Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=O.S([C:18]1[CH:24]=[CH:23][C:21](C)=[CH:20][CH:19]=1)(O)(=O)=O.[OH:25][NH:26][C:27]([NH:29][NH:30]C1C=CC=CC=1)=[NH:28]>CO>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[N:30][NH:29][C:27]([NH:26][OH:25])=[N:28][C:18]1[CH:24]=[CH:23][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc(C=O)c(Cl)c1OC
Reactant: N=C(NO)NNc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COc1ccc(C=NNC(=Nc2ccccc2)NO)c(Cl)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.22 g (1.1 mmol) 2-chloro-3,4 dimethoxybenzaldehyde and 0.34 g (1 mmol) N-hydroxy-N′-phenylaminoguanidine tosylate was mixed in 7 ml methanol. The reaction mixture was refluxed for 80 min after which it was cooled down, to room temperature. The solvent was evaporated and 10 ml acetonitile was added and the solution was stirred for 1 h. The precipitate formed was filtered, washed with ether and subseqently dried. The yield of title compound 2 was 0.40 g (77%) as a crystalline solid M.p. 167–169° C.
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=4)[C:23](O)=[O:24])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:31]([NH2:37])[C:32]1[O:36][CH:35]=[CH:34][CH:33]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=4)[C:23]([NH:37][CH2:31][C:32]4[O:36][CH:35]=[CH:34][CH:33]=4)=[O:24])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)O)ccn1
Reactant: NCc1ccco1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)NCc2ccco2)ccn1
Yield: 63 %

Procedure:
To solution of 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-isonicotinic acid (40 mg, 0.098 mmol), furfuryl amine (19.11 mg, 0.196 mmol) and DMAP (24.06 mg, 0.196 mmol) in DMF was added PyBOP (102.4 mg, 0.196 mmol) at room temperature, and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOH:MC=1:1) to afford 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-N-furan-2-ylmethyl-isonicotinamide as a colorless solid (30 mg, 63% yield).
Reaction SMILES: [NH2:1][CH:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]1([NH:19][C:20](=S)[S:21]C)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(O)C>[CH2:3]([CH:2]1[NH:1][C:20](=[S:21])[N:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]1=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NC(Cc1ccccc1)C(=O)O
Reactant: CSC(=S)Nc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1C(Cc2ccccc2)NC(=S)N1c1ccccc1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A solution of DL-phenylalanine (1.65 g, 10 mmol), methyl N-phenyldithiocarbamate (1.85 g, 10 mmol), and triethylamine (1.4 mL, 10 mmol) in ethanol (30 mL) was heated at reflux for 5 h, the mixture was cooled to room temperature and the solvent removed in vacuo. The residue was dissolved in ethyl acetate, washed with 1N aqueous HCl and water. The organic layer was concentrated and the residue recrystallized form ethanol to provide 2.48 g (88%) of the titled product: mp 187°-189° C.; MS (FD) m/e 282 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:15]2C(=O)[NH:18][C:17](C)(C)[NH:16]2)[CH:5]=[C:6]([Cl:14])[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.O.[C:24]([OH:28])(=O)[CH:25]=O.[OH:29]S(O)(=O)=O.C(O)(=O)C=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:25][C:24](=[O:28])[NH:18][C:17](=[O:29])[NH:16]2)[CH:5]=[C:6]([Cl:14])[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=S(=O)(O)O
Reactant: CC1(C)NC(=O)N(c2cc(Cl)c(-c3ccccn3)c(Cl)c2)N1
Reactant: O=CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: O=C1CN(c2cc(Cl)c(-c3ccccn3)c(Cl)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3 g (8.5 mmol) of 1-[3,5-dichloro-4-(2-pyridyl)phenyl]-3,3-dimethyl-1,2,4-triazolidin-5-one are dissolved in 50 ml of dioxane, and 0.78 g (8.5 mmol) of glyoxylic acid monohydrate and 0.1 ml of concentrated H2SO4 are added. The mixture is initially stirred at room temperature for 2 h and then a further 0.8 g of glyoxylic acid is added. After the reaction mixture has been stirred under reflux for 5 h it is poured onto water and extracted 3 × with ethyl acetate. The solvent is stripped off in vacuo, and the residue is chromatographed on SiO2 with dichloromethane/methanol (95:5). This results in 1.2 g (40% of theory) of the corresponding azauracil.
Reaction SMILES: C(O/[CH:4]=[C:5](\[C:11](=O)[C:12]([F:15])([F:14])[F:13])/[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C(N(C(C)C)CC)(C)C.F.[F:27][C:28]1[CH:29]=[CH:30][C:31]([NH:34][NH2:35])=[N:32][CH:33]=1>C(O)C>[F:27][C:28]1[CH:29]=[CH:30][C:31]([N:34]2[C:11]([C:12]([F:13])([F:14])[F:15])=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=[N:35]2)=[N:32][CH:33]=1
Reactant: NNc1ccc(F)cn1
Reactant: CCO/C=C(/C(=O)OCC)C(=O)C(F)(F)F
Agent: F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(F)cn2)c1C(F)(F)F
Temperature: 80 °C
Yield: 29.7 %

