Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH:13]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[C:9]([C:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH:13]=3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nc(-c3ccccc3)cs2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2nc(-c3ccccc3)cs2)CCNC1
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a solution of tert-butyl 4-(4-phenylthiazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (206 mg, 0.602 mmol) in CH2Cl2 (2.4 mL) was added TFA (0.232 mL). The solution turned bright red immediately, and after stirring overnight the color had become orange. The solution was concentrated under reduced pressure and the crude oil obtained purified with a 5 g SCX-2 column washing first with MeOH, then with 2M NH3 in MeOH leading to elution of basic materials. Upon drying, 4-phenyl-2-(1,2,3,6-tetrahydropyridin-4-yl)thiazole (121 mg, 0.499 mmol, 83%) was obtained as a yellow oil.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1>O1C=CC=C1>[CH:4]12[O:6][CH:1]([CH:3]3[C:4](=[O:5])[O:6][C:1](=[O:7])[CH:2]31)[CH:2]=[CH:3]2
Reactant: O=C1C=CC(=O)O1
Solvent: c1ccoc1
Product: O=C1OC(=O)C2C3C=CC(O3)C12
Yield: 170 %

Procedure:
Maleic anhydride (50 g) and furan (150 ml) were heated under reflux for 1 hour, and then the excess of furan was distilled off. The residue was recrystallised from chloroform, yielding 72 g of 7-oxabicyclo [2.2.1]hept-2-ene-5,6-dicarboxylic acid anhydride (m.pt. 110° C., decomp.). This anhydride (40 g) and 30.75 g of 2-hydroxyethyl acrylate were heated in 250 ml of toluene at 100° C. for 3 hours, and then the toluene was distilled off under reduced pressure, leaving the desired compound as a viscous liquid.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[C:18](Cl)=[N:17][C:16]([Cl:20])=[CH:15][N:14]=1)[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>C1COCC1>[CH2:1]([N:8]1[CH2:12][C:13]2[N:14]=[CH:15][C:16]([Cl:20])=[N:17][C:18]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCN(Cc1ccccc1)Cc1ncc(Cl)nc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of 2-{benzyl[(3,5-dichloropyrazin-2-yl)methyl]amino}ethanol (3.425 g) in THF (100 mL) was added potassium tert-butoxide (1.48 g) under ice-cooling, and the mixture was stirred for 1 hr under ice-cooling. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (solvent gradient: 5→25% ethyl acetate/hexane) to give the title compound (2.59 g, 86%) as a pale-yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:18][N:17]=[C:16]([CH3:19])[N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:21]>C(Cl)Cl.C(OCC)C>[ClH:21].[ClH:21].[CH3:19][C:16]1[N:15]=[C:14]([N:11]2[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]2)[S:18][N:17]=1
Reactant: Cc1nsc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1nsc(N2CCC(N)CC2)n1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of [1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (256 mg, 0.86 mmol) in CH2Cl2 (8.6 mL) was added at room temperature under stirring a 2 M HCl solution in diethyl ether (4.3 mL) and was stirred at room temperature over night. The solvent was removed under reduced pressure. The crude product was treated twice with diethyl ether to yield the title compound as a yellow semi-solid (260 mg, 100%)
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C@H:6]([CH3:30])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])=[CH:21][CH:20]=2)[CH2:11][CH2:10]1)=[O:8].[CH3:31][C:32]([CH3:34])=O>>[CH:27]1([C:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][N:9]([C:7](=[O:8])[C@H:6]([NH:5][CH:32]([CH3:34])[CH3:31])[CH3:30])[CH2:14][CH2:13]3)=[CH:24][CH:23]=2)=[O:26])[CH2:29][CH2:28]1
Reactant: CC(C)=O
Reactant: C[C@@H](N)C(=O)N1CCN(CCCOc2ccc(C(=O)C3CC3)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)N[C@H](C)C(=O)N1CCN(CCCOc2ccc(C(=O)C3CC3)cc2)CC1
Reaction time: 8 h
Yield: 25 %

