Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[N:11]=[CH:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:20](/[CH:38]=[CH:39]/[CH2:40][O:41][CH3:42])=[CH:19][N:18]=2)=[N:14][CH:15]=1)#[N:9]>ClCCl>[CH3:42][O:41][CH2:40]/[CH:39]=[CH:38]/[C:20]1[C:21]([NH:23][CH2:24][CH:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]2)=[CH:22][C:17]([NH:16][C:13]2[N:14]=[CH:15][C:10]([C:8]#[N:9])=[N:11][CH:12]=2)=[N:18][CH:19]=1
Reactant: COC/C=C/c1cnc(Nc2cnc(C#N)cn2)cc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC/C=C/c1cnc(Nc2cnc(C#N)cn2)cc1NCC1CCNCC1
Reaction time: 0.33 h
Yield: 51.4 %

Procedure:
TFA (0.2 mL) was added at room temperature to a solution of (E)-tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(3-methoxyprop-1-enyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (0.020 g, 0.041 mmol) in dichloromethane (2 mL). The reaction mixture was stirred for 20 min. Solvent was removed in vacuo and the mixture was purified by ion exchange on SCX-II acidic resin (500 mg) eluting with methanol, then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo. The crude product was purified by preparative thin layer chromatography, eluting with methanol/dichloromethane/NH3 (9%/90%/1%) to give the title compound as a yellow solid (0.008 g, 51%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[CH:24]=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=1>>[N:16]1([CH2:15][C@@H:11]2[CH2:12][CH2:13][CH2:14][N:10]2[C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:22][C:23]3[CH:24]=[N:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=3)=[CH:3][CH:4]=2)=[O:9])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=C(c1ccc(O)cc1)N1CCC[C@H]1CN1CCCC1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Product: O=C(c1ccc(OCc2ccc(C(F)(F)F)nc2)cc1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C using (4-Hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 3-(chloromethyl)-6-(trifluoromethyl)pyridine. MS (ES+) 434.2
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1>[OH-].[Na+]>[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCBr
Reactant: Oc1ccc(CCCc2ccncc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCOc1ccc(CCCc2ccncc2)cc1

Procedure:
Excess 1-bromobutane was added to a mixture of 0.9 g of 4-[3-(4-hydroxyphenyl)propyl]pyridine in 10 mL of 2N NaOH, and the mixture was refluxed for several hours. Then the mixture was cooled and the pH adjusted to 10. The product was extracted with CH2Cl2. The CH2Cl2 layer was then separated, washed with fresh water, filtered through phase separating paper, and concentrated. The residue was adsorbed onto silica gel and chromatographed over silica gel eluting with CH2Cl2 >15% EtOAc/CH2Cl2. Yield 0.45 g.
Reaction SMILES: CS[CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[NH:5][C:4]1=[O:14]>[Ni].C1COCC1>[O:14]=[C:4]1[CH2:3][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[NH:5]1
Reactant: CSC1C(=O)Nc2ccc(C#N)cc21
Agent: [Ni]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C

Procedure:
To a suspension of Raney nickel in THF (100 ml) there is added the compound obtained in Step A (20 mmoles) dissolved in THF (400 ml). The reaction mixture is stirred at ambient temperature until the starting material has completely disappeared. The reaction mixture is then filtered over a bed of Celite and then evaporated to dryness to yield the title product, which is used directly in the next reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[Se](=O)=[O:13]>O1CCOCC1>[N:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH:1]=[O:13]
Reactant: Cc1ccc2ncccc2n1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1ccc2ncccc2n1
Temperature: 25 °C

