Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[N:34][C:35]([S:38][CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[N:34][C:35]([S:38]([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ccccn4)nc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ccccn4)nc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 53.7 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[(2-pyridinylmethyl)sulfanyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.50 g) in methylene chloride (15 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.16 g) in methylene chloride (10 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[(2-pyridinylmethyl)sulfinyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 268) (275 mg).
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CN(C)C=O.[Cu](I)I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:16]1([C:22]#[C:23][C:2]2[N:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]3=[N:4][C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)c1nc2ccccn2c1I
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2ccccn2c1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
In a flask placed under an argon flow, 1.82 g (5.77 mmol) of ethyl 3-iodoimidazo[1,2-a]pyridine-2-carboxylate were dissolved in 6 ml of dimethylformamide with magnetic stirring. To this solution were added: 0.11 g (0.577 mmol) of copper iodide, 0.776 ml (6.93 mmol) of phenylacetylene and 6 ml (43 mmol) of triethylamine. The reaction medium was degassed with argon for 10 min before adding 0.529 g (0.577 mmol) of Pd2(dba)3. The mixture was stirred at r.t. for 16 h before being filtered on celite. The celite was washed with 50 ml of ethyl acetate, and then the filtrate was washed with 2×50 ml of water. After separation, the aqueous phase was extracted with 2×50 ml of ethyl acetate; the combined organic phases were washed with 70 ml of a saturated NaCl aqueous solution, dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: heptane/ethyl acetate, 6/4, v/v). 1.28 g (yield=57%) of ethyl 3-(phenylethynyl)imidazo[1,2-a]pyridine-2-carboxylate were obtained as a pale yellow solid. LC-MS: m/z=291 (MH+); UV purity at 254 nm=93%. 1H NMR (300 MHz, DMSO) δ 8.70 (d, J=6.8 Hz, 1H), 7.74 (dd, J=22.1, 6.2 Hz, 3H), 7.53 (dd, J=17.6, 6.9 Hz, 4H), 7.23 (t, J=6.3 Hz, 1H), 4.36 (d, J=4.7 Hz, 2H), 1.36 (d, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C[O-].[Na+].[C:14]([O:18][CH3:19])([CH3:17])(C)C.O>CN(C)C=O>[O:18]1[CH2:19][C@H:14]1[CH2:17][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Oc1cccc2[nH]ccc12
Reactant: COC(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reaction time: 0.08 h

Procedure:
A 3.2 g portion of 4-hydroxy-1H-indole was dissolved in 31 mL of dimethylformamide in a 50 mL flask equipped with a magnetic stirrer, nitrogen bubbler and thermometer. To it was added 1.27 g of sodium methoxide and the mixture was stirred until a blue-black solution resulted. The warm mixture was placed under vacuum for 5 minutes to remove most of the resulting methanol. To the mixture was added 6 g of oxiranylmethoxysulfonyl-3-nitrobenzene, resulting in an exotherm to about 37° C. The mixture was stirred at ambient temperature for 1 hour, and was then poured into a separatory funnel containing 55 mL of methyl t-butyl ether and 80 mL of water. The mixture was shaken well, and the layers were separated. The organic layer was removed and the aqueous layer was extracted with 2×55 mL of methyl t-butyl ether. The organic layers were combined and back-extracted with 50 mL of 5% aqueous lithium chloride. The layers were separated again, and the organic layer was dried with magnesium sulfate and filtered. The organic filtrate was concentrated under vacuum to about 15 mL of volume, and was seeded with pure desired product and stirred. The product was crystallized to a thick slurry to which 20 mL of heptane was slowly added. The mixture was stirred for one hour more and filtered, and the filter cake was rinsed with 3:1 heptane:methyl t-butyl ether, and then with heptane. The product was dried in a vacuum oven at 40° C. to obtain about 3.5 g of product.
Reaction SMILES: [CH2:1]([N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:13])[C:2]#[CH:3].[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1I>C(N(CC)CC)C.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.[Cu]I>[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C:3]#[C:2][CH2:1][N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:13]
Reactant: Fc1ccc(I)c(F)c1
Reactant: C#CCN1Cc2ccccc2C1=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2CN1CC#Cc1ccc(F)cc1F
Reaction time: 8 h
Yield: 24.3 %

