Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.C(O)(C(F)(F)F)=O.[CH3:20][O:21][C:22]([C:24]1[CH:50]=[CH:49][C:27]([C:28]([NH:30][CH2:31][C:32]2[CH:48]=[CH:47][C:35]([C:36]([NH:38][NH:39]C(OC(C)(C)C)=O)=[O:37])=[CH:34][CH:33]=2)=[O:29])=[CH:26][CH:25]=1)=[O:23]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:39][NH:38][C:36]([C:35]1[CH:47]=[CH:48][C:32]([CH2:31][NH:30][C:28]([C:27]2[CH:26]=[CH:25][C:24]([C:22]([O:21][CH3:20])=[O:23])=[CH:50][CH:49]=2)=[O:29])=[CH:33][CH:34]=1)=[O:37]
Reactant: COC(=O)c1ccc(C(=O)NCc2ccc(C(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(=O)NCc2ccc(C(=O)NN=C3C(=O)Nc4ccc(I)cc43)cc2)cc1
Temperature: 100 °C
Yield: 86 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFA was added tert-butyl 2-[4-({[4-(methoxycarbonyl)benzoyl]amino)methyl)benzoyl]hydrazinecarboxylate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 70° C. for 15 hrs gave 614 mg of the title compound (86%) as a yellow solid in 97.9% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: CS([Cl:5])(=O)=O.[CH:6]1([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[O:22][CH3:23])[C:15]([C:24]3[N:25]=[C:26]([CH2:29]O)[S:27][CH:28]=3)=[CH:14]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.N1C=CC=CC=1>ClCCl>[Cl:5][CH2:29][C:26]1[S:27][CH:28]=[C:24]([C:15]2[C:16]3[C:21](=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][CH:17]=3)[N:13]([CH2:12][CH:6]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)[CH:14]=2)[N:25]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c(-c3csc(CO)n3)cn(CC3CCCCC3)c12
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc2c(-c3csc(CCl)n3)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
Methanesulfonyl chloride (174 μl, 2.25 mmol) was added to a solution of 1-(cyclohexyl)methyl-3-[2-(hydroxymethyl)thiazol-4-yl]7-methoxy-1H-indole (0.40 g, 1.12 mmol) and pyridine (182 μl, 2.25 mmol) in dichloromethane (8 ml). The resulting mixture was stirred at room temperature overnight. Further methanesulfonyl chloride (87 μl, 1.12 mmol) was added and stirring continued for 0.5 h. The mixture was concentrated in vacuo and the resulting orange residue was purified by flash column chromatography eluting with dichloromethane to afford 3-[2-(chloromethyl)thiazol-4-yl]-1-(cyclohexyl)methyl-7-methoxy-1H-indole as a yellow oil (0.415 g). 3-[2-(Chloromethyl)thiazol-4-yl]-1-(cyclohexyl)methyl-7-methoxy-1H-indole (0.08 g, 0.214 mmol) and diethylamine (221 μl, 2.14 mmol) were dissolved in acetonitrile (2 ml). The resulting mixture was exposed to microwave irradiation at 100° C. for 5 min. The mixture was concentrated in vacuo and the resulting residue was purified by column chromatography eluting with 33% (v/v) ethyl acetate in n-heptane. The resulting product was taken up in diethyl ether and hydrogen chloride (1M solution in diethyl ether; 1 ml) was added. The solution was concentrated in vacuo and the resulting solid triturated with ether, then dried to afford the title compound as a 1:1 hydrochloride salt (0.034 g). 1H NMR (400 MHz, CD3OD) δ 0.99-1.25 (5H, m), 1.43 (6H, t, J 7.5), 1.56-1.90 (6H, m), 3.35-3.42 (4H, m), 3.96 (3H, s), 4.27 (2H, d, J 7.5), 4.75-4.80 (2H, s, masked by H2O peak), 6.75 (1H, d, J 8.0), 7.08 (1H, dd, J 8.0, 8.0), 7.64-7.68 (3H, m). EsIMS: m/z 412.1 [M+H]+, 339.0.
Reaction SMILES: C[NH2:2].[CH2:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([CH:14]=O)=[C:10]2[CH3:16])[CH3:4].[BH4-].[Na+].O>CO>[CH3:4][CH2:3][C:5]1[C:13]2[NH:12][C:11]([CH2:14][NH2:2])=[C:10]([CH3:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CCc1cccc2c(C)c(C=O)[nH]c12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCc1cccc2c(C)c(CN)[nH]c12
Temperature: 0 °C
Reaction time: 5 h
Yield: 75.6 %

