Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:4]1[CH:31]=[C:8]2[C:9]([N:11]([CH:14]([CH2:29][CH3:30])[C:15]([N:17]3[CH:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:19][NH:18]3)=[O:16])[C:12](=[O:13])[C:7]2=[CH:6][CH:5]=1)=[O:10])(O)=O.C(N1CC[O:37][CH2:36]C1)C.P(Cl)(Cl)(Cl)(Cl)Cl>O1CCCC1>[O:37]=[C:36]1[CH2:30][CH2:29][C@H:14]([N:11]2[C:12](=[O:13])[C:7]3=[CH:6][CH:5]=[CH:4][CH:31]=[C:8]3[C:9]2=[O:10])[C:15](=[O:16])[N:17]2[C@H:21]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:19][N:18]12
Reactant: CCN1CCOCC1
Reactant: CCC(C(=O)N1NCCC1C(=O)OC(C)(C)C)N1C(=O)c2ccc(C(=O)O)cc2C1=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCN2C(=O)CC[C@H](N3C(=O)c4ccccc4C3=O)C(=O)N12
Reaction time: 1 h
Yield: 33.3 %

Procedure:
A stirred solution of 3.45 g of tert.butyl 2-(5-carboxy-2-phthalimidobutyryl)-3-pyrazolidinecarboxylate and 0.92 g of N-ethylmorpholine in 50 ml of dry tetrahydrofuran was cooled to 0° C. and treated with 1.66 g of phosphorus pentachloride. After 1 hour, a further 0.92 g of N-ethylmorpholine and 1.66 g of phosphorus pentachloride were added and, after a further 1 hour, another 0.92 g of N-ethylmorpholine was added. The solvent was removed by evaporation and the residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated. The oil obtained was chromatographed on silica gel. Elution with diethyl ether yielded firstly 1.1 g (33%) of tert.butyl 2,3,6,7,8,9-hexahydro-5,9-dioxo-8(S)-phthalimido-1H,5H-pyrazolo[1,2-α][1,2]diazepine-1(S)-carboxylate in the form of a white foam and then 0.52 g (15%) of tert.butyl 2,3,6,7,8,9-hexahydro-5,9-dioxo-8(S)-phthalimido-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1(R)-carboxylate in the form of a white solid of melting point 180°-181° C. (from ethyl acetate/n-hexane).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:7][CH:8]=1)=[O:1]
Reactant: O=S(=O)(Nc1ccc(CO)cc1)c1ccccn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1ccc(NS(=O)(=O)c2ccccn2)cc1
Yield: 60.2 %

Procedure:
To a stirred solution of pyridine-2-sulfonic acid (4-hydroxymethyl-phenyl)-amide (200 mg, 0.76 mmol), and pyridine (612 uL) in anhydrous CH2Cl2 (3 mL) was added Dess-Martin periodiane (450 mg, 1.06 mmol). The resultant solution was stirred at room temperature for 1 h. The mixture was diluted with 100 mL CH2Cl2, filtered through celite, and concentrated. The crude material was purified by recrystallisation from cold CH2Cl2 to give the title compound (120 mg, 60%) as a yellow powder. 1H NMR (300 MHz, CDCl3) δ 7.34 (d, 2H, J=8.4 Hz), 7.49-7.50 (m, 1H), 7.74 (br s, 1H), 7.75 (d, 2H, J=8.4 Hz), 7.89-7.70 (m, 1H), 8.03 (d, 1H, J=8.1 Hz), 8.70 (d, 1H, J=4.2 Hz), 9.87 (s, 1H).
Reaction SMILES: [CH2:1]([N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH:2]([CH3:4])[CH3:3].[CH2:42]([O:49][C:50]([NH:52][C@H:53]([C:58]([OH:60])=O)[CH2:54][C:55](=[O:57])[NH2:56])=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH3:41][C:38]1[CH:39]=[CH:40][C:35]([S:32]([N:5]([C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:58]([C@@H:53]([NH:52][C:50]([O:49][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:51])[CH2:54][C:55]([NH2:56])=[O:57])=[O:60])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:33])=[O:34])=[CH:36][CH:37]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](CC(N)=O)NC(=O)OCc2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from solid phase bound Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine as described in general procedure Bb using commercially available Nα-benzyloxycarbonyl-L-asparagine (319 mg, 1.2 mmol). The final product was purified by preparative HPLC to yield 46 mg (41%) of the desired material.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[CH:10]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]3[CH:37]=[CH:36][NH:35][C:32]3=[N:33][CH:34]=2)O1>>[O:18]1[CH2:19][CH2:20][N:15]([C:4]2[C:5]3[CH:10]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[S:8][C:6]=3[N:7]=[C:2]([C:29]3[CH:30]=[C:31]4[CH:37]=[CH:36][NH:35][C:32]4=[N:33][CH:34]=3)[N:3]=2)[CH2:16][CH2:17]1
Reactant: CC(C)(O)c1cc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Product: CC(C)(O)c1cc2c(N3CCOCC3)nc(-c3cnc4[nH]ccc4c3)nc2s1

Procedure:
2-(2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)propan-2-ol (100) mg was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine via General Procedure A to give 120 mg of 351 following reverse phase HPLC purification. MS (Q1) 396.2 (M)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15](=[O:17])[CH3:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O.COC1C=CC(NC2C(C=CC(C3C=C(OC)C(OC)=C(OC)C=3)=O)=CC=CN=2)=CC=1.Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15](=[O:17])[CH:16]=[CH:23][C:22]3[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1cccnc1Nc1ccc(Cl)cc1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: COc1ccc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: Cl
Solvent: CO
Product: COc1cc(C=CC(=O)c2cccnc2Nc2ccc(Cl)cc2)cc(OC)c1OC
Reaction time: 0.08 h
Yield: 85.2 %

Procedure:
To a solution of 1-(2-(4-chlorophenylamino)pyridin-3-yl)ethanone (100 mg, 0.406 mmol) in methanol (5 mL) was added 2N Ba(OH)2 solution (2 ml) and stirred for 5 minutes. Then added 3,4,5-trimethoxybenzaldehyde (79.65 mg, 0.406 mmol) and the reaction mixture was stirred at a temperature of 30° C. for 6h and the reaction was monitored by TLC. After 8h the reaction mixture is acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (7h) (147 mg, 85% yield).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CN(C=O)C.CCN=C=NCCCN(C)C.Cl.CN.[NH2:49][CH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([NH:49][CH:50]6[CH2:55][CH2:54][O:53][CH2:52][CH2:51]6)=[O:26])=[CH:28][CH:29]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reactant: NC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1CCOCC1)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reaction time: 0.08 h
Yield: 20.5 %

Procedure:
To a solution of example 8 (0.200 g, 0.524 mmol) in DMF (1 ml) HOBT (0.084 g, 0.629 mmol), EDC-HCl (0.250 g, 1.31 mmol) and methylamine (0.2 ml, 1.57 mmol) were added and stirred for 5 min, 4-Aminotetrahydropyran (0.106 g, 1.04 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as an off-white solid (0.050 g, 20%.). M.P.: 202-205° C., 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.69 (d, J=8.8 Hz, 1H), 8.44 (d, J=7.5 Hz, 1H), 8.38 (d, J=7.7 Hz, 1H), 8.33 (d, J=8.5 Hz, 2H), 8.20 (d, J=8.8 Hz, 1H), 8.03-7.99 (m, 4H), 7.85 (dd, J=8.7, 1.9 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.22 (s, 2H), 4.04 (m, 1H), 3.89 (d, J=9.7 Hz, 2H), 3.39 (t, J=10.0 Hz. 2H), 1.78 (d, J=10.5 Hz, 2H), 1.63 (m, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:34](=[O:35])[N:12]2[C:13]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:14](O)[CH2:15][S:16][C@H:11]12)=[O:8].CN(C)C=O.P(Cl)(Cl)[Cl:42]>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:34](=[O:35])[N:12]2[C:13]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:14]([Cl:42])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: ClP(Cl)Cl
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Cl)CS[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4.2 g. of diphenylmethyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate in 44 ml. of dry dimethylformamide was added 865 mg. of phosphorus trichloride. The mixture was stirred for 1.5 hours at room temperature and was poured into an ethyl acetate 5% aqueous hydrochloric acid mixture. The ethyl acetate layer was evaporated, was washed with 5% hydrochloric acid, water and was dried. The dried solution was concentrated in vacuo and the product crystallized. The 3-chloro ester was filtered, washed with cold ethyl acetate and dried to yield 2.2 g.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][C:5]([Cl:10])=[N:6][C:7]=1[CH2:8]Cl.[CH3:12][O-:13].[Na+]>CO>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][C:5]([Cl:10])=[N:6][C:7]=1[CH2:8][O:13][CH3:12]
Reactant: ClCc1nc(Cl)nc(Cl)c1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1nc(Cl)nc(Cl)c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a solution of 5-bromo-2,4-dichloro-6-(chloromethyl)pyrimidine (2) (600 mg, 2.19 mmol) in anhydrous MeOH (15 mL) at 0° C. was added NaOMe (25% wt in MeOH, 521 mg, 2.41 mmol). The mixture was stirred at 0° C. for 30 min and then allow warm to room temperature and stirred overnight. After this time the reaction mixture was concentrated in vacuo. The residue was purified using ISCO chromatography (24 g silica gel, 0-1.5% EtOAc in hexanes in 40 min) to give the title compound (480 mg, 81%) as a white solid. 1H NMR (DMSO, 300 MHz) δ 4.77 (s, 2H), 4.04 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][OH:11])[C:6]=2[CH:12]=1.[CH3:13][CH2:14][O:15][C:16]([C:18]1[N:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:20]2[C:25]([CH:26]=1)=[C:24](O)[CH:23]=[CH:22][CH:21]=2)=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:13][CH2:14][O:15][C:16]([C:18]1[N:19]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:20]2[C:25]([CH:26]=1)=[C:24]([O:11][CH2:10][C:7]1[C:6]3[CH:12]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:9][CH:8]=1)[CH:23]=[CH:22][CH:21]=2)=[O:17]
Reactant: CCOC(=O)c1cc2c(O)cccc2n1C(=O)OC(C)(C)C
Reactant: OCc1coc2ccc(Cl)cc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2n1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
100 (4 g, 21.9 mmol), 102 (6.7 g, 21.9 mmol), triphenylphosphine (17.3 g, 65.8 mmol) and 40% diethyl azadicarboxylate solution (31.8 ml, 65.8 mmol) are dissolved in THF and cooled to 0° C. Then a solution of N-ethyldiisopropylamine (11.2 ml, 65.8 mmol) in THF is added dropwise. After the addition is completed, the mixture is stirred at room temperature for 2 h. Then the mixture is evaporated under reduced pressure. The residue is diluted with ethyl acetate, washed with saturated NaHCO3-solution and dried over Na2SO4. The crude product is purified by Flash-chromatography (ethyl acetate/hexanes (3:7), silicagel).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:29]1[CH2:30][CH2:31][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[CH2:27][CH2:28]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Reactant: c1ccc(N2CCNCC2)nc1
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ccccn2)CC1
Yield: 87 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-pyridyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 87%). 1H NMR (300 MHz, CDCl3): δ 3.73 (m, 8H), 4.15 (s, 3H), 6.68 (d, J=8.4 Hz, 2H), 7.11-7.76 (m, 5H), 8.21 (dd, J=3.6 and 0.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][N:14]=1.[Cl:16]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl>[Cl:16][C:13]1[N:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:10]([NH2:15])=[N:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1nccnc1-c1ccc(Cl)cc1Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1ncc(Cl)nc1-c1ccc(Cl)cc1Cl
Yield: 93.5 %

Procedure:
3-(2,4-Dichlorophenyl)-2-pyrazinamine (1.43 g, 6.0 mmol) was dissolved in chloroform (9 mL), N-chlorosuccinimide (0.96 g, 7.2 mmol) was added thereto, and the mixture was stirred by heating under reflux for 4 hours. After being allowed to cool, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2) to give the title compound (1.54 g) as yellow crystals.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC#N>[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=[C:5]([NH:32][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:10]=2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NCc3ccccc3)n2)cc1
Yield: 80 %

Procedure:
To a stirred solution of 2-(Methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (0.10 g, 0.26 mmol) in MeCN (4 ml) was added benzylamine (5 eq) and the resultant solution heated under reflux for 24 h. The cooled reaction mixture was concentrated in vacuo and purified by SPE chromatography with cyclohexane:ethyl acetate (3:1). Concentration in vacuo of the combined fractions containing pure product gave the title compound as a white solid (0.090 g, 80%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:34])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:17]=[C:16]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:32])[N:15]=3)[C@H:10]([CH3:33])[CH2:9]2)=[N:6][CH:7]=1.[CH3:35][N:36](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[N:17]=[C:16]([N:27]3[CH2:31][CH2:30][CH2:29][C@@H:28]3[CH3:32])[N:15]=[C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:5]4[C:4]([Cl:34])=[CH:3][C:2]([C:35]#[N:36])=[CH:7][N:6]=4)[CH2:9][C@H:10]3[CH3:33])[CH:19]=2)=[CH:21][CH:22]=1
Reactant: C[C@@H]1CN(c2ncc(Br)cc2Cl)CCN1c1cc(-c2ccc(F)cc2)nc(N2CCC[C@@H]2C)n1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: C[C@@H]1CN(c2ncc(C#N)cc2Cl)CCN1c1cc(-c2ccc(F)cc2)nc(N2CCC[C@@H]2C)n1
Temperature: 25 °C

Procedure:
To a mixture of 4-[4-(5-bromo-3-chloro-pyridin-2-yl)-2-(R)-methyl-piperazin-1-yl]-6-(4-fluoro-phenyl)-2-(2-(S)-methyl-pyrrolidin-1-yl)-pyrimidine (700 mg) and Zn(CN)2 (94 mg) in DMF, add Pd(PPh3)4 (77 mg, 0.067 mmol). Purge the reaction mixture for 10 min with dry N2. Heat the stirring reaction mixture overnight at 80° C., cool to room temperature and partition between water and EtOAc. Dry the solution (Na2SO4), concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc-Hexanes (1:1) to afford the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[S:8][C:4]=2[CH:3]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:24](O)=[O:25]>>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[S:8][C:4]=2[C:3]=1[CH:24]=[O:25]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc2ccc(O)cc2s1
Agent: C1N2CN3CN1CN(C2)C3
Product: Cc1nc2ccc(O)c(C=O)c2s1

Procedure:
To a 3-necked flask equipped with a thermometer and an addition funnel were added 6-hydroxy-2-methyl-benzothiazole (1.0 gm, 6.05 mmol) and hexamethylenetetramine (3.4 gm, 24.3 mmol). After cooling in an ice-bath, trifluoroacetic acid (10 mL) was added dropwise with stirring while maintaining the temperature below 60° C. The reaction mixture was stirred overnight at 70°-75° C., cooled, and evaporated. The residue was taken up in ethyl acetate and neutralized with saturated NaHCO3 solution. The organic layer was washed with saturated brine solution and dried (Na2SO4). The solution was filtered, and the filtrate evaporated. The residue was triturated with a mixture of methylene chloride/methanol and filtered. The filtrate was evaporated, and the residue dissolved in a small volume of methylene chloride and chromatographed on a column of silica gel that was eluted with 25% acetone in hexane affording pure title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[O:19][CH2:20][CH3:21])[CH3:10].CCCCCC>C(#N)C>[Br:1][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:9][CH3:10])=[C:13]([O:19][CH2:20][CH3:21])[C:14]=1[F:18]
Reactant: CCOc1cccc(F)c1OCC
Reactant: O=C1CCC(=O)N1Br
Solvent: CCCCCC
Solvent: CC#N
Product: CCOc1ccc(Br)c(F)c1OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A solution of N-bromosuccinimide (NBS) (153.72 g, 864 mmol) in acetonitrile (1.5 L) was added dropwise to a solution of 1,2-diethoxy-3-fluorobenzene (150.00 g, 814 mmol) in acetonitrile (900 mL) on ice, and this was stirred at room temperature overnight. After the solvent was distilled off, ethyl acetate was added to the residue and washed with water. The obtained aqueous layer was extracted again with ethyl acetate, and the extract was combined with the aforementioned organic layer. The organic layer was washed sequentially with water, saturated brine, and water again, and was dried over anhydrous magnesium sulfate. The solution was concentrated and an oily substance was obtained. Following hexane addition to the oily substance, crystals that have precipitated were removed by filtration. The remaining solution was concentrated to yield an oily substance, which was distilled under reduced pressure to obtain 205.65 g of the subject compound (yield: 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][N+:19]([O-])=O)[CH2:9][P:10]([CH3:17])(=[O:16])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:19][CH2:18][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:9][P:10]([CH3:17])(=[O:16])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: [H][H]
Reactant: CC(C)COP(C)(=O)CC(C[N+](=O)[O-])c1ccc(Cl)cc1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(C)COP(C)(=O)CC(CN)c1ccc(Cl)cc1

Procedure:
A solution of 6.8 g of isobutyl 2-(4-chlorophenyl)-3-nitro-propyl(methyl)phosphinate in 80 ml of ethanol is added to 64 g of an 8% solution of ammonia in ethanol. To this are added 8 ml of Raney Nickel slurry and the resulting mixture is hydrogenated at 1 bar until hydrogen uptake ceases. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give isobutyl 3-amino-2-(4-chlorophenyl)-propyl(methyl)phosphinate as a viscous oil, 31P N.M.R. spectrum: δ=+54.0 and +53.4 ppm (CDCl3).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[NH2:5][C:6]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:7]([C:9]#[N:10])C>C1(C)C=CC=CC=1>[NH2:5]/[C:6](/[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:7](/[C:9]#[N:10])\[C:1]([Cl:4])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CCC(CC)C(N)=C(C)C#N
Solvent: Cc1ccccc1
Product: CCC(CC)/C(N)=C(\C#N)C(=O)Cl
Temperature: 25 °C

Procedure:
250 ml toluene were cooled to 0° C. and 40 g (0.4 mol) of phosgene were added. After warming up to 25° C., 13.8 g (0.1 mol) of 3-amino-2-cyano-4-ethyl-2-hexene in toluene were added. The reaction mixture was heated at 70° C. for 4 h, then the unreacted phosgene was removed by blowing out with dry N2. After cooling to 25° C. the product precipitated. Filtration and washing with diethyl ether gave 12 g (60% of theory) of the title compound as a yellow solid (m. p. 102° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH2:11])=[O:5])[CH3:2].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH:25]=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:11][C:10]2[CH:9]=[CH:8][NH:7][C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Product: CCOC(=O)c1[nH]ccc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 10 %

Procedure:
The title compound (0.156 g, 10%) was prepared in accordance with general method A starting from 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.68 g, 4.4 mmol) and 4-formylpiperidine-1-carboxylic acid tert-butyl ester (P. C. Ting et al., Bioorganic & Medicinal Chemistry Letters, 2001, 11, 491-494) (0.98 g, 4.6 mmol.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][CH:5]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:7]=1.[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])=[O:29])[CH:22]=[CH:21]2>C(O)C.CCCCCC>[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([S:28]([N:31]1[CH2:32][CH2:33][N:34]([C:12](=[O:14])[C:11]3[CH:10]=[CH:9][C:8]([C:6]4[N:7]=[C:3]([CH3:2])[NH:4][CH:5]=4)=[CH:16][CH:15]=3)[CH2:35][CH2:36]1)(=[O:29])=[O:30])[CH:22]=[CH:21]2
Reactant: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCNCC1
Reactant: Cc1nc(-c2ccc(C(=O)O)cc2)c[nH]1
Agent: Cl
Solvent: CCCCCC
Solvent: CCO
Product: Cc1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Br)ccc5c4)CC3)cc2)c[nH]1
Yield: 85 %

Procedure:
By an exactly analogous method to that described in Example 1, starting from 4-(2-methylimidazol-4-yl)benzoic acid hydrochloride and 1-(6-bromonaphth-2-ylsulphonyl)piperazine was prepared 1-(6-bromonaphth-2-ylsulphonyl)-4-[4-(2-methylimidazol-4-yl)benzoyl]piperazine (423 mg, 85% yield), m.p. 215-216° C. (from ethanol/hexane), 1H NMR (d6DMSO) 2.3 ppm (s,3H), 3.0-3.2 ppm (broad s,4H), 3.4-3.7 ppm (broad s,4H), 7.2 ppm (d,2H), 7.5 ppm (s,1H), 7.7 ppm (d,2H), 7.8 ppm (t,2H), 8.2 ppm (t,2H), 8.4 ppm (s,1H), 8.45 ppm (s,1H), 11.8 ppm (broad s,1H), the spectrum also contained signals due to ethanol (˜0.33 mol eq.); microanalysis, found: C, 55.4; H, 4.8; N, 9.9; S, 5.8%; C25H23N4O3BrS requires: C, 55.6; H, 4.5; N, 10.1; S, 5.8%; MS (M+H)+ 539/541.