Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[NH2:25][C:26]([CH3:30])([CH3:29])[C:27]#[N:28].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:25][C:26]([C:27]#[N:28])([CH3:30])[CH3:29])=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(Cl)cc21
Reactant: CC(C)(N)C#N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C#N)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 22 %

Procedure:
A mixture of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.07 g, 0.3 mmol), 2-amino-2-methylpropanenitrile hydrochloride (0.05 g, 0.42 mmol), EDCI (0.057 g, 0.3 mmol), DMAP (0.037 g, 0.3 mmol), and DIPEA (0.163 g, 1.26 mmol) in 10 mL of DMF were stirred at room temperature for 5 hours. Then HATU (0.114 g, 0.3 mmol) was added, the final reaction mixture was stirred for additional 15 hours. The solvent was removed under reduced pressure at 70° C., then the residue was triturated with water and ethyl acetate successively then decanted and dried to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(2-cyanopropan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.026 g, 31%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([N:24]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH2:26][CH2:25]3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:34]([F:37])([F:36])[F:35]>Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22]([N:24]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH2:26][CH2:25]3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:34]([F:36])([F:37])[F:35]
Reactant: COCN(c1cc(Cl)cnc1C(=O)N1CCOc2ccccc21)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)N1CCOc2ccccc21
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A solution of 4-chloro-N-[5-chloro-2-(2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (50 mg) in 3 mL HCl (4 M in dioxane) and water (1 mL) was refluxed for 2 h. Upon cooling to room temperature, the mixture was concentrated and the residue was purified via preparative TLC (50% EtOAc in hexane) to afford 4-chloro-N-[5-chloro-2-(2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (27.0 mg) as an off white solid. MS m/z: 532.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl>[C:30]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[S:14]([N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)(=[O:16])=[O:15])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1[nH]c2c(N)cccc2c1S(=O)(=O)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc2c(S(=O)(=O)N3CCOCC3)c(C(N)=O)[nH]c12
Reaction time: 2 h

Procedure:
To a solution of 7-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 7 (52 mg, 0.16 mmol) in 1 mL of dichloromethane at 0° C. was added triethylamine (0.067 mL, 0.91 mmol) and acetic anhydride (0.058 mL, 0.52 mmol). After two hours, the mixture was partitioned between ethyl acetate and 3N HCl solution, and the organic layer was washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled compound. HRMS (ES) exact mass calculated for C15H18N4O5SNa (M+Na+): 389.0890. Found 389.0889.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:18]3[CH2:19][C@H:20]4[CH2:33][C@H:21]4[C:22]=3[N:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:24]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:18]3[CH2:19][C@H:20]4[CH2:33][C@H:21]4[C:22]=3[N:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:24]=2)=[O:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nn(-c3ccc(F)cc3F)c3c2C[C@H]2C[C@@H]32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CCNCC1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
4-{[(1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.218 mmol) was dissolved in 20% TFA/DCM (3 mL). The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated, and the residue was purified by cation exchange resin to give the title compound (66 mg). LCMS m/z=359.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.48 (td, J=4.2 and 3.6 Hz, 1H), 1.10-1.17 (m, 1H), 1.49-1.55 (m, 2H), 1.97-2.05 (m, 2H), 2.06-2.12 (m, 1H), 2.22-2.29 (m, 1H), 2.78 (t, J=11.1 Hz, 2H), 2.95 (d, J=16.5 Hz, 1H), 3.03 (dd, J=16.4 and 6.2 Hz, 1H), 3.11-3.19 (d, J=11.9 Hz, 2H), 3.97-4.05 (m, 1H), 6.85 (d, J=8.1 Hz, 1H), 6.98-6.74 (m, 2H), 7.61-7.67 (m, 1H).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[F:11][C:12]([F:26])([F:25])[C:13]1[CH:14]=[C:15]([CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[F:26][C:12]([F:11])([F:25])[C:13]1[CH:14]=[C:15]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([CH:1]=[O:3])[CH2:20]2)[CH:16]=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1cccc(C2CCCNC2)c1
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=CN1CCCC(c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 151.5 %

