Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[N:26]1[O:27][C:28]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)=[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=12.NC1ON=C2C=CC=CC=12>>[N:26]1[O:27][C:28]([NH:35][C:36]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:37])=[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=12
Reactant: O=C(Nc1onc2ccccc12)Oc1ccccc1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cl
Agent: Nc1onc2ccccc12
Product: O=C(Nc1onc2ccccc12)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1

Procedure:
Following the procedure in Example 1, Step 6, 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (150 mg, 0.40 mmol, from Example 1, Step 5) and phenyl benzo[c]isoxazol-3-ylcarbamate (113 mg, 0.40 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3-amino-2,1-benzisoxazole) were combined to provide the title compound (168 mg). MS (APCI 10V) AP+ 495.2, 376.2, 335.2; 1H NMR (400 MHz, CD3OD) δ ppm 2.56 (dt, J=50.88, 5.69 Hz, 4H) 3.66 (dt, J=37.31, 5.71 Hz, 4H) 6.48 (s, 1H) 6.98-7.07 (m, 2H) 7.13 (ddd, J=8.75, 0.68, 0.56 Hz, 1H) 7.16 (d, J=7.77 Hz, 1H) 7.30 (ddd, J=8.05, 6.80, 1.16 Hz, 1H) 7.41 (t, J=7.99 Hz, 1H) 7.49-7.66 (m, 2H) 7.85 (dt, J=8.13, 1.03 Hz, 1H) 8.09 (ddd, J=8.72, 2.67, 0.38 Hz, 1H) 8.43 (td, J=1.82, 0.93 Hz, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([CH:32]=[CH:33][C:34](Cl)=[O:35])[CH:23]=1>C(Cl)Cl>[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([CH:32]=[CH:33][C:34]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:35])[CH:23]=1
Reactant: O=C(Cl)C=Cc1cnc2ccccc2c1
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C=Cc1cnc2ccccc2c1)NCCCSc1ccncc1
Yield: 83.8 %

Procedure:
To a solution of 396 mg (1.64 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 0.27 ml (1.97 mmol) of triethylamine in 20 ml of methylene chloride, 500 mg (1.96 mmol) of 3-quinolineacryloyl chloride hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature-for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain powder. The powder was washed with ether and dried to obtain the desired compound (480 mg, yield: 83.8%, pale yellow powder). mp: 154.0°-155.0° C.
Reaction SMILES: [CH2:1]([N:4]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:5](=[O:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH:2]=[CH2:3]>C(O)(=O)C.O.O.C([O-])(=O)C.[Mn+3].C([O-])(=O)C.C([O-])(=O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:4]2[CH2:1][CH:2]3[C:6]([C:7]([O:9][CH3:10])=[O:8])([CH2:3]3)[C:5]2=[O:11])=[CH:13][CH:14]=1
Reactant: C=CCN(C(=O)CC(=O)OC)c1ccc(F)cc1
Agent: [Cu+2]
Agent: [Mn+3]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C12CC1CN(c1ccc(F)cc1)C2=O
Reaction time: 72 h
Yield: 12.1 %

Procedure:
A solution of methyl 3-(allyl(4-fluorophenyl)amino)-3-oxopropanoate (10 g, 39.7 mmol) in acetic acid (50 mL) was added into a suspension of manganese(III)acetate dihydrate (21 g, 79.7 mmol) and copper (II) acetate monohydrate (7.9 g, 39.7 mmol) in acetic acid (200 mL). The reaction was stirred for 3 days, then quenched with 10% aqueous sodium bisulfite solution (100 mL). The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, brine, dried with Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (50% EtOAc in hexane) to afford the product (1.2 g, 12% yield) as a brown powder. LRMS (APCI pos) m/e 250.1 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:35]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36]1>C(OCC)(=O)C>[O:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[O:1][C@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1
Reactant: C1=COCCC1
Reactant: COC(=O)CCCCCCC1=C[C@@H](O)CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCCC1=C[C@@H](OC2CCCCO2)CC1=O
Reaction time: 0.08 h

