Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:25]2[OH:33])[CH:6]=1.[C:35](Cl)(Cl)=[O:36]>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:13]=2[CH2:22][N:23]2[CH:24]3[CH2:32][C:31]4[C:26]([CH:25]3[O:33][C:35]2=[O:36])=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CNC2Cc3ccccc3[C@@H]2O)c1
Reactant: O=C(Cl)Cl
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN2C(=O)OC3c4ccccc4CC32)c1

Procedure:
Prepared according to the procedure described in Example 45, Step 4, using the following starting materials: (3-{2-[((S)-1-hydroxy-indan-2-ylamino)-methyl]-4-trifluoromethyl-phenoxy}-phenyl)-acetic acid methyl ester and phosgene (1.9M in toluene).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1.[CH3:32][NH2:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:33][CH3:32])[CH2:14][C:13]=2[CH:12]=[C:11]([O:30][CH3:31])[CH:10]=1
Reactant: COc1cc2c(c(-c3cc(F)ccc3F)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: CN
Product: CNCC1Cc2cc(OC)cc(-c3cc(F)ccc3F)c2O1

Procedure:
The title compound was prepared (0.027 g, 27%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,5-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.129 g, 0.29 mmol) and methylamine (0.090 g, 2.9 mmol). mp 163-165° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[S:5][C:6]2[CH2:7][C:8]3[C:14]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)=[N:13][NH:12][C:9]=3[C:10]=2[CH:11]=1.[CH3:23][Si:24]([CH2:27][CH2:28][O:29][CH2:30]Cl)([CH3:26])[CH3:25]>C1COCC1>[Br:3][C:4]1[S:5][C:6]2[CH2:7][C:8]3[C:14]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)=[N:13][N:12]([CH2:30][O:29][CH2:28][CH2:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[C:9]=3[C:10]=2[CH:11]=1
Reactant: COc1ccc(-c2n[nH]c3c2Cc2sc(Br)cc2-3)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
At 0° C., NaH (60 percent, 1.3 g, 33 mmol) was added to a THF solution (40 mL) containing 2-Bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (8.3 g, 24 mmol). Then SEM-Cl (5.6 mL, 28 mmol) was added to the reaction mixture and the resulting mixture was stirred at 0° C. for 30 min, warmed up to 80° C. and stirred for 2 hr. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and washed with saturated aqueous NH4Cl, dried over MgSO4(s), and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to give 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (9.0 g, 18 mmol) as brown solid in 75% yield.
Reaction SMILES: [H-].[Na+].[CH:3]([CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)=[CH2:4].[C:11]([C:15]1[CH:16]=[C:17]([O:25][C@H:26]([CH3:30])[C:27](Cl)=[O:28])[CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)([CH3:14])([CH3:13])[CH3:12].O>C1(C)C=CC=CC=1>[C:11]([C:15]1[CH:16]=[C:17]([O:25][C@@H:26]([CH3:30])[C:27]([N:9]2[C@H:5]([CH:3]=[CH2:4])[CH2:6][CH2:7][C:8]2=[O:10])=[O:28])[CH:18]=[C:19]([C:21]([CH3:23])([CH3:22])[CH3:24])[CH:20]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: C=CC1CCC(=O)N1
Reactant: C[C@@H](Oc1cc(C(C)(C)C)cc(C(C)(C)C)c1)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C[C@@H]1CCC(=O)N1C(=O)[C@H](C)Oc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 25 °C
Yield: 49.3 %

