Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[C:4]([O:12]CC)(=O)[CH2:5][C:6]([O:8]CC)=O.[F:15][C:16]([F:25])([F:24])[CH:17]1[CH2:22][CH2:21][NH:20][C:19]([NH2:23])=[N:18]1.Cl>CO.O>[OH:8][C:6]1[N:23]=[C:19]2[NH:18][CH:17]([C:16]([F:25])([F:15])[F:24])[CH2:22][CH2:21][N:20]2[C:4](=[O:12])[CH:5]=1
Reactant: NC1=NC(C(F)(F)F)CCN1
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=c1cc(O)nc2n1CCC(C(F)(F)F)N2
Temperature: 40 °C
Yield: 80.4 %

Procedure:
62.10 g (1150 mmol) of sodium methoxide are added to a mixture of 340 mL (2230 mmol) of diethyl malonate heated to 40° C. The mixture is heated at 100° C. until a clear solution is obtained. 59.50 g (360 mmol) of 4-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine dissolved in 100 mL of methanol are then added to the reaction medium. The mixture obtained is maintained at 100° C. for 1 hour and then cooled to room temperature overnight. The reaction mixture is evaporated to dryness under reduced pressure. The residue obtained is taken up in 250 mL of water. 12 N hydrochloric acid is added to the thick suspension obtained, to pH=5-6. The suspension obtained is filtered through a sinter funnel and the insoluble matter is rinsed with acetonitrile to give 68.10 g of 2-hydroxy-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in the form of a yellow solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][N:2]([CH:21]1[C:29]2[C:24](=[C:25]([OH:30])[CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)[CH2:3][C:4]1[O:5][C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][N:2]([CH:21]1[C:29]2[C:24](=[C:25]([O:30][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)[CH2:3][C:4]1[O:5][C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:8]=1
Reactant: CN(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)C1CCc2c(O)cccc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCC2N(C)Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 24 h
Yield: 60.3 %

Procedure:
To a solution of 1-[N-methyl-N-[(4,5-diphenyloxazol-9-yl)methyl]amino]-2,3-dihydro-4-methoxy-1H-indene (109 mg) in dichloromethane (2 ml) was added 1M boron tribromide dichloromethane solution (1 ml) at 0° C. After being stirred for 4 hours at 0° C., the solvent was evaporated in vacuo. The residue was extracted with ethyl acetate. The mixture was washed with brine, dried over MgSO4 and evaporated in vacuo to afford crude 1-[N-methyl-N-[4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-hydroxy-1H-indene (109 mg). To a solution of crude 1-[N-methyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-hydroxy-1H-indene (109 mg) and ethyl bromoacetate (80 mg) in DMF (3 ml) was added K2CO3 (80 mg). After being stirred for 24 hours, the solution was extracted with ethyl acetate. The mixture was washed with brine, dried over MgSO4 and evaporated on vacuo. The residue was purified by chromatography on silica gel to afford 1-[N-methyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-ethoxycarbonylmethoxy-1H-indene (80 mg) MS (m/z): 483 (M+ +1) NMR (CDCl3, δ): 1.29 (3H, t, J=7.1 Hz), 1.98-2.21 (2H, m), 2.41 (3H, s), 2.75-3.18 (2H, m), 3.78 (1H, d, J=12 Hz), 3.82 (1H, d, J=12 Hz), 4.25 (2H, q, J=7.1 Hz), 4.63 (2H, s), 4.55-4.65 (1H, m), 6.62 (1H, m), 7.15-7.18 (2H, m), 7.25-7.45 (6H, m), 7.60-7.75 (4H, m)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11]([CH3:15])([CH3:16])[C:12]([NH:23][C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1nccs1
Reactant: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2[nH]ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C(=O)Nc1nccs1)C(c1ccccc1)c1ccc2[nH]ccc2c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 72.7 %

