Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:8][CH:7]=[CH:6][CH:5]=1.[N+:9]([C:12]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:35])=[CH:20][C:13]=1[O:14][CH:15]([CH3:19])[C:16](Cl)=[O:17])([O-:11])=[O:10]>C(Cl)Cl>[CH3:1][N:2]([CH2:3][C:4]1[O:8][CH:7]=[CH:6][CH:5]=1)[C:16](=[O:17])[CH:15]([O:14][C:13]1[CH:20]=[C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:35])[CH:22]=[CH:23][C:12]=1[N+:9]([O-:11])=[O:10])[CH3:19]
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Reactant: CNCc1ccco1
Solvent: ClCCl
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)N(C)Cc1ccco1
Temperature: -15 °C

Procedure:
N-Methyl-N-furfurylamine (0.015 mole) triethylamine (5 ml) and methylene chloride (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to about -15° C. and a solution of 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionyl chloride (0.01 mole) in methylene chloride (50 ml) is added dropwise with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature with continued stirring. After this time the mixture is transferred to a separatory funnel and is washed with water and dilute aqueous sodium bicarbonate. The washed solution is then dried, filtered and stripped of solvent leaving a residue. This residue is then purified by subjecting it to elution chromatography using mixtures of ethyl acetate and hexane with increasing concentrations of ethyl acetate as the eluant. The desired fractions determined by IR spectroscopy are then stripped of solvent to yield the desired product N-methyl-N-furfuryl-2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionamide.
Reaction SMILES: [CH3:1][C@@H:2]([C:5]([N:7]1[C@H:11]([C:12]([OH:14])=[O:13])[CH2:10][CH2:9][CH2:8]1)=[O:6])[CH2:3][SH:4].[N:15]([O-])=[O:16].[Na+].[OH-].[Na+]>Cl>[CH3:1][C@@H:2]([C:5]([N:7]1[C@H:11]([C:12]([OH:14])=[O:13])[CH2:10][CH2:9][CH2:8]1)=[O:6])[CH2:3][S:4][N:15]=[O:16]
Reactant: O=N[O-]
Reactant: C[C@H](CS)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](CSN=O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
50 mg of Captopril (0.236 mMoles) was dissolved in 10 ml of 0.1 M HCl at room temperature and cooled briefly in an ice bath. A total of 0.25 ml of 1 M NaNO2 was then added in several small portions with rapid swirling. After 2 min on ice, 1.0 ml of 0.5 M Na2HPO4 was added and the solution was adjusted to pH 7.3 with 0.1 M NaOH. The solution displayed absorption maxima at 542 nm (E=19.8 M-1 cm-1) and 330 nm (E=995 M-1 cm-1).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10](=[O:16])[C:11]([O:13]CC)=[O:12])[CH:7]=[CH:8][CH:9]=1>C1COCC1.CO>[Cl:3][C:4]1[CH:5]=[C:6]([C:10](=[O:16])[C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(=O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.2 %

Procedure:
An aqueous 2 mol/L NaOH solution (24 mL) was added to a solution of ethyl (3-chlorophenyl)(oxo)acetate (2.00 g) in THF/MeOH (1:1) (48 mL) in an ice bath, followed by stirring at room temperature overnight. The solvent was distilled off under reduced pressure, and an aqueous 3 mol/L HCl solution was added thereto in an ice bath. The precipitated solid was collected by filtration to yield the title compound (2.00 g, colorless solid).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([C:12](=[N:23][OH:24])[CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=1)[CH3:2].CN(C1C=CC=CN=1)C.[C:35](OC(=O)C)(=[O:37])[CH3:36].O>ClCCl.CCOCC>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([C:12](=[N:23][O:24][C:35](=[O:37])[CH3:36])[CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH:6]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1ccc(N)c(C(CCNC(=O)OC(C)(C)C)=NO)c1
Agent: CN(C)c1ccccn1
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N)c(C(CCNC(=O)OC(C)(C)C)=NOC(C)=O)c1
Yield: 79.9 %

