Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20]C)=[O:19])=[CH:16][C:3]1=2.[OH-].[Na+].O.Cl>CO>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)Cc1ccccc1C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1ccc2c(c1)C(=O)Cc1ccccc1C2
Yield: 86.3 %

Procedure:
In 2 ml of methanol was dissolved 0.1 g of methyl 10,11-dihydro-11-oxo-5H-dibenzo[a,d]cycloheptene-2-acetate obtained in Example 16, and 6 ml of a 10% aqueous solution of sodium hydroxide was added. The mixture was heated under reflux for 2 hours with stirring. After the reaction, the reaction mixture was cooled, and water was added. The mixture was acidified with 10% hydrochloric acid, and the precipitated solid was extracted with ether. The ethereal layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The ether was distilled off. Recrystallization of the residue from a mixture of ether and n-hexane afforded 0.082 g of 10,11-dihydro-11-oxo-5H-dibenzo[a,d]cycloheptene-2-acetic acid as colorless needle-like crystals having a melting point of 171° to 173° C.
Reaction SMILES: C([O:8][C:9]([C:11]1[N:12]([CH3:34])[N:13]=[N:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1)=[O:10])C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[CH2:32]([O:31][C:29]([CH2:28][CH:25]1[CH2:24][CH2:23][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([C:15]3[N:14]=[N:13][N:12]([CH3:34])[C:11]=3[C:9]([OH:10])=[O:8])=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)=[O:30])[CH3:33]
Reactant: [H][H]
Reactant: CCOC(=O)CC1CCC(c2ccc(-c3nnn(C)c3C(=O)OCc3ccccc3)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCC(c2ccc(-c3nnn(C)c3C(=O)O)cc2)CC1
Reaction time: 15 h
Yield: 97.9 %

Procedure:
To a mixture of 5-[4-(4-ethoxycarbonylmethyl-cyclohexyl)-phenyl]-3-methyl-3H-[1,2,3]triazole-4-carboxylic acid benzyl ester (51 mg, 0.11 mmol) and 10% Pd/C (58.8 mg, 0.552 mmol) was added ethyl acetate (5 mL) at room temperature under nitrogen atmosphere. Then, the nitrogen was replaced with a hydrogen gas balloon and the black reaction mixture was stirred for 15 h under hydrogen atmosphere at which time TLC analysis indicated the absence of the starting material. Then, the reaction mixture was filtered and the charcoal was washed with a hot ethyl acetate (50 mL), THF (25 mL), CH3CN (75 mL), and ethanol (25 mL). The filtrate was concentrated under vacuum and the residue was dried under high vacuum to obtain 5-[4-(4-ethoxycarbonylmethyl-cyclohexyl)-phenyl]-3-methyl-3H-[1,2,3]triazole-4-carboxylic acid (40 mg, 97.5% yield) as a white solid. LC/MS calcd. for C20H25N3O4 (m/e) 371, obsd. 372.3 [M+H, ES+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[OH-].[Na+].[CH2:11](O)C.CI>C(OCC)C>[CH3:11][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: CCO
Reactant: Oc1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CI
Product: COc1ccccc1Br
Temperature: 25 °C

Procedure:
Into a three-necked flask of 1liter, 25g (0.145 mol) of o-bromophenol, 6.1 g (0,152mol) of sodium hydroxide and 300 ml of ethanol were charged and refluxed for two hours. Then, 82.0 g (0.578 mol) of methyl iodide was added dropwise and the mixture was refluxed further for four hours. After the mixture was cooled to room temperature, 600 ml of diethyl ether was added. The mixture was charged into a separatory funnel. Separated organic layer was washed successively with, 100 ml of 2N-hydrochloric acid cooled with ice, 300 ml of saturated sodium thiosulfate, and water until the washings were neutral. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The concentrate was distilled under reduced pressure to obtain 25.3 g (0.135 mol) of o-methoxyphenylbromide.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].[S:13](Cl)([CH3:16])(=[O:15])=[O:14].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][S:13]([N:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:12][CH2:11]1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCN(S(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
An ice cold solution of 1-ethoxycarbonylmethylpiperazine (5 g, 29 mmol), mesyl chloride (3.37 mL, 43.5 mmol) and triethyl amine (6.05 mL, 43.5 mmol) in CH2Cl2 (150 mL) was stirred at 0° C. for 5 min then at rt for 30 min, then partitioned between CH2Cl2 and aq. sat. NH4Cl. The organics were washed with aq. NaHCO3, brine, dried (Na2SO4), filtered and concentrated to give 6.88 g of the title compound. MS (APCI) m/z 251 (M+H)+.
Reaction SMILES: [OH-].[K+].C1COCC1.C([O:10][C:11](=[O:43])[C@:12]([N:18]([CH3:42])[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=[O:20])([CH3:17])[C:13]([NH:15][CH3:16])=[O:14])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[C:11]([C@:12]([N:18]([CH3:42])[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=[O:20])([CH3:17])[C:13]([NH:15][CH3:16])=[O:14])([OH:43])=[O:10]
Reactant: CCOC(=O)[C@](C)(C(=O)NC)N(C)C(=O)c1ccc(-c2ccc(OCCN3CCOCC3)cc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)[C@@](C)(C(=O)O)N(C)C(=O)c1ccc(-c2ccc(OCCN3CCOCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.1 %

