Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([NH:51][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C:3]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=2[Cl:1])[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: O=C(O)c1ccccc1Oc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A solution of 2-(2,4-dichlorophenoxy)benzoic acid (AMR01067, 1.24 g, 4.39 mmol) in dry DCM (20 mL) was stirred under nitrogen, and 4-dimethylaminopyridine (DMPA, 40 mg, 0.327 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 2.5, 13.18 mmol) and triethylamine (0.6 mL) were added. The resulting mixture was stirred for 30 min under nitrogen and 4-aminopiperidine-1-carboxylic acid tert-butyl ester (AMR01068, 0.88 g, 4.39 mmol) in dry DCM (410 mL) was added. After stirring at room temperature for 48 h, the mixture was diluted with DCM, washed with HCl (1M, 3×25 mL), water, saturated NaHCO3 (2×25 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated. Flash chromatography on silica gel of the crude product using DCM/MeOH 99:1 as eluenty gave 4-[2-(2,4-dichlorophenoxy)benzoylamino]piperidine-1-carboxylic acid tert-butyl ester (953 mg, 40%) as white solid. Rf: 0.64 (DCM/MeOH 9:1) 1H NMR (270 MHz, CDCl3) δ 1.48 (9H, s, 3CH3), 1.92 (2H, m, CH2), 2.92 (2H, br t, CH2), 3.95 (2H, br d, CH2), 4.11 (1H, m, CH), 6.78 (1H, dd, J=8.2, 1.0 Hz, ArH), 6.87 (1H, d, J=8.9 Hz, ArH), 7.21 (1H, dd, J=8.6, 2.5 Hz, ArH), 7.25 (1H, m, ArH), 7.35 (1H, br s, NH), 7.40 (1H, m, ArH), 7.50 (1H, d, J=2.5 Hz, ArH) and 8.17 (1H, dd, J=7.9, 2.0 Hz, ArH). LC/MS (APCI) tr=5.36 min, m/z 467.36 (18), 465.41 (M++H, 30), 411.33 (67), 409.38 (M+-C4H8, 100). HPLC tr=2.93 min (97.22%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:43]=[C:44]([F:46])[CH:45]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:44]1[CH:43]=[C:4]([CH:3]=[C:2]([F:1])[CH:45]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cc(F)cc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc3[nH]cc(-c4cnn(Cc5cc(F)cc(F)c5)c4)c3c2)cc1NS(C)(=O)=O
Yield: 16.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl)methane sulfonamide (105 mg, 0.1582 mmol) was hydrolyzed by lithium hydroxide (34 mg, 0.791 mmol) in THF/methanol/water (15/7.5/4 ml) to yield 13 mg of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.556-8.551 (d, 2H), 8.51-8.50 (d, 1H), 8.28 (s, 1H), 7.98 (s, 1H), 7.76-7.75 (m, 2H), 7.64-7.76 (dd, 1H), 7.22-7.20 (d, 1H), 6.94-6.84 (m, 2H), 5.44 (s, 2H), 3.99 (s, 3H), 2.99 (s, 3H). MS: m/z=510.1 (M+1), HPLC: 98.06% in method B.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:14]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])([O-:16])=[O:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C.C(O)(=O)C>[N+:14]([C:17]1[CH:18]=[C:19]([NH:20][CH:10]2[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]2)[CH:21]=[CH:22][CH:23]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc([N+](=O)[O-])c2)C1
Reaction time: 10 h
Yield: 57.5 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-3-pyrrolidinone (220 mg) and 3-nitroaniline (164 mg) in methylene chloride (3 mL), sodium triacetoxyborohydride (375 mg) and acetic acid (67 μL) were added at room temperature, and the mixture was stirred at the same temperature for 10 hours. To the reaction mixture, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 50% hexane in ethyl acetate) to obtain tert-butyl 3-((3-nitrophenyl)amino)pyrrolidine-1-carboxylate (C23, 210 mg).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)=[O:7].[CH3:21][NH:22][CH3:23]>O1CCCC1>[CH3:21][N:22]([CH3:23])[CH2:2][CH2:3][O:4][CH2:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)=[O:7]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)COCCBr)C1
