Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[NH:15][C@H:14]([C:16]([OH:18])=[O:17])[CH2:13][S:12]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:25]([S:28][CH2:29][CH2:30][C:31](Cl)=[O:32])(=[O:27])[CH3:26]>O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[N:15]([C:31](=[O:32])[CH2:30][CH2:29][S:28][C:25](=[O:27])[CH3:26])[C@H:14]([C:16]([OH:18])=[O:17])[CH2:13][S:12]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C1N[C@H](C(=O)O)CS1
Reactant: CC(=O)SCCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)Oc1ccccc1C1SC[C@@H](C(=O)O)N1C(=O)CCSC(C)=O
Temperature: 25 °C

Procedure:
2.7 g of (4R)-2-(2-acetoxyphenyl)-4-thiazolidinecarboxylic acid and 2.8 g of potassium carbonate are dissolved in 60 ml of water. To this solution, 1.8 g of S-acetyl-3-mercaptopropanoyl chloride is added dropwise with stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour and at room temperature for additional 1 hour. The reaction solution is washed with ethyl acetate, and acidified with conc. hydrochloric acid to give crystals. The crystals (the titled compound) are collected by filtration, yield 2.8 g (70%), mp. 144°-145° C. (ethyl acetate-benzene), [α]D27 +109.0° (c=1.0, methanol).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[CH3:34][C:35]1[O:39][C:38](B(O)O)=[CH:37][CH:36]=1>O1CCOCC1.C(OCC)(=O)C>[CH3:34][C:35]1[O:39][C:38]([C:2]2[CH:11]=[C:10]([C:12]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:8]=3)[N:3]=2)=[CH:37][CH:36]=1
Reactant: Cc1ccc(B(O)O)o1
Reactant: O=C(Nc1cccnc1)c1cc(Cl)nc2ccc(-c3ccccc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)Nc3cccnc3)c3cc(-c4ccccc4)ccc3n2)o1
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
To a round-bottomed flask under argon atmosphere was added 2-chloro-6-phenyl-N-(pyridin-3-yl)quinoline-4-carboxamide (0.100 g) in 1,4-dioxane (3 ml), and the vessel was purged with argon under stirring for 5 minutes. After 5 minutes, a 2N solution of potassium carbonate in water (11 eq) was added and the flask was purged with argon under stirring for 5 minutes. (5-methylfuran-2-yl)boronic acid (1.5 eq) was then added and the tube was purged with argon under stirring for 15 minutes. Finally, palladium(0)tetrakis triphenylphosphine (0.05 eq) was added under argon and the flask was affixed to a reflux condenser and heated to 90° C. for 5 hours. The completion of the reaction was monitored on TLC using ethyl acetate:hexanes as a mobile phase. After completion of the reaction, reaction mixture was diluted with ethyl acetate (100 ml) and then washed with water (5*100 ml). The ethyl acetate layer was dried over anhydrous sodium sulphate and then solvent was distilled out and the crude was subjected to purification by silica gel column chromatography to provide 0.01 g of 2-(5-methylfuran-2-yl)-6-phenyl-N-(pyridin-3-yl)quinoline-4-carboxamide.
Reaction SMILES: C[C:2]([CH3:5])([O-:4])C.[Na+].S([O:12][CH3:13])(OC)(=O)=O.Cl.C([O-])(O)=O.[Na+].[O:20]1[CH2:24]C[CH2:22][CH2:21]1>O>[CH3:24][O:20][C@H:21]1[C:13](=[O:12])[CH2:5][CH2:2][O:4][CH2:22]1
Reactant: C1CCOC1
