Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)=[CH:6][CH:5]=1.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)=[O:20].N1C=CC=CC=1.Cl>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:16][C:2]([F:1])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[CH:13][N:12]([C:25]3[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=3)[C:19]([O:18][CH3:17])=[O:20])[N:11]=2)=[CH:6][CH:5]=1
Reactant: FC(F)(F)Oc1ccc(-c2cc[nH]n2)cc1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)c1cccc(-n2ccc(-c3ccc(OC(F)(F)F)cc3)n2)c1
Temperature: 60 °C

Procedure:
A solution of 3-(4-trifluoromethoxy-phenyl)-1H-pyrazole (250 mg), 3-methoxycarbonylphenylboronic acid (540 mg) and pyridine (0.18 mL) in dimethylformamide (5 mL) is treated with copper (II) acetate (214 mg) and powdered activated 4 Å molecular sieves (0.5 g). The resulting mixture is heated to 60° C. for 16 h and cooled. The reaction mixture is poured into 1M aq. HCl (300 mL), and the resulting mixture is filtered through a glass microfiber filter pad. The pad is washed with ethyl acetate, and the filtrate is evaporated to afford the product, methyl 3-[3-(4-trifluoromethoxy-phenyl)-pyrazol-1-yl]-benzoate, as a solid (204 mg).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[ClH:27]>>[OH:1][C:3]1([CH2:2][Cl:27])[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:7][CH2:8]1
Reactant: Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CCl)CC3)c(F)c2)C(=O)O1
Temperature: 55 °C

Procedure:
A mixture of (S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (18.0 mmol) and aqueous hydrochloric acid was heated at a temperature 50-60° C. for 12 hours to provide crude (S)—N-{3-[4-(4-hydroxy-4-chloromethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide which was purified by silica gel column chromatography and used further.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](O)[CH2:6][CH2:5]2.[NH:12]1[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[N:14]=[CH:13]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C>[CH3:20][O:19][C:17]([C:15]1[N:14]([CH:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)[CH:13]=[N:12][CH:16]=1)=[O:18]
Reactant: OC1CCc2cc(F)ccc21
Reactant: COC(=O)c1c[nH]cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1CCc2cc(F)ccc21
Temperature: 25 °C

Procedure:
To a solution of 5-fluoro-indan-1-ol (0.293 g, 1.925 mmol) and methyl 4-imidazolecarboxylate (CAS#17325-26-7, 0.163 g, 1.290 mmol) in THF (10 mL) at 0° C. is added pMe2NPhP(Ph)2 (0.619 g, 1.925 mmol) and diisopropyl azodicarboxylate (94%, 0.414 g, 1.925 mmol). After 1 hour the mixture is warmed to room temperature and after 18 hours it is diluted with ethyl acetate and extracted with 1M aqueous HCl. The extracts are cooled to 0° C., and the pH is adjusted to ca. 9 with ice-cold 4M aqueous NaOH. The basic aqueous phase is extracted three times with dichloromethane, and the combined organic phases are dried over magnesium sulfate, filtered through a cotton plug, and concentrated. The resulting residue is purified by silica gel flash chromatography (elution with dichloromethane-methanol, 1:0 to 99:1 to 49:1) to afford 3-(5-fluoro-indan-1-yl)-3H-imidazole-4-carboxylic acid methyl ester; MS: (ESI) m/z 261.0 (M+H)+. The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 3-(5-fluoro-indan-1-yl)-3H-imidazole-4-carboxylic acid methyl ester; 1H NMR (400 MHz, CDCl3) δ ppm 2.06-2.20 (m, 1 H), 2.71-2.85 (m, 1 H), 2.87-3.00 (m, 1 H), 3.00-3.14 (m, 1 H), 3.87 (s, 3 H), 6.47 (dd, J=7.7, 4.7 Hz, 1 H), 6.88-6.97 (m, 1 H), 7.01 (dd, J=8.6, 2.3 Hz, 1 H), 7.16 (dd, J=8.6, 5.1 Hz, 1 H), 7.19 (s, 1 H), 7.77 (s, 1 H).
Reaction SMILES: Cl.Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[C:11]([C:26]([F:29])([F:28])[F:27])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:39])[CH2:33][CH2:32]2)=[C:11]([C:26]([F:28])([F:27])[F:29])[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OC2CCNCC2)c(C(F)(F)F)c1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(C)CC2)c(C(F)(F)F)c1-c1ccc(OC2CCCCC2)cc1
Reaction time: 12 h

