Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([F:13])[CH:7]=1.[CH:17]1([C:20](=[S:22])[NH2:21])[CH2:19][CH2:18]1>>[CH3:1][O:2][C:3]([C:4]1[N:21]=[C:20]([CH:17]2[CH2:19][CH2:18]2)[S:22][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([F:13])[CH:7]=1)=[O:16]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(C)c(F)c1
Reactant: NC(=S)C1CC1
Product: COC(=O)c1nc(C2CC2)sc1-c1ccc(C)c(F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-fluoro-4-methyl-phenyl)-2-oxo-propionic acid methyl ester with cyclopropanecarbothioic acid amide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:11][CH:10]=1.Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[N:24][OH:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:11][CH:10]=1
Reactant: NO
Reactant: O=C(CCCCCO)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCCCCCC(=NO)c1ccc(-c2ccc(Cl)cc2Cl)cc1

Procedure:
1-(2′,4′-Dichloro-biphenyl-4-yl)-6-hydroxy-hexan-1-one (400 mg) was dissolved in a mixture of ethanol (10 mL) and water (5 mL). Hydroxylamine hydrochloride (300 mg) and sodium acetate (350 mg) were added and the mixture refluxed for 5 hours. After cooling, the mixture was diluted with water and extracted with ethyl acetate. Evaporation and recrystallisation from ether/petrol gave the title compound as a white solid. 13C NMR (CDCl3): δ 25.9, 26.2, 26.2, 32.3, 62.8, 126.1, 127.3, 129.6, 129.8, 132.0, 133.2, 134.0, 135.2, 138.4, 139.1 and 159.3. 1H NMR (CDCl3): δ 1.45 (2H, m), 1.59 (4H, m), 2.80 (2H, m), 3.62 (2H, m), 7.26 (2H, m), 7.41 (2H, d, J=7.0 Hz), 7.47 (1H, m) and 7.64 (2H, d, J=7.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][C:7]#[N:8].N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C1(C)C=CC=CC=1>[C:7]([CH2:6][O:5][C:4]1[CH:3]=[C:2]([NH:1][S:19]([CH3:18])(=[O:21])=[O:20])[CH:11]=[CH:10][CH:9]=1)#[N:8]
Reactant: CS(=O)(=O)Cl
Reactant: N#CCOc1cccc(N)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(OCC#N)c1
Temperature: 5 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
To a solution of crude (3-aminophenoxy)acetonitrile (ca 12.1 g) in toluene (50 mL) was added pyridine (6.6 mL) and methanesulfonyl chloride (6.3 mL) at 5° C. and the resultant mixture was warmed to ambient temperature. After 2 h, the crude product mixture was partitioned between 1N hydrochloric acid (100 mL) and ethyl acetate (100 mL). The phases were separated and the aqueous phase extracted with ethyl acetate (50 mL). The combined organic solution was washed with water, then concentrated with concomitant replacement of solvent with isopropanol. After cooling the resultant mixture to 5° C., the white crystalline product was collected, rinsed with cold isopropanol, and dried to afford 12.14 g (65.1% yield based on cyanomethyl tosylate) of N-(3-cyanomethoxyphenyl)methanesulfonamide (99.8% pure by HPLC). This material could optionally be recrystallized from isopropanol.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH2:20])=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32]>CN(C)C=O>[Cl:8][C:9]1[C:10]([CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH:20][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:28]([O:27][CH3:26])[CH:29]=2)=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:14]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CCOC(=O)C(N)c1ncc(C(F)(F)F)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1ccc(OC)c(OC)c1)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.75 h

