Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3O[CH:8]3[C:7]=2[CH:15]=1)#[N:2].[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]([O:27][CH3:28])=[O:26])=[CH:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=[C:8]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([O:27][CH3:28])=[O:26])=[CH:17]3)[C:7]=2[CH:15]=1)#[N:2]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cn(C2=CC(C)(C)Oc3ccc(C#N)cc32)c2ccccc12
Temperature: 90 °C
Yield: 48.4 %

Procedure:
To the solution of 6-cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-benzopyran (1.15 g, 5.71 mmol) (prepared according to Evans et al., J. Med. Chem., 1983, 26, 1582 and J. Med. Chem., 1986, 29, 2194), and indole-3-carboxylic acid, methyl ester (1.0 g, 5.71 mmol) in dimethylformamide (5.0 mL) under argon was added finely ground potassium carbonate (1.93 g, 14.0 mmol). The reaction mixture was heated at 90° C. for 4 hours and cooled to ambient temperature. It was diluted with ethyl acetate and filtered. The filtrate was washed with water, 10% citric acid, brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to yield a colorless foam. It was purified by flash chromatography (5% ethyl acetate in hexanes) to give 1-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-1H-indole-3-carboxylic acid, methyl ester (990 mg), m.p. 177°-180° C. (ether-hexanes): 1H NMR (DMSO-d6) δ 8.3 (s, 1 H), 8.21 (d, J=6.4 Hz, 1 H), 7.80 (dd, J=8.8 and 2.4 Hz, 1 H), 7.35 (m, 3 H), 7.18 (d, 8.2 Hz, 1 H), 6.90 (d, J=1.7 Hz, 1 H), 6.42 (s, 1 H), 3.93 (s, 3 H), 1.68 (s, 6 H); 13C NMR (DMSO-d6) 164.5, 156 9, 136.9, 135.5, 135.2, 130.9, 128.7, 126.7, 126.3, 123.8, 122.7, 121.4, 119.8, 118.8, 118.4, 111.6, 108.4, 103.7, 79.3, 51.3, 27.9 ppm; IR (KBr) 2224, 1705, 1207 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([C:10]([OH:12])=O)=[CH:6][CH:5]=1)[CH3:2].Cl.[Cl:14][C:15]1[CH:16]=[C:17]([NH:27]C(=O)C2C=CN=C(OCC)C=2)[CH:18]=[CH:19][C:20]=1[C@H:21]1[O:26][CH2:25][CH2:24][NH:23][CH2:22]1>>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]([NH:27][C:10](=[O:12])[C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[N:9][CH:8]=2)[CH:18]=[CH:19][C:20]=1[C@@H:21]1[O:26][CH2:25][CH2:24][NH:23][CH2:22]1
Reactant: CCOc1ccc(C(=O)O)cn1
Reactant: CCOc1cc(C(=O)Nc2ccc([C@@H]3CNCCO3)c(Cl)c2)ccn1
Agent: Cl
Product: CCOc1ccc(C(=O)Nc2ccc([C@H]3CNCCO3)c(Cl)c2)cn1

Procedure:
In analogy to Example 83, step a) using 6-ethoxy-3-pyridinecarboxylic acid (CAS 97455-65-7) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-2-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (preparation described in example 91) instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester. White solid. MS (ISP): 362.0 ([M+H]+)
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][N:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][C:20]=3[C:29](=[O:31])[NH2:30])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>CN(C=O)C.C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][N:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:28][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][C:20]=3[C:29](=[O:31])[NH2:30])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Oc2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(Oc2ccccc2)c1
Reaction time: 0.05 h
Yield: 65.3 %

Procedure:
40% Methanolic Triton B (0.054 mL, 0.12 mM) was added to a solution of the 9-[(3-phenoxyphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (39.5 mg, 0.10 mM) in 3 mL DMF at room temperature. After 3 minutes, t-butyl bromoacetate (54.8 mg, 0.27 mM) was added and the resultant mixture stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, once with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 33.0 mg (65%) of the {9-[(3-phenoxyphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as a white solid. 1H NMR (DMSO-d6) δ7.6 (d, 1H, J=8 Hz), 7.5-6.8 (m, 15H), 6.55 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.8 (s, 2H), and 1.45 (s, 9H). IR (KBr, cm−1) 3450, 1748, 1670, 1582, 1486, 1246, 1225, and 1151. MS (ES) m/e 523.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=[O:15])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH:36]=[N:37][NH:38]3)O1>>[NH:38]1[C:39]2[C:35](=[C:34]([C:2]3[N:3]=[C:4]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:5]4[S:10][C:9]([C:11]5[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=5)[C:14]([OH:16])=[O:15])=[CH:8][C:6]=4[N:7]=3)[CH:42]=[CH:41][CH:40]=2)[CH:36]=[N:37]1
Reactant: O=C(O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: O=C(O)c1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (100 mg) via General Procedure A to yield 7.6 mg of 338. MS (Q1) 458.1 (M)+
Reaction SMILES: [Si:1]([O:8][CH:9]([C:11](=[CH2:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>CO>[Si:1]([O:8][C@H:9]([CH3:10])[C@H:11]([CH2:17][NH:25][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=C(C(=O)OCC)C(C)O[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(CN)cc1
Solvent: CO
Product: CCOC(=O)[C@@H](CNCc1ccc(OC)cc1)[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 48 h
Yield: 84.2 %

