Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:9][CH:10]([CH2:19][CH3:20])[CH2:11][CH2:12][CH2:13][C:14](OCC)=[O:15])[CH3:8]>O1CCCC1>[CH2:7]([O:9][CH:10]([CH2:19][CH3:20])[CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH3:8]
Reactant: CCOC(=O)CCCC(CC)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(CC)CCCCO
Temperature: 25 °C

Procedure:
A solution of tetrhydrofuran (2000 ml) and lithium aluminum hydride (46 g, 1.21 moles) is cooled in a -60° C. dry ice/ethanol bath. The starting material prepared in Example 36, ethyl 5-ethoxyheptanoate (302 g, 1.49 moles) is diluted in tetrahydrofuran (300 ml) and added dropwise to the stirring reaction. After the addition is complete the reaction is warmed to room temperature and stirred for an additional hour. The solution is cooled in a -78° C. dry ice/ethanol bath and the excess hydride is destroyed by adding dropwise the following: water (46 ml), 15% sodium hydroxide solution (46 ml), and water (136 ml). The reaction is filtered and the solids washed several times with tetrahydrofuran (3×500 ml). The volume of the filtrate is reduced under vacuum and the residue dried over anhydrous magnesium sulfate. The remaining solvent is then removed leaving a clear, colorless oil suitably pure for the next reaction (238 g, 1.49 moles).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C[CH2:45][N:46](C(C)C)[CH:47](C)C.CNC>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][N:46]([CH3:47])[CH3:45])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCl)c3)c3ccccc23)cc1
Agent: CNC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CN(C)C)c3)c3ccccc23)cc1
Temperature: 40 °C
Reaction time: 12 h
Yield: 37.1 %

Procedure:
To a solution of N-(4-((4-(3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) (50 mg, 0.08 mmol) in DCM (1.0 mL), DMF (0.1 mL) and DIPEA (17 μl, 0.1 mmol) was added dimethylamine (2.0M solution in THF) (41 μl, 0.08 mmol). The reaction mixture was heated to 40° C. and stirred for 12 hr. The crude reaction mixture was purified by column chromatography (12 g silica, 0-10% MeOH in DCM, gradient elution). Product fractions were concentrated in vacuo and the residue triturated with a mixture of diethyl ether, DCM and iso-hexane (2:1:2, 5.0 mL) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(dimethylamino)acetamide (Example 12) as an orange solid (18 mg, 35%): m/z 607 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9 H, s), 2.31 (6 H, s), 2.39 (3 H, s), 3.14 (2 H, s), 5.39 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.29 (1H, d), 7.35 (2H, d), 7.44 (2H, d), 7.65-7.55 (3H, m), 7.94 (1H, m), 8.38-8.28 (3H, m), 8.59 (1H, s), 8.79 (1H, s), 9.93 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[C:8]3[CH:18]=[C:17](/C=C\C4C=CC=CC=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.Cl[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38]O)=O)[CH:31]=1.Cl[CH2:41]Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[C:8]3[CH:18]=[C:17]([C:36]4([C:32]5[CH:31]=[CH:30][CH:35]=[CH:34][CH:33]=5)[CH2:41][O:38]4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCN1c2ncc(/C=C\c3ccccc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: ClCCl
Product: CCN1c2ncc(C3(c4ccccc4)CO3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 21 %

Procedure:
2-Chloro-5,11-dihydro-11-ethyl-5-methyl-8-(cis-2-phenylethen-1-yl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (prepared by procedures analogous to those described in Example 43) (51 mg, 0.13 mmol) was dissolved in 3 mL of dichloromethane and treated with m-chloroperbenzoic acid (50%, 45 mg, 0.13 mmol) at room temperature. Solid Ca(OH)2 was added, and the reaction mixture was filtered and concentrated. Purification by flash chromatography (elution with ethyl acetate-hexanes) and recrystallization (diethyl ether-hexanes) afforded the title compound (11 mg, 21%), m.p. 105°-107° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][C:16]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].Cl[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>CN(C)C=O.C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:29][C:30](=[O:31])[N:32]([CH3:34])[CH3:33])[C:8]2[C:13]([C:14]=1[CH2:15][C:16]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CN(C)C(=O)CCl
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Cc1cccc2ccccc12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cc2cccc3ccccc23)c2ccccc2n1CC(=O)N(C)C
Reaction time: 1 h