Procedure:
To a stirred solution of 3-(1H-indol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid (0.31 g, 1.1 mmol), 2-aminothiazole (0.2 g, 2 mmol), and diisopropylethylamine (0.5 mL) in anhydrous DMF (3 mL) was added HATU (1 g, 2.7 mmol) under argon. After the reaction mixture was stirred at rt for 14 hr and 80° C. for 6 hr, it was concentrated, dissolved in ethyl acetate (20 mL), washed with saturated aqueous sodium bicarbonate solution (10 mL), brine (10 mL), dried (Na2SO4), and concentrated. Silica gel flash chromatography gave 3-(1H-indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide (Example 107, 0.3 g, 0.8 mmol, 75% yield) as a yellow solid. MS found: (M+H)+=376. 1H-NMR (400 MHz, MeOD) δ ppm 7.60 (1H, s) 7.43 (2H, d, J=7.12 Hz) 7.38 (1H, d, J=3.56 Hz) 7.20-7.29 (3H, m) 7.12-7.20 (2H, m) 7.10 (1H, d) 7.04 (1H, d, J=3.56 Hz) 6.38 (1H, d, J=3.05 Hz) 4.70 (1H, s) 4.62 (1H, s) 1.43 (6H, d, J=4.07 Hz).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([O:23]C(=O)C)=[CH:19][CH:18]=2)[CH:8]=[C:9]([O:11]C(=O)C)[CH:10]=1)(=O)C.[OH-].[K+].Cl.C(OCC)(=O)C>CO>[C:7]1([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:8]=[C:9]([OH:11])[CH:10]=[C:5]([OH:4])[CH:6]=1
Reactant: CC(=O)Oc1ccc(/C=C/c2cc(OC(C)=O)cc(OC(C)=O)c2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1ccc(C=Cc2cc(O)cc(O)c2)cc1
Yield: 92.9 %

Procedure:
50 mg (0.14 mmol) of (E)-3,4′,5-triacetoxystilbene was dissolved in 3 ml methanol and degassed with argon. 8 mg (0.14 mmol) of potassium hydroxide in 0.5 ml methanol were added dropwise under a slight argon stream and the mixture was heated for 30 minutes to 65° C. The obtained solution was neutralized with 1 N hydrochloric acid, poured into 10 ml of ethyl acetate and extracted 3× against 5 ml of brine. The organic phase was dried over MgSO4 and the solvent removed in vacuo giving 30 mg of resveratrol (0.13 mmol, 92%).
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([S:11](Cl)(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.C(N(C(C)C)CC)(C)C.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>C(Cl)Cl>[Cl:1][C:2]1[C:6]2[CH:7]=[C:8]([S:11]([NH:31][CH2:30][C:29]3[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1
Reactant: O=S(=O)(Cl)c1ccc2snc(Cl)c2c1
Reactant: COc1ccc(CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CNS(=O)(=O)c2ccc3snc(Cl)c3c2)cc1
Reaction time: 6 h
Yield: 45.2 %

Procedure:
To a solution of 3-chlorobenzo[d]isothiazole-5-sulfonyl chloride (90 mg, 0.33 mmol) in methylene chloride (2 mL), diisopropylethylamine (142 μL, 0.82 mmol) and 4-methoxybenzylamine (85 μL, 0.65 mmol) were added at room temperature. After stirring for 6 h, the reaction mixture was diluted with methylene chloride (20 mL) and washed with 10% HCl aqueous solution and brine. The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a brown residue. Purification by column chromatography, on silica gel, eluting with 2:8 ethyl acetate:hexanes provided 3-chloro-N-(4-methoxybenzyl)benzo-[d]isothiazole-5-sulfonamide (55 mg). 1H NMR (300 MHz, CDCl3): 8.22 (dd, 1H), 7.82 (dd, 1H), 7.75 (dd, 1H), 7.10 (d, 2H), 6.73 (d, 2H), 5.06 (t, 1H), 4.18 (d, 2H), 3.73 ppm (s, 3H). MW=368 confirmed by LC-MS, tr=13.39 min (Method Y) MH+=369.
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[C:13]([O:17][C:18]([NH:20][C:21]1([C:39](O)=[O:40])[CH2:26][CH2:25][N:24]([C:27]2[C:28]3[C:35]([CH:36]4[CH2:38][CH2:37]4)=[CH:34][NH:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CC(N(C)C)=O>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([C@@H:2]([NH:1][C:39]([C:21]2([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:22][CH2:23][N:24]([C:27]3[C:28]4[C:35]([CH:36]5[CH2:37][CH2:38]5)=[CH:34][NH:33][C:29]=4[N:30]=[CH:31][N:32]=3)[CH2:25][CH2:26]2)=[O:40])[CH2:3][CH2:4][OH:5])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]cc(C4CC4)c23)CC1
Reactant: N[C@@H](CCO)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]cc(C4CC4)c23)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 79.4 %

