Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH2:10]Br)[C:6]=2[CH:12]=1.CN(C)C([N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1)=O.N>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH2:10][N:19]3[C:20]([CH3:22])=[CH:21][N:17]=[CH:18]3)[C:6]=2[CH:12]=1
Reactant: Clc1ccc2onc(CBr)c2c1
Reactant: Cc1cn(C(=O)N(C)C)cn1
Agent: N
Solvent: CC#N
Product: Cc1cncn1Cc1noc2ccc(Cl)cc12
Reaction time: 1 h

Procedure:
A solution containing 5-chloro-3-bromomethyl-1,2-benzisoxazole (2.5 g, 0.010 mole) and 1-dimethylcarbamoyl-4-methyl-imidazole (1.84 g, 0.012 mole) in anhydrous acetonitrile (25 mL) is stirred at reflux for 72 hours. The solution is cooled to 5° C. (ice-bath) and ammonia gas is bubbled through the solution for 5 minutes after which the solution is allowed to stand at ambient temperature for 1 hour. The solvent is evaporated and the residue is taken up in methylene chloride (25 mL). This solution is washed with water (2×20 mL), dried over anhydrous sodium sulphate, filtered and evaporated to give 5-chloro-3-[(5-methyl-1H-imidazol-1-yl)-methyl]-1,2-benzisoxazole as an oil. A solution of this product in acetone is treated with a slight excess of ethereal hydrogen chloride to afford the hydrochloride salt, m.p. 245°-247° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[CH:13]1(Br)[CH2:17][CH2:16][CH2:15][CH2:14]1>CN(C=O)C>[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: BrC1CCCC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ncnc2c1ccn2C1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
NaH (3.8 g, 95.3 mmol) was added to a solution of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (10 g, 63.5 mmol) in DMF (50 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min, then warmed to room temperature. At this time Cyclopentylbromide (18.9 g, 127 mmol) was added and the reaction was heated to 60° C. After 4 h the reaction was cooled to 0° C. and quenched with water. The aqueous layer was extracted with EtOAc (3×), the combined organic layers were washed with water (1×), dried over Na2SO4, and concentrated. Purification by flash column chromatography (Hexanes/Ethyl acetate 9:1) afforded the title compound as a clear oil (10.6 g, 75%). MS: 222.1/224.1 (MH+); HPLC Rf: 5.77 min. (HPLC method 4).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([S:9]([C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:19]=1[C:20]([N:22]=[C:23]=[O:24])=[O:21]>C1(C)C=CC=CC=1>[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:19]=1[C:20]([NH:22][C:23]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([S:9]([C:11]([F:16])([F:15])[CH:12]([F:13])[F:14])=[O:10])=[CH:8][C:2]=1[F:1])=[O:24])=[O:21]
Reactant: Nc1ccc(S(=O)C(F)(F)C(F)F)cc1F
Reactant: O=C=NC(=O)c1c(F)cccc1Cl
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(S(=O)C(F)(F)C(F)F)cc1F
Yield: 87 %

Procedure:
To a solution of 0.7 g of 2-fluoro-4-(1,1,2,2-tetrafluoroethylsulfinyl)aniline in 15 ml of toluene was added 0.5 g of 2-fluoro-6-chlorobenzoyl isocyanate. After the reaction was allowed to proceed at room temperature (20° to 25° C.) for 30 minutes, the crystals which separated out were recovered by filtration and washed with toluene to give 1.0 g of N-(2-fluoro-6-chlorobenzoyl)-N'-[2-fluoro-4-(1,1,2,2-tetrafluoroethylsulfinyl)phenyl]urea (Compound No. 31), m.p. of 213°-216° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=O)[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1.[NH:21]([C:23]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=[S:24])[NH2:22].CN(C)C=O>Cl.O>[OH:1][C:2]1[C:3]([C:18](=[N:22][NH:21][C:23]([NH:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)=[S:24])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1nn(C)c(-c2ccc(CC(C)C)cc2)c1O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(CC(C)C)cc2)c1O
Yield: 75.1 %

