Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:16][CH2:17]2)=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(CN2CCN(c3ccncc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CN2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
1-(4-Methoxycarbonylphenylmethyl)-4-(4-pyridyl)piperazine (4.5 g) was dissolved in methanol (50 ml) and treated at ambient temperature with 2M aqueous sodium hydroxide (36 ml). The resulting solution was stirred at room temperature for 3 hours and concentrated by evaporation to an aqueous solution of the sodium salt of the acid. This solution was just acidified with glacial acetic acid (4.3 ml) to give a white precipitate which was collected by filtration, washed with water and dried to give 1-(4-carboxyphenylmethyl)-4-(4-pyridyl)piperazine in 90% yield.
Reaction SMILES: O=C(N[C@@H](C1C=CC=CC=1)C)C([C@@H](NC(=O)[O:12][CH2:13][C:14]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22](Cl)[N:21]=2)[CH2:17][CH2:16][CH2:15]1)CCCC)=O.[CH3:37][N:38]1[CH2:43][CH2:42]C[CH2:40][CH2:39]1.C[N:45](C)C=O>>[CH3:37][N:38]1[CH2:43][CH2:42][N:45]([C:22]2[N:21]=[C:20]([O:19][CH2:18][C:14]3([CH2:13][OH:12])[CH2:15][CH2:16][CH2:17]3)[CH:25]=[CH:24][N:23]=2)[CH2:40][CH2:39]1
Reactant: CN1CCCCC1
Reactant: CN(C)C=O
Reactant: CCCC[C@H](NC(=O)OCC1(COc2ccnc(Cl)n2)CCC1)C(=O)C(=O)N[C@H](C)c1ccccc1
Product: CN1CCN(c2nccc(OCC3(CO)CCC3)n2)CC1
Temperature: 90 °C

Procedure:
To a solution of 0.5 g (2.19 mmol) of (1-{[(2-chloro-4-pyrimidinyl)oxy]methyl}cyclobutyl)methyl (1S)-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate in 5.0 mL of N,N-dimethylformamide was added 0.36 mL (3.28 mmol) of N-methylpiperidine and the contents heated at 90° C. for 3 h. The reaction was concentrated under vacuum and taken directly to the next step. 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=6 Hz, 1H), 5.97 (d, J=6 Hz, 1H), 4.41 (s, 2H), 3.81 (t, J=5 Hz, 4H), 3.63 (s, 2H), 2.45 (t, J=5 Hz, 4H), 2.35 (s, 3H), 1.97-1.91 (m, 6H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].[C:25](Cl)(=O)C(Cl)=O.CO.N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH3:25])=[O:13])(=[O:6])=[O:7]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 83.1 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (0.73 g, 1.9 mmol) dissolved in 20 mL of anhydrous dichloromethane (DCM) was reacted with 1.1 mL (2.2 mmol) of oxalyl chloride (2.0 M in DCM). After the reaction was completed, a solution of 2 mL (1.58 g, 49.4 mmol) of methanol (MeOH) and 0.16 mL of pyridine (0.15 g, 1.9 mmol) in 10 mL of anhydrous dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.62 g (83% yield) of the title compound (24a) as a colorless oil. Rf=0.59 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=1.06 (s, 3H), 1.07 (s, 3H), 2.25-2.32 (m, 2H), 3.22-3.26 (m, 2H), 3.65 (t, J=6.0 Hz, 2H), 3.77 (s, 3H), 3.87 (s, 1H), 3.98 (d, J=9.2 Hz, 1H), 4.21 (d, J=9.6 Hz, 1H), 4.36 (d, J=11.2 Hz, 1H), 4.63 (d, J=11.2 Hz, 1H), 7.32-7.36 (m, 5H) ppm. MS (ESI) m/z 392.90 (M+H)+, 414.91 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]1([CH:19]=O)[CH2:18][CH2:17]1.C([BH3-])#N.[Na+].Cl>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][CH:16]2[CH2:18][CH2:17]2)[CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CC1CC1
Reactant: CNC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(CC1CC1)C1CCN(Cc2ccccc2)CC1
Temperature: 45 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
18.9 g of 1-benzyl-4-methylaminopiperidine in the form of the oil prepared in a) are taken up in 250 ml of methanol, combined with 8.3 g of cyclopropane carboxaldehyde and 11.3 g of sodium cyanoborohydride. The mixture is stirred for 5 hours at 40-50° C., then for about 16 hours at ambient temperature. It is then acidified with 2 N hydrochloric acid, evaporated to dryness in vacuo and the residue is taken up in water. It is washed with ether, made alkaline with concentrated sodium hydroxide solution and extracted with ether/ethyl acetate. The organic extract is dried over sodium sulphate and freed from solvents in vacuo. 22.7 g of 1-benzyl-4-(cyclopropylmethyl-methyl-amino)-piperidine are obtained as a yellowish oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].[C:11](OC(=O)C)(=[O:13])[CH3:12]>CN(C)C1C=CN=CC=1>[C:11]([O:5][CH2:4][C:3]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=1[CH3:1])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C)c1CO
Agent: CN(C)c1ccncc1
Product: CC(=O)OCc1c(C)cccc1C
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A mixture of 2,6-dimethylbenzyl alcohol (17.1 g) and acetic anhydride (14.2 ml) was stirred at 70° C. for 5 hours during which time to the mixture was added 4-dimethylaminopyridine (17 mg). After cooling, the reaction mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate, and the solution was washed with water twice. The organic layer was dried over magnesium sulfate and evaporated in vacuo to give 2,6-dimethylbenzyl acetate (22.50 g) as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[CH:5]=[O:6]
Reactant: C1COCCN1
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=Cc1ccc(N2CCOCC2)c(Br)c1
Yield: 58.2 %

