Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)=[CH:4][CH:3]=1.Br[C:14]1[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[CH:19]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:20][C:18]1[CH:19]=[C:14]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:9][CH:10]([OH:12])[CH2:11]3)=[CH:6][N:7]=2)[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=1
Reactant: Nc1ccc(N2CC(O)C2)cn1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc(N3CC(O)C3)cn2)c1=O
Temperature: 90 °C
Yield: 89 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 314b (792 mg, 4.8 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.9 g, 7.2 mmol), tris-(dibenzylideneacetone)dipalladium(0) (440 mg, 0.48 mmol), XantPhos (555 mg, 0.96 mmol), Cs2CO3 (3.1 g, 9.6 mmol), and 1,4-dioxane (40 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 3.0 hrs. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 20:1) to afford 314c as a yellow solid (1.5 g, 89%). MS-ESI: [M+H]+ 351.1
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH3:12]>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:12])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: N#Cc1ccc(C(N)=O)cc1

Procedure:
By the reaction in the same manner as in Example 25-i) using 4-cyanobenzoyl chloride (5.30 g) and 28% aqueous ammonia (20 ml), the title compound (3.62 g) was obtained by pale-brown needle crystals.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:16]([OH:34])=[C:17]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=2[Cl:33])=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21])(=[O:14])=[O:13])=O)(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[NH2:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:16]([OH:34])=[C:17]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=2[Cl:33])=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21])(=[O:14])=[O:13]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Solvent: O=C(O)C(F)(F)F
Product: NCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Yield: 100 %

Procedure:
Following the general procedure for Boc deprotection outlined in example 36, N-[3-[N″-[2-(tert-butoxycarbonylamino)ethyl]aminosulfonyl]4-chloro-2-hydroxyphenyl]-N′(2,3-dichlorophenyl) urea (56 mg, 0.10 mmol) was stirred in trifluoroacetic acid to form the desired product (57 mg, 100%). LC-MS (m/z) 453.0 (M+).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][C:17]#N)=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][N:30]([CH3:34])[CH2:31]CCl>>[CH:1]1([CH2:6][C@H:7]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][CH2:29][N:30]([CH3:34])[CH3:31])=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(SC#N)s2)cc1
Reactant: CN(C)CCCl
Product: CN(C)CCSc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1

Procedure:
The title compound was prepared from (R)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-thiocyanato-thiazol-2-yl)-propionamide and 2-(dimethylamino)ethyl chloride as described in Example 10. 1H-NMR (CD3OD): δ 7.92 (d, 2H), 7.67 (d, 2H), 7.55 (s, 1H), 3.96 (t, 1H), 3.29 (m, 2H), 3.10 (s, 3H), 3.06 (m, 2H), 2.87 (s, 6H), 2.26-2.19 (m, 1H), 1.89-1.48 (m, 8H), 1.18 (m, 2H); HPLC-MS: m/z: 482 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([CH:19]=[CH:20][O:21][CH3:22])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][CH2:20][O:21][CH3:22])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC=Cc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Agent: [Pd]
Solvent: CCO
Product: COCCc1cc(O)cc(C(=O)OC)c1
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(benzyloxy)-5-[2-methoxyvinyl]benzoate (1 eq.) from the previous step in ethanol was added 10% palladium on activated carbon (5 mol %). The reaction vessel was evacuated and back-filled with hydrogen twice. After 1 h, more 10% palladium on activated carbon (5 mol %) was added and the reaction was stirred for 18 h. The reaction was diluted with DCM and filtered through a pad of celite. Concentration in vacuo afforded the title compound as an oil.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:51][O:52][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:51][OH:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1F
Solvent: CO
Solvent: CC(=O)Cl
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1F
Reaction time: 1 h
Yield: 83.6 %

Procedure:
[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethylsilane 4h (10.52 g, 12.5 mmol) was dissolved in 50 mL methanol, followed by dropwise addition of acetyl chloride (0.13 mL, 1.9 mmol). The reaction mixture was stirred for 1 hour. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 4i (7.6 g, yellow grease), yield: 83.6%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:32])=[C:16]([N:20]3[CH2:23][C:22]([CH3:31])([NH:24]C(=O)C(F)(F)F)[CH2:21]3)[C:17]=2[F:19])[C:12](=[O:33])[C:11]([C:34]([OH:36])=[O:35])=[CH:10]1.[OH-].[Na+].C(O)C>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:32])=[C:16]([N:20]3[CH2:23][C:22]([NH2:24])([CH3:31])[CH2:21]3)[C:17]=2[F:19])[C:12](=[O:33])[C:11]([C:34]([OH:36])=[O:35])=[CH:10]1
Reactant: CC1(NC(=O)C(F)(F)F)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c2F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(N)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c2F)C1
Yield: 22.6 %

