Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.Cl.C(N(CC)CC)C.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:26][CH:25]=1.[N:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:43]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46](=O)[NH:45][N:44]=2)=[CH:38][CH:37]=1.C(=O)([O-])[O-]>O.ClCCl.CO>[C:30]1([C:27]2[CH:26]=[CH:25][C:24]([NH:23][C:46]3[C:47]4[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:43]([CH2:42][C:39]4[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=4)=[N:44][N:45]=3)=[CH:29][CH:28]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: O=c1[nH]nc(Cc2ccncc2)c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: c1ccc(-c2ccc(Nc3nnc(Cc4ccncc4)c4ccccc34)cc2)cc1
Temperature: 200 °C
Reaction time: 20 h

Procedure:
A mixture of 2.41 g (16.98 mmol) phosphorus pentoxide, 2.32 g (16.85 mmol) triethylamine hydrochloride, 3 g (17.73 mmol) 4-aminobiphenyl, and 1 g (4.21 mmol) 4-(4-pyridylmethyl)-1(2H)-phthalazinone is stirred for 20 h at 200° C. under a nitrogen atmosphere. After cooling to RT, the hyalinocrystalline melt is distributed between a dichloromethane/methanol mixture (99:1) and a mixture of water and saturated aqueous carbonate solution on (1:1) with intensive stirring and the use of an ultrasonic bath. The organic phase dried over sodium sulfate is evaporated under vacuum and the residue purified by means of flash chromatography on silica gel with particle size 0.04-0.06 mm, using a dichloromethane/methanol mixture (49:1). Title compound is obtained after evaporation of the product-containing fractions under vacuum and recrystallization of the residue from acetonitrile; m.p. 189-191 °C.; ESI-MS: (M+H)+=389.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>O1CCCC1>[C:27]([O:13][N:10]1[C:11]2[C:6](=[CH:5][C:4]([C:16]([F:19])([F:17])[F:18])=[C:3]([C:1]#[N:2])[CH:12]=2)[NH:7][C:8](=[O:15])[C:9]1=[O:14])(=[O:29])[CH3:28]
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)On1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(C#N)cc21
Yield: 90.6 %

Procedure:
A solution of 0.4 g (1.48 mmol) 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione in 50 ml dry tetrahydrofuran was added 0.3 ml (2.18 mmol) dry triethylamine and 0.15 ml (2.10 mmol) acetyl chloride. The mixture was refluxed for 3 h, and then evaporated in vacuo. The residue was stirred with water to give 0.42 g (92%) of 1-acetoxy-7-cyano-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione. M.p. 230° C. 1H-NMR (DMSO-d6): 8.16 (1H, s), 7.53 (1H, s), 2.37 (3H, s).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][C:34]([CH3:37])([OH:36])[CH3:35].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:21]=3[C:22]([F:25])([F:23])[F:24])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][C:34]([OH:36])([CH3:37])[CH3:35])=[O:5]
Reactant: CC(C)(O)CN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(O)CNC(=O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.33 h
Yield: 38.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII, 40 mg, 0.093 mmol), 1-amino-2-methylpropan-2-ol (12.43 mg, 0.139 mmol), 4-methylmorpholine (37.6 mg, 0.372 mmol), and HATU (45.9 mg, 0.121 mmol) were dissolved in DMF (1 mL). It was stirred for 20 min and was then purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% methanol to 100% methanol over 10 min, 20 mL/min, 220 nM, product retention=11.2 min) to provide (R/S)-2-hydroxy-N-(2-hydroxy-2-methylpropyl)-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (20 mg, 0.036 mmol, 39.2% yield): LCMS=502.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.48 (1 H, s), 8.13 (2 H, d, J=8.35 Hz), 7.52-7.76 (7 H, m), 5.16 (1 H, s), 3.25 (2 H, s), 1.17 (3 H, s), 1.14 (3 H, s); HPLC peak RT=7.3 min (Method A).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH2:15][O:16][S:18]([CH3:17])(=[O:20])=[O:19])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1cc(Br)cc(COS(C)(=O)=O)c1
Reaction time: 16 h

