Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH:18]2[CH:10]([CH2:11][CH:12]([OH:27])[C:13]3([CH3:26])[CH:17]2[CH2:16][CH2:15][CH:14]3[CH:19]([CH3:25])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:9]2([CH3:28])[CH:4]([CH2:5][CH:6]([O:29]S(C)(=O)=O)[CH2:7][CH2:8]2)[CH2:3]1.[CH2:34](N(CC)CC)C.OS(O)(=O)=O.[C:46](Cl)(=[O:48])[CH3:47]>O.CO>[OH:1][CH:2]1[CH:18]2[CH:10]([CH2:11][CH:12]([OH:27])[C:13]3([CH3:26])[CH:17]2[CH2:16][CH2:15][CH:14]3[CH:19]([CH3:25])[CH2:20][CH2:21][C:22]([O:24][CH3:34])=[O:23])[C:9]2([CH3:28])[CH:4]([CH2:5][CH:6]([O:29][CH2:47][CH2:46][OH:48])[CH2:7][CH2:8]2)[CH2:3]1
Reactant: CC(=O)Cl
Reactant: CC(CCC(=O)O)C1CCC2C3C(O)CC4CC(OS(C)(=O)=O)CCC4(C)C3CC(O)C12C
Reactant: CCN(CC)CC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(OCCO)CCC4(C)C3CC(O)C12C
Temperature: 115 °C
Reaction time: 7.5 h

Procedure:
116 g of 4-(7,12-dihydroxy-3-methanesulfonyloxy-10,13-dimethylhexadecahydrocyclopenta[a]phenanthren-17-yl) pentanoic acid and 130 ml of triethylamine are dissolved in 650 ml of glycol and stirred at 100° C. for 3 hours and 115° C. for 7.5 hours. The reaction mixture is poured into a solution of 400 ml of H2SO4 in 3 l of water at 0° C. and extracted 7 times using 750 ml of EA each time. The extract is dried over Na2SO4 and the solvent is removed in vacuo. The intermediate product IP is obtained. 130 ml of acetyl chloride are added dropwise to 900 ml of methanol at 0° C. A solution of IP in 400 ml is then added and the mixture is stirred at RT for 6 hours. It is allowed to stand at RT for 60 hours, then poured into 2.6 l of water and extracted 8 times using 500 ml of diisopropyl ether (DIP) each time. The organic phase is then washed a further 6 times with 600 ml of a semisaturated aqueous NaHCO3 solution each time. It is dried over Na2SO4 and the solvent is removed in vacuo. Chromatography on silica gel using EA yields 32 g of a resinous solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[C:14]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1>>[F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:26]1[CH2:27][CH2:28][N:23]([C:14]2[C:13]([CH3:12])=[CH:18][C:17]([C:19]([F:22])([F:20])[F:21])=[CH:16][N:15]=2)[CH2:24][CH2:25]1)=[O:6]
Reactant: Cc1cc(C(F)(F)F)cnc1N1CCNCC1
Reactant: O=C(O)c1ccc(I)cc1F
Product: Cc1cc(C(F)(F)F)cnc1N1CCN(C(=O)c2ccc(I)cc2F)CC1
Yield: 102.9 %

Procedure:
Using 2-fluoro-4-iodobenzoic acid (266 mg) and 1-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine (245 mg) described in Preparation Example 84 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (507 mg) was obtained.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH2:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)(=[O:23])=[O:22])=[CH:16][CH:15]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[N:1]1[C:10]2[CH:9]([NH:11][CH2:12][C:14]3[CH:15]=[CH:16][C:17]([NH:20][S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(NS(=O)(=O)c2ccccn2)cc1
Reactant: NC1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=S(=O)(Nc1ccc(CNC2CCCc3cccnc32)cc1)c1ccccn1
Yield: 66.7 %

