Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=4)[NH:26][CH:25]=3)[C:13]([C:14]3[N:18]([CH3:19])[CH:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=3)=[C:9]2[C:8](=[O:34])[N:7]([CH3:35])[C:6]1=[O:36])[CH:2]([CH3:4])[CH3:3].Cl.[O:38]([NH2:40])[CH3:39].C(P(=O)(OCC)OCC)#N>>[CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=4)[NH:26][CH:25]=3)[C:13]([C:14]3[N:18]([CH3:19])[CH:17]=[C:16]([C:20]([NH:40][O:38][CH3:39])=[O:22])[CH:15]=3)=[C:9]2[C:8](=[O:34])[N:7]([CH3:35])[C:6]1=[O:36])[CH:2]([CH3:3])[CH3:4]
Reactant: CON
Reactant: Cc1ccc2[nH]cc(Cn3nc4c(c3-c3cc(C(=O)O)cn3C)c(=O)n(C)c(=O)n4CC(C)C)c2c1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Product: CONC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c[nH]c3ccc(C)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-{7-isobutyl-5-methyl-2-[(5-methyl-1H-indol-3-yl)methyl]4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and methoxylamine hydrochloride using diethyl cyanophosphonate as a coupling reagent. Mass: 518.28 (M+H).
Reaction SMILES: [ClH:1].Cl.FC1C=CC(C2C=NC(N3CCNCC3)=NC=2)=CC=1.C(OC([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[N:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=3)=[CH:37][N:36]=2)[CH2:31][CH2:30]1)=O)(C)(C)C>>[ClH:1].[ClH:1].[N:32]1([C:35]2[N:36]=[CH:37][C:38]([C:41]3[CH:42]=[CH:43][C:44]([C:47]([F:49])([F:48])[F:50])=[CH:45][CH:46]=3)=[CH:39][N:40]=2)[CH2:33][CH2:34][NH:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(C(F)(F)F)cc3)cn2)CC1
Agent: Cl
Agent: Fc1ccc(-c2cnc(N3CCNCC3)nc2)cc1
Product: FC(F)(F)c1ccc(-c2cnc(N3CCNCC3)nc2)cc1
Yield: 69 %

Procedure:
Prepared according to the method for the preparation of 5-(4-fluorophenyl)-2-piperazin-1-ylpyrimidine dihydrochloride, from 4-[5-(4-trifluoromethylphenyl)pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester(0.392 g), to furnish the title compound as an off-white solid (0.250 g, 69%).
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C@H:6]1[O:11][C@H:10](Br)[C@H:9]([O:13][C:14]([CH3:16])=[O:15])[C@@H:8]([O:17][C:18]([CH3:20])=[O:19])[C@@H:7]1[O:21][C:22]([CH3:24])=[O:23])=[O:3].[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([O-:34])=[CH:30][CH:29]=1)([O-:27])=[O:26].[Na+].CC(C)=O.[OH-].[Na+]>O>[C:14]([O:13][C@@H:9]1[C@@H:8]([O:17][C:18](=[O:19])[CH3:20])[C@H:7]([O:21][C:22](=[O:23])[CH3:24])[C@@H:6]([CH2:5][O:4][C:2](=[O:3])[CH3:1])[O:11][C@H:10]1[O:34][C:31]1[CH:32]=[CH:33][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=1)(=[O:15])[CH3:16]
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2ccc([N+](=O)[O-])cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 18 h
Yield: 24.9 %

Procedure:
To a mixture of 15 g of acetobromoglucose, 7.92 g of sodium 4-nitrophenolate and 50 ml of acetone was added 300 mg of sodium hydroxide in 15 ml of water. This mixture was stirred for 18 hours, poured into 400 ml of water and the precipitate was filtered off. The residue was dissolved in 200 ml of methylene chloride, washed with 100 ml of aqueous sodium bicarbonate solution, dried and passed through a pad of hydrous magnesium silicate. Evaporation of the solvent and crystallization yielded 4.26 g of 4-nitrophenyl (2,3,4,6-tetra-O-acetyl)-β-D-glucopyranoside as white crystals, mp 173°-175° C.
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13]Br.[CH2:16]([O:18][C:19](=[O:30])[CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[CH3:17].NC1C=CC=CC=1>>[CH2:16]([O:18][C:19](=[O:30])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:13][C:5]3[C:4](=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]=3)[C:3]2=[O:15])=[CH:27][CH:28]=1)[CH3:17]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1CBr
Reactant: CCOC(=O)CCCc1ccc(N)cc1
Solvent: Nc1ccccc1
Product: CCOC(=O)CCCc1ccc(N2Cc3ccc([N+](=O)[O-])cc3C2=O)cc1

Procedure:
By using 2-bromomethyl-5-nitrobenzoic acid methyl ester and 4-(4-amino-phenyl)butyric acid ethyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline used in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain 4-[4-(6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-butyric acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][CH:15](O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.P(Br)(Br)(Br)(Br)[Br:23]>>[Br:23][CH:15]([CH2:14][C:4]1[CH:5]=[CH:6][C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:2]([Cl:1])[CH:3]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(O)Cc1ccc(C2CCCCC2)c(Cl)c1
Reactant: BrP(Br)(Br)(Br)Br
Product: CCOC(=O)C(Br)Cc1ccc(C2CCCCC2)c(Cl)c1

Procedure:
To 15.6 g. (0.0476 moles) of ethyl β-(3-chloro-4-cyclohexylphenyl)lactate there is added slowly with stirring at 40°-50°C 23 g. (0.053 moles) of phosphorus pentabromide. The mixture is stirred at room temperature for 16 hours, then diluted with 70 ml. of petroleum ether, and poured into 125 ml. of ice-cold water. The organic phase is separated, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to obtain ethyl α-bromo-β-(3-chloro-4-cyclohexylphenyl)propionate.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)=[O:9])([CH3:4])[CH3:3].[H][H]>C(O)C.ClCCl.[Pd]>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)=[O:9])([CH3:1])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(C(=O)NCc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)NCc2ccc(N)cc2)cc(C(C)(C)C)c1O
Reaction time: 8 h
Yield: 62.1 %

Procedure:
In a 250 ml Parr flask, 2.85 g (7.4 mmoles) of 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide is dissolved in 30 ml of an absolute ethanol/dichloromethane mixture (1/1) in the presence of 10% Pd/C. The mixture is agitated under 20 PSI of hydrogen, at 30° C., for one hour. After filtration on celite, the filtrate is concentrated under vacuum. The evaporation residue crystallizes spontaneously. It is left to rest overnight, the crystals are filtered out and rinsed with a mixture of diethyl ether (45 ml) and acetone (5 ml). 1.63 g (62%) of a white powder is obtained. Melting point: 188-189° C.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([NH:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[CH:7][N:6]=1)=[O:4].[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:3]([C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][C:13]3[C:14]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[N:15][O:16][C:17]=3[CH3:18])=[CH:7][N:6]=2)=[O:4])[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: COC(=O)c1cnc(NCc2c(-c3ccccc3)noc2C)cn1
Product: Cc1onc(-c2ccccc2)c1CNc1cnc(C(=O)NC2CC2)cn1
Yield: 86 %

Procedure:
As described for example 9b, 5-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-pyrazine-2-carboxylic acid methyl ester (650 mg, 2 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (600 mg, 86%) which was obtained as a white solid. MS: m/e=394.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3C=N[CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1([S:37](Cl)(=O)=O)C=CC=CC=1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:37][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1

Procedure:
The title compound of Step A was prepared from {3-[(4-pyrazin-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13b, and benzenesulfonyl chloride following the method described in Example 3, Step B. 1H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.60 (m, 1H), 8.49 (m, 1H), 7.87 (m, 4H), 7.61-7.51 (m, 3H), 7.26-7.08 (m, 3H), 6.75 (m, 1H), 6.63 (m, 1H), 6.58 (m, 1H), 4.38 (s, 2H), 4.34 (s, 2H), 4.31 (s, 2H), 1.47 (s, 9H); MS 546 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9](=[O:15])[CH2:8][C:7]2([CH3:17])[CH3:16])(=[O:3])[CH3:2].[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:14][N:10]1[C:11]2[C:6](=[CH:5][C:4]([C:1]3([CH3:2])[O:20][CH2:19][CH2:18][O:3]3)=[CH:13][CH:12]=2)[C:7]([CH3:17])([CH3:16])[CH2:8][C:9]1=[O:15]
Reactant: OCCO
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CC(=O)N2C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CN1C(=O)CC(C)(C)c2cc(C3(C)OCCO3)ccc21
Yield: 94.1 %

Procedure:
5.0 g of 6-acetyl-3,4-dihydro-1,4,4-trimethyl-2(1H)-quinolinone were dissolved in 200 ml of benzene and, after the addition of 2.1 g of ethylene glycol and a few crystals of p-toluenesulphonic acid, the mixture was boiled under a water separator for 5 hours. After cooling, the mixture was diluted with ethyl acetate, washed with dilute sodium hydrogen carbonate solution, dried and evaporated. There were obtained 5.6 g of 3,4-dihydro-1,4,4-trimethyl-6-(2-methyl-1,3-dioxolan-2-yl)-2(1H)-quinolinone in the form of a colourless oil which solidified upon standing in a refrigerator; melting point 81°-83° C. This compound was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Si:9](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(CC)CC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[Si:9]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](Oc1ccc(Br)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-bromophenol (16.4 g, 0.1 mole) in CH2Cl2 (300 mL) was added t-butyldiphenylsilyl chloride (29 g, 0.1 mole), Et3N (20 g, 0.2 mole) and 4-dimethylaminopyridine (DMAP) (1 g). The solution was stirred at RT for 2 days, quenched with H2O (1L) and extracted with ether (2L). The ether extracts were dried and evaporated. Flash chromatography of the residue using 5% ethyl acetate in hexane afforded the title compound which was used as such for the next step.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][S:15]([NH:18][CH2:19][CH2:20][NH:21][C:22]1[C:26]([C:27]2[N:31]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([Br:39])[CH:33]=3)[C:30](=[O:40])[O:29][N:28]=2)=[N:25][O:24][N:23]=1)(=[O:17])=[O:16])(C)(C)C>O>[Br:39][C:34]1[CH:33]=[C:32]([N:31]2[C:30](=[O:40])[O:29][N:28]=[C:27]2[C:26]2[C:22]([NH:21][CH2:20][CH2:19][NH:18][S:15]([NH2:14])(=[O:16])=[O:17])=[N:23][O:24][N:25]=2)[CH:37]=[CH:36][C:35]=1[F:38]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 22 L flask containing 98:2 trifluoroacetic acid:water (8.9 L) was added tert-butyl({[2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)ethyl]amino}sulfonyl)carbamate (1931 g, 3.42 mol) in portions over 10 minutes. The resulting mixture was stirred at room temperature for 1.5 h, the solvents removed in vacuo, and chased with dichloromethane (2 L). The resulting solid was treated a second time with fresh 98:2 trifluoroacetic acid:water (8.9 L), heated for 1 h at 40-50° C., the solvents removed in vacuo, and chased with dichloromethane (3×2 L). The resulting white solid was dried in a vacuum drying oven at 50° C. overnight. A total of 5409 g was processed in this manner (4990 g, quant. yield). LCMS for C12H12BrFN7O5S (M+H)+: m/z=463.9, 465.9. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (dd, J=6.2, 2.5 Hz, 1H), 7.72 (m, 1H), 7.59 (t, J=8.7 Hz, 1H), 6.67 (t, J=5.9 Hz, 1H), 6.52 (t, J=6.0 Hz, 1H), 3.38 (dd, J=12.7, 6.3 Hz, 2H), 3.11 (dd, J=12.3, 6.3 Hz).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][CH:5]=1>CC#N>[CH3:1][NH:2][CH2:10][C:7]1[CH:8]=[N:9][C:4]([CH3:3])=[CH:5][CH:6]=1
Reactant: CN
Reactant: Cc1ccc(CCl)cn1
Solvent: CC#N
Product: CNCc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 16.6 g of 40% aqueous MeNH2 solution and 52 ml of CH3CN was cooled with ice and 6.08 g (0.043 mole in terms of pure product) of crude (6-methyl-3-pyridyl)-methyl chloride was added dropwise with constant stirring. After completion of dropwise addition, the mixture was stirred at room temperature for 1.5 hours, at the end of which time the solvent was distilled off. The solid residue was extracted with CH2Cl2 and the CH2Cl2 layer was dried over MgSO4. The CH2Cl2 was distilled off and the residue was diluted with 70 ml of Et2O and filtered to remove the insoluble matter. Finally the filtrate was concentrated to recover 4.60 g of the title compound as a crude oil.
Reaction SMILES: FC(F)(F)S(O/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25]>O1CCOCC1>[C:24]([C:26]1[CH:31]=[C:30](/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:29]=[CH:28][CH:27]=1)#[N:25]
Reactant: CCOC(=O)/C=C/OS(=O)(=O)C(F)(F)F
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1cccc(C#N)c1
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of ethyl (E)-3-{[(trifluoromethyl)sulfonyl]-oxy}-2-propenoate (390 mg, 1.49 mmol) in 5 ml anhydrous dioxane was added potassium phosphate (474 mg, 2.24 mmol), 3-cyanophenyl boronic acid (217 mg, 1.49 mmol), and tetrakis (triphenylphosphine)palladium(0) (43 mg, 0.038 mmol). Reaction mixture was heated to reflux and stirred overnight. Mixture was filtered through a pad of Celite, diluted with 50 ml ethyl acetate, washed with 2×50 ml water, 2×50 ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Residue was chromatographed on silica gel using 5% EtOAc in hexane as the eluent to give ethyl (E) 3-(3-cyanophenyl)-2-propenoate (240 mg, 71%) as a clear yellow oil after drying. H1NMR (CDCl3): 1.2-1.32 (t, 3H); 2.547 (s, 3H); 4.18-4.24 (m, 2H); 6.113 (s, H); 7.47-7.725 (m, 4H). NOE confirmed stereo orientation.
Reaction SMILES: [ClH:1].[S:2]1[C:6]23[CH:14]=[CH:13][CH:12]=[CH:11][C:7]2=[N:8][CH2:9][CH2:10][CH:5]3[CH:4]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH2:3]1.[CH2:23](N(CC)CC)C.CBr>C(Cl)(Cl)Cl>[ClH:1].[CH3:23][CH:3]1[S:2][C:6]23[CH:14]=[CH:13][CH:12]=[CH:11][C:7]2=[N:8][CH2:9][CH2:10][CH:5]3[CH:4]1[C:15]([N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)=[O:16]
Reactant: CCN(CC)CC
Reactant: O=C(C1CSC23C=CC=CC2=NCCC13)N1CCOCC1
Agent: CBr
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC1SC23C=CC=CC2=NCCC3C1C(=O)N1CCOCC1
Yield: 82 %

