Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH:16]([OH:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:16]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=[C:12]([CH3:15])[N:11]=1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccc(OCc2ccccc2)c(C(O)c2ccccc2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(OCc2ccccc2)c(C(=O)c2ccccc2)n1
Yield: 98.1 %

Procedure:
116 g of 3-benzyloxy-2-(α-hydroxybenzyl)-6-methylpyridine was dissolved in 500 ml of chloroform. 400 g of manganese dioxide was added under stirring, followed by heating under stirring at 60 ° C. for one hour in an oil bath. After cooling as it was, the reaction solution was filtered to remove insoluble matters, and the solvent was removed. The resulting crystals were vacuum-dried, to give 113 g of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:22])[CH2:13][CH2:12][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:14]#[N:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:24][CH:25]1[CH2:27][CH2:26]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([O:22][CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH2:9][CH2:10][C:11]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([C:14]#[N:15])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(c2ccccc2)CCC(O)(c2cccc(Br)c2)CC1
Reactant: BrCC1CC1
Product: N#CC1(c2ccccc2)CCC(OCC2CC2)(c2cccc(Br)c2)CC1

Procedure:
The title compound was prepared from 4-(3-bromophenyl)-4-hydroxy-1-phenylcyclohexanecarbonitrile and bromomethylcyclopropane according to the process described in Example 41.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[CH2:18]([C:20]([OH:25])([CH2:23][CH3:24])[C:21]#[CH:22])[CH3:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.CN(C=O)C.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.[Cu]I>[CH2:18]([C:20]([OH:25])([CH2:23][CH3:24])[CH2:21][CH2:22][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1)[CH3:19]
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Reactant: C#CC(O)(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(O)(CC)CCc1cccc(CCCNC(=O)C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
To a degassed solution of N-(3-(3-bromophenyl)propyl)-2,2,2-trifluoroacetamide (3) (0.930 g, 3 mmol) and 3-ethylpent-1-yn-3-ol (4) (0.670 g, 6 mmol) in triethylamine (4 mL) and DMF (12 mL) was added PdCl2(PPh3)2 (0.053 g, 0.075 mmol), tri-o-tolylphosphine (0.046 g, 0.15 mmol), and CuI (0.014 g, 0.075 mmol). The resulting mixture was degassed and stirred under argon at 90° C. for 6 h. The mixture was cooled to room temperature then concentrated under reduced pressure and diluted with EtOAc (100 mL) and water (70 mL). After vigorous shaking, the layers were separated. The organic layer was treated with charcoal, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (7 to 60% EtOAc-hexanes gradient) gave N-(3-(3-(3-ethyl-3-hydroxypentyl)phenyl)propyl)-2,2,2-trifluoroacetamide (5) as a yellow oil. Yield (0.663 g, 65%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.17-7.28 (m, 4H), 5.11 (s, 1H), 3.16 (q, J=7.2 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 1.76 (quint, J=7.2 Hz, 2H), 1.53-1.67 (m, 4H), 0.97 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[O:4].[CH3:14][C:15](C)([O-])[CH3:16].[K+]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH:15]([CH3:16])[CH3:14])[N:6]=1)=[O:4]
Reactant: COC(=O)c1n[nH]c2ccccc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1nn(C(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a solution of indazole-3-carboxylic acid methyl ester (40.7 g, 231 mmol) in anhydrous tetrahydrofuran (700 mL) cooled in an ice bath was added slowly solid potassium tert-butoxide (28.3 g, 252 mmol). The mixture was stirred at the same temperature for 1 hr prior to the addition of 2-iododopropane (34.4 mL, 367 mmol). The final mixture was stirred for 12 h at ambient temperature, and refluxed for 12 h. After cooling to room temperature, the mixture was filtered, and the collected solid was rinsed with tetrahydrofuran (100 mL). The filtrates were combined, and concentrated to dryness under reduced pressure, affording crude 1-isopropyl-1H-indazole-3-carboxylic acid methyl ester (49.7 g) as a pale yellow oil. The crude material was purified by flash silica gel chromatography eluting with hexane/ethyl acetate (9/1 to 3/1) to yield 1-isopropyl-1H-indazole-3-carboxylic acid methyl ester (43 g, 197 mmol, >99% pure). 1H-NMR (CD3OD, 300 MHz): δ (ppm) 8.1-8.0 (1H, d), 7.6 (1H, d), 7.4 (1H, t), 7.2 (1H, t), 5.0 (1H, quin), 3.9 (s, 3H), 1.5 (6H, d).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[CH2:25][C@H:24]2[CH2:26][C@H:22]([C:23]2([CH3:28])[CH3:27])[CH:21]1[NH2:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:32]=[C:33]2[C:39]([C:40]3[N:45]=[C:44](S(C)=O)[C:43]([F:49])=[CH:42][N:41]=3)=[CH:38][N:37]([S:50]([C:53]3[CH:59]=[CH:58][C:56]([CH3:57])=[CH:55][CH:54]=3)(=[O:52])=[O:51])[C:34]2=[N:35][CH:36]=1.C(N(C(C)C)CC)(C)C.[NH4+].[Cl-]>CN(C=O)C>[Si:1]([O:18][CH2:19][C@H:20]1[CH2:25][C@H:24]2[CH2:26][C@H:22]([C:23]2([CH3:28])[CH3:27])[C@@H:21]1[NH:29][C:42]1[C:43]([F:49])=[CH:44][N:45]=[C:40]([C:39]2[C:33]3[C:34](=[N:35][CH:36]=[C:31]([Cl:30])[CH:32]=3)[N:37]([S:50]([C:53]3[CH:59]=[CH:58][C:56]([CH3:57])=[CH:55][CH:54]=3)(=[O:52])=[O:51])[CH:38]=2)[N:41]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Reactant: CC1(C)[C@H]2C[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(N)[C@@H]1C2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@@H]4[C@@H](CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)C[C@H]5C[C@@H]4C5(C)C)n3)c3cc(Cl)cnc32)cc1
Temperature: 75 °C