Solvent: C1CCOC1
Product: CN(C)CCOCC(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A solution of (S)-3-[2-(2-bromoethoxy)acetyl]amino-1-(tert-butoxycarbonyl)pyrrolidine (195 mg) prepared in Step C in tetrahydrofuran (2 ml) was added with dimethylamine (2 M solution in tetrahydrofuran, 4.5 ml, Aldrich) at 0° C., and the mixture was stirred at room temperature for 23 hours. The volatile components were evaporated under reduced pressure, and the residue was added with saturated aqueous sodium hydrogencarbonate, and extracted five times with chloroform. The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (180 mg).
Reaction SMILES: [NH:1]([CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].O>ClCCl>[CH3:30][S:31]([N:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)=[O:10])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CNc1ccccc1)Nc1ccc(-c2ccncc2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)N(CC(=O)Nc1ccc(-c2ccncc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-anilino-N-[4-(4-pyridinyl)phenyl]acetamide (40.0 mg) in dichloromethane (0.80 mL) were added pyridine (0.0533 mL) and methylsulfonyl chloride (0.0204 mL) at 0° C. and the mixture was stirred at ambient temperature for 2 days. Water (4.0 mL) was added to the mixture at ambient temperature and the mixture was extracted with ethyl acetate (6.0 mL). The organic layer was washed successively with saturated sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (4% methanol in chloroform) to afford 2-[(methylsulfonyl)(phenyl)amino]-N-[4-(4-pyridinyl)phenyl]acetamide (31.4 mg) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[C:6]2[NH:13][CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1.[H-].[Na+].[CH3:23]O.CN([CH:28]=[O:29])C>>[F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[C:6]2[N:13]([CH2:23][O:29][CH3:28])[CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: CO
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ccc(Oc2ncnc3cc[nH]c23)c(F)c1
Agent: [H-]
Agent: [Na+]
Product: COCn1ccc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a suspension of 243 (150 mg, 0.547 mmol in DMF (6 mL) was added NaH (66 mg, 1.64 mmol). and the reaction mixture was stirred at 0° C. for 1 hour. Chloromethyl methyl ester (132 mg, 1.641 mmol) was added drop wise and the mixture was stirred at room temperature over night. MeOH (2 mL) was added and the mixture was stirred for an additional hour and partitioned between EtOAc and water. The organic phase was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford title compound 244 (86 mg, 49% yield, crude) as an orange solid. MS (m/z): 319.1 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]([CH:19]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=3[F:39])[C:20](=[O:31])NCC(OC(OC)=O)(C)C)[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1.CC(C)([O-])C.[K+]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:19]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=4[F:39])[C:20](=[O:31])[CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]3=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)CC(=O)N(c1ccc2[nH]cnc2c1)C(C(=O)NCC(C)(C)OC(=O)OC)c1cccc(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)C1C(=O)C(c2cccc(F)c2F)N(c2ccc3[nH]cnc3c2)C1=O