Procedure:
To a stirred solution of ethyl-4-amino-3-[3'-(N-tert-butyloxycarbonylamino)-1'-hydroxyiminopropyl]benzoate (4.8 g, 14 mmol) and dimethylamino pyridine (1.67 g, 14 mmol) in dichloromethane (200 ml) was added acetic anhydride (1.3 ml, 14 mmol), under an atmosphere of nitrogen. After 2 hours the solution was poured into water (200 ml) and partitioned. The organic layer was separated, washed once more with water (200 ml), then the combined organic phases dried (MgSO4). The solvent was removed in vacuo, to afford an oily solid. Ether (200 ml) was added, and the mixture evaporated in vacuo once more to give a white solid. The solid was taken up in more ether (100 ml) and filtered off, to afford the title compound (4.4 g, 82%) as a white solid. m.p. 130°-135° C. NMR δ (250 MHz, CDCl3) 1.40 (12H, m), 2.27 (3H, s), 3.18 (2 H, t, J=7 Hz), 3.43 (2H, m), 4.33 (2H, q, J=7 Hz), 4.70 (1H, br s), 6.69 (1H, d, J=9 Hz), 7.82 (1H, dd, J=9 and 2 Hz), 8.17 (1H, br s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J7) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) according to the general procedure M. Obtained as a light yellow solid (271 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[CH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:18].[Cl-].[Cl:20][C:21](=[O:27])[CH2:22][N+:23]([CH3:26])([CH3:25])[CH3:24]>>[Cl-:20].[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:18])[N:11]([C:21](=[O:27])[CH2:22][N+:23]([CH3:26])([CH3:25])[CH3:24])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: C[N+](C)(C)CC(=O)Cl
Reactant: Cc1cc(C)c(C=C2C(=O)Nc3ccccc32)[nH]1
Agent: [Cl-]
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)C[N+](C)(C)C)c3ccccc32)[nH]1

Procedure:
The title compound was prepared from 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylidene)-1,3-dihydro-indol-2-one and 2-chloro-N,N,N-trimethyl-2-oxoethanaminium chloride (modification of procedure used to prepare (3Z)-1-acetyl-3-[(3,5-dimethyl-4-1H-pyrrol-2-yl)-methylidene]-1,3-dihydro-2H-indol-2-one (15)).
Reaction SMILES: CON(C)[C:4](=[O:12])[C:5]1[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH2:7].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Li]CCCC.Cl>O1CCCC1>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[NH2:7])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CON(C)C(=O)c1ccccc1N
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1ccccc1C(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
To a mixture of N-methoxy-N-methyl anthranilic acid amide prepared as in Example 1(A)(2.00 g, 11.1 mmol) and 4-benzyloxy-bromobenzene (2.92 g, 11.1 mmol) in anhydrous tetrahydrofuran (65 ml) at -78° C. under nitrogen is added, with vigorous stirring, n-BuLi in hexanes (13.8 ml, 1.6M, 22.2 mmol) at 0.60 ml/min. After 20 min, aqueous hydrochloric acid is added (1N, 20 ml), the mixture extracted with ethyl acetate (150 ml), ethyl acetate washed with water, brine, dried over magnesium sulfate, and concentrated. Recrystallization from hexanes gave 4'-benzyloxy-2-aminobenzophenone as yellow crystals; yield: 2.35 g, (70%); m.p. 99°-101° C.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:68]=[CH:69][C:70]([N:73]([CH3:75])[CH3:74])=[N:71][CH:72]=2)[C:56]=1[CH3:76].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:75][N:73]([CH3:74])[C:70]1[N:71]=[CH:72][C:67]([C:57]2[C:56]([CH3:76])=[C:55]([NH:47][C:46]3[C:41]([N:38]4[CH2:39][CH2:40][O:35][CH2:36][CH2:37]4)=[N:42][CH:43]=[C:44]([N:48]4[CH2:49][CH2:50][O:51][CH2:52][CH2:53]4)[CH:45]=3)[C:64]3[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=3[F:65])[N:58]=2)=[CH:68][CH:69]=1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccc(N(C)C)nc2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(N(C)C)nc2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.023 g, 0.048 mmol), 2,5-dimorpholinopyridin-3-amine (0.095 g, 0.36 mmol), 5-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-N,N-dimethylpyridin-2-amine (0.1 g, 0.30 mmol), Pd2dba3 (0.011 g, 0.012 mmol) and sodium tert-butoxide (0.072 g, 0.75 mmol) in toluene (3.0 mL) at 100° C. for 2 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/MeOH/ammonium hydroxide (90/9/1)) to give the desired product 2-(6-(dimethylamino)pyridin-3-yl)-N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methylquinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (1H, dd, J=2.4, 0.6 Hz), 7.85 (1H, dd, J=8.9, 2.4 Hz), 7.74 (1H, d, J=5.9 Hz), 7.57-7.63 (1H, m), 7.55 (1H, d, J=2.7 Hz), 7.34-7.45 (1H, m), 6.78 (1H, d, J=8.4 Hz), 6.40 (1H, d, J=2.5 Hz), 3.61-3.80 (8H, m), 3.16 (2H, br. s.), 3.11 (6H, s), 2.95-3.02 (4H, m), 2.13 (3H, s). Mass Spectrum (ESI) m/e=562.3 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH2:14][O:15][CH2:16][CH2:17][Se]C2C=CC=CC=2)=[C:7]([C:25](=[O:39])[N:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:6]=1)(=[O:3])[CH3:2].OO.C(=O)(O)[O-].[Na+].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:1]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH2:14][O:15][CH:16]=[CH2:17])=[C:7]([C:25](=[O:39])[N:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C(=O)N(c2ccccc2)c2ccccc2)c2ncn(COCC[Se]c3ccccc3)c2n1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C=COCn1cnc2c(C(=O)N(c3ccccc3)c3ccccc3)nc(NC(C)=O)nc21
Temperature: 60 °C

