Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:36].[BrH:37].N([O-])=O.[Na+]>C(#N)C.O>[Br:37][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:36]
Reactant: Br
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(N)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(Br)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A stirred suspension of 6-(N-(4-amino-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide (0.421 g, 0.773 mmol) in 25 mL of acetonitrile was treated with 25 mL of 48% aqueous HBr and the resulting suspension cooled in an ice water bath. To the mixture was added a solution of sodium nitrite (0.056 g, 0.812 mmol) in 2 mL of water. After stirring at 0° C. for 30 minutes an additional 14 mg portion of sodium nitrite in 1 mL of water was added. After stirring at 0° C. for another 30 minutes, the mixture was treated with CuBr (0.130 g, 0.906 mmol) in four portions over 5 minutes. The mixture was warmed to 60° C. for 30 minutes and then cooled to RT. The mixture was partitioned between EtOAc and 5% aqueous sodium bisulfite. The EtOAc solution was washed with 5% aqueous sodium bisulfite (2×), saturated aqueous sodium bicarbonate (2×), brine (1×), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient from hexane to 3:7 hexane/EtOAc) followed by recrystallization from hexane/EtOAc to give the title compound (0.212 g, 45%) as a white solid. LCMS (m/z, ES+)=609 (M+H+).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>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.C1(C)C=CC=CC=1.O1CCCC1>[CH3:13][O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:27]2[CH:26]=[CH:25][C:24]([C:15]3[CH:16]=[CH:17][C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=3)=[CH:29][CH:28]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccc(-c2ccc3ccccc3c2)cc1
Reactant: COc1ccc(Br)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(-c3ccc4ccccc4c3)cc2)c2ccccc12
Temperature: 25 °C
Yield: 68.6 %

Procedure:
1-Bromo-4-methoxynaphthalene (25 g, 0.105 mol), 4-(naphthalen-2-yl)phenylboronic acid (30.4 g, 0.137 mol), potassium carbonate (21.9 g, 0.16 mol), tetrakis(triphenylphosphine)palladium(0) (2.4 g, 0.01 mol), water (25 mL), tetrahydrofuran (75 mL) and toluene (75 mL) were stirred in a 250 mL round-bottom flask for 12 hours under reflux. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with ethyl acetate (300 mL) and water (1000 mL). The organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The resulting solid was dissolved in hot toluene (400 mL) and filtered. The filtrate was recrystallized in methanol (800 mL). The resultant solid was filtered and washed with hexane (300 mL) to obtain a product (26 g, 0.072 mol, 68.4%).
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[Br:7][C:8]1[NH:9][C:10]([Br:16])=[C:11]([Br:15])[C:12]=1[C:13]#[N:14].C(I)C>O1CCCC1.O>[Br:7][C:8]1[N:9]([CH2:1][CH3:2])[C:10]([Br:16])=[C:11]([Br:15])[C:12]=1[C:13]#[N:14]
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Agent: [K+]
Solvent: O
Solvent: CCI
Solvent: C1CCOC1
Product: CCn1c(Br)c(Br)c(C#N)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium t-butoxide (0.75 g, 6.7 mmol) is added in portions at room temperature to a solution of 2,4,5-tribromopyrrole-3-carbonitrile (2.0 g, 6.1 mmol) in anhydrous tetrahydrofuran (20 mL). After 30 minutes, ethyl iodide (1.04 g, 6.7 mmol) is added dropwise. The reaction solution is stirred at room temperature for 30 minutes and then refluxed for 90 minutes. The mixture is cooled, diluted with water and extracted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride and dried (Na2SO). Evaporation of the solvent and crystallization from ether-hexanes gives a solid which is further purified by flash column chromatography on silica gel, packed with methylene chloride and eluted with 3% ethyl acetate in methylene chloride. The analytically pure sample is finally crystallized from methylene chloride-hexanes as a white solid (1.55 g); mp 108.5°-109.5° C.
