Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24](=[S:26])[NH2:25])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH:28]1[C:33](=O)[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24]4[S:26][C:28]5[CH2:29][NH:30][CH2:31][CH2:32][C:33]=5[N:25]=4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC(N)=S
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1nc2c(s1)CNCC2
Temperature: 60 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
To a solution of 2-{[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}ethanethioamide (0.300 g, 0.733 mmol) in DMF (5 mL) was added 1,1-dimethylethyl 3-bromo-4-oxopiperidine-1-carboxylate (0.310 g, 1.11 mmol). The solution was stirred at 60° C. for 72 h. An additional 0.100 g (0.360 mmol) of 1,1-dimethylethyl 3-bromo-4-oxopiperidine-1-carboxylate was added to the reaction mixture, which was then heated at 60° C. for an additional 24 h. The solvent was removed in vacuo and the crude reaction mixture was purified via column chromatography (SiO2, 50% hexanes/ethyl acetate). This intermediate was then subjected to 10% TFA in CH2Cl2 at room temperature. After removal of the solvent, the crude amine salt was taken up in fresh MeOH and treated with Bio-Rad AG 1-X8 resin hydroxide form until pH 8. Filtration and concentration in vacuo provided 0.247 g (69%) of N-(3,4-dichlorophenyl)-6-(methyloxy)-7-[(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-ylmethyl)oxy]quinazolin-4-amine as a brown oil.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([OH:11])[CH2:5][CH2:6][CH:7](O)[CH:8]=C.I(O)(=O)(=O)=[O:13].[OH2:17]>>[OH:17][CH:1]1[CH2:2][CH:3]2[CH:7]([CH:6]=[CH:5][C:4]2=[O:11])[CH2:8][O:13]1
Reactant: C=CC(O)CCC(O)CCC
Reactant: O
Reactant: [O-][I+3]([O-])([O-])O
Product: O=C1C=CC2COC(O)CC12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
At first, 205 mg of compound (III) is dissolved in 3 ml of water, and 202 mg of periodic acid is added thereto. The mixture is stirred at room temperature for 1 hour and 30 minutes, and then chromatographically purified (HP-20SS 20 ml, water : methanol=4:1) to obtain 101 mg of compound (I) (59.5%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:30])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[CH:14][CH:13]=3)=[C:9]([C:27]#[N:28])[CH:8]=[N:7][N:6]2[CH:29]=1.[C:31]([NH:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](O)=[O:39])(=[O:33])[CH3:32].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:31]([NH:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([NH:2][C:3]1[C:4]([CH3:30])=[C:5]2[C:10]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[CH:16][CH:17]=3)=[C:9]([C:27]#[N:28])[CH:8]=[N:7][N:6]2[CH:29]=1)=[O:39])(=[O:33])[CH3:32]
Reactant: CC(=O)Nc1cccc(C(=O)O)c1
Reactant: COc1ccccc1Oc1ccc(Nc2c(C#N)cnn3cc(N)c(C)c23)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1ccc(Nc2c(C#N)cnn3cc(NC(=O)c4cccc(NC(C)=O)c4)c(C)c23)cc1
Yield: 69.5 %

Procedure:
A solution of 430F (42 mg, 0.10 mmol), 3-acetylamino-benzoic acid (27 mg, 0.15 mmol), PyBrop (73 mg, 0.15 mmol) and DIEA 70 μl, 0.40 mmol) in DMF (1 ml) was stirred at room temperature for 16 h under argon. Treated with EtOAc (30 ml), the mixture was washed with H2O (3×10 ml) and brine (10 ml), dried with Na2SO4. Removal of the solvent followed by flash chromatography of the residue on silica gel (50% EtOAc-CH2Cl2) gave 430 (38 mg, 70%) as a light yellow solid. It has a retention time of 6.16 min (standard LC1 method, 8 min run). MS Found: (M+H)+=547.2
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:19]=[C:9]2[N:10]=[C:11](S(C)(=O)=O)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CC#N>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:19]=[C:9]2[N:10]=[C:11]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)nc2n1
Solvent: CC#N
Product: Nc1nc(N2CCNCC2)nc2nc(-c3ccco3)nn12
Temperature: 25 °C

