Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[N:9]O)=[CH:3][CH:2]=1>C(O)(=O)C.[Zn]>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH:8]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[NH2:9])=[CH:5][CH:6]=1
Reactant: ON=C(Cc1ccc(-c2ccccc2)cc1)c1nccs1
Agent: [Zn]
Solvent: CC(=O)O
Product: NC(Cc1ccc(-c2ccccc2)cc1)c1nccs1
Reaction time: 3 h
Yield: 70 %

Procedure:
Zinc (60 mg, 0.9 mmol) was added to a solution of a mixture of 2-biphenyl-4-yl-1-(1,3-thiazol-2-yl)ethanone oxime (60 mg) in acetic acid (1 mL). The reaction was stirred for 3 h., was filtered and concentrated under reduced pressure. The crude was made basic with saturated NaHCO3, and was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 2-biphenyl-4-yl-1-(1,3-thiazol-2-yl)ethanamine (40 mg, 80%) as a white solid. Analytical LCMS (M+H)+: m/z=280.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]1[S:17][CH2:16][CH2:15][N:14]=[C:13]([C:18]2[C:19](=[O:26])[O:20][C:21]([CH3:25])=[CH:22][C:23]=2[OH:24])[CH2:12]1.C(N(C(C)C)CC)(C)C.[C:36](Cl)(Cl)=[O:37]>C(Cl)CCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]1[CH:12]=[C:13]2[C:18]3[C:19](=[O:26])[O:20][C:21]([CH3:25])=[CH:22][C:23]=3[O:24][C:36](=[O:37])[N:14]2[CH2:15][CH2:16][S:17]1
Reactant: COc1ccc(C2CC(c3c(O)cc(C)oc3=O)=NCCS2)c(OC)c1
Reactant: O=C(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2C=C3c4c(cc(C)oc4=O)OC(=O)N3CCS2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-[7-(2,4-Dimethoxyphenyl)-2,3,6,7-tetrahydro-[1,4]thiazepin-5-yl]-4-hydroxy-6-methyl-pyran-2-one (63 mg, 0.168 mmol), prepared as in Reference 5, was dissolved in ethylene dichloride (2 mL) and then 4-(dimethylamino)pyridine (0.020 g), di-iso-propylethylamine (0.5 mL) and phosgene (0.4 ml, 2 M in toluene) were added at room temperature. The reaction was monitored by analytical HPLC. After stirring at room temperature for 30 minutes, the solvent was removed in vacuo. Product was purified by HPLC (RPC18 column, 2-70% acetonitrile/water containing 0.1% HCl) to provide 10-(2,4-dimethoxy-phenyl)-3-methyl-7,8-dihydro-10H-2,5-dioxa-9-thia-6a-aza-cyclohepta[a]naphthalene-1,6-dione (20 mg) as an off-white powder. LCMS: M+ 401.0.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:17]1([C:15]([N:12]2[CH2:11][CH2:10][CH:9]([NH2:8])[CH2:14][CH2:13]2)=[O:16])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)N2CCCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(C(=O)N2CCCC2)CC1
Reaction time: 4 h

