Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[F:28]>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)=[CH:21][C:20]=1[F:28]
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: Cc1c2n(c3c(-c4ccc(Cl)c(F)c4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (57 mg, 66%), MS (ISP) m/z=347.5 [(M+H)+], mp 216° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-chloro-3-fluoro-phenylboronic acid (56.7 mg, 0.325 mmol).
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].N1C=CC=CC=1.[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:22]([O:29][C:30]([N:13]1[CH2:12][CH2:11][N:10]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH2:15][CH2:14]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(c2ncccc2[N+](=O)[O-])CC1
Reaction time: 1.5 h

Procedure:
1-(3--Nitro-2-pyridinyl)piperazine is dissolved in 175 ml of methylene chloride and cooled to 0°. Then pyridine is added followed by benzylchloroformate (16.5 ml). The reaction is stirred 1.5 hr, then poured into saturated aqueous sodium bicarbonate and extracted with chloroform, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound, NMR (300 MHz, CDCl3) 8.34, 8.15, 7.38-7.32, 6.81, 5.17, 3.65 and 3.45 δ.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([NH:16]C=O)[C:6]([SH:15])([CH3:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])C.Cl.[Cl:21]CCl.CO>C(O)(=O)C>[ClH:21].[NH2:16][CH:5]([C:6]([SH:15])([CH3:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:4]([OH:19])=[O:3]
Reactant: ClCCl
Reactant: CCCCCCCC(C)(S)C(NC=O)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCCCC(C)(S)C(N)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
16.7 g of 2-formylamino-3-mercapto-3-methyldecanoic acid ethyl ester as a 6:4 threo/erythro mixture (product 6) were added at room temperature to 606 ml of 6N hydrochloric acid and then stirred for 24 hours under reflux (TLC check: dichloromethane:methanol:glacial acetic acid 35:5:3). After cooling to room temperature the reaction mixture was stirred further while cooling with ice. The precipitated white solid was suction filtered, washed with ether and then dried in vacuo. 13.3 g (94.9% of theory) of rac-2-amino-3-mercapto-3-methyldecanoic acid hydrochloride were thus obtained as a 6:4 threo/erythro mixture (compound 6; product 1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C@H:6]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[CH2:7]2)[CH2:2]1.CCN(CC)CC.[F:26][C:27]1[C:28]2[CH:38]=[C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:36]=[CH:35][C:29]=2[S:30][C:31]=1[C:32](Cl)=[O:33]>C(Cl)Cl>[F:26][C:27]1[C:28]2[CH:38]=[C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:36]=[CH:35][C:29]=2[S:30][C:31]=1[C:32]([N:1]1[CH2:2][CH:3]([NH:5][C@H:6]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[CH2:7]2)[CH2:4]1)=[O:33]
Reactant: O=C(c1ccccc1)N1CC[C@H](NC2CNC2)C1
Reactant: O=C(Cl)c1sc2ccc(-c3ccccc3)cc2c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CC[C@H](NC2CN(C(=O)c3sc4ccc(-c5ccccc5)cc4c3F)C2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.7 %

Procedure:
To a solution of compound 5e (42.7 mg, 0.131 mmol) and Et3N (0.07 mL, 0.5 mmol) in CH2Cl2 (2 mL) at 0° C. was slowly added a solution of compound 13e (36.3 mg, 0.125 mmol) in CH2Cl2 (1 mL). The reaction was stirred at 0° C. for 2 h, diluted with CH2Cl2, and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (silica gel, % MeOH/EtOAc) to give compound Cpd 173 (16.7 mg). MS m/z (M+H+) 500.
Reaction SMILES: C[O:2][C:3](=[O:18])[C@@H:4]([CH3:17])[N:5]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[S:6]([CH3:9])(=[O:8])=[O:7].[Li+].[OH-]>O.CO>[CH3:9][S:6]([N:5]([C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)[C@@H:4]([C:3]([OH:18])=[O:2])[CH3:17])(=[O:7])=[O:8]
Reactant: COC(=O)[C@@H](C)N(c1ccc(Cl)cc1)S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H](C(=O)O)N(c1ccc(Cl)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
To a solution of (2R)-N-methanesulfonyl-(4-chlorophenyl)alanine methylester, prepared in Step A, in water/methanol (5 mL, 1/1) was added portionwise LiOH (70.0 mg, 2.00 mmol). After being stirred at rt for 3 h, the reaction mixture was concentrated, and the residue was diluted with 1N HCl solution. The organic material was extracted with EtOAc, the extracts were concentrated in vacuo to give the title compound (179 mg, 94.3%).
Reaction SMILES: [C:1]1([C:7]2([C:51]([F:54])([F:53])[F:52])[C:28]3[CH:27]=[C:26]4[C:17]([O:18][C:19]5[CH:20]=[C:21](C(O)=O)[C:22](C(O)=O)=[CH:23][C:24]=5[C:25]4([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]([F:32])([F:31])[F:30])=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][C:10](C(O)=O)=[C:11](C(O)=O)[CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C2C(=CC=CC=2)C=CC=1.Cl>O.[Cu]>[C:33]1([C:25]2([C:29]([F:31])([F:32])[F:30])[C:26]3[CH:27]=[C:28]4[C:15]([O:14][C:13]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[C:7]4([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:51]([F:52])([F:53])[F:54])=[CH:16][C:17]=3[O:18][C:19]3[C:24]2=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1cc2c(cc1C(=O)O)C(c1ccccc1)(C(F)(F)F)c1cc3c(cc1O2)Oc1cc(C(=O)O)c(C(=O)O)cc1C3(c1ccccc1)C(F)(F)F
Agent: [Cu]
Agent: Cl
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: FC(F)(F)C1(c2ccccc2)c2ccccc2Oc2cc3c(cc21)C(c1ccccc1)(C(F)(F)F)c1ccccc1O3
Yield: 14.5 %

