Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[C:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])[CH3:39]>>[C:38]([N:41]1[CH2:46][CH2:45][N:44]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:43][CH2:42]1)(=[O:40])[CH3:39]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and N-acetylpiperazine according to conditions described in general procedure C. Mp: 102-104° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.58-1.61 (m, 6 H), 1.96 (s, 3 H), 3.28-3.30 (m, 4 H), 3.36 (s, 4H), 3.47-3.51 (m, 4 H), 6.25 (d, J=5.5 Hz, 1 H), 6.94-6.98 (m, 1 H), 7.15 (d, J=8.8 Hz, 1 H), 7.42 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.54-7.62 (m, 3 H), 7.82-7.84 (m, 1 H), 7.98-8.00 (m, 1H), 8.28 (d, J=5.5 Hz, 1 H), 10.44 (s, 1 H).
Reaction SMILES: COC1C=CC(CC(O)=O)=CC=1.[Cl:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16](OC)=O.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[C:34]([C:37]([O-:39])=[O:38])[S:35]C=2)=[CH:28][CH:27]=1.[OH-].[Na+]>O1CCOCC1.CO>[Cl:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]1[S:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][C:32]=1[C:29]1[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=1
Reactant: COc1ccc(-c2csc(C(=O)[O-])c2)cc1
Reactant: COC(=O)c1ccccc1Cl
Agent: COc1ccc(CC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(C(=O)O)sc2-c2ccccc2Cl)cc1
Temperature: 55 °C

Procedure:
5-(2-Chlorophenyl)-4-(4-methoxyphenyl)thiophene-2-carboxylic acid is prepared, according to the procedure used in stages 1A)-1E), from (4-methoxyphenyl)acetic acid and methyl 2-chlorobenzoate. In the final stage of this procedure, 5 g of methyl 542-chlorophenyl)-4-(4-methoxyphenyl)-2-thiophenecarboxylate and 1.11 g of sodium hydroxide pellets are added to 30 ml of methanol and 3 ml of dioxane. The reaction medium is heated at 50-60° C. for 5 hours. It is evaporated to dryness, water is added and the impurities are extracted with ether. The aqueous phase is acidified and the expected compound is extracted with ether. After drying and evaporating, 3.5 g of the expected compound are obtained.
Reaction SMILES: [Si](O[CH2:9][CH2:10][CH2:11][C:12](=[CH2:29])[C:13]([C:15]1[CH:20]=[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[C:18]([F:27])=[CH:17][C:16]=1[F:28])=[O:14])(C(C)(C)C)(C)C.[NH2:30][C:31]([NH2:33])=[S:32].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CC(O)=O.C1COCC1>[F:28][C:16]1[CH:17]=[C:18]([F:27])[C:19]([C:21]2[CH:26]=[N:25][CH:24]=[N:23][CH:22]=2)=[CH:20][C:15]=1[C@@:13]12[O:14][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:29][S:32][C:31]([NH2:33])=[N:30]2
Reactant: NC(N)=S
Reactant: C=C(CCCO[Si](C)(C)C(C)(C)C)C(=O)c1cc(-c2cncnc2)c(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: NC1=N[C@]2(c3cc(-c4cncnc4)c(F)cc3F)OCCC[C@@H]2CS1
Temperature: 25 °C
Reaction time: 12 h
Yield: 2.3 %

Procedure:
To a solution of 5-((tert-butyldimethylsilyl)oxy)-1-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-2-methylenepentan-1-one (Preparation 16, 606 mg, 1.448 mmol) in HOAc (7239 μL) was added thiourea (441 mg, 5.79 mmol), and a suspension was formed. The reaction mixture was stirred at rt for 12 h, and a clear yellowish solution was formed. TBAF (2172 μL, 2.172 mmol) in THF was added, and the reaction mixture was stirred at rt for 5 h, followed by heating at 60° C. for 12 h. This crude reaction mixture was purified by reverse phase preparative HPLC on a Luna C18 column (10 μM, 30×100 mm) eluting with 0-100% B (A: 10% MeOH/90% water/0.1% TFA; B: 90% MeOH/10% water/0.1% TFA) over 12 min to give a mixture of two isomers. This mixture was purified by preparative TLC on silica gel (0.50 mm thickness) eluting with 90% DCM/9% MeOH/1% ammonium hydroxide to give (4aS,8aS)-8a-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-4,4a,5,6,7,8a-hexahydropyrano[2,3-d][1,3]thiazin-2-amine (13 mg, 0.034 mmol, 2.354% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ 9.22 (s, 1H), 8.91 (d, J=1.4 Hz, 2H), 7.43 (t, J=8.5 Hz, 1H), 7.02 (dd, J=10.8, 10.2 Hz, 1H), 5.0-4.5 (broad s, 2H), 4.00-3.92 (m, 1H), 3.88-3.80 (m, 1H), 2.95 (dd, J=12.6, 4.0 Hz, 1H), 2.81-2.71 (m, 1H), 2.67 (dd, J=12.6, 2.8 Hz, 1H), 2.01-1.83 (m, 2H), 1.75-1.57 (m, 2H). MS (M+H)+: 363.03.