Procedure:
(S)-3-amino-3-(4-chlorophenyl)propan-1-ol (173 mg, 0.93 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 64) (375 mg, 0.93 mmol) and DIPEA (0.489 mL, 2.80 mmol) in DMA (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (391 mg, 1.03 mmol) was added and the resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness then diluted with EtOAc (75 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% MeOH with ammonia in DCM. Fractions were evaporated to afford (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (420 mg, 79%) as a yellow gum.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=O)[CH2:7][CH:8]2[C:13](=O)[CH2:12][CH2:11][S:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH2:23].C(O)C.[ClH:28]>CCOCC>[ClH:28].[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][N:23]1[C:6]([C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:7][C:8]2[CH2:9][S:10][CH2:11][CH2:12][C:13]1=2
Reactant: O=C(CC1CSCCC1=O)c1ccc(F)cc1
Reactant: CN(C)CCCN
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CN(C)CCCn1c(-c2ccc(F)cc2)cc2c1CCSC2

Procedure:
A solution of 4.0 g (0.016 mole) of 3-(4-fluorophenacyl)-2,3,5,6-tetrahydrothiopyran-4-one [Example 5 (a)], 1.62 g of 3-dimethylaminopropylamine and 40 ml. of ethanol is heated under reflux for 2.5 hours, cooled, treated with 4 ml. of saturated ethereal hydrogen chloride, warmed to boiling, and diluted to the cloud point with ether. Upon cooling a solid separates. Recrystallization from ethanol gives off-white crystals of 1-(3-dimethylaminopropyl)-2-(4-fluorophenyl)-1,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrole hydrochloride, m.p. 199° to 201°C. dec.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C>C1COCC1>[C:13]1([S:19]([N:8]2[C:9]3=[N:10][C:2]([Cl:1])=[CH:3][CH:4]=[C:5]3[CH:6]=[CH:7]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1ccc2cc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)n1ccc2ccc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
6-Chloro-7-azaindole (9.3 g, 61.1 mmol), prepared as described (Synthesis, 1992), was dissolved in 100 ml anhydrous THF under N2. At 0° C., a 60% dispersion of NaH 3.5 g (65.9 mmol) in mineral oil was added. After stirring for 1 hour at room temperature, the mixture was cooled (0° C.) and 8.7 ml (67.2 mmol) benzenesulfonyl chloride dissolved in 20 ml anhydrous THF was added. The reaction mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the mixture and the organic layer was washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/PE gradient (1:4 to pure diethyl ether) to give 1-benzenesulfonyl-6-chloro-1H-pyrrolo[2,3-b]pyridine (amorphous, 14.4 g, 80.7%) (TLC diethyl ether/PE (1/1) Rf 0.37). LCMS; Rt: 1.98 min, ([M+H]+=293).
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([O-:13])=[O:12])=[CH:6][CH:5]=1.[Na+].[C:17]([O:23][CH2:24]Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].C(OCC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([O:13][CH2:24][O:23][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:12])=[CH:6][CH:5]=1
Reactant: CC(C)=Cc1ccc(C(C)C(=O)[O-])cc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)=Cc1ccc(C(C)C(=O)OCOC(=O)C(C)(C)C)cc1

