Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22](Cl)[N:21]=3)[CH:14]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl>COCCO.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[Cl:26][C:25]1[CH:24]=[N:23][C:22]2[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH:3]=3)[S:8](=[O:10])(=[O:9])[NH:11][CH2:12][C:13]3[CH:14]=[C:15]([NH:19][C:20]=1[N:21]=2)[CH:16]=[CH:17][CH:18]=3
Reactant: Nc1cccc(S(=O)(=O)NCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCO
Solvent: C1COCCO1
Product: O=S1(=O)NCc2cccc(c2)Nc2nc(ncc2Cl)Nc2cccc1c2
Temperature: 150 °C

Procedure:
To a solution of 3-amino-N-{3-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}benzenesulfonamide (38.0 mg, 0.089 mmol) in 2-methoxyethanol (0.49 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (45 μL). The resulting mixture was heated at 150° C. in the microwave for 15 min. The mixture was diluted with Na2CO3 (aq), extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the crude, which was purified by Combi-Flash column chromatography (4 g column, 0 to 50% EtOAc in Hex) to the desired product as a white powder (7 mg, 20%). LCMS for C17H14ClN5O2S (M+H)+: m/z=388.0, 390.0. 1H NMR (400 MHz, CD3OD): δ 7.62 (m, 1H), 7.54 (s, 1H), 7.28 (t, J=2.0 Hz, 1H), 7.08 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 6.78 (t, J=8.0 Hz, 1H), 6.35 (m, 1H), 6.18 (ddd, J=8.0, 1.6, 1.0 Hz, 1H), 5.98 (m, 1H), 5.82 (ddd, J=7.6, 2.0, 1.0, 1H), 4.20 (s, 2H).
Reaction SMILES: CO[C:3](=[O:18])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:16][CH3:17])=[C:10]2[C:14]=1[N:13]([CH3:15])[CH:12]=[CH:11]2)=O.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:20]1.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28]2[C:29](=[O:30])[NH:31][C:3](=[O:18])[C:4]=2[C:6]2[CH:7]=[CH:8][C:9]([O:16][CH3:17])=[C:10]3[C:14]=2[N:13]([CH3:15])[CH:12]=[CH:11]3)=[CH:20]1
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1ccc(OC)c2ccn(C)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(c3c[nH]c4ccccc34)C(=O)NC2=O)c2c1ccn2C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a mixture of (1-methyl-4-methoxyl-1H-indol-7-yl)-oxo-acetic acid methyl ester (0.27 g, 1.10 mmol) and 2-(1H-indol-3-yl-acetamide (0.17 g, 1 mmol) in DMF (5 mL) was added a solution of potassium tert-butoxide in THF (1.0 M, 4.0 mL, 4.0 mmol) at room temperature. The reaction mixture was heated at 60° C. for 4 hrs, cooled to room temperature, and quenched with hydrochloric acid (1.0 N). After stirring at room temperature for 30 min, the mixture was extracted with ethyl acetate and the extract was washed with water, saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate), filtered and evaporated. Flash column chromatography on silica gel eluting with chloroform and acetone gave 3-(1H-indol-3-yl)-4-(4-methoxy-1-methyl-1H-indol-7-yl)-pyrrole-2,5-dione (270 mg, 72.7%). 1H NMR (d6-DMSO, 400 MHz) 3.65 (s, 3H), 3.84 (s, 3H), 6.46˜6.55 (m, 4H), 6.78 (d, J=7.6 Hz, 1H), 6.95 (t, J=7.2 Hz, 1H), 7.13 (d, J=3.2 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.86 (d, J=3.2 Hz, 1H), 11.05 (s, 1H), 11.79 (s, 1H); MS (ES, m/z): C22H17FN3O3: 372.19(M++1), 370.29 (M+−1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19](Cl)[CH:18]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[Cl:28]C1C=C(S(C)(=O)=O)C=CC=1F.COC(C1C=C(O)C2CC(C)(C)OC=2C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:18]=2[Cl:28])[C:8]2[CH2:9][C:10]([CH3:12])([CH3:13])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)c(Cl)c2)c2c(c1)OC(C)(C)C2
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2Cl)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 118a, from 3-chloro-4-fluoro-1-(methylsulfonyl)benzene and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e). 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=2.27 Hz, 1 H) 7.77 (dd, J=8.59, 2.27 Hz, 1 H) 7.29 (d, J=1.01 Hz, 1 H) 7.18 (d, J=1.26 Hz, 1 H) 6.98 (d, J=8.59 Hz, 1 H) 3.88 (s, 3 H) 3.10 (s, 3 H) 2.93 (s, 2 H) 1.50 (s, 6 H); LCMS for C19H19ClO6S m/z 411.00 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:13]([B:15]([CH2:18][CH3:19])OC)[CH3:14]>>[CH2:13]([B:15]([CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH3:14]
Reactant: Brc1ccncc1
Reactant: CCB(CC)OC
Agent: [Li]CCCC
Product: CCB(CC)c1ccncc1

