Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:16][C:17]([C:19]2[CH:24]=[CH:23][N:22]=[N:21][CH:20]=2)=[O:18])=[CH:11][CH:10]=1.B([C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=1)(O)O>O1CCOCC1>[O:18]=[C:17]([C:19]1[CH:24]=[CH:23][N:22]=[N:21][CH:20]=1)[CH2:16][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=2)=[CH:14][CH:13]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]
Reactant: Cc1ccccc1C(CC(=O)c1ccnnc1)c1ccc(Br)cc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1C(CC(=O)c1ccnnc1)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 80 °C

Procedure:
Water (1 mL) and 2 M aq. sodium carbonate solution (0.39 mL, 0.78 mmol) were added at room temperature to a degassed solution of 3-(4-bromophenyl)-1-(pyridazin-4-yl)-3-o-tolylpropan-1-one (100 mg, 262 μmol), 4-boronobenzoic acid (53.8 mg, 315 μmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (11 mg, 13 μmol) in 1,4-dioxane (1.5 mL). After heating at 80° C. for 4 h the reaction mixture was partitioned between ethyl acetate and sat. aq. ammonium chloride solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. After chromatography (SiO2; gradient heptane/ethyl acetate 1:1 to ethyl acetate) the title compound was obtained (33 mg, 30%). Light yellow solid, MS: 423.2 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([S:27][CH3:28])[N:8]2[C:14]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=3[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[N:11][CH2:10][C:9]=12)=[O:4].[CH3:29][NH2:30].[K+].[Br-]>C(O)C>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]2[N:8]3[C:7]([S:27][CH3:28])=[N:6][C:5]([C:3]([NH:30][CH3:29])=[O:4])=[C:9]3[CH2:10][N:11]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:13]=2[CH:18]=1
Reactant: CN
Reactant: COC(=O)c1nc(SC)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: CNC(=O)c1nc(SC)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2

Procedure:
A mixture of 2.1 g (0.005 mole) of 8-chloro-6-(2-chlorophenyl)-1-methylthio-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid methyl ester and 20 ml of a 28% solution of methylamine in ethanol was heated at 130° in a steel bomb for 18 hrs. The contents of the bomb were evaporated at reduced pressure to give a tan solid. Recrystallization from ethanol gave off-white prisms with mp 224°-227°. Uv λ max 218 mμ (ε=51,400) infl 245 (26,000) sh 275 (12,000); ir (KBr) 3410 cm-1 (NH) 1668, 1527 (CON).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][N:14]=2)[CH3:12])=[O:9])=[CH:3][CH:2]=1.Br[CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8]([NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:27][CH2:28][CH3:29])=[CH:15][N:14]=2)[CH3:12])=[O:9])=[CH:5][CH:6]=1
Reactant: CCCBr
Reactant: C[C@@H](NC(=O)Cc1ccc(-c2ccccc2)cc1)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc([C@@H](C)NC(=O)Cc2ccc(-c3ccccc3)cc2)nc1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-(1,1′-biphenyl-4-yl)-N-[(1R)-1-(5-hydroxypyridin-2-yl)ethyl]acetamide (30 mg, 0.09 mmol) (Example 8), 1-bromopropane (0.02 ml, 0.22 mmol) in DMF (1.2 ml) was added potassium carbonate (37 mg, 0.27 mmol). The reaction was stirred at 40° C. for 18 hours and then filtered through a cotton plug to remove any precipitates, washing with DMSO (2 ml). The collected filtrate was purified using reverse phase prep HPLC chromatography to afford the mono-trifluoroacetate salt of 2-(1,1′-biphenyl-4-yl)-N-[(1R)-1-(5-propoxypyridin-2-yl)ethyl]acetamide as an oil. 1H NMR (CD3OD, 400 MHz) δ 8.34 (s, 1H); 7.97 (dd, J=2.80 and 9.20 Hz, 1H); 7.74 (d, J=8.80 Hz, 1H); 7.56 (m, 4H); 7.40 (m, 2H); 7.33 (m, 3H); 5.07 (m, 1H); 4.11 (t, J=6.40 Hz, 2H); 3.61 (s, 2H); 1.84 (m, 2H); 1.57 (d, J=7.20 Hz, 3H); 1.05 (t, J=7.60 Hz, 3H). HRMS (ES) exact mass calcd for C24H26N2O2: 375.2067, Found: 375.2078.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[C:38]([O:41][CH2:42][CH3:43])(=O)C>CN(C)C=O>[O:41]1[C:42]2[CH:43]=[CH:3][CH:2]=[CH:1][C:7]=2[N:8]=[C:38]1[N:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][S:18][C:9]1[NH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCOC(C)=O
Reactant: CCCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCN(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)c1nc2ccccc2o1

