Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[C:9](N)=[C:8]([CH2:15][CH3:16])[CH:7]=2)=[CH:4][CH:3]=1.C(#N)C.N(OCCCC)=O.[BrH:29]>[Cu]Br>[Br:29][C:9]1[C:10]([CH2:12][CH3:13])=[CH:11][C:6]([C:5]2[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:7][C:8]=1[CH2:15][CH3:16]
Reactant: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1N
Reactant: Br
Agent: [Cu]Br
Agent: CCCCON=O
Solvent: CC#N
Product: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1Br
Temperature: 25 °C

Procedure:
4′-Chloro-3,5-diethylbiphen-4-ylamine (9.6 g, 0.036 mol) is added to acetonitrile (95 ml) and stirred at room temperature until dissolution is complete. The reaction mixture is cooled to between −5° C. and 0° C., tent-butyl nitrite (5.7 ml, 0.044 mol) is added dropwise and the reaction mixture is maintained at between −5° C. and 0° C. for 30-40 minutes. The mixture is added slowly to a preheated (50° C.) suspension of copper (I) bromide (2.87 g, 0.02 mol) in hydrobromic acid (2.8 ml) and stirred at 50° C. for 10-15 minutes. The reaction mixture is cooled to room temperature, then poured into ice-cold water and extracted with ethyl acetate (3×250 ml). The organic extracts are washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to yield 4-bromo-4′-chloro-3,5-diethylbiphenyl (4.5 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](OC(OCC)N(C)C)C>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:19][CH2:18][N:17]2[CH2:16][CH2:15][N:14]3[CH2:13][CH2:12][N:11]([CH:20]23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(OCC)N(C)C
Reactant: c1ccc(CN2CCNCCNCCNCC2)cc1
Solvent: c1ccccc1
Product: c1ccc(CN2CCN3CCN4CCN(CC2)C34)cc1
Yield: 96 %

Procedure:
A solution of 1-benzyl-1,4,7,10-tetraazacyclododecane (4 g; 0.015 mol) and dimethylformamide diethylacetal (6.88 g; 0.0467 mol) in benzene (40 ml) is heated at 80 C. and the azeotropic mixture ethanol-benzene is distilled away. When the conversion is ended, the solvent is evaporated under reduced pressure and the final product is obtained as a yellow oil (4.0 g). Yield 96%
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=1)[CH2:3][NH2:4].[OH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)[CH3:26])=[CH:20][CH:19]=1>>[OH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=2)[CH3:26])=[CH:20][CH:19]=1
Reactant: NCC(O)c1csc(C(F)(F)F)n1
Reactant: CC(=O)Cc1ccc(OCCO)cc1
Product: CC(Cc1ccc(OCCO)cc1)NCC(O)c1csc(C(F)(F)F)n1

Procedure:
Prepared by analogy to Example 13 by reaction of 2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with 1-(4-(2-hydroxyethoxy)phenyl)propan-2-one followed by purification on a silica gel column using ethyl acetate/methanol=9:1 as eluant.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[C:9]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:8]=1>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[C:9]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:8]=1
Reactant: COC(=O)c1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1-c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C)c(Cc2ccc(C(=O)O)c(-c3cccnc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.4 %