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-5-trifluoromethyl-pyridazine dihydrochloride (0.14 mmol, 0.075 g) and aqueous formaldehyde (37%, 0.68 mmol, 0.070 mL) in dry DCM (1.2 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 0.82 mmol, 0.35 g). The mixture was shaken for 12 hours. The reaction was filtered and the resin was washed with DCM (10 mL). The solvent was removed under reduced pressure. The crude product was purified on a 4 g SiO2 cartridge with 4-6% (2N NH3 in MeOH) in DCM to give 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(1-methyl-piperidin-4-yloxy)-5-trifluoromethyl-pyridazine. The neutral amine was treated with 2N HCl in diethyl ether (0.5 mL) and DCM (0.5 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.05 g). LCMS: m/z 493 [M+1]; 1H NMR (400 MHz, CD3OD) δ 7.10-7.19 (2H, m), 7.00-7.09 (2H, d), 5.54-5.82 (1H, m), 4.38-4.43 (1H, m), 3.66 (1 h, d), 3.54 (1H, d), 3.10-3.35 (2H, m), 2.89-2.98 (3H, m), 2.64-2.73 (2H, m), 2.58 (1H, d), 2.46 (1H, d), 2.27 (1H, t), 1.96-2.13 (3H, m), 1.78-1.83 (2H, m), 1.14-1.66 (10H, m), 0.77 (3H, t).
Reaction SMILES: [CH3:1][CH:2]([NH2:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][CH:6]=1.[C:13](C1C=CC(CCC(=O)C)=CC=1)#[N:14]>>[CH3:1][CH:2]([NH2:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:13]#[N:14])=[CH:7][CH:6]=1
Reactant: CC(=O)CCc1ccc(C#N)cc1
Reactant: CC(N)CCc1ccc(Cl)cc1
Product: CC(N)CCc1ccc(C#N)cc1

Procedure:
Using the procedure of Example 3 (a) with 4-(4-cyanophenyl)-2-butanone in place of 4-(4-chlorophenyl)-2-butanone, distillation under reduced pressure gave 1-methyl-3-(4-cyanophenyl)propylamine (b.p. 106°-112°/0.2 mm).
Reaction SMILES: [NH2:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=2)=[N:5][N:4]=[C:3]1[SH:19].[CH3:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=O)=[CH:23][C:22]=1[N+:30]([O-:32])=[O:31]>P(Cl)(Cl)(Cl)=O>[CH3:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]2[S:19][C:3]3=[N:4][N:5]=[C:6]([C:7]4[CH:8]=[C:9]([O:17][CH3:18])[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=4)[N:2]3[N:1]=2)=[CH:23][C:22]=1[N+:30]([O-:32])=[O:31]
Reactant: COc1cc(-c2nnc(S)n2N)cc(OC)c1OC
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(-c2nnc3sc(-c4ccc(C)c([N+](=O)[O-])c4)nn23)cc(OC)c1OC
Yield: 87.9 %

