Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH2:2]([O:9][CH2:10][CH2:11][CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[Br:38][C:39]1[CH:40]=[CH:41][C:42]([OH:47])=[C:43]([CH:46]=1)[CH:44]=O.O>C1COCC1>[CH2:2]([O:9][CH2:10][CH2:11][CH:12]=[CH:44][C:43]1[CH:46]=[C:39]([Br:38])[CH:40]=[CH:41][C:42]=1[OH:47])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(COCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(Br)cc1C=CCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60.0 g (122 mmol) of (3-benzyloxypropyl)triphenylphosphonium bromide are initially introduced in 400 ml of THF, and a solution of 25.0 g (223 mmol) of potassium tert-butoxide in 100 ml of THF is added dropwise at −10° C. A solution of 20.0 g (99.5 mmol) of 5-bromo-2-hydroxybenzaldehyde in 200 ml of THF is subsequently added dropwise at 0° C., and the batch is stirred overnight at room temp. The reaction mixture is subsequently hydrolysed using water and extracted three times with MTB ether. The combined org. phases are washed with water and sat. sodium chloride soln. and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is filtered through silica gel with heptane/ethyl acetate (4:1), giving a mixture of cis- and trans-2-(4-benzyloxybut-1-enyl)-4-bromophenol as a colourless oil, which is reacted without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(N(CC)CC)C.FC(F)(F)S(O[C@H:44]1[CH2:49][CH2:48][O:47][C:45]1=[O:46])(=O)=O.O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:25]=[C:26]([O:30][C@@H:44]2[CH2:49][CH2:48][O:47][C:45]2=[O:46])[CH:27]=[CH:28][CH:29]=1)[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: O=C1OCC[C@@H]1OS(=O)(=O)C(F)(F)F
Reactant: COc1ccc(OCCCN(Cc2cccc(O)c2)c2nc3ccccc3o2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(OCCCN(Cc2cccc(O[C@@H]3CCOC3=O)c2)c2nc3ccccc3o2)cc1
Reaction time: 0.08 h

Procedure:
In an argon atmosphere, N-(benzoxazole-2-yl)-N-(3-(4-methoxyphenoxy)propyl)-3-hydroxybenzylamine (200 mg) was dissolved in dichloromethane (1.5 mL), and triethylamine (0.11 mL) was added dropwise to the solution at room temperature, followed by stirring for 5 minutes at the same temperature. Subsequently, a solution of (S)-2-trifluoromethanesulfonyloxybutyrolactone (174 mg) in dichloromethane (1 mL) was added dropwise to the mixture over 10 minutes at room temperature, followed by stirring for 5 hours at the same temperature. The reaction mixture was added to water (50 mL), and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate anhydrate and concentrating under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane/ethyl acetate=1/1), to thereby yield a colorless oil (242 mg, 100′, 98.1% ee).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.C1C2C(=CC=CC=2)C=CC=1C(O)=O.IC1C=CC(N)=CC=1>>[CH2:1]([S:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:24][C:23]1[CH:25]=[CH:26][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1ccccc1SCc1ccccc1
Agent: Nc1ccc(I)cc1
Agent: O=C(O)c1ccc2ccccc2c1
Product: COc1ccc(NC(=O)c2ccccc2SCc2ccccc2)cc1

Procedure:
The title compound was synthesized by the same procedure as for Example 15, except 2-benzylsulfanyl-benzoic acid and 4-methoxyaniline were used instead of 2-napthoic acid and 4-iodoaniline. M+364.2
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][C:14]#[N:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]CC.[Na+].[C:22](=O)([O:26]CC)[O:23][CH2:24][CH3:25].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]([C:14]#[N:15])[C:22]([O:23][CH2:24][CH3:25])=[O:26])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
The 4-benzyloxybenzyl cyanide from step (450a)(3.2 g, 14.33 mmol), sodium ethoxide (1.07 g, 15.7 mmol), and diethyl carbonate (2.23 g, 18.9 mmol) were combined in toluene (100 mL), heated to reflux for 3 h, cooled to rt, and partioned between ethyl acetate and 1 N HCl. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude was purified by chromatography on silica gel eluting hexane:ethyl acetate (80:20, v:v) to give ethyl 2-(4-benzyloxyphenyl)cyanoacetate (4.2 g, 99%) as an oil. MS (M+NH4)+=313.
Reaction SMILES: CN1C=CC(C(O)=O)=C1.[NH:10]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:11]1.[CH:22]1([N:26]2[CH2:31][CH2:30][CH:29]([O:32][C:33]3[CH:38]=[CH:37][C:36](I)=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)[CH2:25]C[CH2:23]1.IC1C=CC(OC2CCN(C(C)C)CC2)=CC=1>>[CH:22]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][C:33]2[CH:34]=[CH:35][C:36]([N:10]3[CH:14]=[CH:13][C:12]([C:15]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)=[O:16])=[CH:11]3)=[CH:37][CH:38]=2)[CH2:28][CH2:27]1)([CH3:25])[CH3:23]
Reactant: Ic1ccc(OC2CCN(C3CCC3)CC2)cc1
Reactant: O=C(c1cc[nH]c1)N1CCCC1
Agent: CC(C)N1CCC(Oc2ccc(I)cc2)CC1
Agent: Cn1ccc(C(=O)O)c1
Product: CC(C)N1CCC(Oc2ccc(-n3ccc(C(=O)N4CCCC4)c3)cc2)CC1

