Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH2:10]O)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.O=S(Cl)[Cl:16].O>C1COCC1.[Cl-].[Cl-].[Zn+2]>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10][Cl:16])[C:3]=1[O:12][CH3:13]
Reactant: COc1cc(Br)c(OC)c(CO)c1
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Br)c(OC)c(CCl)c1
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 52 (7.5 g, 30 mmol) and ZnCl2 (1 g) in THF (100 ml) was added SOCl2 (5.31 g, 45 mmol) dropwise. After 1 hr at rt, the reaction was poured into water and extracted with ether. The ether was dried, concentrated and the product was purified by column chromatography on silica gel (10% EtOAc/hex) to give 53 as an oil (5.5 g, 75%): 1H NMR(DMSO-d6) δ 7.21 (d, 1 H, J=3.0 Hz), 7.08 (d, 1 H, J=3.0 Hz), 4.73 (s, 2 H), 3.78 (s, 3 H), 3.75 (s, 3 H)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.Cl.[C:24]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH2:32])([CH3:27])([CH3:26])[CH3:25]>>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:32][CH2:31][CH2:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:33])[CH:11]=[CH:10]2
Reactant: CC(C)(C)OC(=O)CCN
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Agent: Cl
Product: CC(C)(C)OC(=O)CCNc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Yield: 28.4 %

Procedure:
Prepared according to the method of example 7 (a), using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1 (a)) (400 mg) and β-alanine tert-butyl ester hydrochloride (1.6 g) to afford the sub-title compound (150 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:43])[C@H:3]([NH:38][C:39](=[O:42])[O:40][CH3:41])[C:4](=[O:37])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[NH:31][C:30]([C@@H:32]5[CH2:36][CH2:35][CH2:34][NH:33]5)=[N:29][CH:28]=4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1.[NH:44](C(OCC1C=CC=CC=1)=O)[C@H:45]([C:49](O)=[O:50])[CH:46]([CH3:48])[CH3:47].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO.[Pd]>[NH2:44][C@@H:45]([CH:46]([CH3:48])[CH3:47])[C:49]([N:33]1[CH2:34][CH2:35][CH2:36][C@H:32]1[C:30]1[NH:31][C:27]([C:24]2[CH:23]=[CH:22][C:21]([C:18]3[CH:19]=[CH:20][C:15]([C:12]4[NH:11][C:10]([C@@H:6]5[CH2:7][CH2:8][CH2:9][N:5]5[C:4](=[O:37])[C@@H:3]([NH:38][C:39](=[O:42])[O:40][CH3:41])[CH:2]([CH3:43])[CH3:1])=[N:14][CH:13]=4)=[CH:16][CH:17]=3)=[CH:26][CH:25]=2)=[CH:28][N:29]=1)=[O:50]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5)[nH]4)cc3)cc2)[nH]1)C(C)C
Agent: [Pd]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)[C@@H](N)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (cj-12) (1.16 g, 1.99 mmol), Z-Val-OH (0.712 g, 2.83 mmol) and iPr2NEt (0.70 mL, 5.42 mmol) in DMF (40 mL) was added HATU (1.10 g, 2.89 mmol) portionwise. The mixture was allowed to stir at room temperature for 1 h and was then poured into ice-water (400 mL) and allowed to stand for 20 min. The mixture was filtered and the solid washed with cold water and allowed to air dry overnight to give the Z-protected intermediate. LCMS: Anal. Calcd. for C46H54N8O6: 814. found: 815 (M+H)+. The obtained solid was dissolved in MeOH (80 mL), 10% Pd—C (1.0 g) was added and the mixture was hydrogenated at room temperature and atmospheric pressure for 3 h. The mixture was then filtered and the filtrate concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO2/5-20% MeOH—CH2Cl2) to afford the title compound (1.05 g, 77%) as a colorless foam. 1HNMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.75-7.79 (m, 3H), 7.61-7.67 (m, 5H), 7.49 (s, 1H), 7.26-7.28 (m, 1H), 5.05-5.09 (m, 2H), 4.03-4.09 (m, 2H), 3.77-3.80 (m, 1H), 3.66-3.70 (m, 1H), 3.52 (s, 3H), 3.40-3.47 (m, 2H), 2.21-2.26 (m, 1H), 2.10-2.17 (m, 3H), 1.81-2.02 (m, 6H), 0.77-0.92 (m, 12H). LCMS: Anal. Calcd. for C38H48N8O4: 680. found: 681 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[O-:6][N+:7]1[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:11]=2[N:10]=[C:9]([CH2:20][CH2:21][CH:22]=O)[N:8]=1)[CH2:17][CH2:16][CH2:15]3.[BH3-]C#N.[Na+].CC(O)=O>CO>[N:1]1([CH2:22][CH2:21][CH2:20][C:9]2[N:8]=[N+:7]([O-:6])[C:12]3[CH:13]=[C:14]4[C:18]([CH2:17][CH2:16][CH2:15]4)=[CH:19][C:11]=3[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: [O-][n+]1nc(CCCN2CCCC2)nc2cc3c(cc21)CCC3
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
