Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:12]([O:15][CH:16]1[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH:17]1[C:24]1[CH:29]=[C:28]([N+:30]([O-])=O)[C:27]([NH:33][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)=O)=[CH:26][C:25]=1F)(=[O:14])[CH3:13]>>[C:12]([O:15][CH:16]1[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH:17]1[C:24]1[C:25]([O:11][C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:26][C:27]2[N:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[NH:30][C:28]=2[CH:29]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC1CCN(C(C)=O)C1c1cc([N+](=O)[O-])c(NC(=O)c2ccccn2)cc1F
Reactant: CS(=O)(=O)c1ccc(O)cc1
Product: CC(=O)OC1CCN(C(C)=O)C1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1

Procedure:
The entitled compound was obtained as a white solid in the same method as in Example 338 (step 5) or in accordance with the method or by combining it with an ordinary method but using 4-(methanesulfonyl)phenol and (1-acetyl-2-(2-fluoro-5-nitro-4-((pyridin-2-ylcarbonyl)amino)phenyl)pyrrolidin-3-yl acetate diastereomer A.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([OH:20])=O.[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.C1CCC(N=C=NC2CCCCC2)CC1>>[CH3:21]/[C:16](/[CH:15]=[CH:14]/[CH:13]=[C:12](\[CH3:22])/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])=[CH:17]/[C:18]([NH:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=[O:20]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Reactant: Nc1ccncc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C\C(=O)Nc2ccncc2)C(C)(C)CCC1
Yield: 86.6 %

Procedure:
Reaction of the reduced retinoic acid (0.83 g, 2.7 mmol) with 4-aminopyridine (0.26 g, 2.7 mmol) was conducted according to the general amide coupling procedure using DCC to obtain the product as a clear yellow oil (0.88 g, 85%). EIMS m/z: 387 ([M+H]+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:26][CH2:27][CH3:28])[C:23]([NH2:25])=O)=[CH:17][CH:16]=1)[CH3:11].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1.O>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:26][CH2:27][CH3:28])[C:23]([NH2:25])=[S:38])=[CH:17][CH:16]=1)[CH3:11]
Reactant: CCOC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(N)=S

Procedure:
3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-ethoxypropanamide (428 mg, 1.1 mmol) was suspended in toluene and Lawesson's reagent (1.1 eq) added. After 3 h at refluxed the suspension was cooled and poured into water. After extraction with chloroform (×3) the extracts were washed with aqueous ammonia, dried and concentrated. Chromatography (methanol/dichloromethane) gave the product as a white solid m.p.=46°-48° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[O:12][CH2:11][CH:10]([CH2:13]O)[CH2:9][O:8]2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=[N:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:37]([NH2:48])(=[O:47])[C:38]1[C:39](=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:40](N)=[O:41].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][N:2]1[C:6]([CH:7]2[O:12][CH2:11][CH:10]([CH2:13][N:48]3[C:37](=[O:47])[C:38]4[C:39](=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:40]3=[O:41])[CH2:9][O:8]2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=[N:3]1
Reactant: Cn1ncc([N+](=O)[O-])c1C1OCC(CO)CO1
Reactant: NC(=O)c1ccccc1C(N)=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1C1OCC(CN2C(=O)c3ccccc3C2=O)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
To a solution of (2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methanol (360 mg, 1.48 mmol, intermediate 68) in dry THF (12 mL) was added polymer supported triphenylphosphine (˜3 mmol/g, 1.5 g, 4.44 mmol) and phthalamide (326 mg, 2.22 mmol) followed by diisopropylazodicarboxylate (450 mg, 2.22 mmol). The reaction mixture was stirred at room temperature for 18 hr then heated at 35° C. for 4 hr. The reaction mixture was filtered and the filtrate diluted with DCM (50 mL) and washed with a saturated aqueous NaHCO3 (25 mL). The organic layer was washed with water (25 mL) and brine (25 mL), separated, dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 2-((2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methyl)isoindoline-1,3-dione as a colourless solid (226 mg) contaminated with diisopropyl azodicarboxylate byproduct. To a suspension of this solid (165 mg, 0.44 mmol) in MeOH (150 mL) and THF (20 mL) was added ammonium formate (300 mg, mmol) and 10% Pd/C (300 mg). The mixture was heated at reflux for 2 hr. The mixture was quickly filtered whilst hot and the cake washed with DCM (50 mL) and EtOAC (50 mL). The filtrate was concentrated under reduced pressure and the crude residue was dissolved in IPA (5 mL) and 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (134 mg, 0.46 mmol) and DIPEA (0.31 mL, 1.76 mmol) were then added. Propylphosphonic anhydride solution (50% wt in EtOAc, 0.33 mL, 0.48 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hr. The mixture was concentrated under reduced pressure and purified via silica gel chromatography (0-5% 7 N NH3 in MeOH/DCM) to give an oil. This oil was dissolved in EtOH (1 mL), hydrazine (1 mL) was added and the mixture heated at reflux for 16 hr. The solvents were removed under reduced pressure and the residue was dissolved in MeOH and passed through an SCX column eluting with 0-5% 7 N NH3 in MeOH/DCM. Purification via preparative HPLC gave 167 as a colourless solid (4 mg, 1% over four steps). 1H NMR (400 MHz, CDCl3) δ 9.82 (s, 1H), 8.25 (s, 1H), 7.36-7.29 (m, 1H), 7.07-6.99 (m, 2H), 6.18 (s, 2H), 5.74 (s, 1H), 4.46 (dd, J=11.4, 4.5 Hz, 2H), 3.88 (s, 3H), 3.67 (t, J=11.3 Hz, 2H), 2.64 (d, J=6.7 Hz, 2H), 2.41-2.32 (m, 1H). Alkyl NH2 not observed. LCMS (ES+) m/z 451 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[F:9][C:10]1[CH:22]=[CH:21][C:13]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=1.[O-]CC.[Na+]>C(O)(=O)C>[C:1]([CH:3]([CH:14]([C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:22][CH:21]=1)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)C=Cc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)CC(c1ccc(F)cc1)C(C#N)C(=O)OCC
Temperature: 5 °C
Yield: 74.9 %