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]([NH:15][C:16]1[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])=[O:14])=O)C1C=CC=CC=1.[BrH:30].CCOCC>C(O)(=O)C>[BrH:30].[NH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=1[C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:19])=[O:14]
Reactant: O=C(CNC(=O)OCc1ccccc1)Nc1ccccc1C(=O)c1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: NCC(=O)Nc1ccccc1C(=O)c1ccccc1

Procedure:
A mixture of N-benzyloxycarbonyl derivative (2a, 3.13 g, 8.06 mmol) obtained in Preparation 1 and a solution of 30% hydrobromic acid in acetic acid is stirred for 1 hour. Excess ether is added, and the resultant precipitate is filtered off. After washing with ether, it is dried to obtain 2.50 g (92%) of hydrobromate (compound 3a).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:16]=[CH:15][C@H:14]([CH3:17])[C@H:13]([OH:18])[C@@H:12]([CH3:19])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.[Si:28](OS(C(F)(F)F)(=O)=O)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].CO>C(Cl)Cl>[C:1]1([S:7]([C:10]2[CH:16]=[CH:15][C@H:14]([CH3:17])[C@H:13]([O:18][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C@@H:12]([CH3:19])[CH:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C[C@H]1C=CC(S(=O)(=O)c2ccccc2)=C[C@H](C)[C@H]1O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CO
Product: C[C@H]1C=CC(S(=O)(=O)c2ccccc2)=C[C@H](C)[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Yield: 97.8 %

Procedure:
A solution of alcohol 32 (550 mg, 1.98 mmol) and 2,6-lutidine (0.34 mL, 2.97 mmol) in CH2Cl2 (20 mL) was cooled to −78° C., and 0.55 mL (2.39 mmol) of TBSOTf was added. The cold solution was stirred and allowed to warm to 0° C. over a 1 h. MeOH (40 μL, 1 mmol) was then added and the resulting mixture was concentrated via rotary evaporation. The crude residue was purified with flash column chromatography (EtOAc/hexanes; 1:5) to afford 760 mg (98%) of 33 as colorless oil. [α]20D=+126.7 (c=0.80, CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.86-7.90 (m, 2H), 7.50-7.64 (m, 3H), 7.09 (d, J=5.4 Hz, 1H), 6.06 (dt, J=11.7 Hz, 1.5 Hz, 1H), 5.80 (dd, J=11.7 Hz, 5.1 Hz, 1H), 3.66 (dd, J=6.3 Hz, 2.1 Hz, 1H), 2.70 (m, 1H), 2.47 (m. 1H), 1.18 (d, J=7.2 Hz, 3H), 1.06 (d, J=7.2 Hz, 3H), 0.81 (s, 9H), 0.038 (s, 3H), 0.032 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 142.8, 140.4, 140.2, 137.8, 133.2, 129.3, 128.0, 118.4, 76.8, 41.4, 38.8, 26.0, 19.1, 18.2, 16.7, −4.1, −4.4; LRMS (CI): m/z 393 [M+H]+; HRMS (CI) calculated for C21H32O3SSi, 392.1841; found, 392.1840.
