Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:13]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:11]=[C:7]([C:8]([OH:10])=O)[CH:6]=1)[CH3:2].O[N:23]1[C:27]2C=CC=C[C:26]=2N=N1.C(N)C>CN(C=O)C.ClCCl>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:13]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:11]=[C:7]([C:8](=[O:10])[NH:23][CH2:27][CH3:26])[CH:6]=1)[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)OCC)c1
Agent: CCN
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)c1cc(C(=O)NCC)cc(C(=O)OCC)c1
Yield: 98 %

Procedure:
Stir a solution of 5-(methyl-propylcarbamoyl)-isophthalic acid monoethyl ester (146 mg, 0.5 mmol), 1-hydroxybenzotriazole (74 mg, 0.55 mmol), 1-(3-dimethylamninopropyl)-3-ethylcarbodiimide hydrochloride (110 mg, 0.55 mmol), ethylamine (2 N in THF, 0.275 mL, 0.55 mmol) in 0.75 mL DMF at room temperature overnight. Dilute with dichloromethane (15 mL) and wash with water (5 mL), 0.1 N aqueous citric acid (5 mL), saturated aqueous sodium bicarbonate (5 mL), and saturated aqueous sodium chloride (5 mL). Dry (magnesium sulfate) and concentrate to give the title compound (157 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26].CCN(CC)CC>C1COCC1>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25](=[O:26])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C=Nc1ccccc1Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1Br
Reaction time: 3 h
Yield: 113.5 %

Procedure:
to a stirred mixture of tert-butyl 4-amino-3-methylphenylacetate (780 mg, 3.30 mmol), 2-bromo phenyl isocyanate (0.41 ml, 3.30 mmol) in THF (7 ml) was added Et3N (0.092 ml, 0.66 mmol) at room temperature. After 3 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane, to give tert-butyl 4-[N′-(2bromophenyl)ureido]-3-methylphenylacetate (1.57 g, 93%) as a pale yellow powder. mp 138-145° C. (dec.); 1H-NMR (CDCl3) δ1.44 (s, 9H), 2.33 (s, 3H), 3.51 (s, 2H), 6.90 (dt, J=9.0, 1.4 Hz, 1H), 7.18-7.31 (m, 4H), 7.39 (dd, J=8.1, 2.9 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 8.22 (d, J=8.3 Hz, 2H); Anal. Calcd. for C20H22BrN2O3.0.2H2O: C, 56.80; H, 5.58; N, 6.62. Found: C, 56.85; H, 5.42; N, 6.62.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH3:10]
Reactant: O=Cc1ccccn1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1ccccn1

Procedure:
prepared by reaction of pyridine-2-carboxaldehyde with 2M ethylamine in THF.
Reaction SMILES: [C:1](=[S:4])([NH2:3])[CH3:2].Br[CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]1=O>C(O)C>[CH3:2][C:1]1[S:4][C:10]2[C:11](=[O:12])[CH2:6][CH2:7][CH2:8][C:9]=2[N:3]=1
Reactant: CC(N)=S
Reactant: O=C1CCCC(=O)C1Br
Solvent: CCO
Product: Cc1nc2c(s1)C(=O)CCC2

Procedure:
To a solution of ethanethioamide (0.75 g, 10 mmol) in ethanol (20 mL) at room temperature was added 2-bromocyclohexane-1,3-dione (1.9 g, 10 mmol) in portions. The reaction solution was refluxed for 2 hours while stirring. After removal of solvents, the residue was diluted with water and washed with diethyl ether. The separated aqueous layer was basified with sodium carbonate solution. The resulting solid was collected by vacuum filtration, rinsed with water. The solid was suspended in methanol and followed by evaporation to dryness to produce the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.O.[NH2:10][NH2:11].CC(O)CC>O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:10][NH2:11])=[N:3][CH:4]=1
Reactant: NN
Reactant: Brc1ccc(Br)nc1
Solvent: O
Solvent: CCC(C)O
Product: NNc1ccc(Br)cn1
Reaction time: 20 h
Yield: 87 %

