Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C@@H:14]([NH:19][C:20](=[O:35])[O:21][CH2:22][C:23]1([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:15][CH2:16][CH2:17][CH3:18])[C:3](=[O:13])[NH:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].OC([C@@H](NC(=O)OCC1(CC2C=CC=CC=2)CCC1)CCCC)C(=O)N[C@@H](C1C=CC=CC=1)C>>[O:13]=[C:3]([NH:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])[C:2]([C@@H:14]([NH:19][C:20](=[O:35])[O:21][CH2:22][C:23]1([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:24][CH2:25][CH2:26][CH2:27]1)[CH2:15][CH2:16][CH2:17][CH3:18])=[O:1]
Reactant: CCCC[C@H](NC(=O)OCC1(Cc2ccccc2)CCCC1)C(O)C(=O)N[C@H](C)c1ccccc1
Agent: CCCC[C@H](NC(=O)OCC1(Cc2ccccc2)CCC1)C(O)C(=O)N[C@H](C)c1ccccc1
Product: CCCC[C@H](NC(=O)OCC1(Cc2ccccc2)CCCC1)C(=O)C(=O)N[C@H](C)c1ccccc1

Procedure:
(1-Benzylcyclopentyl)methyl(1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate was prepared as in example 6c except that (1-benzylcyclopentyl)methyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate was substituted for (1-benzylcyclobutyl)methyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate. M.P.=108-110° C. Elemental analysis: Theory; C=72.77%, H=8.00%, N=5.85%. Found; C=72.62%, H=8.00%, N=5.84%. 1H NMR (300 MHz, 80° C., DMSO-d6) δ 8.82 (d, J=8 Hz, 1H), 7.19-7.39 (m, 11H), 5.02 (qnt, J=7 Hz, 1H), 4.86 (m, 1H), 3.69 (d, J=3 Hz, 2H), 2.69 (s, 2H), 1.20-1.65 (m, 17H), 0.87 (t, J=7 Hz, 3H). ES-LCMS m/z 501 (M+Na). HRMS C29H38N2O4 m/z 501.2729 (M+Na)Cal; 501.2731 (M+Na)Obs.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][Si:5](Cl)(Cl)Cl.[Si:9]([O:13][Na])([CH3:12])([CH3:11])[CH3:10]>CCOCC>[Cl:1][CH2:2][CH2:3][CH2:4][Si:5]([O:13][Si:9]([CH3:12])([CH3:11])[CH3:10])([O:13][Si:9]([CH3:12])([CH3:11])[CH3:10])[O:13][Si:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: C[Si](C)(C)O[Na]
Reactant: ClCCC[Si](Cl)(Cl)Cl
Solvent: CCOCC
Product: C[Si](C)(C)O[Si](CCCCl)(O[Si](C)(C)C)O[Si](C)(C)C
Reaction time: 12 h

Procedure:
Gamma-chloropropyltrichlorosilane (21.2 g., 0.1 mole) is dissolved in 200 ml. of dry ether and an ether slurry of (33.6g, 0.3 mole) sodium trimethylsilanoate, (CH3)3SiONa, is added in small portions. The mixture is allowed to stand for 12 hours and is then refluxed for an additional 3 hours. Filtration of the sodium chloride and removal of the ether from the filtrate leaves gamma-chloropropyltris-trimethylsiloxysilane.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(O)C.Br[CH:19]([CH3:29])[C:20]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH:19]([CH3:29])[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[O:21])[CH2:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: CC(Br)C(=O)c1ccc(O)cc1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(CC2CCN(C(C)C(=O)c3ccc(O)cc3)CC2)cc1

Procedure:
7.57 g (0.04 mol) of 4-(4-methylbenzyl)-piperidine are introduced into 35 ml of ethanol, 9.15 g (0.04 mol) of 2-bromo-4'-hydroxypropiophenone and then 4.24 g (0.04 mol) of sodium carbonate are added and the mixture is heated under reflux for 2 hours. It is then cooled with an ice bath and 200 ml of iced water and 100 ml of toluene are added. The mixture is stirred and left to separate and the organic phase is separated off. The aqueous phase is extracted three times with 100 ml of toluene. The organic phases are combined, washed, dried and then evaporated. This gives 13 g of a pasty oil, which is purified by chromatography on silica using acetone as the eluant. 10 g of a pale oil are collected, which is used as such in the subsequent reduction.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[NH2:8].[C:16](N1C=CN=C1)(N1C=CN=C1)=[O:17].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[O:17]=[C:16]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][C:2]=2[NH:1]1
Reactant: CCOC(=O)C(C)c1ccc(N)c(N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(C)c1ccc2[nH]c(=O)[nH]c2c1

