Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([C:14]2[NH:18][CH:17]=[N:16][N:15]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1>CO.[Pd]>[N:16]1[N:15]=[C:14]([C:11]2([NH2:10])[CH2:13][CH2:12]2)[NH:18][CH:17]=1
Reactant: O=C(NC1(c2nnc[nH]2)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC1(c2nnc[nH]2)CC1
Reaction time: 1.5 h
Yield: 98.1 %

Procedure:
To a solution of [1-(4H-[1,2,4]triazol-3-yl)-cyclopropyl]-carbamic acid benzyl ester (60 mg, 0.23 mmol) in MeOH (5 mL) was added 10% Pd/C (60 mg). The reaction mixture was stirred under H2 atmosphere (balloon) for 1.5 h. The reaction mixture was filtered through diatomaceous earth. The solvent was concentrated in vacuo and dried under high vacuum to afford 28 mg of the title compound, m/z 125.5 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=O.C=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)C(C)C)C>C1(=O)CCCCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Pd+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13]
Reactant: C=Cc1ccccc1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: [Pd+2]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C1CCCCC1
Product: COc1cc(C=Cc2ccccc2)cc(OC)c1OC
Yield: 17.5 %

Procedure:
The procedure described in Example 1 is followed, except that 23.07 g (0.1 mol) of 3,4,5-trimethoxybenzoyl chloride, 13.02 g (0.125 mol) of styrene, 12.93 g (0.125 mol) of ethyl diisopropylamine and 0.3046 g (0.001 mol) of bis-(acetylacetonato)-palladium(II) are used. After a reaction time of 3 hours at 130° C., in 50 ml of cyclohexanone as the solvent, 4.7 g (0.0175 mol) of 3,4,5-trimethoxystilbene, corresponding to a yield of 17.5% of theory, are obtained in the form of white needles; melting point 108° C.
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][CH:30]=O)[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([CH2:29][CH2:30][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[O:9][N:8]=3)[CH2:2][CH2:3]2)[CH2:27][CH2:28]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: c1ccc2c(N3CCNCC3)noc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3noc4ccccc34)CC2)CC1
Reaction time: 12 h

Procedure:
A mixture of 3-piperazin-1-yl-1,2-benzisoxazole (1 g, 4.92 mmol), trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (Intermediate A) (1.3 g, 5.41 mmol), in dichloromethane (15 ml) was stirred for 15 minutes at room temperature and sodium triacetoxyborohydride (1.88 g, 8.86 mmol) was added slowly and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was extracted with saturated NaHCO3-solution and two times dichloromethane. The organic layers were dried over sodium sulfate, filtrated and concentrated to dryness. The crude product was purified with column chromatography on silica gel using heptane:ethyl acetate 80:20->10:90. The product fractions were concentrated to give 1.34 g (64% yield) of a white solid. MS (m/e): 429.4 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][C:13]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][C:13]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1(C)CC=CC(NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(C)CCCC(NC(=O)OC(C)(C)C)C1
Reaction time: 48 h

Procedure:
Methyl 5-(tert-butoxycarbonylamino)-1-methylcyclohex-3-enecarboxylate, 52f, (5.59 g, 20.75 mmol) was dissolved in 100 mL of MeOH. To the stirred solution was added 5% palladium on carbon (1.11 g, 10.38 mmol) and the reaction was stirred under a hydrogen balloon for 2 days. The reaction was filtered through celite, and the filtrate was concentrated in vacuo and used without further purification.
Reaction SMILES: O.O.[OH:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.[C:12]1(=[CH:15][C:16](OC)=[O:17])[CH2:14][CH2:13]1.Cl.FC(F)(F)C(O)=O>O.CN(C)C=O>[OH:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]2[C:5]=1[C:16](=[O:17])[CH2:15][C:12]1([O:11]2)[CH2:14][CH2:13]1
Reactant: COC(=O)C=C1CC1
Reactant: Oc1cc(O)cc(O)c1
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C1CC2(CC2)Oc2cc(O)cc(O)c21
Temperature: 130 °C
Reaction time: 8 h

