Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([C:18]#[N:19])[C:15]3[N:20]=[CH:21][N:22]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[C:14]=3[CH:13]=2)=[CH:8][C:7]=1[C:29]([F:32])([F:31])[F:30].CCN(C(C)C)C(C)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:42][S:43]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([C:18]#[N:19])[C:15]3[N:20]=[CH:21][N:22]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[C:14]=3[CH:13]=2)=[CH:8][C:7]=1[C:29]([F:31])([F:30])[F:32])(=[O:45])=[O:44]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1nc(-c2ccc(OCCCO)c(C(F)(F)F)c2)cc2c1ncn2C1CCCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)OCCCOc1ccc(-c2cc3c(ncn3C3CCCCO3)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 6-(4-(3-hydroxypropoxy)-3-(trifluoromethyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (670 mg) and DIPEA (1.4 ml) in NMP (7.5 ml) at 0° C. was added methanesulphonyl chloride (0.2 ml). The mixture was allowed to stir for 45 minutes at room temperature, then diluted with EtOAc (75 ml) and washed with saturated sodium bicarbonate (70 ml), followed by water (2×40 ml). Organic layer was dried over sodium sulphate and solvent was evaporated under reduced pressure to yield 3-(4-(4-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)propyl methanesulfonate (720 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:22]=[C:21]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]2[CH:40]([F:42])[F:41])[N:20]=1>C1COCC1.C(O)(=O)C.O>[F:42][CH:40]([F:41])[C:32]1[N:31]([C:21]2[N:22]=[C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:24]=[C:19]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][N:3]=3)[N:20]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1
Reactant: Nc1ccncn1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2ccncn2)nc(N2CCOCC2)n1
Reaction time: 0.33 h
Yield: 6.1 %

Procedure:
To a solution of 0.214 g (2.25 mmol) of 4-aminopyrimidine in THF (4.5 mL) at 0° C. was added 1.25 mL of NaHMDS (2 M solution in THF), and the mixture stirred for 20 min. A solution of 0.282 g (0.77 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in THF (6 mL) was added and the resulting mixture was stirred for 1 hr at RT. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried and concentrated. Chromatography on alumina, eluting with CH2Cl2/EtOAc (1:3) gave a white powder. Recrystallization from ethanol gave 0.020 g (6% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(4-pyrimidinyl)-1,3,5-triazin-2-amine: mp 233-235° C.; 1H NMR (CDCl3) δ8.92 (d, J=1.4 Hz, 1H), 8.67 (d, J=5.8 Hz, 1H), 8.39 (dd, J=6.8, 1.7 Hz, 1H), 8.22 (dd, J=5.8, 1.3 Hz, 1H), 8.01 (s, 1H), 7.92 (dd, J=6.8, 1.7 Hz, 1H), 7.56 (t, JHF=53.5 Hz, 1H), 7.49-7.43 (m, 2H), 3.98-3.96 (m, 4H), 3.86-3.85 (m, 4H); Anal. Calcd. for C19H17F2N9O: C, 53.65; H, 4.1; N, 29.6. Found: C, 53.35; H, 4.2; N, 29.4%.
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1)=O.[CH2:14]([N:21](C)C)[C:15]1C=CC=CC=1.C=C.[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:10]([CH:9]=[CH:8][C:7]1[CH:12]=[CH:13][C:4]([CH:2]=[CH:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]=[CH:15][C:14]#[N:21])=[CH:29][CH:28]=2)=[CH:5][CH:6]=1)#[N:11]
Reactant: CN(C)Cc1ccccc1
Reactant: N#CC=Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(C)cc1
Agent: [Pd+2]
Agent: C=C
Agent: CC(=O)[O-]
Product: N#CC=Cc1ccc(C=Cc2ccc(C=CC#N)cc2)cc1
Temperature: 130 °C
Reaction time: 23 h
Yield: 15 %

