Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH:7]([CH3:26])[C:8]([O:10][CH2:11][CH2:12][O:13][C:14](=[O:25])[CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH3:16])=[O:9])=[CH:4][CH:3]=1.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl.[O:41]1CCOC[CH2:42]1>>[N:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH:15]([CH3:16])[C:14]([O:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[CH:7]([O:6][C:5]2[CH:27]=[CH:28][C:2]([N:1]=[C:42]=[O:41])=[CH:3][CH:4]=2)[CH3:26])=[O:25])=[CH:23][CH:22]=1)=[C:30]=[O:32]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1COCCO1
Reactant: CC(Oc1ccc(N)cc1)C(=O)OCCOC(=O)C(C)Oc1ccc(N)cc1
Product: CC(Oc1ccc(N=C=O)cc1)C(=O)OCCOC(=O)C(C)Oc1ccc(N=C=O)cc1
Temperature: 77.5 °C
Yield: 66.5 %

Procedure:
2-(4-Aminophenoxy)propionic acid-2-[2-(4-aminophenoxy)propionyloxy]ethyl ester 50 (5.3 g, 13.6 mmol) was dissolved in dry dioxane (80 ml) under nitrogen atm. and cooled below 20° C. A solution of triphosgene (7 g, 23.6 mmol) in dry dioxane (20 ml) was added dropwise. The mixture was heated slowly to 75-80° C. and maintained for 2½ hours. The condenser was then arranged for distillation and solvent removed by distillation at atmospheric pressure until the volume of reaction mixture was reduced to approximately one third. Fresh dry dioxane (50 ml) was added and the solvents were distilled off under vacuum. The residue was re-evaporated two times from dry dioxane to give pure 51 (4 g, 66.5%) as a light brown liquid.
Reaction SMILES: [C:1]([S:9][C@@H:10]1[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[O:12][C@H:11]1[N:18]1[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]1=[O:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>N1C=CC=CC=1>[Si:31]([O:17][CH2:16][C@H:13]1[O:12][C@@H:11]([N:18]2[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@H:10]([S:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@@H:14]1[OH:15])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: O=C(S[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](SC(=O)c2ccccc2)[C@@H]1O

Procedure:
2'-Deoxy-2'-(benzoylthio)uridine (2.75 mmole) was dried by co-evaporation with dry pyridine (2×20 ml) and dissolved in dry pyridine (50 ml) containing imidazole (5 mmole); tert-butyldimethylsilyl chloride (5 mmole) was added with stirring. The reaction mixture was stirred at room temperature for 16 hr. Solvent was removed under vacuo and the residue was dissolved in CH2Cl2 (100 ml), washed with 5% sodium bicarbonate solution (2×50 ml) and dried over anhydrous sodium sulfate. Removal of solvent gave crude product 5'-O-(tert-butyldimethylsilyl)-2'-deoxy-2'-(benzoylthio) uridine which was purified on silica gel column chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:22]=C)=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].CC(C)=[O:26].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[Cl:1][C:2]1[C:3]([CH:22]=[O:26])=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(OC)cc2)c(C)c1Cl
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(OC)cc2)c(C)c(Cl)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-chloro-5-(4-methoxybenzyl)-4-methyl-2-vinylbenzoate (0.31 g) in a mixed solvent of acetone (3.60 mL)-acetonitrile (3.60 mL)-water (3.60 mL) were added osmium oxide (fixed catalyst I) (0.12 g) and sodium periodate (1.00 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.31 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:10]=[CH:11][C:12]2[O:13]C(C3C=CC=CC=3)[O:15][CH2:16][C:17]=2[N:18]=1)[CH2:3][NH:4][C:5]([CH3:8])([CH3:7])[CH3:6].[ClH:25]>CC(C)=O.O>[ClH:25].[ClH:25].[OH:15][CH2:16][C:17]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]([CH:2]([OH:1])[CH2:3][NH:4][C:5]([CH3:7])([CH3:6])[CH3:8])[N:18]=1
Reactant: CC(C)(C)NCC(O)c1ccc2c(n1)COC(c1ccccc1)O2
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)NCC(O)c1ccc(O)c(CO)n1