Procedure:
Using General Procedure B: Reaction of 5,6,7,8-tetrahydro-quinolin-8-ylamine (68 mg, 0.46 mmol), pyridine-2-sulfonic acid (4-formyl-phenyl)-amide (120 mg, 0.46 mmol), and NaBH(OAc)3 (291 mg, 1.37 mmol) for 1 h at room temperature followed by purification of the crude product by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH 98:1:1) gave the title compound (121 mg, 67%) as a white foam.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:4]([NH:6][CH2:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:5])[CH3:3].[ClH:25].CCOCC>O1CCOCC1>[NH2:1][C@@H:2]([C:4]([NH:6][CH2:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])=[O:5])[CH3:3].[ClH:25]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: C[C@@H](N)C(=O)NCC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
3.4 g of Boc-(D)Ala-Gly-OBzl are dissolved in 50 ml of dioxane containing HCl and left to stand for one hour. The volume of the solution is reduced under vacuum and an excess of ether added. The precipitated salt is filtered off, dried and used as such for the coupling reaction.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][C:21]2[O:25][N:24]=[C:23]([C:26]3[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=3)[N:22]=2)=[CH:18][CH:17]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+]>O>[NH2:32][C:27]1[C:26]([C:23]2[N:22]=[C:21]([CH2:20][C:19]3[CH:18]=[CH:17][C:16]([OH:15])=[CH:34][CH:33]=3)[O:25][N:24]=2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: Nc1ncccc1-c1noc(Cc2ccc(OCc3ccccc3)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncccc1-c1noc(Cc2ccc(O)cc2)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 102.8 %

Procedure:
To a solution of TFA (2 mL) of 3-(5-(4-benzyloxy-benzyl)-[1,2,4]-oxadiazol-3-yl)-pyridin-2-ylamine (52 mg) described in Example 13 was added thioanisole (68 μL) at 0° C., which was stirred for 2 hours and 40 minutes at room temperature. Sodium hydrogencarbonate and water were added at 0° C. to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, and filtered, after which the solvent was evaporated from the filtrate under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1) to obtain the titled compound (40 mg).
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]2[CH2:25][CH2:24][N:23]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[CH2:22][CH:21]=2)[N:17]=[C:16]2[N:39]([CH:42]([CH3:44])[CH3:43])[N:40]=[CH:41][C:15]=12)=[O:13].C(O)(C(F)(F)F)=O>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:41]=[N:40][N:39]([CH:42]([CH3:44])[CH3:43])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:25][CH2:24][N:23]([CH:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)[CH2:22][CH:21]=2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C4CCN(C(=O)OC(C)(C)C)CC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C4CCNCC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl 4-(4-(4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-5,6-dihydropyridin-1(2H)-yl)piperidine-1-carboxylate (0.5 g, 0.829 mmol) was taken in DCM (6 mL), TFA (2 mL) was added and stirred at room temperature for 1 h. After completion of reaction, solvent was removed under reduced pressure, neutralized with saturated NaHCO3 solution. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure, finally the residue was washed with acetonitrile followed by diethyl ether to provide the desired compound. LCMS: 504.35 (M+1)+; HPLC: 99.26% (@ 254 nm) (Rt;4.223); 1H NMR (DMSO-d6, 400 MHz) δ 11.56 (bs, 1H), 10.25 (bs, 1H), 8.87 (t, 1H, J=4.8 Hz), 8.80 (bs, 1H), 8.55 (bs, 1H), 8.34 (s, 1H), 7.89 (s, 1H), 6.93 (bs, 1H), 5.90 (s, 1H), 5.21 (m, 1H), 4.39 (d, 2H, J=4.8 Hz), 4.08 (bs, 2H), 3.75 (bs, 2H), 3.30 (m, 3H), 3.16-3.12 (m, 1H), 2.96 (m, 3H), 2.32 (m, 2H), 2.21 (s, 3H), 2.12 (s, 3H), 1.86 (m, 2H), 1.52 (d, 6H, J=6.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH2:7])=[O:6].[Cl:12][C:13]([Cl:17])([CH3:16])[CH:14]=O.[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:18]1([CH:14]([NH:7][C:5](=[O:6])[C:4]2[CH:3]=[C:2]([Cl:1])[CH:10]=[C:9]([Cl:11])[CH:8]=2)[C:13]([Cl:17])([Cl:12])[CH3:16])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1
Reactant: CC(Cl)(Cl)C=O
Reactant: NC(=O)c1cc(Cl)cc(Cl)c1
Reactant: c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(Cl)(Cl)C(NC(=O)c1cc(Cl)cc(Cl)c1)n1nnc2ccccc21

