Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:22][C:11]2=[CH:12][CH:13]=[C:14]3[C:19]([N:18]=[C:17](SC)[N:16]=[CH:15]3)=[C:10]2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:24]1C=CC=C(C(OO)=O)C=1.C([O-])([O-])=O.[Na+].[Na+].[O-:40][S:41]([O-:44])(=S)=O.[Na+].[Na+]>C(Cl)Cl.[Cl-].[Na+].O.CC(C)=O>[C:1]([O:5][C:6]([C:8]1[S:22][C:11]2=[CH:12][CH:13]=[C:14]3[C:19]([N:18]=[C:17]([S:41]([CH3:24])(=[O:44])=[O:40])[N:16]=[CH:15]3)=[C:10]2[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1ncc2ccc3sc(C(=O)OC(C)(C)C)cc3c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc2c(ccc3cnc(S(C)(=O)=O)nc32)s1
Yield: 88 %

Procedure:
2-Methylsulfanyl-thieno[2,3-h]quinazoline-8-carboxylic acid tert-butyl ester (6.50 g, 19.55 mmol) was suspended/dissolved in DCM (150 mL) and cooled in an ice-bath. 3-chloroperbenzoic acid (22.49 g, 97.76 mmol, 75% pure) was added in one portion and the resultant suspension was stirred at 0° C. for 5 minutes and at room temperature for a further 55 minutes. This mixture was then carefully added to a 1:1:1 mixture of saturated Na2CO3, saturated Na2S2O3 and brine (˜500 mL). The organic layer was separated and the aqueous layer was further extracted with DCM (3×200 mL). The combined organics were washed with brine (1×100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The yellow solid obtained was redissolved in acetone, silica (˜80 mL) was added and the suspension was concentrated under reduced pressure. The solid obtained was subjected to column chromatography (gradient elution, 5-10% EtOAc in DCM, ˜600 mL silica) to give a yellow solid (6.25 g, 88% yield). MS (ES+) 365. δH (CDCl3) 1.7 (9H, s), 3.5-3.6 (3H, s), 8.0 (1H, d), 8,2 (1H, d), 8,9 (1H, s), 9.6 (1H, s)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].[CH:13]([N-]C(C)C)(C)C.[Li+].IC.C([O-])(O)=O.[Na+]>O1CCCC1>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[C:6]2=[O:12]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1CCc2c(F)cc(F)cc21
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1Cc2c(F)cc(F)cc2C1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
According to Scheme 3, step 1: to a solution of 4,6-difluoro-indan-1-one (5.0 g, 29.8 mmol) in dry tetrahydrofuran (100 ml) at −78° C. a 2M solution of lithiumdiisopropylamide (16.4 ml, 32.7 mmol) in tetrahydrofuran was added dropwise and the mixture was stirred for 1 h at −78° C. Then iodomethane (4.64 g, 32.7 mmol) was added and the mixture was slowly warmed to 25° C. After addition of aqueous saturated NaHCO3 the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over Na2SO4 and filtered, solvents were evaporated in vacuo. The crude product was purified by silica gel chromatography (eluting with 0% to 100% ethyl acetate in heptane to give 1.15 g of 4,6-Difluoro-2-methyl-indan-1-one (7a).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH:11]1[CH:16]=O.C([O:20][C:21](=O)[C:22](=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)C>C(O)C>[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH:11]1[CH:16]1[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:21](=[O:20])[C:22]([OH:31])=[C:23]1[C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1
Reactant: CCOC(=O)C(=O)Cc1ccc(O)cc1
Reactant: O=CC1CCC=CO1
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: O=C1C(O)=C(c2ccc(O)cc2)C(C2CCC=CO2)N1CCCn1ccnc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and 3,4-Dihydro-2H-pyran-2-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 3-(4-Hydroxy-phenyl)-2-oxo-propionic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([F:11])=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[F:12].CO[CH:15](OC)[CH2:16][NH2:17].Cl.[S-:21][C:22]#[N:23].[K+]>C(O)C.[Pd].CO>[CH3:1][O:2][C:3]1[C:10]([F:11])=[CH:9][C:6]([CH2:7][N:17]2[CH:16]=[CH:15][NH:23][C:22]2=[S:21])=[CH:5][C:4]=1[F:12]
Reactant: COC(CN)OC
Reactant: N#C[S-]
Reactant: COc1c(F)cc(C=O)cc1F
Agent: [Pd]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CO
Product: COc1c(F)cc(Cn2cc[nH]c2=S)cc1F
Temperature: 95 °C
Yield: 72 %