Procedure:
Methylamine (0.7 mL, 17.6 mmol) was added to a solution of 7-ethyl-3-methyl-1H-indole-2-carbaldehyde (1.1 mg, 5.8 mmol) in methanol (5 mL) and stirred for 5 h. The mixture was cooled to 0° C. and sodium borohydride (218 mg, 5.8 mmol) added slowly. The mixture was warmed to rt and stirred overnight. Water (3 mL) was added slowly at 0° C. and evaporated to a paste. Water was added and the mixture extracted with dichloromethane. The organic phase was washed with water, dried and evaporated to afford the title compound (826 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.01 (t, J=7.6 Hz, 1H), 6.96 (d, J=6.8 Hz, 1H), 3.87 (s, 2H), 2.79 (q, J=7.5 Hz, 2H), 2.45 (s, 3H), 2.24 (s, 3H), 1.31 (t, J=7.6 Hz, 3H)
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([CH2:11][NH2:12])=[CH:9][CH:10]=1)=[NH:4].[C:13](=[O:16])([O-])[O-:14].[K+].[K+]>O1CCOCC1.O>[OH:1][NH:2][C:3]([C:5]1[C:6]([C:13]([O:14][C:5]([CH3:6])([CH3:10])[CH3:3])=[O:16])=[N:7][C:8]([CH2:11][NH2:12])=[CH:9][CH:10]=1)=[NH:4]
Reactant: O=C([O-])[O-]
Reactant: N=C(NO)c1ccc(CN)nc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)c1nc(CN)ccc1C(=N)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.3 %

Procedure:
To a solution of the product of Example 53 (11-5) (0.5 g, 3.01 mmol) in dioxane and water (6 ml each) was added potassium carbonate (832 mg, 6.02 mmol), followed by Boc-anhydride (0.66 g, 3.01 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the remaining residue was dissolved in ethylacetate and washed with sodium bicarbonate (saturated) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. Flash column chromatography in 8/2 ethylacetate/hexanes followed by ethylacetate and 9/1 dichloromethane/methanol afforded 0.43 g product as a white solid. NMR δ (ppm) CDCl3: 8.8 (d, 1H), 7.9 (dd, 1H), 7.3 (d, 1H), 6.6 (bs, 1H), 5.5 (bs, 1H), 4.8 (bs, 1H), 4.4 (d, 2H), 1.4 (s, 9H)
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]([CH:15]([CH3:17])[CH3:16])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][CH:3]=1.C([Li])CCC.C(O[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1)(C)C>C1COCC1>[C:10]([O:9][C:8](=[O:14])[N:7]([CH:15]([CH3:17])[CH3:16])[C:5]1[S:6][C:2]([B:27]2[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]2)=[CH:3][N:4]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)N(C(=O)OC(C)(C)C)c1ncc(Br)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)N(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 48.6 %

