Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(O)(C)(C)C.[CH2:16]([N:23]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:24]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[C:31]([O:33][CH3:34])=[O:32])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:35]([N:23]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:24]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[C:31]([O:33][CH3:34])=[O:32])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COC(=O)[C@@H]1CCCCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCCCC[C@H]1N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
Potassium bis(trimethylsilyl)amide (31.7 mL, 15.9 mmol) was added dropwise to a solution of t-butanol in anhydrous tetrahydrofuran under nitrogen at room temperature. After 30 min, a solution of cis-methyl 2-(dibenzylamino)cycloheptanecarboxylate (1.33 g, 3.78 mmol) in 50 mL anhydrous tetrahydrofuran was added dropwise via syringe. The reaction was stirred for 17 h and then was partitioned between 250 mL diethyl ether and 200 mL brine. The organic layer was concentrated and purified by flash chromatography on 120 g silica gel with 2 to 4% ethyl acetate in hexane to yield trans-methyl 2-(dibenzylamino)cycloheptanecarboxylate (895 mg, 67%). 1H NMR (400 MHz, CDCl3) δ ppm 7.23-7.30 (8H, m), 7.16-7.22 (2H, m), 3.77 (2H, d, J=13.60 Hz), 3.51 (3H, s), 3.26 (2H, d, J=13.35 Hz), 3.02 (1H, ddd, J=11.08, 8.81, 2.77 Hz), 2.77 (1H, ddd, J=11.02, 6.99, 4.41 Hz), 1.88-1.99 (1H, m), 1.28-1.83 (9H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2([CH:22]=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][Mg]Br>C1COCC1.[Cl-].[NH4+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2([CH:22]([OH:23])[CH3:24])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: O=CC1(c2cc(F)cc(OCc3ccccc3)c2)CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)C1(c2cc(F)cc(OCc3ccccc3)c2)CCOCC1
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a stirred solution of 4-[3-(benzyloxy)-5-fluorophenyl]-4-formyl-3,4,5,6-tetrahydro-2H-pyran (1.08 g, 3.4 mmol) in THF (16 ml) at room temperature under a nitrogen atmosphere was added on 0.96M solution of methyl magnesium bromide (5.3 ml, 5.1 mmol) in a dropwise manner. The mixture was stirred overnight, diluted with saturated aqueous ammonium chloride (40 ml) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with water (40 ml) and brine (40 ml), dried (magnesium sulfate) and concentrated to dryness. Purification by column chromatography (silica-gel, 150 g, ethyl acetate in n-hexane as an eluent increasing the amount of ethyl acetate from 40% to 60%) afforded the titled compound as a colorless liquid (0.71 g, 63%).
Reaction SMILES: [Si]([O:8][CH:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[S:19][CH:20]=[CH:21][N:22]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[S:19]1[CH:20]=[CH:21][N:22]=[C:18]1[C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[CH:9]([OH:8])[CH2:10][CH2:11]2
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2cc(-c3nccs3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC1CCc2cc(-c3nccs3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of 2-(1-{[tert-butyl(dimethyl)silyl]oxy}-2,3-dihydro-1H-inden-5-yl)-1,3-thiazole (630 mg, 1.9 mmol) in tetrahydrofuran (10.00 mL) was added a 1.00 M solution of tetrabutylammonium fluoride, trihydrate in tetrahydrofuran (1.90 mL) at 0° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with ether, washed with saturated NaCl aqueous solution, dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to afford the desired product (410 mg, 99%).
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([O:10]CC)=O.[NH2:22][C@H:23]([C:25]([OH:27])=[O:26])[CH3:24].[O-]CC.[Na+].Cl>CN(C=O)C.O>[OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([NH:22][C@H:23]([CH3:24])[C:25]([OH:27])=[O:26])=[O:10]
Reactant: C[C@H](N)C(=O)O
Reactant: CCOC(=O)c1ncc2c(-c3ccccc3)noc2c1O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](NC(=O)c1ncc2c(-c3ccccc3)noc2c1O)C(=O)O
Temperature: 25 °C
Yield: 48 %

