Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22](O)=[O:23])=[N:14]1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:22]([C:15]3[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][N:14]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1n[nH]c2ccccc12

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 1H-indazole-3-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 24H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.23-7.32 (m, 1H), 7.40-7.48 (m, 1H), 7.57-7.63 (m, 1 H), 8.20 (d, J=8.1 Hz, 1H). MS (DCI/NH3) m/z 297.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([O:17]C(=O)C1C=CC=CC=1)=[CH:11][C:10]=2[O:26][CH3:27])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:28][C:29]1[C:30]([CH3:36])=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]=1[CH3:36])=[CH:13][C:12]([OH:17])=[CH:11][C:10]=2[O:26][CH3:27])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)cc(OC(=O)c3ccccc3)cc2c1Cl
Reactant: Cc1cc(O)ccc1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cc(O)cc2c1Nc1ccc(O)cc1C
Yield: 69.8 %

Procedure:
3-Butyryl-4-chloro-6-benzoyloxy-8-methoxyquinoline (6.0 g) and 4-amino-m-cresol (2.0 g) were heated together under reflux in 1,4-dioxan (100 ml) for 2 hours. The solvent was evaporated and the residue heated on a steam bath in 10% methanolic potassium hydroxide for ten minutes. The solution was neutralized with 5M HCl and extracted several times with dichloromethane. The combined extracts were dried and evaporated to give 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-6-hydroxy-8-methoxyquinoline (4.0 g, 70%) m.p. 251°-253°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([S:26](Cl)(=[O:28])=[O:27])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].CCOC(C)=O>N1C=CC=CC=1.C1(C)C=CC=CC=1.CC(O)=O.O>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([S:26]([NH:15][C:12]2[S:13][CH:14]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:11]=2)(=[O:27])=[O:28])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1OC
Temperature: 25 °C
Reaction time: 23 h

Procedure:
4-(3-Nitrophenyl)thiazol-2-amine (1.10 g, 5.0 mmol) was dissolved in dry pyridine (16 mL) and then 3,4-dimethoxybenzene-1-sulfonyl chloride (1.323 g, 5.59 mmol) was added. The reaction mixture was stirred at room temperature for 23 h and then the pyridine was flashed off in vacuo with toluene. The residue was slurried with EtOAc and water. Full solution was achieved and then ice cold 1M NaOH was added. After thorough shaking, the aqueous phase was separated and the organic phase was twice extracted with 1M NaOH and then with water until no yellow color was extracted. The aqueous extract was combined with the NaOH solution and the solution was made slightly acidic with 3M HCl. The product was extracted into EtOAc, then washed successively with H2O and saturated NaCl solution. After drying over Na2SO4, the solvent was removed in vacuo to give a gum which contained HOAc. This was flashed off with toluene. The foam remained slowly solidified and after drying in vacuo, weighed 1.632 g (77.4%) and was greater than 95% pure by TLC. This material was taken up in hot EtOAc, diluted with about one-half the volume of hexane while hot which induced crystallization. The first crop weighed 1.352 g and was pure by TLC, but had no distinct melting point. Yield of pure material (TLC) was 64.2%.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](S(C)(=O)=O)[S:5][C:6]=1[C:7]#[N:8].[NH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1.C(N(CC)C(C)C)(C)C>CS(C)=O.C(OCC)(=O)C.O>[NH2:1][C:2]1[N:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[S:5][C:6]=1[C:7]#[N:8]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: CS(=O)(=O)c1nc(N)c(C#N)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(Nc2nc(N)c(C#N)s2)C1
Temperature: 120 °C

Procedure:
643 mg (3.17 mmol) of 4-amino-2-(methylsulfonyl)-1,3-thiazole-5-carbonitrile (Example 6A) were dissolved in 16 ml of DMSO, and 500 mg (2.11 mmol) of tert-butyl 3-aminopiperidine-1-carboxylate and 3.49 ml (21.12 mmol) of N,N-diisopropylethylamine were added. The mixture was heated in a microwave at 120° C. for 45 min. The reaction mixture was taken up in a mixture of ethyl acetate and water. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated on a rotary evaporator. The crude product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)(=[O:13])(=[O:12])[NH2:11]>>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:18][C:17]2[CH:19]=[CH:20][C:14]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1ccc(C=O)cc1
Product: Cc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-methylbenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a white powder (yield 91%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C>[CH3:26][S:23]([C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][CH:13]([CH2:12][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[O:14]2)=[CH:19][CH:18]=1)(=[O:24])=[O:25]
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc2c(c1)OC(CN1CCCCC1)CC2