Procedure:
A solution of 1.1 g (2.1 mmoles) of 1-(2,4-difluorophenyl)-6,8-difluoro-7-(3-methyl-3-trifluoroacetamido-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (example 34), 4 ml of 10% sodium hydroxide, 5 ml of ethanol and 25 ml of water is heated under reflux for 3 hours. It is cooled, filtered, acetic acid is added and the product filtered and washed with water and cold ethanol. 0.2 g (22%) of 1-(2,4-difluorophenyl)-6,8-difluoro-7-(3-amino-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 185°-6° C.
Reaction SMILES: C([NH:3][C:4]([NH2:6])=[NH:5])#N.[P:7](=[O:11])([OH:10])([OH:9])[OH:8].P(O)(O)(O)=O.C(NC(N)=N)(=O)N.C(O)C(O)C.C(=O)=O.N>>[P:7]([OH:11])([OH:10])([OH:9])=[O:8].[NH2:5][C:4]([NH2:6])=[NH:3]
Reactant: N#CNC(=N)N
Agent: N
Agent: N=C(N)NC(N)=O
Agent: O=C=O
Solvent: CC(O)CO
Product: N=C(N)N
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
Cyanoguanidine 336 parts (4.00 moles) is mixed with 603.2 parts (4.00 moles) of 65.0% phosphoric acid in a stainless steel beaker having a volume about four times that of the reaction mixture. The mixture is stirred with a spatula while maintaining the temperature at 25° C. The resulting smooth fluid slurry is heated in an oil bath from 25° to 90° C. in 0.35 hour when the slurry clears to a solution and boils vigorously. Within 2 minutes the boiling ceases and the liquid solidifies. To the solid carbamoylguanidine phosphate is added 1.9 parts (0.2%) of the polyoxyethylated propylene glycol block copolymer of molecular weight 1,045 identified in Example 1 as a viscosity reducer and foam controller. The heating is continued and at about 180° C. the solid begins to soften and at 190°-195° C. the cake begins to breakup with stirring. At about 200° C., the melt begins to foam (CO2 and NH3 evolution) and by 225° C. has become a uniform melt free of lumps with reduced foaming. The time required to heat from 90° to 225° C. is 1.3 hours. After 0.7 hour at 225° C. foaming has largely subsided. Heating at 225° C. is continued for an additional one hour. The beaker is then removed from the bath and cooled to room temperature. The product, a faint tan opaque glass has a pH of 6.5 (1% aqueous slurry), an amorphous solids content of 3.9% and a guanidine content of 47.9%. The conversion yield of cyanoguanidine to guanidine is 119.2% based on the stoichiometry, 1 cyanoguanidine→1 guanidine. The weight loss at 220° C. for 1 hour is 0.4%. The product is ground to a coarse powder in a Wiley Mill using a 6-mm screen.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=3)[N:11]=2)=[CH:8][N:9]=1)[CH2:3][OH:4].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.O>C(Cl)(Cl)Cl>[CH3:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([NH:16][C:12]2[N:11]=[C:10]([C:7]3[S:6][C:5]([C@@H:2]4[CH2:3][O:4][C:32](=[O:34])[NH:1]4)=[N:9][CH:8]=3)[CH:15]=[CH:14][CH:13]=2)[CH:22]=1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc([C@@H](N)CO)s3)n2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccnc(Nc2cccc(-c3cnc([C@@H]4COC(=O)N4)s3)n2)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 48.3 %

