Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.CCOC(C)=O>C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Oc1cccc(F)c1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Fc1cccc(Oc2cncc(Cl)n2)c1
Yield: 92 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (250 mg, 1.69 mmol) and 3-fluorophenol (166 μL, 1.86 mmol, d=1.25 g/mL), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (347 mg). Yield: 92%. 1H NMR (250 MHz, DMSO-d6) δ 7.13-7.17 (m, 2H, Harom 4+6), 7.25 (d, 1H, Harom 2, JF=10.0 Hz), 7.52 (q, 1H, Harom 5, J=8.1 Hz), 8.54 (s, 1H, HPz 5), 8.56 (s, 1H, HPz 3). m/z: 224.0 [(M)+, calcd for C10H6ClFN2O 224.0].
Reaction SMILES: C1([C@H]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])C)C=CC=CC=1.[S:21]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)([OH:24])(=[O:23])=[O:22]>C(O)C.[Pd]>[S:21]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)([OH:24])(=[O:23])=[O:22].[NH2:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)[C@H]1CCCC[C@H]1N[C@H](C)c1ccccc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)[C@H]1CCCC[C@H]1N
Reaction time: 20 h
Yield: 81 %

Procedure:
10% Pd/C (Degussa, 50% wet, 0.87 g) was carefully wetted down under argon with ethanol, then (1S,2R)-ethyl 2-((R)-1-phenylethylamino)cyclohexane-carboxylate, tosylic acid (8.7 g, 19.4 mmol) in ethanol (75 mL) was added. The mixture was then hydrogenated for 20 hours at 50 psi in a Parr shaker apparatus. Under argon, the catalyst was filtered off. The filtrate was resubjected to hydrogenation, this time with 1.70 grams of 10% Pd/C (Degussa, 50% wet). After 6 hours, the reaction was analyzed by LCMS, which detected little change. Under argon, the reaction was carefully filtered through a fiberglass filter paper. The filtrate was concentrated to give a colorless oil. The oil was resubjected to 10% Pd/C (Degussa, 50% wet, 1.70 grams) in 50 mL of ethanol and hydrogenated for 20 hours at 50 psi. Under argon, the reaction was carefully filtered through a fiberglass filter paper. The filtrate was concentrated to give (1S,2R)-ethyl 2-aminocyclohexanecarboxylate tosylic acid (5.4 g, 15.7 mmol, 81% yield) as a colorless oil. MS (ESI+)=172.16 (M+H)+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:43][NH2:44]>C(O)C.ClCCl.[Cl-].[Na+].O>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH:43][NH2:44])=[O:30])[C:24]=2[CH:33]=1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(=O)NN)noc3c2F)C[C@H](C)O1
Yield: 72.2 %

Procedure:
Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204, 0.5 g, 0.85 mmol) in 4.5 ml ethanol was treated with anhydrous hydrazine (0.490 ml, 15.60 mmol) at room temperature for 2 hour. Reaction was diluted with dichloromethane and brine. Organic layer washed with water, dried over sodium sulfate, and concentrated. The residue purified on silica-gel column (elution 40% etoac in hexanes) to give 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carbohydrazide (0.354 g, 72.5%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:36](O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]1([NH2:46])[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH2:45].N1(O)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(=O)(O)[O-].[Na+]>[NH:45]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:46]=[C:36]1[C@@H:10]1[CH2:11][C@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9]1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: Nc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](c3nc4ccccc4[nH]3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.2 %

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (265 mg), phenylenediamine (54 mg), 1H-benzotriazol-1-ol (95 mg) and N,N-diisopropylethylamine (259 μl) were dissolved in DMF (5 ml), WSC.HCl (144 mg) was added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was is dissolved in acetic acid (5 ml), and the mixture was stirred at 80° C. for 5 hr. The mixture was cooled to room temperature, and the reaction mixture was concentrated. To the residue was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (115 mg).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([NH:22]C(=O)OC(C)(C)C)[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.ClCCCl.FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([NH2:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: CC(C)n1nc(NC(=O)OC(C)(C)C)nc1-c1cn2c(n1)-c1ccc(F)cc1OCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1ccc(F)cc1OCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 11.9 %