Procedure:
To (E)-ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (0.441 g, 1.835 mmol) in ethanol (2 mL) was added diisopropylethylamine (0.427 mL, 2.447 mmol) followed by 5-fluoro-2-hydrazinylpyridine, hydrofluoride (0.3 g, 2.039 mmol) dissolved in 1 mL of ethanol (slightly exothermic). The reaction mixture was heated at 80° C. for 1 h. The reaction mixture was concentrated under reduced pressure, dissolved in dichloromethane (2 mL) and subjected to column chromatography using an ISCO setup (40 g, RediSep® silica gel column). The desired fractions were collected and concentrated to yield ethyl 1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.165 g, 27%) as a white solid. LC/MS M+1=304.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].[CH:11]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[N:18][CH:17]=[CH:16]2)=[O:12].Cl>O.CS(C)=O>[C:24]([NH:23][C:19]1[C:20]2[C:15](=[CH:14][C:13]([C:11]([OH:6])=[O:12])=[CH:22][CH:21]=2)[CH:16]=[CH:17][N:18]=1)(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=Cc1ccc2c(NC(=O)c3ccccc3)nccc2c1
Reactant: O=P([O-])(O)O
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccc2c(NC(=O)c3ccccc3)nccc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 230.9 %

Procedure:
To a stirred solution of 400 mg sodium chlorite and 80 mg sodium dihydrogen phosphate in 2.5 mL of water and 2.5 mL of dimethylsulfoxide in a cooling bath at room temperature was added dropwise a solution of 510 mg N-(6-formyl-1-isoquinolinyl)benzamide (1f) in 2.5 mL of dimethylsulfoxide. After 16 hours at room temperature a solution of 170 mg sodium chlorite in 0.5 mL of water and 1.0 mL of dimethylsulfoxide was added and stirred at room temperature for an additional 6 hours. Then 100 mL water was added, the pH adjusted to three using 2N hydrochloric acid and the resulting suspension was kept at 5° C. for 16 hours. The precipitate was collected to afford 450 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Cl)=[CH:33][N:32]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:37][C:34]4[CH:33]=[N:32][C:31]([Cl:30])=[CH:36][CH:35]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(Cc2ccc(Cl)nc2)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 53.2 %

Procedure:
To a solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (150 mg, 0.46 mmol), prepared as described in Example 244, in DMF (3 mL) was added K2CO3 (80 mg, 0.58 mmol) and 2-chloro-5-(chloromethyl)pyridine (90 mg, 0.556 mmol). The reaction mixture was stirred at 70° C. for 15 min. After this time, the solution was cooled to RT and diluted with water (20 mL). The resulting solid was collected by filtration and the crude product was purified by reverse phase HPLC to give the title compound, 7-(4-chlorophenyl)-2-((6-chloropyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (110 mg, 52%), as a yellow solid. HPLC: 2.61 min; MS, M+H=449; 1H NMR (CDCl3) δ 8.62 (2H, d, J=5.0 Hz), 8.43 (1H, d, J=5.0 Hz), 8.19 (1H, s), 7.33 (1H, d, J=5.0 Hz), 7.29-7.31 (3H, m), 7.20 (2H, d, J=5.0 Hz), 7.08 (2H, d, J=10.0 Hz), 5.17 (2H, s).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].ClCC(C1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=O.[CH2:16]([O:18][CH2:19][CH3:20])C.[OH-].[Na+]>C1COCC1>[O:18]1[CH2:16][C:19]1([C:20]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:1]#[CH:2]
Reactant: C#C[Mg]Br
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: CCOCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C#CC1(c2ccc(F)cc2)CO1
Temperature: 23 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
To a solution of 0.12 mol of ethynylmagnesium bromide in 300 mL of dry THF at 23° C. was added 15.5 g (90 mmol) of 2-chloro-4'-fluoro-acetophenone as a solid. The mixture stirred at 23° C. for 24 hours when it was quenched with 15 mL of saturated NH4Cl and poured int 250 mL of diethyl ether. The ether layer was separated and washed with H2O, dried (MgSO4) and concentrated. The residue was added to 300 mL of dry diethyl ether and 3.6 g (90 mmol) of pulverized NaOH was added. The reaction mixture was stirred at 23° C. for 3 hours, then the ether was washed twice with 100 mL of H2O and once with saturated brine. The organic layer was dried (MgSO4), concentrated and distillation (b.p. 55°-58° C. at 0.34 mmHg) provided 9.5 g (66%) of 3,4-epoxy- 3-(4'-fluorophenyl)-1-butyne as a liquid, homogeneous by spectroscopic criteria; IR (film) 3275, 1595, 1505, 1218 cm-1 ; 1HNMR (80 MHz, CDCl3) δ 7.45 (m, 2H), 7.15 (m, 2H), 3.20 (ABq, 2H, J=8.0 Hz, ΔνAB =39.2 Hz), 2.51 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[Si:24]([O:31][C:32]([CH3:45])([CH3:44])[CH2:33][N:34]1[CH:38]=[C:37]([Sn](C)(C)C)[N:36]=[C:35]1[CH3:43])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>O1CCOCC1.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>[Si:24]([O:31][C:32]([CH3:45])([CH3:44])[CH2:33][N:34]1[CH:38]=[C:37]([C:2]2[CH:23]=[CH:22][C:5]3[C:6]4[N:7]([CH:11]=[C:12]([C:14]5[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=5)[N:13]=4)[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)[N:36]=[C:35]1[CH3:43])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: Cc1nc([Sn](C)(C)C)cn1CC(C)(C)O[Si](C)(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1CC(C)(C)O[Si](C)(C)C(C)(C)C
Temperature: 120 °C
Reaction time: 0.58 h
Yield: 35.6 %

Procedure:
To a mixture of 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (300 mg, 0.8 mmol), Pd(PPh3)4 (93 mg, 0.08 mmol), 1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-2-methyl-4-(trimethylstannyl)-1H-imidazole (690 mg, 1.6 mmol) in dioxane (2 mL) was bubbled with N2 for about 2 min and then stirred at 120° C. for 35 min under the irradiation of microwave. Filtered, concentrated and purified by pre-TLC (pure EtOAc) to give 160 mg of 9-(1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-2-methyl-1H-imidazol-4-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine. Yield=46%. LC-MS: m/z=548 [M+H+]
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:18]([CH3:21])[CH:19]=O)[CH2:5][CH2:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH3:1][O:2][CH2:3][CH:4]([N:18]([CH3:21])[CH3:19])[CH2:5][CH2:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: COCC(CCOc1cccc2ccccc12)N(C)C=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COCC(CCOc1cccc2ccccc12)N(C)C

Procedure:
N-[1-(Methoxymethyl)-3-(1-naphthyloxy)propyl]-N-methylformamide, described in Example 8, is reduced with LiAlH4 in the manner described in Example 4 to give the title compound, nmr (CDCl3) δ2.05 (m, 2H), 2.35 (s, 6H), 3.0 (s, 1H), 3.35 (s, 3H), 3.5 (m, 2H), 4.25 (t, J = 5.5Hz, 2H) and 6.75 - 8.4 (7H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:23]=3)[CH2:12][NH:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][CH:15]=3.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[C:31]([N:13]1[CH2:12][C:11]2[CH:23]=[C:7]([CH:8]=[CH:9][CH:10]=2)[NH:6][C:5]2=[N:21][C:20](=[C:2]([Cl:1])[CH:3]=[N:4]2)[NH:19][C:18]2=[CH:22][C:14]1=[CH:15][CH:16]=[CH:17]2)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Clc1cnc2nc1Nc1cccc(c1)NCc1cccc(c1)N2
Reactant: O=C(Cl)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1Cc2cccc(c2)Nc2ncc(Cl)c(n2)Nc2cccc1c2
Yield: 41.6 %

