Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[C:32]([CH3:37])[N:31]([CH:38]1[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:30]2=[O:46]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:25][CH2:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[N:33]=[C:32]([CH3:37])[N:31]([CH:38]2[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]2=[O:45])[C:30]3=[O:46])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2ccc(CNC(=O)Cc3ccc(Cl)cc3)cc2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a stirred solution of (4-chloro-phenyl)-acetic acid (0.30 g, 1.8 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1,1′ carbonyldiimidazole (0.31 g, 1.9 mmol), and the mixture was stirred for one hour. Then 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.59 g, 1.7 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 2-(4-chloro-phenyl)-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-acetamide as a white solid (550 mg, 70% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.00 min (98.7%); mp, 229.5-231.5° C.; 1HNMR (DMSO-d6) 2.15-2.21 (m, 1H, CHH), 2.57-2.89 (m, 6H, CHCH2, CH3), 3.50 (s, 2H, ArCH2), 4.37 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.27-7.90 (m, 7H, Ar), 8.67 (t, J=5 Hz, 1H, CH2NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.92, 23.40, 30.63, 41.39, 41.87, 56.53, 120.02, 123.99, 126.57, 128.13, 130.87, 131.09, 134.03, 135.21, 137.97, 145.81, 154.61, 160.38, 169.47, 169.85, 172.61. LCMS MH=453, 455; Anal Calcd For C23H21N4O4Cl: C, 61.00; H, 4.67; N, 12.37; Cl, 7.83. Found: C, 60.88; H, 4.60; N, 12.27; Cl, 7.89.
Reaction SMILES: O[NH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.CO.Cl>[Zn].O>[NH2:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)c2c(NO)cccc21
Agent: Cl
Agent: [Zn]
Solvent: CO
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 70 °C

Procedure:
1-Hydroxylaminoanthraquinone 50 parts was stirred into a mixture of methyl alcohol 700 parts, water 100 parts and a 35% aqueous hydrochloric acid 60 parts. The reaction mixture was heated to 70°C and then added with zinc dust 16 parts little by little over 1 hour. After the reaction at 70°C for 3 hours, the reaction mixture was cooled to 25°C, filtered, washed with water and dried to obtain 42.5 parts of crystalline 1-aminoanthraquinone of a purity of 93%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]#[C:10][CH3:11].[Cl:12][C:13]1[C:18]2[NH:19][C:20](=[O:23])[N:21]([CH3:22])[C:17]=2[CH:16]=[CH:15][N:14]=1.C(OCC)(=O)C>CN(C)C=O.O>[CH2:8]([N:19]1[C:18]2[C:13]([Cl:12])=[N:14][CH:15]=[CH:16][C:17]=2[N:21]([CH3:22])[C:20]1=[O:23])[C:9]#[C:10][CH3:11]
Reactant: CC#CCBr
Reactant: Cn1c(=O)[nH]c2c(Cl)nccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCn1c(=O)n(C)c2ccnc(Cl)c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium carbonate (1.17 g) and 1-bromo-2-butyne (0.742 mL) were added to a solution of 4-chloro-1-methyl-1,3-dihydroimidazo[4.5-c]pyridin-2-one in N,N-dimethylformamide (50 mL). This was then stirred at room temperature for 16 hours. Ethyl acetate (300 mL) and water (200 mL) were added, and the organic layer was washed twice with 200 mL of water and then once with 200 mL of saturated aqueous sodium chloride solution, then was dried over anhydrous magnesium sulfate. The organic layer was filtered and concentrated under reduced pressure, and the residue was purified by silica gel chromatography. The ethyl acetate:hexane 3:2 fraction gave the title compound (0.980 g).
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C[C@H]2N(C[C@H]3[C@@H]4CCCCN4C[C@@H]2C3)CC1.[Li]C(CC)C.Br[C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=1)[C:39]([O:41][CH3:42])=[O:40]>CC(OC)(C)C.C1CCCCC1.CCOCC.[Cl-].[Cl-].[Zn+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.O>[C:9]([O:8][C:6]([N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:36]1[CH:45]=[CH:44][CH:43]=[C:38]([C:39]([O:41][CH3:42])=[O:40])[CH:37]=1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCCC1
Reactant: COC(=O)c1cccc(Br)c1
Agent: [Pd+2]
Agent: C1CCN2C[C@@H]3C[C@@H](CN4CCCC[C@@H]34)[C@H]2C1
Agent: CC(=O)[O-]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CCOCC
Product: COC(=O)c1cccc([C@H]2CCCN2C(=O)OC(C)(C)C)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 82.1 %

