Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][C:10]([C:17]([O:19]CC)=[O:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:13]([C:12]1[N:8]([C:4]2[CH:3]=[C:2]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])[CH:7]=[CH:6][CH:5]=2)[N:9]=[C:10]([C:17]([OH:19])=[O:18])[CH:11]=1)([CH3:15])([CH3:16])[CH3:14]
Reactant: CCOC(=O)c1cc(C(C)(C)C)n(-c2cccc(Br)c2)n1
Reactant: OB(O)c1ccccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CCCO
Product: CC(C)(C)c1cc(C(=O)O)nn1-c1cccc(-c2ccccc2Cl)c1

Procedure:
To a solution of ethyl 1-(3-bromophenyl)-5-tert-butyl-1H-pyrazole-3-carboxylate and 2-chlorophenylboronic acid (0.279 g, 1.78 mmol) in n-propanol:water (2.35 ml:0.482 ml) mixture were added palladium acetate (0.005 g), triphenylphosphine (0.016 g) and 2N sodium carbonate (0.497 ml) and the solution was refluxed for 16 hours. To the reaction, a 2N solution of NaOH (1.5 ml) was added and refluxed for an additional 2 hours. The solution was cooled, acidified with 10% citric acid and extracted into ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 0.212 g of 5-tert-butyl-1-(2′-chloro-1,1′-biphenyl-3-yl)-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[C:4]([OH:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]#[CH:30].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[N:10]([CH3:19])[C:9]2=[O:20])=[C:4]([O:21][CH2:30][C:29]#[CH:28])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)cc2O)c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc(Cl)ccc1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
22.6 g (70.5 mmol) of 3-(4-chloro-2-hydroxyphenyl-1-methyl-6-trifluoromethyluracil and 14.5 g (105.1 mmol) of potassium carbonate were suspended in 150 ml of N,N-dimethylformamide, and 11.2 g (94.1 mmol) of propargyl bromide was dropwise added thereto at room temperature. After stirring at 70° C. for 2 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained crude crystals were washed with isopropyl ether to obtain 22.5 g (yield: 89.0%) of the desired product as pale brown powder. Melting point: 147-148° C.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH:5]([Mg]Br)=[CH2:6].C1COCC1.[CH3:14][C@H:15]1[C:19](=[O:20])[CH2:18][CH2:17][N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[OH:20][C@@:19]1([CH:5]=[CH2:6])[CH2:18][CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:15]1[CH3:14]
Reactant: C=C[Mg]Br
Reactant: C[C@H]1C(=O)CCN1C(=O)OC(C)(C)C
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C[C@]1(O)CCN(C(=O)OC(C)(C)C)[C@H]1C

Procedure:
By an operation in the same manner as in Reference Example 3 and using cerium chloride (3.95 g), 1 mol/L vinylmagnesium bromide—THF solution (12.5 mL) and tert-butyl (2S)-2-methyl-3-oxopyrrolidine-1-carboxylate (1.0 g), the title compound was obtained as colorless oil (yield: 0.648 g, yield: 57%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C1C=CC=CC=1.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[C@@H:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C@H:41]([OH:48])[CH2:40]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[CH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41](=[O:48])[CH2:40]1
Reactant: O[C@@H]1C[C@H](c2ccc3ccccc3c2)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C(O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CC(c2ccc3ccccc3c2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triphenylphosphine (1.44 g, 5.49 mmol) and benzoic acid (0.60 g, 4.91 mmol) were added to a solution of cis-3-(2-naphthyl)-indan-1-ol, 6a and 6b (0.645 g, 2.48 mmol) in anhydrous THF (20 mL). The reaction was treated dropwise with a solution of DEAD in THF (4.95 M, 1 mL) then stirred under nitrogen atmosphere at room temperature. After 3 h, the reaction solution was directly filtered through a pad of silica and condensed. The resulting residue was purified by radial chromatography (4 mm plate, 10% ethyl acetate/hexanes) yielding a mixture of enantiomers 8a and 8b as an off-white solid (0.72 g, 80%): Rf=0.46 in 10% ethyl acetate/hexanes; 1H-NMR (CDCl3) δ 8.08–8.05 (m, 2H), 7.84–7.78 (m, 3H), 7.71 (bs, 1H), 7.58–7.41 (m, 4H), 7.35–7.29 (m, 2H), 7.24 (dd, 2H, J=5.7, 2.7), 7.07–7.04 (m, 1H), 6.62 (dd, 1H, J=6.3, 1.9), 4.88 (t, 1H, J=7.7), 2.83 (ddd, 1H, J=2.2, 7.7, 14.6), 2.69–2.60 (ddd, 1H, J=6.6, 7.98, 14.6).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:10]3[C:9]([CH2:19][O:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])=[CH:8]2)=[CH:4][CH:3]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:50][NH:51][OH:52]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:51]([OH:52])[CH3:50])=[O:18])[CH:15]=[C:10]3[C:9]([CH2:19][O:20][C@@H:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH3:22])=[CH:8]2)=[CH:29][CH:30]=1
Reactant: CNO
Reactant: C[C@@H](OCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)O)cc12)c1ccccc1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Product: C[C@@H](OCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)N(C)O)cc12)c1ccccc1

