Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH2:2][CH2:3][CH2:4][N:5]2[C:10]=1[C:9]1[NH:11][C:12]3[C:17]([C:8]=1[CH2:7][CH2:6]2)=[CH:16][CH:15]=[CH:14][CH:13]=3.C(O)C.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23]>ClCCl>[CH2:26]([O:25][C:21]([CH2:22][CH2:23][CH:1]1[CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:9]=32)[CH2:4][CH2:3][CH2:2]1)=[O:24])[CH3:27]
Reactant: C1=C2c3[nH]c4ccccc4c3CCN2CCC1
Reactant: C=CC(=O)OCC
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCC1CCCN2CCc3c([nH]c4ccccc34)C12
Reaction time: 48 h

Procedure:
2.2 g (10 mmoles) of 2,3,4,6,7,12-hexahydro-indolo[2,3-a]quinolizine are dissolved in 100 ml of dichloromethane, 0.5 ml of ethanol and 2.3 g (25 mmoles) of ethyl acrylate are added to the solution, and the mixture is allowed to stand at room temperature for 2 days under argon atmosphere. The solvent is evaporated in vacuo, the residue is triturated with 3×3 ml of petroleum ether, the liquid is decanted, and the solid is dried.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:16])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](C(O)=O)=[C:5]2[O:14][CH3:15].[H-].[Na+].[CH3:19][C@@H:20]1[CH2:22][O:21]1>C1(OC2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[F:1][C:2]1[C:3]([CH3:16])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][C@H:20]([OH:21])[CH3:22])[CH:6]=[C:5]2[O:14][CH3:15]
Reactant: C[C@@H]1CO1
Reactant: COc1c(C(=O)O)[nH]c2ccc(F)c(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cn(C[C@@H](C)O)c2ccc(F)c(C)c12
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A suspension of 1.98 g of 5-fluoro-3-methoxy-4-methylindole-2-carboxylic acid in 16 ml of diphenyl ether was stirred at 260° for 0.5 hour and, after cooling to 0°, diluted with 44 ml of tetrahydrofuran. 0.33 g of sodium hydride dispersion was added and the mixture was stirred for one hour. Subsequently, 1 ml of (R)-methyloxirane was added and the reaction mixture was stirred at room temperature for 90 hours. The mixture was extracted with diethyl ether, water and saturated sodium chloride solution and the organic phase was dried over sodium surfate. The solvent was removed and the residue was chromatographed over 120 g of silica gel with toluene and toluene-ethyl acetate (9:1). 1.69 g (80%) of (R)-1-(5-fluoro-3-methoxy-4-methylindol-1-yl)-propan-2-ol were obtained as a pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[NH:10][CH:9]=[N:8][C:7]2[C:3]=1[N:4]=[CH:5][N:6]=2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C>[Cl:1][C:2]1[NH:10][CH2:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:7]2[C:3]=1[N:4]=[CH:5][N:6]=2
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1[nH]cnc2ncnc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1CNC(Cl)=C2N=CN=C21
Reaction time: 9 h
Yield: 13.9 %

