Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.COP([CH2:17][C:18]([CH:20]1[CH2:22][CH2:21]1)=O)(=O)OC.O.[NH2:24][NH2:25]>>[CH:20]1([C:18]2[N:25]=[N:24][C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]=3[CH:17]=2)[CH2:22][CH2:21]1
Reactant: COP(=O)(CC(=O)C1CC1)OC
Reactant: NN
Reactant: O=C1CCCCCCC1=O
Solvent: O
Product: c1c(C2CC2)nnc2c1CCCCCC2

Procedure:
yellow oil. MS (ESI): 292.9 (MH+). Prepared from cyclooctane-1,2-dione, (2-cyclopropyl-2-oxo-ethyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH3:12])=[CH:6][C:5]=1[O:13][CH2:14][CH3:15])[CH3:2].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH:18]=[CH:17]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)(Cl)(Cl)Cl>[CH2:11]([O:10][C:7]1[CH:6]=[C:5]([O:13][CH2:14][CH3:15])[C:4]([O:3][CH2:1][CH3:2])=[CH:9][C:8]=1[C:16](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[O:22])[CH3:12]
Reactant: CCOc1ccc(OCC)c(OCC)c1
Reactant: O=C1C=CC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1cc(OCC)c(C(=O)/C=C/C(=O)O)cc1OCC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a mixture of 2.1 parts by weight of 1,2,4-triethoxybenzene, 1.2 part by weight of maleic anhydride and 30 parts by volume of carbon tetrachloride is added 5.2 parts by weight of anhydrous aluminum chloride. The mixture is stirred for 1 hour and heated at 50°C for another 1 hour. After cooling, concentrated hydrochloric acid and ice are added to the mixture. The mixture is extracted with methylenechloride and the methylenechloride layer is washed with water and dried over anhydrous sodium sulfate. Upon removing the solvent by distillation, 3-(2',4',5'-triethoxybenzoyl)-trans-acrylic acid is obtained as crystals. Recrystallization from a mixture of ethanol and benzene gives yellow needles melting at 192°-194°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][OH:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[O:11][N:10]=1.[H-].[Na+].F[C:22]1[CH:23]=[CH:24][C:25]([N+:29]([O-:31])=[O:30])=[C:26]([CH3:28])[CH:27]=1>CN(C)C=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:22]2[CH:23]=[CH:24][C:25]([N+:29]([O-:31])=[O:30])=[C:26]([CH3:28])[CH:27]=2)=[C:12]([CH:16]([CH3:18])[CH3:17])[O:11][N:10]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of [3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methanol (500 mg, 1.79 mmol) in dimethylformamide (6 mL) at 0° C. was treated with sodium hydride (60% dispersion in oil, 72 mg, 1.8 mmol) and was maintained for 15 minutes before the addition of 5-fluoro-2-nitrotoluene (182 μL, 1.5 mmol). The reaction was then allowed to stir at ambient temperature for 16 h. The product was extracted by partitioning the mixture in diethyl ether (50 mL) and water (50 mL). The aqueoues phase was extracted with diethyl ether (3×50 mL) then the organics were combined and washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and and concentrated to yield a crude oil. The product was purified by column chromatography on silica gel eluting with 20% ethyl acetate/hexanes. Yield=379 mg (60%) of 3-(2,6-dichlorophenyl)-5-isopropyl-4-[(3-methyl 4nitrophenoxy)methyl]-isoxazole.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]([OH:14])([CH3:13])[CH3:12])[NH:8]2)=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:28]([CH3:33])[C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]([OH:14])([CH3:13])[CH3:12])[N:8]2[CH:28]([CH3:33])[C:29]([O:31][CH3:32])=[O:30])=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[N:3]=1
Reactant: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)n1c(C(C)(C)O)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 50 °C
Yield: 27.8 %

