Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.CCCCCC.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12].[Cl:19][C:20]1[CH:21]=[C:22]([NH:35][C:36]2[C:37]3[C:44]4[CH:45]=[CH:46][C:47](/[CH:49]=[CH:50]/[C:51]([O:53]C)=O)=[CH:48][C:43]=4[S:42][C:38]=3[N:39]=[CH:40][N:41]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1.[NH4+].[Cl-]>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:19][C:20]1[CH:21]=[C:22]([NH:35][C:36]2[C:37]3[C:44]4[CH:45]=[CH:46][C:47](/[CH:49]=[CH:50]/[C:51]([N:16]5[CH2:17][CH2:18][N:13]([CH2:11][CH3:12])[CH2:14][CH2:15]5)=[O:53])=[CH:48][C:43]=4[S:42][C:38]=3[N:39]=[CH:40][N:41]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Reactant: CCN1CCNCC1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCN1CCN(C(=O)/C=C/c2ccc3c(c2)sc2ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To a stirred and cold (0° C.) solution of toluene (5 mL) was added trimethyl aluminum in hexane (2M, 0.77 mL, 1.54 mmol, 4 equiv) and stirred for 10 min at 0° C. followed by addition of 1-ethyl piperazine (48 mg, 0.42 mmol, 1.1 equiv). The resulting mixture was stirred for an additional 5 min at 0° C. and then warmed to rt. A suspension of methyl (2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)[1]benzothieno[2,3-d]pyrimidin-7-yl]acrylate (200 mg) in toluene was added to the above generated mixture. The resulting mixture were heated at 100° C. for 16 h. after cooled to rt, it poured into a cold mixture (0° C.) of NH4Cl aq solution and EtOAc. The resulting gel-like mixture was filtered through a pad of Celite® and pad was washed with EtOAc. The combined EtOAc layers were dried over MgSO4 and concentrated in vacuo. The residue was carefully triturated with ether to yield a yellow solid (200 mg, 86%). 1H-NMR (DMSO-d6) δ 9.08 (s, 1H), 8.54 (m, 3H), 7.92 (dd, 1H), 7.74 (d, 1H), 7.62 (d, 1H), 7.52 (dd, 1H), 7.45 (m, 2H), 7.32 (m, 2H), 7.24 (d, 1H), 7.17 (m, 1H), 5.28 (s, 2H), 3.74 (m, 2H), 3.58 (m, 2H), 2.35 (m, 6H), 1.0 (t, 3H); LCMS RT=3.03 min, [M+H]+=602.0.
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[C:13](O)(=[O:15])[CH3:14].O.OS(O)(=O)=O>>[C:13]([O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])(=[O:15])[CH3:14]
Reactant: CC(=O)O
Reactant: OCCCCCCCCCCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)OCCCCCCCCCCO
Temperature: 25 °C
Yield: 79 %

Procedure:
A solution of 4.36 g (25 mmoles) of 1,10-decanediol in 100 ml (1.77 moles) of glacial acetic acid was mixed with 130 ml (7.22 moles) of H2O containing 0.25 ml (4.5 mmoles) of conc. H2SO4. This mixture, itself at room temperature, was then extracted continuously for two days using refluxing cyclohexane. The cyclohexane layer was then cooled to room temperature and 0.78 g (18% recovery) of crystalline 1,10-decanediol was recovered by simple filtration of this nonpolar organic phase. The cyclohexane was then removed from the filtrate under reduced pressure, affording 4.28 g (approximately 79% yield--97% based on recovered starting material of product. GC analysis showed the presence of less than 2% starting diol; the ratio of monoester to diester was 20 to 1. Hence the desired monoester was approximately 95% pure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]C3C=CC=C4C(NC(=O)C=34)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:28]N>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH2:28])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: O=C1NC(=O)c2c(CCCN3CCC(c4ccc(F)cc4)CC3)cccc21
Solvent: CO
Product: NCCCN1CCC(c2ccc(F)cc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 3-[4-(4-fluorophenyl)piperidin-1-yl] propylphthalimide (4.5 g, 12.3 mmol) in methanol (200 mL) was added 4 ml of hydrazine and the mixture was refluxed for 8 h. It was cooled, and the white solid was filtered and washed with methanol (20 mL). Solvent was evaporated, and the residue was dried under vacuum for 4 h. Chloroform (50 mL) was added to this material, it was stirred for 1 h and filtered. The white solid was washed with more chloroform (20 mL), and the solvent was evaporated from the combined filtrates to leave the crude product as an oil. It was purified by column chromatography on silica gel using dichloromethane/methanol/2M ammonia in methanol (10/3/1) as the eluent.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[CH3:18][C:19]1([CH3:35])[O:24][CH:23]([C:25]([NH:27][CH2:28][CH2:29][C:30](O)=[O:31])=[O:26])[C:22]([CH3:34])([CH3:33])[CH2:21][O:20]1>>[CH2:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[CH2:2][NH:1][C:30](=[O:31])[CH2:29][CH2:28][NH:27][C:25]([CH:23]1[C:22]([CH3:33])([CH3:34])[CH2:21][O:20][C:19]([CH3:35])([CH3:18])[O:24]1)=[O:26])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Reactant: NC[C@H]1CCCN1C(=O)OCc1ccccc1
Product: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)NC[C@H]2CCCN2C(=O)OCc2ccccc2)O1
Yield: 72.3 %

Procedure:
(R)-2-Aminomethyl-1-benzyloxycarbonylpyrrolidine (750 mg) and 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid (829 mg) were Example reacted in the same manner as in Reference Example 25 to obtain 1.10 g of the ojective compound (yield: 72%).
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][OH:14].[Br:15][C:16]1[C:24]2[C:19](=[N:20][C:21](F)=[CH:22][CH:23]=2)[N:18]([CH3:26])[CH:17]=1.O>CN(C=O)C>[Br:15][C:16]1[C:24]2[C:19](=[N:20][C:21]([O:14][CH2:13][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=3)=[CH:22][CH:23]=2)[N:18]([CH3:26])[CH:17]=1
Reactant: Cn1cc(Br)c2ccc(F)nc21
Reactant: OCc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(Br)c2ccc(OCc3ccccn3)nc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.7 %

Procedure:
Potassium tert-butoxide (137.4 g; 1.19 mol) and DMF (1.44 L) are charged into a flask, and a solution of 2-pyridylmethanol (145.8 g, 1.34 mol) in DMF (306 mL) is added over 15 min. The flask is cooled as necessary to maintain room temperature. The mixture is stirred at room temperature for 40 minutes. A solution of 3-bromo-6-fluoro-1-methyl-pyrrolo[2,3-b]pyridine (170 g, 742.2 mmol) in DMF (306 mL) is added over 15 min., maintaining the temperature between 20 and 25° C. The mixture is stirred for 2 h. Water (1.7 L) is added slowly to the mixture, cooling as necessary, followed by extraction with EtOAc (4×1.0 L). The combined extracts are washed with water (4×1.0 L), then brine, and dried over sodium sulphate, filtered and concentrated to leave the product as a yellow solid (235.1 g, 0.74 moles). MS (m/z): 318.0/320.0.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[C:39]1(B2OC(C)(C)C(C)(C)O2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH:40]=1>>[NH2:30][C:29]1[S:28][C:27]([CH:39]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][NH2:8])[CH2:15][CH2:14]1)=[O:24]
Reactant: CC1(C)OB(C2=CCCCCC2)OC1(C)C
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Product: Cn1ncc(NC(=O)c2nc(C3CCCCCC3)sc2N)c1N1CCC(CN)CC1
Yield: 30 %

Procedure:
Following the procedure for Example 281 starting with tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 1-cycloheptenylboronic acid pinacol ester gave 299 as an off-white solid (24 mg, 30% over three steps). 1H NMR (400 MHz, d4-MeOD) δ 7.46 (s, 1H), 3.72 (s, 3H), 3.21-3.08 (m, 4H), 3.07-2.96 (m, 1H), 2.66 (d, J=6.7 Hz, 2H), 2.18-2.09 (m, 2H), 1.85-1.46 (m, 13H), 1.44-1.30 (m, 2H). LCMS (ES+) m/z 432 (M+1)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[F:12][C:13]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccc(F)cc1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 2,4-difluoroaniline to yield 2-[(2,4-difluorophenyl)amino]phenylacetic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][Cl:13])[N:3]=1.O.[NH2:15][NH2:16]>O1CCCC1>[Cl:13][CH2:12][C:4]1[N:3]=[C:2]([NH:15][NH2:16])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: NN
Reactant: ClCc1nc(Cl)c2ccccc2n1
Solvent: O
Solvent: C1CCOC1
Product: NNc1nc(CCl)nc2ccccc12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2.1. 46.0g of 4-chloro-2-(chloromethyl)quinazoline are suspended in 600 ml of absolute tetrahydrofuran. The solution is cooled to 0° C. 23.0 ml of hydrazine hydrate are added dropwise within 5 min., whereby a solution results and the temperature rises to 15° to 20° C. The reaction mixture is stirred at room temperature for 4 h. and then evaporated in a vacuum. The residue is triturated with 0.5 l of dichloromethane and 1 l of a saturated aqueous sodium hydrogen carbonate solution and then filtered. The crystals are washed neutral with water and dried in a vacuum. 38 g of 2-(chloromethyl)-4-hydrazinoquinazoline are obtained. The dichloromethane phase of the filtrate is separated and the aqueous phase is extracted with dichloromethane. By evaporation of the organic phases, there are obtained a further 5.8 g of 2-(chloro-methyl)-4-hydrazinoquinazoline. In total there are obtained 43.8 g of 2-(chloromethyl)-4-hydrazino- quinazoline. M.p. 192° C. (dec.).
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([NH:20][C:21]1[CH:35]=[CH:34][C:24]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[O:26])=[CH:23][N:22]=1)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[N:12]2)=[CH:7][CH:6]=1.[OH-].[Li+].Cl>O.O1CCCC1>[CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([NH:20][C:21]1[CH:35]=[CH:34][C:24]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][N:22]=1)[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[N:12]2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2ccc(-n3cc(C(F)(F)F)cn3)cc2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(Nc1ccc(C(=O)NCCC(=O)O)cn1)c1ccc(-n2cc(C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
Methyl 3-(6-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)butylamino)nicotinamido)propanoate (50 mg, 0.099 mmol) was dissolved in water (5 mL) and tetrahydrofuran (5 mL). Lithium hydroxide (0.387 mL, 2N in water, 0.774 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was neutralized with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by HPLC (column: Boston Analytics Symmetrix ODS-H 150×30 mm, 5 μm; modifier: formic acid 0.225%; gradient: 10 to 80% acetonitrile in water) gave (+/−)-3-(6-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)butylamino)nicotinamido)propanoic acid (25 mg, 52%). 1H NMR (400 MHz, CD3OD, δ): 8.70 (s, 1H), 8.40 (s, 1H), 7.97 (s, 1H), 7.82 (d, 1H), 7.74 (d, 2H), 7.53 (d, 2H), 6.59 (d, 1H), 5.12-5.02 (m, 1H), 3.57 (m, 2H), 2.59 (m, 2H), 1.89-1.69 (m, 2H), 1.68-1.58 (m, 1H), 1.02 (d, 3H), 0.98 (d, 3H). MS (M+1): 490.5.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[N:14]=[CH:13][NH:12][C:11]=3[C:10](=O)[NH:9][C:8]2=[O:17])=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].[OH-].[Na+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[N:14]=[CH:13][NH:12][C:11]=3[C:10](=[S:21])[NH:9][C:8]2=[O:17])=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1[nH]c(=O)n(Cc2ccc(Cl)cc2)c2nc[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=c1[nH]c(=S)c2[nH]cnc2n1Cc1ccc(Cl)cc1
Temperature: 10 °C
Yield: 134.8 %

Procedure:
11.06 g of 3-(4-chlorobenzyl)-xanthine and 11.34 g of phosphorus pentasulfide were heated under reflux in 112 ml of pyridine for 4 hours. After cooling to 10° C., 52 ml of 2N NaOH were added over 30 minutes. The mixture was evaporated to dryness, the residue suspended in 120 ml of water and the pH adjusted to 7.5. The solid was collected, redissolved in 150 ml of 1N NaOH, treated with 0.6 g of charcoal, filtered and neutralized to pH 7.0. The solid was collected again to give the title compound (10.07 g) mp 313-7° C.;
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[CH2:5][CH:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[NH2:7].[C:19]([S:22][CH2:23][CH:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](O)=[O:26])(=[O:21])[CH3:20].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[CH3:2][O:3][C:4](=[O:18])[CH2:5][CH:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[NH:7][C:25](=[O:26])[CH:24]([CH2:23][S:22][C:19](=[O:21])[CH3:20])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: COC(=O)CC(N)c1ccc2ccccc2c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CC(NC(=O)C(CSC(C)=O)Cc1ccccc1)c1ccc2ccccc2c1
Reaction time: 8 h

Procedure:
Mix equimolar parts of β-(2-naphthyl)-β-alanine methyl ester, hydrochloride and 2-acetylthiomethyl-3-phenylpropanoic acid with 1.2 equivalents each of EDC, triethylamine and HOBT in DMF and stir overnight. Evaporate the solvent, partition between EtOAc and water, and concentrate the organic layer. Separate on silica using ether/hexane and crystallize from acetone/hexane to obtain the title compound, m.p. 133°-135° C.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[C:7]=1[C:8](Cl)=[O:9])[CH3:2].[Br:15][C:16]1[C:25]([O:26][CH:27]([C:35]([O:37][CH3:38])=[O:36])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20]([CH2:39][NH3+:40])=[CH:21]2.[Cl-].C(N(CC)CC)C>C(Cl)Cl>[CH3:38][O:37][C:35](=[O:36])[CH:27]([O:26][C:25]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:39][NH:40][C:8]([C:7]3[C:6]4[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=4[O:4][C:3]=3[CH2:1][CH3:2])=[O:9])[CH:21]=2)[C:16]=1[Br:15])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(C[NH3+])ccc2c1Br
Reactant: CCc1oc2ccccc2c1C(=O)Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)OC)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
2-Ethyl-benzofuran-3-carbonyl chloride (0.444 mmol), prepared in step 2 of Example 21, was added under nitrogen to a suspension of 5-bromo-6-(1-methoxycarbonyl-2-phenyl-ethoxy)-naphthalen-2-ylmethyl-ammonium; chloride (0.200 g, 0.444 mmol), prepared in step 3 of Example 53, in 20 mL of methylene chloride. Triethylamine (0.124 mL, 0.888 mmol) was then added to the mixture. The reaction was stirred at room temperature for 18 h (overnight). The reaction was diluted with methylene chloride, extracted one time with 1N HCl and two times with 5% sodium bicarbonate. The organic layer was separated, dried (MgSO4) and the solvent removed under reduced pressure to give 2-(1-bromo-6-{[(2-ethyl-benzofuran-3-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl ester (0.27 g, 100%) as a tan solid, mp 139-143° C.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C@@H:15]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[C:16]2=[O:28])[CH2:3]1.[C:29]([O:33][C:34]([NH:36][C@@H:37]([CH:41]([CH3:43])[CH3:42])[C:38](O)=[O:39])=[O:35])([CH3:32])([CH3:31])[CH3:30].C1CCC(N=C=NC2CCCCC2)CC1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:29]([O:33][C:34]([NH:36][C@@H:37]([CH:41]([CH3:43])[CH3:42])[C:38]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C@@H:7]2[CH2:6][CH2:5][N:4]([C@@H:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=4)[C:16]3=[O:28])[CH2:3][C@H:2]2[F:1])=[CH:9][CH:10]=1)=[O:39])=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(O)cc4)[C@H](F)C3)C2=O)cc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(OC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)cc4)[C@H](F)C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
To a solution of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (0.02 g, 0.052 mmol, example 1) in DCM (3 mL) was added (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (0.059 g, 0.272 mmol) followed by DCC (0.032 g, 0.157 mmol) and DMAP (6.39 mg, 0.052 mmol). The reaction mixture was stirred at room temperature for 18 h. Water (10 mL) was then added, and the layers were separated. The aqueous layer was extracted with DCM (3×10 mL) and the organic layers were combined, dried over Na2SO4, and concentrated to a crude product. The crude product was purified by preparative TLC eluting with 35% ethyl acetate in petroleum ether to provide the purified product (S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (27 mg, 79%). LC/MS (Conditions A) RT=2.523 min, (M+H)+=582.2. 1H NMR (400 MHz, methanol-d4) δ 7.36 (d, J=8.5 Hz, 2H), 7.18 (s, 4H), 7.08 (d, J=8.5 Hz, 2H), 4.80-4.59 (m, J=10.0, 10.0, 5.0 Hz, 1H), 4.51 (d, J=15.0 Hz, 1H), 4.39 (d, J=15.0 Hz, 1H), 4.23 (dd, J=8.3, 6.3 Hz, 1H), 3.72 (t, J=8.8 Hz, 1H), 3.56-3.40 (m, 1H), 3.32-3.22 (m, 2H), 2.86-2.61 (m, 2H), 2.47 (td, J=10.0, 5.0 Hz, 1H), 2.34 (s, 3H), 2.32-2.23 (m, 1H), 2.22-2.01 (m, 2H), 1.88 (dd, J=9.5, 4.0 Hz, 2H), 1.74 (dt, J=13.4, 3.8 Hz, 1H), 1.50 (s, 9H), 1.42-1.30 (m, 1H), 1.09 (dd, J=10.0, 7.0 Hz, 6H). 19F NMR (376 MHz, methanol-d4) δ −184.32.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:14][OH:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)[CH:14]=[O:15])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(CO)cc(C(F)(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=Cc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of [3-nitro-5-(trifluoromethyl)phenyl]methanol (400 mg, 1.88 mmol) in CH2Cl2 (20 mL) was cooled to 0° C. and then Dess-Martin periodinane (1.59 g, 3.76 mmol) was added. The reaction was slowly warmed to room temperature. After stirring at room temperature for twenty minutes, the reaction was poured into 1N NaOH (25 mL). The mixture was extracted with EtOAc (50 mL) and the organic extracts were washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 0% to 15% EtOAc/hexanes afforded 3-nitro-5-(trifluoromethyl)benzaldehyde. Rf=0.39 (15% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 10.18 (s, 1H), 8.91 (s, 1H), 8.74 (s, 1H), 8.48 (s, 1H).
Reaction SMILES: [CH:1]1([N:6]2[CH:10]=[CH:9][CH:8]=[C:7]2[CH:11]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1>[CH:1]1([N:6]2[CH:10]=[CH:9][CH:8]=[C:7]2/[CH:11]=[CH:14]/[C:15]([OH:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=Cc1cccn1C1CCCC1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1cccn1C1CCCC1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
A solution of 1-cyclopentyl-1H-pyrrole-2-carbaldehyde (10.4 g), malonic acid (20.0 g) and piperidine (1.71 mL) in pyridine (64.0 mL) was refluxed overnight. The obtained reaction mixture was allowed to be cooled to room temperature, and then slowly poured into ice and 6N hydrochloric acid (300 mL). The mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.74 g).
Reaction SMILES: BrC1C=NC(N2C3C(=CC=C(C(N(C)C)=O)C=3)C(SC)=C2)=NC=1.Br[C:25]1[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][N:26]=1.CC1C=CN=C(C2C=NC(N3C4C(=CC=C(C(OC)=O)C=4)C(SC)=C3)=NC=2)C=1.CC1C=CN=C([C:67]2[CH:68]=[N:69][C:70]([N:73]3[C:81]4[C:76](=[CH:77][CH:78]=[C:79]([C:82]([N:84]5[CH2:88]CC[CH2:85]5)=[O:83])[CH:80]=4)[C:75]([S:89]([CH3:91])=[O:90])=[CH:74]3)=[N:71][CH:72]=2)C=1>>[NH2:31][C:29]1[CH:28]=[CH:27][N:26]=[C:25]([C:67]2[CH:72]=[N:71][C:70]([N:73]3[C:81]4[C:76](=[CH:77][CH:78]=[C:79]([C:82]([N:84]([CH3:85])[CH3:88])=[O:83])[CH:80]=4)[C:75]([S:89]([CH3:91])=[O:90])=[CH:74]3)=[N:69][CH:68]=2)[CH:30]=1
Reactant: Nc1ccnc(Br)c1
Reactant: Cc1ccnc(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N5CCCC5)cc43)nc2)c1
Agent: COC(=O)c1ccc2c(SC)cn(-c3ncc(-c4cc(C)ccn4)cn3)c2c1
Agent: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N(C)C)ccc12
Product: CN(C)C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4cc(N)ccn4)cn3)c2c1

Procedure:
1-(5-Bromopyrimidin-2-yl)-N,N-dimethyl-3-(methylthio)-1H-indole-6-carboxamide was converted into a boronic ester that was reacted in a Suzuki reaction with 2-bromopyridin-4-amine and the resulting product was then oxidized towards the sulfoxide (analogously to the protocols 269a) and 269d), respectively). White solid. Yield: 0.095 g
Reaction SMILES: [C@@H:1]12[N:8]([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[CH2:4][C@H:3]([OH:10])[CH2:2]2.[Cl:11][C:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13].O>C1C=CC=CC=1>[ClH:11].[O:14]([C:12]([O:10][C@H:3]1[CH2:2][C@H:1]2[N:8]([CH3:9])[C@H:5]([CH2:6][CH2:7]2)[CH2:4]1)=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN1[C@@H]2CC[C@H]1C[C@H](O)C2
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: CN1[C@@H]2CC[C@H]1C[C@H](OC(=O)Oc1ccccc1)C2
Product: Cl
Reaction time: 6 h
Yield: 63.8 %

Procedure:
A solution of 14.1 g (0.1 moles) of tropane-3β-ol (pseudotropine) in 60 ml of absolute benzene is added dropwise to a stirred mixture of 31.3 g (0.2 moles) of phenyl chloroformate and 100 ml of absolute benzene. During addition the mixture is cooled with water. Thereafter the mixture is stirred for 6 hours. The separated crystalline substance is filtered off, washed with benzene and dried. 19.00 g (63.8%) of 3β-phenoxycarbonyloxy-tropane hydrochloride are obtained.