Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:14]=[C:13]([C:15](N(OC)C)=[O:16])[N:12]([CH3:21])[C:11]=2[CH:22]=1>C1COCC1>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:14]=[C:13]([C:15]([CH:1]3[CH2:2][CH2:3]3)=[O:16])[N:12]([CH3:21])[C:11]=2[CH:22]=1
Reactant: Br[Mg]C1CC1
Reactant: CON(C)C(=O)c1nc2ccc(Br)cc2n1C
Solvent: C1CCOC1
Product: Cn1c(C(=O)C2CC2)nc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Cyclopropylmagnesium bromide (0.70 M in THF, 7.19 ml) was added dropwise to a solution of 6-bromo-N-methoxy-N,1-dimethyl-1H-benzimidazole-2-carboxamide (1.00 g) in THF (3 ml) at 0° C. The mixture was stirred at 0° C. under Ar atmosphere for 30 min. The mixture was quenched with saturated NH4Cl solution and extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc), and the resulting solid was washed with hexane to give the title compound (0.625 g) as a white solid.
Reaction SMILES: [N:1]1([OH:14])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[I-]>>[N:1]1([O:14][N:1]2[C:13]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[N:6]=[CH:5][C:4]=3[N:3]=[CH:2]2)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: On1cnc2cnc3ccccc3c21
Agent: [I-]
Product: c1ccc2c(c1)ncc1ncn(On3cnc4cnc5ccccc5c43)c12

Procedure:
In step (3) of Reaction Scheme II a 1H-imidazo[4,5-c]quinolin-1-yl alcohol of Formula XVII is alkylated with an iodide of Formula XVI to provide a 1H-imidazo[4,5-c]quinolin-1-yl ether of Formula XVIII. The alcohol of Formula XVII is reacted with sodium hydride in a suitable solvent such as N,N-dimethylformamide to form an alkoxide. The iodide is added to the alkoxide solution at ambient temperature. After the addition is complete the reaction is stirred at an elevated temperature (˜100° C.). Many compounds of Formula XVII are known, see for example, Gerster, U.S. Pat. No. 4,689,338; others can readily be prepared using known synthetic routes, see for example, Gerster et al., U.S. Pat. No. 5,605,899 and Gerster, U.S. Pat. No. 5,175,296.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[N-:13]=[N+]=[N-].[Na+].O.C(=O)([O-])O.[Na+]>C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:13][CH2:7][CH2:6]2
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)CCC2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc2c(c1)CCNC2=O
Yield: 43 %

Procedure:
To a solution of 5-methoxy-1-indanone (1.0 g) in TFA (20 ml) is added sodium azide (4.0 g), and the mixture is refluxed for 1.5 hour. After cooling, the reaction mixture is poured into water (100 ml), and the pH value of the mixture is adjusted to pH 7 with sodium hydrogen carbonate. The mixture is extracted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, and dried over magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (silica gel; 100 g, chloroform/methanol=20:1). The fractions containing the title compound are concentrated under reduced pressure to give the title compound (470 mg) as a pale brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]#[N:15])=[C:12]([CH2:16]O)[NH:11][C:10]2=[N:18][NH:19][CH:20]=[C:9]12.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]#[N:15])=[C:12]([CH2:16][Br:22])[NH:11][C:10]2=[N:18][NH:19][CH:20]=[C:9]12
Reactant: BrC(Br)(Br)Br
Reactant: N#CC1=C(CO)Nc2n[nH]cc2C1c1ccccc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#CC1=C(CBr)Nc2n[nH]cc2C1c1ccccc1Cl
Yield: 36.9 %

Procedure:
4-(2-Chlorophenyl)-5-cyano-6-(t-butyldimethylsilyloxy)-methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine was prepared from ethyl t-butyldimethylsilyloxyacetate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94. To a solution of 4-(2-chlorophenyl)-5-cyano-6-(t-butyldimethylsilyloxy)methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (10 g) in tetrahydrofuran (100 ml) was added a THF solution (24.9 ml) of 1.0 M tetrabutylammonium fluoride and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ethyl acetate (200 ml), and the resulting mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (5.46 g) as a white solid. To a solution of 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (1.0 g) and carbon tetrabromide (1.27 g) in methylene chloride (35 ml) was added triphenylphosphine (1.0 g) under ice-cooling and the mixture was stirred under ice-cooling for 4 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (0.45 g) as a pale-yellow solid. To a suspension of sodium hydride (25 mg) in DMF (3 ml) was added 1-methylpiperazine (69 μl) and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added a solution of 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (200 mg) in DMF (3 ml) under ice-cooling and the mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:ethyl acetate-methanol (4:1)). The obtained oil was treated with hydrogen chloride-methanol to give the title compound (87 mg) as white crystals.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.N1C=CC=CC=1>O1CCCC1>[N:12]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Clc1ccc2ccccc2n1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: c1ccc2nc(N3CCNCC3)ccc2c1
Yield: 91.4 %

