Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].F[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Oc3ccc(F)cc3[N+](=O)[O-])cccc2[nH]1
Temperature: 25 °C

Procedure:
4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (0.92 g, 4.483 mmol) and 1,4-Difluoro-2-nitro-benzene (0.486 ml, 4.483 mmol) are dissolved in 10 ml of dimethylformamide. After addition of potassium carbonate (1.2 g, 8.96 mmol) the mixture is stirred over night at room temperature. Then the reaction mixture is evaporated under reduced pressure, dissolved with ethyl acetate and washed with water. The organic layers are dried over sodium sulfate and evaporated. The crude product is used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[CH2:25]([O:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[CH2:3][O:2][CH3:1])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COCc1cc([N+](=O)[O-])ccc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1cc([N+](=O)[O-])ccc1OCc1ccccc1
Temperature: 0 °C

Procedure:
18.3 g of 2-methoxymethyl-4-nitrophenol (1) (0.1 mol), 8.3 g (0.06 mol) of potassium carbonate and 40 ml of dimethylformamide were heated on a boiling water bath, and 12.1 ml (0.105 mol) of benzyl chloride were added over 10 minutes. After heating for 1 hour on the boiling water bath, the mixture was poured onto 150 g of ice. The yellow-brown crystals formed were filtered off, reslurried in ice-cold water and washed with petroleum ether. The wet product was recrystallized from 75 ml of isopropanol to give, after drying, 21 g of expected product with a melting point of 108° C. The results of the elementary analyses were as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][NH:10][C:11]([CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14]2)=O)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C([O-])=O.[NH4+:34]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:34]=[C:11]([CH:13]3[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:14]3)[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: O=C(CNC(=O)C1CN(Cc2ccccc2)CCO1)c1cccc(Cl)c1
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: Clc1cccc(-c2c[nH]c(C3CN(Cc4ccccc4)CCO3)n2)c1
Temperature: 150 °C
Reaction time: 2.5 h
Yield: 96.3 %

Procedure:
A mixture of N-[2-(3-chlorophenyl)-2-oxoethyl]-4-(phenylmethyl)-2-morpholinecarboxamide (350 mg, 0.939 mmol) and ammonium trifluoroacetate (615 mg, 4.69 mmol) was stirred for 2.5 hours at 150° C. Water (150 mL) was added to the residue, and the aqueous mixture was extracted with EtOAc (200 mL). The organic phase was dried (Na2SO4), filtered, and concentrated to afford the title compound (320 mg) as a brown oil. LC-MS (ES) m/z=354 [M+H]+.
Reaction SMILES: N12CCCN=C1CCCCC2.CO[C:14](=[O:37])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[C:16]=1[C:33]([O:35]C)=O.Cl.[NH2:39][CH:40]1[CH2:46][CH2:45][C:44](=[O:47])[NH:43][C:41]1=[O:42].O>CN(C=O)C>[CH2:26]([O:25][C:23](=[O:24])[NH:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]2[C:16]=1[C:33](=[O:35])[N:39]([CH:40]1[CH2:46][CH2:45][C:44](=[O:47])[NH:43][C:41]1=[O:42])[C:14]2=[O:37])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)c1cccc(CNC(=O)OCc2ccccc2)c1C(=O)OC
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)OCc4ccccc4)c3C2=O)C(=O)N1
Temperature: 120 °C
Yield: 22.9 %

Procedure:
