Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26](=[S:28])[NH2:27])=[CH:22][N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1.Br[CH2:41][C:42](=O)[CH3:43].C(=O)([O-])O.[Na+]>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]4[S:28][CH:41]=[C:42]([CH3:43])[N:27]=4)=[CH:22][N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1
Reactant: CC(=O)CBr
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(N)=S)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2nc(C)cs2)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 50.8 %

Procedure:
A mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenethioamide (0.46 g), 1-bromo-2-propanone (0.13 g) and ethanol (30 mL) was heated under reflux for 1 hr. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-(2-furyl)-4-({2-methoxy-4-[({4-[(E)-2-(4-methyl-1,3-thiazol-2-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as pale-yellow crystals (0.25 g, yield 51%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 130-131° C.
Reaction SMILES: Br[C:2]1[CH:3]([OH:8])[CH2:4][CH2:5][C:6]=1[CH3:7].[CH2:9]([Mg]Br)[CH3:10]>C1COCC1.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:9]([C:2]1[CH:3]([OH:8])[CH2:4][CH2:5][C:6]=1[CH3:7])[CH3:10]
Reactant: CC[Mg]Br
Reactant: CC1=C(Br)C(O)CC1
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC1=C(C)CCC1O
Temperature: 25 °C

Procedure:
The alcohol (Intermediate V2, 16 mmol) in THF (30 mL) at 0° C. was treated with ethyl magnesium bromide (40 mmol). The catalyst, 1,3-bis(diphenylphosphino)propane nickel (11) chloride (0.75 mmol) (NiCl2dppp) was added in one portion and the mixture was heated to reflux for 3 hours following the procedure of Organ et al. J. Org. Chem. 1997, 62, 1523, incorporated herein by reference.) The reaction mixture was cooled to rt and quenched with sat. NH4Cl solution. The mixture was filtered and partitioned between brine and diethyl ether. The organic layer was removed and dried over Na2SO4, filtered and concentrated under vacuum. The oil was purified by chromatography on SiO2 with 20% EtOAc:Hx to yield 2-ethyl-3-methyl-cyclopent-2-enol (Intermediate V3). Use of the alcohol (Intermediate V3) in the applicable steps of Method A and Method P produced 4-(2-ethyl-3-methyl-cyclopent-2-enylmethyl)-1,3-dihydro-imidazol-2-one (Compound 64). 1H NMR (300 MHz, CD3OD-d4): δ 6.03 (s, 1H), 2.88 (brs, 1H), 2.65–2.59 (m, 1H), 2.27–1.83 (series of m, 6H), 1.62 (s, 3H), 1.54–1.45 (m, 1H), 0.97 (t, J=6 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6](C)[C:5]2(O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.N[OH:23]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N+:6]([O-:23])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN1C(=O)Nc2ccc(Br)cc2C1(O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2ccc(Br)cc2c(-c2ccccc2)[n+]1[O-]
Yield: 77.6 %

Procedure:
A stirred mixture of 28.28 g (0.085 mole) of 6-bromo-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(1H)-quinazolinone and 17.6 g (0.25 mole) of hydroxylamine hydrochloride in 425 ml of ethanol was refluxed for 192 hours and then cooled. The solid portion of the reaction mixture was collected on a filter, washed with ethanol, and dried in air to give 20.92 g (0.066 mole, 78%) of 6-bromo-4-phenyl-2(1H)-quinazolinone 3-oxide as light yellow crystals: mp 275°-276°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.FC(F)(F)C(O)=O.[Cl:21][C:22]1[N:32]=[N:31][C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH2:30][C:24]=2[CH:23]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:28]3[CH2:27][CH2:26][C:25]4[N:31]=[N:32][C:22]([Cl:21])=[CH:23][C:24]=4[CH2:30][CH2:29]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Clc1cc2c(nn1)CCNCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2cc(Cl)nnc2CC1

