Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:30][C:29]([F:32])([F:31])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[F:33][C:34]([F:39])([F:38])[C@@H:35]([OH:37])[CH3:36]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:37][C@@H:35]([CH3:36])[C:34]([F:39])([F:38])[F:33])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:30][C:29]([F:32])([F:31])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Reactant: C[C@H](O)C(F)(F)F
Product: C[C@H](Oc1ccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)NC3(C#N)CC3)[C@H](C(=O)N3CC(F)(F)C3)C2)c(Cl)c1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to Example 134 using (1R,2R,4R)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amid (Example 119) and (S)-1,1,1-trifluoro-propan-2-ol. Off-white solid. MS (EI): 584.1 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[C:11]#[CH:12].[CH:17]1([NH:22][C:23]2[N:31]=[C:30]([N:32]=[N+:33]=[N-:34])[N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3[C@H:35]2[C@H:39]([OH:40])[C@H:38]([OH:41])[C@@H:37]([CH2:42][OH:43])[O:36]2)[CH2:21][CH2:20][CH2:19][CH2:18]1>C1COCC1.[Cu]I>[OH:40][C@@H:39]1[C@H:38]([OH:41])[C@@H:37]([CH2:42][OH:43])[O:36][CH:35]1[N:27]1[CH:26]=[N:25][C:24]2[C:28]1=[N:29][C:30]([N:32]1[CH:12]=[C:11]([C:10]([O:14][CH2:15][CH3:16])=[O:13])[N:34]=[N:33]1)=[N:31][C:23]=2[NH:22][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: [N-]=[N+]=Nc1nc(NC2CCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: C#CC(=O)OCC
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn(-c2nc(NC3CCCC3)c3ncn(C4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)nn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.470 g of diisopropylethylamine and ethyl prop-2-ynoate (1.9 mmol) were dissolved in 20 mL of THF. To the solution was added (4S,2R,3R,5R)-2-[6-(cyclopentylamino)-2-(azido)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol (1.3 mmol) and 350 mg of CuI. The mixture was stirred at room temperature for 24 hours. The solvent was then removed by evaporation and the residue treated with 5 mL of ethanol and ethyl ether. The yellow solid was collected by filtration, and washed with ethanol and ether to afford ethyl 1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}-1,2,3-triazole-4-carboxylate, a compound of Formula I.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2[C@H:33]1[C@@H:37]2[O:38][C:39]([CH3:42])([CH3:41])[O:40][C@@H:36]2[C@@H:35]([CH2:43][OH:44])[O:34]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>[Cl:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2[C@H:33]1[C@@H:37]2[O:38][C:39]([CH3:41])([CH3:42])[O:40][C@H:36]2[C@H:35]([CH:43]=[O:44])[O:34]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(Cl)ncnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)O[C@@H]2[C@@H](O1)[C@H](n1cnc3c(Cl)ncnc31)O[C@H]2C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a suspension of Dess-Martin periodinane (16.42 g, 0.03872 mol) in anhydrous methylene chloride (88.0 mL) cooled in an ice/water bath was added [(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol (11.50 g, 0.03520 mol) in methylene chloride (200 mL). The reaction was stirred under an atmosphere of nitrogen and allowed to warm to ambient temperature. After 2 hours, a further portion of Dess-Martin periodinane (1.00 g, 0.00236 mol) was added. After 3 hours, a solution (200 mL) of sodium thiosulfate (50 g in 200 mL of saturated aqueous sodium bicarbonate) was added and the mixture stirred for 10 min. The aqueous was extracted 2×250 mL methylene chloride and 8×50 mL of chloroform. The combined organics were washed with water and dried over magnesium sulfate and concentrated in vacuo to dryness. The residue was taken up in dry toluene (200 mL) and concentrated in vacuo, and then taken up in dry methylene chloride and concentrated in vacuo to yield the product as a foam (9.83 g, 86%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[N:22]=1>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:20][C:21]1[N:22]=[C:23]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1cccc(-c2ccccn2)n1
Yield: 23.3 %

