Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([O:18][CH3:19])[CH:12]=2)=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1>C(O)(=O)C.[Zn]>[CH:1]1([CH:4]([C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C=C(c1cc(OC)ncc1F)C1CC1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)CC(c1cc(OC)ncc1F)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(5-fluoro-2-methoxypyridin-4-yl)acrylate (entire amount) in acetic acid (100 mL) was added a zinc powder (50.2 g), and the mixture was stirred at room temperature for 30 min. The reaction mixture was filtered, and the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.72 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH2:28][C:29]1[CH:30]=[N:31][C:32]([Cl:35])=[N:33][CH:34]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].C([O-])(O)=O.[Na+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:35][C:32]1[N:33]=[CH:34][C:29]([NH:28][C:2]2[N:3]=[C:4]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=4[N:16]=[C:15]3[CH:25]([F:26])[F:27])[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)=[CH:30][N:31]=1
Reactant: Nc1cnc(Cl)nc1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Nc2cnc(Cl)nc2)nc(N2CCOCC2)n1
Temperature: 100 °C
Yield: 36.5 %

Procedure:
A mixture of 0.28 g (0.71 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole, 0.076 g (0.56 mmol) of the above amine, 0.026 g (0.04 mmol) of BINAP, 0.01 g (0.04 mmol) of Pd(OAc)2, and 0.266 g (0.82 mmol) of Cs2CO3 in 1,4-dioxane (4 mL) was heated at 100° C. for 3 hrs under nitrogen. The mixture was cooled to room temperature, sat. NaHCO3 solution was added, and the resulting mixture was extracted with EtOAc (×4). The organic layer was washed with brine, dried (Na2SO4), and concentrated. Chromatography on silica, eluting with CH2Cl2/EtOAc (6:1), gave 0.10 g (36% yield) of N-(2-chloro-5-pyrimidinyl)-4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine, as a white powder: mp 295° C. (decomp.); 1H NMR (DMSO-d6) δ 10.43 (s, 1H), 9.08 (s, 2H), 8.09-7.69 (m, 2H), 7.42 (t, J=8.0 Hz, 1H), 6.98 (d, J=7.6 Hz, 1H), 3.98 (s, 3H), 3.83 (s, 4H), 3.75-3.73 (m, 4H); Anal. Calcd. for C20H18ClF2N9O2: C, 49.0; H, 3.7; N, 25.7. Found: C, 49.2; H, 3.9; N, 25.45%.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH:8]([C:10]([OH:12])=O)[CH2:9][C:4]=2[N:3]=[CH:2]1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]=1[CH2:16][NH2:17]>>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]=1[CH2:16][NH:17][C:10]([CH:8]1[CH2:7][CH2:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH2:9]1)=[O:12]
Reactant: O=C(O)C1CCc2[nH]cnc2C1
Reactant: NCc1c(Cl)cccc1Oc1ccccc1
Product: O=C(NCc1c(Cl)cccc1Oc1ccccc1)C1CCc2[nH]cnc2C1

Procedure:
83 mg of the title compound was prepared from 4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid and 2-chloro-6-phenoxybenzylamine by a similar procedure as described in Example 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[C:3]=1[O:15][CH2:16][O:17][CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].O.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH2:36][CH2:37][C:38]3=[O:43])O1>CN(C)C=O>[CH:12]1([CH2:11][O:10][C:4]2[C:3]([O:15][CH2:16][O:17][CH3:18])=[C:2]([C:34]3[CH:42]=[CH:41][CH:40]=[C:39]4[C:35]=3[CH2:36][CH2:37][C:38]4=[O:43])[CH:7]=[CH:6][C:5]=2[O:8][CH3:9])[CH2:14][CH2:13]1
Reactant: CC1(C)OB(c2cccc3c2CCC3=O)OC1(C)C
Reactant: COCOc1c(Br)ccc(OC)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OCC1CC1
Temperature: 80 °C
Yield: 51.6 %

