Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1
Reactant: O=S(Cl)Cl
Reactant: O=C(CCc1ccccc1)N1CCC(CCO)CC1
Solvent: ClC(Cl)Cl
Product: O=C(CCc1ccccc1)N1CCC(CCCl)CC1
Temperature: 20 °C

Procedure:
A solution of thionyl chloride (15.7 ml) in dry chloroform (100 ml) was added dropwise to a stirred solution of the product from Example 35 (51.1 g) in dry chloroform (500 ml) over 45 minutes, keeping the temperature between 0° C. and 5° C. The solution was allowed to warm to 20° C. with stirring and then heated under reflux for 2.5 hours. The mixture was cooled to 20° C., washed (saturated sodium bicarbonate solution, water), dried, filtered and evaporated to give 4-(2-chloroethyl)-1-(3-phenylpropionyl)piperidine as oil.
Reaction SMILES: F[C:2]1(F)[CH2:4][CH:3]1[CH2:5][N:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:17]([O:19]CC)=[O:18])=[C:14]([CH3:16])[N:15]=2)[C:7]1=[O:22].C(N1CCN(C2SC(C(OCC)=O)=C(C)N=2)C1=O)C(C)C>>[CH2:5]([N:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:17]([OH:19])=[O:18])=[C:14]([CH3:16])[N:15]=2)[C:7]1=[O:22])[CH:3]([CH3:4])[CH3:2]
Reactant: CCOC(=O)c1sc(N2CCN(CC3CC3(F)F)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(CC(C)C)C2=O)nc1C
Product: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(=O)O
Yield: 96 %

Procedure:
Following the procedure as described in Preparation 14, making variations as required to replace ethyl 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate with ethyl 2-(3-isobutyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colourless solid in 96% yield: 1H NMR (300 MHz, DMSO-d6) δ 4.04-3.98 (m, 2H), 3.58-3.53 (m, 2H), 3.03 (d, J=7.4 Hz, 2H), 2.50 (s, 3H), 1.94-1.85 (m, 1H), 0.87 (d, J=6.6 Hz, 6H); MS (ES+) m/z 283.8 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:10])=[C:5]([C:7](O)=[O:8])[N:6]=1.Cl.C([N:14]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH3:1][C:2]1[NH:3][C:4]([CH3:10])=[C:5]([C:7]([NH2:14])=[O:8])[N:6]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1nc(C(=O)O)c(C)[nH]1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(C(N)=O)c(C)[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 115.1 %

Procedure:
A solution of 2,5-dimethyl-4-imidazolecarboxylic acid (1.4 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.93 g), and N-hydroxybenzotriazole (1.49 g) in N,N-dimethylformamide (14 ml) was stirred at 0° C. for 15 minutes. A solution of (2E,4E)- and (2Z,4E)-4-methyl-2,4-heptadien-1-ylamine (1.79 g) in N,N-dimethylformamide (6 ml) was added dropwise to the solution over a period of 10 minutes. The mixture was stirred at 0° C. for 30 minutes and then at room temperature for 24 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (3% methanol-chloroform) to give N-[(2E,4E)- and (2Z,4E)-4-methyl-2,4-heptadien-1-yl]-2,5-dimethyl-4-imidazolecarboxamide (1.6 g) as an oil.
Reaction SMILES: C(OC(N1C2C(=CC=C(CO)C=2)C=C1)=O)(C)(C)C.[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[C:30]([CH:35]=[O:36])[CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[C:30]([CH2:35][OH:36])[CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)n1ccc2c(C=O)cccc21
Agent: CC(C)(C)OC(=O)n1ccc2ccc(CO)cc21
Product: CC(C)(C)OC(=O)n1ccc2c(CO)cccc21

Procedure:
4-Hydroxymethyl-indole-1-carboxylic acid tert-butyl ester was synthesized by a procedure similar to 6-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester from starting material 4-formyl-indole-1-carboxylic acid tert-butyl ester to yield the product as a clear viscous oil (0.91 g, 78%). LC-MS (ES) calculated for C14H17NO3, 247.1; found m/z 246 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:15]3[C:23]4[O:22][CH2:21][O:20][C:19]=4[CH:18]=[CH:17][C:16]=3[O:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)[C:9]=2[NH:8][CH:7]=1)=[O:5])C.[Li+].[OH-]>O1CCOCC1.O>[CH:26]1([CH2:25][O:24][C:16]2[CH:17]=[CH:18][C:19]3[O:20][CH2:21][O:22][C:23]=3[C:15]=2[C:14]2[C:9]3[NH:8][CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:27][CH2:28]1
Reactant: CCOC(=O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Temperature: 100 °C
Yield: 93.1 %