Procedure:
Ethyl 7-hydroxy-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (0.1 g, 0.35 mmol) was dissolved in 10 mL of DMF. L-Alanine (0.627 g, 7.04 mmol) and sodium ethoxide (0.36 g, 5.28 mmol) were added and the mixture was refluxed for 3 h. The mixture was cooled to room temperature and diluted with 70 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 2. The resulting suspension was filtered and the solid was dried under vacuum to give 55 mg of the title compound. MS: (+) m/z 328.00 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](Cl)=[O:10].[Cl:12][C:13]1[CH:27]=[CH:26][C:16]([CH2:17][N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH2:20][NH:19]2)=[CH:15][CH:14]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:19]1[CH2:20][C:21](=[O:25])[NH:22][C:23](=[O:24])[N:18]1[CH2:17][C:16]1[CH:26]=[CH:27][C:13]([Cl:12])=[CH:14][CH:15]=1)=[O:10]
Reactant: O=C1CNN(Cc2ccc(Cl)cc2)C(=O)N1
Reactant: O=C(Cl)Cc1ccccc1Cl
Solvent: c1ccccc1
Product: O=C1CN(C(=O)Cc2ccccc2Cl)N(Cc2ccc(Cl)cc2)C(=O)N1
Yield: 18.3 %

Procedure:
Into a 100 ml round bottomed flask fitted with a reflux condenser sealed with a calcium chloride tube and a magnetic stirrer, were placed 55 g of 2-chlorophenylacetyl chloride and 20 ml of dry benzene. Stirring was commenced and 1 g of 2-(4'-chlorobenzyl)-hexahydro-1,2,4-triazine-3,5-dione was added in one portion and the mixture was stirred and refluxed for 8 hours. The mixture was then cooled and the precipitated crystals were filtered off and recrystallized from isopropanol to yield 0.3 g of 1-(2'-chlorophenylacetyl)-2-(4'-chlorobenzyl)-hexahydro-1,2,4-triazine-3,5-dione; m.p. 224°.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:24][O:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](O)=[O:33])=[CH:28][CH:27]=1>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:2][CH2:3][N:4]([C:32](=[O:33])[CH2:31][O:30][C:29]3[CH:35]=[CH:36][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[CH2:5][CH2:6]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[S:14][C:9]=2[N:10]=1
Reactant: Cc1ccc(-c2nc3c(N4CCNCC4)nc(N)nc3s2)cc1
Reactant: COc1ccc(OCC(=O)O)cc1
Product: COc1ccc(OCC(=O)N2CCN(c3nc(N)nc4sc(-c5ccc(C)cc5)nc34)CC2)cc1
Yield: 41 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-p-tolylthiazolo[5,4-d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 41%, according to the procedure for the synthesis of example 50.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[C:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([OH:31])=[O:30]>>[Cl:28][C:4]1[CH:3]=[C:2]([C:35]2[CH:36]=[CH:37][C:32]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:27])[C:9]([OH:14])([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=2[CH:26]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: CC(c1ccc(-c2ccc(C(=O)O)cc2)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with 4-carboxyphenylboronic acid to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=518.2 [M−H+].
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.CN.Cl.C[CH2:16][N:17](C(C)C)C(C)C>ClCCl>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:17][CH3:16])=[O:8])=[CH:5][CH:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)c1ccc(CCl)cc1
Reaction time: 1 h
Yield: 102.9 %

Procedure:
To a solution 4-(chloromethyl)benzoyl chloride (1.0 g, 5.29 mmol) and methylamine.HCl (1.0 g, 5.80 mmol) in dichloromethane (40 mL) was added DIPEA (2.01 g, 15.6 mmol) at 0° C. and stirred for 1 h. The reaction mixture was extracted with water (1×50 mL). The organic layer was extracted with brine (1×50 mL), dried over Na2SO4 and the solvent was removed under reduced pressure to afford 1.0 g (quantitative) of 4-(chloromethyl)-N-methylbenzamide (I-30) as an off white solid. 1H NMR (400 MHz, DMSO) δ 8.46 (d, J=3.5 Hz, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.3 Hz, 2H), 4.80 (s, 2H), 2.78 (d, J=4.4 Hz, 3H); ESI-LC/MS (m/z): [M+H]+ 184.2, RT 2.46 min.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.COP([O:18][CH3:19])OC.[CH2:20]([C@@H:27]1[N:30]([Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C:29](=[O:38])C1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O=O>C1COCC1>[CH2:20]([C@@H:27]1[N:30]([Si:31]([C:34]([CH3:36])([CH3:35])[CH3:37])([CH3:32])[CH3:33])[C:29](=[O:38])[C@H:19]1[OH:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COP(OC)OC
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1Cc1ccccc1
Agent: O=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](O)[C@@H]1Cc1ccccc1
Reaction time: 0.25 h
Yield: 60.6 %

