Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:25]=[CH:24][C:9]([CH2:10][NH:11][C:12]2[O:13][C:14]3[C:19]([C:20](=[O:23])[C:21]=2[CH3:22])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:7]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C>ClCCl>[CH3:22][C:21]1[C:20](=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13][C:12]=1[NH:11][CH2:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])=[CH:25][CH:24]=1
Reactant: Cc1c(NCc2ccc(CCCCO)cc2)oc2ccccc2c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCc2ccc(CNc3oc4ccccc4c(=O)c3C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
To a solution of 2-[4-(4-hydroxy-butyl)-benzylamino]-3-methyl-chromen-4-one (100 mg, 0.30 mmol) in dichloromethane (37 mL) was added p-toluenesulfonylchloride (68 mg, 0.36 mmol), dimethylaminopyridine (43.4 mg, 0.36 mmol), and triethylamine (62 μL, 0.44 mmol) in a 0° C. ice bath. The reaction slurry stirred overnight under N2 atmosphere, warming to room temperature slowly overnight. The next day, the reaction mixture was concentrated and purified by flash column chromatography (3:1→1:1 Hexane:ethyl acetate →100% ethyl acetate) to obtain the product as an oil (45 mg, 31% yield). 1H NMR (600 MHz, CDCl3): δ 8.19 (dd, 1H, J=1.5 and 7.9 Hz), 7.76 (d, 2H, J=8.3 Hz), 7.76 (m, 1H), 7.32 (d, 2H, J=7.9 Hz), 7.29 (d, 2H, J=8.1 Hz), 7.26 (d, 2H, J=8.0 Hz), 7.13 (d, 2H, J=8.0 Hz), 4.90 (t, 1H, J=5.1 Hz), 4.64 (d, 2H, J=5.6 Hz), 4.02 (t, 2H, J=5.9 Hz), 2.57 (t, 2H, J=7.3 Hz), 2.43 (s, 3H), 1.96 (s, 3H), 1.65 (m, 4H); 13C NMR (150 MHz, CDCl3): δ 174.9, 160.2, 152.8, 144.7, 141.5, 135.4, 133.1, 131.4, 129.8, 128.9, 127.9, 127.7, 125.9, 124.6, 122.8, 116.2, 93.4, 70.3, 45.5, 34.7, 28.4, 27.1, 21.6, 7.6.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8](C(O)=O)[CH:7]=1.C1C=CC(P([N:28]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.O>C1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([NH2:28])[CH:7]=1
Reactant: O=C(O)c1cc(-c2ccco2)on1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: Nc1cc(-c2ccco2)on1
Yield: 40 %

Procedure:
To a solution of 2.0 g of 5-furan-2-yl-isoxazole-3-carboxylic acid and 6.2 mL of TEA in benzene was added 3.61 mL of DPPA at room temperature. After refluxing for 1.5 hrs, 30 mL of distilled water was added and then the resulting solution was refluxed for an additional 30 min. The reaction solution was concentrated under reduced pressure, and the concentrate was purified by column chromatography on silica gel to obtain 0.6 g of 5-furan-2-yl-isoxazol-3-ylamine (Yield: 40%).
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][C:5]([OH:7])=O)#[N:2].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:24]=1[NH2:25].Cl.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[C:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][C:5]([NH:25][C:24]1[C:26]([O:32][CH3:33])=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:23]=1[O:22][CH3:21])=[O:7])#[N:2]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: N#CC(CC(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC)c(NC(=O)CC(C#N)c2ccccc2)c(OC)c1
Temperature: 25 °C

