Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Cl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Fc1ccccc1CCl
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCCc2nc3ccccc3c(NCc3ccccc3F)c21
Reaction time: 8 h
Yield: 54 %

Procedure:
In a mixture consisting of 150 ml of dichloromethane and 100 ml of 50% NaOH were combined 5.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one, 3 ml (1 eq) of 2-fluorobenzylchloride and 1.20 g (0.15 eq) of tetrabutylammonium hydrogen sulfate. The biphasic mixture was mechanically stirred overnight and 3 ml of 2-fluorobenzylchloride was again added. After 4 hours of further stirring, the reaction was complete based on thin layer chromatography. The reaction mixture was partitioned between water and dichloromethane and the dichloromethane layer was separated, dried over MgSO4, filtered and evaporated to a solid. The solid was purified by chromatography on silica gel (ETOAc) and the resultant product was recrystallized from 1:4 EtOAc/toluene to yield 4.09 g (54%) of a solid, melting point 163.5°-164° C.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][C:8]2[O:9][C:5]([C:2]([F:1])([F:4])[CH3:3])=[CH:6][CH:7]=2)[N:12]=1)=[O:28]
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1Cl
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Product: CC(F)(F)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccc(Cl)cc3Cl)n2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2,4-dichloro-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.18 min; [M+H]+=425.96.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]>[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CCCCCCC=Cc1ccco1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Product: O=C(O)CCCCCCCCc1ccco1
Yield: 93.6 %

Procedure:
This compound was synthesized from 9-(2-furyl)-8-nonenoic acid (0.89 g, 4 mmol) by a hydrogenation reaction using Pd/BaSO4 (90 mg). Crystallization (petroleum ether) afforded the product (0.84 g, 93%) as white crystals (mp 31°-32° C.); IR: 3450-2500, 1720 cm-1 ; 1H-NMR: 1.30 (m, 8H), 1.63 (m, 4H), 2.35 (t, 2H), 2.60 (t, 2H), 5.95 (s, 1H), 6.27 (s, 1H), 7.28 (s, 1H), 9.85 (bs, 1H). Anal. Calcd. for C13H20O3 : C, 69.61, H, 8.99%; Found: C, 69.42, H, 9.04%.
Reaction SMILES: [OH:1][CH:2]([PH:4](=[O:6])[OH:5])[CH3:3].[CH2:7](O)[CH2:8][CH2:9][CH3:10].O>C1C=CC=CC=1>[OH:1][CH:2]([PH:4](=[O:5])[O:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:3]
Reactant: CC(O)[PH](=O)O
Reactant: CCCCO
Solvent: O
Solvent: c1ccccc1
Product: CCCCO[PH](=O)C(C)O
Yield: 81.6 %

Procedure:
A solution of α-hydroxyethylphosphinic acid (2.2 g) and 1-butanol (5.0 g) in benzene (30 ml) was heated for 3 hours with removal of water through a Dean-Stark apparatus. After cooling, the reaction mixture was washed with water, dried over magnesium sulfate and concentrated in vacuo to give 2.71 g (81.6%) of n-butyl α-hydroxyethylphosphinate (Compound No. 5).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:14][C:15]2[C:16]([CH:31]3[CH2:33][CH2:32]3)=[N:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:19][CH:20]=2)[CH3:13])=[CH:8][C:7]=1[CH3:34].[Li+].[OH-]>C1COCC1.CCOCC>[CH:31]1([C:16]2[C:15]([CH2:14][N:12]([CH3:13])[C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]([CH3:34])[CH:8]=3)=[CH:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][CH:22]=3)[N:17]=2)[CH2:33][CH2:32]1
Reactant: COC(=O)COc1ccc(N(C)Cc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(N(C)Cc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)ccc1OCC(=O)O
Yield: 28.2 %