Procedure:
A solution of 0.31 g (2.0 mmol) of 6-chloro-1H-purine and 0.83 g (6.0 mmol) of potassium carbonate in 15 mL of DMF was stirred at 25° C. for 20 min. under argon. To it, 0.53 mL (3.0 mmol) of 1-(chloromethoxy)-2-(trimethylsilyl)ethane (SEM-Cl) was added via syringe, the solution was stirred for 9 h, filtered through Celite, and the filtrate was diluted with diethyl ether, washed with water, and brine, dried (MgSO4), concentrated, and column chromatographed on silica gel using a gradient mixture of hexane and ethyl acetate to give 0.35 g (61% yield) of 115 and 0.08 g (14% yield) of 6-chloro-3-[(2-trimethylsilylethoxy) methyl]-1H-purine (117). Compound 115: mp 33-34° C.; NMR δ 8.70 (s, 1H), 8.24 (s, 1H), 5.62 (s, 2H, NCH2O), 3.60 (t, J=8 Hz, 2H, CH2O), 0.94 (t, J=8 Hz, 2H, CH2Si), −0.12 (s, 9H, MeSi); 13C NMR δ 152.4, 152.2, 151.3, 145.4, 131.5, 72.7 (CN), 67.8 (CO), 17.8, 21.4 (CSi).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([C:16]#[CH:17])=[CH:10][CH:11]=3)[C:6]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[C:5]=2[CH:4]=1)#[CH:2].I[C:27]1[S:31][C:30]([CH:32]=[O:33])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:22]([C:6]1([CH2:18][CH2:19][CH2:20][CH3:21])[C:7]2[CH:8]=[C:9]([C:16]#[C:17][C:27]3[S:31][C:30]([CH:32]=[O:33])=[CH:29][CH:28]=3)[CH:10]=[CH:11][C:12]=2[C:13]2[C:5]1=[CH:4][C:3]([C:1]#[C:2][C:27]1[S:31][C:30]([CH:32]=[O:33])=[CH:29][CH:28]=1)=[CH:15][CH:14]=2)[CH2:23][CH2:24][CH3:25]
Reactant: C#Cc1ccc2c(c1)C(CCCC)(CCCC)c1cc(C#C)ccc1-2
Reactant: O=Cc1ccc(I)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCC1(CCCC)c2cc(C#Cc3ccc(C=O)s3)ccc2-c2ccc(C#Cc3ccc(C=O)s3)cc21
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 97.4 %

Procedure:
Air was removed from a solution of 2,7-diethynyl-9,9-dibutyl-9H-fluorene (0.150 g, 0.460 mmol) and 5-iodothiophene-2-carboxaldehyde (Wu, L.-H.; Chu, C.-S.; Janarthanan, N.; Hsu, C.-S. J. Polym. Res. 2000, 7, 125-134) (0.251 g, 1.06 mmol) in 6.5 mL of toluene/Et3N (4/1) by blowing argon for 20 min. Then CuI (7.0 mg, 0.0037 mmol) and Pd(PPh3)2Cl2 (27 mg, 0.0039 mmol) were added, and deaeration was continued for 10 min. Thereafter the mixture was stirred at 40° C. for 16 h. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (heptane/CH2Cl2 50:50 then 40:60) to yield 245 mg (97%) of 5,5′-(9,9-dibutyl-9H-fluorene-2,7-diyldi-2,1-ethynediyl)bis-2-thiophenecarboxaldehyde; 1H NMR (300.13 MHz, CDCl3) δ 9.80 (s, 2H), 7.61 and 7.26 (AX, JAX=3.9 Hz, 4H), 7.62 (d, J=8.5 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H), 7.45 (s, 2H), 1.93 (m, 4H), 1.02 (m, 4H), 0.60 (t, J=7.3 Hz, 6H), 0.51 (m, 4H); 13C NMR (75.46 MHz, CDCl3) δ 182.4, 151.4, 143.9, 141.4, 136.1, 133.0, 132.5, 131.0, 126.0, 120.9, 120.4, 98.9, 82.6, 55.3, 40.1, 25.9, 23.0, 13.8; HRMS (ESI) calcd for C35H30O2S2 (M+·) m/z 546.16872. found 546.1687.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH:14]=O)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH2:22].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:22][CH3:21])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCC=O)CC2
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCCCN1CCc2cc(OC)c(OC)cc2CC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
Dissolve 50 g (0.18 mol) of 3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-propionaldehyde in 625 mL of methanol. Cool the resulting solution to 0° C. Then add 62.5 mL (0.81 mol; 4.5 equivalents) of 40% aqueous methylamine solution. Stir for one hour at 0° C., and then add 7.5 g (0.2 mol; 1.1 equivalents) of NaBH4. Stir for 30 minutes at 0° C. and then stir for 12 hours at ambient temperature. Evaporate off the methanol. The residue is taken up in aqueous hydrochloric acid solution (1N), washed with ethyl acetate and then the aqueous phase is brought to pH=8 by adding 20% sodium hydroxide solution and extracted with dichloromethane. The organic, phase is washed with water, dried over MgSO4, filtered and then evaporated to dryness to obtain 52 g of an oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([NH:2][CH2:1][C:23](=[O:26])[CH:24]=[CH2:25])=[CH:8][CH:7]=1
Reactant: C=CC(=O)Cl
Reactant: CNc1ccc(CC(=O)OC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)CNc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl (4-methylaminophenyl)acetate (4.00 g, 22.3 mmol) and N,N-diisopropylethylamine (7.78 mL, 44.6 mmol) in DCM (20.0 mL) at 0° C. was slowly added 2-propenoyl chloride (2.18 mL, 26.8 mmol). The reaction mixture was stirred at room temperature for 2 h and then saturated aqueous sodium bicarbonate (20.0 mL) was added. This mixture was extracted with DCM (10 mL) and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: BrCCOc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)N(CCOc3ccccc3)C(C)(C)C2=O)cn1