Procedure:
Under argon, 112 g (690 mmol) of 1,3,5-trihydroxybenzene dihydrate are dissolved in 230 ml abs. dimethylformamide, 28.82 g (230 mmol) of methyl cyclopropylideneacetate (Example 41A) and 20 g of 4 Å molecular sieve (as powder) are added and the mixture is stirred at a bath temperature of 130° C. overnight. 1 liter of 1 N hydrochloric acid is then added, and the mixture is extracted repeatedly with ethyl acetate. The combined organic phases are washed once with water and once with saturated sodium chloride solution, dried over sodium sulfate and concentrated. 230 ml (2.99 mol) of trifluoroacetic acid are added to the product obtained, and the mixture is heated to 75° C. and stirred for 8 hours. The mixture is then cooled, water is added and the mixture is extracted repeatedly with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is purified on silica gel (mobile phase: dichloromethane/methanol 100:1→100:3). The product fractions are combined and concentrated. Dichloromethane is added to the residue obtained, the mixture is stirred briefly and the precipitate is filtered off with suction and dried under high vacuum. This gives 2.25 g (5% of theory) of the target compound. The mother liquor is then purified again on a silica gel column (mobile phase: dichloromethane/methanol 100:1). This gives a further 3.41 g (7% of theory) of the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][CH2:13][C@H:14]2[O:19][C:18]3[CH:20]=[C:21]([NH2:26])[C:22]([O:24][CH3:25])=[CH:23][C:17]=3[O:16][CH2:15]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.Cl[C:29]1[C:30](=O)C2C(C(=O)[C:38]=1Cl)=CC=CC=2.C(C=C)=O.[OH-].[Na+]>C(O)C>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][CH2:13][CH:14]2[O:19][C:18]3=[C:20]4[C:21](=[C:22]([O:24][CH3:25])[CH:23]=[C:17]3[O:16][CH2:15]2)[N:26]=[CH:30][CH:29]=[CH:38]4)(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1cc2c(cc1N)O[C@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Agent: C=CC=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc2c(c3cccnc13)OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 1.50 g (3.73 mmole) of [(2S)-7-amino-6-methoxy-2,3-dihydro-1,4-benzodioxin-2y]methyl 4-methylbenzenesulfonate hydrochloride was added 100 mL of concentrated hydrochloric acid. Then 0.85 g (3.74 mmole) of 2,3-dichloro-1,4-naphthoquinone was added with sufficient ethanol to wash down the solid. The heterogeneous mixture was heated to reflux and a solution of 0.31 g (5.53 mmole) of acrolein in 10 mL of ethanol was added dropwise. Reflux was continued for an additional 1 hour. The mixture was then allowed to come to room temperature and added to ice water. The solution was made basic with 1 N NaOH and extracted with methylene chloride. The extract was dried over magnesium sulfate, filtered and concentrated to a crude brown oil in vacuum. This was column chromatographed on silica gel with a gradient elution commencing with methylene chloride and ending with 3% methanol in methylene chloride and the product-containing fractions concentrated in vacuum to give 0.75 g of the (R)-enantiomer of the title compound as a yellow oil. 1H-NMR (CDCl3): doublet 8.8 δ (1 H); doublet 8.2 δ (1 H); doublet 7.8 δ (2 H); multiplet 7.4 δ (1 H); multiplet 7.2-7.25 δ (3 H); multiplet 4.45 δ (1 H); multiplet 4.1-4.4 δ (4 H); singlet 3.0 δ (3 H); singlet 2.4 δ (1 H).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]2[C:22]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[C:21]([O:32][CH2:33][C:34]#[C:35][CH2:36][OH:37])[N:20]=[CH:19][N:18]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[Br:38][C:39]1[CH:40]=[N:41][C:42](Cl)=[N:43][CH:44]=1>C1COCC1>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]2[C:22]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[C:21]([O:32][CH2:33][C:34]#[C:35][CH2:36][O:37][C:42]3[N:43]=[CH:44][C:39]([Br:38])=[CH:40][N:41]=3)[N:20]=[CH:19][N:18]=2)(=[O:14])=[O:15])=[CH:9][CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: Clc1ncc(Br)cn1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ncnc1OCC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ncnc1OCC#CCOc1ncc(Br)cn1
Reaction time: 0.5 h

Procedure:
To a suspension of 29 mg of a 55% sodium hydride dispersion in mineral oil in 15 ml of dry THF 150 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzene sulfonamide (Example 10) was added. After stirring for 0.5 h, 64 mg of 5-bromo-2-chloropyrimidine was added. Stirring was continued for 40 h at 40° C. Eventually, the solvent was evaporated and the remaining residue was partitioned between 50 ml of 10% aqueous citric acid and 50 ml of ethyl acetate. The organic layer was separated and the aqueous layer was extracted two more times with 50 ml of ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The crude product was crystallised from 2-propanol to give 126 mg of 4-tert.-butyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzene sulfonamide as beige crystals. LC-MS: tR=6.07 min, [M+1]+=656.24, [M−1]+=654.34.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=[O:10])[CH:4]=1)#N.OCC1C=C(C)C=CN=1>>[CH3:1][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=[O:10])[CH:4]=1
Reactant: N#Cc1ccnc(C=O)c1
Agent: Cc1ccnc(CO)c1
Product: Cc1ccnc(C=O)c1
Yield: 78 %

