Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:35]([Cl:36])=[CH:34][C:10]3[N:11](COCC[Si](C)(C)C)[C:12]([O:14][CH:15]4[CH2:20][CH2:19][CH:18]([C:21]([O:23]CC)=[O:22])[CH2:17][CH2:16]4)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:35]([Cl:36])=[CH:34][C:10]3[NH:11][C:12]([O:14][CH:15]4[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]4)=[N:13][C:9]=3[CH:8]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCC(Oc2nc3cc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(O)C1CCC(Oc2nc3cc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3[nH]2)CC1
Temperature: 80 °C

Procedure:
To a solution of ethyl 4-{[5-(biphenyl-4-yl)-6-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl]oxy}cyclohexanecarboxylate (0.075 g, 0.124 mmol) in 2 mL of THF was added TBAF (0.750 mL, 0.750 mmol) dropwise via syringe. The reaction was heated at 80° C. of 2 h, and then the volatiles were removed. The resulting crude ester was dissolved in 4 mL of MeOH and treated with 1 mL of 2.5 N NaOH. The reaction was heated at 45° C. for 1.5 h, and then concentrated. The resulting residue was dissolved in H2O and acidified to pH 1 with 2 N HCl. The acidified aqueous layer was extracted with EtOAc. The combined organic layers were washed with 2 N HCl, H2O, and brine. The organic layers were dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by reverse phase Gilson™ HPLC (30-100% CH3CN/H2O) afforded the title compound as a white solid. LCMS: calculated for C26H23ClN2O3 446.93, observed m/e 446.94 M+ (Rt 2.11/4 min). 1H NMR (500 MHz, CD3OD): δ7.70-7.64 (m, 4H), 7.55 (s, 1H), 7.49 (d, 2H), 7.47-7.42 (m, 2H), 7.39 (s, 1H), 7.37-7.32 (m, 1H), 4.97-4.89 (m, 1H), 2.45-2.35 (m, 1H), 2.36-2.28 (m, 2H), 2.18-2.10 (m, 2H), 1.76-1.61 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:11]3[C:12]4[C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17](COCC[Si](C)(C)C)[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:7]=[CH:8]2)=[N:3]1.CN(C(ON1N=N[C:41]2[CH:42]=CC=N[C:40]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)CC.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+].[F-].[Cs+].C(O)(C(F)(F)F)=O>CCOC(C)=O.CS(C)=O>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:11]3[C:12]4[C:19]([C:20]([O:22][CH2:40][CH2:41][CH3:42])=[O:21])=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:7]=[CH:8]2)=[N:3]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cn1cc2ccc(-c3ncnc4c3c(C(=O)O)cn4COCC[Si](C)(C)C)cc2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CCCO
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCOC(=O)c1c[nH]c2ncnc(-c3ccc4cn(C)nc4c3)c12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4-(2-Methyl-2H-indazol-6-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (50 mg, 0.12 mmol), HATU (90 mg, 0.24 mmol), and propanol (14.2 mg, 0.236 mmol) were added to DMSO (1.0 mL), followed by Hunig's base (0.103 mL, 0.590 mmol). The reaction was then stirred for 17 hours at room temperature at which point additional HATU (90 mg, 0.236 mmol), Hunig's base (0.103 mL, 0.590 mmol) and propanol (14.2 mg, 0.236 mmol) were added and the reaction stirred for an additional 17 hours at room temperature. Saturated aqueous sodium bicarbonate and EtOAc were added to the reaction mixture. The organic layer was separated and the aqueous layer extracted with EtOAc (×3). The combined organic layers were then washed with brine, dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMSO (1 mL) and CsF (179 mg, 1.18 mmol) was then added. The reaction mixture was heated at 140° C. for 2 hours open to the air. Upon cooling, the solution was made acidic by addition of TFA. The reaction mixture was then filtered and purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. Pure fractions were combined and then saturated aqueous sodium bicarbonate was added. The organic layer was separated and the aqueous layer extracted with 3:1 CHCl3:IPA (×3). The combined organic layers were then washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford propyl 4-(2-methyl-2H-indazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate as a solid. LRMS (ESI) calc'd for C18H18N5O2 [M+11]+: 336; found 336. 1H NMR (600 MHz, DMSO-D6) δ 13.01 (s, 1H), 8.91 (s, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 7.78 (s, 1H), 7.76 (d, 1H, J=8.80 Hz), 7.36 (d, 1H, J=8.80 Hz), 4.22 (s, 3H), 3.68 (t, 2H, J=6.45 Hz), 1.03 (m, 2H), 0.55 (t, 3H, J=7.04 Hz).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[C:19]3[N:18]4[CH:20]=[CH:21][CH:22]=[C:17]4[C:16](=O)[C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH:2]=1.[ClH:24].[NH2:25][OH:26]>N1C=CC=CC=1>[ClH:24].[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[C:19]3[N:18]4[CH:20]=[CH:21][CH:22]=[C:17]4[C:16](=[N:25][OH:26])[C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH:2]=1
