Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].[C:9]([C:11]1[CH:12]=[C:13]([N:20]([C:25]2[C:44]([CH:45]3[CH2:47][CH2:46]3)=[CH:43][C:28]3[C:29]([C:39]([NH:41][CH3:42])=[O:40])=[C:30]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[O:31][C:27]=3[CH:26]=2)[S:21]([CH3:24])(=[O:23])=[O:22])[CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)#[N:10]>O.C1COCC1>[NH2:17][C:16]1[CH:15]=[CH:14][C:13]([N:20]([C:25]2[C:44]([CH:45]3[CH2:47][CH2:46]3)=[CH:43][C:28]3[C:29]([C:39]([NH:41][CH3:42])=[O:40])=[C:30]([C:32]4[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=4)[O:31][C:27]=3[CH:26]=2)[S:21]([CH3:24])(=[O:23])=[O:22])=[CH:12][C:11]=1[C:9]#[N:10]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C#N)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(C#N)c3)S(C)(=O)=O)c(C3CC3)cc12
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A solution of Na2S2O4 (7.24 g, 41.6 mmol) in water (70 mL) was added dropwise to a solution of 6-(N-(3-cyano-4-nitrophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (3.8 g, 6.93 mmol) in THF at room temperature under N2. The mixture was stirred overnight. H2O was added to the mixture and then extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4. After concentration, the crude residue was purified by chromatography on silica gel eluted with 0-20% EtOAC in DCM to give the desired product as a white solid (2.67 g, 74.3%). LCMS (m/z, ES+)=519 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](/[N:10]=[CH:11]/[N:12](C)C)=O)=[N:6][CH:7]=1.[NH2:15]N>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:10]=[CH:11][NH:12][N:15]=2)=[N:6][CH:7]=1
Reactant: NN
Reactant: CN(C)/C=N/C(=O)c1ccc(Br)cn1
Product: Brc1ccc(-c2nc[nH]n2)nc1
Yield: 83.2 %

Procedure:
A solution of (E)-5-bromo-N-((dimethylamino)methylene)picolinamide (0.604 mg, 2.36 mmol) and hydrazine (2.12 g, 66.1 mmol) was stirred at 25° C. for 3 h. The reaction was concentrated and diluted with water. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (0.442 g, 83% yield). MS (ESI) m/z 226.1 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[S:11]([C:14]1[N:18]=[CH:17][NH:16][N:15]=1)(=[O:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28]>CN(C)C=O>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[S:11]([C:14]1[N:18]=[CH:17][N:16]([C:27](=[O:28])[N:26]([CH3:30])[CH3:25])[N:15]=1)(=[O:13])=[O:12]
Reactant: Cc1nc2ccccn2c1S(=O)(=O)c1nc[nH]n1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2ccccn2c1S(=O)(=O)c1ncn(C(=O)N(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2-methylimidazo[1,2-a]pyridin-3-yl)sulfonyl-1H-1,2,4-triazole (100 mg), anhydrous potassium carbonate (105 mg) and N,N-dimethylformamide (0.5 ml) was added dimethylcarbamoyl chloride (0.06 ml), and the reaction mixture was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate-water. The organic layer was washed with water, followed by saturated aqueous sodium chloride solution, and concentrated. The residue was subjected to a silica-gel column chromatography with 30 to 50% (20% 2-propanol/ethyl acetate)/hexane to yield the title compound (107 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]([O:15]CC)=O)[C:11](=O)[C:10](=[O:19])[N:9]2[C:20]2[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=2)=[CH:4][CH:3]=1.[CH3:29][NH:30][NH2:31]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:12]3[C:11](=[N:31][N:30]([CH3:29])[C:13]=3[OH:15])[C:10](=[O:19])[N:9]2[C:20]2[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1C(=O)C(=O)N(c2cc(C)c(=O)n(C)c2)C1c1ccc(Cl)cc1
Reactant: CNN
Solvent: ClCCl
Product: Cc1cc(N2C(=O)c3nn(C)c(O)c3C2c2ccc(Cl)cc2)cn(C)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 57 using ethyl 2-(4-chlorophenyl)-1-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dioxopyrrolidine-3-carboxylate (Step 73.2) and methyl hydrazine at reflux for 32 hr. tR: 0.68 min (LC-MS 2); ESI-MS: 385 [M+H]+, ESI-MS: 383 [M−H]− (LC-MS 2); Rf=0.23 (CH2Cl2/7.5% MeOH/1% AcOH); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.90 (s, 3H) 3.34 (s, 3H) 3.44 (m, 3H) 5.62 (s, 1H) 7.09 (d, J=8.6 Hz, 2H) 7.17-7.34 (m, 3H) 7.60 (d, J=2.7 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][C:19]=4[S:20][C:3]=1[C:4]=23.Br>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:19]=4[S:20][C:3]=1[C:4]=23
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1cc(OC)ccc1-2
Agent: Br
Product: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1cc(O)ccc1-2