Procedure:
1-[4-Hydroxy-5-(4-isobutylphenyl)-1-methyl-1H-pyrazol-3-yl]ethanone (0.179 mmol, 48.8 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.179 mmol, 37.9 mg) were stirred with dimethylformamide (2.5 mL) and three drops of concentrated hydrochloric acid at room temperature for 24.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (62.6 mg, yield 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:21]=1.[C:22]1(=[O:28])[O:27][C:25](=[O:26])[CH:24]=[CH:23]1>N1C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][CH:17]([O:20][C:22]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])=[O:28])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:21]=1
Reactant: O=C(Cn1c(=O)sc2ccc(Cl)cc21)N1CCC(O)CC1
Reactant: O=C1C=CC(=O)O1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(O)C=CC(=O)OC1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Reaction time: 8 h
Yield: 50.5 %

Procedure:
A solution of 5-chloro-3-(4-hydroxypiperidinocarbonylmetyl)benzothiazolin-2-one (3.2 g) in dry pyridine (2.5 ml) and dry tetrahydrofuran (50 ml) was cooled, to which a solution of maleic anhydride (1.0 g) in dry tetrahydrofuran (5 ml) was gradually dropwise added under stirring. The mixture was refluxed for two hours and then left overnight. The solvent was evaporated off under vacuum from the reaction mixture, and the residue was dissolved in 5% aqueous sodium bicarbonate (20 ml). The solution was cooled and adjusted to pH 2 with 1% hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and then subjected to chromatography on silica gel eluting with ethanol/benzene (1:1). The solvent was evaporated off under vacuum from the eluate at below 50° C. The residue was recrystallized from isopropyl alcohol to yield the title compound as colorless crystals (2.1 g). m.p. 197°-198° C.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[S:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[CH:7]=1)(C)C.[F-].[Cs+].Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C)C=O>[CH3:13][O:12][C:10]1[CH:11]=[C:6]([S:5][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:7]=[C:8]([O:16][CH3:17])[C:9]=1[O:14][CH3:15]
Reactant: CCOC(=O)CCCBr
Reactant: COc1cc(S[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCSc1cc(OC)c(OC)c(OC)c1
Reaction time: 3 h

