Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]/[CH:7]=[C:8]1\[O:9][C:10](=[O:15])[O:11][C:12]\1([CH3:14])[CH3:13])(=[O:3])[CH3:2].[C:16](OCC)(=O)C.COC1C=CC(O)=CC=1>>[C:1]([O:4][CH2:5][CH2:6]/[CH:7]=[C:8]1\[O:9][C:10](=[O:15])[O:11][C:12]\1([CH3:14])[CH3:13])(=[O:3])[CH:2]=[CH2:16]
Reactant: CC(=O)OCC/C=C1\OC(=O)OC1(C)C
Reactant: CCOC(C)=O
Agent: COc1ccc(O)cc1
Product: C=CC(=O)OCC/C=C1\OC(=O)OC1(C)C
Temperature: 40 °C
Reaction time: 24 h

Procedure:
280 g (1.31 mol) of (3Z)-3-(5,5-dimethyl-2-oxo-1,3-dioxolan-4-ylidene)propyl acetate (exo-VC-OAc), 1307 g (13.1 mol) of ethyl acetate, 0.28 g of 4-methoxyphenol (MeHQ) and 84 g (30% by weight) of Novozym® 435 from Novozymes were combined. The mixture was stirred at 40° C. for 24 h. The mixture was filtered and washed through with acetone, and the solvent was removed at 40° C. on a rotary evaporator. This gave 276.7 g of the product of the title compound with a purity of 92.4% (GC analysis).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:19])[CH3:18])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])[CH:7]=1.F[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[N+:31]([O-:33])=[O:32].[F-].[K+]>CN(C=O)C>[C:17]([NH:16][C:4]1[CH:3]=[C:2]([NH:1][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[N+:31]([O-:33])=[O:32])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])[CH:5]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1cc(N)cc(-c2ccc(F)cc2F)c1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Nc2cc(NC(C)=O)cc(-c3ccc(F)cc3F)c2)c([N+](=O)[O-])c1
Yield: 48.78 %

Procedure:
A solution of N-(5-amino-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)acetamide (1.0 g, 3.813 mmol), methyl 4-fluoro-3-nitrobenzoate (0.835 g, 4.194 mmol, 1.1 eq.) and potassium fluoride (0.265 g, 4.457 mmol, 1.2 eq.) in DMF was heated at 130° C. for 16 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to give the crude residue which was purified by column chromatography (60-120 silica gel, 40% ethyl acetate in hexane) to give the product in 48.78% yield (0.82 g).
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[C:9]1[CH3:29])(C)(C)C.Cl[CH2:32][C:33]1[S:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1>>[S:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=[C:33]1[CH2:32][N:20]1[C:21](=[O:28])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[C:9]=2[CH3:29])=[N:19]1
Reactant: ClCc1nc2ccccc2s1
Reactant: Cc1c(-c2n[nH]c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Product: Cc1c(-c2nn(Cc3nc4ccccc4s3)c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)O

Procedure:
The title compound was prepared from the product of example 16, step c) and 2-chloromethyl-benzothiazole using the procedure described in example 14. 1H NMR (DMSO-d6) δ 8.44-8.41 (m, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.96-7.92 (m, 2H), 7.50 (t, J=7.5 Hz, 1H), 7.44 (t, J=7.5 Hz, 1H), 7.24 (d, J=1.8 Hz, 1H), 7.15 (dd, J=8.7, 2.1 Hz, 1H), 5.86 (s, 2H), 5.12 (s, 2H), 2.28 (s, 3H); MS: ESI (negative): 513, 515 (M−H).
Reaction SMILES: O.[NH2:2][NH2:3].Cl.[C:5]1(=O)[O:10][C:8](=[O:9])[C:7]2[CH2:11][CH2:12][CH2:13][CH2:14][C:6]1=2>O>[OH:9][C:8]1[C:7]2[CH2:11][CH2:12][CH2:13][CH2:14][C:6]=2[C:5]([OH:10])=[N:3][N:2]=1
Reactant: NN
Reactant: O=C1OC(=O)C2=C1CCCC2
Agent: Cl
Solvent: O
Product: Oc1nnc(O)c2c1CCCC2

