Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([N:11]2[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12]2)[C:3]2[N:4]([CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[C:17]1([N:23]2[CH:27]=[N:26][C:25]([C:28](O)=[O:29])=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:17]1([N:23]2[CH:27]=[N:26][C:25]([C:28]([NH:16][C@H:13]3[CH2:14][CH2:15][N:11]([C:2]4[C:3]5[N:4]([CH:8]=[CH:9][CH:10]=5)[CH:5]=[CH:6][N:7]=4)[CH2:12]3)=[O:29])=[N:24]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1ncn(-c2ccccc2)n1
Reactant: N[C@H]1CCN(c2nccn3cccc23)C1
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CCN(c2nccn3cccc23)C1)c1ncn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
To a suspension of (S)-1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-amine hydrochloride salt (60 mg, 0.21 mmol) and 1-phenyl-1H-1,2,4-triazole-3-carboxylic acid (40 mg, 0.21 mmol) in DMF (5 mL) was added diethylisopropyl amine (650 mg, 5 mmol), followed by HATU (80 mg, 0.21 mmol). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was then diluted with ethyl acetate and washed with saturated aqueous solutions of KH2PO4 and NaHCO3, followed by brine. The organic layer was concentrated in vacuo and the residue purified by reverse phase HPLC (acetonitrile-H2O with 0.1% TFA as eluent) to give 15 mg of the title compound (18% yield) as white solid. MS: (ES) m/z found 374.1
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.[NH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1.[Cl:36][C:37]1[CH:38]=[C:39]([CH:53]=[CH:54][C:55]=1[Cl:56])[CH2:40][N:41]([CH3:52])[C:42]([C:44]1[CH2:45]N(C)[C:47](=[O:50])[C:48]=1[OH:49])=[O:43]>>[Cl:36][C:37]1[CH:38]=[C:39]([CH:53]=[CH:54][C:55]=1[Cl:56])[CH2:40][N:41]([CH3:52])[C:42]([C:44]1[CH2:45][N:23]([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([S:32](=[O:33])(=[O:34])[NH2:35])=[CH:30][CH:31]=2)[C:47](=[O:50])[C:48]=1[OH:49])=[O:43]
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCc2ccc(S(N)(=O)=O)cc2)C1
Yield: 19 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 4-(2-amino-ethyl)benzenesulfonamide as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (47.9 mg, 19% yield). Decomposition point=110–113° C. 1H NMR (500 MHz, DMSO) δ: 10.97 (s, 1H), 7.72, (m, 2H), 7.61 (d, 1H, J=8.54), 7.51 (s, 1H), 7.42 (m, 2H), 7.29 (m, 2H), 7.25, (m, 1H), 4.56, (s, 2H), 4.04, (s, 2H), 3.67 (m, 2H), 3.34 (m, 2H), 2.95 (d, 3H, J=6.41). HRMS (M−H) calcd for C21H20SN3Cl2O5: 496.0500. found: 496.0503.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](=[O:32])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](=[O:32])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20](=[O:31])[C:21]2[CH:22]=[CH:23][C:24]([C:27]([CH3:28])([CH3:29])[CH3:30])=[CH:25][CH:26]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(NC(=O)c2ccccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc(OC)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(O)cc(NC(=O)c2ccccc2NC(=O)c2ccc(C(C)(C)C)cc2)c1
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a stirred suspension N-(3,5-dimethoxyphenyl)-2-[(4-tert-butylbenzoyl)amino]benzamide (1.0 g, 2.3 mmol) in dichloromethane (42 mL) was added a solution of boron tribromide (0.66 mL, 6.9 mmol) in dichloromethane (7 mL) via an addition funnel. After 30 min, a second portion of boron tribromide (0.66 mL, 6.9 mmol) in dichloromethane (7 mL) was added. After 30 min, saturated aqueous sodium bicarbonate solution was added and the solvents were removed in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 30% ethyl acetate/70% hexanes) provided 96 mg (10%) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([N:25]2[C:29]([NH2:30])=[CH:28][C:27]([CH3:31])=[N:26]2)=[CH:17][N:16]=1>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:30][C:29]2[N:25]([C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]=[N:16][CH:17]=3)[N:26]=[C:27]([CH3:31])[CH:28]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(N)n(-c2cncc3ccccc23)n1
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n(-c2cncc3ccccc23)n1
Temperature: 80 °C
Yield: 33.3 %

