Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]1.C(N(CC)CC)C.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17].[OH-].[Na+]>O1CCCC1>[C:15]([O:7][CH:3]1[CH2:4][CH2:5][CH2:6][S:1][CH2:2]1)(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: OC1CCCSC1
Reactant: C=C(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC1CCCSC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
Freshly distilled tetrahydrothiapyran-3-ol (8.97 g, 75.3 mmol) and triethylamine (10.6 mL, 75.5 mmol) were dissolved in anhydrous tetrahydrofuran (THF) (40 mL) and cooled to 0° C. Methacryloyl chloride (8.1 mL, 83.2 mmol) was then added slowly, dropwise. The reaction then was warmed slowly to room temperature. After stirring overnight, 30 mL DIW were added and the mixture was made basic with 5 M NaOH. The THF then was removed by rotary evaporation and the product was extracted with diethyl ether (3×40 mL). The ether extracts were combined and washed with 0.1 M NaOH, followed by DIW before being dried over sodium sulfate and filtered. The product was then concentrated by rotary evaporation and dried in vacuo to afford tetrahydro-2H-thiopyran-3-yl methacrylate as a light orange liquid (7.63 g, 54%). 1H NMR (600 MHz, CDCl3, ppm) δ 6.08 (s, 1H), 5.54 (s, 1H), 4.94 (m, 1H), 2.78 (m, 1H), 2.62 (m, 1H), 2.49 (m, 1H), 2.47 (m, 1H), 2.14 (m, 1H), 1.99 (m, 1H), 1.91 (s, 3H), 1.85 (m, 1H), 1.49 (m, 1H). 13C NMR (150 MHz, CDCl3, ppm) δ 166.61, 136.69, 125.62, 71.21, 32.26, 31.82, 28.10, 27.43, 18.43.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:36](O)=[O:37])=[CH:28][CH:27]=1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:36]([C:29]5[C:30]6[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=6)[N:26]=[CH:27][CH:28]=5)=[O:37])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)c1ccnc2ccccc12

Procedure:
The title compound, white solid (29.6 mg, 74.6%), MS (ISP) m/z=486.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and quinoline-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O-:9])=[O:8].[OH-].[Na+].Cl>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C([O-])c1cncc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cncc(Cl)c1
Temperature: 60 °C
Yield: 6.5 %

Procedure:
To 5-chloronicotinate (105 g) was added 1N NaOH (84.9 mL) at ambient temperature. The mixture was heated at 60° C. for 1 hour. The reaction mixture was adjusted to pH 4-5 with HCl. The precipitate was filtered to give 5-chloronicotinic acid (6.9 g) a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([C:18]3[N:19]=[N:20][N:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[O:30])=[CH:25][CH:24]=4)[CH:22]=3)=[N:9]2)=[CH:5][CH:4]=1.Br[CH2:40][CH2:41][CH2:42][OH:43].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:40][CH2:41][CH2:42][OH:43])=[CH:14][CH:15]=3)[C:10]([C:18]3[N:19]=[N:20][N:21]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)=[O:30])=[CH:27][CH:28]=4)[CH:22]=3)=[N:9]2)=[CH:37][CH:38]=1
Reactant: COc1ccc(Cn2nc(-c3cn(-c4ccc(C(=O)N5CCOCC5)cc4)nn3)c3cc(O)ccc32)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(-c3cn(-c4ccc(C(=O)N5CCOCC5)cc4)nn3)c3cc(OCCCO)ccc32)cc1
Yield: 63 %

Procedure:
A solution of 1-(4-methoxybenzyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-ol (60 mg; 0.12 mmol; 1.0 eq.), 3-bromo-1-propanol (24 mg; 0.18 mmol; 1.5 eq.) and cesium carbonate (77 mg; 0.24 mmol; 2.0 eq.) in DMF (1.2 mL) was stirred at RT O/N. The reaction mixture was then diluted with DCM and washed with brine. Organic phase was dried over magnesium sulfate, filtered and concentrated. Purification of the crude by preparative HPLC gave the title compound as a white powder (43 mg, 64%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[C:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]1=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36](O)(=[O:38])[CH3:37].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:36]([O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[C:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[C:3]1=[O:16])(=[O:38])[CH3:37]
Reactant: CC(=O)O
Reactant: O=C1[C@@H](O)CCN1CC#CCN1CCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1CCN(CC#CCN2CCCC2)C1=O
Reaction time: 8 h

