Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[NH:8][CH2:7][C@@H:6]([OH:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:17](Cl)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C(Cl)Cl>[OH:9][C@@H:6]1[CH2:7][N:8]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C@@H:3]([CH3:2])[CH2:4][CH2:5]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H]1CC[C@H](O)CN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CC[C@H](O)CN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of ±trans-6-methylpiperidin-3-ol hydrochloride (14.0 g, 0.092 mol) in CH2Cl2 (150 mL) was cooled at 0° C. Triethylamine (51.5 mL, 0.369 mol) was added slowly. CbzCl (13.59 mL, 0.092 mol) was added dropwise, keeping the temperature below 20° C. The reaction was allowed to warm overnight to room temperature. The reaction was quenched by addition of water and diluted further with additional CH2Cl2. The layers were separated and the organics were dried over MgSO4 and concentrated. The crude material was purified by silica gel gradient chromatography (0-75% ethyl acetate in hexanes), providing the titled compound as an oil.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH:10]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([O:17][C:18]2[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=2)[CH:11]=1>>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[CH:2]([O:1][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:12]3[CH:13]=[CH:14][C:15]([OH:16])=[CH:10][CH:11]=3)=[CH:19][CH:20]=1)[CH2:3]2
Reactant: Oc1ccc(Oc2ccc(O)cc2)cc1
Reactant: OC1CN2CCC1CC2
Product: Oc1ccc(Oc2ccc(OC3CN4CCC3CC4)cc2)cc1

Procedure:
3-Hydroxy quinuclidine (Aldrich, 254 mg, 2 mmol) was treated with 4,4′-dihydroxydiphenyl ether (TCl, 202 mg, 1 mmol) according to the procedure of Example 1A. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3 H2O, 90:10:1, Rf. 0.2) as oil (210 mg, yield, 68%). 1H NMR (MeOH-d4, 300 MHz) δ 1.40–1.55 (m, 1H), 1.60–1.87 (m, 2H), 1.98–2.15 (m, 1H), 2.20–2.25 (m, 1H), 2.75–2.98 (m, 5H), 3.20–3.30 (m, 1H), 4.45(m, 1H), 6.62–6.96 (m, 8(DCl/NH3) m/z 312 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=[O:27])[CH3:26]>>[C:25]([N:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[C:29]1=[O:33])(=[O:27])[CH3:26]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4nc(C)c(C)cc4C)CC3)cc2)C1=O
Yield: 87 %

Procedure:
Using (4-iodophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (1.31 g) described in Preparation Example 120 and 1-acetylimidazolidin-2-one (461 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (1.14 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:17]=[N:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=2[S:26]([OH:29])(=[O:28])=[O:27])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([OH:15])(=[O:14])=[O:13])[CH:6]=[C:5]2[OH:16].[Na:30][Na:31].[OH-].[Na+].[N+:34]([C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1)([O-:36])=[O:35]>CCOCC.C(O)(=O)C>[NH2:1][C:2]1[C:3]([N:17]=[N:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:41](=[O:42])[C:40]3[CH:39]=[CH:38][C:37]([N+:34]([O-:36])=[O:35])=[CH:45][CH:44]=3)=[CH:21][C:20]=2[S:26]([OH:29])(=[O:28])=[O:27])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([OH:15])(=[O:14])=[O:13])[CH:6]=[C:5]2[OH:16].[Na:30][Na:31]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(N=Nc2c(N)ccc3cc(S(=O)(=O)O)cc(O)c23)c(S(=O)(=O)O)c1
Agent: [Na+]
Agent: [Na][Na]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: Nc1ccc2cc(S(=O)(=O)O)cc(O)c2c1N=Nc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc1S(=O)(=O)O
Reaction time: 0.06 h

Procedure:
A solution of 2.0 g of 6-amino-5-(4-amino-2-sulfophenylazo)-4-hydroxy-2-naphthalenesulfonic acid, disodium salt in 14.0 ml of N sodium hydroxide is treated with 2.0 g of p-nitrobenzoyl chloride and a few drops of ether. The reaction mixture is shaken for 3 to 4 minutes and then another 7 ml portion of base is added to the reaction mixture. After shaking for 15 minutes the procedure is repeated with an additional 7 ml portion of base. Finally the reaction mixture is acidified with 2 ml of glacial acetic acid, and extracted several times with ether. After the ethereal layer is separated the aqueous phase is salted with 20 g of sodium acetate trihydrate at 55° C with stirring. The reaction mixture is filtered after standing overnight at room temperature and washed with absolute ethanol and ether to give 6-amino-4-hydroxy-5-[4-(p-nitrobenzamido)-2-sulfophenylazo]-2-naphthalenesulfonic acid, disodium salt.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7](S)=[CH:6][CH:5]=1.Br[CH2:12][S:13]([NH2:16])(=O)=[O:14].C(OCC)(=O)C.C[S:24](C)=O>>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:12][S:13]([NH2:16])(=[S:24])=[O:14])=[CH:6][CH:5]=1
Reactant: NS(=O)(=O)CBr
Reactant: Sc1ccc(Br)cc1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NS(=O)(=S)Cc1ccc(Br)cc1
Temperature: 80 °C
Yield: 81.4 %

