Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.C(OCC)(=O)C>CN(C=O)C>[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:11]2[C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6](=[O:7])[C:5]3[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:9][C:10]2=[O:19])=[CH:27][CH:26]=1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)N1CC(=O)N(Cc2ccc(Br)cc2)c2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 mg (0.067 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 5 ml of DMF. 3 mg (0.8 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 20 mg (0.08 mmol) of 4-bromobenzyl bromide was added to the obtained mixture and they were stirred at 60° C. overnight. The reaction mixture was treated with ethyl acetate as the extracting solvent by an ordinary method to obtain the crude product. After the purification by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[C:8]([C:15]([F:18])([F:17])[F:16])[C:7]=1[NH:19][C:20](=[O:29])[CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1.[Zn]>[NH2:12][C:10]1[CH:9]=[C:8]([C:15]([F:17])([F:18])[F:16])[C:7]([NH:19][C:20](=[O:29])[CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:6]([Br:5])[CH:11]=1
Reactant: O=C(CCC1CCCCC1)Nc1c(Br)cc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1cc(Br)c(NC(=O)CCC2CCCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
Acetic acid (3.70 mL) was added slowly to a mixture of zinc dust (7.88 g) and N-(2-bromo-4-nitro-6-trifluoromethyl-phenyl)-3-cyclohexyl-propionamide (1.99 g) in tetrahydrofuran (40 mL). The reaction mixture was then stirred for 1½ hours at 25° C. The reaction mixture was filtered, diluted with saturated aqueous sodium bicarbonate (400 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with water (100 mL), brine (100 mL), dried over sodium sulfate and concentrated in vacuo to furnish 1.85 g (100% yield) of the title compound as a yellow solid. LC-MS (m/z) 394 (MH+); tR=3.22, (UV, ELSD) 92%, 99%. 1H NMR (500 MHz, DMSO-d6): 0.86 (q, 2H), 1.17 (m, 3H), 1.26 (m, 1H), 1.46 (q, 2H), 1.67 (m, 5H), 2.40 (t, 2H), 5.83 (s, 2H), 6.88 (d, 1H), 7.07 (d, 1H), 9.27 (s, 1H).
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1.[CH:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1>C1COCC1>[Cl:6][C:7]1[C:12]([CH:26]([C:23]2[CH:24]=[CH:25][C:20]([O:19][C:16]3[CH:15]=[CH:14][CH:13]=[CH:18][CH:17]=3)=[CH:21][CH:22]=2)[OH:27])=[N:11][CH:10]=[CH:9][N:8]=1
Reactant: Clc1cnccn1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.5 M of n-BuLi in hexanes (10 mL) in THF (50 mL) was added 2,2,66-tetramethyl-piperidine (5.3 mL, 0.031 mol) slowly at −78° C. The cooling bath was replaced by an ice-water bath for 30 min and the solution was re-cooled to −78° C. After 5 min a solution of 2-chloropyrazine (2.3 mL, 0.026 mol) in THF (10 mL) is added. The reaction mixture turned brown in color. After 10 min, 4-formyldiphenyl ether (6.2 g, 0.031 mol) was added slowly. The reaction mixture was stirred at −78° C. for 2.5 h. The reaction mixture was quenched using sat. aq. NH4Cl at −78° C. After warming up to rt, the reaction mixture was concentrated under vacuo and purified by flash column chromatography (eluting with 10% EtOAc in hexanes) to afford the title compound. 1H NMR (400 MHz, CDCl3): δ 6.02 (s, 1H), 6.93-6.98 (m, 2H), 7.00 (d, J=7.58 Hz, 2H), 7.12 (t, J=7.33 Hz, 1H), 7.29-7.37 (m, 4H), 8.39 (d, J=2.53 Hz, 1H), 8.58 (d, J=2.53 Hz, 1H). MS (ES+): m/z 295.08 (100)[M-18]. HPLC: tR=3.46 min (Open lynx, polar—5 min).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C[Al](C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[N:18]1[C:23]2[N:24]=[C:25]([NH:36][CH2:37][C:38](OC)=[O:39])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[CH3:35])[C:22]=2[CH:21]=[CH:20][C:19]1=[O:42]>>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[N:18]1[C:23]2[N:24]=[C:25]([NH:36][CH2:37][C:38]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:39])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[CH3:35])[C:22]=2[CH:21]=[CH:20][C:19]1=[O:42]
Reactant: COCCN
Reactant: COC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: C[Al](C)C
Product: COCCNC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Yield: 66.2 %

