Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[O:12][CH:11]([CH2:13][OH:14])[CH:10]([O:15][C:16](=[O:29])[CH:17]([NH:21]C(OC(C)(C)C)=O)[CH:18]([CH3:20])[CH3:19])[C:9]2([OH:31])[CH3:30])[C:4](=[O:32])[N:3]=1.[ClH:33]>CCOC(C)=O>[ClH:33].[ClH:33].[NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[O:12][CH:11]([CH2:13][OH:14])[CH:10]([O:15][C:16](=[O:29])[CH:17]([NH2:21])[CH:18]([CH3:20])[CH3:19])[C:9]2([OH:31])[CH3:30])[C:4](=[O:32])[N:3]=1
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC1C(CO)OC(n2ccc(N)nc2=O)C1(C)O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)C(N)C(=O)OC1C(CO)OC(n2ccc(N)nc2=O)C1(C)O

Procedure:
In another method to synthesize the compounds of the invention, shown in FIG. 6, benzoylcytosine, BSA and SnCl4/acetonitrile are reacted with 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose (FIG. 6, compound 1a) to form 4-benzoylamino-1-(3,4-dibenzoyloxy-5-benzoyloxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (FIG. 6, compound 2a); reacting (FIG. 6, compound 2a) with NH3 in methanol and chromatographically separating the product, 4-amino-1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (FIG. 6, compound 3a), also known as β-D-2′-C-methyl-cytidine; reacting (FIG. 6, compound 3a) with Me2NCH(OMe)2 in DMF at room temperature for 1.5 hours to form N-[1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine (FIG. 6, compound 4a); reacting (FIG. 6, compound 4a) with TBDPSCl and pyridine at room temperature for 6 hours to provide N′-{1-[5-(tert-butyl-diphenyl-silanyloxymethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yl]-2-oxo-1,2-dihydro-pyrimidin-4-yl}-N,N-dimethyl-formamidine (FIG. 6, compound 5a); reacting (FIG. 6, compound 5a) with N-Boc-L-valine, DEC and DMAP in THF/DMF at room temperature for 2 days and subjecting the product formed from this reaction to HPLC in order to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid 2-(tert-butyl-diphenyl-silanyloxy-methyl)-5-[4-(dimethylaminomethyleneamino)-2-oxo-2H-pyrimidin-1-yl]-4-hydroxy-4-methyl-tetrahydro-furan-3-yl ester (FIG. 6, compound 6a); refluxing (FIG. 6, compound 6a) with NH4F in MeOH for about 3 hours to remove the silyl and amino-protecting groups, and subjecting the product to chromatographic purification to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester (FIG. 6, compound 7a); and finally reacting (FIG. 6, compound 7a) with HCl in EtOAc at room temperature to provide 2-amino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester, dihydrochloride salt (FIG. 6, compound 8a) as a final product.
Reaction SMILES: C([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][C@H:24]([OH:27])[CH2:25][OH:26])(OCC1C=CC=CC=1)=O>CO.[Pd]>[OH:27][C@H:24]([CH2:25][OH:26])[CH2:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12][NH2:11]
Reactant: O=C(NCCCCc1ccccc1OC[C@H](O)CO)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCCCCc1ccccc1OC[C@H](O)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a vigorously stirred solution of 69 (2 g, 5.4 mmol) in methanol (60 mL) under nitrogen was added Pd/C (10% wet, 0.5 g). The mixture was stirred 2 h at room temperature under an atmosphere of hydrogen then the pressure was released and the mixture was filtered through a pad of silica gel. The solvent was removed and the residue was purified by column chromatography (silica gel, 2:1:0.2 chloroform/ethanol/concentrated ammonium hydroxide) to provide 70 (1.18 g, 92%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.32 (m, 2H), 1.54 (m, 2H) 2.55 (m, 2H), 3.45 (m, 2H), 3.82 (m, 3H), 3.94 (m, 2H), 6.83 (d, 2H), 7.08 (d, 2H).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12](Cl)=[O:13].[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[Cl:10][CH2:11][C:12]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][C:8]#[N:9])=[CH:3][CH:4]=1)=[O:13]
Reactant: O=C(Cl)CCl
Reactant: N#CCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: N#CCc1ccc(C(=O)CCl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 1 liter round bottomed, four-necked flask with condenser, CaCl2 drying tube, pneumatic stirrer and thermometer 88.2 ml of benzylcyanide, 105.6 ml of chloroacetylchloride, and 238.2 ml of carbon disulfide are added. After the solution has been cooled to 0° C., AlCl3 is slowly added. The reaction mixture is heated to 15° C. It is subsequently stirred for another 5 minutes at +2° C., 1.2 hour at room temperature and 2 hours at 40° C. CS2 is separated and the dark oil is placed on 2.5 kg ice while stirring vigorously. The resulting brown precipitate is filtered by suction over a D4 glass filter funnel, washed with 1N hydrochloric acid, sucked quite dry, and dried in a vacuum drying oven for 18 hours at room temperature. The raw product (104.9 g) is dissolved in boiling 6.4 l i-propanol containing 34 g of activated carbon and then the product is recrystallized upon cooling. After the crystals have precipitated at room temperature, the precipitation is completed. The product is left with the mother liquor for at least 24 hours at 4° C. The white crystals are filtered by suction by means of a D4 glass filter funnel, washed with cold i-propanol and dried in a vacuum drying oven for 18 hours at room temperature.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[F:16][C:17]1([F:32])[O:21][C:20]2[CH:22]=[CH:23][C:24]([C:26]3([C:29](Cl)=[O:30])[CH2:28][CH2:27]3)=[CH:25][C:19]=2[O:18]1>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:29]([C:26]2([C:24]3[CH:23]=[CH:22][C:20]4[O:21][C:17]([F:32])([F:16])[O:18][C:19]=4[CH:25]=3)[CH2:28][CH2:27]2)=[O:30])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)n1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.7 %

