Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[C:6]([N:11]=[C:12]=[O:13])(=[O:10])[C:7]([CH3:9])=[CH2:8]>C(Cl)(Cl)Cl.ClCCCl>[C:6]([NH:11][C:12](=[O:13])[O:5][CH2:4][CH:2]1[O:3][CH2:1]1)(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: C=C(C)C(=O)N=C=O
Reactant: OCC1CO1
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)OCC1CO1
Yield: 99.9 %

Procedure:
Glycidol (2.13 g; 28.8 mmol) was dissolved in dry chloroform (20 ml) under ice-cooling, and a solution of methacryloyl isocyanate (3.2 g; 28.8 mmol) in 1,2-dichloroethane (20 ml) was dropwise added thereto under nitrogen stream. After completion of the addition, chloroform and 1,2-dichloroethane were evaporated under reduced pressure to give glycidyl N-methacryloylcarbamate (5.33 g) as a viscous, colorless oil. Viscosity, 3260 cp.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[CH:13]([NH:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)([CH3:15])[CH3:14].C(N(CC)CC)C>S(Cl)(Cl)=O.C1COCC1>[CH:13]([N:16]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([O:11][CH3:12])[CH:4]=1)([CH3:15])[CH3:14]
Reactant: CC(C)NC1CCCCC1
Reactant: COc1cc(C(=O)O)ccc1Br
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-bromo-3-methoxybenzoic acid (2.80 g, 12.1 mmol) in thionyl chloride (30 mL) was refluxed for 3 hr. The reaction was concentrated in vacuo and the residue azeotroped three times with toluene. A solution of the resulting crude solid (3.11 g, 8.75 mmol) in THF (10 mL) was added to a stirred, cold (0° C.) solution of N-isopropylcyclohexyl amine (1.7 g, 11.7 mmol) and triethylamine (1.20 g, 11.7 mmol) in THF (10 mL). The reaction was stirred at room temperature overnight. The reaction was filtered and the filtrate diluted with ethyl acetate and washed three times with 1N HCl, three times with saturated NaHCO3, three times with saturated NaCl solution and dried (Na2SO4). The drying agent was filtered and the filtrate concentrated in vacuo to give a dark brown oil. The oil was purified by chromatography on silica gel using mixtures of ethyl acetate and hexane as eluents. This yielded crystalline amide, m. p. 104-107° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][O:9][C:10](=[O:27])[C@H:11]1[CH2:15][C@@H:14](O)[CH2:13][N:12]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].COC(=O)[C@H]1C[C@H](OC2C=CC3C(=CC=CC=3)C=2)CN1C(OCC1C=CC=CC=1)=O>>[CH3:8][O:9][C:10](=[O:27])[C@H:11]1[CH2:15][C@H:14]([O:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][N:12]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: Oc1cccnc1
Agent: COC(=O)[C@H]1C[C@H](Oc2ccc3ccccc3c2)CN1C(=O)OCc1ccccc1
Product: COC(=O)[C@H]1C[C@H](Oc2cccnc2)CN1C(=O)OCc1ccccc1

Procedure:
The title compound was prepared from 3-hydroxy pyridine and N-Cbz-cis-4-hydroxy-D-proline methyl ester by substantially following the procedure used in the preparation of N-Cbz-trans-4-(2-naphthyloxy)-D-proline methyl ester, Example 6, Steps A and B.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17](O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)CCN.C1(=O)CCCCC1.C([O:44][C:45](=[O:48])CC)C>>[CH:1]1([N:7]([CH2:21][CH2:22][CH:23]([CH3:24])[CH3:28])[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][CH2:17][C:45]([OH:48])=[O:44])=[CH:13][N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CC
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: CC(C)CCN
Solvent: O=C1CCCCC1
Product: CC(C)CCN(C(=O)Nc1ncc(SCCC(=O)O)s1)C1CCCCC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from 3-methylbutylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH:14]2[CH2:18][O:17][C:16]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[S:15]2)=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)Cl>[C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH2:13][CH:14]2[CH2:18][O:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[S:15]2)=[O:43])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1c(OCCCSCC2COC(CCC(=O)O)(CCC(=O)O)S2)ccc(C(C)=O)c1O
Solvent: ClCCl
Product: CCCc1c(OCCCS(=O)CC2COC(CCC(=O)O)(CCC(=O)O)S2)ccc(C(C)=O)c1O
Yield: 44 %