Procedure:
The compound was synthesized starting from ethyl 2-[(1H-benzo[d]imidazol-5-yl)[2,3-difluorophenyl({2-[(methoxycarbonyl)oxy]-2-methylpropyl}carbamoyl)-methyl]-carba-moyl]acetate (which may be prepared in accordance with the procedure described for Intermediate 2; 0.134 g, 0.245 mmol) and potassium tert.-butoxide solution (1M, 0.49 ml, 0.49 mmol) according to the method described in step 2.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.O.[NH2:10][NH2:11]>C(O)C>[CH3:8][C:5]1[N:4]=[N:3][C:2]([NH:10][NH2:11])=[CH:7][CH:6]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc(NN)nn1
Yield: 80 %

Procedure:
To a suspension of 3-chloro-6-methyl-pyridazine (3 g, 23.3 mmol) in ethanol (45 mL) was added hydrazine hydrate (45 mL) and the resultant mixture was heated to reflux for 3 hrs. Most of the solvent was removed under reduced pressure and the white solid was collected by filtration and washed with ethanol. Upon drying 2.3 g of (6-methyl-pyridazin-3-yl)-hydrazine was obtained as a white crystalline solid (80% yield).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:9](=[O:12])([O-])[O-:10].[K+].[K+].Cl[CH2:16]Cl>O>[CH3:16][O:10][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]1)=[O:12]
Reactant: ClCCl
Reactant: O=C([O-])[O-]
Reactant: OCC1CCNCC1
Agent: [K+]
Solvent: O
Product: COC(=O)N1CCC(CO)CC1
Temperature: 5 °C
Yield: 90 %

Procedure:
4-Hydroxymethylpiperidine (47.6 g, 1.0 eq) and water (300 mL) were charged to a flask. The resulting mixture was cooled to 0-10° C. Potassium carbonate (85.7 g, 1.5 eq) dissolved in water (150 mL) and methyl chloro formate (38.4 mL, 1.1 eq) were added while maintaining the temperature at below 10° C. When the addition was complete, the reaction mixture was warmed up to 20-30° C. for 1 hour. After the reaction was complete, dichloromethane (500 mL) was added to the reaction mixture. The organic layer was collected and washed with 1 M phosphoric acid solution (200 mL), saturated sodium bicarbonate solution (200 mL) and saturated sodium chloride solution (200 mL). The organic layer was dried over sodium sulfate (50 g, 1 w/w eq) and then distilled under vacuum to produce the title intermediate. (67.0 g, 90% yield)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]1)=[O:12])C(OCC)=O)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.[Cl-].[Na+].O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:11](=[O:12])[CH:13]1[CH2:14][CH2:15][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:17][CH2:18]1)[CH3:2]
Reactant: CCCC1CCC(C(=O)C(C(=O)OCC)C(=O)OCC)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCCC1CCC(C(=O)CC(=O)OCC)CC1
Yield: 83.1 %

Procedure:
A solution of 3.0 g (9.6 mmol) 2-(4-propyl-cyclohexanecarbonyl)-malonic acid diethyl ester and 0.3 g p-toluenesulfonic acid in 30 mL water was heated to reflux for 3 hr and allowed to stand at room temperature over 3 nights. The reaction was diluted with brine, extracted with ethyl acetate, dried over MgSO4, and concentrated to afford 1.92 g (7.98 mmol) 3-oxo-3-(4-propyl-cyclohexyl)-propionic acid ethyl ester as a clear oil.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:25]N)[CH:22]=[CH:23][CH:24]=1>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:20]=1[C:3]([S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)=[C:2]([CH3:15])[NH:25]2
Reactant: CC(=O)CSc1cccc(CC(=O)O)c1
Reactant: COc1cccc(NN)c1
Agent: Cl
Product: COc1cccc2[nH]c(C)c(Sc3cccc(CC(=O)O)c3)c12

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: [3-(2-oxo-propylsulfanyl)-phenyl]-acetic acid and 3-methoxyphenylhydrazine hydrochloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][N:10]2[C:29](=[O:30])[N:13]3[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[CH:16]=[CH:17][C:12]3=[N:11]2)[CH:3]=1.[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH:31]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][N:10]3[C:29](=[O:30])[N:13]4[CH:14]=[C:15]([C:18]5[CH:19]=[CH:20][C:21]([O:24][C:25]([F:27])([F:28])[F:26])=[CH:22][CH:23]=5)[CH:16]=[CH:17][C:12]4=[N:11]3)[CH:3]=2)[CH2:33][CH2:32]1
Reactant: OB(O)C1CC1
Reactant: O=c1n(CCc2cc(Br)ccn2)nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1n(CCc2cc(C3CC3)ccn2)nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12
Temperature: 100 °C
Yield: 81.1 %