Procedure:
The title compound was prepared in accordance with the general method of example 1 from 6-bromo-pyrazolo[1,5-A]pyrimidine-2-carboxylic acid and 3-chloro-6,7,8,9-tetrahydro-5H-1,2,7-triaza-benzocycloheptene trifluoroacetate. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 27 mg (32% of theory). ESI-MS: m/z=407 (M+H)+; Rt(HPLC): 1.10 min. (Method J).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH2:16])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]#[N:16])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC(=O)Cc1ccc(C2CCCCC2)cc1
Solvent: O=S(Cl)Cl
Product: N#CCc1ccc(C2CCCCC2)cc1

Procedure:
17.3 g of para-cyclohexyl-phenylacetamide and 35 ml of thionyl chloride are stirred at 70°C for 3 hours. The excess thionyl chloride is evaporated, the residue dissolved in ethyl acetate, and the solution washed with sodium bicarbonate solution and water. The solvent is evaporated and the residue distilled in a high vacuum. There is obtained paracyclohexylphenylacetonitrile boiling at 131°-132°C under a pressure of 0.35 mm of Hg and melting at 48°-49°C.
Reaction SMILES: Br[C:2]1[O:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC>>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:2]1[O:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)o1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2ccccn2)o1

Procedure:
The title compound was prepared by a method analogous to that described in Example 14 from (R)-3′-(5-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-(tri-n-butylstannyl)pyridine. The title compound (356 mg) was obtained as an off-white solid, m/z 326 (MH+).
Reaction SMILES: C[O:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1>Cl>[O:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH2:4]1
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Agent: Cl
Product: O=C1Cc2ccccc2Nc2ccccc21

