Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C:11](=[O:17])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.[OH-].[Na+].C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-])=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[Cl-].[Mg+2].[Cl-]>CC(O)C>[CH2:2]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:13][CH2:14]2)[C@H:11]([OH:17])[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CN(Cc2ccccc2)CCC12CC2
Agent: Cl
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Solvent: CC(C)O
Product: O[C@@H]1CN(Cc2ccccc2)CCC12CC2
Temperature: 35 °C
Reaction time: 96 h

Procedure:
A mixture of 300 mg of 6-benzyl-6-aza-spiro[2.5]octan-4-one hydrochloride (1.19 mmol, 1 eq.), 1.5 ml of 2-propanol and 28 ml of 30 mM aq. TRIS-HCl buffer (pH 8.1) was heated to 35° C. The pH was re-adjusted to 8.0. The reaction was started by adding □-NAD (1 mg; free acid; Roche Diagnostics Cat. No. 10 004 626) and ketoreductase KRED-NADH-117 (29.3 mg; Codexis [ex. Biocatalytics]). The suspension was stirred at 35° C. keeping the pH constant at 8.0 by the controlled addition (pH-stat) of 1.0 M aq. sodium hydroxide solution. After roughly 80 area % conversion and 1 d, further 2-propanol (0.3 ml), β-NAD (3 mg; free acid; Roche Diagnostics Cat. No. 10 004 626), ketoreductase KRED-NADH-117 (30 mg; Codexis [ex. Biocatalytics]) and magnesium chloride (12.7 mg) were added. After 4 d, 98.5 area % conversion and 5.9 ml consumption of 1.0 M aq. sodium hydroxide solution the reaction mixture was stopped by the addition of NaCl (9 g), EtOAc (30 ml) and filter aid (1 g Dicalite Speedex). The mixture was stirred 30 min. and filtered. The filtrate was extracted 3 times with 30 ml EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the crude product in over 99.9% e.e. Purification by flash chromatography provided the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:9][C:10]1[CH:11]=[C:12](I)[CH:13]=[C:14]([CH3:16])[CH:15]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].CCCCCCCCCCCC>[Cu]I.CC1C=CC=CC=1C>[CH2:1]([O:8][C:12]1[CH:13]=[C:14]([CH3:16])[CH:15]=[C:10]([CH3:9])[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCO
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1C
Solvent: CCCCCCCCCCCC
Product: CCCCCCCOc1cc(C)cc(C)c1
Temperature: 120 °C
Yield: 64 %

Procedure:
A screw cap test tube was charged with n-heptanol (283 μL, 2.00 mmol), 3,5-dimethyliodobenzene (144 μL, 1.00 mmol), CuI (4.75 mg, 0.025 mmol), 1,10-phenanthroline (1.80 mg, 0.01 mmol), Cs2CO3 (977 mg, 3.00 mmol) and o-xylene (1 mL). The test tube was sealed with a screw cap. The reaction mixture was stirred magnetically and heated at 120° C. for 19 hours. The reaction mixture was allowed to reach room temperature. Dodecane (227 μL, 1.00 mmol; internal standard) was added and a GC sample was filtered through Celite and eluted with CH2Cl2. GC analysis revealed 64% yield of the desired product.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[C:25](OC)(OC)(OC)[CH3:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:25][C:26]1[N:14]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:9]2=[N:10][C:11]([CH3:13])=[CH:12][C:7]([NH:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[C:8]2[N:24]=1
Reactant: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Reactant: COC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(CC)Nc1cc(C)nc2c1nc(C)n2-c1c(C)cc(C)cc1C

Procedure:
A mixture of N4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine (250 mg, 0.77 mmol), trimethyl orthoacetate (0.184 g, 1.532 mmol), p-toluenesulfonic acid monohydrate (0.01 g) in toluene was heated at reflux using Dean-Stark apparatus for 3 hours. The mixture was quenched with water, brine, extracted with ethyl acetate. The organic layer was separated, dried (MgSO4) and concentrated to dryness. After purification, the title compound was obtained as a white crystal, mp 101–103° C. Anal. For C22H30N4 calc. C, 75.39; H, 8.63; N, 15.98; found, C, 75.44; H, 8.95; N, 15.95.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][C:18]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=4)=[CH:19][C:14]=3[CH:13]=[C:12]([C:30]([O:32]C)=[O:31])[CH2:11][CH2:10]2)[CH:5]=[N:4]1)[CH3:2].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][C:18]([C:20]4[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=4)=[CH:19][C:14]=3[CH:13]=[C:12]([C:30]([OH:32])=[O:31])[CH2:11][CH2:10]2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cnn(CC)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cnn(CC)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.1 %

Procedure:
To a solution of methyl 1-[(1-ethylpyrazol-4-yl)methyl]-7-(4-propoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (370 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 1 day. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutral, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give 1-[(1-ethylpyrazol-4-yl)methyl]-7-(4-propoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (330 mg) as yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].S(O)(O)(=O)=O.[NH2:17][OH:18].S(=O)(O)[O-].[Na+].[OH-].[Na+]>O>[OH:1][C:2]1[C:9]([OH:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[C:4](=[N:17][OH:18])[NH2:5]
Reactant: N#Cc1ccc(O)c(O)c1O
Reactant: NO
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: NC(=NO)c1ccc(O)c(O)c1O
Temperature: 25 °C
Yield: 9 %

Procedure:
Following the procedure of Example 2, 3.5 g. of 2,3,4-trihydroxybenzonitrile were reacted in 60 ml. of water with 4 g. of hydroxylamine sulfate and 2 g. of sodium bisulfite at pH=8.0 (adjusted by addition of concentrated aqueous sodium hydroxide). The reaction mixture was maintained at ambient temperature for about one hour and was then cooled. 2,3,4-Trihydroxybenzamidoxime precipitated and the precipitate was collected by filtration. The filter cake was dissolved in dilute aqueous hydrochloric acid and the resulting solution filtered through activated charcoal. Evaporation of the volatile constituents from the filtrate under reduced pressure yielded 2,3,4-trihydroxybenzamidoxime as a hydrochloride salt, melting at 207° C. with decomposition after recrystallization from a methanol/ethyl acetate solvent mixture; yield=9%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>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.COCCOC.O>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cncc(Br)c1
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: O
Solvent: COCCOC
Product: Brc1cncc(-c2ccccc2)c1

Procedure:
A mixture of 3,5-dibromopyridine (10.0 g, 42.2 mmol), phenylboronic acid (4.6 g, 38.0 mmol), tetrakis(triphenylphosphine)palladium(0) (1.45 g, 1.25 mmol), potassium carbonate (17.5 g, 127 mmol), water (63 ml) and 1,2-dimethoxyethane (126 ml) was stirred at reflux overnight. Aqueous sodium hydroxide (1 M, 60 ml) was added followed by extraction twice with diethyl ether (100 ml). Chromatography on silica gel with dichloromethane as solvent gave the title compound. Yield 6.1 g, 68%, Mp 42-44° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]1[CH:15]([CH3:16])[C:14](=[CH2:17])[CH2:13][CH2:12][NH:11]1.[CH2:18]([O:22]C=O)CCC>>[CH:18]([N:11]1[CH2:12][CH2:13][C:14](=[CH2:17])[CH:15]([CH3:16])[CH:10]1[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:22]
Reactant: CCCCOC=O
Reactant: C=C1CCNC(Cc2ccccc2OC)C1C
Product: C=C1CCN(C=O)C(Cc2ccccc2OC)C1C