Procedure:
To a solution of ethyl 2-[1-(t-butyldimethylsilyloxy)ethyl]acrylate (5 g) in methanol (50 ml) was added 4-methoxybenzylamine (2.65 g) at room temperature. After stirring for 2 days, the solvent was removed from the reaction mixture. The residue was column-chromatographed on silica gel in a usual manner (eluent : a mixture of hexane and ethyl acetate, 2:1 to 1:1) to give ethyl (2S*,3R*)-3-(t-butyldimethylsilyloxy)-2-(4-methoxybenzylaminomethyl)butanoate (6.435 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][O:36][CH2:35]1>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]2[CH2:38][CH2:37][O:36][CH2:35]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCCC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCOC3)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 138.8 %

Procedure:
A mixture of 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (200 mg) and potassium carbonate (236 mg) in dry DMF (2 mL) was heated at 60° C. with stirring for 1 h. 3-(2-Bromoethyl)tetrahydrofuran (123 mg) was added and the reaction was continued for 2 h. The mixture was quenched with water and extracted with EtOAc (×3). The combined organics were washed with water and brine, dried using a hydrophobic frit and evaporated to give an oil (265 mg). The crude material was purified by normal phase chromatography (ISCO) using 0-15% MeOH/EtOAc as eluent to give the title compound (102 mg).
Reaction SMILES: [H-].[Na+].[C:3]12([OH:13])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[C:14]([N:18]1[CH2:22][CH2:21][O:20][P:19]1Cl)([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[C:3]12([O:13][P:19]3[N:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:22][CH2:21][O:20]3)[CH2:10][CH:9]3[CH2:8][CH:7]([CH2:6][CH:5]([CH2:11]3)[CH2:4]1)[CH2:12]2
Reactant: CC(C)(C)N1CCOP1Cl
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)N1CCOP1OC12CC3CC(CC(C3)C1)C2
Temperature: 40 °C
Reaction time: 16 h
Yield: 33.6 %