Pyrrolidine (3.0 g, 42 mmol) was added to a stirred solution of propanal 75 (1.5 g, 6.2 mmol) in MeOH (100 mL) at 0° C. and the solution stirred for 30 min. NaCNBH3 (1.5 g, 24 mmol) was added and the solution stirred at 0° C. for 30 min and then HOAc (2 mL) was added and the mixture was stirred at 20° C. for 16 h. The solvent was evaporated and the residue was partitioned between DCM (200 mL) and water (200 mL). The aqueous phase was extracted with DCM (2×200 mL), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 84 (1.5 g, 84%) as a yellow oil: 1H NMR [(CD3)2SO] δ 8.25 (s, 1H, H-9), 7.74 (s, 1H, H-5), 3.10-3.16 (m, 4H, H-6, H-8), 3.02-3.09 (m, 2H, CH2N), 2.80-2.88 (m, 6H, 3×CH2), 2.17-2.28 (m, 4H, H-7, CH2), 1.82-1.90 (m, 4H, 2×CH2); 13C NMR δ 165.0, 154.8, 149.2, 147.2, 132.3, 122.7, 114.3, 55.0, 53.4 (2), 34.8, 33.2, 32.8, 25.7, 25.5, 23.4 (2); HRMS calcd for C17H22N4O (M+) m/z 298.1794, found 298.1794.
Reaction SMILES: C([N:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([CH2:14]Br)[NH:6][C:5]1=[O:16])(=O)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(O)C.O.C(O)C>[ClH:17].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([OH:30])[CH2:25][CH2:26][N:27]([CH2:14][C:7]3[NH:6][C:5](=[O:16])[NH:4][C:8]=3[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:28][CH2:29]2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1c(CBr)[nH]c(=O)n1C(C)=O
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Solvent: CCO
Product: CCOC(=O)c1[nH]c(=O)[nH]c1CN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4.1 g (14.2 mmole) of ethyl 3-acetyl-5-(bromomethyl)-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylate, 3.0 g (14.2 mmole) of 4-(4-chlorophenyl)-4-hydroxypiperidine, 2.0 g (14.2 mmole) of potassium carbonate and 75 ml of ethanol is stirred under argon for 16 hours at 25° C. Water (100 ml) is added and the precipitate which forms is collected and washed with water. It is then suspended in 2-propanol and 1 equivalent of hydrogen chloride in 2-propanol is added. The resulting solid is separated and recrystallized twice from a mixture of 2-propanol and water to give ethyl 5-[[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]methyl]-2,3-dihydro-2-oxo-1H-imidazole-4-carboxylate hydrochloride.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([S:8][C:9]2[N:13]=[CH:12][NH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:14][N:15]([CH3:19])[C:16](Cl)=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[N:7]=[C:6]([S:8][C:9]2[N:13]=[CH:12][N:11]([C:16](=[O:17])[N:15]([CH3:19])[CH3:14])[N:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: Brc1cccc(Sc2nc[nH]n2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)n1cnc(Sc2cccc(Br)n2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(6-bromo-2-pyridyl)thio-1H-1,2,4-triazole (73 mg), dimethylcarbamoyl chloride (40 μl), anhydrous potassium carbonate (80 mg) and N,N-dimethylformamide (0.5 ml) was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate-water. The organic layer was washed with water, followed by saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a silica-gel column chromatography with 20% (20% 2-propanol/ethyl acetate)/hexane to yield the title compound (77 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[N:8]3[CH2:14][CH2:13][CH2:12][C:9]3=[N:10][N:11]=2)[CH2:2]1.Cl[C:16]1[N:21]=[C:20]([NH2:22])[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][CH:17]=1.C(N(CC)CC)C>C(#N)C>[N:10]1[N:11]=[C:7]([CH:3]2[CH2:4][CH2:5][CH2:6][N:1]([C:16]3[N:21]=[C:20]([NH2:22])[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][CH:17]=3)[CH2:2]2)[N:8]2[CH2:14][CH2:13][CH2:12][C:9]=12
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CNCC(c2nnc3n2CCC3)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1nc(N2CCCC(c3nnc4n3CCC4)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a solution of 3-(piperidin-3-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole (900 mg, 4.68 mmol) in acetonitrile (50 mL) was added 6-chloro-3-nitropyridin-2-amine (730 mg, 4.2 mmol) and triethylamine (1.42 g, 14.04 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 30 min at reflux, then allowed to cool down to room temperature and stirred for 16 h. The solvent was removed under reduced pressure and the resulting residue was partitioned between water and ethyl acetate. The organics were dried over sodium sulfate, concentrated under reduced pressure and purified via column chromatography to afford the title compound (1.0 g, 64.9%). MS (ES+) (M+H) 330.33; LCMS retention time: 2.85 min (Method S).
