Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[CH:6]=[O:7])[CH3:2].[CH2:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](C)[C:16]=1O)C.C(C1C=C(C=C(C)C=1O)C(NO)=N)C.C([O-])([O-])=O.[K+].[K+].C(Br)C1C=CC=CC=1>CC#N.O>[CH2:13]([O:11][C:10]1[C:9]([CH3:12])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:1][CH3:2])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCc1cccc(C)c1O
Reactant: CCc1cc(C=O)cc(C)c1O
Agent: BrCc1ccccc1
Agent: CCc1cc(C(=N)NO)cc(C)c1O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CCc1cc(C=O)cc(C)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 3-ethyl-4-hydroxy-5-methyl-benzaldehyde (34.9 g, 0.213 mol, prepared from 2-ethyl-6-methyl-phenol according to the literature cited for 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine) in MeCN (350 mL), K2CO3 (58.7 g, 0.425 mol) and benzylbromide (36.4 g, 0.213 mol) are added. The mixture is stirred at 60° C. for 2 h before it is cooled to rt, diluted with water and extracted twice with EA. The org. extracts are washed with water and concentrated to give crude 4-benzyloxy-3-ethyl-5-methyl-benzaldehyde (45 g) as an orange oil. 1H NMR (CDCl3): δ1.29 (t, J=7.5 Hz, 3H), 2.40 (s, 3H), 2.77 (q, J=7.8 Hz, 2H), 4.90 (s, 2H), 7.31-7.52 (m, 5H), 7.62 (d, J=1.5 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 9.94 (s, 1H). b) To a mixture of 4-benzyloxy-3-ethyl-5-methyl-benzaldehyde (132 g, 0.519 mol) and 2-methyl-2-butene (364 g, 5.19 mol) in tert.-butanol (1500 mL), a solution of NaH2PO4 dihydrate (249 g, 2.08 mol) in water (1500 mL) is added. To this mixture, NaClO2 (187.8 g, 2.08 mol) is added in portions. The temperature of the reaction mixture is kept below 30° C., and evolution of gas is observed. Upon completion of the addition, the orange bi-phasic mixture is stirred well for 3 h before it is diluted with TBME (1500 mL). The org. layer is separated and washed with 20% aq. NaHS solution (1500 mL) and water (500 mL). The org. phase is then extracted three times with 0.5 N aq. NaOH (1000 mL), the aq. phase is acidified with 25% aq. HCl (500 mL) and extracted twice with TBME (1000 mL). These org. extracts are combined and evaporated to dryness to give the title compound; 1H NMR (D6-DMSO): δ 1.17 (t, J=7.5 Hz, 3H), 2.31 (s, 3H), 2.67 (q, J=7.5 Hz, 2H), 4.86 (s, 2H), 7.34-7.53 (m, 5H), 7.68 (s, 2H), 12.70 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=2[OH:15])[CH:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:3]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[C:8]([C:6]2[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH:5]=2)[CH:13]=1
Reactant: Nc1nc(Nc2ccc(Cl)cc2)cc(-c2cc(Br)ccc2O)n1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(COc2ccc(Br)cc2-c2cc(Nc3ccc(Cl)cc3)nc(N)n2)cc1
Yield: 50 %