Procedure:
To 60% sodium hydride (336 mg, 10 mmol) in toluene (20 mL) at 0° C. was added dropwise a solution of 5-vinylpyrrolidin-2-one (1.0 g, 9.0 mmol) in toluene (10 mL) over a 5 min period. The cooling bath was removed and the solution was allowed to warm to 25° C. to ensure complete generation of the anion. To the anion at 25° C. was added dropwise a solution of (2R)-2-(3,5-di-t-butylphenyloxy)propanoyl chloride (11, 3.20 g, 9.8 mmol) in toluene (10 mL) over a 5 min period. TLC indicated that the reaction was complete upon addition of the acid chloride (silica gel plates; hexane and ethyl acetate, 2:1). Water (60 mL) was added to the reaction mixture and the phases were separated. The aqueous phase was extracted with ethylene chloride (1×40 mL). The combined organic phases were washed with a saturated aqeous sodium bicarbonate solution (1×70 mL) and dried (MgSO4). Concentration and purification by flash chromatography on silica gel (EM silica gel 60, 0.040-0.063 partical size, 230-400 Mesh, column size: 6.5 cm diameter×18 cm length) using hexane and ethyl acetate (19:1) afforded 1.65 g (46%) of (5S)-N-((2S)-2-(3,5 -di-t-butylphenyloxy)propanoyl)-5-ethenylpyrrolidin-2-one (15a) as an oil: 1H NMR (CDCl3) δ1.20 (s, 18 H), 1.60-1.62 (d, 3 H), 1.92-2.04 (m, 1 H), 2.21-2.32 (m, 1 H), 2.52-2.80 (m, 2 H), 4.9-4.96 (q, 1 H), 5.11-5.21 (m, 2 H), 5.77-5.88 (m, 1 H), 5.98-6.04 (q, 1 H), 6.71 (s, 2 H), 7.00 (s, 1 H); 13C NMR (CDCl3) δ175.2, 172.7, 157.1, 152.1, 135.2, 115.9, 115.6, 109.6, 72.3, 58.0, 34.9, 31.6, 31.4, 24.4, 18.1; IR (neat) 2966 (vs), 1740 (vs), 1715 (vs), 1593 (s), 1380 (s), 1229 (vs), 706 (w) cm-1.
Reaction SMILES: COC1C=C(OC)C=C[C:4]=1[CH2:5][NH:6][C:7]1[N+:8]([O-:17])=[CH:9][C:10]([CH3:16])=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1.C(OC(=O)C)(=[O:26])C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:16][C:10]1[C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]([NH:6][C:5](=[O:26])[CH3:4])=[N+:8]([O-:17])[CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CNc2cc([N+](=O)[O-])c(C)c[n+]2[O-])c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1cc([N+](=O)[O-])c(C)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
A solution of N-(2,4-dimethoxybenzyl)-5-methyl-4-nitropyridin-2-amine 1-oxide (1.1 g, 3.5 mmol) in DCM (20 mL) and TFA (3 mL) was allowed to stir at rt for 4 h. The reaction mixture was concentrated and the residue was dissolved in DCM (20 mL). To this solution were added TEA (2.5 mL, 17.7 mmol) and acetic anhydride (0.4 g, 4.3 mmol). The reaction mixture was allowed to stir at rt overnight and then filtered to give N-(5-methyl-4-nitro-1-oxidopyridin-2-yl)acetamide (0.73 g, 98%) which was used without further purification.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CCOC(C)=O>[CH2:1]([NH:9][C:17](=[O:18])[O:19][CH2:20][CH3:21])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cl
Reactant: NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of phenethylamine (60.5 g, 0.5 mol) and Na2CO3 (63.6 g, 0.6 mol) in EtOAc/HO (800 mL, 4:1) was added ethyl chloroformate, dropwise, (65.1 g, 0.6 mol) at 0° C. during a period of 1 h. The mixture was warmed to RT and stirred for an additional 1 h. The organic phase was separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with H2O and brine, dried (Na2SO4), concentrated in vacuo and purified by flash chromatography to afford ethyl phenethylcarbamate (90.2 g). 1H NMR (400 MHz, CDCl3) δ 7.32-7.18 (m, 5H), 4.73 (brs, 1H), 4.14-4.08 (q, J=6.8 Hz, 2H), 3.44-3.43 (m, 2H), 2.83-2.79 (t, J=6.8 Hz, 2H), 1.26-1.21 (t, J=6.8 Hz, 3H).
Reaction SMILES: [C:1](=[NH:24])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[N:14]=2)=[CH:8][CH:7]=1)[NH2:2].FC(F)(F)C([O-])=O.[CH:32]([CH:34]([CH2:39][C:40]1[CH:41]=[N:42][C:43]([O:46][CH3:47])=[N:44][CH:45]=1)[C:35](OC)=O)=[O:33].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:35]=[C:34]([CH2:39][C:40]4[CH:41]=[N:42][C:43]([O:46][CH3:47])=[N:44][CH:45]=4)[C:32](=[O:33])[N:24]=3)=[CH:11][CH:10]=2)=[N:14][C:15]=1[C:20]([F:22])([F:23])[F:21]
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)n2)cc1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)n4)cc3)nc2=O)cn1
Temperature: 80 °C
Yield: 2.55 %

