Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9](=O)[CH3:10])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:19][OH:20].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1.O>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9](=[N:19][OH:20])[CH3:10])=[CH:3][CH:2]=1
Reactant: NO
Reactant: CC(=O)CCc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(CCc1ccncc1)=NO
Temperature: 25 °C
Yield: 89.8 %

Procedure:
Next, water (12 ml) and tetrahydrofuran (1.2 ml) were added to 4-(4-pyridyl)-2-butanone (736 mg, 3.96 mmol), and the mixture was stirred at room temperature. Sodium carbonate (483 mg, 4.56 mmol) and hydroxylamine hydrochloride (358 mg, 5.15 mmol) were added to the mixture, and the whole was stirred for 1.5 hours and then diluted with ethyl acetate (50 ml). Sodium hydrogencarbonate was added thereto, layers were separated, and the organic layer was washed with saturated brine (10 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Cyclohexane was added to the resulting crystals, and the crystals were filtered off to give 584 mg (90%) of 4-(4-pyridyl)-2-butanoneoxime as pale yellow crystals.
Reaction SMILES: N[C@H](C(O)=O)CS.OS(O)(=O)=O.N[C@H](C(O)=O)CS.OS(O)(=O)=O.[O:25]=[CH:26][C@@H:27]([C@H:29]([C@@H:31]([C@@H:33]([CH2:35][OH:36])[OH:34])[OH:32])[OH:30])[OH:28]>>[OH:25][CH2:26][C:27]([C@H:29]([C@@H:31]([C@@H:33]([CH2:35][OH:36])[OH:34])[OH:32])[OH:30])=[O:28]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: N[C@@H](CS)C(=O)O
Agent: O=S(=O)(O)O
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The glucose isomerase activity in the particles was determined by placing a 0.1 gram of the enzyme in a 250 ml erlenmeyer flask and adding 50 ml of substrate [2M glucose, 20 mM MgSO4.7H2O, 0.5 mM CoCl2.6H2O and 20 mM HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanosulfonic acid) buffer adjusted to pH 8.0]. The dried particles were allowed to hydrate for about one hour at room temperature. At zero time, the flask was placed in a 60° C. water bath. The flask was agitated by a shaker water bath at a rate that provided particle movement. At 10 minutes and at 70 minutes, a 0.1 ml sample was removed from the assay mixture and added to 4.0 ml of 0.1M HClO4. The amount of fructose formed was determined by the cysteine-H2SO4 method (Dische, Z. J. Biological Chemistry, Vol. 181, p. 379, 1949) by incubating 0.05 ml of sample with 0.5 ml of 5% cysteine and 4.5 ml of 75% H2SO4 at 37° C. for 30 minutes and reading the absorbance at 412 nm. A unit of immobilized glucose isomerase activity (IGIU) is that amount of enzyme that produces one micromole of fructose per minute.
Reaction SMILES: CO[C:3](=[O:11])[CH2:4][C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=1[NH2:16].CO>C1(C)C=CC=CC=1>[CH3:9][C:6]([CH3:7])([CH3:8])[C:5](=[O:10])[CH2:4][C:3]([NH:16][C:15]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:14]=1[O:13][CH3:12])=[O:11]
Reactant: COc1ccc([N+](=O)[O-])cc1N
Reactant: COC(=O)CC(=O)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)CC(=O)C(C)(C)C
Reaction time: 4 h

Procedure:
Methyl-4,4-dimethyl-3-oxovalerate (15.8 g, 0.1 mol) and 2-methoxy-5-nitroaniline (16.8 g, 0.01 mol) were taken up in toluene (150 mL) in a round bottomed flask fitted with a Dean-Stark trap. The mixture was heated to a vigorous reflux while the MeOH side-product was distilled off and removed. After 4 hours, the mixture was cooled and the toluene removed in vacuo. The residue was recrystallized from acetonitrile to yield 27 g of the desired condensation product.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([O:13][CH3:14])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH:15]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:16][C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:35](O)=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18].[OH-].[Na+]>C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CN(C=O)C.O>[NH:15]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:16][C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:35]([NH:2][C@H:3]([C:11]([O:13][CH3:14])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:36])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:25])[CH:21]([CH3:22])[CH3:23])=[O:18]
Reactant: CC(C)[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)CNC(=O)OC(C)(C)C)C(C)C
Yield: 71.2 %

