Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:28](=[O:29])[CH2:27][C:26](=[O:30])[NH:25][C:24]3[C:31]4[C:36]([CH:37]=[CH:38][C:23]2=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:18][CH:17]=1>ClC(Cl)C>[Cl:1][C:2]1[C:3]([C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:28](=[O:29])[CH2:27][C:26](=[O:30])[NH:25][C:24]4[C:31]5[C:36]([CH:37]=[CH:38][C:23]3=4)=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:18][CH:17]=2)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(O)c1ncccc1Cl
Solvent: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ncccc3Cl)cc2)c2ccc3ccccc3c2N1
Yield: 44.9 %

Procedure:
3-Chloropyridine-2-carboxylic acid (47 mg, 0.3 mmol) was treated with thionyl chloride in dichloroethane, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (63 mg, 0.2 mmol) obtained in Example 1, (3), the title compound (41 mg, yield 45%) was obtained as pale brown crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]([OH:9])[C:6]([OH:8])=O)[CH3:3].C(N(CC)C(C)C)(C)C.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:28][CH2:29][NH2:30])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:27][CH2:28][CH2:29][NH:30][C:6](=[O:8])[C@@H:5]([OH:9])[CH2:4][CH:2]([CH3:1])[CH3:3])=[CH:22][CH:21]=1
Reactant: CC(C)C[C@H](O)C(=O)O
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](O)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
L-2-hydroxyisocaproic acid (102 mg, 0.77 mmol) was dissolved in DMF (5 mL) and treated with N,N-diisopropylethylamine (0.53 mL, 3.06 mmol), 4,4-bis-(4-fluorophenyl)-butylamine (200 mg, 0.77 mmol), and HBTU (292 mg, 0.77 mmol), then stirred overnight at room temperature. The reaction was diluted with EtOAc (125 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated. The residue was chromatographed twice on silica gel, eluting with 2-4% MeOH/CH2Cl2 to give 139 mg (48%) of the desired product as an oil. MS: 376.2 (M+1 for C22H27N1O2F2); an oil; TLC (SiO2), Rf 0.73 (8% MeOH/CH2Cl2); HPLC (7:3 CH3CN/H2O with 0.1% TFA, C-18 column) 96.46%, RT=5.448 min.
Reaction SMILES: [CH2:1]([S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[CH2:13]([N:16]([CH2:20][CH2:21][CH3:22])[C:17](Cl)=[O:18])[CH2:14][CH3:15].O1CCCC1>C(N(CC)CC)C>[CH2:13]([N:16]([CH2:20][CH2:21][CH3:22])[C:17]([N:10]1[CH:11]=[N:12][C:8]([S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:6])=[O:7])=[N:9]1)=[O:18])[CH2:14][CH3:15]
Reactant: CCCCS(=O)(=O)c1nc[nH]n1
Reactant: CCCN(CCC)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)c1ncn(C(=O)N(CCC)CCC)n1

Procedure:
A mixture of 5.7 g. 3-n-butylsulphonyl-1,2,4-triazole, 5.4 g. dipropylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 6 ml. dry triethylamine was refluxed under anhydrous conditions for 1.5 hours. The reaction mixture was worked up as described in Example 1 to produce a solid product which was recrystallized from petroleum ether (60° - 80° C.) to give 1-dipropylcarbamoyl-3-n-butylsulphonyl-1,2,4-triazole, m.p. 46° - 47° C. Elemental analysis satisfactory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]2)[OH:9])=[CH:4][CH:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1>>[CH3:16][N:17]1[CH2:22][CH2:21][C:20]2([N:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]3[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[O:9]2)[CH2:19][CH2:18]1
Reactant: CN1CCC(=O)CC1
Reactant: OC(c1ccc(Cl)cc1)C1CCCCN1
Product: CN1CCC2(CC1)OC(c1ccc(Cl)cc1)C1CCCCN12