Procedure:
To the solution of 4-((5-chloro-6-(trifluoromethyl)pyridin-2-yl)oxy)phenethyl carbamimidate, trifluoroacetate (250 mg, 0.264 mmol) and methyl 2-formyl-3-(2-methoxypyrimidin-5-yl)propanoate (71.1 mg, 0.317 mmol) in 1,4-dioxane (2 mL) was added K2CO3 (110 mg, 0.793 mmol). The mixture was heated with a microwave reactor at 80° C. for 0.5 h. Purification via MDAP then afforded the title compound (3.6 mg, 6.74 μmol, 2.55% yield). LCMS: rt=3.31 min, [M+H+]=534
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([B:13]([OH:15])[OH:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].CCN(C(C)C)C(C)C.C[Si](Cl)(C)C.[CH3:30][C:31]1[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[C:32]=1[C:33](Cl)=[O:34]>C(Cl)Cl>[B:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:2]([NH:1][C:33](=[O:34])[C:32]2[C:36]([CH3:41])=[CH:37][C:38]([CH3:40])=[CH:39][C:31]=2[CH3:30])[C:3]([OH:5])=[O:4])=[CH:8][CH:9]=1)([OH:15])[OH:14]
Reactant: NC(Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Agent: C[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C)c(C(=O)NC(Cc2ccc(B(O)O)cc2)C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 g (7.18 mmol) of 2-amino-3-(4-boronophenyl)propionic acid were suspended in 50 ml DCM and 7.4 ml (43.1 mmol) DIPEA and refluxed for 20 min together with 4.5 ml (35 mmol) TMSCl. The solution was cooled in an ice bath and a solution of 1.44 g (7.9 mmol) 2,4,6-trimethylbenzoyl chloride in 5 ml DCM were added dropwise. The reaction mixture was stirred 2 h at room temperature, diluted with 100 ml DCM and washed with 2 N aqueous HCl. During this washing some product precipitated which was collected. The organic phase was extracted with 2 N NaOH twice. Upon acidifying of the combined basic phases the product precipitated, which was collected and dried together with the first precipitate. The crude product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1.[H-].[Na+].[CH2:16]([O:18][C:19]([C:21]1[S:25][C:24](Cl)=[N:23][C:22]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:20])[CH3:17].O>CN1C(=O)CCC1>[CH2:16]([O:18][C:19]([C:21]1[S:25][C:24]([N:9]2[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][C:6]=3[N:7]=[CH:8]2)=[N:23][C:22]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:20])[CH3:17]
Reactant: COc1cc2nc[nH]c2cc1OC
Reactant: CCOC(=O)c1sc(Cl)nc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1-c1ccccc1
Reaction time: 0.33 h
Yield: 83.6 %