Procedure:
2-(2-chloro-6-morpholino-9H-purin-8-yl)propan-2-ol (4.6 g, 15 mmol) was dissolved in DMF (16 mL), treated with cesium carbonate (10 g, 31 mmol) and methyl 2-bromopropanoate (7.6 g, 46 mmol), and heated at 50° C. for 3 hr. Partial conversion prompted addition of cesium carbonate (10 g, 31 mmol) and methyl 2-bromopropanoate (7.6 g, 46 mmol) and the reaction mixture was heated at 50° C. for 20 hr. The reaction mixture was cooled to ambient temperature and diluted with water and ethyl acetate and the layers separated. The aqueous phase was extracted into ethyl acetate (3×), dried over sodium sulfate, filtered, and absorbed onto celite for purification by flash chromatography to afford methyl 2-(2-chloro-8-(2-hydroxypropan-2-yl)-6-morpholino-9H-purin-9-yl)propanoate as a yellow foam (1.6 g, 26%). LC/MS (ESI+): m/z 384 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([CH2:51][N:52]=[S:53]([CH3:60])(=[O:59])[N:54]2[CH2:58][CH2:57][CH2:56][CH2:55]2)=[CH:47][CH:46]=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([C:45]2[CH:50]=[CH:49][C:48]([CH2:51][N:52]=[S:53]([CH3:60])(=[O:59])[N:54]3[CH2:58][CH2:57][CH2:56][CH2:55]3)=[CH:47][CH:46]=2)=[CH:12][CH:13]=1
Reactant: CS(=O)(=NCc1ccc(Br)cc1)N1CCCC1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(-c4ccc(CN=S(C)(=O)N5CCCC5)cc4)cc3)nc21

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and [(4-bromophenyl)-methyl][methyl(oxo)pyrrolidin-1-yl-λ6-sulfanylidene]amine following a procedure analogous to that described for Intermediate 3 (Step 3) using 1,4-dioxane as a solvent. LC (method 1): tR=1.05 min; Mass spectrum (ESI+): m/z=740 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1.Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])[CH2:10][C@@H:9]1[CH3:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccccc1F
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: C[C@H]1CN(c2ccccc2C(=O)O)CCN1C(=O)OC(C)(C)C
Temperature: 150 °C
Reaction time: 48 h
Yield: 55.2 %

Procedure:
To a solution of (S)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (4.10 g, 19.8 mmol) in pyridine (41 mL) is added 2-fluoro-benzoic acid (20.2 g. 140 mmol) followed by DBU (43 ml). The mixture is stirred at 150° C. for 48 h. The mixture is diluted with 600 mL of 2N HCl followed by extraction with EtOAc (3×300 mL). Organics are collected and purified by flash chromoatography to provide 3.50 g, 53% yield of (S)-4-(2-carboxy-phenyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnn(CCOc2ccccc2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 4-nitro-1H-pyrazole (220 mg, 1.95 mmol) in acetonitrile (10 mL), Cs2CO3 (697 mg, 2.14 mmol) and (2-bromoethoxy)benzene (439 mg, 2.14 mmol) was added. The resulting mixture was refluxed (80° C.) for 40 min and then let stir at rt overnight. The reaction mixture was filtered, the filter cake washed with DCM and the filtrate concentrated in vacuo to obtain 4-nitro-1-(2-phenoxyethyl)-1H-pyrazole as a crude solid which was used without further purification. LC-MS conditions A: tR=0.85 min, [M+H]+=no ionization.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:25]([C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1)#[N:26]>CN(C=O)C.O>[C:25]([C:27]1[CH:28]=[C:29]([NH:33][C:34]([N:4]([CH2:3][CH2:2][OH:1])[CH:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:9][CH2:10]2)=[O:35])[CH:30]=[CH:31][CH:32]=1)#[N:26]
Reactant: OCCNC1CCN(Cc2ccccc2)CC1
Reactant: N#Cc1cccc(N=C=O)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1cccc(NC(=O)N(CCO)C2CCN(Cc3ccccc3)CC2)c1
Temperature: 60 °C
Yield: 68.2 %

Procedure:
To a stirred solution of 4-(2-hydroxyethyl)amino-1-benzylpiperidine (1.82 g), and triethylamine (0.789 g, 7.8 mmol) in DMF (50 mL) was added 3-cyanophenylisocyanate (1.12 g, 7.8 mmol). This mixture was heated at 60° C. for 18 under a N2 atmosphere. The reaction was diluted with water and extracted with ethyl acetate, dried with MgSO4, filtered and concentrated to give the desired product, N-(3-cyanophenyl)-N'-(2-hydroxyethyl)-N'-(1-benzylpiperidin-4-yl)urea (2.04 g, 5.3 mmol). LRMS (M+H)+ m/z 379.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:2]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:2]1
Reactant: OCCCc1c[nH]c2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1c[nH]c2ccccc12
Temperature: -40 °C