Procedure:
In a 1 L 3-neck flask fitted with thermocouple, addition funnel, and mechanical stirrer, stir a solution of tert-butyl 1-pyrrolidinecarboxylate (42.0 mL, 232.5 mmol) and (−)-sparteine (54.0 mL, 232.7 mmol) in anhydrous MTBE (350 mL) for 10 min at room temperature then cool to −78° C. To this add sec-BuLi (170 mL of a 1.4 M solution in cyclohexane, 238.0 mmol) dropwise via addition funnel directly into the solution over 90 min keeping the temperature <−73° C. Stir the resulting solution at −78° C. for 3 h. Add a solution of ZnCl2 (235.0 mL of a 1M solution in Et2O, 235.0 mmol) to the solution dropwise with rapid stirring keeping the temperature <−70° C. over 1 h. Stir the resulting light suspension at −75° C. for 20 min, warm to 0° C. over 1 h, then to 20° C. over 15 min. Stir the reaction at room temperature for 40 min. Charge the reaction, in the room temperature water bath, with methyl 3-bromobenzoate (43.4 g, 197.8 mmol), palladium(II) acetate (2.61 g, 11.62 mmol) and tri-tert-butyl-phosphonium tetrafluoroborate (4.172 g, 13.95 mmol) all homogenized and in one portion. A thick suspension develops within 5 min accompanied by a mild exotherm. Stir the suspension 24 h at room temperature. Add MTBE (400 mL) to the reaction to facilitate filtration. Add ammonium hydroxide (16 mL) to the reaction and stir at room temperature 2 h. Filter the slurry over a pad of diatomaceous earth (4×10 cm) washing with Et2O (5×300 mL). Concentrate the organic at room temperature to a volume of 1 L then chill to 5° C. Wash the cold filtrate with cold 1M HCl (1 L) then water (2×μL) and brine (300 mL). Extract the aqueous layers with EtOAc (400 mL) and dry the combined organics (Na2SO4) and concentrate at 35° C. The crude product was purified by silica gel chromatography eluting with 100% hexane to 20% EtOAc/hexane. Pool and concentrate fractions containing product in vacuo at 40° C. to give (R)-2-(3-methoxycarbonyl-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as an oil (49.62 g).
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[NH2:25][C:26]1([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3([OH:39])[CH2:38][CH2:37]3)=[CH:32][CH:31]=2)[CH2:28][CH2:27]1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:25][C:26]2([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4([OH:39])[CH2:38][CH2:37]4)=[CH:32][CH:31]=3)[CH2:27][CH2:28]2)=[CH:11][CH:10]=1
Reactant: NC1(Cc2ccc(C3(O)CC3)cc2)CC1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])C(F)(F)F
Product: O=C1COc2c(C(O)CNC3(Cc4ccc(C5(O)CC5)cc4)CC3)ccc(O)c2N1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 203 mg (1 mmol) 1-[4-(1-amino-cyclopropylmethyl)-phenyl]-cyclopropanol. Yield: 29 mg (6%, trifluoroacetate); mass spectroscopy: [M+H]+=411.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1CCCCC1>C(O)C>[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[C:18]2[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:19]2=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=CCCCCc1ccccc1
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1SC(=CCCCCc2ccccc2)C(=O)N1CCCCSc1cccc2nccn12

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 4.2 g (10 mmol) of 5-phenylpentanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4) to yield 2.627 g (quant., brown oily substance) of the desired product.
Reaction SMILES: [SH:1][C:2]1[S:6][C:5]([S:7][CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:10]2(=[O:12])=[O:11])=[N:4][N:3]=1.Cl.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25]Cl.C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C>[CH3:22][N:23]([CH2:24][CH2:25][S:1][C:2]1[S:6][C:5]([S:7][CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:10]2(=[O:12])=[O:11])=[N:4][N:3]=1)[CH3:27]
Reactant: O=C1c2ccccc2S(=O)(=O)N1CSc1nnc(S)s1
Reactant: CN(C)CCCl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CCSc1nnc(SCN2C(=O)c3ccccc3S2(=O)=O)s1
Yield: 57.6 %