Reaction SMILES: CS(C)=O.C(=O)([O-])O.[K+].Br[CH2:11][CH2:12][CH2:13][C:14]#[N:15].[C:16]([OH:20])(=[O:19])[CH:17]=[CH2:18]>CC1(C)N(O)C(C)(C)CC(O)C1.O>[C:16]([O:20][CH2:11][CH2:12][CH2:13][C:14]#[N:15])(=[O:19])[CH:17]=[CH2:18]
Reactant: N#CCCCBr
Reactant: C=CC(=O)O
Agent: CC1(C)CC(O)CC(C)(C)N1O
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=CC(=O)OCCCC#N
Temperature: 80 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
To a 200 mL three-necked flask, 33 g of dimethyl sulfoxide, 33 g of water, 14.8 g of potassium hydrogencarbonate, 10 g of 4-bromobutyronitrile, and 10 mg of 4-hydroxy TEMPO (4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl free radical) were added. Thereafter, 9.8 g of acrylic acid were added thereto dropwise. Then, the contents of the flask were heated to 80° C., and stirred at 80° C. for 4 hours. The resulting reaction liquid was cooled to room temperature. After cooling, the reaction liquid was washed with water, and was purified by column chromatography, to obtain 9 g of 3-cyanopropyl acrylate.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H][H]>CN(C)C=O.C(OCC)C.[Pt](=O)=O>[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:7][C:5]([O:4][CH3:3])=[O:6])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: [H][H]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: O=[Pt]=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Sodium hydride (60% in mineral oil, 10.55 g, 264 mmol) was washed with hexanes then suspended in N,N-dimethylformamide (200 mL). Mixture was cooled to 0° C. Trimethyl phosphonoacetate (38.0 mL, 249 mmol) was added to the mixture dropwise. The reaction was stirred at 0° C. for 30 minutes. 1-Benzyl-4-piperidone (40.0 mL, 220 mmol) was added to the reaction mixture dropwise. The reaction was warmed to ambient temperature and held with stirring for 1 h. The reaction mixture was diluted with diethyl ether (500 mL), washed with water (2×), then brine. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was dissolved in methanol (220 mL). Platinum(IV) oxide (600 mg, 2.64 mmol) was added to the mixture. The reaction vessel was placed on a Parr apparatus, charged with 40 psi of hydrogen gas, and shaken at room temperature for 5 h. The reaction mixture was removed from the apparatus, filtered through celite, and concentrated. The residue was passed through a short column of silica gel eluting with ethyl acetate. Fractions were concentrated in vacuo. The title compound was obtained as amber oil in 90% yield. 1H NMR (300 MHz, CDCl3): δ 7.31-7.16 (m, 5H), 3.62 (s, 3H), 3.45 (s, 2H), 2.83 (d, J=11.71, 2H), 2.20 (d, J-6.95, 2H), 2.00-1.88 (m, 1H), 1.82-1.69 (m, 1H), 1.69-1.59 (m, 2H), 1.38-1.25 (m, 2H). Mass spec.: 249.3 (MH)+.
Reaction SMILES: C([Cl:4])(=O)C.CC(O)C.[NH2:9][CH2:10][C:11]1([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>O1CCCC1>[ClH:4].[NH2:9][CH2:10][C:11]1([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(=O)Cl
Agent: NCC1(O)CCCCCC1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cl
Reaction time: 0.83 h

Procedure:
Acetyl chloride (264 ml) and tetrahydrofuran (191 ml) were charged to a vessel containing 2-propanol (1143 ml) maintaining the temperature at 10° C. to 15° C. 1-(aminomethyl)cycloheptanol (381 g) in tetrahydrofuran (1613 ml) and tetrahydrofuran (381 ml) were charged maintaining the temperature at 10° C. to 15° C. The reaction mixture was stirred for 50 minutes and filtered. The filter cake was washed with premixed tetrahydrofuran/2-propanol [tetrahydrofuran (267 ml), 2-propanol (114 ml)], and tetrahydrofuran (1905 ml). The filter cake was dried at 40° C. for 23 hours to provide the title compound as a colourless solid (464 g).
