Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([SH:26])[NH:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl[CH2:28][CH2:29]Br.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]3[C:13]([S:26][CH2:28][CH2:29]3)=[N:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2nc(S)[nH]c2-c2ccc(NC(C)=O)cc2)cc1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(-c2nc3n(c2-c2ccc(NC(C)=O)cc2)CCS3)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A mixture of 10.0 g. (0.027 mole) of 4,5-bis-(p-acetamidophenyl)-2-mercaptoimidazole and 4.9 g. (0.034 mole) of 2-chloroethyl bromide in 80 ml. of sieve dried dimethylformamide was refluxed with stirring under nitrogen for 75 minutes. Potassium carbonate (3.8 g., 0.027 mole) was added and the suspension was refluxed for 2 hours, then allowed to cool to room temperature and poured into 650 ml. of water. The gum which formed was filtered off and crystallized from 50 ml. of hot methanol. The crystals were washed with cold methanol and ether and air dried to give 5,6-bis(p-acetamidophenyl)-2,3-dihydroimidazo[2,1-b]thiazole, m.p. 285°-290° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C(Cl)Cl.CO>[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH:21][C:2]1[N:3]=[N:4][C:5]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)nnc(Cc2ccncc2)c1C
Reactant: Cc1cccc(N)c1
Solvent: ClCCl
Solvent: CO
Product: Cc1cccc(Nc2nnc(Cc3ccncc3)c(C)c2C)c1

Procedure:
The compound is prepared starting from 0.070 g 3-chloro-4,5-dimethyl-6-(pyridin-4-yl)methylpyridazine and 0.129 g meta-methylaniline in the manner described in Example 82A. After heating for 20 h to 130° C., significant quantities of 3-chloro-4,5-dimethyl-6-(pyridin-4-yl)methylpyridazine are still present (TLC). For this reason, a further 0.129 g meta-methylaniline is added and heated for another 24 h to 130° C. Processing is in the manner described for Example 82A. Title compound of about 90% purity is obtained after FC in CH2Cl2/methanol 19/1; m.p. 68-90%°. 1H-NMR (250 MHz, CDCl3): δ=8.45 (d, 2H); 7.70 (t, 1H); 7.50 (s, 1H); 7.40-7.10 (m, 4H)); 6.90 (d, 1H); 6.15 (s, wide, 1H); 4.30 (s, 2H); 2.35 (s, 3H); 2.15 (s, 3H); 2.10 (s, 3H). ES-MS 305 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=O.Cl>[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]2[N:11]([CH2:12][CH3:13])[C:9](=[O:10])[N:8]=[N:7]2)[CH:14]=[CH:15][CH:16]=1
Reactant: CCNC(=O)NNC(=O)c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCN1C(=O)N=NC1c1cccc(F)c1

Procedure:
A mixture of the 1-(3-fluorobenzoyl)-4-ethyl semicarbazide and 1N NaOH solution (100 mL) was refluxed for 20 hr, cooled to room temperature and neutrallized with conc. HCl. The suspension was extracted with ethyl acetate and the organic layer was dried over MgSO4. Removal of the solvent in vacuo yielded 7.3 g of 3-(3-fluorophenyl)-4-ethyl-1,2,4-triazolin-5-one as a white solid. mp 135°-140° C.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][NH2:17].C(OCC)(=O)C>CO.[Pd]>[CH3:16][NH:17][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1
Reactant: CN
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNCc1ccc(Oc2ccccc2)cc1

