Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][C:13]2[N:17]3[N:18]=[C:19]([C:22](=O)[CH3:23])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=2)=[C:10]([F:25])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH2:26][NH:27][C:28]([NH2:30])=[O:29].C(=O)(O)[O-].[Na+]>CO>[F:1][C:2]1[C:11]([CH2:12][C:13]2[N:17]3[N:18]=[C:19](/[C:22](=[N:26]/[NH:27][C:28]([NH2:30])=[O:29])/[CH3:23])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=2)=[C:10]([F:25])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: NNC(N)=O
Reactant: CC(=O)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C/C(=N\NC(N)=O)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Temperature: 40 °C
Reaction time: 20 h
Yield: 81.8 %

Procedure:
A mixture of 1-[3-(5,7-difluoro-quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-ethanone (38 mg, 0.112 mmol), semicarbazide (37.5 mg, 0.336 mmol) and sodium bicarbonate (40 mg, 0.67 mmol) in methanol (3 mL) was stirred at 40° C. for 20 h. LC/MS showed the reaction was complete, and the suspension was filtered. The filtrate cake was washed successively with cold water and methanol, and then dried to afford 36.3 mg (82% yield) of the title compound as white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.85 (s, 1H), 8.99 (dd, 1H), 8.49 (d, 1H), 8.35 (d, 1H), 8.18 (d, 1H), 7.73 (d, 1H), 7.62 (dd, 1H), 6.82 (s br, 2H), 4.75 (s, 2H), 2.19 (s, 3H). LCMS (method A): [MH]+=397, tR=4.43 min.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:24](=[O:25])[N:20]3[CH2:21][CH2:22][CH2:23][N:19]3[C:18]=2[C:26]2[CH:31]=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=2)=[CH:13][CH:12]=1>C1COCC1.C([O-])(O)=O.[Na+]>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:24](=[O:25])[N:20]3[CH2:21][CH2:22][CH2:23][N:19]3[C:18]=2[C:26]2[CH:31]=[CH:30][N:29]=[C:28]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:27]=2)=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)c(=O)n3n2CCC3)n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c(-c2ccc(F)cc2)c(-c2ccnc(Oc3ccccc3)n2)n2n1CCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
To a solution of phenol (0.66 g, 7.08 mmol) in THF (5 mL) is added NaH (0.24 g, 5.91 mmol) followed by a solution of the crude 2-(4-fluorophenyl)-3-(2-methanesulfonyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 5, prepared herein above (0.25 g, 0.67 mmol) in THF (2 mL). The reaction mixture is stirred for 1.5 hours at room temperature, diluted with aqueous NaHCO3 and extracted with twice with ethyl acetate. The organic layers are combined, dried over MgSO4, and concentrated in vacuo to afford the crude product which is purified over silica (100% EtOAc, followed by 10% MeOH/EtOAc) to provide 0.35 g (38% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.47 (d, J=5.1 Hz, 1H), 7.49 (dd, J=7.8, 7.8 Hz, 2H), 7.40 (ddd, J=5.4, 5.4 Hz, 2H), 7.35-7.22 (m, 3H), 7.10 (dd, J=8.4, 8.4 Hz, 2H), 6.90 (d, J=6.8 Hz, 1H), 4.05 (t, J=7.2 Hz, 2H), 3.86 (t, J=7.2 Hz, 2H), 2.59 (dt, J=7.2, 7.2 Hz, 2H); HRMS calcd for C22H18FN4O2 (M+H)+ 389.1414; found 389.1407. This compound corresponds to analog 1 from Table I.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14]>CCCCCC.C1COCC1>[Br:8][C:4]1[CH:3]=[C:2]([CH:13]([C:12]2[CH:15]=[CH:16][CH:17]=[C:10]([Br:9])[CH:11]=2)[OH:14])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: O=Cc1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1cccc(Br)c1)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
n-Bui (26.5 mL, 42.4 mmol, 1.6M in hexane) was added to a solution of 1,3-dibromobenzene (10 g, 42.4 mmol) in THF (50 mL) at −78° C. After stirred for 2 h at −78° C., the 3-bromobenzaldehyde (7.84 g, 42.4 mmol) was added to the reaction mixture. The reaction mixture was allowed to warm up to r.t. and stirred at 30° C. for 12 h. The reaction was quenched with aq NH4Cl (100 mL). The mixture was extracted with dichloromethane (80 mL×5). The combined organic layers were dried and concentrated. The residue was purified by column chromatography (on silica gel, eluent with Petroleum ether ˜Petroleum ether: EtOAc=20:1) to afford 8.4 g of the title compound (24.5 mmol, 58%). LC/MS: [M−18+1]=325. 1HNMR (DMSO-d6), 400 MHz: δ 5.74 (d, 1H, J=4.0 Hz), 6.19 (d, 1H, J=4.4 Hz), 7.26-7.31 (m, 2H), 7.37-7.43 (m, 4H), 7.59 (s, 2 H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][C:12]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])[O:13]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:12]2([CH3:11])[C:16](=[O:17])[CH:15]=[C:14]([CH:18]=[CH:7][C:6]3[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[O:13]2)=[CH:20][CH:21]=1
Reactant: CC1=CC(=O)C(C)(c2ccc(F)cc2)O1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(c2ccc(F)cc2)OC(C=Cc2ccc(C#N)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.7 %

