Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@:2]1([C@@H:14]2[CH2:18][S:17][C:16](=[O:19])[N:15]2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:7][C@H:6]([OH:8])[CH2:5][C@@H:4]([CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[O:3]1.O[C@:30]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@@H](O)C[C@@H](CCCC=C)O1>>[OH:8][C@@H:6]1[CH2:5][C@@H:4]([CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[O:3][C@:2]([C@@H:14]2[CH2:18][S:17][C:16](=[O:19])[N:15]2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)([O:1][CH3:30])[CH2:7]1
Reactant: C=CCCC[C@@H]1C[C@H](O)C[C@](O)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Reactant: C=CCCC[C@@H]1C[C@@H](O)C[C@](O)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Product: C=CCCC[C@@H]1C[C@@H](O)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1

Procedure:
Application of the method shown in Example 13, with the modification that (R)-4-((2R,4R,6R)-2,4-dihydroxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one was substituted for (R)-4-((2R,4S,6R)-2,4-dihydroxy-6-(pent-4-enyl)-tetrahydro-2H-pyran-2-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound.
Reaction SMILES: [I-].[Br:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]([C:15]1[CH:20]=[CH:19][N+:18]([CH3:21])=[CH:17][CH:16]=1)([CH3:14])[CH3:13].CO.[BH4-].[Na+]>C(Cl)Cl>[Br:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]([C:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH:16]=1)([CH3:14])[CH3:13]
Reactant: C[n+]1ccc(C(C)(C)c2ccc([N+](=O)[O-])cc2Br)cc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CC=C(C(C)(C)c2ccc([N+](=O)[O-])cc2Br)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[1-(2-Bromo-4-nitro-phenyl)-1-methyl-ethyl]-1-methyl-pyridiniumiodide was mixed with MeOH (400 ml) and CH2Cl2 (200 ml), then treated with NaBH4 (2.5 g) in portions. After stirring at RT for 2 h, the mixture was extracted with CH2Cl2 (300 mL×3). The CH2Cl2 layer was washed with brine, dried over Na2SO4 and concentrated in vacuo, to provide the desired product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH2:17])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5].[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH:17][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][CH:29]=1)=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(CNC(=O)c2ccc(Cl)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 44.9 %

Procedure:
In a 50 mL round-bottomed flask, 3-aminomethyl-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester hydrochloride (intermediate I) (0.30 g, 0.791 mmol) and 4-chlorobenzoyl chloride (138 mg, 0.791 mmol) were added at 0° C. to 15 mL CH2Cl2. The reaction was stirred at 0° C. for 5 min. and then N,N-diisopropylethylamine (511 mg, 3.96 mmol) was added. The reaction mixture was stirred at 0° C. for 1 hr. The mixture was concentrated to dryness and then purified by flash chromatography using 40% ethyl acetate-hexanes. The desired product 7-chloro-3-[(4-chloro-benzoylamino)-methyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (171 mg, 45%) was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1.CN(P(N(C)C)(N(C)C)=O)C.C1OC1C>CCN(CC)CC>[CH3:13][O:12][C:11]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[C:3]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=1)[N:7]=[CH:6][CH:5]=[C:4]2[CH3:17]
Reactant: BrCCCCCc1cccs1
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Agent: CC1CO1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCc1cccs1

Procedure:
To a mechanically stirred mixture of 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline (WRAIR; 5.67 g, 0.023 mol), 1-bromo-5-(2-thienyl) pentane from previous step a (5.32 g, 0.023 mol) and HMPA (40 ml), at 115°-120° C., was added dropwise, during 45 min, a solution of Et3N (5 ml) and propylene oxide (10 ml). The mixture was heated at 115°-120° C. for 5 hr, allowed to cool and extracted with a solution of pet. ether (20°-40° C.) and Et2O (1:1 v/v, 200 ml). The extract was washed with 10% NaOH solution (3×75 ml) and the combined basic washings were re-extracted with pet. ether (20°-40°) and Et2O solution (1:1 v/v, 2×100 ml). The combined organic layers were washed with H2O (2×100 ml), dried (K2CO3), and treated with carbon (Darco G-60). Solvent evaporation gave 6-methoxy-4-methyl-8-nitro-5-[5-(2-thienyl) pentoxy] quinoline as a yellow solid, 5.61 g (61%), mp 51°-54° C. This material was used without further purification.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[CH:21][N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[CH:21][N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cc(OCc2cc(OCC(C)C)c(-c3cc(OC)ccc3F)cn2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2cnc(COc3cc(C(CC(=O)O)C4CC4)ncn3)cc2OCC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.7 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-((5-(2-fluoro-5-methoxyphenyl)-4-isobutoxypyridin-2-yl)methoxy)pyrimidin-4-yl)propanoate (78 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (2.0 ml) was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (19 mg) as a pale-yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=1.[OH-].[K+].[CH3:14]I>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:14])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: CC(=O)Nc1ccnc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(=O)N(C)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 600.9 %

