Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:22]=[C:21]2[C:17]([C:18](=[N:24][NH2:25])[C:19](=[O:23])[NH:20]2)=[C:16]([Br:26])[CH:15]=1)=[O:13].[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][C:37](O)=[O:38])=[CH:35][C:30]=2[CH2:29][CH2:28]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:22]=[C:21]2[C:17]([C:18](=[N:24][NH:25][C:37](=[O:38])[CH2:36][C:34]3[CH:33]=[CH:32][C:31]4[O:27][CH2:28][CH2:29][C:30]=4[CH:35]=3)[C:19](=[O:23])[NH:20]2)=[C:16]([Br:26])[CH:15]=1)=[O:13]
Reactant: O=C(O)Cc1ccc2c(c1)CCO2
Reactant: NN=C1C(=O)Nc2cc(C(=O)NCCCN3CCC[C@H]3CO)cc(Br)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1ccc2c(c1)CCO2)NN=C1C(=O)Nc2cc(C(=O)NCCCN3CCC[C@H]3CO)cc(Br)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
(S)-4-Bromo-3-hydrazono-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid [3-(2-hydroxymethyl-pyrrolidin-1-yl)-propyl]-amide (0.22 g, 0.52 mmol) was added to a solution of (2,3-dihydro-benzofuran-5-yl)-acetic acid (0.93 g, 0.52 mmol), triethylamine (0.01 mL, 0.78 mmol) and HBTU (0.20 g, 0.52 mmol) in DMF (4 mL) and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by column chromatography (20% methanol in dichloromethane) followed by HPLC (10-100% acetonitrile/water) to give 0.040 g (13%) of (S)-4-bromo-3-[(2-2,3-dihydro-benzofuran-5-yl-acetyl)-hydrazono]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid [3-(2-hydroxymethyl-pyrrolidin-1-yl)-propyl]-amide. 1H NMR (400 MHz, CD3OD) δ 7.75 (s, 1H), 7.37 (s, 1H), 7.24 (s, 1H), 7.11 (d, J=7.8 Hz, 1H), 6.65 (d, J=8.2 Hz, 1H), 4.50 (t, J=12.7 Hz, 2H), 4.10 (bs, 2H), 3.88 (dd, J=3.9 Hz, J=12.2 Hz, 1H), 3.74-3.40 (m, 6H), 3.22-3.04 (m, 4H), 2.26-1.81 (m, 6H). Mass spectrum (LCMS, ESI pos.): Calcd for C27H30BrN5O5: 584.46. Found 584.1; (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[N:26]=[CH:25][NH:24][N:23]=2)=[C:4]([NH:7][C:8](=[O:21])[CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][C:11]2=[O:20])[S:5][CH:6]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:28]>>[Cl:1][C:2]1[C:3]([C:22]2[N:26]=[CH:25][N:24]([CH3:28])[N:23]=2)=[C:4]([NH:7][C:8](=[O:21])[CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][C:11]2=[O:20])[S:5][CH:6]=1
Reactant: O=C(CN1C(=O)CCc2ncccc21)Nc1scc(Cl)c1-c1nc[nH]n1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Product: Cn1cnc(-c2c(Cl)csc2NC(=O)CN2C(=O)CCc3ncccc32)n1

Procedure:
The titled compound was synthesized from N-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide and TMSCHN2. HPLC purification afforded a white solid. LCMS method [11], retention time=7.322 min; MS (ESI) 403.2 (MH+, 35C1); 1H NMR (300 MHz, CD3OD) δ 8.43 (s, 1H), 8.29 (d, J=5.3 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.59 (t, J=7.1 Hz, 1H), 6.94 (s, 1H), 4.98 (s, 2H), 3.98 (s, 3H), 3.36 (t, J=7.5 Hz, 2H), 2.97 (dd, J=8.2, 6.3 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:32][CH3:33])=[CH:11][C:12]([N+:29]([O-])=O)=[C:13]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([O:25][CH3:26])[C:19]([O:27][CH3:28])=[CH:18]3)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[NH2:29][C:12]1[CH:11]=[C:10]([O:32][CH3:33])[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][C:13]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([O:25][CH3:26])[C:19]([O:27][CH3:28])=[CH:18]2
Reactant: COc1cc2ccc(-c3cc(OCc4ccccc4)c(OC)cc3[N+](=O)[O-])cc2cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc2ccc(-c3cc(OCc4ccccc4)c(OC)cc3N)cc2cc1OC
Yield: 73.1 %

