Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:55]=[CH:54][CH:53]=[CH:52][C:14]=1[C:15]([NH:17][C:18]1[CH:49]=[CH:48][C:21]([C:22]([N:24]([CH3:47])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:40]2[CH2:45][CH2:44][C:43](=[O:46])[CH2:42][CH2:41]2)=[O:39])=[O:23])=[CH:20][C:19]=1[O:50][CH3:51])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:55]=[CH:54][CH:53]=[CH:52][C:14]=1[C:15]([NH:17][C:18]1[CH:49]=[CH:48][C:21]([C:22]([N:24]([CH3:47])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:40]2[CH2:41][CH2:42][CH:43]([OH:46])[CH2:44][CH2:45]2)=[O:39])=[O:23])=[CH:20][C:19]=1[O:50][CH3:51])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCC(=O)CC2)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCC(O)CC2)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
To a solution of 4-[2-[(3-tert-butoxycarbonylaminoprop-1-yl)oxy]benzoyl]amino-3-methoxy-N-methyl-N-[2-[5-(4-oxopiperidin-1-yl)carbonylpent-1-yl]oxy-4-methylphenyl]benzamide (192 mg) in methanol (5 ml) was added sodium borohydride (19 mg) at ambient temperature and the mixture was stirred at the same temperate for 1 hour. The reaction was quenched with 0.5N hydrochloric acid (10 ml) and the mixture was extracted with chloroform (15 ml×3). The organic layer was washed with aqueous sodium hydrogen carbonate and brine, and the solution was dried over magnesium sulfate. The solvent was evaporated in vacuo to give 4-[2-[(3-tert-butoxycarbonylaminoprop-1-yl)oxy]benzoyl]amino-3-methoxy-N-methyl-N-[2-[5-(4-hydroxypiperidin-1-yl)carbonylpent-1-yl]oxy-4-methylphenyl]benzamide (199 mg).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30]>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=2)=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(C(F)(F)F)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-Trifluoromethyl-benzoic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][Cl:10]>>[Cl:10][CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: ClCCBr
Product: ClCCN1CCOCC1

Procedure:
Morpholine and 1-bromo-2-chloroethane are reacted using the procedure for Example OO to afford 4-(2-chloroethyl)morpholine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@@H:10]([OH:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@@H:10]([O:12][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl(cis-3-hydroxycyclobutyl)carbamate (2.0 g, 10.7 mmol) was dissolved in dry THF (50 mL) under nitrogen atmosphere, and the solution cooled to 0° C. To this clear solution, sodium hydride (60% dispersion in oil, 0.428 g, 10.7 mmol) was added portion wise (evolution of H2 observed). The mixture was stirred at rt for 30 min then benzyl bromide (1.91 mL, 16.04 mmol) added dropwise and the resulting yellow suspension stirred at rt for 16 h. The reaction was quenched with sat aq. NH4Cl solution (20 mL) and partitioned between sat aq. NaHCO3 (40 mL) and DCM (60 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (gradient 0-50% EtOAc in cyclohexane) to afford the title compound as a white solid (2.40 g, 81%). 1H NMR (CDCl3, 400 MHz): δ 7.41-7.22 (5H, m), 4.66 (1H, br, NH), 4.42 (2H, s), 3.83-3.65 (2H, m), 2.79-2.61 (2H, m), 1.86-1.72 (2H, m), 1.46 (9H, s).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][NH:21][C:22]3[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]=[C:24]([N:30]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[C:23]=3[NH2:49])[O:17][N:16]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][N:30]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[C:24]2[C:23]([NH:49][C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2])=[C:22]([NH:21][CH2:20][C:18]3[O:17][N:16]=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=4)[CH:19]=3)[C:27]([CH3:28])=[C:26]([CH3:29])[N:25]=2)=[CH:46][CH:45]=1
Reactant: CCOCC(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c(NCc3cc(-c4ccc(F)cc4)no3)c2N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCC(=O)Nc1c(N(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)nc(C)c(C)c1NCc1cc(-c2ccc(F)cc2)no1
Reaction time: 0.7 h
Yield: 91.3 %