Procedure:
The titled compound was prepared as a colorless amorphous substance by repeating the procedure of Example 1, except that the methyl 1H-pyrrole-3-carboxylic acid was replaced by (1H-pyrrol-3-yl)(pyrrolidin-1-yl)methanone and the 1-cyclobutyl-4-(4-iodophenoxy)piperidine by 4-(4-iodophenoxy)-1-isopropylpiperidine (which can be synthesized in accordance with the method described in WO2004089373).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:11][O:10][CH2:9]1)(=O)=O.[CH3:19][O:20][C:21]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24].CCN(CC)CC>CC#N>[CH3:19][O:20][C:21]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:22]=1[CH2:23][N:24]1[CH2:6][CH2:7][C:8]2([CH2:9][O:10][CH2:11]2)[CH2:12][CH2:13]1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CS(=O)(=O)OCCC1(CCOS(C)(=O)=O)COC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCC3(CC2)COC3)c(OC)c1
Yield: 65.2 %

Procedure:
To a solution of (124) (2.0 g, 6.6 mmol) in MeCN (20 mL) were added 2,4-dimethoxy-benzylamine (1.2 g, 7.3 mmol) and Et3N (2.0 g, 19.8 mmol). The solution was allowed to heat at reflux for 12 h. The reaction mixture was then filtered through a pad of silica (washing with 30 percent EtOAc:Petrol ether), and the solvent removed under reduced pressure to give the product (125) (1.2 g, 4.3 mmol, yield: 65%). ESI-MS (M+1): 278 calc. for C16H23NO3 277.
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.[NH:27]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@@H:28]([C:37](O)=[O:38])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][C@@H:28]([NH:27][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:37](=[O:38])[N:13]2[CH2:12][CH2:11][CH:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([F:2])([F:16])[F:17])[CH2:15][CH2:14]2)=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: FC(F)(F)c1ccccc1C1CCNCC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2C(F)(F)F)CC1
Yield: 69.1 %

Procedure:
The title compound was prepared according to the procedure described in Example 1 (Step f) from 4-[2-(trifluoromethyl)phenyl]piperidine hydrochloride (Step c) (0.792 g, 3.0 mmol), DIEA (0.54 mL, 3.0 mmol), Boc-p-Cl-D-PheOH (PepTech Corporation) (1.36 g, 4.5 mmol), HOAT (Aldrich) (0.615 g, 4.5 mmol) and EDC (Aldrich) (0.864 g, 4.5 mmol) in DMF (5 mL). Purification by silica gel chromatography (5:2 hexane:EtOAc) provided the title compound as a white foam (1.06 g). MS (ESI, pos. ion) m/z: 511 (M+1); MS (ESI, neg. ion) m/z: 509 (M−1). Calc'd for C26H30ClF3N2O3: 510.98.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](OCCOC)=[CH:7][CH:6]=1.[NH2:17][CH2:18][CH2:19][NH:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][O:25][CH2:24]1)=[O:22].CO.[CH2:31]([O:33][C:34](=O)C)[CH3:32]>C(OCC)(=O)C>[CH3:34][O:33][CH2:31][CH2:32][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:16][NH:17][CH2:18][CH2:19][NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][O:25][CH2:24]2)=[O:22])=[CH:10][CH:9]=1
Reactant: NCCNC(=O)C1CCCOC1
Reactant: CCOC(C)=O
Reactant: COCCOc1ccc(OCC2CO2)cc1
Solvent: CO
Product: COCCc1ccc(OCC(O)CNCCNC(=O)C2CCCOC2)cc1

