Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]([Br:15])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].[C:16]([Cu])#[N:17].[C-]#N.[Na+]>O.Cl>[Br:15][C:9]1[CH:8]=[CH:7][C:6]([C:16]#[N:17])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: Nc1ccc(Br)c(C(=O)O)c1
Reactant: N#C[Cu]
Agent: Cl
Agent: O=N[O-]
Agent: [C-]#N
Solvent: O
Product: N#Cc1ccc(Br)c(C(=O)O)c1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
A solution of NaNO2 (0.29 g, 4.2 mmol) in water (1.6 mL) was added dropwise to a solution of 5-amino-2-bromobenzoic acid (0.86 g, 4 mmol) in HCl 2N (6 mL) and water (6 mL) at 0° C. during 15 minutes. The reaction mixture was stirred for 20 minutes and then added dropwise to a solution of CuCN (0.7 g, 8 mmol) and NaCN (0.4 g, 8 mmol) in water (5 mL) at 60° C.; the mixture was heated at 60° C. for further 15 minutes. After cooling at room temperature HCl (2N) was added and the product was extracted twice with AcOEt; the combined organic layers were dried and evaporated to give the title compound as a brown solid. Yield (0.6 g, 67%).
Reaction SMILES: [CH:1]1[C:6]2[NH:7][C:8]3[C:9](=[CH:10][CH:11]=[C:12]4[C:20]=3[NH:19][C:18]3[C:13]4=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[I:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31]>C1COCC1>[I:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([N:7]1[C:8]2[C:9](=[CH:10][CH:11]=[C:12]3[C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[NH:19][C:20]3=2)[C:5]2[C:6]1=[CH:1][CH:2]=[CH:3][CH:4]=2)(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1ccccc1I
Reactant: c1ccc2c(c1)[nH]c1c2ccc2c3ccccc3[nH]c21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1I)n1c2ccccc2c2ccc3c4ccccc4[nH]c3c21
Temperature: 40 °C
Reaction time: 12 h

Procedure:
43 g (169 mmol) of 11,12-dihydroindolo[2,3-a]carbazole are initially introduced in 1000 ml of THF, and 8.9 g (223.3 mmol) of NaH (60% in oil) are added at 0° C. 24 g (80 mmol) of 2-iodobenzenesulfonyl chloride are subsequently added to the mixture, which is then stirred at 40° C. for 12 h. The organic phase is dried over MgSO4, and the solvent is removed in vacuo. The residue is recrystallised from acetone and finally sublimed in a high vacuum. Yield: 29 g (574 mmol), 72% of theory, purity according to HPLC 99.9%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13](Cl)=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:20]1([CH2:19][CH2:18][CH2:17][NH:16][C:13]([C:11]2[O:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)=[O:14])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: NCCCN1CCOCC1
Reactant: O=C(Cl)c1ccc(-c2ccc(Br)cc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(NCCCN1CCOCC1)c1ccc(-c2ccc(Br)cc2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4.06 g of 5-(4-bromphenyl)-2-furancarboxylic acid chloride and 2.55 g of N-(3-aminopropyl)morpholine is refluxed 6 hr with 3.0 g of anhydrous potassium carbonate in 50 ml of acetonitrile. The mixture is allowed to stir at room temperature overnight. Solvents are then evaporated and the residue is triturated with ethyl ether followed by evaporation again. This process is repeated several times. A solution of the residue in ethyl ether is allowed to stand overnight whereupon crystals are formed. After three recrystallizations from ethyl acetate, the product, 2.47 g (37.5%), melts at 83°-100° The CI and EI mass spec. are consistent with the proposed structure. The latter showed M+ =393.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([CH:23]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24](O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1([C@H](CC)C(O)=O)C=CC=CC=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:24](=[O:25])[CH:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(Cc1ccccc1)c1ccccc1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: CC[C@H](C(=O)O)c1ccccc1
Product: O=C(N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)C(Cc1ccccc1)c1ccccc1

