Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:20][C:19]=1[CH2:29][O:30][C:31]1[CH:50]=[CH:49][C:34]([CH2:35][N:36]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43]C=3)[C:38]([CH:47]=O)=[CH:37]2)=[CH:33][CH:32]=1.O.C[N:53](C)C=O>>[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:20][C:19]=1[CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:35][N:36]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:53]=3)[C:38](/[CH:47]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:37]2)=[CH:49][CH:50]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CN(C)C=O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C=O)c(-c3ccccc3)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1-c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Sodium hydride (60%, oily, 0.17 g) was added to a mixture of ethyl diethylphosphonoacetate (1.00 g) and N,N-dimethylformamide (5 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. A solution of 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenylpyrrole-3-carbaldehyde (1.65° g) in N,N-dimethylformamide (10 ml) was added slowly to the mixture, which was stirred at room temperature for 3 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl(E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-(2-pyridyl)-3-pyrrolyl]propenoate (1.83 g, yield: 96%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1 volume ratio).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O[CH2:19][CH:20]1[CH2:24][CH2:23][CH:22]([CH2:25]OS(C2C=CC(C)=CC=2)(=O)=O)[O:21]1)(C1C=CC(C)=CC=1)(=O)=O.COCCOCCOCCOC>[OH-].[Na+]>[C:2]1([N:1]2[CH2:25][CH:22]3[O:21][CH:20]([CH2:24][CH2:23]3)[CH2:19]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(COS(=O)(=O)c3ccc(C)cc3)O2)cc1
Reactant: Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOCCOCCOC
Product: c1ccc(N2CC3CCC(C2)O3)cc1
Temperature: 185 °C

Procedure:
Aniline (1.2 mole, 111.8 grams) was added to a mixture of 2,5-bis(tosyloxymethyl)tetrahydrofuran, represented by formula (II), (0.4 mole, 176.2 grams) and 300 ml of Ansul 161 (triethylene glycol dimethyl ether) and the reaction mixture heated for 4 hours at 185° C. The reaction mixture was cooled to room temperature and neutralized with a methanolic sodium hydroxide solution (32 grams NaOH in 300 ml CH3OH). Sodium tosylate was filtered and Ansul 161 and excess aniline stripped from the filtrate under aspirator pressure. 3-Phenyl-8-oxa-3-azabicyclo(3.2.1)octane, represented by formula (XX), was distilled at 113° C./0.15 mm Hg. The product solidified on standing and after recrystallization from methanol had a melting point of 84°-85° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.N1C=CC=CC=1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N+]([O-])=O)=[CH:29][CH:28]=1)=[O:25]>ClCCl>[C:27]1([O:26][C:24](=[O:25])[NH:13][C:12]2[CH:14]=[CH:15][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NC(=O)Oc3ccccc3)cc2)OC1(C)C
Reaction time: 13 h

