Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:26])[CH2:5][N:6]1[C:12](=[O:13])[C@@H:11]([NH:14]C(OC(C)(C)C)=O)[CH2:10][NH:9][C:8]2[CH:22]=[CH:23][CH:24]=[CH:25][C:7]1=2>C(OCC)(=O)C>[ClH:1].[CH3:2][O:3][C:4](=[O:26])[CH2:5][N:6]1[C:12](=[O:13])[C@@H:11]([NH2:14])[CH2:10][NH:9][C:8]2[CH:22]=[CH:23][CH:24]=[CH:25][C:7]1=2
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)CN1C(=O)[C@@H](N)CNc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Anhydrous hydrogen chloride was bubbled into a solution of (3(S)-tert-butoxycarbonylamino-2-oxo-2,3,4,5-tetrahydro-benzo[b] [1,4]diazepin-1-yl)acetic acid methyl ester (103, 1 g, 2.86 mmol) in 25 ml of ethyl acetate for 2 minutes then stirred for 1 hour at room temperature. The reaction was evaporated to give 2-oxo-3(S)-amino-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl acetic acid methyl ester hydrochloride as a white solid. The hydrochloride salt and hydrocinnamic acid (0.47 g, 3.15 mmol) was dissolved into 20 ml of dimethylformamide and cooled to 0° C. Diisopropylethylamine (1 ml, 5.72 mmol) was added to the solution followed by the addition of N-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. After stirring for 18 hours at room temperature, the mixture was diluted with 150 ml of ethyl acetate and washed with 10% sodium hydrogen sulfate, 10% sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to a crude solid that was purified by flash chromatography eluting with 7:3 ethyl acetate/dichloromethane to afford 600 mg (55%) of the title compound as a white solid. 1H NMR (CDCl3) δ7.3-6.85 (9H,m), 6.55-6.0 (1H, d), 4.88-4.82 (1H, m), 4.72-4.65 (1H, d), 4.28-4.22 (1H, m), 3.95-3.9 (1H, m), 3.78 (3H, s), 3.65 (1H, br. s), 3.28-3.2 (1H, m), 2.95-2.84 (2H, m), 2.55-2.4 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:25]=[C:26]([NH:31][C:32](=[O:45])[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([N:39]([CH2:41][CH2:42][O:43][CH3:44])[CH3:40])[CH:34]=2)[CH:27]=[CH:28][C:29]=1[CH3:30]>>[CH3:44][O:43][CH2:42][CH2:41][N:39]([C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)[C:32]([NH:31][C:26]1[CH:27]=[CH:28][C:29]([CH3:30])=[C:24]([NH:23][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([O:13][CH:10]3[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]3)[CH:15]=2)[CH:25]=1)=[O:45])[CH3:40]
Reactant: COCCN(C)c1cccc(C(=O)Nc2ccc(C)c(N)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)C1
Product: COCCN(C)c1cccc(C(=O)Nc2ccc(C)c(NC(=O)c3cccc(OC4CCN(C(=O)OC(C)(C)C)C4)c3)c2)c1
Yield: 59 %

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 25, 3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzoic acid was reacted with N-(3-amino-4-methylphenyl)-3-[N-(2-methoxyethyl)-N-methylamino]benzamide to give N-(5-{3-[N-(2-methoxyethyl)-N-methylamino]benzamido}-2-methylphenyl)-3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzamide in 59% yield; NMR Spectrum: (DMSOd6) 1.39 (s, 9H), 2.08 (m, 2H), 2.18 (s, 3H), 2.96 (s, 3H), 3.22 (s, 3H),3.25 (m, 2H), 3.52 (m, 6H), 5.07 (s, 1H), 6.87 (d, 1H), 7.2 (m, 5H), 7.43 (t, 1H), 7.55 (m, 3H), 7.79 (s, 1H), 9.86 (s, 1H), 10.06 (s, 1H); Mass Spectrum: M−C3H7+ 547.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].Cl[CH2:15][O:16][CH2:17]Cl>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH2:15][O:16][CH3:17])[CH:7]=1
Reactant: ClCOCCl
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 88 %

