Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C.[CH2:2]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH3:11])[CH3:3].CC1[O:15][CH2:14]1.[CH2:16]1O[CH2:17]1>O>[CH2:2]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:14][OH:15])[CH2:3][CH2:16][CH3:17]
Reactant: CC1CO1
Reactant: CCOCCOCCOC
Reactant: C1CO1
Agent: C
Solvent: O
Product: CCCCOCCOCCOCCO

Procedure:
Ink 27 was prepared with reference to Example 1 of Patent Literature 4 (Japanese Patent Application Laid-Open No. 2010-018741). A mixture of 20.0 parts of carbon black (trade name: Monarch (M) 1000, product of Cabot), 12.0 parts of a polymer dispersant (trade name: BYK190, product of BYK Japan) and 68.0 parts of ion-exchanged water was treated by a Nano mill in which the packing rate of zirconia beads having a diameter of 0.5 mm was set to 80%, thereby preparing a pigment dispersion having a pigment content of 20 mass %. Fifteen parts of the resultant pigment dispersion, 10.0 part of a water-soluble polyurethane polymer (trade name: SF126, product of DAI-ICHI KOGYO SEIYAKU), 30.0 parts of diethylene glycol methyl ethyl ether, 0.2 parts of a silicone compound (trade name: FZ-2105, product of Dow Corning Toray), 0.4 parts of a stabilizer (trade name: ADEKA PLURONIC F-108, product of ADEKA) and 44.4 parts of ion-exchanged water were mixed, sufficiently stirred and dispersed, and the resultant dispersion was then filtered under pressure through a microfilter (product of Fuji Photo Film Co., Ltd.) having a pore size of 3.0 μm to prepare Ink 27.
Reaction SMILES: [C:1]1([C:7](=[N:28][OH:29])[CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O>[C:1]1([C:7](=[N:28][O:29][C:30](=[O:32])[CH3:31])[CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCc2cc(C(=O)N3CCN(CC(=NO)c4ccccc4)CC3)ccc2N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)ON=C(CN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.3 Grams of 6-[4-(2-phenyl-2-hydroxyiminoethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril, 1.91 ml of acetic anhydride and 5.64 ml of triethylamine were dissolved in 60 ml of methylene chloride, and the resulting solution was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was poured into water, and was made alkaline by adding sodium carbonate, then this mixture was extracted with methylene chloride. The methylene chloride extract was dried, then the solvent was removed by evaporation, and the residue was converted into an oxalate by stirring with oxalic acid in acetone. The oxalate was recrystallized from ethanol-water to yield 5.28 g of 6-[4-(2-phenyl-2-acetoxyiminoethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril.oxalate.monohydrate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[N:9]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[CH3:18][O:19][CH2:20][C:21](=[O:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24]>O.CCO>[CH3:18][O:19][CH2:20][C:21](=[O:27])[C:22](=[N:9][NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: O=N[O-]
Reactant: COCC(=O)CC(=O)OC
Reactant: Nc1cccnc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COCC(=O)C(=NNc1cccnc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 98.6 %

Procedure:
A solution of 3-aminopyridine (20 g, 210 mmol) in 6 M HCl aqueous solution (200 ml, 1200 mmol) was cooled with ice bath. To the solution was added dropwise a solution of sodium nitrite (18 g, 260 mmol) in water (40 mL). After stirring at 0° C. for 5 min, the mixture was added to a mixture of sodium acetate (130 g, 1300 mmol) and methyl 4-methoxyacetoacetate (28 ml, 210 mmol) in EtOH (300 ml) and water (150 ml) at 0° C., and the mixture was stirred at 0° C. for 1 h. The mixture was diluted with water (150 ml), extracted with AcOEt (500 ml×3). The combined organic layer was washed with saturated NaHCO3 aqueous solution (300 ml×3) and brine (300 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (52 g, 97% yield) as a brown oil: 1H NMR (300 MHz, CDCl3): δ ppm 3.50 (3H×½, s), 3.51 (3H×½, s), 3.89 (3H×½, s), 3.93 (3H×½, s), 4.67 (2H×½, s), 4.70 (2H×½, s), 7.35-7.43 (1H, m), 7.67-7.74 (1H×½, m), 7.84-7.91 (1H×½, m), 8.41-8.49 (1H, m), 8.64-8.71 (1H, m), 12.90 (1H×½, s), 14.76 (1H×½, brs).
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([CH2:17][O:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:29])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:29])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][O:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC(=O)c1c[nH]c2c(COC(=O)c3ccccc3)cccc2c1=O
Product: CCCC(=O)c1cnc2c(COC(=O)c3ccccc3)cccc2c1Cl

