Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Cl:11])=[N:4][CH:3]=1.[CH3:12][NH2:13].[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:21]=[CH:20][C:17]=1[CH:18]=O>>[Cl:11][C:5]1[N:4]=[CH:3][C:2]2[N:1]=[C:18]([C:17]3[CH:20]=[CH:21][C:22]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:23][C:16]=3[O:15][CH3:14])[N:13]([CH3:12])[C:8](=[O:10])[C:7]=2[CH:6]=1
Reactant: Nc1cnc(Cl)cc1C(=O)O
Reactant: CN
Reactant: COc1cc(OCCCN2CCCC2)ccc1C=O
Product: COc1cc(OCCCN2CCCC2)ccc1-c1nc2cnc(Cl)cc2c(=O)n1C

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 5-amino-2-chloroisonicotinic acid, methylamine and 2-methoxy-4-(3-pyrrolidin-1-ylpropoxy)benzaldehyde.
Reaction SMILES: [O:1]=[C:2]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][C:28]=1[F:39])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[CH2:7][CH:6]1[CH2:22][C:23]([O:25]C)=[O:24].[OH-].[Na+].O1CCOCC1.O>C(OCC)C>[O:1]=[C:2]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][C:28]=1[F:39])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[CH2:7][CH:6]1[CH2:22][C:23]([OH:25])=[O:24]
Reactant: COC(=O)CC1CN(CCSc2cc(F)ccc2F)CCC1CCC(=O)c1c(F)cnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: COc1ccc2ncc(F)c(C(=O)CCC3CCN(CCSc4cc(F)ccc4F)CC3CC(=O)O)c2c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
A mixture of 0.3 g of methyl (3RS,4RS)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylsulfanyl)ethyl]piperidine-3-acetate in 1.34 cm3 of a 1N aqueous sodium hydroxide solution and 5 cm3 of dioxane is brought to a temperature in the region of 60° C. with stirring and under an inert atmosphere for 1 hour. After cooling to around 20° C., the reaction medium is evaporated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50° C. The evaporation residue obtained is taken up with 20 cm3 of water and 20 cm3 of diethyl ether, and the aqueous phase is separated after settling out and neutralized with 1.3 cm3 of 1N aqueous hydrochloric acid solution and is then extracted with 70 cm3 of ethyl acetate. The organic phase is dried over magnesium sulfate, filtered, and then evaporated according to the same conditions above. 0.23 g of (3RS,4RS)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)-propyl]-1-[2-(2,5-difluoro-phenylsulfanyl)ethyl]piperidine-3-acetic acid, in the form of a beige-colored solid, is obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.Cl.[CH3:21][NH:22][C:23]1[S:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=1>>[Cl:17][C:11]1[C:10]([CH3:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:28]([C:26]3[N:27]=[C:23]([NH:22][CH3:21])[S:24][CH:25]=3)=[O:29])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: CNc1nc(C(=O)O)cs1
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Agent: Cl
Product: CNc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3C)n2)cs1
Yield: 4.86 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(methylamino)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (300 mg, 1.092 mmol) and 2-(methylamino)thiazole-4-carboxylic acid hydrochloride (314 mg, 1.613 mmol). The product was purified twice by Flash-chromatography (normal phase and reverse phase). Yield 4.86%. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 2.56 (s, 3H), 2.93 (d, 3H), 4.28-4.43 (m, 2H), 4.47-4.61 (m, 1H), 5.04-5.12 (m, 1H), 6.43 (d, 1H), 7.31 (d, 1H), 7.49-7.56 (m, 3H), 7.67 (m, 1H).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.C(=O)(O)[O-].[Na+].[CH3:16][NH:17][CH2:18][CH2:19][CH2:20][N:21]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH2:29][CH2:28][C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]1=2.Cl>C(Cl)Cl>[CH3:16][N:17]([C:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=[O:9])[CH2:18][CH2:19][CH2:20][N:21]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]1=2
Reactant: CNCCCN1c2ccccc2CCc2ccccc21
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(CCCN1c2ccccc2CCc2ccccc21)C(=O)c1cccnc1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
Freshly prepared nicotinoyl chloride hydrochloride (0.55 g, 0.003 mol) was suspended in methylene chloride (12 ml) cooled to 5° C. and sodium bicarbonate (0.053 g, 0.0063 mol) was added. After 5 minutes, desipramine hydrochloride (0.75 g, 0.0025 mol) was added and the mixture was stirred for 3 hours at 5° C. The sodium chloride was removed by filtration and the organic solution was extracted with aqueous sodium bicarbonate, dried over sodium sulfate, filtered through Celite™ and concentrated. Ethyl ether (5 ml) was added to the oily residue and white crystals formed. Yield 62% (0.58 g), m.p. 84°-86° C. The product has the formula: ##STR1546##
Reaction SMILES: [OH:1][C@@H:2]([C@H:20]([CH3:38])[C@@H:21]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C@@H:22]([CH3:27])/[CH:23]=[CH:24]\[CH:25]=[CH2:26])[C@@H:3]([CH3:19])[C:4]([N:6]1[C@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][O:8][C:7]1=[O:18])=[O:5].N1C(C)=CC=CC=1C.C(Cl)Cl.[Si:50](OS(C(F)(F)F)(=O)=O)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51]>CCOCC>[CH3:54][C:53]([Si:50]([CH3:52])([CH3:51])[O:1][C@@H:2]([C@H:20]([CH3:38])[C@@H:21]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[C@@H:22]([CH3:27])/[CH:23]=[CH:24]\[CH:25]=[CH2:26])[C@@H:3]([CH3:19])[C:4]([N:6]1[C@H:10]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:9][O:8][C:7]1=[O:18])=[O:5])([CH3:56])[CH3:55]
Reactant: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)[C@H](O)[C@@H](C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CCOCC
Solvent: ClCCl
Product: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 86.7 %

