Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].[C:12]([O:16][C:17]([NH:19][C@@H:20]1[CH2:25][C@H:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][NH:22][CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>CN(C=O)C>[C:12]([O:16][C:17]([NH:19][CH:20]1[CH2:25][CH:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][N:22]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=2)[CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CC(NC(=O)OC(C)(C)C)CN(c2cc(C(=O)O)c(Cl)nn2)C1
Temperature: 100 °C
Yield: 51.2 %

Procedure:
A mixture of 3,6-Dichloro-pyridazine-4-carboxylic acid (201) (400 mg, 2 mmol) and (3R,5S)-3,5-bis-tert butoxy carbonyl amino piperdine (4) (1.3 g, 4 mmol) in 14 ml DMF containing iPr2NEt (718 ∥l, 4 mmol) was heated at 100° C. for 25.6 h with shaking. The solvent was removed under reduced pressure. After HPLC purification, compound 207 (483 mg, 51.1%) was obtained as a solid. LC-MS (ESI): m/e=472.3 [M+1]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1([CH3:41])[CH2:31][CH2:30][CH2:29][C:28]2[CH:27]=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=[CH:24][C:23]1=2.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:26]3[CH:25]=[CH:24][C:23]4[C:22]([CH3:41])([CH3:21])[CH2:31][CH2:30][CH2:29][C:28]=4[CH:27]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)n2)CC1
Reactant: CC1(C)CCCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3ccc4c(c3)CCCC4(C)C)n2)CC1

Procedure:
500 mg (1.46 mmol) of 4-(6-bromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester, 460 mg (1.61 mmol) of 2-(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 620 mg (2.92 mmol) of tripotassium phosphate trihydrate are suspended in 10 ml of ethylene glycol monomethyl ether, degassed a number of times, and 82 mg (0.04 mmol) of bis(triphenylphosphine)palladium(II) dichloride are added under nitrogen atmosphere. The reaction mixture is treated in an ultrasound bath for 10 min, subsequently irradiated in the microwave at 100° C. for 90 min, 50 ml of water and 50 ml of ethyl acetate are added, and the mixture is filtered. The residue is discarded. The organic phase of the filtrate is separated off, and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4 and evaporated. The crude product is purified by means of flash chromatography on silica gel.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([C:15]1[CH:19]=[CH:18][S:17][CH:16]=1)#[N:14].[CH3:20]I.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24]>C1COCC1>[C:13]([C:15]1[CH:19]=[C:18]([Si:23]([CH3:25])([CH3:24])[CH3:22])[S:17][C:16]=1[CH3:20])#[N:14]
Reactant: CI
Reactant: N#Cc1ccsc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1sc([Si](C)(C)C)cc1C#N
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.4 M in hexanes, 1.3 ml, 1.8 mmol) was added dropwise to a stirred solution of diisopropylamine (0.25 ml) in dry THF (16 ml) at -5-0° C. and the solution stirred for 30 min. The mixture was cooled to -78° C. and a solution of 3-cyanothiophene (0.20 g, 1.8 mmol) in THF (4 ml) added dropwise, followed by methyl iodide (0.23 ml, 0.35 g, 2.5 mmol) after min. The mixture was stirred for 20 min., warmed to room temperature over 30 min. and evaporated. Meanwhile n-butyllithium (1.4 M in hexanes, 1.31 ml) was added dropwise to a stirred solution of diisopropylamine (0.25 ml) in dry THF (16 ml) at -5-0° C. and the solution stirred for 30 min. The mixture was cooled to 78° C. and the crude 3-cyano-2-methylthiophene prepared above was added dropwise in THF (4 ml), followed by trimethylsilylchloride (0.43 ml) after 1 min. The mixture was stirred for 20 min., warmed to room temperature over 30 min. and evaporated to afford a yellow oil. Purification by flash chromatography on untreated neutral alumina, eluting with 5% diethyl ether in hexane, gave 3-cyano-2-methyl-5-trimethylsilylthiophene as a clear oil (0.20 g). M+ 195; 360 MHz 1H n.m.r (CDCl3) 7.19 (1H, s), 2.66 (3H, s), 0.31 (9H, s).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].OO.[F:16][C:17]1[C:22]([O:23][CH3:24])=[C:21]([F:25])[CH:20]=[CH:19][C:18]=1[NH2:26].[Cl-].[Na+].[OH2:29]>C(Cl)Cl>[F:25][C:21]1[CH:20]=[CH:19][C:18]([N+:26]([O-:4])=[O:29])=[C:17]([F:16])[C:22]=1[O:23][CH3:24]
Reactant: COc1c(F)ccc(N)c1F
Reactant: O
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(F)ccc([N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
To a solution of trifluoroacetic anhydride (26.2 mL, 0.19 mol) in DCM (100 mL) at 0° C. was added, dropwise, hydrogen peroxide (50% in water, 12.9 mL, 0.17 mol) and the reaction mixture was stirred at 0° C. for 1.5 h. 2,4-Difluoro-3-methoxyphenylamine (3 g, 18.9 mmol) was added as a solution in DCM (20 mL) and the reaction mixture stirred at RT for 3 h. The reaction mixture was diluted with brine and extracted with DCM (3×30 mL). The combined organic fractions were washed with sat. aq. NaHCO3 solution, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% Et2O in cyclohexane) to give the title compound as a colourless solid (2.03 g, 57%). 1H NMR 400 MHz δ (CDCl3): 7.83-7.76 (1H, m), 7.03 (1H, td, J=9.4, 2.5 Hz), 4.08 (3H, t, J=1.1 Hz).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.Cl.[CH3:47][O:48][C:49]([C:51]1([NH2:57])[CH2:56][CH2:55][S:54][CH2:53][CH2:52]1)=[O:50].Cl>O.CN(C=O)C>[CH3:47][O:48][C:49]([C:51]1([NH:57][C:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[OH:1])=[O:14])[CH2:52][CH2:53][S:54][CH2:55][CH2:56]1)=[O:50]
Reactant: COC(=O)C1(N)CCSCC1
Reactant: O=C(O)c1ccc2ccccc2c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2ccc3ccccc3c2O)CCSCC1
Reaction time: 16 h
Yield: 100.2 %