Procedure:
To a solution of 6-bromopyridin-2-amine (660 mg, 3.8 mmol) and Et3N (1.1 mL, 7.7 mmol) in dichloromethane (5 mL) was added a solution of 1-(2,2-difluorobenzo-[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (1.0 g, 3.8 mmol) in dichloromethane (5 mL). The resulting reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (5 mL) and was washed with 1 N aqueous HCl (1×10 mL) and saturated aqueous NaHCO3 (1×10 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-70% ethyl acetate in hexane to yield N-(6-bromopyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (780 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.01-7.99 (m, 1H), 7.75-7.71 (m, 1H), 7.54 (m, 1H), 7.41-7.39 (m, 1H), 7.36-7.30 (m, 2H), 1.52-1.49 (m, 2H), 1.20-1.17 (m, 2H).
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1>[CH2:1]([O:21][S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)(=[O:30])=[O:29])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCO
Solvent: c1ccncc1
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 4 h

Procedure:
(5Z,8Z,11Z,14Z)-Icosa-5,8,11,14-tetraen-1-ol (0.58 g, 1.997 mmol) was dissolved in pyridine (8 mL) and to this solution p-toluenesulfonyl chloride (0.762 g, 3.99 mmol) was added at 0° C. (ice-bath) and the reaction mixture was stirred under nitrogen for 4 h as the temperature was slowly allowed to rise to room temperature. The solvent was then removed under reduced pressure and the crude was purified on silica gel column chromatography using 5%-10% ethyl/hexane giving the title product as a clear oil (0.551 g, 62%). 1H NMR (CDCl3): δ 7.79 (d, 2H, J=8.2 Hz), δ 7.34 (d, 2H, J=8.2 Hz), 5.35 (m, 8H), 4.02 (t, 2H, J=6.4 Hz), 2.79 (m, 6H), 2.44 (s, 3H), 2.03 (m, 4H), 1.64 (m, 2H), 1.43-1.25 (m, 8H), 1.04 (t, 3H, J=6.8 Hz). m/z (ESI) 467.27 (M++Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:11][C:12]([N+:15]([O-])=[O:16])([CH3:14])[CH3:13].C(O)(=O)C>C(O)C.[Zn]>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[N+:15]([C:12]([CH3:14])([CH3:13])[CH3:11])[O-:16]
Reactant: CC(C)(C)[N+](=O)[O-]
Reactant: COc1ccccc1C=O
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccccc1C=[N+]([O-])C(C)(C)C
Temperature: 5 °C

