Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=C(C#N)[CH:16]=[CH:17][C:11]=3[CH2:10][CH2:9][C:8]=2[CH:20]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[C:26]([OH:29])(=[O:28])[CH3:27]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[C:27]([C:26]([OH:29])=[O:28])[CH:16]=[CH:17][C:11]=3[CH2:10][CH2:9][C:8]=2[CH:20]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)c1ccc2c(c1)CCc1ccc(C#N)cc1S2
Agent: O=S(=O)(O)O
Product: CC(=O)c1ccc2c(c1)CCc1ccc(C(=O)O)cc1S2
Temperature: 25 °C

Procedure:
Add 8.5 g. of the nitrile of Example 33 to a mixture of 220 ml. of acetic acid (glacial) and 220 ml. of 50% sulfuric acid. Heat the mixture at reflux under a nitrogen atmosphere overnight. Cool to room temperature and separate the solids by filtration. Recrystallize from acetic acid to obtain the title product. (m.p. 230°-232° C.)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][CH:11]=2)[N:7]=[C:6]([C:21](O)=[O:22])[CH:5]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:36][C:37]1[NH:41][N:40]=[N:39][N:38]=1>>[NH:38]1[C:37]([NH:36][C:21]([C:6]2[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][CH:15]=3)[N:7]=2)=[O:22])=[N:41][N:40]=[N:39]1
Reactant: CCOc1cc(C(=O)O)nc(-c2ccc(N(CC)CC)cc2)c1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCOc1cc(C(=O)Nc2nnn[nH]2)nc(-c2ccc(N(CC)CC)cc2)c1
Yield: 76.5 %

Procedure:
In the same manner as described in Example 1-(1), 4-ethoxy-6-(4-diethylaminophenyl)-2-pyridinecarboxylic acid (0.56 g), carbonyldiimidazole (0.32 g) and 5-aminotetrazole (0.17 g) are reacted to give N-(5-tetrazolyl)-4-ethoxy-6-(4-diethylaminophenyl)-2-pyridinecarboxamide (0.52 g). M.P. 228°-230° C. (decomp.) (recrystallized from dimethylformamide-ethanol)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])[CH:13]([C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:34]1[C:35]([CH3:41])=[N:36][CH:37]=[C:38]([CH3:40])[N:39]=1.C(N(CC)CC)C.O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])[CH:13]([C:25]([N:27]3[CH2:28][CH2:29][N:30]([C:37]4[C:38]([CH3:40])=[N:39][CH:34]=[C:35]([CH3:41])[N:36]=4)[CH2:31][CH2:32]3)=[O:26])[CH2:12]2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(F)ccc1N1CCN(S(=O)(=O)c2cccc(Cl)c2)CC1C(=O)N1CCNCC1
Reactant: Cc1cnc(C)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: Cc1cnc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4cccc(Cl)c4)CCN3c3ccc(F)cc3C)CC2)n1

