Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[C:32]([CH:33]=[O:34])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([CH:33]=[O:34])[C:27]=2[F:26])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: O=Cc1cccc(B(O)O)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2cccc(C=O)c2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (2-fluoro-3-formylphenyl)boronic acid (252 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (173 mg), the title compound was obtained as a pale-yellow oil (yield 250 mg, 53%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([NH:28][C@@H:29]2[C:35](=[O:36])[N:34]([CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])[C:33]3[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=3[O:31][CH2:30]2)[C:23]([O:25]CC)=[O:24])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br.C(O)(=O)C>C(O)(=O)C.C(OCC)C>[C:23]([C@@H:22]([NH:28][C@@H:29]1[C:35](=[O:36])[N:34]([CH2:37][C:38]([OH:40])=[O:39])[C:33]2[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=2[O:31][CH2:30]1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([OH:25])=[O:24]
Reactant: CCOC(=O)[C@H](CCCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCCCCC2CCNCC2)C(=O)O)COc2ccccc21
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of tert-butyl 3(S)-[6-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.5 g) in acetic acid (1 ml) is added 30% hydrogen bromide-acetic acid solution (2 ml). The resulting mixture is allowed to stand for 1 hour at room temperature and then diluted with ethyl ether (100 ml). The supernatant layer is removed by decantation and the precipitate is dissolved in 1N sodium hydroxide solution (20 ml). The solution is allowed to stand for 30 minutes at room temperature. After addition of acetic acid (4 ml), the mixture is chromatographed on MCI gel using water-methanol (1:2) as an eluent. The eluate is concentrated in vacuo and lyophilized to give 3(S)-[1(S)-carboxy-6-(4-piperidyl)hexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid (0.23 g) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:14])=[C:7]([CH2:12][OH:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.S(OC)(O[CH3:19])(=O)=O>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[C:7]([CH2:12][OH:13])=[CH:8][N:9]2[CH3:19])=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: OCc1cnc2cc(Cl)ccc2c1O
Product: Cn1cc(CO)c(=O)c2ccc(Cl)cc21

Procedure:
In a similar manner to that described in Example 3 7-chloro-4-hydroxy-3-hydroxymethylquinoline was treated with dimethyl sulphate to give the novel 7-chloro-1-methyl-3-hydroxymethyl-4-quinolone, m.p. 204°-206° (from industrial methylated spirit). Reaction of this product with thionyl chloride gave 7-chloro-3-chloromethyl-1-methyl-4-quinolone hydrochloride, m.p. 205°-207°, which was reacted with sodium methanethiolate to give the novel 7-chloro-1-methyl-3-methylthiomethyl-4-quinolone, m.p. 163°-164° (from industrial methylated spirit).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]([NH2:15])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](Cl)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>ClCCl.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][C:12]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncc(OCc2ccccc2)cn1
Reactant: CCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ncc(OCc2ccccc2)cn1
Yield: 96982.2 %

Procedure:
A solution of 5-(benzyloxy)pyrimidin-2-amine (60.0 g, 0.30 mmol) in dichloromethane (400 mL) was added with pyridine (30 mL, 0.37 mmol), the mixture was added dropwise with a solution of hexanoyl chloride (46 g, 0.34 mmol) in dichloromethane (100 mL) with stirring on an ice bath, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was added with 1 M hydrochloric acid (500 mL), and extracted with chloroform, and the organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was recrystallized froth chloroform-hexane to obtain N-[5-(benzyloxy)pyrimidin-2-yl]hexanamide (87.1 g, 98%) as colorless acicular crystals.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:17]1(B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:17]1([C:2]2[CH:16]=[CH:15][C:5]([O:6][C:7]3[N:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][CH:8]=3)=[CH:4][CH:3]=2)[CH2:19][CH2:18]1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: O=Cc1ccc(Oc2ccc(Br)cc2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(Oc2ccc(C3CC3)cc2)nc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 22.2 %

