Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH2:29]([O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(O)CO>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:40][C:39]4[CH:38]=[CH:37][C:36]([O:35][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:42][CH:41]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: CCCCCCOc1ccc(N)cc1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: OCCO
Product: CCCCCCOc1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1
Temperature: 170 °C
Yield: 23.1 %

Procedure:
To a magnetically stirred solution of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (0.25 g, 0.89 mmol) in ethylene glycol (3.0 mL) under nitrogen at room temperature was added N,N-diisopropylethylamine (0.12 g, 0.89 mmol) followed by 4-hexyloxyaniline (0.27 g, 1.4 mmol). The reaction mixture was heated to 170° C. for 5.5 h, cooled to room temperature and partitioned between water (20 mL) and chloroform (20 mL). The aqueous layer was extracted with chloroform (20 mL) and the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The crude brown solid was purified by chromatography (silica gel, 2:1 hexanes/ethyl acetate) to afford N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-n-hexyloxyphenyl)-2,4-pyrimidindiamine (0.09 g, 23%) as a white solid: Rf0.53 (silica gel, 4:1 chloroform/ethyl acetate); mp 115–117° C.; 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J=3.2 Hz, 1H), 7.40 (d, J=8.9 Hz, 2H), 7.29 (d, J=2.5 Hz, 2H), 6.98 (d, J=8.8 Hz, 1H), 6.88–6.82 (m, 3H), 6.61 (s, 1H), 4.29 (d, J=3.1 Hz, 4H), 3.94 (t, J=6.6, 6.7 Hz, 2H), 1.77 (m, 2H), 1.47 (m, 2H), 1.35 (m, 4H), 0.92 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 156.3, 155.1, 150.3, 143.6, 142.7, 140.3, 140,07 139.4, 133.0, 131.7, 121.9, 117.3, 115.0, 114.7, 110.8, 68.6, 64.6, 31.8, 29.5, 25.9, 22.8, 14.2; IR (ATR) 3357 cm−1; ESI MS m/z 439 [C24H27FN4O3+H]+; HPLC (Method B) 98.5% (AUC), tR=7.9 min. Anal. Calcd for C24H27FN4O3: C, 65.74; H, 6.21; N, 12.78. Found: C, 65.34; H, 6.19; N, 12.96.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH2:11][CH:13]3[CH2:14][O:15]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: ClCC1CO1
Reactant: Oc1ccc2c(c1)CCC2
Product: c1cc2c(cc1OCC1CO1)CCC2

Procedure:
The title compound was prepared from 5-indanol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[C:10](O)(=[O:13])[CH:11]=[CH2:12]>>[C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:13])[CH:11]=[CH2:12]
Reactant: C=CC(=O)O
Reactant: CC(C)CCCCCO
Product: C=CC(=O)OCCCCCC(C)C

Procedure:
Isooctyl alcohol was reacted with acrylic acid to yield isooctyl acrylate.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])=[CH:7][CH:8]=1)[NH2:2].[CH3:15][C:16]([CH3:18])=O>>[C:16](=[N:2][NH:1][C:3]1[N:4]=[N:5][C:6]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])=[CH:7][CH:8]=1)([CH3:18])[CH3:15]
Reactant: CC(C)=O
Reactant: Cc1nccn1-c1ccc(NN)nn1
Product: CC(C)=NNc1ccc(-n2ccnc2C)nn1

