Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]([NH:12][NH2:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]([F:38])([F:37])[C:27]1[N:31]2[CH2:32][CH2:33][NH:34][C:35](=S)[C:30]2=[N:29][N:28]=1.CO>C(OCC)C>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10](=[O:11])[NH:12][NH:13][C:35]1[C:30]2[N:31]([C:27]([C:26]([F:38])([F:37])[F:25])=[N:28][N:29]=2)[CH2:32][CH2:33][N:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1nnc2n1CCNC2=S
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NN)Cc1cc(F)c(F)cc1F
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NNC1=NCCn2c1nnc2C(F)(F)F)Cc1cc(F)c(F)cc1F

Procedure:
A mixture of 207 mg (0.6 mmol) of tert-butyl[(1R)-3-hydrazino-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate (Intermediate 4), 110 mg (0.5 mmol) of 3-(trifluoromethyl)-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrazine-8(5H)-thione (Intermediate 6), and 5.5 mL of methanol was stirred at reflux for 1 day. Diethyl ether was added to the cooled solution, resulting in precipitation. The solid was removed by filtration, and the filtrate was concentrated to dryness. Purification of the residue by preparative HPLC (C18 reverse phase column, 30-80% acetonitrile in water containing 0.05% trifluoroacetic acid) afforded the title compound. LC-MS 536 (M+1).
Reaction SMILES: Br[C:2]1[N:6](S(C2C=CC=CC=2)(=O)=O)[CH:5]=[C:4]([CH:16]=[O:17])[C:3]=1[CH3:18].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>COCCOC.O>[CH3:18][C:3]1[C:4]([CH:16]=[O:17])=[CH:5][NH:6][C:2]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1c(C=O)cn(S(=O)(=O)c2ccccc2)c1Br
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: Cc1c(C=O)c[nH]c1-c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
A suspension of 5-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (1.78 g), phenylboronic acid (1.37 g), dichloro[bis(triphenylphosphine)]palladium (0.19 g) and sodium carbonate (1.72 g) in 1,2-dimethoxyethane (30 mL)-water (10 mL) was stirred at 100° C. for 1 hr. 8 mol/L aqueous sodium hydroxide solution (15 mL) was added, and the mixture was stirred at 90° C. for 3 hr. After cooling, the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1), and the obtained solid was washed with hexane to give the title compound as a pale-yellow solid (yield 815 mg, 69%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[Mg]Br.[C:11]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12]1.Cl>C1COCC1>[C:11]1([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: O=C1CCCC1
Reactant: Fc1ccc([Mg]Br)c(F)c1
Agent: Cl
Solvent: C1CCOC1
Product: Fc1ccc(C2=CCCC2)c(F)c1
Temperature: 0 °C
Yield: 26.3 %

