Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][C:4]=1[OH:16])=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[O:16]1[C:4]2[CH:5]=[C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:14]=[CH:15][C:3]=2[CH:1]=[C:24]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(C(=O)OC(C)(C)C)cc2o1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of tert-butyl 4-formyl-3-hydroxybenzoate (1.2 g, 5.40 mmol) and potassium carbonate (1726 mg, 12.4 mmol) in DMF (17 ml) was admixed dropwise with ethyl bromoacetate (0.56 ml, 5.0 mmol) and stirred at 80° C., for 6 h. Then ethyl bromoacetate (0.28 ml, 2.5 mmol) was added again and the mixture was stirred at 80° C. overnight. After cooling to room temperature, the reaction mixture was added to ice-water and extracted with ethyl acetate. The organic phases were dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:20]1(C)C=CC=CC=1.[Si](C=[N+]=[N-])(C)(C)C>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:12])[C:9]([O:11][CH3:20])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OC(=O)C(C)(C(=O)O)c1cccc(Br)c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C(C)(C(=O)OC(C)(C)C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 2-(3-bromophenyl)-2-(tert-butoxycarbonyl)propanoic acid (11.3 g, 32.8 mmol) in MeOH (35 mL) was added toluene (175 mL) followed by TMSCHN2 (2M in hexane, 44 mL, 98 mmol, 3 eq). The mixture was stirred at RT for 16 h. Solvents were evaporated and the residue was chromatographed on silica by eluting with EtOAc/hexanes to give 11.8 g (100%) of methyl 2-(3-bromophenyl)-2-(tert-butoxycarbonyl)propanoate as a yellow oil. 1H NMR (CDCl3) 7.59 (t, J=1.8 Hz, 1H), 7.36-7.44 (m, 2H), 7.21 (t, J=8.0 Hz, 1H), 5.92 (s, 1H), 3.70 (s, 3H), 1.97 (s, 3H), 1.36 (br s, 9H).
Reaction SMILES: C(O[C:4]([C:6](=[CH:12][NH:13][C:14]1[C:18]([CH3:19])=[CH:17][S:16][CH:15]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:19][C:18]1[C:14]2[NH:13][CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4](=[O:5])[C:15]=2[S:16][CH:17]=1
Reactant: CCOC(=O)C(=CNc1cscc1C)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2c(C)csc2c1=O

Procedure:
Ethyl 2-ethoxycarbonyl-3-(4-methyl-3-thienylamino)prop-2-enoate (10.4 g, 0.036 mol) was added to a refluxing solution of freshly distilled diphenylether (110 ml). The reaction mixture was refluxed for 30 minutes, cooled, petroleum ether (b.p. 40°-60°, 100 ml) added and the mixture stirred. The crystalline solid was collected by filtration, washed with petroleum ether (b.p. 40°-60°) and dried to give 3-methyl-6-ethoxycarbonylthieno[3,2-b]pyridin-7(4H)-one, 7.23 g, m.p. 238-242°.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1>C(N)CN.C(O)(C)C>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:3][CH2:4][CH2:5][NH2:6]
Reactant: Clc1nc2ccccc2[nH]1
Solvent: NCCN
Solvent: CC(C)O
Product: NCCNc1nc2ccccc2[nH]1
Yield: 37.4 %