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CO[C@@H]1COCCC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
To a solution of the product from step 3 (9.5 g, 64.68 mol) in tetrahydrofuran (300 mL) was added sodium tert-butoxide (9.3 g, 97.02 mmol) at ice bath. Then dimethyl sulfate (13.4 g, 106 mmol) was added over 20 minutes, maintaining an internal temp below 36° C. After addition, the reaction mixture was stirred for 4 hours at room temperature. Water (200 mL) was added followed by addition of 2N HCl (100 mL). The apparent pH was below 1. After 16 hours of reaction, NaHCO3 (20 g) was added and the mixture was extracted with ethyl acetate (4×300 mL), dried over Na2SO4, filtered, and concentrated to an oil (6 g, yield: 71%).
Reaction SMILES: C([Li])CCC.C([C:8]([CH2:19][CH3:20])([C:13]1[N:14]=[C:15]([CH3:18])[S:16][CH:17]=1)P([O-])(=O)[O-])C.[Si:21]([O:28][C@@H:29]([CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])C(=O)C)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C1COCC1>[Si:21]([O:28][CH2:29][CH2:33][C@H:34]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:37])[CH3:38])/[C:19](/[CH3:20])=[CH:8]/[C:13]1[N:14]=[C:15]([CH3:18])[S:16][CH:17]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: CCC(CC)(c1csc(C)n1)P(=O)([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C/C(=C\c1csc(C)n1)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
(see D. Schinzer et al., Chem. Eur. J. 2, 1477-1482 (1996)) n-Butyl lithium (23,5 ml [58.7 mmol, 1.2 equiv] of a 2.5 M solution in hexanes) is added dropwise to a stirred solution of diethyl-(2-methylthiazol-4-yl)-methanephosphonate 10 (14,64 g, 58.7 mmol, 1.2 equiv) in THF (150 ml) cooled to −78° C. After stirring at −78° C. for 1 h, a solution of (S)-3,5-di-(tertbutyidimethylsilyloxy)-pentan-2-one 14 (16.96 g, 48,9 mmol, 1.0 equiv) in 100 ml of THF is added dropwise at −78° C. The mixture is warmed to r.t. within 12 h. The reaction is quenched with saturated aqueous ammonium chloride solution (100 ml). The organic layer is seperated and the aqueous layer is extracted with diethyl ether (3×100 ml). The combined organic extracts are dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by flash column chromatography (gradient elution with pentane/dichloromethane 4:1→dichloromethane→diethyl ether→diethyl ether/methanol 10:1) affords (S,4E)-1,3di-(tert-butyldimethylsilyloxy)-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-ene 15 (17,07 g, 38.6 mmol, 79%) as a colourless oil and some starting material (10 and 14). Alternatively, the crude product obtained after extraction can be directly used in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[C:6]([CH2:8]O)[CH:7]=1.[C:17]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(O[C:41](/[N:43]=[N:44]/[C:45](OC(C)(C)C)=O)=[O:42])(C)C>C1COCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[C:6]([CH:7]=1)[CH2:8][N:44]1[CH:45]=[CH:17][C:41]([OH:42])=[N:43]1
Reactant: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCC(CC)COc1ccc(Br)cc1CO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC(CC)COc1ccc(Br)cc1Cn1ccc(O)n1
Temperature: 120 °C

