Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][F:27])[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH3:2]>CO.CCOC(C)=O.[Pt]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][F:27])[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[NH2:10])[CH3:2]
Reactant: CCOc1cc(N2CCN(C3CCN(CCF)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1cc(N2CCN(C3CCN(CCF)CC3)CC2)ccc1N
Reaction time: 16 h
Yield: 71.7 %

Procedure:
A mixture of 1-[3-(ethyloxy)-4-nitrophenyl]-4-[1-(2-fluoroethyl)-4-piperidinyl]piperazine (200 mg, 0.53 mmol) and platinum (sulfided, 5 wt. % on carbon, 50 mg, 0.013 mmol) in 20% MeOH/EtOAc (20 mL) was added to a high-pressure hydrogenation reaction flask. The reaction was purged with N2 and vacuum (3×). The reaction was purged with H2 and vacuum (3×). The reaction was then treated with H2 at 50 psi and stirred for approximately 16 h. The reaction was degassed, then poured through a Teflon filter, washing the solid with MeOH and DCM. The filtrate was concentrated under vacuum to give the title compound of step C (136 mg, 0.38 mmol, 74%) as a brown solid. MS (ESI): 351 [M+H]+.
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([N+:18]([O-:20])=[O:19])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.OS(O)(=O)=O.[OH-].[Na+]>CO.O>[NH2:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([N+:18]([O-:20])=[O:19])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CC(=O)Nc1cc(C(F)(F)F)c([N+](=O)[O-])cc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1cc(C(F)(F)F)c([N+](=O)[O-])cc1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
A solution of 49.5 g (169 mmol) of 2-acetylamino-5-nitro-4-trifluoromethyl-benzoic acid in 600 ml of methanol and 100 ml of water is cooled to 0° C. and 71.1 ml (1.33 mol) of concentrated H2SO4 are added dropwise. Upon completion of the addition, the mixture is heated to reflux for 1 hour. The mixture is then cooled to 0° C., the pH is adjusted to 10 with a 30% aqueous NaOH-solution and it is stirred for 1 hour. The methanol is distilled off and the remaining aqueous solution is diluted with water and extracted with t-butyl methylether. The aqueous phase is acidified with concentrated HCl-solution and the resulting yellow suspension is filtered and washed with water. The solid is dried in vacuo at 100° C. to give 28.3 g (67%) of 2-amino-5-nitro-4-trifluoromethyl-benzoic acid, m.p. 237° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C=O)C.O>[CH2:19]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])[CH:18]=[CH2:17]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(Cl)cc1C=O
Temperature: 50 °C

Procedure:
To a mixture of 5-chlorosalicylaldehyde (8.20 g, 52.37 mmol, 1.00 eq.) and potassium carbonate anhydrous (8.69 g, 62.85 mmol, 1.20 eq.) in DMF (100 mL), allyl bromide (4.7 mL, 54.99 mmol, 1.05 eq.) was added. The mixture was heated at 50° C. for 18 hours. The reaction mixture was allowed to cool to r.t. and poured in water (150 mL). The mixture was extracted with DCM (2×200 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo to give 2-allyloxy-5-chloro-benzaldehyde. The product was used without further purification.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][C:23]2([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:28][C:27](=[O:29])[CH2:26][C:25](=[O:30])[CH2:24]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[I-].[Na+]>C1C=CC=CC=1>[CH2:36]([CH:26]1[C:25](=[O:30])[CH2:24][C:23]([CH2:22][CH2:21][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([Cl:12])[CH:14]=2)([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[O:28][C:27]1=[O:29])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3ccccc3)C(=O)O2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 14.6 %