Procedure:
To a suspension of 2-methoxybenzaldehyde (622.4 mg, 4.57 mmol), 1,1-dimethylnitroethane (942.7 mg, 9.14 mmol) and zinc (896.3 mg, 13.7 mmol) in ethanol (15 ml) was added acetic acid (944.8 mg, 15.7 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for one day. After the mixture was cooled to 5° C., zinc acetate was filtered off and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=2/1).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH2:10][C:11]1[CH:20]=[CH:19][C:18]([C:21]([C:23]2[N:31]3[C:26]([C:27]([OH:32])=[CH:28][CH:29]=[CH:30]3)=[C:25]([O:33][CH3:34])[C:24]=2[CH3:35])=[O:22])=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].S([O-])(O)(=O)=O.[K+]>O1CCCC1>[NH2:10][C:11]1[CH:20]=[CH:19][C:18]([C:21]([C:23]2[N:31]3[C:26]([C:27]([O:32][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[CH:28][CH:29]=[CH:30]3)=[C:25]([O:33][CH3:34])[C:24]=2[CH3:35])=[O:22])=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3c(O)cccn23)ccc1N
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3c(OCC(=O)OC(C)(C)C)cccn23)ccc1N
Reaction time: 2 h
Yield: 63.6 %

Procedure:
5.4 ml (9.31 mmol) of potassium hexamethyldisilylamide (0.5 M solution in toluene) and then 0.69 ml (4.66 mmol) of tert-butyl 2-bromoacetate are added, dropwise, to the solution of 1.50 g (4.23 mmol) of methyl 2-amino-5-[(8-hydroxy-1-methoxy-2-methylindolizin-3-yl)carbonyl]benzoate (Stage F of Example 1) in 15 ml of tetrahydrofuran at −20° C. under argon. The mixture is stirred for 2 hours, allowing it to return to ambient temperature. The reaction medium is poured into a saturated aqueous solution of potassium hydrogen sulphate and the mixture is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, and concentrated under reduced pressure. The oil obtained is purified by flash chromatography on silica gel (dichloromethane/methanol gradient=100/0 to 90/10). 1.26 g (64%) of a yellow powder are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[CH:9]=2)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[Cl:15][C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[C:6]([CH2:4][OH:3])[NH:7]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1cc2ccc(Cl)cc2[nH]1
Yield: 101 %

Procedure:
To a solution of 2.00 g (8.94 mmol) 6-chlorindole-2-carboxylic acid ethyl ester in 50 ml diethyl ether were added 0.475 g (12.5 mmol) lithium aluminum hydride at 0° C. The reaction mixture was heated at reflux for 45 min and quenched by consecutive addition of 10 ml water, 10 ml aqueous 2 M sodium hydroxide solution and 10 ml water at 0° C. The aqueous layer was extracted with tert-butyl methyl ether (3×100 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the crude title compound (1.64 g; 100%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].Br[CH2:11][CH2:12][O:13][CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:14][O:13][CH2:12][CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: OCc1cccc(O)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: COCCOc1cccc(CO)c1
Yield: 71.7 %