Procedure:
Following the method described in Example 165, 2-[2-amino-6-(4-chloro-phenylamino) pyrimidin-4-yl]-4-bromo-phenol and 4-methoxy-benzyl chloride provided the title compound (50% yield). 1H NMR (CD3OD) δ 3.76 (s, 3H, CH3), 5.16 (s, 2H, CH2), 6.37 (s, 1H, Ar), 6.89-6.92 (m, 2H, Ar), 7.28-7.30 (m, 3H, Ar), 7.39-7.42 (m, 2H, Ar), 7.69-7.32 (m, 4H, Ar).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: Oc1ccc(F)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(Oc3ccc(F)cc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-fluoro-phenol to give [1-(4-fluoro-phenoxy)-6-methoxy-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 351(MH+).
Reaction SMILES: COC([CH:5]1[C:14](=[O:15])[C:13]2[C:8](=[C:9]([CH3:17])[N:10]=[C:11]([CH3:16])[CH:12]=2)[N:7]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH:6]1[CH2:28][CH3:29])=O.[OH-].[Na+]>C(O)C>[CH2:21]([O:20][C:18]([N:7]1[C:8]2[C:13](=[CH:12][C:11]([CH3:16])=[N:10][C:9]=2[CH3:17])[C:14](=[O:15])[CH2:5][CH:6]1[CH2:28][CH3:29])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCC1C(C(=O)OC)C(=O)c2cc(C)nc(C)c2N1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC1CC(=O)c2cc(C)nc(C)c2N1C(=O)OCc1ccccc1

Procedure:
This compound can be obtained by reacting a solution of 2-ethyl-6,8-dimethyl-4-oxo-3,4-dihydro-2H-[1,7]naphthyridine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester, in ethanol, with 2N NaOH at reflux temperature, for a time period from about 0.5 h to about 2 h, followed by a typical workup.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:9]([O:12][NH:13][CH3:14])(=[O:11])=[O:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:15][N:16](C=O)C.[NH4+].[OH-]>[C-]#N.[C-]#N.[Zn+2].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.[Pd].CCOC(C)=O>[Br:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([S:9]([O:12][NH:13][CH3:14])(=[O:11])=[O:10])[CH:5]=1)[C:15]#[N:16]
Reactant: CNOS(=O)(=O)c1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: CNOS(=O)(=O)c1cc(Br)cc(C#N)c1
Temperature: 80 °C
Reaction time: 1.17 h
Yield: 31 %

Procedure:
A mixture of 751 mg (2.29 mmol) of O-(3,5-dibromophenylsulfonyl)-N-methylhydroxylamine, 159 mg (1.35 mmol) of Zn(CN)2 and 164 mg (0.142 mmol) of Pd(PPh3)4, 8 mL of DMF (degassed) was stirred at 80° C. After 70 min., 334 mg of Pd((PPh3)4, was added and after 35 min. 414 mg of Pd(PPh3)4 was added. After 1 h, EtOAc and 20 mL of 10% NH4OH (aq) was added, and the layers were separated. The organic layer was washed with 20 mL of 10% NH4OH (aq) and 20 mL of brine. The combined aqueous layer was extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography provided 194 mg of 3-bromo-5-(methylaminooxysulfonyl)benzonitrile as a yellow solid in 31% yield.
Reaction SMILES: [C:1](OC([O-])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(C[NH:16][CH2:17][CH2:18][CH2:19][NH2:20])CN.O>C(Cl)Cl>[C:4]([O:3][C:1]([NH:20][CH:19]([CH2:19][CH2:18][CH2:17][NH2:16])[CH2:18][CH2:17][NH2:16])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: NCCCNCCCN
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC(CCN)CCCN
Yield: 44.7 %

Procedure:
A solution of 33 g of tert-butyl dicarbonate in 200 ml of methylene chloride was added at 5° C. to a solution of 39.3 g of 3,3'-diaminodipropylamine in 300 ml of methylene chloride and after stirringf or 16 hours at 20° C., water was added, followed by decanting and evaporation to dryness. The residue was chromatographed on silica (eluant; methanol-ammonia (98-2)) to obtain 15.5 g of the expected product which was used as is for the next step.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][NH:8][CH2:9]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCc2ccncc2C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2CCNCC2C1
Temperature: 80 °C
Yield: 68.2 %