Procedure:
4-(5-Cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester (9.53 g; 25.0 mmol) from example A48 is suspended in dioxane (170 mL) and water (100 mL). After addition of LiOH (2.99 g; 125.0 mmol) the reaction mixture is stirred at 100° C. over night. The resulting solution is evaporated to dryness. The residue is dissolved in hot (60-90° C.) water (250 mL) and pH is adjusted to 2-3 by addition of 2M citric acid while still hot. After cooling to ambient temperature the precipitated product is collected by suction filtration, washed with water, ethanol and dried in high vacuo at 50° C. to yield 8.22 g of the title compound as pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:19][C:20]([O:22]C)=[O:21])[C:9](=[O:18])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[Li+].Cl>C1COCC1.CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:19][C:20]([OH:22])=[O:21])[C:9](=[O:18])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)CN(C(=O)/C=C/c1ccccc1)c1ccc(Br)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CN(C(=O)/C=C/c1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 9.8 %

Procedure:
A solution of {(4-bromophenyl)-[(E)-(3-phenylacryloyl)]amino}acetic acid, methyl ester 1 (14.61 g, 0.39 mol) in THF (150 mL) and methanol (50 mL) was treated with lithium hydroxide (2.80 g, 0.117 mol) in water (50 mL). The reaction mixture was stirred at room temperature for 45 min and then acidified with conc. hydrochloric acid and concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 10% hydrochloric acid, brine, dried (Na2SO4) and the organic solution evaporated to give the title compound as a viscous oil (13.82 g, 97%). 1HNMR (300 MHz) (CDCl3) δ 4.53 (2H, s), 6.36 (1H, d, J=16 Hz), 7.27 (2H, d), 7.3-7.4 (5H, m), 7.60 (2H, d) and 7.76 (1H, d, J=16 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([N:9]1[CH2:8][C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=2[S:12][CH2:11][CH2:10]1)(=[O:16])[CH3:15]
Reactant: Cc1cccc2c1CNCCS2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)N1CCSc2cccc(C)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.91 g, prepared in a similar manner to its hydrochloride, Example 4 above) in acetic anhydride (10 ml) was stirred at room temperature for one hour. The reaction mixture was poured into ice and extracted with dichloromethane. The organic layer was dried and the solvent removed by evaporation to give 4-acetyl-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from hexane. Yield 0.93 g (m.p. 71°-73° C.).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][CH:8]([C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24]([CH2:25][C@@H:26]([O:41][C:42]([O:44][CH3:45])=[O:43])[CH2:27][C@@H:28]2[O:36][C:37]([O:39][CH3:40])=[O:38])=[CH:23][CH:22]=3)[CH2:19][CH2:18]1)[CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.C(OCC)C>[CH3:7][CH:8]([C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24]([CH2:25][C@@H:26]([O:41][C:42]([O:44][CH3:45])=[O:43])[CH2:27][C@@H:28]2[O:36][C:37]([O:39][CH3:40])=[O:38])=[CH:23][CH:22]=3)[CH2:19][CH2:18]1)[CH2:9][S:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:2]
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CSc5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CS(=O)c5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
To a solution of 20 mg of sodium metaperiodate in 2 ml of tetrahydrofuran was added dropwise an ice-cooled solution of 41 mg of 20-methyl-1α,3β-bis(methoxycarbonyloxy)-21-phenylthiopregna-5,7-diene in 1 ml of diethyl ether. The resulting mixture was stirred with ice cooling for 30 minutes, then the insoluble matter was filtered off and washed with diethyl ether, and the filtrate and washings were combined, washed in sequence with an aqueous solution of sodium thiosulfate, water, an aqueous solution of sodium hydrogen carbonate and an aqueous solution of sodium chloride, then dried and concentrated. The residue was purified by silica gel column chromatography to give 29 mg of 20-methyl-1α,3β-bis(methoxycarbonyloxy)-21-phenylsulfinylpregna-5,7 -diene.
Reaction SMILES: [H-].[NH2:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][C:4]=1[C:15]#N.C[OH:18].O>C1(C)C=CC=CC=1.C1COCC1>[NH2:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][C:4]=1[CH:15]=[O:18]
Reactant: CO
Reactant: Cc1cc(-n2cncn2)cc(C#N)c1N
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(-n2cncn2)cc(C=O)c1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisobutylalumnium hydride (11.1 cm3 of a 1.5M solution in toluene) was added dropwise at 0° to a stirred suspension of 1-(4-amino-3-cyano-5-methylphenyl)-1,2,4-triazole (15 g) in THF (20 cm3). The solution was stirred at room temperature for 0.5 hours, heated under reflux for 2 hours, cooled, and treated with methanol (1 cm3) and water (100 cm3). Solid material was filtered off and washed with methanol (50 cm3) and the filtrate was evaporated in vacuo. The residue was taken into 2M hydrochloric acid (20 cm3), warmed for 10 minutes at 100° , and cooled. The solution was neutralised with saturated aqueous sodium carbonate solution and extracted with chloroform (4×50 cm3). The combined organic extracts were dried (MgSO4) and evaporated to give an oil which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl acetate. Combination and evaporation of appropriate fractions followed by recrystallisation from ethyl acetate/hexan afforded the title compound, m.p. 209°-211° (1.27 g), characterised by n.m.r. and i.r. spectroscopy.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9]>O.Cl>[F:15][C:13]1[CH:12]=[CH:11][C:7]2[C:8](=[O:9])[NH:10][N:1]=[N:5][C:6]=2[CH:14]=1
Reactant: O=N[O-]
Reactant: NC(=O)c1ccc(F)cc1N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=c1[nH]nnc2cc(F)ccc12
Reaction time: 2 h
Yield: 68.3 %

