Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[C:24]1([CH2:30][N:31]=[C:32]=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[C:24]1([CH2:30][NH:31][C:32](=[O:33])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:9]=[CH:10]3)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=NCc1ccccc1
Reactant: Oc1ccc2c(ccn2Cc2ccncc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)Oc1ccc2c(ccn2Cc2ccncc2)c1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-pyridinylmethyl)-1H-indol-5-ol (2.2 g) in 50 ml tetrahydrofuran, was added milled K2CO3 (1.4 g) followed by phenylmethyl isocyanate (1.2 ml). After stirring at ambient temperature for twenty hours, the mixture was filtered, and the filtrate evaporated to an oil, (18 3.5 g) which was eluted on a silica gel column with ethyl acetate/dichloromethane (1:1) via HPLC. The desired fractions were combined and evaporated to yield 2.8 g of 1-(4-pyridinylmethyl)-1H-indol-5-yl phenylmethylcarbamate, m.p. 112°-114° C.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:11]=[C:12]([OH:17])[CH:13]=[C:14]([CH:16]=1)[OH:15])([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C[O:19][C:20]1[CH2:25][CH:24]=[C:23]([C:26](O)([CH3:28])[CH3:27])[CH2:22][CH:21]=1>ClCCl>[OH:17][C:12]1[C:13]2[C@H:22]3[CH2:21][C:20](=[O:19])[CH2:25][CH2:24][C@H:23]3[C:26]([CH3:28])([CH3:27])[O:15][C:14]=2[CH:16]=[C:10]([C:2]([CH3:1])([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:11]=1
Reactant: COC1=CCC(C(C)(C)O)=CC1
Reactant: CCCCCCC(C)(C)c1cc(O)cc(O)c1
Solvent: ClCCl
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(=O)C[C@H]21

Procedure:
The process according to claim 1, said process comprising reacting 5-(1,1-dimethylheptyl)resorcinol with 1-methoxy-4-(1-hydroxy-1-methylethyl)-1,4-cyclohexadiene in the presence of stannic chloride in dichloromethane at a temperature ranging from about -10° C. to about 40° C. to provide dl-cis-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH2:6]([C:10]1([CH2:23][OH:24])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)[CH2:7][CH:8]=[CH2:9].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:6]([C:10]1([CH2:23][O:24][S:1]([CH3:4])(=[O:3])=[O:2])[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15]1)[CH2:7][CH:8]=[CH2:9]
Reactant: C=CCCC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: C=CCCC1(COS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
Ms-Cl (5.59 mL, 71.7 mmol) was added dropwise at 0° C. to a stirred solution of tert-butyl 4-(but-3-en-1-yl)-4-(hydroxymethyl)piperidine-1-carboxylate (16.1 g, 59.8 mmol) TEA (16.66 mL, 120 mmol) and DMAP (0.365 g, 2.99 mmol) in CH2Cl2 (300 mL) and the mixture was stirred at room temp for 2 h. Water was then added and the mixture was extracted with methylene chloride (100 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by Biotage (0-40% Hex/EtOAc) to afford tert-butyl 4-(but-3-en-1-yl)-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (18 g, 51.8 mmol, 87% yield) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 5.88-5.75 (m, 1H), 5.11-4.90 (m, 2H), 4.09 (s, 2H), 3.58-3.44 (m, 2H), 3.40-3.32 (m, 2H), 3.05 (s, 3H), 2.07-2.02 (m, 2H), 1.59-1.54 (m, 2H), 1.53-1.49 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:10]=1[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[O:31]>CO.C(OCC)(=O)C.[Pd]>[CH3:33][O:32][C:30](=[O:31])[CH2:29][CH2:28][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:34]
Reactant: COC(=O)C=Cc1c(C#CCCCCOC2CCCCO2)cccc1OCCCCC(=O)OC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCCCOc1cccc(CCCCCCOC2CCCCO2)c1CCC(=O)OC

Procedure:
A 0.9 g (1.9 mmol) sample of rac-5-[2-(3-methoxy-3-oxo-1-propenyl)-3-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexyn-1-yl]phenoxy]pentanoic acid methyl ester was hydrogenated in 60 mL of 1:1 methanol-ethyl acetate, over 70 mg of 10% palladium on carbon, at room temperature and 1 atmosphere. rac-2-(5-Methoxy-5-oxopentyloxy)-6-[6-[(tetrahydro-2-H-pyran-2-yl)oxy]hexyl]benzenepropanoic acid methyl ester, an oil, was isolated by filtration of the catalyst and concentration of the filtrate, in quantitative yield.
Reaction SMILES: O[C:2]1([C:19]2[O:20][C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:24]1([C:22]2[N:23]=[C:19]([C:2]3[CH:3]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=4)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=3)[O:20][C:21]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1cccc(CC2CCCCCCC2(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cccc(CC2CCCCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 4 h
Yield: 112.9 %

Procedure:
A mixture of 1-(hydroxy)-1-(4,5-diphenyloxazol-2-yl)-2-(3-methoxybenzyl)cyclooctane (3.5 g) and p-toluenesulfonic acid (500 mg) in toluene (50 ml) was stirred for 4 hours under reflux. The solution was washed with water, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-(4,5-diphenyloxazol-2-yl)-8-(3-methoxybenzyl)-1-cyclooctene (3.8 g). MS (m/z): 450 (M+ +1) IR (Neat): 1600 cm-1NMR (CDCl3, δ): 1.4-2.0.(8H, m), 2.2-2.4 (2H, m), 3.0 (1H, m), 3.2-3.5 (2H, m), 3.78 (3H, s), 6.65 (1H, s), 6.7-7.0 (3H, m), 7.18 (1H, t, J=8 Hz), 7.2-7.8 (11H, m)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:8][CH2:7][CH2:6]2.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[N:32]=[C:33]([NH2:36])[S:34][CH:35]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:36][C:33]3[S:34][CH:35]=[C:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)[N:32]=3)=[O:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCN2S(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1nc(-c2ccccn2)cs1
Product: COc1ccc2c(c1)CCCN2S(=O)(=O)c1ccc(C(=O)Nc2nc(-c3ccccn3)cs2)cc1

Procedure:
4-(6-methoxy-3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (17) (118 mg, 0.34 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (50 mg, 0.28 mmol) using method C. The residue was purified using flash chromatography eluting with 50-100% EtOAc in hexanes. The resulting solid was triturated with diethyl ether to give 4-(6-methoxy-3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as an off-white solid. Yield: 56 mg (39%). 1H-NMR: 8.64-8.61 (m, 1H), 8.21 (d, J=8.5 Hz, 2H), 8.01 (d, J=7.5 Hz, 1H), 7.94-7.88 (m, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.58-7.45 (m, 2H), 7.35 (ddd, J=7.5, 5.0, 1.0 Hz, 1H), 6.83 (dd, J=9.0, 3.0 Hz, 1H), 6.67 (d, J=3.0 Hz, 1H), 3.79-3.70 (m, 5H), 2.33 (t, J=7.0, 2H), 1.57-1.48 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:29]([Cl:30])=[CH:28][C:13]3[NH:14][C:15]([O:17][C:18]4[CH:19]=[CH:20][C:21]([CH3:27])=[C:22]([CH:26]=4)[C:23]([OH:25])=[O:24])=[N:16][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:31][Mg+].[Br-]>C1COCC1.CCOCC>[Cl:30][C:29]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:1]([OH:3])([CH3:31])[CH3:2])=[CH:9][CH:8]=2)=[CH:11][C:12]2[N:16]=[C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([CH3:27])=[C:22]([CH:26]=3)[C:23]([OH:25])=[O:24])[NH:14][C:13]=2[CH:28]=1
Reactant: C[Mg+]
Reactant: CC(=O)c1ccc(-c2cc3nc(Oc4ccc(C)c(C(=O)O)c4)[nH]c3cc2Cl)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(Oc2nc3cc(-c4ccc(C(C)(C)O)cc4)c(Cl)cc3[nH]2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. suspension of 5-{[5-(4-acetylphenyl)-6-chloro-1H-benzimidazol-2-yl]oxy}-2-methylbenzoic acid (52 mg, 0.124 mmol) and CeCl3 (244 mg, 0.988 mmol) in THF (4 mL) was added MeMgBr (1.4 M in THF) (0.618 mL, 0.865 mmol) dropwise via syringe. The reaction was stirred at rt for 30 min, diluted with Et2O (50 mL) and washed with 1 M HCl (10 mL). The aqueous phase was extracted with Et2O. The combined organics were washed with H2O and brine, dried (Na2SO4), filtered and concentrated. Purification by reverse phase HPLC eluting with MeCN:H2O afforded the desired product as an off-white solid. LC-MS: calculated for C24H21ClN2O4 436.89, observed m/e 437.2 (M+H)+ (Rt: 1.81 min). 1 H NMR (500 MHz, CD3OD): δ 7.89 (d, 1H), 7.54 (d, 2H), 7.49 (s, 1H), 7.47-7.39 (m, 2H), 7.37 (m, 2H), 7.32 (s, 1H), 2.62 (s, 3H), 1.57 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:13](O)(=[O:16])[C:14]#[CH:15]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:8]=[C:9]1[C:10]([O:12][C:13](=[O:16])[C:14]1=[CH:15]2)=[O:11]
Reactant: C#CC(=O)O
Reactant: O=C(O)C#Cc1ccc(Cl)cc1
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc3cc(Cl)ccc3cc21
Yield: 54.1 %

Procedure:
p-Chlorophenylpropiolic acid (3.3 g) and propiolic acid (7.6 g) in acetic anhydride (80 ml) were refluxed for 12 hr. The solution was concentrated (to 40 ml) and the precipitate which formed on cooling was recrystallised from acetone to give 6-chloro-2,3-naphthalenedicarboxylic anhydride (2.3 g) m.p. 220°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]2([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]2)[C:12](=[O:20])[N:11]([CH2:21][C:22]([OH:24])=O)[C@H:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:55][C:56]1[CH:57]=[C:58]2[C:71](=[CH:72][CH:73]=1)[CH2:70][C@@:60]1([C:68]3[C:63](=[N:64][CH:65]=[CH:66][CH:67]=3)[NH:62][C:61]1=[O:69])[CH2:59]2>CN(C=O)C>[O:20]=[C:12]1[C:13]2([CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]2)[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][C@@H:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]1[CH2:21][C:22](=[O:24])[NH:55][C:56]1[CH:57]=[C:58]2[C:71](=[CH:72][CH:73]=1)[CH2:70][C@:60]1([C:68]3[C:63](=[N:64][CH:65]=[CH:66][CH:67]=3)[NH:62][C:61]1=[O:69])[CH2:59]2
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2ccccc2)N(CC(=O)O)C(=O)C12COCCOC2
Reactant: Nc1ccc2c(c1)C[C@]1(C2)C(=O)Nc2ncccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](c2ccccc2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C(=O)C12COCCOC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.21 g (0.5 mmol) (R)-2-(1-(tert-butoxycarbonyl)-5-oxo-3-phenyl-8,11-dioxa-1,4-diaza-spiro[5.6]dodecan-4-yl)ethanoic acid in 3 ml DMF were combined with 0.38 g (1 mmol) HATU and 0.18 ml (1.3 mmol) TEA and stirred for 10 min at RT. Then 0.13 mg (0.5 mmol) (S)-5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one were added and the mixture was stirred overnight at RT. The reaction mixture was poured onto ice water. The precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21](COCC[Si](C)(C)C)[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:36]=[CH:35][S:34][CH:33]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[S:34]1[CH:35]=[CH:36][C:32]([CH2:31][NH:30][C:26]2[N:25]=[C:24]([C:23]3[C:18]4[C:19](=[N:20][C:15]([NH:14][CH:11]5[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]5)=[N:16][CH:17]=4)[NH:21][N:22]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:33]1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(NCc5ccsc5)n4)nn(COCC[Si](C)(C)C)c3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCC(Nc2ncc3c(-c4cccc(NCc5ccsc5)n4)n[nH]c3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of {4-[3-{6-[(thiophen-3-ylmethyl)-amino]-pyridin-2-yl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (415 mg, 0.638 mmol) in dichloromethane (5 mL) was added CF3COOH (5 mL). The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. A saturated aqueous solution of NaHCO3 was added to the residue, and then extracted with ethyl acetate (3×15 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. After purification by prep-HPLC, concentrated HCl was added to the fractions with product and concentrated under reduced pressure to give N-(3-{6-[(thiophen-3-ylmethyl)-amino]-pyridin-2-yl}-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-cyclohexane-1,4-diamine; hydrochloride. (Yield 27 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CCO.C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:21]2[CH2:22][C:23]([CH3:30])([CH3:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH2:26]2)[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(CCC(=O)O)cc2)CC(C)(C)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 3-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}propanoate (9) (0.20 g, 0.49 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 1 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract washed with brine and dried over Na2SO4. Upon concentration and trituration with hot hexanes (contained 1% methanol), the title compound 170 was obtained as white solid (0.177 g, 92%). mp 243-244° C. 1H NMR (400 MHz, CD3OD): δ 0.91 (s, 6H), 0.92 (s, 6H), 1.29 (s, 2H), 1.95 (s, 2H), 1.98 (s, 2H), 2.58 (t, J=7.7 Hz, 2H), 2.87 (t, J=7.7 Hz, 2H), 6.67 (d, J=8.5 Hz, 2H), 6.94 (d, J=8.5 Hz, 2H), 7.05 (d, J=8.1 Hz, 2H), 7.12 (d, J=8.1 Hz, 2H). LCMS (ESI): m/z 393 (M+H)+, m/z 391 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:13].[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:13])=[O:16]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1c(F)cccc1Cl
Product: COC(=O)c1nc(C)sc1-c1c(F)cccc1Cl

