Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([N:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]3)[CH2:9]2)=[CH:4][C:3]=1[O:23][CH3:24].CS([C:28]1[N:33]=[CH:32][C:31]2=[CH:34][CH:35]=[C:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])[N:30]2[N:29]=1)=O.C(N(CC)C(C)C)(C)C>COCCO.CO>[CH3:24][O:23][C:3]1[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([N:14]3[CH2:15][CH2:16][N:17]([C:20](=[O:22])[CH3:21])[CH2:18][CH2:19]3)[CH2:9]2)[CH:6]=[CH:7][C:2]=1[NH:1][C:28]1[N:33]=[CH:32][C:31]2=[CH:34][CH:35]=[C:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])[N:30]2[N:29]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: COc1cc(N2CCCC(N3CCN(C(C)=O)CC3)C2)ccc1N
Solvent: COCCO
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCCC(N3CCN(C(C)=O)CC3)C2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Yield: 38.2 %

Procedure:
A mixture of 1-{4-[1-(4-amino-3-methoxy-phenyl)-piperidin-3-yl]-piperazin-1-yl}-ethanone (80 mg, 0.24 mmol) and 2-methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (46 mg, 0.16 mmol) in 2-methoxyethanol (0.50 mL) and treated with N,N-Diisopropylethylamine (56 μL, 0.32 mmol). The reaction was microwaved on 300 watts, 200 C for 9.5 hours. The sample was diluted with methanol (10 mL), filtered and concentrated. The crude product was purified by RF-HPLC to afford 34 mg of the title compound as an amber powder after lyophyllization. MS=556 (M-TFA+1); NMR (DMSO-d6, ppm): 9.83 (br, 1H), 8.91 (s, 1H), 7.86 (m, 2H), 7.56 (s, 1H), 7.45 (t, J=7 Hz, 1H), 7.20 (d, J=7 Hz, 1H), 7.10 (t, J=7 Hz, 1H), 6.95 (q, J=5 Hz, 14 Hz, 2H), 6.69 (s, 1H), 6.46 (d, J=7 Hz, 1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.50 (m, 4H), 2.91 (t, J=12 Hz, 2H), 2.70 (t, J=10 Hz, 2H), 2.33 (m, 1H), 2.13 (m, 2H), 2.07 (s, 3H), 1.89 (m, 1H), 1.64 (t, J=10 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17](=[O:19])C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl.C(OCC)(=[O:27])C>O1CCCC1.O>[CH2:1]([O:8][C:9]([NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17]([OH:19])=[O:27])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C1CCCCC1NC(=O)OCc1ccccc1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
The ester of step 1 (26.45 g, 86.62 mmol) was dissolved in 250 mL of tetrahydrofuran and treated with a solution of lithium hydroxide monohydrate (10.65 g, 256 mmol) in 250 mL of water and stirred at ambient temperature for 24 h. The reaction mixture was cooled to 0° C. and neutralized with 300 mL of a 1N HCl solution. Ethyl acetate (400 mL) was added and the organic layer was separated, dried over sodium sulfate, filtered and concentrated to give a crude solid. The product was purified by recrystallizing from ethyl acetate/hexanes to give 19.60 g of a white solid. Yield: 82%, MS: 278 (M+H+), mp=120.1-123.1° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH2:5])[CH3:2].[CH3:10][C:11]([CH3:16])=[CH:12][C:13](Cl)=[O:14]>CCCCCC>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH:5][C:13](=[O:14])[CH:12]=[C:11]([CH3:16])[CH3:10])[CH3:2]
Reactant: CC(C)=CC(=O)Cl
Reactant: CCCCC(CC)CN
Solvent: CCCCCC
Product: CCCCC(CC)CNC(=O)C=C(C)C
Yield: 83.3 %

