Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: CC(=O)N1CCN(c2ccc3nc(N)c(C#N)c(Cl)c3c2)CC1
Solvent: O
Product: CC(=O)N1CCN(c2ccc3nc(N)c(C#N)c(NCc4ccccc4)c3c2)CC1

Procedure:
5 g 2-amino-3-cyano-4-chloro-6-(4-acetylpiperazin-1-yl)quinoline and 15 ml benzylamine is stirred at 125° C. for 1 h. The reaction mixture is then poured onto 30 ml water, the resulting precipitate is filtered off, washed with 20 ml water and dried to obtain 4 g of the title compound (MH+: 401).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][C@H:21]([CH3:25])[NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:26][O:27][CH2:28][CH2:29]Br.[H-].[Na+]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][C@H:21]([CH3:25])[N:22]([CH2:29][CH2:28][O:27][CH3:26])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3C[C@H](C)NC2=O)CC1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Product: COCCN1C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)ccc3n2C[C@@H]1C
Yield: 30 %

Procedure:
The title compound was synthesized in analogy to example 17, from (S)-8-(1-isopropyl-piperidin-4-yloxy)-3-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 13), 2-bromoethyl methyl ether and sodium hydride, to give the desired product as a colorless oil (30%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[CH:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.[CH:21](OC)=[O:22]>O1CCCC1.CCCCCC>[CH2:1]([C:5]1[N:9]([S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[C:8]([CH:21]=[O:22])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nccn1S(=O)(=O)N(C)C
Reactant: COC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCc1ncc(C=O)n1S(=O)(=O)N(C)C
Temperature: -70 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
1.25 g of 2-butyl-3-dimethylaminosulfonylimidazole was dissolved in 25 ml of tetrahydrofuran and cooled to -70° C., and 3.3 ml of n-butyllithium, 1.6 n in hexane, was added. After 1 hour, 0.64 ml of methyl formate was added, and the mixture was heated to room temperature and stirred for 17 hours at this temperature. The mixture was then concentrated, methylene chloride/water was added and the mixture was neutralized by adding 10 percent strength sulfuric acid. The organic phase was dried with Na2SO4 and concentrated by evaporation to give 1.35 g of crude product in the form of a yellow oil, which was purified by chromatography over methylene chloride/methanol/hexane 90:5:5 to give 0.99 g of product. The yield was 76 percent. Other data concerning the roduct was:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH2:9][NH:10][C:11](=[O:21])[CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[C:14]2[N+:18]([O-:20])=[O:19])[N:6]=[N:5]1.[O:22](S(C1C=CC(C)=CC=1)(=O)=O)[S:23]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=O)=[O:24]>C(Cl)Cl>[CH3:30][C:29]1[CH:31]=[CH:32][C:26]([S:23]([O:1][CH2:2][CH2:3][N:4]2[CH:8]=[C:7]([CH2:9][NH:10][C:11](=[O:21])[CH2:12][N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[N+:18]([O-:20])=[O:19])[N:6]=[N:5]2)(=[O:24])=[O:22])=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C(Cn1ccnc1[N+](=O)[O-])NCc1cn(CCO)nn1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCn2cc(CNC(=O)Cn3ccnc3[N+](=O)[O-])nn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.1 %

Procedure:
To a round bottom flask was added the alcohol 20 (106 mg, 0.359 mmol), TEA (36.3 mg, 0.359 mmol) and DCM (10 mL). Ts2O (117 mg, 0.359 mmol) was added in one portion. The reaction was stirred at RT for 4 hrs. The reaction was then concentrated to dryness and purified on a silica gel cartridge using EtOAc:Hex as the eluent to afford 55 mg (34% yield) of 21 as a white solid. Mass Spec (lo-res): Calc'd for C17H19N7O6S: 449.11; found: 450.1 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH2:11][C:12]([C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)=[O:27])=[O:20])=[O:13].S([O-])(O)(=O)=O.[K+]>N1C=CC=CC=1>[C:1]([O:10][CH2:11][C:12]([C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)=[O:27])=[O:20])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(CNC(=O)N2CCC[C@H]2C(=O)N2CCC[C@H]2C(=O)CO)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: c1ccncc1
Product: Cc1ccc(CNC(=O)N2CCC[C@H]2C(=O)N2CCC[C@H]2C(=O)COC(=O)c2ccccc2)cc1

