Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:13][CH2:14][OH:15])[C:10]([NH2:12])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[N:17]1C(=O)C2C(=CC=CC=2)C1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O.NN>C(Cl)Cl>[NH2:17][O:15][CH2:14][CH2:13][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:10]([NH2:12])=[O:11]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CCO)C(N)=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](CCON)C(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 21.2 %

Procedure:
To a solution of (S)-2-(tert-butyldimethylsilyloxy)-4-hydroxybutanamide (4.85 g, 20.8 mmol) in CH2Cl2 (150 mL) was added 2-hydroxyisoindolin-1,3-dione (5.1 g, 31.2 mmol) and triphenylphosphine (8.2 g, 31.2 mmol). The resultant mixture was cooled to 0° C. and diisopropyl azodicarboxylate (6.0 ml, 31.2 mmol) was slowly added dropwise with an addition funnel under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was concentrated to provide clear oil, which was purified by flash chromatography (60% EtOAc-Hexane). The resultant pale yellow compound was dissolved in CH2Cl2 (60 ml). Hydrazine hydrate (670 μL, 8.8 mmol) was added. The reaction mixture was stirred at ambient temperature for 8 h. The resultant solid was filtered off and the filtrate concentrated under reduced pressure to provide a clear yellow oil of (S)-4-(aminooxy)-2-(tert-butyldimethylsilyloxy)butanamide (1.1 g, 4.4 mmol). [M+H] calc'd for C10H24N2O3Si, 249. found, 249.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([NH:19][CH:20]3[CH2:22][CH2:21]3)=[O:18])[N:14]=[N:13]2)=[C:8]([OH:23])[CH:7]=1)=[O:5])[CH3:2].Br[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([NH:19][CH:20]3[CH2:22][CH2:21]3)=[O:18])[N:14]=[N:13]2)=[C:8]([O:23][CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(Br)c1ccccc1
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(OC(C)c2ccccc2)c1
Reaction time: 16 h
Yield: 33.4 %

Procedure:
A solution (500 μl; 70 μmol) of 1-{4-[(ethylamino)carbonyl]-2-hydroxyphenyl}-N-cyclopropyl-1H-1,2,3-triazole-4-carboxamide (0.14M) in DMF, and a solution (500 μl; 105 μmol) of (1-bromoethyl)benzene (0.21M) in DMF, and a powder of potassium carbonate (30 mg) were mixed at room temperature, and the mixture was stirred for 16 hr. Water (2 ml) was added to the reaction mixture, and the mixture was extracted with dichloromethane (3 ml). The solvent was evaporated under reduced pressure, and the residue was dissolved in DMSO (1 ml) and purified by preparative HPLC (Gilson, Inc., high-throughput purification system, column: YMC CombiPrep ODS-A S-5 μm, 50×20 mm, solvent: solution A; 0.1% formic acid aqueous solution, solution B; 0.1% formic acid acetonitrile solution, gradient cycle: 0 min (solution A/solution B=95/5), 1.00 min (solution A/solution B=95/5), 5.20 min (solution A/solution B=5/95), 6.40 min (solution A/solution B=5/95), 6.50 min (solution A/solution B=95/5), 6.60 min (solution A/solution B=95/5), flow rate: 25 ml/min, detection method: UV 220 nm) to give the title compound (9.8 mg) (LC/MS purity 100%, ESI+:420 [M+H]+).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=2)=[O:7])=[C:4]([CH3:21])[CH:3]=1.C(OC([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=O)(C)(C)C.C(C1C=C(NC(=O)C2C=CC(N3CCNCC3)=C(F)C=2)C=CC=1)(C)(C)C>>[C:15]([C:11]1[CH:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:19]=[CH:20][C:2]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:3][C:4]=2[CH3:21])[CH:14]=[CH:13][CH:12]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(Br)ccc1C(=O)Nc1cccc(C(C)(C)C)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)c(F)c2)c1
Product: Cc1cc(N2CCNCC2)ccc1C(=O)Nc1cccc(C(C)(C)C)c1