Procedure:
A mixture of 2-chloroquinoline (10.0 g, 60.5 mmol), piperazine (26.1 g, 303 mmol) and pyridine (15 ml) was heated reflux temperature for 4 h. The hot reaction mixture was poured into a conical flask and diluted with tetrahydrofuran (150 ml). The precipitated solid was filtered off and washed with diethyl ether (3×50 ml) and the combined organic phases were evaporated in vacuo. The residue was suspended in a mixture of diethyl ether (200 ml) and 96% ethanol (80 ml) and undissolved solid was filtered off and washed with diethyl ether. The organic phase was evaporated in vacuo affording a solid which was crushed under water (200 ml) filtered off and washed with water (3×50 ml), diethyl ether (3×40 ml), dried in vacuo at 50° C. affording 11.8 g (92%) of 2-(1-piperazinyl)quinoline as a solid.
Reaction SMILES: C([N:8]1[CH2:16][C@@H:15]2[C@@:10]([CH3:23])([C@@H:11]([CH3:22])[CH2:12][C:13]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)C1C=CC=CC=1.CC(Cl)OC(Cl)=O>C1(C)C=CC=CC=1.Cl.CO>[ClH:21].[Cl:21][C:20]1[C:13]2[CH2:12][C@H:11]([CH3:22])[C@:10]3([CH3:23])[C@@H:15]([CH2:16][NH:8][CH2:9]3)[C:14]=2[CH:17]=[CH:18][CH:19]=1
Reactant: C[C@H]1Cc2c(Cl)cccc2[C@@H]2CN(Cc3ccccc3)C[C@]12C
Agent: CC(Cl)OC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: C[C@H]1Cc2c(Cl)cccc2[C@@H]2CNC[C@]12C
Temperature: 160 °C
Yield: 132.1 %

Procedure:
(3aR*,4S*,9bS*)-2-Benzyl-6-chloro-3a,4-dimethyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.153 mmol, 49.8 mg) was dissolved in toluene (1 ml). ACE-Cl (1.070 mmol, 0.118 ml, 153 mg) was added and the reaction mixture was heated in a microwave reactor at 160° C. for 15 minutes. Methanol (1 ml) was added and the reaction mixture was again heated in a microwave reactor at 160° C. for 5 minutes. The resulting solution was passed through an SCX cartridge and concentrated in vacuo to give a residue that was dissolved in 2 M HCl in MeOH and concentrated in vacuo to afford (3aR*,4S*,9bS*)-6-chloro-3a,4-dimethyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole hydrochloride (27.5 mg). m/z: 236.1 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>O1CCCC1>[CH:10](=[N:9][C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][N:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CSc1ccc(N)nc1
Reactant: O=Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(N=Cc2ccccc2)nc1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
5-(methylthio)-2-aminopyridine (185 g) was dissolved in 2 L tetrahydrofuran, and then 500 mL titanate tetraisopropyl and benzaldehyde (155 g) were added. The reaction mixture was heated for reflux overnight, then cooled to room temperature, and 10 L water was added. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with saturated NaCl solution, and dried with anhydrous sodium sulfate. After filtration, the residual solution was removed under reduced pressure to obtain the target compound (200 g).
Reaction SMILES: C(Cl)Cl.[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([C:18](=O)[CH3:19])[CH:15]=[CH:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:21][C:22]1([CH3:30])[O:27][C:26](=[O:28])[CH2:25][C:24](=[O:29])[O:23]1.N1C=CC=CC=1>C1COCC1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:21][C:22]1([CH3:30])[O:27][C:26](=[O:28])[C:25](=[C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:13]=2)[CH3:19])[C:24](=[O:29])[O:23]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(=O)c1cccc(OCc2ccccc2)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=C1C(=O)OC(C)(C)OC1=O)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
A 1.0M solution of titanium tetrachloride in DCM (9.3 mL, 9.3 mmol) was injected dropwise to THF (15 mL) cooled to 0° C. A solution of 1-(3-(benzyloxy)phenyl)ethanone (1.0 g, 4.42 mmol) (commercially available from Aldrich) and 2,2-dimethyl-1,3-dioxane-4,6-dione (701 mg, 4.86 mmol) (commercially available from Aldrich) in THF (5 mL) was then injected dropwise into the flask followed by dropwise addition of pyridine (1.8 mL, 22.1 mmol). The reaction temperature was allowed to warm to room temperature and the mixture was stirred overnight. The reaction was then quenched with water, extracted with EtOAc, dried over MgSO4, and filtered. The solvent was removed and the resulting crude mixture was purified by silica gel flash chromatography (hexane:EtOAc=4:1 to 1:1) to afford 5-(1-(3-(benzyloxy)phenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 103.B (855 mg, 55% yield).
Reaction SMILES: Cl.[S:2]1[C:6]2[S:7][CH2:8][CH:9]([NH2:11])[CH2:10][C:5]=2[CH:4]=[CH:3]1.C(N(C(C)C)C(C)C)C.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>C(Cl)Cl>[C:21]([NH:11][CH:9]1[CH2:8][S:7][C:6]2[S:2][CH:3]=[CH:4][C:5]=2[CH2:10]1)(=[O:24])[CH2:22][CH3:23]
Reactant: CCC(=O)Cl
Reactant: NC1CSc2sccc2C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)NC1CSc2sccc2C1
Reaction time: 0.5 h

Procedure:
A mixture of 8.31 g of 5,6-dihydro-4H-thieno[2,3-b]- thiopyran-5-amine hydrochloride, 17.4 ml of ethyldiisopropylamine, 4.07 g of propionyl chloride in 80 ml of methylene chloride is kept for 30 minutes at room temperature. The reaction mixture is washed with 1N hydrochloric acid and then with saturated sodium bicarbonate solution, the organic layer is dried over magnesium sulfate and the solvent is removed in vacuo to yield N-propionyl-5,6-dihydro-4H-thieno[2,3-b]-thiopyran-5-amine. This is refluxed for 3 hours with 85 ml of 1M borane in tetrahydrofuran. Water and 3N hydrochloric acid are added and the mixture is heated briefly. Basification of the aqueous layer followed by extraction with ether affords an oil after removal of solvent. Addition of ethanolic hydrochloric acid affords N-propyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-amine hydrochloride, m.p. 107°-110°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N:3]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[O:17]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Oc1ccccc1
Product: Clc1cc(Oc2ccccc2)ccn1
Yield: 42.2 %

Procedure:
The title compound (1.2 g) was prepared by the same procedure as the preparation 1 except for using 2-chloro-4-nitropyridine (2.5 g) and phenol (1.3 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[CH2:16]([C:18]1[C:22]([C:23](Cl)=[O:24])=[C:21]([CH3:26])[O:20][N:19]=1)[CH3:17]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:23]([C:22]2[C:18]([CH2:16][CH3:17])=[N:19][O:20][C:21]=2[CH3:26])=[O:24])[CH:6]=[CH:7][CH:8]=1
Reactant: CCc1noc(C)c1C(=O)Cl
Reactant: Nc1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCc1noc(C)c1C(=O)Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 13.3 grams (0.120 mole) of m-fluoroaniline and 20.9 ml. (0.150 mole of triethylamine in 120 ml. of toluene is treated by dropwise addition with 22.5 grams (0.129 mole) of 3-ethyl-5-methyl-4-isoxazole carbonyl chloride in 100 ml. of toluene while maintaining the temperature between 30°-35° during addition. The mixture is stirred at room temperature overnight, filtered and the filtrate washed with 2N hydrochloric acid. The toluene is dried and evaporated with the residue recrystallized from toluene to give N-(m-fluorophenyl)-3-ethyl-5-methyl-4-isoxazole carboxamide (m.p. 99.5°-101° C.).
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7]1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:27]1([N:33]2[CH2:38][CH2:37][CH:36]([NH:39][C:40](=O)[O:41]C3C=CC=CC=3)[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:2][S:3]([N:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2([CH2:9][CH2:10][N:11]([C:40]([NH:39][CH:36]3[CH2:37][CH2:38][N:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:34][CH2:35]3)=[O:41])[CH2:12][CH2:13]2)[CH2:7]1)(=[O:4])=[O:5]
Reactant: O=C(NC1CCN(c2ccccc2)CC1)Oc1ccccc1
Reactant: CS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)N1CC2(CCN(C(=O)NC3CCN(c4ccccc4)CC3)CC2)c2ccccc21
Yield: 31.6 %

Procedure:
1-Methanesulfonyl-spiro[indoline-3,4′-piperidine] hydrochloride (37 mg) and triethylamine (170 μL) were added to a solution of phenyl N-(1-phenyl-4-piperidyl)carbamate (36 mg) in chloroform (3 mL), and the mixture was heated to reflux for 15 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized from diethyl ether to give the title compound (18 mg) as a colorless crystal.
Reaction SMILES: C(C1C=C([CH2+]=NC2C=CC(OC3C=CN=C(C(NC)=O)C=3)=CC=2F)N(C2C=CC=C(CO)C=2)N=1)(C)(C)C.[C:38]([C:42]1[CH:46]=[C:45]([NH:47][C:48]([NH:50][C:51]2[CH:67]=[CH:66][C:54]([O:55][C:56]3[CH:61]=[CH:60][N:59]=[C:58]([C:62]([NH:64][CH3:65])=[O:63])[CH:57]=3)=[CH:53][C:52]=2[F:68])=[O:49])[N:44]([C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][OH:76])[CH:70]=2)[N:43]=1)([CH3:41])([CH3:40])[CH3:39].N1C=CC=CC=1.[CH3:83][O:84][CH2:85][C:86](Cl)=[O:87]>ClCCl.CCOC(C)=O>[CH3:83][O:84][CH2:85][C:86]([O:76][CH2:75][C:71]1[CH:72]=[CH:73][CH:74]=[C:69]([N:44]2[C:45]([NH:47][C:48](=[O:49])[NH:50][C:51]3[CH:67]=[CH:66][C:54]([O:55][C:56]4[CH:61]=[CH:60][N:59]=[C:58]([C:62](=[O:63])[NH:64][CH3:65])[CH:57]=4)=[CH:53][C:52]=3[F:68])=[CH:46][C:42]([C:38]([CH3:41])([CH3:39])[CH3:40])=[N:43]2)[CH:70]=1)=[O:87]
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(CO)c3)c(F)c2)ccn1
Reactant: COCC(=O)Cl
Agent: CNC(=O)c1cc(Oc2ccc(N=[CH2+]c3cc(C(C)(C)C)nn3-c3cccc(CO)c3)c(F)c2)ccn1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(COC(=O)COC)c3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.5 %

Procedure:
To a 0° C. solution of example 1, (4-{4-[({3-tert-butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}carbamoyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide, (0.15 g, 0.28 mmol) in dichloromethane (1.5 mL)/pyridine (0.5 mL) was added dropwise methoxyacetyl chloride (0.03 mL, 0.34 mmol). The reaction mixture was allowed to warm to room temperature and stir for 72 h. The reaction mixture was diluted with EtOAc and washed with sat. aqueous.NaHCO3. The combined organic layer was washed with brine, dried and concentrated. The crude material was purified via column chromatography (CH2Cl2: MeOH, 100% CH2Cl2 to 98.5:1.5) to afford 0.16 g (96%) of the desired product as a white solid. MS m/z 605.1 (M+H)+; Retention time (LC-MS): 3.44 min.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:11]=1.N1C=CN=C1>CN(C=O)C.CCOCC>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([O:22][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:15]=1
Reactant: CCCCCC(O)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Reaction time: 16 h
Yield: 99.6 %

Procedure:
t-Butyidimethylsilylchloride (2.49 g, 16.5 mmol) was added to a solution of the alcohol 6 (3.6 g, 14.0 mmol) and imidazole (1.91 g, 28.0 mmol) in DMF (22 mL) at 23° C. The reaction was stirred for 16 h, diluted with Et2O and washed with 1 N HCl, saturated aqueous NaHCO3 and brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. FCC (silica gel, 100% hex) afforded 5.18 g (63%) of the silyl ether 7 as a clear, colorless oil.
Reaction SMILES: C([C@@H]1[C@H](N)C2C=CSC=2CC1)CC.[CH2:14]([CH:16]1[CH2:17][CH2:18][C:19]2[O:23][CH:22]=[CH:21][C:20]=2/[C:24]/1=[N:25]\O)[CH3:15]>>[CH2:14]([C@H:16]1[C@H:24]([NH2:25])[C:20]2[CH:21]=[CH:22][O:23][C:19]=2[CH2:18][CH2:17]1)[CH3:15]
Reactant: CCC1CCc2occc2/C1=N\O
Agent: CCC[C@H]1CCc2sccc2[C@H]1N
Product: CC[C@@H]1CCc2occc2[C@H]1N

Procedure:
Following the procedure for the preparation of cis-5-propyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine but substituting (4E) and (4Z)-5-ethyl-6,7-dihydro-1-benzofuran-4(5H)-one oxime and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.02, 1.30–1.73, 2.50–2.67, 4.46, 6.10, 7.24; HRMS (FAB) calcd for C10H15NO+H 166.1232, found 166.1231. Anal. Calcd for C10H15NO: C, 72.69; H, 9.15; N, 8.48. Found: C, 72.33; H, 9.14; N, 8.08.
Reaction SMILES: C(Cl)CCl.[C:5]([OH:13])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[Cl-].[CH3:15][O:16][NH2+:17][CH3:18]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:15][O:16][N:17]([CH3:18])[C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCCCC(=O)O
Reactant: C[NH2+]OC
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: ClCCCl
Solvent: ClCCl
Product: C=CCCCCC(=O)N(C)OC
Reaction time: 14 h
Yield: 97 %

Procedure:
EDC (1.1 eq.) was added in small portions over 1.5 h to a stirred mixture of hept-6-enoic acid, methoxy(methyl)ammonium chloride (1.1 eq.) and DMAP (1.1 eq.) in CH2Cl2 (0.2 M). After 14 h, the mixture was diluted with CH2Cl2, then washed sequentially with hydrochloric acid (1 M), NaOH (1M), brine and dried (Na2SO4). Evaporation of the solvent afforded the title compound (97%) as a colorless oil. 1H NMR (400 MHz, CDCl3, 300 K) δ 5.87-5.75 (m, 1H), 5.01 (d, J 17.1, 1H), 4.95 (d, J 10.1, 1H), 3.68 (s, 3H), 3.18 (s, 3H), 2.48-2.36 (m, 2H), 2.13-2.04 (m, 2H), 1.71-1.60 (m, 2H), 1.50-1.40 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:24])([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[C:16](=O)[C:15]3[C:14]([C:26]([O:28]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:32][NH2:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:32][NH:33][C:26](=[O:28])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[C:17]2([CH3:24])[C:18]2[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(C)(c1nccn1C)C(c1ccc(F)cc1)N2
Solvent: O
Product: Cn1ccnc1C1(C)c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(F)cc1
Temperature: 67 °C
Reaction time: 10 h
Yield: 14 %

Procedure:
Ethyl 2-(4-fluorophenyl)-3-methyl-3-(1-methyl-1H-imidazo 1-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (70 mg, 0.18 mmol) was added to hydrazine monohydrate (5 mL) and the mixture was stirred at 67° C. for 10 hr. The resulting mixture was concentrated and purified by prep-HPLC to obtain the title compound as a white solid (9 mg, yield 14%). LC-MS (ESI) m/z: 376 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.79 (s, 3H), 2.57 (s, 3H), 4.50 (s, 1H), 6.68-6.69 (d, J=0.9 Hz, 1H), 6.78-6.82 (m, 2H), 6.84-6.85 (d, J=0.9 Hz, 1H), 7.05-7.09 (m, 2H), 7.16-7.18 (dd, J1=8.0 Hz, J2=0.8 Hz, 1H), 7.34 (s, 1H), 7.43-7.45 (dd, J1=8.0 Hz, J2=0.8 Hz, 1H), 7.57-7.61 (t, J=7.6 Hz, 1H), 12.30 (s, 1H).
Reaction SMILES: N[C:2]1[C:7]([OH:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH2:10]([NH2:16])[C:11]1[O:15][CH:14]=[CH:13][CH:12]=1>>[Br:9][C:5]1[CH:6]=[C:7]([OH:8])[CH:2]=[N:3][CH:4]=1.[CH2:10]([NH2:16])[C:11]1[O:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ncc(Br)cc1O
Agent: NCc1ccco1
Product: Oc1cncc(Br)c1

Procedure:
In another example, 6-bromooxazolo[4,5-b]pyridine, when submitted sequentially to palladium catalyzed coupling to N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine and deprotection with trifluoroacetic acid, gives (4E)-N-methyl-5-(6-oxazolo[4,5-b]pyridinyl)-4-penten-2-amine. The requisite 6-bromooxazolo[4,5-b]pyridine can be produced from 2-amino-5-bromo-3-pyridinol by condensation with formic acid or a trialkyl orthoformate, using methodology similar to that of M-C. Viaud et al., Heterocycles 41: 2799-2809 (1995). The use of other carboxylic acids produces 2-substituted-6-bromooxazolo[4,5-b]pyridines, which are also substrates for the Heck reaction. The synthesis of 2-amino-5-bromo-3-pyridinol proceeds from furfurylamine (Aldrich Chemical Company). Thus, 5-bromo-3-pyridinol (produced from furfurylamine according to U.S. Pat. No. 4,192,946) can be chlorinated, using methods described by V. Koch et al., Synthesis, 499 (1990), to give 2-chloro-5-bromo-3-pyridinol, which in turn can be converted to 2-amino-5-bromo-3-pyridinol by treatment with ammonia.