Procedure:
EX-604A) To a pyridine (15 mL) solution of 3-bromo-4-fluorobenzaldehyde (1.0 g, 4.9 mmol) was added morpholine (0.5 mL, 5.7 mmol) and K2CO3 (0.69 g, 5.0 mmol), and the slurry was refluxed for 18 h. The solvent was removed, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4) and evaporated to a yellow oil. Purification by flash chromatography on silica gel eluting with 15% ethyl acetate in hexane gave 0.77 g (58%) of the desired 3-bromo-4-(4-morpholinyl)benzaldehyde product as an white solid. 1H NMR (CDCl3) δ3.18 (m, 4H), 3.90 (m, 4H), 7.10 (d, 1H), 7.78 (d, 1H), 8.07 (s, 1H), 9.83 (s, 1H).
Reaction SMILES: [C:1]1([C:7](O)([C:9]#[CH:10])C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1[CH:14]=[N+:15]([O-:23])[CH:16]=[C:17]([C:19]([OH:22])([CH3:21])[CH3:20])[CH:18]=1.[CH:24]([NH:27][C:28]([C:30]1[C:39](=[O:40])[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:32](C2C=CC=C(Br)C=2)[CH:31]=1)=[O:29])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:28]([C:30]1[C:39](=[O:40])[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:32]([C:5]2[CH:4]=[CH:3][CH:2]=[C:1]([C:7]#[C:9][C:10]3[CH:14]=[N+:15]([O-:23])[CH:16]=[C:17]([C:19]([OH:22])([CH3:21])[CH3:20])[CH:18]=3)[CH:6]=2)[CH:31]=1)=[O:29])([CH3:25])[CH3:26]
Reactant: CC(C)(O)c1cc(Br)c[n+]([O-])c1
Reactant: C#CC(C)(O)c1ccccc1
Reactant: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Product: CC(C)NC(=O)c1cn(-c2cccc(C#Cc3cc(C(C)(C)O)c[n+]([O-])c3)c2)c2ncccc2c1=O