Procedure:
3.83 g (20 mmols) of 4-chloroformylcinnamonitrile, 2.70 g (20 mmols) of N-benzyldimethylamine and 0.0448 g (0.2 mmol) of palladium acetate are added under argon to 40 ml of p-xylene. Ethylene is passed through the mixture, which is stirred for 23 hours at 130° C. The reaction mixture is then diluted at 130° C. with 40 ml of p-xylene and is filtered. 10 ml of n-hexane are added to the filtrate. Cooling to room temperature gives 0.39 g (15% of theory) of 4,4'-bis-(2-cyanovinyl)-stilbene, melting point 220° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:11](=[O:13])[CH2:10][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:8][C:7]=2[NH:6][CH:5]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>CN(C)C=O>[CH3:20][S:21]([N:6]1[C:7]2[CH2:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][C:11](=[O:13])[C:12]=2[C:4]([CH3:3])=[CH:5]1)(=[O:23])=[O:22]
Reactant: Cc1c[nH]c2c1C(=O)CC(c1ccccc1)C2
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(S(C)(=O)=O)c2c1C(=O)CC(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
To a suspension of 60% sodium hydride (0.085 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 3-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.4 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of methanesulfonylchloride (0.22 g) in dimethylformamide (2 ml), and the mixture was stirred at the same temperature for 18 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give colorless crystals of 1-methanesulfonyl-3-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.50 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:19])=[C:11](Cl)[C:12]([F:17])=[CH:13]2)=[C:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=1)=[O:5])C.[CH3:23][N:24]([CH3:30])[CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>N1C=CC=CC=1>[C:4]([OH:5])(=[O:3])[CH3:6].[CH3:23][N:24]([CH3:30])[CH:25]1[CH2:29][CH2:28][N:27]([C:11]2[C:12]([F:17])=[CH:13][N:14]3[C:9]([C:10]=2[CH3:19])=[C:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[C:15]3=[O:16])[CH2:26]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: CN(C)C1CCNC1
Solvent: c1ccncc1
Product: CC(=O)O
Product: Cc1c(N2CCC(N(C)C)C2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A 81 mg sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 2.5 mL of dry pyridine under a nitrogen atmosphere. To this solution was added a solution of 114 g of 3-(dimethylamino)pyrrolidine in 2.5 mL of pyridine, and the reaction mixture was heated at 60° C. for 39 hours. The pyridine was removed under vacuum, and the residue was stirred with 1N NaOH in THF/water for at 60° C. for 6 hours. The solution was made acidic with acetic acid, and the product was extracted with chloroform. After drying over MgSO4, the solvent was removed, and the residue was purified by chromatography on silica gel, eluting with 100:40:20:8 chloroform: methanol: acetic acid:water to give the title product. mp 165-170° C. (dec.). MS 374 (M+H)+ ; 1H NMR (D6 -DMSO) δ: 0.53 (m, 2H), 0.82-1.08 (m, 2H), 1.75 (s, 3H), 2.22 (s, 6H), 2.08-2.33 (m, 2H), 2.74 (m, 2H), 3.44-3.94 (m, 5H), 8.01 (br, s, 1H), 8.90 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[O:10]([CH2:17][C:18](N)=[NH:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:18]([CH2:17][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:19]=1
Reactant: N=C(N)COc1ccccc1
Reactant: N#Cc1nccnc1N
Solvent: CCO
Product: Nc1nc(COc2ccccc2)nc2nccnc12

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 3.0 g (0.025 mole) of 3-amino-2-pyrazinecarbonitrile and 3.8 g (0.025 mole) of 2-phenoxyacetamidine [prepared according to C. Djerassi and C. R. Scholz, J. Am. Chem. Soc., 1947, 69, 1688] in 100 ml if absolute ethanol. Refluxing time: 4 hours. Yld: 5.4 g (85%), m.p. 202°-204° C. (ethanol).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:30][CH2:31][CH2:32][CH3:33])[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1>>[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:30][CH2:31][CH2:32][CH3:33])[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)Oc1ccccc1
Yield: 57.8 %