Procedure:
Compound 39 (50 mg, 0.112 mmol) was hydrogenated in ethyl acetate (40 mL) at 30 lb./sq. in. using 10% palladium on carbon (15 mg) as catalyst for 16 hours. The solution was passed through a Celite bed and the catalyst was washed with ethyl acetate (10 mL×3). Concentration of the ethyl acetate solution in vacuo gave a crude product. Column chromatography was performed using a 35:65 mixture of hexanes:ethyl acetate as eluting solvent to give two compounds. The compound having the higher Rf material on thin layer chromatography was isolated as compound 41 (34 mg, 73%); IR (KBr) 3446, 2932, 1610, 1509, 1461, 1421, 1254 cm−1; 1H NMR (CDCl3) δ3.90 (3H, s), 4.01 (3H, s), 4.02 (3H, s), 5.08 (2H. s), 6.42 (1H, s), 6.87 (1H, s), 7.12 (1H, s), 7.15 (1H, s), 7.33-7.48 (6H, m), 7.71-7.75 (2H, m); 13C NMR δ56.40, 56.42, 56.48, 73.07, 101.48, 106.59, 106.78, 119.09, 119.96, 126.24, 126.78, 127.29, 128.16, 128.20, 128.45, 128.90, 129.86, 135.56, 138.19, 138.88, 141.70, 150.07, 150.30, 150.92; HRMS (EI) calcd for C26H25NO4 m/z: 415.1784; found: 415.1775.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13](=O)[CH2:14][C:15](=O)[CH3:16])[C:9]([CH3:19])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([NH:26][NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:16][C:15]1[CH:14]=[C:13]([C:10]2[C:9]([CH3:19])=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[OH:12])[N:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:27]=1
Reactant: CC(=O)CC(=O)C1C(=O)N(c2ccccc2)N=C1C
Reactant: NNc1ccccc1
Product: Cc1cc(-c2c(C)nn(-c3ccccc3)c2O)n(-c2ccccc2)n1

Procedure:
Prepare the title compound from 1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione and phenyl hydrazine according to the procedure of Example 28.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[C:25](=O)[C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=2)([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22][CH2:21]1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][C:22]3[CH2:21][CH2:20][CH2:25][C:24]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=4)([CH2:27][CH2:28][CH3:29])[C:23]=3[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: CCCC1(c2cccc(OC)c2)CCCC(Br)C1=O
Solvent: CCO
Product: CCCC1(c2cccc(OC)c2)CCCc2sc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc21
Temperature: 25 °C
Yield: 2.7 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (100 mg, 0.38 mmol) and of crude 6-bromo-2-(3-methoxy-phenyl)-2-propyl-cyclohexanone (126 mg, 0.39 mmol) in ethanol (5 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound (5 mg, 3%) as a yellow solid. MS ISP (m/e): 489.3 (100) [(M+H)−]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.64 (s, 1H), 7.58 (d, 1H), 7.12-7.19 (m, 2H), 6.68-6.89 (m, 5H), 3.76 (s, 6H), 2.67 (m, 2H), 2.29 (s, 3H), 1.05-2.16 (m, 8H), 0.89 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>CN(C=O)C.O.C(Cl)Cl>[C:20]([O:24][C:25](=[O:32])[NH:26][C@H:27]1[CH2:31][CH2:30][N:29]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:3]=2)[CH2:28]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 12 h
Yield: 81.3 %

Procedure:
To 2-(4-chloro-7-methyl-quinazolin-2-yl)-phenol (551 mg, 2.03 mmol) in 2.5 mL of DMF at room temperature was added sequentially (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (740 mg, 3.9 mmol) and triethylamine (567 μL, 4.0 mmol), and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with water (10 mL) and CH2Cl2 (10 mL). The organic layer was separated and dried (Na2SO4), and the residue was purified via silica gel chromatography with 25-85% ethyl acetate/hexanes to give of (S)-{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (694 mg, 81%). LC/MS: m/z 421 (M+H)+ at 2.79 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].C([Li])CCC.[CH:21]([C:24]1[N:25]=[C:26]([CH2:29][CH2:30][C:31]2[CH:44]=[CH:43][N:34]3[C:35](=[O:42])[C:36]([CH:40]=O)=[C:37]([OH:39])[N:38]=[C:33]3[CH:32]=2)[S:27][CH:28]=1)([CH3:23])[CH3:22].O>O1CCCC1.CN(C)C=O>[F:7]/[C:6](=[CH:40]\[C:36]1[C:35](=[O:42])[N:34]2[CH:43]=[CH:44][C:31]([CH2:30][CH2:29][C:26]3[S:27][CH:28]=[C:24]([CH:21]([CH3:22])[CH3:23])[N:25]=3)=[CH:32][C:33]2=[N:38][C:37]=1[OH:39])/[C:4]([O:3][CH2:2][CH3:1])=[O:5]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(C=O)c(O)nc3c2)n1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C/c1c(O)nc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 25.8 %