Procedure:
DBU (28.6 ul, 0.191 mmol) was added to a solution of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione (60.6 mg, 0.172 mmol) in benzene (2.0 ml), under an atmosphere of argon. Benzyl bromide (20.5 ul, 0.172 mmol) was then added. The reaction mixture was stirred at room temperature for 20 minutes, followed by the addition of 5 crystals of sodium iodide. The reaction mixture was stirred for a further 24 hrs, after which time the mixture was filtered through a plug of Celite. The filtrate was concentrated in vacuo and the residue purified by prep HPLC to afford the title compound as a white solid (11.1 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23](O)=[O:24])[N:9]=2)=[CH:4][CH:3]=1.[C:26](=[O:42])([O:28][CH:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:30][NH2:31])[NH2:27].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C>[C:26](=[O:42])([O:28][CH:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:30][NH:31][C:23](=[O:24])[CH2:22][N:10]1[C:11](=[O:21])[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)[NH2:27]
Reactant: NCC(OC(N)=O)c1ccccc1C(F)(F)F
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NC(=O)OC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 40 mg (111 μmol) of [3-(4-chlorophenyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid [for the preparation see Example 156A in WO 2007/134862], 33 mg (133 μmol) of the compound of Example 37A, 25 mg (133 μmol) of EDC and 21 mg (133 μmol) of HOBt in 2.4 ml of DMF was stirred at RT overnight, 1 ml of 1 M hydrochloric acid was then added and the mixture was separated directly by preparative HPLC [Method 20] into its components. This gave 53 mg (81% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>COCCO>[ClH:1].[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH:15][C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2sccc12
Reactant: Nc1cccc(Br)c1
Solvent: COCCO
Product: Brc1cccc(Nc2ncnc3sccc23)c1
Product: Cl
Temperature: 79 °C
Yield: 72.8 %

Procedure:
A mixture of 4-chlorothieno[2,3-d]pyrimidine (135 mg, 0.79 mmol) and 3-bromoaniline (95 μL, 0.89 mmol) in 2-methoxyethanol (2 mL) is heated to 79° C. for 30 min with stirring. The resulting solid is filtered and washed with CH2Cl2 to yield 4-(3-bromoanilino)thieno[2,3-d]pyrimidine hydrochloride (197 mg, 73%). 1H NMR (DMSO) δ 9.99 (1H, s), 8.60 (1H, s), 8.23 (1H, s), 7.98 (1H, d, J=6.0 Hz), 7.88 (1H, d, J=8.0 Hz), 7.79 (1H, d, J=6.0 Hz), 7.37 (1H, t, J=8.0 Hz), 7.30 (1H, d, J=8.0 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[S:8][C:7]=1[NH2:15])=[O:5])[CH3:2].N1C=CC=CC=1.CO[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1OC)[C:27](Cl)=[O:28].[CH2:35]([Cl:37])Cl>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[S:8][C:7]=1[NH:15][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([CH2:35][Cl:37])[CH:25]=1)=[O:5])[CH3:2]
Reactant: ClCCl
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Solvent: c1ccncc1
Product: CCOC(=O)c1c(NC(=O)c2cccc(CCl)c2)sc2c1CCCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Amino-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid ethyl ester (Compound A) (4.0 g) was dissolved in anhydrous methylene chloride (40.0 ml). Subsequently, pyridine (2.8 ml) and 3-(chloromethyl)benzoyl chloride (compound B) (3.0 ml) were added at 0° C., and the mixture was stirred at 0° C. for one hr. After the completion of the reaction, distilled water was added, and the mixture was subjected to separatory extraction with chloroform, and the organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated to give 2-(3-chloromethyl-benzoylamino)-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester as a useful intermediate (7.42 g, yield 100%).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)(=[O:7])[CH3:6]>>[C:5]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([Cl:3])=[O:17])[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: CC(=O)N1CCC(CC(=O)O)CC1
Reactant: O=S(Cl)Cl
Product: CC(=O)N1CCC(CC(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To 240 parts of thionyl chloride are added portionwise 25 parts of 1-acetyl-4-piperidineacetic acid and the whole is stirred overnight at room temperature. The reaction mixture is evaporated, yielding 26.5 parts (95%) of 1-acetyl-4-piperidineacetyl chloride as an oily residue.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:27])[C:4]=1[OH:28])[CH3:2].[CH2:29]([C@@H:31]1[O:33][CH2:32]1)Cl>[OH-].[Na+].C(O)(C)C.CC(=O)OCC>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:27])[C:4]=1[O:28][CH2:29][C@@H:31]1[CH2:32][O:33]1)[CH3:2]
Reactant: ClC[C@H]1CO1
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C(CC)CC)c3)n2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C(CC)CC)c3)n2)cc(C)c1OC[C@@H]1CO1
Reaction time: 8 h
Yield: 66.8 %

