Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1I>>[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: Brc1ccccc1I
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2ccccc2Br)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (300 mg, 1.59 mmol) and 1-bromo-2-iodobenzene (0.3 mL, 2.34 mmol) according to the general procedure ID to give 340 mg (62%) of an yellow oily product after purification by flash chromatography (SiO2, EtOAc:PE, 1:5). Rf=0.27 (EtOAc:PE, 1:5); 1H NMR (CDCl3) δ 7.61 (dd, J=8.0, 1.1 Hz, 1H), 7.54 (dd, J=7.7, 1.7 Hz, 1H), 7.52-7.48 (m, 2H), 7.28 (td, J=7.6, 1.2 Hz, 1H), 7.22-7.14 (m, 3H), 3.67 (s, 3H), 2.97 (t, J=7.7 Hz, 2H), 2.64 (t, J=7.7 Hz, 2H); 13C NMR (CDCl3) δ 173.1, 141.3, 133.2, 132.4, 131.8, 129.3, 128.4, 127.0, 125.6, 125.5, 120.9, 93.9, 87.8, 51.7, 35.4, 30.9; ESI-MS m/z 365.0 (M+Na+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH:20]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.[Pt]=O>[C:1]([O:5][C:6]([NH:8][NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH:20]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NN=C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NNC1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1

Procedure:
A solution of 9H-fluoren-9-ylmethyl 4-[(t-butoxycarbonyl)hydrazono]piperidine-1-carboxylate (10.0 g, 22.9 mmol) in acetic acid (150 mL) was shaken with platinum oxide (1.0 g) under 45 psi hydrogen on a Parr apparatus for 2 h. The solution was filtered and concentrated to give the title compound.
Reaction SMILES: Cl.[C:2]1([C:8]2[O:9][CH:10]=[C:11]([CH2:13][C:14]([OH:16])=O)[N:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]([CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)=[O:20]>>[F:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][O:37][CH2:36][C@H:18]([NH:17][C:14](=[O:16])[CH2:13][C:11]2[N:12]=[C:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:9][CH:10]=2)[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)=[O:20])=[CH:40][CH:41]=1
Reactant: N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)Cc1coc(-c2ccccc2)n1
Agent: Cl
Product: O=C(Cc1coc(-c2ccccc2)n1)N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 70 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2-phenyloxazol-4-yl)acetic acid hydrochloride and (S)-2-amino-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 44, (S)-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(2-phenyloxazol-4-yl)acetamido)propanamide (160 g, 70%). 1H-NMR (400 MHz, CDCl3): σ 8.45 (s, 1H), 8.00 (m, 2H), 7.50-7.45 (m, 2H), 7.40-7.30 (m, 7H), 7.05-6.80 (m, 8H), 4.79-4.73 (m, 1H), 4.63 (m, 2H), 4.00-3.70 (m, 4H). MS (EI) for C33H27F2N3O5 found 584 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14](=[O:25])[CH2:15][S:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C:14](=[O:25])[CH2:15][S:16]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:17])=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CS(=O)Cc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)CS(=O)Cc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-phenylmethanesulfinyl-ethanone and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:21]=[C:22]2[C:28]([CH2:29][CH2:30][NH:31][C:32]([C:34]3[CH:38]=[C:37]([CH2:39][C:40]4[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=4[F:47])[O:36][N:35]=3)=[O:33])=[C:27]([Si](CC)(CC)CC)[NH:26][C:23]2=[N:24][CH:25]=1.C1C[O:58]CC1>>[Cl:19][C:20]1[CH:21]=[C:22]2[C:28]([CH2:29][CH2:30][NH:31][C:32]([C:34]3[CH:38]=[C:37]([C:39](=[O:58])[C:40]4[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=4[F:47])[O:36][N:35]=3)=[O:33])=[CH:27][NH:26][C:23]2=[N:24][CH:25]=1
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCNC(=O)c1cc(Cc2cc(F)ccc2F)on1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C(NCCc1c[nH]c2ncc(Cl)cc12)c1cc(C(=O)c2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
A solution of tetrabutylammonium fluoride 1M in THF (1 mL; 1 mmol) was added to a solution of N-(2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide (0.105 g, 0.198 mmol) in THF (5 mL). The mixture was stirred overnight at room temperature and was evaporated. The residue was dissolved in dichloromethane, and the organic solution was washed with water and was concentrated under reduced pressure. The crude material was purified twice by flash chromatography on silica gel (eluent: 0 to 40% of ethyl acetate in dichloromethane) to give 0.019 g (22%) of N-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-5-(2,5-difluorobenzoyl)isoxazole-3-carboxamide as a white solid.
Reaction SMILES: CS[C:3]1[N:4]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13][N:5]2[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.CN(C)C=O>[Zn].O>[C:18]1([N:15]2[CH2:14][CH2:13][N:5]3[C:3](=[N:8][C:7]4[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=43)[NH:4][CH2:17][CH2:16]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CSC1=Nc2ccccc2N2CCN(c3ccccc3)CCN12
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(N2CCNc3nc4ccccc4n3CC2)cc1