Procedure:
Using the general method of Example 47, phenyl chloroformate (61 μL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmole) to provide 0.12 g of phenyl N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate as a solid. Analysis: Calculated for C24H28N6O2: %C, 66.65; %H, 6.53; %N, 19.43; Found: %C, 66.49; %H, 6.59; %N, 19.32.
Reaction SMILES: BrC1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CCP(=O)OCCCN4C=C(B5OC(C)(C)C(C)(C)O5)C=N4)=CC=3OC)N=2)=CC=1.[Br:54][C:55]1[N:60]=[C:59]([C:61](=[O:64])[NH:62][CH3:63])[C:58]([NH:65][C:66]2[C:71]([C:72]([F:75])([F:74])[F:73])=[CH:70][N:69]=[C:68]([NH:76][C:77]3[CH:89]=[CH:88][C:80]([CH2:81][P:82](=[O:87])([OH:86])[O:83][CH2:84][CH3:85])=[CH:79][C:78]=3[O:90][CH3:91])[N:67]=2)=[CH:57][CH:56]=1.[CH3:92][C:93]1([CH3:111])[C:97]([CH3:99])([CH3:98])[O:96][B:95]([C:100]2[CH:101]=[N:102][N:103]([CH2:105][C:106]3([CH2:109]O)[CH2:108][CH2:107]3)[CH:104]=2)[O:94]1>>[Br:54][C:55]1[N:60]=[C:59]([C:61](=[O:64])[NH:62][CH3:63])[C:58]([NH:65][C:66]2[C:71]([C:72]([F:75])([F:73])[F:74])=[CH:70][N:69]=[C:68]([NH:76][C:77]3[CH:89]=[CH:88][C:80]([CH2:81][P:82](=[O:86])([O:87][CH2:109][C:106]4([CH2:105][N:103]5[CH:104]=[C:100]([B:95]6[O:94][C:93]([CH3:111])([CH3:92])[C:97]([CH3:99])([CH3:98])[O:96]6)[CH:101]=[N:102]5)[CH2:108][CH2:107]4)[O:83][CH2:84][CH3:85])=[CH:79][C:78]=3[O:90][CH3:91])[N:67]=2)=[CH:57][CH:56]=1
Reactant: CC1(C)OB(c2cnn(CC3(CO)CC3)c2)OC1(C)C
Reactant: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1
Agent: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CC[PH](=O)OCCCn3cc(B4OC(C)(C)C(C)(C)O4)cn3)cc2OC)ncc1C(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Yield: 61.5 %

Procedure:
Prepared analogously to Compound 61A using ethyl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 38C, 670 mg, 1.1 mmol) and (1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methyl}cyclopropyl)methanol (Compound 63B, 300 mg, 1.08 mmol) to afford 584 mg of the title compound as a racemic mixture (62%). MS (ESI): m/z=879.92/881.81 [M+H]+. UPLC: tR=1.61 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[O:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:3]1.Br[C:22]1[S:26][C:25]([NH2:27])=[N:24][N:23]=1>>[CH3:8][CH:6]1[CH2:7][CH:2]([CH3:1])[CH2:3][N:4]([CH2:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[O:13][CH2:14][CH2:15][CH2:16][NH:17][C:22]2[S:26][C:25]([NH2:27])=[N:24][N:23]=2)[CH2:5]1
Reactant: Nc1nnc(Br)s1
Reactant: CC1CC(C)CN(Cc2cccc(OCCCN)c2)C1
Product: CC1CC(C)CN(Cc2cccc(OCCCNc3nnc(N)s3)c2)C1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 3-[3-[(3,5-dimethyl-1-piperidinyl) methyl]phenoxy]-1-propanamine and 5-bromo-1,3,4-thiadiazole-2-amine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH:11]1([NH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+]>O.CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]([CH:11]2[CH2:12][CH2:13]2)[CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)CCCNC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CCCN(c1ccc(Br)cc1C=O)C1CC1
Yield: 23 %

Procedure:
5-bromo-2-fluorobenzaldehyde (20 g), t-butyl N-cyclopropyl-4-aminobutyrate (14.5 g), sodium carbonate (13.8 g), water (70 ml) and DMSO (70 ml) were heated at 80° C. for 5 days and at 110° C. for 3 days, which was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give t-butyl N-(4-bromo-2-formylphenyl)-N-cyclopropyl-4-aminobutyrate (6.4 g) as red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=O)[CH2:9]2)[CH:7]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]2)[CH:7]=1
Reactant: Cc1ccc(Cl)cc1C1CC(=O)c2c(C)ccnc2C1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(Cl)cc1C1CC(=NNC(=N)N)c2c(C)ccnc2C1
Yield: 211.5 %