Procedure:
Reaction of 5-amino-N,N-diethyl-8-methoxy-2H-[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine with 48% HBr as described in Example 64 gave the product.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[C:5]2[N:10]([CH3:11])[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.C(O)(C(F)(F)F)=O>O>[C:14]1([CH3:21])[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=1[O:12][C:4]1[C:5]2[N:10]([CH3:11])[CH:9]=[CH:8][C:6]=2[N:7]=[C:2]([NH:22][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[N:3]=1
Reactant: Cc1cc(C)c(Oc2nc(Cl)nc3ccn(C)c23)c(C)c1
Reactant: N#Cc1ccc(N)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3ccn(C)c23)c(C)c1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
In a sealed tube was added 2-chloro-4-(mesityloxy)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (52.7 mg, 0.18 mmol), 4-aminobenzonitrile (83 mg, 0.70 mmol), TFE (1.0 mL) and TFA (0.11 mL, 1.44 mmol). The reaction mixture was stirred at 90° C. for 48 h. Upon completion of the reaction, the resulting mixture was cooled, diluted with water and washed with EtOAc. The combined organic layers were washed with NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC, eluting with hexanes:ethyl acetate (5:1-2:1), to give the product as a light yellow solid
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:21][CH3:22])=[C:18]([Pb+3])[CH:19]=1.[C:23]1(=[O:30])[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH2:24]1.C1(C)C=CC=CC=1.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:21][CH3:22])=[C:18]([CH:24]2[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][C:23]2=[O:30])[CH:19]=1
Reactant: O=C1CCCC(=O)C1
Reactant: CCc1ccc(Br)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1ccc(Br)cc1C1C(=O)CCCC1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-2-ethylphenyllead triacetate (20.00 g, 35.2 mmol) (described in WO08/071,405) in chloroform (100 ml) is added cyclohexane-1,3-dione (3.94 g, 35.2 mmol) and 4-dimethylaminopyridine (22.36 g, 176 mmol). After stirring the reaction at room temperature for 5 minutes toluene (50 ml) is added and the solution is heated at 80° C. for 4 hours. After cooling to room temperature the mixture is allowed to stand overnight, followed by treatment with 2M aqueous hydrochloric acid. Following filtration of the precipitate the biphasic solution is separated, and the aqueous phase is extracted again with dichloromethane (×2). Organic fractions are combined then evaporated under reduced pressure to yield a crude product which is purified by flash column chromatography (10% ethyl acetate/hexane to 70% ethyl acetate/hexane eluant) to afford 2-(5-bromo-2-ethylphenyl)cyclohexane-1,3-dione as a white solid.
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][C:8]1[C:13]([CH3:14])=[CH:12][N:11]=[C:10]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:9]=1)(C)(C)C.C(C1NC=CN=1)(C1[NH:26]C=CN=1)=O.N>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:14][C:13]1[C:8]([CH2:7][C:6]([NH2:26])=[O:5])=[CH:9][C:10]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[N:11][CH:12]=1
Reactant: Cc1cnc(N2CCN(C)CC2)cc1CC(=O)OC(C)(C)C
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(N2CCN(C)CC2)cc1CC(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[5-Methyl-2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-acetic acid tert-butyl ester (320 mg, 1.05 mmol) is dissolved in a mixture of TFA and CH2Cl2 (10 ml/10 ml) and stirred at RT. After 1 h at RT, TLC analysis indicated complete conversion of starting material. The solvent is removed by rotary evaporation, and replaced by dry DMF (1.5 ml). Under an atmosphere of argon, carbonyl diimidazole (187 mg, 1.16 mmol) is added. After 30 minutes at RT, TLC analysis indicated complete conversion of the carboxylic acid. An aqueous solution of ammonia (25%, 16 ml) is added at RT. After 15 minutes at RT, solvents are removed under high vacuum. The residue is dissolved in CH2Cl2/MeOH (9:1) and purified by FCC (CH2Cl2/MeOH, slow gradient from 95:5 to 40:60) to yield the title compound. 1H NMR (d6-DMSO, 400 MHz): δ 2.07 (s, 3H), 2.38 (s, 3H), 2.64 (s, broad, 4H), 3.34 (s, 2H), 3.46 (s, broad, 4H), 6.72 (s, 1H), 6.95 (s, broad, 1H), 7.44 (s, broad, 1H), 7.87 (s, 1H). ES+−MS: 249.3 [M+H]+, ES−−MS: 247.3 [M−H]−.
Reaction SMILES: [C:1]1([C:7]2[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=2[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1>C(O)(=O)C>[C:1]1([C:7]2[C:8](=[O:9])[CH:10]=[CH:11][C:12](=[O:14])[CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(O)c(-c2ccccc2)c1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C1C=CC(=O)C(c2ccccc2)=C1

