Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8](OCC)[O:9]CC)(=[O:5])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[C:1]([O:6][CH2:7][CH:8]=[O:9])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCC(OCC)OCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(=O)OCC=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A well-stirred solution of 28 (8.16 g, 40 mmol) in DCM (200 ml) at room temperature, was treated with TFA (44.4 g, 30 ml, 390 mmol) and water (7.2 g, 7.2 ml, 400 mmol). After stirring for 2 hours at room temperature the solution was evaporated at 35° C. It was then coevaporated with hexane several times to remove traces of TFA. Compound 24 (5.2 g, 40 mmol, 100%) was obtained as a colorless liquid, and was used in the next step without any further purification.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:11]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:45]1[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=2[N:47]=[C:46]1[C:54](O)=[O:55].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O.CC#N>[NH:45]1[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=2[N:47]=[C:46]1[C:54]([N:2]1[CH2:3][CH:4]([C:6]2[C:11]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:5]1)=[O:55]
Reactant: COc1ccccc1Oc1nccnc1C1CNC1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: COc1ccccc1Oc1nccnc1C1CN(C(=O)c2nc3ccccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
The mixture of 2-azetidin-3-yl-3-(2-methoxy-phenoxy)-pyrazine hydrochloride (108 mg, 0.37 mmol), HATU (280 mg, 0.74 mmol) and TEA (130 mg, 1.3 mmol) in dry DCM (10 mL) was stirred at RT for 30 min, then 1H-benzoimidazole-2-carboxylic acid was added to the solution. The solution was heated to 80° C. overnight. The mixture was poured into saturated aqueous Na2CO3 and extracted with DCM (50 mL×2). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude compound, which was purified by ISCO silica gel column (10% to 80% EtOAc in petroleum ether) and followed by reverse phase prep. HPLC (10% to 80% water/MeCN) to give (1H-benzoimidazol-2-yl)-{3-[3-(2-methoxy-phenoxy)-pyrazin-2-yl]-azetidin-1-yl}-methanone (40 mg, 0.11 mmol, yield 27%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(N)CO
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO)NC(=O)c1cccc(-c2ccc3ncnc(N)c3n2)c1

Procedure:
Following the same reaction and purification procedure, the acid 14 (80 mg, 0.30 mmol) was reacted with 2-amino-2-methylpropan-1-ol (CAS 124-68-5) (53 mg, 0.6 mmol), HATU (129 mg, 0.3 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-(1-hydroxy-2-methylpropan-2-yl)benzamide 18. LC/MS (ESI+): m/z 338 (M+H). 1H NMR (400 MHz, DMSO) δ 8.69-8.55 (m, 2H), 8.51 (d, J=8.9 Hz, 1H), 8.43 (s, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.05 (d, J=39.6 Hz, 2H), 7.91 (d, J=7.7 Hz, 1H), 7.76 (s, 1H), 7.61 (t, J=7.7 Hz, 1H), 4.90 (t, J=6.0 Hz, 1H), 3.57 (d, J=6.0 Hz, 2H), 1.36 (s, 6H).
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[C:9]([NH2:14])=[N:10][CH:11]=[N:12][CH:13]=1.[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C(O)(C)(C)C>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][NH:14][C:9]2[C:8]([Cl:7])=[CH:13][N:12]=[CH:11][N:10]=2)=[CH:29][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: Nc1ncncc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Clc1cncnc1NCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
2.1 g (19 mmol) of potassium tert-butylate are added to a suspension of 2.2 g (17.2 mmol) of 5-chloro-pyrimidin-4-ylamine in tert-butanol (50 ml) and the temperature is kept at 60° C. After stirring for 1 h, a solution of 4.1 g (17.2 mmol) of 4-benzyloxy-benzyl chloride in tert-butanol (40 ml) is added dropwise and the reaction mixture is stirred at this temperature for 1 h. The reaction mixture is cooled to room temperature and poured into water (300 ml). The precipitate is filtered off and the filtrate is extracted with ethyl acetate (2×200 ml). The combined organic layers are dried with magnesium sulphate and concentrated in vacuo. The residue is purified by chromatography on silica gel (toluene/dioxane=6:1) to yield 2.0 g (37%) of the title compound as a beige powder of m.p. 95°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([OH:25])=O)=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:30][S:31][CH2:32][CH2:33][NH2:34]>>[CH3:30][S:31][CH2:32][CH2:33][NH:34][C:23]([C:20]1[C:19]2[N:15]([CH:16]=[CH:17][CH:18]=2)[C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:26]([F:27])([F:28])[F:29])[O:13][N:12]=2)=[CH:22][CH:21]=1)=[O:25]
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reactant: CSCCN
Product: CSCCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12

