Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].CC(C)([O-])C.[K+].Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24]>C1COCC1>[C:2]([CH:3]([CH2:22][C:23](=[O:24])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: O=C(CBr)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)c1ccccc1)C(=O)c1ccccc1
Reaction time: 0.17 h
Yield: 66.7 %

Procedure:
To a stirring solution of ethyl 3-oxo-3-phenylpropanoate 67 (0.754 g, 3.92 mmol) in THF cooled to 0° C. was added potassium tert-butoxide (0.556 g, 4.71 mmol) and the reaction mixture was stirred for 10 minutes followed by the addition of 2-bromo-1-phenylethanone 68 (0.859 g, 4.32 mmol). The reaction mixture was allowed to stir at room temperature for 90 minutes then quenched with ethanol (2) and poured into ethyl acetate and layer separated. The organic layer was washed with water, brine, dried over Na2SO4, then purified by ISCO (40 g column, 0 to 35% ethyl acetate in hexane) to afford compound 69 (0.812 g, 67% yield) as a yellow oil. LRMS (ESI): (calc.) 310.12 (found) 311.08 (MH)+
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:18]=1[NH2:19]>>[Cl:16][C:17]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Nc1ccc(F)cc1Cl
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Product: CCOC(=O)c1cnc2ccnn2c1Nc1ccc(F)cc1Cl
Yield: 86.1 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (5.0 g, 24.1 mmol) and 2-chloro-4-fluoroaniline (2.81 g, 19.3 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (5.56 g, 69%) was obtained.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:19][CH2:20][C:21](Cl)=[O:22]>ClCCl>[CH2:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:21](=[O:22])[CH2:20][Cl:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(Cc1ccccc1)C(=O)CCl
Yield: 101.4 %

Procedure:
To a solution of 5.00 g of N-isopropylbenzylamine and 3.74 g of triethylamine in 60 ml of dry dichloromethane was added dropwise 3.84 g of chloroacetyl chloride with stirring under ice-cooling. The mixture was heated under reflux for 2 hours. After cooling, the reaction mixture was successively washed with water, a 10% hydrochloric acid and an aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 7.67 g of N-benzyl-2-chloro-N-isopropylacetamide in an oil.
Reaction SMILES: O[C:2]1([C:22]([F:25])([F:24])[F:23])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][S:13]([C:10]1[CH:9]=[CH:8][C:7]([N:5]2[CH:6]=[C:2]([C:22]([F:24])([F:25])[F:23])[N:3]=[C:4]2[C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[CH:12][CH:11]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccsc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccsc2)cc1
Yield: 63.6 %

Procedure:
A mixture of the 4,5-dihydro-imidazole of step 2 (1.5 g, 3.8 mmol) and p-toluenesulfonic acid monohydrate (0.30 g, 1.5 mmol) in toluene (250 ml) was heated to reflux for 40 hours. An additional p-toluenesulfonic acid monohydrate (0.15 g, 0.78 mmol) was added. The reaction mixture was heated to reflux for 18 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude mixture (3.5 g) was chromatographed on silica gel using ethyl acetate/toluene (55/45) to give pure 3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]thiophene (0.90 g, 64%) as a white solid: mp 194°-197° C. Anal. Calc'd. for C15H11N2S2O2F3 : C, 48.38, H, 2.98, N, 7.52, S, 17.22. Found C, 48.74, H, 2.98, N, 7.56, S, 17.45.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[F:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:17]([OH:18])[C:16]=1O.[C:23](=[O:26])([O-])[O-].[K+].[K+]>CS(C)=O>[C:12]([C:6]1[CH:5]=[C:4]([CH:11]=[CH:10][C:7]=1[C:8]#[N:9])[O:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([F:14])[C:16]=1[O:26][C:23]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]#[N:13])[CH:5]=1)#[N:13]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(F)c1O