Procedure:
25 ml of purified water was added to 1.7 ml(0.035 mol) of hydrazine monohydrate and then 7 ml(0.07 mol) of conc. hydrochloric acid was added dropwise thereto. Then, the reaction solution was warmed to boil. When the reaction mixture begins to reflux, 5.33 g(0.035 mol) of 3,4,5,6-tetrahydrophthalic acid anhydride was added thereto. The reaction solution was continuously refluxed for 3 hours and then cooled. Then, the reaction solution was treated according to the same manner as Preparation 1 to obtain the title compound as an white needle crystal.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[C:3](=[N:5][OH:6])[CH3:4].[Li+].[OH-].[CH2:11]1[O:13][CH2:12]1>O>[OH:13][CH2:12][CH2:11][O:6][N:5]=[C:3]([C:2]([CH3:8])([CH3:7])[CH3:1])[CH3:4]
Reactant: CC(=NO)C(C)(C)C
Reactant: C1CO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(=NOCCO)C(C)(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 90 %

Procedure:
400 ml of water, 92 g (0.8 mol) of 3,3-dimethylbutan-2-one oxime and 3.4 g of LiOH were initially charged, and 70 g (1.6 mol) of ethylene oxide were introduced such that the gas was taken up completely. Thereafter, the mixture was stirred at room temperature (RT) for 8-12 hours for the continued reaction. The upper phase was removed, admixed with ethyl acetate and washed with water. The organic phase was concentrated under reduced pressure at 100-200 mbar. Residue: 114-120 g of colorless oil, which corresponds to a yield of 90% yield; b.p. 106° C./35 mbar.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:27]3[N:23]([C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:25][N:26]=3)[C:22]3[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=3[N:20]([CH2:38][C:39](=[O:52])[N:40]([CH:49]([CH3:51])[CH3:50])[C:41]3[CH:42]=[N:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=3)[C:19]2=[O:53])=[N:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:27]3[N:23]([C:24]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[N:25][N:26]=3)[C:22]3[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=3[N:20]([CH2:38][C:39]([N:40]([CH:49]([CH3:50])[CH3:51])[C:41]3[CH:42]=[N:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=3)=[O:52])[C:19]2=[O:53])=[N:9]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4ccccc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product of Step A, 3-(6-{[isopropyl-(6-methoxy-pyridin-3-yl)-carbamoyl]-methyl}-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl)-indazole-1-carboxylic acid tert-butyl ester, was dissolved in CH2Cl2 (8 mL) and TFA (2 mL) was added. The reaction was stirred at room temperature for 24 hours and was concentrated in vacuo. Purification by medium pressure chromatography eluting with a solvent gradient (1% MeOH in EtOAc to 5% MeOH in EtOAc) provided 172 mg of 2-[4-(1H-indazol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. 1H NMR (CD3OD) δ 8.04 (d, 1H), 7.88 (d, 1H), 7.64 (m, 2H), 7.56 (d, 2H), 7.49 (t, 2H), 7.39 (q, 3H), 7.31 (t, 1H), 7.19 (t, 1H), 7.11 (t, 1H), 6.95 (d, 1H), 6.86 (m, 1H), 4.72 (m, 1H), 4.59 (m, 1H), 4.41 (t, 1H), 3.99-4.12 (m, 2H), 3.90 (m, 4H), 0.95 (m, 6H); MS 613.8 (M+1), 611.5 (m−1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)[CH3:2].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>O>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Solvent: O
Product: CCOC(=O)c1ccc(N2CCN(C)CC2)c(S(N)(=O)=O)c1

Procedure:
141 Grams of 4-chloro-3-sulfamoylbenzoic acid-ethylester (0.5 mole) were stirred for 1 hour at 110° C. with 250 ml of N-methylpiperazine. The crystalline precipitate obtained after the reaction solution had been poured into 2.0 l of water suction-filtered, was washed with water, dried on the steam bath and recrystallized twice from a mixture of diisopropylether and acetic ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([O:15][CH3:16])[C:12](O)=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>>[CH2:1]([O:8][C:9](=[O:10])[CH:11]([C:12]([Cl:19])=[O:13])[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(C(=O)O)C(=O)OCc1ccccc1
Reactant: O=S(Cl)Cl
Product: COC(C(=O)Cl)C(=O)OCc1ccccc1

