Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[F:3][C@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C:18]2=[O:22])[C@H:14]2[C@H:5]1[C:6]1[CH:7]=[CH:8][C:9]([OH:30])=[CH:10][C:11]=1[CH2:12][C@H:13]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]I>O1CCCC1>[F:3][C@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][C:18]2=[O:22])[C@H:14]2[C@H:5]1[C:6]1[CH:7]=[CH:8][C:9]([OH:30])=[CH:10][C:11]=1[CH2:12][C@H:13]2[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([NH:2][CH3:1])[CH3:28]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCI)[C@H]3[C@@H]1CCC2=O
Reactant: CN
Solvent: C1CCOC1
Product: CNC(C)CCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
718 mg of methylamine is condensed in a solution of 960 mg of 11β-fluoro-3-hydroxy-7α-(6-iodohexyl)-estra-1,3,5(10)-trien-17-one in 9 ml of anhydrous tetrahydrofuran at −78° C., and it is stirred overnight at room temperature in a pressurized reactor. After the pressurized reactor was opened at −20° C., it is allowed to come to room temperature to allow excess methylamine to evaporate off. Then, the reaction solution is added to saturated sodium bicarbonate solution, extracted 3 times with ethyl acetate, dried on sodium sulfate and concentrated by evaporation in a vacuum. 763 mg of 11β-fluoro-3-hydroxy-7α-[5-(methyl-amino)-hexyl]-estra-1,3,5(10)-trien-17-one is obtained as a crude product.
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[C:3]([OH:5])=[O:4].[CH3:7][O:8][C:9](=[O:52])/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[C:24]([CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:30][C:29]=3[O:40][CH3:41])[CH:23]=[C:22]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]Cl)[CH:21]=2)=[C:14]([O:50][CH3:51])[CH:13]=1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[CH3:51][O:50][C:14]1[CH:13]=[C:12](/[CH:11]=[CH:10]/[C:9]([O:8][CH3:7])=[O:52])[CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:23]=[C:24]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:30][C:29]=2[O:40][CH3:41])[CH:25]=1)[O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][O:4][C:3](=[O:5])[C:2]([CH3:1])=[CH2:6]
Reactant: C=C(C)C(=O)O
Reactant: COC(=O)/C=C/c1ccc(OCc2cc(COc3ccc(/C=C/C(=O)OC)cc3OC)cc(OCCCCCCCl)c2)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCCCCCOc1cc(COc2ccc(/C=C/C(=O)OC)cc2OC)cc(COc2ccc(/C=C/C(=O)OC)cc2OC)c1
Temperature: 80 °C
Reaction time: 25 h
Yield: 90.3 %

Procedure:
382 mg (2.5 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) (DBU) in 4 ml N,N-dimethylformamide were added dropwise to a solution of 200 mg (2.3 mmol) 2-methylacrylic acid in 8 ml N,N-dimethylformamide over a period of 35 minutes. After addition of 4 mg phenothiazine, 1.5 g (2.3 mmol) (E)-3-[4-[[3-[(6-chlorohexyl)oxy]-5-[[2-methoxy-4-[(E)-2-(methoxycarbonyl)vinyl]phenoxy]methyl]benzyl]oxy]-3-methoxyphenyl]acrylic acid methyl ester and 84 mg tetrabutylammonium iodide the resulting mixture was stirred at 80° C. for 25 hours. The reaction mixture was poured into 50 ml of an ice cold 1 M HCl solution. The aqueous phase was extracted three times with 50 ml ethyl acetate. The organic phase was washed with 50 ml of a saturated sodium bicarbonate solution and repeatedly with water, dried over magnesium sulfate, filtered and concentrated by vacuum evaporation. Purification of the residue by column chromatography on 275 g silica gel using hexane:ethyl acetate (1:1) as eluent yielded 1.46 g (90%) of 2-methylacrylic acid 6-[3,5-bis[[2-methoxy-4-[(E)-2-(methoxycarbonyl)vinyl]phenoxy]methyl]phenoxy]hexyl ester as a yellowish oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:14][S:15]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([S:15]([CH3:14])(=[O:17])=[O:16])[CH2:3]1)(=[O:17])=[O:16]