Procedure:
Following the procedure of EXAMPLE 15, but substituting N-isopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from EXAMPLE 5 for 2-phenyl-3-butyn-2-ol, and 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine-N-oxide from Step 2 for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, the N-isopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.BrC1C=C2[C:19]([C:20]3[CH2:21][CH2:22]N[C:24](C)([C:29]([O:31][CH3:32])=[O:30])[C:25]=3N2)=[CH:18][CH:17]=1.BrC1C=C2C(C3CCNC(C)(C(OCC)=[O:49])C=3N2)=CC=1.BrC1C=C2C(C3CCNC(C(OCC)=O)C=3N2)=CC=1.BrC1C=C2C(C3CCNC(C(OCC4C=CC=CC=4)=O)C=3N2)=CC=1>>[CH3:22][CH2:21][C@:20]12[CH2:25][C@:24]([OH:49])([C:29]([O:31][CH3:32])=[O:30])[N:12]3[C:11]4=[C:6]([C:5]5[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]=53)[CH2:7][CH2:8][N:9]([C@@H:10]14)[CH2:17][CH2:18][CH2:19]2
Reactant: CCOC(=O)C1(C)NCCc2c1[nH]c1cc(Br)ccc21
Reactant: COC(=O)C1(C)NCCc2c1[nH]c1cc(Br)ccc21
Reactant: Brc1ccc2c(c1)[nH]c1cnccc12
Agent: CCOC(=O)C1NCCc2c1[nH]c1cc(Br)ccc21
Agent: O=C(OCc1ccccc1)C1NCCc2c1[nH]c1cc(Br)ccc21
Product: CC[C@]12CCCN3CCc4c(n(c5cc(Br)ccc45)[C@@](O)(C(=O)OC)C1)[C@@H]32

Procedure:
The method as claimed in claim 1, wherein the 7-bromo-β-carboline compound of the formula (I) is selected from the group consisting of 7-bromo-1-methyl-1-methoxycarbonyl-1,2,3,4-tetrahydro-β-carboline-7-bromo-1-methyl-1-ethoxycarbonyl-1,2,3,4-tetrahydro-β-carboline, 7-bromo-1-ethoxycarbonyl-1,2,3,4-tetrahydro-β-carboline and 7-bromo-1-benzyloxycarbonyl-1,2,3,4-tetrahydro-β-carboline.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:41])[C:18]=1/[CH:19]=[C:20](\[O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)/[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1>>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH:39][C:36]2[CH:37]=[CH:38][C:33]([C:32]([O:31]/[C:20](/[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)=[CH:19]\[C:18]3[C:17]([Cl:41])=[CH:16][N:15]=[CH:14][C:13]=3[Cl:12])=[O:40])=[CH:34][CH:35]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: COc1ccc(/C(=C/c2c(Cl)cncc2Cl)OC(=O)c2ccc(N)cc2)cc1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(/C(=C/c2c(Cl)cncc2Cl)OC(=O)c2ccc(NS(=O)(=O)c3ccc(C)cc3)cc2)cc1OC

Procedure:
The compound was obtained starting from 4-toluenesulfonyl chloride and 4-amino -benzoic acid (Z)-2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy -phenyl)vinyl ester, following the procedure of Example 16.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:17]([CH3:19])[CH3:18])[CH:13]([OH:16])[C:14]#[N:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:17]([CH3:19])[CH3:18])[CH:13]([O:16][C:26](=[O:28])[CH3:27])[C:14]#[N:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)C(NC(=O)OCc1ccccc1)C(O)C#N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C#N)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Yield: 90.6 %

Procedure:
To a solution containing 3-[(benzyloxycarbonyl)amino]-2-hydroxy-4-methylpentanenitrile (32.0 g, 0.12 mol) and pyridine (59 mL) was added acetic anhydride (73.6 g, 68 mL, 0.72 mol) dropwise at RT. After 3 h the reaction was diluted with ethyl acetate and washed with water. The organic layer was separated, dried (anhydrous magnesium sulfate) and evaporated. The residue was purified by column chromatography (silica get, 1:1 hexane:ethyl acetate) to give 33.08 g (94.0%) of 3-(S)-[(benzyloxycarbonyl)amino]-2-acetoxy-4-methylpentanenitrile as a viscous yellow oil; TLC Rf =0.70 (silica gel, 1:1 hexane:ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:36]=[N:35][N:34]([CH:37]([CH3:39])[CH3:38])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:26](=[O:33])[CH2:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]>CCO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:36]=[N:35][N:34]([CH:37]([CH3:39])[CH3:38])[C:16]=2[N:17]=[C:18]([CH:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:33])[CH2:27][CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])[CH2:22][CH2:21]2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)CCCN(C)C)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CCN(C(=O)CCCN(C)C)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 9.5 h