Procedure:
To a solution of p-cyanobenzaldehyde (1.6 g, 11.8 mM) and 2,5-dimethyl-2-(4-fluorphenyl)-3(2H)-furanone (2.0 g, 9.8 mM) in ethanol (75 mL), was added 1N aqueous sodium hydroxide (1.0 mL, 1 mM). After the reaction solution was stirred at room temperature for two days, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with dichloromethane (3×100 mL). The combined dichloromethane extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give an orange liquid. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to give a yellow crystalline solid (1.2 g, 38% yield), m.p. 140°-142° C.
Reaction SMILES: [CH:1]1(/[CH:6]=[CH:7]/[C@H:8]([C@@H:10]2[O:14][C:13](=[O:15])[C@H:12]([O:16][CH3:17])[C@@H:11]2[OH:18])[OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:20][C@H:21]1[CH2:27][CH2:26][C:25]2[CH:28]=[C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:30]=[CH:31][C:24]=2[NH:23][C:22]1=[O:38].C(C(CCCC)C([O-])=O)C.[Na+]>C1COCC1>[CH:1]1(/[CH:6]=[CH:7]/[C@@H:8]([OH:9])[C@H:10]([OH:14])[C@@H:11]([OH:18])[C@@H:12]([O:16][CH3:17])[C:13]([NH:20][C@H:21]2[CH2:27][CH2:26][C:25]3[CH:28]=[C:29]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:30]=[CH:31][C:24]=3[NH:23][C:22]2=[O:38])=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H]1CCc2cc(-c3ccccc3)ccc2NC1=O
Reactant: CO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/C2CCCC2)[C@H]1O
Agent: CCCCC(CC)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H](C(=O)N[C@H]1CCc2cc(-c3ccccc3)ccc2NC1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C1CCCC1
Yield: 46.4 %