Procedure:
An aqueous solution (2.0 mL) of potassium hydroxide (0.11 g) was added to a THF (2.0 mL)-methanol (2.0 mL) solution of 4-{2-[(4′-{[(2S)-1-ethoxy-2-methyl-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl-4-yl)oxy]ethyl}morpholine (93 mg) as obtained in Example 19-(3), and the mixture was stirred for 16 hours at room temperature. The reaction mixture was adjusted to pH 6 with a 10% aqueous solution of citric acid, and extracted with chloroform. The organic layer was separated using a phase separator, and the solvent was distilled off under reduced pressure to obtain 4-{2-[(4′-{[(2S)-2-carboxy-1-(methylamino)-1-oxopropan-2-yl](methyl)carbamoyl}biphenyl-4-yl)oxy]ethyl}morpholine (light brown oil) (58 mg, 65%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@@H:3]1[CH3:18].[H-].[Na+]>C1COCC1.CCOC(C)=O.O>[CH3:18][C@@H:3]1[C@H:2]([N:1]2[CH2:2][CH2:3][NH:4][C:8]2=[O:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: C[C@@H]1[C@H](N)CCCN1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H]1[C@H](N2CCNC2=O)CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 125.5 %

Procedure:
(2R,3R)-Benzyl 3-amino-2-methylpiperidine-1-carboxylate (323, 610 mg, 2.46 mmol) was dissolved in 10 mL dry THF. To it was added 2-chloroethyl isocyante (210 μL, 2.46 mmol), and the mixture was stirred at RT for 2 hours. To it was added NaH (60% in mineral oil, 120 mg, 2.95 mmol) and the mixture was stirred for overnight. Another batch of NaH (120 mg, 2.95 mmol) was then added to drive the cyclization to completion in overnight. The mixture was diluted with 150 mL EtOAc and 50 mL water. The organic phase was separated, washed with water, dried, concentrated in vacuo, and subjected to silica flash column using 0 to 4% MeOH in DCM to isolate (2R,3R)-benzyl 2-methyl-3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (354, 490 mg, 63%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:22]#[N:23])[NH:7][C:8]=1[C:9]1[CH:10]=[CH:11][C:12]2[NH:17][C:16](=[O:18])[O:15][C:14]([CH3:20])([CH3:19])[C:13]=2[CH:21]=1)([O-])=O.[Cl-].[NH4+].O>C(O)C.O.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([C:22]#[N:23])[NH:7][C:8]=1[C:9]1[CH:10]=[CH:11][C:12]2[NH:17][C:16](=[O:18])[O:15][C:14]([CH3:19])([CH3:20])[C:13]=2[CH:21]=1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3[nH]c(C#N)cc3[N+](=O)[O-])cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: CC1(C)OC(=O)Nc2ccc(-c3[nH]c(C#N)cc3N)cc21
Temperature: 80 °C
Yield: 80.3 %

Procedure:
A solution of 4-nitro-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile (0.4 g, 1.28 mmol) in ethanol/water (5:1, 20 mL) was treated sequentially with zinc powder (2.5 wt, 1.0 g) and ammonium chloride (5 wt, 2.0 g). The suspension was heated at 80° C. or 30 min, cooled to room temperature, poured into water (30 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layer was washed with brine, dried over MgSO4 and purified by flash column chromatography on silica gel eluting with ethyl acetate to give 4-amino-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile (0.29 g, 80%) as a yellow solid. 1H NMR (500 MHz, d6-DMSO) δ1.63 (s, 6H), 4.29 (s, 2H); 6.39 (s, 1H), 6.89 (d, 1H, J=8.1 Hz), 7.49 (s, 1H), 7.52 (dd, 1H, J=8.1 and 2.3 Hz), 10.25 (s, 1H), 11.76 (s, 1H). MS (ESI (−)) m/z 281 (M−H)−. Anal. calcd for C15H14N4O2, C, 63.8, H, 5.00, N, 19.9. Found, C, 63.7, H, 5.10, N, 19.82
Reaction SMILES: [Br:1][C:2]1[C:3]([F:16])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH2:13][CH3:14])[C:7]2=[O:15].Cl.[CH3:18][C:19]1([NH2:22])[CH2:21][CH2:20]1>CS(C)=O>[Br:1][C:2]1[C:3]([F:16])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:22][C:19]1([CH3:18])[CH2:21][CH2:20]1)[N:8]([CH2:13][CH3:14])[C:7]2=[O:15]
Reactant: CC1(N)CC1
Reactant: CCn1c(Cl)nc2c(Br)c(F)ccc2c1=O
Agent: Cl
Solvent: CS(C)=O
Product: CCn1c(NC2(C)CC2)nc2c(Br)c(F)ccc2c1=O
Yield: 81.2 %

