Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=O)[C:10]=12)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([Cl:22])[C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncn2c1c(=O)[nH]c1ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ncn2c1c(Cl)nc1ccccc12
Temperature: 25 °C
Yield: 47 %

Procedure:
4-Oxo-4,5-dihydroimidazo[1,5-a]quinoxaline 3-carboxylic acid ethyl ester (9 g) was suspended in 200 ml of phosphorus oxychloride and the mixture was heated with stirring until it became a clear solution. After cooling to room temperature, the solution was concentrated under vacuum. The residual oil was taken up in chloroform and was put through a short silica gel dry column (chloroform as eluant). The product was obtained from column as an off-white colored solid (4.5 g, 47% yield), m.p. 128°-130° C.
Reaction SMILES: O.S(=O)(=O)(O)O.[F:7][C:8]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][C:9]=1[NH2:10].[C:16]1([C:22](O)([CH3:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[F:7][C:8]1[CH:14]=[CH:13][C:12]([S:15][C:22]([CH3:24])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:23])=[CH:11][C:9]=1[NH2:10]
Reactant: CC(C)(O)c1ccccc1
Reactant: Nc1cc(S)ccc1F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Sc1ccc(F)c(N)c1)c1ccccc1
Temperature: 0 °C
Yield: 45.9 %

Procedure:
To a mixture of water (10 mL) and concentrated sulfuric acid (10 mL) were added 2-fluoro-5-mercaptoaniline (1.85 g) and a solution of 2-phenyl-2-propanol (1.76 g) in tetrahydrofuran (10 mL) successively at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1−3/1) to give the title compound (1.55 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]2[CH2:16][CH2:15][CH:14]3[CH:12]([CH2:13]3)[CH:11]2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.C1CN([P+](O[N:37]2N=[N:44][C:39]3C=CC=C[C:38]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.NCC#N.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:38]([CH2:39][NH:44][C:17]([CH:11]1[CH:10]([CH2:9][S:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:16][CH2:15][CH:14]2[CH:12]1[CH2:13]2)=[O:19])#[N:37]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)C1C(CSc2ccc(F)cc2)CCC2CC21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCNC(=O)C1C(CSc2ccc(F)cc2)CCC2CC21
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To (1R/S,2R/S,3R/S,6S/R)-3-{[(4-fluorophenyl)sulfanyl]methyl}bicyclo[4.1.0]heptane-2-carboxylic acid (310 mg, 1.12 mmol), PyBOP (640 mg, 1.23 mmol), and aminoacetonitrile hydrochloride (228 mg, 2.46 mmol) was added dry dimethylformamide (10 mL) under an atmosphere of dry nitrogen followed by triethylamine (550 μL, 3.92 mmol) and the reaction mixture was stirred for 4.5 h at room temperature. The reaction mixture was poured into aqueous saturated sodium hydrogen carbonate, extracted with ether, and dried over anhydrous sodium sulfate. The solvent was concentrated in vacuo and the crude product was purified by flash chromatography over silica gel (ethyl acetate/hexanes, 4/6) to yield (1R/S,2R/S,3R/S,6S/R)-N-(cyanomethyl)-3-{[(4-fluorophenyl)sulfanyl]methyl}-bicyclo[4.1.0]heptane-2-carboxamide. 1H NMR (400 MHz, acetone-d6): δ=7.85 (1H, br s), 7.42-7.35 (2H, m), 7.11-7.05 (2H, m), 4.314.19 (2H, m), 2.98 (1H, dd), 2.83 (1H, m), 2.72 (1H, dd), 1.94 (1H, m), 1.85-1.75 (2H, m), 1.54 (1H, m), 1.27-1.16 (2H, m), 0.98 (1H, m), 0.63 (1H, dt). MS [ESI, (M−H)−] m/z=317.0 amu.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:5]=[CH:4][C:3]=1[CH2:25][C:26]([O:28]CC)=[O:27].[OH-].[K+].C(O)C.O.Cl>O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:5]=[CH:4][C:3]=1[CH2:25][C:26]([OH:28])=[O:27]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)OCC)c(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)O)c(F)c1