Procedure:
A 12 L three-necked round-bottomed flask equipped with a mechanical stirrer and a condenser, connected on top with a nitrogen bubbler and a thermometer, was charged with 2,5-dibromopyridine (442 g, 1.87 moles), hydrazine hydrate (55% wt., 1057 ml, 18.7 moles), poly(ethylene glycol) (average Mn about 300, 1.87 L), 2-butanol (373 ml) and water (1.87 L). The mixture was heated at reflux for 29 hours. The heating source was removed and the mixture was stirred for an additional 20 hours. To the resulting slurry, cold water (2.2 L) was added. The slurry was stirred for an additional 30 minutes and filtered. The cake was washed with cold water (3×200 ml) and dried in a vacuum-oven (40° C.) for 48 hours. The title compound was obtained as off-white flakes (305 g, yield 87%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4](Cl)[CH:3]=1.[CH3:12][NH2:13]>[Cu]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([NH:13][CH3:12])[CH:3]=1
Reactant: CN
Reactant: CC(=O)c1ccc(F)cc1Cl
Agent: [Cu]
Product: CNc1cc(F)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4'-fluoro-2'-chloroacetophenone (40 g), methylamine (33% w/w solution in industrial methylated spirit, 60 ml), industrial methylated spirit (40 ml) and copper powder (0.5 g) was stirred at 80° in a sealed pressure vessel for 3 hours. After cooling to ambient temperature, the reaction mixture was transferred to a conical flask. The reaction vessel was washed out with industrial methylated spirit (2×30 ml) and the washings added to the reaction mixture. Sodium sulphide nonahydrate (2.3 g) in water (23 ml) was added and the mixture heated at 50° for 10 minutes. The mixture was filtered through diatomaceous earth (sold under the trade name CELITE). Solvent was removed from the filtrate under reduced pressure at 40° and hydrochloric acid (5M, 160 ml) was added to the residue. The mixture was stirred for approximately 2 hours and then extracted with dichloromethane (100 ml, then 2×60 ml). The combined extracts were dried over magnesium sulphate and evaporated to give the novel compound 4'-fluoro-2'-(methylamino)acetophenone as an oil which solidified on storing at ambient temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1COCC1>[N:1]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ccccn1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2ccccc2n1
Yield: 60.3 %

Procedure:
A solution of 2-aminopyridine (5.0 g, 53.2 mmol) in THF (150 mL) was treated with ethyl bromopyruvate (10.32 g, 57.0 mmol) at room temperature followed by heating the mixture at reflux for 16 h. The resulting white precipitate was collected by filtration and washed with THF (10 mL). Recrystallization of the solids from boiling EtOH (20 mL) gave ethyl imidazo[1,2-a]pyridine-2-carboxylate (6.10 g, 60% yield). ESI MS: m/z 191 [M+1]+. See, e.g., J. Med. Chem., 2003, 46, 3914-29.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][C:18]([OH:26])([CH2:19]3)[CH2:17]1)[CH2:23]2)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@H:27]12[CH2:32][C@H:31]1[CH2:30][C@@H:29]([C:33]([NH2:35])=[O:34])[NH:28]2.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:33]([C@@H:29]1[CH2:30][C@H:31]2[C@H:27]([CH2:32]2)[N:28]1[C:13](=[O:14])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][C:18]([OH:26])([CH2:19]3)[CH2:17]1)[CH2:23]2)(=[O:34])[NH2:35]
Reactant: NC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1
Reactant: O=C(N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](NC(=O)OCc1ccccc1)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
(2S)-2-{[(Benzyloxy)carbonyl]amino}-2-(3-hydroxyadamantan-1-yl)acetic acid of Formula-XIV (20 gm), 1-ethyl-3-(3-dimethyl aminoporpyl)carbodiimide (13.8 gm), (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide of formula-III (14.8 gm) and 1-hydroxy benzotriazole (10.2 gm) were dissolved in N,N-dimethyl formamide (80 ml). The reaction mixture was cooled to about 20° C. Addition of N,N-diisopropylethylamine (15.8 gm) was then carried out for 15 min. The reaction mixture was stirred for 4 hrs and the solvent was distilled off. To the residue 2N HCl solution was added. Aqueous phase was extracted with ethyl acetate. Organic phase was washed with NaHCO3 solution, dried and evaporated to yield 23.3 gms (90%) of title product. MP: 105-106° C., H1NMR (300 MHz, CDCl3): 0.81 (dd, 1H), 0.96 (m, 1H), 1.46-1.82 (m, 12H), 1.93 (s, 1H), 2.2 (m, 3H), 2.45 (dd, 1H), 3.6 (m, 1H), 4.5-4.61 (dd, 1H), 4.76-4.86 (dd, 1H), 5.0 (s, 2H), 5.34 (d, 1H), 5.69 (s, 1H), 5.82-5.85 (dd, 1H), 6.83-6.89 (s, 1H), 7.31-7.35 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=O)[CH2:12]2)[N:3]=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH2:28][NH2:29].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH2:28][NH:29][C:17]([C@H:13]1[CH2:14][CH2:15][CH2:16][C@@H:11]([NH:10][C:4]2[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH:8][CH3:9])[N:5]=2)[CH2:12]1)=[O:19]
Reactant: CNc1nc(C)nc(NC2CCCC(C(=O)O)C2)n1
Reactant: NCc1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CNc1nc(C)nc(N[C@@H]2CCC[C@H](C(=O)NCc3ccc(Cl)cc3Cl)C2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.5 %