Procedure:
The title compound was prepared as in example 116, step 3, using 1-(4-fluorobenzyl)-3-{[(1R)-1-phenylethoxy]methyl}-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid, 2-chloro-4,6-dimethoxy-1,3,5-triazine, N-methyl morpholine, and N-methyl hydroxylamine hydrochloride. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.35 (d, J=6.32 Hz, 3H) 3.33 (s, 3H) 4.50 (s, 2H) 4.55 (q, J=6.57 Hz, 1H) 5.53 (s, 2H) 7.16 (t, J=8.84 Hz, 2H) 7.29 (td, J=5.49, 3.16 Hz, 1H) 7.34-7.39 (m, 6H) 7.82 (s, 1H) 7.98 (s, 1H) 8.89 (s, 1H)
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:18][C:19]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: NCc1cccnc1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C)cc1
Product: CCOC(=O)c1nc(-c2cccnc2)[nH]c1-c1ccc(C)cc1

Procedure:
Ethyl 2-hydroxyimino-3-(4-methylphenyl)-3-oxopropionate (10.0 g) and 3-aminomethylpyridine (5.3 ml) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-methylphenyl)-2-(3-pyridyl)imidazole-4-carboxylate (4.0 g). 0.5 g therefrom was dissolved in ethyl alcohol (10 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-methylphenyl)-2-(3-pyridyl)-imidazole-4-carboxylic acid (0.39 g), melting point 140-142° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[F:9][C:10]([F:38])([F:37])[C:11]([CH2:32][NH:33][CH2:34][CH2:35][CH3:36])([OH:31])[CH2:12][NH:13][C:14]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1>>[CH2:34]([N:33]([CH2:32][C:11]([CH2:12][NH:13][C:14]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)([OH:31])[C:10]([F:9])([F:37])[F:38])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH2:35][CH3:36]
Reactant: O=C(O)c1cccs1
Reactant: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1cccs1

Procedure:
Prepared similarly to Example 1 from 2-thiophenecarboxylic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([OH:18])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].[CH3:19][C:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([N:23]3[CH2:24][CH2:25][C:20]([CH3:19])([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:22]3)=[O:18])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(O)c(C(=O)O)cnc12
Reactant: CC1(c2ccccc2)CCNCC1
Product: CCOC(=O)c1cnn2c(O)c(C(=O)N3CCC(C)(c4ccccc4)CC3)cnc12
Yield: 68.6 %