Reactant: O[C@H]1CCNC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCN(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a dichloromethane (200 mL) solution of (S)-3-hydroxypyrrolidine (5.0 g, 57 mmol) and triethylamine (24.0 mL, 172 mmol) at 0° C. was added methanesulfonyl chloride (7.23 g, 63.1 mmol). 4-(Dimethylamino)pyridine (0.70 g, 5.7 mmol) was then added, and the mixture was stirred at room temperature for 2 hours. It was diluted with dichloromethane (50 mL), and the combined organic layers were washed with aqueous 1 M hydrochloric acid (30 mL), water (30 mL), brine (30 mL), dried (magnesium sulfate), filtered and concentrated in vacuo to afford the title compound. The crude product was used in the subsequent step without further purification. 1H NMR (500 MHz, CDCl3) δ 5.28 (t, J=4.5 Hz, 1H), 3.71 (d, J=12.9 Hz, 1H), 3.64 (dd, J=12.7, 4.0 Hz, 1H), 3.59 (td, J=9.2, 2.3 Hz, 1H), 3.46 (td, J=10.1, 6.7 Hz, 1H), 3.07 (s, 3H), 2.89 (s, 3H), 2.39-2.33 (m, 1H), 2.29-2.19 (m, 1H); LC-MS: m/z 244.1 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27](B(O)O)[CH:28]=2)[CH:23]=[N:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.ClCCl.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>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:2]3[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=4)[N:3]=3)[CH:28]=2)[CH:23]=[N:22]1
Reactant: OB(O)c1ccc2cn[nH]c2c1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc4cn[nH]c4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 78.3 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 200.0 mg, 0.68 mmol) in 1,4-dioxane (1 mL) was added 1H-indazol-6-ylboronic acid (386.0 mg, 2.38 mmol), K3PO4 (434.0 mg, 2.05 mmol), Pd(PPh3)4 (39.0 mg, 0.03 mmol) under nitrogen atmosphere. After stirring 20 min at 90° C., the reaction mixture was dissolved in dichloromethane (30 mL), washed with water (3×20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 1%-10% ethyl acetate in petroleum ether to afford methyl 2-(1H-indazol-6-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (200 mg, 78%).
Reaction SMILES: C(=O)(O)[O-].[Na+].[N+](C1C=CC(C[O:14][C:15]([C@@H:17]2[N:21]3[C:22](=[O:35])[C@@H:23]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:20]3[S:19][C@:18]2([CH2:37][O:38][C:39](=[O:44])[NH:40][C:41](=[O:43])[CH3:42])[CH3:36])=[O:16])=CC=1)([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[C:41]([NH:40][C:39]([O:38][CH2:37][C@@:18]1([CH3:36])[C@H:17]([C:15]([OH:16])=[O:14])[N:21]2[C:22](=[O:35])[C@@H:23]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:20]2[S:19]1)=[O:44])(=[O:43])[CH3:42]
Reactant: [H][H]
Reactant: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Yield: 87 %

Procedure:
A suspension of 10% palladium on charcoal (400 mg) in ethyl acetate (40 ml) and aqueous 0.5% sodium bicarbonate was prehydrogenated and charged with (2R,3S,5R,6R) 2-(N-acetyl)carbamoyloxymethyl-2-methyl-6-phenoxyacetamidopenam-3-carboxylic acid p-nitrobenzyl ester (400 mg 0.68 mmol). The whole was shaken at 50 psi hydrogen pressure for 30 minutes and polish filtered. The aqueous was washed with ethyl acetate (20 ml), combined with a back extract of H2O (20 ml), overlayed with ethyl acetate (25 ml) and adjusted to pH 2.9 with 35% sulfuric acid. The layers were separated and the rich organic phase was washed with water (20 ml), combined with a back extract (EtOAc, 20 ml), dried (4A sieves), polish filtered and concentrated in vacuo to a colorless foam (270 mg) in 87% yield; nmr 100 MHz (CDCl3 --D2O) ppm 7.32 (2, m, m-phenyl H's) 6.96 (3, m, o,p-phenyl H's), 5.59 (2, br s, mag. equiv. C5,C6 --H's), 4.79 (1, s, C3 --H), 4.59 (HOD and ##STR65## 4.08 (m, AB of C2 --CH2O), 2.25 (3, s, ##STR66## and 1.58 (3, s, C3 --Me) with small ethyl acetate impurity.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[I:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][O:20][C:16]1[CH:15]=[C:14]([I:13])[CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: Oc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1cccc(OCc2ccc3ccccc3c2)c1
Temperature: 25 °C

