Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]C1(Cl)C=CC(C(C(C2C=CC=CC=2)O)=O)=CC1.[CH2:19]([CH2:21][NH2:22])[OH:20].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)=O)=[O:31])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[ClH:1].[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([CH:32]([NH:22][CH2:21][CH2:19][OH:20])[C:30]([C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=2)=[O:31])=[CH:35][CH:36]=1
Reactant: O=C(C1=CCC(Cl)(Cl)C=C1)C(O)c1ccccc1
Reactant: NCCO
Reactant: O=C(C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: Cl
Product: O=C(c1ccc(Cl)cc1)C(NCCO)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
In a closed system equipped with a Dean-Stark trap, a stirred solution of 4,4-dichlorobenzoin (10.0 g, 0.0357 mole), ethanolamine (2.35 g, 0.0385 mole), and a catalytic amount of p-toluenesulfonic aid in 250 ml toluene was heated at reflux temperature for 4 hours and the azeotroped water was collected in the Dean-Stark trap. After cooling, the toluene solution was washed with water, dried over magnesium sulfate and concentrated to an oil. The oil was dissolved in ether, treated with excess ethereal hydrogen chloride and the salt collected under nitrogen. Upon trying to recrystallize the salt from 350 ml of isopropyl ether (necessary for complete solution), 500 ml isopropyl ether, a yellow solid was obtained from this solution which was identified as 4,4'-dichlorobenzil. The filtrate was concentrated to 50 ml and isopropyl ether added to the hot solution until a faint turbidity was obtained. On standing overnight, a white solid was obtained, m.p. 177°-182° C. Recrystallization of the white solid from methanol-isopropyl ether and from acetonitrile-methanol yielded only semisolid salts. These were triturated with methyl ethyl ketone and dried to give 2.04 g total, m.p. 188°-193° C. This material gave a satisfactory elemental analysis for the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)[S:10][C:11]=2[C:12](O)=[O:13])=[CH:4][CH:3]=1.CC[N:26]=C=NCCCN(C)C.O.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)[S:10][C:11]=2[C:12]([NH2:26])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1sc(-c2ccnc(Cl)c2)nc1Cc1ccc(Cl)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1sc(-c2ccnc(Cl)c2)nc1Cc1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 67.8 %

Procedure:
To a mixture of 4-(4-chlorobenzyl)-2-(2-chloropyridin-4-yl)thiazole-5-carboxylic acid (179 mg, 0.490 mmol) in DCM (27.5 mL) was added EDCI (282 mg, 1.47 mmol) and 1-hydroxybenzotriazole hydrate (150 mg, 0.980 mmol) and the solution was stirred for 10 minutes. 28% ammonium hydroxide (2.12 mL, 24.5 mmol) was added and the resulting mixture was stirred at room temperature overnight. Water (20 mL) was added and the mixture was extracted with DCM (2×25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (methanol/DCM=0/100→15/85) to give 121 mg of the title compound as a white solid (67% yield). LC/MS (FA) ES+ 364, 366. 1H NMR (400 MHz, d6-DMSO) δ: 8.54 (dd, 1H, J=5.2, 0.7 Hz), 8.02 (bs, 1H), 7.91 (dd, 1H, J=1.5, 0.7 Hz), 7.84 (dd, 1H, J=5.2, 1.5 Hz), 7.79 (bs, 1H), 7.36-7.29 (m, 4H), 4.43 (s, 2H).
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=O)[C:6]([CH3:27])([CH3:26])[CH2:7][O:8][Si:9]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:29](#[N:31])[CH3:30].Cl>C1(C)C=CC=CC=1>[C:22]([Si:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:8][CH2:7][C:6]([CH3:27])([CH3:26])[C:5](=[O:4])[CH2:30][C:29]#[N:31])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)C(C)(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)CC#N
Yield: 24.5 %

