Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1OC(S(=O)(=O)N)=C(C(O)=O)C=1.C(C1OC=CC=1)C.N1C=CC=CC=1.S(=O)(=O)=O.[Na].[CH2:32]([C:34]1[O:38][C:37]([S:39]([OH:42])(=[O:41])=O)=[CH:36][CH:35]=1)[CH3:33].P(Cl)(Cl)(Cl)(Cl)Cl.[C:49]([NH2:53])([CH3:52])([CH3:51])[CH3:50]>>[CH2:32]([C:34]1[O:38][C:37]([S:39]([NH:53][C:49]([CH3:52])([CH3:51])[CH3:50])(=[O:41])=[O:42])=[CH:36][CH:35]=1)[CH3:33]
Reactant: CC(C)(C)N
Reactant: CCc1ccc(S(=O)(=O)O)o1
Agent: CCc1ccco1
Agent: Cc1cc(C(=O)O)c(S(N)(=O)=O)o1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCc1ccc(S(=O)(=O)NC(C)(C)C)o1
Yield: 48 %

Procedure:
Analogous to the preparation of the 5-methyl-2-sulfamoyl-furan-3-carboxylic acid (see starting compound of Example 1), 2-ethyl furan was sulfonated with sulfur trioxide-pyridine-complex into the sodium salt of the 5-ethyl-furan-2-sulfonic acid with a yield of 32.5% of theory. After chlorinating it with phosphorus pentachloride and reacting it with tert. butyl amine, 5-ethyl-N-tert. butyl-furan-2-sulfonamide [(m.p. 71°-72° C. from petroleum ether); 1H--NMR (CDCl3): δ=6.95 (d, 1, J=2 Hz, 3--H), 6.15 (d, 1, J=2 Hz, 4--H), 4,7 (s, 1, NH, exchangeable), 2.73 (q, 2, CH2), 1.30 (m, 12, --CH2 --CH3 and C(CH3)3)] was obtained with a yield of 48% of theory. The two subsequent reactions were also performed in analogy to the preparation of the 5-methyl-furan compound: By metalizing with butyl lithium and by carboxylating with carbon dioxide, the 5-ethyl-2-(N-tert. butyl)-sulfamoyl-furan-3-carboxylic acid (m.p. 118°-119° C. from cyclo hexane) was obtained with a yield of 59% of theory, which was heated under dry conditions at 160° C. for 2 hours. 5-Ethyl-2-sulfamoyl-furan-3-carboxylic acid [m.p.: 186° C. (from ethyl acetate), 1H--NMR ([d6 ]=DMSO); δ=6.6 (s, 1, 4--H), 2.73 (q, 2, CH2), 1.25 (t, 3, CH3) and two exchangeable protons] was obtained with a yield of 87% of theory.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[N:41]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH2:48][C:49]([OH:51])=O)[CH:42]=1>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:49](=[O:51])[CH2:48][O:47][C:43]1[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=1)[CH2:19][CH2:18]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)COc1cccnc1
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)COc3cccnc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure described for the parallel synthesis of C-17 amides above, using 3-pyridyloxyacetic acid as the reacting carboxylic acid. LCMS: m/e 665.6 (M+H)+, 4.37 min (method 3).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)[C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)C.O1CCCC1.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]=[O:37]>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)[C:12](=[O:15])[CH2:13][CH2:14][C:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=2)=[O:37])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: C=CC(=O)C(CC1CCCO1)c1ccc(S(C)(=O)=O)cc1
Reactant: O=Cc1ccccn1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(CC2CCCO2)C(=O)CCC(=O)c2ccccn2)cc1
Temperature: 25 °C
Yield: 24 %

Procedure:
To a solution of 4-[4-(methylsulfonyl)phenyl]-5-(tetrahydrofuran-2-yl)pent-1-en-3-one (930 mg) in a mixed solvent of ethanol (7.5 mL) and tetrahydrofuran (7.5 mL) were added pyridine-2-carbaldehyde (323 μL), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (89.6 mg) and triethylamine (181 μL), and the mixture was stirred with heating under reflux for 3 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO9) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (302 mg, yield 24%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (19:1, volume ratio). MS: 416 (MH+).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6].[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][CH2:57][CH2:56][C@@:55]1([CH3:63])[C:60](O)=[O:61])=[O:53])([CH3:50])([CH3:49])[CH3:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@@H:40]([NH:41][C:60]([C@:55]1([CH3:63])[CH2:56][CH2:57][CH2:58][CH2:59][N:54]1[C:52]([O:51][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:53])=[O:61])[CH:42]([CH3:44])[CH3:43])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14](=[O:29])[NH:15][C@H:16]([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@]1(C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCCN1C(=O)OC(C)(C)C)C(C)C
Yield: 62.3 %

Procedure:
According to the general procedure D, from #86 (280 mg, 0.4 mmol, 1 eq.), #156 (100 mg, 0.4 mmol, 1 eq.), dichloromethane (5 mL), HATU (182 mg, 0.48 mmol, 1.2 eq.) and N,N-diisopropylethylamine (100 mg, 0.8 mmol, 2 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0.01 to 0.05% methanol in dichloromethane) to afford #187 (220 mg, 62%) as a white solid. HPLC (Protocol V): m/z 883.57 [M+H+], retention time=3.23 minutes (purity=95%).
Reaction SMILES: I[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:14][CH3:15])=[C:10]([N+:11]([O-:13])=[O:12])[C:5]=2[O:4][C:3]=1[C:16]1[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([SH:34])[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31].C([O-])([O-])=O.[K+].[K+].C1(C2C=CC=CC=2O)C=CC=CC=1>C1(C)C=CC=CC=1.[Cu]I>[CH3:15][O:14][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([S:34][C:26]3[CH:25]=[C:24]([O:23][CH3:22])[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=3)=[C:3]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[O:4][C:5]=2[C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1ccc2c(I)c(-c3cnn(C)c3)oc2c1[N+](=O)[O-]
Reactant: COc1cc(S)cc(OC)c1OC
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1ccccc1-c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(Sc2c(-c3cnn(C)c3)oc3c([N+](=O)[O-])c(OC)ccc23)cc(OC)c1OC
Temperature: 110 °C
Reaction time: 30 h
Yield: 25.1 %