Procedure:
A solution of 351 mg (0.72 mmol) (4-{[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl]-methyl-amino}-2-methyl-phenoxy)-acetic acid methyl ester and 1.45 ml 1N LiOH in 4 ml of THF was stirred for 3 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. The crude product was suspended in AcOEt/heptane 1:19 to give 95.64 mg of pure (4-{[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl]-methyl-amino}-2-methyl-phenoxy)-acetic acid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([OH:16])=O.C([O-])(O)=O.[Na+].[OH-].[Na+].[CH3:24][N:25]([CH3:28])[CH:26]=O>>[CH3:24][N:25]([CH3:28])[CH:26]=[C:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[F:6])[CH:14]=[O:16]
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C(C=O)c1ccccc1F
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A flask containing phosphorus oxychloride (3.25 mL, 34.9 mmol) is cooled to ca. 10° C., and dimethylformamide (3.25 mL) is added dropwise. After stirring for 30 min, the resulting mixture is treated dropwise with a solution of 2-fluorophenylacetic acid (1.79 g, 11.6 mmol) in dimethylformamide (6 mL). This solution is heated to 70° C. for 18 h, then cooled and poured into ice. After being allowed to melt, the mixture is neutralized with solid NaHCO3, and then made basic with 50% aq. NaOH solution. After stirring for 1 h, the mixture is extracted twice with diethyl ether (100 mL), and the ether extracts are washed with brine, combined, dried over anhydrous magnesium sulfate, filtered and evaporated to afford 3-dimethylamino-2-(2-fluorophenyl)-acrolein (1.72 g, 8.92 mmol, 77%) as a yellow-brown oil. TLC RF 0.30 (ethyl acetate). 1H NMR (300 MHz, CDCl3): δ 9.08 (1H, s), 7.29-7.19 (2H, m), 7.14-7.01 (2H, m), 6.91 (1H, s), 2.88 (6H, br). MS (ES+): m/e 216 (18), 195 (23), 194 (100).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.ClCl.[CH3:13]O>>[CH3:13][O:9][C:8]([C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:10]
Reactant: Cc1cnc(C(=O)O)cn1
Reactant: CO
Agent: ClCl
Product: COC(=O)c1cnc(C)cn1
Reaction time: 4 h

Procedure:
Commercially available 5-methylpyrazine 2-carboxylic acid (2.05 g) was dissolved in methanol (0.6 ml) and chlorine gas was blown into the solution for 5 minutes. After four hours, the reaction solution was concentrated and 1 mol/l aqueous solution of sodium hydroxide was added, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting solid was recrystallized from hexane/ethyl acetate. The deposited crystals were collected by filtration and dried under reduced pressure to obtain the title compound (1.44 g) as light brown scale-like crystals.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=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.[NH:58]1[CH2:61][CH2:60][C:59]1=[O:62].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.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]>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:58]2[CH2:61][CH2:60][C:59]2=[O:62])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: O=C1CCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1c(N2CCC2=O)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C

Procedure:
2,4-Dichloro-5,7-difluoro-3-methylquinoline (1.90 g, 7.70 mmol), XantPhos™ (670 mg, 1.20 mmol), azetidin-2-one (550 mg, 7.70 mmol), cesium carbonate (3.50 g, 11.0 mmol), 3 A activated molecular sieves (1.0 g) and Pd2(dba)3 (350 mg, 0.39 mmol) were slurried in 1,4-dioxane (26 mL). The reaction was heated in an oil bath at 100° C. for 3 h. After this time the reaction was cooled to rt, diluted with EtOAc and filtered over a pad of Celite™. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, 0 to 30% EtOAc:DCM) to give 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-azetidin-2-one. Mass Spectrum (ESI) m/e=283.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH3:15][O:16][C:17](=[O:22])[C:18](Br)([CH3:20])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:15][O:16][C:17](=[O:22])[C:18]([CH3:20])([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:19]
Reactant: COC(=O)C(C)(C)Br
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 90 °C
Yield: 63 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (5 g, 25.77 mmol) and 2-bromo-2-methyl-propionic acid methyl ester (12.6 g, 27.06 mmol) in DMF (85 mL), was added Cs2CO3 (12.6 g, 38.65 mmol). The reaction mixture was heated to 90° C. in an oil bath overnight. The reaction solution was cooled to room temperature, and partitioned between water and ethyl acetate. The combined ethyl acetate solution was washed with water five times, dried over Na2SO4, and concentrated to give the product 2-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]propionic acid methyl ester (4.776 g, 63% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([OH:10])=O)[N:6]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[O:28]=[C:29]1[N:36]2[C@H:31]([CH2:32][O:33][C:34]([CH:49]3[CH2:53][CH2:52][CH2:51][O:50]3)=[C:35]2[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[O:38])[C@@H:30]1[NH:54]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C)C=O.N1C=CC=CC=1>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([NH:54][C@@H:30]2[C:29](=[O:28])[N:36]3[C@@H:31]2[CH2:32][O:33][C:34]([CH:49]2[CH2:53][CH2:52][CH2:51][O:50]2)=[C:35]3[C:37]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)=[O:38])=[O:10])[N:6]=1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Reactant: COc1ccc(COC(=O)C2=C(C3CCCO3)OC[C@@H]3[C@H](NC(c4ccccc4)(c4ccccc4)c4ccccc4)C(=O)N23)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(C3CCCO3)OC[C@H]12)c1csc(N)n1
Reaction time: 0.5 h
Yield: 107 %