Procedure:
A solution of Ethyl 2-(3,4-diaminophenyl)propanoate (217 mg, 1.04 mmol) in CH2Cl2 (4 mL) was added 1,1′-carbonyldiimidazole (189 mg) and DBU (330 mg, in CH2Cl2 (4 mL)) at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C[Si]([C:14]#[N:15])(C)C.C(N(CC)CC)C>C(#N)C>[C:14]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)#[N:15]
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ncc(Cl)cc1Cl
Yield: 94.8 %

Procedure:
3,5-Dichloropyridine-N-oxide (10.0 g, 61 mmol), trimethysilylcyanide (25 mL, 183 mmol) and triethylamine (17 mL, 122 mmol) combined in acetonitrile (60 mL) and heated to reflux for 6 hr. The solvent was evaporated and the residue was partitioned between diethyl ether and 5% aq. NaHCO3. The organic phase was dried (MgSO4), evaporated, and the product purified by chromatography over silica gel to yield 10.0 g (97%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.92 (d, 1H), 8.58 (d, 1H).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]CCCC.[CH3:33][CH:34]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:35]=O.O>C1COCC1>[CH3:35][CH:34]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:33]=[CH:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCCCCC(C)C=O
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCC(C)C=Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A suspension of benzyltriphenylphosphonium bromide (3.20 g, 7.38 mmol, 1.0 equiv.) in THF (14 mL), was cooled to 0° C. After adding n-BuLi (1.6 M in hexanes, 4.6 mL, 7.38 mmol, 1.0 equiv.) at 0° C., the red suspension was stirred at 65° C. for 1 h. The mixture was re-cooled to 0° C., 2-methylundecanal (2.04 g, 11.1 mmol, 1.5 equiv.) in THF (5 mL) was added, and the mixture was stirred at 65° C. for 18 h. After addition of H2O, the aqueous layer was extracted with cyclohexane (2×), the combined organic phases were washed with brine, dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane) to yield 1.45 g (76%) of the title compound as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][C:8]2[CH2:10][CH2:11][CH2:12][C:7]=2[CH:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:9]1[C:5]([CH2:3][OH:2])=[CH:6][C:7]2[CH2:12][CH2:11][CH2:10][C:8]1=2
Reactant: COC(=O)c1cc2c(o1)CCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2c(o1)CCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
5,6-Dihydro-4H-cyclopenta[b]furan-2-carboxylic acid methyl ester (2.24 g) was added to the THF (59 mL) solution of LiAlH4 (511 mg) under a nitrogen atmosphere at 0° C. and stirred for 1 h at 0° C. The mixture was quenched with 10 mL of water and filtered. The filtrate was concentrated under reduced pressure and the obtained aqueous solution was extracted with CHCl3. The organic layer was washed with brine and dried over MgSO4 and filtered. The filtrate was concentrated to afford titled compound as yellow oil (1.86 g, quant.).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[C:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])=[N:29][C@@H:28]([NH2:44])[C:27]2=[O:45])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[C:47]1[C:55](O)=[O:56].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.O.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([N:20]1[CH:24]=[C:23]([CH2:25][N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[C:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])=[N:29][C@@H:28]([NH:44][C:55]([C:47]3[NH:46][C:54]4[C:49]([CH:48]=3)=[CH:50][CH:51]=[CH:52][CH:53]=4)=[O:56])[C:27]2=[O:45])[N:22]=[CH:21]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1N=C(c2ccccc2F)c2ccccc2N(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C1=O
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(N[C@@H]1N=C(c2ccccc2F)c2ccccc2N(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C1=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
To a solution of (3R)-1,3-dihydro-1-(1-trityl-4-imidazolyl)methyl -3-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one (0.81 g), indole-2-carboxylic acid (0.23 g), N-hydroxybenzotriazole (0.19 g) in N,N-dimethylformamide (8 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.27 g) and triethylamine (0.14 g) under stirring at ambient temperature. The mixture was stirred for 4 hours at ambient temperature. To the reaction mixture were added ethyl acetate and water under stirring. The mixture was adjusted to pH 8 with an aqueous sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The separated organic layer and the extract were combined, washed with water twice and dried over magnesium sulfate. The solvent was removed under reduced pressure to give (3R)-1,3-dihydro-1-(1-trityl-4-imidazolyl)methyl-3-(2-indolylcarbonylamino) -5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one (1.0 g).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=1)[C:5]([C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH3:12])=O.Cl.[CH3:22][CH:23]1[O:28][CH:27]([CH3:29])[CH2:26][N:25]([C:30](=[NH:32])[NH2:31])[CH2:24]1.CC(C)([O-])C.[K+]>C(O)C>[CH3:29][C@H:27]1[O:28][C@@H:23]([CH3:22])[CH2:24][N:25]([C:30]2[N:31]=[C:5]([C:7]3[CH:11]=[CH:10][O:9][C:8]=3[CH3:12])[C:4]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=3)=[CH:3][N:32]=2)[CH2:26]1
Reactant: Cc1cc(C(=CN(C)C)C(=O)c2ccoc2C)ccn1
Reactant: CC1CN(C(=N)N)CC(C)O1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1cc(-c2cnc(N3C[C@@H](C)O[C@@H](C)C3)nc2-c2ccoc2C)ccn1
Temperature: 25 °C
Yield: 11 %

