Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:18]3[CH2:22][N:21]([C:23]4[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=4)[C:26]#[N:27])[C:20](=[O:31])[CH2:19]3)[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:32].[Na+].OO>CCO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:18]3[CH2:22][N:21]([C:23]4[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=4)[C:26]([NH2:27])=[O:32])[C:20](=[O:31])[CH2:19]3)[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [OH-]
Reactant: N#Cc1cccc(N2CC(c3ccc(OCC4CC4)c(OC4CCCC4)c3)CC2=O)c1
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cccc(N2CC(c3ccc(OCC4CC4)c(OC4CCCC4)c3)CC2=O)c1
Temperature: 47.5 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a dry round bottom flask was added 3-[4-(3-cyclopentyloxy-4-cyclopropylmethoxy-phenyl)-2-oxo-pyrrolidin-1-yl]benzonitrile (1 mmol) in 10 mL EtOH. This mixture was then heated, and 50 μL of 25% NaOH solution followed by 0.5 mL 30% H2O2 was added to the solution. The mixture was stirred at 45 to 50° C. for 4 h, cooled to r.t., and concentrated under reduced pressure. The residue was dissolved in EtOAc (or CH3Cl), washed with saturated NH4Cl, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give pure product. Yield: 87%.
Reaction SMILES: CO[C:3](=O)[C:4]1C=C(C=C(N)[CH:15]=1)C(OCC=C)=O.[CH3:18][O:19][C:20](=[O:33])[C:21]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[C:23]([C:24]([O-:26])=[O:25])[CH:22]=1.C(Br)C=C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:18][O:19][C:20](=[O:33])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([N+:30]([O-:32])=[O:31])[CH:29]=1)[C:24]([O:26][CH2:15][CH:4]=[CH2:3])=[O:25]
Reactant: C=CCOC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: COC(=O)c1cc(C(=O)[O-])cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C=CCBr
Product: C=CCOC(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Starting material (3(b)) was synthesised as follows. A mixture of mono-methyl-5-nitroisophthalate (13.8 g), allyl bromide (7.96 g), potassium carbonate (13.94 g) and DMF (160 ml) was stirred at ambient temperature for 4.5 h. The solid was filtered and DMF was evaporated away from the filtrate under reduced pressure. The residue was dissolved in diethyl ether (300 ml) and water (100 ml) and stirred for five minutes. The organic layer was separated and washed with saturated sodium bicarbonate solution (220 ml), brine (200 ml). dried over magnesium sulphate and evaporated under reduced pressure to give 5-nitro-isophthalic acid allyl ester methyl ester (3(a)) as a yellow oil (14.74 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1C=CC=CC=1>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: COCCN
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)CNCCOC
Yield: 75.3 %

Procedure:
To a stirred solution of 165.2 g of 2-methoxyethylamine and 202.4 g of triethylamine in 1 l of benzene was added dropwise a solution of 334.0 g of ethyl bromoacetate in 200 ml of benzene in one hour at room temperature. At the end of this period, the mixture was heated at reflux for 2 hours to complete the reaction. Upon chilling, the triethylamine hydrobromide was removed by filtration and washed with benzene. After removal of the solvent, the product was distilled in vacuo to yield 242.8 g (75.3 percent) of N-(2-methoxyethyl)glycine ethyl ester, B.P. 73°-5° C/4 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].Br[CH2:23][CH:24]=[CH2:25]>CN(C=O)C>[CH2:25]([N:13]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:4]1[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([Cl:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8])[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: COC(=O)c1cc(Cl)cc(NC2CCOCC2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 46.8 %

