Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[NH:8][C:9]3[CH:15]=[C:14]([C:16]([NH2:18])=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:28]=1[CH2:29]Br.O>CN(C=O)C>[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:28]=1[CH2:29][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[NH:8][C:9]3[CH:15]=[C:14]([C:16]([NH2:18])=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:2][CH2:3]1
Reactant: Fc1cccc(F)c1CBr
Reactant: NC(=O)c1ccc2nc(N3CCNCC3)[nH]c2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc2nc(N3CCN(Cc4c(F)cccc4F)CC3)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.3 %

Procedure:
Piperazinyl-benzimidazole-5-carboxamide (0.186 g, 0.5 mMol) was taken in 5 mL DMF and 0.101 g (1 mMol) triethylamine was added and stirred for 15 minutes at room temperature. To this reaction mixture was added 0.104 g 2,6-difluorobenzyl bromide and the mixture was stirred for 20 h. This was poured into water and extracted with methylene chloride (3×50 mL). The combined extract was further washed with brine, water and dried over MgSO4. The solvent was removed in vacuo and the residue chromatographed on silica gel eluting with chloroform-methanol (0 to 5% methanol, gradient). Evaporation of the desired fraction gave 48.9 mg of the desired product; MS(ESI) m/e 356 (M+).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH3:29])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[C:10]([O:30][CH3:31])=[CH:9][C:8]=1[N:32]([CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH3:33])=[O:5].C(N(CC)CC)C.O>C(#N)C>[CH3:38][N:36]([CH3:37])[CH2:35][CH2:34][N:32]([CH3:33])[C:8]1[CH:9]=[C:10]([O:30][CH3:31])[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH3:29])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][C:7]=1[NH:6][C:4](=[O:5])[CH:3]=[CH2:2]
Reactant: COc1cc(N(C)CCN(C)C)c(NC(=O)CCCl)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
Temperature: 80 °C
Reaction time: 12 h
Yield: 65.4 %

Procedure:
To a stirred solution of 3-chloro-N-[2-[2-dimethylaminoethyl(methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]propanamide (Intermediate 174, 31.5 g, 58.76 mmol) in acetonitrile (310 mL) was added triethylamine (17.84 g, 176.28 mmol) at r.t. The resulting mixture was heated to 80° C. for 6 h then cooled to r.t. Water (130 mL) was then added and the mixture stirred for 12 h. The mixture was then filtered, washed with a mixture of water and acetonitrile (160 mL, 1:1) and dried at 50° C. for overnight to give the title compound (19.2 g, 94%) as a solid form identified herein as polymorphic form D. 1H NMR: 2.69 (3H, s), 2.83 (6H, d), 3.35 (4H, s), 3.84 (3H, s), 3.91 (3H, s), 5.75 (1H, d), 6.28 (1H, d), 6.67 (1H, dd), 7.05-7.23 (2H, m), 7.29 (1H, t), 7.43 (1H, d), 7.56 (1H, d), 8.21 (2H, s), 8.81 (1H, s), 9.47 (1H, s), 9.52 (1H, s), m/z: ES+ MH+ 500.26.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[CH:15]=O)=[O:5].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:14][O:13][C:10]1[CH:9]=[C:8]2[C:7](=[CH:12][CH:11]=1)[NH:6][C:4](=[O:5])[C:3]([C:2]([F:18])([F:17])[F:1])=[CH:15]2
Reactant: COc1ccc(NC(=O)CC(F)(F)F)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c(=O)c(C(F)(F)F)cc2c1
Temperature: 60 °C
Yield: 93.2 %

