Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[CH2:13]([C:15]1[C:16]([C:21](O)=[O:22])=[N:17][CH:18]=[N:19][CH:20]=1)[CH3:14].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[CH2:13]([C:15]1[C:16]([C:21]([NH:1][C:2]2[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=2[OH:12])=[O:22])=[N:17][CH:18]=[N:19][CH:20]=1)[CH3:14]
Reactant: CCc1cncnc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)ccc1O
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: CCc1cncnc1C(=O)Nc1cc(C(F)(F)F)ccc1O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 71.7 %

Procedure:
A mixture of 2-amino-4-trifluoromethyl-phenol (0.27 g), 5-ethyl-pyrimidine-4-carboxylic acid (0.27 g), WSC (0.25 g), and pyridine (5 ml) was stirred at 80° C. for 1 hour, at 100 for 1.5 hours, and at 115° C. for 0.5 hours. After standing to cool the reaction mixture to room temperature, to the reaction mixture, water was added, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.34 g of 5-ethyl-N-(2-hydroxy-5-trifluoromethyl-phenyl)-pyrimidine-4-carboxamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:16]2[O:18][CH2:17]2)=[N+:13]([O-:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:16]([OH:18])[CH2:17][NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[N+:13]([O-:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)N
Reactant: [O-][n+]1cc(OCc2ccccc2)ccc1C1CO1
Solvent: CO
Product: CC(C)(C)NCC(O)c1ccc(OCc2ccccc2)c[n+]1[O-]

Procedure:
To 0.50 g. (0.0042 mole) of [5-benzyloxy-2-(1,2-epoxyethyl) pyridine N-oxide] in 20 ml. of methanol was added 0.5 ml. tert-butylamine and the resulting mixture heated to the reflux temperature for 4 hours. Solvent and excess tert-butylamine were removed in vacuo to give 280 mg. (43%) of the desired product after recrystallization from ether/ethyl acetate; m.p. 148°-150° (dec.). Mass spec (70 eV) m/e 300 (M-16), m/e 243 [M-H2NC(CH3)3); NMR (DMSO d6) delta 7.90 (d, 1H, H6), 7.30 (m, 6H, benzyl C6H5 and H4), 7.00 (m, 1H, H3), 5.07 (m, 3H, φCH2 and ##STR15## 4.33 (m, 2H, ##STR16## and 1.13 [s, 9H, C(CH3)3 ]; ir (KBr) 1171 (N+ -O-).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23](O)=[O:24])=[N:21][CH:22]=1>>[CH3:14][N:13]([CH3:15])[CH:10]1[CH2:11][CH2:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:23]([C:20]3[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][N:21]=3)=[O:24])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Product: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(Cl)cn3)cc2)C1

Procedure:
[1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine was reacted with 5-chloropyridine-2-carboxylic acid by method E. This resulted in the product with the molecular weight of 344.85 (C18H21CIN4O); MS (ESI): 345 (M+H+).
Reaction SMILES: [C:1]([O:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(OC(C)(C)C)=O.OC1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.CN(C)C=O.CCOC(C)=O>[C:9](=[O:10])([O:8][C:1]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[CH:19][CH:18]=1)[O:11][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: Oc1ccc2cccnc2c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Oc1ccc2cccnc2c1
Reaction time: 18 h
Yield: 96.7 %

Procedure:
Di-tert-butyl dicarbonate (7.40 g, 33.92 mmol) and 4-(dimethylamino)pyridine (222 mg, 1.81 mmol) were added in sequence to 7-hydroxyquinoline (2.00 g, 13.75 mmol) in anhydrous N,N-dimethylformamide (20.0 mL) at room temperature. After 18 hours, the reaction was diluted with EtOAc (250 mL). The organic layer was washed with 1.0 M NaOH (250 mL), water (3×250 mL), saturated aqueous NaCl solution (250 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 1:1 Hexanes:EtOAc) to give 28 as a colorless amorphous solid (3.26 g, 97%): 1H NMR (CDCl3, 500 MHz) δ 8.93 (dd, J=4.2, 1.7 Hz, 1H), 8.17 (bd, J=8.4 Hz, 1H), 7.90 (d, J=2.2 Hz, 1H), 7.84 (d, J=8.9 Hz, 1H), 7.43 (dd, J=8.8, 2.3 Hz, 1H), 7.40 (dd, J=8.3, 4.3 Hz, 1H), 1.60 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ 151.7, 151.7, 148.9, 135.9, 129.0, 126.3, 122.0, 121.0, 120.2, 84.2, 27.8 (3C); IR (film) νmax 1759, 1277, 1240, 1142, 768, 750 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C14H15NO3, 246.1130. found, 246.1113.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:41])=[C:5]([C:32]([O:39]C)=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[CH2:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[O:12])=[C:9]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:8]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:36][O:35][C:34]1[C:3](=[O:2])[C:4]([CH3:41])=[C:5]([CH2:6][C:7]2[CH:25]=[CH:24][C:10]([C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=3)=[O:12])=[C:9]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:8]=2)[C:32](=[O:39])[C:33]=1[O:37][CH3:38]
Reactant: COc1c(C)c(Cc2ccc(C(=O)Nc3ccc(C(F)(F)F)cc3)c(-c3cccnc3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)Nc3ccc(C(F)(F)F)cc3)c(-c3cccnc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.2 %

