Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[O:13][C:14](=[O:32])[N:15]([CH:17]3[CH2:23][CH:22]4[N:24](C(OC(C)(C)C)=O)[CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[N:16]=2)[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[O:13][C:14](=[O:32])[N:15]([CH:17]3[CH2:18][CH:19]4[NH:24][CH:22]([CH2:21][CH2:20]4)[CH2:23]3)[N:16]=2)[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(n1nc(-c3cc(Cl)c(NC(=O)OCc4ccccc4)c4c3OCCO4)oc1=O)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(Nc1c(Cl)cc(-c2nn(C3CC4CCC(C3)N4)c(=O)o2)c2c1OCCO2)OCc1ccccc1
Reaction time: 19 h

Procedure:
13.75 g (0.022 mol) of phenylmethyl [6-chloro-8-[4-[8-[(1,1-dimethylethoxy)carbonyl]-8-azabicyclo[3.2.1]oct-3-yl]-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1,4-benzodioxin-5-yl)carbamate dissolved in 150 ml of chloroform are introduced into a 500 ml three-necked round-bottomed flask, 17.05 ml (0.221 mol) of trifluoroacetic acid are added slowly, over 20 min, and the mixture is stirred for 19 h. A further 17.05 ml (0.221 mol) of trifluoroacetic acid are added and the mixture is stirred for 5 h.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[Mg]Br>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)[OH:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1
Reactant: COc1cc(C=O)ccc1-c1cccc(C)c1
Reactant: Br[Mg]c1cccs1
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cccs2)ccc1-c1cccc(C)c1
Reaction time: 2 h
Yield: 82.4 %

Procedure:
The aldehyde 5 were dissolved in dry THF and cooled to −20° C. thiphen-2-yl magnesium bromide (1.2 eq, 1.651 mM) was then added to the reaction and the reaction was stirred for an additional 2 hrs. After the completion of the reaction as determined by TLC, the reaction mixture was quenched with 0.1 N HCl, followed by washes with saturated sodium bicarbonate solution and brine. The product was purified by flash chromatography using 20% EtOAc/Hexanes as the solvent system to obtain a white solid. Yield=82.4% (Rf=0.26; 20% EtOAc/Hexanes) 1H NMR, 500 MHz Varian, CDCl3, δ 7.31 (d, J=2 Hz, 1H), 7.29 (d, J=4.00 Hz, 1H), 7.12 (d, J=9.50 Hz, 2H), 6.99 (m, J=9.50 Hz, 2H), 6.75 (s, 2H), 6.08 (d, J=4.00, 1H), 3.73 (s, 3H), 2.37 (s, 3H), MS: m/z (ESI, pos.)=333.5 ([M+23])
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[S:17][C:16]([S:18][CH3:19])=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[C:21]1([CH2:27][C:28]([N:30]=[C:31]=[S:32])=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:20][C:31]([NH:30][C:28](=[O:29])[CH2:27][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[S:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[S:17][C:16]([S:18][CH3:19])=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CSc1cc2ncnc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Product: CSc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Reaction time: 2 h
Yield: 51.6 %

Procedure:
A mixture of 282 (248mg, 0.80 mmol) and 2-phenylacetyl isothiocyanate (214 mg, 1.20 mmol) in THF (8 mL) was stirred for 2 hours, and concentrated. The residue was purified by flash column chromatography, eluent EtOAc/hexane (3:7), to afford title compound 283 (200 mg, 52% yield) as an off-white solid. 1H NMR (DMSO-d6) δ (ppm): 12.42(s, 1H), 11.80(s, 1H), 8.63(s, 1H), 7.85(d, 1H), 7.54-7.44 (m, 3H), 7.35 (m, 4H), 7.30(m, 1H), 3.81(s, 2H), MS (m/z): 485.1 (M+H) (found).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][C:38]=1[F:46])#[N:36]>>[C:35]([C:37]1[CH:42]=[CH:41][C:40]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:34])=[O:3])[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[CH:13]=2)=[CH:39][C:38]=1[F:46])#[N:36]
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: N#Cc1ccc(B(O)O)cc1F
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(C#N)c(F)c2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-cyano-3-fluoro-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, MeOD) δ ppm 0.88 (dd, J=6.60, 2.93 Hz, 6H), 1.46 (dt, J=13.45, 6.72 Hz, 1H), 1.66 (ddd, J=13.69, 7.21, 6.97 Hz, 1H), 1.96 (ddd, J=13.27, 7.95, 7.64 Hz, 1H), 3.78 (t, J=7.83 Hz, 1H), 7.59-7.70 (m, 6H) 7.72-7.82 (m, 4H); Calcd for C26H21F4NO2 (M+H) 456.44, Found 456.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[I:1]
Reactant: Cc1ccccc1I
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccccc1I