Procedure:
A mixture of 6.0 g. of ethyl 2-fluoro-4-(hexadecylamino)phenylacetate, 7.0 g. of potassium hydroxide and 100 ml. of ethanol-water is heated to reflux for 4 hours. While hot, the mixture is adjusted to pH 7 with conc. hydrochloric acid. The mixture is diluted with water, cooled and filtered. Recrystallization of the precipitate yields 2-fluoro-4-(hexadecylamino)phenylacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH:24]1[C:28]2[CH2:29][CH2:30][CH2:31][C:27]=2[C:26]([NH2:32])=[N:25]1>O1CCCC1.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([NH:32][C:26]3[C:27]4[CH2:31][CH2:30][CH2:29][C:28]=4[NH:24][N:25]=3)=[O:17])=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(-c2cccc(F)c2)cc1
Reactant: Nc1n[nH]c2c1CCC2
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(-c2cccc(F)c2)cc1)Nc1n[nH]c2c1CCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
230 mg of 2-(3′-fluoro-biphenyl-4-yl)-acetic acid is dissolved in 5 ml of tetrahydrofuran, mixed with 0.11 ml of oxalyl chloride and one drop of dimethylformamide, and stirred for 2 hours at room temperature. 62 mg of 1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine is added to this solution. The mixture is stirred for 12 hours at room temperature and then concentrated by evaporation. The residue is extracted with ethyl acetate. The extract is washed with sodium bicarbonate solution and water, dried on magnesium sulfate and concentrated by evaporation. The brown residue is dissolved in 5 ml of methanol and mixed with 0.1 ml of a 30% sodium methylate solution. It is stirred for 4 hours at room temperature and then concentrated by evaporation. The residue is extracted with ethyl acetate. The extract is washed with sodium bicarbonate solution and sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation. A yellow, resinous oil is obtained that is purified by HPLC. 2-(3′-Fluoro-biphenyl-4-yl)-N-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl)-acetamide with a melting point of 180-181° C. is obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12]2)=[N:3][CH:2]=1.C(OCC)C>[Pd].C1(OC2C=CC=CC=2)C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12]2)=[N:3][CH:2]=1
Reactant: CCOC(=O)CC1CN(c2ncnc3ccccc23)c2ccccc21
Agent: [Pd]
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)Cc1cn(-c2ncnc3ccccc23)c2ccccc12
Temperature: 25 °C

Procedure:
A mixture of ethyl 1-quinazolin-4-ylindolin-3-yl-acetate (2.6g.) and 10% w/w palladium on charcoal catalyst (1.3g.) in diphenyl ether (20ml.) was heated under reflux for 30 minutes. The mixture was cooled to room temperature, mixed with diethyl ether (50ml.) and filtered through diatomaceous earth. The solid residue was washed with diethyl ether (50ml.). The combined diethyl ether solution was evaporated in vacuo, and the residue was chromatographed on silica gel (ca 150g.) using, as eluant, petroleum ether (b.p. 40°-60° C.) containing an increasing proportion of diethyl ether. Diphenyl ether was recovered from the first fractions (rich in petroleum ether). Evaporation in vacuo of later fractions gave a syrup which crystallised from a mixture of diethyl ether and petroleum ether (b.p. 40°-60° C.) to give ethyl 1-quinazolin-4-ylindol-3-ylacetate, m.p. 65°-67° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NC(C)C)(C)C.Br[C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:37])[CH3:36])=[CH:30][CH:29]=1.[C:38]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47]([NH:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[O:48])=[CH:42][CH:41]=1)#[CH:39]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:35]([NH:34][C:31]1[CH:32]=[CH:33][C:28]([C:39]#[C:38][C:40]2[CH:41]=[CH:42][C:43]([CH2:46][C:47]([NH:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[O:48])=[CH:44][CH:45]=2)=[CH:29][CH:30]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)Nc1ccc(Br)cc1
Reactant: C#Cc1ccc(CC(=O)NNC(=O)OC(C)(C)C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: CC(=O)Nc1ccc(C#Cc2ccc(CC(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 20.2 %