Procedure:
To a solution of 0.50 g 1-hydroxy-2-naphthoic acid in 5 ml abs. DMF under inert atmosphere 0.18 g 1-hydroxybenzotriazole, 0.71 g 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.7 ml N,N-diisopropylethylamine were added. After 15 minutes 0.62 g 4-amino-tetrahydro-thiopyran-4-carboxylic acid methyl ester hydrochloride, followed by 0.55 ml N,N-diisopropylethylamine were added. After 16 h at room temperature and 5 h at 60° C. the reaction was poured unto water, adjusted to pH2 with 2 M HCl and extracted with ethyl acetate twice. The combined organic layers were washed with 2M HCl, 2M aqueous sodium carbonate solution and brine. The organic layer was dried over magnesium sulphate, and concentrated to yield 0.92 g of 4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-tetrahydro-thiopyran-4-carboxylic acid methyl ester.
Reaction SMILES: Cl[Si](C)(C)C.[Br:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=1[CH3:15].[Mg].Br.[C:18]1([S:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[Br-:6].[C:26]1([S+:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:7]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[CH3:15])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cc(C)c(Br)c(C)c1
Reactant: O=S(c1ccccc1)c1ccccc1
Agent: Br
Agent: C[Si](C)(C)Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Product: Cc1cc(C)c([S+](c2ccccc2)c2ccccc2)c(C)c1
Product: [Br-]
Reaction time: 3 h
Yield: 48.1 %