Procedure:
To as solution of 3-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (46 mg, from Example 64.2.) in dimethylformamide (1 ml) was added 8 mg of NaH (55% in oil) and stirring was continued at 22° C. for 1 h. The mixture was treated with a solution of 2-chloro-N,N-dimethylacetamide (18 mg) in dimethylformamide (0.5 ml) and stirring was continued for 16 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with ethylacetate. The organic layer was washed with brine, dried, evaporated and the residue chromatographed on silica (n-heptane/AcOEt, 3:2) to give 1-dimethylcarbamoylmethyl-3-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester as a colorless solid, MS: 415.4 ([M+H]+), which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a colorless solid. MS: 385.4 ([M−H]−).
Reaction SMILES: [C:1]1([CH:7]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:8][C:9]([CH:11]([N:15]2[CH:18]([S:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[CH:17]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:16]2=[O:42])[C:12]([CH3:14])=[CH2:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:49]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClCCCl>[C:43]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][C:9]([CH:11]([N:15]2[CH:18]([S:19][N:20]3[C:21](=[O:30])[C:22]4=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]4[C:24]3=[O:25])[CH:17]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:16]2=[O:42])[C:12]([CH2:14][Br:49])=[CH2:13])=[O:10])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: C=C(CBr)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 10 %

Procedure:
A mixture of 5.6 g (8 mmoles) of 1-(1-diphenylmethoxycarbonyl-2-methylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one, 2.8 g (16 mmoles) of N-bromosuccinimide, 150 mg of benzoyl peroxide and 350 ml of 1,2 -dichloroethane was heated in the dark under nitrogen at 80° C for 2.5 hours. After washing with water, drying and concentrating of the reaction mixture, n-hexane was added to the residue to obtain 3 g of crude material which was chromatographed with silica gel [toluene-ethyl acetate 7:1 (v/v)] to obtain 630 mg (0.8 mmole) of 1-(1-diphenylmethoxycarbonyl-2-bromomethylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([O-])(O)=O.C([O-])([O-])=O.[Na+].[Na+]>[N+]([O-])(O)=O>[C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1c[nH]c(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: O=Cc1c[nH]c(-c2ccccc2)n1
Temperature: 0 °C

Procedure:
A 17.4 gm. portion of 2-phenyl-4-imidazolemethanol and 13.4 ml. of concentrated HNO3 are heated on a steam bath for 21/2 hours. Three drops of fuming HNO3 are added to star the reaction. The pH is adjusted to 8 with concentrated aqueous Na2CO3 and the mixture is cooled to 0° C. overnight. The solid is recovered, washed with water and recrystallized from a mixture of 70 ml. of ethyl acetate and 20 ml. of petroleum ether giving a yellow solid. Treatment of the mother liquor with petroleum ether gives an additional tacky substance which is triturated with 2-propanol giving a second solid. These two solids are taken up in hot 2-propanol and recrystallized as a yellow solid. This solid is recrystallized from ethanol:water (1:1) giving yellow crystals, m.p. 169°-171.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=O)[NH:8][C:7]2=O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:18])=O.C(N(C(C)C)C=O)(C)C.[CH2:30]([NH2:42])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>O>[Cl:18][C:9]1[N:8]=[C:7]([NH:42][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1
Reactant: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CCCCCCCCCCCCN
Reactant: O=P(Cl)(Cl)Cl
Agent: CC(C)N(C=O)C(C)C
Solvent: O
Product: CCCCCCCCCCCCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
To 250 mg (1.21 mmol) of 6-nitroquinazoline-2,4(1H,3H)-dione were added 5.00 ml (53.64 mmol) of phosphorus oxychloride and 0.18 ml (1.21 mmol) of diisopropylformamide, and the resulting mixture was subjected to heating under reflux for 24 hours. After phosphorus oxychloride was removed in vacuo, the mixture was dissolved in 5 ml of acetonitrile, followed by addition of 2.80 ml (12.10 mmol) of dodecylamine under ice cooling and stirring under ice cooling for 30 minutes. To the reaction solution was added water, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 310 mg (67.0%) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8]1(/[CH:14]=[CH:15]/[S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:20][C:21]1[CH:33]=[C:32]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(=O)([O-])O.[Na+]>C(Cl)Cl>[O:34]([C:32]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[C:21]([NH:20][S:16](/[CH:15]=[CH:14]/[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:18])=[O:17])[CH:33]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NS(=O)(=O)/C=C/c1ccccc1
Reaction time: 1 h

