Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[C:3]=1[CH:13]=O.[OH:15][C:16]1[C:17]([C:26]([NH:28][NH2:29])=[O:27])=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[C:3]=1[CH:13]=[N:29][NH:28][C:26]([C:17]1[C:16]([OH:15])=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)=[O:27]
Reactant: NNC(=O)c1cc2ccccc2cc1O
Reactant: O=Cc1c(O)ccc2ccc(O)cc12
Product: O=C(NN=Cc1c(O)ccc2ccc(O)cc12)c1cc2ccccc2cc1O

Procedure:
Following the general procedure of Example 1, condensation of 2, 7-dihydroxy-1-naphthaldehyde and 3-hydroxy-2-naphthoic hydrazide yielded yellow crystals (83%) [recrystallized from DMSO/H2O (8:2, v/v)]: mp225° C. (dec); 1H NMR d 12.75 (s, 1 H), 12.24 (s, 1 H), 11.27 (s, 1 H), 9.93 (s, 1 H), 9.40 (s, 1H), 8.50 (s, 1 H), 7.95 (d, 1 H, J=8.1 Hz), 7.80 (d, 2 H, J=8.7 Hz), 7.73 (d, 1 H, J=8.7 Hz), 7.54 (t, 1 H, J=7.5 Hz), 7.39 (t, 1 H, J=7.5 Hz), 7.37 (s, 1 H), 6.98 (d, 2 H, J=8.7 Hz); HRMS Calcd for C22H16N2O4 :372.1110, found 372.1099; Anal. (C22H16N2O4 1.4 DMSO) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[NH:11][C:10]2=[O:20])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:27]OS(C1C(C)=CC(C)=CC=1C)(=O)=O>O1CCCC1.O>[NH2:27][N:11]1[C:12]([C:16]([F:19])([F:17])[F:18])=[CH:13][C:14](=[O:15])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10]1=[O:20]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: COc1ccc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-n2c(=O)cc(C(F)(F)F)n(N)c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
A solution of 2.10 grams (0.0073 mole) of 3-(4-methoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (recovered from previous reactions) and 1.21 grams (0.0088 mole) of potassium carbonate in 30 mL of tetrahydrofuran was stirred for five minutes at ambient temperature and then 1.58 grams (0.0073 mole) of 1-aminooxysulfonyl-2,4,6-trimethylbenzene (prepared in a manner known by one skilled in the art) was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for three hours. At the conclusion of this period, the reaction mixture was diluted with water, and the resulting mixture was extracted with two 50 mL portions of ethyl acetate. The combined ethyl acetate extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 0.9 gram of crude product. This 0.90 grams of crude product was combined with 0.92 grams of crude product prepared by a similar route to yield a total of 1.82 grams of crude product. The 1.82 grams of crude product was purified by flash chromatography, yielding 1.5 grams of 1-amino-3-(4-methoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 176°-178° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[CH3:12].Cl.[NH2:14][OH:15].C([O-])([O-])=O.[Na+].[Na+]>C(O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:6]([CH:7]=[N:14][OH:15])=[CH:5][C:4]=1[CH3:12]
Reactant: NO
Reactant: COc1c(C)cc(C=O)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1c(C)cc(C=NO)cc1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
4-Methoxy-3,5-dimethylbenzaldehyde (1.86 g, 11.3 mmol) was dissolved in ethanol (30 mL) and stirred with hydroxylamine hydrochloride (2.4 M aq. solution, 5.65 mL, 1.2 eq.) and Na2CO3 (1.2 M solution, 5.65 mL, 0.6 eq.) at room temperature for 2.5 hours. The mixture was then heated to 60° C. and additional hydroxylamine hydrochloride and Na2CO3 was added. The mixture was again stirred overnight at 60° C., transferred to a separatory funnel, diluted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The product was purified by ISCO chromatography with EtOAc/hexanes eluent to yield 1.55 g (8.56 mmol, 77%) of 4-methoxy-3,5-dimethylbenzaldehyde oxime as a white solid. M+1=180.0.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]([Cl:26])([Cl:25])[C:11]1[N:16]=[C:15](C(Cl)(Cl)Cl)[N:14]=[C:13]([C:21]([Cl:24])([Cl:23])[Cl:22])[N:12]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:1]([NH:8][C:15]1[N:16]=[C:11]([C:10]([Cl:9])([Cl:26])[Cl:25])[N:12]=[C:13]([C:21]([Cl:23])([Cl:24])[Cl:22])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)c1nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: ClC(Cl)(Cl)c1nc(NCc2ccccc2)nc(C(Cl)(Cl)Cl)n1
Reaction time: 72 h
Yield: 84.7 %