Procedure:
To a DCM (20 mL) solution of tert-butyl 3-bromo-5-(hydroxymethyl)benzoate (1.2 g, 4.2 mmol) was added methanesulfonyl chloride (0.62 g, 5.5 mmol) and triethylamine (1.2 mL, 8.4 mmol) at 0° C. The mixture was allowed to stir for 16 hours. TLC showed clean conversion. The reaction was diluted with DCM (100 mL), washed with 0.1 N HCl (100 mL) and brine, dried over sodium sulfate, and concentrated to afford tert-butyl 3-bromo-5-{[(methylsulfonyl)oxy]methyl}benzoate as a light yellow oil, which was used without further purification.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)([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.O.[C-:24]#[N:25].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]([N:14]1[CH2:17][CH:16]([C:24]#[N:25])[CH2:15]1)([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
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: [C-]#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 65 °C
Reaction time: 9 h
Yield: 92.3 %

Procedure:
To a solution of 1-benzhydryl-3-(methanesulfonyloxy)azetidine (7.52 g) in N,N-dimethylformamide (60 ml) were added water (7.2 ml) and sodium cyanide (3.48 g), followed by stirring at 65° C. for 9 hr. To the reaction mixture were added water, sodium carbonate and ethyl acetate, and this was partitioned. The aqueous layer was extracted with ethyl acetate. The organic layer was combined, washed with brine, and dried over anhydrous sodium sulfate. This was concentrated under reduced pressure, and the resultant crystals were suspended by addition of diethyl ether (10 ml). The crystals were collected by filtration and washed with diethyl ether. This was dried under aeration to provide the titled compound as pale yellow crystals (5.43 g, 92.3%).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][OH:10])=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]([CH:17]=[CH:18][CH2:19][CH2:20][CH3:21])=[C:5]([CH2:22][CH3:23])[N:4]=1)[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH2:1]([C:3]1[C:8]([CH2:9][OH:10])=[C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:5]([CH2:22][CH3:23])[N:4]=1)[CH3:2]
Reactant: CCCC=Cc1c(CC)nc(CC)c(CO)c1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCc1c(CC)nc(CC)c(CO)c1-c1ccccc1

Procedure:
The title compound was prepared from 2,6-diethyl-3-hydroxymethyl-4-phenyl-5-(1-pentenyl)pyridine (Example 6) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.42 (m, 3 H), 7.18 (m, 2 H), 4.34 (d, J=6 Hz, 2 H), 2.96 (q, J=7.7 Hz, 2 H), 2.84 (q, J=7.7 Hz, 2 H), 2.28 (m, 2 H), 1.34 (m, 9 H), 1.09 (m, 4 H), 0.76 (t, J=7 Hz, 3 H). FAB-MS: calculated for (C21H29NO) 311, found 312 (M+H). mp 76-77C. Rf=0.5 (50% ethyl acetate/hexane).
Reaction SMILES: [N:1]([C:4]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)=[N+]=[N-].FC(F)(F)C1C=CC(C2(O)C3N=CC=CC=3CCC2)=CC=1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1.[N-]=[N+]=[N-].[Na+]>CCOC(C)=O.O.C1(C)C=CC=CC=1>[F:23][C:20]([F:21])([F:22])[C:17]1[CH:18]=[CH:19][C:14]([C:4]2([NH2:1])[C:13]3[N:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH2:7][CH2:6][CH2:5]2)=[CH:15][CH:16]=1
Reactant: [N-]=[N+]=NC1(c2ccc(C(F)(F)F)cc2)CCCc2cccnc21
Agent: OC1(c2ccc(C(F)(F)F)cc2)CCCc2cccnc21
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [N-]=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: NC1(c2ccc(C(F)(F)F)cc2)CCCc2cccnc21
Reaction time: 48 h

