Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[H][H].[CH2:16]([C:19]1([CH:34]=O)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][CH2:22][C:21]2[CH:30]=[CH:31][CH:32]=[CH:33][C:20]1=2)[CH:17]=[CH2:18].[OH-].[Na+]>CCCCCC.C1COCC1.CN(C=O)C>[CH2:16]([C:19]1([CH:34]=[CH:7][C:5]([O:4][CH3:3])=[O:6])[C:20]2[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=2[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]1=2)[CH:17]=[CH2:18]
Reactant: [H][H]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: C=CCC1(C=O)c2ccccc2CCc2ccccc21
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCC1(C=CC(=O)OC)c2ccccc2CCc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
Washed sodium hydride (1.72 g of 60 weight % in oil, 0.0429 mol) two times with hexane under a nitrogen atmosphere. Added 100 mL of dry THF, and cooled to 0° C. Added trimethyl phosphonoacetate (7.81 g, 6.9 mL, 0.0429 mol) dissolved in 15 mL of dry THF dropwise via addition funnel. Hydrogen evolution was observed. Added 50 mL of dry DMF, and stirred at room temperature for 30 mins. Added 10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-carboxaldehyde (7.50 g, 0.0286 mol) dissolved in 25 mL of dry DMF dropwise via addition funnel. Stirred at room temperature for 45 mins then heated at 75° C. for 16 hours. Cooled to room temperature, and added 0.5N NaOH. Extracted with ethyl acetate. Washed combined organic extracts with 0.5N HCl and saturated NaCl, dried with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 2% ethyl acetate-hexane, 5% ethyl acetate-hexane, then 10% ethyl acetate-hexane. Combined appropriate fractions, and evaporated to give 6.03 g (66% yield) of methyl 3-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-propenoate as a colorless oil.
Reaction SMILES: [NH2:1][C:2](=[O:42])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][N:30]3[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:25][CH:24]=2)[N:13]=1.[H][H]>CN(C=O)C.[OH-].[OH-].[Pd+2].CCOC(C)=O>[NH2:1][C:2](=[O:42])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][N:30]3[C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:27][CH:28]=2)[N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3CC(N)=O)n2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.5 %

Procedure:
tert-Butyl 2-(4-((4-((2-(2-amino-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I40) (0.120 g, 0.207 mmol) was dissolved in dry DMF (5 mL) under an atmosphere of nitrogen. 20% Pearlman's catalyst (0.060 g) in EtOAc (5 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with a balloon and stirred at room temperature for 20 hours at room temperature. The catalyst was removed by filtration through Celite, which was washed with EtOAc (5×10 mL). The solvent was removed in vacuo to give a pale yellow gum which was purified by silica gel chromatography (Biotage, Isolera 12 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I41) (0.090 g, 74% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.20 (s, 1H), 8.67 (s, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.43 (s, 1H), 7.26-7.21 (m, 1H), 7.20-7.09 (m, 5H), 6.89 (s, 1H), 5.31-5.19 (m, 1H), 3.92 (d, J=13.2 Hz, 1H), 3.49 (s, 2H), 3.16-2.98 (m, 4H), 2.71 (t, J=11.8 Hz, 1H), 2.29 (d, J=13.2 Hz, 1H), 1.75 (t, J=11.0 Hz, 1H), 1.58-1.50 (m, 2H), 1.46-1.23 (m, 11H). LCMS Method C: rt 6.59 min; m/z 584.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=2)=[C:4]([F:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:29]([CH3:32])[C:30]#[CH:31].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH:30]([C:29]#[CH:32])[CH3:31])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=2)=[C:4]([F:21])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: C#CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CC(C)Oc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 70 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
First, 100 mg of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-61) was dissolved in 0.60 ml of N,N-dimethylformamide, to which 64 mg of potassium carbonate and 45 mg of 3-bromo-1-butyne were added, and the mixture was stirred at 70° C. for 1 hour. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 96 mg (yield, 83%) of 3-{4-chloro-2-fluoro-5-(3-butyn-2-yloxy)phenyl}-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-157).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5](=[O:18])[C:6]1[C:11]([S:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][CH:9]=[CH:8][C:7]=1[F:17].[OH:19]OS([O-])=O.[K+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CO.O>[Cl:1][CH2:2][CH2:3][NH:4][C:5](=[O:18])[C:6]1[C:7]([F:17])=[CH:8][CH:9]=[CH:10][C:11]=1[S:12]([C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19]
Reactant: O=S([O-])OO
Reactant: CC(C)(C)Sc1cccc(F)c1C(=O)NCCCl
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)S(=O)c1cccc(F)c1C(=O)NCCCl
Reaction time: 0.03 h
Yield: 98 %