Procedure:
A mixture of 20 g (0.03 mole) 12,14-Diphenyl-12,14-bis(trifluoromethyl) -12H,14H-5,7-dioxapentacene-2,3,9,10-tetracarboxylic acid, 25 g copper powder and 100 ml quinoline was refluxed vigorously for 4 hours. The cooled mixture was poured into a cold solution of 30 ml concentrated HCl in 300 ml water. The product was extracted with methylene chloride, and the extracts were passed through a column of alumina, and the eluate was stripped. The residue was stirred with methanol, and was filtered yielding 2.5 g (16 %) of a solid in two crops. The crude material melted at 203-213° C., in line with the presence of cis- and trans- isomers. The title compound was purified by vacuum sublimation at 0.6 Torr and 200° C., and melted then at 209-215° C. Analysis: Calc. for C34H20F6O2 : C 71.1; H 3.48, F 19.9; found: C 71.4; H 3.65; F 19.9 %. The mass spectrum showed presence of two isomers in about 2:1 ratio, and a parent peak at 574, with peaks at 505 and 436 m/e showing loss of one and two CF3 groups, respectively. The NMR spectrum had complex multiplets in the 7.2-7.35 and 6.9-7.1 ppm range (totaling 17 Hs), plus two pairs of broad singlets at 6.86+6.84 ppm (2H) and 6.32+6.22 ppm (1H). The coefficient of thermal expansion (CTE) was found to be 34 ppm (0-200° C.) by thermomechanical analysis (TMA) at 10° C. per minute.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[C:9](O)=[N:8][C:7]([NH:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1)=[CH:6]2.O=P(Cl)(Cl)[Cl:28]>>[Cl:28][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])[CH:11]=2)[CH:6]=[C:7]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCOc1cc2c(O)nc(Nc3cc(C)[nH]n3)cc2cc1OC
Product: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1OC
Temperature: 160 °C
Yield: 62.7 %