Procedure:
The title compound was prepared according to the procedure of Example 46 using the sulfide obtained in Example 3 (0.15 g, 0.0003 mol) and m-chloroperbenzoic acid (0.062 g, 0.0003 mol) in methylene chloride (3 ml). The crude product was chromatographed on silica gel using ethyl acetate containing 0.5% acetic acid to give 0.070 g (45%) of the desired product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[H-].[Na+].N1(P(Cl)(N2CCOCC2)=O)CCOCC1.[C:37]([NH:40][NH2:41])(=O)[CH3:38]>O1CCCC1.C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:37]([CH3:38])=[N:40][N:41]=[C:10]3[CH2:9][CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: CC(=O)NN
Reactant: O=C1CC=C(c2ccccc2)c2cc(Cl)ccc2N1
Agent: O=P(Cl)(N1CCOCC1)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.075 g of 7-chloro-5-phenyl-1,3-dihydro-2H-1-benzazepin-2-one in 20 ml of dry tetrahydrofuran is treated with 0.23 g of sodium hydride (50% dispersion in mineral oil) and stirred at 60° for 1 hour. The mixture is then cooled to room temperature, treated with 1.53 g of bis-(4-morpholinyl)phosphinic acid chloride and stirred at this temperature for a further 2 hours. A solution of 0.593 g of acetic acid hydrazide in 50 ml of n-butanol is subsequently added thereto, the mixture is heated to boiling under reflux for 1 hour and then evaporated in vacuo. The residue is partitioned between water and methylene chloride. The methylene chloride solution is evaporated and the residue is chromatographed on 100 g of aluminium oxide (activity grade III). Various impurities and starting material are eluted successively with benzene and ethyl acetate/hexane (1:1). After elution with chloroform/ethanol (96:4) and recrystallization of the crude product from ethyl acetate/benzene/n-hexane, there is obtained 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1]benzazepine of melting point 235°.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[C@@H:3]([N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[N+:17]([O-:19])=[O:18])[C:8]1=[O:20])[C:4]([OH:6])=O.CN.O.O[N:26]1[C:30]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:21][CH:2]([CH3:1])[C@@H:3]([N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[N+:17]([O-:19])=[O:18])[C:8]1=[O:20])[C:4]([NH:26][CH3:30])=[O:6]
Reactant: CC(C)[C@H](C(=O)O)n1ccc2c([N+](=O)[O-])cccc2c1=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CNC(=O)[C@@H](C(C)C)n1ccc2c([N+](=O)[O-])cccc2c1=O

Procedure:
(R)-3-Methyl-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)butanoic acid (2 g, 0.007 mol), methylamine (7 mL, 0.01 mol), 1-hydroxybenzotriazole hydrate (2 g, 0.01 mol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3 g, 0.01 mol), N,N-diisopropylethylamine (4 g, 0.03 mol) were stirred in methylene chloride (20 mL, 0.3 mol) at room temperature for 16 hours. The reaction mixture was diluted with CH2Cl2 (200 mL), washed with sat. NaHCO3, dried over MgSO4, filtered, purified via flash chromatoraphy (40 g of silica gel, 0-50% EtOAc/Hexane) to yield a yellow solid. m/z 304.2 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][N:4]=1.Cl.[OH-].[Na+]>>[C:9]([C:6]1[CH:7]=[CH:8][C:3](=[O:2])[NH:4][CH:5]=1)(=[O:11])[CH3:10]
Reactant: COc1ccc(C(C)=O)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1ccc(=O)[nH]c1

Procedure:
2-methoxy-5-acetyl pyridine (1.51 g, 10 mmol) was treated with 6N HCl at 100° C. for 5 hours. The reaction mixture was neutralized with sodium hydroxide to pH 7 and then extracted several times with DCM. Organic layer was dried over sodium sulfate, evaporated and the residue was crystallized from ethyl acetate to give 5-acetyl-2(1H)-pyridone as a white solid, 1.06 g (78%). This compound (685.7 mg, 5 mmol) was reacted with iodobenzene (0.84 ml, 7.5 mmol) in the presence of CuI (95 mg, 0.5 mmol) and K2CO3 (691 mg, 5 mmol) in DMF (5 ml) at 135° C. overnight. The reaction mixture was diluted with 10% ammonia (15 ml) and extracted with ethyl acetate. The organic extract was washed with saturated sodium chloride, dried over magnesium sulfate and evaporated. Column chromatography (10% ethyl acetate-DCM) afforded 407 mg (38%) of the target compound as a white solid. The 1H NMR spectra was consistent with the structure of Compound 16.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][C:10]1([CH3:19])[O:15][CH2:14][C:13]([CH3:18])([CH2:16]O)[CH2:12][O:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:9][C:10]1([CH3:19])[O:15][CH2:14][C:13]([CH3:18])([CH2:16][O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:12][O:11]1
Reactant: CC1(CO)COC(C)(C)OC1
Reactant: Oc1cccc(Br)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(COc2cccc(Br)c2)COC(C)(C)OC1
Temperature: -2 °C
Reaction time: 72 h
Yield: 85 %

