Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]([CH3:8])[C:6]=1[CH3:7].[Si:16]([O:23][C@@H:24]([CH3:40])[C@H:25]([C:31]1[O:35][N:34]=[C:33]([C:36](O)=[O:37])[C:32]=1[CH3:39])[O:26][CH2:27][C:28]([CH3:30])=[CH2:29])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Si:16]([O:23][C@@H:24]([CH3:40])[C@H:25]([C:31]1[O:35][N:34]=[C:33]([C:36]([NH:1][C:2]2[C:3](=[O:15])[N:4]([CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]3)[N:5]([CH3:8])[C:6]=2[CH3:7])=[O:37])[C:32]=1[CH3:39])[O:26][CH2:27][C:28]([CH3:30])=[CH2:29])([C:19]([CH3:22])([CH3:20])[CH3:21])([CH3:18])[CH3:17]
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Reactant: C=C(C)CO[C@@H](c1onc(C(=O)O)c1C)[C@H](C)O[Si](C)(C)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)CO[C@@H](c1onc(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)c1C)[C@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (2.63 g, 12.55 mmol) was added portionwise to 5-((1R,2S)-2-((tert-butyldimethylsilyl)oxy)-1-((2-methylallyl)oxy)propyl)-4-methylisoxazole-3-carboxylic acid (4.14 g, ˜70% w/w) in DMF (100 mL) followed by DIPEA (7.8 ml, 44.8 mmol) and HATU (4.8 g, 12.55 mmol). After stirring at room temperature for 18 h the reaction mixture was partitioned between EtOAc and brine. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 50-100% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[O-]CC.[Na+].[Na].Br[CH2:12][CH2:13][CH2:14][OH:15]>C(O)C>[N:1]1([CH2:12][CH2:13][CH2:14][OH:15])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: OCCCBr
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: OCCCn1cncn1
Yield: 89.7 %

Procedure:
Under argon, 1,2,4-triazole (13.8 g, 200 mmol) was added to a solution of sodium ethoxide (freshly prepared from sodium (4.6 g) and ethanol (250 ml)). After complete dissolution, 3-bromopropan-1-ol (18 ml, 200 mmol) was added dropwise. The mixture was refluxed for 18 hours and the solid was filtered and washed with ethanol. The filtrate was evaporated and the residue was purified by column chromatography eluting with methylene chloride/methanol (9/1) to give 3-(1,2,4-triazol-1-yl)propan-1-ol (22.8 g, 90%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][CH2:29][C:30]1[N:31]=[N:32][N:33]([CH3:35])[N:34]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])[CH2:29][C:30]3[N:31]=[N:32][N:33]([CH3:35])[N:34]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: Cn1nnc(CNc2ccccc2Cl)n1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2ccccc2Cl)[C@H]1O
Yield: 15 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (450 mg, 1.6 mmol) obtained in step 1 of example 2 and N-(2-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (118 mg, yield: 15%).
