Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:31]=[CH:30][C:24]([CH:25]([N:27]=[C:28]=[S:29])[CH3:26])=[CH:23][CH:22]=1>CN(C)C=O>[CH2:1]([C:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:28]([NH:27][CH:25]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:31][CH:30]=3)[CH3:26])=[S:29])=[CH:17][CH:18]=2)=[N:10][O:11][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(N=C=S)c1ccc(F)cc1
Reactant: Nc1ccc(-c2nocc2Cc2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(NC(=S)Nc1ccc(-c2nocc2Cc2ccccc2)cc1)c1ccc(F)cc1

Procedure:
A solution of 4-(4-benzyl-isoxazol-3-yl)-phenylamine and 4-fluoro-α-methyl-benzyl isothiocyanate in dimethylformamide (5 mL) is stirred for 12 hours at room temperature. The reaction mixture is then partitioned between ethyl acetate and water. The organic layer is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.4 g crude product as a yellow solid. The latter is recrystallized from ethyl acetate/hexane to give 0.9 g product as a yellow solid. MS: m/z 433 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:8][CH:7]=1)[CH2:4][OH:5].C(N(CC)CC)C.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C@H:31]1[CH2:33][C@@H:32]1[C:34](Cl)=[O:35]>ClCCl>[OH:5][CH2:4][C@H:3]([NH:2][C:34]([C@H:32]1[CH2:33][C@@H:31]1[C:27]1[S:26][CH:30]=[CH:29][CH:28]=1)=[O:35])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:8][CH:7]=1
Reactant: O=C(Cl)[C@H]1C[C@@H]1c1cccs1
Reactant: CCCC(C)COc1ccc([C@@H](N)CO)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(C)COc1ccc([C@H](CO)NC(=O)[C@H]2C[C@@H]2c2cccs2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48 %

Procedure:
To a solution of (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic acid (0.110 g, 0.66 mmol) in dichloromethane (10 ml) in an ice-bath was added oxalyl chloride (0.58 ml, 6.60 mmol), then DMF (0.1 ml) under nitrogen. The reaction mixture was stirred for 30 minutes at 0° C. The excessive solvent was removed on ratovapor and dried under high vacuum for 2 hrs to give (1S,2S)-2-thiophen-2-yl-cyclopropanecarboxylic chloride. In a separated 50 ml round-bottom flask was charged with (R)-2-Amino-2-[4-(2-methyl-pentyloxy)-phenyl]-ethanol HCl (0.47 mmol), dichloromethane (6 ml) and triethylamine (0.31 ml, 2.35 mmol) in an ice cold bath under nitrogen. The (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic chloride, made freshly in dichloromethane (10 ml) was added into the reaction mixture dropwise. The final reaction mixture was stirred for 1.5 hrs at room temperature. The finished reaction was quenched with water. The organic phase was washed with brine (3×10 ml), dried over MgSO4, filtrated, concentrated in vacuum and purified via column chromatography on silica gel with a gradient of 0%-100% of ethyl acetate in hexane to give a white solid (0.088 g, 48% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.14 (m, 2H), 6.99 (dd, J=5.2, 1.1 Hz, 1H), 6.81 (m, 3 H), 6.72 (d, J=3.3 Hz, 1H), 6.14 (d, J=6.3 Hz, 1H), 4.95 (m, 1H), 3.80 (m, 2H), 3.67 (m, 2H), 2.72 (dd, J=7.1, 4.8 Hz, 1H), 2.62 (m, 1H), 1.85 (m, 1H), 1.60 (m, 2H), 1.27 (m, 5H), 0.92 (d, J=6.8 Hz, 3H), 0.83 (m, 3H); LCMS (ESI) m/e 374.2 [(M+H)+, calcd for C22H30NO3S 374.5].
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:40])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:38][CH3:39])=[C:17]([O:20][C@@H:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[C@@H:23]([C:34]([NH:36][CH3:37])=[O:35])[CH2:22]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1>O1CCOCC1.C(#N)C>[Cl:2][C:3]1[C:4]([F:40])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:38][CH3:39])=[C:17]([O:20][C@@H:21]4[CH2:26][CH2:25][NH:24][C@@H:23]([C:34]([NH:36][CH3:37])=[O:35])[CH2:22]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CNC(=O)[C@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: CNC(=O)[C@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
4M Hydrogen chloride (7.5 ml) in dioxane was added to a stirred solution of (1) tert-butyl (2R,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-2-[(methylamino)carbonyl]piperidine-1-carboxylate (4.17 g) in acetonitrile (10 ml) and stirred for 2 hours at room temperature. A second portion of 4M Hydrogen chloride (3.75 ml) in dioxane was added and the mixture stirred a further 1½ hours. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residues were purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (96/4). The fractions containing the desired product were combined and evaporated. The resulting solids were triturated with iso-hexane/methylene chloride filtered and dried under high vacuum at 50° C. to give the title product as a white solid (1.94 g, 57%); 1H NMR Spectrum: (DMSO d6) 1.67-1.82 (m, 2H); 1.83-1.94 (m, 1H); 1.98-2.08 (m, 1H); 2.59 (d, 3H); 2.74-2.83 (m, 1H); 2.90-3.01 (m, 1H); 3.48-3.55 (m, 1H); 3.94 (s, 3H); 4.83 (br s, 1H); 7.22 (s, 1H); 7.23-7.30 (m, 1H); 7.43-7.57 (m, 2H); 7.75-7.81 (m, 1H); 7.84 (s, 1H); 8.37 (s, 1H); 9.52 (s, 1H); Mass Spectrum: (M+H)+ 460.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C:10]1([C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([CH2:48][O:49][Si:50]([CH:57]([CH3:59])[CH3:58])([CH:54]([CH3:56])[CH3:55])[CH:51]([CH3:53])[CH3:52])[CH:42]=1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl>[Cl:47][C:44]1[CH:45]=[CH:46][C:41]([CH:10]2[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:11]2)=[CH:42][C:43]=1[CH2:48][O:49][Si:50]([CH:57]([CH3:59])[CH3:58])([CH:51]([CH3:53])[CH3:52])[CH:54]([CH3:56])[CH3:55]
Reactant: CC(C)[Si](OCc1cc(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl)(C(C)C)C(C)C
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)[Si](OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl)(C(C)C)C(C)C
Temperature: -10 °C

Procedure:
To a stirred −50° C. solution of (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-(4-chloro-3-((triisopropylsilyloxy)methyl)phenyl)tetra-hydro-2H-pyran-2-ol (198 mmol) from Step 4 in dichloromethane (500 mL) was added triethylsilane (63 mL, 396 mmol) followed by boron trifluoride diethyl etherate (50 mL, 396 mmol) at a rate such that the reaction temperature was maintained between −40 and −50° C. The solution was allowed to warm to −10° C. over 2 h prior to quenching with saturated potassium carbonate solution. After removal of organic volatiles under reduced pressure, the residue was partitioned between ethyl acetate and water. Following extraction of the aqueous layer with ethyl acetate, the combined organic layers were washed with water prior to drying over magnesium sulfate. Filtration and concentration under reduced pressure yielded the title compound as a yellow oil which was used without further purification.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH2:26][C:27]1[C:28]([I:34])=[CH:29][C:30]([F:33])=[N:31][CH:32]=1>C(#N)C.C(Cl)(Cl)Cl.C(O)(C)C>[F:33][C:30]1[N:31]=[CH:32][C:27]([CH2:26][C:5]#[N:6])=[C:28]([I:34])[CH:29]=1
Reactant: C[Si](C)(C)C#N
Reactant: Fc1cc(I)c(CBr)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: N#CCc1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine trimethylsilyl cyanide (297 mg, 3.0 mmol) and tetrabutylammonium fluoride (785 mg, 3.0 mmol) in 20 mL of acetonitrile under nitrogen. Add 5-bromomethyl-2-fluoro-4-iodo-pyridine (0.63 g, 2.0 mmol) to the above solution. Stir the mixture for 2 h at RT. Dilute the mixture with chloroform/IPA (3/1). Wash the solution with water and subsequently with saturated aqueous sodium chloride. Dry it over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (5% methanol in DCM) to afford the title compound as a yellow, waxy solid (500 mg, 96%). MS (ES) m/z 263 [M+1]+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][NH:3]1.[C:7]1([S:13](Cl)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O1CCCC1.C(Cl)(Cl)Cl>C(N(CC)CC)C>[C:7]1([S:13]([N:3]2[CH2:4][CH2:5][NH:6][C:2]2=[O:1])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1NCCN1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C1NCCN1S(=O)(=O)c1ccccc1

Procedure:
86 parts by weight of 2-oxo-imidazolidine, 194 parts by weight of benzenesulphonyl chloride, 800 parts by volume of tetrahydrofurane, 500 parts by volume of chloroform and 101 parts by weight of triethylamine were stirred overnight at 50°C and subsequently evaporated to dryness in vacuo. The residue was gradually added, while stirring, to 1,000 parts by volume of ice water, the mixture was filtered and the residue was recrystallized from ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34]C(C(O)=O)=C[CH:37]=3)[C:32]([CH3:42])=[C:31]2[CH3:43])=[CH:25][CH:24]=1)=[O:16])(C)(C)C>>[CH3:37][C:38]1[N:30]([CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:18]3[C:17]([C:15]([OH:14])=[O:16])=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:28][CH:27]=2)[C:31]2[C:43]([C:33]=1[CH3:34])=[CH:18][C:17]([C:15](=[O:14])[NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=1)=[CH:42][CH:32]=2
Reactant: Cc1ccc(CN)cc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1ccc(CNC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-methylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH3:9])=[C:4]([Cl:10])[N:3]=1.[O-:11][Mn](=O)(=O)=O.[K+].[OH2:17]>>[Cl:10][C:4]1[N:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[CH:6][C:5]=1[C:9]([OH:11])=[O:17]
Reactant: O
Reactant: Cc1cc(Cl)c(Cl)nc1Cl
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: O=C(O)c1cc(Cl)c(Cl)nc1Cl
Temperature: 100 °C
Yield: 18 %

Procedure:
A suspension of 2,3,6-trichloro-5-methylpyridine (Method 48, 11.8 g, 60.0 mmol) in water (400 ml) was heated to 100° C. Portionwise, KMnO4 (28.5 g, 180.2 mmol) was then added over 12 hours. The reaction was then allowed to stir for 2 days at 100° C., over which time an additional 10 g of KMnO4 was added portionwise. When no starting material remained, the hot reaction was filtered, washed with hot water (2×75 ml), and the resulting filtrate was allowed to cool to room temperature. The aqueous filtrate was then extracted with EtOAc (3×100 ml), and then concentrated to a 50 ml volume. This aqueous solution was then cooled to 0° C. and adjusted to pH 1-2 with 6.0 M HCl. The resulting solid was then collected by filtration, washed with cold water, and dried to give the title compound (2.5 g, 18%) that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][C:16]1[CH:24]=[C:23]([CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:23]([CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:16]=2[CH3:15])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: Cc1cc(CS(C)(=O)=O)ccc1C(=O)O
Product: Cc1cc(CS(C)(=O)=O)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
410 mg of dimethyl 2-methylterephthalate was hydrolyzed via Procedure M and purified by ISCO Combi-Flash to afford 4-(methoxycarbonyl)-3-methylbenzoic acid. 255 mg of 4-(methoxycarbonyl)-3-methylbenzoic acid was cooled to 0° C. in 2 mL of THF before a solution of 2.6 mL of 1M BH3-THF complex in THF was added dropwise. The ice bath was subsequently removed and the reaction was stirred at room temperature until reaction stalled out at ˜50% complete by TLC. The reaction was re-cooled to 0° C. and another 2.6 mL of BH3-THF was added dropwise before the ice bath was removed. Upon completion, the reaction was re-cooled to 0° C. and quenched with 3N HCl dropwise. The aqueous layer was extracted 2 times with Ethyl Acetate and the organic layer was then extracted once with bicarbonate solution and brine, dried over Magnesium Sulfate, filtered and concentrated to give methyl 4-(hydroxymethyl)-2-methylbenzoate. 220 mg of methyl 4-(hydroxymethyl)-2-methylbenzoate was cooled to 0° C. in 5 mL of DCM before adding 260 mg of Triphenylphosphine and 395 mg of NBS. The reaction was concentrated and directly purified via ISCO Combi-Flash to give pure methyl 4-(bromomethyl)-2-methylbenzoate. 255 mg of methyl 4-(bromomethyl)-2-methylbenzoate was reacted via Procedure O to give methyl 2-methyl-4-(methylsulfonylmethyl)benzoate. 250 mg of methyl 2-methyl-4-(methylsulfonylmethyl)benzoate was then hydrolyzed upon heating to 45° C. for 1 hour via Procedure M to give 2-methyl-4-(methylsulfonylmethyl)benzoic acid. 202 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-methyl-4-(methylsulfonylmethyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-4-(methylsulfonylmethyl)benzamide. MS (Q1) 415 (M)+.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.C(Cl)(=O)C.ClCCl.O1[CH2:19][CH2:18][CH2:17]C1.C([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])C>N1C=CC=CC=1>[CH:18]([N:22]([CH:23]([CH3:24])[CH3:1])[CH2:25][CH3:26])([CH3:19])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: C1CCOC1
Reactant: CCN(CC)CC
Solvent: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(C(C)C)C(C)C

Procedure:
Free amine 57 can be converted to the corresponding protected intermediate 58 by reaction with an acetylation agent such as acetic anhydride (Ac2O) or acetyl chloride (AcCl) in a solvent such as dichloromethane (DCM), tetrahydrofuran (THF), or pyridine, optionally in the presence of a base such as pyridine, triethylamine (Et3N, TEA), or diisopropylethylamine (iPr2EtN, DIEA) and/or a nucleophilic acylation catalyst such 4-(N,N-dimethylaminopyridine (DMAP) at temperature from about −20° C. to about 40° C. to provide corresponding protected sulfonyl ester intermediate 58.
Reaction SMILES: Cl[C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=2)[N:3]=1.[C:18]1([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC[N:32]([CH:36]([CH3:38])C)[CH:33]([CH3:35])C>CN(C)C=O>[C:18]1([CH:24]2[CH2:25][CH2:26][N:27]([C:2]3[C:11]([N:32]4[CH2:33][CH2:35][CH:13]([C:7]5[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=5)[CH2:38][CH2:36]4)=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=4)[N:3]=3)[CH2:28][CH2:29]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccc2nc(Cl)c(Cl)nc2c1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2nc(N3CCC(c4ccccc4)CC3)c(N3CCC(c4ccccc4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 20-mL sealed tube, was placed a solution of ethyl 2,3-dichloroquinoxaline-6-carboxylate (150 mg, 0.55 mmol, 1.00 equiv), 4-phenylpiperidine (298 mg, 1.85 mmol, 3.00 equiv), DIEA (398 mg, 3.09 mmol, 5.00 equiv) in N,N-dimethylformamide (10 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 180 mg (62%) of ethyl 2,3-bis(4-phenylpiperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: O[C:2]1[C:12]([I:13])=[C:11]([OH:14])[CH:10]=[C:9]([CH3:15])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].COS([O:21][CH3:22])(=O)=O.[C:23](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[I:13][C:12]1[C:2]([O:21][CH3:22])=[C:3]([C:9]([CH3:15])=[CH:10][C:11]=1[O:14][CH3:23])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1c(C)cc(O)c(I)c1O
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C)cc(OC)c(I)c1OC

Procedure:
A mixture of ethyl 2,4-dihydroxy-3-iodo-6-methylbenzoate (Intermediate 204, 0.144 g), dimethylsulphate (0.085 ml) and potassium carbonate (0.185 g) in acetone (10 ml) was heated at reflux for 2.5 hours. After cooling, the mixture was filtered and the filtrate was evaporated to dryness. The residue was partitioned between DCM and water and the organic layer was filtered through a phase separator. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-20% to give ethyl 3-iodo-2,4-dimethoxy-6-methylbenzoate (0.158 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:10][C:9](=[O:11])[N:8]([CH2:12][C:13]#[N:14])[C:5]2=[N:6][CH:7]=1.BrC1[CH:17]=[C:18]2[O:24]C(=O)N(C)C2=NC=1>>[C:13]([CH2:12][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:18](=[O:24])[CH3:17])[CH:3]=[C:4]2[O:10][C:9]1=[O:11])#[N:14]
Reactant: Cn1c(=O)oc2cc(Br)cnc21
Reactant: N#CCn1c(=O)oc2cc(Br)cnc21
Product: CC(=O)c1cnc2c(c1)oc(=O)n2CC#N

Procedure:
The method of operation is the same as that used for the synthesis of the compound of Example 1 (coupling with 1-ethoxy-1-(trimethylstannyl)ethylene). 6-bromo-3-(cyanomethyl)oxazolo[4,5-b]pyridin-2(3H)-one from Preparation 3 is used instead of the 6-bromo-3-methyloxazolo[4,5-b]pyridin-2(3H)-one from Preparation 2. The yield obtained is 60%. ##STR48##
Reaction SMILES: [C:1]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([Mg]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Cl-].[NH4+]>C1COCC1>[C:2]1([C:1]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([OH:8])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[C:16]3[N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[CH:11][CH:10]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(c2cccc3ccc(C(=O)c4ccccc4)cc23)CC1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCN(c2cccc3ccc(C(O)(c4ccccc4)c4ccccc4)cc23)CC1
Temperature: 0 °C
Yield: 92.1 %

Procedure:
The title product of example 43 (0.072 g, 0.218 mmol) was dissolved in dry THF (10 mL) and chilled to 0° C. Phenyl magnesium bromide (3 M in ether, 0.08 mL, 0.24 mmol) was added dropwise. The mixture turned greenish and then returned to a yellow color. The reaction was allowed to warm to room temperature for 30 minutes and then refluxed for 45 minutes. Additional phenyl magnesium bromide (0.1 mL, 0.26 mmol) was added and the mixture was refluxed 1 hour more. Saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated to a light yellow oil. The product was purified by silica gel flash chromatography (1×6 inches). Elution with 50% ethyl acetate/hexane followed by ethyl acetate gave 0.082 g (92%) of the title product. A sample was recrystallized from chloroform/ether for analysis: mp 217.5°-218.5° C. Analysis calculated for C28H28N2O·0.5 H2P: C, 80.54; H, 7.00; N, 6.71. Found: C, 80.47; H, 6.63; N, 6.78.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH2:24]([N:26]([CH2:29][C:30]([N:32]([C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)[CH3:33])=[O:31])[CH2:27][CH3:28])[CH3:25].[OH-].[Na+]>CN(C=O)C.CO>[CH2:24]([N:26]([CH2:29][C:30]([N:32]([C:34]1[CH:40]=[CH:39][C:37]([NH:38]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:36][CH:35]=1)[CH3:33])=[O:31])[CH2:27][CH3:28])[CH3:25]
Reactant: CCN(CC)CC(=O)N(C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CCN(CC)CC(=O)N(C)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 43 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-(N-diethylaminomethylcarbonyl-N-methyl-amino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.Br[CH2:25][C:26]1[C:37]([C:38]#[N:39])=[C:30]2[N:31]=[C:32]([CH:34]3[CH2:36][CH2:35]3)[O:33][C:29]2=[C:28]([F:40])[C:27]=1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O>[CH:34]1([C:32]2[O:33][C:29]3[C:30](=[C:37]([C:38]#[N:39])[C:26]([CH2:25][F:1])=[C:27]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:28]=3[F:40])[N:31]=2)[CH2:36][CH2:35]1
Reactant: [F-]
Reactant: N#Cc1c(CBr)c(-c2ccccc2)c(F)c2oc(C3CC3)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(CF)c(-c2ccccc2)c(F)c2oc(C3CC3)nc12
Yield: 59.4 %

Procedure:
Under nitrogen atmosphere at 0° C., tetra(n-butyl)ammonium fluoride (1.0 M tetrahydrofuran solution) (1.50 ml, 1.50 mmol) was added to a tetrahydrofuran (12 ml) solution of 5-bromomethyl-2-cyclopropyl-7-fluoro-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-292) (426 mg, 1.15 mmol), followed by stirring with cooling with water for 1.5 hours. The solvent was evaporated away under reduced pressure, then the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=4:1, v/v) to obtain the entitled compound (212 mg, 59%) as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:9][C:10]2[S:11][C:12]3[CH:18]=[C:17]([O:19][S:20]([C:23]4[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[O:8])[CH2:3][CH2:2]1.[N:30]1C=C[CH:33]=[C:32]([C:36]2N=CN(CCCCN)C=2)[CH:31]=1.CN1C(=[O:52])CCC1>>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:9][C:10]2[S:11][C:12]3[CH:18]=[C:17]([O:19][S:20]([C:23]4[CH:28]=[CH:27][C:26]([NH:30][CH2:31][C:32]([OH:52])([CH3:36])[CH3:33])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CCNCC1
Reactant: NCCCCn1cnc(-c2cccnc2)c1
Reactant: CN1CCCC1=O
Product: CC(C)(O)CNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)C4CCNCC4)sc3c2)cc1

Procedure:
A solution of 4-fluorobenzenesulfonic 2-[(piperidine-4-carbonyl)amino]benzo-thiazol-6-yl ester (intermediate 4) (50 mg, 0.114 mmol) and of 4-(4-pyrid-3-yl-imidazol-1-yl)butylamine (40.93 mg, 0.459 mmol) in 0.5 ml of NMP is heated at 130° C. by microwave for 5 minutes. The crude reaction product is purified by preparative LC/MS (basic medium (pH 9)) to give after freeze-drying 21 mg of 4-(2-hydroxy-2-methylpropylamino)benzenesulfonic 2-(cyclo-propanecarbonylamino)benzothiazol-6-yl ester (pale yellow solid).