Procedure:
Method A, Part B. A solution of N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-heptanamine (prepared according to the procedure of U.S. patent application Ser. No. 07/416,606, Billheimer et al. ) (8.57 g, 19.7 mmol), the sulfone prepared in Method A, Part A above (3.52 g, 17.9 mmol) and potassium carbonate (3.00 g, 21.7 mmol) in dimethylformamide (30 mL) was heated to 90° C. for 18 hours. The mixture was allowed to cool and poured into ethyl acetate (200 mL). This solution was washed with water (4×200 mL), and the water washings were back-extracted in sequence with ethyl acetate (200 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residual oil was separated by flash chromatography (1:4 ethyl acetate-hexane), and the title product was obtained as a foam from evaporation from heptane solution, m.p. 58°-60° C. (7.00 g, 12.7 mmol, 71%). 1H NMR (CDCl3): 10.77 (1H, br s); 7.61-6.84 (14H, m); 3.52-3.40 (4H, m); 3.04 (2H, t, J=7.2 Hz); 1.79-1.58 (6H, m); 1.53-1.40 (2H, m); 1.37-1.21 (8H, m); 0.87 (3H, t, J=6.6 Hz). High-resolution mass spectrum: for C34H40N4OS, calc. 552.2923, obs. 552.2925, diff. 0.4 ppm.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([O:13][CH2:14][CH:15]2[CH2:24][CH2:23][CH2:22][C:17]3([CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:16]2)=[CH:11][CH:12]=1)C.O1CCCC1.[OH-].[Na+].[ClH:33]>C(O)C>[ClH:33].[CH2:18]1[C:17]2([CH2:22][CH2:23][CH2:24][CH:15]([CH2:14][O:13][C:10]3[N:9]=[CH:8][C:7]([CH2:6][CH2:5][C:4]([OH:25])=[O:3])=[CH:12][CH:11]=3)[CH2:16]2)[CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)CCc1ccc(OCC2CCCC3(CCCC3)C2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1ccc(OCC2CCCC3(CCCC3)C2)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-[6-(spiro[4.5]dec-7-ylmethoxy)-pyridin-3-yl]-propionic acid ethyl ester (36 mg) obtained in Step 3 in a mixed solvent of tetrahydrofuran (0.36 mL)-ethanol (0.36 mL) was added 1N aqueous sodium hydroxide solution (0.21 mL), followed by stirring the reaction mixture at room temperature for 1.5 hours. Then, to the reaction mixture was added 1N aqueous hydrochloric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was dissolved in a 1,4-dioxane solution of hydrogen chloride (4M, 0.5 mL), and to this was added hexane (0.5 mL) while stirring. The resulting solid was filtered and then dried to give 3-[6-(spiro[4.5]dec-7-ylmethoxy)-pyridin-3-yl]-propionic acid hydrochloride (33 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:23]([C:24]=2[CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]1.Cl.[N:39]1([CH2:44][CH2:45]Cl)[CH2:43][CH2:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH2:45][CH2:44][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[C:18]3[C:23]([C:24]=2[CH:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]1
Reactant: ClCCN1CCCC1
Reactant: O=C(c1[nH]c2ccccc2c1C(c1ccccc1)c1ccccc1)N1CCN(c2ccccc2Cl)CC1
Agent: Cl
Product: O=C(c1c(C(c2ccccc2)c2ccccc2)c2ccccc2n1CCN1CCCC1)N1CCN(c2ccccc2Cl)CC1
Yield: 53.8 %