Procedure:
One and five-tenths grams (4.8 m moles) of the above intermediate 6-(1-hydroxy-2-t-butylaminoethyl)-2-phenyl-4H-pyrido[3,2-d]-1,3-dioxin is dissolved in 20 ml. of acetone-water (1:1 v/v) and is treated with 1 ml. of 12N hydrochloric acid. After heating the solution to reflux for 5 hrs. the mixture is concentrated to an oil and dissolved in 100 ml. of ethanol. The water is azeotroped with 3 × 100 ml. portions of ethanol and the free base of the product generated by the addition of triethylamine. The solution is concentrated in vacuo to an oily slurry and the free base extracted from the triethylamine hydrochloride by extraction with acetone. The acetone extracts are combined, concentrated to an oil and the oil dissolved in 10 ml. of dry ethanol. Ethanol (.184 ml.) containing hydrogen chloride (188 gm. HCl/ml. ethanol) is added and the solution added dropwise to 2 l. of dry isopropyl ether. The product is filtered and dried, 1.05 g. Further purification by recrystallization from methanol-acetone provides 950 mg. of the product which by infrared and nuclear magnetic resonance spectroscopy and thin-layer chromatography are identical to that in U.S. Pat. No. 3,700,681.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([NH:18][CH3:19])=[O:17])[C:5]([CH3:12])=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH2:7]2.[Li]CCCC.[CH3:29][O:30][C:31]1([CH3:42])[C:36]([O:38][CH3:39])([CH3:37])[O:35][C@@H:34](C#N)[CH2:33][O:32]1>C1COCC1>[CH3:39][O:38][C:36]1([CH3:37])[C:31]([O:30][CH3:29])([CH3:42])[O:32][C@@H:33]([C:19]2[NH:18][C:16](=[O:17])[C:15]3[C:14]([C:13]=2[C:4]2[C:5]([CH3:12])=[C:6]4[C:11](=[C:2]([F:1])[CH:3]=2)[O:10][CH2:9][CH2:8][CH2:7]4)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:34][O:35]1
Reactant: CNC(=O)c1ccccc1Cc1cc(F)c2c(c1C)CCCO2
Reactant: COC1(C)OC[C@H](C#N)OC1(C)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1(C)OC[C@H](c2[nH]c(=O)c3ccccc3c2-c2cc(F)c3c(c2C)CCCO3)OC1(C)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
An ice cooled suspension of 2-((8-fluoro-5-methylchroman-6-yl)methyl)-N-methylbenzamide (300 mg, 0.957 mmol) in THF (5 mL) was treated with 2.5M nBuLi in hexanes (804 μl, 2.010 mmol). Upon addition of the n-BuLi, the reaction became homogeneous and dark red in color. After 10 min, a solution of (2S)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-carbonitrile (289 mg, 1.436 mmol) in THF (0.5 mL) was added and the colorless solution was maintained at 0° C. for 5 min. The reaction was quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by ISCO (0-10% MeOH-DCM) to afford the title compound (408 mg, 0.844 mmol, 88% yield) as a 1:1 mixture of diastereomers as a pale yellow foam. LC/MS (m/z) ES+=484 (M+1). Rt=2.17, 2.20.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1[NH:19][C:20]([CH3:25])=[C:21]([CH:23]=O)[N:22]=1.[C:26](O)(=[O:28])C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[CH2:25][C:20]3=[C:21]([CH3:23])[N:22]=[C:18]([CH3:17])[N:19]3[C:26]2=[O:28])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCC1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)O
Reactant: Cc1nc(C=O)c(C)[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc(C)n2c1CN(CCC1CCN(Cc3ccccc3)CC1)C2=O
Yield: 32 %