Procedure:
To a stirring solution of 6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene (20.0 mg, 0.0618 mmol) in N,N-dimethylformamide (0.24 mL) was added triethylamine (17.2 μL), followed by the addition of benzoyl chloride (17.4 mg, 0.12 mmol). The resultant solution was stirred at rt for 30 min. The mixture was quenched with H2O and concentrated. The residue was purified by silica gel column chromatography to give the desired product as an off-white powder (11 mg, 42%). LCMS for C24H19ClN5O (M+H)+: m/z=428.1. 1H NMR (300 MHz, DMSO-d6): δ 9.42 (s, 1H), 9.11 (s, 1H), 8.12 (s, 2H), 7.82 (s, 1H), 7.25 (m, 4H), 7.15 (m, 4H), 7.03 (m, 3H), 4.86 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([C:7]([NH:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)=[O:8])[N:6]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[BrH:1].[NH2:12][CH2:11][CH2:10][NH:9][C:7]([C:5]1[N:6]=[C:2]([Br:1])[S:3][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:8]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1nc(Br)sc1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Br
Product: NCCNC(=O)c1nc(Br)sc1-c1ccccc1
Yield: 184.2 %

Procedure:
0.5 g (1.2 mmol) of t-butyl [2-(2-bromo-5-phenyl-4-thiazolecarboxamido)ethyl]carbamate, 2 ml of trifluoroacetic acid and 10 ml of methylene chloride were heated to reflux for 2 hours and then evaporated. The residue was dissolved in methanol and treated with 1 ml of hydrobromic acid in glacial acetic acid (~30%). Renewed evaporation and recrystallization of the residue from methanol/ether yields 0.45 g (94.2%) of N-(2-aminoethyl)-2-bromo-5-phenyl-4-thiazolecarboxamide hydrobromide as biege crystals, melting point 214°-215° (dec.).
Reaction SMILES: [H-].[Na+].[N+:3]([CH:6]=[C:7]1[NH:11][CH2:10][CH2:9][NH:8]1)([O-:5])=[O:4].[CH2:12](Br)[CH:13]=[CH2:14].S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C)C=O>[N+:3]([CH:6]=[C:7]1[NH:11][CH2:10][CH2:9][N:8]1[CH2:14][CH:13]=[CH2:12])([O-:5])=[O:4]
Reactant: C=CCBr
Reactant: O=[N+]([O-])C=C1NCCN1
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CCNC1=C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31.1 %

Procedure:
To 1.77 grams of a 57% by weight dispersion of sodium hydride in oil in 50 milliliters of dry dimethylformamide was added 5.16 grams of 2-(nitromethylene)imidazolidine. The mixture was cooled with an icebath, stirred and maintained under a nitrogen atmosphere. After 1.5 hours, 5.08 grams of allyl bromide was added. The mixture was stirred at about 10° for an additional hour, then allowed to warm to room temperature and poured into 400 milliliters of saturated aqueous sodium sulfate. The resulting mixture was extracted thrice with 300 milliliter portions of methylene chloride. The combined extract was dried (magnesium sulfate) and the solvent was evaporated. Addition of ether to the residue gave an oily red solid, which on recrystallization from chloroform (charcoal), gave 2.1 grams of 4 as tan crystals, melting point: 97°-98° .
Reaction SMILES: Cl.C([N:9]1[C:18]2[C:13](=[CH:14][C:15]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=2)[N:12]=[C:11](Cl)[C:10]1=[O:36])C1C=CC=CC=1.[OH2:37].[NH2:38][NH2:39]>ClCCl>[CH2:19]([O:37][N:9]1[C:18]2[C:13](=[CH:14][C:15]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=2)[N:12]=[C:11]([NH:38][NH2:39])[C:10]1=[O:36])[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: NN
Reactant: Cc1cn(-c2cc3nc(Cl)c(=O)n(Cc4ccccc4)c3cc2C(F)(F)F)c(-c2ccccc2)n1
Reactant: O
Agent: Cl
Solvent: ClCCl
Product: Cc1cn(-c2cc3nc(NN)c(=O)n(OCc4ccccc4)c3cc2C(F)(F)F)c(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 174.4 %

Procedure:
A mixture of 1-benzyl-3-chloro-6-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7-trifluoromethylquinoxalin-2(1H)-one hydrochloride (2.0 g, 3.6 mmol) and hydrazine hydrate (0.74 ml, 15 mmol) in 40 ml of dichloromethane was stirred at 0° C. for 1 h and evaporated to dryness in vacuo. The residue was triturated with water to give 1.59 g (87%) of the title compound. M.p. 127-130° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([CH:58]=[O:59])=[CH:54][CH:53]=3)[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2].CC(=CC)C.Cl([O-])=[O:79].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]3[CH:53]=[CH:54][C:55]([C:58]([OH:79])=[O:59])=[CH:56][CH:57]=3)[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:69])([CH3:70])[CH3:71])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2]
Reactant: [O-][Cl+][O-]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCc4ccc(C=O)cc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCc4ccc(C(=O)O)cc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(p-formylbenzyloxy)-3"-methoxycyclohexyl)1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (50 mg) in tert-butanol (1.0 mL) was added 2-methyl-2-butene (250 mL) followed by 0.5 mL of an aqueous solution of sodium chlorite (41 mg) and sodium dihydrogen phosphate (48 mg), and the mixture stirred at room temperature. After 1.5 hours, the mixture was concentrated and redissolved in ethyl acetate:hexane (1:1) and washed with water. The organic portion was dried over sodium sulfate, and the concentrate purified by flash chromatography on silica gel (ethyl acetate:hexane (4:1)+1% methanol+0.5% acetic acid) to give the title compound (43 mg). 1H NMR consistent with the desired structure.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:6]=[CH:7][S:8][CH3:9])[C:3](O)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.O>C(OCC)(=O)C>[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:3](=[O:4])[C:2]([CH3:10])([CH3:1])[CH:6]=[CH:7][S:8][CH3:9])=[CH:26][CH:25]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CSC=CC(C)(C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: O
Product: CSC=CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Reaction time: 16 h
Yield: 32.1 %

Procedure:
A solution of 0.5 g of 2,2-dimethyl-4-methylthio-3-butenoic acid in 20 mL of ethyl acetate was treated with 0.6 g of carbonyldiimidazole, and the solution was heated for 10 minutes at reflux. After the solution had cooled, 0.65 g of p-chloroaniline was added and heating continued for 16 hours. The solution was then cooled, poured into water and extracted into ethyl acetate. The organic layer was washed with 50 mL of 1N HCl, dried over MgSO4, and concentrated. The residual solid was recrystallized from CHCl3 /hexane to give 0.27 g of N-(4-chlorophenyl)-2,2-dimethyl-4-(methylthio)-3-butenamide, m.p. 105°-106° C.
Reaction SMILES: [CH2:1]([C:3]([OH:35])([CH2:33][CH3:34])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:30][CH3:31])([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:32])[CH3:2].[CH2:36]([O:38][C:39](=[O:48])[CH2:40][C:41]1[CH:42]=[N:43][C:44](Cl)=[CH:45][CH:46]=1)[CH3:37].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[CH2:36]([O:38][C:39](=[O:48])[CH2:40][C:41]1[CH:42]=[N:43][C:44]([C:18]2[CH:17]=[CH:16][C:15]([C:12]([CH2:30][CH3:31])([C:9]3[CH:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([CH2:33][CH3:34])([OH:35])[CH2:1][CH3:2])=[C:7]([CH3:32])[CH:8]=3)[CH2:13][CH3:14])=[CH:20][CH:19]=2)=[CH:45][CH:46]=1)[CH3:37]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1C)CC
Reactant: CCOC(=O)Cc1ccc(Cl)nc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2ccc(C(CC)(CC)c3ccc(/C=C/C(O)(CC)CC)c(C)c3)cc2)nc1
Temperature: 140 °C
Yield: 73.2 %

Procedure:
A solution of (E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 39-(5); 50.0 mg, 0.10 mmol), (6-chloro-pyridin-3-yl)acetic acid ethyl ester (31.4 mg, 0.15 mmol), tetrakistriphenylphosphine palladium (16.9 mg, 0.0146 mmol) and potassium phosphate (33.4 mg, 0.15 mmol) in N,N-dimethylformamide (0.30 mL) was stirred with microwave heating at 140° C. for 10 minutes. The reaction mixture was filtered through cotton plug, and the residue was purified by silica gel chromatography (30 to 40% ethyl acetate/hexane) to give the title compound (37.6 mg, 69%).