Procedure:
To a 0.497 M solution of (2,4-difluorophenyl)magnesium bromide (32.4 g, 149 mmol) in THF at 0° C. was carefully added cyclopentanone (13.23 mL, 149 mmol). Upon the end of the addition, the reaction mixture was heated at reflux for 2 h. Ice (10 g) and 6 N aqueous hydrochloric acid were added. The reaction mixture was extracted with ether. The combined organic extracts were washed with a saturated aqueous solution of sodium hydrogen sulfite, a saturated aqueous solution of sodium bicarbonate and water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel to give 1-cyclopentenyl-2,4-difluorobenzene (7.064 g, 39.2 mmol, 26.3% yield) as a colorless oil. LC-MS (M+H)+=181.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.22-7.31 (1H, m), 6.75-6.85 (2H, m), 6.26-6.31 (1H, m), 2.68-2.74 (2H, m), 2.51-2.58 (2H, m), 1.93-2.02 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9].[Br:16][C:17]1[CH:22]=[C:21]([CH2:23]O)[CH:20]=[CH:19][N:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:16][C:17]1[CH:22]=[C:21]([CH2:23][N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])[CH:20]=[CH:19][N:18]=1
Reactant: OCc1ccnc(Br)c1
Reactant: CC(C)CNS(=O)(=O)c1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CN(Cc1ccnc(Br)c1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 45, step 1, 2-chloro-N-isobutyl-benzenesulfonamide (example 42, step 1) was reacted with (2-bromo-pyridin-4-yl)-methanol (CAS [118289-16-0]), triphenylphosphine and diethyl azodicarboxylate in tetrahydrofuran to give N-(2-bromo-pyridin-4-ylmethyl)-2-chloro-N-isobutyl-benzenesulfonamide as a colorless oil. MS: 417.2 ([M+H]+)
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].N[CH2:20][CH2:21][S:22][CH2:23][N:24]1N=CC=N1>C(#N)C>[N+:1]([CH:4]=[C:5]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:23]1[S:22][CH:21]=[CH:20][N:24]=1)([O-:3])=[O:2]
Reactant: NCCSCn1nccn1
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Solvent: CC#N
Product: Cc1nc[nH]c1CSCCNC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene with an excess of 2-[(2-aminoethyl)thiomethyl]triazole according to the procedure of Example 3, results in the production of 1-nitro-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene, m.p. 110°-120° (from acetonitrile).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:32]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[CH:23][C:22]=3[O:30]C.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[N:11][C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([CH:32]=3)[CH2:19][CH2:20][C:21]3[CH:29]=[C:25]([NH:26][C:27]=1[N:28]=2)[CH:24]=[CH:23][C:22]=3[OH:30]
Reactant: COc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
A solution of 6-chloro-12-methoxy-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate (157 mg, 0.34 mmol) in methylene chloride (2.5 mL) was cooled to −78° C. and 1 M boron tribromide in methylene chloride (1.68 mL, 1.68 mmol) was added slowly. The mixture was allowed to warm to room temperature and stir for 16 hours. The mixture was cooled to −78° C. and saturated sodium bicarbonate solution was added. The resulting suspension was filtered and the collected solid was washed with water and ethyl acetate to give the desired compound (113 mg, 100%). 1H NMR (300 MHz, DMSO-d6): δ 9.45 (s, 1H), 9.25 (s, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.48 (s, 1H), 7.08 (m, 1H), 6.81 (m, 3H), 6.71 (d, 1H), 2.82 (s, 4H). LCMS for C18H16ClN4O (M+H)+: m/z=339.1.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].[C:10]1([C:16](Br)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>N1C=CC=CC=1>[C:10]1([C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#CCC(O)CCCC
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: C#CCC(CCCC)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 10 g (0.08 moles) of 4-hydroxy-1-octyne [L. Crombie and A. G. Jacklin, J. Chem. Soc., 1632 (1957), also Example 93] and 30.75 g (0.09 moles) of triphenylmethyl bromide in 85 ml of dry pyridine is heated on the steam bath for 2 hours. The cooled mixture is treated with water and extracted with ether. The extract is washed successively with ice cold 2% hydrochloric acid, saturated sodium chloride solution, dried with magnesium sulfate, and taken to dryness. Column chromatography of the residue on Florisil affords an oil; λ max 3.01, 4.72 (acetylenic hydrogen), 6.28, 9.65 and 14.25μ (triphenylmethoxy group).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:12])[CH2:9][CH2:10][S:11][C:6]=2[C:5]([CH3:13])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:18]Br.Cl>C(Cl)Cl.O>[Br:18][C:3]1[CH:4]=[C:5]([CH3:13])[C:6]2[S:11][CH2:10][CH2:9][C:8](=[O:12])[C:7]=2[C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1ccc(C)c2c1SCCC2=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(Br)c(C)c2c1SCCC2=O
Reaction time: 0.25 h
Yield: 46 %