Procedure:
A suspension of 1.4 g of a 60% sodium hydride/oil dispersion was prepared in 10 ml of dry DMSO, under an atmosphere of nitrogen. 4-Bromothiophenol (6.5 g) was dissolved in 11 ml of dry DMSO and added slowly to the above suspension. When frothing had subsided 6.0 g of bromomethanesulfonamide was added and the reaction mixture was heated to 80° C. for 2 hours. The reaction mixture was cooled to room temperature and poured into 150 ml of ethyl acetate, filtered from a solid and extracted with brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The resultant residue was recrystallized from toluene to yield 7.9 g (81.4%) of product.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([CH2:8][C@H:9]([N:13]([C:15](OCC1C=CC=CC=1)=O)C)[C:10](O)=[O:11])=[O:7])([CH3:4])[CH3:3].C1CC[CH:28]([NH:31]C2CCCCC2)CC1.[CH2:38](CN)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[ClH:47].CO>>[ClH:47].[C:2]([O:5][C:6](=[O:7])[CH2:8][C@H:9]([NH:13][CH3:15])[C:10]([N:31]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH3:28])=[O:11])([CH3:4])([CH3:3])[CH3:1]
Reactant: NCCc1ccccc1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: CN(C(=O)OCc1ccccc1)[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CO
Product: CN[C@@H](CC(=O)OC(C)(C)C)C(=O)N(C)Cc1ccccc1

Procedure:
Z-N-Me-Asp(OtBu)—OH DCHA salt (1:1) and N-Benzylmethylamine according to 1.2., followed by deprotection (6.1.) and treatment with HCl/MeOH to give (S)-N-Benzyl-N-methyl-3-methylamino-succinamic acid tert-butyl ester-HCl, MS: 307 (MH+)
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17].[NH:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20]([O:22][CH3:23])=[O:21].[K].O>CN(C)C=O>[C:27]([O:26][C:24]([N:19]([CH2:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17])[C:20]([O:22][CH3:23])=[O:21])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N(Cc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-])C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of tert-butyl 4-bromomethyl-3-nitrobenzoate (2.27 g, 7.2 mmol) (Int. J. Peptide Res. 1990, 36, 31) in dimethylformamide (25 mL) was added a suspension of potassium tert-butyl methyl iminodicarboxylate (J.C.S. Perkin I 1977, 1088-90) (1.56 g, 7.3 mmol) in dimethylformamide (20 mL). The dark brown solution was stirred 1 h and poured into water (400 mL), extracted with ethyl acetate (3×100 mL) and the combined organic layers were washed with water (5×75 mL), dried (sodium sulfate) and concentrated to give a pale orange oil which was purified by flash chromatography on silica gel (20% ethyl acetate/hexane) to give the title compound (2.15 g, 73%): 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.2 (d, 1H), 7.45 (d, 1H), 5.3 (s, 2H), 3.8 (s, 3H), 1.6 (s, 9H), 1.45 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[N:10]([CH2:21][CH2:22][OH:23])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][CH:18]=[CH:17]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH2:1]([O:8][C:9]([N:10]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][CH:18]=[CH:17]2)[CH2:21][CH2:22][O:23][S:33]([CH3:32])(=[O:35])=[O:34])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N(CCO)Cc1cccc2cc[nH]c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN(Cc1cccc2cc[nH]c12)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a solution of (2-hydroxy-ethyl)-(1H-indol-7-ylmethyl)-carbamic acid benzyl ester (2.79 g, 8.61 mmol) in dichloromethane (50 mL) was added triethylamine (1.56 mL, 11.2 mmol). The mixture was cooled to 0° C. and methanesulfonyl chloride (0.74 mL, 9.47 mmol) added in a dropwise manner. The mixture was warmed to room temperature and allowed to stir for 2 hours. The mixture was then quenched with water (30 mL) and 1.0 M sodium hydroxide (10 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (20 mL). The combined extracts were washed with 1.0 M hydrochloric acid (20 mL), water (30 mL), dried over anhydrous sodium sulfate and evaporated to dryness. Methanesulfonic acid 2-[benzyloxycarbonyl-(1H-indol-7-ylmethyl)-amino]-ethyl ester (3.46 g) was obtained as an oil
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][CH2:9][C:10](=O)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])(=O)C.[NH4+:22].[Cl:23][C:24]1[CH:38]=[CH:37][CH:36]=[CH:35][C:25]=1[CH:26]=[C:27]([C:32]([CH3:34])=O)[C:28]([O:30][CH3:31])=[O:29]>C(O)C>[Cl:23][C:24]1[CH:38]=[CH:37][CH:36]=[CH:35][C:25]=1[CH:26]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:32]([CH3:34])[NH:22][C:10]([CH2:9][O:8][CH2:7][C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: COC(=O)C(=Cc1ccccc1Cl)C(C)=O
Reactant: [NH4+]
Reactant: CCOC(=O)CC(=O)COCc1nccn1C
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)C1=C(COCc2nccn2C)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reaction time: 4 h
Yield: 4.4 %