Procedure:
Sodium cyanoborohydride (75 mg, 1.2 mmol) was added to a room temperature solution of Example 138 (401 mg, 1 mmol) in acetone (10 mL). After stirring overnight, the reaction mixture was concentrated, and the concentrate was taken up in dichloromethane and washed with water, and brine, dried (Na2SO4), filtered, concentrated and purified by silica gel column chromatography using dichloromethane:methanol (9:1) as the eluant. The product was obtained in 25% yield.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Mg].[CH3:9][O:10][C:11](=O)[O:12]C>C1COCC1>[CH3:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:11]([O:10][CH3:9])=[O:12]
Reactant: COC(=O)OC
Reactant: Cc1ccsc1Br
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(=O)c1sccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
2-Bromo-3-methylthiophene (10.0 g, 0.0565 mol) was slowly added dropwise over a 60 minute period to a slurry of magnesium turnings (1.72 g, 0.0706) in THF. During the course of the addition, the exotherm was controlled to <40° C. by external cooling with a water bath. After the addition was completed, the resulting mixture was stirred at ambient temperature for 60 minutes. Dimethylcarbonate (7.63 g, 0.0847 mol) was then added dropwise over a 5-minute period, and the reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was quenched by the addition of 6 M HCl (50 mL), and extracted with ethylacetate (100 mL). The organic phase was washed with water (25 mL), followed by saturated aqueous NaHCO3. Concentration of the organic phase then gave 7.38 g (84%) of methyl 3-methyl-2-thiophenecarboxylate as a light yellow oil.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([OH:16])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2)[CH3:3].[H-].[Na+].F[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1>CN(C=O)C>[CH3:3][CH:2]([C:4]1[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([O:16][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2)[CH3:1]
Reactant: COc1ccc2c(O)c(-c3ccccc3)c(C(C)C)cc2c1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(C(C)C)cc2c1
Yield: 91 %

Procedure:
3-(1-Methylethyl)-6-(methyloxy)-2-phenyl-1-naphthalenol (72) (0.35 g, 1.21 mmol) was treated with NaH in DMF followed by addition of 4-fluorobenzaldehyde to give 0.44 g (91%) of the title compound (73) as a light yellow foam. 1H NMR (400 MHz, CDCl3): δ 1.20 (d, J=6.8 Hz, 6H), 2.91 (sept, J=6.8 Hz, 1H), 3.94 (s, 3H), 6.67 (d, J=8.8 Hz, 2H), 7.05 (dd, J1=9.0 Hz, J2=2.4 Hz, 1H), 7.08-7.13 (m, 2H), 7.18-7.26 (m, 4H), 7.61 (d, J=8.6 Hz, 2H), 7.64-7.70 (m, 2H), 9.79 (s, 1H). LCMS (ESI): m/z 397 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2.[N+:19]([O-])([OH:21])=[O:20]>OS(O)(=O)=O>[F:1][C:2]1[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2
Reactant: Fc1cccc(F)c1-c1ccc2ncccc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(F)c(-c2ccc3ncccc3c2)c1F
Yield: 70 %

Procedure:
The title compound was prepared by the method of Example 1B. A 5.00 g sample (70% yield) was made from 6-(2,6-difluorophenyl)-quinoline (6.02 g, 25 mmoles) and 50 ml of concentrated H2SO4 and 1.5 ml of concentrated HNO3. The product was isolated as an off white solid of m.p. 152°-153° C. NMR (DMSO-d6, 250 MHz): 9.05 (d of d, 1H), 8.50 (d, J=5 Hz, 1H), 8.40 (sextet, 1H), 8.24 (s, 1H), 8.20 (d, J=5.0 Hz, 1H), 7.87 (d, J=5.0 Hz, 1H), 7.60 (m, 2H).
Reaction SMILES: CC(C)[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:26])[C:4]([O:6][CH3:7])=[O:5].Br[CH2:29][C:30]1C=CC(C2C=CC([N+]([O-])=O)=CC=2)=C[C:31]=1C(OC)=O.Cl.NC1(C(OC)=O)CCC1>>[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][N:8]([C:3]4([C:4]([O:6][CH3:7])=[O:5])[CH2:31][CH2:30][CH2:29]4)[C:9]3=[O:26])=[CH:14][CH:13]=2)=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: COC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)ccc1CBr
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1=O
Agent: COC(=O)C1(N)CCC1
Agent: Cl
Product: COC(=O)C1(N2Cc3ccc(-c4ccc([N+](=O)[O-])cc4)cc3C2=O)CCC1
Yield: 71 %