Procedure:
A suspension of 3,5-dichlorobenzamide, 2,2-dichloropropionaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 53A to provide the desired product.
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[C:20]3[CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]=3[CH2:11][CH2:10][CH:9]2[CH2:21][OH:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N.[Li].C(O)C>CCOCC>[N:1]1([CH2:7][CH:8]2[CH:20]3[CH:12]([C:13]4[CH2:14][CH:15]=[CH:16][CH2:17][C:18]=4[CH2:19]3)[CH2:11][CH2:10][CH:9]2[CH2:21][OH:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCC2=C(Cc3ccccc32)C1CN1CCCCC1
Agent: N
Agent: [Li]
Solvent: CCOCC
Solvent: CCO
Product: OCC1CCC2C3=C(CC=CC3)CC2C1CN1CCCCC1
Yield: 79.2 %

Procedure:
A solution of 16.3 g of crude 1,2,3,4-tetrahydro-1-(piperidinomethyl)fluorene-2-methanol, in the form of the free base, dissolved in 300 ml of ether is added to 1.5 liter of liquid ammonia. An amount of 8.4 g (1.2 moles) of lithium ribbon is added over 1.5 hr. and then 150 ml of abs. ethanol added over 60 minutes; the ammonia is evaporated and the residue cooled and partitioned between 400 ml of water and 300 ml of ether. The aqueous layer is washed with 2 × 250 ml of ether, and then the extracts are combined, washed with sat. sodium chloride solution, dried, and evaporated in vacuo to give 13.1 g (0.0434 moles) of the above titled compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH2:21][C:22]([OH:24])=O)[CH:18]=[CH:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:65][N:66]([CH3:70])[CH2:67][CH2:68][NH2:69]>CN(C=O)C.CCOCC>[CH3:65][N:66]([CH3:70])[CH2:67][CH2:68][NH:69][C:22](=[O:24])[CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:14][N:13]=2)[CH:16]=1
Reactant: COCc1cc(-c2nc(-c3cccc(CC(=O)O)c3)no2)ccc1-c1ccccc1C
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: COCc1cc(-c2nc(-c3cccc(CC(=O)NCCN(C)C)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution (3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)acetic acid (preparation described in Example 24 Step 1, 100 mg, 0.24 mmol) in DMF (2 mL) at 0° C., was added DIEA (126 4, 0.72 mmol) and HATU (92 mg, 0.24 mmol). After 10 min, a solution of 2-dimethylaminoethylamine (21 mg, 0.24 mmol) in DMF (2 mL) was added and the reaction mixture stirred at RT overnight. Et2O was added and the mixture was washed with water. The organic phase was then dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by preparative HPLC affording the title compound as a colorless oil. LC/MS (Method B): 485.0 (M+H)+. HPLC (Method A) Rt 4.59 min (Purity: 91.3%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[Cl:18])[NH2:14]>O1CCOCC1.C(N(CC)C(C)C)(C)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:11]([Cl:10])[CH:12]=2)[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Clc1cc(Cl)nc(Nc2ccc(Cl)c(Cl)c2)n1
Reaction time: 3 h
Yield: 21.7 %