Procedure:
22 g of 2-iodotoluene, 100 ml of carbon tetrachloride, 19.67 g of N-bromo succinimide and 1 g of benzoyl peroxide are mixed together and heated to reflux for 8 hours. After filtering, the insoluble part is rinsed with carbon tetrachloride and the filtrate is distilled off, firstly under atmospheric pressure, then under reduce pressure. The expected product is obtained, and used just as it is for the continuation of the synthesis.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[NH2:20][CH:21]([CH:26]1[CH2:28][CH2:27]1)[CH2:22][C:23]([NH2:25])=[O:24]>>[NH2:25][C:23](=[O:24])[CH2:22][CH:21]([NH:20][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])[CH:26]1[CH2:28][CH2:27]1
Reactant: NC(=O)CC(N)C1CC1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Agent: Cl
Product: NC(=O)CC(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 3-amino-3-cyclopropylpropanamide hydrochloride (CAN 1354953-76-6) as starting materials and isolated (50 mg, 35%); MS (ESI, m/z): 372.5 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH:6]([CH2:12]Br)[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+]>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH:6]([CH2:12][N:15]=[N+:16]=[N-:17])[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)CC(CBr)C1CCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CC(CN=[N+]=[N-])C1CCCC1
Temperature: 60 °C
Yield: 74.8 %

Procedure:
Preparation of 3-Azidomethyl-3-cyclopentyl-propionic acid ethyl ester—A solution of 3-bromomethyl-3-cyclopentyl-propionic acid ethyl ester (4.4 g, 28.5 mmol) and NaN3 (2.0 g, 31.4 mmol) in 25 mL of DMSO is warmed to 60° C. for 12 hours. The mixture is cooled to room temperature and diluted with 100 mL of H2O. Extraction with Et2O (3×50 mL) and drying over MgSO4 followed by evaporation of the Et2O gives 4.8 g (75% yield) of 3-azidomethyl-3-cyclopentyl-propionic acid ethyl ester as an oil. NMR (1H, 300 MHz, CDCl3) δ1.1 (2H, m); 1.2 (3H, t); 1.6 (4H, m); 1.8 (3H, m); 1.9 (1H, m); 2.4 (2H, dd); 3.4 (2H, dd); 4.1 (2H, q).
Reaction SMILES: [O:1]1[CH2:6][CH2:5]C[O:3][CH:2]1[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1.N1C=CN=C1.[C:23]([Si:27](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl.C(OCC)(=O)C>[Si:27]([O:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH:2]2[O:1][CH2:6][CH2:5][O:3]2)=[CH:15][CH:14]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(CCCC2OCCCO2)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCc1ccc(CCCC2OCCO2)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.9 %