Procedure:
Following a procedure similar to that described in Example 33A above, 1.72 g (0.005 mol) of 2-(5-mercapto-1,3,4-thiadiazol-2-ylthiomethyl)saccharin was reacted with 1.44 g (0.01 mol) of 2-dimethylaminoethyl chloride hydrochloride in 10 ml of DMF in the presence of 1.72 g (0.017 mol) of triethylamine to give 1.2 g (58%) of 2-(5-[2-(N,N-dimethylamino)ethylthio]-1,3,4-thiadiazol-2-ylthiomethyl)saccharin, mp 90.5°-91.5° C. (from ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[CH:9][CH2:10]CCC.Br[C:15]1C=NC=CC=1C=O.[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[C:9]([CH3:10])[CH3:15]
Reactant: CCCCC=Cc1ccncc1Br
Reactant: O=Cc1ccncc1Br
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Product: CC(C)=Cc1ccncc1Br

Procedure:
Following the general method as outlined in Intermediate 12, starting from 3-bromo-4-pyridinecarboxaldehyde (Aldrich) and isopropyltriphenylphosphonium iodide, the title compound was obtained as a yellow liquid after purification by flash column chromatography, eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+].Br[C:27]1[CH:28]=[C:29]([CH2:34][N:35]2[C:43](=[O:44])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]2=[O:45])[CH:30]=[C:31]([CH3:33])[CH:32]=1.[CH3:46][C:47]([Si:50]([CH3:63])([CH3:62])[O:51][CH2:52][C:53]1[CH:54]=[C:55](B(O)O)[CH:56]=[CH:57][CH:58]=1)([CH3:49])[CH3:48]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:46][C:47]([Si:50]([CH3:63])([CH3:62])[O:51][CH2:52][C:53]1[CH:54]=[C:55]([C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH2:34][N:35]3[C:43](=[O:44])[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:36]3=[O:45])[CH:28]=2)[CH:56]=[CH:57][CH:58]=1)([CH3:49])[CH3:48]
Reactant: Cc1cc(Br)cc(CN2C(=O)c3ccccc3C2=O)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(CN2C(=O)c3ccccc3C2=O)cc(-c2cccc(CO[Si](C)(C)C(C)(C)C)c2)c1
Temperature: 60 °C
Yield: 68 %

Procedure:
Pd(OAc)2(102.0 mg, 0.45 mmol, 0.03 eq.), PPh3 (476.4 mg, 1.82 mmol, 0.12 eq.), K2CO3(3.14 g, 22.7 mmol, 1.50 eq.) and 2-[(3-bromo-5-methylphenyl)methyl]-1H-isoindole-1,3(2H)-dione (5.00 g, 13.1 mmol, 1.00 eq.) were suspended in anhydrous 1,4-dioxane (30 mL) under nitrogen. After the mixture was heated to 60° C. for 10 min, [3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]boronic acid (4.84 g, 18.2 mmol, 1.20 eq.) was added. Then the reaction mixture was stirred over night at 100° C. After cooling it to room temperature, the solvent was removed under reduced pressure. Then water (25 mL) was added, extracted with CH2Cl2 twice (70 mL, 50 mL). The organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4. After the solvent was removed, the crude product was purified on silica column chomatography, eluting with PE/EA (20:1 to 10:1), to give 4.2 g of product, 2-{[3′-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-5-methyl-3-biphenylyl]methyl}-1H-isoindole-1,3(2H)-dione, as a colorless liquid (yield: 59%). 1H NMR (400 MHz, CDCl3) δ 0.11 (s, 6H), 0.95 (s, 9H), 2.38 (s, 3H), 4.79 (s, 2H), 4.87 (s, 2H), 7.23 (s, 1H), 7.31-7.49 (m, 6H), 7.70-7.72 (m, 2H), 7.84-7.86 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=1)[O:19][C:20]1[C:25]([F:26])=[CH:24][C:23]([CH2:27][OH:28])=[CH:22][C:21]=1[F:29]>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=1)[O:19][C:20]1[C:25]([F:26])=[CH:24][C:23]([CH2:27][O:28][C:2]2[CH:3]=[C:4]3[N:11]([CH3:12])[CH2:10][CH2:9][N:5]3[C:6](=[O:8])[N:7]=2)=[CH:22][C:21]=1[F:29]
Reactant: OCc1cc(F)c(Oc2cccc(Cl)c2)c(F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3cccc(Cl)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (30 mg, 0.162 mmol), sodium hydride (12.93 mg, 0.323 mmol) and (4-(3-chlorophenoxy)-3,5-difluorophenyl)methanol (43.7 mg, 0.162 mmol) in DMF (1.5 mL).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Mg]Br)[CH:3]=1.C1C[O:13][CH2:12]C1.CN(C=O)C>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:12]=[O:13])[CH:3]=1
Reactant: Cc1ccnc([Mg]Br)c1
Reactant: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccnc(C=O)c1
Yield: 71.5 %