Procedure:
To a solution of tert-butyl 5-bromothiazol-2-yl(isopropyl)carbamate (7.5 g, 23.3 mmol) in THF (50 mL) was added n-butyllithium (1.6 M in hexane, 21.8 mL) dropwise at −78° C. The solution turned orange. The solution was stirred at −78° C. for minutes before 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.49 g, 34.9 mmol) was added dropwise. The mixture was stirred at −78° C. for 2 hours then warmed to room temperature. The reaction was quenched with 1:1 ammonium chloride/water (50 mL). The resulted mixture was extracted with ethyl acetate (100 mL). The organic layer was separated, washed with water, brine and concentrated. To the brown solid residue was added hexane (30 mL). The mixture was filtered and the filter cake was washed with hexane (20 mL) and dried to give as a yellow solid (4.17 g, 48% yield). LCMS (Conditions C): 3.21 min (RT); (M+H)+=247.12 (40%), 245.12 (50%), 233.10 (75%), 231.10 (100%). 1H NMR, 400 MHz, CDCl3: δ 7.95 (s, 1 H), 5.37 (m, 1 H), 1.60 (s, 9 H), 1.44 (d, 6.7 Hz, 6 H), 1.34 (s, 12 H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:35][C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[C:18]([C:23]5[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[CH:25][CH:24]=5)=[N:19][N:20]([CH3:22])[CH:21]=4)=[C:11]3[CH:10]=2)=[CH:5][CH:4]=1)=O.[CH2:36]([NH:38][CH2:39][CH2:40][OH:41])[CH3:37]>>[CH2:36]([N:38]([CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:35][C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[C:18]([C:23]5[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[CH:25][CH:24]=5)=[N:19][N:20]([CH3:22])[CH:21]=4)=[C:11]3[CH:10]=2)=[CH:7][CH:8]=1)[CH2:39][CH2:40][OH:41])[CH3:37]
Reactant: CN(C)C(=O)Nc1ccc(-c2nn(C)cc2-c2ccnc3[nH]c(-c4ccc(C=O)cc4)cc23)cc1
Reactant: CCNCCO
Product: CCN(CCO)Cc1ccc(-c2cc3c(-c4cn(C)nc4-c4ccc(NC(=O)N(C)C)cc4)ccnc3[nH]2)cc1

Procedure:
Following the procedure described for Intermediate 101 using N′-(4-{4-[2-(4-formylphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-methyl-1H-pyrazol-3-yl}phenyl)-N,N-dimethylurea and 2-(ethylamino)ethanol provided the title compound. ESMS [M+H]+: 538.4
Reaction SMILES: C[Si](Cl)(C)C.[I-].[Na+].[CH2:8]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([CH:30](O)[C:31]([NH2:33])=[O:32])=[CH:22]2)[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(#N)C>[CH2:8]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([CH2:30][C:31]([NH2:33])=[O:32])=[CH:22]2)[CH2:17][CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NC(=O)C(O)c1cn(C2CCN(Cc3ccccc3)CC2)c2ccccc12
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: NC(=O)Cc1cn(C2CCN(Cc3ccccc3)CC2)c2ccccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
Dissolve trimethylsilyl chloride (2.1 mL, 6 eq) and sodium iodide (2.5 g, 6 eq) in acetronitrile (15 mL) and cool to 0° C. while under nitrogen. Dissolve 2-[1-(1-benzylpiperidin-4-yl)-1H-indol-3-yl]-2-hydroxyacetamide (1.0 g, 2.75 mmol) in acetonitrile (10 mL) and add dropwise to the reaction. Let stir overnight and gradually warm to room temperature. Extract with 5% NaHSO3 against ethyl acetate then wash with brine. Basify aqueous layer with saturated sodium bicarbonate and wash with ethyl acetate once more. Combine organic layers and dry over magnesium sulfate. Filter and concentrate. Triturate from hot diethyl ether to afford product (0.64 g, 67%) as a white solid. MS (ES, m/z): 348.0 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[O:12]1[CH2:36][CH:13]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]3[O:35][CH2:34]3)=[CH:27][CH:26]=2)([CH3:24])[CH3:23])=[CH:18][CH:17]=1>CO>[OH:12][CH:13]([CH2:36][NH:1][CH:2]1[CH2:3][C:4]([CH3:11])([CH3:10])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7]1)[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]([OH:35])[CH2:34][NH:1][CH:2]3[CH2:3][C:4]([CH3:11])([CH3:10])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7]3)=[CH:27][CH:26]=2)([CH3:23])[CH3:24])=[CH:20][CH:21]=1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Solvent: CO
Product: CC1(C)CC(NCC(O)COc2ccc(C(C)(C)c3ccc(OCC(O)CNC4CC(C)(C)NC(C)(C)C4)cc3)cc2)CC(C)(C)N1

