Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[O:12][CH:13]=2)=[C:5]([O:21][CH3:22])[CH:4]=1.[OH:23][C:24]1[C:28]([CH:29]=[O:30])=[CH:27][N:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]=1.CN(C)C=O.[H-].[Na+]>O>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:11]1[O:12][CH:13]=[C:9]([CH2:8][O:7][C:6]2[CH:19]=[CH:20][C:3]([CH2:2][O:23][C:24]3[C:28]([CH:29]=[O:30])=[CH:27][N:26]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:25]=3)=[CH:4][C:5]=2[O:21][CH3:22])[N:10]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: COc1cc(CCl)ccc1OCc1coc(-c2ccco2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1coc(-c2ccco2)n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-1,3-oxazole (0.80 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.45 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.10 g) at room temperature, and the mixture was stirred at 90° C. for 2 hrs. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration to give 3-[(4-{[2-(2-furyl)-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde as pale-yellow crystals (0.93 g, yield 82%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 162-163° C.
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[CH3:9][C:10]1[N:15]=[C:14]([NH:16][C:17](=[S:19])[S-:18])[CH:13]=[CH:12][CH:11]=1.C([NH+](CC)CC)C.C(OC(C)C)(C)C>C(#N)C>[CH3:9][C:10]1[N:15]=[C:14]([NH:16][C:17](=[S:18])[S:19][CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: Cc1cccc(NC(=S)[S-])n1
Agent: CC[NH+](CC)CC
Solvent: CC(C)OC(C)C
Solvent: CC#N
Product: Cc1cccc(NC(=S)SCC(=O)C(C)(C)C)n1
Temperature: 2 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
1-Bromo-3,3-dimethylbutan-2-one (40.0 g) is added to a suspension of triethylammonium (6-methylpyrid-2-yl)dithiocarbamate (64.0 g) in anhydrous acetonitrile (600 cc) at a maximum temperature of 20° C. The reaction is continued for 2 hours at 20° C. The insoluble hydrobromide of triethylamine is removed by filtration and washed with acetonitrile (50 cc). The organic phases are combined and evaporated under reduced pressure (20 mm.Hg) at 45° C. The residual oil is treated with diethyl ether (1200 cc). After 1 hour at 20° C., the ethereal solution is filtered, washed twice with distilled water (total 400 cc), dried over sodium sulphate and evaporated. The product obtained (60.0 g) is dissolved in boiling diisopropyl ether (870 cc) and the boiling solution is filtered. After 1 hour's cooling at 2° C., the resulting crystals are filtered off, washed twice with ice-cold diisopropyl ether (total 100 cc) and dried under reduced pressure (0.1 mm.Hg) at 40° C. to give 3,3-dimethyl-2-oxobutyl (6-methylpyrid-2-yl)dithiocarbamate (44.1 g) melting at 80° C.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][C:5]=1[CH3:15])([O-])=O.[Cl-].[Cl-].[Ca+2]>C(O)C.O.[Zn]>[CH3:15][C:5]1[CH:6]=[C:7]([C:11]([CH3:13])([CH3:12])[CH3:14])[CH:8]=[C:9]([CH3:10])[C:4]=1[NH2:1]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1[N+](=O)[O-]
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(C)(C)C)cc(C)c1N
Temperature: 65 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
Water, 20 mL, was added to a mixture of 12.0 g (58.0 mmol) of 1-nitro-4-tert-butyl-2,6-dimethylbenzene dissolved in 160 mL of ethanol. To the stirring solution of 1-nitro-4-tert-butyl-2,6-dimethylbenzene was added CaCl2, 4.8 g (43.2 mmol), dissolved in 20 mL of water, followed by the addition of zinc powder, 50.0 g (76.5 mmol). The reaction was stirred overnight at 65° C., then cooled to ambient temperature and filtered. The filtrate was extracted three times with ether, and the organic layer was dried over MgSO4. Removal of the solvent gave 9.58 g (93%) of a brown oil. 1H NMR (300 MHz, CDCl3): δ=6.90, s, 2H, 3.40, broad singlet, 2H, 2.11, s, 6H, 1.21, s, 9H.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[N:6]2[CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1.[CH2:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:31].C(N(CC)CC)C>C(O)C>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:5]1[N:6]([CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]2)[C:7]2[C:3]([N:4]=1)=[C:2]([N:35]1[CH2:36][CH2:37][N:32]([CH2:30][CH3:31])[CH2:33][CH2:34]1)[N:10]=[C:9]([CH3:11])[N:8]=2
Reactant: CCN1CCNCC1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3Cl)n(C3CN(C(=O)OC(C)(C)C)C3)c2n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCN1CCN(c2nc(C)nc3c2nc(-c2ccccc2Cl)n3C2CN(C(=O)OC(C)(C)C)C2)CC1
Yield: 48.8 %

Procedure:
Heat a solution of tert-butyl 3-(6-chloro-8-(2-chlorophenyl)-2-methyl-9H-purin-9-yl)azetidine-1-carboxylate (0.012 mol, 5.5 g), N-ethyl piperazine (0.013 mol, 1.59 g, 1.1 equiv.), and triethylamine (0.013 mol, 1.41 g, 1.1 equiv.) in ethanol (25.0 mL) at 90° C. for 16 hours. Concentrate the reaction mixture under reduced pressure. Dissolve the residue in dry dichloromethane. Wash with saturated sodium bicarbonate solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give the residue. Purify the residue by silica gel chromatography eluting with dichloromethane:methanol 98:2 to give tert-butyl 3-(8-(2-chlorophenyl)-6-(4-ethylpiperazin-1-yl)-2-methyl-9H-purin-9-yl)azetidine-1-carboxylate (3.0 g). MS (m/z): 512.31 (M+1).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>C(Cl)Cl>[Br:15][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=C1OCc2cc(CCO)ccc21
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1OCc2cc(CCBr)ccc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-(2-hydroxyethyl)-2-benzofuran-1(3H)-one (1.2 g, 6.8 mmol) in DCM at 0° C. was added carbon tetrabromide (2.3 g, 6.8 mmol), triphenylphosphine (1.8 g, 6.8 mmol), and imidazole (0.46 g, 6.8 mmol). The mixture was allowed to stir at 0° C. for 5 minutes, and then allowed to warm to RT and stir for 1.5 hours. The crude was concentrated and purified by silica gel chromatography (43% EtOAc with Hexanes) to obtain 5-(2-Bromoethyl)-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 241/243 (M+1)+.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12](I)[CH:11]=1>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:12]=2[CH:11]=1
Reactant: C#Cc1ccccc1
Reactant: Oc1ccc(Cl)cc1I
Product: Clc1ccc2oc(-c3ccccc3)cc2c1

Procedure:
The general procedure was used to convert phenylacetylene and 4-chloro-2-iodophenol to the title product. Purification by flash chromatography (10% CH2Cl2 in hexanes as the eluent) gave the analytically pure product as a white solid (411 mg, 90% yield). 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=6.97, 2H), 7.52 (d, J=2.26, 1H), 7.46-7.35 (m, 4H), 7.21 (dd, J=6.59, 1H), 6.93 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 157.36, 153.22, 130.56, 129.93, 128.98, 128.84, 128.46, 125.03, 124.37, 120.40, 112.10, 100.78. Anal. Calcd. for C14H9ClO: C, 73.53; H, 3.97; Cl, 15.50. Found C, 73.31; H, 3.99; Cl, 15.68. m.p.: 155.5-157° C. (lit., 10156° C.).
Reaction SMILES: [N:1]([CH:4]([CH3:6])[CH3:5])=[C:2]=[O:3].[Br:7][C:8]1[N:12]2[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:15]=[CH:16][C:11]2=[N:10][CH:9]=1>ClCCl>[Br:7][C:8]1[N:12]2[N:13]=[C:14]([N:17]3[CH2:18][CH2:19][N:20]([C:2]([NH:1][CH:4]([CH3:6])[CH3:5])=[O:3])[CH2:21][CH2:22]3)[CH:15]=[CH:16][C:11]2=[N:10][CH:9]=1
Reactant: Brc1cnc2ccc(N3CCNCC3)nn12
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: CC(C)NC(=O)N1CCN(c2ccc3ncc(Br)n3n2)CC1
Reaction time: 17 h
Yield: 109.3 %

Procedure:
2-Isocyanatopropane [1795-48-8] (120 μL, 1.2 mmol) was added, via syringe, to a stirred, ambient temperature, clear, colorless solution of 3-bromo-6-piperazin-1-yl-imidazo[1,2-b]pyridazine (334.6 mg, 1.2 mmol) in dichloromethane (20 mL). The solution was allowed to proceed for 17 h then evaporated to dryness to afford 481.5 mg of light yellow solid foam. LRMS (ESI) m/z 367.0/369.0 [(M+H)]+, calc'd for C14H19BrN6O: 367.25.
Reaction SMILES: Cl[C:2]([F:26])([F:25])[C:3]1[N:8]=[C:7]([CH3:9])[C:6]([C:10]([C:12]2[C:17](=[O:18])[CH2:16][CH2:15][C:14]([CH3:23])([C:19]([O:21][CH3:22])=[O:20])[C:13]=2[OH:24])=[O:11])=[CH:5][CH:4]=1.C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[F:26][CH:2]([F:25])[C:3]1[N:8]=[C:7]([CH3:9])[C:6]([C:10]([C:12]2[C:17](=[O:18])[CH2:16][CH2:15][C:14]([CH3:23])([C:19]([O:21][CH3:22])=[O:20])[C:13]=2[OH:24])=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)C1(C)CCC(=O)C(C(=O)c2ccc(C(F)(F)Cl)nc2C)=C1O
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C1(C)CCC(=O)C(C(=O)c2ccc(C(F)F)nc2C)=C1O
Yield: 76.8 %

Procedure:
200 mg (0.516 mmol) of methyl 3-[6-(chlorodifluoromethyl)-2-methylpyridine-3-carbonyl]-2-hydroxy-1-methyl-4-oxocyclohex-2-enecarboxylate (compound A94-B34) is heated for 3 hours at a temperature of 120° C. in 8 ml of toluene in the presence of 0.18 ml (0.62 mmol) tris(trimethylsilyl)silane. The viscous residue which remains is chromatographed on silica gel. The pale yellow viscous oil which is obtained by eluting with a mixture of toluene, ethyl alcohol, dioxane, triethylamine and water (100:40:20:20:5 by volume) is dissolved in dichloromethane and washed in succession with aqueous hydrochloric acid and water. Evaporation of the organic solution which has been dried with Na2SO4 yields 140 mg (73%) of pure methyl 3-(6-difluoromethyl-2-methylpyridine-3-carbonyl)-2-hydroxy-1-methyl-4-oxocyclohex-2-enecarboxylate in the form of a pale yellow oil. 1H-NMR (CDCl3): 1.28, s, 3H; 1.79-1.97, m, 1H; 2.39-2.46, m, 1H; 2.43, s, 3H; 2.69, dt (J, 19.2 and 4.8 Hz), 1H; 2.82-2.92, m, 1H; 3.67, s, 3H; 6.55, t, (J, 55.5 Hz), 1H; 7.43, d (J, 7.8 Hz), 1H; 7.49, d (J, 7.8 Hz), 1H; 17.20 ppm, brs, 1H.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][CH2:12]Cl.[Si:14]([O:31][CH2:32][CH2:33][C@@H:34]([OH:55])[C@H:35]([C:46]1[CH:51]=[C:50]([F:52])[C:49]([F:53])=[C:48]([F:54])[CH:47]=1)[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCCl>[Si:14]([O:31][CH2:32][CH2:33][C@@H:34]([O:55][CH2:10][O:11][CH3:12])[C@H:35]([C:46]1[CH:51]=[C:50]([F:52])[C:49]([F:53])=[C:48]([F:54])[CH:47]=1)[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:37])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](OCC[C@@H](O)[C@@H](C(=O)OCc1ccccc1)c1cc(F)c(F)c(F)c1)(c1ccccc1)c1ccccc1
Reactant: COCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCO[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H](C(=O)OCc1ccccc1)c1cc(F)c(F)c(F)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
IPEA (0.742 mL) and chloromethyl methyl ether (0.324 mL) were added to a solution of benzyl (2S,3R)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluorophenyl)pentanoate (840 mg) in 1,2-dichloroethane (20 mL) at 0° C. The reaction solution was stirred at 60° C. for 4 hours and then left to cool to room temperature and concentrated under reduced pressure. Ethyl acetate and a saturated ammonium chloride solution were added to the residue, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 875 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH:5]([C:10]2[CH:11]=[C:12]([CH:18]=[C:19]([F:21])[CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([F:9])([CH3:8])[CH3:7])[CH2:2]1.Br[CH:23]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28].CCN(C(C)C)C(C)C>C(#N)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:23]([C:24]2[CH:31]=[CH:30][CH:29]=[C:26]([C:27]#[N:28])[CH:25]=2)[N:1]2[CH2:4][CH:3]([CH:5]([C:10]3[CH:11]=[C:12]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([F:9])([CH3:8])[CH3:7])[CH2:2]2)=[CH:33][CH:34]=1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Reactant: CCOC(=O)c1cc(F)cc(C(C2CNC2)C(C)(C)F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(F)cc(C(C2CN(C(c3ccc(Cl)cc3)c3cccc(C#N)c3)C2)C(C)(C)F)c1

Procedure:
The mixture of 4.90 g (16.40 mmol) of ethyl 3-(1-azetidin-3-yl-2-fluoro-2-methylpropyl)-5-fluorobenzoate, 8.17 g of 3-[bromo(4-chlorophenyl)methyl]benzonitrile, 6 mL(34.36 mmol) of DIEA in 40 mL of acetonitrile was refluxed for 4 h, then concentrated in vacuo. The mixture was poured into 150 mL of CH2Cl2 and 30 mL of aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated. Two pairs of racemic compounds were separated by silica gel chromatography. Single diastereomers were separated by a chiral AD column; Mass Spectrum: m/e=523 (M+1, 35Cl), 525 (M+1, 37Cl).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][CH2:10][C:11](=O)[CH2:12]Cl>CCO>[Cl:9][CH2:10][C:11]1[N:8]=[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]2[CH:12]=1
Reactant: O=C(CCl)CCl
Reactant: Nc1ccc(F)cn1
Solvent: CCO
Product: Fc1ccc2nc(CCl)cn2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
According to the general protocol described in J. Heterocyclic. Chem., 1988, 25, 129-137, to solution of 5-fluoropyridin-2-amine (1.80 g, 16 mmol) in EtOH (24 mL) was added 1,3-dichloropropan-2-one (2.03 g, 16 mmol) and the resulting mixture was stirred overnight at 80° C. The solvent was evaporated, and the residue was dissolved in a minimum volume of water. The solution was neutralized (pH=8) with saturated NaHCO3. The aqueous layer was extracted with AcOEt and the organic layer was washed with saturated NaCl. The solvent was evaporated and the crude product was purified by chromatography (prepacked 25 g silicagel column, DCM as eluent) to afford 1.7 g of 2-(chloromethyl)-6-fluoro-imidazo[1,2-a]pyridine (Yield: 57%) as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([CH2:11][CH2:12][CH:13]1[CH2:15][O:14]1)[C:7]([CH3:16])=[CH:6][CH:5]=2.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[N:27]1[CH2:34][C@H:33]2[NH:35][CH2:36][C@@H:28]1[CH2:29][CH:30]=[CH:31][CH2:32]2.CCN(C(C)C)C(C)C>C(O)C>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([CH2:11][CH2:12][CH:13]([OH:14])[CH2:15][N:35]1[CH2:36][CH:28]3[N:27]([C:18]4[CH:19]=[CH:20][C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH:17]=4)[CH2:34][CH:33]1[CH2:32][CH:31]=[CH:30][CH2:29]3)[C:7]([CH3:16])=[CH:6][CH:5]=2
Reactant: Cc1cc2c(CCC3CO3)c(C)ccc2[nH]1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc2c(CCC(O)CN3CC4CC=CCC3CN4c3ccc4ccccc4c3)c(C)ccc2[nH]1

Procedure:
2,5-Dimethyl-4-(2-oxiranyl-ethyl)-1H-indole (50 mg, 0.23 mmol), Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (45 mg, 0.17 mmol), DIPEA (0.1 mL, 0.55 mmol), ethanol (3 mL) were heated for 900 sec. at 120° C. in a μW reaction tube. The solvent was evaporated under reduced pressure to yield a crude solid that was purified with flash chromatography gradient [20% Ethyl acetate/heptane to 100% Ethyl acetate] to yield the title compound as a residue.
