Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@@H:14]([OH:17])[C@H:13]([F:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:25]([C:29]1[N:30]=[N:31][C:32](Cl)=[CH:33][C:34]=1[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:37][CH:36]=1)[CH2:26][CH2:27][CH3:28]>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@@H:14]([O:17][C:32]2[N:31]=[N:30][C:29]([CH2:25][CH2:26][CH2:27][CH3:28])=[C:34]([C:35]3[CH:36]=[CH:37][C:38]([O:41][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:39][CH:40]=3)[CH:33]=2)[C@H:13]([F:18])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)[C@H](F)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nnc(O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2F)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a stirred solution of (±)-trans-3-fluoro-4-hydroxy-piperidine-1-carboxylic acid benzyl ester (100 mg, 0.4 mmol) at 0° C. in THF (2 mL) was added potassium tert-butoxide (1.0 M in THF, 0.5 mmol, 0.5 mL). After 15 min 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (120 mg, 0.34 mmol) in THF (2 mL) was added. The solution was stirred overnight at 40° C., diluted with EtOAc and washed with water. The organics were dried over sodium sulfate, filtered, concentrated, and purified by column chromatography using 20-40% EtOAc in hexanes to provide (±)-trans-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-3-fluoro-piperidine-1-carboxylic acid benzyl ester (65 mg).
Reaction SMILES: [N:1]1[N:5]2[CH2:6][CH2:7][CH2:8][NH:9][C:4]2=[C:3]([CH2:10][CH2:11][C:12]([O:14]CC)=O)[CH:2]=1.[NH3:17]>>[N:1]1[N:5]2[CH2:6][CH2:7][CH2:8][NH:9][C:4]2=[C:3]([CH2:10][CH2:11][C:12]([NH2:17])=[O:14])[CH:2]=1
Reactant: N
Reactant: CCOC(=O)CCc1cnn2c1NCCC2
Product: NC(=O)CCc1cnn2c1NCCC2

Procedure:
A solution of ethyl 3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)propionate (30 g) in saturated methanolic ammonia solution (700 ml) was stirred at 110° C. for 5 days in an autoclave. After evaporation of the solvent in vacuo, methylene chloride was added to the residue. The resulting solid was collected by filtration and dissolved in methanol. To the solution was added activated charcoal, and the mixture was filtered. The filtrate was concentrated in vacuo. The residue was triturated with acetonitrile and dried in vacuo to give 3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)propionamide (11.3 g) as a solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[N+:12]([O-])([OH:14])=[O:13].O>S(=O)(=O)(O)O>[CH3:1][C:2]([C:4]1[C:5]([OH:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:7]=[C:8]([F:10])[CH:9]=1)=[O:3]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1cc(F)ccc1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)c1cc(F)cc([N+](=O)[O-])c1O
Temperature: -20 °C

Procedure:
5-Fluoro-2-hydroxyacetophenone (20.0 g) was dissolved in concentrated sulphuric acid (150 ml), and the mixture was cooled to -20° C. A mixture of concentrated nitric acid (17.0 ml; s.g. 1.42) in concentrated sulphuric acid (18.0 ml) was then added to it, dropwise with stirring, keeping the temperature of the reaction mixture between -15° and -5° C. The reaction mixture was then allowed to warm up to -5° C. and was poured into iced water (2 liters). The yellow precipitated product was filtered off and recrystallised from ethanol to give 5-fluoro-2-hydroxy-3-nitroacetophenone (11.9 g), m.p. 87°-90° C.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[S:17])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[N:15][CH:16]=1)C.O>CO>[N:13]1[CH:12]=[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:5])=[S:17])[CH:16]=[N:15][CH:14]=1
Reactant: CCOC(=S)CCCCc1cncnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC(=S)CCCCc1cncnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.1 %