Procedure:
Substantially the same procedure as in Example 89 was repeated using Compound 88 (0.95 g, 1.88 mmol) obtained in Example 88 and 2-pyrrolidinylethylchloride hydrochloride (335 mg, 1.97 mmol) to give 0.61 g (yield: 54%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[C:10]([CH:30]=3)[C@@H:11]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:12][CH2:13][CH2:14][C@@H:15]([CH3:21])[C:16](=[O:20])[NH:17][C:18]=2[CH:19]=1.[I:31]Cl>CO.C(Cl)Cl>[NH2:1][C:2]1[C:3]([I:31])=[CH:4][C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[C:10]([CH:30]=3)[C@@H:11]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:12][CH2:13][CH2:14][C@@H:15]([CH3:21])[C:16](=[O:20])[NH:17][C:18]=2[CH:19]=1
Reactant: C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)c2cc(ccn2)-c2ccc(N)cc2NC1=O
Reactant: ClI
Solvent: ClCCl
Solvent: CO
Product: C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)c2cc(ccn2)-c2cc(I)c(N)cc2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To cooled (0° C.) solution of 86A (0.87 g, 2.119 mmol) in MeOH (21.19 ml) was added a solution of iodine monochloride (0.516 g, 3.18 mmol) in DCM (5.0 mL). The reaction was stirred at rt for 1 h and then it was concentrated. The residue was redissolved in EtOAc, washed with sat. NaHCO3, brine, dried over Na2SO4, filtered, and concentrated. Purification by normal phase chromatography afforded 86B (0.9 g, 79% yield) as a brown solid. MS (ESI) m/z: 537.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([I:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:13]([O:15][C:16]([C:18]1[C:22]([CH3:23])=[C:21]([CH:24]=O)[NH:20][CH:19]=1)=[O:17])[CH3:14]>N1CCCCC1.CC(O)C>[CH2:13]([O:15][C:16]([C:18]1[C:22]([CH3:23])=[C:21](/[CH:24]=[C:5]2\[C:6](=[O:11])[NH:7][C:8]3[C:4]\2=[C:3]([I:12])[C:2]([F:1])=[CH:10][CH:9]=3)[NH:20][CH:19]=1)=[O:17])[CH3:14]
Reactant: CCOC(=O)c1c[nH]c(C=O)c1C
Reactant: O=C1Cc2c(ccc(F)c2I)N1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CCOC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1C
Temperature: 80 °C