Procedure:
8-azido-8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroquinoline. To a solution of 8-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroquinolin-8-ol (1.2 g, 4.09 mmol) and toluene (2.5 mL) was added DPPA (2.7 mL, 12.53 mmol) and DBU (0.77 mL, 5.11 mmol). The reaction was then treated with sodium azide (780 mg, 12.00 mmol) and stirred for 2 days. The reaction was poured into a separatory funnel containing water and EtOAc. The aqueous layer was extracted with EtOAc (2×25 mL). The combined EtOAc layers were concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with 0-40% EtOAc in hexane, to provide the title compound as a colorless oil. MS (ESI pos. ion) m/z: 319.0 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(CC)CC>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12]2
Reactant: Nc1ccccc1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C1c2ccc(Br)cc2CN1c1ccccc1
Temperature: 85 °C
Yield: 72.3 %

Procedure:
To a suspension of methyl 4-bromo-2-(bromomethyl)benzoate (0.204 g, 0.662 mmol) in MeOH (5.5 mL) were added aniline (0.063 mL, 0.696 mmol) and Et3N (0.144 mL, 1.027 mmol). The mixture was heated to reflux (85° C.) for 24 hours and subsequently cooled. A white solid that formed was collected by vacuum filtration, rinsed with MeOH, and dried under vacuum to give the title compound as a white solid (0.138 g, 72% yield). 1H NMR (500 MHz, CDCl3) δ ppm 3.89 (s, 2 H), 4.85 (s, 2 H), 7.15-7.24 (m, 1 H), 7.40-7.52 (m, 2 H), 7.62-7.96 (m, 5 H); ESI-MS m/z/[M+H]+ 288.3.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][N:7](C(OC(C)(C)C)=O)[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]1[CH2:8][NH:7][C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1
Reactant: CON=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Product: CON=C1CN[C@H](C(=O)OC)C1
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
A solution was made containing e.g. 1-tert-Butyl 2-methyl (2S,4EZ)-4-(methoxyimino)-1,2-pyrrolidinedicarboxylate (60 mg, 0.22 mmol), in anhydrous DCM (6 ml). At 0° C., HCl gas was bubbled slowly through the reaction and the deprotection was followed by TLC. After approximately 30 minutes, the DCM was evaporated. The product was concentrated in vacuo from DCM (2–3 times) to remove the HCl. The desired product, e.g. methyl (2S,4EZ)-4-(methoxyimino)-2-pyrrolidinecarboxylate (38 mg, quant.) was isolated as a yellow solid and used without further purification.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:39]1([NH2:42])[CH2:41][CH2:40]1>>[CH:39]1([NH:42][C:34](=[O:36])[C:33]2[CH:32]=[CH:31][C:30]([S:27]([CH2:26][C:16]3[C:17]4[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=4[CH:23]=[CH:24][C:15]=3[O:14][C@@H:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)(=[O:29])=[O:28])=[CH:38][CH:37]=2)[CH2:41][CH2:40]1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 72 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and cyclopropylamine (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 41 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 570 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=1.[OH-].[Na+]>CO>[F:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:17])=[O:2])=[CH:7][C:8]=1[C:13]([F:14])([F:15])[F:16]
Reactant: COC(=O)COc1ccc(F)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of (4-fluoro-3-trifluoromethyl-phenoxy)-acetic acid methyl ester (13.300 g; 52.744 mmol) in MeOH (150 ml) was treated with aq. 1N NaOH (79 ml; 1.5 eq.), and the resulting mixture was further stirred at rt for 20 min. MeOH was then removed under reduced pressure, water (150 ml) was added followed by aq. 1N HCl (100 ml). Filtration of the precipitated solid, and drying under HV afforded (4-fluoro-3-trifluoromethyl-phenoxy)-acetic acid as a colorless solid (10.030 g; 80%). LC-MS: tR=0.85 min.; [M+H]+: no ionisation.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[SH:18][C:19]1[N:23]=[CH:22][NH:21][N:20]=1>>[NH:21]1[CH:22]=[N:23][C:19]([S:18][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[N:20]1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: Sc1nc[nH]n1
Product: O=C1CCc2cc(OCCCCSc3nc[nH]n3)ccc2N1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.) and 3-mercapto-1,2,4-triazole.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][CH2:31][O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:19]=2)=[C:9]1[CH3:39])(C)(C)C.C(O)(C(F)(F)F)=O>>[O:32]([CH2:31][CH2:30][N:20]1[N:19]=[C:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:40])=[O:5])[C:9]=2[CH3:39])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21]1(=[O:29])=[O:28])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1c(C2=NN(CCOc3ccccc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2=NN(CCOc3ccccc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)O

