Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)[CH2:23][CH2:22]2)=[CH:15][CH:14]=1)([O-:12])=[O:11].[OH-].[Na+]>C(Cl)Cl>[F:7][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=1)[CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)[CH2:23][CH2:22]1
Reactant: O=[N+]([O-])c1ccc(CCN2CCN(CC(O)c3ccc([N+](=O)[O-])cc3)CC2)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCN2CCN(CC(F)c3ccc([N+](=O)[O-])cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
DAST (6.6 μL, 0.050 mmol) was added to 1-(4-nitrophenyl)-2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethanol (10 mg, 0.025 mmol) in DCM (1 mL) and the resulting mixture was stirred at RT for 72 h. Then 1 N NaOH was added and the mixture was extracted twice with DCM. The combined organic layers were dried over MgSO4, filtered, and evaporated to dryness. The crude product was purified by mass directed preparative HPLC to yield 1-[2-fluoro-2-(4-nitrophenyl)ethyl]-4-[2-(4-nitrophenyl)ethyl]piperazine.
Reaction SMILES: C1C=C(SSC2N=CC=CC=2)N=CC=1.C(N(CC)CC)C.[SH:22][CH2:23][C:24]([OH:26])=[O:25].[CH:27]([SH:30])([CH3:29])[CH3:28]>O1CCCC1.CCOCC>[CH:27]([S:30][S:22][CH2:23][C:24]([OH:26])=[O:25])([CH3:29])[CH3:28]
Reactant: CC(C)S
Reactant: O=C(O)CS
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)SSCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 11 g (50 mmol) of 2-,2′-dipyridyl disulfide and 8.4 mL (60 mmol) of triethyl amine in 100 mL of tetrahydrofuran at 0° C. as added 2.8 mL (40 mmol) of mercaptoacetic acid in 5 mL of tetrahydrofuran. The ice bath was removed and after one hour 6.0 mL (65 mmol) isopropyl thiol was added. The reaction was allowed to stir overnight at ambient temperature before diluting with ether and washing three times with 1N aqueous HCl. The product was then extracted into 10% aqueous NaOH. The aqueous phase was washed twice with ether and then acidified with HCl to pH ˜3.5. The product was extracted with ether, dried with Na2SO4, filtered and evaporated under reduced pressure to give a crude product. This material was distilled by Kugelrohr distillation to give 3.5 g (21 mmol, 42%) of partially purified product. This material was used in the next step without further purification.
Reaction SMILES: [NH2:1][C@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([F:18])[CH:10]=2)=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]>>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][C@H:2]([CH3:19])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:10]=[C:11]([F:18])[C:12]([C:13]#[N:14])=[C:15]([F:17])[CH:16]=3)=[N:5]2)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: C[C@@H](N)Cn1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Product: CC(=O)c1cc(C(=O)N[C@H](C)Cn2ccc(-c3cc(F)c(C#N)c(F)c3)n2)[nH]n1

Procedure:
The title compound was prepared from (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (733 mg, 2.79 mmol) and 3-acetyl-1H-pyrazole-5-carboxylic acid (431 mg, 2.79 mmol) using the method of Example 34(d). Yield 121 mg. 1H NMR (400 MHz; d6-DMSO): δ 1.49 (d, 3H), 2.48 (s, 3H), 3.63 (m, 2H), 4.67 (m, 1H), 6.98 (d, 1H), 7.25 (bs, 1H), 7.76 (m, 2H), 7.89 (d, 1H), 14.16 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][C:11]([F:33])([F:32])[C@:12]([C@@H:15]2[CH2:17][C@H:16]2[C:18](=[O:31])[NH:19][C:20]2[C:24]3=[N:25][CH:26]=[C:27]([C:29]#[N:30])[CH:28]=[C:23]3[S:22][CH:21]=2)([CH3:14])[N:13]=1)(C)(C)C.FC(F)(F)C(O)=O>>[C:29]([C:27]1[CH:28]=[C:23]2[S:22][CH:21]=[C:20]([NH:19][C:18]([C@@H:16]3[CH2:17][C@H:15]3[C@:12]3([CH3:14])[C:11]([F:33])([F:32])[CH2:10][O:9][C:8]([NH2:7])=[N:13]3)=[O:31])[C:24]2=[N:25][CH:26]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)([C@@H]2C[C@H]2C(=O)Nc2csc3cc(C#N)cnc23)C(F)(F)CO1
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1([C@@H]2C[C@H]2C(=O)Nc2csc3cc(C#N)cnc23)N=C(N)OCC1(F)F
Yield: 59 %

