Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]([C:6](=[CH:12][CH:13]([CH3:15])[CH3:14])C(OCC)=O)#[N:5]>O.C(O)C>[CH:13]([CH:12]([CH2:6][C:4]#[N:5])[C:1]#[N:2])([CH3:14])[CH3:15]
Reactant: [C-]#N
Reactant: CCOC(=O)C(C#N)=CC(C)C
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)C(C#N)CC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A solution of potassium cyanide (5.81 g, 89.52 mmol) in water (12 mL) was added to a solution of ethyl 2-cyano-4-methyl-pent-2-enoate (6.5 g, 38.92 mmol) in ethanol (20 mL) at room temperature and the reaction mixture was stirred overnight. The resulting mixture was refluxed for 2 h and then cooled to room temperature. The ethanol was evaporated and the residue dissolved in dichloromethane. The dichloromethane layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-isopropylbutanedinitrile (3.5 g, 74%) as a liquid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][C:15]([C:21](O)=[O:22])=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)#[N:2].S(Cl)(Cl)=O.[C:28]1([NH:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)C(C)C)C>>[C:28]1([N:34]([CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:21]([C:15]2[CH:14]=[C:13]3[C:18]([CH:19]=[N:20][C:11]([CH2:10][CH2:9][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[N:12]3)=[CH:17][CH:16]=2)=[O:22])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: N#Cc1ccc(CCc2ncc3ccc(C(=O)O)cc3n2)cc1
Reactant: COC(=O)CCNc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCN(C(=O)c1ccc2cnc(CCc3ccc(C#N)cc3)nc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.4 g (1.3 mmol) of 2-[2-(4-cyanophenyl)ethyl]quinazoline-7-carboxylic acid and 5 mL of thionyl chloride were stirred for 60 minutes at 50° C. Then the thionyl chloride was distilled off, the residue was dissolved in methylene chloride, mixed with 0.24 g (1.3 mmol) of methyl 3-(N-phenylamino)propionate and 0.22 mL of (1.3 mmol) of N-ethyldiisopropylamine and stirred for 18 hours at ambient temperature. After evaporation of the solvent in vacuo, the residue was chromatographed on silica gel and eluted with methylene chloride containing 1% methanol. Yield: 230 mg (37% of theory); Rf value: 0.64 (silica gel, methylene chloride/methanol=9:1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCCCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6-hydroxyhexyl)carbamate (12.18 g, 56.05 mmol) and TEA (8.51 g, 84.08 mmol) in 100 ml of methylene chloride, methanesulfonyl chloride (9.63 g, 84.08 mmol) was slowly added at 0° C. The mixture was stirred at room temperature overnight. The compound was purified by silica chromatography using heptane/ethyl acetate as eluent.
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:5]=1N)[CH3:3].N(OCCC(C)C)=O>ClC1C=CC=CC=1Cl>[Cl:1][C:5]1[C:4]([CH2:2][CH3:3])=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=1[CH2:12][CH3:13]
Reactant: Cl
Reactant: CCc1cc(C)cc(CC)c1N
Agent: CC(C)CCON=O
Solvent: Clc1ccccc1Cl
Product: CCc1cc(C)cc(CC)c1Cl
Temperature: 45 °C
Yield: 90 %