Procedure:
A stirring solution of 1-bromo-3-(cyclopropylmethoxy)-4-methoxy-2-(methoxymethoxy)benzene (3 g, 9.46 mmol) in dimethylformamide (50 mL) was purged with argon for 1 h, to this cesium carbonate (9.23 g, 28.39 mmol), water (3 mL), tetrakis triphenylphosphine palladium (546 mg, 0.472 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (2.93 g, 11.35 mmol) were added and the resultant reaction mixture was heated to 80° C. for 5 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded 4-(3-(Cyclopropylmethoxy)-4-methoxy-2-(methoxymethoxy)phenyl)-2,3-dihydro-1H-inden-1-one as a solid (1.8 g, 51%).
Reaction SMILES: [F:1][C:2]1([F:23])[CH:6]([NH:7][C:8](=[O:15])[CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:24]>C(#N)C.C(OCC)C>[ClH:24].[F:23][C:2]1([F:1])[CH2:3][NH:4][CH2:5][CH:6]1[NH:7][C:8](=[O:15])[CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CCS(C)(=O)=O)C(F)(F)C1
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: CS(=O)(=O)CCC(=O)NC1CNCC1(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of tert-butyl 3,3-difluoro-4-{[3-(methylsulfonyl)propanoyl]amino}pyrrolidine-1-carboxylate (1.60 g, 4.5 mmol) in acetonitrile (45 mL) was added HCl (4 M in dioxane, 4.5 mL, 18 mmol, 4 mol eq). The resulting solution turned to a white suspension after 1 hr, and was stirred at ambient temperature for 3 hr. The volatiles were removed to dryness to give a white solid, which was suspended in ethyl ether (100 mL). The white solid was collected by filtration, washed with ether (20 mL) and dried to give the title product as a white solid (1.26 g, 96% yield, >95% purity, assumed 1 HCl salt). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.99 (br. s., 2 H) 8.75 (br. s., 1 H) 4.71-4.95 (m, 1 H) 3.58-3.89 (m, 3 H) 3.28-3.43 (m, 2 H) 3.16 (t, J=10.88 Hz, 2 H) 2.99 (s, 3 H) 2.67 (t, J=7.58 Hz, 2 H). 19F NMR (376 MHz, DMSO-d6) δ ppm −108.27-−107.26 (m, 1 F) −109.70-−108.82 (m, 1 F). m/z (APCI+) for C8H14F2N2O3S 257.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([C:30]2[CH:34]=[CH:33][O:32][N:31]=2)[CH2:14][C:15]([N:17]2[C@@H:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:20][O:19][C:18]2=[O:29])=[O:16])=[CH:9][CH:8]=1.[F:38][C:39]([F:51])([F:50])[C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][CH:41]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:22]([C@H:21]1[CH2:20][O:19][C:18](=[O:29])[N:17]1[C:15](=[O:16])[CH2:14][C@@H:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][S:46]([C:43]3[CH:42]=[CH:41][C:40]([C:39]([F:38])([F:50])[F:51])=[CH:45][CH:44]=3)(=[O:48])=[O:47])[CH:37]=[CH:36][CH:35]=2)=[CH:8][CH:9]=1)[C:30]1[CH:34]=[CH:33][O:32][N:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(C[C@@H](c1ccc(OCc2cccc(NS(=O)(=O)c3ccc(C(F)(F)F)cc3)c2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 2 h
Yield: 24.1 %

Procedure:
To a solution of the aniline (27.3) (0.050 g, 0.100 mmol) in DCM (1 mL), was added TEA (28.2 μL, 0.200 mmol) and 4-(trifluoromethyl)benzene-1-sulfonyl chloride (73.8 mg, 0.300 mmol). A catalytic amount (<5.0 mg) of DMAP was then added to drive the reaction to completion. The reaction mixture was stirred for two hours and then concentrated to dryness under reduced pressure. The residue was purified by medium pressure chromatography (silica gel, 10 to 45% EtOAc:hexanes) to give 32.1 (17.0 mg). MS ESI (pos.) m/e: 706.2 (M+H).
Reaction SMILES: C([CH:5]([O:10][C:11](=[O:27])[C@H:12]([CH:24]([CH3:26])[CH3:25])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:6][C:7]([O-:9])=[O:8])=CCC.[Mn]([O-])(=O)(=O)=O.[K+].S(=O)(O)[O-].[Na+].Cl>C1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:17]([O:16][C:14]([NH:13][C@H:12]([C:11]([O:10][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:27])[CH:24]([CH3:26])[CH3:25])=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCC=CC(CC(=O)[O-])OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: O=[Mn](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCC(=O)O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a solution of 3-buten-1-yl-3-(N-benzyloxycarbonyl-L-valyloxy)-propionate (9.2 g, 30 mmole) in 150 ml benzene was added tetrabutylammonium bromide (1.62 g, 5 mmole) and 100 ml water. The mixture was cooled to about 5° C. and potassium permanganate (14.82 g, 90 mmole) was added in portions. The mixture was stirred 2 hours at room temperature, diluted with water and decolorized by the addition of sodium bisulfite. The mixture was acidified with 2M hydrogen chloride and extracted 3 times with ethyl acetate. The combined organic phases were washed with water and dried with sodium sulfate. The solution was evaporated under reduced pressure and the product isolated by silica gel column chromatography with hexane/ethyl acetate. Yield: 5.4 g=55%. The compound can be activated and esterified to a drug or further modified as described below.
Reaction SMILES: [C:1]1([O:11][CH2:12][C@H:13]2[O:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:16]([NH2:19])([CH3:18])[CH3:17]>CO>[CH3:17][CH:16]([NH:19][CH2:14][C@H:13]([OH:15])[CH2:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:18]
Reactant: c1ccc2c(OC[C@@H]3CO3)cccc2c1
Reactant: CC(C)N
Solvent: CO
Product: CC(C)NC[C@H](O)COc1cccc2ccccc12
Yield: 92.6 %