Procedure:
In a manner analogous to that described in Example 62.1b), the deprotection of {(R)-4-[(1R,2R)-2-(6-Cyano-thieno[3,2-b]pyridin-3-ylcarbamoyl)-cyclopropyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-carbamic acid tert-butyl ester with trifluoroacetic acid yielded the title compound (59% yield) as a light yellow solid. MS (ISP): m/z=392.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=S)=[CH:26][CH:25]=1.CI.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:10][C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)[C:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][C:22]([F:21])([F:33])[F:34])=[CH:25][CH:26]=3)=[N:1][C:2]=2[CH:7]=1
Reactant: FC(F)(F)Oc1ccc(N=C=S)cc1
Reactant: COC(=O)c1ccc(CNc2ccc(Cl)cc2N)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Cn2c(Nc3ccc(OC(F)(F)F)cc3)nc3cc(Cl)ccc32)cc1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
The title compound of Example 12, Step B (0.5 mmol, 145 mg) and 4-trifluoromethoxyphenyl isothiocyanate (0.5 mmol, 81 μL) were heated in DCM (1 mL) for 1 h, then allowed to stand at ambient temperature for 16 h. MeI (1.0 mmol, 62 μL), DIEA (1.0 mmol, 174 μL) and DMF (0.5 mL) were added and the solution was heated at 40° C. for 2 h. The reaction mixture was partitioned between EtOAc/brine and the organic phase was dried with Na2SO4 and concentrated in vacuo. Flash chromatography on silica eluting with 18% EtOAc in hexanes afforded the product as a beige solid. LC-MS (ESI, Method C): 3.85 min, m/z 476.1 (M+1).
Reaction SMILES: C([O-])(=O)C.[Na+].[N-:6]=[N+:7]=[N-:8].[Na+].CN(C=O)C.[C:15]([O:19][C:20]([NH:22][C@@H:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:25][C@H:24]1OS(C)(=O)=O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O>[N:6]([C@H:28]1[C@@H:23]([NH:22][C:20]([O:19][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:21])[CH2:24][CH2:25][N:26]([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])[CH2:27]1)=[N+:7]=[N-:8]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Temperature: 80 °C
Reaction time: 4 h
Yield: 26.6 %

Procedure:
Sodium acetate (204 mg) and sodium azide (161 mg) were added to a DMF (5 mL) solution containing (trans)-benzyl 4-((tert-butoxycarbonyl)amino)-3-((methylsulfonyl)oxy)piperidin-1-carboxylate (532 mg), followed by stirring at 80° C. for 4 hours. The pH of the reaction solution was adjusted to pH 12 with the addition of water and a 2M sodium hydroxide aqueous solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 2:1), and a white solid of (cis)-benzyl 3-azido-4-((tert-butoxycarbonyl)amino)piperidin-1-carboxylate (124 mg) was thus obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:33])=[CH:4][C:5]2[C:6]3[CH2:23][CH2:22][C:21]([C:29]([F:32])([F:31])[F:30])([O:24][Si](C)(C)C)[C:7]=3[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:9]=2[CH:10]=1.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[C:3]([Cl:33])=[CH:4][C:5]2[C:6]3[CH2:23][CH2:22][C:21]([C:29]([F:31])([F:30])[F:32])([OH:24])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCC3(O[Si](C)(C)C)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCc2c1[nH]c1cc(Cl)c(Cl)cc21
Yield: 50.6 %

Procedure:
6,7-Dichloro-4-tosyl-3-(trifluoromethyl)-3-(trimethylsilyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indole (0.2 g, 0.37 mmol) was dissolved in THF (10 mL) and KOH (104 mg, 1.8 mmol), in H2O (10 mL), was added and the resulting mixture was refluxed for 18 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude compound which was purified by column chromatography [EtOAc-hexane (3:17) as eluant] to afford the title compound (58 mg, 52%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.05 (bs, 1H), 7.62 (s, 1H), 7.49 (s, 1H), 3.12-3.07 (m, 1H), 3.04-2.99 (m, 1H), 2.91-2.86 (m, 1H), 2.57-2.55 (m, 1H), 2.51 (s, 1H).
Reaction SMILES: C1C=CN2CC3C=C(C(OCC)=O)C=CC=3NCC=12.[N+:20]([C:23]1[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:34]=[CH:33][C:24]=1[CH2:25][N:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]=O)([O-])=O>>[CH:28]1[CH:29]=[CH:30][N:26]2[CH2:25][C:24]3[CH:33]=[CH:34][C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:36][C:23]=3[NH:20][CH2:31][C:27]=12
Reactant: CCOC(=O)c1ccc(Cn2cccc2C=O)c([N+](=O)[O-])c1
Agent: CCOC(=O)c1ccc2c(c1)Cn1cccc1CN2
Product: CCOC(=O)c1ccc2c(c1)NCc1cccn1C2

