Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[O:7][CH2:8][CH2:9][NH2:10].[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25]Cl.C(N(CC)CC)C.O>CS(C)=O>[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][NH:10][CH2:9][CH2:8][O:7][C:6]1[CH:11]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:12][CH3:13]
Reactant: COc1ccc(F)cc1OCCN
Reactant: Fc1ccc2[nH]cc(CCCl)c2c1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(F)cc1OCCNCCc1c[nH]c2ccc(F)cc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
A solution of 2-(5-fluoro-2-methoxy-phenoxy)ethylamine (0.51 g, 2.8 mmol), 2-(5-fluoro-1H-indol-3-yl)ethylchloride (0.44 g, 1.8 mmol) and triethylamine (0.29 g, 3 mmol) in dimethylsulfoxide (20 ml) was allowed to stir for 8 hours at 90° C. The reaction mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (5% methanol-methylene chloride) afforded 0.27 g (43%) of product as a brown oil.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Si]([O:46][CH2:47][CH2:48][N:49]([C:54]1[C:73]([C:74]2[CH:75]=[C:76]([CH:80]=[CH:81][CH:82]=2)[C:77](O)=[O:78])=[CH:72][C:57]2[C:58]([C:68](=[O:71])[NH:69][CH3:70])=[C:59]([C:61]3[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=3)[O:60][C:56]=2[CH:55]=1)[S:50]([CH3:53])(=[O:52])=[O:51])(C(C)(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[C:1]([NH:5][C:77]([C:76]1[CH:75]=[C:74]([C:73]2[C:54]([N:49]([CH2:48][CH2:47][OH:46])[S:50]([CH3:53])(=[O:51])=[O:52])=[CH:55][C:56]3[O:60][C:59]([C:61]4[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=4)=[C:58]([C:68]([NH:69][CH3:70])=[O:71])[C:57]=3[CH:72]=2)[CH:82]=[CH:81][CH:80]=1)=[O:78])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(CCO[Si](C)(C)C(C)(C)C)S(C)(=O)=O)c(-c3cccc(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(CCO)S(C)(=O)=O)c(-c3cccc(C(=O)NC(C)(C)C)c3)cc12
Reaction time: 1 h
Yield: 24.2 %

Procedure:
Tert-butylamine (21 μL, 0.195 mmol) was added to a stirring solution of HATU (45 mg, 0.117 mmol), DIEA (41 μL, 0.234 mmol), and 3-(6-(N-(2-(tert-butyldimethylsilyloxy)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (50 mg, 0.078 mmol) in DMF (780 μL) at rt. It was allowed to stir for 1 hour. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (11 mg, 23%). 1H NMR (500 MHz, CD3OD) d ppm 8.04 (1 H, br. s.), 7.94-8.02 (2 H, m), 7.77-7.86 (2 H, m), 7.66-7.73 (2 H, m), 7.49-7.59 (2 H, m), 7.24-7.34 (2 H, m), 3.56-3.66 (1 H, m), 3.35-3.43 (2 H, m), 3.27 (3 H, s), 2.94 (3 H, s), 2.78-2.87 (1 H, m), 1.47 (9 H, s). LC-MS retention time: 1.57 min; m/z (MH+): 582. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=10.88 min, purity=97%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm, Rt=10.27 min, purity=96%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([C:15]2([C:20]#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:14]=1)[C:9](O)=[O:10])=[O:5])[CH3:2].B.O1CCCC1>C1COCC1>[NH2:21][CH2:20][C:15]1([C:13]2[CH:14]=[C:6]([CH:7]=[C:8]([CH2:9][OH:10])[CH:12]=2)[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:19][CH2:18][CH2:17][CH2:16]1.[C:20]([C:15]1([C:13]2[CH:14]=[C:6]([CH:7]=[C:8]([CH2:9][OH:10])[CH:12]=2)[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:19][CH2:18][CH2:17][CH2:16]1)#[N:21]
Reactant: CCOC(=O)c1cc(C(=O)O)cc(C2(C#N)CCCC2)c1
Agent: B
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(CO)cc(C2(C#N)CCCC2)c1
Product: CCOC(=O)c1cc(CO)cc(C2(CN)CCCC2)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-(ethoxycarbonyl)-5-(1-cyanocyclopentyl)benzoic acid (0.4 g, 1.4 mmol) in 14 mL THF, cooled to 0° C., was added borane-tetrahydrofuran complex (1M in THF, 5.6 mL, 5.6 mmol) dropwise. The reaction was stirred at 0° C. for 1.5 h and then at rt for 3.5 h. The mixture was quenched with MeOH, concentrated, diluted with EtOAc and washed with water and brine. Drying and solvent evaporation gave ethyl 3-(1-(aminomethyl)cyclopentyl)-5-(hydroxymethyl)benzoate and ethyl 3-(1-cyanocyclopentyl)-5-(hydroxymethyl)benzoate. The crude mixture was dissolved in 6.6 mL CH2Cl2, cooled to 0° C. and treated with carbon tetrabromide (0.56 g, 1.7 mmol). A solution of triphenylphosphine (0.42 g, 1.6 mmol) in 6.6 mL CH2Cl2 was added and the reaction was stirred at 0° C. for 1 h. Concentration and flash chromatography (silica gel, 0-20% EtOAc/hexanes) gave ethyl 3-(bromomethyl)-5-(1-cyanocyclopentyl)benzoate. 1H NMR (400 MHz, CDCl3) δ 8.02 (t, J=1.9 Hz, 2H), 7.70 (t, J=1.7 Hz, 1H), 4.52 (s, 2H), 4.41 (q, J=7.1 Hz, 2H), 2.53 (m, 2H), 2.12-1.97 (m, 6H), 1.41 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[C:9]([N+:14]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)([O-])=O.O.C.[H][H]>NC1C=CC=CC=1.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc2c([N+](=O)[O-])cccc12
Agent: [Pt]
Solvent: O
Solvent: Nc1ccccc1
Product: Nc1cccc2c(N)cccc12
Temperature: 18 °C

Procedure:
60 g (0.275 mol) of 1,5-dinitro naphthalene were suspended, in a 700 ml stirrer autoclave, in 340 ml of aniline and treated with 18 g of water-moist, 1%-strength catalyst of platinum and activated charcoal corresponding to 8 g of dry catalyst. Hydrogenation was carried out at 50° C. and a hydrogen pressure of 10 bars, as was described in Example 1. The hydrogen uptake was finished after 2 hours. The catalyst was separated off by filtration at 80° C. and the aniline subsequently removed by water-vapour distillation. The distillation residue was cooled to 18° C. and the precipitated crystallate filtered off and dried. In this way 40 g (92% of the theory) of 1,5-diamino naphthalene of m.p. 188°-189° C. were obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:16][C:17]2[CH:21]=[C:20]([C:22]3[S:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[O:19][N:18]=2)[N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])C.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:27][C:24]1[S:23][C:22]([C:20]2[O:19][N:18]=[C:17]([CH2:16][N:7]3[C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]([C:11]4[S:12][CH:13]=[CH:14][CH:15]=4)=[N:8]3)[CH:21]=2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cc(-c2cccs2)nn1Cc1cc(-c2ccc(Cl)s2)on1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(-c2cccs2)nn1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 4 g 2-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-thiophen-2-yl-2H-pyrazole-3-carboxylic acid ethyl ester in 20 ml THF, 10 ml water and 500 mg lithium hydroxide monohydrate were added. After stirring for 2 h at 60° C. the reaction was cooled to RT. The mixture was acidified with half concentrated hydrochloric acid to pH 3 and the precipitate collected by filtration and washed with 10 ml water The product was obtained as a white solid which was dried under reduced pressure.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[SH:7].CC(C)([O-])C.[K+].Cl[C:15]1[N:20]=[C:19]([C:21]([NH:23][C:24]2[S:28][N:27]=[C:26]([CH3:29])[N:25]=2)=[O:22])[C:18]([S:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)=[CH:17][CH:16]=1.Cl>O.C(Cl)(Cl)Cl.CC(N(C)C)=O>[OH:37][C:34]1[CH:35]=[CH:36][C:31]([S:30][C:18]2[C:19]([C:21]([NH:23][C:24]3[S:28][N:27]=[C:26]([CH3:29])[N:25]=3)=[O:22])=[N:20][C:15]([S:7][C:3]3[N:2]([CH3:1])[CH:6]=[N:5][N:4]=3)=[CH:16][CH:17]=2)=[CH:32][CH:33]=1
Reactant: Cn1cnnc1S
Reactant: Cc1nsc(NC(=O)c2nc(Cl)ccc2Sc2ccc(O)cc2)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nsc(NC(=O)c2nc(Sc3nncn3C)ccc2Sc2ccc(O)cc2)n1
Temperature: 160 °C
Yield: 63.7 %

Procedure:
20 g of 4-methyl-4H-1,2,4-triazole-3-thiol and 19 g of potassium t-butoxide were added to a dimethylacetamide (130 ml) solution of 13 g of 6-chloro-3-[(4-hydroxyphenyl)thio]-N-(3-methyl-1,2,4-thiadiazol-5-yl)pyridine-2-carboxamide, and stirred under heat at 160° C. for 8 hours. At room temperature, chloroform and water were added to it, and its pH was controlled to 3 with aqueous 1 N hydrochloric acid solution added thereto. This was extracted with chloroform, and the organic layer was washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol) to obtain 10.0 g of the entitled compound as a yellow solid.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][O:21][C:22]2[C:30]([CH:31]3[CH2:33][CH2:32]3)=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:34])[CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:1]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][O:21][C:22]2[C:30]([CH:31]3[CH2:33][CH2:32]3)=[CH:29][C:25]([C:26]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:27])=[C:24]([F:34])[CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1F
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1F
Yield: 4.7 %

Procedure:
A solution of 4-((1-benzhydrylpiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid (270 mg, 0.59 mmol), methanesulfonamide (84 mg, 0.88 mmol), EDCI (169 mg, 0.88 mmol) and DMAP (107 mg, 0.88 mmol) in DCM (5 mL) was stirred at room temperature for 16 h. The reaction was quenched with water (5 mL) then adjusted pH to 1 with HCl (1 M). The resulting mixture was extracted with DCM (5 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by reverse phase Combiflash (20%-50% CH3CN/H2O in 0.1% NH4HCO3) to afford the target compound (15 mg, 5%) as a white solid. LCMS (ESI) Method A: RT=6.10 min, m/z: 537.2 [M+H]+. 1H-NMR (500 MHz, MeOD-d4,): δ 7.40-7.42 (m, 4H), 7.15-7.30 (m, 7H), 6.67 (d, J=13 Hz, 1H), 4.30 (s, 1H), 3.87 (d, J=6 Hz, 2H), 2.82 (s, 3H), 1.73-1.98 (m, 7H), 1.37-1.40 (m, 3H), 0.83-0.86 (m, 2H), 0.50-0.53 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]=2[O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:46][O:47][CH2:48][CH2:49]Br>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:49][CH2:48][O:47][CH3:46])=[CH:22][CH:23]=3)[N:18]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:17]=2[O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCBr
Reactant: Cc1ccccc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(O)cc2n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3ccccc3C)n(-c3ccccc3)c2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
The compound of example 8 (63.0 mg, 119 μmol) was dissolved in DMF, and cesium carbonate (116 mg, 358 μmol) and 2-bromoethyl methyl ether (13.5 μl, 143 μmol) were added. The reaction mixture was stirred at 50° C. for 3 h. The cooled mixture was diluted with water and extracted with EA. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (EA/HEP). 60.0 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(NC(=O)c2nc(C)ccc2N)ccn1
Reactant: Brc1cccnc1
Agent: [Pd]
Product: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cccnc2)ccn1

Procedure:
The title compound was prepared from 3-tert-Butoxy-carbonylamino-6-methyl-pyridine-2-carboxylic acid methyl ester in accordance with the general method of example 4; step 2 using 2-methyl-4-aminopyridine (CAS: [18437-58-6]) instead of 2-chloro-4-aminopyridine to yield [2-(2-Methyl-pyridin-4-ylcarbamoyl)-6-methyl-pyridin-3-yl]-carbamic acid tert-butyl ester, MS (ISP): m/e=343.1 (M+H+). Boc-deprotection as described in example 4 step 3 yielded 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide, MS (ISP): m/e=243.4 (M+H+). Palladium catalysed arylation with 3-Bromopyridine as described in example 4 step 4 yielded the final product as a light yellow solid, MS (ISP): m/e=320.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[F:19][C:20]([F:24])([F:23])[CH2:21][OH:22].O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:22][CH2:21][C:20]([F:24])([F:23])[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
To a solution of 4-methylbenzenesulfonyl chloride (3.4 g, 17.83 mmol) and Et3N (3.61 g, 35.66 mmol) in DCM (80 mL) was added 2,2,2-trifluoroethan-1-ol (2.32 g, 23.18 mmol) slowly, the mixture was then stirred at r.t. until TLC showed no starting material. Water was added to the reaction mixture, and extracted with DCM, collected the organic phase and washed with brine, dried with anhydrous Na2SO4, removed the solvent to give 4.2 g of the title compound (93%). 1H NMR (400 MHz, CDCl3): δ 2.47 (3H, s), 4.34 (2H, q, J=8.0 Hz), 7.38 (2H, d, J=8.0 Hz), 7.81 (2H, d, J=8.0 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([CH:23]=[C:24]([CH2:26]Cl)[N:25]=2)[CH:22]=1>>[Br:16][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([CH:23]=[C:24]([CH2:26][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:25]=2)[CH:22]=1
Reactant: ClCc1cn2cc(Br)ccc2n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: Brc1ccc2nc(COc3ccc(CCCn4ccnc4)cc3)cn2c1
Yield: 57 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 6-bromo-2-chloromethylimidazo[1,2-a]pyridine to give 6-bromo-2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]imidazo[1,2-a]pyridine. The yield was 57%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 103-104° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]2[CH2:15][CH2:14]2)[C@H:11]([C:16]([O:18]CC)=[O:17])[O:10][CH:9]1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>CO.O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]2[CH2:15][CH2:14]2)[C@H:11]([C:16]([OH:18])=[O:17])[O:10][CH:9]1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H]1OC(c2ccc(OC)cc2)N(C(=O)OC(C)(C)C)[C@H]1C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C2O[C@@H](C(=O)O)[C@H](C3CC3)N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of 881 mg of ethyl (4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-cyclopropyl-5-oxazolidinecarboxylate (diastereomeric mixture) in 16 ml of methanol is added dropwise a solution of 64.7 mg of lithium hydroxide in 8 ml of water under cooling, and the mixture is stirred at room temperature for 1 hour. After the reaction mixture is evaporated under reduced pressure to remove methanol, the residue is dissolved in chloroform. The pH of the solution is adjusted to pH 2 with 10% hydrochloric acid. After extracted with chloroform, the extract is washed with brine twice, dried and evaporated to remove the solvent to give 792 mg of (4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-cyclopropyl-5-oxazolidinecarboxylic acid.
Reaction SMILES: [O-][CH2:2][CH3:3].[Na+].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[S:17])[CH:14]([CH3:16])[CH3:15])=[CH:8][CH:7]=1.C(O)C.ICC>ClCCl>[CH2:2]([S:17][C:13](=[N:12][C:9]1[CH:8]=[CH:7][C:6]([Br:5])=[CH:11][CH:10]=1)[CH:14]([CH3:15])[CH3:16])[CH3:3]
Reactant: CC[O-]
Reactant: CC(C)C(=S)Nc1ccc(Br)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCI
Solvent: CCO
Product: CCSC(=Nc1ccc(Br)cc1)C(C)C
Temperature: 60 °C
Reaction time: 6 h
Yield: 90.8 %

Procedure:
In a 300 mL three-neck flask were put 3.4 g (50 mmol) of sodium ethoxide, 13 g (50 mmol) of N-(4-bromophenyl)isobutyrthioamide synthesized in Step 2, and 80 mL of ethanol, and the mixture was stirred at room temperature for 2 hours. After the stirring, 4.0 mL of iodoethane was added to this mixture, and the mixture was stirred at 60° C. for 6 hours. After the stirring, ethanol was distilled off to give a brown oily substance. This oily substance was dissolved in dichloromethane, and washed with water and a saturated aqueous solution of sodium hydrogen carbonate. After the washing, anhydrous magnesium sulfate was added to the organic layer for drying. This mixture was subjected to gravity filtration, and the resulting filtrate was concentrated to give 13 g of N-[1-(ethylsulfanyl)isobutylidene]-4-bromoaniline as a brown oily substance in a yield of 88%. The reaction scheme of Step 3 is shown in (b-3) below.
Reaction SMILES: [Br:1]Br.[OH-].[Na+].[C:5]([C:7]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=1)([CH2:14][CH:15]=[CH2:16])[CH2:8][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)#[N:6].O>O1CCOCC1>[C:5]([C:7]([C:17]1[CH:18]=[CH:19][C:20]([C:23]#[C:24][Br:1])=[CH:21][CH:22]=1)([CH2:14][CH:15]=[CH2:16])[CH2:8][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)#[N:6]
Reactant: C#Cc1ccc(C(C#N)(CC=C)Cn2cncn2)cc1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=CCC(C#N)(Cn1cncn1)c1ccc(C#CBr)cc1

Procedure:
0.8 g of bromine are added, at 0°, to 5 ml of 10% NaOH while stirring vigorously. After the solution has become colourless a solution of 1 g 2-cyano-2-(4-ethinylphenyl)-1-(1H-1,2,4-triazol-1-yl)-4-pentene in 3 ml of dioxane are added dropwise, at 0°, within a few minutes. The reaction mixture is then stirred for 3 hours at room temperature, poured into 100 ml of water, extracted with diethylether, the ether extract washed with water (3 times), dried and the ether evaporated. The residue is heated for 3 hours at high vacuum and a temperature of 50°-60° C. The thus obtained title compound has a Rf value of 0.75, employing CH2Cl2 /CH3OH 9:1 as eluant (Compound 4).
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[N:4][N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[CH:15][C:8]=23)[CH:6]=1.[C:17]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)#[N:18].C(=O)([O-])[O-].[Na+].[Na+].COCCOC.O>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>[CH3:16][C:3]1[C:2]([C:23]2[CH:24]=[C:19]([CH:20]=[CH:21][CH:22]=2)[C:17]#[N:18])=[CH:6][N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[CH:15][C:8]=23)[N:4]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1nn(-c2ccnc3[nH]ccc23)cc1Br
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1nn(-c2ccnc3[nH]ccc23)cc1-c1cccc(C#N)c1
Temperature: 130 °C
Reaction time: 4 h
Yield: 41.8 %

Procedure:
A mixture of 4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.032 g, 0.00012 mol), (3-cyanophenyl)boronic acid (0.027 g, 0.00018 mol), sodium carbonate (0.032 g, 0.00030 mol) and tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 0.0000060 mol) in 1,2-dimethoxyethane (0.3 mL, 0.003 mol) and water (0.3 mL, 0.02 mol) was heated at 130° C. (a liquid resulted, but with two layers) for 4 h. The reaction mixture then was cooled to room temperature (rt), filtered and was washed with water (×2) and dimethyl ether (DME) (×2) to give the product as a pale orange solid (15 mg, 44% yield).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:16]=1)[CH2:12][OH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:25](Cl)(=[O:29])[C:26]([CH3:28])=[CH2:27].N1C=CC=CC=1>CCOCC>[C:25]([O:13][CH2:12][C:11]1[CH:10]=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:16]=[C:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH:14]=1)(=[O:29])[C:26]([CH3:28])=[CH2:27]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(CO)cc(O[Si](C)(C)C(C)(C)C)c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCc1cc(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
3,5-Di-tert-butyldimethylsilyloxybenzyl alcohol (13.0 g, 35.2 mmole) and freshly distilled methacryloyl chloride (4.06 g, 38.8 mmole) were dissolved in 75 ml of ether and cooled to 0° C. Pyridine (3.21 g, 40.6 mmole) in ether (10 ml) was added dropwise and the reaction mixture was stirred overnight at room temperature. The pyridinium hydrochloride was filtered off and the filtrate was passed over a silica bed to remove the traces of methacrylic acid. Through the silica bed were passed another 75 ml of ether, and after combination of the fractions, the ether was removed under reduced pressure to obtain an oily product (14.2 g, 32.7 mmole, 93%).