Procedure:
A solution of 4.07 g (0.021 mol) of the title compound of Step B in 25 mL of methylene chloride was added dropwise to a mixture of 7.07 g (0.053 mol) of aluminum chloride (purchased from Aldrich Chemical Company) and 25 mL of methylene chloride. The suspension was stirred for approximately 15 minutes, 1.14 mL (0.022 mol) of bromine (purchased from Janssen) was added dropwise and the mixture was refluxed for 10 minutes. The hot mixture was poured into 10 mL of concentrated hydrochloric acid containing 75 g of ice, stirred for 10 minutes, diluted with 50 mL of water, and extracted with diethyl ether (2×200 mL). The organic layer was washed with water (2×200 mL), dried (Na2SO4), filtered and evaporated to dryness. The crude product was chromatographed over silica gel eluting with ethyl acetate:hexane (5% 95%) to yield 2.62 g of the title compound of Step C as a solid melting at 87-88° C. 1H NMR (CDCl3): δ2.3 (s,3H), 2.6 (s,3H), 3.0 (m,2H), 3.2 (m,2H), 7.45 (s,1H).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([NH:16][C:17]1[CH:26]=[C:25]([C:27]#[CH:28])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.Cl>[Cu]I.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.C(OCC)(=O)C>[C:8]([NH:16][C:17]1[CH:26]=[C:25]([C:27]#[C:28][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C#Cc1ccc(C(=O)OC)c(NC(=O)c2ccccc2)c1
Reactant: Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C#Cc2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 mL of toluene suspension containing 0.15 g of methyl 2-(benzamido)-4-ethynylbenzoate, 0.090 mL of iodinated benzene, 5 mg of copper(I) iodide, 20 mg of bis(triphenylphosphine)palladium(II) chloride and 0.15 mL of triethylamine was stirred under nitrogen atmosphere at room temperature for 2 hours. Ethyl acetate and 1.0 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=8:1] to obtain 0.13 g of methyl 2-(benzamido)-4-(phenylethynyl)benzoate as white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[C:17]3[CH3:19])=[N:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[CH3:19][C:17]1[N:18]2[C:11]([CH:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[OH:10])=[CH:12][N:13]=[C:14]2[S:15][CH:16]=1
Reactant: Cc1csc2ncc(C(=O)CCc3ccccc3)n12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1csc2ncc(C(O)CCc3ccccc3)n12
Yield: 86.9 %

Procedure:
A solution of (2-Phenylethyl)-3-methylimidazo[2,1-b]thiazol-5-yl methanone (Formula B-6) (0.40 g) in ethanol (5.0 mL) was treated with a solution of NaBH4 (0.05 g) in ethanol (5 mL) and reacted for 18 hours. The solvent was removed in vacuo and the residue was treated with 5% acetic acid solution. Precipitated 3-Methyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol (Formula B-8) (0.38 g) was filtered and recrystallized from isopropanol solution to provide pure 3-Methyl-α-(2-phenylethyl)imidazo[2,1-b]thiazole-5-methanol (Formula B-8) (0.35 g), m.p. 144-145°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]2[C:8]3[S:22][C:21]([CH2:23][CH3:24])=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1.C(N(CC)CC)C.[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[Cl:42])[C:36](Cl)=[O:37]>ClC(Cl)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[C:9]2[CH:20]=[C:21]([CH2:23][CH3:24])[S:22][C:8]=2[N:7]2[C:3]([CH2:2][NH:1][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][C:41]([Cl:42])=[C:33]([Cl:32])[CH:34]=3)=[N:4][N:5]=[C:6]2[CH2:12][N:11]=1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCc1cc2c(s1)-n1c(CN)nnc1CN=C2c1ccccc1Cl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1cc2c(s1)-n1c(nnc1CNC(=O)c1ccc(Cl)c(Cl)c1)CN=C2c1ccccc1Cl
Reaction time: 1 h
Yield: 65 %

Procedure:
9-Aminomethyl-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (0.28 g) and triethylamine (0.115 ml) were dissolved in dichloroethane (15 ml). 3,4-Dichlorobenzoyl chloride (0.17 g) was added at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and methanol as a developing solvent. The obtained solid was recrystallized from a mixed solvent of ethyl acetate and hexane to give 0.27 g of N-(4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-9-ylmethyl)-3,4-dichlorobenzamide.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][CH:14]=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)([OH:18])N.Cl([O-])=O.[Na+]>C1COCC1.O>[C:1]1([C:7]2([CH2:13][C:14]([OH:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCC1(c2ccccc2)CCCCO1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1(c2ccccc2)CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-phenyltetrahydro-2H-pyran-2-yl)acetaldehyde (100 mg, 0.490 mmol) and sulfamic acid (57.0 mg, 0.587 mmol) in THF (1.5 mL) was added a solution of sodium chlorite (53.1 mg, 0.587 mmol) in water (1.5 mL) dropwise, and the mixture was stirred at room temperature for 3 hrs. Then the product was extracted with EtOAc (3×) and the combined extracts were washed with brine, dried over Na2SO4, and evaporated to give 2-(2-phenyltetrahydro-2H-pyran-2-yl)acetic acid as oil. LC/MS: m/e 221.14 (M+H)+.
Reaction SMILES: O[C:2]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:29])[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:15][CH:14]=1)([C:4]1[N:5]([CH2:9][CH2:10][O:11][CH3:12])[CH:6]=[CH:7][CH:8]=1)[CH3:3].[CH2:30]([SiH](CC)CC)C.B(F)(F)F.CCOCC>>[CH3:12][O:11][CH2:10][CH2:9][N:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[CH:2]([C:13]1[CH:14]=[CH:15][C:16]([N:19]([CH3:29])[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][CH:18]=1)[CH2:3][CH3:30]
Reactant: CC[SiH](CC)CC
Reactant: COCCn1cccc1C(C)(O)c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1
Agent: FB(F)F
Solvent: CCOCC
Product: CCC(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)c1cccn1CCOC