Procedure:
22.3 g of 10-methoxy-5H-dibenz(b,f)azepine are heated under reflux with 100 ml of 2N hydrochloric acid for 2 hours. The gummy residue is extracted with chloroform (50÷50 ml), the combined extracts are washed with water and evaporated to dryness under vacuum. The residue is taken up into 200 ml of ethanol, treated with charcoal (2 g) for 1 h under reflux, filtered, evaporated to dryness under vacuum, finally taken up into 50÷50 ml of toluene, stripping thoroughly. The residue is kept for further working-up.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.C[O-].[Na+]>C(O)(C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Cl-].[Ru+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(C)=O)c1
Agent: [Ru+2]
Agent: C[O-]
Agent: [Cl-]
Solvent: CC(C)O
Product: COc1cccc(C(C)O)c1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
Tris(triphenylphosphine)ruthenium(II) chloride (3.8 mg, 4 μmol, 1 mol %) and a chiral ligand (M=Ru, R=t-Bu, Ar=C6H5—, 2.6 μmol, 0.65 mol %) were dissolved in i-propanol (3 mL) under nitrogen atmosphere, and then heated and stirred for 0.5 h at 85° C. After the mixture was cooled to room temperature, m-methoxyacetophenone (0.4 mmol), i-propanol (2 mL) and a solution of sodium methoxide in i-propanol (0.4 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 6 h under H2 (5 atm) at 40° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent:ethyl acetate/petroleum ether=1/5). Accordingly, pure m-methoxyphenylethanol was obtained and the ee value (ee=99.2%) was measured by GC analysis.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C@@:8]([S:36]([CH3:39])(=[O:38])=[O:37])([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1)[C:9]([NH:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)=[O:10].Br[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>COCCOC.CO.C(OCC)(=O)C>[C:24]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][C@@:8]([CH3:7])([S:36]([CH3:39])(=[O:38])=[O:37])[C:9]([NH:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[O:10])=[CH:26][CH:25]=1
Reactant: CC1(C)OB(c2ccc(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)cc2)OC1(C)C
Reactant: Brc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CO
Product: C[C@@](CCc1ccc(-c2ccccc2)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Trisdibenzylidine dipalladium (0.19 g, 0.21 mmol) was added to a mixture of potassium carbonate (1.45 g, 10.5 mmol, 5.0 equiv), (2R)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanamide, which may be prepared as in Preparation 8C (1.0 g, 2.1 mmol) and bromobenzene (0.26 mL, 2.5 mmol) in 1,2-dimethoxyethane-methanol (8.0 mL, 1:1). The reaction was heated to 80° C. and allowed to stir overnight. The reaction was diluted with ethyl acetate (60 mL), filtered through a pad of Celite, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (heptane/ethyl acetate system) to provide the title compound as a tan gum-like material (72 mg, 8%). MS (LCMS) m/z 430.8 (M−1).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[C:8]([F:16])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24].N1C=CC=CC=1>ClCCl>[CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12]([NH:17][C:18]3[CH:22]=[CH:21][S:20][C:19]=3[C:23]([O:25][CH3:26])=[O:24])(=[O:14])=[O:13])=[C:8]([F:16])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc(C2CCCC2)cc1F
Reactant: COC(=O)c1sccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C2CCCC2)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-cyclopentyl-2-fluorobenzene-1-sulfonyl chloride, 134 (0.06 g; 0.21 mmol) in dichloromethane (1 mL) at room temperature, methyl 3-aminothiophene-2-carboxylate (0.033 g; 0.21 mmol) was added followed by pyridine (0.033 g; 0.42 mmol) and then stirred at room temperature under a nitrogen atmosphere for 24 hours. The reaction mixture was concentrated under reduced pressure and then taken up in ethyl acetate (10 mL) and washed with water. The aqueous layer was separated and extracted with ethyl acetate (2×10 mL). The combined organic phases were successively washed with water and aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 40% v/v over 900 mL gradient elution) to give the title product as an off-white solid (34 mg).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11]([O:18][C:19]([NH:21][C:22]1([C:25]2[C:26]([F:44])=[C:27](F)[C:28]3[C:38](=[O:39])[C:37]([C:40]([OH:42])=[O:41])=[CH:36][N:30]4[CH:31]([CH3:35])[CH2:32][O:33][C:34]=2[C:29]=34)[CH2:24][CH2:23]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH2:1]([O:8][C:27]1[C:28]2[C:38](=[O:39])[C:37]([C:40]([OH:42])=[O:41])=[CH:36][N:30]3[CH:31]([CH3:35])[CH2:32][O:33][C:34]([C:29]=23)=[C:25]([C:22]2([NH:21][C:19]([O:18][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:20])[CH2:23][CH2:24]2)[C:26]=1[F:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CC1COc2c(C3(NC(=O)OCc4ccccc4)CC3)c(F)c(F)c3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1COc2c(C3(NC(=O)OCc4ccccc4)CC3)c(F)c(OCc3ccccc3)c3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
In 2 ml of N,N-dimethylformamide was dissolved 230 mg of benzyl alcohol. To the resulting solution was added 85 mg of 60% sodium hydride with ice-cooling. The resulting mixture was stirred at room temperature for 30 minutes. Thereto was added, with ice-cooling, 250 mg of 10-(1-benzyloxycarbonylaminocyclopropyl)-8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid. The resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was added to a mixture of 15 ml of ethyl acetate and 15 ml of water. The resulting mixture was adjusted to pH 1 with 2N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: chloroform/ethanol=10/1) to obtain 73.0 mg (yield: 24.6%) of 8-benzyloxy-10-(1-benzyloxycarbonylaminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[C:10](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O.[Cl-].[Na+].O>[CH3:10][O:8][C:7]([CH:2]1[CH2:3][O:4][CH2:5][CH2:6][O:1]1)=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C1COCCO1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1COCCO1
Temperature: 5 °C
Yield: 95.2 %

