Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.O=[C:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]1[C:18](OC)=[O:19]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]2[C:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]=3[C:18](=[O:19])[O:9][C:5]=2[CH:4]=1)[CH3:2]
Reactant: COC(=O)C1CNCCC1=O
Reactant: CCc1cccc(O)c1
Agent: Cl
Product: CCc1ccc2c3c(c(=O)oc2c1)CNCC3
Yield: 28.8 %

Procedure:
Prepared by the method described for Example 1 from 3-ethylphenol (12.2 g, 0.1 moles) and methyl 4-oxo-3-piperidinecarboxylate hydrochloride (19.3 g, 0.1 moles). The crude material is washed with water and dried to give the product (6.6 g), mp 80°-85° C.
Reaction SMILES: [C:1]([N:4]([C:10](=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13])[CH:5]([C:7]([OH:9])=O)[CH3:6])(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[NH2:32][CH:33]([C:35]([OH:37])=[O:36])[CH3:34]>O1CCCC1.[OH-].[Na+]>[C:1]([N:4]([C:10](=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13])[CH:5]([C:7]([NH:32][CH:33]([C:35]([OH:37])=[O:36])[CH3:34])=[O:9])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(N)C(=O)O
Reactant: CC(=O)N(C(=O)c1ccccc1O)C(C)C(=O)O
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N(C(=O)c1ccccc1O)C(C)C(=O)NC(C)C(=O)O
Reaction time: 6 h

Procedure:
Acetylsalicyloyl-(DL)-alanine (2.5 g) was dissolved in dry tetrahydrofuran (15.0 ml) and dry triethylamine (1.36 ml) was added. The reaction mixture was brought to -5° C. and ethyl chloroformate (0.96 ml) was added dropwise over a period of 10 min. (DL)-Alanine (0.89 g) dissolved in aqueous sodium hydroxide (1M, 10.0 ml) was added. The reaction was allowed to proceed at 0° C. for 6 hrs., and the solvent was then removed at 30° C. under reduced pressure. The residual solution was acidified to pH 2-3 using aqueous hydrochloric acid (3M). The whole was extracted with ethyl acetate (50.0 ml), and the extract was dried (anhydrous sodium sulphate). The bulk of the ethyl acetate was removed under reduced pressure to leave a small volume of solution.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.I[C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([C:22]([N:24]([CH3:28])[CH2:25][CH2:26][CH3:27])=[O:23])[CH:21]=1)[C:15]([O:17]C)=[O:16].O.[OH-].[Li+]>O1CCCC1.C(OCC)(=O)C.O1CCCC1.CO.O.C(Cl)(Cl)Cl.[Cl-].[Zn+2].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:28][N:24]([CH2:25][CH2:26][CH3:27])[C:22]([C:20]1[CH:19]=[C:14]([CH:13]=[C:12]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH:21]=1)[C:15]([OH:17])=[O:16])=[O:23]
Reactant: CCCN(C)C(=O)c1cc(I)cc(C(=O)OC)c1
Reactant: c1cocn1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C. stirred solution of oxazole (330 mg, 4.8 mmol) in tetrahydrofuran (4 mL) is added n-butyllithium (1.6 M in hexanes, 3.3 mL, 5.3 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 14.5 mL, 14.5 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is added a solution of methyl 3-iodo-5-{[methyl(propyl)amino]carbonyl}benzoate (1.6 g, 4.5 mmol) in anhydrous tetrahydrofuran (3 mL) followed by palladium(0) tetrakis(triphenylphosphine) (221 mg, 0.19 mmol). The reaction mixture is heated at reflux for 2 h. The reaction mixture is cooled, diluted with ethyl acetate, washed with water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 60% ethyl acetate/hexane) provides a solid. The solid is redissolved in 1:1:1 tetrahydrofuran/methanol/water (9 mL), and lithium hydroxide monohydrate (311 mg, 7.4 mmol) is added and stirred 2 h at room temperature. The reaction is diluted in chloroform and washed with 1N hydrochloric acid (aq), water, and brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give the title compound. ESI MS m/z 287.3 [M−H]−.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3](O)=[O:4].OC(CCSC)C#[N:13]>>[OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([NH2:13])=[O:4]
Reactant: CSCCC(O)C(=O)O