Procedure:
To 100 ml of methanol were added 7.8 g of 4-amino-2,2,6,6-tetramethylpiperidine and 8.5 g of 2,2-bis[p-(2,3-epoxypropoxy)phenyl]propane; the mixture was then reacted in a similar manner to that described in Example 1, giving the desired compound in the form of a white powder. The compound had an Rf value of 0.28 on thin layer chromatography on silica gel developed with a 1:3:1 by volume mixture of methanol, ethyl acetate and triethylamine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18]>C(#N)C>[CH3:9][C:4]1[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:21]([NH:20][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])(=[O:18])=[O:19])=[O:22])[N:3]=1
Reactant: Cc1nc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Solvent: CC#N
Product: Cc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2Cl)n1

Procedure:
To 12.3 g of 2-amino-4,6-dimethyl-1,3,5-triazine in 200 ml of acetonitrile was added with stirring 21.7 g of 2-chlorobenzenesulfonyl isocyanate. All of the solid dissolved after the reagents were added and the mixture was then evaporated to dryness. The solid residue was triturated with ethyl ether and isolated by filtration to give impure N-[(4,6-dimethyl-1,3,5-triazin-2-yl)aminocarbonyl]-2-chlorobenzenesulfonamide melting at 115°-118° C. The nuclear magnetic resonance absorption spectrum of this product, in trifluoroacetic acid, showed singlet peaks at 2.69 and 2.9 parts per million.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].N.CO.CC[N:25](C(C)C)C(C)C>C(Cl)Cl>[NH2:25][S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(N)(=O)=O)s2)s1
Reaction time: 1 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step 1 of Example 9 (200 mg; 0.59 mmol; 1 eq.), is dissolved in DCM (10 ml). A solution of ammonia in MeOH (0.59 ml; 2 M; 1.19 mmol; 2 eq.) and DIEA (460.4 mg; 3.56 mmol; 6 eq.) are added. After one hour, the solvents are evaporated. The crude product is purified by preparative HPLC, affording Compound (17) as white-off solid (36 mg; 17%). 1H NMR (DMSO-d6) δ 2.14 (s, 3H), 2.42 (s, 3H), 7.16 (d, J=4.5 Hz, 1H), 7.50 (d, J=4.5 Hz, 1H), 7.72 (s, 2H), 12.30 (s, 1H). M−(ESI): 316.07; M+(ESI): 318.10. HPLC, Rt: 2.16 min (purity: 99.8%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[NH:9][CH:10]=[C:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])[CH:12]=1)=[O:7])C>CO>[Br:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13][C:11]1[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[NH:9][CH:10]=1
Reactant: CCOC(=O)c1cc(CCc2ccccc2Br)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(CCc2ccccc2Br)c[nH]1
Yield: 51.3 %

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 13.04 mmol) was added to a stirring, room temperature solution of 64 (0.8402 g, 2.608 mmol) in MeOH (6.5 mL, 0.4 M) under N2. The reaction was heated to reflux until the reaction was judged complete by HPLC (10 min): The product was concentrated and then dissolved in 10 mL H2O. The product was extracted with EtOAc until the organic layer no longer turned yellow, then the aqueous layer was made acidic (pH=2) with the dropwise addition of 10% aq. HCl. The product oiled out of solution, so EtOAc was added, and the organic layer was removed, dried with Na2SO4, filter, concentrated to obtain 65 (0.3934 g, 51.3%) as a white solid (Note: An undesired impurity has a retention time of 11.066 min by HPLC): 1H (CD3OD, 400 MHz): δ 7.51 (1H, d, J=7.8 Hz), 7.24-7.16 (2H, m), 7.05 (1H, ddd, J=8.2, 6.3, 2.9 Hz), 6.72 (1H, s), 6.71 (1H, s), 2.96 (2H, t, J=8.0 Hz), 2.73 (2H, t, J=7.8 Hz)) ppm. 13C (CD3OD, 100 MHz): δ 164.48, 142.42, 133.71, 131.80, 128.79, 128.53, 125.89, 125.20, 123.54, 122.61, 116.38, 38.99, 28.20 ppm. DEPT (CDCl3, 100 MHz): CH2 carbons: 38.99, 28.20; CH carbons: 133.71, 131.80, 128.79, 128.53, 122.61, 116.38 ppm. HPLC: 10.035 min.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=O)[CH3:24])=[CH:19][CH:18]=1)[C:5]([O:7][CH3:8])=[O:6].Cl.[CH2:27]([O:34][NH2:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CO>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[N:35][O:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:24])=[CH:19][CH:18]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: NOCc1ccccc1
Reactant: CON=C(C(=O)OC)c1ccccc1COc1ccc(C(C)=O)cc1
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)OC)c1ccccc1COc1ccc(C(C)=NOCc2ccccc2)cc1
Yield: 82.6 %