Procedure:
A solution of (4R)-3-[(2R,3S,4S,5S,6S,7Z)-3-hydroxy-5-[(4-methoxyphenyl)methoxy]-2,4,6-trimethyl-1-oxo-7,9-decadienyl]-4-(phenylmethyl)-2-oxazolidinone (3.4 g, 6.53 mmol), 2,6-lutidine (3.5 g, 32.65 mmol) and methylene chloride (100 mL) is cooled to 0° C. TBSOTf (7.12 g, 26.94 mmol)is added over 30 min and the resultant mixture is allowed to react overnight at 0° C. The mixture is diluted with ether (300 mL), washed with aqueous NaHSO4, brine, and concentrated. Flash chromatography affords the desired compound (3.6 g, 87%) as an oil.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][O:8][C:9]1[C:17]2[O:16][C:15]([S:18][CH3:19])=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[OH2:20]>>[CH3:19][S:18]([C:15]1[O:16][C:17]2[C:9]([O:8][CH3:7])=[CH:10][CH:11]=[CH:12][C:13]=2[CH:14]=1)(=[O:1])=[O:20]
Reactant: O
Reactant: O=S([O-])OO
Reactant: COc1cccc2cc(SC)oc12
Agent: [K+]
Product: COc1cccc2cc(S(C)(=O)=O)oc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of Oxone® (7.37 g) in water (40 ml) was added to a solution of 7-methoxy-2-methylsulfanylbenzofuran (2.24 g) and the reaction mixture was stirred at room temperature overnight. The methanol was removed in vacuo and the resulting slurry was extracted with ethyl acetate (2×200 ml). The combined organic phases were washed with brine (200 ml) and then dried over sodium sulfate. The solvent was removed in vacuo to furnish the title compound as a yellow solid (2.24 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.Cl.[CH2:17]([C:19]([OH:21])=[O:20])[CH3:18].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([S:30]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[NH:8][C:7](=[O:12])[C:6]4[NH:13][CH:14]=[CH:15][C:5]=4[C:4]=3[CH:3]=2)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1.[CH2:17]([C:19]([O-:21])=[O:20])[CH3:18]
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CCC(=O)O
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: Cl
Product: CCC(=O)[O-]
Product: COc1cccc(S(=O)(=O)Nc2ccc3[nH]c(=O)c4[nH]ccc4c3c2)c1
Yield: 23.7 %

Procedure:
This compound is prepared according to synthesis 43, from 60 mg (0.20 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate hydrochloride (synthesis 64) and 30 μL (0.21 mmol) of 3-methoxy-benzenesulfonyl chloride. After recrystallization from methanol then trituration in hot methanol, 21 mg (25%) of 8-(3-methoxy-benzenesulfonylamino)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[C:21]([N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)[CH2:25]1)(=[O:23])[CH3:22]>>[C:21]([N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([NH:20][C:3]3[CH:4]=[CH:5][C:6]([N:8]4[CH2:12][CH2:11][CH:10]([CH2:13][N:14]5[CH2:18][CH2:17][CH2:16][CH:15]5[CH3:19])[CH2:9]4)=[CH:7][C:2]=3[CH3:1])=[O:35])=[CH:37][CH:38]=2)[CH2:25]1)(=[O:23])[CH3:22]
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Reactant: CC(=O)N1CCCC(c2ccc(C(=O)O)cc2)C1
Product: CC(=O)N1CCCC(c2ccc(C(=O)Nc3ccc(N4CCC(CN5CCCC5C)C4)cc3C)cc2)C1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 4-(1-acetyl-piperidin-3-yl)-benzoic acid. MS: 503.3 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[C:27]([C:31]1[O:32][C:33]2[C:39]([NH2:40])=[CH:38][CH:37]=[CH:36][C:34]=2[CH:35]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([C:31]1[O:32][C:33]2[C:39]([NH:40][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[CH:13][C:4]=4[NH:1][S:23]([C:18]4[CH:17]=[C:16]([F:15])[CH:21]=[C:20]([F:22])[CH:19]=4)(=[O:25])=[O:24])[N:9]=3)=[CH:38][CH:37]=[CH:36][C:34]=2[CH:35]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1cc2cccc(N)c2o1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: CC(C)(C)c1cc2cccc(Nc3ccc4c(NS(=O)(=O)c5cc(F)cc(F)c5)cccc4n3)c2o1

Procedure:
The title compound, MS: m/e=508.1 (M+H+), was prepared in accordance with the general method of example 89 from 5-nitro-2-chloroquinoline, 3,5-difluorobenzenesulfonylchloride and 2-tert-butyl-benzofuran-7-ylamine.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:13])[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([OH:22])[CH3:21]>>[CH2:20]([O:22][C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[CH3:21]
Reactant: CC(C(=O)N=C=O)(c1ccccc1)c1ccccc1
Reactant: CCO
Product: CCOC(=O)NC(=O)C(C)(c1ccccc1)c1ccccc1

Procedure:
The title compound, colorless gum, MS: m/e=297.4 (M+H+) was prepared in accordance with the general method of example 1 from crude 2,2-diphenylpropionyl isocyanate and ethanol.
Reaction SMILES: [NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([OH:10])=O)[CH3:7])=[O:4].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl.[NH2:41][C@@H:42]([C:44]([NH:46][CH2:47][C:48]([NH:50][CH2:51][C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:53])=[O:49])=[O:45])[CH3:43].Cl>CN(C=O)C>[NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:41][C@@H:42]([C:44]([NH:46][CH2:47][C:48]([NH:50][CH2:51][C:52]([O:54][CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:53])=[O:49])=[O:45])[CH3:43])=[O:10])[CH3:7])=[O:4]
Reactant: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@@H](N)C(=O)NCC(=O)NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NCC(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of Boc-Gly-Ala prepared as in Example 33B (10.2 g, 41.5 mmol) in anhydrous DMF (300 ml), was added HOBT.H2O (6.21 g, 46.0 mmol), EDC.HCl (8.81 g, 46.0 mmol) and DAla-Gly-Gly-OBzl.HCl (13.7 g, 41.5 mmol). The pH of the resulting solution was adjusted to ~8 (measured by spotting the reaction mixture on moistened Hydrion paper) and the reaction mixture was allowed to stir at room temperature for 12 h thereafter. The solution was concentrated in vacuo and the residue was dissolved in water (40 ml). The resulting solution was extracted with ethyl acetate (3×150 ml). The combined ethyl acetate layers were washed with 1N sodium bisulfate (100 ml), saturated sodium bicarbonate (100 ml) and brine (100 ml). The ethyl acetate solution was dried (magnesium sulfate), filtered and concentrated to half volume. The product crystallized out upon standing at RT for 30 min. Collection of the crystals by filtration and drying at high vacuum afforded 17.4 g (80% yield) of the pure product: 1H NMR (DMSO-d6) δ 1.21 (d, J=7.4 Hz, 3 H), 1.23 (d, J=7.3 Hz, 3 H), 1.38 (s, 9 H), 3.56 (d, J=6.3 Hz, 2 H), 3.75 (d, J=5.7 Hz, 2 H), 3.93 (d, J=6.0 Hz, 2 H), 4.24-4.34 (m, 2 H), 5.14 (s, 2 H), 6.98 (t, J=5.7 Hz, 1 H), 7.34-7.40 (m, 5 H), 7.93 (d, J=7.2 Hz, 1 H), 8.17-8.24 (m, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[O:28]([CH2:35][C:36](Cl)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:25][CH3:26])[C:36](=[O:37])[CH2:35][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)COc1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)COc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and phenoxyacetyl chloride.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:42])[N:20]([CH:39]([CH3:41])[CH3:40])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:42])[N:20]([CH:39]([CH3:41])[CH3:40])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(C(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc(C)n(C(C)C)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
A mixture of hydroxylammonium chloride (0.32 g), sodium hydrogen carbonate (0.48 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-[(4-butyl-1-isopropyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.23 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (4 mL). N,N′-carbonyldiimidazole (0.092 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.085 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.14 g, 53%).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)[CH:25]=3)[C:20]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=3)=[C:19]2[CH2:47][C:48]([CH3:54])([CH3:53])[C:49]([O:51]C)=[O:50])(=O)=O)C=CC=CC=1>>[CH2:1]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH:25]=2)[C:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)=[C:19]1[CH2:47][C:48]([CH3:54])([CH3:53])[C:49]([OH:51])=[O:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)C(C)(C)Cc1c(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc2n1S(=O)(=O)c1ccccc1
Product: CC(C)(Cc1c(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc2n1Cc1ccccc1)C(=O)O