Procedure:
4-(4,4,5,5-tetramethyl 1,3,2 dioxaborolan-2-yl) aniline (3 g, 0.013 mol) was dissolved in dichloromethane (350 mL) to which pyridine (1.02 g, 0.013 mol) and 4-nitrophenyl chloroformate was added. The reaction was stirred for 13 hr where TLC analysis showed consumption of all starting materials. The solution was washed with saturated NaHCO3 (3×50 mL), water (3×50 mL) and brine (3×50 mL). The organic layer was dried over Na2SO4 and solvent removed to yield a white crystalline solid [4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acid phenyl ester, 4.45 g, 91%. 1H NMR (CDCl3 300 MHz) δ 1.4 (s, 12H), 7.1 (brs, 1H), 7.3 (d, 2H), 7.5 (d, 2H), 7.8 (d, 2H), 8.3 (d, 2H).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:57][O:58][CH:59]([F:61])[F:60])[C:27]([NH:29][CH:30]2[C:55](=[O:56])[N:32]3[C:33]([C:39]([O:41][CH:42]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][Cl:38])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=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.ClC1C=CC=C(C(OO)=[O:70])C=1.S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:57][O:58][CH:59]([F:61])[F:60])[C:27]([NH:29][CH:30]2[C:55](=[O:56])[N:32]3[C:33]([C:39]([O:41][CH:42]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[O:40])=[C:34]([CH2:37][Cl:38])[CH2:35][S:36](=[O:70])[C@H:31]23)=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)C(=NOC(F)F)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)C(=NOC(F)F)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A mixture of benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (35 g), m-chloroperbenzoic acid (8.64 g) and ethyl acetate (300 ml) was stirred for 30 minutes at 0° to 5° C. and then, water (300 ml), sodium bisulfite and sodium bicarbonate were added thereto. The organic layer was separated, washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated. The residue was triturated with diisopropyl ether to give benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate-1-oxide (syn isomer) (29.93 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[N:20]=[C:19]([C:21](OCC)=[O:22])[C:18]([N+:26]([O-])=O)=[C:17]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])[N:16]=1)=O)(C)(C)C.ClC1N=C([C:45](OCC)=[O:46])C([N+]([O-])=O)=C(NC2C=CC=CC=2OC)N=1.C([N:69]1CCCC1CN)(OC(C)(C)C)=O.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[N:29]1[C:45](=[O:46])[NH:26][C:18]2[C:17]1=[N:16][C:15]([NH:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[N:20][C:19]=2[C:21]([NH2:69])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCCC1CN
Reactant: CCOC(=O)c1nc(Cl)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: CCOC(=O)c1nc(NC[C@@H]2CCCN2C(=O)OC(C)(C)C)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(NC[C@@H]3CCCN3)nc21
Yield: 95 %

Procedure:
(S)-Ethyl 2-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methylamino)-6-(2-methoxy-phenylamino)-5-nitropyrimidine-4-carboxylate. Ethyl 2-chloro-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate (See Example 30.A) (0.300 g, 0.852 mmol), (S) 1-boc-(aminomethyl)pyrrolidine (0.206 g, 1.02 mmol) and diisopropylethylamine (0.164 g, 1.27 mmol.) were reacted according to General Procedure C, except at room temperature and in dimethylformamide (5 mL). The crude reaction mixture was condensed and purified using Biotage chromatography (0-100% ethyl acetate in hexanes) to afford the title compound (0.416 g, 95%). MS (ESI) m/z 517.3 [M+1]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43](C=O)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:51]1([C:57](OC(C)(C)C)=O)[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:57][N:51]6[CH2:52][CH2:53][NH:54][CH2:55][CH2:56]6)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2OC)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4CCNCC4)c3)ccc2OC)c1
Reaction time: 3 h
Yield: 63.1 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-4-(methyloxy)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide (54 mg, 0.00008 mol) in DCM with 1,1-dimethylethyl 1-piperazinecarboxylate (23.3 mg, 0.00012 mol) and sodium triacetoxyborohydride (34 mg., 0.00016 mol) and AcOH (6 μL) were agitated overnight on a shaker. LC-MS was used to monitor the reaction. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. The residue was taken up in DCM (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on a Gilson instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a white solid [37.6 mg (63%)]. LC-MS m/z 745.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.[Li+].[CH3:11]C([N-]C(C)C)C.[Li]CCCC.C(NC(C)C)(C)C.CI>C1COCC1>[CH2:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][N:7]=1)[CH3:11]
Reactant: CC(C)[N-]C(C)C
Reactant: COc1ccc(C)nc1
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CI
Product: CCc1ccc(OC)cn1
Reaction time: 0.5 h
Yield: 24 %

