Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].C[C:3](C)([O-:5])C.[K+].[CH2:8]([CH:11]1[O:15][CH:14]([CH:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[CH2:13][CH2:12]1)[CH2:9][CH3:10]>C1COCC1>[CH2:8]([CH:11]1[O:15][CH:14]([CH:16]2[CH2:21][CH2:20][CH:19]([CH:3]=[O:5])[CH2:18][CH2:17]2)[CH2:13][CH2:12]1)[CH2:9][CH3:10]
Reactant: CC(C)(C)[O-]
Reactant: CCCC1CCC(C2CCC(=O)CC2)O1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCC(C=O)CC2)O1
Temperature: -20 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
Methoxymethyltriphenylphophnium chloride (55.23 g) and THF (300 ml) were placed in a reaction vessel, and the solution was cooled to −20° C. Potassium t-butoxide (16.0 g) was added, and the stirring was continued for another 1 hour. Then, 4-(5-propyltetrahydro-2-furanyl)cyclohexanone (15 g) in a THF (100 ml) solution was added dropwise, and the stirring was continued for another 1 hour. The reaction mixture was warmed to room temperature, and the mixture was separated after the addition of water (200 ml). The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (toluene:ethyl acetate=18:1), and the resultant product was dissolved in acetone (200 ml) and hydrochloric acid (6 M) (200 ml) was added, and then the stirring was continued at room temperature for another 1 hour. The mixture was extracted with toluene (100 ml) after the addition of water (200 ml). The solution was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 4-(5-propyltetrahydro-2-furanyl)cyclohexanecarboaldehyde (12.2 g)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>C1COCC1>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[O:11])=[CH:15][CH:14]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C=Nc1ccc(F)c(F)c1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Br)cc1)Nc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
3,4-Difluorophenyl isocyanate (0.74 g, 4.8 mmol) was added to a solution of 4-bromo aniline (0.75 g, 4.36 mmol) in THF (20 mL) and stirred at room temperature for 2 hr. The solvent was removed under reduced pressure and the residue was triturated with chloroform (60 mL) to afford title compound (0.6 g, 42%) as solid. 1H NMR (300 MHz, DMSO-d6): δ 8.9 (s, 1H), 8.87 (s, 1H), 7.64 (m, 1H), 7.47-7.41 (m, 4H), 7.39 (m, 1H), 7.2 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[N+:11]([O-])([OH:13])=[O:12]>>[OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(O)nc1
Product: O=C(O)c1cnc(O)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a 250 mL flask were added 6-hydroxynicotinic acid (20 g, Aldrich) and 100 mL of red fuming nitric acid. The mixture was slowly heated to 50° C. (bath temperature) and stirred at this temperature for 8 h. Then the temperature was slowly raised to 80° C. and the mixture was stirred for another 7 h. The mixture was cooled to rt overnight and the yellow precipitate was collected by filtration, washed with water (10 mL) and dried. LC-MS: >95% pure. 1H NMR (CD3OD, 400 MHz): δ=8.45 (d, J=2.5 Hz, 1H), 8.85 (d, J=2.5 Hz, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].[NH2:9]/[C:10](/[CH3:17])=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([NH:9]/[C:10](/[CH3:17])=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CC(C)(CCl)C(=O)Cl
Product: CCOC(=O)/C=C(/C)NC(=O)C(C)(C)CCl
Yield: 42 %

Procedure:
Ethyl N-(β-chloropivaloyl)-3-aminocrotonate was prepared in 42% yield from β-chloropivaloyl chloride and ethyl 3-aminocrotonate by the procedure used in Example 5. M.P. 76°-77.5° C. (after recrystallization from hexanes); IR (KBr) 1705, 1675 cm-1 ; 'HNMR δ 1.06-1.23 (9H, m), 2.3 (3H, s), 3.6 (2H, s), 4.0-4.23 (2H, q) 6.7 (1H, s), 6.8-7.1 (1H, br).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1Cl)=[O:5])[CH3:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1[N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:5])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1c(Cl)c2cnc(-c3ccccc3)nc2n(CC)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N2CCCC2)c2cnc(-c3ccccc3)nc2n(CC)c1=O

