Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(=O)CC.C(Cl)Cl>[C:20]1([CH2:19][CH2:18][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCCc1ccccc1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: c1ccc(CCOc2ccc3[nH]ccc3c2)cc1
Temperature: 25 °C
Yield: 46.6 %

Procedure:
A stirred mixture of 5-hydroxyindole (0.5 g, 3.8 mmol), anhydrous K2CO3 (1.58 g, 11.4 mmol), (2-bromoethyl) benzene (2.11 g, 11.4 mmol), and a catalytic amount of KI in 2-butanone (40 ml) was heated at reflux overnight under nitrogen. Once cooled to room temperature, the reaction mixture was filtered and the flitrate concentrated under reduced pressure to give an oil. The oil was taken up in CH2Cl2 (50 ml) and washed successively with 2N-NaOH (1×20 ml) and water (1×20 ml). The organic portion was dried (MgSO4) and the solvent was removed under reduced pressure to give an oil. The oil was purified by column chromatography using a solvent system of CH2Cl2 /Hexane (40:60) to give 0.42 g (47%) of 5-(2-phenylethyloxy)indole as an oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[O:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.[N-:29]=[N+:30]=[N-:31].[Na+].Cl.[NH+]1C=CC=CC=1>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]2[NH:31][N:30]=[N:29][N:23]=2)=[CH:24][CH:25]=1
Reactant: N#Cc1ccc(COc2cccc(OCc3ccc4ccccc4n3)c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: c1cc(OCc2ccc(-c3nnn[nH]3)cc2)cc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C

Procedure:
A slurry of 2.0 g (5.48 mmol) of 4-(3-(2-quinolinylmethyloxy)phenoxymethyl)benzonitrile, 1.78 g (27.4 mmol) of sodium azide, and 3,16 g (27.4 mmol) of pyridinium hydrochloride in 12 ml of dry DMF is stirred under nitrogen at 100° C. for 20 hrs. The reaction mixture is then cooled to room temperature and concentrated. The residue is taken up on 100 ml of 1N aqueous NaOH and the solution extracted with ether. The aqueous layer is acidified to pH 6 with 1N aqueous HCl, and the precipitate collected, triturated with water, filtered and lyophilized to obtain 5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenyl)tetrazole (M.P. 91° C. dec.)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([N:8]2[C:5]3=[N:6][CH:7]=[C:2]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:3]=[C:4]3[CH:10]=[CH:9]2)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(Br)cnc32)cc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(Nc4ccccc4)cnc32)cc1
Yield: 172.7 %

Procedure:
Put 750 mg of 5-bromo-1-[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridine in 19 cm3 of toluene, 54 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, 970 mg of caesium carbonate, 280 mg of aniline and 40 mg of tri(dibenzylideneacetone)dipalladium(0) in a microwave oven reactor. Irradiate the reactor in a microwave oven for forty-five minutes at 150° C. After cooling, filter the reaction mixture, then reduce to dryness under vacuum in a rotary evaporator. Combine the brown residue with another two residues obtained similarly, then purify by flash chromatography on a silica column with dichloromethane eluent to give 1.34 g of 1-[(4-methylphenyl)sulphonyl]-N-phenyl-1H-pyrrolo[2,3-b]pyridin-5-amine in the form of a beige powder with the following physical characteristics:
Reaction SMILES: C([O:5][C:6]([CH:8]([N:11]1[C:17](=[O:18])[CH2:16][CH2:15][CH:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13][CH2:12]1)[CH2:9][CH3:10])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:22]([O:21][C:19]([CH:14]1[CH2:13][CH2:12][N:11]([CH:8]([CH2:9][CH3:10])[C:6]([OH:7])=[O:5])[C:17](=[O:18])[CH2:16][CH2:15]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C1CCC(=O)N(C(CC)C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CCC(=O)N(C(CC)C(=O)O)CC1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
In a 25 ml three necked flask fitted with magnetic stirrer and dropping funnel under inert atmosphere, 1 g (3.1 mmoles) of pure ethyl 1-[1-(tert-butoxycarbonyl)propyl]-7-oxo-4-azepanecarboxylate 29 was dissolved in 5 ml of CH2Cl2. The mixture was cooled down to 0° C., 5 ml of trifluoroacetic acid was added. The mixture was kept at 0° C. under stirring for 24 hours, concentrated to dryness and used as such in the next step.
Reaction SMILES: [CH3:1][N:2]([C@@H:16]([C:31]1[CH:36]=[CH:35][C:34]([O:37]CC2C=CC=CC=2)=[CH:33][CH:32]=1)[CH2:17][N:18]1[CH2:22][CH2:21][C@H:20]([O:23]CC2C=CC=CC=2)[CH2:19]1)[C:3](=[O:15])[CH2:4][C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[NH:11][C:7]=2[CH:6]=1.[H][H]>C(OCC)(=O)C>[CH3:1][N:2]([C@@H:16]([C:31]1[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=1)[CH2:17][N:18]1[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19]1)[C:3](=[O:15])[CH2:4][C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[NH:11][C:7]=2[CH:6]=1
Reactant: CN(C(=O)Cc1ccc2[nH]c(=O)[nH]c2c1)[C@H](CN1CC[C@H](OCc2ccccc2)C1)c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: CN(C(=O)Cc1ccc2[nH]c(=O)[nH]c2c1)[C@H](CN1CC[C@H](O)C1)c1ccc(O)cc1