Procedure:
Using a procedure similar to that described in Example 1, except using 5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-indolizine-8-carboxylic acid (37 mg, described above in Example 3) and 2-methylthioethylamine, the title compound was isolated as an orange-reddish solid (21.2 mg, 49%). MS (ES): M/Z [M+H]=516. 1H NMR (400 MHz, CHLOROFORM-d): 2.17 (s, 3H), 2.83 (t, J=6.2 Hz, 2H), 3.75 (q, J=6.0 Hz, 2H), 3.91 (d, J=16.6 Hz, 1H), 4.28 (d, J=16.6 Hz, 1H), 6.83 (d, J=7.4 Hz, 1H), 7.02-7.08 (m, 1H), 7.17 (d, J=7.2 Hz, 1H), 7.46 (t, J=1.7 Hz, 1H), 7.55 (s, 2H), 8.73 (d, J=1.6 Hz, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −79.8 (s, 3F).
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.C1C=CC=CC=1.N1CCCC1>C1(C)C=CC=CC=1>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:24]2/[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[NH:26][C:25]/2=[O:30])[NH:11][C:10]=1[CH3:17])=[O:8])[CH2:18][CH3:19]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: c1ccccc1
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C

Procedure:
Accordingly, the present invention provides the crystalline Form-C obtained in non-polar alicyclic hydrocarbon solvent like cyclopentane, cyclohexane or cycloheptane. According to the process of the present invention, 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (IX) and 5-Fluoro-1,3-dihydro-indol-2-one (X) in aromatic hydrocarbon solvents like benzene or toluene are reacted in presence of catalytic amount of pyrrolidine as base at 80-85° C. for 3-9 hours. The resultant Sunitinib base is again triturated with the same solvent at 80-85° C. for 1-2 hours and isolated at a temperature ranging from 20-45° C., preferably at 25-35° and most preferably at 25-30° C. and dried at 60° C. for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26](=[O:30])[C:27]([OH:29])=[O:28])=[CH:18]1.[F:31][C:32]1[C:37](O)=[C:36]([F:39])[C:35]([F:40])=[C:34]([F:41])[C:33]=1[F:42].C(O)(=O)C>O1CCCC1>[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26](=[O:30])[C:27]([O:29][C:37]2[C:36]([F:39])=[C:35]([F:40])[C:34]([F:41])=[C:33]([F:42])[C:32]=2[F:31])=[O:28])=[CH:18]1
Reactant: Cn1cc(C(=O)C(=O)O)c2ccccc21
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cn1cc(C(=O)C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c2ccccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 21.9 %