Procedure:
A solution of 0.216 g (10 mmol) of HCl.H-Phe-OCH3 (MW 215.5) in 40 ml of citric acid buffer solution (pH = 4.0) was added to a solution of 0.421 g of BOC-Gly-Val-Phe-OH (MW 421) in 10 ml of 1N-NaOH and 30 ml of water was further added with stirring. Then, 0.1 g of pepsin (1:10000) was added to the mixture with stirring in an incubator at 40°C for 24 hours to react them. 0.414 g of BOC-Gly-Val-Phe-Phe-OCH3 having a melting point of 193° - 196°C and [α]D30 = -14.8 (c = 1, DMF) was obtained. The yield was 71.2%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(OC)=[O:2].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>C1(C)C=CC=CC=1>[OH:2][C:1]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:11][C:12]=1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: COC(=O)c1ccccc1SCC(=O)OCc1ccccc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)c1sc2ccccc2c1O

Procedure:
5 g (I5.8 mmol) of benzyl S-(2-carbomethoxyphenyl)-thioglycolate and 3 g (19.7 mmol) of diazabicycloundecene are heated under reflux in 100 ml of toluene. At the same time, about 50 ml of toluene are removed by distillation in the course of one hour. After cooling, the mixture is poured into 2 N HCl and extracted with CH2Cl2. The residue is purified by filtration through silica gel using toluene as the eluent.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH:25]([C:28]1[CH:29]=[CH:30][C:31]([O:46][CH3:47])=[C:32]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=2CO)[CH:33]=1)([CH3:27])[CH3:26]>C(Cl)Cl>[Br:5][CH2:1][C:35]1[CH:36]=[C:37]([C:40]([F:41])([F:42])[F:43])[CH:38]=[CH:39][C:34]=1[C:32]1[CH:33]=[C:28]([CH:25]([CH3:27])[CH3:26])[CH:29]=[CH:30][C:31]=1[O:46][CH3:47]
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
CBr4 (112 mg, 0.211 mmol) and Ph3P (55 mg, 0.211 mmol) were added successively to a stirred solution of [5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol (57.1 mg, 0.176 mmol) in dry CH2Cl2 (1 mL) at 0° C. under N2. The solution was stirred at room temperature for 1 h and the reaction mixture was concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-20% EtOAc in hexanes gradient) to give 2-(bromomethyl)-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl as a colorless oil. Rf=0.95 (20% EtOAc/hexanes). LCMS calc.=387.05; found=387.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.83 (br s, 1H), 7.60 (dd, J=8.0, 1.3 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.29 (dd, J=8.5, 2.3 Hz, 1H), 7.14 (d, J=2.3 Hz, 1H), 6.95 (d, J=8.5, 1H), 4.45 (d, J=10.6 Hz, 1H), 4.33 (d, J=10.6 Hz, 1H), 3.76 (s, 3H), 2.94 (septet, J=6.9 Hz, 1H), 1.29 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH2:1]([O:13][C:14]1[N:15]=[C:16]([Si](C(C)C)(C(C)C)C(C)C)[S:17][C:18]=1[C:19]1[S:23][C:22]([Si](C(C)C)(C(C)C)C(C)C)=[N:21][C:20]=1[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:13][C:14]1[N:15]=[CH:16][S:17][C:18]=1[C:19]1[S:23][CH:22]=[N:21][C:20]=1[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1nc([Si](C(C)C)(C(C)C)C(C)C)sc1-c1sc([Si](C(C)C)(C(C)C)C(C)C)nc1OCCCCCCCCCCCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1ncsc1-c1scnc1OCCCCCCCCCCCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
To a solution of 6.0 g (7.06 mmol) of compound 12 in 150 mL of THF at 0° C. was added a solution of 21.2 mL (21.2 mmol) of tetrabutylammonium fluoride (1.0 M in THF) dropwise over 5 minutes. The mixture was stirred for 30 minutes at 0° C. then the ice bath was removed and the mixture was stirred at ambient temperature for 90 minutes. The mixture was treated with 2 mL of water, concentrated in vacuo, and separated by flash chromatography (silica gel, 5.5×35 cm, 1:1 hexane:chloroform to methylene chloride). The resulting solid was recrystallized from hexanes to give 2.98 g (79% yield) of compound 13 as colorless needles. 1H NMR (500 MHz) δ 8.43 (s, 2H), 4.47 (t, 4H, J=6.5 Hz), 1.90-1.20 (m, 40H), 0.90 (t, 6H, J=7.0 Hz).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][NH:5][C:4](=[S:7])[CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH:13](O)(C)C>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH3:1][CH:2]1[CH2:6][NH:5][C:4](=[S:7])[CH:3]1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)O
Reactant: CCOC(=O)C1C(=S)NCC1C
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CC(C)OC(=O)C1C(=S)NCC1C