Procedure:
Following the general procedure outlined in Example 193, 2-methoxy-ethylamine (0.17 mL, 2.2 mmol), trimethylaluminum (1.1 mL, 2.2 mmol) and the product of Example 190 (200 mg, 0.44 mmol) were reacted to give the desired product 145 mg (66%). LC-MS: 498.2 (MH+, m/z), 1.90 (Rt, min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[C:14]([C:19]#[N:20])[CH:15]=[N:16]2)=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:27])=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:27])=[C:14]([C:19]#[N:20])[CH:15]=[N:16]2)=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc2c(O)c(C#N)cnc2cc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)c(C#N)cnc2cc1OCc1ccccc1

Procedure:
To a stirred suspension of 1 g of 7-benzyloxy-4-hydroxy-6-methoxy-quinoline-3-carbonitrile in 10 ml of methylene chloride was added 5 ml of oxalyl chloride (2M in methylene chloride), and 2 drops of N,N-dimethylformamide. The mixture was refluxed for 20 min and to it was slowly added aqueous sodium bicarbonate until the bubbling ceased. Following separation of the layers, the organic layer was evaporated to a small volume, then passed through a plug of magnesol. Elution with 50 ml methylene chloride, followed by evaporation provided 0.6 g of 7-benzyloxy-4-chloro-6-methoxy-quinoline-3-carbonitrile as a pale yellow solid, mp 282-284° C.; mass spectrum (electrospray, m/e) M+H 325.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]([OH:24])([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[CH2:17][CH3:18])[CH:5]=[C:6]([O:8]CC2C=CC=CC=2)[CH:7]=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:16]([OH:24])([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[CH2:17][CH3:18])[CH:5]=[C:6]([OH:8])[CH:7]=1
Reactant: CCC(O)(c1cc(F)cc(OCc2ccccc2)c1)c1nccs1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCC(O)(c1cc(O)cc(F)c1)c1nccs1
Yield: 79 %

Procedure:
To a solution of 5-fluoro-3-[1-hydroxy-1-(thiazol-2-yl)propyl](O-benzyl)phenol (200 mg, 0.58 mmol) in MeOH (9 mL) was added 10% Pd on charcoal (200 mg) and ammonium formate (180 mg, 2.9 mmol). The reaction mixture was refluxed for 2 h and then flitrated through a pad of celite and washed with EtOAc. After evaporation of the solvent, the residue was purified by chromatography on silica gel using a mixture of hexane:EtOAc 7:3 to give 116 mg (79%) of the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:11]([CH3:28])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19](=[N:23]C(C)(C)C)[CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:29]([C:38](OC)=[O:39])([C:34](OC)=[O:35])[C:30]([O:32][CH3:33])=[O:31]>O(C1C=CC=CC=1)C1C=CC=CC=1>[Si:1]([O:8][CH2:9][C:10]1[N:11]([CH3:28])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19]1[NH:23][C:34](=[O:35])[C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:38]([OH:39])[C:20]=1[CH2:21][CH3:22])=[CH:14][CH:13]=2)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCCC(=NC(C)(C)C)c1ccc2c(c1)cc(CO[Si](C)(C)C(C)(C)C)n2C
Reactant: COC(=O)C(C(=O)OC)C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1c(-c2ccc3c(c2)cc(CO[Si](C)(C)C(C)(C)C)n3C)[nH]c(=O)c(C(=O)OC)c1O
Temperature: 230 °C
Yield: 21.2 %

Procedure:
To a solution of N-(1-(2-((tert-butyldimethylsilyloxy)methyl)-1-methyl-1H-indol-5-yl)butylidene)-2-methylpropan-2-amine (2.10 g, ca. 5.2 mmol), prepared according to procedure described in Example 39 Step 5, in Ph2O (5 mL) was added trimethyl methanetricarboxylate (1.68 g, 8.8 mmol, 1.7 eq). The mixture was heated to 230° C. for 2 h. The mixture was cooled to room temperature then purified by flash column chromatography (0-50% EtOAc in CH2Cl2) to afford the title compound (0.51 g, 1.1 mmol, 21%) as a light yellow solid. LC-MS 469.2 [M−H]−, 471.2 [M+H]+, RT 1.67 min.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1>C(O)(=O)C>[Cl:12][C:4]1[CH:3]=[C:2]([N:1]2[CH:15]=[CH:19][CH:18]=[CH:17]2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)c1ccc(N)cc1Cl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-n2cccc2)cc1Cl