Procedure:
tert-Butyl 5-(9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-ylcarbamate (0.200 mg, 0.47 mmol) was dissolved in 1,2-Dichloroethane (3 mL, 40 mmol) and trifluoroacetic acid (3 mL, 40 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours. Complete reaction was confirmed by LCMS and the reaction mixture concentrated in vacuo. The crude solid was purified by HPLC to give 253 (18.3 mg, 12% yield)
Reaction SMILES: F[C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:18]([OH:20])=[O:19])=[CH:8][N:9]2[C@@H:14]2[CH2:16][C@@H:15]2[F:17])=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C:30]1([C@@H:34]2[CH2:38][CH2:37][NH:36][CH2:35]2)[CH2:33][CH2:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>CS(C)=O>[C:22]([O:26][C:27]([NH:29][C:30]1([C@@H:34]2[CH2:38][CH2:37][N:36]([C:2]3[C:11]([O:12][CH3:13])=[C:10]4[C:5]([C:6](=[O:21])[C:7]([C:18]([OH:20])=[O:19])=[CH:8][N:9]4[C@@H:14]4[CH2:16][C@@H:15]4[F:17])=[CH:4][CH:3]=3)[CH2:35]2)[CH2:31][CH2:32][CH2:33]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CCC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1c(N2CC[C@@H](C3(NC(=O)OC(C)(C)C)CCC3)C2)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 80 °C
Reaction time: 112 h

Procedure:
A mixture of 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (290 mg, 0.98 mmol), 3-(R)-[1-(tert-butoxycarbonylamino)cyclobutyl]pyrrolidine (283 mg, 1.18 mmol), triethylamine (0.409 ml, 2.94 mmol), and dimethyl sulfoxide (5 ml) was stirred for 112 hours while heating in an oil bath at 80° C. under an argon-replaced atmosphere. After evaporating the solvent, the residue was partitioned in chloroform (50 ml) and 10% aqueous citric acid solution (30 ml), and after separating the organic layer, the organic layer was washed with saturated saline solution (30 ml). The organic layer obtained was then dried over anhydrous sodium sulfate, and after removing the drying agent by filtration, the solvent was evaporated under a reduced pressure. The residue was subject to a silica gel chromatography and a crude 7-{3-(R)-[1-(tert-butoxycarbonylamino)cyclobutyl]pyrrolidin-1-yl}-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was thereby obtained from a chloroform:methanol=20:1 eluate.
Reaction SMILES: C1(C[O:8][C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([O:19][C@H:20]3[CH2:24][CH2:23][O:22][CH2:21]3)[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])C=CC=CC=1>C1COCC1.C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][C@H:20]2[CH2:24][CH2:23][O:22][CH2:21]2)[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(O[C@H]2CCOC2)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1cc(O)cc(O[C@H]2CCOC2)c1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
Methyl 3-[(phenylmethyl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (25.0 g, 76.2 mmol) was dissolved in THF (150 mL) and ethanol (150 mL). 10% Palladium on carbon (30 mg) was added and the mixture placed under a hydrogen atmosphere and left to stir at RT until the reaction was complete. The catalyst was removed by filtration through diatomaceous earth and the filtrate was concentrated in vacuo to give an orange oil which crystallised on standing. The solid was filtered off and washed with diethyl ether to give the desired product as a white solid (13.75 g).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:10]=[C:9]([OH:11])[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[Na+].[Na+].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>CN(C)C=O>[CH3:18][S:19]([O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([S:4][CH2:1][CH2:2][CH3:3])[N:10]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCCSc1cccc(O)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCSc1cccc(OS(C)(=O)=O)n1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
3.4 g of 6-n-propylthio-2-pyridinol and 2.2 g of anhydrous sodium carbonate were suspended in 25 ml of N,N-dimethylformamide, followed by stirring. 2.4 g of methanesulfonyl chloride was added dropwise to the suspension at 10° C. After the addition, the bath was removed and the resulting mixture was allowed to stand to raise the temperature of the mixture to room temperature. The mixture was heated to 50° C. and stirred for 2.5 hours. The reaction mixture was poured into 200 ml of chilled water and extracted with ether twice. The ether layer was washed with 5% aqueous caustic soda solution and water and dried over anhydrous sodium sulfate. The residue obtained by distilling away the solvent was purified by silica gel column chromatography (with toluene and n-hexane) to obtain 3.9 g of 6-n-propylthio-2-pyridyl methanesulfonate as a pale yellow oil (yield: 78.8%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:29])([CH3:28])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[NH:10][C:11]=2[C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:15][C:12]1[C:11]2[NH:10][CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[C:8]([CH3:29])([CH3:28])[CH2:7][C:6]=2[C:5]([C:3]([OH:4])=[O:2])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(Cl)c2c1CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Cc2c(C(=O)O)ccc(Cl)c2NC1c1cccc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.8 %

