Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].[CH3:26][O:27][C:28]([CH:30]1[CH2:33][CH2:32][CH:31]1[C:34](O)=O)=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:34]([CH:31]5[CH2:32][CH2:33][CH:30]5[C:28]([O:27][CH3:26])=[O:29])[N:24]([CH3:25])[C:3]=4[CH:4]=3)[C:9](=[O:23])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: CNc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1N
Reactant: COC(=O)C1CCC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1CCC1c1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.4 %

Procedure:
A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (830 mg), (1RS, 2SR)-2-(methoxycarbonyl)cyclobutanecarboxylic acid (406 mg), HATU (1.33 g), N,N-diisopropylethylamine (0.611 ml) and DMF (20 ml) was stirred at room temperature for 2 h. The mixture was quenched with water, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4 and concentrated in vacuo. Then a mixture of the obtained residue and AcOH (20 ml) was stirred at 80° C. for 30 min. After concentration of the mixture, the residue was poured into saturated NaHCO3 solution, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4, and concentrated in vacuo. The residual solid was washed with IPE to give the title compound (172 mg) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8]Cl)=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:8][CH:7]=[CH:6][C:5]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: ClCC=Cc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Nc1nc2c(s1)CCN(CC=Cc1ccc(Cl)cc1)CC2
Yield: 26 %

Procedure:
Prepared from 4-chloro-cinnamyl chloride and 1 equivalent of 2-amino-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine in chloroform. Yield: 26% of theory, Melting point: 148°-153° C. (ether).
Reaction SMILES: C(OP([O-])OCC)C.[H-].[Na+].Br[CH:12]([CH3:16])[C:13]([OH:15])=[O:14].[H][H].[C:19]1([C:25]2[CH:26]=[C:27]([CH:30]=O)[S:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>COCCOC>[CH3:16]/[C:12](=[CH:30]\[C:27]1[S:28][CH:29]=[C:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:26]=1)/[C:13]([OH:15])=[O:14]
Reactant: [H][H]
Reactant: CC(Br)C(=O)O
Reactant: O=Cc1cc(-c2ccccc2)cs1
Agent: CCOP([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C/C(=C\c1cc(-c2ccccc2)cs1)C(=O)O
Reaction time: 1 h
Yield: 25.8 %

Procedure:
A 50 ml round bottomed flask was charged with diethylphosphite (684 μl, 5.31 mmol) and treated sequentially with sodium hydride (637 mg, 15.94 mmol, 60% in mineral oil) in DME (20 ml), followed by 2-bromopropionic acid (478 μl, 5.31 mmol). The reaction was stirred at room temperature until hydrogen evolution ceased. Next 4-phenyl-2-thiophenecarboxaldehyde (1.0 g, 5.31 mmol) was added and the reaction stirred for 1 h. The reaction was quenched by the addition of EtOH (5 ml) and the contents of the flask poured into distilled water (20 ml). The strongly basic solution was washed with diethyl ether (25 ml) to remove traces of mineral oil, the aqueous layer acidified to pH 4 with concentrated HCl and extracted with diethyl ether (2×25 ml). The organic layer was dried (MgSO4) and the solvent removed in vacuo. The crude residue was washed with petroleum spirit 40-60° C., and the resulting insoluble solid, fractionally crystallized from dichloromethane to afford the title compound as a white solid (335.2 mg, 29%).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1.CO>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:15]=2[C:16]([O:18][CH3:1])=[O:17])=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1-c1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc([N+](=O)[O-])cc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
Oxalyl chloride (9.35 g; 0.074 mol) was added to a solution of 2-(4-fluorophenyl)-4-nitrobenzoic acid (17.5 g; 0.067 mol) in methylene chloride (150 ml). After addition of DMF (3 drops), the mixture was stirred at ambient temperature for 2 hours. After evaporation to dryness the residue was redissolved in methylene chloride (100 ml); methanol (50 ml) and DMAP (8.2 g; 0.067 mol) was added at 0° C. After stirring at ambient temperature for 2 hours, the mixture was evaporated to dryness. The residue was taken up in methylene chloride washed with a 2N HCl, saturated aqueous sodium bicarbonate and evaporated to give methyl 2-(4-fluorophenyl)-4-nitrobenzoate (17.6 g; 95%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:44][C:45]1[CH:46]=[C:47]([CH:51]=[C:52]([Cl:54])[N:53]=1)[C:48]([OH:50])=O.[N:55]1([CH2:61][CH2:62][NH2:63])[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>CC(N(C)C)=O>[Cl:54][C:52]1[CH:51]=[C:47]([CH:46]=[C:45]([Cl:44])[N:53]=1)[C:48]([NH:63][CH2:62][CH2:61][N:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1)=[O:50]
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(NCCN1CCOCC1)c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 105 %

