Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH3:13].C[O:15]C(OC)N(C)C.I([O-])(=O)(=O)=O.[Na+]>CN(C)C=O.O>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH:11]=[O:15])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: COc1cc(C)c([N+](=O)[O-])cc1Br
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)c([N+](=O)[O-])cc1Br
Temperature: 120 °C
Reaction time: 2 h
Yield: 19.2 %

Procedure:
The crude 1-bromo-2-methoxy-4-methyl-5-nitrobenzene (2.6 g, 11 mmol) was dissolved in N,N-dimethylformamide (15 mL) and N,N-dimethylformamide dimethylacetal (5 mL, 38 mmol) was added. The reaction was heated to 120° C. for 18 hours. The reaction was cooled to room temperature and the mixture was added directly to a 0° C. suspension of sodium periodate (12.2 g, 57.2 mmol) in water (20 mL) and N,N-dimethylformamide (5 mL). The reaction was stirred at 0° C. for 2 hours, then allowed to warm to room temperature and stir for another 6 hours. The reaction mixture was filtered, rinsing with ethyl acetate, toluene, and water. The filtrate was extracted with ethyl acetate (3×). The combined organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-50% ethyl acetate/heptanes) gave the title compound (550 mg, 19%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, δ): 10.47 (s, 1 H), 8.41 (s, 1 H), 7.35 (s, 1 H), 4.05 (s, 3 H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[N:14]=[C:13]([CH2:15]O)[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CS([Cl:30])(=O)=O>ClCCl>[Cl:30][CH2:15][C:13]1[N:14]=[C:9]([CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:10]=[CH:11][CH:12]=1
Reactant: OCc1cccc(CCN2CCOCC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: ClCc1cccc(CCN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[6-(2-Morpholin-4-ylethyl)pyridin-2-yl]methanol (122 mg) and diisopropylethylamine (104 mg) were dissolved in 2.5 mL of dichloromethane, and 47 μL of methanesulfonyl chloride was added dropwise to the solution at ice temperature, and then the mixture was stirred at room temperature overnight. After removing the solvent from the reaction mixture under reduced pressure, the residue was purified by chromatography on silica gel (chloroform-methanol-aqueous ammonia=300:10:1) to give 80 mg of 4-[2-(6-chloromethylpyridin-2-yl)ethyl]morpholine as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]([CH3:14])[CH2:12][C:11](=O)[CH2:10][CH:9]1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>CO.O>[CH2:1]([N:8]1[CH:13]([CH3:14])[CH2:12][C:11](=[N:18][OH:19])[CH2:10][CH:9]1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC1CC(=O)CC(C)N1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1CC(=NO)CC(C)N1Cc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 48.6 %

Procedure:
10 g of 1-benzyl-2,6-dimethyl-4-piperidone (prepared from benzylamine and ethyl crotonate in analogy to Bull. Chem. Soc. Japan 31 (1958) 418) are dissolved in 60 ml of methanol and this solution is added dropwise to a solution of 3.8 g of hydroxylamine hydrochloride and 4.5 g of sodium acetate in 150 ml of water. The mixture is stirred at 60° C. for 2 h and cooled to 0° C., and the oxime which has separated out is filtered off with suction. Drying results in 5.2 g of the title compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:29])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][C:20]([Cl:29])=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[C:15]=2[O:14]1)=[N+:31]=[N-:32]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(Cl)c(-c4ccccc4C)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: Cc1ccccc1-c1c(Cl)ccc2c1OC(CN=[N+]=[N-])C2
Yield: 99 %