Procedure:
N-[4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoyl]-4-trifluoromethylaniline (55 mg, 0.0971 mmol) was dissolved in a mixed solvent of acetonitrile (3 ml) and water (1 ml), then CAN (157 mg, 0.2918 mmol) was added thereto at room temperature and the mixture was stirred for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (10 mg, 0.0186 mmol, 19%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][C:9]=1[CH3:20])=[O:6].C([O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30])C.COCCOC.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:25][O:24][C:23]1[CH:22]=[CH:21][C:4]([C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:10][C:9]=2[CH3:20])=[CH:3][C:2]=1[C:34]1[CH:35]=[CH:36][C:31]([C:29]([OH:30])=[O:28])=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2C)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2C)cc1-c1ccc(C(=O)O)cc1

Procedure:
A mixture of 3-Bromo-4-methoxy-N-(2-methyl-4-morpholin-4-yl-phenyl)-benzamide (432 mg) and 4-(ethoxycarbonyl)-phenyl boronic acid (311 mg) in 2:1 DME:water (15 ml) containing cesium carbonate (697 mg) and tetrakis(triphenylphosphine)palladium0 (127 mg) was heated to reflux for 18 h.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br.[Br:21][C:22]1[CH:23]=[C:24]([CH2:29]Br)[C:25]([NH2:28])=[N:26][CH:27]=1.O>CN(C=O)C>[NH2:28][C:25]1[C:24]([CH2:29][N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:23][C:22]([Br:21])=[CH:27][N:26]=1
Reactant: CCOC(=O)CNc1ccccc1
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(Cc1cc(Br)cnc1N)c1ccccc1
Temperature: 40 °C
Reaction time: 12 h
Yield: 33.9 %

Procedure:
To a solution of phenyl glycine ethyl ester (4.94 g, 27.6 mmol) and K2CO3 (11.42 g, 82.7 mmol) in anhydrous DMF (300 mL) under argon was added 5-bromo-3-(bromomethyl)pyridin-2-amine hydrobromide (9.52 g, 27.6 mmol). The mixture was stirred for 12 h at 40° C. Water (500 mL) was added and the mixture was extracted with ethyl acetate (3×500 mL). Combined organic layers were washed with water (2×400 mL) and brine (400 mL), dried over MgSO4, filtered and concentrated to a brown oil. Purification by column chromatography (silica gel, gradient elution of 30% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) gave ethyl 2-(((2-amino-5-bromopyridin-3-yl)methyl)(phenyl)amino)acetate (3.41 g, 34%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 7.89-7.88 (m, 1H), 7.36-7.35 (m, 1H), 7.17-7.11 (m, 2H), 6.68-6.64 (m, 1H), 6.47-6.44 (m, 2H), 6.09 (s, 2H), 4.30-4.29 (m, 4H), 4.12 (q, J=6.9 Hz, 2H), 1.19 (t, J=6.9 Hz, 3H).
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:19][C:18]([NH2:20])=[N:17][N:16]=3)=[CH:11][CH:10]=2)[CH:3]=1.[Cl:21][C:22]1[C:23]([F:35])=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](Cl)=[O:26]>N1C=CC=CC=1.CO>[Cl:21][C:22]1[C:23]([F:35])=[C:24]([CH:28]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:30]=1)[C:25]([NH:20][C:18]1[O:19][C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)=[CH:14][CH:13]=2)=[N:16][N:17]=1)=[O:26]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(Cl)c1F
Reactant: Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1
Agent: Br
Solvent: CO
Solvent: c1ccncc1
Product: O=C(Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1)c1cc(C(F)(F)F)cc(Cl)c1F
Reaction time: 18 h
Yield: 34.8 %

Procedure:
5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. Neat 3-chloro-2-fluoro-5-trifluoromethylbenzoyl chloride (250 uL) was added directly into the solution. The reaction mixture formed a red solution with a small amount of white precipitate. It was left to stir for 18 hours. Then it was diluted with ca. 1 mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (83.4 mg). Yield 34.8%.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7](=O)[CH2:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.[NH:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH2:17]>CO>[Br:1][C:2]1[O:6][C:5]([C:7]2[N:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:17]=[C:9]([C:10]([F:13])([F:12])[F:11])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Br)o1
Reactant: CCOC(=O)CNN
Solvent: CO
Product: CCOC(=O)Cn1nc(C(F)(F)F)cc1-c1ccc(Br)o1
Temperature: 0 °C
Yield: 23.3 %