Procedure:
In 600 mL of tetrahydrofran, 24.0 g of diphenylsulfoxide was dissolved under nitrogen atmosphere, then the solution was charged with 31.5 g of chlorotrimethylsilane. To this solution, a Grignard reagent prepared with 60 g of 2-bromomesitylene and 4.70 g of magnesium according to the conventional method was added drop-wise with ice-cooling, followed by reacting at the same temperature for 3 hours. After completion of the reaction, 480 mL of a 24% aqueous hydrobromic acid solution and further 600 mL of toluene was poured drop-wise to said reaction solution and stirred. Then, the organic layer separated was extracted twice with 120 mL of a 12% aqueous hydrobromic acid solution and combined together with the water layer, which was further extracted three times with 480 mL of methylene chloride. The organic layer obtained was dried by anhydrous magnesium sulfate, followed by concentrating under reduced pressure, to obtain 22.0 g of diphenyl-2,4,6-trimethylphenylsulfonium bromide as a white crystal. The measurement results of melting point and NMR of the crystal obtained are shown bellow.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][NH:15][CH:16]2[C:19]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[CH2:21][CH2:20]2)=[CH:11][C:10]=1OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](=[O:34])([O-])[O-].[K+].[K+].Br[CH2:38][CH2:39][OH:40]>CC(C)=O>[CH2:1]([O:8][C:9]1([O:34][CH3:31])[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][N:15]([CH2:38][CH2:39][OH:40])[CH:16]2[C:19]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[CH2:20][CH2:21]2)=[CH:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccccc3Cl)CC1)NCC2
Reactant: OCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC1(OCc2ccccc2)C=C2C(=CC1)CCN(CCO)C2C1(c2ccccc2Cl)CC1

Procedure:
A mixture of 7 -benzyloxy-1-[1-(2 -chlorophenyl)cyclopropyl]-6-methoxy-1,2,3,4-tetrahydroisoquinoline (2.83 g, liberated from the hydrobromide salt prepared in a similar manner to that described in Example RC14), acetone (40 ml), anhydrous potassium carbonate (5.5 g) and 2-bromoethanol (3.6 ml) was heated under reflux for 18 hours. The mixture was filtered, the solids washed with acetone, and the filtrate solvent removed in vacuo to give 7-benzyloxy-1-[1-(2-chlorophenyl)cyclopropyl]-2-(2-hydroxyethyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.CCN(C(C)C)C(C)C.CN([C:24]([O:28][N:29]1N=NC2C=CC=N[C:30]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:29]([O:28][CH3:24])[CH3:30])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(Br)cc1Cl
Reaction time: 1 h

Procedure:
To a stirring solution of 4-bromo-2-chlorobenzoic acid (3.45 g, 15 mmol) and DIEA (7.7 ml, 44 mmol) in DMF (30 mL) was added HATU (6.1 g, 16 mmol) at 23° C. under nitrogen. Darkened suspension stirred for 1 h, then added n,o-dimethylhydroxyl amine hydrochloride (2.1 g, 22 mmol). Solution stirred overnight at 23° C. Reaction then partitioned between 2.5% NaHCO3 (250 mL) and diethyl ether (100 mL). Aqueous further extracted with ether (2×50 mL). Combined ethereal extracts dried over MgSO4, then concentrated an amber oil under reduced pressure. 4-bromo-2-chloro-N-methoxy-N-methylbenzamide isolated as a light amber oil.
Reaction SMILES: [OH-].[Na+].Br[CH2:4][C@H:5]([C:7]1[N:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[S:10][CH:11]=1)[OH:6]>O1CCCC1.O>[O:6]1[CH2:4][C@@H:5]1[C:7]1[N:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[S:10][CH:11]=1
Reactant: O[C@H](CBr)c1csc(C(F)(F)F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1nc([C@H]2CO2)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 123.9 %