Procedure:
A solution of 0.5 g of (S)-3-hydroxy-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone, 0.75 g of triphenylphosphine and 0.2 ml of acetic acid in 20 ml of tetrahydrofuran was stirred at room temperature in a tap water bath. A 0.6 g portion of diethyl azodicarboxylate was added dropwise, this mixture was stirred overnight, then the solvent was removed in vacuo. The residue was purified by chromatography (silica gel), giving 0.4 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[I:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>>[I:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:17]
Reactant: O=C(Cl)c1ccccc1I
Reactant: CN1CCc2c(N)cccc2C1
Product: CN1CCc2c(cccc2NC(=O)c2ccccc2I)C1

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline was reacted with 2-iodobenzoyl chloride according to the procedure of Example 19 to yield 5-(2-iodobenzamido)-2-methyl-1,2,3,4-tetrahydroisoquinoline; m.p. 215°-216.5° C. after purification from methanol.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:8]=[CH2:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(Cl)(Cl)[Cl:12]>>[CH2:6]([O:5][C:3](=[O:4])[C:2]([CH3:10])([CH3:1])/[CH:8]=[CH:9]/[Cl:12])[CH3:7]
Reactant: C=CC(C)(C)C(=O)OCC
Reactant: ClC(Cl)Cl
Product: CCOC(=O)C(C)(C)/C=C/Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A five liter four neck round bottom flask equipped with thermometer, cold bath, mechanical stirrer and inlet tube for subsurface gas introduction was charged with 470 g of ethyl 2,2-dimethylbut-3-enoate (prepared according to the procedure of J. L. Hermann, G. R. Kiecgykowski, and R. H. Schessinger, Tetr. Lett., 2425 (1973)) and 2500 mL of chloroform. The solution was cooled to 0° C. and chlorine was bubbled into the solution at a rate that kept the internal temperature below 10° C. (3 hours total addition time). After removal of solvent, the residue (703 g) was taken up in 2500 mL of DMF and cooled to -5° C. Potassium t-butoxide (636 g) was added to the stirred solution at a rate such that the temperature remained below 0° C. (2.3 hours total addition time). After the addition was complete, the solution was stirred an additional 1 hour, then poured onto 3 L of ice and water and extracted into 2× 2 L of hexane. The combined hexane fraction was washed with 2×200 mL of saturated brine solution, dried over Na2SO4 and stripped to give 422 g of (E)-ethyl-4-chloro-2,2-dimethylbut-3-enoate an oil. This was then added over 1/2 hour to a stirred, cooled (-5° C.) solution of KOH (280 g) in methanol (1 L). Stirring was continued for 16 hours at ambient temperature, then the solution was poured into 3 L of ice water and extracted with 2×2 L of ether. The aqueous layer was then acidified to pH 2 using concentrated HCl, and extracted with 2×2 L of ether. The combined acid extracts were dried over Na2SO4 and stripped of solvent to give 222 g of an oil.
Reaction SMILES: [NH:1]([CH:3]1[C:7]2=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4]1)[OH:2].C[Si]([N:19]=[C:20]=[O:21])(C)C.O>C1COCC1>[CH:3]1([N:1]([OH:2])[C:20]([NH2:19])=[O:21])[C:7]2=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)N=C=O
Reactant: ONC1CCn2c1cc1ccccc12
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N(O)C1CCn2c1cc1ccccc12
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step 2 (652 mg, 3.47 mmol) in THF (20 mL) at r.t. there was added 85% trimethylsilyl isocyanate (850 mg, 6.28 mmol) and the mixture was stirred for 30 minutes. There was added H2O (5 mL) and after stirring for another 5 minutes the THF was evaporated. The residual aqueous suspension was diluted with H2O and filtered to afford the title compound as a white solid, m.p.: 194° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][N:25]=[CH:26]2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][N:25]=[CH:26]4)=[CH:21][CH:20]=3)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Brc1ccc2ccncc2c1
Reactant: Fc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: Fc1ccc2c(c1)c1c(n2-c2ccc3ccncc3c2)C2CCN(CC2)C1

