Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[Cl:1][C:2]1[S:6][C:5]([C:11]2[CH:12]=[CH:13][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(Cl)s1
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: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(Cl)s2)cc1
Temperature: 70 °C
Reaction time: 20 h
Yield: 66.5 %

Procedure:
A stirred mixture of 5-chloro-thiophene-2-boronic acid (5.15 g, 0.0317 mol), 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (8.00 g, 0.0294 mol), and tetrakis(triphenylphosphine)palladium(0) (1.09 g, 0.00094 mol) in a two-phase mixture of toluene (62 mL) and 2.0 M aqueous sodium carbonate (31 mL, 0.062 mol) was heated at 70° C. for 20 hours and allowed to cool to room temperature. Additional 5-chloro-thiophene-2-boronic acid (0.369 g, 0.00227 mol) was added, and the mixture was reheated at 65° C. for 20 hours. The mixture was cooled to room temperature and filtered through Celite, eluting with dichloromethane. Filtrate and washings were combined, and the mixture was washed with 0.10 M aqueous sodium hydroxide (100 mL), 3% aqueous ammonium hydroxide (100 mL), water, and brine. The organics were dried (Na2SO4), and rotary evaporated to a solid. The residue was dissolved in chloroform. silica gel (101 g, 230-400 mesh) was added, and the mixture was rotary evaporated to dryness. The residue was purified by chromatography on silica gel (1450 g, 230-400 mesh), eluting with hexanes-acetone (12:1, 16×1L; 9:1, 12×1L) to give 6.04 g of 4-[4-(5-chloro-thiophen-2-yl)-phenyl]-4-oxo-butyric acid, methyl ester as a bright yellow solid; mp 117-118° C.
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:5])C.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>CO>[CH:30]1([NH:33][C:4]([C:6]2[S:10][C:9]([N:11]3[C:15]4[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:14]=4[N:13]=[CH:12]3)=[N:8][C:7]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:5])[CH2:32][CH2:31]1
Reactant: CCOC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1-c1ccccc1
Reactant: NC1CC1
Solvent: CO
Product: COc1cc2ncn(-c3nc(-c4ccccc4)c(C(=O)NC4CC4)s3)c2cc1OC

Procedure:
2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid cyclopropylamide was prepared from 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid ethyl ester (24 mg, 0.06 mmol) and cyclopropylamine in methanol (4 molar) as described above in the general amide formation procedure. Product was isolated by preparative HPLC: 10 mg, 40%. 1H-NMR (DMSO-D6) 8.8 (s, 1H); 8.54 (t, 1H); 7.80-7.87 (m, 2H), 7.41-7.55 (m, 3H); 7.38 (s, 1H); 3.90 (s, 3H); 3.86 (s, 3H); 3.25 (q, 2H); 1.08 (t, 3H). MS M/z 421 (M+1).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9][CH:8]=1.CN(C)[CH:19]=[O:20]>O1CCCC1>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([CH:19]=[O:20])=[CH:8][N:9]=1
Reactant: Brc1cncc2ccccc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cncc2ccccc12
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 32.5 %

Procedure:
n-Butyllithium (1.6 M in hexanes, 11.0 ml, 17.6 mmol) is added dropwise to a stirred solution of 4-bromoisoquinoline (3.02 g, 14.5 mmol) and anhydrous tetrahydrofuran (100 ml) at −78° C. under nitrogen. The reaction is stirred for 45 min at −78° C. and then dimethylformamide (6.0 ml, 77.5 mmol) is added. The reaction is then stirred for 3 h at −78° C. before it is quenched with water. The reaction is then poured into saturated sodium bicarbonate solution (200 ml) and extracted with ethyl acetate (100 ml×3). The ethyl acetate is washed with brine and dried over sodium sulfate. The sodium sulfate is filtered and the crude product is concentrated on a rotary evaporator. The crude product is purified by flash chromatography on silica gel eluting with 50% ethyl acetate/hexanes to yield (0.74 g, 33%) of isoquinoline-4-carboxaldehyde: mass spectrum (ion spray): m/z=158.1 (M+1).
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:6][CH2:5][S:4][C:3]1=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=1.O.[OH-].[Li+]>C(O)C.O>[F:21][C:2]1([F:1])[CH2:6][CH2:5][S:4][C:3]1=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(C)c1ccc(C=C2SCCC2(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1ccc(C=C2SCCC2(F)F)cc1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 85.1 %