Procedure:
Aqueous sodium hydroxide (5N, 11 mL) was added to a solution of (1S)-2-bromo-1-[2-(trifluoromethyl)-1,3-thiazole-4-yl]ethanol (which was obtained in Example 103) (1.52 g, 5.5 mmol) in tetrahydrofuran (6 mL). The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with H2O (30 mL) and extracted with dichloromethane. The organic extracts were washed with H2O and brine, and dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/dichloromethane 6/4) gave a clear oil (1.33 g, 74% yield); MS (ES) m/z: 196 (MH+); 1H NMR (400 MHz, CDCl3) δ 3.09 (m, 1H), 3.19 (m, 1H), 4.11 (m, 1H), 7.48 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8][CH3:9])=[CH:6][NH:5][C:4]=1[CH:10]=O)[CH3:2].[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C(NCC)C>C(O)C>[CH2:18]([O:17][C:15](=[O:16])[C:14]([C:12]#[N:13])=[CH:10][C:4]1[NH:5][CH:6]=[C:7]([CH2:8][CH3:9])[C:3]=1[CH2:1][CH3:2])[CH3:19]
Reactant: CCOC(=O)CC#N
Reactant: CCc1c[nH]c(C=O)c1CC
Solvent: CCNCC
Solvent: CCO
Product: CCOC(=O)C(C#N)=Cc1[nH]cc(CC)c1CC
Temperature: 25 °C

Procedure:
The 3,4-diethyl-2-formylpyrrole (14.1 g, 93.1 mmol) was dissolved in 200 mL of dry ethanol, and ethyl cyanoacetate (20 mL, 137.9 mmol) and diethylamine (20 mL, 193.3 mmol) were added to the solution. The reaction mixture was heated to reflux under an inert atmosphere and stirred under reflux for 2 hours, after which it was cooled to room temperature and then placed in an ice bath. The resulting dark suspension was filtered through a medium filter, and the light brown solids were washed with cold ethanol. The collected filtrates were concentrated under reduced pressure, precipitating more solids. The thick suspension was filtered, and the combined solids were separated and purified to give 2-cyano-3-(3,4-diethyl -1H-pyrrol-2-yl) acrylic acid ethyl ester, a compound of formula 201 in which R1 and R2 are both ethyl.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Cl.[C:18]1([O:24]C2C=CC=CC=2)C=C[CH:21]=[CH:20][CH:19]=1>>[CH2:13]([O:12][C:10]([CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:4]=[C:3]2[C:2](=[CH:16][CH:15]=1)[N:1]=[C:20]([CH3:21])[CH:19]=[C:18]2[OH:24])=[O:11])[CH3:14]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)CCCOc1ccc(N)cc1
Agent: Cl
Product: CCOC(=O)CCCOc1ccc2nc(C)cc(O)c2c1
Yield: 42 %

Procedure:
To a stirring mixture of ethyl 4-(4-aminophenoxy)butanoate (3.12 g, 14 mmol) and acetoacetic ester (1.82 g, 14 mmol) was added a catalytic amount of hydrochloric acid and cyclized in refluxing diphenyl ether as described in Example 5a. The product was obtained as a light yellow solid (1.70 g, 42%). 1H NMR (400 MHz, DMSO-d6): 1.32 (3H, t, J=7.1 Hz), 2.15 (2H, m), 2.50 (3H, s), 2.62 (2H, t, J=7.3 Hz), 4.21 (4H, m), 6.09 (1H, s), 7.42 (1H, dd, J=9.0, 2.7 Hz), 7.58 (1H, d, J=2.7 Hz), 7.65 (1H, d, J=9.0 Hz), 11.8 (1H, s).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.I[CH3:10].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([CH3:10])[CH2:4]1
Reactant: CI
Reactant: O=C1NCC(CCl)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CC(CCl)OC1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
5-(Chloromethyl)-1,3-oxazolidin-2-one (500 mg, 3.69 mmol) and iodomethane (0.27 mL, 4.43 mmol) were dissolved in DMF (5 mL) and the resulting solution was cooled to 0° C. Sodium hydride (60%, 177 mg, 4.43 mmol) was added followed by additional DMF (2 mL). The reaction was warmed to room temperature and stirred for 4 hours. Additional iodomethane (0.14 mL, 2.22 mmol) and sodium hydride (60%, 88 mg, 2.2 mmol) were then added and the reaction mixture stirred at room temperature for two hours. The reaction was diluted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (12 to 100% EtOAc/hexanes) to afford racemic 5-(chloromethyl)-3-methyl-1,3-oxazolidin-2-one as a yellow liquid. 1H NMR (500 MHz, CDCl3) δ 4.82-4.60 (m, 1H), 3.81-3.55 (m, 3H), 3.48-3.44 (m, 1H), 2.90 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]=[C:16]([CH2:23][CH2:24][CH2:25][NH2:26])[C:17]4[S:22][CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[I-:27].[Na+].CN(C)[C@@H]1CCCC[C@H]1N>O1CCOCC1.[Cu](I)I>[I:27][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]=[C:16]([CH2:23][CH2:24][CH2:25][NH2:26])[C:17]4[S:22][CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: NCCCc1nc(N2CCN(c3ccc(Br)cc3)CC2)nc2c1SCC2
Reactant: [I-]
Agent: I[Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: [Na+]
Solvent: C1COCCO1
Product: NCCCc1nc(N2CCN(c3ccc(I)cc3)CC2)nc2c1SCC2
Temperature: 140 °C
Yield: 98.1 %

