Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH2:6][C:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[C:11]=1[CH3:20])=[O:8])[CH3:4].Br[CH:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24].O>O1CCCC1>[CH3:26][O:25][C:23]([CH:22]([N:9]([C:7](=[O:8])[CH2:6][O:5][CH2:3][CH3:4])[C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[C:11]=1[CH3:20])[CH3:27])=[O:24]
Reactant: CCOCC(=O)Nc1c(C)ccc([N+](=O)[O-])c1C
Reactant: COC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCC(=O)N(c1c(C)ccc([N+](=O)[O-])c1C)C(C)C(=O)OC
Temperature: 55 °C

Procedure:
To a solution of 3 g of 55% sodium hydride in 70 ml of anhydrous tetrahydrofuran saturated with nitrogen is added dropwise, at room temperature, with stirring and while simultaneously introducing nitrogen, a solution of 16 g N-ethoxyacetyl-2,6-dimethyl-3-nitroaniline in 30 ml of the same solvent. After the weakly exothermic reaction has subsided, the mixture is heated to 55° C. and 12.7 g of methyl 2-bromopropionate in 20 ml of tetrahydrofurane are added. During this addition the temperature rises to 60° C. The mixture is stirred for 12 hours at 55° C., then cooled to room temperature, poured into 100 ml of water and extracted with two 100 ml portions of ethyl acetate. The combined extracts are washed with water, dried over sodium sulfate, and excess solvent is removed in vacuo. The oily crude product is purified by column chromatography over silica gel, using a 1:1 mixture of chloroform/diethyl ether as eluant. Fractions 5 to 30 are combined and the eluant is removed in vacuo. Compound 31 is a viscous oil with a refractive index of nD24 =1.5325.
Reaction SMILES: ClC1C=CC=C2C=1NC([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=C2.[CH3:20][C:21]1[C:29]2[O:28][CH:27]=[CH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1>>[CH3:20][C:21]1[C:29]2[O:28][C:27]([B:11]3[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]3)=[CH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Reactant: Cc1cccc2ccoc12
Product: Cc1cccc2cc(B3OC(C)(C)C(C)(C)O3)oc12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-methyl-benzofuran.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:13][Mg+].[Br-]>C(Cl)(Cl)Cl>[CH3:13][C:5]1[C:6]2[S:10][CH:9]=[N:8][C:7]=2[CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: C[Mg+]
Reactant: O=[N+]([O-])c1ccc2ncsc2c1
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: Cc1c([N+](=O)[O-])ccc2ncsc12
Reaction time: 2 h
Yield: 45.5 %

Procedure:
To a solution of 6-nitrobenzothiazole (1.4 g, 7.7 mmol) in 50 mL of TMF was added 5.1 mL of MeMgBr (15.3 mmol) dropwise in 0.5 h period at 0° C. The reaction mixture was then stirred for additional 2 h. It was quenched by adding THF solution of 2,3-dichloro-5,6-dicyanobenzoquinone until the color of the solution turns to dark green. The reaction mixture was concentrated in vacuo to yield a dark solid which was subjected to column chromatography (CHCl3, neat) to provide 0.68 g (3.5 mmol, 46%) of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C@@H:10]2[O:19][C@H:13]3[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@H:12]3[C@H:11]2[CH2:20][CH2:21][N:22]2[C:27](=[O:28])[C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[N:24]=[N:23]2)=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C@@H:10]3[O:19][C@H:13]4[O:14][C:15]([CH3:17])([CH3:18])[O:16][C@H:12]4[C@H:11]3[CH2:20][CH2:21][N:22]3[C:27](=[O:28])[C:26]4[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=4[N:24]=[N:23]3)=[CH:6][CH:7]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC1(C)O[C@@H]2O[C@@H](/C=C/c3ccc(Br)cc3)[C@H](CCn3nnc4ccccc4c3=O)[C@@H]2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-c2ccc(/C=C/[C@@H]3O[C@H]4OC(C)(C)O[C@H]4[C@H]3CCn3nnc4ccccc4c3=O)cc2)cc1
Temperature: 120 °C

