Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1C(=O)[C:5](=O)[CH:4]([C:9](F)(F)F)N1.[CH:13]([N:16]1[C:20](=[O:21])[C:19](=[O:22])[CH:18]([C:23]([F:26])([F:25])[F:24])[NH:17]1)([CH3:15])[CH3:14].C(N1C(=O)C(=O)C(C(F)(F)F)N1)C.FC(F)(F)C1C(=O)C(=O)NN1>>[C:13]1([N:16]2[C:20](=[O:21])[C:19](=[O:22])[CH:18]([C:23]([F:26])([F:25])[F:24])[NH:17]2)[CH:15]=[CH:9][CH:4]=[CH:5][CH:14]=1
Reactant: CN1NC(C(F)(F)F)C(=O)C1=O
Reactant: CC(C)N1NC(C(F)(F)F)C(=O)C1=O
Agent: CCN1NC(C(F)(F)F)C(=O)C1=O
Agent: O=C1NNC(C(F)(F)F)C1=O
Product: O=C1C(=O)N(c2ccccc2)NC1C(F)(F)F

Procedure:
1-methyl-3-trifluoromethyl-4,5-pyrazolinedione; 1-isopropyl-3-trifluoromethyl4,5-pyrazolinedione; 1-ethyl-3-trifluoromethyl-4,5-pyrazolinedione; 3-trifluoromethyl-4,5-pyrazolinedione;
Reaction SMILES: C(OC(OCC)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)C.C([Li])CCC.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH3:28])[C:20]=1[CH:21]=[O:22]>O1CCCC1.CCCCCC>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH3:28])[C:20]=1[CH:21]([C:6]1[NH:5][CH:9]=[CH:8][N:7]=1)[OH:22]
Reactant: CCOC(OCC)n1ccnc1
Reactant: CCc1cccc(Cl)c1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1cccc(Cl)c1C(O)c1ncc[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a solution of 1.60 ml (9.79 mmol) 1-(diethoxymethyl)imidazole in 6 ml tetrahydrofuran at −78° C. was added dropwise 6.67 ml (10.7 mmol) of a 1.6 M solution of n-butyllithium in hexane. The resulting solution of 2-(1-diethoxymethyl-1H-imidazol-2-yl)-lithium was stirred at −78° C., and then added dropwise to a solution of 1.50 g (8.90 mmol) 2-chloro-6-ethyl-benzaldehyde in 6 ml tetrahydrofuran at 0° C. The reaction mixture was then stirred at 0° C. for 30 min and at room temperature for 1 h, before being quenched by dropwise addition of 1 M aqueous hydrochloric acid. The mixture was made basic by addition of aqueous sodium bicarbonbate solution and diluted with ethyl acetate. The phases were separated and the organic phase was washed with saturated brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 2.02 g (96%) of the title compound as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[I:12][C:13]1[CH:14]=[N:15][NH:16][CH:17]=1.O>ClCCl>[C:1]([N:15]1[CH:14]=[C:13]([I:12])[CH:17]=[N:16]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Ic1cn[nH]c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)n1cc(I)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Acetyl chloride (38.2 mL, 1.07 equiv) and triethylamine (86 mL, 1.2 equiv) were added at 0° C. to a solution of 4-iodo-1H-pyrazole (100 g, 0.515 mol) in dichloromethane (1 L). The mixture was stirred overnight at room temperature. The reaction mixture was poured into water. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate (Na2SO4), and filtered. The residue obtained by concentration was purified by silica gel column chromatography (Hexane/EtOAc 20:1 to 1:1) to give N-acetyl 4-iodo-1H-pyrazole as a solid (110 g, 91%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[O:15][N:14]=[C:13]([NH2:17])[C:12]=3[CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]2[N:18]([CH3:21])[N:19]=[CH:20][C:3]=12.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:21][N:18]1[C:4]2=[N:5][C:6]([C:8]3[C:16]4[O:15][N:14]=[C:13]([NH2:17])[C:12]=4[CH:11]=[CH:10][CH:9]=3)=[CH:7][C:2]([O:32][C:29]3[CH:28]=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:31][CH:30]=3)=[C:3]2[CH:20]=[N:19]1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4c(N)noc34)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ncc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(-c3cccc4c(N)noc34)nc21
Temperature: 155 °C
Yield: 21.7 %