Procedure:
To a solution of 2-(1-benzyl-4-piperidinyl)ethanamine (2.2 g), 2,5-dimethylimidazole-4-carbaldehyde (1.2 g) and acetic acid (0.3 ml) in 1,2-dichloroethane (25 ml) was added sodium triacetoxyborohydride (8.1 g) under ice-cooling. The reaction mixture was mixed at room temperature for 2 days, and then the reaction solution was washed with an aqueous potassium carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in THF (50 ml). To the reaction solution were added N,N′-carbonyldiimidazole (1.6 g) and DBU (1.6 ml), and mixed at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform. The reaction mixture was then washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified with basic silica gel column (ethyl acetate/methanol=10/1). The product was recrystallized from ethyl acetate-hexane to obtain the title compound as colorless powder (1.3 g, 32%).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[F:28][C:29]([F:41])([F:40])[O:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35]>C1(C)C=CC=CC=1>[F:28][C:29]([F:40])([F:41])[O:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:35]
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1cccc(OC(F)(F)F)c1
Temperature: 103 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.0 g) and triethylamine (0.6 ml), and a solution of 3-trifluoromethoxybenzoyl chloride (0.5 g) dissolved in toluene (10 ml) was gradually added thereto under cooling and the mixture was stirred at 103° C. for 3 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16](N(C)C)=[O:17])=[N:11][C:10]([OH:21])=[C:9]([OH:22])[C:8]=2[C:7]1=[O:23].C[O-:29].[Mg+2].C[O-].Br[CH2:34][CH2:35]Cl>CO.CS(C)=O.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:22])[C:10](=[O:21])[N:11]3[CH2:35][CH2:34][O:29][C:16](=[O:17])[C:12]3=2)[C:7]1=[O:23]
Reactant: CN(C)C(=O)c1nc(O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: ClCCBr
Reactant: C[O-]
Agent: Cl
Agent: [Mg+2]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1OCCn2c1c1c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide (0.15 g, 0.39 μmmol; Example 1, Step 9) and magnesium methoxide in methanol (2 mL, 6-10% methanol solution available from Aldrich) in DMSO (4 mL) was heated at 60° C. for 30 minutes. Methanol was exhaustively removed under vacuum over 45 minutes. The resultant DMSO solution was treated with 1-bromo-2-chloroethane (0.28 g, 1.97 mmol) and stirred at 60° C. under an atmosphere of nitrogen overnight. The reaction mixture was diluted with ethyl acetate and dilute hydrochloric acid. The organic extract was washed with aqueous sodium sulfite, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by reverse phase high pressure liquid chromatography. Collection and lyophilization of appropriate fractions provided the title compound, which was recrystallized from a mixture of ethyl acetate and hexane
Reaction SMILES: ClCI.[Br:4][C:5]1[CH:6]=[N:7][C:8]([OH:22])=[C:9]([CH:21]=1)[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:11].[C:23]([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:4][C:5]1[CH:6]=[N:7][C:8]2[O:22][CH2:23][N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[C:10](=[O:11])[C:9]=2[CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCc1ccc(F)cc1)c1cc(Br)cnc1O
Agent: ClCI
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2cc(Br)cnc2OCN1Cc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 9 %

Procedure:
Chloroiodomethane (897 mg, 5.1 mmol) was slowly added to a mixture of 5-bromo-N-(4-fluorobenzyl)-2-hydroxynicotinamide (1.5 g, 4.6 mmol) and Cs2CO3 (6.0 g, 18.4 mmol) in DMF (20 mL) at 100° C. The mixture was stirred at 100° C. for 2 h. Water was added and the mixture was extracted with EtOAc. After being concentrated, the residue was purified by column chromatography (PE:EtOAc=2:1) to give the product of 6-bromo-3-(4-fluorobenzyl)-2H-pyrido[3,2-e][1,3]oxazin-4(3H)-one (140 mg, yield: 9%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.46 (d, J=2.4 Hz, 1H), 8.44 (d, J=2.4 Hz, 1H), 7.40 (dd, J=5.6, 8.8 Hz, 2H), 7.09 (t, J=8.8 Hz, 2H), 5.40 (s, 2H), 4.74 (s, 2H). MS (M+H)+: 337/339.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]=[CH:12][C:11]2[NH:10][C:9]3[N:14]=[CH:15][C:16]([Br:18])=[CH:17][C:8]=3[C:7]=2[CH:6]=1)=O.O.[NH2:20][NH2:21]>C(O)C>[Br:18][C:16]1[CH:15]=[N:14][C:9]2[NH:10][C:11]3[CH:12]=[N:13][C:5]([C:3]([NH:20][NH2:21])=[O:2])=[CH:6][C:7]=3[C:8]=2[CH:17]=1
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ncc(Br)cc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cc2c(cn1)[nH]c1ncc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (582 mg, 1.90 mmol) and hydrazine hydrate (2.29 mL, 47.0 mmol) in ethanol (4.6 mL) was heated under reflux in an inert atmosphere. After 1 h, the reaction mixture was allowed to cool to ambient temperature. The resultant precipitate was collected by filtration, washed with ethanol, and left to air-dry to afford the title compound as a tan-yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[S:20][C:19]([NH:21][CH3:22])=[N:18][C:17]=3[CH3:23])[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CC#N>[CH3:23][C:17]1[N:18]=[C:19]([NH:21][CH3:22])[S:20][C:16]=1[C:14]1[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][NH:1][S:25]([CH3:24])(=[O:27])=[O:26])[N:15]=1
Reactant: CNc1nc(C)c(-c2ccnc(Nc3cccc(CN)c3)n2)s1
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Product: CNc1nc(C)c(-c2ccnc(Nc3cccc(CNS(C)(=O)=O)c3)n2)s1