Procedure:
A solution of sodium 2-(4-dimethylvinylphenyl)propionate (3 g) and chloro-methyl pivalate (3.9 g) in toluene (50 ml) was refluxed for 6 hours. After cooling, 50 ml of ethyl ether were added and the mixture was washed with 10% NaHCO3. The solvent was removed, and the residue dried at 60° for 3 hours in a vacuum stove to yield the title ester as an oily product (2 g). Found: C% 71.5 (Calc. 71.66); H% 8.2 (8.23).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>CS(C)=O>[CH3:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: CSc1ncnc2c(N3CCCCC3)nc(Cl)nc12
Solvent: CS(C)=O
Solvent: O
Product: CSc1ncnc2c(N3CCCCC3)nc(N3CCNCC3)nc12

Procedure:
2.0 g (6.8 mmol) of 2-chloro-8-methylthio-4-piperidino-pyrimido[5,4-d]pyrimidine is dissolved warm in 70 ml of dimethylsulphoxide and stirred with a solution of 6 g of piperazine in 70 ml of dimethylsulphoxide for 1 hour at ambient temperature. Then the solution is poured into 1 liter of water, the precipitate obtained is suction filtered and washed with water. The residue is taken up in 50 ml of methylene chloride and extracted with 50 ml of 0.05N sodium hydroxide solution. The organic phase is separated off, dried over sodium sulphate and concentrated in a rotary evaporator.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=1)=[O:4].[C:15]([O:19][C:20](=[O:39])[C@@H:21]([NH:24][C:25]([O:27][CH2:28][C:29]12[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2)=[O:26])[CH2:22][NH2:23])([CH3:18])([CH3:17])[CH3:16]>C(OCC)(=O)C.CCCCCCC>[CH3:1][O:2][C:3](=[O:4])[CH:5]=[CH:6][C:7]1[S:11][C:10]([C:12](=[O:14])[NH:23][CH2:22][C@H:21]([NH:24][C:25]([O:27][CH2:28][C:29]23[CH2:36][CH:35]4[CH2:34][CH:33]([CH2:32][CH:31]([CH2:37]4)[CH2:30]2)[CH2:38]3)=[O:26])[C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:39])=[CH:9][CH:8]=1
Reactant: COC(=O)C=Cc1ccc(C(=O)O)s1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCC12CC3CC(CC(C3)C1)C2
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)C=Cc1ccc(C(=O)NC[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)OC(C)(C)C)s1
Yield: 32.4 %

Procedure:
The title compound was synthesized analogously to example 3, step a) from 360 mg (1.84 mmol) of 5-(2-methoxycarbonyl-vinyl)-thiophene-2-carboxylic acid and 650 mg (1.84 mmol) of (2S)-2-(1-adamantylmethoxycarbonylamino)-3-amino-propionic acid tert-butyl ester. After chromatography (silica gel; ethyl acetate/n-heptane (1/1, v/v)) 326 mg of the title compound were obtained as colourless crystals.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12](Cl)=[O:13])[CH2:8]2.[CH3:15][O:16][C:17](=[O:31])[C@@:18]([CH3:30])([CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)[NH2:19].C(N(CC)CC)C>C1COCC1>[CH3:15][O:16][C:17](=[O:31])[C@@:18]([CH3:30])([CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)[NH:19][C:12]([O:11][CH:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)=[O:13]
Reactant: COC(=O)[C@](C)(N)Cc1c[nH]c2ccccc12
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@](C)(Cc1c[nH]c2ccccc12)NC(=O)OC1C2CC3CC(C2)CC1C3
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
To a stirred solution of 2-adamantylchloroformate (0.965 g, 4.5 mmol) in dry THF (10 mL) was added a solution of α-methyl-D-tryptophan methyl ester (0.928 g, 4 mmol) in dry THF (20 mL) followed by a solution of triethylamine (0.808 g, 8 mmol) in dry THF (20 mL) dropwise. After 15 minutes, the reaction mixture was filtered, the solvent removed in vacuo and column chromatographed using 2% MeOH:98% CH2Cl2 as eluant to yield the title compound (1.42 g, 89%) as a syrup. IR (film) 1740-1695 b.r cm-1 ; NMR (CDCl3) δ1.50-1.60 (2H, m), 1.67 (3H, s), 1.70-2.10 (12H, m), 3.38 (1H, d, J =14.5Hz), 3.50-3.60 (1H, br.s), 3.68 (3H, s), 4.86 (1H, br.s), 5.28 (1H, br.s), 6.93 (1H, d, J 2.4Hz); 7.04-7.10 (2H, m), 7.33 (1H, d, J 8.2Hz) 7.54 (1H, d, J 7.8Hz), 8.18 (1H, br.s).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][C:16](Cl)=[O:17].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:14][CH2:15][C:16]([O:13][C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:17]
Reactant: O[C@@H]1CCCC[C@H]1c1ccccc1
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)O[C@@H]1CCCC[C@H]1c1ccccc1