Procedure:
Triethylamine (0.28 ml) was added to a solution of ethyl 2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinate (1 g; prepared in a similar manner to the starting material for Example 3) in dimethylformamide (10 ml) with stiring followed by 3,4-dimethoxybenzoyl chloride (0.70 g). the mixture was stirred for 45 minutes and evaporated. The residue was extracted with ethyl acetate and the extracts worked up to give the title product, m.p. 40-3° C. (Compound 601)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([Cl:8])=[C:4]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:12]([CH3:13])[C:3]=12.[CH2:20](C1OC=NC=1C1C=CC=CC=1)C>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([Cl:8])=[C:4]2[CH:9]=[N:10][C:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:12]([CH2:13][CH3:20])[C:3]=12
Reactant: Cc1c(-c2ccccc2)ncc2c(Cl)nnc(Cl)c12
Reactant: CCc1ocnc1-c1ccccc1
Product: CCc1c(-c2ccccc2)ncc2c(Cl)nnc(Cl)c12

Procedure:
In a procedure similar to (1), 11 g. of 5-ethyl-4-phenyloxazole is used instead of 5-methyl-4-phenyloxazole, whereby 3.2 g. of the above-indicated compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[C:4](=[O:5])[C:3]=1[CH2:14]/[CH:15]=[C:16](/[CH2:18][CH2:19]/[CH:20]=[C:21](/[CH2:23]C/C=C(/CC/C=C(/CC/C=C(/CC/C=C(/CC/C=C(/CC/C=C(/CC/C=C(/CCC=C(C)C)\C)\C)\C)\C)\C)\C)\C)\[CH3:22])\[CH3:17].[O-]S([O-])(=S)=O.[Na+].[Na+]>CCCCCC>[CH3:1][C:2]1[C:8]([OH:9])=[C:7]([O:10][CH3:11])[C:6]([O:12][CH3:13])=[C:4]([OH:5])[C:3]=1[CH2:14]/[CH:15]=[C:16](/[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])\[CH3:17]
Reactant: COC1=C(OC)C(=O)C(C/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C)=C(C)C1=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCCCCC
Product: COc1c(O)c(C)c(C/C=C(\C)CCC=C(C)C)c(O)c1OC
Temperature: 25 °C
Yield: 264.9 %

Procedure:
30 g of ubiquinone (MW: 863.36) was dissolved in 300 ml of hexane. While the solution was stirred at room temperature, 300 ml of a 10% (w/v) sodium hyposulfite solution was poured to the solution. The mixture was stirred at room temperature for 2 hours. The mixture was all introduced into a separating funnel, and the hexane layer was collected. The remaining aqueous layer was then extracted twice each with 50 ml of hexane, and the extract was combined with the previously collected hexane layer. The hexane layer was washed six times each with 50 ml of a deaerated saturated saline solution, thereby obtaining a transparent hexane layer. After hexane was removed under a reduced pressure, nitrogen purging was performed for day and night, resulting in 29.5 g of a cream colored solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>CO.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1
Reactant: c1ccc(CN2CCC(N3CCOCC3)CC2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: C1CC(N2CCOCC2)CCN1
Yield: 91.2 %

Procedure:
4-(1-benzyl-piperidin-4-yl)-morpholine (1.56 g, 6.0 mmol) was hydrogenated using Pd(OH)2 (20% on carbon, 390 mg, 25 wt%), 1.7 M HCl (10.6 mL) in methanol (50 mL) at 50° C. for 10 hours. The resulted amine dihydrochloride off-white solid was subjected to free-basing using excess basic resin to give 932 mg (91%) of 4-piperidin-4-yl-morpholine as waxy crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](=[O:7])[N:6]=1.N1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[CH:8]([CH:4]1[O:3][C:2]([N:1]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:6][C:5]1=[O:7])([CH3:10])[CH3:9]
Reactant: C1COCCN1
Reactant: CC(C)C1OC(N)=NC1=O
Product: CC(C)C1OC(N2CCOCC2)=NC1=O

Procedure:
Synthesis was performed from 2-amino-5-isopropyl-1,3-oxazol-4(5H)-one and morpholine according to Method G+H.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]#[CH:15])(=O)=O)=CC=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17].O1CCOCC1>C(OCC)C>[CH2:16]([N:18]([CH2:19][CH3:20])[CH2:12][CH2:13][C:14]#[CH:15])[CH3:17]
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCNCC
Solvent: C1COCCO1
Solvent: CCOCC
Product: C#CCCN(CC)CC
Temperature: 80 °C
Yield: 64.2 %

