Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18].N12CCN(CC1)CC2.O>CN(C)C=O>[CH3:12][C:10]([CH3:11])([CH3:13])[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:17](=[O:18])[N:16]([CH3:15])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:7][CH:6]=1)=[O:14]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CC(C)(C)C(=O)Nc1ccc(O)nc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)Oc1ccc(NC(=O)C(C)(C)C)cn1)c1ccccc1
Yield: 56 %

Procedure:
A solution of N-(6-hydroxy-pyridin-3-yl)-2,2-dimethyl-propionamide (0.58 g, 3.00 mmol), N -methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.00 mmol) in dimethylformamide (20 ml) was stirred at room temperature for 1 hour. Water was added and a thick oil was being formed. The water was decanted and the residue was dissolved in dichloromethane. The solution was dried over sodium sulphate, filtered and evaporated in vacuo yielding the title compound (0.55 g, 56% yield) as a brown oil that solidified upon standing.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[NH:22][CH2:21][C@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1.[CH3:30][O:31][CH2:32][C:33](O)=[O:34]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[N:22]([C:33](=[O:34])[CH2:32][O:31][CH3:30])[CH2:21][C@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1
Reactant: COCC(=O)O
Reactant: COc1cc(OC[C@@H]2C[C@@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Product: COCC(=O)N1C[C@H](O)C[C@H]1COc1cc(OC)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Yield: 91 %

Procedure:
The procedure described in Example 25 was repeated using (3R,5S)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol (209 mg) with methoxyacetic acid (42 μl) to give the title compound as a white solid in 91% yield; NMR spectrum (DMSO-d6) 9.96 (s, 1H), 8.45 (s, 1H), 8.17-8.14 (m, 1H), 7.76-7.72 (m, 1H), 7.45 (t, 1H), 6.83 (s, 2H), 5.10 (m, 1H), 4.73-4.69 (m, 1H), 4.47-4.38 (m, 2H), 4.25 (dd, 1H), 4.10-3.98 (m, 2H), 3.94 (s, 3H), 3.51 (dd, 1H), 3.40 (s, 1H), 3.29 (s, 3H), 2.05-2.02 (m, 2H); Mass spectrum MH+ 491.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].Cl.Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>COCCO>[N:21]1[CH:22]=[CH:23][C:18]([NH:1][C:2]2[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=2[C:4]([N:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)=[O:5])=[CH:19][CH:20]=1
Reactant: Clc1ccncc1
Reactant: Nc1ccccc1C(=O)N1CCCCC1
Agent: Cl
Solvent: COCCO
Product: O=C(c1ccccc1Nc1ccncc1)N1CCCCC1
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
A solution of 2.77 kg 1-(2-aminobenzoyl)piperidine in 16 liters of 2-methoxyethanol was heated until solvent distillation was about to begin (125° C. internal temperature). A solution of 2.1 kg 4-chloropyridine hydrochloride in 21 liters of 2-methoxyethanol was then slowly added over a period of one hour during which 4 liters of distillate was collected. Heating was continued for another hour while 16 liters of distillate was collected. The reaction mixture was concentrated in vacuo, and the thick residue was dissolved in 10 liters of water. Sodium acetate trihydrate (1.85 kg) was added and the solution washed three times with 3 liters of isopropyl acetate and decolorized with activated charcoal. The aqueous solution was made basic (pH>10) by dropwise addition of sodium hydroxide solution. Seeding during the addition generated a precipitate. A small amount of acetic acid was added to lower the pH to 8.5-9, and after 30 minutes of stirring the product was collected, washed with water and air dried to give 2.51 kg of 1-[2-(4-pyridinylamino)benzoyl]piperidine, m.p. 152°-153° C. The latter product was further purified by recrystallization from acetone to give the compound with m.p. 154°-155° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:21][C@H:20]2[C:22]([OH:24])=O)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=[N:43][C:38]2[CH:39]=[CH:40][CH:41]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NCC1CC1>ClCCl.CN(C=O)C>[CH:39]1([CH2:38][NH:43][C:22]([CH:20]2[CH2:21][CH:19]2[C:16]2[CH:17]=[CH:18][C:13]([NH:12][CH2:11][C:10]3[CH:25]=[CH:26][CH:27]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)=[CH:14][CH:15]=2)=[O:24])[CH2:41][CH2:40]1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCC1CC1)C1CC1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Reaction time: 0.25 h
Yield: 9.7 %