Procedure:
A solution of 2,4,6-trichloropyrimidine (5.00 g), 3,4-dichloroaniline (4.45 g, 1 equivalent) in 1,4-dioxane (20 mL) and N,N-diisopropylethylamine (10 mL) was heated at reflux with stirring for 3 hours. The solvent was removed and the crude material was purified by flash chromatography on silica gel. The column was eluted with a gradient of cyclohexane to ethyl acetate/cyclohexane (1:9). The eluent was removed, giving 4,6-dichloro-N-(3,4-dichlorophenyl)-2-pyrimidinamine (1.83 g, 58%, Rf=0.39 in ethyl acetate/cyclohexane, 2:3).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[C:11](CC(O)=O)[CH:12]=[CH:13][CH:14]=1.CN(C=O)C>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH2:1][C:2]([Cl:4])=[O:3])[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(CC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
An excess of oxalyl chloride was added dropwise to a stirred mixture of 3-methoxyphenylacetic acid (33.2 g), DMF (4 ml) and methylene chloride (800 ml) and the mixture was stirred at ambient temperature for 65 hours. The mixture was evaporated to leave 3-methoxyphenylacetyl chloride (39.6 g).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([C@@H:11]3[O:23][C@H:22]([CH3:24])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[C:7]=2[CH:25]=1.[Br:28]C1N([C@@H]2O[C@H](C)[C@@H](OC(=O)C)[C@H]2OC(=O)C)C2C=CC(C(F)(F)F)=CC=2N=1>CCOC(C)=O.CCCCCC>[Br:28][C:9]1[N:8]([C@@H:11]2[O:23][C@H:22]([CH3:24])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]2[O:13][C:14](=[O:16])[CH3:15])[C:7]2[CH:25]=[C:3]([C:2]([F:1])([F:26])[F:27])[CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cnc2ccc(C(F)(F)F)cc21
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2cc(C(F)(F)F)ccc21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2ccc(C(F)(F)F)cc21
Yield: 52 %

Procedure:
Starting with 6-trifluoromethyl-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole, this compound was prepared in a manner analogous to that described for 2-bromo-5-trifluoromethyl-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole. Following flash column chromatography on silica with EtOAc/hexane (2:3), a 52% yield of the title compound was obtained as an oil. 1H NMR (DMSO-d6) δ1.48 (d, 3H, CH3), 2 (s, 3H, COCH3), 2.1 (s, 3H, COCH3), 4.2-4.3 (m, 1H, CH), 5.2 (t, 1H, CH), 5.63 (t, 1H, CH), 6.22 (d, 1H, CH), 7.6 (d, 1H, aromatic), 7.8 (d, 1H, aromatic), 8.1 (s, 1H, aromatic).
Reaction SMILES: [C:1](=[N:14][NH2:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)C>[C:2]1([C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:14][NH:15][S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NN=C(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=S(=O)(NN=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A four neck flask (2 liters) equipped with a thermometer, a reflux condenser and a stirrer was charged with 78.4 g (0.4 mol) of benzophenone hydrazone, 64.6 g (0.64 mol) of triethylamine and 1 liter of ether, and 105.6 g (0.6 mol) of benzenesulfonic acid chloride was dropwise added thereto in one hour while stirring at room temperature and then heated under reflux for 72 hours. The reaction liquid was cooled down to 20° C. and then washed (separated) twice with 500 ml of deionized water. The ether layer was dried over anhydrous magnesium sulfate and filtered off, and then the mother liquid was concentrated by means of a rotary evaporator to obtain reddish yellow crystal. This crude crystal was added to 1 liter of diethyl ether and heated under reflux for 30 minutes, and then the crystal was filtered off at 30° C. This was dried under reduced pressure to thereby obtain white crystal.
Reaction SMILES: C(O[C:9]([N:11]([CH2:13][C:14]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=1[C@@H:23]([CH2:28][CH3:29])[C:24]([O:26][CH3:27])=[O:25])C)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:20][C:18]1[CH:17]=[CH:16][C:15]([C@@H:23]([CH2:28][CH3:29])[C:24]([O:26][CH3:27])=[O:25])=[C:14]([CH2:13][NH:11][CH3:9])[CH:19]=1
Reactant: CC[C@@H](C(=O)OC)c1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC[C@@H](C(=O)OC)c1ccc(N)cc1CNC
Reaction time: 3 h
Yield: 19.5 %