Procedure:
Ethyl 2-[4-(3,3-difluorothiolan-2-ylidenemethyl)phenyl]propionate (43 mg) obtained in Example 24 was dissolved in a solution of ethanol/water (1/1, 1.0 ml), and to the solution was added lithium hydroxide monohydrate (20 mg), and the reaction mixture was stirred at room temperature for 16.5 hours. After completion of the reaction, to the reaction mixture was added 2.0 M aqueous hydrochloric acid, phase separation was performed with ethyl acetate, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to give the title compound (33.3 mg, 85.1%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][N:20]3[C:26](=[O:27])[CH2:25][C:24]4[CH:28]=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:23]=4[CH2:22][CH2:21]3)[CH2:14]2)[CH:7]=[CH:8][C:9]=1[OH:10].[CH3:36][S:37]([Cl:40])(=[O:39])=[O:38]>>[ClH:40].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][N:20]3[C:26](=[O:27])[CH2:25][C:24]4[CH:28]=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:23]=4[CH2:22][CH2:21]3)[CH2:14]2)[CH:7]=[CH:8][C:9]=1[O:10][S:37]([CH3:36])(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(CCN2CCCC(CN3CCc4cc(OC)c(OC)cc4CC3=O)C2)ccc1O
Agent: Cl
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(CCc3ccc(OS(C)(=O)=O)c(OC)c3)C1)CC2

Procedure:
Prepared from 3-[(N-(2-(3-methoxy-4-hydroxy-phenyl)-ethyl)-piperidin-3-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-hydrochloride and methanesulphonic acid chloride analogously to Example 9.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.[F:14][C:15]1[CH:29]=[CH:28][C:18]2[C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:20][O:21][C:17]=2[CH:16]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[F:14][C:15]1[CH:29]=[CH:28][C:18]2[C:19]([N:22]3[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][N:5]4[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[N:7]=[N:6]4)[CH2:24][CH2:23]3)=[N:20][O:21][C:17]=2[CH:16]=1
Reactant: Fc1ccc2c(N3CCNCC3)noc2c1
Reactant: ClCCCn1nnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Fc1ccc2c(N3CCN(CCCn4nnc5ccccc54)CC3)noc2c1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
1-(3-chloropropyl)-1H-benzotriazole (7.02 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 6-fluoro-3-(piperazine-1-yl)benzisoxazole (6.6 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 7.9 g compound (I-37) with a yield of 69.3%. ESI-MS [M+H]+: m/z 380.2.
Reaction SMILES: [N+:1]([C:4]1[C:14]2[NH:13][CH2:12][CH2:11][O:10][C:9](=[O:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[C:14]2[NH:13][CH2:12][CH2:11][O:10][C:9](=[O:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1OCCNc2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c1NCCOC2=O
Reaction time: 6 h
Yield: 99.7 %

Procedure:
A solution of 500 mg (2.42 mmol) of 9-nitro-2,3-dihydro-4,1-benzoxazepin-5(1H)-one in 500 mL of methanol was inerted with nitrogen. To this solution was added 100 mg of 10% palladium on carbon (50% wet) and the reaction was purged with hydrogen and stirred under balloon pressure hydrogen for 6 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 430 mg (99%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[C:1]([C:5]1[O:6][C:7]2[C:13]([S:14]([N:26]3[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][O:20][CH3:19])[CH2:24][CH2:25]3)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Reactant: COCCN1CCNCC1
Product: COCCN1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1

Procedure:
Followed the general procedure described in Example 1c, 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride coupled with 2-methoxy-ethyl-piperazine to give the desired product 2a, 1.11 g (82%). LC-MS (m/z) 416.2 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:12]([OH:14])=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH2:32][CH2:33][NH2:34])[CH2:27][CH2:26]2>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:12]([NH:34][CH2:33][CH2:32][N:28]1[C:29]2[C:25](=[CH:24][C:23]([F:22])=[CH:31][CH:30]=2)[CH2:26][CH2:27]1)=[O:14]
Reactant: NCCN1CCc2cc(F)ccc21
Reactant: O=C(O)[C@H](CC1CCCCC1)Nc1nc2ccccc2o1
Product: O=C(NCCN1CCc2cc(F)ccc21)[C@H](CC1CCCCC1)Nc1nc2ccccc2o1

