Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:11]=[C:12]([C:17]2([C:32]([F:35])([F:34])[F:33])[O:21][N:20]=[C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[C:24]([CH3:31])[CH:23]=3)[CH2:18]2)[CH:13]=[C:14]([Cl:16])[CH:15]=1.[N:36]1C=CC=CC=1>>[Cl:8][C:5]1([NH:36][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([C:19]3[CH2:18][C:17]([C:12]4[CH:11]=[C:10]([Cl:9])[CH:15]=[C:14]([Cl:16])[CH:13]=4)([C:32]([F:35])([F:34])[F:33])[O:21][N:20]=3)=[CH:23][C:24]=2[CH3:31])[N:6]=[CH:7][CH:2]=[CH:3][NH:4]1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Reactant: Nc1cnc(Cl)nc1
Reactant: c1ccncc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1(Cl)N=CC=CN1

Procedure:
In a solution of 0.12 g of 5-amino-2-chloropyrimidine in 3 mL of pyridine, 0.36 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 was added at room temperature with stirring, and stirred at the same temperature for 18 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, 30 mL of 3N hydrochloric acid was added in the residue, and extracted with ethyl acetate (30 mL×1). The organic phase was washed with water, and then dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (2:3) to obtain 0.24 g of the aimed product as white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]([C:16]4([CH3:23])[NH:21][C:20](=O)[CH2:19][O:18][CH2:17]4)[CH:13]=[CH:14][CH:15]=3)[NH:7][C:6]=2[CH:24]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]([C:16]4([CH3:23])[NH:21][C:20](=[S:34])[CH2:19][O:18][CH2:17]4)[CH:13]=[CH:14][CH:15]=3)[NH:7][C:6]=2[CH:24]=1
Reactant: CC1(c2cccc(-c3nc4ccc(Cl)cc4[nH]3)c2)COCC(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC1(c2cccc(-c3nc4ccc(Cl)cc4[nH]3)c2)COCC(=S)N1
Yield: 98 %

Procedure:
In close analogy to the procedure described for the preparation of Intermediate XVIII-1, the reaction of 5-[3-(6-chloro-1H-benzoimidazol-2-yl)-phenyl]-5-methyl-morpholin-3-one (202 mg, 0.6 mmol) with Lawesson's reagent yielded the title compound (210 mg, 98% of theory).
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:15]1([NH:7][C:2]2[C:1]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1-c1ccccc1
Reactant: Brc1ccccc1
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccccc2-c2ccccc2)cc1
Temperature: 110 °C
Yield: 95.4 %

Procedure:
Trisdibenzylideneacetonedipalladium (0.276 g, 0.3 mmol) and tri-tert-butylphosphine (0.121 g, 0.6 mmol) were put into a flask, and then dissolved in 40 mL of toluene. Subsequently, 2-biphenylamine (2.53 g, 15 mmol), bromobenzene (2.36 g, 15 mmol) and tert-butoxy sodium (2.16 g, 22.5 mmol) were added into the flask, and then refluxed at a temperature of 110° C. for 12 hours. After cooling the flask including the reactant mixture to room temperature, the reactant mixture was washed using an ammonium chloride aqueous solution (150 mL) to separate an organic layer. The separated organic layer was washed with distilled water three times, and was then dried with magnesium sulfate. Thereafter, residues from which volatile components were removed at reduced pressure were purified using a silica gel chromatography tube in a mixed solvent of hexane and ethylacetate (1:10) to produce 3.51 g of colorless N-phenylbiphenyl-2-amine liquid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)=[O:24])=[CH:19][CH:18]=1>>[Cl:31][C:27]1[CH:26]=[C:25]([C:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:22][CH:21]=2)=[O:24])[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccc(O)cc1)c1cccc(Cl)c1
Product: COc1cc2nccc(Oc3ccc(C(=O)c4cccc(Cl)c4)cc3)c2cc1OC
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 40.1 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (89 mg) and 3-chlorophenyl 4-hydroxyphenyl ketone (279 mg) obtained in Example 27 were mixed and stirred at 180° C. for 20 minutes. The reaction mixture was then purified in the same manner as described in Example 24 to obtain 67 mg of the title compound (yield: 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[C:6]([F:15])[C:3]=1[C:4]#[N:5].[C:16]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:21]=CC=C[CH:17]=1.CC(OC(/[N:41]=N/C(OC(C)C)=O)=O)C.Cl>C(OCC)(=O)C.C(Cl)Cl.O>[NH2:41][CH2:17][C@@H:16]([N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[C:6]([F:15])[C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:11]1)[CH3:21]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: N#Cc1c(F)cc(-c2cc[nH]n2)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](CN)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Yield: 31.8 %