Procedure:
A solution of 8-bromo-2-chloro-3-ethyl-7-fluoroquinazolin-4(3H)-one (512c; 200 mg, 0.655 mmol), 1-methylcyclopropanamine hydrochloride (Small Molecules, Inc.; 211 mg, 1.964 mmol), and TEA (0.274 mL, 1.964 mmol) in DMSO (1.5 mL) was heated in a sealed microwave vial at 90° C. for 30 min. The reaction mixture was then partitioned between DCM (60 mL) and water (40 mL). The organic layer was separated and sequentially washed with water (2×40 mL) and brine (40 mL), then dried over Na2SO4, filtered, and concentrated in vacuo to give 8-bromo-3-ethyl-7-fluoro-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one (181.1 mg, 0.532 mmol, 81% yield) as a light-yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.06 (1H, dd, J=8.8, 6.1 Hz), 6.93 (1H, t, J=8.5 Hz), 4.84-5.23 (1H, m), 4.02 (2H, q, J=6.4 Hz), 1.61 (3H, s), 1.30 (3H, t, J=7.2 Hz), 0.91 (2H, br. s.), 0.81-0.88 (2H, m). 19F NMR (376 MHz, CDCl3) δ ppm −96.57 (1F, br. s.). m/z (ESI, +ve) 339.8/341.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].I[CH2:14][CH3:15]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:14][CH3:15])[C:10]([OH:12])=[O:11]
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: CCI
Product: CCC(C(=O)O)c1ccc(Cl)cc1Cl

Procedure:
prepared from 2,4-dichlorophenylacetic acid and iodoethane;
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[NH2:44][C:45]([CH3:57])([CH3:56])[CH2:46][CH2:47][NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52]>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:44][C:45]([CH3:57])([CH3:56])[CH2:46][CH2:47][NH:48][C:49](=[O:55])[O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[O:23])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(N)CCNC(=O)OC(C)(C)C
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CCNC(=O)OC(C)(C)C)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.32 mmol) and DIEA (124 mg, 0.96 mmol) in 6 mL of DMF was added EDCI (123 mg, 0.64 mmol) and DMAP (110 mg, 0.90 mmol) at room temperature followed by tert-butyl 3-amino-3-methylbutylcarbamate (260 mg, 1.28 mmol) in one portion and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 40 mL of water, filtered and the filter cake was washed with petroleum ether to give tert-butyl 3-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-3-methylbutylcarbamate (110 mg, 69.4%) as a yellow solid which was used for the next step without further purification. MS: (M+H)+=496.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=O.O=S(Cl)[Cl:12]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([Cl:12])=[O:9]
Reactant: COCCOCC(=O)O
Reactant: O=S(Cl)Cl
Product: COCCOCC(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To 2-methoxyethoxyacetic acid (670 mg.; 4.00 mmoles) was added at 0°-2° under N2 atmosphere, SOCl2 (5ml.). The mixture was stirred at room temperature under N2 for 2 hours. Excess SOCl2 was evaporated and the residue was diluted with dry benzene (15 ml.), evaporated again, and dried over NaOH (in vacuo) to yield 2-methoxyethoxyacetyl chloride (705 mg.; 4.62 mmoles; yield 92.5%) as a colorless liquid. nmr (CDCl3): δppm 3.40 (3H, s, -OCH3), 3.4-3.9 (4H, m, -CH2CH2 -), 4.56 (2H, s, ClOCH2O-); ir (neat): 1810 cm-1 (νc=o, acid chloride).
Reaction SMILES: C(#N)C.[Si]([O:11][CH:12]1[CH2:15][N:14]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]3=[O:32])=[CH:18][C:17]=2[F:33])[CH2:13]1)(C(C)(C)C)(C)C.F.C(=O)(O)[O-].[Na+]>O>[F:33][C:17]1[CH:18]=[C:19]([N:22]2[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]2=[O:32])[CH:20]=[CH:21][C:16]=1[N:14]1[CH2:15][CH:12]([OH:11])[CH2:13]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CC(O[Si](C)(C)C(C)(C)C)C3)c(F)c2)C(=O)O1
Agent: *CC(*)C
Agent: F
Agent: O=C([O-])O
Solvent: CC#N
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CC(O)C3)c(F)c2)C(=O)O1
Reaction time: 3 h