Procedure:
The compound of example 573 was prepared analogous to compound of example 5 by reaction of compound of example 4 with methyl 1-aminocyclobutanecarboxylate hydrochloride.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:12]([NH:13]C(OC(C)(C)C)=O)=[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:10][CH:9]=1)(C)(C)C.Br.CCOCC>C(O)(=O)C>[C:21]1([C:11]2[S:10][CH:9]=[C:8]([NH2:7])[C:12]=2[NH2:13])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1csc(-c2ccccc2)c1NC(=O)OC(C)(C)C
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: Nc1csc(-c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
To a solution of compound 59 in glacial acetic acid (102 μL) was added a 30% solution of HBr in acetic acid (102 μL). The mixture was stirred for 16 h at r.t. and Et2O (10 mL) was added. The precipitate was collected by filtration and immediately dissolved in water, neutralized by addition of 2N aqueous NaOH and the precipitate was extracted with Et2O. The organic layer was dried over MgSO4 and concentrated in vacuum affording the title compound 60 (34 mg, 69% yield). This procedure is essentially as described in Brugier et al., Tetrahedron, 30: 10331-10344 (1997), which is incorporated by reference in its entirety. 1H NMR: (CDCl3) δ(ppm): 7.49 (dd, J=8.4, 1.4 Hz, 2H), 7.41 (t, J=7.6 Hz, 2H), 7.26 (dd, J=10.2, 7.2 Hz, 1H), 6.22 (s, 1H), 3.51 (bs, 4H). m/z: 191.3 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:27][CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)nc3N21
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCCOC4CCCCO4)nc3N21

Procedure:
This compound was prepared in analogy to Example 15 intermediate c), from (4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and 2-(2-bromoethoxy)tetrahydro-2H-pyran.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9][CH2:8][CH2:7][C:6]2=1.[CH:25](N(C(C)C)CC)(C)C.CI.Cl>C1COCC1>[ClH:1].[Br:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([N:16]([CH3:25])[CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9][CH2:8][CH2:7][C:6]2=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Brc1ccc2[nH]c3c(c2c1)CCCC3NCCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CI
Product: CN(CCc1ccccc1)C1CCCc2c1[nH]c1ccc(Br)cc21
Reaction time: 12 h

Procedure:
6-Bromo-N-methyl-N-(2-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt was prepared from 6-bromo-N-(2-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt (0.05 g, 0.12 mmol), diisopropylethyl amine (0.04 mL, 0.25 mmol) and methyl iodide (0.008 mL, 0.12 mmol) in THF (2.0 mL). The reagents were added to a round bottom flask and allowed to stir for 12 hrs. at room temperature under inert atmosphere. The solvent was evaporated, ethyl acetate was added (10 mL), the organics were washed with water (2.0 mL) and sat. NaCl (2.0 mL), dried over Na2SO4, filtered and evaporated to leave an oily residue. Purification by flash chromatography with gradient 10-50% ethyl acetate/hexanes eluent afforded a clear oil that was converted to the HCl salt to give a white solid (0.01 g, 20%). 1H-NMR (CDCl3): δ 8.30 (s, 1H), 7.53 (d, 2H), 7.38-7.10 (m, 5H), 6.89 (d, 1H), 4.09 (m, 1H), 3.04-2.95 (m, 1H), 2.90-2.80 (m, 2H), 2.70-2.55 (m, 3H), 2.48 (s, 3H), 2.11-1.99 (m, 2H), 1.70-1.60 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].Br[CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18]>>[CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]([CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2]
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Reactant: CC(C)=CCBr
Product: COC(=O)c1c(C=O)c(C)c(C)n1CC=C(C)C

