Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C@@H:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.Br[CH:19]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([F:32])[CH:26]=2)[C:20]1=[O:33].CCN(C(C)C)C(C)C>CN(C=O)C>[F:2][C@@H:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=2)[CH2:7][CH2:6][N:5]([CH:19]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([F:32])[CH:26]=3)[C:20]2=[O:33])[CH2:4]1
Reactant: Cc1ccc(CN2CCC(Br)C2=O)cc1F
Reactant: COc1ccc([C@H]2CCNC[C@@H]2F)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc([C@H]2CCN(C3CCN(Cc4ccc(C)c(F)c4)C3=O)C[C@@H]2F)cc1F
Temperature: 120 °C
Yield: 121.7 %

Procedure:
A mixture of (3R,4R)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine hydrochloride (30 mg, 0.114 mmol, from step K), 3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (54 mg, 0.189 mmol, intermediate 6) and DIPEA (0.020 mL, 0.114 mmol) in DMF (3 mL) was heated to 120° C. for 90 min in the a microwave reactor. The solvent was then removed under reduced pressure to obtain 60 mg of 3-((3R,4R)-3-Fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (diastereomeric pair) which was used in the next step without further purification. LCMS (Method P) RT=1.12 min, m/z 433 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>>[CH:33]1([C:36]([NH:1][C@@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=5[O:28][CH2:29][CH:30]5[CH2:31][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:37])[CH2:35][CH2:34]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)C5CC5)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A151) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:22]=[C:21]([N:23]2C(=O)C3C(=CC=CC=3)C2=O)[CH:20]=[CH:19][CH:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.NN>O1CCCC1>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ncoc1C(=NOCc1cccc(N2C(=O)c3ccccc3C2=O)n1)c1ccccc1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncoc1C(=NOCc1cccc(N)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.3 %

Procedure:
To a solution of 2-{6-[({[(4-methyl-1,3-oxazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione (0.3 g, 0.69 mmol) dissolved in tetrahydrofuran (7 mL) was added hydrazine hydrate (171 mg, 3.4 mmol). After stirring for 24 hours at room temperature the precipitate formed was filtered. The filtrate was evaporated and purified on silica affording 6-[({[(4-methyl-1,3-oxazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine (0.19 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:11](COCC[Si](C)(C)C)[C:10]([O:20][C@H:21]3[C@H:25]4[O:26][CH2:27][C@@H:28]([OH:29])[C@H:24]4[O:23][CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1I.[C:30]1([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([O:20][C@H:21]3[C@H:25]4[O:26][CH2:27][C@@H:28]([OH:29])[C@H:24]4[O:23][CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1[N:39]1[CH2:40][CH2:41][CH:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:37][CH2:38]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(I)c(Cl)cc21
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(N3CCC(c4ccccc4)CC3)c(Cl)cc2[nH]1
Temperature: 90 °C

Procedure:
A 2 dram vial was charged with (3R,3aR,6R,6aR)-6-((6-chloro-5-iodo-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (Intermediate 3, 300 mg, 0.542 mmol), 4-phenylpiperidine (96 mg, 0.596 mmol), L-proline (12.47 mg, 0.108 mmol), cuprous iodide (10.32 mg, 0.054 mmol), potassium carbonate (150 mg, 1.083 mmol), and DMSO (1354 μl). The reaction vial under nitrogen was placed in a heating block set to 70° C. and then heated to 90° C. for 16 hours. The reaction was cooled to r.t. and diluted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The resulting residue was purified via silica gel chromatography using methanol/dichloromethane to afford the title compound as an orange waxy solid. LC-MS: calculated for C29H39ClN4O5Si 586.24 observed m/e: 587.44 (M+H)+ (Rt 1.41/2 min).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14](S(C)(=O)=O)[C:9]=3[CH:8]=2)=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=[CH:3]1.[NH3:26]>O1CCOCC1>[CH3:1][N:2]1[C:6]([C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:26])[C:9]=3[CH:8]=2)=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=[CH:3]1
Reactant: N
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Solvent: C1COCCO1
Product: Cn1cnc(-c2ccccc2)c1-c1cc2c(N)ncnc2s1
Yield: 100 %

