Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]([O:27][CH3:28])=[CH:6][C:7]2[C:16]3[CH2:15][CH2:14][N:13]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20](O)=[O:21])[CH2:12][C:11]=3[CH:10]=[N:9][C:8]=2[CH:26]=1.C(N(CC)C(C)C)(C)C.CCCP(=O)=O.[CH:44]([C:47]1[CH:48]=[C:49]([CH:51]=[CH:52][CH:53]=1)[NH2:50])([CH3:46])[CH3:45]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:2][O:3][C:4]1[C:5]([O:27][CH3:28])=[CH:6][C:7]2[C:16]3[CH2:15][CH2:14][N:13]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20]([NH:50][C:49]4[CH:51]=[CH:52][CH:53]=[C:47]([CH:44]([CH3:46])[CH3:45])[CH:48]=4)=[O:21])[CH2:12][C:11]=3[CH:10]=[N:9][C:8]=2[CH:26]=1
Reactant: COc1cc2ncc3c(c2cc1OC)CCN(c1cccc(C(=O)O)c1)C3
Reactant: CC(C)c1cccc(N)c1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2ncc3c(c2cc1OC)CCN(c1cccc(C(=O)Nc2cccc(C(C)C)c2)c1)C3
Reaction time: 0.08 h
Yield: 16.6 %

Procedure:
To a mixture of 3-(8,9-dimethoxy-1,4-dihydrobenzo[c]-2,7-naphthyridin-3(2H)-yl)benzoic acid hydrochloride (0.25 mmol, 100 mg) and N, N-diisopropylethylamine (0.75 mmol, 0.131 mL) in 2.0 mL DMF at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.325 mmol, 0.193 mL). After 5 min at rt, 3-isopropylaniline (0.375 mmol, 0.053 mL) and catalytic DMAP was added and the reactions continued for 2 hours. Then an additional 0.050 mL propylphosphonic anhydride solution and 0.025 mL 3-isopropylaniline was added and the reaction continued for 19 hours. The reaction was quenched into dilute aqueous Na2CO3 solution, extracted into EtOAc, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting oil was chromatographed eluting with CHCl3/EtOAc and then recrystallized from EtOAc/hexane to give the title compound as a white solid (20 mg, 17%).
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[Cl:13][C:14]1[C:19]([Cl:20])=[C:18]([F:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][C:26](=O)[CH2:25]1)=[O:23].[CH3:31][C:32]1[O:36][C:35]([C:37]([NH:39][NH2:40])=O)=[CH:34][CH:33]=1>ClCCl>[Cl:13][C:14]1[C:19]([Cl:20])=[C:18]([F:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]2[C:37]([C:35]3[O:36][C:32]([CH3:31])=[CH:33][CH:34]=3)=[N:39][N:40]=[C:26]2[CH2:25]1)=[O:23]
Reactant: Cc1ccc(C(=O)NN)o1
Reactant: O=C1CN(C(=O)c2ccc(F)c(Cl)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2nnc3n2CCN(C(=O)c2ccc(F)c(Cl)c2Cl)C3)o1
Reaction time: 1 h

Procedure:
Triethyloxonium tetrafluoroborate (197 mg, 1.039 mmol) was added to a solution of the 4-[(2,3-dichloro-4-fluorophenyl)carbonyl]-2-piperazinone (I34) (275 mg, 0.945 mmol) in Dichloromethane (DCM) (6 mL) and the reaction was stirred for 1 h. To this was added the 5-methyl-2-furancarbohydrazide (I85) (159 mg, 1.134 mmol) and the reaction was stirred for 2 h. The solvent was evaporated and 1-butanol (6.00 mL) was added. The mixture was heated at reflux for 3 h. LCMS: Product peak observed. After cooling the solvent was evaporated and the residue was partitioned between water/EtOAc. The organic layer was dried (Na2SO4) and the solvent evaporated to afford a brown oil. This was purified by MDAP to afford a colourless solid of desired material in 38 mg.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:14])[CH:3]=1.S(Cl)([Cl:17])=O>ClCCl>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[C:4]([Cl:14])[CH:3]=1
Reactant: Nc1cc(Cl)c(C(=O)O)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Nc1cc(Cl)c(C(=O)Cl)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 4-amino-2-chloro-5-nitro-benzoic acid (2.60 g, 12.0 mmol) in 200 mL dichloromethane with 20 mL thionyl chloride was refluxed for 4 h, cooled to ambient temperature, filtrated and concentrated to dryness i.vac. The residue was further reacted without further purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([S:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1CCC[C@@H]1C(O)=O.ClN1C(=O)CCC1=O.[NH2:31][C:32]1[N:33]=[N:34][C:35]([C:38]2[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[C:40]([F:48])[CH:39]=2)=[CH:36][N:37]=1>C(Cl)(Cl)Cl>[F:48][C:40]1[CH:39]=[C:38]([C:35]2[CH:36]=[N:37][C:32]3[N:33]([C:12]([S:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)=[CH:13][N:31]=3)[N:34]=2)[CH:47]=[CH:46][C:41]=1[C:42]([O:44][CH3:45])=[O:43]
Reactant: COC(=O)c1ccc(-c2cnc(N)nn2)cc1F
Reactant: O=CCSc1ccc2ncccc2c1
Agent: O=C(O)[C@H]1CCCN1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(-c2cnc3ncc(Sc4ccc5ncccc5c4)n3n2)cc1F
Temperature: 25 °C

