Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:3]([NH:5][C:6]1[C:7]([O:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)[CH:11]=1)=[O:4].[S:35]1[CH:39]=[C:38]([CH:40]=O)[N:37]=[CH:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CCOC(C)=O.C(O)(=O)C>[CH3:18][C:14]1[CH:13]=[C:12]([C:10]2[CH:11]=[C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:40][C:38]3[N:37]=[CH:36][S:35][CH:39]=3)[CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:7]([O:19][CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[N:8][CH:9]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Cc1cc(-c2cnc(OCC(=O)OC(C)(C)C)c(NC(=O)[C@@H](N)Cc3ccccc3)c2)ccn1
Reactant: O=Cc1cscn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(-c2cnc(OCC(=O)OC(C)(C)C)c(NC(=O)[C@H](Cc3ccccc3)NCc3cscn3)c2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To a flask with tert-butyl 2-(3-((S)-2-amino-3-phenylpropanamido)-5-(2-methylpyridin-4-yl)pyridin-2-yloxy)acetate (78.J) (58 mg, 0.13 mmol) was added thiazole-4-carbaldehyde (15 mg, 0.13 mmol). Dichloromathane was added as the solvent. Then acetic acid, glacial (8 mL, 0.13 mmol) was added followed by sodium triacetoxyborohydride (80 mg, 0.38 mmol). The reaction was stirred at room temperature for 1 hour and worked up with EtOAc and saturated NaHCO3 solution. Reverse phase HPLC purification afforded compound 78 26 mg (37%). 1H NMR (400 MHz, MeOH) δ ppm 8.78-8.96 (m, 2H) 8.45 (d, J=5.48 Hz, 1H) 8.22 (d, J=2.35 Hz, 1H) 7.57 (s, 1H) 7.49 (dd, J=5.48, 1.56 Hz, 1H) 7.36 (d, J=1.96 Hz, 1H) 7.18-7.31 (m, 5H) 4.90 (d, J=3.13 Hz, 2H) 3.87-3.98 (m, 2H) 3.63 (dd, J=8.61, 5.09 Hz, 1H) 3.19 (dd, J=13.89, 4.89 Hz, 1H) 2.92 (dd, J=14.09, 8.61 Hz, 1H) 2.60 (s, 3H) 1.46 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][C:8]2[C:9](=[O:33])[N:10]=[C:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[CH:18][CH:17]=3)[NH:12][CH:13]=2)[CH:4]=[N:3][CH:2]=1.CI.[CH3:36]CN(C(C)C)C(C)C>C(Cl)Cl>[CH3:36][N:12]1[CH:13]=[C:8]([CH2:7][C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)[C:9](=[O:33])[N:10]=[C:11]1[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)=[CH:20][CH:21]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=c1nc(CCc2ccc(Oc3cccc(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Solvent: CI
Solvent: ClCCl
Product: Cn1cc(Cc2cncnc2)c(=O)nc1CCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.5 %

Procedure:
To the solution of 5-(pyrimidin-5-ylmethyl)-2-(4-(3-(trifluoromethyl)phenoxy)phenethyl) pyrimidin-4(1H)-one (200 mg, 0.442 mmol) in DCM (10 mL) was added MeI (4.42 mL, 4.42 mmol) (1.0 M in DCM) and DIPEA (0.772 mL, 4.42 mmol) at 25° C. The mixture was stirred at room temperature for 2 days. The solvent was removed in vacuo. Purification via MDAP then afforded the title compound (87.6 mg, 40.8% yield) as a white solid. LCMS: rt=1.59 min, [M+H+]=467.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][C:8]=1[CH:16]=[O:17])(=O)=O.[CH:20]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28](B(O)O)[CH:27]=[CH:26]2)([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([C:28]2[CH:27]=[CH:26][C:25]3[C:30](=[CH:31][CH:32]=[C:23]([CH:20]([CH3:22])[CH3:21])[CH:24]=3)[CH:29]=2)=[C:8]([CH:9]=1)[CH:16]=[O:17])([CH3:15])[CH3:14]
Reactant: CC(C)c1ccc2cc(B(O)O)ccc2c1
Reactant: CC(C)c1ccc(OS(=O)(=O)C(F)(F)F)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)c1ccc(-c2ccc3cc(C(C)C)ccc3c2)c(C=O)c1
Yield: 70 %