Procedure:
Under a nitrogen atmosphere, ethoxyacetyl chloride (1.4 g, 11 mmol) was added dropwise to a solution of N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-N2,N2-bis(4-methoxybenzyl)-5,6-dimethylpyridine-2,3,4-triamine (5.898 g, 10.39 mmol) and triethylamine (2.2 mL, 15 mmol) in dichloromethane (30 mL) at 0° C. After the reaction was stirred for 0.7 hours, an analysis by HPLC indicated the presence of starting material, and additional ethoxyacetyl chloride (0.54 g) was added. The stirring was continued, and after 1.5 hours, the reaction mixture was diluted with dichloromethane and washed sequentially with saturated aqueous potassium carbonate, water, and brine; dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 6.2 g of N-[2-[bis(4-methoxybenzyl)amino]-4-({[3-(4-fluorophenyl)isoxazol-5-yl]methyl}amino)-5,6-dimethylpyridin-3-yl]-2-ethoxyacetamide as a yellow oil.
Reaction SMILES: C([O:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([CH:19]=[O:20])[CH3:18])[CH2:8][C@@H:7]([O:28]C(=O)C)[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[OH:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([CH:19]=[O:20])[CH3:18])[CH2:8][C@@H:7]([OH:28])[CH2:6]1
Reactant: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.5 %

Procedure:
IN 2 ml of methanol was dissolved 73 mg of 1α,3β-diacetoxypregna-5,7-diene-20-carbaldehyde, followed by addition of 5 mg of potassium carbonate. The mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water and extracted with diethyl ether, and the extract was washed with aqueous sodium chloride solution, dried over sodium sulfate and concentrated. The residue was recrystallized from ether to give 49 mg of 1α,3β-dihydroxypregna-5,7-diene-20-carbaldehyde which showed the same 1H NMR spectrum as the 1α,3β-dihydroxypregna-5,7-diene-20-carbaldehyde obtained in Reference Example 2.
Reaction SMILES: [F:1][C:2]([F:55])([F:54])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C@H:20]([CH2:29][N:30]3[CH2:53][CH2:52][C:33]4([CH2:37][O:36][CH2:35][CH:34]4[O:38]C([C@@]45C(C)(C)[C@@](C)(CC4)C(=O)O5)=O)[CH2:32][CH2:31]3)[CH2:19][CH2:18][O:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[F:55][C:2]([F:1])([F:54])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C@H:20]([CH2:29][N:30]3[CH2:53][CH2:52][C:33]4([CH2:37][O:36][CH2:35][C@H:34]4[OH:38])[CH2:32][CH2:31]3)[CH2:19][CH2:18][O:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H](O[C@H]1OCC[C@@H](CN2CCC3(CC2)COCC3OC(=O)[C@@]23CC[C@@](C)(C(=O)O2)C3(C)C)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: C[C@@H](O[C@H]1OCC[C@@H](CN2CCC3(CC2)COC[C@H]3O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.5 %

Procedure:
A solution of (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid (4RS)-8-{(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-ylmethyl}-2-oxa-8-aza-spiro[4.5]dec-4-yl ester (Description 12; 138 mg, 0.175 mmol) in dichloromethane (5 ml) was cooled to −78° C. and diisobutylaluminium hydride (1.5M in toluene, 0.5 ml, 0.75 mmol) added. The reaction was stirred for 30 minutes then quenched by the addition of 2M aqueous sodium hydroxide solution. The mixture was allowed to warm to room temperature then dried over Na2SO4 and filtered through Celite™. The filtrate was concentrated in vacuo and the residue purified by preparative thin layer chromatography, eluting with 7% methanol/dichloromethane to give the title compound (27 mg, 26%).
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:11][C:12](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:10])[CH3:9]>C(O)C>[C:8]([NH:11][C@@H:12]([C:13]([OH:15])=[O:14])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)NC(=Cc1ccccc1)C(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H](Cc1ccccc1)C(=O)O
Temperature: 50 °C
Reaction time: 20 h