Procedure:
A mixture of 3-(dimethylamino)-1-(2-methyl-3-f uranyl)-2-(2-methyl-4-pyridinyl)-2-propen-1-one (1352 mg, 5 mmol) and 2,6-dimethyl-4-morpholinecarboximidamide hydrochloride (1453 mg, 7.50 mmol) (ca. 2.3:1 mixture of cis:trans isomers) in ethanol (10 ml) was stirred at room temperature. Potassium tert-butoxide (1122 mg, 10.00 mmol) was added and the mixture was heated at reflux for 3 hours. After cooling to room temperature the solvent was evaporated and the residue was diluted with water and extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 50% ethyl acetate in isohexane to give cis-2,6-dimethyl-4-[4-(2-methyl-3-furanyl)-5-(2-methyl-4-pyridinyl)-2-pyrimidinyl]morpholine as an oil (200 mg). The cross-over fractions from the column (˜800 mg) were purified by mass-directed automated HPLC to give additional cis-2,6-dimethyl-4-[4-(2-methyl-3-furanyl)-5-(2-methyl-4-pyridinyl)-2-pyrimidinyl]morpholine (200 mg) and trans-2,6-dimethyl-4-[4-(2-methyl-3-furanyl)-5-(2-methyl-4-pyridinyl)-2-pyrimidinyl]morpholine (49 mg). A solution of cis-2,6-dimethyl-4-[4-(2-methyl-3-furanyl)-5-(2-methyl-4-pyridinyl)-2-pyrimidinyl]morpholine (200 mg, 0.55 mmol) was dissolved in dichloromethane (2 ml) and hydrogen chloride (1M in ether, 0.6 ml) was added. The solvent was evaporated and the residue was evaporated with ether (×2) and then triturated with ether. The solid was collected, washed with ether and dried to give the title compound (178 mg). LC/MS [M+H]+=365. 1H NMR (400 MHz, d6-DMSO): δ 8.61 (1H, d), 8.56 (1H, s), 7.82 (1H, b), 7.58-7.53 (1H, m), 7.52 (1H, d), 6.04 (1H, d), 4.65-4.58 (2H, m), 3.64-3.55 (2H, m), 2.72-2.63 (2H, m), 2.66 (3H, s), 2.36 (3H, s), 1.18 (6H, d).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([NH2:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)=[O:5].C(N(CC)CC)C.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](Cl)=[O:32].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([NH:16][C:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)=[O:32])([CH2:9]3)[CH2:7]1)[CH2:13]2)=[O:5]
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1)C2
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C12CC3CC(CC(NC(=O)c4ccccn4)(C3)C1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a round bottom flask was added 3-amino-adamantane-1-carboxylic acid methyl ester hydrochloride (20.0 g, 81.4 mmol) and methylene chloride (500 mL) and the solution was cooled at 0° C. To this solution was then added triethylamine (57 mL, 0.41 mol) followed by picolinoyl chloride hydrochloride (15.2 g, 85.4 mmol; TCI America, Wellesley Hills, Mass., USA) and the reaction was stirred at 0° C. for 30 minutes, then at room temperature for 6 hours. To the reaction was added saturated aqueous sodium bicarbonate (500 mL) and the biphasic mixture was stirred vigorously for a few minutes, then transferred to a 2-L separatory funnel. The mixture was extracted, the layers separated and the aqueous layer was extracted again with methylene chloride (2×200 mL). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 24.8 g (97%) of the title compound, 3-[(pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid methyl ester, as a pale brown solid. 1H NMR (400 MHz, CDCl3) δ 8.54-8.49 (m, 1H), 8.16 (dt, J=7.8, 1.0 Hz, 1H), 7.96 (br s, 1H), 7.83 (td, J=7.8, 1.8 Hz, 1H), 7.40 (ddd, J=7.6, 4.8, 1.3 Hz, 1H), 3.66 (s, 3H), 2.34-2.30 (m, 2H), 2.29-2.23 (m, 2H), 2.17-2.13 (m, 4H), 1.97-1.80 (m, 4H), 1.78-1.62 (m, 2H). ESI-MS m/z: 315.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: O=C(O)CC(=O)O
Reactant: Cc1cccc(C=O)c1[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: Cc1cccc(C=CC(=O)O)c1[N+](=O)[O-]
Yield: 64 %