Procedure:
To a dichloromethane (150 mL) solution of 3-cyano-3-phenylpropionic acid (5 g, 0.0286 mol) at 0° C. under a nitrogen atmosphere was added triethylamine (4 mL, 0.0286 mol) and 2,4,6-trimethoxyaniline.HCl (6.3 g, 0.0286 mol). To this solution was added DCC (6.2 g, 0.29 mol). The resulting mixture was allowed to warm to room temperature over 3 hours. This was then filtered and the filtrate partitioned between 1N HCl and dichloromethane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid (5.1 g) was recrystallized from dichloromethane/hexanes, mpt 157°-160° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([NH:17][C:18]4[N:19]=[C:20]([C:24]([OH:26])=O)[N:21]([CH3:23])[CH:22]=4)=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:27])[NH:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[C:50]([NH2:54])([CH3:53])([CH3:52])[CH3:51].C(N(CC)C(C)C)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[C:50]([NH:54][C:24]([C:20]1[N:21]([CH3:23])[CH:22]=[C:18]([NH:17][C:15]([C:10]2[CH:11]=[CH:12][C:13]3[CH:14]=[C:6]4[C:5](=[O:27])[NH:4][CH2:3][C:2]([CH3:28])([CH3:1])[N:7]4[C:8]=3[CH:9]=2)=[O:16])[N:19]=1)=[O:26])([CH3:53])([CH3:52])[CH3:51]
Reactant: Cn1cc(NC(=O)c2ccc3cc4n(c3c2)C(C)(C)CNC4=O)nc1C(=O)O
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(NC(=O)c2ccc3cc4n(c3c2)C(C)(C)CNC4=O)nc1C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
To a solution of 4-{[(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-7-yl)carbonyl]amino}-1-methyl-1H-imidazole-2-carboxylic acid (104 mg, 0.27 mmol) in DMF (2 mL) are added N-hydroxybenzotriazole (74 mg, 0.55 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (105 mg, 0.55 mmol). After stifling for 10 min at 50° C., tert-butylamine (0.06 mL, 0.55 mmol), N,N-diisopropylethylamine (0.10 mL, 0.55 mmol) and 4-dimethylaminopyridine (6.7 mg, 0.06 mmol) are added. The reaction mixture is stirred at room temperature for 8 h. The solvent is removed under N2 stream to afford the crude compound which is purified by flash column chromatography to afford the title compound (61 mg, 51%). LCMS (ESMS): m/z 437.78 (M+H+).
Reaction SMILES: [C:1]1([O:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[N:24]2[N:25]=[CH:26][N:27]=[C:23]2[N:22]=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[C:1]1([O:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:19]2[N:24]3[N:25]=[CH:26][N:27]=[C:23]3[N:22]=[CH:21][CH:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccnc2ncnn12
Reactant: c1ccc2c(OC[C@H]3CCCN3)cccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: c1ccc2c(OC[C@H]3CCCN3c3ccnc4ncnn34)cccc2c1

Procedure:
400 mg of (R)-2-(naphthalen-1-yloxymethyl)pyrrolidine, 500 mg of the 7-chloro-[1,2,4]triazolo[1,5-a]pyrimidine prepared above and 650 mg of N-ethyldiisopropylamine are heated at 130° C. in a microwave for 3 h in 40 ml of 1-butanol. The butanol is subsequently removed in vacuo, the residue is taken up in ethyl acetate, mixed with water, adjusted to pH 12 using 1 N NaOH solution, phases are separated, the organic phase is dried over sodium sulfate, evaporated and chromatographed on silica gel, giving 640 mg of “A1”; m.p. 74-75°;
Reaction SMILES: N1C=CC=CC=1NC1C=CC=CC=1N.[CH3:15][O:16]C1C=C(C=CC=1)/C=C/C(Cl)=O.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1/[CH:43]=[CH:44]/[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1/[CH:43]=[CH:44]/[C:45]1[CH:46]=[CH:47][C:48]([O:16][CH3:15])=[CH:49][CH:50]=1
Reactant: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Reactant: COc1cccc(/C=C/C(=O)Cl)c1
Agent: Nc1ccccc1Nc1ccccn1
Product: COc1ccc(/C=C/c2nc3ccccc3n2-c2ccccn2)cc1