Procedure:
Benzylamine (3.21 g., 0.03 mole) is added to 2,4,6-tris(trichloromethyl)-s-triazine (13 g., 0.03 mole) in dry benzene (75 ml.). Triethylamine (3.24 g., 0.03 mole) is then added to the reaction mixture and the solution set aside for 3 days. Evaporation to a residual oil and crystallization from methanol-water (9:1) gives the product 10.7 g., 85%, m.p. 96.5°-97°.
Reaction SMILES: [CH:1](=O)[CH3:2].Cl.[CH2:5]([O:12][NH2:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O.CO>[CH2:5]([O:12][NH:13][CH:1]=[CH2:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NOCc1ccccc1
Reactant: CC=O
Agent: Cl
Solvent: O
Solvent: CO
Product: C=CNOCc1ccccc1
Reaction time: 16 h

Procedure:
Acetaldehyde (24.7 mL, 44.2 mmol) was added dropwise to the cooled solution (0° C.) of O-benzyl-hydroxylamine hydrochloride (7.00 g, 43.85 mmol) in water (100 mL) and MeOH (20 mL). The reaction mixture was stirred for 16 h. The volatiles were removed under reduced pressure, and the water suspension was extracted with EtOAc (2×75 mL). The combined organic extracts were washed with brine, and then dried over Na2SO4 and evaporated to yield O-benzyl-N-vinyl-hydroxylamine (LXVI) in quantitative yield. 400 MHz 1H NMR (DMSO-d6, ppm) 7.48 (0.5H, q, J=5.8 Hz), 7.39-7.26 (5H, m), 6.86 (0.5H, q, J=5.5 Hz), 5.06 (1H, s), 4.97 (1H, s), 1.78 (1.5H, d, J=5.5 Hz), 1.76 (1.5H, d, J=5.8 Hz).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:13]([O:20][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 60 h
Yield: 75.6 %