Procedure:
Benzoyl chloride (0.17 ml) was added to a pyridine solution (4.5 ml) of (S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl]carbonyl]-N-[(4-methylphenyl)methyl]-1-pyrrolidinecarboxamide (0.46 g) obtained in Example 10, and the mixture was stirred under ice-cooling for 4 hours. The reaction mixture was poured into saturated potassium hydrogensulfate and extracted with methylene chloride. The extract was washed with saturated sodium hydrogencarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated to give the title compound (0.37 g) (see Table 2).
Reaction SMILES: Br[C:2]1[CH:6]=[N:5][N:4]2[CH2:7][CH2:8][CH2:9][C:3]=12.C([Li])CCC.C(O[B:19]([O:24][CH:25]([CH3:27])[CH3:26])[O:20][CH:21]([CH3:23])[CH3:22])(C)C.OC(C(O)(C)C)(C)C.C(O)(=O)C>C1COCC1>[CH3:27][C:25]1([CH3:26])[C:21]([CH3:22])([CH3:23])[O:20][B:19]([C:2]2[CH:6]=[N:5][N:4]3[CH2:7][CH2:8][CH2:9][C:3]=23)[O:24]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cnn2c1CCC2
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(C)OB(c2cnn3c2CCC3)OC1(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (73.5 g, 390 mmol) in THF (600 mL) was slowly added n-butyllithium (1.6 M in hexanes, 300 mL, 480 mmol) at −78° C. After 45 minutes, triisopropylborate (111 mL, 480 mmol) was added at −78° C., and the reaction mixture was allowed to warm to ambient temperature. After 1 hour, pinacol (1.8 M in THF, 300 mL, 540 mmol) was added. After 5 minutes, acetic acid (24 mL, 420 mmol) was added. After 30 minutes, the reaction mixture was filtered through CELITE, washed with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate (2×500 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to afford 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole. MS ESI calc'd. for C12H20BN2O2 [M+H]+ 235. found 235. 1H NMR (300 MHz, CDCl3) δ 7.77 (s, 1H), 4.12 (t, J=6.9 Hz, 2H), 2.97 (t, J=6.9 Hz, 2H), 2.60 (t, J=6.9 Hz, 2H), 1.29 (s, 12H).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:35])=[C:5]([C:26]([O:33]C)=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:30][O:29][C:28]1[C:3](=[O:2])[C:4]([CH3:35])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])=[C:11]([CH:16]=2)[C:12]([O:14][CH3:15])=[O:13])[C:26](=[O:33])[C:27]=1[O:31][CH3:32]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1OCC(=O)OC(C)(C)C
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(CC2=C(C)C(=O)C(OC)=C(OC)C2=O)ccc1OCC(=O)OC(C)(C)C
Yield: 68 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(tert-butoxycarbonylmethyloxy)benzoate (1.25 g, 2.56 mmol) was dissolved in a mixed solution of acetonitrile (30 ml) and water (10 ml) and after adding thereto CAN (3.50 g, 6.39 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=2:1) to obtain the titled compound (0.800 g, 1.74 mmol, 68%).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C@@:7]23[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]2[C:10](=[O:16])[N:9]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)[C:8]3=[O:25])=[CH:4][CH:3]=1.[CH3:28][CH2:29][O:30]C(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@:7]23[CH2:14][C@H:13]([O:15][C:29](=[O:30])[CH3:28])[CH2:12][N:11]2[C:10](=[O:16])[N:9]([C:17]2[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=2)[C:8]3=[O:25])=[CH:26][CH:27]=1
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]2(Cc3ccc(Br)cc3)C[C@@H](O)CN12
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)O[C@@H]1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)[C@]2(Cc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5S,7R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-7-hydroxy-1,3-diazabicyclo[3.3.0]octane-2,4-dione (0.21 g) in THF (5 mL) was added DEAD (0.09 mL), triphenylphosphine (0.15 g), and acetic acid (0.035 mL). After stirring overnight at room temperature, the mixture was concentrated. Purification by chromatography (Silica gel: 25% EtOAc/hexane, Chromatotron) afforded the titled compound (0.151 g). MS (m/z) 511 (MH+), mp 149.8° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[CH3:18][N:19]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:20](Cl)=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][N:2]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2)[C:20]([N:19]([CH3:18])[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:21]
Reactant: CN(C(=O)Cl)C1CCCCC1
Reactant: CNCCCOc1ccc2[nH]c(=O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCCOc1ccc2[nH]c(=O)ccc2c1)C(=O)N(C)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
6-(3-Methylaminopropoxy)carbostyril (3 g) is dissolved in dimethylformamide (150 ml), and thereto are added N-methyl-N-cyclohexylaminocarbonyl chloride (2.3 g) and potassium carbonate (2 g). The mixture is stirred at room temperature overnight, and further heated with stirring at 80° C. for 2 hours. The reaction solution is poured into water, and extracted with ethyl acetate. The extract is concentrated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; methylene chloride:methanol=30:1), and recrystallized from ethyl acetate to give 6-[3-(1,3-dimethyl-3-cyclohexylureido)propoxy]carbostyril (2.3 g) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:36][N:37]([C:45]([CH3:49])([CH3:48])[CH:46]=O)[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41].N1CCCCC1>O1CCOCC1.CC(O)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[C:32]([C:33]#[N:34])=[CH:49][C:45]([N:37]([CH3:36])[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:46])[CH3:48])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: CN(C(=O)OC(C)(C)C)C(C)(C)C=O
Solvent: C1COCCO1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CN(C(=O)OC(C)(C)C)C(C)(C)C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 110 °C
Reaction time: 6 h
Yield: 18.3 %