Procedure:
To 5.0 g of ethyl 4-methyl-2-thioxopyrrolidine-3-carboxylate were added 300 ml of isopropyl alcohol and 11.4 g of titanium tetraisopropoxide. The resulting mixture was heated under reflux for 24 hours. After distilling off the excessive isopropyl alcohol under reduced pressure, water and chloroform were added to the residue and insoluble matters were filtered off. The chloroform layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off the chloroform, 5.0 g of the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:29][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([S:19]([N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH2:27][OH:28])(=[O:21])=[O:20])=[CH:11][C:12]=3[C:13]3([O:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:5]2=[N:4][CH2:3]1.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.[Cl-].[Na+].O>[CH3:41][C:31]1[CH:36]=[CH:35][C:34]([S:37]([O:28][CH2:27][C@@H:23]2[CH2:24][CH2:25][CH2:26][N:22]2[S:19]([C:10]2[CH:9]=[CH:8][C:7]3[N:6]4[CH2:29][C:2]([CH3:30])([CH3:1])[CH2:3][N:4]=[C:5]4[C:13]4([O:18][CH2:17][CH2:16][CH2:15][O:14]4)[C:12]=3[CH:11]=2)(=[O:21])=[O:20])(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)CN=C2N(C1)c1ccc(S(=O)(=O)N3CCC[C@H]3CO)cc1C21OCCCO1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2S(=O)(=O)c2ccc3c(c2)C2(OCCCO2)C2=NCC(C)(C)CN23)cc1
Yield: 65.8 %

Procedure:
A solution of {(2S)-1-[(3′,3′-dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indol]-8′-yl)sulfonyl]pyrrolidin-2-yl}methanol (0.100 g, 2.300 mmol), p-toluenesulfonyl chloride (0.070 g, 0.340 mmol), N,N-diisopropylethylamine (0.100 ml, 0.580 mmol) and 4-(dimethylamino)pyridine (0.020 g, 0.070 mmol) in CH2Cl2 (5 mL) was stirred at rt for 2 days. The reaction was poured into brine and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give the title compound as a white foam (0.132 g, 97% ). Anal: Calc'd for C28H35N3O7S2: C, 57.03; H, 5.98; N, 7.13. Found: C, 56.38; H, 5.65; N, 6.81. NMR (400 Mz, DMSO-d6): consistent. MS: (ESI+) m/z 590.3 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:20]4[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=4)[CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1onc(-c2cccc(Br)c2)c1-c1c[nH]cn1
Product: Cc1onc(-c2cccc(Br)c2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Yield: 39 %

Procedure:
As described for Example 44, 3-(3-bromo-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (91 mg, 0.3 mmol) using 1-fluoro-4-nitrobenzene instead of 4-fluoroacetophenone was converted to the title compound (50 mg, 39%) which was obtained as a light yellow solid. MS: m/e=425.1/427.1 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([S:9][C:10]1[S:11][CH:12](O)[C:13](C)(O)[N:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:18]([OH:20])C>>[CH2:2]([S:9][C:10]1[S:11][C:12]([CH2:18][OH:20])=[CH:13][N:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC1(O)N=C(SCc2ccccc2)SC1O
Reactant: CCO
Agent: Cl
Product: OCc1cnc(SCc2ccccc2)s1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
0.2 ml of concentrated hydrochloric acid is added to 3.0 g of 2-benzylsulfanyl-5-hydroxy-methyl-4,5-dihydrothiazol-4-ol in 25 ml of ethanol. The mixture is stirred at 50° C. for 12 hours, the solvent is removed in vacuo, and the residue is chromatographed on silica gel (ethethexane; 1:1). The title compound is obtained in the form of a yellow oil (compound 3.1).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:28])=[C:5]([C@H:11]2[O:16][CH2:15][C@@H:14]3[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20][N:13]3[CH2:12]2)[CH:6]=[C:7]([CH3:10])[C:8]=1[F:9])#[N:2].FC1C(C#N)=C(C)C([C@@H]2OC[C@H]3CNCCN3C2)=CC=1>>[C:1]([C:3]1[C:4]([CH3:28])=[C:5]([C@@H:11]2[O:16][CH2:15][C@H:14]3[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20][N:13]3[CH2:12]2)[CH:6]=[C:7]([CH3:10])[C:8]=1[F:9])#[N:2]
Reactant: Cc1cc([C@@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)c(C)c(C#N)c1F
Agent: Cc1c([C@H]2CN3CCNC[C@@H]3CO2)ccc(F)c1C#N
Product: Cc1cc([C@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3CO2)c(C)c(C#N)c1F

