Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][C:7]([C:10]1[CH:15]=[C:14]([CH:16]([NH:23][OH:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[C:12]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:11]=1[OH:29])([CH3:9])[CH3:8].[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>O.O1CCOCC1>[CH3:26][C:25]([C:12]1[CH:13]=[C:14]([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:23]([OH:24])[C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:15]=[C:10]([C:7]([CH3:6])([CH3:8])[CH3:9])[C:11]=1[OH:29])([CH3:28])[CH3:27]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)c1cc(C(NO)c2ccccc2)cc(C(C)(C)C)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C(=O)N(O)C(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 0.82 g (0.01 mole) of sodium acetate in 7 mL H2O is added to a solution of 1.08 g (0. 0033 mole) of 2,6-bis (1,1-dimethylethyl)-4-[(hydroxyamino)phenylmethyl]phenol in 30 mL dioxane. Isobutyryl chloride (0.51 g, 0. 00477 mole) is added dropwise and the mixture is stirred at room temperature for 17 hours. Water (25 mL) is added to the mixture and the solid material is filtered off and washed with water. After drying it is recrystallized from Et2O-n-hexane to give off-white crystals, 0.477 g (36%), m.p. 179°-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O.C(OCC)C>[C:25]([Si:22]([O:21][CH2:20][CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:9])[CH:4]=1)([CH3:24])[CH3:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)c(F)c1
Temperature: 100 °C
Yield: 67.5 %

Procedure:
To a solution of 4-chloro-3-fluoro-phenol (10 g, 68 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (19 g, 136 mmol), potassium iodide (11 g, 68 mmol), and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (18 g, 75 mmol, Aldrich). The reaction mixture was heated at 100° C. for 24 h. The crude was cooled, diluted with ethyl ether, washed with water, NaHCO3 solution, and brine. The organic layer was separated, dried over Na2SO4, and concentrated. The filtrate was concentrated and the residue was purified by chromatography (EtOAc:Hexanes=1:20) to give tert-butyl-[2-(4-chloro-3-fluoro-phenoxy)-ethoxy]-dimethyl-silane as colorless oil (Yield 14 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=[O:18])[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[N+](=[CH2:23])=[N-]>CO.CCOCC>[CH3:23][O:18][C:7]1[CH2:8][C:9](=[O:17])[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]2[CH:3]=[C:2]([Cl:1])[CH:20]=[CH:19][C:5]=2[N:6]=1
Reactant: C=[N+]=[N-]
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Solvent: CCOCC
Solvent: CO
Product: COC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1
Reaction time: 1 h

Procedure:
To 11.4 g of 7-chloro-5-phenyl-1H-1,5-benzodiazepine-2,4-dione stirred in 150 ml methanol is added, dropwise, approximately 2.1 g of diazomethane in ether. After addition is complete, the reaction is stirred for 1 hour and filtered. The filtrate is evaporated and the residue diluted with a small amount of ether. The suspension is filtered and the filtrate evaporated to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:13]=3[CH:14]=2)[C@H:9]([NH:19][CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH2:8][C@@H:7]1[CH3:35])=[O:5])[CH3:2].N1C=CC=CC=1.[C:42](Cl)(=[O:44])[CH3:43]>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:13]=3[CH:14]=2)[CH:9]([N:19]([C:42](=[O:44])[CH3:43])[CH2:20][C:21]2[CH:22]=[C:23]([C:31]([F:34])([F:32])[F:33])[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=2)[CH2:8][CH:7]1[CH3:35])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc3c(cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C)CCC3
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1c2cc3c(cc2C(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)CC1C)CCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
A solution of cis-4-(3,5-bis-trifluoromethyl-benzylamino)-2-methyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylic acid ethyl ester (Example 1E) (50 mg, 0.1 mmol) and pyridine (0.15 mL, 1.85 mmol) in dichloromethane (2.5 mL) was cooled in an ice water bath as acetyl chloride (0.2 mL, 2.8 mmol) was added by syringe. After stirring overnight at room temperature, the mixture was washed with 2N HCl, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 25% ethyl acetate/hexanes to afford 20 mg of the title compound. MS m/z 542.5 (M+); 1H NMR δ 1.1 (d, 3H), 2.3 (s, 3H), 6.8 (s, 1H), 7.3 (s, 1H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.[C:13]([O:19][CH3:20])(=[O:18])[CH2:14][C:15]([CH3:17])=O.B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:20][O:19][C:13](=[O:18])[CH2:14][C:15]1([CH3:17])[C:2]2[CH2:1][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=2[CH2:10][CH2:11][O:12]1
Reactant: COC(=O)CC(C)=O
Reactant: OCCC1=CCc2ccccc21
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: COC(=O)CC1(C)OCCC2=C1Cc1ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of indene-3-ethanol (8 g) and methyl acetoacetate (6 g) in 250 ml of dry benzene containing hydrated alkali-aluminum silicate (Molecular Sieves No. 4, about 2 g) is added 1 ml of boron trifluoride-etherate and the mixture stirred at room temperature for 4 hr. An additional 1 ml of boron trifluoride-etherate is added, the reaction mixture is stirred at ambient temperature overnight and then heated at reflux for 1 hr. The hydrated alkali-aluminum silicate is collected and the filtrate washed with 10% solution of sodium bicarbonate and water. After drying over magnesium sulfate the benzene is removed under reduced pressure affording 1-methyl-1,3,4,9-tetrahydroindeno[2,1-c]pyran-1-acetic acid methyl ester, νmaxfilm 1724 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH3:11].[Br:13]N1C(=O)CCC1=O>C(#N)C.S(=O)(O)[O-].[Na+].CCOCC.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH2:11][Br:13]
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)c1ccc(Br)cc1CBr
Temperature: 25 °C
Yield: 66.2 %