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and (2-bromoethoxy)benzene. MS 424 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.35 μM.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.Br[C:29]1[C:30]([O:51][CH3:52])=[C:31]([C:36]([CH2:39][S:40]([N:43]2[CH2:48][CH2:47][C:46]([F:50])([F:49])[CH2:45][CH2:44]2)(=[O:42])=[O:41])=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33]>>[F:49][C:46]1([F:50])[CH2:47][CH2:48][N:43]([S:40]([CH2:39][C:36]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([O:51][CH3:52])[C:29]([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=[CH:38][CH:37]=2)(=[O:42])=[O:41])[CH2:44][CH2:45]1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: COC(=O)c1c(CS(=O)(=O)N2CCC(F)(F)CC2)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)N2CCC(F)(F)CC2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-6-(4,4-difluoropiperidine-1-ylsulphonylmethyl)-2-methoxybenzoate (Intermediate 179), as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[S:4].[OH:7][C:8]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([CH3:18])=[CH:12][C:9]=1[CH:10]=[O:11].[OH-].[K+]>O1CCCC1.O>[CH3:1][N:2]([CH3:6])[C:3]([O:7][C:8]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([CH3:18])=[CH:12][C:9]=1[CH:10]=[O:11])=[S:4]
Reactant: CN(C)C(=S)Cl
Reactant: COc1cc(C)cc(C=O)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)cc(C=O)c1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
100 ml (0.8 mol) of dimethylthiocarbamoyl chloride in 150 ml of tetrahydrofuran are added at 5°-10° C. to 100 g (0.6 mol) of 2-hydroxy-3-methoxy-5-methylbenzaldehyde and 33.6 g (0.6 mol) of potassium hydroxide in 400 ml of water. The mixture is stirred at 25° C. for 15 min and, after adding 200 ml of 10% strength aqueous potassium hydroxide solution, extracted with ethyl acetate, the organic phase is washed with water and dried with sodium sulphate and, after concentrating in vacuo, the residue is recrystallised from ethanol.
Reaction SMILES: [C-]#N.[K+].[C:4](#[N:6])C.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH:33]([CH3:35])[CH3:34])[C:15]([O:17][CH:18](Cl)[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=2)=[O:16])=[CH:10][CH:9]=1>CCOCC>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH:33]([CH3:35])[CH3:34])[C:15]([O:17][CH:18]([C:4]#[N:6])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=2)=[O:16])=[CH:10][CH:9]=1
Reactant: CC(C)C(C(=O)OC(Cl)c1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Reactant: CC#N
Agent: [C-]#N
Agent: [K+]
Solvent: CCOCC
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1

