Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH2:25])(=[O:24])=[O:23])=[CH:9][CH:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C.C(OCC)(=O)C>[CH2:30]([O:29][C:27]([NH:25][S:22]([C:14]1[S:15][C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:17][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1)(=[O:23])=[O:24])=[O:28])[CH2:31][CH2:32][CH3:33]
Reactant: CC(C)Cc1cc(-c2ccc(Cn3cncn3)cc2)c(S(N)(=O)=O)s1
Reactant: CCCCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1ccc(Cn2cncn2)cc1
Reaction time: 8 h
Yield: 9.2 %

Procedure:
59 mg (0.16 mmol) of the crude 3-(4-[1,2,4]triazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide from step (c) above was mixed with butyl chloroformate (31 μL, 0.24 mmol) and 4-dimethylaminopyridine (2 mg, 16 μmol) in 5 mL of triethylamine at 0° C. The reaction mixture was stirred overnight and then diluted with ethyl acetate, washed with water and dried over K2CO3. The reaction mixture was then separated on a silica column (dichloromethane+15% methanol), circular chromatography (dichloromethane+10-15% methanol and preparative LC-MS to yield 7.0 mg of the title compound (9% isolated yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[F:19])=[CH:8][CH:7]=[N:6]2.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27](O)=[O:28])[C:23](=[O:30])[N:22]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:27]([C:24]3[C:23](=[O:30])[N:22]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:21]([CH3:20])[C:25]=3[CH3:26])=[O:28])=[CH:14][C:13]=1[F:19])=[CH:8][CH:7]=[N:6]2
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: Nc1ccc(Oc2ccnn3ccc(Br)c23)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnn4ccc(Br)c34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 50 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a solution of 4-(5-bromopyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluoroaniline (57 mg, 0.178 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (124 mg, 0.534 mmol) prepared in Preparation Example 1 in dimethylformamide (2 mL), HATU (270 mg, 0.711 mmol) and triethylamine (0.1 mL, 0.711 mmol) were sequentially added and stirred at 50° C. overnight. The resulting reaction mixture was concentrated under reduced pressure and the resulting residue was extracted with dichloromethane and water. The organic layer was separated, dried with magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (10% ethyl acetate in dichloromethane) to give the target compound as a white solid (60 mg, 0.111 mmol, 63% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nn2cncn2)cc1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(CN(c2ccc(C#N)cc2)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 4-methoxybenzyl chloride
Reaction SMILES: [O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][NH2:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(=O)(O)[O-].[Na+]>ClCCl>[O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][NH:29][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[Si:2]([C:15]([CH3:17])([CH3:18])[CH3:16])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](OCCC1(CCN)CCCCC1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCCC1(CCNS(C)(=O)=O)CCCCC1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethylamine (409 mg) dissolved in dichloromethane (10 mL) was added triethylamine (0.28 mL). Methanesulfonyl chloride (0.12 mL) was added to the solution under ice cooling, and it was stirred at that temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the solution, and it was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=6:1) to give the title compound (327 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)[NH2:21]>C(O)(C)C.C(=O)([O-])O.[Na+]>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:10]1[C:3]2[C:2]([NH:21][C:20]3[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=4)=[C:18]([Cl:17])[CH:19]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)[CH3:16]
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: CCOC(=O)Cn1ccc2ncnc(Cl)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)Cn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 73.9 %

Procedure:
To a solution of ethyl (4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)acetate (530 mg) in isopropyl alcohol (4.0 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (695 mg), and the mixture was stirred in an oil bath at a temperature of 100° C. for 2.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (30 mL×3). The organic layer washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluent:hexane/ethyl acetate=95/5→20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (743 mg) as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12](O)=[O:13])=[CH:9][C:4]=2[CH2:3][CH2:2]1.O1CCCC1.B.O.Cl>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)CCc1ccc2c(c1)CCO2
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: OCCCc1ccc2c(c1)CCO2
Reaction time: 16 h
Yield: 103 %

