Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][C:13]=2[C:24](=[O:41])[NH:25][C:26]2[CH:30]=[CH:29][N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[N:27]=2)=[O:10])[CH:6]=[CH:5][CH:4]=1.[CH3:42][NH:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N:18]1([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:9]([C:7]3[N:8]=[C:3]([CH2:2][N:43]([CH3:42])[CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][C:55]([O:57][C:58]([CH3:60])([CH3:59])[CH3:61])=[O:56])[CH:4]=[CH:5][CH:6]=3)=[O:10])=[C:13]([C:24](=[O:41])[NH:25][C:26]3[CH:30]=[CH:29][N:28]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=4)[N:27]=3)[CH:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C(Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cccc(CCl)n1
Reactant: CNCCOCCOCCOCCC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCOCCOCCOCCC(=O)OC(C)(C)C)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)n1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 6-(chloromethyl)-N-(4-(piperidin-1-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)carbamoyl)phenyl)picolinamide (170 mg, 0.29 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), tert-butyl 3-(2-(2-(2-(methylamino)ethoxy)ethoxy)ethoxy)-propanoate (255 mg, 0.88 mmol, 3.00 equiv), potassium iodide (24.2 mg, 0.15 mmol, 0.50 equiv), and potassium carbonate (79.5 mg, 0.58 mmol, 1.97 equiv). The resulting solution was stirred for 2.5 h at 70° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in
Reaction SMILES: [I-:1].[K+].O[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([C:19]1[CH:20]=[N:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH3:32])[CH2:27][CH2:26]2)=[CH:23][CH:24]=1)=[O:18].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>P(=O)(O)(O)O.O>[I:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([C:19]1[CH:20]=[N:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH3:32])[CH2:27][CH2:26]2)=[CH:23][CH:24]=1)=[O:18]
Reactant: [I-]
Reactant: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: O=S([O-])([O-])=S
Solvent: O
Product: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCI)cn2)CC1
Temperature: 110 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a solution of 0.26 g of potassium iodide in 2 ml of phosphoric acid was added 0.10 g of N-(12-hydroxydodecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide and the mixture was stirred at 110° C. for 3 hours. The reaction solution was diluted with water, and a saturated aqueous solution of sodium hydrogen carbonate and an aqueous solution of sodium thiosulfate were added. The mixture was extracted with chloroform. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to afford 0.11 g of the title compound.
Reaction SMILES: [OH:1][C:2]([CH3:12])([CH:6]([CH3:11])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][NH2:5].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CCO>[OH:1][C:2]([CH3:12])([CH:6]([CH3:11])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][NH:5][C:20](=[O:21])[O:22][CH2:23][CH3:24]
Reactant: CCOC(=O)Cl
Reactant: CCCCC(C)C(C)(O)CCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCC(C)C(C)(O)CCNC(=O)OCC
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a stirred suspension of 3-hydroxy-3,4-dimethyoctylamine (4.91 g; 28.38 mmole) and anhydrous sodium carbonate (5 g) in dry etanol (40 ml) was added ethyl chloroformate (3.65 g; 33.6 mmole) in dry ethanol (25 ml), over 30 min. The mixture was heated under reflux for 1 hr and then poured into water (200 ml). The product was extracted into diethyl ether (3×100 ml), and the combined organic layers washed with dilute hydrochloric acid (1×100 ml) and brine (1×100 ml) and dried. (Na2SO4). Evaporation in vacuo gave ethyl N-[3-hydroxy-3,4-dimethyloctyl]-carbamate (6.2 g; 891).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][O:29][C@H:30]([CH3:34])[C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[C@H:30]([O:29][CH3:28])[CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CO[C@H](C)C(=O)O
Agent: Cl
Product: CO[C@H](C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (69 mg, 66%), MS (ISP) m/z=417.4 [(M+H)+], mp 170.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and (R)-2-methoxy-propanoic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:50])[CH2:7][C@H:8]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33](=[O:49])[CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)[CH2:28]1)=[O:26])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CO.[Pd]>[C:1]([O:5][C:6](=[O:50])[CH2:7][C@H:8]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33](=[O:49])[CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)[CH2:28]1)=[O:26])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[CH:14]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(C#Cc2cccc(O)c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(CCc2cccc(O)c2)c1
