Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]([C:25](O)=[O:26])=[C:17]2[CH2:28][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[C:30](=[O:31])[C:16]=12)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:40][C:41]1[S:42][CH:43]=[N:44][N:45]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[S:42]1[CH:43]=[N:44][N:45]=[C:41]1[NH:40][C:25]([C:18]1[C:19]2[CH:20]=[CH:21][CH:22]=[N:23][C:24]=2[C:15]([OH:14])=[C:16]2[C:30](=[O:31])[N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:28][C:17]=12)=[O:26]
Reactant: Nc1nncs1
Reactant: O=C(O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nncs1)c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.9 %

Procedure:
9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid 213 (0.02 g, 0.0386 mmol) was dissolved in 0.3 mL of dimethylformamide. To this was added 2-amino-1,3,4-thiadiazole (0.0078 mL, 0.0772 mmol), diisopropylethylamine (0.027 mL, 0.1544 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.03 g, 0.0772 mmol) and stirred at room temperature. After 15 hours, starting material was consumed. Purified by reverse phase HPLC (0.1% TFA, H2O/ACN) to give 7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid [1,3,4]thiadiazol-2-ylamide 320 (0.0066 g, 0.015 mmol, 40%.) 1H NMR (CDCl3) δ 9.02 (dd, 1H), 8.81 (s, 1H), 8.65 (d, 1H), 7.65 (dd, 1H), 7.38 (dd, 2H), 7.05 (dd, 2H), 4.74 (s, 2H), 4.64 (s, 2H.) MS: 436 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6](=[O:60])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:59])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:25][C:24]=3[C:35]([C:37]3[N:38](S(C4C=CC=CC=4)(=O)=O)[C:39]4[C:44]([CH:45]=3)=[CH:43][CH:42]=[C:41]([C:46]([F:49])([F:48])[F:47])[CH:40]=4)=[O:36])[CH:16]=2)[CH:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CO.C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6](=[O:60])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:59])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)=[CH:25][C:24]=3[C:35]([C:37]3[NH:38][C:39]4[C:44]([CH:45]=3)=[CH:43][CH:42]=[C:41]([C:46]([F:48])([F:49])[F:47])[CH:40]=4)=[O:36])[CH:16]=2)[CH:8]=1
Reactant: COCCNC(=O)c1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3C(=O)c3cc4ccc(C(F)(F)F)cc4n3S(=O)(=O)c3ccccc3)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCNC(=O)c1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3C(=O)c3cc4ccc(C(F)(F)F)cc4[nH]3)c2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask was placed a solution of N-(2-methoxyethyl)-3-(3-(2-(1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole-2-carbonyl)-4-(piperidin-1-yl)phenylcarbamoyl)benzylthio)-benzamide (200 mg, 0.23 mmol, 1.00 equiv) in methanol (3.5 mL), and 3.5 mL of a 1.0 N solution of tetrabutylammonium fluoride in THF. The resulting solution was stirred overnight at 80° C. The resulting mixture was concentrated under vacuum. The residue was dissolved in 50 mL of ethyl acetate. The resulting mixture was washed with 3×20 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by HPLC with the following conditions (Waters 2767-3): Column, SunFire Prep C18, 19×150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (gradient of 49% to 61% CH3CN over 6 min); Detector, Waters 2545 UV Detector 254 and 270 nm. This resulted in 38.1 mg (17%) of N-(2-methoxyethyl)-3-(3-(4-(piperidin-1-yl)-2-(6-(trifluoromethyl)-1H-indole-2-carbonyl)-phenylcarbamoyl)benzylthio)benzamide as a orange solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.38 (d, J=9 Hz, 1H), 8.01 (d, J=3 Hz, 1H), 7.91-7.87 (m, 2H), 7.78-7.73 (m, 4H), 7.62-7.59 (m, 1H), 7.53-7.51 (m, 1H), 7.47-7.26 (m, 5H), 4.23 (s, 2H), 3.62-3.57 (m, 4H), 3.53 (s, 3H), 3.35-3.34 (m, 2H), 1.98-1.96 (m, 4H), 1.79-1.77 (m, 2H). MS (ES, m/z): 715 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([CH:14]=1)[C:10]([O:12]C)=[O:11])=[O:4].