Procedure:
The title compound was prepared from N-(4-{1-hydroxy-1-[1-(2-methox-yethyl)-1H-pyrrol-2-yl]-ethyl}-phenyl)-N-methyl-benzenesulfonamide (Example 1) using triethylsilane and boron trifluoride diethyl etherate as described in Example 88 of U.S. application Ser. No. 10/354,922, now U.S. Pat. No. 7,071,358, and provided below as Preparative Example B.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:15])[CH:13]=[CH2:14])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH:16]([C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)([CH3:18])[CH3:17].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:11][C:12](=[O:15])[CH2:13][CH2:14][N:20]2[CH:21]=[CH:22][N:23]=[C:19]2[CH:16]([CH3:18])[CH3:17])([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: C=CC(=O)NC(C)(C)c1ccc(Cl)cc1
Reactant: CC(C)c1ncc[nH]1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)c1nccn1CCC(=O)NC(C)(C)c1ccc(Cl)cc1

Procedure:
In a similar manner to Example 68a (alternative procedure), a mixture of N-[1-(4-chlorophenyl)-1methylethyl]acrylamide (6.7 g), 2-isopropylimidazole (3.3 g), 1,4-dioxane (100 ml) and benzyltrimethyl-ammonium hydroxide (Triton B) (5 ml of 40% solution in methanol) gave N-[1-(4-chlorophenyl)-1-methylethyl]-3-(2-isopropylimidazol-1-yl)propionamide as an oil not distilled.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.[C:19]([O:27][CH2:28][CH2:29]Br)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:19]([O:27][CH2:28][CH2:29][N:15]1[CH2:16][CH2:17][O:18][CH:13]([CH2:12][NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])[CH2:14]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Reactant: O=C(OCCBr)c1ccccc1
Product: O=C(NCC1CN(CCOC(=O)c2ccccc2)CCO1)Nc1ccc(Cl)cc1

Procedure:
Example 39 was prepared in an analogous manner to Example 19 using a mixture of Intermediate 9 (0.01 g) and 2-bromoethyl benzoate (6.5 μl) to give the title compound (0.007 g). LC-MS (System A): Rt 2.69 mins, Mass Spectrum m/z 418 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])[CH2:5][C:6]1[C:7](Cl)=[N:8][C:9](Cl)=[N:10][CH:11]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])[CH2:5][C:6]1[C:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:8][C:9]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:10][CH:11]=1
Reactant: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1c(Cl)cccc1Cl
Reactant: Nc1ccccc1
Product: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1c(Cl)cccc1Cl
Temperature: 110 °C

Procedure:
A mixture of 2-(2,6-dichloro-phenyl)-3-(2,4-dichloro-pyrimidin-5-yl)-propionic acid methyl ester (0.20 g, 0.53 mmol) (from Example 2a supra) and aniline (2.0 ml) (Aldrich) was heated at 110° C. for 2 hours. The reaction mixture was washed with hexanes (50 mL×3) and the supernatant was decanted off after each time. The residue was then dissolved in ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-(2,6-dichloro-phenyl)-propionic acid methyl ester as a brown caramel which was used in the next step without further purification. (Yield 0.18 g, 69.3%).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)=[C:6]([O:30][CH3:31])[CH:5]=1)=[S:3].Cl[CH:33]([C:38](C)=O)[C:34]([O:36][CH3:37])=[O:35]>CCO>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C@H:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]3[CH:28]=[CH:29][C:4]([C:2]4[S:3][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][N:1]=4)=[CH:5][C:6]=3[O:30][CH3:31])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)[CH3:27]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C(N)=S)cc3OC)ccc21
Reactant: COC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4ncc(C(=O)OC)s4)cc3OC)ccc21
Temperature: 70 °C
Yield: 49.5 %