Procedure:
To a solution of (S)-2-amino-2-{5-[6-(4-methylpyridin-2-ylamino)pyridin-2-yl]thiazol-2-yl}ethanol (220 mg, 0.67 mmol) obtained in Example 13, triethylamine (0.93 ml, 0.67 mmol) in chloroform (5 ml), triphosgene (70 mg, 0.24 mmol) was added while cooled to −78° C., and the mixture was stirred at the same temperature for 3 hours. The reaction solution was warmed to room temperature and water was added and it was extracted with ethyl acetate. After washed with a saturated saline solution, the organic layer was dried over magnesium sulfate. After concentrated, the residue was washed with ethanol and the title compound (41 mg, 17%) was obtained.
Reaction SMILES: C([O:5][NH:6][C:7]([CH:9]([N:25]1[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]1)[CH2:10][NH:11][C:12](=[O:24])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]#[C:22][CH3:23])=[CH:15][CH:14]=1)=[O:8])(C)(C)C>FC(F)(F)C(O)=O>[CH2:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([NH:11][CH2:10][CH:9]([C:7](=[O:8])[NH:6][OH:5])[N:25]2[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:32])=[O:33])[CH2:27][CH2:26]2)=[O:24])=[CH:18][CH:17]=1)[C:21]#[C:22][CH3:23]
Reactant: CC#CCOc1ccc(C(=O)NCC(C(=O)NOC(C)(C)C)N2CCN(S(C)(=O)=O)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC#CCOc1ccc(C(=O)NCC(C(=O)NO)N2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 192 h
Yield: 34.2 %

Procedure:
100 mg (0.2 mmol) of N-[2-tert-butoxycarbamoyl-2-(4-methanesulphonylpiperazin-1-yl)ethyl]-4-but-2-ynyloxybenzamide are placed in 3 ml of trifluoroacetic acid. After stirring for 8 days at ambient temperature, the mixture is concentrated under vacuum then the crude product is purified by chromatography over silica gel eluted with a 9/1 dichloromethane/methanol mixture. 30 mg (34%) of 4-but-2-ynyloxy-N-[2-hydroxycarbamoyl-2-(4-methanesulphonylpiperazin-1-yl)ethyl]benzamide are obtained in the form of a beige solid.
Reaction SMILES: [I-:1].[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N+:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[C:7]([CH3:20])[C:6]2([CH3:22])[CH3:21].S(=O)(=O)(O)O.[CH2:28](O)[CH3:29]>>[I-:1].[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N+:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:28][CH3:29])=[O:18])=[C:7]([CH3:20])[C:6]2([CH3:22])[CH3:21]
Reactant: CC1=[N+](CCCCCC(=O)O)c2ccc(Br)cc2C1(C)C
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [I-]
Product: CCOC(=O)CCCCC[N+]1=C(C)C(C)(C)c2cc(Br)ccc21
Temperature: 25 °C
Yield: 82 %

Procedure:
To a 250 mL flask were added 16 (2.0 g, 4.17 mmol), ethanol (60 mL) and conc. sulfuric acid (0.2 mL). The mixture was heated at reflux for 2 h and then was cooled to rt. The ethanol was removed in vacuo and the residue was partitioned between water (40 mL) and DCM (80 mL). The organic layer was washed with 1 M HCl (40 mL), water (40 mL) and then with a solution of sodium iodide. It was dried (MgSO4) and evaporated in vacuo to afford 17 as a brown solid (1.74 g, 82%).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH:5]([NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH2:6][CH:7]=[CH2:8])C.[OH-].[Na+].CCOC(C)=O>CCO.C1COCC1>[C:10]([NH:9][CH:5]([CH2:6][CH:7]=[CH2:8])[C:4]([OH:15])=[O:3])(=[O:14])[CH:11]([CH3:13])[CH3:12]
Reactant: C=CCC(NC(=O)C(C)C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCC(NC(=O)C(C)C)C(=O)O
Reaction time: 2.5 h
Yield: 63.5 %