Procedure:
A mixture of the compound (3.22 g) obtained in step (1) above, 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.89 g), tetrakis(triphenylphosphine)palladium(0) (669 mg), cesium carbonate (11.3 g), toluene (20.0 mL) and water (10.0 mL) was stirred at 100° C. for 6 hours. After cooling the reaction mixture to room temperature, the precipitate was removed by filtration through Celite (registered trademark). To the filtrate, water and ethyl acetate were added and extraction was conducted with ethyl acetate. The combined organic layers were washed with water and saturated brine successively and after passage through a phase separator, they were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-50:50) and further purified by preparative HPLC. A saturated aqueous solution of sodium hydrogencarbonate was then added and extraction was conducted with ethyl acetate. The combined organic layers were passed through a phase separator and thereafter concentrated under reduced pressure to give the titled compound as a colorless oil (614 mg).
Reaction SMILES: C([NH:11][C@H:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(OCC1C=CC=CC=1)=O.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:11][C@H:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)[C@H](CCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H](N)CCc1ccccc1

Procedure:
A solution of (N-carbobenzyloxy)-(L)-homophenylalanine, tert-butyl ester (100 mg, 0.281 mmol) in anhydrous ethanol (2 mL) and anhydrous ethyl acetate (2 mL) was degassed and the reaction flask filled with hydrogen. 10% Palladium on carbon catalyst (25 mg) was added and the mixture was hydrogenated under a balloon of hydrogen at room temperature for 2.3 hr. The catalyst was removed by filtration through a pad of celite, and solvent was removed from the filtrate by rotoevaporation. After pumping under reduced pressure at room temperature, the material thus obtained (homogeneous by TLC in 4/1 hexane/ethyl acetate) was used in the subsequent reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1[C:26](=[O:39])[N:27]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH:28]=[CH:29][C:30]=1I)=[O:24].[CH2:40]([NH2:42])[CH3:41]>>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1[C:26](=[O:39])[N:27]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH:28]=[CH:29][C:30]=1[NH:42][CH2:40][CH3:41])=[O:24]
Reactant: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)c4c(I)ccn(-c5ccc(F)cc5)c4=O)cc3F)ccn2)cn1
Reactant: CCN
Product: CCNc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(-c3cnn(C)c3)c2)cc1F
Yield: 34 %

Procedure:
A mixture of Example A5 (100 mg, 0.155 mmol) in a methanolic solution of ethylamine (10 mL) was heated at 80° C. for 3 h. The mixture was concentrated to dryness and purified by HPLC to afford N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-4-(ethylamino)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (30 mg, 34%). 1H-NMR (400 MHz, DMSO-d6): δ 13.29 (s, 1H), 10.51 (t, J=5.2 Hz, 1H), 8.52 (m, 1H), 8.47 (d, J=6.0 Hz, 1H), 8.40 (s, 1H), 8.10 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.59 (dd, J=7.6, 11.2 Hz, 1H), 7.50 (d, J=5.2 Hz, 2H), 7.39 (m, 3H), 6.92 (d, J=4.4 Hz, 1H), 6.30 (d, J=8.0 Hz, 1H), 3.88 (s, 3H), 3.48 (m, 2H; obscured by water), 1.26 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 561.2 (M+H+).
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)OCCCC(C)(OC([NH:19][C@@H:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([O:23]C)=[O:22])=O)C)=CC=1.O1CCCC1.[OH-].[Na+].Cl>CO>[NH2:19][C@H:20]([C:21]([OH:23])=[O:22])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)CCCOC(c1ccccc1)(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of Example 2 (625 mg, 1 mmol), tetrahydrofuran (7 mL) and methanol (3 mL) was treated with 1N sodium hydroxide (1 mL, 1 mmol). The reaction mixture was stirred at room temperature for 6 hours then treated with 1N hydrogen chloride (1 mL, 1 mmol). The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over ahydrous magnesium sulfate, and filtered. Evaporation of solvent afforded Cmoc-protected phenylalanine of sufficient purity for use in solid-supported peptide synthesis. MS (EI−): 610 (M−1).
Reaction SMILES: C(O)(=O)C.[CH:5]1([O:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[N+:20]([O-:22])=[O:21])=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[BH4-].[Na+]>CS(C)=O>[CH:5]1([O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][N+:20]([O-:22])=[O:21])=[CH:16][CH:17]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=[N+]([O-])/C=C/c1ccc(OC2CCCCC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
To an acetic acid (3.3 mL) and dimethyl sulfoxide (55 mL) solution of 1-cyclohexyloxy-4-((E)-2-nitro-vinyl)-benzene (3.3 g, 13.1 mmol) described in Manufacturing Example 79-1-2 was added sodium borohydride (793 mg, 21 mmol) at room temperature while cooling appropriately. This mixture was stirred for 1 hour at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (1.45 g, 44%).
Reaction SMILES: [N:1]([C@@H:4]([C:6]1[C:11]([F:12])=[CH:10][N:9]=[CH:8][C:7]=1[C:13]1[CH:14]=[C:15]2[C:20](=[N:21][CH:22]=1)[N:19]([C:23]([NH2:25])=[O:24])[CH2:18][CH2:17][CH2:16]2)[CH3:5])=[N+]=[N-]>CCOC(C)=O.CO.[Pd]>[NH2:1][C@@H:4]([C:6]1[C:11]([F:12])=[CH:10][N:9]=[CH:8][C:7]=1[C:13]1[CH:14]=[C:15]2[C:20](=[N:21][CH:22]=1)[N:19]([C:23]([NH2:25])=[O:24])[CH2:18][CH2:17][CH2:16]2)[CH3:5]
Reactant: C[C@@H](N=[N+]=[N-])c1c(F)cncc1-c1cnc2c(c1)CCCN2C(N)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@H](N)c1c(F)cncc1-c1cnc2c(c1)CCCN2C(N)=O
Reaction time: 18 h
Yield: 34.4 %