Reactant: CSCCC(O)C#N
Product: CSCCC(O)C(N)=O

Procedure:
A further aspect of the present invention is directed to a process for the preparation of salts of 2-hydroxy-4-(methylthio)-butanoic acid from 2-hydroxy-4-(methylthio)-butanenitrile. 2-Hydroxy-4-(methylthio)-butanenitrile is enzymatically hydrated to form 2-hydroxy-4-(methylthio)-butaneamide, and the resulting 2-hydroxy-4-(methylthio)-butaneamide is hydrolyzed in a basic solution to form a salt of 2-hydroxy-4-(methylthio)-butanoic acid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:32])[C@@H:4]([NH:12][C:13](=[O:31])[C@@H:14]([N:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[N:25]=[C:26]([CH3:29])[S:27][CH:28]=2)[C:19]1=[O:30])[CH:15]([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1C=CC=CC=1.[O:39]([C:44]([N:46]1[CH2:52][CH2:51][CH2:50][C@H:47]1[CH:48]=O)=[O:45])[C:40]([CH3:43])([CH3:42])[CH3:41].[BH4-].[Na+]>C(O)C>[OH:32][C@@H:3]([C@@H:4]([NH:12][C:13](=[O:31])[C@@H:14]([N:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[N:25]=[C:26]([CH3:29])[S:27][CH:28]=2)[C:19]1=[O:30])[CH:15]([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:2][NH:1][CH2:48][CH:47]1[CH2:50][CH2:51][CH2:52][N:46]1[C:44]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:45]
Reactant: Cc1nc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CN)C(C)C)C2=O)cs1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: Cc1nc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CNCC3CCCN3C(=O)OC(C)(C)C)C(C)C)C2=O)cs1
Temperature: 70 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
A solution of the product of Example 274C (59 mg) in ethanol:benzene (1 mL, 1:1) was treated with N-t-butoxylcarbonyl-(L)-prolinal (26 mg, 1 equivalent), stirred at 70° C. for 1 hour, cooled at 25° C., treated with NaBH4 (14 mg, 3 equivalents) at 25° C. and stirred for 16 hours. The mixture was quenched with saturated NH4Cl and partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered and concentrated to give 85 mg of the crude title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1(CN)CCCCC1.[O:15]=[C:16]1[C:24]2([CH2:28][O:27][C:26]3[CH:29]=[C:30]4[C:34](=[CH:35][C:25]2=3)[CH2:33][CH2:32][O:31]4)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]1[CH2:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[N:1]1([C:41]([C:40]2[CH:39]=[CH:38][C:37]([CH2:36][N:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:24]4([CH2:28][O:27][C:26]5[CH:29]=[C:30]6[C:34](=[CH:35][C:25]4=5)[CH2:33][CH2:32][O:31]6)[C:16]3=[O:15])=[CH:45][CH:44]=2)=[O:42])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1)N1CCOCC1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using morpholine to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b']difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, 1′-[4-(morpholin-4-ylcarbonyl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (58%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.44-7.35 (m, 4H), 7.24-7.15 (m, 2H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.76 (d, J=7.5 Hz, 1H), 6.48 (s, 1H), 6.44 (s, 1H), 4.98 (ABq, 2H), 4.85 (ABq, 2H), 4.55 (t, J=8.6 Hz, 2H), 3.87-3.40 (m, 8H), 3.08-2.93 (m, 2H); MS (ES+) m/z 483.1 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:43])[CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[N:37]=[C:38]([CH3:41])[O:39][CH:40]=2)[CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]2[N:7]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]4[N:37]=[C:38]([CH3:41])[O:39][CH:40]=4)[CH:31]=3)[CH2:28][C:27](=[O:43])[NH:20][C:9]=2[CH:10]=1
Reactant: Cc1nc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)co1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3coc(C)n3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.16 g) (Example J8) and 3-oxo-3-[3-(2-methyl-oxazol-4-yl)-phenyl]-propionic acid tert-butyl ester (0.17 g) (Example K29) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.07 g).