1,8-diazabicyclo[5,4,0]undec-7-ene (0.88 g, 6 mmol) was added to a stirred suspension of methyl-3-[(benzyloxycarbonylamino)methyl]-2-(methoxycarbonyl)benzoate (2.07 g, 6 mmol) and aminoglutarimide hydrochloride (0.95 g, 6 mmol) in DMF (15 ml). The mixture was heated to 120° C. for 24 hours. The mixture was cooled to room temperature and poured into water (150 ml). The mixture was extracted with ethyl acetate (3×30 ml) and the combined ethyl acetate extracts were washed with water (2×30 ml), brine (30 ml) and dried. Solvent was removed in vacuo and the residue was purified by chromatography (dichloromethane/ethyl acetate 8 to 2) to give 0.58 g (24%) of the product as a white solid: mp 166–168° C.; 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 7.99–7.71 (m, 4H), 7.37 (m, 5H), 5.19–5.12 (dd, J=5.1 and 17.4 Hz, 1H), 5.07 (s, 2H), 4.70 (d, J=5.7 Hz, 2H), 2.97–2.83 (m, 1H), 2.64–2.51 (m, 2H), 2.08–2.04 (m, 1H); 13C NMR (DMSO-d6) δ 172.55, 169.89, 167.51, 167.01, 156.55, 139.46, 137.02, 134.87, 132.89, 131.57, 128.44, 127.92, 127.83, 127.06, 121.99, 65.69, 48.89, 30.97, 22.02; Anal. Calcd. For C22H19N3O6: C, 62.70; H, 4.54; N, 9.97. Found: C, 62.53; H, 4.57; N, 9.89.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)([O-:3])=[O:2].[BH4-].[Na+]>C1COCC1.CO>[N+:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1ccc2c(C=C[N+](=O)[O-])c[nH]c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1ccc2c(CC[N+](=O)[O-])c[nH]c2c1
Reaction time: 1.5 h

Procedure:
Combine 3-(2-nitrovinyl)-6-ethoxycarbonyl-1H-indole (4.0 g, 15.37 mmol) and NaBH4 (726.7 mg, 19.21 mmol) in 100 ml of THF/Methanol (9:1) and stir at ambient temperature. After 1.5 hours, concentrate to residue. Partition the residue between brine and ethyl acetate, wash with brine, combine the organic layers, dry (Na2SO4), then evaporate to give the title compound as a yellow powder: mp 124–127° C. MS (ACPI): m/e 263.0 (M+1). Analysis for C13H14N2O4: Calcd: C, 59.54; H, 5.38; N, 10.68; found: C, 59.40; H, 5.36; N, 10.53.
Reaction SMILES: C=O.[CH3:3][NH:4][CH3:5].[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1.[OH-].[Na+].[C:18](=O)([O-])[O-].[Na+].[Na+]>O.C(O)(=O)C>[Cl:6][C:7]1[CH:15]=[C:5]2[C:10]([C:11]([CH2:12][N:13]([CH3:18])[CH3:14])=[CH:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: CNC
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CN(C)Cc1c[nH]c2cc(Cl)ccc12

Procedure:
The starting material is prepared as follows: To the solution of 265 ml of acetic acid, 116 ml of 36% aqueous formaldehyde and 190 ml of 40% aqueous dimethylamine, 226.5 g of 6-chloroindole are added portionwise during 45 minutes while stirring at about 40°. The mixture is heated to 60° for 15 minutes and stirred at room temperature for 1 hour. It is cooled to 10°, combined with 500 ml of water, 400 ml of 25% aqueous sodium hydroxide and 100 ml of 20% aqueous sodium carbonate, stirred for 1/2 hour at 10°-20°, and filtered. The filtrate is combined with 250 ml 12% aqueous sodium carbonate, stirred for 1/2 hour, again filtered, both residues are washed with about 3 lt of water, combined and dried, to yield 300 of 6-chloro-3-dimethylaminomethylindole melting at 130°-133°.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][N:14]1[C:21](=[O:31])[C:22]([OH:30])=[C:23]([C:25](OCC)=[O:26])[N:24]=[C:13]21)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH2:40])=[CH:35][CH:34]=1.CCN(CC)CC>C(O)C>[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH:40][C:25]([C:23]2[N:24]=[C:13]3[C:12]4([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20]4)[CH2:15][N:14]3[C:21](=[O:31])[C:22]=2[OH:30])=[O:26])=[CH:35][CH:34]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O)OCc1ccccc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl 10-(((benzyloxy)carbonyl)amino)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (5.00 g, 11.70 mmol), (4-fluorophenyl)methanamine (2.67 mL, 23.39 mmol) and Et3N (3.26 mL, 23.39 mmol) in ethanol (78 mL) was stirred at 90° C. for 16 h, cooled and concentrated. The resulting pale yellow foam was dissolved in ethyl acetate and washed with 1N HCl. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was taken up in hot ethyl acetate and hexane was added until the solution became slightly cloudy. After cooling, the title compound was collected by filtration as a white solid (4.8203 g, 81% yield). 1H NMR (500 MHz, DMSO-D6) δ: 10.25 (s, 1H), 7.52 (s, 1H), 7.34-7.40 (m, 8H), 7.15-7.21 (m, 2H), 5.72 (s, 1H), 4.91 (s, 2H), 4.40 (d, 2H, J=6.4 Hz), 4.15 (s, 2H), 2.48-2.52 9 m, 2H), 2.02-2.08 (m, 2H), 1.94-1.98 (m, 2H), 1.63-1.70 (m, 2H). LCMS (M+H)=507.42.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].[H][H].[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:26](O)=[O:27])=[C:20]2[C:24]=1[O:23][C:22]([CH3:25])=[CH:21]2.S(Cl)(Cl)=O.Cl>O1CCCC1.C1(C)C=CC=CC=1>[Cl:11][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:10])[C:4]=1[NH:3][C:26]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[C:24]2[O:23][C:22]([CH3:25])=[CH:21][C:20]=12)=[O:27]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: [H][H]
Reactant: COc1ccc(C(=O)O)c2cc(C)oc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2cc(C)oc12
Temperature: 0 °C

Procedure:
1.5 g of sodium hydride (80% strength) were added in small portions to a solution of 4.1 g of 4-amino3,5-dichloropyridine in 50 ml of tetrahydrofuran and the suspension was stirred for about 0.5 h until evolution of hydrogen had ended. In parallel to this, 4.1 g of 7-methoxy-2-methylbenzofuran-4-carboxylic acid was stirred at 80° C. for 3 h with 7.25 ml of thionyl chloride in 40 ml of toluene and the mixture was then evaporated in vacuo. About 20 ml of toluene were added to the residue and the solution was evaporated again in vacuo. The residue was then taken up in 50 ml of tetrahydrofuran and this solution was added dropwise at RT to the prepared suspension. After reaction was complete, the mixture was stirred into about 200 ml of ice water, treated with 30 ml of 2 N hydrochloric acid and extracted with ethyl acetate. This extract was dried over calcined sodium sulfate and evaporated in vacuo. The residue was crystallized from ethyl acetate/petroleum spirit (b.p. 50-80° C.): m.p. 233° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([C@H:22]([CH2:34][CH:35]=O)[CH2:23][N:24]([CH3:33])[C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]([C@H:22]([CH2:34][CH2:35][N:11]2[CH2:12][CH2:13][CH:8]([C:7]3[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[CH2:9][CH2:10]2)[CH2:23][N:24]([CH3:33])[C:25](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: Fc1ncccc1C1CCNCC1
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Product: CN(C[C@@H](CCN1CCC(c2cccnc2F)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Product: Cl

Procedure:
Using a procedure similar to that described in Example 1 (alternative preparation), except using 4-(2-fluoropyrid-3-yl)piperidine and (S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide, the title compound was prepared. Conversion to the hydrochloride salt gave a white solid; mp 74°-95° C.; MS: 514; NMR (CD3OD): 1.9-2.3 (b, 6), 2.7-3.2 (m, 9), 3.4-3.9 (m, 4), 7.0-7.2 (m, 3), 7.3-7.4 (m, 5), 7.6 (m, 2), 7.8-7.9 (t, J=8, 1), 8.1 (d, J=4, 1). Analysis for C28H30Cl2FN3O·1.0 HCl·0.5 H2O: Calculated: C, 60.06; H, 5.76; N, 7.50. Found: C, 60.13; H, 6.06; N, 7.02.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)=[CH:5][N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:3]=1.Cl[C:24]1[C:29]([C:30]#[N:31])=[CH:28][CH:27]=[CH:26][N:25]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:24]3[N:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:30]#[N:31])=[CH:13][CH:14]=2)=[CH:5][N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:3]=1
Reactant: Cc1nn(-c2ccccn2)cc1COc1ccc(CO)cc1
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ccccn2)cc1COc1ccc(COc2ncccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
To a mixture of [4-[[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-yl]methoxy]phenyl]methanol (2.00 g), 2-chloro-3-cyanopyridine (1.00 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.30 g) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine dried over anhydrous magnesium sulfate and concentrated to give crystals (2.48 g, 92%) of 2-[4-[[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-yl]methoxy]benzyloxy]nicotinonitrile. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 108-109° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]=[N+]=[N-])=[CH:11][CH:10]=1.O>C1COCC1>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[CH:11][CH:10]=1
Reactant: COc1ccc(CCCCN=[N+]=[N-])cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CCCCN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
Lithium aluminum hydride (55 mL of a 1M solution in THF, 0.055 mol) was added drop wise to a solution of II (7.6 g, 0.037 mol) in dry THF (70 mL) at 0° C. and stirred overnight at room temperature in an argon atmosphere. The reaction mixture was treated with water (1.5 mL), then 15% NaOH (1.5 mL), then with more water (3 mL) and filtered. The solid precipitate was washed with THF. The combined organic fractions were dried over magnesium sulfate and the solvent was removed under reduced pressure to give 6.2 g (94%) of III. The purity of III (99%) was determined by GC. 1H NMR (360 MHz, DMSO-d6) δ1.34 (m, 2H), 1.54 (m, 2H), 2.51 (m, 4H), 3.70 (s, 3H), 6.83 (d, J=8.6 Hz, 2H), 7.08 (d, J=8.3 Hz, 2H), 13C (90 MHz, DMSO-d6) δ28.6, 330, 34.1, 41.5, 54.8, 113.1, 129.1, 132.2, 157.3
Reaction SMILES: C(O[C:6](=[O:31])[NH:7][C@H:8]([C:10](=[O:30])[NH:11][C@H:12]([B:17]1[O:25][C@H:24]2[C@:19]([CH3:29])([C@H:20]3[CH2:26][C@@H:22]([CH2:23]2)[C:21]3([CH3:28])[CH3:27])[O:18]1)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:9])(C)(C)C.[CH:32]([C:35]1[CH:36]=[C:37]([NH:41][C@@H:42]([CH2:46][C:47]2[CH:52]=[C:51]([O:53][CH3:54])[C:50]([O:55][CH3:56])=[C:49]([O:57][CH3:58])[CH:48]=2)C(O)=O)[CH:38]=[CH:39][CH:40]=1)([CH3:34])[CH3:33]>>[CH:32]([C:35]1[CH:36]=[C:37]([NH:41][C@@H:42]([CH2:46][C:47]2[CH:48]=[C:49]([O:57][CH3:58])[C:50]([O:55][CH3:56])=[C:51]([O:53][CH3:54])[CH:52]=2)[C:6]([NH:7][C@H:8]([C:10](=[O:30])[NH:11][C@H:12]([B:17]2[O:25][C@H:24]3[C@:19]([CH3:29])([C@H:20]4[CH2:26][C@@H:22]([CH2:23]3)[C:21]4([CH3:27])[CH3:28])[O:18]2)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:9])=[O:31])[CH:38]=[CH:39][CH:40]=1)([CH3:34])[CH3:33]
Reactant: COc1cc(C[C@H](Nc2cccc(C(C)C)c2)C(=O)O)cc(OC)c1OC
Reactant: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Product: COc1cc(C[C@H](Nc2cccc(C(C)C)c2)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)cc(OC)c1OC

Procedure:
The title compound is prepared as described in example 1 but using {(S)-1-[(R)-3-Methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester and (S)-2-(3-Isopropyl-phenylamino)-3-(3,4,5-trimethoxy-phenyl)-propionic acid.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Br:13])[N:6]([CH3:14])[C:5]=1[C:15]([O:17]C)=O)(=O)[CH3:2].[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)(=O)C>[Br:13][C:11]1[C:12]2[C:4]3[C:1]([CH3:2])=[N:26][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:15](=[O:17])[C:5]=3[N:6]([CH3:14])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1c(C(C)=O)c2c(Br)cccc2n1C
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Product: Cc1nn(-c2ccccc2)c(=O)c2c1c1c(Br)cccc1n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
22 g (71 mmol) of methyl 3-acetyl-4-bromo-1-methyl-1H-indole-2-carboxylate are dissolved with heating in 350 ml of acetic acid. 30 ml (300 mmol) of phenylhydrazine are added, stirring is carried out for 1 h at room temperature and the reaction mixture is heated at reflux for 5 h, at room temperature for 15 h and then again at reflux for 7 h. 28 ml of phenylhydrazine are added and the process is repeated. The mixture is concentrated under reduced pressure, the residue is taken up in water and the precipitate is collected by filtration, washed with water and dried under reduced pressure. It is purified by chromatography on a column of silica gel. 11.1 g (30 mmol) of product are isolated.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19]4[N:20]=[CH:21][CH:22]=[N:23][C:24]=4[C:25]([C:28]4[C:33](Cl)=[C:32](OC)[CH:31]=[C:30](OC)[C:29]=4Cl)=[CH:26][CH:27]=3)=[O:17])=[N:13][CH:14]=2)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[S:62]1C=C(C2C3N=CC=NC=3C(C(O)=O)=CC=2)[C:64]2C=CC=C[C:63]1=2.S1C2C=CC=CC=2C(B(O)O)=C1>C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19]4[N:20]=[CH:21][CH:22]=[N:23][C:24]=4[C:25]([C:28]4[C:29]5[CH:30]=[CH:31][CH:32]=[CH:64][C:63]=5[S:62][CH:33]=4)=[CH:26][CH:27]=3)=[O:17])=[N:13][CH:14]=2)[CH2:6][CH2:7]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Reactant: O=C(O)c1ccc(-c2csc3ccccc23)c2nccnc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: OB(O)c1csc2ccccc12
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(-c4csc5ccccc45)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture at rt overnight and using 2 equiv of 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride (Example 31), TBTU (2 equiv) and 8-benzo[b]thiophen-3-yl-quinoxaline-5-carboxylic acid. The carboxylic acid was synthesized as described in Steps 1.2-1.7 but using benzothiophene-3-boronic acid in Step 1.4. Title compound: ESI-MS: 494.9 [M+H]+; tR=3.77 min (System 1); TLC: Rf=0.17 (DCM/MeOH, 9:1).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]12[C:26](=[O:27])[N:25]([CH2:28][C:29]([F:32])([F:31])[F:30])[N:24]=[C:23]1[CH2:22][CH2:21][NH:20][CH2:19]2>CC(C)=O.O>[C:6]([C@H:4]([C@@H:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]12[C:26](=[O:27])[N:25]([CH2:28][C:29]([F:31])([F:32])[F:30])[N:24]=[C:23]1[CH2:22][CH2:21][NH:20][CH2:19]2
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: O=C1N(CC(F)(F)F)N=C2CCNCC12Cc1ccccn1
