Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[CH:7][N:6]2[N:9]=[CH:10][N:11]=[C:5]2[C:4]=1[CH2:12][CH2:13][CH3:14].[NH:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:20]1[N:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:12]([C:4]1[C:5]2[N:6]([N:9]=[CH:10][N:11]=2)[CH:7]=[N:8][C:3]=1[CH2:2][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:20]1[N:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][CH:21]=1)[CH2:13][CH3:14]
Reactant: CCCc1c(CBr)ncn2ncnc12
Reactant: N#Cc1cccc(-c2ncc[nH]2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(Cn2ccnc2-c2cccc(C#N)n2)ncn2ncnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 169 (97 mg, 0.38 mmol), 172 (64 mg, 0.38 mmol) and K2CO3 (160 mg) in DMF (4 mL) is stirred at room temperature overnight. Solvent is removed in vacuo. Water (10 mL) is added and the mixture is extracted with ethyl acetate (3×25 mL). The combined organic layers are dried and solvent removed. The crude is purified by PTLC (5% MeOH in methylene chloride) to give the title product (171) as a solid. 1H NMR 9.12 (s, 1H), 8.49 (q, 1H), 8.36 (s, 1H), 7.87 (t, 1H), 7.56 (q, 1H), 7.21 (s, 2H), 6.11 (s, 2H), 3.13–3.19 (m, 2H), 1.71–1.79 (m, 2H), 1.02 (t, 3H).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C:5]([N:7]1[CH2:28][CH2:27][C:10]2[C:11]3[C:16]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=4)=[N:15][CH:14]=[N:13][C:12]=3[S:26][C:9]=2[CH2:8]1)=[O:6].[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>CN(C=O)C>[Cl:25][C:20]1[CH:19]=[C:18]([NH:17][C:16]2[C:11]3[C:10]4[CH2:27][CH2:28][N:7]([C:5](=[O:6])/[CH:4]=[CH:3]/[CH2:2][N:38]5[CH2:39][CH2:40][N:35]([C:30]6[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=6)[CH2:36][CH2:37]5)[CH2:8][C:9]=4[S:26][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: O=C(/C=C/CCl)N1CCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CN(C)C=O
Product: O=C(/C=C/CN1CCN(c2ccccn2)CC1)N1CCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.7 %

Procedure:
To a suspension of Example 59A (80 mg, 0.16 mmol) in DMF (1 mL) was added 1-pyridin-2-ylpiperazine (52 mg, 0.32 mmol), and the mixture was stirred at rt for 3 h and then heated to 50° C. for 4 h. After purification by preparative HPLC, the product crystallized upon trituration with dichloromethane to yield 74 mg (79%) of the title compound.
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C@@H:19](/[CH:20]=[CH:21]/[C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:17][CH2:16][C:15]1=[O:29]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:15](=[O:29])[CH2:16][CH2:17][CH2:18][C@@H:19]1/[CH:20]=[CH:21]/[CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCC(=O)/C=C/[C@H]1CCCC(=O)N1CCCCCCC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCCCC(O)/C=C/[C@H]1CCCC(=O)N1CCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Sodium borohydride (28 mg, 0.74 mmol), followed by MeOH (0.25 mL), was added to a solution of 7-[(R)-2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-heptanoic acid methyl ester (55 mg, 0.15 mmol) in CH2Cl2 (0.75 mL) at 0° C. The mixture was allowed to warm to rt. After 1 h at rt, the reaction was quenched with aqueous HCl (1.0 M, 2 mL) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (10 mL) then dried (Na2SO4), filtered and concentrated in vacuo to afford 55 mg (99%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[N:10]=[N:11][C:12](Cl)=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1.C([O-])(=[O:26])C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:26])[NH:11][N:10]=1
Reactant: CC(C)c1cc(Sc2c(Cl)cc(CC(=O)O)cc2Cl)nnc1Cl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cc(Sc2c(Cl)cc(CC(=O)O)cc2Cl)n[nH]c1=O
Temperature: 100 °C
Yield: 47.8 %