Procedure:
100 mg of 19 (0.39 mmol), 112.6 mg of 14a (0.39 mmol) and 162 mg of sodium 2-ethylhexanoate (0.98 mmol) in 2.0 ml of THF are successively introduced into a Wheaton tube, with agitation and under an argon atmosphere. The agitation is maintained at AT for 24 h. The reaction medium is directly evaporated to dryness. The crude is chromatographed on a silica cartridge (12 g, eluent EtOAc). 92 mg of expected product Ex5 (white solid) are obtained.
Reaction SMILES: [CH2:1]([OH:13])[C:2]([C@@H:4]([OH:12])[C@H:5]([OH:11])[C:6]([C:8]([OH:10])=[O:9])=[O:7])=[O:3].C(O)[C@H](O)[C@@H](O)[C@H](O)C(C(O)=O)=O>>[CH2:1]([OH:13])[C@@H:2]([OH:3])[C@@H:4]([OH:12])[C@H:5]([OH:11])[C:6]([C:8]([OH:10])=[O:9])=[O:7]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)C(=O)CO
Agent: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The 2,5-diketo-D-gluconic acid produced by culturing Strain A in the medium or by the direct contact of the substrate with any processed product of Strain A and accumulated in a broth of crude state, may be, without being isolated, utilized by Strain B or reduced by any processed product of Strain B to be converted into 2-keto-L-gulonic acid. Alternately, the 2-keto-D-gluconic acid which would be by-produced, if the pure, unmixed culture of Strain B should be conducted, can be utilized by Strain A or oxidized by any processed product of Strain A to produce 2,5-diketo-D-gluconic acid which may subsequently be converted again into 2-keto-L-gulonic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2=[O:19].C(=O)([O-])[O-].[K+].[K+].[Br:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[C:29]([F:35])[CH:28]=1>CN(C)C=O>[Br:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:8]2[C:9]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=3)[C:5](=[O:19])[N:6]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7]2=[O:12])=[C:29]([F:35])[CH:28]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: CCOC(=O)Cn1c(=O)[nH]c2ccc(Cl)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)c2cc(Cl)ccc2n(Cc2ccc(Br)cc2F)c1=O
Temperature: 0 °C
Yield: 72.2 %

Procedure:
Into 250 ml of dried dimethylformamide were dissolved 10 g of ethyl 6-chloro-1,4-dihydro-2,4-dioxo-3(2H)-quinazolineacetate, and 4.86 g of potassium carbonate were added and 10.40 g of 4-bromo-2-fluorobenzyl bromide were added under stirring. After stirring for 1 hour at 60° C., the reaction mixture was poured into 400 ml of ice water and the crystals were collected by filtration. They were recrystallized from ethanol to obtain 12.0 g of title compound. m.p. 145°-146° C.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)(O)[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].S(C1C=CC=CC=1C(OC(=O)C1C=CC=CC=1S(O)(=O)=O)=O)(O)(=O)=O>C(O)(=O)CC>[C:1]([C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[C:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)C(O)(C1CCN(C)CC1)c1ccccc1S2
Agent: O=C(OC(=O)c1ccccc1S(=O)(=O)O)c1ccccc1S(=O)(=O)O
Solvent: CCC(=O)O
Product: CC(=O)c1ccc2c(c1)C(=C1CCN(C)CC1)c1ccccc1S2

Procedure:
140 grams of the ethylene glycal ketal of 2-acetyl-9-(1-methyl-4-piperidyl)-9-thioxanthenol (MP 206-208 degrees Centigrade) were heated for two hours under reflux with a mixture of 1500 milliliters of propionic acid and 100 grams of 2-sulfobenzoic acid anhydride. Thereafter the mixture was evaporated in vacuum, the residue dissolved in water and made alkaline. The base which separated out was extracted with ether, the ether phase dried over anhydrous potassium carbonate and evaporated until beginning crystallization. The crystals were sucked off and dried. --50 grams of 4-(2-acetyl-9-thioxanthenylidene)-1-methyl-piperidine were obtained melting at 125-127 degrees Centigrade.
Reaction SMILES: [N+]([C:4]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-])=O.[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC(C)([O-])C.[K+]>CN(C)C=O>[CH2:15]([S:22][C:4]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Reactant: SCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C)c1SCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
In a 5 1 pot was charged 483 g of methyl 2-nitro-3-methylbenzoate, 319 g benzyl mercaptan and 100 mL dimethyl formamide. Upon cooling to 0° C., a solution of 321 g potassium tert-butoxide in 1500 mL dimethyl formamide was added dropwise over 2.5 hours at 0°-5° C. The reaction mixture was stirred at 0° C. for 1.5 hours and then at room temperature overnight. The reaction was quenched by addition of 1 1 water and worked up by extraction with 2 1 methylene chloride. Upon washing with water (3×1 1), the methylene chloride layer was dried over MgSO4, filtered and rotovapped to give 517 g of crude methyl 2-benzylthio-3-methylbenzoate (77% yield) as a liquid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:44][C:45]1[CH:46]=[C:47]([CH:51]=[C:52]([Cl:54])[N:53]=1)[C:48]([OH:50])=O.[N:55]1([CH2:61][CH2:62][NH2:63])[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>CC(N(C)C)=O>[Cl:54][C:52]1[CH:51]=[C:47]([CH:46]=[C:45]([Cl:44])[N:53]=1)[C:48]([NH:63][CH2:62][CH2:61][N:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1)=[O:50]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(NCCN1CCOCC1)c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 105 %

