Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH3:21][C:22]1([CH2:26][NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])[CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:24]4[CH2:25][C:22]([CH2:26][NH:27][C:28](=[O:33])[C:29]([F:31])([F:32])[F:30])([CH3:21])[CH2:23]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC1(CNC(=O)C(F)(F)F)CNC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1(CNC(=O)C(F)(F)F)CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Yield: 91.5 %

Procedure:
A mixture of 0.7 g (2.6 mmoles) of 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 0.92 g (3.96 mmoles) of 3-methyl-3-trifluoroacetamidomethylazetidine hydrochloride and 1.6 g of triethylamine are heated under reflux for 2 hours in 12 ml of pyridine. The mixture is evaporated, water is added, the product is filtered, and 1.05 g (90%) of 1-cyclopropyl-6-fluoro-7-(3-trifluoroacetamidomethyl-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 265°-72° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N:10]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:19]([CH2:22][C:23](=[O:25])[CH3:24])(=[O:21])[CH3:20]>C(O)(=O)C.Cl.O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][N:10]=[C:22]([C:23](=[O:25])[CH3:24])[C:19](=[O:21])[CH3:20])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(N)c1
Reactant: CC(=O)CC(C)=O
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cccc(NN=C(C(C)=O)C(C)=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
To a solution of 3-methoxyaniline (1000 mg, 8.13 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrochloride solution, sodium nitrite (673 mg, 9.76 mmol) in 4 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (2000 mg, 24.39 mmol) and acetylacetone (1057 mg, 10.57 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give 3-[(3-methoxyphenyl)hydrazono]pentane-2,4-dione (840 mg, 44%). LCMS: m/z=235 [M++H].
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:56])[C@@H:24]([NH:25][C:26](=[O:55])[C@@H:27](C4C=CC(C(OC(C)(C)C)=O)=CC=4N)[NH:28][C:29]([N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[C:33](=[O:39])[C:32]4=[O:40])=[O:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:57][S:58][C:59]2[N:63]([CH3:64])[N:62]=[N:61][N:60]=2)=[O:16])C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:66]1([CH3:76])[CH:71]=[CH:70][C:69]([S:72]([OH:75])(=[O:74])=[O:73])=[CH:68][CH:67]=1.[C:77](#[N:79])[CH3:78]>>[C:66]1([CH3:76])[CH:67]=[CH:68][C:69]([S:72]([OH:75])(=[O:73])=[O:74])=[CH:70][CH:71]=1.[C:66]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:56])[C@@H:24]([NH:25][C:26](=[O:55])[C@@H:27]([C:1]4[CH:2]=[CH:3][C:77]([NH2:79])=[CH:78][CH:6]=4)[NH:28][C:29]([N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[C:33](=[O:39])[C:32]4=[O:40])=[O:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:57][S:58][C:59]2[N:63]([CH3:64])[N:62]=[N:61][N:60]=2)=[O:16])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1
Reactant: CC#N
Reactant: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CSc4nnnn4C)CS[C@H]23)c2ccc(C(=O)OC(C)(C)C)cc2N)C(=O)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CSc4nnnn4C)CS[C@H]23)c2ccc(N)cc2)C(=O)C1=O

Procedure:
In the manner described in Example 11, 3.40 g of 3-[(1-methyl-1H-tetrazol-5-yl)-thiomethyl]-7β-[(2R)-2-(4-BOC-aminophenyl)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted with 1.38 g of p-toluenesulphonic acid monohydrate in 30 ml of acetonitrile and worked up. 3-[(1-Methyl-1H-tetrazol-5-yl)-thiomethyl]-7β-[(2R)-2-(4-aminophenyl)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester p-toluenesulphonate is obtained. [α]D20 =-32°±1° (0.96% in DMSO).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH:15]3[CH2:27][C:26]4[C:25]5[C:20](=[CH:21][CH:22]=[C:23]([O:28]C)[CH:24]=5)[NH:19][C:18]=4[CH2:17][CH2:16]3)[CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:2]1([C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH2:27][C:26]4[C:25]5[C:20](=[CH:21][CH:22]=[C:23]([OH:28])[CH:24]=5)[NH:19][C:18]=4[CH2:17][CH2:16]3)[CH2:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2[nH]c3c(c2c1)CC(CN1CC=C(c2ccccc2)CC1)CC3
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Oc1ccc2[nH]c3c(c2c1)CC(CN1CC=C(c2ccccc2)CC1)CC3
Reaction time: 3 h

