Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([F:26])=[C:4]2[O:9][CH2:8][C:7]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[N:6]3[CH:14]=[C:15]([C:23]([OH:25])=[O:24])[C:16](=[O:22])[C:17]([C:18]=1[N+:19]([O-])=O)=[C:5]23.CN(C=O)C>C(O)C.C(O)(=O)C.[Pd]>[NH2:19][C:18]1[C:17]2[C:16](=[O:22])[C:15]([C:23]([OH:25])=[O:24])=[CH:14][N:6]3[C:7]4([CH2:13][CH2:12][CH2:11][CH2:10]4)[CH2:8][O:9][C:4]([C:5]=23)=[C:3]([F:26])[C:2]=1[F:1]
Reactant: O=C(O)c1cn2c3c(c(F)c(F)c([N+](=O)[O-])c3c1=O)OCC21CCCC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3C1(CCCC1)CO2
Yield: 84748.2 %

Procedure:
A solution of 9′,10′-difluoro-8′-nitro-7′-oxospiro[cyclopentane-1,3′ (2′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylic acid (3.9 g, 0.01 mmol) in ethanol/acetic acid (1:1, v/v, 100 mL) was hydrogenated under atmospheric pressure over 10% Pd/C (390 mg) at 80° C. for 18 h. Then 200 mL of DMF were added and the reaction mixture was heated until it became clear. The catalyst was removed by filtration over Celite, which was washed two times with hot DMF and the combined filtrates were concentrated in vacuo to dryness to yield the title compound (2.85 g, 73%) which was used crude in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]([O-])([O-])=O.[K+].[K+].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[C:10]([Cl:11])[C:2]=1[NH2:1]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(=O)O)c(N)c1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(Cl)c1N
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a stirred solution of compound 104d (1.9 g, 9.6 mmol) in dry DMF (25 mL) was added K2CO3 (1.32 g, 9.6 mmol) at room temperature. The reaction mixture was stirred for 30 min and methyl iodide (0.77 mL, 12.4 mmol) was added. After 2 hrs at room temperature, 5% aqueous citric acid was added. The mixture was extracted with EtOAc. Organics were washed with water, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by chromatography on silica gel (petroleum ether/EtOAc) to yield compound 105d as beige solid in 50% yield.
Reaction SMILES: B(F)(F)F.[CH3:5][CH2:6]OCC.CO[CH:12]([O:21][CH3:22])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20].[CH2:23]([O:25][P:26]([O:30]CC)[O:27]CC)[CH3:24]>C(Cl)Cl>[PH:26](=[O:25])([OH:30])[OH:27].[CH2:5]([C:12]([CH2:23][CH3:24])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20])[O:21][CH3:22])[CH3:6]
Reactant: CCOP(OCC)OCC
Reactant: CCOCC
Reactant: COC(OC)c1ccc(F)cc1F
Agent: FB(F)F
Solvent: ClCCl
Product: CCC(CC)(OC)c1ccc(F)cc1F
Product: O=[PH](O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Boron trifluoride etherate (56 ml) was added dropwise to a solution of 2,4-difluorobenzaldehyde dimethyl acetal (79 g) and triethylphosphite (73.5 g) in DCM (11) at -25° C. The mixture was stirred at ambient temperature for 16 hours. The organic solution was washed with H2 and brine and dried over MgSO4. The solvent was removed to leave an oil (~160 g). Purification by flash chromatography on silica gel column (elution with 40% heptane: 60% DCM, with DCM, followed by ethyl acetate: DCM) provided 107 g of an oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C([O-])([O-])=O.[K+].[K+].C[N:18](C=O)C.Br[CH2:23][CH2:24][CH2:25][Cl:26]>O>[Cl:26][CH2:25][CH2:24][CH2:23][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][C:9]([NH2:18])=[N:10][C:2]=2[Cl:1]
Reactant: CN(C)C=O
Reactant: ClCCCBr
Reactant: Clc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1nc(Cl)c2ncn(CCCCl)c2n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 36.1 %