Reaction SMILES: C(OC([N:8]1[CH:17]([C:18](=[O:51])[NH:19][CH:20]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=2)[C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[F:42])[CH2:30][NH:31][C:32](=[O:35])[CH2:33][CH3:34])[CH2:25][CH2:24]2)=[O:22])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C>>[ClH:50].[Cl:50][C:47]1[CH:46]=[CH:45][C:44]([CH2:43][CH:20]([NH:19][C:18]([CH:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8]2)=[O:51])[C:21]([N:23]2[CH2:24][CH2:25][N:26]([CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[F:42])[CH2:30][NH:31][C:32](=[O:35])[CH2:33][CH3:34])[CH2:27][CH2:28]2)=[O:22])=[CH:49][CH:48]=1
Reactant: CCC(=O)NCC(c1ccccc1F)N1CCN(C(=O)C(Cc2ccc(Cl)cc2)NC(=O)C2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)NCC(c1ccccc1F)N1CCN(C(=O)C(Cc2ccc(Cl)cc2)NC(=O)C2Cc3ccccc3CN2)CC1
Product: Cl
Reaction time: 3 h
Yield: 53 %

Procedure:
3-(1-(4-Chloro-benzyl)-2-{4-[1-(2-fluoro-phenyl)-2-propionylamino-ethyl]-piperazin-1-yl}-2-oxo-ethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester: To a mixture of 0.30 g (0.65 mmol) of the product from Preparation SM3, 0.17 g (0.59 mmol) of material from part B and 0.25 g (0.65 mmol) of 0-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate in 2 ml of dichlorormethane is added 0.11 mL (0.62 mmol) of N,N-diisopropylethylamine. The mixture is stirred for three hr and washed with 10% aqueous sodium bisulfate. After the organic portion is separated, the aqueous portion is saturated with sodium chloride and extracted three times with dichloromethane. The combined organics are dried (Na2SO4), filtered and concentrated in vacuo. Chromatography (Biotage, 5% ethanol, ethyl acetate) of the residue affords a mixture which is chromatographed again (Biotage, 0.25% NH4OH/2.25% methanol/dichloromethane) affords 0.23 g (53%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]([S:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[C:5]3[CH:15]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][N:6]3[C:7]=2[CH:8]=[C:9]([C:11]#[N:12])[CH:10]=1.[N:29]([Sn](CCCC)(CCCC)CCCC)=[N+:30]=[N-:31].CC(O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]2[C:4]([S:21][C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)=[C:5]3[CH:15]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][N:6]3[C:7]=2[CH:8]=[C:9]([C:11]2[N:29]=[N:30][NH:31][N:12]=2)[CH:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(C#N)cc12
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(-c3nn[nH]n3)cc12
Temperature: 90 °C
Reaction time: 16 h
Yield: 73.4 %

Procedure:
To a solution of (+/−)-methyl {8-bromo-9-[(4-chlorophenyl)thio]-6-cyano-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate (example 31, Step 1, 200 mg, 0.42 mmol) in toluene (3 mL) was added azidotributyltin (279 mg, 0.84 mmol). The reaction mixture was stirred at 90° C. for 16 hours, AcOH (1 mL) was added and the reaction was stirred for 2 hours and concentrated. The residue was swished in acetone/hexane 1:2 to give 160 mg of the title compound as a white solid used as such for next reaction.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][N:9]=2)=[CH:13][CH:12]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccnc(-c2ccc(F)cc2)c1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
A mixture of 2-chloro-isonicotinonitrile (1.9 g), 4-fluorophenylboronic acid (2.9 g), sodium carbonate (4.3 g), tetrakis(triphenylphosphine)palladium (480 mg), 1,2-dimethoxyethane (40 mL), ethanol (20 mL) and water (20 mL) was stirred while heating at 100° C. for 2 hr. The solvent was distilled off under reduced pressure, and the resulting residue was then purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=94:6-50:50) to afford 2-(4-fluorophenyl)pyridine-4-carbonitrile (2.0 g).
Reaction SMILES: [Mg].C(Br)C.C([Mg]Br)C.[NH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.[C:15]([NH:18][C:19]1[S:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[C:20]=1[C:28]([O-])=[O:29])(=[O:17])[CH3:16]>O1CCCC1>[S:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[NH:9][C:28]([C:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[S:23][C:19]=1[NH:18][C:15]([CH3:16])=[O:17])=[O:29]
Reactant: Nc1cccs1
Reactant: CC(=O)Nc1sc2ccccc2c1C(=O)[O-]
Agent: CC[Mg]Br
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: CC(=O)Nc1sc2ccccc2c1C(=O)Nc1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3 g of magnesium curlings and 30 ml of anhydrous tetrahydrofuran are initially introduced into a sulfonation flask and 13.5 g of ethyl bromide are added in order to prepare ethyl-magnesium bromide. After the magnesium has dissolved, 6.1 g of 2-aminothiophen, dissolved in 60 ml of absolute tetrahydrofuran, are added dropwise and the mixture is stirred for one hour at room temperature and then refluxed for a further 15 minutes. 8 g of . . . 2-acetamido-benzo[b]thiophen-3-carboxylate, dissolved in 100 ml of absolute tetrahydrofuran, are then added dropwise at room temperature. The mixture is then refluxed for 15 minutes and stirred for a further 15 minutes at room temperature, the reaction solution is evaporated in vacuo, dilute hydrochloric acid is added to the evaporation residue and the mixture is extracted twice with chloroform. The chloroform extracts are combined, dried over sodium sulfate and evaporated to dryness in vacuo. Crude N-(2-thienyl)-2-acetamino-benzo[b]thiophen-3-carboxamide is obtained and this can be used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][C:55]([NH2:60])([C:58]#[N:59])[CH2:54][CH2:53]1)=[O:51])([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([O:49][C:50]([N:52]1[CH2:53][CH2:54][C:55]([C:58]#[N:59])([NH:60][C:10](=[O:12])[CH2:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:56][CH2:57]1)=[O:51])([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C#N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)Cc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
(2,4-Dichloro-phenyl)-acetic acid (218 mg, 1.07 mmol), 1-ethyl-3-(3′-dimethylamino-propyl)carbodiimide hydrochloride (255 mg, 1.33 mmol), 1-hydroxybenzotriazole hydrate (136 mg, 0.88 mmol) and N,N-diisopropylethylamine (0.378 ml, 2.22 mmol) were sequentially added to a solution of 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.888 mmol) in DMF (4 ml) at room temperature, and the mixture was stirred at room temperature for 16 hours. H2O (20 ml) was added to the reaction mixture, followed by extraction with AcOEt (40 ml and 20 ml). The organic layers were sequentially washed with H2O (20 ml), 1 N HCl (20 ml), H2O (20 ml) and saturated brine (20 ml), and then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/AcOEt) to give 4-cyano-4-[2-(2,4-dichloro-phenyl)-acetylamino]-piperidine-1-carboxylic acid tert-butyl ester as a white powder (285 mg, 78%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1C[CH2:15][CH2:14][CH2:13]1>>[C:2]1([CH2:1][O:8][CH2:9][C@@H:10]([OH:11])[CH2:15][CH:14]=[CH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCOCc1ccccc1
Reactant: C1CCOC1
Product: C=CC[C@H](O)COCc1ccccc1

Procedure:
The optically active tetrahydrofuran derivatives are prepared according to Scheme V. Benzyloxyacetaldehyde is reacted with optically active 2-allyl-1,3,2-dioxaborolane-4,5-dicarboxylic acid ester, XVII, to give optically pure (S)-1-phenylmethoxy-4-penten-2-ol, XVIII. Cyclization of alcohol, XVIII, with iodine in the presence of sodium bicarbonate gives a mixture of optically pure 2,5-anhydro-1,3-dideoxy-1-iodo-D-threopentitol, XIX, ##STR111## and 2,5-anhydro-1,3-dideoxy-1-iodo-D-erythro-pentitol, XX, which is separated by flash chromatography using silica gel. ##STR112##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:24])=[C:14]([C:20](OC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[NH2:29][CH2:30][CH2:31][CH2:32][OH:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:24])=[C:14]([C:20]([NH:29][CH2:30][CH2:31][CH2:32][OH:33])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[C:4]([C:25]([F:26])([F:28])[F:27])[CH:3]=1