Procedure:
Palladium (II) acetate (2.5 mg, 0.011 mmol) and triphenylphosphine (11 mg, 0.044 mmol) were added to diisopropylamine (4 ml), and the mixture was stirred at room temperature for 20 mins. N-(4-Bromophenyl)acetamide (78 mg, 0.365 mmol) and tert-butyl 2-[(4-ethynylphenyl)acetyl]hydrazinecarboxylate (100 mg, 0.365 mmol) were added, and the mixture was stirred at 70° C. for 2 hrs. Anhydrous acetonitrile (2 ml) was added, and the mixture was further stirred at 70° C. for 1 hr. The reaction mixture was cooled and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=97:3) to give tert-butyl 2-({4-[(4-acetamidophenyl)ethynyl]phenyl}acetyl)hydrazinecarboxylate (30 mg, yield 20%).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([CH2:20][CH2:21][C:22]([NH:24][NH2:25])=[O:23])[CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])([CH3:8])[CH3:7].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:19][C:16]([C:13]1[CH:12]=[C:11]([CH2:20][CH2:21][C:22]2[O:23][C:1](=[S:2])[NH:25][N:24]=2)[CH:10]=[C:9]([C:6]([CH3:5])([CH3:7])[CH3:8])[C:14]=1[OH:15])([CH3:17])[CH3:18]
Reactant: S=C(Cl)Cl
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(CCc2n[nH]c(=S)o2)cc(C(C)(C)C)c1O
Reaction time: 0.17 h
Yield: 15.8 %

Procedure:
Thiophosgene (0.55 mL, 6.80 mmol) is added dropwise to a -78° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoic acid hydrazide (2.0 g, 6.8 mmol) in tetrahydrofuran (200 mL). The reaction mixture is stirred for 10 minutes then poured into a separatory funnel containing ethyl acetate and aqueous sodium bicarbonate. The organic phase is washed three times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a heavy oil which is crystallized from ethyl acetate/hexane. The product is chromatographed on a column of silica with ethyl acetate/dichloromethane (5/95) and recrystallized from dichloromethane/hexane to afford 0.36 g (16%) of 5-[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethyl]-1,3,4-oxadiazole-2(3H)-thione, mp 164.5°-165.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.Cl.Cl.[NH:21]1[CH2:26][CH2:25][CH:24]([CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:21]3[CH2:26][CH2:25][CH:24]([CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH2:23][CH2:22]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C1CC(CN2CCOCC2)CCN1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: Cl
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(CN4CCOCC4)CC3)cc2n1
Yield: 43 %

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with 4-piperidin-4-ylmethyl-morpholine, dihydrochloride salt using standard reductive amination conditions. The resulting crude solid was purified on silica using a gradient of 0%-40% methanol in ethyl acetate as the eluent to give 2-chloro-4-morpholin-4-yl-6-(4-morpholin-4-ylmethyl-piperidin-1-ylmethyl)-thieno[3,2-d]pyrimidine as a white solid (43% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with methanol to give 329 as an off white solid (88% yield). NMR (CDCl3, 400 MHz), 1.26-1.34 (2H, m), 1.78 (2H, d, J=11.9), 2.09 (2H, t, J=10.8), 2.21 (2H, d, J 7.2), 2.38-2.43 (4H, m), 2.99 (2H, d, J=11.3), 3.70-3.73 (4H, m), 3.82 (2H, s), 3.88-3.90 (4H, m), 4.03-4.06 (4H, m), 5.21 (2H, br s), 7.28 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=511
Reaction SMILES: C(O)(=O)C.O=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[NH:19]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[OH:24][C@H:21]1[CH2:22][CH2:23][N:19]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O[C@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](O)C2)CC1
Reaction time: 0.17 h
Yield: 49.3 %