Procedure:
To a solution of 3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxylic acid (100 mg, 0.377 mmol) was added [(2,4-dichlorophenyl)methyl]amine (82 mg, 0.47 mmol), DMAP (10 mg, 0.08 mmol) and EDCl (108 mg, 0.56 mmol). The mixture was stirred at room temperature for 4 h. The mixture was filtered and the filtrate concentrated. The crude product was purified by HPLC to provide 55 mg (0.13 mmol, 35% yield) of the desired material as a single major racemic diastereomer. MS (ES+): m/e 423.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[N+](C1C=CC([O:33][S:34]([C:37]([F:40])([F:39])[F:38])(=O)=[O:35])=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:35])=[O:33])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1O
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.4 %

Procedure:
After dissolving 6-methoxy-4-(4-nitrophenoxy)quinolin-7-ol (1.0 g) in dimethylfbrmamide (10 ml), there were added trifluoromethanesulfonic acid4-nitrophenyl ester (640 mg) and potassium carbonate (1.3 g), and the mixture was stirred at room temperature for 5 hours. Water was added, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was used for recrystallization to obtain the title compound (1.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Br)[CH3:2].[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][O:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:21][CH:20]=1)[CH3:2]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Ethylbromoacetate (4.17 g, 25 mmol) was added to a mixture of 4-benzyloxyphenol (5.00 g, 25 mmol) and K2CO3 (3.50 g, 25 mmol) in DMF (75 mL) and stirred for 20 hours at ambient temperature. The mixture was then concentrated in vacuo and the residue partitioned between water and EtOAc. The aqueous phase was further extracted with 2×50 mL of EtOAc and the combined extracts were washed with 2×50 mL of water and dried over Na2SO4. Concentration of the organic solution in vacuo left 7.00 g (97%) of product as a white solid. m.p. 65-68° C.
Reaction SMILES: [Cl:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.S(Cl)([Cl:12])=O>C(Cl)(Cl)Cl.C1C=CC=CC=1>[Cl:1][C:2]1[O:6][N:5]=[C:4]([C:7]([Cl:12])=[O:9])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)on1
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1cc(Cl)on1

Procedure:
A solution of 5-chloroisoxazole-3-carboxylic acid (0.750 g, 4.32 mmol, 1 equiv) and thionyl chloride (9.0 mL, 120 mmol, 28 equiv) in CHCl3 (21 mL) was heated to reflux for 28 h. The volatiles were evaporated to provide a residue which was dissolved in benzene (40 mL), which was subsequently evaporated to give the title intermediate as a yellow oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:18]([O-])=O)[CH:4]=1.[H][H]>CCOC(C)=O.[Pd]>[NH2:18][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: [H][H]
Reactant: COCCOc1cc(C(=O)OC)c([N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCOc1cc(C(=O)OC)c(N)cc1OC
Yield: 92.6 %

Procedure:
According to the procedure described in Example 6A Step 3, a mixture of methyl 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoate (3.67 g, 12.9 mmol) and Pd/C (10%, 0.4 g) in EtOAc (60 mL) was stirred under 1 atmosphere of hydrogen at room temperature overnight, to afford methyl 2-amino-4-methoxy-5-(2-methoxyethoxy)benzoate as a solid (3.05 g, 93%). 1H NMR (300 MHz, DMSO-d6) δ 7.15 (s, 1H), 6.46 (s, 2H), 6.36 (s, 1H), 3.91 (m, 2H), 3.75 (s, 3H), 3.74 (s, 3H), 3.59 (m. 2H), 3.32 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH2:17]([SH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CS(C)=O>[C:18]1([CH2:17][S:24][C:8]2[C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cccnc1SCc1ccccc1
Yield: 49.07 %