Procedure:
2.0 g of methyl 4-amino-2-chlorobenzoate were dissolved in 10 ml of acetic acid, 2.0 ml of 2,5-dimethoxytetrahydrofuran were added thereto, and the mixture was heated under reflux for 15 minutes. After cooling the reaction solution, the solvent was evaporated. The obtained residue was mixed with EtOAc and saturated NaHCO3 aq. and extracted. The organic layer was washed with brine, and dried over sodium sulfate anhydride. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane-EtOAc (4:1)) to obtain 2.1 g of methyl 2-chloro-4-(1H-pyrrol-1-yl)benzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([S:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].Br[CH2:24][C:25]#[C:26][CH3:27]>>[CH2:13]([O:12][C:10](=[O:11])[CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:24][C:25]#[C:26][CH3:27])=[CH:18][CH:17]=1)[CH3:14]
Reactant: CCOC(=O)C(Sc1ccc(O)cc1)c1ccccc1OC
Reactant: CC#CCBr
Product: CC#CCOc1ccc(SC(C(=O)OCC)c2ccccc2OC)cc1
Yield: 87 %

Procedure:
Ethyl(2-methoxyphenyl){[4-(2-butynyloxy)phenyl]sulfanyl}acetate was prepared according to the general method as outlined in example 1 (step 2), starting from ethyl (2-methoxyphenyl)[(4-hydroxyphenyl)sulfanyl]acetate (3.2 g, 10 mmol) and 1-bromo-2-butyne (1.5 g, 11.2 mmol); 3.2 g clear oil. Yield 87%; MS(EI): 371 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[C:16]([F:24])[CH:15]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[N:31]=[CH:32][S:33][CH:34]=1)CCC.[Cl-]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:24][C:16]1[CH:15]=[C:14]([C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[N:31]=[CH:32][S:33][CH:34]=4)=[CH:3][CH:4]=3)[C:12]([CH3:13])=[CH:11][CH:10]=2)[CH:19]=[CH:18][C:17]=1[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)c(F)c2)n1-c1ccc(Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)c(F)c2)n1-c1ccc(-c2cscn2)cc1
Yield: 68.7 %

Procedure:
To a stirred solution of 1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole (0.318 g, 0.78 mmol, Example 35, step 3) in 1,4-dioxane (12 mL) was added 4-(tributylstannyl)thiazole (0.35 g, 0.94 mmol), lithiun chloride (0.083 g, 1.95 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.090 g, 0.078 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 3.5 hours. After cooling, volatiles were removed by evaporation. The residue was redissolved in ethyl acetate (30 mL) and the whole washed with water and brine. After dried over MgSO4 and concentration in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (3/1). The resulting solid was recrystallized from ethyl acetate-hexane to give the title compound (0.221 g, 68.8% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][CH3:22])=[C:19]([C:23](O)=[O:24])[C:18]([CH2:26][CH3:27])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[N:59]1([CH2:66][CH2:67][OH:68])[CH2:65][CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][CH3:22])=[C:19]([C:23]([N:62]4[CH2:63][CH2:64][CH2:65][N:59]([CH2:66][CH2:67][OH:68])[CH2:60][CH2:61]4)=[O:24])[C:18]([CH2:26][CH3:27])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)O
Reactant: OCCN1CCCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)N1CCCN(CCO)CC1
Reaction time: 0.5 h

