Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH2:8][C:7]2[N:6]=[CH:5][C:4]3[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=3[C:2]1=2.[C:15]1([CH2:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH2:21][C:22]([N:1]2[CH2:10][CH2:9][CH2:8][C:7]3[N:6]=[CH:5][C:4]4[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=4[C:2]2=3)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: c1ccc2c3c(ncc2c1)CCCN3
Product: O=C(Cc1ccccc1)N1CCCc2ncc3ccccc3c21

Procedure:
1,2,3,4-Tetrahydrobenzo[c]-1,5-naphthyridine (3.22 g) was treated with cold phenylacetyl chloride (35 ml). Most of the material dissolved and then a precipitate separated. The mixture was diluted with ether (50 ml), and the precipitate was isolated by vacuum filtration and washed twice with ether. The filter cake was dissolved in water (100 ml), and the solution was basified with 10% sodium hydroxide solution and extracted with dichloromethane (2×100 ml). The combined and dried (Na2SO4) organic phase was filtered and concentrated to an oil (5.4 g), which was purified by HPLC (silica gel, eluted with ethyl acetate). The appropriate fractions were combined and concentrated to an oil (4.76 g). Trituration with ether and seeding (seed crystals formed on the neck of the flask which contained the oil) gave 2.68 g of crystals, m.p. 88.5-89.5° C.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:11])[C:7]([CH3:10])=[N:8][CH:9]=1.[C:12](Cl)(=[O:15])[O:13][CH3:14]>N1C=CC=CC=1>[CH3:14][O:13][C:12]([O:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:11])[C:7]([CH3:10])=[N:8][CH:9]=1)=[O:15]
Reactant: Cc1ncc(CO)cc1O
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)OCc1cnc(C)c(O)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 1.8 g. of 5-hydroxymethyl-2-methyl-3-pyridinol hydrochloride in 10 ml. of pyridine was added 1.0 g. of methyl chlorocarbonate dropwise under cooling. After standing overnight, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off to give 1.0 g. of an oily substance. The oily substance was purified by column chromatography (silica gel 20 g.) and 0.6 g. of the desired product as colorless crystal was obtained from the eluate with benzene-ethyl acetate (3:7) and recrystallized from ethyl acetate and n-hexane.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH:10]([CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])[NH:11]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C(CCN1C(=O)C2=CC=CC=C2C1=O)NC(OC(C)(C)C)=O)C=C.[F:61][C:62]([F:75])([F:74])[O:63][C:64]1[CH:69]=[CH:68][C:67]([S:70]([Cl:73])(=[O:72])=[O:71])=[CH:66][CH:65]=1>>[O:63]([C:64]1[CH:69]=[CH:68][C:67]([S:70]([Cl:73])(=[O:72])=[O:71])=[CH:66][CH:65]=1)[C:62]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1.[CH2:1]([O:8][C:9](=[O:32])[CH:10]([CH2:19][CH2:20][N:21]1[C:22](=[O:31])[C:23]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]2[C:25]1=[O:26])[NH:11][S:70]([C:67]1[CH:66]=[CH:65][C:64]([O:63][C:62]([F:61])([F:74])[F:75])=[CH:69][CH:68]=1)(=[O:72])=[O:71])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(CCN1C(=O)c2ccccc2C1=O)C(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Agent: C=CCOC(=O)C(CCN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Product: O=C(OCc1ccccc1)C(CCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(OC(F)(F)F)cc1
Product: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Yield: 52 %