Procedure:
An acetonitrile (55 mL) solution of (S)-N-[[3-[4-[3-[(tert-butyldimethylsilyl)oxy]-1-azetidinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (1.23 g, 2.81 mmol) in a polypropylene bottle was treated with 38% aqueous hydrofluoric acid (15 mL) at ambient temperature. TLC analysis revealed the deprotection to be complete after 3 h. The reaction mixture was diluted with water (15 mL) and neutralized with solid sodium bicarbonate. Additional water was added (50 mL) and the mixture extracted with chloroform. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title oxazolidinone antibacterial agent as an off-white solid with mp 174°-177° C. and MS(EI) 323 (M+).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]1[N:4]=[C:5]2[N:20]=[C:18]([N:19]=1)[NH:17][NH:16][C:15](=[O:21])[C@@H:14]([CH2:22][N:23]([O:26]CC1C=CC=CC=1)[CH:24]=[O:25])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6]2>CO.[Pd]>[CH3:1][N:2]([CH3:34])[C:3]1[N:4]=[C:5]2[N:20]=[C:18]([N:19]=1)[NH:17][NH:16][C:15](=[O:21])[C@@H:14]([CH2:22][N:23]([OH:26])[CH:24]=[O:25])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: CN(C)c1nc2nc(n1)NNC(=O)[C@@H](CN(C=O)OCc1ccccc1)CCCCC=CCC2
Agent: [Pd]
Solvent: CO
Product: CN(C)c1nc2nc(n1)NNC(=O)[C@@H](CN(O)C=O)CCCCCCCC2
Reaction time: 3 h

Procedure:
To a solution of N-{[(5R)-16-(dimethylamino)-4-oxo-2,3,15,17,18-pentaazabicyclo[12.3.1]octadeca-1(18),10,14,16-tetraen-5-yl]methyl}-N-benzoxyformamide (75 mg) in MeOH (15 mL) was added 10% Pd/C (15 mg, 20% w/w). The reaction mixture was subjected to hydrogenation for 3 hours at room temperature. The reaction mixture was then filtered through a pad of Celite, and washed with MeOH (10 mL×2). Removal of the solvent provided the title compound. MH+380.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[CH2:29]([N:31]1[CH2:39][C:38]2[C:33](=[N:34][CH:35]=[C:36](B(O)O)[CH:37]=2)[C:32]1=[O:43])[CH3:30]>>[F:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:36]3[CH:37]=[C:38]4[CH2:39][N:31]([CH2:29][CH3:30])[C:32](=[O:43])[C:33]4=[N:34][CH:35]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Reactant: CCN1Cc2cc(B(O)O)cnc2C1=O
Product: CCN1Cc2cc(-c3n[nH]c4cc(-c5c(F)c(OC)cc(OC)c5F)ncc34)cnc2C1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and (6-ethyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)boronic acid. LCMS (M+H)+=452.1.
Reaction SMILES: [C:1]1([C@@H:7]([CH2:11][CH2:12][OH:13])C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:14]([O-])=O.[Na+]>OS(O)(=O)=O>[C:1]1([C@H:7]([NH2:14])[CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=N[O-]
Reactant: O=C(O)[C@H](CCO)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N[C@H](CCO)c1ccccc1
Temperature: 2.5 °C

Procedure:
The hydrazide of (R)-2-phenyl-4-hydroxybutanoic acid (0.5 gram) is reacted with a solution of 0.5 grams of sodium nitrite in 10 ml of 5% H2SO4. The reaction mixture is maintained for 1 hour at 0-5° C., followed extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (R)-1-phenyl-3-hydroxypropylamine is isolated as a light yellow oil.
Reaction SMILES: N.[Na].C([N:10]1[CH:14]=[C:13]([CH2:15][N:16]2[CH2:20][CH:19]([C:21]3[CH:26]=[C:25](F)[CH:24]=[C:23](F)[C:22]=3F)[CH2:18][C:17]2=[O:30])[CH:12]=[N:11]1)C1C=CC=CC=1.[NH4+].[Cl-]>C1COCC1.O>[C:21]1([CH:19]2[CH2:20][N:16]([CH2:15][C:13]3[CH:12]=[N:11][NH:10][CH:14]=3)[C:17](=[O:30])[CH2:18]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1CC(c2cc(F)cc(F)c2F)CN1Cc1cnn(Cc2ccccc2)c1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CC(c2ccccc2)CN1Cc1cn[nH]c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 11.6 %