Procedure:
Acetic acid (90 mg, 1.2 mmol) was added to solution of tert-butyl 4-oxopiperidine-1-carboxylate (300 mg, 1.5 mmol) and (S)-pyrrolidin-3-ol (140 mg, 1.7 mmol) in DCE (3 mL) at 10-15° C. and stirring was continued at the same temperature for 10 minutes. Sodium triacetoxyborohydride (957 mg, 4.5 mmol) was added portionwise to the reaction mixture and stirring was continued at 20-35° C. for 16 h. The reaction mixture was diluted with DCM, washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 200 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][CH:31]([CH3:38])[CH2:32][CH2:33][CH2:34][C:35](Cl)=[O:36]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:30][CH:31]([CH3:38])[CH2:32][CH2:33][CH2:34][C:35]([O:22][CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[N:12]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[N:11][C:2]([Br:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:36]
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Br)nc2n1
Reactant: CC(C)CCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Br)nc2n1
Yield: 66.7 %

Procedure:
The procedure is as in Example 7, but starting with 2-(7-bromo-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (8.55 g) in methylene chloride (110 cc), triethylamine (11.1 g), 5-methylhexanoyl chloride (7 g) and 4-dimethylaminopyridine (50 mg). After the residue obtained has been crystallized in hexane and then recrystallized in ethanol, 2-(7-bromo-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 5-methylhexanoate (7.5 g), m.p. 136° C., is obtained.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:17]1[CH:21]=[CH:20][C:19]([C:22]([O:24]CC)=[O:23])=[CH:18]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(O)C.O>[CH2:3]([N:17]1[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCn1ccc(C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCn1ccc(C(=O)O)c1
Yield: 79.9 %

Procedure:
To a solution of 2.58 g (61.3 mmol) of 65% sodium hydroxide in 100 ml of ethanol and 40 ml of water was added 5.43 g (15.3 mmol) of ethyl 1-tetradecylpyrrole-3-carboxylate obtained in Example 56. After the mixture was heated under reflux for 5 hours, the ethanol was removed under reduced pressure and 100 ml of water was added thereto. Then the mixture was acidified with concentrated hydrochloric acid to precipitate crystals, which were extracted with 70 ml and with 50 ml of ethyl acetate. The extract was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the remaining crystals were recrystallized from hexane to give 3.76 g (79.9% yield) of 1-tetradecylpyrrole-3-carboxylic acid as white crystals, m.p. 66°-67° C.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([CH2:17][C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=2[Cl:25])=[N:7][N:6]=1>C(O)C>[Cl:25][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:24])[C:18]=1[CH2:17][C:8]1[C:9]2[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([NH:2][NH2:3])=[N:6][N:7]=1
Reactant: NN
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Solvent: CCO
Solvent: O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(NN)c2c1
Yield: 109.1 %

Procedure:
Hydrazine hydrate (0.81 ml, 0.84 g, 16.8 mmoles) was added to a solution under N2 of 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (2 g, 5.6 mmoles), obtained as described in example 13, in ethanol (30 ml), and the mixture was kept under reflux for 24 hours, then cooled in ice and the resultant precipitate was filtered, washed with ethanol and ethyl ether and dried under vacuum at 50° C. to give 2.14 g of the title compound (stoichiometric yield). m.p.: 297-299° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C@@H:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C@@H:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH2:70][CH2:71][CH2:72][S:73]([NH2:76])(=[O:75])=[O:74]>CN(C)C=O.C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C@@H:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[C@@H:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([NH:70][CH2:71][CH2:72][S:73](=[O:75])(=[O:74])[NH2:76])=[O:30])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: NCCS(N)(=O)=O
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CC[C@@H]3[C@@H]2C2CCCC2)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)NCCS(N)(=O)=O)cc4CC[C@@H]3[C@@H]2C2CCCC2)cc1Cl
Yield: 8 %