Procedure:
Gaseous hydrogen chloride (1.05 equiv.) is fed into a solution of 2,6-diethyl-4-methylaniline (1.00 equiv.) in o-dichlorobenzene, allowing the pot temperature to rise to 70° C. The resulting salt suspension is cooled to 45° C. Isoamyl nitrite (1.05 equiv.) and additional gaseous hydrogen chloride (0.50 equiv.) are fed subsurface simultaneously at 45-50° C. over a 2-hour period to afford 1-chloro-2,6-diethyl-4-methylbenzene in 90-93% yield. 20% sodium hydroxide (0.50 equiv.) is added to adjust the pH to 10-12. The bottom aqueous phase is separated off. Isoamyl alcohol and o-dichlorobenzene are stripped off to produce the crude 1-chloro-2,6-diethyl-4-methylbenzene material. The product can be further purified by vacuum distillation at 85° C./5 mmHg to give an assay of 97-99%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C)[CH2:9][CH2:8]1)=[O:6].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[NH2:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][N:7]([C:5]([C:4]2[CH:23]=[CH:24][C:25]([Cl:26])=[C:2]([Cl:1])[CH:3]=2)=[O:6])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)NCCN1CCN(C(=O)c2ccc(Cl)c(Cl)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCN1CCN(C(=O)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
The product from step (ii) above (3.3 g) was dissolved in dichloromethane (50 ml) and trifluoroacetic acid (10 ml) added. After 16 hours at room temperature the solvent was removed to give the sub-titled product as an oil (5.9 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:3]=1.[C:20]1([C:26]2[CH:27]=[C:28](B(O)O)[CH:29]=[N:30][CH:31]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([F:19])=[C:12]([C:4]2[CH:3]=[C:2]([C:28]3[CH:29]=[N:30][CH:31]=[C:26]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:27]=3)[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=1
Reactant: OB(O)c1cncc(-c2ccccc2)c1
Reactant: Fc1ccc(Cl)cc1-c1cc(Cl)c2cccnc2n1
Product: Fc1ccc(Cl)cc1-c1cc(-c2cncc(-c3ccccc3)c2)c2cccnc2n1

Procedure:
150 mg 4-chloronaphthyridine from example 1, 184 mg 5-phenyl-3-pyridyl boronic acid,
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][CH2:14][CH2:15][CH3:16].[Li+].[OH-]>C1COCC1.CO>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:17])=[O:2])=[C:7]([NH:13][CH2:14][CH2:15][CH3:16])[CH:8]=1
Reactant: CCCNc1cc(F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCNc1cc(F)ccc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a solution of 3-(4-fluoro-2-propylamino-phenyl)-acrylic acid methyl ester (0.23 g, 0.95 mmol) in THF (4 mL) and MeOH (2 mL) was added 1 N LiOH (4 mL). The mixture was stirred for 2 hours at room temperature, concentrated under reduced pressure, and then acidified with 3 N HCl. The mixture was diluted with EtOAc, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 3-(4-fluoro-2-propylamino-phenyl)-acrylic acid (0.17 g, 79%) after purification by crystallization form EtOAc and hexane. To a mixture of 3-(4-fluoro-2-propylamino-phenyl)-acrylic acid (50 mg, 0.22 mmol), (R)-[1-(3,5-difluoro-4-methanesulfonylaminophenyl)ethylamine hydrochloride (64 mg, 0.22 mmol) and N-methylmorpholine (36 μL, 0.33 mmol) in THF (5 mL) was added 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholirium chloride hydrate (DMTMM, 68 mg, 0.25 mmol). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was diluted with EtOAc and water, and the aqueous layer was washed with 2 N HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (35 mg, 34%) after purification by crystallization form EtOAc and hexane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]=1.C([Li])(C)(C)C.CN([CH:22]=[O:23])C>C1COCC1>[C:4]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=[C:2]([CH:22]=[O:23])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Brc1cccc(-c2ccccc2)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=Cc1cccc(-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of 1-bromo-3-phenylbenzene (Aldrich) (0.0858 moles) in 300 mL of dry THF cooled to −78° C. was added tert-butyl lithium (2 eq.) (1.7M in hexane) dropwise. The reaction mixture was stirred for 40 min. at −78° C. and then quenched with 2 eq. of DMF (13.24 mL). The resulting mixture was stirred for 20 min. and then poured into a separatory funnel and extracted with CH2Cl2. The organic extracts were washed with water, dried over Na2SO4, filtered and concentrated to give a brown oil. This oil was purified by LC 2000 chromatography, eluting with ethyl acetate/hexanes (5:95) to give 3-biphenylcarboxaldehyde.
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[CH2:13]([N:20]1[C:24](=O)[CH2:23][CH:22]([C:26](O)=[O:27])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.C1COCC1>[CH2:13]([N:20]1[CH2:24][CH2:23][CH:22]([CH2:26][OH:27])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCC1CCN(Cc2ccccc2)C1
Yield: 102.8 %