Procedure:
The title compound was prepared from 2-(S)-(benzooxazol-2-ylamino)-3-cyclohexyl propionic acid and 2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylamine using the procedure analogous to that described in example 2. HPLC-MS calcd. for C26H31FN4O2 (M+H+) 451.24. found 451.5.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][S:14]([CH2:17][C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1)(=[O:16])=[O:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24]O>C1(C)C=CC=CC=1.[Si](C=[N+]=[N-])(C)(C)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][S:14]([CH2:17][C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1)(=[O:15])=[O:16])[C:10]([O:12][CH3:24])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CS(=O)(=O)Cc1cnccn1)C(=O)O
Reactant: CO
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](CS(=O)(=O)Cc1cnccn1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
(R)-tert-Butoxycarbonylamino-3-(pyrazin-2-ylmethanesulfonyl)propionic acid (1.42 g, 4.53 mmol) was dissolved in mixture of MeOH (10 mL) and toluene (33 mL) and Me3SiCHN2 (2.0 M solution in hexanes, 3.06 ml) was added dropwise over 10 min. After stirring the reaction mixture overnight, the solvent was removed and the resulting residure was purified by flash chromatography with EtOAc/hexanes as eluent to afford methyl 2(R)-tert-butoxycarbonylamino-3-(pyrazin-2-ylmethanesulfonyl)propionate (0.755 g).
Reaction SMILES: [Na].[N+](C(C)C)([O-])=[O:3].[Br:8][C:9]1[C:18]([CH2:19]Br)=[CH:17][C:16]2[C:15]([CH3:22])([CH3:21])[CH2:14][CH2:13][C:12]([CH3:24])([CH3:23])[C:11]=2[CH:10]=1>C(O)C>[Br:8][C:9]1[C:18]([CH:19]=[O:3])=[CH:17][C:16]2[C:15]([CH3:22])([CH3:21])[CH2:14][CH2:13][C:12]([CH3:24])([CH3:23])[C:11]=2[CH:10]=1
Reactant: CC1(C)CCC(C)(C)c2cc(CBr)c(Br)cc21
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na]
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(C=O)c(Br)cc21
Reaction time: 8 h
Yield: 60.5 %

Procedure:
0.981 g (42.7 mmol) of sodium was dissolved in 50 mL of ethanol. To this solution was added 4.94 g (55.5 mmol) of 2-nitropropane followed by 17.3 g (42.7 mmol) of crude 2-bromo-3-bromomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 75 mL ethanol. After 8 hours, this mixture was concentrated in vacuo and then partitioned between ethyl acetate and water. The organic layer was sequentially washed with 1M aqueous sodium hydroxide, water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The product was purified by flash chromatography on silica gel with gradient elution (1-2% ethyl acetate/hexane) to afford 7.63 g (61%) of 3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde (m.p.=113.9-114.3° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:15]1[N:16]([CH2:23][C@@H:24]2[CH2:26][O:25]2)[CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[N:19]=1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:26][C@@H:24]3[O:25][C:15]4=[N:19][C:18]([N+:20]([O-:22])=[O:21])=[CH:17][N:16]4[CH2:23]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1cn(C[C@@H]2CO2)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn2c(n1)O[C@@H](CN1CCN(c3ccc(Cl)cc3)CC1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
Then, a mixture of 1-(4-chlorophenyl)-piperazine obtained, (R)-2-chloro-1-(oxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 9 (763 mg, 3.75 mmol) and DMF (5 ml) was stirred at 70° C. for 6 hours. To the solution, sodium hydride (219 mg, 5.48 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 2 hours. To the reaction mixture, ice-water was added, and precipitates were filtered off. The resulting solids were recrystallized from acetone/water to afford (S)-2-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (250 mg, yield 18%) as a light yellow powder.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:14][CH3:15])[C:5]2[S:10][CH:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18].C(=O)([O-])O.[Na+]>>[CH2:16]([NH:19][C:2]1[N:3]=[C:4]([NH:14][CH3:15])[C:5]2[S:10][CH:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1)[CH:17]=[CH2:18]
Reactant: CNc1nc(Cl)nc2c(C(C)C)csc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NC)c2scc(C(C)C)c2n1
Yield: 91.7 %

