Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.C[O:31]C1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:21])([CH3:22])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=[O:31])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C=C(OCC)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Solvent: C1COCCO1
Product: CCOC(=O)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
A suspension of compound 5 (400 mg, 0.99 mmol) and Lawesson's Reagent (402 mg, 0.99 mmol) in anhydrous 1,4-dioxane (15 mL) was stirred at 150° C. for 30 min in a CEM microwave reactor. The mixture was concentrated in vacuo, and the residue was purified by prep-TLC to give compound 6 (140 mg, 34%) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([C:9]3[N:14]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[C:12]([O:22][CH3:23])=[CH:11][N:10]=3)[C:5]=2[CH3:24])[CH2:3][CH2:2]1.Br[CH2:26][C:27]1[C:28]([Cl:38])=[C:29]([CH:34]=[CH:35][C:36]=1[Cl:37])[C:30]([O:32]C)=[O:31].[H-].[Na+]>C1COCC1>[Cl:38][C:28]1[C:27]([CH2:26][N:8]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[C:5]([CH3:24])[C:6]([C:9]3[N:14]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[C:12]([O:22][CH3:23])=[CH:11][N:10]=3)=[N:7]2)=[C:36]([Cl:37])[CH:35]=[CH:34][C:29]=1[C:30]([OH:32])=[O:31]
Reactant: COc1cnc(-c2n[nH]c(C3CC3)c2C)nc1Nc1ccncc1
Reactant: COC(=O)c1ccc(Cl)c(CBr)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cnc(-c2nn(Cc3c(Cl)ccc(C(=O)O)c3Cl)c(C3CC3)c2C)nc1Nc1ccncc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
200 mg of 2-(5-cyclopropyl-4-methyl-1H-pyrazol-3-yl)-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine 1-16-1 (0.62 mmol, 1.0 eq.), 184.86 mg of methyl 3-(bromomethyl)-2,4-dichlorobenzoate (0.62 mmol, 1.0 eq.) and 31.0 mg of 60% sodium hydride in paraffin oil were suspended in 6.3 mL of dry THF and stirred for 20 hours at rt. The reaction mixture was partitioned between water and DCM/propan-2-ol 4:1. The separated aqueous layer was extracted three times with DCM/propan-2-ol 4:1. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The purification by flash chromatography and preparative HPLC of the residue provided 37.5 mg (0.07 mmol, 11%) of analytically pure target compound.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)(=[O:3])[CH3:2].[C:16]([OH:22])([C:18]([F:21])([F:20])[F:19])=[O:17]>C(Cl)Cl>[F:19][C:18]([F:21])([F:20])[C:16]([OH:22])=[O:17].[NH:7]1[CH2:8][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6]1
Reactant: CC(=O)OC1CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OC1CNC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 3-acetoxyazetidine-1-carboxylate (Intermediate 95, 0.914 g) in DCM (5 mL) was added TFA (5 mL) and the mixture was stirred at room temperature for 30 minutes. The resultant mixture was concentrated in vacuo and azeotroped with toluene and diethyl ether to give acetic acid azetidin-3-yl ester trifluoroacetate salt (1.40 g) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]([NH:17][NH2:18])(=O)[CH:13]([CH3:15])[CH3:14]>O=P(Cl)(Cl)Cl>[Br:11][C:8]1[CH:7]=[C:3]([C:4]2[O:6][C:12]([CH:13]([CH3:15])[CH3:14])=[N:17][N:18]=2)[C:2]([NH2:1])=[N:10][CH:9]=1
Reactant: CC(C)C(=O)NN
Reactant: Nc1ncc(Br)cc1C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1nnc(-c2cc(Br)cnc2N)o1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 2-amino-5-bromo-nicotinic acid (1.0 g, 4.60 mmol) in POCl3 (20 mL) was added isobutyric acid hydrazide (705 mg, 6.912 mmol) at RT. The reaction temperature was slowly heated to 100° C. and stirred for 18 h. The solvent was evaporated under reduced pressure, the residue was basified with saturated cold sodium bicarbonate solution (50 mL), extracted with ethyl acetate (3×50 mL), organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Crude compound was purified by column chromatography using 100-200 mesh silica gel. The column was eluted with 40% EtOAc in petroleum ether to afford the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[CH3:20][CH:21]([CH3:25])[CH2:22][CH2:23][NH2:24].O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C@H:7]3[C@H:8]([CH2:13][C:14](=[O:16])[N:24]3[CH2:23][CH2:22][CH:21]([CH3:25])[CH3:20])[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Reactant: CC(C)CCN
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCC(C)C
Reaction time: 10 h
Yield: 56.3 %

Procedure:
4.6 g (0.01755 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 80 ml of toluene, 2.04 ml (0.01755 mol) of 3-methyl-butylamine were added thereto and the mixture was boiled for 24 hours on a water separator. After concentration the residue was hydro-genated with 1.8 g of Raney-nickel in 200 ml of ethanol at 120° and 140 bar for 10 hours. The material obtained was chromatographed over silica gel with cyclohexane/ethyl acetate 3:1. The product was dissolved in hot isopropyl ether and crystallized at room temperature. There were obtained 2.84 g (56%) of rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-3-(3-methyl-butyl)-2H-benzo[e]indol-2-one as white crystals with m.p. 81°-82° and 0.79 g (16%) of oily material from the mother liquors.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][C:6]3([O:13][CH2:14][CH2:15][OH:16])[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([CH2:17][N:18]4[C:22]([CH3:23])=[C:21]([I:24])[CH:20]=[N:19]4)([CH2:5]3)[CH2:3]1)[CH2:9]2.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl.C(OCC)(=O)C>[CH3:32][S:33]([O:16][CH2:15][CH2:14][O:13][C:6]12[CH2:12][C:2]3([CH3:1])[CH2:9][C:8]([CH3:11])([CH2:10][C:4]([CH2:17][N:18]4[C:22]([CH3:23])=[C:21]([I:24])[CH:20]=[N:19]4)([CH2:3]3)[CH2:5]1)[CH2:7]2)(=[O:35])=[O:34]
Reactant: Cc1c(I)cnn1CC12CC3(C)CC(C)(C1)CC(OCCO)(C3)C2
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(I)cnn1CC12CC3(C)CC(C)(C1)CC(OCCOS(C)(=O)=O)(C3)C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cold (0° C.) solution of EXAMPLE 82C (2.1 g) in methylene chloride (30 mL) was added triethylamine (1.42 g) followed by methanesulfonyl chloride (0.542 g). The mixture was stirred at room temperature for 1.5 hours and then was diluted with ethyl acetate (300 mL). The layers were separated, and the organic layer was washed with water (60 mL) and brine (60 mL), dried with Na2SO4, filtered and concentrated to give the title compound, which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40](=[O:46])[N:41]([CH2:43][CH2:44][OH:45])[CH:42]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:38]=[CH:39][C:40](=[O:46])[N:41]([CH2:43][CH2:44][OH:45])[CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=c1ccc(Br)cn1CCO
Product: C[C@@H](c1ccc(-c2ccc(=O)n(CCO)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromo-1-(2-hydroxyethyl)pyridin-2(1H)-one following a procedure analogous to that described in Example 20 Step 2. LC-MS Method 2 tR=1.08 min, m/z=513, 491; 1H NMR (CD3OD) δ 0.95 (s, 3H), 1.24 (s, 3H), 1.26 (s, 1H), 1.52 (d, 3H), 2.12 (s, 2H), 2.18 (m, 1H), 2.40-2.53 (m, 2H), 3.02 (m, 1H), 3.52 (m, 0.5H), 3.64 (m, 0.5H), 3.83 (t, 1H), 4.15 (t, 1H), 5.53 (m, 1H), 6.61 (m, 1H), 7.01 (d, 2H), 7.25-7.40 (m, 7H), 7.79 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.Cl.[N:24]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:29][CH2:28][O:27][CH2:26][C:25]1=[O:30].C([N:39](CC)CC)C.Cl.N1CCCCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[N:24]1([CH:31]2[CH2:36][CH2:35][N:34]([C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])([NH:12][C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:14])[C:9]([NH2:39])=[O:11])[CH2:33][CH2:32]2)[CH2:29][CH2:28][O:27][CH2:26][C:25]1=[O:30]
Reactant: O=C(Nc1ccc(Cl)cc1)NC(C(=O)O)c1ccccc1F
Reactant: CCN(CC)CC
Reactant: O=C1COCCN1C1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)C(NC(=O)Nc1ccc(Cl)cc1)(c1ccccc1F)N1CCC(N2CCOCC2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.5 %

Procedure:
To a solution of 2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (50 mg, 0.15 mmol), 4-(3-morpholinon-4-yl)piperidine hydrochloride (45 mg, 0.20 mmol) and triethylamine (0.086 mL, 0.62 mmol) in DMF (1.0 mL, containing 0.10 mL of H2O to solubilize the piperidine hydrochloride), BOP (100 mg, 0.23 mmol) was added. After being stirred at room temperature for 30 min, the mixture was purified by HPLC to give the titled compound (20 mg). MS 489.4 and 491.4 (M+H, Cl pattern).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].[OH:22][N:23]=[C:24](Br)[Br:25]>CN(C=O)C.O.C(OCC)(=O)C>[Br:25][C:24]1[CH2:3][CH:2]([CH2:1][O:4][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]3)[O:22][N:23]=1
Reactant: ON=C(Br)Br
Reactant: C=CCOc1ccc2c(c1)CCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCc2cc(OCC3CC(Br)=NO3)ccc2N1
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To a solution of 6-(allyloxy)-3,4-dihydroquinolin-2(1H)-one (1.85 g, 9.10 mmol) in DMF (20 mL) and water (5 mL), K2CO3 (3.77 g, 27.3 mmol) were added and the reaction mixture was cooled to 0° C. Hydroxycarbonimidic dibromide (3.69 g, 18.21 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water, brine, and dried over Na2SO4. The organic layer was concentrated and the crude material purified by flash chromatography on silica gel using ethyl acetate/hexane as eluant to give 6-((3-bromo-4,5-dihydroisoxazol-5-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one as a white solid (1.8 g, 59.6%). 1HNMR: 400 MHz, DMSO-d6: δ 2.40 (q, J=7.20 Hz, 2H), 2.83 (t, J=8.00 Hz, 2H), 3.18 (dd, J=7.60, 17.60 Hz, 1H), 3.50 (dd, J=10.80, 17.40 Hz, 1H), 4.01-4.09 (m, 2H), 4.98-5.03 (m, 1H), 6.72-6.81 (m, 3H), 9.92 (s, 1H). LCMS: RT 1.408 min; LCMS (ES-API), m/z 327 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:18]=2[C@@H:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([N:25]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:20]2)=[O:11])=[N:4][C:5](Br)=[C:6]([F:8])[CH:7]=1.[F:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:38]=1B(O)O.C(N(CC)CC)C>CCO.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:18]=2[C@@H:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([NH2:25])[CH2:20]2)=[O:11])=[N:4][C:5]([C:38]2[C:37]([F:36])=[CH:42][CH:41]=[CH:40][C:39]=2[F:43])=[C:6]([F:8])[CH:7]=1
Reactant: Nc1cc(F)c(Br)nc1C(=O)Nc1cnccc1[C@@H]1CCC[C@H](N2C(=O)c3ccccc3C2=O)C1
Reactant: OB(O)c1c(F)cccc1F
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)Nc1cnccc1[C@@H]1CCC[C@H](N)C1

Procedure:
A solution of 3-amino-6-bromo-N-(4-((1R,3S)-3-(1,3-dioxoisoindolin-2-yl)cyclohexyl)pyridin-3-yl)-5-fluoropicolinamide (1.0 equiv), 2,6-difluorophenyl boronic acid (3.0 equiv.), tetrakistriphenylphosphine (0.2 equiv.) and triethylamine (3.0 equiv.) in 1:1 EtOH/toluene (0.1 M) was heated at 120° C. with microwave irradiation for 1200 seconds. Upon cooling, removal of the volatiles in vacuo, the Suzuki product was directly purified by reverse phase HPLC. The product fraction was lyophilized and the resulting phthalimide group was deprotected as described in Method 9 yielding, after RP HPLC purification and lyophilization, 3-amino-N-(4-((1R,3S)-3-aminocyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamideas the TFA salt. LCMS (m/z): 442.2 (MH+); LC Rt=2.24 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14]CC)=O)=[C:5]2[C:17](=O)[C:18]([O:20][CH3:21])=[O:19].[C:23]1([NH:29][NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.CC(C)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:14])[N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:30]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1c(C(=O)C(=O)OC)c2cc(Cl)ccc2n1C
Reactant: NNc1ccccc1
Solvent: CC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1nn(-c2ccccc2)c(=O)c2c1c1cc(Cl)ccc1n2C
Reaction time: 15 h
Yield: 79.7 %

Procedure:
A solution of 19 g (59 mmol) of methyl 5-chloro-2-(ethoxycarbonyl)-1-methyl-α-oxo-1H-indole-3-acetate and 26 g (240 mmol) of phenylhydrazine in 250 ml of acetic acid is heated at reflux for 2 h. The mixture is cooled, 250 ml of a 1/1 mixture of water and of acetone are added and the mixture is left standing at 4° C. for 15 h. The precipitate is collected by filtration, washed with water and with acetone and dried under reduced pressure. 17.4 g (47 mmol) of solid are obtained.
Reaction SMILES: [CH2:1]([OH:8])[C@@H:2]([C@@H:4]([CH2:6][OH:7])[OH:5])[OH:3].[C:9]([O:28]C)(=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C[O-].[Na+]>[C:9]([O:3][C@H:2]([C@@H:4]([CH2:6][O:7][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[O:5][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:1][O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Reactant: OC[C@@H](O)[C@@H](O)CO
Agent: C[O-]
Agent: [Na+]
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC[C@H](OC(=O)CCCCCCC/C=C\CCCCCCCC)[C@@H](COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)CCCCCCC/C=C\CCCCCCCC

Procedure:
Erythritol and a five-fold molar excess of methyl oleate are heated at 180° C. under vacuum, with agitation, in the presence of sodium methoxide catalyst over two reaction periods of several hours each. The reaction product (predominately erytiritol tetraoleate) is refined in petroleum ether and crystallized three times from several volumes of acetone at 1° C.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=O)[CH2:3][CH2:4][S:5][CH3:6].[C:10](=[O:12])=O.[NH2:13][C@H](C([O-])=O)CCSC.[K+]>>[CH3:6][S:5][CH2:4][CH2:3][CH:2]1[NH:1][C:10](=[O:12])[NH:13][C:7]1=[O:9]
Reactant: CSCC[C@H](N)C(=O)[O-]
Reactant: O=C=O
Reactant: CSCCC(N)C(=O)O
Agent: [K+]
Product: CSCCC1NC(=O)NC1=O

Procedure:
To achieve this object, the present invention provides a process for the preparation of D,L-methionine, in which carbon dioxide is fed to an aqueous potassium methioninate solution obtained by hydrolysis of 5-(2-methylmercaptoethyl)hydantoin, in order to precipitate out crude methionine, which is separated off and purified, where, for the purposes of purification, an aqueous solution of the separated-off crude methionine is prepared and subjected to a recrystallization. In the process, the solution from which the recrystallization takes place contains potassium ions and also a crystallization additive, where the crystallization additive is a nonionic or anionic surfactant, or a mixture of different nonionic or anionic surfactants. According to the invention, the recrystallization takes place by introducing a 60 to 110° C.-hot methionine solution into a 35 to 80° C.-warm methionine suspension, the temperature of which is lower than that of the introduced solution, the temperature of the methionine suspension being maintained between 35 and 80° C. during the addition.
Reaction SMILES: [Br-].[C:2]1([CH2:8][CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:34]1([CH:46]=O)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CCOCC>[C:2]1([CH2:8][CH:9]=[CH:46][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=CC1CCCCCCCCCCC1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: C(=CC1CCCCCCCCCCC1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To 11.4 g (25.5 mmol) of phenylethyl triphenylphosphonium bromide in 50 mL of dry ether at 0° C. is added 10.2 mL (25.5 mmol) of 2.5M butyllithium. The suspension is stirred at 0° C. for 1 hour followed by the addition of 5.0 g (25.5 mmol) of cyclododecane carboxaldehyde. The mixture is stirred at room temperature for 3 hours after which time no starting material is evident by TLC. The reaction mixture is quenched with 1N HCl. The layers are separated and the aqueous layer is washed twice with ethyl ether. The combined organic layers are dried over a MgSO4 and the ether is evaporated. The residue is flash chromatographed on silica gel using hexanes to give 6.4g of a colorless oil: NMR (CDCl3) δ1.0-1.6 (m, 10H), 2.6 (m, 1H), 3.4 (d, 2H, J=8 Hz, ), 5.3 (t, 1H, J=7 Hz), 5.45 (q, 1H, J=7 Hz), 7.2 ppm (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:41])[C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:40])[NH:26][C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=2)[C:30]([OH:32])=O)=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CO.[NH2:50][CH:51]([CH2:54][OH:55])[CH2:52][OH:53]>ClCCl.O1CCCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25]([NH:26][C:27]2[CH:35]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:33]=[C:29]([C:30](=[O:32])[NH:50][CH:51]([CH2:54][OH:55])[CH2:52][OH:53])[CH:28]=2)=[O:40])=[CH:22][CH:23]=1)[CH3:41])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2cc(C(=O)O)cc(C(F)(F)F)c2)cc1
Reactant: NC(CO)CO
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2cc(C(=O)NC(CO)CO)cc(C(F)(F)F)c2)cc1
Yield: 60.3 %

Procedure:
In dichloromethane (3.5 mL), 60 mg (0.105 mmol) of 3-(3-{4-[6-(tert-butoxycarbonyl-methylamino)-purin-9-yl]phenyl}ureido)-5-(trifluoromethyl)benzoic acid was dissolved, and 54.9 μL (0.63 mmol) of oxalyl chloride was slowly added thereto and the mixture solution was stirred under refluxing for 1.5 hours. The solvent was distilled under reduced pressure from the reaction solution and the obtained residue was dissolved in tetrahydrofuran (0.75 mL). The tetrahydrofuran solution thus prepared was added dropwise to a methanol (0.5 mL)/tetrahydrofuran (0.25 mL) solution of 28.7 mg (0.315 mmol) of 2-amino-1,3-propanediol and the resulting solution was stirred at room temperature for 1.5 hours. The solvent was distilled under reduced pressure from the reaction solution and the obtained residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1 to 5:1) to obtain 40.8 mg (60%) of a target product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:16]([N:18]1[C:22]([OH:23])=[CH:21][CH:20]=[N:19]1)[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1.Cl>C(#N)C>[CH2:16]([N:18]1[C:22]([OH:23])=[C:21]([C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:10]([Cl:11])[C:2]=2[Cl:1])[CH:20]=[N:19]1)[CH3:17]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1Cl
Reactant: CCn1nccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CC#N
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(Cl)c2Cl)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 500 mg (1.85 mmol) of 2,3-dichloro-4-methylsulfonylbenzoic acid and 240 mg (2.14 mmol) of 1-ethyl-5-hydroxypyrazole in 10 mL of dry acetonitrile was treated with 430 mg (2.08 mmol) of dicyclohexylcarbodiimide with stirring at ambient temperature for 0.5 hr. The precipitate that formed was removed by filtration and the filtrate was treated with 0.5 mL of triethylamine and 1 mL of acetone cyanohydrin. After 1 hr, the reaction mixture was partitioned between dichloromethane and 1N aqueous hydrochloric acid. The organic layer was extracted with dilute aqueous sodium bicarbonate solution and the basic aqueous solution obtained was acidified with dilute aqueous hydrochloric acid and extracted with dichloromethane. The organic extract was dried over sodium sulfate and concentrated by evaporation under reduced pressure to obtain 540 mg (81 percent of theory) of the title compound as an orange syrup.
Reaction SMILES: N[C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30].C([N:39](CC)CC)C>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][CH:2]=[CH:24][C:23]=3[C:34]3([Cl:36])[CH:33]=[CH:32][C:28]([C:29]([NH2:39])=[O:30])=[C:27]([O:26][CH3:25])[CH2:35]3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: CCN(CC)CC
Reactant: COc1cc(Cl)ccc1C(=O)Cl
Solvent: ClCCl
Product: COC1=C(C(N)=O)C=CC(Cl)(c2ccccc2C(=O)N2Cc3ccccc3Cc3ccccc32)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
As described for Example 9, a mixture of 30 0.377 g (1 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.295 g of 2-methoxy-4-chlorobenzoyl chloride, and 0.15 g of triethylamine in 10 ml of dichloromethane is stirred at room temperature for 3 hours. An additional 0.148 g of 2-methoxy-4-chlorobenzoyl chloride and 75 mg of triethylamine is added and the mixture stirred overnight. The solution is worked-up as for Example 9 to give 0.38 g of product (crystallized from dichloromethane-hexane) m.p. 237°-239° C.