Procedure:
To a solution of 7-(5-chloro-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.0 g) and aminoguanidine hydrochloride (0.46 g) in ethanol (30 ml) were added concentrated hydrochloric acid (0.9 ml) and water (0.9 ml), and the mixture was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The mixture was washed with ethyl acetate, and to the aqueous layer was added sodium hydrogen carbonate solution to make it alkaline. The solution was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solution was concentrated, and the residue was dissolved in ethanol. To the solution was added 1N hydrochloric acid (10 ml), and the mixture was concentrated. Precipitated crystals were recrystallized from ethanol to give 7-(5-chloro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 164) (1.4 g) as colorless crystals.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:19][CH2:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)CCc1cccc(CO)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCc1cccc(CBr)n1
Yield: 69.2 %

Procedure:
t-Butyl 3-(6-hydroxymethylpyridin-2-yl)propionate (16.13 g) was dissolved in 200 mL of dry methylene chloride, and 33.8 g of carbon tetrabromide was added to the above solution, additionally 21.5 g of triphenylphosphine was added thereto in small portions under stirring at ice temperature, and then the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was transferred to a separating funnel, washed with saturated aqueous sodium bicarbonate, then brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue, 200 mL of a mixture of hexane-ethyl acetate (2:1) was added, the insoluble portion precipitated was filtrated off, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane-ethyl acetate=5:1) to give 14.12 g of t-butyl 3-(6-bromomethylpyridin-2-yl)propionate as a light yellow oil.
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[F:29][C:30]([F:39])([F:38])[C:31]1[N:36]=[N:35][C:34]([NH2:37])=[CH:33][CH:32]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[C:23]1([C:2]2[N:35]3[N:36]=[C:31]([C:30]([F:38])([F:29])[F:39])[CH:32]=[CH:33][C:34]3=[N:37][C:3]=2[C:5]2[CH:10]=[CH:9][C:8]([C:11]3([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]3)=[CH:7][CH:6]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccc(C(F)(F)F)nn1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(C(F)(F)F)nn4c3-c3ccccc3)cc2)CCC1
Yield: 34 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-1-A (1.85 g, ˜80% purity, 3.45 mmol, 1.0 eq), 6-(trifluoromethyl)pyridazin-3-amine (CAS-Nr. 935777-24-5, 0.674 g, 4.14 mmol, 1.2 eq), N,N-diisopropylethylamine (0.60 mL, 6.89 mmol, 1.0 eq) and activated 3 Å molecular sieves in isopropanol (10.5 mL) was heated for 7 hours under reflux. On cooling, the mixture was partitioned between DCM and water, stirred vigorously and filtered through a silicone coated filter paper. The filtrate was concentrated in vacuo. The crude mixture was purified via MPLC (Biotage Isolera; 100 g SNAP cartridge: hexane→hexane/ethyl acetate 2/1) to give 680 mg (34% yield) of the title compound.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:2]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:1][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: C1=CCCC=C1
Reactant: Nc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C1=CC(Nc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.7 %