Procedure:
2-Tri-n-butylstannylpyridine (3.80 g, 8.2 mmol) was added to a degassed and stirred solution of 2,6-dibromopyridine (2.00 g, 8.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (5 mol %) in tetrahydrofuran (30 ml) under an atmosphere of nitrogen then heated to reflux for 48 h. Solvent was removed in vacuo and purification by chromatography on silica gel eluting with dichloromethane followed by trituration with isohexane gave 6-bromo-2,2′-bipyridine (0.45 g) as a white solid: δH (400 MHz, CDCl3) 7.31-7.34 (1H, m), 7.49 (1H, d), 7.67 (1H, dd), 7.80-7.84 (1H, m), 7.37-8.42 (2H, m), 8.66-8.68 (1H, m); m/z (ES+) 234/236 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([NH2:22])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].C(C1C=CC(OC)=C(C=1)N)(C)(C)C.[C:36]([C:40]1[CH:41]=[CH:42][C:43]([O:69][CH3:70])=[C:44]([NH:46][C:47](NC2C3C(=CC=CC=3)C(OC3C=CN=C(C#N)N=3)=CC=2)=[O:48])[CH:45]=1)([CH3:39])([CH3:38])[CH3:37]>>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([NH:22][C:47]([NH:46][C:44]3[CH:45]=[C:40]([C:36]([CH3:37])([CH3:39])[CH3:38])[CH:41]=[CH:42][C:43]=3[O:69][CH3:70])=[O:48])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COc1ccc(C(C)(C)C)cc1NC(=O)Nc1ccc(Oc2ccnc(C#N)n2)c2ccccc12
Reactant: COC(=O)c1nccc(Oc2ccc(N)c3ccccc23)n1
Agent: COc1ccc(C(C)(C)C)cc1N
Product: COC(=O)c1nccc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)ccc3OC)c3ccccc23)n1

Procedure:
The title compound was prepared from the above amine and 5-tert-butyl-2-methoxyaniline by the procedure described for 1-(5-tert-butyl-2-methoxy-phenyl)-3-[4-(2-cyano-pyrimidin-4-yloxy)-naphthalen-1-yl]-urea (Example 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[NH:11][C:10](=O)[CH:9]=2)=[CH:4][CH:3]=1.P(Br)(Br)([Br:18])=O>>[Br:18][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([CH3:14])[N:11]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1cc(-c2ccc(Cl)cc2)cc(=O)[nH]1
Product: Cc1cc(-c2ccc(Cl)cc2)cc(Br)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-6-methyl-1H-pyridin-2-one (example A.27 step 1) (4.00 g, 18.2 mmol) and phosphoryl bromide (15.66 g, 54.6 mmol) according to the general procedure Ia to d preparation of bromides. Obtained as a light brown solid (2.95 g, 57%). MS (ISP) 282 [(M+H)+], 284 [(M+2+H)+] and 286 [(M+4+H)+]; mp 92° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18](Cl)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18]([N:26]4[CH2:30][CH2:29][CH2:28][C:27]4=[O:31])[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: O=C1CCCN1
Reactant: COC(=O)C1(c2ccc(Nc3nc(Cl)nc4c3CCC4)cc2)CCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)C1(c2ccc(Nc3nc(N4CCCC4=O)nc4c3CCC4)cc2)CCC1
Yield: 77.3 %

Procedure:
A glass tube was charged with 1-[4-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid methyl ester (0.5 g, 1.4 mmol), 2-pyrrolidinone (0.17 g, 2 mmol) and alternatively purged and backfilled with nitrogen. Thereafter, tris(dibenzylideneacetone)dipalladium(0) (0.05 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthine (0.05 g), cesium carbonate (0.7 g, 2.2 mmol) and anhydrous 1,4-dioxane (6 mL) were introduced in the tube and again flushed with nitrogen. The reaction was stirred at a temperature in the range of 40° C. to 100° C. under stirring until complete as evidenced by the disappearance of starting chloro compound (TLC). The resulting mixture was cooled to a temperature in the range of 15° C. to 40° C., diluted with ethyl acetate (20 mL), filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel to afford the title compound as a light yellow solid (0.44 g, 78% yield).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:19][C:20]#[C:21][CH2:22][CH3:23])[C:12](=[O:13])[CH:11]=[CH:10][CH:9]1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CC(C)=O.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[C:1]([O:5][C:6]([C:8]1([CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH3:23])[C:12](=[O:13])[CH:11]=[CH:10][CH:9]1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC#CCC1(C(=O)OC(C)(C)C)C(=O)C=CC1CC(=O)OC
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CC(C)=O
Product: CC/C=C\CC1(C(=O)OC(C)(C)C)C(=O)C=CC1CC(=O)OC