Procedure:
A mixture of compound 44 (4 g, 14.0 mmol), ethyl 2-hydrazinylacetate (2.37 g, 15.0 mmol) and methanol (60 mL) was heated for 1.5 h. The reaction mixture was cooled to 0° C. and solvent was removed under reduced pressure. Water (100 mL) was added and the reaction mixture extracted with ethyl acetate (50 mL×3). Combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by column chromatography using 10% ethyl acetate in n-hexane as an eluent to afford the separated isomer 45 (1.2 g, 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)[NH2:5].C(O)C.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([N:36]=[C:37]=[S:38])=[O:35]>C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([NH:36][C:37]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:2]([Cl:1])[CH:3]=1)=[S:38])=[O:35]
Reactant: O=C(N=C=S)c1ccccc1Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3Cl)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Cl)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 2-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (79 mg, yield 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[C:13]([F:14])([F:15])[F:16]
Reactant: CC(C)C(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)=Cc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
1.50 g (5.9 mmol) 1-(4-chloro-3-trifluoromethyl-phenyl)-2-methyl-propan-1-ol and 0.50 g (2.6 mmol) p-toluenesulphonic acid monohydrate in 50 mL toluene are refluxed for 3 hours using the water separator. After working up analogously to Example 1b) a brown oil is obtained. Yield: 1.4 g; mass spectrometry: [M]+=234/6.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1-c1nc2ccccc2s1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(Cl)cc1-c1nc2ccccc2s1
Temperature: 70 °C

Procedure:
A mixture of 0.65 g (0.00223 mol) of 2-(2′-nitro-5′-chlorophenyl)benzothiazole OF31A and 2.52 g (0.01118 mol) of SnCl2.2H2O in 100 ml of ethanol was heated at 70° C. for 2 hours. A verification step using thin layer chromatography showed that the mixture no longer contained any starting reactant.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])=O.[Cl-].[OH:15][NH3+:16].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])=[N:16][OH:15]
Reactant: Cc1ccccc1C(=O)C(F)(F)F
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C(=NO)C(F)(F)F
Temperature: 0 °C
Yield: 66.4 %

Procedure:
3.7 g (0.020 mol) of 2,2,2-trifluoro-1-(2-methylphenyl)-ethanone are dissolved in 20 ml of ethanol at 80° C. To the solution are added dropwise 1.4 g (0.020 mol) of hydroxylammonium chloride and 2.7 g (0.033 mol) of sodium acetate dissolved in 10 ml of water. The reaction mixture is refluxed for 5 hours, poured into ice water, and extracted with ethyl acetate. The organic phase is washed with water and brine, dried over MgSO4, and concentrated, yielding 2.7 g of 2,2,2-trifluoro-1-(2-methylphenyl)-ethanone oxime as a white solid. The crude product is used in the next reaction step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:9]2[C:10]([CH:15]=[CH2:16])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.[CH3:18][C:19]1[C:24]([CH2:25]O)=[CH:23][CH:22]=[C:21]([CH3:27])[N:20]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:9]2[C:10]([CH:15]=[CH2:16])=[CH:11][C:12]([O:14][CH2:25][C:24]3[C:19]([CH3:18])=[N:20][C:21]([CH3:27])=[CH:22][CH:23]=3)=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: C=Cc1cc(O)cc2scc(CC(=O)OC)c12
Reactant: Cc1ccc(CO)c(C)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: C=Cc1cc(OCc2ccc(C)nc2C)cc2scc(CC(=O)OC)c12
Yield: 88.4 %

Procedure:
To a mixture of methyl(6-hydroxy-4-vinyl-1-benzothiophen-3-yl)acetate (351 mg) and THF (dry) (3 mL) were added (2,6-dimethylpyridin-3-yl)methanol (233 mg), ADDP (535 mg) and tri-n-butylphosphine (0.523 mL) at room temperature. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (459 mg).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[C:41]([O:48][CH3:49])=[N:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[C:41]([O:48][CH3:49])=[N:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: COc1ccc(CCl)c(OC)n1
Agent: Cl
Product: COc1ccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)c(OC)n1
Yield: 72.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 3-chloromethyl-2,6-dimethoxypyridine (0.56 g) as starting materials, 5-benzyloxy-N-({1-[(2,6-dimethoxypyridin-3-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.69 g) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[CH2:10][C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N=C=N.[NH2:18][CH2:19][C:20]1[C:21](=[N:26][NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[C:22]([NH2:25])=[N:23][N:24]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:14])[CH2:10][C:11]([NH:18][CH2:19][C:20]1[C:21](=[N:26][NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[C:22]([NH2:25])=[N:23][N:24]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1=NN=C(N)C1=NNc1cccc(F)c1
Reactant: O=C(O)CC(=O)OCc1ccccc1
Agent: N=C=N
Solvent: CN(C)C=O
Product: NC1=NN=C(CNC(=O)CC(=O)OCc2ccccc2)C1=NNc1cccc(F)c1
Reaction time: 16 h