Procedure:
3-(2,3-Dihydrobenzofuran-5-yl)propionic acid (2.00 g) was dissolved in tetrahydrofuran (20 ml), and a tetrahydrofuran-borane.tetrahydrofuran solution (1 mol/l, 11.5 ml) was added dropwise to the mixture under ice-cooling. The mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 16 hr. Water was added to the reaction mixture, and 1M aqueous hydrochloric acid solution was added. The mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (1.91 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(C)=O.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Sc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCSc1ccc(Cl)cc1Cl

Procedure:
2,4-Dichlorothiophenol (5.04 g, 28.2 mmol), caesium carbonate (10.1 g, 31 mmol) and ethyl 3-bromopropanoate (4.2 mL, 33 mmol) in acetone (100 mL) were refluxed overnight under N2(g). After filtration and concentration under reduced pressure, the residue was partitioned between dichloromethane and water. After separation, the aqueous phase was extracted once with dichloromethane. Drying and removal of the solvent in vacuo afforded a liquid residue that contained ˜30% (HPLC) of unreacted 2,4-dichlorothiophenol. The mixture was refluxed again with caesium carbonate (4.7 g) and ethyl 3-bromopropanoate (2 mL) in acetonitrile (100 mL) under N2(g) for 2 h. After filtration and concentration under reduced pressure, the residue was dissolved in diethyl ether and washed with 2 M aq. sodium hydroxide and water. Drying and removal of the solvent in vacuo afforded the sub-title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([O:26]CC)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li+].[OH-]>CO>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3OC)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Temperature: 70 °C
Yield: 100.4 %

Procedure:
To a suspension of (R)-ethyl 5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.72 g, 1.868 mmol) in MeOH (9.34 mL) was added 1N LiOH (3.74 ml, 3.74 mmol) and the reaction mixture heated to 70° C. for 15 hours. After cooling, the reaction mixture was concentrated and the resulting residue diluted in water. After acidifying with citric acid (solid), the aqueous layer was extracted with DCM. The combined organics were dried with MgSO4, filtered and concentrated to afforded (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.67 g, 100%) as a yellow solid. MS (apci) m/z=357.9 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].S(OCC)(O[CH2:16][CH3:17])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:16]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)[CH3:17]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc([N+](=O)[O-])c(F)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
To a solution of 3-fluoro-4-nitrophenol (9.9 g, 0.063 mol) and diethyl sulfate (12.17 g, 0.079 mol) in DMF (100 mL) was added K2CO3 (17.39 g, 0.126 mol). The resulting mixture was stirred at 80° C. for 90 min and then cooled to rt. The reaction mixture was diluted with H2O (200 mL) and extracted with 25% EtOAc in hexanes (2×100 mL). The combined organic phases were washed with brine (100 mL), filtered through phase separation filter paper, and concentrated in vacuo to give 11.5 g (98%) of 53 as an orange-yellow solid. 1H NMR (60 MHz, CDCl3): δ 8.8-7.7 (m, 1H), 6.6-6.2 (m, 2H), 4.0 (q, 2H), 1.4 (t, 3H) ppm.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]1[C:12]2[CH2:11][O:10][C:9]([C:13]#[N:14])=[CH:8][C:7]3=[CH:15][NH:16][CH:17]=[C:5]([C:6]=23)[CH2:4]1.[OH-:19].[Na+]>>[CH3:1][N:2]([CH3:18])[CH:3]1[C:12]2[CH2:11][O:10][C:9]([C:13]([NH2:14])=[O:19])=[CH:8][C:7]3=[CH:15][NH:16][CH:17]=[C:5]([C:6]=23)[CH2:4]1
Reactant: [OH-]
Reactant: CN(C)C1CC2=CNC=C3C=C(C#N)OCC1=C32
Agent: [Na+]
Product: CN(C)C1CC2=CNC=C3C=C(C(N)=O)OCC1=C32
Temperature: 90 °C
Yield: 62 %

Procedure:
Polyphophoric acid 420 mg was added to compound (48) 31.6 mg under an argon atmosphere and the mixture was heated at 90° C. for 6 h. Ice-water was added to the reaction mixture, which was made alkaline with an aqueous 5 N-sodium hydroxide solution and extracted with chloroform. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform:methanol (97:3) to give the titled compound as colorless crystals, 20.9 mg. Yield 62%. Furthermore, the titled compound was recrystallized from acetone-isopropyl ether to give colorless crystals, m.p. 182-183° C.
Reaction SMILES: CCO[C:4]([S-])=[S:5].[K+].[NH2:8][C:9]1[C:14]([NH2:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[O:17][CH2:18][CH:19]([OH:25])[CH2:20][NH:21][CH:22]([CH3:24])[CH3:23]>>[OH:25][CH:19]([CH2:20][NH:21][CH:22]([CH3:23])[CH3:24])[CH2:18][O:17][C:10]1[C:9]2[NH:8][C:4](=[S:5])[NH:15][C:14]=2[CH:13]=[C:12]([CH3:16])[CH:11]=1
Reactant: Cc1cc(N)c(N)c(OCC(O)CNC(C)C)c1
Reactant: CCOC(=S)[S-]
Agent: [K+]
Product: Cc1cc(OCC(O)CNC(C)C)c2[nH]c(=S)[nH]c2c1

Procedure:
From potassium xanthogenate and 2,3-diamino-1-[2-hydroxy-3-(2-propylamino)-propoxy]-5-methylbenzene, using the process described in Example 3, there is obtained the title compound which, after recrystallisation from ethanol, decomposes at 294°-295° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.[CH:12]1([C:15]#[C:16][CH2:17]O)[CH2:14][CH2:13]1>>[CH:12]1([C:15]#[C:16][CH2:17][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)[CH2:14][CH2:13]1
Reactant: OCC#CC1CC1
Reactant: COC(=O)c1ccc(O)cn1
Product: O=C(O)c1ccc(OCC#CC2CC2)cn1

Procedure:
The title compound was synthesized analogously according to Method KS starting from methyl 5-hydroxypicolinate (Molbridge) and 3-cyclopropylprop-2-yn-1-ol. MS m/z: 218 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([OH:15])[C:5]=2[NH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:22](Br)[CH:23]=[CH2:24]>C1COCC1.CN1C(=O)CCC1>[CH2:24]([N:4]1[C:5]2[C:6]([OH:15])=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[C:2]([CH3:1])=[CH:3]1)[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: Cc1c[nH]c2c(O)nc3ccccc3c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: C=CCn1cc(C)c2c3ccccc3nc(O)c21
Temperature: 40 °C
Reaction time: 12 h
Yield: 54.1 %

Procedure:
A solution of 1-methyl-3H-pyrrolo[2,3-c]quinolin-4-ol (1.2 g, 6.05 mmol) in a mixture of THF (30 mL) and NMP (60 mL) was treated with Cs2CO3 (2.95 g, 9.08 mmol). Allyl bromide (0.524 mL, 6.06 mmol) was added dropwise, and the resulting mixture was stirred at 40° C. for 12 h. The mixture was cooled and quenched with aqueous HCl (1 N) and EtOAc. The organic layer was separated, washed with aqueous HCl (1 N), brine, and dried over Na2SO4. Filtration and removal of the volatiles gave a residue that was triturated with Et2O to give the title compound (0.78 g, 54%) as a solid. LCMS (ES+) m/z 239 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH2:19]([N:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22](Cl)=[O:23])[CH3:20]>C(OCC)(=O)C.CCCCCCC>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][C:22](=[O:23])[N:21]([CH2:19][CH3:20])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CCN(C(=O)Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(4-trifluoromethyl-phenoxy)-phenol and N-ethyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (ethyl acetate/heptane, 1:5) (77%, white crystals. HPLC-MS m/z=402.1 (M+1), Rt: 5.6 min.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=1)C.O.[OH-].[Li+]>O1CCOCC1.O>[C:15]1([C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:21])=[O:3])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CCCOc1cccc(-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCCOc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.1 %

Procedure:
To a solution in 2:1 dioxane/water (36 mL) of 4-(3-phenylphenoxy)butanoic acid ethyl ester (3.42 g, 12 mmol), prepared as in step 1, was added lithium hydroxide hydrate (1.42 g, 33.8 mmol) and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated in vacuo and the resulting solid was mostly dissolved in aqueous Na2CO3. The aqueous solution was decanted from a small amount of residual solid and extracted with ethyl ether. The ether extract was discarded and the aqueous phase was taken to pH 2 with HCl and extracted with ethyl acetate. The ethyl acetate extract was dried over MgSO4, filtered, and concentrated in vacuo to give 4-(3-phenylphenoxy)butanoic acid (3.17 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[N+:21]([O-])=O)C1C=CC=CC=1>ClCCl.C(O)C.[Pd]>[NH2:21][C:10]1[CH:11]=[C:12]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(N2CCOCC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: Nc1cc(N2CCOCC2)ccc1O
Yield: 96 %

Procedure:
Catalytic hydrogenation of 4-(4-benzyloxy-3-nitro-phenyl)-morpholine (5 g, 16 mmol) in dichloromethane (500 ml) and ethanol (500 ml) using palladium on carbon (500 mg, 10%) afforded the title compound as a grey solid (96%), MS: m/e=194(M+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[C:6](OCC)[C:7]2[C:8](=[CH:10][S:11][CH:12]=2)[N:9]=1)[CH3:2].[CH2:16]([NH2:19])[CH2:17][CH3:18]>C(O)C>[CH2:1]([O:3][C:4]1[N:5]=[C:6]([NH:19][CH2:16][CH2:17][CH3:18])[C:7]2[C:8](=[CH:10][S:11][CH:12]=2)[N:9]=1)[CH3:2]
Reactant: CCOc1nc(OCC)c2cscc2n1
Reactant: CCCN
Solvent: CCO
Product: CCCNc1nc(OCC)nc2cscc12

Procedure:
A solution of 2.3 g (0.01 mole) of 2,4-diethoxy-thieno[3,4-d]pyrimidine and 3.6 g (0.06 mole) of n-propylamine in 50 ml absolute ethyl alcohol is heated under reflux for 10 hours. The solution is then evaporated to dryness. The solid is drained off, washed with water and dried. After recrystallization from toluene, 14 g (59% of theory) of 2-ethoxy-4-n-propylamino-thieno[3,4-d]pyrimidine are obtained. M.P. 140°-142°C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[C:22]2[C:12]([NH:13][CH:14]=[C:15]2[CH2:16][CH:17]([C:19]([OH:21])=[O:20])[NH2:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)[C:25]#[C:26][CH3:27]>>[CH2:24]([O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:18][CH:17]([CH2:16][C:15]2[C:22]3[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:23]=3)[NH:13][CH:14]=2)[C:19]([OH:21])=[O:20])(=[O:37])=[O:36])=[CH:31][CH:30]=1)[C:25]#[C:26][CH3:27]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(Cc1c[nH]c2ccc(OCc3ccccc3)cc12)C(=O)O
Product: CC#CCOc1ccc(S(=O)(=O)NC(Cc2c[nH]c3ccc(OCc4ccccc4)cc23)C(=O)O)cc1

Procedure:
The title compound was prepared by the method of Example 6, using 5-benzyloxy-DL-tryptophan and 4-but-2-ynyloxy-benzenesulfonyl chloride as starting materials. 1H NMR (DMSO-d6): 400 MHz δ 12.55 (bs, 1H), 10.64 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.50-7.33 (m, 7H), 7.19 (d, J=12.0 Hz, 1H), 7.03 (d, J=4.0 Hz, 1H), 6.97 (d, J=4.0 Hz, 1H), 6.87 (d, J=8.0 Hz, 2H), 6.76 (dd, J=8.0, 4.0 Hz, 1H), 5.04 (s, 2H), 4.74 (q, J=2.4 Hz, 2H), 3.86 (q, J=8.0 Hz, 1H), 3.00 (dd J=14.4, 6.4 Hz, 1H), 2.83 (dd J=14.4, 8.0 Hz, 1H), 1.82 (t, J=2.4 Hz, 3H); HRMS: calcd for C28H27N2O6S (ESI+, [M+H]1+), 519.1584; found 519.1588; LCMS m/z (ESI) [M+H] 519, retention time=2.99 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C1(C)C=CC=CC=1.ClS([N:22]=[C:23]=[O:24])(=O)=O.Cl>O>[N:1]1([C:23]([NH2:22])=[O:24])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=O)N1C(=O)Cc2ccccc21
Temperature: 25 °C
Yield: 53.7 %

Procedure:
To a stirred mixture of 2-oxindole (5.86 g, 44.0 mmole) and dry toluene (160 ml) was added chlorosulfonyl isocyanate (7.47 g, 52.8 mmole). Hydrogen chloride was immediately evolved. The mixture was stirred under reflux for 15 minutes and then it was cooled to room temperature. Water (50 ml) was added to the cooled mixture (some HCl was initially evolved) and then the mixture was stirred for 1.5 hours. The solid which formed was collected by filtration and dried (4.10 g). The filtrate was extracted with ethyl acetate (100 ml), and the resulting extract was washed with brine (2×100 ml) and dried (MgSO4). Evaporation of the extract under reduced pressure gave 4.16 g of solid. The combined solids were recrystallized by dissolution in acetonitrile (200 ml) followed by concentration of the solution under reduced pressure to about 75 ml. The small amount of amorphous material which separated was filtered off, the filtrate was decolorized and concentrated under reduced pressure to about 50 ml volume, then seeded. This gave the title compound as dark red crystals which were filtered off and dried (3.0 g; 38%).
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[C:6]([OH:8])=O)[CH2:3][CH2:2]1.[CH3:19][O:20][C:21]([CH3:30])([CH3:29])[CH2:22][N:23]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:4][C@H:5]([N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[C:6]([NH:28][C:25]2[CH:26]=[CH:27][N:23]([CH2:22][C:21]([O:20][CH3:19])([CH3:29])[CH3:30])[N:24]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: COC(C)(C)Cn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CC1)N1Cc2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(C)(C)Cn1ccc(NC(=O)[C@H](CC2CC2)N2Cc3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.1 %

Procedure:
To a solution of (S)-3-cyclopropyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (85 mg, 0.35 mmol) and 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 94, 64 mg, 0.38 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (Chemimpex, 0.18 g, 0.42 mmol) in methylene chloride (8 mL) was added N,N-diisopropylethylamine (0.18 mL, 1.0 mmol) dropwise and the resulting solution stirred at room temperature for 4 h. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (25 mL), a saturated sodium bicarbonate solution (25 mL) dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF4-40 g column, 50-70% ethyl acetate/hexanes) to give (S)-3-cyclopropyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide (46 mg, 34%) as an off white solid: [α]30D=−38.1°, (c=0.21, chloroform); HR-ES(+) m/e calcd for C22H28N4O3 [M+H]+ 397.2234, observed 397.2235; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.03-1.69 (m, 9H), 2.00-2.28 (m, 1H), 3.15 (s, 4H), 3.99 (s, 2H), 4.36-5.39 (m, 4H), 6.42 (d, J=1.81 Hz, 1H), 7.25-7.88 (m, 6H), 10.80 (s, 1H).