Procedure:
To a stirred solution of methyl 5-chloro-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (1.0 g, 3.3 mmol) in DMF (10 mL), NaH (0.25 g, 10 mmol) was added at 0° C. and the mixture stirred for 20 minutes. 3-bromoprop-1-ene (1.7 g, 14.13 mmol) was added and the mixture was heated at 80° C. for 15 h. On completion, the reaction was quenched with ice cold water and extraction was carried out using DCM. The combined organic layers were dried, concentrated and resulting crude was purified by column chromatography giving the title compound (0.50 g, 44%).
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[C@@H:3]([NH:12]C(=O)OCC1C=CC=CC=1)[C:4](=[O:11])[NH:5][CH2:6][C:7]([F:10])([F:9])[F:8].[H][H]>CCOC(C)=O.CCO.[Pd]>[NH2:12][C@H:3]([CH:2]([CH3:23])[CH3:1])[C:4]([NH:5][CH2:6][C:7]([F:8])([F:9])[F:10])=[O:11]
Reactant: [H][H]
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)[C@@H](N)C(=O)NCC(F)(F)F
Reaction time: 6 h
Yield: 65 %

Procedure:
A Parr shaker flask charged with (R)-benzyl (3-methyl-1-oxo-1-((2,2,2-trifluoroethyl)amino)-butan-2-yl)carbamate (4.95 g, 14.9 mmol) in 100 mL of EtOAc and 25 mL of EtOH was treated with 175 mg of 10% Pd/C. The mixture was placed under 40 psi of hydrogen and shaken for 6 h. An additional 65 mg of 10% Pd/C was added to the reaction mixture which was then placed under 40 psi of hydrogen and shaken for 3.5 h. The reaction solution was then filtered through a pad of celite, concentrated in vacuo and purified by sublimation (75 to 85° C., 200-230 millibar) to afford the title compound as a white solid (1.92 g, 65%): mp 43-47° C.; 1H NMR (400 MHz, CDCl3) δ 8.04-7.74 (m, 1H), 3.92 (ddd, J=16.0, 9.3, 6.8 Hz, 1H), 3.84-3.60 (m, 1H), 3.23 (d, J=3.8 Hz, 1H), 2.23 (ddd, J=10.7, 7.0, 3.5 Hz, 1H), 0.92 (d, J=7.0 Hz, 3H), 0.75 (d, J=6.9 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −72.70.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:34]=[C:33]([F:35])[C:13]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[CH:23]=2)[C:18](O)=[O:19])=[C:12]([F:36])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37]([O:41][C:42](=[O:51])[NH:43][CH:44]1[CH2:49][CH2:48][CH:47]([NH2:50])[CH2:46][CH2:45]1)([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][C:42](=[O:51])[NH:43][CH:44]1[CH2:45][CH2:46][CH:47]([NH:50][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[CH:23]=[C:15]([O:14][C:13]3[C:12]([F:36])=[CH:11][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[CH:34][C:33]=3[F:35])[CH:16]=2)[CH2:48][CH2:49]1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)NCc1cc(F)c(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Product: CC(C)(C)OC(=O)NCc1cc(F)c(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)c(F)c1
Yield: 48.1 %

Procedure:
3-[4-(tert-butoxycarbonylamino-methyl)-2,6-difluoro-phenoxy]-5-(4-cyano-phenoxy)-benzoic acid (0.6 g, 1.2 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.28 g, 1.3 mmol) and other reagents as described in Example 9(e) were used to afford 0.4 g of the required product. 1H NMR (DMSO-d6): δ 1.24 (4H, m), 1.42 (18H, s), 1.8 (4H, m), 3.18 (1H, m), 3.64 (1H, m), 4.20 (2H, d), 6.74 (1H, d), 7.0 (1H, s), 7.16 (4H, m), 7.24 (1H, s), 7.38 (1H, s), 7.54 (1H, t), 7.88 (2H, d), 36 (1H, d).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1)=[O:28]>>[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:23](=[O:24])[CH2:22][C:20]2[N:21]=[C:17]([C:8]3[CH:7]=[N:6][N:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[C:9]=3[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[S:18][CH:19]=2)=[CH:32][CH:31]=1)(=[O:28])[CH3:26]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: CC(=O)Nc1ccc(N)cc1
Product: CC(=O)Nc1ccc(NC(=O)Cc2csc(-c3cnn(C(C)(C)C)c3-c3ccc(F)cc3)n2)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 4-aminoacetanilide and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28]3)=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:38])[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][NH:27][CH2:28]3)=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cnccc1N1CCC(COc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C=Cc1cnccc1N1CCC(COc2ccc3c(c2)CNCC3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of 3-[4-[4-(2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl)piperidin-1-yl]pyridin-3-yl]-2-propenoic acid ethyl ester (100 mg) in chloroform (1.5 ml) was added trifluoroacetic acid (0.45 ml), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated. To the obtained residue was added aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (70 mg).
Reaction SMILES: [CH:1]([C:4]1[NH:5][CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:8]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:19][Si:20]([CH2:23][CH2:24][O:25][CH2:26]Cl)([CH3:22])[CH3:21]>CN(C=O)C.O>[CH:1]([C:4]1[N:5]([CH2:26][O:25][CH2:24][CH2:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:8]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1c[nH]c(C(C)C)n1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COCC[Si](C)(C)C)c(C(C)C)n1
Temperature: 80 °C