Procedure:
A solution of [5-bromo-2-(2-ethyl-butoxy)-phenyl]-methanol, 2, (1.2 g 4.2 mmol), triphenylphosphine (1.6 g, 6 mmol), di-tert-butylazodicarboxylate (1.4 g, 6 mmol) and 3-methylpyrazolyl-5-one (0.75 g, 7.7 mmol) in a mixture of THF (5 mL) and toluene (10 ml) was heated at 120° C. in an Emrys microwave reactor for 20 min. The volatiles were removed in vacuo. The crude product was purified on silica to yield 1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazol-3-ol, 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH:23]([CH2:26]OS(C)(=O)=O)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][C@@H:23]([CH2:26][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:13])[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: COc1ccc2ccc(=O)[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)C1
Product: COc1ccc2ccc(=O)n(C[C@@H]3CCN(C(=O)OC(C)(C)C)C3)c2c1
Yield: 23 %

Procedure:
Using the procedure of Example 2, step 2.i, but starting from 7-methoxy-2(1H)-quinolinone (prepared according to WO 2006/134378; 500 mg) and 3-[[(methylsulfonyl)oxy]methyl]-1-pyrrolidinecarboxylic acid tert-butyl ester (797 mg; prepared according to J. Med. Chem. (1999), 42, 677-690), the second eluting compound was isolated as a colourless oil (240 mg; 23% yield).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:9][C:10]([C:12]1[CH:16]=[C:15]([CH2:17][CH2:18][OH:19])[O:14][N:13]=1)=[O:11])[CH3:8].[CH:20]1[CH:25]=[CH:24][C:23]([O:26][C:27](Cl)=[S:28])=[CH:22][CH:21]=1>ClCCl>[CH2:7]([O:9][C:10]([C:12]1[CH:16]=[C:15]([CH2:17][CH2:18][O:19][C:27]([O:26][C:23]2[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=2)=[S:28])[O:14][N:13]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1cc(CCO)on1
Reactant: S=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(CCOC(=S)Oc2ccccc2)on1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
Pyridine (2,4 g, 31 mmol) was added to a stirred solution of 5-hydroxyethylisoxazole-3-carboxylic acid ethyl ester (4.75 g, 26 mmol) (prepared analogously to Example 64 part a) in dichloromethane (150 ml) under nitrogen at room temperature. The mixture was cooled to 0° C. and phenyl chlorothionoformate (5.3 g, 31 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 h and at room temperature for 2 h, then diluted with dichloromethane (200 ml) and washed with water (×2). The organic layer was dried (MgSO4) and evaporated in vacuo. Flash chromatography of the residue on silica gel, eluting with 20% ethyl acetate/hexane, gave the title-compound (6.7 g, 81%), 1H NMR (250 MHz, CDCl3) δ 1.43 (3H, t, J=7.1 Hz, CH3), 3.37 (2H, t, J=6.3 Hz, CH2), 4.46 (2H, q, J=7.1 Hz, CH2), 4.83 (2H, t, J=6.3 Hz, CH2), 6.60 (1H, s, Ar—H), 7.08-7.11 (2H, m, 2 of Ar—H), 7.29 (1H, m, Ar—H), 7.38-7.46 (2H, m, 2 of Ar—H); MS (ES30) m/e 322 [MH]+, m/e 168 [MH−154]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(N(CC)CC)C.[Cl:19][CH2:20][S:21](Cl)(=[O:23])=[O:22].Cl>ClCCl>[Cl:19][CH2:20][S:21]([NH:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)CCl
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNS(=O)(=O)CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.9 %

Procedure:
2-Aminoacetophenone hydrochloride (4.56 g, 26.6 mmol) was dissolved in dichloromethane (250 mL). To the solution was added triethylamine (9.30 mL, 66.7 mmol), and the mixture was stirred at room temperature for 10 minutes. After the reaction mixture was cooled to 0° C., chloromethanesulfonyl chloride (purity 90%, 3.60 mL, 36.3 mmol) was added to the mixture, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added 2 mol/L hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added diethyl ether, and the deposited crystals were collected by filtration, and dried to obtain 2-(chloromethylsulfonylamino)acetophenone (5.00 g, 76%).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:27]=[CH:26][N:13]([C@@H:14]2[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[C@H:15]2[O:16][CH2:17][CH2:18][CH3:19])[C:12](=[O:28])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[C:32]([O:51][CH3:52])=[C:33]([CH:48]=[CH:49][CH:50]=1)[C:34](Cl)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:1]([NH:9][C:10]1[CH:27]=[CH:26][N:13]([C@@H:14]2[O:25][C@H:22]([CH2:23][O:24][C:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:33]3[CH:48]=[CH:49][CH:50]=[C:31]([O:30][CH3:29])[C:32]=3[O:51][CH3:52])[C@@H:20]([OH:21])[C@H:15]2[O:16][CH2:17][CH2:18][CH3:19])[C:12](=[O:28])[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1OC
Reactant: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Product: CCCO[C@@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2cccc(OC)c2OC)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Yield: 49 %