Procedure:
Red-Al (160 mL of a 3.5 M solution in toluene, 560 mmol) was added to a solution of 1-benzyl-5-oxo-pyrrolidine-3-carboxylic acid (20 g, 91 mmol) in dry THF (650 mL) under argon. The reaction mixture was refluxed for 2.5 h and then poured onto a mixture of crushed ice and NaOH (20%). The phases were separated, the aqueous phase was extracted with toluene and the combined organic phases were dried and concentrated under reduced pressure to give 17.9 g of the crude product as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[CH:4][N:3]=1.[OH-].[NH4+:12]>>[CH3:10][O:9][CH2:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH2:12])[CH:7]=1
Reactant: [NH4+]
Reactant: COCc1cc(Cl)ncn1
Agent: [OH-]
Product: COCc1cc(N)ncn1
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of 4-chloro-6-(methoxymethyl)pyrimidine (1.2 g, 7.57 mmol) and ammonium hydroxide (20 ml) was heated in a sealed tube for 3 hours. The mixture was cooled to ambient temperature and concentrated. The residue was triturated with ether to afford 6-(methoxymethyl)pyrimidin-4-amine (0.50 g, 3.59 mmol, 48% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.47 (1H, s), 6.55 (1H, s), 5.12 (2H, br. s.), 4.38 (2H, s), 3.45 (3H, s). MS (LC/MS) R.T.=0.42; [M+H]+=140.20.
Reaction SMILES: CN(C)C=O.Br[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([CH2:29][CH2:30][CH3:31])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17]([C:25]([F:28])([F:27])[F:26])([C:21]([F:24])([F:23])[F:22])[O:16][CH2:15]2.C(=O)([O-])[O-].[K+].[K+].[O:38]1[C:42]2[CH:43]=[CH:44][C:45]([C:47]3([CH3:54])[NH:51][C:50](=[O:52])[NH:49][C:48]3=[O:53])=[CH:46][C:41]=2[O:40][CH2:39]1>O>[O:38]1[C:42]2[CH:43]=[CH:44][C:45]([C:47]3([CH3:54])[NH:51][C:50](=[O:52])[N:49]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]4[C:13]([CH2:29][CH2:30][CH3:31])=[C:14]5[C:18](=[CH:19][CH:20]=4)[C:17]([C:25]([F:28])([F:27])[F:26])([C:21]([F:24])([F:23])[F:22])[O:16][CH2:15]5)[C:48]3=[O:53])=[CH:46][C:41]=2[O:40][CH2:39]1
Reactant: CCCc1c(OCCCCBr)ccc2c1COC2(C(F)(F)F)C(F)(F)F
Reactant: CC1(c2ccc3c(c2)OCO3)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCCCCN2C(=O)NC(C)(c3ccc4c(c3)OCO4)C2=O)ccc2c1COC2(C(F)(F)F)C(F)(F)F
Reaction time: 8 h

Procedure:
To a N,N-Dimethylformamide (2 mL) solution of 5-(4-bromobutoxy)-4-propyl-1,1-bis(trifluoromethyl)-1,3-dihydroisobenzofuran (25 mg, 0.0557 mmol), potassium carbonate mg, 0.111 mmol) and 5-(benzo[d][1,3]dioxol-5-yl)-5-methylimidazolidine-2,4-dione (CAS: 308122-40-9:DE335993) (19.6 mg, 0.0835 mmol) were added and the mixture was stirred overnight. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by thin-layer silica-gel column chromatography (hexane:ethyl acetate=2:1) and of the title compound (30.7 mg, 92%) was obtained as colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[C:19]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[C:3]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[N:4][C:5](=[O:8])[N:6]([CH3:19])[CH:7]=1
Reactant: Cc1ccc(C(=O)Nc2nc(O)ncc2F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2nc(=O)n(C)cc2F)cc1
Temperature: 60 °C
Yield: 8 %