Reaction SMILES: C(OC(=O)[N:7]([CH2:23][CH2:24][C:25]([N:27]1[CH2:33][CH2:32][C:31]2[CH:34]=[C:35]([O:40][CH3:41])[C:36]([O:38][CH3:39])=[CH:37][C:30]=2[CH2:29][CH2:28]1)=[O:26])[CH2:8][CH:9]1[CH2:16][C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([O:17][CH2:18][C:19]([NH:21][CH3:22])=[O:20])[CH:14]=2)(C)(C)C.[ClH:43]>C(O)C>[ClH:43].[CH3:39][O:38][C:36]1[C:35]([O:40][CH3:41])=[CH:34][C:31]2[CH2:32][CH2:33][N:27]([C:25](=[O:26])[CH2:24][CH2:23][NH:7][CH2:8][CH:9]3[CH2:16][C:15]4[C:10]3=[CH:11][CH:12]=[C:13]([O:17][CH2:18][C:19]([NH:21][CH3:22])=[O:20])[CH:14]=4)[CH2:28][CH2:29][C:30]=2[CH:37]=1
Reactant: CNC(=O)COc1ccc2c(c1)CC2CN(CCC(=O)N1CCc2cc(OC)c(OC)cc2CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CNC(=O)COc1ccc2c(c1)CC2CNCCC(=O)N1CCc2cc(OC)c(OC)cc2CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
At ambient temperature, 2.63 g (4.5 mmol) of the compound obtained in Step B above are mixed into 120 mL of ethanol together with 25 mL of 3.7N ethanolic HCl. After stirring for 1 day at ambient temperature, the solid formed is filtered off, rinsed with ethanol and with ether and dried in vacuo to obtain the desired compound in the form of the hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:25]2[N:26]=[CH:27][NH:28][CH:29]=2)[C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20]C(C)(C)C)=O)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.O>C(#N)C>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:11]([C:25]2[N:26]=[CH:27][NH:28][CH:29]=2)[CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:13][CH:14]=1)#[N:20]
Reactant: CC(C)(C)NC(=O)c1ccc(C(CCCc2ccc(F)cc2)c2c[nH]cn2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(C(CCCc2ccc(F)cc2)c2c[nH]cn2)cc1
Yield: 85 %

Procedure:
4-[4-(4-fluorophenyl)-1-(4-tert-butylaminocarbonylphenyl)butyl]-1H-imidazole (7 g) is dissolved into dry acetonitrile (200 ml). 3,6 g of phosphorus pentachloride is added and the mixture is poured into water and acetonitrile is evaporated. The water solution is rendered alkaline and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried and evaporated to dryness. Yield 85%.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)[CH2:6][CH2:7]Cl.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])O.[Na+]>C(O)C>[CH:24]1([N:30]2[CH2:7][CH2:6][N:5]([CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[CH2:4][CH2:3]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCCCC1
Reactant: Oc1cccc(CC(c2ccccc2)N(CCCl)CCCl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Oc1cccc(CC(c2ccccc2)N2CCN(C3CCCCC3)CC2)c1
Reaction time: 24 h

Procedure:
In ethanol (60 ml) are dissolved dl-N,N-bis(2-chloroethyl)-1-phenyl-2-(3-hydroxyphenyl)ethylamine hydrochloride (3.7 g) and cyclohexylamine (1.4 g) and thereto is added sodium hydrogen carbonate (3.0 g). The mixture is refluxed with stirring for 24 hours. After the reaction, the solvent is distilled off. The the residue is added a diluted sodium carbonate aqueous solution and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue (crude free base) is dissolved in a small amount of methanol and the mixture is made acidic with a 25% hydrobromic acid-acetic acid solution and allowed to cool. The precipitated crystals are washed with a mixture of acetone and ether and recrystallized from methanol to give the desired compound as dihydrobromide (2.9 g), melting point: 268°-270° C.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([NH:8][C:9](=[O:12])[CH2:10][CH3:11])[CH2:4][C@H:3]1[N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][C:16]([N:37]1[CH:41]=[C:40]([C:42]([OH:44])=O)[CH:39]=[N:38]1)=[N:17][C:18]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[NH2:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[CH2:46][NH:45][C:42]([C:40]1[CH:39]=[N:38][N:37]([C:16]2[N:15]=[C:14]3[C:19]([N:20]=[CH:21][N:13]3[C@@H:3]3[CH2:4][C@H:5]([NH:8][C:9](=[O:12])[CH2:10][CH3:11])[C@@H:6]([OH:7])[C@H:2]3[OH:1])=[C:18]([NH:22][CH2:23][CH:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:17]=2)[CH:41]=1)=[O:44]