Procedure:
A mixture of 4-amino-3-mercapto-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (220 mg, 0.78 mmol) and 4-methyl-3-nitrobenzoyl chloride (156 mg, 0.78 mmol) in phosphoryl chloride (2 mL) was refluxed for 3 h. The solvent was evaporated and the residue was dissolved in dichloromethane (20 mL). It was neutralized by aqueous sodium carbonate. The organic layer was dried over sodium sulfate, and concentrated to give 293 mg (85%) of the title compound as solid. 1H NMR (CDCl3): 8.59 (d, J=2.1 Hz, 1H), 8.05-8.01 (dd, J=7.8, 1.8 Hz, 1H), 7.73 (s, 1H), 7.62 (d, J=8.1 Hz, 1H), 4.02 (s, 6H), 3.95 (s, 3H), 2.75 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:20][CH2:21][CH3:22])=[N:12][C:13]([CH3:19])=[CH:14][C:15]=1[S:16][CH2:17][CH3:18])=[O:8].[SH:23][C:24]1[O:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[O:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[S:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:20][CH2:21][CH3:22])=[N:12][C:13]([CH3:19])=[CH:14][C:15]=1[S:16][CH2:17][CH3:18])=[O:8]
Reactant: Sc1nc2ccccc2o1
Reactant: CCSc1cc(C)nc(SCC)c1NC(=O)CCCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSc1cc(C)nc(SCC)c1NC(=O)CCCCCSc1nc2ccccc2o1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 45.5 %

Procedure:
The reaction and the treatment were conducted in the same manner as in Example 26 except that 6-bromohexanoyl chloride was used instead of bromoacetyl bromide to obtain 6-bromo-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]hexanamide. To a DMF (2 ml) solution of this amide (122 mg, 0.3 mmol) and 2-mercaptobenzoxazole (45 mg, 0.3 mmol) were added potassium carbonate (46 mg, 0.33 mmol) and 18-crown-6 (8 mg, 0.03 mmol), and the mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was allowed to cool, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting residue was purified through preparative thin-layer chromatography (eluent—hexane:acetone=5:2) to obtain 65 mg (yield 46%) of the desired compound as a light brown needle crystal.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:28])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21](Cl)[CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:29][C:30]1[CH:35]=[C:34]([Sn](CCCC)(CCCC)CCCC)[CH:33]=[CH:32][N:31]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:28])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:34]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:29])[CH:35]=4)[CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(C#N)c(Cl)c3)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(C#N)c(-c4ccnc(C)c4)c3)nc2)CC1
Temperature: 118 °C
Reaction time: 8 h

Procedure:
A mixture of N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(3-chloro-4-cyanophenyl)acetamide as solid 237-3 (17 mg, 0.043 mmol), 2-methyl-4-(tributylstannyl)pyridine (24.5 mg, 0.064 mmol), Pd(PPh3)4 (5 mg, 0.0043 mmol) in DMF (0.6 ml) was stirred at 118° C. under argon overnight. After cooled to room temperature, it was filtered through celite while washed and diluted with ethyl acetate (30 ml). Then it was washed with water (40 ml) and extected with 0.5 N HCl (30 ml). After the aqueous extraction was treated with Na2CO3 to have the pH adjusted to around 9, the aqueous phase was extracted with ethyl acetate (30 ml×2). The combined organic phases were dried over Na2SO4, concentrated by rotary evaporation and the residue subjected to silica gel column chromatography with MeOH in ethyl acetate (0 to 5%) as eluent to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-cyano-3-(2-methylpyridin-4-yl)phenyl)acetamide as solid 237. MS m/z 455.2 (M+1); 1H NMR 400 MHz (CDCl3) δ 8.62 (d, 1 H), 8.08 (d, 1 H), 8.02 (bs, 1 H), 7.91 (d, 1 H), 7.79 (d, 1 H), 7.53-7.47 (m, 2 H), 7.34 (bs, 1 H), 7.31-7.26 (m, 2 H), 3.82 (s, 2 H), 3.80-3.75 (m, 2 H), 3.65-3.60 (m, 2 H), 3.16-3.08 (m, 4 H), 2.64 (s, 3 H), 2.14 (s, 3 H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([CH3:29])[C@H:26]([C:30]([N:32]3[CH2:37][CH2:36][N:35]([N+:38]([O-:40])=[O:39])[CH2:34][CH:33]3[C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])=[O:31])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][C@@H:24]1[CH2:28][N:27]([CH3:29])[C@H:26]([C:30]([N:32]2[CH2:37][CH2:36][N:35]([N+:38]([O-:40])=[O:39])[CH2:34][CH:33]2[C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])=[O:31])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN([N+](=O)[O-])CC3C(=O)OCc3ccccc3)N(C)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CN1C[C@@H](S)C[C@H]1C(=O)N1CCN([N+](=O)[O-])CC1C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
130 ml of trifluoroacetic acid and 4.6 ml of trifluoromethanesulfonic acid were added dropwise to a solution of 13.8 g of (2S,4S)-4-(4-methoxybenzylthio)-2-(4-nitrobenzyloxycarbonyl -1-piperazinylcarbonyl)-1-methylpyrrolidine [prepared as described in step (i) above] in 28.3 ml of anisole, and the resulting mixture was stirred for 30 minutes, whilst ice-cooling. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was washed with hexane and ether, in that order, by decantation to give 13.9 g of the title compound as a powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:35])[C:27]4[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=4[F:34])[CH:22]=[CH:23][CH:24]=3)=[N:10][N:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[F:36][C:37]([F:46])([F:45])[C:38]1[CH:39]=[C:40]([CH:42]=[CH:43][CH:44]=1)[NH2:41]>C(O)(C)C>[F:34][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([F:33])[C:27]=1[C:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]4[CH:42]=[CH:43][CH:44]=[C:38]([C:37]([F:36])([F:45])[F:46])[CH:39]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[N:11]3[N:10]=2)[CH:20]=1)=[O:35]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COc1cccc2c(-c3ccnc(Cl)n3)c(-c3cccc(NC(=O)c4c(F)cccc4F)c3)nn12
Solvent: CC(C)O
Product: COc1cccc2c(-c3ccnc(Nc4cccc(C(F)(F)F)c4)n3)c(-c3cccc(NC(=O)c4c(F)cccc4F)c3)nn12