Procedure:
3-Methyl-2-nitrobenzaldehyde, prepared according to Berichte, 47, 406, is reacted with malonic acid in pyridine with the addition of piperidine to give 3-methyl-2-nitrocinnamic acid; yield 64% of theory; m.p. 230°-235° C., after recrystallisation from methanol. After hydrogenation thereof in aqueous sodium hydroxide solution in the presence of palladium catalyst, 2 mole of acetic anhydride are added thereto and the reaction product is purified on an Amberlite IR-120 column (H+ form). There is thus obtained, in a yield of 75% of theory, 3-(2-acetylamino-3-methyl-phenyl)-propionic acid; m.p. 110° C. sinters, 117°-120° C. This is then reacted with phosphorous acid/phosphorus trichloride analogously to Example 16.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30]([CH:35]=O)=[CH:29]3)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.N1CCCCC1>C(O)C>[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30]([CH:35]=[C:11]2[C:10]4[C:14](=[CH:15][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[CH:8][CH:9]=4)[NH:13][C:12]2=[O:16])=[CH:29]3)[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cc(-c3ccccc3)ccc2C1=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Temperature: 100 °C
Yield: 71.6 %

Procedure:
A mixture of 6-phenyl-2-oxindole (44 mg, 0.21 mmol), 5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde (58 mg, 0.21 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 70 mg (71%) of the title compound as an orange solid.
Reaction SMILES: [C:1]1([CH2:7][S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21]C3CCCCO3)=[O:19])=[CH:12]2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.O>[OH:21][NH:20][C:18](=[O:19])[CH:17]=[CH:16][C:13]1[CH:14]=[CH:15][N:11]([S:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])[CH:12]=1
Reactant: O=C(/C=C/c1ccn(S(=O)(=O)Cc2ccccc2)c1)NOC1CCCCO1
Solvent: O
Solvent: CO
Product: O=C(C=Cc1ccn(S(=O)(=O)Cc2ccccc2)c1)NO
Temperature: 25 °C
Reaction time: 91 h
Yield: 97.1 %

Procedure:
0.189 g of (E)-3-(1-phenylmethanesulfonyl-1H-pyrrol-3-yl)-N-(tetrahydropyran-2-yloxy)-acrylamide (compound A2) are dissolved in 50 ml of a methanol/water (3/2) solution. Then 0.102 g of the acidic ion exchange resin amberlyst IR15 are added and the mixture is stirred for 91 hours at ambient temperature. The mixture is filtered. The filtrate is evaporated. The residue is crystallized from methanol to give 0.144 g of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:28][CH:29]=O)[CH:9]([C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.Cl.[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[NH:40]N>[Cl-].[Cl-].[Zn+2].C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[C:35]3[C:34](=[C:33]([Cl:32])[CH:38]=[C:37]([Cl:39])[CH:36]=3)[NH:40][CH:29]=2)[CH:9]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])=[CH:26][CH:27]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC)cc1)C(CC=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: CCCC(c1ccc(C(=O)NCCC(=O)OC)cc1)C(c1ccc(Cl)cc1)c1c[nH]c2c(Cl)cc(Cl)cc12
Temperature: 80 °C