Procedure:
A mixture of 6-Methoxy-7-(2-methoxy-ethoxy)-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol (1.0 g, 1.45 mmol) in POCl3 (20 ml) was sealed in 2 microwave process vial (20 ml). The mixture was heated at 160° C. for 30 minutes under microwave irradiation. After removal of excess solvent, the residue was poured into ice-water, neutralized by 2M NaOH, extracted by EtOAc. The organic layer was concentrated and the residue was purified by flash column chromatography to give product as solid (0.33 g, 62.7%). LC-MS: m/e 363 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18]Br.O>CN(C=O)C>[F:1][C:2]1[C:3]2[O:9][CH2:18][CH2:17][O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: BrCCBr
Reactant: Oc1cccc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3-fluoro-1,2-benzenediol (5.278 g, 41.2 mmol) in DMF (50 ml) was treated with potassium carbonate (17.08 g, 124 mmol) and 1,2-dibromoethane (3.91 ml, 45.3 mmol) and stirred at rt for 72 h. The reaction was treated with water (200 ml) and extracted 3×200 ml (EtOAc). The combined organic extracts were washed with water (200 ml), brine (200 ml), dried (MgSO4), evaporated and chromatographed (0-20% EtOAc-Cyclohexane) to give product as a clear oil. (2.437 g, 38%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[C:4]=1[C:5]([OH:7])=[O:6].C(Cl)(Cl)[Cl:17]>>[Cl:17][C:11]1[C:3]([O:2][CH3:1])=[C:4]([C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: ClC(Cl)Cl
Reactant: COc1ccc(OC)c(C(=O)O)c1OC
Product: COc1cc(Cl)c(OC)c(C(=O)O)c1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
2,5,6-trimethoxybenzoic acid 5.0 g (0.024 mol) was suspended in 75 ml of CHCl3 and cooled to 0° C. 1.9 ml (0.024 mol) of SO2Cl2 was added under N2 -atm. The reaction was stirred for 2 hr and allowed to slowly attain room temperature. The reaction mixture was diluted 100 ml CHCl3 and washed with 200 ml H2O. The aqueous layer was washed with 50 ml CHCl3 and the combined organic layer was dried (Na2SO4) and the solvent was evaporated. Gave 5.5 g (95%) of 3-chloro-2,5,6-trimethoxybenzoic acid (oil). Mw: 246.7.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][C:10](=O)[C:4]=2[CH:3]=1.[C:20](=[N:26][Si](C)(C)C)=[N:21][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][C:10](=[N:26][C:20]#[N:21])[C:4]=2[CH:3]=1
Reactant: O=C1CC(c2ccccc2)COc2ccc(Br)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1CC(c2ccccc2)COc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a solution of 7-bromo-3-phenyl-3,4-dihydrobenzo[b]oxepin-5(2H)-one (158 mg, 0.5 mmol) in DCM (5 mL) was added TiCl4 (1 mL, 1 M in CH2Cl2) dropwise within 15 minutes at room temperature. After stirring for 1 h, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (0.25 mL, 1.11 mmol) was added dropwise. The mixture was stirred at room temperature overnight and poured into ice-water (25 g). The aqueous layer was extracted with CH2Cl2, which was combined with the organic layer. The organic layer was dried and concentrated to give crude N-(7-bromo-3-phenyl-3,4-dihydrobenzo[b]oxepin-5(2H)-ylidene)cyanamide (160 mg, 94%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[N:8]=[CH:7][C:6]([OH:15])=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][CH:24]1[CH2:26][CH2:25]1.O>CS(C)=O>[CH:24]1([CH2:23][O:15][C:6]2[CH:7]=[N:8][C:9]3[C:4]([CH:5]=2)=[CH:3][C:2]([F:1])=[CH:11][C:10]=3[N+:12]([O-:14])=[O:13])[CH2:26][CH2:25]1
Reactant: BrCC1CC1
Reactant: O=[N+]([O-])c1cc(F)cc2cc(O)cnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(F)cc2cc(OCC3CC3)cnc12

Procedure:
A solution of 6-fluoro-8-nitro-quinolin-3-ol (1.285 g, 6.21 mmol) and cesium carbonate (4.046 g, 12.42 mmol) in dimethylsulfoxide (5 ml) was treated with bromomethyl-cyclopropane (1.09 g, 8.1 mmol). After stirring at room temperature overnight water (250 ml) was added and the mixture was extracted with ethyl acetate (2×20 ml) and dichloromethane (2×20 ml). The organic layers were collected, dried and evaporated. The crude product was purified by chromatography on silica gel using a 9:1-mixture of cyclohexane/ethyl acetate as the eluent. 3-Cyclopropylmethoxy-6-fluoro-8-nitro-quinoline was obtained as a yellow solid (600 mg, 45%); (calculated) C13H11FN2O3 [262.2]; (found) [M+H]+=263.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[S:7]([Cl:11])(=O)(=[O:9])[OH:8].Cl.S(Cl)(Cl)=O>>[CH3:1][N:2]1[CH:6]=[C:5]([S:7]([Cl:11])(=[O:9])=[O:8])[N:4]=[CH:3]1
Reactant: O=S(=O)(O)Cl
Reactant: Cn1ccnc1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: Cn1cnc(S(=O)(=O)Cl)c1
Temperature: 150 °C
Reaction time: 6 h