Procedure:
A suspension of 1.78 g of the compound obtained in Step A, 0.835 g of CsF and 1.1 g of ethyl 4-bromobutyrate in 80 ml of dimethylformamide is stirred, under argon, for 3 hours. After removal of the solvent by distillation, the residue is taken up in a mixture of water/dichloromethane, decanted and then dried over sodium sulphate. Chromatography over silica gel eluted with dichloromethane enables the expected product to be isolated.
Reaction SMILES: [OH-].[Na+].[C:3]([C:11]1[CH:12]=[C:13](/[C:17](=[N:23]/[O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[N:35]=[C:36]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[O:37][C:38]=3[CH3:39])=[CH:28][CH:27]=2)/[C:18]([O:20]CC)=[O:19])[CH:14]=[CH:15][CH:16]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO.Cl>O1CCCC1>[C:3]([C:11]1[CH:12]=[C:13](/[C:17](=[N:23]/[O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[N:35]=[C:36]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[O:37][C:38]=3[CH3:39])=[CH:28][CH:27]=2)/[C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1cccc(C(=O)c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\C(=O)O)c2cccc(C(=O)c3ccccc3)c2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (7 ml) was added to a solution of ethyl Z-2-(3-benzoylphenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate (800 mg) in tetrahydrofuran (14 ml)-methanol (7 ml) and stirred at 40° C. for 1 hour. 1N hydrochloric acid (7.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-2(3-benzoylphenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetic acid (608 mg, yield 80%) as orange crystals. m.p. 185-186° C. (decomposition)
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[N:12]1[CH:17]=[CH:16][CH:15]=[N:14][C:13]=1[S:18][CH2:19][N:20]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[S:21]1(=[O:23])=[O:22]>>[N:14]1[CH:15]=[CH:16][CH:17]=[N:12][C:13]=1[S:18]([CH2:19][N:20]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[S:21]1(=[O:23])=[O:22])=[O:9]
Reactant: O=C1c2ccccc2S(=O)(=O)N1CSc1ncccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: O=C1c2ccccc2S(=O)(=O)N1CS(=O)c1ncccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of m-chloroperbenzoic acid (0.9 g, 5.37 mmol) and 2-(2-pyrimidylthiomethyl) saccharin prepared by procedures similar to those of Examples 9 and 11 (1.5 g, 4.8 mmol) in MDC (75 ml) was stirred overnight at room temperature. The reaction mixture was washed with sodium bicarbonate solution, dried (Na2SO4) and freed of solvent under vacuum. Part of this crude product (0.5 g) was saved for direct conversion to the sulfone; the remaining material was chromatographed (silica gel-95:5 CH2Cl2 :acetone). Recrystallization from ethanol:acetonitrile afforded 0.95 g of 2-(2-pyrimidylsulfinylmethyl)saccharin as white crystals, mp 197°-198 ° C. decomp. 1H nmr (90 MHz, CDCl3, DMSO-d6) :5.1-5.5 (2H, q) .
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:19]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: OB(O)c1cccnc1
Product: COc1ccc2c(-c3cccnc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-pyridine-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-(1-pyridin-3-yl-6-methoxy-isoquinolin-3-yl)-amine. LC-MS m/e 332(MH+).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:7][CH:6]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][C@@H:32]2[CH2:34][C@H:29]1[CH2:30][NH:31]2)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(C(C)C)CC)(C)C>CC#N>[C:21]([O:25][C:26]([N:28]1[CH2:33][C@@H:32]2[CH2:34][C@H:29]1[CH2:30][N:31]2[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:7][CH:6]=1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: BrCCOc1ccc(Oc2nc3ccccc3s2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2CCOc1ccc(Oc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
To a stirred solution of 2-[4-(2-bromo-ethoxy)-phenoxy]-benzothiazole (1.5 g, 4.3 mmol) and (S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.0 g, 5.1 mmol) in CH3CN (20 mL) at rt was added diisopropylethylamine ((i-Pr)2NEt) (900 μL, 5.1 mmol). The resulting suspension was stirred at rt for 4 h and then heated for 65 h at 60° C. The solution was cooled to rt and then partitioned between CH2Cl2 (200 mL) and satd. aq. NaHCO3 (80 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 5% CH3OH in CH2Cl2) afforded the title compound as a yellow oil (1.8 g, 92%). MS (ESI): mass calcd. for C25H29N3O4S, 467.19; m/z found, 468.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.75 (d, J=8.0 Hz, 1H), 7.68-7.66 (m, 1H), 7.42-7.38 (m, 1H), 7.31-7.25 (m, 3H), 6.99-6.95 (m, 2H), 4.40 (br s, 0.5H), 4.27 (br s, 0.5H), 4.13-4.03 (m, 2H), 3.66-3.51 (m, 2H), 3.26-2.97 (m, 4H), 2.78 (d, J=9.5 Hz, 0.5H), 2.63 (d, J=9.7 Hz, 0.5H), 1.92-1.85 (m, 1H), 1.79-1.70 (m, 1H), 1.49 (s, 9H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]([NH:9][C:10]1[C:19]([I:20])=[CH:18][CH:17]=[CH:16][C:11]=1[C:12](OC)=[O:13])=O)[CH2:2][CH3:3].O.C([NH2:28])=O>>[CH2:1]([O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]1[NH:28][C:12](=[O:13])[C:11]2[C:10](=[C:19]([I:20])[CH:18]=[CH:17][CH:16]=2)[N:9]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C(=O)Nc1c(I)cccc1C(=O)OC
Reactant: NC=O
Solvent: O
Product: CCCOc1ccccc1-c1nc2c(I)cccc2c(=O)[nH]1

