Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][OH:19])[C:9]=2[CH2:8][CH2:7]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:19][CH2:18][C@@H:16]1[CH2:17][C@@H:15]1[C:14]1[C:9]2[CH2:8][CH2:7][O:6][C:10]=2[CH:11]=[CH:12][CH:13]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.9 %

Procedure:
Methane sulfonyl chloride (6.5 mmol) was added dropwise to a solution of (cis)-2-(2,3-dihydrobenzofuran-4-yl)cycloprop-1-yl methanol (5.0 mmol) and triethylamine (7.5 mmol) in 50 mL of CH2Cl2 at 0° C. The resulting mixture was allowed to warm to RT and stirred for 2 h. The crude reaction mixture was then diluted with CH2Cl2 (50 mL) and washed sequentially with water (2×50 mL), saturated aqueous sodium bicarbonate solution (2×50 mL) and then brine (1×50 mL). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 1.38 g of the desired product as an oil (quantitative yield).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][CH2:28][NH:29][S:30]([C:33]1[S:37][C:36]([NH2:38])=[N:35][C:34]=1[CH3:39])(=[O:32])=[O:31]>>[OH:26][CH2:27][CH2:28][NH:29][S:30]([C:33]1[S:37][C:36]([NH:38][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])=[N:35][C:34]=1[CH3:39])(=[O:31])=[O:32]
Reactant: Cc1nc(N)sc1S(=O)(=O)NCCO
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1nc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NCCO

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-ethyl)-amide (example B.10) according to general procedure II. Yellow solid. MS (ISP) 575.1 [(M−H)−]; mp 134° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][O:6][C:7]1[C:20]2[C:11](=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[N:13]3)[N:10]=[C:9]([CH3:21])[CH:8]=1)[CH3:2].[O:24]1CCOCC1>O>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[C:20]2[C:11](=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[N:13]3)[N:10]=[C:9]([CH:21]=[O:24])[CH:8]=1)[CH3:23]
Reactant: CCN(CC)CCOc1cc(C)nc2c1ccc1cccnc12
Reactant: C1COCCO1
Solvent: O
Product: CCN(CC)CCOc1cc(C=O)nc2c1ccc1cccnc12
Yield: 19 %

Procedure:
A solution of SeO2 (0.83 g, 7.5 mmol) in a mixture of dioxane (38 mL) and water (3 mL) was heated to reflux in a two-neck 100 mL round-bottomed flask. A solution of diethyl-[2-(2-methyl-[1,10]phenanthrolin-4-yloxy)-ethyl]amine (0.93 g, 3.0 mmol) in hot dioxane (20 mL) was added through an addition funnel over a period of 15 minutes and the reaction mixture was refluxed for 45 minutes. The solvent was evaporated in vacuo and the residue was treated with methylene chloride (100 mL) and saturated NaHCO3 (100 mL). The aqueous layer was extracted with methylene chloride (3×100 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (SiO2, MeOH/DCM, 1:40) to afford the pure material as a brown solid (0.19 g, 19%).
Reaction SMILES: [Mg].[F:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[CH:10]1([C:13]([O:15]CC)=O)[CH2:12][CH2:11]1>CCOCC>[CH:10]1([C:13]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[OH:15])[CH2:11][CH2:12]1
Reactant: CCOC(=O)C1CC1
Reactant: Fc1ccc(Br)cc1
Agent: [Mg]
Solvent: CCOCC
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CC1
Temperature: 25 °C