Procedure:
Ethyl ((1S)-5-{3-[4-(aminocarbonothioyl2-methoxyphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (90 mg, 0.2 mmol) (Example 146) and methyl 2-chloroacetoacetate (37 mg, 0.24 mmol) were dissolved in EtOH (8 mL), and the mixture was heated at 70° C. for 6 h. The reaction was cooled to rt, and then concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc:hexane (v/v)=1:2) provided 52 mg (48%) of the title compound as a clear oil. LC-MS: RT=4.18 min, (M+H)+ 540.1.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:16]=3)[C:12]([Cl:30])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[S:31]1(=[O:39])(=[O:38])[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:21][C:20]1[C:15]([C:13]2[C:12]([Cl:30])=[CH:11][N:10]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][CH:34]4[CH2:35][CH2:36][S:31](=[O:39])(=[O:38])[CH2:32][CH2:33]4)[CH2:3][CH2:4]3)[CH:14]=2)=[N:16][C:17]([NH:22][CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:18][CH:19]=1
Reactant: O=C1CCS(=O)(=O)CC1
Reactant: NC1CCC(Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(Cl)cn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S1(=O)CCC(N[C@H]2CC[C@H](Nc3cc(-c4nc(NCC5CCOCC5)ccc4Cl)c(Cl)cn3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound N2′-(4-aminocyclohexyl)-3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (0.100 g, 0.222 mmol) (synthesized in the same manner as in Example 1b), 2,3,5,6-tetrahydro-4H-thiopyran-4-one 1,1-dioxide (0.036 g, 0.244 mmol), and triethylamine (0.251 ml, 0.182 g, 1.798 mmol) were dissolved in anhydrous CH2Cl2 (1.0 ml) and placed under argon. This solution was then treated with sodium triacetoxyborohydride (0.094 g, 0.444 mmol). The reaction was then stirred at room temperature for 18 hours. At this time a LC-MS was run. The reaction was about 25% complete. Additional 2,3,5,6-tetrahydro-4H-thiopyran-4-one 1,1-dioxide (˜4 equivalents) and sodium triacetoxy borohydride (˜8 equivalents) were added and the reaction continued for additional 27 hours. The reaction was about 60% complete as indicated by LC/MS. The reaction was quenched with sat NaHCO3 (15 ml). This was extracted with EtOAc (3×15 ml). The combined extracts were washed with brine (1×15 ml), dried (Na2SO4), filtered and the solvent removed in vacuo. The material was purified using the HPLC and lyophilized to give 19.7 mg off-white powder of the title compound as its TFA salt. LCMS (m/z): 582/584 (MH+), retention time=0.58 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:34]=[CH:33][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH:61]2[CH2:63][O:62]2)=[CH:55][CH:54]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH2:27]([NH:26][C:24]([NH:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]([N:12]2[CH2:13][CH2:14][CH:9]([NH:8][C:7]3[CH:33]=[CH:34][C:4]([CH2:3][CH2:2][NH:1][CH2:63][C@H:61]([OH:62])[CH2:60][O:59][C:56]4[CH:57]=[CH:58][C:53]([OH:52])=[CH:54][CH:55]=4)=[CH:5][CH:6]=3)[CH2:10][CH2:11]2)=[O:16])=[CH:18][CH:19]=1)=[O:25])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCNC(=O)Nc1ccc(C(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Product: CCCCCCNC(=O)Nc1ccc(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 34.2 %

Procedure:
N-[4-({4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}carbonyl)phenyl]-N′-hexylurea (0.394 g, 0.846 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.308 g, 0.761 mmol) according to Procedure G to give the title compound (0.232 g, 0.26 mmol).