Procedure:
To a solution of diisopropylamine (800 μL, 5.7 mmol) in anhydrous THF (40 mL) at −20° was added butyllithium (3.56 mL, 5.7 mmol, 1.6 M in hexane). After 15 min., the reaction was cooled to −78°, and freshly distilled trimethylphosphite (1.12 mL, 7.6 mmol) was added followed by a solution of 4(S)-benzyl-1-(tert-butyldimethylsilyl)azetidin-2-one (from example 1, step C, 1.05 g, 3.8 mmol) in THF (10 mL). A constant stream of oxygen was introduced and the mixture was stirred at −78° for 3 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (120 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (SiO2, 10% EtOAc-hexane to 30% EtOAc in hexane) to give 4(S)-benzyl-1-(tert-butyldimethylsilyl)-3(S)-hydroxyazetidin-2-one (671 mg , 60% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ7.25-7.21 (m, 5H), 4.51 (d, J=2 Hz, 1H), 3.75-3.71 (m, 1H), 3.26 (bs, 1H), 3.20 (dd, J=14, 3.8 Hz, 1H), 2.66 (dd, J=14, 11.1 Hz, 1H), 1.00 (s, 9H), 0.30 (d, J=3.5 Hz, 6H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[F:14][C:15]1[CH:32]=[CH:31][C:18]([C:19]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28](O)=[O:29])[CH2:23][CH2:22]2)=[O:20])=[CH:17][CH:16]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([CH:21]2[CH2:22][CH2:23][N:24]([CH2:27][C:28]([NH:1][CH2:2][C:3]3[NH:4][C:5](=[O:13])[C:6]4[CH2:12][O:11][CH2:10][CH2:9][C:7]=4[N:8]=3)=[O:29])[CH2:25][CH2:26]2)=[O:20])=[CH:31][CH:32]=1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CN1CCC(C(=O)c2ccc(F)cc2)CC1)NCc1nc2c(c(=O)[nH]1)COCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.5 %

Procedure:
To a solution of 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (1.7 g, 9.6 mmol) and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid (2.7 g, 10 mmol) in dichloromethane (50 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.2 g, 11 mmol), 1-hydroxybenzotriazole (1.5 g, 9.6 mmol) and triethylamine (4.0 mL, 29 mmol). The mixture was stirred at ambient temperature for 24 hours. The reaction mixture was washed with ammonium chloride solution, concentrated in vacuo and purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0, methanol:dichloromethane, 1:99 to 10:90) to provide the title compound (2.2 g, 54% yield). 1H NMR (400 MHz, CDC3) δ 11.12 (s, 1H), 8.07 (s, 1H), 7.99 (dd, J=9.0, 5.5 Hz, 2H), 7.18 (t, J=8.5 Hz, 2H), 4.58 (s, 2H), 4.41 (d, J=6.0 Hz, 2H), 3.97 (t, J=5.5 Hz, 2H), 3.22-3.35 (m, 1H), 3.10-3.22 (m, 2H), 2.94-3.07 (m, 2H), 2.66-2.75 (m, 2H), 2.31-2.48 (m, 2H), 1.80-1.99 (m, 4H). HRMS calculated for C22H23N4O4 429.1938. found (ESI, [M+H]+), 429.1925. MS m/z 429.3 (M+1), retention time=1.28 min.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([NH:14]S(C(C)(C)C)=O)[CH2:12][CH3:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[ClH:21]>CO>[ClH:21].[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([NH2:14])[CH2:12][CH3:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CCC(NS(=O)C(C)(C)C)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CO
Product: CCC(N)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(1-(1,4-dioxaspiro[4.5]decan-8-yl)propyl)-2-methylpropane-2-sulfinamide (as prepared in the previous step, 2.55 g, 8.39 mmol) in dry MeOH (50 mL) was added HCl (14 mL, 17.5 mmol, 1.25 M in MeOH) at room temperature. After stirring overnight at ambient temperature, the reaction mixture was concentrated in vacuo. Trituration of the residue with ether, followed by decantation of the supernatant and drying the residue under high vacuum afforded the product as a white foam.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[C:13]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][CH:23]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(OC(F)(F)F)cc2)CC1
Yield: 96 %