Procedure:
The titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-3-methoxycinnamoyl chloride (Wiesler, W. T.; Nakanishi, K. J. Am. Chem. Soc., 1990, 112, 5574) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). MW: 327.39; mp: 145.5-146.5° C.; 1H-NMR (CDCl3) δ: 8.81-8.76 (1H, m), 8.04-7.96 (1H, m), 7.98 (1H, d, J=16.1 Hz), 7.85-7.79 (1H, m), 7.56-7.41 (5H, m), 7.37-7.22 (3H, m), 7.00 (1H, d, J=16.1 Hz), 6.88 (1H, d, J=8.4 Hz), 3.83 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N+:6]([O-:13])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20](=O)([O-])[O-].[K+].[K+].[K].CI>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:20])[C:7](=[O:12])[N+:6]([O-:13])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)[n+]1[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=O)[n+]([O-])c(-c2ccccc2)c2cc(Cl)ccc21
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of 125 g (0.458 mole) of 6-chloro-4-phenyl-2(1H)quinazolinone 3-oxide, 3,250 ml of N,N-dimethylformamide and 75 g of powdered anhydrous potassium carbonate was heated to 50°. After heating for approximately 30 minutes at this temperature, an increased solubility of the suspended solid due to formation of the potassium salt of I was observed. At this point, 150 g (65.8 ml) of methyl iodide was added dropwise at a fast rate. The reaction with the methyl iodide was somewhat exothermic and caused the pot temperature to rise to 58°. Stirring at 50°-55° was continued for 1 hour. The contents of the flask were cooled and filtered and the solid obtained was thoroughly washed with water. The product, 6-chloro-1-methyl-4-phenyl-2(1H)quinazolinone 3-oxide was obtained in 80% yield (103.2 g), mp 253.5°-254°.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.Cl[C:15]1[CH:20]=[CH:19][N:18]([C@@H:21]2[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@@H:32]([O:33][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]2[O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17](=[O:54])[N:16]=1>C1COCC1.[Cu]I>[C:1]([C:15]1[CH:20]=[CH:19][N:18]([C@@H:21]2[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@@H:32]([O:33][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]2[O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17](=[O:54])[N:16]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(OC[C@H]1O[C@@H](n2ccc(Cl)nc2=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: C#CCCCC
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC#Cc1ccn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of bis-triphenylphosphine palladium (II) dichloride (0.35 g, 0.5 mmol) and copper (I) iodide (95 mg, 0.5 mmol) in THF (45 mL, distilled from Na-benzophenone ketyl) is sparged with dry argon gas for 10 min. To this suspension is added 1-hexyne (2.46 g, 30 mmol) followed by triethylamine (5 mL). The suspension is stirred at room temperature under argon for 15 min. A similarly sparged solution of the 2-chloro-1-(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)pyrimidin-4-one (13, 5.75 g, 10 mmol) in THF (15 mL) is added to the suspension of catalyst and the mixture stirred for 1 hr. The dark mixture is filtered through Celite and the filtrate evaporated in vacuo to afford a dark syrup. This syrup was triturated with cold diethylether, filtered and then dissolved in dichloromethane.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:10]([C:12]1[C:13](=[O:26])[N:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:19])[N:16]([CH3:18])[N:17]=1)=[O:11].C(N(CC)CC)C.[CH2:34]([S:37](Cl)(=[O:39])=[O:38])[CH2:35][CH3:36]>ClCCl>[CH2:34]([S:37]([O:1][C:2]1[N:6]([CH:7]([CH3:8])[CH3:9])[N:5]=[CH:4][C:3]=1[C:10]([C:12]1[C:13](=[O:26])[N:14]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15](=[O:19])[N:16]([CH3:18])[N:17]=1)=[O:11])(=[O:39])=[O:38])[CH2:35][CH3:36]
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(C)n1ncc(C(=O)c2nn(C)c(=O)n(-c3ccccc3)c2=O)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)Oc1c(C(=O)c2nn(C)c(=O)n(-c3ccccc3)c2=O)cnn1C(C)C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
0.85 g (2.60 mmol) of 6-(5-hydroxy-1-isopropyl-1H-pyrazol-4-yl carbonyl)-2-methyl-4-phenyl-1,2,4-triazine-3,5 (2H, 4H)-dione was dissolved in 20 ml of dichloromethane. To the solution, 0.27 g (2.60 mmol) of triethylamine and 0.37 g (2.60 mmol) of 1-propane sulfonyl chloride were added at room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residues were purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 0.71 g of the target compound (yield 63%).
Reaction SMILES: [OH:1][CH:2]([CH3:14])[CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2Cl.[NH3:15]>[Cl-].[NH4+]>[OH:1][CH:2]([CH3:14])[CH2:3][N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[NH2:15]
Reactant: N
Reactant: CC(O)Cn1cnc2c(Cl)ncnc21
Agent: [Cl-]
Agent: [NH4+]
Product: CC(O)Cn1cnc2c(N)ncnc21

Procedure:
9-(2-Hydroxy-1-propyl)-6-chloropurine (I, 9 g, 42.5 mmol) was dissolved in saturated methanolic ammonia and ammonium chloride (50 mg). The mixture was heated at 130° in a bomb for 6 hr. The resulting solution was evaporated to dryness and recrystallized from ethanol/acetone. Yield=6.68 g of a colorless crystalline product (81%); mp 193°-194°; uv (H2O; pH 5.5); λmax 260 nm; TLC in CHCl3 :MeOH (5:1); Rf 0.44.
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C(C)=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:36].S>C(O)C>[C:1]1([C:7]2[S:36][C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=3)=[CH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CC(C(=O)c1ccccc1)c1ccccc1)c1ccc(Cl)c(Cl)c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Solvent: Cc1ccccc1C
Solvent: CCO
Product: Clc1ccc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)cc1Cl
Yield: 177.8 %

