Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:46]1([CH2:52][CH2:53][CH2:54][NH:55][C:56](=[O:78])[C@H:57]([CH2:67][CH2:68][CH2:69][NH:70][C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[NH:58][CH2:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C([O-])(=O)C>O1CCCC1>[C:46]1([CH2:52][CH2:53][CH2:54][NH:55][C:56](=[O:78])[C@H:57]([CH2:67][CH2:68][CH2:69][NH:70][C:71]([O:73][C:74]([CH3:76])([CH3:75])[CH3:77])=[O:72])[N:58]([C:10](=[O:12])[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NCCc1ccccc1)C(=O)NCCCc1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC[C@@H](C(=O)NCCCc1ccccc1)N(CCc1ccccc1)C(=O)CNC(=O)OC(C)(C)C
Yield: 70.2 %

Procedure:
cold solution (0° C.) of Boc-glycine (543 mg, 3.1 mmol), diisopropylethylamine (1 ml, 6.2 mmol), and tetrahydrofuran (10 ml) was treated with PyBrop (1.45 g, 3.1 mmol), followed by the addition of Nα-phenethyl-Nδ-Boc-ornithine 3-phenylpropylamide (1.28 g, 2.8 mmol) in tetrahydrofuran (5 ml). The resulting solution was acetate. The filtrate was concentrated in vacuo and the product purified by chromatography (silica gel—hexane/ethyl acetate) to give N-Boc-glycyl-Nα-phenethyl-Nδ-Boc-ornithine 3-phenylpropylamide (1.2 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:12]1[N:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]([CH:35]=[CH:36][CH:37]=2)[CH2:21][N:22]([CH3:34])[C:23](=[O:33])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:14][N:13]=1.O>CN(C=O)C>[C:28]([O:27][C:26](=[O:32])[NH:25][CH2:24][C:23]([N:22]([CH3:34])[CH2:21][C:20]1[CH:35]=[CH:36][CH:37]=[C:18]([C:15]2[CH:16]=[N:17][C:12]([O:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[N:13][CH:14]=2)[CH:19]=1)=[O:33])([CH3:31])([CH3:30])[CH3:29]
Reactant: OCc1ccncc1
Reactant: CN(Cc1cccc(-c2cnc(Cl)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cccc(-c2cnc(OCc3ccncc3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Pyridin-4-ylmethanol (112 mg) was dissolved in DMF (4 ml), and NaH (45 mg) was added thereto under ice-cooling. After stirring at the same temperature for 30 minutes, tert-butyl (2-{[3-(2-chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (200 mg) was added thereto, followed by stirring at room temperature for 2 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 7% MeOH/CHCl3) to obtain tert-butyl[2-(methyl{3-[2-(pyridin-4-ylmethoxy)pyrimidin-5-yl]benzyl}amino)-2-oxoethyl]carbamate (237 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7][CH2:6]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:7][CH2:6]2
Reactant: C1CCNC1
Reactant: COc1ccc2c(c1)CCC(=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CCC(N1CCCC1)=C2

Procedure:
12.0 g of 6-methoxy-2-tetralone were boiled at reflux for 2 hours in 200 ml of benzene and 5.6 ml of pyrrolidine, in the presence of 0.5 g of anhydrous p-toluenesulphonic acid. The toluene was removed in vacuo. 9.70 g of acrylamide and 0.5 g of p-toluenesulphonic acid were added to the thus-obtained crude 1-(6-methoxy-3,4-dihydro-2-naphthyl)pyrrolidine. The mixture was heated under nitrogen to 100° for 2 hours and to 150° for 2 hours. The reaction mixture was partitioned between 400 ml of chloroform and 40 ml of water. The organic phase was washed with 2×40 ml of water and the aqueous phases were extracted with 1×100 ml of chloroform. The chloroform phases were combined, dried over sodium sulphate and concentrated. The residue was chromatographed on 160 g of silica gel (particle size 0.2-0.5 mm). The 8-methoxy-1,4,5,8-tetrahydrobenzo[f]quinolin-3(2H)-one, eluted with methylene chloride and recrystallized from ethyl acetate, exhibits a melting point of 208°-209°.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:26]([C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:29])[N:27]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccccc2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with commercially available 2-methyl-5-phenyl-thiazole-4-carboxylic acid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=1.C(N(CC)CC)C.[CH2:18]([O:25][C:26]1[CH:35]=[C:34]2[C:29]([CH2:30][CH2:31][NH:32][CH2:33]2)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:25][C:26]1[CH:35]=[C:34]2[C:29]([CH2:30][CH2:31][N:32]([CH2:2][C:3]3[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=3)[CH2:33]2)=[CH:28][CH:27]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(COc2ccc3c(c2)CNCC3)cc1
Reactant: Cc1ncc(CCl)c(N)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CCc3ccc(OCc4ccccc4)cc3C2)c(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.9 %