Procedure:
Utilizing the procedure described in Example 1 above, alpha-(4-chlorophenyl)-2-piperidinemethanol (10 g) is reacted with 1-methyl-4-piperidone (7 g) to yield hexahydro-1'-methyl-1-(4-chlorophenyl)spiro[3H-oxazolo[3,4-a]pyridine-3,4'-piperidine]; mp 122°-124° C., after chromatography over silica gel with ethyl acetate.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[F:24][C@@H:25]1[CH2:27][C@H:26]1[C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:34]=[CH:35][C:36]([CH3:40])=[C:37]([CH:39]=2)[NH2:38])[N:29]=1>ClCCl.N1C=CC=CC=1>[F:24][C@H:25]1[CH2:27][C@@H:26]1[C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:34]=[CH:35][C:36]([CH3:40])=[C:37]([NH:38][C:10]([C:3]3[N:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]4=[N:1][CH:2]=3)=[O:12])[CH:39]=2)[N:29]=1
Reactant: Cc1ccc(-c2noc([C@@H]3C[C@H]3F)n2)cc1N
Reactant: O=C(O)c1cnc2ccccn12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2noc([C@H]3C[C@@H]3F)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirring suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (1) (52 mg, 0.32 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under Argon was added dropwise oxalyl chloride (56 μL, 0.64 mmol). Then, a drop of anhydrous DMF was added and the reaction mixture was stirred at room temperature for 1.5 hours. The solvent was concentrated and the crude solid was added portion-wise to a stirring solution of 5-(5-((1S,2R)-2-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (132) (62 mg, 0.27 mmol) in anhydrous pyridine (1 mL) at 0° C. The reaction was stirred at room temperature under Argon for 30 minutes and quenched with water. The crude product was purified by preparative HPLC to yield N-(5-(5-((1R,2S)-2-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F113). MS m/z 378.1 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[F:20])=[CH:11][C:10]([C:21]([OH:23])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[F:20])=[CH:11][C:10]([C:21]([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=[O:23])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2cccc(F)c2F)n(-c2cccc(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Product: O=C1CN(C(=O)c2cc(-c3cccc(F)c3F)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 88A in analogy to the synthesis of the compound of Example 1. 8 mg (100% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:11][C:5]=2[N:4]=[CH:3]1.[C:18]12([CH2:28][C:29](Cl)=[O:30])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2>>[C:18]12([CH2:28][C:29]([NH:1][N:2]3[C:7](=[O:8])[C:6]4[CH:9]=[C:10]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)[S:11][C:5]=4[N:4]=[CH:3]3)=[O:30])[CH2:25][CH:24]3[CH2:23][CH:22]([CH2:21][CH:20]([CH2:26]3)[CH2:19]1)[CH2:27]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nn1cnc2sc(-c3ccccc3)cc2c1=O
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1cnc2sc(-c3ccccc3)cc2c1=O