Procedure:
6-[4-((R)-1-azido-ethyl)-5-fluoro-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (90 mg, 0.24 mmol) is dissolved in a mixture of EtOAc (2 mL) and MeOH (3 mL). The flask is flushed with Argon. Pd/C (26 mg, 0.024 mmol, 10%) is added and the flask is flushed with H2. After stirring for 18 hrs, the reaction is diluted with EtOAc and MeOH (10 mL of a 1:1 mixture), filtered and concentrated. The residue is dissolve in 1 mL of MeOH and 2 drops of water is added. The solution is filtered and purified by reverse phase HPLC to give 26 mg of the titled product.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][N:19]([CH3:39])[C:20]([C:22]3[O:23][C:24]4[CH:38]=[CH:37][CH:36]=[CH:35][C:25]=4[C:26]=3[CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:21])[CH:14]=2)[C:9]=1[Br:40].O.Cl>CO>[Br:40][C:9]1[C:10]2[C:15](=[CH:14][C:13]([CH2:18][N:19]([CH3:39])[C:20]([C:22]3[O:23][C:24]4[CH:38]=[CH:37][CH:36]=[CH:35][C:25]=4[C:26]=3[CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:21])=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[O:7][CH2:6][C:5]([OH:41])=[O:4]
Reactant: COC(=O)COc1ccc2cc(CN(C)C(=O)c3oc4ccccc4c3CCc3ccccc3)ccc2c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(Cc1ccc2c(Br)c(OCC(=O)O)ccc2c1)C(=O)c1oc2ccccc2c1CCc1ccccc1
Yield: 96 %

Procedure:
A mixture of 1 N NaOH (4 mL, 4 mmol) and (1-bromo-6-{[methyl-(3-phenethyl-benzofuran-2-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic acid methyl ester (1.19 g, 2.02 mmol), prepared in the previous step, in 100 mL of methanol plus 4 mL of water was stirred under nitrogen at room temperature overnight. 1 N HCl (4 mL, 4 mmol) was added and the reaction concentrated under reduced pressure to remove the methanol. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (1.11 g, 96%) as an off-white solid, mp 119-122° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[C@@H:10]([CH2:15][O:16][C:17]2[C:18]3[C:32]([Cl:33])=[CH:31][NH:30][C:19]=3[N:20]=[C:21]([NH:23][C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[N:22]=2)[CH2:9]1)=O)(C)(C)C.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[Cl:33][C:32]1[C:18]2[C:17]([O:16][CH2:15][C@@H:10]3[C@@H:11]([O:13][CH3:14])[CH2:12][NH:8][CH2:9]3)=[N:22][C:21]([NH:23][C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)=[N:20][C:19]=2[NH:30][CH:31]=1
Reactant: CO[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1COc1nc(Nc2cnn(C)c2)nc2[nH]cc(Cl)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H]1CNC[C@@H]1COc1nc(Nc2cnn(C)c2)nc2[nH]cc(Cl)c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 122.7 %

Procedure:
To a solution of (3R,4R)-3-[5-chloro-2-(1-methyl-1H-pyrazol-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxymethyl]-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (12.40 g, 26 mmol) in DCM (60 mL) at 0° C. was added TFA (10.1 mL, 208 mmol) and the resulting solution was stirred at ambient temperature for 2.5 hrs. The volatiles were removed and to the residue was added ethyl ether (150 mL). The resulting suspension was stirred for 2 hrs then filtered to afford a light pink solid. This was washed with ethyl ether (30 mL) and dried to give the title compound (15.69 g, quant) as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (br. s., 1H) 9.09 (s, 3H) 7.85 (s, 1H) 7.54 (s, 1H) 7.09 (d, J=2.32 Hz, 1H) 4.48 (d, J=6.48 Hz, 2H) 4.11 (br. s., 1H) 3.81 (s, 3H) 3.46-3.60 (m, 1H) 3.35-3.45 (m, 2H) 3.32 (s, 3H) 3.15 (dq, J=12.01, 6.02 Hz, 1H) 2.88 (m, J=6.42, 6.42 Hz, 1H). m/z (APCI+) for parent molecule C16H20ClN7O2 378.2 (M+H)+ with Cl isotope pattern.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[O:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH3:37][O:38][C:39]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:40]=1[CH:41]=O>ClC(Cl)C>[CH3:37][O:38][C:39]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:40]=1[CH2:41][NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[O:11]
Reactant: COc1ccc(N)c(C(=O)c2cccc(F)c2)c1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc(CNc2ccc(OC)cc2C(=O)c2cccc(F)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-Amino-5-methoxyphenyl)(3-fluorophenyl)methanone (0.984 g, 4.01 mmol) in 15 mL of dichloroethane was added 4 Å powdered molecular sieves (1 g), followed by sodium triacetoxyborohydride (2.55 g, 12.0 mmol) and acetic acid (0.69 mL, 12.0 mmol). 2,4-Dimethoxybenzaldehyde was added (0.667 g, 4.01 mmol), and the reaction was stirred at room temperature for 3 hours. The reaction was partitioned between EtOAc and saturated NaHCO3 solution, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The titled product was isolated as a red oil (1.66 g) which was used in the next step without further purification. ESI+ MS: 396.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([F:12])([F:11])[F:10])=[C:6]([CH:8]=1)[NH2:7].O[CH2:14][CH:15]([CH2:17]O)O.S(=O)(=O)(O)O>C(OCC)(=O)C.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([F:10])([F:11])[F:12])=[C:6]2[C:8]=1[CH:14]=[CH:15][CH:17]=[N:7]2
Reactant: Nc1cc(Br)ccc1C(F)(F)F
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(Br)c2cccnc12
Temperature: 120 °C
Yield: 34.5 %

Procedure:
To a mixture of 5-bromo-2-(trifluoromethyl)aniline (3.0 g, 12.6 mmol), glycerol (4.64 g, 50.0 mmol), and ferrous sulfate (0.56 g, 2.0 mmol) was added conc. sulfuric acid (2.2 mL) dropwise. The reaction mixture was heated at 120° C. for 4 hr. After cooled to RT, the reaction was diluted with ethyl acetate (150 mL), and 2N aq. NaOH was introduced to adjust pH about 13. The organic layer was separated and washed with brine and dried over Na2SO4 and evaporated to give the crude product, which was purified with flash column chromatography to give 5-bromo-8-(trifluoromethyl)quinoline (1.2 g, 48%).
Reaction SMILES: [O:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:28](Cl)(=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC1C=C(C)C=C(C)N=1>[C:28]([O:12][CH2:11][C@H:9]1[O:10][C@@H:2]([O:1][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8])(=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCC(=O)Cl
Reactant: COc1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1cc(C)nc(C)c1
Product: CCCCCC(=O)OC[C@H]1O[C@@H](Oc2ccccc2Cc2ccc(OC)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 3 h
Yield: 23.8 %