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2cccc(F)c2Oc2ccc(C#N)c(C#N)c2)cc1C#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
3.60 g (0.02 moles plus 0.14 g excess) of 4-nitrophthalonitrile was dissolved in 50 ml anhydrous DMSO in a 100 ml three-necked flask fitted with a magnetic stirrer bar under nitrogen. 1.28 g (0.01 moles) of 3-fluorocatechol (Aldrich) was added to the mixture followed by 5 g of anhydrous potassium carbonate. The mixture was stirred at room temperature for 24 hours. The workup was as described in Example 5 and yielded 3.04 g of off-white crystals of the title compound (80% theoretical yield). The product had the formula: ##STR15## The melting point was 198.5°-199.5° C. The elemental analysis for C22H9FN4O2 was calc.: C, 69.47%; H, 2.36%; N, 14.73%; found: C, 69.47%; H, 2.34%; N, 14.80%.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][C:31](=[O:37])[NH:32]2>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1/[C:30](=[CH:16]/[C:13]1[NH:12][C:8]3[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])[C:6](=[O:18])[C:7]=3[C:14]=1[CH3:15])/[C:31](=[O:37])[NH:32]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Reactant: O=C1Cc2c(cccc2-c2c(F)cccc2F)N1
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4c(F)cccc4F)c32)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Yield: 36.4 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 23 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c obtained from step 3 of Example 23 and 4-(2,6-difluoro-phenyl)-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-[4-(2,6-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-(2-dimethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 40 (36 mg, yield 36.4%) as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=O)[N:3]=1.P(Cl)(Cl)([Cl:15])=O>Cl>[Cl:15][C:4]1[N:3]=[C:2]([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1nc(=O)[nH]c2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Product: Cc1nc(Cl)nc2ccccc12

Procedure:
Prepared analogously to Example 27c from 4-methyl-1H-quinazolin-2-one and phosphorus oxychloride in hydrochloric acid.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:19][CH2:20][NH:21][C:22]2[C:23]([CH3:39])=[N:24][C:25]([N:28]3[CH2:32][CH2:31][C@@H:30]([N:33]4[CH2:37][CH2:36][CH2:35][C@@H:34]4[CH3:38])[CH2:29]3)=[CH:26][CH:27]=2)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=O)C>CO.C(Cl)Cl>[C:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:3])[N:21]([C:22]3[C:23]([CH3:39])=[N:24][C:25]([N:28]4[CH2:32][CH2:31][C@@H:30]([N:33]5[CH2:37][CH2:36][CH2:35][C@@H:34]5[CH3:38])[CH2:29]4)=[CH:26][CH:27]=3)[CH2:20][CH2:19]2)[CH2:11][CH2:10]1)=[O:13])([CH3:16])([CH3:18])[CH3:17].[NH3:9]
Reactant: CCOC(=O)C1(CCNc2ccc(N3CC[C@@H](N4CCC[C@@H]4C)C3)nc2C)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Product: N
Yield: 5 %

Procedure:
The title compound was synthesized in essentially the same manner using the procedures as set forth in Step 2 of Example 1, by cyclizing 4-{2-[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamino]-ethyl}-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (111 mg, 0.20 mmol) to obtain 50 mg (50% yield over two steps) of the title compound after flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH2:17][C:18]2([CH3:22])[CH3:21])=[CH:13][CH:12]=1>ClCCl>[CH3:9][O:10][C:11]1[C:12]([C:5](=[O:7])[CH3:6])=[CH:13][C:14]2[CH2:15][CH2:16][CH2:17][C:18]([CH3:22])([CH3:21])[C:19]=2[CH:20]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)C(C)(C)CCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2c(cc1C(C)=O)CCCC2(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a suspension of aluminum chloride (1-2 g, 90 mmol) in dichloromethane (300 mL) at 0° C. was added acetyl chloride (6.8 ml, 90 mmol). After stirring at 0° C. for 20 min