Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:13]([O:21][CH3:22])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[H-].[Na+].I[CH3:26]>C1COCC1>[CH:16]1([O:15][C:14]2[C:5]([N:4]([CH3:26])[C:1](=[O:3])[CH3:2])=[C:6]([CH:11]=[CH:12][C:13]=2[O:21][CH3:22])[C:7]([O:9][CH3:10])=[O:8])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CI
Reactant: COC(=O)c1ccc(OC)c(OC2CCCC2)c1NC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC)c(OC2CCCC2)c1N(C)C(C)=O
Temperature: 25 °C

Procedure:
A solution of methyl 2-acetamido-3-(cyclopentyloxy)-4-methoxybenzoate (1.6 g, 5.2 mmol, Example 1, Step 4) and anhydrous THF (30 mL) was added over 5 min to a mixture of sodium hydride (230 mg, 5.75 mmol) and anhydrous THF (10 mL) at 0° C. under N2. The reaction was allowed to warm to rt and after 20 min, cooled back to 0° C. A solution of iodomethane (1.06 g, 0.0075 mol) and anhydrous THF (10 mL) was added over 3 min. The reaction was allowed to warm to rt and after 30 min, concentrated. The residue was diluted with ethyl acetate (40 mL) and washed with brine (10 mL×2). The organic layer was dried, filtered, and concentrated to give methyl 3-(cyclopentyloxy)-4-methoxy-2-(N-methylacetamido)benzoate: MS (ESI): 322.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:13][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:11]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Br)ccc1F
Yield: 91.9 %

Procedure:
Heat a solution of 5-bromo-2-fluorobenzoic acid (20 g, 92 mmol) and p-toluenesulfonic acid monohydrate (52 g, 275 mmol) in methanol (200 mL) at reflux overnight. Concentrate and dissolve the residue in ethyl acetate, wash twice with an aqueous saturated solution of sodium bicarbonate, once with an aqueous saturated solution of sodium chloride, dry (sodium sulfate), filter and concentrate to give the title compound as a clear liquid (19.7 g, 92%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:21][NH:22][O:23][CH3:24].C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:24][O:23][N:22]([CH3:21])[C:17]([C:15]1[S:14][C:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C:10]=2[CH:16]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C(=O)O)cc2C1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid (968 mg, 3.42 mmol) and N,O-dimethylhydroxylamine hydrochloride (333 mg, 3.42 mmol) were dissolved in MC (50 ml) and the solution was cooled to 0° C. HOAt (46.5 mg, 0.34 mmol), diisopropylethylamine (0.66 ml, 3.76 mmol) and EDCI (720 mg, 3.76 mmol) were added to this mixture and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride (50 ml) and washed with 0.5 M KHSO4 solution (100 ml), NaHCO3 solution and NaCl solution. The combined organic phases were dried with Na2SO4, filtered and concentrated in vacuo. The product obtained in this way (1.13 g) was employed in the next stage without further purification.
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([S:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:30]=2)=[O:27])[C:9]1=[O:42])=[O:6])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:51])C=1>C(Cl)Cl>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([S:35]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:51])[CH:30]=2)=[O:27])[C:9]1=[O:42])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CSc1cccc(NC(=O)NC2CN(c3ccccc3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Solvent: ClCCl
Product: CCOC(=O)CS(=O)c1cccc(NC(=O)NC2CN(c3ccccc3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
1-(1-tert-Butylcarbonylmethyl-2-oxo-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-ethoxycarbonylmethylthiophenyl)urea (460 mg) obtained from Step 2 of Example 33 was dissolved in methylene chloride (20 ml), m-chloroperbenzoic acid (170mg) was added under ice-cooling, stirred for 30 minutes. The reaction mixture was washed subsequently with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodiun sulfate, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2), to thereby obtain 320 mg of the title compound (Yield: 68%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][C:7]=1[CH2:18]Br)=[O:5])[CH3:2].[CH2:20]([O:22][C:23](=[O:37])[CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[O:35][CH3:36])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][C:7]=1[CH2:18][N:25]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[O:35][CH3:36])[CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:37])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Reactant: CCOC(=O)c1sc(Oc2ccccc2)nc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Oc2ccccc2)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.1 %