Procedure:
11.70 g of the above prepared 2-isobutyrylamino-pent-4-enoic acid ethyl ester (67.55 mmol) were dissolved in 110 ml of a 1:1 mixture of EtOH and THF and treated under cooling with an ice bath with 33.80 ml of 2N NaOH (2 eq.). After 2.5 h, the reaction mixture was poured onto crashed ice/AcOEt/HCl, the aqueous phase reextracted once more with AcOEt, the combined organic layers washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Crystallization from AcOEt/hexane afforded 7.95 g of the title product as white solid.
Reaction SMILES: [CH:1]1([C:7]#[N:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:9].[CH2:10]([OH:12])[CH3:11]>>[ClH:9].[CH:1]1([C:7](=[NH:8])[O:12][CH2:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCO
Reactant: N#CC1CCCCC1
Agent: Cl
Product: CCOC(=N)C1CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
Cyclohexanecarbonitrile (1.0 g, 9.2 mmol) was dissolved in anhydrous ethanol under an atmosphere of Ar. The solution was cooled to 0° C., saturated with HCl gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl cyclohexanecarbimidate hydrochloride (1.8 g, 100%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6): δ 11.66 (m, 1H), 11.03 (m, 1H), 4.39 (q, J=7.0 Hz, 2H), 2.62 (m, 1H), 1.84 (d, J=12.6 Hz, 2H), 1.70-1.65 (m, 3H), 1.40-1.38 (m, 2H), 1.33 (t, J=7.0 Hz, 3H), 1.23-1.19 (m, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[NH:12]C(=O)C.[ClH:16]>>[ClH:16].[ClH:16].[ClH:16].[NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[NH2:12]
Reactant: CC(=O)Nc1cc(N)ccc1OCCN
Agent: Cl
Product: NCCOc1ccc(N)cc1N

Procedure:
2 g. (0.0087 mol) of 2-acetylamino-4-aminophenyl β-aminoethyl ether are heated in 5 cm3 of hydrochloric acid for 20 minutes on a boiling waterbath. On cooling, the trihydrochloride crystallizes. The product is filtered off, washed with ether and dried in vacuo over KOH. It melts at 280° C. with decomposition.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([C:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:8]/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[N+:32]([C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)([O-:34])=[O:33].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([O:12][C:11](=[O:13])/[CH:10]=[CH:9]/[CH:8]=[C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:2][CH:3]=2)[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[CH:37][CH:36]=1)([O-:34])=[O:33]
Reactant: O=C(O)/C=C/C=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(/C=C/C=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.5 %

Procedure:
As in Example 115, a solution of (E)-5,5-bis[(1,1'-biphenyl)-4-yl]-2,4-pentadienoic acid (0.673 g) and 4-nitrophenol (0.256 g) in dichloromethane (7 mL) was treated with 1,3-dicyclohexylcarbodiimide (0.345 g). The mixture was stirred at room temperature for 1.5 hours. The usual work up furnished 0.88 g of (E)-5,5-bis[(1,1'-biphenyl)-4-yl]-2,4-pentadienoic acid 4-nitrophenyl ester.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7]C(=O)C)=[N:4][C:3]=1[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:13][C:12]=1[CH3:27].Cl.[OH-].[Na+]>CO>[Br:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:13][C:12]=1[CH3:27]
Reactant: COc1ccc(Oc2cc(C)c(-c3nc(NC(C)=O)sc3Br)c(C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Oc2cc(C)c(-c3nc(N)sc3Br)c(C)c2)cc1
Yield: 61.7 %

Procedure:
A methanol solution (10.0 mL) containing N-{5-bromo-4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-yl}acetamide (2-3, 465 mg, 1.3 mmol) and 6 N hydrochloric acid (6.0 mL) was heated at reflux for 4.0 h. The solution was added with 10% aqueous NaOH and the resultant solids were collected to give 5-bromo-4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (2-4, 325 mg) as white solids in 55% yield: 1H NMR (500 MHz, DMSO-d6) δ 6.97-7.04 (m, 4H), 6.65 (s, 2 H), 3.76 (s, 3 H), 2.03 (s, 6 H). ESI-MS: m/z 405.3, 407.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4]2[CH:13]=[CH:14][C:15]([NH:17][C:18]([NH2:20])=[S:19])=[CH:16][C:3]1=2.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1.C(OCC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C.O1CCCC1>[CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][S:19][C:18](=[NH:20])[NH:17][C:15]1[CH:14]=[CH:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[NH:8][C:2](=[O:1])[C:3]=2[CH:16]=1
Reactant: NC(=S)Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N=C(Nc1ccc2c(c1)C(=O)Nc1ccccc1N2)SCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-2-yl)-thiourea (Example 9, 50 mg, 0.18 mmol) in DMF (1 mL) was added 2-bromomethylnaphthalene (38.8 mg, 0.18 mmol) in one portion. The reaction mixture was stirred at room temperature for 1 hr then heated at 60° C. for 2 hrs. After this time, the solvent was removed in vacuo to leave an oily residue which was triturated with diethyl ether to give a yellow-brown solid. The solid was dissolved in 5 mL of tetrahydrofuran: 5 mL diethyl ether and treated with saturated sodium bicarbonate (10 mL). The organic layer was separated, dried over magnesium sulfate and evaporated to give a yellow oil. The product was purified by chromatography on silica gel (2% methanol: 98% dichloromethane). H1 NMR (acetone d6) δ: 8.81 (bs, 1H), 7.92-7.85 (m, 4H), 7.61 (bs, 1H), 7.50-7.39 (m, 4H), 7.09-6.91 (m, 7H), 5.81 (s, 2H).
Reaction SMILES: [NH2:1][OH:2].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:28][C:29]#[N:30])[C:18]3[S:22][N:21]=[C:20]([N:23]4[CH:27]=[CH:26][N:25]=[CH:24]4)[N:19]=3)=[CH:11][C:6]=2[O:5][CH2:4]1>O.CO>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][N:17]([C:18]3[S:22][N:21]=[C:20]([N:23]4[CH:27]=[CH:26][N:25]=[CH:24]4)[N:19]=3)[CH2:28][C:29]([NH:1][OH:2])=[NH:30])=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: N#CCN(CCCNCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1
Reactant: NO
Solvent: O
Solvent: CO
Product: N=C(CN(CCCNCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1)NO
Temperature: 25 °C
Reaction time: 30 h
Yield: 22 %