Procedure:
In 20 ml of n-hexane was dissolved 1.40 g (0.011 mol) of 2-ethylhexylamine. With stirring, 1.20 g (0.01 mol) of β-methylcrotonyl chloride was added to the solution. After reaction, the reaction mixture was washed first with diluted hydrochloric acid and then with 10% sodium hydroxide solution and subsequently dried with sodium sulfate. The solvent was distilled off and the residue was further distilled in vacuum. A fraction having a boiling point of 133°-134° C./l mmHg was collected, obtaining 1.76 g of N-(2-ethylhexyl)-β-methylcrotonamide as an oil (yield: 82.3%). Usual analysis was carried out to identify the compound. The results are shown below.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17](=O)CC>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC=O
Reactant: CCNC1CCN(C(=O)OC(C)(C)C)CC1
Product: CCCNC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was synthesized by the method, described for 4-Ethylamino-piperidine-1-carboxylic acid tert-butyl ester (16), using propionaldehyde instead of acetaldehyde. Rt=1.43 min (Method B). Detected mass: 243.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH3:19])[C:3]([NH:5][C@@H:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7]1=[O:18])=[O:4].[CH2:21]([O:28][C:29](ON1C(=O)CCC1=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH2:21]([O:28][C:29]([NH:1][C:2]([CH3:20])([CH3:19])[C:3]([NH:5][C@@H:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7]1=[O:18])=[O:4])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(N)C(=O)N[C@@H]1CCc2cc(F)ccc2NC1=O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2cc(F)ccc2NC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.4 %

Procedure:
To a solution of 33 mg (0.12 mmol) of 2-amino-2-methyl- N-[7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]propanamide (Step D) in 1 mL of methylene chloride was 32 mg (0.13 mmol) of N-(benzyloxycarbonyloxy)succinimide. The solution was stirred at room temperature for 24 hours then quenched with 5 drops of 33% aqueous ammonium hydroxide. The solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel eluting with ethyl acetateexanes (75:25) to afford 25 mg (46%) of the product as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 1.48 (s, 3H), 1.50 (s, 3H), 1.82 (m, 1H), 2.56 (m, 1H), 2.71 (m, 1H), 2.86 (m, 1H), 4.42 (m, 1H), 5.05 (s, 2H), 5.43 (s, 1H), 6.90 (m, 2H), 7.09 (d, 8 Hz, 1H), 7.30 (m, 5H), 8.09 (s, 1H). FAB-MS: calculated for C22H24 FN3O4 413; found 414 (M+H, 100%).
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([OH:20])(=O)[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[NH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:37])([C:33]([F:36])([F:35])[F:34])[C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:23]=1[OH:38]>N1C=CC=CC=1>[OH:38][C:23]1[CH:24]=[CH:25][C:26]([C:28]([F:37])([C:29]([F:30])([F:31])[F:32])[C:33]([F:34])([F:35])[F:36])=[CH:27][C:22]=1[NH:21][C:12](=[O:20])[C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1O)c1ccncc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 76.4 %

Procedure:
To a mixture of 0.58 g of WSC and 5 ml of pyridine, 0.37 g of isonicotinic acid was added. The reaction mixture was stirred at room temperature for 25 minutes. To the reaction mixture, 0.75 g of 2-amino-4-(heptafluoroisopropyl)phenol was added and was stirred while heating at 60° C. for three hours. The mixture was cooled to room temperature, and then concentrated under reduced pressure. Then, water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.79 g of N-[2-hydroxy-5-(heptafluoroisopropyl)phenyl]isonicotinamide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:15]Br>C(O)(=O)C.[N+]([O-])([O-])=O.[Ag+]>[CH3:12][C:11]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[CH:9][C:8]=1[Br:15])([CH3:14])[CH3:13]
Reactant: BrBr
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(Br)c(C(C)(C)C)c1
Yield: 99.9 %

