Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12][C:13]([C:15]2([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[C:9]([OH:11])=O)=[CH:3][CH:2]=1.Cl.[NH:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1>CN(C=O)C>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]([NH:12][C:13]([C:15]2([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:14])[C:9]([N:33]2[CH2:37][CH2:36][CH2:35][C@H:34]2[C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])=[O:11])=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC1(C(=O)N[C@@H](Cc2ccc(-c3ccccc3)cc2)C(=O)O)CCCC1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1(C(=O)N[C@@H](Cc2ccc(-c3ccccc3)cc2)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 83.6 %

Procedure:
A solution of (S)-3-(biphenyl-4-yl)-2-(1-(2-ethoxy-2-oxoethyl)cyclopentanecarboxamido)propanoic acid (201.7 mg, 0.476 mmol), (S)-benzyl pyrrolidine-2-carboxylate hydrochloride (138 mg, 0.572 mmol), WSC.HCl (137 mg, 0.714 mmol), DIPEA (0.125 ml, 0.714 mmol) and 1-hydroxy-7-azabenzotriazole (97 mg, 0.714 mmol) in DMF (2 ml) was allowed to stir at room temperature under nitrogen for 14 hours. The reaction was quenched with H2O. The products were extracted with EtOAc. The organic layer was washed with NH4Claq, 0.1 M HCl (twice) and then brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (heptane/EtOAc=100:0 to 0:100) to give (S)-benzyl 1-((S)-3-(biphenyl-4-yl)-2-(1-(2-ethoxy-2-oxoethyl)cyclopentanecarboxamido)propanoyl)pyrrolidine-2-carboxylate (243 mg); Retention time=1.74 minutes (condition B); MS (m+1)=611.2; 1H NMR (400 MHz, CD3CN, mixture of rotamers) δ ppm 0.91-1.06 (m, 3H) 1.33-1.42 (m, 6H) 1.55-2.09 (m, 6H) 2.25-2.42 (m, 2H) 2.57-2.93 (m, 2H) 3.06-3.59 (m, 2H) 3.75-3.91 (m, 2H) 4.14-4.61 (m, 2H) 4.68-5.09 (m, 3H) 6.40-6.52 (m, 1H) 7.00-7.45 (m, 14H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:23])[CH2:11][N:10]([C:12]3[NH:13][C:14](=[O:22])[C:15]4[CH:20]=[CH:19][N:18]([CH3:21])[C:16]=4[N:17]=3)[CH2:9]2)=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:21][N:18]1[C:16]2[N:17]=[C:12]([N:10]3[CH2:9][C:8]([CH3:23])([C:5]4[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=4)[CH2:11]3)[NH:13][C:14](=[O:22])[C:15]=2[CH:20]=[CH:19]1
Reactant: [H][H]
Reactant: Cn1ccc2c(=O)[nH]c(N3CC(C)(c4ccc(Br)cc4)C3)nc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1ccc2c(=O)[nH]c(N3CC(C)(c4ccccc4)C3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
A mixture of 2-(3-(4-bromophenyl)-3-methylazetidin-1-yl)-7-methyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (100.3 mg, 269 μmol) in ethyl acetate (2.7 mL) and methanol (2.8 mL) was treated with 10% palladium on carbon (9.2 mg, ˜10% weight of starting material used). The flask was capped with a rubber septum and a hydrogen balloon was attached. The reaction was stirred at room temperature overnight. At this time, the reaction was concentrated in vacuo onto Celite®. Flash chromatography (24 g silica gel column, 20-100% ethyl acetate/hexanes) afforded 7-methyl-2-(3-methyl-3-phenyl-azetidin-1-yl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as an off-white solid (43.2 mg, 54.6%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.61 (s, 3H) 3.53 (s, 3H) 4.10 (d, J=8.67 Hz, 2H) 4.24 (d, J=8.29 Hz, 2H) 6.23 (d, J=3.01 Hz, 1H) 6.73 (d, J=3.20 Hz, 1H) 7.13-7.50 (m, 5H) 10.90 (s, 1H). LC-MS calcd. for C17H19N4O [(M+H)+] 295, obsd. 295.1.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.[NH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]1>>[ClH:1].[ClH:1].[NH2:22][CH:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:3]=2)[CH2:25][CH2:24]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CCC(C)n1cnc2c(Nc3ccccc3)nc(Cl)nc21
Product: CCC(C)n1cnc2c(Nc3ccccc3)nc(NC3CCC(N)CC3)nc21
Product: Cl
Yield: 127 %