Procedure:
To a mechanically stirred mixture of 3-bromophenol (26.14 g, 0.1511 mol), 2,2,5-trimethyl-5-hydroxymethyl-1,3-dioxane (31.98 g, 0.20 mol), triphenylphosphine (59.32 g, 0.226 mol), and THF (250 mL), cooled to −2° C., a solution of diisopropyl azodicarboxylate (DIAD), 4.6 mL, 0.2265 mol) in THF (50 mL) was added dropwise over 45 min, and the mixture was allowed to warm up to room temperature. After 3 days, THF was removed, and the residue was stirred in a mixture of toluene and heptane (1:1, 300 mL), and filtered. The solids were washed with the same mixture of solvents (200 mL), and the combined filtrates were washed with dilute sodium hydroxide solution, water, and saturated sodium chloride solution, dried, and concentrated. The residue was chromatographed over silica gel. Elution with toluene-heptane (1:1) removed some unreacted triphenylphosphine. The product came in toluene-heptane (3:1) eluates and, on standing with pentane, solidified, 40.69 g (85% yield), m.p. 67-70° C. Mass spec: m/z 314, 316 (M+). Anal Calcd for C14H19BrO3: C, 53.34; H, 6.08; Br, 25.35%. Found: C, 53.37; H, 5.97; Br, 25.35%.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][S:15][C:9]=3[NH:10][C:11](=O)[CH2:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>N1C=CC=CC=1>[C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][S:15][C:9]=3[NH:10][C:11](=[S:19])[CH2:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CN=C(c2ccccc2)c2ccsc2N1
Solvent: c1ccncc1
Product: S=C1CN=C(c2ccccc2)c2ccsc2N1

Procedure:
12.1 g (0.05 mol) of 1,3-dihydro-5-phenyl-2H-thieno[2,3-e]-1,4-diazepin-2-one are heated to reflux for 35 minutes with 12.2 g (0.055 mol) of phosphorus pentasulphide in 400 ml of absolute pyridine, dry nitrogen being conducted through the solution. The solution is concentrated to 200 ml and the mixture separated on a 70 cm long column (φ3.5 cm) filled with 250 g of Silica gel [0.05 to 0.2 mm (Merck)]. The solution is concentrated under a vacuum and yields 1,3-dihydro-5-phenyl-2H-thieno[2,3-e]-1,4-diazepine-2-thione in the form of yellow crystals, melting point 208°-210° C.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][CH2:25][C:26](O)=[O:27])[N:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:69]1[CH2:73][CH2:72][CH2:71][C@H:70]1[C:74]1[NH:78][N:77]=[N:76][N:75]=1>CN(C=O)C.ClCCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:35])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][CH2:25][C:26](=[O:27])[N:69]3[CH2:73][CH2:72][CH2:71][C@H:70]3[C:74]3[NH:78][N:77]=[N:76][N:75]=3)[N:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:20]=2)=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)O)n(-c3ccccc3)n2)CC1
Reactant: C1CN[C@H](c2nnn[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)N3CCC[C@H]3c3nnn[nH]3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 193 mg 4-{2-[(5-Carboxymethoxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester in 2 ml DMF were added 150 mg HATU and 69 μl DIPEA. After 10 minutes a solution of 54 mg (S)-5-Pyrrolidin-2-yl-1H-tetrazole in 1 ml DMF was added and after 36 h the reaction mixture was diluted with dichloromethane and extracted with aqueous LiCl (4%), 0.1 M HCl and brine. The crude product thus 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). The fractions containing the product were immediately lyophilized to yield the title compound
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[F:23][C:24]([F:47])([F:46])[C@H:25]([CH3:45])[O:26][C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:44])[CH3:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1.Br[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[C:56]([F:59])([F:58])[F:57]>>[F:57][C:56]([F:58])([F:59])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[CH2:49][N:34]1[N:33]=[C:31]2[N:32]=[C:27]([O:26][C@@H:25]([CH3:45])[C:24]([F:23])([F:46])[F:47])[N:28]=[C:29]([N:36]3[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:44])[CH3:43])[CH2:37]3)[C:30]2=[N:35]1
Reactant: CC(=O)N[C@H]1CCN(c2nc(O[C@@H](C)C(F)(F)F)nc3[nH]nnc23)C1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC(=O)N[C@H]1CCN(c2nc(O[C@@H](C)C(F)(F)F)nc3nn(Cc4ccccc4C(F)(F)F)nc23)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from N—{(S)-1-[5-((S)-2,2,2-Trifluoro-1-methyl-ethoxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-yl}-acetamide and 1-(bromomethyl)-2-(trifluoromethyl)benzene. MS (m/e): 518.5 (MH+).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30]([OH:32])=O)=[CH:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[OH:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[OH:36][CH:37]1[CH2:42][CH2:41][N:40]([C:30](=[O:32])[CH:29]([C:26]2[CH:25]=[CH:24][C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:35])([F:1])[F:34])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)=[CH:28][CH:27]=2)[CH3:33])[CH2:39][CH2:38]1
Reactant: OC1CCNCC1
Reactant: CC(C(=O)O)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1
Product: CC(C(=O)N1CCC(O)CC1)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 98, Step 9 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanoic acid and 4-hydroxypiperidine. LCMS (M+H)+: m/z=567.3
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:23]([Si:27](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[CH2:10][O:11][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CON(C)C(=O)[C@@H](CO)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 17 h
Yield: 93.8 %