Procedure:
A solution of Benzyloxycarbonyl methoxy-acetic acid (40 g) and Thionyl Chloride (80 ml) was stirred at reflux temperature for 3 hours. Excess Thionyl Chloride was distilled off and to the residue was added Toluene (100 ml). The solvent was distilled off completely to get chlorocarbonyl methoxy-acetic acid benzyl ester (40 g) as a light brown liquid which was used without further purification.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=O)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH2:20]([N:27]1[C:32](=[O:33])[C:31]([CH3:34])=[C:30]([CH3:35])[N:29]=[C:28]1[C@H:36]([NH:40][CH2:41][CH2:42][N:43]1C(=O)C2C(=CC=CC=2)C1=O)[CH:37]([CH3:39])[CH3:38])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O.CCCCCC>C1(C)C=CC=CC=1>[CH2:20]([N:27]1[C:32](=[O:33])[C:31]([CH3:34])=[C:30]([CH3:35])[N:29]=[C:28]1[C@H:36]([N:40]1[CH2:41][CH2:42][N:43]=[C:7]1[C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)[CH:37]([CH3:39])[CH3:38])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1nc([C@H](NCCN2C(=O)c3ccccc3C2=O)C(C)C)n(Cc2ccccc2)c(=O)c1C
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(C2=NCCN2[C@@H](c2nc(C)c(C)c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 59.1 %

Procedure:
p-Toluoyl chloride (0.033 mL, 0.25 mMol) was dissolved in toluene (2 mL) and was treated with DIPEA (0.093 mL, 0.53 mMol) followed by 2-{2-[(R)-1-(1-benzyl-4,5-dimethyl-6-oxo-1,6-dihyro-pyrimidin-2-yl)-2-methyl-propylamino]-ethyl}-isoindole-1,3-dione (0.100 g, 0.22 mMol) The reaction stirred at 110° C. for 3 h. The reaction was cooled to room temperature and was evaporated under reduced pressure and purified by flash chromatography. (EtOAc/hexane 0-55% gradient) to give the title compound 0.075 g (0.13 mMol) MS (ES) m/e 577 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH:7]([CH2:13][NH2:14])[CH2:6]2.C(N(CC)CC)C.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25].Cl>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH:7]([CH2:13][NH:14][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH2:6]2
Reactant: COc1ccc2c(c1)CC(CN)CO2
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)NCC1COc2ccc(OC)cc2C1
Reaction time: 1 h

Procedure:
A solution of 0.4 g (2.06 mmol) of the amine obtained in Step B in 20 ml of anhydrous dichloromethane is cooled to 0° C. 1 ml (7.2 mmol) of triethylamine and also 0.38 g (3.6 mmol) of butyryl chloride are added in succession to the medium. After one hour of stirring s under argon, the reaction mixture is acidified with a 1N hydrochloric acid solution; the aqueous phase is then extracted with dichloromethane. The organic phase is dried over magnesium sulphate and then concentrated in vacuo. The title amide is obtained pure in the form of a white solid after passage over a silica column (eluant:petroleum ether/ethyl acetate 50/50).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[OH-].[Na+].Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1>C(O)C>[CH3:23][N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][S:1][C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:18][CH2:19]1
Reactant: CN1CCN(CCCl)CC1
Reactant: Sc1nc2ccccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCN(CCSc2nc3ccccc3[nH]2)CC1