Procedure:
To a mixture of (+)-(trans)-2-{4-[(3-phenoxybenzyl)amino]phenyl}cyclopropanecarboxylic acid (III-3b) (0.09 g, 0.25 mmol) in dichloromethane (2 mL) and DMF (1 mL) was added HATU (0.14 g, 0.37 mmol). The mixture was stirred for 15 min followed by addition of aminomethylcyclopropane (0.03 g, 0.37 mmol). The solution stirred for 4 h after which the dichloromethane was removed via rotavap. Sat. NaHCO3 and ethyl acetate were added and the organic layer separated and washed with H2O, dried over MgSO4, filtered and concentrated. The crude material was purified on silica gel eluting with an increasing gradient from hexanes to 30% ethyl acetate/hexanes to give the title compound as a white powder (0.01 g, 11%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.28 (m, 3H), 7.10-7.08 (m, 2H), 7.02-6.98 (m, 3H), 6.92-6.89 (m, 3H), 6.55 (d, J=8.3 Hz, 2H), 5.68 (s, 1H), 4.29 (s, 2H), 4.01 (s, 1H), 3.15-3.12 (m, 2H), 2.39 (s, 1H), 1.57-1.46 (m, 2H), 1.17-1.14 (m, 1H), 0.95 (s, 1H), 0.51 (d, J=7.7 Hz, 2H), 0.20 (d, J=4.6 Hz, 2H). ES-MS m/z 413.3 (MH+).
Reaction SMILES: [N+](C(CC)CC)([O-])=O.[CH2:9]([C:11]([N+:24]([O-])=O)([CH2:22][CH3:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH3:10].C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:9]([C:11]([NH2:24])([CH2:22][CH3:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH3:10]
Reactant: CCC(CC)(Cc1c[nH]c2ccccc12)[N+](=O)[O-]
Agent: CCC(CC)[N+](=O)[O-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCC(N)(CC)Cc1c[nH]c2ccccc12

Procedure:
If the procedure of Example 3 is applied to the corresponding quantity of 3-nitropentane instead of 2-nitrobutane, 3-(2'-ethyl-2'-nitrobutyl)-indole is initially obtained with a melting point of 92°-94°C. (from benzine). Reduction yields 3-(2'-ethyl-2'-aminobutyl)-indole with a melting point of 130.5°-131.5°C. (from CCl4).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>>[CH2:2]([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: c1c[nH]cn1
Reactant: BrCCc1ccccc1
Product: c1ccc(CCn2ccnc2)cc1
Yield: 59.1 %

Procedure:
β-Bromoethylbenzene (10 g) and 10.6 g of imidazole were reacted at 200° C. for 5 hours, and the reaction mixture was extracted with 200 ml of chloroform. After being washed with a 10% sodium hydrogen carbonate aqueous solution and then with water, the resultant chloroform layer was separated and dried over salt cake. The solvent was then distilled off under reduced pressure and the residue was purified by distillation under reduced pressure to give 5.50 g (yield 45%) of N-phenethylimidazole as an oily material. B.P. 158° to 159° C./5 mmHg. A solution of 0.43 g of the obtained N-phenethylimidazole in 5 ml of ether was then added to a solution of 2.14 g of α-cyclodextrin in 50 ml of water, and the mixture was stirred at room temperature for 3 hours. The mixture was then lyophilized to give a colorless powder which in turn was washed twice with 50 ml of ether and dried under reduced pressure at 50° C. The product was dissolved in deuterium oxide, and it was confirmed from the proton integration ratio of the proton nuclear magnetic resonance spectra that the product was a clathrate compound of α-cyclodextrin and N-phenethylimidazole in a molar ratio of 1 to 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:19])[C:9]2([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11][CH2:10]2)=[CH:4][C:3]=1[N+:20]([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:20][C:3]1[CH:4]=[C:5]([CH:8]([OH:19])[C:9]2([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:10][CH2:11]2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CC(C)(C)OC(=O)C1(C(O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1(C(O)c2ccc(Cl)c(N)c2)CC1
Reaction time: 72 h