Procedure:
N4-Benzoyl-2'-O-propylcytidine (3.0 g, 0.007 mol) was treated with dimethoxytrityl chloride (1.5 g) as per the procedure of Example 72 to give 1.5 g of pure product. Anal. Calcd. for C40H42N3O8.1/2H2O: C, 68.45; H, 6.18; H, 5.99. Found: C, 68.39; H, 5.99; N, 5.95.
Reaction SMILES: C([C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([NH:7][CH:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:11][NH:10][CH2:9]1)=[O:6])C.[N:28]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)=[C:29]=[O:30].C(N(CC)CC)C>C1COCC1>[C:4]1([C:5]([NH:7][CH:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=3)[CH2:11][N:10]([C:29]([NH:28][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)=[O:30])[CH2:9]2)=[O:6])[CH:3]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCc1ccccc1C(=O)NC1CNCC(c2ccc(C(F)(F)F)cc2)C1
Reactant: O=C=Nc1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Nc2ccncc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80 mg (0.23 mmol) of ethyl-N-{5-[4-(trifluoromethyl)phenyl]piperidin-3-yl}benzamide were initially charged in 2 ml of THF, and 28 mg (0.23 mmol) of 4-isocyanatopyridine and 35 μl (0.25 mmol) of triethylamine were added. The mixture was stirred at RT overnight. The reaction mixture was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 75 mg (70% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH:17]1([C:21](=O)[CH2:22][C:23]#[N:24])[CH2:20][CH2:19][CH2:18]1>>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:21]([CH:17]1[CH2:20][CH2:19][CH2:18]1)[C:22]([C:23]#[N:24])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#CCC(=O)C1CCC1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: N#Cc1c(C2CCC2)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-chlorophenyl)(phenyl)methanone and 3-cyclobutyl-3-oxo-propionitrile. Light yellow powder. MS (ESI): 319.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]2[N:6](CC3C=CC(OC)=CC=3)[C:7](=[O:30])[CH:8]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]4[NH:19][C:18](=[O:20])[NH:17][C:14]4=[N:15][CH:16]=3)[C:4]=2[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1>[Cl:1][C:2]1[CH:41]=[CH:40][C:5]2[NH:6][C:7](=[O:30])[CH:8]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]4[NH:19][C:18](=[O:20])[NH:17][C:14]4=[N:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(CN2C(=O)C(CCc3ccccc3Cl)N=C(c3cnc4[nH]c(=O)[nH]c4c3)c3cc(Cl)ccc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Product: O=C1Nc2ccc(Cl)cc2C(c2cnc3[nH]c(=O)[nH]c3c2)=NC1CCc1ccccc1Cl
Temperature: 85 °C
Reaction time: 2 h
Yield: 25.2 %

Procedure:
7-Chloro-3-(2-chlorophenethyl)-1-(4-methoxybenzyl)-5-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one (50 mg) was dissolved in anisole (2.1 mL) and aluminum chloride (46 mg, 4 eq) was added. The reaction was stirred at 85° C. for 2 h, then poured into ice:EtOAc (1:1). The quenched reaction was stirred vigorously for 1 h, then the organic layer was separated, washed with brine, dried over sodium sulfate, and then concentrated onto silica gel and purified by chromatography (gradient: DCM to 9:1 DCM:MeOH) delivering product (10 mg, 25% yield). HRMS (ES+) m/z calcd for C23H17Cl2N5O2 [M+H]+, 466.0838. found, 466.0838.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:43])[C@:10]3([C@@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[F:22])[C@H:13]([C:23](=[O:33])[NH:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=4)[NH:12][C@H:11]3[CH2:34][C:35]([CH3:42])([CH3:41])[CH2:36][O:37]C(=O)C)[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].CO>O1CCCC1>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:23]([CH:13]2[NH:12][CH:11]([CH2:34][C:35]([CH3:42])([CH3:41])[CH2:36][OH:37])[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:43])[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])=[O:33])=[CH:30][CH:29]=1)#[N:32]
Reactant: CC(=O)OCC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C#N)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(CO)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of acetic acid rac-3-[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-5′-(4-cyano-phenylcarbamoyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidin]-2′-yl]-2,2-dimethyl-propyl ester (17 mg, 0.027 mmol) in tetrahydrofuran (2 mL) was added an aqueous solution (1N) of NaOH (0.5 mL, 0.5 mmol) and methanol (0.2 mL). The reaction mixture was stirred at room temperature for 18 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic extracts were combined, washed with water, brine, dried over MgSO4, and concentrated to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(3-hydroxy-2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a off white solid (14 mg, 88%).
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>N1C=CC=CC=1.O.[OH-].[K+]>[F:21][C:3]1[C:2]([N:27]2[CH2:26][CH2:25][NH:24][CH:23]([CH3:22])[CH2:28]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: CC1CNCCN1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CC1CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C)CCN1
Reaction time: 13 h
Yield: 63.9 %