Procedure:
A 500 ml, three neck flask equipped with a thermometer, an additional funnel and a condenser topped with a nitrogen sweep is charged with 2.62 g (0.06 mol) of sodium hydride. The sodium hydride is washed with two 20 ml portions of hexane and finally suspended in 30 ml of tetrahydrofuran. To the resultant suspension is added dropwise a solution of 9.12 g (0.06 mol) of 1-adamantanol in 75 ml of THF at such rate to keep the reaction temperature between 20°-30° C. The resulting yellow solution is warmed to approximately 40° C. for 1 hour and then cooled in an ice bath. A solution of 10.9 g (0.06 mol) of 3-tert-butyl-2-chloro-1,3,2-oxazaphospholidine in 75 ml of THF is added and stirring continued for 16 hours at room temperature. The resulting cloudy mixture is filtered and the solvent evaporated under reduced pressure. The residue is treated with 200 ml of toluene and the resultant suspension is filtered. The filtrate is concentrated in vacuo to yield a thick syrup. Triturating with methanol gives 6.0 g (33.6%) of a white solid: m.p. 48°-50° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([N:24]2[CH2:28][CH:27]([CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:26][C:25]2=[O:37])[CH:20]=[CH:21][C:22]=1[OH:23]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:22]1[CH:21]=[CH:20][C:19]([N:24]2[CH2:28][CH:27]([CH2:29][O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:26][C:25]2=[O:37])=[CH:18][C:17]=1[F:16]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C1CC(COc2ccccc2)CN1c1ccc(O)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(N4CC(COc5ccccc5)CC4=O)cc3F)c2cc1OC
Temperature: 180 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinoline (0.185 g, 0.83 mmol), 1-(3-fluoro-4-hydroxyphenyl)-4-(phenoxymethyl)pyrrolidin-2-one (Step 4, 250 mg, 0.83 mmol) and DMAP (101 mg, 0.83 mmol) in 8 mL of toluene (in a microwave tube) was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 180° C. for 1.5 h. The mixture was cooled to RT and diluted with 50 mL of EtOAc. The solution was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (50% to 100% EtOAc/hexane) to provide the product as white solid. MS (ESI pos. ion) m/z: 489.3 (M+H). Calc'd Exact Mass for C28H25FN2O5: 488.51.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=2[C:5]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[C:4]([F:25])[CH:3]=1.CC(C)=[O:28].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[C:11]([C:8]1[O:9][C:10]2[C:2]([Cl:1])=[CH:3][C:4]([F:25])=[C:5]([C:13]3[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:20])([F:22])[F:21])=[CH:17][CH:18]=3)[C:6]=2[CH:7]=1)([OH:28])=[O:12]
Reactant: CC(C)=O
Reactant: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3oc(C=O)cc23)c1=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3oc(C(=O)O)cc23)c1=O
Temperature: -20 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
0.37 g (0.99 mmol) of 3-(7-chloro-5-fluoro-2-formylbenzofuran-4-yl)-1-methyl-6-trifluoromethyl-2-(1H)-pyridone was dissolved in 20 ml of acetone, and a Jones reagent (CrO3—H2SO4) was added thereto at −20° C. After stirring at −20° C. for 2 hours, the mixture was poured into water and extracted with ethyl acetate. An aqueous sodium hydroxide solution was added to make the extract alkaline, and the aqueous layer was washed with ethyl acetate and acidified by an addition of hydrochloric acid and then extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. Then, the obtained crude crystals were washed with diisopropyl ether to obtain 0.29 g (yield: 75%) of the desired products Melting point: 233-235° C. 1H-NMR (300 MHz, CDCl3) δ value: 3.79(3H,s), 6.87(1H,d), 7.38(1H,d), 7.47(1H,s), 7.61(1H,d)ppm.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[C:20](=O)[N:10]2[C:11]([C:17]([OH:19])=O)=[C:12]([CH2:15]O)[CH2:13][S:14][C@H:9]12)=[O:6].Cl>CC(C)=O.O>[CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[CH:9]2[S:14][CH:13]=[C:12]3[CH2:15][O:19][CH:17]=[C:11]3[N:10]2[CH2:20]1)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1csc(N)n1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CON=C(C(=O)NC1CN2C3=COCC3=CSC12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.7 %

Procedure:
A solution of 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.3 g) in a mixture of acetone (3 ml) and water (1.5 ml) was adjusted to pH 2 with 6 N hydrochloric acid and stirred for 4 hours at ambient temperature. After the acetone was distilled off, to the residue was added water (1 ml). The mixture was adjusted to pH 7 with a saturated aqueous solution of sodium bicarbonate and ice-cooled for 1 hour. Precipitating crystals were collected by filtration, washed with water and dried to give 6-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]-thiazine-1,7(4H-dione (syn isomer) (0.23 g), mp 210° to 215° C. (dec.).
Reaction SMILES: C([O:5][C:6](/[CH:8]=[CH:9]/[C:10]1[N:18]([CH3:19])[C:17]2[C:16](=[O:20])[N:15]([CH3:21])[C:14](=[O:22])[N:13]([CH3:23])[C:12]=2[N:11]=1)=[O:7])(C)(C)C.[OH-].[Na+]>CN(C=O)C.O>[C:6](/[CH:8]=[CH:9]/[C:10]1[N:18]([CH3:19])[C:17]2[C:16](=[O:20])[N:15]([CH3:21])[C:14](=[O:22])[N:13]([CH3:23])[C:12]=2[N:11]=1)([OH:7])=[O:5]
Reactant: Cn1c(=O)c2c(nc(/C=C/C(=O)OC(C)(C)C)n2C)n(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(nc(/C=C/C(=O)O)n2C)n(C)c1=O
Yield: 49 %