Procedure:
A mixture of 4-bromomethyl-2-phenoxy-thiazole-5-carboxylic acid ethyl ester (1.71 g, 5.01 mmol), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (1.33 g, 5.24 mmol) and potassium carbonate (1.04 g, 7.52 mmol) in anhydrous dimethylformamide (15 mL) was stirred at room temperature for 17 h before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (1.60 g): MS: (+) m/z 514.93 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]#[N:10])[CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:19]1COCC1>>[CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[O:8][N:7]=[C:6]([CH:9]([NH2:10])[CH3:19])[CH:5]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)Cc1cc(C#N)no1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(N)c1cc(CC(C)(C)C)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
The solution of 5-(2,2-dimethyl-propyl)-isoxazole-3-carbonitrile ([943925-83-5] 16 g, 97.5 mmol) in THF (160 ml) was cooled in an ice bath and under an atmosphere of nitrogen methylmagnesium chloride (3 M solution in THF, 51 ml, 127 mmol) was added slowly so that the reaction temperature did not rise above 10° C. The reaction was stirred for 1 h at rt. LiAlH4 (1 M solution in THF, 110 ml, 110 mmol) was added over 10 min keeping the reaction temperature below 40° C. The reaction was heated at reflux temperature for a few minutes and then stirred at rt for 1 h. The reaction was quenched be the slow addition of water (5 ml) keeping the temperature below 50° C., then cooled with an ice bath and aqueous NaOH (4 M, 5 ml) was added. The reaction mixture was diluted with diethylether (200 ml) and extracted with 1 N aqueous hydrochloric acid. The aqueous layers were combined, basified with concentrated aqueous ammonia and extracted with diethylether. The organic layers were dried over sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound as yellow oil (13.8 g, 77%). [1H-NMR (DMSO-d6, 600 MHz) δ 6.21 (s, 1H), 3.95 (q, 1H), 2.49-2.47 (m, 2H), 1.89 (br s, 2H), 1.25 (d, 3H), 0.90 (s, 9H]
Reaction SMILES: O.NN.[CH3:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:6]1>[Pd].C(O)C>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][C:8]2[C:7]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:6][N:5]([CH3:4])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:22][CH:21]=1
Reactant: Cn1nc(-c2ccccc2)c(Oc2ccc([N+](=O)[O-])cc2)c1-c1ccccc1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cn1nc(-c2ccccc2)c(Oc2ccc(N)cc2)c1-c1ccccc1
Yield: 101.9 %

Procedure:
Hydrazine hydrate (3 ml, 60% solution) is added to a well stirred mixture of 1-methyl-4-(p-nitrophenoxy)-3,5-diphenylpyrazole (2.56 g, 0.0069 mole), 5% Pd on carbon (0.4 g) and absolute ethanol (40 ml). Gas bubbles form immediately and an exotherm (ca. 50° C) is observed. After the reaction subsides, the reaction mixture is refluxed for 2 hours. The reaction mixture is cooled slightly and filtered to remove the catalyst. The filtrate is stripped in vacuo to give a white solid 2.4 g (100%), m.p. 167° to 169° C. Recrystallization from benzene (20 ml) affords a white solid, m.p. 167° to 168° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:33]5=[CH:34][C:35]([C:37]6[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=6)=[CH:36][N:32]5[N:31]=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[N:20][CH:21]=2)=[N:9]/[S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:43][Mg]Br.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:9][S@:10]([C:12]([CH3:13])([CH3:14])[CH3:15])=[O:11])([C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:33]5=[CH:34][C:35]([C:37]6[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=6)=[CH:36][N:32]5[N:31]=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[N:20][CH:21]=2)[CH3:43])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: Cn1cc(-c2cc3c(N4CCN(c5ncc(/C(=N\[S@@](=O)C(C)(C)C)c6ccc(F)cc6)cn5)CC4)ncnn3c2)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1cc(-c2cc3c(N4CCN(c5ncc(C(C)(N[S@@](=O)C(C)(C)C)c6ccc(F)cc6)cn5)CC4)ncnn3c2)cn1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 61.4 %