Procedure:
20 ml (40 mmol) of 2N sodium hydroxide solution are added dropwise to 7.8 g (32.5 mmol) of 3-(pyrimidin-5-yl)propylthioacetic acid ethyl ester in 20 ml of methanol. The mixture is then stirred for 16 hours at room temperature; a small amount of water is added and the mixture is extracted with dichloromethane, dried over sodium sulfate and filtered with suction and the filtrate is concentrated. 3.13 g (46% of theory) of 3-(pyrimidin-5-yl)propyl-thioacetic acid are obtained in the form of a brown oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C([N:11]=[S:12]([C:15]1[CH:32]=[CH:31][C:18]([CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[CH:17][CH:16]=1)([CH3:14])=[O:13])=O>CO>[CH3:14][S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[CH:31][CH:32]=1)(=[NH:11])=[O:13]
Reactant: CS(=O)(=NC(=O)C(F)(F)F)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CS(=N)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium carbonate (3.37 g, 24.4 mmol) is added to a solution of 2-(4-(N-trifluoracetyl-S-methylsulfonimidoyl)benzyl)isoindoline-1,3-dione (preparation 17a, 2.00 g, 4.88 mmol) in methanol (20 mL). The mixture is stirred at room temperature for 16 h and filtered. The filtrate is concentrated under reduced pressure, and the residue is purified by flash chromatography on silica (methanol/dichloromethane 7:3). Yield: 0.90 g (58% of theory); ESI mass spectrum: [M+H]+=315, r.t. HPLC: 1.08 min (V003_003).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[N:5]=[C:4]([C:18]([OH:20])=[O:19])[CH:3]=1.[CH2:21](O)[CH3:22]>S(=O)(=O)(O)O>[OH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[N:5]=[C:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:3]=1
Reactant: CCCOc1ccccc1-c1nc(O)cc(C(=O)O)n1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCCOc1ccccc1-c1nc(O)cc(C(=O)OCC)n1

Procedure:
A stirred solution of 6-hydroxy-2-(2-propoxyphenyl)pyrimidine-4-carboxylic acid (1.06 g) in ethanol and concentrated sulfuric acid (0.5 ml) was heated under reflux for 3 hours. Most of the ethanol was removed under reduced pressure, then ice-water was added to the residue. The mixture was made alkaline (pH 10-11) with sodium carbonate solution and then extracted with chloroform (3×25 ml). The combined chloroform extracts were washed with water, dried (magnesium sulfate) and evaporated under reduced pressure to yield after washing with petroleum ether (b.p. 40°-60° C.) the title compound, 0.85 g, m.p. 135.5-137° C. A sample (0.4 g) was recrystallized from ethanol to yield the pure title compound, 0.22 g, m.p. 137°-8° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)[CH:8]=1.[C:16](Cl)(=[O:18])[CH3:17].C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:2][C:3]1[CH:8]=[C:7]([O:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:18])[CH3:17])[CH2:11]2)[CH:6]=[N:5][CH:4]=1
Reactant: Brc1cncc(O[C@@H]2CCCNC2)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC[C@@H](Oc2cncc(Br)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a solution of 3-bromo-5-((R)-piperidin-3-yloxy)-pyridine hydrochloride salt (525 mg, 1.8 mmol) in DMF (10 mL) is added acetyl chloride (0.19 mL, 2.7 mmol) and N,N-diisopropylethylamine (1.4 mL, 8.0 mmol). The mixture is stirred at room temperature for 16 h. The reaction is partitioned between H2O and EtOAc and the layers are separated. The aqueous is extracted with EtOAc and the combined organic layers are dried and concentrated. The crude product is purified by flash column chromatography to provide 271 mg of 1-[(R)-3-(5-bromo-pyridin-3-yloxy)-piperidin-1-yl]-ethanone.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Cl:13][C:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][N:15]=1>>[Cl:13][C:14]1[CH:19]=[C:18]([NH:20][C:2]2[N:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]3)[CH:17]=[CH:16][N:15]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: Cc1ccc2ccnc(Cl)c2n1
Product: Cc1ccc2ccnc(Nc3ccnc(Cl)c3)c2n1

Procedure:
The title compound, MS: m/e=271.2 (M+H+), was prepared in accordance with the general method of example 1 from 8-chloro-2-methyl-[1,7]naphthyridine (Example E) and 2-chloro-4-aminopyridine.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4]>[Ni]>[NH2:1][CH:2]([CH:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4]
Reactant: NC(C(=O)O)c1ccc(O)cc1
Agent: [Ni]
Product: NC(C(=O)O)C1CCC(O)CC1

Procedure:
Bicyclic diamines of general formula (32), wherein P2 is a nitrogen protecting group, can be prepared as described in (Org. Mass Spectrum. (1984) 19(9), 459-460). Amino(4-hydroxyphenyl)acetic acid, purchased commercially, can be treated with Raney nickel and heat to provide amino(4-hydroxycyclohexyl)acetic acid. Amino(4-hydroxycyclohexyl)acetic acid can be treated with benzoyl chloride and then oxidized with Jones' reagent to provide (benzoylamino)(4-oxocyclohexyl)acetic acid. (Benzoylamino)(4-oxocyclohexyl)acetic acid can be subjected to a Beckmann rearrangement using hydroxyl amine and a sulfonyl chloride such as phenyl sulfonyl chloride to provide (benzoylamino)(7-oxo-4-azepanyl)acetic acid. (Benzoylamino)(7-oxo-4-azepanyl)acetic acid can be treated with concentrated HCl and heat to provide 2-amino-3-(2-aminoethyl)hexanedioic acid. 2-Amino-3-(2-aminoethyl)hexanedioic acid can be distilled at 180-200° C./0.1 torr to provide octahydro[1,7]naphthyridine-2,8-dione. Octahydro[1,7]naphthyridine-2,8-dione can be treated with lithium aluminum hydride and monoprotected with a nitrogen protecting reagent such as acetyl chloride/acetic anhydride, di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, or benzyl bromide to provide bicyclic diamines of general formula (32).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[S:11]([OH:14])(=O)=[O:12].O=P(Cl)(Cl)[Cl:17]>C(Cl)Cl>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[S:11]([Cl:17])(=[O:14])=[O:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(S(=O)(=O)O)sc2ccccc12
Solvent: ClCCl
Product: Cc1c(S(=O)(=O)Cl)sc2ccccc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 115.5 %

Procedure:
The 3-methylbenzothiophene-2-sulfonic acid (45 mg, 0.20 mmol) was mixed with POCl3 (2 mL, 20 mmol) and CH2Cl2 (2 mL) and heated at 70° C. for 6 h. The reaction mixture was diluted with CH2Cl2 before the reaction was quenched with ice and stirred at room temperature for 1 h. The organic phase was separated. Evaporation of the solvents afforded 57 mg the title compound (91%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=2[CH3:37])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=[C:13]3[C:12]4[C:16](=[CH:17][C:9]([C:6]5[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=5)=[CH:10][CH:11]=4)[NH:15][C:14]3=[O:18])[NH:31][C:30]=2[CH3:37])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: CCc1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Product: CCc1ccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C)c(C(=O)NCCN3CCCC3)c2C)cc1
Yield: 65.5 %

Procedure:
6-(4-Ethylphenyl)-1,3-dihydroindol-2-one (45 mg, 0.19 mmol) was condensed 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (50 mg) to give 60 mg (65%) of the title compound as a yellow-orange solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH3:19][O:20][C:21]1[CH:32]=[CH:31][CH:30]=[CH:29][C:22]=1[CH:23]=[N+:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:23]([C:22]1[CH:29]=[CH:30][CH:31]=[CH:32][C:21]=1[O:20][CH3:19])[N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1C=[N+]1CCCC1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [Cl-]
Product: COc1ccccc1C(c1c[nH]c2ccc(OCc3ccccc3)cc12)N1CCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-benzyloxy-1H-indole and 1-(2-methoxy-benzylidene)-pyrrolidinium chloride, which had been prepared in accordance with example 24.
Reaction SMILES: [CH3:1]/[C:2](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C:13]1[C:22]([O:23][CH2:24][C:25]#[C:26][CH2:27][CH3:28])=[CH:21][C:20]2[C:19]([CH3:30])([CH3:29])[CH2:18][CH2:17][C:16]([CH3:32])([CH3:31])[C:15]=2[CH:14]=1)=[CH:3]\[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>C1COCC1.C(O)C>[CH3:1]/[C:2](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C:13]1[C:22]([O:23][CH2:24][C:25]#[C:26][CH2:27][CH3:28])=[CH:21][C:20]2[C:19]([CH3:30])([CH3:29])[CH2:18][CH2:17][C:16]([CH3:31])([CH3:32])[C:15]=2[CH:14]=1)=[CH:3]\[C:4]([OH:6])=[O:5]
Reactant: CCC#CCOc1cc2c(cc1/C=C/C=C/C(C)=C/C(=O)OCC)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC#CCOc1cc2c(cc1/C=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
1.02 g of ethyl (2E,4E,6E)-3-methyl-7-(3-pent-2-ynyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-hepta-2,4,6-trienoate were placed in 8 ml of abs. THF/ethanol (1/1) and treated under argon with 3.9 ml of 3N NaOH. The mixture was stirred at room temperature for 2 days and at 40° for 3 h. Then, the mixture was poured on to ice/HCl, extracted with diethyl ether, washed with water, dried and evaporated. Crystallization from diethyl ether yielded 644 mg of (2E,4E,6E)-3-methyl-7-(3-pent-2-ynyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-hepta-2,4,6-trienoic acid as yellow crystals of m.p. 208-209°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH2:22]([CH:24]1[CH2:26][O:25]1)[CH3:23]>>[OH:25][CH:24]([CH2:22][CH3:23])[CH2:26][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: CCC1CO1
Product: CCC(O)CN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 168 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-ethyloxirane and conditions outlined in procedure X. M.p.=180-182° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.9 (m, 1H), 7.75 (m, 2H), 7.55 (m, 1H), 4.2 (s, 1H), 3.5 (br s, 1H), 3.05 (s, 2H), 2.7 (br s, 2H), 2.45-2.25 (m, 4H), 1.9 (m, 2H), 1.8 (m, 2H), 1.5-1.4 (m, 1H), 1.3-1.2 (m, 1H), 0.85 (m, 3H); LCMS: 374 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([NH2:16])[CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:32])[CH2:26][S:27][CH2:28][C:29](O)=[O:30])=[C:20]([C:33]([O:35]C)=[O:34])[CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:32])[CH2:26][S:27][CH2:28][C:29](=[O:30])[NH:16][C:11]2[CH:10]=[C:9]([C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=3)[CH:14]=[CH:13][C:12]=2[CH3:15])=[C:20]([CH:19]=1)[C:33]([OH:35])=[O:34]
Reactant: Cc1cc(C)cc(-c2ccc(C)c(N)c2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CSCC(=O)O
Product: Cc1cc(C)cc(-c2ccc(C)c(NC(=O)CSCC(=O)Nc3ccc(Cl)cc3C(=O)O)c2)c1

Procedure:
Using the same method as in Example 1-(ii), 3′,4,5′-trimethylbiphenyl-3-amine was reacted with the [(2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethyl)sulfanyl]acetic acid obtained in Example 12-(i) to give 5-chloro-2-([((2-oxo-2-[(3′,4,5′-trimethylbiphenyl-3-yl)amino]ethyl)sulfanyl)acetyl]amino)benzoic acid.methyl ester (yield: 87%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[C:8]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH:28]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39])[C:29]([O:31]C)=[O:30]>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:28]([C:29]([OH:31])=[O:30])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])=[CH:13][CH:12]=2)[C:8]([S:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(SCc2ccc(Cl)cc2)n1Cc1ccc(O)cc1
Reactant: COC(=O)C(Br)c1ccccc1Cl
Product: CCCCc1nnc(SCc2ccc(Cl)cc2)n1Cc1ccc(OC(C(=O)O)c2ccccc2Cl)cc1
Yield: 75 %

Procedure:
Reaction of 3-butyl-5-(4-chlorobenzylthio)-4-(4-hydroxybenzyl)-4H-1,2,4-triazole (from Example 5, Step A) with methyl 2-bromo-2-(2-chlorophenyl)acetate, from Step A, according to the procedure of Example 5, Step B, provided a 75% yield of the title compound as a glass; homogeneous by TLC in 97:3 C2Cl2 -MeOH.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)(=[O:6])=[O:5])[CH3:2].Cl>CO>[CH2:16]([N:3]([CH2:1][CH3:2])[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)(=[O:6])=[O:5])[CH3:17]
Reactant: CCN(CC)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Product: CCN(CC)S(=O)(=O)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
The N,N-diethyl-3-(nitro)benzenesulfonamide (3.9 g) was dissolved in methanol (60 ml) and, after an addition of conc. hydrochloric acid (10 ml), reduced iron (4.2 g) was added and the mixture was stirred at room temperature for 2 hours. After filtration, methanol was evaporated under a reduced pressure and the residue was made basic with an addition of 4 N sodium hydroxide. The iron oxide precipitated was separated by filtration, washed with methylene chloride (50 ml). Also the filtrate was extracted with methylene (50 ml ×2) and combined with the methylene chloride washing, followed by drying over anhydrous sodium sulfate Evaporation of the solvent gave N,N-diethyl-3-(amino)benzenesulfonamide (3.0 g) (m.p. 82°-84° C.).
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)C(OCC1C=CC=CC=1)=O>CCOC(C)=O.CCO>[CH3:1][NH:2][CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 106.1 %

Procedure:
Using Deprotection Method A, 4-[(N-methyl)benzyloxycarbonylaminomethyl]-1-Boc-piperidine (0.30 g, 0.83 mmol) in EtOAc (5 mL) and EtOH (14 mL) afforded 201 mg (88%) of the title compound which was used without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.[C:21]1([NH:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(=O)C.[Na+]>C(O)(C)C>[C:21]1([NH:27][N:28]=[C:10]([CH:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2)[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(Cl)cc2Cl)CC1
Reactant: NNc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: CC(=O)N1CCC(C(=NNc2ccccc2)c2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.6 %

Procedure:
A stirred mixture of 1-acetyl-4-(2,4-dichlorobenzoyl)piperidine (33.0 g, 0.11 mol.), phenylhydrazine hydrochloride (34.2 g) and anhydrous sodium acetate in isopropanol was refluxed for 2 hours. The reaction was stirred overnight (about 16 hours) at ambient temperature. The reaction was filtered and the filter cake was washed with ether and then dispersed into water. The water insoluble solid was collected and dried to yield 21.3 g of the product, mp 209°-211° C. Concentration of the filtrate afforded an oil which on standing one week partially solidified. The resultant mixture was triturated with CH3CN and an additional 7.5 g of the product 1-acetyl-4-(2,4-dichlorobenzoyl)piperidine phenylhydrazone was obtained.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]2[CH:27]=[C:26]([O:28][C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=3)[C:20]3[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=3[CH:18]=2)=[O:16])=[N:12][CH:13]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C(Cl)Cl>[OH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]2[CH:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:33][CH:34]=3)[C:20]3[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=3[CH:18]=2)=[O:16])=[N:12][CH:13]=1
Reactant: CC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)Nc3ccc(C(C)(C)O[SiH2]C(C)(C)C)cn3)cc2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)Nc3ccc(CO)cn3)cc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
To a solution of 4-(4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid[5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-yl]-amide (22b) (85 mg, 0.15 mmol) in CH2Cl2 (5 mL) was added TBAF in THF (220 uL, 0.22 mmol). The reaction mixture was stirred at room temperature for 1 hr, quenched with H2O (20 mL), and extracted with CH2Cl2 (2×20 mL). The organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 50% EtOAc in hexanes to give a white solid (23 mg, 34% yield). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1 H) 8.34 (d, J=8.34 Hz, 1 H) 8.30 (s, 1 H) 7.93 (d, J=8.84 Hz, 2 H) 7.74-7.83 (m, 1 H) 7.08-7.17 (m, 4 H) 4.72 (s, 2 H) 3.09 (s, 3 H) 2.91 (s, 2 H) 1.51 (s, 6 H); LCMS for C24H24N2O6S m/z 469.10 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].O.[F:11][C:12]([F:20])([F:19])[C:13]([C:15]([F:18])([F:17])[F:16])=[O:14].[OH-].[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:8]=[C:7]([C:13]([OH:14])([C:15]([F:18])([F:17])[F:16])[C:12]([F:20])([F:19])[F:11])[CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Temperature: 100 °C
Yield: 42 %

Procedure:
At room temperature, 24.4 g of 2,6-dimethylaniline and 50.0 g of hexafluoroacetone hydrate were mixed, and 0.5 g of p-toluenesulfonic acid monohydrate was added. The reaction solution was stirred and heated to 100° C. After the loss of the starting material was confirmed through TLC, ethyl acetate and an aqueous solution of 1N sodium hydroxide were added to the reaction solution, and phase separation was carried out. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was washed by addition of hexane. The suspension was filtered, and thus obtained filtered residue was dried under reduced pressure at room temperature to give 24.3 g (yield 69%) of the title compound as a powder form.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.C(Cl)(=O)C([Cl:14])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(C(=O)O)cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Cl)cn1

Procedure:
6-Methyl nicotinic acid (138 mg, 1.00 mmol) was dissolved in dichloromethane (15 mL) and N,N-dimethylformamide (0.10 mL), and in an ice bath oxalic chloride (192 mg, 1.51 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was moved to react at room temperature for 3 hours, and concentrated under reduce pressure to obtain 6-methyl nicotinoyl chloride as a white solid.