Procedure:
Into a flask containing a solution of methyl 2-isopropyl-1H-imidazole-4-carboxylate (2.7 g, 16.1 mmol) in DMF (20 ml), K2CO3 (5.5 g, 40.2 mmol) and SEM-Cl (3.5 g, 21.0 mmol) were added. The resulting mixture was heated at 80° C. for 18 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The product was purified with flash chromatography. Yield 830 mg. 1H-NMR (400 MHz; CDCl3): δ 0.04 (s, 9H), 0.85-0.89 (m, 2H), 1.28 (d, 6H), 3.15-3.20 (m, 1H), 3.57 (t, 2H), 3.83 (s, 3H), 5.74 (s, 2H), 7.69 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][O:11][CH2:12][C:13]3([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[N:7]([CH2:26][CH:27]3[CH2:29][CH2:28]3)[C:6]=2[CH:30]=1.[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C(C1C=CC(C2C=CC3N(CC4CC4)C(COCC4(C5C=CC=CC=5)CCN(C(OC(C)(C)C)=O)CC4)=NC=3C=2)=CC=1)#N>>[CH:31]1([C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[C:8]([CH2:10][O:11][CH2:12][C:13]4([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]4)[N:7]([CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:6]=3[CH:30]=2)[CH2:33][CH2:32]1
Reactant: CN1CCC(COCc2nc3ccc(Br)cc3n2CC2CC2)(c2ccccc2)CC1
Reactant: OB(O)C1CC1
Agent: CC(C)(C)OC(=O)N1CCC(COCc2nc3cc(-c4ccc(C#N)cc4)ccc3n2CC2CC2)(c2ccccc2)CC1
Product: CN1CCC(COCc2nc3ccc(C4CC4)cc3n2CC2CC2)(c2ccccc2)CC1
Yield: 92 %

Procedure:
Suzuki coupling reaction of 6-Bromo-1-(cyclopropylmethyl)-2-(((1-methyl-4-phenylpiperidin-4-yl)methoxy)methyl)-1H-benzo[d]imidazole (12 mg, 0.026 mmol) with cyclopropylboronic acid (3 equiv.) following the procedure described for the synthesis of tert-butyl 4-(((5-(4-cyanophenyl)-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate, gave 13 mg of the title compound (92% yield). LC/MS (HPLC method 8): tR=0.8 min, 430(MH)+.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:17]=[C:16]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH:21]2[CH3:25])=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)C.[OH-].[Li+].C1COCC1>O>[CH3:14][N:10]([CH2:11][CH2:12][CH3:13])[C:8](=[O:9])[C:7]1[CH:6]=[C:5]([CH:17]=[C:16]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH:21]2[CH3:25])=[O:19])[CH:15]=1)[C:4]([OH:26])=[O:3]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(=O)N2CCCC2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)N2CCCC2C)c1
Yield: 108.3 %