Procedure:
A mixture of 2-(2-(4-bromopyridin-2-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (synthesized according to Example 1, 40 mg, 0.084 mmol), cyclopropyl boronic acid (22 mg, 0.25 mmol), dppf(Pd)Cl2 (9.0 mg, 0.013 mmol), potassium carbonate (46 mg, 0.33 mmol) in degassed dioxane (1 mL) was heated at 100° C. for 3 hours. The reaction was concentrated and the residue was purified by reverse phase HPLC to provide compound 57 as a white powder (30 mg, 81% yield). C23H19F3N4O2, m/z (ESI)=441.1 [M+H]+.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[CH2:10][S:11][C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][C:18]([O:23][CH3:24])=[CH:17][CH:16]=3)=[O:8])C.Cl>O1CCCC1.O>[CH3:24][O:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]1[S:11][CH2:10][C:9]([C:7]([OH:8])=[O:6])=[CH:22][C:21]2=1
Reactant: CCOC(=O)C1=Cc2c(cnc3ccc(OC)cc23)SC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2ncc3c(c2c1)C=C(C(=O)O)CS3
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
Lithium hydroxide monohydrate (731 mg, 17.42 mmol, 15.0 eq) is added at room temperature to a stirred solution of 6-methoxy-2H-1-thia-9-aza-phenanthrene-3-carboxylic acid ethyl ester (350 mg, 1.16 mmol, 1.0 eq) in tetrahydrofuran (5 mL) and water (5 mL). After 2 hours stirring at room temperature, the reaction mixture is acidified until pH=6 with a 1N hydrochloric acid aqueous solution and the resulting precipitate is collected by filtration, dried under vacuum to afford 6-methoxy-2H-1-thia-9-aza-phenanthrene-3-carboxylic acid as a yellow solid (280 mg, 88% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([N:14]3[CH:18]=[CH:17][CH:16]=[N:15]3)[CH:10]=[N:11]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[N:14]1([C:9]2[CH:10]=[N:11][C:12]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[C:4]([NH2:1])[CH:13]=3)[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: O=[N+]([O-])c1ccc2cc(-n3cccn3)cnc2c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2cc(-n3cccn3)cnc2c1
Yield: 63.5 %

Procedure:
A methanol (10 ml) solution containing 7-nitro-3-(1H-pyrazol-1-yl)quinoline (36 mg) was prepared and subjected to a hydrogenation reaction (80° C.; 50 bar; flow rate: 1 ml/min; 10% Pd/C) using H-cube™. Thereafter, the solvent was distilled away under reduced pressure, and a purple solid of 3-(1H-pyrazol-1-yl)quinolin-7-amine (20 mg) was thus obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[NH:13][CH:12]=2)=[O:10])[CH2:3]1.ClCCl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CN(C=O)C>CCOC(C)=O>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[NH:13][CH:12]=2)=[O:10])[CH2:3]1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4CCCC(O)C4)c3n2)c2ccc(Cl)cc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4CCCC(=O)C4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.3 %

Procedure:
A 25 mL round-bottom flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-hydroxy-cyclohexyl) amide (22 mg, 0.052 mmol) and dichloromethane (5 mL). Dess-Martin periodinane (34.0 mg, 0.08 mmol) was added in one portion to the reaction mixture. The reaction mixture was placed under Ar and stirred for 2 h at room temperature. DMF (1.5 mL) was added and the reaction mixture was stirred for an additional 18 h. The reaction mixture was diluted to 100 mL with EtOAc and washed with sat NaHCO3 (3×20 mL). The crude white precipitate was filtered and reserved. The organic layer was dried over Na2SO4 and concentrated in vacuo to give a crude solid. The combined crude solids were triturated with EtOAc (1×20 mL) then purified by chromatography over SiO2 with MeOH/dichloromethane (gradient: 0%-5% MeOH) to afford 6 mg (27%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-oxo-cyclohexyl)-amide as a white solid. MS: [M+H]+=423, 1H NMR (300 MHz, DMSO-d6) δ: 12.89 (br. s., 1H), 9.09 (s, 1H), 8.47 (s, 1H), 8.42 (d, J=8.7 Hz, 1H), 8.16 (d, J=7.6 Hz, 1H), 8.01 (d, J=1.5 Hz, 1H), 7.39 (dd, J=8.7, 1.9 Hz, 1H), 4.23-4.41 (m, 1H), 4.18 (s, 3H), 2.69-2.78 (m, 1H), 2.58 (d, J=10.2 Hz, 1H), 2.42 (dd, J=11.1, 5.9 Hz, 1H), 2.17-2.34 (m, 2H), 1.96-2.08 (m, 1H), 1.80-1.93 (m, 1H), 1.65-1.80 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[S:17][C:16]3[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=3[C:14]=2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:29]([O-])([O-])=O.[K+].[K+].CI.[Na+].[Cl-]>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([C:13]2[S:17][C:16]3[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=3[C:14]=2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:29])(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)c1c(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)sc2c1CCCC2
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CC(C)=O
Product: CN(c1sc2c(c1C(=O)OC(C)(C)C)CCCC2)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 40 °C

