Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[P:3]([O-:8])([O:6][CH3:7])[O:4][CH3:5].[CH2:9]([O:13][C:14](=[O:17])[CH:15]=[O:16])[CH2:10][CH2:11][CH3:12]>>[CH2:9]([O:13][C:14](=[O:17])[CH:15]([P:3]([O:6][CH3:7])([O:4][CH3:5])=[O:8])[OH:16])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCOC(=O)C=O
Reactant: COP([O-])OC
Agent: [Na+]
Agent: [OH-]
Product: CCCCOC(=O)C(O)P(=O)(OC)OC
Yield: 70 %

Procedure:
1.5 ml of a saturated methanolic sodium hydroxide solution are allowed to run rapidly into 22 g of dimethyl phosphite and 26 g of glyoxylic acid butyl ester. The reaction which proceeds is highly exothermic. The mixture is subsequently stirred at 25° for some hours and worked up by distillation to give 33.6 g of dimethoxyphosphinylhydroxy-acetic acid butyl ester (yield: 70%). Boiling point 0.05 : 75°-82° C. (thin film evaporator). 1H-NMR (CDCl3): δ=0.93 (3H, t, J=5 Hz, CH3), 3.86 (6H, d, J=11 Hz, CH3O), 4.23 (2H, t, J=6 Hz, OCH2) and 4.63 ppm (1H, d, J=18 Hz, P-CH)
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:22])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:21])([C:14]([NH:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:6][CH2:5]2.[O:23]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:23][C:7]([CH3:21])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:22])[C:14]([NH:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCC(C)C)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCC(C)C)=C(C)C1=O
Yield: 87.3 %

Procedure:
Oxidation as described in protocol B, using 84 mg (0.278 mmol) of 6-hydroxy-N-isobutyl-2,5,7,8-tetramethylchroman-2-carboxamide and 335 mg CAN (0.612 mmol) yielded 78 mg of 2-hydroxy-N-isobutyl-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow-orange oil.
Reaction SMILES: [F-:1].[K+].[N+:3]([C:6]1[CH:19]=[CH:18][CH:17]=[C:16]([N+]([O-])=O)[C:7]=1[C:8]([NH:10][C@@H:11]([CH3:15])[C:12]([OH:14])=[O:13])=[O:9])([O-:5])=[O:4].C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[F:1][C:16]1[CH:17]=[CH:18][CH:19]=[C:6]([N+:3]([O-:5])=[O:4])[C:7]=1[C:8]([NH:10][C@@H:11]([CH3:15])[C:12]([OH:14])=[O:13])=[O:9]
Reactant: C[C@H](NC(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-])C(=O)O
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](NC(=O)c1c(F)cccc1[N+](=O)[O-])C(=O)O
Temperature: 175 °C
Reaction time: 0.75 h
Yield: 63 %

Procedure:
A mixture of spray-dried KF (1.02 g, 17.6 mmol), intermediate 13 (500 mg, 1.76 mmol) and catalytic amount of 18-crown-6 in dry DMSO (10 mL) was stirred at 170-180° C. for 45 min. Work-up of the reaction mixture as described in example 1 gave the product as a pale brown color solid (284 mg, 63%), mp 142-144° C. 1H NMR (400 MHz, DMSO-d6): δ 9.05 (1H, d, J=7.2 Hz), 8.01 (1H, dd, J=6.6, 1.8 Hz), 7.72-7.78 (2H, m), 4.44 (1H, pentet, J=7.2 Hz), 1.34 (3H, d, J=7.2 Hz); LC-MS (positive ion mode): m/z 279 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:21](#[N:25])[CH2:22][C:23]#[N:24].[O-2].[Al+3].[O-2].[O-2].[Al+3]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[C:22]([C:21]#[N:25])[C:23]#[N:24])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: N#CCC#N
Reactant: COc1cccc(C(=O)c2cc(OC)cc(OC)c2)c1
Agent: [Al+3]
Agent: [O-2]
Product: COc1cccc(C(=C(C#N)C#N)c2cc(OC)cc(OC)c2)c1
Temperature: 160 °C
Yield: 33.4 %