Procedure:
Compound 29 (1.8 g, 5.44 mmol) was transferred to a flame-dried flask filled with argon and dissolved in anhydrous THF then cooled to −40° C. Triethylamine (0.72 g, 7.07 mmol) was added by syringe followed by MeSO2Cl (0.75 g, 6.53 mmol). The temperature of the reaction mixture was allowed to rise to room temperature (10-15 minutes) before it was quickly filtrated and concentrated. The crude oil was dissolved in CH2Cl2 and washed with H2O. The organic phase was dried with MgSO4, filtrated and concentrated in vacuo to a dark, brown oil. The crude product was used immediately in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[F-].[K+].[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH3:24])=[C:16]1[C:25]([NH:27][C@H:28]([C:32]([NH:34][CH:35]([C:44](=[O:47])[CH2:45]Br)[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:26]>>[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH3:24])=[C:16]1[C:25]([NH:27][C@H:28]([C:32]([NH:34][CH:35]([C:44](=[O:47])[CH2:45][O:5][C:4](=[O:6])[C:3]1[C:2]([Cl:1])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:11])[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:26]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CBr)C(C)C)n(C)c2ccccc12
Agent: [F-]
Agent: [K+]
Product: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COC(=O)c2c(Cl)cccc2Cl)C(C)C)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.9 %

Procedure:
To a mixture of 2,6-dichlorobenzoic acid (0.0223 g, 0.12 mmol) and potassium fluoride (0.015 g, 0.25 mmol) at room temperature under nitrogen was added N-[(1,3-dimethyl-indole-2-carbonyl)valinyl]-3-amino-5-bromo-4-oxo-pentanoic acid, tert-butyl ester (0.054 g, 0.10 mmol) in one portion. After stirring at room temperature for further 16 hrs, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated NaHCO3 solution, and brine, dried over sodium sulfate, and concentrated. Trituration with ether gave the title compound as a white powder (0.051 g, 79%). TLC(CH2Cl2/MeOH, 95/5): Rf=0.88.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:13]([CH3:33])[C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[N:17]=[C:16]([CH3:26])[C:15]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9].O.CO.[Li+].[OH-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:13]([CH3:33])[C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[N:17]=[C:16]([CH3:26])[C:15]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:7]([CH:12]=1)[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1cc(OC)ccc1N(C)c1c(-c2ccccc2)c(C)nn1-c1ccccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(N(C)c2c(-c3ccccc3)c(C)nn2-c2ccccc2C)c(C(=O)O)c1
Reaction time: 24 h
Yield: 58 %

Procedure:
To a solution of the compound of step 1 (60 mg, 0.129 mmol) in a mixture of THF (4 mL), water (4 mL), and MeOH (2 mL), was added LiOH (32 mg, 1.32 mmol). The reaction mixture was vigorously stirred for 24 h, after which it was concentrated under reduced pressure, and diluted with water (10 mL). The solution was then acidified to pH ˜1 using 1 N HCl, and then extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was then purified by preparative HPLC to afford the title compound (32 mg, 58%) as a white solid. 1H NMR (400 MHz, acetone-d6) δ 2.12 (s, 3H), 2.23 (s, 3H), 2.9 (s, 3H), 3.74 (s, 3H), 6.87-6.90 (m, 2H), 6.92-6.98 (m, 1H), 7.03-7.11 (m, 1H), 7.16-7.27 (m, 4H), 7.30-7.36 (m, 2H), 7.40-7.45 (m, 2H); ES-MS m/z 428.3 (MH+); HPLC RT (min) 3.54.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[N:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12](=[O:16])[NH:13]2)=[CH:8][C:7]=1[O:17][CH3:18].[CH3:19]C(C)([O-])C.[K+].CI>CN(C=O)C.O>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[N:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12](=[O:16])[N:13]2[CH3:19])=[CH:8][C:7]=1[O:17][CH3:18]
Reactant: CC(C)(C)[O-]
Reactant: COc1cc2c(nc1C1OCCO1)NC(=O)CC2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cc2c(nc1C1OCCO1)N(C)C(=O)CC2
Reaction time: 0.5 h