Procedure:
To a solution of (1R,3S,5R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-6,6-dimethyl-bicyclo[3.1.1]heptan-2-amine, 77e, (0.20 g, 0.46 mmol) and 5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.14 g, 0.30 mmol) in DMF (1.5 mL) was added diisopropylethylamine (0.11 mL, 0.61 mmol). The reaction was heated to 75° C. for 18 hours. The mixture was diluted into aqueous saturated NH4Cl solution and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-5% MeOH/CH2Cl2 gradient) to afford 78 mg of the desired product.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH2:13][CH3:14])[CH2:9]1)=O)(C)(C)C.[NH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[NH:8]1[CH2:9][CH:10]([N:12]([CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:29][CH2:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)[N:23]=3)[CH:19]=[CH:20][CH:21]=2)[CH2:13][CH3:14])[CH2:11]1
Reactant: NCCc1ccc(O)cc1
Reactant: CCN(Cc1cccc(-c2ccnc(Cl)n2)c1)C1CN(C(=O)OC(C)(C)C)C1
Product: CCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1)C1CNC1

Procedure:
Intermediate 105 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 405. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.69 (s, 1H), 8.40 (d, 1H), 8.34 (s, 1H), 7.96 (d, 1H), 7.72 (t, 1H), 7.68 (d, 1H), 7.11 (d, 2H), 6.67 (d, 2H), 4.56 (m, 5H), 3.78 (m, 4H), 3.21 (q, 2H), 2.93 (t, 2H), 1.39 (t, 3H).
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([OH:9])=O.[CH2:10]([C@H:17]1[CH2:21][NH:20][C@H:19]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[O:23])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:21][N:20]([C:7]([CH:3]2[CH2:4][CH2:5][CH2:6][O:2]2)=[O:9])[C@H:19]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[O:23])[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)C1CCCO1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)C1CCCO1
Yield: 33.4 %

Procedure:
Proceeding as in Example 1, but substituting tetrahydrofuran-2-carboxylic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 92, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxamide (9.8 mg, 33.4%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): a 9.97 (s, 1H), 7.54 (m, 2H), 7.27 (m, 2H), 7.21-7.15 (m, 7H), 6.93 (m, 2H), 4.55-4.43 (m, 2H), 3.73 (m, 2H), 2.64 (m, 3H), 2.03-1.90 (m, 4H), 1.86-1.76 (m, 4H). MS (EI) for C29H29FN2O4. found 489.5 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:58]=[CH:57][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:32](=[O:33])[N:31]([C:34]6[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=6)[N:30]=[CH:29][CH:28]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([N:42]3[CH2:46][CH:45]4[CH2:47][N:48](C(OC(C)(C)C)=O)[CH2:49][CH:44]4[CH2:43]3)=[N:9]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:32](=[O:33])[N:31]([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)[N:30]=[CH:29][CH:28]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:58][CH:57]=3)[N:9]=[C:10]([N:42]3[CH2:46][CH:45]4[CH:44]([CH2:49][NH:48][CH2:47]4)[CH2:43]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(N3CC4CN(C(=O)OC(C)(C)C)CC4C3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2nc(N3CC4CNCC4C3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.2 %