Procedure:
To a stirred suspension of 6-chloropurine (5.0 g, 29.48 mmol) and K2CO3 (4.48 g, 32.42 mmol) in dry DMF 1-bromo-3-chloropropane (13.92 g, 88.45 mmol) is added. The reaction mixture is heated to 50° C. for 1 min and stirred at room temperature for additional 3 h. The reaction mixture is poured into 120 mL of water and extracted with CH2Cl2. The combined organic phases are washed with water, dried over MgSO4 and evaporated in vacuo. The residue is purified by flash column chromatography (dichloromethane/methanol 50:1 to 10:1) to yield 2.6 g (10.65 mmol, 35%) of the title compound as a colorless solid. 1H-NMR (400 MHz, DMSO-d6): δ=8.11 (s, 1H, H-8), 6.91 (s, 2H, NH2), 4.16 (t, J=6.8, 2H, CH2), 3.63 (t, J=6.8, 2H CH2), 2.25 (m, 2H, CH2) ppm. MS (ESI) m/z 247.3 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[C:17]([O:21][C:22](=[O:28])[NH:23][S:24](Cl)(=[O:26])=[O:25])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:17]([O:21][C:22](=[O:28])[NH:23][S:24](=[O:26])(=[O:25])[NH:2][CH2:3][CH2:4][O:5][N:6]1[C:7](=[O:16])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]1=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: NCCON1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 74.6 %

Procedure:
To a mixture of 2-(2-aminoethoxy)-1H-isoindole-1,3(2H)-dione hydrochloride 75 (0.53 g, 2.19 mmol, EP 16744522 A1, 2006), tert-butyl(chlorosulfonyl)carbamate 76 (0.71 g, 3.28 mmol, WO 2006/84281 A1) in DCM (10 mL) was added triethylamine (0.92 mL, 6.57 mmol) slowly at 0° C. The resulting mixture was stirred at room temperature for 7 h and concentrated to provide a residue which was subjected to chromatography to give 77 (0.63 g, 74%) as a white foam.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[C:7]([NH:10][C:11]1[S:12][C:13]([S:17](Cl)(=[O:19])=[O:18])=[C:14]([CH3:16])[N:15]=1)(=[O:9])[CH3:8].C(N(CC)CC)C>C1COCC1>[OH:4][CH2:3][CH:2]([NH:1][S:17]([C:13]1[S:12][C:11]([NH:10][C:7](=[O:9])[CH3:8])=[N:15][C:14]=1[CH3:16])(=[O:18])=[O:19])[CH2:5][OH:6]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: NC(CO)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)NC(CO)CO)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 60.1 %

Procedure:
To a stirred solution of 2-amino-1,3-propanediol (2.15 g, 23.6 mmol) in THF (26 ml) was added at 0° C. (ice water bath) commercially available 2-acetamido-4-methylthiazole-5-sulfonyl chloride (2.0 g, 7.85 mmol) and triethylamine (1.2 ml, 8.64 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by column chromatography on silica gel (dichloromethane/MeOH/NH4OH 80:10:1) to yield 2-acetamido-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide (1.46 g, 60%) as a light yellow solid. MS (ISP) 308.1 [(M−H)−]; mp 217° C.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[C:13]([O:15][CH3:16])=[O:14])(=O)=O.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.O>[N:17]([CH2:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[C:13]([O:15][CH3:16])=[O:14])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@@H]1CCCC[C@H]1COS(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCC[C@H]1CN=[N+]=[N-]
Temperature: 100 °C
Yield: 99.6 %