Procedure:
Prepared using methodology described by Olomucki, M., et al. Ann. Chim. 1960, 5, 845. A stirred mixture of but-3-ynyl 4-methylbenzenesulfonate (21.2 g, 94.5 mmol), diethylamine (6.91 g, 94.5 mmol), and p-dioxane (100 mL) was heated to 80° C. under N2 for 6 hours. After cooling to room temperature, the suspension was diluted with diethyl ether (100 mL) and filtered. The solids were washed with diethyl ether (50 mL). The filtrate was concentrated to a brown oil. The crude was co-distilled (55-65° C.) with p-dioxane under a mild vacuum (10-50 torr). The product was obtained as an oil (7.6 g, 27%), in a 42:58 mixture with p-dioxane based on 1H NMR. 1H NMR (400 MHz, CDCl3) δ 2.70 (t, J=8 Hz, 2H), 2.55 (q, J=7 Hz, 4H), 2.32 (m, 2H), 1.97 (t, J=3 Hz, 1H), 1.04 (t, J=7 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([OH:15])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.CN(C=O)C.N1C=CN=C1.[CH:27]([Si:30](Cl)([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])([CH3:29])[CH3:28]>O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([OH:15])=[CH:11][C:12]([O:14][Si:30]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:27]([CH3:29])[CH3:28])=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: COC(=O)Cc1csc2cc(O)cc(O)c12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1csc2cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(O)c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of methyl(4,6-dihydroxy-1-benzothiophen-3-yl)acetate (7.7 g) and DMF (dry) (150 mL) was added imidazole (4.40 g) at room temperature, and the mixture was added slowly triisopropylsilyl chloride (7.61 mL) over a period of 20 min, and the mixture was stirred at room temperature for 48 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (8.10 g).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[CH2:10]([CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][C:14]1=[O:19])[CH:11]=[CH2:12]>>[CH2:10]([CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[CH3:9])[C:14]1=[O:19])[CH:11]=[CH2:12]
Reactant: Cc1cc(N)ccc1I
Reactant: C=CCC1CCCNC1=O
Product: C=CCC1CCCN(c2ccc(N)cc2C)C1=O

Procedure:
Analogously to the process described under example 93A, 2.68 g (11.5 mmol) of 4-iodo-3-methylaniline and 2.0 g (14.3 mmol) of the compound from example 96A are used to obtain, after preparative HPLC, 1.31 g (47% of theory) of the title compound.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1>O1CCCC1>[N:2]1([NH:1][C:11](=[O:12])[CH2:10][C:9](=[O:13])[CH3:8])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: NN1CCOCC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NN1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
18 ml (0.19 mol) of 4-Aminomorpholine were added dropwise to a solution of 15 g of diketene (0.18 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 26.1 g (0.14 mol, 78% yield) of a colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]12[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12]C(=O)O[C:8]2=[O:9]>C1(C)C=CC=CC=1>[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=1[C:8]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Product: Nc1ccccc1C(=O)N1CCCCC1
Reaction time: 0.33 h

Procedure:
Piperidine (1.63 liter) was added over a period of 30 minutes to a slurry of 2.5 kg isatoic anhydride in 12.5 liters of toluene. The reaction mixture was stirred for 20 minutes and extracted four times with 5 liters of 1.2N hydrochloric acid. The extracts were made basic and the product extracted with 12.5 liters of isopropyl acetate. The organic layer was washed with water and saturated sodium chloride solution and then concentrated to a thick slurry with a volume of 4 liters. The solid product was collected, washed with cold isopropyl acetate and dried overnight in vacuo to give 2.22 kg of 1-(2-aminobenzoyl)piperidine. Concentration of the filtrate afforded a second crop of 0.23 kg.
Reaction SMILES: N[CH:2](C1C=CC(OC)=C(OC)C=1)CC(O)=O.[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[CH2:19][C:20]([OH:22])=[O:21]>>[NH2:17][CH:18]([C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1)[CH2:19][C:20]([O:22][CH3:2])=[O:21]
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Reactant: NC(CC(=O)O)c1ccc(Cl)cc1
Product: COC(=O)CC(N)c1ccc(Cl)cc1

Procedure:
The title compound was prepared following the method for preparing Intermediate 6 except that 3-amino-3-(3,4-dimethoxy-phenyl)-propionic acid was substituted with 3-amino-3-(4-chlorophenyl)propionic acid. 1H NMR (CDCl3): δ 7.24-7.32 (m, 5H), 4.38 (t, 1H, J=5 Hz), 3.65 (s, 3H), 2.61 (d, 2H, J=5 Hz), 1.80 (s, 2H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([OH:28])[C@H:7]1[O:12][C@H:11]([O:13][C@:14]2([CH2:23][OH:24])[O:18][C@H:17]([CH2:19]O)[C@@H:16]([OH:21])[C@@H:15]2[OH:22])[C@H:10]([OH:25])[C@@H:9]([OH:26])[C@@H:8]1[OH:27]>N1C=CC=CC=1>[CH2:6]([OH:28])[C@H:7]1[O:12][C@H:11]([O:13][C@@:14]2([CH2:23][OH:24])[O:18][C@H:17]([CH2:19][Cl:4])[C@@H:16]([OH:21])[C@@H:15]2[OH:22])[C@H:10]([OH:25])[C@@H:9]([OH:26])[C@@H:8]1[OH:27]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Product: OC[C@H]1O[C@H](O[C@@]2(CO)O[C@H](CCl)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 29 %

Procedure:
Attempts to synthesize cyclic sulfates of unprotected sugars with sulfuryl chloride and pyridine have been reported. However, the reaction has never been clean and several side products were isolated. For example, reaction of sucrose with sulfuryl chloride at −78° C. affords the 6,6′-dichloro-6,6′-deoxysucrose and 6′-chloro-6′-deoxysucrose in 43% and 29% yield. At room temperature, a complex mixture is formed from which 3′,4′-anhydro-1′,6′-dichloro-1′,6′-dideoxy-β-D-ribo-hexulo-furanoside 2,3-cyclic sulfate is isolated in 17% yield, showing that chlorination occurs as well as inversion of configuration during cyclic sulfate formation. Thus, the reaction of sulfuryl chloride with carbohydrates containing free hydroxyl groups has become a well established method for the preparation of chlorodeoxysugars. The conversion of a vicinal cis diol system to a cyclic sulfate in protected carbohydrates is readily accomplished with sulfuryl chloride. By using SO2Cl2, the methyl 4,6-O-benzilidene-β-D-mannopyranoside 2,3-cyclic sulfate, and 1,6-anhydro-4-O-benzyl-β-D-mannopyranoside 2,3-cyclic sulfate [28] were obtained in 60% and 85% yield.
Reaction SMILES: B(F)(F)F.[CH3:5][CH2:6]OCC.[CH3:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:21])([CH3:20])[CH3:19])[C:12]=1[NH2:13].C(=O)(O)[O-].[Na+]>C(O)C.C(Cl)Cl>[CH3:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:21][CH2:5][CH3:6])([CH3:19])[CH3:20])[C:12]=1[NH2:13]
Reactant: Cc1cccc(C(C)(C)O)c1N
Reactant: CCOCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(C)(C)c1cccc(C)c1N
Reaction time: 48 h
Yield: 93.1 %

Procedure:
In this example 0.03 moles of boron trifluoride ethyl etherate was added dropwise to a mixture containing 0.03 moles of 2-methyl-6-(1-hydroxy-1-methylethyl)-aniline in 50 ml of ethanol and 50 ml methylene chloride. The mixture was refluxed for two hours and then allowed to stand for two days. The mixture was then poured into about 700 ml of saturated aqueous sodium bicarbonate solution stirred and extracted with methylene chloride. The extract was filtered through diatomaceous earth, dried and evaporated affording 5.4 g of the title product as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].Br[C:14]1[CH:19]=[CH:18][C:17](/[C:20](/[CH3:24])=[CH:21]/[CH2:22][OH:23])=[CH:16][CH:15]=1>>[C:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17](/[C:20](/[CH3:24])=[CH:21]/[CH2:22][OH:23])=[CH:16][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: C/C(=C\CO)c1ccc(Br)cc1
Reactant: CC(=O)c1cccc(B(O)O)c1
Product: CC(=O)c1cccc(-c2ccc(/C(C)=C/CO)cc2)c1

Procedure:
3-Acetylphenylboronic acid (7.10 g, 43.3 mmol) was coupled with (E)-3-(4-bromophenyl)-but-2-en-1-ol (5.76 g, 25.0 mmol) by a procedure analogous to that described in example 54 a to give (E)-3-(3′-acetyl-biphenyl-4-yl)-but-2-en-1-ol as an off-white solid; 5.33 g (79%). This solid was recrystallised from aqueous ethanol to give a first crop of very pure (E)-3-(3′-acetyl-biphenyl-4-yl)-but-2-en-1-ol as colourless platelets; 2.78 g (41%) and a second crop of (E)-3-(3′-acetyl-biphenyl-4-yl)-but-2-en-1-ol as an amorphous off-white solid; 2.53 g (37%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:15][C:14]4([CH2:20][CH2:19][N:18](S(C)(=O)=O)[CH2:17][CH2:16]4)[CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:31][N:32]([CH3:36])[C:33](Cl)=[O:34]>>[CH3:31][N:32]([CH3:36])[C:33]([N:18]1[CH2:19][CH2:20][C:14]2([CH2:13][N:12]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:15]2)[CH2:16][CH2:17]1)=[O:34]
Reactant: CN(C)C(=O)Cl
Reactant: CS(=O)(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Product: CN(C)C(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methanesulfonyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using dimethylcarbamoyl chloride in place of methanesulfonyl chloride. The title compound was obtained as a yellow oil (39 mg, 42%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:9]1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:9]1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2cc(OCC)cc(OCc3csc(-c4cnccn4)n3)c2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cc(Cn2cc(CCC(=O)O)c(-c3ccccc3)c2)cc(OCc2csc(-c3cnccn3)n2)c1
Reaction time: 8 h
Yield: 59.7 %

Procedure:
A mixture of ethyl 3-[1-[3-ethoxy-5-[2-(2-pyrazinyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionate (370 mg), 1N aqueous sodium hydroxide solution (6 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred overnight under reflux conditions, and then 1N hydrochloric acid (6 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[3-ethoxy-5-[2-(2-pyrazinyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionic acid (210 mg, yield: 60%). This was recrystallized from ethanol. Melting point: 97–98° C.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1)=[O:2].[CH3:13][C:14]([CH3:16])=O>C(O)(C(F)(F)F)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>[CH3:13][C:14]1([CH3:16])[O:12][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][C:7]=2[C:8](=[O:10])[O:9]1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)OC(=O)c2cc(C=O)ccc2O1
Temperature: 90 °C
Yield: 35 %

Procedure:
A suspension of 5-formylsalicylic acid (Aldrich, 4.12 g, 24.8 mmol) in TFA (30 ml), TFAA (10 ml) and acetone (10 ml) was heated at 90° C. overnight. The reaction mixture was concentrated under reduced pressure. The residual oil was taken up in EtOAc and washed with a saturated aqueous solution of NaHCO3 and brine. The organic layer was dried- over MgSO4 and the solvent was removed under reduces pressure. The crude product was purified by flash chromatography on silicagel (EtOAc/c-Hex (80/20)) to give 1.8 g (35%) of the title compound as a white powder. 1H NMR (CDCl3) δ: 1.80 (s, 6H), 7.09 (d, J=8.7 Hz, 1H), 8.09 (dd, J=8.7, 2.3 Hz, 1H), 8.45 (d, J=1.9 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]#[N:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][SH:21])=[CH:16][CH:15]=1>CN(C)C=O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][S:21][C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=2[C:11]#[N:12])=[CH:16][CH:15]=1
Reactant: N#Cc1ccc(C(=O)O)nc1Cl
Reactant: SCc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)O)nc1SCc1ccc(Cl)cc1
Temperature: 45 °C
Yield: 82 %

Procedure:
A mixture of 6-chloro-5-cyanopicolinic acid (30 mg, 0.16 mmol), 4-chlorophenyl methanethiol (24 ul, 0.18 mmol), and CsCO3 (156 mg, 0.48 mmol) in dimethylformamide (2 ml) was heated for 16 hrs at 45° C. After removal of the solvent, the residue was treated with water (2 ml) and acidified with 1N—HCl to pH2. The precipitate was collected by filtration and dried under vacuum to afford 40 mg (82%) of the desired product 52. 1H NMR (600 MHz, DMSO-d6) δ 13.6 (br s, 1H), 8.46 (d, 1H, J=7.8 Hz), 8.15 (d, 1H, J=7.8 Hz), 7.55 (d, 2H, J=9 Hz), 7.47 (d, 2H, J=9 Hz). MS: m/z Calcd 304.8 Found MH+ 305.0
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH2:13][CH2:12][CH2:11]1)[C:5]#[N:6].[C:19]1(C)C=CC=CC=1>>[CH3:19][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH2:13][CH2:12][CH2:11]1)[C:5]#[N:6]
Reactant: N#Cc1ccc(C2CCCc3cncn32)c(Br)c1
Reactant: Cc1ccccc1
Product: Cc1cc(C#N)ccc1C1CCCc2cncn21

Procedure:
3-Bromo-4-(5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-5-yl)benzonitrile, prepared above, is converted to the corresponding toluene by the method outlined in Tet. Lett. 2000, 41, 6237. MS (ESI) m/z 238.1 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.77-1.89 (m, 2 H), 1.91-2.00 (m, 1 H), 2.29-2.39 (m, 1 H), 2.45 (s, 3 H), 2.86-2.93 (m, 2 H), 5.71 (t, J=6.1 Hz, 1 H), 6.77 (d, J=8.1 Hz, 1 H), 6.81 (s, 1 H), 7.29 (s, 1 H), 7.49 (d, J=8.1 Hz, 1 H), 7.61 (s, 1 H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[CH:6][C:5]=1[C:15]1[C:16]([S:21]([NH:24][C:25]2[O:29][N:28]=[C:27]([CH3:30])[C:26]=2[CH3:31])(=[O:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=1.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=O)=[CH:35][CH:34]=1.C(N=C=NC(C)C)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([C:37]([N:2]([CH2:3][C:4]2[CH:9]=[C:8]([C:10]3[O:11][CH:12]=[CH:13][N:14]=3)[CH:7]=[CH:6][C:5]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21]([NH:24][C:25]2[O:29][N:28]=[C:27]([CH3:30])[C:26]=2[CH3:31])(=[O:22])=[O:23])[CH3:1])=[O:39])=[CH:40][CH:41]=1
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)c2ccc(Cl)cc2)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 2'-[(methylamino)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (24.1 mg, 0.055 mmol, prepared as described in Step (A) of Example 28) and 4-chlorobenzoic acid (7.8 mg, 0.05 mmol) in 0.5 ml of CH2Cl2, 4-dimethylaminopyridine (6.7 mg, 0.055 mmol) was added and followed by 1,3-diisopropylcarbodiimide (6.9 mg, 0.055 mmol). The reaction was stirred at room temperature for 18 hrs and concentrated. The residue was dissolved in MeOH, neutralized to pH>8 with aq. NaHCO3, and filtered. The filtrate was acidified to pH<5 with NaHSO4, and filtered to provide the title compound of this Example (18 mg, 62%) as a white solid, m.p. 122°-132° C. (amorphous).