Procedure:
6-(1-Methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (intermediate 17) (30 mg) and concentrated NH3 (0.75 mL) were stirred in 1,4-dioxane (3 mL) for 1 hour. The solvent was evaporated and the resultant residue dissolved in a small volume of DCM. Isohexane was then added and the resultant solid filtered and dried in vacuo to give the title compound as a pale yellow solid (25 mg, 100%);
Reaction SMILES: [CH:1]([C:13]([O:15]CC)=O)([C:8]([O:10][CH2:11]C)=[O:9])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C[O-].[Na+].[CH3:21][C:22]([OH:41])([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])/[CH:23]=[CH:24]/[CH:25]1[CH2:27][C:26]1(C(OC)=O)[C:28]([O:30][CH3:31])=[O:29]>CO>[C:3]([CH2:2][C:1]1([C:8]([O:10][CH3:11])=[O:9])[C@@H:25]([CH:24]=[CH:23][C:22]([OH:41])([CH3:21])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:27][C@H:26]([C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:15])([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCCCC(C)(O)/C=C/C1CC1(C(=O)OC)C(=O)OC
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCC(C)(O)C=C[C@H]1C[C@H](C(=O)OC)C(=O)C1(CC(=O)OCC)C(=O)OC
Reaction time: 0.25 h

Procedure:
To a solution of triethyl 1,1,2-ethanetricarboxylate (1.36 g) in 3 ml of methanol, a freshly prepared solution of sodium methoxide (from 0.126 g of sodium and 6 ml of absolute methanol) is added. The mixture is heated to 80°. A solution of dimethyl trans-(3-methyl-3-hydroxy-1-octenyl)cyclopropane-1-1-dicarboxylate (1.7 g) is gradually added and the resulting mixture stirred for an additional 15 min. The methanol is removed by distillation at reduced pressure. The residue is then heated at 100° for 45 min. Thereafter the mixture is cooled in an ice bath and rendered neutral with acetic acid. The mixture is extracted with ether. The extract is dried (Na2SO4) and concentrated. Chromatography of the residue on silica gel using ethyl acetate-benzene (1:4) as eluant gives the title compound, νmaxfilm 3350, 1727 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:23]=[CH:22][C:10]([O:11][Si](C(C)C)(C(C)C)C(C)C)=[CH:9][C:8]=2[C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:6][CH2:5]1)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4]1([C:7]2[CH:23]=[CH:22][C:10]([OH:11])=[CH:9][C:8]=2[C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC1(c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC1(c2ccc(O)cc2C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 110.8 %

Procedure:
To a solution of [4-(1-ethoxycyclopropyl)-3-tert-butyl-phenoxy]-triisopropyl-silane (Intermediate 108, 600.0 mg, 1.54 mmol) in 3 mL THF at 0° C. was added tetrabutylammonium fluoride (802.8.0 mg, 3.07 mmols; 3.1 mL of a 1 M solution in THF). The solution was stirred at 0° C. for 30 minutes and then quenched by the addition of H2O The mixture was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous Nacl before being dried (MgSO4) and concentrated under reduced pressure. The title compound (400 mg, 88%) was isolated from the residue by column chromatography (4-10% EtOAc-hexanes) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH3:12][NH:13][CH2:14][CH2:15][OH:16]>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7]([N:13]([CH3:12])[CH2:14][CH2:15][OH:16])=[O:9])=[C:4]([OH:8])[CH:3]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2o1
Reactant: CNCCO
Solvent: CO
Product: CN(CCO)C(=O)Nc1ccc(Cl)cc1O
Temperature: 65 °C

