Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]1[CH2:8][S:7][C:6](=[S:9])[N:5]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[BH4-].[K+].Cl>CO.O>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:5][C:6](=[S:9])[S:7][CH2:8][CH2:4][OH:3]
Reactant: OC1CSC(=S)N1c1ccccn1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: OCCSC(=S)Nc1ccccn1
Reaction time: 1 h
Yield: 66.1 %

Procedure:
A 4 N aqueous solution of sodium hydroxide (150 cc) is added, at a maximum of 20° C., to a suspension of 4-hydroxy-3-(pyrid-2-yl)-thiazolidine-2-thione (127.5 g) in methanol (900 cc), and a solution of potassium borohydride (33.0 g) in water (150 cc) is then added at a maximum of 20° C. The reaction is allowed to proceed for 1 hour at 20° C. A 4 N aqueous solution of hydrochloric acid (300 cc) is added at a maximum of 20° C. The methanol is evaporated off under reduced pressure (20 mm Hg) at 45° C. The aqueous phase is extracted 3 times with methylene chloride (2.5 liters in total). The organic solution is washed 3 times with distilled water (1.5 liters in total), dried over sodium sulphate and evaporated. The resulting product (110.0 g) is purified by recrystallisation from a mixture of acetonitrile (100 cc) and isopropyl ether (200 cc). After drying under reduced pressure (0.2 mm Hg) at 40° C., 2-hydroxyethyl pyrid-2-yldithiocarbamate (85.1 g), which melts at 88° C., is obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11].[CH:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[C:22]([SH:27])[CH:23]=[CH:24]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.O>[CH:21]1[C:20]2[C:25](=[CH:26][CH:17]=[CH:18][CH:19]=2)[CH:24]=[CH:23][C:22]=1[S:27][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11]
Reactant: Sc1ccc2ccccc2c1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC=C(C(=O)OC)c1ccccc1CSc1ccc2ccccc2c1

Procedure:
8 g of methyl α-(2-bromomethylphenyl)-β-methoxyacrylate, 4.5 g of 2-thionaphthol, 4.4 g of potassium carbonate and 100 mg of potassium iodide are refluxed for 20 hours in 200 ml of acetone. 200 ml of water is then added and extraction is carried out three times with methylene chloride. The organic phases are dried over Na2SO4 and evaporated down. The oil which remains is chromatographed on silica gel using a mixture of n-hexane and ethyl acetate. There is obtained 8.19 g of slightly yellow crystals of melting point 52°-58° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]2[S:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:6]2=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[C:4]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>ClCCl>[CH2:29]([N:31]([CH2:2][C:3]1[N:8]=[C:7]2[S:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:6]2=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[C:4]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:32][CH3:33])[CH3:30]
Reactant: CCNCC
Reactant: CCOC(=O)c1c(CCl)nc2sc(C)c(C)c2c1-c1ccc(OC)c(OC)c1
Solvent: ClCCl
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc(C)c(C)c2c1-c1ccc(OC)c(OC)c1
Reaction time: 14 h
Yield: 67.4 %

Procedure:
A mixture of ethyl 6-chloromethyl-4-(3,4-dimethoxyphenyl)-2,3-dimethylthieno[2,3-b]pyridine-5-carboxylate (1.5 g), diethylamine (1.04 g) and dichloromethane (35 ml) was stirred for 14 hours under reflux. The reaction mixture was washed with water and dried (MgSO4), then the solvent was distilled off. The residue was subjected to column chromatography on silica gel. From the fraction eluted with chloroform, ethyl 6-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-2,3-dimethylthieno[2,3-b]pyridine-5-carboxylate (1.1 g, 68%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms, m.p.110°-111° C.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:14])[C@H:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26]>C1COCC1>[CH3:22][O:23][CH2:24][C:25]([NH:9][C@@H:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:14])=[O:26]
Reactant: COCC(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)N[C@H](C(=O)OC(C)(C)C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 114 %

Procedure:
A solution of L-tert-Leucine tert-butyl ester hydrochloride (0.20 g, 0.90 mmol) in THF (9 mL) at 0° C. was treated with triethylamine (0.38 mL, 2.73 mmol) and methoxyacetyl chloride (0.09 mL, 0.98 mmol), stirred at 0° C. for 15 minutes and then at 25° C. for 2 hours. The reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-33% ethyl acetate/chloroform to give the title compound (0.266 g).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[Br:10]C1C=C(C)C(N)=C(C)C=1>C(O)(=O)C>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[Br:10][C:8]1[C:2]([CH3:1])=[C:3]([C:5]([CH3:9])=[CH:6][CH:7]=1)[NH2:4]
Reactant: Cc1cc(Br)cc(C)c1N
Agent: Cc1cccc(C)c1N
Solvent: CC(=O)O
Product: Cc1ccc(Br)c(C)c1N

Procedure:
It is known that 4-bromo-2,6-dialkylanilines are predominantly formed by brominating 2,6-dialkylanilines. The high reactivity of these compounds causes the reaction to proceed non-selectively with the formation of different by-products, depending on the reaction conditions. Thus, for example, the bromination of 2,6-dimethylaniline in the presence of glacial acetic acid gives 4-bromo-2,6-dimethylaniline in a yield of 80-85% of theory (Chem. Ber. (1901), 34, 2242). The bromination of 2,6-dimethylaniline in strongly acid medium always results in the formation of substantial amounts of 3-bromo-2,6-dimethylaniline (Chem. Ber. (1900), 33, 1967). It is further known from published UK patent application A 2 098 210 that, in the halogenation of N-alkyl-2,6-dialkylanilines in the presence of a Lewis acid such as AlCl3, the halogen is even introduced selectively in 3-position.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.[Br:13]Br>C(O)(=O)C>[Br:13][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[C:3]2[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)c1n[nH]c2ccc(Br)cc12
Temperature: 120 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
A suspension of indazole-3-carboxylic acid (CX) (1.0 g, 6.16 mmol) in glacial acetic acid (60 mL) was heated at 120° C. to get a clear solution. The solution was cooled to 90° C. A solution of bromine (0.633 mL, 12.33 mmol) in glacial acetic acid (2 mL) was added slowly to the solution while heating at 90° C. The solution was further heated 16 h at 90° C. The solution was cooled to room temperature, poured into ice water and further stirred at room temperature for 15 min The solids formed were filtered, washed with cold water and dried under vacuum at room temperature to get 5-bromo-1H-indazole-3-carboxylic acid (CXV) as a white solid (1.30 g, 5.39 mmol, 87.5% yield). 1H NMR (DMSO-d6) δ ppm 13.95 (s, 1H), 13.18 (br s, 1H), 8.21 (d, J=1.2 Hz, 1H), 7.65 (d, J=7.0 Hz, 1H), 7.56 (dd, J=7.0, 1.2 Hz, 1H); ESIMS found for C8H4BrN2O2 m/z 242.0 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[N:9].C[N+]([O-:14])(C)C>>[O:14]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[N:9]
Reactant: C[N+](C)(C)[O-]
Reactant: N#CCCCCCCBr
Product: N#CCCCCCC=O

Procedure:
7-bromoheptanenitrile and trimethylamine oxide were processed using the method described in Example 137A to afford the title compound. MS (ESI+) m/z 143 (M+NH4)+.
Reaction SMILES: N.[Na].[C:3](#[N:5])[CH3:4].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]#[N:12]>O1CCCC1.CCOCC>[NH2:12][C:11]([C:7]1[S:6][CH:10]=[CH:9][CH:8]=1)=[CH:4][C:3]#[N:5]
Reactant: CC#N
Reactant: N#Cc1cccs1
Agent: N
Agent: [Na]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CC=C(N)c1cccs1
Reaction time: 0.5 h

