Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:13]([CH2:16][CH3:17])([O-:15])=[O:14].C([O-])(=O)C.[NH4+].O>C(O)C>[CH3:11][N:10]([CH3:12])[C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[C:16]([N+:13]([O-:15])=[O:14])[CH3:17])=[C:2]([Cl:1])[CH:9]=1
Reactant: CC[N+](=O)[O-]
Reactant: CN(C)c1ccc(C=O)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=Cc1ccc(N(C)C)cc1Cl)[N+](=O)[O-]

Procedure:
A solution of 36.8 g of 2-chloro-4-dimethylaminobenzaldehyde, 18 ml of nitroethane and 15 g of ammonium acetate in 150 ml of absolute ethanol is refluxed for 2 hours. The mixture is then poured into 1.5 l of water, whereupon the compound separates as a viscous red oil, which crystallizes on scratching. Recrystallization from ethanol yields 18.0 g of the compound, melting at 93°-94°.
Reaction SMILES: [CH3:1]C1C=CC(Br)=CC=1.BrC1C=CC=CC=1.C(N1N2C3C4C=NNC=4N=CC=3C(=O)N(C3C=CC=CC=3)C2=CC1C)C1OC=CC=1.CC1C=C2N(C3C=CC=CC=3)C(=O)C3C=NC4NN=CC=4C=3N2N=1.[C:70]([N:78]1[C:82]2[N:83]=[CH:84][C:85]3[C:86](=[O:101])[N:87]([C:95]4[CH:100]=[CH:99][CH:98]=[CH:97][CH:96]=4)[C:88]4[N:89]([N:91]=[C:92]([CH3:94])[CH:93]=4)[C:90]=3[C:81]=2[CH:80]=[N:79]1)(=[O:77])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1>>[C:70]([N:78]1[C:82]2[N:83]=[CH:84][C:85]3[C:86](=[O:101])[N:87]([C:95]4[CH:100]=[CH:99][C:98]([CH3:1])=[CH:97][CH:96]=4)[C:88]4[N:89]([N:91]=[C:92]([CH3:94])[CH:93]=4)[C:90]=3[C:81]=2[CH:80]=[N:79]1)(=[O:77])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1
Reactant: Cc1ccc(Br)cc1
Reactant: Cc1cc2n(-c3ccccc3)c(=O)c3cnc4c(cnn4C(=O)c4ccccc4)c3n2n1
Agent: CC1C=C2N(c3ccccc3)C(=O)c3cnc4[nH]ncc4c3N2N1Cc1ccco1
Agent: Cc1cc2n(-c3ccccc3)c(=O)c3cnc4[nH]ncc4c3n2n1
Solvent: Brc1ccccc1
Product: Cc1ccc(-n2c(=O)c3cnc4c(cnn4C(=O)c4ccccc4)c3n3nc(C)cc23)cc1

Procedure:
By substituting p-methylphenyl bromide for the bromobenzene in the procedure of Example 21 (a), and proceeding as in parts (b) and (c), 8-benzoyl-2-methyl-4-(p-methylphenyl)-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([C:24]1[S:28][C:27]([S:29]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:31])=[O:30])=[C:26](B(O)O)[CH:25]=1)[CH:21]([CH3:23])[CH3:22].Br[C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH:44]=[O:45].C(=O)([O-])[O-].[K+].[K+]>COCCOC.[OH-].[Na+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.C(O)C>[CH:44]([C:43]1[CH:42]=[C:41]([C:26]2[CH:25]=[C:24]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:28][C:27]=2[S:29]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:31])=[O:30])[CH:48]=[CH:47][CH:46]=1)=[O:45]
Reactant: O=Cc1cccc(Br)c1
Reactant: CC(C)Cc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)Cc1cc(-c2cccc(C=O)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reaction time: 20 h
Yield: 82 %