Procedure:
A 4.5 g quantity of 5-methoxycarbonyl-4-methoxycarbonylmethyl-5-(2-pentynyl)-2-cyclopentenone (compound (1-a)) is dissolved in a mixture of 50 ml of n-hexhane and 50 ml of acetone, and 7 g of a Lindlar catalyst is added to the solution. Hydrogen gas is introduced into the solution with stirring. The reaction is completed when the solution has absorbed the theoretical amount of the gas. On completion of the reaction, the catalyst is filtered off from the reaction mixture, and the filtrate is concentrated at reduced pressure. The residue is distilled in a vacuum, affording 5-methoxycarbonyl-4-methoxycarbonylmethyl-5-(cis-2-pentenyl)-2-cyclopentenone (compound (1-b), R1 =CH3, R2 =CH3) in a yield of 99.8%, b.p. 81°-85° C./0.005 mm Hg.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:7][CH2:6][C:5](=[O:8])[NH:4][CH:3]1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30]>C1COCC1>[CH3:1][C:2]1([CH3:17])[O:7][CH2:6][C:5](=[O:8])[N:4]([C:29]([O:31][C:32]2[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=2)=[O:30])[CH:3]1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1
Reactant: CC1(C)OCC(=O)NC1c1ccc(F)c(F)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)OCC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of (±)-2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholine (240 mg, 0.996 mmol) in THF (10 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1.10 mL, 1.0 M in THF). The mixture was stirred for 30 min at 0° C. and then cooled back to −78° C. The mixture was transferred via a cannula to a precooled solution of 4-nitrophenyl chloroformate (605 mg, 3.0 mmol) in THF (10 mL) at −78° C. The resulting mixture was stirred while warmed to room temperature over 3 hours. The reaction was quenched with water (2 mL) and extracted with EtOAc (2×100 mL). The organic layer was dried with Na2SO4 and the solvent was evaporated. The residue was purified by column chromatography (SiO2, 40:60 EtOAc/Hexanes) to afford 0.328 g (81%) of the product as a pale oil.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[CH2:15]([C:14]1[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:22]2[C:23](=[O:32])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]2=[O:31])[S:12][CH:13]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1c(Cc2ccccc2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c(Cc2ccccc2)csc1N1C(=O)c2ccccc2C1=O

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-benzyl-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 32, Part E). The mixture is heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.O.O.O.O.O.S([O-])([O-])(=[O:30])=S.[Na+].[Na+].O>C(O)(=O)C>[C:1]1([S:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=2)=[O:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCOc1ccc(Sc2ccccc2)cc1
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCOc1ccc(S(=O)c2ccccc2)cc1
Reaction time: 18 h
Yield: 883.8 %

Procedure:
In 100 g of acetic acid was dissolved 15 g of (4-hexyloxyphenyl) phenyl sulfide obtained in Synthesis Example 1-21. While the solution was maintained at an internal temperature of 30° C., 5.1 g of 35 wt % aqueous hydrogen peroxide was added dropwise. The reaction solution was aged at room temperature for 18 hours, after which under ice cooling, a mixture of 1.3 g sodium thiosulfate pentahydrate and 15 g water was added dropwise to quench the reaction. The solution was combined with 100 g of methylene chloride and 20 g of water for extraction. The organic layer was separated, washed with water, and concentrated in vacuum, obtaining 14 g of the target compound, (4-hexyloxyphenyl) phenyl sulfoxide as amorphous solid. Yield 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:70][CH2:71][CH2:72][NH:73][C:74](=[O:76])[CH3:75]>C1COCC1>[C:74]([NH:73][CH2:72][CH2:71][NH:70][C:25]([C:24]([CH3:28])([O:23][C:17]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=1[CH:15]1[CH2:14][C:13](=[O:29])[NH:12][CH:11]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[CH3:37])[C:10]21[C:5]1[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[NH:8][C:9]2=[O:38])[CH3:27])=[O:26])(=[O:76])[CH3:75]
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)CO)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)NCCNC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxy-1,1-dimethyl-ethoxy)-phenyl]-2′-[5-fluoro-2-methylphenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (35 mg, 0.06 mmol), EDCl (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (2 mL) was added N-(2-amino-ethyl)-acetamide (19 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (11 mg).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][S:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:12][C:11]=3[N:22]([CH3:32])[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:25])=[O:24])=[N:4]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>O1CCCC1>[CH3:33][S:34]([O:1][CH2:2][C@@H:3]1[CH2:7][S:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:12][C:11]=3[N:22]([CH3:32])[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:24])=[O:25])=[N:4]1)(=[O:36])=[O:35]
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=N[C@H](CO)CS3)cc2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=N[C@H](COS(C)(=O)=O)CS3)cc2c1
Yield: 76.7 %

