Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH:13]1[CH2:15][CH2:14]1)(=O)C.[ClH:16]>C(O)C.O>[ClH:16].[NH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH:13]1[CH2:14][CH2:15]1
Reactant: CC(=O)Nc1ccc(C#N)cc1C1CC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(N)c(C2CC2)c1
Reaction time: 12 h

Procedure:
A mixture of 2.39 g of the product of step A dissolved in 45 ml of ethanol with 36 ml of water and 5 ml of concentrated HCl is stirred for 12 hours under reflux. The ethanol is evaporated off under vacuum, and the precipitate is filtered off, washed with 1 ml of water and dried under vacuum to obtain 1.5 g of the expected product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:14]=3)[C:9]2=[O:23])=[CH:4][CH:3]=1.[CH3:24][N:25]([CH3:31])[C@@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>>[CH2:19]([O:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:23])[N:8]([C:5]1[CH:6]=[CH:7][C:2]([N:28]3[CH2:29][CH2:30][C@@H:26]([N:25]([CH3:31])[CH3:24])[CH2:27]3)=[CH:3][CH:4]=1)[CH2:17][CH2:16]2)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCOc1ccc2c(c1)CCN(c1ccc(Br)cc1)C2=O
Reactant: CN(C)[C@@H]1CCNC1
Product: CCCCOc1ccc2c(c1)CCN(c1ccc(N3CC[C@@H](N(C)C)C3)cc1)C2=O

Procedure:
According to Method R, 2-(4-bromophenyl)-6-butoxy-3,4-dihydro-2H-isoquinolin-1-one was reacted with dimethyl-(R)-pyrrolidin-3-yl-amine. In this way the product was obtained with molecular weight 407.56 (C25H33N3O2); MS (ESI): 408 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[CH3:15][C:16]1[C:24]2[O:23][CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:18]2[CH:17]=[C:16]([CH3:15])[C:24]3[O:23][CH2:22][CH2:21][C:20]=3[CH:19]=2)=[O:9])[CH:3]=1
Reactant: Cc1cccc2c1OCC2
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2c1OCC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
0.396 g (2.24 mmol) 6-chloropyrimidine-4-carboxylic acid chloride and 0.328 g (2.46 mmol) aluminium trichloride in 10 mL DCM were stirred for 20 min at RT. Then 0.300 g (2.24 mmol) 7-methyl-2,3-dihydro-benzofuran in DCM were added dropwise to the reaction mixture and this was stirred for 1.5 h at RT. After the addition of water and DCM to the reaction mixture the phases were separated and the aqueous phase was extracted with DCM. The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate solution, dried on sodium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: [NH3:1].F[C:3]1[N:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][C:11]([F:14])([F:13])[F:12])[N:4]=1>C(OCC)C>[NH2:1][C:3]1[N:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][C:11]([F:14])([F:13])[F:12])[N:4]=1
Reactant: N
Reactant: Fc1cc(OC(F)(F)F)nc(F)n1
Solvent: CCOCC
Product: Nc1nc(F)cc(OC(F)(F)F)n1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
At -75° to -70° C. and over a period of 1 hour, 8.7 g (0.51 mol) of gaseous ammonia was gassed, while stirring, into a mixture of 51 g (0.255 mol) of 2,4-difluoro-6-trifluoromethoxypyrimidine in 200 ml of diethyl ether. The mixture was stirred for 1 1/2 hours at -70° C. and for 1 hour at room temperature. The reaction mixture was evaporated down under reduced pressure, taken up in methylene chloride and extracted with water. The organic phase was dried, evaporated down and chromatographed over silica gel (8:1 ligroin/ether mixture) to give 38.1 g (75.6% of theory) of the title compound as colorless crystals of melting point 86°-89° C.
Reaction SMILES: [N:1]1([CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)(=O)C.[N:25]([O-])=O.[Na+].C(=O)([O-])O.[Na+]>O>[N:1]1([CH:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:7]2[CH:12]=[CH:11][C:10]3[NH:13][N:25]=[N:14][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=N[O-]
Reactant: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(C(c2ccc3[nH]nnc3c2)n2ccnc2)cc1
Yield: 85.3 %