Procedure:
To N-(5-fluoro-2-hydroxypyrimidin-4-yl)-4-methylbenzamide (200 mg, 0.81 mmol) in DMF (5 mL) was added K2CO3 (224 mg, 1.6 mmol), and iodomethane (230 mg, 1.6 mmol). The mixture was stirred and heated to 60° C. for 30 min and then stirred for 16 h at room temperature. The mixture was partitioned between ethyl acetate (EtOAc) and water (H2O). The organic phase was dried over magnesium sulfate (MgSO4), filtered and evaporated. The crude material was purified by reverse phase chromatography to yield the title compound as a white solid (17 mg, 8%): mp 229-230° C.; 1H NMR (300 MHz, CDCl3) δ13.2 (br s, 1H), 8.23-8.15 (br m, 2H), 7.42-7.37 (br m, 1H), 7.30-7.25 (br m, 2H), 3.45 (s, 3H), 2.44 (s, 3H); ESIMS m/z 262 ([M+H]+), m/z 260 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2-].[Na+].[Cl:19][CH2:20][CH2:21][CH2:22]I.O>C1(C)C=CC=CC=1>[Cl:19][CH2:20][CH2:21][CH2:22][C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13]
Reactant: COc1ccc(C(C#N)C(C)C)cc1OC
Reactant: ClCCCI
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C(C#N)(CCCCl)C(C)C)cc1OC
Temperature: 25 °C
Yield: 85.7 %

Procedure:
2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile (1.21 g, 5.52 mmol) was added to a suspension of sodium amide (0.59 g, 14.4 mmol) in toluene (12 ml). The mixture was then heated to reflux for 2 hours before the addition of 1-chloro-3-iodopropane (0.9 ml, 8.3 mmol). The mixture was cooled to room temperature over 80 minutes, and worked up by addition of water. The product was extracted with methyl-t-butyl ether (MTBE). After usual work-up, including drying the organic extract using MgSO4 and concentrating under reduced pressure the product was purified on column chromatography eluting with (ethyl acetate: light petroleum (b.p. 40 -60° C.) =1:2), to give 1.4g (82% yield) of the required product.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9].I[CH3:19].O>C1COCC1>[CH3:3][O:4][CH2:5][CH2:6][N:7]([CH3:19])[S:8]([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: COCCNS(=O)(=O)c1ccc(I)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCN(C)S(=O)(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.5 %

Procedure:
Sodium hydride (144 mg, 3.6 mmol) was added in portions to a solution of N-(2-methoxyethyl)-4-iodobenzenesulphonamide (Method 40, 1 g, 3 mmol) in THF (10 ml) and the mixture stirred at ambient temperature for 15 minutes. Iodomethane (230 μl, 3.6 mmol) was added and the reaction stirred for 18 hours. Water (30 ml) was added cautiously and the mixture extracted with ether (40 ml). The combined organics were washed with brine (50 ml), dried and the volatiles evaporated. The residue was purified by flash chromatography on silica gel eluting with iso-hexane/EtOAc (100:0 increasing in polarity to 10:1) to give the title compound (730 mg, 69%) as a clear oil. NMR 2.78 (s, 3H), 3.16 (t, 2H), 3.22 (s, 3H), 3.45 (t, 3H), 7.42 (d, 2H), 7.80 (d, 2H); m/z 356.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.Cl[C:27](=[O:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C)C1C=CN=CC=1>[CH2:1]([N:5]([C:27](=[O:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccc(N2CCC(=O)CC2)cc1
Reactant: CCOC(=O)CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CCCCN(C(=O)CC(=O)OCC)c1ccc(N2CCC(=O)CC2)cc1
Reaction time: 18 h
Yield: 106.5 %