Reaction time: 4 h
Yield: 62.2 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-{5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (200 mg, 0.29 mmol) in ethyl acetate (8.5 mL) and methanol (1.4 mL) was stirred for 7 hours at room temperature under a hydrogen atmosphere in the presence of palladium on charcoal (10%, 20 mg), while the addition of palladium on charcoal (10%, 20 mg) was repeated after 4 hours. The suspension was filtrated through celite, which were washed thoroughly with methanol. The solution was concentrated under reduced pressure and the residue was purified by preparative HPLC to yield 125 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-{5-[2-(3-hydroxyphenyl)ethyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [CH:1]([Si:4]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([CH3:3])[CH3:2].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19]>>[CH:14]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:11]([CH3:13])[CH3:12])[N:5]1[CH2:10][CH2:9][N:8]([CH2:19][CH2:18][C:17]([O:21][CH3:22])=[O:20])[CH2:7][CH2:6]1)([CH3:16])[CH3:15]
Reactant: C=CC(=O)OC
Reactant: CC(C)[Si](C(C)C)(C(C)C)N1CCNCC1
Product: COC(=O)CCN1CCN([Si](C(C)C)(C(C)C)C(C)C)CC1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 194.0 g (0.8 mol) of 1-triisopropylsilylpiperazine (Synthesis Example 2) and heated at 70° C. Once the internal temperature became steady, 75.8 g (0.88 mol) of methyl acrylate was added dropwise over 2 hours. Stirring was continued for 4 hours at the temperature. On distillation of the reaction solution, 250.0 g of a fraction having a boiling point of 163-164° C./0.4 kPa was collected.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:20]1([C:16]2[N:15]=[C:14]([C:12]3[S:4][C:3]4[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=4[C:1](=[O:10])[N:13]=3)[CH:19]=[CH:18][CH:17]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(N2CCCCC2)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(N3CCCCC3)n2)sc2ccccc12
Yield: 11.8 %

Procedure:
A mixture of methyl thiosalicylate (0.36 g, 2.1 mmol), 2-cyano-6-(1-piperidinyl)pyridine (0.40 g, 2.1 mmol), triethylamine (0.45 ml, 3.1 mmol) and toluene (50 ml) was refluxed for 48 hrs as described in Example 1. The solvent was concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (2:1, v/v). The obtained crystals were recrystallized from hexane-ethyl acetate to give the titled compound (0.08 g, 13%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH2:15][C:16]([OH:18])=O)[N:14]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1>>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH:26]2[CH2:31][CH2:30][N:29]([C:16](=[O:18])[CH2:15][C:13]3[N:14]=[C:10]([NH:9][C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:8])[S:11][CH:12]=3)[CH2:28][CH2:27]2)[CH2:22][CH2:21]1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)s2)n1
Product: CN1CCN(C2CCN(C(=O)Cc3csc(NC(=O)c4ccc(Cl)s4)n3)CC2)CC1

Procedure:
53.2 Using general method A, {2-[(5-chloro-thiophene-2-carbonyl)-amino]-thiazol-4-yl}-acetic acid was coupled with 1-methyl-4-(piperidin-4-yl)-piperazine to give 5-chloro-thiophene-2-carboxylic acid (4-{2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide. Light yellow amorphous solid. MS 468.4 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.Br[C:16]1[CH:30]=[CH:29][C:19]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1>>[CH3:28][N:25]1[CH2:26][CH2:27][N:22]([C:20]([C:19]2[CH:29]=[CH:30][C:16]([NH:1][C:2]3[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:3]=3)=[CH:17][CH:18]=2)=[O:21])[CH2:23][CH2:24]1
Reactant: CN1CCN(C(=O)c2ccc(Br)cc2)CC1
Reactant: N#Cc1cn(-c2ccccc2)nc1N
Product: CN1CCN(C(=O)c2ccc(Nc3nn(-c4ccccc4)cc3C#N)cc2)CC1

Procedure:
3-({4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}amino)-1-phenyl-1H-pyrazole-4-carbonitrile was prepared according to the general procedure in Example 7 Step 2 using 3-amino-1-phenyl-1H-pyrazole-4-carbonitrile (50 mg, 0.271 mmol) and 1-(4-bromobenzoyl)-4-methylpiperazine (77 mg, 0.271 mmol) as the starting materials.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([N:19]([CH3:21])[CH3:20])[CH:15]([F:22])[CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH2:29]([C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30]>>[CH2:29]([C:31]1[N:32]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][C@@H:16]([N:19]([CH3:20])[CH3:21])[C@@H:15]([F:22])[CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: CN(C)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC1F