Reactant: NO
Reactant: O=C1c2cccc(-c3cnc4ccccc4c3)c2-n2cccc21
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1c2cccc(-c3cnc4ccccc4c3)c2-n2cccc21
Yield: 102.2 %

Procedure:
In a 100 ml round-bottomed flask, a mixture of 231 mg of 5-quinolin-3-ylpyrrolo[1,2-a]indol-9-one obtained according to the preceding stage and 164 mg of hydroxylamine hydrochloride in 20 ml of pyridine is refluxed under argon. After heating for 1.5 hours, the reaction medium is evaporated to dryness under vacuum. The residue is taken up in a saturated solution of sodium bicarbonate and extracted twice with ethyl acetate. The combined organic phases are washed with a saturated solution of sodium bicarbonate and then a saturated solution of sodium chloride, dried over magnesium sulphate, and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (15-40 μm), elution being carried out with a gradient of methanol (2% to 3% v/v) in dichloromethane. 277 mg of 5-quinolin-3-ylpyrrolo[1,2-a]indol-9-one oxime hydrochloride are obtained in the form of a yellowish solid, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](Cl)=[O:10])[C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:12][C:13]1[C:14]([NH:20][CH2:21][CH3:22])=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1.C([O-])(O)=O.[Na+].O>CC#N>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([NH:12][C:13]2[C:14]([NH:20][CH2:21][CH3:22])=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:10])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CCNc1nc(Cl)ccc1N
Reactant: O=C(Cl)c1cc(Br)cnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCNc1nc(Cl)ccc1NC(=O)c1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A solution of 5-bromo-2-chloro-3-pyridinecarbonyl chloride (30.0 g, 97.0 mmol) in MeCN (100 mL) was added via cannula to a solution of 3-amino-6-chloro-2-(ethylamino)pyridine (16.6 g, 97.0 mmol) in MeCN (180 mL) containing solid NaHCO3 (14.2 g, 169 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. Water (200 mL) was added and the mixture was stirred for 10 min. The resulting suspension was filtered. The solid was washed with Et2O (50 mL) and concentrated from pyridine solution (3×50 mL) to give the title compound (28.4 g, 75% yield).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([O:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:16]=3)[N:11]([CH2:22][C:23]([O:25]C)=[O:24])[C:10]=2[CH3:27])=[CH:6][CH:5]=1.O>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([S:18]([CH3:21])(=[O:19])=[O:20])[CH:16]=3)[N:11]([CH2:22][C:23]([OH:25])=[O:24])[C:10]=2[CH3:27])=[CH:28][CH:29]=1
Reactant: COC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2cc(S(C)(=O)=O)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Oc2ccc(Cl)cc2)c2cc(S(C)(=O)=O)ccc2n1CC(=O)O
Reaction time: 2 h

Procedure:
A solution of 1M sodium hydroxide (1 ml) was added to a stirred mixture of the product from step (iii) (235 mg) in THF (1 ml). After 2 h, water (10 ml) was added and the solution extracted with DCM. The solution was acidified with 2 M hydrochloric acid and extracted with ethylacetate. These later organics were dried and evaporated under reduced pressure. Yield 135 mg
Reaction SMILES: [CH:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH2:15]([O:17][C:18]([C:20]1([NH2:30])[CH2:29][C:23]2=[C:24]([CH3:28])[S:25][C:26]([CH3:27])=[C:22]2[CH2:21]1)=[O:19])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([O:17][C:18]([C:20]1([NH:30][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])[CH2:21][C:22]2=[C:26]([CH3:27])[S:25][C:24]([CH3:28])=[C:23]2[CH2:29]1)=[O:19])[CH3:16]
Reactant: Cc1cccc(C(=O)O)c1OC(C)C
Reactant: CCOC(=O)C1(N)Cc2c(C)sc(C)c2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2c(C)sc(C)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a solution of 2-isopropoxy-3-methyl-benzoic acid (300 mg, 1.54 mmol), 5-amino-1,3-dimethyl-5,6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylic acid ethyl ester (443 mg, 1.85 mmol), HATU (878 g, 2.31 mmol) in anhydrous DMF (10 mL) is added DIPEA (382 μL, 2.31 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (70 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5%-50% EtOAc in heptane) to give a pure product (88) as a pale yellow solid (599 mg, 95%).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]2[O:7][C:8]([CH3:21])([CH3:20])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:12]3=[O:19])[C:5]=2[CH:4]=1)#[N:2].[CH3:24][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[C:1]([C:3]1[CH:23]=[CH:22][C:6]2[O:7][C:8]([CH3:20])([CH3:21])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]([OH:18])[CH3:24])=[CH:13][C:12]3=[O:19])[C:5]=2[CH:4]=1)#[N:2]
Reactant: C[Mg]Br
Reactant: CC1(C)C=C(n2ccc(C=O)cc2=O)c2cc(C#N)ccc2O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccn(C2=CC(C)(C)Oc3ccc(C#N)cc32)c(=O)c1
Reaction time: 0.33 h

Procedure:
In 4 ml of anhydrous tetrahydrofuran, is dissolved 355 mg of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-formyl-1-pyridinyl)-2H-benzo[b]pyran obtained in Example 25. Then, 1.73 ml of 0.94 M solution of methylmagnesium bromide in tetrahydrofuran is added at 0° C. and reacted first at that temperature for 50 minutes and then at room temperature for 20 minutes. After stopping the reaction by adding a saturated aqueous solution of ammonium chloride, the reaction mixture is extracted with ethyl acetate, and the organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by silica gel column chromatography using 1/1 mixture of methylene chloride/ethyl acetate as a developing solvent. Thus, 281 mg of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(1-hydroxy)ethyl-1-pyridinyl}-2H-benzo[b]pyran is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])([OH:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH2:19]([O:21][C:22](=[O:25])[CH2:23]Br)[CH3:20].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:25])([OH:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CCC(O)(c1cccc(Cl)c1)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccccc1C(O)(CC)c1cccc(Cl)c1

Procedure:
A solution of 5.3 g. of 1-(3-chlorophenyl)-1-(2-hydroxyphenyl)-propan-1-ol and 3.8 g. of monobromoacetic acid ethyl ester in 60 ml. of dry acetone is boiled in the presence of 0.8 g. of potassium iodide and 6 g. of anhydrous potassium carbonate for 5 hours, with stirring. After cooling the reaction mixture solvent is distilled off under reduced pressure, to the residue water is added and it is extracted with benzene. The benzene phase is extracted with water and a 5% aqueous sodium hydroxide solution, washed to neutral with water and dried over anhydrous magnesium sulfate. Benzene is then distilled off in vacuo and the residue is crystallized from n-hexane. 5.6 g. of the named compound are obtained, melting at 83°-84° C.
Reaction SMILES: [Cl-:1].[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([C:11]2[CH:16]=[CH:15][C:14]([N+]([O-])=O)=[CH:13][C:12]=2[N+]([O-])=O)=[CH:7][CH:6]=1)(=[O:4])[NH2:3].[Cl:23]C1C=CC=CC=1N>CO>[Cl-:23].[C:2]([C:5]1[CH:6]=[CH:7][N+:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[Cl:1])=[CH:9][CH:10]=1)(=[O:4])[NH2:3]
Reactant: NC(=O)c1cc[n+](-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Reactant: Nc1ccccc1Cl
Agent: [Cl-]
Solvent: CO
Product: NC(=O)c1cc[n+](-c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.7 %

Procedure:
A mixture of 4-carbamoyl-1-(2,4-dinitrophenyl)-pyridinium chloride (41 g) and 2-chloroaniline (20 g) in methanol (500 ml) was stirred at ambient temperature for 24 hours. The mixture was then heated under reflux for 24 hours and then a further portion of 2-chloroaniline (10 g) was added. Heating under reflux was continued for a further 48 hours then another portion of 2-chloroaniline (10 g) was added. The mixture was heated for a further 48 hours, then cooled and the solvent removed in vacuo. The residue was triturated with hot acetone (2×11), cooled and the solid collected by filtration. The solid was dissolved in hot methanol (100 ml), treated with charcoal and hot filtered. Hot ethyl acetate (500 ml) was added to the filtrate and the solution was allowed to cool. The resulting solid was collected by filtration, washed with ethyl acetate and dried to give crude 4-carbamoyl-1-(2-chlorophenyl)-pyridinium chloride (23.69 g) which was used without further purification.
Reaction SMILES: C([Si]([O:8][CH2:9][CH2:10][CH:11]([S:21]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[C:12]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=1[F:20])(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>C1COCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([CH:11]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[F:20])[CH2:10][CH2:9][OH:8])(=[O:22])=[O:23])=[CH:25][CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)OCCC(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCO)c1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl-[3-(4-chloro-benzenesulfonyl)-3-(2,3,6-trifluoro-phenyl)-propoxy]-dimethyl-silane (2.62 g, 5.47 mmol) was dissolved in 80 mL of THF and tetrabutylammonium fluoride (1.96 g, 7.51 mmol) was added at room temperature. The solution was stirred at room temperature overnight. 200 mL of EtOAc and 200 mL of water were added and the organic layer was separated. The organic layer was dried over Na2SO4 and concentrated. The product was purified by column chromatography using hex./EtOAc as the eluent (gradient from 0/100 to 75/25 in 45 min, 1.38 g, 69%). 1H NMR (CDCl3 400 MHz) δ 7.63 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.12 (m, 1H), 6.82 (m, 0.5H), 6.71 (m, 0.5H), 4.91 (m, 1H), 3.89 (m, 1H), 4.44 (m, 1H), 2.60 (m, 2H).
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)C=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].C1(C(C2CCCCC2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)CCCCC1>>[CH:3]1([CH2:2][N:24]2[CH2:25][C@@H:26]3[C@@H:19]([NH:18][C:16](=[O:17])[CH:15]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:14]([CH3:33])[CH3:13])[CH2:20][CH2:21][C@@H:22]3[CH2:23]2)[CH2:4][CH2:5][CH2:8][CH2:9][CH2:10]1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(CC3CCCCC3)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting cyclohexanecarbaldehyde for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.57 (dd, J=7.0, 10.9, 1H), 7.64 (dd, J=4.9, 7.0, 2H), 7.34 (t, J=7.6, 2H), 7.25 (t, J=7.4, 1H), 4.37-4.28 (m, 1H), 3.23 (d, J=10.4, 1H), 2.85 (dd, J=2.8, 9.0, 0.5H), 2.70-2.60 (m, 1H), 2.59-2.53 (m, J=4.6, 11.8, 0.5H), 2.51 (dd, J=3.1, 9.1, 1H), 2.44-2.38 (m, 1H), 2.37-2.32 (m, 0.5H), 2.31-2.28 (m, 0.5H), 2.27-2.08 (m, 3.5H), 2.08-1.99 (m, 1H), 1.93-1.73 (m, 3.5H), 1.73-1.54 (m, 3.5H), 1.47-1.27 (m, 2.5H), 1.22 (dd, J=6.5, 10.5, 3H), 1.19-1.06 (m, 3H), 0.90-0.75 (m, 2H), 0.71 (dd, J=2.2, 6.7, 3H); MS (ESI+) m/z 383 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:9]=3[NH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[OH-].[Na+].OO.C([O-])(O)=[O:24].[Na+]>C1COCC1>[OH:24][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]1[C:7]1[C:8]2[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:9]=2[NH:10][CH:11]=1
Reactant: COC(=O)c1cc2[nH]cc(C3=CCCCC3)c2s1
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1cc2[nH]cc(C3CCCCC3O)c2s1
Temperature: 25 °C
Reaction time: 7 h
Yield: 56 %

Procedure:
A 2M solution in THF of borane dimethylsulfide complex (1.5 eq.) was added at 0° C. to a 0.1M solution of methyl 6-cyclohex-1-en-1-yl-4H-thieno[3,2-b]pyrrole-2-carboxylate in dry THF, and the mixture was stirred at RT for 7 h. After cooling to 0° C., the mixture was treated with 3M aq. NaOH (3 eq.) and 35% hydrogen peroxide (4 eq.). The mixture was allowed to warm to RT overnight. Aq. NaHCO3-solution was added and the mixture was extracted with EtOAc; the organic layer was washed with water and brine, dried over Na2SO4 and concentrated. Chromatography (PE/EtOAc) afforded the title compound (56%). 1H-NMR (300 MHz, CDCl3, 300 K, δ) 8.30 (bs, 1H), 7.68 (s, 1H), 7.08 (d, 1H, J 2.0), 3.89 (s, 3H), 3.70-3.65 (m, 1H), 2.58-2.49 (m, 1H), 2.16-2.12 (m, 1H), 1.98-1.65 (m, 4H), 1.47-1.23 (m, 3H); MS (ES+) m/z 280 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][CH2:16][C@:10]2([O:14][CH2:13][C:12](=C)[CH2:11]2)[C@@H:9]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[OH:26]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][CH2:16][C@:10]2([O:14][CH2:13][C:12](=[O:26])[CH2:11]2)[C@@H:9]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CO
Reactant: C=C1CO[C@]2(CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@]2(CC(=O)CO2)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Through a cooled (-80° C.) solution of (6S,5R)-7-(tert-butoxycarbonyl)-3-methylene-6-phenyl-7-aza-1-oxa-spiro[4.5]decane (0.665 g; Desc.3) in dichloromethane (5 ml) and methanol (5 ml) was bubbled a mixture of ozone and oxygen for 0.75 hours. After the solution had been purged with nitrogen, dimethyl sulphide (0.5 ml) was added and then stirred under nitrogen at room temperature for 16 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was dried (MgSO4), evaporated and the residue purified by chromatography on silica gel elutintg with hexane containing increasing proportions of ethyl acetate between 0% to 10%. Evaporation of the fractions gave the title compound. MS (ES+) m/z 332 (M+H), 232 (M+2H-tBuOCO--), 276 (M+2H-tBu). 1H NMR (250 MHz, CDCl3) δ 7.58 (2H, d, J 6.2 Hz), 7.37-7.26 (3H, m), 5.3 (1H, s), 4.15 and 4.09 (2H, AB d, J 17.4 Hz), 3.97 (1H, m), 2.80 (1H, td, J 12.9 Hz and 4.0 Hz), 2.74 and 2.48 (2H, ABd, J 18.1 Hz), 2.29 (2H, m), 1.88-1.63 (2H, m), 1.44 (9H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([C@@H:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:35][N:36]([CH:38]=O)[CH3:37].O>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>[CH3:35][N:36]([CH2:38][C:2]1[CH:10]=[C:9]([C:2]2[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]3[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[O:17])[C:5]3[C:6]([CH3:15])=[CH:7][N:8]([C@H:11]([CH3:12])[CH2:13][CH3:14])[C:9]=3[CH:10]=2)[CH:5]=[CH:4][CH:3]=1)[CH3:37]
Reactant: CC[C@@H](C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(Br)cc21
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CC[C@@H](C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(-c3cccc(CN(C)C)c3)cc21

Procedure:
(R)-6-bromo-1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-1H-indole-4-carboxamide (100 mg, 0.23 mmol), N,N-dimethyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine, HCl (100 mg, 0.34 mmol) and Palladium Tetrakis (26 mg, 0.023 mmol) in DMF/water (3 mL:1 mL) were stirred for 10 min under nitrogen. Cesium carbonate (220 mg, 0.68 mmol) was added and the insoluble mixture was irradiated (microwave) at 150° C. for 15 min. The contents were evaporated, dissolved in DCM/MeOH (1:1), and pre-absorbed on silica gel and purified using silica gel chromatography (eluent: DCM/MeOH/NH4OH, gradient 0 to 80:20:2 in DCM). The isolated product was first treated with EtOAc along with some hexanes. The product was then dissolved in MeOH and purified by reversed-phase HPLC (30×100 Varian Polaris C18 column, eluent: 10-80% gradient of MeCN in water with 0.1% TFA). The product fractions were combined, most of the solvent was evaporated, and a sat. solution of NaHCO3 was added. Solids that crashed out were filtered, air-dried for 15 min, and dried in vaccum-oven overnight. The solid product was collected as 85 mg (75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (s, 1H) 8.21 (t, J=5.05 Hz, 1H) 7.77 (d, J=1.26 Hz, 1H) 7.60-7.66 (m, 2H) 7.41 (t, J=7.58 Hz, 1H) 7.30 (s, 1H) 7.25 (d, J=7.58 Hz, 1H) 7.22 (d, J=1.52 Hz, 1H) 5.87 (s, 1H) 4.60-4.68 (m, 1H) 4.36 (s, 1H) 4.35 (s, 1H) 3.49 (br. s., 2H) 2.24 (s, 3H) 2.19 (d, J=8.84 Hz, 9H) 2.11 (s, 3H) 1.77-1.88 (m, 2H) 1.41 (d, J=6.57 Hz, 3H) 0.74 (t, J=7.33 Hz, 3H); LCMS: 499.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:7][OH:8])[S:5][CH:6]=1.C1C(=O)N([Br:16])C(=O)C1>CN(C=O)C.O>[Br:16][C:6]1[S:5][C:4]([CH2:7][OH:8])=[N:3][C:2]=1[CH3:1]
Reactant: Cc1csc(CO)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(CO)sc1Br
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of (4-methyl-thiazol-2-yl)-methanol (7.0 g, 54.3 mmol) in DMF (80 mL) was added NBS (10.6 mg, 59.6 mmol), and the mixture was stirred at 50° C. overnight. TLC (petroleum ether:EtOAc 2:1) indicated the reaction was completed. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over sodium sulfate, and concentrated in vacuum to give the residue which was purified by a silica gel column (petroleum ether:EtOAc 10:1) to give the title compound (11.2 g, 99%) as a brown solid.