Procedure:
3.8 g of mixed formic acid-acetic acid anhydride were added to a solution of 9.8 g of 3-(m-trifluoromethylphenyl)-piperidine in 100 ml of anhydrous benzene and the mixture was stirred for 15 minutes at room temperature and was then poured into 100 ml of aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic extracts were washed with aqueous sodium chloride, dried over magnesium sulfate and evaporated to dryness to obtain 10 g of 3-(m-trifluoromethylphenyl)-1-piperidine-carboxaldehyde in the form of a colorless resin which was used as is for the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.Cl.[CH3:26][N:27]([CH3:44])[CH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:32]5[CH:33]=[CH:34][C:29]([CH2:28][N:27]([CH3:44])[CH3:26])=[CH:30][CH:31]=5)=[CH:3][CH:4]=4)[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)Cc1ccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)cc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A solution of 4-(4-bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.256 mmol) in dioxane (1.5 mL) was treated with the HCl salt of N,N-dimethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (0.281 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (10 mg), and 2M aq potassium carbonate (0.767 mmol). The reaction mixture was purged with nitrogen, sealed, and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH˜4 using 1N aq HCl and was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, treated with Si-Thiol (Silicycle, 20 mg), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (20-50% acetonitrile/water+0.1% NH4OH) to afford the title compound as a beige amorphous solid (28%). MS(ES)+ m/e 446.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([CH:12]=O)=[N:11][C:4]=2[NH:3]1.[CH3:14][O:15][C:16]1[N:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[N:26]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][CH:31]([NH2:35])[CH2:32]2)=[N:27]1.[BH4-].[Na+].[OH-].[Na+]>CN(C=O)C.CO>[CH3:14][O:15][C:16]1[N:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[N:26]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][CH:31]([NH:35][CH2:12][C:10]3[CH:9]=[CH:8][C:5]4[O:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=4[N:11]=3)[CH2:32]2)=[N:27]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(N)C4)c2n1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(NCc3ccc5c(n3)NC(=O)CO5)C4)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.5 %

Procedure:
To a solution of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (153 mg, 0.858 mmol) in DMF (1.36 mL) was added 2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (84.4 mg, 0.286 mmol). The reaction mixture was stirred overnight at RT. NaBH4 (37.6 mg, 0.572 mmol) was then added and the suspension was stirred for 1 h at RT. The reaction mixture was diluted with CH3OH and poured into 1 N NaOH. The organic layer was separated, washed with brine (4×), dried (Na2SO4), filtered, and concentrated. The crude material was purified by basic reverse phase HPLC to provide 4.6 mg (3.5%) of the title compound. MS (ESI): exact mass calculated for C24H23N7O3, 457.19; m/z found, 458.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.09 (s, 1H), 8.75 (d, J=5.1, 1H), 8.25 (d, J=9.1, 1H), 8.14 (d, J=5.1, 1H), 7.19 (d, J=8.0, 1H), 7.17 (d, J=9.1, 1H), 6.95 (d, J=8.0, 1H), 4.62 (s, 2H), 4.09 (s, 3H), 3.92 (s, 2H), 3.09-2.98 (m, 3H), 2.83-2.77 (m, 1H), 2.56 (dd, J=14.6, 7.9, 1H), 2.17-2.14 (m, 1H), 1.89-1.82 (m, 1H), 1.24 (s, 1H).
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[O:13][CH:14]=[C:15]([C:17]([OH:20])([CH3:19])[CH3:18])[N:16]=2)[N:7]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:3][C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[O:13][CH:14]=[C:15]([C:17]([OH:20])([CH3:18])[CH3:19])[N:16]=2)[N:7]=1
Reactant: CC(C)(O)c1coc(Cn2ncc([N+](=O)[O-])n2)n1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(C)(O)c1coc(Cn2ncc(N)n2)n1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-(2-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)oxazol-4-yl)propan-2-ol (2.40 g, 10.75 mmol), iron powder (1.82 g, 32.25 mmol) and NH4Cl (2.90 g, 53.76 mmol) in a mixture of EtOH (70 mL) and water (35 mL) was stirred at 85° C. for 15 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (110 mL) was added followed by 1N NaOH (65 mL). The layers were separated and the aq. layer was extracted with CH2Cl2 (5×50 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 06: tR=0.35 min; [M+H]+=224.00.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:24].[CH:25](/B(O)O)=[CH:26]\[CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][S:11][C:9]2[N:8]=[C:7]3[C:3]([N:4]=[CH:5][N:6]3[CH3:24])=[C:2](/[CH:25]=[CH:26]/[CH3:27])[N:10]=2)=[CH:14][C:15]=1[N+:21]([O-:23])=[O:22]
Reactant: COc1ccc(CSc2nc(Cl)c3ncn(C)c3n2)cc1[N+](=O)[O-]
Reactant: C/C=C/B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C/C=C/c1nc(SCc2ccc(OC)c([N+](=O)[O-])c2)nc2c1ncn2C
Yield: 86.3 %