Procedure:
18 mmol of 2-furan-2-yl-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (prepared as described in Caulkett et al., J. Chem. Soc. Perkin Trans I. 801-808 (1995)) was suspended in 50 mL of CH3CN along with 5 eq. of piperazine. The reaction mixture was stirred under reflux for 2 hours. It was then cooled to room temperature and concentrated under reduced pressure. The residue was taken up in CH2Cl2 and washed with H2O, brine, dried with Na2SO4, and concentrated under reduced pressure. The resulting crude product was purified by chromatography (95% CH2Cl2, 4% MeOH, 1% Et3N) to afford 2-furan-2-yl-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine. 1H NMR (DMSO-d6) δ 8.2 (br s, 2H), 7.85 (d, J=1.0 Hz, 1H), 7.07 (d, J=3.6 Hz, 1H), 6.68 (dd, J=3.6 Hz. 1.0 Hz, 1H), 3.20-2.75 (m, 8H) ppm. MS: m/z=287 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([CH:13]=[N:14][OH:15])=[C:11]([I:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[Cl:26]N1C(=O)CCC1=O.O>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([Cl:26])=[N:14][OH:15])=[C:11]([I:20])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C=NO)c(I)cc1OCc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(Cl)=NO)c(I)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 4-benzyloxy-2-iodo-5-methoxy-benzaldehyde oxime (reference example 2-1) (12.8 g) and N,N-dimethylformamide (110 mL) was added N-chlorosuccinimide (4.9 g) at room temperature. After stirring at room temperature for 20 minutes, water and ethyl acetate were added to the mixture under ice-bath cooling. The separated organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4-benzyloxy-N-hydroxy-2-iodo-5-methoxy-benzimidoylchloride.
Reaction SMILES: C([O:8][C:9]1[CH:45]=[CH:44][C:12]([O:13][C:14]2[CH:43]=[CH:42][C:17]([C:18]([NH:20][CH2:21][C:22](=[O:41])[N:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:40])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])[CH2:25][CH2:24]3)=[O:19])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CCCCCC>[Pd].CO>[OH:8][C:9]1[CH:45]=[CH:44][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:20][CH2:21][C:22](=[O:41])[N:23]3[CH2:24][CH2:25][N:26]([C:29](=[O:40])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])[CH2:27][CH2:28]3)=[O:19])=[CH:42][CH:43]=2)=[CH:11][CH:10]=1
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CO
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(Oc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.1 %

Procedure:
Pd/C (20 mg in 3 drops of water) was added to 4-(4-benzyloxy-phenoxy)-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide (80 mg, 0.13 mmol) in MeOH (10 mL). The resulting reaction mixture was stirred at room temperature under an atmosphere of hydrogen for 3 hours. The reaction mixture was then filtered through a bed of celite. The methanol was removed to afford 80 mg of crude product. Purification by column chromatography (using silica gel of mesh size of 60-120 and 80/20 EtOAc:Hexane as the eluent) afforded 33 mg (48% yield) of 4-(4-hydroxy-phenoxy)-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide LC-MS purity: 93%. 1H NMR (DMSO-D6): δ 9.4 (s, 1H), 8.5 (t, 1H), 7.9-7.5 (m, 6H), 6.8-7 (m, 5H), 4.2 (d, 2H), 3.5 (m, 6H), 3.1 (m, 2H).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH3:11])[C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([CH:22](Br)[CH3:23])[CH3:21]>CN(C)C=O>[CH3:11][N:8]1[C:6]2[N:7]=[C:2]3[S:1][CH:22]([CH3:23])[CH:20]([CH3:21])[N:3]3[C:4](=[O:12])[C:5]=2[CH:10]=[N:9]1
Reactant: CC(Br)C(C)Br
Reactant: Cn1ncc2c(=O)[nH]c(S)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1Sc2nc3c(cnn3C)c(=O)n2C1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 12.1 %