Procedure:
4-Phenoxybenzaldehyde (10.0 g, 0.05 mol), excess methylamine and 1.5 g of 10% Pd/C in 200 mL of methanol were stirred under an atmosphere of hydrogen for 16 hours. After removal of the catalyst by filtration through a filter and (CELITE®), the filtrate was concentrated under reduced pressure to give the crude product as an oil. Chromatography on silica gel eluting with ethyl acetate gave the title compound in 80%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[CH:28]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cccc(OC)c3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 3-methoxy-phenylboronic acid (49 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:13]([Br:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH:7]([CH3:9])[CH3:8])=[O:5].[C:15](OC(Cl)(Cl)Cl)(OC(Cl)(Cl)Cl)=[O:16].O>C(Cl)Cl>[Br:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:3]2[C:2]=1[NH:1][C:15](=[O:16])[N:6]([CH:7]([CH3:9])[CH3:8])[C:4]2=[O:5]
Reactant: CC(C)NC(=O)c1cccc(Br)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)n1c(=O)[nH]c2c(Br)cccc2c1=O
Yield: 250 %

Procedure:
A slurry of 2-amino-3-bromo-N-isopropylbenzamide (406a, 1.00 g, 3.89 mmol) and tri-phosgene (Aldrich; 0.462 g, 1.556 mmol) in 50 mL DCM was fitted with a water cooled reflux condenser and drying tube and heated to reflux overnight. In the morning, complete conversion to desired product. The reaction was cooled and concentrated in vacuo to give 8-bromo-3-isopropylquinazoline-2,4(1H,3H)-dione (1.1 g, 3.89 mmol, 100% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.02-8.25 (1H, m), 7.98 (1H, br. s.), 7.78 (1H, dd, J=7.8, 1.4 Hz), 7.11 (1H, t, J=7.9 Hz), 5.27 (1H, dt, J=13.9, 6.9 Hz), 1.56 (6H, s). m/z (ESI, +ve) 282.9/284.9 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([NH2:26])=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.Br[C:28]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=1[C:35]([CH:37]1[CH2:41][CH2:40][CH2:39][O:38]1)=[O:36].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[NH2:26][C:8]1[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:28]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=3[C:35]([CH:37]3[CH2:41][CH2:40][CH2:39][O:38]3)=[O:36])[CH:14]=2)[N:9]=1
Reactant: Cc1cccc(C(=O)C2CCCO2)c1Br
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(C(=O)C2CCCO2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 140 °C

Procedure:
A mixture of 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.099 g, 0.279 mmol), (2-bromo-3-methylphenyl)(tetrahydrofuran-2-yl)methanone (0.050 g, 0.186 mmol), potassium phosphate tribasic (0.077 mL, 0.929 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.018 g, 0.037 mmol), and Pd2(dba)3 (8.51 mg, 9.29 μmol) were treated with dioxane (1.2 mL) and water (0.62 mL) in a medium-sized Smith synthesizer vial. The mixture was heated to 140° C. for 12 min in a microwave reactor. The reaction mixture was filtered then partitioned between EtOAc and water, organics were washed with water and brine and then concentrated in vacuo. The crude product was purified by silica flash chromatography (1-10% MeOH/DCM) and then by HPLC (10-75% acetonitril/H2O; TFA modifier). A single fraction was treated with NH4OH, concentrated, filtered and air-dried to afford (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(tetrahydrofuran-2-yl)methanone. MS (ESI, pos. ion) m/z: 418 (M+1).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][CH:5]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([NH:8][CH2:9][C:10]#[N:11])=[O:7].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:10]([CH2:9][NH:8][C:6]([CH:5]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:4][C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[C:36]1[CH:35]=[CH:34][C:33]([N:30]2[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:32][CH2:31]2)=[CH:38][CH:37]=1)=[O:7])#[N:11]
Reactant: CC(C)CC(Cc1ccccc1Br)C(=O)NCC#N
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CC(Cc1ccccc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)NCC#N
Temperature: 90 °C