Procedure:
(S,Z)—N-((4-Fluorophenyl)(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)methylene)-2-methylpropane-2-sulfinamide (190 mg, 0.324 mmol) was taken up in THF (3 mL) and cooled to 0° C. Methylmagnesium bromide (3 M solution in diethyl ether, 0.50 mL, 1.500 mmol) was added and the resulting mixture stirred at 0° C. for 45 minutes. Additional methylmagnesium bromide (3 M solution in diethyl ether, 0.10 mL, 0.300 mmol) was added and stirring at 0° C. continued for 20 minutes. Saturated ammonium chloride was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo while loading onto Celite. Purification of the residue by MPLC (0-10% MeOH-EtOAc) gave (S)—N-(1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, 0.199 mmol, 61.5% yield) as a yellow solid (mixture of diastereoisomers). MS (ES+) C30H35FN10OS requires: 602. found: 603 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>C(O)C>[Cl:28][C:26]1[CH:25]=[CH:24][C:15]([O:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:27]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(Cl)ccc1Oc1ccc(O)cc1
Solvent: CCO
Product: Cc1ccc2c(Nc3cc(Cl)ccc3Oc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 1d (80 mg, 4.5 mmol) was reacted with the product from Example 165c (106 mg, 4.5 mmol) in ethanol (15 mL) at 85° C. in a sealed tube for 18 h giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid (40 mg, 18%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[OH-].[Na+].O1CCOCC1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[C:18]1([S:24]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=O)C[C@H](N)C(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)C[C@H](NS(=O)(=O)c1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
To a stirred solution of L-asparagine (Aldrich) (10 g, 76 mmol), NaOH (3.4 g, 85 mmol), H2O (50 mL), and dioxane (50 mL) at 0° C. was added PhSO2Cl (10.6 mL, 84 mmol). After 1 min, NaOH (3.4 g) in H2O (50 mL) was added and the reaction mixture stirred for 30 min. The reaction mixture was then concentrated to remove the dioxane then washed with EtOAc. The aqueous phase was then cooled to 0° C. and acidified to pH 3 with conc. HCl to effect product precipitation. The resulting solid was collected by filtration, washed with H2O (20 mL) and dried at 50° C. under vacuum to give 22-1 as a white solid.
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:20])[C:7](=[O:19])[CH2:8][CH2:9][O:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][CH3:18])[CH2:13][CH2:12]1.C(N(CC)C(C)C)(C)C.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)=[O:32].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([O:33][C:31](=[O:32])[N:17]([C@H:14]2[CH2:13][CH2:12][C@H:11]([O:10][CH2:9][CH2:8][C:7](=[O:19])[N:6]([CH2:5][CH2:4][CH2:3][OH:2])[CH3:20])[CH2:16][CH2:15]2)[CH3:18])=[CH:35][CH:36]=1
Reactant: CN[C@H]1CC[C@H](OCCC(=O)N(C)CCCO)CC1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCO)C(=O)CCO[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 158 mg (0.5 mmol) of trans-N-(3-hydroxy-propyl)-N-methyl-3-(4-methylamino-cyclohexyloxy)-propionamide-hydrochloride in 3 mL of CH2Cl2 were added 0.43 mL (2.6 mmol, 5 eq) of N,N-diisopropylethylamine followed by 0.08 mL (0.56 mmol, 1.1 eq) of 4-chlorophenyl chloroformate. The mixture was stirred at RT for 1 h, and the solution was added to a mixture of NaHCO3 solution and CH2Cl2. The phases were separated and the inorganic phase was extracted with CH2Cl2. The organic phase was washed with 1M KHSO4. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated. Column chromatography on silica gel with a gradient of CH2Cl2:MeOH 98:2 to 95:5 yielded 105 mg (48%) of trans-(4-{2-[(3-hydroxy-propyl)-methyl-carbamoyl]-ethoxy}-cyclohexyl)-methyl-carbamic acid 4-chloro-phenyl ester as colorless oil, MS: 427 (MH+,1Cl).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:11](=[O:35])[NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([N:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:29])[C:23]=3[C:22]3=[N:30][O:31][C:32]([CH3:33])=[C:21]3[C:20]2=[O:34])[CH2:14]1)[CH2:9][OH:10])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][CH:8]([CH2:9][OH:10])[C:11]([NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([N:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:29])[C:23]=3[C:22]3=[N:30][O:31][C:32]([CH3:33])=[C:21]3[C:20]2=[O:34])[CH2:14]1)=[O:35]
Reactant: Cc1onc2c1c(=O)n(C1CCCC(NC(=O)C(CO)NC(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1onc2c1c(=O)n(C1CCCC(NC(=O)C(N)CO)C1)c1cccc(Cl)c21
Yield: 50 %