Procedure:
A modified procedure of Buchwald et al (Organic Letters 2002, 4 (20) 3517-3520) was used. A mixture of 4-(3-iodo-6-methoxy-7-nitrobenzofuran-2-yl)-1-methyl-1H-pyrazole (0.0538 g, 0.135 mmol), 3,4,5-trimethoxy thiophenol (Dawson et al, J. Am. Chem. Soc., 2002, 124, 4642-4646), (0.041 g, 0.202 mmol), dry K2CO3 (0.038 g, 0.272 mmol), CuI (0.0051 g, 0.027 mmol) and 2-phenylphenol (0.0091 g, 0.053 mmol) in dry toluene (1.5 ml) was degassed under reduced pressure and saturated with dry N2. The resulting mixture was stirred for 30 h at 110° C. under N2, cooled to room temperature and filtered through a pad of celite. The celite was washed with CH2Cl2 (3×20 ml). The combined filtrates were evaporated to dryness under reduced pressure and the residue was purified by flash column chromatography (silica-gel, CH2Cl2/ethyl acetate 9:1) giving the title compound as a creamy solid (0.016 g, 25%). 1H NMR (300 MHz, CDCl3) 8.17 (s, 1H), 8.06 (s, 1H), 7.46 (d, J=8.75 Hz, 1H), 6.94 (d, J=8.75 Hz, 1H), 6.4 (s, 2H), 3.97 (s, 3H), 3.95 (s, 3H), 3.77 (s, 3H), 3.68 (s, 6H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[I-].[Na+].[CH3:19][N:20]([CH3:23])[CH:21]=O.C(=O)([O-])O.[Na+]>CC(C)=O>[C:6]1([CH3:7])[CH:15]=[CH:14][C:19]([N:20]2[CH2:23][CH2:13][N:12]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3[CH:7]=[C:8]4[C:13](=[CH:14][CH:15]=3)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]4)[CH2:11][CH2:21]2)=[CH:4][CH:5]=1
Reactant: CN(C)C=O
Reactant: O=C1CCc2cc(CCCCCl)ccc2N1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ccc(N2CCN(CCCCc3ccc4c(c3)CCC(=O)N4)CC2)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
2.5 Grams of 6-(4-chlorobutyl)-3,4-dihydrocarbostyril and 1.8 g of sodium iodide were mixed in 80 ml of acetone and stirred at 50° C. for 2 hours. Then to the reaction mixture was added 80 ml of dimethylformamide and the acetone was removed by distillation, and 2.0 g of 4-(4-tolyl)piperazine and 2.0 g of triethylamine were added to the reaction mixture, and stirred at 70°-80° C. for 5 hours. The reaction mixture was concentrated under a reduced pressure to obtain a residue. To the residue was added 50 ml of 5%-sodium hydrogencarbonate aqueous solution and stirred. The precipitates thus formed were collected by filtration, washed with water and dried. Recrystallization from isopropanol-diisopropyl ether, there were obtained 3.1 g of 6-{4-[4-(4-tolyl)- 1-piperazinyl]butyl}-3,4-dihydrocarbostyril in colorless prism-like crystals, having the melting point of 160°-161° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][S:44][CH:43]([C:47]([OH:49])=O)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].[NH2:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[NH:56][N:55]=[C:54]2[C:60]([O:62][CH3:63])=[O:61]>CN(C=O)C>[CH3:63][O:62][C:60]([C:54]1[C:53]2[C:57](=[CH:58][CH:59]=[C:51]([NH:50][C:47]([CH:43]3[S:44][CH2:45][CH2:46][N:41]([C:39]([O:38][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:40])[CH2:42]3)=[O:49])[CH:52]=2)[NH:56][N:55]=1)=[O:61]
Reactant: COC(=O)c1n[nH]c2ccc(N)cc12
Reactant: CC(C)(C)OC(=O)N1CCSC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1n[nH]c2ccc(NC(=O)C3CN(C(=O)OC(C)(C)C)CCS3)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (1.9 g, 5 mmol) and diisopropyl ethyl amine (DIEA) (2.7 mL) was added to a suspension of 4-(tert-butoxycarbonyl)thiomorpholine-2-carboxylic acid (1.3 g, 5 mmol) in DMF (10 mL) and was stirred at room temperature for 15 minutes. Methyl 5-amino-1H-indazole-3-carboxylate (0.95 g, 5 mmol)) was added to the reaction and was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×20 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product (2.1 g) was progressed to the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[C:22]([C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][CH2:31][CH2:32]Cl)=[C:27]([O:36][CH3:37])[CH:26]=1)(=[O:24])[CH3:23].C(=O)(O)[O-].[Na+].[I-].[K+].[C:45]([OH:52])(=[O:51])/[CH:46]=[CH:47]/[C:48]([OH:50])=[O:49]>C(O)CCC.CO.CCOCC>[C:45]([OH:52])(=[O:51])/[CH:46]=[CH:47]/[C:48]([OH:50])=[O:49].[F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH:9]2[CH2:10][CH2:11][N:12]([CH2:32][CH2:31][CH2:30][O:29][C:28]3[CH:34]=[CH:35][C:25]([C:22](=[O:24])[CH3:23])=[CH:26][C:27]=3[O:36][CH3:37])[CH2:13][CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: Fc1cccc(C(c2cccc(F)c2)C2CCNCC2)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCCCO
Solvent: CCOCC
Solvent: CO
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(C(c2cccc(F)c2)c2cccc(F)c2)CC1
Yield: 15.1 %

Procedure:
A mixture of 5.32 g (0.019 mole) of 4-[bis(3-fluorophenyl)methyl]piperidine, 4.80 g (0.020 mole) of 3-(4-acetyl-2-methoxyphenoxy)-1-chloropropane, 2.4 g (0.029 mole) of sodium bicarbonate and 0.20 g (0.0012) mole of potassium iodide in 400 ml of 1-butanol was heated at reflux for 23 hr. The solvent was removed in vacuo and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate and the solvent was removed in vacuo to give an oil. This was dissolved in methanol and the solution was treated with an excess of fumaric acid. Ether was added and a gum formed. The gum was triturated with acetonitrile to give 1.75 g (15.1%) of the title compound as a white crystalline solid, mp 180°-181° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9]C(=O)C)=[C:5]([CH3:13])[C:4]=1[F:14])#[N:2]>Cl.CCO>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:14])[C:5]=1[CH3:13]
Reactant: CC(=O)Nc1ccc(C#N)c(F)c1C
Agent: Cl
Solvent: CCO
Product: Cc1c(N)ccc(C#N)c1F
Temperature: 25 °C
Yield: 96.8 %