Procedure:
A solution of (S)-(+)-glycidyl naphthyl ether (20 g, 0.1 m) and isopropylamine (10 g, 0.17 m) in methanol (100 mL) was refluxed for 1 hour and evaporated to dryness. The residue was taken up with ether (200 mL), washed with water and dried over MgSO4. After filtering, the filtrate was acidified with gaseous HCl. The crude solid was recrystallized from ethanol to afford 24 g (81%) of pure 1-propranolol, mp 198°-200° C., [α]D25 -26.8 (c 1, EtOH). NMR and IR were consistent with the assigned structure.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11].NC1C=CC([C:28]2[NH:29][C:30]3[CH:36]=[CH:35][C:34](N)=[CH:33][C:31]=3[N:32]=2)=CC=1>CN(C=O)C.N1C=CC=CC=1>[CH2:7]([C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]([C:28]2[NH:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[N:32]=2)=[O:20])[CH2:16][CH2:17]1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: Nc1ccc(-c2nc3cc(N)ccc3[nH]2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H](C(=O)c2nc3ccccc3[nH]2)CC1

Procedure:
Bis-trans-4-pentylcyclohexyl carbonyl benzimidazole was synthesized as follows: oxalyl chloride (1.07 ml, 2 M in CH2Cl2) was added to trans-4-pentylcyclohexyl carboxylic acid (0.424 g, 2.14 mmole) followed by one drop DMF. The mixture was allowed react at RT for 1 hour. To the above solution was added 2-(4-aminophenyl)-6-amino-benzimidazole (0.200 g, 0.89 mmole) in pyridine (2 ml). The
Reaction SMILES: [F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[N:13]([O-])=O.[Na+]>CC(O)=O.O>[F:1][C:2]1[CH:8]=[C:6]2[C:5]([CH:9]=[N:13][NH:7]2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1cc([N+](=O)[O-])c(F)cc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc2cn[nH]c2cc1F
Temperature: 25 °C
Reaction time: 28 h
Yield: 42.4 %

Procedure:
The product of Step (b) (1.22 g, 7.17 mmol, 1.0 equiv) was dissolved In AcOH (62 mL). NaNO2 (0.495 g, 7.17 mmol, 1.0 equiv) was dissolved in H2O (1.5 mL) and added all at once via pipet. The reaction was warmed to room temperature and stirred for 28 hours. The reaction mixture was concentrated en vacuo to provide an orange solid, which was dried azeotropically several times with hexanes. The residue was purified by flash chromatography (linear gradient 20→60% EtOAc/hexanes) to afford 550 mg (43%) of the title compound. MS (ES+) m/e 182 [M+H].
Reaction SMILES: C12N([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)CC1CCNC2.[CH:19]12[CH2:25][NH:24][CH:23]1[CH2:22][N:21]([C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35])=[O:27])[CH2:20]2.ClC1C=NC2C(=CC=CC=2)N=1>>[CH3:35][O:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:26]([N:21]1[CH2:22][CH:23]2[CH:19]([CH2:25][N:24]2[C:9]2[CH:18]=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:20]1)=[O:27]
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Reactant: COc1ccccc1C(=O)N1CC2CNC2C1
Agent: Clc1cnc2ccccc2n1
Product: COc1ccccc1C(=O)N1CC2CN(c3cnc4ccccc4n3)C2C1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 22 and 2-chloro-quinoxaline as staring materials. MS (ESI) mass calcd. for O21H20N4O2, 360.42; m/z found, 361.3 [M+H]+.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=C[C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14](NC4C=CC=C(O)C=4)[N:13]=3)=[CH:4][C:3]=2O1.CC1OC(C)=CC=1CN.[Cl:36]C1N=C(Cl)C(F)=CN=1>>[Cl:36][C:14]1[N:13]=[C:12]([NH:11][CH2:5][C:4]2[CH:3]=[C:8]([CH3:7])[O:9][C:10]=2[CH3:1])[C:17]([F:18])=[CH:16][N:15]=1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cc1cc(CN)c(C)o1
Product: Cc1cc(CNc2nc(Cl)ncc2F)c(C)o1