Procedure:
tert-Butyl 2-(3,4-dichlorophenylsulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (21.64 g, 46.8 mmol) was dissolved in acetone (200 ml), and K2CO3 (12.9 g, 93.6 mmol) was added thereto. Methyl iodide (5.83 ml, 93.6 mmol) was then added, and the suspension was heated overnight at 40° C. After cooling to room temperature, water and saturated NaCl solution were added and the product was extracted with ethyl acetate. The organic phase was dried (sodium sulfate) and the product was purified by crystallization from methanol.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH3:6]>C(Cl)Cl>[CH:4]1[CH:3]=[C:2]([CH2:6][C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)[NH:1][CH:5]=1
Reactant: Cc1ccc[nH]1
Solvent: ClCCl
Product: c1c[nH]c(Cc2ccc[nH]2)c1
Yield: 2.1 %

Procedure:
Then 200 mL of CH2Cl2 was added to the reaction mixture and diluted, then rinsed by NaOH aqueous solution. Solvent was removed using a rotary evaporator, and the dipyrromethane product was purified over a silica gel column to give 1-(2,3,4,5,6-pentafluoro-1,1,-(2-pyrryl)methane (6.16 g, 97%). The dipyrromethane (99 μL, 0.8 mmol) thus obtained and 2,3,4,5,6-pentafluoro-benzaldehyde (250 mg, 0.8 mmol) were dissolved in CH2Cl2 (20 mL) in a 50 mL round-bottom flask under nitrogen atmosphere and was added 20 μL of 2.5M trifluoroborane etherate (BF3OEt2). After 2 hours, DDQ (280 mg) was added and the solution was stirred for one day. The solvent was removed using a rotary evaporator and the expanded porphyrin products were separated by a column chromatography. As shown in FIG. 2, only the expended polyphyrins with even pyrrole subunits were formed and the separation process was facilitated significantly. Yields of the expanded porphyrins are shown in Table 2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2.O.O1CCC[CH2:28]1>CO>[CH3:28][O:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2
Reactant: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cn3)cc(O)c2[nH]1
Reactant: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cn3)cc(OC)c2[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of methyl 7-hydroxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylate (3.12 g) in a mixture of tetrahydrofuran (30 mL) and methanol (5 mL) was added dropwise 2M trimethylsilyldiazomethane diethyl ether solution (4.3 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, 2M trimethylsilyldiazomethane diethyl ether solution (8.0 mL) was added dropwise to the mixture again, and the mixture was stirred at 0° C. for 2.5 h. Furthermore, 2M trimethylsilyldiazomethane diethyl ether solution (4.0 mL) was added dropwise to the mixture, and the mixture was stirred at room temperature for 1 h. To quench the reaction, 6M hydrochloric acid (9 mL) was added to the mixture. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual solid was washed with diethyl ether to give the title compound (2.78 g, 86%) as a brown solid. MS 377 (MH+).
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[N+:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=1)([O-:9])=[O:8]>ClCCCl>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:16]=[C:2]=[O:3])=[O:15])=[CH:17][CH:18]=1)([O-:9])=[O:8]
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 17 h

Procedure:
48 ml of oxalyl chloride were added batchwise to a solution of 50 g of 4-nitrobenzamide in 1.2 l of 1,2-dichloroethane and the reaction mixture was boiled for 17 hours with reflux. For workup, the reaction mixture was concentrated and the remaining residue distilled under a high vacuum. 56 g of 4-nitrobenzoylisocyanate were obtained as colorless crystals.