Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.NO.C([N:6](C(C)C)C(C)C)C.C(O)C.C(OC(=O)[NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:32]=2)=[CH:26][N:25]=1)=S)C>CO>[C:41]([O:40][C:38](=[O:39])[NH:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([O:30][C:27]2[CH:28]=[CH:29][C:24]3[N:25]([N:6]=[C:21]([NH2:20])[N:23]=3)[CH:26]=2)[CH:32]=1)([CH3:42])([CH3:43])[CH3:44]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)OC(C)(C)C)c2)cn1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(N)nn3c2)c1
Temperature: 60 °C
Yield: 83.9 %

Procedure:
To a solution of hydroxylamine hydrochloride (4.34 g, 62.4 mmol) and N-ethyl-N-isopropylpropan-2-amine (12.7 mL, 72.8 mmol) in methanol (70 mL)/ethanol (70 mL) was added ethyl{[(5-{3-[(tert-butoxycarbonyl)amino]phenoxy}pyridin-2-yl)amino]carbonothioyl}carbamate (4.50 g, 10.4 mmol), and the mixture was stirred with heating at 60° C. for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (500 mL), and washed with water (200 mL) and saturated brine (200 mL). The organic layer was dried over anhydrous sodium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate, hexane and diisopropyl ether to give the title compound (2.98 g, 83%) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:10]3[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][N:15](COCC[Si](C)(C)C)[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:6]=[C:5]([NH:31][C:32](=[O:36])[C:33]([CH3:35])=[CH2:34])[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:10]3[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:6]=[C:5]([NH:31][C:32](=[O:36])[C:33]([CH3:35])=[CH2:34])[N:4]=1
Reactant: C=C(C)C(=O)Nc1cc(-c2ncnc3c2c(C(=O)OCC)cn3COCC[Si](C)(C)C)cc(OC)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C)C(=O)Nc1cc(-c2ncnc3[nH]cc(C(=O)OCC)c23)cc(OC)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To ethyl 4-{2-methoxy-6-[(2-methylacryloyl)amino]pyridine-4-yl}-7-{[2 (trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (20 mg, 0.039 mmol) in DCM (0.50 mL) was added TFA (500 μL, 6.49 mmol) and the reaction was stirred for 2 hours at room temperature. The reaction was then concentrated in vacuo, and the residue dissolved in acetonitrile (1.0 mL) and ammonium hydroxide (1.0 mL) was added. The reaction was stirred for an additional 1 hour at room temperature before being concentrated in vacuo and purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. The products were collected and lyophilized to afford a colorless solid. LRMS calcd for C19H20N5O4[M+H]+: 382, found 382. 1H NMR (600 MHz, DMSO-D6) δ 13.08 (bs, 1H), 10.05 (s, 1H), 8.92 (s, 1H), 8.33 (d, 1H, J=3.1 Hz), 7.87 (d, 1H, J=0.9 Hz), 6.67 (d, 1H, J=1.1 Hz), 5.87 (s, 1H), 5.52 (s, 1H), 3.90 (q, 2H, J=7.2 Hz), 3.89 (s, 3H), 1.91 (s, 3H), 0.92 (t, 3H, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]([F:40])([CH2:36][CH2:37][CH2:38][CH3:39])[C:3](=[O:35])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11]C2CCCCO2)[CH2:9][C:8](=[O:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].[Cl-].[Na+]>C(#N)C.O.P(=O)(O)(O)O>[F:1][C:2]([C@:3]1([OH:35])[O:11][C@@H:10]2[CH2:9][C:8](=[O:18])[C@H:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C@H:6]2[CH2:5][CH2:4]1)([F:40])[CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCC(F)(F)C(=O)CC[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CCCCCCC(=O)OCc1ccccc1
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCCC(F)(F)[C@@]1(O)CC[C@H]2[C@@H](CC(=O)[C@@H]2CCCCCCC(=O)OCc2ccccc2)O1
Temperature: 20 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
To a solution of benzyl 7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-5-oxo-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (19) (70.49 g, 124.8 mmol) in acetonitrile (705 ml), water (70.5 ml) and 85% phosphoric acid (70.5 ml) were added and the mixture was stirred for 3 hours at approximately 20° C. The solution was supplemented with 10% aqueous sodium chloride (705 ml), and extracted three times with ethyl acetate (276 ml). The organic layers were combined and sequentially washed with 10% aqueous sodium chloride (360 ml), saturated sodium bicarbonate water (360 ml) and saturated aqueous sodium chloride (360 ml). The solution was dried with anhydrous magnesium sulfate (51 g) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 2100 g; ethyl acetate:hexane=1:4). The fractions containing impurities were re-purified by silica gel column chromatography (Fuji Silysia BW-300 1000 g, ethyl acetate:hexane=1:4) to give benzyl 7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxy-6-oxooctahydro cyclopenta[b]pyran-5-yl]heptanate (20) (52.64 g; 109.5 mmol; yield: 87.8%) as a colorless oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:23]C1C=C(N2C[C@H](CO)OC2=O)C=CC=1I>>[Si:1]([O:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:17]=[CH:18][C:19]([I:22])=[C:20]([F:23])[CH:21]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1

Procedure:
Using essentially the same procedure as that used for (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(4-iodophenyl)-1,3-oxazolidin-2-one (above), but starting from (5R)-3-(3-fluoro-4-iodophenyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (2.0 g, 1.0 mM) gave the title compound as a light yellow soild after chromatography using 50% ethyl acetate/hexanes (1.94 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH2:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[S:10])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: Nc1nccs1
Product: Cc1ccc(Cl)cc1NC(=S)Nc1nccs1
Yield: 77.4 %

Procedure:
Prepared using Method C from 3.0 g (16.3 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 1.7 g (16.3 mmol) of 2-amino-thiazole to give 3.58 g of title compound as a beige solid, m.p. 197-198° C. (77% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](CC#N)[C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2].O.S(=O)(=O)(O)O.[C:26]([OH:29])(=[O:28])[CH3:27]>>[N+:1]([C:4]1[CH:9]=[C:8]([CH2:27][C:26]([OH:29])=[O:28])[C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)O
Reactant: N#CCc1cc([N+](=O)[O-])ccc1Sc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1

Procedure:
210.3 g of 3-nitro-6-(phenylthio)-phenylacetonitrile, 210 ml of water, 210 ml of concentrated sulphuric acid and 210 ml of acetic acid are heated to reflux for 20 hours. The mixture is cooled and extracted with ether. The organic phase is washed successively with water and aqueous sodium carbonate solution. The aqueous phase is made acid with hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate, evaporated under reduced pressure and the residue recrystallised from benzene. There is obtained 3-nitro-6-(phenylthio)-phenylacetic acid of melting point 138°-140° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][C:29]=1[CH2:30][N:31]=[N+]=[N-])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[NH4+]>C1COCC1>[CH2:20]([O:27][C:28]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][C:29]=1[CH2:30][NH2:31])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: N#Cc1ccc(OCc2ccccc2)c(CN=[N+]=[N-])c1
Agent: [NH4+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(OCc2ccccc2)c(CN)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
