Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12(CO)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[I:13][C:14]1[CH:15]=[N:16][NH:17][CH:18]=1.[CH3:19]C1C(B2OC(C)(C)C(C)(C)O2)=C(C)NN=1>>[CH:1]12[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH:8]1[CH2:19][N:16]1[CH:15]=[C:14]([I:13])[CH:18]=[N:17]1)[CH2:10]2
Reactant: Ic1cn[nH]c1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: OCC12CC3CC(CC(C3)C1)C2
Product: Ic1cnn(CC2C3CC4CC(C3)CC2C4)c1

Procedure:
The title compound was prepared by substituting EXAMPLE 10A for 1-adamantanemethanol and 4-iodopyrazole for 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 2A.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.[CH3:19][CH:20]([NH2:22])[CH3:21]>O1CCCC1>[CH:20]([NH:22][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])([CH3:21])[CH3:19]
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc([N+](=O)[O-])c(NC(C)C)c1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
A mixture of 2-fluoro-4-methyl-1-nitrobenzene (250 mg, 1.6 mmol), triethylamine (200 mg, 2.0 mmol), and 2-propanamine (200 mg, 3.4 mmol) in tetrahydrofuran (1 mL) was heated at 25° C. for 5 hours. The crude product was purified by preparative thin-layer chromatography [eluent: hexane/EtOAc (1:2)], giving the desired product (150 mg, 48%).
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].[C:6]1([CH:13]=[CH:12][CH:11]=[C:9]([OH:10])[CH:8]=1)O.[CH:14](OC)(OC)[O:15]C.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>>[OH:4][C:3]1[CH:5]=[CH:6][C:13]2[CH2:12][CH2:11][C:9]([O:15][CH3:14])([CH3:8])[O:10][C:2]=2[CH:1]=1
Reactant: COC(OC)OC
Reactant: Oc1cccc(O)c1
Reactant: C=CC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC1(C)CCc2ccc(O)cc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
Methyl vinyl ketone (7.7 g) was added dropwise under ice cooling to a solution composed of 11 g of resorcinol, 11.7 g of trimethyl orthoformate and 0.1 ml of conc. sulfuric acid. After the addition, the mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, and then extracted with ethyl acetate. The residue left after evaporation of the solvent as purified by column chromatography to give 12.5 g (yield 70%) of the desired product as colorless crystals (melting point 107°-108° C.).
Reaction SMILES: C(O[N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])(=O)C(C)=C.[C:12]([O:17][CH3:18])(=[O:16])[C:13]([CH3:15])=[CH2:14].Cl.Cl.N(C(C(=N)N)(C)C)=N[C:23](C(=N)N)(C)C>O>[C:12]([O:17][CH2:18][CH2:23][N:7]([CH2:8][CH3:9])[CH2:10][CH3:11])(=[O:16])[C:13]([CH3:15])=[CH2:14].[C:12]([O:17][CH3:18])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C=C(C)C(=O)ON(CC)CC
Reactant: CC(C)(N=NC(C)(C)C(=N)N)C(=N)N
Agent: C=C(C)C(=O)OC
Agent: Cl
Solvent: O
Product: C=C(C)C(=O)OCCN(CC)CC
Temperature: 60 °C

Procedure:
In a flask equipped with a stirring blade and a tube for nitrogen introduction were charged 1,500 parts of ion-exchanged water and heated to 60° C. Twenty parts of diethylamino methacrylate and 60 parts of methyl methacrylate were added thereto while stirring. To the mixture were further added 20 parts 2,2'-azobis(2-amidinopropane) dihydrochloride ("V-50" produced by Wako Pure Chemical Ind. Ltd.) and 10 parts of 2,2'-azobis(2-methyl-N-(1,1'-bis(hydroxymethyl)-2-hydroxyethyl)propionamide) ("V-080" produced by Wako Pure Chemical Ind. Ltd.), followed by heating to 65° C., at which the mixture was subjected to soap-free polymerization for 24 hours. After completion of the reaction, the fine particles thus produced were washed with 5,000 parts of ion-exchanged water by means of a centrifugal separator to obtain fine particles of a diethylaminoethyl methacrylate/methyl methacrylate copolymer having an amidino hydrochloride group and a hydroxyl group on the surface thereof and having an average particle size of 0.5 μm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:15][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1ccc(F)c(F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1ccc(F)c(F)c1
Reaction time: 8 h