Procedure:
A 0° C. solution of N-(2-chloroethyl)-2-fluoro-6-(1,1-dimethylethylthio)benzamide (2.0 g, 7.0 mmol) in methanol (50 mL) was combined with a 0° C. solution of OXONE® (4.24 g, 7.0 mmol) in water (50 mL). This mixture was stirred for 2 min, then was poured into 25% aq sodium metabisulfite (100 mL) and extracted with ether (3×100 mL). The combined organics were washed with brine followed with water, then were dried (MgSO4), concentrated, and purified by HPLC with 7:3 ethyl acetate/hexanes to afford 2.1 g of the title compound as a white solid, a 98% yield. m.p. 80-90° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([OH:17])=O.C1(C)C=CC=CC=1.[CH2:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:26].S(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:26][CH2:25][N:27]([C:15]([C:3]1[C:4](=[O:14])[N:5]([CH3:13])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([Cl:12])[C:11]=2[C:2]=1[OH:1])=[O:17])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cn1c(=O)c(C(=O)O)c(O)c2c(Cl)cccc21
Reactant: CCNc1ccccc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Temperature: 7.5 °C
Reaction time: 7 h
Yield: 64 %

Procedure:
The mixture of 1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid (1 gm) and toluene (50 ml) was cooled to 5-10° C. under nitrogen atmosphere. Pyridine (1.09 gm) was added to the resulting mass at 5-10° C. to form a clear solution. The solution was followed by the addition of N-ethyl aniline (0.52 gm) in one portion at 5-10° C. and then thionyl chloride (0.61 gm) was added at 5-10° C. The resulting mixture was stirred for 7 hours followed by evaporation of toluene under vacuum. The resulting residue was dissolved in ethyl acetate (25 ml) followed by washings with 5% sodium hydroxide solution (6.5 ml) at 25-30° C. The resulting aqueous layer was cooled to 10-15° C. followed by adjusting pH of the mass to 1 by using 18% aqueous hydrochloric acid solution (2.5 ml). The resulting mass was stirred for 1 hour at 10-15° C. The separated white colored solid was filtered and dried at 55-60° C. to yield 0.9 gm of laquinimod (HPLC Purity: 97.3%).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:10]=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[C:12]([O:18][CH2:19]Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:19][O:18][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([CH:10]=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C=O)[nH]1
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1ncc(C=O)n1COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 79.8 %

Procedure:
A suspension of 2-butylimidazol-5-aldehyde (16.9 g, 0.111 mol), chloromethyl pivalate (21.77 g, 0.145 mol), and potassium carbonate (20.07 g, 0.145) in 200 ml of dimethylformamide was stirred at ambient temperature under argon for four days. The solids were removed by filteration and washed with ether. The combined filtrates were partitioned between diethyl ether and water. The ether phase was washed successively with water and brine, dried over magnesium sulfate and concentrated under vaccum to give 23.6 g of 2-n-butyl-1-pivalyloxymethylimidazol-5-carboxaldehyde.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][OH:22].C(Cl)(Cl)[Cl:24]>>[ClH:24].[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[NH:17])[O:22][CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCCCCOc1cccc(CN2CCCCC2)c1
Reactant: ClC(Cl)Cl
Reactant: CO
Product: COC(=N)CCCCOc1cccc(CN2CCCCC2)c1
Product: Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5-[3-(Piperidinomethyl)phenoxy]pentanenitrile (1.73 g was dissolved in chloroform (20 ml). This solution was cooled to 0° C., which was followed by the addition of methanol (0.81 g). Dry hydrogen chloride gas was bubbled into the solution for 3 hours, which was then stored at 0° C. overnight. Chloroform was removed under reduced pressure to leave as an oily residue methyl 5-[3-(piperidinomethyl)phenoxy]pentaneimidate hydrochloride (1.3 g) which was not isolated. This was taken up in ethanol (20 ml) followed by the addition of orthophenylenediamine (0.41 g) and stirred at room temperature for 2 hours. Ethanol was removed under reduced pressure to leave an oily residue which was taken up in water, neutralised with potassium carbonate and extracted into chloroform (3×50 ml) and dried over magnesium sulphate, filtered, evaporated to low volume under reduced pressure and subjected to medium pressure liquid chromatography (ethyl acetate) to afford the title compound as a solid, m.p. 130°-131° C. (recrystallised from ethyl acetate).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[N:5]=[C:6]([O:13][Si](C)(C)C)[C:7]2[CH2:12][CH2:11][CH2:10][C:8]=2[N:9]=1.Br[CH2:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([O:27][CH3:28])=[O:26].O1CCOCC1.CO>CN(C=O)C>[CH3:28][O:27][C:25]([C:24]1[CH:23]=[C:22]([CH:31]=[CH:30][CH:29]=1)[CH2:21][N:9]1[C:8]2[CH2:10][CH2:11][CH2:12][C:7]=2[C:6](=[O:13])[NH:5][C:4]1=[O:3])=[O:26]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: C[Si](C)(C)Oc1nc2c(c(O[Si](C)(C)C)n1)CCC2
Solvent: CO
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c3c(c(=O)[nH]c2=O)CCC3)c1