Procedure:
A mixture of 7-(4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)benzo[d]isoxazol-3-amine 17 (0.032 g, 0.106 mmol), 4-methylsulfonyl phenol 8a (0.036 g, 0.213 mmol) and potassium carbonate (0.15 g, 1.06 mmol) in 2 mL DMF was heated in a microwave at 155° C. for 30 minutes. The reaction mixture was filtered, solvent removed and diluted with ethyl acetate. The organic portions were pooled and washed with saturated bicarbonate solution and brine, dried over anhydrous sodium sulfate and solvent was removed. The crude material was purified using mass directed purification to give 10 mg of 121. 1H NMR (400 MHz, DMSO) δ=8.02-7.58 (m, 8H), 7.58 (dd, J=26.9, 35.7, 2H), 6.53 (s, 1H), 4.15-4.01 (m, 3H), 3.3-3.06 (m, 3H). MS (ESI) m/z 436.0 (M+1)+
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=[O:17])=[C:8]2[N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:25]([OH:27])[CH3:26]>>[OH:27][CH2:25][CH2:26][N:21]1[CH2:22][CH2:23][N:18]([C:8]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:15]3[C:10]([C:9]=2[CH:16]=[O:17])=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:19][CH2:20]1
Reactant: O=Cc1c(N2CCNCC2)n(-c2ccccc2)c2ccccc12
Reactant: CC(O)Br
Product: O=Cc1c(N2CCN(CCO)CC2)n(-c2ccccc2)c2ccccc12
Yield: 87 %

Procedure:
1-Phenyl-2-piperazin-1-yl-1H-indole-3-carboxaldehyde is reacted with bromoethanol as described in Example 30 to afford 2-[4-(2-hydroxyethyl)piperazin-1-yl]-1-phenyl-1H-indole-3-carboxaldehyde (87% yield) as a yellow solid. TLC (ethyl acetate-10% methanol) Rf=0.13; ESI/MS 350 (M+H); RT=2.67 min; NMR 10.16 (1H, s); 8.13 (1H, d, J=6 Hz); 7.68 (5H, m); 7.20 (2H, m); 6.91 (1H, d, J=6 Hz); 4.39 (1H, t); 3.47 (2H, q); 3.2 (4H, m); 2.34 (6H, m).
Reaction SMILES: I[CH2:2][CH3:3].[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:26]([O:28][CH3:29])=[O:27])=[C:10]([CH3:25])[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:12]2)=[CH:7][C:6]=1[S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[CH2:2]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:26]([O:28][CH3:29])=[O:27])=[C:10]([CH3:25])[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=3)=[N:12]2)=[CH:7][C:6]=1[S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH3:3]
Reactant: CCI
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(S(=O)(=O)C(C)C)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)OC)c2cc1S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
Iodoethane (3.35 mL, 41.4 mmol) was added slowly to a mixture of methyl 7-hydroxy-3-methyl-6-[(1-methylethyl)sulfonyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (12.90 g, 27.6 mmol) and cesium carbonate (27.0 g, 83 mmol) in dimethyl sulfoxide (150 mL) at room temperature. The mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with methylene chloride. The phases were separated, and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified via column chromatography (ISCO, 330 g silica, 0-20% ethyl acetate/methylene chloride) to afford a solid residue that was triturated from methanol to give methyl 7-(ethyloxy)-3-methyl-6-[(1-methylethyl)sulfonyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (11.39 g, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ8.24 (s, 1H), 7.98-8.04 (m, 2H), 7.91 (d, J=7.78 Hz, 1H), 7.76-7.82 (m, 2H), 4.39 (q, J=7.03 Hz, 2H), 4.09 (s, 3H), 3.85 (quin, J=6.84 Hz, 1H), 2.36 (s, 3H), 1.44 (t, J=7.03 Hz, 3H), 1.23 (s, 3H), 1.21 (s, 3H); MS (m/z) 496.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[C:18]([N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][C:22](=[O:30])[CH2:21]1)=[O:19].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]([CH3:12])[CH2:14][C:15]2[CH:33]=[CH:32][CH:31]=[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][C:22](=[O:30])[CH2:21]3)=[O:19])[CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CNCc1cccc(C(=O)N2CC(=O)Nc3ccccc32)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1cccc(C(=O)N2CC(=O)Nc3ccccc32)c1)S(=O)(=O)c1ccc(Br)cc1
Reaction time: 18 h
Yield: 66.1 %