Procedure:
In the same manner as in Example 1, step 2 and using 3-ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid (583 mg, 2.32 mmol) obtained in Example 19, step 2 and 4-methyl-4-phenylpiperidine (Journal of Medicinal Chemistry, vol. 41, page 5320, 590 mg, 2.79 mmol), the title compound (650 mg, 69%) was obtained.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].C([Li])CCC.CO[C:13](=O)[C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[CH3:19].S(=O)(=O)(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:13]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH3:19])[O:5][N:4]=1
Reactant: COC(=O)[C@@H]1CCCN1C
Reactant: CC(C)=NO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc([C@@H]2CCCN2C)on1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
THF (36.4 L) was stirred under nitrogen, and acetone oxime (3.034 kg, 41.5 mol) was added. The solution was cooled to -40° C., and n-butyllithium (10M in hexane, 8.3 L, 83 mol) was added at a rate such that the internal temperature did not rise above 5° C. (very exothermic reaction). Stirring was continued for an additional 2 hr, with the temperature maintained between 0° and 5° C. Under nitrogen THF (16.6 L) was added and the mixture was cooled to -10° C. The solution of N-methyl proline methyl ester, from step 6a above, was diluted with 3.3 L of THF (to a total of 23.5 L) and cooled to 0° C. Into a third reactor containing a small amount to THF, the solutions of the acetone oxime dianion and the ester were simultaneously added dropwise at the ratio of dianion to ester of 2:1. The internal temperature of the reaction vessel was maintained between -12° and -6° C., and the temperatures of the added solutions were 5° C. After addition was complete, the reaction mixture was stirred for 1 hr at -10° C. To the reaction was added a mixture of 97% sulfuric acid (10.99 kg, 108.7 mol) in ice water (6.177 kg) in portions such that the temperature did not rise above 10° C. The solution was heated at reflux for 3 hr with vigorous stirring, and 25 L of THF was distilled off. The mixture was cooled to 25° C., and solid Na2CO3 (7.687 kg, 72.5 mol) was added in portions, with vigorous stirring. The yellow precipitate was filtered and washed with 2×12.5 L portions of THF. The filtrate was evaporated in a rotary evaporator and azeotroped with 3×3 L of toluene. The residue was filtered through a column of silica gel, and the product was eluted with 41.5 L of 3% methanol in ethyl acetate. The eluate was evaporated to dryness, and the product was vacuum distilled (0.1 mbar, 70° C., e.e.=99.5%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[CH2:9][O:10][CH2:11][C:12]1[O:17][CH2:16][CH2:15][CH2:14][CH:13]=1.[OH-:31].[Na+].OO>O1CCCC1.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[CH2:9][O:10][CH2:11][C@H:12]1[C@H:13]([OH:31])[CH2:14][CH2:15][CH2:16][O:17]1
Reactant: [OH-]
Reactant: C1=C(COCC(CCCCCCOC2CCCCO2)OC2CCCCO2)OCCC1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O[C@@H]1CCCO[C@H]1COCC(CCCCCCOC1CCCCO1)OC1CCCCO1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
1.46 ml of a 1M borane-tetrahydrofuran complex was added dropwise, whist ice-cooling, to a solution of 0.934 g of 6-[2,8-bis(tetrahydropyran-2-yloxy)octyloxymethyl]-3,4-dihydro-2H-pyran (prepared as described in Preparation 73) in 3 ml of tetrahydrofuran. The mixture was then stirred at room temperature for 4.5 hours. At the end of this time, 0.80 ml of a 10% w/v aqueous solution of sodium hydroxide and 0.60 ml of a 30% v/v aqueous solution of hydrogen peroxide were added, in turn, to the mixture at 30° to 40° C., and then the mixture was stirred at room temperature for a further 1 hour. The reaction mixture was then diluted with 50 ml of water and extracted twice with ethyl acetate. The combined extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to give a residue, which was purified by column chromatography through 20 g of silica gel and by medium pressure liquid chromatography using a Lobar B column. 0.615 g of the title compound was obtained, as a colorless oil, from the fractions euted with a 7:3 by volume mixture of hexane and ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]([C:18]1[C:26]2[C:21](=[CH:22][C:23]([Cl:35])=[C:24](B3OCC(C)(C)CO3)[CH:25]=2)[NH:20][CH:19]=1)=[O:17].C([O-])(=O)C.[K+]>O1CCOCC1>[Cl:35][C:23]1[CH:22]=[C:21]2[C:26]([C:18]([C:16]([O:15][CH3:14])=[O:17])=[CH:19][NH:20]2)=[CH:25][C:24]=1[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1CCCN1c1ccc(Br)cc1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(N4CCCC4=O)cc3)cc12
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 60.7 %