Procedure:
A 100 mL round bottom flask equipped with a condenser (with a calcium sulfate drying tube) and a magnetic stirbar was charged with 2-methyl-1,5-naphthyridine (CAS#7675-32-3, Synchem-OHG #CDP146FP1, 433 mg, 3.0 mmol). Dioxane (10 mL) was added to give a stirred solution, then selenium dioxide (366 mg, 3.3 mmol) was added and the reaction mixture was heated to reflux with an oil bath. The stirred reaction mixture was maintained at reflux for 2 h, then cooled to ambient temperature and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on an Analogix IF-280 (Varian SF25-60 g, 100:0 to 0:100 hexane/EtOAc). Fractions #10-17 were combined and concentrated under reduced pressure to give a white solid that was dried overnight in a vacuum oven at ambient temperature. The dried solid Intermediate 4B, 1,5-naphthyridine-2-carbaldehyde weighed 229 mg (48%). 1H NMR (300 MHz, CDCl3) δ 10.25 (d, J=0.9 Hz, 1H), 9.12 (dd, J=4.2, 1.6 Hz, 1H), 8.60-8.54 (m, 2H), 8.28 (d, J=8.7 Hz, 1H), 7.77 (dd, J=8.6, 4.2 Hz, 1H). MS (DCI—NH3) m/z=159 (M+H)+, m/z=176 (M+NH4)+.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:11]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]=[C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:12]=1)=O)(C)(C)C.C(N1C(CCNC(=O)OC(C)(C)C)=NC(C2C=CC=CC=2)=N1)C1C=CC=CC=1.[ClH:64]>>[ClH:64].[CH2:16]([N:15]1[C:11]([CH2:10][CH2:9][NH2:8])=[N:12][C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:14]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N(CCc1nc(-c2ccccc2)nn1Cc1ccccc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)NCCc1nc(-c2ccccc2)nn1Cc1ccccc1
Agent: Cl
Product: NCCc1nc(-c2ccccc2)nn1Cc1ccccc1

Procedure:
A solution of 5-[2-bis(tert-butoxycarbonyl)aminoethyl]-1-benzyl-3-phenyl-[1,2,4]triazole (103 mg, 215 μmol) and tert-butyl 2-(1-benzyl-3-phenyl-1H-1,2,4-triazol-5-yl)ethylcarbamate (38.5 mg, 102 μmol) in HCl (4M in Dioxane, 3 mL, 12.0 mmol) was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and the resulting solid was poured on diethyl ether (2.5 mL), filtrated off and washed with little diethyl ether. The obtained white crystals were dried (74 mg, 74%) and used without further purification for the next step.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:11][CH2:12][C:6]=2[C:5]([OH:19])=[CH:4][CH:3]=1.S(Cl)([Cl:23])(=O)=O>C1(C)C=CC=CC=1.C(NC(C)C)(C)C>[Cl:23][C:4]1[CH:3]=[C:2]([F:1])[C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])[CH2:11][CH2:12][C:6]=2[C:5]=1[OH:19]
Reactant: O=C(N1CCc2c(O)ccc(F)c2CC1)C(F)(F)F
Reactant: O=S(=O)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: O=C(N1CCc2c(F)cc(Cl)c(O)c2CC1)C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Dissolve 9-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.0 g, 3.6 mmol) in toluene (36 mL) with diisopropylamine (41 μL, 0.29 mmol). Warm to 60° C. and add dropwise a solution of sulfuryl chloride (0.32 mL, 3.97 mmol) in toluene (10 mL). After 2 h, wash the mixture with brine, dry the organic layer over Na2SO4 and evaporate onto silica gel. Purify by chromatography on silica gel eluting with EtOAc/hexane (0:1 to 1:0) to obtain the desired intermediate (1.0 g, 92%). MS (ES+) m/z: 312 (M+H)+.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C(O[C:22]1[C:39]2[C@@H:38]3[C@H:29]([C@H:30]4[C@@:34]([CH2:36][CH2:37]3)([CH3:35])[C:33]([O:40]C(=O)C)=[CH:32][CH2:31]4)[CH2:28][CH2:27][C:26]=2[CH:25]=[C:24]([O:44][CH3:45])[CH:23]=1)(=O)C.CCOCC>C(OC(=O)C)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[C:1]([O:4][C:22]1[C:39]2[C@@H:38]3[C@H:29]([C@H:30]4[C@@:34]([CH2:36][CH2:37]3)([CH3:35])[C:33](=[O:40])[C@@H:32]([O:7][C:5](=[O:8])[CH3:6])[CH2:31]4)[CH2:28][CH2:27][C:26]=2[CH:25]=[C:24]([O:44][CH3:45])[CH:23]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(OC(C)=O)=CC[C@H]3[C@@H]1CC2
Agent: [Pb+4]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)[C@@H](OC(C)=O)C[C@H]3[C@@H]1CC2
Reaction time: 1 h

Procedure:
Lead tetraacetate (0.65 g) is added to a solution of 1,17-diacetoxy-3-methoxyestra-1,3,5(10),16-tetraene (0.5 g, 1.3 mM) in 0.5 ml acetic anhydride and 10 ml glacial acetic acid with stirring. Solution occurs after 1 hr and stirring is continued at room temperature for 16 hrs. The resulting dark brown solution is evaporated in vacuo at 40° to give an oily residue which is dissolved in 150 ml of benzene. The benzene solution is then washed with H2O, 5% NaHCO3 and saturated NaCl solution. The organic layer is dried over MgSO4 and evaporated in vacuo to give a white solid. Trituration with ether gives 1,16β-diacetoxy-3-methoxyestra-1,3,5(10)-trien-17-one as a white solid, yield 0.31 g (62%). Recrystallization from methanol gives 1,16β-diacetoxy-3-methoxyestra-1,3,5(10)-trien-17-one having a m.p. of 191°-192°.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[N:5]=[C:6]([C:11]([NH:13][CH:14]2[CH2:17][N:16]([C:18]3[S:19][C:20]([C:26]([O:28]CC)=[O:27])=[C:21]([CH:23]([CH3:25])[CH3:24])[N:22]=3)[CH2:15]2)=[O:12])[NH:7][C:8]=1[CH2:9][CH3:10].O>CO.C1COCC1>[Cl:3][C:4]1[N:5]=[C:6]([C:11]([NH:13][CH:14]2[CH2:17][N:16]([C:18]3[S:19][C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH:23]([CH3:24])[CH3:25])[N:22]=3)[CH2:15]2)=[O:12])[NH:7][C:8]=1[CH2:9][CH3:10]
Reactant: CCOC(=O)c1sc(N2CC(NC(=O)c3nc(Cl)c(CC)[nH]3)C2)nc1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)NC2CN(c3nc(C(C)C)c(C(=O)O)s3)C2)nc1Cl
Temperature: 40 °C
Reaction time: 1.17 h
Yield: 80.8 %

Procedure:
A 2 N aqueous lithium hydroxide solution (0.72 mL, 1.43 mmol) was added to a mixed solution of ethyl 2-(3-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}azetidin-1-yl)-4-isopropyl-1,3-thiazole-5-carboxylate obtained in Example (221c) (61 mg, 0.14 mmol) in methanol/THF (1.5 mL/1 mL) at room temperature, and the mixture was stirred at 40° C. for 70 minutes. Water was added to the reaction solution, and then the mixture was washed with ethyl acetate. A 1 N aqueous hydrochloric acid solution (1 mL) was added to the aqueous layer, followed by extraction with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The resulting solid was suspended and washed in diethyl ether to obtain 45 mg of the title compound as a white solid (79%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:23]([O:26][CH2:27][C:28]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=[CH:30][C:29]=1[N:43]1[CH2:55][CH2:54][N:46]2[C:47]3[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=3[CH:53]=[C:45]2[C:44]1=[O:56])(=[O:25])[CH3:24].C([O-])([O-])=O.[Na+].[Na+]>>[C:23]([O:26][CH2:27][C:28]1[C:29]([N:43]2[CH2:55][CH2:54][N:46]3[C:47]4[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=4[CH:53]=[C:45]3[C:44]2=[O:56])=[CH:30][CH:31]=[CH:32][C:33]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)(=[O:25])[CH3:24]
Reactant: CC(C)N(C)Cc1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(CN(C)C(C)C)cn3)c(=O)n(C)n2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 61.7 %

Procedure:
Following Example 179a, 180d (125 mg, 0.39 mmol), 114a (215 mg, 0.47 mmol), 1N Na2CO3 (0.86 mL) and tetrakis(trihenyl-phosphine)palladium(0) (23 mg, 5 mol %) were reacted to give 180e (150 mg, 61% yield).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH:30]([NH:33][CH:34]([CH3:36])[CH3:35])[CH2:31][CH3:32])[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:40](=O)[CH3:41].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[CH:30]([N:33]([CH2:40][CH3:41])[CH:34]([CH3:35])[CH3:36])[CH2:31][CH3:32])[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CC=O
Reactant: CCC(NC(C)C)c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCC(c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C)N(CC)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[1-(isopropylamino)propyl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (28.5 mg, 0.0500 mmol) in dichloroethane (1 mL) was added acetaldehyde (2 mL) and NaBH(OAc)3 (excess). The reaction was stirred at room temperature for 16 hours, and then diluted with EtOAc (10 mL) and washed with water and brine (5 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification by PTLC (50% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2 {1-[ethyl(isopropyl)amino]propyl}-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.53 (50% EtOAc/hexanes). LCMS=599.3 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.90 (s, 1H), 7.81 (s, 2H), 7.56-7.49 (m, 3H), 5.78-5.74 (m, 1H), 5.02 (d, J=16.4 Hz, 1H), 4.74-4.71 (m, 1H), 4.07-4-04 (m, 1H), 3.90-3.87 (m, 1H), 2.89-2.85 (m, 1H), 2.62-2.52 (m, 2H), 2.00-1.96 (m, 1H), 1.79-1.72 (m, 1H), 1.26-0.69 (m, 15H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[OH:20])[CH3:13]>C(Cl)Cl>[CH2:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=[O:20])[CH3:13]
Reactant: CCC1CCCCC1O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC1CCCCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
Celite (25 g) and pyridinium chlorochromate (PCC, 25 g, 1.5 eq, 0.12 moles) were added consecutively to a solution of commercially available 2-ethylcyclohexanol (10 g, 78 mmol) in 300 mL CH2Cl2. The resulting reaction mixture was stirred at room temperature for 1 hour after which it was filtered and concentrated on the rotary evaporator. The residue was purified by column chromatography using EtOAc/hex (1:2) as eluant to give 7.57 g (77%) of the title ketone. Spectroscopic data: 1H NMR (CDCl3, 300 MHz) δ=0.89 (t, 3H, J=7.47 Hz), 1.18-1.45 (m, 2H), 1.63-1.89 (m, 4H), 1.99-2.42 (m, 5H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2]1.[H-].[Na+].Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C>[Si:21]([O:20][CH2:19][CH2:18][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1cc(CCC(=O)O)c2ccccc21
Temperature: 0 °C
Yield: 43 %

Procedure:
To a solution of 3-(1H-indol-3-yl)propanoic acid (5 g, 0.026 mol) in DMF (20 mL) was added at 0° C. sodium hydride (2.11 g, 0.088 mol), the mixture was stirred some minutes at 0° C. and (2-bromoethoxy)(tert-butyl)dimethylsilane (5.67 mL, 0.026 mol) was added. The reaction mixture was stirred overnight at room temperature. The crude mixture was poured into a sodium sulphate saturate solution and extracted with ethyl acetate. The solvent was removed under reduced pressure and the crude obtained was purified over silica gel eluting with hexane:ether (100/0 to 0/100) to obtain the title compound (4g, 43%).
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[CH:18]=[C:17]([O:19][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:16]=[CH:15][C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1c(O)c2ccc(O)cc2oc1=O
Reactant: CCOC(=O)CCBr
Product: CCCCCCOc1c(O)c2ccc(OCCC(=O)OCC)cc2oc1=O

Procedure:
In the same manner as in Reference Example 3, except that an equimolar amount of 3-hexyloxy-4,7-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-hexyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and ethyl 3-bromopropionate was used in place of ethyl bromoacetate in Reference Example 3, 3-hexyloxy-4-hydroxy-7-(2-ethoxycarbonylethoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:3]1.C(N(CC)CC)C.[CH:23]1[C:35]2[N:34]([C:36](Cl)=[O:37])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1.O>C(Cl)Cl>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:36]([N:34]3[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:27]4[C:35]3=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:37])[CH2:3]2)=[CH:14][CH:13]=1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: O=C(Cl)n1c2ccccc2c2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)n1c2ccccc2c2ccccc21
Yield: 47.3 %

Procedure:
(S)-3-Amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine (0.42 g) and triethylamine (0.28 ml) were dissolved in methylene chloride (10 ml), and carbazole-N-carbonyl chloride (0.46 g) was added under ice-cooling. After the completion of the reaction, water was added, and the mixture was extracted with chloroform and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and IPE was added to the obtained residue. The precipitated crystals were collected by filtration to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)carbazole-9-carboxamide (0.38 g), melting point 107-108° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH2:17]S(C)(=O)=O)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:22][C:23]([F:41])([F:40])[C:24]1[CH:25]=[C:26]([CH2:34][S:35]([NH:38][CH3:39])(=[O:37])=[O:36])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:41][C:23]([F:22])([F:40])[C:24]1[CH:25]=[C:26]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:34][S:35]([N:38]([CH2:17][C:10]1[CH:11]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=1)[CH3:39])(=[O:36])=[O:37]
Reactant: COC(=O)c1cc(CS(C)(=O)=O)nn1-c1ncccc1Cl
Reactant: CNS(=O)(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(CN(C)S(=O)(=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)nn1-c1ncccc1Cl
Temperature: 50 °C
Reaction time: 12 h

Procedure:
5.00 g (14.4 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-[(methylsulphonyl)methyl]-1H-pyrazole-5-carboxylate were dissolved in 50 ml of acetonitrile, and 4.64 g (14.4 mmol) of 1-[3,5-bis(trifluoromethyl)phenyl]-N-methylmethanesulphonamide were added a little at a time at room temperature. Then 2.40 g (17.35 mmol) of potassium carbonate were added to the reaction solution, and the mixture was stirred at 50° C. for 12 hours. After cooling to room temperature, the reaction solution was freed from the solvent under reduced pressure. 250 ml of water were added to the residue, and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic phases were dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by chromatography. (logP: 3.83; MH+: 571; 1H-NMR (400 MHz, DMSO, δ, ppm): 2.79 (s, 3H), 3.74 (s, 3H), 4.43 (s, 2H), 4.80 (s, 2H), 7.06 (s, 1H), 7.70 (dd, 1H), 8.12 (s, 2H), 8.15 (s, 1H), 8.26 (d, 1H), 8.57 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:13]=[N:14][NH:15][CH:16]=1)=[CH:7][CH:6]=2.[CH:17]12[O:23][CH:22]1[CH2:21][CH2:20][CH2:19][CH2:18]2>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:16]=[N:15][N:14]([CH:21]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:22]3[OH:23])[CH:13]=1)=[CH:7][CH:6]=2
Reactant: C1CCC2OC2C1
Reactant: Clc1cc2cc(-c3cn[nH]c3)ccc2cn1
Product: OC1CCCCC1n1cc(-c2ccc3cnc(Cl)cc3c2)cn1

Procedure:
The title compound was prepared according to the method described for Preparation 45 using 3-chloro-6-(1H-pyrazol-4-yl)isoquinoline and 7-oxabicyclo[4.1.0]heptane.
Reaction SMILES: C([N:3]1[C:10]2[N:6]([N:7]=[CH:8][C:9]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:5][CH2:4]1)=O.Cl.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:14]([O:13][C:11]([C:9]1[CH:8]=[N:7][N:6]2[CH2:5][CH2:4][NH:3][C:10]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c1N(C=O)CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOC(=O)c1cnn2c1NCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a suspension of 1-formyl-2,3-dihydro-7-ethoxycarbonyl-1H-imidazo[1,2-b]pyrazole (40 g) in methanol (200 ml) was added conc. hydrochloric acid (31.9 ml) under ice-cooling. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice-water (300 ml) and adjusted to pH 6.5 with 40% aqueous potassium carbonate solution. The mixture was evaporated to precipitate the crystals. The crystals were collected by filtration to give 2,3-dihydro-7-ethoxycarbonyl-1H-imidazo[1,2-b]pyrazole (33.4 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:9](=[O:20])[N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)[C:7]2=[O:32])(=[O:3])[CH3:2].[BH4-].[Na+].O.Cl>CO>[CH3:31][O:30][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[O:28][CH3:29])[CH2:21][N:8]1[C:7](=[O:32])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=2)[N:10]([CH:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:9]1=[O:20]
Reactant: COc1ccc(Cn2c(=O)c3cc(C(C)=O)ccc3n(C3CCOCC3)c2=O)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(Cn2c(=O)c3cc(C(C)O)ccc3n(C3CCOCC3)c2=O)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.154 of the compound obtained in Step 7.1 and 0.026 g of NaBH4 in 30 ml of MeOH is stirred for 2 hours at room temperature. Water is added and the mixture is neutralized with 1N HCl. The resulting mixture is evaporated under reduced pressure and the residue is taken up in DCM. This solution is filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with EtOAc to give 0.14 g of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Br[CH:12]([CH2:21][CH3:22])[C:13](=O)[CH2:14][C:15]([O:17]CC)=[O:16]>>[CH2:21]([C:12]1[S:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[N:8][C:13]=1[CH2:14][C:15]([OH:17])=[O:16])[CH3:22]
Reactant: NC(=S)c1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)C(Br)CC
Product: CCc1sc(-c2ccc(F)cc2)nc1CC(=O)O

Procedure:
The title compound was prepared from 6.8 g of 4-fluorothiobenzamide and 7.42 g of ethyl 4-bromo-3-oxo-hexanoate as described in example 2B to give 2.9 grams of intermediate 4B as a solid: 1H NMR (CDCl3, 300 MHz) δ7.96 (dd, 2H, J=8.8, 5.3), 7.11 (t, 2H, J=8.6), 3.61 (s, 2H), 2.69 (q, 2H, J=7.5), 1.27 (t, 3H, J=7.5).