Procedure:
The reaction of 9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (78 mg, 0.34 mmol; Example 161) and 7-bromoisoquinoline (106 mg, 0.51 mmol; Frontier) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.94-2.22 (m, 4H) 2.88-2.96 (m, 1H) 3.08-3.29 (m, 4H) 4.31 (s, 2H) 6.85 (td, J=9, 2 Hz, 1H) 7.06 (dd, J=9, 4 Hz, 1H) 7.12 (dd, J=10, 2 Hz, 1H) 7.74 (dd, J=9, 2 Hz, 1H) 7.96 (d, J=6 Hz, 1H) 8.13 (d, J=2 Hz, 1H) 8.17 (d, J=8 Hz, 1H) 8.55 (d, J=6 Hz, 1H) 9.35 (s, 1H); MS (DCI/NH3) m/z 358 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH:13]=[C:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[O:6])[CH:2]=[CH2:3].I[CH3:20]>[Ag]=O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][CH3:20])[CH2:9][C@H:8]1[CH:13]=[C:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[O:6])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C=C(C)C(C)=O
Agent: O=[Ag]
Product: C=CCOC(=O)N1C[C@H](OC)C[C@H]1C=C(C)C(C)=O
Reaction time: 48 h

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-hydroxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (3.0 g) in iodomethane (15 ml) was added silver oxide (10 g), and the mixture was allowed to stand at ambient temperature for 2 days. The resulting precipitate was removed by filtration and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel (60 ml) eluting with a mixture of n-hexane and ethyl acetate (6:4 V/V) to give (2S,4R)-1-allyloxycarbonyl-4-methoxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (3.23 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][O:23][CH3:24]>CC(C)=O>[Cl:1][C:2]1[C:3]([O:13][CH2:21][CH2:22][O:23][CH3:24])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2
Reactant: COCCBr
Reactant: Cc1ccc2ccc(O)c(Cl)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1ccc2ccc(C)nc2c1Cl

Procedure:
8-chloro-2-methylquinolin-7-ol (80 mg, 0.41 mmol), potassium carbonate (171 mg, 1.2 mmol) and 1-bromo-2-methoxyethane (115 mg, 0.83 mmol) in acetone (10 mL) were stirred at 70° C. in a sealed tube for 20 hours. After dilution with water (50 mL) the reaction was extracted with DCM. The DCM phases were concentrated under reduced pressure and the residue purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 8-chloro-7-(2-methoxyethoxy)-2-methylquinoline as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1[CH2:23][CH2:22]OCC1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:7]1[CH:2]=[C:3]([CH:8]=[CH:22][CH:23]=1)[C:4]#[N:5])=[O:9]
Reactant: O=Cc1cnccc1Br
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: N#Cc1cccc(-c2ccncc2C=O)c1
Reaction time: 8 h

Procedure:
A flask was charged with 4-bromo-pyridine-3-carbaldehyde (186 mg, 1 mmol), 3-cyanophenelboronic acid (176 mg, 1.2 mmol), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), potassium phosphate (319 mg, 1.5 mmol) and 1,4-dioxane (10 mL). The reaction mixture was kept at 50° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with water, then brine. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography to yield 3-(3-formyl-pyridin-4-yl)-benzonitrile as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH:4]([NH:25]C(OCC1C=CC=CC=1)=O)[CH2:5][C:6]1[CH:14]=[C:13]([CH3:15])[C:12]2[C:8](=[CH:9][N:10]([S:16]([CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])(=[O:18])=[O:17])[N:11]=2)[CH:7]=1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:36])[C@H:4]([NH2:25])[CH2:5][C:6]1[CH:14]=[C:13]([CH3:15])[C:12]2[C:8](=[CH:9][N:10]([S:16]([CH2:19][CH2:20][Si:21]([CH3:22])([CH3:24])[CH3:23])(=[O:17])=[O:18])[N:11]=2)[CH:7]=1
Reactant: COC(=O)C(Cc1cc(C)c2nn(S(=O)(=O)CC[Si](C)(C)C)cc2c1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](N)Cc1cc(C)c2nn(S(=O)(=O)CC[Si](C)(C)C)cc2c1
Yield: 100 %

