Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@H:13]([NH:24][C:25]3[C:26]([CH3:34])=[CH:27][C:28]([Cl:33])=[C:29]([CH:32]=3)[C:30]#[N:31])[C@@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:15])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl.N1C=CC=CC=1>[Si:17]([O:16][C@@H:14]([CH3:15])[C@H:13]([C:11]1[O:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:37])[CH3:36])=[CH:7][CH:6]=2)=[N:9][N:10]=1)[NH:24][C:25]1[CH:32]=[C:29]([C:30]#[N:31])[C:28]([Cl:33])=[CH:27][C:26]=1[CH3:34])([C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:19])[CH3:18]
Reactant: Cc1cc(Cl)c(C#N)cc1N[C@@H](c1nnc(-c2ccc(N)cc2)o1)[C@H](C)O[Si](C)(C)C(C)(C)C
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2nnc([C@H](Nc3cc(C#N)c(Cl)cc3C)[C@H](C)O[Si](C)(C)C(C)(C)C)o2)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a pre-cooled (0° C.) solution of 5-((1R,2S)-1-(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-(tert-butyldimethylsilyloxy)propylamino)-2-chloro-4-methylbenzonitrile (intermediate 77d) (200 mg, 0.40 mmol) in CH2Cl2 (4.0 mL) and pyridine (1.04 mL) was added, portion wise, acetyl chloride (0.14 mL, 2.0 mmol). Upon complete addition the reaction mixture was warmed slowly to room temperature and stirred for 23 h. The reaction mixture was then cooled to 0° C. and quenched with 10% ap HCl (5 mL) then H2O (15 mL) was added. The solution was extracted with CH2Cl2 (2×30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide an orange oil, which was used without further purification (199 mg, 92%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.11 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.6 Hz, 2H), 7.80 (br s, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 5.57 (d, J=8.9 Hz, 1H), 4.99 (dd, J=1.8, 8.9 Hz, 1H), 4.76-4.68 (m, 1H), 2.58 (s, 3H), 2.44 (s, 3H), 1.62 (d, J=6.3 Hz, 3H), 1.07 (s, 9H), 0.27 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7][C:6]=2[O:5][C:4](=[O:16])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH:30]([CH3:33])[CH2:31]Cl)[CH2:25][CH2:24]1>>[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH:30]([CH3:33])[CH2:31][O:1][C:2]2[C:11]3[CH2:10][CH:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7][C:6]=3[O:5][C:4](=[O:16])[C:3]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(C)C1CCc2oc(=O)c(-c3ccccc3)c(O)c2C1
Reactant: CC(CCl)CN1CCOCC1
Product: CC(COc1c2c(oc(=O)c1-c1ccccc1)CCC(C(C)(C)C)C2)CN1CCOCC1

Procedure:
Prepared according to the method of Example 9 from 12.8 g. (0.043 mol) of 4-hydroxy-3-phenyl-6-tert.butyl-5,6,7,8-tetrahydro-coumarin and 10.7 g. (0.061 mol) of 3-morpholino-2-methyl-1-chloropropane. The product is a thick oil which cannot be crystallised.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=3)=[O:22])=[C:7]([CH:18]([CH3:20])[CH3:19])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:33].Cl[CH2:35][CH2:36][N:37]=[C:38]=[S:39]>C(Cl)Cl.CCN(CC)CC>[CH2:11]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([F:33])=[C:2]([NH:1][C:38]3[S:39][CH2:35][CH2:36][N:37]=3)[CH:10]=2)[C:6]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[O:22])=[C:7]1[CH:18]([CH3:19])[CH3:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: S=C=NCCCl
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(F)c(N)cc2n1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(F)c(NC3=NCCS3)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
General Procedure AA. To a solution of 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-5-fluoro-2-isopropyl-1H-indole-3-carboxamide (Compound 172, 39 mg, 0.086 mmol) in CH2Cl2 (1 ml) was added 2-chloroethyl isothiocyanate (25 μl, 0.26 mmol) and Et3N (1 drop). The reaction was stirred at room temperature for 16 h and was purified directly by chromatography on silica gel (0→60% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [BrH:1].C1(COC([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:22]4[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=4[O:20][N:19]=3)[CH2:14][CH2:13]2)=O)C=CC=CC=1>C(O)(=O)C>[BrH:1].[CH3:28][O:27][C:25]1[CH:24]=[CH:23][C:22]2[C:18]([CH:15]3[CH2:14][CH2:13][NH:12][CH2:17][CH2:16]3)=[N:19][O:20][C:21]=2[CH:26]=1
Reactant: COc1ccc2c(C3CCN(C(=O)OCc4ccccc4)CC3)noc2c1
Agent: Br
Solvent: CC(=O)O
Product: COc1ccc2c(C3CCNCC3)noc2c1
Yield: 79.8 %

Procedure:
To 30 ml of a saturated solution of hydrogen bromide and acetic acid was added, with stirring, 0.88 g of 4-(6-methoxy-1,2-benzisoxazol-3-yl)-1-piperidine carboxylic acid phenylmethyl ester. The reaction was stirred at ambient temperature for 55 min. The resultant solid was collected, washed with ether and dried to yield 0.5 g (79.8%) of product. Recrystallization from methanol gave the analytical sample, mp 258°-260°.
Reaction SMILES: C([NH:20][C@@H:21]([CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:22]([CH3:24])[CH3:23])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CCOCC>[CH3:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][C@@H:21]([CH:22]([CH3:24])[CH3:23])[NH2:20]
Reactant: COCCOCCOC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Solvent: CCOCC
Product: COCCOCCOC[C@H](N)C(C)C

Procedure:
A solution of N-Trityl-O-[2-(2-methoxyethoxy)-1-ethyl]-(D)-valinol (1.0 g, 2.28 mmol) in dry ether saturated with ECl gaz (20 ml) was kept for 2.5 hours at room temperature. After concentration in vacuo, the resulting solid (1.16 g) was purified by flash chromatography (silica gel, dichloromethane first to elute trityl alcohol and then dichloromethane/diethylamine: 95/5, Rf.: 0.20) to give the title free amine as a colorless oil (0.46 g, quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:33])[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@H:9]([O:20][C:21](=[O:31])[CH2:22][C:23]1[S:24][C:25]([CH2:28][CH2:29][OH:30])=[CH:26][CH:27]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Cl:32][C:6]1[CH:5]=[N+:4]([O-:33])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@H:9]([O:20][C:21](=[O:31])[CH2:22][C:23]1[S:24][C:25]([CH2:28][CH:29]=[O:30])=[CH:26][CH:27]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)Cc2ccc(CCO)s2)cc1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)Cc2ccc(CC=O)s2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a solution of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]2-[5-(2-hydroxyethyl)-2-thienyl]acetate (80 mg, 0.16 mmol) in dichloromethane (2 mL) at −78° C. was added Dess-Martin periodinane (81 mg, 0.19 mmol). The reaction solution was stirred at room temperature for 30 minutes. The reaction solution was washed with saturated aqueous sodium thiosulfate (5 mL) followed by saturated aqueous sodium bicarbonate (5 mL). The organic phase was passed through a hydrophobic fit and concentrated in vacuo to give [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]2-[5-(2-oxoethyl)-2-thienyl]acetate as a brown solid (76 mg, 94%) which was used in the next step without further purification. To a solution of the crude residue (199 mg, 0.39 mmol) in ethanol (20 mL) was added [(3R)-quinuclidin-3-yl]2-amino-2-phenyl-acetate hydrochloride salt (260 mg, 0.78 mmol), triethylamine (219 μL, 1.56 mmol) and acetic acid (102 μL, 0.78 mmol). The resultant solution was stirred at room temperature for 20 minutes. Sodium borohydride (49 mg, 0.78 mmol) was then added and the resultant solution was stirred at room temperature for 18 h. The solvent was removed in vacuo and the residue taken up in water (20 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic phases were extracted with 0.2 N aqueous hydrochloric acid (40 mL) and water (40 mL). The aqueous extracts were combined and sodium chloride (6 g) was added. The mixture was extracted with chloroform (3×30 mL) and the combined organic extracts were passed through a hydrophobic fit and the solvent was removed in vacuo. Purification of the crude material by preparative HPLC afforded the title compound (42 mg, 14%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:15]([C:21]3[C:22]([CH3:38])=[C:23]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:24]=[CH:25][CH:26]=3)[CH:16]([N+:18]([O-])=O)[CH3:17])=[CH:11][NH:12]2)=[CH:8][CH:7]=1.C([O-])(=O)C.[NH4+]>CO.O1CCCC1.CCOC(C)=O.[Zn]>[NH2:18][CH:16]([CH3:17])[CH:15]([C:21]1[C:22]([CH3:38])=[C:23]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=[CH:25][CH:26]=1)[C:10]1[C:9]2[C:13](=[CH:14][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=2)[NH:12][CH:11]=1
Reactant: COCCOc1ccc2c(C(c3cccc(NC(=O)OCc4ccccc4)c3C)C(C)[N+](=O)[O-])c[nH]c2c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOc1ccc2c(C(c3cccc(NC(=O)OCc4ccccc4)c3C)C(C)N)c[nH]c2c1
Reaction time: 5 h
Yield: 91.7 %

Procedure:
A solution of benzyl 3-(1-(6-(2-methoxyethoxy)-1H-indol-3-yl)-2-nitropropyl)-2-methylphenylcarbamate (1.6194 g, 3.13 mmol), ammonium acetate (2.51 g, 46.9 mmol) and zinc (3.07 g, 46.9 mmol) in methanol (Ratio: 1.000, Volume: 57.9 ml) and tetrahydrofuran (Ratio: 1.000, Volume: 57.9 ml) was stirred under nitrogen. After 5 h, the reaction was diluted with EtOAc and filtered through a wad of CELITE®. The filtrate was concentrated in vacuo, and the residue was dissolved in EtOAc (75 mL) and saturated aqueous NaHCO3 (30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2×75 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated in vacuo to give benzyl 3-(2-amino-1-(6-(2-methoxyethoxy)-1H-indol-3-yl)propyl)-2-methylphenylcarbamate (1.3975 g, 2.87 mmol, 92% yield, mixture of 2 isomers) as a colorless oil, LC/MS (M+H)=488.30, 488.30.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=O)[C:3]=12)=[O:6].O.[NH2:14][NH2:15]>C(O)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:3]=1[C:8](=[O:7])[NH:14][NH:15][C:5]2=[O:6]
Reactant: NN
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH][nH]c(=O)c2c(Cl)cccc12
Temperature: 125 °C

Procedure:
3-Chloro-phthalic anhydride (5a, purchased from TCI) (10 g, 54.95 mmol) was dissolved in glacial acetic acid (100 mL), and hydrazine hydrate (20 mL) was added dropwise at 0° C., and then refluxed for two hours at 125° C. When the reaction was completed, the solution was cooled down to room temperature, filtrated, and washed with water until the filtrate pH 6.0, and then dried to give 5-chloro-2,3-dihydrophthalazin-1,4-dione (5b), 10.08 g white solid (yield 93%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6](I)[CH:7]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].CCCCCCC>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1cc(F)cc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCCCCC
Product: Oc1cc(F)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.1 %

