Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2S[C:15]([C:19](O)=O)=[C:16](C)[N:17]=2)N=N1)C1C=CC=CC=1.[F:22][C:23]1[CH:44]=[CH:43][C:26]([CH2:27][CH2:28][N:29]2[CH:33]=[C:32]([C:34]3[S:35][C:36]([C:40]([OH:42])=O)=[C:37]([CH3:39])[N:38]=3)[N:31]=[N:30]2)=[CH:25][CH:24]=1.N1C=CC=C(CN)C=1>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH2:28][N:29]2[CH:33]=[C:32]([C:34]3[S:35][C:36]([C:40]([NH:8][CH2:12][C:11]4[CH:13]=[N:17][CH:16]=[CH:15][CH:19]=4)=[O:42])=[C:37]([CH3:39])[N:38]=3)[N:31]=[N:30]2)=[CH:43][CH:44]=1
Reactant: Cc1nc(-c2cn(CCc3ccc(F)cc3)nn2)sc1C(=O)O
Reactant: Cc1nc(-c2cn(Cc3ccccc3)nn2)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(-c2cn(CCc3ccc(F)cc3)nn2)sc1C(=O)NCc1cccnc1
Yield: 53 %

Procedure:
Following the procedure as described in Example 4, making variations as necessary to replace 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylic acid with 2-(1-(4-fluorophenethyl)-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 53% yield: mp 149-150° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.50 (br s, 1H), 8.42 (br s, 1H), 7.84 (s, 1H), 7.70-7.62 (m, 1H), 7.27-7.16 (m, 1H), 7.12-6.99 (m, 3H), 6.95-6.85 (m, 2H), 4.56 (t, J=7.1 Hz, 2H), 4.55 (d, J=5.5 Hz, 2H), 3.16 (t, J=7.1 Hz, 2H), 2.63 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.0, 161.9, 157.9, 157.1, 149.2, 148.8, 142.4, 135.7, 133.9, 132.2, 132.1, 130.1, 124.1, 121.9, 115.8, 52.0, 41.5, 35.7, 17.3; MS (ES+) m/z 423.3 (M+1).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[C:1]([NH:5][S:20]([C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=1)(=[O:22])=[O:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 80.1 %

Procedure:
Into a DCM solution (50 mL) of tert-butylamine (5.9 mL, 56.5 mmol) and triethylamine (7.16 mL, 51.3 mmol) at 0° C. was slowly added a DCM solution (20 mL) of 4-fluoro-benzenesulfonyl chloride (10 g, 51.3 mmol), and the reaction stirred at RT for 19 h. The reaction was concentrated and the resulting solid recrystalized from ether/hexanes to get the product (9.5 g, 80%) as white crystals. MS: APCI (AP+): 230.1 (M)+.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(#N)C.[F:20][C:21]1[CH:22]=[C:23]([C:28](=[O:60])[C:29](=[C:51]2[NH:55][C:54]3[CH:56]=[CH:57][CH:58]=[CH:59][C:53]=3[NH:52]2)[C:30]([C:32]2[CH:33]=[C:34]([S:38]([NH:41][C:42](N3C(C)=CC(C)=N3)=[NH:43])(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=2)=[O:31])[CH:24]=[C:25]([F:27])[CH:26]=1>C(OCC)(=O)C>[F:27][C:25]1[CH:24]=[C:23]([C:28](=[O:60])[C:29](=[C:51]2[NH:52][C:53]3[CH:59]=[CH:58][CH:57]=[CH:56][C:54]=3[NH:55]2)[C:30]([C:32]2[CH:33]=[C:34]([S:38]([NH:41][C:42](=[NH:43])[N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[O:8])[CH2:2][CH2:3]3)(=[O:39])=[O:40])[CH:35]=[CH:36][CH:37]=2)=[O:31])[CH:22]=[C:21]([F:20])[CH:26]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: Cc1cc(C)n(C(=N)NS(=O)(=O)c2cccc(C(=O)C(C(=O)c3cc(F)cc(F)c3)=C3Nc4ccccc4N3)c2)n1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N=C(NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1)N1CCN(C(=O)OCc2ccccc2)CC1
Yield: 30.5 %

Procedure:
At 0° C., benzyl piperazine-1-carboxylate (1.37 g) was added to an acetonitrile (5 mL) solution of N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)-3,5-dimethyl-1H-pyrazole-1-carboximidamide (205 mg), and heated under reflux for 3 days. After cooling, ethyl acetate was added, then washed with aqueous saturated ammonium chloride solution, water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/4) to obtain benzyl 4-[[({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)amino](imino)methyl]piperazine-1-carboxylate (76 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([SH:14])[CH:4]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)#[N:16]>N1C=CC=CC=1>[CH3:13][O:12][C:11]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[S:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:16][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: N#Cc1ccccn1
Reactant: COc1cc(S)c(C(=O)O)cc1OC
Solvent: c1ccncc1
Product: COc1cc2sc(-c3ccccn3)nc(=O)c2cc1OC
Yield: 55.5 %

Procedure:
A mixture of 4,5-dimethoxy-2-mercaptobenzoic acid (2.20 g, 10.2 mmol), 2-cyanopyridine (1.10 g, 10.2 mmol) and pyridine (15.0 ml) was refluxed for 20 hrs as described in Example 9. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-chlorobenzene to give the titled compound (1.70 g, 55%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>O1CCCC1.ClCCl>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32](=[O:33])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 90 mg of 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide in 5 mL of tetrahydrofuran are added dropwise 50 μL of 2-fluoro-5-(trifluoromethyl)phenyl isocyanate. The reaction mixture is stirred for 16 hours at room temperature under an argon atmosphere and then concentrated under reduced pressure. The residue obtained is stirred for 30 minutes in 2 mL of dichloromethane. The suspended solid is filtered off and drained by suction. After drying under vacuum, at 40° C., 115 mg of 3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]-pyridine-2-carboxamide are obtained, the characteristics of which are as follows:
Reaction SMILES: Cl([O-])=O.[Na+].S(=O)(=O)(O)N.[CH2:10]([O:17][C:18]1[C:19]([CH:36]=[O:37])=[N:20][CH:21]=[C:22]([C:34]=1[OH:35])[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH2:38]>O1CCCC1>[CH2:10]([O:17][C:18]1[C:19]([C:36]([OH:38])=[O:37])=[N:20][CH:21]=[C:22]([C:23](=[O:24])[NH:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[C:34]=1[OH:35])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O
Reactant: O=Cc1ncc(C(=O)NCc2ccc(F)cc2)c(O)c1OCc1ccccc1
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Product: O=C(NCc1ccc(F)cc1)c1cnc(C(=O)O)c(OCc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To an aqueous solution (105 ml) of sodium chlorite (7.13 g, 78.8 mmol), and sulfamic acid (7.65 g, 78.8 mmol) was added a solution of the compound 12 (15.0 g, 39.4 mmol) in tetrahydrofuran (630 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After water (2500 ml) was added to the reaction solution, precipitated crystals were filtered. Washing with diethyl ether afforded 3-benzyloxy-5-(4-fluoro-benzylcarbamoyl)-4-hydroxy-pyridine-2-carboxylic acid 13 (1.4.0 g, 90%) as a colorless crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][NH:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([N:24]([CH3:23])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CNCCc1ccccc1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)CCc4ccccc4)cc3)c2)o1

Procedure:
2′-Methyl-N-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(phenylethyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and N-methyl-N-(phenylethyl)amine using method M. NMR; δH [2H6]—DMSO 7.89,(1H, dd), 7.75,(1H, d), 7.54,(1H, d), 7.47-7.17,(8H, m), 6.99,(1H, d), 3.69,(1H, m), 3.43,(1H, m), 3.04,(1.5H, s), 2.92,(1H, m), 2.87,(1.5H, s), 2.80,(1H, m), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 3.39 min, MH+ 412.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:18]([CH:20]=O)=[O:19])[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>CO>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([CH:18]([OH:19])[CH2:20][NH:25][CH:22]([CH3:24])[CH3:23])[CH:10]=1)[C:15]([OH:17])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N
Reactant: O=CC(=O)c1cc(OCc2ccccc2)cc(C(=O)O)c1
Solvent: CO
Product: CC(C)NCC(O)c1cc(OCc2ccccc2)cc(C(=O)O)c1
Reaction time: 1 h
Yield: 50 %

Procedure:
The 3-benzyloxy-5-carboxyphenylglyoxal (;b 120 moles) was dissolved in MeOH (1 l.) and cooled to 0°. Isopropylamine (200 ml) was added at 0° and the resulting mixture was stirred at 0° for 1 hr. before KBH4 (12.2 g, 228 moles) was added over a period of 2 hrs., portionwise. The resultant mixture was allowed to stir at room temperature overnight before it was evaporated to a residual glass. The residue was acidified with 6N HCl (1 l.) and extracted with CHCl3 (1 142 l.). The solid HCl precipitated from the CHCl3 extract upon standing; yield 21.9 g which gave 20.0 g (50%) mp. 290°- 292° dec. of the free base upon stirring in aqueous NH4OH and collecting by filtration.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([C:14]([OH:16])=O)=[N:3]1.[CH3:17][N:18]1C(C(O)=O)=C2C(C=C([N+]([O-])=O)C=C2)=N1>>[CH3:17][NH:18][C:14]([C:4]1[C:5]2[C:10](=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[N:2]([CH3:1])[N:3]=1)=[O:16]
Reactant: Cn1nc2cc([N+](=O)[O-])ccc2c1C(=O)O
Reactant: Cn1nc(C(=O)O)c2ccc([N+](=O)[O-])cc21
Product: CNC(=O)c1nn(C)c2cc([N+](=O)[O-])ccc12

Procedure:
is obtained by reacting a mixture of 1-methyl-6-nitro-1H-indazole-3-carboxylic acid and 2-methyl-6-nitro-2H-indazole-3-carboxylic acid. The product is purified by chromatography on silica gel.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[N+:18]([O-])=O.CN(C)C=O.[CH3:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[CH3:34])[NH2:30]>>[NH2:18][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[O:8][CH3:7])[C:13]([NH:30][C:29]1[CH:31]=[CH:32][C:33]([CH3:34])=[C:27]([CH3:26])[CH:28]=1)=[O:15]
Reactant: Cc1ccc(N)cc1C
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(C)c(C)c2)cc1N
Yield: 87.4 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 34.4 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g, 25.36 mmol), dimethylformamide (1.0 mL, 12.92 mmol), and 3,4-dimethylaniline (6.2 g, 51 mmol) to afford the product (5.99 g); m.p. 138-142° C.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH3:12][C:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[O:23][CH3:24])=[O:14].[OH-].[Na+]>CO>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6](/[CH:7]=[CH:12]/[C:13]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=3[O:23][CH3:24])=[O:14])=[CH:5][C:4]=2[O:9]1
Reactant: COc1ccc(OC)c(C(C)=O)c1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(OC)c(C(=O)/C=C/c2ccc3c(c2)OCO3)c1
Reaction time: 2 h

Procedure:
To a stirred solution of piperonal (1 g, 6.7 mmol) and 2,5-dimethoxyacetophenone (1.21 g, 6.7 mmol) in methanol (30 ml) was added 15 equivalents of aqueous sodium hydroxide (˜8 ml, 50% w/v) and the mixture stirred for 2 h. The resultant solid was collected by filtration and then recrystallised from methanol as fine, needle-like pale yellow crystals (1.70 g, 81%): mp 101° C.; 1H NMR δ (CDCl3) 3.78 (3H, s, OCH3), 3.85 (3H, s, OCH3), 6.00 (2H, s, CH2O), 6.83 (1H, d, ArH), 6.90 (1H, d, ArH), 7.00 (3H, m, ArH), 7.15 (1H, d, ArH), 7.23 (1H, d, J=15.7 Hz, ArH), 7.52 (1H, d, J=15.8 Hz, ArH); Infra red νmax (KBr)/cm−1 1652.9 (C═O); MS (rel intensity) m/z 313 ([M+H]+, 100%); Anal.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH:10]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:66]([O:70][C:71]([NH:73][C:74]1[S:78][C:77]([C:79]2[C:84]([F:85])=[CH:83][CH:82]=[CH:81][C:80]=2[F:86])=[N:76][C:75]=1[C:87](O)=[O:88])=[O:72])([CH3:69])([CH3:68])[CH3:67]>C(Cl)Cl>[F:86][C:80]1[CH:81]=[CH:82][CH:83]=[C:84]([F:85])[C:79]=1[C:77]1[S:78][C:74]([NH:73][C:71](=[O:72])[O:70][C:66]([CH3:68])([CH3:67])[CH3:69])=[C:75]([C:87](=[O:88])[NH:1][C:2]2[CH:3]=[N:4][N:5]([CH3:23])[C:6]=2[N:7]2[CH2:8][CH2:9][CH:10]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:11]([O:14][CH3:15])[CH2:12][CH2:13]2)[N:76]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: COC1CCN(c2c(N)cnn2C)CCC1NC(=O)C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC1CCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnn2C)CCC1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
To a solution of Intermediate 54, N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-methoxyazepan-4-yl)-2,2,2-trifluoroacetamide (150 mg, 0.45 mmol) in DCM (20 mL) was added DIPEA (1.0 mL), PyBOP (580 mg, 1.12 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid (159 mg, 0.45 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (100 mL) and washed with water (20 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (70-80% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(5-(4-methoxy-5-(2,2,2-trifluoroacetamido)azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as an off-white solid (260 mg, 0.39 mmol) which was stirred with HCl in 1,4-dioxane (4 M, 4.8 mL, 19.3 mmol) in MeOH (5 mL) at room temperature for 3 days. The solvent was removed under reduced pressure and the resulting solid was dissolved in MeOH/water (10 mL/10 mL) and to this was added K2CO3 (267 mg, 19.3 mmol). The reaction mixture was heated at 65° C. for 3 hr. The MeOH was removed under reduced pressure and the aqueous residue was diluted with water (5 mL) and extracted with 5% MeOH in DCM (2×75 mL). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure to give 217 as a beige solid (144 mg, 67% over 3 steps). 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.84 (s, 1H), 7.38-7.28 (m, 1H), 7.02 (t, J=8.8 Hz, 2H), 6.15 (s, 2H), 3.72 (s, 3H), 3.37 (s, 3H), 3.36-3.25 (m, 2H), 3.22-3.08 (m, 3H), 3.07-2.99 (m, 1H), 2.17-2.10 (m, 1H), 2.02-1.93 (m, 1H), 1.88-1.65 (m, 2H). Alkyl NH2 not observed. LCMS (ES+) m/z 478 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH3:43])[S:10]([C:13]2[CH:14]=[C:15]([CH:40]=[CH:41][CH:42]=2)[C:16]([NH:18][CH2:19][C:20]2[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]3[CH:30]=[N:29][N:28]([CH2:31][CH3:32])[C:23]3=[N:24][C:25]=2[CH2:26][CH3:27])=[O:17])(=[O:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.CC(OC([N:51]1[CH2:56][CH2:55][N:54]([CH2:57][C:58]2[CH:59]=[C:60](B(O)O)[CH:61]=[CH:62][CH:63]=2)[CH2:53][C@H:52]1[CH3:67])=O)(C)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH2:31]([N:28]1[C:23]2=[N:24][C:25]([CH2:26][CH3:27])=[C:20]([CH2:19][NH:18][C:16](=[O:17])[C:15]3[CH:40]=[CH:41][CH:42]=[C:13]([S:10]([N:9]([CH3:43])[CH2:8][C:4]4[CH:3]=[C:2]([C:62]5[CH:61]=[CH:60][CH:59]=[C:58]([CH2:57][N:54]6[CH2:55][CH2:56][NH:51][C@@H:52]([CH3:67])[CH2:53]6)[CH:63]=5)[CH:7]=[CH:6][CH:5]=4)(=[O:12])=[O:11])[CH:14]=3)[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]2[CH:30]=[N:29]1)[CH3:32]
Reactant: C[C@@H]1CN(Cc2cccc(B(O)O)c2)CCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(S(=O)(=O)N(C)Cc2cccc(Br)c2)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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(S(=O)(=O)N(C)Cc2cccc(-c3cccc(CN4CCN[C@@H](C)C4)c3)c2)c1
Temperature: 130 °C
Yield: 30.8 %

Procedure:
To a solution of 3-{[[(3-bromophenyl)methyl](methyl)amino]sulfonyl}-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (120 mg, 0.179 mmol) in 1,4-dioxane (3 mL) and H2O (1 mL) was added {3-[((3R)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-3-methyl-1-piperazinyl)methyl]phenyl}boronic acid (59.9 mg, 0.179 mmol), Pd(Ph3P)4 (10.35 mg, 8.96 μmol), and K2CO3 (74.3 mg, 0.538 mmol) and the reaction was heated in microwave at 130° C. for 15 min. The organic layer was separated, filtered, concentrated, and purified using a Gilson HPLC (with 0.1% TFA). Before the sample was concentrated with a GeneVac EZ-2, TFA (5 drops) was added to each tube (12 mL). The resultant mixture was concentrated, purified using a Gilson HPLC (with 0.1% TFA), concentrated, and basified with amino cartridge to afford 0.0429 g (30%) of the title compound. LC-MS m/z 779 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.35-1.45 (m, 6 H) 1.48 (t, J=7.28 Hz, 3 H) 1.82-1.96 (m, 2 H) 2.10 (d, J=12.55 Hz, 2 H) 2.66 (s, 3 H) 3.18 (q, J=7.61 Hz, 3 H) 3.33-3.39 (m, 1 H) 3.42-3.53 (m, 1 H) 3.60-3.79 (m, 6 H) 3.98-4.10 (m, J=8.41, 3.14 Hz, 2 H) 4.27 (s, 2 H) 4.31-4.40 (m, 1 H) 4.41-4.54 (m, 4 H) 4.75 (s, 2 H) 7.31-7.37 (m, 1 H) 7.40-7.65 (m, 5 H) 7.68-7.85 (m, 3 H) 8.05 (d, J=7.28 Hz, 1 H) 8.23 (d, J=7.78 Hz, 1 H) 8.28 (s, 1 H) 8.39 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:29][C:30]1[S:31][CH:32]=[N:33][N:34]=1>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([NH:29][C:30]1[S:31][CH:32]=[N:33][N:34]=1)=[O:15])[CH:10]([CH3:12])[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1nncs1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(O)C(NC(=O)OC(C)(C)C)C(=O)Nc1nncs1
Yield: 79.3 %

Procedure:
Using the same procedure as in Example 1(i), 10 g of N-t-butoxycarbonyl-DL-threonine, 4.6 g of triethylamine, 5.0 g of ethyl chlorocarbonate and 4.6 g of 2-amino-1,3,4-thiadiazole were reacted in 150 ml of tetrahydrofuran to obtain 10.9 g (yield: 79%) of 2-(N-t-butoxycarbonyl-DL-threonylamino)-1,3,4-thiadiazole as white powder having a melting point of 165°-170° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:15][CH:14]3[CH:10]([CH2:11][NH:12][CH2:13]3)[CH2:9]2)[N:3]=1.[F:16][C:17]1[CH:18]=[C:19]([C:23]2[C:24]([C:29](O)=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:21][CH:22]=1>>[F:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([N:12]2[CH2:13][CH:14]3[CH:10]([CH2:9][N:8]([C:4]4[N:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=4)[CH2:15]3)[CH2:11]2)=[O:30])[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccnc(N2CC3CNCC3C2)n1
Reactant: O=C(O)c1ccccc1-c1cccc(F)c1
Product: Cc1ccnc(N2CC3CN(C(=O)c4ccccc4-c4cccc(F)c4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 27 and 3′-fluoro-biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for C24H23FN4O, 402.46; m/z found, 403.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1.Cl[C:11]1[C:16]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:15][CH:14]=[CH:13][N:12]=1.O>C1(C)C=CC=CC=1>[O:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:11]1[C:16]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cccnc1Cl
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1cccnc1N1CCCCC1=O
Reaction time: 5 h

Procedure:
To a suspension of 1.1 g of 60% sodium hydride in 10 ml of toluene is added 5 g of 2-oxopiperidine, followed by addition of 6.4 g of 2-chloro-3-(4-chlorobenzoyl)pyridine. The mixture is stirred at 90°-100° C. for 5 hours. After water is poured into the reaction mixture, the solvent of the toluene layer is distilled off. The residue is recrystallized from methanol to give 2-(2-oxopiperidino)-3-(4-chlorobenzoyl)pyridine, m.p. 154°-156° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([NH2:12])[CH2:9]2)C=CC=CC=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[NH:8]1[CH2:11][CH:10]([NH:12][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:9]1
Reactant: CS(=O)(=O)Cl
Reactant: NC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC1CNC1
Reaction time: 0.5 h

Procedure:
A solution of 1-(diphenylmethyl)-3-azetidinamine (synthesized according to the methods of Arimoto et. al., J. of Antibiotics 39 (9), 1243-56, 1986)(197 mg, 0.83 mmol) in dichloromethane (10 mL) was treated with excess triethylamine at 0° C. followed by methanesulfonyl chloride (71 μL, 0.91 mmol). The reaction was stirred for 30 minutes and then concentrated and purified on silica gel (0-10% methanol/dichloromethane) to provide 185 mg of the desired product as a white solid. LC/MS: M+H 317.19 at 0.31 minutes, Method D.
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[CH3:17][NH2:18].O>C(Cl)(Cl)Cl>[CH3:17][NH:18][CH:2]([CH3:16])[C:3]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: CN
Reactant: CC(Br)C(=O)c1ccc(OCC(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CNC(C)C(=O)c1ccc(OCC(=O)O)cc1
Reaction time: 1.5 h
Yield: 65 %

Procedure:
4-(2-bromopropionyl)phenoxyacetic acid (5 g, 17.5 mmol) in chloroform (50 ml) was stirred vigorously at 35-40° C. and a solution of 40% methylamine in water (4.05 ml, 52 mmol) was added dropwise over 30 mins. Stirring was continued at this temperature for a further 1.5 h after addition. The mixture was evaporated to dryness and the crude residue was purified by column chromatography (silica gel: 10% methanol in chloroform) to give the title product (2.7 g, 65%) as a white foam.