Procedure:
To a solution of 5.00 g (26.3 mmoles) of 1,3-di-t-butylbenzene in 15 ml of acetic acid was added 4.47 g (26.3 mmoles) of silver nitrate. The mixture was stirred in an oil bath at 75°-80° and then bromine (4.21 g, 26.3 mmoles) was added in small portions over 2 hours. After the addition was complete, the reaction mixture was stirred for a further 45 minutes. After cooling, the precipitated silver bromide was filtered off and washed with acetic acid. The combined filtrates were partitioned between dichloromethane and water and the aqueous layer was further extracted with dichloromethane. The combined organic extracts were washed with aqueous sodium bisulfite, dried over sodium sulfate, filtered, and evaporated. Acetic acid was then removed by azeotropic distillation with heptane. Distillation of the residue under reduced pressure gave 7.07 g of the title compound, b.p. 82°-84° C. (1 mm). The structural assignment was supported by 1H NMR and 13C NMR.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][NH:14][CH3:15].C(=O)(O)[O-].[Na+].CO>C(O)(=O)C>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][N:14]([CH3:15])[CH3:13])=[CH:5]1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)CCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 250 mg of 3-(2-bromoethyl)indole in a round-bottomed flask, a 10 M excess of dimethylamine (6 mL of 2M in MeOH) was added and the solution was stirred at r.t. overnight. After adding 5 mL sodium bicarbonate (2%), the reaction mixture was extracted with chloroform (3×5 ml) and back extracted with H2O (1×5 mL). The combined extracts were dried over MgSO4 and evaporation of the solvent gave the product in crystalline form. Yield: 0.21 g, 84%, yellowish crystals. m.p.: 45-47° C.; TLC (EtAc:MeOH:acetic acid, 8:2:0.5 v/v/v): RF=0.33. 1H NMR, δ: 10.43 (s, 1H), 7.42-7.06 (m, 5H), 2.68 (m, 4H), 2.26 (S, 6H). 13C NMR (CDCl3): δ 136.5, 124.3, 123.2, 121.2, 119.7, 117.6, 113.4, 111.1, 61.7, 41.2, 22.4. Anal. calcd for C12H16N2: C, 76.55; H, 8.57; N, 14.88%. Found; C, 76.60; H, 8.70; N, 14.70%.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([CH:24]=O)=[N:22][CH:23]=1)([O-:17])=[O:16].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:24][C:21]2[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:23][N:22]=2)[CH2:29][CH2:28]1
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc([N+](=O)[O-])cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.2 %