Procedure:
A mixture of [3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-ylsulfanyl)-phenyl]-acetic acid (75) (90 mg, 0.23 mmol) and sodium acetate (66 mg, 0.80 mmol) in glacial acetic acid (2.5 mL) was heated to 100° C. for 7 h. At this time, the reaction was concentrated in vacuo. The residue was slurried three times in a 1:1 solution of methylene chloride:hexanes followed by concentration under vacuum. The resulting solid was diluted with water (100 mL) and was then treated with a 1N aqueous sodium hydroxide solution to adjust the pH between 10-11. This solution was extracted with ethyl acetate. The organics were discarded. The aqueous layer was then acidified to pH=2-3 with a 1N aqueous hydrochloric acid solution. This solution was then extracted with ethyl acetate (2×100 mL). The organics were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried with magnesium sulfate, filtered, and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70:30 hexanes/ethyl acetate with 2% glacial acetic acid) afforded [3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]-acetic acid (76) (41 mg, 17.5%) as a white solid; EI(+)-HRMS m/e calcd for C15H14Cl2N2O3S (M+H)+ 373.0175, found 373.0175. Exact Mass=372.0102; Molecular Weight=373.26
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[O:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)[N:17]=2)=[CH:9][CH:8]=[C:7]([F:26])[C:3]=1[C:4]([NH2:6])=[O:5].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[O:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[N:17]=2)=[CH:9][CH:8]=[C:7]([F:26])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: COc1ccc(-c2coc(COc3ccc(F)c(C(N)=O)c3F)n2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)c1c(F)ccc(OCc2nc(-c3ccc(O)cc3)co2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.3 %

Procedure:
A solution of 2,6-Difluoro-3-[4-(4-methoxy-phenyl)-oxazol-2-ylmethoxy]-benzamide (0.20 g, 0.55 mmol) in 10 ml of DCM was cooled to −78° C. followed by addition of BBr3 (0.10 ml, 2.20 mmol). The reaction mixture was stirred at 25° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), solution of NaHCO3 (20 mL) was added at 0° C. and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.012 g, 6%). 1H NMR (DMSO-d6, 400 MHz): δ 5.35 (s, 2H), 6.82 (d, J=8.40 Hz, 2H), 7.14 (m, 1H), 7.38 (m, 1H), 7.58 (d, J=8.40 Hz, 2H), 7.87 (br s, 1H), 8.15 (br s, 1H), 8.47 (s, 1H) and 9.63 (s, 1H). MS ES+ (347.22), HPLC (method I) Rt=14.00 min.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20](C4C=CC=CC=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[Br:32]C1C=C2C(=C(C(N)=O)C=1)NC=C2C1CCNCC1.C(N(CC)CC)C.ClCCCS(Cl)(=O)=O>>[Br:32][C:20]1[CH:21]=[C:22]2[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=1)[NH:16][CH:15]=[C:14]2[CH:11]1[CH2:12][CH2:13][N:8]([S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])[CH2:9][CH2:10]1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: NC(=O)c1cc(Br)cc2c(C3CCNCC3)c[nH]c12
Agent: O=S(=O)(Cl)CCCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Yield: 52 %

Procedure:
The title compound was prepared according to the general procedure for intermediate 11. 5-bromo-3-(4-piperidinyl)-1H-indole-7-carboxamide (875 mg, 2.72 mmol) was reacted with triethyl amine (2.27 mL, 16.32 mmol) and 3-chloropropylsulfonyl chloride (0.64 mL, 5.44 mmol) to give the title compound (656 mg, 52%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N:13]([CH2:17][CH2:18][Cl:19])[CH2:14][CH2:15][Cl:16])[C:6]([O:8]C)=[O:7]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N:13]([CH2:14][CH2:15][Cl:16])[CH2:17][CH2:18][Cl:19])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(N(CCCl)CCCl)c(OC)c1
Agent: Cl
Product: COc1cc(C(=O)O)ccc1N(CCCl)CCCl
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
Methyl 3-methoxy-4-[bis(2-chloroethyl)amino]benzoate (1.0 g; 3.3 mmol) was added to 20 ml of concentrated hydrochloric acid, followed by stirring for 30 minutes under heating and reflux. The solvent was distilled out under reduced pressure, whereby 707 mg of white powder were obtained (yield: 74%).
Reaction SMILES: CCN(C(C)C)C(C)C.Br[CH2:11][CH2:12][CH2:13][CH2:14]Br.[NH2:16][C:17]1[C:18]([CH3:35])=[N:19][S:20][C:21]=1[NH:22][C:23]([C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27](OC)=[O:28])=[O:24]>CN(C=O)C>[CH3:35][C:18]1[C:17]([N:16]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:21]([N:22]2[C:23](=[O:24])[C:25]3[C:26](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:27]2=[O:28])[S:20][N:19]=1
Reactant: COC(=O)c1ccccc1C(=O)Nc1snc(C)c1N
Reactant: BrCCCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nsc(N2C(=O)c3ccccc3C2=O)c1N1CCCC1
Temperature: 130 °C
Reaction time: 0.67 h