Procedure:
To a solution of (trans)-methyl 2-((methylsulfonyloxy)methyl)cyclohexanecarboxylate (1.4 g, 5.6 mmol) in DMF (6 mL) was added NaN3 (0.730 g, 11.0 mmol). The mixture was heated at about 100° C. for about 3 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (2×45 mL). The combined organic layers were washed with aqueous 1 N NaOH (1×40 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give (trans)-methyl 2-(azidomethyl)cyclohexanecarboxylate (1.1 g, 100%.): 1H NMR (400 MHz, CDCL3) δ 3.69 (d, J=6.0, 3H), 3.28-3.15 (m, 2H), 2.24-2.14 (m, 1H), 1.97-1.73 (m, 5H), 1.46 (dd, J=12.2, 3.2, 1H), 1.36-1.05 (m, 3H).
Reaction SMILES: C(N=C=NCCCN(C)C)C.[O:12]=[C:13]1[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15][N:14]1[CH2:30][C:31]([OH:33])=O.Cl.Cl.[F:36][C:37]([F:53])([F:52])[C:38]1[CH:39]=[C:40]([CH:44]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH3:45])[CH:41]=[CH:42][CH:43]=1>ClCCl>[O:33]=[C:31]([N:49]1[CH2:48][CH2:47][N:46]([CH:44]([C:40]2[CH:41]=[CH:42][CH:43]=[C:38]([C:37]([F:52])([F:53])[F:36])[CH:39]=2)[CH3:45])[CH2:51][CH2:50]1)[CH2:30][N:14]1[CH2:15][CH2:16][C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:13]1=[O:12]
Reactant: CC(c1cccc(C(F)(F)F)c1)N1CCNCC1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(c1cccc(C(F)(F)F)c1)N1CCN(C(=O)CN2CCC(c3ccccc3)(c3ccccc3)C2=O)CC1
Reaction time: 8 h

Procedure:
A solution of N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.074 mL, 0.416 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.058 g, 0.198 mmol) and the product from Example 44B (0.066 g, 0.198 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.40-7.56 (m, 4H), 7.20-7.37 (m, 10H), 4.10-4.22 (m, 2H), 3.52-3.63 (m, 2H), 3.50 (t, J=6.6 Hz, 2H), 3.34-3.43 (m, 3H), 2.80 (t, J=6.5 Hz, 2H), 2.43-2.51 (m, 1H), 2.16-2.36 (m, 3H), 1.33 (d, J=6.7 Hz, 3H); MS (ESI+) m/z 536 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:14])[C@@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:5].NC[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C.C(=O)(O)[O-].[Na+].[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40](Cl)(=[O:42])=[O:41]>ClCCl.O>[OH:14][C@@H:3]([CH2:2][NH:1][S:40]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=1)(=[O:42])=[O:41])[C@@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH3:5]
Reactant: C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: C[C@H](NC(=O)OC(C)(C)C)[C@H](O)CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNS(=O)(=O)c1ccccn1
Temperature: 0 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
To a solution of 3.06 g (15.0 mmol) of tert-butyl (1S,2S)-3-amino-2-hydroxy-1-methylpropylcarbamate & tert-butyl (1S,2R)-3-amino-2-hydroxy-1-methylpropylcarbamate in 100 mL of dichloromethane was added 3.78 g (45.0 mmol) of sodium bicarbonate and 50 mL of water. The reaction mixture was cooled to 0° C. and 16.5 mL (16.5 mmol) of a 1.0 M solution of 2-pyridinesulfonyl chloride in dichloromethane was added gradually over 20 min. The reaction mixture was stirred at room temperature for 16 h. The layers were then separated and the organic layer was dried over anhydrous magnesium sulfate, and concentrated under vacuum to afford the crude product. This product was purified via silica gel chromatography eluting with ethyl acetate:hexane (8:2) to afford 2.0 g (34%) of tert-butyl (1S,2S)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate & tert-butyl (1S,2R)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate as a pale yellow oil. 1H-NMR (300 MHz, CDCl3): δ 8.72 (m, 1H), 8.07–7.92 (m, 2H), 7.51 (m, 1H), 6.25, 6.08 (2br s, 1H), 4.83-4.64 (m, 2H), 3.74–3.47 (m, 3H), 3.27–3.19 (m, 1H), 1.23, 1.22 (2s, 9H), 1.12 (m, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][C@H:9]2[NH2:15])=[O:5].C[O:17][C:18](=O)[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:26]Br.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:25][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:19]=1[C:18](=[O:17])[N:15]([C@H:9]1[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([C:4]([O:3][CH3:2])=[O:5])[CH:7]=3)[CH2:11][CH2:10]1)[CH2:26]2
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Reactant: COC(=O)c1c(Cl)cccc1CBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)[C@H](N1Cc3cccc(Cl)c3C1=O)CC2