Procedure:
A solution of {1-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-2-hydroxy-ethyl }-carbamic acid tert-butyl ester, 92.3 mg (0.18 mmol) in 8 mL of 25% TFA in CH2Cl2 was stirred rt. for three hours then concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and saturated aqueous NaHCO3. The organics were washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by radial chromatography using MeOH/chloroform as eluent and concentrated to dryness to yield 37 mg (50%) of the title compound as a white solid. MS (IS) 419.2 (M+).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:22][O:23][CH3:24])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=1>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:9]2[C:10]([CH2:22][O:23][CH3:24])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCc1nn(-c2ccc(OC)cc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: COCc1nn(-c2ccc(OC)cc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 33 %

Procedure:
Using cyclohexyl[3-(methoxymethyl)-1-(4-methoxyphenyl)-1H-pyrazol-4-yl]methanol (0.75 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.54 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.39 g, 33%) was obtained as a white solid.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:12]([C:13]2[N:14]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[C:15]3[C:20]([C:21]=2[C:22](=O)[C:23]([NH2:25])=[O:24])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([CH3:34])[O:10][N:9]=1.Cl.[NH2:36][OH:37]>CCO>[CH3:7][C:8]1[C:12]([C:13]2[N:14]([C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[C:15]3[C:20]([C:21]=2[C:22](=[N:36][OH:37])[C:23]([NH2:25])=[O:24])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([CH3:34])[O:10][N:9]=1
Reactant: NO
Reactant: Cc1noc(C)c1-c1c(C(=O)C(N)=O)c2ccccc2n1-c1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1noc(C)c1-c1c(C(=NO)C(N)=O)c2ccccc2n1-c1ccc(O)cc1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
50 μl Pyridine was added to 8.8 mg 2-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2-oxoacetamide and 32.6 mg hydroxylamine hydrochloride in 1.5 ml EtOH in a microwave vial. The vial was sealed and flushed with nitrogen. The mixture was heated to 150° C. for 7.5 min. and then to 150° C. for 5 min. in a Biotage Initiator microwave oven. The mixture was concentrated in vacuo and purified by preparative HPLC (formic acid buffer/acetonitrile). 2-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2(hydroxyimino)acetamide (E35) was obtained as a mixture of syn and anti oxime isomers. ES/MS m/z: 391.4 (M+H), 389.5 (M−H); 1H NMR (DMSO-d6, 500 MHz): 7.37 (m, 1H), 7.20-7.03 (m, 5H), 6.84 (m, 2H), 2.15 (s, 3H) and 1.77 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[CH:4][N:3]=1.CN(C)[CH:12]=[C:13]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:14](OCC)=[O:15]>C(O)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([N:8]2[C:14](=[O:15])[C:13]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:12][NH:9]2)[CH:7]=1
Reactant: NNc1cc(Cl)ncn1
Reactant: CCOC(=O)C(=CN(C)C)c1cccnc1
Solvent: CC(=O)O
Product: O=c1c(-c2cccnc2)c[nH]n1-c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 30.0 g (207.5 mmol) of the compound from Example 7A and 50.3 g (228.3 mmol) of the compound from Example 3A are stirred in 1000 ml of glacial acetic acid for 16 h. For work-up, the solvent is removed on a rotary evaporator, the residue is taken up in ethyl acetate and washed with saturated sodium bicarbonate solution until neutral, and the organic phase is concentrated under reduced pressure. The residue is dissolved in 1000 ml of ethanol, 42.8 ml (41.1 g, 228.3 mmol) of 30% strength methanolic sodium methoxide solution are added and the mixture is stirred at RT for 2 h. The reaction mixture is then adjusted to pH 5 using 1 N hydrochloric acid and stirred for 16 h. The precipitate is filtered off, the filter residue is washed with water and ethanol and the product is dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][O-:11].[Na+].CO>O>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([O:11][CH3:10])[N:3]=1
Reactant: C[O-]
Reactant: Nc1cc(Cl)nc(Cl)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(N)cc(Cl)n1
Yield: 81.2 %

