Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].Cl>ClCCl.O>[CH3:19][S:20]([NH:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)NCC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 60.5 %

Procedure:
2-Aminoacetophenone hydrochloride (6.10 g, 35.5 mmol) was dissolved in dichloromethane (60 mL), and to the solution was added triethylamine (7.56 g, 74.9 mmol). The solution was cooled to 0° C., and to the solution was added methanesulfonyl chloride (2.84 mL, 36.5 mmol). The solution was stirred at the same temperature for 5 minutes, and then at room temperature for 2 hours. To the reaction mixture was added water and 1 mol/L hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in chloroform (5 mL) and the suspension was stirred, and then, the resulted crystals were collected by filtration to give 2-(methylsulfonylamino)acetophenone (4.58 g, 57%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([CH3:10])[S:7][C:6]=1[NH2:11])=[O:4].O[Li].O>CO.O.C1COCC1>[NH2:11][C:6]1[S:7][C:8]([CH3:10])=[CH:9][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc(C)sc1N
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)O)c(N)s1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of 2-amino-5-methylthiophene-3-carboxylic acid methyl ester (13.7 g, 80 mmol) in MeOH/H2O/THF (400 mL, 1:1:1) is added LiOH.H2O (16 g, 400 mmol). The solution is heated to 50° C. After 4 hours, the solution is concentrated. The resulting residue is dissolved in water. The pH of the solution is adjusted to between 5-6 using 1 N HCl. The precipitate is collected by filtration, washed with a small amount of water and is dried under vacuum. The title compound (12 g, 76 mmol) is obtained as a yellow solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][S@](C(C)(C)C)=O)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]>CO>[CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH2:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc([C@H](C)N[S@@](=O)C(C)(C)C)c1
Solvent: CO
Product: CC(C)c1cccc([C@H](C)N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The mixture of (S)—N—((S)-1-(3-isopropylphenyl)ethyl)-2-methylpropane-2-sulfinamide (6.1 g, 0.023 mol) in methanol was stirred at room temperature for 3 hours and then concentrated and evaporated with toluene for three times to give the titled compound which was without purification for next step.
Reaction SMILES: I/[CH:2]=[CH:3]/[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[C:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)#[CH:19]>>[CH3:10][C:8]1[CH:7]=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[C:4]([CH:3]=[CH:2][C:19]#[C:18][C:20]2[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH:9]=1
Reactant: C#Cc1ccc(C(=O)OC)cc1
Reactant: Cc1ccc(-c2ccc(C)cc2/C=C/I)cc1
Product: Cc1ccc(-c2ccc(C)cc2C=CC#Cc2ccc(C(=O)O)cc2)cc1
Yield: 10.4 %

Procedure:
In a similar manner to that of Example 1(e), by reaction of 4.00 g (12.0 mmol) of 2-((E)-2-iodovinyl)-4,4'-dimethylbiphenyl obtained in Example 12(f) with 1.74 g (10.9 mmol) of methyl 4-ethynylbenzoate, 400 mg (10%) of the expected compound are obtained in the form of yellow flakes with a melting point of 95-97° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:4]([OH:5])[C:3]=1[OH:10].[C:11](=O)([O-])[O-].[K+].[K+].BrCCl.O>CN(C)C=O.CCOCC>[CH3:1][C:2]1[C:3]2[O:10][CH2:11][O:5][C:4]=2[C:6]([CH3:9])=[CH:7][CH:8]=1
Reactant: Cc1ccc(C)c(O)c1O
Reactant: O=C([O-])[O-]
Agent: ClCBr
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C)c2c1OCO2
Temperature: 100 °C
Yield: 62 %