Procedure:
By treatment of (3-aminomethyl-phenyl)-[4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl]-amine with methane-sulfonyl chloride. Yellow solid. Anal. RP-HPLC: tR=12.8 min (0-60% MeCN, purity >95%). 1H-NMR (CD3OD) δ: 2.53 (s, 3H, CH3), 2.88 (s, 3H, CH3), 2.98 (s, 3H, CH3), 4.28 (s, 2H, CH2), 6.94 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.02 (d, 1H, J=7.5 Hz, Ph-H), 7.29 (t, 1H, J=8.0 Hz, Ph-H), 7.52 (d, 1H, J=8.0 Hz, Ph-H), 7.90 (s, 1H, Ph-H), 7.98 (s, 1H, NH), 8.28 (d, 1H, J=5.5 Hz, pyrimidinyl-H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[CH2:14]([NH:21][C:6]1[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCc2ccccc2)c1C
Temperature: 55 °C
Yield: 45.7 %

Procedure:
2,4-Dichloro-5,6-Dimethyl-3-nitro-pyridine (2 g, 9 mmol) was dissolved in acetonitrile (100 mL) and benzylamine (1.0 mL, 9.5 mmol). Potassium carbonate (1.3 g, 9.5 mmol) was added in one portion, and the whole was heated at 55° C. for 16 h. The reaction mixture was diluted with EtOAc and washed with 50 mL water. The aqueous was re-extracted with EtOAc, the organics were combined and then dried over MgSO4 and evaporated to a dark red residue. This residue was purified by column chromatography on silica gel using 8:1 pentane:EtOAc as eluant to afford the title compound as a bright orange solid (1.2 g, 45%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[N:17]=[CH:18][C:19]([C:25]2[CH:26]=[N:27][N:28]([C@H:30]3[CH2:35][CH2:34][C@H:33]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:32][CH2:31]3)[CH:29]=2)=[C:20]2[CH:24]=[CH:23][O:22][C:21]=12)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[B:52](OC)([O:55]C)[O:53]C>C1COCC1>[C:1]([O:5][C:6]([N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:16]1[N:17]=[CH:18][C:19]([C:25]2[CH:26]=[N:27][N:28]([C@H:30]3[CH2:35][CH2:34][C@H:33]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:32][CH2:31]3)[CH:29]=2)=[C:20]2[CH:24]=[C:23]([B:52]([OH:55])[OH:53])[O:22][C:21]=12)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)c2ccoc12
Reactant: COB(OC)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)c2cc(B(O)O)oc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of di-tert-butyl{4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]furo[2,3-c]pyridin-7-yl}imidodicarbonate (1 g, 2 mmol) in anhydrous THF (10 mL) was added lithium diisopropylamide (2 M in THF, 1.47 mL, 2.94 mmol), and the mixture stirred for 30 min. Boric acid, trimethyl ester (0.371 mL, 3.26 mmol) was added, and the mixture stirred for 10 min before warming to 0° C. The mixture was quenched with water (0.2 mL) and warmed to RT. The THF was removed by rotary evaporation, and the residue was partitioned between ethyl acetate and water. Following separation of the layers, the organic layer was dried over sodium sulfate and evaporated. To the resulting foam was added heptane, and the solution was stirred until the particles were reduced to a powdery solid. The mixture was filtered and washed with heptane (10×). The solid was dried under vacuum to afford 0.6 g (60%) of the title compound as a beige solid. 1H NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 8.22 (s, 1 H), 8.01 (s, 1 H), 7.07 (s, 1 H), 4.39-4.18 (m, 1 H), 3.93-3.70 (m, 1 H), 2.26-2.13 (m, 2 H), 2.11-1.92 (m, 4 H), 1.60-1.53 (m, 2 H), 1.33 (s, 18 H), 0.93 (s, 9 H), 0.12 (s, 6 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.Br[CH:14]([CH2:19][CH3:20])[C:15]([O:17][CH3:18])=[O:16].Cl>C1COCC1.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9]([C:8]([CH:14]([CH2:19][CH3:20])[C:15]([O:17][CH3:18])=[O:16])=[CH:7][CH2:6]2)=[CH:10][CH:11]=1
Reactant: CCC(Br)C(=O)OC
Reactant: COc1ccc2c(c1)CCC2=O
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCC(C(=O)OC)C1=CCc2cc(OC)ccc21
Temperature: 60 °C
Yield: 104.4 %