Reaction SMILES: CO.[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([CH3:23])[N:15]=2)[C:12]=1[CH3:13])=[O:7])[CH3:4]>[C].[Pd].O1CCOCC1>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([CH3:23])[N:15]=2)[C:12]=1[CH3:13])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cnn(-c2ccc([N+](=O)[O-])c(C)n2)c1C
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(-c2ccc(N)c(C)n2)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methanol (50 ml), 1,4-dioxane (200 ml) and 10% palladium-carbon (containing ca. 50% water; 5 g) were added to 5-methyl-1-(6-methyl-5-nitropyridin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (15 g) and the mixture was stirred under hydrogen atmosphere at room temperature for four hours. The reaction solution was filtered through Celite, the filtrate was concentrated in vacuo and the resulting solid was washed with n-hexane to give 1-(5-amino-6-methyl-pyridin-2-yl)-5-methyl-1H-pyrazol-4-carboxylic acid ethyl ester as a pale yellow solid.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1>ClCCl>[C:4]([O:3][C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:19]1[CH2:20][CH2:21][CH2:22][C@H:18]1[CH3:17])=[O:12])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: C[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
BOC proline (CAS 15761-39-4) and 2-(R)-methyl-pyrrolidine hydrochloride (CAS 135324-85-5) are coupled in a manner substantially analogous to Procedure A in dichloromethane to give 2(S)-(2(R)-methyl-pyrrolidine-1-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. The material is deprotected by stirring in dichloromethane at 5-10° C. while trifluoroacetic acid (10 eq,) is added and then stirred at room temperature for 18 hours. The reaction is concentrated and is dissolved in H2O. The pH is adjusted to 8-9 with K2CO3, and is extracted several times with CH2Cl2. The extracts are combined, dried (Na2SO4) and concentrated in vacuo to give (2(R)-methyl-pyrrolidin-1-yl)-pyrrolidin-2-yl-methanone. A 1 M lithium aluminum hydride/THF solution (3 eq.) is diluted with an equal volume of THF and stirred under N2 as a THF solution of (2(R)-methyl-pyrrolidin-1-yl)-pyrrolidin-2-yl-methanone is added dropwise, allowing the reaction to mildly exotherm. Reaction is stirred at 40° C. for 45 minutes, then at room temperature 18 hours. Reaction is cooled in an ice bath and is quenched with H2O (3 eq.), 4 N NaOH (3 eq.), and H2O (9 eq.) maintaining the reaction temperature less than 15° C. The reaction is stirred overnight, filtered, and the precipitate is washed three times with THF. The filtrate and washes are combined and concentrated to give 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) m/e 169.3 (M+H)+ Intermediate is used as such or is purified by SCX chromatography or distillation.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=[O:20])=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:53]([N:55]1[N:59]=[N:58][C:57]([CH2:60][N:61]2[C:66]3[CH:67]=[C:68]([C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)[S:69][C:65]=3[C:64](=[O:76])[N:63]([CH:77]3[CH2:82][CH2:81][NH:80][CH2:79][CH2:78]3)[C:62]2=[O:83])=[N:56]1)[CH3:54].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[C:18]([C:19]([N:80]4[CH2:81][CH2:82][CH:77]([N:63]5[C:64](=[O:76])[C:65]6[S:69][C:68]([C:70]7[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=7)=[CH:67][C:66]=6[N:61]([CH2:60][C:57]6[N:58]=[N:59][N:55]([CH2:53][CH3:54])[N:56]=6)[C:62]5=[O:83])[CH2:78][CH2:79]4)=[O:20])[CH:22]=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)O)c1)=N[C@@H]1CCSC[C@H]21
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nnn(CC)n5)c4=O)CC3)c1)=N[C@@H]1CCSC[C@H]21

Procedure:
In analogy to the procedure described for example 14 3-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (120 mg; compound C8) is reacted with HBTU (120 mg), 1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (132 mg; compound B39) and DIPEA (0.16 ml) in DCM (10 ml). After purification by flash column chromatography (silica gel, eluent: EtOAc) the title compound is obtained as a solid.
