Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(OC([NH:52][C@@H:53]([CH:81]([CH3:83])[CH3:82])[C:54]([O:56][CH2:57][O:58][C:59](=[O:80])[C@@:60]([CH2:78][OH:79])([CH3:77])[CH2:61][C@H:62]([NH2:76])[CH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)=[CH:66][CH:65]=1)=[O:55])=O)C1C=CC=CC=1>CN(C=O)C>[NH2:52][C@@H:53]([CH:81]([CH3:83])[CH3:82])[C:54]([O:56][CH2:57][O:58][C:59](=[O:80])[C@@:60]([CH2:78][OH:79])([CH3:77])[CH2:61][C@H:62]([NH:76][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:63][C:64]1[CH:65]=[CH:66][C:67]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)=[CH:68][CH:69]=1)=[O:55]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1c[nH]nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](N)C(=O)OCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 29.8 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (18 mg, 156 μmol), DIPEA (81.6 μL, 468 μmol) and HATU (59.3 mg, 156 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid (S)-2-benzyloxycarbonylamino-3-methyl-butyryloxymethyl ester (90 mg, 160 μmol) dissolved in DMF (1 mL). The resulting mixture was stirred for 20 minutes and the solvent was evaporated. The remaining solid was dissolved in degassed 4.4% formic acid-methanol (5 mL) in a flask containing palladium black (˜100 mg) under nitrogen. The mixture was continuously stirred at room temperature. The mixture was filtered and washed with MeOH. The solvent was evaporated and the product purified by preparative HPLC to yield the title compound (25 mg; purity 95%). MS m/z [M+H]+ calc'd for C28H35N5O6, 538.26. found 538.4.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17]>CN(C=O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:12][C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Oc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(COc2ccc(Br)nc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To a solution of 6-bromopyridin-3-ol (0.500 g, 2.87 mmol) in DMF (3.0 mL) at 0° C. was added NaH (60% in mineral oil, 0.149 g, 3.74 mmol) portion-wise over a period of 10 min. The mixture was warmed to room temperature, stirred for 30 min, and methyl 3-(bromomethyl)benzoate (0.790 g, 3.45 mmol) was added in one portion. The reaction was stirred at room temperature for 16 h. The mixture was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide the crude material. The crude material was purified by flash chromatography (0-50% ethyl acetate:hexanes) to afford the title compound (0.726 g, 78% yield) as an off-white solid. LCMS, [M+H]+=322.0.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:9]=[N:10][CH:11]=[N:12][CH:13]=1.F[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]#[N:18].Cl>O.CS(C)=O>[C:17]([C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[N:12][CH:13]=1)#[N:18]
Reactant: Nc1cncnc1
Reactant: N#Cc1ccccc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccccc1Nc1cncnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To 10 ml of dimethyl sulfoxide was added 1.40 g (12.5 mmol) of potassium tert-butoxide, and to the solution was added 951 mg (10.0 mmol) of 5-aminopyrimidine while cooling with water. After stirring at room temperature for 1 hour, 0.54 ml (5.0 mmol) of 2-fluorobenzonitrile was added thereto while cooling with water, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice-water, and the mixture was adjusted to pH 7.0 with 1 N hydrochloric acid, and filtered. The filter residue was dissolved in 200 ml of acetone, and the acetone solution was filtered. The filtrate was dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain 0.53 g (2.70 mmol) of 5-[N-(2cyanophenyl)amino]pyrimidine.
Reaction SMILES: B(O)O.Br[C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:6]=1[CH:7]=[O:8].[S:14]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15]1>>[F:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:5]([C:16]2[CH:17]=[CH:18][S:14][CH:15]=2)[C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1c(F)cccc1Br
Reactant: OB(O)c1ccsc1
Agent: OBO
Product: O=Cc1c(F)cccc1-c1ccsc1