Procedure:
Palladium acetate (84.6 mg, 0.38 mmol) and triphenylphosphine (0.40 g, 1.52 mmol) in DME (5 mL) were stirred for 30 min under N2(g). The catalyst was then transferred into a nitrogen-flushed mixture of 5-iso-butyl-2-(N-tert-butylaminosulfonyl)thiophene-3-boronic acid (4.0 g, 12.56 mmol, see step (c) above), 3-bromobenzaldehyde (2.96 g, 25.12 mmol) and potassium carbonate (5.21 g, 37.7 mmol) in a solvent mixture of DME (28 mL), ethanol (8 mL), and water (12 mL). After stirring for 20 h at reflux under a N2 atmosphere, the reaction mixture was diluted with NaOH (1M solution, 50 mL) followed by ethyl acetate (150 mL). The organic layer was washed with water, and brine, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue subjected to flash chromatography (20% ethyl acetate in petroleum ether, 230-400 mesh) to afford the title compound as colourless solid (3.9 g, 10.3 mmol, 82%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[C:16]([Br:20])[CH:17]=[CH:18][CH:19]=1.[C:21](O)(=[O:23])C>O1CCCC1.O>[Br:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[C:15]=1[CH:21]=[O:23]
Reactant: CC(=O)O
Reactant: Fc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1c(F)cccc1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of diisopropylamine (15.7 ml 112 mmol) in anhydrous tetrahydrofuran (200 ml) cooled to 0° C. was added dropwise n-butyllithium (2.5M in hexanes, 44.8 ml, 112 mmol). After complete addition the mixture was cooled to −78° C. and 3-fluorobromobenzene (19.6 g, 112 mmol) added over 10 minutes. The mixture stirred at −78° C. for 1 hour then N,N diimethylformamide (9.72 ml, 125 mmol) was added dropwise over 5 minutes. The mixture was stirred for a further 10 minutes, then acetic acid (10 ml) and water (350 ml) were added. The mixture was allowed to warm to room temperature and was extracted with Et2O (250+150 ml). The combined extracts were washed with water (×2) 0.2N HCl, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica eluting with 5% Et2O in iso-hexanes to give the title compound (20 g, 88%) as a white solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:19])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=1)[CH2:2]2.[CH2:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)[CH3:21]>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:19])[NH:11][C:12]1[CH:13]=[C:14]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:20][CH3:21])[CH:27]=3)[CH:15]=[CH:16][CH:17]=1)[CH2:2]2
Reactant: O=C(Nc1cccc(Br)c1)OC1CN2CCC1CC2
Reactant: CCc1cccc(B(O)O)c1
Product: CCc1cccc(-c2cccc(NC(=O)OC3CN4CCC3CC4)c2)c1
Yield: 56 %

Procedure:
Using general procedure E, quinuclidin-3-yl3-bromophenylcarbamate, 3-ethylphenylboronic acid and [PdCl2(pddf)]CH2Cl2 gave the title compound as a white solid (78 mg, 56%). 1H NMR (500 MHz, CDCl3) δ 7.64 (br s, 1H), 7.43-7.27 (m, 6H), 7.24 (br s, 1H), 7.18 (d, J=8.0 Hz, 1H), 4.85 (m, 1H), 3.30 (m, 1H), 2.99-2.73 (m, 5H), 2.70 (q, J=7.5 Hz, 2H), 2.12 (m, 1H), 1.92-1.84 (m, 1H), 1.75-1.67 (m, 1H), 1.62-1.55 (m, 1H), 1.48-1.38 (m, 1H), 1.27 (t, J=7.5 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ 153.5, 144.8, 142.4, 140.8, 138.4, 129.4, 128.8, 127.1, 126.8, 124.6, 122.3, 117.4, 72.1, 55.4, 47.4, 46.5, 29.0, 25.4, 24.5, 19.5, 15.7 ppm. Purity: >98% LCMS (214 nm & 254 nm); retention time 1.66 min; (M+1) 351.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:23])[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[CH:12][CH:11]=1>>[O:23]=[C:16]([C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])=[CH:15][CH:14]=1)[CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: O=C(Cl)c1cccs1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2cccs2)cc1
Yield: 80.4 %

