Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][C:8]([OH:10])=O)=[N+:2]=[N-:3].S(Cl)([Cl:13])=O>>[N:1]([CH2:4][CH2:5][O:6][CH2:7][C:8]([Cl:13])=[O:10])=[N+:2]=[N-:3]
Reactant: O=S(Cl)Cl
Reactant: [N-]=[N+]=NCCOCC(=O)O
Product: [N-]=[N+]=NCCOCC(=O)Cl
Yield: 94.4 %

Procedure:
A solution of 2-azidoethoxyacetic acid (2.09 g, 14.4 mmol) in thionyl chloride (5 ml) was stirred at room temperature for 4 h. The excess thionyl chloride was removed under the vacuum of the water aspirator and the residue dissolved in benzene (10 ml, dried over molecular sieves) was evaporated in vacuo. The oil so obtained was dried in vacuo (water pump) over NaOH for 1 h yielding 2.23 g (13.6 mmol, 94.4%) of 2-azidoethoxyacetyl chloride as a colourless oil: 1Hmr (CDCl3) δ: 3.43 (2H, br. t, J=5 Hz, --CH2O--) 3.78 (2H, br. t, J=5 Hz, --CH2N3) and 4.50 ppm (2H, s, --COCH2O--); ir (neat) νmax : 2100 (azide) and 1800 cm-1 (--COCl). This material was used in the next reaction without any purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[CH:6][C:7]=1[CH:8](Cl)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16].[Cu](C#N)[C:27]#[N:28]>ClC(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[CH:6][C:7]=1[CH:8]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])[C:27]#[N:28]
Reactant: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3Cl)c(Cl)c2)c(=O)[nH]1
Reactant: N#C[Cu]C#N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: N#CC(c1ccc(Cl)cc1Cl)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 180 °C

Procedure:
A mixture of 12 parts of 2-[3-chloro-4-[chloro(2,4-dichlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione and 5.4 parts of copper cyanide is stirred and heated first for 3 hours at 130° C. and for 3 hours at 180° C. After cooling, the precipitated product is dissolved in a mixture of trichloromethane and methanol (90:10 by volume). The inorganic precipitate is filtered off and the filtrate is evaporated in vacuo. The residue is purified by column chromatography over silica gel using first a mixture of trichloromethane and acetonitrile (93:7 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is dissolved in 20 parts of N,N-dimethylformamide and 25 parts of 1,1'-oxybisethane. The product is allowed to crystallize, filtered off and dried, yielding 2-chloro-α-(2,4-dichloro- phenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitrile (intermediate 1).
Reaction SMILES: [CH3:1][N:2]([CH2:16][CH2:17][OH:18])[C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22]>>[CH3:1][N:2]([CH2:16][CH2:17][O:18][C:21](=[O:22])[C:20]([CH3:25])([CH3:24])[CH3:19])[C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCC(=O)N(C)CCO
Reactant: CC(C)(C)C(=O)Cl
Product: CCCCCCCCCCCC(=O)N(C)CCOC(=O)C(C)(C)C

Procedure:
N-methyl-N-(trimethylacetoxyethyl)lauramide was prepared by the procedure of example 1 from 26 gms. (0.1 mole) of N-methyl-N-(2-hydroxyethyl)lauramide and 12 gms. (0.1 mole) trimethylacetyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:3]=1[C:4]([O:6][CH2:7][CH2:8][S:9][CH3:10])=[O:5].[H-].[Na+].Cl[C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=1>CN(C=O)C>[CH3:28][O:27][C:21]1[CH:22]=[C:23]([O:25][CH3:26])[N:24]=[C:19]([O:1][C:2]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:19]3[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=3)[C:3]=2[C:4]([O:6][CH2:7][CH2:8][S:9][CH3:10])=[O:5])[N:20]=1
Reactant: COc1cc(OC)nc(Cl)n1
Reactant: CSCCOC(=O)c1c(O)cccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)OCCSC)n1
Temperature: 0 °C

Procedure:
Methylthioethyl 2,6-dihydroxybenzoate (4.5 g) was dissolved in DMF, and 60% sodium hydride (1.6 g) was added thereto. Then, 2-chloro-4,6-dimethoxypyrimidine (3.5 g) was added thereto, and the mixture was heated and reacted at a temperature within a range of from 90 to 110° C. for two hours. The reaction solution was poured into ice water and then extracted twice with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. After removing inorganic substances by filtration, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain the above identified compound as a colorless viscous liquid. (η20D: 1.5706).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C:16](=O)[C:15]2([CH3:22])[CH3:21])=[CH:11][CH:10]=1>C1COCC1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]2([CH3:22])[CH3:21])=[CH:23][CH:24]=1
Reactant: COc1ccc(CN2CCNC(=O)C2(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN2CCNCC2(C)C)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
LiAlH4 (1M in THF, 27.8 mL, 27.8 mmol, 1.5 equiv) was added to a solution of 4-(4-methoxybenzyl)-3,3-dimethyl-piperazin-2-one (Step 108.3) (4.6 g, 18.5 mmol) in THF (100 mL) at 50° C., under an argon atmosphere. The resulting mixture was stirred for 2 h at 50° C., quenched by sequential addition of H2O (1 mL), 1 N NaOH (1 mL) and H2O (3 mL), filtered through a pad of celite and concentrated to afford 4.0 g of the title compound as a white solid: ESI-MS: 235.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]=[CH2:13])[CH:8]=2)[CH:3]=1.[CH3:14][CH:15]1[CH2:19][CH2:18][CH2:17][NH:16]1.C([Li])CCC>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][CH2:13][N:16]1[CH2:17][CH2:18][CH2:19][CH:15]1[CH3:14])[CH:6]=[CH:5]2
Reactant: C=Cc1ccc2cc(Br)ccc2c1
Reactant: CC1CCCN1
Agent: [Li]CCCC
Product: CC1CCCN1CCc1ccc2cc(Br)ccc2c1

Procedure:
2-Bromo-6-vinyl-naphthalene is treated with a 2-methylpyrrolidine anion generated with n-butyllithium to provide 1-[2-(6-bromo-naphthalen-2-yl)-ethyl]-2-methyl-pyrrolidine. Preferably, about 1.2 to about 2.5 molar equivalents of 2-methylpyrrolidine are used for the reaction. The reaction typically is accomplished in an organic solvent, for example, THF, methyl-t-butyl ether (MTBE), Et2O, and DME. The preferred solvent is tetrahydrofuran (THF). The n-butyllithium is added to a THF solution of 2-methylpyrrolidine in a controlled fashion, typically in a dropwise manner. To this solution is added a THF solution of 2-bromo-6-vinyl-naphthalene. Alternatively, it is also suitable to the THF solution of 2-bromo-6-vinyl-naphthalene to the solution of 2-methylpyrrolidine and n-butyllithium. The reaction is accomplished at below room temperature, typically in a temperature range from about 0° C. to about −20° C. From about 0.3 to about 0.7 molar equivalents of n-butyllithium are used relative to the 2-bromo-6-vinylnaphthalene compound. The resulting compound is 1-[2-(6-bromo-naphthalen-2-yl)-ethyl]-2-methyl-pyrrolidine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:25])[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.[CH:33]1[CH:34]=[CH:35][C:36]2[N:41]([OH:42])[N:40]=[N:39][C:37]=2[CH:38]=1.[H-].[Na+]>CN(C=O)C>[N:41]1([O:42][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[C:8](=[C:18]4[CH2:23][CH2:22][N:21]([C:24]([NH:26][C:27]5[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=5)=[O:25])[CH2:20][CH2:19]4)[C:9]4[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=4[CH2:11][CH2:12][C:3]=23)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:38][C:37]=2[N:39]=[N:40]1
Reactant: O=C(Nc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(Cl)ccnc32)CC1
Reactant: On1nnc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(On4nnc5ccccc54)ccnc32)CC1
Temperature: 25 °C
Yield: 90.8 %

Procedure:
To a solution of the title compound from Example 261 (1.0 grams) in dry DMF (60 mL) was added HOBT (1.4 grams), sodium hydride (0.2 grams, 60% in mineral oil) and distilled water (0.5 mL). The solution was stirred at 25° C. under nitrogen while being irradiated with a 200 Watt lamp for 20 hours. The reaction mixture was concentrated in vacuo, diluted with CH2Cl2 and saturated aqueous sodium bicarbonate and after two hours, the organic phase was separated, dried over MgSO4 and concentrated. Purification by flash column chromatography (silica gel) using 3-5% MeOH-CH2Cl2 afforded the title compound (Yield 1.1 grams, 87%, MH+ 564).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]1([C:17]#[C:18][C:19]#[C:20][C:21]#[C:22][C@@H:23]2[O:25][C@H:24]2[CH:26]=[CH:27][CH:28]=[O:29])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1.O1CCCC1>[C:11]1([C:17]#[C:18][C:19]#[C:20][C:21]#[C:22][C@@H:23]2[O:25][C@H:24]2[CH:26]=[CH:27][CH2:28][OH:29])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=CC=C[C@@H]1O[C@H]1C#CC#CC#Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCC=C[C@@H]1O[C@H]1C#CC#CC#Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
Diisobutylaluminum hydride (0.35 ml of a 1.76 M solution in toluene, 0.61 mmole) was added dropwise to a stirred -78° C. solution of (trans)-3-[3-(6-phenyl-1,3,5-hexatriynyl)oxiranyl]-2-propenal (50 mg, 0.20 mmole; see Example 5) in 6 ml of dry tetrahydrofuran. The mixture was stirred for 2 hours at -78° C. and was then quenched at that temperature by the dropwise addition of ca. 0.5 ml of a solution of methanol-acetic acid 4:1. The mixture was warmed to room temperature, water was added and the mixture was extracted with ether. The combined ether extracts were washed with water and saturated aqueous sodium chloride and were dried over anhydrous magnesium sulfate. Removal of solvent gave an oil which was purified by preparative thin layer chromatography (ethyl acetate-hexane 1:1) to afford 34 mg pure title compound, melting point 65°-66° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][N:12]([CH:14]([CH3:18])[C:15](=[O:17])[CH3:16])[CH:13]=2)[O:3]1.[CH3:20][Mg+].[Br-]>C1COCC1.[Cl-].[Na+].O>[CH3:16][C:15]([OH:17])([CH:14]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:19])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:18])[CH3:20]
Reactant: CC(=O)C(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(n1cc(B2OC(C)(C)C(C)(C)O2)cn1)C(C)(C)O
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butan-2-one (Preparation 133, in THF (6 mL) at 0° C. was added MeMgBr (3M, 0.24 mL, 0.71 mmol). After stirring for 3 hours, another portion of MeMgBr was added. The solution was stirred at room temperature for 16 hours. The reaction was diluted with brine and extracted with EtOAc. The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford the title compound as a yellow oil (99 mg, 70%).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3](=N)[O-:4].[C:18](OCC)(=[O:20])C>O>[OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([O:20][CH3:18])=[O:4]
Reactant: N=C([O-])C(O)CCCCCCc1ccccc1
Reactant: CCOC(C)=O
Solvent: O
Product: COC(=O)C(O)CCCCCCc1ccccc1

Procedure:
A two-phase solution of the 2-hydroxy-8-phenyloctanimidate, ethyl acetate (50 mL), and water (50 mL) was stirred overnight. The layers were separated and the organic phase was dried (Na2SO4), filtered and concentrated to yield methyl 2-hydroxy-8-phenyloctanoate as an oil. The oil was dissolved in 9:1 dioxane-water (50 mL) containing LiOH (1.7 g). After 2 h of stirring, the mixture was acidified with 2N HCL to pH˜3. The resulting mixture was extracted twice with EtOAc and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated to yield 2-hydroxy-8-phenyloctanoic acid as a solid.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:4]>C(Cl)Cl>[Br:1][C:7]1[CH:6]=[C:5]([CH2:3][CH3:4])[CH:10]=[CH:9][C:8]=1[OH:11]
Reactant: BrBr
Reactant: CCc1ccc(O)cc1
Solvent: ClCCl
Product: CCc1ccc(O)c(Br)c1
Reaction time: 0.08 h
Yield: 9.5 %

Procedure:
Bromine (11.6 mL, 0.23 mol) was added slowly to a cooled 0° C. of 4-ethylphenol (2 g, 0.21 mol) dissolved in CH2Cl2 (125 mL). After the addition was complete the reaction mixture was stirred for 5 mins and then quenched with 1N NaOH. The reaction mixture was diluted with H2O and the layers separated. The organic layer was concentrated to an orange oil. Purification by flash column chromatography (0% to 5% EtOAc in hexanes) gave the title compound as a clear oil (4 g, 98%). 1H NMR (400 MHz, CDCl3): δ 1.20 (t, J=7.6 Hz, 3 H), 2.58 (q, J=7.5 Hz, 2 H), 5.36 (s, 1 H), 6.93 (d, J=8.3 Hz, 1 H), 7.03 (d, J=8.3 Hz, 1 H), 7.28 (s, 1 H).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:40])[C@H:6]([CH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([O:22][CH2:23][C:24]2[C:32]3[O:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[N:29][C:28]=3[CH:27]=[CH:26][CH:25]=2)=[C:17]([Cl:39])[CH:16]=1)[NH:7]C(=O)C(F)(F)F.Cl>O1CCCC1.O>[Cl:21][C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([Cl:39])[C:18]=1[O:22][CH2:23][C:24]1[C:32]2[O:31][C:30]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[N:29][C:28]=2[CH:27]=[CH:26][CH:25]=1)[CH2:14][C@@H:6]([C:5]([OH:40])=[O:4])[NH2:7]
Reactant: COC(=O)[C@H](Cc1cc(Cl)c(OCc2cccc3nc(-c4ccccc4)oc23)c(Cl)c1)NC(=O)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H](Cc1cc(Cl)c(OCc2cccc3nc(-c4ccccc4)oc23)c(Cl)c1)C(=O)O
Yield: 99.8 %

Procedure:
0.5 N Lithium hydroxide (4.5 ml, 2.25 mmol) was added to a solution of 3,5-dichloro-N-trifluoroacetyl-O-[(2-phenyl)-benzoxazol-7-yl]methyl-L-tyrosine methyl ester (246 mg, 0.434 mmol) in tetrahydrofuran (2 ml) at 5° C. and the mixture was reacted at 5° C. for 84 hrs. The reaction mixture was diluted with water, adjusted to pH 3-4 with 1N hydrochloric acid under ice cooling and allowed to stand at 5° C. The precipitates were collected by filtration, washed with water and then dried to give 3,5-dichloro-O-[(2-phenyl)-benzoxazol-7-yl]methyl-L-tyrosine (198 mg, 94%) as a colorless solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=O)[CH2:3][CH2:2]1.Cl.[CH3:12][NH:13][O:14][CH3:15].C([Mg]Cl)(C)C.O>C1COCC1>[CH3:15][O:14][N:13]([CH3:12])[C:7]([CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)=[O:9]
Reactant: CNOC
Reactant: COC(=O)C1CCOCC1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CCOCC1
Yield: 57.7 %

Procedure:
Methyl tetrahydropyran-4-carboxylate (1.33 mL, 10.0 mmol) was dissolved in THF (20 mL), and N,O-dimethylhydroxylamine hydrochloride (1.51 g, 15.5 mmol) added thereto, then the mixture was stirred. Under an argon atmosphere, THF solution of isopropyl magnesium chloride (2.0 mol/L; 15.0 mL, 30.0 mmol) was added dropwise to the reaction mixture at −30° C., and the mixture was stirred at −5° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was purified by distillation under reduced pressure to give N-methoxy-N-methyltetrahydropyran-4-carboxamide (1.00 g, 58%). Boiling point: 125-129° C./8.0 hPa, 1H NMR (CDCl3, δ ppm): 1.57-1.66 (m, 2H), 1.77-1.93 (m, 2H), 2.85-2.94 (m, 1H), 3.18 (s, 3H), 3.44 (ddd, J=2.4, 11.9, 11.9 Hz, 2H), 3.69 (s, 3H), 4.00 (ddd, J=2.4, 11.9, 11.9 Hz, 2H). Step 2: 2-(Benzoimidazol-2-yl)-4-(2-furyl)thiazole (167 mg, 0.625 mmol) obtained in Reference Example 562 was dissolved in THF (5 mL). To the solution was added n-hexane solution of n-butyl lithium (1.58 mol/L; 1.01 mL, 1.56 mmol) at −78° C. under an argon atmosphere, and the mixture was stirred at −78° C. for 10 minutes. The THF solution (1 mL) of N-methoxy-N-methyltetrahydropyran-4-carboxamide (270 mg, 1.56 mmol) obtained in Step 1 was added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give a title compound (191 mg, 81%).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=3)=[N:10][C:5]2=[N:4][CH:3]=1.[CH3:25][Si:26]([CH3:43])([CH3:42])[C:27]#[C:28][Sn](CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]1([C:8]2[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=3)=[N:10][C:5]3[N:6]([C:2]([C:28]#[C:27][Si:26]([CH3:43])([CH3:42])[CH3:25])=[CH:3][N:4]=3)[CH:7]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(-c2nc3ncc(Br)n3cc2-c2ccccc2)cc1
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#Cc1cnc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn12
Temperature: 130 °C

Procedure:
400 mg 4-(3-bromo-6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde (prepared as described under example 11), 820 mg trimethyl[(tributylstannyl)ethynyl]silane and 60 mg Pd(PPh3)4 are suspended in 8 ml toluene under a nitrogen atmosphere. The mixture is heated (microwave) to 130° C. for 1 h. The solvent is evaporated and the crude product is purified by column chromatography (dichloromethane/methanol)
Reaction SMILES: [SH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].Br[CH2:8][C:9]([C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=1)=[O:10]>>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][S:1][CH2:8][C:9]([C:11]1[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=1)=[O:10]
Reactant: COc1cc(C(=O)CBr)cc(OC)c1OC
Reactant: OCC(O)CS
Product: COc1cc(C(=O)CSCC(O)CO)cc(OC)c1OC
Yield: 94.8 %

Procedure:
Substantially the same procedure as in Reference Example 13 was repeated using 1-mercapto-2,3-propanediol (12.25 g) and 2-bromo-3',4',5'-trimethoxyacetophenone (Compound XIa, 16.39 g) obtained in Reference Example 1 to give 2-(2,3-dihydroxypropylthio)-3',4',5'-trimethoxyacetophenone (Compound IX-13, 17.00 g).
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]=1[NH2:33].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[Cl:17][C:18]1[CH:23]=[C:22]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]4[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=4)=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:21]=[CH:20][C:19]=1[NH2:33]
Reactant: CC1(C)OB(c2ccc(N)c(Cl)c2)OC1(C)C
Reactant: Ic1cnc2cc(-c3ccncc3)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1Cl
Yield: 46 %

Procedure:
Combine 3-iodo-7-pyridin-4-yl-imidazo[1,2-a]pyridine (2.18 g, 6.8 mmol), 2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (crude material from previous step, excess), potassium carbonate (2.8 g, 3 equiv.), dioxane (30 mL), and water (15 mL). De-gas thoroughly with nitrogen then add dichloro-bis(triphenylphosphine) palladium (II) (0.143 g, 3 mol %). Heat reaction at 80° C. overnight. Concentrate to dryness then slurry in DCM and filter via Celite®, washing with DCM. Concentrate filtrate then purify by silica plug (Hexanes→1:1 Hexanes:Ethyl Acetate→2.5% Methanol:DCM→5% Methanol:DCM) to give an orange-yellow solid (1.42 g, 46%). MS (ES), m/z 321.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:20][C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:22])[CH2:16][C:17]([OH:19])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([NH2:33])[C:31]#[CH:32].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:20][C:21](=[O:22])[NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:16][C:17](=[O:19])[NH:33][CH2:30][C:31]#[CH:32])=[CH:11][CH:10]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)CNC(=O)NC(CC(=O)O)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: C#CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CCNC(=O)CC(NC(=O)NCC(=O)OCC)c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66 %

Procedure:
3-(4-(tert-butoxycarbonylamino)phenyl)-3-(3-(2-ethoxy-2-oxoethyl)ureido)propanoic acid (1 equivalent, 150 mg, 0.37 mmol), propargylamin hydrocholoride (1 equivalent, 33 mg, 0.37 mmol), DIPEA (2.2 equivalent, 140 μl, 0.81 mmol), and HOBt (1.2 equivalent, 60 mg, 0.45 mmol) were dissolved in 2 ml of DMF. The reaction mixture was stirred at room temperature for 20 minutes. Then EDAP (1.2 equivalent, 84 mg, 0.45 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was washed by 30 ml of NaHCO3, and extracted by 3×20 ml of EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated. The crude was purified by flash chromatography (EDP/EtOAc) to afford the compound 200 (108 mg, 66%) as a white solid, Rf=0.25 (EtOAc). 1H NMR (200 MHz, DMSO) δ 9.28 (s, 1H), 8.29 (t, J=5.2 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.16 (d, J=8.5 Hz, 2H), 6.72 (d, J=8.5 Hz, 1H), 6.34 (t, J=6.1 Hz, 1H), 4.99 (q, J=7.0 Hz, 1H), 4.09 (q, J=7.2 Hz, 2H), 3.86-3.78 (m, 2H), 3.76 (d, J=5.9 Hz, 2H), 3.41-3.32 (m, 2H), 3.13-3.08 (m, 1H), 1.50 (s, 9H), 1.20 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:8][NH:9]2)=[CH:5][CH:4]=1)#N.C(O)(=[O:21])C>N1C=CC=CC=1.O.[Ni]>[CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:8][NH:9]2)=[CH:5][CH:4]=1)=[O:21]
Reactant: CCOC(=O)/C=C/c1n[nH]c2cc(C#N)ccc12
Reactant: CC(=O)O
Agent: [Ni]
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)/C=C/c1n[nH]c2cc(C=O)ccc12
Temperature: 55 °C
Yield: 65 %

Procedure:
To a solution of (E)-ethyl 3-(6-cyano-1H-indazol-3-yl)acrylate (723 mg, 3 mmol) in pyridine (10 mL) was added acetic acid (3 mL), followed by a solution of NaH2PO2 (1.056 g, 12 mmol) in H2O (3 mL). The resulting mixture was stirred for 0.5 min at rt before Raney-Nickel 2400 (slurry in H2O, 0.6 mL) was added in one portion. The resulting mixture was heated at 55° C. (oil temp.) for 1 h before cooling to rt. H2O (30 mL) was added and the mixture was extracted with EtOAc (50 mL×2). Combined extracts were washed with H2O (20 mL), 2 M HCl (20 mL), H2O (20 mL×2), brine (15 mL) and dried (Na2SO4). Removal of solvent gave an orange red oil which solidified upon standing O/N under high vacuum. It was then triturated with H2O (30 mL) and suction filtered, rinsed with H2O, dried to give the title compound (476 mg, 65%) as an orange red solid. 1H NMR (400 MHz, DMSO-d6) δ 14.16 (s, 1H, NH), 10.14 (s, 1H, CHO), 8.30 (d, J=8.8 Hz, 1H), 8.22 (s, 1H), 7.92 (d, J=16.4 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 4.22 (q, J=6.8 Hz, 2H), 1.28 (t, J=6.8 Hz, 3H); MS ESI 245.0 [M+H]+, calcd for [C13H12N2O3+H]+ 245.1.