Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:6]1[O:10][N:9]=[C:8]([NH2:11])[CH:7]=1)([CH3:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>ClCCl>[F:13][C:2]([F:1])([F:12])[C:3]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)([CH3:5])[CH3:4]
Reactant: CC(C)(c1cc(N)no1)C(F)(F)F
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(c1cc(NC(=O)Oc2ccccc2)no1)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
To a stirred mixture of 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine prepared as described in Example 259A (2.34 g, 12.06 mmol) and potassium carbonate (5 g, 36 mmol) in dry dichloromethane (50 mL) at 0° C., was added a solution of phenyl chloroformate (2.83 g, 18 mmol) in anhydrous dichloromethane (5 mL). The reaction mixture was warmed to room temperature and stirred for a further 15 h, then additional phenyl chloroformate (1 g, 6.3 mmol) was added and stirring was continued for a further 3 h. The reaction mixture was partitioned between water (200 mL) and dichloromethane (500 mL). The organic layer was separated, washed with brine (100 mL), dried over MgSO4, and then concentrated under reduced pressure to give a yellow oil. Purification via silica gel flash chromatography (eluting with 5% to 50% ethyl acetate in hexanes) afforded phenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (2.63 g, 69%) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ 8.16 (brs, 1H), 7.38-7.43 (m, 2H), 7.17-7.29 (m, 3H), 6.85 (s, 1H), 1.57 (s, 6H); LC-MS (ESI) m/z 315 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH2:46])[O:45][C:41]=2[C:40]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:39][CH:38]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH:46][C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:45][C:41]=2[C:40]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:39][CH:38]=1
Reactant: COc1ccc(C2CCOCC2)c2oc(N)nc12
Reactant: O=C(O)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(C2CCOCC2)c2oc(NC(=O)Cc3ccccc3)nc12

Procedure:
From phenylacetic acid, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 367 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH2:26]([CH2:28][NH2:29])[OH:27]>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]([NH:29][CH2:28][CH2:26][OH:27])=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)O)cc2)=C(C)C1=O
Reactant: NCCO
Product: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)NCCO)cc2)=C(C)C1=O
Yield: 6.9 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (200 mg, 0.58 mmol) obtained in Example 2 and ethanolamine (46 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (14 mg, 0.04 mmol, yield 6%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]=[C:10](SC)[N:9]=2)[CH:3]=1.OOS([O-])=O.[K+].C([O-])(O)=O.[Na+].[F:36][C:37]1[CH:38]=[CH:39][C:40]([C@@H:43]([NH2:45])[CH3:44])=[N:41][CH:42]=1.CCN(C(C)C)C(C)C>CO.C(Cl)Cl.O.CCOC(C)=O>[F:36][C:37]1[CH:38]=[CH:39][C:40]([C@@H:43]([NH:45][C:10]2[N:9]=[C:8]([NH:7][C:4]3[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=3)[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]=2)[CH3:44])=[N:41][CH:42]=1
Reactant: CSc1nc(Nc2cc(C)[nH]n2)c([N+](=O)[O-])c(N2CCOCC2)n1
Reactant: C[C@H](N)c1ccc(F)cn1
Agent: O=C([O-])O
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)nc(N3CCOCC3)c2[N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 147.7 %

Procedure:
To a solution of N-(5-methyl-1H-pyrazol-3-yl)-2-(methylthio)-6-morpholin-4-yl-5-nitropyrimidin-4-amine (Intermediate 57, 118 mg) in MeOH (2 ml) and DCM (2 ml) were added Oxone® (302 mg) and NaHCO3 (56 mg) and the resulting mixture was stirred at ambient temperature for 16 hours. [(1S)-1-(5-fluoropyridin-2-yl)ethyl]amine (Intermediate 8, 250 mg) and DIPEA (3 ml) were added and the resulting mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with H2O and EtOAc and the aqueous layer was extracted with EtOAc (4×). The combined organic layers were washed with brine, saturated NaHCO3 (aq) solution, dried and evaporation of the volatiles under reduced pressure gave a colored residue. Purification by column chromatography (60% EtOAc/hexanes) gave the title compound (220 mg). LCMS: 444 [M+1].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][C:8]([CH:11]=O)=[CH:9][N:10]=1.Cl.[NH2:14]O>CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][C:8]([C:11]#[N:14])=[CH:9][N:10]=1
Reactant: NO
Reactant: O=Cc1cnc(-c2cccs2)s1
Agent: Cl
Solvent: CN(C)C=O
Product: N#Cc1cnc(-c2cccs2)s1
Yield: 72.3 %