Procedure:
The title compound was prepared through standard displacement conditions by microwaving N-{3-[3-(2-chloropyrimidin-4-yl)-7-methoxypyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 3-trifluoromethylaniline in isopropanol at 150° C. for 15 min. 1H (400 MHz, DMSO d-6) 4.15 (s, 3H), 6.59 (d, J=5.2 Hz, 1H), 6.62 (d, J=7.6 Hz, 1H), 7.24 (m, 3H), 7.33 (d, J=8.0 Hz, 1H), 7.46 (m, 2H), 7.58 (m, 2H), 7.80 (d, J=8.4 Hz, 1H), 7.92 (d, J=7.6 Hz, 1H), 8.00 (s, 1H), 8.05 (d, J=8.8 Hz, 1H), 8.27 (s, 1H), 8.31 (d, J=5.2 Hz, 1H), 9.91 (s, 1H), 10.9 (s, 1H); LCMS (APCI): [M+H]+=617.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[CH3:40][N:41]1[C:45]([CH3:46])=[C:44](B(O)O)[CH:43]=[N:42]1>>[NH2:32][C:4]1[S:3][C:2]([C:44]2[CH:43]=[N:42][N:41]([CH3:40])[C:45]=2[CH3:46])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cc1c(B(O)O)cnn1C
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cc1c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@@H](F)CO3)c(N)s2)cnn1C

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid gave 255. 1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 7.84 (s, 1H), 7.65 (s, 1H), 7.25 (s, 2H), 4.96-4.76 (m, 2H), 4.16-3.89 (m, 2H), 3.79 (s, 3H), 3.72 (s, 3H), 3.29-3.15 (m, 1H), 2.56 (s, 3H), 2.11-2.00 (m, 1H), 1.90-1.71 (m, 4H), 1.66-1.58 (m, 1H). LCMS (ES+) m/z 449 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:17][CH2:18][CH3:19])[C:5]1[O:6][C:7]2[CH:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:8]=2[CH:9]=1)[CH3:2].[ClH:20].Cl.[NH2:22][C@@H:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1>>[ClH:20].[N:25]12[CH2:30][CH2:29][CH:28]([CH2:27][CH2:26]1)[C@@H:23]([NH:22][C:14]([C:12]1[CH:11]=[CH:10][C:8]3[CH:9]=[C:5]([CH:4]([O:3][CH2:1][CH3:2])[O:17][CH2:18][CH3:19])[O:6][C:7]=3[CH:13]=1)=[O:16])[CH2:24]2
Reactant: CCOC(OCC)c1cc2ccc(C(=O)O)cc2o1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: CCOC(OCC)c1cc2ccc(C(=O)N[C@H]3CN4CCC3CC4)cc2o1
Yield: 69.9 %