Procedure:
Using general procedure A, 4-trifluoromethoxy-phenylamine (354 mg, 2.00 mmol) and 1-Boc-4-piperidone (418 mg, 2.10 mmol) gave 4-(4-trifluoromethoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (692 mg, 96%) as a white crystalline solid.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:34][N:35]([CH:44]=[O:45])[O:36]CC2C=CC=CC=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2C(OCC2C=CC=CC=2)=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>[OH-].[OH-].[Pd+2].CO>[CH:1]1([CH2:6][C@H:7]([CH2:34][N:35]([CH:44]=[O:45])[OH:36])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2ccncn2)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)N1NCC[C@H]1C(=O)Nc1ccncn1
Reaction time: 2 h
Yield: 72.4 %

Procedure:
A mixture of phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[(4-pyrimidinylamino)carbonyl]-1-pyrazolidinecarboxylate (1.21 g, 1.96 mmol) and Pearlman's catalyst (0.276 g, 0.39 mmol) in methanol (109 ml) was degassed and placed under 1 atm of H2 at 25° C. After 2 hrs, the reaction mixture was filtered and concentrated. Purification by reverse phase HPLC (Gilson) provided (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-N-4-pyrimidinyl-3-pyrazolidinecarboxamide (554 mg, 70% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH2:28][C:29]#[N:30])[CH2:14][CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][C:39]2=[O:44])=[CH:34][CH:33]=1>>[O:44]=[C:39]1[N:38]([C:35]2[CH:34]=[CH:33][C:32]([NH:31][C:2]3[N:7]=[C:6]([C:8]4[CH:9]=[N:10][N:11]([CH:13]([CH2:14][CH:15]5[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]5)[CH2:28][C:29]#[N:30])[CH:12]=4)[CH:5]=[CH:4][N:3]=3)=[CH:37][CH:36]=2)[CH2:43][CH2:42][O:41][CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(CC#N)n2cc(-c3ccnc(Cl)n3)cn2)CC1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Product: N#CCC(CC1CCNCC1)n1cc(-c2ccnc(Nc3ccc(N4CCOCC4=O)cc3)n2)cn1

Procedure:
This compound was prepared as a racemic mixture, by coupling of tert-butyl 4-(2-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyanopropylpiperidine-1-carboxylate (from example 1, step 4) with 4-(4-aminophenyl)-3-morpholinone (from Affinitis Pharma) according to the procedure described in example 1, step 6. LCMS (M+H) 487.1.
Reaction SMILES: CO[C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([NH:19][C:20](=[O:26])[CH2:21][O:22]C(=O)C)[C@@H:16]([OH:27])[C@H:15]2[OH:28])=[C:7]([NH:29][C@H:30]([CH2:38][OH:39])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:6]=1)=[O:4].[CH2:40]([NH2:43])[CH2:41][NH2:42]>>[NH2:42][CH2:41][CH2:40][NH:43][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([NH:19][C:20](=[O:26])[CH2:21][OH:22])[C@@H:16]([OH:27])[C@H:15]2[OH:28])=[C:7]([NH:29][C@H:30]([CH2:38][OH:39])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(N[C@H](CO)Cc2ccccc2)c2ncn([C@@H]3C[C@H](NC(=O)COC(C)=O)[C@@H](O)[C@H]3O)c2n1
Reactant: NCCN
Product: NCCNC(=O)c1nc(N[C@H](CO)Cc2ccccc2)c2ncn([C@@H]3C[C@H](NC(=O)CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
9-[(1R,2S,3R,4S)-4-(2-Acetoxy-acetylamino)-2,3-dihydroxy-cyclopentyl]-6-((S)-1-hydroxymethyl-2-phenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester (Intermediate WF) is dissolved in ethylenediamine (>10 eq.). The reaction mixture is stirred at 90° C. for 1 hour. The reaction mixture is cooled and reduced in vacuo. The title compound is obtained by column chromatography.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([N:23]([CH:30]([CH3:32])[CH3:31])[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=S)=[O:22])=[CH:3]1.CN(C=[O:37])C>>[O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([N:23]([CH:30]([CH3:32])[CH3:31])[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:37])=[O:22])=[CH:3]1
Reactant: CN(C)C=O
Reactant: CC(C)NC(=S)N(C(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Product: CC(C)NC(=O)N(C(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C