Procedure:
Under an atmospheric argon gas flow, 2-hydroxy-5-isopropylbenzaldehyde in an amount of 4.4 g (27 mmol), trifluoromethane sulfonic acid anhydride in an amount of 11.2 g (40 mmol), pyridine in an amount of 6 milliliter (80 mmol) and dichloromethane in an amount of 100 milliliter were placed into a three necked-flask equipped with a cooling pipe and having a capacity of 500 milliliter, and the resultant solution was stirred at the room temperature for 2 hours. After the reaction terminated, the resultant was separated by filtration, and after washing the resultant crude product with the use of hexane and dichloromethane, the resultant solution was vacuum dried at a temperature of 50° C. for 8 hours and as a result, 6.0 g of 2-formyl-4-isopropylphenyltrifluoromethanesulfonate (white crystal) was obtained (yield: 75%). Subsequently, under an atmospheric argon gas flow, 2-formyl-4-isopropylphenyl trifluoromethanesulfonate in an amount of 5.9 g (20 mmol), 6-isopropylnaphthalene-2-boronic acid in an amount of 4.7 g (22 mmol), (tetrakistriphenylphosphine)palladium in an amount of 1.1 g (1 mmol), 2N sodium carbonate aqueous solution in an amount of 30 milliliter and dimethoxyethane in an amount of 40 milliliter were placed into a three necked-flask equipped with a cooling pipe and having a capacity of 500 milliliter, and the resultant solution was refluxed under heating for 8 hours. After the reaction terminated, adding water in an amount of 100 milliliter into the reacted solution, an organic layer was separated and washed with the use of sodium chloride solution, followed by drying with the use of magnesium sulfate. After removing the solvent by distillation by means of a rotary evaporator, the resultant crude product was refined by means of column chromatography (silicagel, hexane/dichloromethane=60/40), and as a result, 4.4 g of an aimed compound (white crystal) was obtained (yield: 70%).
Reaction SMILES: O[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([OH:18])[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)([CH3:4])[CH3:3].B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:17][N:14]1[CH2:13][CH2:12][C:11]2([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:2]([CH3:3])([CH3:4])[O:18]2)[CH2:16][CH2:15]1
Reactant: CN1CCC(O)(c2ccccc2C(C)(C)O)CC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: CN1CCC2(CC1)OC(C)(C)c1ccccc12
Reaction time: 40 h
Yield: 55.8 %

Procedure:
To a stirred solution of 4-[2-(1-hydroxy-1-methylethyl)phenyl]-1-methylpiperidin-4-ol (step 2, 4.62 g, 18.5 mmol) in benzene (200 mL) was added dropwise boron trifluoride diethyl etherate (11.0 mL, 86.8 mmol) at room temperature and the mixture was stirred for 40 h at the same temperature. The reaction mixture was quenched by the addition of water (200 mL) and 2 N sodium hydroxide aqueous solution (200 mL), and the benzene layer was separated. The aqueous layer was extracted with diethyl ether, and then combined organic layer washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on an amine coated silica gel (100 g) eluting with dichloromethane to afford 2.39 g (56%) of the title compound as a colorless solid:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([C:18]2[N:19]=[C:20](OS(C(F)(F)F)(=O)=O)[C:21]3[S:27][CH2:26][CH2:25][CH2:24][C:22]=3[N:23]=2)[CH:15]=[CH:16][CH:17]=1.CN(C=O)C>O>[Cl:11][C:12]1[CH:13]=[C:14]([C:18]2[N:19]=[C:20]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=3)[C:21]3[S:27][CH2:26][CH2:25][CH2:24][C:22]=3[N:23]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Oc1nc(-c2cccc(Cl)c2)nc2c1SCCC2)C(F)(F)F
Reactant: N#CCc1ccc(N)cc1
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2SCCC3)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
A 8-mL vial was charged with 2-(4-aminophenyl)acetonitrile (40 mg, 0.3 mmol, 1.25 eq.), [2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]trifluoromethanesulfonate (100 mg, 0.24 mmol, 1. eq.) and DMF (1 ml). The resulting mixture was stirred at 70° C. overnight. After cooling to room temperature, water was added to the mixture (5 ml). The precipitate was collected by filtration and washed with water (20 ml). After drying, the crude product was purified by chromatography on silica gel using hexane/dichloromethane (1:1, 1:1.5 then 1:2) as eluent to give the title compound (35 mg, 37% yield).
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH:6]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]2)[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.[CH3:18][N:19]=[C:20]=[O:21]>C1C=CC=CC=1>[CH3:18][NH:19][C:20]([N:8]1[CH2:9][CH2:10][CH2:11][CH:6]([N:5]2[C:4](=[O:12])[C:3]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]3[C:1]2=[O:17])[CH2:7]1)=[O:21]
Reactant: CN=C=O
Reactant: O=C1c2ccccc2C(=O)N1C1CCCNC1
Solvent: c1ccccc1
Product: CNC(=O)N1CCCC(N2C(=O)c3ccccc3C2=O)C1