Procedure:
In a manner similar to that described for the preparation of 4-cyano-2-pyridinecarboxaldehyde, 2-hydroxymethyl-4-methylpyridine (2.60 g, 21.14 mmol) provided 2.0 g (78%) of the 4-methyl-2-pyridinecarboxaldehyde.
Reaction SMILES: [N:1]([C@H:4]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5]1)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[NH2:1][C@H:4]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N=[N+]=[N-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 4 °C
Reaction time: 1.5 h
Yield: 93.8 %

Procedure:
To 3β-azido-5-cholestene (14, 3.30 g, 8.02 mmol) in dry diethyl ether (150 mL) at 4° C. was added lithium aluminum hydride (4.60 g, 121.18 mmol) in three equal portions. The reaction was maintained at 4° C. for 30 min, warmed to 23° C., and stirred for an additional 1.5 h. The reaction was quenched by addition of diethyl ether (50 mL) followed by careful dropwise addition of deionized H2O (60 mL). The organic layer was washed with saturated aqueous NaCl (2×100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to afford 2.90 g (85%) of crude 3β-amino-5-cholestene. This aminosteroid was dissolved in dry THF (150 mL), and diisopropylethylamine (2.61 mL, 15.03 mmol) was added. 2-Nitrobenzenesulfonyl chloride (2.20 g, 9.92 mmol) in dry THF (40 mL) was added by addition funnel over 30 min. After 2 h at 23° C., solvents were removed in vacuo, CH2Cl2 was added (75 mL), and this organic solution was washed with aqueous NaHCO3 (10%, 1×100 mL) and saturated aqueous NaCl (2×100 mL). The organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to yield a crude yellow solid. Recrystallization (CH2Cl2/MeOH, 1:5) followed by flash column chromatography (EtOAc/hexanes, 1:5) afforded off-white 15 (3.50 g, 83%), mp 202-203° C.; 1H NMR (300 MHz, CDCl3) δ 8.16-8.12 (m, 1H), 7.86-7.82 (m, 1H), 7.75-7.67 (m, 2H), 5.19 (s, 1H), 5.16 (s, 1H), 3.28-3.18 (m, 1H), 2.18-0.83 (m, 40H), 0.63 (s, 3H); 13C NMR (75.41 MHz, CDCl3) δ 148.1, 139.9, 135.4, 133.6, 133.1, 131.0, 125.6, 122.7, 56.9, 56.3, 55.2, 50.2, 42.5, 40.3, 39.9, 39.7, 38.0, 36.6, 36.4, 36.0, 32.0, 31.9, 30.2, 28.4, 28.2, 24.4, 24.0, 23.0, 22.8, 21.1, 19.4, 18.9, 12.0; IR (film) νmax 3331, 2936, 2359, 1541 cm−1; CI m/z 571.3567 (MH+, C33H51N2O4S requires 571.3569).
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][NH:5][C:6]([NH2:8])=[S:7].Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=O.C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=2)[N:8]=1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)CCNC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)CCNc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Yield: 27.3 %

Procedure:
A solution of N-(3-methylbutyl)thiourea (3.00 g, 20.5 mmol), 2-bromo-1-[4-(trifluoromethyl)phenyl]ethanone (5.45 g, 20.5 mmol) and sodium acetate (2.19 g, 26.7 mmol) in ethanol (50 mL) was stirred at 90° C. for 4 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained solid was recrystallized from dichloromethane-hexane to give the title compound (1.76 g, yield 74%) as pale-yellow crystals.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(O[C:10](=O)[CH2:11][C:12]1[N:17]=[C:16]([NH:18][CH3:19])[CH:15]=[CH:14][CH:13]=1)C.[OH2:21].[OH-].[Na+]>C1COCC1>[CH3:19][NH:18][C:16]1[N:17]=[C:12]([CH:11]([OH:21])[CH3:10])[CH:13]=[CH:14][CH:15]=1
Reactant: O
Reactant: CCOC(=O)Cc1cccc(NC)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1cccc(C(C)O)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 67 %