Procedure:
N-(3-tert-Butyl-phenyl)-2-methyl-4-piperazin-1-yl-benzamide was synthesized from 4-bromo-N-(3-tert-butyl-phenyl)-2-methyl-benzamide and piperazine-1-carboxylic acid tert-butyl ester in a manner similar to the one described in the synthesis of N-(3-tert-butyl-phenyl)-3-fluoro-4-piperazin-1-yl-benzamide above. LCMS calcd for C22H29N3O (m/e) 351, obsd 352 (M+H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]#[N:11])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Br:12]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:12][C:3]1[C:4]2[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=2[S:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc2ccsc2c1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(Br)csc2c1
Temperature: 25 °C

Procedure:
To a solution of 1-benzothiophene-6-carbonitrile (2.13 g, 13.4 mmol) in dry DMF (20 mL) at −10° C. was added freshly recrystallised N-bromosuccinimide (2.38 g, 13.4 mmol). The solution was allowed to warm to room temperature and stirred over the weekend. The mixture was diluted with water and extracted into diethyl ether, and the organic extract washed with water, then brine. The extracts were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica, eluting with ethyl acetate/hexane (1:9), to yield the title compound as a white solid.
Reaction SMILES: [OH-].[K+].[C:3]([C:7]1[C:8]([OH:16])=[CH:9][C:10]([CH3:15])=[C:11]([CH:14]=1)[CH:12]=[O:13])([CH3:6])([CH3:5])[CH3:4].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[S:20].CN(C)C(Cl)=S.C1COCC1>O.C1COCC1>[C:3]([C:7]1[CH:14]=[C:11]([CH:12]=[O:13])[C:10]([CH3:15])=[CH:9][C:8]=1[O:16][C:19](=[S:20])[N:18]([CH3:22])[CH3:17])([CH3:6])([CH3:5])[CH3:4]
Reactant: CN(C)C(=S)Cl
Reactant: Cc1cc(O)c(C(C)(C)C)cc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OC(=S)N(C)C)c(C(C)(C)C)cc1C=O
Temperature: 45 °C
Reaction time: 0.17 h

Procedure:
Ten percent KOH (80 mL) was added to a mixture of 5-tert-butyl-4-hydroxy-2-methylbenzaldehyde (Example T 99.0 g, 515 mmol) in water (180 mL) and THF (135 mL.) The mixture was treated with a solution of N,N-dimethylthiocarbamoyl chloride (86.1 g) in THF (108 mL) over a 2-hour period with simultaneous addition of 10% KOH in order to hold the pH of the reaction mixture between 12.0 and 12.3. After approximately 70% of the dimethylthiocarbamoyl chloride-THF solution had been added, vacuum was applied to the reaction mixture to remove the THF; during this distillation, the simultaneous additions of 10% KOH and the dimethylthiocarbamoyl chloride-THF solution were continued while maintaining the pH range between 12.0 and 11.6 and the reaction temperature between 23° C. to 25° C. The distillation was continued for 10 minutes after all the dimethylthiocarbamoyl chloride solution had been added. Stirring at ambient pressure and temperature was continued for another 90 minutes, during which time the pH was stable between 11.6 and 1.75. A solution of EtOAc (150 mL) and heptane (150 mL) was added to the reaction mixture, and after stirring and settling, the layers were separated and the aqueous layer extracted with 1:1 heptane:EtOAc. The combined organic extracts were extracted with 10% KOH (2×100 mL) and water (2×90 mL) and concentrated. The residue was diluted with MeOH (120 mL). The solution was warmed to 45° C. and H2O (20 mL) was added. The solution was cooled to room temperature. 50% NaOH (170 mg) was added, and the solution was concentrated. This residue was redissolved in MeOH (120 mL) at 50° C. and H2O (15 mL) was added. The solution was cooled slowly to −5° C. with the addition of dimethylthiocarbamic acid O-(2-tert-butyl-4-formyl-5-methyl-phenyl)ester seed crystals to promote crystallization. The mixture was filtered and the solid washed with 4:1 MeOH:H2O to give the title compound, mp 80-81° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:26]=[CH:25][C:14]3[C@:15]4([CH3:24])[C@@H:20]([CH2:21][CH2:22][C:13]=3[CH:12]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]4)[N:2]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C[Si](C([Si](C)(C)C)(C(F)(F)F)C(N)=O)(C)C>O1CCOCC1.C(OCC)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:26]=[CH:25][C:14]3[C@:15]4([CH3:24])[C@@H:20]([CH2:21][CH2:22][C:13]=3[CH:12]=2)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]4)[N:2]=1
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3cc4ccccc4cn3)ccc12
Agent: C[Si](C)(C)C(C(N)=O)(C(F)(F)F)[Si](C)(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@]12C=CC(=O)N[C@@H]1CCc1cc(-c3cc4ccccc4cn3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a suspension of (+)-(4aR)-(10bR)-8-(3-isoquinolinyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (80 mg, 0.230 mmol), in 1.0 mL of 1,4-dioxane was added DDQ (58 mg, 1.1 equiv.) followed by bistrimethylsilyltrifluoromethyl acetamide (270 mg, 4.5 equiv.), and the solution was stirred at room temperature for 2 h, then heated at 100° for 20 h. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with 2M sodium hydroxide. The organic phase was washed with brine, dried over sodium sulfate, concentrated and chromatographed on silica gel (ethyl acetate eluent) to give, after trituration from ether/hexanes, 18 mg (24%) of the title compound as a white solid. mp 248° (decomp.) FDMS m/e=340.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1(C)C=CC(S(O)(=O)=O)=C[CH:19]=1>C(O)C>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Oc2ccccc2)cc1
Yield: 404.9 %