Procedure:
A suspension of 0.23 g (0.0012 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine in 10 ml of dimethylformamide was treated with 0.42 ml (0.0030 mol) of triethylamine and 0.29 g (0.0012 mol) of 7-benzyloxy-1,2,3,4-tetrahydro-isoquinoline and the mixture was stirred at room temperature under argon for 18 hours. The solvent was distilled off in a high vacuum. The residue was partitioned between dichloromethane/water, extracted and dried over MgSO4. After removing the solvent the residue was chromatographed on silica gel with ethyl acetate as the eluent. 0.22 g (51%) of 5-(7-benzyloxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-2-methyl-pyrimidin-4-ylamine was obtained as a colourless solid; m.p. 151°-153°.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH2:26][CH2:27][O:28][CH2:29][CH2:30][N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]([CH2:40][CH:41]3[CH2:45][CH2:44][CH2:43][N:42]3[C:46](=[O:62])[CH:47]([NH:54]C(OC(C)(C)C)=O)[CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)=[CH:32]2)[CH:18]=1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH:8]([CH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH2:26][CH2:27][O:28][CH2:29][CH2:30][N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]([CH2:40][CH:41]3[CH2:45][CH2:44][CH2:43][N:42]3[C:46](=[O:62])[CH:47]([NH2:54])[CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)=[CH:32]2)[CH:18]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCCC1Cc1cn(CCOCCn2cc(CC3CCCN3C(=O)C(NC(=O)OC(C)(C)C)C3CCCCC3)c3ccccc32)c2ccccc12)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(C(=O)N1CCCC1Cc1cn(CCOCCn2cc(CC3CCCN3C(=O)C(N)C3CCCCC3)c3ccccc32)c2ccccc12)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 113.5 %

Procedure:
A solution containing 48 (0.085 g, 0.08 mmol) in DCM (8 mL) was cooled to 0° C. Trifluoroacetic acid (2 mL) was added and the reaction mixture was maintained at 0° C. for 30 min. An additional portion of TFA (1 mL) was added and the reaction mixture was stirred for 1 h at 0° C. The reaction was quenched by the careful addition of saturated aqueous NaHCO3 and the product was extracted with EtOAc. The combined organic extracts were washed with aq. NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 0.068 g of 49 as a pale yellow oil. The crude product was used directly in the next reaction. 1H NMR (CDCl3, 300 MHz) δ7.90 (d, J=7.6 Hz, 2H), 7.31-7.12 (m, 6H), 6.84 (app t, J=14 Hz, 2H), 4.47 (m, minor rotomer), 4.15 (m, 4H), 3.66-3.36 (m, 8H), 2.80 (m, 2H), 2.42 (m, 2H), 2.04-0.83 (m, 30H) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([Li])CCC.[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]([OH:19])[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: Clc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccc(Cl)cc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.8 %

Procedure:
A solution of 4-bromochlorobenzene (20.0 g, 104 mmol) in 125 mL of dry tetrahydrofuran under nitrogen was cooled to -78° and 70 mL of 1.5M n-butyllithium in hexane was added dropwise over 20 minutes. After stirring another 10 minutes, 12.5 mL (104 mmol) of 3-bromobenzaldehyde was added dropwise and the reaction was stirred for another 10 minutes at -78°. Saturated aqueous ammonium chloride (100 mL) was added and the reaction was warmed to room temperature and extracted with 300 mL of ether. The ethereal layer was extracted with three 75 mL portions of 1M sodium bisulfite, 75 mL of 1M sodium hydroxide, 75 mL of water, and 75 mL of brine. The ether layer was dried over magnesium sulfate and the solvent removed to give 31.2 g of 3-bromo-4'-chlorobenzhydryl alcohol as a pale yellow solid. A portion was recrystallized from hexanes containing 5% ether to give white needles, m.p. 67°-68°. Calc. for C13H10Br C10: C, 52.47; H, 3.39; Br, 26.85; Cl, 11.91. Found: C, 52.25; H, 3.25; Br, 26.72; Cl, 12.09.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[F:32][C:33]1[CH:34]=[C:35]([S:42](Cl)(=[O:44])=[O:43])[CH:36]=[CH:37][C:38]=1[N+:39]([O-:41])=[O:40]>C(Cl)Cl>[F:32][C:33]1[CH:34]=[C:35]([S:42]([N:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=3)[CH2:18][CH2:19]2)(=[O:43])=[O:44])[CH:36]=[CH:37][C:38]=1[N+:39]([O-:41])=[O:40]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1F
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 0 °C
Yield: 52.7 %