Procedure:
prepared by reaction of 3-chloro-3-(2-chloro-6-fluoro-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.92 min; [M+H]+=286.2.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2Cl)[CH2:6]1)(=[O:3])[CH3:2].[N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[NH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2[N:27]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[N:29]=[CH:28]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(Cl)=C(C=O)C[C@@H]32)C1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4cnc5ccccc54)=C(C=O)C[C@@H]32)C1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 88.5 %

Procedure:
A mixture of 3β-Acetoxy-17-chloro-16-formylandrosta-5,16-diene (2, 2.5 g, 6.65 mmol), benzimidazole (2.35 g, 19.9 mmol), and K2CO3 (2.76 g, 23.9 mmol) in dry DMF (20 mL) is stirred at ca. 80° C. under Ar for 1.5 h. After cooling to room temperature, the reaction mixture is poured onto ice-cold water (250 mL) and the resulting precipitate is filtered, washed with water, and dried to give a crude dirty white solid (ca. 2.9 g). Purification by FCC [petroleum ether/EtOAc/Et3N (6:4:0.3)] gives 2.7 g (88.7%) of pure compound 3: mp 227-230° C.; IR (CHCl3) 3691, 3024, 2951, 2359, 1725, 1670, 1604, 1491, 1452, 1375, 1253, 1032, 897, 852, 818, 700, 657, 618, 576, 565, 550, 529, 511, 476 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.07 (s, 6H, 18- and 19-CH3), 2.04 (s, 3H, 3β-OCH3), 4.60 (m, 1H, 3α-H), 5.43 (br s, 1H, 6-H), 7.35 (br. s, 2H, aromatic-Hs), 7.85 (s, 1H, aromatic-H), 7.98 (s, 1H, aromatic-H), 7.98 (s, 1H-21-H) and 9.59 (s, 1H, 16-CHO). HRMS calcd 481.2462 (C29H34O3N2.Na+). found 481.2454.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:20]([O:22]C)=[O:21])[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1.[OH-].[Na+].O1CCOC[CH2:27]1>>[CH3:27][C:2]1[CH:3]=[C:4]([C:20]([OH:22])=[O:21])[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1
Reactant: CCCC(CCC)N1CCc2c(C(=O)OC)cc(Cl)cc2C1=O
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Product: CCCC(CCC)N1CCc2c(C(=O)O)cc(C)cc2C1=O