Procedure:
A mixture of 10 g (59 mmol) N-(2-chloropyridin-4-yl)acetamide (commercially available), 9.8 g (17.6 mmol) pulverized KOH and 4.1 ml (6.4 mmol) methyl iodide in 60 ml acetone was stirred at room temperature for 2 h. After evaporation of all volatiles the residue was taken up in water and extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated to yield 7.1 g (66%) of the title compound as off-white solid. MS: (m/e): 345.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[NH2:5].[CH3:17][CH:18]([C:24]([CH3:26])=O)[C:19](OCC)=[O:20].ClC1C(OC2C=CC(Cl)=CC=2)=CC=C2C=1C(O)=C(C)C(C)=N2>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:6]([C:19]([OH:20])=[C:18]([CH3:17])[C:24]([CH3:26])=[N:5]2)=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)c(Cl)c1
Agent: Cc1nc2ccc(Oc3ccc(Cl)cc3)c(Cl)c2c(O)c1C
Solvent: CCO
Product: Cc1nc2cc(Cl)c(Oc3ccc(Cl)cc3)cc2c(O)c1C
Temperature: 150 °C
Yield: 93 %

Procedure:
A mixture composed of 2.2 g of 3-chloro-4-(4-chlorophenoxy)-aniline, 2.63 g of ethyl 2-methylacetoacetate, and 0.5 mL of ethanol was added dropwise to 3.8 g of polyphosphoric acid heated to 150° C. The mixed solution was stirred at 150 to 160° C. while removing ethanol by evaporation for 3 hr. The reaction solution was poured into 175 mL of iced water containing 2 mL of concentrated hydrochloric acid to produce crystals. The crystals were collected by filtration and were recrystallized from water/methanol to give 2.8 g of a mixture of 5-chloro-6-(4-chlorophenoxy)-4-hydroxy-2,3-dimethyl-quinoline with 7-chloro-6-(4-chlorophenoxy)-4-hydroxy-2,3-dimethyl-quinoline (yield 93%). The mixture (2.8 g) was stirred in 42 mL of acetic anhydride with heating at 120 to 125° C. for one hr. The reaction solution was concentrated, ethyl acetate was then added to the concentrate, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and the solvent was removed under the reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane/ethyl acetate) to give 1.03 g of 4-acetoxy-5-chloro-6-(4-chlorophenoxy)-2,3-dimethyl-quinoline (yield 32.6%) and 0.68 g of 4-acetoxy-7-chloro-6-(4-chlorophenoxy)-2,3-dimethyl-quinoline (yield 21.0%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].[H-].[Na+].[Cl:17][CH2:18][CH2:19][CH2:20]I>CN(C=O)C>[Cl:17][CH2:18][CH2:19][CH2:20][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Reactant: ClCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCCl

Procedure:
6-nitro-3,4-dihydroquinolin-2(1H)-one (1.50 g, 7.81 mmol) was dissolved in anhydrous DMF (30 mL) in an argon purged round bottom flask. The reaction was stirred in an ice-water bath and 60% sodium hydride in mineral oil (1.25 g, 31.25 mmol) was added in one portion. The reaction became dark red-orange. This solution was transferred using a cannulating needle to a solution of 1-chloro-3-iodopropane (2.52 mL, 23.47 mmol) in DMF (20 mL). The reaction was stirred at room temperature for 5 hours. The reaction was quenched with brine (25 mL), transferred to a separatory funnel and partitioned with ethyl acetate (30 mL). The aqueous was extracted twice more with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried with sodium sulphate, decanted and concentrated to afford a yellow solid. Purification by flash column chromatography afforded a yellow solid (Ethyl acetate:hexanes, 30:70-100:0); Yield: 1.58 g (75%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[CH:9]=O.[NH2:11][NH:12][C:13]([NH2:15])=[S:14]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][CH:9]=[N:11][NH:12][C:13](=[S:14])[NH2:15]
Reactant: O=C/C=C/c1ccccn1
Reactant: NNC(N)=S
Product: NC(=S)NN=CC=Cc1ccccn1
Yield: 43 %

Procedure:
The compound is prepared according to the method described in example 1A from (E)-3-pyridin-2-yl-propenal (0.2 mmoles) and from thiosemicarbazide (0.2 mmoles). Yield 43%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([CH2:7][OH:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.[CH2:16]([S:32](Cl)(=[O:34])=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CC(C)=O.C1(NC2CCCCC2)CCCCC1>[CH2:16]([S:32]([O:8][CH2:7][C:6]1[CH:9]=[C:10]([O:11][CH3:12])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:13]([O-:15])=[O:14])(=[O:34])=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: COc1cc(CO)c([N+](=O)[O-])cc1OC
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Cl
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCS(=O)(=O)OCc1cc(OC)c(OC)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of 5.33 g (0.025 mol) of 4,5-dimethoxy-2-nitrobenzyl alcohol and 8.15 g (0.025 mol) hexadecanesulfonyl chloride in 100 ml of acetone, dicyclohexylamine (5 ml, slight excess) was added via motor driven syringe over 30 minutes. After the addition was complete, the reaction was stirred an additional 30 minutes. The precipitated dicyclohexylamine hydrochloride was removed by filtration and the acetone filtrate reduced in volume in vacuo until most of the product had precipitated (yield 9.5 g, m.p. 81°-82° C.).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8](Cl)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.BrC1C(C(O)=O)=NC=CC=1.S(Cl)(Cl)=O.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27]O.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[C:3]([C:8]2[O:9][CH2:27][C:26]([CH3:30])([CH3:29])[N:25]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ncccc1Br
Reactant: CC(C)(N)CO
Agent: O=C(O)c1ncccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(c2ncccc2Br)=N1

Procedure:
A solution of 5.0 g. of 3-bromopicolinoyl chloride (prepared by refluxing 3-bromopicolinic acid with thionyl chloride by the procedure of Example 2) in 25 ml. of dichloromethane is added to a solution of 3.9 g. of 2-amino-2-methylpropanol in 25 ml. of dichloromethane at 0°C. The resulting hydroxyalkylpicolinamide is cyclized by refluxing with thionyl chloride by the method of Leffler and Adams, J. Am. Chem. Soc. 59:2252 (1937) and the resulting hydrochloride salt is neutralized with aqueous sodium hydroxide solution to give 3-bromo-2-(4,4-dimethyl-2-oxazolinyl)pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][CH2:10][Cl:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[CH2:9][CH2:10][Cl:11])=[CH:6][CH:7]=1
Reactant: O=C(CCCl)c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OC(CCCl)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-Bromo-phenyl)-3-chloro-propan-1-one (1 g, 4.04 mmol) in tetrahydrofuran (9 ml) and water (0.58 ml) was added sodium borohydride (0.16 g, 4.28 mmol). The reaction mixture was stirred at room temperature for 2 hours, quenched with careful addition of water and extracted with ethyl acetate. The organic layers were separated, dried (MgSO4), filtered and concentrated to afford the title compound, which was used in the next step without further purification. LC/MS. (PS-A2) Rt 3.07 [M+H]+ No Ionization.
Reaction SMILES: [C:1]1(/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9]C)=[O:8])[CH:2]=1.[OH-].[Na+]>COCOC.CO>[C:1]1(/[CH:11]=[CH:12]/[C:13]2[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=[O:8])[CH:2]=1
Reactant: COC(=O)c1ccc(/C=C/c2cccc(C(=O)OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCOC
Solvent: CO
Product: O=C(O)c1ccc(/C=C/c2cccc(C(=O)O)c2)cc1