Procedure:
A solution of 1.0 M LiAlH4 in THF (95 mL, 95 mmole) was added dropwise to a mechanically stirred suspension of ethyl-2-(methylamino)-6-pyridylacetate (7.34 g, 31.82 mmole) in dry THF (64 mL) at 0° C. under argon. The addition was done slowly until gas evolution subsided, then the remaining solution was added rapidly. Addition required 5-7 min. The reaction was warmed to RT and stirred for 45 min, then was heated to reflux. After 10 min, the reaction was cooled to 0° C. and worked up by sequential dropwise addition of H2O (3.6 mL), 15% NaOH (3.6 mL), and H2O (10.8 mL). The mixture was stirred for 15 min at 0° C. and 15 min at RT, then was filtered through a Buchner funnel. The filter pad was washed with plenty of THF, and the filtrate was concentrated. The residue was reconcentrated from toluene, then was chromatographed on silica gel (5% MeOH in 1:1 EtOAc/CHCl3) to afford the title compound (3.23 g, 67%) as a yellow oil which solidified to a waxy solid: 1H NMR (250 MHz, CDCl3) δ7.36 (dd, J=8.3, 7.3 Hz, 1 H), 6.42 (d, J=7.3 Hz, 1 H), 6.26 (d, J=8.3 Hz, 1 H), 4.93-5.28 (m, 1 H), 4.38-4.60 (m, 1 H), 3.96 (t, J=5.4 Hz, 2 H), 2.90 (d, J=5.2 Hz, 3 H), 2.84 (t, J=5.4 Hz, 2 H); MS (ES) m/e 153 (M+H)+.
Reaction SMILES: COC1C=CC(NC2N=NC(C(NC(C3OC=CC=3)=O)C)=CN=2)=CC=1.[NH2:26][CH:27]([C:29]1[N:34]=[N:33][C:32]([NH:35][C:36]2[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([O:46][CH3:47])[CH:37]=2)=[N:31][CH:30]=1)[CH3:28].C(N(CC)CC)C.[CH:55]1([C:61](Cl)=[O:62])[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1>>[CH3:43][O:42][C:40]1[CH:41]=[C:36]([NH:35][C:32]2[N:33]=[N:34][C:29]([CH:27]([NH:26][C:61]([CH:55]3[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]3)=[O:62])[CH3:28])=[CH:30][N:31]=2)[CH:37]=[C:38]([O:46][CH3:47])[C:39]=1[O:44][CH3:45]
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Reactant: O=C(Cl)C1CCCCC1
Agent: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccco3)nn2)cc1
Solvent: CCN(CC)CC
Product: COc1cc(Nc2ncc(C(C)NC(=O)C3CCCCC3)nn2)cc(OC)c1OC
Yield: 60.2 %