Procedure:
2-Benzyloxycarbonylamino-3-[7-methyl-2-(2-trimethylsilanyl-ethanesulfonyl)-2H-indazol-5-yl]-propionic acid methyl ester, (1.35 g, 2.54 mmol) and 10% palladium on carbon (135 mg) in methanol (40 mL) were agitated for 3.0 h under 55 psi hydrogen using a Parr apparatus. The reaction mixture was purged with 3 vacuum/nitrogen purge cycles. The reaction mixture was then filtered through a pad of celite and the pad was rinsed with several portions of methanol. The methanol filtrate was evaporated to give the title compound (1.01 g, quantitative yield) as a sticky gum. 1H-NMR (CDCl3, 300 MHz) δ 8.45 (s, 1H), 7.29 (s, 1H), 6.97 (s, 1H), 3.79-3.73 (m, 1H), 3.73 (s, 3H), 3.56-3.50 (m, 2H), 5.12 (dd, J=13.5, 5.12 Hz, 1H), 4.85 (dd, J=13.5, 8.1 Hz, 1H), 2.58 (s, 3H), 0.87-0.81 (m, 2H), 0.01 (s, 9H). 13C-NMR (CDCl3, 75 MHz) δ 175.5, 151.8, 133.7, 129.9, 129.4, 125.0, 121.3, 117.9, 55.5, 52.1, 51.1, 41.4, 17.1, 9.8, −2.1. Mass spec.: 398 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25][NH2:26])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].Cl.[N:29]1([C:34]([NH2:36])=O)C=CC=N1>CO>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25][NH:26][C:34]([NH2:36])=[NH:29])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: NC(=O)n1cccn1
Reactant: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCON)ccc21
Agent: Cl
Solvent: CO
Product: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCONC(=N)N)ccc21
Reaction time: 120 h
Yield: 97 %

Procedure:
3-[5-(2-aminooxy-ethoxy)-indol-1-yl]-3-phenyl-propionic acid ethyl ester (0.28 g, 0.75 mmol) and 1H-pyrazole-1-carboxamide hydrochloride (0.99 g, 0.67 mmol) were dissolved in methanol (3 mL) and stirred for 5 days. The solvent was evaporated under vacuum and the crude mixture was purified via column chromatography with silica gel, eluting with 10% methanol/dichloromethane to afford the title compound (97% yield). 1H NMR (CDCl3), δ 7.11-7.26 (m, 7H), 7.00 (d, 1H, J=2.3 Hz), 6.75 (dd, 1H, J=2.3, 8.8 Hz), 6.43 (d, 1H, J=3.2 Hz), 5.98 (t, 1H, J=7.6 Hz), 4.08 (m, 2H), 3.99 (m, 4H), 3.23 (m, 2H), 1.05 (t, 3H, J=7.2 Hz).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]([C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)(O)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH4+:23].[OH-]>>[C:3]1([CH2:2][N:9]2[CH2:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([NH2:23])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OC1(c2ccc(Br)cc2)CCN(Cc2ccccc2)CC1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: Nc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Temperature: 180 °C
Reaction time: 12 h

Procedure:
A mixture of 1-benzyl-4-(p-bromophenyl)-4-piperidinol hydrochloride (0.23 mol) and Cu2O (2 g) in NH4OH (500 ml) was stirred at 180° C. for 12 hours. The mixture was cooled, extracted with DCM and washed with water. The organic layer was dried, filtered off and evaporated, yielding 60 g of 4-[1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinyl]benzenamine (intermediate 47).
Reaction SMILES: [N+:1]([CH:4]([N+:6]([O-:8])=[O:7])[CH3:5])([O-:3])=[O:2].C(N(CC)CC)C.[CH2:16]=[C:17]([C:22]([O:24][CH3:25])=[O:23])[C:18]([O:20][CH3:21])=[O:19]>CCOCC>[N+:1]([C:4]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:16][CH:17]([C:22]([O:24][CH3:25])=[O:23])[C:18]([O:20][CH3:21])=[O:19])([O-:3])=[O:2]
Reactant: CC([N+](=O)[O-])[N+](=O)[O-]
Reactant: C=C(C(=O)OC)C(=O)OC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)C(CC(C)([N+](=O)[O-])[N+](=O)[O-])C(=O)OC
Yield: 72 %

Procedure:
Carefully controlled reaction conditions are required because the addition of a nucleophile (nitro- or halonitroalkyl ion) to a methylenemalonate ester gives the salt of an alkylmalonate which is itself capable of undergoing further nucleophilic reactions. Nitroform, a strong acid, reacts with diethyl methylenemalonate in aqueous methanol at ambient temperature, without a base as catalyst, to produce diethyl 2,2,2-trinitroethylmalonate. The same conditions may also be used to produce dimethyl 2,2,2-trinitroethylmalonate. The reaction of 1,1-dinitroethane with methylenemalonates does not take place under these conditions, presumably because the nitro compound is not sufficiently ionized. However, the addition of triethylamine to an ether solution of 1,1-dinitroethane and dimethyl methlenemalonate at 0° C. resulted in a 72% yield of dimethyl 2,2-dinitropropylmalonate. In the same manner, diethyl 2,2-dinitropropylmalonate may be prepared. Finally, the addition fluorodinitromethane to methylenemalonates in ether solution in the presence of catalytic amounts of pyridine produces good yields of dimethyl and diethyl 2-fluoro-2,2-dinitroethylmalonates.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]2[CH2:32][CH2:31][CH2:30][NH:29]2)[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][N:29]2[CH2:30][CH2:31][CH2:32][CH:28]2[C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C2CCCN2)c1
Reactant: Fc1ccc(C(OCCBr)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(C2CCCN2CCOC(c2ccc(F)cc2)c2ccc(F)cc2)c1
Yield: 52 %