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of (2,5-dimethyl-3-furyl)methylamine (188 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gave 2-chloro-N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-4-pyrimidineamine. The reaction of 2-chloro-N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-4-pyrimidineamine and 3-aminophenol (200 mg, 1.83 mmol) gave N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (50 mg, 51%). 1H NMR (CDCl3): δ 2.22 (s, 3H), 2.23 (s, 3H), 4.39 (d, J=5.1 Hz, 2H), 5.24 (br, 1H), 5.90 (s, 1H), 6.52 (d, J=6.6 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 7.13 (t, J=8.1 Hz, 1H), 7.29 (s, 1H), 7.71 (m, 2H); 19F NMR (282 MHz, CDCl3): 6-167.84; LCMS: ret. time: 19.83 min.; purity: 96.32%; MS (m/e): 329.05 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH2:26][CH:27]=[N:28][OH:29])[CH:21]=4)[C:16]3=[O:30])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[OH-].[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C.C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH2:26][CH2:27][NH:28][OH:29])[CH:21]=4)[C:16]3=[O:30])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1c2ccc(OCC=NO)cc2CCN1Cc1ccc(-c2ccc(F)cc2)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1c2ccc(OCCNO)cc2CCN1Cc1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of the above oxime (9 g, 22.28 mmol) in glacial acetic acid (50 ml) and CH2Cl2 (75 ml) is added sodium cyanoborohydride (1.7 g). The solution is stirred for 45 minutes at room temperature and subsequently diluted with H2O (200 ml). The resulting mixture is then neutralized with 5N NaOH and solid NaHCO3. The reaction mixture is extracted with EtOAc (2×200 ml) and the combined organic layers washed with saturated NaCl solution, dried over MgSO4, and concentrated in vacuo to yield 2-(4'-fluoro-4-biphenylylmethyl)-6-[2-(N-hydroxyamino)ethoxyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:8])=[C:5]([Br:7])[N:6]=1.[H-].[Na+].[CH3:11][Si:12]([CH2:15][CH2:16][O:17][CH2:18]Cl)([CH3:14])[CH3:13]>CN(C=O)C>[Br:1][C:2]1[N:3]([CH2:18][O:17][CH2:16][CH2:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[C:4]([Br:8])=[C:5]([Br:7])[N:6]=1
Reactant: Brc1nc(Br)c(Br)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(Br)nc(Br)c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
A dried 500 mL round bottom flask was charged with 2,4,5-tribromoimidazole (20.0 g, 65.6 mmol) and anhydrous DMF (100 mL), the resulting solution was cooled to 0° C. To this cold solution was added NaH (60% in mineral oil, 2.80 g, 70.0 mmol) portionwise with gas evolution under control and an internal temperature maintained below 10° C. After addition, the cold bath was removed and the resulting mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was cooled back to 0° C., and SEMCl (12.2 mL, 69.5 mmol) was added to the reaction via syringe pump over 30 minutes. The reaction was stirred at 0° C. for an additional 30 minutes and at room temperature for another 30 minutes. The reaction was deemed complete by LCMS and the mixture was partitioned between EtOAc (150 mL) and water (300 mL), and the layers separated. The organic phase was sequentially washed with dilute aqueous NaCl (5% w/w) twice, then brine (100 mL), dried (Na2SO4), concentrated and a light yellow solid was obtained. The crude material was recrystallized from hot petroleum ether (30 mL) and the solids were harvested from the mother liquor at 0° C. The product was washed with cold petroleum ether (30 mL) and dried under vacuum to afford 2,4,5-tribromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (26.3 g, 92% yield): 1H NMR (400 MHz, CDCl3) δ 5.31 (s, 2H), 3.59 (t, J=7.2 Hz, 2H), 0.92 (t, J=7.2 Hz, 2H), −0.01 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@@H:7]([O:9][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccccc1