Procedure:
To a cooled (0° C.) mixture of (quinolin-6-ylthio)acetaldehyde (40.6 mg, 0.2 mmol) and D-proline (4.6 mg, 0.04 mmol) in chloroform (1.0 mL) was added N-chlorosuccinimide (26.7 mg, 0.2 mmol) with stirring. The mixture was stirred at 0° C. for 30 min, then gradually warmed to ambient temperature for 2 h. To the mixture was added methyl 4-(3-amino-1,2,4-triazin-6-yl)-2-fluorobenzoate (24.8 mg, 0.1 mmol). The reaction mixture was stirred for 1 h. The solvent was removed under reduced pressure. The residue was dissolved in isopropanol (2 mL) and heated to 100° C. overnight. After cooling, the mixture was filtered and the filtrate was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=432.3.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:9][CH2:8][C:7]1=[O:17])[CH3:4].Br[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=1.BrCCBr.C[Si](C)(C)[Cl:33].O>CCOCC>[ClH:33].[CH3:4][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([O:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:9][CH2:8][C:7]1([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=1)[OH:17])[CH3:2]
Reactant: CC(C)COC1CCC(=O)C(CN(C)C)C1
Reactant: CSc1cccc(Br)c1
Reactant: C[Si](C)(C)Cl
Agent: Cl
Solvent: BrCCBr
Solvent: CCOCC
Solvent: O
Product: CSc1cccc(C2(O)CCC(OCC(C)C)CC2CN(C)C)c1
Yield: 32 %

Procedure:
Compound (22) was reacted with 1-bromo-3-methylsulphanyl-benzene corresponding to the conditions described in Example 1. In departure from the conditions described in Example 1, ether was used as the solvent and 1,2-dibromoethane was added to the batch in order to increase the yield. The crude product obtained was purified with diisopropyl ether via a silica gel column, and was taken up in tetrahydrofuran/ether. The crystals obtained after adding trimethylchlorosilane/water were recrystallised from ethyl acetate. Compound (23) was obtained in a yield of 32% theoretical.
Reaction SMILES: [C:1]1([C@H](N)C)C=CC=CC=1.[OH:10][C:11]1[CH:23]=[CH:22][C:14]2[C@H:15]([CH2:18][C:19]([OH:21])=[O:20])[CH2:16][O:17][C:13]=2[CH:12]=1.S(=O)(=O)(O)O.CCCCCCC>CO.C1(C)C=CC=CC=1>[OH:10][C:11]1[CH:23]=[CH:22][C:14]2[C@H:15]([CH2:18][C:19]([O:21][CH3:1])=[O:20])[CH2:16][O:17][C:13]=2[CH:12]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=C(O)C[C@@H]1COc2cc(O)ccc21
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C[C@@H]1COc2cc(O)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a solution of [(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetic acid (1R)-1-phenylethylamine salt (1.0 g) in methanol (3 mL)-toluene (8 mL) was added concentrated sulfuric acid (0.412 mg), and the mixture was stirred at 60° C. for 2 hr. The mixture was concentrated, toluene (5 mL) was added, and the mixture was concentrated again. To the residue were added toluene (5 mL), tetrahydrofuran (8 mL) and 1N hydrochloric acid (5 mL) to perform an extraction operation. The organic layer was washed with water, 5% aqueous sodium bicarbonate and water, and concentrated, and the residue was dissolved in toluene (8 mL). The activated carbon (100 mg) was added, and the mixture was stirred at room temperature for 30 min. After filtration, the filtrate was concentrated. The obtained crude product was dissolved in toluene (2 mL), seed crystal was added, and the mixture was stirred at room temperature for 16 hr. n-Heptane (6 mL) was added, and the mixture was stirred at room temperature for 5 hr and at 0° C. for 1 hr. The precipitated crystals were collected by filtration, and dried at 50° C. to give the title compound (554 mg) as white crystals. 99.7% ee.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH3:13][NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CC#N.O>[CH3:13][N:14]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1)[CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: CNCC(=O)OC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)CN(C)Cc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Yield: 72.6 %