the mixture turned into clear solution. The mixture was then cooled to −78° C. and 7-methoxy-1,1-dimethyl-1,2,3,4-tetrahydro-naphthalene (Compound A-85, 13.2 g, 69 mmol) in dichloromethane (20 mL) was added. After stirring at 78° C. for 2 h the mixture was poured onto ice and extracted with diethyl ether. The combined organic layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 10% ethyl acetate in hexane) to give the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)[CH2:28][CH2:27][C:26]([C:36]([OH:38])=O)=[CH:25][C:24]=3[CH:39]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:39]=[CH:24][C:23]3[N:29]([CH2:30][C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)[CH2:28][CH2:27][C:26]([C:36]([NH:29][C:23]4[CH:24]=[CH:39][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:38])=[CH:25][C:22]=3[CH:21]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cccs2)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2cccs2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(2-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (110 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (82 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (20 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (61 mg) and triethylamine (279 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature for 3 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(2-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 60) (86 mg) as yellow crystals.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH:17][C:18]([C:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:19])=[CH:7][C:8]2[O:12][C:11](=[O:13])[C:10]([CH3:15])([CH3:14])[C:9]=2[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:31].[Na+]>CO>[C:1]([C:5]1[C:6]([NH:17][C:18]([C:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:19])=[CH:7][C:8]([OH:31])=[C:9]([C:10]([CH3:15])([CH3:14])[C:11]([OH:12])=[O:13])[CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: CC(C)(C)c1cc2c(cc1NC(=O)c1c[nH]c3ccccc3c1=O)OC(=O)C2(C)C
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1cc(C(C)(C)C(=O)O)c(O)cc1NC(=O)c1c[nH]c2ccccc2c1=O
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound 21 (0.9 g, 2.45 mmol) in MeOH (50 mL) was added NaOH (1.5 g, 37.5 mmol) at 0° C. After stirring for 16 hours at 40° C., the solvent was evaporated in vacuo, then the residue was dissolved in H2O (50 ml). The precipitate was filtered and the filtrate was washed with DCM (100 mL×1) and ethyl acetate (100 mL×1). The aqueous layer was acidified with 2N HCl to pH 1-2. The precipitate was filtered and washed with H2O (80 mL) and heptane (50 mL). It was dried in vacuo to give compound 28 as a white solid. 1H NMR (DMSO-d6; 400 MHz) δ 12.85 (s), δ 11.84 (s), δ 11.77 (s), δ 9.39 (s), δ 8.86 (s), δ 8.33 (s), δ 7.79 (m), δ 7.52 (m), δ 7.18 (s), δ 7.09 (s), δ 1.44 (s), δ 1.40 (s). MS found (M+H) 423.08
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[F:32][C:33]1[CH:47]=[CH:46][C:36]2[C:37]([CH:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)=[N:38][O:39][C:35]=2[CH:34]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:43]4[CH2:42][CH2:41][CH:40]([C:37]5[C:36]6[CH:46]=[CH:47][C:33]([F:32])=[CH:34][C:35]=6[O:39][N:38]=5)[CH2:45][CH2:44]4)=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-(6-fluorobenzo[d]isoxazol-3-yl)piperidine as in General Procedure 10 to give the title compound. LCMS: m/z=649.96 (M+H+); retention time=1.00 minutes.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[C:4](=[O:8])[NH:3]1.[H-].[Na+].[H][H].[CH2:14]([O:16][C:17](=[O:20])[CH2:18]Br)C>CN(C)C=O>[CH3:14][O:16][C:17]([CH2:18][N:3]1[C:4](=[O:8])[C:5](=[O:7])[N:6]([CH2:18][C:17]([O:16][CH3:14])=[O:20])[C:2]1([CH3:9])[CH3:1])=[O:20]
Reactant: CC1(C)NC(=O)C(=O)N1
Reactant: CCOC(=O)CBr