Procedure:
6.6 g 2-thiophen-2-yl-thiazole-5-carbaldehyde, 2.8 g hydroxylamine hydrochloride in 45 ml dimethylformamide are heated to 150° C. for 2 hours. The solvent is removed under reduced pressure. The crude product is purified by flash column chromatography in ethylacetate:hexane=1:5. 4.7 g of 2-thiophen-2-yl-thiazole-5-carbonitrile (11) are obtained. 1H (CDCl3): 8.2, 1H, d; 7.6, 1H, d; 7.5, 1H, d; 7.1, 1H, dd. 13C (CDCL3) 166.8 Cq, 152.5 Cq, 135.6 CH, 130.7 CH, 129.0 CH, 128.5 CH, 111.9 Cq 104.4 Cq.
Reaction SMILES: [CH2:1]([O:10][C@@H:11]1[C@H:15]([OH:16])[C@@H:14]([CH2:17][OH:18])[O:13][C@H:12]1[N:19]1[CH:26]=[CH:25][C:23]([NH2:24])=[N:22][C:20]1=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:27]([O:36][C@@H]1[C@@H](CO)O[C@@H](N2C=CC(N)=NC2=O)[C@@H]1O)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]CC.C(NC1C=CN([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCCCCCCC)C(=O)N=1)(=O)C1C=CC=CC=1>>[C:27]([C:23]1([NH2:24])[CH:25]=[CH:26][N:19]([C@@H:12]2[O:13][C@H:14]([CH2:17][OH:18])[C@@H:15]([OH:16])[C@H:11]2[O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:20](=[O:21])[NH:22]1)(=[O:36])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O
Reactant: CCCCCCCCCO[C@H]1[C@@H](O)[C@H](n2ccc(N)nc2=O)O[C@@H]1CO
Agent: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Product: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C=CC(N)(C(=O)c2ccccc2)NC1=O

Procedure:
The mixture of 2'-O-nonylcytidine and 3'-O-nonylcytidine (11.5 g) is converted to N4-benzoyl-2'-O-nonylcytidine as per the procedure of Example 71, Step 2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH3:20])=[C:18]([C:21](O)=[O:22])[N:17]=[C:16]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:45][N:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>C(Cl)Cl.CN(C=O)C.O>[N:46]1([NH:45][C:21]([C:18]2[N:17]=[C:16]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][CH:11]=3)[C:19]=2[CH3:20])=[O:22])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: Cc1c(C(=O)O)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OCc2ccccc2)cc1
Reactant: NN1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution of 1-(4-benzyloxyphenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylic acid, from Ex 1, Step 3 (3.38 g, 7.5 mmol) in 60 ml CH2Cl2 was added 3 drops of DMF followed by oxalyl chloride (1.3 ml, 14.9 mmol). The mixture was refluxed for 2 hours, cooled to room temperature and evaporated to dryness. The residue was dissolved in 50 ml CH2Cl2 and cooled to 0° C. Triethylamine (2.1 ml, 14.9 mmol) was added followed by 1-aminopiperidine (0.9 ml, 8.2 mmol) and the mixture was stirred at room temperature for 2 hours. Water (300 ml) was added, the mixture extracted with CH2Cl2 (3×100 ml), dried (Na2SO4), filtered and concentrated. Flash chromatography (silica, hexane:EtOAc 1:2, EtOAc) afforded 2.94 g (74%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)[CH:7]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:34])=[O:33])[CH2:14][C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc3c(c2)OCCO3)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc3c(c2)OCCO3)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared following the method described in Step B of Example 1 from 3-(3-{[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester of Step A and benzenesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.84 (m, 2H), 7.60-7.49 (m, 3H), 7.14 (m, 1H), 7.04 (d, 1H), 6.89 (d, 1H), 6.78 (s, 1H), 6.69 (d, 1H), 6.51 (m, 2H), 4.29 (s, 2H), 4.20 (m, 6H), 3.67 (s, 3H), 2.81 (t, 2H), 2.51 (t, 2H).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:10]([OH:12])=[O:11])[CH2:6][C:7]([OH:9])=O)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C>>[C:1]([NH:4][C@@H:5]1[C:10](=[O:11])[O:12][C:7](=[O:9])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](CC(=O)O)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N[C@H]1CC(=O)OC1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 88.5 %