Procedure:
A mixture of the compound obtained from step d above (1 g), 4-methoxyphenyl boronic acid (0.61 g), tetrakistriphenylphosphine palladium (0) (0.232 g), and potassium carbonate (0.832 g) was dried under high vacuum for 10 minutes and dry dimethylformamide (20 mL) was added at room temperature. The reaction mixture was heated at 120° C. for 2 hours, and then quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 50% ethyl acetate in hexane as eluant to afford the title compound (0.62 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]([F:34])([F:33])[F:32])=[C:6]([CH:30]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:19]=3)=[CH:17][C:9]1=2.[C:35](Cl)(=[O:37])[CH3:36].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]([F:32])([F:34])[F:33])=[C:6]([CH:30]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:25][CH2:26][N:27]([C:35](=[O:37])[CH3:36])[CH2:28][CH2:29]4)[CH:19]=3)=[CH:17][C:9]1=2
Reactant: CC(=O)Cl
Reactant: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(-c3ccnc(N4CCNCC4)c3)cc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2cc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)ccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of 1-[5-chloro-2-(trifluoromethyl)benzyl]-7-(2-piperazin-1-yl-pyridin-4-yl)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine (63 mg, 0.000129 mol) in anhydrous DMF (1 mL) was added acetyl chloride (0.012 mL) and triethylamine (0.020 mL). The mixture was stirred at room temperature under nitrogen overnight and then concentrated. The residue was purified on normal phase silica gel chromatography to give the title compound as a yellow solid (56% yield). m.p.=241° C., LCMS: m/z=531.31 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.15 (3H, s), 3.47 (2H, m), 3.52 (2H, m), 3.57 (2H, m), 3.62 (2H, m), 3.73 (4H, m), 4.61 (2H, s), 5.25 (1H, bs), 6.55 (2H, m), 6.69 (1H, d, J=5.3 Hz), 7.37 (1H, d, J=8.3 Hz), 7.52 (1H, s), 7.65 (1H, d, J=8.3 Hz), 7.78 (1H, bs), 8.12 (1H, d, J=5.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Br:20])=[CH:15][C:14]=1[CH3:21].[CH2:23]([CH:25]([NH2:28])[CH2:26][CH3:27])[CH3:24]>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:28][CH:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Br:20])=[CH:15][C:14]=1[CH3:21]
Reactant: CCC(N)CC
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(Br)cc1C
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C(=O)OC
Temperature: 120 °C

Procedure:
A mixture of 4-chloro-6-methyl-2-(4-bromo-2,6-dimethyl-phenoxy)-nicotinic acid methyl ester and 1-ethyl-propyl-amine in DMSO was heated at 120° C. for 16 hr. The mixture was quenched with water, brine and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness. The residue was purified through silica gel column chromatography using hexane to 3% ethyl acetate in hexane as eluent to give the title compound as a white solid. 1H NMR(CDCl3) d 8.1(d,1H), 7.18(s,2H), 6.08(s,1H), 3.87(s,3H), 3.35(m,1H), 2.10(s,3H), 2.08(s,6H), 1.4–1.7(m,4H), 0.96(t,6H) ppm.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].[OH-].[Li+]>CO.O>[F:16][C:13]([F:14])([F:15])[CH2:12][O:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ncccc1OCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ncccc1OCC(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of 3-hydroxy-pyridine-2-carboxylic acid methyl ester (200 mg, 1.3 mmol) in N,N-dimethylformamide (2.0 ml) was added at 22° C. sodium hydride (55% in oil, 64 mg) and stirring was continued until gas evolution ceased. The suspension was cooled to 0° C. and treated with trifluoroethyl trifluormethanesulfonate (728 mg) and stirring was continued at 22° C. for 2 hours. The mixture was partitioned between saturated sodium hydrogen-carbonate solution and ethyl acetate, and the organic layer was dried and evaporated. The residue was purified by chromatography on silica using n-heptane and ethyl acetate (3:1) as the eluent to give 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester as a pale green oil. Mass (calculated) C9H8F3NO3 [235.16]; (found) [M+H]+=236. b) A solution of 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester (216 mg, 0.9 mmol) in methanol (1 ml) was treated with a solution of lithium hydroxide (78 mg, 3.3 mmol) in water (0.1 ml) and stirring was continued at 22° C. for 2 hours. The solution was evaporated and the residue triturated with 1N aqueous hydrochloric acid. The suspension was filtered, the residue washed with water and dried to give 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid as a colorless solid. Mass (calculated) C8H6F3NO3 [221.14]; (found) [M−H]−=220.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH:10][CH:11]([CH3:14])[CH2:12][NH2:13].C(N(C(C)C)C(C)C)C>O>[OH:10][CH:11]([CH3:14])[CH2:12][NH:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: CC(O)CN
Reactant: N#Cc1ccc(F)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)CNc1ccc(C#N)cc1

