Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1I)[CH3:7])[CH3:2].C(N(CCC)CCC)CC.C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=2)[NH:8][C:6]=1[CH3:7])=[O:22])[CH3:2]
Reactant: CCOC(=O)C=C(C)Nc1ccc(CC(=O)OCC)cc1I
Agent: CCCN(CCC)CCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc2[nH]c(C)c(C(=O)OCC)c2c1
Temperature: 120 °C
Yield: 38 %

Procedure:
To a solution of 3-(4-ethoxycarbonylmethyl-2-iodo-phenylamino)but-2-enoic acid ethyl ester (12.5 g, 30 mmol) in DMF (30 mL), tripropylamine (4.3 g, 30 mmol), and Pd(II)acetate (0.33 g, 1.5 mmol) are added, and the reaction mixture is heated at 120° C. for 1 hour. After cooling to room temperature, ethyl acetate (150 mL) is added. The organic layer is washed with water (2×100 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude material is recrystallized from hexane/ethyl acetate to give a yellow-orange solid (3.3 g, 38%). MS: 290 (M+1)+.
Reaction SMILES: [C:1]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:14]N1C(C)(C)C(=O)N(Br)C1=O>C1(C)C=CC=CC=1>[Br:14][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8]
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Br)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 18 h
Yield: 176.5 %

Procedure:
t-Butyl ethyl malonate (25.00 g, 0.13 mol) was dissolved in toluene and warmed to 80° C. To the resulting solution was added 1,3-dibromo-5,5-dimethylhydantoin (25.00 g, 0.07 mol). The reaction was stirred at elevated (80° C.) temperature 18 h. The reaction was cooled concentrated and taken up in Et2O. The organic layer was washed, with sat. NaHCO3 (2×), brine (3×), dried (MgSO4), filtered and concentrated. Purification by filtration on silica (70:30; hept:EtOAc) yielded 33.0 g (93%) of a light yellow oil. NMR and MS indicated a mixture of three compounds SM (20%), monobrominated (55%) and dibromonated diesters (25%). The material was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=3)[O:10][C:3]=12.[CH3:19][C:20]1[C:28]([NH2:29])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][NH:24]2>>[CH3:19][C:20]1[C:28]([NH:29][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=4)[O:10][C:3]=23)=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][NH:24]2
Reactant: OCc1ccc(-c2cc3nccc(Cl)c3o2)cc1
Reactant: Cc1c(N)ccc2[nH]ccc12
Product: Cc1c(Nc2ccnc3cc(-c4ccc(CO)cc4)oc23)ccc2[nH]ccc12

Procedure:
The title compound was prepared by procedure E using [4-(7-chlorofuro[3,2-b]pyridin-2-yl)phenyl]methanol (20.40 mg; 0.08 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (12.06 mg; 0.08 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a beige solid (8 mg, 28%). (HPLC (method F): 97%, RT: 3.30 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 11.14 (s, 1H), 8.54 (s, 1H), 7.94 (d, J=5.4, 1H), 7.91 (d, J=8.2, 2H), 7.42 (d, J=8.1, 2H), 7.40-7.35 (m, 2H), 7.30 (d, J=8.3, 1H), 7.00 (d, J=8.4, 1H), 6.52 (s, 1H), 6.09 (d, J=5.4, 1H), 5.26 (s, 1H), 4.55 (d, J=5.6, 2H), 2.36 (s, 3H); MS (m/z) 370 [M+H]+, RT: 3.2 min.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[OH:14][C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH:24]=O)[O:18][C:17](=[O:26])[C:16]=1[C:27](=[O:30])[CH2:28][CH3:29]>C1COCC1>[OH:14][C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:7]/[C:5]([O:4][CH3:3])=[O:6])[O:18][C:17](=[O:26])[C:16]=1[C:27](=[O:30])[CH2:28][CH3:29]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CCC(=O)c1c(O)cc(CCCC=O)oc1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=O)c1c(O)cc(CCC/C=C/C(=O)OC)oc1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (0.4 g; 10 mmol; 60% dispersion in mineral oil; Aldrich) was added to trimethyl phosphonoacetate (1.90 g; 10 mmol; Aldrich) in 25 ml THF. The reaction was stirred at 25° C. for 15 min, after which 4-(4-hydroxy-2-oxo-3-propionyl-2H-pyran-6-yl)butanal (XVI; 1.01 g; 4.3 mmol) in 40 ml THF was added. The reaction mixture was stirred at 25° C. for 2 h, quenched with saturated NH4Cl, extracted with 3×30 ml EtOAc, dried with anhydrous Na2SO4, and evaporated. The product was purified via silica flash chromatography (EtOAc gradient in hexanes).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Br-]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:8][CH:17]([CH3:22])[CH2:18][CH2:19][CH3:20])=[CH:21][CH:22]=1)[CH2:9][N:10]1[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCN(C[C@H](NC(=O)OC(C)(C)C)c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC(C)COc1ccc([C@H](CN2CCN(C)CC2)NC(=O)OC(C)(C)C)cc1
Temperature: 55 °C