Procedure:
A solution of 2.2 g of dimethyl (E)-stilbene-3,4'-dicarboxylate in 25 ml of dimethoxymethane and 12 ml of methanol was treated with 10 ml of 2M sodium hydroxide solution and heated under reflux for 18 hours. The reaction solution was concentrated. The aqueous residue was again diluted with water and acidified to pH 1 with 2N hydrochloric acid. The precipitate was filtered off under suction, rinsed with ice-water and dried at 60° C. overnight in a drying oven. There was obtained (E)-stilbene-3,4'-dicarboxylic acid as a light coloured powder, MS: m/z 268 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:34]=[CH:33][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH:30]=O)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:35][NH2:36].[BH4-].[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:34]=[CH:33][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][NH:36][CH3:35])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3C=O)cc2)cc1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNCc1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-formylphenyl)benzamide (150 mg), methylamine (38% in methanol, 0.5 ml) and 3 Å molecular sieves (500 mg) in methanol (10 ml) was stirred at ambient temperature overnight. Sodium borohydride (39 mg) was added to the solution and the mixture was stirred at ambient temperature for 4 hours. The mixture was diluted with chloroform and the solution was washed with saturated aqueous sodium hydrogen carbonate and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give crude oil. The oil was purified by silica gel column (10 g, 2% methanol in chloroform) and the product was solidified with diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-methylaminomethylphenyl)benzamide (160 mg) as a white powder.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O.O>CO>[OH:16][C:8]1[CH:7]=[CH:6][C:5]([C@@H:3]([OH:4])[C@@H:2]([NH:1][CH2:23][C:22]2[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=2)[CH3:17])=[CH:10][C:9]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Solvent: O
Solvent: CO
Product: COc1cc(CN[C@@H](C)[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.4 %

Procedure:
To a solution of the amine (4) (111 mg, 0.43 mmol) and 3,4,5-trimethoxybenzaldehyde (111 mg, 0.55 mmol) in methanol (4 mL) was added borane-pyridine complex (135 μL, 1.28 mmol) at 40° C. and the resulting mixture was stirred for 1.5 hours. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with a mixed solvent (ethyl acetate:methanol=10:1) and subsequent washing of the organic layer with saturated brine. The organic layer was dried and concentrated and the obtained crude product was purified by amine silica gel column chromatography (eluent; chloroform:methanol=7:1) to obtain the desired amine (8) as a white solid (67 mg, Yield: 36%).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]3[CH:20]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[O:18][N:17]=3)=[CH:13][C:8]=2[O:7][CH:6]=1.O.[OH-].[Li+].O.Cl>O1CCCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[O:18][N:17]=[C:16]([CH2:15][O:14][C:12]3[CH:11]=[CH:10][C:9]4[C:5]([CH2:4][C:3]([OH:28])=[O:2])=[CH:6][O:7][C:8]=4[CH:13]=3)[CH:20]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)Cc1coc2cc(OCc3cc(-c4ccc(Cl)cc4)on3)ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1coc2cc(OCc3cc(-c4ccc(Cl)cc4)on3)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of {6-[5-(4-chloro-phenyl)-isoxazol-3-ylmethoxy]-benzofuran-3-yl}-acetic acid methyl ester (0.20 g, 0.50 mmol) in 8.0 ml of tetrahydrofuran was treated with lithium hydroxide monohydrate (0.10 g, 2.4 mmol), followed by 2.5 ml of water. The mixture was stirred at room temperature for 16 hours and added to 75 ml of water. The solution was made strongly acidic by the addition of 4.0 N hydrochloric acid. The precipitated product was extracted with ethyl acetate (4×75 ml). The combined organic layers were washed with brine (2×150 ml), then dried over anhydrous sodium sulfate and evaporated to a white solid. The crude product was recrystallized from aqueous acetonitrile. mp 193–194° C.; IR (thin film) cm−1: 1716, 1611, 1434, 1288, 1224, 1146; 400 MHz 1H NMR (DMSO-d6) 12.39 (br s, 1H), 7.87 (d, 2H, J=8.8 Hz), 7.73 (s, 1H), 7.55 (d, 2H, J=8.8 Hz), 7.44 (d, 1H, J=8.6 Hz), 7.28 (d, 1H, J=2.0 Hz), 7.19 (s, 1H), 6.93–6.96 (m, 1H), 5.24 (2, 2H), 3.59 (s, 2H); MS m/z 382 (M−1). Anal. Calc'd for C20H14ClNO5: C, 62.59; H, 3.68; N, 3.65; found: C, 62.87; H, 3.67; N, 3.61.
Reaction SMILES: [NH2:1][C:2]1([NH:7][C:8](=[O:17])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][NH:4][C:3]1=[O:6].N1C=CC=CC=1.[C:24](OC=O)(=[O:26])C>ClCCl>[CH:24]([NH:1][C:2]1([NH:7][C:8](=[O:17])[CH2:9][O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:5][NH:4][C:3]1=[O:6])=[O:26]
Reactant: NC1(NC(=O)COc2ccccc2)CNC1=O
Reactant: CC(=O)OC=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=CNC1(NC(=O)COc2ccccc2)CNC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
The amine (27) (66 mg) in dry dichloromethane (5 ml) was cooled to 0° and treated with pyridine (49 mg) followed by formic-acetic anhydride (27 mg). The mixture was stirred at 0° for 15 minutes then allowed to warm to room temperature over 15 minutes, and evaporated to dryness. The residue was chromatographed on silica gel to give the product (28) (53 mg).
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(O[CH2:22][CH2:23][F:24])(=O)=O>CN(C)C=O>[F:24][CH2:23][CH2:22][O:16][C:13]1[CH:12]=[CH:11][C:10]([O:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:15][CH:14]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CS(=O)(=O)OCCF
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FCCOc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.2 %