Procedure:
90 mg (0.37 mmol) of 2-chloro-7-isopropyl-4-methylaminothieno[3,2-d]pyrimidine and 340 mg (5.96 mmol) of allylamine were heated in a sealed tube at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 89 mg (yield: 91.1%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[OH:16])=[O:8]>C(O)(C)C.CCCCCCC>[Br:1][C:2]1[C:3]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])=[N:4][C:5]([C:18]([F:21])([F:19])[F:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[OH:16])=[O:8]
Reactant: O=C(NC1CCCCC1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Solvent: CC(C)O
Solvent: CCCCCCC
Product: O=C(N[C@@H]1CCCC[C@@H]1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F

Procedure:
5-Bromo-N-((1RS,2SR)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide (103 g) was subjected to chiral chromatography on ChiralPak AD with 5% isopropanol/n-heptane as eluent. The product eluted as second peak to give after evaporation of the solvent the title compound (43.3 g) as a white solid, MS (ISP) 465.0, 467.0 (M+H)+; [α]D20+19.1°.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[C:3]=1[OH:15].BrBr>>[OH:15][C:3]1[C:4]([C:12]([OH:14])=[O:13])=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=1
Reactant: O=C(O)c1cc2ccccc2c(Br)c1O
Agent: BrBr
Product: O=C(O)c1cc2ccccc2cc1O

Procedure:
A similar procedure is used to prepare 1-bromo-2-hydroxy-3-naphthoic acid except that bromine is used instead of chlorine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([Cl:9])[CH:3]=1.N1C=CC=CC=1.[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:19](=[O:20])[CH2:18][CH2:17][Cl:16])=[C:4]([Cl:9])[CH:3]=1
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccc(Br)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCCl)Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
To a solution of 4-bromo-2-chloro-phenylamine (32 g, 0.15 mol) and pyridine (13.45 g, 0.17 mol) in DCM (200 mL) was added 3-chloropropionyl chloride (21.65 g, 0.17 mol) dropwise at 15° C. After stirring at room temperature for 1 hour, the mixture was washed with water and then hydrochloric acid (2 N, aqueous). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford title compound (10.9 g, yield: 90%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([CH2:13]O)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:17])=O>>[C:1]1([C:7]2[N:12]=[C:11]([CH2:13][Cl:17])[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccnc(-c2ccccc2)n1
Product: ClCc1ccnc(-c2ccccc2)n1

Procedure:
A solution of 55 mg 2-phenyl-4-hydroxymethylpyrimidine in 1 mL of thionyl chloride was heated at reflux temperature for 1 hr and the excess thionyl chloride removed by evaporation under reduced pressure to yield 50 mg of 2-phenyl-4-chloromethylpyrimidine as an oil which was used in the next step without further purification or characterization.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=1[CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH3:17])[C:10]1=[O:18].Br>ClCCl.C(O)(=O)C>[OH:8][C:7]1[CH:2]=[C:3]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH3:17])[C:10]2=[O:18])[CH:4]=[CH:5][CH:6]=1
Reactant: CCCN1CCCC(C2=C(Br)C(=O)CCC2)C1=O
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCN1CCCC(c2cccc(O)c2)C1=O
Yield: 87.2 %

Procedure:
The product of Example 8 (10.5 g, 33.4 mM) in dichloromethane (70 ml) was treated with 48% hydrogen bromide in acetic acid (ca 0.5 ml). After 16 h the solvent was evaporated under reduced pressure and the residue was partitioned between chloroform and water. The organic phase was dried and evaporated and the residue was chromatographed on alumina (neutral, grade 3) using 4% methanol in chloroform as eluant. The appropriate fractions were avaporated and recrystallised from ether to yield the title compound (6.8 g) m.p. 61°-3° (Found: C, 71.9; H, 7.8; 5.6% C14H19NO2 requires C, 72.1; H, 8.2; 6.0%).
Reaction SMILES: C(OCC)C.C([Mg]Br)C.[C:10]1([S:16]([N:19]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=3[F:28])[C:21](I)=[CH:20]2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:31]([N:38]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@@H:39]([CH3:42])[CH:40]=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[CH2:43]([N:38]([CH:39]([CH3:42])[CH:40]([C:21]1[C:22]2[C:27](=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[N:19]([S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[CH:20]=1)[OH:41])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(F)cc(F)c21
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C(O)c1cn(S(=O)(=O)c2ccccc2)c2c(F)cc(F)cc12)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 76.8 %