Procedure:
4-Bromopyridine was reacted with n-butyllithium and then with diethylmethoxyborane using a procedure similar to that in Preparation 49. This gave the title compound, which was used without characterisation.
Reaction SMILES: Cl.[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:4]=1[C:5]#[N:6].[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].C(N(CC)CC)C>>[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][O:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:3]([F:2])[C:4]=2[C:5]#[N:6])[CH2:14][CH2:15]1)=[O:23]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: N#Cc1c(F)cccc1OCC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: N#Cc1c(F)cccc1OCC1CCN(C(=O)c2ccccc2Cl)CC1
Yield: 86 %

Procedure:
A mixture of 2-fluoro-6-(piperidin-4-ylmethoxy)-benzonitrile hydrochloride (200 mg; 0.7 mmol) (Example 126, Step 3) was stirred at room temperature with 2-chlorobenzoyl chloride (129 mg; 0.7 mmol) and triethylamine (0.3 mL; 2.1 mmol) for 16 hours. Reaction was cooled and quenched with dilute HCl and mixture extracted with ethyl acetate (2×20 mL). Combined organics washed with water, saturated sodium bicarbonate, brine and dried over Na2SO4. Crude material was purified by chromatography using 0.5-2% methanol/DCM gradient to afford 2-[1-(2-chloro-benzoyl)-piperidin-4-ylmethoxy]-6-fluoro-benzonitrile as a white solid. (225 mg; 86% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:24])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:32][C:33]1[N:34]=[CH:35][S:36][CH:37]=1.Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C(N(CC)CC)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:18])([OH:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:32][C:33]3[N:34]=[CH:35][S:36][CH:37]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: ClCc1cscn1
Reactant: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOCc1nc2c(N)nc3cc(OCc4cscn4)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (100 mg, 0.3 mmol), cesium carbonate (488 mg, 1.5 mmol), 4-(chloromethyl)thiazole.HCl (102 mg, 0.6 mmol), tetrabutylammonium bromide (96 mg, 0.3 mmol), triethylamine (0.5 ml), and DMF (10 mL) were combined and stirred at ambient temperature overnight. The reaction was concentrated under reduced pressure and dichloromethane was added to the residue. Undissolved solids were removed by filtration. The filtrate was concentrated under reduced pressure and subsequently purified by flash column chromatography on silica gel, eluting with a gradient of 0-4% methanol in dichloromethane. The clean fractions were combined and concentrated under reduced pressure. The resulting solid was recrystallized from acetonitrile to yield 62 mg of 1-[4-amino-2-ethoxymethyl-7-(thiazol-4-ylmethoxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white powder, mp 190.0-191.0° C.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:33])[C@H:11]([N:16]([P@:24]([CH3:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][CH:13]([CH3:15])[CH3:14])C1C=CC=CC=1.CO.[H][H].CCCCCC>C(OCC)(=O)C.[Pd]>[OH:8][NH:9][C:10](=[O:33])[C@H:11]([N:16]([P@@:24]([CH3:32])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:25])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: [H][H]
Reactant: CC(C)C[C@H](C(=O)NOCc1ccccc1)N(Cc1ccccc1)[P@@](C)(=O)c1ccccc1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](C(=O)NO)N(Cc1ccccc1)[P@](C)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Benzyloxy-2(R)-[[(S)-methylphenylphosphinyl]benzylamino]-4-methylpentanamide (334 mg, 0.719 mmol) and 80 mg 10% Pd/C were evacuated in a flask. To this is added 10 mL methanol and a hydrogen atmosphere is introduced. The reaction is allowed to stir at room temperature for 2 hours at which time the reaction appears complete by TLC. The mixture is filtered through celite; the filtrate is collected and evaporated to give a white glassy solid. The product is dissolved in ethyl acetate and hexane is added dropwise until the product begins to precipitate to give N-hydroxy-2(R)-[[(R)-methylphenylphosphinyl]benzylamino]-4-methylpentanamide as colorless solid: MS-IS: m/z 375 [M+H]+, 397 [M+Na]+, 413 [M+K]+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:7](C=S(=O)=O)=[N:8][C:4]=2[CH:3]=1.ClC1C=CC2N=C(C=S(=O)=O)N(CC3C=C[C:42]4[O:45]COC=4C=3)C=2C=1.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:7]([O:45][CH3:42])=[N:8][C:4]=2[CH:3]=1
Reactant: O=S(=O)=Cc1nc2cc(Cl)ccc2n1Cc1ccc2c(c1)OCO2
Reactant: O=S(=O)=Cc1nc2ccc(Cl)cc2n1Cc1ccc2c(c1)OCO2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc2cc(Cl)ccc2n1Cc1ccc2c(c1)OCO2