Procedure:
(tert-Butoxy)-N-[1-(pyrrolidinylcarbonyl)(4-piperidyl)]carboxamide (2.0 g, 6.73 mmol) was dissolved in 40 mL dichloromethane and trifluoroacetic acid (15 mL, 201.94 mmol) were added. The reaction mixture was stirred for 4 hours. The solvent was evaporated to give the product as a light brown semi-solid, which was used directly for the next step. (2.09 g, 6.73 mmol, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]2[CH:40]=[CH:39][N:38](C3CCCCO3)[N:37]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]2[NH:37][N:38]=[CH:39][CH:40]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCC[C@@H]3c3ccn(C4CCCCO4)n3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ccncn1)c1cc(Cl)c(O[C@H]2CCC[C@@H]2c2ccn[nH]2)cc1F
Yield: 99.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)-4-({(1S,2R)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]cyclopentyl}oxy)benzenesulfonamide (281 mg, 0.418 mmol) prepared in Example 150a, triethylsilane (0.60 mL), trifluoroacetic acid (4.0 mL) and dichloromethane (6.0 mL), to yield the title compound (182 mg, 99%) as a colorless solid.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:16][CH2:15][CH:12]1[CH2:13][CH2:14][N:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10][CH2:11]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1ccccc1)N1CCC(CO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCN(C(=O)c2ccccc2)CC1
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
7.5 g (0.0342 mol) of 1-benzoyl-4-hydroxymethyl-piperidine were dissolved in 170 ml of dichlormethane and 17 ml (0.122 mol) of triethylamine, cooled to 0° and treated with a solution of 3.14 ml (0.0404 mol) of methanesulfonyl chloride in 20 ml of dichloromethane. The mixture was stirred at 0° for 1/2 hr. Then, 100 ml of 1N aqueous HCI were added, the mixture was stirred for 5 min., the organic phase was washed with 1N aqueous HCI, with saturated bicarbonate solution and with saturated sodium chloride solution and dried over sodium sulfate. 10.2 g (100%) of 1-benzoylpiperidin-4-ylmethyl methanesulfonate were obtained as yellow crystals; m.p. 87°-90°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:18])=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:32][C@H:33]2[CH2:35][O:34]2)(=O)=O)=CC=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:32][C@H:33]2[CH2:35][O:34]2)=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CC(=O)c1cc(OCc2ccccc2)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(OCc2ccccc2)ccc1OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
To a stirred solution of 1-(5-benzyloxy-2-hydroxyphenyl)ethanone (3.0 g, 12.4 mmol) in anhydrous DMF (15 ml) was added NaH (0.55 g, 13.6 mmol). The mixture was allowed to stir at RT for 30 min and then heated to 60° C. A solution of (R)-oxiran-2-ylmethyl 4-methylbenzenesulfonate (2.83 g, 12.4 mmol) in DMF was added dropwise at 60° C. during 1 h. Stirring was then continued at 60° C. for 3 h. The cooled reaction was quenched by addition of water (80 ml) and extracted three times with EtOAc. The combined organic layers were extracted twice with aq 1 M NaOH and washed with water and brine. The organic layer was dried with Na2SO4 and concentrated. The crude product obtained was purified by column chromatography with EtOAc/toluene as eluent to afford the title compound (2.35 g) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C@H:14]2[CH2:19][CH2:18][CH2:17][NH:16][C@H:15]2[CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=3[CH3:32])[C@H:15]2[CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CC(C)(C)c1cccc(NC(=O)[C@H]2CCCN[C@H]2C2CCCC2)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)N1CCC[C@H](C(=O)Nc2cccc(C(C)(C)C)c2)[C@@H]1C1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of the cis-2-cyclopentylpiperidine-3-carboxylic acid (3-tert-butyl-phenyl)amide prepared above (123 mg, 0.34 mmol) in dry CH2Cl2 (1 mL) containing Et3N (142 μL, 1.02 mmol) was added 2-methylbenzoyl chloride (53 mg, 0.34 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with ethyl acetate (20 mL), washed with 1 N aqueous HCl, water, and brine. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (20-95% gradient of CH3CN—H2O) and dried (Lyophilizer) to give the title compound in 65% yield (109 mg). 1H NMR (400 MHz, CDCl3): δ 1.22-1.48 (m, 11H), 1.56-1.80 (m, 5H), 1.84-2.06 (m, 4H), 2.10-2.23 (m, 1H), 2.30 (s, 1.6H), 2.39 (s, 1.4H), 2.41-2.50 (m, 1H), 2.71-2.76 (m, 1H), 3.02-3.09 (m, 1H), 3.25-3.39 (m, 1H), 5.11 (bs, 1H), 7.05-7.30 (m, 6H), 7.47-7.55 (m, 2H), 8.32 (bs, 1H). LC-MS Rt (retention time): 3.16 min; MS: (ES) m/z 447 (M+H)+. LC-MS method: Agilent Zorbax SB-C18, 2.1×50 mm, 5 g, 35° C., 1 mL/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.0 min wash at 100% B; A=0.1% formic acid/5% acetonitrile/94.9 water, B=0.1% formic acid/5% water/94.9 acetonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[CH2:23]([Sn](CC)(CC)CC)[CH3:24]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:23][CH3:24])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3ccccc3)sc2c1O
Reactant: CC[Sn](CC)(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(CC)c2nc(-c3ccccc3)sc2c1O
Temperature: 130 °C
Yield: 66.8 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (100 mg, 0.26 mmol), tetraethyltin (106 μL, 0.52 mmol) and bis(triphenylphosphine)-palladium(II) dichloride (19 mg, 0.03 mmol) in dimethylformamide (2.5 mL) was stirred at 130° C. for 1H before it was cooled to room temperature, quenched with water, filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a white solid (57 mg): MS: (+) m/z 328.99 (M+1).
Reaction SMILES: CCN(CC)CC.[CH2:8]([C:10]1[N:11]=[C:12]([CH2:55][CH2:56][CH3:57])[N:13]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:14]=1[C:15]([O-:17])=[O:16])[CH3:9].[C:58](=[O:67])([O:64][CH2:65]Cl)[O:59][C:60]([CH3:63])([CH3:62])[CH3:61]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C1COCC1>[CH2:8]([C:10]1[N:11]=[C:12]([CH2:55][CH2:56][CH3:57])[N:13]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=2)[C:14]=1[C:15]([O:17][CH2:65][O:64][C:58]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:67])=[O:16])[CH3:9]
Reactant: CC(C)(C)OC(=O)OCCl
Reactant: CCCc1nc(CC)c(C(=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1nc(CC)c(C(=O)OCOC(=O)OC(C)(C)C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 47.6 %