Procedure:
In a similar manner to the procedures described in Example 1(2)-a and b, reactions were carried out using (±)-N-(tert-butoxycarbonyl)-2-(2-phthalimidoethyl)glycine benzyl ester, the product of Example 19(1), instead of (±)-N-(tert-butoxycarbonyl)-2-(2-phthalimidoethyl)glycine allyl ester, and using 4-trifluoromethoxybenzenesulfonyl chloride, instead of 4-phenoxybenzenesulfonyl chloride, to afford the desired compound (yield 52%) as a yellow powder.
Reaction SMILES: [C:1]([S:9][C@@H:10]([CH2:14][CH2:15][CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])[C:11](O)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]([CH3:45])([CH3:44])[C@H:30]([NH:35][C:36](=[O:43])[C@@H:37]([NH2:42])[CH2:38][CH:39]([CH3:41])[CH3:40])[C:31](=[O:34])[NH:32][CH3:33]>C(OCC)(=O)C.O>[CH3:45][C:29]([CH3:28])([CH3:44])[C@H:30]([NH:35][C:36](=[O:43])[C@@H:37]([NH:42][CH2:11][C@@H:10]([S:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:14][CH2:15][CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])[CH2:38][CH:39]([CH3:41])[CH3:40])[C:31](=[O:34])[NH:32][CH3:33]
Reactant: O=C(S[C@@H](CCCN1C(=O)c2ccccc2C1=O)C(=O)O)c1ccccc1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC[C@H](CCCN1C(=O)c2ccccc2C1=O)SC(=O)c1ccccc1)C(C)(C)C
Reaction time: 0.17 h

Procedure:
(S)-2-Benzoylsulfanyl-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid (62.6 g, 0.163 mol) and (S)-2-amino-4-methylpentanoic acid (2,2-dimethyl-1-(S)-methylcarbamoylpropyl)amide (40 g, 0.155 mol) were dissolved in a biphasic mixture of ethyl acetate (480 mL) and water (240 mL) at 45° C. and stirred to equilibrate for 10 min. An HPLC reference sample was removed for t=0. The PeptiCLEC-TR enzyme (40 mL) is added to the reaction and the reaction is stirred at 45° C. Samples are removed at regular intervals for HPLC analysis which shows that the reaction is complete in 2 hours. Filtration of tile enzyme followed by acidic then basic aqueous washes gives a solution of (S)-2-[(S)-2-benzoylsulfanyl-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanylamino]-4-methylpentanoic acid (2,2-dimethyl-1(S)-methylcarbamoylpropyl)amide which is then evaporated to dryness to give the product as a glass foam 80 g, 83%.
Reaction SMILES: O[C@@H:2]([C-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[CH3:3].[C-:9]1([C@H:14](O)[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:17].C(OC(=O)C)(=O)C.CCCCCC.[N:31]1[CH:36]=CC=C[CH:32]=1>>[CH3:32][N:31]([CH3:36])[C@@H:2]([C-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[CH3:3].[C-:9]1([C@H:14]([N:31]([CH3:36])[CH3:32])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:17]
Reactant: c1ccncc1
Reactant: C[C@@H](O)[c-]1cccc1
Agent: [Fe+2]
Solvent: CC(=O)OC(C)=O
Solvent: CCCCCC
Product: C[C@H]([c-]1cccc1)N(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
32.7 g (about 111 mmol) of crude (R,R)-1,1'-bis(1-hydroxyethyl)ferrocene were dissolved in 30 ml of pyridine and admixed with 30 ml of acetic anhydride. After stirring for 16 hours at 25° C., the excess anhydride was hydrolysed with 200 ml of ice water and the mixture was extracted three times with 100 ml each Time of diethyl ether. The combined organic phases were washed once more with about 150 ml of water, dried over magnesium sulphate and evaporated. The residue was admixed with 200 ml of hexane and the solvent was removed on a rotary evaporator (<40° C). This procedure was repeated two more times. The resulting dark brown oil was dissolved in 200 ml of isopropyl alcohol and admixed with 120 ml of dimethylamine (50% in water). After stirring at 25° C. (16 hours), 200 ml of water were added and the pH of the reaction mixture was adjusted to 1 using 100 ml of 32% strength HCl and the aqueous phase was washed twice with 100 ml each time of diethyl ether. The aqueous phase was basified with sodium hydroxide solution (40% strength) to a pH of 12-14 and extracted three times with 100 ml each time of diethyl ether. The combined organic phases were dried over magnesium sulphate and evaporated. In order to remove isopropyl alcohol still present, the oil obtained was admixed with about 100 ml of hexane and again evaporated on a rotary evaporator. This procedure was repeated two more times. Drying in a high vacuum gave 24.1 g (66%, based on 1,1'-diacetylferrocene) of the title compound in the form of a dark brown oil. (Without hydrochloric acid treatment, the yield rises to 86%).
Reaction SMILES: [C:1]([C:5]1[NH:13][C:12]2[C:7](=[N:8][C:9](S(C)(=O)=O)=[N:10][C:11]=2[NH:14][C@H:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16]O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[O-:29][CH2:30][CH3:31].[Na+]>C(O)C>[CH2:18]([C@@H:15]1[CH2:16][N:10]2[C:11]([C:12]3[NH:13][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][C:7]=3[N:8]=[C:9]2[O:29][CH2:30][CH3:31])=[N:14]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC[O-]
Reactant: CC(C)(C)c1nc2nc(S(C)(=O)=O)nc(N[C@@H](CO)Cc3ccccc3)c2[nH]1
Agent: [Na+]
Solvent: CCO
Product: CCOC1=Nc2nc(C(C)(C)C)[nH]c2C2=N[C@H](Cc3ccccc3)CN12
Temperature: 70 °C
Yield: 54 %

