Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:14]([N:16]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[N:17]1)[CH3:15].C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[C:12]([C:8]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([C:19]2[CH:18]=[N:17][N:16]([CH2:14][CH3:15])[CH:20]=2)[N:11]=[CH:10][CH:9]=1)#[N:13]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)c1c(C#N)ccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCn1cc(-c2nccc(C#N)c2C(=O)OC)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 114.4 %

Procedure:
A mixture of methyl 2-chloro-4-cyanonicotinate (207 mg, 1.053 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (201 mg, 0.905 mmol) and tetrakis(triphenylphosphine)palladium(0) (122 mg, 0.105 mmol) in DME (2 mL), and saturated aq Na2CO3 (2 mL) was stirred at 80° C. for 3 h under N2 atmosphere. Water and EtOAc were subsequently added. The organic phase was washed with H2O and brine, dried over MgSO4, and evaporated to yield the title compound (265.3 mg, 98%). [M+H] calc'd for C13H12N4O2, 257; found, 257.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH2:16][C:17]([OH:19])=O)=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](N1C=CN=C1)([N:22]1C=CN=[CH:23]1)=O.CNC>O1CCCC1>[CH3:20][N:22]([CH3:23])[C:17](=[O:19])[CH2:16][C:15]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1c(-c2ccccc2)nn2cccnc12
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1c(-c2ccccc2)nn2cccnc12
Reaction time: 4 h
Yield: 76 %

Procedure:
A mixture of 3.5 g (0.013 mole) of 2-phenylpyrazolo[1,5-a]pyrimidine-3-acetic acid and 2.24 g (0.013 mole) of 1,1'-carbonyldiimidazole in 150 ml of anhydrous tetrahydrofuran was stirred for 4 hours under a nitrogen atmosphere. A solution of dimethylamine in tetrahydrofuran (14.0 ml of a 2.95M solution; 0.0414 mole) was added. The mixture was stirred at room temperature for one hour. The solvent was evaporated under reduced pressure, and the residue was dissolved in methylene chloride (100 ml). The solution was extracted with 7% aqueous sodium bicarbonate, and with water, and then dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The crystalline residue (4.6 g) was recrystallized from isopropanol to give 2.77 g (72%) of product, mp 156°-157.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[CH2:35]([O:37][CH2:38][CH2:39][N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[N:49]1[CH2:55][CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH3:36].C(N(CC)C(C)C)(C)C.CO.C(OCC)(=O)C>C(#N)C.C(OCC)(=O)C>[CH3:33][O:32][C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:52]2[CH2:53][CH2:54][CH2:55][N:49]([C:41]3[N:40]([CH2:39][CH2:38][O:37][CH2:35][CH3:36])[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)[CH2:50][CH2:51]2)([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccc(Cl)cc3)C2)cc(OC)c1OC
Agent: I
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCn1c(N2CCCN(CCC3(c4ccc(Cl)cc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 20 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(4-chlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (1.0 g, 2.0 mmol), 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (1.2 g, 2.2 mmol), and N,N-diisopropylethylamine (1.4 mL, 8.1 mmol) in acetonitrile (60 mL). Heat to reflux. After 20 hours, cool and dilute the reaction mixture with ethyl acetate. Extract three times with a saturated aqueous sodium bicarbonate solution, and then brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 25% methanol/ethyl acetate containing concentrated aqueous ammonia 20 mL/3 L to give the title compound: Rf=0.49 (silica gel, 30% methanol/ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[CH3:27][C:28]1([CH3:40])[CH2:32][C:31]2[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:30]=2[O:29]1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:27][C:28]1([CH3:40])[CH2:32][C:31]2[CH:33]=[C:34]([N:3]3[C:4](=[O:26])[C:5]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([C:18]5[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=5)=[CH:14][CH:13]=4)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]3[CH3:1])[CH:35]=[CH:36][C:30]=2[O:29]1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1(C)Cc2cc(B(O)O)ccc2O1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCCc1nc(C)n(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.1 %

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (4.0 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (4.0 g), triethylamine (8.0 mL), pyridine (4.0 mL) and molecular sieves 4 A (8.0 g) in methylene chloride (60 mL) was added copper(II) acetate (4.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (4.28 g, 75%).
Reaction SMILES: [NH2:1][CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11].F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].C(N(CC)CC)C>O1CCOCC1>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:1][CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11])([O-:21])=[O:20]
Reactant: CCCC1CC(=O)N(CN)C1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCC1CC(=O)N(CNc2ccccc2[N+](=O)[O-])C1