Procedure:
A solution of [1,4]dioxane-2-carboxylic acid (supplied by Enamine Ltd.), (2.90 g, 22.0 mmol) in N,N-dimethylformamide (15 mL) was stirred at room temperature. Potassium carbonate (6.07 g, 44.0 mmol) was added and the suspension was stirred at 5° C. Iodomethane (6.25 g, 2.75 mL, 44.0 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 24 h. Water and brine were added and the mixture was extracted with diethyl ether. The aqueous layer was saturated with sodium chloride and the mixture was extracted with ethyl acetate (3×). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 4:1 to 1:1 to afford the title compound (3.06 g, 95%) as a volatile, pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 3.68-3.78 (m, 4H), 3.81 (s, 3H), 3.97-4.05 (m, 2H), 4.29 (dd, J=8.5, 3.1 Hz, 1H). LCMS (m/z) 169.2 [M+Na], Tr=0.69 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:22]([CH3:30])[CH2:23][CH:24]([CH3:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([O:20]C)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[Li+].[OH-]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:22]([CH3:30])[CH2:23][CH:24]([CH3:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 115 %

Procedure:
(2S,4R)-methyl 1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (10.8 g, 25.3 mmol) was dissolved in THF (50 mL), MeOH (50 mL) and to this solution was added LiOH (2.425 g, 101 mmol) in Water (50.0 mL). The reaction mixture was stirred at rt for 16 h. The solvent was removed under vacuum and the resulting aqueous residue was diluted with water, and EtOAc. The mixture was neutralised with 1 N HCl and adjusted the pH ˜2.5 and the mixture was extracted with EtOAc. The organic layer was collected, washed with brine, dried over Na2SO4, and concentrated to give (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (12 g, 29.1 mmol, 115% yield) as yellow viscous oil. MS: MS m/z 413.2 (M++1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH2:15][CH2:16][OH:17])[C@H:8]1[CH2:13][CH2:12][C@H:11]([CH3:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br.[H-].[Na+].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:18])[N:7]([CH2:15][CH2:16][O:17][CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=1[Cl:19])[CH:8]1[CH2:9][CH2:10][CH:11]([CH3:14])[CH2:12][CH2:13]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CCO)[C@H]1CC[C@H](C)CC1
Reactant: Clc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCC(N(CCOCc2ccccc2Cl)C(=O)OC(C)(C)C)CC1
Reaction time: 16 h

Procedure:
To a mixture of (2-hydroxy-ethyl)-(trans-4-methyl-cyclohexyl)-carbamic acid tert-butyl ester (0.75 g, 2.91 mmol) and 2-chlorobenzylbromide (0.90, 4.37 mmol) in DMF (8 mL) was added NaH (60% in mineral oil, 0.23 g, 5.83 mmol) and the reaction mixture was stirred for 16 h. H2O (4 mL) was added and the mixture was extracted with diethyl ether (3×5 mL). The organic phase was collected and the solvent was removed in vacuo to give the crude product of [2-(2-chloro-benzyloxy)-ethyl]-(4-methyl-cyclohexyl)-carbamic acid tert-butyl ester. This was dissolved in DCM (4 mL) and TFA (4 mL) was added and the mixture was stirred for 2 hs before the volatiles were removed in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([NH:20]C(OCC1C=CC=CC=1)=O)[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:11]=1.C[Si](I)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:31])[CH:4]([NH2:20])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)C(Cc1ccc(OCc2ccccc2)nc1)NC(=O)OCc1ccccc1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(N)Cc1ccc(OCc2ccccc2)nc1
Reaction time: 1 h

Procedure:
To a stirred solution of 2-benzyloxycarbonylamino-3-(6-benzyloxy-pyridin-3-yl)-propionic acid methyl ester (130 mg, 0.31 mmol) in methylene chloride (5 mL, 0° C.) was added trimethylsilyl iodide (44 μL, 1.0 equiv). The ice bath was removed and stirring continued for 1 h. Reaction was poured into saturated sodium bicarbonate, extracted with ethyl acetate (3×), washed with brine, dried over magnesium sulfate, and concentrated to give 81 mg (91%) which was used without purification. Mass spec.: 287.37 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([CH:19]([F:21])[F:20])[CH:15]=[CH:16][CH:17]=3)[C:12]([N:22]([S:32]([C:35]3[S:36][C:37]([Cl:40])=[CH:38][CH:39]=3)(=[O:34])=[O:33])[S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:48](OC(=O)C)(=[O:50])[CH3:49]>ClCCl>[Cl:31][C:28]1[S:27][C:26]([S:23]([N:22]([S:32]([C:35]2[S:36][C:37]([Cl:40])=[CH:38][CH:39]=2)(=[O:33])=[O:34])[C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][C:14]=3[CH:19]([F:20])[F:21])[N:10]([CH2:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:48](=[O:50])[CH3:49])[CH:8]=[CH:7][CH:6]=3)[N:11]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: NCc1cccc(Cn2nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c3c(C(F)F)cccc32)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1cccc(Cn2nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c3c(C(F)F)cccc32)c1
Reaction time: 1 h