Procedure:
A mixture of 2-ethyl-4-{5-[2-(1-ethyl-propyl)-6-methoxy-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenol (355 mg, 931 μmol) and (R)-epichlorohydrine (861 mg, 9.31 mmol) in 3 M aq. NaOH (4 mL) and isopropanol (15 mL) is stirred at rt for 18 h before a second portion of (R)-epichlorohydrine (430 mg, 4.65 mmol) is added. Stirring is continued at rt for 8 h. The mixture is diluted with EA (100 mL) and washed twice with 1 N aq. NaOH solution (2×15 mL) followed by brine (25 mL). The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give 4-[(2S)-3-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(1-ethyl-propyl)-6-methoxy-pyridine (272 mg) as a white powder; LC-MS: tR=1.25 min, [M+H]+=438.09.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1)=[O:21]>N1C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)=[O:21])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1
Reactant: CN1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Reactant: N#Cc1ccc(OC(=O)Cl)cc1
Solvent: c1ccncc1
Product: CN1CCC(OC(=O)Oc2ccc(C#N)cc2)N(c2nnc(C(F)(F)F)s2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C. and 4-cyanophenyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(4-cyanophenoxycarbonyloxy)-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [S:1]1(=[O:12])(=[O:11])[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]([OH:10])[CH2:3][NH:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:24]([O:26][CH2:27][CH3:28])=[CH2:25].C(=O)(O)[O-].[Na+].[CH2:34]1[CH2:38][O:37][CH2:36][CH2:35]1>>[CH2:24]([O:26][CH:27]([O:10][CH:4]1[C:5]2[CH:9]=[CH:8][S:7][C:6]=2[S:1](=[O:12])(=[O:11])[N:2]([CH:36]([O:37][CH2:38][CH3:34])[CH3:35])[CH2:3]1)[CH3:28])[CH3:25]
Reactant: C=COCC
Reactant: O=S1(=O)NCC(O)c2ccsc21
Reactant: C1CCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(C)OC1CN(C(C)OCC)S(=O)(=O)c2sccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of the product from Step C (106.9 g, 0.521 mol) in THF (360 mL) was cooled to 0° C. and para-toluenesulfonic acid (3.6 g) was added. Ethyl vinyl ether (250 mL, 2.6 mol) was added over a period of 1.75 hr while maintaining the temperature of the reaction mixture below 5° C. The yellow solution was stirred at 0° C. for 1 hr, a saturated aqueous sodium bicarbonate solution (400 mL) was added and this mixture was extracted with ethyl acetate (3×250 ml). The combined extracts were dried (Na2SO4) and evaporated to give a residue which was purified by column chromatography (silica, hexane to 20% hexane/ethyl acetate) to give the desired product (78%) as a light yellow oil. This material was used in the next step.
Reaction SMILES: COC[O:4][C:5](=O)[C:6]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][CH2:14][O:15][CH3:16])=[CH:8][C:7]=1[O:17][CH2:18][O:19][CH3:20].O.[NH2:23][NH2:24]>C(O)C>[Br:12][C:10]1[C:9]([O:13][CH2:14][O:15][CH3:16])=[CH:8][C:7]([O:17][CH2:18][O:19][CH3:20])=[C:6]([CH:11]=1)[C:5]([NH:23][NH2:24])=[O:4]
Reactant: NN
Reactant: COCOC(=O)c1cc(Br)c(OCOC)cc1OCOC
Solvent: O
Solvent: CCO
Product: COCOc1cc(OCOC)c(C(=O)NN)cc1Br
Temperature: 70 °C
Reaction time: 27 h
Yield: 45.1 %