Procedure:
3-Hydroxybenzyl alcohol (3.76 g, 30 mmol), 2-bromoethylmethyl ether (8.0 ml, 85 mmol) and cesium carbonate (14.7 g, 45 mmol) were heated at 60° C. for 3 h. The reaction was diluted with water, extracted (3×) with ethyl acetate and dried over sodium sulfate. The solution was filtered, concentrated and purified by silica chromatography (DCM followed by DCM/MeOH 19:1, then 9:1) to yield [3-(2-methoxyethoxy)phenyl]methanol as an orange oil (3.92 g, 72%).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([Cl:22])[CH2:5][CH:6]([CH3:21])[C:7]1[C:15]2([CH3:16])[CH:10]([CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][CH2:13][CH2:14]2)[CH2:9][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:18]([O:17][CH:11]1[CH:10]2[C:15]([CH3:16])([C:7]([CH:6]([CH3:21])[CH2:5][CH:4]([Cl:22])[CH2:3][OH:2])=[CH:8][CH2:9]2)[CH2:14][CH2:13][CH2:12]1)(=[O:20])[CH3:19]
Reactant: COC(=O)C(Cl)CC(C)C1=CCC2C(OC(C)=O)CCCC12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)OC1CCCC2(C)C(C(C)CC(Cl)CO)=CCC12
Temperature: 0 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of 1.01 g (2.95 mmol) of [3aS-[3(αS*, γR*),3aα,7β,7aβ]-7-(acetyloxy)-α-chloro-3a,4,5,6,7, 7a-hexahydro-γ,3a-dimethyl-1H-indene-3-butanoic acid methyl ester in 25 mL of anhydrous tetrahydrofuran was cooled at 0° C. and treated under argon with 1.47 mL (1.47 mmol) of a 1M solution of lithium aluminum hydride in tetrahydrofuran. After stirring for 2 hours at 0° C., additional 0.20 mL of lithium aluminum hydride solution was added and the reaction allowed to proceed for 1 additional hour. It was then quenched by careful addition of 8 mL of a 2N aqueous Rochelle salt solution, then 0.5 mL of 2N hydrochloric acid. After dilution with water, it was extracted with ethyl acetate. The combined extracts were washed with 2N aqueous Rochelle salt solution, then brine, dried and evaporated to dryness to give 0.90 g (93% yield) of the title compound as a colorless, thick oil: [α]23D -30.1° (c 0.6, EtOH); 1H NMR (200 MHz, CDCl3) δ0.93 (s, 3H), 1.07 (d, J=7.2 Hz, 3H), 2.04 (s, 3H), 2.52 (br m, 1H), 3.73 (m, 2H), 4.00 (m, 1H), 4.97 (td, J=12.0, 4.4 Hz, 1H), 5.27 (br s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[CH:20]=[CH:19][C:11]([O:12][CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:23]([S:25][CH2:26]CO)[CH3:24]>[Na]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[CH:20]=[CH:19][C:11]([O:12][CH:13]([CH3:18])[C:14]([O:16][CH2:17][CH2:26][S:25][CH2:23][CH3:24])=[O:15])=[CH:10][CH:9]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)C(C)Oc1ccc(COc2ccc(Cl)cc2)cc1
Reactant: CCSCCO
Agent: [Na]
Product: CCSCCOC(=O)C(C)Oc1ccc(COc2ccc(Cl)cc2)cc1
Temperature: 100 °C
Yield: 76.1 %

Procedure:
A mixture consisting of 6.4 gm of methyl 2-[4-(4-chlorophenoxy-methyl)-phenoxy]-propionate and 2.12 gm of 2-ethylmercapto-ethanol was heated to 100° C. on an oil bath, 0.02 gm of sodium was added to the hot mixture, and it was then heated at 150° C. for five hours, the pressure being periodically reduced to 150 mm Hg. Thereafter, the reaction product was isolated as an oil, yielding 6.0 gm (76% of theory) of the ester named in the heading.
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:9]2[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:12]=[CH:13][CH:14]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]1([C:7]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:10]3[C:9]2=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(C2(c3ccccc3)c3ccccc3-c3ccccc32)cc1

Procedure:
9,9-diphenylfluorene was prepared from α,α-diphenyl-2-biphenylmethanol by the following method. To a solution of the starting carbinol (0.50 g, 1.49 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (10 mL). After refluxing for 1 hour, the reaction was cautiously neutralized by the addition of aqueous NaHCO3. The mixture was then extracted with Et2O (2×100 mL) that was subsequently washed with additional H2O (100 mL) and brine, dried over MgSO4 and concentrated to white solid (0.47 g, 99% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:25][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:31])[CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:47]1([CH2:53][C:54]([N:56]=[C:57]=[S:58])=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(=O)([O-])O.[Na+]>C(O)C.C1(C)C=CC=CC=1.CCCCCC.C(OCC)C.C(OCC)(=O)C>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:57]([NH:56][C:54](=[O:55])[CH2:53][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[S:58])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:23][CH:24]([N:26]([CH3:27])[CH3:28])[CH2:25]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ccn3)CC2)C1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.7 %

