Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH2:12][CH2:13][NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:31].O>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH2:12][CH2:13][N:14]([CH3:31])[C:15](=[O:19])[O:16][CH2:17][CH3:18])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)NCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)N(C)CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
In tetrahydrofuran (4 ml) was dissolved ethyl N-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propyl]carbamate (100 mg, 0.239 mmol), followed by the addition of sodium hydride (60% dispersion in mineral oil, 11.5 mg, 0.287 mmol). The resulting mixture was stirred at room temperature for 3 hours. Iodomethane (17.8 μl, 0.287 mmol) was added and the mixture was stirred at room temperature for 15 hours. Sodium hydride (60% dispersion in mineral oil, 5.00 mg, 0.125 mmol) and iodomethane (10.0 μl, 0.161 mmol) were added, followed by stirring at room temperature for 24 hours. Water (5 ml) was added, and the mixture was concentrated. The residue thus obtained was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and then concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated, whereby the title compound (83.2 mg, 0.193 mmol, 81%) was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>CS(C)=O>[CH3:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: CSc1ncnc2c(N3CCCCC3)nc(Cl)nc12
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: O
Product: CSc1ncnc2c(N3CCCCC3)nc(N3CCNCC3)nc12

Procedure:
2.0 g (6.8 mmol) of 2-chloro-8-methylthio-4-piperidino-pyrimido[5,4-d]pyrimidine is dissolved warm in 70 ml of dimethylsulphoxide and stirred with a solution of 6 g of piperazine in 70 ml of dimethylsulphoxide for 1 hour at ambient temperature. Then the solution is poured into 1 liter of water, the precipitate obtained is suction filtered and washed with water. The residue is taken up in 50 ml of methylene chloride and extracted with 50 ml of 0.05N sodium hydroxide solution. The organic phase is separated off, dried over sodium sulphate and concentrated in a rotary evaporator.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([O:7][C:8]2[CH:9]=[C:10]([CH3:22])[C:11]3[CH:15]([CH2:16][C:17]([OH:19])=[O:18])[O:14][B:13]([OH:20])[C:12]=3[CH:21]=2)[S:4][N:3]=1.[Li+].C[Si]([N-:28][Si](C)(C)C)(C)C.Cl>C1COCC1.O>[NH2:28][C:2]1[N:6]=[C:5]([O:7][C:8]2[CH:9]=[C:10]([CH3:22])[C:11]3[CH:15]([CH2:16][C:17]([OH:19])=[O:18])[O:14][B:13]([OH:20])[C:12]=3[CH:21]=2)[S:4][N:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1cc(Oc2nc(Cl)ns2)cc2c1C(CC(=O)O)OB2O
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2nc(N)ns2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
To a solution of [6-(3-chloro-[1,2,4]thiadiazol-5-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (100 mg, 0.27 mmol) in THF (1.5 mL) was added LHMDS (1M in Hexanes, 0.54 mL, 0.54 mmol). The resulting solution was stirred at room temperature for overnight. LC-MS showed still half starting material left. The mixture was added LHMDS (1M in Hexanes, 0.54 mL, 0.54 mmol) again. After 3 hours, the mixture was diluted with H2O and acidified to pH 3 with 1N HCl at 0° C. The resulting mixture was extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The crude mixture was purified by prep HPLC to give title compound (30 mg, 40%) as a white solid. 1H NMR (CD3OD) δ7.38 (d, 1H), 7.26 (d, 1H), 5.66 (dd, 1H), 3.16 (dd, 1H), 2.39 (s, 3H), 2.34 (dd, 1H). MS found: (M+H)+: 322.
Reaction SMILES: I.[NH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([C:11]2[N:15]([CH2:16][C:17]3[O:18][CH:19]=[C:20]([Br:22])[CH:21]=3)C(=O)[O:13][N:12]=2)=[N:8][O:9][N:10]=1.[S:24](N)([NH2:27])(=[O:26])=[O:25].[OH-].[Na+].O.C(O)(=O)C>N1C=CC=CC=1>[NH2:27][S:24]([NH:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([C:11](=[N:12][OH:13])[NH:15][CH2:16][C:17]2[O:18][CH:19]=[C:20]([Br:22])[CH:21]=2)=[N:8][O:9][N:10]=1)(=[O:26])=[O:25]
Reactant: NS(N)(=O)=O
Reactant: NCCNc1nonc1-c1noc(=O)n1Cc1cc(Br)co1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)O
Product: NS(=O)(=O)NCCNc1nonc1C(=NO)NCc1cc(Br)co1
Temperature: 130 °C
Yield: 40.9 %

Procedure:
In a microwave vial, 3-{4-[(2-aminoethyl)amino]-1,2,5-oxadiazol-3-yl}-4-[(4-bromo-2-furyl)methyl]-1,2,4-oxadiazol-5(4H)-one hydroiodide (30 mg, 0.060 mmol) and sulfamide (29 mg, 0.30 mmol) were suspended in pyridine (1 mL). The reaction mixture was flushed with nitrogen and heated at 130° C. for 3 minutes in a microwave reactor. The solvent was removed and the crude intermediate was suspended in methanol (1 mL). A 2.0 N solution of NaOH in water (0.30 mL, 0.60 mmol) was added in one portion and the reaction was heated to 45° C. for 30 minutes. After neutralization with acetic acid (68 μL, 1.2 mmol), the product was purified by preparative LCMS to give the desired product (10.4 mg, 41%). LCMS calculated for C10H15BrN7O5S (M+H): m/z=423.9, 426.0. 1H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 7.75 (s, 1H), 6.83 (t, J=7.3 Hz, 1H), 6.68 (t, J=6.0 Hz, 1H), 6.56 (s, 2H), 6.30 (t, J=6.0 Hz, 1H), 6.23 (s, 1H), 4.56 (d, J=7.0 Hz, 2H), 3.32 (q, J=6.3 Hz, 2H), 3.07 (q, J=6.3 Hz, 2H).
Reaction SMILES: O=C(OC1C=C([NH2:31])C=CC=1OC(=O)CCCCCCCCC)CCCCCCCCC.Br[CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.[I-].[Na+]>C(#N)C.CN(C=O)C>[C:38]1([CH2:37][O:36][C:34](=[O:35])[CH2:33][NH2:31])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCCCCCCCCC(=O)Oc1ccc(N)cc1OC(=O)CCCCCCCCC
Reactant: O=C(CBr)OCc1ccccc1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: NCC(=O)OCc1ccccc1

Procedure:
A mixture of 2.5 g (5.77 mmol) of 3,4-bis[(1-oxodecyl)oxy]benzenamine, 9.1 ml (57.7 mmol) of benzyl bromoacetate, 3.1 g (14.4 mmol) of 1,8-bis(dimethylamino)naphthalene and 0.34 g (2.3 mmol) of sodium iodide in 50 ml of acetonitrile and 10 ml of DMF was stirred at reflux for 48 hours. The solvents were removed at reduced pressure and the residue was treated with methylene chloride and water. The organic phase was separated, dried and concentrated to an oil which was purified by HPLC using 20% ethyl acetate-hexane to give 2.2 g (52% yield) of N-[3,4-bis[(1-oxodecyl)oxy]phenyl]-N-[2-oxo-2-phenylmethoxy)ethyl]glycine phenylmethyl ester as an oil. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2([OH:22])[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].CO.C(OCC)(=O)C>C(O)C>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2([OH:22])[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)=[CH:10][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(C#CC2(O)CN3CCC2CC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(C#CC2(O)CN3CCC2CC3)cc1
Reaction time: 18 h
Yield: 53 %

Procedure:
To a solution of 3-[2-(4-ethoxycarbonylphenyl)ethynyl]-3-hydroxyquinuclidine (250 mg) in ethanol (20 ml) was added 4N aqueous sodium hydroxide solution (0.7 ml). The reaction mixture was stirred for 18 hours. The reaction mixture was evaporated and the residue was acidified with 5N hydrochloric acid. The mixture was evaporated to give a solid which was treated with methanol/ethyl acetate to give 3-[2-(4-carboxyphenyl)ethynyl]-3-hydroxyquinuclidine (120 mg), m.p. 288°-290° C.; microanalysis, found: C, 59.4; H, 5.8; N, 4.1; Cl, 13.1%; C16H17NO3.0.5NaCl. 0.5HCl requires: C, 60.3; H, 5.53; N, 4.39; Cl, 11.1%; NMR: 1.66-1.82(1H,m), 1.86-2.31(4H,m), 3.03-3.45(5H,m), 3.51-3.63(1H,d), 6.55(1H,s), 7.54-7.62(2H,d), 7.89-7.98(2H,d), 12.1(1H,br); m/z 272(M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[C:6]1([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CC(C)=[O:20]>[OH-].[Na+]>[Cl:5][CH2:4][CH2:3][CH2:2][O:20][N:15]1[CH2:16][CH2:17][N:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:13][CH2:14]1
Reactant: CC(C)=O
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Product: ClCCCON1CCN(c2ccccc2)CC1

Procedure:
N1 -(3-chloropropoxy)N4 -phenylpiperazine was prepared as described in Ind. J. Chem. 435 (1982) by adding dropwise 87 g (0.55 mole) of 1-bromo-3-chloropropane to a stirred solution of 81 g (0.5 mole) of N-phenylpiperazine in 100 ml acetone and 75 ml of 25% aqueous sodium hydroxide. The organic layer was separated, concentrated, slurried with ethyl acetate, washed, dried over magnesium sulfate, and concentrated to an oil weighing 85 g and analyzed by thin layer chromatography and mass spectrometry to be the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=O)[CH2:10][S:11]([CH:13]2[N:16]([C:17]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=P(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:15](=[O:44])[CH:14]2[NH:45][C:46]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCOCC1>[C:1]1([CH2:7][CH2:8][C:9]2[CH2:10][S:11](=[O:12])[C@@H:13]3[CH:14]([NH:45][C:46]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:59]4[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[C:15](=[O:44])[N:16]3[C:17]=2[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C(N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1S(=O)CC(=O)CCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C1=C(CCc2ccccc2)CS(=O)[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N12

Procedure:
4-(4-phenyl-2-oxobutylsulphinyl)-1-(1-t-butoxycarbonyl-1-triphenylphosphoranylidenemethyl)-3-(triphenylmethylamino) azetidin-2-one (200 mg) was refluxed in dry dioxan (5 ml) under nitrogen for 8 hours. The mixture was evaporated to give a foam. The crude foam was chromatographed on silica gel eluting with ethyl acetate/petroleum ether mixtures to give t-butyl 3-β-phenylethyl-7-triphenylmethylamino-3-cephem-4-carboxylate-1-oxide as a yellow solid (87 mg.)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1)=[O:4].[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:8]([C:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH2:6]2)=[O:10])=[CH:14][CH:13]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)C1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1(C(=O)Nc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.6 %

Procedure:
Cyclopropane-1,1-dicarboxylic acid monomethylester (2 g, 13.88 mmol) was dissolved in DMF (28 mL) and 4-fluoroaniline (1.999 mL, 20.82 mmol) was added, followed by diisopropylethylamine (12.12 mL, 69.4 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (8.91 g, 27.8 mmol). The mixture stirred at room temperature for 15 hours and was then diluted with ethyl acetate (200 mL) and washed with 10% aqueous lithium chloride (3×100 mL) and brine (100 mL). The organic layer was dried over magnesium sulfate and evaporated to yield the crude product as a brown solid. It was purified by silica gel chromatography (0 to 20% ethyl acetate/hexane) to give methyl 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylate (3.28 g, 99% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 7.60 (m, 2H), 7.12 (m, 2H)), 3.66 (s, 3H), 1.38 (m, 4H); MS (ESI) m/z: 238.1 (M+H+).
Reaction SMILES: CS([C:4]1[N:19]=[C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:10]=[C:11]([NH2:12])[N:6]2[N:5]=1)=O.[N:20]12[CH2:30][CH2:29]C[N:27]=[C:26]1[CH2:25]CCCC2>CC1NC=CN=1>[CH3:25][C:26]1[N:20]([C:4]2[N:19]=[C:7]3[CH:8]=[C:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[CH:10]=[C:11]([NH2:12])[N:6]3[N:5]=2)[CH:30]=[CH:29][N:27]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CS(=O)c1nc2cc(-c3ccccn3)cc(N)n2n1
Agent: Cc1ncc[nH]1
Product: Cc1nccn1-c1nc2cc(-c3ccccn3)cc(N)n2n1

Procedure:
The title compound, MS m/e (%):292 (M+H+,100), was prepared in accordance with the method of example 339b) from 2-methanesulfinyl-7-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and 1,8-diazabicyclo[5.4.0]undec-7-en in 2-methylimidazole at 170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:5][CH:4]=1.[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(C#CCCCO)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CCCCCO)cc1
Yield: 93.2 %

Procedure:
A solution of 16 (7.1 g, 37 mmol) in 150 dry ethanol (150 mL) was placed in a 0.5 L Parr flask and palladium on carbon (0.92 g, 5% wet. Pd/C) was added as a suspension in ethanol (25 mL). The reaction mixture was shaken at 50 psi of hydrogen pressure at room temperature for 24 hours. After this time, the mixture was filtered through a silica gel pad and the solvent was removed at reduced pressure. The residue was purified by flash chromatography (silica gel, 1:3 ethyl acetate/hexanes) to provide 17 (6.7 g, 92%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.48 (m, 2H), 1.60 (m, 4H), 2.58 (m, 2H), 3.63 (m, 2H) 3.80 (s, 3H), 6.83 (d, 2H), 7.10 (d, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@@H:6]([C:25]1[CH:26]=[N:27][C:28]([CH3:31])=[N:29][CH:30]=1)[CH:7]=[CH:8][CH2:9][N:10]1[C@H:14]([CH3:15])[CH2:13][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]1=[O:24])[CH3:2]>CO.C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@@H:6]([C:25]1[CH:26]=[N:27][C:28]([CH3:31])=[N:29][CH:30]=1)[CH2:7][CH2:8][CH2:9][N:10]1[C@H:14]([CH3:15])[CH2:13][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[C:11]1=[O:24])[CH3:2]
Reactant: CCOC(=O)C[C@H](C=CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1C)c1cnc(C)nc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CCOC(=O)C[C@H](CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1C)c1cnc(C)nc1
Reaction time: 1.5 h

Procedure:
To stirred solution of 5-3 (180 mg) in methanol (8 mL) was added a suspension of 10% Pd on carbon (60 mg) in ethanol (1 mL). The resulting suspension was stirred under an atmosphere of hydrogen for 1.5 hours. The mixture was filtered through Celite. The solvent was evaporated to give 5-4 as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[P:12](=[O:23])([N:20]=[C:21]=[O:22])([S:16][CH2:17][CH2:18][CH3:19])[O:13][CH2:14][CH3:15]>CCOCC>[CH2:14]([O:13][P:12]([NH:20][C:21]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1)=[O:22])([S:16][CH2:17][CH2:18][CH3:19])=[O:23])[CH3:15]
Reactant: CCCSP(=O)(N=C=O)OCC
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCOCC
Product: CCCSP(=O)(NC(=O)N1CCC(C(=O)OCC)CC1)OCC
Reaction time: 8 h

Procedure:
To a solution of 2.36 g of ethyl 4-piperidine-carboxylate in 50 ml of ether at ambient temperature was added dropwise with stirring 3.14 g of O-ethyl S-n-propyl phosphoroisocyanatidothioate. The mixture was allowed to stir overnight and was then concentrated by evaporation under reduced pressure using a rotary evaporator and then a Kugelrohr apparatus at 55° C. and 13 Pascals pressure. The residue, which was the title compound, amounted to 5.2 g (94 percent of theory) and was an amber colored viscous oil having a refractive index at 25° C. of 1.5083.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5]1)(=[O:3])[CH3:2].[CH2:12](O)[CH:13]=[CH2:14].C([O-])(=O)C.[Na+]>>[C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5]1)(=[O:3])[CH2:2][CH2:14][CH:13]=[CH2:12]
Reactant: C=CCO
Reactant: CC(=O)C1CCCC(C)(C)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: C=CCCC(=O)C1CCCC(C)(C)C1
Temperature: 150 °C

Procedure:
Into a 2 liter autoclave is placed 672 grams of the dimethyl ketal of 1-acetyl-3,3-dimethyl cyclohexane prepared according to Example I; 348 grams of allyl alcohol; and 15 grams of sodium acetate. The autoclave is sealed and the contents are heated to 150° C. and maintained at 150° C. for a period of five hours. At the end of the five hour period the autoclave contents are cooled and the autoclave is opened. The resulting product is distilled on a 12" Goodloe column yielding the following fractions:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH:7]=[C:8]1[NH:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])([O-])=O.NC1SC=C(C2C=CC(N)=CC=2)N=1.CCO>CN(C=O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH:7]=[C:8]1[NH:12][C:11](=[O:13])[NH:10][C:9]1=[O:14]
Reactant: O=C1NC(=O)C(=Cc2cccc([N+](=O)[O-])c2)N1
Agent: [Ni]
Agent: Nc1ccc(-c2csc(N)n2)cc1
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1cccc(C=C2NC(=O)NC2=O)c1