Procedure:
The hydrogenation conditions of ethyl 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine-7-carboxylate are used with 1-[2-nitro-4-(ethoxycarbonyl)-benzyl]-pyrrole-2-carboxaldehyde to give 5.0 g of the desired product as a solid; mass spectrum (M+H)255.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[N+:9]([C:12]1[O:16][C:15]([C:17]2[C:21]([CH:22]=O)=[CH:20][N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:18]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10].O>CN(C)C=O>[N+:9]([C:12]1[O:16][C:15]([C:17]2[C:21]([CH:22]=[N:7][OH:8])=[CH:20][N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:18]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: O=Cc1cn(-c2ccccn2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2nn(-c3ccccn3)cc2C=NO)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
Add 1.18 g of anhydrous sodium acetate and 1.0 g of hydroxylamine hydrochloride to 3.9 g of 3-(5-nitro-2-furyl)-1-(2-pyridyl)pyrazole-4-carboxaldehyde in 12 ml of dimethylformamide, whereupon the temperature of the formed mixture rises slightly. Stir the resulting mixture at room temperature for 4 hours before pouring onto ice and water to obtain a 99% yield of 3-(5-nitro-2-furyl)-1-(2-pyridyl)pyrazole-4-carboxaldehydeoxime [m.p. 234.5° to 235° C].
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[C:5]([C:4]1[C:3]([CH3:11])=[C:2]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)[CH:10]=[CH:9][CH:8]=1)(=[O:6])[NH2:7]
Reactant: Cc1c(Br)cccc1C(N)=O
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(C(N)=O)cccc1-c1ccc2cc(NC(=O)c3ccsc3)ccc2c1
Temperature: 25 °C
Yield: 29.2 %

Procedure:
3-bromo-2-methylbenzamide (12.5 mg, 0.0584 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (45.8 mg, 0.121 mmol), Fibercat palladium catalyst (Johnson-Matthey, 31.9 mg), and K2CO3 (2 M in water, 0.15 ml, 0.30 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (0.7 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C for 10 minutes and then cooled to room temperature. The reaction was diluted with water (5 ml) and extracted with dichloromethane (3×10 ml) and EtOAc (10 ml). The organic extracts were combined, dried over magnesium sulfate, filtered, concentrated, and purified on HPLC (10%->95% MeCN/water with 0.1% TFA) to afford title compound (6.6 mg, 29%). MS (ESI pos. ion) m/z: 387 (M+H). Calc'd Exact Mass for C23H18N2O2S: 386.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[NH:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)=[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[CH:25][CH:24]=[CH:23]4)[N:19]=2)=[CH:10][C:3]=1[O:4][CH2:5][C:6](OC)=[O:7].[NH4+:37].[OH-]>O>[F:1][C:2]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[NH:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)=[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[CH:25][CH:24]=[CH:23]4)[N:19]=2)=[CH:10][C:3]=1[O:4][CH2:5][C:6]([NH2:37])=[O:7]
Reactant: [NH4+]
Reactant: COC(=O)COc1cc(Cc2nc(-c3ccc4ncccc4c3)c(-c3cccc(C)n3)[nH]2)ccc1F
Agent: [OH-]
Solvent: O
Product: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(OCC(N)=O)c3)nc2-c2ccc3ncccc3c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Methyl 2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetate (Example 93) (32.5 mg, 0.067 mmol) was treated with aqueous NH4OH (28-30%, 1 mL). The suspension was stirred at room temperature. After 2 hours, the reaction mixture was diluted with H2O (3 mL) and stirred for 30 min. The precipitate was filtered, washed with water, and dried under vacuum for overnight to afford the title compound (26.8 mg, 86%). (300 MHz, CDCl3) δ 2.49 (3H, s), 4.15 (2H, s), 4.51 (2H, s), 5.80 (N—H, 1H, bs), 6.71 (N—H, 1H, bs), 6.63-7.06 (4H, m), 7.25-7.28 (1H, m), 7.37-7.44 (2H, m), 7.94 (1H, dd), 8.10 (1H, d), 8.16-8.18 (2H, m), 8.91 (1H, dd), 11.00 (1H, bs). MS (ESI) m/z 468 (MH+).
Reaction SMILES: [C:1]([C:4]([C:14](=[O:16])[CH3:15])=[CH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)(=O)[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][NH:21][C:20](=[O:24])[CH:19]=1>C(O)(C)C>[C:14]([C:4]1[CH:5]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[C:19]2[C:20](=[O:24])[NH:21][CH:22]=[CH:23][C:18]=2[NH:17][C:1]=1[CH3:2])(=[O:16])[CH3:15]
Reactant: Nc1cc[nH]c(=O)c1
Reactant: CC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O
Solvent: CC(C)O
Product: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc(C#N)cc1