Procedure:
6-Chlorobenzoxazolinone (20 g) and N-methylethanolamine (17.7 g) in methanol (40 ml) were stirred and heated at 65° C. for 3 hours. The mixture was cooled to ambient temperature, filtered, and the residue was washed with diethyl ether to give the desired urea which melted at 178° C. (decomp.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:20](OC)=[O:21])[C:17]2[C:12](=[C:13]([F:19])[CH:14]=[C:15]([F:18])[CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[C:17]2[C:12]=1[CH2:11][CH2:10][C:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:20][OH:21]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCc2c(F)cc(F)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CO)CCc2c(F)cc(F)cc21
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 1-[(tert-butoxycarbonyl)amino]-4,6-difluoroindane-1-carboxylate from Step D (2.80 g, 8.55 mmol) in THF (30 mL) at −78° C. was added LiAlH4 (18.0 mL of a 1 M solution in THF, 18.0 mmol), dropwise, over 30 min. The reaction mixture was stirred at −78° C. for 2 h, then quenched with H2O (1 mL), then 1 N aqueous NaOH (2 mL), then H2O (2 mL), then EtOAc (2 mL). The reaction mixture was warmed to ambient temperature, saturated aqueous NaHCO3 (150 mL) was added, and the mixture was extracted with EtOAc (200 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 50:50, to give the title compound. MS: m/z=244 (M−C4H7).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>O1CCCC1>[N:9]1([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: O=C1CCCC(=O)O1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=C(O)CCCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 52.3 %

Procedure:
Glutaric anhydride (1.14 g) is dissolved in tetrahydrofuran (20 ml), and thereto is added morpholine (0.87 g). The mixture is then stirred at room temperature for 19 hours. The reaction solution is concentrated under reduced pressure, and the residue is diluted with chloroform and washed with 10% hydrochloric acid. The organic layer is dried over sodium sulfate and evaporated to remove the solvent under reduced pressure to give the title compound (1.05 g). ESI-MS M/Z:200[M−H]−
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH2:14][C:15](=[O:19])[NH:16]3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[N:20]1([CH2:25][CH2:26][NH:27][C:28]([C:30]2[C:34]([CH3:35])=[C:33]([CH:36]=O)[NH:32][C:31]=2[CH3:38])=[O:29])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([CH2:25][CH2:26][NH:27][C:28]([C:30]2[C:34]([CH3:35])=[C:33]([CH:36]=[C:14]3[C:13]4[C:17](=[CH:18][C:10]([C:6]5[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=5)=[CH:11][CH:12]=4)[NH:16][C:15]3=[O:19])[NH:32][C:31]=2[CH3:38])=[O:29])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: CC(C)c1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(-c4cccc(C(C)C)c4)ccc32)c(C)c1C(=O)NCCN1CCCC1
Yield: 62.6 %

Procedure:
6-(3-Isopropylphenyl)-1,3-dihydroindol-2-one (48 mg, 0.19 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (50 mg) to give 59 mg (63%) of the title compound as an orange solid.
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.C1C=CC(COC([NH:34][C@H:35]([C:40](O)=[O:41])[CH2:36][C:37]([NH2:39])=[O:38])=O)=CC=1>>[NH2:34][C@@H:35]([CH2:36][C:37](=[O:38])[NH2:39])[C:40]([NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19][P:10]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:11])[OH:9])=[O:41]
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: Cl
Product: NC(=O)C[C@H](N)C(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1