Procedure:
A solution of 0.20 g (0.50 mmol) of 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-diethyl-1H-pyrazole-4-carboxylic acid (intermediate 1) and 0.21 g (0.50 mmol) of HATU were dissolved in 8 ml of DMF at RT. While stirring, 0.16 g=0.22 ml (1.60 mmol) of Et3N were added drop by drop. After 30 min, a solution of 0.076 g (0.50 mmol) of 2-[1,4]diazepan-1-yl-ethanol in 2 ml of DMF were added drop by drop and stirring was continued for 20 hours at RT. The reaction mixture was poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0-9:1) to afford the title compound as colorless oil. MS: 507.4 (MH+, 1 Cl).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][CH2:6][C@H:7]([CH2:10][CH:11]=[CH2:12])[CH2:8][OH:9]>CN(C=O)C>[CH2:6]([C@H:7]1[CH2:10][CH2:11][CH2:12][O:9][CH2:8]1)[CH:5]=[CH2:4]
Reactant: C=CC[C@H](CO)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@H]1CCCOC1
Temperature: 7.5 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
DMF (350 mL) was added to a round bottom flask containing NaH (60% w/w, 15 g, 0.376 mmol) and a magnetic stir bar. The suspension was cooled to 5-10° C. in an ice bath and stirred for 5 min A solution of (R)-2-(3-chloropropyl)pent-4-en-1-ol (30.6 g, 188 mmol) in DMF (350 mL) was added via addition funnel over 25 min. Caution: Gas evolution and exotherm. The resulting creamy suspension was stirred for 30 min. The reaction was warmed to room temperature and the resulting beige suspension was stirred for 2 h, at which time it was judged complete by TLC. The reaction mixture was cooled to 0° C. and quenched by addition of H2O (250 mL) and HCl (3N, 250 mL). The phases were separated and the aqueous phase was extracted with petroleum ether (4×250 mL). The combined with organic layers were washed with H2O, brine, dried over MgSO4, filtered, and concentrated under reduced pressure to furnish the crude product as a yellow oil. The crude material was purified by flash chromatography (ISCO; 120 g column; Hexane to 30% EtOAc/Hexane) to provide (R)-3-allyl-tetrahydro-2H-pyran as a clear oil (19.8 g, 157 mmol, 83%); 1H NMR (400 MHz. CDCl3) δ 5.72-5.82 (m, 1H), 5.00-5.06 (m, 2H), 3.86-3.91 (m, 2H), 3.37 (m, 1H), 3.08 (t, J=12 Hz, 1H), 1.85-1.98 (m, 3H), 1.59-1.69 (m, 3H), 1.15-1.21 (m, 1H).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:23]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:37]([O:41][C:42]([NH:44][CH2:45][C:46]([NH:48][C@H:49]1[CH2:53][N:52]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[C@H:51]([C:61](O)=[O:62])[CH2:50]1)=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38]>ClCCl.C(Cl)(Cl)Cl>[CH2:23]([C:30]1[CH:31]=[CH:32][C:33]([NH:34][C:61](=[O:62])[C@@H:51]2[CH2:50][C@@H:49]([NH:48][C:46](=[O:47])[CH2:45][NH:44][C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:43])[CH2:53][N:52]2[C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])=[CH:35][CH:36]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1ccc(Cc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)Nc2ccc(Cc3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
1-Hydroxybenzotriazole (21 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (65 mg) were added to a solution of 4-benzylaniline (57 mg) and trans-4-(N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-proline (Compound D103 (B), 120 mg) in dichloromethane (3 mL) at 0° C. The mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with chloroform and washed with saturated sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1, v/v) to give the title compound (158 mg) as a colorless foam: 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 18H), 2.01 (m, 1H), 2.70 (m, 1H), 3.26 (m, 1H), 3.75 (m, 3H), 3.91 (s, 2H), 4.50 (m, 2H), 5.53 (m, 1H), 6.79 (m, 1H), 7.08-7.28 (m,7H), 7.40 (d, J=7.8 Hz, 2H), and 9.28 (m, 1H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=2)[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:13][C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([N:17]3[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]3)[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cccc(-c2csc(Br)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2csc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)c1
Yield: 69.6 %

Procedure:
A solution of 2-bromo-4-(3-methylphenyl)-1,3-thiazole (2.03 g, 7.99 mmol), tert-butyl piperazine-1-carboxylate (2.98 g, 16.0 mmol) and potassium carbonate (1.10 g, 7.99 mmol) in dimethylformamide (25 ml) was stirred at 120° C. for 12 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.00 g (69.7%) of the desired product as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cn1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cc1ccc(C=CC(=O)O)cn1
Reaction time: 3 h
Yield: 59.4 %