Procedure:
A mixture of 5-fluoro-2-nitrobenzonitrile (15 g, 90 mmol), benzyl alcohol (10.8 g, 100 mmol) and potassium carbonate (18.7 g, 135 mmol) in DMF (20 ml) was stirred at room temperature for 60 h. Water (60 ml) was added to the reaction, and the resultant yellow precipitate out filtered, washed with water, and dried under reduced pressure to provide 17.3 g (75.4%) of 5-benzyloxy-2-nitrobenzonitrile. The compound was used directly for the next step without further purification. MS GC-MS M+=211, RT=6.15 min.
Reaction SMILES: OO.O[Li].O.C([C@@H]1COC(=O)N1[C:19](=[O:43])[C@H:20]([C@H:29]1[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:32]([CH3:42])([CH3:41])[CH2:31][CH2:30]1)[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([F:28])[CH:22]=1)C1C=CC=CC=1.[O-:44]S([O-])=O.[Na+:48].[Na+]>C1COCC1.O>[Na+:48].[C:37]([O:36][C:34]([N:33]1[C:32]([CH3:42])([CH3:41])[CH2:31][CH2:30][C@H:29]1[C@H:20]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([F:28])[CH:22]=1)[C:19]([O-:43])=[O:44])=[O:35])([CH3:38])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccc(Cl)c(F)c2)CCC1(C)C
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)[O-])c2ccc(Cl)c(F)c2)CCC1(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
30% H2O2 (0.159 mL, 1.65 mmol) was added to a solution of LiOH—H2O (0.055 g, 1.32 mmol) in 2:1 THF:H2O (40 mL). The mixture was stirred for 20 minutes and then cooled to 0° C. A solution of (S)-tert-butyl 5-((S)-2-((R)-4-benzyl-2-oxooxazolidin-3-yl)-1-(4-chloro-3-fluorophenyl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.360 g, 0.660 mmol) in THF (3 mL) was next added slowly. Upon completion of the addition, the reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was then recooled to 0° C., and 1M Na2SO3 (4 mL) was added. The reaction was stirred for 10 minutes at 0° C. and then warmed to room temperature and stirred for an additional 10 minutes. The reaction was then concentrated in vacuo to remove THF, and the resulting mixture was washed with EtOAc. The organic fraction was then dried over sodium sulfate, filtered and concentrated to give (S)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)-2-(4-chloro-3-fluorophenyl)acetic acid sodium salt (0.24 g, 94%) as a powder. MS ESI (+) m/z 386 detected.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][NH:11]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:28](=[O:29])[CH2:27][C:26]([CH3:31])([CH3:30])[CH2:25][C:24]1=[O:32]>>[CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]3[C:28](=[O:29])[CH2:27][C:26]([CH3:31])([CH3:30])[CH2:25][C:24]3=[O:32])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC1(C)CC(=O)N(CCCCCCBr)C(=O)C1
Reactant: COc1cccc2c1CC[C@@H]1NCC[C@H]21
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCCCN1C(=O)CC(C)(C)CC1=O
Yield: 72 %

Procedure:
In an analogous manner to that described in Example 20a), from rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole by reaction with N-(6-bromo-hexyl)-3,3-dimethylglutarimide there was obtained rac-cis-1-[6-(6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)-hexyl]-4,4-dimethylpiperidine-2,6-dione; m.p. of the hydrochloride 99°-101°, yellowish crystals, yield 72%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.[Br:24]Br>Br>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[C:23]=1[Br:24]
Reactant: BrBr
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc(N)ccc21
Agent: Br
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2c1ccc(N)c2Br
Reaction time: 1 h

Procedure:
6.6 g (0.021 mol) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one, dissolved in 50 ml of concentrated aqueous hydrobromic acid, are treated slowly at between 0° and 5° with 1.2 l of bromine and stirred at 0° for 1 hour. Subsequently, the reaction mixture is poured into a mixture of ice and soda solution, extracted with methylene chloride and the organic extract is evaporated. The residue is purified on 300 g of silica gel with methylene chloride/ethyl acetate (20:1). From ethyl acetate/ether there is obtained 7-amino-6-bromo-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one of melting point 217°-220°.
Reaction SMILES: [O:1]=[S:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[NH:14][C:15](=O)[C:16]3[S:21][C:20]([CH3:22])=[CH:19][C:17]=3[N:18]=2)[CH2:4][CH2:3]1.[F:24][CH:25]([CH2:28][NH2:29])[CH2:26][NH2:27]>>[F:24][CH:25]([CH2:28][NH2:29])[CH2:26][NH:27][C:15]1[C:16]2[S:21][C:20]([CH3:22])=[CH:19][C:17]=2[N:18]=[C:13]([N:5]2[CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:2](=[O:1])[CH2:3][CH2:4]2)[N:14]=1
Reactant: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)[nH]c(=O)c2s1
Reactant: NCC(F)CN
Product: Cc1cc2nc(N3CCS(=O)c4ccccc4C3)nc(NCC(F)CN)c2s1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 3 by using 2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylthieno[3,2-d]pyrimidin-4(3H)-one and 2-fluoro-1,3-propanediamine. MS obsd. (ESI+) [(M+H)+] 420, 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.73 (d, J=6.6 Hz, 1H), 7.68 (d, J=6.8 Hz, 1H), 7.39-7.51 (m, 2H), 6.81 (s, 1H), 5.19 (d, J=14.7 Hz, 1H), 4.83 (d, J=9.3 Hz, 1H), 4.69 (br. s., 2H), 4.46 (br. s., 1H), 3.71-3.96 (m, 2H), 3.30-3.48 (m, 2H), 2.80-3.05 (m, 2H), 2.54 (s, 3H).
Reaction SMILES: O[CH2:2][C:3]1[CH:14]=[N:13][C:6]2[N:7]([CH3:12])[CH2:8][C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>C(#N)CC.O>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([N:40]2[CH2:45][CH2:44][N:43]([CH2:2][C:3]3[CH:14]=[N:13][C:6]4[N:7]([CH3:12])[CH2:8][C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:42][CH2:41]2)=[CH:38][CH:39]=1
Reactant: CN1CC(=O)Nc2cc(CO)cnc21
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(=O)Nc2cc(CN3CCN(c4ccc(Cl)cc4)CC3)cnc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 9 %