Procedure:
N-(4-cyano-3-fluoro-2-methyl-phenyl)-acetamide (72C) (450 mg, 2.34 mmol) was dissolved in 1:1 conc. HCl/EtOH (20 mL), and the mixture was refluxed for 1 h. The reaction was cooled to rt and concentrated. The residue was dissolved in EtOAc (30 mL), washed with sat. aq. NaHCO3 and brine, dried (MgSO4), filtered and concentrated. The residue was recrystallized from EtOAc/Hexane to provide the title compound (340 mg). LC/MS: m/z 151 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)(O)[CH3:13])[C:6]3[CH2:21][CH:22]([CH3:26])[N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1.S(Cl)(Cl)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH2:13])[C:6]3[CH2:21][CH:22]([CH3:26])[N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC1Cc2c(c3cc(Cl)ccc3n2CC(C)(O)c2ccncc2)CN1C
Solvent: O=C(O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: C=C(Cn1c2c(c3cc(Cl)ccc31)CN(C)C(C)C2)c1ccncc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 9.4 %

Procedure:
1-(8-Chloro-2,3-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-4-yl-propan-2-ol (900 mg, 2.43 mmol) was dissolved in 5 mL DCM. To this, thionyl Chloride (2 mL in DCM) was added dropwise at 0° C. and stirred for 2.5 h at RT. After completion of starting material (TLC) excess thionyl chloride and solvent was evaporated under vacuum. The residue was neutralized with saturated solution of Sodium bicarbonate at 0° C. and extracted with EtOAc (3 times). The combined organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated to obtain 720 mg of crude which was subjected to reverse phase chromatography to obtain 80 mg of product as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.70 (d, 2H), 7.95 (d, 2H), 7.55 (s, 1H), 7.42 (d, 1H), 7.20 (d, 1H), 5.85 (s, 1H), 5.30 (s, 2H), 4.78 (s, 1H), 4.70 (m, 1H), 4.40 (m, 1H), 4.10 (m, 1H), 3.85 (m, 1H), 3.05 (s, 3H), 2.95 (m, 1H), 1.50 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:13][CH2:12][O:11][C:9](=[O:10])[CH2:8][CH2:7]1.N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>CN(C)C=O>[O:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:13][CH2:12][O:11][C:9](=[O:10])[CH2:8][CH2:7]1)[Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: O=C1CCC(CCCCO)CCO1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCCC1CCOC(=O)CC1
Reaction time: 16 h

Procedure:
To a solution of 8.77 g (47 mmol) of 4-(4-hydroxybutyl)-epsilon-caprolactone (Example 28) in 52 mL dry dimethylformamide is added 6.16 g (90 mmol) of imidazole followed by 11.1 g (71 mmol) of t-butyldimethylsilyl chloride (97% pure) and then the mixture is stirred for 16 hours. The reaction mixture is poured into water and extracted twice with ether. The combined organic extracts are washed twice with water, brine, dried, filtered and concentrated to give an oil which is purified by flash chromatography using 3:2 hexane/ether to yield 4-(4-t-butyldimethylsiloxybutyl)-epsilon-caprolactone as an oil; NMR (CDCl3): delta 4-4.3 (m,2H), 3.6 (t,2H), 0.88 (s,9H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=O)=[CH:25][CH:24]=1.CCOCC>ClCCl>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=2)=[CH:25][CH:24]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Fc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 79.8 %

Procedure:
N-phenyl-1,2-phenylenediamine (1.84 g, 10 mmol) and 30 ml of dichloromethane were charged in a 250 ml round bottle, 3 ml of triethylamine was then added, and the mixture was cooled to 0° C. 4-Fluoro-benzoyl chloride (1.58 g, 10 mmol) was dissolved in 30 ml of dichloromethane and then slowly added to the 250 ml round bottle. The reaction was conducted under a nitrogen atmosphere for 6 hours. After the reaction was complete, ether was added to form precipitation. The solid product was collected by filtration, washed with ether several times, and heated under reduced pressure to form 2-(4-fluoro-phenyl)-1-phenyl-1H-benzoimidazole (yield=2.3 g, 80%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[N+:19]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][C:26](=O)[CH2:25]2)([O-:21])=[O:20].C([BH3-])#N.[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[N+:19]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][CH:26]([N:16]1[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][C:8]3[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=3)[CH2:14][CH2:15]1)[CH2:25]2)([O-:21])=[O:20]
Reactant: O=C1Cc2ccc([N+](=O)[O-])cc2C1
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Product: O=[N+]([O-])c1ccc(CCN2CCN(C3Cc4ccc([N+](=O)[O-])cc4C3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-[2-(4-Nitrophenyl)ethyl]piperazine hydrochloride (50 mg, 0.18 mmol), 5-nitro-1,3-dihydro-2H-inden-2-one (39 mg, 0.22 mmol), sodium cyanoborohydride (58 mg, 0.92 mmol, and Titanium (IV) Isopropoxide (0.54 mL, 1.8 mmol) was allowed to stir at RT for 3 hours. LC showed formation of the desired product. The reaction was diluted with EtOAc, washed with brine, dried over sodium sulfate, filtered, concentrated and purified by mass-directed HPLC (0.1% TFA in water and acetonitrile). LC-MS (IE, m/z): 397 (M+1)+. (0.31 μM)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9](=[O:11])[CH3:10])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:14][C:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:21](Cl)=[O:22])([CH3:17])[CH3:16]>O1CCCC1>[C:9]([N:8]([CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[C:18]([C:15]([CH3:17])([CH3:16])[CH3:14])[CH:19]=1)(=[O:11])[CH3:10]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1C(C)(C)C
Reactant: CC(=O)NCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccncc2)C(C)=O)cc1C(C)(C)C
Yield: 8.8 %

Procedure:
The title compound is prepared by the procedure of Example 27, using 0.90 g of product from Example 15, 0.316 g of washed 50% sodium hydride, 2.57 g of product from Example 33 and 25 ml of dry tetrahydrofuran. The residue is purified by chromatography (silica gel: 40% ethyl acetate/hexane) to give 0.275 g of desired product as a yellow oil which crystallizes on standing.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[F:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[F:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[C:17]1[CH:22]=[CH:21][C:20]([C:5](=[O:7])[CH3:6])=[CH:19][CH:18]=1
Reactant: CC(=O)Cl
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2ccc(Br)cc2F)cc1
Temperature: 25 °C

Procedure:
In a reactor were placed 113 g of anhydrous aluminum chloride and 600 1 of methylene chloride, to which was added 113 g of acetylchloride under stirring at 0° C. or less. Subsequently, a solution of 100 g of 2-fluoro-4-bromobiphenyl in 400 ml methylene chloride was added dropwise, stirred and reacted together for 7 hours while increasing the temperature up to room temperature. After adding the reaction solution to ice/dilute hydrochloric acid, the methylene chloride layer was washed sequentially with water, aqueous sodium hydrogencarbonate solution, and water, followed by dehydration over Glauber's salt and distillation of the solvent. The remaining fraction was recrystallized with acetone to obtain 2-fluoro-4-bromo-4'-acetylbiphenyl.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:14])([CH3:13])[CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C@@H:49]1[CH2:53][CH2:52][O:51][CH2:50]1.Cl>>[CH3:13][C:7]1([CH3:14])[CH2:6][C:5]2[C:10](=[CH:11][C:2]([O:1][C@H:49]3[CH2:53][CH2:52][O:51][CH2:50]3)=[CH:3][CH:4]=2)[C:9](=[O:12])[CH2:8]1
Reactant: O[C@@H]1CCOC1
Reactant: CC1(C)CC(=O)c2cc(O)ccc2C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC1(C)CC(=O)c2cc(O[C@H]3CCOC3)ccc2C1

Procedure:
7-Hydroxy-3,3-dimethyl-3,4-dihydronaphthalen-1(2H)-one (0.95 g, 4.99 mmol) was dissolved in 30 ml DCMand triphenylphosphine (1.96 g, 7.49 mmol) and diisopropyl azodicarboxylate (1.23 ml, 6.24 mmol) and (r)-(−)-3-hydroxytetrahydrofuran (0.600 ml, 7.49 mmol) was added. The mixture was stirred over night. 0.5M HCl (aq.) was added and the mixture was extracted 3 times with EtOAc. Glass col. Chrom. (5-30% EtOAc in Hex.) provided (S)-3,3-dimethyl-7-(tetrahydrofuran-3-yloxy)-3,4-dihydronaphthalen-1(2H)-one as a yellow oil. MS m/z: 261.1 (M+1).