Procedure:
An oven dried 5-L four-necked round-bottomed flask was fitted with a thermometer, a condenser, an addition funnel, and a mechanical stirrer. Under Ar protection, a suspension of 5-methoxy-1-indanone (80.0 g, 494 mmol), Zn powder (Lancaster, 56.2 g, 865 mmol) in 2 L anhydrous THF was stirred at 60° C. (internal temperature), while a solution of methyl bromobutyrate (134.1 g, 741 mmol) in 400 mL anhydrous THF was added slowly through an addition funnel. After completion of the addition, the reaction mixture was stirred at 60° C. (internal temperature) for 1 hour. The reaction was followed by TLC analysis of aliquots following 1N aqueous HCl work-up. After the reaction was completed, it was cooled in an ice-water bath followed by slow addition of 3 L of 1N HCl solution. The pot temperature was kept below 20° C. The mixture was then extracted with 1 L EtOAc. The organic layer was washed with water until pH 6.0–7.0, then saturated NaCl solution, and dried over Na2SO4. The product (127 g, >99%), a yellow oil, was obtained after solvent removal and drying under vacuum. 1H NMR (DMSO-d6) δ 7.28(d, 1H), 7.05(d, 1H), 6.82(dd, 1H), 6.22(s, 1H), 3.72(s, 3H), 3.60(m, 1H), 3.58(s, 3H), 3.28(s, 2H), 1.95(m, 1H), 1.80(m, 1H), 0.88(t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N=C=NC(C)C)(C)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH2:36][CH2:37][NH2:38])[CH:33]=[CH:34][CH:35]=1>CN(C)C=O>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH2:36][CH2:37][NH:38][C:16](=[O:18])[CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: COc1cccc(CCN)c1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COc1cccc(CCNC(=O)Cc2ccc(OCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
To a solution of 4-benzyloxyphenylacetic acid (4.85 g 20 mmol) in dimethylformamide (30 mL) under nitrogen was added 1,3-diisopropylcarbodiimide. After 2 hours, to the solution was added 2-(3-methoxyphenyl)ethylamine (3.02 g, 20 mmol) and stirred at room temperature for 20 hours. The reaction was quenched with a saturated sodium carbonate solution and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 30-70% ethyl acetate/hexane) to provide the title compound (5.74 g, 76% yield): 1H NMR (CDCl3) 7.38 (m, 5H), 7.14 (t, 1H), 7.07 (d, 2H), 6.91 (d, 2H), 6.74 (dd, 1H), 6.62 (m, 2H), 5.37 (br, 1H), 5.06 (s, 2H), 3.77 (s, 3H), 3.47 (s, 2H), 3.44 (t, 2H), 2.70 (t, 2H); ES-MS (m/z) 376 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:17]2[CH2:18][CH2:19][CH:14]([OH:13])[CH2:15][CH2:16]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: OC1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Reaction time: 72 h
Yield: 98.2 %

Procedure:
A mixture of 4-fluoro-2-(methyloxy)-1-nitrobenzene (7.52 g, 44 mmol), 4-hydroxypiperidine (4.45 g, 44 mmol) and potassium carbonate in 100 mL DMSO was stirred for 72 h. The reaction was diluted with water and extracted twice with Ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, and concentrated to give 1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinol (10.9 g, 99% yield). 1H NMR (400 MHz, d6-DMSO) δ 7.84 (d, J=9.2 Hz, 1H), 6.54 (d, J=9.6 Hz, 1H), 6.46 (s, 1H), 4.73 (d, J=4.4 Hz, 1H), 3.86 (s, 3H), 3.80-3.69 (m, 3H), 3.18-3.12 (m, 2H), 1.79-1.76 (m, 2H), 1.42-1.34 (m, 2H).