Procedure:
(3R)-3-Amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-01) (1.757 mmol, 1 eq) was added to a solution of 2-bromomethyl-6-chlorobenzoic acid methyl ester (1 eq) in toluene (5.4 ml) and triethylamine (2.1 eq). The reaction mixture was refluxed for 16 h. Then sat. NaHCO3 solution (20 ml) and ethyl acetate (50 ml) were added to the mixture and the phases were separated. The organic phase was extracted with 0.05 N HCl solution and sat. NaCl solution and dried over MgSO4. Concentration of the organic phase yielded the crude product, which was purified by column chromatography (ethyl acetate:cyclohexane, 3:1). The desired product (R)-methyl 3-(7-chloro-1-oxoisoindolin-2-yl)-2,3-dihydro-1H-indene-5-carboxylate (D-01) was thus obtained. Yield: 72%
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:10])[CH2:8][CH3:9].Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[O:19]>CN(C)C=O>[CH2:7]([S:10][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[O:19])[CH2:8][CH3:9]
Reactant: CCCS
Reactant: O=C(c1cccs1)c1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1ccccc1C(=O)c1cccs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a cloudy solution of 400 mL of dry dimethylformamide containing 224 g or potassium-t-butoxide, cooled to 0° under a nitrogen atmosphere, was added 18 mL of n-propanethiol dropwise at such a rate to maintain the temperature below 5° C. The resulting mixture was stirred for 5 minutes and then a solution of 44 g of the product of Example 1 dissolved in 100 mL of dimethylformamide was added. The reaction mixture was stirred for 24 hours at room temperature, poured into 2 L of ice-water and extracted with methylene chloride. The organic layer was separated, washed with 1N NaOH (aq), water, and dried (MgSO4). Filtration, followed by concentration of the filtrate in vacuo gave a dark residue which after column chromatography on silica (methylene chloride as eluant) provided 40 g of the subject compound as a red oil.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][C:6]3([CH2:13][N:14]4[CH:18]=[CH:17][CH:16]=[N:15]4)[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([O:19][CH2:20][CH2:21][OH:22])([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH2:23]([Li])CCC.IC>O1CCCC1>[CH3:11][C:8]12[CH2:7][C:6]3([CH2:13][N:14]4[C:18]([CH3:23])=[CH:17][CH:16]=[N:15]4)[CH2:12][C:2]([CH3:1])([CH2:3][C:4]([O:19][CH2:20][CH2:21][OH:22])([CH2:5]3)[CH2:10]1)[CH2:9]2
Reactant: CC12CC3(C)CC(Cn4cccn4)(C1)CC(OCCO)(C2)C3
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccnn1CC12CC3(C)CC(C)(C1)CC(OCCO)(C3)C2
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a cold (−78° C.) solution of the 2-{[3,5-dimethyl-7-(1H-pyrazol-1-ylmethyl)tricyclo[3.3.1.13,7]dec-1-yl]oxy}ethanol (3.69 g) in tetrahydrofuran (50 mL) was added n-butyllithium (20 mL, 2.5 M in hexane) under nitrogen. The mixture was stirred at −78° C. for 1.5 hours. Iodomethane (10 mL) was added by syringe, and the mixture was stirred for an additional 3 hours. The reaction mixture was then quenched by the addition of aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried with sodium sulfate, filtered and concentrated. The residue was purified by normal phase chromatography to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:11])=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:13]1(Br)[NH:18][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:15]=[CH:14]1.[C:26](=[O:29])([O-])[O-].[Na+].[Na+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:11][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:21]1[N:20]=[C:19]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:26]=3[OH:29])[N:18]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: BrC1(Br)C=CC=C(c2ccccn2)N1
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1cccc(F)c1O
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Oc1c(F)cccc1-c1cccc(-c2cccc(-c3cccc(F)c3O)n2)n1
Yield: 39 %