Procedure:
HATU (989 mg, 2.6 mmol), HOAT (354 mg, 2.6 mmol) and DIEA (907 μl, 5.21 mmol) were added to a stirred solution of 2,6-dichloroisonicotinic acid (500 mg, 2.60 mmol) in anhydrous DMA (4 ml). The mixture was stirred for 10 minutes after which 2-morpholin-4-yl-ethylamine (420 μl, 2.86 mmol) was added. The mixture was stirred at room temperature for 12 h and the mixture was partitioned between EtOAc and water. The EtOAc layer was washed well with water, dried over sodium sulphate and concentrated in vacuo to give the title compound as an oil (830 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:14]=[C:15]([S:20](Cl)(=[O:22])=[O:21])[CH:16]=[CH:17][C:18]=1[F:19]>>[Cl:12][C:13]1[CH:14]=[C:15]([S:20]([NH:8][C:7](=[NH:9])[C:6]2[CH:10]=[CH:11][C:3]([Cl:2])=[CH:4][CH:5]=2)(=[O:21])=[O:22])[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: N=C(N)c1ccc(Cl)cc1
Agent: Cl
Product: N=C(NS(=O)(=O)c1ccc(F)c(Cl)c1)c1ccc(Cl)cc1

Procedure:
4-chlorobenzamidine hydrochloride (0.025 g, 0.133 mmol) and 3-chloro-4 fluorophenyl sulfonylchloride (0.0304 g, 0.133 mmol); were used essentially as described in Example 114 to prepare the title compound. ES Positive Ion MS [M+H]+ ions observed: m/z 347 (35Cl, 35Cl), m/z 349 (37Cl, 37Cl) and m/z 351 (37Cl, 37Cl).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[C:17]([C:20]1[CH:28]=[CH:27][C:23]2[NH:24][N:25]=[N:26][C:22]=2[CH:21]=1)(O)=O>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:17]([C:20]2[CH:28]=[CH:27][C:23]3[N:24]=[N:25][NH:26][C:22]=3[CH:21]=2)=[N:16][N:15]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc3nn[nH]c3c2)o1
Yield: 39 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 5-carboxy-benzotriazole instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:20:10 to 20:70:10, 125 mg, 39%) which was obtained as a white solid. MS: m/e 345.1 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][C:9]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:10]=2[O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+].C1COCC1.Cl>CO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:10]=2[O:11][C:12]([CH3:18])([CH3:19])[C:13]([OH:15])=[O:14])=[CH:26][CH:27]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc(C)cc(C)c1Cc1ccc(C(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)c(Cc2ccc(C(C)C)cc2)c(OC(C)(C)C(=O)O)c1
Yield: 91 %

Procedure:
A mixed solution of ethyl 2-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)-2-methylpropanoate obtained in Reference Example 153 (6.65 g, 18.1 mmol) and a 8 N aqueous sodium hydroxide solution (4.5 mL) in methanol (40 mL)-THF (20 mL) was stirred at room temperature for 16 hours. The reaction solution was acidified with hydrochloric acid, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain 5.59 g (yield 91%) of the title compound. Oily matter.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10](=O)[CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.Cl.[CH3:25][O:26][NH2:27].N1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[C:3]([C:10](=[N:27][O:26][CH3:25])[CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CON
Reactant: COc1cnc(C(=O)CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(OC)cc1Cl
Temperature: 80 °C
Reaction time: 6 h
Yield: 77.4 %