Reaction SMILES: C1COCC1.I[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][CH2:24][C:25]#[CH:26])([CH3:19])([CH3:18])[CH3:17]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][CH2:24][C:25]#[C:26][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: C#CCCNC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC#Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
To a mixture of anhydrous THF and triethylamine (20 mL, 1/1) were sequentially added 1-iodo-4-nitrobenzene (2.0 g, 8.032 mmol) and copper (I) iodide (0.31 g, 1.606 mmol). The mixture was stirred at room temperature for 15 min. The flask was evacuated and re-filled with argon four times to ensure no oxygen remained. The catalyst, dichlorobis(triphenylphosphine)-palladium(II) (0.56 g, 0.803 mmol) was added into the mixture under argon protection, followed by dropwise addition of but-3-ynyl-carbamic acid tert-butyl ester (1.62 g, 9.638 mmol). The newly formed reaction mixture was further stirred at room temperature overnight. The solid in the reaction mixture was vacuum filtered. The filtrate was concentrated. The residue was re-dissolved in methylene chloride and purified by column chromatography, eluting with a mixture of ethyl acetate (0–10%) and hexanes (100–90%) to afford 2.08 g (89%) of the product 51 as an orange solid. 1H NMR (CDCl3) δ 1.46 (s, 9H), 2.66 (t, J=6.5 Hz, 2H), 3.36–3.43 (m, 2H), 4.86 (br s, 1H), 7.53 (d, J=8.7 Hz, 2H), 8.16 (d, J=8.7 Hz, 2H). m/z (APCI)=291 [C15H18N2O4+H]+, 191 [C15H18N2O4-Boc+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[S:14][C:13]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][NH:17][N:16]=2)=[CH:12][CH:11]=1.C(OCC)(=O)C>CN(C)C=O>[Br:1][C:18]1[NH:17][N:16]=[C:15]([C:13]2[S:14][C:10]([Cl:9])=[CH:11][CH:12]=2)[C:19]=1[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccc(-c2n[nH]cc2-c2ccncc2)s1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2n[nH]c(Br)c2-c2ccncc2)s1
Temperature: 80 °C
Reaction time: 2 h
Yield: 123.6 %

Procedure:
N-Bromosuccinimide (1 eq, 0.38 mmol) was added to a solution of 4-[3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (1 eq, 0.38 mmol) in 2 mL of N,N-dimethylformamide. The mixture was then stirred at 80° C. for 2 h. Further N-Bromosuccinimide (0.3 eq, 0.12 mmol) was added and the mixture was stirred for one more hour. After cooling to room temperature, ethyl acetate was added and the organic layer was washed with water, dried over MgSO4, filtered and evaporated. The residue was suspended in diisopropylether and dichloropethane, filtered and dried in a vacuum oven at 50° C. to afford 0.16 g of 4-[5-bromo-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine.
Reaction SMILES: [O:1]([CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[C:21](O)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.Cl.[CH3:56][O:57][C:58](=[O:64])[C:59]([NH2:63])([CH3:62])[CH2:60][CH3:61]>CN(C=O)C>[CH3:56][O:57][C:58](=[O:64])[C:59]([CH3:62])([NH:63][C:21]([C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22])[CH2:60][CH3:61]
Reactant: CCC(C)(N)C(=O)OC
Reactant: O=C(O)c1ccc2ccccc2c1OCCOc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)(NC(=O)c1ccc2ccccc2c1OCCOc1ccccc1)C(=O)OC
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a solution of 487 mg 1-(2-phenoxy-ethoxy)-naphthalene-2-carboxylic acid in 6 ml abs. DMF under inert atmosphere 216 mg 1-hydroxybenzotriazole, 306 mg 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 293 μl of N,N-diisopropylethylamine were added at 0° C. After 30 minutes at 0° C. 252 mg of 2-amino-2-methyl-butyric acid methyl ester hydrochloride, followed by 293 μl of N,N-diisopropylethylamine were added. After 16 h at room temperature the reaction mixture was concentrated, the residue was taken up in ethyl acetate and washed with 2 M HCl, aqueous sodium carbonate solution (10%) and brine. The organic layer was dried over magnesium sulphate and concentrated. The resulting residue was purified by chromatography on silica (ethyl acetate/heptane) to yield 419 mg of 2-methyl-2-{[1-(2-phenoxy-ethoxy)-naphthalene-2-carbonyl]-amino}-butyric acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:23])[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21]O.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:23])[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21][N:28]1[C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]2[C:24]1=[O:34]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(c1ccccc1Cl)c1cc(F)ccc1-n1ccnc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(c1ccccc1Cl)c1cc(F)ccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 17, 2'-chloro-5-fluoro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone is treated with phthalimide and triphenylphosphine and finally with diethyl azodicarboxylate to give 2'-chloro-5-fluoro-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [Cl:1]C1C=CC=C(C(OO)=O)C=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][O:20][CH3:21])=[N:17][CH:18]=1>C(Cl)Cl.P(Cl)(Cl)(Cl)=O>[Cl:1][C:18]1[C:13]([Cl:12])=[CH:14][CH:15]=[C:16]([CH2:19][O:20][CH3:21])[N:17]=1
Reactant: COCc1ccc(Cl)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COCc1ccc(Cl)c(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 1.6 %

Procedure:
3-chloroperbenzoic acid (80%, 4.83 g, 13.96 mmol) was added portion-wise to a solution of 5-chloro-2-(methoxymethyl)pyridine (Preparation 57, 2 g, 12.69 mmol) in DCM (50 mL) at 0° C. The reaction was stirred for 18 hours at room temperature. The reaction mixture was quenched with 2M aqueous sodium hydroxide (25 mL) and brine (25 mL) and stirred vigorously. The organic layer was collected, washed with 2M aqueous sodium hydroxide (2×10 mL), water (10 mL), dried over sodium sulfate and concentrated in vacuo. A portion of the residue (100 mg, 0.576 mmol) was stirred in phosphoryl chloride (2 mL) at 80° C. for 2 hours. The reaction was concentrated in vacuo and vigorously stirred in DCM (10 mL) and saturated aqueous sodium bicarbonate solution (10 mL) for 5 hours. The organic layer was collected dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with DCM to afford the title compound (38 mg, 34%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].C[S-](C)[C:7]([S-])=[N:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11]>C(O)C>[F:11][C:10]([F:13])([F:12])[C:9]([N:8]=[C:7]1[NH:1][CH2:2][CH2:3][S:4]1)=[O:14]
Reactant: C[S-](C)C([S-])=NC(=O)C(F)(F)F
Reactant: NCCS
Solvent: CCO
Product: O=C(N=C1NCCS1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
Ethanol (20 mL) was added to 77 mg (1.0 mmol) of 2-aminoethanethiol, 216 mmol (1.0 mmol) of the dimethyl(2,2,2-trifluoroacetyl)carbonimidodithioate synthesized by the method described in Comparative Example 7 was added, and the mixture was stirred overnight at room temperature. Following reaction completion, the solvent was distilled off under reduced pressure, and purification was carried out by silica gel column chromatography (hexane/ethyl acetate=1:1), giving 100 mg of 2,2,2-trifluoro-N-(thiazolidin-2-ylidene)acetamide (yield, 51%). This reaction was carried out once more by the same synthesis method, giving a combined amount of 350 mg of 2,2,2-trifluoro-N-(thiazolidin-2-ylidene)acetamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1(O)[CH2:10][N:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[N:7]1)=[O:5])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(O)CN(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2Cl)=N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Yield: 69.7 %

Procedure:
A mixture of 1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylic acid ethyl ester I-7b (45 g, 108.8 mmol) and p-toluenesulfonic acid monohydrate (2.1 g, 10.8 mmol) in toluene (540 ml) was heated to reflux overnight. The reaction mixture was cooled and the solvent removed in vacuo. The crude residue was taken up in methylene chloride and washed with water, aqueous sodium bicarbonate, and brine. After drying over anhydrous magnesium sulfate and concentrating, the residue was purified by plug filtration on 600 g silica gel using ethyl acetate/hexanes (20:80) to give pure 1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester I-7c (30 g, 69.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH:15]([CH3:17])[CH3:16])[C:6]=2[CH:18]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:39][CH3:40])[C:23]([Cl:41])=[CH:22][N:21]=1>>[Cl:41][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:28]=2[O:39][CH3:40])=[N:25][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH:15]([CH3:16])[CH3:17])[C:6]=3[CH:18]=2)=[N:21][CH:22]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CC(C)N1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)N(C(C)C)C(=O)CCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-isopropyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine to yield an off-white solid (26%). mp 231° C.; LCMS: m/z=565.57 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.24 (d, 1H, J=8.8 Hz), 8.06 (s, 3H), 7.65 (m, 1H), 7.63 (m, 1H), 6.89 (s, 1H), 6.56 (d, 1H, J=2.3 Hz), 6.48 (m, 1H), 4.69 (m, 1H), 3.94 (s, 3H), 3.91 (m, 4H), 3.18 (m, 4H), 2.39 (m, 1H), 2.21 (m, 2H), 1.84 (m, 1H), 1.50 (m, 1H), 1.43 (m, 6H), 1.36 (s, 1H), 1.30 (s, 3H), 1.26 (s, 1H), 1.02 (d, 3H, J=7.1 Hz).
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:3]([OH:5])=[O:4].[NH4+:11].C([O-])=O.C(O)(=O)C(C)=O.N>O>[NH2:11][C@H:2]([C:3]([OH:5])=[O:4])[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)CCC(=O)C(=O)O
Reactant: [NH4+]
Agent: CC(=O)C(=O)O
Agent: N
Agent: O=C[O-]
Solvent: O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
0.16 mmol of keto glutaric acid whose R1 is (CH2)2COOH and R2 is H in FIG. 2(a) and 3.2 mmol of formate ammonium were poured into 3 mL of water so as to have the pH 4.5. 0.2 μmol of (η5-tetramethylcyclopentadienyl) rhodium (III)(2,2′-bipyridyl) aqua complex was added to the pyruvic acid aqueous solution, and the resulting mixture was reacted at 80° C. under argon atmosphere for an hour. After completion of the reaction, the resulting product was analyzed by 1H NMR. In isolation of the product, the reaction solution was condensed, and the condensed residue was dissolved in water, and the resulting water was made to pass through a cation exchange resin (DOWEX 50W-X2). After flowing 50 mL of water, 200 mL of 0.1M aqueous ammonia was flown, and the solution was condensed to give glutamic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14].O>CN(C=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: CC(C)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(=O)Nc1ccc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of 2-amino-5-chloro-benzoic acid (3.43 g, 20 mmol) in DMF (10 mL) cooled in an ice-water bath was added isobutyryl chloride (2.11 mL, 20 mmol). The reaction was stirred for 2 hours while warming to room temperature. Water (20 mL) was added and the mixture was stirred vigorously for 1 hour. The precipitate was then collected by vacuum filtration to give the product as a pale yellow solid (3.20 g, 66%). 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.52 (d, J=9.0 Hz, 1H), 7.92 (d, J=2.6 Hz, 1H), 7.66 (dd, J=9.0, 2.7 Hz, 1H), 2.58 (septet, J=6.9 Hz, 1H), 1.16 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][CH2:13][CH2:14][CH3:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.B(F)(F)F.CCOCC.[CH2:26]([SH:29])[CH2:27][SH:28]>C(Cl)Cl>[CH2:12]([C:11]1([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=2)[S:29][CH2:26][CH2:27][S:28]1)[CH2:13][CH2:14][CH3:15]
Reactant: SCCS
Reactant: CCCCC(=O)c1cc(OC)cc(OC)c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCC1(c2cc(OC)cc(OC)c2)SCCS1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.8 %

Procedure:
To a stirred solution of Compound 5 (3.52 g, 15.9 mmol) in anhydrous CH2Cl2 (58 ml); was added BF3-Et2O (0.58 ml, 4.8 mmol) and ethane-1,2-dithiol (2.71 g, 28.8 mmol) and stirred at room temperature for 16 h. The organic phase was then extracted with 10% NaOH (20 ml) followed by water and brine. The organic phase was dried, concentrated and the residue resolved over silica gel eluting with EtOAc/hexanes (5:10) to yield 4.50 g (95.2%) of Compound 9 as a colorless oil. Rf=0.51 (hexane:ethyl acetate 9:1); IR (neat) 2955, 1205, 1067 694 cm−1; 1H NMR δ 6.89 (d, J=2.22 Hz, 2H), 6.34 (t, J=2.21 Hz, 1H), 3.81 (s, 6H). 3.40–3.20 (m, 4H), 2.33 (t, J=7.53 2H), 1.31–1.20 (m, 4H), 0.85 (t, J=6.78 Hz, 3H). 13C NMR δ 160.56, 148.04, 106.01, 98.74, 74.58, 55.60, 45.92, 39.33, 30.23, 23.03, 14.13; MS: (ESI, Pos.) m/z 299 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][C:12](=[O:17])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:4].[Br:18]Br>ClCCl>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[C:16]2[CH2:15][CH2:14][CH:13]([Br:18])[C:12](=[O:17])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: BrBr
Reactant: COC(=O)COc1cccc2c1CCCC2=O
Solvent: ClCCl
Product: COC(=O)COc1cccc2c1CCC(Br)C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-methoxycarbonylmethoxy-5-oxo-5,6,7,8-tetrahydronaphthalene (0.5 g) in dry dichloromethane (3 ml) was added bromine (0.14 ml) at 0° C. The mixture was warmed up to room temperature, stirred for 2 hours. The mixture was washed with an aqueous saturated sodium bicarbonate, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (30 ml) using a mixture of dichloromethane-n-hexane. The desired fractions were collected and evaporated in vacuo to give 1-methoxycarbonylmethoxy-5-oxo-6-bromo-5,6,7,8-tetrahydronaphthalene (0.41 g). The crude crystal (50 mg) was recrystallized from ethyl acetate-n-hexane to give 31 mg as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH2:15][NH2:16])[O:8][CH2:7][CH2:6]2.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1C=CC=CC=1>[CH2:17]([NH:16][CH2:15][CH:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:7][O:8]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc2c(cc1OC)C(CN)OCC2
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)C(CNCc1ccccc1)OCC2
Reaction time: 8 h

Procedure:
A mixture of 6,7-dimethoxy-1-isochromanmethylamine (18.0 g), benzaldehyde (9.7 g) and dry benzene (400 ml) is heated under reflux (Dean-Stark) for 18 hr. The solvent is removed under reduced pressure and the residue (27.0 g) is dissolved in ethanol (400 ml). Sodium borohydride (17.0 g) is added portionwise to the stirred solution. When the addition is complete the mixture is stirred and heated under reflux for 1.5 hr. and then left at room temperature overnight. The mixture is concentrated, diluted with water and extracted with ether. The ether extracts are in turn extracted with 10% HCl and these extracts are made alkaline and re-extracted with ether. These extracts are washed with brine, dried and evaporated to give the title compound, λmax EtOH 285 nm (3750) and 281 nm (4000).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC(S(O[CH2:28][C:29]([F:32])([F:31])[F:30])(=O)=O)=CC=1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:28][C:29]([F:32])([F:31])[F:30])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)ccc1OCC(F)(F)F
Temperature: 100 °C
Reaction time: 40 h
Yield: 32 %

Procedure:
A stirred mixture of 3.14 g of 4-fluoro-2-nitrophenol, 13 g of cesium carbonate and 20 mL of anhydrous dimethylformamide was heated at 100° C. for 4 hours. 6.65 g of 2,2,2-trifluoroethyl p-toluenesulphonate was then added and the mixture was stirred at the same temperature for 40 hours. The solvent was removed under reduced pressure, and 50 mL of water was added to the residue. The mixture was acidified with 37% hydrochloric acid and extracted with 3×40 mL of ethyl acetate. The organic layer was washed with 20 mL of brine, dried over sodium sulphate and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (petroleum ether/ethyl acetate 100:7) to afford 1.53 g (32%) of Compound 8A as an oil.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[C:15]([C:16](=[O:18])[CH3:17])=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[C:15]([C:16](=[O:18])/[CH:17]=[CH:30]/[N:31]([CH3:33])[CH3:32])=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2C(C)=O)cc1
Reactant: COC(OC)N(C)C
Solvent: O
Product: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2C(=O)/C=C/N(C)C)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of 1-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (5.56 g, 15.9 mmol) in N,N-dimethylformamide dimethyl acetal (25 mL) was heated at reflux for 5 days. The mixture was allowed to cool to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated. The resulting residue was purified by flash chromatography (7:3 ethyl acetate:acetone) to give (2E)-1-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (5.97 g, 93%) as a colored syrup: 1H NMR (CDCl3): δ 7.96-7.59 (m, 3H), 7.53 (d, 1H), 7.23 (dd, 1H), 6.93 (d, 2H), 5.97-5.94 (m, 2H), 5.07 (d, 1H), 3.95 (m, 1H), 3.81 (s, 3H), 3.0-2.3 (m, 6H), 2.07 (m, 2H), 1.76-1.60 (m, 6H); MS m/z 405 (M+1).