Procedure:
1-Methylimidazole (250 g, 3.05 mol) is added dropwise to chlorosulfuric acid (600 ml, 9.03 mol), in such a way that an internal temperature of 30° C. is not exceeded, without aspirating the hydrogen chloride formed. After addition is complete, the reaction mixture is stirred at 150° C. for 6 h. Thionyl chloride (340 ml, 4.66 mol) is added at 60° C. and the mixture is then heated at a bath temperature of 100° C. for 6 h. After cooling to room temperature, the viscous reaction mixture is poured onto sufficient ice such that that the end about 7.5 l of a water-ice mixture remains. The precipitate deposited is filtered off with suction and briefly sucked dry in air. It is then either dried in a thin layer in a vacuum drying oven at 50° C. and 15 torr, or it is preferably taken up using dichloromethane, dried over sodium sulfate and freed from solvent in vacuo. Yield: 176 g (32% of theory) of colorless crystals were obtained (melting point: 89°-90° C.). To remove the isomeric 5-imidazolesulfonic acid formed as a by-product from the mother liquor, the latter is largely concentrated in vacuo at 15 torr in a rotary evaporator. On addition of ethanol, an imidazolesulfonic acid mixture crystallizes out, which can be recrystallized from ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH:30]([OH:33])([CH3:32])[CH3:31]>O1CCOCC1.CN(C=O)C>[CH:30]([O:33][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])([CH3:32])[CH3:31]
Reactant: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(OC(C)C)c3)nc12

Procedure:
From 2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide with sodium hydride and isopropanol in dioxane and DMF. ES-MS m/e (%): 414 (M+H+, 100).
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([OH:21])=[O:20])=[C:8]([CH2:11][S:12][C:13]3[S:14][C:15]([CH3:18])=[N:16][N:17]=3)[CH2:9][S:10][C@H:5]12)=[O:2].[C:24]1([C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N+]=[N-])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.C(O)(=O)C>[CH:1]([NH:3][C@@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O:21][CH:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:20])=[C:8]([CH2:11][S:12][C:13]3[S:14][C:15]([CH3:18])=[N:16][N:17]=3)[CH2:9][S:10][C@H:5]12)=[O:2]
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC=O)[C@H]3SC2)s1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC=O)[C@H]3SC2)s1
Reaction time: 16 h

Procedure:
A solution of 7β-formamido-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethylceph-3-em-4-carboxylic acid (8.5 g) in tetrahydrofuran (300 ml) was treated with an excess of a solution of diphenyldiazomethane in petroleum (300 ml) and the mixture was kept at 20° for 16 hours. A few drops of acetic acid were added and solvents were removed under reduced pressure. The resulting yellow syrup was dissolved in ethyl acetate and washed with sodium bicarbonate solution. A solid (7.5 g) precipitated and was dried in vacuo. A sample (5.77g) of the wet solid was dissolved in methylene chloride, and the solution was dried and concentrated under reduced pressure. The residue was crystallised from methanol to give the title ester (5.08 g),m.p. 108° (decomp.), λmax. (EtOH) 268nm (ε 12,400), τ (CDCl3 + a little DMSO-d6) values include 1.50 (d, J 9 Hz; NH), 1.72 (s; HCO), 6.30 (singlet; C-2 CH2) and 7.31 (singlet;CH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:44]=[CH:43][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:29]([C:26]1[CH:25]=[C:24]([C:20]2[CH:19]=[C:18]([O:17][C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:10]([NH:9][C:3]4[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=4[F:1])=[O:11])=[CH:44][CH:43]=3)[CH:23]=[CH:22][N:21]=2)[NH:28][CH:27]=1)=[O:30]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCNC(=O)OC(C)(C)C)c[nH]4)c3)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of tert-butyl (3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)carbamate (70 mg, 0.12 mmol) in 10 ml of methylene chloride was added 1 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 2 hours and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8-9. The precipitates were filtered, washed with water and dried in vacuo to give N-(3-aminopropyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as yellow solid. Yield: 40 mg, 63%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[N:14]=[CH:15][C:16]([C:19]2[CH:20]=[C:21]([C:29]3[C:33](=[O:34])[C:32]([CH3:36])([CH3:35])[O:31][N:30]=3)[CH:22]=[CH:23][C:24]=2[C:25]([CH3:28])([CH3:27])[CH3:26])=[N:17][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[C:25]([C:24]1[CH:23]=[CH:22][C:21]([C:29]2[C:33](=[O:34])[C:32]([CH3:36])([CH3:35])[O:31][N:30]=2)=[CH:20][C:19]=1[C:16]1[N:17]=[CH:18][C:13]([NH:12][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=2[F:11])=[N:14][CH:15]=1)([CH3:26])([CH3:27])[CH3:28]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CC1(C)ON=C(c2ccc(C(C)(C)C)c(-c3cnc(N)cn3)c2)C1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)ON=C(c2ccc(C(C)(C)C)c(-c3cnc(NC(=O)c4c(F)cccc4F)cn3)c2)C1=O
Temperature: 0 °C