Procedure:
A mixture of 1-aminomethyl-4-propyl-pyrrolidin-2-one a27 (1 eq, 17.09 mmol, 2.67 g), 2-fluoro-nitrobenzene (1 eq, 17.09 mmol, 2.411 g, 1.802 ml) and triethylamine (1.1 eq, 18.8 mmol, 1.902 g, 2.62 ml) in dioxane (20 ml) was refluxed 48 h. After cooling, the crude mixture was filtrated and the dioxane was distilled under vacuum. The residue was purified by preparative chromatography on reverse phase to give (2-nitrophenyl){(2-oxo-4-propyl-pyrrolidin-1-yl)methyl}amine a28 (2.747 g, 58%). LC/MS (MH+): 278.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][NH:32][CH3:33])[CH3:28]>C(Cl)Cl>[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][N:32]([CH3:33])[S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17])[CH3:28]
Reactant: CCN(CC)CCNC
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)CCN(C)S(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (500 mg; 1.48 mmol; 1.00 eq) is dissolved in DCM (30 ml). The solution is degassed with N2 and cooled down to 0° C. Triethylamine (1.0 ml; 7.42 mmol; 5.00 eq) followed by N,N-diethyl-N′-methylethylenediamine (1.2 ml; 7.42 mmol; 5.00 eq) are added. After 1 hour at 0° C., the reaction is complete. The reaction mixture is washed with NaHCO3 sat. (twice) and water (twice). The organic phase is dried over MgSO4, filtered and concentrated under vacuum, affording Compound (20) as a beige solid (570 mg; 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH2:9]1[O:11][CH2:10]1.FC1C=C(CCO)C=CN=1>>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(F)c1
Reactant: C1CO1
Agent: OCCc1ccnc(F)c1
Product: OCCCc1ccnc(F)c1
Yield: 528.6 %

Procedure:
This compound was prepared, starting from compound 41 (7.00 g, 6.30 mmol) and ethylene oxide (4.20 mL, 84.1 mmol), according to the procedure developed for compound 42. The purification was performed using colomm chromatography (SiO2, AcOEt/pentane, 6/4, v/v) to give alcohol 48 (5.16 g, 33.3 mmol) as a yellow oil. Yield 53%; Rf (SiO2, AcOEt/pentane 6/4, v/v) 0.52; IR (CCl4) ν 1412, 1613, 2939, 3639 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.84 (m, 2H), 2.72 (t, 2H, J=7.4 Hz), 3.14 (se, 1H), 3.62 (t, 2H, J=6.2 Hz), 6.72 (s, 1H), 6.98 (m, 1H), 8.01 (d, 1H, J=5.1 Hz); MS m/z 155 (M+, 6), 137 (25), 124 (12), 111 (100), 91 (21), 77 (14), 57 (14), 51 (16).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[CH:25]=[CH:24][CH:23]=[N:22]1>>[N:21]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH2:29][N:1]2[CH:2]([C:11]3[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]2=[O:7])[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: O=Cc1cccc(-n2cccn2)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-n2cccn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 3-(1H-pyrazol-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.81 min.; [M+H]+: 392.18 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1B(O)O.Br[C:13]1[CH:14]=[C:15]2[C:19]3=[C:20]([CH2:22][S:23][CH2:24][CH2:25][N:18]3[C@H:17]3[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C@@H:16]23)[CH:21]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:19]3=[C:20]([CH2:22][S:23][CH2:24][CH2:25][N:18]3[CH:17]3[CH2:26][CH2:27][NH:28][CH2:29][CH:16]23)[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCSC3
Reactant: OB(O)c1c(F)cccc1F
Product: Fc1cccc(F)c1-c1cc2c3c(c1)C1CNCCC1N3CCSC2