Procedure:
A mixture of [(R)-1-(4-hydroxy-phenyl)-2-(4-methyl-piperazin-1-yl)-ethyl]-carbamic acid tert-butyl ester (57 mg, 0.17 mmol), K2CO3 (72 mg, 0.52 mmol) and 2-methylpenthyl bromide (60 ul, 0.42 mmol) in DMF (1 ml) was stirred at 55° C. for over night. After cool to rt, the mixture was diluted with EtOAc and washed with H2O and dried (MgSO4). Removal of the solvent provided the titled compound. MS (MH+).
Reaction SMILES: [F:1][C:2]1[C:3](B2OC(C)(C)C(C)(C)O2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([Si](C(C)C)(C(C)C)C(C)C)[CH:8]=[CH:7]2.[NH2:30][C:31]1[C:36]([F:37])=[C:35](Cl)[N:34]=[C:33]([C:39]([O:41][CH3:42])=[O:40])[C:32]=1[Cl:43].[F-].[Cs+].[Na+].[Cl-]>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.C(OCC)(=O)C.C(#N)C.O>[NH2:30][C:31]1[C:36]([F:37])=[C:35]([C:3]2[C:2]([F:1])=[C:10]3[C:6]([CH:7]=[CH:8][NH:9]3)=[CH:5][CH:4]=2)[N:34]=[C:33]([C:39]([O:41][CH3:42])=[O:40])[C:32]=1[Cl:43]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c21
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc3cc[nH]c3c2F)c(F)c(N)c1Cl
Temperature: 115 °C
Yield: 54.3 %

Procedure:
7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(triisopropylsilyl)-1H-indole (500 mg, 1.2 mmol), methyl 4-amino-3,6-dichloro-5-fluoropicolinate (290 mg, 1.2 mmol), cesium fluoride (360 mg, 2.4 mmol) and bis(triphenylphosphine)palladium(II) chloride (84 mg, 0.12 mmol) were combined in 4 mL of a 1:1 v/v acetonitrile-water and heated at 115° C. for 25 min in a Biotage Initiator microwave reactor. The mixture was partitoned between ethyl acetate and sat. NaCl and the organic phase was dried and evaporated. Purification by flash chromatography (SiO2; eluting with 0-20% ethyl acetate in dichloromethane) provided impure product. The material was purified by flash chromatography again (SiO2; eluting with 0-30% ethyl acetate in hexanes) to provide the title compound as a white solid (220 mg, 52%).
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:23]=2)[N:20]=[CH:19][CH:18]=[CH:17]3)[CH2:10][CH2:9]1)=[O:7])C>C1COCC1.CO>[F:30][C:26]1[CH:25]=[C:24]([C:22]2[N:23]=[C:14]([CH:11]3[CH2:10][CH2:9][CH:8]([C:6]([OH:7])=[O:5])[CH2:13][CH2:12]3)[CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CCC(c2cc3cccnc3c(-c3cccc(F)c3)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCC(c2cc3cccnc3c(-c3cccc(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide (1M (aq), 24.3 ml, 24.3 mmol) is added to a solution of 4-[8-(3-fluorophenyl)-[1,7]naphthyridin-6-yl]-cyclohexanecarboxylic acid ethyl ester (4.60 g, 12.14 mmol) in THF/methanol (40 ml:20 ml) and stirred at room temperature overnight. The organic solvents are removed by evaporation, then the aqueous residue diluted with water and basified to pH9 with 1M KOH. The aqueous layer is then washed with ethyl acetate (3×). The aqueous layer is acidified to pH 4 with 1M HCl to give a white precipitate, which is extracted into ethyl acetate. The ethyl acetate layer is then dried over sodium sulfate, filtered and concentrated to yield the desired product as a yellow foam. Further trituration with 1M HCl yields the product as a pale yellow powder (2.153 g). MS (AP+) 350.6
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[C:9]([NH2:11])[N:10]=3)[CH:7]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Nc1nc2ccc(Br)cn2n1
Product: CS(=O)(=O)c1ccc(-c2ccc3nc(N)nn3c2)cc1