Procedure:
The title compound was prepared in an analogous fashion to that described for the synthesis of (3R,9aS)-tert-butyl 3-(3-cyano-4-fluoro-2,5-dimethylphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate starting from 6-fluoro-2-methyl-3-((3S,9aR)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl)benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:21])=O>CN(C)C=O>[Cl:21][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:17]=1
Reactant: O=c1[nH]c(-c2cccc(Cl)c2)nc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1cccc(-c2nc(Cl)c3ccccc3n2)c1

Procedure:
A mixture of 5.5 g of 2-(3-chlorophenyl)quinazolin-4(3H)-one and 40 ml of thionyl chloride was treated as described in Example I with 1.57 g of dimethylformamide to give, after recrystallization from cyclohexane, 4.4 g of white 4-chloro-2-(3-chlorophenyl)quinazoline, m.p. 157°-158.5°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([CH2:9][C:10](OC)=[O:11])#[N:8]>CC(OC)(C)C>[N:1]1([C:10](=[O:11])[CH2:9][C:7]#[N:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)CC#N
Reactant: C1COCCN1
Solvent: COC(C)(C)C
Product: N#CCC(=O)N1CCOCC1
Temperature: 55 °C
Yield: 90.2 %

Procedure:
A nitrogen inerted reactor equipped with reflux condenser, nitrogen inlet and mechanical stirring is charged with morpholine (1.2 mol), methyl cyanoacetate (1.0 mol) and MtBE (52 mL). The homogeneous solution is heated to ca. 55° C. and stirred at that temperature for 12 to 18 hours. MtBE (33 mL) is added over ca. 15 minutes, and the solution is slowly cooled below 50° C. where nucleation becomes evident. Additional MTBE (66 μL) is added over a 1-hour period. During this time, the reaction is allowed to cool to near ambient temperature. After complete MtBE addition, the reaction is cooled with stirring to ca. 0° C. The resulting precipitate is collected via filtration and the cake is washed with additional MtBE (ca. 40 mL). The solid is dried under vacuum at ca. 45° C. to provide 3-morpholin-4-yl-3-oxo-propionitrile (139 g). This material is used in subsequent steps without further purification.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[NH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1)=[N:13][CH:14]=[N:15]2>>[OH:3][CH2:2][C:1]([NH:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1)=[N:13][CH:14]=[N:15]2)=[O:5]
Reactant: O=C(O)CO
Reactant: Cc1cc(Nc2ncnc3cccc(OCCN)c23)ccc1O
Product: Cc1cc(Nc2ncnc3cccc(OCCNC(=O)CO)c23)ccc1O
Yield: 58 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using glycolic acid and 4-{[5-(2-aminoethoxy)quinazolin-4-yl]amino}-2-methylphenol to give 2-hydroxy-N-[2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)ethyl]acetamide as a light brown solid in 58% yield; NMR spectrum (DMSO-d6) 2.16 (s, 3H), 3.69 (q, 2H), 3.76 (d, 2H), 4.43 (t, 2H), 6.82 (d, 1H), 7.30 (m, 4H), 7.90 (t, 1H), 8.20 (t, 1H), 8.66 (s, 1H), 9.42 (s, 1H), 10.55 (s, 1H); Mass spectrum MH+ 369.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:53])[C@@H:20]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][CH2:38][CH2:37][C@H:36]3[C:40](=[O:46])[NH:41][CH:42]3[CH2:45][CH2:44][CH2:43]3)=[O:34])[N:28]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[N:27]=2)=[O:25])[CH2:21][NH2:22])[CH2:15][CH2:14]1)=[O:12])[CH3:9].N1C=CC=CC=1.CC(OC(C)=O)=O>ClCCl.CN(C1C=CN=CC=1)C>[CH2:8]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:53])[C@@H:20]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][CH2:38][CH2:37][C@H:36]3[C:40](=[O:46])[NH:41][CH:42]3[CH2:45][CH2:44][CH2:43]3)=[O:34])[N:28]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[N:27]=2)=[O:25])[CH2:21][NH:22][C:3](=[O:4])[CH3:2])[CH2:15][CH2:14]1)=[O:12])[CH3:9]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CN)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CNC(C)=O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 1 h

