Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:10])[CH2:7][CH2:8][CH3:9])=[CH:2]1.C(O)(=O)C.[Br:15]Br>C(OCC)C>[Br:15][CH:7]([CH2:8][CH3:9])[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:10]
Reactant: CCCC(=O)c1ccsc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCC(Br)C(=O)c1ccsc1
Temperature: 25 °C
Yield: 60.9 %

Procedure:
1-Thiophen-3-yl-butan-1-one (6.7 g. 43 mmol) in 210 mL diethyl ether was cooled to zero degrees C., and 0.6 ml glacial acetic acid was added dropwise, followed by bromine (2.26 ml, 46 mmol) dropwise. The reaction mixture was allowed to warm to room temperature over hours. The reaction mixture was washed the with water, 1 N sodium thiosulfate, brine, and then dried over magnesium sulfate. Solvent was removed under reduced pressure to give an oil which was chromatographed (5% EtOAc/Hexanes) to give 6.1 g 2-Bromo-1-thiophen-3-yl-butan-1-one, 79%, as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=2[C:15]([CH3:17])=[CH2:16])[CH2:6][CH2:5]1)[CH3:2].[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1)[CH3:19]>C(N(CC)CC)C.[Cu]I.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>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:25]3[CH:26]=[CH:27][C:22]([C:21]([O:20][CH2:18][CH3:19])=[O:29])=[CH:23][CH:24]=3)=[CH:9][C:8]=2[CH:15]([CH3:17])[CH3:16])[CH2:6][CH2:5]1)[CH3:2]
Reactant: C#Cc1ccc(C2(OCC)CC2)c(C(=C)C)c1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC)CC3)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-isopropenylbenzene (Intermediate 103, 50.0 mg, 0.22 mmol) and ethyl-4-iodo benzoate (Reagent A, 60.0 mg, 0.22 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (14.0 mg, 0.07 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (51 mg, 0.07 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (1-2% EtOAc-hexanes) afforded 28.0 mg (34%) of the title compound.
Reaction SMILES: [S-:1][C:2]#N.[K+].[CH2:5]([O:12][C:13]1[C:22]2[CH2:21][CH:20]3OC3[CH2:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[CH2:5]([O:12][C:13]1[C:22]2[CH2:21][CH:20]3[S:1][CH:2]3[CH2:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#C[S-]
Reactant: c1ccc(COc2cccc3c2CC2OC2C3)cc1
Agent: [K+]
Solvent: CCO
Product: c1ccc(COc2cccc3c2CC2SC2C3)cc1
Reaction time: 48 h

Procedure:
To 0.125 mole of potassium thiocyanate in 20 ml. of 50% ethanol is added 0.10 mole of 6,7-epoxy-5,6,7,8-tetrahydro-1-naphthyl benzyl ether and the mixture stirred vigorously for 48 hours. The product is extracted into ether, washed with salt solution, dried and freed of solvent. Ref: O.S. IV 232.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[I:14])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].FC(F)(F)S(O[CH2:24][C:25]([F:28])([F:27])[F:26])(=O)=O.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:15])[N:7]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[I:14])[CH2:24][C:25]([F:28])([F:27])[F:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cnccc1I
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cnccc1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (280 mg, 875 μmol) in DMF (4 mL) was added NaH (42.0 mg, 962 μmol, 60% dispersion in mineral oil) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes. 2,2,2-Trifluoroethyl trifluoromethanesulphonate (203 mg, 126 μL, 875 μmol, CAS RN 6226-25-1) was added and the reaction stirred at room temperature for 2 hours. The reaction mixture was poured on 30 mL 10% aqueous NaHCO3 solution and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc and the combined organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 30:70). Colorless solid (207 mg, 59%). MS (ESI): m/z=403.012 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)C=C.[CH3:14][C:15]1C=CC(C)=C(C)[C:16]=1C>>[CH2:16]([C:6]1[C:5]([OH:4])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)[CH:15]=[CH2:14]
Reactant: Cc1ccc(C)c(C)c1C
Reactant: C=CCOc1ccc2[nH]ccc2c1
Product: C=CCc1c(O)ccc2[nH]ccc12
Temperature: 190 °C
Yield: 70 %