Procedure:
A mixture of 4.19 g of 3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridylmethyl)-6-methoxy-1,2,3,4-tetrahydrocarbazole hydrochloride and 3.5 g of pyridine hydrochloride is stirred at 160° for 3 hours. After the usual work-up, 3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridylmethyl)-6-hydroxy-1,2,3,4-tetrahydrocarbazole, Rf 0.2 (toluene/triethylamine 9:1), is obtained.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]([CH:19]1[CH2:23][CH2:22][C:21]([CH3:27])([C:24](O)=[O:25])[C:20]1([CH3:29])[CH3:28])=[O:18].C(N(CC)CC)C>C(#N)C>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:24]([C:21]1([CH3:27])[CH2:22][CH2:23][CH:19]([C:17]([O:16][CH3:15])=[O:18])[C:20]1([CH3:29])[CH3:28])=[O:25])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Reactant: COC(=O)C1CCC(C)(C(=O)O)C1(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)OC)C1(C)C
Temperature: 60 °C

Procedure:
To a 20-mL scintillation vial containing a magnetic stir bar were added the product from Example 92B (637 mg, 3.00 mmol), racemic 3-(methoxycarbonyl)-1,2,2-trimethylcyclopentanecarboxylic acid (Maybridge, 771 mg, 3.60 mmol), and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (TBTU, Bachem, 1.16 g, 3.60 mmol). Anhydrous acetonitrile (8 mL) was added to form a white slurry. Neat triethylamine (Aldrich, 1.09 g, 10.8 mmol) was added via syringe to form a tan solution. The reaction flask was heated to 60° C. in a shaker block and mixed for 2 hours. The volatiles were removed by rotary evaporator to give a brown oil. The product was purified by flash chromatography (silica gel: 2-20% ethyl acetate in hexanes) to afford the title compound. 1H NMR (DMSO-d6) δ 0.50 (s, 3H), 0.90 (t, J=7.5 Hz, 3H), 1.21 (s, 3H), 1.24-1.36 (m, 2H), 1.30 (s, 3H), 1.41-1.51 (m, 1H), 1.57 (s, 9H), 1.57-1.67 (m, 2H), 1.73-1.87 (m, 1H), 2.01-2.11 (m, 1H), 2.62-2.67 (m, 2H), 2.70-2.81 (m, 1H), 2.85-2.91 (m, 1H), 3.60 (s, 3H), 8.50 (s, 1H). MS (ESI+) m/z 409 (M+H)+. Anal. calcd. for C22H36N2O3S: C, 64.67; H, 8.88; N, 6.86. Found: C, 64.20; H, 8.71; N, 6.59.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:33]C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:51]1[CH2:55]OC[CH2:52]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:33][CH:51]([CH3:52])[CH3:55])[CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CCNCC4)cc(Nc4cccc(Cl)c4)nc23)N1
Reactant: CC(=O)O
Reactant: C1CCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)CN1CCC(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=C4NC(=O)NC4=O)cnn23)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 5-((5-(3-chlorophenylamino)-7-(piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (30 mg, 0.06 mmol) in THF and AcOH (4.8 mg, 0.08 mmol) was added isobutryldehyde (2.2 mL, 0.2 mmol) and sodium triacetoxy borohydride (85.0 mg, 0.4 mmol). The mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated, diluted with MeOH, and purified by prep HPLC to yield 5-((5-(3-chlorophenylamino)-7-(1-isobutylpiperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=509)
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([OH:3])=[O:2].[NH2:12][C@@H:13]([C:18]([OH:20])=[O:19])[C:14]([SH:17])([CH3:16])[CH3:15]>O>[C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]1[NH:12][C@@H:13]([C:18]([OH:20])=[O:19])[C:14]([CH3:16])([CH3:15])[S:17]1)([OH:3])=[O:2]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: O=Cc1ccccc1C(=O)O
Solvent: O
Product: CC1(C)SC(c2ccccc2C(=O)O)N[C@H]1C(=O)O
Reaction time: 3 h