Procedure:
5-bromo-2,4-bis-methoxymethoxybenzoic acid methoxymethylester (IM3-d: 4.36 g, 11.9 mmol), ethanol (15 mL) and hydrazine monohydrate (0.96 mL, 29.8 mmol) were placed in a 100 mL eggplant shaped flask and stirred at 70° C. for 27 hours. After completing the reaction, the reaction mixture was extracted with methylene chloride, and the organic layer was washed with saturated sodium chloride solution and then concentrated under reduced pressure. The solid material thus obtained was suspended in hexane for purification to obtain the title compound (IM4-d: 1.8 g, 46%).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(OC)[C:11]([C@@H:13]1[CH2:17][C:16](=[O:18])[N:15]([C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[CH2:14]1)=[O:12].Cl>O1CCCC1>[C:1]1([C:11]([C@H:13]2[CH2:14][N:15]([C@@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[C:16](=[O:18])[CH2:17]2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Agent: Cl
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@H](C(=O)c2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
In an atmosphere of nitrogen, phenylmagnesium bromide (3 N diethyl ether solution, 15 ml) was added dropwise to tetrahydrofuran solution (50 ml) of N-methyl-N-methoxy-1-[1-(R)-phenylethyl]-5-oxopyrrolidine-3-(R)-carboxamide (2.49 g, 9.0 mmol), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was mixed with 1 N hydrochloric acid (50 ml) under ice-cooling and extracted with ethyl acetate (8 ml×2). The organic layer was washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and the residue was subjected to a silica gel column chromatography. By eluting with n-hexane:ethyl acetate (1:1), 2.36 g (89%) of the title compound was obtained as a light yellow oil.
Reaction SMILES: C(OC([CH:7]([NH2:17])[C@@H:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=O)(C)C.Cl.O.CN>C1(C)C=CC=CC=1>[NH2:17][CH2:7][C@@H:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:9][C:10]([OH:12])=[O:11]
Reactant: CC(C)C[C@@H](CC(=O)O)C(N)C(=O)OC(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 90 °C
Reaction time: 0.21 h
Yield: 88 %

Procedure:
A 500 ml three-necked round-bottom flask, under nitrogen atmosphere, is added with (S)-3-(isopropoxycarbonyl-amino-methyl)-5-methyl-hexanoic acid salt of (S)-(−)-phenyl-ethyl-amine (70.0 g, 0.190 moles), 35% hydrochloric acid (29.7 g, 0.285 moles), water (200 ml) and toluene (100 ml) and the mixture is vigorously stirred for 10-15 minutes. The phases are separated and the aqueous phase is extracted with toluene (2×100 ml). The collected organic phases are concentrated to small volume to obtain an oil which is added with 30% hydrochloric acid (57.8 g, 0.475 moles). The mixture is heated at 90° C. for 24-48 h. At end-reaction 41% aqueous monomethylamine (26.7 ml) is added till pH of about 6 and left to cool to room temperature. The mixture is cooled to 0-5° C. for at least 1 h and then the solid is filtered off and washed with a 1:1 water/isopropanol mixture cooled to 0-5° C. (3×15 ml). The solid is dried in oven at 50-60° C. for 16-18 h. 26.6 g of a white solid are obtained having an enantiomer ratio 99.94:0.06, with a yield of 88%. The XRPD spectrum of the so obtained product has the most intense peaks at 9.4; 12.2; 14.4; 16.6; 18.2; 19.0; 19.7; 20.1; 22.1; 22.6; 23.1; 23.4; 24.6; 26.8; 27.5; 27.9; 29.8±2θ, as illustrated in FIG. 1. The product has a mean particle size D50 of about 50 micrometers.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([CH3:8])=[CH:6][N:7]=1.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:2][C:3]1[O:4][C:5]([CH3:8])=[CH:6][N:7]=1)[CH3:10]
Reactant: Cc1cnc(CCl)o1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1ncc(C)o1