Procedure:
In a manner similar to that in Example 66, a cyclized compound was obtained from Compound C8 prepared in Reference Example 43, to a solution of the cyclized compound (4.88 g, 14.3 mmol) in ethanol (30 mL) was added a 21% solution of sodium ethoxide (30 mL, 93.0 mmol, 6.5 equivalents) in ethanol, and then the mixture was stirred with heating at 70° C. for 3 hours. The reaction solution was concentrated, and the deposited crystals were collected by filtration and recrystallized from ethyl acetate to obtain the title compound (2.67 g, 54%) as white crystals.
Reaction SMILES: Br[CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].[Na].[C:9]([NH2:13])([CH3:12])([CH3:11])[CH3:10].C(S(O)(=O)=O)=C>O.O1CCOCC1>[C:9]([NH:13][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(O)CCBr
Agent: C=CS(=O)(=O)O
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)NCCS(=O)(=O)O
Temperature: 60 °C
Reaction time: 18 h
Yield: 24 %

Procedure:
A solution of 2-bromoethanesulfonic acid, sodium salt (4.2 g, 20 mmol) in water (total 12 mL) was added over 6 hours to a 42° C. solution of t-butylamine (10 mL, 94 mmol) in a mixture of water (10 mL) and 1,4-dioxane (10 mL). The mixture was stirred at 42° for 18 hours. The mixture was then heated to 60° C. for 24 h. By proton NMR, 30% of elimination product (vinylsulfonic acid) was observed. The mixture was concentrated to dryness and treated with ethanol at refluxing temperature. The solid material was collected (crop 1). The mother liquor was concentrated to dryness and the solid was again treated with ethanol at refluxing temperature, and the solid material was collected (crop 2). Both crops of the solid material were dissolved in water, and the resultant aqueous solutions passed in sequence through a Dowex 50 W X 8 ion-exchange column (100 g resin). The fractions containing the title compound were collected and concentrated to dryness. The solid material obtained was recrystallized from a mixture of ethanol (20 mL) and water (2 mL). The crystals were collected by filtration, dried in a vacuum oven at 60° C. for 18 hours. Compound DU was obtained as fine white needles (860 mg, 24% yield). 1H NMR (500 MHz, D2O) δ 1.16 (s, 9H), 3.02 (t, J=6.8 Hz, 2H), 3.19 (t, J=6.8 Hz, 2H). 13C NMR (125 MHz, D2O) δ 24.8, 37.3, 47.0, 57.8. ES-MS 182 (M+1)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13].[CH3:19][N:20]([CH3:33])[CH2:21][CH2:22][C@@H:23]([NH2:32])[CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:33][N:20]([CH3:19])[CH2:21][CH2:22][C@@H:23]([NH:32][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])[CH2:24][S:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)CC[C@@H](N)CSc1ccccc1
Reactant: NS(=O)(=O)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (685 mg, 2.3 mmol), (R)—N1,N1-dimethyl-4-phenylsulfanyl-butane-1,3-diamine (500 mg, 2.3 mmol), and DIPEA (0.78 mL, 4.5 mmol) in DMA (18.8 mL) was heated to 100° C. for 6 hours. The reaction was cooled to room temperature and diluted with EtOAc/heptanes (1:1, 50 mL). This solution was washed with water, the layers were separated, and the aqueous layer was extracted with EtOAc/heptanes (1:1) (50 mL×3). The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated to afford the title compound as a yellow solid (965 mg, 82% yield). MS (ESI) m/e (M+H+): 512.2
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:20]#[N:21])=[N:16][NH:17]2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:20]#[N:21])=[N:16][N:17]2[CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])=[CH:13][CH:12]=1
Reactant: Fc1ccccc1CBr
Reactant: N#Cc1n[nH]c2cc(Cl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1nn(Cc2ccccc2F)c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
Under argon, 2.45 ml (14.2 mmol) of 2-fluorobenzyl bromide, dissolved in 10 ml DMF, were added to a mixture of 2.3 g (12.9 mmol) of 6-chloro-1H-indazole-3-carbonitrile (WO 2011/149921, Expl. 58C) and 2.15 g (15.5 mmol) of potassium carbonate in 40 ml of DMF, and the mixture was stirred at RT overnight. Then the mixture was poured onto 90 ml of water and the mixture was stirred at room temperature for 30 min. The precipitated solids were filtered off, washed with water and dried under high vacuum overnight. 3.77 g of the title compound were obtained as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=4)[N:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.O1CCCC1.CO.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:36][CH:37]=4)[N:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: COC(=O)c1ccc(Cn2ncc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Cn2ncc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a solution of methyl 4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]methyl}benzoate (25 mg) in a mixed solvent of tetrahydrofuran/methanol (1:1, 1 mL) was added 1N aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at room temperature for 1 hr. After the completion of the reaction, 1N aqueous hydrochloric acid solution (0.5 mL) and water (1 mL) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The resultant solid was collected by filtration, and washed with diisopropyl ether and dried to give the title compound (16 mg) as pale-yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH2:12][C:13]#N.[OH:15]S(O)(=O)=O.[OH2:20]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH2:12][C:13]([OH:15])=[O:20]
Reactant: O=S(=O)(O)O
Reactant: O
Reactant: Cc1ccc2ccccc2c1CC#N
Product: Cc1ccc2ccccc2c1CC(=O)O
Temperature: 25 °C
Yield: 67 %