Procedure:
A stirred mixture of 2-(Z)-methoxyimino-2-(2-aminothiazol-4-yl)acetic acid (III) (54 mg) and N,N-diisopropylethylamine (0.047 ml) in dimethylformamide (0.3 ml) was cooled to -55° to -60° C. and methanesulphonyl chloride (0.021 ml) was added. The mixture was stirred at the same temperature for 0.5 h and then a solution of 4-methoxybenzyl (6S,7S)-7-amino-8-oxo-3-(tetrahydrofuran-2-yl)-1-aza-4-oxabicyclo[4.2.0]oct-2-ene-2-carboxylate (II) (91 mg)in dimethylformamide (1 ml) was added, followed by pyridine (0.022 ml). The mixture was then stirred at 0° C. for 1 h and then at room temperature for 0.5 h. The mixture was partitioned between ethyl acetate and aqueous citric acid solution and the organic phase was washed twice with water, then brine, dried over magnesium sulphate and evaporated. Column chromatography (silica gel, ethyl acetate as eluent) gave the title compound (88 mg). νmax (CHCl3) 1769, 1709, 1679 and 1613 cm-1 ; δ(CDCl3) 1.72-2.12 (4H, m), 3.35 (3H, s), 3.68-3.96 (4H, m), 3.76 (3H, s), 4.64 (1H, dd, J 9.19 and 15.89 Hz), 5.13 (3H, s), 5.20 (1H, t, J 6.77 Hz), 5.72 (1H, dd, J 4.14 and 8.91 Hz), 6.80 (1H, s), 6.93 (2H, d, J 8.68 Hz), 7.24 (2H, s), 7.37 (2H, d, J 8.66 Hz), 9.23 (1H, d, J 9 Hz).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16](B4OC(C)(C)C(C)(C)O4)[CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[C:6]([F:28])[CH:5]=[CH:4][C:3]=1[NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31].Br[C:37]1[CH:38]=[C:39]2[CH:45]=[N:44][NH:43][C:40]2=[N:41][CH:42]=1.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[F:1][C:2]1[C:7]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:37]4[CH:38]=[C:39]5[CH:45]=[N:44][NH:43][C:40]5=[N:41][CH:42]=4)[CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[C:6]([F:28])[CH:5]=[CH:4][C:3]=1[NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(B4OC(C)(C)C(C)(C)O4)cc23)c1F
Reactant: Brc1cnc2[nH]ncc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cnc5[nH]ncc5c4)cc23)c1F
Temperature: 145 °C

Procedure:
In a microwave vial, propane-1-sulfonic acid {2,4-difluoro-3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (30, 0.050 g, 0.099 mmol) is combined with 5-bromo-1H-pyrazolo[3,4-b]pyridine (31, 0.030 g, 0.15 mmol), 1 mL of tetrahydrofuran, 1 mL of acetonitrile, tetrakis(triphenylphosphine)palladium(0) (0.050 g, 0.043 mmol), and potassium carbonate (0.400 mL, 1.00 M in water). The reaction is heated at 145° C. for 45 minutes in a microwave, then extracted with ethyl acetate, and the organic layer is washed with water and brine. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with a gradient of methanol:dichloromethane. Appropriate fractions are combined, concentrated under vacuum and the resulting solid is further washed with a mixture of ethyl acetate:hexane to provide the desired compound. MS (ESI) [M−H+]−=495.05.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]Br.[Cl:7][C:8]1[C:13]([O:14][C:15]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:12][C:11]([N:25]=[C:26]2[S:30][C:29](=[O:31])[NH:28][NH:27]2)=[C:10]([F:32])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:7][C:8]1[C:13]([O:14][C:15]2[C:20]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:12][C:11]([N:25]=[C:26]2[N:27]3[N:28]([CH2:2][CH2:3][CH2:4][CH2:5]3)[C:29](=[O:31])[S:30]2)=[C:10]([F:32])[CH:9]=1
Reactant: O=c1[nH][nH]c(=Nc2cc(Oc3ncccc3C(F)(F)F)c(Cl)cc2F)s1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1sc(=Nc2cc(Oc3ncccc3C(F)(F)F)c(Cl)cc2F)n2n1CCCC2
Yield: 57.4 %

