Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]#[CH:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Si:1]([O:18][CH2:19][C:20]#[C:21][C:2]1[CH:3]=[CH:4][C:25]2[C:26](=[C:10]3[C:23](=[CH:22][N:24]=2)[CH2:12][CH2:13][CH2:8][CH2:9]3)[CH:7]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNCC
Reactant: C#CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCC#Cc1ccc2ncc3c(c2c1)CCCC3)(c1ccccc1)c1ccccc1
Reaction time: 11 h
Yield: 149.1 %

Procedure:
To a mixture of Compound 277 (1.28 g, 3.86 mmol), 3-[(tert-butyldiphenylsilyl)oxy]propyne (Compound 278, 1.48 g, 5.02 mmol), and diethylamine (800 mL, 7.73 mmol) in dry degassed N,N-dimethylformamide (7.7 mL) was added copper (I) iodide (74 mg, 0.39 mmol) followed by bis(triphenylphosphine)palladium(II) chloride (135 mg, 0.19 mmol). After being stirred in the dark for 11 hours under argon, the mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (20 mL×2) and brine (20 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo, and the residue was purified by flash column chromatography (silica, 10 percent ethyl ether in dichloromethane) to give 1.78 g (97 percent) of Compound 279: Rf =0.39 (10 percent ethyl acetate in dichloromethane); IR (film) νmax 3048, 2932, 2857, 2227, 1589, 1568, 1502, 1428, 1370, 1112 cm-1 ; 1H NMR (500 MHz, CDCl3) δ 8.59 (s, 1 H, H6), 7.95 (d, J=8.6 Hz, 1 H, H4), 7.92 (d, J=1.5 Hz, 1 H, H1), 7.84-7.78 (m, 4 H, aromatic), 7.53 (dd, J=8.6, 1.5 Hz, 1 H, H3), 7.48-7.39 (m, 6 H, aromatic), 4.62 (s, 2 H, C≡CCH2O), 3.04 (t, J=5.8 Hz, 2 H, H10), 2.87 (t, J=5.8 Hz, 2 H, H7), 2.01-1.93 (m, 2 H, CH2), 1.93-1.85 (m, 2 H, CH2), 1.12 (s, 9 H, t-Bu); 13C NMR (125 MHz, CDCl3) δ 152.8, 145.6, 141.0, 135.6, 133.1, 130.6, 130.2, 129.7, 129.6, 127.6, 127.5, 120.7, 88.4, 85.3, 53.2, 27.0, 26.7, 24.8, 22.2, 22.1, 19.2; MS (FAB+) m/e (rel intensity) 476 (M+H, 100), 418 (9), 388 (12), 220 (11), 197 (9); HRMS for C32H34NOSi (M+H), calcd 476.2410, found 476.2410.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([C:27]([OH:29])=O)[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)[CH2:43][CH2:44][CH2:45][N:46]=[C:47]=NCC.ON1C2C=CC=CC=2N=N1.N1CCCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([C:27]([N:46]3[CH2:47][CH2:43][CH2:44][CH2:45]3)=[O:29])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(C(=O)O)c(Cl)cc3[nH]c2=O)c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCNC1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(C(=O)N4CCCC4)c(Cl)cc3[nH]c2=O)c1
Reaction time: 0.17 h
Yield: 48.7 %

Procedure:
To a solution of 4-[2-(1-tert-butoxycarbonyl-piperidin-2-yl)-ethoxy]-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydro-quinoline-6-carboxylic acid (15 mg in 0.6 mL of dry methylene chloride) was added 8.0 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) followed by 6.0 mg 1-hydroxybenzotriazole (HOBt) and the mixture stirred for 10 minutes. At this time, 9.4 mg of pyrrolidine and the reaction allowed to proceed at room temperature. After 4 hours, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:10% ammonium hydroxide in methanol, 95:5) to give the tilte compound (8 mg).
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.CO[CH:33]1[CH2:37][CH2:36][CH:35](OC)O1>C(O)(=O)C>[N:1]1([CH:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]([C:13](=[O:30])[C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[CH:16][CH:15]=3)[CH2:5][CH2:4][CH2:3]2)[CH:33]=[CH:37][CH:36]=[CH:35]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N)c3ccccc32)cc1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(n3cccc3)c3ccccc32)cc1

Procedure:
To a solution of 5-amino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in acetic acid (10 ml) is added dropwise 2,5-dimethoxytetrahydrofuran (0.19 ml), and the mixture is refluxed for 1 hour. The reaction solution is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1), and recrystallized from ethyl acetate/n-hexane to give 5-(1-pyrrolyl)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.31 g) as colorless prisms, m.p. 208°-210° C.
Reaction SMILES: C([NH:8][C:9]1([CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[F:60])[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:22]=[C:21]3[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([CH3:52])[CH:47]=2)=[O:17])[CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[NH2:8][C:9]1([CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[F:60])[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:22]=[C:21]3[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([CH3:52])[CH:47]=2)=[O:17])[CH2:10]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(Cc5ccccc5F)(NCc5ccccc5)C4)cc23)ccn1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(N)(Cc5ccccc5F)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(3-(benzylamino)-3-(2-fluorobenzyl)cyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide in MeOH was added palladium on charcoal (10%). The reaction mixture was stirred under an atmosphere of H2 at room temperature for overnight. The product, N-(3-amino-3-(2-fluorobenzyl)cyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was obtained after evaporation of solvent.
Reaction SMILES: [C:1]([N:6]([C:22]1[C:27]([N+:28]([O-])=O)=[C:26]([CH3:31])[CH:25]=[CH:24][N:23]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]2[C:20]#[N:21])=[CH:10][CH:9]=1)(=O)[CH2:2][CH2:3][CH3:4].C(O)(=O)C>[Fe].C(O)C>[Cl:19][C:17]1[CH:16]=[C:15]([C:20]#[N:21])[N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][N:6]3[C:22]4=[N:23][CH:24]=[CH:25][C:26]([CH3:31])=[C:27]4[N:28]=[C:1]3[CH2:2][CH2:3][CH3:4])=[CH:9][CH:10]=2)[CH:18]=1
Reactant: CCCC(=O)N(Cc1ccc(-n2cc(Cl)cc2C#N)cc1)c1nccc(C)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(Cl)cc2C#N)cc1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A mixture of 2-[N-butyryl-N-[4-(4-chloro-2-cyano-1-pyrrolyl)benzyl]amino]-4-methyl-3-nitropyridine (700 mg), iron powder (894 mg), acetic acid (1.8 ml) and ethanol (15 ml) was stirred under reflux for 15 hours. After being cooled to room temperature, the reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was partitioned into ethyl acetate (100 ml) and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography (n-hexane-ethyl acetate =1:1) to give 3-[4-(4-chloro-2-cyano-1-pyrrolyl)benzyl]-7-methyl-2-propyl-3H-imidazo-[4,5-b]pyridine (565 mg) as a pale yellow powder.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([Cl:20])=[C:18](I)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1COCC1.C([Mg]Cl)(C)C.CO[B:34]1[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]1.[NH4+].[Cl-]>>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([Cl:20])=[C:18]([B:34]3[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]3)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2ncc(I)c2Cl)CC1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2Cl)OC1(C)C
Reaction time: 0.33 h

Procedure:
To a solution of 1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-chloro-4-iodo-1H-pyrazole (30.0 mg, 0.0680 mmol) in THF (1 mL, 20 mmol) at rt was added 2 M isopropylmagnesium chloride in THF (0.10 mL, 0.20 mmol), and the mixture was stirred for 20 min. The reaction was quenched with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.045 mL, 0.27 mmol), and allowed to stir at rt for 1 h. Sat. NH4Cl was added, and the organic solvent was removed in vacuo. The material was extracted with DCM and water. The organic layer was concentrated in vacuo to afford the title compound as a white solid. The material was used in the next step without further purification. 1H NMR (400 MHz, CD3OD): δ=0.12 (s, 6H), 0.93 (s, 9H), 1.33 (s, 8H), 1.46-1.60 (m, 2H), 1.86-2.09 (m, 6H), 3.70-3.82 (m, 1H), 4.38 (ddd, J=10.5, 5.2, 5.1 Hz, 1H), 7.69 (s, 1H).
Reaction SMILES: Cl.[NH2:2]O.[CH2:4]([O:6][C:7](=[O:39])[C:8](O)=[CH:9][C:10]([C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:14][C:13]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:11])[CH3:5].O>C(O)C>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:14][C:13]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:11][N:2]=1)=[O:39])[CH3:5]
Reactant: CCOC(=O)C(O)=CC(=O)c1cc(C(C)(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cc(C(C)(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Yield: 89.1 %

Procedure:
Hydroxylamine hydrochloride (3.6 g, 52 mmol) was added to a solution of 4-(2,4-Bis-benzyloxy-5-tert-butyl-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester (9.0 g, 18.5 mmol) in ethanol (75 ml) and the suspension heated under reflux for ˜4 hrs. The resulting solution was allowed to cool and poured into water (200 ml) to give an off-white precipitate. The solids were removed by filtration and taken up in dichloromethane (150 ml). The solution was washed with water (150 ml) and saturated aqueous sodium chloride solution (50 ml). The solution was dried over anhydrous sodium sulphate and concentrated to an off-white solid. Solids were washed with hexane and dried in vacuo (40° C.), to give 5-(2,4-bis-benzyloxy-5-tert-butyl-phenyl)-isoxazole-3-carboxylic acid ethyl ester as a pale brown powder (8.0 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[N:11]=[C:12]([NH:20][CH3:21])[S:13][C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH3:28]I.[OH-].[Na+].Cl>C1C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[N:11]=[C:12]([N:20]([CH3:28])[CH3:21])[S:13][C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CI
Reactant: CCOC(=O)c1sc(NC)nc1C(C)c1ccc(-c2ccccc2)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1sc(N(C)C)nc1C(C)c1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 100 %

Procedure:
To a solution of ethyl 4-(1-(2-fluoro-4-biphenylyl)-ethyl)-2-methylamino-5-thiazolecarboxylate (3.55 g, 9.23 mmoles) and methyl iodide (2.81 g, 18.8 mmoles) in benzene (70 ml) were added 50% aqueous solution of sodium hydroxide (35 ml) and tetra-n-butylammonium hydrogen sulfate (3.13 g, 9.22 mmoles) and the resulting mixture was stirred at room temperature for 5.5 hours. The reaction mixture was diluted with water, acidified to pH 6 with 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. Purification of the residue by means of silica gel column gave the desired ethyl 4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-dimethylamino-5-thiazolecarboxylate (3.68 g, 9.23 mmoles, quantitative yield) as a colorless oil.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12](Cl)=[C:13]([NH:15][C:16]([NH:18][CH2:19][CH2:20][OH:21])=[S:17])[CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CN(C)C(=O)C>O>[OH:21][CH2:20][CH2:19][NH:18][C:16]1[S:17][C:12]2[CH:11]=[CH:10][C:9]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])=[CH:14][C:13]=2[N:15]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c(NC(=S)NCCO)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)c1ccc2sc(NCCO)nc2c1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of 6 parts of N-(5-benzoyl-2-chlorophenyl)-N'-(2-hydroxyethyl)thiourea, 2.5 parts of sodium hydride dispersion 75% and 90 parts of N,N-dimethylacetamide is stirred and heated quickly to 130° C. The reaction mixture is cooled, water is added and the whole is allowed to stand overnight. The precipitated product is filtered off, washed with water and crystallized from ethanol, yielding 2.8 parts of {2-[(2-hydroxyethyl)amino]-5-benzothiazolyl} phenylmethanone; mp. 159° C.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[CH2:7][CH2:6][NH:5][C:4]2=[O:3]
Reactant: CCOC(=O)NCCc1ccccc1OC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc2c1CCNC2=O
Temperature: 110 °C
Reaction time: 3 h
Yield: 12697.5 %

Procedure:
Using the same procedure and workup as described in example 1, step 4, [2-(2-methoxy-phenyl)-ethyl]-carbamic acid ethyl ester (I-13c: 0.9 g, 0.0040 mmol) in POCl3 (5 mL) was reacted with P2O5 (1.19 g, 0.0084 mmol). The resulting mixture was stirred at 110° C. for 3 hours to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 90 mg of the product (12.8% yield).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:11][OH:12].[OH-].[Na+]>CO>[C:1](=[N:11][OH:12])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: NO
Reactant: CC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
Acetophenone (5.0 mL, 43 mmol) was dissolved in methanol (50 mL). Hydroxylamine hydrochloride (6.1 g, 88 mmol) was added to the mixture followed by 10N sodium hydroxide (10 mL, 100 mmol). Reaction was stirred at room temperature for 20 minutes. 10N Sodium hydroxide (5 mL, 50 mmol) was added to the mixture. Reaction was heated at reflux for 1 hour. Mixture was cooled to room temperature and stirred for 4 hours. Reaction mixture was concentrated in vacuo. Residue was treated with water. Mixture was extracted 2× diethyl ether. Combined extracts were washed 1× water, 1× brine. Organic layer was dried (magnesium sulfate), filtered and concentrated. Title compound was obtained as white solid in 76% yield. MS m/e (M+H)+=136.0.
Reaction SMILES: CC(C)N=C=NC(C)C.[CH3:10][NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH2:14][CH2:13]1.[C:23]1([C:29]#[C:30][C:31](O)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC#N>[CH3:10][N:11]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH2:14][CH2:13]1)[C:31](=[O:32])[C:30]#[C:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CNC1CCN(c2nccs2)CC1
Reactant: O=C(O)C#Cc1ccccc1
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Product: CN(C(=O)C#Cc1ccccc1)C1CCN(c2nccs2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
685 μl (4.38 mmol) DIC was added to a solution of 785 mg (4.00 mmol) N-methyl-1-(thiazol-2-yl)piperidin-4-amine and 640 mg (4.38 mmol) 3-phenyl-propiolic acid in MeCN (40 ml) and the reaction solution was stirred for 3 h at RT. Subsequently, concentration took place in vacuo and the residue was taken up by chloroform, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. 421 mg (1.30 mmol, 32%) (N-methyl-3-phenyl-N-(1-(thiazol-2-yl)piperidin-4-yl)propiolamide was obtained by CC (SiO2, 1.DCE 2.Chloroform). MS [MH+] 326.1
Reaction SMILES: ClC1C=C([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[F:32][C:33]1[CH:34]=[C:35]([C:41](=[O:47])CCC(O)=O)[CH:36]=[CH:37][C:38]=1[O:39][CH3:40].C(OC(=O)CSC1SC(N)=NC=1)C>>[F:32][C:33]1[CH:34]=[C:35]([CH:41]([OH:47])[CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:36]=[CH:37][C:38]=1[O:39][CH3:40]
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1F
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COc1ccc(C(O)CCCN(C(=O)Nc2ncc(SCC(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1F

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(3-fluoro-4-methoxy-phenyl)-4-oxo-butyric acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]#[N:24])[CH2:18][CH2:17]2)=[O:13])=[CH:4][C:3]=1[Cl:25].[H][H]>C1COCC1.[Ni]>[NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][NH2:24])[CH2:18][CH2:17]2)=[O:13])=[CH:4][C:3]=1[Cl:25]
Reactant: [H][H]
Reactant: N#CCN1CCC(COC(=O)c2cc(Cl)c(N)c3c2OCCO3)CC1
Agent: [Ni]
Solvent: C1CCOC1
Product: NCCN1CCC(COC(=O)c2cc(Cl)c(N)c3c2OCCO3)CC1
Yield: 65.9 %

Procedure:
A mixture of intermediate 14 (6 g) in THF (250 ml) was hydrogenated with Raney nickel (3 g) as a catalyst. After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent CH2Cl2/(CH3OH/NH3) 90/10). The pure fractions were collected and the solvent was evaporated, yielding 4 g (68%) [1-(2-amino-ethyl)-4-piperidinyl]methyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate (intermediate 15).
Reaction SMILES: [CH2:1]([CH:5]([C:9](O)=O)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4].C=O.N1CCCCC1>C(O)C>[CH2:1]([C:5](=[CH2:9])[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(C(=O)O)C(=O)O
Agent: C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: C=C(CCCC)C(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 125 %

Procedure:
Butylmalonic acid (25 g, 156 mmol) was dissolved in ethanol (250 ml) and 37% formaldehyde solution (15.45 ml, 156 mmol) was added followed by piperidine (47 ml, 624 mmol). The mixture was stirred overnight at 80° C. under a reflux condenser. The solvents were removed under reduced pressure and the residue was diluted with 1M hydrochloric acid and extracted with dichloromethane (3×30 ml). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to afford the desired product as a yellow oil (25 g, with residual solvent). 1H-NMR: δ (CDCl3), 10.04 (1H, br s), 6.22 (1H, s), 5.57 (1H, d, J=1.3 Hz), 2.30 (2H, t, J=6.9 Hz), 1.38 (4H, m), and 0.91 (3H, t, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[N+](=[C:39]([CH2:45][CH:46]=[CH2:47])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N-]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:10](=[O:28])[N:11]([C@H:21]3[CH2:26][CH2:25][C@H:24]([O:27][CH:39]([CH2:45][CH:46]=[CH2:47])[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:23][CH2:22]3)[C:12]3[N:13]([N:18]=[CH:19][N:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[C:2]([F:1])[CH:3]=1)#[N:36]
Reactant: C=CCC(=[N+]=[N-])C(=O)OCC
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: C=CCC(O[C@H]1CC[C@H](n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3F)c(CCC)n3ncnc32)CC1)C(=O)OCC
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2.0 g), rhodium(II) acetate (dimer) (0.018 g) and toluene (20 mL) was heated to 80° C. under an argon atmosphere, a solution of ethyl 2-diazopent-4-enoate (3.8 g) in toluene (20 mL) was added dropwise, and the mixture was stirred at 80° C. for 10 min. A solution of ethyl 2-diazopent-4-enoate (3.8 g) in toluene (10 mL) was further added, and the mixture was stirred at 80° C. for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.81 g, 32%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:14]1[S:22][C:21]2[C:20]([NH:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[NH:29][CH:28]=[CH:27]4)=[N:19][CH:18]=[N:17][C:16]=2[CH:15]=1>>[NH:29]1[C:30]2[C:26](=[CH:25][C:24]([NH:23][C:20]3[C:21]4[S:22][C:14]([C:6]5[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=5)=[CH:15][C:16]=4[N:17]=[CH:18][N:19]=3)=[CH:32][CH:31]=2)[CH:27]=[CH:28]1
Reactant: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: O=[N+]([O-])c1cccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)c1

Procedure:
The title compound was prepared from 3-nitrobenzeneboronic acid and (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 2. 1H NMR (400 MHz, DMSO) d 11.3 (s, 2H), 8.83 (s, 1H), 8.47 (s, 1H), 8.31 (m, 1H), 8.05 (m, 2H), 7.77 (m, 2H), 7.47 (m, 2H), 7.25 (m, 1H), 6.50 (s, 1H). M.P. 175-183° C.; LC-MS: 388 (MH+); HPLC RT: 4.80 minutes.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)=[CH:11][CH:10]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].BrC1C=CC(C(C)(C)C(OCC)=O)=CC=1>>[CH3:8][C:2]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][N:16]=2)=[CH:13][CH:14]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Agent: CCOC(=O)C(C)(C)c1ccc(Br)cc1
Product: CC(C)(C(=O)O)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1

Procedure:
The title compound was prepared according to the method of Example 22B, substituting the product of Example 26B for the product of Example 22A.