Procedure:
A suspension of tert-butyl 3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (1.00 g, 4.27 mmol, 1 eq) and Pd(OH)2 (400 mg, 0.1 eq) in 150 mL of acetic acid was heated at 80° C. overnight under Hz, then cooled to room temperature, filtered and concentrated in vacuo. To this, 100 mL of water was added. The mixture was adjusted to pH 7-8 with NH3—H2O, extracted with CH2Cl2 (50 mL×3). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo, and the residue was purified by a silica gel column chromatography (10:1 (v/v) EtOAc/MeOH) to give the title compound as pale yellow oil (700 mg, 69%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 241.1 (M+1).
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([C@@H:9]([NH2:23])[C@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[CH2:11][CH2:12][CH:13]=[CH2:14])=[N:5][CH:6]=[CH:7][N:8]=1.[C:24]([O:28][C:29](OC([O-])=O)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>C(Cl)Cl>[Br:2][C:3]1[C:4]([C@@H:9]([NH:23][C:29](=[O:30])[O:28][C:24]([CH3:27])([CH3:26])[CH3:25])[C@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[CH2:11][CH2:12][CH:13]=[CH2:14])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: C=CCC[C@@H](c1cccc(F)c1F)[C@H](N)c1nccnc1Br
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC[C@@H](c1cccc(F)c1F)[C@H](NC(=O)OC(C)(C)C)c1nccnc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
In a 250 mL round-bottomed flask was (R)—N-((1S)-1-(3-bromopyrazin-2-yl)-2-(2,3-difluorophenyl)hex-5-enyl)-2-methylpropane-2-sulfinamide (1.96 g, 4.16 mmol) in methanol (17 mL) to give a tan solution. HCl (4M in dioxane, 4.2 mL, 17 mmol) was added, and the mixture was stirred at rt for 1 h. Volatiles were removed in vacuo and the tan residue was diluted with ether and concentrated. The remaining tan foam was directly used in the next reaction. In the same round-bottomed flask was dissolved (1S,2S)-1-(3-bromopyrazin-2-yl)-2-(2,3-difluorophenyl)hex-5-en-1-amine (1.532 g, 4.16 mmol) (crude HCl salt) and t-butylpyrocarbonate (1.449 mL, 6.24 mmol) in methylene chloride (22 mL) to give a tan solution. triethylamine (1.28 mL, 9.15 mmol) was added dropwise, and the mixture was stirred at rt for 2 h. LCMS showed complete conversion. It was concentrated to dryness, and directly subject to flash column chromatography up to 40% ethyl acetate/hexane to afford the desired product (1.80 g, 92% for 2 steps) as colorless oil: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.27 (d, J=17.07 Hz, 2H) 6.92-7.14 (m, 3H) 5.69 (dd, J=10.29, 5.77 Hz, 1H) 5.63 (dd, J=9.41, 5.90 Hz, 1H) 5.41 (d, J=9.54 Hz, 1H) 4.84-4.95 (m, 2H) 3.65 (br. s., 1H) 1.88-2.08 (m, 3H) 1.81 (br. s., 1H) 1.30-1.41 (m, 9H). A slightly more polar diastereomer (generally <10% if there was minimum epimerization at the aldehyde stage) could be removed at this stage: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.46 (d, J=2.26 Hz, 1H) 8.20 (d, J=2.51 Hz, 1H) 6.88-7.11 (m, 3H) 5.66-5.81 (m, 1H) 5.60 (t, J=8.91 Hz, 1H) 5.51 (d, J=9.29 Hz, 1H) 4.83-5.00 (m, 2H) 3.55 (d, Hz, 1H) 1.87-2.06 (m, 3H) 1.73-1.86 (m, 1H) 1.44 (s, 9H).
Reaction SMILES: [O:1]([CH:8]([CH3:11])[CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH2:18][C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC=CC=1>[O:1]([CH:8]([CH3:11])[CH2:9][NH:10][C:19](=[O:20])[CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CN)Oc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC(CNC(=O)Cc1ccccc1)Oc1ccccc1

Procedure:
2-Phenoxypropylamine (4.6 g.) was added to a mixture of phenylacetyl chloride (4.6 g.) and anhydrous sodium carbonate (3.3 g.) in dry benzene (20 ml.); there was an exothermic reaction and effervescence. The mixture was heated to reflux for 1 hour, cooled, treated with water, and then shaken. The benzene layer was separated, dried over anhydrous sodium sulphate, filtered, and diluted with light petroleum (b.p. 60°-80°) to give pure N-(2-phenoxypropyl) phenylacetamide, m.p. 94°-96°.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[C:8](=[O:18])[NH:7]1)C.[OH-].[Na+].Cl.CCOC(C)=O>C1COCC1>[N+:15]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][C:4]([OH:19])=[O:3])[NH:7][C:8]2=[O:18])([O-:17])=[O:16]
Reactant: CCOC(=O)Cn1[nH]c(=O)c2cc([N+](=O)[O-])ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)Cn1[nH]c(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of (5-nitro-3-oxo-2,3-dihydro-indazol-1-yl)-acetic acid ethyl ester (0.24 g) in THF (9 mL), was added 2 N NaOH (aq.) (1.8 mL). The reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was acidified with 2 N HCl (aq.) and extricated with EtOAc. Evaporation of the organic phases afforded the desired crude (5-nitro-3-oxo-2,3-dihydro-indazol-1-yl)-acetic acid (0.146 g) which was taken into the next step without further purification.
Reaction SMILES: [N+](C1O[C:7]([C:9]2[N:13]3NC(=COCC)[C:16]([NH2:18])=[CH:17][C:12]3=NN=2)=CC=1)([O-])=O.NO.Cl.NO.[Na].[N+:29]([C:32]1[O:36][C:35]([C:37]2[N:41]3[NH:42][C:43](=[CH:47][NH:48]O)[C:44]([NH2:46])=[CH:45][C:40]3=[N:39][N:38]=2)=[CH:34][CH:33]=1)([O-:31])=[O:30]>C(O)C.O1CCOCC1>[N+:29]([C:32]1[O:36][C:35]([C:37]2[N:41]3[NH:42][C:43](=[CH:47][NH:48][C:17]4[CH:16]=[N:18][C:9]([CH3:7])=[N:13][CH:12]=4)[C:44]([NH2:46])=[CH:45][C:40]3=[N:39][N:38]=2)=[CH:34][CH:33]=1)([O-:31])=[O:30]
Reactant: CCOC=C1Nn2c(nnc2-c2ccc([N+](=O)[O-])o2)C=C1N
Reactant: NC1=Cc2nnc(-c3ccc([N+](=O)[O-])o3)n2NC1=CNO
Agent: Cl
Agent: NO
Agent: [Na]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1ncc(NC=C2Nn3c(nnc3-c3ccc([N+](=O)[O-])o3)C=C2N)cn1

Procedure:
In an analogous manner, from 0.6 g. 3-(5-nitro-2-furyl)-6-(ethoxy-methylene)-amino-s-triazolo[4,3-b]pyridazine in 12 ml. anhydrous dioxan and an ethanolic solution of hydroxylamine (prepared from 0.6 g. hydroxylamine hydrochloride in 15 ml. absolute ethanol by adding 0.14 g. sodium, dissolved in 5 ml. absolute ethanol, and filtering off with suction the precipitated sodium chloride) at 50° - 60°C., there was obtained, after a reaction period of 15 minutes and cooling of the reaction mixture, 0.55 g. 3-(5-nitro-2-furyl)-6-(hydroxylaminomethylene)-amino-s-triazolo[4,3-b]pyridazine, which melted, with foaming, at 251° - 253°C.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:13][C:12]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:11]1)C1C=CC=CC=1>CO.[Pd]>[CH2:11]1[C:12]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:13][CH:10]1[CH2:9][OH:8]
Reactant: c1ccc(COCC2CC3(C2)OCCO3)cc1
Agent: [Pd]
Solvent: CO
Product: OCC1CC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Palladium/carbon (10%) was added to a solution of 2-[(benzyloxy)methyl]-5,8-dioxaspiro[3.4]octane (22.0 gm, 94.0 mmol) (step c) in methanol and the mixture was stirred at room temperature under hydrogen balloon for about 4 hours. It was filtered through celite bed and residue was washed with methanol. The combined filtrate was concentrated under reduced pressure.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH2:9]([O:11][C:12](=[O:24])[CH2:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([CH3:23])=[CH:16][N:15]=1)[CH3:10]>CN(C=O)C>[CH2:9]([O:11][C:12](=[O:24])[C:13]([C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([CH3:23])=[CH:16][N:15]=1)=[CH:3][N:4]([CH3:5])[CH3:6])[CH3:10]
Reactant: CCOC(=O)Cc1ncc(C)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN(C)C)c1ncc(C)cc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
A solution of dimethylformamide dimethyl acetal (4 g, 0.033 mol) in dry DMF (10 mL) is added to a solution of (5-methyl-3-nitro-pyridin-2yl)-acetic acid ethyl ester (5 g, 0.022 mol) in dry DMF (20 mL) to give a red solution. This solution is heated at 60° C. under reduced pressure for 3 h. DMF and other volatile components are evaporated under reduced pressure to obtain 3-dimethylamino-2-(5-methyl-3-nitro-pyridin-2-yl)-acrylic acid ethyl ester as an viscous oil which was used without further purification.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]2[N:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=2)=[C:5]([Br:7])[N:6]=1.[Cl-].[Li+].O1CCOCC1.[CH2:29]([Sn](CCCC)(CCCC)C#CC)[CH2:30][CH2:31]C>C(Cl)Cl.[Cu]I.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>[Br:7][C:5]1[N:6]=[C:2]([C:29]#[C:30][CH3:31])[S:3][C:4]=1[C:8]1[N:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2sc(Br)nc2Br)n1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC#Cc1nc(Br)c(-c2ncn(COCC[Si](C)(C)C)n2)s1
Temperature: 100 °C
Yield: 76.2 %

Procedure:
A mixture of 3-(2,4-dibromo-1,3-thiazol-5-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole (6.00 g, 13.6 mmol), lithium chloride (1.73 g, 40.9 mmol), copper(I) iodide (0.779 g, 4.09 mmol) and tetrakis(triphenylphosphine)platinum (0) (0.848 g, 0.681 mmol) in anhydrous 1,4-dioxane (120 mL, 1500 mmol) was sonicated under an argon atmosphere for 2 minutes in a 250 mL RBF. Tributyl(1-propynyl)tin (4.80 mL, 15.0 mmol) was added. The mixture was heated to 100° C. for 1 hour under an argon atmosphere. The mixture was cooled to rt., diluted with DCM (˜150 mL), filtered through celite, and washed with DCM. The filtrate was rotavaped to give a crude residue which was then purified by column chromatography (SiO2, elution with 0-100% EtOAc in hexane) to afford a pure solid product (4.14 g, 76% yield). LCMS: (FA) ES+ 399, 401. 1H NMR (400 MHz, CDCl3) δ: 8.29 (s, 1H), 5.54 (s, 2H), 3.69-3.74 (m, 2H), 2.15 (s, 3H), 0.93-0.97 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:5])[C:3]#[CH:4].N1C2C(=CC=CC=2)C=CC=1>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:5][C:2]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:1])[CH:3]=[CH2:4]
Reactant: C#CC(C)(C)NC(=O)c1ccc(F)cc1F
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: C=CC(C)(C)NC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.7 %

Procedure:
Five percent Pd/BaSO4 (100 mg) was added to a solution of N-(1,1-dimethyl-2-propynyl)-2,4-difluorobenzamide obtained in Example 36 (1.0 g, 4.5 mmol) and quinoline (100 mg) in methanol (20 ml), and stirred under a hydrogen atmosphere at room temperature for 1.5 hours. The catalyst was removed by filtration and the filtrate was concentrated under a reduced pressure. The residue was diluted with ethyl acetate and washed, with 1N hydrochloric acid (×3), saturated aqueous NaHCO3 and brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to give the title compound (0.95 g; 94%).
Reaction SMILES: C(O[K])(C)(C)C.[OH:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].Cl[CH2:17][O:18][CH3:19]>CN(C=O)C>[CH3:17][O:18][CH2:19][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11]
Reactant: COCCl
Reactant: O=Cc1ccccc1O
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Product: COCOc1ccccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
Into a solution of tert-butoxy potassium (30.0 g, 0.27 mol) in DMF (200 mL) was dropped a solution of 2-hydroxybenzaldehyde (30.0 g, 0.25 mol) in DMF (100 mL) at 0° C. followed by stirring at room temperature for 1 hour. After addition of DMF (200 mL) thereto, a solution of chloromethylmethyl ether (21 mL, 0.27 mol) in DMF (200 mL) was dropped thereinto at 0° C. following by stirring at room temperature for 20 hours. The reaction mixture was poured over ice water followed by extracting with diethyl ether. The organic layer was washed with a 10% aqueous sodium hydroxide and a saturated saline solution successively and then dried over anhydrous sodium sulfate. The solvent was evaporated therefrom in vacuo to give the title compound (32.6 g, 80%) as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]#[N:15])=[C:12]([C:16]([O:18]CC)=[O:17])[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-:21].[K+].Cl>C(O)C>[C:16]([C:12]1[CH:11]=[N:10][N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:13]=1[C:14]([NH2:15])=[O:21])([OH:18])=[O:17]
Reactant: [OH-]
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)c(Cl)c2)c1C#N
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: NC(=O)c1c(C(=O)O)cnn1-c1ccc(Cl)c(Cl)c1

Procedure:
Fifteen g. of ethyl 1-(3,4-dichlorophenyl)-5-cyano-4-pyrazolecarboxylate was dissolved in 200 ml. of ethanol, and 5.6 g. of potassium hydroxide was added. The reaction mixture was stirred under reflux for 1 hour, and was then poured over a large amount of ice and made acid with concentrated hydrochloric acid. The mixture was filtered, and the solids were found by nuclear magnetic resonance analysis to consist of the partially hydrolyzed 4-carboxy-5-cyanopyrazole. A 2 g. portion of that intermediate was held out for further examination, and the rest of the solids were redissolved in 200 ml. of ethanol and stirred under reflux for 18 hours with 5.6 g. of potassium hydroxide. The mixture was then poured over ice, made acid, and filtered. The solids were recrystallized from ethanol, and the mother liquor was chromatographed over a silica gel column with methanol as the eluent. The product-containing fractions were evaporated to dryness and the residues were recrystallized from methanol to obtain the desired product, m.p. 249°-250°. The elemental analysis was as follows.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5](=[O:22])[CH2:6][N:7]([CH:9]1[CH2:14][CH2:13][N:12](CC2C=CC=CC=2)[CH2:11][CH2:10]1)[CH3:8]>[Pd]>[ClH:1].[ClH:1].[CH3:3][O:4][C:5](=[O:22])[CH2:6][N:7]([CH3:8])[CH:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1
Reactant: COC(=O)CN(C)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Product: COC(=O)CN(C)C1CCNCC1

Procedure:
Prepared from N-[1-benzyl-4-piperidinyl]-N-methyl-glycine methyl ester dihydrochloride by exhaustive hydrogenation over palladium on charcoal (10%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[Cl:39])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=2[Cl:39])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cc(Cl)ccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cc(Cl)ccc2Cl)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 15.2 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (750 mg, 0.004 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (2.6 g, 0.02 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2,5-dichloro-phenoxy)-but-2-enoic acid ethyl ester (1.5 g, 0.004 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2,5-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (250 mg, 15%) as yellow oil.