Procedure:
The title compound was prepared as a pale yellow-orange solid in 85.4% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 1-bromo-3-methyl-2-butene.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([CH2:15][S:16][CH3:17])[CH:7]=1.[Cl-].[NH4+]>O1CCCC1>[F:5][C:6]1[CH:11]=[C:10]2[C:9](=[C:8]([CH2:15][S:16][CH3:17])[CH:7]=1)[NH:12][CH:2]=[CH:1]2
Reactant: C=C[Mg]Br
Reactant: CSCc1cc(F)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSCc1cc(F)cc2cc[nH]c12
Temperature: -40 °C
Reaction time: 3 h

Procedure:
180 ml (180 mmol) of a 1N solution of vinylmagnesium bromide in tetrahydrofuran were added dropwise to a solution of 9.00 g (44.7 mmol) of the compound from Example 4A in 100 ml of tetrahydrofuran under argon at −40° C., and the mixture was stirred at −40° C. for 3 h. The reaction mixture was then added to saturated aqueous ammonium chloride solution and extracted with tert-butyl methyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (mobile phase: petroleum ether/ethyl acetate 9/1) to result in 5.00 g (57% of theory) of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH:14][C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[O:16])[CH:6]=1)=[O:4].CO.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[N:20]1[CH:21]=[CH:22][C:17]([C:15]([NH:14][CH2:13][CH2:12][N:7]2[C:8](=[O:11])[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6]2)=[O:16])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(=O)n(CCNC(=O)c2ccncc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1ccc(=O)n(CCNC(=O)c2ccncc2)c1

Procedure:
1,6-dihydro-1-[2-(4-pyridinylcarbonylamino)ethyl]-6-oxo-3-pyridinecarboxylic acid methyl ester (0.600 g, 2.0 mmol) was hydrolysed in a mixture consisting of methanol (4.0 ml), water (0.7 ml), and 15% aqueous sodium carbonate (6.0 ml) at 75°-80° C. for 1.25 hours. The solution was acidified (to pH 5.5 with acetic acid). The precipitated product was recovered by filtration, washed with water, and dried, MP: >300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.[CH:43]1([CH2:46][NH:47][CH3:48])[CH2:45][CH2:44]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:47]([CH2:46][CH:43]1[CH2:45][CH2:44]1)[CH3:48])=[O:25]
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Reactant: CNCC1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN(CC1CC1)C(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and cyclopropylmethyl-methylamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[O:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][N:39]=2)[CH2:34][CH2:33]1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:41]3[CH:40]=[N:39][C:38]([N:35]5[CH2:34][CH2:33][O:32][CH2:37][CH2:36]5)=[CH:43][CH:42]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: OB(O)c1ccc(N2CCOCC2)nc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(N2CCOCC2)nc1)N1CCN(C2CCC2)CC1
Yield: 29 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 2-morpholino-5-pyridineboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (29%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[CH2:4][N:5]1[C:17]2[CH:16]=[N:15][C:14]([C:18]([O:20]C)=O)=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.[NH2:27][NH2:28]>CO>[Cl:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[CH2:4][N:5]1[C:17]2[CH:16]=[N:15][C:14]([C:18]([NH:27][NH2:28])=[O:20])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: COC(=O)c1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Reactant: NN
Solvent: CO
Product: NNC(=O)c1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
A mixture of methyl 9-(2,5-dichlorobenzyl)-9H-β-carboline-3-carboxylate (4.8 g, 12.5 mmole), hydrazine (6 mL) and methanol (50 mL) was refluxed for 5 hours. The reaction mixture was cooled to room temperature, and the precipitate was collected by filtration. The solid was treated with methanol (50 mL) and the slurry stirred for 10 minutes, filtered, and dried, affording 4.6 grams (98%) of the title compound. 1H NMR (DMSO-d6) δ9.5 (s, 1H), 8.8 (s, 1H), 8.7 (s, 1H), 8.25 (d, 1H), 7.6-7.4 (m, 3H), 7.2-7.1 (m, 2H), 6.5 (s, 1H), 5.7 (s, 2H), 4.3 (s, 2H) MS (APCI; (M+H)+) m/z 385.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.C([Li])CCC.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[CH:22]=[O:23].CC(O)C>C1COCC1.O>[O:6]1[C:5]2[CH:10]=[CH:11][C:2]([CH:22]([C:21]3[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=[C:19]([O:18][CH3:17])[CH:20]=3)[OH:23])=[CH:3][C:4]=2[O:9][CH2:8][CH2:7]1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: Brc1ccc2c(c1)OCCO2
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
A solution of 6-bromo-2,3-dihydrobenzo[1,4]dioxine (1.09 g, 5.07 mmol) in anhydrous THF (10 ml) was cooled to −78° C., evacuated and refilled with nitrogen for ten cycles. To this clear solution was slowly added n-butyl lithium (2.03 ml, 5.07 mmol) and stirred for 30 min. Then a solution of 3,5-dimethoxybenzaldehyde (0.77 g, 4.61 mmol) in anhydrous THF (10 ml) was added via a syringe. The mixture was stirred at −78° C. under nitrogen for 4 h then quenched with 2-propanol (2.10 ml, 27.65 mmol) and stirred overnight. To the orange colored mixture was added 30 ml of water and extracted with ether (3×60 ml). The combined ether extracts was washed with water (2×60 ml), dried over MgSO4, filtered and concentrated in vacuo to an oil, which was purified via flash column chromatography (10% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3,5-dimethoxy-phenyl)-methanol as a light brown oil (1.27 g, 91%), HPLC purity was 93.4% at 3.45 min. (50/50 ACN/0.1% H3PO4): 1HNMR (CDCl3) δ 6.88-6.79 (m, 3H, Ar), 6.54 (d, J=2 Hz, 2H, Ar), 6.35 (t, J=2 Hz, 1H, Ar), 5.65 (d, J=3 Hz, 1H, CH), 4.22 (m, 4H, 2CH2), 3.77 (s, 6H, OCH3), 2.25 (d, J=3 Hz, 1H, OH). The product was carried over to the next step.
Reaction SMILES: C(OC([NH:8][C@H:9]([C@@H:17]([OH:22])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][C@H:9]([C@@H:17]([OH:22])[CH2:18][CH:19]([CH3:20])[CH3:21])[CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CC(C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](O)[C@@H](N)CC1CCCCC1
Yield: 100.4 %

