Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:15][N:14]([CH3:16])[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CN(C)C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)C1CCNCC1

Procedure:
A solution of the 1-benzyl-4-dimethylaminopiperidine in 125 ml. of methanol was shaken with 1.0 gm. of 10 percent palladium on carbon under 50 psi of hydrogen at 50°C. until one equivalent of hydrogen was consumed. The suspension was filtered and the filtrate concentrated at atmospheric pressure. The residue was distilled at 20 mm. Hg. to give 4-dimethylaminopiperidine, b.p. 90°-92°C.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:18]([O:20][C:21](=[O:26])[CH2:22][CH2:23][CH2:24]Br)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:26])[CH2:22][CH2:23][CH2:24][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)=[CH:16][CH:15]=1)[CH3:19]
Reactant: Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: CCOC(=O)CCCBr
Product: CCOC(=O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
Analogously to the method described in Example 5, the use of p-(1-adamantyl)-phenol and 4-bromobutyric acid ethyl ester as starting materials gives 4-[4-(1-adamantyl)-phenoxy]butyric acid ethyl ester of boiling point 150°C (0.03 mm).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[S:5](=[O:7])=[O:6].N#[N+][O-:10].[N+]([O-])=O.[OH2:14]>>[S:5](=[O:10])(=[O:7])([OH:6])[OH:14].[N+:1]([O-:4])([OH:3])=[O:2]
Reactant: O
Reactant: N#[N+][O-]
Reactant: O=S=O
Agent: O=[N+][O-]
Solvent: O=[N+]([O-])O
Product: O=S(=O)(O)O

Procedure:
In carrying out the process of the invention, an aqueous nitric acid solution containing about 1/11 to about 1/1.3 and preferably about 1/6 to about 1/2 by weight nitric acid is introduced into reactor 2 through line 10. The nitric acid solution is evenly distributed across the top of the reactor to establish a uniform flow of nitric acid downwardly through column 2. At the same time, gaseous sulfur dioxide is introduced into the bottom of column 2 through line 12. The sulfur dioxide flows through a gas distributor (not shown) positioned in the bottom of column 2, to establish an even flow of sulfur dioxide upwardly through column 2. The nitric acid and sulfur dioxide enter column 2 at a nitric acid to sulfur dioxide molar ratio of at least 0.7 to 1, and these reactants preferably enter at a molar ratio of at least 1 to 1. As the reactants pass through column 2 they come into intimate contact and react to produce nitric oxide product gas. Because the ratio of nitric acid to sulfur dioxide everywhere in column 2 is significantly greater than the stoichiometric ratio, very little or no nitric acid is reduced to nitrous oxide or nitrogen. Furthermore, the ratio of water to sulfur dioxide entering column 2 is sufficient to minimize nitrogen dioxide formation during the reaction stage of the process. Sulfuric acid waste, together with excess nitric acid and water leave column 2 via line 16 and are sent downstream to a spent acid treatment facility (not shown).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]([F:41])([F:40])[CH2:11][C@H:12]([C@@H:14]1[C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@H:28]([CH2:29][CH2:30]2)[C@:26]2([CH3:27])[C:21]([CH2:22][C@@H:23]([O:33]C4CCCCO4)[CH2:24][CH2:25]2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)[CH3:13]>CCOCC>[F:40][C:10]([F:41])([CH2:11][C@H:12]([C@@H:14]1[C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@H:28]([CH2:29][CH2:30]2)[C@:26]2([CH3:27])[C:21]([CH2:22][C@@H:23]([OH:33])[CH2:24][CH2:25]2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)[CH3:13])[CH2:9][OH:8]
Reactant: COC(=O)C(F)(F)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C[C@H](CC(F)(F)CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 103.2 %

Procedure:
To a suspension of lithium aluminium hydride (63 mg, 1.65 mmol) in ether (10 ml) the difluoroester (6) (1.40 g, 2.76 mmol) in ether (10 ml) was added and the mixture was stirred at 0° C. for 10 min and then stirred at room temperature for 10 min. The usual work-up (ether for extraction) gave a crude product, which was applied to a column of silica gel (100 g). Elution with n-hexane-ether (5:1) gave the alcohol (7) (1.13 g, 86%), viscous oil. 1H-NMR δ: 0.73 (3H, s, 18-H3), 1.03 (3H, s, 19-H3), 1.13 (3H, d, J=6 Hz, 21-H3), 3.33-4.10 (5H, m, 24-H2, 3-H, and THP), 4.76 (1H, m, THP), 5.38 (1H, m, 6-H). 19F-NMR δ: +43.3. MS m/z: 396 (M+ -DHP), 378.
Reaction SMILES: [ClH:1].Cl.[C@H]1(CN2CCC([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([F:44])=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])CC2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.N[CH:49]1[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][N:57]2[CH2:62][CH2:61][CH:60]([OH:63])[CH2:59][CH2:58]2)[CH2:51][CH2:50]1>>[ClH:1].[ClH:1].[OH:63][CH:60]1[CH2:61][CH2:62][N:57]([CH2:56][CH2:55][N:52]2[CH2:53][CH2:54][CH:49]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([F:44])=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:50][CH2:51]2)[CH2:58][CH2:59]1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(F)cc(F)c34)cccc2[nH]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCc3coc4cc(F)cc(F)c34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(4,6-difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (115, see example 66)) and amine 21 analogously to the method described in example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:13]=[N:14][S:15][CH:16]=[CH:17][C:18]=2[C:19]([O:21]C)=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-:23].[K+].O[NH2:26].Cl>CO>[OH:23][NH:26][C:19]([C:18]1[CH:17]=[CH:16][S:15][N:14]=[CH:13][C:12]=1[S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])=[O:21]
Reactant: NO
Reactant: [OH-]
Reactant: COC(=O)C1=C(S(=O)(=O)c2ccc(OC)cc2)C=NSC=C1
Agent: Cl
Agent: [K+]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2=C(C(=O)NO)C=CSN=C2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The methyl 4-[(4-methoxyphenyl)sulfonyl]-thiazepine-5-carboxylate (1 g, 2.90 mmol) in methanol (50 mL) is stirred at room temperature and the potassium hydroxide, hydroxyl amine solution (Fieser & Fieser Vol 1 ) is added (5 equiv). The resulting solution is stirred at room temperature for 6 h. The reaction mixture is acidified with 1N HCl and then extracted with dichloromethane. The organic extracts were dried (Na2SO4) and concentrated to a solid under reduced pressure. The solid is recrystallized from CH3CN/H2O to provide a white powder. MS (ESI): 347 (M+H+), 364 (M+NH4+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7](S([O-])(=O)=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Na+].[NH2-:17].[Na+].N>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([NH2:17])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2c(S(=O)(=O)[O-])cccc12
Reactant: [NH2-]
Agent: N
Agent: [Na+]
Product: Nc1cccc2c(N)cccc12
Yield: 89.5 %

Procedure:
In a 200-ml autoclave were placed 29.2 grams (0.13 mole) of anhydrous sodium 1-aminonaphthalene-5-sulfonate, 13.2 grams (0.33 mole) of sodium amide and 110 ml of liquid ammonia in the same manner as in Example 1. The resultant mixture was heated at 200° C for 5 hours. The reaction pressure in the autoclave was 180 atm. during the reaction. After the ammonia was removed, 50 ml of methanol was added to the reaction mixture for solvolysis. The product was extracted with chloroform and the chloroform was distilled off to produce crude 1,5-diaminonaphthaline. The recrystallization thereof from ether gave 18.4 grams of 1,5-diaminonaphthalene having a melting point of 187° to 189.5° C. Yield was 89.1%.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH2:13][CH2:14][NH2:15].C(OC1C=CC=CC=1)(=O)C.[Na].CC(O)C>O>[C:2]1([CH2:1][C:16]([OH:18])=[O:17])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: O=C(O)c1ccccc1
Agent: NCCC[C@H](N)C(=O)O
Agent: [Na]
Solvent: CC(=O)Oc1ccccc1
Solvent: CC(C)O
Solvent: O
Product: O=C(O)Cc1ccccc1
Temperature: 4 °C
Reaction time: 0.17 h

Procedure:
7.6 g (0.03 moles) of the L-ornithine benzoate was dissolved in 38 mL H2O and about 4.4 g of sodium phenyl acetate was dissolved 22 mL H2O, Subsequently, the sodium phenyl acetate solution was added to the L-ornithine benzoate solution and left to stir for about 10 minutes. About 240 mL of IPA (8:2 IPA:H2O) was added and the solution stirred for 30 minutes before cooling to 4° C. A crystalline solid precipitated after about 3 hours at 4° C. (L-ornithine phenyl acetate). The precipitate was isolated by vacuum filtration and washed with 48-144 mL of IPA. Yield: 57%.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.[F:17][C:18]1[CH:23]=[C:22](F)[CH:21]=[CH:20][C:19]=1[S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[CH3:29][N:28]([CH3:30])[S:25]([C:19]1[CH:20]=[CH:21][C:22]([O:1][C:2]2[C:7]3[CH:8]=[C:9]([CH3:11])[O:10][C:6]=3[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=2)=[CH:23][C:18]=1[F:17])(=[O:27])=[O:26]
Reactant: CN(C)S(=O)(=O)c1ccc(F)cc1F
Reactant: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2ccc(S(=O)(=O)N(C)C)c(F)c2)c2cc(C)oc2c1
Temperature: 100 °C
Yield: 88.9 %

Procedure:
A mixture of ethyl 4-hydroxy-2-methyl-1-benzofuran-6-carboxylate (500 mg, 2.27mmol), 2,4-difluoro-N,N-dimethylbenzenesulfonamide (553 mg, 2.75 mmol), Cs2CO3 (1.1 g, 4.12 mmol) and CuI (100 mg, 1 mmol) in DMF (20 mL) was heated to 100° C. for 4 hours. The solvent was removed under reduced pressure. The residue was poured into water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layers was washed with brine (20 mL×2), dried over Na2SO4 and concentrated. The product was purified via gradient silica gel column chromatography using EtOAc/Hex (10/90 to 30/70) to afford the desired compound (850 mg, 91%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.41 (t, J=7.16 Hz, 3 H) 2.48 (s, 3 H) 2.78-2.94 (m, 6 H) 4.40 (q, J=7.10 Hz, 2 H) 6.24 (s, 1 H) 6.66-6.94 (m, 2 H) 7.65 (s, 1 H) 7.79 (t, J=8.38 Hz, 1 H) 8.04 (s, 1 H); MS (ESI, pos): 422.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:14]3[O:15][CH:16]=[C:17]([CH2:19][NH:20][C:21](=[O:32])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:31])([F:30])[F:29])[N:18]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.[H-].[Na+].[CH3:35]I.O>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:14]3[O:15][CH:16]=[C:17]([CH2:19][N:20]([CH3:35])[C:21](=[O:32])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:31])([F:29])[F:30])[N:18]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: CI
Reactant: COc1ccc(-c2nc(CNC(=O)c3ccccc3C(F)(F)F)co2)cc1OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(CN(C)C(=O)c3ccccc3C(F)(F)F)co2)cc1OCC1CC1

Procedure:
N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-trifluoromethylbenzamide obtained in Example 25 was dissolved in 1 ml of dimethylformamide. A 30 mg quantity of sodium hydride was added thereto with ice-cooling and stirring, and the mixture was stirred for 30 minutes. A 30 mg quantity of methyl iodide was added thereto, and the reaction mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were then added thereto, and extraction was performed. The organic layer was washed with water twice and concentrated by removing the solvent under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=3:1) to give 35 mg of colorless oily N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-N-methyl-2-trifluoromethylbenzamide.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=1.[OH-].[Na+].Cl>CO.O1CCOCC1.O>[C:20]1([CH2:19][O:18][C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=2)[C:3]([OH:26])=[O:2])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Yield: 96.2 %

Procedure:
A solution of 41.4 g (0.12 mol) of 3,5-bis(phenylmethoxy)benzoic acid methyl ester and 59 ml (0.36 mol) of 6N NaOH in 700 ml of methanol and 350ml of dioxane was stirred at reflux for 17 hours. The solvents were removedat reduced pressure and the residue was dissolved in water and acidified topH 3 with 6N HCl. The resultant solid was filtered and recrystallized from methylene chloride-methanol to give 38.6 g (97% yield, mp 211°-213°) of 3,5-bis(phenylmethoxy)benzoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:16](=[O:17])[C:15](=[O:18])[NH:14][C:13](=[S:19])[N:12]1[CH3:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N+]=[N-])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[C:16](=[O:17])[C:15](=[O:18])[N:14]=[C:13]([S:19][CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:12]1[CH3:20])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: Cn1c(=S)[nH]c(=O)c(=O)n1C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cn1c(SC(c2ccccc2)c2ccccc2)nc(=O)c(=O)n1C(=O)OCc1ccccc1
Reaction time: 40 h

Procedure:
13.2 g of tetrahydro-2-methyl-5,6-dioxo-3-thioxo-as-triazine-1(2H)-carboxylic acid benzyl ester are dissolved in 500 ml of ethyl acetate and treated with a solution of diphenyldiazomethane in 90 ml of low-boiling petroleum ether. The initially violet solution is left to stand for 40 hours at 25° C., the colour becoming pink. 3 ml of glacial acetic acid are added and, after 1 hour, the mixture is evaporated in vacuo at 40° C. A yellow oil is obtained as the evaporation residue. This is separated by column chromatography on silica gel using benzene, benzene/ethyl acetate (95:5) and benzene/ethyl acetate (90:10) for the elution. The fractions containing the desired substance are combined and evaporated in vacuo at 40° C. After recrystallization from ethanol, there is obtained colourless pure substance of m.p. 90°-92° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9](Cl)=[N:10][CH:11]=1)=[O:5])C.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([NH:19][C:9]2[CH:8]=[CH:7][C:6]([C:4]([OH:3])=[O:5])=[CH:11][N:10]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH:13]1([NH-:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: NC1CCCCC1
Product: O=C(O)c1ccc(NC2CCCCC2)nc1
Product: [NH-]C1CCCCC1

Procedure:
2-Chloro-5-pyridinecarboxylicacid ethylester (g,,5.0 mMol) was treated with 10 mMol cyclohexylamine and the mixture heated for 6 hours at 100° in a sealed tube. Preparative HPLC of the crude product gave the title compound along with equal amounts of the N-cyclohexylamide of the starting ester.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:15]=[C:10]3[CH:9]=[C:8]2[C:20]2[C:25]([F:26])=[C:24](Cl)[N:23]=[CH:22][N:21]=2)=[CH:4][CH:3]=1.C(O)C>[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([S:16]([CH3:19])(=[O:17])=[O:18])[CH:15]=[C:10]3[CH:9]=[C:8]2[C:20]2[C:25]([F:26])=[CH:24][N:23]=[CH:22][N:21]=2)=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncnc(Cl)c1F)n2Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncncc1F)n2Cc1ccc(F)cc1
Temperature: 22.5 °C
Reaction time: 1.5 h
Yield: 81.5 %

Procedure:
A mixture of 1-(4-fluorobenzyl)-5-methanesulfonyl-2-(6-chloro-5-fluoropyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine obtained in Example 36 (5) (12 mg), ethanol (1 ml), ethyl acetate (1 ml) and 10% palladium on carbon (10 mg) was stirred under hydrogen stream at 15 to 30° C. for 1.5 hour. The catalyst was filtered through Celite. The filtrate was concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (methanol:dichloromethane=1:99) to obtain the desired product (9 mg) as a white powder.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[C@@H:6]([C:17]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])[CH2:5]1)([CH3:3])[CH3:2].[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([NH:39][C:40](=O)[O:41]C2C=CC=CC=2)[CH:36]=[CH:37][CH:38]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C1COCC1>[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([NH:39][C:40]([N:22]2[CH2:21][CH2:20][N:19]([C:17]([C@H:6]3[CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8][NH:7]3)=[O:18])[CH2:24][CH2:23]2)=[O:41])[CH:36]=[CH:37][CH:38]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)N2CCNCC2)C1
Reactant: O=C(Nc1cccc(OCc2ccccc2)c1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)N1CCN[C@@H](C(=O)N2CCN(C(=O)Nc3cccc(OCc4ccccc4)c3)CC2)C1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of tert-butyl (2R)-4-isopropyl-2-(piperazin-1-ylcarbonyl)piperazine-1-carboxylate (0.2 g, 0.59 mmol) and phenyl [3-(benzyloxy)phenyl]carbamate (0.189 g, 0.59 mmol) in THF (5 μL) was added triethylamine (91 uL, 0.65 mmol) and the reaction heated to 60° C. for 6 hours. The solvents were then removed in vacuo and the residue dissolved in DCM (3 ml), added TFA (3 ml) and stirred at room temperature for a further 90 mins. The reaction mixture was then concentrated under reduced pressure, residue partitioned between DCM/1M NaOH, extracted twice, combined organics passed through phase separating cartridge and evaporated to dryness to give a yellow gum. This was then purified by silica gel chromatography (Isco Companion™; 12 g column; 10% methanolic ammonia/DCM)
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][NH:6][CH:7]=1.[CH2:14](SSCCCC)[CH2:15][CH2:16]C.IC1C(C2C=NC=CC=2)=NNC=1>C(OCC)(=O)C.C(OCC)C>[CH2:1]([S:2][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][NH:6][CH:7]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCSSCCCC
Reactant: CSc1c[nH]nc1-c1cccnc1
Agent: Ic1c[nH]nc1-c1cccnc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCSc1c[nH]nc1-c1cccnc1
Yield: 18.4 %

Procedure:
Compound 21F was prepared following the procedure as described for the synthesis of compound 21A (see Scheme 3) using 1-butyldisulfanyl-butane as the disulfide and 3-(4-iodo-1H-pyrazol-3-yl)-pyridine (compound 20B). (flash chromatography conditions ethyl acetate/diethyl ether 3/1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]#[N:11])[CH:3]=[CH:2]1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14].C1COCC1>ClCCCl.C(Cl)Cl>[C:10]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[C:3]2[CH2:14][CH2:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])#[N:11]
Reactant: N#Cc1cccc2cc[nH]c12
Reactant: C=CC(=O)OCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCOC(=O)CCc1c[nH]c2c(C#N)cccc12
Temperature: 120 °C

Procedure:
A mixture of 1H-indole-7-carbonitrile (D2) (3.0 g), FeCl3 (3.4 g) and ethyl acrylate (7.5 mL) in DCE (3 mL) was added into 4 tubes respectively. In the fifth tube was added a mixture of 1H-indole-7-carbonitrile (2.0 g), FeCl3 (2.3 g) and ethyl acrylate (5 mL) in DCE (2 mL). The tubes were sealed and heated at 120° C. for 2 hours. After cooling to room temperature, the combined mixture was diluted with DCM and a little amount of THF. The solid was filtered off through celite. The mixture was washed with 0.5 M HCl solution three times and then brine. The organic solution was dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash chromatography to give Ethyl 3-(7-cyano-1H-indol-3-yl)propanoate (13.4 g). δH (CDCl3, 400 MHz): 1.23 (3H, t), 2.70 (2H, t), 3.10 (2H, t), 4.13 (2H, q), 7.16 (2H, m), 7.51 (1H, dd), 7.83 (1H, d), 8.88 (1H, br s).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CCN(CC)CC>C(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]([N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:4]
Reactant: O=C(Br)CBr
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CBr
Yield: 60.5 %

Procedure:
This novel compound was prepared as follows: Bromoacetyl bromide (4.25 g; 21 mmol) was added dropwise to a solution of dioctadecylamine (10 g; 19 mmol) and Et3N (2.13 g; 21 mmol) in CHCl3 (400 mL). After 4 h at room temperature the reaction solution was washed with H2O, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (n-hexane/Et2O=8/2 (v/v) to give the desired product (7.5 g; 11.5 mmol). Yield 61%. K. F.: <0.1%; The 1H-NMR, 13C-NMR, MS and IR spectra were consistent with the postulated structure
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:15].[CH2:16]([O:18][C:19](=[O:24])[CH:20]=[C:21](Cl)[CH3:22])[CH3:17]>O1CCCC1>[CH2:16]([O:18][C:19](=[O:24])/[CH:20]=[C:21](/[O:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[CH3:7])\[CH3:22])[CH3:17]
Reactant: CCOC(=O)C=C(C)Cl
Reactant: Cc1cccc(O)c1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(C)c1C
Temperature: 23 °C
Yield: 35 %

Procedure:
Potassium t-butoxide (11.2 g, 0.100 mol) was added to a stirred solution of 2,3-dimethyl-phenol (6.18 g, 0.051 mol) in tetrahydrofuran (40 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 7.50 g, 0.050 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(2,3-dimethyl-phenoxy)-but-2-enoic acid ethyl ester (4.10 g, 35%) as a yellow oil.