Procedure:
Ethyl 4-(1-methyl-2-imidazolylmethoxy)acetoacetate (crude, 12 g) and ammonium acetate (4 g) in ethanol (40 ml) were heated gently under reflux for 20 minutes. Then methyl 2-(2-chlorobenzylidene)acetoacetate (13 g) was added and heating under reflux was continued for 4 hours. The cooled reaction mixture was evaporated to dryness and the residue dissolved in toluene (150 ml) and washed with 10% sodium hydroxide solution to remove acetic acid. The toluene solution was extracted with 2N hydrochloric acid (150 ml and 50 ml), the combined acid extracts washed with fresh toluene (50 ml) and the pH of the aqueous solution was adjusted to 3-4 with aqueous sodium carbonate. The aqueous solution was extracted with ethyl acetate (2×200 ml). These extracts were dried (Na2CO3) and the solution was filtered and evaporated to dryness. The residue, in a little toluene, was chromatographed on silica (t.l.c. grade, 17 g), eluting with petrol plus 30% v/v methylene chloride initially, changing gradually to 100% methylene chloride. Appropriate fractions were combined, evaporated, and the residue crystallized from diethyl ether plus a little petrol. Recrystallisation from ethyl acetate and petrol (1:1) gave the title compound (1 g), m.p. 137°-8° C.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=1.S(Cl)([Cl:15])=O>>[Cl:15][CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=1
Reactant: Cn1c(CO)nc2ccccc21
Reactant: O=S(Cl)Cl
Product: Cn1c(CCl)nc2ccccc21
Yield: 36 %