Procedure:
3.0 g (15.8 millimoles) of 3-hydrazino-6-(2-methyl-imidazol-1-yl)-pyridazine are suspended in 40 ml of acetone and the suspension is heated for 10 minutes on a steam bath under reflux.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])#[N:2].[CH:11]([Mg]Br)=[CH2:12].C([O-])(=O)C.[NH4+]>C1COCC1>[OH:7][CH:6]([C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[C:1]#[N:2])[CH:11]=[CH2:12]
Reactant: C=C[Mg]Br
Reactant: N#Cc1cccc(C=O)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1cccc(C#N)c1
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To 3-cyanobenzaldehyde (25 g, 0.190 mmol) in THF (576 mL) was added dropwise at -10° C. vinyl magnesium bromide in THF (202 mL, 0.201 mmol). After 15 min, the reaction mixture was poured on cold 25% aqueous ammonium acetate solution and extracted with EtOAc. The resulting mixture was purified by flash chromatography to provide 17.5 g (60%) of the title product.
Reaction SMILES: CO[C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[NH2:5].[CH3:15][NH2:16]>C(O)C>[CH3:15][NH:16][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[NH2:5]
Reactant: COC(=O)[C@@H](N)Cc1ccc(N)cc1
Reactant: CN
Solvent: CCO
Product: CNC(=O)[C@@H](N)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a stirred solution of p-aminophenylalanine methyl ester (1.7 g, 8.8 mmol) in ethanol (150 ml) was added methylamine in ethanol (33%/8M) (100 ml). After stirring at room temperature for 24 hours the reaction mixture was reduced under pressure to yield the title compound as a brown solid (1.7 g, 100%)
Reaction SMILES: CO[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([O:21][CH3:22])=[CH:16][C:15]=3[CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:11][CH:12]=2)[N:7](C2CCCCO2)[N:6]=1)=[NH:4].C(OC([N:41]1[CH2:46][CH2:45][C:44](OCC)(OCC)[CH:43]([NH2:53])[CH2:42]1)=O)(C)(C)C.C(O)(=O)C.[ClH:58]>C(O)C>[ClH:58].[ClH:58].[ClH:58].[F:20][C:18]1[C:17]([O:21][CH3:22])=[CH:16][C:15]([CH2:23][C:24]([F:27])([F:26])[F:25])=[C:14]([C:10]2[CH:9]=[C:8]3[C:13]([C:5]([C:3]4[NH:53][C:43]5[CH2:42][NH:41][CH2:46][CH2:45][C:44]=5[N:4]=4)=[N:6][NH:7]3)=[CH:12][CH:11]=2)[CH:19]=1
Reactant: COC(=N)c1nn(C2CCCCO2)c2cc(-c3cc(F)c(OC)cc3CC(F)(F)F)ccc12
Reactant: CCOC1(OCC)CCN(C(=O)OC(C)(C)C)CC1N
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CNCC5)n[nH]c3c2)cc1F
Temperature: 50 °C
Yield: 96.8 %

Procedure:
To a solution of 6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoro-ethyl)-phenyl]-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carboximidic acid methyl ester (Preparation 37, 1.64 g, 3.78 mmol) in ethanol (5 mL) was added a solution of 3-amino-4,4-diethoxy-piperidine-1-carboxylic acid tert-butyl ester (US-2004/0229862, 1.15 g, 3.97 mmol) in ethanol (7.5 mL). Acetic acid (430 μL, 7.56 mmol) was added and the reaction mixture was heated at 50° C. for 18 hours and then concentrated in vacuo to give a brown oil. The oil was dissolved in ethanol (15 mL) and the resulting solution was treated with concentrated hydrochloric acid (12M, 4.75 mL, 56.7 mmol) and then heated at 80° C. for 18 hours. The solvent was removed in vacuo to yield the title compound (2.03 g) in a 97% yield.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].S(OC)(O[CH3:22])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:22][O:1][C:2]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Cc1ccccc1Oc1cccc(C=O)c1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C=O)cccc1Oc1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
2-Hydroxy-3-(o-tolyloxy)benzaldehyde (64.20 g), dimethyl sulfate (46.10 g) and powdered potassium carbonate (50.50 g) were added to dimethylformamide (150 ml) and stirred at room temperature for 2 hrs. The reaction mixture was poured into water (1 l), and the precipitating crystals were collected by filtration. The aqueous filtrate was extracted with diethyl ether, and the crystals obtained above were dissolved in the extract. The ether solution was washed with water, dried over magnesium sulfate and evaporated. The crystalline residue was recrystallized from methanol to give colorless crystals of 2-methoxy-3-(o-tolyloxy)benzaldehyde (48.70 g). mp 53°-55° C.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9].Cl[C:18]1[N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([N:10]1[CH2:11][CH2:12][CH:13]([O:16][C:18]2[N:23]3[CH:24]=[CH:25][N:26]=[C:22]3[CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:15]1)=[O:9]
Reactant: Clc1cccc2nccn12
Reactant: O=C(c1cccs1)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cccs1)N1CCC(Oc2cccc3nccn23)CC1
Yield: 4.6 %