[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.[ClH:36]>O1CCCC1.C(OCC)C>[ClH:36].[CH3:16][O:15][C:8]1[CH:7]=[CH:6][C:5]([C:3](=[O:4])[CH2:2][N:26]2[CH2:27][CH2:28][N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24][CH2:25]2)=[CH:14][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COC(=O)c1cc(C(=O)CBr)ccc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)CN2CCN(c3ccccc3)CC2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 15.0 g (0.0522 mol) of methyl 5-(bromoacetyl)-2-methoxybenzoate in 500 ml of anhydrous tetrahydrofuran is added dropwise over 2-4 hours to a solution of 8.48 g (0.0522 mol) of 1-phenylpiperazine and 5.28 g (0.0522 mol) of triethylamine in 100 ml of tetrahydrofuran. The mixture is stirred at room temperature under exclusion of moisture overnight. The precipitated triethylamine hydrobromide is removed by filtration and the filtrate is evaporated to dryness. Addition of 2 equivalents of methanolic HCl and precipitation by addition of ethyl ether yields crude 2-methoxy-5-[2-(4-phenyl-1-piperazinyl)acetyl]benzoate hydrochloride (21.0 g) that can be used without further purification.
Reaction SMILES: [F:1][CH:2]([C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=1)[C:3]([OH:5])=O.[NH2:14][C@H:15]([C:17]([NH:19][CH:20]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]2[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=2[N:22]([CH3:37])[C:21]1=[O:38])=[O:18])[CH3:16]>>[F:13][C:8]1[CH:7]=[C:6]([CH:2]([F:1])[C:3]([NH:14][C@H:15]([C:17]([NH:19][CH:20]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24]3[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=3[N:22]([CH3:37])[C:21]2=[O:38])=[O:18])[CH3:16])=[O:5])[CH:11]=[C:10]([F:12])[CH:9]=1
Reactant: C[C@H](N)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reactant: O=C(O)C(F)c1cc(F)cc(F)c1
Product: C[C@H](NC(=O)C(F)c1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenyl-α-fluoroacetic acid (Example S) and 3-(L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-Y), the title compound was prepared as a solid. The product was purified by LC 2000 chromatography, eluting with hexanes/ethyl acetate (35:65).
Reaction SMILES: O1CCOCC1.Cl[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9].[NH2:15][CH2:16][C:17]([OH:19])=[O:18]>[OH-].[Na+]>[CH2:11]([O:10][C:8]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:9])[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)COC(=O)Cl
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)COC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.3 ml of dioxane and 872 μl (6.66 mmol) of isobutyl chloroformate are added to a solution of 500 mg (6.66 mmol) of glycine in 14 ml of 2N NaOH solution. The mixture is stirred overnight at RT and then extracted with methylene chloride. The aqueous phase is acidified with 4N HCl solution and extracted twice with methylene chloride. Drying (Na2SO4) and concentration of the extracts by evaporation yield N-isobutyloxycarbonyl-glycine; FAB-MS: (M+H)+=176; 1H-NMR (CDCl3) 8.0 (sb), 6.93 and 5.21 (2m, 1H), 4.02 and 3.88 (2m, each 2H), 1.93 (m, 1H), 0.94 (d, J=7, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].O.[N+:11]([CH:14]([CH:17]=O)[CH:15]=[O:16])([O-:13])=[O:12].[Na].C(O)(=O)/C(=C(\C=O)/Br)/Br>Cl.O>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([NH:1][CH:17]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=[O:16])[CH:9]=[CH:8][CH:7]=1