Procedure:
A suspension of sodium hydride (60% dispersion in oil) (2.12 g, 52.9 mmol) in toluene (65 mL) at reflux under N2 was added over 55 mins a solution of Intermediate 153a (15.93 g, assumed 37.8 mmol) and acetonitrile (2.87 mL, 54.9 mmol) in toluene (31 mL). The mixture was heated at reflux for 67 h. The cooled reaction mixture was slowly acidified to pH 5 with aqueous 1N HCl and extracted with EtOAc. The aqueous layer was extracted with EtOAc (×2) and the combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by FCC, using 0-50% ether in pentane, to give the title compound (3.52 g, 25%) as a yellow oil. LCMS (Method 3): Rt 4.94 min, m/z 402.3 [M+Na+].
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([F:16])=[C:14]([F:17])[CH:13]=[C:12]([O:18][Si](C(C)(C)C)(C)C)[C:11]=2[O:26][CH3:27])=[O:9])=[CH:6][N:5]=[C:4]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:31][CH2:30]2)[N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:11]([O:26][CH3:27])=[C:12]([OH:18])[CH:13]=[C:14]([F:17])[C:15]=2[F:16])=[O:9])=[CH:6][N:5]=[C:4]([NH:28][CH:29]2[CH2:30][CH2:31][N:32]([S:35]([CH3:38])(=[O:36])=[O:37])[CH2:33][CH2:34]2)[N:3]=1
Reactant: COc1c(O[Si](C)(C)C(C)(C)C)cc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1c(O)cc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a solution of [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-[3-(tert-butyl-dimethyl-silanyloxy)-5,6-difluoro-2-methoxy-phenyl]-methanone (675 mg, 1.181 mmol, Example 270) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (1.240 mL, 1.24 mmol, 1 M solution in tetrahydrofuran, Aldrich). The mixture was stirred at room temperature for 15 minutes and then concentrated to dryness. The residue was taken up in methylene chloride and washed with saturated solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, 60 Å silica gel, eluting with 65–80% ethyl acetate in hexanes then 5% methanol in ethyl acetate) yielded [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-5-hydroxy-6-methoxy-phenyl)-methanone as white solids (315 mg, 58%). HR-MS (ES, m/z) calculated for C18H22N5O5SF2 [(M+H)+] 458.1308, observed 458.1304.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[Cl:11][SiH:12]([Cl:14])[Cl:13]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Si:12]([Cl:14])([Cl:13])[Cl:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cl[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: COc1ccc(C[Si](Cl)(Cl)Cl)cc1
Yield: 74.7 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.19 g (0.64 mmol) of tetrabutylphosphonium chloride, 1.00 g (6.39 mmol) of 4-methoxybenzyl chloride, and 2.46 ml (18.2 mmol) of trichlorosilane were reacted at 130° C. for 4 hrs. The resulting mixture was distilled to give 1.22 g of (4-methoxybenzyl)trichlorosilane (yield; 86%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].[CH2:13]([OH:16])[CH2:14][CH3:15]>>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:16][CH2:13][CH2:14][CH3:15])[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: CCCO
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Product: CCCOc1cc[n+]([O-])c(C)c1C
Reaction time: 384 h