Procedure:
[4-(3-Chloro-benzenesulfonyl)-1-(4-fluoro-2-methyl-phenyl)-piperazin-2-yl]-piperazin-1-yl-methanone (60 mg), 3-chloro-2,5-dimethylpyrazine (18.1 μL) and triethylamine (20.8 μL) in acetonitrile (1 mL) were heated to 170° C. in the microwave. Water was added and the reaction mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated. Purification by chromatography (SiO2, n-heptane/ethyl acetate 1:2) gave [4-(3-chloro-benzenesulfonyl)-1-(4-fluoro-2-methyl-phenyl)-piperazin-2-yl]-(3′,6′-dimethyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-methanone as a yellow oil, MS: 587.3 ([M+H, 1Cl]+).
Reaction SMILES: [CH3:1][C@@:2]([S:19]([CH3:22])(=[O:21])=[O:20])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:9]1)[C:3]([OH:5])=O.CCN(C(C)C)C(C)C.[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:38][NH2:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O.O>[CH3:1][C@@:2]([S:19]([CH3:22])(=[O:21])=[O:20])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:9]1)[C:3]([NH:39][O:38][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][O:32]1)=[O:5]
Reactant: NOC1CCCCO1
Reactant: C[C@@](CCn1cc(-c2ccccc2)cn1)(C(=O)O)S(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@](CCn1cc(-c2ccccc2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-(4-phenyl-1H-pyrazol-1-yl)butanoic acid (0.855 g, 2.65 mmol, 1 eq) in DMF (20 mL) was added DIPEA (1.06 g, 7.96 mmol, 1.45 mL, 3.eq), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.621 g, 5.30 mmol, 2 eq) and HATU (1.54 g, 3.98 mmol, 1.5 eq). The reaction was allowed to stir at RT overnight. The mixture was diluted with EtOAc and water. The aqueous layer was extracted several times with EtOAc, dried (MgSO4), filtered and concentrated. The crude product mixture was purified by flash chromatography on a 40 g silica column eluting with 0-100% EtOAc/DCM to give (2R)-2-methyl-2-(methylsulfonyl)-4-(4-phenyl-1H-pyrazol-1-yl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (685 mg, 61% yield). LC-MS M−H 420.3.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][Cl:21])[OH:19])[CH3:9].[C:22]([N:27]=[C:28]=[O:29])(=[O:26])[C:23]([CH3:25])=[CH2:24]>>[C:22]([NH:27][C:28]([O:18][CH:14]1[CH2:13][CH2:12][C:11]([CH2:20][Cl:21])([OH:19])[CH:10]([C:2]2([CH3:9])[O:1][CH:3]2[CH2:4][CH:5]=[C:6]([CH3:7])[CH3:8])[CH:15]1[O:16][CH3:17])=[O:29])(=[O:26])[C:23]([CH3:25])=[CH2:24]
Reactant: COC1C(O)CCC(O)(CCl)C1C1(C)OC1CC=C(C)C
Reactant: C=C(C)C(=O)N=C=O
Product: C=C(C)C(=O)NC(=O)OC1CCC(O)(CCl)C(C2(C)OC2CC=C(C)C)C1OC
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
As in Example 2, a mixture of 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol (1.13 g) and methacryloylisocyanate (800 mg) was stirred for 30 minutes at room temperatures. The reaction mixture was purified by means of a silica gel column chromatography (carrier 50 g, developing solvent:hexane-ethyl acetate=3:1) to afford 4-O-(methacryloylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol (520 mg, yield 34%) as colorless crystals.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:9]([CH2:16]/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].[H][H]>CO.[Pd]>[OH:1][C@@H:2]([C@@H:9]([CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:21][CH:20]=1)[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4]
Reactant: [H][H]
Reactant: CC(C)OC(=O)[C@@H](O)[C@@H](C/C=C/c1ccc(OC(F)(F)F)cc1)C(=O)OC(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)OC(=O)[C@@H](O)[C@@H](CCCc1ccc(OC(F)(F)F)cc1)C(=O)OC(C)C
Yield: 99.1 %

Procedure:
To a solution of diisopropyl (2S,3R)-2-hydroxy-3-{(2E)-3-[4-(trifluoromethoxy)phenyl]-2-propenyl}butanedioate (6.98 g; 16.68 mmol; 1.00 eq.) in methanol (105 mL) under N2 atmosphere was added Pd—C (10%; 200 mg; 0.17 mmol; 0.01 eq.). The mixture was then hydrogenated under 2 bars of hydrogen for 14 h at RT. The reaction mixture was then filtered and evaporated to obtain the title compound (6.95 g; 99.1%).
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1.[C:12]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>[Cu]Br>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([C:4]1[CH:9]=[N:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)[C:12]([O:20][CH2:21][CH3:22])=[O:19])[CH3:18]
Reactant: COc1ccc(Br)cn1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C(=O)OCC)c1ccc(OC)nc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 36.2 mmoL, 1.45 g) was added into a solution of 5-bromo-2-methoxy-pyridine (16.5 mmoL, 2.13 mL), copper(I) bromide (32.9 mmoL, 4.72 g) and diethyl malonate (32.9 mmoL, 5.0 mL) in 1,4-dioxlane (20 mL) slowly at room temperature. After the addition, the resulting mixture was heated to 100° C. and stirred overnight. The mixture was then passed through a pad of Celite to remove brown solid. The filtrate was then concentrated in vacuo to afford a brown oil, which was then purified by column chromatography using hexanes:ethyl acetate (4:1˜2:1 ratio) as eluent to afford the title compound as a slight yellow oil.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:34])[NH:18][C:19]2[CH:24]=[C:23]([C:25]3[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=3[F:33])[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[F:33][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:25]=1[C:23]1[N:22]=[CH:21][N:20]=[C:19]([NH:18][C:17]([CH:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[O:34])[CH:24]=1
Reactant: COc1cccc(F)c1-c1cc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)ncn1
Agent: [Pd]
Solvent: CO
Product: COc1cccc(F)c1-c1cc(NC(=O)C2CCNCC2)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
4-[6-(2-Fluoro-6-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XXIII) (0.05 g, 0.1 mmol) was dissolved in methanol (5 ml) and 10% Pd/C (0.03 g) was added under an atmosphere of nitrogen. The mixture was stirred at room temperature under hydrogen balloon pressure for 18 hours. The catalyst was removed from the reaction mixture by filtration through a celite bed and the filtrate was evaporated to dryness. The resulting crude product was triturated with dry diethyl ether (2 ml) and concentrated to yield piperidine-4-carboxylic acid [6-(2-fluoro-6-methoxy-phenyl)-pyrimidin-4-yl]-amide (compound #12A) (0.029 g, 81%) as a white solid.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[NH:14][N:13]=1.CN(C)CC(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.C(OCC)(=O)C.[Cu-]=O>[F:22][C:11]([F:10])([F:21])[C:12]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[N:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[N:13]=1
Reactant: N#Cc1ccc(I)cc1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Agent: O=[Cu-]
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 130 °C
Yield: 59.2 %

