Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:32](=[O:34])=[O:33]>C1COCC1.C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C>[C:15]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:6]2[N:7]=[C:2]([CH2:1][C:32]([OH:34])=[O:33])[CH:3]=[CH:4][CH:5]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: Cc1cccc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)n1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: O=C(O)Cc1cccc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)n1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Biphenyl-4-sulfonic acid (6-methyl-pyridin-2-yl)-amide (0.5 g, product of example 5) under an argon atmosphere in THF (5 mL) was cooled to −20° C. and treated dropwise at −20° C. with 1.54 mL of a 2 M solution of lithium diisopropylamide in THF/heptane/ethylbenzene (Fluka). The solution was stirred 1 h at −20° C., cooled to −70° C. and then treated with an access of dry ice. The mixture was allowed to warm to RT (1 h), partitioned between diluted aqueous HCl and AcOEt. The layers were separated, the aqueous layer extracted twice with AcOEt, the combined organic layers dried over Na2SO4, filtered and evaporated to give [6-(biphenyl-4-sulfonylamino)-pyridin-2-yl]-acetic acid as light yellow gum (0.779 g) that was used without further purification in the next step.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@H:5]([NH2:22])[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:8]=2[N:7]=1)[CH3:2].Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:1]([O:3][CH2:4][CH:5]([NH:22][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2)[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:8]=2[N:7]=1)[CH3:2]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CCOC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CCOCC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Yield: 22.3 %

Procedure:
A mixture of (R)-2-ethoxy-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine (510 mg, 1.7 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (410 mg, 1.7 mmol) and DIPEA (1.5 mL, 8.5 mmol) in n-butanol (6 mL) was heated at 90° C. for 18 h in a sealed vial. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 200 as a white solid (158 mg, 22%). LCMS (Method K): RT 3.80 min [M+H]+ 418.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.60 (1H, s), δ 8.22-8.05 (2H, m), 7.87 (1H, br s), 7.75-7.49 (6H, m), 7.11 (1H, td, J=9.32, 2.48 Hz), 6.89 (1H, dd, J=8.92, 2.50 Hz), 5.63 (1H, br s), 3.88 (2H, br d, J=6.76 Hz), 3.40-3.33 (2H, m), 1.01-0.91 (3H, m)
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:31]3[CH:32]=[N:33][CH:34]=[C:29]([F:28])[CH:30]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncc(F)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1) and (5-fluoropyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (Condition 3) tR=1.03 min, m/z=479.1 [M+H]+, m/z=523.0 [M+ formic acid-H]; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.79 (m, 1H) 1.80-1.91 (m, 1H) 2.87 (d, J=11.17 Hz, 1H) 3.17-3.29 (m, 2H) 3.35-3.45 (m, 1H) 4.20 (br. s, 1H) 4.89 (d, J=2.51 Hz, 1H) 7.35 (d, J=9.16 Hz, 2H) 7.82-7.89 (m, 3H) 8.08 (d, J=2.38 Hz, 1H) 8.51 (t, J=1.63 Hz, 1H) 8.60 (d, J=2.76 Hz, 1H) 8.78 (d, J=2.38 Hz, 1H) 10.20 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH:7]([OH:8])[C:5](=[O:6])[O:4][CH2:3]1>[O-][V](=O)=O.[O-][V](=O)=O.[Cu+2]>[CH3:1][C:2]1([CH3:9])[C:7](=[O:8])[C:5](=[O:6])[O:4][CH2:3]1
Reactant: CC1(C)COC(=O)C1O
Agent: O=[V](=O)[O-]
Agent: [Cu+2]
Product: CC1(C)COC(=O)C1=O

Procedure:
Copper vanadate on ceramic is used as the catalyst in the reactor described in Example 1 and the temperature of the air bath is adjusted to 250° C. 60 l of air and 32 g of pantolactone are added hourly to the evaporator. 99.0% of the pantolactone are transformed and ketopantolactone is formed with a selectivity of 77.5%.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Br:8][C:9]1[C:10]([O:29][CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:11][C:12]2[N:13]([N:16]=[CH:17][C:18]=2[C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=1[NH2:15].C(N(CC)CC)C>CN(C=O)C>[Br:8][C:9]1[C:10]([O:29][CH2:30][CH:31]2[CH2:32][CH2:33][N:34]([S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])[CH2:35][CH2:36]2)=[N:11][C:12]2[N:13]([N:16]=[CH:17][C:18]=2[C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=1[NH2:15]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Nc1c(Br)c(OCC2CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1c(Br)c(OCC2CCN(S(=O)(=O)C3CC3)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.7 %

