Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C:21]3([NH:25][C@@H:24]([C:26]([O:28][CH3:29])=[O:27])[CH2:23][CH:22]3I)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C>CO.[Pd]>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C@:21]3([NH:25][C@@H:24]([C:26]([O:28][CH3:29])=[O:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: COC(=O)[C@H]1CC(I)C2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Reaction time: 8 h

Procedure:
To a solution of methyl (2R,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-4-iodo-1,8-diazaspiro[4.5]decane-2-carboxylate (860 mg, 1.179 mmol) in methanol (20 ml), triethylamine (0.822 ml, 5.89 mmol) was added followed by palladium on carbon 10% (172 mg, 0.162 mmol). Resulting mixture was hydrogenated at atmospheric pressure of H2 at room temperature overnight.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([O:39][CH3:40])=[O:38])=[CH:33][CH:32]=1)(C(OCC=C)=O)[C:18]([O:20]CC=C)=[O:19])#[N:12]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:18]([CH:17]([CH2:16][CH2:15][CH2:14][CH2:13][C:11]#[N:12])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([O:39][CH3:40])=[O:38])=[CH:33][CH:32]=1)([OH:20])=[O:19]
Reactant: C=CCOC(=O)C(CCCCC#N)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CC(CCCCC#N)C(=O)O)cc1
Temperature: 10 °C
Reaction time: 12 h
Yield: 74.7 %

Procedure:
17.24 ml (123.71 mmol) of triethylamine and 4.24 ml (112.46 mmol) of formic acid in 500 ml of dioxane is added to a solution of 15.5 g (37.49 mmol) of diallyl 2-(4-cyanobutyl)-2-(4 methoxycarbonylbenzyl)malonate from Example 115A, 690 mg (2.62 mmol) of triphenylphosphine and 170 mg (0.75 mmol) of palladium acetate in 500 ml of dioxane at room temperature. The reaction mixture is then stirred at 10° C. for 12 hours. After conversion is complete, the reaction solution is cooled and the solvent is removed in vacuo. The residue is then taken up in ethyl acetate and water and acidified with 1 N hydrochloric acid and the organic phase is separated off. The aqueous phase is extracted three times more with ethyl acetate, and then the organic phases are combined, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solution is concentrated in vacuo. 8.1 g (74% yield) of a colorless solid are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[S:27][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][N:32]([C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:31][CH2:30]2)[S:27][CH:28]=1
Reactant: Fc1cccc(-c2csc(N3CCNCC3)n2)c1F
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3cccc(F)c3F)cs2)CC1
Temperature: 70 °C
Reaction time: 15 h
Yield: 55 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (211 mg, 0.782 mmol), 1-[4-(2,3-difluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.711 mmol) and diisopropylethylamine (0.248 ml, 1.42 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 157 mg (55.0%) of the desired product as a solid. mp 172-173° C.
Reaction SMILES: NC1C(N)=CC=CN=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[N:20][CH:21]=2)[N:16]=1>>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[N:23][C:22]2[C:21](=[N:20][CH:19]=[CH:18][CH:17]=2)[N:16]=1
Reactant: c1ccc(-c2nc3ccncc3nc2-c2ccccn2)nc1
Agent: Nc1cccnc1N
Product: c1ccc(-c2nc3cccnc3nc2-c2ccccn2)nc1

Procedure:
The preparation of 62 is identical to that of 61 substituting 2,3-diaminopyridine for 3,4-diamino pyridine (Example K), giving 900 mg of the title compound as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][C:14]([N:16]([CH:25]([CH3:27])[CH3:26])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:15]>C(O)C.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH2:13][C:14]([N:16]([CH:25]([CH3:27])[CH3:26])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: COc1ccc(N(C(=O)CN)C(C)C)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc(N(C(=O)CNc2ccc(F)cc2[N+](=O)[O-])C(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.4 %