Procedure:
2-chloro-6-fluoro-4-(1H-pyrazol-3-yl)benzonitrile (5.0 g, 22.56 mmol), N-t-BOC-(R)-1-amino-2-propanol (7.91 g, 45.1 mmol) and triphenylphosphine (11.84 g, 45.1 mmol) were dissolved in dry ethyl acetate under nitrogen atmosphere and stirred. DIAD (9.12 g, 45.1 mmol) was added dropwise and the reaction flask was cooled by ice bath. The reaction was stirred at RT overnight. Water and concentrated HCl (18.53 ml, 226 mmol) were added to the reaction mixture and the reaction was stirred at RT overnight. Water and DCM were added to the reaction mixture, stirred and water phase was separated. Organic phase was extracted twice with water and water phases were combined. The combined water phase was washed twice with DCM and pH of water was adjusted to ˜12 by addition of NaOH. Water phase was extracted twice with DCM and combined DCM phase was washed twice with water. Organic phase was evaporated to dryness and the product was purified by Flash-chromatography. Yield 31.8%. 1H-NMR (400 MHz; DMSO): δ 1.42 (d, 3H), 2.80-3.00 (m, 2H), 4.27-4.38 (m, 1H), 7.03 (d, 1H), 7.84-7.95 (m, 2H), 8.00 (m, 1H).
Reaction SMILES: [CH2:1]([C:4]1([OH:27])[C@@H:8]([NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:7][N:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:5]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.OO.CC([O-])=[O:41].[Na+].O>C1COCC1.O>[CH2:13]([O:12][C:10]([NH:9][C@H:8]1[CH2:7][N:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:5][C:4]1([OH:27])[CH2:1][CH2:2][CH2:3][OH:41])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=CCC1(O)CN(C(=O)OC(C)(C)C)C[C@@H]1NC(=O)OCc1ccccc1
Reactant: CC(=O)[O-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C(O)(CCCO)C1
Reaction time: 48 h

Procedure:
To a solution of 0.85 g of allyl alcohol of step C in 20 mL of anhydrous THF was added a solution of 15 mL of 0.5 N 9-BBN. The reaction was stirred for 2 days. Water (0.5 mL) was added followed with 1 mL of 30% H2O2 and 1 mL of NaOAc/water. After being stirred for 1 h, the organic phase was separated. The water solution was neutralized with HCl and extracted with EtOAc twice. The combined organic phase was dried over Na2SO4. Solvent was removed under vacuum. Column chromatography on silica gel using pure EtOAc as eluent provided 0.80 g of the title compound. MS (M+H)+395.
Reaction SMILES: O.[C:2]([NH:12][NH2:13])(=[O:11])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][NH2:10])=[O:8].C([O-])(=O)[C:15]([CH3:17])=[CH2:16].[CH3:20][C:21](=O)[CH3:22]>>[CH:16](=[N:10][NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([NH:12][N:13]=[CH:20][CH2:21][CH3:22])=[O:11])[CH2:15][CH3:17]
Reactant: NNC(=O)CCCCC(=O)NN
Reactant: CC(C)=O
Reactant: C=C(C)C(=O)[O-]
Solvent: O
Product: CCC=NNC(=O)CCCCC(=O)NN=CCC

Procedure:
In a stainless steel flask equipped with an agitator, 45.6 grams of water were added, the agitator was turned on, then 25 grams of adipic acid dihydrazide were added. The mixture was agitated for at least 10 minutes until a stable dispersion was formed. 16.4 grams of 2-propanone were then added under mixing. A clear solution formed after a few minutes. Mixing was continued for at least another hour until reaction product precipitated and formed a stable dispersion. The temperature of the dispersion was allowed to drop to 105° F. or below, and 10 grams of an acrylic latex containing 51% of methacrylate and butyl acrylic polymer were added, followed by 3.0 grams of AQUAFLOW NLS-200. The Stormer viscosity of the dispersion was 105 Kreb units at 77° F.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:8][NH:9][CH3:10].[CH2:11]=[O:12]>O>[CH3:8][N:9]([CH2:7][C:6]1[C:11]([OH:12])=[CH:2][CH:3]=[CH:4][N:5]=1)[CH3:10]
Reactant: C=O
Reactant: Oc1ccncc1
Reactant: CNC
Solvent: O
Product: CN(C)Cc1ncccc1O
Temperature: 50 °C
Reaction time: 4 h
Yield: 64.8 %