Procedure:
To a suspension of sodium hydride (60% oil dispersion; 4.0 g) in N,N-dimethylformamide (100 ml), 4-phenoxyphenol (18.6 g) was added at a temperature of 0 to 5° C., and the resultant suspension was stirred at room temperature for 1 hour. 2-Fluoroethyl methanesulfonate (14.2 g) was added thereto. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was subjected to post-treatment as in Example 1 to give 1-(2-fluoroethoxy)-4-phenoxybenzene (Compound No. 22) (20.0 g). nD25.0 1.5622.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5](=[O:7])[N:4]([CH2:8][C:9](=O)[CH3:10])[N:3]=1.O.[NH2:13][NH2:14].C(O)(=O)C(O)=O>CC(O)C.O>[CH3:10][C:9]1[CH2:8][N:4]([NH:3][C:2](=[O:6])[CH3:1])[C:5](=[O:7])[NH:13][N:14]=1
Reactant: NN
Reactant: CC(=O)Cn1nc(C)oc1=O
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: O
Product: CC(=O)NN1CC(C)=NNC1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.9 %

Procedure:
To a solution of 5-methyl-3-(2-oxo-propyl)-3H-1,3,4-oxadiazol-2-one (2.052 g, 13.14 mmol) in a mixture of 2-propanol (12 mL) and water (0.3 mL) is added hydrazine monohydrate (0.96 mL, 19.8 mmol). The mixture is stirred at rt under N2 for 15 h, and then heated to reflux for 7 h. A solution of oxalic acid (0.363 g, 4.032 mmol) in 2-propanol (6 mL) is added to the warm reaction solution. The resulting precipitate is removed by filtration through a coarse porosity sintered glass funnel, and the filtrate is concentrated in vacuo to approximately 10 mL in total volume. The concentrated solution is chilled to −12° C., and the resulting crystals are collected by filtration and dried to afford N-(6-methyl-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl)-acetamide (1.562 g, 70%). MS: 171 (M+H); 1H NMR (300 MHz, CDCl3) δ 8.10 (br s, 1H), 7.57 (br s, 1H), 4.20 (s, 2H), 2.04 (s, 3H), 1.95 (s, 3H); 1H NMR (300 MHz, DMSO-d6) δ 9.98 (s, 1), 9.74 (s, 1), 4.04 (s, 2), 1.84 (s, 6).