Procedure:
Cyclopropanesulfonyl chloride (24 mg, 0.167 mmol) was added into a solution of 6-bromo-5-(piperidin-4-ylmethoxy)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine (50 mg, 0.111 mmol) and triethylamine (56 mg, 0.553 mmol) in DMF at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h, concentrated and purified by prep-LC to afford the title compound (21.5 mg): LC/MS RT=4.17 min. Mass calculated for, M+H 557.09, observed 557.09.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].N12CCCN=C1CCCCC2.Cl[C:22]([CH3:26])([CH3:25])[C:23]#[CH:24]>C(#N)C.[Cu]>[CH3:25][C:22]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:26])[C:23]#[CH:24]
Reactant: N#Cc1ccc(O)cc1
Reactant: C#CC(C)(C)Cl
Agent: [Cu]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C#CC(C)(C)Oc1ccc(C#N)cc1
Temperature: 12.600000381469727 °C

Procedure:
To a solution of 4-cyanophenol (9.0 g, 75.55 mmol, commercially available) and anhydrous acetonitrile (120 mL) at ~0° C. under argon was added 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU, 14.0 mL, 93.61 mmol, 1.24 eq based on the input of 4-cyanophenol). A temperature increase to 12.6° C. was observed. After the solution had cooled to 0° C., copper bronze (cooper powder, 49.8 mg, 0.783 mmol, 0.0104 eq, 1.04 mol %) was added followed by the addition of a portion of the cuprous chloride in acetonitrile solution prepared above (600 μL, 15.49 μmole, 0.000205 eq., 0.0205 mol %). To the resulting mixture was added, dropwise over 12 minutes, 3-chloro-3-methyl-1-butyne (7.03 g, 68.54 mmol, 0.907 eq. based on the input of 4-cyanophenol). The resulting mixture was allowed to stir at 0° C. under argon. After stirring for 10 hours, the reaction mixture was filtered through a small pad of Celite (to remove the remaining copper bronze) using additional acetonitrile to complete the transfer and to wash the filter bed. The filtrate was concentrated at reduced pressure (bath temperature 40° C.) and the residue was partitioned between 1N HCl (100 mL) and toluene (400 mL). The organic fraction was washed with 1N HCl (2×60 mL), 1N NaOH (2×60 mL), and brine. After drying (magnesium sulfate), the solvent was removed at reduced pressure to give crude title compound as a pale yellow oil (10.68 g). Distillation of the crude material (bulb-to-bulb, ~70°-90° C., ~15 mm Hg) afforded the title compound as a colorless, low melting (mp 28°-29° C.) solid (10.40 g).
Reaction SMILES: C([O:8][NH:9][C:10]([C@H:12]1[CH2:19][C:16]2([CH2:18][CH2:17]2)[CH2:15][N:14]([C:20]([O:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:21])[C@@H:13]1[C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:33][CH2:32]1)=[O:30])=[O:11])C1C=CC=CC=1>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[OH:8][NH:9][C:10]([C@H:12]1[CH2:19][C:16]2([CH2:17][CH2:18]2)[CH2:15][N:14]([C:20]([O:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:21])[C@@H:13]1[C:29]([N:31]1[CH2:32][CH2:33][N:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:30])=[O:11]
Reactant: O=C(NOCc1ccccc1)[C@H]1CC2(CC2)CN(C(=O)OC2CCOCC2)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: O=C(NO)[C@H]1CC2(CC2)CN(C(=O)OC2CCOCC2)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reaction time: 1.5 h
Yield: 75.1 %

Procedure:
Tetrahydro-2H-pyran-4-yl(6S,7S)-7-(((benzyloxy)amino)carbonyl)-6-((4-phenylpiperazin-1-yl)carbonyl)-5-azaspiro(2,5)octane-5-carboxylate (6.0 mg, 0.0104 mmole) was dissolved in methanol (0.3 ml) and 2 mg of 5% Pd/BaSO4 was added to the resulting reaction mixture. The mixture was stirred under hydrogen (1 atm) for 1.5 hours. After filtration, the product was purified with prep. RP-HPLC. The desired fractions were collected and freeze dried to give 3.8 mg solid. LC-MS: m/z 487.1 (M+H)+; 509.0 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:21]=[C:20](Cl)[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[C:9](=[O:23])[CH2:8][CH2:7][C:6]=2[CH:24]=1.[CH2:25]([NH2:28])[CH2:26][NH2:27]>>[NH2:27][CH2:26][CH2:25][NH:28][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([N:10]2[C:9](=[O:23])[CH2:8][CH2:7][C:6]3[CH:24]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[CH2:11]2)[CH:21]=1
Reactant: NCCN
Reactant: O=C1CCc2cc(Br)ccc2CN1c1cc(Cl)c2ccccc2n1
Product: NCCNc1cc(N2Cc3ccc(Br)cc3CCC2=O)nc2ccccc12
Temperature: 170 °C
Yield: 98 %