Procedure:
13D (103 mg, 2.81 mmol) was dissolved in MeOH (5 mL). 10% Pd/C was added. The reaction mixture was stirred under a hydrogen balloon for 3 h. Pd/C was removed by filtration and the filtrate was concentrated under reduced pressure to give 13E (169 mg, 0.547 mmol, 97% yield). MS (ESI) m/z: 237.0 (M+H)+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12.[CH3:10][C:11]([CH3:31])([O:13][C:14]([NH:16][C@H:17]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1)[CH2:18][C:19](O)=[O:20])=[O:15])[CH3:12].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH3:12][C:11]([CH3:31])([O:13][C:14]([NH:16][C@H:17]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1)[CH2:18][C:19]([N:7]1[CH2:8][CH2:9][N:4]2[CH:3]=[CH:2][N:1]=[C:5]2[CH2:6]1)=[O:20])=[O:15])[CH3:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(F)c(F)c1
Reactant: c1cn2c(n1)CNCC2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1ccc(F)c(F)c1
Yield: 70.3 %

Procedure:
The title compound was prepared from 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (31.3 mg, 0.254 mmol, from Step B), (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoic acid (80 mg, mmol), DIPEA (32.8 mg, 0.254 mmol), HOBT (41.2 mg, 0.305 mmol) and EDC (73 mg, 0.381 mmol) in 5 mL of dichloromethane, using a procedure analogous to that described in Example 1, Step C. Purification by HPLC (Gilson; YMC-Pack Pro C18 column, 100×20 mm I.D.; solvent gradient system from 10% acetonitrile, 90% water, and 0.1% trifluoroacetic acid to 90% acetonitrile, 10% water, and 0.1% trifluoroacetic acid) gave 75 mg of the title compound as a viscous oil. 1H NMR (500 MHz, CDCl3) δ 1.38 (s, 9H), 2.05 (bs, 1H), 2.62 (m, 2H), 2.89 (m, 2H) 3.81-4.04 (m, 5H), 4.64-4.88 (m, 2H). 5.38 (m, 1H) 6.88 (m, 2H), 7.05 (m, 3H). ESI-MS 421 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[O:6]=[CH:7][C@@H:8]([C@H:10]([C@@H:12]([C@@H:14]([CH2:16][OH:17])[OH:15])[OH:13])[OH:11])[OH:9].[C:18]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.O1[CH2:30][CH2:29]OCC1>>[CH2:18]1[CH2:23][CH2:22][C:21]2([O:9][CH:8]([C@H:10]3[O:11][C@@H:16]4[O:17][C:30]5([CH2:29][CH2:12][CH2:10][CH2:8][CH2:7]5)[O:15][C@@H:14]4[C@H:12]3[OH:13])[CH2:7][O:6]2)[CH2:20][CH2:19]1
Reactant: O=C1CCCCC1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C1COCCO1
Agent: O=S(=O)(O)O
Product: O[C@@H]1[C@H]2OC3(CCCCC3)O[C@H]2O[C@@H]1C1COC2(CCCCC2)O1
Reaction time: 0.5 h
Yield: 169.3 %

Procedure:
20 ml (375 mmol; 1.03 eq) of concentrated sulphuric acid are added dropwise to 65 g of D-glucose (361 mmol; 1 eq) and 85 ml (820 mmol ; 2.27 eq) of cyclohexanone in 50 ml of 1,4-dioxane (587 mmol; 1.62 eq) at ambient temperature. Once the addition is complete, after 30 minutes, the product precipitates from the reaction medium. The precipitate is broken up, filtered off and washed with water. The crude product is then purified by recrystallisation from cyclohexane to give to 104 grams of 1,2: 5,6-di-O-cyclohexylidene-α-D-glucofuranose.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])[C:5](=[O:13])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:3]=1[CH3:24].[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[C:29]#[CH:30])[CH3:26].CCN(CC)CC>C1COCC1.[Cu]I>[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[C:29]#[C:30][C:2]1[N:7]=[C:6]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])[C:5](=[O:13])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:3]=1[CH3:24])[CH3:26]
Reactant: Cc1c(Br)nc(C(=O)N(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: C#CC(OCC)OCC
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(C#Cc1nc(C(=O)N(C)C)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C)OCC
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 25.1 %