Procedure:
A solution of malonic acid monobenzyl ester (1.5 eq, 0.26 mmol) in anhydrous DMF (3 mL) was added to a 10 mL reaction vessel containing PS-carbodiimide (2 eq, 380 mg). The reaction mixture was stirred at ambient temperature under argon for 10 minutes before a solution of 5-aminomethyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (40 mg, 0.17 mmol) in anhydrous DMF (3 mL) was added. The mixture was further stirred for approximately 16 hours before it was filtered, washed with DMF (3×3 mL) and concentrated under reduced pressure. The title compound was obtained in a yield of 38 mg (55%) as a yellow powder with no further purification. MS (m/z, ES+): 411 (M+1, 100%); 1H NMR (ppm, 300 MHz, DMSO-d6) δ 11.40 (brs, 1H, N—H pyrazole), 8.45 (s, 1H, N—H amide), 7.40-7.60 (m, 3H, Ar—H), 7.28-7.35 (m, 5H, Ar—H), 7.05-7.15 (t, 1H, F—Ar—H), 5.15 (s, 2H, benzyl CH2), 4.47 (s, 1H, CHaHb amide), 4.43 (s, 1H, CHaHb amide), 3.35 (2H, CH2 pyrazole-overlap with H2O).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([CH:11]=[O:12])[N:8]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:7]=1.[OH:18]OS([O-])=O.[K+].O>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([OH:18])=[O:12])[N:8]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:6]=2[N:7]=1
Reactant: O=S([O-])OO
Reactant: O=Cc1cc2cnc(Cl)nc2n1C1CCCC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reaction time: 6 h
Yield: 92 %

Procedure:
A mixture of 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (2.69 g, 11 mmol) in DMF is added oxone (7.2 g, 12 mmol) and stirred for 6 h. After the reaction is complete, water is added and a yellow solid is precipitated to give 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (2.69 g, 85%). MS (ESI) m/z 266.4 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][NH:12][CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:26][C:27]1[N:32]=[N:31][CH:30]=[C:29]([C:33](O)=[O:34])[CH:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:33]([C:29]3[CH:28]=[C:27]([CH3:26])[N:32]=[N:31][CH:30]=3)=[O:34])[CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C(=O)Cc1ccc(F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(C(=O)O)cnn1
Product: Cc1cc(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(N(C)C(=O)Cc3ccc(F)cc3)C2)cnn1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(6-methyl-pyridazine-4-carbonyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared from N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide using 6-methyl-pyridazine-4-carboxylic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light yellow oil. MS m/e: 501.1 [M]+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH3:24])[C:17]=2[CH3:25])[NH:12]1)=[O:10])[CH3:7].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:6]([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH3:24])[C:17]=2[CH3:25])[N:12]1[C:3](=[O:4])[CH2:2][Cl:1])=[O:10])[CH3:7]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2ccc(OC)c(C)c2C)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@@H](c2ccc(OC)c(C)c2C)N1C(=O)CCl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Chloroacetyl chloride (1.7 mL, 21.5 mmol) To a solution of cis-5-(4-methoxy-2,3-dimethylphenyl)pyrrolidine-2-carboxylic acid ethyl ester (16.56 mmol) and Et3N (3.5 mL, 24.8 mmol) in CH2Cl2 (80 mL) at 0° C. The reaction mixture is stirred at 0° C. for 15 min and then at room temperature for 45 min. The mixture then poured into half-saturated aq. NaHCO3 (100 mL) and extracted with EtOAc. The extract is further washed with water (1×50 mL) and brine (1×50 mL). The aqueous washes are reextracted once with EtOAc, and the combined extracts are dried over Na2SO4, and concentrated. The crude material is used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): 7.90 (d, J=8.6 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 5.30 (dd, J=7.6, 3.6 Hz, 1H), 4.53 (t, J=8.0 Hz, 1H), 4.37-4.21 (m, 2H), 3.81 (s, 3H), 3.77, 3.65 (ABq, J=13.2 Hz, 2H), 2.50-2.41 (m, 1H), 2.26 (s, 3H), 2.24-2.14 (m, 1H), 2.19 (s, 3H), 2.09-2.00 (m, 1H), 1.96-1.89 (m, 1H), 1.35 (t, J=7.2 Hz, 3H). Electrospray MS: m/z 354 [M+1].