Procedure:
To a solution of 7-bromo-2-(4-chloroquinolin-2-yl)-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one (40 mg, 0.1 mmol) was added ethane-1,2-diamine (0.5 mL) in a microwave vessel, which was degassed and refilled with nitrogen. The resultant mixture was heated at 170° C. under microwave irradiation for 30 minutes. After cooled to room temperature, the mixture was diluted with methanol (10 mL) and concentrated under reduced pressure to give a residue which was purified by preparative HPLC to afford 42 mg of product as a solid (yield was 98%). MS obsd. (ESI+) [(M+H)+] 424. 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (d, J=8.0 Hz, 1 H), 7.73 (d, J=8.0 Hz, 1 H), 7.58 (m, 2 H), 7.47 (s, 2 H), 7.32 (td, J=1.2, 8.8 Hz, 1 H), 6.04 (s, 1 H), 5.48 (s, 2 H), 3.42 (t, J=6.4 Hz, 2 H), 3.11 (t, J=7.6 Hz, 2 H), 2.98 (t, J=6.0 Hz, 2 H), 2.86 (t, J=7.2 Hz, 2 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH2:13]([N:15]([CH2:16][CH3:17])[C:10]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[CH:3]2)=[O:12])[CH3:14]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1cccc2cc[nH]c12
Yield: 98.6 %

Procedure:
A solution of 1H-indole-7-carboxylic acid (0.48 g, 3 mmol), diethylamine (0.93 mL, 9 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.74 g, 9 mmol), 1-hydroxybenzotriazole (1.23 g, 9 mmol), triethylamine (1.26 mL, 12 mmol) in dimethylformamide (30 mL) is stirred at room temperature for 4 hours. The mixture is diluted with ethyl acetate, washed with 1N HCl, water, a saturated aqueous sodium hydrogen carbonate solution, water, and a saturated brine, dried over magnesium sulfate, and concentrated to give the desired 1H-indole-7-carboxylic acid diethylamide (0.64 g, yield: 99%).
Reaction SMILES: CNC1C=CC=CC=1.C(NNC1C=CC(N=C=S)=CC=1)=O.[CH:22]([NH:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([N:35]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46]C=2)[CH2:36]C2C=CC=CC=2)=[S:34])=[CH:28][CH:27]=1)=[O:23]>>[CH:22]([NH:24][NH:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:33]([N:35]([CH3:36])[C:43]2[CH:44]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[S:34])=[CH:30][CH:31]=1)=[O:23]
Reactant: O=CNNc1ccc(NC(=S)N(Cc2ccccc2)Cc2ccccc2)cc1
Agent: O=CNNc1ccc(N=C=S)cc1
Solvent: CNc1ccccc1
Product: CN(C(=S)Nc1ccc(NNC=O)cc1)c1ccccc1

Procedure:
N-Methylaniline (0.11 g, 0.001 mole) and 4-(2-formylhydrazino)phenyl isothiocyanate (0.19 g, 0.001 mole) were reacted according to the procedure described for NA-11 in Example 3. Yield 0.15 g (50 percent), m.p. 137°-139° C.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:30])[C:9]2[CH:14]=[C:13]([OH:15])[C:12]([OH:16])=[CH:11][C:10]=2[NH:17][C:18]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[Cl:29])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][C:32]([CH3:37])([CH3:36])[C:33](Cl)=[O:34]>C(Cl)Cl.N1C=CC=CC=1>[C:1]1([NH:7][C:8](=[O:30])[C:9]2[CH:14]=[C:13]([OH:15])[C:12]([O:16][C:33]([C:32]([CH3:37])([CH3:36])[CH3:31])=[O:34])=[CH:11][C:10]=2[NH:17][C:18]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[Cl:29])=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(Nc1ccccc1)c1cc(O)c(O)cc1NC(=O)c1sc2ccccc2c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1cc(NC(=O)c2sc3ccccc3c2Cl)c(C(=O)Nc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.6 %