Procedure:
A solution of 8-(4-nitro-phenyl)-1,4-dioxa-8-aza-spiro[4.5]decane (13.01 g, 49 mmol) was hydrogenated under 45 psi for one hour using 10% palladium on carbon (2.5 g) as catalyst. The reaction mixture was filtered through celite pad and the filtrate was concentrated down to give a white solid (11.46 g, 100%). This material was taken onto next step immediately. To a stirred mixture, under N2 atmosphere, of the aniline (11.46 g, 49 mmol), butryaldehyde (4.43 mL, 49 mmol) in tetrahydrofuran (250 mL) was added sodium triacetoxyborohydride (14.62 g, 68.6 mmol), and glacial acetic acid (2.82 mL, 49 mmol). The reaction was stirred for two hours. The reaction was quenched with 1N NaOH (50 mL), diluted with water, extracted with ether 3 times and dried over sodium sulfate. The product was purified by flash silica gel chromatography eluting with 1:1 ethyl acetate/hexanes to give an oil (5.80 g, 41%). This material was immediately taken onto next step. A solution of the N-butyl aniline (5.80 g, 19.9 mmol) in a 1:1 mixture of perchloric acid and hydrochloric acid (100 mL) was stirred at room temperature for three days. The reaction mixture was poured onto ice and made basic with concentracted ammonium hydroxide, extracted with ether four times, dried over sodium sulfate and concentrated to give a yellow oil. The yellowish oil was purified by flash silica gel chromatography eluting with 1:1 ethyl acetate/hexanes to give 1-[4-(butylamino)phenyl]-4-piperidineone as an oil (3.84 g, 82%). To a stirred mixture of 1-[4-(butylamino)phenyl]-4-piperidineone (2.46 g, 10 mmol), triethylamine (1.81 mL, 13 mmol), and 4-(dimethylamino)pyridine (DMAP) (catalytic amount) was added ethyl 3-chloro-3-oxopropionate (2.18 g, 13 mmol) dropwise. The reaction was stirred for 18 hours. The reaction mixture was filtered, concentrated in vacuo, taken up in methylene chloride, and washed with saturated sodium bicarbonate two times and dried over sodium sulfate. The product was purified by flash silica gel chromatography eluting with 1:1 ethyl acetate/hexanes to give a yellow oil (3.84 g, 68%); MS (ES) m/z: 361.3 (MH+, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]([C:17]#[N:18])=[C:4]([S:19][CH2:20][CH2:21][NH2:22])[N:3]=1.[CH3:23][N:24]=[C:25]=[O:26]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:19][CH2:20][CH2:21][NH:22][C:25]([NH:24][CH3:23])=[O:26])[C:5]([C:17]#[N:18])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[C:7]=1[C:8]#[N:9]
Reactant: CN=C=O
Reactant: N#Cc1c(N)nc(SCCN)c(C#N)c1-c1ccc(O)cc1
Solvent: CN(C)C=O
Product: CNC(=O)NCCSc1nc(N)c(C#N)c(-c2ccc(O)cc2)c1C#N
Reaction time: 8 h

Procedure:
62.2 mg (0.2 mmol) of 2-amino-6-[(2-aminoethyl)sulfanyl]-4-(4-hydroxyphenyl)-3,5-pyridinedicarbonitrile are suspended in 0.4 ml of DMF, and 11.4 mg (0.2 mmol) of methyl isocyanate are added at room temperature. The mixture is stirred overnight, filtered and purified by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:24](#[N:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cu]Br>[NH2:8][C:6]1[CH:5]=[CH:4][N:3]2[N:31]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:1]=[C:2]2[CH:7]=1
Reactant: Nc1ccnc(N)c1
Reactant: N#Cc1ccccc1
Agent: [Cu]Br
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Product: Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 150 °C
Yield: 29 %