Procedure:
6,6′-bis(2-Hydroxy-3-fluorophenyl)-2,2′-bipyridine was prepared by reaction of 3-fluoro-2-hydroxyphenylboronic acid (600 mg, 3.84 mmol) with 6,6-dibromo-2,2′-bipyridyl (520 mg, 1.64 mmol), sodium carbonate (2N solution, 4 ml) and tetrakis(triphenylphosphine) palladium (40 mg) in ethylene glycol dimethyl ether (16 ml) at reflux under nitrogen for 7 hours. The solid was filtered from the cooled reaction and washed with ethylene glycol dimethyl ether and water to give the desired product as a beige solid (240 mg, 39%); δH [2H6]-DMSO 8.49,(2H, d), 8.30,(4H, m), 8.00,(2H, d), 7.37,(2H, t), 6.99,(2H, dd).
Reaction SMILES: Cl.[N:2]1[C:6]2[CH2:7][CH2:8][CH:9]([C:11](N3CCCC3)=[O:12])[CH2:10][C:5]=2[NH:4][CH:3]=1.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.P(Cl)(Cl)(Cl)=O.O>C(Cl)CCl>[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:11]([CH:9]2[CH2:8][CH2:7][C:6]3[N:2]=[CH:3][NH:4][C:5]=3[CH2:10]2)=[O:12])=[CH:20]1
Reactant: Cn1ccc2ccccc21
Reactant: O=C(C1CCc2nc[nH]c2C1)N1CCCC1
Agent: Cl
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cn1cc(C(=O)C2CCc3nc[nH]c3C2)c2ccccc21
Reaction time: 7 h
Yield: 89.9 %

Procedure:
In a suspension of 7.0 g of N-[(4,5,6,7-tetrahydrobenzimidazol-5-yl)carbonyl]pyrrolidine hydrochloride and 5.4 g of N-methylindole in 70 ml of ethylene chloride was added 12.6 g of phosphorus oxychloride, and the mixture was stirred at 80° to 85° C. for 7 hours. After allowing the mixture to cool, the mixture was cooled to 0° to 5° C., and 70 ml of cold water was slowly added to the reaction mixture while maintaining the temperature of the mixture below room temperature to thereby decompose the excess of phosphorus oxychloride. The organic layer was removed, and the aqueous layer was adjusted to a pH of 9 with a 20% sodium hydroxide aqueous solution under cooling, followed by extracting from chloroform. To the chloroform layer was added 70 ml of water, and 6N hydrochloric acid was added thereto under ice-cooling while stirring to adjust to a pH of from 2.4 to 2.8. The chloroform layer was removed. The aqueous layer was washed with chloroform, and 40 ml of methanol was added thereto. The solution was made alkaline with a 20% sodium hydroxide aqueous solution while cooling. The formed crystal was collected by filtration and washed with a cold 1:1 (by volume) mixture of methanol and water to give 6.87 g (89.9%) of 5-[(1-methylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]([O-])=O.[Na+].Cl[Sn]Cl.Cl>Cl>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][NH2:10]
Reactant: O=N[O-]
Reactant: Nc1ccc(F)cc1Br
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: NNc1ccc(F)cc1Br
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
Commercially available 2-bromo-4-fluoroaniline 1 (2.36 ml, 20.75 mmol) was added to a stirring solution of concentrated hydrochloric acid (40 ml) that was cooled to −5° C. This solution was allowed to age while stirring for 10 minutes. An aqueous solution of NaNO2 was added over 15 minutes. SnCl2/HCl (10.40 g, 46.1 mmol, 10 ml HCl) was added over 15 minutes and aged for an additional 30 minutes to 1 hour. The mixture was filtered and washed with dichloromethane. The resulting solid was dissolved in 1.0M HCl and extracted 3 times with dichloromethane. The organic layer was vacuum dried overnight to give 3.53 g (83% yield). 1H NMR (400 MHz, CDCl3): 7.169 (dd, J=8 Hz, J=2.8 Hz 1H), δ 7.076 (dd, J=5.2 Hz, J=9.2 Hz, 1H), 6.982 (td, J=8.4 Hz, J=2 Hz 1H), 5.540 (bs, 1H), δ 3.590 (bs, 1H).
Reaction SMILES: [C:1]([CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[CH:29]([CH:31]=[CH2:32])=[O:30]>O1CCCC1>[OH:30][CH:29]1[NH:2][C:1](=[O:3])[C:4]2([C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:32][CH2:31]1
Reactant: NC(=O)C1c2ccccc2-c2ccccc21
Reactant: C=CC=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1NC(O)CCC12c1ccccc1-c1ccccc12
Temperature: 50 °C
Yield: 112.7 %