Procedure:
25 g of 2,3-dimethyl-4-nitropyridine 1-oxide are dissolved in 1250 ml of n-propanol and the solution is stirred at 120° under argon for 16 days. The reaction mixture is concentrated, whereupon the residue is treated with methylene chloride-water and extracted. The organic phases are dried and concentrated. The residue is chromatographed on silica gel and purified with methylene chloride-methanol (20:1, 10:1), the medium pressure flash chromatography method being used and the pressure being produced with nitrogen gas. The 2,3-dimethyl-4-propoxypyridine 1-oxide obtained is processed directly.
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)=C2N=C(C3C=CC(CN4CCOCC4)=CC=3)NC2=NC=1.[NH2:42][C:43]1[C:48]([NH2:49])=[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])[C:46]([Cl:61])=[CH:45][N:44]=1.[CH3:62][O:63][C:64]1[CH:71]=[C:70]([N:72]2[CH2:77][CH2:76][O:75][CH2:74][CH2:73]2)[CH:69]=[CH:68][C:65]=1[CH:66]=O>>[Cl:61][C:46]1[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])=[C:48]2[N:49]=[C:66]([C:65]3[CH:68]=[CH:69][C:70]([N:72]4[CH2:77][CH2:76][O:75][CH2:74][CH2:73]4)=[CH:71][C:64]=3[O:63][CH3:62])[NH:42][C:43]2=[N:44][CH:45]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc(N2CCOCC2)ccc1C=O
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCOCC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 65 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 2-methoxy-4-morpholin-4-yl-benzaldehyde were reacted to produce the title compound (65%). 1H NMR (d-chloroform): 13.88 (br s, 1H), 8.25 (m, 2H), 7.77 (s, 1H), 7.18 (s, 1H), 7.07 (d, J=7 Hz, 1H), 6.42 (m, 3H), 5.81 (s, 1H), 5.29 (t, J=7 Hz, 1H), 4.53 (d, J=9 Hz, 1H), 4.10-3.94 (m, 10H), 3.68 (m, 1H), 3.35 (m, 1H), 3.16 (s, 1H), 2.92 (s, 1H), 2.77 (d, J=8 Hz, 1H), 2.38 (d, J=9 Hz, 1H), 1.63 (d, J=9 Hz, 1H). MS: 509.16 (M+H). HPLC retention time: 1.82 minutes (G Method).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([CH:19]=1)[C:7]([C:9](=[CH:15][N:16]([CH3:18])C)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].[CH3:21][N:22]1[CH2:27][CH2:26][CH:25](CN)[CH2:24][CH2:23]1>C1COCC1>[Br:1][C:2]1[CH:19]=[C:6]2[C:5](=[N:4][CH:3]=1)[N:16]([CH2:18][CH:25]1[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]1)[CH:15]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7]2=[O:8]
Reactant: CN1CCC(CN)CC1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Br)cnc1F
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(CC2CCN(C)CC2)c2ncc(Br)cc2c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
To a solution of ethyl 2-(5-bromo-2-fluoronicotinoyl)-3-(dimethylamino)acrylate (Intermediate 3, 784 mg, 2.27 mmol) dissolved in THF (12 mL) was added (1-methylpiperidin-4-yl)methanamine (291 mg, 2.27 mmol). The reaction mixture was stirred at 60° C. for 2 h, then cooled to room temperature, concentrated under reduced pressure, and the resulting residue was resuspended in DMF (12 mL). Potassium carbonate was added (942 mg, 6.81 mmol, 3 equiv.) to the suspension, and the reaction was stirred at 70° C. for 18 h. The reaction mixture was cooled to room temperature then quenched with 1 N HCl. The reaction mixture was partitioned between water (15 mL) and dichloromethane (15 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2×15 mL), and the combined organic layers were concentrated to provide ethyl 6-bromo-1-((1-methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (945 mg, >99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:19].Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:26][C:21]([NH:19][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:22][CH:23]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COCCNC1CCc2ccc(N)c(OC)c2CC1
Product: COCCNC1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)c2CC1
Yield: 10.1 %

Procedure:
In an analogous manner to Experimental 691, part c, 1-methoxy-N*7*-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide were combined to yield N-((1R,2R)-2-{5-Chloro-2-[1-methoxy-7-(2-methoxy-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide (21.60 mg, 10.1% yield) as a beige foam. Purification again separated the compound into its corresponding enantiomers. 1H-NMR (CDCl3) δ 7.93 (s, 1H), 7.91 (d, J=8.2 Hz, 1H), 7.29 (s, 1H), 6.87 (d, J=8.2 Hz, 1H), 5.42 (d, J=7.4 Hz, 1H), 3.92 (m, 1H), 3.71 (s, 3H), 3.51 (t, J=4.8 Hz, 2H), 3.36 (s, 3H), 3.24 (m, 2H), 2.85 (m, 8H), 2.69 (m, 1H), 2.48 (m, 1H), 2.22 (d, J=10.4 Hz, 2H), 2.10 (m, 2H), 1.38 (m, 7H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].Cl.[F:20][C:21]1([F:27])[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1.C(O)(=O)C.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:20][C:21]1([F:27])[CH2:26][CH2:25][CH2:24][N:23]([CH:15]2[CH2:16][CH2:17][N:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:13][CH2:14]2)[CH2:22]1
Reactant: FC1(F)CCCNC1
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COc1cc(N2CCC(N3CCCC(F)(F)C3)CC2)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
A mixture of 1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinone (600 mg, 2.4 mmol), commercially available 3,3-difluoropiperidine hydrochloride (753 mg, 4.8 mmol), acetic acid (0.20 mL, 3.6 mmol) and triethylamine (0.33 mL, 3.6 mmol) in 1,2-dichloroethane was stirred for 30 minutes. Sodium triacetoxyborohydride (615 mg, 2.9 mmol) was added. When LC/MS indicated the absence of starting material, the reaction was quenched with the addition of sat'd NaHCO3. The reaction was diluted with dichloromethane and the layers were separated. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with water, dried over MgSO4 and concentrated onto silica gel. The crude material was purified by flash column chromatography to give 3,3-difluoro-1′-[3-(methyloxy)-4-nitrophenyl]-1,4′-bipiperidine (584 mg, 68%). 1H NMR (400 MHz, d6-DMSO) δ 7.84 (d, J=9.6 Hz, 1H), 6.55 (dd, J=9.6 and 2.0 Hz, 1H), 6.46 (d, J=2.0 Hz, 1H), 4.04 (d, J=12.8 Hz, 1H), 3.87 (s, 3H), 2.90 (t, J=12.0 Hz, 2H), 2.72-2.60 (m, 3H), 2.47 (m under DMSO peak, 2H), 1.87-1.74 (m, 4H), 1.61-1.58 (m, 2H), 1.48-1.38 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:14]1)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][CH2:35][CH2:36][C:37](O)=[O:38].C(Cl)CCl.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][CH2:35][CH2:36][C:37]([NH:1][C@H:2]([C:11]([N:13]1[CH2:14][CH2:15][CH:16]([O:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:18]1)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:38]
Reactant: O=C(O)CCNc1ccccn1
Reactant: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@@H](N)Cc2ccc(O)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@H](Cc2ccc(O)cc2)NC(=O)CCNc2ccccn2)CC1