Procedure:
In 200 ml of dimethylformamide was dissolved 10.0 g (54.9 mmol) of 4,5-dihydro-6-mercapto-1-methylpyrazolo[3,4-d]pyrimidin-4(1H)-one [Helv. Chim. Acta, 42, 349 (1959)], and 15.2 g (110 mmol) of potassium carbonate and 10.1 ml (82.3 mmol) of 2,3-dibromobutane were added to the solution, followed by stirring at 80° C. for 3 hours. After evaporation of the solvent, the residue was subjected to partition between chloroform and water, and the chloroform layer was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform to give 1.57 g (12%) of Compound 41. The compound was recrystallized from ethyl acetate/hexane for purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[F:16])[C:12]([F:18])([F:17])[O:11][C:10]3([F:20])[F:19])[N:5]=[C:4]([C:21]#[N:22])[CH:3]=1.[F:23][C:24]([F:29])([F:28])[S:25]([O-])=O.[Na+].S(C1C=CC(C)=CC=1)(O)(=O)=O.CNC.S(Cl)(Cl)=O>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[F:16])[C:12]([F:18])([F:17])[O:11][C:10]3([F:20])[F:19])[N:5]=[C:4]([C:21]#[N:22])[C:3]=1[S:25][C:24]([F:29])([F:28])[F:23]
Reactant: N#Cc1cc(N)n(-c2cc3c(cc2F)C(F)(F)OC3(F)F)n1
Reactant: O=S([O-])C(F)(F)F
Agent: CNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: N#Cc1nn(-c2cc3c(cc2F)C(F)(F)OC3(F)F)c(N)c1SC(F)(F)F
Temperature: 55 °C
Reaction time: 10 h
Yield: 28.7 %

Procedure:
To a suspension wherein 5-amino-3-cyano-1-(6-fluoro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-5-yl)pyrazole (900 mg, 2.85 mmol), sodium trifluoromethanesulfinate (890 mg, 5.70 mmol) and dimethylamine tosylate (1.550 g, 7.13 mmol) are in toluene (5 ml), thionyl chloride (678 mg, 5.70 mmol) was added dropwise under ice cooling over a period of about 10 minutes and stirred at 50 to 60° C. for 10 hours. After allowing time to cool, the reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to give 340 mg of 5-amino-3-cyano-1-(6-fluoro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-5-yl)-4-trifluoromethylsulfenylpyrazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>C(Cl)Cl>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH:3]=[N:4][CH:5]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1cncc(Br)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 15 h
Yield: 71 %

Procedure:
3-Amino-5-bromo pyridine (XXII) (1 eq) was dissolved in DCM and cooled to 0° C. before adding pyridine (2.2 eq) and isobutyryl chloride (XXIII) (1.1 eq). The reaction mixture was stirred at room temperature for 15 h until TLC showed the reaction was complete. The reaction mixture was diluted with DCM and washed with water. The organic extract was dried, concentrated and purified by column chromatography using silica gel (100-200 mesh) to afford N-(5-bromopyridin-3-yl)isobutyramide (XXIV) as an off-white solid, (71% yield). 1H NMR (CDCl3) δ ppm 8.55-8.35 (m, 3H), 7.32 (s, 1H), 2.59-2.48 (m, 1H), 1.28-1.27 (d, 6H); ESIMS found C9H11BrN2O m/z 243.05(M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25](=[O:59])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[C:39]2[CH:44]=[C:43]([C:45](=[O:58])[NH:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:57])([F:56])[F:55])[CH:49]=3)[CH:42]=[CH:41][N:40]=2)[N:20]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13]C(C)(C)C)=O)[CH2:7][CH2:6]1.Cl[CH2:61]Cl.C(O)(C(F)(F)F)=O.C(N(CC)C(C)C)(C)C.C(Cl)(=O)C>ClCCl>[C:11]([N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][N:2]([CH2:18][C:19]2[N:20]=[C:21]([C:25]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]4)=[CH:29][C:28]=3[C:39]3[CH:44]=[C:43]([C:45](=[O:58])[NH:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:55])([F:57])[F:56])[CH:49]=4)[CH:42]=[CH:41][N:40]=3)=[O:59])[CH:22]=[CH:23][CH:24]=2)[CH3:1])[CH2:10][CH2:9]1)(=[O:13])[CH3:61]
Reactant: ClCCl
Reactant: CN(CCN1CCN(C(=O)OC(C)(C)C)CC1)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Product: CC(=O)N1CCN(CCN(C)Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)n2)CC1
Temperature: 0 °C