Procedure:
6-Bromo-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (0.10 g, 0.247 mmol), propargylaldehyde diethyl acetal (0.48 mg, 0.370 mmol), copper(I) iodide (0.001 mg, 0.005 mmol) and Et3N (1 ml) in THF (1 ml) were placed in a glass tube for microwave synthesis. The mixture was degassed with argon and Pd(Cl2) (PPh3)2 (0.007 g) was added. The tube was sealed and heated with stirring at 60° C. (150 W) in a microwave heater for 20 minutes. The mixture was diluted with EtOAc (5 ml) and filtered. The solution was concentrated in vacuo and was then purified on silica to give the title compound (28 mg, 25%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)[CH3:2]>[C].[Pd].O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(/C=C/c2ccco2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CCC2CCCO2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.4 %

Procedure:
To an anhydrous tetrahydrofuran (25 mL) solution of 4-((E)-2-furan-2-yl-vinyl)benzoic acid ethyl ester (2.2 g, 9.39 mmol) described in Manufacturing Example 80-1-1 was added 10% palladium-carbon (50% hydrate, 1 g), which was stirred for 6 hours under hydrogen atmosphere at room temperature. The reaction liquid was filtered, and the filtrate was concentrated under a reduced pressure to obtain the title compound (2.2 g, 100%) as a crude product.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[S:3].Cl.[O-:11][Mn](=O)(=O)=O.[K+].[N:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:18]=[O:19]>>[CH2:8]([O:7][C:5]([CH2:4][N:1]1[C:2](=[O:11])[S:3][N:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:18]1=[O:19])=[O:6])[CH3:9]
Reactant: CCOC(=O)CN=C=O
Reactant: CCOC(=O)CN=C=S
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Product: CCOC(=O)Cn1sc(=O)n(CC(=O)OCC)c1=O

Procedure:
Reagents: Ethyl isothiocyanatoacetate (0.8 ml, 6.5 mmol), 35% HCl (3.1 ml), KMnO4 (0.5 g), ethyl isocyanatoacetate (0.73 ml, 6.5 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:44][CH3:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41](Cl)=[O:42])[CH:29]=[C:28]([CH2:46][CH3:47])[N:27]=1.C(N(CC)CC)C.[NH:55]1[CH:59]=[CH:58][N:57]=[CH:56]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:44][CH3:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]([N:55]2[CH:59]=[CH:58][N:57]=[CH:56]2)=[O:42])[CH:29]=[C:28]([CH2:46][CH3:47])[N:27]=1
Reactant: c1c[nH]cn1
Reactant: CCc1cc(NC(CC)CCCCCCOC(=O)Cl)nc(Cl)n1
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCc1cc(NC(CC)CCCCCCOC(=O)n2ccnc2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
In 20 ml of toluene was dissolved 1.00 g of dl-5-chloro-6-ethyl-4-[1-ethyl-7-(chlorocarbonyloxy)heptyl]aminopyrimidine, and 0.50 g of triethylamine and 0.22 g of imidazole were added to the solution and the mixture was stirred at room temperature for one hour. After completion of the reaction, the reaction mixture was filtered, and excessive triethylamine and the solvent was removed under reduced pressure. The resulting oily product was isolated through a column chromatography (Wako gel C-200, trade name, eluent; toluene:ethyl acetate=3:1) to give 0.80 g of the title compound as pale yellow oily product. nD21.9 1.5332.