Procedure:
The title compound was prepared substantially following the procedures as set forth in Step 4, Example 1, Method A, and employing ((R)-3-Amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-L-asparagine-OH as the starting materials. Subsequent hydrogenation of the resulting product in accordance with the procedures of Step 5, Example 1, Method B, and RP-HPLC purification yielded the title compound. 1H NMR (CD3OD, 300 MHz): δ 4.26-4.13 (m, 1H), 4.12-3.98 (m, 1H), 3.42-3.32 (m, 2H), 2.98-2.71 (m, 2H), 1.93 (br.d, 2H), 1.84-1.58 (m, 6H), 1.51 (dd, 2H), 1.42-1.15 (m, 3H), 1.13-0.94 (m, 2H). 31P NMR (CD3OD, 300 MHz): δ 40.16. LCMS m/z: [M+H]+=350.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]=C)[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].I([O-])(=O)(=O)=[O:18].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]=[O:18])[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: C=Cc1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(Cl)nc(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 2-chloro-6-vinylisonicotinate (9.6 g, 40.1 mmol) in THF (100 mL) and water (100 mL) were added osmium tetroxide (4% in water; 6.3 mL, 0.80 mmol) and sodium periodate (25.7 g, 120.0 mmol). The mixture was stirred at ambient temperature. After 30 min, saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:21][CH:22]=O)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:24]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=[O:30].C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:21][CH2:22][N:34]2[CH2:33][CH2:32][CH:31]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C:25]3=[O:30])[CH2:36][CH2:35]2)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCCCN1C1CCNCC1
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C[C@@H](CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
(S)—N-[2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methylbenzamide (0.78 g) in methanol (3 mL) was added to a solution of [1,4′]bipiperidinyl-2-one (0.34 g) and acetic acid (0.15 mL) in methanol (8 mL). After 10 minutes, sodium cyanoborohydride (0.17 g) in methanol (4 mL) was added in a single portion. After being stirred overnight, the reaction mixture was diluted with saturated aqueous sodium bicarbonate, stirred for 30 minutes, and extracted with dichloromethane (4×50 mL). The organic extracts were dried, evaporated, and purified by chromatography, with dichloromethane:methanol (gradient 95:5, 90:10) as eluent to give the title compound (0.95 g). MS: m/z=516(M+). The product was dissolved in methanol (2 mL) and citric acid was added. The solution was concentrated and the residue was triturated with ether. The product was obtained as a white foam (1.2 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[C:6]([I:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1.B(Br)(Br)Br>ClCCl>[I:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[C:6]([I:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1
Reactant: COc1ccc(Oc2c(I)cc(O)cc2I)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(I)cc(O)cc2I)ccc1O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
To a stirred solution of 3,5-diiodo-4-(4′-methoxy-3′-iso-propylphenoxy)phenol (0.28 g, 0.55 mmol) in dichloromethane (17.0 mL) at −78° C. was added BBr3 (13.1 mL, 13.1 mmol, 1.0 M solution in CH2Cl2). The reaction mixture was stirred at −78° C. for 10 min, allowed to warm to room temperature and stirred for 16 h. The reaction mixture was poured into ice and extracted with CH2Cl2 (20 mL×2). The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with acetone-hexanes (3:7) to afford 3,5-diiodo-4-(4′-hydroxy-3′-iso-propylphenoxy)phenol as an off-white solid (0.18 g, 66%): 1H NMR (300 M , DMSO-d6): δ 9.95 (s, 1 H), 8.91 (s, 1 H), 7.27 (s, 2 H), 6.62 (d, J=9.0 Hz, 1 H), 6.56 (d, J=3.0 Hz, 1 H), 6.18 (m, 1 H), 3.72 (s, 3 H), 3.14 (m, 1 H), 1.10 (d, J=6.0 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-acetone (7:3); Rf=0.28.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:15])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[Li]CCCC.CN([CH:24]=[O:25])C>C1COCC1>[CH3:15][N:6]1[C:5]2[CH:4]=[CH:3][C:2]([CH:24]=[O:25])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: Cn1c2ccccc2c2cc(Br)ccc21
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c2ccccc2c2cc(C=O)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 2b (1.8 g, 6.9 mmol) in dried THF (45 mL) was added n-BuLi (3.3 mL 8.3 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 1 h and then added with dried DMF (8 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight before quenched with aqueous ammonia chloride solution. Water was added and extracted with ethyl acetate three times. The combined organic phase was washed with brine and dried over anhydrous sodium sulfate. After removing the solvent, the residue was purified by silica gel chromatography using ethyl acetate and petroleum ether (EA:PE=1:4) as eluent to afford 3b (0.86 g) in 60% yield. 1H NMR (400 MHz, CDCl3) δ 9.58 (s, 1H), 7.79 (s, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.09 (t, J=7.6 Hz), 6.90 (t, J=7.6 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 6.61 (d, J=8.4 Hz, 1H), 3.00 (s, 3H). 13C NMR (400 MHz, CDCl3) δ 190.9, 143.2, 140.5, 127.4, 125.8, 122.7, 121.7, 119.6, 119.4, 108.3, 107.6, 28.0.
Reaction SMILES: [N+:1]([N:3]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[C-:2].[C:23]1([CH2:33][C:34]([NH:36][C:37]2[CH:41]=[CH:40][S:39][C:38]=2[C:42]([OH:44])=O)=[O:35])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[O:44]1[CH:2]=[N:1][N:3]=[C:42]1[C:38]1[S:39][CH:40]=[CH:41][C:37]=1[NH:36][C:34](=[O:35])[CH2:33][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cc1cccc2ccccc12)Nc1ccsc1C(=O)O
Reactant: [C-]#[N+]N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C(Cc1cccc2ccccc12)Nc1ccsc1-c1nnco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
To a solution of (isocyanoimino)triphenylphosphorane (978 mg, 3.24 mmol) in anhydrous CH2Cl2 (30 mL) was added dropwise a solution of 3-(2-(naphthalen-1-yl)acetamido)thiophene-2-carboxylic acid (340 mg, 1.09 mmol) in anhydrous CH2Cl2 (27 mL). The resulting mixture was stirred at room temperature under nitrogen overnight and evaporated under reduced pressure. Purification by flash chromatography (silica, 30:70 ethyl acetate/hexane) gave N-(2-(1,3,4-oxadiazol-2-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide (45 mg, 12%). Method [7] m/z 357.9 (M+Na); retention time=5.919. 1H-NMR (CDCl3) δ 8.18 (d, J=1.1 Hz, 1H), 8.16 (d, J=1.4 Hz, 1H), 8.05 (d, J=8.3 Hz, 1H), 7.88 (d, J=8.0 Hz, 2H), 7.61-7.41 (m, 5H), 4.27 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:24])OC3C=CC=CC=3)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH3:35][C:36]1[S:37][C:38]([S:42]([NH2:45])(=[O:44])=[O:43])=[C:39]([CH3:41])[N:40]=1>>[CH3:35][C:36]1[S:37][C:38]([S:42]([NH:45][C:16]([NH:15][CH2:14][CH2:13][C:10]2[CH:9]=[CH:8][C:7]([N:6]3[C:2]([CH3:1])=[C:3]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:4]([C:25]([F:26])([F:27])[F:28])=[N:5]3)=[CH:12][CH:11]=2)=[O:24])(=[O:43])=[O:44])=[C:39]([CH3:41])[N:40]=1
Reactant: Cc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reactant: Cc1nc(C)c(S(N)(=O)=O)s1
Product: Cc1nc(C)c(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C(F)(F)F)c(-c4ccccc4)c3C)cc2)s1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-{4-[5-methyl-4-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}ethylcarbamate (step 7 of Example 52) and 2,4-dimethyl-1,3-thiazole-5-sulfonamide: MS (ESI) m/z 564 [M+H]+, 562 [M−H]−, 1H-NMR (CDCl3) δ 7.45-7.32 (9H, m), 6.19 (1H, br.s), 3.49 (2H, t, J=6.6 Hz), 2.89 (2H, t, J=6.6 Hz), 2.67 (3H, s), 2.60 (3H, s), 2.21 (3H, s).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].O>C1(C)C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][OH:6]
Reactant: CSc1ccccc1C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CSc1ccccc1CO
Reaction time: 5 h
Yield: 100.3 %