Procedure:
2-(Diethoxymethyl)-1-benzofuran-6-carboxylic acid (264 mg, 1.0 mmol) is coupled with (R)-3-aminoquinuclidine dihydrochloride (219 mg, 1.1 mmol) and salt made according to Method A with non-critical changes to afford 286 mg (70%) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-(diethoxymethyl)-1-benzofuran-6-carboxamide hydrochloride as a white solid. HRMS (FAB) calcd for C21H28N2O4+H: 373.2127, found 373.2121 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[CH3:5].[CH3:27][C:28]1[C:33]([C:34](O)=[O:35])=[C:32]([CH3:37])[N:31]=[CH:30][N:29]=1>>[C:23]([Si:20]([CH3:21])([CH3:22])[O:19][C:16]1[CH:15]=[CH:14][C:13]([NH:12][CH:9]2[CH2:10][CH2:11][N:6]([C@H:4]([CH3:5])[CH2:3][CH2:2][NH:1][C:34]([C:33]3[C:28]([CH3:27])=[N:29][CH:30]=[N:31][C:32]=3[CH3:37])=[O:35])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1)([CH3:25])([CH3:24])[CH3:26]
Reactant: C[C@H](CCN)N1CCC(Nc2ccc(O[Si](C)(C)C(C)(C)C)cc2)CC1
Reactant: Cc1ncnc(C)c1C(=O)O
Product: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(Nc2ccc(O[Si](C)(C)C(C)(C)C)cc2)CC1

Procedure:
Using general procedure E, [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-amine (see EXAMPLE 233) (940 mg, 2.5 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (490 mg, 3.2 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[4-(tert-butyl-dimethyl-silanyloxy)-phenylamino]-piperidin-1-yl}-butyl)-amide as a peach solid (790 mg, 62%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].Br[CH2:11][CH:12]1[O:16][CH2:15][CH2:14][O:13]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:11][CH:12]1[O:16][CH2:15][CH2:14][O:13]1)[CH3:2]
Reactant: BrCC1OCCO1
Reactant: CCOC(CN)OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(CNCC1OCCO1)OCC

Procedure:
2,2-Diethoxyethylamine (23.3 grams), 2-bromomethyl-1,3-dioxolane (29.2 grams), triethylamine (25 ml) and toluene (150 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux overnight. After this time the mixture was cooled and filtered. The filtrate was then distilled under reduced pressure to yield the desired product N-(2,2-diethoxyethyl)-N-(1,3-dioxolan-2-ylmethyl)amine having a boiling point of 125° C at 0.1 mm of Hg pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[S:8](=[O:10])(=[O:9])[NH:7][C:6]2=[O:16].F[B-](F)(F)F.[CH2:22]([O+](CC)CC)[CH3:23]>ClCCl>[CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[S:8](=[O:9])(=[O:10])[N:7]=[C:6]([O:16][CH2:22][CH3:23])[C:5]=2[CH:4]=1
Reactant: CC[O+](CC)CC
Reactant: COc1cc2c(cc1OC)S(=O)(=O)NC2=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC1=NS(=O)(=O)c2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5,6-dimethoxysaccharin (0.8 g) in dichloromethane (100 ml) was added triethyloxonium tetrafluoroborate (3.5 ml, 1M soln in CH2Cl2) and the solution stirred at room temperature for 3 hrs. After extraction with aqueous sodium bicarbonate, the organic phase was dried and concentrated. Purification by column chromatography (silica, chloroform) gave the title compound (0.2 g).
Reaction SMILES: [CH2:1]([Cl:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([NH:12][C:13](=[O:16])[CH:14]=[CH2:15])O.CS(O)(=O)=O>>[C:13]([NH:12][CH2:10][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][CH2:1][Cl:9])=[CH:4][CH:5]=1)(=[O:16])[CH:14]=[CH2:15]
Reactant: C=CC(=O)NCO
Reactant: ClCCc1ccccc1
Agent: CS(=O)(=O)O
Product: C=CC(=O)NCc1ccc(CCCl)cc1
Temperature: 15 °C
Yield: 75 %