Reactant: NCc1ccccn1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(C(=O)O)cn4)nc32)[C@H](O)[C@@H]1O
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(C(=O)NCc5ccccn5)cn4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture comprising 1-[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid (0.06 g, 0.01 mmol) in dry DCM (10 ml) is treated with 2-aminomethylpyridine (0.021 g, 0.2 mmol) followed by HOBt (0.027 g, 0.2 mmol), 1-[Bis(dimethylamino)methylene]-1H-benzotriazoliumhexafluorophosphate-3-oxide HBTU (0.076 g, 0.2 mmol), N-methyl morpholine (0.02 g, 0.2 mmol) and DMAP (1 ml). The resulting mixture is stirred at room temperature for 24 h and then concentrated in vacuo. The resulting residue purified by preparative TLC eluting with 10% MeOH in chloroform to afford the title compound. (MH+ 687.1)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=O.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][C:11]=1[CH3:19].[OH-].[Na+].Cl>CCO>[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])/[CH:17]=[CH:7]/[C:6]2[S:5][CH:4]=[N:3][C:2]=2[CH3:1])=[CH:12][C:11]=1[CH3:19]
Reactant: Cc1ncsc1C=O
Reactant: CC(=O)c1ccc(O)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=O)/C=C/c2scnc2C)ccc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Commerically available 4-methylthiazole-5-carbaldehyde (0.59 g, 4.6 mmol) and 4′-hydroxy-3′-methylacetophenone (0.7 g, 4.6 mmol) were dissolved in 10 mL of absolute EtOH. The solution was cooled with an ice-water bath, and NaOH (0.36 g, 9.0 mmol) was added. The reaction mixture was stirred for 18 h at room temperature. Upon completion, the reaction mixture was acidified to pH=4-5 with 1 M HCl. The resulting orange precipitate was filtered out, washed with an additional 5 mL of water, and dried under air. The resulting ((E)-1-(4-hydroxy-3-methylphenyl)-3-(4-methylthiazol-5-yl)prop-2-en-1-one (1.03 g, 87%) was submitted to the next step without further purification. MS (EI) for C14H13NO2S: 260 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH2:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]1([N:21]2[C:30]3[N:29]=[C:28]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([C:41](O)=[O:42])=[C:36]5[C:40]=4[O:39][CH2:38][CH2:37]5)[N:27]=[CH:26][C:25]=3[N:24]([CH3:44])[C:23](=[O:45])[C@H:22]2[CH2:46][CH3:47])[CH2:20][CH2:19][CH2:18][CH2:17]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:41]([C:35]2[CH:34]=[CH:33][C:32]([NH:31][C:28]3[N:27]=[CH:26][C:25]4[N:24]([CH3:44])[C:23](=[O:45])[C@@H:22]([CH2:46][CH3:47])[N:21]([CH:16]5[CH2:17][CH2:18][CH2:19][CH2:20]5)[C:30]=4[N:29]=3)=[C:40]3[O:39][CH2:38][CH2:37][C:36]=23)=[O:42])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1CN(Cc2ccccc2)CCO1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NCC4CN(Cc5ccccc5)CCO4)c4c3OCC4)nc2N1C1CCCC1
Reaction time: 12 h
Yield: 44 %

Procedure:
The crude compound (4-benzylmorpholin-2-yl)methanamine 2d (141 mg, 0.69 mmol), 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 1q (300 mg, 0.69 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (221 mg, 0.69 mmol) and diisopropylethylamine (260 mL, 1.52 mmol) were dissolved in 40 mL of dichloromethane, stirred for 12 hours. The resulting mixture was added with 50 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound N-[(4-benzylmorpholin-2-yl)methyl]-7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxamide 2e (190 mg, yield: 44.0%) as a white solid.