Procedure:
Methyl 4-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoate (70 mg, 0.1601 mmol) was dissolved in a mixed solution of a 1N aqueous solution of sodium hydroxide (5 ml) and 1,4-dioxane (5 ml) followed by stirring at room temperature for 16 hours. The reaction solution was diluted with water (20 ml), washed with ether, acidified with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom to give the title compound (45 mg, 0.1063 mmol, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[F:15])[CH2:10][OH:11])=[CH:4][CH:3]=1.[H-].[Na+].[F:20][C:21]([F:35])([F:34])[C:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=1)=[CH:23]Cl.[Cl-].[Na+]>CN(C)C=O.O>[F:20][C:21]([F:34])([F:35])[C:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=1)=[CH:23][O:11][CH2:10][C:9]1[CH:12]=[CH:13][C:14]([F:15])=[C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:8]=1
Reactant: OCc1ccc(F)c(Oc2ccc(Cl)cc2)c1
Reactant: CCOc1ccc(C(=CCl)C(F)(F)F)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C(=COCc2ccc(F)c(Oc3ccc(Cl)cc3)c2)C(F)(F)F)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
A solution of 3-(4-chlorophenoxy)-4-fluorobenzyl alcohol (6.3 g) in N,N-dimethylformamide (20 cm3) was added to a stirred suspension of sodium hydride (1.2 g of a 50% dispersion in oil) in N,N-dimethylformamide. After 30 minutes, this mixture was added to a stirred solution of EZ-1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-chloroprop-2-ene (5 g) in N,N-dimethylformamide (25 cm3) at a temperature maintained at -10° C. during the addition. After 45 minutes the reaction mixture was poured into water (150 cm3) and sodium chloride added. The products were extracted into diethyl ether (4×100 cm3), and the combined organic layers were dried over anhydrous sodium sulphate and concentrated by evaporation under reduced pressure. The crude residue was purified by column chromatography on a silica gel support, eluted with n-hexane containing 6% by volume diethyl ether, to give 1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-[3-(4-chlorophenoxy)-4-fluorobenzyloxy]prop-2-ene (6 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:20][C:19]([C:21]5([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23][CH2:22]5)=[CH:18][C:17]=4[CH:37]=3)[N:9]=2)=[CH:4][C:3]=1[Cl:38].[S:39]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40]1.C([O-])(O)=O.[Na+]>O1CCOCC1.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>[Cl:38][C:3]1[CH:4]=[C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:20][C:19]([C:21]5([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23][CH2:22]5)=[CH:18][C:17]=4[CH:37]=3)[N:9]=2)[CH:6]=[CH:7][C:2]=1[C:41]1[CH:42]=[CH:43][S:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)NC1(c2cc3cc(-c4noc(-c5ccc(Br)c(Cl)c5)n4)ccc3o2)COC(C)(C)OC1
Reactant: OB(O)c1ccsc1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2cc3cc(-c4noc(-c5ccc(-c6ccsc6)c(Cl)c5)n4)ccc3o2)COC(C)(C)OC1
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a stirred mixture of the product of Example 38, Step C (0.09 g, 0.15 mmol) and 3-thiophene-boronic acid (0.028 g, 0.22 mmol) in a mixture of dioxane and H2O (5 ml:1 ml), Pd(PPh3)4 (0.03 g) was added at 80° C., followed by the NaHCO3 solution (0.065 g in 1 ml H2O) and this was stirred for 2 h. The solvent was distilled off and the residue was diluted to 20 ml with EtOAc, washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated and the residue was purified by FCC (SiO2, hexane/EtOAc), to give the title compound (0.065 g, 71%), as pale paste. 1H-NMR (CDCl3) 8.45 (d, 1H, J=1.53 Hz); 8.25-8.22 (m, 2H); 7.94 (dd, 1H, J=8.7, 1.8 Hz); 7.55-7.42 (m, 3H); 7.38-7.37 (m, 2H); 6.78 (s, 1H); 5.43 (bs, 1H); 4.29-4.13 (m, 4H); 1.46 (s, 9H); 1.27 (b, 6H).
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.C(N(CC)CC)C.P(Cl)(OCC)(OCC)=O.[Si]([O:36][C@@H:37]1[C@H:41]([O:42][Si](C(C)(C)C)(C)C)[C@@H:40]([CH3:50])[O:39][C@H:38]1[N:51]1[CH:58]=[C:57]([F:59])[C:55]([NH2:56])=[N:54][C:52]1=[O:53])(C(C)(C)C)(C)C>C(#N)C.CN(C)C1C=CN=CC=1>[F:59][C:57]1[C:55]([NH:56][C:1](=[O:12])[C:2]2[CH:10]=[CH:9][C:8]3[O:7][CH2:6][O:5][C:4]=3[CH:3]=2)=[N:54][C:52](=[O:53])[N:51]([CH:58]=1)[C@@H:38]1[O:39][C@H:40]([CH3:50])[C@@H:41]([OH:42])[C@H:37]1[OH:36]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H]1O[C@@H](n2cc(F)c(NC(=O)c3ccc4c(c3)OCO4)nc2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.2 %