Procedure:
5-(Allyloxy)-1H-indole (514 mg, 2.97 mmol) (Example 53) was dissolved in 1,2,3,4-tetramethylbenzene (2.5 mL), and the reaction mixture was heated at 190° C. for 2 h. The mixture was cooled to rt and sonicated for 30 min. The mixture was then purified by silica gel column chromatography (EtOAc/hexane (v/v)=1:9) to give 361 mg (70%) of the title compound as a white crystalline solid. 1H NMR (400 MHz, CDCl3): δ 3.68 (d, 2H), 5.13 (d, 1H), 5.18 (d, 1H), 6.07 (m, 1H), 6.45 (s, 1H), 6.79 (d, 1H), 7.12-7.18 (m, 2H), 8.06 (br, 1H).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([N+:18]([O-:20])=[O:19])=[CH:8][C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[K+].[Br-]>>[N+:18]([C:9]1[CH:8]=[C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]([O:5][CH2:4][C:3]([OH:27])=[O:2])=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=1)([O-:20])=[O:19]
Reactant: COC(=O)COc1c(-c2ccccc2)cc([N+](=O)[O-])cc1-c1ccccc1
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1c(-c2ccccc2)cc([N+](=O)[O-])cc1-c1ccccc1

Procedure:
The title compound was prepared as a white solid (0.229 g, 86%) from (5′-nitro-[1,1′;3′,1″]terphenyl-2′-yloxy)acetic acid methyl ester using a procedure similar to step2 of Example 36, mp 153.5-156° C.; 1H NMR (DMSO-d6) δ3.92 (s, 2H), 7.42-7.52 (m, 6H), 7.61-7.65 (m, 4H), 8.13 (s, 2H), 12.15-13.20 (bs, 1H); IR (KBr) 3410, 3070, 2910, 2570, 1750, 1705, 1590, 1525, 1500, 1450, 1410, 1395, 1350, 1305, 1290, 1250, 1220, 1110, 1070, 910, 745, 725, and 710 cm−1; mass spectrum [EI], m/z 349 (M)+; Anal. Calcd. for C20H15NO5: C, 68.76; H, 4.33; N, 4.01, Found: C, 68.66; H, 4.33; N, 3.89.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.O[C:9]([CH3:19])([CH3:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11]>C1(C)C=CC=CC=1>[C:6]([C:9]([CH3:19])([CH3:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])(=[O:7])[NH2:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(O)C(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C(N)=O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
A solution of chlorosulfonyl isocyanate in toluene was added to a solution of 2-hydroxy-2-methyl propiophenone in anhydrous toluene at 0° C. The mixture was stirred at room temperature for 1.5 hours then the resulting precipitate was collected. The precipitate was taken up in dioxane, cooled to 0°, then triturated with water. Prior to extraction with ether the dioxane solution was stirred overnight at room temperature. Extracted ether phase was treated with aqueous sodium bicarbonate until neutral, dried over sodium sulfate, and concentrated to leave a clear colorless oil. Upon trituration with petroleum ether the oil crystallized to leave a white solid. After drying the solid, 2-carbamoyl-2-methyl propiophenone was obtained in 60% yield. This carbamate was heated at 180° C. under a weak vacuum to form the imine. The carbamate melted at 120° C., was stirred at 180° C. for 30-50 minutes, then solidified upon cooling. The crude product was recrystallized from benzene/cyclohexane to give a 73% yield of the desired product with mp. 106°-108.5° C. (lit. 111-111.5). The product was confirmed by NMR, MS, and IR analysis. ##STR15##
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=[C:10]([C:11]([O:13]C)=O)[C:4]=2[O:3]1.[CH2:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][NH2:27])[CH3:20].O>C(O)COCCO>[CH2:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][NH:27][C:11]([C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=1)=[O:13])[CH3:20]
Reactant: CCN1CCCC1CN
Reactant: COC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Solvent: O
Solvent: OCCOCCO
Product: CCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 10 g of methyl 2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylate and 7.0 g of 1-ethyl-2-aminomethylpyrrolidine in 50 ml of diethylene glycol is heated at 120°-130° C. and stirred for 18 hours. The reactant solution is cooled to room temperature and added slowly with stirring to 300-400 ml of water. Under ice-cooling crystals are thoroughly deposited. The crude crystals are collected by suction filtration and washed with cold water. The crude crystals obtained are dried and recrystallized from about 220-230 ml of ethyl acetate by the use of decolorizing charcoal to give crystals of N-(1-ethyl-2-pyrrolidinylmethyl)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide, m.p. 167°-169° C.
Reaction SMILES: [Na+].[C:2]([S:5][CH2:6][CH:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([O-:16])=[O:15])=[O:9])(=[O:4])[CH3:3].Cl>O>[C:2]([S:5][CH2:6][CH:7]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:9])(=[O:4])[CH3:3]
Reactant: CC(=O)SCC(Cc1ccc(F)cc1)C(=O)Nc1cccc(C(=O)[O-])c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=O)SCC(Cc1ccc(F)cc1)C(=O)Nc1cccc(C(=O)O)c1
Yield: 84.7 %