Procedure:
N-(5-bromo-2-pyridinyl)-N′-carboethoxy-thiourea was prepared from 2-amino-5-bromopyridine (10.0 g, 0.0578 mol) in a manner analogous to Step 2a. The reaction product was isolated as a yellow solid and used without further purification. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 12.14 (br s, 1H), 11.72 (br s, 1H), 8.67-8.55 (m, 1H), 8.53 (d, J=2.4 Hz, 1H), 8.13 (dd, J=9.0, 2.5 Hz, 1H), 4.23 (q, J=7.0 Hz, 2H), 1.26 (t, J=7.0 Hz, 3H). MS=304, 306 (MH)+. 36b) 6-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from N-(5-bromo-2-pyridinyl)-N′-carboethoxy-thiourea in a manner analogous to Step 2b. The reaction product was isolated as a white solid (7.84 g, 63%). MP=187-189° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.92 (d, J=1.9 Hz, 1H), 7.55 (dd, J=9.2, 1.9 Hz, 1H), 7.33 (d, J=9.4 Hz, 1H), 6.13 (br s, 2H). MS=213, 215 (MH)+. 36c) 6-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (200.0 mg, 0.9388 mmol) and (4-methylsulfonylphenyl)boronic acid (210.0 mg, 1.050 mmol) in a manner analogous to Step 2c. The reaction product was isolated as an off-white solid (0.158 g, 58%). MP=301-303° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.08-9.05 (m, 1H), 8.06-7.97 (m, 4H), 7.86 (dd, J=9.2, 1.7 Hz, 1H), 7.48 (d, J=9.1 Hz, 1H), 6.15 (s, 2H), 3.26 (s, 3H). MS=289 (MH)+. 36d) 6-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from 6-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (50.0 mg, 0.173 mmol) and 4-(4-bromo-phenyl)-morpholine (51.0 mg, 0.211 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (20.0 mg, 0.0366 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.011 g, 14%). MP=>300° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.41 (s, 1H), 9.28 (s, 1H), 8.09 (d, J=7.7 Hz, 2H), 8.03-7.96 (m, 3H), 7.64 (d, J=8.8 Hz, 1H), 7.59 (d, J=7.9 Hz, 2H), 6.93 (d, J=8.0 Hz, 2H), 3.77-3.71 (m, 4H), 3.28 (s, 3H), 3.05-3.00 (m, 4H). MS=450 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH:5]=[CH:6][C:7]([CH:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15])=[O:8]>C(O)C.[Pd]>[OH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][CH2:6][C:7]([CH:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15])=[O:8]
Reactant: O=C(C=Cc1cccc(O)c1)C1C(=O)CCC1=O
Agent: [Pd]
Solvent: CCO
Product: O=C1CCC(=O)C1C(=O)CCc1cccc(O)c1