Procedure:
A mixture of 2,3,4,5-tetrahydro-7-(methylthio)-3-phenyl-1H-[1,2,5]-triazepino[1,2-a][1,2,4]benzotriazine (0.5000 g), zinc dust (2.0 g), N,N-dimethylformamide (16 ml) and water (4 ml) was stirred magnetically and heated under reflux for 20 hours. The cooled mixture was filtered through Celite and the filter pad washed with N,N-dimethylformamide. The filtrate and washings were evaporated under oil pump vacuum to a syrup. The syrup was dissolved in dichloromethane and applied to the edges of 4 plates of Alox-100 uv254 (20×20 cm×1 mm). The plates were developed twice in dichloromethane and several times in chloroform. The major band was excised and the component eluted by stirring with methanol. The adsorbent was filtered and washed with methanol. The filtrate and washings were evaporated to a syrup. The syrup was extracted with dichloromethane and the solution was evaporated to a syrup which crystallized. The crystals were dissolved in dichloromethane and the solution was treated with charcoal and filtered through Celite. Evaporation gave a syrup which was crystallized from dichloromethane-heptane; wt. 0.127 g (30%), mp=155°-157°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(N2CCCCC2=O)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(=O)O)ccc1N1CCCCC1=O

Procedure:
Prepared analogously to Example 2d from methyl 3-methyl-4-(piperidin-2-on-1-yl)-benzoate and 1-molar sodium hydroxide solution in methanol.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([O:8][C@H:9]([CH3:15])[C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:7])(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([NH:4][C@H:5]1[C@H:10]([C:11]([O:13][CH3:14])=[O:12])[C@@H:9]([CH3:15])[O:8][C:6]1=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)C1=C(NC(C)=O)C(=O)O[C@@H]1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1[C@H](NC(C)=O)C(=O)O[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
169.2 g of (R)-2-acetamido-3-methoxycarbonyl-2-penten-4-olide are dissolved in 800 ml of methanol, 10 g of Pd/C (5%) are added and the whole is hydrogenated for 8 hours at 30° C. and 3-5 bars. The catalyst is filtered off, washed with methanol and the filtrate is concentrated by evaporation. The ratio of the diastereoisomers of the crude product exhibited by HPLC analysis is (2S,3S,4R):(2R,3S,4R):(2S,3R,4R)=approximately 5:3:2. The proportion of the (2R,3R,4R)-diastereoisomer is less than 1%. The mixture is dissolved in 500 ml of methanol, 12 g of 1,8-diazabicyclo[5.4.0]undec-7-ene are added and the whole is stirred at room temperature for 48 hours, resulting in a mixture, 86-88% of which consists of the desired (2S,3S,4R)-diastereoisomer. The solution is concentrated, neutralised with 2N hydrochloric acid, taken up in ethyl acetate and extracted with saturated sodium chloride solution. Diastereoisomerically pure title compound is obtained by crystallisation from ethyl acetate/cyclohexane, [α]D20 =-49.5° (3% in CH3OH), m.p. 105°-106° C., IR 1787, 1740, 1689, 1510 cm-1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([CH2:18][C:19]#[CH:20])[CH:15]=[C:14]([O:21][CH3:22])[C:13]=1[O:23][CH3:24]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:20]#[C:19][CH2:18][C:16]2[CH:15]=[C:14]([O:21][CH3:22])[C:13]([O:23][CH3:24])=[C:12]([O:11][CH3:10])[CH:17]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(I)c(N)n1
Reactant: C#CCc1cc(OC)c(OC)c(OC)c1
Product: COc1cc(CC#Cc2cnc(N)nc2N)cc(OC)c1OC
Yield: 79.9 %