Procedure:
To a solution of 2.58 g (11.6 mmol) of alcohol 170 and 1.19 g (17.5 mmol) of imidazole in 50 mL of CH2Cl2 was added 3.4 mL (13.1 mmol) of tert-butylchlorodiphenyl silane and the resulting mixture was allowed to stir at room temperature for 1 h. The mixture was then diluted with ethyl acetate and washed with 0.5N HCl. The organic layer was dried over MgSO4, filtered and concentrated. Flash chromatography (elution with 5% ethyl acetate in hexane) afforded 5.5 g of 171. 1H NMR consistent with the product.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[N:12]=[C:11]([N:17]([CH3:19])[CH3:18])[N:10]=1.[N:20]1[N:21]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27](O)=[O:28])[N:22]=[CH:23][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH3:16][O:15][C:13]1[CH:14]=[C:9]([N:2]2[CH2:3][CH:4]3[CH:5]([CH2:6][N:7]([C:27]([C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[N:21]4[N:22]=[CH:23][CH:24]=[N:20]4)=[O:28])[CH2:8]3)[CH2:1]2)[N:10]=[C:11]([N:17]([CH3:18])[CH3:19])[N:12]=1
Reactant: O=C(O)c1ccccc1-n1nccn1
Reactant: COc1cc(N2CC3CNCC3C2)nc(N(C)C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC3CN(C(=O)c4ccccc4-n4nccn4)CC3C2)nc(N(C)C)n1
Yield: 47 %

Procedure:
A mixture of [4-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-methoxy-pyrimidin-2-yl]-dimethyl-amine (60.0 mg, 0.23 mmol), 2-[1,2,3]triazol-2-yl-benzoic acid (47.4 mg, 0.25 mmol), HATU (130.0 mg, 0.34 mmol) and DIPEA (0.12 mL, 0.68 mmol) was stirred into DMF (4.0 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (47.0 mg, 47.5%). MS (ESI) mass calcd. for C22H26N8O2, 434.5; m/z found [M+H]+. 1H NMR (CDCl3): 7.98 (d, J=8.1, 1H), 7.73 (s, 2H), 7.75 (s, 2H), 7.55-7.47 (m, 1H), 7.45-7.37 (m, 2H), 5.00-4.90 (m, 1H), 3.91-3.80 (m, 5H), 3.70 (dd, J=12.5, 3.9, 2H), 3.60-3.29 (m, 4H), 3.19-3.04 (m, 8H).
Reaction SMILES: C[N:2]([C@H]1C2C(=CC=CC=2)[C@H](C2C=CC(Cl)=C(Cl)C=2)C1)C.[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25]>C(O)C>[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]\[C:24]([O-:26])=[O:25].[NH4+:2]
Reactant: CN(C)[C@@H]1C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: O=C([O-])/C=C\C(=O)O
Product: [NH4+]
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Trans-1-(N,N-dimethylamino)-3-(3′,4′-dichlorophenyl)indan (13 g, 0.042 mole) was dissolved in ethanol (60 mL) at 50° C. In a separate flask, maleic acid (4.95 g, 0.042 mol) was dissolved in 20 mL of ethanol at 50° C., then added to the solution of trans-1-(N,N-dimethylamino)-3-(3′,4′-dichlorophenyl)indan. The mixture was stirred at 50° C. for 1 h, then at 10° C. for 2 h. The precipitated product was collected by filtration, then washed with cold ethyl acetate (40 mL). The solid was dried under high vacuum to give 13.8 g (77%) of N,N-dimethyl [3-(3′,4′-dichlorophenyl) indan-1-γ1] ammonium hydrogen maleate. The ratio of the undesired cis isomer was 0.3% as detected by HPLC.
Reaction SMILES: C(=O)([O-])[O-].[Li+].[Li+].[Br:7][C:8]1[C:9]([OH:20])=[C:10]([C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH:11]=[CH:12][C:13]=1[OH:14].I[CH2:22][C:23]1[CH:38]=[CH:37][C:26]([CH2:27][NH:28][C:29]([C:31]2[N:32]=[CH:33][N:34]([CH3:36])[CH:35]=2)=[O:30])=[CH:25][CH:24]=1>CN(C)C=O>[Br:7][C:8]1[C:9]([OH:20])=[C:10]([C:15](=[O:19])[CH:16]([CH3:17])[CH3:18])[CH:11]=[CH:12][C:13]=1[O:14][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][NH:28][C:29]([C:31]2[N:32]=[CH:33][N:34]([CH3:36])[CH:35]=2)=[O:30])=[CH:37][CH:38]=1
Reactant: CC(C)C(=O)c1ccc(O)c(Br)c1O
Reactant: Cn1cnc(C(=O)NCc2ccc(CI)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)c1ccc(OCc2ccc(CNC(=O)c3cn(C)cn3)cc2)c(Br)c1O
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 16.7 %