Procedure:
The hydrogenation of 2-(3-hydroxycinnamoyl)-1,3-cyclopentanedione as prepared in the preceding step was carried out by dissolving in ethanol in the presence of 5% palladium on charcoal at room temperature and under atmospheric pressure. 2-(3-Hydroxyhydrocinnamoyl)-1,3-cyclopentanedione was obtained in a quantitative yield, m.p 162°-165° C.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][C@H:14]([CH2:16]OS(C)(=O)=O)[O:13][C:12]2=[O:22])=[CH:7][CH:6]=1.[NH:23]1[CH:27]=[CH:26][CH:25]=[N:24]1>CN(C)C=O.O>[CH3:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][C@H:14]([CH2:16][N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)[O:13][C:12]2=[O:22])=[CH:7][CH:6]=1
Reactant: c1cn[nH]c1
Reactant: CSc1ccc(N2C[C@H](COS(C)(=O)=O)OC2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(N2C[C@H](Cn3cccn3)OC2=O)cc1
Reaction time: 1.5 h
Yield: 33.1 %

Procedure:
Sodium hydride (80% in oil, 63 mg, 2.1 mM) was stirred under nitrogen in N,N-dimethylformamide (2 ml), (5R)-3-(4-methylthiophenyl)-5-methanesulfonyloxymethyl-oxazolidin-2-one (630 mg, 2 mM) dissolved in N,N-dimethylformamide (10 ml) added, followed by pyrazole (140 mg, 2 mM) dissolved in N,N-dimethylformamide (2 ml). Stirring was continued for 1.5 hours at ambient temperature. After diluting with water (30 ml) and stirring for 1 hour, the precipitate was filtered to give the desired product (190 mg, mp 72–73°).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:14](O)(=O)[CH:15]([CH3:17])[CH3:16]>>[CH:15]([C:14]1[N:12]([CH3:13])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)([CH3:17])[CH3:16]
Reactant: CNc1c(N)cnc2ccccc12
Reactant: CC(C)C(=O)O
Product: CC(C)c1nc2cnc3ccccc3c2n1C

Procedure:
Using the method of Example 147, 3-amino-4(methylamino)quinoline (the hydrochloride salt of which having been obtained in Exmple 27) was reacted with isobutyric acid to provide 2-isopropyl-1-methyl-1H-imidazo[4,5-c]quinoline. The crude product was dissolved in ethyl acetate and an excess of concentrated hydrochloric acid was added. The precipitate was separated by filtration and recrystallized from ethanol to provide 2-isopropyl-1-methyl-1H-imidazo[4,5-c]quinoline hydrochloride, m.p. 260°-263° C. This salt was suspended in water and the mixture was basified (pH 8-10) with 50% aqueous sodium hydroxide. The solid was separated by filtration, washed with water and recrystallized from hexane to provide the free base as the hydrate, m.p. 76°-81° C. Analysis: Calculated for C14H15N3.0.25H2O: %C, 73.2; %H, 6.8; %N, 18.3; Found: %C, 73.0 %H, 7.0; %N, 18.4.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:37]([OH:38])[C@@H:36]([CH3:39])[C@@H:35]([OH:40])[C@@H:34]([CH3:41])[C@H:33]([O:42][C:43]([CH3:45])=[O:44])[C@H:32]([CH3:46])[C@@H:31]([O:47][CH3:48])[CH:30]=[CH:29][O:28][C@:25]2([CH3:49])[C:26](=[O:27])[C:15]3[C:16]([O:24]2)=[C:17]([CH3:23])[C:18]([OH:22])=[C:19]2[C:20](=[O:21])[C:10](=[C:11](Br)[C:12]([C:14]=32)=[O:13])[NH:9][C:7](=[O:8])[C:6]([CH3:51])=[CH:5][CH:4]=[CH:3]1.[OH:52]P([O-])(O)=O.[K+].O>CO.P([O-])([O-])([O-])=O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:1][C@@H:2]1[C@H:37]([OH:38])[C@@H:36]([CH3:39])[C@@H:35]([OH:40])[C@@H:34]([CH3:41])[C@H:33]([O:42][C:43]([CH3:45])=[O:44])[C@H:32]([CH3:46])[C@@H:31]([O:47][CH3:48])[CH:30]=[CH:29][O:28][C@@:25]2([CH3:49])[O:24][C:16]3[C:15]([C:26]2=[O:27])=[C:14]2[C:12]([C:11](=[O:52])[C:10](=[C:20]([OH:21])[C:19]2=[C:18]([OH:22])[C:17]=3[CH3:23])[NH:9][C:7](=[O:8])[C:6]([CH3:51])=[CH:5][CH:4]=[CH:3]1)=[O:13]
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(Br)=C(NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Reactant: O=P([O-])(O)O
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(Br)=C(NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Agent: CO[C@H]1/C=C\O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(=O)C(=C4O)NC(=O)/C(C)=C\C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Solvent: O
Solvent: CO
Product: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(=O)C(=C4O)NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C