Procedure:
1,4-Dibromobutane (0.64 g) was mixed with 5-[4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenylimino]-1,3,4-thiadiazolidin-2-one (1.0 g) in acetone (25 ml) and potassium carbonate (0.85 g) added. The mixture was heated at reflux for 2 hours and the solvent evaporated. The residue was processed and the resulting oil chromatographed (silica gel, hexane:ethyl acetate, 4:1) to give the product (0.65 g, 57%).
Reaction SMILES: C([O:8][C:9]([C:11]1[N:12]=[CH:13][O:14][C:15]=1[CH2:16][CH2:17][NH:18][C:19](=[O:48])[C@H:20]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:21][C@H:22]([C:31]([O:33]CC1C=CC=CC=1)=[O:32])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:10])C1C=CC=CC=1>CN(C)C=O.[Pd]>[C:9]([C:11]1[N:12]=[CH:13][O:14][C:15]=1[CH2:16][CH2:17][NH:18][C:19](=[O:48])[C@H:20]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:21][C@H:22]([C:31]([OH:33])=[O:32])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([OH:10])=[O:8]
Reactant: O=C(OCc1ccccc1)c1ncoc1CCNC(=O)[C@H](Cc1ccccc1)N[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C(O)c1ncoc1CCNC(=O)[C@H](Cc1ccccc1)N[C@@H](CCc1ccccc1)C(=O)O
Yield: 84.8 %

Procedure:
1.8 g of 4-benzyloxycarbonyl-5-{2-[N-((1S)-1-benzyloxycarbonyl-3-phenylpropyl)-(L)-phenylalanyl]aminoethyl}oxazole was subjected to catalytic hydrogenolysis in 50 ml of dimethylformamide in the presence of 100 mg of palladium-black at 3 atmospheric pressure for 5 hours. After removal of the catalyst by filtration, the solvent was removed. The crystals obtained were recrystallized from methanol to obtain 1.1 g of 4-carboxy-5-{2-[N-((1S)-1-carboxy-3-phenylpropyl)-(L)-phenylalanyl]aminoethyl}oxazole.
Reaction SMILES: Br[CH:2]([C:4]1[S:8][C:7]([S:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[C:6]([N+:18]([O-:20])=[O:19])[CH:5]=1)[CH3:3].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[S:9][C:7]1[S:8][C:4]([CH:2]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH3:3])=[CH:5][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: COc1ccc(CN)cc1
Reactant: CC(Br)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(CNC(C)c2cc([N+](=O)[O-])c(Sc3ccc(Cl)cc3Cl)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.2 %

Procedure:
5-(1-bromoethyl)-2-(2,4-dichlorophenyl)sulfanyl-3-nitro-thiophene (0.8 g, 1.9 mmol), 4-methoxybenzylamine (0.4 mL, 2.85 mmol) and potassium carbonate (0.524 g, 3.8 mmol) were mixed in N,N-dimethylformide (15 mL). The resulting reaction mixture was stirred at ambient temperature for 3 hours. After this time, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was combined and was washed with brine. The organic layer was separated, dried (Na2SO4), concentrated and purified by preparative TLC using a 4:1 mixture of hexane and ethyl acetate as eluent to afford the title compound (100 mg, 11% yield). 1H NMR (400 MHz, CDCl3) δ: 7.71 (2H, m), 7.64 (2H, m), 7.51 (1H, m), 7.40 (1H, m), 7.11 (1H, m), 6.85 (1H, m), 3.93 (1H, q), 3.83 (3H, s), 3.58 (2H, m), 1.34 (3H, d). MS m/z: 468.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11]C(=O)CC(=O)C(C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11]
Reactant: CC(C)(C)C(=O)CC(=O)Nc1cc([N+](=O)[O-])ccc1Cl
Solvent: ClCCl
Product: Nc1cc([N+](=O)[O-])ccc1Cl