Procedure:
A mixture of 4-iodobenzonitrile (2.41 g, 10.5 mmol), 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (2.0 g, 10.5 mmol), copper (I) oxide (20 mol %, 2.1 mmol, 300 mg), N,N-dimethylglycine (10.5 mmol, 1.082 g), and cesium carbonate (21 mmol, 6.84 g) in dimethylsulfoxide (5 ml) was heated in an oil bath at 130° C. under argon for 4 h. The reaction mixture was diluted with ethyl acetate. Solid filtered off through kieselguhr. The filtrate was partitioned between ethyl acetate and water. The organic layer was separated and dried over sodium sulphate. The solvent was removed by rotary evaporation and triturated with diethyl ether to give the title compound as a light brown solid (1.812 g, 59.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([CH2:7][C:8]([NH2:10])=[O:9])=[O:6].C(O[CH:17](OCC)[CH2:18][C:19](=O)[CH2:20][CH3:21])C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([C:7]1[C:8](=[O:9])[NH:10][C:19]([CH2:20][CH3:21])=[CH:18][CH:17]=1)=[O:6]
Reactant: CCOC(CC(=O)CC)OCC
Reactant: NC(=O)CC(=O)c1cccc(Cl)c1
Solvent: CCO
Product: CCc1ccc(C(=O)c2cccc(Cl)c2)c(=O)[nH]1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
α-(3-Chlorobenzoyl)acetamide (19.76 g, 0.1 mol) was dissolved in 250 ml of ethanol, and the solution was mixed with 19.15 g (0.11 mol) of 1,1-diethoxy-3-pentanone and heated under reflux for 40 hours. After cooling to room temperature, the reaction solution was poured into ice water and extracted with chloroform. The organic layer was washed with 1 N hydrochloric acid, brine and dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and then the resulting filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was mixed with diethyl ether and the thus formed crystals were collected by filtration and washed with diethyl ether to give 18.50 g of 3-(3-chlorobenzoyl)-6-ethyl-2-pyridone in the form of crystals. The yield was 71%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[CH:4][C:3]=1[NH:13][C:14](=[O:38])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[CH:17][CH:16]=1.[C:39](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:39])[N:9]=2)=[CH:4][C:3]=1[NH:13][C:14](=[O:38])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[N:31]=[C:30]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2nnn[nH]2)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nnn(C)n2)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a stirred solution of N-[2-methyl-5-(1H-tetrazol-5-yl)phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide (100 mg, 0.20 mmol) in dimethylformamide (2 mL) was added potassium carbonate (83 mg, 0.60 mmol) and methyl iodide (100 μL, 1.6 mmol) and the mixture was allowed to stir at rt overnight. The mixture was purified by preparative reverse phase HPLC to give N-[2-methyl-5-(2-methyl-2H-tetrazol-5-yl)phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide (51 mg, 50%). 1H NMR (400 MHz, DMSO-d6): δ10.34 (s, 1H), 9.84 (s, 1H), 8.20 (d, 2H), 8.16 (d, 1H), 8.02 (d, 2H), 7.91-7.78 (m, 5H), 7.66-7.64 (m, 3H), 7.47 (d, 1H), 7.42 (ddd, 1H), 4.43 (s, 3H), 2.35 (s, 3H). MS (EI) for C30H24N8O: 513.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][N:10]([CH3:15])[C:11](=O)[O:12]C>CN(C)CCCCCCCCCCCCCCCC>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]([N:10]([CH3:15])[CH3:9])=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)N(C)C
Reactant: Nc1ccc(Cl)cc1
Agent: CCCCCCCCCCCCCCCCN(C)C
Product: CN(C)C(=O)Nc1ccc(Cl)cc1