Procedure:
(2-Methyl-naphthalen-1-yl)-acetonitrile (4.9 g, 27 mmol) was stirred with H2SO4 (50 mL) and H2O (50 mL) at 150° C. for 25 minutes in a round-bottom flask fitted with a condenser. TLC analysis (silica, 20% acetone-hexanes) indicated complete consumption of the starting material. The reaction was allowed to cool to room temperature and then was carefully diluted with H2O. The acidic dilution was extracted three times with EtOAc. The organic extracts were combined and extracted twice with aqueous 10% NaOH. The basic H2O extracts were combined, acidified to pH<3 with 1N HCl, and extracted three times with EtOAc. The organic extracts were combined, washed with brine solution, dried over Na2SO4, decanted, and concentrated to give (2-methyl-naphthalen-1-yl)-acetic acid (3.6 g, 18 mmol) in 67% yield. MS (APCI) m/z 199.1 (M−H). 1H NMR (300 MHz) CDCl3 7.97 (d, J=8.6 Hz, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.47 (m, 2H), 7.33 (d, J=8.2 Hz, 1H), 4.13 (s, 2H), 2.53 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH2:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[N:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=1.C(N(C(C)C)CC)(C)C.O>CN1CCCC1=O>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:24]2[N:23]=[N:22][C:21]([Cl:20])=[CH:26][CH:25]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Reactant: Clc1ccc(Cl)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(Cl)nn2)cs1
Temperature: 130 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
2-{[4-(2-Aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (5.0 g) synthesized in Example 7 and 3,6-dichloropyridazine (4.92 g) were dissolved in N-methylpyrrolidone (25 mL), diisopropylethylamine (4.27 g) was added, and the mixture was heated at 130° C. with stirring for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1 to 1:1) to give the title compound (5.5 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:16][CH:15]=3)=[N:12][N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:26](I)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[OH-].[K+].C(O)CCC>CO>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:16][CH:15]=3)=[N:12][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCI
Reactant: CCCCCCc1ccc(-c2nnc(-c3ccc(O)c(F)c3)s2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCO
Product: CCCCCCOc1ccc(-c2nnc(-c3ccc(CCCCCC)cc3)s2)cc1F
Temperature: 25 °C
Yield: 35.1 %