Reaction SMILES: C([O:3][C:4](=O)[C@@:5]([OH:33])([CH3:32])[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[F:31])=[CH:20][CH:19]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])C.[CH2:35]([OH:39])[CH:36]([CH3:38])[CH3:37].Cl.O1CCOCC1>>[CH2:35]([O:39][C:4](=[O:3])[C@@:5]([OH:33])([CH3:32])[CH2:6][N:7]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[F:31])=[CH:22][CH:23]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)CO
Reactant: CCOC(=O)[C@](C)(O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(O)no1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)COC(=O)[C@](C)(O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(O)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
(R)-3-[N-(5′-Chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-hydroxy-isoxazole-5-carbonyl)-hydrazino]-2-hydroxy-2-methyl-propionic acid ethyl ester (100 mg, 0.2 mmol) was dissolved in isobutyl alcohol (6 mL, 60 mmol), followed by the addition of 4 M HCl in dioxane (1 mL, 4 mmol). The resulting mixture was stirred at room temperature for 8 hours, then evaporated under reduced pressure and purified by preparative HPLC. The clean fractions were combined and lyophilized to yield the title compound (52 mg, 100% purity). MS m/z [M+H]+ calc'd for C25H27ClFN3O6, 520.16; Found 520.2.
Reaction SMILES: I[C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]([CH3:7])[N:6]=1.C([Mg]Cl)(C)C.[CH2:16]([Sn:20]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])Cl)[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH3:7][N:5]1[C:4]2[CH:8]=[CH:9][S:10][C:3]=2[C:2]([Sn:20]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:16][CH2:17][CH2:18][CH3:19])=[N:6]1
Reactant: Cn1nc(I)c2sccc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccsc12
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 63.4 %

Procedure:
To a solution of 3-iodo-1-methyl-1H-thieno[3,2-c]pyrazole (290 mg, 1.10 mmol) in THF (6 mL) at −15° C. was slowly added isopropylmagnesium chloride (2.0 M in THF, 0.66 mL, 1.32 mmol). The bright yellow heterogeneous reaction mixture was stirred at −15° C. for 20 min then tributylchlorostannane (0.36 mL, 1.32 mmol) was added dropwise. Stirring was continued at −15° C. for 20 min then at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 10% to 20% EtOAc/heptane (0.5% Et3N) gave 298 mg (63%) of 1-methyl-3-tributylstannanyl-1H-thieno[3,2-c]pyrazole as a pale yellow oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.36 (d, J=5.3 Hz, 1H), 6.90 (d, J=5.3 Hz, 1H), 4.06 (s, 3H), 1.54-1.67 (m, 6H), 1.36 (dq, J=14.7, 7.3 Hz, 6H), 1.13-1.22 (m, 6H), 0.90 (t, J=7.3 Hz, 9H).
Reaction SMILES: [C:1]1([C:7]2([NH:13][C:14](=[O:16])[CH3:15])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]1[CH:43]=[CH:42][C:21]([CH2:22][N:23]([CH3:41])[C:24]([C@@:26]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=3)[CH2:28][C@H:27]2/[CH:29]=[CH:30]/[CH:31]=O)=[O:25])=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>C(O)C>[F:17][C:18]1[CH:43]=[CH:42][C:21]([CH2:22][N:23]([CH3:41])[C:24]([C@@:26]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=3)[CH2:28][C@H:27]2/[CH:29]=[CH:30]/[CH2:31][N:10]2[CH2:11][CH2:12][C:7]([NH:13][C:14](=[O:16])[CH3:15])([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9]2)=[O:25])=[CH:20][CH:19]=1
Reactant: CC(=O)NC1(c2ccccc2)CCNCC1
Reactant: CN(Cc1ccc(F)cc1)C(=O)[C@@]1(c2ccc(Cl)c(Cl)c2)C[C@H]1/C=C/C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(=O)NC1(c2ccccc2)CCN(C/C=C/[C@@H]2C[C@@]2(C(=O)N(C)Cc2ccc(F)cc2)c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 2 h

Procedure:
N-(4-Phenyl-piperidin-4-yl)-acetamide (140 mg, 0.64 mmol) dissolved in ethanol (3 ml) is added to (1S,2S)-1-(3,4-Dichloro-phenyl)-2-((E)-3-oxo-propenyl)-cyclopropanecarboxylic acid (4-fluoro-benzyl)-methyl-amide dissolved in ethanol (5 ml) followed by dropwise addition of sodium cyanoborohydride (1.0M in THF, 1.97 ml, 1.97 mmol) at 0° C. After complete addition the mixture is kept at ambient temperature for 2 hours. The reaction is quenched by addition of sodium bicarbonate (3 ml, sat.) and the ethanol is removed by means of evaporation. Ethyl acetate (30 ml) is added to the remanence. The organic fraction is washed successively with sodium bicarbonate (10 ml, sat.) and brine (10 ml, sat.), dried (MgSO4) and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with ethyl acetate:ethanol:triethylamine (95:0:5)-(90:5:5) to furnish the title compound as an oil. Yield 81 mg (27%). LC/MS (m/z) 610.3 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH2:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:18][CH2:19][CH3:20]>>[CH2:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][CH:34]([NH:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]3[C:14]4[NH:13][C:12](=[O:15])[NH:11][C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:23])=[O:24])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCNS(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: CCCCNS(=O)(=O)c1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from 4-((2S)-3-amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one and Reference Example 11, N-butyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as an off-white solid; mp 69-75° C.; 1H NMR (300 MHz, DMSO-d6) δ 0.79 (t, 3H), 1.10-1.40 (m, 6H), 1.75-1.90 (m, 2H), 2.67 (t, 2H), 2.10-3.00 (m, 5H), 3.70-4.10 (m, 5H), 6.55 (d, 3H), 6.62 (d, 1H), 6.83 (t, 1H), 7.00 (d, 2H), 7.52 (d, 2H), 10.45-10.80 (m, 2H); MS (ES) m/z: 518.1 (MH+); HRMS Calcd. for C25H36N5O5 S (MH+): 518.2437. Found: 518.2446.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-])(=O)=O)=CC=1.C(O)(C)(C)C.[CH3:19][C:20]1([CH3:27])[CH2:25][C:24](=O)[CH2:23][CH2:22][O:21]1.CC(C)([O-])C.[K+]>C(COC)OC.C(OCC)C>[CH3:19][C:20]1([CH3:27])[CH2:25][CH:24]([C:10]#[N:11])[CH2:23][CH2:22][O:21]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC1(C)CC(=O)CCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: CC1(C)CC(C#N)CCO1
Temperature: -20 °C
Yield: 84.4 %

Procedure:
p-Toluenesulfonylmethyl isocyanide (693 mg) and tert-butanol (438 μl) were added to a solution of 2,2-dimethyltetrahydro-4H-pyran-4-one (350 mg) in dimethoxyethane (10 ml) with stirring. Potassium tert-butoxide (766 mg) were added in three portions under cooling at −20° C. The mixture was heated to room temperature and then stirred for 18 hours. Diethyl ether was added and the mixture was filtered through Celite. Thereafter, the solvent was evaporated under reduced pressure to give the title compound (321 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH:10](=O)[CH:11]([CH3:13])[CH3:12].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>ClCCl.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([C:10]([CH:11]([CH3:13])[CH3:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: CC(C)C=O
Reactant: NNc1ncc(Br)cn1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: CC(C)c1nnc2ncc(Br)cn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round bottom flask was added 5-bromo-2-hydrazinopyrimidine (2.65 mmole) in dichloromethane (40 mL). To this solution was added isobutyraldehyde (2.65 mmole) followed by 2 drops of acetic acid. The reaction mixture was stirred at room temperature for 2 hours after which was added iodobenzene diacetate (2.77 mmole). The resulting reaction mixture was stirred at RT for another 2 hours. The mixture was evaporated in vacuo and purified by preparative TLC eluting with 5% methanol and dichloromethane mixture to give 6-bromo-3-isopropyl-[1,2,4]triazolo[4,3-a]pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([Li])CCC.CCCCCC.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[C:31](Cl)=[O:32]>O1CCCC1>[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[C:31]([C:7]1[C:2]([Cl:1])=[CH:3][C:4]([CH3:9])=[CH:5][C:6]=1[Cl:8])=[O:32]
Reactant: Cc1cc(Cl)cc(Cl)c1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(Cl)c(C(=O)c2ccc3ccccc3c2)c(Cl)c1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a cold (-60° C.) stirred solution of 3,5-dichlorotoluene (2.5 g, 15.5 mmol) in 30 ml of dry tetrahydrofuran under a nitrogen atmosphere, a 2.6 M solution of n-butyllithium in hexane (6.3 ml, 16.3 mmol) was added slowly over 15 minutes. The reaction mixture was stirred for an additional 30 minutes at -60° C. and then treated dropwise with a solution of 2-naphthoyl chloride (2.95 g, 15.5 mmol) in 15 ml of dry tetrahydrofuran over 15 minutes. The reaction mixture was stirred for 4 hours at -60° C. and then quenched with 4 ml of saturated NH4Cl solution. The mixture was permitted to come to room temperature at which point it was diluted with 20 ml of water and 20 ml of ether. The layers were separated and the aqueous layer further extracted with ether. The combined extracts were washed with brine, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to give 4.76 g of crude product. This material was chromatographed on silica gel (20:1 hexane:ethyl acetate) to give 1.71 g of pure product.