Procedure:
59.23 g (0.387 mol) of benzotriazol-1-ol, 65.776 ml (0.387 mol) of N-ethyldiisopropylamine and 74.15 g (0.387 mol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were added successively at room temperature to a solution of 50.0 g (0.322 mol) of 2-amino-4-fluorobenzoic acid in 600 ml of dimethylformamide. 64.46 ml (0.451 mol) of ammonia in methanol (7 mol/l) were added dropwise with stirring, and the mixture was stirred for 18 hours. Water (2 l) and concentrated sodium chloride solution (0.5 l) were added to the batch. The mixture was extracted three times with ethyl acetate (0.75 l each time). The organic phase was dried over sodium sulfate, filtered, and the solvent was subsequently stripped off in a Rotavapor. The residue was triturated with 2-methoxy-2-methylpropane (0.2 l) and ligroin (0.1 l). The crystalline precipitate was filtered off with suction and dried in a drying cabinet, giving 44.5 g of 2-amino-4-fluorobenzamide as solid. 35.85 g (0.520 mol) of sodium nitrite in 75 ml of water were added dropwise at room temperature to a suspension of 44.5 g (0.289 mol) of 2-amino-4-fluorobenzamide in 1.4 l of hydrochloric acid (25%). The mixture was stirred for 2 hours with ice-cooling. The deposited precipitate was filtered off with suction, rinsed with water and dried at 60° C. in a vacuum drying cabinet, giving 32.58 g of 7-fluoro-3H-benzo[d]-1,2,3-triazin-4-one as solid; HPLC/MS (M+H)+=166; 1H NMR (300 MHz, DMSO) δ 8.32 (dd, J=8.8, 5.7, 1H), 7.87 (dd, J=9.0, 2.5, 1H), 7.64 (td, J=8.7, 2.5, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH2:25][O:26][CH3:27])[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:28])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH2:25][O:26][CH3:27])[C:17]([OH:19])=[O:18])[C:10](=[O:28])[CH:9]=2)[CH:7]=1
Reactant: COCCC(C(=O)OC(C)(C)C)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O

Procedure:
201 mg (purity 91%, 0.39 mmol) of tert-butyl 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methoxybutanoate (racemate) were hydrolysed with TFA according to General Method 6A. Yield: 212 mg (purity 82%, quant.)
Reaction SMILES: C(Cl)(Cl)Cl.CC([O:8][CH2:9][C:10]1[CH2:29][S:28][CH:13]2[C@H:14]([NH:17][C:18]([CH2:20][CH2:21][CH2:22][CH:23]([NH2:27])[C:24]([OH:26])=[O:25])=[O:19])[C:15](=[O:16])[N:12]2[C:11]=1[C:30]([O-:32])=[O:31])=O.[Na+].CC(OCC1CS[C@@H]2[C@H](NC(CCC[C@@H](N)C(O)=O)=O)C(=O)N2C=1C(O)=O)=O.C>C(O)C>[CH2:29]1[S:28][C@@H:13]2[C@H:14]([NH:17][C:18]([CH2:20][CH2:21][CH2:22][C@@H:23]([NH2:27])[C:24]([OH:26])=[O:25])=[O:19])[C:15](=[O:16])[N:12]2[C:11]([C:30]([OH:32])=[O:31])=[C:10]1[CH2:9][OH:8]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)CCCC(N)C(=O)O)C2SC1
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(=O)O)[C@H]2SC1
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: N[C@H](CCCC(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)C(=O)O
Reaction time: 0.5 h

