Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH3:14])=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>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>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:7]2[NH:6][C:5]([CH:9]=[O:10])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=2[CH2:1][CH3:2])=[CH:26][CH:25]=1
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OC
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCc1c(-c2ccc(F)cc2)[nH]c(C=O)c1C(=O)OC
Temperature: 85 °C

Procedure:
Methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate was obtained following the procedures described in Example 3. To a solution of methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate (0.123 g, 0.40 mmol) in dimethoxyethane (4.0 mL) was added K3PO4 (0.426 g, 2.00 mmol), Pd(PPh3)4 (0.0463 g, 0.04 mmol), and 4-fluorophenylboronic acid (0.0842 g, 0.60 mmol). The reaction was deoxygenated by bubbling argon through the solution prior to being heated to 85° C. and refluxed for 16 h under argon. After cooling to ambient temperature, the reaction was filtrated through a pad of silica gel and concentration. The resultant residue was dissolved in acetonitrile and purified by reverse phase HPLC. Proton NMR for the product was consistent with the title compound. 1H NMR (500 MHz, CDCl3) δ 10.15 (s, 1H); 7.43 (dd, J=3.4, 5.2 Hz, 2H); 7.18 (app t, 8.6 Hz, 2H); 3.94 (s, 3H); 2.80 (q, J=7.4 Hz, 2H); 1.22 (t, J=7.4 Hz, 3H). HRMS (ES) exact mass calculated C15H15FNO3 (M+H): 276.1312. Found 276.1264
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].C(OC([NH:26][CH2:27][CH:28]1[CH2:31][CH2:30][NH:29]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:26][CH2:27][CH:28]1[CH2:31][CH2:30][N:29]1[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18]
Reactant: CC(C)(C)OC(=O)NCC1CCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC3CN)nc21
Yield: 51.5 %

Procedure:
A suspension of 1.08 g (4.0 mmol) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 0.93 g (5.0 mmol) of 2-[(t-butoxycarbonylamino)methyl]azetidine, 1.01 g (10 mmol) of triethylamine and 50 ml of acetonitrile was stirred at reflux for two hours. The solvent was removed in vacuo and the residue was dissolved in 25 ml of trifluoroacetic acid. After stirring at room temperature for two hours, the solvent was removed in vacuo. The residue was suspended in water and the pH adjusted to 11 with 10% sodium hydroxide. The resulting solution was filtered through a fiber glass pad to clarify and the filtrate acidified to pH 7.2 with 1 M hydrochloric acid. The resulting precipitate was removed by filtration, washed successively with water, ethanol, ether and dried in vacuo to give 0.66 g (52%) of the title compound, mp 198°-200° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1OS(C1C=CC(C)=CC=1)(=O)=O)=[O:4].[C:21]1([C:27]#[CH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCCCC.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:28]#[C:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:4]
Reactant: C#Cc1ccccc1
Reactant: COC(=O)c1sccc1OS(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: COC(=O)c1sccc1C#Cc1ccccc1

Procedure:
This product was prepared from 3-(toluene-4-sulfonyloxy)-thiophene-2-carboxylic acid methyl ester and phenylacetylene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (91 mg, 75%); 1H NMR δ (CDCl3): 7.53 (m, 2H), 7.39 (d, J=5.02 Hz, 1H), 7.3 (m, 3H), 7.12 (d, J=5.10 Hz, 1H), 3.82 (s, 3H); LCMS m/z: 242.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[CH3:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([N:1]2[CH2:2][CH:3]([N:5]3[C:9]4=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]4[C:7]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:19][CH:20]=4)=[N:6]3)[CH2:4]2)[CH2:31][CH2:30]1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CN1CCC(N2CC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)C2)CC1
Temperature: 25 °C
Yield: 37.6 %

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.06 g, 0.00017 mol), 1-methyl-4-piperidinone (0.057 g, 0.0005 mol), and acetic acid (0.03 g, 0.0005 mol) in dichloroethane (2.5 mL) was stirred at room temperature under an atmosphere of nitrogen for one and a half hours. Sodium triacetoxyborohydride (0.072 g, 0.00034 mol) was added to the mixture and stirred at ambient temperature under an atmosphere of nitrogen for two hours. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel using ammonium hydroxide/methanol/dichloromethane (2:15:83) as mobile phase to yield 1-[1-(1-methyl-4-piperidyl)-3-azetanyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.029 g, 0.000064 mol).
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].[Cl:18][C:19]1[C:24]2[NH:25][C:26]([CH3:28])=[N:27][C:23]=2[CH:22]=[C:21]([O:29][C:30]2[CH:35]=[C:34](Cl)[N:33]=[CH:32][N:31]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:18][C:19]1[C:24]2[NH:25][C:26]([CH3:28])=[N:27][C:23]=2[CH:22]=[C:21]([O:29][C:30]2[N:31]=[CH:32][N:33]=[C:34]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:35]=2)[CH:20]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Cc1nc2cc(Oc3cc(Cl)ncn3)cc(Cl)c2[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(Oc3cc(N4CCC5(CC4)OC(=O)Nc4ncccc45)ncn3)cc(Cl)c2[nH]1

Procedure:
90 mg (0.35 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 110 mg (0.37 mmol) 7-chloro-5-(6-chloropyrimidin-4-yloxy)-2-methyl-1H-benzo[d]imidazole and 0.14 mL (0.81 mmol) DIPEA in 2.0 mL DMF were stirred for 3 h at RT and 4 h at 40° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O-:10].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:2]2[CH:7]=[CH:6][C:5]([CH:9]=[O:10])=[CH:4][CH:3]=2)=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Oc1ccc(Cl)cc1
Agent: [Na+]
Solvent: CO
Product: O=Cc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 127.3 %

Procedure:
4-Chlorophenol (22.6 g) was added to a stirred solution of sodium methoxide (9.5 g) in methanol (80 ml). After 30 min the solvent was evaporated in vacuo. Residual traces of methanol were removed by addition of toluene and evaporating again in vacuo. The residue was taken up in DMF (200 ml) and 4-fluorobenzaldehyde (19.85 g) added. The mixture was stirred and heated at 120° for 4 hr, cooled, poured into water and extracted with toluene (2×200 ml). The combined extracts were washed with water, 2M sodium hydroxide and satd. brine, dried over magnesium sulphate and concentrated to leave a brown oil. Distillation gave the title compound (26.03 g), b.p.=140°-50°/0.5 mm.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[O:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH2:23])[CH2:17][CH2:16]1>>[CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([NH:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1)=[O:13]
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Reactant: NCCN1CCOCC1
Product: Cc1[nH]c2c(c1C(=O)NCCN1CCOCC1)CCCC2=O
Yield: 81.9 %