Procedure:
A solution of N2-(tert-butoxycarbonyl)-N-methoxy-N-methyl-D-serinamide (1, 1.93 g, 7.78 mmol) and imidazole (1.21 g, 17.81 mmol) in DMF (9 ml) stirred under N2 at room temperature, was treated with neat tert-butyl(chloro)diphenylsilane (2.2 ml, 8.56 mmol) and further stirred for 17 h. Diluted with EtOAc, washed with 5% KHSO4 in water, then sat NaHCO3, dried over Na2SO4, filtered and concentrated. Purified through a chromatographic cartridge of silicagel (50 g) eluted with 10% to 60% EtOAc in hexane to give 3.55 g (94% yield) of title compound as colorless oil. MS: m/z=509.2 (MNa+).
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[OH:5][C@@H:6]([CH3:17])[CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1.CCOC(C)=O>C(#N)C.CN(C)C1C=CN=CC=1>[CH3:17][C@@H:6]1[O:5][S:1](=[O:2])[N:9]([C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH2:8][CH2:7]1
Reactant: C[C@H](O)CCNC(=O)OC(C)(C)C
Reactant: O=S(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@H]1CCN(C(=O)OC(C)(C)C)S(=O)O1
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
To a solution of thionyl chloride (192 mL, 2.6 mol) in acetonitrile (1.0 L) at −40° C. is added dropwise a solution of tert-butyl [(3S)-3-hydroxybutyl]carbamate (200 g, 1.1 mol) in acetonitrile (2.5 L). The mixture is stirred for 10 min and 4-dimethylaminopyridine (12.9 g, 105.66 mmol) is added. After stirring for another 10 min, pyridine (427 mL, 5.3 mol) is added over 90 min, keeping the temperature below −40° C. EtOAc is added at −40° C. and the suspension is filtered to remove the solid. To the filtrate is added saturated Na2HPO4 solution and the mixture is stirred vigorously for 30 minutes at room temperature. The organic layer is separated, washed with 1M NaHSO4 solution, dried (Na2SO4) and concentrated to afford the title crude compound (250 g) as an oil which is used in the next step without purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:17]([O:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])=[N:16][C:15](F)=[N:14][C:13]=2[CH:12]=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[N:31]1[C:35](=O)[CH2:34][CH2:33][CH2:32]1>O>[CH2:3]([N:10]1[C:18]2[C:17]([O:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])=[N:16][C:15]([NH:10][C:3]3[CH:32]=[CH:33][C:34]([C:35]#[N:31])=[CH:5][CH:4]=3)=[N:14][C:13]=2[CH:12]=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(C)c(Oc2nc(F)nc3ccn(Cc4ccccc4)c23)c(C)c1
Reactant: CN1CCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3ccn(Cc4ccccc4)c23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A stirred suspension of NaH (63.8 mg, 2.66 mmol) in dry NMP (1.5 mL) was added 4-aminobenzylnitrile (188 mg, 2.66 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-2-fluoro-4-(mesityloxy)-5H-pyrrolo[3,2-d]pyrimidine (115 mg, 0.32 mmol) in dry NMP (1.7 mL) and stirred at room temperature for 2 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc 3 times. The combined organic layers were washed with water, NH4Cl, water×2, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with 1% MeOH:CH2Cl2, which afforded the product as a tan solid (120 mg, 80%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH:13]([OH:18])[CH2:14][C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.C([O-])(O)=O.[Na+]>[CH2:19]([O:16][C:15](=[O:17])[CH2:14][CH:13]([OH:18])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CC(O)CNC(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Product: O=C(CC(O)CNC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 5.0 g (19.7 mmol) 4-benzyloxycarbonylamino-3-hydroxy-butyric acid and 6.36 g (1 equiv.) tetra-n-butyl ammonium bromide in 70 ml dichloromethane and 50 ml of an aqueous saturated NaHCO3-solution were added 2.35 ml (1 equiv.) benzyl bromide. The resulting mixture was stirred vigorously for 72 h at room temperature. The organic layer was separated, washed three times with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: heptane/ethyl acetate) gave pure 4-benzyloxycarbonylamino-3-hydroxy-butyric acid benzyl ester as colorless oil.
Reaction SMILES: C(=O)([O-])[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=3)[NH:15][C:14](=[O:23])[C@@H:13]2[CH2:24][CH3:25])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:29][CH2:30][CH2:31][CH3:32].C([C@@H]1N(S(C2C=CC(O)=CC=2)(=O)=O)C2C(=CC=C(F)C=2)N(CCC)C1=O)C>>[CH2:29]([N:15]1[C:16]2[C:21](=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)(=[O:10])=[O:11])[C@@H:13]([CH2:24][CH3:25])[C:14]1=[O:23])[CH2:30][CH2:31][CH3:32]
Reactant: CC[C@H]1C(=O)Nc2ccc(F)cc2N1S(=O)(=O)c1ccc(OC(=O)[O-])cc1
Reactant: CCCCBr
Agent: CCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21
Product: CCCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21