Procedure:
4-Bromobenzenesulphonyl chloride (29 mg, 0.11 mmol) was added to a solution of 1-(3-(methylaminomethyl)benzoyl-1,2,3,4-tetrahydroquinoxalin-3-one (30 mg, 0.10 mmol) in dichloromethane (10 ml). The pH was adjusted to pH9 with triethylamine and the mixture stirred for 18 h. The mixture was reduced in vacuo, taken up in ethyl acetate, washed with water and brine, dried and reduced. Chromatography (50% EtOAc/50% 60-80 pet ether) afforded 4-bromo-N-methyl-N-(3-(1,2,3,4-tetrahydroquinoxalin-3-one-1-carbonyl)benzyl)-benzenesulphonamide (34 mg, 60%) as a white solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:44]=[CH:43][C:12]([CH2:13][N:14]([CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)[C:15](=[O:32])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]4[C@H:30]([CH3:31])[CH2:29][CH2:28][C:24]=4[N:25]=[CH:26][N:27]=3)=[CH:18][CH:17]=2)=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:35][CH2:34][CH2:33][N:14]([CH2:13][C:12]1[CH:11]=[CH:10][C:9]([Cl:8])=[CH:44][CH:43]=1)[C:15](=[O:32])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]3[C@H:30]([CH3:31])[CH2:29][CH2:28][C:24]=3[N:25]=[CH:26][N:27]=2)=[CH:18][CH:17]=1
Reactant: C[C@@H]1CCc2ncnc(-c3ccc(C(=O)N(CCNC(=O)OC(C)(C)C)Cc4ccc(Cl)cc4)cc3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(-c3ccc(C(=O)N(CCN)Cc4ccc(Cl)cc4)cc3)c21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22.7 %

Procedure:
TFA (182 μL, 2.36 mmol) was added to a solution of (R)-tert-butyl 2-(N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamido)ethylcarbamate (49 mg, 0.094 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated in vacuo. The crude product was purified by reverse phase HPLC to give (R)-N-(2-aminoethyl)-N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide as an oil (9 mg, 22%). MS (APCI+) [M+H]+ 421.2. 1H NMR (D2O, 500 MHz) δ 9.09 (s, 1H), 7.81 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.15 (D, J=8.0 Hz, 2H), 4.63 (s, 2H), 3.87 (t, J=6.5 Hz, 2H), 3.82-3.79 (m, 1H), 3.26-3.11 (m, 4H), 2.63 (s, 2H), 2.50-2.42 (m, 1H), 1.86-1.81 (m, 1H), 0.86 (s, J=7.00 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[Br-:13].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]2[CH:12]=[CH:11][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCCBr
Reactant: Clc1ccc(-n2ccnc2)cc1
Product: CCCCCCCn1cc[n+](-c2ccc(Cl)cc2)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 5.6 mmol (1.00 g) 1-(4-chlorophenyl)imidazole and 6.7 mmol (1.20 g, 1.1 ml) 1-bromoheptane are dissolved in 5 ml TIE and heated for 12 h to 80° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:35])=[C:21]([NH:25][S:26]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH3:36].CC(O)C>>[NH2:36][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:35])=[C:21]([NH:25][S:26]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH2:15]([O:16][CH2:17][CH3:18])[CH3:14]
Reactant: N
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cccnc1
Solvent: CC(C)O
Product: CCOCC
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cccnc3)c2F)n1
Temperature: 100 °C
Yield: 45 %

Procedure:
A suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-pyridinesulfonamide (195 mg, 0.366 mmol) and ammonia in i-PrOH 2M (8 mL, 16.0 mmol) was heated in a sealed tube at 100° C. overnight. The reaction mixture was evaporated onto silica gel and chromatographed (10-100% 1:9 MeOH:EtOAc in DCM). The title compound was obtained as a yellow solid after trituration in diethyl ether (88 mg, 45% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.56 (s, 1H), 8.84 (d, J=1.7 Hz, 1H), 8.75 (dd, J=4.7, 1.0 Hz, 1H), 7.99-8.15 (m, 1H), 7.82 (d, J=5.3 Hz, 1H), 7.55 (dd, J=7.9, 5.0 Hz, 1H), 7.33-7.46 (m, 1H), 7.24 (d, J=6.3 Hz, 2H), 6.55 (br. s., 2H), 5.56 (d, J=5.2 Hz, 1H), 3.59-3.72 (m, 4H), 3.34-3.49 (m, 4H). MS (ESI): 514.1 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13]([Cl:17])[N:12]=1.Cl>FC(F)(F)CO.C(O)C.C(O)(C)C>[ClH:10].[Cl:17][C:13]1[N:12]=[C:11]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:5][CH2:6]2)[CH:16]=[N:15][CH:14]=1
Reactant: C1CN(C2CC2)CCN1
Reactant: Clc1cncc(Cl)n1
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Solvent: OCC(F)(F)F
Product: Clc1cncc(N2CCN(C3CC3)CC2)n1
Yield: 36.1 %

Procedure:
Crude N-cyclopropylpiperazine (2.8 g) and 2,6-dichloropyrazine (3.0 g) are combined in 5 ml 2,2,2-trifluoroethanol and the mixture refluxed 4 hours under N2. The mixture is concentrated under vacuum and the residue partitioned between aqueous sodium carbonate and methylene chloride. The combined methylene chloride extracts are extracted with dilute hydrochloric acid which is made basic with sodium hydroxide. The crude base is extracted with methylene chloride and chromatographed on silica gel. Elution with CHCl3 gives fractions containing 2.4 g pure title base which is treated with hydrogen chloride in ethanol-isopropanol to give 2.0 g of the title salt, mp greater than 340° C. with decomposition at 245° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[CH2:9][O:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]>[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[C:1]([CH2:5][C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[CH2:9][O:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])#[N:2]
Reactant: CC(C)(C)OC(=O)NCCOCc1cccc(CBr)c1
Reactant: [C-]#N
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCOCc1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 97.5 %

Procedure:
Sodium cyanide (284 mg, 5.78 mmol) and benzyl triethylammonium bromide (63 mg, 0.23 mmol) were added to a solution of tert-butyl 2-{[3-(bromomethyl)benzyl]oxy}ethylcarbamate (preparation 103) (798 mg, 2.31 mmol) in acetonitrile (5 ml), and the reaction stirred at room temperature for 4 days. The mixture was partitioned between water and ethyl acetate and the layers separated. The organic phase was dried over MgSO4 and evaporated under reduced pressure, to afford the desired product as an oil, (654 mg, 97%).
Reaction SMILES: [C:1]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CCOC(C)=O>[C:4]([O:3][C:1]([NH:8][C:9]([CH3:14])([C:11]([O:13][CH3:15])=[O:12])[CH3:10])=[O:2])([CH3:6])([CH3:7])[CH3:5]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of Boc-α-methylalanine in DMF (0.4 M) was added K2CO3 (1 eq) and MeI (1.2 eq). The mixture was stirred at RT for 6 h and then diluted with EtOAc, washed with water and sat. aq. NaHCO3. The organic phase was dried over Na2SO4, filtered and concentrated under vacuum to provide the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ: 7.20 (1H, br. s), 3.58 (3H, s), 1.40-1.27 (15H, m). MS (ES) C10H19NO4 requires: 217. found: 240 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O.[C:13]([O:18][CH3:19])(=[O:17])[C:14]([CH3:16])=O.S([O-])([O-])(=O)=O.[Mg+2].[H][H]>CO.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][CH:14]([CH3:16])[C:13]([O:18][CH3:19])=[O:17]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: COC(=O)C(C)=O
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Product: COC(=O)C(C)Nc1ccc(F)c(F)c1F
Reaction time: 2 h
Yield: 97.4 %