Procedure:
A solution of N-[2-[(4R)-4-(hydroxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-5-(2-methoxyethoxy)-1H-indol-7-yl]-N-methylpyridine-2-sulfonamide (0.28 g), methanesulfonyl chloride (0.10 g) and triethylamine (0.16 mL) in tetrahydrofuran (5.0 mL) was stirred at room temperature for 2 hr, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:4, volume ratio) to give the title compound (0.25 g, yield 77%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:13]2=[C:14]3[N:9]([CH2:10][CH2:11][CH2:12]2)[CH2:8][CH2:7][CH2:6][C:5]3=[CH:4][C:3]=1[CH:15]=[O:16].CI.[C:19](=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O.C(OCC)(=O)C>[CH3:19][O:1][C:2]1[C:13]2=[C:14]3[N:9]([CH2:10][CH2:11][CH2:12]2)[CH2:8][CH2:7][CH2:6][C:5]3=[CH:4][C:3]=1[CH:15]=[O:16]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc2c3c(c1O)CCCN3CCC2
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CI
Product: COc1c(C=O)cc2c3c1CCCN3CCC2
Temperature: 50 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
In 20 ml of 1-methyl-2-pyrrolidone was dissolved 2.5 g (11.5 mmol) of 8-hydroxy-2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine-9-carboaldehyde, and 4.1 g (28.9 mmol) of methyl iodide and 4.8 g (34.7 mmol) of anhydrous potassium carbonate were added thereto. The mixture was stirred at 50° C. for 4 hours. After the reaction mixture was added to water, extraction with ethyl acetate, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 2.63 g of a yellow crystal (yield: 99.0%).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:15]=[CH:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Product: CCCCCCCn1ccc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.22 g (4.45 mmol) pulverized, 88% potassium hydroxide, 0.5 g (2.24 mmol) 5-benzyloxyindole and 0.07 g (0.22 mmol) tetrabutylammoniumbromide are weighed out in the given order and mixed with 1.41 ml (8.96 mmol) 1-bromoheptane with vigorous stirring. The mixture is stirred at room temperature overnight. Having added 30 ml water, three extractions using diethyl ether are carried out. The organic phase is washed three times with saturated NaCl solution, dried on sodium sulfate and the solvent is removed in vacuo. The residue is purified on silica gel by means of column chromatography (flow agent: hexane/ethyl acetate 95:5). The product accrues as an oil.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[S:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[C:14]=2[CH3:15])[CH2:17][CH2:18]1)(=[O:23])=[O:24]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)c3ccccc3Cl)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(S(=O)(=O)c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 85 %

Procedure:
To a clear, almost colorless solution of {4-[1-(2-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (108 mg, 0.23 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (106 mg, 4.4 mmol) in water (2.0 mL) The mixture was heated with a heat gun to give a clear solution. The resulting solution was stirred for 15 hours at room temperature. The solvent was removed under vacuum. The residue was diluted with water (˜20 mL) and the mixture was neutralized with 1.0 N HCl. The precipitated white solids were collected by filtration and washed with water and hexanes. After air drying, {4-[1-(2-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (93 mg, 87%) was isolated as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.42 (br. s, 1H), 8.07 (d, J=7.53 Hz, 2H), 783-7.96 (m, 1H), 7.65-7.82 (m, 3H), 7.56-7.64 (m, 1H), 7.28-7.40 (m, 1H), 3.91 (d, J=11.29 Hz, 4H), 3.76 (br. s, 3H), 3.05 (br. s, 2H), 2.36 (s, 3H), 1.68 (d, J=12.3 Hz, 2H). MS cald. for C24H24ClFNO4S [(M+H)+] 476, obsd. 476.1.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7](=[C:9]([CH3:11])[CH3:10])[CH:8]=1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH:9]([C:7]1[CH2:6][CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=1)([CH3:11])[CH3:10]
Reactant: CC(C)=C1C=CC(C(C)C)=C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)C1=CCC(C(C)C)=C1

Procedure:
Therefore, 1,3-diisopropylcyclopentadiene was selected as the starting point for the synthesis. Unfortunately, the reported syntheses of 1,3-diisopropylcyclopentadiene gave low yields since the final step was always separation of the 1,3 product from the 1,2 product. A more selective method was found by extension of work by Nile in which he prepared a number of 1,3 disubstituted cyclopentadienes using a fulvene route. Using this method, reaction of isopropylcyclopentadiene with acetone catalyzed by pyrrolidine gave the 3-isopropyl-6,6-dimethylfulvene. Subsequent reduction of the fulvene with LAH and hydrolysis provided 1,3-diisopropylcyclopentadiene, "iPr2Cp." ##STR10##