Procedure:
A solution of 3-butyryl-8-(benzoyloxymethyl)-4(1H)-quinolone (17.93 g) in phosphoryl chloride (150 ml) was heated at reflux for 1.5 hours, then the excess phosphoryl chloride evaporated. The residue was poured onto ice, extracted with dichloromethane, dried and evaporated to give 3-butyryl-4-chloro-8-(benzoyloxymethyl)quinoline. The crude product was used without further purification.
Reaction SMILES: [C:1]([C:9]1[C:14]2[NH:15][CH2:16][CH2:17][O:18][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:25][CH2:26][C:27](Br)=[O:28].O>C(Cl)Cl>[Br:25][CH2:26][C:27]([N:15]1[C:14]2[C:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=[CH:12][C:13]=2[O:18][CH2:17][CH2:16]1)=[O:28]
Reactant: O=C(Br)CBr
Reactant: O=C(c1ccccc1)c1cccc2c1NCCO2
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccccc1)c1cccc2c1N(C(=O)CBr)CCO2
Yield: 69.4 %

Procedure:
To a solution of 5-benzoyl-3,4-dihydro-2H-1,4-benzoxazine (5.74 g), pyridine (1.9 g) and methylene chloride (100 ml) was dropwise added a solution of bromoacetyl bromide (5.82 g) in methylene chloride (5 ml) at room temperature. After the mixture was stirred for 1.0 hour at the same temperature, water (100 ml) was added thereto under stirring. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated. The residue was crystallized with a mixture of diisopropyl ether and ethyl acetate. The crystals were collected by filtration to give 4-bromoacetyl-5-benzoyl-3,4-dihydro-2H-1,4-benzoxazine (6.0 g).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]1([CH2:19][O:20][C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([OH:25])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.[CH2:40]([CH2:42][NH2:43])[OH:41]>C1COCC1>[OH:41][CH2:40][CH2:42][NH:43][C:23]([C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[O:20][CH2:19][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:25]
Reactant: NCCO
Reactant: O=C(O)c1ccccc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(NCCO)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Yield: 101 %

Procedure:
1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (EDAC) (1.3 g, 6.57 mmol) was slowly added to a solution of 2-(phenylmethoxy)benzoic acid (1.5 g, 6.57 mmol), 1-hydroxybenzotriazole (HOBt) (0.89 g, 6.57 mmol), and ethanolamine (0.40 mL, 6.57 mmol) in 50 mL of anhydrous THF at 0° C. The suspension was stirred and warmed up slowly to room temperature over 24 hrs. The reaction mixture was concentrated to dryness under reduced pressure and the resulting residue was diluted with dichloromethane and washed with 0.5N HCl twice followed by the addition of a saturated NaHCO3 solution and brine. The organic layer was separated, dried through a MgSO4 pad and concentrated under reduced pressure to afford 1.8 g (100%) of N-(2-Hydroxyethyl)[2-(phenylmethoxy)phenyl]carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1.[NH:27]1[CH:31]=[CH:30][CH:29]=[CH:28]1.C(N)CN.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:27]2[CH:31]=[CH:30][CH:29]=[CH:28]2)=[CH:22][CH:21]=1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(I)cc2)c(Cl)c1
Reactant: c1cc[nH]c1
Agent: [Cu]I
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: NCCN
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(-n3cccc3)cc2)c(Cl)c1

Procedure:
200 mg of 1,3-dichloro-5-(3,3-dichloro-allyloxy)-2-[3-(4-iodo-phenoxy)-propoxy]-benzene, 29 mg of pyrrole, 6.9 mg of copper(I) iodide, 2.2 mg of ethylenediamine and 155 mg of potassium triphosphate are stirred for 24 hours at 110° C. in 4 ml of dioxane. The reaction mixture is diluted with ethyl acetate and filtered. Concentration and purification over silica gel yield the title compound (compound 1.1).
Reaction SMILES: [NH:1]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C@H:2]([C:10]([NH:12][C@H:13]([C:23](O)=[O:24])[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:36][C@H:37]([C:43]([O:45][CH3:46])=[O:44])[CH2:38][CH2:39][CH:40](C)C.[C:47]1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1>>[NH:1]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C@H:2]([C:10]([NH:12][C@H:13]([C:23]([NH:36][C@H:37]([C:43]([O:45][CH3:46])=[O:44])[CH2:38][CH:39]([CH3:40])[CH3:47])=[O:24])[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H](N)CCC(C)C
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 69 %

