Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=1[CH3:16].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].CCOC(C)=O>CN(C=O)C>[C:22]([CH2:21][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=1[CH3:16])([O:24][CH2:25][CH3:26])=[O:23]
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccccc1O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1-c1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.9 %

Procedure:
A dispersion of 530 mg of 60% sodium hydride in mineral oil and 10 ml of DMF is treated, dropwise, with a solution of 1.50 g (6.6 mmol) of 5-(2-hydroxyphenyl)-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile in 20 ml of DMF. The reaction is stirred 30 min at RT, then cooled in an ice bath and 1.11 g (6.6 mmol) of ethyl bromoacetate in 30 ml of DMF is added dropwise. The reaction is allowed to slowly come to RT and stirred overnight under N2. The mixture is concentrated under vacuum, the residue taken up in 80 ml of water and extracted with EtOAc. The aqueous phase is acidified to pH=5 with 10% HCl and extracted with EtOAc (4×80 ml). The combined EtOAc extracts are dried (MgSO4) and the solvent removed to leave an orange solid. This solid is recrystallizedfrom EtOAc to give 740 mg of 5-(2-carboethoxymethoxyphenyl)-6-methyl-2-oxo-1,2 -dihydro-3-pyridinecarbonitrile as a yellow solid, m.p. 188°-190° C. Yield, 37%. 1H-NMR (d6 -DMSO): δ 1.20 (t,3H): 2.18 (s,3H); 4.15 (q,2H); 4.80 (s,2H); 7.0 (q,2H); 7.20 (d,1H); 7.35 (t,1H); 8.00 (s,1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][C@@H:4]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:5]([CH2:23][CH:24]=C)([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].I([O-])(=O)(=O)=O.[Na+].C(OCC)C.[OH2:48]>[Os](=O)(=O)(=O)=O>[CH:24]([CH2:23][C:5]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])([C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])[C@H:4]([C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])[CH2:3][CH:2]([CH3:36])[CH3:1])=[O:48]
Reactant: O
Reactant: C=CCC(C(=O)OCc1ccccc1)(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)OCc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOCC
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(CC=O)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.23 g of 1,2-dibenzyl 1-tert.butyl 4-methyl-1-(prop-2-en-1yl)-1,1,2(R)-pentanetricarboxylate, 3 ml of a 1% aqueous solution of osmium tetroxide, 2.44 g of sodium periodate, 15 ml of diethyl ether and 15 ml of water was stirred at room temperature for 1 hour. A further 3.25 g of sodium periodate were added and the mixture was stirred at room temperature for 24 hours. The ether layer was separated and the aqueous layer was extracted with diethyl ether. The combined ether layers were washed repeatedly with 5% aqueous ascorbic acid solution and saturated sodium chloride solution. After drying over magnesium sulfate, the solution was evaporated and the residue was purified by flash chromatography on silica gel using hexane/diethyl ether (8:1) for the elution. There was obtained 0.955 g of 1,2-dibenzyl 1-tert.butyl 1-(formylmethyl)-4-methyl-1,1,2(R)-pentanetricarboxylate in the form of a colorless oil; MS: 497 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C@@H:10]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].CO>O.[Pd]>[Si:25]([O:24][CH2:23][C@@H:10]1[C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[CH:14]=2)[CH2:12][NH:8][CH2:9]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 101.8 %

Procedure:
At room temperature, 1.0 g of 10% palladium/carbon was added, while suspending in 10 ml of water, to a mixture of 9.69 g of (3R,4S)-1-benzyl-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-[3-(trifluoromethyl)phenyl]pyrrolidine, 5.70 mg of ammonium formate and 100 ml of methanol. This was vigorously stirred at 50° C. for 4 hours and then cooled down to room temperature, and the insoluble matter was removed by filtration through a celite layer. The filtrate was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-ethyl acetate) to obtain 7.89 g of (3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-[3-(trifluoromethyl)phenyl]pyrrolidine as a pale yellow oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18](OCC4C=CC=CC=4)[C:19]=3[C:11]=2[CH2:10][CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2].Cl.[CH2:29]([O:36]C1C=CC=C2C=1C(CCN)=CN2)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[C:15]([O:36][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1cccc(OCc3ccccc3)c21
Reactant: NCCc1c[nH]c2cccc(OCc3ccccc3)c12
Agent: Cl
Product: CCOC(=O)C1=CNCCc2c1[nH]c1c(OCc3ccccc3)cccc21

Procedure:
10-benzyloxy-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester and 4-benzyloxytryptamine hydrochloride.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[N:11]=[C:12]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28]Cl)=[CH:21][CH:20]=2)[O:13][C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][CH:31]1[CH2:35][CH2:34][CH2:33][NH:32]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[CH2:1]([NH:8][CH2:9][C:10]1[N:11]=[C:12]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:32]3[CH2:33][CH2:34][CH2:35][CH:31]3[CH3:30])=[CH:21][CH:20]=2)[O:13][C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1oc(-c2ccc(OCCCCl)cc2)nc1CNCc1ccccc1
Reactant: CC1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1oc(-c2ccc(OCCCN3CCCC3C)cc2)nc1CNCc1ccccc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A suspension of methyl 4-[(benzylamino)methyl]-2-[4-(3-chloropropoxy)phenyl]-1,3-oxazole-5-carboxylate i94 (0.11 g, 0.27 mmol, 1 eq), 2-methylpyrrolidine (30 μl, 0.32 mmol, 1.2 eq) and potassium carbonate (0.15 g, 1.06 mmol, 4 eq) in acetonitrile (5 ml) is stirred at 110° C. overnight. The mixture is then poured into ethyl acetate (50 ml) and washed with water. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. Two successive purifications over silicagel (eluent: dichloromethane, methanol, ammonia 90/10/1) and one purification by preparative liquid chromatography (gradient: acetonitrile/water/trifluoroacetic acid 95:5:01 to 5:95:01) yield 6 mg of methyl 4-[(benzylamino)methyl]-2-{4-[3-(2-methyl-1-pyrrolidinyl)propoxy]phenyl}-1,3-oxazole-5-carboxylate 99.
Reaction SMILES: [Cl:1][C:2]1[C:17]([CH2:18][S:19][C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)=[C:16]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:15]=[CH:14][C:3]=1[C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5].C(Cl)(=O)C([Cl:33])=O>ClCCl.CN(C)C=O>[Cl:33][C:7]1[CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:6]=1[C:4](=[O:5])[C:3]1[CH:14]=[CH:15][C:16]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:17]([CH2:18][S:19][C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)[C:2]=1[Cl:1]
Reactant: Cn1nnnc1SCc1c(S(C)(=O)=O)ccc(C(=O)C2C(=O)CCCC2=O)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1nnnc1SCc1c(S(C)(=O)=O)ccc(C(=O)C2=C(Cl)CCCC2=O)c1Cl
Yield: 68.2 %

Procedure:
To a solution of 2-{2-chloro-4-methylsulfonyl-3-{[(1-methyl-1Htetrazol-5-yl)thio]-methyl}benzoyl}cyclohexane-1,3-dione (1.0 g) in dichloromethane (100 ml), oxalyl chloride (0.91 g) and 2 drops of N,N-dimethylformamide were added dropwise and the mixture was refluxed for 3 hours. The residue obtained by distilling off the solvent after the reaction was purified by silica gel column chromatography (eluant:ethyl acetate:hexane=7:3) to obtain the objective 3-chloro2-{2-chloro-4-methylsulfonyl-3-{[(1-methyl-1H-tetrazol-5-yl)thio]methyl}benzoyl}-2-cyclohexen-1-one (0.71 g). IR (NaCl):=1662,1310,1279, 1150 cm−1.