Procedure:
In a stirred suspension of 96.37 gm potassium carbonate in 700 gm dimethyl sulphoxide, 100 gm 2-chloro nicotinic acid was charged. A solution of 82.38 gm benzyl mercaptan in 300 gm dimethyl sulphoxide was added in a period of two hours maintaining reaction temperature 80-90 deg. c. The temperature of the reaction was raised up to 140 deg. c. and then maintained for another three hours. 500 gm water was added after completion of the reaction and solvent recovery. Product precipitation achieved by lowering the pH of the reaction mass by using dilute HCl. Product 2-(Phenyl methyl thio)-3-pyridine carboxylic acid precipitated completely till pH 4.5. After filtration and washing, cake was dried to get 75.5 gm white to off white solid product 2-(Phenyl methyl thio)-3-pyridine carboxylic acid with 49.07% yield (Assay by HPLC 99.16%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=O)[CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C(O)(=O)C.O.[NH2:22][NH2:23].C([O-])(O)=O.[Na+]>O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:23][N:22]=1)=[O:16])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)[nH]n1
Yield: 87.7 %

Procedure:
A solution of 2,4-dioxo-4-phenyl-butyric acid ethyl ester (1.68 g, 0.0076 mole), acetic acid (10 mL) and hydrazine hydrate (0.42 g, 0.0083 mole) was heated to reflux for 5 hours. The reaction mixture was then poured into iced water, basified with saturated aqueous NaHCO3 solution and the product was extracted with ethyl acetate. The ethyl acetate layer was collected and washed with brine solution, dried over sodium and concentrated under reduced pressure. The resulting residue was purified by column chromatography using basic aluminium oxide (50% ethyl acetate in hexane) to afford 1.442 g (88%) of 5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 217.09 (M+1)+, 97.92%. To a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.4 g, 0.00667 mol) in a mixture of THF (30 mL), methanol (15 mL) and H2O (10 mL) was added LiOH.H2O (0.839 g, 0.0199 mol) at ambient temperature. The resulting mixture was stirred at 45° C. overnight. Volatiles were evaporated and the residue was diluted with water, acidified with concentrated HCl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 1.26 g (86%) of 5-phenyl-1H-pyrazole-3-carboxylic acid. LCMS: 189.06 (M+1)+, 97.7%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17]>C(O)(=O)C>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:16][NH:17][C:4]2=[O:5]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: N=CN
Solvent: CC(=O)O
Product: O=c1[nH]cnc2ccc(I)cc12
Temperature: 130 °C
Yield: 99.8 %

Procedure:
A mixture of 2-amino-5-iodobenzoic acid (9.00 g, 34.2 mmol) and formamidine acetate (18.00 g, 173 mmol) in acetic acid (50 mL) was heated at 130° C. for 3 hours. After it was cooled down to room temperature, it was quenched with water, filtered, washed with water, and dried under vacuum with P2O5 to afford 6-iodoquinazolin-4(3H)-one as solid (9.289 g, 99.8%). 1H NMR (300 MHz, DMSO-d6) δ 8.38 (d, 1H), 8.13 (s, 1H), 8.09 (dd, 1H), 7.46 (d, 1H); LC-MS (ESI) m/z 273 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12].[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14]>ClCCl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12]
Reactant: CC(C)(C)N
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Br
Solvent: ClCCl
Solvent: O
Product: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1Br
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a stirred, ice-cold solution of 4-bromo-3-methyl-benzenesulfonyl chloride (11 g, 40.8 mmol) and N′N-diisopropylethylamine (8.5 ml, 49 mmol, 1.2 equiv.) in dichloromethane was added dropwise tert. butylamine (5.2 ml, 49 mmol, 1.2 equiv.). After two hours at room temp., the reaction mixture was diluted with water and extracted with dichloromethane. The organic extracts were concentrated under reduced pressure, the residue stirred with n-heptane and filtered to obtain 11.2 g of the desired compound as a yellow solid. MS (ES): m/e 304.2 (M−H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:12](O)[CH2:13][OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:7]2[O:14][CH2:13][CH2:12][O:8]2)[CH:9]=1
Reactant: OCCO
Reactant: COc1ccc(Br)cc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(Br)cc1C1OCCO1
Yield: 62.3 %