Procedure:
2-fluoro-6-(thiophen-3-yl)benzaldehyde was prepared using the boronic acid coupling procedure with 2-bromo-6-fluorobenzaldehyde and thiophen-3-ylboronic acid (66 mg, 102 mg theoretical, 64.7%). LC-MS m/z 207 (M+1).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([CH3:18])[C:16]=1[OH:17])[C:11]([OH:13])=[O:12].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[CH3:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([CH3:18])[C:16]=1[O:17][C:19](=[O:21])[CH3:20])[C:11]([OH:13])=[O:12]
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)cc(C(=O)O)cc1C
Reaction time: 12 h
Yield: 56.8 %

Procedure:
To 60 ml of benzene was suspended 10 g/60 mmol of 3,5-dimethyl-4-hydroxybenzoic acid, and 7.5 g/74 mmol of acetic anhydride and 150 μl of pyridine were added to the suspension. The reaction mixture was refluxed under heat for 12 hours, and allowed to stand at room temperature for 12 hours. The precipitated crystals were separated by filtration and washed with a small amount of benzene and air dried to obtain 7.1 g of the desired 3,5-dimethyl-4-acetoxybenzoic acid. 1H-NMR (CDCl3): δ2.22 (6H, s), 2.37 (3H, s), 7.85 (2H, s), 11.53 (1H, s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CS(O[C@@H:16]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[C:17]1=[O:34])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C@H:16]3[CH2:20][CH2:19][N:18]([CH:21]4[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:25][CH2:26]4)[C:17]3=[O:34])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](OS(C)(=O)=O)C2=O)CC1
Reactant: Oc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Oc3ccc4[nH]ncc4c3)C2=O)CC1
Temperature: 130 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
A flask was charged with 1H-indazol-5-ol (0.89 g, 0.66 mmol), (R)-tert-butyl 4-(3-(methylsulfonyloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (Preparation D; 0.2 g, 0.55 mmol), K2CO3 (0.092 g, 0.66 mmol), and DMSO (4 mL). The reaction was stirred at 130° C. overnight. Added water and extracted with ethyl acetate. The organic layers were combined, dried, filtered and concentrated. The residue was purified using silica gel column chromatography with 50-100% ethyl acetate in hexanes to provide (S)-tert-butyl 4-(3-(1H-indazol-5-yloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (0.198 g, 90% yield).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:7][C:1]1[CH:6]=[CH:5][C:4]([C:12](=[O:13])[CH2:11][CH2:10][CH2:9][Cl:8])=[CH:3][CH:2]=1
Reactant: O=C(Cl)CCCCl
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(C(=O)CCCCl)cc1

Procedure:
53 ml of toluene and 70.5 g of 4-chlorobutyryl chloride are dissolved in 100 ml of dichloromethane, and the solution is added at 10° C. to a suspension of 74 g of aluminium chloride in 200 ml of dichloromethane. The temperature is then allowed to rise for a quarter of an hour and the mixture is treated with ice-cold water. The organic phase is dried over magnesium sulphate and evaporated under vacuum to give 96.9 g of 4'-methyl-4-chlorobutyrophenone in the form of an oil, which is used without further purification for the next step.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][C:3]([OH:5])=[O:4].[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O.N1CCCCC1.Cl>N1C=CC=CC=1>[C:3]([C:2]1[C:1](=[O:7])[NH:8][C:9]2[C:10]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)([OH:5])=[O:4]
Reactant: Nc1ccccc1C=O
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)c1cc2ccccc2[nH]c1=O
Temperature: 90 °C
Reaction time: 5 h