Procedure:
In 5 ml of chloroform were dissolved 0.34 g of 4-(1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine-3-carbonyl)morpholine hydrochloride, 0.31 ml of triethylamine, and 0.11 g of methyl bromide, and the solution was refluxed for 30 minutes. Chloroform was distilled off under reduced pressure, 20 ml of an aqueous 5% sodium hydrogencarbonate solution and 50 ml of ethyl acetate were added to the residue, and the ethyl acetate layer was washed with a saturated sodium chloride solution and dried by sodium sulfate. Then, ethyl acetate was distilled under reduced pressure and the residue was purified by silica gel thin layer chromatography. Then, 1 ml of a mixture of 1N hydrochloric acid in ethyl acetate was added to the residue and crystals deposited were collected by filtration to provide 0.29 g (yield of 82%) of 4-(2 -methyl-1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine-3-carbonyl)morpholine.hydrochloride.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C(Cl)(=O)C(C)C.FC1C=CC=CC=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:10][CH:9]([CH3:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:3][CH:4]=1)=[O:12]
Reactant: CC(C)C(=O)c1ccc(F)cc1
Reactant: C1CCNCC1
Agent: CC(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Fc1ccccc1
Solvent: CS(C)=O
Product: CC(C)C(=O)c1ccc(N2CCCCC2)cc1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
49.86 (0.30 mol) of 1-(4-fluorophenyl)-2-methylpropan-1-one, prepared by a Friedel-Crafts reaction from isobutyryl chloride with fluorobenzene analogously to European Patent Application No. 3,002, and 25.5 g (0.30 mol) of piperidine are dissolved in 120 ml of dimethyl sulfoxide, and the solution is heated to 110° C. together with 41.5 g (0.30 mol) of potassium carbonate. After 16 hours of stirring at 110° C. the suspension is cooled down and is poured onto an ice-water mixture. The crystals are filtered off, are washed with water and are recrystallised from hexane.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:15]([O:19][C:20](Cl)=[O:21])[CH:16]([CH3:18])[CH3:17]>O.O1CCOCC1>[CH2:15]([O:19][C:20]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:21])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 132 %

Procedure:
L-Valine (5.86 g, 50 mmol) was dissolved in a mixture of water (200 mL) containing sodium carbonate (10.6 g, 100 mmol). The solution was cooled to 0° C., then a solution of isobutylchloroformate (6.76 g, 49.5 mmol) in dioxane (100 mL) was added dropwise over 50 min. The ice-bath was removed and the reaction stirred overnight. Dioxane was evaporated, the aqueous phase was extracted once with diethylether and the brought to pH 2 by addition of hydrochloric acid. Extraction with DCM (3×, 150 mL each), drying of the organic phase (sodium sulfate) and evaporation gave 21 (14.2 g) as a colorless solid. 1H-NMR (DMSO-d6) δ 12.48 (bs, 1 H), 7.24 (d, J=8.2 Hz, 1 H), 3.95 (dd, J=6.2, 8.3 Hz, 1 H), 3.73 (d, J=6.7 Hz, 1 H), 2.01 (m, 1 H), 1.83 (m, 1 H), 0.87 (bs, 12 H).
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][C:17]([OH:23])=[CH:18][C:19]2=4)[NH:14][CH:13]=3)[N:9]([CH3:24])[CH2:8]1)=[O:5])[CH3:2].[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:23][C:17]1[CH:16]=[C:15]2[C:22]3[C:12]([CH2:11][C@@H:10]4[C@@H:20]([C:19]=3[CH:18]=1)[CH2:21][C@H:7]([NH:6][C:4](=[O:5])[N:3]([CH2:1][CH3:2])[CH2:25][CH3:26])[CH2:8][N:9]4[CH3:24])=[CH:13][NH:14]2)(=[O:29])[CH3:28]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(O)cc4[nH]cc(c34)C[C@H]2N(C)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(OC(C)=O)cc4[nH]cc(c34)C[C@H]2N(C)C1
Reaction time: 1 h

Procedure:
At room temperature, 100 mg of 1,1-diethyl-3-(13-hydroxy-6-methyl-8α-ergolinyl)urea is dissolved in 1 ml of pyridine and 1 ml of acetic anhydride. After one hour, the mixture is poured on ice, extracted, after 15 minutes of stirring, with methylene-chloride, the organic phase is dried with sodium sulfate, and evaporated. The residue is crystallized from ethyl acetate.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH:21]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:22][C:23]([O:25][CH3:26])=[O:24]>>[CH3:31][O:30][C:28](=[O:29])[CH2:27][N:21]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:15](=[O:17])[C:14]1[CH:18]=[CH:19][CH:20]=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:13]=1
Reactant: CCCCCCCCCCOc1cccc(C(=O)O)c1
Reactant: COC(=O)CNCC(=O)OC
Product: CCCCCCCCCCOc1cccc(C(=O)N(CC(=O)OC)CC(=O)OC)c1

Procedure:
The conversion of 3-(decyloxy)benzoic acid to the acid chloride followed by treatment with dimethyl iminodiacetate as in Example 1 gave N-(2-methoxy-2-oxoethyl)-N-[3-(decyloxy)benzoyl]glycine methyl ester as an oil. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [C:1]1(=[O:10])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][O:2]1.[C:11]1(Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:9]23[C:1](=[O:10])[O:2][CH2:3][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8]3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1OCC2CCCCC12
Reactant: Brc1ccccc1
Product: O=C1OCC2CCCCC12c1ccccc1

Procedure:
The title compound was prepared from hexahydro-isobenzofuran-l-one (10 g, 1.3 eq) and phenyl bromide (5.4 mL, 51.27 mmol) according to General Procedure K. It was obtained as a clear oil (7.40 g, 67%). HPLC Rt (5-100-8)=9.8 min. 1H NMR (CDCl3, δ): 7.4-7.2 (m, 5H), 4.05 (dd, 1H), 3.90 (dd, 1H), 2.8 (m, 1H), 2.3 (m, 1H), 2.0 (m, 1H), 1.8-1.3 (m, 6H). 13C NMR (CDCl3, δ, mult): 178.6 (0), 140.5 (0), 128.8 (1), 127.3 (1), 126.3 (1), 70.3 (2), 52.5 (0), 41.0 (1), 34.2 (2), 27.5 (2), 23.4 (2), 23.2 (2).
Reaction SMILES: [C:1]([C:3]([CH3:30])([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][OH:29])=[CH:22][CH:21]=1)[C:4]([N:6]([CH:16]1[CH2:18][CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[Cl:15])=[O:5])#[N:2].[Cl:31][C:32]1[C:37]([F:38])=[CH:36][CH:35]=[C:34]([F:39])[C:33]=1O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>CCOCC.C1(C)C=CC=CC=1>[Cl:31][C:32]1[C:37]([F:38])=[CH:36][CH:35]=[C:34]([F:39])[C:33]=1[O:29][CH2:28][CH2:27][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:3]([C:1]#[N:2])([CH3:30])[C:4]([N:6]([CH:16]2[CH2:18][CH2:17]2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[O:5])=[CH:25][CH:24]=1
Reactant: Oc1c(F)ccc(F)c1Cl
Reactant: CC(C#N)(Cc1ccc(CCCO)cc1)C(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C#N)(Cc1ccc(CCCOc2c(F)ccc(F)c2Cl)cc1)C(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Temperature: 80 °C

Procedure:
2-Cyano-N-cyclopropyl-N-(2,3-dichlorobenzyl)-3-[4-(3-hydroxypropyl)phenyl]-2-methylpropanamide from the previous step (1 eq.) and 2-chloro-3,6-difluorphenol (4 eq.) were taken up in freshly deoxygenated toluene (0.05 M). To this solution was then added 1,1′-(azodicarbonyl)-dipiperidine (4 eq.) and finally tributylphosphine (4 eq.). The resulting yellow solution was heated at 80° C. for 3 h. The reaction mixture was cooled to RT, diluted with ether, and washed with 1 N aq. NaOH. The aqueous wash was back extracted with ether and the combined organic extracts were dried over MgSO4. Filtration and concentration of the filtrate in vacuo afforded a yellow semi-solid. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→3:2 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.