Procedure:
Following the general procedure of Example 1, 20.9 g (0.1 mole) of 9-carbamoylfluorene were added to 300 ml of tetrahydrofuran. The solution was heated to 50° C. and stirred while 6 ml of benzyltrimethylammonium hydroxide were added in one portion. After stirring the reaction mixture at 50° C. for thirty minutes, 6.2 g (0.11 mole) of acrolein were added and the mixture was then heated at reflux for four hours. The reaction mixture was cooled to 25° C. and the solvent was removed by evaporation under reduced pressure to provide 29.9 g of 6'-hydroxyspiro(9H-fluorene-9,3'-piperidine)-2'-one and its tautomeric isomer 9-carbamoyl-9-(3-oxopropyl)fluorene. m.p. 199°-201° C.
Reaction SMILES: C(OC1C=C(CCCC(=O)[CH2:15][CH2:16][C:17]2([CH3:24])[C:21](=O)[CH2:20][CH2:19][C:18]2=[O:23])C=CC=1)(=O)C.C([O:29][C:30]1[CH:31]=[C:32]([CH2:36][CH2:37][CH2:38][C:39](=O)CCN(CC)CC)[CH:33]=[CH:34][CH:35]=1)(=O)C.C(OC1C=C(CCCC(=O)C=C)C=CC=1)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.CCOCC>[CH3:24][C@:17]12[CH2:16][CH2:15][C:39]3[C:33]4[CH:34]=[CH:35][C:30]([OH:29])=[CH:31][C:32]=4[CH2:36][CH2:37][C:38]=3[C:21]1=[CH:20][CH2:19][C:18]2=[O:23]
Reactant: CCN(CC)CCC(=O)CCCc1cccc(OC(C)=O)c1
Reactant: CC(=O)Oc1cccc(CCCC(=O)CCC2(C)C(=O)CCC2=O)c1
Agent: C=CC(=O)CCCc1cccc(OC(C)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: C[C@]12CCC3=C(CCc4cc(O)ccc43)C1=CCC2=O

Procedure:
Reflux 2-(6-m-acetoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione (0.8 g, the product of Michael condensation of 2-methylcyclopentanedione and a mixture of 6-m-acetoxyphenyl-1-diethylaminohexan-3-one and 6-m-acetoxyphenylhex-1-en-3-one, and containing some of the corresponding free phenolic compound) in benzene (25 cc) with toluene-p-sulfonic acid (0.3 g) for 50 minutes. On cooling add ether (50 cc) and wash the mixture in turn with water, saturated aqueous potassium bicarbonate, and brine; dry over anhydrous magnesium sulfate. The residue after removal of solvent is a purple gum (0.6 g), part of which can be induced to crystallize. Dissolve a portion (0.45 g) of this gum in benzene and adsorb on an activated Fuller's earth (40 g); elute with benzene to obtain 13β-methyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one, which one recrystallizes from diisopropyl ether, m.p. 225°-226°; ultraviolet absorption peak at 312.5 mμ (ε23,000); infrared absorption peaks at 2.99 μ, 5.81 μ, and 8.00μ. This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.