Procedure:
2.72 g (8.30 mmol) of tert-butyl 1-[(4-chloro-3-nitrophenyl)(hydroxy)methyl]cyclopropane-carboxylate were dissolved in 100 ml of ethyl acetate, and 177 mg of palladium on carbon (10%) were added. For three days, the reaction mixture was stirred vigorously under a stationary atmosphere of hydrogen at atmospheric pressure. The mixture was then filtered through Celite and the filtrate obtained was evaporated to dryness. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 1.97 g of the target compound (80% of theory).
Reaction SMILES: CO[C:3]1[CH2:7][CH2:6][CH2:5][N:4]=1.[C:8]1([C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCCCCC>[C:8]1([C:14](=[O:19])[C:15](=[C:3]2[CH2:7][CH2:6][CH2:5][NH:4]2)[C:16](=[O:18])[CH3:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC1=NCCC1
Reactant: CC(=O)CC(=O)c1ccccc1
Solvent: CCCCCC
Product: CC(=O)C(C(=O)c1ccccc1)=C1CCCN1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
9.9 g (0.1 mole) of 2-methoxy-1-pyrroline and 24.4 g (0.15 mole) of 1-phenyl-1,3-butanedione are mixed together and, in a nitrogen atmosphere, heated with stirring for 18 hours in an oil bath at 100°. The dark reaction mixture is cooled to 60° and 500 ml of hexane is added. Upon further cooling to room temperature, the reaction product crystallises out. Recrystallisation from ethyl acetate/hexane yields 1-phenyl-2-(2-pyrrolidinylidene)-1,3-butanedione m.p. 106°-108°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([N:11]1[CH2:18][CH2:17][C@@H:16]2[C@@H:13]([N:14]([C:19]3[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=3)[CH2:15]2)[CH2:12]1)=[O:10].[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[CH3:26][C:21]1[CH:22]=[C:23]([CH3:25])[N:24]=[C:19]([N:14]2[C@@H:13]3[C@@H:16]([CH2:17][CH2:18][N:11]([C:9]([C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[C:31]4[CH:32]=[N:27][CH:28]=[N:29][CH:30]=4)=[O:10])[CH2:12]3)[CH2:15]2)[N:20]=1
Reactant: OB(O)c1cncnc1
Reactant: Cc1cc(C)nc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4Br)C[C@@H]32)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)nc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-c4cncnc4)C[C@@H]32)n1
Temperature: 150 °C
Yield: 24 %

Procedure:
Example 198 was prepared by the following procedure: (1R,6S)-3-[(2-bromo-5-fluorophenyl)carbonyl]-8-(4,6-dimethylpyrimidin-2-yl)-3,8-diazabicyclo[4.2.0]octane (100 mg, 0.24 mmol), pyrimidine-5-boronic acid (44 mg, 0.36 mmol), Pd(ddpf)Cl2 (19 mg, 0.02 mmol) and K2CO3 (98 mg, 0.72 mmol) were suspended a 1.2 ml of a mixture of 1,4-dioxane and water (5:1) in a sealed tube and heated to 150° C. for 2 h. The reaction was cooled to 23° C., and purified directly on 16 g SiO2 with 0-50% ethyl acetate/hexanes to give 24 mg (24% yield). MS (ESI) mass calcd. for C23H23FN6O, 418.5; m/z found, 419.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22][CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26](=[O:27])[C:23]3[CH:24]=[CH:25][C:20]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:21][CH:22]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccc(-c2ccccc2)cc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 4-biphenylcarbonyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]4-phenylbenzamide as a white powder, m.p. 215.4° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 8.54 (t, J=5.7 Hz, 1H), 8.22 (s, 1H), 8.05 (d, J=7.2 Hz, 1H), 7.88 (d, J=5.4 Hz, 2H), 7.75-7.70 (m, 4H), 7.62 (dd, J=8.4, 1.5 Hz, 1H), 7.52-7.38 (m, 4H), 7.22 (dt, J=7.5, 1.2 Hz, 1H), 6.61 (s, 2H), 4.65 (t, J=7.2 Hz, 2H), 3.30 (m, 2H), 1.93 (quintet, J=7.5 Hz, 2H), 1.60 (quintet, J=7.5 Hz, 2H); MS (EI) m/e 435.2054 (435.2059 calcd for C27H25N5O).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:15][C:16]([OH:18])=O)[CH2:11][C:12](O)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:19]C(N)=O>CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][C:16](=[O:18])[NH:19][C:12](=[O:13])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)CC(CC(=O)O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(N)=O
Solvent: CCOC(C)=O
Product: O=C1CC(c2ccc([N+](=O)[O-])cc2)CC(=O)N1
Temperature: 150 °C
Yield: 22.5 %