Procedure:
To a mixture of 1-(4-bromophenyl)pyrrolidin-2-one (120 mg, 0.50 mmol), methyl-6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (160 mg, 0.50 mmol) and potassium acetate (147 mg, 1.50 mmol) in 1,4-dioxane (3 mL) was added PddppfCl2 (36.5 mg, 0.050 mmol). The mixture was degassed and purgerd with nitrogen for 5 minutes, then allowed to heat to 100° C. and stirred under microwave irradiation for 40 minutes. The reaction mixture was concentrated in vacuo to give a brown residue. The residue was purified by combi flash silica gel chromatography to give the title compound (112 mg, 61% yield) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:33][C:32]([CH3:35])([CH3:34])[C:31](=[O:36])[CH2:30][N:9]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=2[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[C:8]1=[O:12]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)C(C)(C)C)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 1-bromo-3,3-dimethylbutan-2-one (0.52 mL) and N,N-dimethylformamide (8 mL) was added 60% sodium hydride (0.16 g), and the mixture was stirred at room temperature for 24 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.76 g, 61%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[CH:5]=1)=[O:3].[N+:11]([O-])([OH:13])=[O:12].OS(O)(=O)=O>>[CH3:1][C:2]([C:4]1[CH:5]=[C:6]([Cl:10])[CH:7]=[CH:8][C:9]=1[N+:11]([O-:13])=[O:12])=[O:3]
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
The intermediates, 5-alkylamino-2-aminoacetophenones (60-62) were prepared according to the methods reported before. As shown in Scheme 6, the starting 3-chloroacetophenone (54) was first nitrated with HNO3/H2SO4 to form the 5-chloro-2-nitroacetophenone (55) and 5-chloro-4-nitroacetophenone (56). Compound 55 was reacted separately with various alkylamines to yield the corresponding 5-alkylamino-2-nitroacetophenones (57-59). Catalytic hydrogenation of compounds 57-59 yielded the corresponding 5-alkylamino-2-aminoacetophenones (60-62). L. Ll, K. K. Wang, S. C. Kuo, T. S. Wu, D. Lednicer, C. M. Lin, E. Hamel and K. H. Lee, J. Med. Chem., 37, 1126-35. (1994), which is herein incorporated by reference in its entirety.
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH2:9][C:10]([C:12]2([CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:37][NH2:38]>C(O)C>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][C:12]([CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])([C:10]2[NH:38][N:37]=[C:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:9]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCC(CCO[Si](C)(C)C(C)(C)C)(C(=O)CC(=O)Cc2ccccc2)CC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCO[Si](C)(C)C(C)(C)C)(c2cc(Cc3ccccc3)n[nH]2)CC1
Temperature: 85 °C
Yield: 71.5 %

Procedure:
To a solution of tert-butyl 4-(4-phenyl-1,3-dioxobut-1-yl)-4-(2-(tert-butyldimethylsilyloxy)eth-1-yl)piperidine-1-carboxylate (343 mg, 0.68 mmol) from Step G in ethanol (7 mL) was added hydrazine hydrate (0.040 mL, 0.82 mmol). The reaction was heated at 85° C. for 3 h and was then concentrated in vacuo. The residue was purified by flash chromatography (30% ethyl acetate in hexanes) to afford the title product (243 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]([P:14]([O:19]CC)(=[O:18])[O:15]CC)[P:6]([O:11]CC)(=[O:10])[O:7]CC.[N+]([O-])(O)=O.C[C:27]1C=C(C)[N:29](C(N)=N)[N:28]=1>CN(C=O)C>[NH2:29][N:28]=[CH:27][NH:1][CH2:2][CH2:3][CH2:4][CH:5]([P:14]([OH:19])(=[O:18])[OH:15])[P:6]([OH:11])(=[O:10])[OH:7]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: CCOP(=O)(OCC)C(CCCN)P(=O)(OCC)OCC
Solvent: O=[N+]([O-])O
Solvent: CN(C)C=O
Product: NN=CNCCCC(P(=O)(O)O)P(=O)(O)O