Procedure:
1.55 g (3.6 mmol) of {2-[4-(4-bromophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl}propylamine (VII), 1.1 g (7.2 mmol) of sodium iodide, and 0.036 g (0.19 mmol) of copper iodide are taken, and under an argon atmosphere 0.060 mL (0.38 mmol) of trans-N,N-dimethyl-1,2-cyclohexanediamine and 7 mL of anhydrous/degassed dioxane are added. The reaction mixture is heated for 1.5 hours at 140° C. in the microwave, then diluted with dioxane, and suction filtered through Alox. The dioxane was concentrated by evaporation. 1.70 g of product VIII (81%) is obtained as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:34]#[N:35])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C@H:25]3[CH2:30][CH2:29][C@H:28]([O:31][CH3:32])[CH2:27][CH2:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:33])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:34]#[N:35])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C@H:25]3[CH2:30][CH2:29][C@H:28]([O:31][CH3:32])[CH2:27][CH2:26]3)[C:17]([OH:19])=[O:18])[C:10](=[O:33])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C[C@H]2CC[C@H](OC)CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(C[C@H]2CC[C@H](OC)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
1.70 g (purity 87%, 3.39 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(trans-4-methoxycyclohexyl)propanoate (racemate) in 6 ml of dichloromethane and 5.04 ml (67.9 mmol) of TFA were reacted according to General Method 6A. Yield: 1.70 g (quant.)
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][N:6]1C(=O)C2C(=CC=CC=2)C1=O.[CH2:18]([NH2:21])[CH2:19][CH3:20]>>[NH2:6][O:5][CH2:4][C:3]([NH:21][CH2:18][CH2:19][CH3:20])=[O:2]
Reactant: CCCN
Reactant: COC(=O)CON1C(=O)c2ccccc2C1=O
Product: CCCNC(=O)CON

Procedure:
Using (1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-acetic acid methyl ester obtained in Step A of Example 19 and n-propylamine as an amine, synthesis was performed according to the procedure described in Step A of Example 20 to give 2-aminooxy-N-propyl-acetamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH:7]=[CH:8][CH:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[NH3:34]>CO>[C:1]([O:5][C:6](=[O:33])[CH2:7][CH:8]([NH2:34])[CH:9]1[O:13][N:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:18][CH:19]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(COc2ccc(C3=NOC(C=CC(=O)OC(C)(C)C)C3)cc2)c2ccccc2n1
Reactant: N
Solvent: CO
Product: Cc1cc(COc2ccc(C3=NOC(C(N)CC(=O)OC(C)(C)C)C3)cc2)c2ccccc2n1
Temperature: 60 °C
Yield: 97 %