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C(=O)N(CC(=O)OC)C1(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
A solution of 12.8 g (0.1 mole) of 2,2-dimethylimidazolidine-4,5-dione in 70 ml of dimethyl formamide is slowly added dropwise, with stirring, at 20°-30° C to a suspension of 4.8 g (0.2 mole) of sodium hydride in 60 ml of dimethyl formamide. When the uptake of hydrogen has ceased, a solution of 33.4 g (0.2 mole) of bromacetic acid ethyl ester in 30 ml of dimethylformamide is added dropwise at 40°-50° C. After it has been stirred for 1 hour at 80° C, the reaction mixture is evaporated to dryness in vacuo. The residue is washed with ether and taken up in chloroform. The insoluble potassium bromide is filtered off and the chloroform solution evaporated. The residue is recrystallised from n-butanol to yield 7.8 g of colourless crystals with a melting point of 129°-130° C. The infra-red and nuclear magnetic resonance spectra confirm the presumed structure and the results of the elemental analysis are:
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][C:8]([CH3:15])([O:10][Si](C)(C)C)[CH3:9])[N:5]=[CH:4][C:3]=1[N+:16]([O-])=O.[Cl-].[NH4+]>CCO.[Fe]>[NH2:16][C:3]1[CH:4]=[N:5][N:6]([CH2:7][C:8]([CH3:15])([OH:10])[CH3:9])[C:2]=1[Cl:1]
Reactant: CC(C)(Cn1ncc([N+](=O)[O-])c1Cl)O[Si](C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(O)Cn1ncc(N)c1Cl
Yield: 90 %

Procedure:
To a solution of 5-chloro-1-(2-methyl-2-((trimethylsilyl)oxy)propyl)-4-nitro-1H-pyrazole (1 equiv) in EtOH (0.13 M) was added iron powder (5.2 equiv) and ammonium chloride (14.3 equiv). The mixture was heated to reflux for 24 h and then filtered through celite. The filtrate was concentrated and dissolved in ethyl acetate. The organic solution was washed with aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated. The product was purified by reverse phase silica gel chromatography (5-95% acetonitrile in water) to afford the title compound as an oil (90% yield). 1H NMR (400 MHz, CHLOROFORM-d1) δ ppm 7.27 (s, 1H), 4.06 (s, 1H), 3.99 (s, 2H), 2.95 (bs, 2H), 1.67 (s, 1H), 1.77 (s, 6H). MS (ESI) m/z 190.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([C@@H:17]([CH3:19])[OH:18])[NH:5][C:6](=[O:16])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[C@H:4]([C@@H:17]([CH3:19])[O:18][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28])[NH:5][C:6](=[O:16])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1
Reactant: COC(=O)[C@@H](NC(=O)COc1ccc(Cl)cc1)[C@@H](C)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COC(=O)[C@@H](NC(=O)COc1ccc(Cl)cc1)[C@@H](C)OS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
After the reaction was completed, the mixture was extracted twice with ethyl ether to eliminate unreacted p-chlorophenoxychloride, and the extracted aqueous phase was acidified with hydrochloric acid to precipitate a product which was then extracted three times with ethyl acetate. The extract was evaporated to dryness, and the residue was recrystallized from ethyl acetate/benzene/hexane to obtain a color-less crystal of N-(p-chlorophenoxy)acetyl-L-threonine. To a solution of 5 m moles of N-(p-chlorophenoxy)acetyl-L-threonine in ethyl ether, a solution of an excess amount of diazomethane in ethyl ether was added, and the mixture was allowed to stand for 30 minutes at a room temperature. The mixture was evaporated to dryness under a reduced pressure to obtain N-(p-chlorophenoxyacetyl)-L-threonine methyl ester. 3.4 m moles of N-(p-chlorophenoxyacetyl)-L-threonine methyl ester was dissolved in dried pyridine, and the resulting solution was added with 3.6 m moles of p-toluenesulfonyl chloride, stirred at 0° C. for two hours and at a room temperature for two hours. The reaction mixture was then partitioned between water and ethyl acetate, and organic phase was washed with 1N hydrochloric acid and water, and dried on anhydrous sodium sulfate. The solution was evaporated to dryness, and the resulting residue was purified by a middle pressure column chromatography with silica gel to obtain N-(p-chlorophenoxyacetyl)-O-(p-toluenesulfonyl)-L-threonine methyl ester. 