Procedure:
Similar procedure as Example 2, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and 2-morpholinoethanamine 0.27 g (2.1 mmol) was reacted to give 0.25 g (82%) of the titled compound as a white solid.
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][N:8]=1.[C:15](=[O:17])=[O:16].O>C1COCC1>[F:6][C:7]1[N:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][C:12]=1[C:15]([OH:17])=[O:16]
Reactant: COc1ccc(F)nc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cnc(F)c(C(=O)O)c1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
To a solution of DIPA (54.0 mL, 385 mmol) in THF (1101 mL, 385 mmol) at −60° C. was added BuLi, 2.5 M in hexanes (154 mL, 385 mmol) over 5 minutes such that the internal temperature was maintained below −60° C. After stirring for 45 minutes at −65° C. a solution of 2-fluoro-5-methoxypyridine (49 g, 385 mmol) in 200 mL of THF was added over the course of 2 minutes maintaining an internal temperature <−65° C. The reaction was stirred at −70° C. for 1.5 hours then reaction was poured into a 3 L flask containing 1200 g of crushed dry ice. The reaction was allowed to warm to 0° C. and then poured into 1000 mL of water. The organics were removed under reduced pressure and the aqueous layer was acidified with 1100 mL of 2 N HCl. The resulting thick white slurry was stirred for 1 hour then filtered to provide 2-fluoro-5-methoxynicotinic acid as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21]C=1)(C)(C)C.[C:26]1(C2C=CC=CC=2)[CH:31]=[CH:30][C:29]([C:32]2[O:33][C:34]([CH3:50])=[C:35]([CH2:37][CH2:38]OS(C3C=CC(C)=CC=3)(=O)=O)[N:36]=2)=[CH:28][CH:27]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CCOCC>[CH:29]1([C:32]2[O:33][C:34]([CH3:50])=[C:35]([CH2:37][CH2:38][O:15][C:12]3[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:6]([OH:5])=[O:25])=[C:10]([CH2:16][O:17][C:18]4[CH:19]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:11]=3)[N:36]=2)[CH2:28][CH2:27][CH2:26][CH2:31][CH2:30]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1COCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CCC(=O)O)c(COc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
General procedure for the parallel synthesis of analogs using the DynaVac Carousel apparatus: A 50 mL glass tube with screw cap and nitrogen inlet was charged with 3-(2-benzyloxymethyl-4-hydroxy-phenyl)-propionic acid tert-butyl ester (0.050 g, 0.146 mmol), toluene-4-sulfonic acid 2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethyl ester (0.078 g, 0.18 mmol), anhydrous DMF (0.5 mL), and then cesium carbonate (0.072 g, 0.22 mmol). The mixture was stirred at ambient temperature for 16 h. MS analysis of the reaction indicated that the intermediate ester was formed, MS (ES) m/e 534 (M+1). The crude reaction was poured into ether (30 mL), and washed with brine (2×), dried (Na2SO4), and concentrated in vacuo. The crude residue was dissolved in CH2Cl2 (2 mL) and trifluoroacetic acid was added (1.0 mL). The reaction mixture was stirred at ambient temperature for 2 h and was concentrated under a stream of N2. The crude product was purified by mass-directed reverse phase HPLC to provide 0.053 g (71%) of 3-{4-[2-(2-Cyclohexyl-5-methyloxazol-4-yl)ethoxy]-2-phenoxymethylphenyl}propionic acid. MS (ES) m/e 478 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=1[OH:26].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][C:17]=1[O:26][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Reactant: Oc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2c(Oc3cc(C(F)(F)F)ccc3F)ccnc12
Yield: 85.2 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-11, step-3 using 4-chloro-8-nitroquinoline (Intermediate-11, step-2, 300 mg, 1.44 mmol), 2-fluoro-5-(trifluoromethyl)phenol (389 mg, 2.16 mmol), K2CO3 (596 mg, 4.32 mmol) in CH3CN (4 mL) to afford 432 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.82 (d, J=4.8 Hz, 1H), 8.60 (d, J=8.4 Hz, 1H), 8.36 (d, J=7.5 Hz, 1H), 8.11 (d, J=5.7 Hz, 1H), 7.86-7.75 (m, 3H), 6.93 (d, J=4.8 Hz, 1H); MS (m/z): 353.21 (M+H)+.
Reaction SMILES: C(N)CN.C(C1OC(C)=NC=1Cl)C1C=CC=CC=1.[CH2:19]([C:26]1[O:30][CH:29]=[N:28][C:27]=1[CH2:31][NH:32][CH2:33][CH2:34][NH2:35])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:36][N:37]=[C:38]=[S:39]>>[CH3:36][NH:37][C:38]([NH:35][CH2:34][CH2:33][NH:32][CH2:31][C:27]1[N:28]=[CH:29][O:30][C:26]=1[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[S:39]
Reactant: CN=C=S
Reactant: NCCNCc1ncoc1Cc1ccccc1
Agent: Cc1nc(Cl)c(Cc2ccccc2)o1
Solvent: NCCN
Product: CNC(=S)NCCNCc1ncoc1Cc1ccccc1