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:21]=[C:20]([CH2:22][N:23]4[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[CH:19]=[CH:18][CH:17]=3)=[O:15])=[C:9]([C:37]3[CH:42]=[C:41]([C:43](=[O:56])[NH:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:54])[F:53])[CH:47]=4)[CH:40]=[CH:39][N:38]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[N:23]1([CH2:22][C:20]2[N:21]=[C:16]([C:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:8][C:9]=3[C:37]3[CH:42]=[C:41]([C:43](=[O:56])[NH:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:53])([F:55])[F:54])[CH:47]=4)[CH:40]=[CH:39][N:38]=3)=[O:15])[CH:17]=[CH:18][CH:19]=2)[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)n2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CN3CCCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 4-((6-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)pyridin-2-yl)methyl)-1,4-diazepane-1-carboxylate (150 mg, 0.18 mmol, 1.00 equiv, 95%) in dichloromethane (5 mL), and trifluoroacetic acid (1 mL). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 50 mL of dichloromethane. The solution was adjusted to pH 9 with aqueous sodium bicarbonate. The resulting solution was extracted with 3×50 mL of dichloromethane and the organic layers combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The product was obtained as 120 mg (97%) of a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[H-].[Na+].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][Cl:29])=[CH:21][CH:20]=1)=[O:18].O>CN(C)C=O>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][Cl:29])=[CH:21][CH:20]=1)=[O:18])[CH3:12]
Reactant: CCOC(=O)Cc1ccccn1
Reactant: O=C(CBr)c1ccc(OCCCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CC(=O)c1ccc(OCCCCl)cc1)c1ccccn1
Reaction time: 14 h

Procedure:
In a 500 mL round bottom flask ethyl 2-pyridylacetate (2.0 g, 12.1 mmol), and 60% sodium hydride (508 mg, 12.7 mmol) in dimethylformamide (50 mL) was stirred 1 h. 2-Bromo-1-[4-(3-chloro-propoxy)-phenyl]-ethanone (3.53 g, 12.1 mmol) was then added in dimethylformamide (50 mL) via dropping funnel. The reaction was stirred 14 h. Water (300 mL) was added and the organics were extracted three times with ethyl acetate, and then dried over MgSO4. Purification with silica gel chromatography eluting with hexanes/ethyl acetate (3:1) produced 2.8 g (62%). MS m/z 376 (M+H).
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:17]([O:24][CH3:25])=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([CH3:14])[C:6]1=[O:15].[CH2:26]([O:33][C:34]1[C:39](B(O)O)=[CH:38][CH:37]=[CH:36][N:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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>[CH2:26]([O:33][C:34]1[C:39]([C:2]2[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:17]([O:24][CH3:25])=[CH:16][C:3]=2[CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N:7]([CH3:14])[C:6]2=[O:15])=[CH:38][CH:37]=[CH:36][N:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: OB(O)c1cccnc1OCc1ccccc1
Reactant: COc1cc(Cn2c(=O)n(C)c3ccccc32)c(Br)cc1C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(Cn2c(=O)n(C)c3ccccc32)c(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Yield: 78 %

Procedure:
step 2—A sealed tube containing 96 (100 mg, 0.25 mmol), 2-benzyloxy-pyridin-3-yl boronic acid (85 mg, 0.37 mmol), Na2CO3 (80 mg, 0.74 mmol) and Pd(PPh3)4 (29 mg, 0.025 mmol) in a mixture of MeOH (1.5 mL) and DCM (0.5 mL) was irradiated on a microwave synthesizer at 100° C. for 30 min. The reaction mixture was diluted with DCM, filtered through a pad of CELITE, and the filtrate was concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 30% EtOAc/hexanes to afford 99 mg of 1-[2-(2-benzyloxy-pyridin-3-yl)-4-tert-butyl-5-methoxy-benzyl]-3-methyl-1,3-dihydro-benzoimidazol-2-one (98).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:11][CH:10]=1)C.[NH:36]1[CH2:41][CH2:40][CH2:39][N:38]=[C:37]1[NH2:42]>CN(C=O)C>[C:31]([O:30][C:28](=[O:29])[C@@H:16]([NH:17][S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)(=[O:19])=[O:20])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4](=[O:3])[NH:42][C:37]2[NH:38][CH2:39][CH2:40][CH2:41][N:36]=2)=[CH:10][CH:11]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](NS(=O)(=O)c2ccc(C)cc2)C(=O)OC(C)(C)C)cc1