Procedure:
6-chloro-2-(4-methoxy-3-nitrobenzylsulfanyl)-9-methyl-9H-purine (100 mg, 0.273 mmol) was dissolved in dimethoxyethane (4 ml), then trans-propenylboronic acid (70 mg, 0.815 mmol) and tetrakis(triphenylphosphine)palladium (0) (30 mg, 0.025 mmol) were added. Then 106 mg (1.0 mmol) of sodium carbonate dissolved in water (2 ml) was added, and the mixture was heated to reflux for 2 hours. After cooling it, the insolubles were filtered off with Celite, the filtrate was distilled away under reduced pressure, ethyl acetate (20 ml) and water (20 ml) were added to the residue and extraction was performed. After washing with water, drying was carried out with anhydrous magnesium sulfate, the insolubles were filtered off, the filtrate was distilled away under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: methanol=50:1) to obtain 2-(4-methoxy-3-nitrobenzylsulfanyl)-9-methyl-6-(1-trans-propenyl)-9H-purine (87.5 mg, 86%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[NH2:6].[ClH:13].[H][H]>[Pd].C(O)C>[ClH:13].[CH3:1][S:2][C:3]1[CH:4]=[C:5]([NH2:6])[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: CSc1cc(N)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CSc1cc(N)ccc1N

Procedure:
In a Paar hydrogenation bottle, a mixture of 3-methylthio-4-nitroaniline (7.7 g), 5% Pd/C catalyst (8.0 g), concentrated hydrochloric acid (7 ml) and ethanol (200 ml) is treated with hydrogen at 3.43 kg/cm2 for 45 minutes (until 0.8 kg/cm2 hydrogen is absorbed). The mixture is filtered through diatomaceous earth and the filtrate evaporated to dryness afford 3-methylthio-p-phenylenediamine hydrochloride. The salt is dissolved in water, the solution made alkaline (pH 9-10) with 50% sodium hydroxide and the diamine extracted with methylene chloride (3×150 ml). The combined extracts are dried over magnesium sulfate and evaporated to dryness to afford 4.75 g of title product, a brown solid, which is used as is.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][O:14][C:15](=[O:41])/[CH:16]=[CH:17]/[C:18]1[CH:19]=[C:20]2[C:37](=[CH:38][CH:39]=1)[O:36][C:23]1([CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]1)[CH2:22][C:21]2=[O:40]>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:41])/[CH:16]=[CH:17]/[C:18]1[CH:19]=[C:20]2[C:37](=[CH:38][CH:39]=1)[O:36][C:23]1([CH2:24][CH2:25][N:26]([CH2:2][CH2:3][C:4]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[NH:6][CH:5]=3)[CH2:27][CH2:28]1)[CH2:22][C:21]2=[O:40]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: BrCCc1c[nH]c2ccccc12
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3c[nH]c4ccccc34)CC1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
TEA (0.46 ml, 3.3 mmol) and 3-(2-bromoethyl)-1H-indole (193 mg, 0.863 mmol) were added to a suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester hydrochloride (220 mg, 0.66 mmol, Intermediate 1) in DCM (5 ml), and the mixture was stirred at RT overnight. DCM was evaporated and the residue was dissolved in DMF and heated at 60° C. overnight. The mixture was partitioned between water and AcOEt and the aqueous phase was extracted with DCM. The collected organic phases were dried over Na2SO4 and evaporated. The crude mixture was purified by column chromatography (eluent:DCM/MeOH/NH4OH 94:6:0.2) to give (E)-3-{1′-[2-(1H-indol-3-yl)ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (130 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+]([O-])=O)=[CH:4][C:3]=1[CH2:11][C:12]([NH:14][C:15]1[CH:33]=[CH:32][CH:31]=[CH:30][C:16]=1[O:17][C:18]1[CH:19]=[C:20]([C:27]([OH:29])=[O:28])[C:21](=[CH:25][CH:26]=1)[C:22]([OH:24])=[O:23])=[O:13].COC(=O)C1C(=CC(OC2C=CC=CC=2NC(=O)CC2C=C([N+:63]([O-:65])=[O:64])C=CC=2Cl)=CC=1)C(OC)=O>O>[N+:63]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([NH:14][C:15]1[CH:33]=[CH:32][CH:31]=[CH:30][C:16]=1[O:17][C:18]1[CH:19]=[C:20]([C:27]([OH:29])=[O:28])[C:21](=[CH:25][CH:26]=1)[C:22]([OH:24])=[O:23])=[O:13])([O-:65])=[O:64]
Reactant: O=C(Cc1cc([N+](=O)[O-])ccc1Cl)Nc1ccccc1Oc1ccc(C(=O)O)c(C(=O)O)c1
Reactant: COC(=O)c1ccc(Oc2ccccc2NC(=O)Cc2cc([N+](=O)[O-])ccc2Cl)cc1C(=O)OC
Solvent: O
Product: O=C(Cc1ccccc1[N+](=O)[O-])Nc1ccccc1Oc1ccc(C(=O)O)c(C(=O)O)c1