Procedure:
To a solution of 120 mg of N-[2-(3-chloro-5-methoxypyridin-2-yl)-2-oxoethyl]phthalimide and 60 mg of methoxyamine hydrochloride in 5 ml of ethanol, 85 mg of pyridine was added, and the mixture was stirred at 80° C. for 6 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 101 mg of the desired product as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:14])[N:5]([CH3:13])[C:6]([CH3:12])=[CH:7][C:8]=1[C:9]([OH:11])=[O:10].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].Cl.CN(C)CCCN=C=NCC>ClCCl>[O:22]=[C:17]1[CH2:18][CH2:19][C:20](=[O:21])[N:16]1[O:10][C:9]([C:8]1[CH:7]=[C:6]([CH3:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[O:2][CH3:1])=[O:11]
Reactant: COc1c(C(=O)O)cc(C)n(C)c1=O
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1c(C(=O)ON2C(=O)CCC2=O)cc(C)n(C)c1=O
Reaction time: 15 h
Yield: 97.8 %

Procedure:
To a solution of 5 (5.36 g, 27.2 mmol) in dichloromethane (500 mL) was added N-hydroxysuccinimide (4.23 g, 36.7 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.89 g, 35.9 mmol), and the resulting reaction mixture was stirred under dinitrogen for 15 h. The reaction mixture was washed twice with a 0.01 N HCl solution (150 mL), dried over sodium sulfate, and concentrated under reduced pressure. Purification was performed using silica gel chromatography (1:49 methanol/dichloromethane) to yield 7.83 g (98%) of 6 as a tan solid. 1H NMR (300 MHz, CDCl3): δ=2.31 (s, 3H, C—CH3), 4.08 (s, 4H, CH2), 3.50 (s, 3H, N—CH3), 3.98 (s, 3H, O—CH3), 6.29 (s, 1H, CH); 13C NMR (75 MHz, CDCl3): δ=20.6 (C—CH3), 25.8 (CH2), 32.0 (N—CH3), 60.8 (O—CH3), 103.0 (CH), 122.8, 140.7, 148.8, 159.9, 160.3, 169.0; TLC: Rf=0.33 (1:19 methanol/dichloromethane); ESI-MS calcd for C13H14N2O6 [M+H]+: 295.0930. found 295.0931.
Reaction SMILES: Cl.C(OC(=O)[NH:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[CH:18][C:17]=2[F:33])[CH:12]=[CH:11][N:10]=1)(C)(C)C.C(OCC)C.[OH-].[Na+]>C(OCC)(=O)C>[CH2:26]([O:25][C:23](=[O:24])[NH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:8])[CH:14]=2)=[C:17]([F:33])[CH:18]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)OCc3ccccc3)cc2F)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Nc1cc(Oc2ccc(NC(=O)OCc3ccccc3)cc2F)ccn1
Temperature: 25 °C
Yield: 11.7 %

Procedure:
To a 4N solution of hydrochloric acid in ethyl acetate (30 ml) was added [4-(4-benzyloxycarbonylamino-2-fluorophenoxy)pyridin-2-yl]carbamic acid tert-butyl ester (510 mg) while stirring in an ice water bath. The reaction mixture was allowed to warm up to room temperature, followed by stirring for 16 hr. To the reaction mixture were added diethyl ether (10 ml) and a 5N aqueous solution of sodium hydroxide (1 ml), followed by stirring for 30 min. The separated organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:2) and fractions containing the target compound were concentrated under reduced pressure. To the resultant residue were added diethyl ether (4 ml) and hexane (6 ml) to suspend the precipitated solid. The solid was collected by filtration and dried under aeration to provide the titled compound as pale yellow powder (46.6 mg, 11.7%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:7])[CH:6]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.C(S[C:28]1[S:29][C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[N+:32]=1[CH2:33][CH3:34])C.C(N(CC)CC)C>CO>[CH2:33]([N:32]1[C:31]2[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=2[S:29](=[C:6]2[C:5](=[O:7])[N:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:3][CH:2]2[CH3:1])[CH2:28]1)[CH3:34]
Reactant: Cc1cc(=O)n(-c2ccccc2)[nH]1
Reactant: CCSc1sc2ccccc2[n+]1CC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN1CS(=C2C(=O)N(c3ccccc3)NC2C)c2ccccc21
Reaction time: 0.17 h