Procedure:
A mixture of ethyl 2-(3,4-difluorophenyl)acetate (1.20 g, 5.99 mmol), N-bromosuccinimide (1.17 g, 6.59 mmol), and 2,2′-azobis(isobutyronitrile) (0.148 g, 0.899 mmol) in CCl4 (20 mL) was gradually heated to reflux and stirred at this temperature overnight. The solvent was removed in vacuum. The residue was purified by flash column chromatography (100% hexanes for 5 minutes, then 0 to 5% of EtOAc in hexanes over 23 minutes). The desired product was obtained as a colorless oil (1.14 g, 68%). 1H NMR (300 MHz, CDCl3) δ 1.31 (d, J=6.0 Hz, 3H), 4.17-4.35 (m, 2H), 5.27 (s, 1H), 7.11-7.20 (m, 1H), 7.24-7.30 (m, 1H), 7.42-7.52 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:11]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:40][C:41]1([CH3:48])[O:45][CH:44]([CH2:46]O)[CH2:43][O:42]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][CH2:46][CH:44]2[CH2:43][O:42][C:41]([CH3:48])([CH3:40])[O:45]2)[CH:13]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:11]=1)#[N:2]
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2C#N)c1
Reactant: CC1(C)OCC(CO)O1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(OCC2COC(C)(C)O2)cc(-c2ccc(C)cc2C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 2′-cyano-5-hydroxy-4′-methylbiphenyl-3-carboxylate (150 mg, 0.56 mmol), triphenylphosphine (220 mg, 0.84 mmol), 2,2-dimethyl-1,3-dioxolane-4-methanol (82 mg, 0.62 mmol) in CH2Cl2 (5 mL) at room temperature was slowly added a solution of diisopropyl azodicarboxylate (340 mg, 1.7 mmol) in CH2Cl2 (3 mL). The reaction mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[OH:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:11]1([CH3:23])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[S:19](Cl)(=[O:21])=[O:20].CCOCC>C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[O:9][S:19]([C:12]1[C:13]([CH3:18])=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=1[CH3:23])(=[O:21])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CN(O)C(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)ON(C)C(=O)OC(C)(C)C)c(C)c1

Procedure:
A solution of 16 g. of N-t-butoxycarbonyl-N-methyl hydroxylamine and 23.8 g. of mesitylenesulfonyl chloride in 400 ml. of ether was cooled to 0° C. and treated with 15.4 ml. of triethylamine dropwise with stirring. Thirty minutes after the addition was complete, the mixture was filtered, and the filter cake was washed with 2 portions of ether. The filtrate and washings were evaporated to a heavy oil. The oil was dissolved in 40 ml. of benzene, filtered through diatomaceous earth and concentrated to dryness to give a crystalline residue of N-t-butoxycarbonyl-N-methyl mesitylenesulfonylhydroxylamine, which was used directly in the next step without characterization.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C([C:11]1[C:12]([OH:21])=[C:13]([C:17]([CH3:20])=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])C.C(N[CH:26]([CH3:28])C)(C)C>C(Cl)Cl>[Br:1][C:11]1[C:12]([OH:21])=[C:13]([C:17]([CH3:20])=[CH:18][CH:19]=1)[C:14]([O:16][CH2:26][CH3:28])=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)NC(C)C
Reactant: CCc1ccc(C)c(C(=O)O)c1O
Solvent: ClCCl
Product: CCOC(=O)c1c(C)ccc(Br)c1O
Temperature: 5 °C
Reaction time: 8 h

Procedure:
A solution of N-bromosuccinimide (3.97 g) in DCM (170 ml) was added dropwise to a stirred, cooled solution of ethyl 2-hydroxy-6-methylbenzoic acid (prepared according to Hauser et al, Synthesis, 1980 814, 4.02 g) and di-isopropylamine (0.31 ml) in DCM (50 ml) while maintaining the temperature at 0° C. (±5° C.). On completion of the addition, the cooling bath was removed and the mixture was stirred at room temperature overnight. The mixture was concentrated and ether was added. The resultant solid was removed by filtration and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ether and pentane with a gradient of 0-50% to give ethyl 3-bromo-2-hydroxy-6-methylbenzoate (5.19 g) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][N:35]2[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]2)=[CH:4][N:3]=1.C(O)C.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O.[H][H]>[OH-].[OH-].[Pd+2].C(O)(=O)C>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([CH2:32][CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][CH:38]([OH:41])[CH2:39][CH2:40]2)=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: COc1cc(-c2csc3c(/C=C/CN4CCC(O)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: [Pd+2]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(-c2csc3c(CCCN4CCC(O)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Yield: 26.7 %

Procedure:
N-(4-{4-Amino-7-[(1E)-3-(4-hydroxypiperidin-1-yl)prop-1-enyl]thieno [3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (130 mg, 0.23 mmol), ethanol (25 mL), and acetic acid (0.65 mL) were combined in a hydrogenation vessel, purged, and palladium hydroxide on carbon (45 mg, 50% weight dispersion in oil, 0. 16 mmol) was added. 50 Psi of hydrogen was applied for 16 hours. The mixture was filtered and purified by RP-HPLC to yield the title compound (35 mg, 25% yield) after lyophilization: 1H NMR (DMSO, 400 MHz) δ 9.50 (s, 1H), 7.98 (d, 1H), 7.70-7.72 (m, 2H), 5.59 (d, 1H), 7.54 (s, 1H), 7.07-7.35 (m, 3H), 5.34 (bs, 2H), 4.58 (bs, 1H), 4.04 (s, 3H), 3.91 (s, 3H), 2.71 (t, 2H), 2.28 (t, 2H), 1.97 (t, 2H), 1.90 (s, 3H), 1.82 (t, 2H), 1.70 (m, 1H), 1.40 (q, 2H); RP-HPLC (Conditions i) Rt 10.0 min. MS: 568.3 MH−.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][N:12]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:21])[C:15]=2[CH:14]=[N:13]1.N1C=CC=CC=1>C(Cl)(Cl)Cl.C1COCC1>[CH3:11][N:12]1[C:20]2[C:15](=[C:16]([NH:21][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:17]=[CH:18][CH:19]=2)[CH:14]=[N:13]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cn1ncc2c(N)cccc21
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cn1ncc2c(NC(=O)Oc3ccccc3)cccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of phenyl chloroformate (1.1 mmol) in chloroform was cooled to 0° C. 1-methyl-1H-indazole-4-amine in dry THF was added to the reaction mixture dropwise at 0° C. Pyridine (1 mmol) was added to the reaction mixture. Reaction mixture was stirred at 0° C. for 30 minutes and was then stirred at room temperature for 15 hours.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](=O)[CH2:8][CH3:9])[S:5][CH:6]=1.[Br-].[C:12]([CH2:15]CC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:14])=[O:13].[CH3:37][C:38](C)([O-])C.[K+]>>[Br:1][C:2]1[CH:3]=[C:4](/[C:7](/[CH2:37][CH3:38])=[CH:8]/[CH2:9][CH2:15][C:12]([OH:14])=[O:13])[S:5][CH:6]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(=O)c1cc(Br)cs1
Agent: [Br-]
Agent: [K+]
Product: CC/C(=C\CCC(=O)O)c1cc(Br)cs1

Procedure:
In a manner similar to that of Example 6(i), by reaction of 16 g (73 mmol) of 1-(4-bromo-2-thienyl)-1-propanone with 47 g (109 mmol) of (3-carboxypropyl)triphenylphosphonium bromide and 24.6 g (219 mmol) of potassium tert-butoxide, the desired product is obtained in the form of an orange-coloured solid (m=16.7 g; Y=80%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH:8]([CH3:14])[N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[O:31][CH3:32].C(O)C>Cl.O>[CH:15]1([N:7]2[CH:8]([CH3:14])[CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC1CC(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)C(C)CC(=O)N2C
Yield: 72.9 %

Procedure:
A mixture of 0.059 g (0.0002 mole) of (rac)-2-chloro-9-cyclopentyl-5,8-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-3), 0.033 g (0.0002 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated to 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.062 g of (rac)-4-(9-cyclopentyl-5,8-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid (I-3) as an off-white solid.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])([O:3][CH2:4][CH3:5])=[O:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[C:18]([O:17][C:13]1[CH2:14][CH2:15][CH2:16][C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:20])[CH3:19]
Reactant: CCOC(=O)CCCCCCC1CCCC1=O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCCCCCC1=C(OC(C)=O)CCC1
Reaction time: 16 h

Procedure:
A stirred solution of 100 g. of 2-(6-carbethoxyhexyl)cyclopentan-1-one (Example 9) in 250 ml. of acetic anhydride containing 0.940 g. of p-toluenesulfonic acid monohydrate is heated to boiling under partial reflux allowing distillate at 118°C. or less (i.e., acetic acid) to escape through a Vigreaux column equipped with a condenser to collect the distallate. After 16 hours, during which period acetic anhydride is added in portions in order to keep the solvent level at at least 100 ml., the solution is cooled and poured cautiously into a stirred cold mixture of saturated sodium bicarbonate solution (400 ml.) and hexane (250 ml.). The resulting mixture is stirred for an additional 30 minutes during which period solid sodium bicarbonate is added periodically to insure a basic solution. The hexane layer is separated and washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation of the residual oil gives 102 g. (87%) of pale yellow oil, b.p. 118°C. (0.07 mm).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[C:10](=[O:24])[NH:11][C:12](=[O:23])[N:13]([CH:22]=1)[C@@H:14]1[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]1)=[O:4].[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].N1C=CN=C1>CN(C=O)C>[Si:27]([O:20][CH2:19][C@H:18]1[O:21][C@@H:14]([N:13]2[CH:22]=[C:9]([C:8]#[C:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:25])([F:1])[F:26])[C:10](=[O:24])[NH:11][C:12]2=[O:23])[CH2:15][C@@H:16]1[OH:17])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: O=C(NCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1) (656 mg, 1.74 mmol) in dry DMF (15 ml) was added t-butyldimethylsilylchloride (288 mg, 1.91 mmol) in small portions, followed by imidazole (130 mg, 1.91 mmol). The reaction was followed by TLC and was completed after stirring for 8 h at room temperature. The reaction was quenched with sat. aq. NaCl solution. EtOAc (25 ml) was added to the reaction mixture and the aqueous layer was extracted with EtOAc three times. After drying the combined organics (MgSO4), the solvent was removed under vacuum. Purification by chromatography on silica (EtOAc:petroleum ether 8:2) gave (2) as slightly yellow crystals (676 mg, 83%). 1H NMR (d6 DMSO) δ 0.00 (s, 6H, CH3), 0.79 (s, 9H, tBu), 1.93-2.00 (m, 1H, H-2′), 2.06-2.11 (m, 1H, H-2′), 3.63-3.75 (m, 2H, H-5′), 3.79-3.80 (m, 1H, H-4′), 4.12-4.14 (m, 3H, H-3′, CHO, 5.22 (d, J=4.1 Hz, 1H, OH), 6.03 (t, J=6.9 Hz, 1H, H-1′), 7.86 (s, 1H, H-6), 9.95 (t, J=5.4 Hz, 1H, NH), 11.61 (br s, 1H, NH). Mass (−ve electrospray) calcd for C20H28F3N3O6Si 491.17. Found 490.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2)#[N:2].[CH2:14]=[O:15].C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)O>C(Cl)(Cl)Cl.O.C(O)(=O)C>[CH:14]([C:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[OH:13])=[O:15]
Reactant: C=O
Reactant: N#Cc1ccc2cc(O)ccc2c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#Cc1ccc2c(C=O)c(O)ccc2c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
65 milliliters of acetic acid was added to 20 g of 6-cyano-2-naphthol, 3.6 g of paraformaldehyde and 16.6 g of hexamethylenetetramine, followed by stirring at 80° C. for 4 hours. Furthermore, to the reaction mixture was added a solution comprising 53 ml of acetic acid, 10.5 ml of water and 17.8 g of concentrated sulfuric acid at 60° C., followed by stirring at 80° C. for 4 hours. After cooling, 95 ml of water was added to the resulting solution, followed by stirring, and the precipitate was collected by filtration and washed with 40 ml of warm water. To the collected precipitate was added 350 ml of chloroform, followed by refluxing for 1 hour. Thereafter, the precipitate was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. This product was subjected to silica gel column chromatography using chloroform as an eluent, and the desired fractions were collected, and the solvent was distilled off under reduced pressure. To the residue was added 100 ml of n-hexane and the mixture was stirred for a while, and the precipitate was collected by filtration to obtain 11.2 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28](OCC)=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:34]([CH2:36][NH2:37])[OH:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28]([NH:37][CH2:36][CH2:34][OH:35])=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O
Reactant: NCCO
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.27 (1H, t, J=5 Hz), 8.51 (1H, s), 7.75 (1H, s), 7.31 (2H, dd, J=9, 6 Hz), 7.12 (2H, t, J=9 Hz), 5.03 (2H, s), 4.90 (1H, br), 4.12 (2H, s), 3.58 (2H, t, J=6 Hz), 3.54 (2H, m), 3.42 (2H, t, J=7 Hz), 3.40 (2H, t, J=7 Hz), 1.96 (2H, m, J=7 Hz), 1.80 (2H, m, J=7 Hz); HRMS calcd for C24H25FN4O5+H+: 469.1887. Found: 469.1896.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@@H:5]([C:13]([NH:15][CH2:16][C:17](=[O:20])[CH2:18][CH3:19])=O)[O:4]1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:11])([CH3:12])[O:10][C@@H:6]2[C@@H:5]([C:13]2[O:20][C:17]([CH2:18][CH3:19])=[CH:16][N:15]=2)[O:4]1
Reactant: CCC(=O)CNC(=O)[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@H]21
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1cnc([C@H]2O[C@@H](OC)[C@@H]3OC(C)(C)O[C@@H]32)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 119.7 %