Procedure:
A solution of 2-hydroxymethyl-1-methylbenzimidazole (1.1 g, 6.7 mmol) in thionyl chloride (10 ml) was stirred at ambient temperature for 15 minutes and then heated at reflux for 15 minutes. The volatiles were removed by evaporation and the residue purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 2-chloromethyl-1-methylbenzimidazole (506 mg, 36%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14].CCCCCC>C1COCC1>[CH2:20]([Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
Thiophene (2.0 g, 12 mmol) was dissolved in anhydrous THF (20 mL) and n-BuLi (9.52 mL, 23.8 mmol, 2.5 M in hexane) slowly added at −30° C. under nitrogen flow. After stirring for 1 hour, tributyltin chloride (7.75 mL, 23.8 mmol) was added. After heating to room temperature, followed by stirring for 3 hours, the reaction was terminated. The produced compound was extracted with n-hexane and distilled water, dried with anhydrous MgSO4 and filtered under reduced pressure. The final product tributyl-2-thienylstannane (2.5 g, yield: 46%) was obtained by column chromatography (neutral alumina, n-hexane). The product was used in the next step after removing the solvent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:18])([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:10](O)=[O:11])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:22])=O.CN(C)C=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:18])([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:10]([Cl:22])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)(CCC(C)C)C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(C)(CCC(C)C)C(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution of Example 155C (8.52 g, 0.034 mol) in 200 mL anhydrous dichloromethane was added 2 N oxalyl chloride in dichloromethane (26 mL, 0.052 mol) and drops of dimethylforamide. The solution was stirred for 30 minutes at 0° C. and then room temperature for 2 hours. The solvent was removed under vacuum and the crude product used directly.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O>C(Cl)Cl>[CH2:5]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][Br:2])=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: BrP(Br)Br
Reactant: CCCCCCCCCCCCOc1ccc(CO)cc1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
A solution of PBr3 (2.0 mL, 20 mmol) in anhydrous CH2Cl2 (25 mL) was added slowly to a stirred solution of 4-(dodecyloxy)benzyl alcohol (3.0 g, 10 mmol) in CH2Cl2 (50 mL) at 0° C. The reaction mixture was stirred for 3 h at room temperature and slowly poured into a large amount of water (ca. 600 mL). The product was extracted with CHCl3 (3×50 mL). The combined organic phase was washed with brine (3×20 mL), dried over anhydrous Na2 SO4, and concentrated in vacuo to give a yellow solid (3.01 g, 90%). 1H NMR (300 MHz, CDCl3, δ): 7.32 (d, J=6.6 Hz, 2H), 6.86 (d, J=6.6 Hz, 2H), 4.50 (s, 2H), 3.97 (t, J=6.6 Hz, 2H), 4.05-4.00 (m, 6H), 1.79-1.72 (m, 2H), 1.45-1.21 (m, 12H), 0.90 (t, J=6.3 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][C:26]=1[N+:34]([O-:36])=[O:35]>C1COCC1.O>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:11]=[C:10]3[C:5]([N:6]=[CH:7][C:8]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:9]3)=[CH:4][CH:3]=2)=[CH:27][C:26]=1[N+:34]([O-:36])=[O:35]
Reactant: O=[N+]([O-])c1cc(B(O)O)ccc1F
Reactant: Brc1ccc2ncc(N3CCOCC3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(-c2ccc3ncc(N4CCOCC4)nc3c2)ccc1F
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To a suspension of 7-bromo-2-morpholin-4-yl-quinoxaline (1 g, 3.4 mmol), potassium carbonate (0.56 g, 4.1 mmol) and [1,1,-Bis(diphenlyphosphino)ferrocene]palladium(II)chloride (0.83 g, 1.0 mmol) in THF (38 mL) and water (3.8 mL) was added (4-fluoro-3-nitrophenyl)boronic acid (1.26 g, 6.8 mmol). The reaction mixture was allowed to reflux for 6 h. After cooling to room temperature, the solvent was removed and the residue was purified by chromatography (silica gel, Hexane/EtOAc: 20%->100% EtOAc) giving rise to 1.1 g (92%) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10](Cl)(Cl)Cl)[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH3:19])[C:6]=2[CH:20]=1.[CH3:21][CH:22]([CH3:46])[CH2:23][NH:24][C@H:25]1[CH2:30][C@@H:29]([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:28][N:27]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:26]1.C(=O)([O-])[O-:48].[K+].[K+]>C(#N)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]([N:24]([CH2:23][CH:22]([CH3:46])[CH3:21])[C@H:25]3[CH2:30][C@@H:29]([C:31]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[O:32])[CH2:28][N:27]([C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[CH2:26]3)=[O:48])[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH3:19])[C:6]=2[CH:20]=1
Reactant: O=C([O-])[O-]
Reactant: COCCCCn1c(C(Cl)(Cl)Cl)nc2ccc(F)cc21
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccc(F)cc21
Temperature: 60 °C
Reaction time: 17 h
Yield: 32.1 %

Procedure:
6-Fluoro-1-(4-methoxybutyl)-2-(trichloromethyl)-1H-benzimidazole (1.02 g) and tert-butyl (3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (1.11 g) were dissolved in acetonitrile (50 ml) and water (25 ml), potassium carbonate (4.15 g) was added, and the mixture was stirred at 60° C. for 17 hr. The reaction mixture was cooled to room temperature, and the mixture was extracted with ethyl acetate. The extract was washed successively with 10% aqueous citric acid solution, aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (595 mg).
Reaction SMILES: [OH:1][C:2]1([CH2:10][O:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]4[CH:40]=[CH:39][C:30]5[C@H:31]([CH2:34][C:35]([O:37]C)=[O:36])[CH2:32][O:33][C:29]=5[CH:28]=4)[CH:20]=3)=[C:14]([CH3:41])[CH:13]=2)[CH2:7][CH2:6][S:5](=[O:9])(=[O:8])[CH2:4][CH2:3]1.CO.[OH-].[Na+].Cl>O.O1CCCC1>[OH:1][C:2]1([CH2:10][O:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]4[CH:40]=[CH:39][C:30]5[C@H:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:32][O:33][C:29]=5[CH:28]=4)[CH:20]=3)=[C:14]([CH3:41])[CH:13]=2)[CH2:3][CH2:4][S:5](=[O:8])(=[O:9])[CH2:6][CH2:7]1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OCC5(O)CCS(=O)(=O)CC5)cc4C)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(OCC2(O)CCS(=O)(=O)CC2)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a solution of methyl [(3S)-6-({4′-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate (0.482 g, 0.830 mmol) in a mixed solvent of methanol (2 mL) and tetrahydrofuran (4 mL) was added 2 M aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was diluted with water, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were recrystallized from heptane-ethyl acetate to give the title compound (0.358 g, yield 76%) as colorless crystals.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[C:9]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH:10]=[C:11]([F:13])[CH:12]=1>O>[F:13][C:11]1[CH:10]=[C:9]2[C:8](=[C:7]([F:6])[CH:12]=1)[C:17](=[O:19])[CH2:16][CH2:15][CH2:14]2
Reactant: O=C(O)CCCc1cc(F)cc(F)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CCCc2cc(F)cc(F)c21
Temperature: 45 °C
Yield: 64.4 %