Procedure:
2,3,4-Trifluoronitrobenzene (100 g) and methyl pyruvate (57.6 g) were dissolved in methanol (1000 ml). After adding 5% Pd-C (20.0 g) and anhydrous magnesium sulfate (90 g), the mixture was stirred at room temperature in a hydrogen atmosphere for 16 hours. Then the liquid reaction mixture was filtered through celite to thereby eliminate Pd-C and magnesium sulfate. The obtained filtrate was concentrated under reduced pressure and Florisil (100 g) and diethyl ether (700 ml) were added to the residue. After stirring for 2 hours, the liquid reaction mixture was filtered. The obtained organic layer was evaporated and the crystals thus precipitated were filtered while washing with hexane. Thus the title compound (128.2 g) was obtained as slightly yellowish crystals.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([C:22]([OH:24])=[O:23])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].CO.[C:31]([O-])(O)=O.[Na+]>OS(O)(=O)=O.CCOC(C)=O>[CH3:31][O:23][C:22]([C:17]12[CH2:20][CH2:21][C:14]([C:7]3[NH:6][C:5]4[C:4](=[O:25])[N:3]([CH2:26][CH2:27][CH3:28])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=4[N:8]=3)([CH2:19][CH2:18]1)[CH2:15][CH2:16]2)=[O:24]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)OC)(CC3)CC4)nc2n(CCC)c1=O
Yield: 97 %

Procedure:
4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylic acid (Example 13) (1.50 g, 3.86 mmol) was combined with 60 ml of MeOH, and 10 drops of conc'd H2SO4. The reaction solution was brought to reflux until consumption of starting material ceased. Sat'd NaHCO3 was then added until neutral pH and the reaction mixture was conc'd in vacuo. The residue was taken up in EtOAc and washed with sat'd NaHCO3, brine, and dried over Na2SO4. The EtOAc solution was conc'd in vacuo to give 1.51 g (97% yield) of a white solid. (MH+=403.13)
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17]>C1COCC1>[Br:12][C:13]1[CH:14]=[C:15]([CH:16]([OH:17])[CH2:2][C:1]#[N:3])[CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CC#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCC(O)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a −78° C. solution of acetonitrile (1.05 mL, 20 mmol) in anhydrous THF (25 mL) under argon, was added lithium diisopropylamide (11 mL of a 2 M solution in THF, 22 mmol) dropwise. The resulting mixture was stirred at −78° C. for 15 min. A solution of 3-bromobenzaldehyde (22) (2.78 g, 15 mmol) in anhydrous THF (10 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature, then concentrated under reduced pressure and diluted with EtOAc (75 mL). The solution was washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (20 to 100% EtOAc-hexanes gradient) gave 3-(3-bromophenyl)-3-hydroxypropanenitrile (23) as a light yellow oil. Yield (2.75 g, 81%): 1H NMR (400 MHz, DMSO-d6) δ 7.60 (t, J=1.6 Hz, 1H), 7.46 (ddd, J=7.6, 2.0, 1.2 Hz, 1H), 7.40 (dd, J=7.6, 2.0 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 6.05 (d, J=4.8 Hz, 1H), 4.87-4.92 (m, 1H), 2.94-2.80 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][CH:11](NCC2C=CC=CC=2)[CH:10]([OH:21])[CH2:9]1)=[O:7])([CH3:4])[CH3:3]>C(O)C.C(OCC)(=O)C.[Pd]>[CH3:4][C:2]([CH3:1])([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:11]([O:21]2)[CH2:12]1)=[O:7])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)C(NCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2OC2C1
Yield: 92.3 %