Procedure:
12.1 g of 4-fluoro-benzonitrile, 7.5 g of 2-hydroxypropylamine and 17.4 ml of N-ethyl-diisopropylamine were heated together to 100° C. for 2.5 hours. The mixture was poured onto 250 ml of water, extracted five times with 50 ml of ethyl acetate and the combined organic phases were evaporated down. The product remaining was purified by column chromatography (silica gel; eluant: ethyl acetate) and crystallised by triturating with a 1:1-mixture of tert.butyl-methylether and petroleum ether.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:22]2[CH2:25][CH2:24][CH2:23]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([O-:35])=[O:34]>O1CCCC1>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:40](=[O:41])[C:39]3[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:44][CH:43]=3)[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:22]2[CH2:25][CH2:24][CH2:23]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3ccc([N+](=O)[O-])cc3)CC2)n1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
0.91 g of 4-[4-(2-tert-Butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]-butylamine (2.64 mmol) and 0.53 g of triethylamine (5.28 mmol) were dissolved in 20 ml of tetrahydrofuran. 0.49 g of 4-nitro-benzoyl-chloride (2.64 mmol) were added at 0-5° C. After stirring for 2 h at 0-5° C., the solvent was evaporated and the residue partitioned between ethyl acetate and water. The aqueous phase was re-extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using ethyl acetate and ethyl acetate-methanol (2%). Fractions containing the product were combined. The solvent was evaporated to yield 0.51 g of the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.C1C(=O)N([I:19])C(=O)C1.CCOC(C)=O>S(O)(C(F)(F)F)(=O)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[I:19]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1OCc2cc(Br)ccc21
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1OCc2c1ccc(Br)c2I
Temperature: 25 °C

Procedure:
To a solution of 5-bromo-2-benzofuran-1(3H)-one (5.00 g, 23.5 mmol) at 0° C. in TfOH (100 mL) was added NIS (5.55 g, 24.6 mmol). The mixture was stirred at room temperature over night; LC analysis of the reaction mixture indicated completion of the reaction. The reaction mixture was then poured slowly into ice-water (1 L) with stirring. To the solution was then added EtOAc (500 mL) and subsequently stirred for 10 min. The mixture was filtered and the organic layer separated. The aqueous layer was extracted with EtOAc (2×200 mL). The combined organic layers were washed with water (500 mL), brine (500 mL), dried over Na2SO4, filtered, concentrated to dryness; it was absorbed into silica gel and separated with the solvent systems of (hexanes/EtOAc=1/1) to yield 5-bromo-4-iodo-2-benzofuran-1(3H]-one. 1H-NMR (400 MHz, CDCl3) δ ppm 7.80 (d, J=7.8 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 5.07 (s, 2H).
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O>[Pd].CO>[CH3:5][O:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COCCNc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COCCNc1ccccc1N
Temperature: 25 °C
Yield: 88.4 %

Procedure:
Ammonium formate (727 mg, 11.3 mmol) followed by a catalytic amount of palladium on carbon (5%) is added to a solution of N-(2-methoxyethyl)-2-nitroaniline (426 mg, 2.17 mmol) in methanol. The mixture may be refluxed for an appropriate time period (such as overnight), cooled to an appropriate temperature (such as room temperature) and filtered. The filtrate may be concentrated and the residue may purified by Biotage column chromatography to give N1-(2-methoxyethyl)benzene-1,2-diamine (319 mg)
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1)#[N:2].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>[N+](C1C=CC=CC=1)([O-])=O>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: N#Cc1ccc(Nc2ccccn2)c([N+](=O)[O-])c1
Temperature: 200 °C
Yield: 45.9 %