Procedure:
19.4 g (44.17 mmoles) of the compound from Example I is stirred for 10 hours at 180° C. in 216 ml of formamide. After cooling, 500 ml of water is added and extracted 4 times with 300-ml portions of CH2Cl2. The combined organic phases are dried over MgSO4, the solvent is evaporated under vacuum, and the residue is stirred in a mixture of 100 ml of diethyl ether and 50 ml of petroleum ether. The product (17.8 g) is filtered off by suction and recrystallized from 250 ml of absolute ethanol.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:4](=[O:5])[CH:3]([O:8][CH3:9])[O:2][CH3:1])=[CH:13][CH:12]=1
Reactant: COC(=O)C(OC)OC
Reactant: NCc1ccc(F)cc1
Product: COC(OC)C(=O)NCc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
Into a sealable tube were added methyl dimethoxyacetate (0.98 g, 7.3 mmol) and 4-fluorobenzylamine (0.91 g, 7.3 mmol); mixture was stirred at 60° C. for 2 days. The compound was purified by column chromatography on silica gel (10 g/70 mL prepacked cartridge, eluting with 5% EtOAc in hexanes→5% MeOH in hexanes), affording the title compound. HPLC: tR=2.58 min. (ZQ2, polar—5 min.). MS (ES+): m/z=249.92 (24) [MNa+], 227.91 (100) [MH+].
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:36]([CH2:38][NH2:39])[OH:37]>CN(C=O)C.C(OCC)(=O)C>[OH:37][CH2:36][CH2:38][NH:39][C:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[O:13]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCCO)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
To a solution of quinaldic acid (5.0 g, 28.87 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.5 g, 28.87 mmol), and 1-hydroxybenzotriazole (5.1 g, 37.49 mmol) in DMF (60 mL) at 0° C. was added ethanolamine (1.74 mL, 28.87 mmol) and 4-methylmorpholihne (4.76 mL, 43.31 mmol). The reaction was stirred at 0° C. for an additional 10 minutes and then warmed to room temperature and stirred for 2 hours. The reaction mixture was then diluted with ethyl acetate, washed 3 times with H2O, once with NaHCO3 (sat), once with brine, dried over MgSO4, and concentrated in vacuo to provide 1.5 g (24% yield) of a pale yellow solid. Electrospray Mass Spec: m/z 216.8 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[Br:31][C:32]1[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=1[NH2:34]>ClCCl>[Br:31][C:32]1[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=1[NH:34][C:10]([C@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: Nc1ccccc1Br
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)Nc1ccccc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
In a 500 mL flask, N-Boc-D-Proline (300 mg, 1.39 mmol) was dissolved in dichloromethane (35 mL) and cooled to 0° C. under nitrogen. N-Methylmorpholine (153 μL, 1.39 mmol) was added followed by dropwise addition of iso-butyl chloroformate (180 μL, 1.39 mmol) and the reaction mixture stirred at 0° C. for 1 h. 2-Bromoaniline (1.31 mL, 1.39 mmol) was dissolved in dichloromethane (5 mL) then added quickly to the activated acid at 0° C. The mixture was stirred overnight from 0° C. to room temperature. The reaction mixture was diluted with dichloromethane, washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified on column chromatography (eluent: Pentane/EtOAc, 50/50 to 0/100 then EtOAc/MeOH 80/20) to give the product (394 mg, 77%) as a yellow oil. This product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH2:13]([Mg]Br)[CH3:14].CCOCC>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:13][CH3:14])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1nc(SC)nc(Cl)c1C#N
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a 100 mL round-bottom flask was added 4,6-dichloro-2-(methylthio)pyrimidine-5-carbonitrile (300 mg, 1.363 mmol) in tetrahydrofuran (10 mL). The reaction mixture was cooled to −78° C. Ethylmagnesium bromide in ether (3.0 M, 0.454 mL, 1.363 mmol) was added and the reaction mixture was allowed to stir for 1 hour at room temperature. LCMS indicated the reaction was complete. The reaction mixture was quenched with a few drops saturated aqueous NH4Cl and allowed to warm to room temperature. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (ISCO 12 g, 20-100% EtOAc/hexane gradient) to give the title compound as a pasty yellow solid. ESI-MS m/z [M+H]+ calc'd for C8H8ClN3S, 214. found 214.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].[CH3:14][NH:15][CH2:16][CH2:17][C:18]#[C:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([N:15]([CH3:14])[CH2:16][CH2:17][C:18]#[C:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:6]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CNCCC#Cc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1cccc(OC)c1C(=O)N(C)CCC#Cc1ccccn1
Temperature: 0 °C
Reaction time: 14 h
Yield: 11.9 %

Procedure:
2,6-Dimethoxy-benzoyl chloride (81 mg, 0.41 mmol) was added to a solution of methyl-(4-pyridin-2-yl-but-3-ynyl)-amine (50 mg, 0.31 mmol) and DIEA (69 μL, 0.41 mmol) in chloroform (2 mL) at 0° C. The reaction mixture was stirred at 0° C. for 10 min., at room temperature for 14 hours, quenched by the addition of water and extracted twice with chloroform. The organic phase was washed with saturated solution of NaHCO3, brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (DCM/MeOH 95:5) to yield 2,6-dimethoxy-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide (12 mg, 37 μmol, 12%).