Procedure:
To a stifled solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(1-(4-(dimethylamino)butanoyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) in EtOH, 10% Pd/C in catalytic amount was added and stirred it at room temperature under hydrogen pressure (bladder pressure) for 3-16 h hr. On completion of reaction, reaction mass was filtered through celite bed, then filtrate was concentrated under reduced pressure to give the desired product. LCMS: 536.40 (M+1)+; HPLC: 83.00% (@ 254 nm) (Rt:4.917); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (s, 1H), 8.75 (t, 1H), 8.27 (s, 1H), 7.52 (s, 1H), 5.89 (s, 1H), 5.20-5.17 (m, 1H), 4.57-4.54 (m, 1H), 4.36 (d, 2H, J=4.8 Hz), 4.01-3.98 (m, 1H), 3.32 (1H merged with DMSO peak), 3.19-305 (m, 2H), 2.72-2.67 (m, 2H), 2.40 (m, 2H), 2.40 (s, 6H) 2.20 (s, 3H), 2.12 (s, 3H), 2.04-1.91 (m, 2H), 1.79-1.63 (m, 4H), 1.48 (d, 6H, J=6.4 Hz).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:18][C:19]2[CH:26]=[CH:25][C:22]([CH3:23])=[CH:21][CH:20]=2)[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Cc1ccc(CBr)cc1
Product: Cc1ccc(CN2N(C3C4CC5CC(C4)CC3C5)C(=O)C2(C)C)cc1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 4-methylbenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: C([NH:3][C@H:4]([C:8]([O-:10])=[O:9])[CH2:5][CH2:6][CH3:7])C.[CH2:11]([O:18][C:19](=[O:23])[C@H:20](Br)[CH3:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:24](N(CC)CC)[CH3:25]>C(#N)C.C(OC(C)C)(C)C.O>[CH2:11]([O:18][C:19](=[O:23])[C@H:20]([CH3:21])[NH:3][C@H:4]([C:8]([O:10][CH2:24][CH3:25])=[O:9])[CH2:5][CH2:6][CH3:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCN(CC)CC
Reactant: CCC[C@H](NCC)C(=O)[O-]
Reactant: C[C@@H](Br)C(=O)OCc1ccccc1
Solvent: CC#N
Solvent: O
Solvent: CC(C)OC(C)C
Product: CCC[C@H](N[C@@H](C)C(=O)OCc1ccccc1)C(=O)OCC
Yield: 407.6 %

Procedure:
To a solution of ethyl-L-norvalinate (IV, 62 g, 0.427 moles) in acetonitrile (300 ml) were added successively benzyl-(R)-2-bromo-propionate (V1, 20 g, 0.0822 moles) and triethyl amine (28 ml, 0.2016 moles). The reaction mixture was refluxed for 7-8 hrs. The excess solvent was removed by distillation under reduced pressure to afford a thick oil. The oil was dissolved in a mixture of diisopropyl ether (80 ml) and water (40 ml). The organic phase was extracted in 10% hydrochloric acid solution (40 ml×2). The combined acidic extracts were made alkaline by addition of an aqueous solution of sodium carbonate. The aqueous phase was again extracted with diisopropyl ether (200 ml×2). The combined organic layer was concentrated under reduced pressure to afford 103 g of the title compound as an oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][S:6][C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])[N:8]=1)C.O.[NH2:25][NH2:26].C(O)C>O>[Cl:13][C:11]1[CH:10]=[C:9]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])[N:8]=[C:7]([S:6][CH2:5][C:4]([NH:25][NH2:26])=[O:3])[N:12]=1
Reactant: NN
Reactant: CCOC(=O)CSc1nc(Cl)cc(Nc2cccc(C)c2C)n1
Solvent: CCO
Solvent: O
Product: Cc1cccc(Nc2cc(Cl)nc(SCC(=O)NN)n2)c1C
Reaction time: 8 h