Procedure:
To a solution of N-phenyl-2-[((3-chlorobenzo(b]thien-2-yl)carbonyl)amino]-4,5-dihydroxybenzamide (0.09 g, 0.21 mmol) in CH2Cl2 (1 mL) and pyridine (1 mL) at 0° C. was added trimethylacetyl chloride (0.027 mL, 0.22 mmol). The solution was allowed to warm to ambient temperature with stirring. After 16 hours, the reaction mixture was partitioned between ethyl acetate and dilute HCl. The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel to afford 0.038 g (40% yield) of N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-hydroxy4-((1,1-dimethylethyl)carbonyl)oxybenzamide as a white solid; NMR(DMSO-d6) 12.2 (s, 1), 10.8 (s, 1), 10.4 (s, 1), 8.3 (s, 1), 8.2 (d, 1), 8.0 (d, 1), 7.6-7.7 (m, 4), 7.4 (t, 1), 1.3 (s, 9) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:27]([C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:17](=[O:19])[CH3:18])=[CH:26][CH:25]=1)(=[O:29])=[O:28])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 117 mg of 4-Acetylamino-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 2.16 (s, 3H), 7.26 (b, 1H), 7.33 (d, 1H, J=2.4 Hz), 7.39 (m, 6H), 7.46 (dd, 1H, J=8.4 Hz, 2.4 Hz), 7.55 (m, 3H), 7.71 (d, 1H, J=8.8 Hz), 9.74 (s, 1H). MS: m/z 429.0 (M++1).
Reaction SMILES: CS[C:3](=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])[CH3:4].[NH2:16][C:17]1[C:21]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[C:20]([CH2:27][CH3:28])[NH:19][N:18]=1>O1CCOCC1>[Cl:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[C:6]1[N:18]2[N:19]=[C:20]([CH2:27][CH3:28])[C:21]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[C:17]2[N:16]=[C:3]([CH3:4])[N:5]=1
Reactant: CSC(C)=NC(=O)c1ccc(Cl)cc1Cl
Reactant: CCc1[nH]nc(N)c1C(CC)CC
Solvent: C1COCCO1
Product: CCc1nn2c(-c3ccc(Cl)cc3Cl)nc(C)nc2c1C(CC)CC
Temperature: 25 °C
Yield: 47.4 %

Procedure:
A mixture of N-(1-(methylthio)ethylidene)-2,4-dichlorobenzamide (100 mg, 0.38 mmol) and 3-amino-5-ethyl-4-(3-pentyl)pyrazole (69 mg, 0.38 mmol) in dioxan (1 mL) was stirred at reflux temperature for 2 h. After being cooled to room temperature, the reaction mixture was concentrated in vacuo. Preparative TLC using EtOAc:hexanes::1:1 generated the title product (68 mg, 47% yield), which was identical to the product obtained by the method described in Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[Cl:24][C:25]1[CH:30]=[C:29]([C:31](O)=[O:32])[CH:28]=[C:27]([Cl:34])[N:26]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:24][C:25]1[CH:30]=[C:29]([CH:28]=[C:27]([Cl:34])[N:26]=1)[C:31]([NH:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)[CH:3]=1)=[O:32]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cc(Cl)nc(Cl)c1
Yield: 83.6 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (95 mg, 0.307 mmol), 2,6-dichloropyridine-4-carboxylic acid (65 mg, 0.337 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (65 mg, 0.337 mmol), 1-hydroxybenzotriazole (46 mg, 0.337 mmol) and N,N-dimethylformamide (5 mL) as starting materials and in the same manner as in Example 377, the title compound (124 mg, 84%) was obtained as a pale-green powder.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:20]=[CH:19][C:7]2[N:8]3[C:14](=[O:15])[N:13]=[CH:12][C:11]([C:16]([OH:18])=[O:17])=[C:9]3[S:10][C:6]=2[CH:5]=1.O=P(N(C)C)(N(C)C)N(C)C.[CH2:32](I)[CH3:33]>O>[CH2:32]([O:17][C:16]([C:11]1[CH:12]=[N:13][C:14](=[O:15])[N:8]2[C:7]3[CH:19]=[CH:20][C:4]([O:3][CH3:2])=[CH:5][C:6]=3[S:10][C:9]=12)=[O:18])[CH3:33]
Reactant: COc1ccc2c(c1)sc1c(C(=O)O)cnc(=O)n12
Reactant: CCI
Agent: [Na]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1cnc(=O)n2c1sc1cc(OC)ccc12
Reaction time: 1.33 h