Procedure:
A mechanically stirred mixture of 4-bromo-2-methyl-benzoic acid methyl ester (115 g, 500 mmol), N-bromosuccinimide (90 g, 500 mmol) and AIBN (3.1 g) in acetonitrile (700 mL) was warmed over 45 minutes to a gentle reflux, and held at reflux for 21 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bisulfite, and concentrated in vacuo. The residue was partitioned between water and 1:1 hexanes:ethyl acetate. The organic phase was washed with water, brine, and filtered through a pad of silica gel. The solvent was removed under vacuum to give an oil/solid mixture, which was digested in ether and filtered. The filtrate was chromatographed on silica gel using a hexanes-ethyl acetate gradient, eluting the product at 4:1 hexanes-ethyl acetate and providing 102 g of 4-bromo-2-bromomethyl-benzoic acid methyl ester, in 66% yield; 1H NMR (DMSO-d6) δ 3.87 (s, 3H), 4.99 (s, 2H), 7.67-7.97 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[N:6][CH:7]=1.[CH2:12](O)[CH3:13]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)Cc1cncc(Br)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cncc(Br)c1
Temperature: 25 °C

Procedure:
15 drops of concentrated sulfuric acid are added to 5.0 g (23.1 mmol) of (5-bromopyridin-3-yl)acetic acid in 30 ml of ethanol, and the mixture is heated under reflux for 16 h. After cooling to RT, the mixture is concentrated under reduced pressure and the residue is taken up in ethyl acetate and washed with semiconcentrated sodium bicarbonate solution. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([CH:11]([CH2:23][CH2:24][CH2:25][CH:26]([OH:36])[CH2:27]OC1C=CC(F)=CC=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:10])[CH3:9]>>[C:8]([CH:11]([CH2:23][CH2:24][CH2:25][CH:26]([OH:36])[CH2:27][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:10])[CH3:9]
Reactant: CCOC(=O)CCCCCCC(CCCC(O)COc1ccc(F)cc1)C(C)=O
Reactant: Oc1cccnc1
Product: CCOC(=O)CCCCCCC(CCCC(O)COc1cccnc1)C(C)=O

Procedure:
The synthesis of this compound is carried out by the procedure of Example 1, Step E, except that an equivalent quantity of 3-hydroxypyridine is substituted for the 4-fluorophenol of Example 1, Step E.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@@H:9]1[C:15](=[O:31])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]2=[O:29])=[CH:19][C:18]=1[F:30])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:30][C:18]1[CH:19]=[C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]2=[O:29])[CH:21]=[CH:22][C:17]=1[NH:16][C:15]([C@H:9]1[CH2:10][C@@H:11]([O:13][CH3:14])[CH2:12][NH:8]1)=[O:31]
Reactant: CO[C@@H]1C[C@H](C(=O)Nc2ccc(N3CCCCC3=O)cc2F)N(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H]1CN[C@@H](C(=O)Nc2ccc(N3CCCCC3=O)cc2F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a solution of 8 (0.329 g, 0.761 mmol) in anhydrous CH2Cl2 (5 mL) was added TFA (5 mL). The solution was stirred at RT for 0.5 h before concentrating under reduced pressure to reveal 9 (0.255 g, 100%) as a tan oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:6].[CH2:22]([O:24][P:25]([CH2:30]/[CH:31]=[CH:32]/[C:33]1[CH:38]=[C:37]([CH3:39])[C:36]([CH:40]=O)=[C:35]([CH3:42])[CH:34]=1)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23]>>[CH2:27]([O:26][P:25]([CH2:30][CH2:31][CH2:32][C:33]1[CH:34]=[C:35]([CH3:42])[C:36]([C:40]2[NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)[CH:18]=[CH:19][C:20]=3[N:21]=2)=[C:37]([CH3:39])[CH:38]=1)(=[O:29])[O:24][CH2:22][CH3:23])[CH3:28]
Reactant: CCOP(=O)(C/C=C/c1cc(C)c(C=O)c(C)c1)OCC
Reactant: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1N
Product: CCOP(=O)(CCCc1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(C)c1)OCC