Procedure:
In a manner similar to that described in Example 3, thiophen-2-yl-carbonyl chloride (0.049 g, 0.00033 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.061 g of 4-oxo-4-[4-(thiophen-2-yl-carbonylamino)-phenyl]-butyric acid as a yellow solid; MS-(AP+) MH+304.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28](O)=[O:29])[CH:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.C(Cl)(=O)C(Cl)=O.[C:46]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])(=[O:49])[NH:47][NH2:48]>C(Cl)Cl.CN(C=O)C>[C:51]([O:50][C:46]([NH:47][NH:48][C:28]([C:24]1[CH:23]=[C:22]([O:21][C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[N:12]([C:10](=[O:11])[NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:32])([F:1])[F:31])[CH:4]=2)[CH:13]=[CH:14]3)[CH:27]=[CH:26][N:25]=1)=[O:29])=[O:49])([CH3:54])([CH3:53])[CH3:52]
Reactant: O=C(O)c1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)c1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1

Procedure:
To a solution of acid 4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyridine-2-carboxylic acid, Example 28-A, (0.100 g, 0.226 mmol) in DCM (5 mL) is added Et3N (0.09 mL), DMF (2 drops) and oxalyl chloride (0.17 mL, 0.340 mmol, 2.0 M DCM). After 0.5 h tert-butyl carbazate is added (0.045 g, 0.340 mmol). After 1.5 h the solution is diluted with DCM (10 mL) and then washed with pH 7 buffer (15 mL). The organic layer is then dried (Na2SO4), filtered, and concentrated. The residue is separated via FCC (30-60% EtOAc/heptane) to give N′-{4-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyridine-2-carbonyl}-hydrazinecarboxylic acid tert-butyl ester. MS (ESI) m/z 484.3 (M+1).
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:19]1([CH3:29])[CH2:24][CH2:23][CH:22]([CH:25]([CH3:27])[CH3:26])[CH:21](Cl)[CH2:20]1>O1CCCC1>[CH3:29][C@@H:19]1[CH2:20][C@@H:21]([P:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C@@H:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]1
Reactant: CC1CCC(C(C)C)C(Cl)C1
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[C@H]1CC[C@H](C)C[C@H]1P(c1ccccc1)c1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
Diphenylphosphine (140 g, 0.75 mol) was charged into a 2-L, 3-neck, round-bottom flask in a glove box under a nitrogen atmosphere. The reactor was connected to a nitrogen manifold. Freshly distilled tetrahydrofuran (400 mL) was added to the mixture and the mixture was cooled to -20° C. Normal butyllithium (1.6 M in hexanes, 468 mL, 0.75 mol) was added over a 2 hour period. The cold bath was removed and the orange solution was warmed to room temperature. After stirring at room temperature for 0.5 hour, (-)-menthyl chloride (129 g, 0.74 mol) was added. The mixture was stirred at room temperature for 21 hours and then heated at reflux for 40 hours. The reaction mixture was cooled to room temperature and quenched with H2O (125 mL). After stirring for 2 hours, the organic layer was separated, washed with H2O (125 mL) and concentrated to an oil. The resulting material was distilled under vacuum until crystal formation was observed in the distillation condenser to give about 130 g of crude NMDPP in the pot.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH:4]([NH:7][C:8](=[O:10])[CH3:9])[CH:5]=O.O=S(Cl)Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1[N:7]=[C:8]([CH3:9])[O:10][CH:5]=1)=[O:11]
Reactant: COC(=O)C(C=O)NC(C)=O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1coc(C)n1
Temperature: 0 °C