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), piperidine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 309 (M+, 1), 131 (4), 99 (7), 98 (bp), 77 (3), 55 (5).
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[N:5][N:4]([CH3:8])[C:3]=1[C:9](Cl)=[O:10].OC=[C:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([C:25]3[CH:26]=[C:27]([NH:31]C(=O)C)[CH:28]=[CH:29][CH:30]=3)=[O:24])=[CH:20][CH:21]=2)[NH:16][C:15]1=[O:35]>C1COCC1>[O:35]=[C:15]1[CH2:14][C:22]2[C:17](=[CH:18][C:19]([C:23]([C:25]3[CH:26]=[C:27]([NH:31][C:9]([C:3]4[N:4]([CH3:8])[N:5]=[C:6]([CH3:7])[C:2]=4[Cl:1])=[O:10])[CH:28]=[CH:29][CH:30]=3)=[O:24])=[CH:20][CH:21]=2)[NH:16]1
Reactant: Cc1nn(C)c(C(=O)Cl)c1Cl
Reactant: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: Cc1nn(C)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)c1Cl
Temperature: 25 °C
Yield: 57.7 %

Procedure:
A dry 25 mL flask was charged with 4-Chloro-2,5-dimethyl-2H-pyrazole-3-carbonyl chloride (0.152 g, 0.794 mmol) and THF (2 mL). 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.200 g, 0.794 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 4 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo. The tan solids were washed with THF (˜3 mL) and filtered to afford the pure 4-Chloro-2,5-dimethyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.187 g, 0.458 mmol, 58%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2([CH3:28])[CH2:27][O:26][CH2:25]2)[CH:19]=[C:18]([CH3:29])[C:17]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36]O)[CH:31]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:29][C:18]1[CH:19]=[C:20]([O:22][CH2:23][C:24]2([CH3:28])[CH2:27][O:26][CH2:25]2)[CH:21]=[C:16]([CH3:15])[C:17]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[CH2:10][CH:9]3[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=2)[CH:31]=1
Reactant: COC(=O)C1CC1c1ccc(O)cc1
Reactant: Cc1cc(OCC2(C)COC2)cc(C)c1-c1cccc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)C1CC1c1ccc(OCc2cccc(-c3c(C)cc(OCC4(C)COC4)cc3C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
A solution of methyl 2-(4-hydroxyphenyl)cyclopropanecarboxylate (0.157 g, 0.816 mmol), (2′,6′-dimethyl-4′-[(3-methyloxetan-3-yl)methoxy]biphenyl-3-yl}methanol (0.231 g, 0.741 mmol) and tributylphosphine (0.298 g, 1.47 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.372 g, 1.47 mmol) was added, and the mixture was stirred at room temperature for 4 hr. Hexane (15 mL) was added to the reaction mixture, and the precipitated insoluble material was filtrated. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-40:60) to give the title compound (0.326 g, yield 82%) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+].[CH3:22][C:23]([CH3:25])=O>C(Cl)Cl>[CH:23]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[CH:6]=[CH:7][CH:8]=1)([CH3:25])[CH3:22]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cccc(CN)c1
Reactant: CC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])cc1-c1cccc(CNC(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
2-(3-Aminomethylphenyl)-4-nitroanisole (0.10 g, 0.39 mmol) was dissolved in anhydrous acetone (25 mL). The solution was distilled at atmospheric pressure until the volume was reduced to approximately 5 mL. The solution was then distilled under reduced pressure at room temperature to remove the last traces of acetone. The resultant oil was re-dissolved in CH2Cl2/MeOH (2 mL: 1 mL). Sodium borohydride (44 mg, 3 equiv) was added, and the reaction mixture stirred at room temperature for 2 h. The solution was then diluted with CH2Cl2 (10 mL), extracted with 1M NaOH (4×5 mL), dried (Na2SO4), and evaporated to afford 2-(3-(N-isopropylamino)methylphenyl)-4-nitroanisole (120 mg, 0.39 mmol, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[N:28]1[CH:32]=[CH:31][C:30](B(O)O)=[N:29]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:30]3[CH:31]=[CH:32][N:28]([CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27][O:22]4)[N:29]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1ccn(C2CCCCO2)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(C4CCCCO4)n3)c3cc(Br)cnc32)cc1

Procedure:
Using the same reaction conditions as described in step-i of example 1,5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 1) (100 mg, 0.209 mmol) was coupled with (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)boronic acid (103 mg, 0.524 mmol) using sodium carbonate (66 mg, 0.627 mmol) and Pd(PPh3)2Cl2 (7 mg, 0.0104 mmol) in DME/water (3/0.7 ml) to afford 60 mg (crude) product. MS: m/z=501.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[OH-].[Na+].[Br:11][CH2:12][C:13](Cl)=[O:14]>ClCCl>[Br:11][CH2:12][C:13]([N:4]1[CH2:5][CH2:6][CH2:7][C:2]([CH3:8])([CH3:1])[CH2:3]1)=[O:14]
Reactant: O=C(Cl)CBr
Reactant: CC1(C)CCCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1(C)CCCN(C(=O)CBr)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,3-dimethylpiperidine (250 mg) in dichloromethane (3 ml) was added an aqueous solution of 5N sodium hydroxide (1.1 ml), bromoacetyl chloride (0.2 ml) was added dropwise thereto on an ice bath, and the solution was stirred for 1 hour at room temperature. The solution was extracted with diethyl ether, then sequentially washed with an aqueous solution of 10% citric acid and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo to provide the title compound (420 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([NH2:12])[CH3:11].C(N(CC)CC)C.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([NH:12][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=1[C:21]([F:20])([F:31])[F:32])[CH3:11]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(N)Cc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(Cc1ccc(Cl)cc1Cl)NC(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
To a solution of crude [2-(2,4-dichlorophenyl)-1-methylethyl]amine (about 0.8 g, 3.9 mmol) and triethylamine (0.6 g, 5.9 mmol) in tetrahydrofuran (20 ml) was slowly added dropwise 2-trifluoromethylbenzoyl chloride (0.8 g, 3.8 mmol) at room temperature. After stirring at room temperature for 0.5 hr, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography and recrystallized from a mixed solvent of acetone/n-hexane to give a desired compound (white solid, yield; 0.4 g, 27%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.S([O-])([O-])(=O)=O.[Mg+2].[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][O:23][C:24]2=[O:29]>C(#N)C>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[N:19]/[C:20]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=2[CH2:22][O:23][C:24]3=[O:29])=[CH:5][CH:4]=1
Reactant: Nc1cccc2c1COC2=O
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: O=C1OCc2c(/N=C/c3ccc(C(F)(F)F)cc3)cccc21
Yield: 68.5 %

Procedure:
To a stirred mixture of 4-(trifluoromethyl)benzaldehyde (2.8 g, 16.1 mmol) and anhydrous Magnesium sulfate (16 g, 134 mmol) in anhydrous acetonitrile (200 mL) was added 4-aminoisobenzofuran-1(3H)-one (2 g, 13.4 mmol) at room temperature. After the addition, the mixture was stirred at reflux for overnight. The mixture was filtered and the cake was washed with ethyl acetate (50 mL×3). The filtrate was concentrated to give crude product. The crude product was washed with petroleum ether and re-crystallized from ethyl acetate to give the title compound (2.8 g, yield: 68%). LC-MS (ESI) m/z: 306 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[C:6]([N+:16]([O-])=O)[C:5]=1[S:19][C:20]#[N:21].N>C(O)(=O)C.O.[Fe]>[CH3:1][O:2][C:3]([C:4]1[C:5]2[S:19][C:20]([NH2:21])=[N:16][C:6]=2[CH:7]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:9]=1)=[O:22]
Reactant: COC(=O)c1cc(-c2cccnc2)cc([N+](=O)[O-])c1SC#N
Agent: [Fe]
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2cccnc2)cc2nc(N)sc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.2 %

Procedure:
A solution of 3-Nitro-5-pyridin-3-yl-2-thiocyanato-benzoic acid methyl ester (1.1 g, 3.49 mmol) in glacial acetic acid (23 ml) was treated with iron powder (0.97 g, 17.5 mmol) and stirred at ambient temperature for 16 h. The resultant mixture was diluted with water (200 ml) and made alkaline by the addition of concentrated ammonia solution. The mixture was filtered and the filtrate extracted with ethyl acetate (3×200 ml). The filtered solid was extracted with boiling ethanol (3×250 ml) and the combined organic fractions evaporated to dryness to give 2-Amino-5-pyridin-3-yl-benzothiazole-7-carboxylic acid methyl ester as an off-white solid (0.46 g, 46%).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH:26][CH2:25]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:25]2
Reactant: Brc1ccc2c(c1)CNC2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC1COc2c(N3Cc4ccc(Br)cc4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 27.2 %