Procedure:
DIEA (332.7 mg, 448.4 μL, 2.574 mmol), 1,4-dibromobutane (555.8 mg, 307.4 μL, 2.574 mmol) was added to a solution of methyl 2-[(4-amino-3-methyl-isothiazol-5-yl)carbamoyl]benzoate (150 mg, 0.5149 mmol) in DMF (4 mL) and the mixture was stirred at 130° C. for 40 min in a microwave. The reaction mixture was concentrated in vacuo to yield 2-(3-methyl-4-(pyrrolidin-1-yl)isothiazol-5-yl)isoindoline-1,3-dione that was used in next step without further purification. MS (ES+) 314.1.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@@H:7]([C@H:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[S:11])[CH3:9])[NH:6][C:5]1=[O:19])[CH3:3].N1C=CN=C1.[CH2:25]([Si:27]([CH2:31][CH3:32])([CH2:29][CH3:30])Cl)[CH3:26]>CN(C)C=O.C(OCC)(=O)C>[CH2:25]([Si:27]([CH2:31][CH3:32])([CH2:29][CH3:30])[O:1][C@@H:2]([C@@H:4]1[C@@H:7]([C@H:8]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[S:11])[CH3:9])[NH:6][C:5]1=[O:19])[CH3:3])[CH3:26]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=S)c1ccc(Cl)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)O[C@H](C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=S)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55 %

Procedure:
(3S,4S)-3-[(1R)-1-Hydroxyethyl]-4-[(1R)-1-p-chlorophenylthiocarbonylethyl]-2-azetidinone (477 mg, 1.51 mmol) is dissolved in dry N,N-dimethylformamide (3 ml), and thereto are added imidazole (260 mg, 3.79 mmol) and triethylchlorosilane (456 mg, 3.0 mmol), and the mixture is stirred at room temperature for five hours. The reaction solution is diluted with ethyl acetate (30 ml) and washed with water. The aqueous layer is extracted with ethyl acetate (20 ml), and the organic layers are combined, washed twice with brine, dried over sodium sulfate, and evaporated to remove the solvent. The resulting oily residue is purified by silica gel chromatography to give (3S,4S)-3-[(1R)-1-triethylsilyloxyethyl]-4-[(1R)-1-p-chlorophenylthiocarbonylethyl]-2-azetidinone (342 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:15][CH:16]=1.[OH-].[Na+]>C1C=CC=CC=1>[C:11]1([CH3:10])[CH:12]=[CH:13][C:14]([S:17]([OH:20])(=[O:18])=[O:19])=[CH:15][CH:16]=1.[CH2:10]([O:8][C:7](=[O:9])[C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[NH2:1])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCOC(=O)[C@@H](N)CC(C)C

Procedure:
Proteinaceous Emulsifier 13 was prepared by using L-leucine in place of L-alanine. Specifically, L-leucine myristyl ester p-toluenesulfonate was synthesized in the same manner as described in Example 18 for the synthesis of an L-alanine ester p-toluenesulfonate, except that L-leucine was used in place of L-alanine. The resulting p-toluenesulfonate was dissolved in 200 ml of benzene, and this solution was treated three times with 300-ml portions of 0.1N NaOH. Thereafter, the benzene layer was isolated and washed thoroughly with water. After washing with water, the benzene layer was isolated and dried overnight over anhydrous sodium sulfate. After drying, the benzene layer was filtered and the resulting benzene solution was evaporated to remove the solvent. Thus, purified L-leucine myristyl ester was obtained in the form of an oily material. Using this ester, an enzymatic reaction was carried out in the same manner as in Example 18 to obtain Proteinaceous Emulsifier 13.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH2:19][CH2:20][NH:21][CH2:22]3)=[CH:5][CH:4]=[N:3]1.O=C1N([S:33]([NH:36][C:37]2[N:42]=[CH:41][CH:40]=[CH:39][N:38]=2)(=[O:35])=[O:34])CCO1.C(N(CC)CC)C>C(#N)C>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH2:19][CH2:20][N:21]([S:33]([NH:36][C:37]2[N:42]=[CH:41][CH:40]=[CH:39][N:38]=2)(=[O:35])=[O:34])[CH2:22]3)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cccc2c1CCNC2
Reactant: O=C1OCCN1S(=O)(=O)Nc1ncccn1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cccc2c1CCN(S(=O)(=O)Nc1ncccn1)C2
Temperature: 130 °C
Yield: 41.7 %