Procedure:
To a stirred and cooled (5° C.) solution of 5.2 parts of 4-[(1H-imidazol-1-yl)phenylmethyl]-1,2-benzenediamine in 4.8 parts of acetic acid and 20 parts of water was added a solution of 1.38 parts of sodium nitrite in 10 parts of water. The whole was stirred for 1 hour at room temperature. The reaction mixture was treated with a sodium hydrogen carbonate solution and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 64 parts of ethyl acetate. The product was filtered off and dried, yielding 4.7 parts (85.3%) of 5-[(1H-imidazol-1-yl)phenylmethyl]-1H-benzotriazole; mp. 178.8° C. (compound 146).
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.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=O>>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: O=Cc1cccs1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cccs4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with thiophene-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(thiophen-2-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1.Cl>CN(C=O)C.N1CCCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[O:12][C:21]([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)=[CH:22][C:2]=2[CH:3]=1)=[O:6]
Reactant: C#Cc1ccc(OC)cc1
Reactant: COC(=O)c1ccc(O)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COC(=O)c1ccc2oc(-c3ccc(OC)cc3)cc2c1
Temperature: 6 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
A mixture of Methyl 3-Iodo-4-hydroxybenzoate (0.7 g, 2.5 mmol), 4-Methoxyphenylacetylene (0.33 g, 2.5 mmol), Pd(Cl)2(PPh3)2 (0.05 g) and Cul (0.03 g) in DMF/Piperidine (20 ml) was heated at 6° C. After 2 hr, the reaction was cooled and poured into 2N HCl. The aqueous layer was extracted with EtOAc and then separated, dried, concentrated to give a solid. The solid was triturated with MeOH, filtered to give 142 (0.5 g, 71%): Mp=157–159° C.; 1H NMR (CDCl3) δ 8.28 (d, 1 H, J=1.3 Hz), 7.97 (dd, 1 H, J=8.5 Hz, 1.7 Hz), 7.82–7.79 (m, 2 H), 7.51 (d, 1 H, 8.5 Hz), 6.99 (d, 2 H, J=8.3 Hz), 6.93 (d, 1 H, J=9 Hz), 3.94 (s, 3 H), 3.87 (s, 3 H); MS 283 (M+H)+
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]([CH3:20])[CH2:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[OH:5][CH2:4][CH2:3][CH2:2][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]([CH3:20])[CH2:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:9][CH:8]=1
Reactant: CC1CC(=O)NN=C1c1ccc(O)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CC(=O)NN=C1c1ccc(OCCCO)cc1
Temperature: 100 °C

Procedure:
A solution of 361 mg (1.62 mmol) of the THP-derivative of 3-bromo-1-propanol prepared above, 220 mg (1.08 mmol) of 6-(4-hydroxyphenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone and 298 mg (2.15 mmol) of powdered anhydrous potassium carbonate in 3 ml of DMF is heated at 100° C. for 2 hr. After cooling the reaction mixture is diluted with 25 ml of water and extracted with EtOAc (3×25 ml). The combined organic extracts are washed once with water, dried (MgSO4), filtered, and the solvent removed under vacuum. The residue is taken up in 5 ml of methanol, about 200 mg of pyridinium p-toluenesulfonate added, and the mixture heated at 60° C. for 2 hr under N2. solvent is removed under vacuum and the residue is flash chromatographed on silica gel (95:5 CHCl3 :CH3OH) to give 252 mg of 6-[4-(3-hydroxypropyloxy)phenyl]-5-methyl-4,5-dihydro-3 (2H)-pyridazinone as a white solid. 1H-NMR (CDCl3): δ1.18 (d, 3H); 1.83 (t, 1H); 2.00 (quintuplet, 2H); 2.40 (d, 1H); 2.63 (d pair, 1H); 3.25 (m, 1H); 3.80 (m, 2H); 4.10 (t, 2H); 6.90 (d, 2H); 7.63 (d, 2H); 8.65 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Br:10])[CH2:5]O.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Br:10])[CH2:5][Cl:13]
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Br)c(Br)c1
Solvent: ClC(Cl)Cl
Product: ClCc1ccc(Br)c(Br)c1