Procedure:
(3,5-dimethoxyphenyl)-(3-methoxyphenyl)methanone (0.31 g, 1.12 mmol), malononitrile (0.08 ml, 1.23 mmol), and aluminum oxide (0.57 g, 5.6 mmol) were mixed and heated in an oil bath at 160° C. overnight. After cooling down to r.t., the brown mixture was extracted with CH2Cl2 (˜50 ml), filtered through a Celite pad and concentrated to an oil, which was purified via flash column chromatography (5% EtOAc in hexane gradient to 20% EtOAc in hexane in about 40 min.) and lyophilized to give 2-[(3,5-dimethoxy-phenyl)-(3-methoxy-phenyl)-methylene]-malononitrile as a greenish solid (0.12 g, 34%): mp, 100-102° C.; 1HNMR (DMSO-d6) δ 7.47 (t, J=8 Hz, 1H, Ar), 7.22 (dd, J=2.36, 8 Hz, 1H, Ar), 7.16 (t, J=1 Hz, 1H, Ar), 6.96 (d, J=7 Hz, 1H, Ar), 6.78 (t, J=2 Hz, 1H, Ar), 6.62 (d, J=2 Hz, 2H, Ar), 3.79 (s, 3H, OCH3), 3.76 (s, 6H, 2OCH3); 13C NMR (DMSO-d6) δ 173.4, 160.3, 158.9, 137.5, 136.8, 130.1, 122.4, 118.0, 115.3, 114.1, 114.0, 108.1, 103.6, 82.9, 55.6, 55.5; Anal. Calcd. For C19H16N2O3: C, 71.24; H, 5.03; N, 8.74. Found: C, 71.10; H, 4.87; N, 8.59.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[NH2:40]>>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[C:4]3[CH:3]=[C:2]([NH:40][C:33]4[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:32]=4[O:31][CH3:30])[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:27])([CH3:29])[CH3:28]
Reactant: COc1ccc(N)c(OC)c1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Product: COc1ccc(Nc2cc3c(cn2)cc(-c2cnn(C(=O)OC(C)(C)C)c2)n3C(=O)OC(C)(C)C)c(OC)c1
Yield: 53 %

Procedure:
The title compound was prepared in 53% yield from compound (10) and 2,4-dimethoxyphenylamine using the method described for Preparation 35. 1H-NMR (CDCl3, 500 MHz): δ 1.50 (s, 9H), 1.69 (s, 9H), 3.83 (s, 3H), 3.87 (s, 3H), 6.52 (dd, J=2.52, 8.51 Hz, 1H), 6.56 (d, J=0.95 Hz, 1H), 6.57 (d, J=2.52 Hz, 1H), 6.66 (br s, 1H, NH), 7.43 (m, 1H), 7.67 (d, J=8.83 Hz, 1H), 7.82 (m, 1H), 8.20 (d, J=0.95 Hz, 1H), 8.43 (d, J=0.95 Hz, 1H).
Reaction SMILES: C([O:8][CH2:9][C:10]([C:13]1[NH:17][C:16](=[O:18])[N:15]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]4[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=4)[CH:27]=3)=[C:21]([CH3:38])[N:20]=2)[N:14]=1)([CH3:12])[CH3:11])C1C=CC=CC=1.C(O)=O>CCOC(C)=O.[Pd]>[OH:8][CH2:9][C:10]([C:13]1[NH:17][C:16](=[O:18])[N:15]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]4[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=4)[CH:27]=3)=[C:21]([CH3:38])[N:20]=2)[N:14]=1)([CH3:12])[CH3:11]
Reactant: Cc1nc(-n2nc(C(C)(C)COCc3ccccc3)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Agent: [Pd]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: Cc1nc(-n2nc(C(C)(C)CO)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Reaction time: 12 h
Yield: 15.7 %

Procedure:
3-(1-(Benzyloxy)-2-methylpropan-2-yl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.41 g, 0.80 mmol), and palladium(0) on carbon (10% w/w, 0.20 g, 0.19 mmol) were combined in EtOAc (4.0 mL) under an atmosphere of Ar. The reaction flask was depressurized and back-filled with H2 (g). This process was repeated (2×) and the reaction mixture was stirred under a balloon of H2 (g) for 12 h. Formic acid (0.5 mL) was added and stirring was continued an additional 12 h at RT. The reaction mixture was transferred to a Parr hydrogenation shaker and reaction was continued under 40 psi H2 (g) atmosphere. After 5 h, the Pd was removed by filtration through a pad of diatomaceous earth and the filter cake was washed with EtOAc (4×25 mL). The combined filtrates were concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 3-(1-hydroxy-2-methylpropan-2-yl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.053 g, 15%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.85-11.83 (m, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 6.65 (dd, J=5.7, 2.4 Hz, 1H), 4.92-4.91 (m, 1H), 3.84 (s, 3H), 3.45-3.43 (m, 2H), 2.33 (s, 3H), 1.20 (s, 6H); MS (ESI) m/z: 422.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:3]=1[C:4]([CH:6](C(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].O>O1CCOCC1>[F:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:3]=1[C:4](=[O:5])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1F
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CC(=O)c1cc(F)c(F)cc1F
Temperature: 102 °C
Reaction time: 7 h
Yield: 58.7 %

Procedure:
A solution of 23.8 g of (2,4,5-trifluorobenzoyl)propanedioic acid, diethyl ester, 2.7 ml of water and 740 ml of p-dioxane was placed in an oil bath and stirred at 102° C. for 7 hours. The solution was then evaporated to dryness, heptane was added and the mixture refrigerated overnight. The resulting crystals were collected, washed with 10 ml of cold heptane and dried, giving 10.8 g of 2,4,5-trifluoro-β-oxobenzenepropanoic acid, ethyl ester.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([CH2:15][CH2:16][CH:17]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:17][CH2:16][CH2:15][C:9]3[CH:10]=[C:11]([CH2:12][CH2:13][CH3:14])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=3)[CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: CCCc1cc(CCC=O)nn1-c1ccccc1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(OC)cc3)CC2)nn1-c1ccccc1

Procedure:
42 mg (28%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (80 mg, 0.330 mmol), 1-(4-methoxyphenyl)piperazine (64 mg, 0.330 mmol), DIPEA (0.090 mL, 0.495 mmol) and NaBH(OAc)3 (210 mg, 0.990 mmol).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1B(O)O>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: CSc1ccc(C2=C(c3ccc(Cl)cc3Cl)CCC2)cc1
Yield: 89.8 %

Procedure:
Following the synthetic procedure outlined in Step 3 of Example 1, 280 mg (0.93 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methythio)benzene (Example 1, Step 2) was reacted with 350 mg (1.9 mmol) of 2,4-dichlorophenylboronic acid (Lancaster). Purification by silica gel chromatography (MPLC) with hexane gave 280 mg of 1-[2-(2,4-dichlorophenyl)cyclopenten-1-yl]-4-(methylthio)benzene as an oil: NMR (CDCl3) δ 2.10 (m, J=7 Hz, 2H), 2.41 (s, 3H), 2.81 (t, J=8 Hz, 4H), 2.92 (m, J=8 Hz, 2H), 6.95-7.21 (m, 6H), 7.40 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6](F)=[C:5]([C:16]([O:18][CH3:19])=[O:17])[C:4]=1[CH3:20])#[N:2].C(N(CC)CC)C.[CH3:28][N:29]([CH3:35])[C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6]([N:32]2[CH2:33][CH2:34][C@H:30]([N:29]([CH3:35])[CH3:28])[CH2:31]2)=[C:5]([C:16]([O:18][CH3:19])=[O:17])[C:4]=1[CH3:20])#[N:2]
Reactant: COC(=O)c1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Reactant: CN(C)[C@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)c(C#N)c2nc(C3CC3)oc2c1N1CC[C@H](N(C)C)C1
Temperature: 90 °C
Reaction time: 10 h
Yield: 86.6 %

Procedure:
Methyl 4-cyano-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-6-carboxylate (I-183) (100 mg, 0.37 mmol) was dissolved in dimethyl, then at room temperature, triethylamine (76 μl, 0.55 mmol) and (3S)-3-(dimethylamino)pyrrolidine (56 μl, 0.44 mmol) were added. The solution was stirred under nitrogen atmosphere at 90° C. for 10 hours, then cooled to room temperature. This was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=92:8) to obtain the entitled compound (118 mg) as a roughly-purified product. This was washed with diisopropyl ether to obtain the entitled compound (109 mg, 81%) as a white solid.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:33]=1)[C:18](=[O:32])[C:19]1[CH2:24][CH2:23][C:22](=[CH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]=1[N:21]=2)=[O:12]>CN(C)C=O.C(O)(=O)C>[CH3:9][O:10][C:11]([C:13]12[CH2:2][CH:33]1[N:17]1[C:18](=[O:32])[C:19]3[CH2:24][CH2:23][C:22](=[CH:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:20]=3[N:21]=[C:16]1[CH:15]=[CH:14]2)=[O:12]
Reactant: COC(=O)c1ccc2nc3c(c(=O)n2c1)CCC3=Cc1ccccc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C12C=Cc3nc4c(c(=O)n3C1C2)CCC4=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethyl-sulphoxonium iodide (1.8 g) was reacted with 50% sodium hydride (0.39 g) in dimethyl formamide (30 ml) under stirring at room temperature for 60 minutes, then a solution of 3-benzylidene-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid methyl ester, m.p. 248°-250° C., (2.49 g) in dimethylformamide (30 ml) was added. The mixture was allowed to react at room temperature for 1 hour then it was diluted with ice water and neutralized with acetic acid. The precipitate was filtered and washed with water to give 2.55 g of 3-benzylidene-7,8-methylene-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid methyl ester, m.p. 185°-187° C., which was treated with 0.5% KOH in 95% ethanol solution (90 ml) at reflux temperature for 15 minutes. After cooling the reaction mixture was acidified with acetic acid and diluted with water: the precipitate was filtered, washed with water until neutral and crystallized from CH 2 Cl2 /methanol to give 1.8 g of 3-benzylidene-7,8-methylene-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid, m.p. 230°-240° C. dec., NMR (CF3COOD) δ ppm: 1.19 (t) (1H, 7,8-methylene proton), 2.91 (d d) (1H, 7,8-methylene proton), 3.32 (br s) (4H, cyclopentane protons), 3.51 (d.d.) (1H, C-8 proton), 7.01 (d) (1H, C-5 proton), 7.45 (m) (1H, =CH--), 7.58 (br s) (5H, phenyl protons), 8.26 (d) (1H, C-6 proton).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([NH:9][C:10]2[O:11][C:12]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)=[N:13][N:14]=2)=[O:8])[S:5][CH:6]=1.[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:2]3[CH:3]=[C:4]([C:7]([NH:9][C:10]4[O:11][C:12]([C:15]5[O:16][CH:17]=[CH:18][CH:19]=5)=[N:13][N:14]=4)=[O:8])[S:5][CH:6]=3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH3:21]
Reactant: CCc1ccc(-c2ccc(B(O)O)cc2)cc1
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1cc(Br)cs1
Product: CCc1ccc(-c2ccc(-c3csc(C(=O)Nc4nnc(-c5ccco5)o4)c3)cc2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 4-bromo-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-2-thiophenecarboxamide prepared in Reference Example 12 instead of compound Ia-50 and using commercially available 4′-ethyl-4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH2:8][CH2:9][C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=O)[CH:2]=1.[CH3:19][Si:20]([CH3:29])([CH3:28])[CH2:21][CH2:22][O:23][C:24]([NH:26][NH2:27])=[O:25].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:19][Si:20]([CH3:29])([CH3:28])[CH2:21][CH2:22][O:23][C:24](=[O:25])[NH:26][N:27]1[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:8][CH:9]=[C:10]1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(CCC(=O)c1cccnc1)c1cccnc1
Reactant: C[Si](C)(C)CCOC(=O)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOC(=O)Nn1c(-c2cccnc2)ccc1-c1cccnc1
Temperature: 25 °C

Procedure:
A solution of 1,4-di-Pyridin-3-yl-butane-1,4-dione (1 g, 4.2 mmol) in toluene (40 mL) is treated with hydrazinecarboxylic acid 2-trimethylsilanyl-ethyl ester (888 mg, 5.0 mmol) and p-toluenesulfonic acid (30 mg). The reaction vessel is fitted with a Dean Stark trap, and the resulting solution is heated to reflux, with azeotropic removal of water until no starting materials are detected by TLC. The solution is cooled to rt, and washed with water. The organic layer is dried over Na2SO4, filtered and concentrated to afford (2,5-di-pyridin-3-yl-pyrrol-1-yl)-carbamic acid 2-trimethylsilanyl-ethyl ester, which is not purified further.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1.C(O)C.Cl>O>[F:1][C:2]([F:14])([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
In a nitrogen atmosphere, 30.1 g (0.14 mol) of p-(2,2,2-trifluroethoxy) nitrobenzene, 82.1 g (1.47 mol) of reduced iron, 120 ml of ethanol and 40 ml of water were placed in a three-necked flask, to which 1.4 ml of concentrated hydrochloric acid was dropped under stirring and then refluxed for one hour. After cooling to a room temperature, it was separated by filtration, and the reaction solution was poured into iced water (about 2 liter), and precipitated solids were washed with water and then dried, to obtain 24.4 g (0.13 mol) of p-(2,2,2-trifluoroethoxy) aniline as pink solids. The yield was 94% and the melting point was 69.4° C.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:2].[CH2:15]([B-](F)(F)F)/[CH:16]=[CH:17]\[CH3:18].[K+]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[OH:2][C@@H:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:17]([CH3:18])[CH:16]=[CH2:15]
Reactant: C/C=C\C[B-](F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: C=C[C@H](C)[C@@H](O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 13 h
Yield: 101.8 %