Procedure:
A mixture of 4-methoxy-3,5-difluorobenzaldehyde (17.2 g, 0.1 mol), aminoacetaldehyde dimethyl acetal (10.5 g, 0.1 mol), and methanol (1 ml) was heated at 95° C. for 10 minutes. The resulting mixture was dissolved in ethanol (150 ml) and hydrogenated over 10% Pd on carbon (1 g) until H2 uptake slowed (about 2 hours). The catalyst was filtered and the filtrate was treated with 1.5N hydrochloric acid (80 ml) and potassium thiocyanate (10.4 g, 0.11 mol). The resulting mixture was boiled until the volume was reduced to 100 ml, then it was heated a reflux an additional 1 hour and cooled to 5° C. The crystalline precipitate was filtered, washed with water, and dried. Recrystallization from ethanol gave 1-(4'-methoxy-3',5'-difluorobenzyl)-1,3-dihydro-2H-imidazole-2-thione, 72% yield, m.p. 156°-158° C.
Reaction SMILES: [O:1]1[C:5](=[O:6])[CH:4]=[CH:3][C:2]1=[O:7].[CH:8]1[CH2:14][CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C(C)=CC=CC=1>[CH:9]12[CH:8]=[CH:14][CH:13]([CH:12]3[CH:10]1[CH2:11]3)[CH:4]1[CH:3]2[C:2](=[O:7])[O:1][C:5]1=[O:6]
Reactant: O=C1C=CC(=O)O1
Reactant: C1=CC=CCC=C1
Solvent: Cc1ccccc1C
Product: O=C1OC(=O)C2C3C=CC(C4CC34)C12
Temperature: 144 °C
Reaction time: 5 h
Yield: 8.5 %

Procedure:
Furan-2,5-dione (5.32 g, 54.26 mmol) was partially dissolved in xylene (100 mL). Cyclohepta-1,3,5-triene (5 g, 54.26 mmol) was added. The reaction was stirred at 144° C. for 5 h. The mixture was allowed to cool to 25° C. and concentrated in vacuo. Purification by flash column chromatography (Teledyne Isco RediSep column; 0 to 20% ethyl acetate in hexanes) afforded the desired products, rac-(1R,2R,6S,7S,8S,10R)-4-Oxatetracyclo[5.3.2.02,6.08,10]dodec-11-ene-3,5-dione (7.46 g, 39.22 mmol, 72%) and rac-(1R,2S,6R,7S,8S,10R)-4-Oxatetracyclo[5.3.2.02,6.08,10]dodec-11-ene-3,5-dione (0.88 g, 4.63 mmol, 8%), as white solids. 1H NMR (400 MHz, CDCl3) 6: exo: 0.27-0.42 (2H, m), 1.11-1.15 (2H, m), 3.25 (2H, t, J=1.6 Hz), 3.46-3.50 (2H, m), 5.89 (2H, dd, J1=4.8 Hz, J2=3.2 Hz); endo: 0.14-0.26 (2H, m), 1.12-1.16 (2H, m), 3.09 (2H, s), 3.40-3.44 (2H, m), 5.94 (2H, dd, J1=4.8 Hz, J2=3.2 Hz). LC-MS (ESI) calcd for C11H10O3 190.20. found exo 191.0; endo 191.3 [M+H+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O.ClCCl>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:19])=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccccc1OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(O)Cc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
A mixture of 2-benzyloxyphenylacetic acid (242 mg, 11.0 mmol), N-bromosuccinimide (178 mg, 1.9 mmol) and dichloromethane (4 ml) was stirred overnight at room temperature under argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give the title compound (280 mg, 87.2%) as a white solid.
Reaction SMILES: Cl.[CH2:2]([NH:6][C:7](=[O:43])[C@H:8]([CH3:42])[CH2:9][C@H:10]([OH:41])[C@@H:11]([NH:33]C(OC(C)(C)C)=O)[CH2:12][C:13]1([CH2:16][C:17]([N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH:21]([C:29]([NH:31][CH3:32])=[O:30])[CH2:20]2)=[O:18])[CH2:15][CH2:14]1)[CH2:3][CH2:4][CH3:5].C1(C)C=CC=CC=1>O1CCOCC1>[CH2:2]([NH:6][C:7](=[O:43])[C@H:8]([CH3:42])[CH2:9][C@H:10]([OH:41])[C@@H:11]([NH2:33])[CH2:12][C:13]1([CH2:16][C:17]([N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH:21]([C:29]([NH:31][CH3:32])=[O:30])[CH2:20]2)=[O:18])[CH2:15][CH2:14]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1(CC(=O)N2CC(C(=O)NC)Cc3ccccc32)CC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC1(CC(=O)N2CC(C(=O)NC)Cc3ccccc32)CC1
Reaction time: 2 h