Procedure:
A solution of 2,6-dichloropyridin-4-amine 41.6.A (available from Aldrich) (3.10 g, 19.0 mmol) in 20% NaOMe/MeOH (15 mL) was refluxed for 72 hr. The reaction mixture was diluted with H2O (40 mL) and extracted with 30% iPrOH/CHCl3 (3×30 mL). The combined organic layers were washed with water (2×20 mL), brine (15 mL) and dried over MgSO4. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel using 0-10% MeOH/CH2Cl2 for elution gave title product 41.6.B as white solid (2.45 g, 81.2%).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10](SC)[N:11]=[CH:12][C:7]=2[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CS(C)=O>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[N:11]=[CH:12][C:7]=2[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(SC)nc21
Solvent: CS(C)=O
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C)CC3)nc21
Temperature: 110 °C
Yield: 116.9 %

Procedure:
A mixture containing 1.33 g of 5,8-dihydro-8-ethyl-2-methylthio-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid, 1.30 g of 4-methylpiperazine, and 20 ml of dimethyl sulfoxide was heated at 110°C for 1 hour with stirring. The separated solid was collected by filtration, washed with ethanol, and recrystallized from dimethylformamide to give 1.86 g of the product, as nearly coloress needles, m.p. 232 - 233°C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[N+:14]([O-])=O>CCO>[NH2:14][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:6]=1[NH:5][CH2:4][CH2:3][CH2:2][OH:1])[C:10]#[N:11]
Reactant: N#Cc1ccc(NCCCO)c([N+](=O)[O-])c1
Solvent: CCO
Product: N#Cc1ccc(NCCCO)c(N)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.2 %

Procedure:
To a suspension of 4-[(3-hydroxypropyl)amino]-3-nitrobenzonitrile (Intermediate 95, 13.4 g, 0.06 mol) in EtOH (500 mL) was added, under argon atmosphere, palladium over carbon (350 mg, 3.3 mmol of a 10% Pd/C) and the mixture was degassed. Then, H2 was added up to an internal pressure of 20 psi, and the final suspension was stirred at room temperature for 2.5 hours. The crude was filtered through a Whatmann glass micro fibre filter and the solvent was removed under reduced pressure to afford the title compound as a brownish solid (11.5 g, 95% yield) which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([NH:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[N:23]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([NH:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:29]=2)[N:23]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1cccc(C(=O)NCc2ccccc2)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 70.2 %

Procedure:
A mixture of methyl thiosalicylate (1.3 g, 7.6 mmol), N-benzyl-6-cyano-2-pyridinecarboxamide (0.88 g, 3.7 mmol), triethylamine (2.0 ml, 14 mmol) and toluene (4 ml) was refluxed for 10 hrs as described in Example 1. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (0.97 g, 97%) as crystals.