Procedure:
4-{2-[2-(2-Chloro-5-nitrophenyl)acetylamino]phenoxy}phthalic acid (Compound 175) from 4-{2-[2-(2-chloro-5-nitrophenyl)acetylamino]phenoxy}phthalic acid dimethyl ester as white crystals (yield: 26 mg (74%)). Mp: 176-178.2° C. LC/MS: m/e 470 (MH+), 453 (MH+-H2O).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]=[C:8](Cl)[S:7][N:6]=1)[CH:2]=[CH2:3].NC(N)=[S:13].O1CCCC1>O>[CH2:1]([S:4][C:5]1[N:9]=[C:8]([SH:13])[S:7][N:6]=1)[CH:2]=[CH2:3]
Reactant: NC(N)=S
Reactant: C=CCSc1nsc(Cl)n1
Solvent: O
Solvent: C1CCOC1
Product: C=CCSc1nsc(S)n1
Reaction time: 8.5 h
Yield: 57.4 %

Procedure:
A mixture of 3-allylthio-5-chloro-1,2,4-thiadiazole (15.0 g), thiourea (5.95 g), tetrahydrofuran (45 ml) and water (15 ml) was gently boiled for 8.5 hours at 65° C. The reaction mixture was post-treated according to conventional manner to give powder of 3-allylthio-1,2,4-thiadiazole-5-thiol (8.5 g), mp. 107° to 108° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2=[O:23])[C@H:15]2[C@H:6]1[C@@H:7]1[C:12]([CH2:13][C@H:14]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][Si](C(C)(C)C)(C)C)=[CH:11][C:10](=[O:41])[CH2:9][CH2:8]1)(=[O:3])[CH3:2].S(=O)(=O)(O)O>CO.C(OCC)(=O)C>[C:1]([O:4][C@@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2=[O:23])[C@H:15]2[C@H:6]1[C@@H:7]1[C:12]([CH2:13][C@H:14]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])=[CH:11][C:10](=[O:41])[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2[C@H](CCCCCCCCCO[Si](C)(C)C(C)(C)C)CC3=CC(=O)CC[C@@H]3[C@H]21
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2[C@H](CCCCCCCCCO)CC3=CC(=O)CC[C@@H]3[C@H]21
Reaction time: 2.5 h
Yield: 98.6 %