Procedure:
2 ml of 4N hydrochloric acid in dioxane are added to 116 mg of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-6-[1-[3(R,S)-methylaminocarbonyl-1,2,3,4-tetrahydroquinolin-1-ylcarbonylmethyl]cyclopropyl]-2(R)-methyl-hexanoic acid (N-butyl)amide at 0° C. and the mixture is stirred for 2 h. 2 ml of toluene are added and the reaction mixture is concentrated. The oily residue is chromatographed over 10 g of silica gel (mobile phases K and L). This gives the title compound as a diastereomer mixture: Rf (P)=0.11; Rt (IV)=32.6 min; FAB-MS: (M+H)+ =487.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:9]=1[F:17])(=O)C.O.ClCCl>O1CCOCC1>[F:17][C:9]1[C:10]([CH:14]([CH3:16])[CH3:15])=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][OH:6]
Reactant: CC(=O)OCc1cccc(C(C)C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)c1cccc(CO)c1F
Reaction time: 5 h
Yield: 97.7 %

Procedure:
44 g of 8% strength sodium hydroxide solution are added to a solution of 15.3 g (73 millimoles) of 2-fluoro-3-isopropylbenzyl acetate in 100 ml of dioxane. After 5 hours at 50° C., the mixture is poured into 100 ml of water. 12 g (98%) of 2-fluoro-3-isopropylbenzyl alcohol are obtained by extraction with dichloromethane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C@H:22]2[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]2)[CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:14])=[N:9][CH:8]=1)[CH3:2].[CH3:30][N:31]([CH3:36])[S:32](Cl)(=[O:34])=[O:33]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH:16]2[CH2:21][CH2:20][N:19]([S:32](=[O:34])(=[O:33])[N:31]([CH3:36])[CH3:30])[CH2:18][CH2:17]2)[C@H:22]2[CH2:23][CH2:24][C@H:25]([CH3:28])[CH2:26][CH2:27]2)=[O:14])=[N:9][CH:8]=1)[CH3:2].[CH3:30][N:31]([CH3:36])[S:32]([N:19]1[CH2:18][CH2:17][CH:16]([N:15]([C@H:22]2[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:29])=[CH:8][N:9]=2)[CH2:21][CH2:20]1)(=[O:34])=[O:33]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C2CCNCC2)[C@H]2CC[C@H](C)CC2)s1
Product: CCOC(=O)CSc1cnc(NC(=O)N(C2CCN(S(=O)(=O)N(C)C)CC2)[C@H]2CC[C@H](C)CC2)s1
Product: CN(C)S(=O)(=O)N1CCC(N(C(=O)Nc2ncc(SCC(=O)O)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
{2-[3-(1-Dimethylsulfamoyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester was prepared in a similar manner to Example 554 using {2-[3-(trans-4-methyl-cyclohexyl)-3-piperidin-4-yl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester and dimethylsulfamoyl chloride. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[S:12][C:11]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:10][N:5]2[C:6](=[O:9])[C:7]=1[CH3:8].[F-:21].[K+].S1(CCCC1)(=O)=O>O>[F:21][C:2]1[N:3]=[C:4]2[S:12][C:11]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:10][N:5]2[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: CCCCCCCSc1nn2c(=O)c(C)c(Cl)nc2s1
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: CCCCCCCSc1nn2c(=O)c(C)c(F)nc2s1
Yield: 63 %

Procedure:
A solution of 8.6 g of the thus obtained 7-chloro-2-heptylthio-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one, 3.0 g of spray dry potassium fluoride and 32 ml of sulfolane was heated at 205°~225° C. in a stream of nitrogen for 1 and half hours. After cooling, water was added to the mixture, and the mixture was extracted with toluene. The toluene layer was collected and washed with water. The toluene phase was dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by column chromatography on a silica gel with an ethyl acetate/n-hexane (1:3) mixture as an eluent. After the solvent was distilled off, 5.2 g of 7-fluoro-2-heptylthio-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=O)=[CH:5][CH:4]=1)#[N:2].C(Cl)[Cl:17].C(Cl)(=O)C(Cl)=O>CN(C=O)C>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([Cl:17])=[O:15])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)c2ccccc12
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)Cl)c2ccccc12
Reaction time: 3 h

