Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].C([O:4][C:5]([C:7]1[C:8]([N:15]([CH:23]2[CH2:28][CH:27]3[CH2:29][CH:24]2[CH2:25][CH2:26]3)[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:9][C:10]([S:13][CH3:14])=[N:11][CH:12]=1)=O)C.CC(C)([O-])C.[Na+].Cl>C1(C)C=CC=CC=1.C(O)(C)(C)C>[CH2:21]([O:20][C:18]([CH:17]1[CH2:16][N:15]([CH:23]2[CH2:28][CH:27]3[CH2:29][CH:24]2[CH2:25][CH2:26]3)[C:8]2[N:9]=[C:10]([S:13][CH3:14])[N:11]=[CH:12][C:7]=2[C:5]1=[O:4])=[O:19])[CH3:22]
Reactant: CCOC(=O)CCN(c1nc(SC)ncc1C(=O)OCC)C1CC2CCC1C2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CCOC(=O)C1CN(C2CC3CCC2C3)c2nc(SC)ncc2C1=O
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
3-(Bicyclo[2.2.1]hept-2-ylamino)-propionic acid ethyl ester (1.5 g, 7.1 mmol) and 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.6 g, 7.1 mmol) were combined in CH2Cl2 (20 mL) and triethylamine (1.0 g, 10 mmol) was added. After 16 h, water (10 mL) was added the organic layer was separated, dried (MgSO4), and concentrated. Chromatography (10-50% EtOAc/hexanes gradient) provided 1.8 g of 4-[bicyclo[2.2.1]hept-2-yl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester. Sodium (30 wt % dispersion in paraffin wax, 0.55 g, 7.2 mmol) was added to t-butanol (5.0 mL) at rt. After 30 minutes, a solution of 4[bicyclo[2.2.1]hept-2-yl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.8 g, 4.4 mmol) in 20 mL of toluene was added to the sodium t-butoxide solution and the resulting mixture was heated at 90° C. for 30 minutes. The reaction mixture was then cooled and the solution was adjusted to pH 7 using a 1N HCl solution. The solution was then extracted with EtOAc (2×20 mL) and the organic layer was dried (MgSO4), and concentrated. Recrystallization from i-PrOH provided 0.51 g of 8-bicyclo[2.2.1]hept-2-yl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 8-Bicyclo[2.2.1]hept-2-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (46 mg, 0.12 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (22 mg, 0.12 mmol) were combined in i-PrOH (2 mL) and heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (C-18 column, 32 mL/min 5-100% MeCN/H2O gradient over 15 min) and lyophilized to provide 11.4 mg of 8-bicyclo[2.2.1]hept-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.21 (s, 1H), 8.59 (s, 1H), 7.52 (d, 2H, J=8.9 Hz), 6.87 (d, 2H, J=9.0 Hz), 4.31 (q, 2H, J=7.1 Hz), 3.52-3.62 (m, 4H), 3.28 (br s, 2H), 2.98 (br s, 2H), 2.82 (s, 3H), 2.14-2.53 (m, 5H), 1.58-1.75 (m, 4H), 1.22-1.42 (m, 5H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(O)(=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][N:20]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:2]3[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=3)=[CH:28][CH:29]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N)cc2)CC1
Reactant: Cc1cnc(Cl)nc1N
Solvent: CC(=O)O
Product: Cc1cnc(Nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1N
Temperature: 70 °C

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.35 g, 2:4 mmol) and 4-(4-amino-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (0.80 g, 2.8 mmol) in acetic acid (20 mL) was heated at 70° C. for 1 d. After cooling to room temperature, the mixture was concentrated. The residue was taken in water (30 mL) and neutralized with 10% NaOH solution until pH˜10. The resulting aqueous layer was extracted with EtOAc (2×30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the title compound used in the next step without purification. MS (ES+): m/z 399 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=[O:9])[CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>>[C:8]([C:4]1[CH:3]=[C:2]([O:18][C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[NH2:11])[CH:7]=[CH:6][N:5]=1)(=[O:9])[NH2:10]
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1cccc(O)c1
Product: NC(=O)c1cc(Oc2cccc(N)c2)ccn1

Procedure:
Entry 44: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[CH2:7].Br[C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:7]/[C:21]2[CH:22]=[CH:23][CH:24]=[CH:14][C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: CCOC(=O)c1ccccc1Br
Reactant: C=Cc1ccc(OC)c(OC)c1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1/C=C/c1ccc(OC)c(OC)c1