Procedure:
A mixture of 9.06 g of 2,5-difluoro-nitrobenzene (60 mmol) and 12.64 g of 2-amino-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part A, (60 mmol, 1.0 equiv) were combined in 225 mL of 2:1 ethanol/water and heated to reflux under nitrogen and stirred vigorously overnight (approx. 16 hrs.). The resulting slurry is cooled to ambient temperature, filtered and washed with 2:1 water/ethanol. The wet solid is dissolved in methylene chloride, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue is triturated with hexane, filtered and washed with hexane. The product is dried under high vacuum to provide 9.32 g of 2-(4-Fluoro-2-nitro-phenylamino)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as an orange solid: 1H NMR (300 MHz, CDCl3) δ7.89 (dd, 1H, J=3.1, 9.3), 7.12 (m, 3H), 6.99 (m, 2H), 6.35 (dd, 1H, J=4.8, 9.2), 5.03 (m, 1H), 3.89 (s, 3H), 3.57 (s, 2H), 1.09 (d, 6H, J=6.8); low resolution MS (ESI)m/e 362 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:24][C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[CH:13]=[C:14]3[C:18]=2[NH:17][C:16]([C:19]([O:21]CC)=[O:20])=[CH:15]3)[CH:5]=[CH:4][CH:3]=1>O1CCCC1.C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:24][C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=3)[CH:13]=[C:14]3[C:18]=2[NH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15]3)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OCc3cccc(Cl)n3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3cccc(Cl)n3)c3[nH]c(C(=O)O)cc3c2)cc1
Temperature: 50 °C
Reaction time: 0.83 h
Yield: 89 %

Procedure:
Ethyl 7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (1.0 g) was dissolved in a mixed solvent of tetrahydrofuran (10 mL)-ethanol (10 mL), 1M aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at 50° C. for 50 min. The reaction solution was allowed to cool to room temperature, and concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1M hydrochloric acid. The obtained crystals were collected by filtration, and washed successively with water and diethyl ether to give the title compound (840 mg, yield 90%) as a white solid. The obtained crystals were recrystallized from N,N-dimethylformamide-water to give colorless crystals. melting point 249-250° C. (decomposition).
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[NH:23][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][OH:33])[CH:27]=4)=[CH:25][C:18]=23)[C:14]([C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:41]([N:43]([CH3:45])[CH3:44])=[O:42])=[CH:36][CH:35]=2)=[N:13]1)[C:7](=[O:9])[O-:8])(C)C>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:44][N:43]([CH3:45])[C:41]([NH:40][C:37]1[CH:36]=[CH:35][C:34]([C:14]2[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[NH:23][C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=[O:33])[CH:27]=5)=[CH:25][C:18]=34)=[CH:16][N:12]([CH2:11][CH2:10][N:6]([CH3:5])[C:7](=[O:9])[O:8][C:15]([CH3:17])([CH3:16])[CH3:14])[N:13]=2)=[CH:39][CH:38]=1)=[O:42]
Reactant: CN(C)C(=O)Nc1ccc(-c2nn(CCN(CC(C)(C)C)C(=O)[O-])cc2-c2ccnc3[nH]c(-c4cccc(CO)c4)cc23)cc1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)Nc1ccc(-c2nn(CCN(C)C(=O)OC(C)(C)C)cc2-c2ccnc3[nH]c(-c4cccc(C=O)c4)cc23)cc1
Temperature: 70 °C
Yield: 154.7 %