Procedure:
Stir a solution of N-methyl-5-(2-methylpyrrolidine-1-carbonyl)-N-propyl-isophthalamic acid ethyl ester (218 mg, 0.6 mmol), 1 N lithium hydroxide (2.4 mL, 2.4 mmol) and THF (2.4 mL) at room temperature overnight. Add 50 mL water and extract with dichloromethane (3×10 mL). Acidify the aqueous with 1 N HCl (3 mL) and extract with dichloromethane (3×10 mL). Dry (sodium sulfate) and concentrate to give the title compound (216 mg, 100%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([F:19])[C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7]=2[CH:18]=1.C(N(CC)CC)C.[O:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]([F:19])[C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:13][CH2:14][N:15]([CH:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)[CH2:16][CH2:17]3)[C:7]=2[CH:18]=1
Reactant: O=C1CCOCC1
Reactant: O=c1[nH]c2c(F)cc(Cl)cc2n1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1[nH]c2c(F)cc(Cl)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Chloro-4-fluoro-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride D9 (0.36 mmol, 0.1 g) was dissolved in dichloromethane (10 ml) and triethylamine (3 eq., 1.08 mmol, 80 microliters), tetrahydro-4H-pyran-4-one (4.5 eq., 1.62 mmol, 162 mg), sodium triacetoxyborohydride (4.5 eq., 1.62 mmol, 345 mg) were added at room temperature and the mixture was stirred at room temperature for 2 hours. Additional tetrahydro-4H-pyran-4-one (2 eq., 0.72 mmol, 72 microliters) and sodium triacetoxyborohydride (2 eq., 0.72 mmol, 0.015 g) were added at room temperature and the mixture was stirred at room temperature for two further hours. The mixture was quenched with water and brought to pH≈10 by sodium hydroxide (aqueous solution). The organic phase was separated from the aqueous phase (by hydrophobic filters) and the organic solvent was evaporated to afford the crude product that was purified by chromatography (methanol-NH3-dichloromethane) to afford 6-chloro-4-fluoro-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, 15 mg, 11%, M++H=354 and 356, which was converted to the hydrochloride salt using 1M HCl in diethyl ether.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:6]1[C:11]([C:12]([CH2:14][CH2:15][CH2:16]Cl)=[O:13])=[CH:10][CH:9]=[C:8]([Cl:18])[CH:7]=1>CN(C)C=O>[Cl:18][C:8]1[CH:7]=[CH:6][C:11]([C:12](=[O:13])[CH2:14][CH2:15][CH2:16][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:10][CH:9]=1
Reactant: O=C(CCCCl)c1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: O=C(CCCn1ccnc1)c1ccc(Cl)cc1

Procedure:
To a 0° C. slurry of 10.5 g. of imidazole in 15 ml. dry dimethylformamide was added 6.5 g. of γ,p-dichlorobutyrophenone and the mixture was stirred overnight at room temperature then one day at 60° C. The above solution was poured into 400 ml. of water and extracted three times with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and the solvent evaporated to afford 1-[4-(4-chlorophenyl)butan-4-onyl]imidazole, which was used in the next step. This material may be further purified, if necessary, through the nitrate salt.
Reaction SMILES: C=[CH:2][C@@H:3]([CH3:24])[C@@H:4]1[C@:21]2(C)[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2(C)[C:11](=CC(=O)[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.N1C=CC=CC=1.[C:31]([O:34]C(=O)C)(=[O:33])[CH3:32]>C(OCC)(=O)C>[C:31]([O:34][C:19]1[CH:20]=[CH:21][C:7]2[C@@H:6]3[C:11]([C@H:16]4[C@@:3]([CH2:4][CH2:5]3)([CH3:24])[CH:2]=[CH:14][CH2:15]4)=[CH:10][CH2:9][C:8]=2[CH:18]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)CC=C1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Yield: 35.1 %