Procedure:
A solution of the respective 2-acetylamino-3-oxo-propionic acid methyl ester derivative (0.63 mmol, 1.0 eq.) in CHCl3 (0.4 mL) was cooled to 0° C. in an ice/NaCl bath. SOCl2 (0.88 mmol, 1.4 eq.) was added to the stirred solution and the temperature was maintained at 0° C. for 30 minutes. Then the solution was stirred and refluxed for one hour. Another 0.25 eq. of SOCl2 was added and the reaction mixture was refluxed for another hour. The excess SOCl2 was quenched with 1M aq. K2CO3. The aq. layer was extracted twice with ether. The combined organic phases were washed once with water and dried over MgSO4, filtered and concentrated yielding the corresponding 2-methyl-oxazole-4-carboxylic acid methyl ester derivative. The respective 2-methyl-oxazole-4-carboxylic acid methyl ester derivative was dissolved in a mixture of EtOH (0.7 ml) and 2N aq. NaOH (0.7 mL, 2.5 eq.). The mixture was stirred at rt for 2 hours. The reaction mixture was washed once with ether and this organic layer was discarded. The aq. layer was then acidified with conc. HCl and extracted twice with ether. Both organic layers were combined, dried over MgSO4 and concentrated in vacuo to afford the corresponding 2-methyl-oxazole-4-carboxylic acid derivatives.
Reaction SMILES: [OH:1][CH:2]([CH2:25][OH:26])[CH2:3][O:4][NH:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[C:8]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][C:17]=1[F:23].C(N(CC)CC)C>O1CCCC1.[Ni]>[OH:1][CH:2]([CH2:25][OH:26])[CH2:3][O:4][NH:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[C:8]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:23]
Reactant: O=C(NOCC(O)CO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NOCC(O)CO)c1ccc(F)c(F)c1Nc1ccccc1F
Yield: 31.8 %

Procedure:
A solution of N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (0.260 g, 0.539 mmol) and triethylamine (2.0 mL, 14.3 mmol) in tetrahydrofuran (14 mL) was hydrogenated over Raney Nickel (0.2 g wet) at 50 psig at room temperature for 20 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The afforded residue was partitioned between ethyl acetate and water. The organics were washed twice with saturated sodium bicarbonate solution, twice with water, collected, dried over sodium sulfate, filtered and concentrated in vacuo. HPLC purification was performed using a YMC 30×100 mm 5u (C18) column in 0-100% acetonitrile (3.0% n-propanol)/100-0% water (3.0% n-propanol) at 30 ml/min. The desired fractions were collected and concentrated. The afforded residue was extracted with ethyl acetate/water. Organic layers were washed with saturated NaCl solution, collected and dried in vacuo to afford N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-phenylamino)-benzamide as a white solid (0.061 g, 31%): m.p.=113-115° C.; 1NMR (400 MHz; DMSO-d6) δ 11.90 (s, 1H), 8.73 (s, 1H), 7.37 (m, 1H), 7.10-7.19 (m, 2H), 7.02 (t, 1H, J=7.4 Hz), 6.84-6.93 (m, 2H), 4.82 (m, 1H), 4.57-4.58 (m, 1H), 3.86-3.88 (m, 1H), 3.67-3.73 (m, 2H), 3.3 (2H, under HDO); MS(APCI+)=357.1; Anal. calcd/found for C16H15F3N2O4: C, 53.94/53.97; H, 4.24/4.37; N, 7.86/7.83.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([N:11]=[N+]=[N-])[CH2:8][N:7]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:5]>CO.[Pd]>[CH3:1][CH2:2][O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH2:11])[CH2:8][N:7]1[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[O:5]
Reactant: CCOC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 175.1 %