Procedure:
448 mg of a mixture comprising 5-chloro-2-sulfonylmethyl-1-(3,4-methylenedioxybenzyl)benzimidazole and 6-chloro-2-sulfonylmethyl-1-(3,4-methylenedioxybenzyl)benzimidazole was dissolved in 20 ml of methanol, followed by the addition of 10 ml of 28% sodium methoxide. The obtained mixture was heated under reflux for 1.5 hours, cooled with ice, neutralized with 10% aqueous hydrochlic acid, and extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated in a vacuum. The residue was subjected to silica gel column chromatography to give the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=2[C:14]2[C:9](=[CH:10][CH:11]=[N:12][C:13]=2[O:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:8]=1)(=O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH:37]1(P(C2CCCCC2)C2CCCCC2)[CH2:42]CCC[CH2:38]1.C(B1OC(C)(C)C(C)(C)O1)(C)=C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH2:23]([O:22][C:13]1[N:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C:7]([C:37]([CH3:42])=[CH2:38])=[N:8]2)[CH2:24][CH2:25][CH3:26]
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: CCCCOc1nccc2nc(OS(=O)(=O)C(F)(F)F)c3ccc(F)cc3c12
Agent: [Pd+2]
Agent: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)c1nc2ccnc(OCCCC)c2c2cc(F)ccc12
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
1-butoxy-9-fluorobenzo[c]-1,6-naphthyridin-6-yl trifluoromethanesulfonate (1.00 g, 2.39 mmol), potassium phosphate tribasic (1.52 g, 7.17 mmol), palladium(II) acetate (0.0540 g, 0.239 mmol), and tricyclohexylphosphine (0.134 g, 0.478 mmol) were combined in pressure vessel. Toluene (20 ml), water (6.67 ml), and isopropenylboronic acid pinacol ester (0.899 ml, 4.78 mmol) were added. The resulting suspension was purged with argon (subsurface bubbling) for 10 min. The reaction mixture was stirred in a sealed pressure vessel at 100° C. for 2.5 h. After cooling the reaction mixture was diluted with EtOAc, and washed with aqueous ammonium chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated to a crude residue that was adsorbed on to silica gel and purified by column chromatography on silica gel eluting with an EtOAc/hexane gradient to afford 1-butoxy-9-fluoro-6-isopropenylbenzo[c]-1,6-naphthyridine. LRMS (ESI) calc'd for (C19H19FN2O) [M+H]+, 311.1; found 311.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1.[F:21][C:22](I)([F:24])[F:23]>[Cu].CN(C)C=O>[F:21][C:22]([F:24])([F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1
Reactant: FC(F)(F)I
Reactant: CCOC(=O)C(O)c1ccc(-c2ccccc2Br)cc1
Agent: [Cu]
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)c1ccc(-c2ccccc2C(F)(F)F)cc1
Temperature: 140 °C
Reaction time: 5 h