Procedure:
A mixture of 2-bromomethylnaphthalene, 3-iodophenol, potassium carbonate and dimethylformamide was stirred at ambient temperature to provide 3-(naphth-2-ylmethoxy)phenyl iodide.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.Br[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>>[I:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([O:9][CH:11]([CH3:13])[CH3:12])[CH:3]=1
Reactant: CC(C)Br
Reactant: Oc1cc(O)cc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(O)cc(I)c1
Temperature: 65 °C
Reaction time: 18 h
Yield: 37.8 %

Procedure:
A mixture of 5-Iodo-benzene-1,3-diol (2 g, 8 mmol), 2-bromopropane (0.88 mL, 9.3 mmol) and potassium carbonate (1.3 g, 9.3 mmol) in DMF (15 mL, 190 mmol) was stirred at 65° C. After 18 h, the mixture was cooled to RT and the solvent was evaporated. The residue was dissolved in DCM, washed with water and brine. The solvent was evaporated and the residue was purified on silica gel using an ISCO instrument and eluting with hexanes:EtOAc (4:1) to afford the title product (841 mg). MS m/z: 279 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26](Cl)=[N:25][S:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC(C)([O-])C.[K+].C(O)(C)(C)C.[F:41][C:42]1[CH:47]=[C:46]([CH2:48][OH:49])[CH:45]=[CH:44][N:43]=1>CO>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26]([O:49][CH2:48][C:46]4[CH:45]=[CH:44][N:43]=[C:42]([F:41])[CH:47]=4)=[N:25][S:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OCc1ccnc(F)c1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2Cl)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CO
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2OCc2ccnc(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.5 %

Procedure:
To a solution of 4-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (117.7 mg, 0.265 mmol, prepared in Example 10b) and 1M solution of potassium tert-butoxide in tert-butanol (0.75 mL, 0.75 mmol) was added 2-Fluoro-4-pyridinemethanol (65.6 mg, 0.516 mmol, prepared in Example 15a). The resulting suspension was stirred at room temperature for 2 h. The crude reaction mixture was diluted with methanol and purified by preparative HPLC (50 mM NH4OAc(aq), Acetonitrile system). The pure fractions were combined and the acetonitrile was removed in vacuo. The remaining aqueous solution was made basic with NaHCO3 and the free based product was extracted into EtOAc. The organic phase was concentrated in vacuo, and the solids were re-dissolved in acetonitrile/water and lyophilized to obtain pure product 4-[4-(2-Fluoro-pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide. (19.0 mg, 13.5% yield). 1H NMR (CDCl3) 8.26 (d, 1H), 7.88 (s, 2H), 7.53 (s, 1H), 7.22 (d, 1H), 6.98 (s, 1H), 6.88 (s, 1H), 5.53 (s, 2H), 3.73-3.50 (m, 8H) ppm.
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[CH3:16][O:17][C:18](=[O:34])[CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1.[Cl:35][C:36]1[N:41]=[C:40]([Cl:42])[C:39]([CH2:43]I)=[CH:38][N:37]=1>O1CCCC1.C(OCC)(=O)C>[CH3:16][O:17][C:18](=[O:34])[CH:19]([C:20]1[CH:21]=[C:22]([C:30]([F:33])([F:31])[F:32])[CH:23]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:25]=1)[CH2:43][C:39]1[C:40]([Cl:42])=[N:41][C:36]([Cl:35])=[N:37][CH:38]=1
Reactant: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Clc1ncc(CI)c(Cl)n1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-isopropylcyclohexylamine (1.44 g, 10.0 mmol) (Aldrich) in dry tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M in hexanes, 4.0 mL, 10.0 mmol) (Aldrich) at −78° C. under argon. After 10 minutes, a solution of 3,5-bis-trifluoromethylphenylacetic acid methyl ester (2.20 g, 7.7 mmol) (from Example 8a supra) in tetrahydrofuran (5 mL) was added by injection via a syringe and the reaction mixture was stirred at −78° C. for another 10 minutes. To the reaction mixture was added a solution of 2,4-dichloro-5-iodomethyl-pyrimidine (1.45 g, 5.0 mmol) (from Example 1c supra) in tetrahydrofuran (5 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 2 hours then slowly allowed to warm up to −20° C. and stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (100 mL), water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give 2-(3,5-bis-trifluoromethyl-phenyl)-3-(2,4-dichloro-pyrimidin-5-yl)-propionic acid methyl ester as a colorless oil. (Yield 1.71 g, 76.5%).