Procedure:
5 g (30.5 mmol) of 3,4-dimethoxystyrene were reacted with ethyl 2-bromobenzoate in dimethylformamide at 120° C. by the method of procedure 31a. 1.2 g (4%) [sic] of the product were obtained.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[C:11]([CH3:12])=[N:10][N:9]=[C:8]1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.Br[CH:20]([C:22]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[O:24][N:23]=1)[CH3:21]>C1COCC1>[Cl:33][C:29]1[CH:28]=[C:27]([C:25]2[O:24][N:23]=[C:22]([CH:20]([CH3:21])[CH2:12][C:11]3[N:7]([CH3:6])[C:8]([C:13]4[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=4)=[N:9][N:10]=3)[N:26]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CC(Br)c1noc(-c2cccc(Cl)c2)n1
Reactant: Cc1nnc(-c2ccncc2)n1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(Cc1nnc(-c2ccncc2)n1C)c1noc(-c2cccc(Cl)c2)n1
Yield: 9.6 %

Procedure:
84 microl (0.21 mmol, 2.5 M) n-BuLi was added dropwise to a solution of 37 mg (0.21 mmol) 4-(4,5-dimethyl-4H-[1,2,4]triazol-3-yl)-pyridine in 2.1 ml THF at 0° C. After 20 min a solution of 60 mg (0.21 mmol) 3-(1-bromo-ethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole was added dropwise. The reaction mixture was allowed to reach room temperature and stirred over night. NH4Cl(sat) was added and the mixture was extracted twice with EtOAc. The organic phase was dried and concentrated. Flashchromatography (CH2Cl2/MeOH 20:1) afforded 7.7 mg (10%) of the desired product. 1H NMR (CDCl3), d (ppm): 1.57 (d, 3 H) 3.16 (m, 1 H) 3.38 (m, 1 H) 3.71 (s, 3 H) 3.84 (d, 1 H) 7.46 (t, 1 H) 7.55 (m, 1 H) 7.58 (m, 2 H) 7.98 (m, 1 H) 8.10 (t, 1 H) 8.77 (d, 2 H)
Reaction SMILES: Br[C:2]1[S:6][C:5]([O:7][CH3:8])=[N:4][CH:3]=1.C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17].C(=O)(O)[O-].[Na+]>C(OCC)C>[CH3:8][O:7][C:5]1[S:6][C:2]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:3][N:4]=1
Reactant: COc1ncc(Br)s1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(OC)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A diethyl ether (1.8 mL) solution of 5-bromo-2-methoxythiazole (200 mg) was cooled to −78° C. followed by the dropwise addition of normal butyllithium (1.6 M, 0.7 mL; KANTO). The resulting mixture was stirred as it was for 1 hour, followed by the addition of tri-n-butyltin chloride (0.35 mL; TCI), and the resulting mixture was slowly raised to room temperature and then stirred for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture solution, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried and the solvent was evaporated under reduced pressure to give the'title compound.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][C:14]=1[F:22]>C1COCC1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH3:8])[CH2:20][O:21]2)=[CH:15][C:14]=1[F:22]
Reactant: CC(=O)c1ccc(Cl)c(F)c1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(c2ccc(Cl)c(F)c2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(4-chloro-3-fluorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.[NH:14]1[CH2:19][CH2:18][C:17]2([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:21](=[O:28])[O:20]2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:14]3[CH2:19][CH2:18][C:17]4([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[C:21](=[O:28])[O:20]4)[CH2:16][CH2:15]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(CC3)OC(=O)c3ccccc34)nn2)n1

Procedure:
The object product (187 mg, 52%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (200 mg) obtained in Example 43(2), 3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (240 mg) and potassium carbonate (140 mg).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[N:23]=3)[N:18]=[CH:17][C:16]=2[F:27])[OH:14])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:27][C:16]1[C:15]([CH:13]2[CH2:12][O:14]2)=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([O:25][CH3:26])=[N:23]2)=[N:18][CH:17]=1
Reactant: COc1ccc2ncc(F)c(C(O)COS(=O)(=O)c3ccc(C)cc3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc2ncc(F)c(C3CO3)c2n1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 94.4 %