Procedure:
3-[[2-Acetylthiomethyl-3-(4-fluorophenyl)propionyl]amino]benzoic acid sodium salt (compound of Example 40) (0.5 g) is dissolved in water (10 ml), and the mixture is adjusted to pH 2.5 with 1N hydrochloric acid with stirring under ice cooling, and the mixture is extracted with ethyl acetate (20 ml). The extract is washed with water and dried over anhydrous magnesium sulfate, and then ethyl acetate is distilled off to give the title compound (0.4 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].CS(C)=O.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[C:16]1([S:22]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of indole (11.7 g, 0.1 mol) in THF is added to a stirred mixture of NaH (60% dispersion in mineral oil, 4.2, g 0.105 mol), DMSO and THF. The reaction mixture is stirred for 1 h at room temperature, cooled to 0° C., treated with phenylsulfonyl chloride (13.3 mL, 0.15 mol), stirred at ambient temperatures for 3 h, quenched with water and extracted with ethyl acetate. The extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue is crystallized in ethanol and filtered. The filtercake is air-dried to give 1-phenylsulfonylindole. A portion of this 1-phenylsulfonylindole (257 mg, 1.0 mmol) and cyclohexylcarbonyl chloride (0.175 mL, 1.3 mmol) in methylene chloride is treated with tin tetrachloride (97 μL, 1.9 mmol) at room temperature, shaken for 6 h, quenched with saturated NaHCO3 and extracted with ethylacetate. The extracts are combined and concentrated in vacuo to give a residue. The residue is suspended in isopropanol, treated sequentially with concentrated HCl (50 μL) and aminoguanidine bicarbonate (100 mg, 0.5 mmol), heated at 80° C. for 4 h, cooled to room temperature and concentrated in vacuo. The resultant residue is purified by HPLC to afford the title product 37.7 mg (17% yield), identified by HPLC1 and mass spectral analyses.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[NH:12][CH:11]=2)=[CH:5][N:4]=1.[H-].[Na+].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[C:21]1([S:27]([N:12]2[C:13]3[N:14]=[CH:15][N:16]=[CH:17][C:18]=3[C:10]([CH2:9][C:6]3[CH:5]=[N:4][C:3]([S:2][CH3:1])=[N:8][CH:7]=3)=[CH:11]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CSc1ncc(Cc2c[nH]c3ncncc23)cn1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncncc23)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54 %

Procedure:
To 5-(2-methylsulfanyl-pyrimidin-5-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (56, 1.20 g, 4.66 mmol) in 55.0 mL of N,N-dimethylformamide, sodium hydride (0.280 g, 7.00 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes, followed by addition of benzenesulfonyl chloride (40, 0.714 mL, 5.60 mmol). The reaction was stirred at room temperature for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (57, 1.00 g).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[S:7][C:6]([CH3:8])=[C:5]([Cl:9])[C:4]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:30]([C:32]([CH3:44])=[CH:33][CH:34]=[CH:35][C:36]([CH3:43])=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=O>C1OCCC1>[CH2:41]([O:40][C:38](=[O:39])[CH:37]=[C:36]([CH3:43])/[CH:35]=[CH:34]/[CH:33]=[C:32]([CH3:44])[CH:30]=[CH:10][C:4]1[C:5]([Cl:9])=[C:6]([CH3:8])[S:7][C:3]=1[Cl:2])[CH3:42]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Reactant: Cc1sc(Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)/C=C/C=C(C)C=Cc1c(Cl)sc(C)c1Cl