Procedure:
5-Fluoro-2-nitrophenol (10 g, 63 mmol, 99%) was dissolved in anhydrous DMF (100 mL) in an oven-dried flask. The solution was stirred under an atmosphere of nitrogen and cooled in an ice-water bath. Sodium hydride (3.0 g, 75 mmol) was added with stirring, after which chloro methylether (5.3 g, 66 mmol) was added dropwise. The resulting mixture was aged at room temperature for 1 h. The reaction was quenched with MeOH, diluted with ether and washed with water and brine. The ether layer was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification of the product by silica gel chromatography (hexanes/EtOAc=1/7) gave the title compound in 88% yield. 1H NMR (500 MHz, CDCl3) δ 3.53 (s, 3H), 5.30 (d, J=2.0 Hz, 2H), 6.78 (dd, J=7.3, 9.1 Hz, 1H), 7.06 (dt, J=2.3, 10.4 Hz, 1H), 7.91 (dd, J=6.0, 9.0 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 57.0, 95.6, 105.0 (d, J=26.3 Hz), 108.8 (d, J=23.0 Hz), 127.8 (d, J=10.7 Hz), 152.8 (d, J=11.5 Hz), 165.5 (d, J=255.9 Hz). HRMS (FAB) calcd for C8H8FNNaO4 (M+Na+) 224.0330. found 224.0328.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([OH:26])=[C:15]([C:21](OCC)=[O:22])[C:16](=[O:20])[NH:17]2)=[N:12][CH:11]=1.[NH2:27][CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([OH:26])=[C:15]([C:21]([NH:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:22])[C:16](=[O:20])[NH:17]2)=[N:12][CH:11]=1
Reactant: NCCCN1CCOCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3F)cc2[nH]c1=O
Product: O=C(NCCCN1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3F)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(2,4-difluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-(3-aminopropyl)morpholine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) tautomers are observed δ 11.75 (1H, br s), 10.7 (1H, br s), 10.20 (1H, br s), 8.17 (0.45H, s), 8.15 (0.55H, s), 7.45-7.21 (3H, m), 7.10-7.04 (1H, m), 4.02 (2H, s), 3.56-3.51 (4H, m), 3.31-3.24 (2H, m), 2.48-2.32 (6H, m), 1.65-1.61 (2H, m); HRMS calcd for C23H24F2N4O4+H+: 459.1844. Found 459.1856.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]2[CH2:19][CH2:18][CH:17]([C:20](N)=[O:21])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1.[OH-:23].[K+].O.Cl>C(O)CO>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:21])=[O:23])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1
Reactant: [OH-]
Reactant: NC(=O)C1CCC([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: O=C(O)[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Temperature: 180 °C

Procedure:
42 g of crude 4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]cyclohexanecarboxamide were suspended in 500 ml of ethylene glycol while gassing with argon and then treated with 19 g of solid potassium hydroxide. The mixture was heated to 180° C. (bath temperature) for 5 hours while stirring. After cooling the reaction mixture was poured into 500 ml of water, acidified to pH about 3 with 10 percent hydrochloric acid and extracted three times with 300 ml of methylene chloride each time. The combined organic phases were washed once with 500 ml of 1 percent hydrochloric acid and twice with 500 ml of water each time, dried over magnesium sulfate, filtered and evaporated. The dark brown crude product (41 g) was purified by chromatography on silica gel with ethyl acetate. Crystallization of the product obtained (36 g) from acetone gave 13.8 g of pure trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]cyclohexanecarboxylic acid. Working-up of the mother liquor gave a further 2.5 g of pure product.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:25][O:26][C:27]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=[C:29]([NH:42][CH3:43])[N:28]=1>>[CH2:20]([N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[C:27]([O:26][CH3:25])=[N:28][C:29]([NH:42][CH3:43])=[N:30][CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:24])[C:13]2=[O:23])[C:16]([CH3:22])=[N:17]1)[CH3:21]
Reactant: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1
Reactant: CNc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Product: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(-c5cnc(NC)nc5OC)cc4c32)c(C)n1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F) and [4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-methyl-amine (stage 236.1.1) to give the title compound as a white solid. (HPLC: tR 2.19 min (Method A); M+H=445 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.91 (s, 1H), 8.11 (s, 1H), 8.08-8.02 (m, 1H), 8.01-7.97 (m, 1H), 7.74-7.69 (m, 1H), 7.50-7.48 (m, 1H), 7.27-7.16 (m, 1H), 4.15 (q, 2H), 3.85 (s, br, 3H), 3.56 (s, 3H), 2.82 (d, 3H), 1.95 (s, 3H) 1.36 (t, 3H))
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH2:13]([O:15][C:16](=[O:22])[C:17](=O)[CH:18](Br)[CH3:19])[CH3:14]>O1CCOCC1>[CH2:13]([O:15][C:16]([C:17]1[N:1]=[C:2]2[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:10])[F:11])=[CH:4][N:3]2[C:18]=1[CH3:19])=[O:22])[CH3:14]
Reactant: CCOC(=O)C(=O)C(C)Br
Reactant: Nc1ncc(C(F)(F)F)cc1Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1nc2c(Cl)cc(C(F)(F)F)cn2c1C