Procedure:
To a solution of tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (10 g, 50 mmol, 1 eq.) in dichloromethane (120 mL, 0.42 M) was added potassium (2Z)-2-buten-1-yltrifluoroborate (9.76 g, 60.2 mmol, 1.2 eq.) followed by tetra-n-butylammonium bromide (3.24 g, 5.02 mmol, 0.1 eq.) and water (60 mL). After 13 hours, the reaction was diluted with dichloromethane (150 mL) and water (150 mL). The aqueous layer was separated and back-extracted with dichloromethane (100 mL). The combined organic layers were washed with aqueous sodium chloride solution (5% wt, 200 mL), washed with water (200 mL), and concentrated in vacuo to afford #9 (˜13 g) as an orange oil, which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 5.61-5.86 (br m, 1H), 4.97-5.09 (m, 2H), 3.80-3.98 (br m, 2H), 3.45-3.67 (br m, 1H), 3.21-3.29 (m, 1H), 2.14-2.26 (m, 1H), 1.80-2.04 (m, 3H), 1.65-1.76 (m, 1H), 1.47 (s, 9H), 1.12 (d, J=6.6 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C:9]1[N:10]=[CH:11][C:12]([N:36]2[CH2:40][C@@H:39]3[CH2:41][CH2:42][CH:43](CS([O-])(=O)=O)[C@H:38]3[CH2:37]2)=[N:13][C:14]=1[C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:28])=[CH:22][CH:21]=2)=[N:18][N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:56]=[N+:57]=[N-:58].[Na+]>CN(C=O)C>[N:56]([CH:43]1[C@@H:38]2[CH2:37][N:36]([C:12]3[N:13]=[C:14]([C:15]4[O:16][C:17]([C:20]5[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:28])[C:29](=[O:30])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[CH:22][CH:21]=5)=[N:18][N:19]=4)[C:9]([N:8]([C:49]([O:51][C:52]([CH3:54])([CH3:53])[CH3:55])=[O:50])[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[N:10][CH:11]=3)[CH2:40][C@@H:39]2[CH2:41][CH2:42]1)=[N+:57]=[N-:58]
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(N4C[C@@H]5CCC(CS(=O)(=O)[O-])[C@H]5C4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(-c2nnc(-c3nc(N4C[C@@H]5CCC(N=[N+]=[N-])[C@@H]5C4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Yield: 94.3 %

Procedure:
A solution of [(3aR,6aS)-2-[5-[bis(tert-butoxycarbonyl)amino]-6-[5-[4-[[tert-butoxycarbonyl(methyl)amino]methyl]phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-6-yl]methanesulfonate (460 mg, 0.58 mmol) and sodium azide (190 mg, 573 μL, 2.9 mmol) in DMF (4 mL) was heated at 70° C. for 48 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc. The organic layer was washed with H2O, followed by washing with brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain tert-butyl N-[[4-[5-[6-[(3aR,6aS)-6-azido-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-3-[bis(tert-butoxycarbonyl)amino]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (401 mg, 93%). LC/MS m/z 733.7 [M+H]+.
Reaction SMILES: [N:1]1([CH:6]([C:13]2[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][N:3]=[CH:2]1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=O)=[CH:24][CH:23]=1.[OH-].[NH4+]>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]2[NH:19][C:16]3[CH:17]=[CH:18][C:13]([CH:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:14][C:15]=3[N:20]=2)=[CH:24][CH:23]=1
Reactant: CCCCCCC(c1ccc(N)c(N)c1)n1ccnc1
Reactant: O=C(O)c1ccc(F)cc1
Agent: [NH4+]
Agent: [OH-]
Product: CCCCCCC(c1ccc2[nH]c(-c3ccc(F)cc3)nc2c1)n1ccnc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
A mixture of 9 parts of 4-[1-(1H-imidazol-1-yl)heptyl]-1,2-benzenediamine, 5 parts of 4-fluorobenzoic acid and 100 parts of polyphosphoric acid was stirred for 2 hours at 100° C. After cooling, the reaction mixture was poured into ice water and treated with ammonium hydroxide. The product was extracted three times with 120 parts of trichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 1,1'-oxybisethane. The product was filtered off and dried, yielding 5.8 parts (47%) of 2-(4-fluorophenyl)-5-[1-(1H-imidazol-1-yl)heptyl]-1H-benzimidazole; mp. 121.9° C. (compound 39).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[F:36]>>[CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:27][C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=2[F:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: Oc1ccccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Product: N#Cc1ccc(COc2ccccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol and 4-bromomethyl-3-fluoro-benzonitrile (105942-09-4). Brown sticky solid (69%). MS (Turbo Spray): m/z=476.4 (M+H).