Procedure:
8-(trans-2-tert-Butyloxycarbonylvinyl)-1,3,7-trimethylxanthine (76 mg, 238 μmol) was dissolved in 3 ml TFA and stirred for 1 h. After evaporation, the residue was triturated with ether to provide the pure product 8-(trans-2-Carboxyvinyl)-1,3,7-trimethylxanthine (55 mg, 88% yield). mp: 278d °C. 1H NMR DMSO-d6 : d 3.27 (s, 3H, NCH3), 3.44 (s, 3H, NCH3), 4.02 (s, 3H N7CH3), 6.78 (d, 1H, J=15.4 Hz), 7.55 (d, 1H, J=15.4 Hz), 8.4 (br s, 1H, COOH). MS (CI NH3) m/e 265 (MH+). Alternatively, compound 8-(trans-2-Carboxyvinyl)-1,3,7-trimethylxanthine was prepared from 8-(trans-2-tert-Butyloxycarbonylvinyl)-1,3,7-trimethylxanthine in DMF/water (1:1) solution by saponification with sodium hydroxide in 49% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=2)[CH2:16]1.[CH3:39][O:40][CH2:41][C:42](Cl)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:5][N:6]([CH2:42][CH2:41][O:40][CH3:39])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=2)[CH2:16]1
Reactant: COCC(=O)Cl
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Product: COCCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1

Procedure:
Synthesized from [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (450 mg) and methoxyacetyl chloride (0.48 ml) according to an analogous synthetic method to Example 152, the title compound (400 mg) was obtained.
Reaction SMILES: C(OC([N:11]1[C@H:15]([CH3:16])[C@H:14]([CH2:17][OH:18])[C@H:13]([NH:19][CH2:20][C:21]2[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:22]=2[O:30][CH3:31])[C@@H:12]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[OH:18][CH2:17][C@@H:14]1[C@@H:15]([CH3:16])[NH:11][C@@H:12]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:13]1[NH:19][CH2:20][C:21]1[CH:26]=[C:25]([CH:27]([CH3:28])[CH3:29])[CH:24]=[CH:23][C:22]=1[O:30][CH3:31]
Reactant: COc1ccc(C(C)C)cc1CN[C@H]1[C@@H](CO)[C@@H](C)N(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(C)C)cc1CN[C@H]1[C@H](CO)[C@@H](C)N[C@H]1c1ccccc1
Yield: 91.8 %

Procedure:
20% Pd(OH)2 --C (Pearlman's catalyst, Aldrich; 0.44 g) was added to a solution of (2S*,3S*,4R*,5R*)-1-benzyloxycarbonyl-4-hydroxymethyl-3-[N-(5-isopropyl-2-methoxybenzyl)amino]-5-methyl-2-phenylpyrrolidine(0.70 g, 1.36 mmol) and HCO2NH4 (0.51 g, 8.16 mmol) in MeOH (20 ml). The reaction mixture was stirred and heated at a gentle reflux for 30 minutes. The catalysts were filtered off by the aid of a Celite pad, and washed with MeOH. The combined filtrate and washings were concentrated in vacuo. The residue was basified to pH 10 with 1M NaOH aq. solution, and extracted with AcOEt (×4). The combined AcOEt extracts were dried (K2CO3), and concentrated in vacuo to give a pale yellow viscous oil (0.46 g), which crystallized spontaneously on standing in a refrigerator for 2 days. This was recrystallized from AcOEt-n-hexane to give title compound (0.33 g, 63%) as white crystals. The yellow mother liquor was chromatographed over SiO2 (Merck Kieselgel 60, 2.0 g). Elution with CH2Cl2 --MeOH (50:1→20:1) gave an additional amount of title compound (0.06 g, 12%) as a pale yellow viscous oil, which crystallized spontaneously on standing at room temperature; the total yield of title compound amounted to 0.39 g (76%): mp 76.0-78.0 C. (white powders); IRmax (nujol): 3180(w), 1610(w), 1509(s), 1240(s), 1050(m), 800(m), 750(m), 696(m) cm-1 ; 1H-NMR δ: 7.47-7.22(m, 5H), 7.01(dd, J=8.4, 2.2 Hz, 1H), 6.68(d, J=8.4 Hz, 1H), 6.65(d, J=2.2 Hz, 1H), 4.50(d, J=7.7 Hz, 1H), 3.78(dd, J=10.3, 4.3 Hz, 1H), 3.66(dd, J=10.3, 9.4 Hz, 1H), 3.64(s, 3H), 3.61(d,J=12.3 Hz, 1H), 3.47(d,J=12.3 Hz, 1H), 3.39(dd, J=9.7, 7.7 Hz, 1H), 2.92(dq, J=9.4, 6.0 Hz, 1H), 2.76(sep, J=6.8 Hz, 1H), 2.13(br.s, 3H), 1.84(ddd, J=9.4, 9.4, 4.3 Hz, 1H), 1.27(d, J=6.0 Hz, 3H), 1.16(d, J=6.8 Hz, 6H) ppm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH:10](=[N:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCCN1CCNCC1
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: C(=NCCN1CCNCC1)c1ccccc1
Temperature: 25 °C