Procedure:
{3-[2-(2-Phenoxy-ethyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-acetic acid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.12 (d, 1H), 7.92 (t, 1H), 7.82 (t, 1H), 7.46 (m, 2H), 7.22 (m, 2H), 6.96 (m, 5H), 4.58 (s, 2H), 4.39 (t, 2H), 4.28 (t, 2H), 2.21 (s, 3H) ppm. MS calculated for C26H22FN3O5S—H: 506, observed: 506.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C)C=O>[CH:6]1[CH:5]=[C:4]2[C:3]([CH2:10][C:11]([Cl:17])=[O:13])=[CH:2][NH:1][C:9]2=[CH:8][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To indole-3-acetic acid (186 mg, 1.06 mmol) in 3.5 mL of methylene chloride and 0.009 mL of dimethylformamide, oxalyl chloride (2 M in methylene chloride, 0.64 mL, 1.27 mmol) was added. The mixture was stirred at room temperature for 1 hour and concentrated to give 1H-indole-3-acetyl chloride.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[CH:26]=[CH:25][C:24](=[O:27])[C:23]([OH:28])=[CH:22][CH:21]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]([NH:19][C:20]1[CH:26]=[CH:25][C:24](=[O:27])[C:23]([OH:28])=[CH:22][CH:21]=1)=[O:17]
Reactant: Nc1ccc(O)c(=O)cc1
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccc(O)c(=O)cc2)=C(O)c2ccccc2S1(=O)=O
Reaction time: 8 h
Yield: 53.3 %

Procedure:
In a nitrogen atmosphere, a solution of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (0.54 g) and 5-amino-2-hydroxy-2,4,6 -cycloheptatrien-1-one (0.33 g) in xylene (15 ml) is refluxed for 7.5 hours. The reaction mixture is then allowed to stand at room temperature overnight. The crystals that have separated out are collected by filtration and recrystallized from dimethylformamidemethanol to give 4-hydroxy-2-methyl-N-(2-hydroxy-1-oxo-2,4,6-cycloheptatrien-5-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (0.4 g), m.p. 258°-265° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.B1(C=C)OB([CH:14]=[CH2:15])OB(C=C)O1.C1C=CN=CC=1.Br[C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH2:29]>COCCOC.C(OCC)(=O)C.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>[CH:14]([C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH2:29])=[CH2:15]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: Nc1ccc(F)cc1Br
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: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C=Cc1cc(F)ccc1N
Temperature: 105 °C
Reaction time: 7 h
Yield: 111.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium (289 mg, 0.250 mmol), potassium carbonate (829 mg, 6.00 mmol), water (4 mL) and 2,4,6-trivinylcyclotriboroxane-pyridine complex (722 mg, 3.00 mmol) were successively added to a solution of 2-bromo-4-fluoroaniline (950 mg, 5.00 mmol) in 1,2-dimethoxyethane (10 mL) under an argon atmosphere. The mixture was heated to an external temperature of 105° C. and stirred for 7 hr. The mixture was diluted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. Thereafter, the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1) to afford 2-ethenyl-4-fluoroaniline as a reddish brown oil (458 mg).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.II.[I:16](O)(=O)(=O)=O>C(O)(=O)C>[I:16][C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:13](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:12][C:11]=2[CH:10]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Solvent: CC(=O)O
Product: Ic1ccc2c(c1)Cc1ccccc1-2
Temperature: 80 °C
Reaction time: 4 h
Yield: 644.4 %