Reaction SMILES: COCN[C:5](=O)[C@@H:6]([C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1)[C@H:7]([O:21][CH3:22])[C@H:8]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:9]=[CH2:10].[CH:30]([Mg]Br)=[CH2:31].[NH4+].[Cl-].C1COCC1.[OH2:41]>C1COCC1>[C:23]1([C@@H:6]([C@H:7]([O:21][CH3:22])[C@H:8]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH:9]=[CH2:10])[C:5](=[O:41])[CH:30]=[CH2:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: O
Reactant: C=C[Mg]Br
Reactant: C=C[C@@H](OCc1ccc(OC)cc1)[C@@H](OC)[C@@H](C(=O)NCOC)C1=CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(=O)[C@@H](C1=CCCCC1)[C@H](OC)[C@@H](C=C)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
279 mg (0.69 mmol) of (2S,3S,4R)-2-(cyclohex-1-enyl)-3-methoxy-4-p-methoxybenzyloxyhex-5-enoic acid methoxymethylamide are dissolved in THF (4 mL) and treated, at 0° C., with an excess of vinylmagnesium bromide (as a 1M solution in THF, 2.76 mL, 2.76 mmol, 4 equivalents). After addition, the mixture is allowed to warm to room temperature and is stirred overnight. An excess of saturated NH4Cl in a 1:1 THF/water mixture is then added. After extraction and evaporation of the solvents, the residue is chromatographed on silica (eluent (5/1 Cy/EtOAc)) to give 187 mg (73%) of (4S,5S,6R)-4-(cyclohex-1-enyl)-5-methoxy-6-p-methoxybenzyloxyocta-1,7-dien-3-one.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:12])[S:4](=[O:11])(=[O:10])[N:5]=[C:6]([O:8][CH3:9])[N:7]=1.[CH:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]([OH:22])[CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:7]=[C:2]([O:22][C:15]2[CH:14]=[CH:13][C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=2)[N:3]([CH3:12])[S:4](=[O:11])(=[O:10])[N:5]=1
Reactant: COC1=NS(=O)(=O)N(C)C(Cl)=N1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=NS(=O)(=O)N(C)C(Oc2ccc([N+](=O)[O-])cc2)=N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-chloro-5-methoxy-2-methyl-2H-1,2,4,6-thiatriazine-1,1-dioxide (48 g) in methylene chloride (25.5 ml) is added dropwise to a stirred mixture of p-nitrophenol (38 g) and triethylamine (55 g) in methylene chloride (1 l). The mixture is stirred at RT for about 12 hours, refluxed for about 31/2 hours, concentrated in vacuo, the residue is treated with sat'd aq. Na2CO3 solution, and the resulting insoluble solid filtered and washed with water and CH2Cl2. The solid is recrystallized from ethyl acetate/acetonitrile yielding the p-nitrophenoxy compound as a crystalline solid, M.P.=220°-221° C.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].Br[C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=1>>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:32]4[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:11][CH2:12]1)=[O:6])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)CC1
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(C#N)cc4)ccc3O2)CC1
Yield: 66 %

Procedure:
The title compound is prepared from 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid isopropyl ester and 4-bromo-benzonitrile following a procedure analogous to that described in Example 1. Yield: 66% of theory; LC (method 1): tR=1.52 min; Mass spectrum (ESI+): m/z=391 [M+H]+.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][C:41](=[O:49])[NH:42][C:43](C(O)=O)([CH3:45])[CH3:44])=[CH:33][C:32]=2[CH3:50])=[C:28]([CH:51]([CH3:53])[CH3:52])[NH:27][N:26]=1)(=O)C.C(O[C:62]([N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)=[O:63])C1C=CC=CC=1.C(N1CCNCC1)C1C=CC=CC=1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][C:41](=[O:49])[NH:42][C:43]([C:62]([N:64]4[CH2:65][CH2:66][NH:67][CH2:68][CH2:69]4)=[O:63])([CH3:44])[CH3:45])=[CH:33][C:32]=3[CH3:50])=[C:28]([CH:51]([CH3:53])[CH3:52])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCC(=O)NC(C)(C)C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: c1ccc(CN2CCNCC2)cc1
