Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([S:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[C:19](=[O:30])[CH2:18]3)(=[O:16])=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.Cl[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.C(=O)(O)[O-].[Na+]>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([S:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH:24]4[CH2:29][CH2:28][N:27]([C:37]5[CH:36]=[CH:35][N:34]=[CH:33][CH:38]=5)[CH2:26][CH2:25]4)[C:19](=[O:30])[CH2:18]3)(=[O:16])=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: Clc1ccccn1
Reactant: O=C1CN(S(=O)(=O)c2ccc(-c3ccc(Cl)cc3)s2)CCN1CC1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CN(S(=O)(=O)c2ccc(-c3ccc(Cl)cc3)s2)CCN1CC1CCN(c2ccncc2)CC1
Temperature: 130 °C
Reaction time: 15 h

Procedure:
To 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-[5-(4-chlorophenyl)-2-thiophenesulfonyl]-2-piperazinone (115 mg) were added 4N hydrochloric acid in ethyl acetate (10 ml) and methanol (4 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated to give crude crystals of 4-[5-(4-chlorophenyl)-2-thiophenesulfonyl]-1-(piperidin-4-ylmethyl)-2-piperazinone hydrochloride. A mixture of the obtained 4-[5-(4-chlorophenyl)-2-thiophenesulfonyl]-1-(piperidin-4-ylmethyl)-2-piperazinone hydrochloride and chloropyridine hydrochloride (85 mg) was added to sodium bicarbonate solution, and the mixture was extracted with dichloromethane (twice), dried and concentrated. To the residue was added isoamylalcohol (10 ml), and the mixture was stirred at 130° C. for 15 hours. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. The solution was washed with 1N sodium hydroxide solution, dried and concentrated, and the residue was purified with silica gel column chromatography (dichloromethane:methanol containing 10% ammonia solution=10:1) to give colorless solid of the title compound (42 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3]1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[C:27]1[C:31]([C:32](O)=[O:33])=[C:30]([CH3:35])[O:29][N:28]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>C1COCC1>[C:12]1([CH2:11][CH2:10][CH2:9][C:8]([N:4]2[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][C:32]([C:31]3[C:27]([C:21]4[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:20]=4[Cl:19])=[N:28][O:29][C:30]=3[CH3:35])=[O:33])[CH2:3]2)=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NC1CCCN(C(=O)CCCc2ccccc2)C1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)NC1CCCN(C(=O)CCCc2ccccc2)C1
Yield: 66 %

Procedure:
Combine 1-(3-amino-piperidin-1-yl)-4-phenyl-butan-1-one (250 mg, 1.02 mmol) with 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid (260 mg, 1.02 mmol), 1.3-dicyclohexylcarbodiimide (209 mg, 1.01 mmol) and 1-hydroxybenzotriazole (138 mg, 1.02 mmol) in THF and stir overnight at room temperature. Concentrate and elute over silica gel using THF/dichloromethane to give the desired product (326 mg, 66%). MS(ES): (M+1)+ 484.1, 486.1 m/z.
Reaction SMILES: BrCCCCCC(C)C(OCC)=O.CC(C)(CCCCCI)C(OC)=O.O1CCCCC1[O:33][CH:34]([CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:35][CH2:36][CH2:37][N:38]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48](C)(C)[C:49]([O:51]C)=[O:50])[S:39]([CH3:42])(=[O:41])=[O:40]>>[OH:33][C@H:34]([CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:35]#[C:36][CH2:37][N:38]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50])[S:39]([CH3:42])(=[O:40])=[O:41]
Reactant: CCCCCC(CCCN(CCCCCC(C)(C)C(=O)OC)S(C)(=O)=O)OC1CCCCO1
Agent: CCOC(=O)C(C)CCCCCBr
Agent: COC(=O)C(C)(C)CCCCCI
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
The synthesis of this compound is carried out as described in Example 8 except that, in Step A, the ethyl 7-bromo-2-methylheptanoate is replaced by an equimolar amount of methyl 2,2-dimethyl-7-iodoheptanoate. The product of Step A is thus methyl 7-{N-[4-(2-tetrahydropyranyloxy)nonyl]methanesulfonamido}-2,2-dimethylheptanoate. The subsequent step yields 7-[N-(4-hydroxynonyl)methanesulfonamido]-2,2-dimethylheptanoic acid (B).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].[C:11](Cl)(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].S(=O)(=O)(O)O>CC(C)=O.O>[C:11]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 20 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
294 g (2.51 mol) of L-valine was dissolved into 786 g of ion-exchange water, 358 g (2.42 mol) of an aqueous solution of 27% sodium hydroxide and 363 g of acetone. With stirring the solution, 533 g (2.43 mol) of lauroyl chloride and 358 g (2.47 mol) of an aqueous solution of 27% sodium hydroxide were simultaneously added dropwise thereto so that pH=12±0.2 and the temperature is kept at 19 to 20° C. After completion of the addition, the solution was stirred at 20° C. for 60 minutes. Then, it was heated up to 40° C., and 171 g of 75% sulfuric acid was added thereto in order to adjust pH=1.5. The layers of the oily substance and water phase that separated at 60° C. were split, and 1950 g of warm water of 60° C. was added to the oily substance. After the mixture was cooled down to 20° C., the precipitated solid substance was filtered out and washed with water. Then, the substance was vacuum-dried at 50° C. to obtain 710 g of N-lauroyl-L-valine (2.37 mol, yield 98%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1>>[C:34]([O:33][C:31]([N:27]1[CH2:28][CH2:29][CH2:30][CH:25]([NH:24][C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:26]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(C(=O)OC(C)(C)C)C2)cn1
Yield: 61 %

Procedure:
As described for example 34, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using (+/−)-3-amino-1-N-Boc-piperidine instead of 1-methylpiperidin-4-amine, to the title compound (96 mg, 61%) which was obtained as a white foam. MS: m/e=493.3 [M+H]+.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[C:15]([CH2:27][OH:28])[CH:14]=1>C(Cl)Cl>[F:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([NH:20][C:21](=[O:26])[C:22]([CH3:23])([CH3:24])[CH3:25])=[C:15]([CH:27]=[O:28])[CH:14]=1
Reactant: CC(C)(C)C(=O)Nc1cc(F)c(F)cc1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(F)c(F)cc1C=O
Reaction time: 3 h
Yield: 26 %

Procedure:
Pyridiniumchlorochromate (9.36 g, 43.4 mmol) was added to the solution of the crude N-(4,5-difluoro-2-(hydroxymethyl)phenyl)pivalamide in CH2Cl2 (150 mL) at rt. The yellow solution turned into dark brown in 10 min, and the mixture was continued stirring for 3 hr, and then passed through a thin silica gel pad with CH2Cl2 (2×50 mL). The combined organic solution was concentrated on rotary vacuum, and purified on flash chromatography eluting with 20˜60% EtOAc/hexanes(1300 mL) to afford the expected product as a brown solid(1.91 g, 26% yield after three step); 1H NMR (400 MHz, CDCl3) δppm 1.29 (s, 9H), 7.42-7.48 (m, 1H), 8.75 (dd, J=13.35, 7.30 Hz, 1H), 9.77-9.80 (m, 1H), 11.40 (s, 1H); Mass spec. 242.08 (MH+), Calc. for C12H13F2NO2 241.09.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](B4OC(C)(C)C(C)(C)O4)[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.Br[C:27]1[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[N:31][CH:32]=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]4[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[N:31][CH:32]=4)[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:5][CH:6]=1
Reactant: CC1(C)OB(c2ccc3nccc(-c4ccncc4)c3c2)OC1(C)C
Reactant: NS(=O)(=O)c1cncc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cncc(-c2ccc3nccc(-c4ccncc4)c3c2)c1
Temperature: 120 °C

Procedure:
A mixture of 4-(4-pyridinyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (250 mg, 0.75 mmol), 5-bromopyridine-3-sulfonamide (213 mg, 0.9 mmol), tetrakistriphenylphosphine palladium (0) (95 mg, 0.08 mmol), and saturated aqueous NaHCO3 (2.5 mL), and dioxane (5 mL)) was heated at 120° C. for 1 h and cooled to room temperature. The reaction mixture was filtered through Celite and the solvent was removed under reduced pressure. The crude product was purified by Gilson reverse phase HPLC (8-25% 6 min gradient 0.1% TFA in H2O/CH3CN) followed by neutralization with saturated aqueous NaHCO3 and extracted into EtOAc. Evaporation provided the title compound as an off white solid. (85 mg, 31%). ESMS [M+H]+=363.1
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH3:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]=O>CO.C(OCC)C>[N:1]1([CH2:10][N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:19])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: C=O
Reactant: c1ccc2[nH]nnc2c1
Reactant: CNCc1ccccc1
Solvent: CO
Solvent: CCOCC
Product: CN(Cc1ccccc1)Cn1nnc2ccccc21
Temperature: 50 °C
Yield: 85 %

Procedure:
Benzotriazole (6 g, 50 mmol) and N-methylbenzylamine (10.57 ml, 55 mmol) were dissolved in methanol (MeOH) (25 ml) followed by drop wise addition of formaldehyde (4.9 ml, 37% in H2O). The resulting mixture was heated at 50° C. for 15 h and cooled to ambient temperature. It was then diluted with diethyl ether (Et2O) (100 ml), washed with saturated sodium chloride aqueous solution (brine) (2×70 ml) and dried over magnesium sulfate (MgSO4) and concentrated. Upon further drying under reduced pressure, the material solidified to afford the depicted compound (13.2 g, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1.C(N(CC)CC)C>CCO>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC1CCN(c2ncc(Br)cn2)CC1
Temperature: 90 °C

Procedure:
A mixture of 5-bromo-2-chloropyrimidine (5 g, 25.8 mmol), piperidin-4-ol (2.88 g, 28.4 mmol) and triethylamine (5.40 mL, 38.8 mmol) in EtOH (51.7 mL) was heated at 90° C. for 0.5 h. The solvent was evaporated, the residue was diluted with 1N HCl (20 mL) and extracted with EtOAc (3×15 mL). The combined organic fractions were dried over Na2SO4 and the solvent was evaporated. The product was recrystallized from CH2Cl2/hexanes, filtered and washed with hexanes to afford the title product.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][CH:32]([O:35][CH2:36][C:37](=[O:39])[CH3:38])[CH2:31][CH2:30]1.[CH3:40][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[OH:39][C:37]([CH3:40])([CH3:38])[CH2:36][O:35][CH:32]1[CH2:31][CH2:30][CH:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:34][CH2:33]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OCC(C)=O)CC2)c2ncnn12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OCC(C)(C)O)CC2)c2ncnn12
Reaction time: 3 h
Yield: 78 %

Procedure:
4′-({5-Oxo-4-[4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.17 g) was dissolved in tetrahydrofuran (15 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 0.27 mL) was added at room temperature. The reaction mixture was stirred for 3 hr, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.14 g, 78%).
Reaction SMILES: [CH3:1][N:2]1[C:16]2[C:17]3[C:4]([CH2:5][C@@H:6]4[C:11]([C:12]=3[CH:13]=[CH:14][CH:15]=2)=[CH:10][C@@H:9]([CH2:18][N:19]=[N+]=[N-])[CH2:8][N:7]4[CH3:22])=[CH:3]1.[BH4-].[Na+].O>C(O)(C)C>[CH3:1][N:2]1[C:16]2[C:17]3[C:4]([CH2:5][C@@H:6]4[C:11]([C:12]=3[CH:13]=[CH:14][CH:15]=2)=[CH:10][C@@H:9]([CH2:18][NH2:19])[CH2:8][N:7]4[CH3:22])=[CH:3]1
Reactant: CN1C[C@H](CN=[N+]=[N-])C=C2c3cccc4c3c(cn4C)C[C@H]21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CN1C[C@H](CN)C=C2c3cccc4c3c(cn4C)C[C@H]21
Reaction time: 24 h
Yield: 54.9 %

Procedure:
3.2 g 1,6-dimethyl-8β-azidomethyl-9, 10-didehydroergoline in 150 mls of isopropyl alcohol are treated with 6.4 g NaBH4 and heated to reflux under stirring and under nitrogen atmosphere for 24 hours. After this time further 2 g of NaBH4 are added and the heating is continued for 24 hours more. The reaction mixture is poured into water and extracted with chloroform. The chloroform extract is chromatographed onto SiO2 and the product is eluted with CH2Cl2 /MeOH/NH4OH (9/1/0.5). 1.6 g of 1,6-dimethyl-8β-aminomethyl-9, 10-didehydroergoline are thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>CN(C=O)C>[F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=C(O)c1ccncc1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccncc1F

Procedure:
A mixture of 1.658 g (11.75 mmol) of 3-fluoroisonicotinic acid, 15 ml of thionyl chloride and three droplets of DMF was heated under reflux for 2 hours. The reaction mixture was allowed to cool, and then concentrated under reduced pressure to obtain 3-fluoroisonicotinoyl chloride. The compound thus obtained was then dissolved in 10 ml of acetone. The solution thus obtained was then added dropwise to a solution of 984 mg of ammonium thiocyanate in 15 ml of acetone with stirring in 5 minutes. After the termination of dropwise addition, the reaction mixture was heated to a temperature of 40° C. with stirring for 5 minutes. The resulting insoluble matters were then removed by filtration to obtain an acetone solution of 3-fluoroisonicotinoyl isothiocyanate. To the solution thus obtained was then added dropwise a solution of 1.55 g of 4-chloro-N-methylaniline in 10 ml of acetone with stirring for 5 minutes. The reaction mixture was stirred at room temperature for 17 hours, and then poured into about 1,000 ml of ice-water. The resulting crystal was collected by filtration, washed with water, and then dried under reduced pressure. The resulting crude product was then purified through silica gel column chromatography (eluant: CHCl3 +2% methanol) to obtain 1.452 g of 1-(4-chlorophenyl)-3-(3-fluoroisonicotinoyl)-1-methylthiourea.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([S:11]([CH2:13][CH3:14])=[O:12])[CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[CH2:13]([S:11]([C:4]1[CH:3]=[C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:9]=[C:8]([CH3:10])[C:5]=1[C:6]#[N:7])=[O:12])[CH3:14]
Reactant: CCS(=O)c1cc(Cl)cc(C)c1C#N
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCS(=O)c1cc(N2CCOCC2)cc(C)c1C#N
Temperature: 100 °C
Yield: 58.1 %

Procedure:
4-Chloro-2-(ethylsulfinyl)-6-methyl-benzonitrile (0.31 g, 1.36 mmol), morpholine (0.36 ml, 4.09 mmol) and potassium carbonate (0.24 g, 1.77 mmol) are taken up in N-methyl-2-pyrrolidone (3 ml) in a sealed tube and the resulting mixture is heated at 100° C. for 16 h. The mixture is then diluted with water (6 ml) and extracted with ethyl acetate (3×10 ml). The organic layer is washed with water (2×10 ml), brine (20 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 50% ethyl acetate/hexane) to yield 2-(ethylsulfinyl)-6-methyl-4-morpholin-4-yl-benzonitrile (0.22 g, 0.79 mmol, 58%).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:38][C@@H:39]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=1)[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>CN(C=O)C.CC(=O)OCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:38][C@H:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:47][C:48]2[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=2)=[O:11])=[CH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 5 h
Yield: 77.1 %

Procedure:
Prepared using General Procedure 7. Into a solution of 4-(tert-butyl)benzoic acid (8.3 g, 46.4 mmol) in DMF (100 mL) were added HATU (19.2 g, 50.6 mmol), TEA (17.6 mL, 126.4 mmol) and (S)-tert-butyl 2-amino-3-(4-hydroxyphenyl)propanoate (10.0 g, 42.1 mmol). After 5 h, the reaction mixture was diluted with EA, washed with saturated aqueous NaHCO3 and brine, then dried (Na2SO4), concentrated, and purified by chromatography (EA/hexanes) to provide 12.9 g (69%) of tert-butyl (4-(tert-butyl)benzoyl)-L-tyrosinate. LCMS-ESI (m/z) calculated for C24H31NO4: 397.5; no m/z observed, tR=3.59 min (Method 1). 1H NMR (400 MHz, CDCl3) δ7.71-7.65 (m, 2H), 7.47-7.39 (m, 2H), 7.04 (t, J=5.7 Hz, 2H), 6.78-6.70 (m, 2H), 6.59 (d, J=7.5 Hz, 1H), 4.91 (dt, J=7.5, 5.6 Hz, 1H), 3.15 (qd, J=14.0, 5.6 Hz, 2H), 1.45 (s, 9H), 1.33 (s, 9H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH:11]=[CH2:12].O>C(#N)C>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:12][CH2:11][C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(C)N1CCNCC1
Solvent: CC#N
Solvent: O
Product: CC(C)N1CCN(CCC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-Isopropylpiperazine (650 mg) is dissolved in acetonitrile (7 ml) and thereto is added t-butyl acrylate (743 μl) under ice-cooling. The reaction solution is warmed to room temperature and stirred for 4 hours, and thereto is added additional t-butyl acrylate (148 μl), and then the mixture is stirred at room temperature for another 10 hours. Additional t-butyl acrylate (222 μl) is added to the reaction solution, and the mixture is stirred for 6 hours, thereto is poured water and the solution is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 followed by 10/1) to give t-butyl 3-(4-isopropylpiperazin-1-yl)propionate (1.18 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[N:4][C:5](F)=[C:6]([Cl:8])[CH:7]=1.[OH-:11].[Na+].[OH2:13]>C(O)CO>[Cl:8][C:6]1[C:5]([O:11][CH2:3][CH:2]=[CH:7][CH2:6][OH:13])=[N:4][C:3]([F:10])=[C:2]([Cl:1])[CH:7]=1
Reactant: [OH-]
Reactant: O
Reactant: Fc1nc(F)c(Cl)cc1Cl
Agent: [Na+]
Solvent: OCCO
Product: OCC=CCOc1nc(F)c(Cl)cc1Cl
Reaction time: 2 h

Procedure:
To a solution of 11 grams (0.06 mole) of 3,5-dichloro-2,6-difluoropyridine in 35 milliliters of ethylene glycol was added over a 15 minute period 2.44 grams of sodium hydroxide in 35 milliliters of butenediol(2-butene-1,4-diol). The mixture was heated to ~70° C. and agitated for ~31/2 hours. Thereafter the mixture was poured into water and extracted with hot hexane. Most of the hexane was removed and upon cooling the 4-(3,5-dichloro-6-fluoro-2-pyridyloxy)-2-buten-1-ol product precipitated out. The product was recovered in a yield of 9 grams (60 percent of theoretical) and melted at 30° C. Upon analysis, the product was found to have carbon, hydrogen, chlorine and nitrogen contents of 43.3, 2.8, 27.8 and 5.6 percent, respectively, as compared with the theoretical contents of 42.9, 3.2, 28.1 and 5.6 percent, respectively, as calculated for the above named structure.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH:17]([CH3:19])[CH3:18])=[C:7]([CH:16]=1)[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Br[CH2:21][CH2:22][CH2:23][N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH:17]([CH3:19])[CH3:18])=[C:7]([CH:16]=1)[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:21][CH2:22][CH2:23][N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])[CH2:12][CH2:11]1
Reactant: Cc1ccc(C(C)C)c(OCC2CCNCC2)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(C)C)c(OCC2CCN(CCCN3C(=O)c4ccccc4C3=O)CC2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
11.35 g (0.04 mol) of 4-[[5-methyl-2-(1methylethyl)phenoxy]methyl]piperidine hydrochloride, 10.72 g (0.04 mol) of 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione and 13.8 g (0.1 mol) of potassium carbonate are reacted in 113 ml of N,N-dimethylformamide. The mixture is stirred for 3 h at 100° C. It is poured into ice-cold water. The solution is extracted with ethyl acetate and it is washed with water. The organic phase is dried over sodium sulphate, filtered and concentrated under reduced pressure. The product obtained is used as is in the following stage.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:6]([CH3:14])[C:7](=[O:13])[NH:8]2.C1C(=O)N([Br:28])C(=O)C1>C(Cl)Cl>[Br:28][C:12]1[C:3]([O:2][CH3:1])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:13])[N:6]([CH3:14])[CH:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc2c1C(c1ccccc1)N(C)C(=O)N2
Solvent: ClCCl
Product: COc1c(Br)ccc2c1C(c1ccccc1)N(C)C(=O)N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-Methoxy-3-methyl-4-phenyl-3,4-dihydro-1H-quinazolin-2-one (1.38 g, 0.005 mol) and NBS (0.82 g, 0.0046 mol) in DCM (150 mL) is stirred at r.t. for 4 h. The mixture is extracted with DCM from water and purified by column chromatography on silica gel using an ethylacetate and petrol ether gradient to give the desired product.