Procedure:
1.5 g of potassium cyanide were added to a mixture of 80 ml of acetonitrile and the solution obtained in Example 9 and the mixture was stirred at 20° C. for 72 hours. Ether was added to the mixture which was then filtered to remove insolubles. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 95-5 cyclohexane-acetone mixture yielded 6.5 g of RS α-cyano-3-phenoxy-benzyl 2-(p-chlorophenyl)-2-isopropyl-acetate.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1.C(N(CC)CC)C.Cl[C:30]([O:32][CH3:33])=[O:31].Cl>ClCCl>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:30]([O:32][CH3:33])=[O:31])[CH2:17]1
Reactant: Cn1c(OC2CCCNC2)nc(-c2ccncn2)cc1=O
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCCC(Oc2nc(-c3ccncn3)cc(=O)n2C)C1
Reaction time: 2 h
Yield: 42.9 %

Procedure:
To a solution of 1-methyl-2-(piperidine-3-yloxy)-1H-[4,4′]bipyrimidinyl-6-one (0.10 g, 0.35 mmol) and triethylamine (70 μl, 0.5 mmol) in dichloromethane (5 ml) was added methyl chloroformate (40 μl, 0.5 mmol) at 0° C. The resulting mixture was stirred for 2 hours and poured into 1N aqueous hydrochloric acid. The partitioned organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent; chloroform/methanol=100/0 to 90/10) to afford methyl 3-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yloxy)piperidine-1-carboxylate as a white solid (52 mg, 0.15 mmol, 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([CH2:13][O:14]C)=[C:6]2[C:16]([O:18][CH3:19])=[O:17].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl.O>[CH:13]([C:7]1[N:8]([CH3:12])[C:9]2[C:5]([C:6]=1[C:16]([O:18][CH3:19])=[O:17])=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)=[O:14]
Reactant: COCc1c(C(=O)OC)c2cc(OC)ccc2n1C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1c(C=O)n(C)c2ccc(OC)cc12
Temperature: 30 °C
Yield: 47.7 %

Procedure:
24.7 g (100 mmol) of 5-methoxy-3-methoxycarbonyl-2-methoxymethyl -1-methylindole obtained in Example 2 or 4 was dissolved in 494 ml of methylene chloride and 27.4 ml of water, followed by the addition of 25.0 g (110 mmol) of DDQ and subsequent 8 hours of stirring at 30° C. The reaction mixture was filtered and the thus collected insoluble materials were washed with 120 ml of methylene chloride. The filtrate and the washings were combined and applied to a column packed with 123.5 g of alumina. The eluate was combined with another eluate obtained by further elution of the alumina column with 2,260 ml of methylene chloride, and the thus combined eluates were concentrated under reduced pressure. The thus obtained residue was recrystallized from 111 ml of ethyl acetate, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain 11.8 g of the title compound with a yield of 80.1%. The compound thus obtained showed the same properties as those of the compound obtained in Example 5 in terms of NMR, IR and TLC data.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:16]=2)=[N:2]1.N1C=CC=CC=1.C(N(CC)CC)C.[C:43](OC(=O)C)(=[O:45])[CH3:44].[OH-].[NH4+]>>[NH:2]1[C:3]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[O:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:43](=[O:45])[CH3:44])[CH2:26][CH2:25]2)=[N:4][CH:5]=[N:1]1
Reactant: c1cc(OCCN2CCNCC2)cc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Reactant: CC(=O)OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(CCOc2cccc(-c3n[nH]c4ccc(-c5ncn[nH]5)cc34)c2)CC1
Reaction time: 2 h
Yield: 8.8 %

Procedure:
1-(5-(1H-1,2,4-triazol-3-yl)(1H-indazol-3-yl))-3-(2-piperazinylethoxy)benzene (0.066 g, 0.169 mmol) was stirred with pyridine (0.50 mL, 6.18 mmol), triethylamine (0.10 mL, 0.717 mmol) and acetic anhydride (0.10 mL, 1.06 mmol) at ambient temperature. After 2 h, ammonium hydroxide (0.50 mL) was added and the mixture stirred for 1 h. The mixture was evaporated and gave the title compound (0.0064 g, 9% yield). 1H NMR (CD3OD) δ 8.71 (s, 1H), 8.35 (s, 1H), 8.08 (dd, 1H), 7.66 (d, 1H), 7.61 (dt, 1H), 7.55 (m, 1H), 7.44 (t, 1H), 7.01 (m, 1H), 4.25 (t, 2H), 3.58 (dt, 4H), 2.85 (t, 2H), 2.60 (dt, 4H), 2.08 (s, 3H). ES-MS (m/z) 432 [M+1]+.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[N+:13]([CH2:16][CH3:17])([O-:15])=[O:14].C(N)CCC>C(O)C>[CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:16]([N+:13]([O-:15])=[O:14])[CH3:17])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC[N+](=O)[O-]
Reactant: CCCCc1ccc(C=O)cc1
Solvent: CCCCN
Solvent: CCO
Product: CCCCc1ccc(C=C(C)[N+](=O)[O-])cc1

Procedure:
A stirred solution of 4-butylbenzaldehyde (13.5 g), nitroethane (9.0 ml) and butylamine (1.6 ml) in ethanol (20 ml) was heated under reflux for 6 hours and evaporated. The residue was distilled under vacuum to give 1-(4-butylphenyl)-2-nitropropene (bp 124°-125° C./0.15 mm).
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].Br[C:9]([C:15]1[O:16][C:17]([CH3:20])=[CH:18][N:19]=1)([CH3:14])[C:10]([O:12][CH3:13])=[O:11]>CN(C=O)C>[C:5]([CH:4]([C:3]#[N:7])[C:9]([CH3:14])([C:15]1[O:16][C:17]([CH3:20])=[CH:18][N:19]=1)[C:10]([O:12][CH3:13])=[O:11])#[N:6]
Reactant: COC(=O)C(C)(Br)c1ncc(C)o1
Reactant: N#CCC#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(c1ncc(C)o1)C(C#N)C#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To NaH (60%, 0.085 g, 2.1 mmol) in 5 mL of DMF at 0° C. was added dropwise malononitrile (0.141 g, 2.13 mmol) in 3 mL of DMF. After stirring at room temperature for 15 minutes, the intermediate from Step C in 5 mL of DMF was added. After stirring overnight the reaction mixture was quenched with saturated aqueous NH4Cl. The solution was extracted with EtOAc, dried with MgSO4, and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated compound (a pale yellow oil). 1H NMR (CDCl3, 500 MHz) δ 6.82 (1H, s), 4.86 (1H, s), 3.87 (3H, s), 2.38 (3H, s), 2.05 (3H, s).
Reaction SMILES: FC(F)(F)C(O)=O.CO[CH:10]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH2:13][CH:12](OC)O1.C(#[N:31])C>>[N:22]1[CH:23]=[CH:24][CH:25]=[N:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:14]2[CH:13]=[CH:12][NH:31][CH:10]=2)=[CH:16][CH:17]=1
Reactant: CC#N
Reactant: COC1CC(c2ccc(-c3ncccn3)cc2)C(OC)O1
Solvent: O=C(O)C(F)(F)F
Product: c1cnc(-c2ccc(-c3cc[nH]c3)cc2)nc1
Temperature: 55 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
Trifluoroacetic acid (61 μL, 0.80 mmol) was added to a solution of Compound 5 (39 mg, 0.06 mmol) and 2-[4-(tetrahydro-2,5-dimethoxy-3-furanyl)phenyl]pyrimidine (24 mg, 0.08 mmol, prepared as described in Reference Example 441) in acetonitrile (1 mL) at room temperature. The reaction mixture was stirred at 55° C. for 3 h, cooled to room temperature, quenched with sat. aq. NaHCO3, extracted with dichloromethane, dried with Na2SO4, and concentrated in vacuo. Purification by medium pressure liquid chromatography (SiO2, 95:5:0.2 dichloromethane/methanol/conc. NH4OH) gave 22 mg (70%) of the title compound. MS 861 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(O)(=O)C.[Br:17]N1C(=O)CCC1=O>>[Br:17][C:4]1[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[F:12]
Reactant: CC(=O)c1cc(Cl)c(F)cc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c(F)c(Br)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To a stirred solution of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (7.9 g, 42 mmol) in acetic acid (80 mL, 1.0 mol) was added N-bromosuccinimide (9.0 g, 50 mmol) and the resulting mixture was stirred at rt for 18 h. The reaction mixture was concentrated in vacuo, neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified on silica gel, eluting with 0 to 20% ethyl acetate in hexane, to yield the desired product (93% yield). 1H NMR (300 MHz, CDCl3): δ 13.15 (s, 1H), 7.79 (m, 1H), 2.62 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([F:30])[CH:21]=3)[N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH3:14].[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>C(Cl)Cl.N1C=CC=CC=1>[C:31]([NH:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([F:30])[CH:21]=3)[N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH3:14])(=[O:34])[CH2:32][CH3:33]
Reactant: CCC(=O)Cl
Reactant: COC(=O)c1ccc(-c2noc(-c3ccc(N4CCCCC4C)c(N)c3)n2)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)Nc1cc(-c2nc(-c3ccc(C(=O)OC)c(F)c3)no2)ccc1N1CCCCC1C
Temperature: 40 °C

