Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]3[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=3)=[CH:20][CH:21]=2)[C:16]([CH2:30][NH2:31])=[CH:15]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(N(CC)CC)C>C1COCC1>[CH2:6]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]3[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=3)=[CH:20][CH:21]=2)[C:16]([CH2:30][NH:31][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:15]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCn1cc(CN)c2cc(-c3cccc(C)c3)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCn1cc(CNS(C)(=O)=O)c2cc(-c3cccc(C)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
Methanesulfonyl chloride (33 μl, 0.434 mmol) was added to a solution of (1-octyl-5-m-tolyl-1H-indol-3-yl)methanamine (152 mg, 0.434 mmol) and triethylamine (91 μl, 0.651 mmol) in THF (4 mL) at 0° C. The reaction mixture was allowed to stir at room temp for 60 min, the precipitate formed was filtered off, the filtrate was concentrated, and the residue was subjected to column chromatography (silica gel, CH2Cl2) to give sulphonamide 22 in 61% yield.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[O:20]([C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Reactant: Oc1ccccc1
Product: O=Cc1ccc(C(F)(F)F)cc1Oc1ccccc1
Yield: 78 %

Procedure:
Preparation analogous to Example 12 from 2-fluoro-4-trifluoromethyl-benzaldehyde and phenol. Yield: 78%, light-coloured crystals, crystallised from hexane; melting point: 57°-59° C.; TLC (silica gel; ethyl acetate/hexane=1:1; UV): Rf =0.71; 1H-NMR (CDCl3, 200 MHz): 7.08-7.50 (m, 7H): 8.05 (d, 1H) 10.60 (s, 1H). MS: 266/265 (M+), 217, 188.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=NOC)[CH2:15][CH2:14]3)[N:10]=1)=[O:5])[CH3:2].[ClH:29].CC(C)=[O:32]>O1CCOCC1>[ClH:29].[ClH:29].[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:32])[CH2:15][CH2:14]3)[N:10]=1)=[O:5])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)CCC3=NOC)c(-c2ccncc2)[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccc3c(c2)CCC3=O)c(-c2ccncc2)[nH]1
Temperature: 100 °C
Yield: 88 %

Procedure:
A mixture of the product of Step 5 (1.0 g, 2.7 mmol) and 5M HCl (15 ml) in dioxane (30 ml)/acetone (30 ml) was heated to 100° C. for 3 hour. The mixture was cooled to room temperature and the solvent evaporated in vacuo. The residue was co-evaporated with acetone (2×20 ml) and ethanol/acetone (1:1, 20 ml) to give the title compound (1.0 g, 88%); MS(ES−) m/e 346 [M−H]−.
Reaction SMILES: [SH:1][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:16]([CH:18]1[CH2:20][O:19]1)=[CH2:17]>CN(C)C=O>[OH:19][CH:18]([CH:16]=[CH2:17])[CH2:20][S:1][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1
Reactant: CC1(CS)COC(=O)N1
Reactant: C=CC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CC(O)CSCC1(C)COC(=O)N1
Temperature: 60 °C

Procedure:
To a solution of 4-(mercaptomethyl)-4-methyloxazolidin-2-one (1.79 g, 12.2 mmol) in N,N-dimethylformamide (20 ml) was added cesium carbonate (520 mg, 1.60 mmol) and 2-vinyloxirane (2.34 g, 33.4 mmol). The solution was heated to 60° C. for 14 hours, cooled to room temperature, concentrated in vacuo, and purified by flash chromatography (30% to 100% ethyl acetate in hexanes) to afford the title compound as a clear oil (quantitative). LRMS (ESI/APCI) m/z 218 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CCCCCC.[H-].[Na+].[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]Br)[CH3:18]>CN(C)C=O>[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:18]
Reactant: CCOC(CBr)OCC
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(COc1ccc(F)cc1)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.8 %