Procedure:
3,4-Dibromobenzoic acid (28 g, described by Miller, J.C.S. 61, 1033 (1892)) was suspended with stirring in toluene (150 ml) at 50° C. Sodium dihydrobis(2-methoxyethoxy)aluminate (70% w/v, in toluene, 52 ml) was added over 30 minutes at 50° C. The mixture was heated on a steam bath for 1 hour, cooled to 20° C. and hydrolysed by the addition of hydrochloric acid (6N; 150 ml) with cooling. The mixture was separated and the aqueous phase was extracted with diethyl ether (100 ml). The combined organic extracts were washed with saturated sodium bicarbonate solution and water, dried over sodium sulphate, filtered and evaporated to give 3,4-dibromobenzyl alcohol (19 g) as a light red oil. The unpurified alcohol was dissolved in chloroform (60 ml) and the solution was heated at reflux. Thionyl chloride (20 ml) was added in portions over 10 minutes and the solution was heated at reflux for 1 hour. The reaction mixture was evaporated to give a light oily residue, which was repeatedly diluted with chloroform (3×50 ml) and the combined chloroformic solutions evaporated. The residue was dissolved in diethyl ether, washed with saturated sodium bicarbonate solution, dried over sodium sulphate, filtered and evaporated. 3,4-Dibromobenzyl chloride (20 g) was obtained as a clear mobile oil of sufficient purity for further reaction.
Reaction SMILES: [F:1][C:2]([F:38])([CH2:34][CH2:35][CH2:36][CH3:37])[C:3](=[O:33])[CH2:4][CH2:5][C@H:6]1[C@H:10]([OH:11])[CH2:9][C:8](=[O:12])[C@@H:7]1[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC(C1C=CC=CC=1)=O)=[O:22]>C(O)(=O)C.[Zn]>[F:1][C:2]([F:38])([CH2:34][CH2:35][CH2:36][CH3:37])[C:3](=[O:33])[CH2:4][CH2:5][C@H:6]1[C@H:10]([OH:11])[CH2:9][C:8](=[O:12])[C@@H:7]1[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: CCCCC(F)(F)C(=O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCCCC(=O)OCC(=O)c1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCCC(F)(F)C(=O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCCCC(=O)O

Procedure:
A solution of the compound (46) (0.272 g) in acetic acid (10 ml) was treated with zinc (3.5 g) added in portions at the room temperature for 2.5 hours. The resultant mixture was worked up with the conventional procedure and the residue was subjected to silicagel column chromatography to give the titled compound (57). Yield: 0.177 g (81%).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:13])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([Cl:12])[CH:8]=[CH:7][CH:6]=2.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(O)(O)=O>CC#N.O.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>[Cl:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:2]([C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([F:14])[CH:20]=1)[C:3]([CH3:13])=[N:4]2
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1nc2cccc(Cl)c2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)O
Solvent: O
Solvent: CC#N
Product: Cc1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
A mixture of 3,5-dichloro-2-methylquinoxaline (Prepared in Example 85, 0.3361 g, 1.577 mmol), 3-fluorobenzeneboronic acid (0.2428 g, 1.735 mmol), tetrakis(triphenylphosphine)palladium (0.09114 g, 0.07887 mmol), and sodium carbonate anhydrous (0.8360 g, 7.887 mmol) in CH3CN—H2O (3:1) (16.00 mL) was stirred at 100° C. After 3.5 h, the mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give red syrup. The red syrup was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min and then 50% isocratic of EtOAc for 10 min as eluent to give 5-chloro-3-(3-fluorophenyl)-2-methylquinoxaline as a solid: 1H NMR (400 MHz, DMF) δ ppm 8.05 (1 H, dd, J=8.4, 1.4 Hz), 8.00 (1 H, dd, J=7.6, 1.4 Hz), 7.83 (1 H, dd, J=8.4, 7.6 Hz), 7.60-7.67 (3 H, m), 7.38-7.46 (1 H, m), 2.74 (3 H, s); LC-MS (ESI) m/z 273.1 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[N:3]1[CH:4]=[CH:5][N:6]2[C:11]=1[CH:10]=[CH:9][C:8]([C:12](OC)=[O:13])=[N:7]2>C1COCC1.CO>[N:3]1[CH:4]=[CH:5][N:6]2[C:11]=1[CH:10]=[CH:9][C:8]([CH2:12][OH:13])=[N:7]2
Reactant: COC(=O)c1ccc2nccn2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc2nccn2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
Sodium borohydride (1.1 g, 31.1 mmol) was added to a solution of methyl imidazo[1,2-b]pyridazine-6-carboxylate (2.4 g, 15.5 mmol) in THF (35 mL) and methanol (2.5 ml) at RT. The reaction mixture was stirred at RT for 2 h (the reaction was monitored by TLC) upon which the mixture was concentrated under reduced pressure. The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford imidazo[1,2-b]pyridazin-6-ylmethanol (1.6 g, 81%) as a white solid. 1H NMR: 200 MHz, DMSO-d6: δ 8.5 (s, 1H), 8.3 (d, 1H), 7.9 (s, 1H), 7.55 (d, 1H), 5.65 (t, 1H), 4.6 (d, 2H). MS: [M+H]+: m/z=311.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: CC(C)(C)Oc1cccc(Br)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(OC(C)(C)C)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-tert-butoxy-pyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1B1OC(C)(C)C(C)(C)O1)[O:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[N:7]=1.C([O-])(O)=O.[Na+].Br[C:32]1[CH:37]=[CH:36][N:35]([CH2:38][CH:39]2[CH2:41][CH2:40]2)[C:34](=[O:42])[C:33]=1[C:43]#[N:44]>O1CCOCC1.CCOC(C)=O.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:39]1([CH2:38][N:35]2[CH:36]=[CH:37][C:32]([C:16]3[CH:15]=[CH:14][C:4]([O:5][C:6]4[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[N:7]=4)=[CH:3][C:2]=3[F:1])=[C:33]([C:43]#[N:44])[C:34]2=[O:42])[CH2:40][CH2:41]1
Reactant: Cc1cc(C)nc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)c1
Reactant: N#Cc1c(Br)ccn(CC2CC2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(C)nc(Oc2ccc(-c3ccn(CC4CC4)c(=O)c3C#N)c(F)c2)c1