Procedure:
A 3.0 M diethyl ether solution of ethylmagnesium bromide (7.3 ml, 21.8 mmol) is added under N2 at 0° C. to a 95 ml tetrahydrofuran solution of N-benzenesulfonyl-3-iodo-5,7-difluoro-indole (8.4 g, 20 mmol). The resulting mixture is stirred for 20 minutes at 0° C., allowed to warm to room temperature over 20 minutes, then recooled to 0° C. A 20 ml tetrahydrofuran solution of (S)N,N dibenzyl-2-aminopropanal (Syn. Lett., 1997,2, 223-224, 5.1 g, 22 mmol) is added to the reaction mixture and the resulting mixture is stirred 1 hour as it warmed to room temp. The reaction is quenched with aqueous NH4Cl, extracted with ethyl acetate, washed with brine, dried (Na2SO4), filtered, concentrated, and the residue is purified by flash chromatography (SiO2, ethyl acetate/hexane gradient) to yield 8.4 g of 2-(N,N-dibenzylamino)-1-(1-benzenesulfonyl-5,7-difluoro-1H-indol-3-yl)-propan-1-ol. (77%)
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][C:15]=3[N:14]=[CH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH2:7]1.[CH3:24]O>>[CH3:24][O:22][C:21]([C:19]1[CH:18]=[CH:17][C:16]2[N:12]([C:6]3([Br:5])[CH:7]=[CH:8][CH:9]=[CH:10][CH2:11]3)[CH:13]=[N:14][C:15]=2[CH:20]=1)=[O:23]
Reactant: CO
Reactant: O=C(O)c1ccc2c(c1)ncn2C1(Br)C=CC=CC1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(c1)ncn2C1(Br)C=CC=CC1

Procedure:
Thionyl chloride (10 mL, 0.137 mol) was added dropwise to a stirred suspension of the 1-bromophenyl-1H-benzimidazole-5-carboxylic acid (20 g, 0.063 mol) in MeOH (200 mL) at 0-5° C. The reaction was stirred at reflux for 18 h and then concentrated under reduced pressure. The solid residue was triturated with cold water, basified with aqueous ammonium hydroxide solution and extracted with DCM. The extract was washed with water, aqueous brine solution, dried over MgSO4 and concentrated in vacuo to give the corresponding 1-bromophenyl-1H-benzimidazole-5-carboxylic acid methyl ester: e.g. 1-(4-bromophenyl)-1H-benzimidazole carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1.[CH3:24][C:25]1([NH2:29])[CH2:28][O:27][CH2:26]1>>[CH3:24][C:25]1([NH:29][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][C:9]([O:8][CH2:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][C:5]=3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:10][CH:11]=2)[CH2:28][O:27][CH2:26]1
Reactant: CC1(N)COC1
Reactant: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)NC2(C)COC2)cn1
Yield: 93 %

Procedure:
As described for example 26b, 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (80 mg, 0.26 mmol) was converted, using 3-methyl-3-oxetanamine instead of 4-aminotetrahydropyran, to the title compound (91 mg, 93%) which was obtained as an off white solid. MS: m/e=381.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[O:9]=[C:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1>C(#N)C>[Cl:8][C:4]1[N:3]=[C:2]([N:14]2[CH2:13][CH2:12][NH:11][C:10](=[O:9])[CH2:15]2)[CH:7]=[N:6][CH:5]=1
Reactant: O=C1CNCCN1
Reactant: Clc1cncc(Cl)n1
Solvent: CC#N
Product: O=C1CN(c2cncc(Cl)n2)CCN1

Procedure:
A mixture of 10.0 g (0.0067 mole) of 2,6-dichloropyrazine and 14 g (0.14 mole) of 2-oxopiperazine in 100 ml of acetonitrile is refluxed 1.5 hour with stirring under N2. The mixture is concentrated under vacuum, the residue titrated with water and filtered, and the crude solid recrystallized from water (charcoal treatment) to give off-white plates of the subject compound, 7.7 g, mp 192°-193° C.