Reactant: NC1=NCCCN1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccc(OCCCC(=O)NC3=NCCCN3)cc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
295 mg of 4-{4-[(2S)-2-tert-Butoxycarbonyl-2-(toluene-4-sulfonylamino)-ethyl]-phenoxy}-butyric acid ethyl ester were dissolved in 15 ml of anhydrous DMF and 287 mg of 1,4,5,6-tetrahydropyrimidin-2-ylamine were added to the solution. The reaction mixture was stirred overnight at room temperature, and the solvent was removed in vacuo. The residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic phase was dried with anhydrous magnesium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with a gradient of ethyl acetate/isopropanole/water (8/3/1 to 4/3/1). Yield 241 mg. MS: m/e=559.2 (M+H)+; 503.2.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][O:25][CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][O:25][CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C)OCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)OCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-{3-[(2-ethoxy-1-methyl-2-oxoethoxy)methyl]-1,2,4-oxadiazol-5-yl}hexanoate (Preparation 88) (480 mg, 1.06 mmol) in dichloromethane (8 ml) was treated with trifluoroacetic acid (3.5 ml) and stirred at room temperature for 5 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene and dichloromethane. The oil was purified by column chromatography on silica gel eluting with a gradient system of 100:0:0 (dichloromethane:methanol:acetic acid) gradually changing to 95:5:0.5 (dichloromethane:methanol:acetic acid) to afford the title compound as a colourless oil (395 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][CH:8]2[OH:11])=[CH:4][CH:3]=1.[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([Mg]Br)=[CH:16][CH:15]=1)[CH3:13]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][OH:7])=[C:9]([CH:8]([C:17]2[CH:18]=[CH:19][C:14]([CH2:12][CH3:13])=[CH:15][CH:16]=2)[OH:11])[CH:10]=1
Reactant: CCc1ccc([Mg]Br)cc1
Reactant: OC1OCc2ccc(Br)cc21
Solvent: C1CCOC1
Product: CCc1ccc(C(O)c2cc(Br)ccc2CO)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
Step 2) To a solution of compound 145 (2.1 g, 9.77 mmol) in tetrahydrofuran (40.0 mL) was slowly added 4-ethylphenylmagnesium bromide (39 mL, 0.5 M solution in THF) at 0° C., and the reaction mixture was stirred for 12 h at room temperature. The resulting mixture was quenched with sat. NH4Cl, diluted with EtOAc and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude was purified by silica gel column chromatography to provide (5-bromo-2-(hydroxymethyl)phenyl)(4-ethylphenyl)methanol (146, 1.53 g, 49%) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=2.0 Hz, 1H), 7.42 (dd, J=8.0, 2.0 Hz, 1H), 7.26-7.17 (m, 5H), 5.97 (s, 1H), 4.58 (d, J=12.8 Hz, 1H), 4.43 (d, J=12.4 Hz, 1H), 2.65 (q, J=7.6 Hz, 2H), 1.23 (t, J=7.6 Hz, 3H).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[C:19]([CH2:20][NH:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:18][C:17]([Br:26])=[CH:16][N:15]=1>ClCCCl>[Br:26][C:17]1[CH:16]=[N:15][C:14]2[NH:13][C:1](=[O:2])[N:21]([CH2:22][CH2:23][O:24][CH3:25])[CH2:20][C:19]=2[CH:18]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COCCNCc1cc(Br)cnc1N
Solvent: ClCCCl
Product: COCCN1Cc2cc(Br)cnc2NC1=O
Temperature: 65 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
1,1′-Carbonyldiimidazole (0.74 g, 4.60 mmole) was added to a solution of 2-amino-5-bromo-3-[(2-methoxyethyl)aminomethyl]pyridine (1.00 g, 3.80 mmole) in 1,2-dichloroethane (35 mL) at RT. The reaction was heated at 65° C. with stirring overnight, then was concentrated in vacuo. Flash chromatography on silica gel (5% MeOH/CHCl3) gave title compound (0.90 g, 83%) as a yellow solid after drying in vacuo: MS (ES) m/e 286/288 (M+H)+.