Procedure:
Using 2,6-difluorophenyl boronic acid and following the procedures described in EXAMPLE 9, tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate was converted into the title compound of EXAMPLE 14. 1H NMR (CDCl3, 300 MHz): δ 7.19 (m, 1H), 6.93 (m, 2H), 6.83 (m, 3H), 3.81 (m, 2H), 3.59 (m, 1H), 3.41 (m, 1H), 3.21 (m, 2H), 3.0 (m, 2H), 2.82 (m, 3H), 2.60 (m, 1H), 1.80 (m, 2H). LRMS (ES+): 359 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([S:11][CH3:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:13][C:14]1[CH:15]=[C:16]([C:20]#[CH:21])[CH:17]=[CH:18][CH:19]=1>CO>[C:20]([C:16]1[CH:15]=[C:14]([NH:13][C:2]2[C:3]3[C:10]([S:11][CH3:12])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:19]=[CH:18][CH:17]=1)#[CH:21]
Reactant: CSc1c[nH]c2ncnc(Cl)c12
Reactant: C#Cc1cccc(N)c1
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3[nH]cc(SC)c23)c1
Temperature: 125 °C
Yield: 27.1 %

Procedure:
To 4-chloro-5-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine (150 mg, 0.75 mmol) in dry methanol (2 ml) was added m-aminophenyl acetylene (110 mg, 0.90 mmol). The solution was heated in a sealed pressure tube at 125° C. for 5.5 hours. The reaction mixture was cooled to ambient temperature, filtered with a small amount of methanol and dried in vacuo to afford the title compound as a tan powder (57 mg, 27%). TS-MS: 281 (MH+); anal. RP18-HPLC RT:4.74 min.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[OH:28][C@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 118 using (S)-5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 124.1) and pyrimidin-5-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=2.22 min, m/z=460.0 [M+H]+, m/z=458.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.21-1.39 (m, 2H) 1.56-1.65 (m, 1H) 1.77-1.86 (m, 1H) 2.63 (dd, J=11.86, 8.19 Hz, 1H) 2.75-2.84 (m, 1H) 3.35-3.39 (m, 1H) 3.43-3.49 (m, 1H) 3.49-3.55 (m, 1H) 4.74 (s, 1H) 7.37 (d, J=8.31 Hz, 2H) 7.83-7.89 (m, 2H) 8.19 (d, J=2.20 Hz, 1H) 8.80 (d, J=2.20 Hz, 1H) 9.08 (s, 2H) 9.21 (s, 1H) 10.30 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11])(=[O:4])=[O:3].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[N:19]=1.C1N2CCN(CC2)C1>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH:25][C:14]([NH:13][S:10]([C:9]2[CH:8]=[CH:7][S:6][C:5]=2[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:11])=[O:12])=[O:15])[N:19]=1
Reactant: CS(=O)(=O)c1sccc1S(=O)(=O)N=C=O
Reactant: COc1cc(C)nc(N)n1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccsc2S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The crude 2-methylsulfonyl-3-thiophenesulfonyl isocyanate described above was dissolved in 100 ml of methylene chloride and 10 ml of this solution (0.3 g of crude isocyanate) was added to 200 mg of 4-methoxy-6-methyl-2-pyrimidinamine in methylene chloride containing a few crystals of DABCO. After stirring 3 days at room temperature, the precipitate was filtered and washed with ether to afford 250 mg of product, m.p. 204.5°-206°d. The IR spectrum showed a carbonyl absorption at 1680 cm-1 indicative of a sulfonylurea.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=O)[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:35])[CH3:34].[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:14])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=4)[CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:35])[CH3:34]
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(N2CCN(c3cccc(C4CC(C)(C)c5cc(F)cc(C(=O)O)c5N4)c3)CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(N2CCN(c3cccc(C4CC(C)(C)c5cc(F)cc(C(=O)NS(C)(=O)=O)c5N4)c3)CC2)cc1
Yield: 19.9 %

Procedure:
A mixture of 6-fluoro-4,4-dimethyl-2-[3-(4-p-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (150 mg, 0.32 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (91 mg, 0.48 mmol), 4-dimethylaminopyridine (59 mg, 0.48 mmol), methane sulfonamide (91.2 mg, 0.96 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-{6-fluoro-4,4-dimethyl-2-[3-(4-p-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carbonyl}-methanesulfonamide (35 mg, 20%) as a light yellow solid: MS (ESI) M+1=551.3.
Reaction SMILES: C([O:4][CH2:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([N+:19]([O-:21])=[O:20])=[C:11]([NH:15]C(=O)C)[CH:12]=2)[CH2:7]1)(=O)C.Cl>CO>[NH2:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[N+:19]([O-:21])=[O:20])[CH2:7][CH:6]([CH2:5][OH:4])[CH2:14]2
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CC(COC(C)=O)C2
Agent: Cl
Solvent: CO
Product: Nc1cc2c(cc1[N+](=O)[O-])CC(CO)C2
Yield: 110.6 %