Procedure:
3-Amino-6-phenylthieno[2,3-d]pyrimidin-4(3H)-one and 1-adamantaneacetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.65-1.75 (m, 12H), 2.01-2.05 (m, 3H), 2.23 (s, 2H), 7.35-7.46 (m, 3H), 7.63-7.65 (m, 2H), 7.69 (s, 1H), 7.99 (s, 1H), 8.10 (s, 1H); MS (DCI/NH3) m/z 420 (M+H)+; Elemental Analysis: Calculated for C24H25N3O2S: C, 68.71; H, 6.01; N, 10.02. Found: C, 68.53; H, 5.65; N, 9.98.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][P:13]([CH2:22][CH2:23][CH2:24][NH2:25])([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])=[O:14])[CH3:11].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:10]([O:12][P:13]([CH2:22][CH2:23][CH2:24][NH:25][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])=[O:14])[CH3:11]
Reactant: CCOC(OCC)P(=O)(CCCN)OCC
Reactant: O=Cc1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(OCC)P(=O)(CCCNCc1ccc(Cl)cc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.41 g of p-chlorobenzaldehyde are added to a solution of 2.53 g of 3-aminopropyl(diethoxymethyl)phosphinic acid ethyl ester in 10 ml of anhydrous methanol, and the resulting clear solution is stirred at room temperature for 30 minutes. There are then added first 0.6 g of glacial acetic acid and then, dropwise, 0.21 g of sodium cyanoborohydride in solution in 5 ml of methanol. An exothermic reaction begins. The mixture is stirred at 20° for 3 hours and adjusted to pH 8, and the solvent is removed. The residue is dissolved in dichloromethane and washed with water. The organic phase is separated off, dried over sodium sulfate and concentrated to dryness by evaporation. The oil that remains is purified by chromatography on silica gel, yielding 3-(p-chlorobenzylamino)propyl(diethoxymethyl)phosphinic acid ethyl ester in the form of a yellowish oil.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][C@@H:12]1[CH2:16][O:15][CH2:14][C@H:13]1[NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl>[O:11]=[C:12]1[CH2:16][O:15][CH2:14][CH:13]1[NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(N[C@@H]1COC[C@H]1O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(NC1COCC1=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
Dimethyl sulfoxide (3.54 mL, 49.8 mmol) was added dropwise over 10 min to a vigorously stirred mixture of a 2 M dichloromethane solution of oxalyl chloride (12.46 mL, 24.91 mmol) and dichloromethane (40 mL) at −78° C. After another 15 min at −78° C., a solution of benzyl trans-4-hydroxytetrahydrofuran-3-ylcarbamate (3.94 g, 16.61 mmol, from Step 2) in dichloromethane (20 mL) was added dropwise over 15 min. After 30 min at −78° C., the mixture was diluted with dichloromethane (20 mL). Triethylamine (9.26 mL, 66.4 mmol) was added. The mixture became a thick slurry (a large stir bar was necessary for efficient stirring). The mixture was stirred at −78° C. for 30 min, at ambient temperature for 40 min, quenched with water (150 mL) and extracted with dichloromethane (3×100 mL). The combined extracts were dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 20-50% ethyl acetate in hexanes, gave benzyl 4-oxotetrahydrofuran-3-ylcarbamate as tan solid (3.579 g, 92% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.28-7.47 (5 H, m), 5.21 (1H, br. s.), 5.01-5.16 (2 H, m), 4.69 (1 H, t, J=8.58 Hz), 4.15-4.31 (2 H, m), 3.92 (1 H, d, J=17.61 Hz), 3.79 (1 H, t, J=9.57 Hz).
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH3:4].[CH2:6]([NH:8][C:9](=[O:21])[O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[CH3:7].C([O-])(=O)C.[Na+].[BH4-].[Na+]>O.C(O)(=O)C>[CH2:6]([NH:8][C:9](=[O:21])[O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:18][CH:19]=1)[CH3:7]
Reactant: CCC(C)=O
Reactant: CCNC(=O)OCCOc1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCNC(=O)OCCOc1ccc(NC(C)CC)cc1