Procedure:
The tert-butoxycarbonyl group of tert-butyl 4-(2-(methyl((6-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)pyridin-2-yl)-methyl)amino)ethyl)piperazine-1-carboxylate 52 was cleaved by stirring for 1 hour in 1:1 dichloromethane/TFA and the resultant amine converted to the free base by partitioning between ethyl acetate and aqueous sodium bicarbonate solution. Into a 50-mL round-bottom flask, was placed a solution of this amine (110 mg, 0.15 mmol, 1.00 equiv) in dichloromethane (5 mL), and N,N-diisopropylethylamine (30 mg, 0.23 mmol, 1.50 equiv). This was followed by dropwise addition of a solution of acetyl chloride (14.4 mg, 0.18 mmol, 1.20 equiv) in dichloromethane (1 mL) with stirring at 0° C. The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 90.3 mg (44%) of as a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.77 (s, 1H), 9.56 (t, J=5.7 Hz, 1H), 9.06 (d, J=5.1 Hz, 1H), 8.49 (d, J=8.7 Hz, 1H), 8.28 (s, 1H), 8.15-8.09 (m, 2H), 7.90-7.79 (m, 2H), 7.72-7.56 (m, 5H), 7.34 (s, 1H), 4.64 (d, J=5.7 Hz, 2H), 4.20 (s, 2H), 3.56 (s, 4H), 3.34 (s, 4H), 3.18-2.95 (m, 7H), 2.56-2.49 (m, 4H), 1.96 (s, 3H), 1.74 (s, 4H), 1.60 (d, J=4.2 Hz, 2H). MS (ES, m/z): 757 [M+H]+.
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6](=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[C:9]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=1.[C:26]([O:30][C:31](=[O:38])[CH2:32][C@H:33]([NH2:37])[C:34]([NH2:36])=[O:35])([CH3:29])([CH3:28])[CH3:27].N1C=CC=CC=1>C(OCC)(=O)C>[CH3:4][O:5][C:6](=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([S:13](=[O:15])(=[O:14])[NH:37][C@H:33]([C:34](=[O:35])[NH2:36])[CH2:32][C:31]([O:30][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:38])=[C:9]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(N)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(N)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
To a room temperature CH2Cl2 solution (400 mL) of 3-benzyloxy-4-chlorosulfonyl-benzoic acid methyl ester (11.43 g, 33.50 mmol) was added (S)-3-amino-succinamic acid tert-butyl ester (6.32 g, 33.50 mmol) and pyridine (10.80 mL). The reaction mixture was allowed to stir for 12 h at room temperature. The reaction was then diluted with ethyl acetate and washed with 5% citric acid and saturated NaHCO3. The organic phase was dried (MgSO4), and then the solvent was removed under vacuum. The resulting crude product was purified using silica gel flash chromatography (3% MeOH in CH2Cl2). 3-Benzyloxy-4-((S)-2-tert-butoxycarbonyl-1-carbamoyl-ethylsulfamoyl)-benzoic acid methyl ester was obtained in 45% yield (7.40 g) as an off white foam. MS m/z 491.2 (M−1).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH:53]1[CH2:58][CH2:57][CH:56]([NH:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]([F:69])([F:68])[F:67])[CH2:55][CH2:54]1>CN(C=O)C.O>[O:13]=[C:11]([N:53]1[CH2:54][CH2:55][CH:56]([NH:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]([F:67])([F:68])[F:69])[CH2:57][CH2:58]1)[CH2:10][NH:9][C:7]([C:4]1[CH:3]=[CH:2][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)=[O:8]
Reactant: FC(F)(F)c1ccccc1NC1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid (0.03219 g, 0.00012 mol) in DMF (1 mL), was added, DIPEA (0.065 g, 0.0005 mol), HOBt (0.017 g, 0.00012 mol) and EDCI.HCl (0.2689 g, 0.00013 mol) at ambient temperature. After 2 minutes piperidin-4-yl-(2-trifluoromethyl-phenyl)-amine dihydrochloride (0.04 g, 0.00012 mol) was and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with cold water, and the resulting precipitate was isolated by filtration. The solid was recrystallized from a mixture of ethyl acetate and hexane to afford 0.042 g (61%) of biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-phenylamino)-piperidin-1-yl]-ethyl}-amide. LCMS: 482.1 (M+1)+, 97.99%, 1H NMR (DMSO-d6): δ 8.6 (t, 1H), 8.0 (m, 2H), 7.78-7.5 (m, 4H), 7.6-7.4 (m, 5H), 7.0 (d, 1H), 6.7 (t, 1H), 4.7 (d, 1H), 4.3 (m, 1H), 4.2 (d, 2H), 4.0-3.7 (m, 2H), 3.2 (m, 2H), 2.8 (m, 2H), 2.0 (m, 3H), 1.6-1.2 (m, 4H).
Reaction SMILES: [CH:1]1([CH2:11][CH2:12]O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.[N:14]1([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[C@@H:1]1([CH2:11][CH2:12][N:17]2[CH2:18][CH2:19][N:14]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH2:15][CH2:16]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1
Reactant: NS(=O)(=O)c1ccc(N2CCNCC2)cc1
Reactant: OCCC1OCCc2ccccc21
Product: NS(=O)(=O)c1ccc(N2CCN(CC[C@H]3OCCc4ccccc43)CC2)cc1