Procedure:
A solution of piperonylic acid (0.42 g) in dry acetonitrile (5 ml) containing triethylamine (0.36 ml) was treated with diethyl chlorophosphate (0.37 ml) for 1 hour. To the reaction mixture were added 2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-fluorocytidine (1.0 g) obtained in Reference example (a), triethylamine (0.36 ml) and 4-dimethylaminopyridine (0.05 g). After stirring of the mixture for 12 hours at room temperature, acetonitrile was evaporated under reduced pressure. The residue was partitioned between water and ether. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained powder was dissolved in tetrahydrofuran (6.3 ml) containing tetrabutylammonium fluoride (1.65 g) and the reaction mixture was stirred for 1 hour. After removal of the solvent under reduced pressure, the residue was purified by silica gel column chromatography (isopropanol-dichloromethane) followed by recrystallization from ethyl acetate to give 0.5 g of 5'-deoxy-5-fluoro-N4 -piperonyloylcytidine, mp 124°~125° C.: MS 394 (MH+).
Reaction SMILES: [C:1]([C:8]1[C:17](=O)[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(=O)([O-])O.[Na+].P(Cl)(Cl)([Cl:28])=O>C(Cl)(Cl)Cl>[Cl:28][C:17]1[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)c1c[nH]c2c(OC)cccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCC(=O)c1cnc2c(OC)cccc2c1Cl

Procedure:
3-hexanoyl-8-methoxy-4(1H)-quinolone (4.6 g, 0.017 mol) was heated under reflux in a mixture of phosphorus oxychloride (8 ml) and chloroform (50 ml) for 1.5 hours. When cool, the mixture was poured into a vigorously stirred mixture of sodium hydrogen carbonate solution, ice and chloroform. The layers were separated and the organic solution was washed with sodium hydrogen carbonate solution and brine. Evaporation of the chloroform solution afforded 4-chloro-3-hexanoyl-8-methoxyquinoline as a yellow-brown oil (5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[O:26]1[C:28]([CH3:30])([CH3:29])[CH2:27]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:27][C:28]([OH:26])([CH3:30])[CH3:29]
Reactant: CC1(C)CO1
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCC(C)(C)O)c(F)c3)oc2c1

Procedure:
Using N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide and 1,2-epoxy-2-methylpropane, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[CH:8][C:7]=1[CH3:12])=[O:4].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O.O>[CH2:13]([NH:20][CH2:2][C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[CH:8][C:7]=1[CH3:12])=[O:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: Cc1cnn(C)c1NC(=O)CCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnn(C)c1NC(=O)CNCc1ccccc1
Temperature: 100 °C

Procedure:
35 g of 5-(chloroacetamido)-1,4-dimethyl-pyrazole are dissolved in 300 ml of absolute dimethyl formamide and the solution, subsequent to the addition of 46 g of benzylamine, heated to 100° C. for 3 h. The cooled solution is diluted with water and extracted with dichloromethane. The dichloromethane phase is washed with a saturated table-salt solution, dried on sodium sulfate, and concentrated by evaporation. The residue is recrystallized from ethyl acetate.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:23][CH3:24])[O:21][CH3:22])[N:16]([C:25](OC1C=CC=CC=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:34][C:35]1[CH:42]=[C:41]([NH:43][CH2:44][CH2:45][O:46][CH3:47])[C:38]([C:39]#[N:40])=[CH:37][N:36]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:21][CH3:22])[O:23][CH3:24])[N:16]([C:25]([NH:34][C:35]1[CH:42]=[C:41]([NH:43][CH2:44][CH2:45][O:46][CH3:47])[C:38]([C:39]#[N:40])=[CH:37][N:36]=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Oc1ccccc1
Reactant: COCCNc1cc(N)ncc1C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CO[Si](C)(C)C(C)(C)C)c(C(OC)OC)nc32)ncc1C#N
Temperature: -25 °C