Procedure:
A mixture of acetate 122 (5.60 g, 19.2 mmol) and 5 M HCl (80 mL) in MeOH (80 mL) was stirred at reflux temperature for 30 min. The solvent was evaporated to give the hydrochloride salt of 123 (4.42 g, 94%) as an orange solid: mp (MeOH) 143-145° C.; 1H NMR [(CD3)2SO] δ 7.73 (s, 1H, H-7), 7.43 (br s, 4H, NH2, OH, HCl), 6.84 (s, 1H, H-4), 3.31-3.38 (m, 2H, CH2O), 2.77-2.90 (m, 2H, CH2), 2.44-2.64 (m, 3H, CH2, CH); 13C NMR [(CD3)2SO] δ 153.2, 145.7 131.4, 129.1, 119.8, 113.7, 63.8, 41.5, 35.2, 33.6; HRMS calcd for C10H12N2O3 (M+) m/z 208.0848, found 208.0850. Anal. calcd for C10H12N2O3.HCl: C, 49.1; H, 5.4; N, 11.5. Found: C, 49.4; H, 5.4; N, 11.5%.
Reaction SMILES: [CH2:1]1[O:22][C:4]([O:20]C)([C:5]2[CH:10]=[CH:9][C:8]([C:11]([N:13]3[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]3)=[O:12])=[CH:7][CH:6]=2)[O:3][CH2:2]1.O.[OH-].[Li+].Cl>C1COCC1.O>[CH2:2]1[O:3][C:4]([OH:20])([C:5]2[CH:10]=[CH:9][C:8]([C:11]([N:13]3[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]3)=[O:12])=[CH:7][CH:6]=2)[O:22][CH2:1]1
Reactant: COC1(c2ccc(C(=O)N3CCC(=O)CC3)cc2)OCCO1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCN(C(=O)c2ccc(C3(O)OCCO3)cc2)CC1
Yield: 98.1 %

Procedure:
A solution of methyl 4-(4-oxopiperidinocarbonyl)benzoate ethylene ketal (1.5 g, 4.9 mmol) and lithium hydroxide monohydrate (309 mg, 7.4 mmol) in THF/water (1:1) (50 ml) was stirred for 18 h, then acidified with dilute HCl. The product was extracted into ethyl acetate, and the extracts dried over sodium sulphate and concentrated to leave a white solid (1.4g), MS (+CI) 292 ([M+H]+), 1H NMR (CDCl3) 8.10 (2H, d, J 8.2 Hz), 7.45 (2H, d, J 8.3 Hz), 3.99 (4H, s), 3.86 (2H, br. s), 3.44 (2H, br. s), 1.81 (2H, br. s), 1.65 (2H, br. s)
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:41]=[CH:40][C:10]([C:11]([C:13]3[CH:33]=[CH:32][C:16]([O:17][CH2:18][C:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([O:30]C)=[O:29])[C:22]=5[S:21][CH:20]=4)=[C:15]([CH2:34][CH2:35][C:36]([O:38]C)=[O:37])[CH:14]=3)=[O:12])=[C:9]([OH:42])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.Cl.C(Cl)(Cl)Cl>CO.O1CCCC1.[OH-].[Na+]>[C:36]([CH2:35][CH2:34][C:15]1[CH:14]=[C:13]([C:11](=[O:12])[C:10]2[CH:40]=[CH:41][C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:8][C:9]=2[OH:42])[CH:33]=[CH:32][C:16]=1[O:17][CH2:18][C:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([OH:30])=[O:29])[C:22]=2[S:21][CH:20]=1)([OH:38])=[O:37]
Reactant: COC(=O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1csc2c(C(=O)OC)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1csc2c(C(=O)O)cccc12
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
1.15 g of methyl 3-{[4-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-methoxy-3-oxopropyl)phenoxy]methyl}-1-benzothiophene-7-carboxylate was dissolved in a mixed solvent of 10 mL of methanol and 10 mL of tetrahydrofuran, to which 2 mL of a 5M aqueous solution of sodium hydroxide was added at room temperature, and then this mixture was stirred for 30 minutes at the same temperature, followed by addition thereto of 2 mL of water, and this mixture was stirred for another 30 minutes at temperatures of 50 to 60° C. The reaction mixture was cooled to room temperature, to which water was added, and then adjusted to pH 2 with 6M hydrochloric acid. Chloroform was added to this reaction mixture, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water, the organic phase was separated and the solvent was distilled out thereof under reduced pressure. The resultant residue was washed with hexane to yield 1.00 g of 3-({2-(2-carboxyethyl)-4-[4-(cyclopentyloxy)-2-hydroxybenzoyl]phenoxy}methyl)-1-benzothiophene-7-carboxilic acid as light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]1[C:10]([O:11]CC2C=CC=CC=2)=[CH:9][N:8]=[C:7]([N:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([C:30]#[N:31])=[CH:20]2)[CH:6]=1)[CH3:2].CO>[C].[Pd].C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:32])[C:5]1[C:10]([OH:11])=[CH:9][N:8]=[C:7]([N:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:21]([C:30]#[N:31])=[CH:20]2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(-n2cc(C#N)c(-c3ccccc3)c2)ncc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(-n2cc(C#N)c(-c3ccccc3)c2)ncc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-benzyloxy-2-(3-cyano-4-phenylpyrrole-1-yl)isonicotinic acid ethyl ester in a mixed solvent of methanol (2 mL) and ethyl acetate (2 mL) was added palladium-carbon powder (0.020 g), and this mixture was stirred at room temperature under a hydrogen atmosphere for 30 minutes. The insoluble material was removed by suction through a Celite pad. This filtrate was concentrated under reduced pressure. This obtained solid was washed with diethyl ether, dried to give the title compound (0.040 g).
Reaction SMILES: [OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][C@@H:5]1[C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][CH2:6]1.C1C2B3C(CCC2)CCCC3CC1.[Li].[OH-].[Na+].OO.Cl>CCOCC.O1CCCC1>[OH:19][C@H:8]1[CH2:7][CH2:6][C@H:5]([CH2:4][CH2:3][CH:2]([OH:1])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCCCCC(O)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)O
Agent: C1CC2CCCC3CCCC(C1)B23
Agent: Cl
Agent: OO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC(O)CC[C@H]1CC[C@H](O)[C@@H]1CCCCCCC(=O)O