Procedure:
A mixture of 5.0 g of [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid ethyl ester and 5.0 g of hydrazine hydrate (98%) in 40 ml. of ethanol was allowed to stand overnight at room temperature. Water was added to the mixture until a precipitate appeared. This material was recrystallized from ethanol affording 4.8 g of product, mp. 185°-189°C.
Reaction SMILES: [CH3:1][C:2]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:7]([S:16][C:17]#N)[CH:6]=[CH:5][C:3]=1[NH2:4].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].CI>C(O)C.O>[CH3:1][C:2]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:7]([S:16][CH3:17])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Cc1ccccc1-c1c(SC#N)ccc(N)c1C
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CI
Solvent: CCO
Product: CSc1ccc(N)c(C)c1-c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.0 g (7.9 mmol) of 2-methyl-3-(2-methylphenyl)-4-thiocyanoaniline in 15 mL of ethanol was added dropwise over a 20-min period with stirring to a solution of 2.2 g of sodium sulfide nonahydrate (9.1 mmol) in 5 mL of water. The mixture was stirred at ambient temperature for 2 hours and was then cooled with an ice/salt bath. A solution of 1.5 g (11 mmol) of methyl iodide in 5 mL of ethanol was added with stirring over a 10-min period. The mixture was diluted with water and the resulting mixture was extracted with ether. The ethereal extract was washed with water, dried over sodium sulfate, and concentrated by evaporation under reduced pressure. The 2.0 g of residue was the title compound of about 80 percent purity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][CH:19]([F:36])[C:20]([C:22]1[S:26][C:25]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])=[CH:24][CH:23]=1)=[O:21]>>[F:36][CH:19]([F:18])[C:20]([C:22]1[S:26][C:25]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:15][CH2:14][C:13]([C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:9][CH:10]=2)([CH3:17])[CH3:16])=[O:31])=[CH:24][CH:23]=1)=[O:21]
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cccc(-c2ccc(C(=O)C(F)F)s2)c1
Product: CC(C)(CNC(=O)c1cccc(-c2ccc(C(=O)C(F)F)s2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 34 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 3-(5-(2,2-difluoroacetyl)thiophen-2-yl)benzoic acid as described in example 8 step 6 (60 mg, yield 34%). 1H NMR (400 MHz, DMSO-d6) δ 8.51-8.48 (t, J=6.2 Hz, 1H), 8.19-8.15 (m, 2H), 8.02-7.97 (m, 3H), 7.90-7.88 (m, 1H), 7.84-7.83 (d, J=4.3 Hz, 1H), 7.61-7.57 (t, J=7.8 Hz, 1H), 7.35-7.31 (t, J=8.8 Hz, 2H), 7.16-6.90 (m, 1H), 3.52-3.50 (d, J=6.4 Hz, 2H), 1.29 (s, 6H). MS (ESI) m/z: Calculated for C26H21F3N2O3S: 498.12. found: 499.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)([CH3:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.CS(OS(C)(=O)=O)(=O)=O.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]([CH3:10])=[CH2:9])[N:7]=1
Reactant: CC(C)(O)c1cccc(Br)n1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)c1cccc(Br)n1
Reaction time: 3 h

Procedure:
To a solution of 2-(6-bromopyridin-2-yl)propan-2-ol (Example 2, Step 1) (2.44 g, 11.29 mmol) and methansulfonic anhydride (5.90 g, 33.9 mmol) in dichloromethane (35 mL) was added triethylamine (6.26 mL, 45.2 mmol). After three hours, the reaction mixture was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (25 mL). The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate (25 mL) and brine (2×25 mL), dried over sodium sulfate, filtered, and concentrated. The resulting yellow liquid was purified by silica gel chromatography (2-20% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: [CH:1]1[C:2]([C:10]([O:12][C@@H:13]2[O:18][C@@H:17]3[CH2:19][O:20]C(C4C=C(O)C(O)=C(O)C=4C4C(O)=C(O)C(O)=CC=4C([O:40][C@@H:15]([C@@H:16]3[OH:44])[C@H:14]2[OH:45])=O)=O)=[O:11])=[CH:3][C:4](O)=[C:5]([OH:8])[C:6]=1[OH:7].Cl>>[CH:1]1[C:6]([OH:7])=[C:5]([OH:8])[C:4]2[O:12][C:10](=[O:11])[C:2]3=[CH:1][C:6]([OH:7])=[C:5]([OH:8])[C:4]4[O:12][C:10](=[O:11])[C:2]=1[C:3]=2[C:3]=43.[O:12]=[CH:13][C@@H:14]([C@H:15]([C@@H:16]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:44])[OH:40])[OH:45]
Reactant: O=C(O[C@@H]1O[C@@H]2COC(=O)c3cc(O)c(O)c(O)c3-c3c(cc(O)c(O)c3O)C(=O)O[C@H]([C@H]1O)[C@@H]2O)c1cc(O)c(O)c(O)c1
Agent: Cl
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=c1oc2c(O)c(O)cc3c(=O)oc4c(O)c(O)cc1c4c23
Reaction time: 1 h