Triphenylphosphine (1.64 g, 6.24 mmol) was added to a solution of 2-benzyloxy-5-cyano-benzylazide (1.1 g, 4.16 mmol) in anhydrous THF (10 mL) at 0° C. After 1 hour, ammonium hydroxide (0.5 mL) was added and the mixture was warmed to room temperature and stirred overnight. The mixture was concentrated and the residue purified by flash chromatography (3% methanol/dichloromethane) to afford 677 mg (69%) of the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.6-7.3 (m, 7H); 6.95 (d, 1H, J=9.1 Hz); 5.18 (s, 2H); 3.9 (s, 2H).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[N:7]=[C:8]2[N:13]([CH:14]=1)[CH2:12][C@H:11]([OH:15])[CH2:10][O:9]2)([O-:5])=[O:4].[Cl:16][C:17]1[CH:22]=[N:21][C:20]([CH2:23]I)=[CH:19][N:18]=1>CN(C=O)C>[Cl:16][C:17]1[N:18]=[CH:19][C:20]([CH2:23][O:15][C@@H:11]2[CH2:10][O:9][C:8]3=[N:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][N:13]3[CH2:12]2)=[N:21][CH:22]=1
Reactant: O=[N+]([O-])c1cn2c(n1)OC[C@@H](O)C2
Reactant: Clc1cnc(CI)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn2c(n1)OC[C@@H](OCc1cnc(Cl)cn1)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
Triethylamine (4.17 mL, 3.0 mmol) and mesyl chloride (1.57 mL, 2.00 mmol) were added to a solution of (5-chloro-2-pyrazinyl)methanol (1.44 g, 10.0 mmol) in anhydrous THF (20 mL) at 0° C. The mixture was stirred at 0° C. for 0.5 h then partitioned between EtOAc/water. The organic fraction was dried (MgSO4) and the solvent was removed under reduced pressure to give the crude mesylate. The mesylate was dissolved in acetone (40 mL), sodium iodide (7.5 g, 50 mmol) was added and the mixture was refluxed for 1 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc/water. The residue was chromatographed on silica gel (DCM) to give 2-chloro-5-(iodomethyl)pyrazine. Sodium hydride (60% w/w, 0.36 g, 9.0 mmol) was added to a solution of (S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxa-zin-6-ol (0.93 g, 5.02 mmol) and 2-chloro-5-(iodomethyl)pyrazine (1.54 g, 6.05 mmol) in DMF (10 mL) at −78° C. The mixture was stirred at 0° C. for 1 h and then quenched with ice. EtOAc (200 mL) was added, the organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with a gradient (0-5%) MeOH/EtOAc to give the title compound (1.015 g, 65%) as a white solid. APCI MS m/z 312.6 (M+H). 1H NMR (400 MHz, (CD3)2SO) δ 8.76 (d, J=1.4 Hz, 1H), 8.50 (d, J=1.4 Hz, 1H), 8.02 (s, 1H), 4.85 (d, J=13.7 Hz, 1H), 4.81 (d, J=13.7 Hz, 1H), 4.70 (td, J=12.1, 2.6 Hz, 1H), 4.49 (bd, J=12.0 Hz, 1H), 4.29-4.38 (m, 2H), 4.25 (dd, J=13.5, 3.3 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][N:10]3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Al](C)C.[Br:21][C:22]1[CH:23]=[C:24]([CH3:32])[C:25]([C:28](OC)=[O:29])=[N:26][CH:27]=1>O1CCOCC1>[C:1]1([C:7]2[N:8]=[C:9]3[N:14]=[C:13]([NH:15][C:28]([C:25]4[C:24]([CH3:32])=[CH:23][C:22]([Br:21])=[CH:27][N:26]=4)=[O:29])[CH:12]=[CH:11][N:10]3[CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ncc(Br)cc1C
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: Cc1cc(Br)cnc1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To an argon purged solution of 2-phenylimidazo[1,2-a]pyrimidin-7-amine (example 1, step 1, 80 mg, 0.381 mmol) in dioxane (5 ml) was added trimethyl aluminum solution (0.571 ml, 1.14 mmol, 3 eq). The resulting solution was stirred for 1 hour at RT. Then methyl 5-bromo-3-methylpicolinate (88 mg, 0.381 mmol) was added and the mixture was heated to reflux and stirred for 18 hours. The title compound (84 mg, 54%) was isolated from the crude product by flash chromatography on a 20 g SiO2 column using dichloromethane/methanol 0-10% as eluent. MS (m/e)=408.2 [M+H+].