Procedure:
142 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 150 mg of 5-bromoisoindoline, 114 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 63 mg of the target compound.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[N:18]([C:24]1[CH:25]=[N:26][CH:27]=[C:28]([S:30][CH3:31])[CH:29]=1)[CH2:17][CH2:16]2.[OH-].[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[N:18]([C:24]1[CH:25]=[N:26][CH:27]=[C:28]([S:30]([CH3:31])=[O:9])[CH:29]=1)[CH2:17][CH2:16]2
Reactant: CSc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)c1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.7 %

Procedure:
MCPBA (17.3 mg, 0.1 mmol) was added into a solution of 6-chloro-2-(5-methylsulfanyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (example 59) (30.5 mg, 0.1 mmol) in DCM (2 mL). The reaction mixture was stirred at RT for 2 hours before it was neutralized with 5% aq. NaOH and extracted with DCM (5 mL, 2×). The organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give title compound (6 mg, 19%) as a white solid. MS: 321.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:11]=3[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.[CH:23](Br)([CH3:25])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+].[NH4+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][C:11]=3[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:7]=1
Reactant: CC(C)Br
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2ccc(OC(C)C)cc12
Temperature: 60 °C
Reaction time: 20 h
Yield: 82 %

Procedure:
Ethyl 2-(4-chlorophenyl)-5-hydroxybenzofuran-3-carboxylate (26 g, 0.051 mol) in NMP (160 mL) was added isopropyl bromide (15 mL), then cesium carbonate (33 g, 0.101 mol) was added. The reaction mixture was stirred in a 60° C. oil bath for 20 hrs then cooled to ambient temperature. The reaction mixture was treated with 5% ammonium solution and stirred for 15 min. This mixture was then diluted with water and extracted with hexane. The organic layer was washed with water, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl 2-(4-chlorophenyl)-5-isopropoxybenzofuran-3-carboxylate (15 g, 82%).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][CH:7]=[C:6]([Br:12])[CH:5]=2.S(=O)(=O)(O)[OH:14].O1CCOCC1>O>[Br:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]([CH3:11])[C:2](=[O:14])[NH:3]2)=[CH:8][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1c(Br)[nH]c2cc(Br)ccc12
Solvent: O
Solvent: C1COCCO1
Product: CC1C(=O)Nc2cc(Br)ccc21

Procedure:
To 2,6-dibromo-3-methyl-1H-indole (15.7 g) were added 3N aqueous sulfuric acid solution (100 ml) and dioxane (100 ml), and the mixture was refluxed for 5 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. This ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give the title compound (11.2 g) as a brown crystal.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][S:4][CH:3]1[C:8](OCC)=O.[CH3:13][S:14][C:15](=[NH:17])[NH2:16].[OH-].[K+].[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+].[H-].[Na+].C[O-].[Na+].[O-]CC.[Na+]>CN(C)C=O.C(O)(C)C.C(O)C.CO>[CH3:13][S:14][C:15]1[N:17]=[CH:8][C:3]2[S:4][CH2:5][CH:6]=[CH:7][C:2]=2[N:16]=1
Reactant: CCOC(=O)C1SCCCC1=O
Reactant: CSC(=N)N
Agent: CC[O-]
Agent: C[O-]
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: CCO
Solvent: CO
Product: CSc1ncc2c(n1)C=CCS2

Procedure:
According to the above reaction scheme, ethyl 3-oxotetrahydrothiopyran-2-carboxylate is reacted with S-methylisothiourea in the presence of a basic catalyst such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium hydride, sodium methoxide, sodium ethoxide and the like, in a solvent such as methanol, ethanol, isopropyl alcohol, N,N-dimethylformamide to produce a 2-methylthio-thiopyranopyrimidine compound (V), and the resulting compound (V) is then heated under acidic conditions, preferably in a mixture of acetic acid and water to produce a 2,4-dihydroxythiopyranopyrimidine compound (VI). Subsequently, the resulting 2,4-dihydroxy compound (VI) is reacted with phosphorus oxychloride in the absence or presence of a tertiary amine such as N,N-dimethylaniline, N,N-diethylaniline and the like to obtain the starting material of the formula (III).