Procedure:
To a solution of 3,3,3-trifluoro-N-(2-formyl-4-methoxyphenyl)propanamide (5.30 g, 20.3 mmol) in DMF (100 mL) was added K2CO3 (14.0 g, 101 mmol). The mixture was heated to 60° C. for 1.5 hours. The mixture was diluted with EtOAc (200 mL) and filtered off. The filtrate was washed with H2O (100 mL) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo to give the desired product (4.60 g, yield 94%). 1H NMR (CDCl3 300 MHz): δ 12.25 (brs, 1H), 8.18 (s, 1H), 7.40 (d, J=9.0 Hz, 1H), 7.25 (dd, J=9.0, 2.7 Hz, 1H), 7.02 (d, J=2.7 Hz, 1H), 3.87 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([C:15]([OH:17])=[O:16])[CH2:9]1)=[O:7])([CH3:4])(C)C.Cl.C([O-])(O)=O.[Na+].C(=O)(ON1C(=O)CCC1=O)OCC1[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2>O1CCOCC1.O>[CH:36]1[C:35]2[CH:4]([CH2:1][O:5][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([C:15]([OH:17])=[O:16])[CH2:9]3)=[O:7])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]=2[CH:39]=[CH:38][CH:37]=1
Reactant: CC1CCN(C(=O)OC(C)(C)C)CC1C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1C(=O)O
Temperature: 60 °C
Reaction time: 16 h
Yield: 31.9 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (1.50 g, 6.17 mmol, Example #13, Step G) in 1,4-dioxane (10 mL) was added aqueous HCl (4N in 1,4-dioxane (4.62 mL, 18.5 mmol). The reaction mixture was heated at about 60° C. for about 16 h before being allowed to cool to ambient temperature. To the mixture was added NaHCO3 (2.07 g, 24.7 mmol) and water (10.0 mL) followed by (9H-fluoren-9-yl)methyl 2,5-dioxopyrrolidin-1-yl carbonate (4.16 g, 12.3 mmol). The reaction was stirred at about 25° C. for about 16 h. The reaction was acidified to about pH 1 with aqueous 1N HCl and was extracted with EtOAc (75 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (40 g column) eluting with a gradient of 1-5% MeOH in DCM to give 1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-methylpiperidine-3-carboxylic acid (0.72 g, 31%) as a clear oil: LC/MS (Table 2, Method a) Rt=2.44 min; MS m/z: 366 (M+H)+.
Reaction SMILES: Br[CH2:2][C@@H:3]1[O:7][C@@H:6]([P:8]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4]1.[NH2:16][C:17]1[N:25]=[C:24]2[C:20]([NH:21][CH:22]=[N:23]2)=[C:19]([Cl:26])[N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:16][C:17]1[N:25]=[C:24]2[C:20]([N:21]=[CH:22][N:23]2[CH2:2][C@@H:3]2[O:7][C@@H:6]([P:8]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4]2)=[C:19]([Cl:26])[N:18]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CCOP(=O)(OCC)[C@H]1CC[C@H](CBr)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)[C@H]1CC[C@H](Cn2cnc3c(Cl)nc(N)nc32)O1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A mixture of (±)-trans-5-bromomethyl-2-diethoxyphosphinoyl-tetrahydrofuran (example 66) (529 mg, 1.76 mmol), 2-amino-6-chloropurine (358 mg, 2.11 mmol) and cesium carbonate (860 mg, 2.64 mmol) in dry DMF (2 mL) was stirred at 90° C. for 6 h. The mixture was then cooled and filtered. Concentration of the filtrate gave a residue which was purified by chromatography eluting with 2→5% MeOH in methylene chloride. The desired product was obtained a foam (384 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@H:23]([C@H:24]([C:31]([CH3:33])=[CH2:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35][C:36](=[O:38])[CH3:37])=[O:17])[CH2:15][C@@:7]3([OH:39])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)(C)C.[Pt]>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:32])[CH3:33])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35][C:36](=[O:38])[CH3:37])=[O:17])[CH2:15][C@@:7]3([OH:39])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: C=C(C)[C@@H]1CC[C@@H](C)[C@@]2(O)[C@H]1C=C(C)[C@@H](OC(C)=O)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Agent: [Pt]
Solvent: CC(C)O
Product: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)C)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Yield: 7.4 %

