Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:30]=O>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:30][C:26]1[O:25][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccco1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1ccco1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Mix carbon tetrabromide (49.8 g, 150 mmol) and methylene chloride (75 mL) and cool to 0° C. Add, by dropwise addition, a solution of triphenylphosphine (78.6 g, 300 mmol) in methylene chloride (75 mL). Stir at 0° C. for 30 minutes. Add, by dropwise addition, a solution of 2-furancarboxaldehyde (7.57 g , 78.8 mmol) in methylene chloride (75 mL). Remove the cooling bath and stir at room temperature until the reaction is complete. Pour onto ethyl ether and water, separate the organic layer and dry (MgSO4). Filter and evaporate the solvent in vacuo. Purify by silica gel chromatography to yield the title compound.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[Cl:18].[CH:19](=[O:21])[CH3:20]>CCOCC>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:12]([Cl:13])[C:7]=1[CH:19]([OH:21])[CH3:20]
Reactant: CC=O
Reactant: FC(F)(F)c1cc(Cl)c(Br)c(Cl)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 0.33 h

Procedure:
To a mixture of 65.2 ml of n-butyllithium (1.61M in hexane) and 100 ml of anhydrous ether was added dropwise 29.3 g of 4-bromo-3,5-dichlorobenzotrifluoride (3) in 30 ml of anhydrous ether at -78° C., followed by stirring for 20 minutes. Subsequently, 6.2 ml of acetaldehyde in 50 ml of anhydrous ether was added dropwise to the mixture at the same temperature, followed by stirring at 0° C. Ice waster was added to the reaction mixture, followed by extraction with ether, drying over anhydrous magnesium sulfate and concentration under reduced pressure to give 23.5 g of the desired product in the form of a colorless oil (crude yield 90.7% ).
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[C:15](OCC)(OCC)(OCC)[CH3:16]>>[C:9]1([C:8]2[C:3]3[N:4]([C:15]([CH3:16])=[N:2][N:1]=3)[CH:5]=[CH:6][N:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NNc1nccnc1-c1ccccc1
Product: Cc1nnc2c(-c3ccccc3)nccn12

Procedure:
A solution of 0.78 g. of 2-hydrazino-3-phenylpyrazine in 6.0 ml. of triethyl orthoacetate is heated under reflux for one hour. The reaction mixture is cooled in an ice bath and the precipitated solid is collected by filtration. The solid is recrystallized from ethanol to give 0.49 g. of the desired product as tan crystals, m.p. 178°-180° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[OH:22][CH2:23][C@H:24]1[C@H:28]([C:29]([F:32])([F:31])[F:30])[CH2:27][NH:26][CH2:25]1.C(N(CC)CC)C>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:26]4[CH2:27][C@@H:28]([C:29]([F:31])([F:32])[F:30])[C@H:24]([CH2:23][OH:22])[CH2:25]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: OC[C@@H]1CNC[C@H]1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3C[C@@H](CO)[C@H](C(F)(F)F)C3)c(F)cc2c1=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
In 6 ml of dimethylsulfoxide, is dissolved 283 mg (1 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. To the above solution, are added 411 mg (2 mmol) of trans-3-hydroxymethyl-4-trifluoromethylpyrrolidine hydrochloride and 0.42 ml (3 mmol) of triethylamine. The mixture is stirred at 50° C. for 18 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue. The resulting precipitate was obtained by filtration and washed successively with water, isopropanol and diethyl ether to give 412 mg of the objective substance as a slightly yellow powder (yield 95.4%).
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH2:26][S:27][CH3:28])[NH2:24].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:24][C@H:23]([C:22]([OH:29])=[O:21])[CH2:25][CH2:26][S:27][CH3:28])=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSCC[C@H](NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1)C(=O)O

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to methionine methyl ester using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.Cl.Cl.Cl[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:32]=[N:33][N:34]([CH3:37])[C:35]=4[CH3:36])[CH2:26][CH2:25]3)=[N:20][CH:21]=[CH:22][N:23]=2)=[CH:14][CH:13]=1>CN(C=O)C>[CH3:37][N:34]1[C:35]([CH3:36])=[C:31]([CH2:30][N:27]2[CH2:26][CH2:25][N:24]([C:19]3[C:18]([C:15]4[CH:16]=[CH:17][C:12]([CH2:11][N:3]5[CH:7]=[CH:6][CH:5]=[N:4]5)=[CH:13][CH:14]=4)=[N:23][CH:22]=[CH:21][N:20]=3)[CH2:29][CH2:28]2)[CH:32]=[N:33]1
Reactant: c1cn[nH]c1
Reactant: Cc1c(CN2CCN(c3nccnc3-c3ccc(CCl)cc3)CC2)cnn1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(CN2CCN(c3nccnc3-c3ccc(Cn4cccn4)cc3)CC2)cnn1C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
Add sodium hydride (0.172 g of 60% weight suspension in mineral oil; 2.59 mmol) to a solution of pyrazole (0.183 g; 2.69 mmol) in DMF (5 mL). Cool the mixture to 5° C., stir for 30 min., remove the cooling bath, warm to room temperature and stir for 30 min. Add 3′-(4-chloromethyl-phenyl)-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride (0.253 g; 0.540 mmol) in 6 mL of DMF and stir for 20 hr. at room temperature. Quench with a solution of 10% aq. acetic acid (9 mL), add methanol (minimal volume to achieve a homogeneous solution) and add to a 5 gm SCX column (Varian; pre-rinsed with MeOH). Elute the crude product with 2 M ammonia in methanol (18 mL) and concentrate. Purify via chromatography on silica gel eluting 0-10% methanol/dichlormethane to give 4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3′-(4-pyrazol-1-ylmethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.140 g; 61%). MS (ES+) m/z: 429 (M+H)+. Purify by high pH reverse phase HPLC, and concentrate to give the pure free base. Dissolve the free base in acetonitrile and convert to the hydrochloride salt by adding 1 eq 2 M aq HCl solution. Add water and lyophilize to give the title compound as an off white powder (126 mg). MS (ES): m/z=429 [M+H]+.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2Br)[CH2:8][C@@H:7]([CH2:22][O:23]C(=O)C)[C@@H:6]1[O:27]C(=O)C)(=O)C.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.CO.N>C(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([C@@H:9]3[C@@H:5]([OH:4])[C@@H:6]([OH:27])[C@H:7]([CH2:22][OH:23])[CH2:8]3)[C:11]([NH:34][CH:31]3[CH2:33][CH2:32]3)=[N:12][C:13]=2[CH:18]=1
Reactant: NC1CC1
Reactant: CC(=O)OC[C@@H]1C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: N
Solvent: CCO
Solvent: CO
Product: OC[C@@H]1C[C@H](n2c(NC3CC3)nc3cc(Cl)c(Cl)cc32)[C@@H](O)[C@H]1O
Reaction time: 18 h

Procedure:
(±)(1R*,2S*,3S*,5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (500 mg, 0.958 mmol) was dissolved in absolute ethanol (5 mL) and cyclopropylamine (0.66 mL, 9.6 mmol) was added. The solution was refluxed under nitrogen for two hours. Additional cyclopropylamine (0.66 mL) was added and reflux continued for an additional 18 hours. The solution was cooled and methanol saturated with ammonia at 0° C. (5 mL) was added. After two days at ambient temperature, volatiles were removed in vacuo and the residue chromatographed on silica gel. (±)-(1R*,2S*,3S*,5S*)-5-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol was eluted with 7% methanol-chloroform and solidified from ethyl acetate-hexanes to white powder (210 mg, 59%), m.p. 223°-224° C.; 1H-NMR(DMSO-d6) δ: 7.64 and 7.46 (both s, 2, aromatic CH), 7.11 (m, 1, NH), 5.11 (t, J=4.3 Hz, 1, OH), 4.77 (d, J=7.0 Hz, 1, OH), 4.67 (d, J=3.7 Hz, 1, OH), 4.65-4.30 (m, 2, OCH and NCH), 3.85-3.75 (m, 1, OCH), 3.7-3.4 (m, 2, OCH2), 2.85-2.70 (m, 1, NCH of cyclopropyl), 2.15-1.80 (m, 3, CH2 and CH of cyclopentane), 0.80-0.50 (m, 4,2 CH2 of cyclopropyl); mass spectrum (CI): 372(M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[H-].[Na+].[Cl:15][C:16]1[C:21]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:19]=[C:18]([Cl:26])[C:17]=1[CH2:27]OS(C)(=O)=O.O>CN(C)C=O>[Cl:15][C:16]1[C:21]([O:22][CH2:23][O:24][CH3:25])=[CH:20][CH:19]=[C:18]([Cl:26])[C:17]=1[CH2:27][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2
Reactant: COCOc1ccc(Cl)c(COS(C)(=O)=O)c1Cl
Reactant: Cc1ccc2cccc(O)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Reaction time: 1 h

Procedure:
A solution of 8-hydroxy-2-methylquinoline (737 mg) in dimethylformamide was dropwise added to a solution of sodium hydride (60% in oil, 185 mg) in dimethylformamide under ice-bath cooling, and the mixture was stirred for 1 hour at the same temperature. To the mixture was added 2,6-dichloro-1-methylsulfonyloxymethyl-3-(methoxymethoxy)benzene (1.46 g) under ice-bath cooling, and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate-n-hexane) to give 8-[2,6-dichloro-3-(methoxymethoxy)-benzyloxy]-2-methylquinoline as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](N(CC)CC)=[O:7])=[C:4]([CH2:15][C@H:16]([OH:18])[CH3:17])[CH:3]=1>Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:13][CH:14]=1)[C:6](=[O:7])[O:18][C@H:16]([CH3:17])[CH2:15]2
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1C[C@@H](C)O
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1Cc2cc(Br)ccc2C(=O)O1
Temperature: 25 °C

Procedure:
A solution of 4-bromo-N,N-diethyl-2-[(2R)-2-hydroxypropyl]benzamide (12.2 g, 38.8 mmol) dissolved in 4N HCl in dioxane (200 mL) was stirred at room temperature and monitored by TLC. After 3 days the reaction was partitioned between EtOAc (300 mL) and water (300 mL). The aqueous phase was further extracted with EtOAc (2×250 mL). The combined organic layers were then washed with water (200 mL), brine (200 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was then purified via MPLC (15-30% EtOAc/Hexane) to afford (3R)-6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one: 1H NMR (500 MHz; CDCl3): 7.98 (d, J=8.2 Hz, 1H), 7.56 (dd, J=1.5, 8.2 Hz, 1H), 7.45 (s, 1H), 4.71 (m, 1H), 2.94 (m, 2H), 1.55 (d, J=6.3 Hz, 3H); LC-MS: (M+1)+ 241.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[C:13]1[N:18]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=[CH:15][N:14]=1>CN(C)C=O>[N+:9]([C:3]1[CH:4]=[C:5]([O:8][C:13]2[N:18]=[C:17]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[CH:7][C:2]=1[NH2:1])([O-:11])=[O:10]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: Clc1nccc(-c2cccnc2)n1
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2nccc(-c3cccnc3)n2)cc1[N+](=O)[O-]

Procedure:
A solution of 4-amino-3-nitro-phenol (1 eq) and 2-chloro-4-(3-pyridyl)pyrimidine (1 eq) in N,N-dimethylformamide was microwaved at 150° C. for 10 mins. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was concentrated and purified on silica gel to yield 2-nitro-4-(4-(3-pyridyl)pyrimidin-2-yloxy)phenylamine. MS: MH+=309.
Reaction SMILES: C[O:2][C:3](=[O:10])[CH2:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].[OH-].[Na+]>O.C(Cl)Cl>[CH3:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH2:4][C:3]([OH:10])=[O:2]
Reactant: COC(=O)CCC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)CCC(=O)O
Reaction time: 4.5 h
Yield: 84.7 %

Procedure:
4,4-Dimethyl-pentanoic acid methyl ester (7.0 g, 48.5 mmol, 1.0 eq.) was treated with a solution of NaOH (4.0 g, 100 mmol, 2.1 eq.) in water (5 mL). The homogeneous solution was allowed to stir for 4-5 hours. The reaction was diluted with CH2Cl2 and the aqueous layer was extracted with CH2Cl2 (50 mL×3). The aqueous layer was acidified with 6M HCl to pH˜1.5 and extracted with ethyl acetate (50 mL×3). The combined ethyl acetate fractions were dried over MgSO4, filtered and evaporated to provide 4,4-dimethyl-pentanoic acid (5.35 g, 41.1 mmol, 85%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 0.89 (s, 9H), 1.53-1.57 (m, 2H), 2.26-2.30 (m, 2H).
Reaction SMILES: ClC(Cl)(Cl)C([N:5]=C=O)=O.[CH:10]([C:13]1[N:14]([O:27][CH3:28])[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:18]([O-])=[CH:17][C:16]=2[N:26]=1)([CH3:12])[CH3:11].CO>ClCCl>[CH:10]([C:13]1[N:14]([O:27][CH3:28])[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]([NH2:5])[C:16]=2[N:26]=1)([CH3:12])[CH3:11]
Reactant: COn1c(C(C)C)nc2c[n+]([O-])c3ccccc3c21
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COn1c(C(C)C)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.2 %

Procedure:
Trichloroacetyl isocyanate (3.3 mL, 28 mmol) was added to a solution of 2-isopropyl-1-methoxy-5-oxido-1H-imidazo[4,5-c]quinoline (4.7 g, 118 mmol) in dichloromethane (100 mL), and the reaction was stirred three hours at room temperature. Methanol (20 mL) was added, and the mixture was stirred for 15 minutes and concentrated under reduced pressure. The residue was dissolved in methanol (25 mL), and sodium methoxide (0.5 mL of a 4.5 N solution in methanol) was added. The mixture was stirred at room temperature for three days and concentrated under reduced pressure. The residue was stirred with dichloromethane (25 mL). A solid was present and was collected by filtration, recrystallized from methanol/water, and dried overnight in a vacuum oven at 70° C. to provide 0.878 g of 2-isopropyl-1-methoxy-1H-imidazo[4,5-c]quinolin-4-amine as tan needles, mp 217-219° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:21])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[OH:13])[C:7]=1Br.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:27][NH2:28]>C(N(CC)CC)C>[Br:1][C:2]1[C:3](=[O:21])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[OH:13])[C:7]=1[NH:28][CH2:27][C:26]1[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=1
Reactant: O=c1[nH]nc(OCCC(O)c2ccc(Cl)cc2)c(Br)c1Br
Reactant: COc1ccc(CN)cc1OC
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2c(OCCC(O)c3ccc(Cl)cc3)n[nH]c(=O)c2Br)cc1OC
Yield: 68.5 %

Procedure:
From 300 mg of 4,5-dibromo-6-[3-(4-chlorophenyl)-3- hydroxypropyloxy]-3(2H)pyridazinone, 228 mg of 3,4-dimethoxybenzylamine and 69 mg of triethylamine, 246 mg of the title compound was prepared in the same manner as in Example 1, as white crystals having a melting point of 190°-196° C.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH2:16][C:17]([OH:19])=O)=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](N1C=CN=C1)([N:22]1C=CN=[CH:23]1)=O.CNC>O1CCCC1>[CH3:20][N:22]([CH3:23])[C:17](=[O:19])[CH2:16][C:15]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=12
Reactant: O=C(O)Cc1c(-c2ccccc2)nn2cccnc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1c(-c2ccccc2)nn2cccnc12
Reaction time: 4 h
Yield: 76 %

Procedure:
A mixture of 3.5 g (0.013 mole) of 2-phenylpyrazolo[1,5-a]pyrimidine-3-acetic acid and 2.24 g (0.013 mole) of 1,1'-carbonyldiimidazole in 150 ml of anhydrous tetrahydrofuran was stirred for 4 hours under a nitrogen atmosphere. A solution of dimethylamine in tetrahydrofuran (14.0 ml of a 2.95M solution; 0.0414 mole) was added. The mixture was stirred at room temperature for one hour. The solvent was evaporated under reduced pressure, and the residue was dissolved in methylene chloride (100 ml). The solution was extracted with 7% aqueous sodium bicarbonate, and with water, and then dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The crystalline residue (4.6 g) was recrystallized from isopropanol to give 2.77 g (72%) of product, mp 156°-157.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:30]=2)[NH:25][CH:24]=1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:25]3[C:26]4[C:31](=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=4)[C:23]([CH3:22])=[CH:24]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: Cc1c[nH]c2ccc(S(C)(=O)=O)cc12
Product: Cc1cn(-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c2ccc(S(C)(=O)=O)cc12

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and 3-methyl-5-(methylsulfonyl)-1H-indole (intermediate-23).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[ClH:13].[CH2:14]=O>CO>[ClH:13].[NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:14][Cl:13])[CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: NC(C(=O)O)c1ccc(O)cc1
Reactant: C=O
Agent: Cl
Solvent: CO
Product: NC(C(=O)O)c1ccc(O)c(CCl)c1
Reaction time: 0.12 h

Procedure:
To a solution of (-)-α-amino-4-hydroxybenzeneacetic acid (100 g, 0.6 mole) in a minimum amount of concentrated hydrochloric acid at 35°-40° C. is added 50 ml of aqueous formaldehyde (35-37%) (0.6 mole). The addition of hydrogen chloride gas is begun. After 5-10 minutes, a solid begins to precipitate. Stirring is continued for 30 minutes, and the solid is then collected. The crude product is washed with ether and with acetone. A second crop is obtained from the filtrate after standing at room temperature overnight. Total yield is 102 g (67%) m.p.>300° C., [α]D18 =-134° (c 4.75, CH3OH) MNR (DMSO-D6) ppm (δ) 4.68 (s,2), 4.9 (broad s,1), 6.9-7.6 (superimposed q and s,3).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].CO[C:15](OC)([CH3:17])[CH3:16].Cl>CC(C)=O>[CH3:16][C:15]1([CH3:17])[O:10][CH:9]([CH:7]2[O:8][C:2](=[O:1])[C:3]([OH:4])=[C:5]2[OH:6])[CH2:11][O:12]1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: COC(C)(C)OC
Agent: Cl
Solvent: CC(C)=O
Product: CC1(C)OCC(C2OC(=O)C(O)=C2O)O1
Reaction time: 1 h

Procedure:
In a 12-L round bottom flask was placed 8,000 mL acetone, 1,600 g L-ascorbic acid, 1,880 mL 2,2-dimethoxypropane and the mixture was stirred for 1/4 hr; hydrogen chloride was added slowly through bubbler over 2-4 min (color of solution changed from colorless to dark yellow). The mixture was stirred for 1 hr and became very viscous. The product was filtered, washed with cold acetone and the solid was then air dried in hood to give 1,521 g of 1st crop of 5,6-O-isopropylidene-L-ascorbic acid. The mother liquor was concentrated to give 225 g of 2nd crop and 162 g of 3rd crop of 5,6-O-isopropylidene-L-ascorbic acid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][O:15][C:16]2[CH:27]=[CH:26][C:19]([C:20]([O:22]CC=C)=[O:21])=[C:18]([OH:28])[CH:17]=2)=[CH:9][C:8]=1[C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:3])[CH3:2].Cl.[NH2:35][OH:36]>N1C=CC=CC=1>[C:1]([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:35][OH:36])[CH2:14][O:15][C:16]2[CH:27]=[CH:26][C:19]([C:20]([OH:22])=[O:21])=[C:18]([OH:28])[CH:17]=2)=[CH:9][C:8]=1[C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)c1ccc(OCC(=O)c2ccc(NCCC(C)=O)c(C(C)(C)C)c2)cc1O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)CCNc1ccc(C(COc2ccc(C(=O)O)c(O)c2)=NO)cc1C(C)(C)C

Procedure:
In a manner similar to that of Example 1.g, by reaction of 370 mg (0.8 mmol) of allyl 4-{2-[4-(acetylethylamino)-3-tert-butylphenyl]-2-oxoethoxy}-2-hydroxybenzoate with 284 mg (4 mmol) of hydroxylamine hydrochloride and 320 μl of pyridine. A yellowish paste is obtained (m=380 mg, yield=99%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].C([Li])CCC.[C:21]([NH:28][CH2:29][CH:30]=O)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O>C1COCC1>[C:24]([O:23][C:21]([NH:28][CH2:29]/[CH:30]=[C:6](/[F:7])\[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C\CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.9 %

Procedure:
To a stirred solution of triethyl 2-fluoro-2-phosphonoacetate (0.61 mL, 3 mmol) in dry THF (40 mL) at −10° C. under nitrogen was added n-butyllithium (2.5 M solution in hexanes; 1.16 mL, 2.9 mmol) dropwise. The contents of the vessel were allowed to stir for 5 mins at −10° C. before addition of N-Boc-aminoacetaldehyde (0.378 g, 2.5 mmol, in 5 mL THF). The reaction mixture was then allowed to warm to room temperature and stirred for 16 hours. Water (50 mL) was added to the mixture and the organic layer extracted with diethyl ether (50 mL) and washed with brine (20 mL), dried over MgSO4, filtered and the solvent removed under reduced pressure to afford the crude product as a clear oil (0.850 g). Purification by flash chromatography (silica, ˜4 g) eluting in 5-15% EtOAc in n-hexane afforded (E)-ethyl 4-(tert-butoxycarbonylamino)-2-fluorobut-2-enoate (0.525 g, 85%) as a clear oil and a mixture of 10:1 E:Z; E(major)-isomer 1H-NMR (200 MHz, CDCl3): δppm: 1.36 (3H, t, J 7.0 Hz), 1.45 (9H, s), 4.17 (2H, m), 4.32 (2H, q, J 7.0 Hz), 4.88 (1H, br s), 6.01 (1H, dt, J 19.5, 7.2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][CH2:24][O:25][CH2:26][CH2:27]Cl.C(=O)([O-])[O-].[K+].[K+].O>C(O)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCOCCCl
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(N)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(N3CCOCC3)cc2)CC1
Yield: 69.9 %

Procedure:
1-tert-Butoxycarbonyl-4-(4-aminobenzyl)piperidine (1 g, 3.45 mmol) was dissolved in 1-butanol (20 mL). To the solution were added bis(2-chloroethyl) ether (490 mg, 3.45 mmol) and potassium carbonate (1 g, 7.23 mmol), and the mixture was heated for 30 hours under reflux. The reaction mixture was poured into water (50 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to give 1-tert-butoxycarbonyl-4-(4-morpholinobenzyl)piperidine (869 mg) as a colorless oily substance. This compound (859 mg, 2.39 mmol) was dissolved in ethyl acetate (10 mL). To the solution was added 4N-hydrogen chloride in ethyl acetate (5 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure to give the titled compound (562 mg) as colorless powders.