Procedure:
2 Grams of malonic acid was dissolved in 15 ml of pyridine, then 1.2 g of o-aminobenzaldehyde and 2 ml of piperidine were added thereto, and the mixture was stirred at 90° C. for 5 hours. The reaction mixture was poured in an aqueous solution of hydrochloric acid and the crystals precipitated were collected by filtration. Recrystallized from methanol-chloroform to obtain 1.2 g of 3-carboxycarbostyril in the form of colorless needle-like crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:10]([C:11]([CH3:18])([CH3:17])[CH2:12][O:13][CH2:14][O:15][CH3:16])=[CH:9][C:8](Br)=[CH:7][C:6]=1[C:20]([CH3:23])([CH3:22])[CH3:21].[Li]C(C)(C)C.CN([CH:32]=[O:33])C.[Cl-].[NH4+]>C1COCC1>[C:20]([C:6]1[CH:7]=[C:8]([CH:9]=[C:10]([C:11]([CH3:18])([CH3:17])[CH2:12][O:13][CH2:14][O:15][CH3:16])[C:5]=1[O:4][CH2:3][O:2][CH3:1])[CH:32]=[O:33])([CH3:23])([CH3:22])[CH3:21]
Reactant: COCOCC(C)(C)c1cc(Br)cc(C(C)(C)C)c1OCOC
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCOCC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1OCOC
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A solution of 48 (925 mg, 2.38 mmol) in THF (20 ml) was cooled to −50° C., and t-BuLi (1.7 M in pentane, 3.08 ml, 5.24 mmol) was dropwise added to the solution while maintaining the temperature below −40° C. After completion of the addition, the mixture was stirred at this temperature, and DMF (0.12 ml) in THF (5 ml) was added. The mixture was warmed slowly to room temperature. Aqueous solution of saturated ammonium chloride (50 ml) was added, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with saturated brine (50 ml), and after dryness, the solvent was removed in vacuo. The residue was purified by column chromatography to yield 669 mg (83.1%) of 49 as colorless oil. 1H NMR (CDCl3) δ: 1.47 (9H, s, tBu), 1.48 (6H, s, 2×CH3), 3.29, 3.66 (each 3H, s, CH3), 3.84 (2H, s, CH2), 4.60, 4.95 (each 2H, s, CH2), 7.81 (1H, d, J=2.2 Hz, Ar—H), 7.84 (1H, d, J=2.2 Hz, Ar—H), 9.92 (1H, s, CHO).
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=3)[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CO>[C:1]1([C:7]2[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]3[CH:30]=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:37][CH:38]=3)[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OCCCCn2c(-c3ccccc3)nc(-c3ccccc3)c2-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCCCCn2c(-c3ccccc3)nc(-c3ccccc3)c2-c2ccccc2)cc1
Yield: 89.2 %

Procedure:
Methyl 4-[4-(2,4,5 triphenylimidazolyl]butyloxy)-benzoate (1.5 g) was dissolved in methanol (50 ml) and treated with 10% potassium hydroxide solution (15 ml) for 0.5 hours. The methanol was removed under reduced pressure and the remaining aqueous was acidified (pH 4) and the pre-cipitate was collected by filtration and recrystallised from methanol to give 4-[4-(2,4,5-triphenylimidazolyl)-butyloxy]-benzoic acid (1.3 g) as white prisms m.p. 202°-203° C.; Found: C, 78.79; H, 5.75; N, 5.81% (C32H28N2O3); Requires: C, 78.66; H, 5.78; N, 5.73%
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].[Cl:9][C:10]1[CH:11]=[C:12]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH:24]([CH3:31])[CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:19]1[CH:18]=[C:17]([C:32](=S)N)[CH:16]=[CH:15][C:14]=1[S:13]2>C(OCC)(=O)C>[Cl:9][C:10]1[CH:11]=[C:12]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH:24]([CH3:31])[CH2:25][N:26]1[CH2:27][CH2:28][CH2:29][CH2:30]1)[C:19]1[CH:18]=[C:17]([C:32]3[NH:8][CH:3]4[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]4[N:1]=3)[CH:16]=[CH:15][C:14]=1[S:13]2
Reactant: NC1CCCCC1N
Reactant: CC(CN1CCCC1)N1c2ccc(Cl)cc2Sc2ccc(C(N)=S)cc21
Solvent: CCOC(C)=O
Product: CC(CN1CCCC1)N1c2ccc(Cl)cc2Sc2ccc(C3=NC4CCCCC4N3)cc21
Temperature: 150 °C