Procedure:
To a stirred mixture solution of 8-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (200 mg, 0.5 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 8-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (180 mg, 90%) as a light yellow solid: LC/MS m/e calcd for C22H25ClN2O3 (M+H)+: 401.91, observed: 401.1.
Reaction SMILES: O=[C:2]([CH3:11])[CH2:3][CH:4]1[C:9](=O)[CH2:8][CH2:7][O:6][CH2:5]1.Cl.[NH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:11][C:2]1[N:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]2[CH2:8][CH2:7][O:6][CH2:5][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CN
Reactant: CC(=O)CC1COCCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)cc2c1CCOC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.8 %

Procedure:
3-(2-oxopropyl)dihydro-2H-pyran-4(3H)-one (0.41 g, 2.63 mmol) in dichloromethane (3 ml) was stirred at room temperature, and ethyl 2-aminoacetate hydrochloride (0.366 g, 2.63 mmol) was added, followed by sodium bicarbonate (0.441 g, 5.25 mmol). The resulting mixture was stirred at 25° C. for 15 hours, after which TLC showed that the reaction was complete. DCM was added, the organic layer was separated, washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel using an automated Biotage system, EtOAc/Hexane 5-30%, to give the desired product (0.41 g, yield 70%). 1H NMR (400 MHz, CDCl3) δ (ppm) 5.69 (s, 1H), 4.62 (s, 2H), 4.44 (s, 2H), 4.21 (q, 2H), 3.95-3.94 (m, 2H), 2.58-2.55 (m, 2H), 2.18 (s, 3H), 1.28 (t, 2H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]([OH:26])[CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:3]=1.[CH2:33]([C:35]1[NH:36][C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[N:39]=1)[CH3:34].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:33]([C:35]1[N:36]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH:12]([OH:26])[CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:17][CH2:18]4)[N:8]3[CH3:11])=[C:4]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:3]=2)[C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[N:39]=1)[CH3:34]
Reactant: Cn1c(C(O)C2CCN(C(=O)OC(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(O)C3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Temperature: 140 °C
Yield: 69.1 %

Procedure:
A mixture of tert-butyl 4-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)(hydroxy)methyl)piperidine-1-carboxylate (0.375 g, 0.803 mmol), 2-ethylbenzimidazole (0.182 g, 1.23 mmol), Xphos (0.040 g, 0.084 mmol), Pd2(dba)3 (0.040 g, 0.042 mmol) and cesium carbonate (0.52 g, 1.67 mmol) in DMF (4.0 mL) was heated in a Biotage microwave at 140° C. for 30 minutes. The reaction mixture was then filtered through paper and then partitioned between brine and EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (0-5% MeOH in DCM) to give the title compound (0.32 g, 69%). LCMS m/z: 577.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:15]([C:16]([O:18]C)=[O:17])C3C=C(C=CC(OC)=O)C=C(OC)C=3O2)[CH:6]=[CH:7][C:8]=1[O:9]C.CC(C)=O.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[OH:9])[CH:11]=[CH:15][C:16]([OH:18])=[O:17]
Reactant: COC(=O)C=Cc1cc(OC)c2c(c1)C(C(=O)OC)C(c1ccc(OC)c(OC)c1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(C=CC(=O)O)ccc1O
Yield: 330.9 %