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: Nc1cccc(CO)c1
Agent: Cl
Agent: O=C/C(Br)=C(/Br)C(=O)O
Agent: [Na]
Solvent: O
Product: O=CC(=CNc1cccc(CO)c1)[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
3-Aminobenzyl alcohol (4.97 g, 0.0404 mol) was dissolved in 4 mL conc HCl. Sodium nitromalonaldehyde monohydrate (prepared from mucobromic acid according to the procedure in Organic Syntheses Vol IV, pp 844, 1963) (4.25 g, 0.0269 mol) was dissolved in 35 mL water and added to the amine solution (a yellow precipitate formed immediately)—a further 80 mL of water being added to aid stirring. After 10 min, the precipitate was filtered, washed with water and air dried overnight to give the product (4.3 g) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[NH:13][CH2:12][C:11]2[O:14][C:15]([CH:17]=[O:18])=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-]#N.[Na+].[CH3:22][OH:23]>[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6]([CH:8]1[NH:13][CH2:12][C:11]2[O:14][C:15]([C:17]([O:23][CH3:22])=[O:18])=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1Cc2nc(C=O)oc2CN1
Reactant: CO
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Product: COC(=O)c1nc2c(o1)CNC(C(=O)OC(C)(C)C)C2
Reaction time: 0.5 h

Procedure:
To a solution of 6-(tert-butoxycarbonyl)-2-formyl-4,5,6,7-tetrahydrooxazol[5,4-c]pyridine (225 mg) in methanol (9.0 ml) were added sodium cyanide (220 mg) and manganese dioxide (780 mg) at room temperature, followed by stirring for 30 minutes. The reaction mixture was subjected to Celite filtration by using ethyl acetate. The filtrate was washed with water (50 ml) and saturated saline (50 ml), dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=3:2→1:1), whereby the title compound (120 mg) was obtained as a colorless transparent glassy substance.
Reaction SMILES: C[C:2]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[C:23](C)[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][C:8]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][C:6]1=[O:22].Br[C:38]1[CH:43]=[CH:42][N:41]([CH:44]2[CH2:46][CH2:45]2)[C:40](=[O:47])[CH:39]=1>>[CH:44]1([N:41]2[CH:42]=[CH:43][C:38]([C:25]3[CH:24]=[CH:23][C:3]([CH2:4][N:5]4[CH2:10][CH2:9][C:8]([CH2:17][C:18]([OH:21])([CH3:19])[CH3:20])([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[O:7][C:6]4=[O:22])=[CH:2][CH:26]=3)=[CH:39][C:40]2=[O:47])[CH2:46][CH2:45]1
Reactant: O=c1cc(Br)ccn1C1CC1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1CN1CCC(CC(C)(C)O)(c2ccccc2)OC1=O
Product: CC(C)(O)CC1(c2ccccc2)CCN(Cc2ccc(-c3ccn(C4CC4)c(=O)c3)cc2)C(=O)O1

Procedure:
The title compound was prepared from 3-[2,6-dimethyl-4-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-benzyl]-6-(2-hydroxy-2-methyl-propyl)-6-phenyl -[1,3]oxazinan-2-one and 4-bromo-1-cyclopropyl-1H-pyridin-2-one following a procedure analogous to that described in Step 5 of Example 96. LC-MS (Method 5): tR=3.53 min; Mass spectrum (ESI+): m/z=501 [M+H]+.
Reaction SMILES: [SH:1][C:2]([CH3:17])([CH3:16])[CH2:3][S:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:14][OH:15])[CH:9]=[C:10]([CH2:12][OH:13])[CH:11]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:26][S:27](=O)(SC)=O>C(O)C.ClCCl>[CH3:16][C:2]([S:1][S:27][CH3:26])([CH3:17])[CH2:3][S:4][CH2:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[C:8]([CH2:14][OH:15])[CH:7]=1
Reactant: CC(C)(S)CSCc1cc(CO)cc(CO)c1
Reactant: CSS(C)(=O)=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: CSSC(C)(C)CSCc1cc(CO)cc(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
(5-((2-mercapto-2-methylpropylthio)methyl)-1,3-phenylene)dimethanol (0.120 g, 0.440 mmol) was dissolved in ethanol (5 mL) and 1.0 M potassium phosphate buffer (pH 7) (5.00 mL) and cooled in an ice bath (a ppt formed but it was ignored). S-methyl methanesulfonothioate (0.083 mL, 0.881 mmol) was added and the mixture stirred overnight with gradual (over 30 minutes) warming to room temperature. The reaction was diluted with dichloromethane and the organic layer was removed, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was dissolved in dichloromethane and loaded onto a 500 micron ptlc plate and developed with 66% ethyl acetate in hexane. The band corresponding to the product was scraped, filtered using ethyl acetate, and concentrated to give (5-((2-methyl-2-(methyldisulfanyl)propylthio)methyl)-1,3-phenylene)dimethanol (0.091 g, 0.286 mmol, 64.9% yield). 1H NMR (400 Hz, CDCl3): δ 7.27 (s, 3H), 4.71 (s, 4H), 3.78 (s, 2H), 2.77 (s, 2H), 2.41 (s, 3H), 1.94 (br s, 2H), 1.38 (s, 6H); 13C NMR (400 Hz, CDCl3): δ 141.6, 139.0, 126.7, 124.2, 65.0, 51.8, 44.0, 38.2, 26.7, 25.3; MS (m/z), expected: 341.5. found 341.1 (M+Na). See FIG. 30.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[CH:11]=[CH:10]N=[N:8][C:7]=2[O:6][CH2:5]1.[CH3:13][C:14]1N=C2OCC(=O)C2=CC=1>>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[N:8][C:13]([CH3:14])=[CH:10][CH:11]=2)[O:6][CH2:5]1
Reactant: CON=C1COc2nnccc21
Reactant: Cc1ccc2c(n1)OCC2=O
Product: CON=C1COc2nc(C)ccc21

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime (A.2.3.3), 6-methylfuro[2,3-b]pyridin-3(2H)-one replacing furo[2,3-c]pyridazin-5(6H)-one. Purification by (KP-SIL™ from Biotage) using Hept to Hept/EtOAc (1/1) gives the desired product as white solid;
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([NH:16][CH2:17][CH:18]=[O:19])[CH2:14][CH3:15]>C1C=CC=CC=1>[CH2:13]([N:16]([CH2:17][CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]=1)=[O:12])[CH2:14][CH3:15]
Reactant: CC(C)(C)c1nnc(N=C=O)s1
Reactant: CCCNCC=O
Solvent: c1ccccc1
Product: CCCN(CC=O)C(=O)Nc1nnc(C(C)(C)C)s1

Procedure:
A mixture of 5-t-butyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-propylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-propyl-3-(5-t-butyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[N:10][OH:11].C(OC(=O)C)(=O)C.CCN(CC)CC.O.[Cl-].[Na+].O>>[OH:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=3[O:11][N:10]=2)=[CH:2][CH:7]=1
Reactant: ON=C(c1ccc(O)cc1)c1ccc(O)cc1O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: Oc1ccc(-c2noc3cc(O)ccc23)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.7 %

Procedure:
A mixture of (2,4-dihydroxyphenyl)(4-hydroxyphenyl)methanone oxime (0.46 g, 1.87 mmol), acetic anhydride (0.19 g, 1.87 mmol) and Et3N (0.25 g, 2.44 mmol) was stirred at room temperature for 24 h. The mixture was pored into water/brine and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (CH2Cl2/hexanes/EtOAc/MeOH 5/3.5/1/0.05) gave an off-white solid (0.19 g, 42% yield, m.p. 192-194° C.); MS m/e 226 (M−H)+.