Procedure:
70 parts (0.5 mole) of phenethyl chloride and 51.5 parts (0.51 mole) of N-methylolacrylamide are stirred, in succession, into 300 parts by volume of methanesulfonic acid which has been cooled to 15° C. Stirring is continued for 6 hours at from 15° to 20° C., and hydrolysis is effected by adding 1,500 parts of crushed ice. After the ice has thawed, the product is filtered off and dried in the air to give 84 parts (yield: 75%) of crude p-acrylamidomethylphenethyl chloride, which is recrystallized from methyl alcohol to give a pure product of melting point 145°-147° C.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH:9]([CH2:13][OH:14])[CH2:8][O:7]2)([O-:3])=[O:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19](F)=[N:20][CH:21]=1.[H-].[Na+]>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:14][CH2:13][CH:9]2[CH2:8][O:7][C:6]3=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]3[CH2:10]2)=[N:20][CH:21]=1
Reactant: Fc1ccc(Br)cn1
Reactant: O=[N+]([O-])c1cn2c(n1)OCC(CO)C2
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1cn2c(n1)OCC(COc1ccc(Br)cn1)C2
Yield: 67 %

Procedure:
Alkylation of oxazine alcohol 180 with 5-bromo-2-fluoropyridine (91) (2.0 equiv.) and NaH (1.74 equiv.) as in Example 2OO for 3 h, followed by chromatography of the product on silica gel, eluting with 0-0.25% MeOH/CH2Cl2 (foreruns) and then with 0.25-0.5% MeOH/CH2Cl2, gave 6-{[(5-bromo-2-pyridinyl)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (181) (67%) as a white solid: mp (MeOH/CH2Cl2/hexane) 233-235° C.; 1H NMR [(CD3)2SO] δ 8.27 (dd, J=2.5, 0.4 Hz, 1H), 8.07 (s, 1H), 7.93 (dd, J=8.8, 2.6 Hz, 1H), 6.85 (dd, J=8.9, 0.5 Hz, 1H), 4.60 (dd, J=11.0, 2.7 Hz, 1H), 4.44 (dd, J=11.1, 7.4 Hz, 1H), 4.36 (dd, J=11.0, 6.7 Hz, 1H), 4.33 (dd, J=11.0, 6.7 Hz, 1H), 4.27 (dd, J=12.5, 5.4 Hz, 1H), 4.04 (dd. J=12.6, 7.1 Hz, 1H), 2.85 (m, 1H). Anal. (C12H11BrN4O4.) C, H, N.
Reaction SMILES: [P:1]([O-:47])([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N+:43]([CH3:46])([CH3:45])[CH3:44])([O:3][CH2:4][CH:5]([O:26]CC1C=CC=CC=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2].[H][H]>C(O)(=O)C.[Pd]>[P:1]([O-:47])([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N+:43]([CH3:46])([CH3:45])[CH3:44])([O:3][CH2:4][CH:5]([OH:26])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCCCCCCC[N+](C)(C)C)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCOCC(O)COP(=O)([O-])OCCCCCCCC[N+](C)(C)C
Yield: 28.2 %

Procedure:
290 mg (0.43 mmole) of 2-(benzyloxy)-3-(octadecyloxy)propyl 8-trimethylammoniooctyl phosphate was dissolved in 30 ml of 70% acetic acid, and 0.2 g of 10% Pd-C as a catalyst was added to the mixture. The mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere and filtrated. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by silica gel (3 g, Merck & Co., Art. 7734; eluent: chloroform:methanol:water=65:25:4) column chromatography to give 72 mg (yield: 28.7%) of the above-mentioned compound.