Procedure:
A mixture of ethyl cyanoacetate (13.56 g) and ethyl 4-fluorocinnamate (19.4 g) was added to a solution of sodium ethoxide (2.3 g sodium in 50 ml ethanol) at 60° C. over 2-3 minutes and the mixture heated under reflux for 1 hour then cooled to 5° C. Glacial acetic acid (6 ml) was added slowly to the reaction mixture at below 5° C. The bulk of the ethanol was removed by distillation at reduced pressure the residue diluted with water (40 ml), extracted with toluene (3×30 ml), and the combined organic phases dried over anhydrous magnesium sulphate. The solution was filtered, evaporated to an oil (28.6 g), and distilled at 166-180° C. at 3.5 mbar to produce diethyl 2-cyano-3-(4-fluorophenyl)-glutarate (23 g, 74% yield, 98% purity).
Reaction SMILES: O1C=CC=C1CCC[C:9]([O:11][CH:12](C)C)=[O:10].[CH2:15]([O:18][C:19]1([CH2:28][CH2:29][CH2:30][C:31](OC(C)C)=O)[CH:23]=[CH:22][CH:21]([O:24][CH2:25][CH2:26]C)[O:20]1)[CH2:16]C.O1C=CC=C1CCCCC(OC)=O>[PH4+].C(O)CC.C(O)C>[CH2:15]([O:18][C:19]1([CH2:28][CH2:29][CH2:30][CH2:31][C:9]([O:11][CH3:12])=[O:10])[CH:23]=[CH:22][CH:21]([O:24][CH2:25][CH3:26])[O:20]1)[CH3:16]
Reactant: CCCOC1C=CC(CCCC(=O)OC(C)C)(OCCC)O1
Reactant: CC(C)OC(=O)CCCc1ccco1
Agent: COC(=O)CCCCc1ccco1
Agent: [PH4+]
Solvent: CCO
Solvent: CCCO
Product: CCOC1C=CC(CCCCC(=O)OC)(OCC)O1

Procedure:
Adaptation of the above-described procedures to the preparation of the other compounds of this invention essentially involves the lengthening or shortening of, or the introduction of one or two lower alkyl groups into, the side-chains in furans (I) or (XVII) or in phosphonium derivative (III). These adaptations can be accomplished by procedures well-known to the art. For example, isopropyl γ-(2-furyl)-butyrate provides 2,5-dihydro-2,5-di-n-propoxy-2-(3'-carboisopropoxypropyl)furan in n-propanol whereas methyl δ-(2-furyl)valerate provides 2,5-dihydro-2,5-diethoxy-2-(4'-carbomethoxybutyl)furan in ethanol when treated in the manner described for the conversion of (I) to (II). Similarly, ω-(2-furyl)caproic acid and ω-(2-furyl)enanthic acid provide 2,5-dihydro-2,5-diethoxy-2-(5'-carboxyentyl)furan and 2,5-dihydro-2,5-diethoxy-2-(6'-carboxyhexyl)furan when treated in ethanol in the manner described for the conversion of (XVII) to (XVIII). Optionally, the furyl acids may be first esterified prior to oxidative alkoxylation, and all 2,5-dihydro-2,5-dialkoxy-2-(carboalkoxyalkyl)furans may be converted to the corresponding aldehydes in the manner described for the conversion of (II) to (IV). Also, the reaction of 3-carboxypropyltriphenylphosphonium bromide and 5-carboxy-3,4-dimethylamyltriphenylphosphonium bromide with 2,5-dihydro-2,5-diethoxy-2-(4'-oxobutyl)furan and 2,5-dihydro-2,5-diethoxy-2-(2'-oxoethyl)furan, respectively, provides the 2,5-dihydro-2,5-diethoxy-2-(7'-carboxy-4'-cis-heptenyl)furan and 2,5-dihydro-2,5-diethoxy-2-(7'-carboxy-5',6'-dimethyl-2-cis-heptenyl)furan.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C.O>[N:2]1[NH:10][N:11]=[N:12][C:1]=1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccccc1-c1nn[nH]n1
Temperature: 130 °C
Yield: 96.8 %

Procedure:
A stirred mixture of 2-cyanophenol (2.38 g, 20 mmol), sodium azide (3.9 g, 60 mmol) and ammonium chloride (1.39 g, 26 mmol) in dry DMF (10 mL) was heated at 130° C. for 48 h. After cooling to room temperature, the raction mixture was poured into water (100 mL), and the solution acidified with 6 N hydrochloric acid to pH 1. The precipitate formed was collected by filtration, and dried to give subtitled compound (3.14 g, 97%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[CH:14]([NH2:20])[CH2:13]2>C(N(CC)CC)C.ClCCl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[CH:14]([NH:20][C:2](=[O:3])[O:4][CH2:5][CH3:6])[CH2:13]2
Reactant: CCOC(=O)Cl
Reactant: COc1cc2c(cc1OC)C(N)C2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1Cc2cc(OC)c(OC)cc21
Reaction time: 8 h
Yield: 80 %

Procedure:
1.5 mL of ethyl chloroformate are poured into a suspension of 3.4 g of the compound obtained in Step 1 in 4.5 mL of triethylamine and 50 mL of dichloromethane and left overnight, whilst stiffing at ambient temperature; washing with water and with 1N hydrochloric acid is then carried out. Drying is carried out and the solvent is evaporated off to dryness. 3.2 g of an oil corresponding to the expected product are obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][NH:22][CH2:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6].C[C@@H]1NCCOC1.[OH:38][C:39]([CH3:44])([CH3:43])[C:40](O)=[O:41]>>[OH:38][C:39]([CH3:44])([CH3:43])[C:40]([N:22]1[CH2:21][CH2:20][C:18]2[N:19]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([NH:7][C:5]([NH:4][CH2:3][CH2:2][OH:1])=[O:6])=[CH:13][CH:12]=3)[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]=2[CH2:23]1)=[O:41]
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCO)cc2)nc2c1CNCC2
Reactant: CC(C)(O)C(=O)O
Agent: C[C@H]1COCCN1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCO)cc2)nc2c1CN(C(=O)C(C)(C)O)CC2

Procedure:
Compound hr was prepared generally following the procedures described in Examples 1, 27 and 30 and 147 except that (S)-1-(2-hydroxyethyl)-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea was used instead of tert-butyl 2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate and 3S-3-methylmorpholine was used instead of morpholine in step 1 of Example 1. Additionally, 2-hydroxyisobutyric acid was used instead of oxazole-5-carboxylic acid in Example 147: LC/MS-m/z+499 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.F[C:8]1[CH:18]=[CH:17][C:11]([C:12](OCC)=[O:13])=[C:10]([CH3:19])[CH:9]=1>>[CH3:19][C:10]1[CH:9]=[C:8]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])[CH:18]=[CH:17][C:11]=1[CH2:12][OH:13]
Reactant: CCOC(=O)c1ccc(F)cc1C
Reactant: Cc1ncc[nH]1
Product: Cc1cc(-n2ccnc2C)ccc1CO

Procedure:
Prepared from 2-methylimidazole and ethyl 4-fluoro-2-methylbenzoate.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].OO.S([O-])([O-])(=[O:29])=S.[Na+].[Na+].C(O)C.O>C(O)C>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:29])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:12])([F:11])[F:13]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reaction time: 0.17 h
Yield: 287 %

Procedure:
Vanadium(IV) acetylacetonate (40 mg) was dissolved in ethanol (150 ml), to which 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylthio]benzimidazole (monohydrate) (20.0 g) was added and then 35% aqueous solution of hydrogen peroxide (6.14 g) was added dropwise at 20°-25° C., and the mixture was allowed to react at 20°-25° C. for about 5 hours. After completion of the reaction, a solution of sodium thiosulfate (2.7 g/16 ml) was added to the reaction mixture and stirred vigorously for about 10 minutes. The crystals were collected by filtration and washed with an ice-cooled mixture of ethanol-water (8:2). The crystals thus obtained were treated with a mixture of ethanol-water (9:1, 90 ml), heated (60°-70° C.), and stirred so that the crystals were dissolved, then the insoluble matters were removed by hot filtration. The filtrate was ice-cooled for crystallization and the crystals were collected by filtration, washed with ice-cooled ethanol-water mixture (8:2) and dried in vacuo, to give white needles of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylsulfinyl]benzimidazole (18.1 g). (yield: 91.0%).
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>C(O)C>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(C(=O)N2CCCCC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(c1ccc(CO)cc1)N1CCCCC1
Yield: 65.1 %

Procedure:
The aldehyde (28.6 mmol) thus formed was dissolved in 40 mL of absolute ethanol, and 540 mg NaBH4 was added over 2 hours. When thin-layer chromatography revealed no remaining aldehyde, the reaction was quenched with 2.5 mL acetic acid. The ethanol was removed on a rotary evaporator and the residue was taken up in 30 mL water. The product alcohol was extracted with two 25-mL volumes of CH2Cl2 plus 25 mL ether. The organic extracts were combined and dried over Na2SO4. Removal of the solvents on a rotary evaporator yielded 4.08 g of 1-(4'-hydroxymethylbenzoyl)piperidine, which was collected by filtration and washed with petroleum ether. The product (Compound IV, 1-(4'-hydroxymethylbenzoyl)piperidine) had a melting point of 119.6°-122.7° C. 1H NMR showed the methylene protons at 4.715 (2H, d, J=5.5 Hz) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=O)[NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:5])[CH3:2].O.Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)NCCN1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)c[nH]c1CCNCCN1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A stirred solution of 4-methyl-2-[(2-piperidin-1-yl-ethyl carbamoyl)-methyl]-1H-pyrrole-3-carboxylic acid ethyl ester (3.46 g, 10.8 mmol) in anhydrous tetrahydrofuran (20 ml) was added dropwise slowly with 1M borane-tetrafuran complex in tetrafuran (32.4 ml, 32.4 mmol) under an argon atmosphere. Upon completion of the addition, the mixture was stirred at room temperature for 1 hour and heated to reflux for another 5 hours. The mixture was added with cold water (5 ml) and 1N hydrochloric acid (15 ml) dropwise and stirred for 5 minutes. The mixture was adjusted to pH 10 with 10% aqueous sodium hydroxide solution and extracted with ethyl acetate (10 ml×5). The combined organic extracts were washed with brine (15 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-methyl-2-[2-(2-piperidin-1-yl-ethylamino)-ethyl]-1H-pyrrole-3-carboxylic acid ethyl ester (3.07 g) as a brown oil which was used as such.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH3:14])[CH:7]=[C:6]2[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH3:27])=O.C1(P(=[CH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:51]([O:50][C:48](/[CH:47]=[CH:1]/[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH3:14])[CH:7]=[C:6]2[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH3:27])=[O:49])([CH3:54])([CH3:53])[CH3:52]
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C=O)ccc21
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(/C=C/C(=O)OC(C)(C)C)ccc21

Procedure:
Using a similar procedure to that described in Example 8, part e, except starting from methyl 4-(5-formyl-1-propylindol-3-ylmethyl)-3-methoxybenzoate, and using tert-butyl (triphenylphosphoranylidene)acetate, methyl E-4-[5-[2-(t-butoxycarbonyl)vinyl]-1-propylindol-3-ylmethyl]-3-methoxybenzoate was obtained (98%) as a viscous oil; partial NMR (250 MHz, DMSO-d6): 0.81(t, 3H, CH2CH3), 1.48(s, 9H, C(CH3)3), 1.75(m, 2H, CH2CH3), 3.82(s, 3H, OCH3), 3.91(s, 3H, OCH3), 6.38(d, J=15.8 Hz, 1H, CH=CH), 7.6(d, J=15.8 Hz, 1H, CH=CH).
Reaction SMILES: [NH2:1][C@@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[C@H:3]1[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[C:33](O)=[O:34].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][C@H:3]2[C@H:2]([NH:1][C:33]([C:25]3[O:24][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[CH:26]=3)=[O:34])[CH:7]3[CH2:6][CH2:5][N:4]2[CH2:9][CH2:8]3)[CH:12]=1
Reactant: N[C@@H]1C2CCN(CC2)[C@H]1Cc1cccnc1
Reactant: O=C(O)c1cc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1C2CCN(CC2)[C@H]1Cc1cccnc1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
The (2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane was transferred to a 50 L glass reaction flask equipped with a mechanical stirrer under an inert atmosphere. Dichloromethane (16.5 L), triethylamine (847 mL, 6.08 mol), benzofuran-2-carboxylic acid (948 g, 5.85 mol) and O-(benzotriazol-1-yl)-N,N,N,1-tetramethyluronium hexafluorophosphate (HBTU) (2.17 kg, 5.85 mol) were added to the reaction mixture. The mixture was stirred for a minimum of 4 h at ambient temperature, and the reaction was monitored by HPLC. Upon completion of the reaction, 10% aqueous potassium carbonate (12.7 L, 17.1 mol) was added to the reaction mixture and the mixture was stirred for a minimum of 5 min. The layers were separated and the organic phase was washed with 10% brine (12.7 L). The layers were separated and the organic phase was cooled to 15° C.±10° C. 3 M Hydrochloric acid (8.0 L) was slowly added to the reaction mixture to adjust the pH of the mixture to pH 1. The mixture was then stirred for a minimum of 5 min, and the layers were allowed to partition for a minimum of 5 min. The solids were filtered using a table top filter. The layers of the filtrate were separated, and the aqueous phase and the solids from the funnel were transferred to the reaction flask. 3 M Sodium hydroxide (9.0 L) was slowly added to the flask in portions to adjust the pH of the mixture to pH 14. The aqueous phase was extracted with dichloromethane (2×16.5 L). The combined organic phases were dried over anhydrous sodium sulfate (1.71 kg). The mixture was filtered, and the filtrate was concentrated to give (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-yl)benzofuran-2-carboxamide (1.63 kg, 77.0% yield) as a yellow solid.
Reaction SMILES: Br[CH2:2][C@@H:3]1[CH2:9][C@:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:10][C@H:4]1[CH2:5][CH2:6][C@H:7]2[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([O:25][C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:21][C:20]=1[O:30][CH:31]1[CH2:33][CH2:32]1.[Na].[CH3:35][S:36]([OH:38])=[O:37].[ClH:39]>CN(C)C=O.C(OCC)(=O)C.O>[ClH:39].[ClH:39].[CH:31]1([O:30][C:20]2[CH:21]=[CH:22][C:23]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:24][C:19]=2[CH2:18][NH:17][C@@H:7]2[CH2:6][CH2:5][C@@H:4]3[NH:10][C@@:8]2([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][C@H:3]3[CH2:2][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:32][CH2:33]1
Reactant: FC(F)(F)Oc1ccc(OC2CC2)c(CN[C@@H]2CC[C@@H]3N[C@@]2(c2ccccc2)C[C@H]3CBr)c1
Reactant: CS(=O)O
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)C[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2NCc1cc(OC(F)(F)F)ccc1OC1CC1
Temperature: 110 °C

Procedure:
(1R*,2R*,5S*,6R*)-6-(Bromomethyl)-2-(2-cyclopropoxy-5-(trifluoromethoxy)benzylamino)-1-phenyl-8-azabicyclo[13.2.1]octane (Example 20; 200 mg, 0.38 mmol) was dissolved in N,N-dimethylformamide (5 mL) and the solution treated with the sodium salt of methanesulfinic acid (388 mg, 3.8 mmol). The resulting suspension was heated at 110° C. for 1 hour, then cooled and poured into water (50 mL). The mixture was extracted with ethyl acetate (2×20 mL), the extracts were dried (MgSO4) and then concentrated to give a gum. This was purified by silica chromatography to give the pure free base, which was dissolved in ethyl acetate (10 mL). Ethereal hydrogen chloride (2 mL, 1M) solution was added and the solid formed was removed by filtration and recrystallized from methanol/diethyl ether to give the title compound as a white powder (120 mg, 0.20 mmol).