Procedure:
A mixture containing 4-cyano-1-naphthoic acid (0.090 g, 0.45 mmol), DCM (3 mL), oxalyl chloride (0.063 g, 0.50 mmol) and DMF (approximately 5 μL) was stirred for 3 h and concentrated to provide 4-cyano-1-naphthoyl chloride as an off-white solid which was used directly. Using standard acylation conditions 4-cyano-1-naphthoyl chloride (0.090 g) was reacted with N-[(S)-2-(3,4-dichlorophenyl)-4-[4-[(S)-2-methylsulfinylphenyl]-1-piperidinyl]butyl]-N-methylamine to afford the free base (0.215 g) which was converted to the citrate salt.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.CS(O[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[O:8]=[C:4]1[CH:3]=[C:2]([O:1][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:7]=[CH:6][NH:5]1
Reactant: CC(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: O=c1cc(O)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(Oc2cc[nH]c(=O)c2)CC1
Temperature: 140 °C
Yield: 44 %

Procedure:
A stirring mixture of 4-hydroxypyridin-2(1H)-one (1.5 g, 13 5 mmol), isopropyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (5.0 g, 18.9 mmol, prepared according to the procedure described in Step C of Example 1) and potassium carbonate (3.7 g, 27 0 mmol, EMD) in DMF (80 mL) was heated at 140° C. for 2 h and then cooled to room temperature. The resulting mixture was diluted with EtOAc and H2O and the aqueous layer was extracted further with EtOAc (7×). The combined extracts were washed with saturated NH4Cl aqueous solution (2×), dried (Na2SO4) and evaporated. The residual was purified by flash chromatography (0 to 100% EtOAc/Hexanes and then 5% MeOH/CH2Cl2) to yield 1.67 g (44%) of the product as an off-white solid. MS (ESI) 281 (M+H).
Reaction SMILES: [NH2:1][N:2]1[C:11]([OH:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:20]([O-:22])=[O:21])[CH:9]=2)[N:4]=[CH:3]1.[C:23]1(=[O:37])[N:27]([CH2:28][C:29](Cl)=[O:30])[C:26](=[O:32])[C:25]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:24]12>N1C=CC=CC=1>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]([C:10]1[CH:9]=[C:8]([N+:20]([O-:22])=[O:21])[CH:7]=[CH:6][C:5]=1[N:4]([CH:3]=[N:2][NH:1][C:29](=[O:30])[CH2:28][N:27]1[C:23](=[O:37])[C:24]2[C:25](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:26]1=[O:32])[C:29](=[O:30])[CH2:28][N:27]1[C:26](=[O:32])[C:25]2[C:24](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:23]1=[O:37])=[O:19]
Reactant: NN1C=Nc2ccc([N+](=O)[O-])cc2C1(O)c1ccccc1Cl
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Solvent: c1ccncc1
Product: O=C(CN1C(=O)c2ccccc2C1=O)NN=CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1, 3-amino-6-nitro-3,4-dihydro-4-hydroxy-4-(o-chlorophenyl)quinazoline with pyridine is reacted with α-phthalimidoacetyl chloride to give 1,3-dioxo-2-isoindolineacetic acid, [[N-[2-(o-chlorobenzoyl)-4-nitrophenyl]-1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:17][CH2:18][C@H:19]([OH:21])[CH3:20]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][O:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:17]([CH2:18][C@H:19]([OH:21])[CH3:20])[C:5]=32)=[CH:10][CH:9]=1
Reactant: C[C@@H](O)CN
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of 2 g of (RS)-2-(2-oxoethyl)-6-methoxy-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.94 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 30 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.5 g (63%) of (R)-1-(7-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a solid with m.p. 75°.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[NH:9][N:10]=[C:11]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27].O>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[N:10]([CH2:25][C:26](=[O:27])[NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)[N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOCCOCc1cc(C(=O)OC(C)(C)C)[nH]n1
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCOCc1cc(C(=O)OC(C)(C)C)nn1CC(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 350 mg 5-[2-(2-Methoxy-ethoxy)-ethoxymethyl]-2H-pyrazole-3-carboxylic acid tert-butyl ester in 5 ml of DMF and 46 mg of sodium hydride (60% in mineral oil) were added at RT. After stirring for 20 min at room temperature 290 mg of 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide were added. The reaction was stirred at room temperature for 3 h. Then 10 ml of water were added and the mixture was filtered through a Chem Elut® cartridge by elution with DCM. After concentration under reduced pressure the crude was subjected to the next reaction without further purification. Yield: 400 mg.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:10]([CH2:17][NH:18][CH2:19][CH:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=2)[C:21]1=[O:31])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(OCC)C>[CH2:10]([CH2:17][NH:18][CH2:19][CH:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=2)[C:21]1([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:31])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1c2ccc(F)cc2CCC1CNCCc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: OC1(c2ccccc2)c2ccc(F)cc2CCC1CNCCc1ccccc1