Procedure:
Condensation of ZPheOSu (6.96 g.) and HLDap(Boc)OH (6.0 g.) by the salt coupling method gave ZPhe-LDap(Boc)OH in 64% yield. Condensation of ZPhe-LDap(Boc)OH (4.85 g.) and HLeuOMe (2.73 g.) by the mixed anhydride method using diphenylphosphinic chloride gave ZPhe-LDap(Boc)-LeuOMe in 69% yield. Debenzyloxycarbonylation of ZPhe-LDap(Boc)-LeuOMe (4.15 g.) by hydrogenation with palladium catalyst gave HPhe-LDap(Boc)-LeuOMe in 100% yield. Condensation of BocPro-PheOH (1.09 g.) and HPhe-LDap(Boc)-LeuOMe (1.44 g.) using dicyclohexylcarbodiimide and N-hydroxynorbornenedicarboximide gave BocPro-Phe-Phe-LDap(Boc)-LeuOMe in 75% yield. Hydrazinolysis of BocPro-Phe-Phe-LDap(Boc)-LeuOMe (1.69 g.) gave BocPro-Phe-Phe-LDap(Boc)- LeuNHNH2 in 36% yield.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([OH:18])[CH2:10][CH:11]=[CH:12][CH2:13][Si](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].[B-](F)(F)(F)[F:25].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.CCCCCC>C(#N)C.CCOCC>[F:25][CH:11]([CH:12]=[CH2:13])[CH2:10][CH:9]([OH:18])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CC=CCC(O)CCc1ccccc1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOCC
Product: C=CC(F)CC(O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
A solution of 1-phenyl-7-trimethylsilanyl-hept-5-en-3-ol (776 mg, 2.96 mmol, 1 eq) in acetonitrile (30 mL), with sodium bicarbonate (497 mg, 5.92 mmol, 2 eq), was treated with Selectflour™ (2.097 g, 5.92 mmol, 2 eq) and stirred at room temperature under an atmosphere of argon for 18 h. The reaction was then concentrated under reduced pressure and water (10 mL) was added and then extracted with ether (3×15 mL). The combined organic phases were dried over MgSO4, filtered and the solvent removed under reduced pressure. Column chromatography (hexane:ether, 95:5, 9:1, 85:15) gave 5-fluoro-1-phenylhept-6-en-3-ol as a colourless oil (397 mg, 64% yield). For major diastereomer: 1H NMR (400 MHz, CDCl3) δ 1.63-2.04 (m, 4H, CH2CHF, CH2CHOH), 2.67-2.74 (m, 1H, PhCH2), 2.78-2.86 (m, 1H, PhCH2), 3.92-3.98 major (m, 1H, CHOH), 5.05-5.20 (m, 1H, CHF), 5.22-5.27 (m, 2H, CHCH2), 5.86-5.99 (m, 1H, CHCH2), 7.19-7.33 (m, 5H, Ph); 13C NMR (100 MHz, CDCl3) δ 31.8 (PhCH2), 39.1 (PhCH2CH2), 42.4 (CHOHCH2), 67.2 (CHOH), 90.0-91.7 (d, CHF, J=165 Hz), 116.7 (CHCH2), 125.9 (Ph), 128.4 (Ph), 136.0 (CHCH2), 141.7 (Ph); 19F NMR (376.5 MHz , CDCl3) δ −177. For minor diastereomer: 1H NMR (400 MHz, CDCl3) δ 1.63-2.04 (m, 4H, CH2CHF, CH2CHOH), 2.67-2.74 (m, 1H, PhCH2), 2.78-2.86 (m, 1H, PhCH2), 3.85-3.91 (m, 1H, CHOH), 5.05-5.20 (m, 1H, CHF), 5.22-5.27 (m, 2H, CHCH2), 5.33-5.39 (m, 1H, CHCH2), 7.19-7.33 (m, 5H, Ph); 13C NMR (100 MHz, CDCl3) δ 31.8 (PhCH2), 39.1 (PhCH2CH2), 42.4 (CHOHCH2), 68.9 (CHOH), 92.3-93.9 (d, CHF, J=164 Hz), 116.7(CHCH2), 125.9 (Ph), 128.4 (Ph), 136.0 (CHCH2), 141.7 (Ph); 19F NMR (376.5 MHz, CDCl3) δ −180. IR (v, cm−1) 3418 (OH), 1651 (C═C), 1496 (Ar), 1455 (Ar); MS (GCT, CI+) m/z 226.2 [M+NH4]+ HRMS required for C13H21FON: 226.1607, found 226.1611.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1)=[O:20]>>[C:19]([C:21]1[CH:22]=[C:23]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:24]=[CH:25][CH:26]=1)(=[O:20])[CH3:18]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: CC(=O)c1cccc(N)c1
Product: COc1cc2ncc(C#N)c(Nc3cccc(C(C)=O)c3)c2cc1OC