Procedure:
1,2-Diaminocyclohexane (15.78 cc) is added to an ethanolic solution (70 cc) of 7-chloro-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (5.20 g). The mixture is heated in an autoclave to 150° C. for 17 hours. After cooling, the reaction mixture is diluted with ethyl acetate (250 cc) and washed with j distilled water (5×250 cc). The organic phase is extracted with normal hydrochloric acid solution (300 cc). After separation of the organic phase when settling has taken place, the acidic aqueous phase is alkalinized with concentrated caustic soda and extracted with ethyl acetate (200 cc). The organic phase is separated after settling has taken place, dried over magnesium sulpate, filtered and evaporated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is chromatographed on a column (height: 52 cm; diameter: 2.5 cm) of silica gel (0.2-0.06 mm), eluting with pure ethyl acetate (2 liters) and collecting 120-cc fractions. The first liter is discarded, and fractions 4 to 7 containing the pure product are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 7-chloro-2-(3a, 4, 5, 6, 7, 7a-hexahydro-1H-benzimidazol-2 -yl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]phenothiazine (0.72 g) in the form of a yellow solid, m.p. 120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:23](=N)(OCC)[CH3:24]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:14]=[CH:13][C:12]3[NH:15][C:23]([CH3:24])=[N:16][C:11]=3[CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(c2cccc(Cl)c2)n2ccnc2)cc1N
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CO
Product: Cc1nc2cc(C(c3cccc(Cl)c3)n3ccnc3)ccc2[nH]1
Yield: 89.8 %

Procedure:
A solution of 2.99 parts of 4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-1,2-benzenediamine, 1.85 parts of ethyl ethanimidate hydrochloride and 40 parts of methanol was stirred for 16 hours at room temperature. The solvent was evaporated and the residue was dissolved in a dilute hydrochloric acid solution. The whole was alkalized with ammonia and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol saturated with ammonia (90:5:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was dried in vacuo, yielding 2.9 parts (89.8%) of 5-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-2-methyl-1H-benzimidazole; mp. 117.1° C. (compound 122).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)(=O)=O.O[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:21]([C:20]1[CH:23]=[CH:24][C:17]([O:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:18][CH:19]=1)=[O:22]
Reactant: O=Cc1ccc(O)cc1
Reactant: CS(=O)(=O)OCCc1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#Cc1ccc(CCOc2ccc(C=O)cc2)cc1
Yield: 16.8 %

Procedure:
8.55 g (38 mmole) 4-cyanophenethyl methanesulfonate, 4.64 g (38 mmole) p-hydroxybenzaldehyde and 18.7 g (57 mmole) cesium carbonate in 150 ml acetonitrile was refluxed over night. The salt was filtered off and the solvent evaporated in vacuo. The residue was treated with 2 M sodium hydroxide and dichloromethane. The organic phase was dried and evaporated in vacuo. Purification by chromatography on silica gel using dichloromethane as eluent gave 1.6 g (yield 17%) of 4-[2-(4-formylphenoxy)ethyl]benzonitrile.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:33])=[C:9]([CH2:11][O:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([OH:30])=[N:19]3)=[CH:15][CH:14]=2)[N:10]=1.[H-].[Na+].I[CH2:37][CH3:38].O>CN(C)C=O>[CH2:37]([O:30][C:20]1[C:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][N:18]([CH2:17][C:16]2[CH:31]=[CH:32][C:13]([O:12][CH2:11][C:9]3[N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[O:7][C:8]=3[CH3:33])=[CH:14][CH:15]=2)[N:19]=1)[CH3:38]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of ethyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-hydroxy-1H-pyrazol-4-yl]propionate (452 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 40.0 mg) was added at 0° C., and the solution was stirred at room temperature for 30 minutes. Iodoethane (0.240 ml) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-1H-pyrazol-4-yl]propionate (348 mg, yield: 73%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[N:5]=[CH:4][N:3]=1.[Se](=O)=[O:21].O>O1CCOCC1>[CH3:15][O:14][C:12]1[CH:13]=[C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([CH:1]=[O:21])[CH:7]=2)[CH:9]=[C:10]([O:18][CH3:19])[C:11]=1[O:16][CH3:17]
Reactant: O=[Se]=O
Reactant: COc1cc(-c2cc(C)ncn2)cc(OC)c1OC
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cc(C=O)ncn2)cc(OC)c1OC
Temperature: 105 °C
Reaction time: 8 h

