Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N+:9]2[O-])=[CH:4][CH:3]=1.C[Si]([C:17]#[N:18])(C)C.CN(C)C(Cl)=O>ClCCCl>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:17]#[N:18])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2ccc[n+]([O-])c2c1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: ClCCCl
Product: Cc1ccc2ccc(C#N)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-methylquinoline-1-oxide (18.3 g, 115 mmol) in 1,2-dichloroethane (750 mL) was added trimethylsilyl cyanide (30.8 mL, 230 mmol) followed by dimethylcarbamoyl chloride (21.2 mL, 230 mmol) and stirred at room temperature overnight. The solution was quenched slowly with a sat. solution of sodium bicarbonate, diluted with water and extracted two times with dichloromethane. The combined organic extracts were dried (MgSO4) and concentrated to give the crude compound. Flash chromatography of the residue on silica gel (eluting with 3% acetone in dichloromethane) provided the title compound. 1H NMR (400 MHz, acetone-d6): δ 8.56 (d, 1H), 8.03 (d, 1H), 7.95 (s, 1H), 7.88 (d, 1H), 7.67 (d, 1H), 2.62 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.CN([CH:17]=[O:18])C.[NH4+].[Cl-]>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:17]=[O:18])=[CH:4][N:3]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: O=Cc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To a suspension of 2,5-dibromopyridine (18.6 g, 78.5 mmol) in dry diethyl ether (400 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 31.4 mL, 78.5 mmol) over a period of 20 min. After stirring 30 min at this temperature, anhydrous DMF (9.1 mL, 118 mmol) was added over a period of 5 min, and the reaction mixture was stirred for 30 min then warmed to room temperature. Saturated NH4Cl (10 mL) was added to the reaction mixture. The layers were separated, and the organic layer was dried (Na2SO4), concentrated. The crude product was purified by column chromatography (1:5 ethyl acetate/hexanes) to afford a brown solid (12.5 g, 86%); 1H NMR (300 MHz, CDCl3) δ 7.61 (dd, J=8.10, 0.60 Hz, 1 H), 7.95 (dd, J=8.10, 2.10 Hz, 1 H), 8.74 (dd, J=2.10, 0.60 Hz, 1 H), 10.02 (s, 1 H); 13C NMR (75 MHz, CDCl3) 129.2, 130.8, 137.7, 148.4, 152.6, 189.7.
Reaction SMILES: C([Mg]Cl)CCC.C([Li])CCC.CCCCCC.[Br:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=1.CN([CH:29]=[O:30])C>C1(C)C=CC=CC=1.C1COCC1>[Br:18][C:19]1[N:20]=[CH:21][C:22]([CH:29]=[O:30])=[CH:23][CH:24]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Br)nc1
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=Cc1ccc(Br)nc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
40.1 ml of a 2M solution of n-butylmagnesium chloride in THF (80.2 mmol) were added to a solution 100.2 ml of a 1.6M solution of n-butyllithium in hexane (160.41 mmol) in 50 ml of toluene and 50 ml of THF at −10° C. to 0° C. over 0.5 h, and the mixture was stirred at −10° C. for 0.5 h. A solution of 50 g (211 mmol) of 2,5-dibromopyridine in 200 ml of toluene and 200 ml of THF was added dropwise over 1 h while maintaining the temperature of the mixture below −5° C. The resulting suspension was stirred at −10° C. for 2.5 h and then transferred into a cooled (−10° C.) solution of 21.2 ml of DMF (274.3 mmol) in 100 ml of toluene and 100 ml of THF over 0.5 h. The mixture was left at −10° C. to −5° C. for 0.5 h and then quenched with 400 ml of water. After stirring the mixture below 20° C. for 10 min, the organic layer was separated and the aqueous layer was extracted three times with 400 ml each of ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica gel, cyclohexane/ethyl acetate 9:1) to give 23.9 g (60.8%) of the title compound as a white solid.
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:37][CH2:38][C:39]1[CH:46]=[CH:45][C:42](C#N)=[C:41](F)[CH:40]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([NH:37][CH2:38][C:39]1[CH:46]=[CH:45][CH:42]=[CH:41][CH:40]=1)=[O:5]
Reactant: N#Cc1ccc(CN)cc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
To an ice cooled solution of Boc-Aze-OH (0.194 g, 0.96 mmol) in 5 mL of DMF was added TBTU (0.50 g, 9.6 mmol). After 30 min another solution, comprising 4-aminomethyl-2-fluorobenzonitrile (0.17 g, 0.81 mmol; see step (v) above) and diisopropylethyl amine (0.326 g, 2.53 mmol) in 7 mL of DMF was added. The resulting solution was stirred overnight at room temperature. The solvent was evaporated and the product was purified by preparative RPLC using CH3CN:0.1M NH4OAc (50:50). Freeze-drying gave 0.237 g (74%) of the desired sub-title compound.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9](O)[N:8]=1.C(=O)([O-])O.[Na+]>O>[Cl:3][C:9]1[N:8]=[C:7]([CH3:6])[CH:12]=[C:11]([CH3:13])[N:10]=1
Reactant: Cc1cc(C)nc(O)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, phosphorus oxychloride (2 ml) was added to 4,6-dimethyl-2-hydroxypyrimidine (400 mg), and the resulting mixture was stirred for 1 hour while heating the mixture to reflux. The reaction solution was cooled to room temperature, and the cooled solution was added in small portions to water. After adding sodium hydrogen carbonate in small portions to the resulting mixture to neutralize it, the mixture was extracted with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to obtain 2-chloro-4,6-dimethylpyrimidine (350 mg). (2) In the same manner as in Reference Example 8, 4-iodophenol (223 mg) and 2-chloro-4,6-dimethylpyrimidine (157 mg) were reacted by using sodium hydride to obtain 2-(4-iodophenoxy)-4,6-dimethylpyrimidine (226 mg),
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[NH2:16].CO.O>CN(C=O)C>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:16][C:15]2[C:14]([F:13])=[CH:20][CH:19]=[CH:18][C:17]=2[F:21])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: Nc1c(F)cccc1F
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CSc1nc(Cl)c(C#N)c(Nc2c(F)cccc2F)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To the solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbonitrile (2.20 g, 10.0 mmol) in DMF (10 mL) was added 2,6-difluoroaniline (2.17 mL, 20.0 mmol). The solution was stirred at 50° C. for about 60 minutes. The mixture was slowly added into a solution of MeOH (20 mL) and water (30 mL). The resultant solid was filtered and washed with MeOH/H2O (20 mL, 1:1) to give 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbonitrile as a white solid (2.82 g, 90%). LC-MS m/z 313 (M+H)+; 1H-NMR (CDCl3) δ 2.33 (s, 3 H), 6.94 (s, 1 H), 7.04 (m, 2 H), 7.35 (m, 1 H).
Reaction SMILES: N#N.[O-:3][CH2:4][CH3:5].[Na+].[S:7]1[CH:11]=[CH:10][CH:9]=C1CC(O)=O.ClCCC[Si:20]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>S1C=CC=C1C(O)=O.C(O)C>[C:4]([S:7][CH2:11][CH2:10][CH2:9][Si:20]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])(=[O:3])[CH3:5]
Reactant: CCO[Si](CCCCl)(OCC)OCC
Reactant: CC[O-]
Reactant: O=C(O)Cc1cccs1
Agent: N#N
Agent: O=C(O)c1cccs1
Agent: [Na+]
Solvent: CCO
Product: CCO[Si](CCCSC(C)=O)(OCC)OCC
Temperature: 25 °C
Yield: 78 %

Procedure:
This example illustrates the preparation of a thiocarboxylate alkoxysilane from a salt of a thiolcarboxylic acid using as a solvent the alcohol corresponding to the silane alkoxy group. Into a 250 ml, 3 neck round bottomed flask equipped with magnetic stir bar, temperature probe/controller, heating mantle, addition funnel, condenser, and N2 inlet was charged 63 grams of a 21 weight percent sodium ethoxide in ethanol. 15 grams of thiolacetic acid was added slowly, keeping the temperature below 65° C. The solution was allowed to cool to room temperature, and 48 grams of chloropropyltriethoxysilane was added via the addition funnel. After addition was complete, the solution was heated to 70° C. for 24 hours whereupon a white solid formed. Analysis of the solution by gas chromatography showed a 78 percent yield of acetylthiopropyltriethoxysilane.