Procedure:
To a solution of 4-hydroxypyridine (200 g, 2.10 mol) in water (500 mL) were added 50% aqueous dimethylamine (228 g) solution and 36% aqueous formalin (210 g) solution, and the mixture was stirred at 50° C. for 4 hr. The solvent was evaporated under reduced pressure, and the resulting crystals were collected by filtration to give the title compound (207 g, yield 65%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:10][C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:6]=2[C:15]=1[CH3:16].[CH3:19][O:20][CH2:21]Br.C(O)(=O)C>N1C=CC=CC=1>[CH3:19][O:20][CH2:21][O:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:10][C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:6]=2[C:15]=1[CH3:16]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: COCBr
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: COCOc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)O)O2
Reaction time: 2 h

Procedure:
50 grams (0.2 mol) of 6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid are dissolved in 150 cm3 of anhydrous pyridine. 16.34 cm3 (0.2 mol) of bromomethyl methyl ether are added dropwise. The mixture is stirred for 2 hours and then the solution is poured onto ice. The mixture is acidified with acetic acid and then extracted with methylene chloride. The organic phase is washed with water and dried over anhydrous sodium sulfate, then the title product is purified by passing through a column of silica gel, eluting with methylene chloride.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:31])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]([CH2:28][NH2:29])=[N:15][C:14]=2[N:13]([CH3:30])[C:11]1=[O:12])(=[O:3])[CH3:2].[F:32][C:33]([F:44])([F:43])[C:34]([O:36]C(=O)C(F)(F)F)=[O:35]>C(Cl)(Cl)Cl>[C:1]([O:4][C@H:5]([CH3:31])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]([CH2:28][NH:29][O:36][C:34](=[O:35])[C:33]([F:44])([F:43])[F:32])=[N:15][C:14]=2[N:13]([CH3:30])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(CN)n2Cc2ccccc2)n(C)c1=O
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(CNOC(=O)C(F)(F)F)n2Cc2ccccc2)n(C)c1=O
Reaction time: 3 h
Yield: 95 %

Procedure:
A stirring solution of (R)-1-(5-acetoxyhexyl)-8-aminomethyl-7-benzyl-3-methylxanthine in chloroform (30 ml) was treated with trifluoroacetic anhydride (1.0 g, 4.76 mmol) and stirred for 3 hours. Concentration under reduced pressure gave a residue which was purified by flash chromatography on silica gel eluting with ethyl acetate to provide (R)-1-(5-acetoxyhexyl)-7-benzyl-3-methyl 8-(N-(trifluoroacetoxy)aminomethyl)xanthine (1.0 g, 95% yield) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:23])[O:17][CH2:18][CH:19]1[CH2:22][NH:21][CH2:20]1)([O-:3])=[O:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:23])[O:17][CH2:18][CH:19]1[CH2:20][N:21]([C:24](=[O:26])[CH3:25])[CH2:22]1)([O-:3])=[O:2]
Reactant: O=C(Nc1cc(-c2cccs2)ccc1[N+](=O)[O-])OCC1CNC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CC(COC(=O)Nc2cc(-c3cccs3)ccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
To a solution of azetidin-3-ylmethyl (2-nitro-5-(thiophen-2-yl)phenyl)carbamate (0.35 g, 1.05 mmol, 1 eq.) in dichloromethane (10 mL) was added TEA (0.22 mL, 1.57 mmol, 1.5 eq.) and acetic anhydride (0.11 mL, 1.15 mmol, 1.1 eq.) at 0° C. The reaction was warmed to room temperature and stirred for 1 h. The reaction was diluted with dichloromethane. The organic layer was washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 4% MeOH/CH2Cl2) to obtain (1-acetylazetidin-3-yl)methyl (2-nitro-5-(thiophen-2-yl)phenyl)carbamate (0.31 g, 79% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH2:23][OH:24])=[C:21]([Cl:25])[N:20]=[C:19]2[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3]C)=[O:2].C(O)(=[O:32])C>O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][N:18]2[C:22]([C:23]([OH:24])=[O:32])=[C:21]([Cl:25])[N:20]=[C:19]2[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:15][CH:16]=1)([OH:3])=[O:2]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 1.03 g of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole in 10 mL of anhydrous acetic acid at 25° was added a solution of 0.62 g of chromium trioxide in 10 mL of water. The mixture was stirred at 25° for 15 minutes and then poured into water. The precipitated solids were recovered by filtration and then dissolved in 50 mL of 1.0 N aqueous sodium hydroxide solution. The alkaline solution was allowed to stand at 25° overnight and then was acidified to pH 3 with 10% aqueous hydrochloric acid. The precipitated solid was recovered by filtration and recrystallized from ethyl acetate to afford 0.10 g of 1-[(2'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxylic acid (m.p. 186°-187° (decomp.)). NMR (DMSO-d6) δ12.97 (br s, 2H); 7.68 (d, 1H); 7.53 (t, 1H); 7.41 (t, 1H); 7.34 (d, 1H); 7.28 (d, 2H); 7.02 (d, 2H); 5.61 (s, 2H); 2.60 (t, 2H); 1.53 (quint., 2H); 1.27 (sext., 2H); 0.81 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1Br.[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[F:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=2[C:16]2[CH:17]=[CH:18][C:13]([S:12][CH3:11])=[CH:14][CH:15]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: Fc1cc(Br)c(Br)cc1F
Product: CSc1ccc(-c2cc(F)c(F)cc2-c2ccc(F)c(Cl)c2)cc1
Yield: 64 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VII, 4.1 g (15 mmol) of 1,2-dibromo-4,5-difluorobenzene, 3.0 g (18 mmol) of 4-methylthiophenylboronic acid (Example 1, Step 2) and 2.9 g (16.5 mmol) of 3-chloro-4-fluorophenylboronic acid were reacted. Purification by silica gel chromatography gave 3.5 g of 1-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-[4-(methylthio)phenyl]benzene as a semi-solid which was used without further purification.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH2:16]Br)[C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K]>CN(C=O)C>[C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH2:16][N:22]3[C:21](=[O:23])[C:20]4=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]4[C:18]3=[O:28])[C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(=O)Oc1ccc2cc(CBr)c(=O)oc2c1
Agent: [K]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2cc(CN3C(=O)c4ccccc4C3=O)c(=O)oc2c1
Yield: 48.7 %