Procedure:
0.0025 m-mol of rhodium-1,5-cyclooctadienechloride complex, 0.0065 m-mol of one of the asymmetric ligand compounds indicated in Table 1 and 0.25 m-mol of triethylamine were dissolved in 20 ml of ethanol, and 5 m-mol of α-acetamidocinnamic acid was added to the solution. The mixture was stirred for 20 hours at 50° C. and under a hydrogen atmosphere of 20 atm. The reaction mixture was concentrated under reduced pressure and then dissolved in 0.5N aqueous solution of caustic soda. Insolubles were filtered off and the filtrate was made acid with diluted hydrochloric acid and extracted with ether. The organic layer was washed with water and dried. The solvent was distilled off to obtain optically active (R)-N-acetylphenylalanine. The results of Synthesis Nos. 1-5 are shown in Table 1.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=O)=[CH:2]1.C([O-])(=O)C.[NH4+].[N+:17]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])([O-:19])=[O:18]>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[CH2:22][CH2:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1
Reactant: COC(=O)CCC[N+](=O)[O-]
Reactant: O=Cc1c[nH]c2ncccc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)CCC(=Cc1c[nH]c2ncccc12)[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 1.47 g (10 mM) of 1H-Pyrrolo[2,3-b]pyridine-3-carbaldehyde (J. Am. Chem. Soc., 1955, 77, 457-459), 77 mg (10 mM) of ammonium acetate and 2.55 mL (20 mM) of methyl 4-nitrobutyrate (Aldrich) was refluxed in 10 mL of THF for 1 hour. An additional 500 mg of ammonium acetate was added and the mixture refluxed for an additional 3 hours. The reaction was cooled to room temperature, the solvent evaporated, and the residue chromatographed on silica using ethyl acetate as the elutant. Appropriate fractions were combined to yield 410 mg of the desired product as an oil. NMR (D6DMSO) δ12.80 (s, 1H), 8.42 (s, 1H), 8.37 (m, 2H), 8.18 (s, 1H), 7.25 (m, 1H), 3.62 (s, 3H), 3.25 (t, 2H), 2.68 (t, 2H). 13C NMR (D6DMSO) 172.4, 148.7, 144.5, 144.4, 130.0, 127.3, 126.9, 119.9, 117.3, 106.1, 51.6, 30.5, 23.6. Mass Spectrum: m/e=276 (P+1).
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].O[CH2:7][C:8]1[CH:9]=[NH+:10][CH:11]=[CH:12][CH:13]=1>>[ClH:3].[Cl:5][CH2:7][C:8]1[CH:9]=[NH+:10][CH:11]=[CH:12][CH:13]=1
Reactant: OCc1ccc[nH+]c1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: ClCc1ccc[nH+]c1

Procedure:
reacting thionyl chloride with 3-hydroxymethyl pyridinium hydrochloride to form 3-chloromethyl pyridinium hydrochloride, at least a portion of which forms as a solid in the reaction mixture.
Reaction SMILES: [SH:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15](OC(=O)C)(=[O:17])[CH3:16].Cl>C(O)(=O)C>[C:15]([S:1][C:2]1[C:10]([C:11]([F:12])([F:13])[F:14])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:17])[CH3:16]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1S
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)Sc1c(C(=O)O)cccc1C(F)(F)F

Procedure:
2-Mercapto-3-trifluoromethyl-benzoic acid (4.0 g, 18 mmol), acetic anhydride (2.2 g, 22 mmol), and glacial acetic acid (6 ml) were refluxed 30 minutes, cooled and combined with dilute hydrochloric acid, thereby affording the product as a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.ClC1N=C(N[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)C(F)=CN=1>>[F:1][C:2]1[C:3]([NH:9][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(F)c(N)n1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: Nc1ncc(F)c(Nc2cccc(O)c2)n1
Yield: 41 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-N2-(3-hydroxyphenyl))-5-fluoro-2,4-pyrimidinediamine, 4-(aminocarbonylmethyleneoxy)aniline (198 mg, 1.2 mmol) and 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine (95 mg, 0.4 mmol) gave N2-[4-aminocarbonylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (60 mg, 41%). 1H NMR (CD3OD): δ 4.55 (s, 2H), 6.75 (dm, J=7.5 Hz, 1H), 7.08 (d, J=9.3 Hz, 2H), 7.18 (m, 2H), 7.22 (d, J=8.7 Hz, 1H), 7.46 (d, J=9.0 Hz, 2H), 8.09 (d, 1H); LCMS: ret. time: 14.38 min.; purity: 100%; MS (m/e): 370.00 (MH+).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([O:13]C)[CH:10]=[CH:9][C:8]=1[O:15]C.[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=O)[CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].O>O1CCCC1>[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[C:10]3[CH:9]=[C:8]([OH:15])[CH:7]=[CH:12][C:11]=3[O:13][C:27]2([CH3:29])[CH3:28])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: CC(C)C(=O)c1ccc(C(C)C)cc1
Reactant: COc1ccc(OC)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccc(C2c3cc(O)ccc3OC2(C)C)cc1
Reaction time: 0.33 h
Yield: 24.8 %

Procedure:
n-Butyllithium (1.6 M, 20.8 mL, 33.2 mmol) was added to a solution of 1-bromo-2,5-dimethoxybenzene (7.2 g, 33.2 mmol) in tetrahydrofuran (20 mL) at −78° C., and the mixture was stirred for 20 minutes at the same temperature. To the reaction mixture was added 1-(4-isopropylphenyl)-2-methylpropan-1-one (5.70 g, 30.0 mmol), and the mixture was stirred for 30 minutes at room temperature. Water (30 mL) was poured into the reaction mixture, which was then extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. A mixture of the residue and 48% hydrobromic acid (30 mL) was heated under reflux for 24 hours in an argon atmosphere. After cooling, water (30 mL) was added to the reaction mixture, which was then extracted twice with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from isopropyl ether-hexane to obtain the title compound (2.1 g, yield 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][C:23]2=[O:32])[CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([N:16]2[CH2:17][CH2:18][CH:19]([N:22]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[CH2:20][CH2:21]2)=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCC(=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: O=C(CCC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)c1ccc(Cl)c(Cl)c1
Yield: 73 %

Procedure:
Prepared analogously to Example 2 from 3,4-dichloro-γ-oxobenzenebutanoic acid and 3-(4-piperidinyl)-3,4-dihydro-2(1H)-quinazolinone in the presence of TBTU in a yield of 73% of theoretical. Colourless crystals, m.p. 224–226° C. and Rf 0.15 (El EE).
Reaction SMILES: Br[CH2:2][C:3](=[O:6])[CH2:4][CH3:5].[C:7]([O-:10])(=[O:9])[CH3:8].[K+].CN(C)C=O>O>[C:7]([O:10][CH2:2][C:3](=[O:6])[CH2:4][CH3:5])(=[O:9])[CH3:8]
Reactant: CC(=O)[O-]
Reactant: CCC(=O)CBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)COC(C)=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 95.6 %