Procedure:
0.30 g (0.84 mM) of 2-(3-fluoro-4-hydroxyphenyl)-5-(4-hexylphenyl)-1,3,4-thiadiazole, 0.23 g (1.09 mM) of hexyl iodide, 0.08 g of 85%-potassium hydroxide and 6 ml of butanol were mixed, followed by refluxing for 5 hours under stirring. After the reaction, 10 ml of methanol was added to the reaction mixture, followed by cooling to room temperature and further cooling in a freezer to precipitate a crystal. The crystal was recovered by filtration and washed with methanol. The resultant crystal was dissolved in toluene and washed with water, followed by drying with anhydrous magnesium sulfate. The magnesium sulfate was recovered by filtration and the filtrate was condensed into a solid. The solid was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (ethanol/hexane) to obtain 0.13 g of 2-(3-fluoro-4-hexyloxyphenyl)-5-(4-hexylphenyl)-1,3,4-thiadiazole (Yield: 35.1%). ##STR23##
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:8]2[CH:23]=[C:24]([Cl:26])[CH:25]=[C:7]2[C:6]=1[OH:27])=[O:4].[NH2:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30].C[O-].[Na+]>>[Cl:26][C:24]1[CH:25]=[C:7]2[C:6]([OH:27])=[C:5]([C:3]([NH:28][C@@H:29]([CH3:30])[C:31]([OH:33])=[O:32])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][CH:14]=3)[N:8]2[CH:23]=1
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(C(F)(F)F)cc2)c1=O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Product: C[C@H](NC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(C(F)(F)F)cc2)c1=O)C(=O)O

Procedure:
Prepared according to the reaction condition used in Example 19 step a) from 6-chloro-4-hydroxy-2-oxo-1-(4-trifluoromethyl-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester, L-alanine and NaOMe. ESI (m/z): 458 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.[NH2:39][CH2:40][C:41]([NH2:43])=[O:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:43][C:41](=[O:42])[CH2:40][NH:39][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1
Reactant: NCC(N)=O
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: NC(=O)CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 42.9 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.07 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.061 mL, 0.556 mmol), 2-aminoacetamide (6.70 mg, 0.090 mmol), and HATU (39.7 mg, 0.104 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM) to give (R/S)-N-(2-amino-2-oxoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (17.4 mg, 0.030 mmol, 43.2% yield): LCMS=488.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.18 (2 H, d, J=8.35 Hz), 7.66-7.80 (4 H, m), 7.51-7.65 (3 H, m), 5.20 (1 H, s), 3.80-4.02 (2 H, m); HPLC Peak RT=8.1 min (Analytical Method D).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25]SC)=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.Cl[C:29]1C=CC=C(C(OO)=O)C=1.[S:39]([O-:42])([O-])=[O:40].[Na+].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][S:39]([CH3:29])(=[O:42])=[O:40])=[CH:23][CH:24]=2)=[O:17])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc(/C=C/C(=O)Nc2ccc(CS(C)(=O)=O)cc2)c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
A mixture of (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-{4-[(methylthio)methyl]phenyl}acrylamide (600 mg), m-chloroperbenzoic acid (780 mg) and tetrahydrofuran (50 mL) was stirred at 0° C. for 20 min. A saturated aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was further stirred for 10 min. and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate, and then with saturated brine, dried (MgSO4) and concentrated. The obtained solid was recrystallized from acetone-hexane to give (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-(4-[(methylsulfonyl) methyl]phenyl)acrylamide (490 mg, yield 75%) as colorless prism crystals. melting point: 251-252° C.
Reaction SMILES: Br.[F:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH3:13])=[N:10]2)=[C:5]([OH:14])[CH:4]=1.[Br:15][CH2:16][CH2:17]Br>>[Br:15][CH2:16][CH2:17][O:14][C:5]1[CH:4]=[C:3]([F:2])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([CH3:13])=[N:10]2
Reactant: Cc1ccc2c(O)cc(F)cc2n1
Reactant: BrCCBr
Agent: Br
Product: Cc1ccc2c(OCCBr)cc(F)cc2n1
Yield: 91 %

Procedure:
The title compound was prepared from 7-fluoro-5-hydroxy-2-methylquinoline hydrobromide and 1,2-dibromoethane using a similar procedure to Description 13, in 91% yield.