Procedure:
The procedure described in Example 3 is repeated using 3.8 g (0.02 mole) of phenylhydroquinone as the aromatic diol reactant and 10 mL toluene and 40 mL acetic acid as the solvent. The yield of phenyl-p-benzoquinone obtained is 60%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:26]4[CH:31]=[C:30]([C:32](=[O:43])[NH:33][C:34]5([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)[CH2:36][CH2:35]5)[CH:29]=[CH:28][C:27]=4[CH3:44])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.Br[CH2:46][CH2:47][O:48][Si](C(C)(C)C)(C)C.Cl>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH2:46][CH2:47][OH:48])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:26]4[CH:31]=[C:30]([C:32](=[O:43])[NH:33][C:34]5([C:37]6[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=6)[CH2:35][CH2:36]5)[CH:29]=[CH:28][C:27]=4[CH3:44])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(-c3cc(C(=O)NC4(c5ccccc5)CC4)ccc3C)cc12
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(CCO)S(C)(=O)=O)c(-c3cc(C(=O)NC4(c5ccccc5)CC4)ccc3C)cc12

Procedure:
2-(4-Fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-N-methyl-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide was prepared from the alkylation of 2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)-6-(methylsulfonamido)benzofuran-3-carboxamide using (2-bromoethoxy)(tert-butyl)dimethylsilane (K2CO3, DMF 55° C.) followed by deprotection using HCl in 1,4-dioxane at r.t. Purification was preformed by Shimadzu-VP preparative reverse phase HPLC using the separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, Fraction Collection: 6.32-6.81 min. (UV detection at 220 nm). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XTERRA® MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)+=656.06, HPLC Rt=1.563 min. Analytical HPLC were performed by using Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H2O-0.1% TFA, Solvent B=95% MeCN-5% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, Rt=6.05 min; XBridge phenyl 3.5 um, 4.6×150 mm, Rt=5.38 min. Analytical HPLC method: Solvent A=5% MeOH-95% H2O-10 mM NH4HCO3, Solvent B=95% MeOH-5% H2O-10 mM NH4HCO3, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: XBridge phenyl 3.5 um, 4.6×150 mm, Rt=11.42 min.
Reaction SMILES: [CH:1]([C:4]1[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)([CH3:3])[CH3:2].[NH2:20][C@@H:21]([CH3:37])[CH2:22][N:23]1[CH:27]=[CH:26][C:25]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([Cl:36])[CH:29]=2)=[N:24]1>>[Cl:36][C:30]1[CH:29]=[C:28]([C:25]2[CH:26]=[CH:27][N:23]([CH2:22][C@@H:21]([NH:20][C:9]([C:7]3[N:8]=[C:4]([CH:1]([CH3:2])[CH3:3])[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=3)=[O:11])[CH3:37])[N:24]=2)[CH:35]=[CH:34][C:31]=1[C:32]#[N:33]
Reactant: CC(C)c1nc(C(=O)O)cn1COCC[Si](C)(C)C
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CC(C)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1COCC[Si](C)(C)C