Procedure:
In the next step, (±)-trans-2-phenylcyclohexanol is reacted with chloroacetyl chloride at reflux in a basic solvent such as a mixture of methylene chloride and pyridine or, more preferably, 4-dimethylaminopyridine and methylene chloride. The resulting (±)-trans-2-phenylcyclohexyl chloroacetate of the formula ##STR29## can be isolated by conventional means such as extraction followed by distillation of the organic layer.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[C:11]([CH3:18])=[N:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[C:3]=1[N+:19]([O-:21])=[O:20].[CH2:22]([CH:24]([NH2:27])[CH2:25][CH3:26])[CH3:23]>C1COCC1>[CH2:22]([CH:24]([NH:27][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[C:4]([NH:9][C:10]2[C:11]([CH3:18])=[N:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[N:5]=[C:6]([CH3:8])[N:7]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: CCC(N)CC
Reactant: Cc1cc(C)c(Nc2nc(C)nc(Cl)c2[N+](=O)[O-])c(C)n1
Solvent: C1CCOC1
Product: CCC(CC)Nc1nc(C)nc(Nc2c(C)cc(C)nc2C)c1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
To a cooled solution of (6-chloro-2-methyl-5-nitro-pyrimidin-4-yl)-(2,4,6-trimethyl-pyridin-3-yl)-amine (88 mg, 0.29 mmol) in 1 ml of dry THF was added 1-ethyl-propyl-amine (80 mg, 0.92 mmol) at −78° C. The mixture was stirred at that temperature for 3 hrs, then warmed to −10° C. for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give the title compound (88 mg, 86%) as an orange solid, mp 151–152° C. 1H NMR (CDCl3) δ 9.16 (d, 1H), 6.92 (s, 1H), 4.35 (m, 1H), 2.50 (s, 3H), 2.39 (s, 3H), 2.18 (s, 3H), 2.16 (s, 3H), 1.5–1.80 (m, 4H), 0.94 (t, 6H) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:17]1[N:22]2[N:23]=[C:24]([NH2:26])[N:25]=[C:21]2[CH:20]=[C:19]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:18]=1.C(Cl)Cl>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:17]2[N:22]3[N:23]=[C:24]([NH2:26])[N:25]=[C:21]3[CH:20]=[C:19]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:18]=2)[CH:2]=1
Reactant: Nc1nc2cc(-c3cccnc3)cc(Cl)n2n1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Nc1nc2cc(-c3cccnc3)cc(-c3cccnc3)n2n1