Procedure:
2,4-Diamino-5-iodopyrimidine (236 mg) was allowed to react with 1,2,3-Trimethoxy-5-(prop-2-ynyl)benzene (412 mg) as per the general procedure to afford 2,4-Diamino-5-(3-(3,4,5-trimethoxyphenyl)prop-1-ynyl)pyrimidine as a white powder (251 mg, 80%): Rf=0.23 (9:1, CHCl3:MeOH); mp=decomposed above 190° C.; 1H NMR (DMSO-d6) δ 7.84 (s, 1H), 6.71 (s, 2H), 6.26 (s, 2H), 3.80 (s, 2H), 3.77 (s, 6H), 3.63 (s, 3H); 13C NMR (DMSO-d6) δ 163.8, 162.2, 158.7, 152.8, 136.0, 132.8, 105.2, 93.1, 90.1, 76.5, 60.1, 55.8, 25.6; Anal. (C16H18N4O3) C, H, N.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C[O:17][C:18](=[O:29])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][C:22]=1[CH3:28]>>[CH3:28][C:22]1[CH:23]=[C:24]([S:27][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:5][CH:4]=2)[CH:25]=[CH:26][C:21]=1[O:20][CH2:19][C:18]([OH:29])=[O:17]
Reactant: COC(=O)COc1ccc(S)cc1C
Reactant: ClCc1ccc(Oc2ccccc2)cc1
Product: Cc1cc(SCc2ccc(Oc3ccccc3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1F with 1-chloromethyl-4-phenoxy-benzene and 2C. MS m/z 321 (M-methylacetate).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+].[S:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[S:28]>C(O)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[C:32]2[S:26][C:27](=[S:28])[NH:29][C:30]2=[O:31])=[CH:15][CH:14]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc(OCc2ccc3ccccc3c2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(OCc2ccc3ccccc3c2)cc1

Procedure:
Under a nitrogen atmosphere in a round bottom flask 4-[(naphth-2-yl)methoxy]benzaldehyde (5.24 g, 20 mmol) was dissolved in 100 ml of acetic acid. To this solution was added sodium acetate (5.74 g, 70 mmol) and rhodanine (2.66 g, 20 mmol). The reaction mixture was raised to the reflux temperature and maintained at this temperature. The progress of the reaction was monitored by thin layer chomratography.
Reaction SMILES: [Cl:1][C:2]([Cl:22])=[CH:3][C:4]1([CH3:21])[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([CH3:20])[C:8]([CH3:19])=[C:9]([O:15]COC)[C:10]=2[CH3:14])[O:5]1>CO.Cl>[Cl:22][C:2]([Cl:1])=[CH:3][C:4]1([CH3:21])[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([CH3:20])[C:8]([CH3:19])=[C:9]([OH:15])[C:10]=2[CH3:14])[O:5]1
Reactant: COCOc1c(C)c(C)c2c(c1C)CCC(C)(C=C(Cl)Cl)O2
Agent: Cl
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C=C(Cl)Cl)O2
Yield: 50.1 %

Procedure:
A solution 160 mg of 2-(2,2-dichloro-vinyl)-6-methoxymethoxy-2,5,7,8-tetramethyl-chroman in 5 ml of methanol and 0.1 ml of conc. HCl was stirred overnight. The methanol was removed and the residue was mixed with ethyl acetate and water. Regular work-up and flash column chromatography on silica gel(15% ethyl acetate in hexane) afforded 70 mg of 2-(2,2-Dichloro-vinyl)-2,5,7,8-tetramethyl-chroman-6-ol. NMR (1H, CDCl3): 6.01 (1H, s), 4.26 (1H, s), 2.63 (2H, m), 2.48 (1H, m), 2.19 (3H, s), 2.16 (3H, s), 2.13 (3H, s), 1.78 (1H, m), 1.62 (3H, s). LC-MS: 301 (M+H, 100%), 323 (M+Na, 78%)
Reaction SMILES: [NH2:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:22]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)/[CH:23]=[CH:24]/[CH3:25]>CO>[CH2:22]([O:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([NH:1][CH:2]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:15][CH:16]=2)[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])=[O:32])=[CH:34][CH:35]=1)/[CH:23]=[CH:24]/[CH3:25]
Reactant: CC(C)(C)OC(=O)C(N)Cc1ccc(OC(F)(F)F)cc1
Reactant: C/C=C/COc1ccc(C(=O)O)cc1
Solvent: CO
Product: C/C=C/COc1ccc(C(=O)NC(Cc2ccc(OC(F)(F)F)cc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 87.8 %