Procedure:
To a solution of 0.1 g (0.4 mmol) 7-[1,3]dioxolan-2-yl-6-methoxy-3,4-dihydro-1H-[1,8]naphthyridin-2-one in 1 ml of DMF cooled to 5° C. was added 0.5 ml (0.5 mmol) of potassium t-butoxide (1M solution in THF). The reaction mixture was stirred fo 30 minutes. To this mixture was added 0.06 ml (1 mmol) of methyl iodide and the reaction stirred at ambient temperature for 2 hours. The reaction mixture was diluted with 5 ml of water and extracted with ethyl acetate. The ethyl acetate extract was dried (Na2SO4) and evaporated to yield intermediate 7-[1,3]dioxolan-2-yl-6-methoxy-1-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one as a dark oil. Mass spectrum: m/e=205.1 (p+1). This material was dissolved in 5 ml of acetone containing 0.1 g of para-toluenesulfonic acid and refluxed for 2 hours. The reaction mixture was evaporated and the residue triturated with saturated NaHCO3. This mixture was extracted with ethyl acetate. The ethyl acetate extract was dried (Na2SO4) and evaporated and the residue chromatographed on silica using 3:1 chloroform/ethyl acetate as the elutant. Appropriate fractions were combined to yield 12 mg of 3-methoxy-8-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridine-2-carbaldehyde as an oil. Mass spectrum: m/e=221.1 (p+1). 1H NMR (CDCl3) δ 10.1 (s, 1H), 7.25 (s, 1H), 3.95 (s, 3H), 3.50 (s, 3H), 3.0 (m, 2H), 2.90 (m, 2H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16].CCN(C(C)C)C(C)C.[F:39][C:40]([F:45])([F:44])[CH2:41][CH:42]=O>ClCCCl>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][N:27]([CH2:42][CH2:41][C:40]([F:45])([F:44])[F:39])[CH2:26][CH:25]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(C2=CCNCC2)cc1
Reactant: O=CCC(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(C2=CCN(CCC(F)(F)F)CC2)cc1
Temperature: 50 °C
Yield: 45.3 %

Procedure:
Sodium triacetoxyborohydride (6.2 g, 29.4 mmol, 2 eq.) was added to a solution of 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine (3.0 g; 14.7 mmol; 1.0 eq.), DIEA (2.5 mL; 14.7 mmol; 1.0 eq.) and 3,3,3-Trifluoropropanal (2.4 mL; 29.4 mmol; 2.0 eq.) in DCE (60 mL). The reaction mixture was heated at 50° C. for 2 h and quenched by addition of a saturated solution of NH4Cl (50 mL). The phases were separated and organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated to give a brown crude. Purification by flash chromatography on silica (EtOAc:heptane) afforded the title compound as a yellow solid (2.0 g, 45%). UPLC/MS: (MS+) 301.4.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[C:21]#[C:22][CH3:23].O>N1C=CC=CC=1>[CH2:18]([O:17][C:15]([CH:11]1[CH2:10][N:9]([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:8])[CH2:14][CH2:13][N:12]1[S:31]([C:28]1[CH:27]=[CH:26][C:25]([O:24][CH2:20][C:21]#[C:22][CH3:23])=[CH:30][CH:29]=1)(=[O:33])=[O:32])=[O:16])[CH3:19]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C1CN(C(=O)N2CCOCC2)CCN1
Solvent: O
Solvent: c1ccncc1
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)N3CCOCC3)CC2C(=O)OCC)cc1
Reaction time: 8 h
Yield: 80.7 %

Procedure:
The ethyl 4-(4-morpholinylcarbonyl)-2-piperazinecarboxylate (0.41 g, 1.55 mmol) was dissolved in pyridine (1.44 mL). To this solution was added a solution of 4-but-2-ynyloxy-benzenesulfonyl chloride (0.38 g, 1.55 mmol) in pyridine (1 mL). The reaction was stirred overnight and then poured into water. The mixture was extracted three times with chloroform. The organics were combined, washed with 10% HCl, twice with water, then brine and dried over Na2SO4. The solution was filtered and concentrated in vacuo to provide 0.6 g (81%) of 1-(4-but-2-ynyloxy-benzenesulfonyl)-4-(morpholine-4-carbonyl)-piperazine-2-carboxylic acid ethyl ester as a gold oil. Electrospray Mass Spec 480.2 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>CCOCC.C1COCC1>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]([OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:13][CH:12]=1
Reactant: CCCCCCCCBr
Reactant: O=Cc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCC(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
In a 100 ml round bottom flask with a Y-adapter, condensor, and a 10 ml addition funnel was added 0.38 g (15.63 mmol) of Mg turnings which had been ground with a mortar and pestle. The apparatus was then flushed with argon and flamed dried. After allowing the apparatus to cool under argon, 4 ml of anhydrous diethyl ether was added to the Mg. While vigorously stirring the Mg in the ether, 2.52 g (13.05 mmol) of 1-bromooctane in 3 ml of diethyl ether was added dropwise. After 5 drops, the Grignard reaction started and the addition was continued at a rate sufficient to maintain a steady reflux. After addition was complete, 4 ml of dry THF was added to the Grignard reagent and it was stirred at R.T. for an additional 1/2 hour. A warm water bath was then placed under the flask, and refluxing was continued for 15 minutes. Afterwards, the reaction was cooled to 0° C. with an ice bath and 2.00 g (16.81 mmol) of p-bromobenzaldehyde in 4 ml of THF was added. The reaction was stirred at R.T. for 1.5 hr., whereupon the Grignard was quenched with saturated NH4Cl. The organic layer was washed with H2O and brine, then dried (MgSO4). Rotary evaporation of the solvent under reduced pressure produced 2.96 g of a crude yellow oil. The oil was dissolved in a diethyl ether and loaded onto a silica gel column. Elution with diethyl ether/hexane yielded 2.22 g of the titled product as a yellow oil.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21])=[O:13].[C:22](=O)([O:26]CC)[O:23][CH2:24][CH3:25].Cl>C1COCC1>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([OH:21])=[C:14]([C:12](=[O:13])[CH2:11][C:22]([O:23][CH2:24][CH3:25])=[O:26])[CH:19]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: CCOC(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(Cl)ccc1O
Temperature: -10 °C
Reaction time: 1 h
Yield: 407.9 %

Procedure:
A solution of lithium hexamethyldisilazide (800 mL of 1.0 M solution in THF, 800.0 mmol) was chilled to -78° C. under a nitrogen atmosphere. A solution of 5-chloro-2-hydroxyacetophenone (45.493 g, 266.67 mmol) in THF (130 mL) was added dropwise to the stirred solution over 0.5 hour. The reaction was held at -78° C. for 1 hour, warmed to -10° C. for 2 hours, warmed to 0° C. for 1 hour, then cooled to -78° C. Diethyl carbonate (35.54 mL, 34.65 g, 29.34 mmol) was added via syringe in one portion. The temperature was maintained at -78° C. for 0.5 hour, warmed to room temperature over 0.5 hour, and stirred for 3 hours. The crude reaction mixture was carefully poured over a mixture of rapidly stirred ice (1200 mL)/conc HCl (222 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo yielding an oil that began to crystallize. Hexanes (150 mL) was added and crystallization proceeded. The crystalline product was collected by vacuum filtration to afford the title compound (29.04 g, 45%) as tan crystalline needles: mp 71.8-73.1° C. 1H NMR (CDCl3 /300 MHz) 7.63 (d, 1H, J=2.4 Hz), 7.45 (dd, 1H, J=8.9, 2.6), 6.98 (d, 1H, J=8.9 Hz), 4.25 (q, 2 H, J=7.3 Hz), 3.98 (s, 2H), 1.29 (t, 3H, 7.3 Hz). FABLRMS m/z 249 (M+Li). EIHRMS m/z 242.0346 (M+, Calc'd 242.0346). Anal. Calc'd for C11H11ClO4 : C, 54.45; H, 4.57. Found: C, 54.48; H, 4.62.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=2[CH3:35])=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:31]([CH3:32])=[C:30]([CH:33]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[NH:12][C:11]3=[O:16])[NH:29][C:28]=2[CH3:35])=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(-c4ccccc4)cc32)c(C)c1C(=O)NCCN1CCCC1

Procedure:
5-Phenyl-1,3-dihydroindol-2-one (0.04 g, 0.2 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (0.04 g) to give the title compound as a yellow-orange solid.
Reaction SMILES: [NH2:1]/[C:2](/[C:7]#[N:8])=[C:3](\[NH2:6])/[C:4]#[N:5].[C:9](OCC)(OCC)(OCC)[CH2:10][CH3:11]>>[CH2:10]([C:11]1[NH:1][C:2]([C:7]#[N:8])=[C:3]([C:4]#[N:5])[N:6]=1)[CH3:9]
Reactant: N#C/C(N)=C(/N)C#N
Reactant: CCOC(CC)(OCC)OCC
Product: CCc1nc(C#N)c(C#N)[nH]1
Yield: 82.6 %

Procedure:
Following a procedure similar to that described in Preparation 1, but using 53.3 g of diaminomaleonitrile and 91.3 g of triethyl orthopropionate. 59.5 g of the title compound were obtained as crystals, melting at 179°-181° C.