Reaction SMILES: Br[CH2:2][CH:3]1[C:7]2[C:8]([CH3:15])=[C:9]([OH:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:6]=2[O:5][C:4]1([CH3:17])[CH3:16].C1(O)C=CC=CC=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(#N)C>[CH3:16][C:4]1([CH3:17])[CH:3]([CH2:2][N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)[C:7]2[C:8]([CH3:15])=[C:9]([OH:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:6]=2[O:5]1
Reactant: CN1CCNCC1
Reactant: Cc1c(C)c2c(c(C)c1O)C(CBr)C(C)(C)O2
Solvent: Oc1ccccc1
Solvent: CC#N
Product: Cc1c(C)c2c(c(C)c1O)C(CN1CCN(C)CC1)C(C)(C)O2
Yield: 22.8 %

Procedure:
A solution of 3-bromomethyl-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-ol (81 g, 270 mmol), phenol (26.75 g, 284 mmol) and N-methylpiperazine (28.47 g, 284 mmol) in acetonitrile (300 ml) is stirred at reflux temperature for 60 hrs. The precipitate that formed is collected, washed with acetonitrile and slurtied in 10% sodium bicarbonate solution. The product is extracted twice with ethyl acetate, and the extract is washed with water and brine, dried (sodium sulfate) and evaporated. The resulting solid is dissolved in ethanol (150 mL) and 2N hydrochloric acid (150 mL), and evaporated to near dryness. The resulting solid is recrystallized in ethanol/ethyl acetate to give after drying at 60° C. under 13 Pa and equilibration in a moist atmosphere for 24 hrs, 48.60 g (44%) of 2,2,4,6,7-pentamethyl-3-[(4-methylpiperazino)-methyl]-2,3-dihydro-1-benzofuran-5-ol dihydrochloride hydrate, mp=172°-3° C.(dec.). A second crop of 19.63 g of 2,2,4,6,7-pentamethyl-3-[(4-methylpiperazino)-methyl]-2,3-dihydro-1-benzofuran-5-ol (total yield 63%) could be obtained from the filtrate after purification of the free base by column chromatography on silica gel eluting with dichloromethane/methanol 9:1.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H]([C@@H](CO)CC5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.C([C@@H:32]1[CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]3)[CH2:33]1)#N>>[OH:2][CH2:1][C@H:33]1[CH2:32][CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@@H:34]1[C@H:35]1[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]1
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12CCCCC1C[C@H](CO)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1C[C@H](CO)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
7β-Hydroxymethylandrostane-3,17-dione (II-by) was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-7β-hydroxymethylandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.66 (m, 2H), 3.64 (t, 1H), 2.51-0.80 (m, 21H), 1.07 (s, 3H), 0.89 (s, 3H)
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([C:11]2[N:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[OH:10])[CH2:4]1.[CH3:19][C:20]1[C:28]2[CH2:27][O:26][C:25](=[O:29])[C:24]=2[CH:23]=[CH:22][C:21]=1[C@@H:30]1[CH2:32][O:31]1>>[OH:10][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][N:16]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@@H:3]([NH:2][CH2:32][C@H:30]([OH:31])[C:21]2[C:20]([CH3:19])=[C:28]3[C:24](=[CH:23][CH:22]=2)[C:25](=[O:29])[O:26][CH2:27]3)[CH2:4]1
Reactant: N#Cc1ccc(C(O)CN2CC[C@@H](N)C2)nc1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Agent: Cl
Product: Cc1c([C@@H](O)CN[C@@H]2CCN(CC(O)c3ccc(C#N)cn3)C2)ccc2c1COC2=O

Procedure:
6-(1-Hydroxy-2-((R)-3-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethylamino)pyrrolidin-1-yl)ethyl)nicotinonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 1 starting from 6-{2-[(3R)-3-aminopyrrolidin-1-yl]-1-hydroxyethyl}pyridine-3-carbonitrile hydrochloride [INTERMEDIATE 11] and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one [INTERMEDIATE 2B].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([F:20])[F:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH:22]([O:25][C:26]1[CH:32]=[C:31]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[C:30]([CH3:39])=[CH:29][C:27]=1[NH2:28])([CH3:24])[CH3:23].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([F:20])[F:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:28][C:27]2[CH:29]=[C:30]([CH3:39])[C:31]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:32][C:26]=2[O:25][CH:22]([CH3:24])[CH3:23])=[N:3][CH:4]=1
Reactant: Cc1cc(N)c(OC(C)C)cc1C1CCNCC1
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)C(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: Cc1cc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(F)F)n2)c(OC(C)C)cc1C1CCNCC1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
To a suspension of 2,5-dichloro-N-(2-(difluoromethylsulfonyl)phenyl)-pyrimidin-4-amine (0.5 mmol) in 1 mL of isopropanol, was added 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline (0.5 mmol) and 4-methylbenzenesulfonic acid (0.5 mmol). The suspension was stirred at 150° C. for 3 hours. After work-up and prep-HPLC, product was obtained. MS (ES+): 566.17 (M+1)+.