Procedure:
Following the general procedure for EXAMPLE 49 and making non-critical variations 2-(isochroman-1-yl)ethanol (LXXIX, (+)-enantiomer, 0.6045 g) and 4-(piperazin-1-yl)benezenesulfonamide (IV, 0.9824 g ) are combined to give the title compound, mp 189°-190°; MS (m/z) 401; [α]D +48 (c 0.877, DMF); IR (mineral oil) 1162, 1594, 1150, 1101, 614 cm-1.
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:6])[CH2:2][CH3:3].[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)#[N:18].C(O)(=O)C.[K+].[Br-]>C(O)C>[CH2:14]([N:7]1[C:8](=[O:9])[C:10]2[NH:13][C:23]([C:22]3[CH:25]=[CH:26][C:19]([C:17]#[N:18])=[CH:20][CH:21]=3)=[N:12][C:11]=2[N:4]([CH2:1][CH2:2][CH3:3])[C:5]1=[O:6])[CH2:15][CH3:16]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(-c3ccc(C#N)cc3)nc2n(CCC)c1=O
Temperature: 0 °C

Procedure:
1,3-Dipropyl-8-(4-cyanophenyl)xanthine was prepared by treatment of 1,3-dipropyl-5,6-diaminouracil (6.37 g, 28.15 mmol) with 4-cyanobenzaldehyde (3.72 g, 28.37 mmol) in absolute ethanol (175 ml) with acetic acid (5 ml) heated at reflux for 2 hours. The reaction mixture was then cooled to 0° C., and the resulting precipitate collected, and recrystallized from ethanol yielding a white solid (8.1 g, 24.0 mmol, 85%) IR (KBr) 3142 (N--H), 2965 (C--H), 2232 (C=N), 1695 (C=O), 1651 (C=O) cm-1 ; 1H NMR (DMSO d6) δ8.2 (d,J=8 Hz, 6H). Anal. Calcd. for C18H19N4O21, MW. 337.38: C, 64.08; H, 5.68; N, 20.76. Found: C, 64.15, H, 5.69; N, 20.72.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][C:17]([F:30])([F:29])[CH2:18][O:19][C:20]1[N:25]=[CH:24][C:23]([CH:26]([NH2:28])[CH3:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[Cl:14][C:13]1[C:3]2[CH2:2][N:28]([CH:26]([C:23]3[CH:24]=[N:25][C:20]([O:19][CH2:18][C:17]([F:30])([F:16])[F:29])=[CH:21][CH:22]=3)[CH3:27])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(c1ccc(OCC(F)(F)F)nc1)N1Cc2c(ccnc2Cl)C1=O
Temperature: 25 °C
Yield: 32.3 %

Procedure:
A mixture (suspension) of ethyl 3-(bromomethyl)-2-chloroisonicotinate (698 mg, 2.5 mmol, Step-1), 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (643 mg, 2.5 mmol, Amine-1, single enantiomer) and cesium carbonate (3.3 g, 10.0 mmol) in THF (20 mL) is heated at refluxed temperature overnight. After cooling to rt, the reaction mixture is filtered through a pad of Celite™, and washed with EtOAc. The filtrate is concentrated to give a brown suspension. The residue is purified by column chromatography on NH-gel eluting with n-hexane/EtOAc (4:1) to give 300 mg (32% yield) of the title compound as clear brown oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH3:9][C@@H:10]1[N:15]([CH3:16])[CH2:14][CH2:13][N:12]([CH2:17][CH2:18][OH:19])[CH2:11]1.