Procedure:
To a stirred solution of 2.97 g of 3,6-dimethylcatechol and 3.86 g of potassium carbonate in 60 mL of N,N-dimethylformamide is added 1.69 mL of bromochloromethane. A reflux condenser is attached and the mixture heated in an oil bath to 100° C. for 24 hours. The mixture is allowed to cool to room temperature and then is distributed between 100 mL of water and 200 mL of ether. The aqueous layer is separated and extracted with ether. The combined ether layers are dried over magnesium sulfate and concentrated under reduced pressure to yield a red liquid, which is purified by chromatography on silica gel to afford 2.0 g of 4,7-dimethyl-1,3-benzodioxole as a light yellow liquid.
Reaction SMILES: S(Cl)(Cl)=O.CC1C=CC=CC=1CCC(O)=O.CC1C=CC=CC=1CCC(Cl)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][N:35]=[C:34]2[O:43][C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1.[CH3:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[CH2:58][CH2:59][C:60]([N:62]=[C:63]=[S:64])=[O:61]>C1(C)C=CC=CC=1.C(O)C>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][N:35]=[C:34]2[O:43][C:44]1[CH:50]=[CH:49][C:47]([NH:48][C:63]([NH:62][C:60](=[O:61])[CH2:59][CH2:58][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=2[CH3:51])=[S:64])=[CH:46][CH:45]=1
Reactant: Cc1ccccc1CCC(=O)N=C=S
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: Cc1ccccc1CCC(=O)Cl
Agent: Cc1ccccc1CCC(=O)O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)CCc4ccccc4C)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3-(2-methylphenyl)propanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3-(2-methylphenyl)propanoyl isothiocyanate was prepared using the resultant 3-(2-methylphenyl)propanoyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-(2-methylphenyl)propanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (48 mg, yield 57%).
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=S)[C:10]([C:19]([O:21]CC)=O)=[CH:9]2)=[CH:3][CH:2]=1.[C:30]1([NH:36][NH2:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>C(O)C>[C:1]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3=[N:37][N:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:19](=[O:21])[C:10]3=[CH:9]2)=[CH:5][CH:6]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)c2ccccc2c1=S
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCO
Product: O=c1c2cn(Cc3ccc(-c4ccccc4)cc3)c3ccccc3c-2nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 1-(biphenyl-4-ylmethyl)-4-thioxo-1,4-dihydroquinoline-3-carboxylate [(Example 8, Step 2), 72 mg, 0.18 mmol] and phenylhydrazine (0.19 g, 1.8 mmol, 10 equiv) were combined in absolute ethanol (5 mL) and placed into a preheated oil bath at 75° C. for 18 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in dichloromethane (10 mL) and treated with di-tert-butyldicarbonate (0.30 g, 1.4 mmol, 7.8 equiv). After stirring for 5 hours at ambient temperature, the mixture was concentrated in vacuo and the residue was purified by silica gel gradient chromatography (100:0 to 95:5; dichloromethane:methanol), providing the titled compound: 1H-NMR (500 MHz, d6-DMSO) δ 9.17 (1H, s), 8.31 (1H, dd, J=7.8, 1.4 Hz), 8.22 (2H, d, J=7.6 Hz), 7.81 (1H, d, J=8.8 Hz), 7.67-7.62 (5H, m), 7.57 (1H, t, J=7.8 Hz), 7.48-7.40 (6H, m), 7.35 (1H, t, J=7.4 Hz), 7.20 (1H, t, J=7.4 Hz), 5.80 (2H, s) ppm; high resolution mass spectrometry (ES+) m/z 428.1757 [(M+H)+; calculated for C29H22N3O: 428.1758].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.N1C=CN=C1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23])[CH:6]=[CH:5]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Reaction time: 3 h
Yield: 155 %