Procedure:
A stirred suspension of N-Acetyl-L-aspartic acid (35.0 g, 199.9 mmol) in acetic anhydride (100 mL, 1.06 mol) was heated to 80° C. for ˜1 h until all the solid material had dissolved. The heating bath was removed, and the reaction mixture was stirred 4 h at ambient temperature. The product was collected by filtration and washed with tert-butyl methyl ether to afford N-acetyl-L-aspartic anhydride (27.8 g, 88%) as white crystals, [α]D−49.0° (c=2.5, Ac2O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:15](=[O:26])[C:16]4[C:21]([C:22](=[O:25])[C:23]=3Cl)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:27].[K+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([C:14]3[C:15](=[O:26])[C:16]4[C:21]([C:22](=[O:25])[C:23]=3[OH:27])=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C1C(Cl)=C(C2CCC(c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C1C(O)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21

Procedure:
The product of stage (b) was suspended in 10 ml of boiling methanol and 0.55 g of potassium hydroxide in 5.5 ml of water was added dropwise over 15 mins. The mixture was refluxed until a dark red solution formed. (after ca. 6 hrs) when 2 ml of concentrated hydrochloric acid was cautiously added dropwise. The mixture was cooled and filtered, and the solid residue washed thoroughly with water. The water washings were re-acidified and filtered. The combined solid residues (500 mg) mp 200-200°, were recrystallised form acetonitrile to give the title product as the trans-isomer (300 mg) m.p. 216-219° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[N:7]([CH2:8][C@H:9]2[CH2:14][NH:13][CH2:12][CH2:11][NH:10]2)[CH2:6][CH2:5][NH:4][C:3]1=[O:15].C(N(CC)CC)C.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:1][C:2]1([CH3:16])[N:7]([CH2:8][C@H:9]2[CH2:14][N:13]([S:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)(=[O:31])=[O:30])[CH2:12][CH2:11][NH:10]2)[CH2:6][CH2:5][NH:4][C:3]1=[O:15]
Reactant: CC1(C)C(=O)NCCN1C[C@H]1CNCCN1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C(=O)NCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
A 20-mL vial was charged with 3,3-dimethyl-4-((2R)-2-piperazinylmethyl)-2-piperazinone (0.104 g, 0.461 mmol), triethylamine (0.200 mL, 1.44 mmol), and CH2Cl2 (3 mL). To this mixture thiophene-2-sulfonyl chloride (0.0951 g, 0.521 mmol, Sigma-Aldrich, St. Louis, Mo.) in CH2Cl2 (1 mL) was added drop wise at room temperature. The clear solution was stirred at room temperature for 30 min and then the mixture was concentrated and dissolved in CH2Cl2 (20 mL). The organic phase was washed with water (2×20 mL) and saturated aqueous NaCl (20 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3,3-dimethyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)-2-piperazinone (0.166 g) as an off-white foam.
Reaction SMILES: [CH2:1]([OH:10])[C:2]([CH2:4][O:5]P(O)(O)=O)=[O:3].[N:11]([CH2:14][C@@H:15]([OH:18])[CH:16]=[O:17])=[N+:12]=[N-:13].[OH-].[Na+].CO>C(O)C(N)(CO)CO>[N:11]([CH2:14][C@@H:15]([OH:18])[C@H:16]([OH:17])[C@@H:1]([OH:10])[C:2](=[O:3])[CH2:4][OH:5])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=NC[C@@H](O)C=O
Reactant: O=C(CO)COP(=O)(O)O
Agent: NC(CO)(CO)CO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [N-]=[N+]=NC[C@@H](O)[C@H](O)[C@@H](O)C(=O)CO
Reaction time: 48 h
Yield: 30 %