Procedure:
A mixture of 4-t-butylbenzenesulfonyl chloride (0.10 g, 0.43 mmol) and 1-(isoquinolin-4-yl)-3-methyl-1H-pyrazol-5-amine (0.080 g, 0.36 mmol) in pyridine (5 mL) was heated at 80° C. for 15 h with stirring. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 50-100% ethyl acetate in hexanes) to give the title compound as a white solid (0.18 g, 0.12 mmol, 27%). 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.02 (s, 1H), 8.87 (dd, J=1.6, 6.8 Hz, 1H), 7.58-7.53 (m, 2H), 7.58 (s, 1H), 7.56 (s, 1H), 7.39-7.35 (m, 3H), 6.25 (s, 1H), 2.34 (s, 3H), 1.32 (s, 9H); MS: (ES) m/z calculated for C23H25N4O2S [M+H]+ 421.2. found 422.2.
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:22]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>>[CH3:1][C:2]1[C:11]([NH:12][C:13]([N:35]2[CH2:34][CH2:33][N:32]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[CH2:37][CH2:36]2)=[O:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: Cc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Product: Cc1nc2ccccc2cc1NC(=O)N1CCN(c2cccc3ccccc23)CC1
Yield: 64 %

Procedure:
Phenyl N-(2-methylquinolin-3-yl)carbamate and 1-(1-naphthyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4]2([CH2:12][CH2:11][N:10](C(OCC3C=CC=CC=3)=O)[CH2:9][CH2:8]2)[NH:3]1.C(OC(N1CCCCC1=O)=O)C1C=CC=CC=1.[H][H].N1CC(=O)NC1=O>C(O)C.[Pd].C(O)(=O)C>[NH:3]1[C:4]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5](=[O:7])[NH:6][C:2]1=[O:1]
Reactant: [H][H]
Reactant: O=C1NC(=O)C2(CCN(C(=O)OCc3ccccc3)CC2)N1
Agent: [Pd]
Agent: O=C1CCCCN1C(=O)OCc1ccccc1
Agent: O=C1CNC(=O)N1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1NC(=O)C2(CCNCC2)N1
Temperature: 60 °C

Procedure:
To a solution of 14.6 g (48.1 mmol) benzyl 2,4-dioxo-1,3,8-triaza-spiro[4.5]decan-8-carboxylate (prepared from N-(benzyloxycarbonyl)piperidone by the method from J. Med. Chem. 1995, 38, 3772) in 250 ml dry ethanol were added 500 mg 10% Pd/C, and the mixture was filled into an autoclave. After stirring at 60° C. and 10 atm of hydrogen for 3 h no starting hydantoin could be detected by TLC. A precipitate had been formed which was redissolved by addition of 100 ml acetic acid. The catalyst was removed by filtration and the solution was concentrated in vacuo. Aqueous sodium bicarbonate solution was added until the mixture became a clear solution, and the title compound precipitated in two crops upon concentration in vacuo.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:16][O:17][CH2:18][CH3:19])[CH2:12][C:13]([OH:15])=O)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[NH2:20][C:21](=[N:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[S:22][CH3:23].C(N(CC)CC)C>ClCCl>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](=[N:16][O:17][CH2:18][CH3:19])[CH2:12][C:13](=[O:15])[NH:20][C:21](=[N:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[S:22][CH3:23])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(CC(=O)O)=NOCC)cc1
Reactant: CSC(N)=NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOc1ccc(C(CC(=O)NC(=NC(=O)OC(C)(C)C)SC)=NOCC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.1 %