Reaction SMILES: [Br:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15](S(C)=O)[O:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[Br:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]5[OH:32])[O:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)c(Cl)cc43)cc2o1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)c(Cl)cc43)cc2o1
Temperature: 120 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
A mixture of 6-((5-bromo-6-chloro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (460 mg, 1.08 mmol), (1R,2R)-2-aminocyclohexanol (245 mg, 2.13 mmol) and DIEA (366 mg, 2.84 mmol) in DMA (10 mL) was stirred at 120° C. for 1 h. The reaction mixture was cooled to rt, poured into water (30 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:5 petroleum ether/ethyl acetate to give (1R,2R)-2-((6-((5-bromo-6-chloro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol as a light yellow solid (470 mg, 82.3%). 1H NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.41 (s, 1H), 7.14 (s, 1H), 5.48 (s, 2H), 4.68 (d, J=4.2 Hz, 1H), 3.33 (br s, 2H), 1.91 (br s, 2H), 1.63 (br s, 2H), 1.25 (br s, 4H). LCMS (ESI) m/z 477 (M+H)+.
Reaction SMILES: [OH:1][C:2]([C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:11][CH2:10]1)([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3].[Br:20]N1C(=O)CCC1=O>CN(C=O)C.O.C(OCC)(=O)C>[Br:20][C:6]1[S:5][C:4]([C:2]([C@H:9]2[CH2:10][CH2:11][C@H:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:13][CH2:14]2)([OH:1])[CH3:3])=[N:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(O)(c1nccs1)[C@H]1CC[C@H](NS(C)(=O)=O)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(O)(c1ncc(Br)s1)[C@H]1CC[C@H](NS(C)(=O)=O)CC1
Temperature: 50 °C

Procedure:
To a solution of N-{trans-4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexyl}methanesulfonamide (178 mg, 0.59 mmol) in DMF (4.0 mL) was added N-bromosuccinimide (104 mg, 0.585 mmol) and the reaction was heated at 50° C. for one hour. The reaction was then cooled to room temperature and another portion of N-bromosuccinimide (52 mg, 0.292 mmol) was added. The reaction was then heated at 50° C. for one hour. The solution was then cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford N-{trans-4-[1-(5-bromo-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexyl}methanesulfonamide. MS ESI calc'd. for C12H20N2O3S2 [M+H]+ 383, 385. found 383, 385. 1H NMR (500 MHz, DMSO-d6) δ 7.73 (s, 1H), 6.91 (d, J=7.4, 1H), 5.95 (s, 1H), 2.99-2.87 (m, 1H), 2.54 (s, 3H), 1.94-1.72 (m, 4H), 1.52 (t, J=11.9, 1H), 1.47-1.39 (m, 4H), 1.30-0.92 (m, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.C(N(CC)CC)C>O1CCOCC1>[N:11]1([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnccc1-n1ccnc1
Yield: 96.4 %

Procedure:
4-Chloro-3-nitropyridine (2.00 g, 12.6 mmol) and imidazole (2.25 g, 33.0 mmol) were dissolved in 10 ml of 1,4-dioxane, and 2 ml of triethylamine was added thereto. followed by reaction at 90° to 100° C. for 1.5 hours. Then, the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: dichloromethane:methanol=10:1 (v/v)] to obtain 2.31 g of a yellow liquid (yield: 96.4%).