Procedure:
Palladium (II) acetate (2.4 mg, 0.01 mmol) was added to a suspension of 3-fluoro-5-iodophenol (250 mg, 1.05 mmol), phenylboronic acid (154 mg, 1.26 mmol) and sodium carbonate (3.34 g, 3.15 mmol) in water (5 mL), under an atmosphere of nitrogen. The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was then filtered through a plug of dicalite to remove black precipitate. The dicalite was washed with MeOH. The filtrate was diluted with water (250 mL) and then adjusted to pH2 using 2M HCl (aq). The product was extracted into DCM, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by chromatography on silica gel. Elution with 10:90 ethyl acetate:heptane afforded 5-fluorobiphenyl-3-ol (186 mg, 0.988 mmol, 94%) M.S. (ESI) (m/z): 187 [M−H]−.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][CH3:11])[N:5]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16].[I-].C[N+]1C=CN(C)C=1>O1CCOCC1>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][CH3:11])[N:5]=1)=[O:16]
Reactant: CSc1nccc(Cl)n1
Reactant: O=Cc1ccccc1F
Agent: Cn1cc[n+](C)c1
Agent: [H-]
Agent: [I-]
Solvent: C1COCCO1
Product: CSc1nccc(C(=O)c2ccccc2F)n1
Yield: 27.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 598 mg, 14.94 mmol) was added to a stirring solution of 4-chloro-2-methylthiopyrimidine (1.45 mL, 12.45 mmol), 2-fluorobenzaldehyde (1.57 mL, 14.94 mmol) and 1,3-dimethylimidazolium iodide (517 mg, 4.15 mmol) (prepared as described in Org. Synth. (1986) 64:9) in 1,4-dioxane (20 mL). The resulting mixture was heated at reflux for 1 hour; it was then cooled and partitioned between EtOAc and water. The organic layer was separated and dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 95/5) to give 840 mg of (2-fluorophenyl)-(2-methylsulfanyl-pyrimidin-4-yl)-methanone.
Reaction SMILES: [C:1]1([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]3[CH2:25][CH:24]([CH2:26][C:27]([O:29]CC)=[O:28])[C:23]4[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=4[CH2:21][C:20]=3[CH:36]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.N1C=CC=CC=1NCCCOC1C=CC2C[C@H](CC(OCC)=O)C3C=CC=CC=3CC=2C=1.C(O)(C(F)(F)F)=O>O>[C:1]1([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:36]=[C:20]3[CH2:21][C:22]4[CH:35]=[CH:34][CH:33]=[CH:32][C:23]=4[CH:24]([CH2:26][C:27]([OH:29])=[O:28])[CH:25]=[C:19]3[CH2:18][CH:17]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCOC(=O)CC1Cc2ccc(OCCCNc3nccc4ccccc34)cc2Cc2ccccc21
Agent: CCOC(=O)C[C@H]1Cc2ccc(OCCCNc3ccccn3)cc2Cc2ccccc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1C=C2CC=C(OCCCNc3nccc4ccccc34)C=C2Cc2ccccc21

Procedure:
According to the procedure of Example 6 (c), except substituting ethyl (±)-10,11-dihydro-3-[3-(isoquinoline-1-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate for the ethyl (R)-10,11-dihydro-3-[3-(pyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate, the title compound was prepared as an amber solid: MS (ES) m/e 453.2(M+H)+. Anal. Calcd for C29H28N2O3.1.3 TFA.0.25 H2O: C, 62.71; H, 4.96; N, 4.63. Found: C, 62.45; H, 4.92; N, 4.41.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:12]2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[CH:39]([N:42]=[C:43]=[O:44])([CH3:41])[CH3:40]>C(Cl)Cl.CO>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[N:11]([CH2:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][NH:2][C:43]([NH:42][CH:39]([CH3:41])[CH3:40])=[O:44])[CH:5]=3)[N:12]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: CC(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)NC(C)C)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 75 %