Procedure:
5,6-Dimethoxybenzimidazole (470 mg, 2.64 mmol) was added to a suspension of NaH (60% in mineral oil, 112 mg, 2.8 mmol) in NMP (5 ml) at <5° C. The mixture was stirred for 20 min, then a solution of 2-chloro-4-phenylthiazole-5-carboxylic acid ethyl ester (589 mg, 2.2 mmol) in NMP (1.5 ml) was added over 2-3 min. The mixture was stirred 2.5 hrs at RT. Water (15 ml) was added and stirred for 20 min. Solid was collected by filtration to provide the product 2-(5,6-dimethoxy-benzoimidazol-1-yl)-4-phenylthiazole-5-carboxylic acid ethyl ester (753 mg. Yield 84%). 1H-NMR (300 MHz, CDCl3) 8.44(s, 1H); 7.87-7.90(m, 2H); 7.72(2, 1H); 7.44-7.49(m, 3H); 7.30(s, 1H); 4.32(q, J=Hz, 2H); 3.98(s, 3H); 3.97(s, 3H); 1.33(t, J=Hz, 3H). MS M/z 410(M+1).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([C:14]([OH:21])([CH2:19][CH3:20])[C:15]#[C:16][CH2:17][OH:18])[CH3:13].[OH-].[K+].O>CCOCC>[CH2:12]([C:14]([OH:21])([C:15]#[C:16][CH2:17][O:18][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:19][CH3:20])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(O)(C#CCO)CC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCC(O)(C#CCOS(=O)(=O)c1ccc(C)cc1)CC
Temperature: 0 °C
Yield: 78 %

Procedure:
An ice-cold solution of 4-toluenesulfonyl chloride (6.4 g) and 4-ethylhex-2-yn-1,4-diol (McLamore, W. M. et al., J. Org. Chem., 19, 570-574 (1954) and Gouge, M., Ann. Chim., 6, 648-702 (1951)) (4.0 g) in ether (40 ml) was stirred with powdered potassium hydroxide (15 g) for 2 h. Water was added and the mixture was extracted with ether (2×250 ml). Work-up with chromatography using ether/pentane 1:1 (v/v) gave the title compound (6.5 g). 1H NMR: 0.91 (t, 6H), 1.55 (q, 4H), 1.83 (s, 1H), 2.45 (s, 2H), 4.76 (s, 2H), 7.36 (d, 2H), 7.82 (d, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([CH3:26])=[N:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].C(=O)([O-])[O-].[K+].[K+].[OH:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>CN(C)C=O>[CH3:28][O:27][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][N:39]1[CH2:40][CH2:41][CH:36]([OH:35])[CH2:37][CH2:38]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:15][C:16]1[C:17]([CH3:26])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][N:20]=2
Reactant: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCCCl
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCCN1CCC(O)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (compound 398) (32 mg) was suspended in N,N-dimethylformamide (2 ml). Potassium carbonate (34 mg) and 4-hydroxypiperidine (25 mg) were added to the suspension, and the mixture was stirred at 80° C. overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (22 mg, yield 60%).
Reaction SMILES: CO[C:3]1[CH:31]=CC(CS[C@@H]2CN(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H](C(O)=O)C2)=C[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.FC(F)(F)C(O)=O.[N+](C1C=CC(COC(N=C(NC(OCC2C=CC([N+]([O-])=O)=CC=2)=O)N[CH2:65][C:66]([NH:68][CH:69]2[CH2:72]N[CH2:70]2)=O)=O)=CC=1)([O-])=O>C(#N)C>[CH:3]([N:68]([CH2:66][CH3:65])[CH:69]([CH3:70])[CH3:72])([CH3:31])[CH3:4]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: O=C(CNC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC1CNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (1.43 g) in anhydrous acetonitrile (22 ml), N,N-carbonyldiimidazole (545 mg) was added. The resulting mixture was stirred at room temperature for 30 minutes. To the reaction mixture, N,N-diisopropylethylamine (581 μl) and a solution of the compound (2.78 g), which had been obtained in (2), in anhydrous acetonitrile (23 ml) were added and the mixture was stirred overnight at room temperature. To the reaction mixture, dichloromethane was added. The resulting mixture was washed with water and saturated saline, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure, whereby 2.57 g of the title compound were obtained as a colorless amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[C:4]([CH3:10])[C:3]=1[C:11]#[N:12].[C:13]1([C:19]2[CH:23]=[C:22]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([CH2:31][NH2:32])[CH2:27][CH2:26]3)[O:21][N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:1][C:2]1[S:6][C:5]([C:7]([NH:32][CH2:31][CH:28]2[CH2:27][CH2:26][N:25]([CH2:24][C:22]3[O:21][N:20]=[C:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:23]=3)[CH2:30][CH2:29]2)=[O:9])=[C:4]([CH3:10])[C:3]=1[C:11]#[N:12]
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Reactant: Cc1c(C(=O)O)sc(N)c1C#N
Product: Cc1c(C(=O)NCC2CCN(Cc3cc(-c4ccccc4)no3)CC2)sc(N)c1C#N