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and 2,3-diphenylpropanoic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.53 (dd, J=7.3, 13.7, 1H), 7.66 (d, J=7.4, 2H), 7.44 (d, J=7.1, 1H), 7.41-7.22 (m, 12H), 4.36-4.23 (m, J=7.5, 14.9, 1H), 3.97 (dt, J=4.9, 9.9, 1H), 3.77 (ddd, J=3.7, 10.1, 13.5, 1H), 3.52 (dt, J=13.1, 18.6, 1H), 3.33 (d, J=13.1, 0.5H), 3.05 (dt, J=4.7, 13.0, 1H), 2.77 (dd, J=2.6, 9.0, 0.5H), 2.55 (d, J=6.3, 0.5H), 2.38-2.24 (m, 3H), 2.21 (d, J=9.2, 1.5H), 2.03-1.86 (m, 1.5H), 1.72-1.56 (m, 1H), 1.52-1.20 (m, 2.5H); MS (ESI+) m/z 425 (M+H)+.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@H:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([NH:20][C:21]2[N:22]=[C:23]3[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:24]3=[N:25][CH:26]=2)=[O:19])[CH2:13]1.NN.CC(O)=O>CN(C=O)C>[NH2:3][C@H:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([NH:20][C:21]2[N:22]=[C:23]3[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:24]3=[N:25][CH:26]=2)=[O:19])[CH2:13]1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)N[C@H]3CC[C@H](N4C(=O)c5ccccc5C4=O)C3)cnc21
Agent: NN
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)N[C@H]3CC[C@H](N)C3)cnc21
Yield: 68.6 %

Procedure:
Trans 1-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-cyclopentyl]-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (0.288 g, 0.50 mmol) was dissolved with heating in DMF (10 mL) and placed in a 45° C. oil bath. The flask was evacuated and refilled with nitrogen three times. Hydrazine (0.16 mL, 5.1 mmol) was added via syringe. After 30 minutes AcOH (0.6 mL) was added and the mixture heated for 30 minutes more before being evaporated. MeOH was added, filtered and the filtrate was evaporated. H2O was added, filtered and the filtrate was evaporated. The residue was purified by reverse phase column chromatography (20-80% MeOH in 0.1% aqueous AcOH) to give trans 1-(3-amino-cyclopentyl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (0.134 g, 60% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:11]=[CH2:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].[CH3:24][CH2:25][O:26][C:27]([CH2:29]Br)=[O:28]>O.C1COCC1>[CH3:1][C:2]1[N:3]([CH2:29][C:27]([O:26][CH2:25][CH3:24])=[O:28])[C:4]([CH:11]=[CH2:12])=[C:5]([C:7]([F:10])([F:8])[F:9])[N:6]=1
Reactant: C=Cc1[nH]c(C)nc1C(F)(F)F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1c(C(F)(F)F)nc(C)n1CC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a solution of 2-methyl-4-(trifluoromethyl)-5-vinyl-1H-imidazole (911 mg, 5.17 mmol) was added DMF (7 mL) and THF (3 mL), followed by K2CO3 (1.43 g, 10.35 mmol) and ethyl bromo acetate (687 mL, 6.2 mmol). The resulting mixture was then stirred overnight at room temperature. Water (50 mL) was added and the mixture was extracted with EtOAc (3×100 mL). The combined EtOAc layers were dried (MgSO4), concentrated in vacuo, and purified by flash chromatography (SiO2, 60% EtOAc/hexanes) to obtain the desired ethyl 2-[2-methyl-4-(trifluoromethyl)-5-vinyl-imidazol-1-yl]acetate (796 mg, 3.03 mmol, 59% yield) as a yellow oil.
Reaction SMILES: [C:1]([CH:3]([CH:9]([CH3:11])[CH3:10])[C:4]([O:6]CC)=O)#[N:2].[CH2:12]([NH:14][C:15]([NH2:17])=[O:16])[CH3:13].C[O-].[Na+].Cl>CO.O>[CH2:12]([N:14]1[C:1]([NH2:2])=[C:3]([CH:9]([CH3:10])[CH3:11])[C:4](=[O:6])[NH:17][C:15]1=[O:16])[CH3:13]
Reactant: CCNC(N)=O
Reactant: CCOC(=O)C(C#N)C(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCn1c(N)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 12.25 h
Yield: 70.8 %