Procedure:
A mixture of 1-(bromomethyl)-4-nitrobenzene (1 g, 4.63 mmol), methyl 2-(methylamino)acetate hydrochloride (0.646 g, 4.63 mmol), and K2CO3 (0.960 g, 6.94 mmol) in CH3CN (20 ml) was heated under MW irradiation at 60° C. for 1.5 hours. The mixture was portioned between EtOAc and water, and the organic layer was washed with brine ad dried over Na2SO4. The solvent was removed and the crude was purified by filtration on SCX cartridge (DCM/MeOH 1/1; MeOH/conc.aq.NH4OH 90/10). The basic fraction was evaporated to dryness to give methyl 2-(methyl(4-nitrobenzyl)amino)acetate (0.800 g, 3.36 mmol, 72.5% yield, MS/ESI+ 239.1 [MH]+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[CH2:10][C:5]2=[CH:4][CH:3]=1.[C:12]([O:15][CH:16](OCC)OCC)(=O)[CH3:13]>>[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[C:10](=[CH:16][O:15][CH2:12][CH3:13])[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)nc2N1
Reactant: CCOC(OCC)OC(C)=O
Product: CCOC=C1C(=O)Nc2nc(Cl)ccc21

Procedure:
This compound was synthesized from 6-chloro-1H-pyrrolo[2,3-b]pyridin-2-one and diethoxymethyl acetate according to Procedure A. 1H NMR 400 MHz (DMSO-d6): δ 11.06 (s, 1H); 7.84 (s, 1H); 7.63 (d, 1H); 6.98 (d, 1H); 4.39 (m, 2H); 1.32 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=1[F:27])[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.Cl>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18][C:19]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=1[F:27])[CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Temperature: 0 °C
Reaction time: 6 h
Yield: 73.8 %

Procedure:
1.31 g of (R)-t-butyl 3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate, 16 mL of methylene chloride, and 16 mL of trifluoroacetic acid were added to 100 mL flask and the resulting reaction solution was stirred for 6 hours. After completing the reaction, the reaction solution was concentrated under reduced pressure and 16 mL of methanol was added to the concentrated residue. The reaction solution was cooled to 0° C., 2.82 g of sodium hydrogen carbonate and 0.77 mL of di-t-butyl dicarbonate were added, and then stirred for 6 hours while the reaction temperature was naturally increased to room temperature. After completing the reaction, the reaction solution was concentrated under reduced pressure; then 30 mL of ethyl acetate and 30 mL of water were added; and then stirred for 10 minutes. An aqueous layer was isolated, cooled to 0° C., and then 2 N hydrochloric acid aqueous solution was dropped to adjust to pH 3-4. The aqueous layer was extracted with methylene chloride:methanol=10:1 solvent, dehydrated with magnesium sulfate, and then concentrated under reduced pressure to obtain 828 mg of a title compound.
Reaction SMILES: [CH:1]([S:4]([CH2:7][C@H:8]1[C@@H:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:15]2=[O:32])[CH2:12][CH2:11][NH:10][CH2:9]1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH3:33][C:34]([CH3:36])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:34]([N:10]1[CH2:11][CH2:12][C@H:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:28])[F:30])[CH:22]=3)[C:15]2=[O:32])[C@H:8]([CH2:7][S:4]([CH:1]([CH3:3])[CH3:2])(=[O:5])=[O:6])[CH2:9]1)([CH3:36])[CH3:33]
Reactant: CC(C)=O
Reactant: CC(C)S(=O)(=O)C[C@@H]1CNCC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)N1CC[C@H](N2CC[C@H](NC(=O)c3cccc(C(F)(F)F)c3)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
A sample of N-((S)-1-((3R,4S)-3-(isopropylsulfonylmethyl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide (0.05 g) was dissolved in 1,2-dichloroethane (3 mL) prior to the addition of acetone (0.38 mL, 0.525 mMol). After stirring at rt for 1 h, sodium triacetoxyborohydride (0.445 g, 0.21 mMol) was added to the reaction. Stirring was continued for 2 h when the reaction was quenched with saturated NaHCO3. Partitioned between EtOAc and water. Organic layer was washed with brine and dried (MgSO4). Filtered, concentrated and chromatographed. The desired product, N-((S)-1-((3R,4S)-1-isopropyl-3-(isopropylsulfonylmethyl)piperidin-4-yl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide (0.0086 g, yield=16%) was obtained as a white solid. MS found: (M+H)+=518.2
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:5]=2[CH:6]=1.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](=O)[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]1([CH3:18])[C:8]2[NH:9][C:4]3[C:5]([C:7]=2[CH2:10][CH2:11][O:12]1)=[CH:6][CH:1]=[CH:2][CH:3]=3
Reactant: CC(=O)CCCCl
Reactant: OCCc1c[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(CCCCl)OCCc2c1[nH]c1ccccc21
Reaction time: 1 h