Procedure:
A solution of 0.69 g (2 mmol) of tetraethyl 4-aminobutane-1,1-bisphosphonate (according to DE 3,225,469 A1, 01.05.1984) and 0.402 g (2 mmol) of 3,5-dimethylpyrazole-1-carboxamidine nitrate in 10 ml of DMF is heated at boiling point for 3 hours. The DMF is then distilled off in vacuo and the residue is dissolved in a little water. After extraction with diethyl ether and ethyl acetate (the organic extracts are discarded), the aqueous phase is distilled in vacuo. A dark oil (0.89 g) remains. This is heated at boiling point for 8 hours in 15 ml of concentrated hydrochloric acid. The excess hydrochloric acid is distilled off and the residue is treated with a little water, DMF and acetone. The precipitate is filtered off with suction and dried in vacuo.
Reaction SMILES: [C:1]12([C:11]3[CH:24]=[C:23](Br)[CH:22]=[CH:21][C:12]=3[O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([Li])CCC.[C:31](=[O:33])=[O:32].[Cl-].[NH4+].Cl>O1CCCC1.CCCCCC>[C:1]12([C:11]3[CH:24]=[C:23]([CH:22]=[CH:21][C:12]=3[O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:31]([OH:33])=[O:32])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
9.3 g of (2-adamantan-1-yl-4-bromo-phenoxy)-tert-butyl-dimethylsilane were dissolved in 120 ml of absolute tetrahydro-furan and treated dropwise at -78° C. with 15.5 ml of a 1.6 molar solution of n-butyl-lithium in hexane. After stirring at -78° C. for 1.5 hours, a vigorous stream of carbon dioxide was introduced for one hour. Subsequently, the reaction mixture was firstly poured into ice-cold, saturated, aqueous ammonium chloride solution, acidified cautiously to pH 3 with cold 2N hydrochloric acid and extracted with ethyl acetate. After washing once with water, drying over sodium sulfate and evaporation there was obtained a white, crystalline mass which was recrystallized from ethyl acetate and gave 7 g of 3-adamantan-1-yl-4-(tert-butyl-dimethyl-silanyloxy)-benzoic acid. m.p. 250-252° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][C:7](=[O:17])[C:6]=2[CH:18]=1.C(O)C.[BH4-].[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7]([OH:17])[C:6]=2[CH:18]=1
Reactant: Cc1ccc2c(c1)CC(=O)c1cc(F)ccc1S2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)CC(O)c1cc(F)ccc1S2

Procedure:
103 G. of 8-fluoro-2-methyl-dibenzo[b,f]-thiepin-10(11H)-one is suspended in 550 ml. of ethanol and mixed with 24.3 g. of sodium borohydride. The reaction mixture is heated for about 10 minutes under reflux conditions. The reaction mixture, after the addition of water, is extracted with chloroform. The organic phase is again washed with water, dried over sodium sulfate and evaporated, whereby there is obtained 8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]-thiepin-10-ol as an oil.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:30])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[C:24]1([S:21]([N:18]2[CH2:17][CH2:16][CH:15]([C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([F:30])[CH:11]=4)[CH:6]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[CH:14]=3)[CH2:20][CH2:19]2)(=[O:23])=[O:22])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccccc3)CC2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(C2CCN(S(=O)(=O)c3ccccc3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.9 %

Procedure:
To a stirred solution of [4-(1-benzenesulfonyl-piperidin-4-yl)-6-fluoro-naphthalen-2-yl]-acetic acid methyl ester (90 mg, 0.2 mmol) in THF (8 mL) was added a solution of lithium hydroxide monohydrate (26 mg, 0.6 mmol) in water (2 mL) and the reaction mixture was stirred for 24 h at RT. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether (3×5 mL). The washings were discarded. Water (5 mL) was added to the residue, and the mixture acidified (pH ˜2-3) with an aqueous solution of hydrochloric acid (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to give [4-(1-benzenesulfonyl-piperidin-4-yl)-6-fluoro-naphthalen-2-yl]-acetic acid (35 mg, 40%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.36 (br s, 1H), 7.92-7.98 (m, 1H), 7.88 (d, J=11.2 Hz, 1H), 7.81 (d, J=7.8 Hz, 2H), 7.76 (d, J=6.8 Hz, 1H), 7.65-7.73 (m, 3H), 7.33-7.42 (m, 2H), 3.82 (d, J=11.7 Hz, 2H), 3.71 (s, 2H), 1.90 (d, J=11.2 Hz, 2H), 1.69-1.82 (m, 2H); MS cald. for C23H23FNO4S [(M−H)−]: 426, obsd. 426.2.