Procedure:
To a solution of intermediate 8 (1.42 mmol) in 1,4-dioxane (6 ml) and a saturated solution of NaHCO3 (5 ml) was added intermediate 5 (0.329 g, 1.3 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.15 mg, 0.13 mmol). The reaction was then microwaved in a sealed tube at 140° C. for 5 minutes. The resulting cooled reaction mixture was then diluted with EtOAc and filtered through a pad of diatomaceous earth. The filtrate was washed with water, dried (Na2SO4) and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 10% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 1 that was washed with diethyleter and dried in vacuum (0.207 g, 41%). Melting point: 137.0° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[Cl:14][C:15]1[C:16]([CH2:25][CH2:26][NH2:27])=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:14][C:15]1[C:16]([CH2:25][CH2:26][NH:27][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[N:11][C:3]=2[C:2]([F:1])([F:13])[F:12])=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=1
Reactant: O=C(O)c1cccnc1C(F)(F)F
Reactant: NCCc1ncc(C(F)(F)F)cc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCc1ncc(C(F)(F)F)cc1Cl)c1cccnc1C(F)(F)F

Procedure:
A solution of 204 mg (1 mmol) of 2-trifluormethyl nicotinic acid, 200 mg (0.9 mmol) of 2-(3-chloro-5-trifluormethyl-pyridin-2-yl)-ethylamine and 620 mg (1.3 mmol) of bromotripyrrolidinophosphonium hexafluorophosphate and 230 mg (1.8 mmol) N,N-Diisopropylethylamine in 8 ml methylene chloride is stirred for 20 h at room temperature.
Reaction SMILES: ClN1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[C:12]([SH:16])[CH:13]=[CH:14][CH:15]=1.[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH3:18]>C(Cl)Cl>[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]2[C:29]([C:30]=1[S:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([Br:9])[CH:11]=1)=[CH:28][CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH3:18]
Reactant: Sc1cccc(Br)c1
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1Sc1cccc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
N-Chlorosuccinimide (1.59 g, 12 mmol) was dissolved in DCM (100 mL) and the solution was cooled to −78° C. 3-Bromothiophenol (1.24 mL, 12 mmol) was added dropwise and the reaction stirred for 30 minutes. Then, 6-chloro-1H-indole-2-carboxylic acid ethyl ester (2.2 g, 10 mmol) as a solution in DCM was added in 3 portions and the reaction was allowed to slowly warm to room temperature and continued stirring overnight. The reaction mixture was concentrated then purified by silica gel chromatography (0-30% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][C@@H:10]([CH3:12])[N:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([N+:20]([O-])=O)=[CH:15][N:14]=3)[CH2:8][C@@H:7]2[CH3:23])=[O:5])[CH2:3][CH2:2]1>CCO.[Pd]>[NH2:20][C:16]1[CH:17]=[C:18]([CH3:19])[C:13]([N:9]2[C@H:10]([CH3:12])[CH2:11][N:6]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[C@@H:7]([CH3:23])[CH2:8]2)=[N:14][CH:15]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1N1C[C@H](C)N(C(=O)C2CC2)C[C@H]1C