Procedure:
In a 1-liter stainless steel autoclave equipped with electrically-driven stirrer were placed 38.3 g. (0.100 mole) of 1,2-diphenyl-4-(3,4-dichlorophenyl)butane-1,4-dione, 100 ml of xylene, 20 g of phosphorus pentasulfide and 140 g of hydrogen sulfide. The reactor was heated for three hours at 160°-164° C. The crude product remaining after cooling and venting the reactor was stirred with ethanol. Filtration gave 30.5 g (80%) of solid m.p. 101°-103° C. Recrystallization from 30 ml of dioxane and 60 ml of ethanol gave 22.5 g (59%) of pure product, m.p. 106.2°-107.8° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.[CH2:34]([S:36]([CH2:39][CH2:40]O)(=[O:38])=[O:37])[CH3:35]>C(#N)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:35][CH2:34][S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(O)c2ccccc2c1O
Reactant: CCS(=O)(=O)CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CCS(=O)(=O)CCOc1cc(C(=O)O)c(O)c2ccccc12
Temperature: 95 °C
Yield: 53 %

Procedure:
20.4 g (0.1 mol) of 1,4-dihydroxy-2-naphthoic acid and 19 g (0.1 mol) of p-toluenesulfonic acid were added to 200 ml of dehydrated toluene. To the mixture, 27.6 g (0.2 mol) of β-ethylsulfonylethanol was added dropwise for 30 minutes under heating at 95° C. with stirring. After heating with stirring for 7 hours, the mixture was cooled to 20° to 30° C. 100 ml of acetonitrile was added to the mixture, the solid deposited was separated by filtration to obtain 17.2 g (53%) of 1-hydroxy-4-(β-ethylsulfonylethoxy)-2-naphthoic acid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][N:14]=[N:13][C:12]=2[SH:16])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[K].[CH2:18](Br)[CH:19]=[CH2:20]>C(O)C>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:15][N:14]=[N:13][C:12]=2[S:16][CH2:20][CH:19]=[CH2:18])=[CH:9][CH:10]=1)([CH3:1])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)c1ccc(-c2snnc2S)cc1
Agent: [K]
Solvent: CCO
Product: C=CCSc1nnsc1-c1ccc(C(C)(C)C)cc1
Yield: 72.8 %

Procedure:
A solution of 1.45 g of 5-[4-(1,1-dimethylethyl)phenyl]-1,2,3-thiadiazole-4-thiol, potassium salt in 50 ml of ethanol was stirred overnight with 3.0 g of allyl bromide. The solvent was removed in vacuo, the residue taken up in ether, filtered and concentrated in vacuo. The residual oil was dissolved in a small amount of dichloromethane and purified on thick layer silica gel plates, eluting with the same solvent. The active fraction gave 1.225 g of the desired compound as a yellow oil. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90MHz: 1.39 (s, 9H, t-butyl); 3.98 (bd, 2H, SCH2); 5.05 (bd, 1H, CH=); 5.20 (bd, 1H, =CH); 5.87 (m, 1H, CH2CH=); 7.55 (s, 4H, C6H4). Infrared absorption spectrum (neat): 1640(w); 1615(w); 1525(w); 1480(w); 1475(w); 1450(w); 1410(w); 1370(w); 1270(w); 930(s); 820(s).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CCC(O)C1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][CH:26]([OH:25])[CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: OC1CCNC1
Product: CC(C)(C)c1nc(N2CCC(O)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and pyrrolidin-3-ol. MS (m/e): 387.4
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[N:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[CH:19][NH:18][CH2:17]2)=[CH:12][CH:11]=1.[OH-].[Na+]>>[N+:6]([CH:17]1[N:16]([C:13]2[CH:12]=[CH:11][N:10]=[CH:15][CH:14]=2)[CH:20]=[CH:19][NH:18]1)([O-:9])=[O:7]
Reactant: C1=CN(c2ccncc2)CN1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])C1NC=CN1c1ccncc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a stirred solution of sulfuric acid (21 ml, 95-97%) and HNO3 (15 ml, fum.) was added at 0° C. 3-(4-pyridinyl)-1H-imidazole [CAS No. 51746-87-3] (6.36 g, 43.8 mmol). The reaction mixture was stirred at room temperature for 45 min, at 55° C. for 23 h and at 100° C. for 2 h and poured into ice-water (200 ml). Sodium hydroxide solution (32%) was added to the stirred mixture until the pH reached 5-6, the precipitated product was collected by filtration and washed with water and hexane to yield 2-nitro-3-(4-pyridinyl)-1H-imidazole (7.95 g, 95%) as a light yellow solid; mp 234° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[OH2:25]>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)([O-:22])(=[O:21])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O
Agent: O[C@@H]1CCN(Cc2ccccc2)C1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 92 %

Procedure:
To a stirred solution of (R)-1-benzyl-3-pyrrolidinol (1.77 g, 10 mmol) in pyridine (30 ml) was added p-toluenesulfonyl chloride (9.53 g, 50 mmol) by portions a, 0° C. After 90 h stirring it room temperature, water was added to the reaction mixture and the mixture was extracted with ether (150 ml). The extract was washed with water brine, dried (Na2SO4), and concentrated to give 3.06 g (92%) of brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[C:12]([CH2:17][CH3:18])=[N:13][O:14][C:15]=2[CH3:16])=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]Cl>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])[C:9]([C:11]2[C:12]([CH2:17][CH3:18])=[N:13][O:14][C:15]=2[CH3:16])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCCl
Reactant: CCc1noc(C)c1C(=O)Nc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1noc(C)c1C(=O)N(CCN(C)C)c1cccc(F)c1
Temperature: 60 °C

Procedure:
A mixture of 22.0 grams (0.0887 mole) of N-m-fluorophenyl-3-ethyl-5-methyl-4-isoxazole carboxamide and 4.4 grams (0.0921 mole) of 50% sodium hydride in oil in 500 ml. of dimethylformamide is stirred at room temperature for five hours. The resulting mixture is treated by dropwise addition with 9.68 grams (0.09 mole) of 2-dimethylaminoethyl chloride). The resulting mixture is heated at 60° C. for 20 hours. The mixture is cooled, poured onto ice water and extracted with ether. The ether is washed with 2N hydrochloric acid and the aqueous acidic layer made basic with sodium hydroxide and extracted with methylene chloride. The methylene chloride extract is dried with magnesium sulfate and evaporated to give N-(m-fluorophenyl)-N-(2-dimethylaminoethyl)-3-ethyl-5-methyl-4-isoxazole carboxamide as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[NH2:16][CH2:17][CH:18]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20]>>[CH2:31]([O:30][C:28]([NH:27][CH:18]([C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:17][NH:16][C:13]([CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)=[O:14])=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: NCC(NC(=O)OCc1ccccc1)C(=O)N1CCCCC1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: O=C(NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1)OCc1ccccc1
Yield: 44 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 1-[-3-amino-2-(benzyloxycarbonylamino)propionyl]piperidine to give N-[2-(benzyloxycarbonylamino)-2-(piperidinocarbonyl)ethyl]-1-(4-pyridyl)piperidine-4-carboxamide in 44% yield;
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[N:10]=[CH:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7]1)=[NH:5])[CH3:2].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[CH3:33][C:34]1[CH:35]=[C:36]([S:47](Cl)(=[O:49])=[O:48])[CH:37]=[CH:38][C:39]=1[NH:40][C:41](=[O:46])[C:42]([F:45])([F:44])[F:43].Cl>CN(C=O)C>[CH2:7]1[C:8]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:9]=[N:10][N:6]1[C:4](=[N:5][S:47]([C:36]1[CH:37]=[CH:38][C:39]([NH:40][C:41](=[O:46])[C:42]([F:43])([F:44])[F:45])=[C:34]([CH3:33])[CH:35]=1)(=[O:49])=[O:48])[NH:3][CH2:1][CH3:2]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)C(F)(F)F
Reactant: CCNC(=N)N1CC2(C=N1)CCCC2
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=NS(=O)(=O)c1ccc(NC(=O)C(F)(F)F)c(C)c1)N1CC2(C=N1)CCCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35.8 %

Procedure:
To a solution of 0.23 g N-ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboxamidine in 5 mL dry DMF was added 0.87 mL (3.0 equiv.) BEMP and the light brown mixture was stirred for 10 minutes at room temperature. Subsequently, 0.33 g (1.1 equiv.) 3-methyl-4-(2,2,2-trifluoro-acetylamino)-benzenesulfonyl chloride was added in one portion and the resulting bright yellow solution was stirred overnight at room temperature. The mixture was cooled in an ice bath, acidified with 1 N HCl, and then extracted three times with EtOAc/Et2O 1:1. The combined organic layers were washed once with water, then with brine, dried over Na2SO4 and evaporated onto silica. Purification with flash chromatography (EtOAc/PA 4:6→5:5) yielded 0.18 g (39%) of a white solid. 1H NMR (400 MHz, CDCl3) δ 1.16 (t, J=7.2 Hz, 3H), 1.63-1.86 (m, 8H), 2.33 (s, 3H), 3.43-3.52 (m, 2H), 3.83 (s, 2H), 6.77-6.85 (br.s., 1H), 6.83 (s, 1H), 7.73-7.79 (m, 2H), 7.86 (d, J=8.3 Hz, 1H), 8.10 (br.s., 1H).