Procedure:
To a 0° C. cooled and stirred, solution of 2,6-difluorobenzoyl chloride (0.083 mL, 0.66 mmol, 1.5 eq) in DCM (200 mL) was added drop wise a solution of 3-(3-(5-aminopyrazin-2-yl)-4-(tert-butyl)phenyl)-5,5-dimethylisoxazol-4(5H)-one, Intermediate 4b, (150 mg, 0.44 mmol, 1.0 eq) in DCM (50 mL) followed by pyridine (0.053 mL, 0.66 mmol, 1.5 eq). The resulting mixture was stirred at room temperature for 2 h. The reaction was diluted with DCM (100 mL), and washed with 10% hydrochloric acid (100 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, 10% ethyl acetate in hexane) to afford 40 mg of the title product as a white solid. 1HNMR (400 MHz, CDCl3) δ 9.72 (s, 1H), 8.55 (s, 1H, D2O exchangeable), 8.28 (s, 1H), 8.14 (dd, J=9.0, 2.5 Hz, 1H), 7.86 (s, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.52-7.45 (m, 1H), 7.07 (t, J=8.5 Hz, 2H), 1.43 (s, 6H), 1.23 (s, 9H); ESI-MS (m/z) 479 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1I.[C:10]([OH:14])(=[O:13])[C:11]#[CH:12].C(NC(C)C)(C)C>CN(C=O)C.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>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:12]#[C:11][C:10]([OH:14])=[O:13]
Reactant: Fc1ccc(I)c(F)c1
Reactant: C#CC(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: O=C(O)C#Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
4.95 ml (41.4 mmol) of 2,4-difluoroiodobenzene and 2.56 ml (41.4 mmol) of propiolic acid were dissolved in DMF (16 ml). Following cooling of the reaction medium to 0° C. (ice-water bath), 578 mg (0.83 mmol) of Pd(PPh3)2Cl2 and 308 mg (1.66 mmol) of Cul were added. The reaction solution was then cooled to −10° C. (ice methanol bath) and 14.5 ml (103.4 mmol) of diisopropylamine were added dropwise at this temperature. The cooling bath was then removed and the reaction mixture was stirred a further 16 h after RT had been re-established. The reaction solution was then diluted with EA and washed successively with a 2N HCl solution and a satd aq. NaCl solution. Following drying over MgSO4, filtration, and removal of solvent in vacuo, the residue was boiled with hexane and filtered after cooling to RT. The residue was dissolved in diethyl ether at 30° C. and filtered at this temperature. By removal of solvent in vacuo there were obtained from the filtrate 6.43 g (35.3 mmol, 85%) of (2,4-difluorophenyl)propiolic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([S:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Sc1ccccc1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 6.0 kg. of 1-amino-2-nitro-4-chlorobenzene and 7.2 kg. of potassium carbonate in 25 l. of DMF under nitrogen is treated with 4.0 kg. of thiophenol. The mixture is stirred for 2 hours, cooled, and diluted with 140 l. of ice water. The mixture is stirred for 1 hour, and 1-amino-2-nitro-5-phenylthiobenzene is isolated by filtration.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[C:5][CH2:6][O:7][CH3:8].[F:9][C:10]([F:22])([F:21])[C:11]([NH:13][CH:14]([CH2:18][C:19]#[CH:20])[CH2:15][C:16]#[CH:17])=[O:12]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(O)C>[F:9][C:10]([F:21])([F:22])[C:11]([NH:13][CH:14]1[CH2:15][C:16]2[C:19](=[CH:20][C:5]([CH2:6][O:7][CH3:8])=[C:4]([CH2:3][O:2][CH3:1])[CH:17]=2)[CH2:18]1)=[O:12]
Reactant: C#CCC(CC#C)NC(=O)C(F)(F)F
Reactant: COCC#CCOC
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: COCc1cc2c(cc1COC)CC(NC(=O)C(F)(F)F)C2
Temperature: 80 °C

Procedure:
According to the procedure of Magnus et. al (Tetrahed. Lett., 34, 23-26 (1993)) a solution of commercially available 1,4-dimethoxy-2-butyne (1.32 g, 11.5 mmol) in nitrogen-degassed ethanol is heated to 80° C. with stirring under a nitrogen atmosphere. Tris(triphenylphosphine)rhodium chloride (64 mg, 0.07 mmol) and a solution of 2,2,2-trifluoro-N-[1-(2-propynyl)-3-butynyl]acetamide (470 mg, 2.32 mmol; prepared from literature procedure: Romero, Arthur G.; Leiby, Jeffrey A PCT Int. Appl. WO 9623760) in nitrogen-degassed ethanol (2 ml) are added in portions over 2 hours. The mixture is stirred under nitrogen at 80° C. for a further 3 hours. The solvent is removed under vacuo and the residue is purified by flash chromatography on silica gel, eluting with hexane/ethyl acetate (2:1)