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC[C@@H](N(C)C)[C@@H](F)C3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, racemic 1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-3-fluoro-N,N-dimethylpiperidin-4-amine and 2-ethylbenzimidazole were reacted. The enantiomers were separated by SFC to give 227. LCMS m/z: 522.3 (MH+)
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[CH:40][CH:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[CH:40][CH:39]=[N:38]2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cccn2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cccn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) (319 mg, 1.0 mmol) and 3-oxo-3-(3-pyrazol-1-yl-phenyl)-propionic acid tert.-butyl ester (Example K16) (286 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow amorphous substance (485 mg).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:12][C:13]([CH3:29])([CH2:16][N:17]1[CH:25]=[C:24]2[C:19]([C:20]([Cl:28])=[C:21]([Cl:27])[CH:22]=[C:23]2[Cl:26])=[N:18]1)[C:14]#[N:15]>C1COCC1>[C:14]([C:13]([NH:12][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:29])[CH2:16][N:17]1[CH:25]=[C:24]2[C:19]([C:20]([Cl:28])=[C:21]([Cl:27])[CH:22]=[C:23]2[Cl:26])=[N:18]1)#[N:15]
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(C#N)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-cyanobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (10.5 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=432, RT=0.66 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.[CH2:17]([C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][C:29]([F:32])([F:31])[F:30])[CH:26]=2)[N:21]([NH2:33])[CH:20]=1)[CH3:18].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[CH2:17]([C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][C:29]([F:30])([F:32])[F:31])[CH:26]=2)[N:21]([NH:33][C:8]([C:7]2[C:2]([CH3:1])=[N:3][C:4]([C:11]3[N:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:5][CH:6]=2)=[O:10])[CH:20]=1)[CH3:18]
Reactant: Cc1nc(-c2ncccn2)ncc1C(=O)O
Reactant: CCc1cn(N)c2ccc(OC(F)(F)F)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCc1cn(NC(=O)c2cnc(-c3ncccn3)nc2C)c2ccc(OC(F)(F)F)cc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
A solution of 4-methyl-[2,2′]bipyrimidinyl-5-carboxylic acid (250 mg, 1.1 mmol) and 3-ethyl-5-trifluoromethoxy-indol-1-ylamine (244 mg, 1 mmol) in DMF (5 mL) is stirred at 50° C. for 1 h. The mixture is treated with DMTMM (276 mg, 1.0 mmol) and stirred at 50° C. for 1 h. The mixture is diluted with saturated aqueous Na2CO3 (5 mL) and stirred for 10 min. The precipitate is collected by filtration, washed with H2O (50 mL) and heptane (50 mL), and dried in vacuo to afford 4-methyl-[2,2′]bipyrimidinyl-5-carboxylic acid (3-ethyl-5-trifluoromethoxy-indol-1-yl)-amide (130 mg, 29%). MS: 443 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.25 (s, 1H), 9.05 (d, 2H), 7.69 (t, 1H), 7.64 (s, 1H), 7.54 (m, 2H), 7.14 (d, 1H), 2.80 (s, 3H), 2.76 (q, 2H), 1.29 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([CH3:22])([CH3:21])[CH2:18][CH:19]=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CC(C)=[O:25].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([CH3:22])([CH3:21])[CH2:18][C:19]([OH:25])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: CC(C)(CC=O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC(C)(CC(=O)O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
To a stirred solution of the above 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutanal in acetone (3 mL) was added Jones' reagent (1 mL) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 30 min before being concentrated under reduced pressure. The residue was neutralized with saturated aqueous sodium bicarbonate solution and 10% aqueous citric acid solution, and then extracted with ethyl acetate (3×10 mL). The combined ethyl acetate extracts were dried (Na2SO4), concentrated and purified by reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) to give 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutanoic acid (100 mg, 0.32 mmol, 43% yield for 2 steps) as a yellow oil.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:33]([OH:35])[CH3:34])[C@@H:3]1O[C@H:4]1[CH2:6][C@@H:7]1[C@@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19])[O:9][CH2:8]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[K+].[Se-]C#N.[K+].C(O)(CC)(C)C.O>COC(OC)(C)C.C(OCC)(=O)C>[CH3:1][C@@H:2]([C@@H:33]([OH:35])[CH3:34])/[CH:3]=[CH:4]/[CH2:6][C@@H:7]1[C@@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19])[O:9][CH2:8]1