Procedure:
N-(2-Aminoethyl)piperazine (24.4 g) and benzaldehyde (26.9 ml) were dissolved in toluene (250 ml), and a Dean-Stark device was attached thereto, and the mixture was heated under reflux for 3 hours. After cooled to room temperature, a part (10 ml) of the reaction mixture was removed and concentrated to give N-[2-(benzylidene)aminoethyl]piperazine (1.4 g). Di (t-butyl) dicarbonate (45 g) was added to the remainder (about 240 ml) of the reaction mixture, and the mixture was stirred overnight at room temperature. 1 N aqueous potassium hydrogen sulfate (220 ml) was added thereto, and the mixture was vigorously stirred for 5 hours at room temperature, and the aqueous layer was partitioned by adding diethyl ether. The aqueous layer was basified by adding sodium hydroxide (solid), and the organic layer was partitioned by adding chloroform, washed with water, dried, and evaporated to give the title compound (14.9 g).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=C[CH2:7][CH2:6][CH:5]=1.C([O:15][C:16](=[CH2:19])[C:17]#N)(=O)C.C[O-].[Na+]>CO>[CH:17]12[CH2:7][CH2:6][CH:5]([C:4](=[O:3])[CH2:9]1)[CH2:15][C:16]2=[O:19]
Reactant: C=C(C#N)OC(C)=O
Reactant: C[Si](C)(C)OC1=CCCC=C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CC2CCC1CC2=O
Temperature: 150 °C
Reaction time: 3 h

Procedure:
25 mL of 2-(trimethylsilyloxy)-1,3-cyclohexadiene and 13 mL of α-acetoxyacrylonitrile were mixed and heated at 150° C. in a closed vessel for 22 h. The obtained dark orange viscous oil was dissolved in 200 mL of MeOH. After dropwise addition of a solution of 2.2 g of sodium methoxide in 150 mL of MeOH the reaction mixture was stirred for 3 h at rt, poured into ice/water and extracted with DCM. The organic phases were concentrated in vacuo and the crude residue was purified by CC with EtOAc-Hept (1:2) to yield 7.9 g of rac-(1R*,4R*)-bicyclo[2.2.2]octane-2,5-dione.
Reaction SMILES: Br[C:2]1[CH:10]=[N:9][C:8]([Cl:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[NH4+].[Cl-].[CH3:14][O-:15].[Na+]>>[CH3:14][O:15][C:2]1[CH:10]=[N:9][C:8]([Cl:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Clc1ncc(Br)c2cc[nH]c12
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: COc1cnc(Cl)c2[nH]ccc12
Temperature: 110 °C

Procedure:
A mixture of 4-bromo-7-chloro-6-azaindole (6 g), CuBr (3.7 g) and NaOMe (30 mL, 5% in MeOH) was heated at 110° C. for 24 hours in a sealed tube. After cooling to room temperature, the reaction mixture was added to saturated aqueous NH4Cl. The resulting aqueous solution was extracted with EtOAc (3×30 mL). The combined organic layer was dried over MgSO4, filtered and the filtrate was concentrated in vacuo to afford a residue, which was purified by using silica gel chromatography to give 1.8 g of 4-methoxy-7-chloro-6-azaindole, Precursor 2e.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[NH2:11].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[F:13])=[CH:6][C:5]=1[NH2:11])=[O:12]
Reactant: COC(=O)c1ccc(Br)cc1N
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccccc2F)cc1N
Temperature: 90 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
Step 1 A mixture of methyl-2-amino-4-bromobenzoate (3.06 g, 13.3 mmol), 2-fluorophenylboronic acid (2.23 g, 16.0 mmol), tetrakis(triphenylphosphine)palladium (1.54 g, 1.33 mmol) and 1 M aqueous sodium carbonate (16.6 mL, 16.6 mmol) in 1,2-dimethoxyethane (66.5 mL) was stirred at 90° C. overnight. The mixture was cooled to rt, filtered through a pad of Celite and the solids were rinsed with EtOAc. The filtrate was washed with water and brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from hexane to 90:10 hexane-EtOAc) to provide methyl-3-amino-2′-fluorobiphenyl-4-carboxylate (2.63 g, 81%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 7.90 (d, J=8.25 Hz, 1H), 7.38-7.46 (m, 1H), 7.27-7.35 (m, 1H), 7.08-7.22 (m, 2H), 6.85 (s, 1H), 6.82 (d, J=8.25 Hz, 1H), 5.83 (br s, 1H), 3.88 (s, 3H). Mass spectrum m/z 246.1 (M+H)+.