Procedure:
A 25-mL round-bottomed flask was cooled to 0° C. and charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydro chloride (500 mg, 1.25 mmol, Example 91, Step 1), CH2Cl2 (10 mL) and triethylamine (0.52 mL, 3.74 mmol). 3-Fluoro-4-nitrobenzenesulfonyl chloride (328 mg, 1.371 mmol, Matrix Scientific, Columbia, S.C.) was added and after 10 min the reaction was concentrated onto silica gel and purified via column chromatography (40 g silica gel, 0 to 100% hexanes in EtOAc) to give 2-(4-(4-((3-fluoro-4-nitrophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (350 mg).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[CH3:10][N:11]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]([CH:25]2[CH2:30][CH2:29][N:28](C)[CH2:27][CH2:26]2)[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][N:11]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]([CH:25]2[CH2:30][CH2:29][N:28]([C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3])[CH2:27][CH2:26]2)[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2
Reactant: CN1CCC(C2c3ccccc3N(C)c3ccccc32)CC1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN1c2ccccc2C(C2CCN(C(=O)OCC(Cl)(Cl)Cl)CC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
Trichloroethyl chloroformate (1.06 mL, 7.7 mmol) is added over a 10 minute period to a solution of 9,10-dihydro-10-methyl-9-(1-methyl-4-piperidinyl)acridine (453 mg, 1.55 mmol) [(Tetrahedron Letters, 29, 5701 (1988)] and triethylamine (649 μl, 4.65 mmol) in 20 mL of dry toluene at 85° C. The reaction is worked up after 30 minutes by extracting with EtOAc and washing with a 10% NaOH solution. The crude product is obtained after the solvent is removed.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[CH2:11][CH3:12].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]=[C:20]=[O:21])[CH:14]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:20](=[O:21])[NH:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:3]=1[CH2:11][CH3:12]
Reactant: CCc1cc2c(cc1Cl)NCC2
Reactant: O=C=Nc1cccnc1
Product: CCc1cc2c(cc1Cl)N(C(=O)Nc1cccnc1)CC2
Yield: 59 %

Procedure:
6-Chloro-5-ethylindoline (D52) (0.42 g, 2.33 mmol) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The crude product was recrystallised from ethanol/diethyl ether to give the title compound (0.42 g, 59%) as a white crystalline solid m.p.=227° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]2[CH:15]=[CH:16][S:17][C:3]=12.[NH:18]1[CH2:26][CH2:25][CH:21]([C:22]([NH2:24])=[O:23])[CH2:20][CH2:19]1.C([O-])(=O)C.[Na+]>CN1CCCC1=O.C(OCC)(=O)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]3[CH:15]=[CH:16][S:17][C:3]3=[C:2]([N:18]3[CH2:26][CH2:25][CH:21]([C:22]([NH2:24])=[O:23])[CH2:20][CH2:19]3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2cc(Cl)c3sccc3n2)cc1
Reactant: NC(=O)C1CCNCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: NC(=O)C1CCN(c2cc(-c3ccc(F)cc3)nc3ccsc23)CC1
Temperature: 160 °C
Yield: 59.5 %