Procedure:
A solution of [trans-(+/-)]-3-hydroxy-4-[(phenylmethyl)amino]-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester (1.1 g, 3.76 mmol) in ethanol (150 ml) was hydrogenated over 10% palladium-on-carbon (0.05 g) for 3.5h. The catalyst was removed by filtration, washed with ethanol (50 ml) and the combined ethanolic solution was evaporated to leave an oil which was taken up in ethyl acetate (75 ml). The solution was filtered and the filtrate evaporated to leave a solid which was crystallised from ethyl acetate/cyclohexane to give the title compound (0.643 g), nmr(δ,CDCl3) 1.45(s, 9H), 1.6-2.2(bm, 3H), 3.1(m,1H), 3.3(m,2H), 3.68(m,2H), 3.98(m,1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3=[CH:12][CH:13]=[N:14][N:7]3[CH:6]=[CH:5][C:4]=2[C:3]=1[C:15]([O:17][CH3:18])=[O:16].[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1.C(Cl)Cl>[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3=[CH:12][CH:13]=[N:14][N:7]3[CH:6]=[CH:5][C:4]=2[C:3]=1[C:15]([O:17][CH3:18])=[O:16])(=[O:29])=[O:28]
Reactant: COC(=O)c1c(N)ccc2c1ccn1nccc21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1ccn1nccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
A mixture of methyl 8-aminopyrazolo[5,1-a]isoquinoline-7-carboxylate (Intermediate 6, 0.140 g) and 2-bromo-4-fluorobenzenesulfonyl chloride (0.190 g) in pyridine (4 mL) and DCM (3 mL) was stirred at room temperature overnight. The resultant mixture was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-60%. The resultant glass was triturated with ether to give methyl 8-(2-bromo-4-fluorobenzenesulfonylamino]-pyrazolo[5,1-a]isoquinoline-7-carboxylate (0.103 g) as an off-white solid.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].N1([C:16]2[CH2:21][CH2:20][S:19](=[O:23])(=[O:22])[CH2:18][CH:17]=2)CCCC1.CN(C)C=[O:27]>O>[CH2:1]([CH:20]1[CH2:21][C:16](=[O:27])[CH2:17][CH2:18][S:19]1(=[O:23])=[O:22])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CN(C)C=O
Reactant: O=S1(=O)CC=C(N2CCCC2)CC1
Reactant: O=C(CBr)c1ccccc1
Solvent: O
Product: O=C1CCS(=O)(=O)C(CC(=O)c2ccccc2)C1
Reaction time: 18 h

Procedure:
22.8 g (0.11 mole) of phenacyl bromide are added dropwise to a cold stirred solution of 23.0 g (0.11 mole) of 5,6-dihydro-4-(1-pyrrolidinyl)-2H-thiopyran-1,1-dioxide and 100 ml. of dimethylformamide. The mixture is stirred for 18 hours, diluted with water, and extracted with chloroform. The chloroform solution is dried over magnesium sulfate and concentrated to a solid. Chromatography on silica gel with a benzene and methanol mixture followed by recrystallization from methanol gives colorless crystals of 2-phenacyl-2,3,5,6-tetrahydrothiopyran-4-one- 1,1-dioxide, m.p. 157.5° to 159°C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[Br:16][CH2:17][C:18](Br)=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:8]([C:7]1[C:2]([NH:1][C:18](=[O:19])[CH2:17][Br:16])=[N:3][CH:4]=[CH:5][N:6]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Br)CBr
Reactant: Nc1nccnc1C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CBr)Nc1nccnc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2 g. (0.01 mol) of 2-amino-3-benzoylpyrazine and 20.2 g. (0.1 mol) of 2-bromo-acetyl bromide in 50 ml. of methylene chloride was layered with 25 ml. of 10% aqueous sodium carbonate solution. The two-phase mixture was stirred for 1 hour at room temperature. The methylene chloride layer was separated, washed several times with 10% aqueous sodium carbonate solution and was dried over sodium sulfate. The residue obtained after evaporation was crystallized from methylene chloride/hexane to yield 2.9 g. (90.6%) of the above-named product as tan crystals, m.p. 130°-135° dec.