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a dry and nitrogen purged 5 L round bottom flask equipped with a mechanical stirrer, D(−) tartaric acid (129 g, 0.86 mol) was added to the product from step C (243 g, 0.78 mol) in acetone/water (9:1, 2430 mL) at about 17° C. The mixture was stirred at room temperature overnight, filtered, the solid was collected and washed with cold acetone and dried under vacuum. The product was obtained as a yellow solid (284 g, yield 78.8%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](=[O:12])([O-])[O-:10].[K+].[K+].[CH3:15][C:16]([CH3:18])=[O:17]>>[CH2:1]([O:17][C:16]1[CH:18]=[C:3]([CH2:4][C:9]([OH:10])=[O:12])[CH:2]=[CH:1][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Reactant: CC(C)=O
Agent: [K+]
Product: O=C(O)Cc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To 50 ml of methanol was added 3-hydroxyphenyl acetic acid (7.61 g, 0.05 mol). The mixture was cooled in an ice bath and then thionyl chloride was added (3.6 ml, 0.05 mol). The mixture was refluxed for 4 hrs and methanol was evaporated. The residue was extracted with ethyl acetate and sodium bicarbonate solution. The organic layer was dried and evaporated to give an oil (8.90 g). This oil was dissolved in 150 ml of acetone containing benzyl bromide (9.17 g, 0.053 mol) and potassium carbonate (16.9 g, 0.16 mol). The mixture was stirred at room temperature overnight. The solid was removed through filtration and solvents was evaporated. The residue was extracted with ethyl acetate and sodium bicarbonate solution. The organic layer was dried and evaporated. The residue was suspended in 70 ml of methanol and 1N sodium hydroxide solution was added (70 ml). The mixture was refluxed for 1 hr and solvents were evaporated. The residue was dissolved in 150 ml of water and extracted with ether. The aqueous layer was acidified with 1N hydrochloric acid and the white precipitate was filtered to give 3-benzyloxyphenyl acetic acid (11.0 g, 91%).
Reaction SMILES: [C:1](OCCOC(=O)C(C)=C)(=O)[C:2](C)=[CH2:3].COC.[C:18]1([CH:25]=[CH:24][C:22](O)=[CH:21][CH:20]=1)O>>[CH:2]([C:18]1[CH:25]=[CH:24][CH:22]=[CH:21][CH:20]=1)([CH3:3])[CH3:1]
Reactant: Oc1ccc(O)cc1
Reactant: C=C(C)C(=O)OCCOC(=O)C(=C)C
Agent: COC
Product: CC(C)c1ccccc1

Procedure:
85.6 g ethylene glycol dimethacrylate (Aldrich, 98%, 100 ppm methyl ether of hydroquinone (MEHQ)
Reaction SMILES: [CH3:1][C:2]([N:4](C)C)=O.[C:7]1(=[O:17])[O:12][C:10](=O)[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.[K+].[Br-].[C:20]1(C)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:24]([C:25]1[CH:1]=[C:2]([N:4]2[C:7](=[O:17])[C:8]3=[CH:16][CH:15]=[CH:14][CH:13]=[C:9]3[C:10]2=[O:12])[CH:22]=[CH:21][CH:20]=1)#[CH:23]
Reactant: CC(=O)N(C)C
Reactant: Cc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Br-]
Agent: [K+]
Product: C#Cc1cccc(N2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a reaction apparatus as described in Example 1 which was maintained under a positive pressure of argon was added 20 g (0.171 mole) APA and 125 ml of DMA. To this stirred solution was slowly added 25.3 g (0.171 mole) phthalic anhydride at such a rate as to maintain the temperature of the mixture below 50° C. The mixture was then stirred for 1 hour at room temperature. Seventy (70) ml of toluene was added to the flask and the mixture was heated to azeotropic distillation to remove the water of imidization. When no further water was collected the remainder of the toluene was distilled. The reaction solution (at 50° C.) was poured into 1500 ml of distilled water. The imide (V) precipitated, was filtered, washed with water, and then dried in an air circulating oven at 95° C. overnight to yield 39.5 g (0.160 mole, 93% theoretical). The imide had a melting point of 197°-198° C. (387° F.). IR (KBr) analysis: 3280 cm-1 (--C≡CH), 1780 and 1720 cm-1 (imide C=0 ).