Procedure:
A mixture of tert-butyl [(1-tyrosyl-4-piperidinyl)oxy]acetate, Alig, et. al., EP 372486, (1 mmol), N-(2-pyridinyl)-β-alanine, Chowdhary, et. al., Indian J. Chem., 1990, 29A, 280-284, (1 mmol), EDC (1.5 mmol), and DIEA (3 mmol) in DMF (25 mL) is stirred at RT. The mixture is poured into 5% NaHCO3 and extracted with EtOAc. The combined orgainic phase is washed with H2O, dried (MgSO4) and concentrated. The residue is chromatographed (silica gel) to give the title compound.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[O:9]=[C:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]1.O>CS(C)=O>[O:9]1[C:10]2([CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]2)[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC2(CC1)CO2
Yield: 240.8 %

Procedure:
to a stirred solution of trimethylsulfoxonium iodide (56.1 g, 255 mmol) in anhydrous DMSO (150 ml) was added a mixture of NaH (18.5 gram 1.5 equiv., 60% in mineral oil) under a nitrogen atmosphere. The mixture was stirred at 65° C. for 1 hour, whereafter compound 2 (32 g, 150 mmol) was added as a solution in DMSO (10 ml). The mixture was refluxed overnight under a nitrogen atmosphere. The solution was allowed to reach room temperature, water was added and the mixture was extracted with diethyl ether (3×200 ml). The combined organic layer was washed with H2O, with brine and dried over Na2SO4. The Et2O was evaporated to yield 82.1 gram (32 g, 95%) compound 3. 1H-NMR (300 MHz, CDCl3): δ (ppm)=1.45 (s, 9H, BOC); 1.50-2.10 (m, 6H), 2.60-2.70 (m, 2H), 3.5-3.60 (m, 2H).
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:22][CH:23]([C:27](O)=[O:28])[C:24](O)=[O:25])[CH:19]=[CH:20][CH:21]=1>>[OH:28][C:27]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:24](=[O:25])[C:23]=1[S:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=1
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: COc1cccc(SC(C(=O)O)C(=O)O)c1
Product: COc1cccc(Sc2c(O)cc(-c3ccccc3)oc2=O)c1