Procedure:
To the solution of (2S,4S)-4-azido-pyrrolidin-1,2-dicarboxylic acid-1-tert-butyl ester-2-ethyl ester (29) (1.8 g, 2.1 mmol) in CH3OH (40 ml) was added Pd/C 10% (50 mg). The resulting slurry was hydrogenated at 1 atm for 24 hours. The catalyst was filtered through Celite and filtrate evaporated under reduced pressure to give 0.95 g of desired product.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([N:21]([CH2:30][CH3:31])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])=[O:20])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[Li+].[OH-].Cl>C(#N)C>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([N:21]([CH2:30][CH3:31])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])=[O:20])=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(CC)Cc2ccccc2F)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Product: CCO[C@@H](Cc1ccc(OCC(=O)N(CC)Cc2ccccc2F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
To a solution of ethyl(2S)-2-ethoxy-3-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)propanoate (0.980 g, 2.27 mmol) in acetonitrile (120 mL) was added aqueous 0.10 M LiOH (57 mL) and the reaction mixture was stirred at room temperature overnight. After neutralisation with 5% HCl, the solvent volume was reduced in vacuo and the remaining aqueous phase was acidified with 5% HCl and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed brine (100 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.868 g (95%) of a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:8][C:4]=2[CH:3]=1.[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18].Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:15][N:16]([C:17]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:9]([NH2:10])(=[O:11])=[O:12])=[CH:8][C:4]=2[CH:3]=1)=[O:18])[CH3:20]
Reactant: CN(C)C(=O)Cl
Reactant: NS(=O)(=O)c1cc2cc(O)ccc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)C(=O)Oc1ccc2sc(S(N)(=O)=O)cc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.9 %

Procedure:
A solution of 2.3 g (10 mmoles) of 5-hydroxy-2-sulfamoylbenzo[b]thiophene in 50 ml of pyridine was treated with 200 mg of 4-dimethylaminopyridine and finally 2.5 ml (2.9 g, 27 mmoles) of dimethylcarbamyl chloride. The resultant clear solution was stirred at room temperature for 48 hours, when it was poured into a mixture of 200 g of chopped ice and 100 ml of concentrated HCl. The precipitated solid was collected and washed with cold H2O until the washings were neutral. Drying gave 2.25 g (75%) of tan powder which was crystallized from isopropyl alcohol to give 1.6 g of product, m.p. 192°-194° C.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][C:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12])=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd].O>[NH2:1][C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][C:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:12])[CH3:13])=[O:9])=[CH:6][CH:5]=1
Reactant: CC(C)(C)CC(C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)CC(C)(C)NC(=O)c1ccc(N)cc1
Reaction time: 1 h
Yield: 76.1 %

Procedure:
4-Nitro-N-(tert-octyl)benzamide (30 g, 0.108 mol) dissolved in 200 ml of ethyl acetate is hydrogenated, in a 500 ml hydrogenator, in the presence of 4.8 g of 10% palladium-on-charcoal containing 50% of water, as catalyst (hydrogen pressure: 8-10 bar), at a temperature of 70-75° C. for 1 hour and 15 minutes. After filtration, concentration of the solvent and drying under vacuum, 20.4 g (yield: 76%) of 4-amino-N-(tert-octyl)benzamide are obtained in the form of a light yellow powder, which is used as it is in the following stage.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[NH:22])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)(O)[O-].[Na+].Br[CH2:29][C:30](=[O:35])[C:31]([F:34])([F:33])[F:32]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:14][CH:13]=3)[CH2:29][C:30]([OH:35])([C:31]([F:34])([F:33])[F:32])[N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=C(CBr)C(F)(F)F
Reactant: COc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cc1Cl