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][N:15]([CH2:23][CH2:24][CH2:25][NH:26][CH3:27])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].Cl.C(N=C=NCCCN(C)C)C>>[Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([N:26]([CH3:27])[CH2:25][CH2:24][CH2:23][N:15]([CH3:14])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=C(O)c1ccc2nc(Br)sc2c1
Reactant: CNCCCN(C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CN(CCCN(C)C(=O)c1ccc2nc(Br)sc2c1)C(=O)OC(C)(C)C
Yield: 77.1 %

Procedure:
The compound (100 mg, 0.387 mmol) obtained in Example 93a, tert-butyl methyl[3-(methylamino)propyl]carbamate (78 mg, 0.387 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (89 mg, 0.464 mmol) were used to give the title compound (132 mg; yield, 77%) as a yellow oily substance according to the method described in Example 89b.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][NH:9][C:10]([NH:12][CH2:13][CH3:14])=[S:11])=O)=[CH:4][CH:3]=1.[OH-].[Na+]>O.C(O)(=O)C>[NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]2[N:12]([CH2:13][CH3:14])[C:10](=[S:11])[NH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCNC(=S)NNC(=O)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCn1c(-c2ccc(N)cc2)n[nH]c1=S
Temperature: 24 °C
Yield: 82.1 %

Procedure:
A mixture of 3.0 g (12.6 mmol) of 1-(4-aminobenzoyl)-4-ethylthiosemicarbazide and 4.8 mL of 2N sodium hydroxide in 38 mL of water was heated at reflux for 2 hours. The reaction mixture was cooled to 24° C. and diluted with glacial acetic acid to pH=3. The precipitate which formed was collected by filtration and washed with ethyl acetate:methanol (1:1 v/v) to provide 2.28 g (82%) of 5-(4-aminophenyl)-4-ethyl-2,4-dihydro-[1,2,4]triazol-3-thione, mp 240°-250° C.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[SH:10])[CH:3]=[CH:2]1.S(Cl)(Cl)(=O)=O>ClCCl>[S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[S:10][S:10][C:8]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:3]=[CH:2][S:1][C:9]=23)[CH:3]=[CH:2]1
Reactant: Sc1ccnc2ccsc12
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: c1cc(SSc2ccnc3ccsc23)c2sccc2n1
Temperature: 0 °C
Reaction time: 48 h
Yield: 37.7 %

Procedure:
Thieno[3,2-b]pyridine-7-thiol (1.00 g, 5.9 mmol) was dissolved in dichloromethane (40 mL). The solution was cooled to 0° C. and sulfuryl chloride (1M in dichloromethane, 2.9 mL, 2.9 mmol) was added dropwise and the reaction stirred while warming to ambient temperature. The solution stirred for 5 hours at ambient temperature and then concentrated to dryness. The residue was left standing under open air for two days. The residue was then diluted in dichloromethane and was neutralized with saturation NaHCO3 solution. The organic layer was separated, dried, and concentrated. The residue was triturated with ether and the solid was filtered and dried to provide the title compound (0.37 g, 46% yield) as a tan solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[F:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc(F)cc1F

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,4-difluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [CH:1]([C@:4]1([C:20]([N:22]2[CH2:31][CH2:30][C:29]3[N:28]=[CH:27][C:26]([C:32]([F:35])(F)[F:33])=[CH:25][C:24]=3[CH2:23]2)=[O:21])[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([O:18]C)=[O:17])[CH2:11][CH2:10]2)[CH2:5]1)([CH3:3])[CH3:2].[OH-].[Li+].Cl.[CH3:39]O>>[F:35][C:32]([C:26]1[CH:27]=[N:28][C:29]2[CH2:30][CH2:31][N:22]([C:20]([C@@:4]3([CH:1]([CH3:2])[CH3:3])[CH2:8][CH2:7][CH:6]([N:9]4[CH2:10][CH2:11][CH:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:14]4)[CH2:5]3)=[O:21])[CH2:23][C:24]=2[CH:25]=1)([F:33])[CH3:39]
Reactant: COC(=O)CC1CCN(C2CC[C@@](C(=O)N3CCc4ncc(C(F)(F)F)cc4C3)(C(C)C)C2)CC1
Reactant: CO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: CC(C)[C@]1(C(=O)N2CCc3ncc(C(C)(F)F)cc3C2)CCC(N2CCC(CC(=O)O)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of methyl [1-((3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)piperidin-4-yl]acetate (470 mgs, 0.92 mmol) in methanol (5 ml) was added 2N Lithium Hydroxide solution (1.8 ml, 3.7 mmol), the reaction was then stirred overnight at room temperature. The reaction was neutralized to pH=5 using 3N HCl. The crude was purified on reverse phase HPLC using 5%-100% ACN/H2O to yield [1-((3S)-3-{[3-(1,1-difluoroethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}-3-isopropylcyclopentyl)piperidin-4-yl]acetic acid (320 mgs, 91%), LC-MS 482 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C.O>[CH2:13]([C:9]1[CH:10]=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=1[C:6]([OH:8])=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(O)cc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