Procedure:
The title compound was prepared under the conditions described in Step A and Step B of Example 38, but substituting benzyl chloride for the benzenesulfonyl chloride from Example 38 (Step A).
Reaction SMILES: [N:1]1([C:7]([O:9][C@H:10](/[CH:12]=[CH:13]\[C:14]([NH:16][C@@H:17]2[CH2:22][C@H:21]([CH3:23])[C@H:20]([CH2:24]/[CH:25]=[C:26](\[CH3:49])/[CH:27]=[CH:28]/[C@H:29]3[O:36][C@H:35]([CH2:37][C:38]([NH2:40])=[O:39])[CH2:34][C@:31]4([O:33][CH2:32]4)[C@@H:30]3[O:41][Si](C(C)(C)C)(C)C)[O:19][C@@H:18]2[CH3:50])=[O:15])[CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+](C1C=CC(OC(=O)OC2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=O.N1CCCCC1.CN(CCSC)C(=O)O[C@H](/C=C\C(N[C@@H]1C[C@H](C)[C@H](C/C=C(\C)/C=C/[C@H]2O[C@H](CC(N)=O)C[C@]3(OC3)[C@@H]2O[Si](C(C)(C)C)(C)C)O[C@@H]1C)=O)C>>[N:1]1([C:7]([O:9][C@H:10](/[CH:12]=[CH:13]\[C:14]([NH:16][C@@H:17]2[CH2:22][C@H:21]([CH3:23])[C@H:20]([CH2:24]/[CH:25]=[C:26](\[CH3:49])/[CH:27]=[CH:28]/[C@H:29]3[O:36][C@H:35]([CH2:37][C:38]([NH2:40])=[O:39])[CH2:34][C@:31]4([O:33][CH2:32]4)[C@@H:30]3[OH:41])[O:19][C@@H:18]2[CH3:50])=[O:15])[CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(/C=C/[C@H]1O[C@H](CC(N)=O)C[C@@]2(CO2)[C@@H]1O[Si](C)(C)C(C)(C)C)=C\C[C@@H]1O[C@H](C)[C@H](NC(=O)/C=C\[C@H](C)OC(=O)N2CCCCC2)C[C@@H]1C
Agent: CSCCN(C)C(=O)O[C@@H](C)/C=C\C(=O)N[C@@H]1C[C@H](C)[C@H](C/C=C(C)/C=C/[C@H]2O[C@H](CC(N)=O)C[C@@]3(CO3)[C@@H]2O[Si](C)(C)C(C)(C)C)O[C@@H]1C
Agent: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCNCC1
Solvent: CCN(CC)CC
Product: CC(/C=C/[C@H]1O[C@H](CC(N)=O)C[C@@]2(CO2)[C@@H]1O)=C\C[C@@H]1O[C@H](C)[C@H](NC(=O)/C=C\[C@H](C)OC(=O)N2CCCCC2)C[C@@H]1C