Procedure:
To a suspension of 60% sodium hydride in oil (0.40 g, 10 mmoles) in dimethylformamide (30 ml) was added 1-(2-thienylcarbonyl)-4-hydroxypiperidine (2.11 g, 10 mmoles) with stirring under ice-cooling and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added 5-chloroimidazo[1,2-a]pyridine (1.53 g, 10 mmoles) with stirring under ice-cooling, followed by stirring at room temperature for 7 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate and dried. After the solvent was distilled off, the residue was purified with column chromatography [eluent: ethyl acetate/hexane (1:1)→ethyl acetate/hexane (2:1)→ethyl acetate/ethanol (50:1)] to obtain 0.15 g of the desired product (4.6%, pale yellow oily product).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH:23](I)([CH3:25])[CH3:24].Cl>CN(C)C=O.C(OCC)(=O)C>[N+:18]([C:17]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=1[NH:6][C:1](=[O:5])[CH2:2][CH2:3][CH2:4][CH:23]([CH3:25])[CH3:24])([O-:20])=[O:19]
Reactant: CC(C)I
Reactant: CCCC(=O)Nc1cc(C(=O)OCC)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(NC(=O)CCCC(C)C)c1
Reaction time: 0.5 h
Yield: 11.3 %

Procedure:
A solution of 2.00 g of ethyl 3-butyrylamino-4-nitrobenzoate in 10 ml of N,N-dimethylformamide was added dropwise to a slurry of 0.428 g of 60% sodium hydride and 10 ml of N,N-dimethylformamide at room temperature, and the mixture was stirred for 30 minutes. A solution of 1.46 g of isopropyl iodide in 10 ml of N,N-dimethylformamide was then added dropwise thereto, and the mixture was stirred at 100° C. for 5 days. The reaction solution was poured into a mixed solution of 80 g of dilute hydrochloric acid and 80 g of ethyl acetate for separation. The resulting organic layer was washed with 50 g of water, and was then concentrated under reduced pressure. The residue was purified through silica-gel column chromatography (eluent: a mixture of hexane and ethyl acetate at a ratio of 4:1) to obtain 0.260 g of crude ethyl 4-nitro-3-(N-i-propylbutyrylamino)benzoate. Subsequently, 3 ml of ethanol and 2 ml of acetic acid were added to 0.260 g of ethyl 4-nitro-3-(N-i-propylbutyrylamino)benzoate at room temperature, and 0.519 g of reduced iron were further added thereto. The mixture was heat-refluxed for 4 hours. The solid material was removed using a filtration aid, and the filtrate was concentrated. The residue were added 30 ml of ethyl acetate and 30 ml of dilute hydrochloric acid for separation. The organic layer was washed with 30 ml of water, and was then concentrated under reduced pressure. The residue was purified through preparative thin-layer silica-gel chromatography (developing eluent: a mixture of hexane and ethyl acetate at a ratio of 1:1) to give 0.06 g of ethyl 4-amino-3-(N-i-propylbutyrylamino)benzoate.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:41]I>C1COCC1>[I:41][CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To N-Boc-4-piperidine-ethanol (5.00 g, 21.8 mmol) in THF (100 mL) was added triphenylphosphine (6.29 g, 24.0 mmol), imidazole (1.64 g, 24.1 mmol) and iodine (6.09 g, 24.0 mmol). The reaction was stirred at rt for 2 h. The mixture was filtered through Celite® purified by flash chromatography to provide the title compound of step A (6.31 g, 18.6 mmol, 85%). 1H NMR (400 MHz, CDCl3) δ ppm 1.07 (dq, J=12.2, 4.3 Hz, 2H), 1.42 (s, 9H), 1.49-1.58 (m, 1H), 1.62 (d, J=13.2 Hz, 2H), 1.75 (q, J=7.1 Hz, 2H), 2.67 (td, J=12.9, 2.5 Hz, 2H), 3.18 (t, J=7.1 Hz, 2H), 4.06 (d, J=13.0 Hz, 2H).
Reaction SMILES: C1O[CH:4]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[C:7]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=2)[O:3]C1>C(O)C.O.Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]=[O:3])=[CH:6][C:7]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Fc1ccc(C2OCCO2)cc1Oc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=Cc1ccc(F)c(Oc2ccccc2)c1
Yield: 90.7 %