0.5 m moles of N-(p-chlorophenoxyacetyl)-O-(p-toluenesulfonyl)-L-threonine methyl ester was then dissolved in 10 ml of methanol, the resulting solution was added with 1.5 ml of 1N sodium hydroxide and stirred for 20 minutes at a room temperature, and methanol was distilled off. The residue was acidified with 1N hydrochloric acid, and extracted with ethyl ether, and an organic phase was dried on anhydrous magnesium sulfate. Solvent was distilled off from the mixture to obtain a residue. The residue was then chromatographically purified to obtain the title compound N-(p-chlorophenoxyacetyl)-α,β-dehydrohomoalanine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][OH:21])[N:19]=2)([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][O:21][S:23]([CH3:22])(=[O:25])=[O:24])[N:19]=2)([CH3:14])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(CO)cs2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C)(c2nc(COS(C)(=O)=O)cs2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-hydroxymethyl-thiazol-2-yl)-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.42 g, 1.3 mmol) in methylene chloride (10 mL) was added methanesulfonyl chloride (0.19 g, 1.7 mmol) and triethylamine (0.2 g, 2 mmol) at 0° C. After stirring at 0° C. for 1 hour, the mixture was diluted with EtOAc and washed with H2O and brine. After drying (Na2SO4), the solvent was removed in vacuo, and the residue was purified by silica column chromatography with EtOAc/hexanes to afford the desired product.
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.[NH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[C:32]#[N:33].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[C:32]([C:31]1[CH:30]=[C:29]([CH:36]=[CH:35][CH:34]=1)[O:28][CH2:27][CH2:26][NH:25][C:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]2)=[O:9])=[CH:6][CH:5]=1)=[O:3])#[N:33]
Reactant: N#Cc1cccc(OCCN)c1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(C(=O)NCCOc3cccc(C#N)c3)cc2)CC1

Procedure:
1.60 g (4.8 mmol) of t-butyl 4-(4-carboxybenzoyl)piperazine-1-carboxylate, 1.58 g (8.0 mmol) of 3-(2-aminoethoxy)benzonitrile, 1.67 ml (12 mmol) of triethylamine, 650 mg (4.8 mmol) of 1-hydroxybenzotriazole and 920 mg (4.8 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were stirred in 20 ml of dimethylformamide at room temperature overnight. After the treatment with ethyl acetate as the extractant in an ordinary manner, the title compound was obtained.
Reaction SMILES: [OH:1][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CC(=O)CC>[CH2:24]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([OH:1])([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:3]1=[O:11])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: O=C1Nc2ccccc2C1(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: O
Product: O=C1N(Cc2ccccc2)c2ccccc2C1(O)c1ccccc1
Yield: 64.7 %

Procedure:
Combine 3-hydroxy-3-phenyl-1,3-dihydro-indol-2-one (225 mg, 1 mmol) and cesium carbonate (977 mg, 3 mmol) in 2-butanone (5 mL). Add benzyl bromide (0.13 mL, 1 mmol) and heat at 60° C. for 3 h. with vigorous stirring. Dilute the reaction with water and wash with ethyl acetate (2×). Wash combined organic portions with brine and then dry (MgSO4), filter and concentrate in vacuo to give an oil. Purify with radial chromatography (gradient of 10% EtOAc/hexanes to 25% EtOAc/hexanes) to give 204 mg (65%) of the title compound as a white solid. MS (ES): m/z=298 (M+1−H2O); 1H NMR(DMSO-d6); δ7.37-7.27 (m, 11H), 7.18 (m, 1H), 7.05 (m, 1H), 6.98 (m, 1H), 6.87 (s, 1H), 4.92 (s, 2H).