Reactant: C/C(=C\C(=O)OCCCCCCCCC(=O)O)C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#C[Se-]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCC(C)(C)O
Solvent: COC(C)(C)OC
Product: C/C(=C\C(=O)OCCCCCCCCC(=O)O)C[C@@H]1OC[C@H](C/C=C/[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Reaction time: 1 h
Yield: 57.8 %

Procedure:
Pseudomonic acid A (500 mgs) was dissolved in 2,2-dimethoxypropane (20 ml) and ethyl acetate (20 ml) then p-toluene sulphonic acid (few crystals) added. The solution was stirred for 1 hour then washed with brine and dried (MgSO4). After evaporation of the solvent in vacuo, the residue was dissolved in watermethanol (1:1, 20 ml) and potassium bicarbonate (100 mgs, 1 eq) added. The solvents were removed in vacuo and potassium selenocyanate (432 mgs, 3 eq), tert-amyl alcohol-water (9:1, 15 ml) added and the reaction refluxed for 4 days,. After filtering the solution was evaporated to dryness, water (20 ml) added and solution adjusted to pH2 (5 M-HCl) under a layer of ethyl acetate (20 ml). The organic layer was separated and the aqueous layer further extracted with ethyl acetate (3×20 ml). The combined extracts were dried (MgSO4) and evaporated to an oil which was redissolved in 80% acetic acid (10 ml) and stirred at room temperature overnight. The solution was evaporated to dryness and the residual oil chromatographed on silica (10 g) eluting with 0 to 6% methanol-chloroform. Fractions containing pure product (tlc) were combined and evaporated to give pseudomonic acid C (280 mgs, 58%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][C:36]=1[NH:50][S:51]([CH3:54])(=[O:53])=[O:52].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:15]=4)=[CH:9][N:8]([S:24]([C:27]4[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:5]3=[N:6][CH:7]=2)=[CH:37][C:36]=1[NH:50][S:51]([CH3:54])(=[O:53])=[O:52]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2ccc(F)c(NS(C)(=O)=O)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(F)c(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 64.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-phenethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (190 mg, 0.364 mmol) was coupled with N-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (Intermediate 65) (115 mg, 0.364 mmol) using sodium carbonate (115 mg, 1.093 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.0182 mmol) in DME/water (15/2 ml). This afforded 147 mg (64.1% yield) after purification by column (Silica gel 60/120) using 25% ethyl acetate in chloroform as eluent. MS: m/z=630.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[C:8]([Cl:21])=[CH:9][C:10]([F:20])=[C:11]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:12]=2)=[C:4]([C:24]#[N:25])[CH:3]=1.[S-:26][C:27]#[N:28].[K+].BrBr>C(O)(=O)C>[NH2:28][C:27]1[S:26][C:3]2[C:4]([C:24]#[N:25])=[C:5]([O:6][C:7]3[C:8]([Cl:21])=[CH:9][C:10]([F:20])=[C:11]([NH:13][C:14](=[O:19])[C:15]([F:16])([F:17])[F:18])[CH:12]=3)[CH:22]=[CH:23][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: N#Cc1cc(N)ccc1Oc1cc(NC(=O)C(F)(F)F)c(F)cc1Cl
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: N#Cc1c(Oc2cc(NC(=O)C(F)(F)F)c(F)cc2Cl)ccc2nc(N)sc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.5 %

Procedure:
To a solution of N-[5-(4-amino-2-cyanophenoxy)-4-chloro-2-fluorophenyl]-2,2,2-trifluoroacetamide (1.0 g, 2.68 mmol) in acetic acid (20 mL) was added potassium thiocyanate (1.3 g, 13.4 mmol), and the mixture was stirred at room temperature for 10 min. A solution of bromine (513 mg, 3.21 mmol) in acetic acid (10 mL) was slowly added dropwise to the obtained solution. After the completion of the dropwise addition, the mixture was stirred at room temperature for 12 hr. The resulting yellow insoluble material was filtered off and washed with acetic acid. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (150 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (150 mL×2) and saturated brine (150 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→80/20), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (0.71 g, 60%) as a white powder.