Procedure:
To 0.7 g. (0.002 mole) of 5-chloro-8-ethyl-7,8-dihydro-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester in ethanol was added 0.14 g. (0.002 mole) of pyrrolidine and 0.21 g. (0.002 mole) of sodium carbonate and this mixture was refluxed 3 hours. At that point, the solid inorganic material was filtered and the filtrate allowed to stand several days. Pale yellow crystals of the title compound formed which were removed by filtration--m.p. 149°-153° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:11]([CH3:10])(=[O:13])=[O:12])[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 3-amino-5-bromo-2-chloropyridine (stage 152.1.2, 3.59 mmol) in pyridine (7 ml) was added methanesulfonyl chloride (Fluka, Buchs, Switzerland, 0.365 ml). The RM was stirred for 22 h at rt then was added methanesulfonyl chloride (0.2 ml), the RM was stirred for 5 h at rt. Methanesulfonyl chloride (0.2 ml) was added and the RM was stirred for 17 h at rt. The RM was evaporated to dryness and then taken in EtOAc, washed with aqueous NaHCO3, with brine, dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (heptane/EtOAc 0% to 40%). The fractions containing product were evaporated together to give the title compound as a pink solid. (HPLC: tR 2.91 min (Method A); M+H=285, 287 MS-ES)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([N:22]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:17](=[O:21])[CH2:18][C:19]#[N:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37]([Mg]Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[NH2:20][C:19]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[CH:18][C:17](=[O:21])[C@@H:16]([N:22]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: N#CCC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)N(Cc1ccccc1)Cc1ccccc1
Solvent: C1CCOC1
Product: NC(=CC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)N(Cc1ccccc1)Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 23B (19.0 g, 40.1 mmol) in THF (48 mL) was treated dropwise with a solution of benzyl magnesium bromide (120 mL, 1 M in ether) at 0° C. The mixture was allowed to warm to 25° C. and was stirred for 16 hours. The reaction was cooled to 0° C. and quenched with 10% citric acid, followed by partitioning between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the crude product (23.2 g), which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[N+:14]([C:17]1[CH:23]=[CH:22][C:21](Cl)=[CH:20][C:18]=1[NH2:19])([O-:16])=[O:15]>CN(C)C=O>[NH2:19][C:18]1[CH:20]=[C:21]([O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:22]=[CH:23][C:17]=1[N+:14]([O-:16])=[O:15]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccncc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccncc2)ccc1[N+](=O)[O-]
Temperature: 17.5 °C
Reaction time: 2 h

Procedure:
A 2-liter round-bottomed flask is charged with 35.2 g (0.369 mol) of 4-hydroxypyridine and 250 ml of anhydrous dimethylformamide (DMF). Under nitrogen, 42 g (0.369 mol) of potassium tert-butylate are added portionwise while the temperature is maintained at 15-20° C. with a water/ice bath. After the addition, the mixture is stirred for 2 hours and a pale yellow solution is obtained. 60 g (0.358 mol) of 2-nitro-5-chloroaniline are then added and an intense red coloration is obtained. The mixture is brought to 100° C. for 6 hours and then allowed to cool overnight. The DMF is evaporated off and water is then added; a precipitate is obtained, which is filtered off and washed with isopropanol in the heated state and then dried.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.S(=O)(=O)(O)O.[CH3:24]O>>[CH3:24][O:15][C:14](=[O:16])[CH2:13][C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=1
Reactant: CO
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
To a solution of 3,5-bis-trifluoromethylphenylacetic acid (3.0 g, 11.03 mmol) (Aldrich) in methanol (20 mL) was added concentrated sulfuric acid (1.0 mL) and the reaction mixture was heated at reflux overnight. The reaction mixture was concentrated in vacuo. The residue was then diluted with ethyl acetate (100 mL) and successively washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography to give 3,5-bis-trifluoromethylphenylacetic acid methyl ester as a colorless oil. (Yield 2.27 g, 72.1%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].CCN(CC)CC.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1NCCN1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN1CCNC1=O
Reaction time: 8 h
Yield: 44.9 %