Procedure:
1-[3-oxo-androst-4-ene-17β-carbonyl]-1,3-diisopropylthiourea m.p. 180°-183° C., [α]D +146° (C=1, DMF).
Reaction SMILES: [CH:1]([NH:4][C:5](=[NH:7])[CH3:6])([CH3:3])[CH3:2].Br[CH:9]([CH:13](OC)OC)[C:10](=[O:12])[CH3:11].C(N(CC)CC)C.S(=O)(=O)(O)O>C(O)(C)C>[C:10]([C:9]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([CH3:6])=[N:7][CH:13]=1)(=[O:12])[CH3:11]
Reactant: COC(OC)C(Br)C(C)=O
Reactant: CC(=N)NC(C)C
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(=O)c1cnc(C)n1C(C)C
Temperature: 80 °C
Reaction time: 20 h
Yield: 53.6 %

Procedure:
In a 300 mL-volume glass vessel equipped with a stirrer, a thermometer and a dropping funnel, the isopropyl alcohol solution containing 16.2 g (0.162 mol) of N-isopropylacetamidine (which was prepared in the above-mentioned Reference Example 1), 22.8 g (0.108 mol) of 3-bromo-4,4-dimethoxy-2-butanone and 16.4 g (0.162 mol) of triethylamine were placed. The mixture was heated to 80° C. under stirring for 20 hours, for carrying out reaction. After the reaction was complete, 80 mL of sulfuric acid (2 mol/L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The concentrate was washed with methyl isobutyl ketone, and the aqueous portion was taken out. The aqueous portion was made basic by adding an aqueous 48% sodium hydroxide, while the mixture was kept at a temperature of not higher than 40° C. The aqueous basic portion was subjected to extraction with methyl isobutyl ketone, and the extracted portion was concentrated under reduced pressure. The concentrate was distilled under reduced pressure (0.4 kPa, 85° C.) to give 9.63 g (yield: 54%) of 5-acetyl-1-isopropyl-2-methylimidazol as pale yellow liquid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[C:9](Cl)(=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1.Cl>O>[C:9]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])(=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1
Reactant: NCCC(=O)O
Reactant: COc1cccc(C(=O)Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(C(=O)NCCC(=O)O)c1
Reaction time: 5 h
Yield: 81.3 %

Procedure:
Ten grams of β-alanine and 9 g of sodium hydroxide were dissolved in 100 mL of purified water, and 17.4 g of m-anisoylchloride were added dropwise under freezing conditions. After stirring for five hours, hydrochloric acid was added and the pH was adjusted to 2 or less. After extraction with 500 mL of ethyl acetate, the product was desiccated over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized with aqueous ethanol, and 18.5 g of the desired product was obtained (yield of 81%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:15]([NH2:18])(=[O:17])=[O:16])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1.CC(C)([O-])C.[K+].[CH2:25]([SH:27])[CH3:26]>C(O)(C)(C)C>[CH2:25]([S:27][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:15]([NH2:18])(=[O:17])=[O:16])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1)[CH3:26]
Reactant: CCS
Reactant: NS(=O)(=O)c1c(C(F)(F)F)nc2ccc(Cl)nn12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCSc1ccc2nc(C(F)(F)F)c(S(N)(=O)=O)n2n1
Temperature: 25 °C

Procedure:
6-Chloro-2-trifluoromethylimidazo[1,2-b]pyridazin-3-ylsulfonamide (1.00 g, 3.33 mmol) was suspended in t-butyl alcohol (20.0 ml) and stirred at room temperature, during which potassium t-butoxide (80%, 1.40 g, 9.98 mmol) and ethanethiol (0.54 ml, 7.29 mmol) were added thereto. After the mixture was heated for 4 hours under reflux, the reaction solution was left and cooled to room temperature, poured into ice-water (200 ml) and adjusted to pH 3. The precipitated crystals were filtered and washed with water to give the title compound as colorless crystals. The yield was 0.54 g (50.0%).