Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:4])(=O)C.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][CH2:13][C:14]([OH:16])=[O:15]>CO>[ClH:4].[CH3:1][O:15][C:14](=[O:16])[CH2:13][NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[F:5]
Reactant: CC(=O)Cl
Reactant: O=C(O)CNc1ccccc1F
Solvent: CO
Product: COC(=O)CNc1ccccc1F
Product: Cl
Reaction time: 24 h

Procedure:
Acetyl chloride (4 ml) was added cautiously and dropwise to methanol (20 ml) at 0° C. over 2 minutes. When the addition was completed, the 2-fluorophenylglycine (1 g, 5.9 mmol, Aldrich) was introduced in a single portion. The mixture was stirred until dissolved then allowed to stand at RT for 24 hours. The solvent was evaporated then coevaporated twice from toluene to afford the title compound as a white crystalline solid in quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[F:16])=[O:6]
Reactant: Nc1ccccc1F
Reactant: Nc1ncc(Br)cc1C(=O)O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Nc1ncc(Br)cc1C(=O)Nc1ccccc1F
Temperature: 130 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
A mixture of 2-Amino-5-bromo-nicotinic acid (1 g, 4.61 mmol) and SOCl2 (5 mL) in toluene (15 mL) was stirred at 130° C. for 2 h. After concentrated, the residue was dissolved in tetrahydrofuran (20 mL), and then 2-fluoro-phenylamine (1.09 g, 9.81 mmol) was added dropwise at 0° C. The reaction mixture was heated to 90° C. for 4 h. After being cooled to room temperature and quenched with saturated aqueous K2 CO3 (10 mL), the mixture was extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with silica gel column chromatograph (PE:EtOAc=2:1) to give 2-amino-5-bromo-N-(2-fluorophenyl)nicotinamide (1.0 g, 70% yield) as yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.25˜8.28 (m, 2H), 7.86 (d, J=2.4 Hz, 2H), 7.13˜7.22 (m, 3H), 6.36 (s, 2H). MS (M+H)+: 311/313.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH:12]([C:14]1[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=1)[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=O>C(O)C>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2](/[N:1]=[CH:12]/[C:14]2[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=2)[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])=[CH:11][CH:10]=1)=[O:7]
Reactant: O=Cc1cccc(C(=O)OCc2ccccc2)c1
Reactant: COC(=O)c1ccc(N)cc1
Solvent: CCO
Product: COC(=O)c1ccc(/N=C/c2cccc(C(=O)OCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-aminobenzoate (7.94 g, 52.5 mmol) in ethanol (100 mL) was added benzyl 3-formylbenzoate in ethanol (50 mL) and the resulting mixture was stirred at room temperature for 2 h. The white solid precipitated was collected by filtration and washed with ethanol, dried in vacuo (50° C.) to give 15.6 g of (E)-benzyl 3-((4-(methoxycarbonyl)phenylimino)methyl)benzoate as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:7]=[CH:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[O:1][CH2:2][CH:3]1[CH:7]=[CH:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: COc1ccc(Br)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CC=CC1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(Br)c(OCC2C=CCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 9.5 %

Procedure:
To a solution of tert-butyl 2-(hydroxymethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8.96 g, 0.45 mol, from Specialty Chemicals, Inc.) and 2-bromo-5-methoxyphenol (9.32 g, 0.46 mol) in THF (180 mL) was added DEAD (20.5 mL) in toluene (40 wt %) dropwise at 0° C. The reaction was stirred for 21 h at RT and the solvent was evaporated. The residue was suspended in methyl tert-butylether (50 mL) and the solution was filtered and concentrated. The resulting residue was dissolved in DCM, washed with 0.6N NaOH (2×25 mL) and the layers were separated. The organic layer was dried with Na2SO4 and the solvent was evaporated. The crude product was purified using an ISCO instrument (330 g RediSep® column), eluting with a gradient of ethyl acetate in heptane (from 0%-20% ethyl acetate over 6 minutes, then 29% ethyl acetate for 20 min) to afford 16.4 g of the title product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:20][C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[C:23]([F:29])[CH:22]=2)[C:9]([O:11][C@@H:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:30][CH2:31][C:32]([C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)=[O:33]>C(#N)C>[Cl-:30].[F:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:20][C:21]2[CH:22]=[C:23]([F:29])[C:24]([F:28])=[C:25]([F:27])[CH:26]=2)[C:9]([O:11][C@@H:12]2[CH:17]3[CH2:18][CH2:19][N+:14]([CH2:31][C:32](=[O:33])[C:34]4[S:35][CH:36]=[CH:37][CH:38]=4)([CH2:15][CH2:16]3)[CH2:13]2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(Nc1cc(F)c(F)c(F)c1)c1cccc(F)c1
Reactant: O=C(CCl)c1cccs1
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(Nc1cc(F)c(F)c(F)c1)c1cccc(F)c1)C2)c1cccs1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.6 %

Procedure:
(R)-Quinuclidin-3-yl 2-(3-fluorophenyl)-2-(3,4,5-trifluorophenylamino)acetate (I43) (85 mg, 0.21 mmol) and 2-chloro-1-(thiophen-2-yl)ethanone (35.1 mg, 0.22 mmol) were dissolved in acetonitrile (5 ml) and stirred at room temperature for 48 hours. The solvent was evaporated, and the resulting crude compound was purified by flash chromatography (DCM/MeOH=9/1) to obtain (3R)-3-(2-(3-fluorophenyl)-2-(3,4,5-trifluorophenylamino)acetoxy)-1-(2-oxo-2-(thiophen-2-yl)ethyl)-1-azoniabicyclo[2.2.2]octane chloride (70 mg; 59% yield).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C@H:14]([C:22]([OH:24])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:25]1([Se:31][CH2:32][CH2:33]O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1C[O:38][CH2:37][CH2:36]1>C(OCC)(=O)C>[C:25]1([Se:31][CH2:32][CH2:33][O:23][C:22](=[O:24])[C@H:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13][C:37](=[O:38])[CH3:36])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: OCC[Se]c1ccccc1
Reactant: C1CCOC1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)OCC[Se]c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a 50 ml round bottomed flask, 2.55 g (13.3 mmol) of 1-(3-dimethylamino propyl)-3-ethyl carbodiimide hydrochloride and 1.7 g of (8.2 mmol) phenylalanine were added to a solution of 1.87 g (9.3 mmol) of 2-(phenylseleno)ethanol in 20 ml of THF. The reaction mixture was then stirred for 12 hours at room temperature. The mixture was then diluted with 50 ml of ethyl acetate and extracted with 50 ml of a 0.5 M HCl solution. The organic phase was dried over sodium sulfate, filtered, and the solvent was removed in vacuo. Purification by column chromatography (PE:EE=2:1) yielded 2.9 g (91% of th., 98% of lit.) of a yellowish liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:21])=[C:4]([C:10]2[N:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[N:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([F:9])[C:7]=1I.[Cu][C:23]#[N:24]>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([F:21])=[C:4]([C:10]2[N:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[N:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([F:9])[C:7]=1[C:23]#[N:24]
Reactant: Fc1cc(-c2ccnn2C2CCCCO2)c(F)c(Cl)c1I
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: N#Cc1c(F)cc(-c2ccnn2C2CCCCO2)c(F)c1Cl
Temperature: 170 °C
Reaction time: 7 h
Yield: 50.6 %

Procedure:
5-(3-Chloro-2,5-difluoro-4-iodophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1.686 mmol, 0.716 g) and copper(I) cyanide (1.686 mmol, 0.151 g) were suspended in NMP. The resulting mixture was stirred at 170° C. for 7 h. The reaction was quenched by, pouring the mixture onto 12% ammonia solution and stirred for 20 min. The formed precipitate was filtered and washed with water. 0.276 g of the title product was obtained. Identification after the next step due to low solubility of the product.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([C:6]1[C:7]([F:17])=[C:8]([F:16])[C:9]([F:15])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])(=[O:5])=[O:4].[CH3:19]O>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:19][O:12][C:11](=[O:13])[C:10]1[CH:14]=[C:6]([S:3](=[O:4])(=[O:5])[N:2]([CH3:18])[CH3:1])[C:7]([F:17])=[C:8]([F:16])[C:9]=1[F:15]
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)c(F)c(F)c1F
Reactant: CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)c1cc(S(=O)(=O)N(C)C)c(F)c(F)c1F
Yield: 10 %

Procedure:
The solid 5-dimethylsulfamoyl-2,3,4-trifluoro-benzoic acid (1.47 g, 0.00519 mol) and p-toluenesulfonic acid catalyst (17.1 mg) were dissolved in methanol (125 ml). The stirring mixture was brought to reflux under a nitrogen atmosphere for 51 hours. The reaction mixture was concentrated in vacuo to give a solid. The product was partitioned between diethyl ether (200 ml) and saturated aqueous potassium carbonate (75 ml). The layers were separated and the organic phase was washed with water (75 ml), brine (75 ml), was dried over anhydrous potassium carbonate, and was concentrated in vacuo to afford 0.15 g of an off-white solid; 10% yield; 1H-NMR (400 MHz; CDCl3) δ8.23-8.19 (m, 1H), 3.92 (s, 3H), 2.83 (s, 6H); 19F-NMR (376 MHz; CDCl3) δ−120.79 to −121.02 (m), −153.69 to −153.80.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH:20]([O:22][C:23](=[O:40])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[CH3:21])=[O:18].N1C=CC=CC=1.[C:47]([O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][C:80](Cl)=[O:81])(=[O:63])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]>C1COCC1>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH:20]([O:22][C:23](=[O:40])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:80](=[O:81])[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75][CH2:74][CH2:73][CH2:72][CH2:71][CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][CH2:65][O:64][C:47](=[O:63])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH3:21])=[O:18]
Reactant: CC(OC(=O)CCCCCCCCCCCCCCCO)OC(=O)CCCCCCCCCCCCCCCO
Reactant: CCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)OC(C)OC(=O)CCCCCCCCCCCCCCCO
Reaction time: 2 h
Yield: 29.4 %

Procedure:
Ethylidene bis (16-hydroxyhexadecanoate) (4.38 g, 7.67 mmol) was dissolved in THF (80 ml) and pyridine (0.61 g, 7.71 mmol) was added. 16-hexadecanoyloxyhexadecanoyl chloride (4.18 g, 7.90 mmol) was dissolved in THF (20 ml) and added dropwise. After 3 days at room temperature the mixture was filtered and the filtrate was left -20° C. for 2 hours. The precipitated product was filtered and purified by flash chromatography (silicagel, chloroform) to give 2.4 g (29%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 0.85 (t, 3H, CH3), 1.2-1.4 (s, 90H, --CH2 --), 1.45 (d, 3H, --O--CH(CH3)--O--), 1.5-1.7 (m, 14H, --CH2 --), 2.25 (m, 8H, --CH2 --C(O)--O--), 3.60 (t, 2H, --CH2 --OH), 4.05 (t, 4H, --C(O)--O--CH2 --), 6.85 (q, 1H, --O--CH(CH3)--O--). 13C NMR (75 MHz, CDCl3): δ 13.7, 19.1, 22.2, 24.2, 24.6, 25.2, 25.5, 28.2, 28.5, 28.7, 28.8, 29.0, 29.2, 31.5, 32.3, 33.7, 34.0, 62.5, 64.0, 88.0, 171.5, 173.5.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1.C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccc(Cl)nn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2ccc(Cl)nn2)CC1

Procedure:
2.0 g (13.4 mmol) of 3,6-dichloropyridazine, 2.3 g (14.8 mmol) of ethyl piperidine-4-carboxylate and 4.6 ml (33 mmol) of triethylamine were stirred in 20 ml of DMF at 50° C. for 4 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][CH:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH3:4].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:12]([N:5]([CH:2]([CH3:1])[CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCC(C)Nc1ccccc1
Reactant: CCCCCCCBr
Product: CCCCCCCN(c1ccccc1)C(C)CC

Procedure:
N-n-heptyl-N-(1-methylpropyl)aniline was prepared from N-(1-methylpropyl)aniline and 1-n-heptylbromide using the same method as in Example 2ii).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[Br:10]Br>CCOCC.[Fe]>[Br:10][C:6]1[CH:7]=[C:2]([F:1])[C:3]([CH3:9])=[CH:4][C:5]=1[F:8]
Reactant: BrBr
Reactant: Cc1cc(F)ccc1F
Agent: [Fe]
Solvent: CCOCC
Product: Cc1cc(F)c(Br)cc1F
Temperature: -5 °C
Reaction time: 3 h

Procedure:
A mixture of 2,5-difluorotoluene (25 g, 0.20 mol) and iron powder (11 g, 0.2 mol) was cooled to −5° C. Bromine was added dropwise such that the internal temperature of the reaction did not rise above 0° C. After stirring for 3 hours, the mixture was diluted with ether, filtered and washed with aqueous sodium thiosulfate solution. The aqueous layer was extracted with ether, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Distillation at atmospheric pressure gave 34 g of 1-bromo-2,5-difluoro-4-methyl-benzene as a colorless oil (b.p. 180 oC). 1H NMR (300 MHz, CDCl3) δ 7.20 (dd, 1H, J=6.0, 8.5 Hz), 6.93 (m, 1H), 2.23 (s, 3H) ppm.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([C:14]2[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27].O>C1COCC1>[O:1]([C:8]1[N:13]=[CH:12][C:11]([C:14]2[C:15]3=[N:20][S:26](=[O:28])(=[O:27])[CH2:25][CH2:24][N:16]3[CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1-c1ccc(Oc2ccccc2)nc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccccc4)nc3)C2=N1
Temperature: 50 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A mixture of 6′-phenoxy-3,3′-bipyridin-2-amine (350 mg) in THF (dry) (15 mL) was added to a mixture of NaH (60%, 266 mg) and 2-chloroethanesulfonyl chloride (542 mg) in THF (dry) (15.0 ml) at room temperature. The mixture was stirred at 50° C. overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (419 mg) as a pale yellow solid. The solid was crystallized from CH3CN-IPE to give a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:16]1CC[CH2:18][CH2:17]1.C(N(CC)CC)C.C(Cl)(=O)C>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:17](=[O:16])[CH3:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Oc1ccc(OCc2ccccc2)cc1
Reaction time: 24 h

Procedure:
To 35.0 g (175.0 mmol) of 4-(benzyloxy)phenol were added 100 ml of dried tetrahydrofuran and 17.7 g (175.2 mmol) of triethylamine, and the mixture was homogeneously dissolved. Next, 13.75 g (175.2 mmol) of acetyl chloride was added to the resultant mixture with cooling with ice. The reaction was conducted at a room temperature for 24 hours. The reaction mixture was poured into 500 ml of an iced water and a solid was formed by stirring. The resultant solid was collected by filtration, dried, and recrystallized from a mixed solvent of hexane/toluene to give 40.3 g (166.5 mmol) of benzyl-(4-acetoxyphenyl)ether.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[O:9][N:8]=[C:7]([C:10]2[N:14]3[N:15]=[C:16]([OH:23])[C:17]4[C:22]([C:13]3=[N:12][N:11]=2)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=1.O>CN(C)C=O>[OH:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2=[N:12][N:11]=[C:10]([C:7]3[CH:6]=[C:5]([O:2][CH3:1])[O:9][N:8]=3)[N:14]2[N:15]=1
Reactant: Oc1nn2c(-c3cc(Cl)on3)nnc2c2ccccc12
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc3c4ccccc4c(O)nn23)no1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Sodium methoxide (165 mg, 0.3 mmol) was added to a stirred suspension of 3-(5-chloroisoxazol-3-yl)-6-hydroxy-1,2,4-triazolo[3,4-a]phthalazine (400 mg, 0. 14 mmol) (prepared from Intermediate 7 using the procedure described in Example 15 part b) in N,N-dimethylformamide (20 ml) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 3 h then water was added (5 ml) and the solvents evaporated in vacuo. The residue was taken up in water and acidified to pH 2 using 2M hydrochloric acid. The resulting precipitate was filtered off, washed with hexane and azeotroped with ethanol to give crude 6-hydroxy-3(5-methoxyisoxazol-3-yl)-1,2,4-triazolo[3,4-a]phthalazine, MS (ES30) 284 [MH]+. The title-compound was prepared from this material using the procedure described in Example 103 part a, 1H NMR (250 MHz, CDCl3) δ 2.49 (3H, s, CH3), 4.15 (3H, s, CH3), 6.10 (1H, s, Ar—H), 7.45 (2H, d, J=8.5 Hz, Ar—H), 7.92 (1H, m, Ar—H), 8.06 (1H, m, Ar—H), 8.26-8.32 (3H, m, 3 of Ar—H), 8.64 (1H, d, Ar—H); MS (ES30) 438 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH3:9][S:10]S(C)(=O)=O>CO>[CH:2]([NH2:1])([CH3:7])[CH3:3].[CH3:9][S:10][S:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(S)cc1
Reactant: CSS(C)(=O)=O
Solvent: CO
Product: CC(C)N
Product: CSSc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 1 %
Yield: 163.5 %

Procedure:
To a solution of p-aminobenzenethiol (125 mg, 1 mmol) in methanol (1 ml) was added MMTS (94 μl, 1 mmol) in a single portion. The reaction was stirred at RT under N2. After 2 hr, the solution was loaded onto an SCX column and eluted with methanol, followed by 1M ammonia in methanol. The basic eluents were concentrated in vacuo to a yellow oil. Chromatography (1:1 hexanes:CH2Cl2 with 1% isopropylamine) yielded 39a (140 mg, 82%) as a pale yellow oil. 1H NMR (250 MHz, CDCl3): δ 7.28 (d, J=8.6 Hz, 2H); 6.54 (d, J=8.6 Hz, 2H); 3.60 (broad s, 2H); 2.34 (s, 3H). Treatment with HCl/ether gave 5 mg of the HCl salt. Biological testing was performed on the acid salt. 1H NMR (400 MHz, d6-DMSO): δ 7.46 (broad s, 2H); 7.05 (broad s, 2H); 2.47 (s, 3H); 2.43 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]1([C:27]2[O:28][C:29]([C:35]([F:38])([F:37])[F:36])=[C:30]([C:32](O)=[O:33])[N:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:32]([C:30]3[N:31]=[C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:28][C:29]=3[C:35]([F:37])([F:38])[F:36])=[O:33])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(5-Amino-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester was mixed with 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid (771 mg, 3.0 mmol) and bromotrispyrrolidinophosphonium hexafluorophosphate (1.40 g, 3.0 mmol) in N,N-dimethylformamide (20 mL) and methylene chloride (5 mL) containing triethylamine (0.85 mL). The mixture was stirred at room temperature overnight and the solvents were evaporated. The residue was extracted with ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was triturated with ethyl acetate and the solid was filtered to give 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester (1.09 g). LC-MS calcd for C25H26F3N5O4 (m/e) 517.5, obsd 518.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[C:20]([C:24]5[CH:29]=[C:28]([F:30])[N:27]=[CH:26][C:25]=5[CH2:31][N:32]5[CH2:36][CH2:35][CH:34]([N:37](C)[C:38](=O)OC(C)(C)C)[CH2:33]5)=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)[C:12]([F:46])=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1.Cl.O1CCOCC1>C(Cl)Cl.CO>[N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[C:20]([C:24]5[C:25]([CH2:31][N:32]6[CH2:36][CH2:35][CH:34]([NH:37][CH3:38])[CH2:33]6)=[CH:26][N:27]=[C:28]([F:30])[CH:29]=5)=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)[C:12]([F:46])=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(Cc2cnc(F)cc2-c2cccc3cc(-c4nc(NCCn5ccnn5)ncc4F)sc23)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: CNC1CCN(Cc2cnc(F)cc2-c2cccc3cc(-c4nc(NCCn5ccnn5)ncc4F)sc23)C1
Temperature: 35 °C
Yield: 89.3 %

Procedure:
Dilute tert-butyl 1-((4-(2-(2-(2-(1H-1,2,3-triazol-1-yl)ethylamino)-5-fluoropyrimidin-4-yl)benzo[b]thiophen-7-yl)-6-fluoropyridin-3-yl)methyl)pyrrolidin-3-yl(methyl)carbamate (118 mg, 0.18 mmol) in DCM (3 mL) and treat with 4 M hydrochloric acid in dioxane (0.45 mL, 1.8 mmol). Heat the mixture at 35° C. for 2 h. Remove the organic solvent to give the crude deprotected product. Dilute in DCM (3 mL) and methanol. Pour the mixture onto a strong cation exchange (SCX) (10 g) column. Elute the desired product with 2 N methanolic ammonia (40 mL) and concentrate. Dry the concentrated material from 1:1 acetonitrile/water by lyophilizing to afford the title compound (88 mg, 46%). MS (ES) m/z 548 [M+1]+.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[OH:6][CH2:7][C@@H:8]1[CH2:13][N:12]2[N:14]=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[C:11]2[C:10](=[O:25])[NH:9]1.Cl>C(#N)C>[O:18]([CH2:17][C:15]1[CH:16]=[C:11]2[C:10](=[O:25])[NH:9][C@H:8]([CH2:7][O:6][Si:2]([CH3:5])([CH3:4])[CH3:3])[CH2:13][N:12]2[N:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1N[C@H](CO)Cn2nc(COc3ccccc3)cc21
Reactant: C[Si](C)(C)Cl
Agent: Cl
Solvent: CC#N
Product: C[Si](C)(C)OC[C@@H]1Cn2nc(COc3ccccc3)cc2C(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
Chlorotrimethylsilane (0.30 mL, 2.41 mmol) was added to a solution of (S)-6-hydroxymethyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.33 g, 2.4 mmol) and TEA (0.33 mL, 2.4 mmol) in ACN (6 mL) at 0° C. The reaction was stirred for 30 minutes at room temperature. Then a 1N solution of HCl was added and the mixture extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield (S)-2-phenoxymethyl-6-trimethylsilanyloxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.375 g, 90% yield) as an off-white solid that was used in the next step without further purification.