Procedure:
Methyl 4-{5-[3-amino-4-(2-methylpiperidin-1-yl)phenyl]-1,2,4-oxadiazol-3-yl}-2-fluorobenzoate, prepared as in example 67, Steps 1 and 2, (100 mg; 0.24 mmol) was suspended in a DCM/Pyridine mixture (4 mL, 1:1). Propionyl chloride (25 μL, 0.29 mmol) was added and the mixture was heated to 40° C. for 18 h. After this time, solvents were removed under vacuum and title compound was obtained as an off-white powder after trituration with MeOH (96 mg; 83%). LC/MS (Method B): 467.4 (M+H)+. HPLC (Method A) Rt. 5.69 min (purity: 93.6%).
Reaction SMILES: [C:1]1([C@@H:7]([N:9]2[C:13](=[O:14])[CH2:12][C@H:11]([C:15]([O:17]C)=O)[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:19]>CO>[C:1]1([C@@H:7]([N:9]2[C:13](=[O:14])[CH2:12][C@H:11]([C:15]([NH2:19])=[O:17])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: COC(=O)[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Solvent: CO
Product: C[C@@H](c1ccccc1)N1C[C@@H](C(N)=O)CC1=O
Reaction time: 8 h

Procedure:
Methyl (3S)-1-((S)-1-phenylethyl)-5-oxo-3-pyrrolidinecarboxylate (738 g) was dissolved in methanol (3.5 l). The solution was stirred for 8 hr under ice-cooling while blowing in ammonia gas, and concentrated under reduced pressure to give 537 g of (3S)-1-((S)-1-phenylethyl)-5-oxo-3-pyrrolidinecarboxamide.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=1[O:26][CH3:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN1CCCC1=O>CO>[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:21][C:20]=1[O:26][CH3:27])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc(N)ccc1OCc1ccccc1
Reactant: Clc1ncnc2cc[nH]c12
Solvent: CO
Solvent: CN1CCCC1=O
Product: COc1cc(Nc2ncnc3cc[nH]c23)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 59.7 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg), 4-(benzyloxy)-3-methoxyaniline (298 mg) and 1-methyl-2-pyrrolidone (5 mL) was stirred at 80° C. for 4 hrs. Methanol and activated carbon were added to the reaction mixture and the mixture was stirred. The activated carbon was filtered off, aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=10:80→20:80) and recrystallized from methanol-ethyl acetate to give the title compound (269 mg) as a pale-gray powder.