Product: Cc1cc(OCCCC(=O)NC(C)(C)C(=O)N2CCNCC2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 99 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(benzyloxycarbonyl)piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 1-benzylpiperazine, respectively.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH2-:6][C:7]([CH3:9])=[O:8].[CH:10]([NH:13][CH2:14][C@H:15]([OH:18])[CH2:16][OH:17])([CH3:12])[CH3:11].C(N(CC)CC)C>O1CCCC1.[Cl-].[Na+].O>[CH2-:6][C:7]([CH3:9])=[O:8].[S:1]([N:13]([CH:10]([CH3:12])[CH3:11])[CH2:14][C@H:15]([OH:18])[CH2:16][OH:17])([CH3:4])(=[O:3])=[O:2]
Reactant: CC(C)NC[C@H](O)CO
Reactant: CS(=O)(=O)Cl
Agent: [CH2-]C(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)N(C[C@H](O)CO)S(C)(=O)=O

Procedure:
90 ml mesyl chloride was added with stirring to a previously chilled (-10°) solution of (2S)-3-isopropylamino-1,2-propanediol acetonide (188 g; 1.087 mol) and triethylamine (228 ml; 1.63 mol) in dry tetrahydrofuran at such a rate that the reaction temperature did not exceed 5°. Reaction was then stirred at 10°-15° for 30 minutes whereupon it was diluted with 1.5 L brine. The layers were separated and the aqueous layers were extracted with ether (3×500 ml). The organic layers were washed in turn with brine (2×500 ml) and then were combined, dried over sodium sulfate, and evaporated to give 264 g of (2S)-3-[N-mesyl-(1-methylethyl)amino]-1,2-propanediol acetonide as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]5[N:28]=[CH:27][C:26]([C:29](=[NH:31])[NH2:30])=[CH:25][C:24]=5[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[CH:19][CH:18]=4)[CH2:12][CH2:11]3)[NH:7][C:6]=2[CH:38]=1.Cl[CH2:40][CH:41]=O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]5[C:24]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)=[CH:25][C:26]([C:29]6[NH:30][CH:40]=[CH:41][N:31]=6)=[CH:27][N:28]=5)=[CH:19][CH:18]=4)[CH2:12][CH2:11]3)[NH:7][C:6]=2[CH:38]=1
Reactant: N=C(N)c1cnc(-c2ccc(CN3CCC(c4nc5ccc(F)cc5[nH]4)CC3)cc2)c(-c2ccccc2)c1
Reactant: O=CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Fc1ccc2nc(C3CCN(Cc4ccc(-c5ncc(-c6ncc[nH]6)cc5-c5ccccc5)cc4)CC3)[nH]c2c1
Temperature: 110 °C

Procedure:
To a solution of 6-(4-{[4-(6-fluoro-1H-benzimidazol-2-yl)piperidin-1-yl]methyl)phenyl)-5-phenylpyridine-3-carboximidamide (3-2, 0.030 g, 0.059 mmol) in Dioxane (1.5 mL) was added chloroacetaldehyde (50% solution in H2O, 0.019 mL, 0.119 mmol) followed by sodium carbonate (0.016 mg, 0.149 mmol). The reaction was heated to 110° C. for 1 hr. The mixture was cooled and partitioned between saturated aqueous sodium bicarbonate and CH2Cl2 and extracted 3×. The combined organics were dried (anhd. Na2SO4), filtered and concentrated. The residue was purified by silica gel chromatography (6-8% MeOH in CH2Cl2). 1H-NMR (500 MHz, d6 DMSO) δ 12.83 (s, 1H), 12.31 (s, 1H), 9.21 (d, J=1.95, 1H), 8.74 (s, 1H), 8.30 (d, J=2.2, 1H), 7.08-7.42 (m, 12H), 6.97 (bs, 1H), 3.61 (bs, 2H), 3.50 (bs, 1H), 3.13 (bs, 2H), 2.87 (bs, 2H), 1.98 (bs, 2H), 1.84 (bs 2H). HRMS m/z (M+H) Calcd: 529.2511, found: 529.2532.