Procedure:
A solution of 26 g (0.1 mol) of 4-fluoro-3-phenoxy-benzaldehyde ethyleneacetal in 60 ml of ethanol, 20 ml of water and 1 ml of concentrated hydrochloric acid was stored at room temperature for 3 hours. The ethanol was then distilled off in vacuo, and 100 ml of toluene were added to the residue. The water was separated off and the organic phase was washed twice with 50 ml of water each time, dried over sodium sulphate and evaporated in vacuo. The residue was distilled in vacuo. 19.6 g (91% of theory) of 4-fluoro-3-phenoxy-benzaldehyde were obtained in this manner in the form of a colorless oil with a boiling point of 102°-104° C./0.1 mm Hg.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][C:40](O)=[O:41]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[C:40](=[O:41])[CH2:39][O:38][CH2:37][CH2:36][O:35][CH3:34])=[CH:32][CH:33]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COCCOCC(=O)O
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)COCCOC)cc2)cc1

Procedure:
The titled compound was prepared following the procedure H using methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]phenoxy}acetate and (2-methoxyethoxy)acetic acid as a yellow oil (96%). HPLC, Rt: 5.17 min (Purity: 94.8%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@:15]([CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:14][C@H:11]([O:12][CH3:13])[C@@H:10]1[OH:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:32]([O:31][C@@H:10]1[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@@:15]([CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH2:16][O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:14][CH:11]1[O:12][CH3:13])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CO[C@H]1O[C@@](COCc2ccccc2)(COS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H]1O
Solvent: c1ccncc1
Product: COC1O[C@@](COCc2ccccc2)(COS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.8 %

Procedure:
To a stirred solution of 201 (687 mg, 1.52 mmol) in anhydrous pyridine (4 mL) at 0° C. was added dropwise acetic anhydride (0.43 mL, 4.56 mmol). The reaction mixture was stirred for 2 days at room temperature, quenched with saturated aqueous sodium hydrogen carbonate (75 mL) and extracted with dichloromethane (150+75 mL). The combined extract was dried (MgSO4), the solvent was removed by distillation under reduced pressure and the residue was purified by chromatography over silica gel with dichloromethane as eluent to give the product 209 as a clear oil (β:α˜3:1, 750 mg, 100%); MS FAB: 463 (M−OCH3, 100%), 517 (M+Na, 28%); Found: C, 58.53; H, 6.16; C24H30O9S requires C, 58.29; H, 6.11%. Methyl 2-O-acetyl-3,5-di-O-benzyl-4-C-methanesulfonyloxymethyl-β-D-ribofuranoside (209□). 1H NMR (CDCl3): δ 7.36-7.18 (10 H, m, Bn), 5.27 (1 H, d, J 4.9 Hz, H-2), 4.88 (1 H, s, H-1), 4.55-4.44 (6 H, m, H-5′, Bn), 4.35 (1 H, d, J 5.0 Hz, H-3), 3.73 (1 H, d, J 9.2 Hz, H-5), 3.38 (1 H, d, J 9.3 Hz, H-5), 3.30 (3 H, s, OCH3), 2.95 (3 H, s, SO2CH3), 2.11 (3 H, s, OCCH3); 13C NMR (CDCl3): δ 169.91 (C═O), 137.83, 137.28, 128.49, 128.44, 127.99, 127.87, 127.77 (Bn), 105.40 (C-1), 82.65, 81.05, 74.55, 73.62, 73.56, 71.86, 70.22 (C-2, C-3, C-4, C-5, C-5′, Bn), 55.03 (OCH3), 37.14 (SO2CH3), 20.73 (OCCH3). Methyl 2-O-acetyl-3,5-di-O-benzyl-4-C-methanesulfonyloxymethyl-□-D-ribofuranoside (209β). 1H NMR (CDCl3): δ 7.36-7.18 (10 H, m, Bn), 5.09 (1 H, d, J 4.5 Hz, H-1), 4.95 (1 H, dd, J 4.5, 6.8 Hz, H-2), 4.65-4.44 (6 H, m, H-5′, Bn), 4.27 (1 H, d, J 6.6 Hz, H-3), 3.49 (1 H, d, J 9.9 Hz, H-5), 3.46 (3 H, s, OCH3), 3.36 (1 H, d, J 9.9 Hz, H-5), 2.92 (3 H, s, SO2CH3), 2.14 (3 H, s, OCCH3); 13C NMR (CDCl3): δ 170.41 (C═O), 137.59, 137.28, 128.56, 128.51, 128.49, 128.44, 127.98, 127.88 (Bn), 102.35 (C-1), 84.25, 77.53, 74.66, 73.67, 72.12, 70.39, 70.28 (C-2, C-3, C-4, C-5, C-5′, Bn), 56.07 (OCH3), 36.94 (SO2CH3), 20.63 (OCCH3).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[C:13]2[N:14]([CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=[CH:16][CH:17]=1.[OH-].[NH4+]>O>[Cl:11][C:12]1[C:13]2[N:14]([C:18]([CH:3]=[O:4])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Fc1ccc(-c2cn3cccc(Cl)c3n2)cc1
Reactant: CN(C)C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccc(F)cc2)nc2c(Cl)cccn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
N,N-Dimethylformamide (10 mL) was cooled to 0° C. and treated with phosphorous oxychloride (1.0 mL, 11 mmol). After the addition was complete, the mixture was warmed to room temperature and stirred for 10 minutes. To this was added 8-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridine (1.15 g, 4.7 mmol) and the resulting solution was stirred overnight. Water was added to the reaction. The mixture was neutralized to pH 7 with ammonium hydroxide. The aqueous phase was extracted with dichloromethane (3×50 mL). The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from acetonitrile to give 8-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridine-3-carbaldehyde (1.1 g, 85%) as a white solid. 1H NMR (CDCl3): δ 10.05 (s, 1H), 9.60 (d, 1H), 7.86 (q, 2H), 7.65 (d, 1H), 7.23 (t, 2H), 7.08 (t, 1H); 19F NMR (CDCl3) δ −110.8; MS m/z 275 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Br[CH2:16]CCC.C(Cl)Cl>O>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([CH3:1])[CH:7]=1)[CH2:10][CH2:11][CH3:16]
Reactant: CCCOc1ccc([N+](=O)[O-])c(C)c1
Reactant: CCCCBr
Solvent: O
Solvent: ClCCl
Product: CCCCOc1ccc([N+](=O)[O-])c(C)c1
Yield: 99 %

Procedure:
This compound was prepared in a similar manner to that for 404b except 1-bromobutane was deployed for the alkyl ether adduct and the partition step during workup utilized DCM (150 mL) and water (150 mL) to provide a yellow oil (2.0 g, 99%): TLC Rf 0.70 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 8.09-8.07 (d, 1H, J=8.88 Hz), 6.79-6.76 (m, 2H), 4.03-4.01 (t, 2H, J=6.48 Hz), 2.63 (s, 3H), 1.80-1.78 (quin, 2H, J=7.44 Hz), 1.53-1.47 (sex, 2H, J=7.44 Hz), 1.0-0.97 (t, 3H, J=7.38 Hz). 13C NMR (150 MHz, CDCl3) δ 162.7, 141.9, 137.1, 127.6, 117.9, 112.2, 68.3, 31.0, 21.8, 19.1, 13.8. Elemental analysis calculated for C11H15NO3: C, 63.14; H, 7.23; N, 6.69. Found: C, 63.25; H, 7.09; N, 6.69.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[OH:18])[C:12]([OH:14])=[O:13].S(=O)(=O)(O)O>S(=O)(=O)(O)O.O>[C:1]([O:18][C:17]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[F:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(O)c(F)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)O)cc1F
Temperature: 25 °C
Yield: 79.4 %

Procedure:
6.40 ml of acetic anhydride was added to 5.00 g (32.00 mM) of 3-fluoro-4-hydroxybenzoic acid. Under stirring at room temperature, two drops of concentrated sulfuric acid was added thereto (the mixture solidified as soon as the concentrated sulfuric acid was added), followed by heat-stirring for 10 minutes at 107°-111° C. on an oil bath (the mixture became transparent and melted by heating). After the reaction, the reaction mixture was poured into 150 ml of iced water to precipitate a crystal. The crystal was recovered by filtration and recrystallized from 20 ml of methanol to obtain 5.04 g of 4-acetoxy-3-fluorobenzoic acid (Yield: 79.4%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH2:22][CH:23](OC)OC)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[OH:20].Cl.[OH2:29]>CC(O)=O>[Cl:1][C:2]1[C:3]([O:21][CH2:22][CH2:23][N:10]2[CH2:11][CH2:2][O:29][CH2:8][CH2:9]2)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:18])[CH3:19])[N:16]=1)[CH:8]=[C:7]2[OH:20]
Reactant: COC(COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1Cl)OC
Reactant: O
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)c1csc(-c2cc(O)c3ccc(OCCN4CCOCC4)c(Cl)c3n2)n1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
8-Chloro-7-(2,2-dimethoxy-ethoxy)-2-(4-isopropyl-thiazol-2-yl)-quinolin-4-ol (5.0 g, 12.3 mmol) was dissolved in HOAc (100 mL) and 1.4 N HCl/H2O (50 mL). The reaction mixture was heated to 60° C. with stirring for 2 hrs. After cooled back to room temperature and concentrated, the residue was co-evaporated with toluene (2×50 mL). Then the crude was dissolved in DCM (100 mL) and cooled to 0° C. with stirring. Morphiline (1.6 g, 18.4 mmol) and NaHB(OAc)3 (3.9 g, 18.4 mmol) were added to the reaction mixture. After stirring at room temperature for 1 h, the reaction mixture was washed with sat. NaHCO3, brine and dried by Na2SO4. After concentration, the crude was purified by silica gel chromatography to afford 5.0 g of 8-chloro-2-(4-isopropyl-thiazol-2-yl)-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-ol as a white solid.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:16][O:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]2)[CH2:15][CH2:14]1.IC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH:13]1([CH2:16][O:17][CH:18]2[CH2:23][CH2:22][C:21]([CH3:1])([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]2)[CH2:14][CH2:15]1
Reactant: O=C(O)[C@H]1CC[C@H](OCC2CC2)CC1
Reactant: CC(C)NC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C(=O)O)CCC(OCC2CC2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Diisopropylamine (15 mL, 105 mmol) in THF (100 mL) was cooled to 0° C. under Ar. n-Butyllithium (38 mL, 95 mmol, 2.5M in hexane) was added dropwise over 10 min. The reaction mixture was left to stir for 15 min at 0° C. A solution of 4-[(cyclopropylmethyl)oxy]cyclohexanecarboxylic acid (D100, 9.47 g, 43.0 mmol) in THF (50 mL) was added and the resulting yellow solution was heated at 50° C. for 2 h. The reaction mixture was cooled to 0° C. and iodomethane (8 mL, 128 mmol) was added dropwise, the reaction was then allowed to warm to rt and left to stir for 3 days. 10% Citric acid (200 mL) was then added and the reaction mixture was concentrated by rotary evaporation. The residual mixture was diluted with H2O and extracted with Et2O (2×). The organics were combined, dried (Na2SO4) and concentrated by rotary evaporation to give a mixture of cis and trans 4-[(cyclopropylmethyl)oxy]-1-methylcyclohexanecarboxylic acid (D101, 10.0 g, 93%) as a brown oil.