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (0.430 g, 1.5 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.395 g, 1.5 mmol). Yield 360 mg. 1H-NMR (400 MHz; DMSO-d6): δ 0.06 (s, 9H), 0.80-0.85 (m, 2H), 1.10 (d, 3H), 1.21-1.24 (m, 6H), 3.08-3.15 (m, 1H), 3.43-3.47 (m, 2H), 4.30-4.44 (m, 3H), 5.32 (s, 2H), 6.96 (d, 1H), 7.63 (s, 1H), 7.85-7.87 (m, 2H), 7.93-7.95 (m, 2H), 8.09 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:29][CH2:28][CH2:27][C@@:3]1([CH3:30])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C@H:16]([O:21][CH3:22])[CH2:17][C:18]([OH:20])=[O:19])[CH3:14])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5].N1C=CC=CC=1.FC(F)(F)C(O[C:42]1[C:47]([F:48])=[C:46]([F:49])[C:45]([F:50])=[C:44]([F:51])[C:43]=1[F:52])=O>ClCCl>[CH3:1][N:2]1[CH2:29][CH2:28][CH2:27][C@@:3]1([CH3:30])[C:4]([NH:6][C@H:7]([C:11]([N:13]([C@@H:15]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C@H:16]([O:21][CH3:22])[CH2:17][C:18](=[O:20])[O:19][C:42]1[C:43]([F:52])=[C:44]([F:51])[C:45]([F:50])=[C:46]([F:49])[C:47]=1[F:48])[CH3:14])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCN1C)C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCN1C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 125.1 %

Procedure:
To a cooled solution (0° C.) of #203 (7.0 g, 10.77 mmol, 1 eq.) in dichloromethane (15 mL) was added dropwise pyridine (3.41 g 43.08 mmol, 4 eq.) followed by a solution of pentafluorophenyl trifluoroacetate (6.03 g, 21.54 mmol, 2 eq.) in dichloromethane (7 mL). The mixture was stirred at room temperature for one hour, and the solvent was concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 1 to 10% methanol in dichloromethane) to afford compound #204 (8 g, 82% over two steps) as yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[CH3:13][CH:14](O)[CH:15]=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:13]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][C:10]([F:11])=[C:2]([F:1])[CH:3]=2)[C:7]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: O=C1CCc2cc(F)c(F)cc21
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1Cc2cc(F)c(F)cc2C1=O
Yield: 38 %

Procedure:
A solution of 10.6 g of 5,6-difluoro-1-indanone, 13.1 ml of 3-buten-2-ol and 110 mg of p-toluenesulfonic acid in 110 ml of 2,2-dimethoxy-propane was boiled under reflux for 64 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 2:1). In addition to 3.6 g of educt there were obtained 5.32 g (38%) of (RS)-2-(2-buten-1-yl)-5,6-difluoro-1-indanone as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([NH:7][C:10](=[O:12])[CH3:11])[CH:8]=1
Reactant: Nc1cc(Br)ccc1F
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(Br)ccc1F

Procedure:
5-Bromo-2-fluoroaniline (14.79 g, 78 mmol) was heated at reflux in acetic acid (50 ml) and acetic anhydride (50 ml) for 8 hours. The solution was concentrated in vacuo, azeotroping with toluene. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was washed with water (×3), brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (gradient of hexane to ethyl acetate) to afford the title compound. MS (ES+) m/e 232/234 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:19]>CN(C)C=O>[C:3]([O:7][C:8]([N:10]([CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CI
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(N(C)C(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 472.4 %

Procedure:
To a suspension of NaH (2.63 g 6.6 mmol) in 200 mL of N,N-dimethylformamide at 0° C. was added a solution of (tert-butoxy)-N-[6-methyl-(2-pyridyl)]carboxamide (12.3 g, crude), as prepared in the preceding step, in 50 mL of N,N-dimethylformamide. The reaction stirred at 0° C. for 15 min then at ambient temperature for 1 h. Then iodomethane (10.22 g, 7.2 mmol) was added and the mixture was stirred at ambient temperature overnight (16 h). The reaction mixture was concentrated in vacuo, diluted with saturated NH4Cl (400 mL), and extracted with ethyl acetate (2×250 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel (10% ethyl acetate in hexane) to give the title compound as a yellow oil (7.56 g, 57%). 1H-NMR (400 MHz, DMSO-d6) δ 7.63 (t, J=7.2 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 6.97 (d, J=6.9 Hz, 1H), 3.27 (s, 2H), 2.42 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([S:18]([CH3:21])(=[O:20])=[O:19])([CH3:17])[CH2:3][C:4]1[N:8]([CH2:9][CH2:10][CH3:11])[N:7]=[C:6]([C:12](OCC)=[O:13])[CH:5]=1.[NH3:22]>CO>[CH3:1][C:2]([S:18]([CH3:21])(=[O:20])=[O:19])([CH3:17])[CH2:3][C:4]1[N:8]([CH2:9][CH2:10][CH3:11])[N:7]=[C:6]([C:12]([NH2:22])=[O:13])[CH:5]=1
Reactant: CCCn1nc(C(=O)OCC)cc1CC(C)(C)S(C)(=O)=O
Reactant: N
Solvent: CO
Product: CCCn1nc(C(N)=O)cc1CC(C)(C)S(C)(=O)=O
Temperature: 150 °C