Procedure:
A solution of phenyl 6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 38, 2.98 g, 6.29 mmol) and 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 1.10 g, 5.72 mmol) in THF (45 ml) at −70° C. (dry ice/2-PrOH bath, internal temperature) under argon was treated with LHMDS (1 M in THF, 12.6 ml, 12.6 mmol). The resulting solution was stirred with cooling for 35 min. The cooling bath was then removed and the reaction mixture was allowed to warm to −25° C., before being re-cooled to −70° C. The resulting solution was quenched with sat. aq. NH4Cl, allowed to warm to room temperature and extracted twice with EtOAc/heptanes 1:1. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (80 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100). The product containing fractions were concentrated and dried under vacuum to give the title compound as a white solid. (UPLC-MS 3) tR 1.60; ESI-MS 571.4 [M+H]+. 1H NMR (400 MHz, CDCl3-d) δ 13.81 (s, 1H), 8.23 (s, 1H), 7.74 (s, 1H), 7.57 (s, 1H), 5.45 (s, 1H), 5.26 (br s, 1H), 4.87 (s, 2H), 4.07-3.99 (m, 2H), 3.63 (t, 2H), 3.52-3.38 (m, 11H), 2.86 (t, 2H), 2.05-1.94 (m, 2H), 0.95 (s, 9H), 0.12 (s, 6H).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].O>ClCCl>[O:20]([C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
To a solution of estrone (100 g, 0.37 mole) in 400 ml of dichloromethane, imidazole (50.36 g, 0.74 mole) and t-butyl-dimethylsilyl chloride (61.3 g, 0.41 mole) were added. The solution was stirred at room temperature for 24 hours. Then water (200 ml) was added. The organic layer was partially evaporated and diisopropyl ether added. The white solid formed was collected by filtration and dried. It weighed 135.2 g, yield 95%, mp 172° C.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:16]([O-])=O)=[C:9]([O:14][CH3:15])[CH:10]=2)[CH2:5]1)[CH3:3].[H][H]>C(OCC)(=O)C.[Pd].CO>[CH3:3][CH:2]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH2:16])=[C:9]([O:14][CH3:15])[CH:10]=2)[CH2:5]1)[CH3:1]
Reactant: [H][H]
Reactant: COc1cc2c(cc1[N+](=O)[O-])CN(C(C)C)CC2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N)CN(C(C)C)CC2
Yield: 100 %

Procedure:
2-(1-methylethyl)-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (0.24 g, 0.94 mmol) was dissolved in ethyl acetate (5 mL), treated with 10% palladium on carbon (50 mg, Aldrich), and then diluted with methanol (10 mL). The mixture was stirred under 60 psi of hydrogen pressure for 16 h in a Fischer-Porter apparatus. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 2-(1-methylethyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-isoquinolinamine (206 mg, 0.94 mmol, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 1.13 (d, J=6.6 Hz, 6 H), 2.71-2.81 (m, 4 H), 2.87 (tt, J=6.5, 6.5 Hz, 1 H), 3.59 (s, 2 H), 3.63 (bs, 2 H), 3.81 (s, 3 H), 6.40 (s, 1 H), 6.50 (s, 1 H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:10]=[C:11]([SH:16])[CH:12]=[C:13]([CH3:15])[CH:14]=1>>[CH3:8][C:9]1[CH:10]=[C:11]([S:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: Ic1ccccc1
Reactant: Cc1cc(C)cc(S)c1
Product: Cc1cc(C)cc(Sc2ccccc2)c1

Procedure:
The general procedure was used to convert iodobenzene and 3,5-dimethylthiophenol to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (417 mg, 97% yield). 1H NMR (300 MHz, CDCl3) δ 7.17–7.01 (m, 5H; Hc, Hc′, Hd, Hd′, He), 6.84 (s, 2H; Ha, Ha′), 6.72 (s, 1H; Hb), 2.10 (s, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 138.81 (C3, C5), 136.35 (C9), 134.69 (C1), 130.44 (C10, C14), 129.10 (C11, C13), 129.02 (C2, C6), 128.68 (C4), 126.61 (C12), 21.13 (C7, C8). Anal. Calcd. for C14H14S: C, 78.45; H, 6.58; S, 14.96; Found C, 78.53; H, 6.62; S, 14.89.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:22]=1[C:23]([NH:25][NH2:26])=[O:24].CC(O)=O>CCO>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[N:26][NH:25][C:23](=[O:24])[C:22]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:21]=1[F:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)c1ccccc1
Reactant: NNC(=O)c1cc(F)ccc1F
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCC(=NNC(=O)c1cc(F)ccc1F)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 101.8 %