Procedure:
Proceeding as in Example 9, using 9.8 g (30 mmole) of 1-[bis(4-fluorophenyl)methoxy]-2-bromoethane, 5.3 g (30 mmole) of (2-(3-methoxyphenyl)pyrrolidine and 8.3 g (60 mmole) of potassium carbonate, there was obtained after silica gel column filtration, 6.7 g (yield: 52%) of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-2-(3-methoxyphenyl)pyrrolidine.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([C:22]3([CH2:25]OS(C)(=O)=O)[CH2:24][CH2:23]3)[O:13][N:12]=2)=[CH:7][CH:6]=1.[C-:31]#[N:32].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([C:22]3([CH2:25][C:31]#[N:32])[CH2:23][CH2:24]3)[O:13][N:12]=2)=[CH:9][CH:10]=1
Reactant: [C-]#N
Reactant: COCOc1ccc(-c2noc(C3(COS(C)(=O)=O)CC3)c2-c2ccccc2)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1ccc(-c2noc(C3(CC#N)CC3)c2-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 100.6 %

Procedure:
To a mixture consisting of methanesulfonic acid 1-[3-(4-methoxymethoxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropylmethyl ester (synthetic intermediate prepared in Example 11, Step iv, 0.45 g) in N,N-dimethylformamide (4 mL) is added potassium cyanide (0.17 g.) The mixture is stirred at 80° C. for five hours and is subsequently diluted with ethyl acetate (30 mL.) The mixture is sequentially washed with water (15 mL) and brine solution (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the synthetic intermediate {1-[3-(4-methoxymethoxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropyl}-acetonitrile (0.38 g.)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[O:10][CH2:11]C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)COC(=O)Nc1ccc(N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Nc1ccc(N)cc1
Reaction time: 2 h

Procedure:
Intermediate 10A (2.6 g, 9.77 mmol) was deprotected with 30% TFA in DCM (40 mL). After 2 h, the reaction was concentrated and the residue was partitioned with EtOAc (75 mL) and saturated NaHCO3 (50 mL). The organic layer was washed with brine (20 mL) and dried (MgSO4). Crude Intermediate 10B was carried onto the next step. 1H NMR (400 MHz, DMSO-d6) δ 9.86 (1H, s), 7.56 (2H, d, J=8.84 Hz), 7.28 (2H, d, J=8.84 Hz), 6.90 (2H, s), 3.68 (3H, s) ppm.
Reaction SMILES: CN(C1C=CC=CN=1)C.[OH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>N1C=CC=CC=1>[C:25]([O:10][CH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1)(=[O:29])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CC(C)C(=O)OC[C@H]1CCCN(C(=O)OC(C)(C)C)C1

Procedure:
170 mg of dimethylaminopyridine and 3.4 mg of pyridine are added to 3.0 g of t-butyl (S)-3-hydroxymethyl-l-piperidinecarboxylate. 1.66 ml of isobutyryl chloride are added dropwise thereto. The reaction mixture is then concentrated. The residue is taken up in ether and the ether phase is washed in succession with 20 ml of citric acid, water, sodium bicarbonate solution and water. After drying and evaporation of the ether phase there are obtained 3.9 g of t-butyl (S)-3-isobutyroxymethyl-1-piperidinecarboxylate, Rf=0.87 (ether). 3.09 g of this ester are dissolved in 80 ml of methylene chloride and treated with 20 ml of trifluoroacetic acid. After stirring for 30 minutes the solution is concentrated. 30 ml of methanol are added to the residue and saturated sodium bicarbonate solution is then added dropwise. The aqueous phase is extracted with methylene chloride and the methylene chloride extracts are dried and concentrated. There are obtained 2.82 g of (S)-3-iso- butyroxymethyl-1-piperidinecarboxylic acid trifluoroacetic acid salt, Rf=0.4 (Takeda solution).