Procedure:
In the manner of Example 274 reaction of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile with 3-aminoacetophenone gave the tide compound as a tan solid, mp 204-206° C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][N:11]([CH2:24][CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:10]1=[O:30].Cl[C:32](OC1C=CC([N+]([O-])=O)=CC=1)=[O:33].Cl.Cl.[O:46]=[C:47]1[NH:55][C:50]2=[N:51][CH:52]=[CH:53][CH:54]=[C:49]2[N:48]1[CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>O1CCCC1>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH2:12][N:11]([CH2:24][CH2:25][S:26]([CH3:29])(=[O:27])=[O:28])[C:10](=[O:30])[C@H:9]([NH:8][C:32]([N:59]2[CH2:60][CH2:61][CH:56]([N:48]3[C:49]4[C:50](=[N:51][CH:52]=[CH:53][CH:54]=4)[NH:55][C:47]3=[O:46])[CH2:57][CH2:58]2)=[O:33])[CH2:15][CH2:14]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](N)C1=O
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Triethylamine (0.010 mL, 0.023 mmol) was added to a solution of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-[2-(methylsulfonyl)ethyl]azepan-2-one (8 mg, 0.023 mmol) and 4-nitrophenyl chloroformate (4.6 mg, 0.023 mmol) in tetrahydrofuran (0.700 mL) at 0° C. After min, 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (6.7 mg, 0.023 mmol) and triethylamine (0.040 mL, 0.092 mmol) were added and the mixture allowed to warm to ambient temperature. After 16 h, the mixture was concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound. MS 591 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C(S[C:15](=[O:28])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:17](=[O:19])[CH3:18])(C)(C)C>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][CH:16]([C:17](=[O:19])[CH3:18])[C:15]([NH:1][C:2]2[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=2[Cl:8])=[O:28])=[CH:26][CH:25]=1
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)C(=O)SC(C)(C)C
Reactant: Nc1cc(O)ccc1Cl
Product: CC(=O)C(Cc1ccc(Cl)cc1)C(=O)Nc1cc(O)ccc1Cl

Procedure:
The title compound was prepared by the method of Preparation 34b using 3-amino-4-chlorophenol and 2-(4-chlorobenzyl)-3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [C:1]([NH:4][C@H:5]([CH2:9][O:10][CH3:11])[C:6]([OH:8])=O)(=[O:3])[CH3:2].ClC(OCC(C)C)=O.CN1CCOCC1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[C:1]([NH:4][C@H:5]([CH2:9][O:10][CH3:11])[C:6]([NH:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: COC[C@@H](NC(C)=O)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Temperature: -10 °C
Reaction time: 0.67 h
Yield: 56.7 %

Procedure:
(R)-2-Acetylamino-3-methoxypropionic acid (8.06 g, 0.05 mol) was dissolved in tetrahydrofuran (80 mL). Isobutyl chloroformate (7.8 mL, 0.06 mol) was added at −10° C. within 10 minutes, followed by 4-methylmorpholine (6.6 mL, 0.06 mol), and the mixture was stirred at −10° C. for 40 minutes. A solution of benzylamine (6.55 mL, 0.06 mol) in tetrahydrofuran (10 mL) was then added at −10° C. The mixture was allowed to warm to room temperature, the solvent evaporated and the residue dissolved in dichloromethane. The solution was successively washed with water (30 mL), 1M HCl (30 mL), 5% sodium hydrogencarbonate solution (30 mL) and again with water (30 mL). The solvent was evaporated and the residue crystallized in ethyl acetate to afford the title compound (7.09 g, 57%). LCMS analysis: 98.0%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=[C:11]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:7][C:8](O)=[O:9])=[O:5])[CH3:2].CO>O1CCCC1>[F:28][C:24]1[CH:23]=[C:22]([C:11]([C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=2)=[C:6]([CH2:7][CH2:8][OH:9])[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(CC(=O)O)=C(c1ccc(S(C)(=O)=O)cc1)c1cccc(F)c1
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C(CCO)=C(c1ccc(S(C)(=O)=O)cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
15.5 ml (0.155 mol) of borane/methyl sulfide complex are added dropwise to a solution of 31.5 g (0.0775 mol) of 3-ethoxycarbonyl-4-(3-fluorophenyl)-4-(4-methanesulfonylphenyl)-3-butenoic acid, prepared in Example 11, in 90 ml of anhydrous tetrahydrofuran. The mixture is stirred at room temperature for 8 hours and 23.5 ml of methanol are added dropwise. The mixture is evaporated to dryness under vacuum and the residue is taken up with ethyl acetate and then treated with an aqueous solution of 7.6 g of potassium carbonate. The organic phase is decanted and then dried over magnesium sulfate and evaporated to dryness under vacuum to give 29.3 g of ethyl 3-(3-fluorophenyl)-3-(4-methanesulfonylphenyl)-2-(2-hydroxyethyl)-2-propenoate in the form of a viscous oil, which is used as such in the next step.
Reaction SMILES: FC1C=C(N)C=CC=1OC1C=CN=C2C=CSC=12.[F:19][C:20]1[CH:21]=[C:22]([NH:46][C:47]([NH:49][C:50](=[O:58])[CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[S:48])[CH:23]=[CH:24][C:25]=1[O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]2[CH:33]=[C:34](C3C=CC(S(C)(=O)=O)=CC=3)[S:35][C:28]=12>>[F:19][C:20]1[CH:21]=[C:22]([NH:46][C:47]([NH:49][C:50](=[O:58])[CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)=[S:48])[CH:23]=[CH:24][C:25]=1[O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]2[CH:33]=[CH:34][S:35][C:28]=12
Reactant: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1
Agent: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Yield: 29 %