Procedure:
To a solution of (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 (100 mg, 0.24 mmol) in N,N-dimethylformamide (3 mL) was added 1-hydroxybenzotriazole (48 mg, 0.36 mmol), triethylamine (0.07 mL, 0.48 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (115 mg, 0.36 mmol). The solution was stirred for fifteen minutes followed by addition of 2-aminoethanesulfonamide (44 mg, 0.36 mmol). The solution was stirred for twenty hours at ambient temperature. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. Chromatography (reverse phase, acetonitrile/water) provided (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-N-(2-sulfamoylethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide (yellow solid, 10 mg, 8% yield). LC/MS on 4.6×50 mm C-18 column, tR=5.80 minutes (10 to 90% acetonitrile/water over 6 minutes at 2 mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 526 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:3].[C:18](Cl)(=[O:20])[CH3:19].C(N(CC)CC)C>>[C:18]([O:17][C@H:14]1[CH2:15][CH2:16][C@H:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=2)[CH2:12][CH2:13]1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CN(C)Cc1ccc([C@H]2CC[C@H](O)CC2)cc1
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1CC[C@H](c2ccc(CN(C)C)cc2)CC1

Procedure:
from trans-4-(4-dimethylaminomethylphenyl)-cyclohexanol and acetylchloride/triethylamine. Colourless syrup.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([CH3:33])([CH3:32])[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]([C:30]#[N:31])[C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH3:29])[CH:14]=2)=[O:9])C.[OH-].[Na+]>O1CCCC1.CO>[C:30]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:28][CH3:29])[CH:14]=2)[C:19]([OH:20])=[C:10]([C:8]([NH:7][CH2:6][C:5]([CH3:32])([CH3:33])[C:4]([OH:34])=[O:3])=[O:9])[N:11]=1)#[N:31]
Reactant: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3CC)ccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccccc1Oc1ccc2c(O)c(C(=O)NCC(C)(C)C(=O)O)nc(C#N)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.5 %

Procedure:
A mixture of 3-{[1-Cyano-7-(2-ethyl-phenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-2,2-dimethyl-propionic acid ethyl ester (20.3 mg, 0.04 mmole) and 1N NaOH (0.4 ml, 0.4 mmole) in a mixture of tetrahydrofuran (0.5 ml) and methanol (1 ml) was stirred room temperature for three days before it was concentrated and acidified with 1N HCl to pH=3. The precipitated was filtered, dried to give the title compound as a white solid (15 mg): MS: (+) m/z 434.21 (M+1), (−) m/z 432.15 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N+:5]([O-])=[C:4]([O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:3]=1[CH3:21].P(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:3]=1[CH3:21]
Reactant: CCc1cc(Cl)c(C)c(Oc2c(C)cc(C)cc2C)[n+]1[O-]
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: CCc1cc(Cl)c(C)c(Oc2c(C)cc(C)cc2C)n1
Temperature: 25 °C

Procedure:
To a solution of 4-Chloro-6-ethyl-3-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine 1-oxide in methylene chloride was added PCl3 and the resulting mixture was heated at reflux for 20 min, cooled to rt. The mixture was concentrated to dryness. The residue was worked-up using standard procedure to give the title compound. After silica gel purification, the title compound was prepared as a white solid, mp. 42-44° C. Anal. For C17H20ClNO calc. C. 70.46; H, 6.96; N, 4.83; found, C, 70.35; H, 7.13; N, 4.58.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].[C:9]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[C:14]([CH2:20][CH2:21][CH3:22])[C:13]=1[OH:23])(=[O:11])[CH3:10]>O>[C:9]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:8])=[C:14]([CH2:20][CH2:21][CH3:22])[C:13]=1[OH:23])(=[O:11])[CH3:10]
Reactant: OCCCCO
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCCc1c(COCCCCO)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 9.6 g. of a 50% oil dispersion of sodium hydride in 100 ml. of 1,4-butanediol were added 11.3 g. of 4-acetyl-3-hydroxy-2-propylbenzyl chloride. The reaction was stirred overnight at room temperature and then heated to 60° C. for six hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The ethyl acetate solution was evaporated to dryness and the residue was purified by chromatography over silica gel to provide 14.1 g. of the desired title product. NMR.