Procedure:
The product from step 10c (0.3 g, 0.67 mmol) was dissolved in methanol (10 mL) and condensed ammonia (10 mL) in a stainless steel pressure reactor and heated to 60° C. for 5 h. The reaction was complete and was concentrated to give 3-amino-3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid tert-butyl ester (0.3 g, 97%) as an oil. MS found: (M+H)+=462.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16](Cl)([CH3:18])=[O:17].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][CH2:12][N:13]([C:16](=[O:17])[CH3:18])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 110 %

Procedure:
To a solution of 4-(4-Nitro-phenyl)-piperidin (206 mg, 1 mmol) in CH2Cl2 (3 mL) is added AcCl (0.106 mL, 1.5 mmol) at 0° C. Then Et3N (0.253 mL, 1.8 mmol) is added slowly. The mixture is stirred at 0° C. for 10 minutes. Then saturated NaHCO3 aqueous solution is added. The aqueous layer is extracted with CH2Cl2, and the organic extracts are dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, MeOH:CH2Cl2=0.7:99.3 to 6:93) to give 273 mg of the title compound as yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][O:18][CH3:19])[C:11](=[O:20])[CH2:10][CH2:9]2.C([O:25][N:26]=O)CCC.Cl>CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][O:18][CH3:19])[C:11](=[O:20])[C:10](=[N:26][OH:25])[CH2:9]2
Reactant: COCCOc1cc2c(cc1OCCOC)C(=O)CC2
Reactant: CCCCON=O
Agent: Cl
Solvent: CO
Product: COCCOc1cc2c(cc1OCCOC)C(=O)C(=NO)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
To a solution of 5,6-Bis-(2-methoxy-ethoxy)-indan-1-one (2.6 g, 9.28 mmol) in the methanol (20 ml) was added n-butylnitrite (1.25 ml, 10.2 mmol) followed by concentrated HCl (0.8 ml). The solution was stirred at room temperature overnight during which time a precipitate was formed. The precipitate was collected and dried to yield product as a yellow solid (1.11 g, 38.58%). LC-MS: m/e 310 (MH+).
Reaction SMILES: [CH2:1]([N:7]1[C:11](=O)[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=O)CCCC#C.C=O.C[NH:21]C.O.NN>>[CH3:1][N:7]([CH3:11])[CH2:8][C:9]#[C:16][CH2:15][CH2:14][CH2:13][CH2:10][NH2:21]
Reactant: CNC
Reactant: C#CCCCCN1C(=O)c2ccccc2C1=O
Agent: C=O
Agent: NN
Solvent: O
Product: CN(C)CC#CCCCCN

Procedure:
In a manner similar to Description 1 (iii) and (iv) reaction of N-5-hexynylphthalimide, paraformaldehyde and dimethylamine, followed by treatment with hydrazine hydrate gave the title compound b.p. 110°-20° C. (0.3 mm Hg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([CH3:12])[CH:4]=1.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>S(Cl)(Cl)=O.O>[CH2:13]([N:15]([CH2:16][CH3:17])[C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH3:12])[CH3:14]
Reactant: CCNCC
Reactant: COc1ccc(C(=O)O)c(C)c1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1ccc(OC)cc1C
Temperature: 80 °C
Yield: 57.6 %

Procedure:
4-methoxy-2-methylbenzoic acid (3.0 g, 18.05 mmol) was taken in thionyl chloride (20 ml) and refluxed for 1 h at 80° C. The reaction mixture was evaporated under reduced pressure. Under nitrogen the crude was quenched with diethyl amine (1.870 ml, 18.05 mmol) slowly under cooling conditions. The reaction mixture was dissolved in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get desired compound (2.3 g, 54.7%) as oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.06-7.04 (d, J=8 Hz, 1H), 6.79 (s, 1H), 6.78-6.76 (d, J=8 Hz, 1H), 3.75 (s, 3H), 3.43 (br, s, 2H), 3.06-3.05 (m, 2H), 2.16 (s, 3H), 1.14 (d, J=8 Hz, 3H), 0.95 (d, J=8 Hz, 3H).