Procedure:
To a solution of 2-amino-3-chloro-5-(trifluoromethyl)pyridine (11.3 g, 57.5 mmol) in dioxane (200 mL) at room temperature was added dropwise 3-bromo-2-oxo-butyric acid ethyl ester (12.017 g, 57.49 mmol, the product of Step A). The reaction mixture was heated to reflux for 24 h, cooled, and the dioxane was removed under reduced pressure. Chromatography on silica gel eluting with a hexane/ethyl acetate gradient afforded 17.3 g of 8-chloro-3-methyl-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.N1C=CC=CC=1.[Cl:18][C:19]([Cl:24])([Cl:23])[C:20](Cl)=[O:21]>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([C:20](=[O:21])[C:19]([Cl:24])([Cl:23])[Cl:18])=[CH:6][NH:7]2
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: COc1cccc2[nH]ccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc2[nH]cc(C(=O)C(Cl)(Cl)Cl)c12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-methoxy-1H-indole (7.15 g, 49 mmol) and pyridine (19.7 mL, 243 mmol) in dichloromethane (50 mL) at 0° C. under Nitrogen was added dropwise a solution of trichloroacetyl chloride (27.1 mL, 243 mmol) in dichloromethane (50 mL). After stirring at 0° C. for an additional 1.5 h, the mixture was concentrated in vacuo. The residue was taken up in the minimal volume of methanol necessary and placed in a freezer overnight. The precipitate was filtered, rinsed well with methanol, and dried to yield 4-methoxy-3-trichloroacetyl-1H-indole. To a stirring solution of sodium methoxide (3.5 mL of a 25 weight % solution in methanol) in methanol (200 mL) at ambient temperature was added 4-methoxy-3-trichloroacetyl-1H-indole (9.07 g, 31.0 mmol) in portions over 0.75 h. After stirring an additional 0.75 h, the mixture was cooled in an ice bath, diluted with ice water, acidified with concentrated hydrochloric acid, and the methanol removed in vacuo. The resulting heterogeneous mixture was cooled in an ice bath, the precipitate filtered, rinsed with water, and dried to afford methyl 4-methoxy-1H-indole-3-carboxylic ester. A slurry of this ester (5.6 g 27 mmol) in 50% aqueous sodium hydroxide (50 mL) and methanol 50 mL) was stirred at ambient temperature for 19 h. The mixture was cooled in an ice bath, acidified with concentrated hydrochloric acid, the precipitate filtered, rinsed with ice water, and dried to afford 4-methoxy-1H-indole-3-carboxylic acid.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=13)=[O:10])[NH:2]2.[CH3:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1>>[CH3:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[O:19][CH:18]=[CH:17][C:16]=34)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:27])[N:25]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2occc12
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2[C@H](CNC(=O)c3cccc4occc34)C[C@@H]3C[C@@H]32)c1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.42 min; [M+H]+=472.1.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]2[CH2:8][CH:9]=[C:10]([CH:12]=O)[CH:11]=[C:5]2[O:4][CH2:3]1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:12][C:10]3[CH:9]=[CH:8][C:6]4[NH:7][C:2](=[O:1])[CH2:3][O:4][C:5]=4[CH:11]=3)[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: O=CC1=CCC2NC(=O)COC2=C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccc(N2CCN(Cc3ccc4c(c3)OCC(=O)N4)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.8 %