Procedure:
A microwave vial was charged with 5-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (Intermediate O, 55.90 mg, 0.156 mmol), 2-oxo-N-(pyrimidin-2-yl)oxazolidine-3-sulfonamide (Intermediate Q, 96 mg, 0.391 mmol), and acetonitrile (587 μl) to give a suspension. Triethylamine (218 μl, 1.564 mmol) was added resulting in the formation of a yellow solution. The vial was sealed and heated in a microwave reactor for 30 min at 130° C. The mixture was concentrated, then chromatographed on a 12 g silica gel column with 0 to 10% MeOH/DCM to provide 5-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (33.42 mg, 0.065 mmol) as a light-yellow solid. [M+H]+=515.2. 1H NMR (400 MHz, DMSO-d6) δ ppm=11.19 (br. s., 1H), 8.48 (d, J=4.9 Hz, 2H), 7.88 (dd, J=1.4, 8.1 Hz, 1H), 7.83 (br. s, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H), 7.20-7.10 (m, 2H), 7.03 (t, J=4.8 Hz, 1H), 6.89 (dd, J=1.3, 7.4 Hz, 1H), 5.88 (d, J=1.9 Hz, 1H), 4.62-4.49 (m, 2H), 3.59-3.52 (m, 1H), 3.48 (s, 3H), 3.23 (ddd, J=4.3, 8.0, 12.4 Hz, 1H), 2.59 (ddd, J=4.9, 8.3, 16.1 Hz, 1H), 2.28-2.19 (m, 1H).
Reaction SMILES: CC([O:5][C:6](=[O:32])[CH2:7][CH2:8][CH2:9][NH:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:31])[C:17]=2[NH:21][C:22](=[O:30])[CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:12]=1)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:31][C:16]1[C:17]([NH:21][C:22](=[O:30])[CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:10][CH2:9][CH2:8][CH2:7][C:6]([OH:32])=[O:5])[CH:20]=[CH:19]2
Reactant: CC(C)(C)OC(=O)CCCNc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCCNc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Reaction time: 3 h
Yield: 11.4 %

Procedure:
4-[[6-Chloro-5-[(cyclohexylacetyl)amino]-2-quinolinyl]amino]-butanoic acid 1,1-dimethylethyl ester (Example 7 (a)) (200 mg) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added and the mixture stirred for 3 hours. The resultant suspension was evaporated to dryness and recrystallised from acetonitrile to give the title compound (20 mg).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][N:10]2[CH2:20][C:19]3[N:21]4[C:12](=[CH:13][N:14]=[C:15]4[CH:16]=[CH:17][CH:18]=3)[C:11]2=[O:22])[CH2:5][CH2:4]1.C(N(CC)CC)C.FC(F)(F)C(F)(F)C([O:35][C:36](=O)[C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39])=O>C(#N)C>[F:42][C:37]([F:43])([C:38]([F:41])([F:40])[F:39])[C:36]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][N:10]2[CH2:20][C:19]3[N:21]4[C:12](=[CH:13][N:14]=[C:15]4[CH:16]=[CH:17][CH:18]=3)[C:11]2=[O:22])[CH2:5][CH2:4]1)=[O:35]
Reactant: O=C1c2cnc3cccc(n23)CN1CC1CCNCC1
Reactant: O=C(OC(=O)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1c2cnc3cccc(n23)CN1CC1CCN(C(=O)C(F)(F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
In 10 ml of acetonitrile was suspended 687 mg (2.0 mM) of 4,5-dihydro-4-(piperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-one dihydrochloride, followed by addition of 2.23 ml (16.0 mM) of triethylamine and 1.97 ml (10.0 mM) of pentafluoropropionic anhydride in the order mentioned. This mixture was stirred at room temperature for 1 hour and the solvent was then distilled off under reduced pressure. The residue was extracted with 50 ml of chloroform and the organic layer was washed with 50 ml of saturated aqueous NaCl solution and dried over MgSO4. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-ethanol=10:1) to provide 526 mg (yield 63.2%) of the title compound as light-yellow amorphous substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([Cl:9])[CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Bromo-3-chlorophenol (1 g, 4.82 mmol) was dissolved in DMF (10 ml) and K2CO3 (1.332 g, 9.64 mmol) and benzyl bromide (0.630 ml, 5.30 mmol) added. The mixture was stirred under N2 for 1 hr at RT. The mixture was diluted with water (15 mL) and extracted with EtOAc (2×10 mL). The organic fractions were combined, washed with brine (saturated, 1×8 mL), dried over MgSO4, filtered and the volatiles removed in vacuo. The residue was purified by column chromatography on silica gel Biotage 25M, using a gradient eluant of EtOAc/Hexane (0-50%) to afford the title compound. LC/MS (m/z): 297 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1B(O)O.CC(C)([O-])C.[K+]>COCCOC.C(O)(C)(C)C.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>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:11]2[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[CH3:9])[N:3]=1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CC(C)(C)O
Product: Cc1cc(C)c(-c2cccc(Br)n2)c(C)c1
Temperature: 50 °C
Yield: 67.7 %