Procedure:
To the wet mycelia (10 g) was added a small volume of chloroform. The mixture was allowed to stand at ambient temperature for 30 minutes. To the mixture was added distilled water (20 ml). After allowing to stand at ambient temperature for a day, the mixture was centrifuged to give enzyme extracts (20 ml). The enzyme extracts was added to an aqueous solution (300 ml) containing cephalosporin C sodium.dihydrate (25 mg/ml). The reaction mixture was stirred at pH 4.5 and 30° C. for 10 hours until cephalosporin C in the mixture disappeared. To the resultant mixture was added activated charcoal (3 g) and the mixture was filtered. The filtrate was adjusted to pH 7.0 and concentrated under reduced pressure to give crystals, to which was added a small volume of 75% aqueous ethanol and the mixture was triturated. The crystals were separated by filtration and dried in vacuo to give crystalline deacetylcephalosporin C (3.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11]#[N:12].[S:13]([OH:17])(=[O:16])(=[O:15])[CH3:14].[CH2:18]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23])[CH3:19]>ClC1C=CC=CC=1>[S:13]([OH:17])(=[O:16])(=[O:15])[CH3:14].[CH2:18]([C:20]1[CH:21]=[C:22]([NH:23][C:11]([NH:10][C:3]2[CH:4]=[C:5]([CH2:8][CH3:9])[CH:6]=[CH:7][C:2]=2[Cl:1])=[NH:12])[CH:24]=[CH:25][CH:26]=1)[CH3:19]
Reactant: CCc1cccc(N)c1
Reactant: CCc1ccc(Cl)c(NC#N)c1
Agent: CS(=O)(=O)O
Solvent: Clc1ccccc1
Product: CCc1cccc(NC(=N)Nc2cc(CC)ccc2Cl)c1

Procedure:
A mixture of 2-chloro-5-ethylphenylcyanamide (0.6 g, 3.08 mmol), 3-ethylaniline mesylate (0.64 g, 2.93 mmol), and chlorobenzene (12 mL) were combined in a dry round bottom flask equipped with a water cooled condenser under nitrogen and placed in a preheated oil bath (150-160° C.). The reaction mixture was heated for 3 hours. After cooling, the crude reaction product was purified by crystallization from chlorobenzene/diethylether. The resulting crystals were collected by filtration, washed with diethylether, and dried in a vacuum oven (40° C., 15 hours) to yield the title compound, N-(3-ethylphenyl)-N'-(2-chloro-5-ethylphenyl)guanidine mesylate, as a white solid (1.1 g, 91 % yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][OH:11])[CH:9]=1)=[O:4].[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=2)[O:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][O:11][C:24]2[CH:25]=[CH:26][C:21]([B:16]3[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:28])([CH3:13])[O:15]3)=[CH:22][CH:23]=2)[CH:9]=1)=[O:4]
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: COC(=O)c1cc(CO)c(C)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
A mixture of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (0.5 g), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (1.9 g) and triphenylphosphine (2.3 g) in dry tetrahydrofuran (20 mL) under a nitrogen atmosphere was cooled to 0° C. Di-isopropylazodicarboxylate (1.8 mL) was added drop-wise and the mixture was stirred at room temperature for 72 hours. After concentrating in vacuo, the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was extracted with pentane and the pentane phase was decanted and concentrated to give compound 51 as an oil. This was used without further purification.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[S:15]([NH:18][C:19]1[C:20]([O:34][CH3:35])=[N:21][CH:22]=[C:23]([C:25]2[S:29][C:28]3=[N:30][CH:31]=[C:32](I)[N:27]3[N:26]=2)[CH:24]=1)(=[O:17])=[O:16].[N:36]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][N:37]=1>O1CCOCC1>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[S:15]([NH:18][C:19]1[C:20]([O:34][CH3:35])=[N:21][CH:22]=[C:23]([C:25]2[S:29][C:28]3=[N:30][CH:31]=[C:32]([C:40]4[CH:39]=[CH:38][N:37]=[N:36][CH:41]=4)[N:27]3[N:26]=2)[CH:24]=1)(=[O:17])=[O:16]
Reactant: COc1ncc(-c2nn3c(I)cnc3s2)cc1NS(=O)(=O)c1ccc(F)cc1F
Reactant: CC1(C)OB(c2ccnnc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ncc(-c2nn3c(-c4ccnnc4)cnc3s2)cc1NS(=O)(=O)c1ccc(F)cc1F
Yield: 5.5 %