Procedure:
A solution of 1 g of N-methyl-N-[(1S)-1-(p-benzyloxyphenyl)-2-((3S)-3-benzyloxypyrrolidino)ethyl]-2-(2-oxo-2,3-dihydrobenzimidazol-5-yl)acetamide in 25 ml of ethyl acetate is hydrogenated on 0.5 g of 5% Pd--C at 20° and under 1 bar until hydrogen uptake ceases, the mixture is filtered, the filtrate is evaporated, and N-methyl-N-[(1S)-1-(p-hydroxyphenyl)-2-((3S)-3-hydroxypyrrolidino)ethyl]-2-(2-oxo-2,3-dihydrobenzimidazol-5-yl)acetamide is obtained.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][NH2:20]>C1COCC1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:20][CH3:19])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(CBr)cc1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Mix 4-(bromomethyl)benzenesulfonyl chloride (2.7 g, 10 mmol), anhydrous potassium carbonate (1.4 g, 10 mmol) and anhydrous THF (60 mL) under nitrogen. Cool the mixture in an ice bath, add dropwise a 2M solution of methylamine in THF, and stir at this temperature for 30 min. Remove the ice bath and stir at ambient temperature for 16 h. Dilute with EtOAc then wash with 1N aqueous HCl. Separate the organic layer, dry over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 4:1, 7:3 and 13:7) to obtain the title compound (1.5 g, 71%). MS (ES+) m/z: 266 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@H:7]([NH:16]C(=O)C(F)(F)F)[CH2:6]1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH2:1]([O:4][C@@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@H:7]([NH2:16])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@H]1C[C@@H](NC(=O)C(F)(F)F)c2cc(OC)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C=CCO[C@H]1C[C@@H](N)c2cc(OC)ccc21
Yield: 99.6 %

Procedure:
Step C (3): cis-N-(3-(Allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide (650 mg, 2.06 mmol) from stepC (2), potassium carbonate (1.42 g, 10.3 mmol) and MeOH (70 mL)/H2O (4.4 mL) were heated at reflux for 7 h. The reaction mixture was concentrated in vacuo. Added water to the residue, extracted with EtOAc, washed the organic layers with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 450 mg (99% yield) of cis-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-amine as a light brown oil: LC-MS (M+H)+=220.2; 1H NMR (500 MHz, DMSO-d6) δ 7.19 (d, J=8.24 Hz, 1H), 6.97 (d, J=2.14 Hz, 1H), 6.78 (dd, J=8.24, 2.44 Hz, 1H), 5.81-6.07 (m, 1H), 5.30 (dd, J=17.09, 1.83 Hz, 1H), 5.15 (dd, J=10.53, 1.68 Hz, 1H), 4.72 (t, J=6.87 Hz, 1H), 4.02-4.21 (m, 2H), 3.96 (t, J=7.48 Hz, 1H), 3.73 (s, 3H), 2.64-2.88 (m, 1H), 1.39-1.58 (m, 1H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccc(F)cc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccc(N2CCCCC2)cc1
Temperature: 120 °C
Reaction time: 20 h
Yield: 91.7 %

Procedure:
A mixture of 4-fluorobenzonitrile (1 g, 8.26 mmol), piperidine (0.90 mL, 9.08 mmol) and potassium carbonate (2.28 g, 16.51 mmol) in dry 1-methyl-2-pyrrolidinone (10 mL) was stirred at 120° C. under nitrogen for 20 hours. The cooled reaction mixture was then diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic extract was washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford an orange oil. Purification by flash chromatography using a solvent gradient of 1 to 7% ethyl acetate in hexane gave an orange oil that was crystallized from hexane to afford the title compound (1.41 g, 92%) as an orange crystalline solid, m.p. 54° C.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:15](=[O:17])[CH3:16])[CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10]>C(Cl)(Cl)Cl.CO>[Br:1][CH2:16][C:15]([C:11]1([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[CH2:14][CH2:13][CH2:12]1)=[O:17]
Reactant: BrBr
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(CBr)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of bromine (96 ml) in chloroform (427 ml) was added dropwise at 10°-15° C. over 1.5 hours to a stirred solution of 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone (477.2 g; prepared in a similar manner to that described above) in a mixture of methanol (643 ml) and chloroform (107 ml). After the addition was complete, the mixture was stirred at ambient temperature for 3 hours, then poured into ice-water (21). The aqueous layer was separated and washed with dichloromethane (3×500 ml), then the combined organic solutions were washed with saturated aqueous sodium hydrogencarbonate solution (2×400 ml) and water (500 ml), dried over calcium chloride, and the, solvents were removed in vacuo to leave 2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone as an orange oil (593.5 g) which was used without purification.
Reaction SMILES: Br[C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:6]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:28]1[N:32]([C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=2)[N:31]=[CH:30][CH:29]=1)CCC>>[CH3:11][C:9]1[N:10]=[C:5]2[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[C:3]([CH3:22])[C:2]([C:28]3[N:32]([C:33]4[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=4)[N:31]=[CH:30][CH:29]=3)=[CH:7][N:6]2[CH:8]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(C#N)cc1
Reactant: Cc1cn2cc(Br)c(C)c(-c3cccc(C(F)(F)F)c3)c2n1
Product: Cc1cn2cc(-c3ccnn3-c3ccc(C#N)cc3)c(C)c(-c3cccc(C(F)(F)F)c3)c2n1

Procedure:
The title compound was prepared from 6-bromo-2,7-dimethyl-8-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (Int. 8, 50 mg, 0.136 mmol) and 4-(5-tributylstannanyl-pyrazol-1-yl)-benzonitrile (Int. 3, 125 mg, 0.270 mmol) using a similar method to that used in Example 1 (Step 4) (61 mg).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]([O:17][C:18]2[C:23]([Br:24])=[CH:22][C:21]([CH2:25][CH2:26][C:27]([O:29]CC4C=CC=CC=4)=[O:28])=[CH:20][C:19]=2[Br:37])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.Br>O>[CH:11]1[C:12]2[C:7](=[N:6][C:5]3[C:14]([C:13]=2[C:15]([O:17][C:18]2[C:19]([Br:37])=[CH:20][C:21]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:22][C:23]=2[Br:24])=[O:16])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(CCc1cc(Br)c(OC(=O)c2c3ccccc3nc3ccccc23)c(Br)c1)OCc1ccccc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCc1cc(Br)c(OC(=O)c2c3ccccc3nc3ccccc23)c(Br)c1
Temperature: 100 °C
Yield: 70.3 %

Procedure:
A mixture of 2,6-dibromo-4-(2-benzyloxycarbonylethyl)-phenyl acridine-9-carboxylate (191 mg, 0.309 mmol), glacial acetic acid (20 ml) and 48% hydrobromic acid (5 ml) was heated at 100° C. for 3 h and then cooled. The mixture was added to water (100 ml) and extracted with 20% methanol in chloroform (100 ml×4). The organic extracts were combined and evaporated and the residue was suspended in chloroform (50 ml) and neutralised with a slight excess of triethylamine. The mixture was washed with water (70 ml×3), and the organic layer was dried over sodium sulphate and evaporated to dryness. The residue was recrystallised from CHCl3 to give the desired product (115 mg, 74%.), mp 240–2° C. FAB-MS m/z 529 [M+, 75%], 511 [10], 486 [10], 207 [100].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[F:23])[CH2:35][CH2:34]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 67.5 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(2-fluorophenyl)-piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1[Cl:7].[CH3:12][N:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:7][C:6]1[O:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:17]1[N:13]([CH3:12])[N:14]=[CH:15][CH:16]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)c(Cl)o1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(Cl)o1
Yield: 55.1 %

Procedure:
A solution of methyl 4-bromo-5-chloro-2-furancarboxylate (1.1 g, 4.59 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.05 g, 5.05 mmol) [prepared according to Preparation 7], potassium carbonate (3.17 g, 22.97 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.117 g, 0.23 mmol) in 1,4-dioxane (19.14 ml) and water (3.83 ml) was stirred at 80° C. in a sealed tube for 1 h. The reaction mixture was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 4-25% EtOAc in hexanes) yielding methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (800 mg, 2.53 mmol, 55% yield) as a yellow oil: LCMS m/e ES 240, 242 (M, M+2)+.
Reaction SMILES: C[Si]([CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]=[N:7]1)(C)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]=[N:7]1
Reactant: C[Si](C)(C)Cn1cc(-c2ccccn2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccccn2)nn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of 2-(1-trimethylsilanylmethyl-1H-[1,2,3]triazol-4-yl)-pyridine (6.05 g, 26 mmol) in THF (435 mL) was added water (0.94 mL, 52 mmol) and then tetrabutylammonium fluoride (1 M in THF, 31.2 mL, 31 mmol) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The resulting mixture was poured into water and then the THF was evaporated. The aqueous layer was then extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (3.53 g, 85%) as a light brown solid. MS: m/e=161.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[Cl:20])[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: O=C(O)Cc1ccccc1Nc1ccc(Cl)c(Cl)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 3,4-dichloroaniline to yield 2-[(3,4-dichlorophenyl)amino]phenylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1>[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1ccc(Cl)cc1
Agent: [Fe]
Product: O=C(CCc1ccc(Cl)cc1)CCc1ccc(Cl)cc1
Temperature: 290 °C

Procedure:
3-(4-Chlorophenyl)propionic acid (0.20 mole) and iron (hydrogen reduced, 0.11 mole) are heated for 1.5 hours at 195° C. under a nitrogen atmosphere. After that time, the temperature is increased to 290° C. and maintained at that temperature for 3 hours. The cooled reaction mass is extracted well with ether, filtered through Celite, and the ethereal extracts concentrated under vacuum. The residue is stripped under vacuum to leave the product.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1.[C:23]([O:38][CH3:39])(=[O:37])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O-:36])=O>C(Cl)Cl>[C:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:36])([O:38][CH3:39])=[O:37]
Reactant: COC(=O)CCCCCCCCCCC(=O)[O-]
Reactant: CNc1ccccc1OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCCCCCCCCC(=O)N(C)c1ccccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a stirred ice-cold solution of (27) (0.21 g., 1.0 mM) in dried methylene chloride (10 mL) containing anhydrous pyridine (0.3 mL) is added (7) (0.27 g., 1.03 mM), dissolved in 5 methylene chloride (5 mL), dropwise over 1 minute (some methylene chloride used as a rinse). After stirring cold for 30 minutes, the mixture is allowed to stir at ambient temperature for completion of the reaction. The reaction mixture is washed 1× with , 1N HCL, dried (Na2SO4) and filtered. Flash chromatography (silica gel, 20% ethyl acetate/hexane as eluant) of the residue obtained gives the title compound (28) (0.33 g) as a colorless oil.
Reaction SMILES: [CH2:1]([N:9]1[C:13](=[O:14])[CH:12]=[CH:11][S:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>C(OCC)C.O1CCCC1>[CH2:1]([NH:9][C:13](=[O:14])/[CH:12]=[CH:11]\[S:10][C:21](=[O:24])[CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCn1sccc1=O
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCNC(=O)/C=C\SC(=O)CC
Temperature: 0 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a cooled (0° C.), stirred solution of 21.3 g (0.10 mol) of 2-octyl-4-isothiazolin-3-one in 400 ml of anhydrous ethyl ether was added dropwise 30 ml (0.03 mol) of a 1.0M solution of lithium aluminum hydride in tetrahydrofuran over a 20 min period. After the addition the mixture was stirred at 0° C. for 1 hr. Over a 15 min period 8.96 ml (0.10 mol) of propionyl chloride was added. After this addition the mixture was allowed to warm to room temperature. After 12 hr the reaction mixture was a white solid suspended in an orange solution. The mixture was filtered and the filtrate was diluted with 300 ml of ethyl acetate and washed once with 300 ml of 10% aqueous hydrochloric acid. The organic layer was set aside and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water until the washes were neutral in pH, washed with brine, and dried over anhydrous magnesium sulfate. Filtration and removal of solvents gave N-octyl-cis-3-(propanoylthio)acrylamide as an oil which crystallized upon standing. These crude crystals were recrystallized from ethyl ether/hexane to give 16 g (59% yield) as white crystals, m.p. 68°-70° C., and is reported in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([Sn](CCCC)(CCCC)CCCC)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:26][NH:27][C:28]([C:30]1[C:31](=[O:48])[N:32]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)[C:33]([CH3:37])=[C:34](I)[CH:35]=1)=[O:29]>COCCOC>[CH3:26][NH:27][C:28]([C:30]1[C:31](=[O:48])[N:32]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:45])[F:46])[CH:39]=2)[C:33]([CH3:37])=[C:34]([C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[CH:10][CH:11]=2)[CH:35]=1)=[O:29]
Reactant: CNC(=O)c1cc(I)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(Cl)cc1
Solvent: COCCOC
Product: CNC(=O)c1cc(-c2ccnn2-c2ccc(Cl)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 100 °C
Yield: 18.7 %

Procedure:
1-(4-Chloro-phenyl)-5-tributylstannanyl-1H-pyrazole (0.107 g, 0.22 mmol), 5-iodo-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid methylamide (0.05 g, 0.11 mmol), Pd(PBut3)2 (10 mg) and DME (2 ml) were placed in a tube for microwave synthesis. The mixture was degassed with argon and heated in a synthesis microwave heater (CEM) at 100° C. (max 150 W) for 10 minutes. The solvent was removed in vacuo giving a crude product which was purified on silica and then further purified on preparative HPLC. The pure fractions were freeze-dried giving 10 mg (17%) of the title compound.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[N:17]1([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[CH:21]=[CH:20][N:19]=[CH:18]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:27]([OH:28])[C:26]2[CH:25]=[CH:24][C:23]([CH2:22][N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)=[CH:31][CH:30]=2)[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2cc([N+](=O)[O-])ccc21
Reactant: O=C(O)c1ccc(Cn2ccnc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)C(=C(O)c2ccc(Cn3ccnc3)cc2)c2cc([N+](=O)[O-])ccc21

Procedure:
Prepared analogously to Example 10(a) from 1-acetyl-5-nitro-indolinone and 4-(imidazol-1-ylmethyl)benzoic acid in dry DMF in the presence of TBTU, HOBT and Hunig's base.