Procedure:
A mixture containing 6 g (30 mmoles) of 2-carboxybenzaldehyde and 6 g (30 mmoles) of D-penicillamine in 44 ml of water is stirred for 3 hours. The precipitate is filtered out and washed with aqueous methanol to given the crude title acid in a yield of 9.86 g (82.6%) which can be recrystallized from methanol containing water, m.p.: 185°-186° C. [α]D18 =+385° (c=0.51, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23][C:24](OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.NC1C=[CH:52][N:51]=[CH:50][CH:49]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@@H:19]([C:20]([NH:22][C:23]2[CH:24]=[CH:52][N:51]=[CH:50][CH:49]=2)=[O:21])[CH2:31][CH3:32])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Reactant: Nc1ccncc1
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1ccncc1

Procedure:
Instead of the starting material compound of Example 220, that is, glycine tert-butyl ester hydrochloride, 4-aminopyridine was used for the similar procedure as in Example 220 to obtain the title compound.
Reaction SMILES: [NH2:1][C:2](=O)[CH:3]([NH:13][C:14](=O)[CH2:15][C:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])([CH3:18])[CH3:17])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][CH3:12].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1.N1C=CC=CC=1>C(Cl)Cl>[Si:20]([O:19][C:16]([CH3:18])([CH3:17])[CH2:15][C:14]1[S:38][C:2]([NH2:1])=[C:3]([C:4]2[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=2[O:11][CH3:12])[N:13]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: COc1ccc(Cl)cc1C(NC(=O)CC(C)(C)O[Si](C)(C)C(C)(C)C)C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1-c1nc(CC(C)(C)O[Si](C)(C)C(C)(C)C)sc1N
Temperature: 95 °C
Yield: 33 %

Procedure:
A mixture of N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)-3-(tert-butyldimethylsilyloxy)-3-methylbutanamide (327 mg, 0.76 mmol), Lawesson's reagent (308 mg, 0.76 mmol) and pyridine (2.5 mL) was heated to 95° C. for 18 hours. DCM was added, the organics washed with sodium hydrogen carbonate (sat. aq.) and brine, then evaporated to dryness. The residues were purified by flash chromatography on silica gel (DCM) to afford 107 mg (33%) of 2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methoxyphenyl)thiazol-5-amine LCMS (ESI) m+H=427.3.
Reaction SMILES: [CH3:1][CH:2]([S:4]([Cl:7])(=[O:6])=[O:5])[CH3:3].[CH3:8][O:9][C:10](=[O:42])[NH:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:22](=[O:41])[CH2:23][C:24]([CH3:40])([CH3:39])[CH2:25][C@H:26]([NH:31]C(OC(C)(C)C)=O)[C@@H:27]([OH:30])[CH2:28][NH2:29])[CH2:13]1.C(N(CC)CC)C>ClCCl>[ClH:7].[CH3:8][O:9][C:10](=[O:42])[NH:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:22](=[O:41])[CH2:23][C:24]([CH3:40])([CH3:39])[CH2:25][C@H:26]([NH2:31])[C@@H:27]([OH:30])[CH2:28][NH:29][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])[CH2:13]1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: COC(=O)NC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H](N)[C@@H](O)CNS(=O)(=O)C(C)C)C1
Product: Cl
Reaction time: 5 h