Procedure:
A flask was charged with ethyl 2-cyano-3-methylbutanoate (3b, 20.72 g, 133.5 mmol), ethyl urea (3a, 12.35 g, 140.2 mmol) and MeOH (97.2 mL). To the slurry at room temperature was added sodium methoxide in methanol (25% w/w soln, 36.8 mL), mild exotherm detected. The heterogeneous reaction mixture was then heated to reflux. The reaction was refluxed for 4-12 h. Upon reaction completion, as determined by TLC analysis, the reaction mixture was concentrated and solvent exchanged to acetonitrile (ACN) through 3×50 mL co-evaporations leaving a basic 1-2 vol. solution in ACN. To the reaction mixture was added 1-2 vol. of water followed by a pH adjustment with 2N HCl (aq.). As the pH approached 10, white to off-with solids began forming and, as the pH was further reduced to 3 to 4, (by pH paper) white slurry resulted. This slurry was aged for 0.5 to 24 h and then filtered. The resulting solids were washed with 1 vol. of water and 2×2 vol. MTBE. The white to off-white solids were then dried in a vacuum oven at 40 to 50° C. giving 18.63 g (60%) of 1-ethyl-5-isopropyl-6-amino uracil 2 (HCl salt).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(Cl)(Cl)(Cl)[Cl:26]>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[Cl:26])=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][N:16]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(F)(F)F)cn3)ccc2[nH]1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2ccc(-c3ccc(C(F)(F)F)cn3)cc2c1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
N-Chlorosuccimimide (480 mg, 3.86 mmol) and 5-(5-trifluoromethylpyrid-2-yl)-1H-indole-2-carboxylic acid ethyl ester (800 mg, 2.4 mmol; see Example 8 (b)) were mixed in CCl4 (50 mL) and stirred at 80° C. for 2 h. The mixture was diluted with EtOAc and washed with Na2S2O3 (aq., sat.), NaHCO3 (aq., sat.), brine and dried over Na2SO4 Concentration gave the sub-title compound (870 mg, 98%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[NH:14][C:15](=[O:23])[C:16]2[CH2:22][O:21][CH2:20][CH2:19][C:17]=2[N:18]=1)(C(C)(C)C)(C)C.[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>ClCCl>[OH:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[NH:14][C:15](=[O:23])[C:16]2[CH2:22][O:21][CH2:20][CH2:19][C:17]=2[N:18]=1)[C:32](=[O:33])[CH2:31][CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OCCNCc1nc2c(c(=O)[nH]1)COCC2
Reactant: O=C(Cl)CCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)N(CCO)Cc1nc2c(c(=O)[nH]1)COCC2
Reaction time: 24 h
Yield: 22.2 %