Procedure:
A mixture of 4-Cyano-2-nitroaniline (10.8 g, 66 mmol), 2-bromopyridine (12.6 g, 80 mmol), anhydrous potassium carbonate (9.12 g, 66 mmol) and copper-bronze (1.0 g, 15.7 mmol) in nitrobenzene (100 ml) was heated overnight at 200° C. The reaction mixture was cooled and filtered through a pad of celite. The filter cake was washed with dichloromethane (500 ml) and the filtrate was evaporated. The resultant residue was purified by column chromatography (silica gel, 500 g; n-hexane/ethyl acetate/dichloromethane (4/1/1)) to afford 7.28 g (46%) of 4-Cyano-2-nitro-N-(2-pyridyl)aniline as orange solids. 1H-NMR (CDCl3) δ: 10.53 (1H, br.s), 9.08 (1H, d, J=8.8 Hz), 8.58 (1H, d, J=8.8 Hz), 8.41 (1H, ddd, J=5.8, 1.8, 0.7 Hz), 7.78-7.69 (2H, m), 7.12-7.06 (1H, m), 7.02 (1H, d, J=8.8 Hz).
Reaction SMILES: [CH:1]([O:4][C:5]([O:7][C:8]1[CH:9]=[C:10]([CH2:21][C@H:22]([NH:38]C(OC(C)(C)C)=O)[C:23]([O:25][C@H:26]([CH3:37])[CH2:27][O:28][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])=[O:24])[CH:11]=[CH:12][C:13]=1[O:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[O:6])([CH3:3])[CH3:2].[ClH:46]>O1CCOCC1>[ClH:46].[NH2:38][C@@H:22]([CH2:21][C:10]1[CH:11]=[CH:12][C:13]([O:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[C:8]([O:7][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH:9]=1)[C:23]([O:25][C@H:26]([CH3:37])[CH2:27][O:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30])=[O:24]
Reactant: CC(C)OC(=O)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H](C)COC(=O)c2ccccc2)cc1OC(=O)OC(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)OC(=O)Oc1ccc(C[C@H](N)C(=O)O[C@H](C)COC(=O)c2ccccc2)cc1OC(=O)OC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
(1R)-1-Methyl-2-phenylcarbonyloxyethyl(2S)-3-[3,4-bis(isopropoxycarbonyloxy)phenyl]-2-[(tert-butoxy)carbonylamino]propanoate (9) (1.06 g, 1.63 mmol) was dissolved in 10 mL of 4M HCl in dioxane. The reaction mixture was stirred at room temperature for 60 min. Dioxane was evaporated completely under reduced pressure. The resulting white solid was dissolved in water (15 mL) and washed with methyl tert-butyl ether. The aqueous phase was collected and mixed with acetonitrile (10 mL). Lyophilization gave the title compound (8) (0.926 g, 100% yield) as a white solid. 1H NMR (400 MHz, CD3OD): δ 1.30 (3H, d, J=6.4 Hz), 1.35 (12H, d, J=6.4 Hz), 3.16 (1H, dd, J=14.4, 6.8 Hz), 3.23 (1H, dd, J=14.4, 6.4 Hz), 4.28 (1H, t, J=6.8 Hz), 4.31 (1H, dd, J=12.4, 6.4 Hz), 4.48 (1H, dd, J=12, 2.8 Hz), 5.33 (1H, m), 7.19 (1H, dd, J=8.2 Hz), 7.24 (1H, d, J=2 Hz), 7.25 (1H, d, J=8 Hz), 7.48 (2H, t, J=7.2 Hz), 7.60 (1H, t, J=7.2 Hz), 8.00 (2H, d, J=7.6 Hz). MS (ESI) m/z 532.21 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22](=O)[CH2:23][C:24]([O:26]CC)=O)=[C:9]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].O.[NH2:36][NH2:37]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]2[N:37]=[N:36][C:24](=[O:26])[CH:23]=2)=[C:9]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: NN
Reactant: CCOC(=O)CC(=O)COCC1=C(C(=O)OCC)C(c2ccccc2Cl)C(C(=O)OC)=C(C)N1
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=C(COCC2=CC(=O)N=N2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 38.7 %