Procedure:
0.22 mL Et3N was added to a mixture of 0.700 g 4-ethyl-2-propyl-1-[[2'-(N-triphenylmethyl(tetrazol-5-yl))biphenyl-4-yl]methyl]imidazole-5-carboxylate, 0.26 g t-butyl chloromethyl carbonate and 0.59 g n-Bu4NI in 5 mL dry THF under Ar. The reaction was stirred 6 days at room temperature and then concentrated on a rotary evaporator. The residue was partitioned between H2O and CH2Cl2, and the organic extracts dried with MgSO4. Flash chromatography using 1:1 EtOAc/petroleum ether(bp 40°-60° C.) gave 0.40 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].B.CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:5][OH:6]
Reactant: COc1ccc(C(=O)O)cc1Br
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CO)cc1Br
Temperature: 75 °C

Procedure:
To a solution of 9.8 g (42 mmol) of 3-bromo-4-methoxybenzoic acid in THF (100 mL) was added 1M solution of borane in THF (130 mL) at r.t. under nitrogen. The resulting solution was then heated at 75° C. for 30 min. The reaction mixture was then cooled to r.t. and MeOH (0.5 mL) was slowly added. The mixture was concentrated and successively treated with MeOH (0.5 mL), evaporated (2×) and finally triturated with Et2O and filtered to yield the title product as a solid, m.p.: 49°-54° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:7]=[C:8]([CH:15]2[O:20]CCCO2)[C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=1)CCC.Br[C:30]1[C:31]([CH3:36])=[N:32][O:33][C:34]=1[CH3:35]>>[CH3:36][C:31]1[C:30]([C:6]2[CH:7]=[C:8]([CH:15]=[O:20])[C:9]3[O:13][CH:12]=[CH:11][C:10]=3[CH:14]=2)=[C:34]([CH3:35])[O:33][N:32]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C2OCCCO2)c2occc2c1
Reactant: Cc1noc(C)c1Br
Product: Cc1noc(C)c1-c1cc(C=O)c2occc2c1