Procedure:
7-(hydroxymethyl)-4-methyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one (85.0 mg, 0.44 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 1-(4-chlorophenyl) piperazine hydrochloride (104.8 mg, 0.45 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was then cooled to room temperature and diluted with water (3 mL) and filtered. The solids were collected and refluxed in ethanol (5 mL) for 1 h. The suspension was cooled back to room temperature and filtered. The precipitate was filtered off and dried in vacuum to afford the title compound (14.7 mg, 8%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.50 (s, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.21 (d, J=9.1 Hz, 2H), 6.96 (d, J=2.0 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H), 3.93 (s, 2H), 3.34 (s, 2H), 3.10 (br. s., 4H), 2.91 (s, 3H), 2.46 (br. s., 4H). [M+H] calc'd for C19H22ClN5O, 372. found, 372.
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]([CH3:30])([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].[F:34][C:35]([F:45])([F:44])[C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1>CN(C=O)C.CCOCC.Cl>[CH3:30][C:5]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:40][C:39]3[CH:38]=[CH:37][C:36]([C:35]([F:34])([F:44])[F:45])=[CH:43][CH:42]=3)[C:18](=[O:21])[N:17]2[CH3:22])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:31]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
To a mixture of 54 mg of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester in 2 mL of dry DMF at 0° C. under an atmosphere of nitrogen, 10 mg of NaH (0.253 mmol) is added. The resulting solution is allowed to stand at ambient temperature for 20 min. Then 61 mg of 4-trifluoromethylbenzyl bromide is added and resulting mixture is allowed to stand at ambient temperature for overnight. Reaction mixture is diluted with Et2O and 1N HCl. Organic layer is then washed with 1N HCl (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material is in 5 mL of EtOH and 0.3 mL of 5N NaOH. The mixture is heated to reflux for 1 h. The organic solvent is then removed under vacuum and residue is dissolved in CH2Cl2 and 1N HCl. Aqueous layer is washed with CH2Cl2 (2×10 mL). Combined organic layer is dried over Na2SO4, filtered and concentrated under vacuum. The crude material is purified by MS/LC to give 35 mg (49%) of the title product. 1H NMR (400 MHz, CDCl3): δ 7.56 (d, 2H, J=8.0 Hz), 7.35 (d, 2H, J=8.0 Hz), 7.28-7.18 (m, 4H), 7.05 (t, 1H, J=7.2 Hz), 6.91 (d, 2H, J=8.0 Hz), 6.74 (d, 2H, J=8.0 Hz), 5.49 (bs, 1H), 4.45, 4.39 (ABq, 2H, J=15.4 Hz), 3.98 (t, 2H, J=5.8 Hz), 3.77-3.65 (m, 1H), 3.42 (t, 1H, J=8.5 Hz), 3.28, 3.14 (ABq, 2H, J=14.0 Hz), 3.05 (t, 1H, J=8.5 Hz), 2.86 (s, 3H), 2.28-2.20 (m, 1H), 1.95-1.85 (m, 1H), 1.43 (s, 3H). HRMS (ES+) m/z exact mass calcd for C30H32N2O5F3 (m+1) 557.2263, found 557.2257.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:18]2[CH:19]=[C:20]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=3)[C:21]([OH:34])=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH:23]=2)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:46]([C:49]1[CH:57]=[CH:56][C:52]([C:53]([OH:55])=[O:54])=[C:51]([OH:58])[CH:50]=1)(=[O:48])=[O:47].[K+].[Br-]>>[OH:58][C:51]1[CH:50]=[C:49]([S:46]([O:34][C:21]2[C:20]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:42])([F:43])[F:44])[CH:36]=3)=[CH:19][C:18]([C:16](=[O:17])[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:23][C:22]=2[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)(=[O:48])=[O:47])[CH:57]=[CH:56][C:52]=1[C:53]([OH:55])=[O:54]
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Agent: [Br-]
Agent: [K+]
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared as an white foam (0.541 g, 78%) from 2′-Hydroxy-3,3″-bis-trifluoromethyl-[1,1′:3′1″]terphenyl-5′-carboxylic acid (8-phenyl-octyl)-amide and 4-chlorosulfonyl-2-hydroxy-benzoic acid using a procedure similar to step 3 of Example 179. 1H NMR (DMSO-d6) δ11.60 (bs, 2H); 8.70 (t, 1H); 7.94 (s, 2H); 7. 88-7.80 (m, 4H); 7.69-7.57 (m, 5H); 7.26-7.10 (m, 5H); 6.68 (dd, 1H); 6.57 (d, 1H); 3.25 (dd, 2H); 2.52 (t, 2H); 1.53 (m, 4H); 1.28 (m, 8H); IR (KBr) 3400, 2950, 2840, 1690, 1640, 1600, 1550, 1460, 1380, 1320, 1280, 1200, 1170, 1120, 1080 cm−1; mass spectrum [(−)ESI], m/z 812 (M−H)−; Anal. Calcd. for C42H37F6NO7S: C, 61.99; H, 4.58; N, 1.72, Found: C, 61.40; H, 4.80; N, 1.68.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[N:7]=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=1)[CH3:2].Br[CH2:15][CH2:16]Br>>[CH2:1]([O:3][C:4]([C:5]1([C:6]2[N:7]=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=2)[CH2:16][CH2:15]1)=[O:13])[CH3:2]
Reactant: BrCCBr
Reactant: CCOC(=O)Cc1ccc(Cl)nn1
Product: CCOC(=O)C1(c2ccc(Cl)nn2)CC1
Yield: 20 %