Procedure:
A mixture of 3-(4-(Allyloxy)phenyl)-3-(ethoxyimino)propanoic acid from Step C (850 mg), tert-butyl amino(methylthio)methylenecarbamate (675 mg), Py.Bop (2.01 g), and triethylamine (0.68 mL) in dichloromethane (1.8 mL) was stirred at room temperature for 12 h. The crude reaction mixture was purified directly by Boitage flash chromatography eluting with 15-30% ethyl acetate/85-70% hexanes to give the title compound as a white solid (1.14 g). HPLC retention time: 2.37 min (method A). MS (ESI) (M+Na)+ 436.25.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:37]1[N:38]=[N:39][CH:40]=[CH:41][CH:42]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:37]4[N:38]=[N:39][CH:40]=[CH:41][CH:42]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Clc1cccnn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2cccnn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 3-chloropyridazine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.067, m/z=436.1; 1H NMR (CDCl3) 0.82 (m, 3H), 1.52 (d, 3H), 1.65 (m, 1H), 1.80-1.98 (m, 2H), 2.11-2.28 (m, 3H), 2.91 (m, 1H), 3.51 (t, 3H), 5.68 (m, 1H), 6.94-7.04 (m, 4H), 7.18 (m, 2H), 7.47 (m, 1H), 7.71 (d, 1H), 7.78 (d, 2H), 9.08 (d, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[C@H:6]([CH3:9])[NH:7][CH3:8])[CH3:3].[H-].[Na+].[C:13]([S:16][CH2:17][CH2:18][C:19](Cl)=[O:20])(=[O:15])[CH3:14].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:2]([O:4][C:5](=[O:10])[C@@H:6]([N:7]([C:19](=[O:20])[CH2:18][CH2:17][S:16][C:13](=[O:15])[CH3:14])[CH3:8])[CH3:9])[CH3:3]
Reactant: CCOC(=O)[C@H](C)NC
Reactant: CC(=O)SCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)N(C)C(=O)CCSC(C)=O
Yield: 75.2 %

Procedure:
The solution of 15 g (89.5 mmol) of N-methylalanine ethyl ester-hydrochloride in 850 ml of anhydrous tetrahydrofuran is mixed at 23° C. with 4.1 g of an approximately 60% sodium hydride dispersion and, after 3 hours, with 23.5 g of 3-acetylsulfanyl-propanoic acid chloride. It is allowed to react for two days, mixed with saturated sodium bicarbonate solution, and extracted several times with ethyl acetate. The combined organic extracts are washed with saturated sodium chloride solution, dried over sodium sulfate, and the residue that is obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel. 17.6 g (67.3 mmol, 75%) of the title compound is isolated as a colorless oil.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[C:15]([O:18][C:19]3[CH:20]=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:34])[C:8]1=[O:35])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:35])[N:9]([CH3:34])[C:10]=3[N:17]=[CH:16][C:15]=2[O:18][C:19]2[CH:20]=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=2)=[CH:32][CH:31]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cncc(Cl)c3)cnc21
Agent: [Li]O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cncc(Cl)c3)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-6-((5-chloropyridin-3-yl)oxy)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (40 mg, 0.078 mmol) in THF (6 mL) and water (6 mL) was added LiOH.H2O (6.51 mg, 0.156 mmol) at 20° C. The reaction was stirred at RT for 30 min. then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-6-((5-chloropyridin-3-yl)oxy)-3-(3-hydroxypropyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (8 mg, 21.2% yield) as a white solid. 1H NMR (CDCl3) δ: 8.52 (s, 1H), 8.39 (d, J=3.0 Hz, 1H), 8.10 (s, 1H), 7.71 (d, J=3.0 Hz, 1H), 7.17 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 4.24 (t, J=6.1 Hz, 2H), 4.19 (s, 2H), 3.72 (s, 3H), 3.57 (d, J=5.0 Hz, 2H), 2.99 (s, 1H), 2.00-1.85 (m, 2H). LCMS MH+ 487 and TR=2.436 min.
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8]O)[O:4][C@H:3]1[N:10]1[CH:17]=[C:16]([CH2:18][CH3:19])[C:14](=[O:15])[NH:13][C:11]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:39]=[N+:40]=[N-:41].[Na+].C(Br)(Br)(Br)Br>CO.CN(C)C=O>[N:39]([CH2:8][C@H:5]1[O:4][C@@H:3]([N:10]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[C@@H:2]([F:1])[C@@H:6]1[OH:7])=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: CCc1cn([C@@H]2O[C@H](CN=[N+]=[N-])[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.6 %