Procedure:
Synthesis of (2S,3Z)-5-{[(2R,3R,5S,6S)-6-{(2E,4E)-5-[(3R,4R,5R,7S)-7-(2- amino-2-oxoethyl)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,6-dioxaspiro[2.5]oct-5-yl]-3-methylpenta-2,4-dien-1-yl}-2,5-dimethyltetrahydro-2H-pyran-3-yl]amino}-5-oxopent-3-en-2-yl piperidine-1-carboxylate (#B135). Using the procedure described in step 3 of example A42, the title compound was prepared in 18% yield from 63.2 mg (0.104 mmol, 1.0 eq) of #B132, triethylamine (73 μL, 0.520 mmol, 5 eq), 4-N,N-dimethylamino pyridine (8.9 mg, 0.073 mmol, 0.7 eq.) and bis-(4-nitrophenyl)-carbonate (106 mg, 0.343 mmol, 3.3 eq.) and piperidine (14.8 mg, 0.174 mmol, 1.7 eq.) using the procedure described for preparation of compound #B133. LCMS (Protocol D): m/z 740.5 [M+Na]+, retention time=1.13 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH3:27].O>CN(C=O)C>[CH2:26]([N:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]1=[O:18])[CH3:27]
Reactant: CCI
Reactant: O=c1[nH]cc(-c2cccc(Cl)c2)c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(-c2cccc(Cl)c2)c2ncccc2c1=O
Temperature: 21 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a suspension of 8-(3-chlorophenyl)-1,6-naphthyridin-5-one (128 mg, 0.5 moles) and potassium carbonate (83 mg, 0.6 moles) in 10 ml DMF was added dropwise iodoethane (0.06 ml, 0.75 moles) under an atmosphere of nitrogen. The reaction mixture was stirred overnight at 21° C. The mixture was poured into 50 ml water and after stirring for one hour a white precipitate was collected and dried. Crystallization from ether/hexanes gave 117 mg (82% yield) of the desired 6-ethyl-8-(3-chlorophenyl)-1,6-naphthyridin-5-one as a white solid. Characteristic analytical data are as follows: mp 127°-128° C.; TLC 1:4 EtOAc/Hex; 1H NMR (CDCl3, 300 MHz) δ1.42 (t, 3H, J= 7.2), 4.11 (q, 2H, J=7.2), 7.35-7.60 (m, 6H), 8.76 (dd, 1H, J=8.0, 1.9), 8.93 (dd, 1H, J=4.5, 1.8); 13C NMR (75 MHz, CDCl3) δ161.54, 154.13, 151.62, 137.15, 136.60, 134.29, 134.16, 129.96, 129.53, 128.24, 127.70, 121.95, 119.63, 108.46, 44.62, 14.67; IR (KBr) vmax 3439, 1647, 1622, 1591, 1564, 1552, 1483, 1458, 1439, 1417, 1375, 1298, 1176, 1167, 1099, 794, 729, 711, 696, 603 cm-1 ; mass spectrum (EI), m/e 284. Anal. (C16H13ClN2O .1/8 H2O) Calcd.: C, 66.96; H, 4.57; N, 9.76. Found: C, 66.82; H, 4.55; N, 9.61.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:9])=[C:6]([O:20][CH3:21])[CH:5]=1)([O-])=O.C(O)C>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[O:9])=[C:6]([O:20][CH3:21])[CH:5]=1
Reactant: CCN(CC)CCNC(=O)c1ccc([N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1ccc(N)cc1OC
Yield: 106.4 %

Procedure:
5.7 g (19.3 mmol) of 4-nitro-N-(2-diethylamino-ethyl)-2-methoxy-benzamide is dissolved in 120 ml of tetrahydrofuran:ethanol=1:1, mixed with 2 g of palladium on carbon (10%×50% water) and hydrogenated for 1 hour at room temperature and normal pressure. After being drawn off on diatomaceous earth and after concentration by evaporation, 5.45 g of 4-amino-N-(2-diethylamino-ethyl)-2-methoxy-benzamide is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:13])([CH3:12])[CH2:9][NH:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.Br[C:15]#[N:16]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:12])[CH2:9][N:10]([CH3:11])[C:15](=[NH:16])[NH:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CBr
Reactant: CNCC(C)(N)c1cccc(Br)c1
Solvent: CCO
Product: CN1CC(C)(c2cccc(Br)c2)NC1=N
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.4 %

Procedure:
To a solution of 2-(3-bromophenyl)-N1-methylpropan-1,2-diamine (0.12 g, 0.50 mmol) in EtOH (10 mL) was added BrCN (0.073 g, 0.70 mmol, 1.4 eq). The mixture was stirred at RT for 16 h and then concentrated in vacuo. The residue was redissolved in CHCl3 (20 mL) and the solution was washed with 15% NaOH (10 mL). The aqueous layer was extracted with CHCl3 (3×10 mL) and the combined organic layer was dried (MgSO4), and concentrated to give 0.14 g (100%) of 4-(3-bromophenyl)-1,4-dimethylimidazolidin-2-imine (CD4; R1=Me, R4=Me) as a colorless oil. 1H NMR (CDCl3) δ 7.42 (t, J=1.7 Hz, 1H), 7.35 (dd, J=8.1, 1.7 Hz, 2H), 7.15 (t, J=8.1 Hz, 1H), 3.62 (d, J=9.3 Hz, 1H), 3.53 (d, J=9.0 Hz, 1H), 3.08 (s, 3H), 1.56 (bs, 3H). MS (ESI) m/e 268.1, 270.1 (M+H)+.