Procedure:
According to the same procedure described in Example 225, using the compound prepared in Example 227 instead of 4-amino-5-cyano-6-ethoxypicolinic acid, and using the compound prepared in Example 9 instead of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, the title compound having the following physical data was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5](I)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)O1>>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:4][N:3]=1
Reactant: COc1nc(Cl)ncc1I
Reactant: CC1(C)OB(c2cccs2)OC1(C)C
Product: COc1nc(Cl)ncc1-c1cccs1
Yield: 54 %

Procedure:
Preparation according to procedure 3 with the use of 2-chloro-5-iodo-4-methoxy-pyrimidine and 4,4,5,5-tetramethyl-2-(2-thienyl)-1,3,2-dioxaborolane for 36 hrs at 95° C. In this way, a yield of 54% is obtained.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][CH2:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.O1CCO[CH2:19]1>>[CH:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([CH2:9][N:10]2[CH2:19][C:17]3[CH:16]=[CH:15][S:14][C:13]=3[CH2:12][CH2:11]2)[CH:5]=1.[ClH:1]
Reactant: Clc1ccccc1CNCCc1cccs1
Reactant: C1COCO1
Agent: Cl
Product: Clc1ccccc1CN1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
N-[(2-chlorophenyl-methyl)]-2-(2-thienyl)ethylamine HCl (28.8 g) is suspended in 75 ml of 1,3-dioxolane. Hydrochloric acid at 37% concentration (0.25 ml) is added and the temperature of the reaction mixture is brought to 80° C. for 5 hours. Thereafter the reaction is complete. The mixture is cooled to room temperature, and the compound precipitates out. To complete the precipitation and simplify filtration, 75 ml of ethyl acetate is added to the reaction mixture. The filter cake is washed with ethyl acetate (2×20 ml) and dried at 60° C. UV. Ticlopidine HCl (28.5 g, 95% yield) is obtained with m.p. 208-210° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]([CH:31]([OH:34])[CH2:32][OH:33])([CH2:29]O)[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]2([CH2:29][O:33][CH2:32][CH:31]2[OH:34])[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CO)(C(O)CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC2(CC1)COCC2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
Diethyl azodicarboxylate (1.4 g, 8.1 mmol) was added to a solution of 4-(1,2-dihydroxyethyl)-4-hydroxymethyl-piperidine-1-carboxylic acid benzyl ester (Description 3; 2 g, 6.5 mmol) and triphenylphosphine (2.4 g, 9.1 mmol) in tetrahydrofuran (40 ml). The reaction was stirred at room temperature for 2 hours then the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica, eluting with 1, 2 and 4% methanol/dichloromethane, to give the title compound (1.43 g, 76%).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]2[N:17](CC3C=CC=CC=3)[CH:16]=[N:15][N:14]=2)[O:4]1>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]2[NH:17][CH:16]=[N:15][N:14]=2)[O:4]1
Reactant: CO[C@@H]1O[C@H](c2nncn2Cc2ccccc2)[C@H]2OC(C)(C)O[C@@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CO[C@@H]1O[C@H](c2nnc[nH]2)[C@H]2OC(C)(C)O[C@@H]12
Reaction time: 24 h
Yield: 92.1 %