Procedure:
0.007 ml Propan-2-sulfonyl chlorid are added to a solution of 0.026 g [1-(7-amino-5(S)-tert-butoxycarbonylamino-6(S)-hydroxy-3,3-dimethyl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamic acid methyl ester (Example 18b) and 0.007 ml triethylamine in 1 ml dichlormethane at 0° C. After 5 hours, the reaction mixture is concentrated. The intermediate N-Boc derivative is identified from the residue by means of flash chromatography (SiO2 60 F) based on its Rf value. This is dissolved in 0.82 ml 4N HCl (in dioxane), stirred for 4 hours and concentrated. The residue is dissolved in 0.5 ml tert-butanol, frozen in liquid nitrogen and lyophilized to give the title compound which is identified from the residue based on its Rf value.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[F:35][CH:36]1[CH2:40][NH:39][CH:38]([CH2:41][O:42][C:43]2[CH:53]=[CH:52][C:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][C:44]=2[O:54][CH3:55])[CH2:37]1>CN(C=O)C.CCOC(C)=O>[F:35][CH:36]1[CH2:40][N:39]([C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:38]([CH2:41][O:42][C:43]2[CH:53]=[CH:52][C:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][C:44]=2[O:54][CH3:55])[CH2:37]1
Reactant: CCOC(=O)c1ccc(OCC2CC(F)CN2)c(OC)c1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OCC2CC(F)CN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
A mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (404.0 mg, 0.840 mmol), ethyl 4-(4-fluoro-2-pyrrolidinyl)methoxy-3-methoxybenzoate (250.0 mg, 0.840 mmol), Et3 N (141 μl, 1.009 mmol) in DMF (4.0 mL) was stirred for 1 hr at room temp. The mixture was diluted with EtOAc, washed with water, brine, and dried over Na2SO4. The solvent was removed under a reduced pressure and the residue was chromatographed on silica-gel with n-hexane:EtOAc (1:3, v/v) to afford 502 mg (q.y.) of ethyl 4-[[4-fluoro-1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]-3-methoxybenzoate as a yellow oil. To a stirred solution of this compound in THF (8.0 mL) and H2O (2.0 mL) was added LiOH (60.4 mg, 2.520 mmol), and the mixture was stirred at room temp. overnight, and 50° C. for 1 day. The mixture was diluted with CHCl3, and extracted with 1 N NaOH. The aqueous layer was acidified by the addition of 1 N HCl and extracted with CHCl3. The extract was washed with brine and dried over Na2SO4. The solvent was removed under a reduced pressure and the obtained crude solid was recrystallized from EtOAc—CHCl3-EtOH-n-hexane to afford 294.8 mg (62%) 45 as a white crystalline powder. IR (KBr) 2958, 2937, 1687, 1601, 1531, 1454, 1419, 1267, 1214, 1029 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ 1.86–2.09 (m, 5H), 2.06 (s, 3H), 2.25 (s, 3H), 3.47–3.67 (m, 6H), 3.76 (s, 3H), 4.05–4.12 (m, 2H), 4.30–4.31 (m, 1H), 6.51 (s, 1H), 6.55 (s, 1H), 6.73–6.95 (m, 2H), 7.11–7.17 (m, 2H), 7.64 (s, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 8.47 (s, 1H), 8.55 (s, 1H); MS (FAB) m/z 566 (M++1); Anal. Calcd for C30H32FN3O7.1/2H2O: C, 62.71; H. 5.79; F, 3.31; N, 7.31. Found: C, 63.13; H. 6.17; F, 3.12; N, 7.04.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[Cl:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=3[Cl:42])=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Clc1ccc(Sc2ccc(Br)cc2)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3ccc(Cl)cc3Cl)cc2)c1C
Yield: 37.6 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-(4-bromo-phenylsulfanyl)-2,4-dichlorobenzene (0.196 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(2,4-dichloro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.10 g, 36%) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][S:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[N:6][CH:7]=1.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]1B(O)O>>[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]1[C:2]1[CH:3]=[C:4]([O:8][S:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(=O)(Oc1cncc(Br)c1)N1CCOCC1
Reactant: Cn1c(B(O)O)cc2ccccc21
Product: Cn1c(-c2cncc(OS(=O)(=O)N3CCOCC3)c2)cc2ccccc21