Procedure:
1 g of methyl 3-[2-(3,4-dimetoxyphenyl)-7-methoxy-3-methoxycarbonyl-2,3-dihydro -1-benzofuran-5-yl]prop-2-enoate, 10 mL of acetone and 2.5 mL of water were mixed and stirred to dissolve. Then, 3% NaOH (6 mL) was added to the mixture and stirred for 0.5 hr. After reaction completed, the mixture was acidified and purified by chromatography on silica gel column with a 1:2:0.8 V/V mixture of petroleum ether, ethyl acetate and acetic acid as eluent. After removing solvent, it gave 1.5 g yellow solid of 5-[(E)-2-carboxyethenyl]-2-(3,4-dimetoxyphenyl)-2,3-dihydro-7-methoxy-3-benzofurancarboxylic acid (IM2).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1Cl)[C:14]([OH:16])=[O:15])(=[O:10])=[O:9].Cl.N([O-])=O.[Na+].O(CC)C([S-])=[S:28].[K+].[OH-].[Na+]>O>[C:14]([C:13]1[CH:17]=[CH:18][C:19]2[S:28][C:2]3[C:3]([S:8](=[O:10])(=[O:9])[C:11]=2[CH:12]=1)=[CH:4][CH:5]=[CH:6][CH:7]=3)([OH:16])=[O:15]
Reactant: CCOC(=S)[S-]
Reactant: Nc1ccccc1S(=O)(=O)c1cc(C(=O)O)ccc1Cl
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1S2
Reaction time: 0.25 h

Procedure:
3-(o-Aminophenylsulphonyl)-4-chlorobenzoic acid (6.00 g) was stirred with concentrated hydrochloric acid (8.0 ml) and water (12.0 ml) and treated at 0°-5° C. with a solution of sodium nitrite (1.50 g) in water (30 ml) over 30 min. After a further 15 min. stirring the suspension was pipetted into a solution of potassium ethyl xanthate (10.2 g) and sodium hydroxide (1.60 g) in water (50 ml) at 45°-50° C. Vigorous nitrogen evolution took place. After the addition was complete the now clear solution was heated to boiling and further sodium hydroxide (3.20 g) was added. Boiling was continued for a further 20 min., and the solution then cooled, filtered and acidified with hydrochloric acid. The solid precipitated acid was filtered off, washed with water, and recrystallised from acetic acid to give 3-carboxythianthrene-5,5-dioxide, m.p. 297°-304° C.; on further recrystallisation from ehtanol it had m.p. 302°-305° C.
Reaction SMILES: [NH2:1][CH:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[OH:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].N1C=CN=C1.C1CCC(N=C=NC2CCCCC2)CC1>CCOC(C)=O>[OH:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH:1][CH:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:17]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(N)CNC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: CC(CNC(=O)OC(C)(C)C)NC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
To a solution of tert-butyl 2-aminopropylcarbamate (3.6 g, 20.6 mmol), 2-hydroxybenzoic acid (2.79 g, 20.6 mmol) and imidazole (1.41 g, 20.6 mmol) in EtOAc (100 mL) at 0° C. was slowly added a solution of DCC (4.26 g, 20.6 mmol) in EtOAc (50 mL). The reaction mixture was stirred (RT, 16 h), filtered and concentrated under reduced pressure. The crude product was purified by silica chromatography, EtOAc/Petroleum ether (0-20%) to afford tert-butyl 2-(2-hydroxybenzamido)propylcarbamate (2.4 g, 40%) as a white solid.
Reaction SMILES: C([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:6]=2[C:5]=1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(O)=O.Cl>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[CH3:14][O:13][C:12]1[C:6]2[C:5]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:4][S:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc2sc(C(=O)O)c(CCc3ccccc3)c12
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: COc1cccc2scc(CCc3ccccc3)c12
Temperature: 25 °C
Yield: 89.6 %