Procedure:
5-Methoxy-2-methyl-pyridine (9.5 g, 77 mmol) was added to a cooled −78° C. solution of LDA prepared from n-BuLi (37 mL, 93 mmol, 2.5 M in hexanes) and diisopropylamine (13 mL, 93 mmol) dissolved in THF (100 mL). The deep red reaction mixture was stirred for 30 mins and then treated with methyl iodide (5.4 mL, 85 mmol). After 2 hours the mixture was quenched with conc NH4OH (15 mL). The mixture was poured into H2O and extracted with EtOAc. The organic extracts were washed with brine, drived over Na2SO4 and concentrated to a red oil. Purification by flash column chromatography (0% to 40% EtOAc in hexanes) gave the product as a clear oil (2.5 g, 24%) and unreacted starting material (3.8 g, 40%). 1H NMR (400 MHz, CDCl3): δ 1.28 (t, J=7.3 Hz, 3H), 2.76 (q, J=7.3 Hz, 2H), 3.84 (s, 3H), 7.08 (d, J=8.3 Hz, 1H), 7.14 (d, J=8.3 Hz, 1H), 8.23 (s, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[C:12]([C:20]3[S:24][C:23]([CH:25]=O)=[CH:22][CH:21]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C([BH3-])#N.[Na+]>C(O)(=O)C>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[C:12]([C:20]3[S:24][C:23]([CH2:25][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][CH:21]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3c(F)cccc23)s1
Reactant: C1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccc(CN3CCCC3)s2)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the crude 5-(1-benzenesulfonyl-7-fluoroindol-3-yl)-thiophene-2-carboxaldehyde was sequentially added 4 Å molecular sieves (1 g), pyrrolidine (0.44 ml, 5.36 mmol), sodium cyanoborohydride (0.034 g, 0.54 mmol) and glacial acetic acid (1 drop). The resulting mixture was then stirred at room temperature for 18 h, filtered and the filter cake washed with methanol (2×30 ml) and dichloromethane (2×30 ml). The combined filtrate was concentrated in vacuo, dissolved in dichloromethane (20 ml), washed with aqueous sodium hydroxide (2M; 15 ml), dried with sodium sulphate and concentrated in vacuo. The residue was then purified by flash column chromatography eluting with 0-10% (v/v) methanol in dichloromethane to afford 1-benzenesulfonyl-7-fluoro-3-(5-pyrrolidin-1-ylmethyl-thiophen-2-yl)-indole as a yellow oil (0.22 g, 0.46 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[N:17][C:9]2[C@H:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:28]1[S:32][C:31]([C:33]([OH:35])=O)=[CH:30][CH:29]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].CCN=C=[N:40][CH2:41][CH2:42][CH2:43]N(C)C.[CH:47]1[CH:48]=[CH:49][C:50]2N(O)N=N[C:51]=2[CH:52]=1.Cl>C(Cl)Cl>[C@H:41]1([NH:40][C:33]([C:31]2[S:32][C:28]([C:7]3[C:8]4[C:15](=[O:16])[N:14]5[C@H:10]([C:9]=4[N:17]=[C:18]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:12][CH2:13]5)=[CH:29][CH:30]=2)=[O:35])[C:51]2[C:50](=[CH:49][CH:48]=[CH:47][CH:52]=2)[CH2:43][CH2:42]1
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)O)s1)C(=O)N1CCC[C@@H]21
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)N[C@@H]3CCc4ccccc43)s1)C(=O)N1CCC[C@@H]21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-{(9aS)-3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizin-4-yl}-2-thiophenecarboxylic acid (0.100 g, 0.202 mmol) was dissolved in CH2Cl2 (2 mL). R-(−)-1-aminoindane (0.026 mL, 0.303 mmol) was added followed by EDCI (0.047 g, 0.243 mmol) and HOBt (0.033 g, 0.243 mmol). After 14 h of stirring at ambient temperature the reaction mixture was poured onto 5% HCl solution and extracted with CH2Cl2. The organics were washed with sat'd NaHCO3, brine and then dried (Na2SO4), filtered and concentrated to a brown residue. Chromatography on silica gel using 4:1 EtOAc:Hexanes eluted the product to provide the title compound upon concentration as a white solid (0.066 g, 0.108 mmol, 54% yield): 1H NMR (CDCl3, 400 MHz) δ 7.48 (d, J=3.7 Hz, 1H), 7.36 (d, J=6.7 Hz, 1H), 7.28–7.20 (m, 2H), 7.19–15 (m, 3H), 6.97 (t, J=8.6 Hz, 2H), 6.24–6.20 (m, 1H), 5.67 (dd, J=15.3, 7.6 Hz, 1H), 4.69 (dd, J=10.3, 6.4 Hz, 1H), 4.19 (dd, J=14.3, 7.1), 3.76–3.66 (m, 1H), 3.42–3.36 (m, 1H), 3.18–3.01 (m, 5H), 2.96–2.87 (m, 1H), 2.71–2.66 (m, 1H), 2.48–2.40 (m, 1H), 2.37–2.25 (m, 2H), 1.96–1.86 (m, 1H), 1.42–1.35 (m, 1H), 1.13 (t, J=7.1 Hz, 3H); ESMS m/z 610 (M+H)+, 608 (M−H)+; Anal. Calcd. For C35H32F1N3O4S.½H2O: C 67.94 H, 5.38; N, 6.79; found C, 68.09 H 5.31 N 6.80.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][NH:33][CH:34]=2)O1>>[NH:32]1[CH:31]=[C:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:14]4[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:34]=[N:33]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#Cc1ccc(C2(c3ccc(Cl)cc3)CCNCC2)cc1
Product: N#Cc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)cc1
Temperature: 100 °C