Procedure:
To a stirred solution of 1,1-dimethylethyl[2-(3-(4-{[(dimethylamino)carbonyl]amino}phenyl)-4-{2-[3-(hydroxymethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-1-yl)ethyl]methylcarbamate (1.24 g, 2.0 mMol) in CHCl3 (100 mL) was added activated MnO2 (2.5 g, 28.7 mMol). The reaction was stirred and refluxed (70° C. oil bath) for 8 h, cooled to RT, filtered through a pad of Celite®, rinsed with CHCl3, and evaporated to dryness under vacuum. Purification by flash chromatography on silica gel (5 to 10% MeOH in (1:1) EtOAc/CHCl3) provided the title compound (0.94 g, 77%) as a pale yellow solid. ESMS [M+H]+: 608.6.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:8]([CH:11]=1)[C:9]#[N:10])([O-])=O.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1-c1ccccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#Cc1cc(N)ccc1-c1ccccn1

Procedure:
A mixture of 5-nitro-2-pyridin-2-ylbenzonitrile (370 mg, 1.69 mmol), iron powder (473 mg, 8.45 mmol), ammonium chloride (99 mg, 1.86 mmol), ethanol (20 mL) and water (10 mL) was heated at reflux for 1 h. Upon cooling, the reaction mixture was filtered through Celite, rinsed with ethyl acetate, and the filtrate was concentrated. The resulting residue was purified by flash column chromatography on silica gel eluting with 0-50% ethyl acetate hexanes to provide 5-amino-2-pyridin-2-ylbenzonitrile.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]([O:14][CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])=[O:13])[CH2:10][CH:9]3[CH2:20][CH2:21][CH2:22][N:8]3[C:7](=[O:23])[C:6]=2[CH:24]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.O.C(O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]1([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([C:12]([O:14][CH2:15][C:16]([Cl:18])([Cl:19])[Cl:17])=[O:13])[CH2:10][CH:9]4[CH2:20][CH2:21][CH2:22][N:8]4[C:7](=[O:23])[C:6]=3[CH:24]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CC2CCCN2C(=O)c2cc(I)ccc21
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: O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(OCC(Cl)(Cl)Cl)N1CC2CCCN2C(=O)c2cc(-c3ccccc3)ccc21
Yield: 94.8 %

Procedure:
A suspension of 134 (0.5 g, 1.0 mmol), benzeneboronic acid (0.15 g, 1.22 mmol), Pd(PPh3)4 and anhydrous Na2CO3 (0.16 g, 1.48 mmol) in distilled benzene (20 mL), water (2 ml) and ethanol (2 mL) was heated at reflux overnight. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (2×20 mL). The organic phase was dried over MgSO4 and evaporated to yield a crude yellow oil. Purification by flash chromatography (ethyl acetate/petroleum ether 30/70 to 70/30) furnished the title compound (0.43 g, 95%): 1H NMR (270 MHz, CDCl3) δ1.98-2.09 (m, 2H); 2.12-2.15 (m, 2H); 3.51-3.62 (m, 2H); 3.7-3.79 (m, 1H); 4.28 (d, J=12.1 Hz, 1H); 4.73 (d, J=4.4 Hz, 1H); 5.18 (d, J=12.1 Hz, 1H); 5.66-5.73 (dd, J=4.8, J=9.8 Hz, 1H); 7.33-7.48 (m, 4H); 7.61-7.70 (m, 3H); 8.02 (d, J=2.2 Hz, 1H). 13C NMR (CDCl3) δ22.9, 28.7, 46.4; 59.8; 75.0; 77.3; 86.0; 94.9; 127.0; 127.3; 128.0; 128.9; 129.6; 130.8; 132.9; 133.5; 139.2; 141.1; 154.4; 166.9. MS: m/e (relative intensity) 468 (M+., 10), 292 (25), 222 (100), 195 (10), 166 (35), 140 (10), 70 (70). HRMS Calculated for C21H19C13N2O4: 468.0411. Found: 468.0410. [α]25D=+103.80 (c=0.42, CHCl3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1C(C1C=CC(Cl)=CC=1)O)=[O:5])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][C:31]=1[F:32])[NH2:28]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:21])[CH3:22])[C:10]=1[N:28]([C:27]1[CH:29]=[CH:30][C:31]([F:32])=[C:25]([Cl:24])[CH:26]=1)[C:29]1[CH:27]=[CH:26][C:25]([Cl:24])=[CH:31][CH:30]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Reactant: Nc1ccc(F)c(Cl)c1
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1N(c1ccc(Cl)cc1)c1ccc(F)c(Cl)c1