Procedure:
Phenylmagnesium bromide (3 M solution in diethyl ether, 9 cm3) was added to dry diethyl ether (20 cm3) under nitrogen with stirring. This was then cooled to below 0° C. (salt-ice bath) and 2-(N-benzylmethylamino)methyl-6-fluoro-3,4-dihydro-2H-naphthalene-1-one hydrochloride was added in small portions at such a rate as to maintain the temperature below 0° C. (approx. 15 mins). The reaction mixture was stirred for a further 1 h at 0° C. and then poured onto ice. Water (100 cm3) and diethyl ether (100 cm3) were added and the aqueous layer was separated and extracted with further diethyl ether (100 cm3). The combined ether layers were extracted with hydrochloric acid (5 M, 3×50 cm3). The acidic extracts were basified (K2CO3) and re-extracted with dichloromethane (3×75 cm3). The combined extracts were dried (Na2SO4) and the solvent was removed under reduced pressure to provide the title compound (1.55 g) as a brown oil which solidified on standing.
Reaction SMILES: [CH3:1][N:2]1[CH:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[C:28]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CCC12
Reactant: Clc1nc(-c2ccccc2)cc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc(-c5ccccc5)cc5ccccc45)cc3CC[C@@H]12
Yield: 41.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (86 mg, 0.33 mmol), potassium carbonate (158 mg, 1.14 mmol), 1-chloro-3-phenyl- isoquinoline (95 mg, 0.40 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 64 mg (42%) of the title compound as an off white solid. mp 183°-189°. FDMS: m/e=464. α[D]589 =+54.61 (c=0.53, chloroform).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.Cl.[N+:12]([C:15]1[CH:16]=[C:17]([C:21]2[N:22]=[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[NH:24][CH:25]=2)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C(O)(C)C.C(N(C(C)C)CC)(C)C>>[N+:12]([C:15]1[CH:16]=[C:17]([C:21]2[N:22]=[C:23]([CH:26]3[CH2:31][CH2:30][N:29]([C:2]4[N:7]=[CH:6][N:5]=[C:4]5[NH:8][N:9]=[CH:10][C:3]=45)[CH2:28][CH2:27]3)[NH:24][CH:25]=2)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]
Reactant: Clc1ncnc2[nH]ncc12
Reactant: O=[N+]([O-])c1cccc(-c2c[nH]c(C3CCNCC3)n2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccc(-c2c[nH]c(C3CCN(c4ncnc5[nH]ncc45)CC3)n2)c1
Temperature: 70 °C

Procedure:
Place 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine (150 mg; 1.16 equiv; 970.50 μmoles; 150.00 mg), and 4-[4-(3-Nitro-phenyl)-1H-imidazol-2-yl]-piperidine hydrochloride salt (258 mg 1.00 equiv; 835.58 μmoles; 258.00 mg) in a microwave vial and dissolve in isopropyl alcohol (3 mL; 39.24 mmoles; 3.00 mL) and add diisopropylethylamine (0.5 mL; 2.87 mmoles; 500.00 μL). Heat the mixture to 70° C. in a Emrys Optimizer microwave for 1 hour while stirring. Filter, and concentrate filtrate to an oil. Combine solid and oil and dissolve in 3% MeOH/DCM. Purify using ISCO chromatography over a biotage 40S column eluting with a gradient of 2.5% MeOH/DCM to 10% MeOH/DCM at a flow rate of 40 mL/min. Collect appropriate fractions, concentrate to an oil. Dissolve oil in 10% MeOH/DCM and wash with a mixture of aqueous sodium bicarbonate/saturated aqueous sodium chloride three times. Wash the combined organic layers with saturated aqueous sodium chloride and dry over sodium sulfate. Concentrate and dry under reduced pressure to obtain the title compound.