Procedure:
The title compound was prepared from 3,4-diamino-N-quinolin-2-yl-benzamide and [(E)-3-(4-formyl-3,5-dimethylphenyl)-allyl]-phosphonic acid diethyl ester analogous to Example 6-32 (steps 2 and 3). 1H NMR (Methanol-d4, 400 MHz): δ 8.46 (d, 1H), 8.39 (d, 1H), 8.30 (s, 1H), 8.05 (d, 1H), 7.93 (d, 2H), 7.83 (s, 1H), 7.76 (m, 1H), 7.55 (m, 1H), 7.09 (s, 2H), 4.14 (m, 4H), 2.78 (t, 2H), 2.18 (s, 6H), 1.96 (m, 2H), 1.85 (m, 2H), 1.34 (t, 6H). MS (m/z) 571.4 (M+1); Retention time: 1.41 min (Method 10).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[C:32]([C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)#[CH:33].C(NCC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:33]#[C:32][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#Cc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#Cc3cccnc3)c21
Reaction time: 48 h
Yield: 86 %

Procedure:
A flame-dried flask under an atmosphere of nitrogen gas containing N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Preparation # 15) (0.28 g) is treated with copper (I) iodide (0.01 g), dichlorobis(triphenylphosphine)palladium (II) (0.03 g) and 3-ethynylpyridine (0.10 g). The solids are treated with dimethylformamide (DMF) (3 mL) and diethylamine (3 mL). The resulting suspension is stirred for 2 days and is then concentrated under reduced pressure. The residue is flash column chromatographed on silica eluting with 2% to 4% methanol in dichloromethane. The product-containing fractions are combined and concentrated under reduced pressure. The resulting material is crystallized from methanol:acetonitrile to afford the title compound (0.23 g) as a tan solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:18]([C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Oc2ccccc2)s1
Temperature: 80 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
Ethyl 2-bromo-5-thiazolecarboxylate (10 g), phenol (4.38 g) and potassium carbonate powder (11.7 g) are suspended in dimethylformamide (50 ml) and the suspension is stirred for 3 hours at 80° C. The reaction mixture is treated in the same manner as in Example 1 to give ethyl 2-phenoxy-5-thiazolecarboxylate (10.2 g) boiling at 127°-128° C at 1 mmHg.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.Cl[C:10]1[O:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1>CN1C(=O)CCC1.O>[O:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[NH:7][C:4]1[CH:5]=[CH:6][C:1]([NH2:8])=[CH:2][CH:3]=1
Reactant: Nc1ccc(N)cc1
Reactant: Clc1nc2ccccc2o1
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
To a solution of benzene-1,4-diamine (5.0 g) in NMP (30 ml) was added dropwise, over 0.5 h, a solution of 2-chlorobenzo[d]oxazole (6.03 g) in NMP (50 mL). After the addition was complete, the mixture was stirred at ambient temperature for 1 h. After this time, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (150 ml), dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:19 methanol/methylene chloride) to afford N-(1,3-benzoxazol-2-yl)benzene-1,4-diamine (9.20 g) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11]([O:13][C:14](=[O:33])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:33])[CH2:15][C:16]1[CH:17]=[C:18]([C:2]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=2[CH:4]=[O:5])[C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH3:12]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=Cc1cc(F)ccc1Br
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-bromo-5-fluorobenzaldehyde and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [N:1]12[CH2:6][CH:5]1[CH2:4][CH2:3][S:2]2(=[O:8])=[O:7].[Br:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]=1[CH3:18].[H-].[Na+].O>CN(C)C(=O)C>[Br:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH:5]2[CH2:4][CH2:3][S:2](=[O:8])(=[O:7])[NH:1][CH2:6]2)=[CH:12][C:11]=1[CH3:18]
Reactant: O=S1(=O)CCC2CN21
Reactant: Cc1cc(O)cc(C)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(OC2CCS(=O)(=O)NC2)cc(C)c1Br
Temperature: 130 °C
Reaction time: 5 h