Procedure:
To a mixture of 2-butanone (5 ml), 2-(4-aminophenoxy)ethyl N-ethylcarbamate (1.00 g) and sodium acetate (2.50 g) in a solution of 5 ml of acetic acid and 10 ml of water, cooled to -5°, is added sodium borohydride (4.00 g) in portions. After addition is complete, the reaction mixture is adjusted to alkaline pH and is extracted with ether. The combined organic extracts are concentrated and the crude product is purified by column chromatography to give 2-[4-(1-methylpropylamino)phenoxy]ethyl N-ethylcarbamate (compound 35, Table B).
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([O:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]3)[CH:9]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[CH:31][C:5]=2[N:4]=1.[C:33]([O:37][C:38]([N:40]([CH3:49])[C@H:41]([C:46](O)=[O:47])[CH2:42][CH2:43][S:44][CH3:45])=[O:39])([CH3:36])([CH3:35])[CH3:34].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[F:32][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([O:20][C@H:21]3[CH2:22][CH2:23][C@H:24]([NH:27][C:46](=[O:47])[C@@H:41]([N:40]([CH3:49])[C:38](=[O:39])[O:37][C:33]([CH3:34])([CH3:36])[CH3:35])[CH2:42][CH2:43][S:44][CH3:45])[CH2:25][CH2:26]3)[CH:9]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[CH:31][C:5]=2[N:4]=1
Reactant: N[C@H]1CC[C@H](Oc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Reactant: CSCC[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CSCC[C@@H](C(=O)N[C@H]1CC[C@H](Oc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexanamine (700 mg) and N,N-dimethylformamide (7.0 mL) were added N-(tert-butoxycarbonyl)-N-methyl-L-methionine (622 mg), 1H-benzotriazol-1-ol (319 mg), and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (452 mg), followed by stirring at room temperature overnight. After the completion of the reaction, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=90:10-40:60) to obtain tert-butyl [(2S)-1-{[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]amino}-4-(methylsulfanyl)-1-oxobutan-2-yl]methylcarbamate (859 mg).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.C[O:33][C:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:35]=1B(O)O>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:33][C:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:35]=1[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: COc1cc(C)ccc1B(O)O
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C)cc1O
Yield: 65 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.10 g; 0.314 mmol), tetrakis(triphenylphosphine) palladium(0) (0.036 mg; 0.031 mmol), N,N-diisopropylethylamine (0.216 mL; 1.25 mmol) and 2-methoxy-4-methylphenylboronic acid (0.078 g; 0.47 mmol in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.082 g (65%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:33](Cl)(Cl)=[O:34].Cl.[CH2:38]([NH:45][OH:46])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1(C)C=CC=CC=1>[CH2:38]([N:45]([OH:46])[C:33]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:11][CH2:12]1)=[O:34])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)Cl
Reactant: ONCc1ccccc1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)N(O)Cc2ccccc2)CC1
Yield: 77 %

Procedure:
To a solution of COMPOUND 249 (0.115 g, 0.37 mmol) in toluene (4 mL) was added DIPEA (0.16 mL, 0.92 mmol) followed by phosgene solution (20% in toluene, 0.20 mL, 0.44 mmol). The resultant mixture was stirred at room temperature for 90 minutes then concentrated under reduced pressure. The residue was dissolved in DMF (4 mL) and treated with DIPEA (0.60 mL, 3.44 mmol) followed by N-benzylhydroxylamine hydrochloride (0.194 g, 1.22 mmol) and the resultant mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was partitioned between CH2Cl2 (50 mL) and saturated aqueous NaHCO3 (15 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 25:1:1 CH2Cl2-MeOH—NH4OH) provided 131 mg (74%) of COMPOUND 272 as a white solid. 1H NMR (CDCl3) δ 1.64-1.76 (m, 2H), 1.918-1.96 (m, 2H), 2.08 (s, 6H), 2.68-2.79 (m, 3H), 3.81 (s, 4H), 4.20 (d, 2H, J=13.2 Hz), 4.30 (s, 2H), 6.81 (s, 1H), 7.08 (dd, 2H, J=7.5, 4.8 Hz), 7.27-7.38 (m, 7H), 8.32 (d, 2H, J=3.6 Hz); 13C NMR (CDCl3) δ 18.35, 27.54, 46.12, 54.86, 57.74, 59.70, 122.87, 127.94, 128.68, 129.35, 133.88, 136.61, 138.59, 146.15, 157.28, 164.68; ES-MS m/z 460 (M+H). Anal. Calcd. For C27H33N5O2.0.2CH2Cl2: C, 68.55; H, 7.06; N, 14.70. Found: C, 68.85; H, 7.21; N, 14.79.
Reaction SMILES: F[C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[C:3]([C@H:8]3[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:28][CH:27]=1)=[O:25]
Reactant: O[C@H]1CCC[C@H](c2nccnc2F)C1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(c1ccc(Oc2nccnc2[C@H]2CCC[C@H](O)C2)cc1)c1nc2ccccc2[nH]1
Temperature: 150 °C