Procedure:
To a solution of tryptophol (15 g, 0.09 M) in 150 ml of benzene, 5-chloro-2-pentanone (12 g, 0.10 M) is added. The mixture is heated in the presence of 200 mg of p-toluene sulfonic acid and hydrated alkali-aluminum silicate (Molecular Sieves No.4). After 1 hr. of refluxing, 400 mg more of acid is added. After a total of 2 hr. the reaction is cooled, filtered and washed with 5% sodium bicarbonate, water and dried over sodium sulfate. Evaporation under reduced pressure affords an oil. This oil is purified by chromatography on silica gel. Elution with benzene and concentration of the eluent gives 1-(3-chloropropyl)-1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole, nmr (CDCl3) δ1.33 (3H); 1.93 (4H), 2.75 (2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:25])[F:24])[CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27](=O)[CH3:28].C([BH3-])#N.[Na+].[CH3:34][CH2:35]O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:25])([F:26])[F:24])[CH2:15][N:16]([CH2:27][CH3:28])[CH2:34][CH3:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccccc2C(F)(F)F)CC1
Reactant: CC=O
Reactant: CCO
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CC)CC(c1ccccc1C(F)(F)F)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a solution of a 4-[2-Amino-1-(2-trifluoromethyl-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (204) (0.75 g, 2.01 mmol) in EtOH (50 mL) was added acetaldehyde (3.37 mL, 60.3 mmol) via RT distillation (warming flask with hand). Halfway through the addition of the acetaldehyde, sodium cyanoborohydride (0.631 g, 10.05 mmol) was added. The reaction was allowed to stir at room temperature for 18 h. The reaction mixture was concentrated to dryness. The resulting residue was taken up in EtOAc (50 mL) and washed with sat. NaHCO3 (50 ml) and brine (50 mL). The organic phase was concentrated to dryness yielding 0.860 g (99%) product.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])=[CH:4][CH:3]=1.[CH3:15][CH:16]([S-:18])[CH3:17].[Na+]>>[CH:16]([S:18][C:2]1[N:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])=[CH:4][CH:3]=1)([CH3:17])[CH3:15]
Reactant: O=C1NCC[C@H]1Oc1ccc(Br)nc1
Reactant: CC(C)[S-]
Agent: [Na+]
Product: CC(C)Sc1ccc(O[C@@H]2CCNC2=O)cn1

Procedure:
Typical Procedure 8 was followed. Reaction of (R)-3-(6-bromo-pyridin-3-yloxy)-pyrrolidin-2-one with sodium 2-propanethiolate provided the title compound. MS ESI+: m/z=253 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([CH:18]=[N:19][OH:20])=[CH:16][CH:15]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2].Cl.[OH-].[Na+]>CO.C1COCC1.O1CCOCC1>[CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][NH:19][OH:20])=[CH:21][CH:22]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2]
Reactant: CCc1nc(C)cc(=O)n1CCOc1ccc(C=NO)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: CCc1nc(C)cc(=O)n1CCOc1ccc(CNO)cc1
Reaction time: 0.17 h
Yield: 89.7 %

Procedure:
To a stirred solution of 4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde oxime (301 mg, 1.0 mmol) (obtained from preparation 17) in a mixture of methanol (7 ml) and THF (3 ml) was added 4N HCl (2 ml) in dioxane at 30° C. and stirred for 10 min. at the same temperature. The reaction mixture was basified to pH 9 with 1N NaOH and extracted with EtOAc (3×10 ml). The combined organic layers were washed with brine and dried over anhydrous Na2SO4 and concentrated to yield the of title compound (272 mg, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].CO[CH:12]=[C:13]1[C:18](=[O:19])[O:17][C:16]([CH3:21])([CH3:20])[O:15][C:14]1=[O:22]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH:12]=[C:13]2[C:14](=[O:22])[O:15][C:16]([CH3:20])([CH3:21])[O:17][C:18]2=[O:19])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Reactant: Cc1ccc(N)cc1Br
Solvent: CC(C)O
Product: Cc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1Br
Temperature: 90 °C
Yield: 84 %