Procedure:
5 g of 2-methylsulfanylbenzoic acid were dissolved in 50 ml of toluene, treated in portions at 20° C. with 14.5 ml of a solution of sodium dihydridobis(2-methoxy-ethoxy)aluminate (Red-AI®; 65% strength in toluene) and stirred for 5 h. The reaction mixture was added to 200 ml of water and extracted three times with 100 ml each of EA. The combined organic phases were dried with magnesium sulfate and the solvent was removed in vacuo. 4.6 g of the crude title compound were obtained as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4](/[CH:12]=[CH:13]\[S:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:5]([C:7](OCC)=[O:8])[N:6]=1.[NH3:34].O1CCOCC1>>[NH2:1][C:2]1[S:3][C:4](/[CH:12]=[CH:13]\[S:14][C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:5]([C:7](=[O:8])[NH2:34])[N:6]=1
Reactant: CCOC(=O)c1nc(N)sc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N
Solvent: C1COCCO1
Product: NC(=O)c1nc(N)sc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
In the same manner as in step b) in Example 3 and step c) in Example 3, 197 mg of the title compound was prepared from 501 mg of 2-amino-4-ethoxycarbonyl-5-((Z)-2-tritylthioethen-1-yl)thiazole and 8 ml of a 0.5 M ammonia/dioxane solution.