Procedure:
4-[4-(4-chloro-phenyl)-piperidin-4-yl]-benzonitrile was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, but using tetrakis(tiphenylphosphine) palladium (0) as the catalyst and heating at 100° C. for 15 minutes, to obtain the title compound. LCMS (PS-A3) Rt 6.68 min [M+H]+ 329. 1H NMR (Me-d3-OD) δ 2.65-2.73 (4H, m), 2.77-2.85 (4H, m), 3.75 (3H, s), 7.46 (2H, d), 7.59 (2H, d), 7.68 (2H, d), 7.71 (2H, d), 8.42 (2H, br.s).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([Cl:23])[CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.O>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:7]([O:6][C:5]2[CH:21]=[CH:22][C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[CH:3][C:4]=2[Cl:23])[CH:12]=1
Reactant: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc(Br)cc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc(-c2ccccn2)cc1Cl

Procedure:
The subtitle compound was prepared by using the product from example 30 step ii) (0.20 g) which was dissolved in dry dioxane (10 ml). 2-pyridyl tributyl tin (0.181 g) and palladium (0) tetrakistriphenylphosphine (0.028 g) were added and the mixture was heated at 80 C for 16 hours. The mixture was diluted with water, extracted with ethyl acetate, dried and concentrated under reduced pressure to give an oil. Yield 0.20 g.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8].C(=O)([O-])[O-].[Na+].[Na+].C([N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])(OCC)=O.Cl>O.O1CCOCC1>[C:27]1(=[O:28])[N:23]([NH:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:24](=[O:33])[C:25]2=[CH:32][CH:31]=[CH:30][CH:29]=[C:26]12
Reactant: N[C@@H](Cc1cccs1)C(=O)O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@H](Cc1cccs1)NN1C(=O)c2ccccc2C1=O
Temperature: 0 °C