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 using 2-bromo-5-[(4-chlorophenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (intermediate B) and 3-chloro-4-fluoro-aniline as starting materials. tR 1.38 min (LC-MS 2); ESI-MS: 530.1 [M+H]+ (LC-MS 2).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[CH3:9][S:10]([OH:13])(=[O:12])=[O:11].[H][H]>[Pt].CO>[CH3:9][S:10]([OH:13])(=[O:12])=[O:11].[NH2:1][CH:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: [H][H]
Reactant: COC(=O)/C=C(/C)N
Agent: [Pt]
Agent: CS(=O)(=O)O
Solvent: CO
Product: COC(=O)CC(C)N

Procedure:
5.0 g (43.4 mmol) of methyl 3-aminocrotonate, 70 ml of anhydrous methanol, 1.0 equivalent of methanesulfonic acid and 0.22 g of Pt/C catalyst (Heraeus K0129) were introduced into a 160 ml Parr autoclave. The hydrogenation was carried out for 2 hours at approximately 20° C. under 5-10 bar of hydrogen. The catalyst was then filtered off and the solvent was completely removed by distillation on a rotary evaporator. 6.2 g of pure methyl (RS)-3-aminobutyrate methanesulfonate were obtained as an oil.
Reaction SMILES: C[C:2]1(C)[O:6][CH:5]([CH2:7][CH:8]([OH:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4](=[O:18])[O:3]1.Cl>C1(C)C=CC=CC=1.C[O-].[Na+]>[OH:6][CH:5]([CH2:7][CH:8]([OH:17])[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[C:4]([O:3][CH3:2])=[O:18]
Reactant: CC(C)(C)OC(=O)CC(O)CC1OC(C)(C)OC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C(O)CC(O)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a solution of tert.-butyl 4-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)-3-hydroxybutanoate (5.49 g, 20.0 mmol) in toluene (40.0 ml), sodium methoxide (1M in methanol) (30 ml) was added at 0° C. in an argon atmosphere and stirred at 0° C. for 30 minutes. After dropwise adding 1N hydrochloric acid (30.5 ml) at 0° C. over 10 minutes, the mixture was stirred at 0° C. for 10 minutes. After evaporating off the most of the organic solvent under reduced pressure, the residual mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline and a phosphate buffer (pH 7.0). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:acetone=2:1) to give pure 1-methyl 6-tert.-butyl 2,4-dihydroxyadipate (3.69 g, 14.9 mmol). Yield, 74.3 %.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15]C(=O)C(F)(F)F)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CNC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCCC1CN
Reaction time: 16 h
Yield: 70.2 %

Procedure:
(S)-2-[(2,2,2-Trifluoro-ethanoylamino)-methyl]-piperidine-1-carboxylic acid tert butyl ester (18.2 g) was dissolved in methanol (500 ml) and treated with potassium carbonate (16.1 g). After stirring for 16 h solvent was removed at reduced pressure and the residue partitioned between dichloromethane/water. The organic phase was separated, washed with brine, dried and solvent removed at reduced pressure, the residue was column chromatographed (silica gel, 0-10% (9:1 methanol/ammonia) in dichloromethane eluant) to give the title compound (8.82 g) of description 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][N:2]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[CH:3][N:2]=1
Reactant: Nc1ccnnc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccnnc1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 4.4 %