Procedure:
0.056 mL of triethylamine and 61 mg of ((E)-2-phenylvinyl)sulfonyl chloride were added to 5.0 mL of methylene chloride solution containing 57 mg of tert-butyl 2-amino-4-phenoxybenzoate at room, temperature sequentially and stirred at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 4-phenoxy-2-(((E)-2-phenylvinyl)sulfonamido)benzoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.[Br:16]N1C(=O)CCC1=O.S(=O)(=O)(O)O>>[Br:16][C:7]1[CH:6]=[CH:5][C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1cccc(OCc2ccccc2)c1
Agent: O=S(=O)(O)O
Product: Fc1cc(OCc2ccccc2)ccc1Br

Procedure:
In analogy to the procedure described in example 8 b], 1-fluoro-3-(phenylmethoxy)-benzene (for the preparation of 1-fluoro-3-(phenylmethoxy)-benzene see: A. A. Durrani, J. H. P. Tyman, J. Chem. Soc., Perkin Trans. 1 1979, 8, 2079-2087) was treated with N-bromosuccinimide in the presence of concentrated sulfuric acid to give 1-bromo-2-fluoro-4-(phenylmethoxy)-benzene as colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[C:6]2[N:17]=[C:16]([C:18]3[CH:32]=[C:31]([CH3:33])[C:21]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:20]([CH3:34])[CH:19]=3)[O:15][C:7]=2[N:8]=[C:9](S(C)(=O)=O)[N:10]=1)[CH:2]([CH3:4])[CH3:3].[Cl:35][C:36]1[CH:37]=[C:38]([OH:42])[CH:39]=[CH:40][CH:41]=1>>[Cl:35][C:36]1[CH:37]=[C:38]([CH:39]=[CH:40][CH:41]=1)[O:42][C:9]1[N:10]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]2[N:17]=[C:16]([C:18]3[CH:32]=[C:31]([CH3:33])[C:21]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:20]([CH3:34])[CH:19]=3)[O:15][C:7]=2[N:8]=1
Reactant: Cc1cc(-c2nc3c(CC(C)C)nc(S(C)(=O)=O)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Reactant: Oc1cccc(Cl)c1
Product: Cc1cc(-c2nc3c(CC(C)C)nc(Oc4cccc(Cl)c4)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Yield: 100 %

Procedure:
Analogously to example 1 (i), the reaction of 60 mg of tert-butyl [4-(7-isobutyl-5-methanesulfonyloxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenoxy]acetate with 3-chlorophenol gave 65 mg (100%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][NH:18][CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22].CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][N:18]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CNCC4C3)nc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CN(S(C)(=O)=O)CC4C3)nc21
Reaction time: 0.08 h

Procedure:
1-(2,2-Dimethylpropyl)-5-(1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (84, 100 mg, 0.30 mmol, 1.0 equiv), and DIPEA (0.16 mL, 0.91 mmol, 3.0 equiv) were added to anhydrous methylene chloride (3 mL). Stirred for 5 min and methanesulfonyl chloride (26.3 μL, 0.33 mmol, 1.1 equiv) was added. After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 10-1 as a pale yellow oil. MS m/z (M+H): calculated=405.1957; observed=405.1969.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]1([C:28]2[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][C:29]=2[OH:38])[CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:38][C:29]3[CH:30]=[CH:31][CH:32]=[C:33]([C:34]([F:35])([F:36])[F:37])[C:28]=3[CH:25]3[CH2:26][CH2:27]3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: Oc1cccc(C(F)(F)F)c1C1CC1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1coc(Oc2cccc(C(F)(F)F)c2C2CC2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 57.8 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 2-cyclopropyl-3-trifluoromethyl-phenol (53 mg, 0.26 mmol) to give the title compound (41 mg, 58%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: I(Cl)(=O)=O.[I:5](Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.[CH2:20]1[CH2:24][N:23](C(OC(C)(C)C)=O)[CH:22]2[CH2:32][O:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:39]=3[CH:21]12.C(Cl)Cl.O>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[I:5][C:37]1[CH:36]=[CH:35][C:34]2[O:33][CH2:32][CH:22]3[CH:21]([C:39]=2[CH:38]=1)[CH2:20][CH:24]=[N:23]3
Reactant: O=I(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccccc3OCC21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: Ic1ccc2c(c1)C1CC=NC1CO2
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Zinc chloride (2.49 g, 18.3 mmol) and benzyltrimethylammonium dichloroiodate (4.25 g, 12.2 mmol) were added to a suspension of tert-butyl 1,3a,4,9b-tetrahydrochromeno[3,4-b]pyrrole-3(2H)-carboxylate (2.8 g, 10.2 mmol) in acetic acid (30 mL). The reaction mixture was stirred at 50° C. for 16 h, cooled to r.t. and DCM (60 mL) was added followed by H2O (60 mL). The layers were separated. The organic layer was washed with H2O (2×) and saturated NaHSO3 (15 mL), and the solvent was evaporated to afford 8-iodo-1,3a,4,9b-tetrahydrochromeno[3,4-b]pyrrole, which was taken directly in the next step.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[CH:12]2.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C>C1COCC1>[B:21]([OH:22])([OH:20])[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[CH:12]2
Reactant: Brc1cccc2cnccc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc2cnccc12
Temperature: 25 °C
Yield: 57.8 %

Procedure:
A 2.5 M solution of n-BuLi (1.2 equiv., 3 mmol, 1.2 ml) in 20 ml of freshly distilled THF, cooled to −78° C., was added with a solution of 5-bromoisoquinoline (2.5 mmol, 520 mg) in 5 ml of THF. The resulting mixture was allowed to react at this temperature over 45′. A solution of triisopropylborate (1.2 equiv., 3 mmol, 0.7 ml) was then added and the mixture was stirred at the same temperature for 5′ and then allowed to warm to room temperature and stirred for an additional hour. The mixture was quenched by slow addition of a 5% NaOH solution (30 ml). The aqueous layer was separated and acidified to pH 5/6 by addition of 10% HCl at O° C. Extraction with ethyl acetate, evaporation of the organic phase and crystallisation from diethyl ether gave 250 mg of a white solid. Yield=58%. 1H NMR (d6-DMSO, 200 MHz) δ 7.66 (1H, t, J=7.2 Hz), 8.07 (1H, d, J=5.8 Hz), 8.13 (1H, d, J=8.0 Hz), 8.34 (1H, d), 8.47 (1H, d), 8.50 (2H, bs), 9.29 (1H, s); [M+1] 174.1 (C9H8BNO2 requires 172.98)
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([CH3:6])[CH3:5].C(N(CC)CC)C.Cl.[F:15][C:16]([F:50])([F:49])[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[N:20]=[C:19]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=3)[CH:34]=2)[N:18]=1>C1COCC1>[CH2:3]([N:2]([CH3:1])[S:45]([C:41]1[CH:42]=[CH:43][CH:44]=[C:39]([C:35]2[CH:34]=[C:33]([C:19]3[N:18]=[C:17]([C:16]([F:15])([F:49])[F:50])[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=4)[N:20]=3)[CH:38]=[CH:37][N:36]=2)[CH:40]=1)(=[O:46])=[O:47])[CH:4]([CH3:6])[CH3:5]
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Reactant: CNCC(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CN(C)S(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 75.7 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of N-methylisobutylamine (0.26 g, 3.0 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.45 g, 80%). MS (ISP) 594.7 [(M+H)+]; mp 144° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([P:25]([O:31]C(C)C)([O:27]C(C)C)=[O:26])=[O:24])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](Br)(C)C.CO>C(Cl)(Cl)Cl.CC#N>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([P:25]([OH:31])([OH:27])=[O:26])=[O:24])(=[O:15])=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OP(=O)(OC(C)C)C(=O)NCCCCNS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCCCCNS(=O)(=O)c1ccc(Oc2ccccc2)cc1)P(=O)(O)O
Temperature: 50 °C
Yield: 95.1 %

Procedure:
To 1-[4-phenoxybenzenesulfonamido]-4-[diisopropylphosphonoformamido] butane (0.14 g, 0.27 mmol) in 5 ml CHCl3 was added TMSBr (5 eq, 1.9 ml, 14 mmol) and reaction was stirred and heated at 50° C. for 3 h. The reaction mixture was followed by 31P NMR. To the mixture reaction was added 5 ml MeOH for 1 h and the solvent was evaporated to give yellow oil, which solidified in MeCN to give 0.11 g (96%) white solid, m.p.=143-145° C. m/z [M+H]+ calcd/found 429/429.4.
Reaction SMILES: [NH2:1][C:2]1[C:11](I)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1.[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15].CCN(CC)CC>C1COCC1.[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>[NH2:1][C:2]1[C:11]([C:15]#[C:14][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1
Reactant: COC(=O)c1cc(I)c(N)cc1Cl
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(C#C[Si](C)(C)C)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of compound 70n (0.642 mmol, 200 mg), CuI (0.064 mmol, 12.2 mg) and Pd(PPh3)2Cl2 (0.064 mmol, 45 mg) in THF (2 mL) was added ethynyltrimethylsilane (0.963 mmol, 95 mg) followed by Et3N (7.19 mmol, 1 mL) under N2. The reaction mixture was stirred at room temperature for 1.5 h and then partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 70p.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[N:4][C:5]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([C:16](=O)[CH3:17])=[C:11]([CH3:19])[CH:10]=2)=[N:6][CH:7]=1.CC(O)=O.[NH2:31][O:32][CH2:33][CH2:34][OH:35]>CO>[OH:35][CH2:34][CH2:33][O:32][N:31]=[C:16]([C:12]1[CH:13]=[C:14]([CH3:15])[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:10][C:11]=1[CH3:19])[CH3:17]
Reactant: NOCCO
Reactant: CC(=O)c1cc(C)c(Nc2ncc(Cl)c(Nc3cc(C)[nH]n3)n2)cc1C
Solvent: CO
Solvent: CC(=O)O
Product: CC(=NOCCO)c1cc(C)c(Nc2ncc(Cl)c(Nc3cc(C)[nH]n3)n2)cc1C
Temperature: 60 °C

Procedure:
To a solution of 1-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)ethanone (60 mg, 0.16 mmol) in MeOH (1 mL) was added AcOH (15 mg, 0.25 mmol), followed by the addition of 2-(aminooxy)ethanol (20 mg, 0.26 mmol). The mixture was heated to 60° C. for 14 h and cooled down to room temperature. The mixture was then purified directly by preparative RP-HPLC to provide 1-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)ethanone O-2-hydroxyethyl oxime; ESMS m/z 430.2 (M+H+).