Procedure:
The operation is carried out as in Stage 2 of Example 44 starting from 166 mg of the product obtained in Stage 1 above and 629 mg of trans-1,4-diaminocyclohexane. In this way 158 mg of expected product is obtained in the form of crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[O:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[NH:23]1[CH:27]=[N:26][CH:25]=[N:24]1>CN1C(=O)CCC1.ClCCl.[Cu]I>[CH3:9][N:8]([CH3:10])[CH2:7][CH2:6][O:5][C:4]1[CH:3]=[C:2]([N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=1
Reactant: CN(C)CCOc1cc(Br)cc([N+](=O)[O-])c1
Reactant: c1nc[nH]n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CN(C)CCOc1cc(-n2cncn2)cc([N+](=O)[O-])c1
Yield: 57 %

Procedure:
Intermediate 16A (200 mg, 0.69 mmol), copper(I) iodide (65.9 mg, 0.35 mmol), potassium carbonate (287 mg, 2.1 mmol) and 1H-1,2,4-triazole (143 mg, 2.075 mmol) in NMP (2 mL) were heated at 120° C. for 6 hours. The reaction mixture was diluted with dichloromethane, and filtered through a plug of silica gel and washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by reverse phase HPLC to obtain Intermediate 16B (109 mg, 56.8% yield) as a yellow solid. HPLC: Rt=0.74 min. (PHENOMENEX® Luna 5 micron C18 4.6×30 mm, 10-90% aqueous methanol containing 0.1% TFA, 2 min. gradient, flow rate=5 mL/min, detection at 254 nm). MS (ES): m/z=278.08 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3].F[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[C:26]#[N:27].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[C:26]#[N:27])=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3]
Reactant: N#Cc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@H]1C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(Oc3ccccc3C#N)cc2)CC[C@H]1C(N)=O
Yield: 75.3 %

Procedure:
A solution of 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-1-pyrrolidinecarboxylate (D13, 50 mg, 0.163 mmol), 2-fluorobenzonitrile (40 mg, 0.326 mmol) and K2CO3 (34 mg, 0.245 mmol) in DMF (1 ml) was heated under microwave irradiation for 30 min at 120° C. Then water and ethyl acetate were added to the mixture. The organic layer was washed with ice cold brine. The solution was dried over Na2SO4 and the solvent removed under reduced pressure. The crude material was purified by chromatography on silica gel using cyclohexanes/ethyl acetate (75:25) to afford the title compound (50 mg, 75%); Rf (cyclohexanes:ethyl acetate=1:1): 0.10; Rt (HPLC) 5.17 min.; MS: (ES/+) m/z: 430 [M+Na+], C23H25N3O4 requires 407.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Cl>CN(C)C=O>[Br:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[C:5]([N:8]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)nc1-c1ccc(Cl)cc1
Reactant: ClCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(-c2nc(Br)cnc2N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.8 %

Procedure:
To a solution of 0.5 g (0.0018 mol) 5-bromo-3-(4-chloro-phenyl)-pyrazin-2-ylamine in 10 ml dimethylformamide was added at room temperature 0.240 g sodium hydride 55% in oil (0.006 mol) and 0.49 g 1-bromo-5-chloro-pentane (0.0025 mol) and the mixture was stirred at room temperature for 0.5 hours. Another 0.130 g sodium hydride 55% in oil was added and the mixture was stirred at room temperature for 2.5 h. The resulting mixture was partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated, the organic phase was dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel using a gradient of 30% ethyl acetate in heptane to ethyl acetate to yield 0.043 g (83% yield) of the title compound as slightly brownish oil. MS (ISP) (M+H+)=354.1 and 356.0.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[O:22])[CH2:4][N:5]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:24](OC(C)(C)C)(=[O:32])[C:25](OC(C)(C)C)=[O:26].CC(C)([O-])C.[K+].C(O)(=O)C>C(O)(C)(C)C.C1COCC1>[CH3:23][N:2]([CH3:1])[C:3]([C:4]1[N:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:25]([OH:26])[C:24]=1[OH:32])=[O:22]
Reactant: COc1ccc(N(CC(=O)OC(C)(C)C)CC(=O)N(C)C)cc1
Reactant: CC(C)(C)OC(=O)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: COc1ccc(-n2c(C(=O)OC(C)(C)C)c(O)c(O)c2C(=O)N(C)C)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 38.5 %