Procedure:
DHAP (0.5 mmole) was added to an aqueous solution of (R)-3-azido-2-hydroxypropanal (1 mmole in 40 ml) and the pH value adjusted to 7.0 with 10N NaOH. To this solution was added fuculose-1-phosphate aldolase from E. coli (4 g), which had been treated with egg white lysozyme (40 mg) in Tris buffer (pH 7.5, 25 ml) for 1 hour at 35° C., to form a mixture and the mixture stirred slowly for 2 days. The stirred mixture was adjusted to a pH value of 4.7, and acid phosphatase (400 units) added. The resulting mixture was incubated at 37° C. for 48 hours, neutralized to a pH value of 7.0 and lyophilized. The residue was treated with MeOH and filtered to remove the insoluble material. The MeOH was removed under reduced pressure and the crude product purified with silica gel column chromatography (CHCl3 :MeOH=6:1) to give 6-azido-6-deoxy-D-xylo-hexulose in 30% yield.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:31](=[O:32])[N:11]3[N:12]=[C:13](Cl)[C:14]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[C:10]3=[N:9]2)=[CH:5][CH:4]=1.[CH3:37][NH2:38]>C1COCC1.O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:31](=[O:32])[N:11]3[N:12]=[C:13]([NH:38][CH3:37])[C:14]([C:23]4[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=4)=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[C:10]3=[N:9]2)=[CH:33][CH:34]=1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c(Cl)nn12
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNc1nn2c(=O)n(Cc3ccc(C(F)(F)F)cc3)nc2c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-(4-(trifluoromethyl)benzyl)-6-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (50 mg, 0.091 mmol), prepared as described in Example 3, and 2.0 M methyl amine in THF (0.4 mL) was stirred at reflux for 12 h. After this time, the reaction mixture was cooled to RT and diluted with water (5 mL). The resultant solution was extracted with EtOAc (5 mL×3). The combined organic layers were washed with water (5 mL×2) followed by saturated aqueous NaCl (5 mL×2). The organic layer was dried over MgSO4, filtered and concentrated to obtain a crude product. The crude product was purified by preparative reverse phase HPLC to give the title compound, 2-(4-(trifluoromethyl)benzyl-7,8-bis(4-chlorophenyl)-6-(methylamino)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (31.5 mg, 64%) as pale yellow solid. HPLC: 4.17 min; MS: M+H=544; 1H NMR (CDCl3), ppm: 7.55 (2H, d, J=10.0 Hz), 7.47 (2H, d, J=10.0 Hz), 7.34 (2H, d, J=10.0 Hz), 7.21 (2H, d, J=10.0 Hz), 7.09 (2H, d, J=10.0 Hz), 7.05 (2H, d, J=10.0 Hz), 5.18 (2H, s), 4.19-4-21 (1H, br), 2.95 (3H, d, J=5.0 Hz).
Reaction SMILES: [I:1][C:2]1[C:3](=[O:19])[C:4]2[CH:9]=[CH:8][C:7](=O)[NH:6][C:5]=2[O:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C=O)C.S(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][C:7]1[N:6]=[C:5]2[O:11][C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:2]([I:1])[C:3](=[O:19])[C:4]2=[CH:9][CH:8]=1
Reactant: O=c1ccc2c(=O)c(I)c(-c3ccccc3)oc2[nH]1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1c(I)c(-c2ccccc2)oc2nc(Cl)ccc12
Reaction time: 144 h
Yield: 74 %

Procedure:
To a suspension of 3-iodo-2-phenyl-8H-pyrano[2,3-b]pyridine-4,7-dione (13 mg, 0.036 mmol) in DCM (3 mL) was added DMF (0.03 mL) and thionyl chloride (0.1 mL). The mixture was heated under reflux for 3 hours, followed by standing at RT for 6 days. Upon evaporation, the residue was subjected to flash chromatography (SiO2, gradient 10 to 25% ethyl acetate in cyclohexane) to afford the title compound (10 mg, 74%) as a colourless gum. LCMS (Method B): RT=4.35 min, [M+H]+=384/386.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:5][NH2:6].C1CCC(N=C=NC2CCCCC2)CC1.[C:31](=S)=[S:32]>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]([F:13])([F:14])[F:15])[CH2:5][N:6]=[C:31]=[S:32]
Reactant: NCc1ccc(OCC(F)(F)F)c(F)c1
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: Fc1cc(CN=C=S)ccc1OCC(F)(F)F
Temperature: -10 °C
Reaction time: 3 h

Procedure:
The crude 3-fluoro-4-(2,2,2-trifluoroethoxy)benzylamine (7.54 g) was added dropwise to a mixture of 7.45 g of DCC, 15 ml of carbon disulfide and 30 ml of diethyl ether with stirring at -10° C. The temperature of the mixture was returned to room temperature, and it was left to stand for 3 hours. The reaction mixture was filtered, and the residue was washed with ethyl ether and combined with the filtrate. The solvent was evaporated under reduced pressure. The resulting oily product was purified by column chromatography (silica gel; developing
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:7]=[N:6][CH:5]=[N:4]1.[OH-].[Na+].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21]>C(Cl)Cl>[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:20]([C:16]2[O:15][CH:19]=[CH:18][CH:17]=2)=[O:21])[CH:7]=[N:6][CH:5]=[N:4]1
Reactant: NCCCCn1cncn1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCCn1cncn1)c1ccco1
Reaction time: 16 h

Procedure:
A mixture of about 2.13 g of 1H-1,2,4-triazole-1-butanamine dihydrochloride, about 50 ml of methylene chloride, about 30 ml of 1N sodium hydroxide and about 1.47 ml of furoyl chloride was stirred for 16 hours and then treated with about 5 ml of 1N sodium hydroxide and about 50 ml of methylene chloride. The layers were separated and the organic layer was washed with water, dried and concentrated, giving the desired product, mp 78°-79° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[CH3:21][C:22]1[C:26]([C:27](O)=O)=[C:25]([C:30]([F:33])([F:32])[F:31])[O:24][N:23]=1>>[CH3:21][C:22]1[C:26]([C:27]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)=[C:25]([C:30]([F:32])([F:33])[F:31])[O:24][N:23]=1
Reactant: Cc1noc(C(F)(F)F)c1C(=O)O
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: Cc1noc(C(F)(F)F)c1-c1nc(Cn2ccc3c(C(F)(F)F)c(C#N)ccc32)no1

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-methyl-5-(trifluoromethyl)-4-isoxazolecarboxylic acid: MS (ESI): m/z 442 (M+1).
Reaction SMILES: [OH-].[Na+].C([O-])=O.[Na+].Cl[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Pd]>[C:8]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Product: c1ccc(-c2ccccc2)cc1
Yield: 50 %

Procedure:
Aromatic compounds containing more than one ring may be referred to as ring assemblies. Many compounds of this type are not readily available and have to be produced by condensation of aromatic compounds containing fewer rings, in particular derivatives of benzene. Ring assemblies containing substituent groups, for example --OH or --COOH groups are difficult to obtain and hence such compounds are expensive. Chemical Abstracts, Vol 95 (1981), abstract 115039y discloses the preparation of bisphenols by a coupling reaction of a halophenol in the presence of a palladium catalyst and a base. Using 4-chlorophenol a yield of about 30% of 4,4'-dihydroxybiphenyl was obtained. A coupling reaction using haloaryl compounds in the presence of sodium hydroxide, sodium formate, a surfactant and a palladium on charcoal is disclosed in Synthesis, July 1978, pages 537 and 538. Using the chloro compounds such as chlorobenzene, a yield of only about 50% of biphenyl is obtained in 24 hours. Furthermore, using this process we have found the reaction to be slow, in some instances giving conversions of about 20 % after two hours, and we have been unable to prepare 4,4'-dihydroxybiphenyl.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:7].Br[C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH3:36][C:30]([O:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:16][CH:15]=2)=[CH:18][CH:19]=1)([CH3:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: COc1cc(OC)cc(C(=O)NCCc2ccc(-c3ccc(O)cc3)cc2)c1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)c3cc(OC)cc(OC)c3)cc2)cc1
Yield: 20 %

Procedure:
Ethyl 2-methyl-2-{4-[2-(3,5-dimethoxy-benzamido)-ethyl]-biphenyl-4'-oxy}-propionate was prepared from 4-[2-(3,5-dimethoxy-benzamido)-ethyl]-4'-hydroxy-biphenyl and ethyl 2-bromo-2-methyl-propionate analogous to Example 31. Yield: 20% of theory; m.p. 74° C.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]2[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=3)[C:8]([CH2:10][CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2].CS(C)=[O:25].OO.[OH-].[Na+]>O.CO>[CH2:10]([C:8]1[N:7]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=2)[C:6]2[CH:21]=[CH:22][C:3]([C:1]([NH2:2])=[O:25])=[CH:4][C:5]=2[N:9]=1)[CH3:11]
Reactant: CS(C)=O
Reactant: CCc1nc2cc(C#N)ccc2n1-c1ccc(CCO)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nc2cc(C(N)=O)ccc2n1-c1ccc(CCO)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-[4-(5-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4 of Example 82, 200 mg, 0.68 mmol), DMSO (0.06 mL, 0.82 mmol) and methanol (10 mL) was added 30% aqueous solution of hydrogen peroxide (0.12 mL, 1.0 mmol) and 0.2 M aqueous NaOH (0.06 mL). The mixture was stirred at 50° C. for 4 h, then cooled. The mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with 2N aqueous NaOH (50 mL) and brine (50 mL), then dried (Na2SO4), and concentrated to afford the title compound as pale yellow solids: 1H-NMR (CDCl3) δ 8.23 (1H, d, J=1.1 Hz), 7.96 (1H, br.s), 7.76 (1H, dd, J=1.1 Hz, 8.4 Hz), 7.42–7.51 (4H, m), 7.25 (1H, br.s), 7.09 (1H, d, J=8.4 Hz), 3.70 (2H, t, J=6.6 Hz), 2.85 (2H, t, J=6.9 Hz), 2.76 (2H, q, J=7.4 Hz), 1.24 (3H, t, J=7.4 Hz).