Procedure:
5.3 g (0.016 mol) of methyl 2-(4-acetylphenoxymethyl)phenylglyoxylate O-methyloxime and 3.0 g (0.019 mol) of benzyloxyamine hydrochloride in 60 ml of methanol are stirred at room temperature for 24 hours. The mixture is then hydrolyzed with water and extracted with methyl tert-butyl ether. The organic phase is washed with water, dried and concentrated. 5.9 g (83%) of the title compound are obtained in the form of colorless crystals (melting point 104°-106° C., compound no. 590).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[C:21]([CH:23]([C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)[CH2:24][C:25]([O:27]CC1C=CC=CC=1)=[O:26])#[N:22]>>[C:21]([CH:23]([C:35]1[CH:40]=[CH:39][C:38]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)=[CH:37][CH:36]=1)[CH2:24][C:25]([OH:27])=[O:26])#[N:22]
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Reactant: N#CC(CC(=O)OCc1ccccc1)c1ccc(O)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1)c1ccccc1
Yield: 39.91 %

Procedure:
Compound 74 was synthesized from (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.04 g, 2.2 mmol) and benzyl 3-cyano-3-(4-hydroxyphenyl)propanoate (0.66 g, 2.2 mmol) by following the procedure described in scheme 24 (0.2 g, yield: 39.91%); Purity: 98.51%.
Reaction SMILES: [CH:1]1([N:4]([CH2:17][C:18](O)=[O:19])[S:5]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CO>C1COCC1>[Cl:14][C:13]1[CH:12]=[C:11]([Cl:15])[CH:10]=[C:9]([Cl:16])[C:8]=1[S:5]([N:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:17][CH2:18][OH:19])(=[O:7])=[O:6]
Reactant: O=C(O)CN(C1CC1)S(=O)(=O)c1c(Cl)cc(Cl)cc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(c1c(Cl)cc(Cl)cc1Cl)N(CCO)C1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 2 M soln. of borane-dimethylsulfide complex in THF (4.96 ml, 9.92 mmol) was added to a soln. of [cyclopropyl-(2,4,6-trichlorobenzenesulfonyl)-amino]-acetic acid (1.77 g, 4.96 mmol) in anhydrous THF (30 ml) and the mixture was stirred for 1 h, while cooling with ice. The reaction mixture was stirred at RT for approx. 18 h, MeOH (2 ml) was then cautiously added and the mixture was concentrated i. vac. MeOH was repeatedly added to the residue and the mixture concentrated i. vac. 5% strength NaHCO3 soln. was added to the crude product, the mixture was extracted with EtOAc and the organic phase was dried with Na2SO4 and concentrated i. vac. Yield: 1.02 g (60%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C.O[CH2:56][CH2:57][N:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1.[CH3:64][S:65]([OH:68])(=[O:67])=[O:66]>C1COCC1.C(Cl)Cl>[CH3:64][S:65]([OH:68])(=[O:67])=[O:66].[CH3:64][S:65]([OH:68])(=[O:67])=[O:66].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH2:56][CH2:57][N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: COc1cc2c(N3CCc4ccc(Cl)cc43)ncnc2cc1O
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: CS(=O)(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc2c(N3CCc4ccc(Cl)cc43)ncnc2cc1OCCN1CCOCC1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-(6-chloro-2,3-dihydro-indol-1-yl)-6-methoxy-quinazolin-7-ol (200 mg, 0.610 mmol; from Example 70) and triphenylphosphine(160 mg, 0.610 mmol) in dry THF (3 mL) under N2(g) was added diethyl-azodicarboxylate (106 μL, 0.671 mmol) dropwise at 0° C. over 10 minutes followed by a solution of 4-(2-hydroxyethyl)-morpholine (81 μL, 0.671 mmol) in dry THF (0.8 mL). The mixture was allowed to warm to 20° C. and stirred 16 hours before quenching with H2O (20μL) and concentrating in vacuo. Flash chromatography of the residue on silica using first 45% acetone/CH2Cl2 followed by 10% MeOH/CH2Cl2 eluted the product as its free-base (180 mg), which was precipitated as its bis(methanesulfonate) salt by addition of 2.0 eq. of methanesulfonic acid to a solution in CH2Cl2. (M.P. 150°-158° C. (dec); LC-MS: 441 (MH+); anal. RP18-HPLC RT: 3.76 min.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:24]([O-])=O)=[C:7]([NH:9][S:10]([C:13]2[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:8]=1.[H][H]>CN(C)C(=O)C.[Pt](=O)=O>[NH2:24][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=1[NH:9][S:10]([C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])c(NS(=O)(=O)c2ccc(OCC(N)=O)cc2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)N(C)C
Product: COc1ccc(N)c(NS(=O)(=O)c2ccc(OCC(N)=O)cc2)c1
Yield: 93 %