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:20][S:17]([C:13]1[CH:12]=[C:11]([NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:35][C:32]4[CH:31]=[CH:30][C:29]([N:26]5[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]5)=[CH:34][CH:33]=4)[N:21]=3)[CH:9]=[CH:8][CH:7]=2)[CH:16]=[CH:15][CH:14]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)c1cccc(Nc2cccn3nc(Cl)nc23)c1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(Nc5cccc(S(C)(=O)=O)c5)cccn4n3)cc2)CC1

Procedure:
N(8)-(3-Methanesulfonyl-phenyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methanesulfonyl-phenyl)-amine (75.0 mg, 0.232 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (50.0 mg, 0.261 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.009 g, 8%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.02 (d, J=6.2 Hz, 1H), 7.81 (s, 1H), 7.59-7.43 (m, 5H), 7.20 (d, J=8.0 Hz, 1H), 6.97 (d, J=7.5 Hz, 2H), 6.85 (s, 1H), 6.79 (t, J=7.4 Hz, 1H), 6.59 (s, 1H), 3.19-3.14 (m, 4H), 3.07 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=478 (MH)+.
Reaction SMILES: [C:1]1([CH:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([OH:21])=O)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:22]2[C@H:26]([OH:27])[C@H:25]([OH:28])[C@@H:24]([C:29]([NH:31][CH2:32][CH3:33])=[O:30])[O:23]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:40][C:41]([F:52])([F:51])[C:42]([NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:43].Cl.CN(C)CCCN=C=NCC>ClCCl>[C:1]1([CH:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([N:48]3[CH2:49][CH2:50][CH:45]([NH:44][C:42](=[O:43])[C:41]([F:51])([F:40])[F:52])[CH2:46][CH2:47]3)=[O:21])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:22]2[O:23][C@H:24]([C:29]([NH:31][CH2:32][CH3:33])=[O:30])[C@@H:25]([OH:28])[C@H:26]2[OH:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC1CCNCC1)C(F)(F)F
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)O)nc32)[C@H](O)[C@@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)N4CCC(NC(=O)C(F)(F)F)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
A solution of 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxylic acid (Preparation 39) (0.2 g, 0.38 mmol), 2,2,2-trifluoro-N-(4-piperidinyl)acetamide (83 mg, 0.42 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (81 mg, 0.42 mmol) in dichloromethane (5 ml) was stirred at room temperature for 48 hours and then heated under reflux for a further 96 hours. The solution was allowed to cool to room temperature and then solvent removed by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:concentrated aqueous ammonia (95:5:1, by volume) changing to dichloromethane:methanol:concentrated aqueous ammonia (80:20:1, by volume). After evaporation of appropriate fractions the target compound was obtained as a white solid, (43 mg, 18%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1O)[C:17](O)=O.C(OC)(OC)OC>>[CH2:22]([CH:14]([NH:13][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[N:3][C:4]=2[CH:9]=1)=[O:12])[CH2:15][CH2:16][CH3:17])[CH2:21][CH3:20]
Reactant: O=C(O)c1ccc2ocnc2c1
Reactant: Nc1cc(C(=O)O)ccc1O
Solvent: COC(OC)OC
Product: CCCC(CCC)NC(=O)c1ccc2ocnc2c1
Temperature: 65 °C
Yield: 15 %

Procedure:
benzooxazol-5-carboxylic acid: A mixture of 3-amino-4-hydroxybenzoic acid (500 mg, 3.26 mmol) and trimethyl orthoformate (5 mL) was heated at 65° C. for 2 h under argon. The reaction mixture was cooled to room temperature, filtered and washed with hexanes. The filtrate was concentrated in vacuo to afford the product as a white solid (78 mg, 15%): 1H NMR (500 MHz, CDCl3): δ 8.57 (d, J=1.5 Hz, 1H), 8.20 (dd, J=8.4, 1.8 Hz, 1H), 8.20 (s, 1H), 7.67 (d, J=9.0 Hz, 1H). MS (M+H, 164).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[N:9]=[C:8]([Cl:10])[NH:7][C:6]=2[CH:11]=1.C(N(CC)CC)C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>C1COCC1.C(OCC)(=O)C>[Cl:10][C:8]1[NH:7][C:6]2[CH:11]=[C:2]([NH:1][C:27]([C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[C:24]([F:23])([F:34])[F:35])=[O:28])[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]=2[N:9]=1