Procedure:
5-Benzyl-4-oxazolecarboxylic acid is converted to 5-benzyl-4-hydroxymethyl xazole by the procedure of Example 135. Treating this hydroxy ethyl compound with thionyl chlroide gives 5-benzyl-4-chloromethyloxazole. Reacting ethylenediamine with 5-benzyl-4-chloro-methyloxazole by the procedure of Example 34, then reacting the resulting N-(5-benzyl-4-oxazolylmethyl)ethylenediamine with methyl isothiocyanate by the procedure of Example 3(b) and chromatographing gives N-methyl-N'-[2-((5-benzyl-4-oxazolyl)methylamino)ethyl]-thiourea. Reacting this thiourea with lead cyanamide by the procedure of Example 3(b) gives N-[2-((5-benzyl-4-oxazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine.
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3].Cl.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:1]([C:5]1[S:6][C:7]([C:11]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:21]=2)=[O:13])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CCOC(=O)COc1ccc(N)cc1
Reactant: Cc1nc(NC(=N)N)sc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(NC(=O)c2sc(NC(=N)N)nc2C)cc1
Yield: 48.8 %

Procedure:
400 mg of 2-guanidino-4-methyl-thiazole-5-carboxylic acid, 463 mg of ethyl 4-amino-phenyloxyacetate hydrochloride, 6 ml of DMF, 0.67 ml of N-MM and 759 mg of HBTU are stirred at RT for 22 hrs. The working up and purification are effected as described in Example 1. Crystallization from acetonitrile (MeCN) gives 368 mg of ethyl {4-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-phenoxy}-acetate, m.p. 223° C.;, MS: 378 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[CH2:11][C@H:12](O)[CH3:13].CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([F:1])=[C:3]([CH2:11][C@H:12]([S:23]([CH3:22])(=[O:25])=[O:24])[CH3:13])[C:4]=1[F:10]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)Cc1c(F)c(F)cc(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](Cc1c(F)c(F)cc(F)c1F)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.6 %

Procedure:
A solution of (2R)-1-(2,3,5,6-tetrafluorophenyl)-propan-2-ol (E-1) (1.9 g, 9.13 mmol) and Et3N (0.85 mL, 10.95 mmol) in 40 mL anhydrous DCM was cooled in ice-water bath. Then methylsulfonyl chloride (0.85 mL, 10.95 mmol) was added slowly and the mixture was stirred for 30 min at rt. And then, saturated NaHCO3 solution (10 mL) was added to the solution and extracted with DCM, dried over anhydrous MgSO4 and concentrated, and crystallized with DCM/hexane to give white solid (2.58 g, 99%). MS (ESI) m/z 309.0 [M+Na]+, 1H NMR (CDCl3, 500 MHz) δ 7.02 (m, 1H), 5.04 (m, 1H), 3.14-3.07 (m, 2H), 2.90 (s, 3H), 1.49 (d, =6.0 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH3:38])([NH:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:37])[C:19](=[O:36])[N:20](COCC[Si](C)(C)C)[N:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC(N)(C)C1)=O)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH3:38])([NH:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:37])[C:19](=[O:36])[NH:20][N:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3ccc(NC4(C)CCN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: CC1(N)CCN(C(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC1C(=O)NN=C2COc3ccc(NC4(C)CCN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 80 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
A mixture of 3-methyl-3-[4-methyl-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared using a similar procedure as detailed in Example #162, Step C from 3-amino-3-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester, 1.1 g, 2.016 mmol) in a solution of TBAF in THF (1 M, 20 mL, 20 mmoL) was stirred at 80° C. for 16 h. The reaction mixture was cooled to ambient temperature and diluted with water (25 mL). The aqueous solution was extracted with EtOAc (3×25 mL) and the combined organic phase was washed with brine (10 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum) to give 3-methyl-3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.45 g, 54%). LC/MS (Table 1, Method 2) Rt=0.890 min; MS m/z: 438 [M+Na]+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1O[C:6](=[O:8])[CH2:5][CH2:4]1.[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.Cl>C(Cl)(Cl)Cl>[F:9][C:10]1[CH:16]=[CH:15][C:13]([N:14]2[C@@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]2=[O:8])=[CH:12][CH:11]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C1CC[C@@H](CO)O1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C1CC[C@H](CO)N1c1ccc(F)cc1
Yield: 109.8 %