Procedure:
A mixture of 11.5 g. of 3-phthalimidopiperidine and 2.85 g. of methyl isocyanate in 100 ml. of dry benzene is stirred at 25° C. for 2 hours. The resulting mixture is concentrated in vacuo and filtered to give 1-(N-methylcarbamoyl)-3 -phthalimidopiperidine. Treating this phthalimidopiperidine with hydrazine hydrate by the procedure of Example 17 gives 1-(N-methylcarbamoyl)-3-aminopiperidine.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].N1C=CC=CC=1.Cl>>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:7]
Reactant: OCCCCCCCCCl
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(OCCCCCCCCCl)c1ccco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
A solution of 2-furoyl chloride (6.5 g; 50 mmol) was added dropwise at 0° C. to a solution of 8-chloro-1-octanol (6.6 g; 40 mmol) and pyridine (20 g; 253 mmol) and stirred at room temperature for 2 h. The resulting mixture was added to a mixture of 1N-hydrochloric acid and ice (200 ml) and extracted with ethyl acetate (3×80 ml). The combined organic layers were washed with saturated sodium chloride solution (2×80 ml), dried over magnesium sulphate and filtered. The organic solvent was removed in vacuo to give 8-chlorooctyl-2-furancarboxylate (9.7 g) (94%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7]Br.[C:9]([O-:12])(=[O:11])[CH3:10].[K+].O>CC(C)=O>[C:9]([O:12][CH2:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[Cl:1])(=[O:11])[CH3:10]
Reactant: Clc1sccc1CBr
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OCc1ccsc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-Methylthiophene (19.63 g) was dissolved in acetonitrile (100 ml), and sulfuryl chloride (16.64 ml) was added dropwise. The mixture was stirred at room temperature for 1 hour, stirred under reflux for another 1 hour, then cooled to room temperature, and 10% aqueous sodium thiosulfate (200 ml) was added. The mixture was stirred at room temperature for 2 hours and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-chloro-3-methylthiophene (21.52 g). A mixture of 2-chloro-3-methylthiophene (3.53 g), N-bromosuccinimide (4.73 g), 2,2'-azobis(isobutyronitrile) (0.87 g) and carbon tetrachloride (25 ml) was stirred under reflux for 4 hours. The mixture was cooled to room temperature and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure to give a crude product of 2-chloro-3-bromomethylthiophene. A suspension of the crude product of 2-chloro-3-bromomethylthiophene and potassium acetate (9.82 g) in acetone (50 ml) was stirred at room temperature for 48 hours. The mixture was poured into water and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 3-acetoxymethyl-2-chlorothiophene. This crude product was dissolved in a mixture of ethanol (25 ml) and tetrahydrofuran (25 ml), and 1N aqueous sodium hydroxide (50 ml) was added. The mixture was stirred at room temperature for 30 minutes. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-hydroxymethyl-2-chlorothiophene (3.22 g). 3-Hydroxymethyl-2-chlorothiophene (3.16 g) was dissolved in methylene chloride (50 ml), and manganese dioxide (9.66 g) was added. The mixture was stirred at room temperature for 15 hours, and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure to give a crude product of 2-chloro-3-thiophenecarbaldehyde (3.16 g). The crude product of 2-chloro-3-thiophenecarbaldehyde was dissolved in acetonitrile (20 ml), and sodium dihydrogen phosphate (0.67 g) in water (10 ml) and 30% aqueous hydrogen peroxide (2.6 ml) were added. Further, sodium chlorite (3.41 g) in water (30 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours, alkalified with 1N aqueous sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhdrous magnesium sulfate to give 2-chloro-3-thiophenecarboxylic acid (1.92 g) as crystals.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:43])[CH2:23][NH:24][C:25](=[O:42])[CH:26]=[CH:27][C:28]4[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:30][CH:29]=4)[CH3:21])[C:14]=3[Cl:44])[C:5]2=[N:4][C:3]=1[CH3:45].[CH2:46](O)[CH3:47].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(OCC)(=O)C.CN(C)C=O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:43])[CH2:23][NH:24][C:25](=[O:42])[CH:26]=[CH:27][C:28]4[CH:29]=[CH:30][C:31]([NH:34][C:35](=[O:41])[CH2:36][CH2:37][C:38]([O:40][CH2:46][CH3:47])=[O:39])=[CH:32][CH:33]=4)[CH3:21])[C:14]=3[Cl:44])[C:5]2=[N:4][C:3]=1[CH3:45]
Reactant: CCO
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=O)CCC(=O)O)cc4)c3Cl)cccn2c1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(=O)Nc1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccn4c(Br)c(C)nc34)c2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.2 %

Procedure:
A mixture of 3-bromo-8-[2,6-dichloro-3-[N-[4-(3-carboxypropionamido)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (60 mg), ethanol (12 mg), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (21 mg), 1-hydroxybenzotriazole (17 mg) and N,N-dimethylformamide (0.6 ml) was stirred for 3 hours at ambient temperature. Ethyl acetate was added thereto, and the mixture was washed with water four times, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=10:1, V/V) to give 3-bromo-8-[2,6-dichloro-3-[N-[4-(3-ethoxycarbonylpropionamido)cinnamoylglycyl]-N-methylamino]benzyloxy]-2- methylimidazo[1,2-a]pyridine (7 mg) as an amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[C:14](=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=1)[C:5]([O:7][CH3:14])=[O:6]
Reactant: O=C(O)c1cc(Cl)ncc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a solution of 2-chloro-5-nitroisonicotinic acid (Intermediate 25A) (0.64 g, 3.17 mmol) in DMF (15 mL) under nitrogen was added sodium carbonate (1.0 g, 9.51 mmol). Reaction cooled in an ice bath and methyliodide (1.35 g, 9.51 mmol) was added dropwise. After complete addition, reaction allowed to warm to room temperature and stirred overnight under nitrogen. The reaction mixture was filtered and concentrated. The resultant crude material was purified by a 20 g silica column eluting with 40% ethylacetate in hexane to afford methyl 2-chloro-5-nitroisonicotinate (0.62 g, 2.86 mmol).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:9])[CH2:5][CH2:6][CH2:7][OH:8].Cl[C:11]1[C:16]2[CH:17]=[N:18][C:19]3[N:23]([CH2:24][CH3:25])[N:22]=[CH:21][C:20]=3[C:15]=2[N:14]2[N:26]=[CH:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:13]2[N:12]=1>C1C=CC=CC=1>[CH3:3][N:4]([CH3:9])[CH2:5][CH2:6][CH2:7][O:8][C:11]1[C:16]2[CH:17]=[N:18][C:19]3[N:23]([CH2:24][CH3:25])[N:22]=[CH:21][C:20]=3[C:15]=2[N:14]2[N:26]=[CH:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:13]2[N:12]=1
Reactant: CCOC(=O)c1cnn2c1nc(Cl)c1cnc3c(cnn3CC)c12
Reactant: CN(C)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)c1cnn2c1nc(OCCCN(C)C)c1cnc3c(cnn3CC)c12
Reaction time: 10 h

Procedure:
To a suspension of 3.6 g of sodium hydride in 100 ml of dry benzene 15.3 g of 3-(dimethylamino)propanol are added dropwise at reflux temperature with stirring. Heating is continued for 10 hours. After this time, 34.4 g of 5-chloro-8-ethyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]-pyrimidine-3-carboxylic acid, ethyl ester are added and the solution is refluxed for 5 additional hours. The solution is evaporated to dryness and the residue is treated with water, filtered off and recrystallized from ethyl acetate. 12 g of 5-[3-(dimethylamino)propoxy]-8-ethyl-8H-pyrazolo-[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester are obtained (29.3%); m.p. 106°-107°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][CH:20]([N:23](C)[C:24](=O)OC(C)(C)C)[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2.Cl.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:24][NH:23][CH:20]1[CH2:21][CH2:22][CH:17]([O:16][C:7]2[C:6]3[C:5]4[C@@H:4]([CH2:3][CH2:2][OH:1])[CH2:15][CH2:14][C:13]=4[S:12][C:11]=3[N:10]=[CH:9][N:8]=2)[CH2:18][CH2:19]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO)CC4)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
For the preparation of the starting material compound 34.2, please refer to the experimental procedure for the synthesis of compound Example 34. A 50-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with a solution of tert-butyl N-(4-[[(3R)-3-(2-hydroxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (197 mg, 0.44 mmol, 1.00 equiv) in dichloromethane (15 mL). Hydrochloric acid (conc., 0.5 mL) was added at 0° C. and the resulting solution was stirred for 2 h at room temperature. The pH value of the solution was adjusted to 10 with aqueous sodium bicarbonate (sat.) and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 2-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethan-1-ol (118 mg, 77%) as a yellow solid. MS (ES): m/z 348[M+H]+.
Reaction SMILES: [C:1]([NH2:6])([CH2:4][CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:14][C:15]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:2][C:1]([NH:6][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:15]=1[F:14])([CH3:3])[CH2:4][CH3:5]
Reactant: CCC(C)(C)N
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)(C)NC(=O)c1ccc(F)cc1F
Reaction time: 1 h
Yield: 103.4 %

Procedure:
To a solution of t-amylamine (0.35 ml, 3.0 mmol) and triethylamine (0.56 ml, 4.0 mmol) in methylene chloride (3 ml) was added a solution of 2,4-difluorobenzoyl chloride (0.36 g, 2.0 mmol) in methylene chloride (2 ml) with cooling in an ice-bath, and stirred for 1 hour. The reaction mixture was poured over saturated aqueous NaHCO3 and extracted with ethyl acetate. The extract was washed with saturated aqueous NaHCO3 and dried over MgSO4. The solvent was evaporated to give the title compound (0.47 g; >99%).
Reaction SMILES: C([N:8]1[CH2:36][CH2:35][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][C:18]3[N:28]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:21]4[N:22]=[C:23]([C:26]#[N:27])[N:24]=[CH:25][C:20]=4[CH:19]=3)[C:12]2=[O:34])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:38]([O:40][CH2:41][C:42]([Cl:45])([Cl:44])[Cl:43])=[O:39].[NH4+].[Cl-]>CC#N>[Cl:43][C:42]([Cl:45])([Cl:44])[CH2:41][O:40][C:38]([N:8]1[CH2:36][CH2:35][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][C:18]3[N:28]([CH2:29][C:30]([CH3:32])([CH3:33])[CH3:31])[C:21]4[N:22]=[C:23]([C:26]#[N:27])[N:24]=[CH:25][C:20]=4[CH:19]=3)[C:12]2=[O:34])[CH2:10][CH2:9]1)=[O:39]
Reactant: CC(C)(C)Cn1c(CN2C(=O)OC3(CCN(Cc4ccccc4)CC3)C2=O)cc2cnc(C#N)nc21
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Product: CC(C)(C)Cn1c(CN2C(=O)OC3(CCN(C(=O)OCC(Cl)(Cl)Cl)CC3)C2=O)cc2cnc(C#N)nc21
Reaction time: 18 h
Yield: 97.2 %

Procedure:
To a solution of 0.22 g (0.45 mmoles) of 6-(8-benzyl-2,4-dioxo-1-oxa-3,8-diaza-spiro[4.5]dec-3-ylmethyl)-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 4 ml of CH3CN is added 2,2,2-trichloroethyl chloroformate(0.91 mmol) at ambient temperature and the mixture is stirred for 18 hours. Aqueous NH4Cl is added and the organic layer is extracted with AcOEt, washed with brine, dried over Na2SO4 and concentrated. The crude product is purified by silica gel column chromatography (n-Hexane:AcOEt=1:1) to give 0.25 g of 3-[2-cyano-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-2,4-dioxo-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylic acid 2,2,2-trichloro-ethyl ester in 96% yield.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(O)(=[O:39])CCCCCCC/C=C\C/C=C\C/C=C\CC>>[OH:39][CH:13]([CH2:14][CH:15]=[CH:16][CH2:17][CH3:18])[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19]
Reactant: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Product: CCC=CCC(O)CCC=CCCCCCCCC(=O)O

Procedure:
The same procedure as in Example 2 was repeated, except that linoleic acid was replaced by α-linolenic acid, whereby 13-hydroxy-9,15-octadecadienoic acid was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([C:19]([O:21]CC)=[O:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:24]=1.[Li+].[OH-].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([C:19]([OH:21])=[O:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:24]=1
Reactant: CCOC(=O)C1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Temperature: 80 °C
Reaction time: 2 h
Yield: 105.8 %

Procedure:
A mixture of ethyl 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxylate (606 mg, 1.75 mmol) and LiOH (168 mg, 7.00 mmol) in dioxane/H2O (6 mL/5 mL) was stirred at 80° C. for 2 hours. The reaction was monitored using TLC. When the reaction was completed, 1 N HCl aqueous was added to the mixture until pH 4. The mixture was extracted with EtOAc (10 mL*3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated under reduce pressure, afforded 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxylic acid (590 mg, yield: 99%). 1H-NMR (400 MHz, DMSO-d6) δ 7.74 (d, J=8.8 Hz, 1H), 7.43˜7.56 (m, 2H), 7.37 (s, 1H), 7.25˜7.34 (m, 1H), 7.15 (s, 1H), 6.92˜7.02 (m, 1H). MS (M+H)+: 319.