Procedure:
Sodium triacetoxyborohydride (1.4 g, 6.6 mmol, 2 equiv) was added portionwise to a cold (5° C.) solution of 5-nitro-pyridine-2-carbaldehyde (Step 39.3) (0.5 g, 3.3 mmol) and N-methyl-piperazine (0.4 mL, 3.6 mmol, 1.1 equiv) in DCM (10 mL). The reaction mixture was allowed to warm to rt, stirred for 16 h, diluted with DCM and saturated solution of NaHCO3, and extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 91:8:1) to provide 0.532 g of the title compound as a yellow solid: ESI-MS: 237.2 [M+H]+; TLC: Rf=0.31 (DCM/MeOH/NH3aq, 91:8:1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]3[CH:52]=[CH:51][C:16]([CH2:17][N:18]([CH2:43][C:44]([O:46]C(C)(C)C)=[O:45])[C:19](=[O:42])[C:20]4[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:41])[CH2:28][C:29]5[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=5[C:37]([F:40])([F:39])[F:38])=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.[C:53](O)([C:55](F)(F)F)=O>C(Cl)Cl>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([C:19]([N:18]([CH2:43][C:44]([OH:46])=[O:45])[CH2:17][C:16]3[CH:15]=[CH:14][C:13]([C:11]4[N:12]=[C:8]([C:5]5[CH:6]=[CH:7][C:2]([C:2]6[CH:7]=[CH:6][C:53]([CH3:55])=[CH:4][CH:3]=6)=[CH:3][CH:4]=5)[O:9][CH:10]=4)=[CH:52][CH:51]=3)=[O:42])=[CH:21][CH:22]=2)=[O:41])=[C:30]([C:37]([F:38])([F:40])[F:39])[CH:31]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(-c4coc(-c5ccc(Br)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4coc(-c5ccc(-c6ccc(C)cc6)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a stirring solution of tert-butyl 2-(N-(4-(2-(4-bromophenyl)oxazol-4-yl)benzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-45 (118 mg, 0.152 mmol) in THF (1 mL) and acetonitrile (1 mL) were added sodium carbonate (0.30 mL, 0.30 mmol, 1 M aqueous solution) and p-tolylboronic acid (25.0 mg, 0.18 mmol). The reaction mixture was de-gassed and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (5.50 mg, 7.60 μmol) was added. The reaction mixture was heated in a microwave at 130° C. for 30 min. The reaction mixture was diluted with DCM (4 mL) and NaHCO3 (10 mL), stirred for 15 min and split through a hydrophobic frit. The organics were evaporated and purified by column chromatography (EA/isohexanes) to yield tert-butyl 2-(N-(4-(2-(4-bromophenyl)oxazol-4-yl)benzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate. To tert-butyl 2-(N-(4-(2-(4-bromophenyl)oxazol-4-yl)benzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate in DCM (2 mL) was added TFA (2 mL) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was evaporated and re-slurried from acetonitrile (4 mL) to afford 59 mg (53%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(2-(4′-methyl-[1,1′-biphenyl]-4-yl)oxazol-4-yl)benzyl)benzamido)acetic acid 364 as a white solid. LCMS-ESI (m/z) calculated for C42H34F3N3O6: 733; found 734 [M+H]+, tR=9.36 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.76 (s, 1H), 10.34 (s, 1H), 8.75 (s, 1H), 8.13 (d, J=6.7 Hz, 2H), 7.90-7.85 (m, 4H), 7.70-7.59 (m, 4H), 7.50-7.42 (m, 2H), 7.41-7.31 (m, 5H), 7.25-7.16 (m, 2H), 4.70 (s, 1H), 4.62 (s, 1H), 4.02 (s, 1H), 3.92 (s, 1H), 3.86 (s, 2H), 3.83 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: O=[C:2]1[CH2:17][NH:16][CH2:15][CH2:14][N:13]([CH2:18][CH2:19][OH:20])[CH2:12][C:11](=O)[NH:10][CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.B.C1COCC1.O>O1CCCC1>[OH:20][CH2:19][CH2:18][N:13]1[CH2:12][CH2:11][NH:10][CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3][CH2:2][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: O=C1CNCCN(CCO)CC(=O)NC2CCCCC2N1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: OCCN1CCNCCNC2CCCCC2NCC1

Procedure:
Into a dry flask under nitrogen was placed 3.00 g. (10 mmol.) of compound (A) and 100 ml. of a 1M solution of BH3.THF in anhydrous tetrahydrofuran. The reaction mixture was refluxed for 12 hours. Water was added dropwise until no reaction was taking place with the excess of BH3.THF. The solvent was stripped off on a rotary evaporator after addition of a few ml. of methanol to avoid excessive foaming. The solid residue was treated with about 10 ml. of a concentrated solution of LiOF.H2O until the pH reached 12-13. This aqueous phase was extracted 6 times with 100 ml. of methylene chloride. The extracts were collected and dried over magnesium sulfate. The solvent was removed under vacuum to yield 2.62 g. of Compound (B) as a white powder that was used in the next step without further purification.
Reaction SMILES: CN1CCCC1=O.[F:8][C:9]1[C:10]([NH:17][CH3:18])=[N:11][C:12](F)=[C:13]([F:15])[CH:14]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[CH2:19]([NH:26][C:12]1[C:13]([F:15])=[CH:14][C:9]([F:8])=[C:10]([NH:17][CH3:18])[N:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CNc1nc(F)c(F)cc1F
Reactant: NCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Product: CNc1nc(NCc2ccccc2)c(F)cc1F
Temperature: 140 °C
Reaction time: 19 h

Procedure:
To 20 ml of N-methylpyrrolidone were added all amount of the above-described 3,5,6-trifluoro-2-(methylamino)-pyridine together with 10 g of benzylamine, and the mixture was stirred at 140° C. for 19 hours and allowed to cool. To the solution was added 50 ml of chloroform and the mixture was washed six times with 200 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound as a crude oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.Cl.[OH:21][NH2:22].CCN(CC)CC>CCO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:22][OH:21])=[NH:19])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: NO
Reactant: N#Cc1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: N=C(NO)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 80 °C