Procedure:
A solution of 4-fluorophenol (28.1 g., 0.25 mole) in dry dimethylformamide (30 ml.) is added dropwise to a suspension of hexane (2 × 30 ml.)--prewashed sodium hydride (50% dispersion in mineral oil, 12.5 g., 0.26 mole) in dry dimethylformamide (120 ml.). After stirring at 25° C. for 10 minutes, the reaction mixture is treated with bromoacetaldehyde diethyl acetal (49.3 g., 0.25 mole) and heated at 100° C. for 4 hours. Upon cooling to 25° C., the reaction mixture is filtered to remove insoluble sodium bromide. The filtrate is evaporated in vacuo, leaving an oily residue which is triturated with acetone (100 ml.) at 25° C. and filtered to remove additional sodium bromide. Evaporation of the filtrate in vacuo provides a residual oil which is distilled to afford the title compound as a colorless oil (46.7 g., 82%), bp0.05 87° C.; pmr (CCl4) δ1.17 (6 H, t) 3.57 (2H, q), 3.61 (2H, q), 3.85 (2H, d), 4.68 (H, t) and 6.6-7.1 (4H, m).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[C:15]2[O:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([CH3:22])[C:11](=[O:23])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[ClH:1].[ClH:1].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][O:4][CH2:5][C:6]2[C:15]3[O:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[C:12]([CH3:22])[C:11](=[O:23])[C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:34][CH2:33]1
Reactant: Cc1c(-c2ccccc2)oc2c(COCCCl)cccc2c1=O
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N1CCN(CCOCc2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Product: Cl
Temperature: 90 °C
Reaction time: 7 h
Yield: 153.6 %

Procedure:
A mixture of 4 g of Intermediate XVIII, 2.4 g of 1-(2-methoxyphenyl)piperazine, 1.96 g of potassium iodide and 1.65 g of anhydrous potassium carbonate in 40 ml of anhydrous dimethylformamide was stirred at 90° C. for 7 hours. After cooling to ambient temperature, the mixture was poured into water and extracted with dichloromethane. The combined extracts were washed with aqueous sodium chloride solution, dried on anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was crystallized from ethyl acetate and the collected crystals were dissolved in ethanol and treated with excess ethanolic hydrogen chloride to give 5.21 g of the title compound, m.p. 199°-201° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=[C:10]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:24])[CH:3]=1.Cl.[NH2:26][OH:27]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=3)([C:11]([F:14])([F:13])[F:12])[O:27][N:26]=2)=[C:4]([CH3:24])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(Br)ccc1C1=NOC(c2cc(Cl)cc(Cl)c2)(C(F)(F)F)C1
Temperature: 25 °C
Yield: 24.5 %

Procedure:
To a stirred solution of 1-(4-bromo-2-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one (200 mg, 0.45 mmol) in pyridine (3 mL) at room temperature was added hydroxylamine hydrochloride (47 mg, 0.68 mmol). The reaction mixture was heated to reflux for 4 h. The resulting mixture was cooled to room temperature and then concentrated, and the residual oil was purified by chromatography on silica gel using 20:80 ethyl acetate/hexanes as eluent to afford the title product as a pale yellow oil (50 mg, 24% yield).
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:11]1[CH2:23][N:21]2[C:22]3[CH:14]([CH:15]([NH:24][C:25](=[O:38])[CH:26]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH:27]([CH2:31][CH2:32][CH3:33])[C:28]([NH2:30])=[O:29])[CH2:16][CH2:17][C:18]=3[CH:19]=[CH:20]2)[C:13](=[O:39])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40][O:41]C1C=C(C=CC=1)CN>>[CH2:34]([CH:26]([CH:27]([CH2:31][CH2:32][CH3:33])[C:28]([NH2:30])=[O:29])[C:25]([NH:24][CH:15]1[CH:14]2[C:13](=[O:39])[CH2:12][CH:11]([C:9](=[O:10])[NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[C:6]([O:41][CH3:40])[CH:7]=3)[CH2:23][N:21]3[C:22]2=[C:18]([CH:19]=[CH:20]3)[CH2:17][CH2:16]1)=[O:38])[CH:35]([CH3:36])[CH3:37]
Reactant: CCCC(C(N)=O)C(CC(C)C)C(=O)NC1CCc2ccn3c2C1C(=O)CC(C(=O)NCc1ccccc1)C3
Reactant: COc1cccc(CN)c1
Product: CCCC(C(N)=O)C(CC(C)C)C(=O)NC1CCc2ccn3c2C1C(=O)CC(C(=O)NCc1cccc(OC)c1)C3
Yield: 56 %

Procedure:
The compound of Example 3e was synthesized in a manner similar to the synthesis of the compound of Example 3a, but using 3-methoxybenzylamine as the amine in the last step. Cleavage of 100 mg of functionalized resin (0.53 mmol/g) and purification by RP-HPLC provided 17.0 mg (56%) of the title compound as a white powder. MS (M+H)+=563.43.
Reaction SMILES: [C:1](O)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[O:11]1[C:16]2C=CC=C[C:15]=2C=CN1>>[NH:4]1[C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]=[CH:15][C:16]1=[O:11]
Reactant: Nc1ccccc1C(=O)O
Reactant: C1=Cc2ccccc2ON1
Product: O=c1ccc2ccccc2[nH]1

Procedure:
The required 1-H-4-quinolones for the above reactions were prepared in a similar way to that described in Example 6. The appropriate anthranilic acid was converted to the benzoxazine X which was then converted to the β-ketosulphoxide XI which then underwent ring closure to give the 1-H-quinolone XII ##STR11##
Reaction SMILES: FC1[C:11]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=CC2NC=C3C(=O)N(C4C=CC=CC=4)N=C3C=2C=1.F[C:29]1[C:30]([F:50])=[CH:31][C:32]2[C:33]3[C:34]([C:39](=[O:49])[N:40]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=4[F:48])[N:41]=3)=[CH:35][NH:36][C:37]=2[CH:38]=1.CN1CCNCC1>>[F:50][C:30]1[C:29]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[CH:38][C:37]2[NH:36][CH:35]=[C:34]3[C:39](=[O:49])[N:40]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=4[F:48])[N:41]=[C:33]3[C:32]=2[CH:31]=1
Reactant: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccccc1F
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)c(F)cc3c-2nn1-c1ccccc1
Agent: CN1CCNCC1
Product: CN1CCN(c2cc3[nH]cc4c(=O)n(-c5ccccc5F)nc-4c3cc2F)CC1

Procedure:
The title compound was prepared following the procedure described in the synthesis of 28a using 27c and 1-methylpiperazine. 1H-NMR (CD3OD) δ (ppm): 2.23 (3H, s), 2.48 (4H, brm), 2.68 (4H, brm), 7.05 (1H, d, J=7.7 Hz), 7.16 (2H, m), 7.31 (1H, m), 7.40 (1H, m), 7.66 (1H, d, J=13.1 Hz), 8.44 (1H, s). m/z 396.2
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:34])[C:18]=3[C:22](=[O:33])[NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)[N:13]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+]>>[Cl:34][C:17]1[C:18]([C:22](=[O:33])[NH:23][CH2:24][CH:25]2[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]2)=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[CH:21]=[CH:20]2
Reactant: CCOC(=O)C1CCCN(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)C1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CCCC(C(=O)O)C3)ccc12

Procedure:
1-{6-Chloro-5-[(4,4-difluoro-cyclohexylmethyl)-carbamoyl]-quinolin-2-yl}-piperidine-3-carboxylic acid ethyl ester was hydrolysed to the desired product with 2.5 M aqueous sodium hydroxide. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.41 (s, 1H), 8.72-8.75 (m, 1H), 7.73 (d, J=9.41 Hz, 1H), 7.50-7.56 (m, 2H), 7.35 (d, J=9.51 Hz, 1H), 4.48-4.51 (m, 1H), 4.18-4.21 (m, 1H), 3.15-3.25 (m, 4H), 2.48-2.52 (m, 1H), 1.97-2.03 (m, 3H), 1.82-1.85 (m, 3H), 1.63-1.76 (m, 4H), 1.45-1.51 (m, 1H), 1.27-1.31 (m, 2H). m/z: 466.3 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[CH3:9]>[Pd].C1(C)C=CC=CC=1>[C:3]1([CH3:9])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1.[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1ccc(Cl)cc1Cl
Agent: [Pd]
Solvent: Cc1ccccc1
Product: Cc1ccccc1Cl

Procedure:
This example shows the utility of sulfided noble metals as a dehalogenation catalyst for substituted chlorobenzenes. The catalyst used was 0.5% palladium on 1/8" alumina. 2,4-Dichlorotoluene was used as the feed and the feed rate was maintained at about 1.25 g/min. The dehalogenation reaction catalysed by non-sulfided palladium at a temperature of 300° C. was found to be very vigorous. Up to 81% toluene was formed during such dehalogenation, yielding a mole ratio of toluene-chlorotoluene of 4.24. When the dehalogenation was catalysed by a sulfided palladium, the reaction rate was reduced considerably and the selectivity to chlorotoluene was improved. Only 41% toluene was found in the dehalogenated product which corresponded to a toluene/chlorotoluene mole ratio of 1.19. Thus sulfided palladium was found to be effective in improving selectivity to substituted chlorobenzene.
Reaction SMILES: [NH:1]1[C:7](=[O:8])[C:6](=[N:9]O)[CH2:5][CH2:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.C(O)(=O)C.[H][H]>CO.[Pd]>[NH2:9][CH:6]1[C:7](=[O:8])[NH:1][C:2]2[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=2[CH2:4][CH2:5]1
Reactant: O=C1Nc2ccccc2CCC1=NO
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: NC1CCc2ccccc2NC1=O
Temperature: 50 °C
Yield: 67.3 %

Procedure:
5 g (26,3 mmol) of 4,5-dihydro-1H-benzo[b]azepine-2,3-dione 3-oxime is taken in 50 ml of methanol then 6,3 g (105 mmol) acetic acid is added. The reaction mixture is left to stir at 50° C. and 5 bar hydrogen pressure for 21 hours in the presence of 1,1 g Pd catalyst (5% on charcoal, containing 50% water). The reaction mixture is evaporated after filtration and the residue is dissolved in 16,5 ml water. 9,5 ml dichloromethane is added and the pH value is adjusted to pH 12–14 with NaOH (32%). After phase separation the aqueous layer is extracted two times with 5,5 ml dichloromethane each. The organic phases are dried over sodium sulfate and evaporated to give 3,12 g 3-amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one, yield 67,4%, HPLC 94,5 area %, RT=2.45.
Reaction SMILES: [C:1](=[O:9])([O:5][CH:6]([CH3:8])[CH3:7])[O:2][CH2:3]Cl.[Na+].[I-].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([F:48])=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]([CH2:42][C@@H:43]([OH:47])[C:44]([OH:46])=[O:45])[NH:27][C:28]([C:30]3[O:34][N:33]=[C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[F:41])[CH:31]=3)=[O:29])=[CH:21][CH:20]=2)[CH:18]=1.CCN(CC)CC>CC(C)=O>[CH:6]([O:5][C:1]([O:2][CH2:3][O:46][C:44](=[O:45])[C@H:43]([OH:47])[CH2:42][N:26]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[CH:18]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=2[F:48])=[CH:20][CH:21]=1)[NH:27][C:28]([C:30]1[O:34][N:33]=[C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[F:41])[CH:31]=1)=[O:29])=[O:9])([CH3:8])[CH3:7]
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cc(-c2ccccc2F)no1
Reactant: CC(C)OC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)OC(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(-c2ccccc2F)no1
Temperature: 60 °C
Reaction time: 5 h
Yield: 7.4 %

Procedure:
Chloromethyl isopropyl carbonate (17.3 mg, 114 μmol) and NaI 17.0 mg, 114 μmol) were combined in acetone (1.0 mL, 14 mmol) and heated at 60° C. for 1 hour. The mixture was then cooled to room temperature. A mixture of (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid (20.0 mg, 38 μmol) dissolved in acetone (1.0 mL) and treated with Et3N (10.6 μL, 76 μmol) was added and the resulting mixture was stirred at room temperature for 5 hours. The mixture was concentrated and the residue was dissolved in AcOH (2.0 mL), filtered and purified by reverse phase preparative HPLC. The product was freeze dried and purified by reverse phase preparative HPLC to yield the title compound (1.8 mg, purity 100%). MS m/z [M+H]+ calc'd for C31H28ClF2N3O8, 644.15. found 644.1.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[CH2:28]([NH:32][CH3:33])[CH2:29][CH2:30][CH3:31]>>[CH2:28]([N:32]([CH3:33])[C:9]([C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)=[O:27])[CH2:29][CH2:30][CH3:31]
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Reactant: CCCCNC
Product: CCCCN(C)C(=O)c1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and n-butyl-methyl-amine. The crude product was subjected to preparative HPLC (20%, oil). HPLC-MS: m/z=341.2 (M+1); Rt: 3.96 min.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.O.C(O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=2[CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1ccc(N2CCN(Cc3ccccc3Br)CC2)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1

Procedure:
A mixture of EXAMPLE 2A (13.83 g), 4-chlorophenylboronic acid (7.04 g), bis(triphenylphosphine)palladium dichloride (481 mg) and 2M sodium carbonate (22.5 mL) in 7:3:2 DME/water/ethanol (200 mL) at 90° C. was stirred for 4.5 hours and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated. The concentrate was flash chromatographed on silica gel with 5%-40% ethyl acetate/hexanes.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][CH2:15][OH:16].[CH3:17][C:18]1[N:19]=[C:20]([N:33]2[C:37](=[O:38])[NH:36][N:35]=[CH:34]2)[S:21][C:22]=1[C:23]([NH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:24]>>[OH:16][CH2:15][CH2:14][N:36]1[C:37](=[O:38])[N:33]([C:20]2[S:21][C:22]([C:23]([NH:25][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:24])=[C:18]([CH3:17])[N:19]=2)[CH:34]=[N:35]1
Reactant: OCCBr
Reactant: Cc1nc(-n2cn[nH]c2=O)sc1C(=O)NCc1cccnc1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: Cc1nc(-n2cnn(CCO)c2=O)sc1C(=O)NCc1cccnc1
Yield: 76 %

Procedure:
Following the procedure as described in Example 19, making variation as required to replace 4-(trifluoromethyl)benzyl bromide with 2-bromoethanol to react with 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 76% yield: mp 201-202° C. (ethyl acetate/hexane); 1H NMR (300 MHz, DMSO-d6) δ 8.87 (t, J=5.8 Hz, 1H), 8.71 (s, 1H), 8.51 (br s, 1H), 8.47-8.39 (m, 1H), 7.73-7.66 (m, 1H), 7.37-7.30 (m, 1H), 4.83 (t, J=5.8 Hz, 1H), 4.40 (d, J=5.8 Hz, 2H), 3.78 (t, J=5.5 Hz, 2H), 3.68-3.58 (m, 2H), 2.53 (s, 3H); MS (ES+) m/z 361.2 (M+1).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[C:27]([Cl:28])=[CH:26][N:25]([CH2:29][CH3:30])[N:24]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[C:27]([Cl:28])=[CH:26][N:25]([CH2:29][CH3:30])[N:24]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCn1cc(Cl)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n1
Solvent: C1CCOC1
Product: CCn1cc(Cl)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
A small screw cap test tube was charged with 4-Chloro-1-ethyl-1H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 85 mg, 0.1946 mmol) and THF (2.0 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (37.3 mg, 0.195 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was redissolved in EtOAc (˜5 mL) and Hexane (˜50 mL) was added to the solution. The precipitate that formed was collected by filtration and washed with acetone (10 mL) to afford the title compound in 43% yield (0.051 g, 0.084 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[S:11][S:10][C:9](=O)[CH:8]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14]>O1CCOCC1.C(#N)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[S:11][S:10][C:9](=[S:14])[CH:8]=1
Reactant: O=c1cc(-c2cnccn2)ss1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1COCCO1
Solvent: CC#N
Product: S=c1cc(-c2cnccn2)ss1
Temperature: 100 °C
Yield: 170.2 %

Procedure:
A mixture of 5-(pyrazin-2-yl)-1,2-dithiole-3-one (2 g.) and phosphorus pentasulphide (2.3 g.) in dioxan (35 cc.) is heated for 15 minutes at 100° C., whilst stirring. The red suspension obtained is diluted whilst hot with acetonitrile (35 cc.). The solution is decanted and the precipitate obtained is taken up with a hot mixture (2 × 50 cc.) of dioxan and acetonitrile (50:50 by volume). The combined organic phases are filtered hot, diluted with distilled water (250 cc.), and the requisite amount of a 4N aqueous ammonia solution to adjust the pH to 7. The brown precipitate formed is filtered off, washed with distilled water (2 × 25 cc.) and then with diethyl ether (2 × 10 cc.) and dried. 5-(Pyrazin-2-yl)-1,2-dithiole-3-thione (1.87 g.) melting at 200°-201° C. is thus obtained.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)=[O:11].[Li+].[OH-].Cl>O1CCCC1>[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:22])=[O:2])=[O:11]
Reactant: COC(=O)CCCCCNC(=O)c1ccc2ccccc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCNC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
(Method J5B) The crude 6-[(naphthalene-2-carbonyl)amino]hexanoic acid methyl ester (3/53) was dissolved in tetrahydrofuran (5 ml) and 1N LiOH (5.5 ml, 5 mmol) was added. The reaction mixture was stirred for three hours at room temperature and acidified with 2N HCl up to pH 3. The mixture was extracted with ethyl acetate (3×20 ml) the organic layer was washed with saturated NaCl (3×10 ml) and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel with ethyl acetate as eluent to give pure title compound (0.618 g, 79%). 1H NMR (CDCl3, HMDSO), δ: 1.11-1.77 (6H, m); 2.22-2.39 (2H, m); 3.47 (2H, dd, J=7.0 Hz); 6.26 (1H, br s); 7.17 (1H, s); 7.33-7.57 (2H, m); 7.64-7.93 (4H, m); 8.22 (1H, s).