Procedure:
To a solution of 2-acetamido-6-diphenylcarbamoyl-9-[2-(phenylselenyl)ethoxymethyl]purine (4.92 g, 8.16 mmol) in dioxane (80 mL) was added 30% H2O2 (4 mL, 35 mmol) and sodium bicarbonate (2.1 g, 24.5 inmol). The mixture was heated at 60° C. for 20 min. The reaction was then concentrated to about 10 mL, diluted with ethyl acetate (100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was dissolved in dioxane (40 mL), diisopropylethylamine (1.27 g, 10 mmol) was added and the solution was heated at 80° C. for 30 min under nitrogen. The solvent was evaporated in vacuo and the residual oil was chromatographed on silica gel using CH2Cl2 -ethyl acetate (1:1) as eluent to give the title compound as a yellowish powder: yield 2.3 g (65%).
Reaction SMILES: C([C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]2[C:10]([C:11]=1[CH2:12][C:13]([NH2:15])=[O:14])=[C:9]([OH:16])[CH:8]=[CH:7][CH:6]=2)C.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C.O>[CH3:31][O:30][C:28](=[O:29])[CH2:27][O:16][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:11]([CH2:12][C:13]([NH2:15])=[O:14])=[CH:3][N:4]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CBr
Reactant: CCc1c(CC(N)=O)c2c(O)cccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cccc2c1c(CC(N)=O)cn2Cc1ccccc1
Reaction time: 1.5 h
Yield: 21.9 %

Procedure:
2-Ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide (135 mg, 0.44 mmol) was added to 17.6 mg (0.44 mmol) of NaH/mineral oil (washed with hexanes) in 5 mL of DMF, stirred 1.5 hours, 0.04 mL (0.44 mmol) of methyl 2-bromoacetate added and stirring maintained for 3 hours. The mixture was diluted with water, extracted with ethyl acetate. The ethyl acetate was washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel eluting with 2% MeOH/ethyl acetate to give 34 mg (34% yield) of 2-[[3-(2-amino-2-oxoethyl)-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][N:12](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:11]([C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8])#[N:12]
Reactant: CN(C)C=O
Reactant: O=Cc1cc(Br)ccc1F
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(F)c(C=O)c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (10 g) in dimethylformamide (60 mL) were added zinc cyanide (6.92 g) and tetrakis(triphenylphosphine)palladium(O) (2.28 g), and the mixture was stirred at 80° C. for 6 hours. The resulting mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (3:1) to give 5-cyano-2-fluorobenzaldehyde (5.3 g) as a solid substance.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:42]1[C:47]([O:48][CH3:49])=[C:46]([O:50][CH3:51])[CH:45]=[CH:44][C:43]=1[C:52]1[CH:53]=[C:54]2[C:58](=[CH:59][CH:60]=1)[C:57](=[O:61])[O:56][CH2:55]2>O1CCCC1.C(OCC)(=O)C>[CH3:49][O:48][C:47]1[C:46]([O:50][CH3:51])=[CH:45][CH:44]=[C:43]([C:52]2[CH:53]=[C:54]3[C:58](=[CH:59][CH:60]=2)[C:57](=[O:61])[O:56][CH2:55]3)[C:42]=1[O:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC
Reactant: COC(=O)C(C)(C)CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)COc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OC
Temperature: 70 °C
Yield: 28.6 %