Procedure:
To a stirred solution of 5-bromo-2-methoxybenzaldehyde (5.0 g, 23.25 mmol) in toluene (50 mL) was added ethylene glycol (2.6 mL, 46.5 mmol) and p-toluenesulfonic acid monohydrate (0.45 g, 2.32 mmol) and the reaction mixture was azeotroped for 2 h, quenched with sat. NaHCO3 (50 mL). Reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate (2×100 mL), washed with water, brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish 2-(5-bromo-2-methoxy-phenyl)-[1,3]dioxolane (3.75 g).
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:10])[CH2:4][C:5]([O:7]CC)=[O:6].[CH3:11][N:12]([CH3:14])[CH3:13].[OH-].[Na+]>O>[OH:10][C@H:3]([CH2:4][C:5](=[O:6])[O-:7])[CH2:2][N+:12]([CH3:14])([CH3:13])[CH3:11]
Reactant: CCOC(=O)C[C@@H](O)CCl
Reactant: CN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 250 mL reactor, ethyl (R)-4-chloro-3-hydroxybutyrate (content 94%, 12.00 g, 67.7 mmol) was stirred with water (75.04 g) and cooled to 0° C. Aqueous trimethylamine (25%, 17.71 g, 1.1 eq.) was added at once at 0° C., followed by dropwise addition of aqueous sodium hydroxide (25%, 15.30 g, 1.4 eq.) within 3 h. After another 1 h at 0° C. the reaction mixture was allowed to warm to 20° C. and analyzed by HPLC.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[Br:1][CH2:2][CH2:3][O:4][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1
Reactant: OCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: BrCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 5 h
Yield: 896.8 %

Procedure:
To a solution of 2-bromoethanol 24 (50.0 g, 40 mmol) in methylene chloride (500 mL) cooled to 0° C. was added 3,4-dihydro-2H-pyran (40.32 g, 48 mmol) followed by p-TSA.H2O (100 mg) was added. Reaction mixture was stirred at 0° C. for 5.0 h. The reaction mixture was washed with aq NaHCO3 and brine, dried over Na2SO4 and evaporated to give the product 25 (75.0 g, 90%). This crude product was taken to next step without purification.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][OH:10]>CCCCCC>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][Br:7]
Reactant: OCCBr
Reactant: C1=COCCC1
Solvent: CCCCCC
Product: BrCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mechanically stirred solution of dihydropyran (1000 mL) and a strong acid resin (10.0 g) in hexane (2000 mL) was added 2-bromoethanol (985 g) dropwise over a period of 1.5 hours in a cold water bath to maintain an internal temperature of 35°-40° C. After being stirred overnight at room temperature, the reaction mixture was chromatographed, with hexane as the eluent. The hexane was evaporated to give an amber liquid which was distilled through a 2 inch (5 cm) diameter vigreux cole, collecting the material boiling between 75°-95° C. (3,300-4,700 Pa). This material was redistilled to give the ether as an oil (1195.5 g); bp 80°-90° C. (2666 Pa); NMR: 4.68 (m, 1), 4.01 (m, 1), 3.89 (m, 1), 3.77 (m, 1), 3.52 (m, 3), 1.75-1.50 (m, 6).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([I:10])[N:3]=1.[CH3:11][O-:12].[Na+].CO>CN(C=O)C>[CH3:11][O:12][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([I:10])[N:3]=1
Reactant: C[O-]
Reactant: COc1ccc(I)nc1Br
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(I)nc1OC
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-bromo-3-methoxy-6-iodopyridine (3-3, 34 g, 108 mmol) in DMF (65 mL) was added sodium methoxide in methanol (37 mL, 162 mmol, 4.37M) and heated to 100° C. The mixture was stirred for 10 minutes and partitioned between saturated NaHCO3 and DCM. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica (0 to 20% EtOAc in hexanes) to afford the title compound (3-4) as a white powder. ESI+MS[M+H]+C7H8INO2: 265.8 found, 266.0 required.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:9]=[N+:10]=[N-:11].[Na+]>C(O)C>[CH2:1]([N:9]=[N+:10]=[N-:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1ccccc1
Yield: 139.4 %

Procedure:
The reaction of this crude benzyl bromide (6.56 g) and sodium azide (1.92 g) in ethanol (90 ml) as in Example 33 gave 5.48 g of crude benzyl azide. Chromatography on silica gel yielded 3.29 g of pure 3-(trichlorovinyl)benzyl azide.