Procedure:
A mixture of (rac)-trans-3-(3-fluoropyrazin-2-yl)cyclohexanol (106 mg, 0.540 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (257 mg, 1.080 mmol), and cesium carbonate (352 mg, 1.080 mmol) was heated in a Biotage™ microwave reactor at 150° C. for 30 min. The mixture was partitioned between H2O (10 ml) and CH2Cl2 (20 ml), the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×20 ml). The combined organic layers were dried (MgSO4), concentrated under reduced pressure, and the resulting brown oil was purified by reversed phase HPLC (Gilson Gemini-NX 10u C18 110A, 100×50.0 mm, 10% to 95% H2O/MeCN, 0.1% TFA). The product containing fractions were combined, neutralized by the addition of solid Na2CO3, and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to deliver (rac)-trans-(1H-benzo[d]imidazol-2-yl)(4-(3-(3-hydroxycyclohexyl)pyrazin-2-yloxy)phenyl)methanone as a light yellow solid. MS (ESI, pos. ion) m/z: 415.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14](N3CCN(C(OC(C)(C)C)=O)C[C@@H]3C)=[CH:13]C=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:31][N:32]1CCC2N=C(N)[S:40][C:34]=2[CH2:33]1.BrC1C(=O)N(C)C=C(Br)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[S:40][C:34]3[CH2:33][N:32]([CH3:31])[CH2:13][CH2:14][C:15]=3[N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Reactant: CN1CCc2nc(N)sc2C1
Agent: Cn1cc(Br)cc(Br)c1=O
Product: CN1CCc2nc(Nc3cc(Br)cn(C)c3=O)sc2C1
Yield: 44 %

Procedure:
Following the procedures described for 191g and starting with 203a (4.0 g, 23.5 mmol) and 3,5-dibromo-1-methylpyridin-2(1H)-one (3.0 g, 17.8 mmol) afforded 203b as yellow solid (2.8 g, 44%). MS: [M+H]+ 357.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH3:13])=[C:5]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].C[Si](/N=C(/O[Si](C)(C)C)\C(F)(F)F)(C)C.CCN(CC)CC.[C:36](Cl)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38]>C1COCC1>[CH3:13][C:4]1[C:3]([CH2:2][NH:1][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:11][CH:10]=[C:9]([CH3:12])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(CN)c(C)c1C(=O)O
Agent: C[Si](C)(C)/N=C(/O[Si](C)(C)C)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1C(=O)O
Temperature: 0 °C
Reaction time: 18 h
Yield: 69.5 %

Procedure:
To a solution of 2,6-dimethyl-3-((2,2,2-trifluoroacetamido)methyl)benzoic acid (3.2 g) in THF (15 mL) was added 1N HCl (15 mL) and the reaction mass was heated at reflux for 3 h. The reaction mixture was concentrated and the crude was co-distilled with toluene to afford 2.0 g of the 3-(aminomethyl)-2,6-dimethylbenzoic acid which was used in the next step without further purification. To a solution of 3-(aminomethyl)-2,6-dimethylbenzoic acid (500 mg, 2.46 mmol) in THF was added N,O-bis(trimethylsilyl)trifluoroacetamide (948 mg, 3.69 mmol) and the reaction mass was heated at reflux for 20 minutes. The reaction mass was cooled to 0° C. and Et3N (1.77 mL, 9.85 mmol) was added, followed by pivaloyl chloride (0.44 mL, 3.69 mmol). The reaction mixture was stirred at rt for 18 h before it was quenched with water and was extracted with chloroform. The organic layer was separated, dried, filtered and concentrated to afford 450 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 13.15 (br s, 1H), 7.93 (br t, 1H), 7.08-7.01 (m, 2H), 4.19 (d, J=5.7 Hz, 2H), 2.21 (s, 3H), 2.17 (s, 3H), 1.12 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=1
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2cccc(Br)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-3′-bromoacetophenone. 1H-NMR (CDCl3) δ: 8.25 (1H, d, J=1.5 Hz), 7.90 (1H, t, J=1.8 Hz), 7.64-7.59 (2H, m), 7.54 (1H, d, J=8.4 Hz), 7.34-7.26 (2H, m), 5.87 (2H, br s). 3.84 (2H, q, J=7.0 Hz), 0.89 (3H, t, J=7.0 Hz)