Procedure:
In a 250 ml, three-necked flask fitted with a magnetic stirrer under inert atmosphere, 20 ml of liquid ammonia is condensed and sodium is added until the solution turns blue. A solution of 1-[(1-benzyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one 160 (1 g, 2.6 mmol) in THF (5 ml) is added and the mixture is stirred at −78° C. for 5 minutes. NH4Cl and water are added, ammonia is evaporated in vacuo and the aqueous phase is extracted with CH2Cl2. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated to dryness. The residue is purified by preparative chromatography on C18 reversed phase (CH3CN/H2O/NH4HCO3, gradient) to afford 73 mg of 4-phenyl-1-(1H-pyrazol-4-ylmethyl)pyrrolidin-2-one 162.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][C:9]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)=[C:10]([CH:11]=[O:12])[C:6]=2[C:5](=[O:25])[N:4]([CH2:26][CH2:27][CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[C:3]1=[O:36].[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([Mg]Br)=[CH:40][CH:39]=1>C1COCC1.C(Cl)Cl.O>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([CH:11]([OH:12])[C:10]2[C:6]3[C:5](=[O:25])[N:4]([CH2:26][CH2:27][CH2:28][O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)[C:3](=[O:36])[N:2]([CH3:1])[C:7]=3[S:8][C:9]=2[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:22])([F:23])[F:24])[CH:15]=2)=[CH:40][CH:39]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C=O)c(Oc3cccc(OC(F)(F)F)c3)sc21
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cccc(OC(F)(F)F)c3)sc21
Reaction time: 0.03 h
Yield: 49.3 %

Procedure:
To a solution of 1-methyl-2,4-dioxo-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoro methoxy)phenoxy)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbaldehyde (50 mg, 0.095 mmol) in THF (2 mL) was added (4-chlorophenyl)magnesium bromide (0.19 mL, 0.190 mmol). The reaction was stirred for 2 min then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography PE/EA (5:1 to 3:1) to give 5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy)phenoxy)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 49.5% yield) as a solid. LCMS: [M+-THP-OH] 539 and TR=2.159 min.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][OH:8].[C:9](OC(=O)C)(=[O:11])[CH3:10]>N1C=CC=CC=1.CCOC(C)=O>[C:9]([O:8][CH2:7][C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])(=[O:11])[CH3:10]
Reactant: Cc1ccsc1CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCc1sccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 62.2 (0.87 g, 6.79 mmol) in pyridine (20 mL) was added acetic anhydride (0.8 mL, 8.14 mmol) at room temperature. The mixture was stirred overnight at room temperature, diluted with EtOAc, washed with 1N HCl and brine, dried (Na2SO4), and concentrated. The crude product was chromatographed on silica gel (0-15% EtOAc/hexane) to afford 62.3. 1H NMR (400 MHz, CDCl3) δ 7.21 (d, 1H), 6.84 (d, 1H), 5.20 (s, 2H), 2.26 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[F:10][C:11]1[CH:25]=[CH:24][C:14]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=O)=[CH:13][CH:12]=1>CN1CCCC1=O.C1(N2CCCC2=O)CCCCC1>[NH:6]1[CH:7]=[C:2]([N:1]=[C:15]([C:14]2[CH:24]=[CH:25][C:11]([F:10])=[CH:12][CH:13]=2)[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: Nc1c[nH]c(=O)[nH]c1=O
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=C1CCCN1C1CCCCC1
Solvent: CN1CCCC1=O
Product: O=c1[nH]cc(N=C(c2ccc(F)cc2)c2ccc(F)cc2)c(=O)[nH]1
Temperature: 180 °C

Procedure:
In a round bottom flask equipped with an overhead stirrer, 1.16 grams (0.009 mole) of 5-aminouracil was charged along with 6 grams (0.027 mole) of 4,4′-difluorobenzophenone and a N-methylpyrrolidone/N-cyclohexylpyrrolidone solvent mixture (50/50, 20 milliliters). The reaction mixture was then heated to 180° C. for 3 days. A charge of hexanes (100 milliliters) was added to fully induce precipitation, and the solid was isolated by filtration and twice recrystallized from isopropanol. The product was rinsed with isopropanol, suction dried, and vacuum dried in an oven overnight.