Separately, 60 g of 4-hydroxybenzoic acid was dissolved in 500 ml of ethanol, and a solution of 15 g of NaOH in 500 ml of water was added thereto. To the mixture was added 50 g of benzyl chloride, followed by stirring for 2 hours at room temperature and 2 hours of heat refluxing. After distilling off the solvent, the product was recrystallized from ethanol to obtain 40 g of benzyl-4-hydroxybenzoic acid. Then, 17 g of the benzyl-4-hydroxybenzoic acid was dissolved in 100 ml of pyridine, and 8 g of terephthaloyl chloride was added thereto, followed by stirring for 2 hours at room temperature and for 1 hour at 70° C. The reaction mixture was added to 500 ml of 2M-HCl to obtain 10 g of bis(4-benzyloxycarbonylphenyl)terephthalate, which was then added to 150 ml of trifluoroacetic acid, followed by addition of 10 ml of 33% HBr solution in acetic acid and reaction for 12 hours at room temperature. Acetone was added to the reaction mixture to result in a precipitate, which was then separated and washed with acetone to obtain 4 g of bis (4-carboxyphenyl)terephthalate. Then, 2 g of the diacid was mixed with 40 ml of SOCl2, followed by 2 hours of heat refluxing, reduced pressure distillation for removal of an excess of SOCl2, addition of 1,2-dichloroethane and addition of a solution of 1 g of the compound of the formula (IX) in 5 ml of pyridine. The mixture was subjected to reaction at 60° C. for 3 hours and at room temperature for 10 hours. The reaction product was re-precipitated from acetone and washed with water to obtain a polymer mesomorphic compound of the following formula (X) (ηinh =0.02 dl/g): ##STR38##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18].[F:20][C:21]([F:36])([F:35])[C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](Cl)=[O:26]>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]([C:25](=[O:26])[C:24]1[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:22]([C:21]([F:20])([F:35])[F:36])[CH:23]=1)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)CNc1cnccc1-c1ccccc1Cl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Yellow solid (26%). MS (ESI): m/z=517.075 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][S:5](=[O:8])(=[O:7])[N:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:3]1.[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.O>[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:13]([C:12]4[CH:11]=[CH:10][C:9]([N:4]5[CH2:3][CH:2]([CH3:1])[CH2:6][S:5]5(=[O:7])=[O:8])=[CH:17][CH:16]=4)=[O:15])[CH2:31][CH2:32]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1
Reactant: CC1CN(c2ccc(C(=O)O)cc2)S(=O)(=O)C1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CC(C)CS3(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
4-(4-Methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (200 mg) described in Preparation Example 15 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (170 mg) described in Preparation Example 83 were dissolved in tetrahydrofuran (10 mL), 1-hydroxybenzotriazole 1 hydrate (139 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (225 mg) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (120 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)Nc1ccccc1N
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To a solution of N-(2-nitrophenyl)methanesulfonamide (800 mg, 3.70 mmol) in methanol (20 mL) was added palladium on carbon (10% by weight, 394 mg, 0.37 mmol). The vessel was purged with hydrogen and then stirred for 4 hours under 1 atm of hydrogen. The reaction was filtered, concentrated and purified by chromatography to provide N-(2-aminophenyl)methanesulfonamide (600 mg, 87% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.67 (bs, 1H), 7.05 (dd, J=7.8, 1.5 Hz, 1H), 6.98 (m, 1H), 6.73 (dd, J=7.8, 1.5 Hz, 1H), 6.54 (m, 1H), 5.11 (bs, 2H), 2.90 (s, 3H).