Procedure:
A suspension of 1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (0.5 g, 1.8 mmol) (Example 2A) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (0.39 g, 2.17 mmol) (Example 116A above) in 1% piperidine in 2-propanol (6 mL) was heated at 80° C. for 3 h. The precipitate was collected and washed with water to give (Z)-5-(5-Fluoro-4-iodo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester. (Yield 0.67 g, 85%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26](Cl)=[O:27]>ClCCl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([NH:10][C:26](=[O:27])[C:25]3[C:24]([Cl:23])=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:33])[CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(N)cc1OC1CCCC1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
A stirred solution of 3-cyclopentyloxy-4-methoxyaniline (1 g) and triethylamine (0.69 mL) in dry dichloromethane (20 mL) at 0° C. is treated dropwise with 2,6-dichlorobenzoyl chloride (1.17 g). After stirring at this temperature for 30 minutes, the mixture is warmed to room temperature and stirred for a further 3 hours. The organic layer is washed with water (100 mL), dried and concentrated. The residue is recrystallized from a mixture of isopropanol and hexane, to give N-(3-cyclopentyloxy-4-methoxyphenyl)-2,6-dichlorobenzamide (0.6 g), m.p. 184-185° C. [Elemental analysis: C,60.2,H,5.0; N,3.6; Cl,18.9%; calculated: C,60.0; H,5.0; N,3.7; Cl,18.65%].
Reaction SMILES: [C:1]([C:3](=[CH:11]N(C)C)[C:4]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=O)#[N:2].[N+]([O-])([O-])=O.[N+:19]([C:22]1[CH:23]=[C:24]([NH:28][C:29]([NH2:31])=[NH2+:30])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20].[OH-].[Na+]>>[C:1]([C:3]1[C:4]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[N:30][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)=[N:31][CH:11]=1)#[N:2]
Reactant: CN(C)C=C(C#N)C(=O)c1cccs1
Reactant: NC(=[NH2+])Nc1cccc([N+](=O)[O-])c1
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cnc(Nc2cccc([N+](=O)[O-])c2)nc1-c1cccs1

Procedure:
5-Cyano-N-3-nitrophenyl-4-thien-2-ylpyrimidine-2-amine was prepared from 2-cyano-3-dimethylamino-1-thien-2-ylpropen-1-one (3.20 g, 15.51 mmol), 3-nitrophenylguanidinium nitrate (3.74 g, 15.53 mmol) and sodium hydroxide (652 mg, 7.82 mmol) to give the desired material (841 mg) as an off-white solid, m.p.275-277°. δH (d6 DMSO) 10.87 (1H, bs), 8.98 (1H, s), 8.90 (1H, bs), 8.31-8.29 (1H, m), 8.09-8.05 (2H, m), 7.91 (1H, dd, J 7.7,2.0 Hz), 7.64 (1H, t ,J 8.1 Hz) and 7.37-7.35 (1H, m).
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([C:15]1[N:19]=[CH:18][NH:17][N:16]=1)(=[O:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].[Cl:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[N:31]=[C:30](S(C)(=O)=O)[N:29]=1.S(=O)(=O)(O)O>CN(C)C=O>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([C:15]1[N:19]=[CH:18][N:17]([C:30]2[N:29]=[C:28]([Cl:27])[CH:33]=[C:32]([O:34][CH3:35])[N:31]=2)[N:16]=1)(=[O:14])=[O:13]
Reactant: COc1cc(Cl)nc(S(C)(=O)=O)n1
Reactant: Cc1cccc(OC(F)F)c1NS(=O)(=O)c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)nc(-n2cnc(S(=O)(=O)Nc3c(C)cccc3OC(F)F)n2)n1
Temperature: 10 °C
Reaction time: 0.75 h

Procedure:
1.8 g (6 mmol) N-(2-Difluoromethoxy-6-methylphenyl)-1H-1,2,4-triazole-3-sulphonamide in 10 ml dimethylformamide was stirred with 1.68 g (12 mmol) potassium carbonate for 10 minutes at 50° C. It was then cooled to 10° C. and treated with 1.33 g (6 mmol) 4-chloro-6-methoxy-2-methylsulphonylpyrimidine and the mixture stirred for 45 minutes at 10° C. It was then added to ice-water, acidified to pH 4 with sulphuric acid and the solid collected and purified by silica gel chromatography using a mixture of methylene chloride and methanol (95/5).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:23][O:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C>CN(C=O)C>[CH3:23][O:24][CH:25]1[CH2:30][CH2:29][N:28]([C:4]([C:3]2[CH:7]=[C:8]([CH:9]=[CH:10][CH:2]=2)[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[O:6])[CH2:27][CH2:26]1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: COC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4ccccc34)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.7 %

Procedure:
2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.379 g, 1.00 mmol) was added to 3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1b) (0.200 g, 0.71 mmol), 4-methoxypiperidine (0.090 g, 0.78 mmol) and triethylamine (0.249 mL, 1.78 mmol) in DMF (3 mL). The resulting solution was stirred at room temperature for 16 hours. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (0.211 g, 78% yield); 1H NMR (400.132 MHz, DMSO) δ 1.24-1.49 (2H, m), 1.63-1.93 (2H, m), 2.94-3.14 (2H, m), 3.30 (3H, s), 3.34-3.44 (2H, m), 3.88 (1H, s), 4.35 (2H, s), 7.21 (1H, m), 7.30-7.43 (3H, m), 7.80-7.90 (2H, m), 7.96 (1H, d), 8.27 (1H, m), 12.58 (1H, s); m/z (LC-MS, ESI+), RT=1.57 min (M+H=378.20).
Reaction SMILES: [CH3:1][C:2]([CH3:44])([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[C:10]2[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:31][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4].Br[C:46]1[CH:47]=[N:48][N:49]([CH3:51])[CH:50]=1>>[CH3:44][C:2]([CH3:1])([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:46]3[CH:47]=[N:48][N:49]([CH3:51])[CH:50]=3)=[CH:15][CH:14]=2)[C:10]2[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:31][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)O
Reactant: Cn1cc(Br)cn1
Product: Cn1cc(-c2ccc(Cn3c(CC(C)(C)C(=O)O)nc4cc(OCc5ccc6ccccc6n5)ccc43)cc2)cn1

Procedure:
The title compound was prepared with similar methods to those in Example 147 using 2,2-dimethyl-3-(5-(quinolin-2-ylmethoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazol-2-yl)propanoic acid and 4-bromo-1-methyl-1H-pyrazole. MS (ESI): mass calcd. for C33H31N5O3, 545.24; m/z found, 546.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.92 (d, J=8.6, 1H), 8.41 (d, J=8.5, 1H), 8.24 (d, J=8.1, 1H), 8.15 (s, 1H), 8.06-8.01 (m, 2H), 7.87-7.79 (m, 2H), 7.64 (d, J=9.1, 1H), 7.53 (d, J=8.2, 2H), 7.49 (d, J=2.3, 1H), 7.34 (dd, J=9.1, 2.3, 1H), 7.27 (d, J=8.3, 2H), 5.79 (s, 2H), 5.76 (s, 2H), 3.84 (s, 3H), 3.56 (s, 2H), 1.32 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(Cl)c(Cl)c2)CC1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 8 h
Yield: 102.9 %

Procedure:
Platinum oxide (0.3 g) was added to a solution of 1-(tert-butoxycarbonyl)-4-(3,4-dichlorobenzylidene)piperidine (29 g, 84.7 mmol) in ethyl acetate (500 ml) and the mixture was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered through celite and the filtrate was concentrated to give 1-(tert-butoxycarbonyl)-4-(3,4-dichlorobenzyl)piperidine (30 g) as a tan oil.
Reaction SMILES: [OH:1][CH:2]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[C:7]1[S:11][C:10]([C:12](=[O:20])[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:9][CH:8]=1.[BH4-].[Na+]>CO>[OH:20][CH:12]([C:10]1[S:11][C:7](/[CH:6]=[CH:5]/[CH:4]=[CH:3]/[CH:2]([OH:1])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:8][CH:9]=1)[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: CCCCCCCCC(O)/C=C/C=C/c1ccc(C(=O)CCCC(=O)OC)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCC(O)/C=C/C=C/c1ccc(C(O)CCCC(=O)OC)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
Into 3 ml of methanol was dissolved 50 mg of the titled product of Example 28. The methanol solution was cooled to 0° C. (ice bath) and 5 mg of NaBH4 was added. The reaction mixture was stirred for 1 hour at 0° C. and then quenched with acetone. The solvent was removed from the quenched reaction mixture under reduced pressure. Water was added to the residue and it was extracted 3x with ethyl acetate. The combined extracts were dried MgSO4, filtered, and the solvent removed under reduced pressure. The oily residue was chromatographed on a silica gel column. Elution with 3:7 ethyl acetate: hexane produced 35 mg of the titled product as a light yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH2:17]([OH:21])[CH2:18][CH2:19][CH3:20].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:17]([O:21][C:10]1[C:11]([I:12])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:7]=[C:8]([NH2:16])[N:9]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCO
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCOc1nc(N)nc(-c2ccco2)c1I

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, butanol and DBU in THF. ES-MS m/e (%): 360 (M+H+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:11][CH:10]=[N:9][C:8]=2[CH:12]=1)([O-:3])=[O:2].Br[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:26][O:25][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:15]=1[CH2:14][N:9]1[C:8]2[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[N:11]=[CH:10]1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=[N+]([O-])c1ccc2[nH]cnc2c1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(Cn2cnc3ccc([N+](=O)[O-])cc32)c(OC)c1
Yield: 25.6 %

Procedure:
A solution of 6-nitrobenzimidazole (2.0 g.) and methyl 4-bromomethyl-3-methoxybenzoate (B) (3.5 g.) in methyl ethyl ketone (61 ml.) was treated with potassium carbonate (1.9 g.) and then heated under reflux for 24 hours. The solvent was then evaporated. The residue was extracted with ethyl acetate and inorganic material removed by filtration. The filtrate was evaporated. The resultant residue was purified by flash chromatography on a 6×30 cm. silica gel column using 1:1 v/v hexane:ethyl acetate as the eluent to give methyl 3-methoxy-4-(6-nitrobenzimidazol-1-ylmethyl)benzoate (K) (1.07 g., 26%); NMR: 3.9 (s,3H, OCH3), 4.0(s,3H, OCH3), 5.7(s,2H, NCH2), 7.4(d, 1H, Ar), 7.8(d,1H, H4 -benzimidazole), 8.1(dd, 1H, H5 -benzimidazole), 8.6(br s,2H, H2,7 -benzimidazole).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([F:10])[C:3]=1[F:11].[C-:12]#[N:13].[Na+]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:12]#[N:13])=[C:4]([F:10])[C:3]=1[F:11]
Reactant: [C-]#N
Reactant: Fc1c(Br)ccc(CBr)c1F
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ccc(Br)c(F)c1F
Temperature: 10 °C
Reaction time: 12 h

Procedure:
To a solution of 1-bromo-4-(bromomethyl)-2,3-difluorobenzene (330 mg, 1.154 mmol) in EtOH (10 mL) stirred under N2 at 0° C. was added NaCN (73.5 mg, 1.500 mmol) in one charge. The reaction mixture was stirred at 10° C. for 12 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting 2-(4-bromo-2,3-difluorophenyl)acetonitrile was used in the next step without further purification. TLC (PE/EA=5:1, Rf 0.6): 1H NMR (400 MHz, CDCl3) δ 7.39 (ddd, J=1.8, 6.1, 8.2 Hz, 1H), 7.15 (t, J=6.8 Hz, 1H), 3.78 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:22]([CH:24]1[O:26][CH2:25]1)Br>CC(CC)=O>[O:26]1[CH2:25][CH:24]1[CH2:22][O:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5]
Reactant: COC(=O)CCC(=O)c1ccccc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)CCC(=O)c1ccccc1OCC1CO1
Yield: 104.7 %

Procedure:
A well stirred mixture of methyl 3-(2-hydroxybenzoyl)-propionate (63.3 g, 0.3 mole), potassium carbonate (48.4 g, 0.35 mole). epibromohydrin (117 ml, 1.4 mole), and dry ethyl methyl ketone (2000 ml) was heated under reflux for 28 hours. Evaporation of the filtered solution under reduced pressure gave methyl 3-[2-(2,3-epoxypropoxy)benzoyl]propionate (83 g, 100%).