[OH-].[K+]>CS(C)=O.O>[CH3:9][C@@H:10]1[N:15]([CH3:16])[CH2:14][CH2:13][N:12]([CH2:17][CH2:18][O:19][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:11]1
Reactant: Nc1cc(Cl)ccn1
Reactant: C[C@H]1CN(CCO)CCN1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H]1CN(CCOc2ccnc(N)c2)CCN1C
Temperature: 95 °C
Yield: 49.7 %

Procedure:
4-Chloropyridin-2-amine (0.500 g, 3.89 mmol), (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol (1.23 g, 7.78 mmol), and crushed potassium hydroxide (0.546 g, 9.72 mmol) were combined in 8 mL of DMSO in a pressure tube and heated to 95° C. for 16 hours. The mixture was then diluted with water (100 mL), extracted 2 times with EtOAc, extracts washed with brine, dried and concentrated under reduced pressure. Column chromatography (5% MeOH/DCM) afforded 0.484 g (50%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11](NCC(OC)=O)=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.ClC([O:30][CH2:31][CH:32](C)[CH3:33])=O.[BH4-].[Na+]>O1CCCC1C([O-])=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][C:11](/[CH:33]=[CH:32]/[CH2:31][OH:30])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)CNc1ccn(-c2ccc(OC)cc2)n1
Reactant: CC(C)COC(=O)Cl
Agent: O=C([O-])C1CCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(-n2ccc(/C=C/CO)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112.5 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-3-[E-2-(carboxy)ethenyl]-1H-pyrazole-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)carboxyamide (1.0 g, 1.93 mmol) in 20 mL of tetrahydrofuran at-20° C. was added triethylamine (0.27 mL, 1.93 mmol) and iso-butyl chloroformate (0.25 mL, 1.93 mmol). This mixture was stirred for 30 min and then there was added sodium borohydride (0.22 g, 5.78 mmol) in a minimal amount of water. The reaction mixture was stirred with slow warming to room temperature for 1 h and then was quenched with 10% aq HCl. After diluting with ethyl acetate, the organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and lyophilized to afford 0.5 g (52%) of the title compound as a white powder. LRMS (ES+): 504.9 (M+H)+.