Procedure:
5 g of 1-(2,3-epoxypropoxy)-4-(2-methoxyethoxy)benzene and 6 g of N-(2-aminoethyl)tetrahydropyran-3-carboxamide are heated together at 130° for 30 minutes. The mixture is allowed to cool and then dissolved in ethyl acetate and worked up in the usual manner. The title compound is obtained (M.P. 107°-108°--from methanol/ethylacetate).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=O.Cl.[OH:18][NH2:19]>N1C=CC=CC=1>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[N:19][OH:18]
Reactant: NO
Reactant: COc1cccc(C(=O)c2sccc2Br)c1
Agent: Cl
Solvent: c1ccncc1
Product: COc1cccc(C(=NO)c2sccc2Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture prepared from 7 g of (3-bromothien-2-yl) (3-methoxyphenyl)methanone, 3.09 g of hydroxyamine hydrochloride and 40 ml of pyridine was stirred at room temperature overnight and thereafter heated at 100°-115° C. for 4 hours. The mixture was then quenched with water, the organics were extracted into ether, and the ether solution was washed with 3N hydrochloric acid and water and dried over anhydrous magnesium sulfate. Evaporation of the ether left a residue which crystallized upon standing overnight. The crude solid was passed through a column (alumina packed in hexane) with 15% ether/hexane used as an eluent. The solid was recrystallized from ether/hexane to give a crystalline product (6.4 g, m.p. 100°-103° C.).
Reaction SMILES: CC[N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1[C:51]([C:59]2[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=2)=CN2C=CC=CC=12>CN(C=O)C>[N:3]1[CH:4]=[CH:6][C:51]([C:59]2[CH:60]=[C:61]([NH:65][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=2)=[CH:9][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccncc4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 75.9 %

Procedure:
DIEA (43.5 μL, 0.25 mmol) was added to 8-methoxy-3-carboxy-coumarin (50.0 mg, 0.23 mmol) and HATU (95.0 mg, 0.25 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (38.7 mg, 0.23 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 65.0 mg of product in 76% yield: LCMS (ESI) m/z 373 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[C:36]([C:37](Cl)=[O:38])=[C:35]([CH3:40])[O:34][N:33]=1.[OH-].[Na+]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:16][N:15]([CH3:17])[C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:12][CH:11]([NH:14][C:37]([C:36]2[C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[Cl:25])=[N:33][O:34][C:35]=2[CH3:40])=[O:38])[CH2:10][CH2:9]1
Reactant: CN(C)C1(c2cccc(F)c2)CCC(N)CC1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NC1CCC(c2cccc(F)c2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The non-polar diastereoisomer of 1-(3-fluorophenyl)-N,N-dimethylcyclohexane-1,4-diamine (350 mg) was placed with 220 μI triethylamine (1.05 molar equivalents) and catalytic amounts of DMAP (about 5 mg) in 3.5 ml dichloromethane, 400 mg 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonylchloride (1.05 molar equivalents), dissolved in 2 ml dichloromethane, were added dropwise at −10° C. to and the mixture was stirred overnight while being heated to room temperature. For working up, the mixture was made alkaline (pH>10) with 2-molar sodium hydroxide solution, with ice cooling, the organic phase was separated, the aqueous phase extracted with dichloromethane (20 ml) and the combined organic phases dried over sodium sulphate, filtered and evaporated to dryness. The resultant crude product (690 mg) was chromatographed on silica gel (4.0×15 cm) with methanol/ethyl acetate (V:V=1:1). 530 mg of the non-polar diastereoisomer of 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxylic acid [4-dimethylamino-4-(3-fluorophenyl)cyclohexyl]amide were obtained, which, dissolved in 50 ml 2-butanone were converted overnight into the corresponding hydrochloride by adding 21 μl water and 150 μl chlorotrimethylsilane, then evaporating to dryness, and stirring with 10 ml ethyl acetate (380 mg, Mp. 231-232° C.).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([O:15]C)=O)[CH3:5].O>C1COCC1>[CH3:5][N:4]([N:6]=[N:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([NH:2][CH3:1])=[O:15])[CH3:3]
Reactant: COC(=O)c1sccc1N=NN(C)C
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1sccc1N=NN(C)C
Temperature: 25 °C
Reaction time: 36 h
Yield: 76 %