Procedure:
A mixture of 12.8 g (0.1 mole) of 4-chloroaniline, 10.3 g (0.1 mole) of methyl N,N-dimethyl-carbamate, 20 ml of dimethyl-hexadecylamine and 100 ml of high boiling petroleum fractions (bp.: 160°-180° C.) is reacted as described in Example 12. When the reaction has proceeded to about 90%, as indicated by the chromatogram, the reaction is terminated. A solution of N-(4-chlorophenyl)-N',N'-dimethyl-urea (monuron) is obtained, which can be applied directly in the preparation of herbicidal compositions, such as spray liquids or impregnated granules.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][CH:10]1[CH2:11][CH2:12][CH:13]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.C(#N)C>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1CCC2CN1C(=O)N2OCc1ccccc1
Solvent: CO
Solvent: CC#N
Product: CC(C)(C)OC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Yield: 46 %

Procedure:
30.3 g of (2R/S,5S/R)-tert-butyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate was applied to chiral column chromatography (CHRAL PAK 1A, methanol/acetonitrile=95/5), and the active fraction corresponding to the first peak was collected to afford 13.9 g of the title compound as a colorless solid (yield 46%). Enantiomeric excess: 99.9% ee or more (CHIRALPAK AD-H, 4.6×150 mm, hexane/ethanol=2/1, UV 210 nm, flow rate 1 mL/min., retention time 4.2 min.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15](=[O:17])[CH3:16])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>C1COCC1.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]([OH:17])[CH3:16])=[N:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(C(C)=O)nc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(-c2ccc(C(C)O)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a stirred solution of 1-(5-(4-methoxyphenyl)pyridin-2-yl)ethanone (1.5 g, 6.6 mmol) in THF (8 mL) and methanol (8 mL) was added NaBH4 (0.4 g, 13.2 mmol) at 0° C. and the reaction was stirred at rt for about 1 h. The reaction mixture was diluted with water (100 mL), extracted with ethylacetate (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), organic layer was dried over Na2SO4 and concentrated under vacuum to obtain 1-(5-(4-methoxyphenyl)-pyridin-2-yl)ethanol as an off-white solid (1.0 g, 66% yield). 1H NMR (400 MHz, DMSO-d6): 8.72 (d, 1H), 7.84 (dd, 1H), 7.51 (d, 2H), 7.32 (d, 1H), 7.01 (d, 2H), 4.93 (s, 1H), 4.11 (d, 1H), 3.86 (s, 3H), 1.54 (d, 3H), LC-MS m/z calcd for [M+H]+ 230.1. found 230.3.
Reaction SMILES: [F:1][C:2]1[C:7]([B:8](C2C(F)=C(F)C(F)=C(F)C=2F)[C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=2[F:19])=[C:6]([F:31])[C:5]([F:32])=[C:4]([F:33])[C:3]=1[F:34].[OH2:35]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([B:8]([C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=2[F:19])[OH:35])=[C:6]([F:31])[C:5]([F:32])=[C:4]([F:33])[C:3]=1[F:34]
Reactant: O
Reactant: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: Cc1ccccc1
Product: OB(c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F
Temperature: 100 °C
Reaction time: 2 h

Procedure:
20 g (39 mmol) of tris(pentafluorophenyl)borane together with 150 ml of toluene are placed in a reaction vessel and the mixture is subsequently heated 100° C. 1.8 ml (97.5 mmol) of water in 40 ml of toluene are subsequently added dropwise to this solution over a period of 30 minutes. The mixture is subsequently stirred for another two hours at 100° C. After this time, the solvent is taken off in an oil pump vacuum. The residue does not have to be purified further. This gives 12.6 g (89%) of colorless bis(pentafluorophenyl)hydroxyborane. The boroxin content is 5%. 1H-NMR(C6D6, 400 MHz): −133.1 (m, 4 F, o-B(C6F5)2), −147.9 (m, 2 F, p-B(C6F5)2), −161.1 (m, 4 F, m-B(C6F5)2) ppm.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](OCC(F)(F)F)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:44])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH:41]([CH3:43])[CH3:42])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.[C:46](O)([C:48]([F:51])([F:50])[F:49])=[O:47]>C(Cl)Cl>[CH:41]([C:37]1[CH:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:44])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:22])([F:21])[F:23])[C:12]([O:47][CH2:46][C:48]([F:51])([F:50])[F:49])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[CH:40]=[CH:39][N:38]=1)([CH3:42])[CH3:43]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)c1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Product: CC(C)c1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from [2-{3-[3-(2-isopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M253) (0.33 g, 0.52 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (230 mg, 85%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[O:14][C:13]([C:15]3[CH:24]=[N:23][C:22]4[C:21]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[N:20][C:19]([C:31]5[CH:32]=[N:33][C:34]([NH:37]C(=O)OC(C)(C)C)=[N:35][CH:36]=5)=[N:18][C:17]=4[CH:16]=3)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH2:37][C:34]1[N:33]=[CH:32][C:31]([C:19]2[N:20]=[C:21]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:22]3[N:23]=[CH:24][C:15]([C:13]4[O:14][C:10]([C:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[O:9])=[CH:11][CH:12]=4)=[CH:16][C:17]=3[N:18]=2)=[CH:36][N:35]=1
Reactant: CN1CCN(C(=O)c2ccc(-c3cnc4c(N5CCOCC5)nc(-c5cnc(NC(=O)OC(C)(C)C)nc5)nc4c3)o2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(N5CCOCC5)nc(-c5cnc(N)nc5)nc4c3)o2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.9 %

Procedure:
To a 25 mL flask, tert-butyl (5-(7-(5-(4-methylpiperazine-1-carbonyl)furan-2-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-yl)carbamate (0.06 g, 0.0001 mol) and DCM (10 mL) were added. To the reaction mixture, trifluoroacetic acid (0.076 mL, 0.001 mol) was added. The reaction mixture was stirred at room temperature for 3 hours. The volatiles were evaporated under reduced pressure to provide a residue. The residue was basified to pH 8.0 with saturated sodium bicarbonate solution and extracted with DCM. The organic layer was washed with water and brine, dried over sodium sulfate and evaporated to provide the crude product. The crude product was purified by preparative TLC (5% methanol in chloroform) to provide the title compound (0.01 g, 20%). 1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 2H), 9.02 (d, J=2.4; H, 1H), 8.35 (d, J=2.0 Hz, 1H), 7.23 (d, J=3.6 Hz, 1H), 7.08 (d, J=3.6 Hz, 1H), 5.40 (br s, 2H), 4.63 (br s, 4H), 3.99 (t, J=4.8 Hz, 8H), 2.61 (t, J=4.4 Hz, 4H), 2.43 (s, 3H): LC-MS (ESI): Calculated mass: 501.2; Observed mass [M+H]+: 502.0 (RT=0.08 min).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:11]=2[CH:12]=[O:13])=[CH:7][CH:6]=1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22].N1C=CN=C1>CN(C)C=O>[C:21]([Si:25]([CH3:28])([CH3:27])[O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:11]=2[CH:12]=[O:13])=[CH:19][CH:20]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=Cc1cc(I)ccc1Oc1ccc(OCCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Oc2ccc(I)cc2C=O)cc1
Yield: 96.2 %

Procedure:
In a manner similar to the method described in Example 60b, 2-[4-(2-hydroxy-ethoxy)-phenoxy]-5-iodo-benzaldehyde (3.8 g, 9.8 mmol) was reacted with tert-butyldimethylchlorosilane (1.8 g, 12 mmol) and imidazole in N,N-dimethylformamide to give 2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenoxy}-5-iodo-benzaldehyde as a white solid (Yield 4.7 g, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][C:6]([C:13]([O:15]CC)=[O:14])=[C:5]2[OH:18].[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][C:6]([C:13]([OH:15])=[O:14])=[C:5]2[OH:18]
Reactant: CCOC(=O)c1cnc2c(C)cc(Br)cc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Br)cc2c(O)c(C(=O)O)cnc12
Yield: 100.1 %

Procedure:
A mixture of ethyl 6-bromo-4-hydroxy-8-methyl-3-quinolinecarboxylate (1.89 g, 6.09 mmol) and 6 N NaOH (1.22 g, 30.45 mmol, 5.1 mL) in ethanol (30 mL) was heated at reflux for 2.0 h and concentrated in vacuo. The residue was diluted with water and acidified with 6 N HCl to pH 4. The resulting solid was filtered, washed with water and diethyl ether, and dried overnight in a Buchner funnel to give the title compound (1.72 g, 99%) as a tan solid. MS(ES)+ m/e 282 [M+H].