Procedure:
To a solution of 100 mg 4-[(S)-3-amino-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester trifluoroacetate in 2 ml dichloromethane were added 32 μl pyridine, 1.6 mg DMAP and 16 μl Ac2O at 0° C. After 1 h stirring at this temperature the reaction mixture was diluted with dichloromethane and washed with 0.1 M HCl and half-saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). Yield: 35 mg MS (ES+): m/e=681.
Reaction SMILES: Cl[Sn]Cl.[F:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:9][N:8]=[C:7]2[NH:16][CH:17]=[C:18]([N+:19]([O-])=O)[C:6]=12.[OH-].[Na+]>Cl>[F:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:9][N:8]=[C:7]2[NH:16][CH:17]=[C:18]([NH2:19])[C:6]=12
Reactant: COCCOc1cnc2[nH]cc([N+](=O)[O-])c2c1F
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: COCCOc1cnc2[nH]cc(N)c2c1F
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
SnCl2 (1337 mg, 7.05 mmol) was added to 4-fluoro-5-(2-methoxyethoxy)-3-nitro-1H-pyrrolo[2,3-b]pyridine (360 mg, 1.41 mmol) in 6N HCl (10 mL) at 0-5° C., and the reaction was stirred at 0-5° C. for 1 hour. The solution was neutralized by addition of 6N NaOH and then extracted with CHCl3/IPA 3/1. The combined organic phases were dried over MgSO4 and concentrated to leave 4-fluoro-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-b]pyridin-3-amine (300 mg, 95% yield) as an oil.
Reaction SMILES: [N:1]([CH2:4][CH:5]([OH:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+]=[N-].[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][CH:5]([OH:13])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [N-]=[N+]=NCC(O)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NCC(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 1-azido-3-phenyl-propan-2-ol (590 mg, 3.4 mmol) in 20 mL methanol under a nitrogen atmosphere was added 10 mg of Pd(OH)2/C (10%). Hydrogen gas was delivered via balloon. The solution was stirred overnight at room temperature. The catalyst was removed by filtering the solution through a bed of celite, and the filtrate was concentrated to give a clear oil under reduced pressure. M+1=152.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[S:51][C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=1.N1C=CC=CC=1>C(Cl)Cl.O>[S:51]1[C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=[C:50]1[NH:49][C:40](=[O:42])[C@@H:39]([C:31]1[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=1)[CH2:43][CH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: Nc1nc2ccccc2s1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2nc3ccccc3s2)cc1Cl
Temperature: 0 °C
Yield: 72.6 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it became homogeneous. The resulting light purple reaction mixture was then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.61 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminobenzothiazole (136 mg, 0.91 mmol) and pyridine (0.15 mL, 1.81 mmol), and the reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate) afforded N-benzothiazol-2-yl-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (205 mg, 73%) as a white foam: [α]23589=−38.6° (c=0.044, chloroform); EI-HRMS m/e calcd for C22H23ClN2O3S2 (M+) 462.0839, found 462.0839.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:26])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:17])=[C:11]([F:27])[CH:10]=1)C1C=CC=CC=1>CO.[C].[Pd]>[F:27][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[N:15]([CH3:26])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:17]
Reactant: CN(C(=O)Nc1ccc(F)cc1)c1ccc(OCc2ccccc2)cc1F
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)Nc1ccc(F)cc1)c1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71.1 %

Procedure:
After dissolving N-(4-benzyloxy-2-fluorophenyl)-N′-(4-fluorophenyl)-N-methylurea (105 mg, 0.2881 mmol) in methanol (10 ml), 10% palladium carbon (20 mg) was added and the mixture was stirred for 45 minutes at room temperature under a hydrogen atmosphere. The catalyst was filtered off, the filtrate was washed with ethanol, and the solvent of the filtrate was distilled off under reduced pressure. The precipitated crystals were suspended in diethyl ether, and then filtered out, washed with diethyl ether and dried by aspiration to obtain the title compound (57 mg, 0.2048 mmol, 71.10%) as colorless crystals.