Procedure:
To a suspension of (4'-phenoxyphenyl)acetic acid (0.456 g) in 4 ml of ethanol is added para-toluensulfonic acid (0.076 g) and the resulting mixture is refluxed for 2 hours. The solvent is evaporated off, the residue is dissolved in diethyl ether and the organic phase is washed with saturated aqueous solution of sodium hydrogencarbonate and then with brine. The organic phase is dried over sodium sulfate and concentrated to dryness to give 0.458 g of the product as a brown oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1([C:16]2[N:21]=[C:20]([CH:22]3[CH2:24][CH2:23]3)[N:19]=[C:18]([NH:25][CH:26]3[CH2:28][CH2:27]3)[CH:17]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C(Cl)(Cl)Cl.ClCCl>[N:9]1([C:16]2[N:21]=[C:20]([CH:22]3[CH2:24][CH2:23]3)[N:19]=[C:18]([NH:25][CH:26]3[CH2:28][CH2:27]3)[C:17]=2[Br:1])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1c(NC2CC2)nc(C2CC2)nc1N1CCCCCC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Brc1c(NC2CC2)nc(C2CC2)nc1N1CCCCCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 20.7 %

Procedure:
N-Bromosuccinimide (0.39 g, 2.2 mmol) is added to a solution of 6-(1-azepanyl)-N,2-dicyclopropyl-4-pyrimidinamine 62 (0.5 g, 1.84 mmol) in chloroform (2 ml). The mixture is stirred at 60° C. overnight then cooled, diluted with dichloromethane and washed two times with water. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo. The crude mixture is purified by column chromatography (dichloromethane/ethanol: 97/3) to give pure 6-azepan-1-yl-5-bromo-N,2-dicyclopropylpyrimidin-4-amine 61 (134 mg, 21%) as a brownish paste.
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][S:8][C:9]=1[CH3:10])(=[O:4])=[O:3].C(N=[C:21]=[O:22])CCCC.C(Cl)(Cl)=O>>[N:1]([S:2]([C:5]1[C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][S:8][C:9]=1[CH3:10])(=[O:4])=[O:3])=[C:21]=[O:22]
Reactant: CCCCCN=C=O
Reactant: COC(=O)c1csc(C)c1S(N)(=O)=O
Agent: O=C(Cl)Cl
Product: COC(=O)c1csc(C)c1S(=O)(=O)N=C=O