Procedure:
Dioxane (2 mL) and 2M aq Na2CO3 (0.5 mL) were added to 2,4-difluoro-N-[2-methoxy-5-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-pyridin-3-yl]-benzenesulfon-amide (100 mg) and pyridazin-4-boronic acid pinacol ester (80 mg), and the suspension was degassed under vacuum and filled with argon (2×). The catalyst (30 mg) was quickly added, and the reaction mixture was stirred at reflux for 2 h. Further boronate (50 mg) was added, and the mixture was degassed again, then more catalyst was added (25 mg) and stirring was continued at reflux for 4 h. The solvents were evaporated, and the residue was stirred in water for 36 h. The precipitate that had formed was removed by filtration, and the filtrate was concentrated and taken up in aq. NH4Cl. A precipitate formed overnight and was filtered off, washed with water followed by ether and dried. The solid was purified by flash chromatography (DCM/MeOH 98:2 to 9:1, affording 24 mg of crude product) and subsequently by preparative HPLC to give the desired product (5 mg). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=4.57 min, [M+H]+ m/z 502.1; 1H NMR (300 MHz, DMSO) δ=10.56 (s, 1H), 9.82 (s, 1H), 9.25 (d, J=5.5 Hz, 1H), 8.57 (s, 1H), 8.35-8.16 (m, 2H), 8.06 (s, 1H), 7.79 (dd, J=15.0, 8.6 Hz, 1H), 7.50 (s, 1H), 7.20 (t, J=8.3 Hz, 1H), 3.70 (s, 3H) ppm.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][C:29]1[CH:33]=[C:32]([C:34](O)=[O:35])[O:31][N:30]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([C:32]5[O:31][N:30]=[C:29]([CH3:28])[CH:33]=5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: Cc1cc(C(=O)O)on1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: Cc1cc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4CCO5)CC3)CC2)on1

Procedure:
The title compound, off-white solid (62 mg, 71%), MS (ISP) m/z=440.4 [(M+H)+], mp 218° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and 3-methylisoxazole-5-carboxylic acid.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6](=[O:14])[C:7]([C:12]#[N:13])=[CH:8]OCC)C.[CH2:16]([O:18][CH:19]([O:23][CH2:24][CH3:25])[CH2:20][CH2:21][NH2:22])[CH3:17]>O>[CH2:16]([O:18][CH:19]([O:23][CH2:24][CH3:25])[CH2:20][CH2:21][N:22]1[CH:8]=[C:7]([C:12]#[N:13])[C:6](=[O:14])[NH:5][C:4]1=[O:3])[CH3:17]
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Reactant: CCOC(CCN)OCC
Solvent: O
Product: CCOC(CCn1cc(C#N)c(=O)[nH]c1=O)OCC
Temperature: 80 °C
Yield: 92.2 %

Procedure:
(2-Cyano-3-ethoxy-acryloyl)-carbamic acid ethyl ester (Prep 33, 300 mg, 1.42 mmol) was suspended in water (20 mL); 3,3-diethoxypropylamine (460 μl, 2.84 mmol) was added and the mixture warmed at 80° C. for 10 minutes. The reaction mixture was lyophilized and the residue was purified by flash chromatography with petroleum ether-ethyl acetate (1-1) to give 350 mg of the title compound (91% yield)
Reaction SMILES: [C:1]1([N:11]=[C:12]=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C:21]1([C:29](=[O:30])[NH:28][C:27](=[O:31])[NH:26]1)[CH2:20][CH2:19]2.C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]1([NH:11][C:12]([NH:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH2:22][C:21]2([C:29](=[O:30])[NH:28][C:27](=[O:31])[NH:26]2)[CH2:20][CH2:19]3)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc2c(c1)CCC1(C2)NC(=O)NC1=O
Reactant: O=C=Nc1cccc2ccccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)CCC1(C2)NC(=O)NC1=O)Nc1cccc2ccccc12

Procedure:
A mixture of 1-naphthyl isocyanate (9.5 mg, 0.056 mmol), (±)-6′-amino-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione hydrochloride (described in Intermediate 2) (15 mg, 0.056 mmol), and N,N-diisopropylethylamine (0.010 mL, 0.056 mmol) was stirred in THF (0.5 mL) at ambient temperature for 18 h. The crude mixture was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound as a white solid. MS: m/z=401 (M+1). HRMS: m/z=401.1638; calculated m/z=401.1608 for C23H21N4O3.