Procedure:
To a solution of pyridazine-4-amine (1.73 g, 18.2 mmol) and pyridine (4.41 ml, 54.6 mmol) in tetrahydrofuran (100 ml) was added 2,2,2-trichloroethyl chloroformate (3.76 ml, 27.3 mmol) was added, the mixture was stirred for 1.5 hours with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the desired product (218 mg, 4.4%) as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[CH3:34][C:35]1([O:38][CH2:37]1)[CH3:36]>>[CH3:34][C:35]([OH:38])([CH3:37])[CH2:36][N:15]1[CH2:16][CH2:17][CH:12]([CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[C:8]([N:9]=2)=[C:7]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:6]=[C:5]([N:24]2[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[N:26]=[C:25]2[CH3:33])[N:4]=3)[CH2:13][CH2:14]1
Reactant: CC1(C)CO1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(CC(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure C, 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperidin-4-ylmethyl)-9H-purin-6-yl)morpholine and isobutylene oxide were reacted to give 542. LCMS m/z: 519.3 (MH+)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[C:21](OCC)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[H-].C([Al+]CC(C)C)C(C)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH:21]=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 127.1 %

Procedure:
To a solution of 5.0 g (13.9 mmoles) of ethyl 1,4-dibenzylpiperazin-2-carboxylate [prepared in the manner described in Helv. Chim. Acta, 298, 2646(1963) by E. Jucker and E. Rissi] in 40 l ml of dry ether is dropwise added 30 ml of a solution of 1.46 moles of diisobutylaluminium hydride in toluene at -56° to -66° C. under nitrogen atmosphere in a period of 15 minutes, and the mixture is stirred at the same temperature for 1 hour. 10% Aqueous sodium hydroxide solution (20 ml) is slowly dropwise added thereto, and the mixture is warmed up to room temperature and extracted with ether. The extract is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to yield 5.2 g of crude 1,4-dibenzyl-2-formylpiperazine.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=1)(=[O:1])[CH:3]([CH3:4])[CH3:5]
Reactant: CCOC(=O)c1ccc(C(O)C(C)C)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C(=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 2.08 g (9.36 mmol) of ethyl 4-(1-hydroxy-2-methylpropyl)benzoate (from Step A) and 1.64 g (14.04 mmol) of 4-methylmorpholine N-oxide in 20 mL of CH2Cl2 were added 164 mg (0.47 mmol) of tetrapropylammonium perruthenate and few specks of ground 4 A molecular sieves. After stirring at rt for 2 h, the mixture was filtered through a cake of Celite and the filtrate was concentrated. Chromatography on a Biotage 40M cartridge using 1:19 v/v EtOAc/hexanes as the eluant gave 2.0 g of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.23 (t, J=6.9, 6H), 1.41 (t, J=7.1, 3H), 3.56 (m, 1H), 4.41 (q, J=7.1, 2H), 7.99 (dd, J=1.7, 6.5, 2H), 8.13 (dd, J=1.9, 6.7, 2H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH2:10][P:11](=[O:20])([O:16][CH:17]([CH3:19])[CH3:18])[O:12][CH:13]([CH3:15])[CH3:14]>>[CH:1](=[N:9][CH2:10][P:11](=[O:20])([O:12][CH:13]([CH3:15])[CH3:14])[O:16][CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OP(=O)(CN)OC(C)C
Reactant: O=Cc1ccccc1
Product: CC(C)OP(=O)(CN=Cc1ccccc1)OC(C)C

Procedure:
The desired imine is obtained in a quantitative yield by reacting 10.6 g. (0.1 mol) benzaldehyde with 19.5 g. (0.1 mol) diisopropyl aminomethylphosphonate under the conditions described in Example 1.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[C:37](O)=[O:38])=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[C:37]([N:6]2[CH2:5][C@H:4]3[C@H:8]([CH2:9][CH:2]([CH3:1])[CH2:3]3)[C@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])=[O:38])=[CH:29][CH:30]=1
Reactant: COc1ccc(-c2sc(C)nc2C(=O)O)cc1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Product: COc1ccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)cc1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(4-methoxy-phenyl)-2-methyl-thiazole-4-carboxylic acid.