Procedure:
Under the conditions specified above, 23.5 g of methyl 4-(aminosulfonyl)-5-methylthiophene -3-carboxylate (1) were reacted with 11.3 g of pentyl isocyanate (100 mmol) in the presence of phosgene to give methyl 4-(isocyanatosulfonyl)-5-methylthiophene-3-carboxylate (2). 22 g of this isocyanate (83% of theory, content: 99%, b.p.: 120° C., 0.4 mbar) were likewise obtained. The identification and the determination of content were conducted by means of derivatization with methanol to the corresponding carbamate (1H NMR (400 MHz, d6DMSO): 2.72 (s), 3.61 (s), 3.79 (s), 8.00 (s), 11.96 (s)).
Reaction SMILES: [Mg].[CH3:2]I.[I:4][CH:5]=[CH:6][C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl-].[NH4+]>CCOCC>[OH:13][C:7]([CH3:2])([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][I:4]
Reactant: CI
Reactant: CCCCCC(=O)C=CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCC(C)(O)C=CI
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a Grignard solution prepared from 1.05 g (0.41 moles) of magnesium and 6.2 g (0.435 moles) of methyl iodide in 30 ml of dry ether under argon is added dropwise 10 g of 1-iodo-1-octen-3-one (Example 183) in 45 ml of ether. The resulting solution is stirred at ambient temperature for one hour. After the addition of 75 ml of saturated ammonium chloride the ether layer is separated and the aqueous layer is separated and the aqueous layer is extracted several times with ether. The combined ether extracts are washed successively with ammonium chloride and water, dried and taken to dryness to give 9.24 g of product as an oil; λ max 2,89, 3,23,6.24 and 10.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24](OS(C(F)(F)F)(=O)=O)=[CH:23][CH:22]=1.[C:35]([C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)#[CH:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:36]#[C:35][C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[CH:23][CH:22]=1
Reactant: C#Cc1cccnc1
Reactant: O=S(=O)(Oc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1)C(F)(F)F
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(C#Cc4cccnc4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The compound was obtained starting from 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-trifluoromethylsulfonyloxy-benzyl)-benzene and 3-ethynyl-pyridine.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][N:7]([CH3:12])[S:8](Cl)(=[O:10])=[O:9]>>[CH3:6][N:7]([CH3:12])[S:8]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:10])=[O:9]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: c1c[nH]cn1
Product: CN(C)S(=O)(=O)n1ccnc1

Procedure:
Imidazole was treated with dimethyl amino sulfonyl chloride providing 1-(dimethylaminosulfonyl)-imidazole, which was subsequently treated with n-butyl lithium and t-butyldimethylsilyl chloride to afford 1-(dimethylaminosulfonyl)-2-(t-butyldimethylsilyl)-imidazol e. This material was treated with n-butyllithium and tri-n-butyltin chloride to afford the target compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][N:8]=1.[H-].[Na+].Cl[CH2:23][C:24]1[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])[O:27][CH:28]=1.O>CN(C=O)C>[F:38][C:32]1[CH:33]=[C:34]([F:37])[CH:35]=[CH:36][C:31]=1/[CH:30]=[CH:29]/[C:26]1[O:27][CH:28]=[C:24]([CH2:23][O:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][N:5]3[CH:6]=[CH:7][N:8]=[C:4]3[CH2:3][CH2:2][OH:1])=[CH:18][CH:17]=2)[N:25]=1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(F)cc3F)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a solution of 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl ]butyl]phenol (260 mg) in DMF (4 ml), 60% oily sodium hydride (44 mg) was added under ice cooling. After stirring at room temperature for 30 minutes, (E)-4-chloromethyl-2-[2-(2,4-difluorophenyl) ethenyl]oxazole (281 mg) was added under ice cooling. After stirring at room temperature for 3 days, water was added under ice cooling. The precipitate was collected by filtration and washed with water. The precipitate was dissolved in a mixture of ethyl acetate-THF and dried over magnesium sulfate, after which it was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to yield the titled compound (275 mg) as pale-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8](=[O:16])[NH:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:4]C=1C.[Li+].[OH-:21]>CO.O>[C:5]([O:21][C:8]([NH:7][C:2]1[N:1]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:16])[NH:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:17][CH:18]=1)=[O:16])([CH3:17])([CH3:6])[CH3:4]
Reactant: [OH-]
Reactant: CCOC(=O)CNC(=O)NCc1ccc(N)c(C)c1
Agent: [Li+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(CNC(=O)NCC(=O)O)cn1
Temperature: 50 °C
Yield: 195.1 %