Procedure:
Starting from the amine 169 and following the procedure described above for the synthesis of compound 50 (scheme 10, example 55), title compound 170a was obtained in 29% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.46 (s, 1H), 11.81 (s, 1H), 8.52(d, J=5.2 Hz, 1H), 8.17(d, J=5.2 Hz, 1H), 8.01(dd, J=2.0 and 11.2 Hz, 1H), 7.60(d, J=5.2 Hz, 1H), 7.58-7.48 (m, 2H), 7.36-7.30 (m, 4H), 7.30-7.22 (m, 1H), 6.64(d, J=5.2 Hz, 1H), 3.82 (s, 2H). LRMS (M+1) 437.5 (100%).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH3:29])[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=3)=[CH:17][C:11]=2[N:10]([CH3:30])[C:9]1=[O:31])(=O)C.O[Li].O>C1COCC1.O.C(Cl)Cl>[OH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH3:29])[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=3)=[CH:17][C:11]=2[N:10]([CH3:30])[C:9]1=[O:31]
Reactant: CC(=O)OCCCn1c(=O)c2c(cc(-c3cccc(OC(F)(F)F)c3)n2C)n(C)c1=O
Agent: [Li]O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)cc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
To a solution of 3-(1,5-dimethyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (30 mg, 0.068 mmol) in THF (5 mL) and water (5 mL) was added LiOH.H2O (5.73 mg, 0.136 mmol). The reaction was stirred at RT for 30 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 Prep HPLC to give 3-(3-hydroxypropyl)-1,5-dimethyl-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (10 mg, 36.9% yield) as a white solid. 1H NMR (CDCl3) δ: 7.54 (t, J=7.9 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.32 (d, J=11.0 Hz, 2H), 6.03 (s, 1H), 4.29-4.17 (m, 2H), 3.98 (s, 3H), 3.72 (s, 1H), 3.54 (t, J=5.1 Hz, 2H), 3.50 (s, 3H), 1.99-1.84 (m, 2H). LCMS: MH+ 398 and TR=2.507 min.
Reaction SMILES: O1CCN([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3[CH:34]=[C:33]([C:35](=[O:48])[NH:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=4)[CH:32]=[CH:31][N:30]=3)[CH:8]=2)CC1.[CH3:49][OH:50]>>[CH3:49][O:50][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=2)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]2[CH:34]=[C:33]([C:35](=[O:48])[NH:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:47])[F:46])[CH:39]=3)[CH:32]=[CH:31][N:30]=2)[CH:8]=1
Reactant: CO
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Product: COc1ccc(NC(=O)c2cccc(CSCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of 3-((3-((4-morpholino-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzyl)thio)propanoic acid 14, using methanol in place of morpholine. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.40 (s, 1H), 9.55 (m, 1H), 8.98-8.96 (m, 1H), 8.39-8.36 (m, 2H), 7.87-7.47 (m, 10H), 7.16-7.14 (m, 1H), 4.62-4.61 (m, 2H), 3.88 (s, 1H), 3.86 (s, 3H), 2.62-2.58 (m, 2H). MS (ES, m/z): 624 [M+H]+.