Procedure:
To a solution of 2-((2-(tert-butyldimethylsilyloxy)ethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (10 mg, 0.029 mmol) in dichloromethane (0.1 mL) was added 3-phenylpropanoyl chloride (4.4 μL, 0.029 mmol) and then triethylamine (12 μL, 0.088 mmol) at 0° C. The mixture was stirred at 0° C. to ambient temperature for 24 h. Tetra-N-butylammonium fluoride (29 μL, 0.029 mmol, 1 M in THF) was added and the reaction was stirred at ambient temperature for 1 h. The mixture was concentrated in vacuo then purified via prep thin layer chromatography to provide the title compound (2.3 mg, 22% yield). 1H NMR (400 MHz, CDCl3) δ 7.18-7.34 (m, 3H), 7.14 (d, J=7.5 Hz, 2H), 4.56 (s, 2H), 4.38 (s, 2H), 3.95 (t, J=5.5 Hz, 2H), 3.65-3.82 (m, 2H), 3.58 (t, J=4.5 Hz, 2H), 2.87-3.06 (m, 2H), 2.81 (t, J=7.5 Hz, 2H), 2.67 (br. s., 2H). HRMS calculated for C19H23N3O4 358.1767. found (ESI, [M+H]+), 358.1767. Retention time=0.99 min.
Reaction SMILES: ClC1C(Cl)=C(C)NC=1C(NC1CCN(C2SC(C#N)=C(O)N=2)CC1)=O.[Cl:26][C:27]1[C:31]([Cl:32])=[C:30]([C:33]#[N:34])[NH:29][C:28]=1[C:35]([NH:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]2[S:45][C:46]([C:49]([O:51]C)=[O:50])=[CH:47][N:48]=2)[CH2:40][CH2:39]1)=[O:36]>>[Cl:26][C:27]1[C:31]([Cl:32])=[C:30]([C:33]#[N:34])[NH:29][C:28]=1[C:35]([NH:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]2[S:45][C:46]([C:49]([OH:51])=[O:50])=[CH:47][N:48]=2)[CH2:40][CH2:39]1)=[O:36]
Reactant: COC(=O)c1cnc(N2CCC(NC(=O)c3[nH]c(C#N)c(Cl)c3Cl)CC2)s1
Agent: Cc1[nH]c(C(=O)NC2CCN(c3nc(O)c(C#N)s3)CC2)c(Cl)c1Cl
Product: N#Cc1[nH]c(C(=O)NC2CCN(c3ncc(C(=O)O)s3)CC2)c(Cl)c1Cl

Procedure:
The title compound was prepared by a procedure analogous to Intermediate 3 starting from methyl 2-(4-{[(3,4-dichloro-5-cyano-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-thiazole-5-carboxylate (Example 271). The reaction mixture was concentrated to remove MeOH. Water was added and the pH was adjusted to pH 4 with NaHCO3. The product was extracted with CHCl3:isopropanol (3:1). Drying (MgSO4) and removal of solvent yielded a white solid. The was dried in drying pistol at 75° C. under vacuum.
Reaction SMILES: C([O:4][C:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:6])C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCCCC1>O1CCCC1.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>[CH2:16]([O:15][C:13]([C:12]([CH3:18])([O:11][C:10]1[CH:9]=[C:8]([CH2:7][C:5]([OH:6])=[O:4])[CH:22]=[CH:21][CH:20]=1)[CH3:19])=[O:14])[CH3:17]
Reactant: C=CCOC(=O)Cc1cccc(OC(C)(C)C(=O)OCC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CCOC(=O)C(C)(C)Oc1cccc(CC(=O)O)c1