Procedure:
Treatment of 1-bromo-2-methylbenzene (5.0 g, 26.88 mmol) with (2-chloro-6-methyoxyphenyl)boronic acid (13.8 g, 80.6 mol) generally according to the procedure described for Intermediate 37 afforded 3.85 g (62%) of 6-chloro-2′-methylbiphenyl-2-yl methyl ether. Treatment of 6-chloro-2′-methylbiphenyl-2-yl methyl ether with hydrogen bromide (100 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded brown oil. The oil was reacted with sodium hydride (0.61 g, 25.38 mmol) and allyl bromide (3.07 g, 25.38 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-6-chloro-2′-methylbiphenyl-2-ol. Treatment of 3-allyl-6-chloro-2′-methylbiphenyl-2-ol (4.38 g, 16.92 mmol) with m-chloroperoxybenzoic acid (4.38 g, 25.38 mmol, 77%) and potassium carbonate (2.81 g, 20.30 mmol) generally according to the procedure described for Intermediate 9 afforded 2.4 g (52%) of (±)-[7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol (2.4 g, 8.73 mmol) with p-toluenesulfonyl chloride (2.50 g, 13.1 mmol) generally according to the procedure described for Intermediate 10 gave 3.2 g (85%) of (±)-[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.21 g, 0.49 mmol) with sodium azide (0.35 g, 5.38 mmol) generally according to the procedure described for Intermediate 98 afforded 0.14 g, (99%) of (±)-2-(azidomethyl)-7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran (0.14 g, 0.468 mmol) in tetrahydrofuran (10 m]L) with polymer-supported triphenylphosphine (0.24 g, 0.936 mmol) generally according to the procedure described for Example 154 provided 0.028 g (18%) of (±)-{[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 204-206° C.
Reaction SMILES: C[Al](C)C.[CH2:5]([NH2:8])[CH2:6][NH2:7].C(O[C:12](=O)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[CH:16]=1)C>C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:12]2[NH:7][CH2:6][CH2:5][N:8]=2)=[CH:16][C:17]=1[F:22]
Reactant: NCCN
Reactant: CCOC(=O)COc1ccc(Cl)c(F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Fc1cc(OCC2=NCCN2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To dry toluene (4 ml) under an inert atmosphere at 0° C. was added a toluene solution of trimethylaluminium (3.44 ml, 6.88 mmol, 2 M solution). A solution of ethylenediamine (0.46 ml, 6.88 mmol) in toluene (1.5 ml) was then added dropwise and the reaction mixture was then allowed to warm to room temperature and stirred for 1 h at this temperature before being re-cooled to 0° C. To this mixture was added dropwise a solution of (4-chloro-3-fluoro-phenoxy)-acetic acid ethyl ester (0.80 g, 3.44 mmol) in toluene (3 ml). The reaction mixture was then heated at 95° C. for 45 min and then cooled first to room temperature and finally to 0° C. The mixture was quenched by dropwise addition of methanol (1 ml) and when all gas evolution had ceased the mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo. The residue was triturated in ether to yield a white solid (0.73 g, 92%) which was collected by filtration; MS (ISP): 231.2, 229.3 ([M+H]+.).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[N:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([S:39]([NH:42][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:18]=[N:19][C:14]([N:4]3[C:5]([CH3:13])=[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:2]([CH3:1])=[N:3]3)=[CH:15][CH:16]=2)=[O:24])(=[O:40])=[O:41])=[CH:37][CH:38]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cn2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(Cl)cc3)cn2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[6-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)pyridin-3-yl]ethylcarbamate (step 5) and 4-chlorobenzenesulfonamide: 1H-NMR (CDCl3) δ 8.20 (1H, br.s), 7.83-7.77 (22H, m), 7.63-7.26 (9H, m), 6.68 (1H, br.s), 3.52-3.45 (2H, m), 2.84-2.79 (2H, m), 2.48 (3H, s), 2.67 (3H, s).
Reaction SMILES: [C:1]([C@@H:4]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[C:14](Cl)[N:13]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:3])[NH2:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[C:1]([C@@H:4]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([O:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[N:13]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:3])[NH2:2]
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)C[C@H](NC(=O)c1ccc(Br)c(Cl)n1)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C[C@H](NC(=O)c1ccc(Br)c(Oc2ccc(F)cc2)n1)C(N)=O
Temperature: 120 °C
Yield: 37.9 %