Procedure:
To a suspension of 2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]-2-hydroxyethyl 4-methylbenzenesulfonate (10.5 g, 26.7 mmol) in anhydrous methanol (160 mL), cooled in an ice-bath, potassium carbonate (7.03 g, 50.9 mmol) was added. After 15 minutes with cooling, the mixture was stirred at room temperature for a further 1.75 hours. It was then diluted with water, extracted several times with dichloromethane, dried over magnesium sulfate and evaporated under vacuum. The residue was chromatographed on silica gel eluting with dichloromethane, chloroform then 20% ethyl acetate in chloroform to afford the title product as an oil (5.55 g, 94%). MS (+ve ion electrospray) m/z 221 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([CH2:6][CH2:7]O)[C:3]2[CH:9]=[CH:10][C:11]3[C:16]([C:2]1=2)=[CH:15][CH:14]=[CH:13][CH:12]=3.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:36]I.N1C=CN=C1>C1COCC1>[I:36][CH2:7][CH2:6][C:4]1[C:3]2[CH:9]=[CH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:2]=2[O:1][CH:5]=1
Reactant: OCCc1coc2c1ccc1ccccc12
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ICCc1coc2c1ccc1ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-naphtho[1,2-b]furan-3-yl ethanol (1.06 g, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hrs and quenched with water. It was extracted with chloroform, washed well with 5% Na2S2O3 solution and the organic layer was dried over anhydrous MgSO4. It was filtered and concentrated. The residue was purified by silica-gel column chromatography by eluting it with 30% ethyl acetate:hexane. The product, namely 3-(2-iodo-ethyl)-naphtho[1,2-b]furan, was obtained as brown liquid. Yield: 1.4 g (87%); 322 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.N1C=CN=C1.[C:18]([Si:22](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19].O>CN(C)C=O>[Si:22]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(OCCO)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OCCOc1ccc(C=O)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-hydroxyethoxy)benzaldehyde (0.50 g) and imidazole (0.41 g) in N,N-dimethylformamide (6 mL) was added tert-butylchlorodiphenylsilane (0.94 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethylether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give 4-[2-(tert-butyl-diphenylsilyloxy)ethoxy]benzaldehyde (1.21 g). The title compound was prepared in a similar manner to that described in Reference Example 45 using this material instead of 4-isobutylbenzaldehyde.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:36]=[CH:35][C:23]([O:24][CH2:25][C:26]([O:31][C:32](=[O:34])[CH3:33])([CH2:29][CH3:30])[CH2:27][CH3:28])=[C:22]([CH3:37])[CH:21]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:38])C1C=CC=CC=1>[Pd].CCO>[CH2:27]([C:26]([O:31][C:32](=[O:34])[CH3:33])([CH2:25][O:24][C:23]1[CH:35]=[CH:36][C:20]([C:15]([CH2:18][CH3:19])([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH3:38])[CH:11]=2)[CH2:16][CH3:17])=[CH:21][C:22]=1[CH3:37])[CH2:29][CH3:30])[CH3:28]
Reactant: CCC(CC)(COc1ccc(C(CC)(CC)c2ccc(OCc3ccccc3)c(C)c2)cc1C)OC(C)=O
Agent: [Pd]
Solvent: CCO
Product: CCC(CC)(COc1ccc(C(CC)(CC)c2ccc(O)c(C)c2)cc1C)OC(C)=O
Yield: 92.6 %

Procedure:
Acetic acid 1-{4-[1-(4-benzyloxy-3-methyl-phenyl)-1-ethyl-propyl]-2-methyl-phenoxymethyl}-1-ethyl-propyl ester (0.14 g g, 0.27 mmol), EtOH (20 ml), and 10% Pd/C (25 mg) is hydrogenated at atmospheric pressure for 18 h. The reaction is filtered through diatomaceous earth with EtOAc wash. The filtrate is concentrated to give the title compound (0.11 g, 0.25 mmol, 94%).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[C:7]([CH2:16][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)=[O:5].[C:36](=O)([O-])[O-].[Na+].[Na+].C=O>C(Cl)(Cl)Cl.O>[CH:16]([C:7]1[N:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:6]=1[C:4]([O:3][CH3:2])=[O:5])=[CH2:36]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(C(F)(F)F)nc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C=O
Agent: [Br-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=Cc1nc(C(F)(F)F)ccc1C(=O)OC
Reaction time: 1.5 h