Reaction SMILES: [O:1]=[C:2]([CH3:12])[C:3](=[N:9][O:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:13]Br>C(Cl)(Cl)Cl>[Br:13][CH2:12][C:2](=[O:1])[C:3](=[N:9][O:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NOC)C(C)=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=NOC)C(=O)CBr
Temperature: 40 °C
Yield: 91.1 %

Procedure:
In 120 ml of chloroform is dissolved 27.3 g of ethyl 3-oxo-2-methoxyiminobutyrate and the solution is warmed to 40° C. Then, a solution of 25.3 g of bromine in 30 ml of chloroform is added dropwise over a period of 30 minutes. The mixture is stirred and reacted at room temperature for 1 hour. The reaction mixture is washed with a 5% aqueous solution of sodium hydrogen carbonate and water in that order and the organic layer is dried. The solvent is then distilled off under reduced pressure to obtain 36.2 g of ethyl 4-brom-3-oxo-2-methoxyiminobutyrate as an oily product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([OH:9])=[O:8].IC.[C:15](=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O.C(OCC)(=O)C>[CH3:15][O:8][C:7](=[O:9])/[CH:6]=[CH:5]/[C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)/C=C/c1cccc(F)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1cccc(F)c1
Temperature: 65 °C
Yield: 87.6 %

Procedure:
To a mixture of trans-3-fluorocinnamic acid (50 g, 300 mmol) and iodomethane (300 mL) in acetone (1 L) was added portion wise cesium carbonate (147 g, 450 mmol, 1.5 equivalents), and the mixture was heated at 65° C. for 1.5 hours in a sealed reaction vessel. Upon cooling to room temperature, the reaction mixture was diluted with ethyl acetate (1 L), filtered through a pad of silica gel, and concentrated to give 47.33 g (87%) of trans-3-fluorocinnamic acid methyl ester as a colorless oil. MS (ES) m/z 180.0 (M+•).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.[CH2:31]([OH:35])[CH2:32][C:33]#[CH:34]>C(NCC)C.[Pd](Cl)Cl.[Cu]I>[OH:35][CH2:31][CH2:32][C:33]#[C:34][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1
Reactant: C#CCCO
Reactant: COC(=O)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COC(=O)c1ccc(C#CCCO)cc1
Yield: 75.8 %

Procedure:
To a mixture of 0.082 g (0.005 eq) of palladium chloride, and 0.244 g (0.01 eq) of triphenylphosphine, and 20.00 g (1.0 eq) of methyl 4-bromobenzoate in diethylamine which is stirred under nitrogen is added 0.178 g (0.01 eq) of copper (I) iodide and 6.52 g (1.0 eq) of 3-butyn-1-ol. The reaction mixture is stirred under nitrogen at room temperature (about 25° C.) for eighteen hours. Diethylamine is then removed under reduced pressure, water is added, and the mixture extracted with benzene. The benzene extracts are filtered through silica to remove the metal residue and the filtrate concentrated under reduced pressure to yield methyl 4-(4-hydroxybut-1-yn-1-yl)benzoate. Recrystallization from a mixture of benzene and hexane yields pure material in 75.8% yield, m.p. 95.5°-96.0° C.; IR (KBr) ν max 3310, 2955, 1718, 1604, 1433, 1275, 1177, 1108, 1040, 955, 852, and 769 cm-1 ; 1H NMR (CDCl3) delta 7.98 (d, J=8.3 Hz, 2H, Ar), 7.49 (d, J=8.3 Hz, 2H, Ar), 3.93 (s, 3H, --CH3), 3.87 (m, 2H, --CH2OH), 2.74 (t, J=6.2 Hz, 2H, --yl--CH2 --), 1.88 (m, 1H, --OH).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[O-].[Na+].O.[C:18]([O:25][CH3:26])(=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21]>[Cu]Br>[C:4]([C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[CH:19]([C:18]([O:25][CH3:26])=[O:24])[C:20]([O:22][CH3:23])=[O:21])([OH:6])=[O:5]
Reactant: COC(=O)CC(=O)OC
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Cu]Br
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C(C(=O)OC)c1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
2-Chloro-4-nitrobenzoic acid (7.5 g, 37.2 mmol) was dissolved in deaerated dimethyl malonate (90 mL). Copper (I) bromide (0.54 g, 3.7 mmol) and sodium methoxide (4.83 g, 89.4 mmol) were added to the solution. The mixture was stirred at room temperature for 15 minutes, and then stirred at 70 to 75° C. overnight. After the reaction solution was allowed to return to room temperature, water was added thereto and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (7.0 g, 68%).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[SiH3]Cl.[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].N1C=CN=C1>C1CCCCC1>[Si:1]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Cl:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCCl
Agent: [SiH3]Cl
Agent: c1c[nH]cn1
Solvent: C1CCCCC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCCl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 250 ml, three-necked flask was fitted with a large magnetic, egg-shaped stir bar, a thermocouple, reflux condenser, and an argon inlet. This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon. The flask was charged with 15.09 grams (0.100 mole, 1.00 equivalents) of t-butyldimethylsilyl chloride, and 100 grams of cyclohexane. The silyl chloride rapidly dissolved, endothermically. 6-Chloro-1-hexanol, 13.96 grams (0.100 mole, 1.00 equivalent) was then weighed into the flask. After stirring at room temperature for fifteen minutes, the reaction mixture appeared hazy. The stirrer was halted, and a second, immiscible layer was observed in the bottom of the flask. Imidazole, 6.81 grams (0.100 mole, 1.00 equivalent) was then added to the reaction mixture. A fine white precipitate rapidly developed. The reaction mixture was stirred at room temperature, and monitored by GC analysis. An aliquot of the clear supernatant was injected into the GC. After five hours, both starting materials were still present, and the conversion to the desired product was 82.2%. The reaction mixture was stirred overnight at room temperature, under a blanket of argon. The sample after 30 hours indicated all the starting material had been consumed, with the formation of a single, higher boiling component. The reaction mixture was transferred to a small, dry, Chemglass pressure filter. The filtrate was collected in a dry, 500 ml flask. The filter cake was rinsed with additional cyclohexane (2×100 ml). The solvent was removed on the rotary evaporator, with the bath temperature set at 40° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[O:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: OCCCCCCCl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCCCCCCl
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a stirred solution of 6-chloro-1-hexanol (8.1 g, 60 mmol), triethylamine (9.2 g, 12.7 mL, 90 mmol), and DMAP (750 mg, 0.1 equiv., 6.1 mmol) in methylene chloride (100 mL) was added tert-butyldimethylchlorosilane (10.85 g, 1.2 equiv, 72 mmol). The reaction was allowed to proceed overnight under a nitrogen atmosphere. TLC analysis in ethyl acetate indicated complete disappearance of staring alcohol (Rf =0.43) and the appearance of a new spot (Rf =0.67). The organic solution was washed with water (2×30 mL) and saturated ammonium chloride solution (1×25 mL) and dried over MgSO4. Solvents were removed by rotary evaporation and the residue distilled to afford the title compound (12.03 g, 80%) as a colorless liquid: bp 70° C./0.1 Torr; 1H NMR (200 MHz, CDCl3) δ 3.58 (2 H, t, (J=6.26 Hz), 3.50 (2 H, t, (J=6.70 Hz), 1.86-1.69 (2 H), 1.60-1.28 (6 H), 0.86 (9 H, s), 0.02 (6 H, s); mass spectrum m/z (M+) calcd for C12H27CIOSi 250.1520, found 250.1396.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H][H]>CO.[Pd]>[NH:1]1[CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([O:5][C:6]([CH3:8])([CH3:9])[CH3:7])=[O:4]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1

Procedure:
9.15 g of Z-Pro-OtBu are hydrogenated in 100 ml of methanol and 1.0 g of Pd on charcoal (10%) at room temperature. The hydrogen uptake has ended after 30 minutes. The solution is freed of catalyst by filtration and evaporated in a waterpump vacuum at 30° C. The resulting oil is homogeneous in a thin layer chromatogram on silica gel. Rf = 0.55 in the system chloroform-methanol (1:1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[SH:10][CH2:11][CH2:12][C:13]([O:15]C)=O.C(N(CC)C(C)C)(C)C.[O:26]1CCOC[CH2:27]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[F:9][C:5]1[CH:4]=[CH:3][C:2]([S:10][CH2:11][C:12](=[C:13]=[O:15])[O:26][CH3:27])=[CH:8][C:6]=1[NH2:7]
Reactant: COC(=O)CCS
Reactant: Nc1cc(Br)ccc1F
Reactant: C1COCCO1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=C=O)CSc1ccc(F)c(N)c1

Procedure:
To a mixture of 5-bromo-2-fluoroaniline (4.15 g), methyl 3-mercaptopropionate (2.62 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.63 g) and N,N-diisopropylethylamine (5.64 g) in 1,4-dioxane (80 mL) was added tris(dibenzylideneacetone)-dipalladium(0) (0.3 g), and the mixture was heated at reflux under an argon atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=20/1−5/1−2/1) to give 2-fluoro-5-(2-methoxy-carbonylethylthio)aniline (4.62 g). This material was dissolved in tetrahydrofuran (120 mL). To the solution was added potassium tert-butoxide (1 mol/L tetrahydrofuran solution, 80.6 mL) at −78° C., and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added 1 mol/L hydrochloric acid (81 mL), and the reaction mixture was allowed to warm to room temperature, and stirred for 5 minutes. The mixture was poured into ethyl acetate, and the organic layer was separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give the title compound (1.85 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)[CH:3]=1.[C:14]([O:18][C:19](=[O:27])[NH:20][C:21]1[S:22][CH:23]=[C:24]([CH3:26])[N:25]=1)([CH3:17])([CH3:16])[CH3:15]>CCOC(C)=O>[C:14]([O:18][C:19](=[O:27])[NH:20][C:21]1[S:22][C:23]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]3)[CH:3]=2)=[C:24]([CH3:26])[N:25]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: N#CC1(c2cc(Br)ccn2)CCC1
Reactant: Cc1csc(NC(=O)OC(C)(C)C)n1
Solvent: CCOC(C)=O
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C2(C#N)CCC2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
The title compound is prepared in analogy to the procedure described in Step 1.3, but using 1-(4-bromo-pyridin-2-yl)-cyclobutanecarbonitrile (Step 19.3) and (4-methyl-thiazol-2-yl)carbamic acid tert-butyl ester (Step 18.4). The reaction mixture is stirred for 3 h at 100° C. Title compound: ESI-MS: 371.1 [M+H]+; tR=4.86 min (System 1); TLC: Rf=0.66 (Hex/EtOAc, 1:1).
Reaction SMILES: [Na].[CH:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C1(NC2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>O.C(O)CCC>[CH:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: O=Nc1ccc(Nc2ccccc2)cc1
Agent: [Na]
Agent: c1ccc(Nc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCO
Solvent: O
Product: Nc1ccc(Nc2ccccc2)cc1
Yield: 95 %

Procedure:
In this example the sodium salt of p-nitrosodiphenylamine was hydrogenated in a continuous manner over a fixed bed of catalyst. Diphenylamine (338 g, 2 mols) was converted to the sodium salt of p-nitrosodiphenylamine as in Example 2. A solution of approximately equal weights of toluene and 1-butanol was added to dilute the solution of the sodium salt to a concentration of about 13.5 wt. %, and enough water was added to dissolve all the inorganic salts present in the aqueous phase. The two phases were separated and simultaneously pumped into a tube reactor over a 0.4 wt. % palladium on charcoal catalyst at 125° C., 1000 psig hydrogen pressure at 1 liquid hourly space velocity based on total liquid. Thin layer chromatography indicated 100% conversion of p-nitrosodiphenylamine. Distillation of the residue after separation of the aqueous phase and removal of the organic solvents gave 95% p-aminodiphenylamine exclusive of losses from column hold-up.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.I[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CC(=O)CC>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 30 °C

Procedure:
Anhydrous K2CO3 (416 g, 3 mol) was added to a mixture of 4-bromo-4′-hydroxybiphenyl (300 g, 1.2 mol), 1-iodopentane (234 ml, 1.79 mol) and 2-butanone (600 ml). The reaction mixture was refluxed for 44 h until TLC (85:15 hexanes/EtOAc) showed complete consumption of the bromo alcohol. The mixture was cooled to about 30° C., diluted with CH2Cl2 (600 ml) and then filtered. The filtrate was washed twice with H2O and twice with a saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered and then dried at reduced pressure to provide a solid. This solid was isolated by filtration, washed repeatedly with a total of 2 L of ice-cold heptane to remove all traces of iodopentane and then dried overnight under high vacuum. Yield: 340 g (88%) of a white powder.