Procedure:
A mixture of 3-pyridine boronic acid pinacolate ester (500 mg, 2.44 mmol), Na2CO3 (649 mg, 6.12 mmol) and 5-chloro-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine, which may be produced as in Example 1A, (500 mg, 2.04 mmol) in toluene (30 mL), ethanol (15 mL) and water (15 mL) was degassed by purging with N2 for 10 min. [PdCl2(dppf)].CH2Cl2 (56 mg, 0.082 mmol) was added and the mixture was brought to reflux for 36 h. The solvent was evaporated and the residue was extracted into hot EtOH/MeOH, filtered through Celite, and pre-adsorbed onto SiO2. Column chromatography (0-10% MeOH in CH2Cl2) afforded the product 5,7-di-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine as a solid. MS m/z 289 (M+H+).
Reaction SMILES: [ClH:1].[CH3:2][NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O1[CH2:14][CH2:13][NH:12]C1=O>COCCOCCO>[ClH:1].[CH3:2][N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:14][CH2:13][NH2:12]
Reactant: O=C1NCCO1
Reactant: CNc1ccccc1
Agent: Cl
Solvent: COCCOCCO
Product: CN(CCN)c1ccccc1

Procedure:
In a procedure similar to Example 1, N-methylaniline hydrochloride (17.4 g, 0.10 mole), 2-oxazolidinone (8.7 g, 0.10 mole) and 50 ml of 2-(2-methoxyethoxy)-ethanol were heated for four hours. Removal of the solvent in vacuo gave a quantitative yield of N-methyl-N-phenyl-1,2-ethanediamine hydrochloride as a purplish solid. Workup as before afforded the crude diamine in also a quantitative crude yield as a dark yellow liquid. Distillation at 95° C. to 100° C. (0.5 mm Hg) gave a 79 percent yield of the purified product as a clear liquid. Spectral data and gas chromatographic analysis as compared to an authentic sample confirmed its structure.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.OCCOCN1C=C(C=C)C(=O)NC1=O.[N-]=[N+]=[N-].[Na+].[OH:28][CH2:29][CH2:30][O:31][CH2:32][N:33]1[CH:40]=[C:39]([CH:41]([N:44]=[N+:45]=[N-:46])[CH2:42]Br)[C:37](=[O:38])[NH:36][C:34]1=[O:35]>COCCOC.O>[OH:28][CH2:29][CH2:30][O:31][CH2:32][N:33]1[CH:40]=[C:39]([CH:41]([N:44]=[N+:45]=[N-:46])[CH2:42][Cl:1])[C:37](=[O:38])[NH:36][C:34]1=[O:35]
Reactant: O=C1CCC(=O)N1Cl
Reactant: [N-]=[N+]=NC(CBr)c1cn(COCCO)c(=O)[nH]c1=O
Agent: C=Cc1cn(COCCO)c(=O)[nH]c1=O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: [N-]=[N+]=NC(CCl)c1cn(COCCO)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
N-Chlorosuccinimide (NCS, 88 mg, 0.65 mmol) was added slowly to a precooled (−5° C.) suspension prepared by mixing a solution of 1 (116 mg, 0.55 mmol) in 1,2-dimethoxyethane (20 ml) with a solution of sodium azide (143 mg, 2.2 mmol) in water (0.35 ml). The reaction was stirred for 3 h at 0° C. Completion of the reaction, as described for the isolation of 2a, gave a residue which was purified by silica gel column chromatography. Elution with chloroform:methanol (97:3, v/v) as eluent yielded 2b as a syrup (56 mg, 35%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([CH2:13][N:14]([C:16](=[O:18])[CH3:17])[OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]=[C:23]=[O:24]>N12CCCN=C1CCCCC2.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([CH2:13][N:14]([C:16](=[O:18])[CH3:17])[O:15][C:23](=[O:24])[NH:22][CH3:21])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CN=C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CNC(=O)ON(Cc1ccc(OCc2ccccc2)cc1)C(C)=O
Reaction time: 3 h
Yield: 82.6 %

Procedure:
A mixture of N-(4-benzyloxybenzyl)acetohydroxamic acid (1.35 g), methyl isocyanate (0.65 g) and 1,8-diazabicyclo [5.4.0]undec-7-ene catalyst (1 drop) in tetrahydrofuran (10 ml) was stirred for 3 hours then left overnight to provide N-(4-benzyloxybenzyl)-O-methylcarbamoylacetohydroxamic acid (1.35 g) m.pt. 101°-102°[from ethyl acetate-light petroleum (b.pt. 60°-80°)].