Procedure:
Hydrolysis of corilagin with 0.1N HCl was performed for 1 hr and the solution was chromatographed over Sephadex LH-20 using (H2O -MeOH, 10:0-3:7) to give ellagic acid (1H-NMR in DMSO-d6 : δ 7.45, 2H, s), gallic acid (1H-NMR in acetone-d6 : δ 7.14, 2H, s) and glucose (Rf=0.45, cellulose plate, n-BuOH:pyridine:H2O=6:4:3, under aniline hydrogen phthalate spray as brown spot)
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.[F:14][C:15]1([F:20])[CH2:18][CH:17]([NH2:19])[CH2:16]1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:11][C:6]1[C:7]([CH2:8][CH2:9][OH:10])=[C:2]([NH:19][CH:17]2[CH2:18][C:15]([F:20])([F:14])[CH2:16]2)[N:3]=[C:4]([S:12][CH3:13])[N:5]=1
Reactant: NC1CC(F)(F)C1
Reactant: CSc1nc(Cl)c(CCO)c(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(Cl)c(CCO)c(NC2CC(F)(F)C2)n1
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 92.9 %

Procedure:
To a vial containing 2-[4,6-dichloro-2-(methylsulfanyl)pyrimidin-5-yl]ethanol (600 mg, 2.51 mmol) and 3,3-difluorocyclobutylamine (540 mg, 3.76 mmol) in acetonitrile (12.5 mL) was added DIPEA (2.21 mL, 12.5 mmol) at room temperature, and the mixture was stirred at 100° C. in an oil bath for 6.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified via silica gel chromatography using a gradient of EtOAc/heptane (20-40%) to afford the title compound (722.5 mg, 93%) as light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J=5.5 Hz, 1 H), 4.82 (br s, 1 H), 4.38-4.26 (m, 1 H), 3.56-3.47 (m, 2 H), 3.03-2.87 (m, 2 H), 2.83-2.65 (m, 4 H), 2.42 (s, 3 H). m/z (APCI+) for C11H14ClF2N3OS 310.1 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[C:6]([F:21])=[C:7]([C:12]([C:14]2[CH:15]=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=2)=[O:13])[C:8]([Cl:11])=[CH:9][CH:10]=1)[CH2:3][CH3:4].C=O.[C:24](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.[OH-].[Na+].O>[NH2:20][C:17]1[N:16]=[CH:15][C:14]([C:12]([C:7]2[C:8]([Cl:11])=[CH:9][CH:10]=[C:5]([C@H:2]([NH:1][CH3:24])[CH2:3][CH3:4])[C:6]=2[F:21])=[O:13])=[CH:19][CH:18]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccc(N)nc2)c1F
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CC[C@@H](NC)c1ccc(Cl)c(C(=O)c2ccc(N)nc2)c1F
Reaction time: 18 h
Yield: 3.2 %

Procedure:
A mixture of [3-((R)-1-Amino-propyl)-6-chloro-2-fluoro-phenyl]-(6-amino-pyridin-3-yl)-methanone (100 mg, 0.29 mmol), paraformaldehyde (26 mg, 0.87 mmol), sodium triacetoxyborohydride (92 mg, 0.44 mmol) and acetic acid (67 μL, 1.16 mmol) in DCM (0.5 mL) was stirred for 18 h. Chromatographic analysis showed mainly bis-addition peaks, but a small peak for product. Further DCM (5 mL) and water (5 mL) were added and the mixture was made basic with a few drops of 5M NaOH. Separated and aqueous extracted with further DCM (5 mL). The combined organic phase was washed with brine (4 mL), dried (MgSO4), filtered and concentrated. Purified by prep LCMS (basic 3) and concentrated to give (6-Amino-pyridin-3-yl)-[6-chloro-2-fluoro-3-((R)-1-methylamino-propyl)-phenyl]-methanone (3 mg). Dissolved in d6-DMSO (160 uL) and concentration determined by NMR—53 mM. Used as solution for assays. [MH]+ 322.