Procedure:
A solution of (2S,3S)-2-t-butoxycarbonylamino-1-cyclohexyl-3-hydroxy-5-methylhexane (120 mg) in trifluoroacetic acid (3 ml) was stirred at 0° C. for 30 minutes. After evaporation of the solvent, the residue was dissolved in ethyl acetate (10 ml). The solution was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, and evaporated in vacuo to give (2S,3S)-2-amino-1-cyclohexyl-3-hydroxy-5-methylhexane (82 mg) as an oil. Rf: 0.30 (chloroform: methanol: acetic acid, 16:1:1, V/V)
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][N:13]=2)[CH:6]=[CH:7][CH:8]=1.Br>C([O-])(O)=O.[Na+]>[O:10]1[CH:11]=[CH:12][N:13]=[C:9]1[C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(-c2ncco2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1cccc(-c2ncco2)c1
Temperature: 115 °C
Reaction time: 8 h

Procedure:
The product obtained in Step A above (250 mg, 1.13 mmol) is suspended in 10 ml of aqueous 48% HBr solution, and the reaction mixture is stirred overnight at 115° C. After cooling to ambient temperature, the mixture is poured into 10 ml of 10% NaHCO3 solution. The pH is adjusted to 7 and the aqueous phase is extracted with ethyl acetate. The organic phase is washed (saturated NaCl) and dried (MgSO4) to yield, after filtration and evaporation, the title product in the form of a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:35])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[N:30]([CH3:34])[N:31]=[CH:32][CH:33]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[N:30]([CH3:34])[N:31]=[CH:32][CH:33]=4)[CH:24]=3)[CH2:20][C:19](=[O:35])[NH:18][C:9]=2[CH:10]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnn3C)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnn3C)c1)=N2

Procedure:
The title compound was prepared from (4-chloro-5-dimethylamino-2-{3-[3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert.-butyl ester (Example M16) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (67 mg).