Procedure:
8 g (34 mmol) of 2-(2-methoxyphenyl)methyl-3-methyl-4-methylene-piperidine 16 as base and 30 mL of n-butylformate were used. Yield: 9.1 g (100%) as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C([O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1)C.Cl>C1COCC1.C(OCC)(=O)C.O>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([CH:7]2[CH2:8][C:2]3[S:1][CH:5]=[CH:4][C:3]=3[C:6]2=[O:9])=[O:14])[CH:17]=1
Reactant: O=C1CCc2sccc21
Reactant: CCOC(=O)c1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1cccnc1)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 35 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one (3.34 g, 24.2 mmol) in 40 mL of THF was treated with NaH (60 percent, 1.45 g, 36.25 mmol). After the addition of Nicotinic acid ethyl ester, the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (80 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(Pyridine-3-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.23 g, 5 mmol) as red solid in 35% yield.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:20]1([O:26][C:27]2[CH:28]=[C:29]([CH2:33]Br)[CH:30]=[CH:31][CH:32]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:12](=[O:19])[CH:13]([CH2:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([O:26][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:28]=3)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)CC(=O)C1(c2ccc(Cl)cc2)CC1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1cccc(Oc2ccccc2)c1)C(=O)C1(c2ccc(Cl)cc2)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A mixture of sodium (0.31 g, 13.5 mmol) in ethanol (90 mL) is stirred at room temperature until the sodium dissolves. The resultant solution is heated to 70° C., treated dropwise with a solution of ethyl 1-(p-chlorophenyl)-β-oxocyclopropanepropionate (3.4 g, 12.8 mmol) in ethanol, stirred at 70° C. for one hour, treated dropwise with a solution of α-bromo-m-tolyl phenyl ether (4.0 g, 15.2 mmol) in ethanol, stirred at reflux overnight, stirred at room temperature for two days, and concentrated in vacuo to obtain a residue. A solution of the residue in ethyl acetate is washed sequentially with water, 10% sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an oil. Chromatography of the oil using silica gel and a 19:1 hexanes/ethyl acetate solution gives the title product as a colorless oil (5.24 g, 92%) which is identified by NMR spectral analysis.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]2[CH3:24])[C:5]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.[F:25][C:26]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][C:27]=1[NH2:28]>>[NH2:28][C:27]1[CH:29]=[CH:30][C:31]([C:2]2[N:3]=[C:4]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]3[CH3:24])[C:5]3[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=3[N:7]=2)=[CH:32][C:26]=1[F:25]
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C(=O)OC(C)(C)C)C2
Product: C[C@H]1COCCN1c1nc(-c2ccc(N)c(F)c2)nc2c1CN(C(=O)OC(C)(C)C)C2
Yield: 22 %

Procedure:
Method as intermediate 5 using (S)-tert-butyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 1) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as starting materials. The crude reaction mixture was then partitioned between water and EtOAc, the phases separated and the organic layer washed with brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (0-80% EtOAc/Petroleum Ether 40-60) to yield a white solid (660 mg, 1.54 mmol, 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1>CO.[Ni]>[NH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc(C(F)(F)F)c1
Agent: [Ni]
Solvent: CO
Product: Nc1cc(Cl)cc(C(F)(F)F)c1

Procedure:
92 g (0.408 mol) of 5-chloro-3-trifluoromethyl-nitrobenzene in 1 l of methanol are hydrogenated in the presence of 10.17 g of Raney nickel. The reaction mixture is filtered through Celite/activated carbon and the residue washed with methanol. Concentration of the filtrate by evaporation yields the oily 5-amino-3chlorobenzotrifluoride; 1H-NMR (DMSO-d6) δ 6.80 (m, 3H), 5.92 (s, H2N).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=[O:8].[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[C:9]([C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=[O:8])#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C#CCCCCCC
Reactant: O=Cc1occc1Br
Product: CCCCCCC#Cc1ccoc1C=O
Yield: 71.8 %

Procedure:
Reaction of 3-bromofuran-2-carboxaldehyde (4.71 g, 27 mmole from Example 5) with 1-octyne (3 g, 27 mmole) as described in Example 8 afforded 3.96 g (72%) of the title compound, as an oil, after chromatography on silica (DCM:Hexane 1:2), νmax (film) 2950, 2930, 2850, 2230, 1680, 1570, 1420, 1360, 1275, 890, 775 cm-1 ; δ(CDCl3) 0.92(3H, distorted t), 1.42(8H, complex m), 2.48(2H, t, J=6.5 Hz), 6.59(1H, d, J=3 Hz), 7.62(1H, d, J=3 Hz), 9.82(1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:16][C:15]=3[CH3:29])[N:10]=2)[CH:5]=[N:6][C:7]=1Cl.[CH3:30][CH:31]([NH2:33])[CH3:32]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[CH:16][C:15]=3[CH3:29])[N:10]=2)[CH:5]=[N:6][C:7]=1[NH:33][CH:31]([CH3:32])[CH3:30]
Reactant: CC(C)N
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1noc(-c2cnc(Cl)c(Cl)c2)n1
Solvent: C1CCOC1
Product: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1noc(-c2cnc(NC(C)C)c(Cl)c2)n1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A solution of 31 mg (0.07 mmol) of tert-butyl 3-(4-(5-(5,6-dichloropyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)propanoate (from EXAMPLE 15, Step A) and 120 μL (1.4 mmol) of 2-propylamine in 5.0 mL of THF was heated to 100° C. in a sealed tube overnight. The mixture was cooled to rt and concentrated. Chromatography on a Biotage 40S cartridge using 1:9 v/v Et2O/hexanes as the eluant gave 28 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.32 (d, J=6.4, 6H), 1.43 (s, 9H), 2.57 (t, J=7.7, 2H), 2.64 (s, 3H), 2.94 (t, J=7.7, 2H), 4.41 (m, 1H), 5.32 (d, J=7.5, 1H), 7.16-7.17 (m, 2H), 7.99 (d, J=8.5, 1H), 8.18 (d, J=1.8, 1H), 8.85 (d, J=1.8, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([NH2:13])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4].[F:14][C:15]([F:27])([F:26])[C:16]1[CH:21]=[CH:20][C:19]([S:22](N)(=[O:24])=[O:23])=[CH:18][CH:17]=1.ClC1C=CC(S(N[C@H]2CC[C@H](C(OC)=O)CC2)(=O)=O)=CC=1[N+]([O-])=O>>[F:27][C:15]([F:14])([F:26])[C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:13][C:8]23[CH2:9][CH2:10][C:5]([C:3]([O:2][CH3:1])=[O:4])([CH2:12][CH2:11]2)[CH2:6][CH2:7]3)(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: COC(=O)C12CCC(N)(CC1)CC2
Reactant: NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Product: COC(=O)C12CCC(NS(=O)(=O)c3ccc(C(F)(F)F)cc3)(CC1)CC2

Procedure:
Methyl 4-(4-(trifluoromethyl)phenylsulfonamido)bicyclo[2.2.2]octane-1-carboxylate was prepared from 4-aminobicyclo[2.2.2]octane-1-carboxylic acid methyl ester and 4-trifluoromethylbenzene sulfonamide using a method analogous to the method used to prepare Intermediate 1.
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:13]([O:23][CH2:24][CH3:25])(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH2:24]([O:23][C:13](=[O:22])[CH:14]=[C:15]([C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:25]
Reactant: COc1ccc2[nH]ccc2c1Br
Reactant: CCOC(=O)C=Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(c1ccccc1)c1c(OC)ccc2[nH]ccc12
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of 4-bromo-5-methoxyindole XLVI (104 mg, 0.46 mmol), ethyl cinnamate (162 mg, 0.92 mmol), tetra-butylammonium bromide (29.6 mg, 0.092 mmol), TEA (128 μl, 0.092 mmol) and palladium-dichloro-[bis(tri-ortho-tolyl)phosphine] (18 mg, 0.023 mmol) in DMF (2 ml) was stirred at 110° C. for 3 hours. The reaction mixture was cooled to room temperature and partitioned between brine and EtOAc. The organic layers were combined, dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording 3-(5-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester XLVIII (37 mg, impure).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25].C([O-])([O-])=O.[K+].[K+].N>CO.C(Cl)Cl.CN(C=O)C>[CH3:3][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][CH2:21][N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)[CH3:1]
Reactant: CCN(CCO)CCCCl
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CCN(CCO)CCCOc1ccc(C2(CN(C)C)CCOCC2)cc1
Yield: 19.3 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500 mg, 2.13 mmol), 2-[(3-chloro-propyl)-ethyl-amino]-ethanol (353 mg, 2,13 mmol), DMF (10 ml) and K2CO3 (1.18 g, 8.52 mmol) were reacted together according to general procedure B. The isolated material was subjected to chromatography on silica, eluant 95:4:1 (DCM:MeOH:NH3) to give the title compound as a white solid (150 mg, 19%). 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.86 (d, 2H), 4.00 (t, 2H), 3.75 (dt, 2H), 3.60-3.49 (m, 4H), 2.68 (t, 2H), 2.62 (t, 2H), 2.59 (q, 2H), 2.40 (s, 2H), 2.14-1.82 (m, 6H), 1.97 (s, 6H), 1.62 (br s, 1H), 1.03 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]3[O:23][C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[N:26]=3)[S:21][C:14]=12>>[O:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[C:20]1[S:21][C:14]2[C:15](=[N:16][CH:17]=[CH:18][C:13]=2[NH:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2]([CH3:1])=[CH:10]3)[CH:19]=1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: Clc1ccnc2cc(-c3nc4ccccc4o3)sc12
Product: Cc1cc2cc(Nc3ccnc4cc(-c5nc6ccccc6o5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-5-aminoindole and 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-benzooxazole by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.18 (d, 1H), 8.10 (s, 1H), 7.70 (m, 2H), 7.40 (m, 4H), 6.98 (d, 1H), 6.68 (d, 1H), 6.14 (s, 1H), 2.43 (s, 3H); RP18-HPLC RT: 6.13 minutes; API MS 397 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]1([CH:12]=[CH:11][C:9]([OH:10])=[CH:8][CH:7]=1)[OH:6]>>[C:1]([O:6][C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Oc1ccc(O)cc1
Product: CC(=O)Oc1ccc(O)cc1

Procedure:
Acetyl chloride is reacted with hydroquinone to give 4-acetoxy phenol expressed by the formula (16) shown below.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([S:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:8])=[O:7])=[N:2]1.[CH2:16]([N:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17].Cl>N1C=CC=CC=1>[CH2:16]([N:18]([CH2:22][CH3:23])[C:19]([N:1]1[CH:5]=[N:4][C:3]([S:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:7])=[O:8])=[N:2]1)=[O:20])[CH3:17]
Reactant: O=S(=O)(Oc1ccccc1)c1nc[nH]n1
Reactant: CCN(CC)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCN(CC)C(=O)n1cnc(S(=O)(=O)Oc2ccccc2)n1

Procedure:
To a flask was added 9.76 g of phenyl 1,2,4-triazole-3sulfonate and 40 ml of dry pyridine. The mixture was stirred under nitrogen until a solution became apparent. Diethylcarbamoyl chloride, 5.6 ml, was then added and the resulting mixture stirred under nitrogen at room temperature for 16 hours. The mixture was then poured into 100 ml of 2N hydrochloric acid and extracted twice with 100 ml portions of ethyl acetate. The ethyl acetate solution was dried using sodium sulfate, filtered and concentrated to yield 11.12 g of the desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](C=O)=[CH:5][CH:4]=1.OO.[OH:13]S(O)(=O)=O.[O-]S([O-])=O.[Na+].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([OH:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COc1ccc(O)cc1

Procedure:
To a solution of 13.6 g 4-methoxybenzaldehyde and 1.1 equivalents 50 percent H2O2 in 55 ml methanol at about 20° C. is added 0.10 equivalent of 98 percent H2SO4. The mixture is refluxed for about 1.5 hours, then Na2SO3 is added to destroy excess H2O2. Then, NaHCO3 is added to neutralize any acid. The solvent is removed under reduced pressure. The resulting solid is taken up in about 50 ml CH2Cl2, is dried over Na2SO4, and is filtered. The sol-vent is removed under reduced pressure from the filtrate giving approximately a 94 mole percent yield of 4-methoxyphenol as is determined by nuclear magnetic resonance and gas chromatography.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=O)=[C:4]([F:24])[CH:3]=1.P(Cl)(Cl)([Cl:27])=O>N1C=CC=CC=1>[Br:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]2[Cl:27])=[C:4]([F:24])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Br
Solvent: c1ccncc1
Product: CC(C)Oc1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Br

Procedure:
using 3-(4-bromo-2-fluoro-5-isopropoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with phosphorus oxychloride and pyridine there is obtained 1-(4-bromo-2-fluoro-5-isopropoxyphenyl)-2-chloro-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 102° C.;