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(3-methoxyphenyl)thio]propanedioic acid (1.51 g, 5.07 mmol). m.p. 130-131° C. 1H NMR (400 MHz, DMSO-d6) δ3.69 (s, 3H), 6.69 (dd, 1H), 6.72 (dd, 1H), 6.89 (s, 1H), 7.2 (dt, 2H), 7.58 (m, 3H), 7.88 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]([N:18]4[CH2:21][CH:20]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:19]4)=[O:17])[S:15][C:8]=23)=[C:4]([F:32])[CH:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH:41][C:42](=[O:47])[CH2:43][C:44](O)=[O:45].C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[Si:23]([O:22][CH:20]1[CH2:21][N:18]([C:16]([C:14]2[S:15][C:8]3[C:9](=[N:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]3[CH:30]=[CH:31][C:2]([NH:1][C:44](=[O:45])[CH2:43][C:42]([NH:41][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[O:34][CH3:33])=[O:47])=[CH:3][C:4]=3[F:32])[CH:13]=2)=[O:17])[CH2:19]1)([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OC1CN(C(=O)c2cc3nccc(Oc4ccc(N)cc4F)c3s2)C1
Reactant: COc1ccccc1NC(=O)CC(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)N4CC(O[Si](C)(C)C(C)(C)C)C4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
A mixture of (7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)methanone 274 (145.2 mg, 0.31 mmol), 27 (77 mg, 0.367 mmol), and EDC (70.3 mg, 0.367 mmol) in DMF (4.4 mL) was stirred overnight at room temperature. The crude mixture was diluted with EtOAc, extracted with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure affording crude 275 (178.4 mg, 0.269 mmol, 87% yield) that was used in the next step without further purification. MS (m/z): (M+1) 665.1 (100%).
Reaction SMILES: [SH:1][CH2:2][CH:3](O)[CH2:4][SH:5].F[C:8]([O:20]CC)(F)[C:9](F)(F)C(F)(F)C(F)(F)F.CN(C)C=O.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[N-:65]=[C:66]=[O:67]>>[S:5]1[CH:4]=[CH:3][CH2:2][S:1]1.[NH2:65][C:66]([O:20][CH2:8][CH3:9])=[O:67]
Reactant: OC(CS)CS
Reactant: CCOC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [N-]=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CN(C)C=O
Product: C1=CSSC1
Product: CCOC(N)=O

Procedure:
The perfluoropolyether bis(isocyanate) described above was heated with 2.2 equivalents of 1,3-dimercapto-2-propanol in 1:1 ethyl perfluorobutyl ether/dimethylformamide with catalytic dibutyltin dilaurate at reflux for four hours. The reaction was followed by monitoring the disappearance of the isocyanate stretching band and the growth of the carbonyl band by FTIR. Upon completion of the reaction mixture was washed well with water. Concentration by evaporation yielded the perfluoropolyether bis(urethane dithiol), which has the putative formula:
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH:14]=2)=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.CCO>CCOC(C)=O.[Pd]>[F:1][C:2]1[C:3]([CH:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1
Reactant: CN1CC=C(c2c(N)cncc2F)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN1CCC(c2c(N)cncc2F)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.2 %

Procedure:
Pd on C, wet, Degussa (25 mg, 0.1175 mmol) was added to a stirred solution of 5-fluoro-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)pyridin-3-amine (61 mg, 0.2943 mmol) in EtOAc (5 mL)/EtOH (5 mL). The reaction was placed under an atmosphere of hydrogen and stirred at ambient temperature for 15 hours. A further portion of Pd on C, wet, Degussa (25 mg, 0.1175 mmol) was added and the reaction was placed under an atmosphere of hydrogen and stirred at ambient temperature for 24 hours. The catalyst was removed by filtration through a pad of celite and the filtrate concentrated in vacuo to give 5-fluoro-4-(1-methylpiperidin-4-yl)pyridin-3-amine as an off-white solid (58 mg, 95% Yield). MS (ES+) 210.1.
Reaction SMILES: [Cl:1]C1C=CC=CC=1C=O.[CH3:10][O:11][C:12](=[O:33])[CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:34]1([CH3:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[Cl:1][C:36]1[CH:35]=[C:34](/[CH:40]=[CH:13]/[C:12]([O:11][CH3:10])=[O:33])[CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1Cl
Reactant: Cc1ccccc1
Product: COC(=O)/C=C/c1cccc(Cl)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a solution of 2-chlorobenzaldehyde 7-6 (5.0 g, 35.6 mmol) in toluene (50 mL) at 25° C. was added methyl(triphenylphosphoranylidene)acetate (13.0 g, 39.1 mmol) and the reaction mixture was stirred at 110° C. for 3 h. The mixture was concentrated in vacuo and purified by normal phase silica gel chromatography (0 to 20% EtOAc in hexanes) to afford the title compound a clear oil. ESI+ MS: [M+H]+ 197.2.