Procedure:
A solution of estra-1,3,5(10),7,16-pentaen-3-ol (5, 192.1 mg, 0.7612 mmol) in anh. pyridine (2.6 ml, 32 mmol) and acetic anhydride (0.36 ml, 3.8 mmol) was stirred 6 h, after which 30 ml of ethyl acetate were added. The mixture was washed with three 10 ml portions of 1 N hydrochloric acid+10 ml of saturated sodium bicarbonate+10 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. See Example 15. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Preparative TLC (5% ethyl acetate/hexanes on silica gel GF, 1000μ thickness) and recrystallization from aqueous ethanol gave fine white needles (78.6 mg, 0.267 mmol, 35%), m.p. 77-80° C. TLC (4% ethyl acetate/hexanes on silica gel) showed 2 spots at Rf 0.21 and 0.24.
Reaction SMILES: [ClH:1].[CH:2]1([C:5](=[O:33])[CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([SH:20])/[C:16](=[CH:21]/[C:22]3[N:23]=[CH:24][N:25]([CH2:27][C:28]([O:30]CC)=[O:29])[CH:26]=3)/[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[CH2:4][CH2:3]1.O1CCCC1.[OH-].[Na+].Cl>O>[ClH:1].[C:28]([CH2:27][N:25]1[CH:26]=[C:22](/[CH:21]=[C:16]2\[CH2:15][N:14]([CH:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[F:13])[C:5]([CH:2]3[CH2:3][CH2:4]3)=[O:33])[CH2:19][CH2:18][CH:17]\2[SH:20])[N:23]=[CH:24]1)([OH:30])=[O:29]
Reactant: CCOC(=O)Cn1cnc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1cnc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)c1
Yield: 80.9 %

Procedure:
To a solution of (E)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[1-(ethoxycarbonylmethyl)-1H-imidazol-4-yl]methylidene}-4-sulfanylpiperidine hydrochloride (72.6 mg) in a mixed solvent of tetrahydrofuran (2 ml) and water (1 ml) was added 1N aqueous sodium hydroxide solution (0.55 ml) with stirring under ice-cooling, and the resulting mixture was stirred at the same temperature for 3 minutes. To the reaction mixture was added 1N hydrochloric acid solution (1.00 ml). The reaction mixture was concentrated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of methanol and dichloromethane (1:4) as the eluent to afford the title compound (55.4 mg, yield: 80%) as a pale yellow solid.
Reaction SMILES: ClC1C(C2C=CC=C(F)N=2)=CC(N[C@H]2CC[C@H](O)CC2)=NC=1.NC1CCN(C(OC(C)(C)C)=O)CC1.[Cl:37][C:38]1[C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([NH:58][CH:59]3[CH2:64][CH2:63][N:62](C(OC(C)(C)C)=O)[CH2:61][CH2:60]3)[N:53]=2)=[CH:40][C:41]([NH:44][C@H:45]2[CH2:50][CH2:49][C@H:48]([OH:51])[CH2:47][CH2:46]2)=[N:42][CH:43]=1>CS(C)=O>[Cl:37][C:38]1[C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([NH:58][CH:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)[N:53]=2)=[CH:40][C:41]([NH:44][C@H:45]2[CH2:50][CH2:49][C@H:48]([OH:51])[CH2:47][CH2:46]2)=[N:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3cc(N[C@H]4CC[C@H](O)CC4)ncc3Cl)n2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O[C@H]1CC[C@H](Nc2cc(-c3cccc(F)n3)c(Cl)cn2)CC1
Solvent: CS(C)=O
Product: O[C@H]1CC[C@H](Nc2cc(-c3cccc(NC4CCNCC4)n3)c(Cl)cn2)CC1
Temperature: 105 °C
Reaction time: 40 h