Procedure:
Hydroamination of 1,3-Dienes with Arylamines: Sixteen examples of hydroamination of 1,3-dienes with arylamines are shown in Table 3 below (Entries 1-16). Typical reaction conditions are 0.5 mmol amine, 2 mmol cyclohexadiene, 2 mol % Pd(PPh3)4, 10 mol % TFA, toluene, 25° C., mixed for 24 hours. A typical procedure is given for Entry 1, Table 1: Pd(PPh3)4 (5.8 mg, 0.0050 mmol) was suspended in 0.1 mL of toluene in a screw-capped vial. 1,3-Cyclohexadiene (160 mg, 190 μL, 2.00 mmol) and aniline (46.6 mg, 45.6 μL, 0.500 mmol) were added to the reaction mixture. The vial was sealed with a cap containing a PTFE septum and removed from the drybox. Trifluoroacetic acid (5.7 mg, 3.9 μL, 0.050 mmol) was added to the reaction mixture by syringe. The reaction mixture was then stirred at room temperature for 24 h. All volatile compounds were evaporated under reduced pressure, and the residue was adsorbed onto silica gel. The product was eluted using 0.5% ethyl acetate/hexanes to give 85.5 mg (99%) of N-cyclohex-2-en-1-ylaniline as a colorless oil. Additional compounds were made in a similar fashion and analyzed as follows.
Reaction SMILES: C(OC([O:8][N:9]([CH2:17][C:18]1[CH:23]=[C:22]([I:24])[C:21]([O:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[C:20]([I:33])[CH:19]=1)C(=O)OC(C)(C)C)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[OH:8][NH:9][CH2:17][C:18]1[CH:19]=[C:20]([I:33])[C:21]([O:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[C:22]([I:24])[CH:23]=1
Reactant: CC(C)(C)OC(=O)ON(Cc1cc(I)c(Oc2ccc(O)cc2)c(I)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: ONCc1cc(I)c(Oc2ccc(O)cc2)c(I)c1
Reaction time: 2 h

Procedure:
A solution containing tert-butyl N-(tert-butoxycarbonyloxy)-N-[3,5-diiodo-4-(4-hydroxyphenoxy)benzyl]carbamate (150 mg, 0.21 mmol) in 4 ml of 30% TFA in CH2Cl2 was stirred for 2 h and then evaporated to dryness to afford 4-(4-hydroxyaminomethyl-2,6-diiodophenoxy)phenol (M+1=484). This residue was then treated with triethylamine (0.5 ml) and the mixed anhydride (0.5 ml) [made from formic acid and acetic anhydride (1:2 v/v) at 50° C. for 1 h] in 2 ml of CH2Cl2 for 0.5 h. All volatiles were removed and the residue dissolved in methanol then treated with 10% NaOH for 0.5 h. This was diluted with ethyl acetate and water and adjusted to pH of 6. The layers were separated and the organic extract was evaporated in vacuo. Purification by preparative HPLC afforded the title compound (27 mg, 25%) as an off white solid. 1H NMR (400 MHz, CD3OD): δ 8.38, 8.18* (s, 1H); 7.89*, 7.86 (s, 2H); 6.69 (d, j=8.8 Hz, 2H); 6.55 (d, j=8.8 Hz, 2H),; 4.67, 4.63* (s, 2H). M+1=512. *: minor rotamer
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24][CH:23]=1)=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:23]=[CH:24][C:25](/[CH:28]=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:27]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: CCOC(=O)/C=C/c1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CCOC(=O)/C=C/c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with ethyl (E)-3-(4-formylphenyl)prop-2-enoate was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give ethyl (E)-3-[4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]phenyl]prop-2-enoate.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:23][CH:22]=3)[S:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH3:33].[OH-:35].[Na+].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:33][C:7]1[CH:8]=[C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:23][CH:22]=3)[S:18][C:19]=2[CH3:20])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:34])=[O:2].[C:9]([O:12][CH2:13][CH3:14])(=[O:35])[CH3:8]
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(-c4cccnc4)cc3)sc2C)cc1C
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(OCCc2nc(-c3ccc(-c4cccnc4)cc3)sc2C)ccc1CCC(=O)O

Procedure:
3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-3-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid methyl ester (47 mg, 0.100 mmol) is dissolved in tetrahydrofuran (1 mL) and 5N sodium hydroxide (1 mL) solution is added at room temperature. The reaction is heated to reflux and monitored by HPLC. Upon complete conversion, the reaction is allowed to cool to room temperature and neutralized with 5N hydrochloric acid (1 mL), diluted with ethyl acetate, and extracted. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-3-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid (40 mg, 0.087 mmol) may also be obtained by recrystalization from ethyl acetate (87% yield). MS (ES): 459.2 (M++1). Alternatively, the acid may be obtained after reversed phase preparative HPLC as the hydrochloride salt.