Procedure:
A 250 mL round-bottomed flask was charged with 20.0 g (120 mmol) fluorene, 16.0 g (60 mmol) iodine and 4.0 g (17 mmol) periodic acid. 150 mL (80%) acetic acid was added to the reaction mixture. The mixture was stirred under nitrogen at 80° C. for 4 hours. The mixture was then allowed to cool to ambient temperature. The solid residue was vacuum filtered, dissolved in toluene and then washed with 5% sodium hydrogen sulphite (to remove excess iodine). The toluene solution was concentrated under vacuo and then passed through a flash column using toluene as the eluent to give 32.0 g (91% yield) of the product (off white solid).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([NH2:14])[CH2:6][CH:5]1[CH3:15])(=[O:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C([O-])(=O)C.N1C=CC=CC=1>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([NH:14][C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cccnc2C(N)CC1C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)N1c2cccnc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.3 %

Procedure:
[Step 4] 15 mg of the 1-acetyl-4-amino-2-methyl-3,4-dihydro-2H-[1,5] naphthyridine and 23 mg of 4-chlorophenylboronic acid were dissolved in 0.3 mL of DMF followed by adding 27 mg of divalent capper acetate and 18 μL of pyridine and stirring for 5 hours at room temperature in the presence of air. Following completion of the reaction, the solution was filtered with celite followed by the addition of water and extracting three times with ethyl acetate. After washing with saturated brine and dehydrating with anhydrous sodium sulfate, the solution was concentrated under reduced pressure and the resulting residue was purified using silica gel chromatography (ethyl acetate:hexane=1:1) to obtain 13 mg of the target compound in the form of a pale yellow solid (57%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[F:18])[CH:3]=[CH:2]1.N1C2C(=NC=CC=2OC2C=CC(NC(NC(=O)CC3C=CC=CC=3)=S)=CC=2F)C=C1.[N-]=C=S.[Cl:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([Cl:59])[C:54]=1[CH2:60][C:61]([N:63]=[C:64]=[S:65])=[O:62].[ClH:66]>CO>[ClH:52].[ClH:66].[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:64]([NH:63][C:61](=[O:62])[CH2:60][C:54]3[C:53]([Cl:52])=[CH:58][CH:57]=[CH:56][C:55]=3[Cl:59])=[S:65])=[CH:13][C:12]=2[F:18])[CH:3]=[CH:2]1
Reactant: Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Reactant: O=C(Cc1c(Cl)cccc1Cl)N=C=S
Agent: Cl
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Agent: [N-]=C=S
Solvent: CO
Product: O=C(Cc1c(Cl)cccc1Cl)NC(=S)Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Yield: 48 %

Procedure:
Starting from the compound 268 and following the procedure described above for the synthesis of compound 269a (example 221) but replacing 2-phenylacethyl isothiocyanate with 2-(2,6-dichlorophenyl)acetyl isothiocyanate, a white solid was obtained. This material was dissolved in MeOH and treated with HCl (1 mL, 1.0M in ether). Solvents were removed under the reduced pressure and the residue was lyophilized, to afford the title compound 269b (48% yield) as a yellowish solid. 1H NMR (DMSO-d6) δ (ppm): 13.29(s, 1H), 12.32(s, 1H), 12.05(s, 1H), 8.52(d, 1H,), 8.14(m, 2H), 7.64(m, 2H), 7.51(d, 1H), 7.37(dd, 1H), 6.86(m, 1H), 6.81(dd, 1H), 4.22(s, 2H), MS (m/z): 489.1(M+H) (found).