Procedure:
A mixture of 250 mg (0.987 mmol) of 3-(4-nitro-phenyl)-pentanedioic acid (as prepared in the previous step) and 119 mg (1.98 mmol) of urea was heated to 150° C. for 40 min (until all solid melted and gas evolution stopped). The mixture was cooled to RT, taken up in EtOAc (70 mL), washed with saturated aqueous NaHCO3 (2×40 mL), dried (MgSO4), and concentrated in vacuo to afford 52.0 mg (22%) of the title compound as a brown solid: 1H-NMR (CDCl3; 400 MHz): δ 8.28 (d, 2H, J=8.8 Hz), 7.44 (d, 2H, J=8.8 Hz), 3.64-3.54 (m, 1H), 3.04-2.96 (m, 2H), 2.86-2.76 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl.[CH2:23]([N:30]([CH2:34][CH2:35]Cl)[CH2:31][CH2:32]Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:23]([N:30]1[CH2:34][CH2:35][C:4]2([C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Br:1])[NH:6][C:5]2=[O:11])[CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1Cc2c(Br)cccc2N1
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1Nc2cccc(Br)c2C12CCN(Cc1ccccc1)CC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
A stirred solution of 4-bromoindolin-2-one (13.0 g, 61.3 mmol) in THF (500 mL) was treated by the dropwise addition of a 1.0M THF solution of NaHMDS (306 mL, 306 mmol) at −78° C. under nitrogen. After stirring at −78° C. for 30 minutes, N-benzylbis(2-chloroethyl)amine hydrochloride (18.05 g, 67.4 mmol) was added as a solid. The reaction mixture was stirred at −78° C. for 30 minutes and then allowed to warm to room temperature. The reaction mixture was then heated to reflux for 12 hours. After cooling to 0° C., the reaction was quenched by the addition of saturated aqueous NH4Cl solution. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3×200 mL) The combined organics layers were washed with brine, dried with MgSO4 and concentrated under reduced pressure. The resulting solid was triturated with DCM/EtOAc to give 1′-benzyl-4-bromospiro[indoline-3,4′-piperidin]-2-one (19.3 g, 85%) as a solid. LCMS (APCI+) m/z 371/373 [M+H]+; Rt=2.71 min.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12].C([Li])CCC>C(OCC)C.C1COCC1>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([CH:9]([OH:14])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:7][N:6]=1
Reactant: CC(C)CC=O
Reactant: Clc1ncc(Br)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CC(O)c1cnc(Cl)nc1
Temperature: -78 °C
Yield: 38.2 %

Procedure:
To a solution of 5-bromo-2-chloropyrimidine (5.0 g, 25.8 mmol) in diethyl ether (129 mL) and THF (129 mL) was added isovaleraldehyde (4.45 g, 51.7 mmol). The reaction mixture was cooled to −78° C., and n-butyllithium (15.4 mL of a 1.6 M solution in hexanes, 24.6 mmol) was added. The mixture was stirred for 30 m at −78° C. The reaction mixture was quenched by addition of saturated aqueous NH4Cl, and extracted with ethyl acetate (300 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 1-(2-chloropyrimidin-5-yl)-3-methylbutan-1-ol (1.98 g) as yellow oil. 1HNMR (400 MHz, CDCl3) δ 8.54 (s, 2H), 4.76-4.80 (m, 1H), 1.75-1.66 (m, 2H), 1.45-1.37 (m, 1H), 0.89 (d, J=6.35 Hz, 6H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:9]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:44][C:45]#[N:46]>CC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:44][C:45]#[N:46])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:9]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: Oc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3Cc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCOc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3Cc2ccccc2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(1,3-dibenzyl-2-phenyl-1H-indol-5-yl)-phenol (0.542 g, 1.163 mmol) was reacted with K2CO3 (0.225 g, 1.628 mmol) and bromoacetonitrile (0.195 g, 1.628 mmol) in acetone (10 ml) to give the product (0.486 g, 0.963 mmol, 83%) as a viscous, yellow oil. 1H NMR (DMSO-d6) δ 4.08 (s, 2H), 5.19 (s, 2H), 5.36 (s, 2H), 6.89 (d, J=7.3 Hz, 2H), 7.10-7.24 (m, 10H), 7.37-7.51 (m, 7H), 7.57 (d, J=8.9 Hz, 2H), 7.63 (s, 1H); [ESI(+)], m/z 505 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:37]([NH:39][CH2:40][C:41]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:42]=2[C:43]([O:45]CC)=[O:44])=[O:38])=[N:11][C:12]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][CH2:20]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O.Cl>C1COCC1.O>[CH2:1]([O:8][C:9]1[C:10]([C:37]([NH:39][CH2:40][C:41]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:42]=2[C:43]([OH:45])=[O:44])=[O:38])=[N:11][C:12]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][CH2:20]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(F)ccc1CNC(=O)c1nc(N2CCN(CCCCNC(=O)OC(C)(C)C)CC2)c2cccnc2c1OCc1ccccc1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCN1CCN(c2nc(C(=O)NCc3ccc(F)cc3C(=O)O)c(OCc3ccccc3)c3ncccc23)CC1
Reaction time: 24 h

Procedure:
Ethyl 2-((8-(benzyloxy)-5-(4-(4-(tert-butoxycarbonylamino)butyl)piperazin-1-yl)-1,6-naphthyridine-7-carboxamido)methyl)-5-fluorobenzoate (Example 4.3; 1.4 mmol) was dissolved in THF (4.5 ml) and water (4.5 ml). Solid LiOH hydrate (1.6 mmol) was added at room temperature. The reaction mixture was stirred for 24 h, after which 2N HCl was added until pH=6-7 was reached. The mixture was extracted twice with EtOAc and the combined organic fractions dried with magnesium sulfate. The crude material containing the title compound (0.27 gr) was used as such in the next step.
Reaction SMILES: [O:1]1[CH2:5]/[C:4](=[N:6]\O)/[C:3](=[N:8]/[OH:9])/[C:2]1=[O:10].S(Cl)(Cl)=O>O1CCOCC1>[N:6]1[O:9][N:8]=[C:3]2[C:2](=[O:10])[O:1][CH2:5][C:4]=12
Reactant: O=C1OCC(=N\O)/C1=N/O
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: O=C1OCc2nonc21
Reaction time: 8 h

Procedure:
4H,6H-Furo[3,4-c][1,2,5]oxadiazol-4-one was synthesized according to literature procedures (Pollet, et al., Synthesis Communications, 1979, 977-979.) To a stirred solution of (3Z,4Z)-furan-2,3,4(5H)-trione 3,4-dioxime (3.0 g, 0.021 mol) in 1,4-dioxane (21 mL) under nitrogen, thionyl chloride (2.1 mL, 0.029 mol) was added dropwise. The resulting yellow solution was stirred overnight and then concentrated in vacuo. The resultant crystalline material was recrystallized once from a minimum amount of ethanol (EtOH) to give the desired compound as an off-white powder. The filtrate was concentrated down and recrystallized again. Combined solids yielded the desired product (2.0 g, 76%). 1H NMR (400 MHz, DMSO-d6) δ: 5.67 (s, 2H). MF=C4H2N2O3; LCMS calculated for C4H3N2O3(M+H)+: m/z=127.014.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].O.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(OC(C)(C)C)(=O)C>[CH3:2][C:3]([O:8][C:7](=[O:9])[C@H:2]([C@H:3]([CH2:5][CH3:6])[CH3:4])[NH2:1])([CH3:5])[CH3:4]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)(C)C
Solvent: O
Product: CC[C@H](C)[C@H](N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 240 h
Yield: 61 %

Procedure:
To an ice-bath cooled slurry of L-isoleucine (301.0 g; 2.29 mol) in tert-butyl acetate (2.5 L), 70% aq HClO4 (208 mL, 2.43 mol) was slowly added. The mixture was kept stirring for 10 days at room temperature. Then water (0.5 L) was poured into, followed by cooling in an ice bathand addition of NaOH pellets (100 g) and Na2CO3 (110 g) so that pH turned to basic. The mixture was extracted with EtOAc (4×0.5 L); the combined organic phases were washed with water (2×0.5 L) and brine (0.3 L), at last dried over Na2SO4. After careful removal of solvents in vacuo, the desired compound was obtained (262.2 g; 1.40 mol) and stored at −18° C. No further purification was required on the basis of TLC and NMR data. Yield 61%.
Reaction SMILES: O.[H-].[Na+].[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH2:12][C:13]#[N:14].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]Br)=[CH:18][CH:17]=1>CS(C)=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH:12]([C:6]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=2[Cl:4])[C:13]#[N:14])=[CH:18][CH:17]=1
Reactant: BrCCOc1ccc(Br)cc1
Reactant: N#CCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC(CCOc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
To a stirred and cooled (water-bath) suspension of 7 parts of a sodium hydride dispersion 78% and 75 parts of dimethylsulfoxide is added dropwise, during a 30 minutes-period, a solution of 37 parts of 2,4-dichlorobenzeneacetonitrile in 100 parts of dimethylsulfoxide. The whole is stirred for 30 minutes while cooling in a water-bath. Then there is added dropwise, during a 30 minutes-period, a solution of 56 parts of 1-bromo-4-(2-bromoethoxy)benzene in 125 parts of dimethylsulfoxide and stirring is continued for another 30 minutes. The reaction mixture is poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed twice with water, dried, filtered and evaporated. The residue is triturated in petroleumether. The product is filtered off and crystallized from ethanol, yielding 38 parts of α-[2-(4-bromophenoxy)ethyl]-2,4-dichlorobenzeneacetonitrile; mp. 73.9° C.