Procedure:
About 100 ml. of ammonia is condensed in the reaction flask and a small piece of sodium is added, giving a blue color. The color is discharged with ferric chloride and 2.7 g. of sodium is added. When the blue color disappears, 4.91 ml. of acetonitrile in 10 ml. of ether is added. The reaction is cooled in a dry ice-acetone bath and 9.28 g. of 2-thiophenecarbonitrile in 25 ml. of tetrahydrofuran is added dropwise. Cooling is continued for 30 minutes, then the ammonia and solvent are allowed to evaporate. A 50 ml. portion of water is added and the mixture is extracted with methylene chloride. The methylene chloride extracts are dried over sodium sulfate and then passed through Magnesol. Hexanes are added and the filtrate is evaporated on a steam bath to an oil. The oil is dry column chromatographed on silica gel, eluting with methylene chloride. The fraction containing the desired product is taken up in methylene chloride, passed through Magnesol and the filtrate is evaporated on a steam bath with the addition of hexanes until an oil comes out. Cooling and seeding gives the desired product as crystals, mp. 50°-45° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[C:21]2[CH3:29])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].CN(C)[CH:34]=[O:35]>>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([CH:34]=[O:35])=[C:21]2[CH3:29])=[CH:16][CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: Cc1cc2ccccc2n1-c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)c2ccccc2n1-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Phosphorous oxychloride (3 mL) was added to anhydrous dimethylformamide (6 mL) and the mixture was stirred at room temperature for 15 min. A mixture of 1-(4-benzyloxyphenyl)-2-methyl-1H-indole (0.94 g, 3 mmol) in dimethylformamide (10 mL) was added and the mixture heated to 80° C. for 18 hr. The reaction mixture was poured onto ice and adjusted to a pH of 7 by the addition of 2 N NaOH. The mixture was extracted with ethyl acetate (2×100 mL). The organic layer washed with water and brine and dried over MgSO4. Evaporation to provide the product as a dark solid. Purification by silica gel chromatography (10% EtOAC-hexanes) provided a white solid (63%): mp 150-152° C.; 1H NMR (DMSO-d6): δ 2.54 (3H, s), 5.22 (2H, s), 6.99 (1H, d, J=7.9 Hz), 7.17-7.42 (4H, m), 7.45-7.54 (7H, m), 8.17 (1H, d, J=7.5 Hz), 10.19 (1H, s); MS m/z (M+H)+ 342. Anal. for C23H19NO2: Calc'd: C, 80.92; H, 5.61; N, 4.10. Found: C, 80.76; H, 5.70; N, 3.93.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=O)([CH3:3])[CH3:2].P(Br)(Br)([Br:22])=O>>[Br:22][C:13]1[C:12]2[C:11]([N:10]=[C:5]3[C:6]=1[CH:7]=[CH:8][CH:9]=[C:4]3[CH:1]([CH3:3])[CH3:2])=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: CC(C)c1ccccc1Nc1ccccc1C(=O)O
Reactant: O=P(Br)(Br)Br
Product: CC(C)c1cccc2c(Br)c3ccccc3nc12
Temperature: 120 °C
Yield: 102.5 %

Procedure:
2-(2′-Isopropylphenylamino)benzoic acid 8 (1.0 g, 3.9 mmol) was suspended in 11.0 g (38 mmol) of phosphorus oxybromide, and the mixture was heated to 120° C. for 2 hours. Excess phosphorus oxybromide was removed by distillation and the residual solution was poured into a 1:1 mixture of aqueous ammonium hydroxide:CH2Cl2. The CH2Cl2 solution was separated, dried, filtered, and the combined organic layers was dried in vacuum to give 10 (1.2 g, 79%) as yellow powder. 1H-NMR δ=1.45 (d, J=6.9 Hz, 6H), 4.56 (sept, J=6.9 Hz, 1H), 7.56-7.70 (m, 3H), 7.78 (ddd, J=1.5 Hz, J=6.6 Hz, J=6.6 Hz, 1H), 8.24 (d, J=8.4 Hz, 1H), 8.29 (dd, J=1.5 Hz, J=8.5 Hz, 1H), 8.41 (d, J=8.8 Hz, 1H). 13C-NMR δ=24.00, 28.21, 125.20, 125.62, 125.86, 126.49, 127.38, 127.64, 129.90, 130.58, 130.83, 135.69, 147.44, 148.01, 148.14. Anal. calcd. for C16H14NBr: C, 64.02; H, 4.70; N, 4.67. Found: C, 64.23; H, 4.78; N, 4.59.
Reaction SMILES: Cl.[CH:2]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([Cl:19])=[O:18])=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[F:52][C:53]1[CH:54]=[C:55]2[C:59](=[CH:60][CH:61]=1)[CH2:58][NH:57][CH2:56]2>C(Cl)Cl>[ClH:19].[CH:2]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([N:57]4[CH2:56][C:55]5[C:59](=[CH:60][CH:61]=[C:53]([F:52])[CH:54]=5)[CH2:58]4)=[O:18])=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Cl)c1ccc(OC2CCN(C3CCC3)CC2)cc1
Reactant: Fc1ccc2c(c1)CNC2
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: O=C(c1ccc(OC2CCN(C3CCC3)CC2)cc1)N1Cc2ccc(F)cc2C1
Reaction time: 16 h
Yield: 57.5 %

Procedure:
A stirred mixture of 4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoyl chloride hydrochloride (D25) (0.20 g) and diethylaminomethyl polystyrene (3.2 mmol/g, 0.80 g) in DCM (10 ml) at rt was treated with 5-fluoroisoindoline (0.101 g) and stirred for 16 h. The reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM)]. Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (1 M solution in diethyl ether) and then concentrated. The residue was crystallised from acetone to yield the title compound (E60) as a white powder (150 mg). MS electrospray (+ion) 395 (MH+). 1H NMR δ (DMSO-d6): 10.60 (1H, s), 7.62 (2H, m), 7.42-7.06 (5H, m), 4.85 (4H, m), 4.66 (1H, m), 3.75-3.55 (1H, m), 3.45-3.20 (2H, m), 2.90 (2H, m), 2.41-1.62 (10H, m).
Reaction SMILES: C[O-].[Na+].[CH:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:14][C:15]1([CH3:25])[CH2:20][O:19][CH:18]([C:21](=[O:24])[CH2:22][CH3:23])[O:17][CH2:16]1>CO>[CH3:25][C:15]1([CH3:14])[CH2:16][O:17][CH:18]([C:21](=[O:24])[C:22]([CH3:23])=[CH:4][CH:5]=[CH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:19][CH2:20]1
Reactant: CCC(=O)C1OCC(C)(C)CO1
Reactant: O=CC=Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=CC=Cc1ccccc1)C(=O)C1OCC(C)(C)CO1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
7.2 g of a 30% strength by weight solution of sodium methylate in methanol were added dropwise to a solution of 52.9 g of cinnamaldehyde and 68.9 g of 5,5-dimethyl-2-propionyl-1,3-dioxane in 200 ml of methanol in the course of 15 minutes at 0-5° C., and the mixture was stirred for a further 2 hours at 0-5° C. Thereafter, the reaction solution was seeded with a few crystals of the product and stirred overnight at room temperature. After the precipitate had been filtered off under suction and washed with cold methanol, 29.8 g of the product were obtained in the form of colorless crystals of melting point 122-125° C.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([CH:12]=[O:13])[CH:9]=[CH:8][C:7]=1[O:14][CH2:15][CH:16]1[CH2:18][CH2:17]1)(=[O:4])=[O:3].S(=O)(=O)([OH:21])N.Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH:16]1([CH2:15][O:14][C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:21])=[O:13])=[CH:11][C:6]=2[O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18]1
Reactant: CS(=O)(=O)Oc1cc(C=O)ccc1OCC1CC1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)Oc1cc(C(=O)O)ccc1OCC1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
A mixture of 2-(cyclopropylmethoxy)-5-formylphenyl methanesulfonate (0.565 g, 2.090 mmol) and sulfamic acid (0.223 g, 2.299 mmol) in acetic acid (8 ml) was cooled to 0° C., and a solution of sodium chlorite (0.378 g, 4.18 mmol) in water (3 ml) was added. The resulting yellow mixture was allowed to warm to RT and stirred for 2 hours. Additional sulfamic acid (0.081 g, 0.836 mmol) and sodium chlorite (0.133 g, 1.463 mmol) in water (2 ml) were added over 1 hour. The reaction mixture was diluted with water (15 ml), and the precipitate was collected by filtration, washed with water and dried to obtain 4-(cyclopropylmethoxy)-3-(methylsulfonyloxy)benzoic acid (0.521 g, 1.820 mmol, 87% yield, MS/ESI+ 286.9 [MH]+). This product was employed in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cc(O)c(C)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)c(C)c([N+](=O)[O-])c1

Procedure:
A mixture of 433 g. 2,5-dimethyl-3-nitrophenol, 360 g. potassium carbonate, 326 ml. benzyl chloride and 2 liters dimethyl formamide is stirred overnight at 50° C. The reaction mixture is then filtered with suction and the filtrate is evaporated to dryness in a vacuum. The residue is poured on to 4 liters of ice-water and, after suction filtration and drying in the air, there are obtained 668 g. of yellowish crystals; m.p. 66°-68° C.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:36])[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:14]3[C:23]4[CH2:22][NH:21][C:20](=[O:24])[N:19]([C:25]5[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=5[F:32])[C:18]=4[N:17]=[C:16](S(C)=O)[N:15]=3)[CH:8]=2)[CH2:3][CH2:2]1.[NH2:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1>C1COCC1>[CH:1]1([CH2:4][NH:5][C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:14]3[C:23]4[CH2:22][NH:21][C:20](=[O:24])[N:19]([C:25]5[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=5[F:32])[C:18]=4[N:17]=[C:16]([NH:37][CH:38]4[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]4)[N:15]=3)[CH:8]=2)=[O:36])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F

Procedure:
To the solution of N-(Cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzamide (100 mg) in THF (10 mL) was added 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (195 mg) at r.t. The reaction mixture was heated at reflux for 4 h. The solution was then evaporated in vacuo and the residue was purified by column chromatography to provide the title compound as a white solid. LC-MS m/z 648.4 (M+H)+, 2.16 min (ret. time).
Reaction SMILES: [CH2:1]([N:8]([C@@H:19]([CH3:22])[CH2:20][OH:21])[CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:18])O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O.O>[CH2:1]([N:8]1[C@@H:19]([CH3:22])[CH2:20][O:21][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=2[O-:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](CO)N(Cc1ccccc1)CC(O)c1cccc[n+]1[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: C[C@H]1COC(c2cccc[n+]2[O-])CN1Cc1ccccc1
Yield: 45.5 %

Procedure:
2-(2-(Benzyl((S)-1-hydroxypropan-2-yl)amino)-1-hydroxyethyl)pyridine 1-oxide (7 g, 23.17 mmol) was dissolved in 70% sulfuric acid (70 mL) and the mixture was heated at reflux for 7 h. The mixture was cooled and then was diluted with water, neutralized with an aqueous sodium carbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by alumina chromatography (1% methanol in dichloromethane) to afford 2-((5S)-4-benzyl-5-methylmorpholin-2-yl)pyridine 1-oxide as a yellow liquid (3 g, 45%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:20]4[S:19][C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[CH:21]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1cc2ccccc2s1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cc5ccccc5s4)cc3CC[C@@H]12
Yield: 80.9 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 2-benzothiopheneboronic acid (140 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of toluene, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 17 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (70% ethyl acetate/hexanes eluent), to give 190 mg (81%) of the title compound as a white solid. mp 247°-250°. FDMS: m/e=361. α[D]589 =+93.33 (c=0.36, chloroform).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:39])[C:9]2[C:13]([CH2:14][N:15]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)(=[O:25])=[O:24])C(=O)OC(C)(C)C)=[CH:12][N:11]([CH2:36][O:37][CH3:38])[N:10]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:39])[C:9]2[C:13]([CH2:14][NH:15][S:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)(=[O:24])=[O:25])=[CH:12][N:11]([CH2:36][O:37][CH3:38])[N:10]=2)=[CH:4][CH:3]=1
Reactant: COCn1cc(CN(C(=O)OC(C)(C)C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)c(C(O)c2ccc(F)cc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCn1cc(CNS(=O)(=O)c2ccc(C(F)(F)F)cc2)c(C(O)c2ccc(F)cc2)n1
Temperature: 25 °C
Yield: 33.5 %

Procedure:
tert-Butyl (3-((4-fluorophenyl)(hydroxy)methyl)-1-(methoxymethyl)-1H-pyrazol-4-yl)methyl(4-(trifluoromethyl)phenylsulfonyl)carbamate (44) (434 mg, 0.757 mmol) was dissolved in CH2Cl2 (4 mL) and stirred at rt under nitrogen. Trifluoroacetic acid (4 mL) was added and the reaction stirred for 1 hr before concentration in vacuo. The resulting crude product was purified by column chromatography using EtOAc/hexane gradients to yield N-((3-((4-fluorophenyl)(hydroxy)methyl)-1-(methoxymethyl)-1H-pyrazol-4-yl)methyl)-4-(trifluoromethyl)benzenesulfonamide (45) (120 mg, 35%) as a white solid.
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([C:15]1[CH:20]=[CH:19][C:18]([N+]#N)=[CH:17][CH:16]=1)[C:7]1[CH:12]=[CH:11][C:10]([N+]#N)=[CH:9][CH:8]=1.F[B-](F)(F)F.[CH2:28]([C:31]#[N:32])[CH:29]=[CH2:30].O>C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:31]([CH2:28][CH:29]=[CH:30][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:15]2[CH:20]=[CH:19][C:18]([CH:30]=[CH:29][CH2:28][C:31]#[N:32])=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)#[N:32]
Reactant: C=CCC#N
Reactant: N#[N+]c1ccc(Cc2ccc([N+]#N)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCO
Product: N#CCC=Cc1ccc(Cc2ccc(C=CCC#N)cc2)cc1
Temperature: 40 °C
Yield: 60.8 %

Procedure:
A suspension of 4,4′-methanediyl-bis-benzenediazonium tetrafluoroborate (11.9 g, 0.03 mol), prepared according to the method of example 6.1, allyl cyanide (8.05 g; 0.12 mol), and palladium acetate (0.135 g, 0.6 mmol) in 80 ml of ethanol is heated at 40° C. during 22 h. The heterogeneous reaction mixture is poured into 300 ml of water, extracted with ethyl acetate, washed with water, brine, dried over MgSO4, and evaporated. The crude beige product is recrystallized from 130 ml of ethanol, yielding 5.44 g (61%) of 4-{4-[4-(3-cyano-propenyl)-benzyl]-phenyl}-but-3-enenitrile as light beige crystals, melting point 128-130° C.