Procedure:
To a solution of tert-butyl 2-((2-(dimethylamino)-2-oxoethyl)(4-methoxyphenyl)amino)acetate (16) (1.98 g, 6.14 mmol) and di-tert-butyl oxalate (1.37 g, 6.76 mmol) in anhydrous tert-butanol (6 mL) was added potassium tert-butoxide (20 wt. % in THF) (10.77 ml, 15.35 mmol) and the reaction was stirred at 100° C. for 1.5 h, di-tert-butyl oxalate (300 mg, 1.5 mmol), potassium tert-butoxide (20 wt. % in THF) (4 mL, 5.71 mmol), THF (10 mL), and tert-butanol (4 mL) were added and the mixture stirred for a further 1 h. The mixture was allowed to cool to RT and acetic acid (4 ml, 69.9 mmol) added, the mixture was poured on to ice-cold water (50 mL) and the resulting precipitate was collected by vacuum filtration and recrystallised from hot ethanol to afford tert-butyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-036) (890 mg, 37%) as a white powder: m/z 377 (M+H)+ (ES+); 375 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 8.62 (s, 1H), 8.45 (s, 1H), 7.12-6.99 (m, 2H), 6.94-6.81 (m, 2H), 3.76 (s, 3H), 2.83 (br s, 6H), 1.17 (s, 9H).
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([NH2:28])[C:16]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=[CH:17][CH:18]=1.[C:29]1(=[O:39])[C@@H:37]2[C@@H:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[C:31](=O)[O:30]1.CCN(C(C)C)C(C)C.Cl>C(#N)C>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]2[N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([Br:27])=[CH:25][CH:26]=3)[C:31]([C@H:32]3[CH2:33][CH2:34][CH2:35][CH2:36][C@H:37]3[C:29]([OH:39])=[O:30])=[N:28][C:15]=2[CH:14]=1
Reactant: Nc1cc(OCc2nc3ccccc3s2)ccc1NCc1ccc(Br)cc1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a 4 mL microwave vial were added 4-(benzo[d]thiazol-2-ylmethoxy)-N1-(4-bromobenzyl)benzene-1,2-diamine hydrochloride (100 mg, 0.21 mmol), cis-hexahydroisobenzofuran-1,3-dione (34 mg, 0.21 mmol), DIPEA (27 mg, 0.21 mmol), and acetonitrile (2 mL). The mixture was irradiated for 1 h at 82° C. in a microwave reactor. The reaction was cooled to RT, HCl (1 mL, 6 N) was added and the reaction was irradiated for 1 h at 82° C. in a microwave reactor. The reaction was cooled to RT and the solid byproducts were removed by filtration and filtrate was purified using reverse phase HPLC to provide the title compound. MS (ESI): mass calcd. for C29H26BrN3O3S, 575.10; m/z found, 576.1 [M+H]+. 1H-NMR (500 MHz, CDCl3) δ 8.03 (d, J=8.0, 1H), 7.89 (d, J=8.0, 1H), 7.56-7.48 (m, 4H), 7.45-7.38 (m, 2H), 7.19-7.16 (m, 1H), 7.16-7.11 (m, 1H), 6.97 (d, J=8.4, 2H), 5.59-5.49 (m, 1H), 5.46 (s, 2H), 3.40-3.24 (m, 1H), 2.93 (d, J=4.5, 1H), 2.39-2.19 (m, 2H), 1.96-1.83 (m, 2H), 1.82-1.69 (m, 1H), 1.65-1.50 (m, 2H), 1.35 (d, J=13.0, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[N:7][C:6]([C:9]([OH:11])=O)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[F:48][C:49]([F:62])([F:61])[C:50]1[NH:51][C:52]2[C:57]([CH:58]=1)=[CH:56][C:55]([CH2:59][NH2:60])=[CH:54][CH:53]=2>C(#N)C>[F:12][C:2]([F:1])([F:13])[C:3]1[N:8]=[N:7][C:6]([C:9]([NH:60][CH2:59][C:55]2[CH:56]=[C:57]3[C:52](=[CH:53][CH:54]=2)[NH:51][C:50]([C:49]([F:62])([F:48])[F:61])=[CH:58]3)=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)nn1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1ccc(C(F)(F)F)nn1
Reaction time: 18 h

Procedure:
A solution of 6-(trifluoromethyl)-3-pyridazinecarboxylic acid (Intermediate 9, 60 mg, 0.312 mmol), HATU (131 mg, 0.344 mmol) and DIPEA (0.164 ml, 0.937 mmol) in acetonitrile (3 ml) was stirred at room temperature under argon for 15 mins and then treated with {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine hydrochloride (Intermediate 5, 78 mg, 0.312 mmol). The reaction mixture was stirred for 18 hrs and evaporated under reduced pressure to remove the acetonitrile. The residue was dissolved in DCM and washed with water. The organic solution was dried over MgSO4 and evaporated under reduced pressure to afford the crude product which was purified by MDAP the title compound (39 mg) as a pale solid;
Reaction SMILES: O1[CH:24]2[C:25](=[O:26])[C@:2]31[O:29][C@:3]13[C@:22]([CH3:27])([CH2:23]2)[C@@H:21]2[C@H:6]([C@H:7]3[C@:18]([CH3:28])([CH2:19][CH2:20]2)[C@@H:10]([CH:11]([CH3:17])[CH:12]([O:15][CH3:16])[O:13][CH3:14])[CH2:9][CH2:8]3)[CH:5]=[CH:4]1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[OH2:44].OO>O1CCCC1>[CH3:16][O:15][CH:12]([O:13][CH3:14])[CH:11]([CH3:17])[C@@H:10]1[C@:18]2([CH3:28])[C@H:7]([C@H:6]3[C@H:21]([CH2:20][CH2:19]2)[C@:22]2([CH3:27])[C@:3]([OH:29])([CH2:2][C@@H:25]([OH:26])[CH2:24][C@@H:23]2[OH:44])[CH:4]=[CH:5]3)[CH2:8][CH2:9]1
Reactant: O
Reactant: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3C=C[C@@]45O[C@]46OC(C[C@]5(C)[C@H]3CC[C@]12C)C6=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3C=C[C@@]4(O)C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 50 ml of tetrahydrofuran was dissolved 8.5 g of the 1α,2α;4α,5α-diepoxy-21,21-dimethoxy-20-methylpregn-6-en-3-one obtained in Example 76, followed by dropwise addition of 100 ml of a 1.0M solution of lithium tri-sec-butylborohydride in tetrahydrofuran under ice-cooling. After completion of dropwise addition, the mixture was stirred at room temperature for 2 hours. The excess reducing agent was decomposed with water and the residual alkylborane was decomposed with alkaline hydrogen peroxide, followed by extraction with ethyl acetate. The extracts were pooled, washed with aqueous sodium chloride solution, and dried over sodium sulfate, followed by concentration under reduced pressure. Recrystallization of the concentrate from ethyl acetate gave 2.90 g of 21,21-dimethoxy-20-methylpregn-6-ene-1α,3β,5a-triol showing the following physical properties.
Reaction SMILES: OC1CN[C@H](C(O)=O)C1.[C:10]([C:12]1[CH:39]=[CH:38][C:15]([CH2:16][C:17]2([C:34]([O:36][CH3:37])=[O:35])[CH2:21][C@@H:20]([OH:22])[CH2:19][N:18]2[C:23](=[O:33])[CH2:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)=[CH:14][CH:13]=1)#[N:11].N1C=CN=C1.[Si:45](Cl)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]>CN(C=O)C.O>[Si:45]([O:22][C@H:20]1[CH2:19][N:18]([C:23](=[O:33])[CH2:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)[C:17]([CH2:16][C:15]2[CH:14]=[CH:13][C:12]([C:10]#[N:11])=[CH:39][CH:38]=2)([C:34]([O:36][CH3:37])=[O:35])[CH2:21]1)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]
Reactant: COC(=O)C1(Cc2ccc(C#N)cc2)C[C@@H](O)CN1C(=O)Cc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C(O)[C@@H]1CC(O)CN1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(Cc2ccc(C#N)cc2)C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)Cc1cc(Cl)cc(Cl)c1
Reaction time: 20 h
Yield: 89 %

Procedure:
A 4-Hydroxy-L-proline derivative, methyl (4R)-2-(4-cyanobenzyl)-1-[(3,5-dichlorophenyl)acetyl]-4-hydroxypyrrolidine-2-carboxylate 21 (10 mmol) and imidazole (1.5 g, 22.5 mmol) were suspended in DMF (25 mL) and treated with tert-butyl(dimethyl)silyl chloride (1.6 g, 10.5 mmol). The reaction was stirred for 20 h, poured into water (100 mL) and extracted with diethyl ether (Et2O) (4×30 mL). The organic extracts were combined and washed with 1N HCl aq. (2×30 mL), water (1×50 mL), sat. aqueous NaHCO3 solution (1×30 mL) and sat. aq. NaCl solution (1×30 mL). The organic layer was dried (MgSO4) and solvent removed in vacuo to give methyl (4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-cyanobenzyl)-1-[(3,5-dichlorophenyl)acetyl]pyrrolidine-2-carboxylate (23) (˜5 g, 90%), which was used as such in subsequent reaction without further purification, LCMS, (m/z) 561 (M++H).
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH2:15])[CH:9]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([S:29]([CH2:32][C:33]2[N:34]=[C:35]([C:39]3[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=3)[O:36][C:37]=2[CH3:38])(=[O:31])=[O:30])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:43]([C:42]2[CH:41]=[CH:40][C:39]([C:35]3[O:36][C:37]([CH3:38])=[C:33]([CH2:32][S:29]([CH:26]4[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:24][CH2:25]4)(=[O:30])=[O:31])[N:34]=3)=[CH:47][CH:46]=2)=[O:44])[CH:9]=1
Reactant: NCc1cccnc1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
Triethylamine (440 mg, 4.36 mmol, 3.00 equiv) was added dropwise with stirring to a solution of pyridin-3-ylmethanamine (170 mg, 1.57 mmol, 1.10 equiv), 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-ylsulfonyl)methyl)-5-methyloxazol-2-yl)benzoic acid (670 mg, 1.44 mmol, 1.00 equiv), EDCI (330 mg, 1.73 mmol, 1.20 equiv) and HOBT (230 mg, 1.70 mmol, 1.20 equiv) in N,N-dimethylformamide (10 mL) contained in a 50-mL round-bottom flask. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 30 mL of water/ice. The precipitate was collected by filtration and dried in an oven under reduced pressure to give 0.74 g (93%) of tert-butyl 4-((2-(4-((pyridin-3-ylmethyl)carbamoyl)phenyl)-5-methyloxazol-4-yl)methylsulfonyl)piperidine-1-carboxylate as a yellow solid. LC-MS: (ES, m/z): 555 [M+H]+, 455.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15]O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[I-].[C:18]([CH2:20][P+](C)(C)C)#[N:19].C(N(C(C)C)CC)(C)C.O>C(#N)CC>[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][CH2:20][C:18]#[N:19])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1c2ccccc2cc2ccccc12
Reactant: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#CCCc1c2ccccc2cc2ccccc12
Temperature: 97 °C
Reaction time: 20 h
Yield: 94.8 %

Procedure:
To a solution of anthracen-9-yl-methanol (6.58 g, 31.6 mmol) and (cyanomethyl)trimethylphosphonium iodide (19.19 g, 78.96 mmol) in propionitrile (77 mL) was added diisopropylethylamine (DIPEA, 49.4 mL, 94.74 mmol) and the mixture was stirred at 97° C. for 20 hours. Water (3.82 mL) was added, nitrogen was bubbled though the mixture, and the mixture was stirred for 20 hours. Water (480 mL) and concentrated HCl (19 mL) were added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated. The resulting solid was purified by silica gel column chromatography (hexane:CHCl3=1:1) to give 3-anthracen-9-yl-propionitrile as brown crystals (6.93 g, 95% yield). 1H NMR (CDCl3) δ 8.43 (1H, s), 8.19 (2H, d), 8.05 (2H, d), 7.60 (2H, dd), 7.51 (2H, dd), 4.02 (2H, t), 2.79 (2H, t).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:35])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11].[C:36](=[O:48])([O:40][C@H:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH3:42])[O:37][CH2:38][Cl:39]>C(#N)C>[Cl-:39].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:35])([C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11])[CH2:29][NH+:30]1[CH2:34][N:33]([CH2:38][O:37][C:36]([O:40][C@H:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH3:42])=[O:48])[CH:32]=[N:31]1
Reactant: C[C@@H](N1CCN(c2ccc(-n3cnnn3)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCOC(=O)[C@H](C)OC(=O)OCCl
Solvent: CC#N
Product: CCOC(=O)[C@H](C)OC(=O)OCN1C=N[NH+](C[C@](O)(c2ccc(F)cc2F)[C@@H](C)N2CCN(c3ccc(-n4cnnn4)cc3)C2=O)C1
Product: [Cl-]
Temperature: 95 °C
Reaction time: 68 h
Yield: 30.5 %

Procedure:
To a mixture of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-tetrazol-1-yl)phenyl]-2-imidazolidinone(0.50 g) and chloromethyl [(1S)-1-(ethoxycarbonyl)ethyl] carbonate(1.09 g) was added acetonitrile (5 ml), and the mixture was stirred for 68 hours at 95° C. The reaction mixture was concentrated under reduced pressure. To the residue was added diisopropyl ether (6 ml), and the resulting powder was collected by filtration. The powder was subjected to silica gel flush chromatography (eluent: ethyl acetate→ethyl acetate/acetone=1/1→acetone→acetone/ethanol=5/1). The fraction containing the desired compound was concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent: methanol/water=3/2). The eluate was concentrated in vacuo and dissolved in water (50 ml). The solution was lyophilized to give 1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-[[(1S)-1-ethoxycarbonylethoxy]carbonyloxymethyl]-1H-1,2,4-triazolium chloride (Compound 23,0.22 g) as a white powder.