Procedure:
Ethyl 2-[3-(allyloxycarbonylmethyl)phenoxy]-2-methylpropionate (6.40 g, 20.9 mmol) was dissolved in tetrahydrofuran (150 mL). Subsequently, triphenylphosphine (2.42 g, 2.09 mmol) and piperidine (41.34 mL, 41.8 mmol) were added thereto. Under argon atmosphere, tetrakis(triphenylphosphine)palladium (2.42 g, 2.09 mmol) was added, the resultant mixture was stirred for three hours at room temperature. After completion of reaction, the reaction mixture was concentrated under reduced pressure, followed by addition of chloroform and washing sequentially with 3M hydrochloric acid, water, and saturated brine. The resultant mixture was subjected to drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol/acetic acid=50/1/0.5), whereby the target compound was obtained (6.88 g, 25.84 mmol, >q.).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[CH:16][C:17]=3[O:22][CH3:23])[N:12]=2)=[CH:7][CH:6]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C=O)C>[CH3:23][O:22][C:17]1[CH:16]=[C:15]([O:24][CH3:25])[CH:14]=[C:13]2[C:18]=1[C:19](=[O:21])[NH:20][C:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:6][CH:7]=1)=[N:12]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCBr)cc3)nc2c1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCN4CCCC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 2-[4-(2-bromo-ethoxy)-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.25 g, 0.61 mmol) in anhydrous DMF (10 mL) was added pyrrolidine (0.20 mL, 2.45 mmol) and the reaction mixture was stirred at room temperature under nitrogen for about 20 hours. Solvent was removed under reduced pressure and the residual solid was triturated with water. The resulting slurry was filtered and washed with ether and hexanes. The crude product was purified by column chromatography (silica gel 230-400 mesh; 10% methanol in dichloromethane as eluent) to give the title compound as a white solid. Yield: 0.11 g (44%). MP 226-227° C. 1H NMR (400 MHz, CDCl3): δ 10.08 (br s, 1H), 8.07 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.8 Hz, 2H), 6.81 (d, J=1.95 Hz, 1H), 6.45 (d, J=1.95 Hz, 1H), 4.21 (t, J=5.6 Hz, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 2.97 (t, J=5.6 Hz, 2H), 2.68 (br s, 4H), 1.84 (br s, 4H). MS (ES+): m/z 198.65 (100%), 396.10 (M+1, 70%).
Reaction SMILES: C([O:8][C:9]1[C:10]([O:35][CH3:36])=[CH:11][C:12]2[CH2:21][CH2:20][N:19]3[CH:14]([CH2:15][C:16]4[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[C:22]([O:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:17]=4[CH2:18]3)[C:13]=2[CH:34]=1)C1C=CC=CC=1>[Ni]>[OH:8][C:9]1[C:10]([O:35][CH3:36])=[CH:11][C:12]2[CH2:21][CH2:20][N:19]3[CH:14]([CH2:15][C:16]4[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[C:22]([O:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:17]=4[CH2:18]3)[C:13]=2[CH:34]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)C1Cc3c(Cl)cc(OC)c(OS(C)(=O)=O)c3CN1CC2
Agent: [Ni]
Product: COc1cc2c(cc1O)C1Cc3c(Cl)cc(OC)c(OS(C)(=O)=O)c3CN1CC2
Yield: 87.7 %

Procedure:
A product obtained in Example 14 (0.035 g, 0.07 mmol) was hydrogenated in the present of Raney-Ni. The desired product as pale yellow powder (0.027 g, 92.9%) was obtained following the synthetic procedure described in Example 1, 4 or 7. 1HNMR (CDCl3) δ: 2.58˜2.70 (3H, m, CH2), 3.04˜3.24, 3.38˜3.39 (3H, m, CH2), 3.34 (3H, s, SO2CH3), 3.54˜3.66 (2H, m, CH2 and N—CH), 3.87 (3H, s, Ar—OCH3), 3.88 (3H, s, Ar—OCH3), 4.25 (1H, d, CH2), 5.52 (1H, brs, Ar—OH), 6.60 (1H, s, ArH), 6.87 (1H, s, ArH), 6.93 (1H, s, ArH). MS (EI) m/z: 439 (M+), 360 (base), 344, 183, 176, 77.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]2[C@H:33]3[CH2:38][CH2:37][CH2:36][C@H:34]3[N:35]=[C:3]12.[OH:39]OS([O-])=O.[K+]>CC#N.CO>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:39])[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]2[C@H:33]3[CH2:38][CH2:37][CH2:36][C@H:34]3[N:35]=[C:3]12
Reactant: CN1C(=O)c2c(nn(Cc3ccc(-c4cccc(F)n4)cc3)c2Sc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: CN1C(=O)c2c(nn(Cc3ccc(-c4cccc(F)n4)cc3)c2S(=O)c2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 25 °C