Procedure:
7-acetoxy-3-bromomethylcoumarin (630 mg) was stirred overnight with potassium phthalimide (432 mg, 2.33 mmol) in DMF (100 mL). The reaction solvent was evaporated and the reaction partitioned between CH2Cl2 and water, then washed several times with water, then with aqueous NaHCO3. The organic layer was dried with brine, then with anhydrous sodium sulfate and evaporated. The crude product was recrystallized in acetic acid to give 7-acetoxy-3-phthalimidomethylcoumarin (375 mg, >95% purity), an off-white solid. 1H NMR (CDCl3): δ7.73-7.97 (m, 4H), 7.53 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.13 (s, 1H), 7.03 (dd, J=7.5, 2.1, 1H), 4.82 (s, 2H), 2.33 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([N:10]=[C:11]=[O:12])[CH2:7][CH2:8][CH2:9][C:2]1=2.Cl.[NH2:14][OH:15]>C(N(CC)CC)C>[OH:15][NH:14][C:11]([NH:10][CH:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:9][CH2:8][CH2:7]1)=[O:12]
Reactant: NO
Reactant: O=C=NC1CCCc2sccc21
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(NO)NC1CCCc2sccc21

Procedure:
The above compound is prepared in the manner described in Example 6, by allowing 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate to react with hydroxylamine hydrochloride in the presence of triethylamine. The product melts at 158.5° C. to 160.5° C.
Reaction SMILES: [BrH:1].C(O[CH:6]1[S:23][CH2:22][C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:7]1[O:8][C:9](=[O:11])[CH3:10])(=O)C>C(O)(=O)C.ClC(Cl)C>[C:9]([O:8][C@@H:7]1[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[CH2:22][S:23][C@H:6]1[Br:1])(=[O:11])[CH3:10]
Reactant: CC(=O)OC1SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Br
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Br
Reaction time: 2.5 h
Yield: 39 %

Procedure:
3.50 ml of a 30% solution of hydrobromic acid in glacial acetic acid are added at 10° C. to a solution of 2.10 g (6.3.10-3 mol) of 1,2,3,4-tetra-O-acetyl-5-thio-D-xylopyranose in 10 cm3 of dichloroethane. After 2 to 3 h, the reaction medium is hydrolyzed, washed with a solution of sodium bicarbonate and dried over sodium sulfate (Na2SO4) and the solvent is evaporated off to dryness under reduced pressure. 0.87 g (yield: 39%) of the expected product is obtained after precipitation in ether.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][CH2:24][CH2:25][C:26](O)=[O:27].COC1C=CC(C(O)=O)=CC=1>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH:16]2[CH2:17][CH2:18][N:19]([C:26](=[O:27])[CH2:25][CH2:24][O:23][CH3:22])[CH2:20][CH2:21]2)[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCC(=O)O
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2CCNCC2)CC1
Agent: COc1ccc(C(=O)O)cc1
Product: COCCC(=O)N1CCC(CN2CCC(NC(=O)OC(C)(C)C)CC2)CC1