Procedure:
Hydroxylamine (1.0 mL of a 50 wt % in H2O, 15 mmol) was added all at once a solution of [{3-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-propyl}-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-acetonitrile (30 mg, 75 μmol) in MeOH (1.0 mL) at r.t. The reaction mixture stirred at r.t. for 30 h prior to concentrating to a white solid. The residue was purified using column chromatography (CH2Cl2 to 4:1 CH2Cl2/MeOH) to afford 7.0 mg (22%) of 2-[{3-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-propyl}-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-N-hydroxy-acetamidine as a white solid. [M+H]+ 430.91; 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 7.79 (s, 1H), 7.76 (s, 1H), 7.07 (s, 1H), 6.82 (s, 1H), 6.76-6.70 (m, 2H), 5.89 (s, 2H), 4.19 (s, 2H), 3.65 (s, 2H), 3.58 (m, 2H), 2.63 (t, 2H), 1.94 (tt, 2H).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][CH2:12][C:13]([NH2:15])=[NH:14])=[CH:5][CH:4]=1.[OH:16]O>C(O)(=O)C>[ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:10][CH2:11][CH2:12][C:13]([NH2:15])=[NH:14])=[O:16])=[CH:5][CH:4]=1
Reactant: N=C(N)CCCSc1ccc(F)cc1
Reactant: OO
Agent: Cl
Solvent: CC(=O)O
Product: N=C(N)CCCS(=O)c1ccc(F)cc1
Reaction time: 8 h
Yield: 76 %

Procedure:
15 g (0.06 mol) of 4-(p-fluorophenylthio)-butyramidine hydrochloride dissolved in 50 ml of acetic acid are oxidised with 5.6 ml of hydrogen peroxide of 120 volumes strength in 1 hour at 50° C.The mixture is left to stand overnight and is then evaporated in vacuo and the residue is taken up in acetone, filtered off and recrystallised from isopropanol. CRL 40,267 is obtained in a yield of 76%; it is in the form of small white crystals. Melting point = 138° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[C:16]=1[NH2:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH2:22][C:16]1[C:17]([NH:21][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:18][CH:19]=[CH:20][N:15]=1
Reactant: Nc1cccnc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccnc2N)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 48 %

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (9.59 g, 48.1 mmol) and pyridine-2,3-diamine (5.0 g, 45.8 mmol) were combined and dissolved in 1,2-dichloroethane (75 ml). Sodium triacetoxyborohydride (14.5 g, 68.4 mmol) was added to the mixture. Reaction stirred at room temperature for 7 hours. Additional sodium triacetoxyborohydride (3.60 g, 16.99 mmol) was added to the mixture. Reaction stirred at room temperature for 18 hours. Reaction was quenched with 1N sodium hydroxide. Material was extracted twice with dichloromethane and the aqueous phase was discarded. Material was washed successively with 1N sodium hydroxide, water, and brine and the aqueous phases were discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Silica gel chromatography eluting methanol-dichloromethane afforded the title compound as tan foam in 48% yield. MS (M−H)−=291.2.