Procedure:
To a solution of (3aR,4S,6R,6aR)-6-methoxy-2,2-dimethyl-N-(2-oxobutyl)tetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide (740 mg) in dry toluene (10 ml), under nitrogen was added phosphorous oxychloride (1.44 ml) and the mixture was heated under reflux for 3.5 h. The reaction mixture was cooled to 0° C., quenched with saturated aqueous sodium bicarbonate (30 mls), stirred vigorously for 30 min and extracted with ethyl acetate (4×50 ml); the organic layers were combined, washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo to give a crude product, which was purified by flash column chromatography on silica gel, eluting with a mixture of 5:1 to 7:2 cyclohexane:ethyl acetate, to give the title compound as a yellow oil (0.83 g).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([C:24](=[O:26])[CH3:25])[CH:21]=[CH:22][CH:23]=3)=[CH:14][C:12]=2[CH:13]=1.[BH4-].[Na+]>C(O)C.O1CCCC1>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([CH:24]([OH:26])[CH3:25])[CH:21]=[CH:22][CH:23]=3)=[CH:14][C:12]=2[CH:13]=1
Reactant: CC(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Temperature: 60 °C
Yield: 11 %

Procedure:
The product from Example 136C (46 mg, 0.12 mmol) in ethanol (2 mL) and tetrahydrofuran (0.5 mL) was treated with sodium borohydride. The mixture was concentrated and passed through a short column of silica with a gradient of 2 to 10% MeOH/CH2Cl2. The resulting residue rinsed with ether, dissolved into methanol (1 mL), treated with 0.1 M aqueous hydrochloric acid (0.2 mL) heated at 60° C. for three hours, treated with more 0.1 M aqueous hydrochloric acid (0.05 mL), heated at 60° C. for one hour, concentrated, and chromatographed through a short column of silica with a gradient of 2 to 10% 2 M NH3 in MeOH/CH2Cl2 to provide the title compound as a white powder (11% yield). 1HNMR (300 MHz, CD3OD) δ 1.17 (d, 3H), 1.4-1.54 (m, 1H), 1.49 (d, 3H), 1.73-1.86 (m, 2H), 1.95-2.08 (m, 1H), 2.24-2.36 (m, 1H), 2.43-2.60 (m, 2H), 2.93-3.14 (m, 2H), 3.19-3.33 (m, 2H), 4.89 (q, 1H), 6.59 (s, 1H), 7.32 (ddd, 1H), 7.39 (dd, 1H), 7.45-7.47 (m, 2H), 7.49 (ddd, 1H), 7.62 (m, 1H), 7.71 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C(O[CH2:14][C:15](=O)[CH2:16][C:17]([O:19][CH2:20]C)=[O:18])(=O)C.[NH2:23]/[C:24](/[CH3:30])=[CH:25]\[C:26]([O:28]C)=[O:27].Cl>C(O)(C)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:14])[NH:23][C:24]3[CH2:30][O:28][C:26](=[O:27])[C:25]2=3)=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)COC(C)=O
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccc(Cl)cc1

Procedure:
3 g (21.3 mmol) of 4-chlorobenzaldehyde, 4.0 g (21.3 mmol) of ethyl 4-acetoxyacetoacetate and 2.5 g (21.3 mmol) of methyl 3-aminocrotonate are dissolved in 40 ml of isopropanol and heated to reflux for 12 h. The mixture is then treated with 10 ml of dilute aqueous HCl and heated to reflux for a further 30 min. The mixture is partitioned between toluene and water. Drying (MgSO4) and concentration of the organic phase yields a white solid which is purified by filtration through 50 g of silica gel (ethyl acetate/petroleum ether 1+1) and subsequent recrystallization from ethyl acetate/petroleum ether. 2.6 g (8.13 mmol, 38%) are obtained.