Procedure:
5-Bromo-6-chloro-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide (50 mg, 143 μmol) was dissolved in DMF (0.5 mL) to give a colorless solution. 4-Fluorophenol (19.3 mg, 172 μmol) and sodium carbonate (45.6 mg, 430 μmol) were added successively to give a yellow solution. The reaction mixture was stirred at 120° C. over the weekend, cooled to ambient temperature and poured into 40 mL water. The mixture was extracted with isopropyl acetate (2×40 mL), organic phases were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (silica gel, 2.0 mm, isopropyl acetate) to give the title compound (23 mg, 38%) as colorless oil, MS (ESI): m/e=421.9 [M−H]−.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C[Si]([C:23]#[C:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33])(C)C>C1COCC1>[C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33])#[CH:23]
Reactant: COC(=O)C(C)c1ccccc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccccc1C(C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 89.5 %

Procedure:
A solution of TBAF (1 M solution in THF; 2.28 mL, 2.28 mmol) was added to a solution of methyl 2-(2-((trimethylsilyl)ethynyl)phenyl)propanoate (I50) (0.297 g, 1.14 mmol) in THF (10 mL) at 0° C. The reaction was stirred for 50 minutes at 0° C. then concentrated under reduced pressure and the residue taken up in EtOAc (20 mL). The organic solution was washed with saturated NaHCO3 (20 mL), water (20 mL) and dried over Na2SO4. The solvent was removed in vacuo to yield a brown oily residue. The oil was purified using column chromatography on silica gel (0-5% EtOAc in cyclohexane) to afford the title compound (I51) (0.192 g, 89%) as a pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.53-7.48 (m, 1H), 7.36-7.28 (m, 2H), 7.24-7.20 (m, 1H), 4.31 (q, J=7.2 Hz, 1H), 3.67 (s, 3H), 3.28 (s, 1H), 1.50 (d, J=7.2 Hz, 3H).
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([NH:24][CH:25]2[CH2:28][CH2:27][CH2:26]2)[N:20]=[C:19]([Cl:29])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.Cl>CO.O1CCOCC1>[Cl:29][C:19]1[NH:20][C:21]([NH:24][CH:25]2[CH2:28][CH2:27][CH2:26]2)=[C:22]([F:23])[C:17](=[N:9][NH2:8])[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NC2CCC2)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NN=c1nc(Cl)[nH]c(NC2CCC2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
To a solution of tris(1,1-dimethylethyl)2-[2-chloro-6-(cyclobutylamino)-5-fluoro-4-pyrimidinyl]-1,1,2-hydrazinetricarboxylate (0.495 g, 0.96 mmol) in MeOH (10 mL) was added 4M HCl in 1,4-dioxane (10 mL). The reaction was stirred at room temperature overnight, then the solvent was evaporated, and the residue was treated with a standard K2CO3 aqueous workup to provide 2-chloro-6-(cyclobutylamino)-5-fluoro-4(1H)-pyrimidinone hydrazone as a reddish brown oil (0.225 g). LCMS: (M+H)+=232.0.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[Br:18][C:19]1[CH:20]=[N:21][C:22](I)=[N:23][CH:24]=1>CS(C)=O.O>[Br:18][C:19]1[CH:20]=[N:21][C:22]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)=[N:23][CH:24]=1
Reactant: Brc1cnc(I)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
A solution of N-Boc-4-piperidinemethanol (1.0 g, 4.50 mmol) in DMSO (2 mL) was added dropwise to a suspension of NaH (60% in mineral oil, 0.27 g, 6.76 mmol) in DMSO (4 mL). The mixture was stirred at ambient temperature for 1 h, then 30 minutes at 50° C. Cooled to ambient temperature, a solution of 5-bromo-2-iodopyrimidine (1.38 g, 4.73 mmol) in DMSO (4 mL) was added dropwise, and the reaction mixture was stirred at ambient temperature overnight, then heated at 100° C. for 5 h. Cooled to ambient temperature, the mixture was poured in water, extracted with EtOAc. The organic extract was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a dark brown oil. The crude product was purified by chromatography on ISCO silica gel column eluted with a EtOAc:hexane gradient (hexane to 15% EtOAc) to give 0.455 g (28%) of 1,1-dimethylethyl 4-{[(5-bromo-2-pyrimidinyl)oxy]methyl}-1-piperidinecarboxylate as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 2H), 4.20-4.10 (m, 4H), 2.80-2.65 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.75 (m, 2H), 1.45 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 372/374 (M+H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][N:14]=2)=[CH:8][CH:7]=1>C(Cl)Cl>[Cl:3][CH2:19][C:16]1[CH:15]=[N:14][C:13]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=2)=[N:18][CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnc(Nc2ccc(Cl)cc2)nc1
Solvent: ClCCl
Product: ClCc1cnc(Nc2ccc(Cl)cc2)nc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 112.9 %

Procedure:
Thionyl chloride (0.427 mL, 5.86 mmol) was added to a suspension of (2-((4-chlorophenyl)amino)pyrimidin-5-yl)methanol (0.23 g, 0.976 mmol) in DCM (10 mL) cooled to 0° C. The mixture was stirred for 18 h while warming to room temperature. The reaction mixture was concentrated and the residue triturated with ether to give 5-(chloromethyl)-N-(4-chlorophenyl)pyrimidin-2-amine as a pale yellow solid (0.28 g, 99%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.03 (s, 1H), 8.60 (s, 2H), 7.85-7.64 (m, 2H), 7.41-7.20 (m, 2H), 4.77 (s, 2H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[OH:28][CH2:29][CH2:30][C:31](O)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:29](=[O:28])[CH2:30][CH2:31][OH:32])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)CCO
Agent: Cl
Product: O=C(CCO)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (80 mg, 66%), MS (ISP) m/z=403.4 [(M+H)+], mp 173° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (132 mg, 0.3 mmol) and 3-hydroxy-propionic acid
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[O:25][CH:26]([CH3:28])[CH3:27]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[O:25][CH:26]([CH3:28])[CH3:27])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: CC(C)Oc1ccc(F)cc1Br
Product: CCSc1ncc(C(=O)c2cc(F)ccc2OC(C)C)c(N)n1

Procedure:
The compound was prepared from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 2-bromo4-fluoro-1-isopropoxy-benzene (prepared from 2-bromo-4-fluoro-phenol, Aldrich) in an analogous manner as described in Example 169.
Reaction SMILES: [CH3:1][C:2]([CH3:35])([O:4][C:5]([NH:7][CH2:8][C@@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH2:21][N:20](C(OCC2C=CC=CC=2)=O)[CH2:19][CH2:18]3)[CH2:10]1)=[O:6])[CH3:3]>CO.[OH-].[OH-].[Pd+2]>[O:14]=[C:12]1[N:11]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:10][C@H:9]([CH2:8][NH:7][C:5](=[O:6])[O:4][C:2]([CH3:3])([CH3:1])[CH3:35])[O:13]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc3c(c2)CCN(C(=O)OCc2ccccc2)C3)C(=O)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc3c(c2)CCNC3)C(=O)O1
Reaction time: 1.25 h

Procedure:
A mixture of phenylmethyl 6-[(5S)-5-[[[(1,1-dimethylethoxy)carbonyl]amino]-methyl]-2-oxo-3-oxazolidinyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Step 1, 1.11 g, 2.31 mmol) and 20% Pd(OH)2/C (324 mg) in MeOH (23 mL) in a Parr bottle is shaken under 20 psi H2 for 1.25 hr. The resulting mixture is filtered through Celite to remove the catalyst, and the filtrate is concentrated under reduced pressure to give a quantitative yield of the product as an amorphous solid which is used without further purification. 1H NMR (400 MHz, CD3OD) δ 7.35 (bd, 1H), 7.31 (s, 1H), 7.08 (d, 1H), 4.75 (m, 1H), 4.14 (t, 1H), 3.97 (s, 2H), 3.87 (m, 1H), 3.42 (m, 2H), 3.11 (m, 2H), 2.87 (m, 2H), 1.42 (s, 9H); MS (ESI+) for C18H25N3O4 m/z 348 (M+H)30.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[CH:4][C:3]=1[C@@H:17]([CH3:27])[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].CI.[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[Na+]>>[F:1][C:2]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:15])([CH3:16])[O:9]2)[CH:5]=[CH:4][C:3]=1[C@@H:17]([CH3:27])[CH2:18][N:19]([CH3:30])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Product: C[C@@H](CN(C)C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Yield: 83.9 %

Procedure:
Following the procedure described for Example 647, (R)-tert-butyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (400 mg, 1 mmol) was reacted with methyl iodide (1M solution in toluene, 2 mL, 2 mmol) and NaHMDS (1 M solution, 2 mL, 2 mmol) to afford the desired product (330 mg, 82%) as viscous mass. ESI MS m/z 394 [C21H38BFNO4+H]+
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH2:4][N:3]1[C@@H:8]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH3:20][C:21]1[N:26]=[C:25]([CH2:27]O)[CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.O>[CH3:17][C:16]([CH3:19])([CH3:18])[C@H:8]([N:3]1[CH2:4][C:5](=[O:7])[N:6]([CH2:27][C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:20])[N:26]=2)[C:2]1=[O:1])[C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10]
Reactant: Cc1cccc(CO)n1
Reactant: CC(C)(C)OC(=O)[C@@H](N1CC(=O)NC1=O)C(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(CN2C(=O)CN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.4 %

Procedure:
A solution containing the product from Example 46C (0.112 g, 0.413 mmol) in dichloromethane (3 mL) at 0° C. was treated with 6-methyl-2-pyridinemethanol (0.056 g, 0.454 mmol), triphenylphosphine (0.141 g, 0.537 mmol), followed by diethyl azodicarboxylate (0.084 mL, 0.537 mmol), stirred at 25° C. for 16 hours, treated with water (3 mL), stirred for 2 hours at 25° C., and partitioned between dichloromethane and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-30% ethyl acetate/dichloromethane to give the title compound (0.151 g, 97% yield).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]#[N:16])=[CH:5][CH:4]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:37]>C1COCC1>[Br:37][CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]#[N:16])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(CO)cc1-c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CBr)cc1-c1ccccc1
Reaction time: 16 h

Procedure:
5-Hydroxymethyl-biphenyl-2-carbonitrile from step 3 (1.3 g, 6.2 mmol) was dissolved in THF (31 ml) and treated with Ph3P (2.4 g, 9.3 mmol) followed by CBr4 (3 g, 9.3 mmol). The reaction was mixture stirred at room temp. for 16 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography (10% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:37]=[CH:36][C:7]([O:8][CH2:9][C:10]2[N:14]([CH2:15][CH2:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)[C:13]3[CH:31]=[CH:32][CH:33]=[C:34]([CH3:35])[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[N:14]([CH2:15][CH2:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:19]3)[C:13]3[CH:31]=[CH:32][CH:33]=[C:34]([CH3:35])[C:12]=3[N:11]=2)=[CH:36][CH:37]=1
Reactant: Cc1cccc2c1nc(COc1ccc([N+](=O)[O-])cc1)n2CCCC1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc2c1nc(COc1ccc(N)cc1)n2CCCC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A mixture of 2-(4-nitrophenoxymethyl)-4-methyl-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]benzimidazole (395 mg, 0.78 mmol) and 10% palladium on activated carbon (400 mg) in 10 ml of ethanol was stirred under a hydrogen atmosphere at room temperature. After two hours, the reaction mixture was filtered through a CELITE™ cake. The filtrate was condensed on a rotoevaporator to yield 310 mg (83%) of the desired title product.