Procedure:
The title compound was prepared from (6-chloro-pyridazin-3-yl)-acetic acid ethyl ester and 1,2-dibromoethane following a procedure analogous to that described in Step 3 for Intermediate 4. Yield: 20% of theory; LC (method 1): tR=1.45 min; Mass spectrum (ESI+): m/z=227/228 (Cl) [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[Cl:11][C:12]([Cl:16])([CH3:15])[CH:13]=O.[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:17]1([CH:13]([NH:7][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[C:12]([Cl:16])([Cl:11])[CH3:15])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: NC(=O)c1cccc(Cl)c1
Reactant: CC(Cl)(Cl)C=O
Reactant: c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(Cl)(Cl)C(NC(=O)c1cccc(Cl)c1)n1nnc2ccccc21

Procedure:
3-Chlorobenzamide, the product from Example 24A, benzotriazole, and p-toluenesulfonic acid were processed as described in Example 1C to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].[S:11](Cl)(=[O:14])(=[O:13])[NH2:12]>>[C:4]([C:3]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=1[NH:1][S:11]([NH2:12])(=[O:14])=[O:13])#[N:5]
Reactant: NS(=O)(=O)Cl
Reactant: N#Cc1cc(Cl)ccc1N
Product: N#Cc1cc(Cl)ccc1NS(N)(=O)=O