Procedure:
2,6-Dibromopyridine (9.47 g, 40 mmol) was dissolved in 80 mL of 1,2-dimethoxyethane (1,2-dimethoxyethane). Tetrakis(triphenylphosphine)palladium(0) (2.31 g, 2.00 mmol) was added and the mixture was heated at 50° C. for 15 min. The solution was cooled and 2,4,6-trimethylbenzeneboronic acid (6.56 g, 40 mmol) dissolved in 40 mL of 1,2 dimethoxyethane was added. Finally, potassium t-butoxide (8.97 g, 80 mmol) was added as a solution in 40 mL of t-butanol. The reaction was heated for 0.5 h at 90° C. The solution was cooled and filtered through celite. Flash chromatography (2% ethyl acetate/hexanes) gave 7.48 g (68% yield) of the title compound.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:20])[CH2:16][CH:17]([CH3:19])[CH3:18]>>[CH3:18][CH:17]([CH3:19])[CH2:16][CH2:15][NH:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)CCN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Product: CC(C)CCNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
Using the general method of Example 41, 4-hydroxy-3-nitroquinoline (19 g, 0.10 mole) was chlorinated and then reacted with isoamylamine (10.5 g, 0.12 mole) to provide the crude product as a yellow solid. This solid was recrystallized from hexane to provide the desired product as a solid, m.p. 99-100° C. Analysis: Calculated: %C, 64.8; %H, 6.6; %N, 16.2; Found: %C, 64.8; %H, 6.6; %N, 16.1.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C@@H:11]([NH2:13])[CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C@@H:11]([NH:13][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1nc([C@H](C)N)n2-c1ccccc1
Reactant: Clc1ncnc2[nH]cnc12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2c1nc([C@H](C)Nc1ncnc3[nH]cnc13)n2-c1ccccc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of (S)-1-(4-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 3 (100 mg, 0.398 mmol), 6-chloro-9H-purine (68 mg, 0.438 mmol) and DIPEA (83 μL, 0.478 mmol) in n-butanol (1 mL) was stirred in a sealed vial at 100° C. for 20 h. After cooling to RT, the mixture was partitioned between DCM and water. The organic layer was then separated, dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and then sonicated in cyclohexane affording 108 as an off-white solid (56 mg, 38%) LCMS: RT 3.17 min [M+H]+ 370.1. 1H NMR (DMSO, 400 MHz): δ 8.13 (1H, bs), 8.08 (1H, s), 7.96-7.85 (1H, m), 7.67-7.44 (5H, m), 7.12-6.99 (2H, m), 6.86 (1H, d, J=7.80 Hz), 5.49 (1H, br), 2.56 (3H, s), 1.57 (3H, d, J=6.86 Hz)
Reaction SMILES: [C:1]([C:4]1[O:8][N:7]=[C:6]([CH3:9])[CH:5]=1)(=[O:3])[CH3:2].[Br:10]C1(Br)C(=O)NC(=O)NC1=O>C1COCC1>[Br:10][CH2:2][C:1]([C:4]1[O:8][N:7]=[C:6]([CH3:9])[CH:5]=1)=[O:3]
Reactant: CC(=O)c1cc(C)no1
Reactant: O=C1NC(=O)C(Br)(Br)C(=O)N1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CBr)on1
Temperature: 25 °C
Yield: 68.5 %

Procedure:
A solution of 0.43 g (3.43 mmol) of 5-acetyl-3-methylisoxazole (for synthesis see S. Chimichi, B. Cosimelli, Synth. Comm. 1992, 22, 2909-2920) in 10 mL of THF was added to a solution of 688 mg (2.41 mmol) of dibromobarbituric acid in 10 mL of THF. The colorless solution was heated at reflux for 20 h, cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated and the aqueous phase re-extracted with ethyl acetate. The combined organic phase was washed with water, brine, dried(MgSO4) and the solvent removed in vacuo. Flash chromatography (silica gel, 40-50% dichloromethane-hexanes) afforded 337 mg (48%) of the title compound: 1H NMR (400 MHz, CDCl3) 6.87 (s, 1H), 4.39 (s, 2H), 2.38 (s, 3H).