Procedure:
To a 25 ml rbf was added 0.100 g (0.347 mmol) of 2-(2,6-Dichloro-phenyl)-3H-benzoimidazole-5-carbonitrile, 2 mL of EtOH, 0.0482 g (0.694 mmol) of hydroxyl amine HCl, and 0.048 mL (0.694 mmol) of Et3N. It was allowed stir at 80° C., under reflux, for 4 h. It was reduced in vacuo and the crude was used directly in the next reaction. MS (m/z) 321.1 M (+1), tR=0.93, Meth 10
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[Br-:24].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Br:24][CH2:20][C:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:14]=1)=[O:21]
Reactant: [Br-]
Reactant: CC(=O)c1cccc(OCCCOCc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CBr)c1cccc(OCCCOCc2ccccc2)c1

Procedure:
To a solution of 1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanone (10.59 g) in tetrahydrofuran (50 mL) was added methanol (50 mL) and a solution of tetrabutylammonium tribromide (16 g) in tetrahydrofuran (50 mL). The reaction was stirred at ambient temperature for 45 min at which time tetrabutylammonium tribromide (0.89 g) was added, followed by further addition of 0.6 g. 10% aqueous sodium thiosulfate was added to the reaction and the mixture was concentrated in vacuo to a minimum volume. Ethyl acetate was added and the resultant organic solution was washed with aqueous sodium thiosulfate, saturated sodium bicarbonate and brine and concentrated to an oil to afford the title compound.
Reaction SMILES: FC(F)(F)C(NC1N=C2C=CC(C(=O)C3C=CC=CC=3)=CN2C=1C1C(F)=C(F)C(F)=C(F)C=1F)=O.FC(F)(F)C([NH:40][C:41]1[N:42]=[C:43]2[CH:48]=[CH:47][C:46]([C:49](=[O:56])[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:45][N:44]2[C:57]=1[C:58]1[C:63]([C:64]([F:67])([F:66])[F:65])=[CH:62][CH:61]=[CH:60][C:59]=1[F:68])=O>CC(=O)OCC>[NH2:40][C:41]1[N:42]=[C:43]2[CH:48]=[CH:47][C:46]([C:49](=[O:56])[C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)=[CH:45][N:44]2[C:57]=1[C:58]1[C:63]([C:64]([F:66])([F:65])[F:67])=[CH:62][CH:61]=[CH:60][C:59]=1[F:68]
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3c(F)cccc3C(F)(F)F)n2c1
Agent: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3c(F)c(F)c(F)c(F)c3F)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1c(F)cccc1C(F)(F)F