Procedure:
In 10 ml of methylene chloride, was dissolved 2.9 g (0.01 mol) of N-(2-chloro-5-nitrophenyl)-α-pivaloylacetic acid amide, which is easily obtained by a reaction of 2-chloro-5-nitroaniline with pivaloylacetic acid ester; and then to this was added, slowly, 1.50 g (0.00525 mol) of 1,3-dibromo-5,5-dimethylhydantoin, on an ice bath, followed by stirring for 1 hour.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO.[I:28]N1C(=O)CCC1=O>[Al].C1COCC1>[NH2:1][C:2]1[C:9]([I:28])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: N#Cc1cc(I)c(N)cc1C(F)(F)F

Procedure:
4-Amino-2-trifluoromethyl-benzonitrile (20.44 g, 109.79 mmoles) and p-toluenesulfonic acid monohydrate (1.05 g, 5.52 mmoles) were dissolved methanol (200 mL) and THF (200 mL), and the reaction mixture was stirred under a nitrogen atmosphere. The reaction vessel was wrapped in aluminium foil, while the solution was stirred for 20 min., then N-iodosuccinimide (30.41 g, 135.17 mmoles) was added and the reaction was allowed to stir overnight (16 hrs). The reaction mixture was concentrated in vacuo, triturated with hexanes (3×400 mL) and concentrated to dryness. The crude solid was dissolved in diethyl ether (400 mL), washed with water (3×), the organic extracts were diluted with hexanes (400 mL) and a white solid precipitated. The solid was filtered and dried in a vacuum oven (35° C. @ 762 Torr) overnight to yield the title compound.
Reaction SMILES: Br[C:2]1[C:3](=[O:30])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[CH3:57][O:58][C:59]1[N:64]=[CH:63][C:62](B(O)O)=[CH:61][CH:60]=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][S:25](=[O:28])(=[O:29])[CH2:24][CH2:23]3)=[CH:7][CH:8]=2)[C:3](=[O:30])[C:2]=1[C:62]1[CH:63]=[N:64][C:59]([O:58][CH3:57])=[CH:60][CH:61]=1
Reactant: O=C1C(Br)=C(c2ccc(F)cc2F)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3ccc(F)cc3F)c3ccc(OCCN4CCS(=O)(=O)CC4)cc3C2=O)cn1
Yield: 67 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-[2-(1,1-dioxothiomorpholin-4-yl)ethoxy]-1H-inden-1-one obtained in Step 1 of Example 112 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and 6-methoxy-3-pyridinylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (67%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:10][NH2:11])=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH:12](O)=O>>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]2[N:4]([CH:12]=[N:11][N:10]=2)[N:3]=1
Reactant: Cc1c(Cl)nnc(NN)c1C
Reactant: O=CO
Product: Cc1c(Cl)nn2cnnc2c1C

Procedure:
In a procedure similar to those of the preceding examples, 40 grams of 3-chloro-4,5-dimethyl-6-hydrazinopyridazine and 200 milliliters of aqueous 80 percent formic acid were heated at reflux for 90 minutes to obtain 6-chloro-7,8-dimethyl-s-triazolo[4,3-b]pyridazine. This triazolopyridazine (9.18 grams, 0.05 mole) was mixed with 12.25 grams N-methylpiperazine in 80 milliliters of ethanol, and the mixture was heated at reflux for 3 hours. The product was recovered by evaporation, partitioning the oily residue between methylene chloride and water and evaporation of the organic layer. The resulting 6-(N-methylpiperazino)-7,8-dimethyl-s-triazolo[4,3-b]pyridazine was obtained as colorless crystals. Thin layer chromatography on silica gel developed with 90 percent chloroform: 10 percent methanol indicated the presence of triazolopyridazine intermediate in the product. The product was taken up in excess N-methylpiperazine and heated at reflux for 12 hours, followed by 2 hours of reflux in 20 milliliters of N-methylpiperazine. The resulting 6-(N-methylpiperazino)-7,8-dimethyl-s-triazolo[4,3-b]pyridazine was obtained as colorless crystals. Thin layer chromatography on silica gel developed with 90 percent chloroform: 10 percent methanol indicated the presence of triazolopyridazine intermediate in the product. The product was taken up in excess N-methylpiperazine and heated at reflux for 12 hours, followed by 2 hours of reflux in 20 milliliters of N-methylpiperazine. The resulting 6-(N-methylpiperazino)-7,8-dimethyl-s-triazolo[4,3-b]pyridazine was separated as before, crystallized from benzene-hexane and found to melt at 170°-172° C. (Calculated: C, 58.51; H, 7.37; N, 34.12. Found: C, 58.70; H, 7.27; N, 34.18.)