Procedure:
To a stirring solution of methyl 3-hydroxy-2,2-dimethylpropanoate (2.76 g, 20.94 mmol, in portions) in tetrahydrofuran (25 mL) was added diethylazodicarboxylate (2.43 g, 13.96 mmol), triphenylphosphine (3.59 g, 13.96 mmol) and 5-(2-hydroxy-3,4-dimethoxyphenyl)isobenzofuran-1(3H)-one (2 g, 6.98 mmol) and the resultant reaction mixture was heated to 70° C. for 6 h. The reaction mixture was diluted with ethyl acetate layer, washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by flash, column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford Methyl 3-(2,3-dimethoxy-6-(1-oxo-1,3-dihydroisobenzofuran-5-yl)phenoxy)-2,2-dimethylpropanoate as a solid (800 mg, 28.6%)
Reaction SMILES: CO[C:3](=[O:5])O.[NH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[CH2:20][C@@H:19]([CH2:21][OH:22])[CH:18]=[CH:17]2)=C(Cl)[N:8]=1.[OH-].[Na+]>O>[NH2:6][C:7]1[NH:8][C:3](=[O:5])[C:10]2[N:11]=[CH:12][N:13]([C@H:16]3[CH2:20][C@@H:19]([CH2:21][OH:22])[CH:18]=[CH:17]3)[C:14]=2[N:15]=1
Reactant: COC(=O)O
Reactant: Nc1nc(Cl)c2ncn([C@@H]3C=C[C@H](CO)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2c(ncn2[C@@H]2C=C[C@H](CO)C2)c(=O)[nH]1
Temperature: 75 °C

Procedure:
To a 5 mL round-bottom flask equipped with a reflux condenser is added cis-2-amino-6-chloro-9-[4-(hydroxymethyl)-2-cyclopenten-1-yl]-9H-purine methylcarbonate as prepared in Example 3 (10 mg, 0.03I mmol), sodium hydroxide (2.5 mg, 0.062 mmol), and deionized water (1 mL). The resultant heterogeneous mixture is heated at 75° C. for 12 hours. The reaction mixture becomes a pale amber solution which is filtered hot through a bed of diatomaceous earth. The pH of the filtrate is adjusted to pH 7 with 1N hydrochloric acid. Acetonitrile is added and the solution is concentrated in vacuo to a solid via azeotropic removal of water. The solid is tritriated with 2 mL of methanol and the solution is filtered. The filtrate is concentrated in vacuo to give cis-2-amino-1,9-dihydro-9-[4-(hydroxymethyl)-2-cyclopenten-1-yl ]-6H-purine-6-one as a white solid which exhibits the following physical data: IR (nujol mull, cm-1) 3500- 3600 (br, m), 1725 (m), 1630 (s), 1605 (s); UV (EtOH, nm) λmax=275, 255; λmin=225; and mp 268-270° C.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=1[O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[Cl:11])[N:28]=2)=[CH:25][C:24]=1[O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCOc1cc(C#N)ccc1Cl
Reactant: CN(N=C(Cl)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCOc1cc(-c2nc(-c3ccccc3Cl)nn2C)ccc1Cl
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chlorobenzohydrazonoyl chloride (1.50 g), 4-chloro-3-octyloxybenzonitrile (1.30 g), anhydrous iron (III) chloride (0.80 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (100 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexaneethyl acetate as eluent to give 0.80 g of desired compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][N:13]=[C:14]=[O:15].[H-].[Na+].[NH2:18][C:19]([C:26]([F:29])([F:28])[F:27])=[CH:20][C:21](OCC)=[O:22]>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][N:13]1[C:21](=[O:22])[CH:20]=[C:19]([C:26]([F:29])([F:28])[F:27])[NH:18][C:14]1=[O:15]
Reactant: CCOC(=O)C=C(N)C(F)(F)F
Reactant: O=C=NCc1cc([N+](=O)[O-])cc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1Cc1cc([N+](=O)[O-])cc(Cl)c1Cl
Yield: 55.8 %