Procedure:
A pressure vessel containing ethyl 5-[2-methyl-2-(methylsulfonyl)propyl]-1-propyl-1H-pyrazole-3-carboxylate (9.4 g, 29.7 mmol) and ammonia (50 mL of a 7 N solution in methanol), and the vessel was sealed and heated at 150° C. for 41 hours and allowed to cool to room temperature. The volatiles were removed under reduced pressure to provide 8.5 g of 5-[2-methyl-2-(methylsulfonyl)propyl]-1-propyl-1H-pyrazole-3-carboxamide as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([OH:21])=[CH:15][C:4]=2[S:5][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8].[Br:22]Br.O>C(O)(=O)C>[Br:22][C:15]1[C:4]2[S:5][C:6]([C:7]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[O:8])=[C:2]([Cl:1])[C:3]=2[CH:18]=[C:17]([O:19][CH3:20])[C:16]=1[OH:21]
Reactant: BrBr
Reactant: COc1cc2c(Cl)c(C(=O)N3CCOCC3)sc2cc1O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2c(Cl)c(C(=O)N3CCOCC3)sc2c(Br)c1O

Procedure:
(3-Chloro-6-hydroxy-5-methoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone (6.9 g) was slurried in acetic acid. A solution of bromine (3.51 g) in acetic acid (31 ml) was gradually added. The reaction mixture was stirred at room temperature and after 15 minutes water (125 ml) was added. The reaction mixture was stirred at cool for 1.5 hours. The solid was filtered and dried in vacuum. The product was a mixture of two compounds and was used for the next step without any purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[N+](C1C=CC(S(O[C@@H:36]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]2)(=O)=O)=CC=1)([O-])=O>>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][C@H:40]3[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Yield: 95 %

Procedure:
4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline was reacted with tert-butyl (3R)-3-[(4-nitrophenyl)sulfonyloxy]pyrrolidine-1-carboxylate to give 4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yloxy]-7-methoxyquinazoline as a dry foam (2.9 g, 95%); 1H NMR Spectrum: (DMSO d6) 1.40 (s, 9H); 2.07-2.29 (m, 21-1); 3.32-3.50 (m, 3H); 3.64-3.70 (dd, 1H); 3.92 (s, 3H); 5.08-5.18 (m, 1H); 7.21 (s, 1H); 7.23-7.30 (m, 1H); 7.43-7.55 (m, 2H); 7.79 (s, 1H); 8.36 (s, 1H); 9.6 (s, 1H); Mass Spectrum: (M+H)+ 489.
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[O:12][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[F:32][C:33]([F:42])([F:41])[CH2:34][S:35]([CH2:37][C:38](O)=[O:39])=[O:36]>CN(C)C=O>[F:32][C:33]([F:42])([F:41])[CH2:34][S:35]([CH2:37][C:38]([NH:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[O:12][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12)=[O:39])=[O:36]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CC(=O)O)o3)CS[C@H]12
Reactant: O=C(O)CS(=O)CC(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CS(=O)CC(F)(F)F)[C@H]3SC2)o1
Reaction time: 0.25 h

Procedure:
A suspension of 3.4 g (0.01 mol) of 7-amino-3-(5-carboxymethyl-1,3,4-oxadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid in 50 ml of dry dimethylformamide is treated with 2 of triethylamine and the mixture is stirred for 15 minutes at 25°. A slight excess of 0.01 mol of the activated ester of 2,2,2-trifluoroethylsulfinylacetic acid is added to the mixture and it is stirred an additional hour. The reaction mixture is evaporated to dryness in vacuo and water and ethyl acetate are added to the residue. The layers are separated, the ethyl acetate layer is discarded, fresh ethyl acetate is added to the aqueous phase and it is acidified to pH 2.5 by addition of 6N hydrochloric acid. The mixture is filtered, the layers are separated and the aqueous phase is extracted with ethyl acetate. The combined extracts are washed with water, dried (MgSO4) and evaporated to dryness to give the title compound.