Procedure:
A solution of 3-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4-benzyl-4H-1,2,4-triazole (Preparation 19) (1.5 g, 4.5 mmol) in ethyl acetate (45 ml) and ethanol (5 ml) was hydrogenated over palladium black (0.4 g) at 2758 kPa (400 p.s.i) and 100 □C. for 24 hours. Additional palladium black (0.2 g) was then added and hydrogenation was continued for a further 72 hours. The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure to give the title compound (1.0 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[N:15]([CH2:36][C:37]([F:40])([F:39])[F:38])[C:16]3[C:21]([N:22]=2)=[C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:19]=[C:18]([C:29]2[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=2)[N:17]=3)[CH2:9]1)[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[CH2:6]([C@@H:8]1[N:13]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12][CH2:11][N:10]([C:14]2[N:15]([CH2:36][C:37]([F:40])([F:39])[F:38])[C:16]3[C:21]([N:22]=2)=[C:20]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[N:19]=[C:18]([C:29]2[CH:34]=[N:33][C:32]([NH2:35])=[N:31][CH:30]=2)[N:17]=3)[CH2:9]1)[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1S(C)(=O)=O
Reaction time: 2 h
Yield: 68.5 %

Procedure:
Methanesulfonyl chloride (0.022 ml, 0.28 mmol) was added dropwise to a methylene chloride solution (6 ml) of 5-{8-[(3S)-3-ethylpiperazin-1-yl]-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl}pyrimidin-2-amine (107 mg, 0.22 mmol) and triethylamine (0.061 ml, 0.44 mmol) with ice cooling and the resulting mixture was stirred at the same temperature for 2 hours. The resulting mixture was partitioned with ethyl acetate and saturated aqueous ammonium chloride solution and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (chloroform:methanol=95:5) to give the title compound (86 mg) as a pale yellow solid.
Reaction SMILES: [OH-].[K+].Cl.[NH2:4]O.[C:6]([C:10]1[N:14]([CH3:15])[N:13]=[C:12](C2C=C(C)NC=2C)[CH:11]=1)([O:8][CH3:9])=[O:7]>O.C(O)C>[C:6]([C:10]1[N:14]([CH3:15])[N:13]=[C:12]([NH2:4])[CH:11]=1)([O:8][CH3:9])=[O:7]
Reactant: NO
Reactant: COC(=O)c1cc(-c2cc(C)[nH]c2C)nn1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(N)nn1C
Yield: 81.2 %

Procedure:
A solution of potassium hydroxide (5.08 g, 90.7 mmol) in water (76 mL) and ethanol (76 mL) was added to a slurry of hydroxylamine hydrochloride (11.44 g, 169.5 mmol) in ethanol (127 mL). Then, 5-carbomethoxy-3-(2,5-dimethylpyrrolyl)-1-methylpyrazole (8.5 g, 36.6 mmol) was added and the mixture was refluxed under a nitrogen atmosphere for 65 h. The solvents were removed at reduced pressure and the residue was triturated with ether. Sodium sulfate was added and the heterogenous mixture was filtered. The filtrate was concentrated and the residue was chromatographed on Silica Woelm®TSC (300 g, ethyl acetate-hexane gradient) to give 4.61 g, 81% of 5-carbomethoxy-3-amino-1-methylpyrazole as a white solid mp 114° to 118° C.; 1H-NMR (CDCl3) σ 6.17 (s, 1H), 4.02 (s, 3H), 3.88 (s, 1H), 3.7 (br s, 2H); IR (KBr) 1719, 1551, 1263, 1102, 756 cm-1.