Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=2)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.Cl>CO>[Cl:1][C:2]1[C:3]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=2)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cnc(-c2nc(N3CCC(NC(=O)OC(C)(C)C)CC3)ccc2Cl)c(C)c1
Agent: Cl
Solvent: CO
Product: Cc1cnc(-c2nc(N3CCC(N)CC3)ccc2Cl)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 144.7 %

Procedure:
To a suspension of tert-butyl [1-(3-chloro-3′,5′-dimethyl-2,2′-bipyridin-6-yl)piperidin-4-yl]carbamate (220 mg, 0.528 mmol) in MeOH (5.28 mL) was added HCl (2.64 mL, 4M in dioxane, 2.64 mmol). The resulting yellow solution was stirred at rt for 4 h and concentrated to get 242 mg (99%) of the title compound as a yellow solid. m/z (APCI+) for C17H21N4Cl 317.20 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65 (s, 1H) 8.30 (br. s., 3 H) 8.28 (br. s., 1 H) 7.84 (d, J=9.09 Hz, 1 H) 7.14 (d, J=9.35 Hz, 1 H) 4.29 (d, J=13.39 Hz, 2 H) 3.22-3.34 (m, 1 H) 2.95 (t, J=12.25 Hz, 2 H) 2.48 (s, 3 H) 2.24 (s, 3 H) 1.96 (d, J=10.86 Hz, 2 H) 1.48-1.60 (m, 2 H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=1[C:22]#[N:23])[C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])C1C=CC=CC=1.Br>C(O)(=O)C>[C:22]([C:21]1[CH:20]=[CH:19][C:11]([C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:10][C:9]=1[OH:8])#[N:23]
Reactant: N#Cc1ccc(C(=O)CCC(=O)O)cc1OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: N#Cc1ccc(C(=O)CCC(=O)O)cc1O
Temperature: 0 °C

Procedure:
3-(3-Benzyloxy-4-cyanobenzoyl)propionic acid was warmed with 33% hydrogen bromide in acetic acid and the solution was poured into ice-water to give 3-(4-cyano-3-hydroxybenzoyl)propionic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][C:17]=1[F:24]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][C:2]2[CH:3]=[C:4]3[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]3[C:6](=[O:8])[N:7]=2)=[CH:18][C:17]=1[F:24]
Reactant: OCc1ccc(Cl)c(F)c1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3ccc(Cl)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (4-chloro-3-fluorophenyl)methanol.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[F:10][C:11]1[N:16]=[C:15]([CH:17]=O)[CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.C(O)(=O)C.C1COCC1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:17][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([F:10])[N:16]=1)[CH3:2]
Reactant: O=Cc1cccc(F)n1
Reactant: CCOC(CN)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(CNCc1cccc(F)n1)OCC
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
To a mixed solution of a commercially available product of 2,2-diethoxyethan-1-amine (926 μL, 6.39 mmol), THF (10.0 mL) and acetic acid (1.00 mL) was added a commercially available product of 6-fluoropyridine-2-carbaldehyde (800 mg, 6.39 mmol) at room temperature. The resultant mixture was stirred at room temperature for 25 minutes. Subsequently, sodium triacetoxyborohydride (2.71 g, 12.8 mmol) was added to the reaction mixture at room temperature and then stirred for 1 hour and 10 minutes. To the reaction mixture was added sodium hydrogen carbonate and water to terminate the reaction. The resultant solution was extracted with ethyl acetate. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1), and was then further purified by silica gel column chromatography (ethyl acetate:methanol=20:1) to give the title compound (1.14 g, yield: 74%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.Cl.[NH2:13][OH:14].C([O-])(=O)C.[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:13]/[OH:14])/[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: C/C(=N\O)c1cc(Br)ccc1O
Yield: 98.2 %

Procedure:
To a solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (2.0 g, 9.30 mmol) in ethanol (20 mL) were added hydroxylamine hydrochloride (0.7 g, 10.2 mmol) and potassium acetate (1.0 g, 10.2 mmol). The mixture was stirred at reflux temperature for 16 h. After this time, the mixture was cooled, concentrated and the residue was diluted with CH2Cl2 (25 mL) and washed with H2O (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford title compound (11) (2.1 g, 95%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.40 (s, 1H), 7.20 (dd, J=8.8, 2.0 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 2.50 (bs, 1H), 2.20 (s, 3H); MS (ESI, M+H+) C8H9BrNO2, calcd. 230.0. found 230.0, 232.0.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].Cl[CH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[O:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([O:12][CH2:14][C:15]3[CH:32]=[CH:31][CH:30]=[C:17]([O:18][CH2:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)[CH:16]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: N#Cc1nc2ccc(O)cc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1nc2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc2o1
Temperature: 0 °C