Procedure:
To 2-(2-bromobenzyl)-N-(cyanomethyl)-4-methylpentanamide (260 mg, 0.805 mmol) and 4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenylboronic acid (275 mg, 0.886 mmol) in DMF (10 mL) under dry nitrogen was added aqueous sodium carbonate (2 M, 1.2 mL, 2.42 mmol) followed by the catalyst PdCl2(dppf) (25 mg, 0.025 mmol). The reaction was heated to 90° C. for 0.5 hours and more PdCl2(dppf) (25 mg, 0.025 mmol) was added and the reaction mixture was heated for another 4 hours. Water was added and the product extracted with ether (2×), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (EtOAc/Hex, 35/65) to afford tert-butyl 4-[2′-(2-{[(cyanomethyl)amino]carbonyl}-4-methylpentyl)[1,1 ′-biphenyl]-4-yl]-1-piperazinecarboxylate.
Reaction SMILES: [OH:1][C:2]1([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:3]1=[O:17].[C:25](OC(=O)C)(=[O:27])[CH3:26]>CN(C)C1C=CN=CC=1.ClCCl>[C:25]([O:1][C:2]1([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:3]1=[O:17])(=[O:27])[CH3:26]
Reactant: O=C1N(N2CCOCC2)c2ccccc2C1(O)Cc1ccccn1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1(Cc2ccccn2)C(=O)N(N2CCOCC2)c2ccccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of alcohol from Example 26 (63 mg, 0.194 mmole) 4-dimethylaminopyridine (78 mg, 0.639 mmole), acetic anhydride (0.06 ml, 0.639 mmole) in dichloromethane (10 ml) was stirred at 0° C. for 8 hours. The volatiles were removed and the crude mixture applied directly to a silica gel column and eluted with 5% methanol in chloroform (Rf =0.34). The product slowly crystallized from hexane-ethyl acetate at 0° C. to give 41 mg of colorless cubes, m.p. 107°-110° C. after filtration. IR (KBr): 1702 cm-1. High Res. Mass Spec. Calcd. for C20H21N3O4 : 368.1610(M+H). Found: 368.1611.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[CH:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)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.[Cu]I>[C:12]1([C:10]#[C:11][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=2)[CH:7]=[O:8])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#Cc1ccccc1
Reactant: O=Cc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=Cc1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
A solution of 5-bromonicotinaldehyde (15 g, 81 mmol) and ethynylbenzene (9.74 mL, 89 mmol) in triethylamine (150 mL) was purged with nitrogen for 30 min. The reaction was treated with triphenylphosphine (0.656 g, 2.50 mmol), and purged 10 minutes longer. To this was added bis(triphenylphosphine)palladium dichloride (0.147 g, 0.210 mmol) and copper(I) iodide (0.032 g, 0.169 mmol). After purging 10 min longer, the reaction was warmed to a gentle reflux. The reaction was heated at reflux for 24 h. The reaction was cooled to room temperature, diluted with ethyl acetate, poured into water, and the layers were separated. The organics were washed again with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (20% EtOAc/Hex) gave 16.05 g (96%) as faint yellow crystalline solid. 1H NMR (CDCl3) δ: 10.16 (s, 1H), 9.01 (dd, J=17.1, 1.8 Hz, 2H), 8.30 (t, J=2.0 Hz, 1H), 7.54-7.66 (m, 2H), 7.38-7.47 (m, 3H). 13C NMR (CDCl3) δ: 190.2, 156.8, 150.3, 138.2, 131.9, 130.9, 129.4, 128.7, 122.0, 121.5, 94.5, 84.7. Mass spec.: 208.0 (MH)+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:6][C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]1([CH3:19])[CH3:18].I([O-])(=O)(=O)=[O:21].[Na+].C(#N)C>C(Cl)(Cl)(Cl)Cl.O.O.[Ru](Cl)(Cl)Cl>[CH2:10]([O:9][C:8]([NH:7][C@@H:5]1[CH2:6][C@H:3]([C:2]([OH:21])=[O:1])[C:4]1([CH3:19])[CH3:18])=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC1(C)[C@@H](CO)C[C@H]1NC(=O)OCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)[C@@H](C(=O)O)C[C@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of benzyl ((1R,3S)-3-(hydroxymethyl)-2,2-dimethylcyclobutyl)carbamate (2.75 g, 10.4 mmol) in carbon tetrachloride (14 mL) was added sodium periodate (6.68 g, 31.2 mmol), water (21 mL) and acetonitrile (14 mL), followed by ruthenium(III) chloride hydrate (52 mg, 0.2 mmol, in 0.5 mL of water) at room temperature. The resulting biphasic mixture was stirred vigorously at room temperature for 1 h. The reaction mixture was diluted with water and extracted with DCM (2×150 mL). The combined organic layers were dried over sodium sulfate and concentrated to give the title compound (2.6 g, crude), which was used directly in the next step without further purification. MS (ESI) m/z 278.1 [M+H]+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[C@H:23]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClCCCl.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>CN(C)C1C=CN=CC=1.O.ClCCl>[Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[C@H:23]1[CH2:24][CH2:25][C@H:26]([NH:29][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:27][CH2:28]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](N)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](NS(C)(=O)=O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine (248 mg, 0.57 mmol) and 1,2-dichloroethane (25 ml). To the stirred solution was added triethylamine (191 μl, 1.37 mmol) followed by methanesulfonyl chloride (53 μl, 0.68 mmol) and three crystals of 4-dimethylaminopyridine. The resulting solution was stirred at room temperature for 18 hr and then poured into a separating funnel containing dichloromethane (100 ml) and water (20 ml). The layers were separated and the aqueous phase extracted with dichloromethane (1×50 ml). The combined organic phases were washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo affording the title compound as a pale yellow oil (320 mg, 100%). δH(CDCl3) 0.02 (6H, s), 0.05 (6H, s), 0.78 (9H, s), 0.82 (9H, s), 1.22 (4H, m), 1.70 (2H, m), 1.99 (2H, m), 2.61 (1H, m), 2.81 (3H, s), 3.19 (1H, m), 3.92 (1H, d), 6.13 (1H, d), 6.22 (11H, dd), 6.66 (1H, d).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[Cl:10][S:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18])(=[O:13])=[O:12].N1C=CC=CC=1>O1CCCC1>[C:1]([O:6][CH2:7][CH2:8][O:9][C:17]([C:16]1[CH:15]=[C:14]([S:11]([Cl:10])(=[O:13])=[O:12])[CH:22]=[CH:21][CH:20]=1)=[O:18])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: C=C(C)C(=O)OCCO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Yield: 84.1 %

Procedure:
With stirring, a solution of 13 g (0.1 mole) of 2-hydroxyethyl methacrylate in 80 ml of tetrahydrofuran is slowly added dropwise at 0° C. to a solution of 23.9 g (0.1 mole) of 3-chlorosulfonylbenzoyl chloride and 7.9 g (0.1 mole) of pyridine in 150 ml of tetrahydrofuran. The reaction mixture is subsequently stirred for 15 hours at room temperature. The precipitated pyridine salt is removed by filtration, and the filtrate is concentrated by evaporation in vacuo. The oily residue is dried under high vacuum, affording 28 g of viscous product.
Reaction SMILES: [OH:1][CH:2]([C:8]1[N:9]([CH3:23])[C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:24](Br)([CH3:27])([CH3:26])[CH3:25]>C1CCCCC1.[Ag-]=O>[C:24]([O:1][CH:2]([C:8]1[N:9]([CH3:23])[C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCOC(=O)C(O)c1c(-c2ccccc2)c2ccccc2n1C
Reactant: CC(C)(C)Br
Agent: O=[Ag-]
Solvent: C1CCCCC1
Product: CCOC(=O)C(OC(C)(C)C)c1c(-c2ccccc2)c2ccccc2n1C
Reaction time: 2 h
Yield: 10.3 %