Reaction SMILES: [F:1][CH:2]([F:29])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([OH:27])[CH:20]=2)[O:17][CH:18]=1.Br[CH2:31][CH2:32][CH:33]=[CH2:34]>>[CH2:34]([O:27][C:21]1[CH:20]=[C:19]([C:16]2[O:17][CH:18]=[C:14]([CH2:13][CH2:12][C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3][CH:2]([F:1])[F:29])=[O:28])[N:15]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26])[CH2:33][CH:32]=[CH2:31]
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3OCC(F)F)co2)cc1O
Reactant: C=CCCBr
Product: C=CCCOc1cc(-c2nc(CCC(=O)c3ccccc3OCC(F)F)co2)ccc1OC

Procedure:
Using the compound obtained in Example 272 and 4-bromo-1-butene, white powdery 3-[2-(3-but-3-enyloxy-4-methoxyphenyl)oxazol-4-yl]-1-[2-(2,2-difluoroethoxy)phenyl]propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: C([O:3][CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6](OCC)=O)C.[NH2:16][NH2:17].[OH-].[Na+]>CCO>[OH:3][C:4]1[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][NH:17][N:16]=1
Reactant: NN
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1c[nH]nc1O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of diethyl (ethoxymethylene)malonate (20 g, 92.5 mmol) in 200 mL of EtOH is treated with hydrazine (2.9 mL, 92.5 mmol) by dropwise addition. After 10 min, 100 mL of 1 N NaOH is added (slightly exothermic), and the reaction mixture is stirred for a further 30 min. The EtOH is removed in vacuo, and the aqueous solution is diluted with a little more water and extracted with EtOAc. The aqueous phase is cooled to 0° C. and acidified to pH=5 with conc. HCl. The resulting precipitate is collected by vacuum filtration and dried in vacuo to give the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Na+].[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Si:28]([CH3:32])([CH3:31])[CH2:29][OH:30])=[CH:24][CH:23]=1)[CH3:20].Cl>C1(C)C=CC=CC=1>[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Si:28]([CH3:31])([CH3:32])[CH2:29][O:30][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:4]=2)=[CH:24][CH:23]=1)[CH3:20]
Reactant: CCOc1ccc([Si](C)(C)CO)cc1
Reactant: Fc1ccc(CCl)cc1Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOc1ccc([Si](C)(C)COCc2ccc(F)c(Oc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.0 g (0.0042 mole) of (4-fluoro3-phenoxyphenyl)methyl chloride in 5 mL of dry toluene was added 0.15 g (0.0063 mole) of sodium hydride. Dropwise a solution of 0.98 g (0.0047 mole) of 2-(4-ethoxyphenyl)-2-methyl-2-silapropanol in 5 mL of dry toluene was added to the reaction mixture. The reaction mixture was stirred at room temperature for one hour and then was heated at reflux for three hours. Aqueous 10% hydrochloric acid was added to the reaction mixture which was then extracted twice with diethyl ether. The combined extracts were dried, filtered through silica gel, and the solvent was evaporated under reduced pressure, leaving a residue. This residue was subjected to Kugelrohr distillation to remove remaining starting materials. The residue from this distillation was separated into two major fractions using a Chromatotron (eluant=ethyl acetate/ hexane (2:98). The smaller fraction, weighing 0.19 g, was determined to be (4-fluoro-3-phenoxyphenyl)methyl 2-(4-ethoxyphenyl)-2-methyl-2-silapropyl ether from its nmr spectrum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7]([C:13](OC)=[O:14])=[C:6]2[C:17]([O:19]C)=O.O.[NH2:22][NH2:23]>C(O)C>[Cl:12][C:11]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[C:6]3[C:17](=[O:19])[N:23]=[N:22][C:13](=[O:14])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: NN
Reactant: COC(=O)c1[nH]c2cc(Cl)c(OC)cc2c1C(=O)OC
Solvent: CCO
Solvent: O
Product: COc1cc2c3c([nH]c2cc1Cl)C(=O)N=NC3=O
Temperature: 25 °C
Yield: 30.3 %

Procedure:
To a solution of ethanol (15 ml) and dimethyl 5-methoxy-6-chloroindole-2,3-dicarboxylate (0.67 g, 2.30 mM), was added hydrazine hydrate (3.45 g, 0.69 mM). The resulting heterogeneous mixture was refluxed for 5 hr and then cooled to room temperature. The ethanol was removed under reduced pressure, acetic acid (15 ml) was added, and the resulting mixture refluxed for 2 hr. The reaction was cooled to room temperature, filtered, and dried. This afforded the titled compound as a white solid (0.18 g, 30%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][C@H:9]([C:11]2[CH:12]=[C:13]([C:17](O)=[O:18])[CH:14]=[CH:15][CH:16]=2)[CH3:10])[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][OH:31])=[CH:24][CH:23]=2)[C:3]=1[C:32]#[N:33].[CH3:34][N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH:9]([C:11]2[CH:12]=[C:13]([C:17]([NH:35][CH3:34])=[O:18])[CH:14]=[CH:15][CH:16]=2)[CH3:10])[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][OH:31])=[CH:24][CH:23]=2)[C:3]=1[C:32]#[N:33]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[C@H](Sc1nc(N)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N)c1cccc(C(=O)O)c1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc(C(C)Sc2nc(N)c(C#N)c(-c3ccc(OCCO)cc3)c2C#N)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
33 mg (0.072 mmol) of rac-3-[(1S)-1-({6-amino-3,5-dicyano-4-[4-(2-hydroxyethoxy)phenyl]-pyridin-2yl}sulfanyl)ethyl]benzenecarboxylic acid (Example 16) were initially charged in 0.66 ml of DMF. At 0° C., 54.5 mg (0.143 mmol) of HATU were added, and the reaction solution was stirred at 0° C. for 20 min. After addition of 6.7 mg (0.215 mmol) of methylamine (2N in tetrahydrofuran) and 18.5 mg (0.143 mmol) of N,N-diisopropylethylamine, the mixture was stirred at RT overnight. The reaction solution was purified by preparative HPLC (Chromasil, water/acetonitrile).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][N:3]=1.[C:10](Br)(Br)([Br:12])[Br:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:11][C:10]([Br:12])=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[N:3][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(C=O)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(C=C(Br)Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
6-Methylnicotinaldehyde (1.0 g, 0.00826 mol) was dissolved in DCM (100 mL). Carbon tetrabromide (5.48 g, 0.0165 mol) and triphenylphosphine (8.66 g, 0.033 mol) was added to the solution followed by stirring at RT for 3 h. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified through column chromatography (8% EtOAc:hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to provide the desired compound as a yellow colored oil (1.6 g, 70% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11](Br)[CH2:12][CH3:13])=[CH:5]2.[N-:15]=[N+:16]=[N-:17].[Na+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]([N:15]=[N+:16]=[N-:17])[CH2:12][CH3:13])=[CH:5]2
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(Br)c1cc2cc(F)ccc2[nH]1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(N=[N+]=[N-])c1cc2cc(F)ccc2[nH]1
Temperature: 60 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
A solution of 5-fluoro-indolyl-3-propylbromide (10.67 g, 41 mmol) and sodium azide (3.9 g, 60 mmol) in anhydrous N,N-dimethylformamide (60 ml) was allowed to stir at 60° C. for 18 hours. The mixture was poured into water (150 ml), extracted with methylene chloride (3×150 ml), washed with water (3×100 ml). The organic layer was dried over sodium sulfate, filtered and the solvent was removed under vacuurml Chromatography (30% ethyl acetate-hexanes) afforded 8.10 g (89%) of product as a clear oil.