Procedure:
To a vial charged with 3-bromo-4-methylaniline (1.00 g, 5.37 mmol) was added IPA (10.75 ml) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.001 g, 5.37 mmol) respectively. The mixture was heated to 90° C. for 2 hrs, providing a brown solution which was cooled to room temperature, yielding an orange precipitate which was collected by vacuum filtration affording 5-(((3-bromo-4-methylphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.535 g, 4.51 mmol, 84% yield). This solid was transferred to a 5-20 ml microwave vial and 9 ml (0.5M 1,2-dichlorobenzene) was added and the mixture irradiated at 225° C. for 15 min, affording conversion to desired product according to LC-MS. To the suspension was added diethyl ether (˜5 ml) to aid in product precipitation. The precipitate was collected via vacuum filtration and washed with ether, affording a brown solid as an isomeric mixture (560 mg). To the filtrate which had some precipitate forming was added heptane affording additional precipitate. This second crop was collected affording another 115 mg of product (53% yield total). m/z (ESI) 238.1/240.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1.O>CN(C=O)C>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:15]2[C:14](=[O:17])[N:11]3[N:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[C:9]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C:10]3=[N:16]2)=[CH:34][CH:33]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(Cl)cc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 60 °C
Yield: 60.4 %

Procedure:
To a solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (0.4 g, 1.1 mmol), prepared as described in Example 1 in DMF (5 mL) was added K2CO3 (0.46 g, 3.3 mmol) and 4-chlorobenzyl bromide (0.28 g, 1.3 mmol). The reaction mixture was heated at 60° C. for 20 min. After this time, water (50 mL) was added to the reaction mixture and the resultant solid was collected by filtration. The final product (0.32 g, 60%) was obtained by purification using reverse phase preparative HPLC. MS (M+H)=481; 1H NMR (CDCl3): δ 8.18 (1H, s), 7.25-7.40 (10H, m), 7.08 (2H, d, J=10.0 Hz), 5.18 (2H, s).
Reaction SMILES: C(C1C=CC(CCCCC2C=CC=CC=2[C:21]2[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[N:25]=2)=CC=1)CCC.[CH3:28][I:29]>>[I-:29].[CH3:28][N+:25]1[C:24]([CH3:27])([CH3:26])[CH2:23][O:22][CH:21]=1
Reactant: CI
Reactant: CCCCc1ccc(CCCCc2ccccc2C2=NC(C)(C)CO2)cc1
Product: C[N+]1=COCC1(C)C
Product: [I-]

Procedure:
Following the procedures of Example 1(a), (b) and (c), to 4-(4-butylphenyl)butylmagnesium bromide (from 21.47 mmoles of 4-(4-butylphenyl)butyl bromide and 18.96 mmoles of magnesium) in distilled tetrahydrofuran (35 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (16.32 mmoles) in tetrahydrofuran (15 ml). Workup of the reaction mixture furnished 2-[2-(4-(4-butylphenyl)butyl)phenyl]-4,4-dimethyloxazoline as an oil. A solution of the oxazoline (14.41 mmoles) in methyl iodide (20 ml) was refluxed under argon for 18 hours. Removal of the volatiles afforded the corresponding 3,4,4-trimethyloxazolinium iodide as a white solid (mp 91°-94° C.). To an ice cold solution of the iodide (14.07 mmoles) in methanol was added in portions sodium borohydride (14.30 mmoles). Similar treatment of the reaction mixture resulted in the isolation of the desired benzaldehyde product as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][NH2:12])[CH3:2].[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22](O)=[O:23])=[CH:16][CH:15]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.CCOC(C)=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][NH:12][C:22](=[O:23])[CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCOc1ccccc1CCN
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccccc1CCNC(=O)CCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 104.2 %

Procedure:
2-(2-Ethoxyphenyl)ethanamine (0.55 g, 3.33 mmol) and 3-(4-hydroxyphenyl)propanoic acid (0.50 g, 3.00 mmol) was dissolved in dimethyl formamide (5 ml) and cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (1.18 g, 3.66 mmol) and diisopropylethylamine (0.90 g, 7.0 mmol) were added and the solution was warmed to room temperature and stirred overnight. EtOAc (15 ml) was added and the organic phase was washed with two portions of sodium hydrogencarbonate (aq, 10 ml). The organic phase was dried (MgSO4) and EtOAc was removed by evaporation to give 0.98 gram of N-[2-(2-ethoxyphenyl)ethyl]-3-(4-hydroxyphenyl)propanamide (yield 93.9%).