Procedure:
To an ice cold (0-5° C.) solution of methyl amine (3 mL) in THF (5 mL) was added a solution of methyl 3-[(dimethylamino)diazenyl]thiophene-2-carboxylate (500 mg) in THF (5 mL) for 5 min and stirred at rt for 36 h. The solution was poured into ice cooled water and the solution was extracted with chloroform (3×100 mL). The combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (98:2) as eluents to give the product, which was recrystallized from chloroform-hexane gave the product as a pale orange color solid (380 mg, 76%), mp 98-102° C. IR (neat) νmax 3297, 3082, 2929, 1637, 1380, 1348, 1299, 1221, 1109, 1016, 882, 776 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.35 (1H, br s), 7.29 (1H, d, J=5.2 Hz), 7.27 (1H, d, J=5.2 Hz), 3.57 (3H, br s), 3.21 (3H, br s), 3.00 (3H, d, J=4.8 Hz); LC-MS (positive ion mode): m/z 213 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8](=[NH:10])[NH:7][C:6]=1[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>O1CCCC1>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:25](=[O:26])[C:24]2[CH:28]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=2[O:29][CH3:30])/[NH:7][C:6]=1[CH3:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1[nH]c(=N)sc1C(C)(C)C
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)/N=c1/[nH]c(C)c(C(C)(C)C)s1
Temperature: 60 °C
Reaction time: 18 h
Yield: 96.4 %

Procedure:
A mixture of 5-tert-butyl-4-methylthiazol-2(3H)-imine (250 mg, 1.5 mmol) in tetrahydrofuran (10 mL) was treated with triethylamine (0.25 mL, 1.8 mmol) and 5-chloro-2-methoxybenzoylchloride (307 mg, 1.5 mmol). The reaction mixture was stirred at 60° C. for 18 hours then concentrated under reduced pressure. The residue was diluted with ethyl acetate and H2O. The organic extract was dried over MgSO4, filtered, concentrated under reduced pressure and dried under vacuum to afford the title compound (490 mg, 96% yield). MS (ESI) m/z 339 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][CH2:9][OH:10])[CH:2]=1.[C:11]1([CH3:22])[CH:16]=[CH:15][C:14]([S:17]([O:20]C)(=[O:19])=[O:18])=[CH:13][CH:12]=1>CC(C)=O>[C:11]1([CH3:22])[CH:12]=[CH:13][C:14]([S:17]([O-:20])(=[O:18])=[O:19])=[CH:15][CH:16]=1.[OH:10][CH2:9][CH:8]=[CH:7][C:3]1[CH:2]=[N+:1]([CH3:11])[CH:6]=[CH:5][CH:4]=1
Reactant: OCC=Cc1cccnc1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CC(C)=O
Product: C[n+]1cccc(C=CCO)c1
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
Ethyl 3-(3-pyridyl)acrylate was reduced using lithium aluminum hydride to give 3-(3-pyridyl)-2-propen-1-ol. In 30 ml of acetone 710 mg of 3-(3-pyridyl)-2-propen-1-ol and 980 mg of methyl p-toluenesulfonate were heated under reflux for 22 hours. The reaction mixture was subjected by decantation to remove the solvent and then washed with acetone and ether. The residue was dried under reduced pressure to give 1.3 g of the desired compound as an orange-colored oil.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][OH:21])[O:16]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>CN(C)C1C=CN=CC=1.C(#N)C>[CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][O:21][C:29](=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[O:16]2)[CH2:2][CH2:3]1
Reactant: CCCCCCC(=O)Cl
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCC(=O)OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 51.4 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.310 g, 1.1 mmoles), 4-dimethylaminopyridine (10 mg, 0.1 mmoles, Aldrich Chemical Co., Madison, Wis.), and triethylamine (1.0 mL, 7 mmoles, Aldrich Chemical Co., Madison, Wis.) were dissolved in 50 mL acetonitrile. Heptanoyl chloride (800 μm, 5.0 mmoles, Aldrich Chemical Co., Madison, Wis.) was added and the reaction was stirred at room temperature for 6 hours. The reaction was quenched with methanol and solvents were evaporated in vacuo. The residue was dissolved in acetone and passed over a silica gel column (4.8×13 cm). The product containing fractions were combined, concentrated, and loaded onto preparative silica gel plates (20×20×0.2 cm). The plates were developed in a mixture of chloroform:acetone (80:20). The product was scraped from the preparative plate (Rf 0.5) and eluted from the silica gel with ethanol. After evaporation of the solvent the product was further purified on a Chromatotron (2 mm silica gel plate) with a mixture of hexane:acetone (80:20). Lyophilization afforded 0.227 g of 6-(cyclopropylmethylamino)-9-[(2R,5S)-5-[(heptanoyloxy)methyl]-tetrahydro-2-furyl]-9H-purine as an oil (51% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[H-].[Na+].[N+:28]([C:31]1[CH:32]=[C:33]([S:37]([CH2:40][CH2:41][O:42][C:43](=[O:65])[CH2:44][CH2:45][CH2:46][NH:47][C:48](=[O:64])[CH2:49][O:50][C:51]2[CH:56]=[CH:55][C:54]([S:57](Cl)(=[O:59])=[O:58])=[C:53]([CH:61]([CH3:63])[CH3:62])[CH:52]=2)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1)([O-:30])=[O:29].O>C(Cl)Cl>[N+:28]([C:31]1[CH:32]=[C:33]([S:37]([CH2:40][CH2:41][O:42][C:43](=[O:65])[CH2:44][CH2:45][CH2:46][NH:47][C:48](=[O:64])[CH2:49][O:50][C:51]2[CH:56]=[CH:55][C:54]([S:57]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:3]3[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=3)=[O:16])(=[O:59])=[O:58])=[C:53]([CH:61]([CH3:62])[CH3:63])[CH:52]=2)(=[O:38])=[O:39])[CH:34]=[CH:35][CH:36]=1)([O-:30])=[O:29]
Reactant: CC(C)c1cc(OCC(=O)NCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)ccc1S(=O)(=O)Cl
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(=O)NCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc1C(C)C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a heterogeneous mixture of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-ylmethanesulfinyl]-1H-benzimidazole (500 mg, 1.36 mmol) in CH2Cl2 (10 mL) was added NaH (40 mg, 1.65 mmol) at room temperature resulting in a clear solution. To this clear mixture was added 4-(4-chlorosulfonyl-3-Isopropylphenoxyactamido)-butyric acid 2-(3-nitrobenzenesulfonyl)ethyl ester (Intermediate 26, 1.0 g, 1.70 mmol, 1.25 eq) in CH2Cl2 (5 mL) at room temperature, and then the mixture was stirred for 2 h. Thereafter water was added, the mixture was extracted with CH2Cl2, the organic layers were dried and concentrated under reduced pressure. The residual oil was purified by column chromatography (CH2Cl2 to 3% MeOH in CH2Cl2) to yield Intermediate 27 (1.0 g, 80%) as an off-white foam.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Br.[N-:11]=[N+:12]=[N-:13].[Na+].[N-]=[N+]=[N-]>O>[N:11]([CH2:4][C:3]1[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:6]=1[F:10])=[N+:12]=[N-:13]
Reactant: Fc1cccc(F)c1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCc1c(F)cccc1F
Temperature: 25 °C
Yield: 93.6 %