Procedure:
A suspension of 3.5 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 4.6 g of 2-methylpiperazine in 40 cm3 of pyridine is heated at a temperature close to 115° C., with stirring, for 13 hours. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at 60° C. The residue is twice taken up with 30 cm3 of ethanol and concentrated under reduced pressure under the above conditions. The solid obtained is taken up in 60 cm3 of water and 10 cm3 of 30% aqueous potassium hydroxide solution. The aqueous phase is washed with twice 100 cm3 of trichloromethane, 10.28 g of methanesulphonic acid are added and the aqueous phase is again washed with twice 100 cm3 of trichloromethane. 10 cm3 of 30% aqueous potassium hydroxide solution are added. The precipitate formed is drained and washed with 3 times 10 cm3 of water and twice 10 cm3 of ethanol. 2.7 g of 7-fluoro-1-methyl-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 360°-363° C.
Reaction SMILES: [CH:1]1([CH:6]([OH:10])[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.N[C@H](C([NH:17][CH:18]1[C:24](=[O:25])[N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[N:20]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:19]1=[O:42])=O)C>>[CH:1]1([CH:6]([OH:10])[C:7]([NH:17][C@H:18]([C:24]([C:18]2([NH2:17])[C:19](=[O:42])[N:20]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:21]3[CH:35]=[CH:34][CH:33]=[CH:32][C:22]=3[N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:24]2=[O:25])=[O:25])[CH3:19])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[C@H](N)C(=O)NC1C(=O)N(c2ccccc2)c2ccccc2N(c2ccccc2)C1=O
Reactant: O=C(O)C(O)C1CCCC1
Agent: Cl
Product: C[C@H](NC(=O)C(O)C1CCCC1)C(=O)C1(N)C(=O)N(c2ccccc2)c2ccccc2N(c2ccccc2)C1=O

Procedure:
Following General Procedure I above using cyclopentyl-α-hydroxyacetic acid (Example P) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-W), the title compound was prepared as a white solid (melting point=139-149° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:2). Rf=0.50 and 0.39 (CH2Cl2/EtOAc, 1:2).
Reaction SMILES: CCOP(O[CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1)[C:10]#[N:11])(CC)=O.[H-].[Na+].[CH3:20][O:21][C:22](=[O:46])[C@H:23]([CH2:42][CH2:43][S:44][CH3:45])[NH:24][C:25](=[O:41])[C:26]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][C:27]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40]>COCCOC>[C:10](/[C:9](/[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:32]/[C:29]1[CH:30]=[CH:31][C:26]([C:25]([NH:24][C@H:23]([C:22]([O:21][CH3:20])=[O:46])[CH2:42][CH2:43][S:44][CH3:45])=[O:41])=[C:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:40])[CH:28]=1)#[N:11]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=O)cc1-c1ccccc1C
Reactant: CCOP(=O)(CC)OC(C#N)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(/C=C(/C#N)c2cccnc2)cc1-c1ccccc1C
Reaction time: 0.5 h

Procedure:
To a solution of diethyl 3-pyridylcyanomethyl phosphonate (269 mg) in DME (3 mL) was added NaH (39 mg@60%). To the red solution was added N-[4-formyl-2-(2-methylphenyl)benzoyl] methionine methyl ester (example 10756, 340 mg). After 30 min, the reaction was warmed to reflux for 2.5 h. The reaction was cooled, quenched with water (5 mL), and extracted into EtOAc (20 mL). The organic extracts were washed with brine (5 mL), dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 50%-100% EtOAc/hexane to afford two products as colorless oils. The more mobile isomer (68 mg, 13%) was assigned the Z configuration based on a ROESY experiment. MS (APCI(+)) m/e 486 (M+H)+. MS (APCI(−)) m/e 485 M−. The less mobile isomer (246 mg, 48%) was assigned the E configuration based on a ROESY experiment. MS (APCI(+)) m/e 486 (M+H)+. MS (APCI(−)) m/e 485 M−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[CH:24]([OH:27])[CH2:25][CH3:26].C1CCN2C(=NCCC2)CC1.[Cl-].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[C:24](=[O:27])[CH2:25][CH3:26]
Reactant: CCC(O)c1cc(OC)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCC(=O)c1cc(OC)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
Under an argon atmosphere, 1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxyphenyl}-1-propanol (compound 11) (65.9 mg) was dissolved in methylene chloride (2 ml) to prepare a solution. 1,8-Diazabicyclo[5.4.0]-7-undecene (72 mg) was then added to the solution, and the mixture was cooled to −78° C. N-Tert-butylbenzenesulfineimidoyl chloride (71.4 mg) was dissolved in methylene chloride to prepare a solution, and the solution was added to the reaction solution. The mixture was stirred at −78° C. for 30 min and at 0° C. for 30 min. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (56.2 mg, yield 86%).