Procedure:
A mixture of 2-chloro-1H-benzoimidazole (1 g) in 4 mL of ethane-1,2-diamine was heated to 100 C for several hours until complete by HPLC. The reaction was allowed to cool and diluted with a mixture of chlororform and isopropanol (3:1). The organic phase was washed with water then dried and concentrated to give 216 mg of product as a solid which was used in the next step without further purification. MS(ES): m/e (El*) 177.1 [M+H]
Reaction SMILES: C(OC([NH:8][CH:9]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15]2[C:24]([F:25])=[C:23]3[C:18]([C:19](=[O:32])[C:20]([C:29]([OH:31])=[O:30])=[CH:21][N:22]3[CH:26]3[CH2:28][CH2:27]3)=[CH:17][C:16]=2[F:33])[CH2:10]1)=O)(C)(C)C.[ClH:34]>CO>[ClH:34].[NH2:8][CH:9]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15]2[C:24]([F:25])=[C:23]3[C:18]([C:19](=[O:32])[C:20]([C:29]([OH:31])=[O:30])=[CH:21][N:22]3[CH:26]3[CH2:28][CH2:27]3)=[CH:17][C:16]=2[F:33])[CH2:10]1
Reactant: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7-(3-t-Butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.27 g) was dissolved in a mixture of methanol (5 ml) and concentrated hydrochloric acid (5 ml) and stirred at room temperature for 30 minutes. After the reacting mixture was concentrated under reduced pressure, the resulting residue was dissolved in ethanol (10 ml) and crystallized with cooling. The resulting precipitate was recrystallized from methanol to give the title compound (0.14 g) as pale yellow powder, mp 272°-274° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1([O:27][CH2:28][CH3:29])[CH2:9][N:8]([C:10]([C:12]2[N:13]=[C:14]([CH3:24])[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:11])[CH:7](CO)[CH2:6][CH2:5]1)[CH3:2].[CH3:30][CH2:31][OH:32]>>[CH2:1]([O:3][C:4]1([O:27][CH2:28][CH3:29])[CH2:9][N:8]([C:10]([C:12]2[N:13]=[C:14]([CH3:24])[S:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[O:11])[CH:7]([CH2:7][N:8]2[C:31](=[O:32])[C:30]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:10]2=[O:11])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCO
Reactant: CCOC1(OCC)CCC(CO)N(C(=O)c2nc(C)sc2-c2ccc(F)cc2)C1
Product: CCOC1(OCC)CCC(CN2C(=O)c3ccccc3C2=O)N(C(=O)c2nc(C)sc2-c2ccc(F)cc2)C1

Procedure:
The title compound was prepared according to general procedure I using rac-(5,5-diethoxy-2-(hydroxymethyl)piperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone. 1H NMR (CDCl3, 400 MHz) δ 7.73-7.71 (m, 2H), 7.63-7.62 (m, 2H), 7.38-7.35 (m, 2H), 7.21-6.91 (m, 2H), 4.86-4.81 (m, 1H), 4.10-4.03 (m, 2H), 3.10 (d, 1H), 2.27 (s, 3H), 1.89-1.83 (m, 1H), 1.70-1.61 (m, 1H), 1.32-1.28 (m, 2H), 1.19-1.03 (m, 6H). MS (ESI) 506 (M+H): desired product lost EtOH in LC/MS.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:23])[N:4]([C:19]([CH3:22])([CH3:21])[CH3:20])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=1.[CH2:24]([NH2:27])[CH:25]=[CH2:26]>>[Cl:1][C:2]1[C:3](=[O:23])[N:4]([C:19]([CH3:20])([CH3:22])[CH3:21])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([NH:27][CH2:24][CH:25]=[CH2:26])=[O:18])=[CH:14][CH:15]=1
Reactant: CC(C)(C)n1ncc(NCc2ccc(C(=O)O)cc2)c(Cl)c1=O
Reactant: C=CCN
Product: C=CCNC(=O)c1ccc(CNc2cnn(C(C)(C)C)c(=O)c2Cl)cc1

Procedure:
The compounds as identified in Table 13 were prepared in the synthetic manner and after-treatment similar to those in Example 6 except that the carboxylic acids with R1, R2, R3, Y1, Y2 and Y3 as identified in Table 13 were used instead of the starting 4-chloro-5-(4-carboxybenzylamino)-2-t-butyl-3(2H)pyridazinone used in Example 6, and the amines with Y1, Y2 and Y3 as identified in Table 13 were used instead of the starting allylamine. In the NMR data, only the characteristic absorptions are given in Table 13.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=2[NH2:20])=[N:6][CH:7]=1.[CH3:22][S:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[C:26]([O:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=2[NH:20][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([S:23][CH3:22])=[CH:25][C:26]=2[O:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])=[N:6][CH:7]=1
Reactant: CSc1ccc(C(=O)O)c(OCCCNC(=O)OC(C)(C)C)c1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(N)c1
Product: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NC(=O)c2ccc(SC)cc2OCCCNC(=O)OC(C)(C)C)c1
Yield: 50 %

Procedure:
Using a procedure analogous to Example 4-E, N-(5-chloropyridin-2-yl)-4-methoxycarbonyl-2-aminobenzamide and 4-(methylthio)-2-(3-(t-butoxycarbonylamino)-propoxy)benzoic acid gave the title compound as a white solid (12 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15]1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2ccccc2)cc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.6 %