Procedure:
Grams 2.2 2-mercapto-1H-benzimidazol and 2.4 g NaOH were dissolved in 40 ml 90% ethyl alcohol, then 3.5 g 1-(2-chloroethyl)-4-methylpiperazine hydrochloride were added thereto. The reaction mixture was refluxed for 2 hours, the solid precipitate removed by filtration, the limpid solution evaporated to dryness and the residue dissolved in chloroform and washed with water. The organic phase was made anhydrous, then evaporated to dryness and the residue chromatographed on a column eluting with chloroform, methyl alcohol, cyclohexane, ammonium hydroxide (68:15:15:0.2). The fractions which contained the product, were collected together and evaporated to dryness and the residue which was triturated with isopropyl ether, gave 0.65 g 2-[2-(4-methylpiperazin-1-yl)ethylthio] benzimidazole melting at 93°-95° C. (with a slight decomposition).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[C:13]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:20]3[CH:21]=[CH:22][C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:18][CH:19]=3)[CH:3]=[CH:4][CH:5]=2)[C:9]1=[O:11]
Reactant: CC1Cc2cccc(Cl)c2C1=O
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: OCCO
Solvent: O
Product: CC1Cc2cccc(-c3ccc(C(C)(C)C)cc3)c2C1=O
Temperature: 125 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
Using a method similar to Example 16 d), 2.0 g (0.011 mol) of (1), 2.31 g (0.013 mol) of 4-tert-butylphenylboronic acid and 2.6 g (24.6 mmol) of sodium carbonate were placed in 55 ml of ethylene glycol/5 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. After addition of 18 mg (0.09 mmol) of palladium acetate and 0.15 g (0.27 mmol) of TMSPP, the reaction mixture was stirred for 2 hours at 125° C. After addition of 60 ml of water, the aqueous phase was extracted 4 times with 60 ml each time of ether, the combined ether phases were washed with 60 ml of water and 60 ml of saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave 2.8 g of 2-methyl-7-(4-tert-butylphenyl)-1-indanone.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:33][C@H:32]([CH2:34][O:35]C(=O)C3C=CC=CC=3)[C@@H:22]([O:23]C(=O)C3C=CC=CC=3)[C@@:12]2([CH3:44])[O:13]C(=O)C2C=CC=CC=2)=[C:4]([Cl:45])[N:3]=1.[Li+].[OH-]>C1COCC1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:33][C@H:32]([CH2:34][OH:35])[C@@H:22]([OH:23])[C@@:12]2([CH3:44])[OH:13])=[C:4]([Cl:45])[N:3]=1
Reactant: C[C@@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nc(N)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the crude compound from Step A (2.54 g) in THF (18 mL) was added aqueous 2N LiOH (6 mL). The resulting mixture was stirred at room temperature for 3 h, the THF evaporated in vacuo and the resulting aqueous phase neutralized by addition of aqueous 2N hydrochloric acid. The mixture was adsorbed onto silica gel by evaporation in vacuo and purified on silica gel using methanol/dichloromethane (1:4) as the eluent. Fractions containing the product were combined and evaporated in vacuo to give the desired product as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](/[C:17](=[CH:24]\[CH:25]([CH3:27])[CH3:26])/[C:18]([CH3:23])([CH3:22])[C:19](O)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:28]1[CH:32]=[N:31][N:30]=[C:29]1[NH2:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](/[C:17](=[CH:24]\[CH:25]([CH3:26])[CH3:27])/[C:18]([CH3:23])([CH3:22])[C:19]([NH:33][C:29]4[S:28][CH:32]=[N:31][N:30]=4)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)/C=C(\c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)C(=O)O
Reactant: Nc1nncs1
Product: CC(C)/C=C(\c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)C(=O)Nc1nncs1
Yield: 25 %

Procedure:
Example 139 was prepared from (E)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhex-3-enoic acid (105 mg, 0.29 mmol) and 1,3,4-thiadiazol-2-amine using General Coupling Method B to give 30 mg (25% yield). MS found: (M+H)+=450.
Reaction SMILES: CC1(C)[O:6][C:5](=[O:7])[CH:4]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)[O:3]1.[C:17]1([CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[OH:3][C@@H:4]([C@H:8]([C:9]([N:25]1[CH2:26][CH2:27][CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24]1)=[O:11])[CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:6])=[O:7]
Reactant: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Reactant: c1ccc(C2CCNC2)cc1
Product: CCCC[C@@H](C(=O)N1CCC(c2ccccc2)C1)[C@H](O)C(=O)O

Procedure:
The title compound is prepared from 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid B-5 and commercially available 3-phenyl-pyrrolidine A-5 according to General Procedure B.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]([OH:22])[CH2:15][CH2:14]4)[CH2:11][CH:10]=[C:9]1[CH2:8][C@@H:7]([OH:23])[CH2:6][CH2:5]2>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[C:3]([O:23][C@H:7]1[CH2:6][CH2:5][C@@:4]2([CH2:3][O:2][CH3:1])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[O:22][C:16](=[O:22])[CH3:15])[CH2:8]1)(=[O:2])[CH3:4]
Reactant: COC[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC[C@]12CC[C@H](OC(C)=O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Reaction time: 8 h

Procedure:
19-Methoxyandrost-5-ene-3β,17β-diol is dissolved in a mixture of acetic anhydride and pyridine and the solution allowed to stand overnight at room temperature. The solvents are removed under vacuum and the remaining residue crystallized from an acetone-hexane solution to yield 19-methoxyandrost-5-ene-3β,17β-diol diacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:33].C(N(CC)CC)C.[CH3:41][C:42]([CH3:48])([CH3:47])[CH2:43][C:44](Cl)=[O:45]>ClCCl>[F:33][C:3]1[CH:4]=[C:5]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:24]([F:25])([F:26])[F:27])[C:28]([F:30])([F:31])[F:29])=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][C:44](=[O:45])[CH2:43][C:42]([CH3:48])([CH3:47])[CH3:41]
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reactant: CC(C)(C)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reaction time: 2 h
Yield: 9.9 %

Procedure:
(4-Amino-3-fluorophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-benzyl)piperazin-1-yl)methanone (100 mg, 0.209 mmol) was stirred in dichloromethane (1 mL) with triethylamine (53 mg, 0.073 mL, 0.521 mmol) at 0° C. 3,3-Dimethylbutanoyl chloride (42 mg, 0.313 mmol) was added and the reaction allowed to stir for 2 hours. The reaction mixture was washed with water and the organic phase was purified by reverse phase acidic preparative HPLC to afford the title compound (12 mg). MS (ESI) m/z 578.5 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=1.[Cl:22][C:23]1[CH:38]=[CH:37][C:26]([CH2:27][O:28][CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[CH2:9][O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([N:34]2[CH2:35][CH2:36][CH:31]([CH2:30][CH2:29][O:28][CH2:27][C:26]3[CH:37]=[CH:38][C:23]([Cl:22])=[CH:24][CH:25]=3)[CH2:32][CH2:33]2)[CH:7]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: Clc1ccc(COCCC2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CCC(CCOCc3ccc(Cl)cc3)CC2)c1
Temperature: 99 °C
Yield: 85 %

Procedure:
To a solution of 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(R)-pyrrolidinyl]methoxy]pyridine (346 mg, 0.97 mmol) and 4-[2-(4-chlorobenzyloxy)ethyl]piperidine (270 mg, 1.06 mmol, 1.1 equiv.) in anhydrous toluene (6 mL) were added successively sodium tert-butoxide (139 mg, 1.45 mmol, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium(0) (17.7 mg, 19 μmol, 0.02 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 33.6 mg, 58 μmol, 0.06 equiv.). The mixture was degassed and purged with Ar (3 cycles), then warmed to 98-100° C. for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc, and the solution was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by CC on SiO2 with CH2Cl2/EtOAc 4:1, then 1:1. After evaporation, 3-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-[4-[2-(4-chlorobenzyloxy)ethyl]-1-piperidinyl]pyridine (437 mg, 85%) was obtained as a pale yellow oil.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:16])[CH2:14]Br)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([O-])(=[O:19])C.[Na+].CCO.[OH-].[Na+]>O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:16])[CH2:14][OH:19])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(C(=O)CBr)ccc21
Reactant: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)N1CCc2cc(C(=O)CO)ccc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To a solid mixture of 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-2-bromoethanone (1.0 g, 3.54 mmol) and sodium acetate (1.45 g, 17.71 mmol, 5 equiv) in a 40 mL vial was added EtOH (8 mL) and water (8 mL). The resulting suspension was heated in an oil bath at 70° C. for 3.5 hours. The mixture was cooled in an ice bath, to which was added 0.7 mL of 6 N NaOH. After 2 h, the cold mixture was quenched with 2 ml of 1N HCl, and then concentrated in vacuo. The residue was partitioned between 10% MeOH in DCM and water. The organic was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was taken up between DCM and ether to give a suspension, which was filtered. The yellow solids collected were washed with ether and dried under vacuum to give 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-2-hydroxyethanone (534 mg) as a light yellowish solid, which was used without further purification.