Procedure:
Similar procedures as Example 60 are repeated except that 4-(t-butoxycarbonylamino)-1-(4-piperidinylmethyl)piperidine, and 3-methoxypropionic acid are used instead of 4-methoxybenzoic acid in Example 60 as described below to give 4-(t-butoxycarbonylamino)-1-[1-(3-methoxypropionyl)-4-piperidinylmethyl]piperidine.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:21][C@H:20]2[C:22](O)=[O:23])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:52][C:53]([F:57])([F:56])[CH2:54][NH2:55]>ClCCl.CN(C=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:21][C@H:20]2[C:22]([NH:55][CH2:54][C:53]([F:57])([F:56])[F:52])=[O:23])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Reactant: NCC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Reaction time: 0.25 h
Yield: 55 %

Procedure:
To a mixture of racemic-(trans)-2-{4-[(3-phenoxybenzyl)amino]phenyl}cyclopropanecarboxylic acid (I-2a) (0.15 g, 0.41 mmol) in dichloromethane (3 mL) and DMF (1 mL) was added HATU (0.23 g, 0.62 mmol). The mixture was stirred for 15 mins followed by addition of 2,2,2-trifluoroethylamine (0.08 g, 0.82 mmol). The solution stirred for 6 h after which the dichloromethane was removed via rotavap. Sat. NaHCO3 and ethyl acetate were added and the organic layer separated and washed with H2O, dried over MgSO4, filtered and concentrated. The resulting oil was triterated with Et2O and formed a white ppt which was filtered and dried under high vacuum to give the title compound as a white powder (0.109, 55%). 1H NMR (400 MHz, CDCl3) δ7.34-7.25 (m, 3H), 7.12 (t, J=7.5 Hz, 2H), 7.01 (t, J=7.7 Hz, 3H), 6.91 (t, J=8.4 Hz, 3H), 6.54 (d, J=8.4 Hz, 2H), 5.81 (s, 1H), 4.29 (s, 2H), 4.01-3.88 (m, 3H), 2.48-2.43 (m, 1H), 1.62-1.49 (m, 2H), 1.27-1.20 (m, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]1[N:9]=[C:8]([C:10](O)=[O:11])[C:7]([C:13]([OH:15])=O)=[N:6]1.[ClH:16]>CN(C)C=O>[O:5]1[N:9]=[C:8]([C:10]([Cl:16])=[O:11])[C:7]([C:13]([Cl:3])=[O:15])=[N:6]1
Reactant: Cl
Reactant: O=C(O)c1nonc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1nonc1C(=O)Cl
Reaction time: 1 h

Procedure:
In a glass reactor under a blanket of nitrogen was placed 120 ml of thionyl chloride and 15.8 g of 1,2,5-oxadiazole-3,4-dicarboxylic acid (Grundmann, Ber. 97 (2), 575-8, 1964). The mixture was heated to reflux and 0.5 ml of dimethylformamide was added. In the ensuing vigorous reaction HCl and SO2 were given off. Refluxing was continued for about 1 hour until all the free acid was dissolved. Excess thionyl chloride was removed at 50° C under vacuum and the residue distilled at 35° C/0.5 mm. Two redistillations gave 13.5 g of 1,2,5-oxadiazole-3,4-dicarbonyl chloride in the form of a colorless liquid boiling at 62°-64° C/9 mm. Infrared absorption at 1760 cm-1 (C=O) and at 1525 cm-1 and 1440 cm-1 (-C=N) was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[C:11]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[N:12].N1CCCCC1.O>C(O)C>[C:11]([C:13](=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[N:12]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: O=Cc1ccc(O)c(O)c1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)C(C#N)=Cc1ccc(O)c(O)c1
Yield: 63.8 %

Procedure:
2 g (15 mmol) 3,4-Dihydroxybenzaldehyde, 3 g (21 mmol) of tert-butyl cyanoacetate and 0.5 ml of piperidine in 50 ml ethanol were heated to reflux for 1 hour, poured into water, filtered, washed and dried to yield 2.5 g (yield 66%) of tert-butyl α-cyano-3,4-dihydroxycinnamate as a yellow solid.