Procedure:
To a solution of trans-1-benzyloxycarbonyl-4-hydroxy-L-proline methyl ester (83.7 g) in dry dimethylformamide (80 ml), imidazole (36.76 g) and t-butyldimethylsilyl chloride (54.26 g) were added, and the resultant mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water, dilute hydrochloric acid and water and dried over magnesium sulfate. Removal of the solvent gave trans-1-benzyloxycarbonyl-4-t-butyldimethylsilyloxy-L-proline methyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:3]=1.[Cl:27][CH2:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:31]([CH2:30][CH2:29][CH2:28][Cl:27])(=[O:33])=[O:32])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: O=S(=O)(Cl)CCCCl
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 107) and chloropropanesulfonyl chloride (Aldrich) in an analogous manner as described in Example 177. HR-MS (ES, m/z) calculated for C20H25N5O4SF2CI [(M+H)+] 504.1279, observed 504.1284.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[CH2:14]1[O:24][C:23]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=2[O:15]1.C(O)(C(F)(F)F)=O>>[CH2:14]1[O:24][C:23]2[CH:22]=[CH:21][C:18]([CH:19]3[C:7]4[NH:6][C:5]5[C:12](=[CH:13][C:2]([F:1])=[CH:3][CH:4]=5)[C:8]=4[CH2:9][CH2:10][NH:11]3)=[CH:17][C:16]=2[O:15]1
Reactant: NCCc1c[nH]c2ccc(F)cc12
Reactant: O=Cc1ccc2c(c1)OCO2
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2[nH]c3c(c2c1)CCNC3c1ccc2c(c1)OCO2
Yield: 84.7 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with 5-fluorotryptamine (1.59 g, 8.9 mmol), 3,4-methylenedioxybenzaldehyde (1.47 g, 1.1 equiv.) and TFA (1.4 mL, 2 equiv.) to give the title compound (2.34 g, 85%) as white crystals. MP: 172° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][S:10][CH2:11][CH:12]=1)(=O)=O.[F:15][C:16]1[C:21](B(O)O)=[CH:20][CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.O.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[S:10]1[CH2:11][CH:12]=[C:7]([C:21]2[C:16]([F:15])=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:8][CH2:9]1
Reactant: OB(O)c1cccnc1F
Reactant: O=S(=O)(OC1=CCSCC1)C(F)(F)F
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ncccc1C1=CCSCC1
Temperature: 135 °C

Procedure:
A mixture of 3,6-dihydro-2H-thiopyran-4-yl trifluoromethanesulfonate (4.0 g, 16.11 mmol), 2-fluoropyridin-3-ylboronic acid (2.498 g, 17.72 mmol), sodium carbonate (5.12 g, 48.3 mmol), and dichlorobis(tri-o-tolylphosphine)palladium(ii) (0.633 g, 0.806 mmol) in p-dioxane/H2O (10:1, 22 mL) was heated at 135° C. in 30 min. by microwave. The reaction mixture was cooled, diluted with H2O, extracted with EtOAc (3×), dried over MgSO4, concentrated and purified by ISCO (0-40% EtOAc/Hexanes) to give the expected product was a light brown oil. MS (M+1): 196.2.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([N:15]=[C:16]=[S:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.Cl>O1CCOCC1.O>[C:5]1([N:15]2[C:16](=[S:17])[N:1]=[N:2][NH:3]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: S=C=Nc1cccc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: S=c1nn[nH]n1-c1cccc2ccccc12
Temperature: 102 °C
Yield: 63.1 %

Procedure:
To a solution of NaN3 (1.76 g, 27.0 mmol) in a mixture of 1,4-dioxane (25 mL) and water (25 mL) was added 1-naphthalenylisothiocyanate (5.00 g, 27.0 mmol) at room temperature. The yellow solution containing a white solid was heated at 102° C. for 2 h. The reaction mixture was then cooled to room temperature and aqueous 1 N HCl solution was added until pH 2 was reached. The aqueous mixture was extracted with EtOAc (250 mL). The organic layer was extracted with aqueous 1 N NaOH solution. The aqueous layer was acidified with aqueous 6 N HCl solution and a white precipitate formed. The suspension was filtered and the resulting solid was triturated with Et2O/hexane (1/1) to give the title compound (3.89 g, 63% yield) as an off white solid.