Procedure:
Morpholine-4-sulfonic acid 5-bromo-pyridin-3-yl ester and N-methyl-indoleboronic acid are processed according to the method described in Example 100 to give morpholine-4-sulfonic acid 5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl ester. MS (ESI) m/z 374.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](SC)[CH:5]=[CH:4][C:3]=1[C:10]1[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[C:11]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O[O:25][S:26]([O-:28])=O.[K+].CO.[CH2:32]1COCC1.O>>[Cl:1][C:2]1[CH:7]=[C:6]([S:26]([CH3:32])(=[O:28])=[O:25])[CH:5]=[CH:4][C:3]=1[C:10]1[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[C:11]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Reactant: CSc1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)c(Cl)c1
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2Cl)=C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
350 mg of 5-{2-chloro-4-(methylthio)phenyl}-2,2-dimethyl-4-phenyl-3(2H)-furanone (Example 387) was dissolved in 75 ml of 1:1:1 methanol/THF/water, to which was added 1.0 g of OXONE. The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated in vacuo and the resulting residue was extracted with 25 ml water and ethylacetate (50 ml×3). The organic layer was concentrated in vacuo and was purified by column chromatography (hexane/ethylacetate=3:1) to give 252 mg of 5-{2-chloro-4-(methylsulfonyl)phenyl}-2,2-dimethyl-4-phenyl-3(2H)-furanone as a solid. mp: 89-90° C. NMR: δ1.59 (s, 6H), 3.11 (s, 3H), 7.19 (m, 2H), 7.25 (m, 3H), 7.60 (d, J=8.1 Hz, 1H), 7.87 (dd, J=8.1, 1.8 Hz, 1H), 8.07 (d, J=1.8 Hz, 1H). IR (cm−1): 1701, 1625, 1586, 1391, 1319, 1153.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:9]2[CH:21]=[CH:22][CH:23]=[C:8]2[C:7]=1[OH:24])=[O:5])C.[NH2:25][CH2:26][C:27]([O-:29])=[O:28].[Na+]>>[F:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:10]1[C:11](=[O:12])[C:6]([C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])=[C:7]([OH:24])[C:8]2=[CH:23][CH:22]=[CH:21][N:9]12
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2cccc(F)c2)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2cccc(F)c2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-(3-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 360 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: NC(=O)c1ccc(OCCCCl)cc1

Procedure:
A mixture composed of 0.004 mol of 4-hydroxybenzamide, 0.004 mol of 1-bromo-3-chloropropane and 0.006 mol of caesium carbonate in 10 ml of acetonitrile is heated at reflux for 5 hours.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:22])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[NH:17][CH2:18][CH2:19][CH2:20]O)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:25])=O>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:22])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[NH:17][CH2:18][CH2:19][CH2:20][Cl:25])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCNC1=Nc2ccccc2C1(O)c1cccc(F)c1
Reactant: O=S(Cl)Cl
Product: OC1(c2cccc(F)c2)C(NCCCCl)=Nc2ccccc21

Procedure:
Reaction of 3-(m-fluorophenyl-2-(3-hydroxypropylamino)-3H-indol-3-ol with thionylchloride by a procedure analogous to that described in Example 2 gives 3-(m-fluorophenyl)-2-(3-chloropropylamino)-3H-indol-3-ol.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>COCCO>[CH2:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:2]2[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:12][CH2:13]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Fc1cccnc1Cl
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncccc2F)CC1

Procedure:
A solution of 2-chloro-3-fluoropyridine (prepared in a manner similar to that described by W. J. Link, R. F. Borne and F. L. Setliff, J. Heterocyclic Chem. 4, 641–3, 1967) (131 mg 1 mmol), benzyl 4-(aminomethyl)-piperidine-1-carboxylate (EXAMPLE 13, STEP 1) (248 mg, 1 mol) and diisopropylethylamine (129 mg, 1 mmol) were heated to reflux in 2-methoxyethanol for 2 days under nitrogen. The reaction mixture was concentrated, partitioned between ethyl acetate and water, the organic layer washed with brine, dried over anhydrous sodium sulfate and solvent evaporated to give the crude product purified by chromatography on silica. M.S. (M+1): 344.3