Procedure:
4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorphorinium chloride (DMT-MM, 332 mg, 1.20 mmol) was added to a methanol (6 mL) solution of tert-butyl 2-amino-3-[4-(trifluoromethoxy)phenyl]propanoate (305 mg, 1.00 mmol) and 4-[(2E)-buten-2-yloxy]benzoic acid (192 mg, 1.00 mmol) prepared in Example 32 (32a). The mixture was stirred at room temperature for 4 hours and 50 minutes. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate, 19:1 and 4:1, V/V) to give 421 mg of tert-butyl 2-({4-[(2E)-but-2-en-1-yloxy]benzoyl}amino)-3-[4-(trifluoromethoxy)phenyl]propanoate (colorless oil). This oily compound (492 mg, 1.03 mmol) was dissolved in methylene chloride (20 mL), and trifluoroacetic acid (4 mL) was added thereto at room temperature. The resulting mixture was stirred at the same temperature for 4.5 hours. The solvent was evaporated, and the residue was suspended in diisopropyl ether. The insoluble substance was collected by filtration, washed with diisopropyl ether, and dried to give 284 mg of the title compound (white powder, yield: 57%).
Reaction SMILES: [Na].[CH3:2][C:3]1[C:8]([CH3:9])=[C:7]([N+]([O-])=O)[C:6]([CH3:13])=[CH:5][N+:4]=1[O-:14].Cl.[CH3:16][OH:17]>C(OCC)(=O)C>[CH3:16][O:17][C:7]1[C:6]([CH3:13])=[CH:5][N+:4]([O-:14])=[C:3]([CH3:2])[C:8]=1[CH3:9]
Reactant: CO
Reactant: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Product: COc1c(C)c[n+]([O-])c(C)c1C

Procedure:
22.6 g of sodium were dissolved in 4 1 of methanol under argon. 120 g of 2,3,5-trimethyl-4-nitropyridine 1-oxide were then added portionwise thereto and the solution was left to boil under reflux overnight. The pH was adjusted to 7 by means of 5N hydrogen chloride in ethyl acetate while cooling and the mixture was then evaporated in vacuo. The residue was taken up in 1.5 1 of methylene chloride, the solution was filtered through silica gel, which was rinsed with 0.5 1 of methylene chloride, the combined filtrates were evaporated in vacuo and the residue was crystallized from petroleum ether. There was obtained 4-methoxy-2,3,5-trimethylpyridine 1-oxide of melting point 48-50° .
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[O:12])[C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(CCc1ccc(O)c(Br)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: CC(C)(C)OC(=O)COc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1Br

Procedure:
Tert-butyl 2-(2-bromo-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-acetate is prepared from 3-(3-bromo-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl bromoacetate according to general procedure D.
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=S(Cl)Cl
Reactant: O=c1[nH]c(-c2cccc(Cl)c2)nc2ccccc12
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: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[CH:8][C:9]=2[CH3:11])[S:4][C:3]=1[C:22]([NH2:24])=[O:23].Cl[C:26]([O:29]C(Cl)=O)(Cl)Cl.N>O1CCOCC1.O>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([C:7]2[CH:8]=[C:9]([CH3:11])[C:10]3[C:2]4[NH:1][C:26](=[O:29])[NH:24][C:22](=[O:23])[C:3]=4[S:4][C:5]=3[N:6]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(-c2cc(C)c3c(N)c(C(N)=O)sc3n2)cc1OC
Agent: N
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2cc(C)c3c(n2)sc2c(=O)[nH]c(=O)[nH]c23)cc1OC
Yield: 95.8 %

Procedure:
3.0 g (8.7 mmol) 3-amino-6-(3,4-dimethoxyphenyl)-4-methyl-thieno[2,3-b]pyridine-2-carboxamide is suspended in 100 ml absolute dioxane. Then, 1.1 ml (8.7 mmol) chloroformic acid trichloromethylester (diphosgene) is added and refluxed for 3 h. Following cooling, the precipitate is sucked off and then suspended in 50 ml water. The suspension is adjusted to pH 8 using concentrated ammonia solution and the precipitate is sucked off, washed with some water, suck dried and in vacuo at 50° C. 3.08 g (96%) 7-(3,4-dimethoxyphenyl)-9-methyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine-2,4-dione is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:10]([CH2:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)[C:11](N([C@H](C)[C@H](O)C2C=CC=CC=2)C)=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].S(=O)(=O)(O)[OH:31]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:10]([CH2:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)[C:11]([OH:12])=[O:31])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: O=S(=O)(O)O
Reactant: CSc1ccc([C@@H](CC2CCC2)C(=O)N(C)[C@H](C)[C@H](O)c2ccccc2)cc1Cl
Solvent: O
Solvent: C1COCCO1
Product: CSc1ccc([C@@H](CC2CCC2)C(=O)O)cc1Cl
Temperature: 110 °C
Yield: 71 %

Procedure:
A solution of (R)-2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclobutyl-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-propionamide (330 mg, 0.76 mmol) in dioxane (4 mL) was treated with a 9 N aqueous sulfuric acid solution (2 mL). The resulting solution was then heated at 110° C. for 16 h. The reaction was then cooled and diluted with water (75 mL) and extracted with a chloroform/methanol solution (3:2, 2×50 mL) and then concentrated. The resulting residue was then dissolved in acetonitrile and concentrated with silica gel (3 g) and purified on Biotage Flash chromatography system (40S column, silica gel, 80% ethyl acetate/hexanes) to afford (R)-2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclobutyl-propionic acid (154 mg, 71%) as a yellow viscous oil: [α]30589=−48.3° (c=0.18, methylene chloride); ES-HRMS m/e calcd for C14H17O2SCl (M+Na)+ 307.0530, observed 307.0530; 1H NMR (300 MHz, DMSO-d6) δ 1.47-2.16 (m, 9H, CH and 4×CH2), 2.47 (s, 3H, SCH3), 3.40 (t, J=7.3 Hz, 1H, ArCHCO), 7.25 (s, 2H, Ar), 7.34 (s, 1H, Ar), 12.41 (s, 1H, CO2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CC(N(C)C)=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: FC(F)(F)c1ncc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(C(F)(F)F)nc2)CC1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
0.26 mmol 5-Chloro-2-trifluoromethyl-pyrimidine was added to 0.26 mmol piperazine-1-carboxylic acid tert-butyl ester in 1.5 ml dimethylacetamide, and the reaction mixture was stirred at 150° C. for 10 min. in a microwave oven. After such time, the reaction mixture was concentrated and the residue was then purified by column chromatography (SiO2, Heptane/EtOAc) to yield the title compound. MS (m/e): 333.2 (M+H+, 100%)
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=1>CN(C=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])=[N:14][CH:15]=1
Reactant: CN1CC(=O)NC1=NC(=O)O
Reactant: Nc1ccc(Cl)cn1
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1ccc(Cl)cn1

Procedure:
A mixture of 2.3 g. (10 mM) of the phenyl carbamate 8 and 3.0 g. (23 mM) of 2-amino-5-chloropyridine in 25 ml of anhydrous DMF was heated at 45°-50° C. for 2 hrs., cooled and filtered. The collected solid was washed successively with cold DMF, ethyl acetate, and ether to give 1.6 g of the above urea as a yellow solid, m.p. 250°-251° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[F:12][C:13]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=1[CH:15]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](/[N:10]=[CH:15]/[C:14]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:13]=2[F:12])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(F)cc1F
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(/N=C/c2ccc(F)cc2F)cc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
The mixture solution of 4-aminobenzoic acid methyl ester (10.8 g, 71.4 mmol), 2,4-difluoro-benzaldehyde (10.3 g, 72.4 mmol) and p-toluenesulfonic acid (271.8 mg, 1.4 mmol) in toluene (150 mL) was heated to reflux for 12 h. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(2,4-difluoro-phenyl)-meth-(E)-ylidene]amino}-benzoic acid methyl ester (19.64 g, quant.) as a light yellow solid: MS (ESI) M+1=276.1.