Reaction SMILES: [NH:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.S(Cl)(Cl)=O.[NH2:30][C:31]1[NH:32][C:33]([Cl:36])=[CH:34][N:35]=1>O1CCCC1.O.C(N(CC)CC)C>[NH:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:30][C:31]2[NH:32][C:33]([Cl:36])=[CH:34][N:35]=2)=[O:11])=[CH:12][CH:13]=1)[C:2]([NH2:4])=[NH:3]
Reactant: Nc1ncc(Cl)[nH]1
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: N=C(N)Nc1ccc(C(=O)Nc2ncc(Cl)[nH]2)cc1
Reaction time: 16 h

Procedure:
A mixture of 970 mg. (4.48 m. mol) of 4-guanidinobenzoic acid and 910 mg. (4.48 m. mol) of bis-trimethylsilylacetamide in dry tetrahydrofuran was heated to reflux for five minutes. After cooling the resulting solution of thionylchloride, 1.07 g. (8.95 m. mol) was added, followed after 20 minutes by the addition of 1.5 g. (8.95 m. mol) of 2-amino-5-chloroimidazole and 1.81 g. (17.9 m. mol) of triethyl amine in 10 ml. of tetrahydrofuran. After 16 hours at room temperature 0.40 ml. of water was added and the solids filtered, washed with chloroform and recrystallized from methanol-chloroform-diethyl ether, 435 mg., m.p. 263°-265° C.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH3:13])[CH:7]=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2].Cl[CH2:16][CH:17]1[O:19][CH2:18]1.[OH-].[Na+]>>[N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH3:13])[CH:7]=[CH:6][C:5]=1[O:14][CH2:16][CH:17]1[O:19][CH2:18]1)([O-:3])=[O:2]
Reactant: Cc1ccc(O)c([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(OCC2CO2)c([N+](=O)[O-])c1[N+](=O)[O-]
Yield: 78 %

Procedure:
2,3-Dinitro-4-methylphenol (see H. E. Dadswell and J. Kenner, J. Chem. Soc., 1927, 583) is reacted with 3-chloro-1,2-epoxypropane and 25% aqueous sodium hydroxide solution to give, in a yield of 78% of theory, 2,3-dinitro-1-(2,3-epoxypropoxy)-4-methylbenzene (m.p. 121°-123° C.). This compound is reacted in boiling ethanol with tert.-butylamine to give 2,3-dinitro-1-(2-hydroxy-3-tert.-butylaminopropoxy, 4-methylbenzene (m.p. 104°-106° C.), catalytic hydrogenation of which, in the presence of platinum dioxide, gives amorphous 2,3-diamino-1-(2-hydroxy-3-tert.-butylaminopropoxy)-4-methylbenzene trihydrochloride.
Reaction SMILES: [CH:1]([C:4]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:5]=1[O:6][CH:7]([CH3:26])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([O:24][CH3:25])[CH2:18][C:19]([O:21]CC)=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:3])[CH3:2].O.Cl>[OH-].[Na+].C1COCC1.[OH-].[Na+]>[CH:1]([C:4]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:5]=1[O:6][CH:7]([CH3:26])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([O:24][CH3:25])[CH2:18][C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(OC)c1ccc(NC(=O)C(C)Oc2cc(C)ccc2C(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(CC(=O)O)c1ccc(NC(=O)C(C)Oc2cc(C)ccc2C(C)C)cc1
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A solution of 287 mg (0.67 mmol) of ethyl 3-{4-[2-(2-isopropyl-5-methylphenoxy)-propionylamino]phenyl}-3-methoxypropionate in 10 ml of 2N NaOH/THF/NaOH in a ratio of 1:1:1 was left to stand at RT for 30 minutes. The reaction mixture was admixed with water and adjusted to pH=6-7 with 1 N HCl (aq) and then extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under high vacuum. The crude mixture was purified by means of preparative HPLC (Merck Hibar Purospher Star RP-18e 10 μm 25×250 mm; A: H2O+0.05% TFA; B: ACN+0.05% TFA; flow rate: 50 ml/min; in 10 minutes 10% B→80% B; in 10 minutes 80% B→90% B). This gave 138 mg of 3-{4-[2-(2-isopropyl-5-methylphenoxy)propionylamino]phenyl}-3-methoxypropionic acid in 51% yield over the two stages.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH:9]1[C:14](/[CH:15]=[N:16]/[OH:17])=[CH:13][CH:12]=[C:11]([F:18])[CH:10]=1.[C:19]([O:22][CH2:23][C:24]#[CH:25])(=[O:21])[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[C:19]([O:22][CH2:23][C:24]1[O:17][N:16]=[C:15]([C:14]2[CH:13]=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)[CH:25]=1)(=[O:21])[CH3:20]
Reactant: C#CCOC(C)=O
Reactant: O/N=C/c1ccc(F)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1cc(-c2ccc(F)cc2)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-chlorosuccinimide (0.53 g, 4.00 mmol) in methylene chloride (20 mL) was added syn-4-fluorobenzaldoxime (0.56 g, 4.00 mmol) in one portion. The resulting mixture was stirred at room temperature for 3 hours. Propargyl acetate (0.10 g, 1.00 mmol) was then added in one portion, followed by triethylamine (0.28 mL, 2.00 mmol) in methylene chloride (5 mL) over a period of 20 min. The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was purified by prep-TLC (ethyl acetate:hexanes=1:4) to give [3-(4-fluorophenyl)isoxazol-5-yl]methyl acetate.