Procedure:
A solution of 3.0 g of 3-bromorifamycin S in 50 ml of methanol and 70 ml of phosphate buffer of pH 8.0 (0.065 mole of Na2HPO4 and 0.004 mole of KH2PO4 per liter of water) is refluxed for 4 hours. The colour of the reaction solution changes during this time from blue-violet to yellow-brown. The reaction solution is then oxidised with excess potassium ferricyanide and, after acidification to pH ~3, is extracted with chloroform. After drying and concentration by evaporation of the chloroform extract, the residue is dissolved in ether and the ether solution is exhaustively extracted with phosphate buffer of pH=6. The wine-red aqueous buffer extract is acidified until the colour changes to yellow, and the precipitated 3-hydroxyrifamycin S is taken up with chloroform. After evaporating off the chloroform, 3-hydroxyrifamycin S is obtained in the form of a yellow foam, and the fact that it is identical with the fermentation product obtained earlier can be verified by thin-layer chromatography, 360-MHz-1H-NMR spectra, and by UV and IR spectra.
Reaction SMILES: Cl.Cl.[N+:3]([C:6]1[CH:28]=[CH:27][C:9]([O:10][CH2:11][CH:12]([OH:26])[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:3][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH:12]([OH:26])[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:21]=[CH:22][CH:23]=[CH:24][N:25]=3)[CH2:16][CH2:15]2)=[CH:27][CH:28]=1
Reactant: O=[N+]([O-])c1ccc(OCC(O)CN2CCN(c3ncccn3)CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ccc(OCC(O)CN2CCN(c3ncccn3)CC2)cc1
Reaction time: 5 h
Yield: 99 %

Procedure:
α-[(4-Nitrophenoxy)methyl]-4-(2-pyrimidinyl)-1-piperazineethanol dihydrochloride (1.32 g, 3.68 mmol) was hydrogenated in a Parr reactor using 5% Pd/C (0.198 g, 15% by wt) in ethyl acetate (40 mL). After 5 hours, the mixture was filtered through solka floc and the filtrate was concentrated to afford 1.2 g (100%) of product as a pale oil of sufficient purity for use in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[Li]CCCC.[NH2:14][C:15]1[C:26]([O:27][CH:28]2[CH2:30][CH2:29]2)=[CH:25][CH:24]=[CH:23][C:16]=1[C:17](N(OC)C)=[O:18].Cl>O1CCCC1>[NH2:14][C:15]1[C:26]([O:27][CH:28]2[CH2:29][CH2:30]2)=[CH:25][CH:24]=[CH:23][C:16]=1[C:17]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:18]
Reactant: Fc1cccc(I)c1
Reactant: CON(C)C(=O)c1cccc(OC2CC2)c1N
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1c(OC2CC2)cccc1C(=O)c1cccc(F)c1
Reaction time: 1 h
Yield: 69.1 %

Procedure:
A solution of 1-fluoro-3-iodobenzene (1.009 mL, 8.59 mmol) in tetrahydrofuran (100 mL) was cooled to −78° C. in a dry ice/acetone bath under nitrogen. Then a solution of n-BuLi (1.8 M in hexanes, 5.37 mL, 8.59 mmol) was added via syringe over 15 minutes and stirred for 60 minutes to give gave a dark-yellow suspension. Then a solution of 2-amino-3-cyclopropoxy-N-methoxy-N-methylbenzamide (0.58 g, 2.455 mmol) in 10 mL of THF was added via syringe and the reaction mixture was stirred for 40 minutes at −78° C. After 40 minutes the mixture was poured into a mixture of ice and 1N HCl and extracted into ethyl acetate to give a light-yellow solution. The organic layer was washed with water and brine and concentrated to give a dark-yellow oil residue. The crude product mixture was purified via ISCO (0%-100% of EtOAC/heptane in 15 minutes, 40 g column) to give (2-amino-3-cyclopropoxyphenyl)(3-fluorophenyl)methanone (0.46 g, 1.696 mmol, 69.1% yield). HPLC: RT=3.481 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES):m/z=272.16 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ 7.48-7.40 (m, 2H), 7.36 (ddd, J=9.3, 1.9, 1.1 Hz, 1H), 7.27-7.18 (m, 2H), 7.08 (dd, J=8.3, 1.2 Hz, 1H), 6.58 (t, J=8.0 Hz, 1H), 6.39 (br. s., 2H), 3.83 (t, J=4.5 Hz, 1H), 0.86 (d, J=4.4 Hz, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([CH:13]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH:30]4[CH2:32][CH2:31]4)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)=[N:6][CH:7]=1.[SH:33][CH2:34][CH2:35][OH:36]>CN(C)C=O.C(OCC)(=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>[CH:30]1([S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:13]([C:10]3[NH:9][C:8]([C:5]4[N:6]=[CH:7][C:2]([S:33][CH2:34][CH2:35][OH:36])=[CH:3][CH:4]=4)=[CH:12][CH:11]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH2:32][CH2:31]1
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(Br)cn3)[nH]2)cc1)C1CC1
Reactant: OCCS
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: CCOC(C)=O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(SCCO)cn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Yield: 57 %

Procedure:
To a solution of 5-bromo-2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine (200 mg) in N,N-dimethylformamide (1 mL) were added 2-sulfanylethanol (63 μL) and tetrakistriphenylphosphinepalladium(0) (230 mg), and the mixture was stirred using a microwave synthesis apparatus at 120° C. for 3 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (114 mg, yield 57%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 513 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][CH:9]([C:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[O:21][C:16]([CH2:17][CH:18]([CH3:20])[CH3:19])=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(F)cc1)C(=O)CC(C)C
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1CC(C)C
Yield: 75.6 %

Procedure:
3.5 g of ethyl 3-(4-fluorobenzoylamino)-3-isovalerylpropionate, 20 ml of dimethylformamide and 4.1 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 2.5 g of ethyl 2-[2-(4-fluorophenyl)-5-isobutyl-4-oxazolyl]acetate are thereby obtained. Yield: 75.5%.
Reaction SMILES: O.NN.[CH3:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:30]>C(O)C>[NH2:19][CH2:18][CH2:17][CH2:16][O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:5]([CH3:4])[C:6](=[O:30])[CH:7]=[CH:8]2
Reactant: Cn1c(=O)ccc2cc(OCCCN3C(=O)c4ccccc4C3=O)ccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: Cn1c(=O)ccc2cc(OCCCN)ccc21
Yield: 77 %

Procedure:
Hydrazine hydrate (6.54 ml) was added to a ethanol solution (250 ml) of 2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propyl]isoindole-1,3-dione (16.28 g), and stirred while heating under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure. A 1N-sodium hydroxide aqueous solution was added to the residue, and stirred for 30 minutes, and extraction with dichloromethane was performed. The organic layer was washed with water and a saturated sodium chloride aqueous solution, in this order. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (8.04 g) as a colorless oil.