Procedure:
A mixture of 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine (68 mg, 0.26 mmole), isonipecotamide (66 mg, 0.52 mmole), and sodium acetate (21 mg, 0.26 mmole) in 1-methyl-2-pyrrolidone (3 mL) is stirred and heated in an oil bath at 160° C. for about 4 hours. The reaction mixture is then cooled, diluted with ethyl acetate (15 mL) and washed with water (3×15 mL). The organic layer is dried over sodium sulfate, filtered, and concentrated. The residue is recrystalized with ethyl acetate to give 1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)piperidine-4-carboxamide (55 mg, 60% yield) as a white solid product (m.p. 251° C.-253° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:10])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[Cl:11][C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>C(Cl)Cl.N1C=CC=CC=1>[Br:10][C:3]1[C:2]([NH:1][C:14]([C:13]2[C:12]([Cl:11])=[N:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=1
Reactant: COc1ccc(N)c(Br)n1
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2cccnc2Cl)c(Br)n1
Reaction time: 0.33 h
Yield: 95.7 %

Procedure:
To a solution of 3-amino-2-bromo-6-methoxypyridine (2.7 g) in methylene chloride (20 ml) and pyridine (1 ml) was added 2-chloronicotinoyl chloride (2.2 g), and the resulting mixture was stirred 20 min. The mixture was then diluted with methylene chloride (100 ml), washed with water (100 ml), dried (anhydrous magnesium sulfate), and concentrated. The semisolid residue was saturated with hexane, filtered, and dried to give 4.1 g of product suitable for use in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:22][CH2:23][CH:24]=[CH2:25]>O1CCCC1.O>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH:22][CH2:23][CH:24]=[CH2:25])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: C=CCN
Reactant: O=C(Cl)N1CC(Oc2ccc(F)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCNC(=O)N1CC(Oc2ccc(F)cc2)C1
Temperature: 25 °C
Yield: 162.6 %

Procedure:
A stirred and cooled (32° C.) mixture of 5.52 g (0.022 mole) of crude 3-(4-fluorophenoxy)-1-azetidine carbonyl chloride and 3 g (0.02 mole) of potassium carbonate in 30 ml of tetrahydrofuran was treated with 1.5 g (0.02 mole) of 3-aminopropylene. The reaction mixture was still exothermic and was stirred for 5 hr as it cooled to ambient temperature. The reaction mixture was diluted with 200 ml of water to produce an oil phase separation. The oil portion was dissolved by extracting with 2×50 ml of benzene. The extracts were combined, dried over magnesium sulfate and concentrated in vacuo to yield 8.14 g of orange-red oil. The oil partially crystallized from benzene-ligroin with charcoal treatment, yielding first a reddish oil followed by a crystalline product, The total material was concentrated in vacuo to yield 7.45 g of amber-red oil. This oil solidified and was repeatedly triturated with isopropyl ether until only a red oil residue remained. The isopropyl ether portions were repeatedly cooled to the crystallization of residue, decanted from residue and heated to reduce volume until only a straw colored isopropyl ether solution remained. Upon cooling of this solution the title product crystallized and yielded 2.3 g (42.3%) of white crystalline product, m.p. 92°-94° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C>[C:12]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1nccc2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: c1ccc(-c2nccc3ccccc23)cc1
Yield: 81.2 %

Procedure:
1-Chloroisoquinoline (5.0 g, 30 mmol) and phenylboronic acid (4.5 g, 37 mmol) was dissolved into 100 mL of ethylene glycol dimethyl ether, followed by the addition of triphenylphosphine (0.7 g, 3 mmol) and Pd(II) acetate (0.17 g, 0.75 mmol). The reaction mixture was refluxed for 16 hours. The reaction mixture was cooled and the aqueous layer discarded. Additional ethyl acetate was added and the solvent was washed with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated to give 1-phenylisoquinoline (5.0 g, 79% yield)
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:4][OH:5].[CH3:12][O:13][CH:14]([OH:19])[C:15](OC)=O.C(O)(=O)C>CO.[Pd]>[CH:6]1([CH:3]([CH2:4][OH:5])[CH2:2][NH:1][CH2:15][C:14]([O:13][CH3:12])=[O:19])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: NCC(CO)C1CCCCC1
Reactant: COC(=O)C(O)OC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CNCC(CO)C1CCCCC1
Yield: 53.4 %