Procedure:
To a suspension of N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (52 mg, 0.10 mmol) in dry DCM (0.5 mL) was added triethylamine (15 μL, 0.11 mmol), followed with isopropyl isocyanate (11 μL, 0.11 mmol). The reaction mixture was stirred at room temperature for 45 min. LCMS showed mainly product. The reaction mixture was diluted with DCM and methanol and then concentrated in vacuo. The resultant residue was dissolved in 1:1 MeOH:DMSO (1 mL) and purified MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid). The solvent was evaporated in vacuo to give the title compound (43 mg, 75%) as a white powder. LCMS (System A) RT=1.11 min, ES+ve m/z 548/550 (M+H)+.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[CH2:25][CH:26]=[O:27])[C:5]1=[O:30])[CH:2]=[CH2:3].[CH3:32][Mg]Br>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:25][CH:26]([OH:27])[CH3:32])[CH2:28][CH3:29])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC=O)C1=O
Reactant: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC(C)O)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)pentanal (540 mg, 1.18 mmol; Example 130, Step A) in THF (12 mL) was added 1.4 M methylmagnesium bromide in toluene and THF (75:25) (2.52 mL, 3.53 mmol) at 0° C. Then the reaction was allowed to warm to rt and stirred for 3 h. The reaction was quenched (sat NH4Cl solution), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide the crude title compound as a mixture of diastereomers.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[OH:19].Br[CH:21]([CH2:27][CH2:28][CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:18])[C:10]3[CH2:17][CH2:16][CH2:15][CH2:14][C:11]=3[C:12]2=[O:13])=[CH:4][C:3]=1[O:19][CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:27][CH2:28][CH3:29]
Reactant: CCCC(Br)C(=O)OCC
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCC(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 15.0 g. of N-(4-bromo-3-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide, 12.0 g. of ethyl α-bromovalerate, 7.7 g. of potassium carbonate, 2.5 g. of potassium iodide and 50 ml. of acetone was refluxed with stirring for 3 hours and then, the reaction mixture was cooled to room temperature and the salt was separated by a filtration. The filtrate was concentrated under a reduced pressure and 2N-HCl was added to the residue to crystallize the product. The crystal was separated by a filtration and washed with water and dried. The residue was purified by a chromatography on a column of silica gel (developing solvent: ethyl acetate: n-hexane of 1:3) to obtain 17.6 g. of Compound No. 90 shown in table 1.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([C:16]2[N:21]=[C:20]([CH3:22])[C:19]([C:23]([NH2:25])=[O:24])=[CH:18][N:17]=2)=[N:8]1.[CH3:30]N(C)C=O>C(#N)C>[F:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([C:16]2[N:17]=[CH:18][C:19]3[C:23](=[O:24])[NH:25][CH:30]=[CH:22][C:20]=3[N:21]=2)=[N:8]1
Reactant: Cc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1C(N)=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: O=c1[nH]ccc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc12
Temperature: 150 °C
Reaction time: 48 h

Procedure:
Under argon, 21 mg (0.522 mmol) of sodium hydride (60% suspension in mineral oil) were initially charged and washed repeatedly with hexane. Subsequently, dimethylformamide (0.18 ml) was added, and a solution of 158 mg (0.435 mmol) of the compound from example 46A in dimethylformamide (6.0 ml) was added to the suspension. The reaction mixture was stirred at 150° C. for two days, then diluted with acetonitrile at RT, then filtered, and the filtrate was concentrated. The residue was separated by means of preparative HPLC (eluent: acetonitrile-water with 0.1% formic acid gradient) and the product fractions were concentrated. This gave 31 mg (18% of theory) of the title compound in solid form.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2Br)[C@H:10]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22]C=2O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](=[O:31])([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O>O1CCOCC1.[Cu]I>[Cl:26][C:24]1[CH:23]=[CH:22][C:28]2[O:31][C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C@H:11]3[CH2:12][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][C@@H:10]3[C:20]=2[CH:25]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Cl)cc1[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1Br
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: [Cs+]
Solvent: C1COCCO1
Product: Clc1ccc2c(c1)[C@H]1CN(Cc3ccccc3)C[C@@H]1c1ccccc1O2

Procedure:
A mixture of racemic trans-2-(1-benzyl-4-(2-bromophenyl)pyrrolidin-3-yl)-4-chlorophenol (1.8 g, 4.07 mmol), cesium carbonate (2.65 g, 8.13 mmol, 2.0 eq.), N,N-dimethylglycine (165 mg, 1.6 mmol; 0.4 eq.) and CuI (310 mg, 1.6 mmol; 0.4 eq.) in dioxane (20 ml) was heated to reflux temperature while stirring under inert nitrogen atmosphere. After one hour the title product was formed according to mass analysis (M+1=362, 364 found), but the conversion was not yet complete. Heating was continued overnight to give 98% conversion according to LC-MS. The reaction mixture was cooled to room temperature and was then filtered over a glass filter. The residual salts were washed with dioxane (25 ml). The combined filtrates were concentrated under vacuum to give the crude product as a brown oil. Toluene (150 ml) was added and the resulting solution was washed with concentrated aqueous ammonia (25 ml; 25%). The toluene layer was separated and dried with Na2SO4. Concentration under vacuum gave the title compound (1.47 g, 4.06 mmol) in quantitative yield as a brown oil, with ca. 78% purity according to LC-MS analysis. The product was used without further purification. MS: M+1=362, 364 found.