Procedure:
A mixture of 2,4-diamino-pyridine (1.26 g, 11.5 mmol), copper (I) bromide (82.8 mg, 0.57 mmol), 1,10-phenanthroline monohydrate (114.0 mg, 0.57 mmol) and benzonitrile (13 mL) was heated in a 50 mL 3-necked flask to 150° C. During 41 h a gentle flow of O2/N2 (5:95) was bubbled through the reaction mixture (conversion 42%, HPLC method see below). The reaction mixture was then filtered. The resulting clear brown solution was evaporated to dryness and the crude was product purified by silica gel chromatography (hexane/EtOAc 2:8) to yield 7-amino-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (0.72 g, 29%) as a light yellow solid with 99.0% purity (HPLC area-%, HPLC method: X-Bridge C18 column, 150×4.6 mm; mobile phase, A: water/NCMe (95:5), B: NCMe, C: NBu4HSO4 buffer pH 3-4; flow: 1.5 ml/min; gradient from 90/0/10 (A/B/C) to 5/85/10 (A/B/C) within 6 min, isocratic 5/85/10 (A/B/C) for 4 min. Retention time: 0.95 min (2,4-diamino-pyridine), 4.08 min (7-amino-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine)).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[F:11][C:12]([F:21])([F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:13]([C:12]([F:11])([F:21])[F:20])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:9]=1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=Cc2cc(Cl)ccc2OC1C(F)(F)F
Temperature: 60 °C
Yield: 138.4 %

Procedure:
A mixture of 5-chlorosalicylaldehyde (20.02 g, 0.128 mole) and ethyl 4,4,4-trifluorocrotonate (23.68 g, 0.14 mole) was dissolved in anhydrous DMF, warmed to 60° C. and treated with anhydrous K2CO3 (17.75 g, 0.128 mole). The solution was maintained at 60° C. for 20 hours, cooled to room temperature, and diluted with water. The solution was extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford 54.32 g of an oil. The oil was dissolved in 250 mL of methanol and 100 mL of water, whereupon a white solid formed that was isolated by filtration, washed with water and dried in vacuo, to afford the ester as a yellow solid (24.31 g, 62%): mp 62–64° C. 1H NMR (CDCl3/90 MHz) 7.64 (s, 1H), 7.30–7.21 (m, 2H), 6.96 (d, 1H, J=Hz), 5.70 (q, 1H, J=Hz), 4.30 (q, 2H, J=7.2 Hz), 1.35 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:17])=[C:6]([C:9]([CH:15]=[O:16])=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:7]#[N:8])[CH3:2].C(OCC)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH2:1]([O:3][C:4]1[C:5]([F:17])=[C:6]([C:9]([CH2:15][OH:16])=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:7]#[N:8])[CH3:2]
Reactant: CCOc1cc(C=O)c(C#N)c(F)c1OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1cc(CO)c(C#N)c(F)c1OCC
Temperature: 40 °C
Reaction time: 8 h

Procedure:
3,4-Diethoxy-2-fluoro-6-formylbenzonitrile (5.90 kg, 24.87 mol) and ethyl acetate (59.0 L) were transferred to a reaction vessel under a nitrogen atmosphere, and while stirring, sodium triacetoxyborohydride (NaB(OAc)3H) (11.70 kg) was added. After 30 minutes of stirring, the internal temperature was heated up to 40° C., and the reaction solution was stirred for another 2 hours. The reaction solution was cooled, and at 15° C. internal temperature, water (2 L) was slowly added in drops, and excess sodium triacetoxyborohydride was degraded. Then more water (27.5 L) was added. The insoluble material was dissolved by increasing the outer bath temperature to 40° C., and the solution was separated after cooling. Following separation, the obtained organic layer was washed twice with an aqueous sodium bicarbonate solution and then with brine. The obtained organic layer was cooled in a 10° C. outer bath, and left to stand overnight.