Procedure:
To a solution of 1-(2-hydroxyethyl)imidazolidin-2-one (100 mg; 0.77 mmol) and Et3N (81 mg; 0.80 mmol) in dry DCM (10 mL) was added MsCl (137 mg; 1.20 mmol) under nitrogen. The reaction mixture was stirred overnight, diluted with DCM (20 mL), washed with saturated aqueous Na2CO3, dried over anhydrous Na2SO4, concentrated to afford 72 mg (44%) of the title compound as a yellow oil, which was used directly without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[NH:30])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:16]([CH:17]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)[CH2:15][CH2:14][S:13][C:12]=2[CH:29]=1.Cl>CO>[NH:19]1[CH2:20][CH2:21][CH:17]([N:16]2[CH2:15][CH2:14][S:13][C:12]3[CH:29]=[C:8]([NH:7][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[NH:30])[CH:9]=[CH:10][C:11]2=3)[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCSc3cc(NC(=N)c4cccs4)ccc32)C1
Agent: Cl
Solvent: CO
Product: N=C(Nc1ccc2c(c1)SCCN2C1CCNC1)c1cccs1
Yield: 78.6 %

Procedure:
A solution of tert-butyl 3-(7-(thiophene-2-carboximidamido)-2H-benzo[b][1,4]thiazin-4(3H)-yl)pyrrolidine-1-carboxylate (0.24 g, 0.554 mmol) in MeOH (5 mL) was treated with 1N HCl solution (9.98 mL, 9.98 mmol) at room temperature. The resulting mixture was refluxed for 30 minutes and brought to room temperature. The mixture was filtered and quenched with 1N NaOH (10 mL). The mixture was diluted with water (50 mL) and extracted with CH2Cl2 (2×50 mL). The organic phase was washed with brine (50 mL) and dried (Na2SO4). The crude material was subject to flash chromatography on silica gel (5-20% 2M NH3MeOH/CH2Cl2). The collected fractions gave compound 30 as yellow foam (0.15 g, 79%). 1H NMR (DMSO-d6) δ 7.69 (d, J=3.0 Hz, 1H), 7.56 (dd, J=0.9, 4.9 Hz, 1H), 7.07 (dd, J=3.9, 4.9 Hz, 1H), 6.79 (d, J=9.0 Hz, 1H), 6.52-6.49 (m, 2H), 6.31 (brs, 2H), 4.26-4.17 (m, 1H), 3.42-3.22 (m, 2H), 3.10-2.90 (m, 4H), 2.83-2.69 (m, 2H), 2.07-1.96 (m, 1H), 1.68-1.57 (m, 1H); ESI-MS (m/z, %): 347, 345 (MH+, 72), 278, 276 (100).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([CH2:21][OH:22])[O:15][CH:13]2[OH:14])[CH3:10])[C:4](=[O:23])[CH2:3]1.C(O[C:29](=[O:31])[CH3:30])(=O)C>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:24])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:18]([O:19][C:13](=[O:14])[CH3:12])[C@H:17]([O:20][C:16](=[O:15])[CH3:17])[C@@H:16]([CH2:21][O:22][C:29](=[O:31])[CH3:30])[O:15][C@@H:13]2[O:14][C:6](=[O:8])[CH3:5])[CH3:10])[C:4](=[O:23])[CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O)=C1C(=O)CC(C)(C)CC1=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A mixture of 2-deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl-amino]-D-glucopyranose (1.55 g, 4.51 mmol), pyridine (11 ml) and acetic anhydride (20 ml) was stirred at room temperature overnight. The reaction mixture was evaporated, and the product was crystallised from MeOH (10 ml) at −15° C. to give 2-Deoxy-2-[1-(-4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl-amino]-1,3,4,6-tetra-O-acetyl-α-D-glucopyranose (2) (1.95 g, 86%).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[CH:3]=1.[CH2:10](I)[CH3:11]>C(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([O:9][CH2:10][CH3:11])[CH:3]=1
Reactant: Oc1cc(Br)c(F)cn1
Reactant: CCI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCOc1cc(Br)c(F)cn1

Procedure:
Educt: 4-bromo-5-fluoro-pyridin-2-ol/ethyl iodide using silver carbonate in methylene chloride as a base
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:30].[C:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])[CH3:41]>>[C:40]([N:43]1[CH2:48][CH2:47][N:46]([C:16]2[N:17]=[C:18]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[C:9]3[C:8](=[O:30])[N:7]([CH2:6][C:5]4[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=[C:3]([C:2]([F:1])([F:39])[F:38])[CH:4]=4)[CH2:14][CH2:13][CH2:12][NH:11][C:10]=3[N:15]=2)[CH2:45][CH2:44]1)(=[O:42])[CH3:41]
Reactant: CC(=O)N1CCNCC1
Reactant: CS(=O)(=O)c1nc2c(c(-c3ccc(F)cc3)n1)C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Product: CC(=O)N1CCN(c2nc3c(c(-c4ccc(F)cc4)n2)C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCN3)CC1
Yield: 81.5 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 17; 86.5 mg) was reacted with 1-acetylpiperazine (23.1 mg) to obtain 2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-5-oxopyrimido[4,5-b][1,5]diazocine (76.4 mg, 82%).
Reaction SMILES: [N+:1]([CH:4]([CH3:7])[CH2:5][OH:6])([O-:3])=[O:2].S(=O)(=O)(O)[O-].[Na+].[CH2:14]=[C:15]([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[C:15]([O:6][CH2:5][CH:4]([N+:1]([O-:3])=[O:2])[CH3:7])([CH3:17])([CH3:16])[CH3:14]
Reactant: CC(CO)[N+](=O)[O-]
Reactant: C=C(C)C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(COC(C)(C)C)[N+](=O)[O-]
Temperature: 60 °C

Procedure:
To a solution of 36.6 g (0.34 mol) of crude 2-nitro-propan-1-ol [prepared according to Example 1a]in 200 ml of toluene in a pressure vessel is added 2 g of sodium bisulfate [NaHSO4]. Through the closed autoclave is added at room temperature 48 g (0.85 mol) of isobutene. The reaction mixture is maintained at 60° C. for 8 hours. The reaction mixture is cooled to room temperature, diluted with toluene and filtered to give a crude solution of 1-tert-butoxy-2-nitro-propane in toluene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][NH:16][CH2:15]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:25]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30]>C(#N)C>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([C@H:25]([N:16]2[CH2:15][CH:14]([C@@H:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)[C:10]([F:13])([CH3:12])[CH3:11])[CH2:17]2)[C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[C:29]#[N:30])=[CH:39][CH:38]=1
Reactant: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CNC1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A solution of the crude amine from Step 3 and 6.51 g (20 mmole) of Cs2CO3 in 30 mL dry acetonitrile was stirred at rt in a flask fitted with a small Dean-Stark trap. After 15 minutes, 4.6 g (15 mmole) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile was added and the mixture was heated at 60° C. After 18 h, the solution was filtered through CELITE and the residue was washed with acetonitrile. The combined filtrates were concentrated and the residue was purified by flash chromatography using a step gradient of 5 to 20 % ethyl acetate-hexane. Fractions containing the faster product diastereomer were pooled and concentrated to afford the title compound; 1H-NMR(CDCl3) δ 1.25 (t, J=22 Hz, 6H), 2.33 (t, J=6.5 Hz, 1H), 2.83-2.89 (m, 2H), 3.09-3.11 (m, 2H), 3.60 (m, 1H), 4.24 (s, 1H), 6.68-6.71 (m, 3H), 7.21-7.8 (m, 8H); Mass Spectrum: m/e=469 (M+1, 35Cl) and 471 (M+1, 37Cl).
Reaction SMILES: N1C2C(=CC([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=CC=2)C=N1.Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[C:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:26][CH:25]=1>>[CH3:33][Si:32]([C:31]#[C:30][C:27]1[CH:28]=[CH:29][C:24]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:25][CH:26]=1)([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3[nH]ncc3c2)CC1
Reactant: C[Si](C)(C)C#Cc1ccc(Br)cc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Yield: 67 %

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 62.4, except ((4-bromophenyl)ethynyl)trimethylsilane (compound 76.1, 850 mg, 3.36 mmol) was used in place of 5-bromo-1H-indazole to yield the title compound as a yellow oil (0.80 g, 67%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:27]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9]2)[O:7][NH:27]1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccccc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-phenylpiperidine-1-carboxylate (1.104 g, 3.31 mmol) (from example 77, step 1) was dissolved in MeOH (10 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.132 g, 3.31 mmol) dissolved in water (1.000 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 30 min. Hydroxylamine (50% by weight in water, 0.203 mL, 3.31 mmol) was added during 6 min. The resulting solution was stirred at −40° C. for 2 h 30 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (14 mL, 84.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and MTBE/water was added. The phases were separated and the organic phase evaporated to yield a brown oil. The residue was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-phenylpiperidine-1-carboxylate (722 mg, 72%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.66 (dq, 1H), 1.86-2.09 (m, 2H), 2.72 (d, 1H), 2.79-3.03 (m, 2H), 3.78 (s, 3H), 4.26 (br. s, 1H), 5.68 (br. s, 2H), 7.20-7.32 (m, 3H), 7.34-7.43 (m, 2H). MS m/z 303 (M+H)+
Reaction SMILES: CS(C1C=CC(C[Cl:9])=CC=1)=O.[Cl-].[CH3:13][S:14]([C:16]1[CH:41]=[CH:40][C:19]([CH2:20][P+:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=O>>[Cl-:9].[CH3:13][S:14][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][P+:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:40][CH:41]=1
Reactant: CS(=O)c1ccc(CCl)cc1
Reactant: CS(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Product: CSc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
In a similar manner, when p-methylsulfinylbenzyl chloride is used, the product is p-methylsulfinylbenzyltriphenylphosphonium chloride, melting point 258°-262°C with gasing.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5](/[C:8](=[N:11]/[S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])/[CH2:9][CH3:10])=[CH:4][CH:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[BH4-].[Li+]>C1COCC1>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([NH:11][S:12]([C:14]([CH3:15])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CC/C(=N\S(=O)C(C)(C)C)c1ccc(Br)nc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H](NS(=O)C(C)(C)C)c1ccc(Br)nc1
Reaction time: 6 h

Procedure:
To a chilled (−78° C.) solution of 2-methyl-propane-2-sulfinic acid [1-(6-bromo-pyridin-3-yl)-prop-(E)-ylidene]-amide (10.4 g, 32.78 mmol) in THF (150 mL) was added a 1 M solution of L-Selectride (33.0 mL, 33.0 mmol) in THF. The reaction was monitored by TLC (ethyl acetate-ether 3:7) indicating a single diastereomer (when compared to a mixture of diastereomers prepared by a reduction of 2-methyl-propane-2-sulfinic acid [1-(6-bromo-pyridin-3-yl)-prop-(E)-ylidene]-amide with lithium borohydride in THF). After 6 hours, the mixture was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (2×50 mL), brine (50 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography eluting with ether-dichloromethane (0:100, then 5:95, then 1:9, then 2:8). The material from the chromatography was triturated with ether to afford in two crops material which by 1H NMR is consistent with a single diastereomer however an impurity is present by TLC (ethyl acetate-ether 3:7). This material and the filtrate was purified by silica gel chromatography separately using ethyl acetate-dichloromethane (0:100, then 4:96, then 8:98, then 12:88, then 2:8, then 3:7, then 4:6). The material from the two purifications was combined and crystallized from dichloromethane-hexanes-ether to afford in 3 crops 2-methyl-propane-2-sulfinic acid [(S)-1-(6-bromo-pyridin-3-yl)-prop yl]-amide.