Procedure:
To a 250 ml round bottom flask, 2,6-difluorobenzylbromide (0.024 mol, 5 g), sodium azide (0.026 mol, 1.72 g) and water (50 ml) were charged. The reaction mixture was heated to 70° C. to 75° C. for 30 hours and formation of azide intermediate (99.4%) was monitored by gas chromatography. After completion of the reaction, the contents were cooled to room temperature. The layers of the reaction mixture were separated to obtain an upper water layer and a lower azide intermediate layer. The lower layer was then concentrated and dried under vacuum to obtain 3.8 g of the product.
Reaction SMILES: [C:1]([N:4]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:5]1[CH2:10][C:9]([CH:11]=O)=[N:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1=[O:20])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].Cl.[CH2:34]([O:36][NH2:37])[CH3:35]>CCO>[C:1]([N:4]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:5]1[CH2:10][C:9](/[CH:11]=[N:37]/[O:36][CH2:34][CH3:35])=[N:8][N:7]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C:6]1=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(=O)OC(C)(C)C)N1CC(C=O)=NN(C(=O)OC(C)(C)C)C1=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCO/N=C/C1=NN(C(=O)OC(C)(C)C)C(=O)N(N(C(C)=O)C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-[acetyl(tert-butoxycarbonyl)amino]-6-formyl-3-oxo-5H-1,2,4-triazine-2-carboxylate (192 mg, 0.500 mmol) and sodium acetate (45 mg, 0.55 mmol) in EtOH (1.0 mL) at room temperature was added O-ethylhydroxylamine HCl-salt (54 mg, 0.55 mmol). The mixture was heated to 70° C. and stirred for 2 h. The obtained reaction mixture was filtered hot and the solid residual washed with EtOH. The filtrate was concentrated to give the desired product which was used without further purification. LCMS (Method I) RT 1.94 min. [M+Na]+ 450.