Procedure:
A mixture of 0.4 g of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil, 0.44 g of triphenylphosphine, 0.48 g of sodium azide and 6 ml of dry dimethylformamide was stirred at room temperature under nitrogen while 0.48 g of carbon tetrabromide was added portionwise. The mixture was stirred at room temperature under nitrogen for 20 hours. 3 ml of methanol were added, the mixture was stirred for 0.5 hour and then evaporated. The residue was stirred for 0.5 hour with 8 ml of 0.5M sodium hydroxide solution. The resulting suspension was filtered and the insoluble triphenylphosphine oxide was washed with water. The filtrate was acidified to pH 5 by the addition of hydrochloric acid and then extracted three times with 20 ml of ethyl acetate. The extracts were dried over magnesium sulfate, filtered and evaporated. The residual solid was washed on to a filter with 10 ml of diethyl ether/petroleum ether (1:1) and then dried in vacuo to give 0.4 g of 1 -(5-azido-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil as a white solid of melting point 185°-188° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C@@H:5]([O:21][CH2:22][CH:23]=[CH2:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[C@@H:5]([O:21][CH2:22][CH2:23][CH3:24])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: C=CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCCO[C@@H](Cc1ccc(O)cc1)C(=O)OCC
Reaction time: 18 h

Procedure:
A mixture of (S)-2-allyloxy-3-(4-benzyloxy-phenyl)-propionic acid ethyl ester (1.33 mmol, 450 mg) and 10% Pd/C (45 mg) in EtOH (15 mL) were stirred under hydrogen atmosphere (1 atm) for 18 hours. The mixture was filtered through celite and concentrated under vacuum to afford the title product. 1H-NMR (200.15 MHz, CDCl3): δ 7.10 (d, 4H, J=8.6), 6.73 (d, 2H, J=8.4), 5.90 (brs, 1H), 4.16 (q, 2H, J=7.3), 3.94 (t, 1H, J=6.7), 3.53–3.45 (m, 1H), 3.27–3.16 (m, 1H), 2.93 (d, 2H, J=6.5), 1.54 (m, 2H), 1.22 (t, 3H, J=7.3), 0.84 (t, 3H, J=7.5).
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.C(=O)([O-])[O-].[K+].[K+].[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:22][SH:23]>CN(C=O)C>[NH2:7][C:6]1[C:5]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:4]=2[S:23][C:22]=1[C:21]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc([N+](=O)[O-])ccc2c1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.4 %

Procedure:
2,4-Dinitrobenzonitrile (5.08 g, 26.3 mmol) was dissolved in DMF (55 ml). Potassium carbonate (4.36 g, 31.6 mmol) and ethyl thioglycolate (3.17 g, 26.3 mmol) were added, and the mixture was stirred at room temperature for three days. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was recrystallized from ethyl acetate/hexane to obtain 2.27 g of the title compound as crystals (32%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5]2.N1C=CN=C1C(OCC)=O.[H-].[Na+].BrC1CC2C(=CC([Cl:44])=CC=2)C1=O>ClCCl.C(OCC)(=O)C.CN(C)C=O>[Cl:44][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH:6]([N:12]3[CH:16]=[CH:15][N:14]=[C:13]3[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]2=[O:11])=[CH:3][CH:2]=1
Reactant: O=C1c2cc(Cl)ccc2CC1Br
Reactant: CCOC(=O)c1nccn1C1Cc2cc(F)ccc2C1=O
Agent: CCOC(=O)c1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nccn1C1Cc2ccc(Cl)cc2C1=O

Procedure:
The ethyl 1-(6-chloro-1-oxo-1-indanyl)imidazole-2-carboxylate can be prepared as in Example 1 for the preparation of ethyl 1-(5-fluoro-1-oxo-2-indanyl)imidazole-2-carboxylate but starting with 2.5 g of ethyl imidazole-2-carboxylate, 0.7 g of 80% sodium hydride, 5.4 g of 2-bromo-6-chloro-1-indanone and a total of 70 ml of anhydrous dimethylformamide. After silica gel chromatography with a dichloromethane-ethyl acetate mixture (70-30 by volume), 1 g of ethyl 1-(6-chloro-1-oxo-2-indanyl)imidazole-2-carboxylate is obtained which melts at 180° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N+:37]([O-])=O)=[S:29])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.Cl.C(O)C.N>[Fe].CO.O>[NH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[NH:30][C:28]([NH:27][CH2:26][CH2:25][N:22]1[CH2:21][CH2:20][CH:19]([NH:18][C:10]2[N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH2:24][CH2:23]1)=[S:29]
Reactant: O=[N+]([O-])c1ccccc1NC(=S)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Solvent: CCO
Product: Nc1ccccc1NC(=S)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1