Procedure:
51 (7.5 g, 21.3 mmol) was dissolved in 50 ml of MeOH and 50 ml of water, LiOH (4 équivalent, 2.0 g) was added and the reaction mixture was heated to 50° C. for 2 h. The reaction mixture is concentrated and 200 ml of water are added, then extracted twice with AcOEt. The water is acidified to pH 5 with concentrated HCl 36%, then extracted twice with AcOEt. The combine organic phase are dried over Na2SO4, filtered and concentrated to afford 57 (6.74 g, 98%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[C:7]([O:10][CH3:11])[N:6]=[C:5]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:18]=3)[CH2:13]2)[N:4]=1.N1C=CC=CC=1.[C:32]([CH2:36][C:37](Cl)=[O:38])([CH3:35])([CH3:34])[CH3:33]>ClCCl>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:37](=[O:38])[CH2:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[C:7]([O:10][CH3:11])[N:6]=[C:5]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]([F:24])([F:25])[F:23])[CH:18]=3)[CH2:13]2)[N:4]=1
Reactant: COc1nc(N2CCc3cc(C(F)(F)F)ccc3C2)nc(OC)c1N
Reactant: CC(C)(C)CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1nc(N2CCc3cc(C(F)(F)F)ccc3C2)nc(OC)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a mixture of 5c (0.69 g, 1.96 mmol) and pyridine (0.156 g, 2.0 mmol) in dichloromethane (20 ml) was added tert-butylacetyl chloride (0.269 g, 2.0 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed to yield the title compound (0.657 g, 1.45 mmol, 72%). 1H NMR (CDCl3, 400 MHz) δ 1.10 (s, 9H), 2.20 (s, 2H), 2.95 (t, J=5.8 Hz, 2H), 3.92 (s, 6H), 4.04 (t, J=5.8 Hz, 2H), 4.92 (s, 2H), 6.18 (s, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.42 (s, 1H), 7.44 (d, J=7.8 Hz, 1H).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]/[CH2:4]O.P(Br)(Br)[Br:13]>C(OCC)C>[Br:13][CH2:4]/[CH:3]=[C:2](/[CH3:1])\[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]
Reactant: BrP(Br)Br
Reactant: CC(C)=CCC/C(C)=C\CO
Solvent: CCOCC
Product: CC(C)=CCC/C(C)=C\CBr
Reaction time: 0.5 h

Procedure:
A stirred solution of 51.4 grams of (Z)-3,7-dimethyl-2,6-octadien-1-ol in 400 milliliters of dry ethyl ether, protected from light, is treated with 29.8 grams of phosphorous tribromide, dropwise, over a 1/2 hour period. The mixture is refluxed for about 2.5 hours, then cooled, poured on ice water and extracted with ether. The ethereal extract is washed with sodium bicarbonate, then with water and dried over sodium sulfate. Solvent is removed under reduced pressure to yield (Z)-1-bromo-3,7-dimethyl-2,6-octadiene.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:9][CH2:8][C@H:7]([N:10]2[C:14]3[CH:15]=[C:16]([CH2:19][N:20]4[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]4)[CH:17]=[CH:18][C:13]=3[NH:12]/[C:11]/2=[N:30]\[C:31](=[O:39])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[CH2:6][CH2:5]1)(=O)[CH3:2].[CH3:40][CH:41]([NH2:43])[CH3:42].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClC(Cl)C>[F:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[C:31](/[N:30]=[C:11]1\[NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:27])[CH3:28])[CH2:22][CH2:21]3)=[CH:15][C:14]=2[N:10]\1[C@H:7]1[CH2:8][CH2:9][C@@H:4]([CH:1]([NH:43][CH:41]([CH3:42])[CH3:40])[CH3:2])[CH2:5][CH2:6]1)=[O:39]
Reactant: CC(C)N
Reactant: CC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3cccc(F)c3)[nH]c3ccc(CN4CCC(C(C)(C)O)CC4)cc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)NC(C)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3cccc(F)c3)[nH]c3ccc(CN4CCC(C(C)(C)O)CC4)cc32)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 15.5 %