Procedure:
Similarly, compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 3. Reaction of cyclopentanone with diethyl carbonate in THF in the presence of NaH produced ethyl 2-oxocyclopentanecarboxylate. Reaction of ethyl 2-oxocyclopentanecarboxy late with urea at 175-185° C. produced 6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione. Reaction of 6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione with hexamethyldisilazane (HMDS) in toluene in the presence of concentrated sulfuric acid, produced the intermediate 2,4-di(trimethylsilyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine. Reaction of 2,4-di(trimethylsilyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine with methyl 3-(bromomethyl)benzoate in DMF, followed by treatment with 1,4-dioxane and methanol, produced 1-(3-methoxycarbonylbenzyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione. Treatment of the ester with NaOH in water-methanol produced 1-(3-carboxybenzyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione. Coupling of the acid with a substituted amine, such as 1-(pyrimidin-2-yl)piperazine, in the presence of coupling agents, such as HATU and DIPEA in DMF, produced the targeted compound 1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][N:3]=1.[CH3:19][C:20]1(C)[C:24](C)(C)OB(C(C)=C)O1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(COC)OC>[N+:16]([C:5]1[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:7][C:2]([C:20]([CH3:24])=[CH2:19])=[N:3][CH:4]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cnc(Cl)cc1NCc1ccccn1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: C=C(C)c1cc(NCc2ccccn2)c([N+](=O)[O-])cn1

Procedure:
2-Chloro-5-nitro-N-(pyridin-2-ylmethyl)pyridin-4-amine E-2.17″ (125 mg; 0.47 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (200 μl; 1.06 mmol), cesium carbonate (300 mg; 0.90 mmol) and [1,1′-Bis[diphenylphosphino]-ferrocene]dichloropalladium (30 mg; 0.04 mmol) are suspended in 7.5 ml dimethoxyethane and 2.5 ml water and heated for 1 h at 100° C. The solvent of the reaction mixture is removed under reduced pressure and the crude product is purified using reversed phase chromatography (Method: prep. HPLC1).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[OH:14])(=[O:5])=[O:4].[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[N:24]=[C:25]=[S:26]>CN(C)C=O>[Cl:12][C:11]1[CH:10]=[CH:9][C:8]([NH:13][C:25]([NH:24][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:17]=2[Cl:16])=[S:26])=[C:7]([OH:14])[C:6]=1[S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4]
Reactant: S=C=Nc1cccc(Cl)c1Cl
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(Cl)c2Cl)c1O
Yield: 68.1 %

Procedure:
A solution of N,N-dimethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (356 mg, 1.42 mmol) and 2,3-dichlorophenylisothiocyanate (318 mg, 1.57 mmol) in 1.0 mL of N,N-dimethylformamide was stirred at room temperature for 3 hours. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (30/70, v/v) to give the desired product (440 mg, 68%). EI-MS (m/z) 455.5 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:10]=[C:11]([N+:14]([O-])=O)[NH:12][CH:13]=2)[CH2:4][CH2:3]1.CO.C1COCC1.CO.C(N1CCN(C2C=C(N[C:41]([C:43]3[C:44]4[N:45]=[CH:46][CH:47]=[N:48][C:49]=4[C:50]([C:53]4[C:62]5[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=5)[CH:56]=[N:55][CH:54]=4)=[CH:51][CH:52]=3)=[O:42])C=CC=2)CC1)C>[Ni].C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:10]=[C:11]([NH:14][C:41]([C:43]3[C:44]4[N:45]=[CH:46][CH:47]=[N:48][C:49]=4[C:50]([C:53]4[C:62]5[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=5)[CH:56]=[N:55][CH:54]=4)=[CH:51][CH:52]=3)=[O:42])[NH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)c2)CC1
Reactant: CN1CCN(Cc2c[nH]c([N+](=O)[O-])n2)CC1
Agent: [Ni]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCN(Cc2c[nH]c(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)n2)CC1