Procedure:
N-[1-{[3-(Aminomethyl)phenyl]methyl}-4-(difluoromethyl)-1H-indazol-3-yl]-5-chloro-N-[(5-chloro-2-thienyl)sulfonyl]-2-thiophenesulfonamide (for a preparation see Intermediate 70) (26 mg, 0.039 mmol) was suspended in dichloromethane (0.5 mL) and triethylamine (0.055 mL, 0.39 mmol) and then acetic anhydride (0.004 mL, 0.043 mmol) was added to the suspension. The mixture was stirred for 1 h, and concentrated under a stream of nitrogen to give N-[(3-{[3-{Bis[(5-chloro-2-thienyl)sulfonyl]amino}-4-(difluoromethyl)-1H-indazol-1-yl]methyl}phenyl)methyl]acetamide, which was used without further purification. The residue was dissolved in methanol (2 mL) and treated with NaOH (0.553 mL, 1.105 mmol) and the reaction mixture was stirred at 60° C. for 3 h. LCMS showed the reaction had gone to completion so the mixture was concentrated in vacuo and acidified with 5% citric acid. The solution was extracted with ethyl acetate and the organic layer was washed twice with water (25 mL) and once with brine (25 mL). The organic layer was dried over anhydrous magnesium sulfate before being evaporated in vacuo to give a yellow residue which was dissolved in 1:1 MeOH-DMSO (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier (Method A). The solvent was evaporated in vacuo to give the title compound (7 mg, 36%). LCMS (System A) RT=1.02 min, ES+ve m/z 525/527 (M+H)+.
Reaction SMILES: Cl[C:2]([C:9]1[C:10]([O:25][CH2:26][CH3:27])=[CH:11][C:12]([C:15]2[C:20]([CH2:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:23][CH3:24])=[N:13][CH:14]=1)([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>O>[CH2:23]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH2:21][CH3:22])[C:15]=1[C:12]1[N:13]=[CH:14][C:9]([C:2]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5])=[C:10]([O:25][CH2:26][CH3:27])[CH:11]=1)[CH3:24]
Reactant: C1COCCN1
Reactant: CCCC(Cl)(CCC)c1cnc(-c2c(CC)cccc2CC)cc1OCC
Solvent: O
Product: CCCC(CCC)(c1cnc(-c2c(CC)cccc2CC)cc1OCC)N1CCOCC1
Temperature: 80 °C

Procedure:
A mixture of 5-(1-chloro-1-propyl-butyl)-2-(2,6-diethyl-phenyl)-4-ethoxy-pyridine (prepared using a synthetic method similar to that given in Example 10) (20 mg, 0.052 mmol) and morpholine (0.5 mL) is heated to 80° C. for 2 hours. Water (1 mL) is added and the aqueous solution is extracted with ethyl acetate (2×2 mL). The combined organic layers are dried and concentrated in vacuo. The crude product is purified with PTLC (hexanes/ethyl acetate 4:1) to give 4-{1-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-1-propyl-butyl}-morpholine. 1H NMR: (CDCl3) 8.66 (s, 1H), 7.26 (m, 1H), 7.12 (d, 2H), 6.71 (S, 1H), 4.02 (q, 2H), 3.70 (m, 4H), 2.64 (m, 4H), 2.34 (m, 4H), 1.88 (m, 4H), 1.43 (t, 3H), 1.07 (m, 4H), 1.02 (t, 6H), 0.84 (t, 6H).