Procedure:
A round-bottomed flask was charged with tert-butyl 5-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (42.5 mg, 0.0537 mmol), 2,2,2-trifluoroacetic acid (123 mg, 1.07 mmol) and CH2Cl2 (10 mL). The reaction mixture was stirred at ambient temperature for 4 hours. The solvent was removed and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give product (13.8 mg, 37.2%). LRMS (APCI neg): m/e 690 (M).
Reaction SMILES: CN(C)[CH:3]=[O:4].S(Cl)(Cl)=O.[Cl:10][C:11]([Cl:24])([Cl:23])[CH:12]1[NH:17][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[O:13]1>O>[CH:3]([N:17]1[C:16](=[O:18])[C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[O:13][CH:12]1[C:11]([Cl:10])([Cl:23])[Cl:24])=[O:4]
Reactant: O=C1NC(C(Cl)(Cl)Cl)Oc2ccccc21
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: O=CN1C(=O)c2ccccc2OC1C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Dimethylformamide (20 ml.) and thionyl chloride (5 ml.) were stirred together, 3,4-dihydro-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one (2.0 g.) was added in small portions over 15 minutes, and the mixture was stirred at ambient temperature for 48 hours. The reaction mixture was added to water (100 ml.), stirred for 1 hour and filtered. The solid product was dissolved in toluene, and purified by column chromatography on "Kieselgel"-60 (trade mark), eluting with a mixture of 5% by volume of ethyl acetate in toluene. The solvent was evaporated, and the product was crystallised from petroleum ether (b.p. 60°-80° C.) to give 3-formyl-3,4-dihydro-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one, m.p. 114° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:12][C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(=S)=S>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:23]1[CH:24]=[CH:25][C:20]([C:13]([CH3:12])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:21][CH:22]=1)=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: CCOC(=O)C(C)(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To 700 ml of carbon disulfide containing 36.5 g (0.254 mole) of 4-chlorobutyryl chloride is added 74.5 g (0.56 mole) of aluminum chloride with stirring at -10° C. Stirring is continued for about 15 minutes at about 25° C. then the mixture is recooled to 5° C. and 48.4 g (0.294 mole) of ethyl α,α-dimethylphenylacetate in 100 ml of carbon disulfide is added. The reaction mixture is stirred on an ice bath for 31/2 hours then stirred to 151/2 hours at 25° C. then poured into HCl-ice water and extracted with chloroform. The extract is washed with dilute sodium carbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate, and evaporated giving as a solid ethyl 4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetate.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7](Cl)[N:6]=1.[OH:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.Cl.C(OCC)C>CN1C(=O)CCC1>[F:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:22][C:21]2[CH:23]=[CH:24][C:18]([OH:17])=[CH:19][CH:20]=2)[N:6]=1
Reactant: Cc1ccc(F)c(Nc2ccnc(Cl)n2)c1
Reactant: Nc1ccc(O)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: Cc1ccc(F)c(Nc2ccnc(Nc3ccc(O)cc3)n2)c1
Temperature: 100 °C

Procedure:
4-(2-Fluoro-5-methylanilino)-2-chloropyrimidine (Reference Example A-10, 1.00 g, 4.2 mmol) was dissolved in NMP (5 ml) and 4-hydroxyaniline (0.41 g, 3.7 mmol) and 1M HCl in diethyl ether (4.22 ml, 4.2 mmol) was added. The reaction mixture was heated at 100° C. for 15 hours, and then allowed to cool to ambient temperature. The mixture was evaporated under high vacuum to give the title product as a brown oil. The residue was purified by chromatography on a Mega Bond Elute column (10 g) eluting with DCM (4×25 ml), 2% NH3/MeOH in DCM (3×25 ml), 4% NH3/MeOH in DCM (3×25 ml), 6% NH3/MeOH in DCM (10×25 ml to give the title product as a white solid (0.80 g, 61%). NMR (300 MHz): 2.2 (s, 3H), 6.2 (d, 1H), 6.6 (d, 2H), 6.9 (m, 1H), 7.1 (m, 1H), 7.4 (d, 2H), 7.8 (d, 1H), 7.9 (d, 1H), 8.7 (s, 1H), 8.8 (s, 1H), 8.9 (s, 1H); m/z: (ES+) 311.0 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26](F)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN1[C:36]([C:37](Cl)=[O:38])=[CH:35]N=C1>>[CH2:15]1[C:26]2[C:27](=[CH:28][CH:29]=[C:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:37](=[O:38])[C:36]6[CH:35]=[CH:6][CH:7]=[CH:2][CH:3]=6)[CH:7]=[CH:6][CH:5]=5)=[N:9][N:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=45)[CH:22]=[CH:21][N:20]=3)[CH:25]=2)[CH2:12][CH2:11][NH:10]1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1
Reactant: Cn1cncc1C(=O)Cl
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluorophenyl)-2-pyrimidinamine and 1-methyl-1H-imidazole-5-carbonyl chloride in a manner analogous to Example 66. 1H NMR (400 MHz, DMSO-d6): δ 10.14 (s, 1H), 9.80 (s, 1H), 8.84 (d, 1H), 8.50 (d, 1H), 8.30 (d, 1H), 8.04 (s, 1H), 7.87-7.76 (m, 4H), 7.52-7.41 (m, 3H), 7.29-7.22 (m, 2H), 7.13 (m, 1H), 6.72 (m, 1H), 6.57 (d, 1H), 3.83 (s, 3H); HRMS: calc. C28H22N8OF (M+H)+ 505.1901 found 505.1903.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([NH:5][C:6]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]2[C:9]([CH:10]=[CH:11][CH2:12][O:13]2)=[CH:8][CH:7]=1)=[O:4].Cl[C:23]([F:28])([F:27])C([O-])=O.[Na+]>COCCOCCOC>[CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([NH:5][C:6]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]2[C:9]([CH:10]3[C:23]([F:28])([F:27])[CH:11]3[CH2:12][O:13]2)=[CH:8][CH:7]=1)=[O:4]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCC=C2
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Solvent: COCCOCCOC
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCC1C2C1(F)F
Temperature: 160 °C
Yield: 56.3 %

Procedure:
Methyl 7-(2,2-dimethylpropionylamino)-2H-chromene-8-carboxylate (Intermediate 45, 1.0 g) was dissolved in diglyme (30 mL) and the solution was heated to 160° C. Sodium chlorodifluoroacetate (4.27 g) was added in portions over 15 minutes with the final portion being washed in with diglyme (15 mL). On completion of the addition the mixture was heated at 180° C. for 15 minutes. After cooling, the mixture was poured into water and extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane with a gradient of 2.5-15% to give methyl (1aRS,7bSR)-5-(2,2-dimethylpropionylamino)-1,1-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (0.66 g) as a colourless oil.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO.COCCOC.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>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:10]3[S:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[N:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(=O)Nc1nc2cccc(Br)c2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COc1ccc(-c2cccc3nc(NC(C)=O)sc23)cc1
Temperature: 85 °C
Reaction time: 0.83 h