Procedure:
A suspension of 10.83 g. (22.6 mmol) of (2,4-dichloro-5-methyl-3-thenyl)triphenyl phosphonium chloride and 5.15 g. (24.8 mmol) of ethyl 7-formyl-3-methyl-2,4,6-octatrienoate in 350 ml. of butylene oxide was heated to 70° C. for 4.5 hrs. The resulting clear solution was cooled, poured into 500 ml. of a methanol/water mixture (6:4) and extracted with hexane. The combined hexane extracts were washed with methanol/water (6:4), dried and evaporated. The resulting crude material was purified by chromatography (silica gel, hexane/ethyl acetate=4:1) to yield after recrystallization from hexane, all trans-3,7-dimethyl-9-(2,4-dichloro-5-methyl-3-thienyl)-2,4,6,8-nonatetraenoic acid ethyl ester, m.p. 99°-100° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[N:10]1([S:16]([C:19]2[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)(=O)C>[CH3:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([S:16]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)(=[O:18])=[O:17])[CH:20]=2)=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)nc1N
Reactant: Nc1cccc(S(=O)(=O)N2CCCCC2)c1
Solvent: CC(=O)O
Product: Cc1cnc(Nc2cccc(S(=O)(=O)N3CCCCC3)c2)nc1N
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.25 g, 1.74 mmol) and 3-(piperidine-1-sulfonyl)-phenylamine (0.50 g, 2.1 mmol) in acetic acid (4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 130° C. for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and pH adjusted to 9 with 10% NaOH solution. The resulting solution was extracted with EtOAc (2×30 mL) and the organic layer separated. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the crude product (˜0.6 g) used in the next step without purification. MS (HS t): m/z 348 (M+H)+.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[O:10])[O:5][C@@H:4]([N:18]2[CH:25]=[C:24](I)[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:3]1.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>C(N(CC)CC)C.CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[O:10])[O:5][C@@H:4]([N:18]2[CH:25]=[C:24]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:3]1
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3cc(I)c(=O)[nH]c3=O)C[C@@H]2F)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3cc(C#C[Si](C)(C)C)c(=O)[nH]c3=O)C[C@@H]2F)cc1
Reaction time: 8 h

Procedure:
A solution of the product of Stage b), (0.8 g, 1.69 mmoles), bis(triphenylphosphine) palladium (II) chloride (25 mg) and copper (I) iodide (25 mg) in dry triethylamine (40 ml) and N,N-dimethylformamide (3 ml) was degassed thoroughly with nitrogen. (Trimethylsilyl) acetylene (0.47 ml, 3.37 mmoles) was added and the mixture stirred under N2 at 50° for 8 hours. The solvent was removed under reduced pressure, the residue dissolved in methylene chloride (40 ml) and the solution washed with 2% aqueous disodium EDTA solution (4 ml), water (50 ml) and dried (sodium sulphate). Evaporation of the solvent and purification of the residue by silica column chromatography eluting with 2% MeOH/CH2Cl2 afforded the title compound. Trituration with ether/hexane afforded analytically pure title compound as an off-white powder.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[NH2:22][C@@H:23]([CH2:29][CH:30]1[CH2:32][CH2:31]1)[C:24]([N:26]([CH3:28])[CH3:27])=[O:25]>>[CH:30]1([CH2:29][C@H:23]([NH:22][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[C:24](=[O:25])[N:26]([CH3:27])[CH3:28])[CH2:32][CH2:31]1
Reactant: CN(C)C(=O)[C@@H](N)CC1CC1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: CN(C)C(=O)[C@H](CC1CC1)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (S)-2-amino-3-cyclopropyl-N,N-dimethylpropanamide hydrochloride (Example 222 b) as starting materials. MS (EI): m/e=423.0 [M+H]+.
Reaction SMILES: CO[C:3]1[C:6](=[O:7])[C:5](=[O:8])[C:4]=1[NH:9][C:10]1[CH:11]=[C:12]([S:16]([N:19]2[CH2:23][CH2:22][CH2:21][C@@H:20]2[C:24]([O:26][CH3:27])=[O:25])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1.[CH3:28][C:29]1[O:33][C:32]([CH:34]([NH2:40])[C:35]2([CH3:39])[CH2:38][O:37][CH2:36]2)=[CH:31][CH:30]=1>C(O)C>[CH3:28][C:29]1[O:33][C:32]([CH:34]([NH:40][C:3]2[C:6](=[O:7])[C:5](=[O:8])[C:4]=2[NH:9][C:10]2[CH:11]=[C:12]([S:16]([N:19]3[CH2:23][CH2:22][CH2:21][C@@H:20]3[C:24]([O:26][CH3:27])=[O:25])(=[O:17])=[O:18])[CH:13]=[CH:14][CH:15]=2)[C:35]2([CH3:39])[CH2:36][O:37][CH2:38]2)=[CH:31][CH:30]=1
Reactant: COC(=O)[C@H]1CCCN1S(=O)(=O)c1cccc(Nc2c(OC)c(=O)c2=O)c1
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Solvent: CCO
Product: COC(=O)[C@H]1CCCN1S(=O)(=O)c1cccc(Nc2c(NC(c3ccc(C)o3)C3(C)COC3)c(=O)c2=O)c1
Temperature: 60 °C
Yield: 76.7 %

Procedure:
A mixture of 408.4 mg of methyl (R)-1-[3-(2-methoxy-3,4-dioxocyclobut-1-enylamino)benzenesulfonyl]pyrrolidine-2-carboxylate and 350 mg of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine in 30 ml of ethanol was heated at 60° C. overnight. The solvent was evaporated off and the residue was taken up with 50 ml of ethyl acetate and washed twice with a 1 M sodium hydrogen phosphate solution. The organic phase was dried over magnesium sulfate and evaporated. 432 mg of methyl (R)-1-[3-(2-{[(5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methyl]amino}-3,4-dioxocyclobut-1-enylamino)benzenesulfonyl]pyrrolidine-2-carboxylate were obtained. Yield=79%.
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=O.[CH2:34]([NH2:37])[CH2:35][CH3:36]>>[OH:1][CH:2]([C:3](=[O:5])[NH:37][CH2:34][CH2:35][CH3:36])[CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCN
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Product: CCCNC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 2-hydroxy-4-phenyl-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with n-prop-1-ylamine; ESI-MS [M+H]+: 484.2
Reaction SMILES: [OH:1][CH:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14](S(C)(=O)=O)[N:13]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([O:1][CH:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4])[N:13]=1
Reactant: Cc1cc(C)nc(S(C)(=O)=O)n1
Reactant: COC(=O)C(O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1nc(C)cc(C)n1)C(C)(C)C
Temperature: 100 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
2.9 g of methyl 2-hydroxy-3,3-dimethybutyrate, 4.1 g of 4,6 -dimethyl-2-methylsulfonylpyrimidine and 3.3 g of potassium carbonate were added to 50 ml of N,N-dimethylformamide, and the mixture was stirred at 100° C. for 4 hours. The reaction solution was cooled to room temperature, poured into water and extracted with 100 ml of ethyl acetate. The organic layer was washed twice with a sodium chloride aqueous solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The liquid substance thereby obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate =6/1) to obtain 4.2 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[CH2:29][CH2:30][O:26][C:27]4=[O:31])=[CH:3][C:4]=3[F:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: O=C1NCCO1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3F)CC2)c(C)c1
Yield: 71.1 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (863 mg) described in Preparation Example 100 and oxazolidin-2-one (261 mg), the title compound (623 mg) was obtained.