Procedure:
prepared by reaction of the commercially available 2-chloromethyl-5-methyl-oxazole with 2M ethylamine in THF.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](=[O:32])(=[O:31])[NH2:30])=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([NH:30][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])(=[O:32])=[O:31])=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCOc1cccc(C(=O)Nc2ccccc2S(N)(=O)=O)c1
Reactant: CCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCOc1cccc(C(=O)Nc2ccccc2S(=O)(=O)NC(=O)CCCCC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
In a stream of nitrogen and at 0° C., 0.16 ml (1.10 mmol) of hexanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 390 mg (1.00 mmol) of 3-heptyloxy-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 9 and 249 mg (2.00 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 412 mg (yield: 84.4%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]([CH3:13])[CH3:12].[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH:11]([N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[C:24]1[CH:25]=[CH:26][C:21]([O:20][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][O:14]2)=[CH:22][CH:23]=1)([CH3:13])[CH3:12]
Reactant: OB(O)c1ccc(OC2CCCCO2)cc1
Reactant: CC(C)n1cnc2c(Cl)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)n1cnc2c(-c3ccc(OC4CCCCO4)cc3)ncnc21
Temperature: 25 °C

Procedure:
Compound 52B (165 mg, 0.84 mmol) in toluene (5 ml) was treated sequentially with 4-(tetrahydro-2H-pyran-2-yloxy)phenylboronic acid (280 mg, 1.26 mmol), tetrakis(triphenylphosphine)palladium(0) (48.6 mg, 0.042 mmol) and sodium carbonate (2N aq.) (1.26 ml, 2.52 mmol). The reaction vessel was purged with nitrogen and heated at reflux overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by column chromatography on silica gel eluting with a gradient of 0 to 5% MeOH in CH2Cl2: 1H NMR (300 MHz, DMSO-d6) δ ppm 8.92 (1H, s), 8.83 (2H, m), 8.74 (1H, s), 7.22 (2H, m), 5.63 (1H, t), 4.92 (1H, septet), 3.79 (1H, ddd), 3.60 (1H, m), 1.82 (4H, m), 1.60 (6H, d), 1.55 (2H, m).
Reaction SMILES: CS(O[CH2:6][CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[C:18]([O:25][C@@H:26]3[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:27]3[O:28][C:29](=[O:31])[CH3:30])=[N:19][NH:20][C:21]=2[CH:22]([CH3:24])[CH3:23])=[C:12]([CH3:49])[CH:11]=1)(=O)=O.Cl.[CH2:51]1[C:56]2([CH2:61][CH2:60][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:58][CH2:57]2)[CH2:55][CH2:54][CH2:53][NH:52]1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:49][C:12]1[CH:11]=[C:10](/[CH:9]=[CH:8]/[CH2:7][CH2:6][N:52]2[CH2:53][CH2:54][CH2:55][C:56]3([CH2:57][CH2:58][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:60][CH2:61]3)[CH2:51]2)[CH:15]=[CH:14][C:13]=1[CH2:16][C:17]1[C:18]([O:25][C@@H:26]2[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:27]2[O:28][C:29](=[O:31])[CH3:30])=[N:19][NH:20][C:21]=1[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2)CC1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCOS(C)(=O)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CCCC4(CCN(C(=O)OC(C)(C)C)CC4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
Heat a mixture of (3E)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)oxy]-1H-pyrazol-4-yl}methyl)phenyl]but-3-en-1-yl methanesulfonate (1.0 g, 1.41 mmol), tert-butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (451 mg, 1.55 mmol), and diisopropylethylamine (730 mg, 5.64 mmol) in acetonitrile (4 mL) at 80° C. overnight. Remove the solvent under the reduced pressure. Purify the resulting residue by flash chromatography (silica gel, gradient ethyl acetate/dichloromethane from 25-85% over 15 min, then with methanol/dichloromethane from 1-3% over 10 min, 40 g column) to provide the title compound (630 mg, 0.73 mmol). MS (m/z): 867.2, 868.4 (M+1), 865.2, 866.4 (M−1).