Procedure:
2-Prop-2-ynyl-2,3-dihydro-isoindol-1-one (50.0 mg, 0.29 mmol) was dissolved in triethylamine (2 mL). To this was added Pd(PPh3)4 (13 mg, 0.012 mmol), CuI (6.7 mg, 0.035 mmol) and 2,4-difluoro-1-iodo-benzene (52.0 μL, 0.438 mmol) and the reaction was allowed to stir overnight. The solvent was evaporated and the residue was purified by prep. TLC (30% EtOAc/Hexanes) to afford the title compound (20.0 mg, 24%) as a brown oil. 1H NMR (300 MHz, CDCl3): δ 7.90 (d, 1H), 7.45 (m, 4H), 6.84 (t, 2H), 4.72 (s, 2H), 4.59 (s, 2H).
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][N:9]=1)(=O)C.O1CCCC1.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2cccnc2)s1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ncc(Sc2cccnc2)s1
Yield: 79.1 %

Procedure:
A mixture of 2-acetylamino-5-(3-pyridylthio)thiazole (8.5 g) in a mixture of ethanol (160 ml), tetrahydrofuran (50 ml) and aqueous 6N hydrochloric acid (100 ml) was refluxed for 4 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8.5 using aqueous sodium bicarbonate and the precipitates were collected by filtration, washed with water and dried in vacuo to give 2-amino-5-(3-pyridylthio)thiazole (5.6 g yield: 78.9%). mp: 140°-142° C. IR (Nujol): 3400, 3300, 3125, 1630, 1530, 1490 cm-1
Reaction SMILES: C1C2C(COC([NH:18][CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:54][C:55]3[N:56]([CH2:60][C:61]([N:63]([CH2:72][C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH2:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:62])[CH:57]=[CH:58][N:59]=3)[CH2:28][C:29]3[N:30]([CH2:34][C:35](=[O:53])[N:36]([CH2:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:31]=[CH:32][N:33]=3)[C:20]([OH:22])=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:18][C@@H:19]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:28][C:29]1[N:30]([CH2:34][C:35]([N:36]([CH2:37][C:38]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:44])[CH2:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:53])[CH:31]=[CH:32][N:33]=1)[CH2:54][C:55]1[N:56]([CH2:60][C:61](=[O:62])[N:63]([CH2:72][C:73](=[O:74])[O:75][C:76]([CH3:79])([CH3:78])[CH3:77])[CH2:64][C:65](=[O:71])[O:66][C:67]([CH3:69])([CH3:68])[CH3:70])[CH:57]=[CH:58][N:59]=1)[C:20]([OH:22])=[O:21]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCCCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Yield: 79.1 %