Procedure:
To 2-cyano-6-hydroxybenzoxazole (11.87 mmoles) and 2-((3-chloromethylphenoxy)methyl)quinoline (11.87 mmoles) in dimethylsulfoxide (20 ml) is added powdered sodium hydroxide (0.475 q). After one week the reaction mixture is poured into ice water and the resulting precipitate collected and purified by HPLC to give 2-cyano-6-(3-(quinolin-2-ylmethyloxy)benzyloxy)-benzoxazole which is used directly in the next step.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:13](=O)[CH3:14]>>[CH2:13]([NH:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:14]
Reactant: CC=O
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Product: CCN[C@H](Cc1ccccc1)C(=O)O

Procedure:
According to a further embodiment of the present invention D-phenylalanine is submitted to hydrogenolysis in the presence of acetaldehyde, the resulting N-ethyl-D-phenylalanine is provided with a benzyloxycarbonyl protecting group, its 2,4,5-trichlorophenyl ester is formed, then it is condensed with L-proline. The N-benzyloxycarbonyl-N-ethyl-D-phenylalanyl-L-proline obtained is coupled by the mixed anhydride method to Nω -benzyloxycarbonyl-L-arginine lactam. The protected tripeptide lactam obtained is reduced by lithium aluminum hydride to N-benzyloxycarbonyl-N-ethyl-D-phenylalanyl-L-prolyl-Nω-benzyloxycarbonyl-L-arginine-aldehyde, the protecting groups are removed by hydrogenolysis in the presence of sulfuric acid and the resulting N-ethyl-D-phenylalanyl-L-prolyl-L-arginine-aldehyde sulfate is isolated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5][SH:6])[CH3:2].[H-].[Na+].F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20]>CN(C=O)C>[CH:15]([C:14]1[CH:17]=[CH:18][C:11]([S:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:7])=[C:12]([N+:19]([O-:21])=[O:20])[CH:13]=1)=[O:16]
Reactant: CCOC(=O)CS
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ccc(C=O)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 24.4 %

Procedure:
To a solution of ethyl-2-mercaptoacetate (0.7 mmol) in dry DMF (2.5 ml), sodium hydride (0.85 mmol) was added 0° C. After 15 minutes, 4-fluoro-3-nitrobenzaldehyde (0.7 mmol) was added and the mixture was heated at 60° C. overnight and monitored by TLC until completion. After cooling, the solvent was removed under reduced pressure. The residue was chromatogaphed on a silica gel column (cyclogexane/ethyl acetate 4/1 as eluent) to give 46 mg of ethyl 2-(4-formyl-2-nitrophenylthio)acetate as yellow compound (yield 24%). 1H NMR, (250 MHz, CDCl3): δ 1.25 (t, J=7.5 Hz, 3H), 3.80 (s, 2H), 4.21 (q, J=7.75, 2H), 7.64 (d, J=9.75, 1H), 8.03 (d, J=9.75, 1H), 8.68 (s, 1H), 10.00 (s, 1H) 13C NMR (126 MHz, CDCl3): δ 15.4, 36.5, 63.8, 128.5, 129.3, 133.9, 145.6, 147.1, 169.5, 190.1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][N:22]=1.O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:14][C:12]2[S:13][C:9]([C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[O:8])=[C:10]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[N:11]=2)=[O:26])=[CH:23][N:22]=1
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccc(Cl)nc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
Compound 454 (125 mg, 0.450 mmol) and DMAP (3.0 mg, 0.022 mmol) were suspended in pyridine (2 mL), and 6-chloronicotinoyl chloride (158 mg, 0.897 mmol) was added thereto, followed by stirring at 80° C. for 1 hour. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was reslurried with ethanol to afford the entitled Compound 502 (138 mg, 73%) as a pale brown solid.
Reaction SMILES: [C:1]([O:4][C@@:5]1([C:25]#[CH:26])[CH:11]=[CH:10][C@H:9]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH2:7][CH3:8])[C@@H:20]1[C:15](=[CH:16][C:17](=O)[CH2:18][CH2:19]1)[CH2:14][CH2:13]3)(=[O:3])[CH3:2].CO.Cl.[NH2:30][OH:31].C(=O)(O)[O-].[Na+]>O>[C:1]([O:4][C@@:5]1([C:25]#[CH:26])[CH:11]=[CH:10][C@H:9]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH2:7][CH3:8])[C@@H:20]1[C:15](=[CH:16][C:17](=[N:30][OH:31])[CH2:18][CH2:19]1)[CH2:14][CH2:13]3)(=[O:3])[CH3:2]
Reactant: C#C[C@]1(OC(C)=O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C#C[C@]1(OC(C)=O)C=C[C@H]2[C@@H]3CCC4=CC(=NO)CC[C@@H]4[C@H]3CC[C@@]21CC
Reaction time: 1.5 h

Procedure:
As described in Example 22, 2.4 g. of 17β-acetoxy-17α-ethynyl-18-methyl-4,15-estradien-3-one in 60 ml. of methanol and 2 ml. of water is reacted with 1.0 g. of hydroxylamine hydrochloride and 1.0 g. of sodium bicarbonate. After 1.5 hours, the reaction mixture is worked up analogously to Example 22. After the crude product has been chromatographed on silica gel with acetone-hexane, 760 mg. of 17β-acetoxy-17α-ethynyl-18-methyl-4,15-estradien-3-one oxime is obtained.
Reaction SMILES: CO[C:3](=[O:38])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[CH:17][N:16](S(C4C=CC(C)=CC=4)(=O)=O)[C:13]3=[N:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[OH:37].[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][NH:43][CH3:44].N=C=N.CN(C=O)C>N1C=CC=CC=1>[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][N:43]([CH3:44])[C:3](=[O:38])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[CH:17][NH:16][C:13]3=[N:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[OH:37]
Reactant: COC(=O)c1cc(-c2cnc3c(c2)c(-c2ccccc2OC)cn3S(=O)(=O)c2ccc(C)cc2)ccc1O
Reactant: CNCCN(C)C
Agent: N=C=N
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(O)c(C(=O)N(C)CCN(C)C)c3)cc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 12 %

Procedure:
To a solution of 2-hydroxy-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid methyl ester (52 mg, 0.10 mmol) in pyridine (0.5 mL) was added an excess of N,N,N′-trimethylethylenediamine (0.5 mL). The reaction was stirred for 16 hours at 100° C. in a scintillation vial. There appeared to be ˜50% product formation and ˜50% hydrolysis of the methyl ester to the carboxylic acid. PS-carbodiimide resin (244 mg, 0.29 mmol, 1.21 mmol/g load capacity) and DMF (1 mL) were added to the reaction solution and heating was continued for 16 hours at 70° C. The resin was filtered off and rinsed well with THF and MeOH. The filtrate was concentrated down to a yellow oil and then redissolved in a 1:1 MeOH/acetone solution (4 mL total). The solution was treated with 200 uL of a 50% KOH (aq) solution and stirred at ambient temperature for 3 hours. Glacial acetic acid was added dropwise until the pH=7. The product was extracted into ethyl acetate, whereupon the organic layer was washed with H2O, dried over Na2SO4, filtered, and concentrated under vacuum. The material was dissolved in MeOH and filtered through a 0.45 μm syringe filter. The solution was purified by reverse phase chromatography using a gradient of H2O and acetonitrile (with 0.1% formic acid as a modifier). Clean fractions were lyophilized, affording the title compound as a white powder (5.2 mg, 12% yield). 1H NMR (500 MHz, d6-DMSO) δ 11.80 (d, J=2.5 Hz, 1H), 8.49 (s, 1H), 8.19 (s, 1H), 8.10 (s, 1H), 7.74 (d, J=2.5 Hz, 1H), 7.63 (dd, J=2.0, 6.0 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.43 (s, 1H), 7.33 (m, 1H), 7.17 (d, J=8.5 Hz, 1H), 7.09 (t, J=6.5 Hz, 1H), 7.01 (d, J=9.0 Hz, 1H), 3.85 (s, 3H), 3.01 (br s, 3H), 2.90 (br s, 2H), 2.59 (m, 2H), 2.36 (br s, 3H), 2.00 (br s, 3H). MS: m/z 445.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][CH:34]([CH3:38])[CH2:35][O:36][CH3:37]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][CH:34]([CH3:38])[CH2:35][O:36][CH3:37])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COCC(C)N
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: COCC(C)NCCCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and 2-amino-1-methoxy-propane (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H36N6O5SF [(M+H)+]539.2447, observed 539.2450.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][N:33](C)[C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:27]=2)=[CH:22][CH:21]=1)=O.O>C1COCC1>[CH3:9]/[C:8](=[CH:18]\[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH:33][C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:41])[CH:27]=2)=[CH:22][CH:21]=1)/[C:6]([O:5][CH2:4][CH3:3])=[O:7]
Reactant: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)c1ccccc1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C(C)=C/c1ccc(-c2cccc(CNC(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
440 mg (11 mmol) of sodium hydride (80% in oil) and 10 ml of THF are introduced into a three-necked flask under a stream of nitrogen. A solution of 2.2 ml of triethyl 2-phosphonopropionate in 10 ml of THF is added dropwise, followed by a solution of 3 g (9.1 mmol) of N-(4′-formylbiphenyl-3-ylmethyl)-N-methylbenzamide (prepared in Example 1(e)), and the mixture is stirred at room temperature for 3 hours. The reaction medium is poured into water and extracted with dichloromethane, and the organic phase is separated out after settling of the phases has taken place, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a column of silica eluded with a mixture of heptane and ethyl acetate (70/30). After evaporation of the solvents, 3 g (80%) of ethyl (E)-2-methyl-3-(3′-{[(1-phenyl-methanoyl)amino]methyl}biphenyl-4-yl)acrylate are collected in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[C:12]2[CH:22]=[CH:21][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N(CCCc2ccc(Cl)cc2)CCCc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(N(CCCc2ccc(Cl)cc2)CCCc2ccc(Cl)cc2)cc1

Procedure:
A solution of 5.6 g. of 4-[bis[3-(p-chlorophenyl)propyl]amino]benzoic acid, ethyl ester and 3 g. of 85% potassium hydroxide in 50 ml. of ethanol is stirred at 75° C. for 4 hours, cooled, diluted with 100 ml. of water, and adjusted to pH 6.0 with 37% hydrochloric acid. The solution is extracted with two 150 ml. portions of ether. The ether extracts are combined, washed with 100 ml. of water, then 100 ml. of brine, dried over magnesium sulfate, and evaporated to an orange solid. This solid is recrystallized twice from 50 ml. of acetonitrile, giving 1.39 g. of the desired product, m.p. 128°-131° C.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:28]=[CH:27][C:7]([C:8]([NH:10][C:11]2[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)=[O:14])=[O:9])=[C:6]([O:29]COC)[CH:5]=1)[CH3:3].FC(F)(F)C(O)=O.O>C(Cl)Cl>[NH2:1][CH:2]([C:4]1[CH:28]=[CH:27][C:7]([C:8]([NH:10][C:11]2[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)=[O:14])=[O:9])=[C:6]([OH:29])[CH:5]=1)[CH3:3]
Reactant: COCOc1cc(C(C)N)ccc1C(=O)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(N)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)c(O)c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 97.4 %

Procedure:
To a solution of 2-[4-(1-aminoethyl)-2-(methoxymethoxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide (0.205 g, 0.45 mmol) in CH2Cl2 (4.1 mL) was added trifluoroacetic acid (4.1 mL) followed by H2O (4.1 mL). The reaction was stirred at room temperature for 20-30 min. Then the volatile solvent was removed under a reduced pressure and the residue was diluted with H2O (20 mL) and carefully neutralized with solid NaHCO3. The aqueous solution was extracted with EtOAc (5×25 mL), dried (Na2 SO4) and concentrated to afford the expected product (0.180 g, 97%), TLC Rf: 0.36 (5% 2 N NH3/MeOH in CH2Cl2). 1H NMR (400 MHz, CD3OD): δ 8.44 (d, 1H, J=8.0 Hz); 8.31 (d, 1H, J=2.4 Hz); 8.23 (d, 1H, J=8.8 Hz); 7.93 (d, 1H, J=8.8 Hz); 7.86-7.82 (m, 2H); 7.59 (dt, 1H, J=2.0 and 8.8 Hz); 7.29 (dt, 1H, J=0.8 and 7.6 Hz); 7.00 (m, 2H); 4.39 (q, 1H, J=7.2 Hz); 1.58 (d, 3H, J=6.8 Hz). IS-MS (m/e): 411 (m+1) and 409 (m−1) H. Wang's Resin-linked 2-[4-(1-aminoethyl)-2-hydroxybenzoylamino]-N-(5-chloro-pyridin-2-yl)benzamide
Reaction SMILES: C(OC(C1C(=O)N(CC2C=CC=C(F)C=2)C2C=CSC=2C=1N1CCNCC1)=O)C.[CH:30]([O:33][C:34]([C:36]1[C:41](=[O:42])[N:40]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[CH:45]=2)[C:39]2[CH:51]=[CH:52][S:53][C:38]=2[C:37]=1[N:54]1[CH2:59][CH2:58][N:57]([C:60]([C:62]2[S:63][C:64]([F:67])=[CH:65][CH:66]=2)=[O:61])[CH2:56][CH2:55]1)=[O:35])(C)[CH3:31]>>[CH2:30]([O:33][C:34]([C:36]1[C:41](=[O:42])[N:40]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[CH:45]=2)[C:39]2[CH:51]=[CH:52][S:53][C:38]=2[C:37]=1[N:54]1[CH2:55][CH2:56][N:57]([C:60]([C:62]2[S:63][C:64]([F:67])=[CH:65][CH:66]=2)=[O:61])[CH2:58][CH2:59]1)=[O:35])[CH3:31]
Reactant: CC(C)OC(=O)c1c(N2CCN(C(=O)c3ccc(F)s3)CC2)c2sccc2n(Cc2cccc(F)c2)c1=O
Agent: CCOC(=O)c1c(N2CCNCC2)c2sccc2n(Cc2cccc(F)c2)c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3ccc(F)s3)CC2)c2sccc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared from 4-(3-fluoro-benzyl)-5-oxo-7-piperazin-1-yl-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (19) by applying the same procedure as described for 4-(3-fluoro-benzyl)-7-[4-(5-fluoro-thiophene-2-carbonyl)-piperazin-1-yl]-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid isopropyl ester (21). Yield 2.22 g (85%). 1H-NMR (DMSO-d6) δ 1.29 (t, J=7.2 Hz, 3H), 3.39 (m, 4H), 3.82 (m, 4H), 4.27 (q, J=7.2 Hz, 2H), 5.38 (s, 2H), 6.80 (m, 1H), 7.10 (m, 3H), 7.29 (t, J=3.6 Hz, 1H), 7.33 (d, J=5.6 Hz, 1H), 7.36 (m, 1H), 8.03 (d, J=5.6 Hz, 1H); EIMS m/z 544 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.C([Li])CCC.[F:26][C:27]([F:33])([F:32])[C:28](OC)=[O:29].[Cl-].[NH4+]>C1COCC1>[CH2:18]([S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=[C:2]([C:28](=[O:29])[C:27]([F:33])([F:32])[F:26])[CH:3]=[C:4]2[N:10]=1)[CH3:19]
Reactant: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Reactant: COC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCSc1ccccc1-c1nc2cc(C(=O)C(F)(F)F)cnc2n1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 6-bromo-2-(2-ethylsulfanyl-phenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (1 g) and THF (20 ml), n-butyllithium (1.5 M in hexane, 2.1 ml) was added dropwise at −78° C. The mixture was stirred at −78° C. for 30 minutes, and then methyl trifluoroacetate (577 μl) was added dropwise. The mixture was heated to room temperature, and then saturated aqueous ammonium chloride solution was poured, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give 778 mg of crude 1-[2-(2-ethylsulfanyl-phenyl)-3-methyl-3H-imidazo[4,5-b]pyridin-6-yl]-2,2,2-trifluoro-ethanone (hereinafter referred to as Present Compound 91).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:6]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:26]1C=CC(C(C)(C)C)=C(OC2C=CC(CC)=CC=2)C=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si:13]([CH3:15])([CH3:14])[CH3:16])=[CH:7][C:6]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH3:26])=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ccc(Oc2cc(Br)ccc2C(C)(C)C)cc1
Reactant: Cc1ccc(Oc2cc(C#C[Si](C)(C)C)ccc2C(C)(C)C)cc1
Product: CCc1ccc(Oc2cc(C#C[Si](C)(C)C)ccc2C(C)(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of 2-tert-butyl-5-trimethylsilanylethynyl-1-[(4'-methyl)phenoxy]benzene (Compound U), 52 mg (0.16 mmol) 5-bromo-2-tert-butyl-1-[(4'-ethyl)phenoxy]benzene (Compound T) was converted into the title compound using 28 mg (0.04 mmol) of bis(triphenylphosphine)palladium (II) chloride, 7 mg (0.04 mmol) of cuprous iodide, 0.2 mL (150 mg, 1.5 mmol) of trimethylsilyl acetylene and 3 mL of triethylamine. An additional 28 mg (0.04 mmol) of bis(triphenylphosphine)palladium (II) chloride, and 0.2 mL (150 mg, 1.5 mmol) of trimethylsilyl acetylene were added after 3 days of heating, and the resultant mixture was then heated at 75° C. for 4 more days. Purification by flash chromatography (preabsorbed onto silica with 100% chloroform, eluted with 100% hexane) gave the title compound as a yellow oil.