Procedure:
Magnesium metal (98.2 g) was stirred with 100 ml of anhydrous ether under nitrogen for 1 hr. 4-Fluorobromobenzene (700 g) was dissolved in 1750 ml of anhydrous ether. A 20 ml aliquot of the solution was added to the magnesium metal to initiate reaction. Once reflux had begun, the 4-fluorobromobenzene solution was added at such a rate as to maintain a gentle reflux. After the addition was complete, the mixture was heated under reflux for 1 hr. Ethyl cylopropylcarboxylate (180.6 g) was dissolved in 500 ml of anhydrous ether. After the Grignard solution had been cooled to ambient temperature, the solution was added dropwise such that a gentle reflux was maintained. After complete addition of the ester, the mixture was heated under reflux for 45 mins and cooled to ambient temperature. The reaction mixture was quenched with 500 ml of saturated aqueous ammonium chloride and 2 l of ice water. The ether layer was separated and the aqueous layer was extracted twice with ether. The ether extracts were combined and washed with water and saturated brine. The ethereal mixture was dried over sodium sulfate, filtered and the solvent removed under vacuum to provide a quantitative yield or cyclopropyl-bis-(4-fluorophenyl)methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N-:12][C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17]Cl)[C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10])([O-:3])=[O:2].[OH-].[Na+].Cl>O1CCCC1.O>[N+:1]([C:4]1[CH:5]=[C:6]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=[O:19])[C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10])([O-:3])=[O:2]
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1[N-]C(=O)CCCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c([N+](=O)[O-])cc1N1CCCCC1=O

Procedure:
77 g (0.27 mol) of N-(3-nitro-4,6-dimethylphenyl)-δ-chlorovaleroylamide are stirred vigorously in a mixture of 50 ml of tetrahydrofurane and 500 ml of 22% strength aqueous sodium hydroxide solution for 5 hours at 60°-65°. The reaction mixture is diluted with water, cooled and acidified with hydrochloric acid. The product which has precipitated is washed until neutral and dried in a desiccator at 70°. This gives 62.8 g (93%); melting point 134°-135° .
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([NH2:9])=[O:8])[NH:5][CH:6]=1.[C:10]([NH:14][C:15]1[C:24]([CH3:25])=[N:23][C:22]2[C:17](=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=[CH:20][CH:21]=2)[N:16]=1)([CH3:13])([CH3:12])[CH3:11].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O>[C:10]([NH:14][C:15]1[C:24]([CH3:25])=[N:23][C:22]2[C:17]([N:16]=1)=[C:18]([C:2]1[CH:3]=[C:4]([C:7]([NH2:9])=[O:8])[NH:5][CH:6]=1)[CH:19]=[CH:20][CH:21]=2)([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1nc2cccc(B3OC(C)(C)C(C)(C)O3)c2nc1NC(C)(C)C
Reactant: NC(=O)c1cc(Br)c[nH]1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2cccc(-c3c[nH]c(C(N)=O)c3)c2nc1NC(C)(C)C
Temperature: 100 °C
Reaction time: 16.5 h
Yield: 50.7 %

Procedure:
A mixture of 4-bromo-1H-pyrrole-2-carboxamide (100 mg, 0.529 mmol), N-(tert-butyl)-3-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-2-amine (174b; 311 mg, 0.529 mmol), K3PO4 (337 mg, 1.587 mmol), XPhos (Strem Chemicals, Inc.; 25.2 mg, 0.053 mmol), and (Aldrich; 24.22 mg, 0.026 mmol) in a mixture of dioxane (4.0 mL) and water (1.0 mL) was stirred under argon at 100° C. for 16.5 h. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 0-100% EtOAc/hexanes) to provide 4-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-2-carboxamide (86.7 mg, 0.268 mmol, 51% yield) as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br. s.), 7.78 (1H, dd, J=2.6, 1.5 Hz), 7.61 (1H, dd, J=7.3, 1.3 Hz), 7.54 (1H, dd, J=8.1, 1.5 Hz), 7.44 (1H, br. s.), 7.31 (1H, t, J=7.7 Hz), 7.22-7.26 (1H, m), 6.94 (1H, br. s.), 5.78 (1H, s), 2.53 (3H, s), 1.53 (9H, s). m/z (ESI, +ve) 324.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[S:16][C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH2:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=2)[C:22]#[N:23])=[N:14][N:13]=1)[CH3:2].[NH:29]1[CH2:36][CH2:35][CH2:34][C@H:30]1[C:31]([OH:33])=[O:32].CC(O)=O.C([BH3-])#N.[Na+]>C(O)C>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH2:10][N:29]4[CH2:36][CH2:35][CH2:34][C@H:30]4[C:31]([OH:33])=[O:32])[CH:7]=[CH:6][CH:5]=3)=[N:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[CH2:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CCc1c(CC=O)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1c(CCN2CCC[C@H]2C(=O)O)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.9 %

Procedure:
To a solution of 5-{5-[2-ethyl-3-(2-oxoethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(2-methylpropyl)benzonitrile (D31) (99 mg, 0.254 mmol) in Ethanol (15 mL) stirred at room temperature was added L-proline (117 mg, 1.017 mmol) and AcOH (0.15 mL, 2.62 mmol). The reaction mixture was stirred at room temperature for 10 min, and sodium cyanoborohydride (31.9 mg, 0.508 mmol) was added. The reaction mixture was continuously stirred overnight. The reaction was quenched with water and DCM was evaporated in vacuo. The mixture was extracted by EA/THF for 3 times. The combined organic solution was washed with brine, concentrated and purified by Mass Directed AutoPrep to afford 1-[2-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-ethylphenyl)ethyl]-L-proline (E59) (52 mg) as a off-white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:33][CH2:34][CH2:35][OH:36])[C:23]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:18]([OH:20])=O)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:33][CH2:34][CH2:35][OH:36])[C:23]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:18]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:20])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Nc1ccccc1
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(C(=O)O)cc2OCCO)c1
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc(C(=O)Nc3ccccc3)cc2OCCO)c1

Procedure:
Analogously to Example 74, by condensing 3-(4-tert-butyl-benzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-benzoic acid with aniline there was obtained 3-(4-tert-butylbenzenesulphonylamino)-5-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-N-phenyl-benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.Br[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([Br:19])[N:11]=1.C(N(CC)CC)C>CC(O)C>[Br:19][C:12]1[N:11]=[C:10]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(Br)nc1Br
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Br)nc1Nc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-pyridin-4-ylamine (1 eq, 6.6 mmol, 850 mg) and 2,6-dibromo-3-nitro pyridine (2 eq, 13.2 mmol, 3.85 g) are dissolved in IPA (15 ml) and heated using microwave radiation at 150° C. for 6 hours. After cooling to room temperature, triethylamine (1 eq) is added and reaction mixture is stirred for 1 hour. The majority of solvent is removed in vacuo and the residue is diluted using 6% DCM in iso-hexane (75 ml). The solvent is decanted off and the process repeated 3 times. The resulting brown solid is dissolved in DCM and excess amine is scavenged using SCX-2 resin (6 g) and discarded. The solid is triturated in hexane, DCM and IPA (50 ml of a 58:40:2 mixture) and the resulting yellow solid is collected by filtration. The solid is dissolved in DCM and washed with water. The organic portion is dried (MgSO4) and concentrated in vacuo to afford the title compound; [M+H]+ 330.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[CH:6][CH2:7][N:8]1[C:13]([C:14](=[O:24])[C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=2)=[C:12]([CH:25]([CH3:27])[CH3:26])[C:11](=[O:28])[NH:10][C:9]1=[O:29])C.[NH4+:31].[OH-]>CO>[C:22]([C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([CH3:21])[CH:18]=1)[C:14]([C:13]1[N:8]([CH2:7][CH:6]=[CH:5][C:4]([NH2:31])=[O:3])[C:9](=[O:29])[NH:10][C:11](=[O:28])[C:12]=1[CH:25]([CH3:26])[CH3:27])=[O:24])#[N:23]
Reactant: CCOC(=O)C=CCn1c(C(=O)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C#N)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC=CC(N)=O)c1
Temperature: 120 °C
Yield: 6.6 %

Procedure:
In a 5 mL microwave reaction tube, 4-[6-(3-cyano-5-methyl-benzoyl)-5-isopropyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-but-2-enoic acid ethyl ester (69 mg, 0.168 mmol) and 0.5 mL MeOH was added, followed by 0.7 mL NH4OH (30% in water, excess). The reaction mixture was heated in the microwave at 120° C. for 30 minutes. The reaction mixture concentrated down and purified by reverse phase prep HPLC (MeCN/water) to give a white powder (4.2 mg, 6.6%). 1H NMR (300 MHz, CD3OD): δ 8.8 (d, 1H), 7.64 (m, 2H), 7.4-7.28 (m, 2H), 3.19 (dd, 1H), 2.52 (m, 1H), 0.95 (d, 3H), 0.65 (dd, 3H). LC-MS shows 381.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C@H:8]([OH:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([C@H:8]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc([C@@H](C)O)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc([C@@H](C)OS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a stirred solution of (R)-1-(6-methyl-pyridin-2-yl)-ethanol (175 mg, 1.28 mmol) and triethylamine (355 μl, 2.56 mmol) in DCM (5 mL) at 0° C. add methanesulfonyl chloride (148 μl, 1.92 mmol). Stir at 0° C. for 30 min and quench the reaction mixture with saturated aqueous NaHCO3 at the same temperature. Extract the mixture three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (8:2) to give the title compound as a colorless oil (274 mg, 100%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](Br)[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O)[CH3:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH2:16][CH3:17])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(Br)c([N+](=O)[O-])cc1O
Reactant: CCOc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccccc1-c1cc(C(C)(C)C)c(O)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 97.2 %

Procedure:
To a solution of 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) (8.22 g, 30 mmol) in DMF (90 mL) was added 2-ethoxyphenyl boronic acid (5.48 g, 33 mmol), potassium carbonate (4.56 g, 33 mmol), water (10 ml) and Pd(PPh3)4 (1.73 g, 1.5 mmol). The mixture was heated at 90° C. for 3 h under nitrogen. The solvent was removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The combined organic layers were washed with water and brine, dried and purified by column chromatography (petroleum ether-ethyl acetate, 10:1) to afford 2-tert-butyl-4-(2-ethoxyphenyl)-5-nitrophenol (9.2 g, 92%). 1HNMR (DMSO-d6) δ 10.38 (s, 1H), 7.36 (s, 1H), 7.28 (m, 2H), 7.08 (s, 1H), 6.99 (t, 1H, J=7.35 Hz), 6.92 (d, 1H, J=8.1 Hz), 3.84 (q, 2H, J=6.6 Hz), 1.35 (s, 9H), 1.09 (t, 3H, J=6.6 Hz); ESI-MS 314.3 m/z (MH+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[C:8]([Cl:11])([Cl:10])[Cl:9])[CH3:2].C(N(CC)CC)C.[Cl:20][C:21]([SH:24])([Cl:23])[Cl:22]>CCOCC>[Cl:20][C:21]([Cl:23])([Cl:22])[S:24][N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:7](=[NH:12])[C:8]([Cl:9])([Cl:11])[Cl:10]
Reactant: CCOCCNC(=N)C(Cl)(Cl)Cl
Reactant: SC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOCCN(SC(Cl)(Cl)Cl)C(=N)C(Cl)(Cl)Cl
Reaction time: 4 h
Yield: 83.6 %

Procedure:
To 4.7 g (0.02 mole) N-(2-ethoxyethyl)trichloroacetamidine, 2.1 g (0.02 mole) triethylamine, and 50 ml ether, cooled in an ice bath, was added 3.8 g (0.02 mole) perchloromethylmercaptan over 15 minutes. The temperature rose from 1.5° C. to 8.5° C. The solution was stirred 11/4 hours longer, filtered and rotary evaporated to give 6.4 g solid. Recrystallization from petroleum ether (cooling in dry ice) gave 4.0 g (54% yield; mp 65°-66° C.). The structure was confirmed via IR and elemental analysis.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Li])CCC.CCCCCC.[O:20]1[CH:25]=[CH:24][C:23](=[O:26])[CH:22]=[CH:21]1>C1COCC1>[Br:8][C:4]1[CH:3]=[C:2]([C:23]2([OH:26])[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=c1ccocc1
Reactant: Brc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2cccc(Br)c2)CCOCC1
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a stirred −78° C. solution of 1,3-dibromobenzene (19.71 g, 81.05 mmol) in THF (150 mL) is added 1.6 M butyl lithium in hexane (50.66 mL, 81.05 mmol) and the reaction is stirred 10 minutes. 4H-Pyran-4-one, tetrahydro- (5.41 g, 54.04 mmol) is added dropwise and the reaction is stirred at −78° C. for 2 h. The reaction is quenched by addition of saturated aqueous ammonium chloride (25 mL) and is then diluted with minimal water and extracted with EtOAc. The organic layer is dried over Na2SO4 and the solvent is removed under reduced pressure to afford a residue that is purified by silica gel chromatography eluting with a linear gradient of 5% to 100% EtOAc in hexanes to give the title compound (11.18 g, 76%). GC-MS (m/e): (79Br/81Br) 256, 258 (M−1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:25]([O:29][C:30](Cl)=[O:31])[CH2:26][CH2:27][CH3:28]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:30]([O:29][CH2:25][CH2:26][CH2:27][CH3:28])=[O:31])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 4.4 g 4-amino-piperidine-1-carboxylic acid benzyl ester hydrotrifluoroacetate and 5.3 ml triethylamine in 100 ml dichloromethane were added 1.8 ml butylchloroformate dropwise at 0° C. The suspension was stirred for 12 h, diluted with dichloromethane and washed with 0.1 M HCl and aqueous NaHCO3. The crude product was purified by flash chromatography on silica using ethyl acetate/heptan 1:2 as eluent.
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7](=[O:9])[CH:8]=1.[CH2:29]([NH2:32])[CH2:30][CH3:31]>C(O)C.O>[OH:1][CH2:2][C:3]1[N:32]([CH2:29][CH2:30][CH3:31])[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7](=[O:9])[CH:8]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1coc(CO)cc1=O
Reactant: CCCN
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1cn(CCC)c(CO)cc1=O

Procedure:
A mixture of 20.0 g (51 mMole) 2-hydroxymethyl-5-octadecyloxy-4-pyranone and 30 mL of a 40% solution of propylamine in ethanol is heated in an autoclave at 100°-110° C. for 5 hours. After cooling, the crystallizate formed is taken up in water, stirred, filtered off, dried and recrystallized from ethyl acetate, colorless crystals thereby being obtained; m.p 120°-121° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8](O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.P(Br)(Br)[Br:12]>C(Cl)(Cl)(Cl)Cl.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([Br:12])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: BrP(Br)Br
Reactant: CC(O)c1cccc(F)c1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1cccc(F)c1
Yield: 78.6 %

Procedure:
Dissolve (±)-1-(3-fluorophenyl)ethanol (250 mg, 1.786 mmol) in carbon tetrachloride (10 mL). Add phosphorus tribromide (0.1 mL, 1.786 mmol) at 0° C. and stir the solution at room temperature overnight. Dilute the reaction mixture with dichloromethane and wash with brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo to obtain the title compound (285 mg) that was used without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17](=[O:19])[CH3:18]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17](=[O:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a mixture of para-fluorophenol (15 g) and K2CO3 (18.5 g) in 100 mL acetone were added chloroacetone (10.4 mL) and of Kl (22 g). After heating at reflux for 18 h the reaction mixture was cooled down and left at RT overnight. The reaction mixture was filtered, washed with acetone, and evaporated to dryness. The residue was partitioned between dichloromethane and water, the organic layer was separated and washed with water, dried over MgSO4, and evaporated to yield 15 g of 1-(4-fluoro-phenoxy)-propan-2-one as a yellow liquid.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:18][Mg]Br.[Cl-].[NH4+].O>O1CCCC1>[N:1]1[C:2]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[CH3:18])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(-c2cn3ccccc3n2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2cn3ccccc3n2)cc1

Procedure:
Subsequently, 4-imidazo[1,2-a]pyridin-2-ylbenzaldehyde g) was dissolved in tetrahydrofuran (100 mL), followed by stirring under ice cooling. Methyl magnesium bromide (3.0M diethyl ether solution, 4.4 mL) was added dropwise to the reaction mixture, followed by stirring at room temperature for 1 hour. Saturated aqueous ammonium chloride solution (5 mL) was added dropwise to the reaction mixture, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform, followed by drying over magnesium sulfate. The solvent was evaporated, and the solid was recovered through filtration by use of dichloromethane-methanol (30:1) mixture. The filtrate was concentrated under reduced pressure, and the residue was subjected to flash chromatography. Fractions eluted by dichloromethane-methanol (30:1) were concentrated under reduced pressure, and the solid was recovered through filtration by use of diethyl ether. Through the above procedure, 1-(4-imidazo[1,2-a]pyridin-2-ylphenyl)-1-ethanol (2.43 g) was yielded.