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)cnc1N1C[C@H](C)N(C(=O)C2CC2)C[C@H]1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Add NH4COOH (0.23 g, 3.5 mmol) to rac-cyclopropyl-[(trans)-2,5-dimethyl-4-(3-methyl-5-nitro-pyridin-2-yl)-piperazin-1-yl]-methanone (0.114 g, 0.35 mmol) and Pd/C 10% (0.043 g) in EtOH (5 mL) under N2 atmosphere and heat at 80° C. After 2 hours let reaction mixture cool down and filter through Celite®. Concentrate under reduced pressure to give 0.1 g the title compound (quantitative). MS(ES): m/z=289.3[M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C([Cl:40])=O.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([Cl:40])=[O:27])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(=O)O)c3)n2)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(=O)Cl)c3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid (600 mg, 1.13 mmol) was suspended in methylene chloride (6 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (567 μL, 1.13 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (264 μL, 2.27 mmol) was added dropwise. The reaction continued to stir at 0° C. for 10 min to afford the crude 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoyl chloride as a 0.166 M solution in methylene chloride which was used in the following step with no further purification.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].S(Cl)(Cl)=O.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[NH2:23]>O1CCCC1>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[NH:23][C:1](=[O:10])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: O=C(O)c1ccccc1O
Reactant: Nc1ccc(F)cc1F
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1F)c1ccccc1O

Procedure:
To a solution of salicylic acid (1.38 g, 10 mmole) in tetrahydrofuran (40 mL) was added thionyl chloride (2.5 mL, 35 mmole) and refluxed 3 hr. The mixture was steamed (110° C.) by Dean-Stark. The residue was directly reacted with 2,4-difluorobenzenamine (1 mL, 10 mmole) in THF (40 mL) for 3 hr. The reaction mixture was concentrated and extracted with ethyl acetate, dried over anhydrous magnesium sulfate. Recrystallization of desired products from hot dichloromethane afforded the compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][S:5][CH:6]=1.[CH3:7][O:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12](B(O)O)=[CH:11][N:10]=1.C([O-])(O)=O.[Na+]>COCCOC.O>[S:5]1[CH:6]=[C:2]([C:12]2[C:13]([O:15][CH3:16])=[N:14][C:9]([O:8][CH3:7])=[N:10][CH:11]=2)[CH:3]=[N:4]1
Reactant: Brc1cnsc1
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ncc(-c2cnsc2)c(OC)n1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
4-bromoisothiazole (commercially available from Aurora, 500 mg, 3.05 mmol) was dissolved in degassed 1,2-Dimethoxyethane (DME) (5 ml). Pd(Ph3)4 (176 mg, 0.152 mmol) was added thereto. The reaction mixture was stirred at room temperature for 15 min. [2,4-bis(methyloxy)-5-pyrimidinyl]boronic acid (commercially available from Aldrich, 1178 mg, 6.40 mmol) and 5 mL of degassed 1M/H2O solution of NaHCO3 were added to the reaction mixture under N2 atm. After 2 h 30 min stirring at 90° C. the mixture was diluted with water and extracted with DCM. The collected organic phases were evaporated. The residue was purified by flash chromatography eluting with cyclohexane/EtOAc 5:1. 686 mg of the title compound were isolated as a yellow solid.