Procedure:
A suspension of 4-chlorobiphenyl (9.43 g, 0.0500 mol), succinic anhydride (5.50 g, 0.0550 mol), and anhydrous aluminum chloride (14.8 g, 0.111 mol) in nitrobenzene (25 mL) at 5° C. under nitrogen was stirred 4 hours, then allowed to warm to room temperature. After 3 days, the mixture was heated at 95° C. to 120° C. for 1 hour, cooled to 5° C., and quenched with a mixture of ice (15 g), water (8 mL), and concentrated hydrochloric acid (HCl) solution (8 mL). Additional water (150 mL) was added, followed by ethyl acetate. The ethyl acetate layer was washed with 0.2 M HCl and extracted with saturated aqueous sodium bicarbonate solution. The bicarbonate layer was rotary evaporated briefly to remove residual ethyl acetate, then acidified by the dropwise addition of concentrated HCl solution. The resulting tan precipitate was filtered off, washed with 0.2 M HCl, and air dried. The solids were dissolved in hot toluene/acetone, and the solution was decolorized with activated carbon, and filtered hot through celite. The filtrate was concentrated, and the resulting crystals were filtered, washed, and dried in vacuo to give 1.96 g of 4-(4′-chloro-biphenyl-4-yl)-4-oxo-butyric acid as pale yellow plates; mp 184-185° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:22].C(OCC)(=O)C.CCCCCC>C(OCC)(=O)C>[ClH:22].[O:14]([C@H:11]1[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccccc2)CC1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@H](Oc2ccccc2)CC1
Reaction time: 1 h

Procedure:
The compound (1.80 g) obtained in Step 1 of this Reference Example was dissolved in ethyl acetate (18.0 mL). To the solution, 4 M hydrochloric acid/ethyl acetate (18.0 mL) was added at room temperature, and the mixture was stirred for 1 hour. To the reaction solution, hexane (18.0 mL) was added, and the precipitated solid was then collected by filtration and washed with a mixed solvent of hexane and ethyl acetate (50:50) to obtain the title compound (1.01 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12][CH:13]=[CH2:14])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:28](Cl)=[O:29]>C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:28]([N:10]([CH2:9][C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:12][CH:13]=[CH2:14])[CH3:11])=[O:29]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: C=CC[C@H](CNC)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@H](CN(C)C(=O)c1cc(Cl)cc(Cl)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
[(2S)-2-(4-Fluorophenyl)pent-4-en-1-yl]methylamine (see Bioorg. Med. Chem. Lett; 2001; 265-270; 150 mg, 0.78 mmol) was dissolved in CH2Cl2 (5 mL) and to the resultant solution were added DIPEA (221 mg, 1.71 mmol) and 3,5-dichlorobenzoyl chloride (178 mg, 0.85 mmol) in the given order. The mixture was stirred for 4 h at room temperature, diluted with CH2Cl2 (20 mL), and then washed with water (10 mL), aqueous KHSO4 (1M, 10 mL) and brine (10 mL). The organic solution was dried over Na2SO4. The solvent was removed by evaporation and there was obtained 214 mg (75%) of 3,5-dichloro-N-[(2S)-2-(4fluorophenyl)pent-4-en-1-yl]-N-methylbenzamide as an oil. 1H NMR (500 MHz, CDCl3): 2.2-2.4 (cm, 2H), 2.6 (s, 2H), 2.9-3.9 (cm, 4H), 4.9-5.1 (m, 2H), 5.5-5.8 (m, 1H), 6.7 (s, 1H), 6.9-7.4 (cm, 6H); LCMS: m/z 367 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2([CH3:16])[CH2:15][O:14][CH2:13]2)=[C:6]([CH:9]=1)[CH:7]=O.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1.N1CCCC1>CO>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21](/[C:22](=[CH:7]/[C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:11][C:12]3([CH3:16])[CH2:15][O:14][CH2:13]3)/[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC1(COc2ccc(Cl)cc2C=O)COC1
Solvent: CO
Solvent: C1CCNC1
Product: CC1(COc2ccc(Cl)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)COC1
Temperature: 70 °C
Yield: 77.5 %

Procedure:
To the mixture of 5-chloro-2-(3-methyl-oxetan-3-ylmethoxy)-benzaldehyde (2 g, 8.3 mmol) and 6-Chloro-1,3-dihydro-indol-2-one (1.27 g, 7.6 mmol) in methanol (20 mL) was added pyrrolidine (0.6 g, 9.1 mmol) dropwise. The mixture was then heated at 70° C. for 2 h. After cooled to room temperature, the mixture was filtered and resulting precipitate was collected, dried to give title compound as a yellow solid (2.3 g).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CO.[NH2:9][NH2:10].[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([O:19][CH3:20])=[CH:14][N:13]=1>C1(C)C=CC=CC=1>[Cl:11][C:12]1[N:17]=[C:16]([NH:9][NH2:10])[C:15]([O:19][CH3:20])=[CH:14][N:13]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cnc(Cl)nc1NN
Temperature: 42 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Anhydrous sodium carbonate (5.83 g, 0.055 mole), methanol (60 mL), and 35% aqueous hydrazine (11.0 g, 0.120 mole) were loaded into a 500 mL three necked flask equipped with a thermometer, magnetic stirrer, condenser, and addition funnel. A solution/partial slurry of 2,4-dichloro-5-methoxy-pyrimidine (17.91 g, 0.100 mole) in toluene (30 mL) was added dropwise over 39 min. During the addition, the reaction temperature rose from 15° C. to 39° C. and the solids dissolved to form a clear, pale yellow solution. The reaction mixture was heated to 42° C. for 4.1 h, after which the heat source was removed. Slow, dropwise addition of water (180 mL), caused the product to crystallize out of solution. The resulting slurry was stirred for 2 h at room temperature, then the product was recovered by filtration through Whatman #1 filter paper using a Buchner funnel and aspirator vacuum. After washing the filter cake with water, the product was dried overnight in vacuo at 40° C., to give 15.02 g of white 2-chloro-4-hydrazino-5-methoxypyrimidine (purity 96.2%, yield=82.8%): 1H NMR (300 MHz, DMSO-d6) 3.33 (s, 3H), 3.78 (s, 3H), 4.39 (br s, 2H), 7.59 (s, 1H), 8.73 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10](Br)=[CH:11][CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([S:16][CH3:17])[N:3]=1.[CH3:18][O-:19].[Na+]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([O:19][CH3:18])=[CH:11][CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([S:16][CH3:17])[N:3]=1
Reactant: CSc1nc(N)nc(-c2ccc(Br)o2)c1C#N
Reactant: C[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2nc(N)nc(SC)c2C#N)o1
Temperature: 50 °C
Yield: 87.6 %

Procedure:
To a stirred solution of 493 mg (1.58 mmol) 2-amino-4-(5-bromo-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile in 10 ml DME was added 2.1 ml (11,3 mmol) sodium methylate solution (5.4M in methanol) and the mixture heated at 50° C. for 1 h. The reaction mixture was then poured into 100 ml ice-water and the resulting precipitate collected by filtration and washed with water. Chromatography (ethyl acetate/hexane 1/1) afforded 363 mg (87%) 2-amino-4-(5-methoxy-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a light yellow crystalline solid. EI-MS m/e (%): 262 (M+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]2([N:29](C)[C:30](=O)OC(C)(C)C)[CH2:28][CH2:27]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:26]2([NH:29][CH3:30])[CH2:28][CH2:27]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: CN(C(=O)OC(C)(C)C)C1(c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CNC1(c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)cyclopropyl(methyl)carbamate (0.03 g, 0.058 mmol) in chloroform (0.5 mL) was added trifluoroacetic acid (0.5 mL, 6.5 mmol) and stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo, and the resulting crude product was purified via reverse phase preparative HPLC to afford ′1-(3-fluoro-4-(5-(1-phenyl-cyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)-N-methylcyclopropanamine as a white amorphous solid. MS (ESI) m/z: Calculated: 415.5; Observed: 416.1 (M++1).
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(F)=CC=1)C.C=O.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][CH2:28][NH2:29].[F:30][C:31]1[CH:49]=[CH:48][C:34]([CH2:35][N:36]([CH3:47])[C:37]([C:39]2[CH2:40]N(C)[C:42](=[O:45])[C:43]=2[OH:44])=[O:38])=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:49]=[CH:48][C:34]([CH2:35][N:36]([CH3:47])[C:37]([C:39]2[CH2:40][N:29]([CH2:28][CH2:27][C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)[C:42](=[O:45])[C:43]=2[OH:44])=[O:38])=[CH:33][CH:32]=1
Reactant: NCCc1cccs1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(F)cc2)=C(O)C1=O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(F)cc1
Product: CN(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(CCc2cccs2)C1

Procedure:
3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-thiophen-2-yl-ethylamine as described in the preparation of Compound 1. HRMS (M−H) calcd for C19H18FN2O3S: 373.1022. found: 373.1029. 1H NMR (500 MHz, CDCl3) δ: 2.95 (s, 3), 3.14 (t, 2, J=7), 3.76 (t, 2, J=7), 3.97 (s, 2), 4.57 (s, 2), 6.81–7.21 (overlapping m, 7). 13C NMR (125 MHz, CDCl3) δ: 28.76, 34.49, 44.93, 49.46, 51.47, 109.48, 115.65, 115.82, 124.20, 125.59, 127.15, 129.28, 129.34, 132.12, 132.14, 140.34, 152.72, 161.37, 163.33, 164.94, 166.11.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[CH2:18][CH2:19][CH:20]1[O:24][C:23](=[O:25])[N:22]([CH3:26])[CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC.CC(O)C>[CH3:26][N:22]1[CH2:21][CH:20]([CH2:19][CH2:18][N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=3)[CH2:10][CH2:11]2)[O:24][C:23]1=[O:25]
Reactant: CN1CC(CCCl)OC1=O
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCCCO
Product: CN1CC(CCN2CCN(c3ccc(C(F)(F)F)cc3)CC2)OC1=O
Yield: 69 %

Procedure:
This compound was prepared according to the procedure of Example 2. A mixture of 3.5 g (0.015 mol) of 1-(4-trifluoromethylphenyl)piperazine (Emka-Chemie), 2.5 g (0.015 mol) of 5-(2-chloroethyl)-3-methyl-2-oxazolidinone, 5.3 g (0.05 mol) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave 3.7 g (69%) of white solid, mp 116°-117° C. (2-propanol).
Reaction SMILES: [C:1]1([SeH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[Se:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [SeH]c1ccccc1
Reactant: Nc1ccccc1I
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Nc1ccccc1[Se]c1ccccc1
Yield: 60 %

Procedure:
Using this protocol (see example 4 below), phenyl selenol was coupled with electron-rich aryl iodides in very good yields (Table 5). Sterically hindered iodides such as those with ortho-functionalities (entries 3, 5, 7 and 11), were coupled, as well as aryl iodides containing heteroatoms (entry 8 and 10). When o-iodoaniline was used as the aryl halide, in addition to the desired selenide, products were observed arising from the self-coupling of o-iodoaniline. This problem also persisted with K3PO4. However, when K2CO3 was used as the base, 1-amino-2-phenylselanyl-benzene was isolated in 60% yield (entry 12). With electron-poor aryl iodides, in addition to the desired diaryl selenides, diaryl diselenides were observed if NaOt-Bu or K3PO4 was used. In addition, with NaOt-Bu, transesterifcation products were observed when aryl halides with ester groups were used. Such complications can be avoided if K2CO3 is used instead of NaOt-Bu or K3PO4. Using this modified protocol a variety of diaryl selenides were obtained from electron-poor aryl halides (Table 6). The protocol tolerates even base sensitive groups such as esters and ketones (entries 3, 4, and 6).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([N:15]2[CH2:19][CH:18]3[CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH:17]3[CH2:16]2)=[O:14])=[N:5][CH:4]=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]1[CH:17]2[CH2:22][NH:21][CH2:20][CH:18]2[CH2:19][N:15]1[C:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][N:5]=1)=[O:14]
Reactant: Cn1ncnc1-c1ccccc1C(=O)N1CC2CN(C(=O)OC(C)(C)C)CC2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ncnc1-c1ccccc1C(=O)N1CC2CNCC2C1
Reaction time: 2 h

Procedure:
Intermediate 60 (100 mg, 0.252 mmol), DCM (2.5 mL), TFA (0.5 mL) were stirred at room temperature for 2 h and then concentrated in vacuo. The residue was dissolved in DCM and treated with Dowex 550 A resin. After stirring for 2 h the resin was removed by filtration and the filtrate was concentrated in vacuo to a colorless oil which was taken on to the next step without further purification. MS (ESI) mass calculated for C16H19N5O, 297.16; m/z found, 298.0.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[N:4]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(-c2nn(C3CCCCO3)c3ccc(C#N)cc23)cc1
Yield: 73.6 %

Procedure:
A mixture of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (5.0 g, 16.3 mmol), 4-methoxyphenylboronic acid (3.7 g, 24.5 mmol), Pd(dppf)Cl2 (1.33 g, 1.63 mmol) and K3PO4 (17.31 g, 81.66 mmol) in 120 mL DME was refluxed for 24 h. The reaction was cooled and diluted with EtOAc. The mixture was filtered through a celite pad and the filtrate was washed with water, brine, dried (Na2SO4) and filtered. Removal of solvent in vacuo followed by chromatographic purification of the residue (10–50% EtOAc in hexanes) furnished 4 g (73% yield) of the title compound as a white solid. ES-MS (m/z) 334 [M+H]+.