Procedure:
2-Thia-1-aza-bicyclo[3.1.0]hexane 2,2-dioxide (Liang, Jiang-Lin et al., Organic Letters, 2002, vol. 4, #25 p. 4507-4510) (300 mg) is added to a suspension of 4-bromo-3,5-dimethylphenol (1.14 g) and sodium hydride (140 mg of a 60% mineral oil suspension) in 25 mL of N,N-dimethylacetamide. The reaction mixture is stirred at 130° C. for 5 h. Water is added and the reaction mixture is extracted with ethyl acetate. The organic phase is separated, dried over sodium sulfate and concentrated under vacuum. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 100:0→30:70) to give the title compound. Yield: 220 mg.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([CH:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[OH:13])=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]1([C:7]2[S:8][C:9]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[O:13])=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(C(O)c2cnc(-c3ccccc3)s2)cc(OC)c1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cc(C(=O)c2cnc(-c3ccccc3)s2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To a solution of 40e (0.357 g, 1 mmoL) in 40 mL anhydrous CH2Cl2 was added Dess-Martin reagent (0.848 g, 2 mmol). The mixture was allowed to stir for 30 min and quenched with sat. Na2S2O3 solution, extracted with ethyl acetate and dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to give pure compound 1e (80.1%). 1H NMR (CDCl3) δ 8.33 (s, 1H), 8.04 (m, 2H), 7.51 (m, 3H), 7.18 (s, 2H), 3.96 (s, 3H), 3.93 (s, 6H); MS (ESI) m/z 378.1 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:14]=[N:13]2)=[C:8]([OH:22])[CH:7]=1)=[O:5])[CH3:2].Br[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:14]=[N:13]2)=[C:8]([O:22][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: BrCCCc1ccccc1
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)OCC)nn2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2cc(C(=O)OCC)nn2)c(OCCCc2ccccc2)c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of ethyl 1-{4-[(ethylamino)carbonyl]-2-hydroxyphenyl}-1H-1,2,3-triazole-4-carboxylate (0.30 g) obtained in Example 133c) in DMF (10 ml) were added (3-bromopropyl)benzene (0.18 ml) and potassium carbonate (0.14 g), and the mixture was stirred overnight at 75° C. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound as a pale-yellow powder (0.25 g, 57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][NH2:8].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1.[BH4-].[Na+]>CO>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][NH:8][CH2:7][CH2:6][O:5][C:4]2[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH:14]=1
Reactant: O=Cc1cccnc1
Reactant: COc1ccccc1OCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1OCCNCc1cccnc1
Temperature: 105 °C
Reaction time: 3 h

Procedure:
10 g (0.06 mol) o-Methoxy-phenoxyethylamine were mixed with 6.4 g (0.06 mol) pyridine-3-aldehyde, heated to 105° C and kept at this temperature for 3 hours. The cooled mixture was dissolved in 400 ml methanol. The solution was cooled to 5° C and 5.7 g (0.15 mol) sodium borohydride added in small portions. The mixture was stirred for half an hour at room temperature and then refluxed for 6 hours.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]1[CH:49]=[CH:48][C:39]([C:40]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[O:41])=[CH:38][CH:37]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[CH:49]=[CH:48][C:39]([C:40]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[O:41])=[CH:38][CH:37]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C(c1ccc(CCl)cc1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccc(C(=O)N3CCOCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 4-[4-(chloromethyl)benzoyl]morpholine (0.87 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.16 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(OCC)(=O)C>[C:11]([NH:10][NH:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])(=[O:13])[CH3:12]
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)NNc1ccc(Cl)cc1Cl

Procedure:
Generally in a process of condensing a hydrazonoyl derivative of formula (A) to form a compound of formula (1), the free hydrazine (1) as described above, for example, 2,4-dichlorophenylhydrazine (1) is reacted with acetic anhydride at a temperature of about 10° C. in an appropriate solvent such as ethyl acetate, yielding the corresponding 1-acetyl-2-(2,4-dichlorophenyl)hydrazine (2). The hydrazine (2) is then chlorinated with phosphorous oxychloride at a temperature of about 110° C. in an appropriate solvent such as toluene, yielding the hydrazonoyl derivative of formula (A), N-(2,4-dichlorophenyl)ethanehydrozonoyl chloride. The hydrozonoyl chloride (A) is condensed with a ring forming agent, for example, potassium cyanate at a temperature of about 40° C. to about 65° C. in an appropriate solvent such as DMAC, yielding the corresponding compound of formula (1), 45-dihydro-1-(2,4-dichlorophenyl)-3-methyl-1,2,4-triazol-5(1H)-one. The condensing of hydrozonoyl chloride (A) to the compound of formula (1) in solvents such as DMAC is routinely aided by the presence of a catalyst, such as potassium fluoride. A detailed procedure for the preparation, and the potassium fluoride-catalized condensing of the hydrozonoyl chloride (A) with the ring forming agent potassium cyanate in DMAC to yield a compound of formula (1) is set forth in Example 1 hereinbelow.