, J=3.5 Hz), 6.61 (1H, dd, J=2.3, 8.8 Hz), 6.84 (1H, d, J=2.3 Hz), 7.49 (1H, d, J=8.8 Hz), 7.86-7.92 (1H, m), 8.06 (1H, t, J=7.8 Hz), 8.18-8.26 (1H, m), 9.23 (1H, s), 9.55 (2H, s), 11.40 (1H, br s).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:3]1.Br[CH2:30][CH2:31][CH2:32][N:33]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43].C([O-])([O-])=O.[K+].[K+].[CH3:50][C:51]([O:54][C:55](OC(OC(C)(C)C)=O)=[O:56])([CH3:53])[CH3:52].CCN(C(C)C)C(C)C>CN(C=O)C>[C:51]([O:54][C:55](=[O:56])[N:1]([C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:3]1)[CH2:30][CH2:31][CH2:32][N:33]1[C:37](=[O:38])[C:36]2[C:35](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:34]1=[O:43])([CH3:53])([CH3:52])[CH3:50]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N(CCCN5C(=O)c6ccccc6C5=O)C(=O)OC(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C
Reaction time: 24 h
Yield: 69.1 %

Procedure:
To DMF (10 mL) were added 3β-amino-5-cholestene (Compound 8, 386 mg, 1.0 mmol), N-(3-bromopropyl)phthalimide (295 mg, 1.1 mmol), and K2CO3 (276 mg, 2.0 mmol). The solution was heated to 60° C. and stirred for 24 h. The reaction was cooled to 22° C., and DMF was removed in vacuo. To the resulting residue was added CH2Cl2 (10 mL). The insoluble material was removed by filtration and washed with additional CH2Cl2 (2×5 mL). To the combined filtrate and wash solutions containing the crude secondary amine product was added (Boc)2O (327 mg, 1.5 mmol) and DIEA (0.5 mL, 3.0 mmol). The reaction was stirred for 4 h at 22° C. and concentrated in vacuo. Flash column chromatography (hexanes/ethyl acetate, 8:1) afforded Compound 9 (465 mg, 69%) as a white foam, mp 59-61° C.; 1H NMR (400 MHz, CDCl3) δ 7.83 (m, 2H), 7.69, (m, 2H), 5.30 (d, 1H), 3.68 (t, 2H), 3.13 (br, 3H), 2.01-0.83 (m, 51H), 0.65 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.2 (×2), 155.2, 141.3, 133.8 (×2), 132.0 (×2), 123.2 (×2), 79.3, 56.6, 56.1 (×2), 50.1, 42.6 (×2), 39.8, 39.4 (×2), 38.3, 36.8, 36.5, 36.1, 35.9, 35.7, 31.2 (×2), 28.4 (Boc, Me3), 28.2, 27.9, 26.7, 24.2, 23.8 (×2), 22.8, 22.5, 20.9, 19.3, 18.7, 11.8; IR (film) ν max 2935, 2867, 1772, 1715, 1689, 1467, 1395, 1365, 1238, 1172, 1146, 1031, 888, 756, 720 cm−1; HRMS (CI+) m/z 673.4946 (M+H+, C43H65N2O4, requires 673.4944).