Procedure:
19.9 g of 11α-acetoxy-7α-(9-tert-butyldimethylsilyloxynonyl)-estr-4-ene-3,17-dione in 90 ml of methanol is mixed at room temperature with 20 ml of 8% sulfuric acid. After 2.5 hours, it is diluted with ethyl acetate, washed neutral with saturated sodium bicarbonate solution and water and dried. The chromatography of the crude product on silica gel with a methylene chloride-acetone gradient yields 15.8 g of 11α-acetoxy-7α-(9-hydroxynonyl)-estr-4-ene-3,17-dione as a foam.
Reaction SMILES: [CH:1]([S:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].S([O-])([O-])(=O)=O.[Na+].[Na+].CCOC(C)=O>C1COCC1>[CH:1]([S:4][C:5]1[C:6]([CH2:7][OH:8])=[CH:10][CH:11]=[CH:12][N:13]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Sc1ncccc1C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Sc1ncccc1CO
Reaction time: 0.5 h
Yield: 67 %

Procedure:
2-Isopropylsulfanyl-nicotinic acid obtained in Step A was dissolved in THF (50 mL), and the solution was cooled to 0˜5° C. LAH (3.06 g, 80.55 mmol) was added thereto slowly, and the mixture was stirred at 0˜5° C. for 30 minutes and then at room temperature for 2 hours. After the termination of the reaction, saturated sodium sulfate aqueous solution was added thereto and the mixture was stirred for 30 minutes. After the addition of EtOAc, solid material was removed by using cellite. The organic layer was dried with MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc/Hex=1/3) to obtain the title compound (3.94 g, 67%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:6]=1[F:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1.[OH-].[Li+].[OH-].[Na+].Cl>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:22][C:20]2[N:19]([C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[CH:25]=[CH:26][CH:27]=[N:28]4)[N:18]=[C:17]([CH3:16])[CH:21]=2)(=[O:13])=[O:12])=[CH:7][C:6]=1[F:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1F
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Li+]
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)c(F)c2)n(-c2cccc3ncccc23)n1
Temperature: 85 °C
Yield: 6.4 %

Procedure:
A mixture of 4-t-butyl-3-fluorobenzene-1-sulfonyl chloride (0.075 g, 0.30 mmol), 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.050 g, 0.22 mmol), and DMAP (0.027 g, 0.22 mmol) in pyridine (1 mL) was heated at 85° C. for 2.5 h with stirring. After cooling to room temperature, 1 M aqueous lithium hydroxide (1 mL) and 1 M aqueous sodium hydroxide (1 mL) were added to the reaction mixture. The resulting mixture was stirred at room temperature for 15 h and neutralized with 1 N aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with aqueous saturated sodium bicarbonate, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude residue was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.006 g, 0.014 mmol, 6%). 1H NMR (400 MHz, CD3OD) δ 8.83 (dd, J=1.6, 4.4 Hz, 1H), 8.08 (dd, J=1.2, 8.4 Hz, 1H), 7.79 (dd, J=7.2, 8.4 Hz, 1H), 7.69 (ddd, J=0.8, 1.6, 7.6 Hz, 1H), 7.44 (dd, J=1.2, 7.2 Hz, 1H), 7.40-7.31 (m, 3H), 7.20 (dd, J=1.6, 7.2 Hz, 1H), 5.88 (s, 1H), 2.21 (s, 3H), 1.39 (s, 9H); MS: (ES) m/z calculated for C23H24FN4O2S [M+H]+ 439.2. found 439.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[C:24]([F:23])([F:33])[F:34])=[O:22])=[CH:18][CH:19]=1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccccc4C(F)(F)F)cc3)c2)o1

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 2-trifluoromethylbenzylamine using method N. NMR; δH [2H6]—DMSO 9.23,(1H, t), 8.04,(2H, d), 7.91,(1H, dd), 7.78,(1H, d), 7.75,(1H, d), 7.67,(1H, t), 7.56,(4H, m), 7.49,(1H, t), 4.70,(2H, d), 2.57,(3H, s),2.33,(3H, s). LCMS; retention time 3.58 min, MH+ 452.