Procedure:
5.7 g (10 mmol) of (3-methoxycarbonyl-6-trifluoromethylpyridine-2-ylmethyl)triphenylphosphonium bromide are dissolved at room temperature in a 2-phase system of 25 ml of chloroform and 2.1 g (20 mmol) of sodium carbonate and reacted, in 10 ml of water, with a 35% aqueous solution of 1.7 g (20 mmol) of formaldehyde. After 1.5 hours, the organic phase is separated off and filtered through silica gel. Methyl 2-vinyl-6-trifluoromethylnicotinate is obtained as an oil, 1H-NMR (CDCl3): 8.31, d, CH, 7.10, dd, CH, 7.09, d, CH, 6.68, dd, CH, 5.68, dd, CH, 3.97 ppm, s, OCH3.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5].[F:13][C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:15]=1[Mg]Br>C1COCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[F:13][CH:14]1[CH:15]([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[O:5])[CH:16]=[CH:17][CH:18]=[C:19]1[C:20]([F:21])([F:22])[F:23]
Reactant: Fc1c([Mg]Br)cccc1C(F)(F)F
Reactant: CON(C)C(=O)c1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccccn1)C1C=CC=C(C(F)(F)F)C1F

Procedure:
Then a solution of pyridine-2-carboxylic acid methoxy-methyl-amide (1.5 g, 9 mmoles) was allowed to react with 2-flouro-3-trifluoromethylphenylmagnesium bromide (2.72 g, 10 mmoles) in THF (30 mL) at 60° C. overnight. The reaction mixture was cooled and diluted with ethyl acetate and ammonium chloride. The organic portion was washed with brine and dried over MgSO4 and stripped to afford a crude product, which was purified by chromatography with CH2Cl2 to give (6-fluoro-5-trifluoromethyl-cyclohexa-2,4-dienyl)-pyridin-2-yl-methanone as a colorless liquid (1.6 gr., 65%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH:16]1[CH2:20][CH:19]([CH3:21])[C:18](=[O:22])[O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].BrC[CH:26]=[C:27]([CH3:29])[CH3:28]>>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([C@@H:16]1[CH2:20][C@@H:19]([CH2:21][CH:26]=[C:27]([CH3:29])[CH3:28])[C:18](=[O:22])[O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC1CC([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)OC1=O
Reactant: CC(C)=CCBr
Product: CC(C)=CC[C@@H]1C[C@@H]([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)OC1=O
Yield: 84 %

Procedure:
Prepared analogously to the synthesis of [(S)-1-(4-methyl-5-oxo-tetrahydrofuran-2-yl)-2-phenylethyl]-carbamic acid t-butyl ester in Journal of Organic Chemistry (1986) 51(21), 3921, using 4-bromo-2-methyl-2-butene in place of methyl iodide, to afford D5 in 84% yield.
Reaction SMILES: COC(=O)CC1C(C)=NN([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)C=1C.[C:23]([O:27][C:28](=[O:42])[CH2:29][C:30]1[C:31]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[N:32][NH:33][C:34]=1[CH3:35])([CH3:26])([CH3:25])[CH3:24].C(OC(=O)CC1C(CC)=NNC=1CC)(C)(C)C.C1(C(=O)CC(=O)C)CCCCC1.COC(=O)CC1C(C)=NNC=1C>>[C:23]([O:27][C:28](=[O:42])[CH2:29][C:30]1[C:31]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[N:32][N:33]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:34]=1[CH3:35])([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1[nH]nc(C2CCCCC2)c1CC(=O)OC(C)(C)C
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc([N+](=O)[O-])cc2)c1C
Agent: CC(=O)CC(=O)C1CCCCC1
Agent: CCc1n[nH]c(CC)c1CC(=O)OC(C)(C)C
Agent: COC(=O)Cc1c(C)n[nH]c1C
Product: Cc1c(CC(=O)OC(C)(C)C)c(C2CCCCC2)nn1Cc1ccc([N+](=O)[O-])cc1