Procedure:
To a solution of (4-oxo-4-phenylbutyl)-carbamic acid tert-butyl ester (3.2 g, 12.2 mmol) and 2,5-difluorobenzoic acid hydrazide (2.1 g, 12 mmol) in EtOH (40 mL) was added HOAc (0.5 mL). The reaction was then heated to reflux and stirred for 3 days. The reaction mixture was then cooled to room temperature and concentrated to give desired product (5.1 g).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[C:3]=1[C:14]([NH2:16])=[O:15].C(N(CC)C(C)C)(C)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[N:34]=[C:35]=[O:36]>O1CCOCC1>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:35]([NH:34][C:28]3[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:27]=3[F:26])=[O:36])=[CH:11][CH:12]=2)[C:3]=1[C:14]([NH2:16])=[O:15]
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: NC(=O)c1c(-c2ccc(N)cc2)nsc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3nsc(N)c3C(N)=O)cc2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.7 %

Procedure:
A mixture of 5-amino-3-(4-aminophenyl)isothiazole-4-carboxamide (18 mg, 0.079 mmol), N,N-diisopropylethylamine (0.034 mL, 0.20 mmol), and 2-fluoro-5-methylphenyl isocyanate (0.014 mL, 0.11 mmol) in 1.0 mL dioxane was reacted at room temperature for 2.5 hours. The reaction was quenched with 0.5 mL MeOH, stirred 5 min at room temperature, and then evaporated. The residue was recrystallized from EtOAc/CHCl3 to give the title compound as a pale yellow solid (27 mg, 88%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:38]([O:55][CH2:56][CH2:57][N:58]1[CH2:63][CH2:62][N:61]([CH2:64][CH2:65][C@@H:66]([NH:75][C:76]2[CH:81]=[CH:80][C:79]([S:82]([NH2:85])(=[O:84])=[O:83])=[CH:78][C:77]=2[S:86]([C:89]([F:92])([F:91])[F:90])(=[O:88])=[O:87])[CH2:67][S:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH2:60][CH2:59]1)([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:85][S:82]([C:79]3[CH:80]=[CH:81][C:76]([NH:75][C@H:66]([CH2:65][CH2:64][N:61]4[CH2:62][CH2:63][N:58]([CH2:57][CH2:56][O:55][Si:38]([C:51]([CH3:52])([CH3:53])[CH3:54])([C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)[C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH2:59][CH2:60]4)[CH2:67][S:68][C:69]4[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=4)=[C:77]([S:86]([C:89]([F:90])([F:92])[F:91])(=[O:87])=[O:88])[CH:78]=3)(=[O:83])=[O:84])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CC(C)(C)[Si](OCCN1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCN(CCO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.6 %

Procedure:
(R)-4-(4-((tert-butyldimethylsilyloxy)(4 ′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 56.5 mg, 0.11 mmol), (R)-4-(4-(4-(2-(tert-butyldiphenylsilyloxy)ethyl)piperazin-1-yl)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 22, 80 mg, 0.1 mmol), DMAP (35.1 mg, 0.29 mmol), and EDC (36.7 mg, 0.19 mmol) were placed in a 50 ml flask and flushed with nitrogen. DCM (0.96 ml) was added, and the solution was stirred at room temperature overnight. The reaction mixture was diluted with DCM (40 ml) and washed with 1N sodium bisulfate (35 ml) followed by a saturated aq. sodium bicarbonate (40 ml). The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure to give the title product (147 mg, yield: quantitative), that was used in the preparation of EXAMPLE 1 without further purification.