Procedure:
From tributyl-(7-[1,3]dioxan-2-yl-benzofuran-5-yl)-stannane (1.43 g) and 4-bromo-3,5-dimethylisoxazole (0.51 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[O:30][CH3:31])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O-:26])=[S:25])=[C:15]([CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:33]([O:39][CH2:40]I)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[O:30][CH3:31])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O:26][CH2:40][O:39][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[S:25])=[C:15]([CH:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C([O-])=S)=C(C3CCOCC3)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OCOC(=O)C(C)(C)C)=C(C3CCOCC3)CS[C@H]12)c1csc(N)n1
Yield: 77.1 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(tetrahydropyran-4-yl)thio-3-cephem-4-carboxylate (90 mg) was reacted with iodomethyl pivalate (84 mg), followed by purifying the reaction product in accordance with the procedure of Example 2, affording the titled compound (82 mg; 77%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[N:15]=[CH:14][C:13]3[NH:16]/[C:17](=[N:25]\[C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)/[N:18]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:12]=3[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][CH:42]([CH3:44])[CH3:43]>CN(C=O)C>[CH2:41]([N:22]1[CH2:21][CH2:20][CH:19]([N:18]2[C:12]3[CH:11]=[C:10]([O:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[N:15]=[CH:14][C:13]=3[NH:16]/[C:17]/2=[N:25]\[C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:23]1)[CH:42]([CH3:44])[CH3:43]
Reactant: O=C(/N=c1\[nH]c2cnc(OCCN3CCCCC3)cc2n1C1CCNCC1)c1ccccc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CN1CCC(n2/c(=N/C(=O)c3ccccc3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
A suspension of (E)-N-(6-(2-(piperidin-1-yl)ethoxy)-1-(piperidin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide (0.089 g, 0.198 mmol) and potassium carbonate (0.082 g, 0.595 mmol) in DMF (2 mL) was cooled to 0° C. under nitrogen. To this mixture was added 1-bromo-2-methylpropane (0.054 g, 0.397 mmol). The ice bath was removed, and the resulting mixture was stirred for 16 hours at RT. The reaction mixture was diluted with water (10 mL) and DCM (30 mL), and the organic layer was collected, concentrated and purified by silica gel chromatography (5-30% MeOH/DCM) to afford (E)-N-(1-(1-isobutylpiperidin-4-yl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide as an off-white solid (20 mg, 19.97% yield). MS m/z=505.2 [M+H]. Calc'd for C29H40N6O2: 504.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:5]([N+:16]([O-])=O)=[CH:4][N:3]=1>C1COCC1.[Ni]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[C:5]([NH2:16])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Nc1ccc(F)cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cnc(Cl)nc1Nc1ccc(F)cc1

Procedure:
A solution of 3.46 g (12.89 mmol) (2-chloro-5-nitro-pyrimidin-4-yl)-(4-fluoro-phenyl)-amine in 40 ml THF is hydrogenated with 2.0 g sponge-nickel as catalyst at room temperature and under atmospheric pressure. The catalyst is filtered off and the filtrate is evaporated giving 2-chloro-N4-(4-fluoro-phenyl)-pyrimidine-4,5-diamine as dark oil; HPLC/MS (B): 1.88 min, [M+H] 239.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:22][CH3:23])[C:5]([O:20][CH3:21])=[C:6]([CH:19]=1)[CH2:7][O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11].C([Li])CCC.Cl.[C:30](OCC)(=[O:32])C>C1COCC1>[CH3:23][O:22][C:4]1[CH:3]=[C:2]([CH:19]=[C:6]([CH2:7][O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])[C:5]=1[O:20][CH3:21])[CH:30]=[O:32]
Reactant: COc1cc(Br)cc(CO[Si](C(C)C)(C(C)C)C(C)C)c1OC
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C=O)cc(CO[Si](C(C)C)(C(C)C)C(C)C)c1OC
Reaction time: 0.25 h

Procedure:
To a solution of the 3.616 g of (5-bromo-2,3-dimethoxybenzyloxy)triisopropylsilane in 60 ml of THF there was added dropwise 3.6 ml of n-butyllithium (2.66 M, hexane solution) at −78° C. under a nitrogen atmosphere. After stirring for 15 minutes, 2 ml of N-follnylmorpholine was added and the mixture was stirred at room temperature for 20 minutes. Next, 1N hydrochloric acid was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (2.605 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:9][C:10]1(Cl)[CH2:15][O:14][CH2:13][CH2:12][O:11]1>>[Cl:9][CH2:10][CH2:15][O:14][CH2:13][C:12]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1)=[O:11]
Reactant: Nc1cccc(F)c1
Reactant: ClC1(Cl)COCCO1
Product: O=C(COCCCl)Nc1cccc(F)c1
Temperature: 100 °C