Procedure:
A mixture of 1-bromobutan-2-one (10 g, 66.2 mmol), potassium acetate (7.8 g, 79.4 mmol), and N,N-dimethylformamide (50 ml) was stirred at room temperature for 5 days. Water was added to the reaction mixture and extracted with diethyl ether twice. The organic layers were combined and washed with a saturated saline solution, dried over magnesium sulfate, and filtrated. The filtrate was concentrated under reduced pressure to obtain the title compound (8.24 g) in the form of a mixture with N,N-dimethylformamide.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]1[N:10]=[C:9]([NH:11][C:12]2[C:13]3[CH2:24][NH:23][C:22]([CH3:26])([CH3:25])[C:14]=3[N:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=2)[C:8]([F:27])=[CH:7][N:6]=1)[CH3:3].CCN(C(C)C)C(C)C.[Cl:37][C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1.C(Cl)Cl>[Cl:37][C:38]([N:23]1[CH2:24][C:13]2[C:12]([NH:11][C:9]3[C:8]([F:27])=[CH:7][N:6]=[C:5]([NH:4][CH2:2][CH3:3])[N:10]=3)=[N:16][N:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:14]=2[C:22]1([CH3:25])[CH3:26])=[O:40]
Reactant: CCNc1ncc(F)c(Nc2nn(C(=O)OCC)c3c2CNC3(C)C)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNc1ncc(F)c(Nc2nn(C(=O)OCC)c3c2CN(C(=O)Cl)C3(C)C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of B1(iv) (4.43 g, 9.6 mmol) in dioxane (25 mL) was added HCl (20 mL, 4M in dioxane). The reaction was stirred at room temperature for 2 h then concentrated. To a solution of the HCl salt of ethyl 3-{[2-(ethylamino)-5-fluoropyrimidin-4-yl]amino}-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate (1.27 g, 2.7 mmol) in CH2Cl2 (40 mL) was added DIPEA (1.57 g, 12.1). The reaction was cooled to −78° C. and triphosgene (0.48 g, 0.6 mmol) was added in a solution of CH2Cl2 (10 mL) with an addition funnel over 15 min. The reaction was quenched at −78° C. with water then warmed to room temperature. The mixture was made to pH 8-9 with NaHCO3 and extracted with CH2Cl2 (2×15 mL). The combined extracts were washed with brine (15 mL) then dried, filtered and concentrated. The crude material was purified by silica gel column chromatography using 0-3% 7N NH3/MeOH in CH2Cl2 to give the desired compound B1(v) as a white foam (489 mg, 36%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.07 (t, J=7.2 Hz, 3H), 1.33 (t, J=7.2 Hz, 3H), 1.78-1.84 (m, 6H), 3.12-3.28 (m, 2H), 4.42 (q, J=7.2 Hz, 2H), 4.78 (s, 2H), 6.69-6.97 (m, 1H), 7.77-8.08 (m, 1H), 10.41 (s, 1H). Mass spectrum: Calcd for C17H22ClFN7O3 (M+H): 426. Found 426.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[OH-].[K+].[CH2:8]=[CH:9][CH2:10][CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O.Cl>O>[CH2:8]=[CH:9][CH2:10][CH2:11][O:4][CH2:3][CH2:2][CH2:1][OH:5]
Reactant: C=CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: OCCCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=CCCOCCCO
Temperature: 75 °C
Reaction time: 3 h
Yield: 13.8 %

Procedure:
Into a reactor, 1,3-propanediol (46.7 g) and potassium hydroxide (34.5 g) were charged and stirred, and heated at the internal temperature of 75° C. for 30 minutes. At the internal temperature of 80° C., CH2═CH(CH2)2OTs (69.5 g) obtained in EXAMPLE 3-1 was added thereto over 3 hours and standed as it is after stirring for 1 hour. The reaction mixture was poured into water (250 ml) and neutralized by adding hydrochloric acid. After filtration, the filtrate was extracted with t-butyl methyl ether (300 ml) four times. The organic layer put together was dried over magnesium sulfate and subjected to filtration, and the solvent was distilled off to obtain 5.5 g of CH2═CH(CH2)2O(CH2)3OH.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]1([CH2:11][CH:12]([OH:14])[CH3:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCOCC>[C:1]([O:14][CH:12]([CH3:13])[CH2:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(O)Cc1ccccc1
Reactant: CC(=O)Cl
Solvent: CCOCC
Product: CC(=O)OC(C)Cc1ccccc1

Procedure:
Acetyl chloride (16.7 g) in dry ether (50 ml) was added dropwise to a stirred solution of 1-phenylpropan-2-ol (26.4 g) in dry ether (250 ml). The mixture was refluxed for 2 h, washed with sodium bicarbonate solution, dried (MgSO4) and evaporated to a colourless oil (27.5 g).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.O[C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]>>[CH:1]1([CH2:4][O:5][C:7]2[CH:8]=[C:9]([CH:14]=[C:15]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])[CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: COC(=O)c1cc(O)cc(N2CCCC2=O)c1
Product: COC(=O)c1cc(OCC2CC2)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to D14 (first part of synthesis) from cyclopropylmethanol and methyl 3-hydroxy-5-(2-oxopyrrolidin-1-yl)-benzoate (D41).