Reactant: NCCCO
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3C(F)(F)F)cc2[nH]c1=O
Product: O=C(NCCCO)c1c(O)c2ncc(Cc3ccc(F)cc3C(F)(F)F)cc2[nH]c1=O

Procedure:
This compound was prepared from methyl 7-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-1-propanol employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.74 (1H, br), 10.26 (1H, m), 8.49 (1H, s), 7.70 (1H, d, J=9 Hz), 7.56 (2H, m), 7.32 (1H, s), 4.58 (1H, t, J=5 Hz), 4.32 (2H, s), 3.51-3.40 (4H, m), 1.70 (2H, m, J=6 Hz); HRMS calcd for C20H17F4N3O4+H+: 440.1233. Found: 440.1241.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH4+].[F-:23]>CN1CCCC1=O.C(Cl)Cl>[F:23][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: [F-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: COc1ccc(N(C)c2nc(F)nc3ccccc23)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 10 %

Procedure:
A mixture of 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine 0.150 g (0.5 mmol) and NH4F 0.5 g in 1-methyl-2-pyrrolidinone 3 mL was stirred at 120° C. for 16 h. The reaction mixture was diluted with CH2Cl2 10 mL and directly subjected to gradient column chromatography (EtOAc/hexanes, 0% to 100%) to give the crude titled compound product in 10% yield, which was further purified with preparative HPLC. 1H NMR (CD3OD, 400 MHz): δ 7.48-7.43 (m, 1H), 7.25-7.19 (m, 3H), 7.02 (d, 2H, J=9.0 Hz), 6.82-6.73 (m, 2H), 3.84 (s, 3H), 3.58 (s, 3H). 19F NMR (CD3OD):−77 (s). m/e: 284.1 (M+1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:17][CH:16]3[C:18]([O:20]CC)=[O:19])=[CH:11][CH:10]=2)O1.Br[C:25]1[CH:26]=[C:27]([N:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][N:39]=3)[C:34](=[O:41])[C:33]([C:42]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[O:43])=[CH:32]2)[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:44]1([C:42]([C:33]2[C:34](=[O:41])[C:35]3[C:40](=[N:39][CH:38]=[CH:37][CH:36]=3)[N:31]([C:27]3[CH:26]=[C:25]([C:9]4[CH:10]=[CH:11][C:12]([C@@H:15]5[CH2:17][C@H:16]5[C:18]([OH:20])=[O:19])=[CH:13][CH:14]=4)[CH:30]=[CH:29][CH:28]=3)[CH:32]=2)=[O:43])[CH2:45][CH2:46][O:47][CH2:48][CH2:49]1
Reactant: O=C(c1cn(-c2cccc(Br)c2)c2ncccc2c1=O)N1CCOCC1
Reactant: CCOC(=O)C1CC1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(-c2cccc(-n3cc(C(=O)N4CCOCC4)c(=O)c4cccnc43)c2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of acid from step 2 (1 eq), amide from step 1 (1 eq), Na2CO3 (3.5eq.; 2M in H2O), Pd(PPh3)4 (0.15eq.) in n-propanol-DMF (1:1, 0.1M) was stirred at 80° C. for 2 h. The mixture was cooled to rt, quenched with brine and diluted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CHCl3:THF; 50:50), triturated in ether/acetone and then isolated by filtration to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20]OS(C)(=O)=O)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:26]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][N:39]4[CH2:40][CH2:41][N:36]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[O:29][CH:26]([CH3:28])[CH3:27])[CH2:37][CH2:38]4)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)Oc1ccccc1N1CCNCC1
Reactant: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)Oc1ccccc1N1CCN(CC2CCCN(C(=O)C3(c4ccc(Cl)cc4)CCC3)C2)CC1
Yield: 36.9 %

Procedure:
Compound 11 was prepared using the method described in Example 3, starting with compound 2 (1.0 g, 2.60 mmol), 1-(2-isopropoxyphenyl)piperazine (0.63 g, 2.86 mmol), and cesium carbonate (1.27 g, 3.90 mmol) to give 11 (0.49 g, 37%); C30H40ClN3O2, LRMS (m/z)=511 (MH+).