Procedure:
4-Methyl-pyridine-2-carbaldehyde (433 mg, 71.5%) was obtained from 0.25 M 4-methyl-2-pyridinylmagnesium bromide of THF solution (20 mL, 5 mmol) with DMF (0.773 mL, 10 mmol) at room temperature under argon.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][NH2:19])=[CH:4][CH:3]=1.[CH2:22]([N:30]=[C:31]=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][NH:19][C:31]([NH:30][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:32])=[CH:4][CH:3]=1
Reactant: NCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Reactant: O=C=NCCc1ccccc1
Product: O=C(NCCc1ccccc1)NCCN1Cc2ccccc2CC1Cc1ccc(F)cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 2-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine obtained in Example 210-a) as a starting material, and using phenethyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([N:25]([CH3:27])[CH3:26])[CH:5]=2.[C:28](Cl)(=[O:34])[CH2:29][CH2:30][C:31](Cl)=[O:32]>>[C:12]([C:11]1[CH:10]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=2)[C:9]2[C:4](=[CH:5][C:6]([N:25]([CH3:27])[CH3:26])=[CH:7][CH:8]=2)[O:3][C:2]=1[N:1]1[C:31](=[O:32])[CH2:30][CH2:29][C:28]1=[O:34])#[N:13]
Reactant: O=C(Cl)CCC(=O)Cl
Reactant: COc1cc(C2C(C#N)=C(N)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Product: COc1cc(C2C(C#N)=C(N3C(=O)CCC3=O)Oc3cc(N(C)C)ccc32)cc(Br)c1OC

Procedure:
The title compound was prepared from 2-amino-3-cyano-7-dimethylamino-4-(3-bromo-4,5-dimethoxyphenyl)-4H-chromene and succinyl chloride as a yellow solid by a procedure similar to that described for Example 80. 1H NMR (CDCl3): 7.12 (d, J=1.8, 1H), 6.89-6.85 (m, 2H), 6.47 (m, 1H), 6.26 (d, J=2.7, 1H), 4.79 (s, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 2.96 (s, 4H), 2.92 (s, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1O[CH:6]=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.[CH2:20]([NH2:22])[CH3:21].[OH-].[Na+]>C(O)C>[CH2:20]([N:22]1[CH:6]=[CH:7][C:8](=[O:18])[C:9]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:4]1[CH2:3][O:2][CH3:1])[CH3:21]
Reactant: CCN
Reactant: COCc1occc(=O)c1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCn1ccc(=O)c(OCc2ccccc2)c1COC
Temperature: 70 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 2-methoxymethyl-3-benzyloxy-pyran-4(1H)-one (2.46 g, 10 mmol, 1 eq.) in ethanol (10 ml)/water (10 ml) was added 1.93 g (30 mmol, 3 eq.) of 70% aqueous ethylamine followed by 2N sodium hydroxide solution until pH 13 was obtained. The reaction mixture was sealed in a thick-walled glass tube and stirred at 70° C. overnight. After adjustment to pH 1 with concentrated hydrochloric acid, the solvent was removed by rotary evaporation prior to addition of water (50 ml) and washing with diethyl ether (3×50 ml). Subsequent adjustment of the aqueous fraction to pH 7 with 10N sodium hydroxide solution was followed by extraction into dichloromethane (4×50 ml), the combined organic layers then being dried over anhydrous sodium sulphate, filtered and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel (eluant: 15% CH3OH/85% CHCl3) to afford the title compound (2.05 g, 75.1%) as a yellow oil.
Reaction SMILES: C(N)C1C=CC=CC=1.[NH2:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[F:17][C:18]1[CH:43]=[CH:42][C:21]([O:22][CH2:23][CH2:24][N:25]([CH3:41])[C:26]2[N:31]=[C:30]([C:32]3[S:33][C:34]([C:38](O)=[O:39])=[C:35]([CH3:37])[N:36]=3)[CH:29]=[N:28][CH:27]=2)=[CH:20][CH:19]=1>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][NH:9][C:38]([C:34]2[S:33][C:32]([C:30]3[CH:29]=[N:28][CH:27]=[C:26]([N:25]([CH2:24][CH2:23][O:22][C:21]4[CH:20]=[CH:19][C:18]([F:17])=[CH:43][CH:42]=4)[CH3:41])[N:31]=3)=[N:36][C:35]=2[CH3:37])=[O:39])[CH:12]=1
Reactant: Cc1nc(-c2cncc(N(C)CCOc3ccc(F)cc3)n2)sc1C(=O)O
Reactant: NCc1cccnc1
Solvent: NCc1ccccc1
Product: Cc1nc(-c2cncc(N(C)CCOc3ccc(F)cc3)n2)sc1C(=O)NCc1cccnc1
Yield: 85 %