Procedure:
Add lithium carbonate (24 mg, 324 μmol) to 1-(3-bromo-2,4-dihydroxy-phenyl)-2-methyl-propan-1-one (70 mg, 270 μmol) and N-(4-(iodomethyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (106 mg, 297 μmol) in anhydrous dimethylformamide (4 mL). Warm the reaction mixture to 50° C. and stir for 1.5 hrs. Add additional N-(4-(iodomethyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (20 mg, 56 μmol) and stir for 1 hr at 50° C. Add additional lithium carbonate (24 mg, 324 μmol) and N-(4-(iodomethyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (20 mg, 56 μmol) and stir overnight at 50° C. Cool the reaction mixture to room temperature and quench with water. Extract the aqueous mixture with ethyl acetate (3×). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate. Purify the residue by reverse phase HPLC using gradient 90/10 to 20/80 (water/0.1% trifluoroacetic acid)/acetonitrile as eluent to give the title compound (22 mg, 45 μmol). MS (m/z): 487 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([CH:15]([CH3:17])[CH3:16])[C:3]([NH:5][C@@H:6]([CH3:14])[C:7]([O:9]C(C)(C)C)=[O:8])=[O:4].[I:18][CH2:19][C:20](N)=[O:21].NC1C=CC=CC=1C1C[C@@H]2N(C=1)C(=O)C1C=C(OC)C(OCCCOC3C(OC)=CC4C(=O)N5C=C(C6C=CC(OC)=CC=6)C[C@H]5C(=O)N(COCC[Si](C)(C)C)C=4C=3)=CC=1N(COCC[Si](C)(C)C)C2=O>ClCCl>[I:18][CH2:19][C:20]([NH:1][C@@H:2]([CH:15]([CH3:16])[CH3:17])[C:3]([NH:5][C@@H:6]([CH3:14])[C:7]([OH:9])=[O:8])=[O:4])=[O:21]
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Reactant: NC(=O)CI
Agent: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7ccccc7N)C[C@H]5C(=O)N6COCC[Si](C)(C)C)cc4N(COCC[Si](C)(C)C)C(=O)[C@@H]3C2)cc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)CI)C(=O)N[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of the 97 (100 mg, 0.41 mmol) in dichloromethane was added iodoacetamide-NHS ester (103) (115 mg, 0.41 mmol) and the mixture was stirred at an ambient temperature. After 30 min, the mixture was aspirated onto a 1 mm chromototron plate and eluted with ethyl acetate in hexanes (1:1). A single band was collected and the structure was confirmed: 1H-NMR (400 MHz, CDCl3) δ 6.70 (d, J=7.8 Hz, 1H), 6.27 (d, J=7.0 Hz, 1H), 4.45 (m, 1H), 4.26 (dd, J=8.6, 6.3 Hz, 1H), 3.72 (quart, J=11.3 Hz, 2H), 2.13 (sept, J=6.5 Hz, 1H), 1.47 (s, 9H), 1.38 (d, J=7.1 Hz, 3H), 0.99 (m, 6H); MS (ES+) m/z 412.87 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:23]([O:25][CH3:26])=[O:24])[C:15](OC(=O)C(F)(F)F)=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[CH2:29]([O:31]/[CH:32]=[CH:33]/[Sn](CCCC)(CCCC)CCCC)[CH3:30].C(N(CC)CC)C>CN(C=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>[CH2:32]([O:31]/[CH:29]=[CH:30]/[C:15]1[C:14]([C:23]([O:25][CH3:26])=[O:24])=[N:13][CH:12]=[C:11]2[N:7]([CH2:6][C:5]3[CH:27]=[CH:28][C:2]([F:1])=[CH:3][CH:4]=3)[CH:8]=[CH:9][C:10]=12)[CH3:33]
Reactant: CCCC[Sn](/C=C/OCC)(CCCC)CCCC
Reactant: COC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1OC(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCO/C=C/c1c(C(=O)OC)ncc2c1ccn2Cc1ccc(F)cc1
Temperature: 140 °C
Yield: 35 %