Procedure:
To a solution of (1S,2R,4aS,5R,8R,8aR)-2-(acetyloxy)-8a-hydroxy-3,8-dimethyl-5-(1-methylethenyl)-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b -hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 1,200 mg) in isopropanol (20 ml) was added platinum on carbon (10% w/w, 20 mg) and the resulting mixture was hydrogenated at room temperature with stirring under 1 atmosphere pressure of hydrogen for 18 hours. The mixture was filtered through celite and concentrated in vacuo to give a white solid. The solid was purified by preparative HPLC (1 inch diameter Ultrasphere C18 column, 2 injections; 70:30 acetonitrile:water) to give the product as a white solid (89 mg).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:15][CH2:16][CH2:17][C:18](O)=[O:19].C1(C)C(C)=CC=CC=1>CCCCCC>[NH:7]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:18](=[O:19])[CH2:17][CH2:16][SH:15])=[CH:10][CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: O=C(O)CCS
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Product: O=C(CCS)Nc1ccc(Nc2ccccc2)cc1
Temperature: 140 °C

Procedure:
A mixture of 18.4 grams of N-phenyl-p-phenylene diamine, 10.6 grams of β-mercaptopropionic acid and 120 milliliters of xylene (technical grade) was heated to reflux (about 140° C.) under nitrogen atmosphere, with stirring. A 1.6 milliliter quantity of water (90% of theory) was removed from this mixture by azeotropic distillation through a Vigreux column with the aid of a Dean-Stark trap, during a 13-hour period. A solid product was isolated in 18.7 grams quantity from the reaction mixture by cooling the latter, pouring into hexane, collecting the resultant crystalline product by filtration, washing the crushed crystalline product with more hexane and evaporating to dryness. The product was recrystallized from hot toluene to 17.6 grams (64.5%) of white platelets melting at 98.3°-99.5° C. The resultant new compound, N-(4-anilino-phenyl)beta-mercaptopropionamide, sometimes referred to hereafter as MPDA, had mercaptan assay of 93.8% of theoretical, on the basis of a potentiometric titration with an isopropyl alcohol solution of silver nitrate, following a method described by R. M. Pierson, A. J. Costanza and A. H. Weinstein, J. Polymer Sci., 17, 234 (1955).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([S:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([O:24]C)=[O:23])[CH:17]=3)=[CH:13][N:14]=2)[CH:3]=1.[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([S:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=3)=[CH:13][N:14]=2)[CH:3]=1
Reactant: COC(=O)c1cc(Sc2cnc(Nc3cc(Cl)nc(C)n3)s2)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(Nc2ncc(Sc3ccnc(C(=O)O)c3)s2)n1
Reaction time: 6 h
Yield: 84.9 %

Procedure:
To a stirring solution of methyl 4-(2-(6-chloro-2-methylpyrimidin-4-ylamino)thiazol-5-ylthio)picolinate (292 mg, 0.741 mmol) in THF (8 mL) was added NaOH (8 mL, 1M in water). After 6 h, the reaction was acidified with 10% HCl to pH ˜6 at which time a solid precipitated. The solid was collected by filtration, washed with water and allowed to dry overnight to give the title material (239 mg, 85%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.55 (1H, s), 8.33 (1H, d, J=5.31 Hz), 7.84 (1H, s), 7.57 (1H, d, J=1.77 Hz), 7.16 (1H, dd, J=5.31, 2.02 Hz), 6.90 (1H, s), 2.51 (3H, s). LC/MS (M+H)+: 380, 382. HPLC ret. time (Condition I): 1.175 min.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)[C:20]([C:38](=[O:40])[NH2:39])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C(O)(C(F)(F)F)=O>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[C:20]([C:38]([NH2:39])=[O:40])=[CH:19][N:18]=3)=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCN(C(=O)OC(C)(C)C)CC4)n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCNCC4)n3)cc2)CC1
Yield: 104.7 %