Procedure:
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylthio)-2-(4-(6-fluoropyridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (12 mg, 0.023 mmol) is dissolved in CH3CN (2 mL) and CH3OH (2 mL), and then an aqueous solution of oxone is added. The reaction mixture is stirred at room temperature for a week, and then purified by a semi-preparative HPLC to give pure product as white solids. MS (ESI) m/z 541.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][C:16]=2[O:27][CH3:28])[C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.C(N(CC)CC)C.Cl.Cl[CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>O1CCCC1>[Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH2:43][CH2:44][N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[CH2:23][CH2:22]3)=[CH:17][C:16]=2[O:27][CH3:28])[C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: ClCCN1CCOCC1
Reactant: COc1cc(N2CCNCC2)ccc1Nc1cc(Cc2c(F)cccc2Cl)cnc1C(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(N2CCN(CCN3CCOCC3)CC2)ccc1Nc1cc(Cc2c(F)cccc2Cl)cnc1C(N)=O

Procedure:
A solution of EXAMPLE 42B (25 mg, 0.053 mmol) in tetrahydrofuran (1 mL), triethylamine (22.24 uL, 0.16 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (9.9 mg, 0.053 mmol) were heated to 75° C. over 18 hours. The reaction mixture was concentrated under reduced pressure and purified on RP-HPLC (10 mM ammonium acetate/acetonitrile) to afford the title compound. 1H NMR (CDCl3) δ ppm 9.76 (s, 1H), 7.88 (s, 1H), 7.76 (s, 1H), 7.23-7.06 (m, 4H), 7.06-6.91 (m, 1H), 6.58-6.53 (d, J=2.5, 6H), 6.47 (dd, J=8.6, 2.5, 5H), 5.46 (s, 1H), 4.02 (d, J=1.9, 2H), 3.83-3.68 (m, 7H), 3.27-3.09 (m, 4H), 2.77-2.49 (m, 12H); MS (ESI) m/z 584 (M+H)+.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[K].Br[C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][NH:18]2)=[CH:14][CH:13]=1.[Li]C(C)(C)C.CN([CH:29]=[O:30])C>C(OCC)C>[NH:18]1[C:19]2[C:15](=[CH:14][CH:13]=[C:12]([CH:29]=[O:30])[CH:20]=2)[CH:16]=[CH:17]1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: O=Cc1ccc2cc[nH]c2c1
Temperature: 25 °C

Procedure:
Potassium hexamethyldisilazane (0.5M in toluene) (56 ml) was added dropwise to a ice cold solution of 6-bromoindole (5.0 g) in diethyl ether (50 ml). The reaction mixture was warmed to room temperature for 30 mins and then cooled to −78° C. tBuLi (1.7M) (31.5 ml) was added to the mixture keeping the temperature below −65° C. the mixture was further stirred at −78° C. for 30 mins after which time a solution of DMF (6 ml) in diethyl ether (10 ml) was added, the reaction mixture was warmed to room temperature and quenched with ice cold 2N HCl the product was then extracted into diethyl ether (×3). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with Dichloromethane/Methanol (97/3, v/v) to afford the title compound as a solid (1.49 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].CO.C(N(CC)CC)C.Cl.[NH2:25][C@H:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27]([NH2:29])=[O:28]>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:25]([C@H:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27]([NH2:29])=[O:28])[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: NC(=O)[C@H](N)c1ccccc1
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: NC(=O)[C@@H](c1ccccc1)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 50 °C

Procedure:
A round bottom flask was charged with 5-nitro-isochromen-1-one (2 g, 0.01 mol), methanol (20 mL, 0.5 mol), triethylamine (3 mL, 0.02 mol) and (R)-2-amino-2-phenylacetamide hydrochloride (2.3 g, 0.012 mol) and the reaction heated at 50° C. for 3 hours. The starting material disappeared and the solvent was removed under reduced pressure and the residue purified by flash chromatography (40 g silica gel, 0-10% MeOH/DCM) to yield the product as a brown solid. MS m/z=324.3 (M+H).