Procedure:
By the method of Example 1, Step G, 19.67 grams (0.080 mole) of 2,3-dichloro-5-nitrophenylmethyl isocyanate, 2.102 grams (0.088 mole) of sodium hydride, and 14.59 grams (0.080 mole) of ethyl 3-amino-4,4,4-trifluoro-2-butenoate were reacted in 80 mL of N,N-dimethylformamide, yielding 17.14 grams of 3-(2,3-dichloro-5-nitrophenylmethyl)-6-trifluoromethyluracil as a brown solid. The NMR spectrum was consistent with the proposed structure. This reaction was repeated.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[Cl:30][C:31]([Cl:35])([Cl:34])[CH2:32]O.C([C@@H](O)C1C=CC=C(OC2C=CC=CC=2)C=1)#N>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:9])[O:8][CH2:32][C:31]([Cl:35])([Cl:34])[Cl:30])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Reactant: OCC(Cl)(Cl)Cl
Agent: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccccc1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCC(Cl)(Cl)Cl

Procedure:
Using the procedure of Step F of Example 9, the ester of Step A after reaction with 2,2,2-trichloroethanol and (S)α-cyano-3-phenoxy-benzyl alcohol was reacted to obtain (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[(Z)3-oxo-3-(2,2,2-trichloroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+42.5°±2° (c=0.5% in benzene).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][CH2:8][CH2:9][NH:10][C:11](=O)[CH3:12])[C:3]=1[C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>C1COCC1>[S:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[C:3]1[C:4]([NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH3:12])=[N:5][NH:6][C:2]=1[NH2:1]
Reactant: CC(=O)NCCNc1n[nH]c(N)c1-c1nc2ccccc2s1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCNCCNc1n[nH]c(N)c1-c1nc2ccccc2s1

Procedure:
N-[2-(5-Amino-4-benzothiazol-2-yl-1H-pyrazol-3-ylamino)ethyl]acetamide (80 mg, 0.25 mmol) and lithium aluminum hydride (92 mg) were refluxed in anhydrous THF (10 mL) for 3 hrs. The resulting mixture was poured into a saturated ammonium chloride solution (50 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to yield 54 mg of crude product. The crude product was purified by flash column chromatography eluting with CH2Cl2:MeOH=5:1 with 0.5% NH3. The title compound was isolated in a yield of 36 mg (48%). MS (m/z, ES+): 303.1 (M+1, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH:21]=1)[CH:19]=[O:20]>C1COCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH:19]([C:2]2[CH:3]=[N:4][CH:5]=[N:6][CH:7]=2)[OH:20])[CH:21]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Brc1cncnc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1cncnc1)c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an oven-dried flask was added anhydrous THF (40 mL) and 5-bromopyrimidine (6.36 g, 40 mmol). 2M isopropylmagnesium chloride in THF (22 mL) was then added dropwise over several minutes at 0° C. The mixture was stirred at 0° C. for 30 minutes, and then 5-bromo-2-fluorobenzaldehyde (2.4 mL, 20 mmol) was added. After warming to room temperature, the reaction was quenched with saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc, dried over MgSO4, and purified by column chromatography (gradient 0 to 60% EtOAc in hexanes) to afford the product. 1H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 8.74 (s, 2H), 7.71 (dd, J=6.4, 2.5 Hz, 1H), 7.43 (ddd, J=8.7, 4.6, 2.6 Hz, 1H), 6.95 (dd, J=9.5, 8.9 Hz, 1H), 6.15 (s, 1H).