Procedure:
A solution of tert-butyl 4-((2-(4-(4-acetylpiperazin-1-yl)phenylamino)-5-carbamoylpyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (0.105 g, 0.190 mmol) in TFA (2 mL) was stirred at room temperature for 4 h. TFA was removed in vacuo. The residue was purified by HPLC to give the titled compound (90 mg). MS 453.41 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:32])[CH3:33])[CH:24]=3)[CH2:19][CH2:18]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CC(C(=O)O)c1ccc(Cl)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 37 was prepared from 2-(4-chlorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.61 (d, 2H, J=6.5 Hz), 7.26 (s, 6H), 7.05–6.99 (m, 1H), 6.94 (d, 1H, J=7.1 Hz), 3.37–3.25 (m, 2H), 2.89 (d, 1H, J=9.6 Hz), 2.57–2.43 (m, 2H), 2.37 (t, 2H, J=6.1 Hz), 2.22–2.16 (m, 2H), 2.00–1.91 (m, 2H), 1.89–1.77 (m, 2H), 1.69–1.58 (m, 4H), 1.48 (d, 3H, J=7.0 Hz), 1.24 (d, 6H, J=7.0 Hz); ESMS m/e: 470.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[O:13]1[CH2:17][CH2:16][CH:15]([CH2:18]O)[CH2:14]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)(=O)C.O>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:18][CH:15]2[CH2:16][CH2:17][O:13][CH2:14]2)[CH:3]=1
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: OCC1CCOC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(F)cc1OCC1CCOC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
To a solution of 3 g of methyl 4-fluoro-2-hydroxybenzoate in 60 mL of tetrahydrofuran were added 1.98 g of tetrahydrofuran-3-ylmethanol and 4.28 g of tributylphosphine, followed by ice-cooling. To a mixture was gradually added 6.67 g of 1,1′-(azodicarbonyl)dipiperidine, followed by stirring for 20 minutes. The mixture was warmed to room temperature, stirred for 16 hours, and then poured into a mixture of water and ethyl acetate. The aqueous layer was separated, the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 3.14 g of methyl 4-fluoro-2-(tetrahydrofuran-3-ylmethoxy)benzoate.
Reaction SMILES: CO[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C@@H]3[C@@H](CC[C:20]=2[CH:21]=1)[C@H]1[C@@](C)([C@@H](OCOC)CC1)CC3.COCCl.[CH3:31][C@@:32]12[C@@H:40]([OH:41])[CH2:39][CH2:38][C@H:37]1[C@@H:36]1[CH2:42][CH2:43][C:44]3[CH:49]=[C:48]([OH:50])[CH:47]=[CH:46][C:45]=3[C@H:35]1[CH2:34][CH2:33]2.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:3][O:4][CH2:5][CH2:21][CH2:20][CH2:8][CH2:7][CH2:6][C@@H:43]1[CH2:42][C@@H:36]2[C@H:35]([CH2:34][CH2:33][C@@:32]3([CH3:31])[C@H:37]2[CH2:38][CH2:39][CH:40]3[OH:41])[C:45]2[CH:46]=[CH:47][C:48]([OH:50])=[CH:49][C:44]1=2
Reactant: COCOc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OCOC)CC[C@@H]12
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: COCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCCCCC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(O)CC[C@@H]23)c2ccc(O)cc21
Reaction time: 18 h

Procedure:
(8R,9S,13S,14S,17S)-3,17-bis(methoxymethoxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene—Chloromethyl methyl ether (7.0 mL, 92.0 mmol) is added to a solution of β-estradiol (5 g, 18.4 mmol) and diisopropylethylamine (16.0 mL 92 mmol) in 100 mL of THF. The reaction mixture is heated to reflux and stirred for 18 hours. The THF is removed in vacuo, and the yellow/brown oil is partitioned between water and CH2Cl2. The organic layer is separated, washed with brine, dried (Na2SO4), filtered, and evaporated in vacuo to give a golden oil. Purification by silica gel column chromatography (10% EtOAc/Hex) affords the title compound as a viscous, clear oil (5.7 g, 86%).
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:9](=[N:10][C:11](C#N)=[C:12]([C:15]#[N:16])[N:13]=2)[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.Cl.[OH-:20].[Na+]>>[OH:20][C:11]1[N:10]=[C:9]2[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:2](=[O:1])[C:14]2=[N:13][C:12]=1[C:15]#[N:16]
Reactant: [OH-]
Reactant: N#Cc1nc2c(nc1C#N)-c1ccccc1C2=O
Agent: Cl
Agent: [Na+]
Product: N#Cc1nc2c(nc1O)-c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A suspension of 1 (5.66 g, 24.3 mmol) in aqueous NaOH (2% w/v, 81 ml) was stirred at room temperature for 16 hours. The mixture was acidified with 3N HCl to pH 1, the precipitate was collected by filtration, washed with water and dried under vacuum, affording 6 (4.88 g, 90%) as light brown solid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=3[F:51])[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:54][OH:55])[CH:52]=[O:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=3[F:51])[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:54][OH:55])[CH2:52][OH:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@@](C=O)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Product: CCOc1ccc(Cc2cc([C@]3(OC)OC(CO)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Reaction time: 2 h
Yield: 61.4 %

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 3k (1.6 g, 2.1 mmol) was dissolved in 35 mL of mixed solution (THF and MeOH, v:v=2:5), followed by addition of sodium borohydride (78 mg, 4.2 mmol). The reaction mixture was stirred for 2 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound [(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 3m (1.0 g, yellow grease), yield: 62.5%.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[S:24][CH:25]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[S:24][CH:25]=4)=[CH:17][CH:18]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.6 %

Procedure:
A mixture of ethyl 3-[4-phenyl-1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-pyrrolyl]propionate (706 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 6 hours, and 1N hydrochloric acid (2.5 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-pyrrolyl]propionic acid (619 mg, yield: 93%). This was recrystallized from ethanol-hexane. Melting point: 111–112° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[N:14]=[CH:13][C:12]([O:15][C:16]2[C:17]([CH:31]3[CH2:35][CH2:34][CH2:33][N:32]3[C:36](=[O:38])[CH3:37])=[CH:18][C:19]3[NH:23][C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[N:21][C:20]=3[CH:30]=2)=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:36]([N:32]1[CH2:33][CH2:34][CH2:35][CH:31]1[C:17]1[C:16]([O:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:1](=[O:3])[CH3:2])=[N:14][CH:13]=2)=[CH:30][C:20]2[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[NH:23][C:19]=2[CH:18]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(N)nc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2C(C)=O)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.005 ml of acetic anhydride was added to a pyridine (1 ml) solution of 13.7 mg of 1-(2-(6-(6-amino-pyridin-3-yloxy)-2-pyridin-2-yl-3H-benzimidazol-5-yl)-pyrrolidin-1-yl)-ethanone, and the reaction liquid was stirred at room temperature for 3 hours. The reaction liquid was evaporated away under reduced pressure, the resulting residue was dissolved in 1 ml of trifluoroacetic acid, and the reaction liquid was stirred at room temperature for 3 hours. The reaction liquid was distilled under reduced pressure, and the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid] and through silica gel column chromatography (developing solvent: chloroform/methanol=9/1) to obtain the entitled compound as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.[OH:16][CH:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.[Na]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:20]3[CH2:21][CH2:22][CH:17]([OH:16])[CH2:18][CH2:19]3)[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Reactant: O=C1CCC(O)CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na]
Solvent: ClCCl
Product: OC1CCC(N2C[C@@H]3COCCN3c3nc(Cl)ncc32)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8.4 %

Procedure:
To (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 250 mg, 1.103 mmol) and 4-hydroxycyclohexanone (126 mg, 1.103 mmol) in CH2Cl2 (8 mL) was added titanium(IV) chloride in CH2Cl2 (1M, 2.427 mL, 2.427 mmol) dropwise to give an orange suspension. The reaction mixture was stirred at ambient temperature for 4 hours and then cooled to 0° C. Sodium triacetoxyhydroborate (514 mg, 2.427 mmol) was added in two portions. The reaction mixture was stirred for 1 hour and then quenched with aqueous saturated NH4Cl (1 mL). The reaction mixture was diluted with ethyl acetate and washed with aqueous saturated NH4Cl (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was then loaded onto an ISCO® silica gel cartridge (12 g) and eluted using an ethyl acetate/hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a colorless foam (30 mg, 8%). ESI-MS m/z [M+H]+ calc'd for C15H21ClN4O2, 325.14. found 325.2.