Procedure:
20 g. of the sodium salt of 7-methoxy-1-oxo-1H-pyrimido[6,1-b]benzthiazole-4-carboxylic acid prepared according to Example 1C are slurried in 200 ml. hexametapol and mixed at ambient temperature with 23.45 g. ethyl iodide. The reaction mixture is stirred for 80 minutes and the resultant solution poured into 3 liters of water. The precipitate obtained is separated off and, while still moist, boiled with 500 ml. ethanol and brought into solution by the addition of some nitromethane. After cooling, 12.9 g. (63.3% of theory) ethyl 7-methoxy-1-oxo-1H-pyrimido[6,1-b]benzthiazole-4-carboxylate crystallize out; m.p. 231°-232° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Br:17])[CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.[OH-].[Na+]>O.[Zn]>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][C:9]([Br:17])=[CH:8][CH:7]=3)[CH:3]=1
Reactant: O=C1c2ccc(Br)cc2C(=O)c2ccc(Br)cc21
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Product: Brc1ccc2cc3cc(Br)ccc3cc2c1
Yield: 54.5 %

Procedure:
30 g of 2,6-dibromoanthraquinone, 5 g of Zn and 25 g of NaOH were stirred in 200 mL of water at 100° C. for 24 hours and when the reaction was complete, the reaction materials were filtered. The thus-obtained organic material and inorganic material were dissolved in chloroform and the resulting mixture was re-filtered. The obtained filtrate was applied to a silica gel short column, thereby separating the inorganic material. The separated material was recrystallized from MC and MeOH, thereby obtaining 15 g of 2,6-dibromoanthracene.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[CH3:14][C:15]([NH2:19])([CH3:18])[CH2:16][CH3:17]>>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:19][C:15]([CH3:18])([CH3:14])[CH2:16][CH3:17])[NH:7][C:6]=2[CH:8]=1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Reactant: CCC(C)(C)N
Product: CCC(C)(C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1
Yield: 56.5 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (5.0 g, 19.45 mmol) in 1,1-dimethylpropylamine (10 ml, 85.7 mmol) was stirred for 30 h at 125° C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue was stirred with water (25 ml) followed by adjustment to pH 2 with 4M hydrochloric acid. The resulting precipitate was isolated by filtration, washed with water, and then redissolved by slightly heating in 1N sodium hydroxide (130 ml) followed by treatment with decolorising charcoal. After filtration, the clear solution was acidified to pH 2 and the precipitate was filtered off and recrystallised from methanol to give 3.38 g (56%) of the pure title compound; mp 359-360° C.; 1H-NMR (DMSO-d6): δ0.82 (t, 3H), 1.31 (s, 6H), 1,73 (q, 2H), 6.67 (br s, 1H), 7,12 (s, 1H), 10.57 (br s, 1H); MS: m/e 307/309 (M+); (C10H14N3Cl1O2S2) calc. C, 39.02; H, 4.58; N, 13.65; Cl, 11.52; S, 20.83; found C, 39.10; H, 4.58; N, 13.48; Cl, 11.69; S, 20.97.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:5]([NH:7][CH:8]1[C:37](=[O:38])[N:10]2[C:11]([C:21]([O:23]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:22])=[C:12]([C:15]3[S:16][C:17]([CH3:20])=[N:18][N:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH3:1][O:2][N:3]=[C:4]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:5]([NH:7][CH:8]1[C:37](=[O:38])[N:10]2[C:11]([C:21]([OH:23])=[O:22])=[C:12]([C:15]3[S:16][C:17]([CH3:20])=[N:18][N:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3nnc(C)s3)CS[C@H]12)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(c3nnc(C)s3)CS[C@H]12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
A mixture of 0.07 g of benzhydryl 7-(2-methoxyimino-2-phenylacetamido)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate (obtained in Example 59), 2 ml of anisole and 4 ml of trifluoroacetic acid is stirred for 30 minutes at room temperature. After removal of the solvent under reduced pressure, the residue is triturated with the addition of absolute ether. The precipitates are filtered, and washed with ether to give 0.046 g of 7-(2-methoxyimino-2-phenylacetamido)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylic acid.