Procedure:
(E)-N-(1-(cis-4-acetylcyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-3-fluorobenzamide (0.06 g, 0.112 mmol) was suspended in 0.37 mL of dichloroethane. To this mixture was added propan-2-amine (7.30 mg, 0.123 mmol) followed by sodium triacetoxyborohydride (0.033 g, 0.157 mmol) and AcOH (6.42 pt, 0.112 mmol). The resulting mixture was stirred for 6 hours at RT and quenched with 1N aqueous NaOH (5 mL). DCM (20 mL) was added and the layers were separated. The organic portion was dried over sodium sulfate and concentrated to afford a yellow residue which was purified by silica gel chromatography (5-30% MeOH/DCM) to afford (E)-3-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(1-(isopropylamino)ethyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide as an off-white solid (10 mg, 15.42% yield). MS m/z=578.4 [M+H]. Calc'd for C34H48FN5O2: 577.4
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:4])#[C-:2].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][C:17]=1[F:24].C([O-])([O-])=O.[K+].[K+].O>CO>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[O:21][CH:2]=[N:1][C:3]=2[CH3:4])=[CH:18][C:17]=1[F:24]
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ncoc1-c1ccc(Cl)c(F)c1
Yield: 85.7 %

Procedure:
A mixture of 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (1.56 g, 7.44 mmol), 4-chloro-3-fluorobenzaldehyde (1.18 g, 7.44 mmol), and K2CO3 (2.06 g, 14.9 mmol) in MeOH (35 mL) was heated to reflux. After 1.5 hr water (200 mL) was added and the product was extracted with EtOAc (200 mL). The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated to an orange oil. Chromatography on silica gel (Analogix® SF25-40G, 0%-30% EtOAc/hexanes, 30 mL/min) afforded 1.35 g (86%) of the title compound as a yellow solid. 1H NMR (300 MHz, CH3OH-d4) δ 8.18 (s, 1H), 7.62-7.55 (m, 1H), 7.52 (dd, J=1.9, 10.3, 1H), 7.49-7.44 (m, 1H), 2.42 (s, 3H). MS (DCI+) m/z 212 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][CH:3]=1.[CH2:11]1CCCCC1.CI>C1COCC1>[Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[CH3:11]
Reactant: Brc1csc2cccnc12
Reactant: C1CCCCC1
Solvent: C1CCOC1
Solvent: CI
Product: Cc1sc2cccnc2c1Br
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
674 mg of 3-Bromo-thieno[3,2-b]pyridine (3.15 mmol) is dissolved in 12 ml of dry THF and cooled to −78° C. 2.3 ml of LDA-mono-tetrahydrofuran (1.5 M) solution in cyclohexane (3.46 mmol) is added to the mixture at −78° C. and stirred at −78° C. for 20 min. 0.22 ml of methyliodide (3.46 mmol) is added to the mixture and stirred at −78° C.→room temperature for 2 h. the reaction mixture is quenched by sat. NH4Cl and extracted with CH2Cl2. The separated CH2Cl2 is dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=20:4:1) to give 618 mg of the title compound. Yield 86%. mass spectrum (m/e): 230 (M+1); 1H-NMR (CDCl3): 8.78 (dd, 1H, J=4.8 Hz, 1.4 Hz), 8.10 (dd, 1H, J=8.2 Hz, 1.4 Hz), 7.30 (dd, 1H, J=8.2 Hz, 4.8 Hz), 2.67 (s, 3H).