Procedure:
To a stirred solution of methyl 1-(4-fluorobenzyl)-4-[(trifluoroacetyl)oxy]-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (1.4 g, 3.24 mmol) and (E)-2-ethoxyvinyl tributyltin (E [prepared according to A. Leusik, H. A. Budding, J. W. Marsman, J. Organomet. Chem., 1967, 9, 285-294] (2.2 g, 6.48 mmol) in DMF (10 mL) under a nitrogen atmosphere were added triethylamine (0.48 mL, 3.24 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.24 g, 0.32 mmol). The resulting mixture was heated to 140° C. for 2 hours. It was quenched with water, and extracted with ethyl acetate three times. The combined organic extracts were washed with water (2×30 mL), dried over sodium sulfate, concentrated in vacuo and purified by Biotage flash chromatography. Elution with hexane:ethyl acetate (1:1) provided the title compound as brown glue (0.40 g, 35% yield). 1H NMR (MeOD) δ; 8.50 (s, 1H), 7.64 (d, 1H, J=3.3 Hz), 7.22 (t, 2H, J=6.8 Hz), 7.05 (t, 2H, J=6.8 Hz), 6.89 (d, 1H, J=3.3 Hz), 5.53 (s, 2H), 4.02 (q, 2H, J=7.1 Hz), 1.37 (t, 3H, J=7.1 Hz). LCMS (APCl, M+H+): 355.2.
Reaction SMILES: [Br:1][CH:2]([CH2:16][CH3:17])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH3:18][NH:19][C:20]([NH:22][CH3:23])=[S:21]>CO>[BrH:1].[CH2:16]([CH:2]1[S:21][C:20](=[N:19][CH3:18])[N:22]([CH3:23])[C:3]1([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)[OH:4])[CH3:17]
Reactant: CCC(Br)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: CNC(=S)NC
Solvent: CO
Product: Br
Product: CCC1SC(=NC)N(C)C1(O)c1ccc(Cl)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.6 g of 2-bromo-4'-chloro-3'-sulfamoyl-butyrophenone and 1.7 g of 1,3-dimethylthio urea were heated in 50 ml of methanol for 10 minutes to 40° C and stirred for another 2 hours at room temperature. Precipitation followed by adding diisopropyl ether and the oily end product was crystallized with diethyl ether. Colorless solid body: decomposition from 98° C on, γC=N 1620 cm-1.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[CH:24])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].I[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38].CCN(CC)CC.O>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.[Cu]I.CCOC(C)=O>[O:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[C:24][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[Si:5]([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:6])[CH3:7]
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(I)c1
Reactant: C#CCCCCCCCCCCCCCCO[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(NC(=O)OC(C)(C)C)c(C#CCCCCCCCCCCCCCCO[Si](C)(C)C(C)(C)C)c1
Yield: 91.9 %