Procedure:
4-Methyl-6-(3,4,5-trimethoxyphenyl)pyrimidine (920 mg) was dissolved in dioxane (100 mL), and to the solution selenium dioxide (784 mg) was added, and the mixture was stirred overnight at 105° C. Water was added to the reaction mixture to conduct extraction with ethyl acetate, and the resultant organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the title compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[OH:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1>C(Cl)Cl.O=[Mn]=O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1cccc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1cccc(C(=O)c2ccc3c(c2)OCCO3)c1

Procedure:
To a stirred solution of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3-methoxy-phenyl)-methanol (2.08 g crude, 6.7 mmol) in CH2Cl2 (15 mL) at room temperature was added activated MnO2 powder (3.6 g, 41.4 mmol) and kept adding 23 equivalents of MnO2 every 35 h until HPLC showed disappearance of the starting material. The black suspension was filtered through a Celite pad, concentrated in vacuo to give (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3-methoxy-phenyl)-methanone as an oil (2.0 g, 109% crude yield): 1H NMR (CDCl3) δ 3.86 (s, 3H, OCH3), 4.26-4.36 (m, 4H, CH2CH2), 6.84-7.42 (m, 7H, Ar). The product was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:28])([CH3:27])[C:10]([NH:12][C@H:13]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[N+:43]([O-:45])=[O:44])=[CH:33][CH:32]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:28])([CH3:27])[C:10]([NH:12][C@H:13]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:14]([NH:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[N+:43]([O-:45])=[O:44])=[CH:35][CH:36]=1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 56.9 %

Procedure:
The acid (338 mg, 0.87 mmol) from Step D and 4-aminomethyl-2'-nitro-1,1'-biphenyl (200 mg, 0.87 mmol) and triethylamine (0.245 mL, 1.76 mmol) were dissolved in methylene chloride (8 mL) and stirred at room temperature. Benzotriazolyl-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (388 mg, 0.87 mmol) was added in a single portion. The reaction mixture was stirred together for 3.5 hours then the reaction was quenched by adding saturated aqueous sodium chloride (10 mL) and extracted with methylene chloride (3×20 mL). The combined extracts were dried over magnesium sulfate, filtered and evaporated under vacuum. The resulting thick gum was chromatographed on silica gel using ethyl acetate/hexanes (1:2 v/v) to give 297 mg (50%) of an orange semi-solid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35]N)[CH:30]=1>>[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: COC(=O)c1cccc(NN)c1
Product: COC(=O)c1cccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 3-hydrazino-benzoic acid methyl ester according to example 43 gave the desired product. MS: M=456.9 (M+H)+
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][S:12][CH:11]2[CH2:16][C:17]2[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[H][H]>C(O)C.[Pd]>[OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][S:12][CH:11]2[CH2:16][C:17]2[CH:27]=[CH:26][C:20]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(O)C=Cc1ccc(CC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCc1ccc(CC2SCC(=O)N2CCC2(O)CCCCC2)cc1

Procedure:
p-{3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinylmethyl}cinnamic Acid (7.8 g., 0.02 mole) in ethanol (125 ml.) is hydrogenated over 2.5 g. of a 5% Pd on charcoal catalyst at 1 atmosphere pressure and 27° C. When the theoretical amount (0.02 mole) of hydrogen has been absorbed, the catalyst is filtered off, the solvent evaporated, and the residue chromatographed on silica gel with 4% methanol in chloroform as the eluant. The title compound is obtained as a colorless, viscous oil.