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10]B(O)O.C([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1>[Br:8][C:7]1[C:2]([CH3:10])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: CB(O)O
Reactant: Clc1cnc(Br)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ncc(Cl)cc1Br
Temperature: 50 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
2,3-Dibromo-5-chloropyridine (1.3 g, 4.70 mmol), methylboronic acid (0.30 g, 5.01 mmol), bis(triphenylphosphine)palladium(II) chloride (0.50 g, 0.70 mmol) and dioxane (10 mL) were added. K2CO3 (2 M aq. solution, 7.0 mL, 14.0 mmol) was added and the reaction was put under N2 (g) atmosphere. The reaction was heated to reflux for 5 h. The reaction was stirred at 50° C. overnight and then heated to reflux for additionally 1 h. Methylboronic acid (0.14 g, 2.35 mmol) was added and the reaction was refluxed for 4 h and the allowed to cool down to r.t. The mixture was filtered through a silica plug. EtOAc and water were added and the phases were separated. The organic phase was washed two more times with water. The organic phase was dried with MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (12 g SiO2, 0-20% MeOH containing 0.1 M NH3 in DCM). The fractions containing pure product were pooled and concentrated, yielding the title compound (123 mg, 13% yield): 1H NMR (DMSO-d6) δ ppm 2.56 (s, 3H), 8.29 (d, 1H), 8.52 (d, 1H); MS (CI) m/z 206 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][C:8](=[O:10])[NH:7]/[C:6](=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)/[C:5]1=[O:20])(=[O:3])[CH3:2].CI.[C:23](=O)([O-])[O-].[Na+].[Na+].[C:29]([O:32][CH2:33][CH3:34])(=O)C>CN(C=O)C>[C:1]([N:4]1[CH2:9][C:8](=[O:10])[N:7]([CH3:23])/[C:6](=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)/[C:5]1=[O:20])(=[O:3])[CH3:2].[C:1]([N:4]1[CH2:34][C:33]([O:32][CH3:29])=[N:7][C:6](=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[C:5]1=[O:20])(=[O:3])[CH3:2]
Reactant: COc1ccc(/C=C2\NC(=O)CN(C(C)=O)C2=O)cc1
Reactant: O=C([O-])[O-]
Reactant: CCOC(C)=O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC1=NC(=Cc2ccc(OC)cc2)C(=O)N(C(C)=O)C1
Product: COc1ccc(/C=C2/C(=O)N(C(C)=O)CC(=O)N2C)cc1
Reaction time: 72 h
Yield: 11.8 %
Yield: 66 %

Procedure:
A mixture of (3Z)-1-Acetyl-3-(4-methoxybenzylidene)-2,5-piperazinedione (9) (2.0 g, 7.3 mmol), methyl iodide (0.46 ml, 7.3 mmol), and sodium carbonate (800 mg, 7.5 mmol) in dry DMF (50 ml) was stirred under an atmosphere of dry nitrogen for 3 days. The reaction mixture was then poured into ethyl acetate (500 ml) and washed with water (4×100 ml) and brine. The organic phase was separated, dried (MgSO4), and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, EtOAc:Hexane, 1:1) to give (3Z)-1-acetyl-3-(4-methoxybenzylidene)-4-methyl-2,5-piperazinedione (10) 1.38 g (66%) as a yellow solid and 1-acetyl-5-methoxy-3-(4-methoxybenzylidene)-3,6-dihydropyrazin-2-one (11) 248 mg (11.8%) as a bright yellow solid.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][N:9]2[C:13]([CH2:14][CH2:15][NH:16][C:17]([C@@H:19]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][NH:20]3)=[O:18])=[CH:12][N:11]=[CH:10]2)=[CH:6][CH:5]=1)#[N:3].CCN(CC)CC.[CH:38](=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C([BH3-])#N.[Na+]>CO>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:13]([CH2:14][CH2:15][NH:16][C:17]([C@@H:19]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][N:20]3[CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:18])=[CH:12][N:11]=[CH:10]2)=[CH:29][CH:30]=1)#[N:3]
Reactant: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@@H]2Cc3ccccc3CN2)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@@H]2Cc3ccccc3CN2Cc2ccccc2)cc1
Reaction time: 18 h

Procedure:
1,2,3,4-Tetrahydro-isoquinoline-3(S)-carboxylic acid {2-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl}-amide hydrochloride (0.15 g, 0.33 mmol) was dissolved in MeOH (7 mL). Et3N was added to this solution dropwise until the pH=5. To the solution was added benzaldehyde (0.069 mL, 0.65 mmol) and sodium cyanoborohydride (0.041 g, 0.65 mmol). After stirring for 18 hr. the mixture was evaporated in vacuo and the residue was partitioned between EtOAc (50 mL) and saturated NaHCO3 (30 mL). The organic layer was washed with saturated NaCl solution (30 mL) and dried (MgSO4). Filtration and concentration to dryness gave the title compound after purification on silica gel eluting with CH2Cl2 :