Procedure:
1.5 g (7.04 mmol) of 4-(2-acetyl-3-oxobut-1-en-1-yl)benzonitrile are mixed with 0.77 g (7.04 mmol) of 4-aminopyridin-2(1H)-one [Searls, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)], dissolved in 40 ml of isopropanol and heated under reflux under argon for 4 days. The mixture is then concentrated and the residue is recrystallized from methanol. 0.67 g (31% of theory) of the title compound is obtained as a pale yellow solid.
Reaction SMILES: [C:1]([C:6]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:8]([CH:18]=[O:19])[C:9]([CH:15]([CH3:17])[CH3:16])=[N:10][C:11]=1[CH:12]([CH3:14])[CH3:13])([O:3]CC)=O.[C:27]1([Li])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)(=O)C.CCCCCC>[CH:15]([C:9]1[C:8]([CH2:18][OH:19])=[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:6]([CH:1]([OH:3])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:11]([CH:12]([CH3:13])[CH3:14])[N:10]=1)([CH3:17])[CH3:16]
Reactant: [Li]c1ccccc1
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)c1nc(C(C)C)c(C(O)c2ccccc2)c(-c2ccc(F)cc2)c1CO

Procedure:
The title compound was prepared from 5-carboethoxy-2,6-diisopropyl-4-(4-fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and phenyllithium, according to the procedures described in Example 93. 1H NMR (300 MHz, CDCl3): δ 7.23 (m, 7 H), 7.06 (m, 2 H), 5.71 (d, J=5.14 Hz, 1 H), 4.38 (d, J=5.5 Hz, 2 H), 3.47 (septet, J=6.6 Hz, 1 H), 3.12 (septet, J=6.6 Hz, 1 H), 2.12 (d, J=5.1 Hz, 1 H), 1.57 (s, 1H), 1.29 (m, 10 H), 0.797 (d, J=6.6 Hz, 3 H). FAB-MS: calcd for (C25H28NFO2) 393, found 394 (M+H). Anal. Calcd for C25H28NO2F: C, 76.84; H, 8.69; N, 3.90. Found: C, 76.67; H, 8.76; N, 3.77. mp 202-204° C. Rf=0.2 (20% ethyl acetate/hexane).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[N:7]=1)=[O:5])[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([CH:30]([CH3:32])[CH3:31])[CH:29]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:25]3[CH:26]=[N:27][N:28]([CH:30]([CH3:32])[CH3:31])[CH:29]=3)[C:14]=2[CH3:23])[N:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)n1cc(Br)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)n1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(C(C)C)c3)c3cc(Cl)ccc23)n1

Procedure:
Prepared according to the procedure described in Example 9, Step 4, using the following starting materials: 6-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-pyridine-2-carboxylic acid ethyl ester and 4-bromo-1-isopropyl-1H-pyrazole.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.O.[F-].[K+]>C1(C)C=CC=CC=1.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>[CH3:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=[C:7]([CH3:8])[C:2]=1[C:18]1[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Br
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1-c1ccc(C(F)(F)F)cc1
Yield: 43.4 %