Procedure:
A solution of 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (190 mg, 0.173 mmol) and piperidine (0.50 mL) in DMF (0.50 mL) was stirred at room temperature for 1 hrs. The solvent was evaporated under reduced pressure to give a crude product. The crude product was purified by Biotage SP4 with a gradient method of 5-50% methanol in DCM to give (S)-2-amino-6-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (0.120 g, 79%). 1H NMR (400 MHz, DMSO-d6) □6.92 (s, 2H), 6.76 (s, 2H), 5.01 (s, 4H), 4.32 (s, 2H), 4.31 (s, 2H), 3.92 (s, 4H), 3.44 (s, 4H), 3.01-2.99 (m, 1H), 2.30 (t, J=7.2 Hz, 2H), 1.60-1.57 (m, 2H), 1.43 (s, 18H), 1.35 (m, 18H). 1.30-1.12 (m, 4H); MS (ESI), 439.4 (M/2+H)+.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[CH:34]([CH3:35])[CH:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH:27](C(OC)=O)[C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45].O>N1C(C)=CC(C)=CC=1C>[CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[C@@H:34]([CH3:35])[C@H:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH2:27][C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4)[C@@H](CCC(=O)OC)[C@@H]3C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
To a solution of methyl pheophorbide-a (100 mg, 0.17 mmol) in 2,4,6-collidine (25 mL, distilled) was added distilled water (48 μL, 2.7 mmol, 16 equiv.) and the mixture was refluxed under argon with stirring. The reaction was monitored by HPLC (hexaneacetone, 90:10-mobile phase, LiChrospherCN-column, detection at 425 and 410 nm). After 10 min, the reaction was shown to have reached 100% completion by HPLC peak area. The solution was cooled to room temperature and solvent removed under reduced pressure. Hexane (10 mL) was added to the flask and the precipitated residue collected by filtration and rinsed with hexane to give methyl pyropheophorbide-a (70 mg, 77%).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:5][C:6](=[O:25])[CH2:7][N:8]1[C:12](=[O:13])[CH2:11][CH:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[N:22][NH2:23])=[CH:17][CH:16]=2)[C:9]1=[O:24].Cl>>[NH2:23][N:22]=[CH:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:10]2[CH2:11][C:12](=[O:13])[N:8]([CH2:7][C:6]([NH:5][CH:4]([C:3]([OH:34])=[O:2])[CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[C:9]2=[O:24])=[CH:20][CH:19]=1
Reactant: COC(=O)C(CCc1ccccc1)NC(=O)CN1C(=O)CC(Cc2ccc(C=NN)cc2)C1=O
Agent: Cl
Product: NN=Cc1ccc(CC2CC(=O)N(CC(=O)NC(CCc3ccccc3)C(=O)O)C2=O)cc1
Yield: 55 %

Procedure:
45 mg of {3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-D,L-homophenylalanine methyl ester are allowed to stand at room temperature for 1 h with 5 ml of concentrated hydrochloric acid. The mixture is then concentrated to dryness in vacuo, and the residue is taken up in a little water and freeze-dried. 24 mg of {3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-D,L-homophenylalanine are obtained.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.C[Li].[C:10]([O:14][C:15]([N:17]1[CH2:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28](=O)[CH2:29][C:30]([C:36]3[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38]([Cl:43])[CH:37]=3)([OH:35])[C:31]([F:34])([F:33])[F:32])=[CH:24][CH:23]=2)([F:21])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>COCCOC>[C:10]([O:14][C:15]([N:17]1[CH2:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH2:29][C:30]([C:36]4[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38]([Cl:43])[CH:37]=4)([C:31]([F:32])([F:33])[F:34])[O:35][CH:1]=3)=[CH:26][CH:27]=2)([F:21])[CH2:18]1)=[O:16])([CH3:12])([CH3:13])[CH3:11]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C(=O)CC(O)(c3cc(Cl)cc(Cl)c3)C(F)(F)F)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]C
Solvent: CC(=O)O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C3=COC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reaction time: 2 h
Yield: 9.1 %