Procedure:
A mixture of 3-oxo-dihydro-2H-benzo[1,4]oxazine-7-carbaldehyde (0.5 g, 2.8 mmol), 1-(4-methyl-phenyl)-piperazine (0.5 g, 2.8 mmol), acetic acid (0.17 g, 2.8 mmol) and sodium triacetoxyborohydride (1.2 g, 5.9 mmol) in 20 mL of 1,2-dichloroethane is stirred at room temperature for 3 hours. The reaction is quenched with 50 mL of water, and the layers are separated. The aqueous phase is extracted with ethyl acetate (3×50 mL). The organic phases are combined and dried over sodium sulfate. Evaporation of the solvent gives a solid which is recrystallized twice from acetonitrile to give 0.31 g (33% yield) of 7-[4-(4-methyl-phenyl)-piperazin-1-ylmethyl]-4H-benzo[1,4]oxazine-3-one; mp 208-210° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18]1[O:21][C@@H:19]1[CH3:20]>CN(C=O)C>[OH:21][C@H:19]([CH3:20])[CH2:18][N:3]1[CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=[C:2]1[CH3:1]
Reactant: CCOC(=O)c1c[nH]c(C)n1
Reactant: C[C@@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C[C@@H](C)O)c(C)n1
Temperature: 60 °C
Reaction time: 5.5 h
Yield: 76.3 %

Procedure:
Ethyl 2-methyl-1H-imidazole-4-carboxylate (3.24 mmol, 500 mg) and potassium carbonate (32.4 mmol, 4482 mg) were dissolved in DMF (10 ml). (R)-(+)-propylene oxide (48.6 mmol, 3.41 ml) was added and the resulting mixture was stirred at 60° C. for 5.5 h. More (R)-(+)-propylene oxide (1.5 ml) was added and the heating continued for another hour. The mixture was evaporated and the residue was purified by flash chromatography. 525 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.06 (d, 3H), 1.25 (t, 3H), 2.30 (s, 3H), 3.68-4.00 (m, 3H), 4.18 (q, 2H), 4.95 (d, 1H), 7.73 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9](C)[C:10]([N:12]([CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH:13]([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1.C([NH:27]CC)C.C(Cl)Cl>>[NH2:27][CH:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10]([N:12]([CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH:13]([CH3:15])[CH3:14])=[O:11]
Reactant: CCNCC
Reactant: CCOC(CN(C(=O)C(C)Cc1ccc(Cl)cc1)C(C)C)OCC
Solvent: ClCCl
Product: CCOC(CN(C(=O)C(N)Cc1ccc(Cl)cc1)C(C)C)OCC

Procedure:
A solution of 530 mg (0.915 mmol) of 3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl-2-methylpropionamide in 15 ml of a 20% diethylamine DCM solution is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo and purified by chromatography on 5 g of SiO2 (eluent DCM followed by 20% EtOAc/DCM followed by 20% MeOH/DCM). 320 mg of the desired product are obtained as an oil. MW=356.19 (calculated, monoisotopic); measured value (M+H)+=357
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:28][CH2:29]O>>[CH2:28]([O:21][C:20](=[O:22])[CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([S:12][C:6]2[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]=2[CH3:11])[CH:14]=1)[CH3:29]
Reactant: Cc1[nH]c2cc(Cl)ccc2c1Sc1cccc(CC(=O)O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid (from the previous step) was dissolved in EtOH (100 mL), conc. H2SO4 (2 mL) was added, and the reaction was stirred at room temperature for 2 hours. The reaction was submitted to standard workup procedures then purified via silica gel chromatography to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([C@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([OH:12])=[O:11])[CH:8]=1)([O-:3])=[O:2].[CH3:19]C1C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[CH3:19][O:11][C:10](=[O:12])[C@H:9]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCCC[C@H](C(=O)O)n1cnc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCC[C@H](C(=O)OC)n1cnc([N+](=O)[O-])c1
Yield: 2813.6 %

Procedure:
(R)-2-(4-nitro-1H-imidazol-1-yl)-octanoic acid (16.0 g, 63.0 mmol) was dissolved in 1L of anhydrous methanol. To this solution was added pTsOH (300 mg). The reaction was then heated to reflux for 16 hours. Upon cooling, the solvent was removed in vacuo, to give an oil that was dissolved in 300 mL of ethyl acetate. The solution was washed (2×250 mL) with saturated NaHCO3 solution The organic was then dried (Na2SO4) and concentrated in vacuo to provide 13.2 g (78%) of (R)-methyl-2-(4-nitro-1H-imidazol-l-yl)-octanoate as an amber oil.
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[Cl:27])[CH:23]([C:28](Cl)=[O:29])[CH2:22][CH2:21]2>C(N(CC)CC)C>[ClH:17].[ClH:1].[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[Cl:27])[CH:23]([C:28]([N:8]1[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH:7]1[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:29])[CH2:22][CH2:21]2
Reactant: CN1CCNC(CN2CCCC2)C1
Reactant: O=C(Cl)C1CCc2cc(Cl)c(Cl)cc21
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)C2CCc3cc(Cl)c(Cl)cc32)C(CN2CCCC2)C1
Yield: 109.2 %

Procedure:
The procedure described in Example 24 was repeated, but using 1.67 g of 1-methyl-3-(pyrrolidin-1-ylmethyl)-piperazine trihydrochloride, 3.6 ml of triethylamine and 1.5 g of 5,6-dichloroindan-1-carbonyl chloride, to afford 1.54 g of the title compound, melting at 245°-250° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][NH:28][CH3:29].O>CN(C=O)C>[CH3:24][O:25][CH2:26][CH2:27][N:28]([CH3:29])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:3]=1
Reactant: CNCCOC
Reactant: O=[N+]([O-])c1ccc(F)cc1OCCc1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: O
Product: COCCN(C)c1ccc([N+](=O)[O-])c(OCCc2cccc(C(F)(F)F)c2)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Dissolved 4-fluoro-1-nitro-2-[2-(3-trifluoromethylphenyl)ethoxy]benzene (200 mg, 0.61 mmol) in DMF (1 mL) and added N-(2-methoxyethyl)methylamine (270 mg, 3.04 mmol). Reaction Mixture was warmed to 60° C. and stirred for 18 h. The reaction mixture was poured into H2O and extracted with EtOAc (2×). The combined organics were washed with brine and dried over Na2SO4. The title compound was carried on crude to the next step.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][C:26]1[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[C:33]([CH3:39])[C:27]=1[CH2:28][C:29]1([NH2:32])[CH2:31][CH2:30]1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:32][C:29]2([CH2:28][C:27]3[C:33]([CH3:39])=[C:34]([CH3:38])[CH:35]=[C:36]([CH3:37])[C:26]=3[CH3:25])[CH2:31][CH2:30]2)=[CH:11][CH:10]=1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: Cc1cc(C)c(C)c(CC2(N)CC2)c1C
Agent: O=C([O-])C(F)(F)F
Product: Cc1cc(C)c(C)c(CC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)c1C

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 203 mg (1 mmol) 1-(2,3,5,6-tetramethyl-benzyl)-cyclopropylamine. Yield: 93 mg (18%, trifluoroacetate); mass spectroscopy: [M+H]+=411.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[CH:19][C:18]=2[CH3:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].CCO>O>[F:25][CH:24]([F:26])[O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:28])=[C:18]([CH3:27])[CH:19]=1
Reactant: CCOC(=O)C1(NC(=O)c2ccc(OC(F)F)cc2C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(OC(F)F)ccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
The mixture of 2-(4-difluoromethoxy-2-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (243) (301 mg, 0.77 mmol), KOH (50% aqueous solution, 1.73 g, 15.5 mmol), EtOH (10 mL) and water (1 mL) are stirred in a 20 mL vial at 50° C. for 30 min. After concentration in vacuo, the residue is dissolved in water (10 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The filtration affords 2-(4-difluoromethoxy-2-methyl-benzoylamino)-indan-2-carboxylic acid (244) as white solid (245 mg, 88%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[C:7]([NH:11][C:12]([C:14]1[S:47][C:17]2[N:18]=[C:19]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29](OC4C=CC([N+]([O-])=O)=CC=4)=[O:30])[CH:23]=3)[C:16]=2[C:15]=1[NH2:48])=[O:13])([CH3:10])([CH3:9])[CH3:8]>ClCCl>[C:7]([NH:11][C:12]([C:14]1[S:47][C:17]2[N:18]=[C:19]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29]([N:1]4[CH2:6][CH2:5][S:4][CH2:3][CH2:2]4)=[O:30])[CH:23]=3)[C:16]=2[C:15]=1[NH2:48])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: C1CSCCN1
Reactant: CC(C)(C)NC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(NC(=O)Oc4ccc([N+](=O)[O-])cc4)c3)c2c1N
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(NC(=O)N4CCSCC4)c3)c2c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thiomorpholine (300 μl) was added to a solution of tert-butyl 5-amino-2-phenyl-4-(3-(p-nitro-phenoxycarbonylamino)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 31(h), 150 mg) in dichloromethane (5 ml) and the reaction mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was diluted with CH2Cl2 and washed with H2O. The organic layer was concentrated under reduced pressure. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: H2O/CH3CN=80/20 to 0/100 (v/v) in 45 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.