Procedure:
2-(4-{[(5-methoxy-2-nitrophenyl)amino]sulfonyl}phenoxy)acetamide (Intermediate A60, 2.0 g, 0.0052 mol) was hydrogenated in N,N-dimethylacetamide with platinum(IV)oxide catalyst (0.2 g) until hydrogen uptake ceased. The catalyst was removed by filtration and the resulting mixture was concentrated under reduced pressure. The resulting solid was triturated with ethyl acetate to give 1.7 g (93%) of the title compound, “amine sulfonamide”.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]([C:7]2[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[CH:5][CH2:4][CH2:3]1.[H-].[Na+].[Br:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30](F)[CH:29]=1>CN(C=O)C.O>[Br:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([O:14][CH2:13][C:11]2[CH:10]=[CH:9][C:8]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=3[F:23])=[C:7]([C:6]3[C:2]([CH3:24])([CH3:1])[CH2:3][CH2:4][CH:5]=3)[CH:12]=2)[CH:29]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2=CCCC2(C)C)c1
Reactant: Fc1cc(Br)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)c(-c2ccc(COc3cc(Br)ccn3)cc2C2=CCCC2(C)C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
A dry round bottom flask containing 14.3 (0.0937 g, 0.287 mmol) in dry DMF (1 mL) was cooled in an ice bath. After 10 minutes, sodium hydride (60% wt. in oil) (15.4 mg, 0.385 mmol) was added carefully, and the mixture was stirred at 0° C. After 10 minutes, 4-bromo-2-fluoropyridine (commercially available from Synthonix Corporation) (0.0511 g, 0.290 mmol) was added. The reaction was allowed to stir overnight at room temperature. After 18 hours, the reaction was diluted with water and extracted five times with EtOAc. The combined organic layers were then washed one time with brine and dried over anhydrous magnesium sulfate. The solid was filtered off, and the solvent was concentrated. The residue was purified by silica gel flash chromatography (0-45% EtOAc/hexane) to afford 95.A (105.9 mg, 76% yield). 1H NMR (400 MHz) (CDCl3) δ ppm 8.02 (1H, d, J=4.7 Hz), 7.41 (1H, m), 7.35 (2H, m), 7.08 (2H, m), 7.00 (1H, m), 6.79 (2H, dt, J=5.1, 2.5 Hz), 5.52 (1H, s), 5.42 (2H, s), 3.76 (3H, s), 2.25 (2H, td, J=6.9, 2.5 Hz), 1.67 (2H, t, J=7.0 Hz), 0.87 (6H, s).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[C@@H:7]([OH:15])[CH2:6][C@@H:5]1[CH3:16])(=[O:3])[CH3:2].[C:17]1(O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[C@H:7]([O:15][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:6][C@@H:5]1[CH3:16])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc(F)ccc2[C@@H](O)C[C@@H]1C
Reactant: Oc1ccccc1
Product: CC(=O)N1c2cc(F)ccc2[C@H](Oc2ccccc2)C[C@@H]1C
Yield: 26.1 %

Procedure:
(Step 4) A compound was produced in the same manner as in Example 2, using 100 mg of trans-1-acetyl-7-fluoro-4-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline and 84 mg of phenol, and thus 35 mg (26%) of the title compound was obtained as a white solid.