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1) instead of 2-nitroimidazole in Step 14.3, Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2, and 8-isoquinolin-4-yl-quinoxaline-5-carboxylic acid (Example 52) in Step 14.1. Title compound: ESI-MS: 479.0 [M+H]+; TLC: Rf=0.16 (DCM/MeOH, 9:1).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:30])[C:8]4[CH:20]=[C:19]([O:21][CH2:22][C@H:23]5[CH2:27][O:26]C(C)(C)[O:24]5)[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1>CO.C1COCC1.Cl>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:30])[C:8]4[CH:20]=[C:19]([O:21][CH2:22][C@H:23]([OH:24])[CH2:27][OH:26])[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)C(=O)c2c([nH]c4cc(Br)ccc24)C3(C)C)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)c2ccc(OC[C@H](O)CO)cc2C(=O)c2c1[nH]c1cc(Br)ccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
3-Bromo-9-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ3-1, 18.7 mg, 0.0398 mmol) was dissolved in methanol (1 mL) and THF (0.3 mL), added with 1 N hydrochloric acid (5 drops) and stirred at 50° C. for 1 hr. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residues were added with dichloromethane, and the solid was separated by filtration to obtain the title compound (yellow powder, 16.8 mg, 98%).
Reaction SMILES: N#N.Cl[CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[Cl:11][C:12]1[CH:13]=[C:14]([S:18][CH2:19][C:20]2[C:21]([C:26](N(OC)C)=[O:27])=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:15]=[CH:16][CH:17]=1.CCOC(C)=O>C1COCC1>[Cl:11][C:12]1[CH:13]=[C:14]([S:18][CH2:19][C:20]2[C:21]([C:26]([CH:4]3[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]3)=[O:27])=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CON(C)C(=O)c1ncccc1CSc1cccc(Cl)c1
Reactant: CN1CCC(Cl)CC1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(C(=O)c2ncccc2CSc2cccc(Cl)c2)CC1
Temperature: -40 °C
Reaction time: 1.25 h
Yield: 64 %

Procedure:
Anhydrous CeCl3 (1.1 g, 4.46 mmol) was placed in a 50 ml 2-necked flask and flamed out under vacuum. The vacuum was replaced with N2, and dry THF (20 ml) was added. The CeCl3/THF solution was stirred at room temperature for 16 hours and then cooled to -40° C., and the Mg-Grignard reagent from 4-chloro-1-methyl-piperidine (3 ml of an 0.8M stock solution in THF) was added. The resulting solution was stirred at -40° C. for 75 minutes, and then 3-[(3-chlorophenyl)thiomethyl]-N-methoxy-N-methyl-2-pyridinecarboxamide (345 mg, 1.07 mmol) was added dropwise. After 40 minutes, the mixture was poured into 5% HCI/EtOAc, stirred for 5 minutes, and then basified to pH ~8. The organic product was extracted with EtOAc (6×100 ml), the extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The product was chromatographed on silica and eluted with 5-10%MeOH/CH2Cl2 to afford [3-[(3-chlorophenyl)thiomethyl]-2-pyridinyl][1-methyl-4-piperidinyl]methanone (251 mg, 64%); HRMS, FAB, calcd. 361.1141; found. 361.1141.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH2:10][C:9]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[O:8][N:7]=1.C(N(CC)CC)C.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:13]2[CH2:14][CH2:15][C:9]3([O:8][N:7]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][N:3]=4)[CH2:10]3)[CH2:11][CH2:12]2)=[O:35])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: c1csc(C2=NOC3(CCNCC3)C2)n1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(NC(=O)N2CCC3(CC2)CC(c2nccs2)=NO3)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 52 %