Procedure:
Following the procedure described in Example 1 (Part A), making variations as required to replace benzylamine with 3-(aminomethyl)-pyridine to react with 2-(6-{[2-(4-fluoro-phenoxy)-ethyl]-methyl-amino}-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid, the title compound was obtained in 85% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.51 (s, 1H), 8.47-8.62 (m, 2H), 8.12 (s, 1H), 7.67-7.73 (m, 1H), 7.25-7.30 (m, 1H), 6.90-6.96 (m, 2H), 6.78-6.84 (m, 2H), 6.31 (bs, 1H), 4.59 (d, J=4.0 Hz, 2H), 4.16-4.21 (m, 2H), 3.95-4.01 (m, 2H), 3.23 (s, 3H), 2.70 (s, 3H); MS (ES+) m/z 479.2 (M+1), Rt=1.36 min.
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].Cl[C:10]1[N:15]=[C:14]([O:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:19][CH:18]=2)[CH:13]=[CH:12][N:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:30]([O:29][C:28]([NH:27][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([O:16][C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[N:15]=2)=[CH:18][CH:19]=1)=[O:34])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(Cl)n2)c2ccccc12
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nccc(Oc2ccc(NC(=O)OC(C)(C)C)c3ccccc23)n1
Temperature: 75 °C
Yield: 56.1 %

Procedure:
To a degassed suspension of tert-butyl carbamate (1.89 g, 16.1 mmol), tert-butyl 4-(2-chloropyrimidin-4-yloxy)naphthalen-1-ylcarbamate (2.00 g, 5.38 mmol), Cs2CO3 (4.38 g, 13.45 mmol) and Xanthphos (0.249 g, 0.430 mmol) in THF (50 mL) was added Pd2dba3 (197 mg, 0.215 mmol) and the reaction mixture was heated at 75° C. for 16 hr. The reaction mixture was cooled to RT and was partitioned between EtOAc (40 mL) and water (40 mL). The aq layer was separated and extracted with EtOAc (40 mL) and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 15-60%, gradient elution to afford the title compound as an off-white solid (1.365 g 53%.); Rt 2.53 min (Method 2); m/z 453 (M+H)+, (ES+)+
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3](O)[CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)=O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CC#N.O.CC(O)C>[CH3:16][C:15]1[C:13](=[O:14])[N:12]=[C:10]2[N:9]([C@@H:1]3[O:8][C@H:5]([CH2:6][OH:7])[C@H:3]([O:11]2)[CH2:2]3)[CH:17]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)O
Solvent: O
Solvent: CC#N
Product: Cc1cn2c(nc1=O)O[C@@H]1C[C@H]2O[C@@H]1CO
Temperature: 20 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a dried round bottom flask containing thymidine(10.0 g, 41.6 mmol) was added triphenylphosphine (21.8 g, 82.2 mmol) and CH3CN (160 mL). The suspension was cooled to −20° C. ((40:60 iPrOH:H2O) and dry ice). To the reaction mixture was added diisopropylazodicarboxylate (16.8 g, 82.2 mmol) as CH3CN solution (60 mL) dropwise via an addition funnel, over a period of 1 hour. After the addition, the mixture was stirred for an additional 90 minutes at 20° C. The mixture was allowed to warm to 10° C. over a period of 5 hours. The reaction was then quenched with H2O (6 mL) forming a white suspension. The reaction was allowed to stand for 30 minutes and then was filtered. The collected solid was washed with cold CH3CN and dried under vacuum to afford 7.7 g (83% yield) of a white solid. If desired, the solid may be recrystallized in EtOH.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:20][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:34])([CH3:35])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2ccc(F)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2ccc(F)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 90 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 69b (1 g, 1.9 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1 g, 90%).