Procedure:
To a solution of 0.01 moles of ethyl 2'-bromo-4-biphenylylglycolate in 50 ml. of dimethylformamide is added 0.15 moles of trifluoromethyl iodide and 0.02 g. of copper powder. The reaction is shaken in a sealed tube for 5 hours at 140°C, cooled and then filtered and evaporated in vacuo. 200 ml. of water is added to the residue and extracted with ether. The ether extract is dried, evaporated to dryness and distilled to obtain ethyl 2'-trifluoromethyl-4-biphenylylglycolate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)(=[O:37])=[O:36])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3ncccn3)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3ncccn3)cc2)S(=O)(=O)c2ccccn2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step B of Example 1 from 3-{3-[(4-pyrimidin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11z, and pyridine-2-sulfonyl chloride hydrochloride salt, of Preparation 47, using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.80 (d, 2H), 8.68 (m, 1H), 8.27 (d, 2H), 7.98 (m, 1H), 7.86 (m, 1H), 7.46 (m, 1H), 7.20 (m, 3H), 7.12 (m, 1H), 7.02 (d, 1H), 6.96 (d, 1H), 6.91 (s, 1H), 4.55 (s, 2H), 4.48 (s, 2H), 3.65 (s, 3H), 2.80 (t, 2H), 2.50 (t, 2H); MS 503 (M+1).
Reaction SMILES: [CH3:1][Si:2]([CH3:6])([CH3:5])[CH2:3][Cl:4].[Mg].[CH3:8][SiH:9]([CH3:11])Cl>C1COCC1>[CH3:1][Si:2]([CH3:6])([CH3:5])[CH2:3][Cl:4].[CH3:1][Si:2]([CH2:3][SiH:9]([CH3:11])[CH3:8])([CH3:6])[CH3:5]
Reactant: C[SiH](C)Cl
Agent: C[Si](C)(C)CCl
Agent: [Mg]
Solvent: C1CCOC1
Product: C[SiH](C)C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 177.6 %

Procedure:
The Grignard reagent of trimethylchloromethylsilane (TMCMS) was prepared by reaction of 12.3 g (0.1 mol) TMCMS and 2.88 g (0.12 mol) magnesium chips in THF (50 mL). The Grignard reagent was then added dropwise into 9.46 g (0.1 mol) dimethylchlorosilane (DMCS), which dissolved in THF (50 mL). The mixture was stirred at room temperature overnight and quenched with 20 mL HCl-acidified water, and then extracted with diethylether (100 mL). The organic layer washed with distilled water three times and dried with anhydrous sodium sulfate. The mixture was purified by distillation at 118-119° C. to yield 13.0 g (89%) (trimethylsilylmethyl)dimethylsilane product as a clear, colorless fluid.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([F:36])[CH:3]=1.[BrH:37].N([O-])=O.[Na+]>C(#N)C.O>[Br:37][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([F:36])[CH:3]=1
Reactant: Br
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)cc3F)S(C)(=O)=O)c(C3CC3)cc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)cc3F)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a solution of 6-(N-(4-amino-2-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (360 mg, 0.7 mmol) in acetonitrile (20 mL) was added hydrobromic acid (5 mL, 40% in water) followed by sodium nitrite (49 mg, 0.77 mmol in 2 mL water) dropwise at 0° C. After stirring for 10 minutes at 0° C., cuprous bromide (115 mg, 0.8 mmol) was added. The mixture was warmed to 80° C. and stirred for 1 hour. The mixture was cooled to room temperature and diluted with water (20 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL), dried over sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography to afford 6-(N-(4-bromo-2-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (240 mg, 0.42 mmol, 60% yield) as an off-white solid. LCMS (m/z, ES+)=575, 577 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH:6]=[CH:5][B:4]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C([N-]C(C)C)(C)C.[Li+:21]>CCOCC>[CH2:1]([N:3]1[CH:7]=[CH:6][CH-:5][B:4]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[Li+:21]
Reactant: CCN1CC=CB1c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Product: CCN1C=C[CH-]B1c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 75.5 %

Procedure:
1,5-Dihydro-1-ethyl-2-phenyl-1,2-azaborole (5.0 g, 29.2 mmol) was dissolved in 15 mL of ether at −78° C. To this was added a solution of lithiumdiisopropylamide (3.13 g, 29.2 mmol) in 15 mL of ether. The mixture was stirred at −78° C. for 2 hours and at 25° C. for 10 hours. After removal of the solvent the residue was washed with 3×20 mL of pentane. The residue was dried under vacuum to give the product as a light yellow powder (3.9 g, 77 percent).
Reaction SMILES: O=[C:2]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][CH:4]([CH:10]=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH3:26]>>[CH2:12]([C:2]1[NH:26][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: N
Reactant: CCCCCCCCCCCCCCC(=O)CC(C=O)C(=O)OCC
Product: CCCCCCCCCCCCCCc1cc(C(=O)OCC)c[nH]1
Yield: 90 %