Procedure:
A solution of ethyl 4-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}acetoacetate (0.50 g) and hydrazine hydrate (0.50 g) in ethanol (20 ml) was kept at room temperature for 4 days and then evaporated. The residue was purified by chromatography on silica gel (1.0 g) using dichloromethane plus 0-5% by volume of methanol as eluant. Appropriate fractions were combined and evaporated and the residue crystallised from ethyl acetate to give the title compound (0.18 g), m.p. 207° C. Found: C,57.11; H,5.15; N,9.19. C22H24ClN3O6 requires: C,57.20; H,5.24; N,9.10%.
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:37][CH2:38][C:39]1[CH:46]=[CH:45][C:42](C#N)=[C:41](F)[CH:40]=1>CN(C=O)C>[N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([NH:37][CH2:38][C:39]1[CH:46]=[CH:45][CH:42]=[CH:41][CH:40]=1)=[O:5]
Reactant: N#Cc1ccc(CN)cc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
To an ice cooled solution of Boc-Aze-OH (0.194 g, 0.96 mmol) in 5 mL of DMF was added TBTU (0.50 g, 9.6 mmol). After 30 min another solution, comprising 4-aminomethyl-2-fluorobenzonitrile (0.17 g, 0.81 mmol; see step (y) above) and diiisopropylethyl amine (0.326 g, 2.53 mmol) in 7 mL of DMF was added. The resulting solution was stirred overnight at room temperature. The solvent was evaporated and the product was purified by preparative RPLC using CH3CN:0.1M NH4OAc (50:50). Freeze-drying gave 0.237 g (74%) of the desired sub-title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH3:12][NH2:13].CCO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:13][CH3:12])=[N:6][CH:7]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CNc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-2-chloro-3-nitropyridine (Matrix, Columbia, USA, 9.8 g, 41.3 mmol) in 250 ml THF was added 8 M methylamine in EtOH (Aldrich, Buchs, Switzerland, 12.9 ml, 103 mmol). The reaction mixture was stirred 1 h at rt then was quenched with 300 ml water. The precipite was filtered and the filtrate concentrated before being filtered again. The yellow solids were combined and dried to give the title compound as a yellow solid (HPLC: tR 3.13 min (Method A)).
Reaction SMILES: C[N:2]([CH3:14])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=1)=O.N[C:16]1[C:20]([C:21]#[N:22])=C[NH:18][N:17]=1>C(O)(=O)C>[CH3:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:5]2[N:18]3[N:17]=[CH:16][C:20]([C:21]#[N:22])=[C:14]3[N:2]=[CH:3][CH:4]=2)[CH:12]=1
Reactant: Cc1ccnc(C(=O)C=CN(C)C)c1
Reactant: N#Cc1c[nH]nc1N
Solvent: CC(=O)O
Product: Cc1ccnc(-c2ccnc3c(C#N)cnn23)c1

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-1-(4-methyl-2-pyridyl)-2-propen-1-one and 0.01 mole of 3-aminopyrazole-4-carbonitrile in glacial acetic acid is refluxed for 8 hours and worked up as for Example 53 to give the product of the example.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1.N([O-])=[O:13].[Na+].S(=O)(=O)(O)O>Cl.O>[OH:13][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: CC(C#N)c1ccc(N)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C#N)c1ccc(O)cc1
Reaction time: 0.33 h
Yield: 81 %

Procedure:
Finely ground 2-(4-aminophenyl) propionitrile (73 g., 0.5 mole) was suspended in concentrated hydrochloric acid (125 ml.). The stirred suspension was diazotised at 0°-5°C by the dropwise addition of a solution of sodium nitrite (36.23 g., 0.525 mole) in water (60 ml.) during 1-2 hours. The almost clear solution was stirred for a further 20 minutes at 5°-10°C, then poured into a stirred, boiling solution of concentrated sulphuric acid (250 ml.) in water (2.5 l.). After 6 minutes it was cooled in an ice-bath, then extracted with ether (x4). The combined ether extracts were extracted with 2N-sodium hydroxide solution (x6). The combined alkaline extracts were cooled in ice-bath, acidified with concentrated hydrochloric acid and extracted with ether (x3). The combined ether extracts were washed with saturated sodium chloride solution (x3), dried (Na2SO4) and evaporated to leave a dark brown oil (66.7 g.) which on distillation gave 2-(4-hydroxyphenyl) propionitrile (59.58 g.), b.p. 112°-122°C/0.125 m.m., m.p. 41°-46°C.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30]CC)=[O:29])=[CH:26][CH:25]=3)[CH:5]=[CH:4][C:3]1=2>C1COCC1.O>[CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(C)(C)C)cc2)=CCC3(C)C)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1

Procedure:
A solution of 80.0 mg (0.173 mmol) of ethyl 4- [(5,6-dihydro-5,5-dimethyl-8-(4-(1,1- dimethylethyl)phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 6) and 18.1 mg (0.432 mmol) of LiOH--H2O in 6 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction mixture was extracted with hexanes, and the remaining aqueous layer acidified with 1M HCl, and then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6 -DMSO): δ 7.82 (2H, d, J=8.2 Hz), 7.44 (6H, m), 7.25 (2H, d, J=8.3 Hz), 7.02 (1H, s), 6.01 (1H, t, J=4.6 Hz), 2.32 (2H, d, J=4.7 Hz), 1.32 (9H, s), 1.29 (6H, s).