Procedure:
Compound O (0.150 g, 0.578 mmol) was dissolved in toluene (15 ml) and mixed successively with triethylamine (0.12 ml, 0.867 mmol) and 4-tert-butylphenyl isocyanate (0.102 ml, 0.578 mmol). The reaction mixture was heated to boiling point and boiled under reflux for 3 h. After cooling to RT, the mixture was stirred for 36 h. The reaction mixture was extracted with EtOAc (3×20 ml). The combined organic phases were washed with sat. Na2HCO3 solution (10 ml), dried over Na2SO4 and concentrated to dryness under vacuum. After purification of the residue by column chromatography (hexane:EtOAc 1:1), the desired product was obtained in a yield of 52% (0.120 g).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1.CC([O-])=O.[K+].CC(O)=O>CO.O>[C:22]([O:21][CH2:20][C@H:18]1[O:19][C@@H:7]([N:6]2[C:5]3[CH:25]=[C:26]([Cl:30])[C:27]([Cl:29])=[CH:28][C:4]=3[N:3]=[C:2]2[Cl:1])[C@H:8]([OH:9])[C@@H:13]1[OH:14])(=[O:24])[CH3:23]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 42 (0.48 g, 1.0 mmol) and KOAc (0.49 g, 5.0 mmol) in MeOH/H2O (20 ml/2 mL) was stirred at room temperature for 24 h. AcOH (0.286 mL 5.0 mmol) was added and stirring was continued at room temperature for 15 min. The reaction mixture was evaporated and the residue was partitioned between H2O/CHCl3 (50 mL/50 mL). The CHCl3 layer was washed with sat. NaCl solution (50 mL), dried (Na2SO4), and evaporated. The residue was chromatographed on a silica column (1.9×20 cm, eluted with CHCl3, 1%, 2%, 4% MeOH/CHCl3). Evaporation of fractions 42-51 (15 mL per fraction) and recrystallization from MeOH gave 0.178 g (2 crops, 45%) of 42a as white crystals. MP: 82°-87° C. MS: (EI) m/e 393.9875 (20%, M+ =393.9890). 1H NMR (DMSO-d6): d 8.00, 7.96 (2×s, 2, 7-H and 4-H), 5.91 (d, 1, 1'-H, J1'-2' =7.5 Hz), 5.59 (d, 1, 2'-OH, J2'-2'OH =6.0 Hz), 5.45 (d, 1, 3'-OH, J3'-3'OH =4.5 Hz), 4.44 (dd, 1, 5'-H, J5'-4' =4.5 Hz, J5'-5" =12.5 Hz), 4.42 (m, 1, 2'-H, J2'-3' =6.0 Hz), 4.25 (dd, 1, 5"-H, J5"-4' =2.5 Hz), 4.17 (m, 1, 4'-H, J3'-4' =3.5 Hz), 4.11 (m, 1, 3'-H), 2.14 (s, 3, 5'-OAc). 13C NMR (DMSO-d6): d 169.95 (COCH3), 142.03 (C2), 140.92 (C3a), 132.30 (C7a), 125.96, 125.86 (C5 and C6), 120.28 (C4), 113.47 (C7), 89.32 (C1'), 82.63 (C4'), 71.41 (C2'), 69.03 (C3'), 63.35 (C5'). 20.56 (COCH3). Anal. Calcd. for C14H13Cl3N2O5 : C, 42.50; H, 3.31; N, 7.08. Found: C, 42.45; H, 3.20; N, 6.97.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].[C:6]([O:15]C)(=O)[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH2:9].[CH2:17]1[CH2:21]OC[CH2:18]1.[Cl-].[NH4+]>CCOC(C)=O>[NH2:9][C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[C:6]([OH:15])([CH2:18][CH2:17][CH3:21])[CH2:1][CH2:2][CH3:3]
Reactant: COC(=O)c1ccccc1N
Reactant: C1CCOC1
Reactant: CCC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCCC(O)(CCC)c1ccccc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
90.0 mL (180.00 mmol) of propylmagnesium chloride (2 M in ether) are added dropwise within 30 min. to a solution of 7.00 mL (54.04 mmol) methyl anthranilate in abs. THF (70 mL) at 0° C. The mixture is stirred for 1 h at RT and then combined with 100 mL 3 M aqueous ammonium chloride solution and EtOAc. The phases are separated and the aqueous phase is exhaustively extracted with EtOAc. The combined org. phases are washed with aqueous KHCO3 and sat. aqueous NaCl and dried with sodium sulphate. The crude product is used in the next reaction step without any further purification.