Procedure:
Prepared as in Example 77a from 2-amino-5-chlorobenzonitrile and sulfamoyl chloride. 1H NMR (400 MHz, DMSO-d6) 7.3 (S, 2H), 7.54-7.56 (d J=9.2 Hz, 1H), 7.74-7.77 (dd J=8.4 Hz, 2 Hz, 1H) 9.67 (s, 1H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Cl[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:7].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][CH3:21].C(OCC)(=O)C>C(Cl)(Cl)Cl.CCCCCC>[F:13][C:14]1[CH:19]=[C:18]([C:6](=[O:7])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:17]=[CH:16][C:15]=1[S:20][CH3:21]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CSc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=O)c1ccc(SC)c(F)c1
Reaction time: 0.62 h
Yield: 64.6 %

Procedure:
To a solution of AlCl3 (9.2 g, 0.06 mol, 2 eq) in chloroform (50 mL) cooled at 0° C., ethyl (chlorocarbonyl)formate (7.3 g, 0.05 mol, 1.6 eq) was added drop wise and the reaction mixture was stirred for 30-45 min at the same temperature. (2-fluorophenyl)(methyl)sulfane (5 g, crude) was added at 0° C. and the reaction mixture was stirred for 4 h at room temperature. Progress of the reaction was monitored by TLC (5% ethyl acetate in n-hexane, Rf˜0.5). On completion of the reaction, crushed ice was added and the mixture was stirred for some time. The organic layer was separated and the aqueous layer was extracted with DCM (2×50 mL). The combined extract was washed with NaHCO3 solution, dried over sodium sulfate and concentrated under reduced pressure to yield ethyl 2-(3-fluoro-4-(methylthio)phenyl)-2-oxoacetate as an yellow colored liquid (5.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[N:14][C:13]([CH3:16])=[C:12]3[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:11]=23)[OH:9])=[CH:4][CH:3]=1.C(Cl)(Cl)[Cl:24]>O=[Mn]=O>[Cl:24][C:3]1[CH:4]=[C:5]([C:8]([C:10]2[CH:15]=[N:14][C:13]([CH3:16])=[C:12]3[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:11]=23)=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Cc1ncc(C(O)c2ccc(F)cc2)c2c1OC(C)(C)OC2
Reactant: ClC(Cl)Cl
Agent: O=[Mn]=O
Product: Cc1ncc(C(=O)c2ccc(F)c(Cl)c2)c2c1OC(C)(C)OC2

Procedure:
6.6 g of (4-fluorophenyl)(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)methanol was dissolved with heat in 150 mL of CHCl3. 12 g of MnO2 was added to this solution and the suspension was refluxed for 2 h. The MnO2 was then filtered over a 1 cm pad of silica gel and the clear organic phase evaporated to yield pure (3-Chloro-4-fluorophenyl) (2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)methanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[NH:11][CH2:12][C:13](O)=[O:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1(S(O)(=O)=O)C=CC=CC=1.O>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH2:12][NH:11][C:10]2=[O:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)CNC(=O)Nc1cc(Cl)cc(Cl)c1
Agent: O=S(=O)(O)c1ccccc1
Solvent: Clc1ccccc1
Solvent: O
Product: O=C1CNC(=O)N1c1cc(Cl)cc(Cl)c1
Temperature: 15 °C
Yield: 90.6 %

Procedure:
To a suspension of 3-(3,5-dichlorophenyl)-ureidoacetic acid (26.3 g.) in chlorobenzene (180 cc.) is added benzenesulphonic acid (1.2 g. representing 0.068 mol per mol of ureidoacetic acid). The water formed in the reaction is removed by azeotropic distillation. After 30 minutes' distillation, a limpid solution is obtained. After cooling to about 15° C, the precipitate formed is filtered off and washed on the filter with ethanol (25 cc.) at 10° C. After drying, 3-(3,5-dichlorophenyl)-hydantoin (22.2 g.) melting at 199° C is obtained. Yield: 90.5%.