Procedure:
2-Fluoro-2-phosphonoacetic acid triethyl ester (384 mg) was dissolved in tetrahydrofuran (3ml) and dimethylformamide (1.5 ml), added with n-butyl lithium (1.6 M, 1 ml) at −78° C. under nitrogen atmosphere, and then the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was added with a solution of 8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-hydroxy-4-oxo-4H-pyrido[1,2-a]-pyrimidine-3-carbaldehyde (108 mg) dissolved in tetrahydrofuran (2 ml). The reaction temperature was gradually raised to room temperature, and the reaction mixture was stirred overnight at the same temperature. The reaction mixture was added with water and extracted with methylene chloride, and the organic layer was dried over magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (35 mg) as a mixture of (E)- and (Z)-isomers.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH3:16])=[O:14].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH3:16])=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1c(C)nc2ccccc2c1N
Product: COC(=O)c1c(C)nc2ccccc2c1NCc1ccccc1

Procedure:
Methyl 4-benzylamino-2-methylquinoline-3-carboxylate was synthesized by the same method as described for 1-(4-(4-bromobenzylamino-2-methylquinolin-3-yl)ethanone (Example 1, Intermediate 2c) starting from methyl 4-amino-2-methylquinoline-3-carboxylate and benzyl bromide. MS(ES+): M++H=307.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:7][CH:8]=1.Cl.C(N=C=N)C.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH2:32])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].CCOC(C)=O>C1COCC1>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH:32][C:11](=[O:13])[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1cccc(CCC(=O)O)c1
Agent: CCN=C=N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(CCC(=O)NCCc2ccc(OC)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a suspension of 3-(3-methoxy-phenyl)-propionic acid (1.19 g, 6.62 mmol) and 3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (1.33 g, 6.95 mmol) in THF (20 mL) is added 2-(3,4-dimethoxy-phenyl)-ethylamine (1.20 g, 6.62 mmol). The mixture is stirred at rt for 14 h. The mixture is poured onto H2O (100 mL) and EtOAc (100 mL). The organic layer is washed successively with saturated sodium hydrogen carbonate solution, 10% citric acid and saturated sodium chloride solution. The resulting organic layer is concentrated under reduced pressure to give the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][O:18]C)[C:4](=[O:16])[C:5]1[C:10]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:15])[CH3:2]>C(#N)C.Cl>[CH2:1]([N:3]([CH2:17][OH:18])[C:4](=[O:16])[C:5]1[C:10]([Si:11]([CH3:12])([CH3:13])[CH3:14])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:15])[CH3:2]
Reactant: CCN(COC)C(=O)c1c(C)cccc1[Si](C)(C)C
Agent: Cl
Solvent: CC#N
Product: CCN(CO)C(=O)c1c(C)cccc1[Si](C)(C)C
Reaction time: 2 h
Yield: 20.8 %

Procedure:
The compound of Example 127 (0.80 g, 2.9 mmol) was refluxed in a mixture of acetonitrile (20 mL) and 2N HCl (20 mL). Within 2 h the reaction was complete by GLC, and was cooled and partitioned between ether and water. The ether phase was concentrated and purified by RC with 1:4 ethyl acetate/hexanes, then recrystallized from hexanes to give 160 mg of the title compound as a solid, a 21% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:10]=2[S:9][C@@H:8]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([F:31])[CH:24]=2)[C@@H:7]([OH:32])[C:6]1=[O:33].[C:35](OC(=O)C)(=[O:37])[CH3:36]>N1C=CC=CC=1>[C:35]([O:32][C@H:7]1[C:6](=[O:33])[N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:34])[C:11]2[CH:12]=[CH:13][C:14]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][C:10]=2[S:9][C@H:8]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([F:31])[CH:24]=1)(=[O:37])[CH3:36]
Reactant: COc1ccc([C@@H]2Sc3cc(Oc4ccccc4)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(Oc4ccccc4)ccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1F

Procedure:
455 mg of (±)-cis-5-(2-dimethylaminoethyl)-2-(3- fluoro-4-methoxyphenyl)-2,3-dihydro-3-hydroxy-8-phenoxy-1,5-benzothiazepin-4(5H)-one (prepared as described in Example 3) were acetylated in the same manner as described in Example 2 in 2 ml of pyridine using 1 ml of acetic anhydride and the product was isolated and purified also as described in Example 2, to give 480 mg of the title compound as a gum.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C([O:17][CH2:18][CH3:19])(=O)C>S(=O)(=O)(O)O.O.C(O)CCCCCCC.C1(C)C=CC=CC=1>[C:18]([O:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C@@H:2]([C:11]([OH:13])=[O:12])[NH2:1])=[CH:9][CH:8]=1)(=[O:17])[CH2:19][CH2:11][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCCCCO
Product: CCCCCCCC(=O)Oc1ccc(C[C@H](N)C(=O)O)cc1
Temperature: 25 °C

Procedure:
9.06 g of tyrosine was dissolved in a solution of 10 g of concentrated sulfuric acid, 20 mL water, 10 mL of octanol, and 200 mL of toluene in a 500 mL round bottom flask equipped with a condenser and a Dean-Stark apparatus. The resulting solution was heated at reflux temperature until no more water could be distilled. The resulting solution was then cooled to room temperature and washed with saturated aqueous sodium bicarbonate to neutralize acidic impurities to provide an emulsion. About 150 mL of ethyl acetate was added to the emulsion to provide two phases. The aqueous phase was discarded and the organic phase washed with saturated Brine and dried over anhydrous sodium sulfate. The solvent was the removed under reduced pressure to provide tyrosine octanoate as a white solid that was purified using a silica gel column eluted with a 1:9 methanol:dichloromethane mixture.
Reaction SMILES: C([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(C)(C)C.[C:15]([C:23]([OH:25])=O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:8]([N:6]([C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:5][C:23]([C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:25])([CH3:13])([CH3:9])[CH3:7]
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Reactant: O=C(O)C(=O)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)C(=O)c1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
N'-t-butyl-N-benzoylhydrazine (1 g), benzoyl formic acid (1 g), and methanesulfonyl chloride (0.7 g) were stirred in toluene (35 ml) and saturated sodium bicarbonate (15 ml) at approximately 5° C. Triethylamine was added slowly, dropwise to the reaction mixture, and slowly warmed to room temperature. After stirring for 1 hour, the reaction mixture was diluted with toluene (20 ml) and the organic layer was washed several times with water. The organic layers were dried over magnesium sulfate, filtered and the toluene rotavapped off to afford a white gum. The crude product was chromatographed on silica gel (G:230-400 mesh) using a methylene chloride ether solvent system as eluent to afford a 65% yield of a white solid.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:34]([C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=1)=O>>[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][C:4]=1/[CH:14]=[CH:34]/[C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=1
Reactant: Cc1oc(-c2ccccc2)nc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Cl-]
Product: COC(=O)c1ccc(/C=C/c2nc(-c3ccccc3)oc2C)cc1

Procedure:
(5-Methyl-2-phenyl-4-oxazolylmethyl)triphenylphosphonium chloride and methyl 4-formylbenzoate were reacted in the same manner as in Reference Example 10 to yield methyl (E)-4-[2-(5-methyl-2-phenyl-4-oxazolyl)vinyl]benzoate, which was then recrystallized from ethyl acetate to yield colorless prisms having a melting point of 164°-165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:25]2[CH2:24][CH:23]3[CH:27]([C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:20][CH2:21][C:22]3=[O:28])[CH2:26]2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccc(Cl)cc3)CC12
Reaction time: 1 h
Yield: 67.8 %

Procedure:
N,N'-Carbonyldiimidazole (1.3 g) is added to a solution of 2-(4-chlorophenyl)acetic acid (1.36 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 1 hour at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.62 g) and triethylamine (1.12 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred for 2 hours at +5° C. and 16 hours at 20° C.; it is washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile (5 cc) and isopropyl ether (10 cc). The crystals obtained are drained and dried. The residue is recrystallized from acetonitrile (40 cc). The crystals obtained are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-2-[(4-chlorophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (2.4 g) melting at 213° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:20][NH:21][OH:22].C(N(CC)CC)C.Cl>O1CCCC1.O1CCCC1.O>[CH3:20][N:21]([C:8](=[O:9])[CH:7]=[CH:6][C:5]1[CH:11]=[CH:12][C:2]([CH3:1])=[CH:3][CH:4]=1)[OH:22]
Reactant: CNO
Reactant: Cc1ccc(C=CC(=O)O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C=CC(=O)N(C)O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of 4-methylcinnamic acid (1.62 g, 10 mmol) and oxalyl chloride (2.0 ml, 23 mmol) in 50 ml anhydrous tetrahydrofuran (THF) was stirred at reflux for two hours, then concentrated in vacuo. The residue was redissolved in 30 ml THF, and added dropwise to a solution of N-methyl-hydroxylamine hydrochloride (1.26 g, 15 mmol) and triethylamine (5.0 ml, 36 mmol) in 50 ml of 2:1 THF-water at 0° C. The mixture was stirred for one hour at 0° C., then for one hour at room temperature, and then poured into excess 5% aqueous hydrochloric acid. The resulting mixture was extracted with ethyl ether, and the ether extract washed successively with 5% aqueous hydrochloric acid and brine, dried over sodium sulfate, and evaporated. Recrystallization of the residue from ethyl acetate provided 1.48 g (77% yield) of the titled compound, mp 142°-144° C.
Reaction SMILES: [Cl-].Cl[CH:3]=[N+:4]([CH3:6])[CH3:5].[CH3:7][N:8]([CH3:35])[C:9](=[O:34])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=1[S:17]([NH:20][C:21]([NH:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[N:25]=1)=[O:22])(=[O:19])=[O:18]>CN(C=O)C>[CH3:35][N:8]([CH3:7])[C:9](=[O:34])[C:10]1[CH:15]=[CH:14][C:13]([N:16]=[CH:3][N:4]([CH3:6])[CH3:5])=[CH:12][C:11]=1[S:17]([NH:20][C:21]([NH:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[N:25]=1)=[O:22])(=[O:19])=[O:18]
Reactant: C[N+](C)=CCl
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cc(N)ccc2C(=O)N(C)C)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cc(N=CN(C)C)ccc2C(=O)N(C)C)n1
Yield: 71.2 %

Procedure:
0.24 g of (chloromethylene)dimethylammonium chloride is added to a mixture of 0.80 g of N,N-dimethyl-4-amino-2-[[[[(4,6-dimethoxypyrimidin-2-yl)amino]carbonyl]amino]sulfonyl]benzamide and 8 ml of DMF. Stirring is then continued at room temperature until the reaction has ended. Volatile components are then distilled off under reduced pressure. The residue is washed with water and ethyl acetate. After drying, 0.64 g of the desired product is obtained. Melting point: 140-141° C. (decomp.)
Reaction SMILES: CC(C)([O-])C.[K+].C(O[C:10]([C:12]1[C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=[C:14]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[N:13]=1)=O)C.[NH2:28][C:29]([CH3:36])([CH:33]([CH3:35])[CH3:34])[C:30]([NH2:32])=[O:31]>C1(C)C=CC=CC=1>[S:25]1[CH:26]=[CH:27][C:23]([C:14]2[N:13]=[C:12]([C:10]3[NH:28][C:29]([CH:33]([CH3:35])[CH3:34])([CH3:36])[C:30](=[O:31])[N:32]=3)[C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[CH:24]1
Reactant: CCOC(=O)c1ccc(-c2ccsc2)nc1C(=O)OCC
Reactant: CC(C)C(C)(N)C(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)C1(C)NC(c2nc(-c3ccsc3)ccc2C(=O)O)=NC1=O
Temperature: 80 °C
Yield: 85.7 %

Procedure:
12 g of potassium tert.-butoxide are added to a solution of 14 g of 6-(thiophen-3-yl)-pyridine-2,3-dicarboxylic acid diethyl ester and 6 g of 2-amino-2,3-dimethyl- butyramide in 100 ml of dry toluene while stirring and the solution is heated at 80° C. for 5 hours. The reaction solution is then poured onto ice, the phases are separated and the aqueous phase is acidified with 10 ml of glacial acetic acid. After some time the above acid crystallises out and is filtered off with suction and dried. In this manner 13.5 g of 6-(thiophen-3-yl)-2-(5-isopropyl-5-methyl-4-oxo-imidazol-2-yl)-pyridine-3-carboxylic acid having a melting point of 253°-257° C. are obtained.