Procedure:
To a solution of 1.74 parts of methyl 7-(3(S)-hydroxy-5-oxocyclopent-1-en-1-yl)heptanoate in 12 parts by volume of dry benzene is added 0.005 part of p-toluenesulfonic acid and 1.74 parts of dihydropyran. The reaction mixture is stirred for 5 minutes under a nitrogen atmosphere and then allowed to stand at room temperature for a further 2 hours. The resulting solution is diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and stripped of solvent under reduced pressure to afford methyl 7-(3(S)-tetrahydropyran-2-yloxy-5-oxocyclopent-1-en-1-yl)-heptanoate.
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([N:30]([CH3:29])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:26])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2cc(F)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3cc(F)ccc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a mixture of 4-{[cyclohexyl(6-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}benzoic acid (350 mg) synthesized in Example A96(5), ethyl 3-(methylamino)propanoate (181 mg), 1-hydroxybenzotriazole monohydrate (211 mg), triethylamine (383 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (265 mg), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title object compound (432 mg, 95%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=O)=[CH:13][CH:12]=3)=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[S:37])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)N4CCCCC4)cc3c2c1C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncc2[nH]c3ccc(C(=S)N4CCCCC4)cc3c2c1C
Yield: 127.2 %

Procedure:
400 mg of 6-piperidinocarbonyl-4-methyl-β-carboline-3-carboxylic acid ethyl ester is heated in 16 ml of toluene with 200 mg of Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithiaphosphetane-2,4-disulfide] for one hour to 100° C. Thereafter the mixture is combined with water and extracted twice with ethyl acetate. The ethyl acetate phase is dried, filtered, concentrated, and chromatographed over silica gel with methylene chloride/ethanol=10:1. Recrystallization of the corresponding fractions from ethanol/water yields 240 mg of 6-piperidinothiocarbonyl-4-methyl-β-carboline-3-carboxylic acid ethyl ester, mp 225°-230° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11]O)=[CH:2]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[F:35][C:36]1[CH:37]=[C:38]2[C:43](=[C:44]([N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)[CH:45]=1)[N:42]=[CH:41][CH:40]=[CH:39]2.C(N(CC)C(C)C)(C)C>N1C=CC=CC=1.CS(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:49]2[CH2:50][CH2:51][N:46]([C:44]3[CH:45]=[C:36]([F:35])[CH:37]=[C:38]4[C:43]=3[N:42]=[CH:41][CH:40]=[CH:39]4)[CH2:47][CH2:48]2)=[CH:2]1
Reactant: Fc1cc(N2CCNCC2)c2ncccc2c1
Reactant: OCCc1coc2ccccc12
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: Fc1cc(N2CCN(CCc3coc4ccccc34)CC2)c2ncccc2c1
Reaction time: 48 h

Procedure:
To a stirred solution of 2-(1-benzofuran-3-yl)ethanol (815 mg, 5 mmol) in anhydrous pyridine (20 ml), p-toluenesulfonyl chloride (1.14 g, 6.0 mmol) was added. The reaction mixture was kept at 0° C. for 48 hrs and quenched with ice cold water. The reaction mixture was extracted with chloroform, washed well with water, and dried over anhydrous MgSO4. It was then filtered and concentrated. The crude product obtained was taken to next step without any purification. A mixture of tosylate (316 mg. 1 mmol) (obtained by the above mentioned process) and 6-fluoro-8-piperazino quinoline (231 mg, 1 mmol) was heated at 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end, reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO4 and concentrated to dryness. The dark colored solid was purified by silica-gel column chromatography by initially eluting it with 70% ethyl acetate:hexane and then with 55% methanol:ethyl acetate. The product, 8-{4-[2-(1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-fluoroquinoline, was isolated as yellow oil. Yield: 220 mg (58%); (M+H): 376. 1HNMR (400 MHz, CDCl3):δ 8.82˜8.80 (dd, J1=1.7 Hz, J2=1.7 Hz, 1H), 8.08˜8.03 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H), 7.69˜6.32 (m, 8H), 3.50˜2.63 (m, 12H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:27][CH2:28][CH3:29])[CH:13]3[CH2:18][CH2:17][N:16]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])[CH2:15][CH2:14]3)[CH2:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:46](Cl)(=[O:48])=[O:47]>C1COCC1>[N:21]1([C:19]([N:16]2[CH2:15][CH2:14][CH:13]([N:12]([CH2:27][CH2:28][CH3:29])[CH:8]3[CH2:9][C:10]4[CH:11]=[C:2]([O:1][S:46]([C:41]5[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=5[Cl:39])(=[O:48])=[O:47])[CH:3]=[CH:4][C:5]=4[CH2:6][CH2:7]3)[CH2:18][CH2:17]2)=[O:20])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CCCN(C1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(O)cc2C1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCN(C1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(OS(=O)(=O)c3ccccc3Cl)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of {4-[(7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone (50 μmole in 420 μL DCM) was added 30 μL of DIEA followed by 220 μL of a 0.25M solution of 2-chlorobenzenesulfonyl chloride in THF. The solution was allowed to stir for 24 h at 25° C. under N2. Concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford 2-Chloro-benzenesulfonic acid 7-{[1-(morpholine-4-carbonyl)-piperidin-4-yl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl ester 40 (5.1 mg), [M+H]+=690.
Reaction SMILES: [C:1]1(=O)[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:9]([O:14]C)([O:12][CH3:13])(=[O:11])=[O:10].[Cl:16][C:17]1[CH:18]=[C:19]([NH:23][NH2:24])[CH:20]=[CH:21][CH:22]=1>CO>[CH3:13][O:12][S:9]([OH:14])(=[O:11])=[O:10].[Cl:16][C:17]1[CH:18]=[C:19]([NH:23][N:24]=[C:1]2[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:20]=[CH:21][CH:22]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C1CCCCCN1
Reactant: NNc1cccc(Cl)c1
Solvent: CO
Product: COS(=O)(=O)O
Product: Clc1cccc(NN=C2CCCCCN2)c1
Reaction time: 2 h
Yield: 56.9 %

Procedure:
56.6 G (0.5 mole) of caprolactam were fused and 63.1 g (0.5 mole) of dimethyl sulfate were allowed to run into the melt at 70° to 80°C. The mixture was kept at 80° to 90°C for a further 2 hours and cooled, and the viscous melt was taken up in 250 ml of methanol. Reaction with 72 g (0.5 mole) of 3-chlorophenylhydrazine was then carried out in the same manner as indicated in Example 1a, and 99.5 g (57% of theory) of caprolactam-(3-chlorophenylhydrazone) monomethylsulfate were obtained as colorless crystals of melting point 135°C. On concentrating the mother liquors and treating with excess sodium hydroxide solution, 33.3 g (28% of theory) of caprolactam-(3-chlorophenylhydrazone) of boiling point 180°C/0.08 mmHg were obtained. The total yield was 85% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].IC.C(OCC)(=O)C>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:27])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(CC(c1ccc(Br)cc1)c1ccc(F)cc1F)c1ccc(=O)[nH]c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccc(F)cc2F)ccc1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 5-(3-(4-bromophenyl)-3-(2,4-difluorophenyl)propanoyl)pyridin-2(1H)-one (0.225 g, 538 μmol) in N,N-dimethylacetamide (3 mL) was added potassium carbonate (81.8 mg, 592 μmol) and iodomethane (80.2 mg, 35.3 μL, 565 μmol) and the resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was poured on water and ethyl acetate and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were washed twice with water and once with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100). Colourless foam (0.20 g, 86%). MS (ESI+): m/z=432.0 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[CH:19][CH:18]=1)[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:58][CH2:59][CH2:60][CH2:61][CH2:62][O:63][C:64]1[CH:73]=[CH:72][CH:71]=[C:70]([OH:74])[C:65]=1[C:66]([O:68][CH3:69])=[O:67].C(N(CC)C(C)C)(C)C>C(#N)C.CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[CH:19][CH:18]=1)[C:13]([NH:58][CH2:59][CH2:60][CH2:61][CH2:62][O:63][C:64]1[CH:73]=[CH:72][CH:71]=[C:70]([OH:74])[C:65]=1[C:66]([O:68][CH3:69])=[O:67])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)cc2)S(=O)(=O)N1
Reactant: COC(=O)c1c(O)cccc1OCCCCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)cc1)NC(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 31.1 %

Procedure:
A solution of (2S)-2-[(benzyloxy)carbonyl]amino-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoic acid (10 mg, 23.1 μmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (10.7 mg, 24.3 μmol) and N,N-dimethylformamide (1 mL) was stirred at 0° C. After stirring for 15 min, methyl 2-(4-aminobutoxy)-6-hydroxybenzoate (6.09 mg, 25.4 μmol) and N,N-diisopropylethylamine (12.1 μL) were added to the reaction. The resulting mixture was stirred at 25° C. for 3 h. The reaction solution was diluted with acetonitrile and purified by preparative LCMS to yield the desired product (4.7 mg, 31%). MF=C32H35N3O10S; LCMS found for C32H36N3O10S (M+H)+: m/z=654.
Reaction SMILES: [C:1](Br)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:9][CH:10]([CH:14]([CH3:17])[CH2:15][CH3:16])[C:11]([O-:13])=[O:12].[Na+]>>[C:1]([O:12][C:11](=[O:13])[CH:10]([NH2:9])[CH:14]([CH3:17])[CH2:15][CH3:16])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)Br
Reactant: CCC(C)C(N)C(=O)[O-]
Agent: [Na+]
Product: CCCCCC(=O)OC(=O)C(N)C(C)CC
Temperature: 0 °C

Procedure:
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 10.81 g (60 mmol) of the prepared hexanoyl bromide, and side arm water condenser fixed with a dry receiving flask, is placed 11.03 g (72 mmol) of sodium 2-amino-3-methylpentanoate. The round bottomed flask is placed in an ice bath and the hexanoyl bromide is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield 2-amino-3-methylpentanoic hexanoic anhydride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][C@H:9]1[CH2:15][C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.NO.CCN=C=NCCC[N:30]([CH3:32])C.Cl.CN1CC[O:38][CH2:37]C1>C(Cl)Cl>[CH3:37][O:38][N:30]([CH3:32])[C:16]([CH2:15][C@@H:9]1[CH2:10][C:11]([F:13])([F:14])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:18]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1CC(=O)O
Reactant: CN1CCOCC1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: ClCCl
Product: CON(C)C(=O)C[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a CH2Cl2 (10 ml) solution of 2-((R)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)acetic acid and hydroxylamine hydrogen chloride (713.8 mg, 7.32 mmol), EDCI.HCl (1.64 g, 8.54 mmol) and NMM (1.5 ml, 13.4 mmol) were added, the reaction mixture was stirred at room temperature for 15 hours. The reaction went to completion monitored by LC-MS and was quenched by addition of saturated aqueous NaHCO3 solution (˜25 ml). Two layers were separated, aqueous layer was extracted with CH2Cl2 (˜20 ml). Organic layers were combined, dried (Na2SO4), filtered, solvent was removed in vacuo. Crude product was purified by silica gel chromatography (Hexane/EtOAc, gradient from 100:0 to 70:30). Compound (R)-tert-butyl 2-((N-methoxy-N-methylcarbamoyl)methyl)-4,4-difluoropyrrolidine-1-carboxylate was obtained as a light yellow oil: 1.20 g; additional product was obtained from recovered carboxylic acid: 0.2 g (53% combined overall yield over 2 steps).
Reaction SMILES: [CH2:1]([C:8]1[C:13]([NH:14][NH2:15])=[N:12][CH:11]=[C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OCC)(=O)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:1]([C:8]1[C:13]2[N:12]([C:22]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:15][N:14]=2)[CH:11]=[C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ncc(-c2cccnc2)nc1Cc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)Cc1nnc2c(Cc3ccccc3)nc(-c3cccnc3)cn12

Procedure:
In a manner analogous to Example 1, by condensing 2-benzyl-3-hydrazino-6-(3-pyridyl)pyrazine with diethyl malonate there is obtained ethyl 8-benzyl-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, which is converted by basic saponification into the above acid, MS: 301 (M-CO2)+.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CN(C=O)C>[C:3]1([CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCBr
Reactant: N#CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC(C#N)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a suspension of 2 g of 60% NaH in 50 mL of DMF cooled to 0° C. are added dropwise 5 g (42.7 mmol) of phenylacetonitrile. After stirring for 30 minutes at 0° C., 5.32 mL (42.7 mmol) of bromopentane are added dropwise. The reaction medium is stirred for 16 hours at room temperature and then treated with ice and extracted with ethyl ether. The organic phase is washed with saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, filtered and evaporated under pressure. An orange-yellow oil is obtained and purified by fractional distillation under reduced pressure (70-75° C. at 1×10−1 mbar). 5.14 g in the form of an orange-coloured oil are obtained in a yield of 64%.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:24]1[CH:25]=[C:26]([CH:40]=[CH:41][C:42]=1[CH3:43])[C:27]([NH:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=1)=[O:28].C(N(C(C)C)CC)(C)C>CN(C=O)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.[Cu]I>[CH3:43][C:42]1[CH:24]=[CH:25][C:26]([C:27]([NH:29][C:30]2[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:32][N:31]=2)=[O:28])=[CH:40][C:41]=1[C:2]#[C:1][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[C:6]2=[N:5][CH:4]=1
Reactant: C#Cc1cnc2c(Nc3ccc(S(C)(=O)=O)cc3)cccn12
Reactant: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1C#Cc1cnc2c(Nc3ccc(S(C)(=O)=O)cc3)cccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
A mixture of 3-ethynyl-N-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-8-amine 5 (0.048 g, 0.154 mmol), 0.069 g (0.170 mmol) of 3-iodo-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide, 0.009 g (0.008 mmol) of Pd(PPh3)4, 0.002 g (0.012 mmol) of CuI, and 0.04 mL (0.23 mmol) of diisopropylethylamine in 0.8 mL of DMF was stirred at ambient temperature overnight under an atmosphere of N2. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (triethylamine-treated silica gel; eluted with 10% EtOAc/hexanes to 100% EtOAc) to provide 0.047 g of product as a solid: 590 m/z (M+H).