Procedure:
N-(7-Bromobenzo[d]thiazol-2-yl)acetamide (56.5 mg, 0.208 mmol), 4-methoxybenzeneboronic acid (47.8 mg, 0.315 mmol), dichlorobis(triphenyl-phosphine)palladium (II) (30.7 mg, 43.7 μmol), and sodium carbonate (0.31 mL, 2 M, 0.62 mmol) were suspended in EtOH (0.25 mL) and 1,2-dimethoxyethane (0.9 mL). The flask was fit with a reflux condensor and placed in a preheated oil bath (85° C.) and stirred under nitrogen for 50 minutes. The reaction was cooled to RT, and filtered through a pad of Celite® (diatomaceous earth). This pad was washed with DCM and MeOH, and the filtrate was concentrated and filtered through a silica gel pad with 10:1 DCM/MeOH. The filtrate was concentrated and purified on HPLC (10-95% MeCN/water with 0.1% TFA over 30 minutes) to provide N-(7-(4-methoxyphenyl)benzo[d]thiazol-2-yl)acetamide. MS (ESI pos. ion) m/z: 299 (MH+). Calculated exact mass for C16H14N2O2S: 298. 1H NMR (400 MHz, DMSO-d6): 12.34 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.5 Hz, 5H), 7.51 (t, J=7.8 Hz, 1H), 7.34 (d, J=7.5 Hz, 1H), 7.12 (d, J=8.5 Hz, 2H), 3.81 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][S:11]([CH:14]2[CH2:16][CH2:15]2)(=[O:13])=[O:12])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:17][C:18]1[S:19][CH:20]=[C:21]([C:23]([NH:25][C:26]2[CH:34]=[C:33]([Sn](C)(C)C)[CH:32]=[C:31]3[C:27]=2[CH:28]=[N:29][N:30]3S(C2C=CC=CC=2)(=O)=O)=[O:24])[N:22]=1.CN(C=O)C>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.CO>[CH:14]1([S:11]([NH:10][C:4]2[CH:3]=[C:2]([C:33]3[CH:32]=[C:31]4[C:27]([CH:28]=[N:29][NH:30]4)=[C:26]([NH:25][C:23]([C:21]4[N:22]=[C:18]([CH3:17])[S:19][CH:20]=4)=[O:24])[CH:34]=3)[CH:7]=[N:6][C:5]=2[O:8][CH3:9])(=[O:13])=[O:12])[CH2:16][CH2:15]1
Reactant: Cc1nc(C(=O)Nc2cc([Sn](C)(C)C)cc3c2cnn3S(=O)(=O)c2ccccc2)cs1
Reactant: COc1ncc(Br)cc1NS(=O)(=O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ncc(-c2cc(NC(=O)c3csc(C)n3)c3cn[nH]c3c2)cc1NS(=O)(=O)C1CC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
N-[5-Bromo-2-(methyloxy)-3-pyridinyl]cyclopropanesulfonamide (208 mg, 0.371 mmol), 2-methyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (128 mg, 0.417 mmol) and Pd(PPh3)4 (43 mg, 0.037 mmol) were weighed to a microwave vial. DMF (3 ml) was added and the reaction was heated in the microwave at 120° C. for 30 min. LCMS showed incomplete reaction, therefore the mixture was reheated at 120° C. for a further 30 min. The residue was passed through a 1 g silica cartridge, pre-conditioned with methanol, washing with methanol. The solvent was evaporated in the blow down unit. The residue was purified on a 40 g silica cartridge on the ISCO Companion, using a 0.5-6% methanol in DCM gradient over 14 mins at a flow rate of 40 ml/min. Fractions containing desired material were combined and concentrated in vacuo, then subjected to further purification on the ISCO companion using a reverse phase 13 g column, with 0.1% TFA in MeCN and 0.1% TFA in water as eluents and a gradient of 15-65% MeCN over 14 mins. Fractions containing desired material were combined and concentrated in vacuo. The residue was dissolved in IPA (3 ml) and 2M NaOH (aq., 3 ml) was added and the reaction mixture left overnight. The IPA was evaporated and the aqueous was acidified using 2M HCl (aq). The precipitate was filtered, washing with water, then dissolved in 1 ml DMSO:methanol (1:1, v/v) and purified by MDAP (Method E) to afford the title compound (27 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:17]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([C:10]4[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=4)=[N:7][C:6]=3[CH:17]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1ccc(-c2nc3cc(Br)ccc3o2)cc1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc3oc(-c4ccc(C)cc4)nc3c2)cc1
Temperature: 150 °C
Yield: 38.1 %

Procedure:
To a solution of 5-bromo-2-p-tolylbenzo[d]oxazole (146.1 mg, 0.50 mmol) in dioxane (1.5 mL) was added water (0.5 mL), 4-methoxyphenylboronic acid (114 mg, 0.75 mmol), potassium carbonate (138 mg, 1.00 mmol) and tetrakis(triphenylphosphine)palladium(0) (3 mg). The resulting suspension was heated in the microwave at 150° C. for 15 min. After cooling, the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 1:99 v/v to afford 60 mg (38%) of the title compound (LCMS RT=9.18 min, MH+ 316.1)