Procedure:
To a solution of 433 mg. of 15-hydroxy-9-oxoprostanoic acid (Example 186) in 4.5 ml. of tetrahydrofuran, stirred in an ice-bath under nitrogen atmosphere, is added dropwise 3.7 ml. of 0.76 M lithium perhydro-9b-boraphenalylhydride. After 40 minutes at 0°C. there is added 1.62 ml. of 3N sodium hydroxide followed by 1.62 ml. of 30% hydrogen peroxide. Ether is added and the resulting solution is acidified with 2N hydrochloric acid. The ether layer is washed several times with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 300 mg. (70%) of waxy solid; nmr 3H singlet δ 4.64 (hydroxyl and carboxyl protons), 1 H singlet 4.22 (9β-carbinolic proton, 80%), 1 H singlet 3.88 (9α-carbinolic protons, 20%), 1 H singlet 3.61 (15-carbinolic proton), and 3 H distorted triplet 0.90 (terminal methyl).
Reaction SMILES: CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[Cl:14][CH:15]([Cl:28])[C:16]([C@H:18]1[C@H:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]1([CH3:27])[CH3:26])=[O:17].Cl>C(O)(C)C>[Cl:14][CH:15]([Cl:28])[CH:16]([C@H:18]1[C@H:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]1([CH3:27])[CH3:26])[OH:17]
Reactant: CCOC(=O)[C@H]1[C@H](C(=O)C(Cl)Cl)C1(C)C
Agent: CC(C)[O-]
Agent: Cl
Agent: [Al+3]
Solvent: CC(C)O
Product: CCOC(=O)[C@H]1[C@H](C(O)C(Cl)Cl)C1(C)C

Procedure:
Aluminium isopropoxide (0.97 g, 0.005 M) and (±) trans ethyl 3-dichloroacetyl-2,2-dimethylcyclopropane-1-carboxylate (1.0 g, 0.004 M) were refluxed in isopropanol (6.0 ml) for 16 hours. On cooling, the mixture was poured into 2 N hydrochloric acid (50 ml) and then extracted with ether (3×30 ml). The combined organic layers were extracted with water (2×50 ml), dried and evaporated in vacuo to yield a colourless oil. This product was identical (n.m.r. and i.r. spectra and g.l.c.) to the title product obtained from the sodium borohydride reduction described above in Example 3.