Procedure:
4-{[(2S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydroquinoxalin-1 (2H)-yl]sulfonyl}phenyl carbonate (see Example 20) was treated with 1-bromobutane according to the procedure for the preparation of (3S)-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-propyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 20) to yield (3S)-1-Butyl-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-3,4-dihydroquinoxalin-2(1H)-one. [α]D25=−4° (c=0.0058 G/ML, DMSO); MS (ESI) m/z 407 ([M+H]+); MS (ESI) m/z 405 ([M−H]−);
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH:6]1[C:13](=[O:14])[CH2:12][C:10](=O)[NH:9][C:7]1=[O:8]>O>[Cl:3][N:6]1[C:13](=[O:14])[CH:12]=[CH:10][NH:9][C:7]1=[O:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: O
Product: O=c1cc[nH]c(=O)n1Cl

Procedure:
Phosphoryl chloride (55 ml) is carefully added to barbituric acid (10 g, 78.1 mmol) at 0° C. Water (1.7 ml) is then added dropwise such that the temperature does not exceed 5° C. The mixture is boiled under reflux for 5 h and, after it has cooled down, poured onto ice. The product is extracted with ethyl acetate (3×100 ml) and dried (Na2 SO4). The mixture is filtered and the solvent is distilled off in vacuo.
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].CO[C:7](OC)([N:9]([CH3:11])[CH3:10])[CH3:8]>>[CH3:10][N:9]([CH3:11])/[C:7](=[N:4]\[C:1](=[O:3])[CH3:2])/[CH3:8]
Reactant: CC(N)=O
Reactant: COC(C)(OC)N(C)C
Product: CC(=O)/N=C(/C)N(C)C

Procedure:
A slurry of acetamide (500 mg, 8.46 mmol, 1 eq.) was heated neat in 1,1-dimethoxy-N,N-dimethylethanamine (5 mL) for 16 hours. The 1,1-dimethoxy-N,N-dimethylethanamine was removed by roto-evaporation to afford (Z)-N-(1-(dimethylamino)ethylidene)acetamide (2-1) as a dark yellow oil.