Procedure:
To a solution of 2-(4-methoxybenzyl)phenyl β-D-glucopyranoside (0.10 g) in 2,4,6-trimethylpyridine (2 mL) was added hexanoyl chloride (0.072 g) at 0° C., and the mixture was stirred for 3 hours. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous citric acid solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 2-(4-methoxybenzyl)phenyl 6-O-hexanoyl-β-D-glucopyranoside (0.030 g).
Reaction SMILES: Cl[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:6](=[O:24])[N:5]([CH2:25][CH3:26])[C:4]=2[N:3]=1.[CH3:27][C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[N:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:6](=[O:24])[N:5]([CH2:25][CH3:26])[C:4]=3[N:3]=[C:2]2[O:34][C:30]2[CH:31]=[N:32][CH:33]=[C:28]([CH3:27])[CH:29]=2)=[CH:13][CH:14]=1
Reactant: CCn1c(=O)n(CCCO)c(=O)c2c1nc(Cl)n2Cc1ccc(Cl)cc1
Reactant: Cc1cncc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(CCCO)c(=O)c2c1nc(Oc1cncc(C)c1)n2Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 21.3 %

Procedure:
To a solution of 8-chloro-7-(4-chlorobenzyl)-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (30 mg, 0.08 mmol, intermediate 78) in DMF (2 mL) was added 5-methylpyridin-3-ol (12.36 mg, 0.12 mmol), followed by potassium carbonate (15.66 mg, 0.11 mmol). The reaction was stirred at 80° C. for 3 h. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give a crude product, which was purified by preparative HPLC to give 7-(4-chlorobenzyl)-3-ethyl-1-(3-hydroxypropyl)-8-((5-methylpyridin-3-yl)oxy)-1H-purine-2,6(3H,7H)-dione (8 mg, 22.5%) as white solid. 1H-NMR (CD3OD) δ 8.35-8.42(d, 2H), 7.68(s, 1H), 7.38-7.48(m, 4H), 5.52(s, 2H), 4.01-4.14(m, 4H), 3.61-3.64(m, 2H), 2.43(s, 3H), 1.87-1.90(m, 2H), 1.22-1.26(m, 3H). LCMS retention time 2.511 min; LCMS MH+ 470.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=O)[NH:9]2)=[CH:4][CH:3]=1.[CH2:13]([N:15]([CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH:19]([NH2:21])[CH3:20])[CH3:14]>>[CH3:14][CH2:13][N:15]([CH2:16][CH2:17][CH2:18][CH:19]([NH:21][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=12)[CH3:20])[CH2:22][CH3:23]
Reactant: O=C1CCc2ccc(Cl)cc2N1
Reactant: CCN(CC)CCCC(C)N
Product: CCN(CC)CCCC(C)Nc1ccnc2cc(Cl)ccc12
Yield: 90 %

Procedure:
3.665 millimols, i.e. a yield of 90% relative to the 7-chloro-1,2,3,4-tetrahydroquinolinone converted, and a yield of 91.2% relative to the 1-diethylamino-4-aminopentane converted, and
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][C:14](=[O:16])[CH:13]=[CH:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.C(N(CC)CC)C.[Pd]>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][C:14](=[O:16])[CH2:13][CH2:12][O:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=COC(COCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1CCOC(COCc2ccccc2)C1
Yield: 56.8 %

Procedure:
A mixture of (RS)-2-benzyloxymethyl-2,3-dihydro-4H-pyran-4-one (0.82 g, J. Org. Chem., 44,811 (1979)) in ethanol (15 ml) containing 10% Pd-C (0.089 g) and triethylamine (10 drops) was hydrogenated until NMR spectroscopy indicated almost complete reaction. The solution was evaporated and the residue purified by silica-gel MPLC [25% EtOAc/hexanes] and then bulb-to-bulb distillation [220° C./2 mmHg] to give the title ketone (0.47 g, 56%).