Procedure:
3-Methyl-1-phenylpyrazolin-5-one (1.74 g, 0.01 mol) was mixed with a methanol solution of 2-ethylthio-3-ethylbenzothiazolium tosylate. Triethylamine (1.01 g, 0.01 mol) was added. The mixture was stirred for 10 minutes, then concentrated and treated with isopropanol. The mixture was heated to dissolve the product, then water was added to cloud, and the mixture cooled to give crystals: 3.22 g (48%), mp 144°-147.5° C., λmax=379 (ε=25,000).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][C:13](=[O:35])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:21])=[CH:16][C:15]=3[O:33][CH3:34])[C:5]=2[N:4]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].CCOCC>N1C=CC=CC=1>[CH3:34][O:33][C:15]1[CH:16]=[C:17]([C:20]([N:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[CH:18]=[CH:19][C:14]=1[C:13]([NH:12][C:11]1[C:5]2[N:4]=[C:3]([CH2:2][NH:1][S:37]([CH3:36])(=[O:39])=[O:38])[NH:7][C:6]=2[CH:8]=[CH:9][CH:10]=1)=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)N2CCCCc3ccccc32)ccc1C(=O)Nc1cccc2[nH]c(CN)nc12
Solvent: CCOCC
Solvent: c1ccncc1
Product: COc1cc(C(=O)N2CCCCc3ccccc32)ccc1C(=O)Nc1cccc2[nH]c(CNS(C)(=O)=O)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To an ice-bath-cooled solution of N-(2-aminomethyl-1H-benzimidazol-4-yl)-2-methoxy-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonylbenzamide (100 mg) in pyridine (5 ml) was added methanesulfonyl chloride (24.4 mg) and the solution was stirred at room temperature for 4 hours. After removing the solvent by evaporation, the product was purified by silica gel column chromatography (chloroform) to give a syrup and the syrup was solidified with ether to give 2-methoxy-N-(2-methanesulfonylaminomethyl-1H-benzimidazol-4-yl)-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonylbenzamide (98 mg).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[S:14][C:13]([N:15](C)[CH:16]=O)=[N:12][C:11]=2[CH3:19])[N:9]=1)[C:2]([NH2:4])=[NH:3].O.C(=O)([O-])[O-].[K+].[K+]>CO.Cl>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[S:14][C:13]([NH:15][CH3:16])=[N:12][C:11]=2[CH3:19])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: Cc1nc(N(C)C=O)sc1-c1csc(NC(=N)N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CNc1nc(C)c(-c2csc(NC(=N)N)n2)s1
Reaction time: 2 h
Yield: 77.3 %

Procedure:
A solution of 5-(2-guanidinothiazol-4-yl)-2-(N-methylformamido)-4-methylthiazole (1.5 g) in a mixture of methanol (25 ml) and 10% hydrochloric acid was stirred for 2 hours under refluxing. After addition of water (100 ml), the reaction mixture was adjusted to pH 7.0 with 20% aqueous potassium carbonate. The resulting precipitate was collected by filtration, washed with water (10 ml×2) and methanol (15 ml×2) successively and dried over phosphorus pentoxide under reduced pressure to give 5-(2-guanidinothiazol-4-yl)-4-methyl-2-methylaminothiazole (1.05 g).