Procedure:
A mixture of ethyl 2-hydroxy-2-(1-methyl-3-phenyl-1H-indol-2-yl)acetate (1c) (300 mg, 0.97 mmol), silver (I) oxide (674 mg, 2.91 mmol) and tert-butylbromide (544 μL, 4.85 mmol) in cyclohexane (10 mL) was vigorously stirred for 2 hours under a nitrogen atmosphere. The reaction mixture was then filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired ether oxide (1d) as a white solid (35 mg, 0.1 mmol, 10%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:19][CH2:20][CH3:21])[N:15]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[C:14]=2[CH:29]=1.ClC1C=CC=C(C(OO)=[O:39])C=1.S(OS([O-])=O)([O-])=O.[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18]([CH2:19][CH2:20][CH3:21])=[O:39])[N:15]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[C:14]=2[CH:29]=1
Reactant: CCCSc1nc2ccc(OCCCCCC(=O)OC)cc2n1-c1ccc(C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCS(=O)c1nc2ccc(OCCCCCC(=O)OC)cc2n1-c1ccc(C)cc1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
600 mg of 6-[[1-(4-methylphenyl)-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was dissolved in 10 ml of dichloromethane, mixed with 405 mg of m-chloroperbenzoic acid (about 60%), and the mixture was stirred for 15 minutes at 20° C. It was mixed with sodium disulfite solution, extracted twice with dichloromethane, the combined organic phases were washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 525 mg of 6-[[1-(4-methylphenyl)-2-propanesulfinyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=2)=[CH:6][C:7]=1[CH3:8].[NH4+].[OH-]>[Pd].CO>[CH3:8][C:7]1[CH:6]=[C:5]([C:9]2[CH:10]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:12]=[CH:13][CH:14]=2)[N:4]=[N:3][CH:2]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)nnc1Cl
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cc1cnnc(-c2cccc(C(F)(F)F)c2)c1
Yield: 78.5 %

Procedure:
To 3-chloro-4-methyl-6-(α,α,α-trifluoro-m-tolyl)pyridazine(7 g) is added 10% palladium on carbon catalyst (0.7 g) and 300 mL of MeOH containing 30 mL of concentrated NH4OH. The mixture is shaken with H2 until the uptake of H2 ceases. The mixture is filtered to remove catalyst and concentrated in vacuo and then diluted with CH2Cl2 /H2O. The organic phase is washed with water and dried over MgSO4 to yield a solid which, on recrystallization from Et2O, gives 4.8 g (78%) of an off-white solid with a melting point of 114°-116° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:39]=[CH:38][C:20]([O:21][C:22]2[C:27]([F:28])=[CH:26][C:25](/[CH:29]=[C:30](\[CH3:36])/[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:24][C:23]=2[F:37])=[CH:19][CH:18]=1)(=[O:16])=[O:15].[CH3:40][N:41]([CH:43]=[O:44])C>>[O:44]=[C:43]([NH:41][CH2:40][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:18]=[CH:19][C:20]([O:21][C:22]2[C:23]([F:37])=[CH:24][C:25]([CH:29]=[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:36])=[CH:26][C:27]=2[F:28])=[CH:38][CH:39]=1)(=[O:16])=[O:15])[NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:39]=[CH:38][C:20]([O:21][C:22]2[C:23]([F:37])=[CH:24][C:25]([CH:29]=[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:36])=[CH:26][C:27]=2[F:28])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: CN(C)C=O
Reactant: CCOC(=O)/C(C)=C/c1cc(F)c(Oc2ccc(S(=O)(=O)NCCOCCOCCOCCN)cc2)c(F)c1
Product: CCOC(=O)C(C)=Cc1cc(F)c(Oc2ccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)NCCOCCOCCOCCNS(=O)(=O)c3ccc(Oc4c(F)cc(C=C(C)C(=O)OCC)cc4F)cc3)cc2)c(F)c1
Reaction time: 23 h

Procedure:
Carbonyldiimidisole (16.2 mg, 0.10 mmol) was added to a solution of (E)-ethyl 3-(4-(4-(N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)sulfamoyl)phenoxy)-3,5-difluorophenyl)-2-methylacrylate (intermediate 44.2) (125 mg, 0.22 mmol) in DMF (2 mL) and stirred for 23 hours at which time the solvent was removed under vacuum. The residue was dissolved in EtOAc, washed with water (4×10 mL), dried (Na2SO4) and concentrated to give the title compound (132 mg).