Procedure:
HATU (989 mg, 2.6 mmol), HOAT (354 mg, 2.6 mmol) and DIEA (907 μl, 5.21 mmol) were added to a stirred solution of 2,6-dichloroisonicotinic acid (500 mg, 2.60 mmol) in anhydrous DMA (4 ml). The mixture was stirred for 10 minutes after which 2-morpholin-4-yl-ethylamine (420 μl, 2.86 mmol) was added. The mixture was stirred at room temperature for 12 h and the mixture was partitioned between EtOAc and water. The EtOAc layer was washed well with water, dried over sodium sulphate and concentrated in vacuo to give the title compound as an oil (830 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:31](=[O:32])[N:30]([CH3:33])[C:12]2[N:13]([CH3:29])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]([CH2:27][CH3:28])[N:22]=[C:23]([CH2:25][OH:26])[CH:24]=1)=[CH:16][CH:15]=3.Cl[CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:31](=[O:32])[N:30]([CH3:33])[C:12]2[N:13]([CH3:29])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]([CH2:27][CH3:28])[N:22]=[C:23]([CH2:25][O:26][CH2:35][CH2:36][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[CH:24]=1)=[CH:16][CH:15]=3
Reactant: ClCCN1CCCC1
Reactant: CCn1nc(CO)cc1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Product: CCn1nc(COCCN2CCCC2)cc1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Product: Cl

Procedure:
The process is carried out as in Example 101 above, with the compound from Example 61, 3-(2,4-dichlorophenyl)-6-(2-ethyl-5-hydroxymethyl-2H-pyrazol-3-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and chloroethylpyrrolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=O)NC(=O)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].CI.[OH2:23].[CH3:24][N:25]([CH3:28])[CH:26]=[O:27]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH3:15])[C:24](=[O:23])[N:25]([CH3:28])[C:26](=[O:27])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(=O)[nH]c(=O)[nH]2)cc1OC
Reactant: CN(C)C=O
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COc1ccc(-c2cc(=O)n(C)c(=O)n2C)cc1OC
Temperature: 60 °C

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-2,4(1H,3H)-pyrimidinedione (8.0 g) in N,N-dimethylformamide (50 ml) and added sodium hydride (50% in oil, 3.40 g) and the mixture was heated at 60° C. for 30 minutes with stirring. To this mixture which was cooled to ambient temperature was added methyl iodide (40 ml) and the resulting mixture was stirred at the same temperature for 90 minutes. To the reaction mixture was added water and evaporated under reduced pressure. The residue was diluted with water (300 ml) and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol. The fractions containing the object compound were combined and concentrated under reduced pressure to give 6-(3,4-dimethoxyphenyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (1.94 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=3[O:26][CH3:27])[CH2:15][CH2:14]2)=[N:11][CH3:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:34](=[O:36])[CH3:35])=[CH:21][C:20]=3[O:26][CH3:27])[CH2:15][CH2:14]2)=[N:11][CH3:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CN=C(Nc1cc(Cl)cc(Cl)c1)N1CCN(c2ccc(O)cc2OC)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CN=C(Nc1cc(Cl)cc(Cl)c1)N1CCN(c2ccc(OC(C)=O)cc2OC)CC1

Procedure:
A solution of 0.10 mole of N-[3,5-dichlorophenyl]-N'-methyl-4-[2-methoxy-4-hydroxy phenyl]-1-piperazine-carboxamidine, 0.12 mole of pyridine and 0.12 mole of acetic anhydride in 250 ml of dichloromethane was stirred 12 hours at room temperature and poured into 2 L water. The organic phase was separated, washed with cold water, dried on sodium sulfate and evaporated. The residue (oil) was purified by flash chromatography on silica gel (200 mesh) using ethylacetate (60)/methanol (40) as eluant. The first 250 ml of eluant were collected and evaporated, and the residue further purified by recrystallization, to give N-[3,5-dichlorophenyl]-N'-methyl-4-[2-methoxy-4-acetyloxy-phenyl]-1-piperazine-carboxamidine, m.p. 144° C.
Reaction SMILES: Cl[CH2:2][CH:3]1[S:11][C:10]2[N:5]([C:6](=[O:16])[N:7]([CH2:13][CH2:14][CH3:15])[C:8](=[O:12])[CH:9]=2)[CH2:4]1.[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(Cl)Cl.O>[C:17]1([S:23][CH2:2][CH:3]2[S:11][C:10]3[N:5]([C:6](=[O:16])[N:7]([CH2:13][CH2:14][CH3:15])[C:8](=[O:12])[CH:9]=3)[CH2:4]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Sc1ccccc1
Reactant: CCCn1c(=O)cc2n(c1=O)CC(CCl)S2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCCn1c(=O)cc2n(c1=O)CC(CSc1ccccc1)S2
Yield: 95 %

Procedure:
A mixture of 2-chloromethyl-6-propyl-2,3-dihydro-5H-thiazolo[3,2-c]pyrimidine-5,7(6H)-dione (0.8 g), thiophenol (0.47 ml) and potassium carbonate (0.63 g) was refluxed in ethanol (20 ml) for 42 hours. The solution was concentrated to dryness, and the resulting residue thus obtained was dissolved in methylene chloride and water. After washing with water and drying, the organic solution was concentrated to dryness. The resulting syrup was purified by column chromatography on silica gel to give colorless syrup. This syrup was allowed to stand in a refrigerator to obtain colorless crystals (1.2 g, 95%).
Reaction SMILES: C([O:5][C:6]([C:8](NC(=O)OC(C)(C)C)=[CH:9][C:10]1[N:11]=[CH:12][O:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7])(C)(C)C.[O:27]1CCNC1>C1COCC1>[C:15]([C:14]1[O:13][CH:12]=[N:11][C:10]=1[CH:9]=[C:8]([OH:27])[C:6]([OH:5])=[O:7])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC(=Cc1ncoc1C(C)(C)C)C(=O)OC(C)(C)C
Reactant: C1COCN1
Solvent: C1CCOC1
Product: CC(C)(C)c1ocnc1C=C(O)C(=O)O
Temperature: -40 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of Ethyl 5-(tert-butyl)oxazole-4-carboxylate 2 (20 g, 101 mmol) in anhydrous THF (250 mL) was added LiAl (3.84 g, 101 mmol, Kanto Chemical, Tokyo, Japan, Cat. No. 24115-35) portionwise under argon atmosphere at −60° C., and the bath temperature was gradually increased up to −40° C. with stirring for 2 h. (In case that the temperature was more than −40° C., the reduction of the oxazole ring (oxazolidine formation) predominantly proceeded). After the reaction mixture was quenched with saturated NH4Cl aq (50 ml) at −60° C. (Please avoid rapid elevation of temperature. Some impurity increased.), AcOEt (250 ml) was-added and stirred for a few minutes, and the resulting precipitate was removed by celite filtration (Celite-535, Nacalai Tesque, Kyoto, Japan, Cat. No. 07509-05). The filtrate was washed with water (×2), 10% citric acid (×3, a byproduct, oxazolidine, can be removed by this separation) and saturated NaCl (×3), dried over anhydrous Na2SO4, and concentrated in vacuo to give an oil of corresponding oxazole alcohol 3 (10.6 g, 67%). Rf 0.50 (CHCl3:MeOH=10:0.5), 1H NMR (300 MHz CDCl3) δ 7.71 (s, 1H), 4.66 (s, 2H), 1.36 (s, 9H); HRMS(EI): m/z 155.0852 (M+) (Calcd for C8H13NO2: 155.0854). This oil was used to the next oxidation without further purification.
Reaction SMILES: C(Cl)Cl.[S:4]([NH:14][C@H:15]([C:22]([OH:24])=O)[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)([C:7]1[CH:13]=[CH:12][C:10]([CH3:11])=[CH:9][CH:8]=1)(=[O:6])=[O:5].Cl.[CH2:26]([O:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(N(CC)CC)C>[CH2:26]([O:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[C:22](=[O:24])[C@H:15]([CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)[NH:14][S:4]([C:7]1[CH:8]=[CH:9][C:10]([CH3:11])=[CH:12][CH:13]=1)(=[O:5])=[O:6])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]cn2)C(=O)O)cc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 100 ml of desiccated methylene chloride were added 10 g of Nα -t-butyloxycarbonyl-Nim -tosyl-L-histidine (47) and 6.50 g of L-proline benzyl ester hydrochloride and the mixture was cooled in an ice bath. After adding thereto 2.72 g of triethylamine, 6.05 g of DCC was further added to the mixture and the resultant mixture was stirred for 30 minutes in an ice-bath and stirred overnight at room temperature. Insoluble matters were filtered off and the filtrate was concentrated. The residue thus formed was purified by silica gel column chromatography. By eluting the product with ethyl acetate-benzene (1:1), 13.5 g of Nα -t-butyloxycarbonyl-Nim -tosyl-L-histidyl-L-proline benzyl ester (49) was obtained.
Reaction SMILES: NCCN[C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[NH2:22][CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25]>>[OH:25][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:23][NH:22][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6]
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: NCC(O)c1ccccc1
Product: O=C(NCC(O)c1ccccc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using 2-amino-1-phenyl ethanol instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 379 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br. s.) 10.17 (1H, s) 8.07 (1H, t, J=5.37 Hz) 8.02 (1H, d, J=5.47 Hz) 7.77 (1H, d, J=5.47 Hz) 7.45 (1H, d, J=5.27 Hz) 7.27-7.38 (6H, m) 7.18-7.26 (1H, m) 6.79 (1H, d, J=5.47 Hz) 6.44 (1H, d, J=3.51 Hz) 5.51 (1H, d, J=3.90 Hz) 4.77 (1H, ddd, J=7.86, 4.30, 4.05 Hz) 3.47 (1H, dt, J=13.13, 5.15 Hz)
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]([N:13]2[CH2:14][CH2:15][CH:10]([OH:9])[CH2:11][CH2:12]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccc1Br
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC1CCN(c2ncccc2Br)CC1
Temperature: 120 °C
Yield: 64.1 %

Procedure:
3-Bromo-2-chloropyridine (5.95 g, 30.92 mmol), 4-hydroxypiperidine (5 g, 49.43 mmol) and potassium carbonate (15.03 g, 108.75 mmol) were combined in DMF (200 ml) and heated to 120° C. overnight. The solvent was removed and the residues partitioned between EtOAc and water. The aqueous layer was re-extracted with EtOAc and the combined organics washed with water, dried and concentrated. The crude product was purified by column chromatography. Elution with 20-75% EtOAc/pet. ether yielded the product as a yellow oil (5.1 g). δH (CDCl3, 400 MHz): 1.60-1.61 (1H, m), 1.68-1.79 (2H, m), 2.01-2.07 (2H, m), 2.98-3.04 (2H, m), 3.64-3.69 (2H, m), 3.86-3.91 (1H, m), 6.74-6.77 (1H, m), 7.77-7.79 (1H, dd), 8.21-8.22 (1H, m).
Reaction SMILES: C([S-])C.[Na+].CN(C)C=O.C[O:11][C:12]1[CH:34]=[CH:33][C:15]([C:16]([C:18]2[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([OH:28])=[C:20]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:19]=2)=[O:17])=[CH:14][CH:13]=1.Cl>C1C=CC=CC=1>[OH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([C:18]2[CH:23]=[C:22]([C:24]([CH3:26])([CH3:27])[CH3:25])[C:21]([OH:28])=[C:20]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:19]=2)=[O:17])=[CH:33][CH:34]=1
Reactant: COc1ccc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Agent: CC[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(C(=O)c2ccc(O)cc2)cc(C(C)(C)C)c1O
Temperature: 23 °C
Reaction time: 16 h

Procedure:
To a freshly prepared, stirred solution of 0.25 mole of sodium ethanethiolate in 250 ml. of N,N-dimethylformamide at 0° C. is added 34 g. (0.10 mole) of 4-(4-methoxybenzoyl)-2,6-di(t-butyl)phenol, and the resulting solution is refluxed for 3 hours. The solution is stirred at 23° C. for about 16 hours, then acidified with 10 percent hydrochloric acid and extracted with dichloromethane. The organic extracts are washed twice with 10 percent hydrochloric acid, then with water, then dried and evaporated to provide an oil residue. The residue is dissolved in benzene and cooled. A solid crystallizes after many hours. It is recrystallized from a benzene-hexane mixture, then sublimed to provide white crystals of 4-(4-hydroxybenzoyl)-2,6-di(t-butyl)-phenol, m.p. 188°-189.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:31])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][N:43](C(OC(C)(C)C)=O)[CH:44]=2)O1>>[CH3:31][C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[CH:22][C:14]=2[NH:13][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([C:40]4[CH:41]=[N:42][NH:43][CH:44]=4)=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:12])[N:18]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=2)[N:17]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(Br)ccn45)cccc32)n1
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(-c6cn[nH]c6)ccn45)cccc32)n1

Procedure:
Prepared according to procedure of Example 68 using 7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate. MS (ES+APCI) m/z=463 (M+H) detected.
Reaction SMILES: Br.C[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH:8]2[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O.C>C(O)(=O)C.C(#N)C>[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH:8]2[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cccc2c1CCC2N1CCCCC1
Agent: Br
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: Oc1cccc2c1CCC2N1CCCCC1
Temperature: 0 °C

Procedure:
Hydrobromic acid (47-49%, 750 ml) is added to a stirred solution of the 4-methoxy-1-piperidinylindan (75 g) in glacial acetic acid (750 ml) under nitrogen. The mixture is refluxed for four hours, allowed to cool and poured into crushed ice and water. The pH of the ice mixture is adjusted to about 9 and the aqueous mixture extracted with methylene chloride. The methylene chloride extract is washed with water thereby forming a precipitate which is filtered and the solid dried. The methylene chloride layer is evaporated yielding an oil. The solid is dissolved in acetonitrile and treated with charcoal. The oil is treated with charcoal and dissolved in acetonitrile. Both dissolved materials are recrystallized from acetonitrile yielding the desired product, M.P. 134.5°-136.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18](Br)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2].[CH2:23]([O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:32]=3)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3cccc(OCc4ccccc4)c3)o2)c1
Temperature: 85 °C

Procedure:
The furyl bromide (99) (100 mg, 0.28 mmol) was coupled to 3-benzyloxy-phenylboronic acid (69 mg, 0.30 mmol) acid using Method E, except that the reaction was heated at 85° C. The crude product was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=1.[Li]CCCC.[F:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#N)=[CH:24][C:23]=1[O:30][CH3:31].CC[O:34]CC>C1COCC1>[F:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]([C:2]2[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=2)=[O:34])=[CH:24][C:23]=1[O:30][CH3:31]
Reactant: COc1cc(C#N)ccc1F
Reactant: CCOCC
Reactant: Fc1cc(Br)cc(OC(F)(F)C(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: -60 °C
Yield: 71 %

Procedure:
To a solution of 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (15 g, 51.7 mmol) in Et2O (100 mL) was added n-BuLi (20.7 mL, 2.5 M, 51.7 mmol) at −75° C. The reaction mixture was allowed to warm up to −60° C., followed by the addition of 4-fluoro-3-methoxy-benzonitrile (7.5 g, 46.6 mmol) in a mixture of THF and Et2O (6 mL/6 mL). The reaction was quenched immediately by addition of H2O. The aqueous portion was extracted with Et2O. The separated organic portion was washed by 1N HCl, concentrated under reduced pressure and purified by ISCO chromatography using hexanes/EtOAc (0-10%) to afford (4-fluoro-3-methoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone as white powder (13 g, 71%). LCMS: RT=4.101 min, [M+H] 345.1 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm)