Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][O:21][CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH3:22][O:21][CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COCc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COCc1ccccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(2-methoxymethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (prepared as described herein below) in dioxan was treated with 4 eq. of 4M HCl in dioxane and stirred at RT for 16 h. After neutralization, the mixture was completely evaporated to give the crude title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][NH:14][CH2:15][CH2:16][NH:17][CH3:18].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:13][N:14]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH2:15][CH2:16][NH:17][CH3:18]
Reactant: CNCCNC
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNCCN(C)Cc1ccc(C(=O)OC)cc1
Yield: 62 %

Procedure:
A mixture of methyl 4-(bromomethyl)benzoate (2 g, 8.73 mmol) and N,N′-dimethylethan-1,2-diamine (7.5 mL, 70 mmol) was heated with triethylamine (9.8 mL, 70 mmol) in tetrahydrofuran (80 mL) to reflux for two hours. After cooling, the mixture was treated with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 1.28 g of methyl 4-[(methyl(2-(methylamino)ethyl)amino)methyl]benzoate, 1H NMR (300 MHz, CD3OD) δ 7.97 (d, 2H), 7.45 (d, 2H), 3.59 (s, 2H), 2.67 (m, 2H), 2.54 (m, 2H), 2.35 (s, 3H), 2.22 (s, 3H) ppm.
Reaction SMILES: C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:5](C)=O.[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>ClCCCl.C(Cl)Cl>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][N:32]2[CH3:5])[CH2:28][CH2:29]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCN(CC2CCCCN2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CCCCC1CN1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 48 h

Procedure:
1.91 ml of 37% aqueous formaldehyde and a few beads of 4 Å molecular sieve, followed by 5 g of NaBH(OAc)3, are added to a solution of 3.34 g of the compound prepared in step 6.2, in 40 ml of DCE, and the medium is stirred at AT for 48 h. The medium is diluted in DCM, and filtered through cotton wool. The organic phase is washed twice with a saturated NaHCO3 solution, and then with a saturated NaCl solution. After drying over MgSO4 and evaporation of the solvents, 3.28 g of the expected product are recovered.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1CCC[C@H]1CO)(OCC1C=CC=CC=1)=O>>[C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH:10]=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O

Procedure:
(R)-N-Boc-2-Formyl-pyrrolidine was prepared by Swern oxidation of (R)-N-Boc prolinol (Fluka) using the procedure for the oxidation of CBZ-prolinol described by of M. G. B. Drew et al. supra.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[N-:13]=[N+:14]=[N-:15].[Na+].Cl>[Zn+2].[Br-].[Br-]>[N+:10]([C:3]1[CH:4]=[C:5]([C:6]2[NH:15][N:14]=[N:13][N:7]=2)[CH:8]=[CH:9][C:2]=1[NH2:1])([O-:12])=[O:11]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Product: Nc1ccc(-c2nnn[nH]2)cc1[N+](=O)[O-]
Yield: 86.8 %

Procedure:
A mixture of 4-amino-3-nitrobenzonitrile (8-1) (163 mg, 1.0 mmol), NaN3 (1.5 mL of 2.0 M solution, 3.0 mmol) ZnBr2 (1.0 mL of 2.0 M solution, 2.0 mmol) was microwaved (Smith-Synthesizer) at 160° C. for 15 min with stirring. After this time, the reaction was completion according to LCMS. The reaction mixture was acidified to pH=2 with concentrated HCl. The precipitated product was collected by filtration and washed with water (2×3 mL). After drying, 179 mg (87%) of desired product were obtained as a yellow solid. Analytical LCMS: single peak, (214 nm), 1.909 min; 1H NMR (500 MHz, DMSO-d6): δ 8.70 (d, J=2.0 Hz, 1H), 8.02 (dd, J=8.9, 2.0 Hz, 1H), 7.92 (s, 2H), 7.21 (d, J=8.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[Li+].[OH-].O.Cl>>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(-c2ccccn2)c(Cl)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(-c2ccccn2)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a solution of methyl 2,4-dichloro-5-(pyridin-2-yl)benzoate (Preparation 44, 3.96 g, 14 mmol) in industrial methylated spirit (60 mL) was added a 2M solution of LiOH in water (35 mL, 70 mmol) and the reaction was stirred at room temperature for 3 hours. The reaction was acidified with 2M HCl (aq) (35 mL) to afford a white precipitate that was filtered and washed with industrial methylated spirit to afford the title compound (3.76 g, quant.).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1Br)(=[O:3])[CH3:2].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:32]1[CH:33]=[CH:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cnccc1Br
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cnccc1-c1ccc(C(F)(F)F)cc1

Procedure:
By following a procedure analogous to Example 27 starting from 4-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 4-(trifluoromethyl)-phenylboronic acid, 4-[4-(trifluoromethyl)phenyl]-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=31%).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([CH:10](O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([CH:10]([C:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:21][C:22]=2[C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=1
Reactant: CN(C)CCOc1ccc(C(O)c2ccccc2)cc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: CCOC(=O)c1[nH]c2ccccc2c1C(c1ccccc1)c1ccc(OCCN(C)C)cc1
Yield: 86.2 %

Procedure:
Substantially the same procedure as in Reference Example 5 was repeated using 4-(2-dimethylaminoethoxy)benzhydrol (14.78 g, 54.5 mmol) and ethyl indole-2-carboxylate (11.3 g, 59.9 mmol) to give 20.8 g (yield: 86%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[O:18])[CH:11]=[CH:12][C:13]=1[O:14]C.[Al+3].[Cl-].[Cl-].[Cl-].CCOC(C)=O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[O:18])[CH:11]=[CH:12][C:13]=1[OH:14]
Reactant: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(Br)cnn1C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.4 %

Procedure:
1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea (Compound 8, 1.44 g, 3.30 mmol) was dissolved in anhydrous CH2Cl2 (30 mL). The solution was stirred while cooling the temperature to 0° C. in an ice water bath. After allowing it to stir for another 10 minutes, AlCl3 (1.76 g, 13.20 mmol) was added slowly. This was followed by stirring the reaction for an additional 20 minutes, and subsequently increasing the temperature to 80° C. After one hour, the reaction was shown to be complete by TLC and LC/MS. It was worked up with EtOAc (2×50 mL) and 10% Potassium Sodium Tartrate (2×50 mL). Upon being treated to this work up, the aluminum was removed from the solution. The organic layer was then dried with Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was then purified by HPLC, yielding 1.43 g (100%) of Compound 103 LCMS m/z (%)=425 (M+H81Br, 100), 423 (M+H79Br, 88). 1H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.87 (s, 1H), 8.40 (s, 1H), 8.08-8.03 (m, 1H), 7.58 (s, 1H), 7.36 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.33-7.27 (m, 1H), 7.28 (d, J=2 Hz, 1H), 7.04-7.01 (m, 1H), 6.95 (d, J=8 Hz, 1H), 3.67 (s, 3H).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1.[F:20][C:21]1[CH:22]=[C:23]2[C:29]3([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH2:28][N:27]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:24]2=[CH:25][CH:26]=1>CCO>[F:20][C:21]1[CH:22]=[C:23]2[C:29]3([CH2:34][CH2:33][N:32]([CH2:3][CH:2]([OH:1])[CH:4]4[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)=[O:11])[CH2:6][CH2:5]4)[CH2:31][CH2:30]3)[CH2:28][N:27]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:24]2=[CH:25][CH:26]=1
Reactant: O=C(OCc1ccccc1)N1CCC(C2CO2)CC1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)c2cc(F)ccc21
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2(CCN(CC(O)C3CCN(C(=O)OCc4ccccc4)CC3)CC2)c2cc(F)ccc21
Temperature: 95 °C
Reaction time: 8 h

Procedure:
Phenylmethyl 4-(2-oxiranyl)-1-piperidinecarboxylate (990 mg) was added to a solution of 1,1-dimethylethyl 5-fluorospiro[indole-3,4′-piperidine]-1(2H)-carboxylate (1.16 g) in EtOH (20 mL). The reaction was heated to 95° C. for 7 h and then stirred at room temperature overnight. The solvent was removed and the title compound was obtained as crude oil. MS (ES) m/e 568 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([OH:49])=O)[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.O[N:52]1[C:56]2C=CC=CC=2N=N1.CN>C1COCC1.[Pd]>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([NH:52][CH3:56])=[O:49])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: On1nnc2ccccc21
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Agent: [Pd]
Agent: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(NC1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (100 mg, 0.15 mmol) in THF (2 mL) was added 10% Pd/C and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 4 h. The reaction mixture was filtered without exposure to air into another flask containing polystyrene-carbodiimide (260 mg, 0.29 mmol) and the mixture was stirred for 10 min. A solution of 1-hydroxybenzotriazole hydrate (40 mg, 22 mmol) in THF (1 mL) and methylamine (0.08 mL, 2.0 M solution in THF, 0.16 mmol) were added and the reaction mixture was stirred at room temperature under nitrogen for 4 h. The reaction was filtered through a micro filter and concentrated. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic) to afford (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-N,3-dimethyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide as a mixture of diastereomers (7.5 mg, 7%) and as a dark red solid: 1H NMR (500 MHz, CD3OD) δ 8.11 (s, 1H), 6.59 (s, 1H), 6.15 (s, 0.3H), 5.99 (s, 0.7H), 5.19-5.17 (m, 0.3H), 4.94 (s, 0.7H), 3.75 (s, 3H), 3.57 (s, 3H), 3.54 (s, 1H), 3.51 (s, 1H), 3.48-3.35 (m, 6H), 3.26-3.21 (m, 1H), 3.08 (t, J=9.0 Hz, 0.3H), 3.04 (t, J=9.0 Hz, 0.7H), 2.78 (s, 3H), 2.22 (s, 3H), 1.27 (d, J=9.0 Hz, 2H), 1.22 (d, J=6.5 Hz, 1H); MS (ESI+) m/z 697 (M+H); HPLC >99% (AUC), tR 10.63 min.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:20]=[C:19]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32]C)=[O:31])[O:18][N:17]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:20]=[C:19]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([OH:32])=[O:31])[O:18][N:17]=1
Reactant: COC(=O)Cc1ccccc1OCc1cc(OCCc2nc(-c3ccccc3)sc2C)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1sc(-c2ccccc2)nc1CCOc1cc(COc2ccccc2CC(=O)O)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
To a mixture of methyl 2-[2-[[3-[2-(5-methyl-2-phenyl-4-thiazolyl)ethoxy]-5-isoxazolyl]methoxy]phenyl]acetate (0.77 g), tetrahydrofuran (5 mL) and methanol (5 mL) was added a 1N aqueous sodium hydroxide solution (5 mL) and the mixture was stirred at room temperature for 3 hrs. 1N Hydrochloric acid (5 mL) and water were added to the reaction mixture and the precipitated crystals were collected by filtration and dried with air to give crystals (0.71 g, 96%) of 2-[2-[[3-[2-(5-methyl-2-phenyl-4-thiazolyl)ethoxy]-5-isoxazolyl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 159-160° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]2)[CH:5]=[N:4][CH:3]=1.[H-].[Na+].[CH3:17]I>CN(C)C=O.C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:17])[C:10](=[O:14])[CH2:9]2)[CH:5]=[N:4][CH:3]=1
Reactant: O=C1CN(c2cncc(Cl)n2)CCN1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CCN(c2cncc(Cl)n2)CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 1 (2.13 g, 0.01 mole) and sodium hydride-oil suspension (50%, 0.50 g, 0.01 mole) are combined in 10 ml N,N-dimethylformamide and the stirred mixture treated with 0.65 ml (0.01 mole) of methyl iodide in 5 ml toluene. The mixture is stirred 1 hour at room temperature, diluted with water and extracted with toluene. The toluene extracts are washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product which is chromatographed on neutral (activity III) alumina. Elution with chloroform gives fractions containing 1.4 of a white solid which is recrystallized from n-butylchloride-cyclohexane to give white crystals of the title compound, mp 122°-123° C.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:28][CH:25]4[CH2:27][CH2:26]4)=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Yield: 46 %

Procedure:
As described for example 342 g, 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.58 mmol) was converted, using cyclopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (100 mg, 46%) which was obtained as a white solid. MS: m/e=370.0 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:40])([CH3:39])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:38]=[CH:37][C:21]([C:22]([CH:24](C(OCC)=O)[C:25]([O:27][C:28](C)(C)[CH3:29])=[O:26])=[O:23])=[CH:20][CH:19]=1.FC(F)(F)C(O)=O.[OH-].[K+]>>[CH3:40][Si:2]([CH3:1])([CH3:39])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:23])=[CH:37][CH:38]=1
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)C(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1
Reaction time: 3 h

Procedure:
A solution of 3.0 g. of tert-butyl ethyl 4-[14-(trimethylsilyl)tetradecylamino]benzoylmalonate and 10 ml. of trifluoroacetic acid is warmed with stirring for 3 hours. The solution is poured onto ice and neutralized with potassium hydroxide. The resulting precipitate is collected by filtration, washed with water and dried. Recrystallization affords the product as a white solid.
Reaction SMILES: OO.[C:3]([OH:7])([CH3:6])([CH3:5])[CH3:4].[OH:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([OH:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1.N=O>O>[OH:8][CH:9]1[CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([O:17][CH2:4][C:3]([OH:7])([CH3:6])[CH3:5])[C:11]([CH3:19])([CH3:18])[CH2:10]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CC(C)(C)O
Agent: N=O
Agent: OO
Solvent: O
Product: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Temperature: 47.5 °C

Procedure:
A solution of 9.4 g (140 mmol) of 50% aqueous hydrogen peroxide mixed with 20 mL of tert-butyl alcohol is added over four hours at 45-50° C. to a mixture of 3.44 g (20.0 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 0.125 g (0.77 mmol) of anhydrous ferric chloride, 30 mL of tert-butyl alcohol and 10 mL of water. The temperature is then maintained at 45-50° C. for 19 hours. Analysis by gas chromatography shows less than 1% of the starting nitroxyl compound is present.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]2[N:26]=[CH:27][S:28][C:24]=2[CH:23]=1)(=[O:21])=[O:20])[C:11]1[S:12][C:13]([CH:16]=O)=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][C:32]([S:35]([NH2:37])=[O:36])([CH3:34])[CH3:33]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Si:1]([O:8][CH2:9][C@@H:10]([NH:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]2[N:26]=[CH:27][S:28][C:24]=2[CH:23]=1)(=[O:21])=[O:20])[C:11]1[S:12][C:13](/[CH:16]=[N:37]\[S:35]([C:32]([CH3:34])([CH3:33])[CH3:31])=[O:36])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](NS(=O)(=O)c1ccc2ncsc2c1)c1ccc(C=O)s1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)/N=C\c1ccc([C@@H](CO[Si](C)(C)C(C)(C)C)NS(=O)(=O)c2ccc3ncsc3c2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(5-formylthiophen-2-yl)ethyl]-1,3-benzothiazole-6-sulfonamide (5.0 g, 10.4 mmol) and 2-methylpropane-2-sulfinamide (1.51 g, 12.4 mmol) in THF (69 mL) was added titanium isopropoxide (6.52 mL, 31.1 mmol). The mixture was stirred at room temperature overnight.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[Cl:16])C=O)(C)(C)C.CC1(C)[O:27][C:25](=[O:26])[CH2:24][C:22](=O)O1.C(N(CC)CC)C.C(O)=O>CN(C=O)C.O>[Cl:16][C:15]1[CH:14]=[CH:13][C:10]([CH2:22][CH2:24][C:25]([OH:27])=[O:26])=[CH:9][C:8]=1[CH2:7][OH:6]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(C=O)ccc1Cl
Solvent: CN(C)C=O
Solvent: O=CO
Solvent: CCN(CC)CC
Product: O=C(O)CCc1ccc(Cl)c(CO)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A mixture of 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzaldehyde (1.84 g, 6.46 mmol), Meldrum acid (931 mg, 6.46 mmol), and formic acid-triethylamine 5:2 complex (1.62 mL, 23.4 mmol) in DMF (6.00 mL) was heated to 100° C. for 3.5 h. Meldrum acid (466 mg, 3.23 mmol) was added again, and the mixture was stirred for 1 h at 100° C. The mixture was allowed to cool to rt, and was diluted with a mixture of water and ice. The resulting mixture was extracted several times with EtOAc. The combined org. extracts were washed with water, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The residue was dissolved in Et2O, and the resulting mixture was extracted several times with aq. 1M NaOH. The combined aq. extracts were acidified to pH 2 with aq. 1M HCl, and this aq. mixture was extracted back with Et2O several times. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (1.20 g, 87%) that was used further without purification. LC-MS: tR=0.71 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]([CH2:8][Cl:9])=[O:7])[CH3:2].[S:11]1[CH:15]=[CH:14][C:13](C=O)=[CH:12]1.C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1.CCOCC.O>[CH2:1]([O:3][C:4](=[O:10])[C:5](=[C:14]1[CH:13]=[CH:12][S:11][CH2:15]1)[C:6](=[O:7])[CH2:8][Cl:9])[CH3:2]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: O=Cc1ccsc1
Solvent: O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)C(C(=O)CCl)=C1C=CSC1
Reaction time: 7 h

Procedure:
55.3 g of 4-chloroacetoacetic acid ethyl ester, 41 g of thiophene-3-aldehyde, 3.8 ml of glacial acetic acid and 1.5 ml of piperidine were dissolved in 30 ml of benzene. The solution was boiled for 7 hours, using a water separator, and, after the solution had been cooled, 400 ml of ether were added and the mixture was extracted three times with water. After the extract had been dried over sodium sulphate and the solvent had been evaporated off, the crude product was subjected to incipient distillation and the residue was then purified over a short silica gel column (70 to 230 mesh) (Mobile phase: petroleum ether/ether 8/2). The E/Z mixture was obtained as an oil.
Reaction SMILES: N1C=CC=CC=1.[C:7]([NH:14][CH2:15][CH2:16]O)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>CCOCC>[C:7]([NH:14][CH2:15][CH2:16][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)CCNC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Pyridine (1.5 mL, 18.5 mmol) was added to 2-(N-Boc-amino)-ethanol (280 mg, 1.7 mmol) at 0° C. Tosyl chloride (1.65 g, 8.7 mmol) was then added and the reaction was allowed to stir at 0° C. overnight. The resulting cloudy reaction was diluted with Et2O and washed with water, saturated NaHCO3 and brine, dried over MgSO4 and concentrated. The resulting white solid was purified using SiO2 with AcOEt/petroleum ether 20:80 to 30:70. A white solid was obtained (250 mg, 46%). NMR 1H (ppm, CDCl3): 7.77 (d, J3=8.3 Hz, 2H), 7.33 (d, J3=8.0 Hz, 2H), 4.82 (br. s., 1H), 4.05 (t, J3=5.08 Hz, 2H), 3.38-3.33 (m, 2H), 2.43 (s, 3H), 1.39 (s, 9H).