Procedure:
To a solution of 3-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (236 mg, 0.5 mmol, 1 equiv) and tert-butyl methyl(2-methyl-1-oxopropan-2-yl)carbamate (2.01 g, 10 mmol, 20 equiv) in dioxane (30 mL) was added 0.5 mL piperidine, 1 drop AcOH and 2 g of 4 A molecular sieves. The resulting mixture was stirred for 6 h at 110° C. The solids was filtered out, the filtrate was diluted with 50 mL of EA, washed with brine, dried over Na2SO4, concentrated. The residue was purified on silica gel column (EA to EA/MeOH 10/1) to give 60 mg of tert-butyl 5-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl(methyl)carbamate as white solid.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][CH:7]1[CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[C:12](=O)([O:18]C(C)(C)C)[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]>C(O)C.O.C1COCC1>[C:14]([O:13][C:12]([NH:1][C@H:2]([CH2:6][CH:7]1[CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4])=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: N[C@H](CC1CC1)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](CC1CC1)C(=O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.3 %

Procedure:
To a solution of (R)-2-amino-3-cyclopropylpropanoic acid (1.0 g, 7.7.4 mmol) in Ethanol (15 mL) and water (8 mL) was added 1N NaOH (10 mL) and Di-tert-butyl carbonate (1.86 g, 8.52 mmol) in THF (8 mL). After stirring at room temperature for 15 h, the solution was diluted with water, extracted with ether, the aqueous layer was separated and was acidified to pH 2 with conc. HCl, the aqueous layer was extracted with EtOAc, organic layer was separated, washed with brine, dried and concentrated to give (R)-2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoic acid (1.0 g).
Reaction SMILES: C(O)(=O)C.[C:5]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=1)#[N:6].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:5]([C:7]1[CH:12]=[C:11]([CH2:13][Br:14])[CH:10]=[CH:9][N:8]=1)#[N:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc(C#N)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(CBr)ccn1
Temperature: 50 °C
Yield: 24.6 %

Procedure:
0.146 ml of acetic acid is added to a solution of 0.236 g of 2-cyano-4-methylpyridine in 5 ml of carbon tetrachloride, under an inert atmosphere of argon at a temperature in the region of 20° C. The mixture is brought, with stirring, to a temperature of 50° C. 0.712 g of N-bromosuccinimide and 0.096 g of benzoyl peroxide are successively added at this temperature. The mixture is maintained at 80° C. for about 18 hours. After cooling, the reaction medium is placed on a cartridge 27 mm in diameter packed with 25 g of 20-40 μm silica not conditioned beforehand, and then eluted with dichloromethane at a flow rate of 10 ml/minute. The fractions between 140 and 175 ml are concentrated to dryness under reduced pressure. 0.097 g of 2-cyano-4-(bromomethyl)pyridine is thus obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])=[CH:8][CH:7]=2)[CH2:3]1.[F:18][C:19]1[CH:24]=[C:23](F)[CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:18][C:19]1[CH:24]=[C:23]([O:1][CH:2]2[CH2:3][N:4]([C:6]3[CH:7]=[CH:8][C:9]([C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])=[CH:10][CH:11]=3)[CH2:5]2)[CH:22]=[CH:21][N:20]=1
Reactant: CC(=O)N[C@@H](C)c1ccc(N2CC(O)C2)cc1
Reactant: Fc1ccnc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccnc(F)c3)C2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
1.0 g (4.3 mmol) (S)—N-{1-[4-(3-Hydroxy-azetidin-1-yl)-phenyl]-ethyl}-acetamide (V.1), 0.6 g (5.2 mmol) 2,4-difluoropyridine and 2.0 g (6.2 mmol) cesium carbonate are combined in 40 mL DMF and the mixture is stirred for 12 h at 80° C. Water is added and the mixture is extracted twice with ethylacetate. After concentration in vacuo the residue is purified by chromatography (silica; ethylacetate) to yield the desired product.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([C:9]1[C:17]([Cl:18])=[C:16]([Cl:19])[C:15]([Cl:20])=[C:14]([Cl:21])[C:10]=1[C:11]([OH:13])=[O:12])=O.[CH3:22][N:23]([CH3:33])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]([CH3:32])[CH3:31])[CH:25]=1>C(OC(=O)C)(=O)C>[CH3:31][N:30]([CH3:32])[C:26]1[CH:25]=[C:24]([N:23]([CH3:33])[CH3:22])[CH:29]=[CH:28][C:27]=1[C:7]1([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)[C:9]2[C:10](=[C:14]([Cl:21])[C:15]([Cl:20])=[C:16]([Cl:19])[C:17]=2[Cl:18])[C:11](=[O:13])[O:12]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: Cn1cccc1C(=O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3cccn3C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(N(C)C)c1

Procedure:
Employing the procedure of part B of Example 17 hereinabove, 3.70 g (0.01 mole) of 2-[(1-methyl-2-pyrrolyl)carbonyl]-3,4,5,6-tetrachlorobenzoic acid, prepared as described in part A above, and 2.0 g (0.012 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine were interacted in the presence of 10 ml of acetic anhydride to obtain 3-[(2,4-bis(dimethylamino)phenyl]-3-(1-methyl-2-pyrrolyl)-4,5,6,7-tetrachlorophthalide (Formula IV: R°=R1 =R2 =R3 =Cl; R=R7 =CH3 ; R4 =N(CH3)2).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:7][CH:6]=1.CO[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[C:24]1[O:25][CH2:26][C:27]([CH3:30])([CH3:29])[N:28]=1.[NH4+].[Cl-]>CCOCC.C1COCC1>[CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[C:24]2[O:25][CH2:26][C:27]([CH3:29])([CH3:30])[N:28]=2)=[CH:6][CH:7]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1ccc(Br)cc1
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(OC)c1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C2=NC(C)(C)CO2)c(-c2ccc(C(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
To a suspension of magnesium (0.69 g) in Et2O (5 mL) containing a trace of iodine was added dropwise a solution of 1-bromo4-isopropyl-benzene (5.97 g) in Et2O (50 mL). Following the addition, the mixture was heated under reflux for 1 hour. The resulting grignard solution was then carrefully added to a solution of 2-(2,4-dimethoxy-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole (3.52 g) in THF (60 mL) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was then poured into saturated aqueous solution of NH4Cl and the mixture was extracted with Et2O, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with CH2Cl2/AcOEt (85/15) to give the title compound (3.5 g) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:24]([O:31][C:32]([NH:34][C@@H:35]([C:38](O)=[O:39])[CH2:36][OH:37])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1C=CC2N(O)N=NC=2C=1.O.CCN(CC)CC.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:15][N:16]([C:36](=[O:37])[C@@H:35]([CH2:38][OH:39])[NH:34][C:32]([O:31][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:33])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(N[C@H](CO)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(F)c(CNCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(F)c(CN(Cc2ccccc2)C(=O)[C@@H](CO)NC(=O)OCc2ccccc2)c1
Yield: 19.4 %

Procedure:
According to the procedure of Preparation 4 (c), except using tert-butyl 4-fluoro-3-(benzylaminomethyl)benzoate (4.80 g, 15.2 mmole), N-(benzyloxycarbonyl)-D-serine (3.83 g, 16 mmole), HOBt.H2O (2.16 g, 16 mmole), Et3N (2.24 mL, 16 mmole), EDC.HCl (3.07 g, 16 mmole), and 1:1 DMF/CH2Cl2 (75 mL), the title compound (1.58 g, 19%) was prepared as a thick oil following flash chromatography on silica gel (40% EtOAc/hexanes): 1H NMR (300 MHz, DMSO-d6) mixture of amide rotamers δ 7.39-8.18 (m, 2H), 7.18-7.37 (m, 11H), 4.25-5.11 (m, 7H), 3.33-4.04 (m, 2H), 1.53 (s, 9H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.C1(C)C=CC=CC=1.[OH-].[Na+].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][N:13]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](c4ccccc4)CC3)n1-2
Reactant: Brc1ccccn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Clc1ccc2c(c1)CN(c1ccccn1)Cc1nnc([C@H]3CC[C@H](c4ccccc4)CC3)n1-2
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A mixture of trans-8-chloro-1-(4-phenyl-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.10 g, 0.24 mmol), 2-bromopyridine (0.057 g, 0.36 mmol) and cetyltrimethylammonium bromide (0.0040 g, 0.012 mmol) in toluene (2 ml) and 50% aqueous sodium hydroxide solution (0.04 ml) was degassed by freeze/thaw cycles. Addition of bis(tri-t-butylphosphine)palladium (0.012 g, 0.024 mmol) was followed by stirring at 90° C. for 18 h. The reaction mixture was partitioned between water (50 ml) and dichloromethane (50 ml). The layers were separated. The aqueous layer was extracted with one 50-ml portion of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash-chromatography with n-heptane/ethyl acetate and ethyl acetate/2-propanol as eluent gave the title compound (0.004 g, 4%) as colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Si:7]([O:14][CH2:15][C@H:16]([OH:24])[CH2:17][C:18]#[C:19][Si](C)(C)C)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>CO>[Si:7]([O:14][CH2:15][C@H:16]([OH:24])[CH2:17][C:18]#[CH:19])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](O)CC#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC[C@@H](O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
Potassium carbonate (2.14 g, 15.5 mmol) was added to a solution of (R)-1-(tert-butyldimethylsilyloxy)-5-(trimethylsilyl)pent-4-yn-2-ol (3 g, 10.6 mmol) in methanol (100 mL) and the mixture stirred at room temperature for 8 hours. The solvent was removed under reduced pressure and aqueous ammonium chloride solution (100 mL) was added to the resulting oil. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The crude material was purified by flash chromatography (biotage) using a gradient of EtOAc in hexane to afford (R)-1-(tert-butyldimethylsilyloxy)pent-4-yn-2-ol (1.81 g, 8.44 mmol, 80%).