Procedure:
A mixture of trans-4-(5′-chloro-6-fluoro-2,4′-bipyridin-2′-yl-amino)cyclohexanol (15.5 mg, 0.048 mmol), DMSO (0.4 ml), and tert-butyl 4-aminopiperidine-1-carboxylate (48.2 mg, 0.241 mmol) reaction mixture was stirred at 105° C. for 40 hr. LCMS indicated formation of the intermediate tert-butyl 4-(5′-chloro-2′-(trans-4-hydroxycyclohexylamino)-2,4′-bipyridin-6-yl-amino)piperidine-1-carboxylate (LCMS (m/z): 502.4 (MH+), retention time=0.70 min.). The Boc protecting group was removed from the intermediate by adding HCL 6M aq (140 μl, 0.840 mmol) to the crude reaction mixture, followed by stirring the mixture at 90° C. for 45 minutes. The reaction mixture was cooled, 0.5 ml of DMSO was added, filtered and purified by prep LC. Lyapholization of the material yielded 9.8 mg of the title compound, as a TFA salt. LCMS (m/z): 402.3 (MH+), retention time=0.41 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.32-1.52 (m, 4H) 1.71-1.87 (m, 2H) 1.96-2.12 (m, 4H) 2.27 (dd, J=14.21, 3.37 Hz, 2H) 3.06-3.18 (m, 2H) 3.39-3.50 (m, 2H) 3.54-3.68 (m, 2H) 4.05-4.17 (m, 1H) 6.72 (d, J=8.50 Hz, 1H) 6.90 (d, J=7.33 Hz, 1H) 7.00 (s, 1H) 7.56-7.64 (m, 1H) 8.01 (s, 1H)
Reaction SMILES: [Br-].[Mg+2].[Br-].[O:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[NH4+].[Cl-:19]>C1COCC1>[Cl:19][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:6][CH2:5][O:4][CH2:9][CH2:8]3)=[CH:17][CH:16]=2)[OH:15])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: [Cl-]
Agent: [Br-]
Agent: [Mg+2]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)c1ccc(N2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 4-fluorophenyl)magnesium bromide (1M in THF, 10.6 ml. 10.6 mmol) at 0° C. was added a solution of 4-morpholinobenzaldehyde (1 g, 5.233 mmol) in THF (10 ml) dropwise. After being stirred at 0° C. for 10 minutes and room temperature for 4 hours, the reaction mixture was poured onto an iced aqueous NH4Cl. The solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated to give (4-chlorophenyl)(4-morpholinophenyl)methanol as a pinkish white solid (1.49 g, 99 yield). HPLC (Column: Shimadzu VP-0DS, C-18 Ballistic; 10-90% aq CH3OH/0.1% H3PO4, same for compounds hereafter unless noted) Rt: 2.117 min.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[CH3:6][O:7][CH2:8][CH:9]=O.C1CCCCC1>O>[CH3:6][O:7][CH2:8][CH:9]1[O:5][CH2:1][CH2:2][CH2:3][O:4]1
Reactant: COCC=O
Reactant: OCCCO
Solvent: O
Solvent: C1CCCCC1
Product: COCC1OCCCO1
Yield: 89 %

Procedure:
A mixture of 380 g (5 moles) of 1,3-propanediol, 479 g (5.5 moles) of 85% strength methoxyacetaldehyde and 250 ml of cyclohexane was heated with 5 g of the ion exchanger Lewasorb® AC 10 (Bayer Aktiengesellschaft) under a water separator until water no longer separated off. The ion exchanger was filtered off, the solvent was stripped off under reduced pressure and the residue was subjected to fractional distillation under reduced pressure. 587 g (89% yield) of 2-methoxymethyl-1,3-dioxane having a boiling range of 104° to 115° C./150 mbar were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:32])[N:10]([C@:12]2([CH3:31])[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14](CC3C=CC=CC=3)[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.ClC(OC(Cl)C)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:32])[N:10]([C@:12]2([CH3:31])[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@]1(C)CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@]1(C)CNC[C@@H]1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 1.65 g (3.64 mmol) rac-[(3R,4S)-1-Benzyl-4-(4-chloro-phenyl)-3-methyl-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester, 0.75 g (5.83 mmol) DIPEA and 0.78 g (5.46 mmol) 1-chloroethyl chloroformate in 40 mL toluene was stirred at room temperature and evaporated to dryness. The residue was taken up in 40 mL methanol and stirred for 2 h at room temperature and evaporated to dryness to yield the crude title compound which was used without further purification in the consecutive step.