Procedure:
The 2-trifluoroacetamido-3-(2-fluoro-6-trifluoromethylphenyl)-6-benzoyl-imidazo[1,2-a]pyridine 2-trifluoroacetamido-3-(2,3,4,5,6-pentafluorophenyl)-6-benzoyl-imidazo[1,2-a]pyridine (1.80 g, 3.64 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 1.28 g. (88.3%). EA, MS(FD).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl:19][C:20]1[C:21]([C:49]2[CH:50]=[C:51]3[C:55](=[CH:56][C:57]=2[F:58])[N:54]([CH2:59][CH2:60][OH:61])[CH:53]=[CH:52]3)=[CH:22][C:23]2[N:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:39])=[C:33]([CH:38]=3)[C:34]([O:36]C)=[O:35])[N:25](COCC[Si](C)(C)C)[C:24]=2[CH:48]=1>C1COCC1.CCOC(C)=O>[Cl:19][C:20]1[C:21]([C:49]2[CH:50]=[C:51]3[C:55](=[CH:56][C:57]=2[F:58])[N:54]([CH2:59][CH2:60][OH:61])[CH:53]=[CH:52]3)=[CH:22][C:23]2[N:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:39])=[C:33]([CH:38]=3)[C:34]([OH:36])=[O:35])[NH:25][C:24]=2[CH:48]=1
Reactant: COC(=O)c1cc(Oc2nc3cc(-c4cc5ccn(CCO)c5cc4F)c(Cl)cc3n2COCC[Si](C)(C)C)ccc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2nc3cc(-c4cc5ccn(CCO)c5cc4F)c(Cl)cc3[nH]2)cc1C(=O)O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
TBAF (1 M in THF) (2 mL, 2 mmol) was added to a solution of methyl 5-[(6-chloro-5-[6-fluoro-1-(2-hydroxyethyl)-1H-indol-5-yl]-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]-2-methylbenzoate in THF (2 mL). The reaction was heated at 80° C. for 3 h. Volatiles were removed and the residue was dissolved in MeOH (4 mL) and treated with 2.5 N aqueous NaOH (1.5 mL). The reaction was stirred at 45° C. for 1 h, then at rt overnight. Reaction mixture was diluted with EtOAc and washed with 1 M aqueous HCl and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. Chromatography over silica eluting with 8% MeOH/DCM afforded the title compound as a beige solid. 1H NMR (500 MHz, CD3OD): δ 7.86 (d, 1H), 7.48 (s, 1H), 7.44-7.37 (m, 3H), 7.33 (s, 1 H), 7.27 (d, 1H), 7.23 (d, 1H), 6.46 (d, 1H), 4.25 (t, 2H), 3.88 (t, 2H), 2.61 (s, 3H). LC-MS: m/e 480.2 (M+H)+ (1.79 min).
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([C:28]([NH2:30])=O)[CH2:24][CH:23]2[C:25](N)=O)=[CH:18][CH:17]=1.[H-].[OH-].[Na+]>C1C=CC=CC=1.O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]23[CH2:24][CH:23]2[CH2:25][NH:30][CH2:28]3)=[CH:20][CH:21]=1
Reactant: NC(=O)C1CC1(C(N)=O)c1ccc(Cl)cc1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Clc1ccc(C23CNCC2C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 30 ml of sodium bis(2-methoxyethoxy)aluminum hydride (70% benzene solution) is added dropwise a solution of 4.5 g of (+)-1-(p-chlorophenyl)-1,2-cyclopropanedicarboxamide in 400 ml of benzene during a 45 minute period with stirring at room temperature under nitrogen. The clear yellow solution is heated at reflux under nitrogen for 90 minutes and stored overnight at room temperature. The excess hydride reagent is decomposed by the cautious addition of 25 ml of 5 N sodium hydroxide. The mixture is diluted with 200 ml of water and the benzene phase is removed. The aqueous phase is extracted with chloroform. The combined benzene and chloroform phases are dried over magnesium sulfate and concentrated under reduced pressure to give (+)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane as a tacky yellow solid. This solid is dissolved in ethanol and acidified with 20 ml of 2.3 N ethanolic hydrogen chloride. A 200 ml volume of ether is added and crystals form. These are recrystallized from acetonitrile to give the hydrochloride as white crystals, m.p. 190°-192° C.; [α]DCH3OH =+63° C.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:20])[O:19][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:18])([CH3:17])[CH2:8]3.[N-:21]=[N+:22]=[N-:23].[Na+]>C(OCC)(=O)C.CCCCCC>[N:21]([CH2:2][C:3]1([CH3:20])[O:19][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:18])([CH3:17])[CH2:8]3)=[N+:22]=[N-:23]
Reactant: Cc1cc2c(c3c1NC(=O)C(C)(C)C3)OC(C)(CBr)C2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc2c(c3c1NC(=O)C(C)(C)C3)OC(C)(CN=[N+]=[N-])C2
Yield: 81.1 %

Procedure:
Using 2-bromomethyl-2,5,8,8-tetramethyl-2,3,6,7,8,9-hexahydrofuro[2,3-f]quinoline-7-one (1.28 g, 3.78 mmol) and sodium azide (1.96 g, 30.1 mmol), the procedure of Example 300 was followed (reaction, post-treatment, and recrystallization from ethyl acetate-hexane) to obtain 921 mg of the title compound as colorless needles (81%).