Procedure:
To 4.13 g (12 mmol) of the resulting ethyl γ-keto-α-formyloctadecanoate was added 150 ml of an ammonia-saturated ethanol solution and the mixture was then heated under reflux for 14 hours. After removing the solvent under reduced pressure, the residue was purified by subjecting it to silica gel column chromatography (eluent: ethyl acetate/hexane=1/10) to obtain 3.53 g (90% yield) of ethyl 5-tetradecylpyrrole-3-carboxylate, m.p. 59°-62° C.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[H-].[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=1>C1COCC1.C(=O)=O>[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[N:13]=1
Reactant: OCCCCCCS
Reactant: CS(=O)(=O)c1nccc(Cl)n1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCCCCCSc1nccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6-Mercapto-1-hexanol (1.4 mL, 10.2 mmol) was added to a suspension of NaH (60% in mineral oil, 0.42 g, 10.5 mmol) in THF (20 mL) and stirred at room temperature for 10 min then cooled down to −78° C. in dry ice bath. A suspension of the product Example 46a (1.74 g, 9.03 mmol) was added to the above mixture and stirred at −78° C. for 2.5 hours. The reaction was quenched with water (20 mL) and extracted with Et2O (100 mL). The extract was washed with water (2×100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography eluting with 1:2 EtOAc:Hex to obtained the title compound as a viscous oil, 1.8 g (81%). 1H NMR (300 MHz, CDCl3) δ 8.67 (d, J=5.3 Hz, 1H), 7.00 (d, J=5.3 Hz, 1H), 3.63 (t, J=6.6 Hz, 2H), 3.14 (t, J=7.4 Hz, 2H), 2.60 (S, 1H), 1.8-1.4(mult, 8H); 13C NMR (75 MHz, CDCl3) δ 173.4, 160.7, 157.8, 116.2, 62.3, 32.3, 30.8, 28.6, 28.3, 25.1; mass spectrum (API-TIS) m/z 247 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([OH:11])[CH:5]=1)([O-:3])=[O:2].[Br:12][C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=1[N:20]=[C:21]=[O:22]>>[OH:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=1[NH:8][C:21]([NH:20][C:14]1[CH:15]=[CH:16][C:17]([Br:19])=[CH:18][C:13]=1[Br:12])=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1ccc(Br)cc1Br
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccc(Br)cc1Br
Yield: 39.4 %

Procedure:
The urea was prepared from 4-nitro 2-hydroxy aniline(308 mg, 2 mmol) and 2,4-dibromo phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.34 g, 39%). EI-MS m/z 430(M+H)+
Reaction SMILES: CN(C)C(=O)C[NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl.Cl[CH2:48][C:49]1[N:50]=[C:51]([CH3:54])[S:52][CH:53]=1>>[CH3:24][C@:21]12[C@@:20]3([CH3:25])[C@@H:11]([C@:12]4([CH3:37])[C@@H:17]([CH2:18][CH2:19]3)[C:16]([CH3:26])([CH3:27])[C:15]([C:28]3[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=3)=[CH:14][CH2:13]4)[CH2:10][CH2:9][C@@H:8]1[C@H:7]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:6]1([NH:5][CH2:48][C:49]1[N:50]=[C:51]([CH3:54])[S:52][CH:53]=1)[CH2:23][CH2:22]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCc3csc(C)n3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 4-(chloromethyl)-2-methylthiazole hydrochloride as the alkylating agent in Step 1. MS: m/e 641.5 (M+H)+, 1.56 min (method 12). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96 (s, 3H) 0.97 (s, 3H) 1.02 (s, 3H) 1.10 (s, 3H) 1.26 (s, 3H) 1.71 (s, 3H) 0.88-1.83 (m, 16H) 1.89-2.04 (m, 3H) 2.08-2.21 (m, 1H) 2.14 (dd, J=17.19, 6.15 Hz, 1H) 2.22-2.30 (m, 1H) 2.33-2.45 (m, 1H) 2.68 (s, 3H) 4.09 (d, J=13.05 Hz, 1H) 4.64 (d, J=12.80 Hz, 1H) 4.69 (s, 1H) 4.80 (s, 1H) 5.32 (d, J=4.52 Hz, 1H) 7.24 (d, J=8.28 Hz, 2H) 7.28 (s, 1H) 8.00 (d, J=8.28 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)#[N:12]>>[CH3:7][N:6]1[C:2]([N:16]2[CH2:17][CH2:18][CH:13]([C:11]#[N:12])[CH2:14][CH2:15]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: N#CC1CCNCC1
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(C#N)CC1
Yield: 79 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 4-cyanopiperidine gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine-4-carbonitrile as an off-white solid (0.23 g, 79%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 3.78 (s, 3H), 3.35-3.19 (m, 4H), 2.88-2.79 (m, 1H), 2.19-2.11 (m, 2H), 2.06-1.95 (m, 2H)