Procedure:
To a solution of 2-bromo-1,3-dimethyl-5-nitrobenzene (2.7 g, 11.7 mmol) in toluene (36 mL) was added tetrakis(triphenylphosphine)palladium(0) (1.36 g, 1.17 mmol), 4-(trifluoromethyl)phenylboronic acid (4.46 g, 23.5 mmol), and potassium fluoride hydrate (3.31 g, 43 mmol). The reaction was purged with nitrogen three times. Water (9 mL) was added and the reaction was refluxed overnight. The reaction was diluted with saturated ammonium chloride and the layers were separated. The organic layer was washed with water (3×40 mL) and brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave 2,6-dimethyl-4-nitro-4′-(trifluoromethyl)biphenyl (1.5 g, 43%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 7.99 (s, 2H), 7.75 (d, 2H), 7.26 (s, 1H), 7.25 (s, 1H), 2.10 (s, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.CN(C=O)C.S(Cl)(Cl)=O.[C:22](O)([CH3:25])([CH3:24])[CH3:23]>C1COCC1.O>[C:22]([O:11][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:12])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.00 g (6.21 mmol) indole-3-carboxylic acid is dissolved in 150 ml absolute THF, mixed with 0.05 g (0.68 mmol) absolute DMF as well as with 1.48 g (12.5 mmol) thionylchloride and stirred at room temperature for 1 hour. Following the drop-wise addition of 2.51 g (24.8 mmol) tiethylamine and of 9.20 g (124 mmol) tert-butanol and heating under reflux for 2 hours, hydrolysis of the cooled reaction mixture is carried out in water. Three extractions with diethyl ether, concentration to half the volume on the rotary evaporator, washing with 5% sodium carbonate solution and with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a brown oil which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 90:10) and yields the product as a yellow oil.
Reaction SMILES: FC1(F)CC1CN1CCN(C2SC(C(OCC)=O)=C(C)N=2)C1=O.[F:24][C:25]1[CH:48]=[CH:47][C:28]([CH2:29][N:30]2[CH2:34][CH2:33][N:32]([C:35]3[S:36][C:37]([C:41]([O:43]CC)=[O:42])=[C:38]([CH3:40])[N:39]=3)[C:31]2=[O:46])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:30]2[CH2:34][CH2:33][N:32]([C:35]3[S:36][C:37]([C:41]([OH:43])=[O:42])=[C:38]([CH3:40])[N:39]=3)[C:31]2=[O:46])=[CH:47][CH:48]=1
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(CC3CC3(F)F)C2=O)nc1C
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Yield: 97 %

Procedure:
Following the procedure as described in Preparation 14, making variations as required to replace ethyl 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate with ethyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 97% yield: 1H NMR (300 MHz, DMSO-d6) δ 7.84-7.07 (m, 4H), 4.32 (s, 2H), 3.93 (t, J=8.1 Hz, 2H), 3.22 (t, J=8.1 Hz, 2H), 2.46 (s, 3H); MS (ES+) m/z 336.2 (M+1).
Reaction SMILES: F[C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=C2\NC3C=CC(CO)=CC=3N\2[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.Cl.N1CC(C(O)(C)C)C1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[C:6]([NH2:8])(=[O:7])[C:5]1[CH:32]=[CH:33][CH:2]=[CH:3][CH:4]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Agent: CC(C)(O)C1CNC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a 0° C. cooled solution of (E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (100 mg, 0.221 mmol) in DCM (5 mL) was added thionyl chloride (0.081 mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30 minutes. The solvent was removed on a rotovap, and the residue suspended in ACN (2 mL) and re-concentrated to remove residual thionyl chloride. The residue was resuspended in DMF (2 mL), cooled to 0° C., and 2-(azetidin-3-yl)propan-2-ol hydrochloride (101 mg, 0.663 mmol) and DBU (0.10 mL, 0.663 mmol) were added. After stirring for 16 hours at RT, the reaction mixture was concentrated and purified by reverse-phase preparative HPLC, using 0.1% TFA in ACN/water, (gradient 15% to 90%). The product fractions were combined, neutralized with saturated aqueous NaHCO3, and extracted with EtOAc (×2). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to provide (E)-4-fluoro-N-(6-((3-(2-hydroxypropan-2-34)azetidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene) as a white powder benzamide (26 mg, 21.4% yield). MS, m/z (C31H40FN5O3): calcd, 549.3. found, 549.9 [M+H].
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18]CC=C)=[CH:17][C:12]=3[O:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:23]1[CH:28]=CC=C[C:24]=1Cl>>[C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([OH:18])=[C:17]([CH2:28][CH:23]=[CH2:24])[C:12]=3[O:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CCOc1ccc2c(CCc3ccccc3)coc2c1
Reactant: Clc1ccccc1Cl
Product: C=CCc1c(O)ccc2c(CCc3ccccc3)coc12
Temperature: 50 °C

Procedure:
The product from Step D (1.245 grams), dissolved in 1,2-dichlorobenzene (20 mL) was refluxed under nitrogen for 11 hours. The solution was cooled to approx. 50° C. High vacuum was applied and the solvent removed until the residue solidified. The solid was dissolved in CH2Cl2 (100 mL), recovered, re-evaporated and chromatographed over silica gel (5:1 hex/ethyl acetate). Evaporation of the appropriate fractions gave the title compound as a pale yellow solid.