Procedure:
An acetic acid solution (5 ml) containing the intermediate from Step B (200 mg, 0.47 mmol), 2,4-dichlorophenyl hydrazine hydrochloride (120 mg, 0.56 mmol) and ZnCl2 (2.29M in AcOH, 0.61 ml, 1.4 mmol) was heated at 80° C. for 30 minutes. The solution was concentrated and the residue dissolved in EtOAc. The EtOAc solution was washed with water, brine and dried over Na2SO4. The filtered solution was concentrated and the residue purified by silica gel chromatography using a hexanes/EtOAc gradient to give the title compound as a mixture of diastereomers. The mixture was purified further using reverse phase HPLC. The major (and more active) diastereomer, which is also the slower (second) eluting on HPLC, was resolved on a Chiralpak AD-H column (2 cm×25 cm) eluting with 10% EtOH/Heptane at 9 ml/min.
Reaction SMILES: C1(N)(N)CCCCC1.Br[C:10]1[CH:11]=[C:12]([NH2:20])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.[CH3:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]I.COCCOCCOC>[CH3:21][C:22]1[N:23]=[CH:24][N:25]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([NH2:20])[CH:11]=2)[CH:26]=1
Reactant: Cc1c[nH]cn1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: [Cu]I
Agent: NC1(N)CCCCC1
Agent: O=C([O-])[O-]
Solvent: COCCOCCOC
Product: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a single neck flask fitted with a condenser are added CuI (89.5 mg, 0.47 mmol), cyclohexanediamine (107.3 mg, 0.94 mmol) and diglyme (10 mL). The mixture is stirred for 10 minutes at ambient temperature. To the purple heterogeneous mixture, 3-bromo-5-trifluoromethyl-phenylamine (XVI) (1.13 g, 4.7 mmol), 4-methyl-1H-imidazole (0.77 g, 9.4 mmol) and Cs2CO3 (1.53 g, 4.7 mmol) are added. The mixture is heated at 150° C. and stirred for an additional 24 hours. The mixture is cooled to 25° C. and purified by column chromatography (silica gel; EtOAc/MeOH 95:5) to afford (I) as the major product (840 mg).
Reaction SMILES: [Cl:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]2[N:6]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].CI.[CH2:36](Cl)Cl>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]2[N:6]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)[C:7](=[N:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[N:8]([CH3:36])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc(Cn2c(Nc3ccc(OC)cc3)nc3cc(Cl)c(Cl)cc32)cc1
Reactant: ClCCl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cn2c(=Nc3ccc(OC)cc3)n(C)c3cc(Cl)c(Cl)cc32)cc1
Reaction time: 2 h

Procedure:
To a solution of the title compound of Example 19, Step B (0.45 mmol, 203 mg) in DMF (3 mL) was added NaH (0.54 mmol, 21 mg of 60% suspension in mineral oil). After 10 min MeI (0.9 mmol, 56 μL) was added and the reaction was allowed to stand at ambient temperature for 2 h. Aqueous workup with CH2Cl2/saturated NaHCO3, followed by flash chromatography on silica eluting with 30% and 40% EtOAc in hexanes, afforded the product as a white solid. LC-MS (ESI, Method B): 1.93 min. m/z 470.2 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:31])[C@@H:4]([NH:8][C:9](=[O:30])[C@@H:10]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]=[CH2:21])=[CH:14][CH:13]=1)[CH:5]([CH3:7])[CH3:6].[OH-].[Na+].CO>C1COCC1.O>[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C@H:10]([NH:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C:9]([NH:8][C@@H:4]([CH:5]([CH3:6])[CH3:7])[C:3]([OH:31])=[O:2])=[O:30])=[CH:13][CH:14]=1)[CH:20]=[CH2:21]
Reactant: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OC)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl ester 42 (4.90 g, 11.3 mmol) was dissolved in THF (35 mL) and sodium hydroxide (17 mmol) pre-dissolved in water (10 mL) was added. A further 15 mL of THF and 20 mL of methanol were added to obtain a homogenous solution. The reaction mixture was stirred at rt for 18 h before being concentrated in vacuo. The residue was partitioned between EtOAc and 1M hydrochloric acid. The aqueous phase was extracted twice more with EtOAc and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to yield a white foam, 4.60 g, 97%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:16][C:15](=[O:17])[NH:14][S:13]1(=[O:19])=[O:18])[CH:8]=[C:7]([CH2:20][CH2:21][CH:22]([CH3:25])[C:23]#[N:24])[CH:6]=[CH:5]2.CC(C)([O-])C.[K+].[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[C:23]([CH:22]([CH3:25])[CH2:21][CH2:20][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([O:1][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:11]([N:12]1[CH2:16][C:15](=[O:17])[NH:14][S:13]1(=[O:19])=[O:18])=[CH:10]2)#[N:24]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C#N)CCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C#N)CCc1ccc2cc(OC(=O)c3ccccc3)c(N3CC(=O)NS3(=O)=O)cc2c1
Temperature: 25 °C

Procedure:
To a solution of 4-[6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-naphthalen-2-yl]-2-methylbutyronitrile (Example 9-3, 29 mg, 0.08 mmol) in DMF (0.6 mL) is added potassium t-butoxide (0.097 mL, 0.097 mmol) followed by benzoyl chloride. The reaction is stirred at RT until the reaction is completed. The reaction mixture is then purified by HPLC to give the title compound: Retention time 1.23 min (Method A); (M+H)+=462.