Procedure:
2.3 g (10 mmol) of crude 3-nitro-benzylidene-hydantoin, melting point 280-284° C., (prepared as described in Example 6 in (a)) are hydrogenated in 60 ml of DMF and 40 ml EtOH on 2 g of Raney nickel for 36 hours at 20° C. and 3.5 bar. It is filtered over kieselguhr and the filtrate is evaporated down in vacuo. The evaporation residue is crystallised with ether.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][OH:10].[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O>CO>[C:12]([N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])[CH2:8][CH2:9][OH:10])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:11]
Reactant: OCCNCCNCCO
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCO)CCN(CCO)C(=O)OC(C)(C)C

Procedure:
The product was prepared by treating N,N′-bis(2-hydroxyethyl)ethylenediamine in methanol with (BOC)2O at room temperature. The reaction mixture was chilled to −15° C. to −20° C. to precipitate the product. After filtration, the precipitate was desiccated to yield the product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]2[O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:6][CH:5]=1.[S:35]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36]1>>[CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[CH2:24][O:23][CH:11]1[CH:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][O:1][C:41](=[O:42])[CH2:40][C:37]3[CH:38]=[CH:39][S:35][CH:36]=3)=[CH:5][CH:6]=2)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12]1
Reactant: O=C(O)Cc1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(=O)Cc3ccsc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 24(g), by condensing tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethyl)-phenyl)-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate and 3-thiopheneacetic acid using 1,1-carbonyldiimidazole as the condensation agent there was obtained tert-butyl (3RS,4RS)-3-naphthalen-2-ylmethoxy-4-[4-(2-thiophen-3-ylacetoxy-ethyl)-phenyl]-piperidine-1-carboxylate as a colourless solid, MS: 603 (M+NH4)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:4][CH3:5])[CH3:2].[Mg+].[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14]C([O-])=O>O1CCCC1>[CH2:4]([N:3]([CH2:6][CH2:7][CH2:8][C:9](=[O:11])[CH2:14][C:13]([O:19][CH2:20][CH3:21])=[O:18])[CH2:1][CH3:2])[CH3:5]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CCN(CC)CCCC(=O)O
Agent: [Mg+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCCN(CC)CC
Temperature: 25 °C
Reaction time: 6 h
Yield: 52.8 %

Procedure:
N,N'-Carbonyldiimidazole (11.2 g) was added to a suspension of 4-(N,N-diethylamino)butanoic acid (10.0 g) in tetrahydrofuran (400 ml), and the mixture was stirred at room temperature for 6 hours. Then monoethyl malonate magnesium salt (Mg(OCOCH2COOC2H5)2)(19.8 g) was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in chloroform. The chloroform layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-methanol (5:1, v/v) gave ethyl 6-(N,N-diethylamino)-3-oxohexanoate (7.6 g, 53%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:20][C:19](=[O:21])[NH:18][CH2:17]3)=[O:15])=[CH:11][C:10]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH:5]=[CH:6][C:7]=1[F:8].BrC1OC([C:35]([N:37]2CC(=O)NC2)=O)=CC=1C1C=CC=C(Cl)C=1>>[Cl:28][C:24]1[CH:23]=[C:22]([C:10]2[CH:11]=[C:12]([C:14]([N:16]3[CH2:20][C:19](=[O:21])[NH:18][CH2:17]3)=[O:15])[O:13][C:9]=2[C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:35]#[N:37])[CH:3]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(Br)o2)CN1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(-c3ccc(F)c(Cl)c3)o2)CN1
Product: N#Cc1cc(-c2oc(C(=O)N3CNC(=O)C3)cc2-c2cccc(Cl)c2)ccc1F

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 25 starting with the compound from Example 30A. 11.0 mg (20% of theory) of the title compound are obtained.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].C[O:25][C:26]([C:28]1[NH:29]N=C(OCC2C(C3C=CC=CC=3)=NOC=2C)[CH:32]=1)=O.N[C@H](CO)C>>[OH:25][CH2:26][C@@H:28]([NH:29][C:3]([C:5]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[NH:7][N:6]=1)=[O:4])[CH3:32]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)n[nH]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Agent: C[C@H](N)CO
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)N[C@@H](C)CO)n[nH]1
Yield: 50 %

Procedure:
As described for example 6, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (70 mg, 0.22 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted, using L-alaninol instead of ethanolamine, to the title compound (40 mg, 50%) which was obtained as a colorless oil. MS: m/e=358.2 [M+H]+.