Procedure:
1.13 g (5.5 mol) of dicyclohexylcarbodiimide were added to a solution, cooled in ice, of 1 g (5 mmol) of 1-methylindole-3glyoxylic acid and 1.01 g (5 mmol) of pentafluorophenol in 50 ml of dry tetrahydrofuran. After stirring for 4 hours under a nitrogen atmosphere at 0° C., the mixture was allowed to warm to room temperature and left to stand for 60 hours. Then, 3 ml of glacial acetic acid were added and the mixture obtained was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using dichloromethane for the elution to give 404 mg (22%) of pentafluorophenyl 1-methylindole-3-glyoxylate in the form of a pale yellow solid of melting point 168°-9° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](N)[S:9][CH:10]=1)=[O:5])[CH3:2].N([O-])=O.[Na+].[BrH:16]>O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:16])[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(N)n1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1csc(Br)n1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
A solution of 30 g (174.3 mmol) ethyl-2-aminothiazole-4-carboxylate [prepared as in Example 1a)] in a mixture of 100 ml HBr (65%) and 100 ml of water was cooled to -15° C. and a solution of 12.03 g (174.3 mmol) sodium nitrite in 40 ml water was added over a period of 30 minutes and the mixture stirred for another 30 minutes at -15° C. After warming to room temperature, the solid was collected, washed with 50 ml cold water and dried to give 23.7 g (57.6%) ethyl-2-bromothiazole-4-carboxylate m.p. 63°-65° C.
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:8]=[N:9][N:10]([CH3:12])[CH:11]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C@:31]([CH:33]=[O:34])([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1.O>O1CCCC1.ClCCl>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C:31]([C@@H:33]([OH:34])[C:7]5[CH:8]=[N:9][N:10]([CH3:12])[CH:11]=5)([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C=O)C1
Reactant: Cn1cc(I)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cn1cc([C@H](O)C23Cc4cnn(-c5ccc(F)cc5)c4C=C2CCN(C(=O)OC(C)(C)C)C3)cn1
Reaction time: 1 h

Procedure:
A second reaction was performed with inverse addition of n-butyl lithium. To a solution of 4-iodo-1-methyl-1H-pyrazole (157 mg, 0.755 mmol) in tetrahydrofuran (2 mL) was added n-butyl lithium (2.5 M in Hexanes) (312 μl, 0.780 mmol) at −78° C. The mixture was stirred at this temperature for 1 hour, then a solution of (R)-tert-butyl 1-(4-fluorophenyl)-4a-formyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (100 mg, 0.252 mmol) in tetrahydrofuran (1 mL) was added dropwise to the reaction mixture. The mixture was stirred at this temperature for 30 minutes. Water (6 mL) and dichloromethane (8 mL) were added and the phases were separated using a phase separator cartridge. The solvent was removed in vacuo to give an orange oil, with a similar composition to the previous reaction product according to LC/MS analysis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1Br)([O-:15])=[O:14].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: COc1ccc(F)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1-c1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 172.4 %

Procedure:
A mixture of 4-fluoroanisole-2-boronic acid (3.3 g, 19.4 mmol), 2-nitrobromobenzene (3.56 g, 17.6 mmol), triphenylphosphine (367 mg, 1.4 mmol), triethylamine (4.6 g, 45.8 mmol), and 40 mL of dimethylformamide was sparged with nitrogen for 5 minutes before adding palladium acetate (160 mg, 0.7 mmol) and heating the mixture to 100° C. for 5 hours. The reaction was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was shaken with 0.1N sodium hydroxide, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via flash silica gel chromatography eluting with 2% ethyl acetate/hexanes followed-by 4% ethyl acetate/hexanes to give 7.5 g of the title compound. Yield: 86%. EA. MS(FD).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH2:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1COCC1>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](=[S:34])[NH2:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OCCn2c1nc(C(N)=O)c(OCc1ccccc1)c2=O
Solvent: C1CCOC1
Product: CC1(C)OCCn2c1nc(C(N)=S)c(OCc1ccccc1)c2=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a solution of 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.54 g, 1.64 mmol, 1.0 equiv) in THF (33 mL) under a nitrogen atmosphere, was added Lawesson's reagent (0.40 g, 0.98 mmol, 0.6 equiv). The yellow solution was then heated to 70° C. (oil bath). After stirring for 1 h, the reaction was cooled to ambient temperature and concentrated in vacuo. The crude product was purified by silica gel chromatography (30-100% ethyl acetate/hexane) to provide the title compound (0.28 g, 49% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.04 (s, 1H), 7.63 (s, 1H), 7.50-7.57 (m, 2H), 7.27-7.41 (m, 3H), 5.30 (s, 2H), 3.96-4.08 (m, 4H), 1.62 (s, 6H); LCMS (ES+, (M+H)+) m/z 346.17.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[CH:10]1(B(O)O)[CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>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>[CH:10]1([C:2]2[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:8]=2)[NH2:7])[CH2:12][CH2:11]1
Reactant: Nc1cc(Br)ccc1F
Reactant: OB(O)C1CC1
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: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(C2CC2)ccc1F
Yield: 54.3 %

Procedure:
Stir the mixture of 5-bromo-2-fluoroaniline (800 mg, 4.26 mmol), cyclopropylboronic acid (434 mg, 5.05 mmol), tetrakis(triphenylphosphine)palladium(0) (242 mg, 0.21 mmol), cesium carbonate (2.7 g, 8.28 mmol) in dioxane (5 mL) and water (0.3 mL) under N2 atmosphere at 100° C. for 17 hrs. TLC (EtOAc:PE=1:3) shows the reaction is complete. Filter off the solid, concentrate the filtrate. Purify by flash chromatography (silica gel, EtOAc:PE=3:7) to afford the title compound (350 mg, 55%). MS: (M+1): 152.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.ON1C(=O)N(O)C(=O)N(O)C1=O.[C:21]([OH:24])(=[O:23])[CH3:22].O=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:22]([C:21]([OH:24])=[O:23])=[CH:4][CH:3]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: CC(=O)O
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: O
Solvent: Cc1ccc(Cl)cc1
Product: O=C(O)c1ccc(Cl)cc1

Procedure:
A mixture of 0.380 g of 4-chlorotoluene, 0.027 g of hexahydro-1,3,5-trihydroxy-1,3,5-triazine-2,4,6-trione (5% by mole relative to 4-chlorotoluene), 5 g of acetic acid and 0.004 g of cobalt(II) acetate.4 H2O was stirred at 100° C. in an atmosphere of oxygene gas (1 atm=0.1 MPa) for 14 hours. The resulting product in the reaction mixture was analyzed by gas chromatography and was found to yield 4-chlorobenzoic acid in 99% yield at 100% conversion of 4-chlorotoluene.
Reaction SMILES: O.C([O-])(=O)C.[Na+].[Cl:7][C:8]1[C:9]([OH:18])=[C:10]([CH:12]=[C:13]([Cl:17])[C:14]=1[CH2:15][CH3:16])[NH2:11].[CH3:19][C:20]([C:24]1[CH:36]=[C:35]([C:37]([CH3:41])([CH3:40])[CH2:38][CH3:39])[CH:34]=[CH:33][C:25]=1[O:26][CH:27]([CH2:31][CH3:32])[C:28](Cl)=[O:29])([CH3:23])[CH2:21][CH3:22]>CCCCCCC.C1(C)C=CC=CC=1>[CH3:23][C:20]([C:24]1[CH:36]=[C:35]([C:37]([CH3:40])([CH3:41])[CH2:38][CH3:39])[CH:34]=[CH:33][C:25]=1[O:26][CH:27]([CH2:31][CH3:32])[C:28]([NH:11][C:10]1[CH:12]=[C:13]([Cl:17])[C:14]([CH2:15][CH3:16])=[C:8]([Cl:7])[C:9]=1[OH:18])=[O:29])([CH3:19])[CH2:21][CH3:22]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Cl
Reactant: CCc1c(Cl)cc(N)c(O)c1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Solvent: O
Product: CCc1c(Cl)cc(NC(=O)C(CC)Oc2ccc(C(C)(C)CC)cc2C(C)(C)CC)c(O)c1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a 4-neck flask with a gas inlet, condenser, thermometer, and addition funnel, 50 mL of deionized water and 31 g of sodium acetate was added and stirring was continued until the solid dissolved. At this point, 57 g of heptane, 20 g of toluene, and 30 g (0.146 moles) of 3,5-dichloro-4-ethyl-2-hydroxyaniline was added and the 2-phase mixture was warmed to 60° C. A solution of 53.2 g of 2-[2,4-bis(1,1-dimethylpropyl)phenoxy]butyryl chloride (0.157 moles, 8% excess) in 53 g of heptane was then added at 60° C.-65° C. The reaction was held for 2 hr at 60° C. -65° C., upon which time the area percent product by HPLC was 92% on a solvent-free basis. The two-phase mixture was heated to 75° C.-80° C. and held for 15 minutes. The agitator was stopped and the lower layer was decanted. The product solution was washed twice with 42 g of deionized water, cooled to 70° C. and seeded. The product slurry was cooled to 0° C.-5° C., and the product was collected by filtration, washed with cold heptane, and dried to give 66.9 g (90% yield), with an assay of 99.5% (wt.).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.C(N(CC)CC)C.[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCCCCC>COCCOC.[Cu]I.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.C(OCC)(=O)C>[Br:7][C:5]1[N:6]=[C:2]([C:22]#[C:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:3][CH:4]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1csc(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Brc1csc(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.2 %

Procedure:
2,4-Dibromo-1,3-thiazole (2.0 g, 8.2 mmol) and CuI (312 mg, 1.64 mmol) were combined in DME (25 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (5.7 mL, 41 mmol) and PdCl2(PPh3)2 (580 mg, 0.82 mmol) were added, and then phenylacetylene (0.90 mL, 8.6 mmol) was added dropwise. The reaction was stirred for 4 h at ambient temperature at which point GC/MS analysis showed the reaction to be complete. The mixture was filtered through Celite™, the filter pad was washed thoroughly with Ethyl acetate and the combined filtrates were then concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL), washed with water (200 mL), brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with hexane, then 97:3 hexane:ethyl acetate to afford pure 4-bromo-2-(phenylethynyl)-1,3-thiazole (1.0 g, 46% yield) as a colorless solid. M.p. 79–82° C.; 1H NMR (CDCl3, 300 MHz) δ 7.60–7.56 (m, 2H) 7.45–7.26 (m, 3H), 7.26 (s, 1H). MS (EI ionization) 263 (M+, 79Br), 265 (M+, 81Br).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][OH:17])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7].C(N(CC)CC)C>ClCCl.O>[CH3:1][S:2]([O:17][CH2:16][CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=1)(=[O:4])=[O:3]
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Reaction time: 5 h
Yield: 84 %

Procedure:
Methanesulfonyl chloride (0.28 mL) was added dropwise to a stirred solution of 2-(3-nitrophenyl)ethanol (0.5 g; 1 eq) in dichloromethane (3 mL) and triethylamine (0.5 mL; 1.2 eq) at 0° C. under an inert atmosphere. The solution was allowed to reach r.t. and stirred for 5 hours. The reaction mixture was diluted with water (3 mL) and extracted into dichloromethane (3×3 mL). The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by flash chromatography, eluting with a gradient from dichloromethane to dichloromethane/MeOH (98/2) affording the title compound in 84% yield (0.62 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[C:14](=[O:15])[NH:13][CH2:12][CH2:11][N:10]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:4][CH:3]=1.CI.[CH2:25](OC1C=CC(CCl)=CC=1)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2([CH3:25])[C:14](=[O:15])[NH:13][CH2:12][CH2:11][N:10]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1Sc1ccc(Cl)cc1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Solvent: CI
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1(C)Sc1ccc(Cl)cc1

Procedure:
When in the procedure of Example 3a, 27a is substituted for 2 and methyl iodide substituted for p-benzyloxybenzyl chloride, the title compound is obtained.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH3:5][N:6]1[C:10]([C:11](=[O:28])[NH:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([N:19]=[C:20]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[N:21]=3)[CH:18]=2)=[C:9]([C:29](O)=[O:30])[CH:8]=[N:7]1>>[N:1]1([C:29]([C:9]2[CH:8]=[N:7][N:6]([CH3:5])[C:10]=2[C:11]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([N:19]=[C:20]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[N:21]=3)[CH:18]=2)=[O:28])=[O:30])[CH2:4][CH2:3][CH2:2]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1
Reactant: C1CNC1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1

Procedure:
Using azetidine and 1-methyl-5-(2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. White solid (75 mg, 48%). Mp.: 272° C. MS: m/z=403.2 (M+H+).