Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([N:22]3[CH2:27][CH2:26][CH:25]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:24][CH2:23]3)=[CH:15]4)=[N:9][N:10]=2)[CH:7]=1.[Sn].[O:37]1[CH2:42][CH2:41]O[CH2:39][CH2:38]1>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>[Si:29]([O:28][CH:25]1[CH2:26][CH2:27][N:22]([C:16]2[CH:17]=[N:18][C:19]3[C:14]([CH:15]=2)=[CH:13][C:12]([S:11][C:8]2[N:6]4[CH:7]=[C:2]([C:38]([O:37][CH2:42][CH3:41])=[CH2:39])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=2)=[CH:21][CH:20]=3)[CH2:23][CH2:24]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: C1COCCO1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(c2cnc3ccc(Sc4nnc5ccc(Br)cn45)cc3c2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Sn]
Product: C=C(OCC)c1ccc2nnc(Sc3ccc4ncc(N5CCC(O[Si](C)(C)C(C)(C)C)CC5)cc4c3)n2c1
Temperature: 120 °C
Yield: 90 %

Procedure:
The solution of (76.1) (100 mg, 0.175 mmol) and PdCl2(PPh3)2 (12.30 mg, 0.018 mmol) in 1,4-Dioxane (2 ml) was bubbled with Argon for 5 mins, Tin reagent (95 mg, 0.263 mmol) was added by injection and the mixture was bubbled with Argon for another 5 mins, and the tube was sealed and heated to 120° C. for 3 hr. Monitored the reaction by TLC. The solvent was evaporated and the residue was purified by flash chromatography and eluented with DCM/MeOH (40:1˜20:1) to give pure desired product (76.2) as orange oil (90 mg, yield 90%). 1H-NMR (400 MHz, CDCl3) δ ppm 8.73 (s, 1H), 8.41 (s, 1H), 7.97 (d, 1H), 7.78 (d, 1H), 7.57 (s, 2H), 7.42-7.49 (m, 2H), 7.21 (s, 1H), 4.68 (s, 1H), 4.36 (s, 1H), 3.88-3.98 (m, 3H), 3.48-3.53 (m, 2H), 3.18-3.23 (m, 2H), 1.88-1.91 (m, 2H), 1.66-1.74 (m, 2H), 1.38 (t, 3H), 0.91 (s, 9H), 0.09 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH:8]=O.[NH2:16][C:17]1[C:18]([C:31]([NH:33][CH3:34])=[O:32])=[N:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH2:30])[CH:24]=2)=[CH:21][N:22]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[NH2:16][C:17]1[C:18]([C:31]([NH:33][CH3:34])=[O:32])=[N:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH:30][CH2:8][C:7]3[CH:6]=[CH:5][C:4]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:3][C:2]=3[F:1])[CH:24]=2)=[CH:21][N:22]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1F
Reactant: CNC(=O)c1nc(-c2cccc(CN)c2)cnc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC(=O)c1nc(-c2cccc(CNCc3ccc(-c4ccccc4)cc3F)c2)cnc1N
Yield: 20.2 %

Procedure:
A solution of 3-fluorobiphenyl-4-carbaldehyde (0.030 g, 0.15 mmol), 3-amino-6-[3-(aminomethyl)phenyl]-N-methylpyrazine-2-carboxamide (0.038 g, 0.15 mmol), glacial AcOH (0.010 mmol, 0.15 mmol) and NaBH(OAc)3 (0.047 g, 0.22 mmol) in THF (0.6 mL) was stirred at r.t. for 12 h. Saturated NaHCO3 (aq) was added (25 mL) and the aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified via HPLC (reverse-phase, CH3CN/H2O with 0.1% TFA). Upon removal of CH3CN/H2O, the product was taken up in MeOH and treated with Bio-Rad AG 1-X8 resin (hydroxide form) until pH 8. The product was filtered and concentrated in vacuo, to provide 13.4 mg (20% yield) of 3-amino-6-[3-({[(3-fluorobiphenyl4-yl)methyl]amino}methyl)phenyl]-N-methylpyrazine-2-carboxamide: 1H NMR (400 MHz, d6-DMSO): 8.84 (s, 1H), 8.79 (d, 1H), 8.09 (bs, 1H), 8.05 (m, 1H), 7.70 (m, 2H), 7.61 (t, 1H), 7.36-7.53 (m, 8H), 3.80 (d, 4H), 2.86 (d, 3H); MS (EI) for C26H24N5OF: 442 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([OH:20])=[O:19])=[CH:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19])=[CH:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)OCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.7 %

Procedure:
A solution of compound 31 (2.03 g, 7.4 mmol) in DMF (50 mL) was treated with sodium bicarbonate (1.8 g, 21.4 mmol), and benzyl bromide (4 mL, 33.6 mmol). The reaction mixture was stirred for 18 h at room temperature. Water (50 mL) was added and the product was extracted with ethyl acetate (80 mL×3). The solution was dried with sodium sulfate, concentrated in vacuo to give compound 32 (2.27 g, 84% yield) as a white solid. m.p.180°-182° C. 1H NMR (DMSO-d6, ppm): 11.93 (s, 1 H, NH), 7.51-7.02 (m, 9 H, Ar--H), 5.38 (s, 2 H, CH2C6 H5), 1,48 (s, 9 H, C(CH3)3). Anal. (C21H22 N2O4 0.25H2O), C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[CH2:4][C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:6]=1[C:15]#[C:16][C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[C:19]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)[N:18]=1>CCOC(C)=O.C(N(CC)CC)C.[Pd]>[CH3:1][O:2][C:3](=[O:47])[CH2:4][C:5]1[C:10]([C:11]([F:12])([F:13])[F:14])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:15][CH2:16][C:17]1[C:22]([C:23]([F:25])([F:26])[F:24])=[CH:21][N:20]=[C:19]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH2:39]3)=[CH:30][CH:29]=2)[N:18]=1
Reactant: COC(=O)Cc1c(C#Cc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)cccc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1c(CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)cccc1C(F)(F)F
Reaction time: 20 h

Procedure:
A suspension of tert-butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A94) (0.127 g, 0.192 mmol) and 10% Pd/C (53% water; 0.234 g) in EtOAc (4.0 mL) and triethylamine (0.2 mL) was stirred under a hydrogen atmosphere for 20 hours. The resulting mixture was filtered through Celite and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15-30% EtOAc in petroleum benzine 40-60° C.) to give the title compound A95 (0.106 g, 83%); 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.56 (m, 3H), 7.46 (d, J=7.3 Hz, 1H), 7.36 (m, 2H), 7.21 (d, J=8.5 Hz, 2H), 4.25 (m, 2H), 3.98 (s, 2H), 3.68 (s, 3H), 3.11 (m, 4H), 2.81 (m, 2H), 2.64 (m, 1H), 1.83 (m, 2H), 1.62 (m, 2H), 1.49 (s, 9H). LCMS-A: rt 7.19 min; m/z 665.1 [M−H]−.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].C([NH+]([CH2:21][CH3:22])CC)C>C(Cl)(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:22]2[CH2:21][CH2:4][CH2:3][CH:2]2[OH:1])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[NH+](CC)CC
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: [I-]
Solvent: ClC(Cl)Cl
Product: OC1CCCC1Oc1ccc(Oc2ccccc2)cc1
Temperature: 150 °C
Reaction time: 7 h

Procedure:
A mixture of 18.6 g of 4-phenoxyphenol, 12.8 g of 1,2-carbonyldioxycyclopentane and 4.6 g of triethylammonium iodide is stirred for 7 hours at 150° C. After cooling, the reaction mixture is taken up in chloroform. The solution is washed with water and once with saturated sodium chloride solution, dried over sodium sulphate and concentrated by rotary evaporation. Fractional distillation of the residue yields (2-(4-phenoxyphenoxy)-cyclopentan-1-ol as a colourless oil with a melting point of 181°-185° C./0.001 torr.
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]([NH:11][C:12](=[O:34])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)[CH:14]=1)[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:35][CH2:36][CH2:37][NH2:38].O.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([O:5][CH2:6][C@H:7]([NH:11][C:12](=[O:34])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15](/[CH:21]=[CH:22]/[C:23]2[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=2)[CH:14]=1)[C:8](=[O:9])[NH:38][CH2:37][CH2:36][OH:35])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(=O)N[C@@H](COC(C)(C)C)C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)N[C@@H](COC(C)(C)C)C(=O)NCCO)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
(S)-3-t-butoxy-2-{4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoylamino}propionic acid (25 mg), 2-hydroxyethylamine (9 μL), benzotriazol-1-ol monohydrate (19 mg), and (3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (25 mg) were dissolved in 2 mL of N,N-dimethylformamide, and then, N,N-diisopropylethyl-amine (53 μL) was added to the solution. The solution was stirred overnight at room temperature. Then, 2-hydroxyethylamine (9 μL), benzotriazol-1-ol monohydrate (19 mg), and (3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (25 mg) were added again to the solution, and the solution was further stirred overnight. After removal of the solvent under reduced pressure, to the obtained residue was added water, and the mixture was extracted three times with dichloromethane. The respective organic layers were combined, whereafter the combined organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and washed with dichloromethane. The filtrate and the washings were combined, and dichloromethane was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 44 mg (76%) of N-[(S)-2-t-butoxy-1-(2-hydroxyethylcarbamoyl)ethyl]-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]-benzamide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH:15]=O.[C:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[CH:27][CH:26]=1)(=[O:24])[CH3:23]>CCCCCC.CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14](/[CH:15]=[CH:23]/[C:22]([C:25]2[CH:26]=[CH:27][C:28]([S:31]([N:34]([CH3:35])[CH3:36])(=[O:33])=[O:32])=[CH:29][CH:30]=2)=[O:24])[CH:17]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)N(C)C)cc1
Reactant: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)N(C)C)cc1
Yield: 12 %

Procedure:
The title compound was prepared in an analogous manner as Ex-1 using 5-(1H-indol-2-yl)-2,4-dimethoxybenzaldehye (Ex-32B) and 4-acetyl-N,N-dimethylbenzenesulfonamide (Ex-31A), 12% yield after silica gel column chromatography (hexane/EtOAc, 2:1), yellow solid, mp 158–162° C. 1H-NMR (300 MHz, CDCl3) δ 9.39 (br, 1H), 8.15 (m, 2H), 8.08 (d, J=9 Hz, 2H), 7.91 (d, J=9Hz, 2H), 7.64 (d, J=7 Hz, 1H), 7.57 (d, J=15 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.09–7.21 (m, 2H), 6.87 (d, J=2Hz, 1H), 6.60 (s, 1H), 4.10 (s, 3H), 4.01 (s, 3H), 2.76 (s, 6H). HRMS (ESI) Calcd. for C27H26N2O5S: 491.1641 (M+H)+; Found: 491.1638.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4].[NH2:23][C@@H:24]([CH2:26][OH:27])[CH3:25]>>[OH:27][CH2:26][C@H:24]([NH:23][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4])[CH3:25]
Reactant: C[C@@H](N)CO
Reactant: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)OC)s1
Product: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)N[C@H](C)CO)s1
Yield: 75 %

Procedure:
As described for example 53, 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (100 mg, 0.31 mmol) was converted, using D-alaninol instead of 2-amino-1,3-propandiol, to the title compound (85 mg, 75%) which was obtained as an off white oil. MS: m/e=366.0 [M+H]+.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[F:6][C:7]([F:17])=[CH:8][CH2:9][CH2:10][S:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1.CN(C)C=O.O>C(Cl)(Cl)Cl>[Cl:4][C:14]1[S:13][C:12]([S:11][CH2:10][CH2:9][CH:8]=[C:7]([F:6])[F:17])=[N:16][CH:15]=1
Reactant: FC(F)=CCCSc1nccs1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)=CCCSc1ncc(Cl)s1
Temperature: 45 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
A solution of sulfuryl chloride (0.66 g) and chloroform (2.0 ml) was added dropwise over a period of 1.5 hour to a stirred mixture of 2-(4,4-difluorobut-3-enylthio)thiazole (1.01 g), and dimethylformamide (10 ml) maintained at 45° C. under a nitrogen atmosphere and the resultant mixture stirred for a further 2.5 hour. A further aliquot of sulfuryl chloride (0.07 g) dissolved in chloroform (1.0 ml) was then added over 15 minutes and the mixture stirred at 45° C. for 16 hours. A third portion of sulfuryl chloride (0.07 g) in chloroform (1.0 ml) was added over 30 minutes with the mixture being stirred for a further 2 hours, following which a final portion of the sulfuryl chloride (0.07 g) in chloroform (1.0 ml) was added and the mixture stirred for a final period of 30 minutes. After cooling the reaction mixture to the ambient temperature water (20 ml) was added and the mixture extracted with hexane (25 ml). The pH of the aqueous portion was adjusted to pH7 with 10% sodium hydroxide solution and extracted with hexane (25 ml). The combined hexane extracts were washed with water (2×20 ml) and then dried over anhydrous magnesium sulfate. Removal of the solvent by evaporation under reduced pressure yielded of 5-chloro-2-(4,4-difluorobut-3-enylthio)thiazole (1.13 g, 88%), identical to the product of Example 3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][N:16]([C:18]([O:20]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:15][CH:14]([C:30]([O:32][CH3:33])=[O:31])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH:34]1[CH2:39][CH2:38][S:37][CH2:36][CH2:35]1.C(N(CC)C(C)C)(C)C.CN1CCCC1=O>C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][N:16]([C:18]([N:34]3[CH2:39][CH2:38][S:37][CH2:36][CH2:35]3)=[O:20])[CH2:15][CH:14]([C:30]([O:32][CH3:33])=[O:31])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: C1CSCCN1
Reactant: COC(=O)C1CC(c2ccc(C(F)(F)F)c(F)c2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(c2ccc(C(F)(F)F)c(F)c2)CN(C(=O)N2CCSCC2)C1
Temperature: 150 °C

Procedure:
651 mg (1.38 mmol) of the compound from Example 83A, 0.99 g (9.69 mmol) of thiomorpholine and 0.84 ml (0.63 g, 4.84 mmol) of N,N-diisopropylethylamine were added to 9 ml of 1-methyl-2-pyrrolidone and heated in a single-mode microwave (Emrys Optimizer) at 150° C. for 1 h. For workup, the reaction solution was admixed with water. After addition of ethyl acetate and phase separation, the organic phase was washed with aqueous 1 N hydrochloric acid solution, dried (magnesium sulphate), filtered and concentrated under reduced pressure. This gave 550 mg of crude product in 80% purity (LC-MS), which was reacted without any further purification steps.
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[C:15]([Br:16])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[Br:17].[CH3:18]O>>[NH2:6][C:7]1[C:8]([Br:17])=[CH:9][C:10]([C:11]([O:13][CH3:18])=[O:12])=[CH:14][C:15]=1[Br:16]
Reactant: CO
Reactant: Nc1c(Br)cc(C(=O)O)cc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)c(N)c(Br)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
conc. H2SO4 (1.35 mL, 25.48 mmol) was added dropwise to a stirred solution of 4-amino-3,5-dibromobenzoic acid (5.0 g, 16.99 mmol) in MeOH (50 mL) at ambient temperature and the reaction mixture was then stirred at 80° C. for 8 h. The reaction mixture was brought to ambient temperature, volatiles were evaporated and ice cold water was added to the residue and which was then extracted with EtOAc. The organic layer was washed with an aqueous NaHCO3 solution followed by brine and water. The solution was then dried (Na2SO4), filtered and concentrated to afford the title compound as an off white solid (5.0 g, 95%): 1H NMR (300 MHz, DMSO-d6) δ 7.91 (s, 2H), 6.20 (bs, 2H), 3.78 (s, 3H); ESIMS m/z 307.0 ([M]+); IR (thin film) 3312, 2953, 1726, 595 cm−1.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][O:12][C:13](=[O:25])[C@H:14]([CH2:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[O:19])[NH2:15].[Cl:26][C:27]1[CH:35]=[C:34]([C:36]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([OH:46])[CH:41]=2)=[O:37])[CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:26][C:27]1[CH:35]=[C:34]([C:36]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([OH:46])[CH:41]=2)=[O:37])[CH:33]=[CH:32][C:28]=1[C:29]([NH:15][C@H:14]([C:13]([O:12][CH3:11])=[O:25])[CH2:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[O:19])=[O:30]
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)O)c(Cl)c1
Reactant: COC(=O)[C@@H](N)CNC(=O)c1cccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 96 h
Yield: 70.2 %

Procedure:
Diisopropylethylamine (7.00 g, 64.2 mmol) was added to a solution of 3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester hydrochloride (Example 301; 7.00 g, 26.4 mmol), 2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acid (Example 26; 7.00 g, 22.9 mmol), and HBTU (13.00 g, 34.3 mmol) in DMF (75 mL). The solution was allowed to stir at room temperature for 4 days, and it was then concentrated to remove most of the DMF. Ethyl acetate (200 mL) was added, followed by water (200 mL) and 1 M HCl (100 mL). The layers were separated; the ethyl acetate layer was evaporated, and the residue was chromatographed (50-100% ethyl acetate/hexanes) to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester (8.30 g, 70%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:11])[NH:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl.C(=O)([O-])[O-].[Ag+2]>[CH2:12]([O:11][C:4]1[C:3]([C:1]#[N:2])=[C:8]([CH3:9])[CH:7]=[C:6]([CH3:10])[N:5]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(C)c(C#N)c(=O)[nH]1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cc1cc(C)c(C#N)c(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-cyano-4,6-dimethyl-1H-pyridin-2-one (4.6 g) in dichloromethane (150 mL) were added benzyl bromide (5.6 mL) and silver carbonate (26 g), and the mixture was stirred under shading for 3 hours at 50° C. The reaction mixture was cooled to room temperature, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=7/1) to give 2-benzyloxy-3-cyano-4,6-dimethylpyridine (7.1 g). To diisobutylaluminum hydride (1.5 mol/L solution in toluene, 8.7 mL) was added a solution of 2-benzyloxy-3-cyano-4,6-dimethylpyridine (2.4 g) in tetrahydrofuran (4.3 mL) at 0° C., and the mixture was stirred for 4 hours at 0° C. The reaction mixture was poured into 1 mol/L hydrochloric acid solution (40 mL), and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=50/1-20/1-10/1) to give 2-benzyloxy-3-formyl-4,6-dimethylpyridine (0.90 g). To a solution of 4-ethylbromobenzene (0.044 g) in tetrahydrofuran (1.2 mL) was added tert-butyllithium (1.5 mol/L solution in hexane, 0.17 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. A solution of 2-benzyloxy-3-formyl-4,6-dimethylpyridine (0.048 g) in tetrahydrofuran (1.3 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes for 0° C. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with diethylether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=5/1) to give 2-benzyloxy-4,6-dimethylpyridin-3-yl-4-ethylphenylmethanol (0.066 g). To a solution of the obtained 2-benzyloxy-4,6-dimethylpyridin-3-yl-4-ethylphenylmethanol (0.061 g) in ethanol (3.5 mL) was added 10% palladium carbon powder (0.037 g), and the mixture was stirred for 12 hours at room temperature under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: dichloro-methane/methanol=10/1) to give 3-(4-ethylbenzyl)-4,6-dimethyl-1H-pyridin-2-one (0.039 g).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>CCCCCC.C1COCC1>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1
Reactant: BrCCCCBr
Reactant: CC(C)(C)OC(=O)C1CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(CCCCBr)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
21.2 ml (52.7 mmol) of a 2.5 M solution of n-butyllithium in n-hexane were added dropwise to a solution, cooled to −78° C., of 7.4 ml (52.7 mmol) of diisopropylamine in 20 ml of abs. THF. During the addition, the reaction temperature was kept below −60° C. After 30 min of stirring at −60° C. to −70° C., this solution was added dropwise to a solution, cooled to −78° C., of 5.0 g (35.2 mmol) of tert-butyl cyclopropanecarboxylate and 15.2 g (70.3 mmol) of 1,4-dibromobutane in 20 ml of abs. THF. After the end of the addition, cooling was removed and the mixture was slowly warmed to RT with stirring. After a further 5 h of stirring at RT, the reaction mixture was added to saturated aqueous ammonium chloride solution. The mixture was extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The product was purified by chromatography on silica gel (mobile phase cyclohexane/dichloromethane 50:1). This gave 4.62 g (44.6% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCC#CCCCC(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)CCCC#CCNS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 24 h
Yield: 19 %

Procedure:
4-Chlorobenzenesulphonyl chloride (0.31 g) in chloroform (2 ml) was added to a rapidly stirred solution of 7-aminohept-5-ynoic acid (0.2 g) and sodium hydroxide (0.21 g) in water (3 ml) and stirring was continued for 24 hours. The solution was extracted with chloroform (4×10 ml). The remaining aqueous layer was cooled, treated with hydrochloric acid and the resulting precipitate was collected by filtration and recrystallised from isopropanol-water to give the title compound (0.085 g). m.p. 91°-93° C.