Procedure:
A suspension of 2-carboxy-4-methoxy-3-(2-phenylethyl)benzo[b]thiophene (1 g) and a catalytic amount of copper powder in quinoline (15 mL) was stirred at 200° C. for 2 hours. The reaction mixture was cooled to room temperature and poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give the title compound (0.77 g).
Reaction SMILES: NCC1C=CC=C(C)C=1N.[NH2:11][C:12]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:13]=1[C:14]([NH2:16])=O>>[NH2:16][CH2:14][C:13]1[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:12]=1[NH2:11]
Reactant: Cc1ccc(N)c(C(N)=O)c1
Agent: Cc1cccc(CN)c1N
Product: Cc1ccc(N)c(CN)c1

Procedure:
The title compound was prepared in analogy to a) (2-aminomethyl-6-methyl-phenylamine) from 2-amino-5-methylbenzamide.
Reaction SMILES: N[C:2]1C=CC2N=CSC=2C=1.[S:11]1[C:22]2[C:14](=[CH:15][CH:16]=[C:17]3[C:21]=2[C:20](=[O:23])[C:19](=[O:24])[NH:18]3)[N:13]=[CH:12]1.[CH:25]1[C:30]([NH:31][NH2:32])=[CH:29][CH:28]=[C:27]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:26]=1.Cl>>[S:11]1[C:22]2[C:14](=[CH:15][CH:16]=[C:17]3[C:21]=2[C:20](=[O:23])[C:19](=[O:24])[NH:18]3)[N:13]=[CH:12]1.[CH3:2][NH:36][S:33]([C:27]1[CH:26]=[CH:25][C:30]([NH:31][N:32]=[C:20]2[C:21]3[C:17](=[CH:16][CH:15]=[C:14]4[C:22]=3[S:11][CH:12]=[N:13]4)[NH:18][C:19]2=[O:24])=[CH:29][CH:28]=1)(=[O:34])=[O:35]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: Nc1ccc2ncsc2c1
Agent: Cl
Agent: O=C1Nc2ccc3ncsc3c2C1=O
Product: CNS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc4ncsc4c32)cc1

Procedure:
6H-1-Thia-3,6-diaza-as-indacene-7,8-dione was prepared from 6-aminobenzothiazole according to Procedure A: 1H NMR (DMSO-d6): δ 7.10 (d, J=8.4 Hz, 1H), 8.31 (d, J=8.5 Hz, 1H), 9.35 (s, 1H), 11.19 (s, 1H); ESI-MS m/z 204 (M)−. The title compound was prepared from 6H-1-thia-3,6-diaza-as-indacene-7,8-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: mp>260° C.; 1H NMR (DMSO-d6): δ 2.39 (d, J=5.1 Hz, 3H), 7.12 (d, J=8.4 Hz, 1H), 7.32 (q, J=5.1 Hz, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.76 (d, J=8.7 Hz, 2H), 7.99 (d, J=8.6 Hz, 1H), 9.30 (s, 1H), 11.26 (s, 1H), 12.69 (s, 1H); APCI-MS m/z 387 (M)−. Anal. Calcd for C16H13N5O3S2.0.33H2O: C, 48.85; H, 3.50; N, 17.80; S, 16.30. Found: C, 48.89; H, 3.40; N, 17.67; S, 16.23.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.C[C@H](C(O)=O)C1C=CC2C=C(OC)C=CC=2C=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=[CH2:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Agent: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Product: C=C(C(=O)O)c1ccc2cc(OC)ccc2c1

Procedure:
Using the method described in Example 1 b) 2-(6-methoxy-2-naphthyl)-propionic acid or naproxen in DL-form was obtained from 2-(6-methoxy-2-naphthyl)-propenoic acid.