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4]COC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][C:38]=3[C:44]([F:47])([F:46])[F:45])=[N:33][CH:32]=2)=[CH:27]1.Cl.ClCCN(C)C>C(Cl)Cl.CO>[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]2[S:35][C:31]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)=[CH:32][N:33]=2)=[C:38]([C:44]([F:47])([F:46])[F:45])[CH:39]=1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1
Reactant: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: CN(C)CCCl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCOc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-ylamino)-3-trifluoromethyl-phenol (Example 28) and using (2-chloroethyl)-dimethylamine hydrochloride. The title compound: ES-MS: 413.9 [M+H]+; single peak at tR=3.17 min (System 2); Rf=0.22 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][OH:33])=[CH:27][CH:26]=2)[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:7](=[O:24])[C:6]=12.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[OH:33][CH2:32][CH2:31][C:28]1[CH:27]=[CH:26][C:25]([N:3]2[C:2]([NH:1][C:34](=[O:36])[CH3:35])=[C:6]3[C:7](=[O:24])[N:8]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:5]3=[N:4]2)=[CH:30][CH:29]=1
Reactant: COc1ccc(Cn2c(=O)c3c(N)n(-c4ccc(CCO)cc4)nc3c3ccccc32)cc1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(Cn2c(=O)c3c(NC(C)=O)n(-c4ccc(CCO)cc4)nc3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-amino-2-[4-(2-hydroxyethyl)phenyl]-5-(4-methoxybenzyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (0.2 g) and acetic anhydride (2 ml) was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added thereto, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and concentrated after drying. To the obtained crystal was added methanol (20 ml) and an 1N aqueous sodium hydroxide solution (0.5 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, a 1N hydrochloric acid (0.5 ml) was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous sodium hydrogen carbonate solution, water and saturated brine, dried and concentrated to obtain the target compound (0.2 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].I[CH2:15][CH2:16][CH2:17][C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20].O>O1CCCC1>[F:23][C:18]([F:24])([C:19]([F:22])([F:21])[F:20])[CH2:17][CH2:16][CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: FC(F)(F)C(F)(F)CCCI
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Sodium hydride (60%, 2.87 g, 71.87 mmol) was added to anhydrous tetrahydrofuran (250 ml) and cooled to 0° C. To this mixture, diethyl malonate (12.12 ml, 79.86 mmol) was slowly added dropwise, followed by stirring for 1 hour at room temperature. 1-Iodo-4,4,5,5,5-pentafluoropentane (11.5 g, 39.93 mmol) dissolved in anhydrous tetrahydrofuran (50 ml) was then slowly added dropwise to the reaction mixture, followed by stirring for 12 hours at room temperature. Water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/40) to give diethyl 2-(4,4,5,5,5-pentafluoropentyl)malonate (11.2 g, Yield 88%).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][C:9]=1[C:18]#[N:19].