Procedure:
To a stirred solution of trimethylsilyldiazomethane (2M in diethyl ether, 18.64 mL, 37.289 mmol) in 1,2-dimethoxyethane (DME, 100 mL) was added methyl lithium (1.6M in diethyl ether, 23.32 mL, 37.289 mmol) at −78° C. over period of 10 minutes and stirred reaction mixture for 30 minutes at −78° C. Pre-dissolved 3-{4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-hydroxy-butyryl]-phenyl}-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester (Example 1, Intermediate 1) (5 g, 9.322 mmol, 1eq.) in DME (50 mL) was added at −78° C. in drop wise manner over period of 10 minutes. Resulting reaction mixture was stirred for 1 hour at same temperature and then at room temperature for 2 hours. Acetic acid (1.60 mL, 27.967 mmol, 3 eq.) was added at room temperature over period of 5 minutes followed by addition of TBAF (27.92 mL, 27.967 mmol, 3 eq.) at room temperature over period of 10 minutes. After consumption of starting material, reaction mixture was quenched with water (150 mL) and extracted with ethyl acetate (5×150 mL). Combined organic layer was dried over sodium sulphate and concentrated in vacuo to get orange semisolid (6.1 g, crude). Crude was purified by column chromatography using 100-200 mesh silica gel. Desired compound was eluted in 10% ethyl acetate in hexane to afford off white semisolid (1.6 g, Impure). The product was again purified by trituration using DCM: pentane (1:5, 2×20 mL) to afford product as off white solid (0.45 g, 9.18%). Yield: −0.45 g (9.18%). 1H NMR (400 MHz, CDCl3) δ: 1.46 (s, 9H), 3.20 (d, J=17.24 Hz, 1H), 3.30 (d, J=17.24 Hz, 1H), 4.14-4.21 (m, 2H), 4.33-4.41 (m, 2H), 7.32-7.38 (m, 4H), 7.40 (t, J=1.78 Hz, 1H), 7.52 (d, J=1.36 Hz, 2H). LC-MS (m/z): =529.9 (M−H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].Cl[C:14]1[N:19]=[C:18]([S:20][CH3:21])[N:17]=[C:16]([NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=2)[CH:15]=1>>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][NH:22][C:16]2[N:17]=[C:18]([S:20][CH3:21])[N:19]=[C:14]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:1]([OH:3])=[O:2])[CH:15]=2)[CH:30]=[CH:29][C:28]=1[O:31][CH3:32]
Reactant: COc1ccc(CCNc2cc(Cl)nc(SC)n2)cc1OC
Reactant: O=C(O)c1cccc(B(O)O)c1
Product: COc1ccc(CCNc2cc(-c3cccc(C(=O)O)c3)nc(SC)n2)cc1OC

Procedure:
By proceeding in a similar manner to Example 16(a) above but using commercially available 3-carboxy-phenyl-boronic acid, and (6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine (0.57 g) in Step 2, and extracting the reaction mixture (adjusted to pH 2) with EtOAc followed by evaporation of the organic extract, there is prepared 3-{6-[2-(3,4-dimethoxy-phenyl)-ethylamino]-2-methylsulfanyl-pyrimidin-4-yl}-benzoic acid [0.48 g, Example 16(b)]. LCMS: RT=2.75 minutes, MS: 426 (M+H). IC50=243 nM
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([O:10][C:11](=[O:25])[CH:12]([CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13](=O)[CH3:14])[CH3:9].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.CCOCC>[CH2:8]([O:10][C:11]([C:12]1[CH:16]=[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[C:13]=1[CH3:14])=[O:25])[CH3:9]
Reactant: Nc1cccnc1
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccnc2)c1C

Procedure:
3-Aminopyridine (5 mmol, 0.5 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g) and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was resuspended in ether, then washed with water and brine. The organic layer was dried over MgSO4, then the solids were separated and the solvents were removed under vacuum. The named product was purified over silica gel and analyzed by 1H-NMR (CDCl3, ppm) 1.35 t (3H), 2.40 s (3H), 4.3 q (2H), 6.78 s (1H), 7.03-7.39 m (7H), 8.4 sd (1H), and about 8.6 dd (1H).
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]1[N:12]=[C:13]([N:16]2[CH2:19][CH:18](OS(C)(=O)=O)[CH2:17]2)[S:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O-:28])(=[S:27])[CH3:26].[K+].C(OCC)(=O)C>CN(C)C=O>[C:25]([S:27][CH:18]1[CH2:17][N:16]([C:13]2[S:14][CH:15]=[C:11]([CH2:10][NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:12]=2)[CH2:19]1)(=[O:28])[CH3:26]
Reactant: CS(=O)(=O)OC1CN(c2nc(CNC(=O)c3ccccc3)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)SC1CN(c2nc(CNC(=O)c3ccccc3)cs2)C1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 99.9 %