Procedure:
In a similar manner as described for Intermediate 59, using 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (170 mg, 0.56 mmol), triethylamine (0.120 mL, 0.84 mmol) and cyclohexanecarbonyl chloride (0.082 mL, 0.61 mmol) to afford N-[1-(3-{[3,4,5-tris(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]cyclohexanecarboxamide (140 mg) as a yellow solid. MS m/z 416 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9]1)=[O:7])([CH3:4])(C)C.Cl.[OH-].[Na+].ClC(OC[C:23]1[CH:28]=[CH:27]C=[CH:25][CH:24]=1)=O>CO.O1CCOCC1>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12]([OH:14])=[O:13])[CH2:11]1)=[O:7])[C:4]1[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (3.00 g, 14.9 mmol) in MeOH (12.5 mL) was added 4M HCl in 1,4-dioxane (12.5 mL). The reaction was stirred at rt for 16 h. The mixture was evaporated to dryness. To a cooled (0° C.) solution of the residue in 1,4-dioxane (15 mL) and 2N aqueous NaOH (75 mL) was added benzyl chloroformate (2.67 g, 15.7 mmol), dropwise. The reaction was warmed to rt and was allowed to stir for 4 h. The mixture was washed with ethyl acetate (75 mL) and the aqueous layer was acidified (pH 5) with the addition of conc HCl. The mixture was extracted with ethyl acetate (3×75 mL) and the combined organic layers were washed with brine, dried (Na2SO4) and evaporated to give 2.10 g (60%) of the desired product. ES-MS m/z 235.90 [M+H]+, HPLC RT (min) 2.53.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Cl:10][C:11]1[CH:12]=[C:13]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34]O)=[CH:30][CH:29]=3)[N:24]=2)[CH:14]=[CH:15][C:16]=1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+]>ClCCl.O>[Cl:10][C:11]1[CH:12]=[C:13]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][Cl:3])=[CH:30][CH:29]=3)[N:24]=2)[CH:14]=[CH:15][C:16]=1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-c2noc(-c3ccc(C4CCCCC4)c(Cl)c3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: ClCc1ccc(-c2noc(-c3ccc(C4CCCCC4)c(Cl)c3)n2)cc1
Temperature: 42.5 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.27 mL, 0.0037 mol) and N,N-dimethylformamide (0.1 mL) are added to a stirred solution of {4-[5-(3-chloro-4-cyclohexylphenyl)-[1,2,4]-oxadiazol-3-yl]phenyl}methanol (0.45 g, 0.0012 mol) in dichloromethane (10 mL) at 0° C. The reaction mixture is heated at 40-45° C. and is stirred at this temperature for 1 hr. It is then cooled to 0-5° C. temperature, treated with demineralized water (3 mL) and is neutralized with 4N sodium hydroxide solution at 0-5° C. to adjust the pH 8-9. Finally it is extracted with dichloromethane (2×10 mL) and the combined extract is dried over sodium sulfate. Removal of solvent under reduced pressure gives 5-(3-chloro-4-cyclohexylphenyl)-3-(4-chloromethylphenyl)-[1,2,4]-oxadiazole.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([O:14][CH3:15])[C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=1)([OH:3])=O.[CH2:16]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(OCC)C>[CH2:16]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:1]([C:4]2[CH:5]=[C:6]([O:14][CH3:15])[C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=2)=[O:3])=[CH:25][CH:24]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: COC(=O)c1ncc(C(=O)O)cc1OC
Reactant: CCCCCCOc1ccc(N)cc1
Solvent: CCOCC
Product: CCCCCCOc1ccc(NC(=O)c2cnc(C(=O)OC)c(OC)c2)cc1

Procedure:
Methyl 5-(((4-n-hexyloxyphenyl)amino)carbonyl)-3-methoxypyridine-2-carboxylate was prepared from methyl 5-carboxy-3-methoxypyridine-2-carboxylate and 4-hexyloxyaniline, m.p. 118°-119° C. (from diethyl ether).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][CH2:20][OH:21])[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[C:11]=1F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([N:8]1[C:9](=[O:18])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[C:11]=2[O:21][CH2:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cccc(Br)c1F)N(CCO)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2cccc(Br)c2OCCN1Cc1ccccc1
Temperature: 0 °C
Yield: 75.1 %

Procedure:
To a solution of N-benzyl-3-bromo-2-fluoro-N-(2-hydroxyethyl)benzamide (11.4 g, 32.4 mmol) in N,N-dimethylformamide (160 ml) was added under ice-cooling sodium hydride (60%, 1.68 g, 42.1 mmol), and the mixture was stirred under ice-cooling for 1 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (8.08 g, 74.8%) as an oil.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH2:1]([N:12]1[CH2:13][CH2:14][C:15](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([F:9])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Fc1cnccc1/C=C/c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: FC1=C(/C=C/c2ccccc2)CCN(Cc2ccccc2)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 10.6 %

Procedure:
Benzyl bromide (0.45 ml, 3.8 mmol) was added to a solution of (E)-3-fluoro-4-(2-phenylethenyl)pyridine (0.6781 g, 3.40 mmol) in anhydrous dimethylformamide (5 ml) and the mixture stirred at 90° C. under nitrogen for 1 hour. The mixture was allowed to cool and diluted with ethanol (50 ml). Sodium borohydride (0.1580 g, 4.18 mmol) was added portionwise and the resulting reaction mixture stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, water (100 ml) added and extracted with diethyl ether (2×100 ml). The extracts were washed with brine (100 ml), combined, dried (MgSO4) and concentrated in vacuo. Careful purification by first flash chromatography, eluting with ethyl acetate/petrol (60°-80°), followed by preparative layer chromatography, eluting with ethyl acetate/dichloromethane/petrol (60°-80°), gave the title compound (0.1058 g, 11%) as a pale yellow solid; δH (CDCl3) 2.43 (2H, m, tetrahydropyridinyl CH2), 2.69 (2H, m, tetrahydropyridinyl CH2), 3.18 (2H, br s, tetrahydropyridinyl CH2), 3.67 (2H, s, PhCH2N), 6.42 (1H, d, J 16.4Hz, CH=CHPh) and 7.20-7.49 (11H, m, CH=CHPh and ArH).