Procedure:
To a solution of 4-(3-dimethylaminoazetidin-1-yl)piperidine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (156 mg) in ethanol (5.0 ml) was added (1S)-(+)-10-camphorsulfonic acid (152 mg), followed by stirring at room temperature for 15 min. A solution of 2-phenylacetyl isothiocyanate in toluene (0.25 M, 4.37 ml) was added to the reaction mixture, followed by stirring at room temperature for 2 hrs. Ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml) were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing a crude product were concentrated to give a residue, to which diethyl ether (5 ml) and hexane (5 ml) were added to give a precipitate. The precipitate was suspended in the solvent. Then the precipitate was filtered off, washed with hexane, and dried under aeration to provide the titled compound (56.6 mg, 25.7%) as pale yellow powder.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.O.S(=O)(=O)(O)O>CC(O)C>[CH2:11]1[C:10]2[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[NH:7][C:9]=2[CH2:13][CH2:12]1
Reactant: NNc1ccccc1
Reactant: O=C1CCCC1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: c1ccc2c3c([nH]c2c1)CCC3
Temperature: 20 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
A solution of phenylhydrazine (32.44 g, 300 mmol) in 2-propanol (300 mL) was treated with cyclopentanone (27 mL, 25.7 g, 305 mmol). The solution was stirred at 20° C. for 1 h and poured onto mixture of ice (900 g) and water (300 mL). The chilled mixture was stirred until the ice had melted then filtered. The filter-cake was washed with water (2×300 mL) an the resultant damp solid (85 g) was added to water (540 mL). The stirred suspension was treated with concentrated sulfuric acid (33 mL, 61 g, 600 mmol) then heated under reflux for 30 min, cooled to 0° C. and stirred for 15 min. The dark red solid was filtered off, washed with water (2×60 mL) and air-dried for 18 h. The crude product was added to dichloromethane (300 mL), stirred for 30 min then filtered, washing with dichloromethane (100 mL). The filtrate was treated with silica (48 g), stirred for 1 h, filtered and washed with dichloromethane (400 mL). The filtrate was concentrated to give a solid, which was triturated with hexane to give 1,2,3,4-tetrahydrocyclopent[b]indole (30 g, 65%) as a pink solid. Analytical data for 1,2,3,4-tetrahydrocyclopent[b]indole are included in Table 3 below.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][S:7][C:6](=[S:9])[N:5]1[C:10](=[O:12])[CH3:11])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:28][C@H:22]([CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27])[CH2:11][C:10]([N:5]1[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][S:7][C:6]1=[S:9])=[O:12]
Reactant: C=CCCCC=O
Reactant: CC(=O)N1C(=S)SC[C@H]1C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC[C@@H](O)CC(=O)N1C(=S)SC[C@H]1C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.8 %

Procedure:
A solution of (R)-1-(4-isopropyl-2-thioxothiazolidin-3-yl)ethanone (11.8 g, 58.1 mmol) in dichloromethane (380 mL) under an atmosphere of nitrogen was cooled to −78° C., titanium tetrachloride (6.37 mL, 58.1 mmol) was added, and the mixture was stirred for 10 min. Diisopropylethylamine (10.12 mL, 58.1 mmol) was added, and the mixture was stirred for 1 h at −78° C. A 1 M solution of hex-5-enal (58.1 mL, 58.1 mmol) in dichloromethane was added, and the mixture was stirred for 2 h at −78° C. The reaction was quenched by addition of half-saturated NH4Cl (30 mL) and warmed to room temperature. The mixture was extracted twice with dichloromethane, and the organic phase was dried and evaporated to provide a residue. Chromatography on silica gel afforded the title compound (12.92 g, 74%). This procedure has also been carried out using the (R)-1-(4-benzyl-2-thioxothiazolidin-3-yl)ethanone auxiliary, with a similar result.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4](F)[CH:3]=1.[H-].[Na+].[SH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]2[CH:6]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[S:13][C:4]=2[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2ccc(Br)cc2s1

Procedure:
Starting from 6.54 g (32.2 mmol) of 4-bromo-2-fluorobenzaldehyde, by general method A with 1.93 g (48.3 mmol) of sodium hydride (60% in liquid paraffin) and 3.76 g (35.5 mmol) of methyl mercaptoacetate, 4.06 g (46% of theory) of the title compound are obtained.