Procedure:
A mixture of 3.7 parts of N-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl]-N'-(2-nitrophenyl)thiourea, 7 parts of iron-powder, 0.25 parts of concentrated hydrochloric acid, 48 parts of ethanol and 15 parts of water is stirred and refluxed for 1 hour. The reaction mixture is alkalized with methanol saturated with ammonia. The whole is filtered and the filtrate is evaporated, yielding 3.5 parts of N-(2-aminophenyl)-N'-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}-ethyl]thiourea as a residue.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]2[CH:10]=[CH:11][O:12][C:6]=2[C:5]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[C:25](=[O:37])[N:26]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH:27]=[CH:28][CH:29]=2)=[O:23])=[CH:17][CH:16]=1)([O-])=O.CCO.[NH4+].[Cl-]>[Fe].ClCCCl>[NH2:1][C:4]1[N:9]=[CH:8][C:7]2[CH:10]=[CH:11][O:12][C:6]=2[C:5]=1[O:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]2[C:25](=[O:37])[N:26]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[CH:27]=[CH:28][CH:29]=2)=[O:23])=[CH:19][CH:20]=1
Reactant: O=C(Nc1ccc(COc2c([N+](=O)[O-])ncc3ccoc23)cc1)c1cccn(-c2ccc(F)cc2)c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CCO
Product: Nc1ncc2ccoc2c1OCc1ccc(NC(=O)c2cccn(-c3ccc(F)cc3)c2=O)cc1
Temperature: 75 °C

Procedure:
The mixture of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid [4-(6-nitrofuro[3,2-c]pyridin-7-yloxymethyl)phenyl]amide (13.8 mg, 0.0248 mmol), iron powder (62 mg, 1.1 mmol), EtOH (1.5 ml), 1,2-Dichloroethane (1.5 ml), and saturated NH4Cl (0.3 ml) was heated at 75° C. for 30 min. After that time, the solvent was removed, and it was then dissolved in DMSO for Gilson HPLC purification. It gave the title compound as a light-yellow solid. 1H NMR (400 MHz, CDCl3): δ=4.55 (brs, 2H), 5.35 (s, 2H), 6.60 (dd, J=6.8 & 7.2 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 7.24-7.29 (m, 2H), 7.38-7.43 (m, 4H), 7.43 (d, J=2.4 Hz, 1H), 7.60 (dd, J=2.0 & 6.8 Hz, 1H), 7.73 (dd, J=2.0 & 6.4 Hz, 2H), 8.07 (s, 1H), 8.75 (dd, J=2.0 & 6.8 Hz, 1H), 11.85 (brs, 1H). MS (ES+): m/z 471.05 [MH+]. HPLC: tR=2.60 min (polar—5 min, ZQ3).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18]Br.O>C1COCC1>[CH3:9][C:7]1[CH:6]=[CH:5][C:3]2[NH:4][CH2:18][CH2:17][O:1][C:2]=2[CH:8]=1
Reactant: Cc1ccc(N)c(O)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)OCCN2
Yield: 57.6 %

Procedure:
A solution of 2-hydroxy-4-methyl aniline (5.0 g, 40 mmol), potassium carbonate (16.56 g, 120 mmol) and 1,2-dibromoethane (3.8 g, 20 mmol) in THF (20 mL) was heated at 100° C. in pressure-gauge-steel vessel for 16 h. The completion of reaction was monitored by LCMS. The reaction mixture was poured into water (40 mL) and extracted with EtOAc (250 mL). The organic layer was dried over sodium sulfate, evaporated and the residue purified by column chromatography to obtain 1.72 g of 3,4-dihydro-7-methyl-2H-benzo[b][1,4]oxazine (free base).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:55][OH:56])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:55]=[O:56])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCc4ccccc4)cc3)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: ClCCl
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCc4ccccc4)cc3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[(4-benzyloxyphenyl)methyl]-4-chloro-phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 25h (1.0 g, 1.3 mmol) in dichloromethane (20 mL) was added 2-iodoxybenzoic acid (1.09 g, 3.9 mmol) at room temperature. The mixture was refluxed for 16 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give the title compound 25i as a yellow solid (1.0 g, 100%). This material was not further purified.