Procedure:
A mixture of concentrate sulfuric acid (10.21 kg) and crude 4-(3,5-difluoro-phenyl)-butyric acid (2.8 kg) was stirred at 45° C. until the cyclization reaction was complete by HPLC. The reaction mixture was diluted with water (6.15 kg), and the product was extracted with THF/methylene chloride (2.71/7.33 kg) mixture. The organic layer was sequentially washed with water (4 liters), saturated aqueous sodium bicarbonate (2.64 kg), water (3.0 kg) and 50% diluted brine (8.4 kg). Removal of the solvents provided 1.64 kg (62% yield) of 6,8-difluoro-3,4-dihydro-2H-naphthalen-1-one as a light yellow solid (92.75% pure by HPLC): MP=58.1-58.8° C.; MS (M+1)=183; H1 NMR (300 MHz): δ(DMSO): 2.00 (2H, p, J=6.4 Hz), 2.57 (2H, t, J=6.40 Hz), 2.96 (2H, t, J=6.40 Hz), 7.08-7.20 (2H, m, J=2.26 Hz).
Reaction SMILES: [NH:1]1[CH:5]([C:6]([OH:8])=[O:7])[CH2:4][C:3]2([CH2:13][CH:12]3[CH2:14][CH:9]2[CH2:10][CH2:11]3)[CH2:2]1.S(Cl)([Cl:17])=O.[CH2:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[ClH:17].[NH:1]1[CH:5]([C:6]([O:8][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:7])[CH2:4][C:3]2([CH2:13][CH:12]3[CH2:14][CH:9]2[CH2:10][CH2:11]3)[CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CC2(CN1)CC1CCC2C1
Reactant: OCc1ccccc1
Product: Cl
Product: O=C(OCc1ccccc1)C1CC2(CN1)CC1CCC2C1

Procedure:
4.3 g of spiro[bicyclo[2.2.1]heptane-2,3'-pyrrolidine]-5'-carboxylic acid are esterified with 43 ml of thionyl chloride and 43 ml of benzyl alcohol is analogy to the procedure described in Example 6, yield 6.7 g,
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([O:9]C)=O)=[N:3]1.[NH3:11].O>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([NH2:11])=[O:9])=[N:3]1
Reactant: COC(=O)c1ccn(C)n1
Reactant: N
Solvent: O
Product: Cn1ccc(C(N)=O)n1

Procedure:
A solution of methyl 1-methyl-1H-pyrazole-3-carboxylate (1.1 g, 7.9 mmol) in NH3.H2O (10 mL) was stirred for 2 h at room temperature. The solvent was evaporated to give the crude product which was used for the next step without further purification.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:18]([OH:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].[O:34]1CC[CH2:36][CH2:35]1>>[CH3:28][C:27]([O:19][C@@H:18]1[C@@:2]2([CH3:1])[CH2:3][CH2:4][C@@H:5]3[C:6]4[CH:7]=[CH:8][C:9]([O:20][C:35]([CH3:36])=[O:34])=[CH:10][C:11]=4[CH2:12][CH2:13][C@H:14]3[C@@H:15]2[CH2:16][CH2:17]1)=[O:29]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12

Procedure:
Estradiol (50 g), pyridine (90 g), and dry tetrahydrofuran (400 ml) were placed in a four-neck flask (1 liter). Then, acetic anhydride (94 g) was added thereto and the mixture was refluxed for 6 hours under stirring. The pyridine in the solution was concentrated to about ≠ volume. Then, ethyl acetate (400 ml) and distilled water (300 ml) were added, and the mixture was shaken for extraction. The organic layer was washed two times with equal volumes of distilled water. The organic layer was dried over magnesium sulfate, and then dried under reduced pressure to obtain white crystals (estradiol-3,17β-diacetate; 64.1 g).