Procedure:
A mixture of 12.0 g (108 mmol) of 3-fluoraniline and 16 g of 2-chlorodioxene (contains 6% of 2,2-dichlorodioxane) is heated at 100° C. for 24 hours. The mixture is allowed to cool, and excess 2-chlorodioxene is removed under reduced pressure, giving 25 g of 2-(2-chloroethoxy)-N-(3-fluorophenyl)acetamide as brown oil; ESI 232. This oil is dissolved in 400 ml of acetonitrile, and 84.7 g (260 mmol) of caesium carbonate are added. The suspension formed is stirred at room temperature for 18 hours. The reaction mixture is filtered, and the filtrate is evaporated, giving 21.0 g of 4-(3-fluorophenyl)morpholin-3-one as brown oil; ESI 196. 1H-NMR (d6-DMSO): δ=3.77 (t, J=5 Hz; 2H), 3.97 (t, J=5 Hz; 2H), 4.23 (s; 2H), 7.11 (dddd, J1=8 Hz, J2=8 Hz, J3=2 Hz, J4=0.5 Hz, 1H), 7.26 (ddd, J1=8 Hz, J2=2 Hz, J3=0.5 Hz, 1H), 7.34 (ddd, J1=10 Hz, J2=2 Hz, J3=2 Hz, 1H), 7.45 (ddd, J1=8 Hz, J2=8 Hz, J3=7 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:19]=[C:18]([C:20](O)=[O:21])[N:17]=[C:16]2[N:23]([CH:26]([CH3:28])[CH3:27])[N:24]=[CH:25][C:15]=12)=[O:13].CN.C1C[N:34]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:33]C1.F[P-](F)(F)(F)(F)F.O>CS(C)=O.CO.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:25]=[N:24][N:23]([CH:26]([CH3:27])[CH3:28])[C:16]=2[N:17]=[C:18]([C:20]([NH:34][CH3:33])=[O:21])[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C(=O)O)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CNC(=O)c1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Reaction time: 8 h
Yield: 8 %

Procedure:
4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (1 equiv.) was dissolved in DMSO and methylamine (2 equiv.) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (1.5 equiv.) was added to it and stirring was continued overnight. After completion of the reaction, water was added to it and extraction was carried out using 20% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography/prep. HPLC to give the desired compound (8% yield). LCMS: 397.15 (M+1)+; HPLC: 93.04% (@ 254 nm) (Rt; 5.597); 1H NMR (DMSO-d6, 400 MHz) δ 11.53 (s, 1H), 9.04 (t, 1H, J=4.4 Hz), 8.95 (d, 1H, J=4.8 Hz), 8.43 (s, 1H), 8.17 (s, 1H), 5.88 (s, 1H), 5.49-5.43 (m, 1H), 4.36 (d, 2H, J=4.8 Hz), 2.88 (d, 3H, J=4.4 Hz), 2.21 (s, 3H), 2.12 (s, 3H), 1.52 (d, 6H, J=6.8 Hz).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH2:12][NH:13][CH:14]=O)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[O:11][C:10]3=[CH:12][N:13]=[CH:14][N:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CNCc1ncc(-c2ccccc2)o1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: c1ccc(-c2cn3cncc3o2)cc1

Procedure:
To 0.6 g (3 mmol) (2) in 15 ml toluene was added dropwise 1 ml phosphorus oxychloride and the resulting solution was heated at 90° overnight. Then, the solvent was removed in vacuo and the residue carefully diluted with 50 ml water. This solution was made basic with 40% NaOH solution and extracted with 4×50 ml portions of methylenechloride. The combined organic extracts were washed with brine, dried and the solvent removed in vacuo to give a dark gum. This was purified by chromatography on silica gel eluting with methylene chloride (97%)-isopropanol (3%) to give pure (3) as a waxy, tan solid, m.p. 128°-131° (dec).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:9]=1[O:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH3:25][P:26]([CH2:29]Cl)([CH3:28])=[O:27].O>CN(C)C=O>[CH3:25][P:26]([CH2:29][N:14]1[CH2:15][CH2:16][CH:11]([O:10][C:9]2[C:17]([F:24])=[C:18]([F:23])[C:19]([F:22])=[C:20]([F:21])[C:8]=2[F:7])[CH2:12][CH2:13]1)([CH3:28])=[O:27]
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: CP(C)(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CP(C)(=O)CN1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 80 °C
Reaction time: 30 h
Yield: 22.2 %

Procedure:
To a stirring mixture of 9.0 g of potassium carbonate in 100 ml of dimethylformamide was added 8.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine and 9.5 g of dimethylphosphinylmethyl chloride. After stirring at 80° C. for 30 hours, the reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, evaporation afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 5% methanol/dichloromethane). The desired fractions were evaporated to yield a solid which was sublimed to afford 2.37 g (22.1%) of 1-[(dimethylphosphinyl)methyl]-4-(2,3,4,5,6-pentafluorophenoxy) piperidine, m.p. 120°-123° C.