Procedure:
To (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (500 mg, 4.31 mmol), 4-fluoroaniline (574 mg, 5.17 mmol) was added and the resultant mixture was stirred at 150° C. for 3 days. After completion of the reaction, chloroform and hydrochloric acid were added to the reaction solution and extraction from the resultant mixture with chloroform was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product of the title compound (990 mg).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].[Cs+].[N+](C1C=C(S(O[CH2:42][C@H:43]2[O:45][CH2:44]2)(=O)=O)C=CC=1)([O-])=O>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:42][C@@H:43]2[CH2:44][O:45]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3O)[nH]c2c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3OC[C@@H]3CO3)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of the foregoing product from Step 1 in DMF (0.04 M) were added cesium fluoride (3 eq) and (S)-glycidyl 3-nitrobenzenesulfonate (1.1 eq). The resulting mixture was stirred at RT overnight, then diluted with EtOAc and washed with water and brine. Drying over Na2SO4, filtration and concentration in vacuo gave the crude product, which was purified by flash chromatography on silica gel (1:5 EtOAc/PE) to afford the title compound as a colourless foam (74%); MS (ES+) m/z 406 (M+H)+; [α]D20=+22 (c=0.5, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.O[N:28]=[C:29]([NH2:33])[CH:30]([CH3:32])[CH3:31].[H-].[Na+]>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]3[O:20][N:33]=[C:29]([CH:30]([CH3:32])[CH3:31])[N:28]=3)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Reactant: CC(C)C(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1-c1nc(C(C)C)no1
Yield: 17 %

Procedure:
The title compound was prepared by following the procedure as described for Example-40 by using methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.100 g, 0.25 mmol), N′-hydroxyisobutyrimidamide (0.077 g, 0.529 mmol), sodium hydride (0.020 g, 0.50 mmol) and dry THF (5.0 mL) at RT to afford 0.019 g of desired product. 1HNMR (DMSO-d6): δ 1.31 (d, J=6.9 Hz, 6H), 3.12 (m, 1H), 3.95 (s, 3H), 7.65-7.78 (m, 4H), 7.56 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 12.83 (br s, 1H); MS (m/z): 447.96 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:36]=[CH:35][C:7]2[N:8]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])=[O:23])=[CH:15][CH:14]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[CH3:37][Mg]I.O>O1CCCC1>[CH2:11]([C:9]1[N:8]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:26])=[O:27])=[O:23])=[CH:17][CH:18]=2)[C:7]2[CH:35]=[CH:36][C:4]([C:1]([OH:3])([CH3:37])[CH3:2])=[CH:5][C:6]=2[N:10]=1)[CH3:12]
Reactant: CCc1nc2cc(C(C)=O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: C[Mg]I
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2cc(C(C)(C)O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
A solution of N-[({2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide (Example 78, 100 mg, 0.19 mmol) in tetrahydrofurane (15 ml) was added MeMgI (1.2 ml, 0.99 mmol) dropwise under nitrogen at 0° C. The mixture was stirred at 0° C. for 1 h and then was stirred at rt for 30 min. The mixture was added water (10 ml) and extracted with CH2Cl2(50 ml). The organic layer was washed with brine (10 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with CH2Cl2:methanol (30:1/20:1/10:1) to afford 100 mg (97%) of the title compound as white solids.