Procedure:
A mixture of tert-butyl-hexadecane-15-ynyloxy-dimethylsilane (757 mg, 2.15 mmol, 1.5 eq), tert-butyl (2-iodo-4-methoxyphenyl)carbamate (500 mg, 1.43 mmol, 1 eq), [Pd(PPh3)2Cl2] (45 mg, 0.064 mmol, 0.05 eq), CuI (12 mg, 0.064 mmol, 0.05 eq), and Et3N(5 mL) was refluxed for 24 hours. Water (50 mL) and AcOEt (60 mL) were added to the reaction mixture, and the solution was filtered through celite. The filtrate was extracted three times with AcOEt (100 mL). The extract was washed with aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting concentrate was subjected to silica gel flush chromatography (eluate: hexane-AcOEt=98-2) to obtain pale yellow liquid of the title compound (754 mg, yield 92%).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:31])[CH2:14][CH2:15][CH:16]3[C@@:21]4([CH3:30])[CH2:22][CH2:23][CH:24]([O:26][C:27](Cl)=[O:28])[CH2:25][C:20]4=[CH:19][CH2:18][CH:17]3[CH:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[NH2:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35].Cl.C(N(CC)CC)C>C(Cl)Cl.CO>[OH:35][CH2:34][CH:33]([NH:32][C:27](=[O:28])[O:26][C@H:24]1[CH2:23][CH2:22][C@@:21]2([CH3:30])[C:20](=[CH:19][CH2:18][C@@H:17]3[C@@H:16]2[CH2:15][CH2:14][C@@:13]2([CH3:31])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:25]1)[CH2:36][OH:37]
Reactant: NC(CO)CO
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NC(CO)CO)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 45 h
Yield: 76.7 %

Procedure:
A solution of 5.00 g of cholesteryl chloroformate in 20 ml of methylene chloride is added dropwise to a mixture of 1.4 g of DL-serinol.HCl and 3.1 ml of triethylamine in 30 ml of methylene choride. After stirring for 45 hours the mixture is taken up in aqueous methanol and extracted with chloroform. The organic phase is dried and concentrated. After chromatography over SiO2 with chloroform and then with ether there are obtained 4.3 g of cholest-5-en-3β-yl [2-hydroxy-1-(hydroxymethyl)ethyl]carbamate, m.p. 158° C. (decomposition). b) A solution of 3.7 g of the product of a) in 30 ml of methylene chloride, 10 ml of THF and 0.6 ml of pyridine is treated under argon with 1 ml of phenyl chloroformate in 15 ml of methylene chloride. After stirring for 1 hour the solution is taken up in 200 ml of water and 50 ml of 0.1N HCl and extracted with 150 ml of methylene chloride. The organic phase is dried and concentrated. After chromatography over SiO2 with n-hexane/ether (1:1) and ether there are obtained 2.1 g of cholest-5-en-3β-yl [(RS)-2-hydroxy-1-[(phenoxycarbonyl)oxymethyl]ethyl]carbamate.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:6][N:7]([CH2:11][CH2:12][O:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:8][CH2:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl.[Cl:34]CCl>C(O)C.O>[ClH:34].[CH3:30][O:29][C:25]1[CH:24]=[C:23]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:14][O:13][CH2:12][CH2:11][N:7]2[CH2:8][CH2:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH2:6]2)[CH:28]=[CH:27][CH:26]=1
Reactant: ClCCl
Reactant: COC(=O)C1=CCCN(CCOC=C(c2cccc(OC)c2)c2ccccc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cccc(C(=COCCN2CCC=C(C(=O)O)C2)c2ccccc2C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
1-(2-((2-(3-Methoxyphenyl)-2-(2-methylphenyl)ethenyl)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester (1.15 g, 0.0027 mol, prepared similarly to the method described in Example 70) was dissolved in ethanol (15 ml) and 12 N sodium hydroxide solution (0.5 ml) was introduced. After stirring the solution at room temperature for 4 h, ice (30 g) was added, and pH of the reaction mixture was adjusted to ca. 7 with 37% hydrochloric acid solution. Dichloromethane (200 ml) was added, and the pH was further adjusted to ca. 1 with 37% hydrochloric acid solution. Water was added until the solid material was dissolved, and the dichloromethane phase was dried (Na2SO4) and evaporated to an oil, which was co-evaporated three times with acetone. The residue was triturated with diethyl ether to give the title compound (0.60 g, 52%).