Procedure:
[3-Cyclohexyl-5-methyl-1-(4-nitro-benzyl)-1H-pyrazol-4-yl]-acetic acid tert-butyl ester was prepared according to the preparation of intermediate 1.1.2, using in the alkylation reaction (3-cyclohexyl-5-methyl-1H-pyrazol-4-yl)-acetic acid tert-butyl ester (preparation according to the preparation of (3,5-diethyl-1H-pyrazol-4-yl)-acetic acid tert-butyl ester, WO2007/141267, employing 1-cyclohexyl-butane-1,3-dione instead of heptane-3,5-dione) instead of (3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10].C([Li])CCC.[NH2:18][C:19]1[N:30]=[CH:29][C:28]([Br:31])=[CH:27][C:20]=1[C:21](N(OC)C)=[O:22]>C1COCC1>[NH2:18][C:19]1[C:20]([C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][C:9]([F:12])([F:11])[F:10])=[O:22])=[CH:27][C:28]([Br:31])=[CH:29][N:30]=1
Reactant: CON(C)C(=O)c1cc(Br)cnc1N
Reactant: FC(F)(F)Oc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1ncc(Br)cc1C(=O)c1ccccc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 51.7 %

Procedure:
To a flame-dried 100 ml round bottomed flask was added 1-bromo-2-(trifluoromethoxy)benzene (2.39 g, 9.9 mmol). The flask was fitted with a rubber septum, purged with nitrogen then charged with anhydrous THF (20 ml). The solution was cooled to −78° C. for 10 min, then a 2.5 M solution of n-butyl lithium in hexanes (3.9 ml, 9.8 mmol) was added dropwise over 3 minutes. The resulting solution was stirred at −78° C. for 40 minutes under nitrogen, then a solution of 739 mg (2.84 mmol) of 2-amino-5-bromo-N-methoxy-N-methyl-nicotinamide in 5 ml of THF was added dropwise over 3 minutes. The resulting red solution was allowed to warm to room temperature over 5 hours, then the reaction was quenched by addition of 10 ml of a saturated aqueous solution of ammonium chloride. Ethyl acetate (50 ml) was added, and the layers were separated. The aqueous fraction was extracted three times with ethyl acetate, and the combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes gave 530 mg (52%) of (2-amino-5-bromo-pyridin-3-yl)-(2-trifluoromethoxy-phenyl)-methanone as a yellow-orange solid. 1H-NMR (CDCl3) δ=8.29 (d, 1H), 7.60 (m, 2H,), 7.45 (t, 1H), 7.42 (m, 3H), 1.79 (br. s, 2H); MS m/z: 361 [MH]+.
Reaction SMILES: [BH4-].[Na+].CO.[C:5]([C:9]1[S:13][C:12]([N:14]2[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([CH3:21])[C:15]2=[O:22])=[N:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6]>C(O)(=O)C>[C:5]([C:9]1[S:13][C:12]([N:14]2[C:15](=[O:22])[C:16]([CH3:21])=[C:17]([CH3:20])[CH:18]2[OH:19])=[N:11][N:10]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC1=C(C)C(=O)N(c2nnc(C(C)(C)C)s2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1=C(C)C(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reaction time: 3 h
Yield: 77.3 %

Procedure:
Sodium borohydride (0.07 g) was added at room temperature to a methanol solution (100 ml) of N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-2,3-dimethylmaleinimide (0.95 g), and the mixture was stirred for 3 hours. After the reaction, glacial acetic acid (0.5 ml) was added and the solvent was evaporated under reduced pressure. Water (30 ml) was added to the residue, and potassium carbonate was added to make the mixture alkaline. It was extracted with dichloromethane (50 ml×2). The extractants were dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude crystals were washed with a small amount of diethyl ether to give the desired N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3,4-dimethyl-2-hydroxy-5-oxo-2,5-dihydropyrrole (0.74 g), mp. 179°-182° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][N:5]1[C:10](=[O:11])[CH:9]=[CH:8][C:7]([C:12](=O)[CH2:13][C@H:14]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:6]1.C(=O)([O-])O.[Na+]>>[OH:3]/[N:2]=[C:12](/[C:7]1[CH:8]=[CH:9][C:10](=[O:11])[N:5]([CH3:4])[CH:6]=1)\[CH2:13][C@H:14]([C:22]1[CH:23]=[CH:24][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(CC(=O)O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@H](C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(CC(=O)O)cc1

Procedure:
In analogy to example 1, step 2, from and (R)-2-(4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)phenyl)acetic acid hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as an off-white solid, MS (ESI+): m/z=405.4 [M+H]+.