Reactant: COC(=O)c1cc(N)cc2[nH]c(Cl)nc12
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(Cl)nc12
Reaction time: 1 h

Procedure:
To a stirring solution of methyl 6-amino-2-chloro-1H-benzimidazole-4-carboxylate (400 mg, Example 135, Step 3) and triethylamine (209 μL) in THF (18 mL), 2-(trifluoromethyl)benzoyl chloride (316 μL) was dropped slowly under ice-cooling. After 1 hour, the reaction mixture was diluted with ethyl acetate, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crude methyl 2-chloro-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxylate. This was dissolved in THF (15 mL) and MeOH (7 mL), 1N aqueous lithium hydroxide solution (9 mL) was added, and it was stirred at room temperature overnight. THF and MeOH were removed under reduced pressure. To the residue was added water, and it was neutralized with 1N hydrochloric acid under ice-cooling. The precipitation was collected by filtration to obtain crude 2-chloro-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxylic acid. This was dissolved in THF (10 mL), 40% aqueous dimethylamine solution (7 mL) was added, and it was stirred at 120° C. for 14 hours. The reaction mixture was cooled to room temperature, and THF was removed under reduced pressure. To the residue was added water, and the pH was adjusted to 3-4 with 1N hydrochloric acid under ice-cooling. The precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain the titled compound (589 mg) as slightly yellow solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[N:6]=[CH:5]2.[C:18]1([C:24]2[O:32][C:31]3[CH:30]=[CH:29][NH:28][C:27](=[O:33])[C:26]=3[CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+].N[C@@H]1CCCC[C@H]1N>CN1CCCC1=O.[Cu]I>[C:18]1([C:24]2[O:32][C:31]3[CH:30]=[CH:29][N:28]([C:2]4[CH:3]=[C:4]5[C:8](=[CH:9][CH:10]=4)[N:7]([CH2:11][CH2:12][N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)[N:6]=[CH:5]5)[C:27](=[O:33])[C:26]=3[CH:25]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Ic1ccc2c(cnn2CCN2CCCC2)c1
Reactant: O=c1[nH]ccc2oc(-c3ccccc3)cc12
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: O=c1c2cc(-c3ccccc3)oc2ccn1-c1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 110 °C
Reaction time: 48 h
Yield: 7.6 %

Procedure:
A solution of 5-iodo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazole (0.316 g, 0.923 mmol) in N-methylpyrrolidone (NMP) (2.7 mL) was added to 2-phenyl-5H-furo[3,2-c]pyridine-4-one (0.232 g, 1.10 mmol), Cs2CO3 (0.601 g, 1.84 mmol), trans-1,2-diaminocyclohexane (21.2 mL, 0.184 mmol) and CuI (0.210 g, 1.10 mmol) and deoxygenated with argon for 30 minutes. After stirring at 110° C. for 48 hours, the reaction mixture was cooled and diluted with MeOH (3 mL) and a solution of 7:1 MeOH/NH4OH (3 mL) and filtered through Celite. The filtrate was concentrated and then suspended with CH2Cl2 (20 mL) and water (20 mL) and extracted with CH2Cl2 (4×50 mL). The combined organics were dried (Na2SO4) and concentrated. Purification by flash chromatography (silica gel, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) yielded the title compound (29.6 mg, 7%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 7.80 (d, J=7.5 Hz, 2H), 7.73 (d, J=2.0 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.47-7.42 (m, 3H), 7.37-7.33 (m, 3H), 6.68 (d, J=7.5 Hz, 1H), 4.60 (t, J=7.0 Hz, 2H), 3.06 (br m, 2H), 2.62 (br m, 4H), 1.81 (br m, 4H); ESI MS m/z 425 [M+H]+; HPLC (Method A) 96.4% (AUC), tR=15.0 mm.