Procedure:
To a solution of compound 6-bromonaphthalen-2-ol (10 g, 0.044 mol, 1.0 equiv) and imidazole (6 g, 0.088 mol, 2.0 equiv) in dry DMF (100 mL) was added TBDMSCl (10 g, 0.066 mol, 1.5 equiv) at 0° C. Then the reaction mixture was warmed to r.t and stirred for 3 h. Then DMF was removed under reduced pressure. The mixture was extracted with ethyl acetate and washed with brine, dried over Na2SO4 and concentrated to obtain crude product. The crude product was purified by silica gel chromatography (PE:EA=30:1) to give compound to give the title compound as a yellow solid (23 g, 76%). ESI-MS (M+H)+: 336.9. 1H NMR (400 MHz, CDCl3) δ: 7.91-7.92 (m, 1H), 7.64-7.46 (m, 3H), 7.15-7.08 (m, 2H), 1.01 (s, 9H), 0.24 (s, 6H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][C:7]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:52][C@@H:53]([CH2:56][CH:57]([CH3:59])[CH3:58])[CH2:54][OH:55]>CN(C=O)C>[OH:55][CH2:54][C@@H:53]([NH:52][C:12]([C:10]1[CH:9]=[N:8][C:7]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:56][CH:57]([CH3:59])[CH3:58]
Reactant: O=C(O)c1cnc(N2CCCCC2)c(OCC2CC2)n1
Reactant: CC(C)C[C@H](N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](CO)NC(=O)c1cnc(N2CCCCC2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
A mixture of 11 mg (0.04 mmol) 6-cyclopropylmethoxy-5-piperidin-1-yl-pyrazine-2-carboxylic acid, 15.3 mg (0.048 mmol) TBTU, 15.3 mg (0.119 mmol) DIPEA and 7 mg (0.059 mmol) (S)-2-amino-4-methyl-pentan-1-ol (commercially available) in 1 mL DMF was shaken at room temperature for 16 h. The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The combined product fractions were evaporated to yield 10.5 mg (70%) of the title compound. m/z (ES+): 377.5 (M+H).
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:10](=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(O)C=CC=CC=1.[OH-].[Na+].[OH-].[K+].[H-].[Na+].[Na]>>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(c2ccccc2)O1
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: Oc1ccccc1
Product: O=C(O)CCCc1ccccc1

Procedure:
For example, a known compound, γ-phenyl-γ-butyrolactone having a melting point of 36° C. to 37° C. is reacted with a phenol derivative having the general formula: ##STR9## wherein R2 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms in the presence of a base such as sodium alkoxide, potassium alkoxide, sodium hydroxide, potassium hydroxide, sodium hydride, or sodium metal to form a 4-phenyl butyric acid derivative having the general formula: ##STR10## wherein R2 is the same as defined above,
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH:11]([C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH:21]=1)[CH2:19]Cl)([CH3:13])[CH3:12].Cl>C1COCC1.CCCCCC>[CH:11]([C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH2:19][CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH3:10])=[O:8])[CH:21]=1)([CH3:13])[CH3:12]
Reactant: COc1ccc(C(C)C)cc1CCl
Reactant: COC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CCc1cc(C(C)C)ccc1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 108.5 %

Procedure:
To a stirred suspension of sodium hydride (60% oil suspension, 0.44 g,11 mmol) in THF (25 ml) was added methyl acetoacetate (1.08 ml, 10 mmol) dropwise at 0° C. After 10 min stirring at 0° C., n-buthyllithium (1.31M in hexane, 8 ml, 10.5 mmol) was added to the reaction mixture at 0° C. To this orange color solution was added a solution of 5-isopropyl-2-methoxybenzyl chloride (1.99 9, 10 mmol) in THF (5 ml) at 0° C. After 40 min stirring at 0° C. to room temperature, the reaction mixture was poured into 1N HCl (20 ml) and extracted with ethyl acetate. The extract combined was dried (MgSO4) and concentrated to give 3.02 g of yellow oil, which was purified by column chromatography on silica gel (hexane/ethyl acetate: 10/1 as eluent) to afford 1.55 g (55.8%) of title compound as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([CH2:11][CH:12]([CH3:16])[CH2:13]2)[C@H:9]1[CH2:17][NH:18]CC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([CH2:11][CH:12]([CH3:16])[CH2:13]2)[C@H:9]1[CH2:17][NH2:18])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC1C[C@H]2CN(C(=O)OC(C)(C)C)[C@H](CNCc3ccccc3)[C@H]2C1
Agent: [Pd]
Solvent: CCO
Product: CC1C[C@H]2CN(C(=O)OC(C)(C)C)[C@H](CN)[C@H]2C1
Reaction time: 16 h

Procedure:
A solution of (1S,2S,5R)-2-(benzylamino-methyl)-7-methyl-3-aza-bicyclo[3.3.0]-octane-3-carboxylic acid tert.-butyl ester (264 mg) in EtOH (12 mL) was treated with Pd/C 10% (100 mg) and stirred under hydrogen (1 bar) for 16 h. After filtration through celite and removal of the solvents the title compound was obtained as a colourless oil which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B#B.[OH2:25]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: O
Agent: B#B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 3 h

Procedure:
To a room temperature solution of 1-(tert-butoxycarbonyl)-4-(3,4-dichlorobenzylidene)piperidine (6.4 g, 18.7 mmol) in dry THF (100 mL) under argon was added diborane (22.4 ml, 1 M in THF, 22.4 mmol) and the reaction mixture was stirred for 3 h. Water (20 ml) was slowly added dropwise to kill excess diborane. Tetrahydrofuran was remove in vacuo and ether (200 mL) was added. The reaction mixture was cooled in an ice bath and Jones reagent (take 18.6 g sodium dichromate hydrate, 14 mL conc. sulfuric acid and add enough water to make 93 mL solution) was added dropwise at a rate such that the reaction temperature stayed at about 25° C. The orange solution was stirred at room temperature 2 h. The organic layer was separated and the aqueous layer was extracted twice with ether. The combined organic layers were washed twice with dilute aqueous potassium carbonate solution, dried over anhydrous magnesium sulfate, and the organics were removed. The crude reaction mixtures was flash chromatographed on flash silica gel with a gradient of 10% ethyl acetate/hexane through 15% ethyl acetate/hexane to give 4-(3,4-dichlorobenzoyl)piperidine-1-carboxylic acid tert-butyl ester (3.8 g, 10.6 mmol).
Reaction SMILES: O[N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Br[C:14]1[C:23]2[C:18](=[C:19]([Cl:24])[CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1>>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[N:17]=[CH:16][CH:15]=[C:14]2[C:5]12[CH:8]=[CH:9][CH:10]=[CH:11][CH:4]1[C:3]([NH:2][C:6]2=[O:7])=[O:12]
Reactant: Clc1cccc2c(Br)ccnc12
Reactant: O=C1c2ccccc2C(=O)N1O
Product: O=C1NC(=O)C2(c3ccnc4c(Cl)cccc34)C=CC=CC12

Procedure:
N-hydroxy-phthalimide and 4-bromo-8-chloro-quinoline (a known compound) were reacted to obtain 0-(8-chloro-4-quinolyl)-phthalimide which was reacted to obtain 0-(8-chloro-4-quinolyl)-hydroxylamine melting at 194° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24](Br)[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH:35]1[CH:39]=[CH:38][CH:37]=[N:36]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(N)CN.[Br-]>O1CCOCC1.[Cu]I>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([N:35]5[CH:39]=[CH:38][CH:37]=[N:36]5)[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(Br)ccn4c3-c3ccccc3)cc2)CCC1
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [Br-]
Solvent: C1COCCO1
Solvent: NCCN
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(-n5cccn5)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 110 °C
Yield: 89.9 %

Procedure:
A mixture of {1-[4-(7-bromo-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (230 mg, 0.44 mmol), pyrazole (39 mg, 0.58 mmol), copper (I) iodide (8.5 mg, 0.044 mmol), potassium phosphate (186 mg, 0.88 mmol) and ethylene diamine (3 μL, 0.044 mmol) in dioxane (2.4 mL) was degassed, placed under an argon atmosphere and heated at 110° C. for 5 hours. On cooling, the reaction was partitioned between aqueous sodium hydrogen carbonate solution and DCM and the organic phase was washed with brine, dried and concentrated in vacuo to give the crude title compound (100 mg). The reaction was repeated using a further 150 mg of the bromide intermediate to give a further batch of the crude title compound (140 mg). Purification by chromotagraphy gave the title compound (200 mg), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][N:18]=[N+]=[N-])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][NH2:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCC1CCCN(C(=O)OCc2ccccc2)C1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCC1CCCN(C(=O)OCc2ccccc2)C1
Yield: 78.5 %

Procedure:
Dissolved 1-benzyloxycarbonyl-3-azidomethylpiperidine (1.27 g, 4.63 mmol, 1 eq) in THF (50 mL). Added water (10 mL). Added triphenylphosphine (1.5 g, 5.79 mmol, 1.25 eq) and let stir overnight. Removed solvent under reduced pressure and diluted the residue with 80 mL 1N HCl. Extracted the solution 3× with ethyl acetate to remove neutral organics. Basified the aqueous layer with 5N NaOH and extracted 3× with ethyl acetate. Combined the organic layers, dried over anhydrous Na2SO4, filtered and concentrated giving 903 mg of the desired amine.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]([CH3:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1)=O.[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:25][C:26]2[C:31]([CH3:33])([CH3:32])[CH2:30][CH2:29][CH2:28][C:27]=2[CH3:34])C=CC=CC=1>>[CH3:34][C:27]1[CH2:28][CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[C:26]=1/[CH:25]=[CH:1]/[C:3]1[CH:4]=[C:5]([CH:9]([CH3:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(C)c1cccc(C=O)c1
Reactant: CC1=C(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)C(C)(C)CCC1
Agent: [Br-]
Product: CCOC(=O)CC(C)c1cccc(/C=C/C2=C(C)CCCC2(C)C)c1

Procedure:
Coupling of ethyl 3-(3-formylphenyl)butanoate with Wittig reagent 24 following the method used in Example 1 gave (E)-ethyl 3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)butanoate as a colorless oil. Yield (0.383 g, 81%): 1H NMR (500 MHz, CDCl3) δ 7.25 (m, 3H), 7.07 (m, 1H), 6.66 (dd, J=16.3, 0.68 Hz, 1H), 6.31 (d, J=16.3 Hz, 1H), 4.09 (q, J=7.0 Hz, 2H), 3.28 (m, 1H), 2.65-2.52 (m, 2H), 2.04 (t, J=6.2 Hz, 2H), 1.76 (s, 3H), 1.64 (m, 2H), 1.49 (m, 2H), 1.30 (d, J=6.9 Hz, 3H), 1.20 (t, J=7.0 Hz, 3H), 1.06 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.[CH3:20][CH2:21]N=C=NCCCN(C)C.C(Cl)Cl>CN(C1C=CN=CC=1)C.C(O)C>[CH2:20]([O:14][C:13]([C:12]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:11]=1)=[O:15])[CH3:21]
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 25 °C

Procedure:
Into a 500 mL flask was weighed 11.5 g (39.6 mmol) of 2-(2-chlorophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid, 8.95 g (46.7 mmol) of EDCI, 530 mg (4.34 mmol) of DMAP, and 200 mL of CH2Cl2. Ethanol (8.6 mL) was then added to the stirred solution which was maintained at room temperature for 3 h. The reaction was then concentrated in vacuo to remove CH2Cl2. The residue was washed into a separatory funnel with ethyl acetate and 1.0 M sodium carbonate. The ethyl acetate was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Jones Flashmaster, 2×70 g Silica gel, gradient elution from 100% hexanes to 40% ethyl acetate over 30 minutes). Appropriate fractions were combined and concentrated in vacuo affording 2-(2-chlorophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid ethyl ester as a viscous yellow oil, yield: 10.0 g (79.3%); 1H NMR (400 MHz, CDCl3): δ 7.32-7.46 (m, 4H), 7.19 (d, J=6 Hz, 1H), 4.16 (q, J=7 Hz, 2H), 1.13 (t, J=7 Hz, 3H); MS (ES): 319 [M+H]+.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[F:9][C:10]1[CH:11]=[C:12]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([N+:23]([O-])=O)=[C:19]([CH:22]=1)[C:20]#[N:21].[OH-].[Na+]>O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[NH2:23][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]2[CH:26]=[C:27]([F:29])[CH:28]=[C:10]([F:9])[CH:11]=2)=[CH:22][C:19]=1[C:20]#[N:21]
Reactant: N#Cc1cc(OCc2cc(F)cc(F)c2)ccc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: N#Cc1cc(OCc2cc(F)cc(F)c2)ccc1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of 85% sodium hydrosulfite (38.1 g, 186 mmol) in water (200 mL) was added dropwise to a mixture of 5-[(3,5-difluorobenzyl)oxy]-2-nitrobenzonitrile (9 g, 31 mmol) and tetrabutylammonium chloride (5.86 g, 21.1 mmol) in dichloromethane (200 mL) under vigorous stirring. After 2 hours, the reaction mixture was cooled at 0° C. and 2N NaOH (200 mL) was added to reach a pH value of 12. The organic phase was separated and the acqueous layer was washed with dichloromethane. Organic phases were collected and treated for 3 hours with 4M hydrochloric acid in dioxane (50 mL). The reaction mixture was washed with water, NaHCO3 saturated solution and brine. Organic phase was dried over sodium sulphate, filtered and evaporated to dryness affording 7.6 g (yield 94%) of the title compound.