Procedure:
33 mg of methyl 7-chloro-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate are dissolved in 6 cm3 of dioxane at a temperature close to 20° C. 1.8 cm3 of a 1N aqueous solution of sodium hydroxide are added, then the reaction mixture is heated at a temperature close to 60° C. for 1 h. The mixture is then concentrated to dryness under reduced pressure (5 kPa), taken up by 10 cm3 of ethyl ether and 10 cm3 of water. The aqueous phase is decanted, acidified with 1 cm3 of a 2N aqueous solution of hydrochloric acid. The reaction medium is washed two times with 10 cm3 of dichloromethane. The organic liquors are combined, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa). 215 mg of 7-methyl-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid are obtained in the form of yellow crystals that are used directly in the following reaction.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:15]1([CH2:14][C:10]2[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][N:11]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(CN2CCOCC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccnc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a stirred solution of 45 (150 mg, 0.513 mmol) in DCM (5 mL) was added TFA (1 mL) at 0° C. and allowed to stir at rt for 2 h. The reaction mixture was concentrated, the residue was dissolved in MeOH and treated with Ambersep-900-OH resin to basify the solution, then filtered to separate the resin and concentrated the filtrate to obtain the desired amine (90 mg, 88%) as a gummy liquid. (m/z): 194 [MH]+; 1H NMR (400 MHz, DMSO-d6) δ 7.87 (1H, d, J=5.6 Hz), 6.57 (1H, d, J=2.4 Hz), 6.33 (1H, dd, J=5.2, 2.4 Hz), 5.90 (2H, br s), 3.58-3.56 (4H, m), 3.34 (2H, s), 2.38-2.36 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH:9]([F:16])([F:15])[C:10]([CH:12]([F:14])[F:13])=[O:11]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]([OH:11])([CH:9]([F:16])[F:15])[CH:12]([F:14])[F:13])=[CH:4][C:3]=1[OH:8]
Reactant: Nc1ccccc1O
Reactant: O=C(C(F)F)C(F)F
Solvent: Cc1ccccc1
Product: Nc1ccc(C(O)(C(F)F)C(F)F)cc1O

Procedure:
A mixture of 2-amino-hydroxybenzene, toluene and sym-tetrafluoroacetone can be heated in a Hastelloy® bomb. The solvent can be removed by evaporation and the residual material can be purified by chromatography on silica gel to give 4-amino[2,2-difluoro-1-hydroxy-1-(difluoromethyl)ethyl]-3-hydroxybenzene.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:42][CH:43]1[CH2:46][O:45][CH2:44]1>CN(C)C=O>[C:1]([C:3]1([NH:6][C:7]([CH:9]2[CH2:13][CH:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:42][CH:43]4[CH2:46][O:45][CH2:44]4)=[CH:19][C:18]=3[C:24]([F:25])([F:26])[F:27])(=[O:15])=[O:16])[CH2:11][CH:10]2[C:28]([N:30]2[CH2:31][C:32]([F:34])([F:35])[CH2:33]2)=[O:29])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Reactant: OC1COC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)C2CC(S(=O)(=O)c3ccc(OC4COC4)cc3C(F)(F)F)CC2C(=O)N2CC(F)(F)C2)CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 36.8 %

Procedure:
A mixture of (1R,2R,4R)-2-(3,3-Difluoro-azetidine-1-carbonyl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 118, 87 mg, 0.16 mmol), cesium carbonate (162 mg, 0.49 mmol) and 3-hydroxyoxetane (35 mg, 0.5 mmol) in N,N-dimethylformamide (3 mL) was stirred at 50° C. for 16 h. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogenocarbonate. The aqueous layer was extracted with ethyl acetate then the combined organic layers were washed with water and brine then dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of dichloromethane/methanol (98:2 v/v) as eluant to afford the title compound (34 mg, 35%) as a white solid. MS (EI): 578.13 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:3]=1[NH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:23][Si:24]([C:27]#[C:28][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:3]=1[NH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:26])[CH3:25]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)Nc1c(F)cc(F)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1c(F)cc(F)cc1C#C[Si](C)(C)C
Yield: 67.3 %

Procedure:
In a 2 L flask, 2-bromo-4,6-difluoro-N-carbethoxy aniline (42 g, 150 mmol) in CH3CN (500 mL) is degassed with vacuum and purged with N2. Dichlorobis(triphenylphosphine)palladium(II) (10.5 g, 15 mmol, 10 mol %), followed by CuI (710 mg, 4 mmol, 2.5 mol %) and triethyl amine (41 mL) are added and rinsed in with 100 mL of CH3CN. Trimethylsilyl acetylene (31.8 ml, 225 mmol) is added and reaction is refluxed under N2. Approximately 2 hours later, the starting material is consumed, indicated by TLC (20% ethyl acetate/hexane, UV). The reaction is cooled, filtered, concentrated, and the residue is dissolved in ethyl acetate, washed with H2O, brine, dried (Na2SO4), filtered, concentrated, and is purified by flash chromatography (SiO2, ethyl acetate/hexane gradient) to yield 30 g of 2-(trimethylsilylethynyl)-4,6-difluoro-N-carbethoxyaniline (71%).