Procedure:
3-(2-Thienyl)-L-alanine(2.24 g., 13.1 mmol.) was suspended in water/p-dioxane (20 ml./10 ml.) at room temperature under argon. Sodium carbonate (1.39 g.) was added and the mixture was stirred until homogeneous. N-Carbethoxyphthalimide (2.87 g.) was added, and the resulting mixture was stirred for 4.5 hours and then cooled to 0° C. The pH was adjusted to 1.5 with 6 N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 10% potassium bisulfate and brine, dried (sodium sulfate), filtered, and concentrated. The crude product was flash chromatographed (Merck silica gel) eluting with 1:1 ethyl acetate/hexane/1% acetic acid. The fractions containing clean desired product were combined, concentrated, azeotroped with ethyl acetate, and washed with water to remove the acetic acid. The organic layer was dried (sodium sulfate), filtered, and concentrated to give 2.70 g. of the title compound as a white crystalline product; m.p. 166°-168° C.; [α]D =-153.6° (c=0.46, methylene chloride). TLC (1% acetic acid in 1:1 ethyl acetate/hexane) Rf =0.5.
Reaction SMILES: C([Cl:4])(=O)C.O1CCCCC1[O:11][C:12]1[CH:13]=[C:14]([CH:46]=[C:47]([O:49]C2CCCCO2)[CH:48]=1)[C:15]([NH:17][CH2:18][C@@H:19]([C:42]([O:44][CH3:45])=[O:43])[NH:20][C:21](=[O:41])[C:22]1[C:27]([Cl:28])=[CH:26][C:25]([C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([OH:39])[CH:34]=2)=[O:30])=[CH:24][C:23]=1[Cl:40])=[O:16]>CO>[ClH:4].[Cl:28][C:27]1[CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([OH:39])[CH:34]=2)=[O:30])[CH:24]=[C:23]([Cl:40])[C:22]=1[C:21]([NH:20][C@H:19]([C:42]([O:44][CH3:45])=[O:43])[CH2:18][NH:17][C:15](=[O:16])[C:14]1[CH:13]=[C:12]([OH:11])[CH:48]=[C:47]([OH:49])[CH:46]=1)=[O:41]
Reactant: CC(=O)Cl
Reactant: COC(=O)[C@H](CNC(=O)c1cc(OC2CCCCO2)cc(OC2CCCCO2)c1)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Solvent: CO
Product: COC(=O)[C@H](CNC(=O)c1cc(O)cc(O)c1)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Product: Cl
Reaction time: 0.17 h

Procedure:
A solution of HCl in methanol was prepared by adding acetyl chloride (10 Ml) to methanol at approx. 0° C. The solution was allowed to stir for 10 min and then it was added to 3-[[3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoyl]amino]-N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine, methyl ester (1.60 g, 2.1 mmol). The resulting solution was allowed to stir overnight at room temperature and then the volatiles were evaporated to give N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(3,5-dihydroxybenzoylamino)-L-alanine, methyl ester (1.26 g, quantitative yield) as an off-white solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[CH3:13][C:14]1([CH3:22])[S:18][CH2:17][NH:16][CH:15]1C(O)=O>C1(C)C=CC=CC=1>[CH3:13][C:14]1([CH3:22])[S:18][CH2:17][N:16]2[CH:15]1[CH2:3][CH:2]1[CH:11]2[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]1
Reactant: CC1(C)SCNC1C(=O)O
Reactant: C=CCN(CC=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CC3N(CSC3(C)C)C2C1

Procedure:
8.6 g (50 mmol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are heated under reflux overnight with 8.1 g (50 mmol) of 5,5-dimethylthiazolidine-4-carboxylic acid in 200 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([NH2:22])=[O:21])=[CH:14][CH:13]=1)([O-])=O.C[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCO.CN(C=O)C.O>[N:10]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:1][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([NH2:22])=[O:21])=[CH:14][CH:13]=1
Reactant: NC(=O)c1ccccc1-c1ccc(CNc2ccccc2[N+](=O)[O-])cc1
Agent: C[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccccc1-c1ccc(-c2nc3ccccc3[nH]2)cc1
Temperature: 60 °C

Procedure:
To a solution of 4-[(2-nitro-phenylamino)-methyl]-phenylbenzamide (14) (74.9 mmol) in anhydrous EtOH and anhydrous DMF (75 mL) was slowly added sodium methoxide (30% w/w) (375 mmol) at room temperature under argon atmosphere, followed by heating to 60° C. for 2 h. After cooling to ambient termperature, the solution was diluted with water (700 mL) and then acidified with saturated citric acid. The resulting precipitate was collected on a sintered funnel while rinsing with water. The crude product was recrystallized in hot EtOH.