[F:26][C:27]1[C:32]([OH:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=1[F:37].CCN(CC)CC>ClCCl>[F:26][C:27]1[C:32]([O:33][S:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:9]([C:18]#[N:19])[CH:10]=2)(=[O:16])=[O:15])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=1[F:37]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1Oc1ccccc1-c1ccccc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(S(=O)(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1Oc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(biphenyl-2-yloxy)-3-cyano-benzenesulfonyl chloride (Preparation 55, 500 mg, 1.35 mmol) in dichloromethane (5 ml) was added slowly to pentafluorophenol (249 mg, 1.35 mmol) and Et3N (137 mg, 1.35 mmol) in dichloromethane (5 ml) and stirring continued overnight at ambient temperature. The reaction was concentrated in vacuo and purified using silica gel column chromatography (dichloromethane/heptane 40/60, then 60/40, then 80/20, then dichloromethane) to furnish the title compound. LCMS Rt=1.92 minutes 1H NMR (400 MHz; CDCl3) δ (ppm): 6.69 (d, J=8.98 Hz, 1H) 7.21-7.30 (m, 2H) 7.31-7.38 (m, 2H) 7.43-7.53 (m, 4H) 7.53-7.58 (m, 1H) 7.79 (dd, J=8.98, 2.34 Hz, 1H) 8.06 (d, J=2.34 Hz, 1H) 19F NMR (376 MHz, CDCl3) δ (ppm): 160.82 (t, J=19.50 Hz)-154.87 (t, J=21.80 Hz)-151.09 (d, J=17.21 Hz)
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[F:12][C:13]([F:28])([F:27])[O:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]([OH:26])=[O:25])=[N:20][NH:21]2)=[CH:17][CH:16]=1.[N:29]12[CH2:36][CH2:35][CH:32]([CH2:33][CH2:34]1)[C@H:31](O)[CH2:30]2>N1C=CC=CC=1>[F:28][C:13]([F:12])([F:27])[O:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]([O:26][C@H:31]3[CH:32]4[CH2:35][CH2:36][N:29]([CH2:34][CH2:33]4)[CH2:30]3)=[O:25])=[N:20][NH:21]2)=[CH:17][CH:16]=1
Reactant: O[C@@H]1CN2CCC1CC2
Reactant: O=C(O)c1n[nH]c2cc(OC(F)(F)F)ccc12
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: O=C(O[C@@H]1CN2CCC1CC2)c1n[nH]c2cc(OC(F)(F)F)ccc12
Temperature: 25 °C
Yield: 16 %

Procedure:
p-Toluenesulfonyl chloride (0.16 mmol) was added to a 0° C. solution of 6-(trifluoromethoxy)-1H-indazole-3-carboxylic acid (0.81 mmol) in pyridine. (5.00 mL). (3S)-Quinuclidin-3-ol (0.81 mmol) was added and the reaction mixture was allowed to warm to rt. The reaction mixture was maintained for 16 h and was filtered and concentrated. The residue was redissolved in methanol and loaded on a 5 g SCX column. The column was washed with methanol and the product was eluted with methanol/dimethylethylamine (9/1) and concentrated. The residue was purified by preparative HPLC to produce the desired product in 16% yield. Note: this procedure works equally well when p-toluenesulfonyl chloride is replaced with oxalyl chloride. 1H NMR (CDCl3) δ 8.52 (s, 1 H), 7.96 (d, J=8.9, 1H), 7.49 (s, 1 H), 7.09 (d, J=8.9, 1H), 5.31 (m, 1 H), 3.72-3.29 (m, 6 H), 2.56 (m, 1 H), 2.32 (m, 1 H), 2.06-1.88 (m, 3 H); LC/MS (EI) tR 4.9 min, m/z 356 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH3:22].[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28](Cl)=[O:29].C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:33]([F:34])=[C:25]([F:24])[CH:26]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH3:22]
Reactant: CC1CCCN1CCOc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1CCCN1CCOc1ccc(NC(=O)c2ccc(F)c(F)c2)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.2 %

Procedure:
A mixture of 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(2-methyl-pyrrolidin-1-yl)-ethoxy]-phenylamine (95 mg, 0.25 mmole), 3,4-difluoro-benzoyl chloride (40 μL, 0.301 mmole), and triethylamine (70.2 μL, 0.501 mmole) in 1 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TFA salt, 60 mg, 46% yield). 1H NMR (DMSO-d6, 400 MHz) δ 1.22 (dd, J=19.71, 6.57 Hz, 3H), 1.45-1.53 (m, 1H), 1.72-1.89 (m, 2H), 2.07-2.14 (m, 1H), 2.79-2.98 (m, 1H), 3.08-3.15 (m, 1H), 3.31-3.44 (m, 2H), 3.59-3.65 (m, 1H), 3.68 (d, J=4.80 Hz, 3H), 4.21-4.46 (m, 2H), 7.29 (dd, J=9.85 Hz, 6.82 Hz, 1H), 7.60-7.67 (m, 1H), 7.66 (s, 1H), 7.70-7.72 (m, 1H), 7.84-7.88 (m, 1H), 7.94 (dt, J=9.09, 2.78, 2.53 Hz, 1H), 8.01-8.06 (m, 1H), 9.22-9.48 (m, 1H from TFA), 10.4 (s, NH). Exact mass calculated for C24H2579BrF2N4O2, 518.1, found 519.3, 521.5 (MH+).