Procedure:
To a mixture of 3-chloro-4-methoxy-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (10 mmol) and sodium bicarbonate (20 mmol) in isopropanol (100 mL), 3-bromo-1,1,1-trifluoroacetone (20 mmol) is added. After heating the reaction mixture at 70°-75° C. for 20 hours, the solvent is removed. The residue is redissolved in methylene chloride and washed with water. The organic fractions are combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture is chromatographed (silica gel, toluene/ethyl acetate, 7/3) to give 2-(3-chloro-4-methoxyphenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-4,5-dihydro-1H-imidazole.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:25])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([OH:22])=O)=[C:14]([O:23][CH3:24])[CH:13]=2)[CH2:4][CH2:3]1.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[N:42]1([CH:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([N:51]3[CH2:52][CH2:53][CH:48]([N:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)[CH2:49][CH2:50]3)=[O:22])=[C:14]([O:23][CH3:24])[CH:13]=2)=[O:25])[CH2:6][CH2:7]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCC(=O)O
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCC(=O)N1CCC(N2CCCCC2)CC1

Procedure:
Using 1.9 g of N-(trans-4-methylcyclohexyl)-4-(carboxymethoxy)-3-methoxycinnamamide (Example 172), 1.2 ml of diethyl chlorophosphate, 2.3 ml of triethylamine, 0.92 g of 4-piperidinopiperidine, 0.04 g of 4-dimethylaminopyridine, and 100 ml of methylene chloride, a reaction similar to that conducted in Example 188 was carried out. As a result, 1.51 g of 1-{4-{2-[N-(trans-4-methylcyclohexyl)carbamoyl]vinyl}-2-methoxyphenoxyacetyl}-4-piperidinopiperidine (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]([C:28]1[S:32][CH:31]=[C:30]([C:33]([OH:35])=O)[CH:29]=1)([CH3:27])[CH3:26].[O:36]1[C:41]2([CH2:46][CH2:45][N:44]([CH2:47][C:48]3[C:49]([F:57])=[C:50]([CH2:54][CH2:55][OH:56])[CH:51]=[CH:52][CH:53]=3)[CH2:43][CH2:42]2)[CH2:40][NH:39][CH2:38][CH2:37]1.C(N(CC)CC)C>CN(C=O)C>[F:57][C:49]1[C:50]([CH2:54][CH2:55][OH:56])=[CH:51][CH:52]=[CH:53][C:48]=1[CH2:47][N:44]1[CH2:45][CH2:46][C:41]2([O:36][CH2:37][CH2:38][N:39]([C:33]([C:30]3[CH:29]=[C:28]([CH:25]([CH3:26])[CH3:27])[S:32][CH:31]=3)=[O:35])[CH2:40]2)[CH2:42][CH2:43]1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reactant: CC(C)c1cc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (0.183 g) was added in one portion to a stirred solution at 0° C. of 5-isopropylthiophene-3-carboxylic acid (0.063 g) and 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.114 g) and triethylamine (0.155 mL) in DMF (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 2.5% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.100 g.
Reaction SMILES: [OH-:1].[Na+].C[O:4][C:5]([C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:6]>CO>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:5]([OH:6])=[O:4])[C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:21][CH:22]=1)(=[O:1])[NH2:27]
Reactant: [OH-]
Reactant: COC(=O)c1cccc2c1c1ccccc1n2-c1ccc(C#N)cn1
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(-n2c3ccccc3c3c(C(=O)O)cccc32)nc1
Temperature: 60 °C

Procedure:
1.6 ml of 2M sodium hydroxide are added to a solution of 0.33 g of 9-(5-cyanopyridin-2-yl)-9H-carbazole-4-carboxylic acid methyl ester, obtained according to the preceding stage, in 30 ml of methanol, and then the mixture is heated at 60° C. for 2 hours. After a return to ambient temperature, the reaction mixture is concentrated under reduced pressure, and then 20 ml of water and a 1M aqueous solution of HCl are added in order to bring the pH to around 6. The aqueous phase is extracted with 3×100 ml of ethyl acetate, and the organic phases are then combined, dried over magnesium sulphate and concentrated under reduced pressure. 0.24 g of 9-(5-carbamoylpyridin-2-yl)-9H-carbazole-4-carboxylic acid is thus obtained in the form of a rubbery residue, the characteristics of which are the following: