Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.CCN(C(C)C)C(C)C.C([Mg]Cl)(C)C.[Cl:22][C:23]1[CH:54]=[CH:53][C:26]([C:27]([C:29]2[CH:30]=[C:31]3[C:36](=[N:37][CH:38]=2)[N:35]([CH3:39])[C:34](=[O:40])[CH:33]=[C:32]3[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([C:47]#[C:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[CH:42]=2)=[O:28])=[CH:25][CH:24]=1>C(Cl)Cl>[Cl:22][C:23]1[CH:54]=[CH:53][C:26]([C:27]([OH:28])([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=2)[C:29]2[CH:30]=[C:31]3[C:36](=[N:37][CH:38]=2)[N:35]([CH3:39])[C:34](=[O:40])[CH:33]=[C:32]3[C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([C:47]#[C:48][Si:49]([CH3:50])([CH3:52])[CH3:51])[CH:42]=2)=[CH:25][CH:24]=1
Reactant: Cn1c(=O)cc(-c2cccc(C#C[Si](C)(C)C)c2)c2cc(C(=O)c3ccc(Cl)cc3)cnc21
Reactant: Cn1cncc1Br
Agent: CC(C)[Mg]Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1cnc2c(c1)c(-c1cccc(C#C[Si](C)(C)C)c1)cc(=O)n2C
Reaction time: 1.5 h
Yield: 35.8 %

Procedure:
To a solution of 5-bromo-1-methylimidazole (0.68 g, 4.26 mmol) in dry DCM (15 mL), DIPEA (0.77 mL, 4.47 mmol) and iPrMgCl (2.13 mL, 4.26 mmol, 2.0 M solution in THF) was added at 10° C. The reaction mixture was stirred for 1.5 h and a solution of compound J (0.5 g, 1.06 mmol) in DCM was added to it. The reaction mixture was refluxed for 2 h and quenched with saturated NH4Cl solution. The product was extracted with DCM (30 mL). The organic layer was dried, filtered and concentrated to give crude c. Purification of the crude product provided 210 mg (36%) of compound K.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:20]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:19]([CH2:28][CH3:29])=[N:18][C:12]=3[C:13]([NH2:17])=[N:14][C:15]=2[CH:16]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[NH2:17][C:13]1[C:12]2[N:18]=[C:19]([CH2:28][CH3:29])[N:20]([CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][NH:3][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:16][C:15]=2[N:14]=1
Reactant: CCc1nc2c(N)nc3cc(OCCN)ccc3c2n1CC1CCOCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(N)nc3cc(OCCNS(C)(=O)=O)ccc3c2n1CC1CCOCC1
Reaction time: 0.17 h
Yield: 39.9 %

Procedure:
7-(2-Aminoethoxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (0.450 g, 0.97 mmol; prepared as in Example 552), dichloromethane (10 mL), and triethylamine (0.418 mL, 3.00 mmol) were combined and then stirred for 10 minutes. Methanesulfonyl chloride (0.075 mL, 0.97 mmol) was added and the reaction was stirred for an additional 16 hours. The reaction mixture was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-20% CMA in chloroform) followed by recrystallization from acetonitrile to provide 0.173 g of N-(2-{[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)methanesulfonamide as white needles.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=[O:14])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([Mg]Br)[CH2:18][CH:19]=[CH2:20].[NH4+].[Cl-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH:13]([OH:14])[CH2:20][CH2:19][CH:18]=[CH2:17])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCC[Mg]Br
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)COC1(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(O)C1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 8 h

Procedure:
5 g (21.81 mmol) of (S)-4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester are dissolved in 33 ml of THF, placed under argon and cooled to −78° C. 43.62 ml (21.81 mmol) of a 0.5 M 3-butenylmagnesium bromide solution in THF are added dropwise. The mixture is stirred further at room temperature overnight. After TLC check, about 90 ml of a saturated NH4Cl solution are added to the mixture with cooling, the mixture is stirred further overnight and diluted with about 50 ml of water. The phases are separated, and the aqueous phase is extracted a further twice with EA. The combined organic phases are dried over sodium sulfate, filtered and evaporated. The oily residue is subjected to flash chromatography on silica gel.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][CH:5]=[CH:6][N:7]=1.COC1C=CC(CCl)=CC=1.[NH:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:23]1[NH:24][CH:25]=[CH:26][N:27]=1>>[S:4]1[CH:5]=[CH:6][N:7]=[C:3]1[CH2:2][N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:23]1[NH:27][CH:26]=[CH:25][N:24]=1
Reactant: c1c[nH]c(-c2ncc[nH]2)n1
Reactant: BrCc1nccs1
Agent: COc1ccc(CCl)cc1
Product: c1c[nH]c(-c2nccn2Cc2nccs2)n1

Procedure:
If the procedure of Example 1 is repeated using 2- bromomethylthiazole rather than 4-methoxybenzyl chloride of Example 1, the products obtained are title compounds (7) and (8).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:19]=[C:18]([NH2:28])[N:17]=3)=[CH:11][CH:10]=2)[CH:3]=1.ClC1N=CC=CN=1.Br[C:37]1[CH:42]=[CH:41][N:40]=[C:39]([O:43][C:44]2C=CC(NC3N=C(N)C=C(C4C=CC=CC=4)N=3)=CC=2)[CH:38]=1.COC[C@@H]1CCCN1>>[CH3:44][O:43][CH2:39][C@@H:38]1[CH2:37][CH2:42][CH2:41][N:40]1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:19]=[C:18]([NH2:28])[N:17]=3)=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Nc1nc(Nc2ccc(Oc3cc(Br)ccn3)cc2)cc(-c2ccccc2)n1
Reactant: Nc1cc(-c2ccccc2)nc(Nc2ccc(Oc3cc(Br)ccn3)cc2)n1
Agent: COC[C@@H]1CCCN1
Agent: Clc1ncccn1
Product: COC[C@@H]1CCCN1c1ccnc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)c1
Temperature: 108 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
N4-{4-[(4-Bromopyridin-2-yl)oxy]phenyl}-6-phenylpyrimidine-2,4-diamine (75 mg, 0.17 mmol, was prepared by the method of Example 1 using and Intermediates 2T and 1A as starting materials. N-[4-(4-bromo-pyridin-2-yloxy)-phenyl]-6-phenyl-pyrimidine-2,4-diamine, was then combined with (S)-(+)-2-(methoxymethyl)pyrrolidine (99.5 mg, 0.86 mmol) in a 5-mL reaction flask and heated at 108° C. with stirring for 24 h. TLC and LC-MS indicated that the reaction was complete. After cooling to rt, the reaction mixture was extracted with EtOAc and washed with 1N aqueous sodium hydroxide solution (2×) and H2O (3×). The organic layer was dried and concentrated to give 75 mg of the crude product. The residue was purified by Prep-TLC (CH3OH:EtOAc=2:8) to obtain 32 mg (40%) of the title product as a yellowish oil. 1H NMR (CD3OD) δ 7.82 (m, 2H), 7.70 (m, 3H), 7.41 (m, 3H), 7.04 (d, 2H), 6.41 (m, 2H), 5.94 (s, 1H), 3.86 (s, 1H), 3.38 (m, 2H), 3.30 (m, 3H), 3.18 (m, 1H), 2.01 (m, 4H), 1.30 (m, 1H); MS ES 469 (M+H)+, calcd 469, RT=1.9 min; TLC (EtOAc) Rf=0.2.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C1(C)C=CC=CC=1.Cl[C:17]1[O:18][C:19]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=1.C(N(CC)CC)C>>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:17]1[O:18][C:19]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:20]([C:22]([F:24])([F:23])[F:25])[N:21]=1)[CH3:3]
Reactant: CCOC(=O)c1oc(Cl)nc1C(F)(F)F
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1nc(C(F)(F)F)c(C(=O)OCC)o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
By the procedure of Example 15, 4.19 g (0.03 mol) of glycine ethyl ester hydrochloride was added to a mixture of 100 ml toluene containing 4.87 g (0.02 mol) of ethyl 2-chloro-4-trifluoromethyl-5-oxazolecarboxylate and 6.07 g (0.06 mol) of triethylamine. The reaction mixture was stirred at ambient temperature for 48 hours. The product was separated and then recrystallized from methylcyclohexane to yield 3.55 g of a yellow powder product (m.p.=62°-63° C.) identified in Table I.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[CH2:7][C:8](=[O:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:12]=[O:13].C(N(CC)CC)C.[O:21]1CCOC[CH2:22]1>O1CCCC1>[C:1]([O:5][C:6](=[O:11])[C:7]([CH2:12][OH:13])([CH2:22][OH:21])[C:8](=[O:10])[CH3:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1COCCO1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)C(CO)(CO)C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A solution of 3-oxo-butyric acid tert-butyl ester (15.8 g, 100 mmol) and aqueous formaldehyde (37% solution in water, 18 mL, 230 mmol) in 1,4-dioxane (50 mL) was stirred at 0° C. under nitrogen. A solution of triethylamine (505 mg, 0.7 mL, 5 mmol) in tetrahydrofuran (5 mL) was added dropwise and the reaction mixture was stirred at 40° C. for 1 h and then at room temperature for 20 h. The majority of the solvent was evaporated, water was added and the mixture was extracted with ethyl acetate. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 7:3 to 1:1 to afford 2,2-bis-hydroxymethyl-3-oxo-butyric acid tert-butyl ester (8.67 g, 40%) as a clear oil. 1H NMR (300 MHz, d6-DMSO) 61.38 (s, 9H), 2.07 (s, 3H), 3.81-3.86 (m, 4H), 4.77 (t, J=5.1 Hz, 2H). LCMS (m/z) 217.0 [M−H], Tr=1.45 min.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[CH:4][C:3]=1[CH3:11].ClC1C=C[N:16]=CC=1[N+]([O-])=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.NC1C=CC=CN=1>>[CH3:11][C:3]1[C:2]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:16]=[N:8][C:7]=2[CH:6]=[N:5][CH:4]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Nc1ccccc1
Reactant: Cc1cncc([N+](=O)[O-])c1Cl
Agent: Nc1ccccn1
Product: Cc1cncc2nnn(-c3ccccc3)c12

Procedure:
The title compound was prepared in a manner analogous to Intermediate 17, Step 1 through Intermediate 19, Step 3 substituting 4-chloro-3-methyl-5-nitro-pyridine for 4-chloro-3-nitropyridine, and aniline for 2-aminopyridine. MS (ESI) mass calcd. C12H10N4, 210.1. m/z found, 225.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl-].[CH3:12][C:13]1[CH:22]=[CH:21][C:16]([CH:17]=[N+:18]([CH3:20])[CH3:19])=[CH:15][CH:14]=1.CC1C=CC(C=O)=CC=1.CNC>>[CH3:19][N:18]([CH3:20])[CH:17]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1])[C:16]1[CH:21]=[CH:22][C:13]([CH3:12])=[CH:14][CH:15]=1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: Cc1ccc(C=[N+](C)C)cc1
Agent: CNC
Agent: Cc1ccc(C=O)cc1
Agent: [Cl-]
Product: Cc1ccc(C(c2c(C)[nH]c3ccccc23)N(C)C)cc1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-methyl-1H-indole and (4-methyl-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 4-methyl-benzaldehyde and dimethylamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH:10]([O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:35][CH2:36][C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:38]>>[CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[CH2:24][O:23][CH:10]1[CH:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18](=[O:19])[NH:35][CH2:36][C:37](=[O:38])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:21][CH:22]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: NCC(=O)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)NCC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 36(b), by condensing (3RS,4RS)-4-(1-tert-butoxycarbonyl-3-naphthalen-2-ylmethoxy-piperidin-4-yl)-benzoic acid with 2-amino-1-phenyl-ethanone there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(2-oxo-2-phenyl-ethylcarbamoyl)-phenyl]-piperidine-1-carboxylate as a colourless foam; MS: 579 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])=[N:12][C:11]=2[CH3:21])=[O:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:34]N1C(=O)CCC1=O>O1CCCC1>[Br:34][CH:17]1[CH2:18][CH2:19][N:15]([C:13]2[S:14][C:10]([C:8]([NH:7][CH2:6][C:5]3[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=3)=[O:9])=[C:11]([CH3:21])[N:12]=2)[C:16]1=[O:20]
Reactant: Cc1nc(N2CCCC2=O)sc1C(=O)NCc1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(N2CCC(Br)C2=O)sc1C(=O)NCc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 50.8 %

Procedure:
To a solution of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide (0.35 g, 1.05 mmol) in anhydrous tetrahydrofuran (25 mL) at −78° C. was added lithium bis(trimethylsilyl)amide in tetrahydrofuran (2.31 mL, 2.31 mmol) dropwise. The reaction mixture was stirred at −78° C. for 5 minutes, followed by the addition of N-bromosuccinimide (0.19 g, 1.05 mmol) dropwise. The reaction mixture was stirred at −78° C. for 10 min, quenched with aqueous saturated ammonium chloride solution (10 mL) and extracted with dichloromethane (3×10 mL). The combined organic solutions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with ethyl acetate/hexanes (1/1) to afford the title compound as a white solid (0.22 g, 51%): 1H NMR (300 MHz, CDCl3) δ 7.34-7.24 (m, 2H), 7.07-6.97 (m, 2H), 5.98 (b s, 1H), 4.66-4.59 (m, 1H), 4.58 (d, J=5.8 Hz, 2H), 4.30-4.14 (m, 2H), 2.86-2.69 (m, 1H), 2.64 (s, 3H), 2.56-2.45 (m, 1H); MS (ES+) m/z 412 (M+1), 414 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([O:11][CH3:12])[C:5]=1[OH:13])[CH:2]=[CH2:3].N1C=CN=C1.Cl[Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22].Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([O:11][CH3:12])[C:5]=1[O:13][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(Br)cc(OC)c1O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCc1cc(Br)cc(OC)c1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
After dissolving 3 g of 2-allyl-4-bromo-6-methoxy-phenol [CAS No. 352019-92-2] in 10 ml of DMF, 1.3 g of imidazole and 2 g of chlorotriisopropylsilane were added and the mixture was stirred at 50° C. for 4 hours. Next, 1N hydrochloric acid was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give (2-allyl-4-bromo-6-methoxyphenoxy)triisopropylsilane.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])[CH2:3][C:4](=[O:8])[C:5]([OH:7])=O.S(Cl)(Cl)=O.[Br:20][C:21]1[C:30]([NH2:31])=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][O:24][C:25]2=[O:26].O>CC(N(C)C)=O>[Br:20][C:21]1[C:30]([NH:31][C:5](=[O:7])[C:4](=[O:8])[CH2:3][C:2]([CH3:1])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][O:24][C:25]2=[O:26]
Reactant: CC(C)(CC(=O)C(=O)O)c1ccccc1
Reactant: Nc1ccc2c(c1Br)COC2=O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1Br)COC2=O)c1ccccc1
Reaction time: 0.33 h
Yield: 86.5 %

Procedure:
412 mg of 4-methyl-4-phenyl-2-oxovaleric acid is dissolved in 10 ml of dimethylacetamide and mixed under argon at −8° C. with 261 mg of thionyl chloride. After 20 minutes of stirring at −3 to +3° C., 228 mg of 4-bromo-5-aminophthalide is added. It is stirred for 1.5 hours at room temperature, then mixed with water, extracted with ethyl acetate, the organic phase is washed with water, dried (Na2SO4) and after the solvent is concentrated by evaporation and after treatment with diethyl ether, 360 mg of 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide, melting point 150-152° C., is obtained.
Reaction SMILES: C1C[O:4][CH2:3]C1.C[N+]1([O-])[CH2:12][CH2:11][O:10]CC1.CCOC(C)=O.C=C([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C>O.[Os](=O)(=O)(=O)=O>[C:23]1([C:11]([OH:10])([CH3:12])[CH2:3][OH:4])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C=C(C)c1ccccc1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(O)(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of in prop-1-en-2-ylbenzene (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (2 g, 16.9 mmol) in a THF (20 mL): H2O (10 mL) mixture were added N-methylmorpholine N-oxide (1.98 g, 16.9 mmol) and osmium tetroxide (429.90 mg, 1.6 mmol) at 0° C. The resulting reaction mixture was stirred for 2 hours at ambient temperature. After completion of reaction (monitored by TLC (TLC eluent: 30% EtOAc in petroleum ether)), the reaction mixture was diluted with water and extracted with EtOAc. The organic layers were combined and washed with water, washed with saturated NaCl solution, and dried on anhydrous Na2SO4. Then the organic layer was filtered and concentrated under vacuum to provide a residue which was purified by column chromatography eluting with 50-60% EtOAc in hexane to afford 2-phenylpropane-1,2-diol, 1.5 g (58.25%) as a colorless liquid. 1H NMR (400 MHz, DMSO-d6): δ 7.45-7.43 (m, 2H), 7.30-7.26 (m, 2H), 7.20-7.16 (m, 1H), 4.86 (s, 1H), 4.68 (t, J=6 Hz, 1H), 3.39 (d, J=6 Hz, 1H), 1.38 (s, 3H). (no MS ionization).
Reaction SMILES: [C:1]([CH:4]([CH2:10][CH2:11][C:12]([O-:14])=[O:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:8]([O:7][C:5]([C:4]1[CH2:10][CH2:11][C:12](=[O:13])[O:14][C:1]=1[CH3:2])=[O:6])[CH3:9]
Reactant: CCOC(=O)C(CCC(=O)[O-])C(C)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)OC(=O)CC1
Yield: 58 %

Procedure:
55.2 g of monoethyl 2-acetylglutarate was dissolved in 500 ml of methylene chloride, and 52.06 g of oxalyl chloride and 5 drops of DMF were added at 0° C. They were reacted for 2 hours at room temperature. 500 ml of methylene chloride was added to the obtained acid-chloride solution, and, at temperature below 10° C., 33.12 g of triethylamine was dropped. They were reacted for an hour at room temperature. The reaction solution was washed with water, with an aqueous solution of sodium hydrogen carbonate and then with saturated salt water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The obtained residue was purified by distillation under reduced pressure to give 29.30 g of the title compound as a colorless liquid. Boiling point: 130-150° C./17 mmHg.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:10]=[C:11]([C:15]#[CH:16])[CH:12]=[CH:13][CH:14]=1.C(OC(=O)C)(=O)C>O.O.O.O.O.C([O-])(=O)C.[Ni+2].C([O-])(=O)C>[C:15]([C:11]1[CH:10]=[C:9]([N:8]2[C:4](=[O:5])[CH:3]=[CH:2][C:1]2=[O:7])[CH:14]=[CH:13][CH:12]=1)#[CH:16]
Reactant: O=C1C=CC(=O)O1
Reactant: C#Cc1cccc(N)c1
Agent: [Ni+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: C#Cc1cccc(N2C(=O)C=CC2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
Maleic anhydride (79.6 g, 0.81 mole) was added to a solution of distilled 3-aminophenylacetylene (95.1 g, 0.81 mole) dissolved in 500 mL of dry N,N'-dimethylacetamide (DMAc) at 5°-10° C. After addition, another 300 mL of DMAc was added and the mixture stirred at room temperature for two hours. Nickel acetate tetrahydrate (0.8 g) and acetic anhydride (300 mL) were added to the reaction mixture and stirring was continued for 12 hours at room temperature to affect cyclodehydration. The crude product was isolated by precipitation in water and recrystallized from methanol to provide N-(3-ethynylphenyl)maleimide (128 g, 80% yield) as a yellow crystalline solid, mp 129°-131° C. Elemental analysis calculated for C12H7NO2 : C, 73.09%; H, 3.58%; N, 7.10%. Found: C, 72.94%, H, 3.61%; N, 7.04%.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:10][CH2:11][C:12]([OH:14])=O)=[CH:8][N:9]=1)(=[O:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.C(N=C=NCCCN(C)C)C.Cl.[NH2:38][CH2:39][C:40](=[O:43])[CH2:41][CH3:42].C(N(CC)CC)C>CN(C=O)C.O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:10][CH2:11][C:12]([NH:38][CH2:39][C:40](=[O:43])[CH2:41][CH3:42])=[O:14])=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CCC(=O)CN
Reactant: CC(=O)Nc1ncc(SCC(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)CNC(=O)CSc1cnc(NC(C)=O)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A mixture of [[2-(acetylamino)-5-thiazolyl]thio]acetic acid (9.0 g, 38.8 mmol), HOBT (5.94 g, 38.8 mmol) and ethyldimethylaminopropylcarbodiimide hydrochloride salt (11.16 g, 58.2 mmol) in DMF (50 mL) was stirred at 0° C. for 0.5 h. To this mixture was added 1-amino-2-butanone hydrochloride (5.27 g, 42.7 mmol) followed by triethylamine (15 mL, 107.5 mmol). The mixture was stirred at 0° C. for 0.5 h and at rt for 1 h. Water (200 mL) was added to the mixture and the product was extracted with methylene chloride containing 10% MeOH (5×100 mL). The methylene chloride extract was dried over Na2SO4 and concentrated. The residue was triturated with water and the precipitated solid product was collected by filtration. It was dried to obtain the desired product (10.5 g, 90%), mp 195-196° C.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH:11]3[CH2:14][CH2:13][CH2:12]3)=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[C:25]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:26]=[CH:27][CH:28]=2)O1>>[CH:11]1([C:9]2[CH:8]=[CH:7][N:6]3[C:2]([C:27]4[CH:26]=[C:25]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:24]=[CH:23][CH:28]=4)=[CH:3][N:4]=[C:5]3[N:10]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: Brc1cnc2nc(C3CCC3)ccn12
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Product: N#Cc1ccccc1-c1cccc(-c2cnc3nc(C4CCC4)ccn23)c1

Procedure:
3-Bromo-7-cyclobutylimidazo[1,2-a]pyrimidine was coupled with 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3′-(7-cyclobutylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile as a white powder: δH (400 MHz, CDCl3) 1.90-2.55 (6H, m), 3.77 (1H, quintet, J 8), 6.83 (1H, d, J 7), 7.48-7.75 (7H, m), 7.82 (1H, dd, J 8 and 1), 7.86 (1H, s), 8.85 (1H, d, J 7); m/z (ES+) 351 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C(O[CH:18]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])C>C(O)C>[CH2:28]([O:27][C:25]([C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:26])[CH3:29]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(C2=NNC(=O)CC2)cc1)C(=O)OCC

Procedure:
A solution containing 0.38 g of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)one and 0.45 g of diethyl ethoxymethylenemalonate in 5 ml of dry ethanol was refluxed for 1.5 h. After cooling the product was filtered and washed with ethanol. Yield 0.3 g, mp 164° C.