Procedure:
A solution of 3-amino-2-cyclohexyl-1-propanol (1 g, 6.37 mmole) and methyl glyoxylate methylhemiacetal (790 mg, 6.56 mmole; see Tetrahedron, 881, 1977) in methanol (9 ml) was stirred at room temperature under argon for 24 hours. The resulting solution was transferred to a Parr bottle, treated with additional methanol (22 ml), acetic acid (3.6 ml), and 10% Pd on carbon (857 mg) and hydrogenated at 50 psi overnight. The catalyst was filtered off and the filtrate was concentrated in vacuo. Acetic acid was removed by evaporation from toluene. The residue was partitioned between ethyl acetate and 1N HCl. The organic layer was extracted with additional HCl and the combined aqueous extracts were washed with ethyl acetate. The pH of the product rich aqueous solution was raised to 10.2, and sodium chloride was added to saturation. Extraction with ethyl acetate followed by drying (sodium sulfate), filtration and concentration in vacuo produced 780 mg (53%) of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Si:21]([O:28][CH2:29][C@H:30]([C:32]1[CH:33]=[N:34][C:35]([O:38][CH3:39])=[N:36][CH:37]=1)[NH2:31])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(#N)C.C(N(CC)C(C)C)(C)C>[Si:21]([O:28][CH2:29][C@@H:30]([NH:31][C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:32]1[CH:37]=[N:36][C:35]([O:38][CH3:39])=[N:34][CH:33]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: COc1ncc([C@H](N)CO[Si](C)(C)C(C)(C)C)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc([C@@H](CO[Si](C)(C)C(C)(C)C)Nc2ncnc3c2CN(c2ccc(C)cc2C#N)CC3)cn1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (500 mg, 1.76 mmol) and (S)-2-(tert-butyldimethylsilyloxy)-1-(2-methoxypyrimidin-5-yl)ethanamine (800 mg, 2.82 mmol) in acetonitrile (10 mL) and N,N-diisopropylethylamine (1 mL) was subjected to microwave irradiation at 185° C. for 3 h. The reaction mixture was concentrated and the residue was purified by silica-gel column to afford a light yellow solid.
Reaction SMILES: [Br:1]C1C=C(C2C(C(Cl)=O)=CC=CC=2)[ClH]C=1.[NH2:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[C:19](Cl)[N:18]=1.[Cl:27][C:28]1[CH:33]=[C:32](Cl)[CH:31]=[CH:30][C:29]=1[C:35]1[C:40]([C:41]2[NH:42][CH:43]=[C:44]([CH3:46])[N:45]=2)=[CH:39][N:38]=[C:37]([NH:47][CH2:48][CH2:49][NH:50]C2N=CC(C#N)=CC=2)[N:36]=1>>[NH2:16][C:17]1[N:18]=[C:19]([NH:50][CH2:49][CH2:48][NH:47][C:37]2[N:36]=[C:35]([C:29]3[CH:30]=[CH:31][C:32]([Br:1])=[CH:33][C:28]=3[Cl:27])[C:40]([C:41]3[NH:42][CH:43]=[C:44]([CH3:46])[N:45]=3)=[CH:39][N:38]=2)[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1c[nH]c(-c2cnc(NCCNc3ccc(C#N)cn3)nc2-c2ccc(Cl)cc2Cl)n1
Product: Cc1c[nH]c(-c2cnc(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc2-c2ccc(Br)cc2Cl)n1

Procedure:
{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[4-(4-bromo-2-chlorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]amine was prepared from 4-bromo-2-chlorolbenzoyl chloride and 2-amino-6-chloro-3-nitropyridine using the general method for 6-[(2-{[4-(2,4-dichlorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile.
Reaction SMILES: [C-]#N.[Na+].C(O)(=O)C.[C:8](#[N:10])C.[CH2:11]([N:15]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH:24]=[O:25])[N:17]=[C:16]1[N:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)[C:12]#[C:13][CH3:14]>C(OCC)(=O)C>[CH2:11]([N:15]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH:24]([C:8]#[N:10])[OH:25])[N:17]=[C:16]1[N:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)[C:12]#[C:13][CH3:14]
Reactant: CC#N
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=O)c1C(=O)OC
Agent: [C-]#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(O)C#N)c1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.200 g of sodium cyanide and 0.010 ml of acetic acid were added to a 15 ml acetonitrile solution of t-butyl 4-[1-(2-butynyl)-5-methoxycarbonyl-4-formyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the mixture was stirred at room temperature for 16 hours. 100 ml of ethyl acetate was added to the solution, and the mixture was washed twice with 50 ml of water and then with 50 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.274 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2:3).