Procedure:
To a solution of 1-[4-(benzoylaminomethyl)-1,3-thiazol-2-yl]-3-methanesulfonyloxyazetidine (739 mg, 2.01 mmol) (obtained as described in Reference Example 64(3)) in dimethylformamide (20 ml) was added potassium thioacetate (1.38 g, 12.1 mmol) at room temperature, and the mixture was stirred in an oil bath (90° C.) for 3.5 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate=(1:1)→ethyl acetate as the eluant to afford 3-acetylthio-1-[4-(benzoylaminomethyl)-1,3-thiazol-2-yl]azetidine (698 mg, yield 100%) as a pale brown solid.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][C:26]#[N:27])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.[CH3:28]I.[H-].[Na+]>C1COCC1>[C:1]([N:20]1[CH:24]=[C:23]([CH:25]([CH3:28])[C:26]#[N:27])[N:22]=[CH:21]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([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: CI
Reactant: N#CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C#N)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: -5 °C
Reaction time: 12 h

Procedure:
9.2 g (1-trityl-1H-imidazol-4-yl)-acetonitrile are dissolved in 120 mL THF, the solution is cooled to −5° C. and 1.8 mL methyl iodide and 1.08 g sodium hydride (60%) are added. The suspension is stirred for 12 h at RT and then applied directly to RP gel and purified by RP chromatography (C18, 10/90 to 90/10 acetonitrile/water in 15 min-0.2% formic acid is added to both solvents).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH:18]([O:20][CH3:21])[CH3:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:22]([O-])([N+]([O-])=O)=[O:23]>>[Cl:1][CH2:2][CH2:3][N:4]([N:22]=[O:23])[C:5]([N:7]([CH2:17][CH:18]([O:20][CH3:21])[CH3:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: COC(C)CN(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Product: COC(C)CN(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 69.6 %

Procedure:
3.3 g of 1-(2-chloroethyl)-3-(2-methoxy-n-propyl)-3-(L-arabinopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 10-(2). 2.5 g of 1-(2-chloroethyl)-1-nitroso-3-(2-methoxy-n-propyl)-3-(L-arabinopyranosyl)urea are thereby obtained as yellow powder.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].[C:12]([N:15]1[C:24]2[C:19](=[CH:20][C:21](Br)=[CH:22][CH:23]=2)[C@H:18]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:17][C@@H:16]1[CH2:33][CH3:34])(=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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:12]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([C:6]3[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)=[CH:22][CH:23]=2)[C@H:18]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:17][C@@H:16]1[CH2:33][CH3:34])(=[O:14])[CH3:13]
Reactant: CC[C@H]1C[C@@H](Nc2ccccc2)c2cc(Br)ccc2N1C(C)=O
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC[C@H]1C[C@@H](Nc2ccccc2)c2cc(-c3ccc(C=O)cc3)ccc2N1C(C)=O
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
A mixture of (4-formylphenyl)boronic acid (31.7 mg, 0.212 mmol), (cis)-1-acetyl-6-bromo-2-ethyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see intermediate 90) (79 mg, 0.212 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) in 1,4-dioxane (1 mL) and water (0.5 mL) was treated with potassium carbonate (45 mg, 0.326 mmol) and the resulting mixture was stirred at 130° C. for 15 min under microwave irradiation then cooled to room temperature and concentrated in vacuovacuo. Purification of the residue by SP4 using a 25 G silica cartridge (gradient:0 to 100% AcOEt in Hexanes) gave 4-[(cis)-1-acetyl-2-ethyl-4-(phenylamino)-1,2,3,4-tetrahydro-6-quinolinyl]benzaldehyde (67.8 mg, 0.17 mmol, 80%) as a yellow oil.