Procedure:
A mixture of 6-methylpyridine-3-carboxaldehyde (51.57 g), malonic acid (44.30 g), piperidine (6 ml) and pyridine (300 ml) was stirred at 100° for 3 hours and was allowed to cool. The mixture was evaporated to dryness, water was added to the residue and the solid was filtered off and recrystallised from ethanol-acetic acid to give 3-(6-methyl-3-pyridyl)acrylic acid (41.25 g) m.p. 213.5°-215.5°.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH2:17][C:18]([OH:20])=[O:19]>C(O)(=O)C>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH:16]([N:15]2[C:10](=[O:11])[C:5]3=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[CH:13][CH:12]=[C:6]3[C:7]2=[O:9])[CH2:17][C:18]([OH:20])=[O:19])=[CH:26][CH:25]=1
Reactant: COc1ccc(C(N)CC(=O)O)cc1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc(C(CC(=O)O)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)cc1
Yield: 79 %

Procedure:
A mixture of 3-nitrophthalic anhydride (1.54, 8.0 mmol) and 3-amino-3-(4-methoxyphenyl)propionic acid (1.56 g, 8.0 mmol) in 15 mL of acetic acid was refluxed for 3.5 h under nitrogen. The reaction was cooled and removed some of the solvent. The slurry was filtered and the solid was dried to afford 2.34 g (79%) of 3-(4-methoxyphenyl)-3-(3-nitrophthalimido)propionic acid as a white powder: mp 178-180° C.; 1H NMR (DMSO-d6, 250 MHz) δ8.07-8.02 (m, 3H), 7.38 (d, 2H, J=8.7), 6.90 (d, 2H, J=8.7, 5.68-5.07 (m, 1H), 3.72 (s, 3H), 3.48-3.22 (m, 2H); 13C NMR (DMSO-d6) δ171.6, 165.7, 163.0, 158.8, 144.4, 136.4, 133.0, 130.2, 128.6, 128.5, 127.0, 122.4, 113.9, 55.1, 50.0, 35.8. Anal. Calcd for C18H14N2O7. Theoretical: C, 58.38; H,3.81; N, 7.56. Found: C, 58.18; H, 3.79; N, 7.36.
Reaction SMILES: B.[CH3:2][C:3]1([CH3:28])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3([CH3:27])[C:19]4[CH:20]=[C:21]([C:24](O)=[O:25])[CH:22]=[CH:23][C:18]=4[O:17][CH2:16]3)[CH:6]=[CH:5][C:4]1=2.O>C1COCC1>[CH3:2][C:3]1([CH3:28])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3([CH3:27])[C:19]4[CH:20]=[C:21]([CH2:24][OH:25])[CH:22]=[CH:23][C:18]=4[O:17][CH2:16]3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C3(C)COc4ccc(C(=O)O)cc43)ccc21
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C3(C)COc4ccc(CO)cc43)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7.7 ml of a 1M solution of borane in THF are added dropwise at 0° C. to a solution of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-3-methyl-2,3-dihydrobenzofuran-5-carboxylic acid (1.7 g, 4.7 mol) in THF (10 ml). The mixture is stirred for 4 hours at ambient temperature and then 2 ml of a solution of THF and water (1:1) are added. After concentration in vacuo at 40° C. in a rotary evaporator. The mixture is extracted with ethyl acetate. The organic phase is washed with water, dried over anhydrous magnesium sulphate, concentrated in vacuo at 40° C. in a rotary evaporator. The product is purified by flash chromatography on a silica column.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[C:2]1([NH:1][C:15](=[O:16])[C:12]2[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 39.8 %

Procedure:
Aniline (0.87 mL, 9.57 mmol) was added slowly to a mixture of 4-Bromo-1-benzenecarbonyl chloride (2.0 g, 9.11 mmol) and triethyl amine (1.9 mL, 13.67 mmol) in dichloromethane (95 mL). After 3 hours, solvent was removed under reduced pressure. Ethyl acetate was added and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was re-crystallized from ethyl acetate/heptane to give N1-phenyl-4-bromobenzamide (1.00 g, 40%). 1H NMR (DMSO-d6) δ 7.11 (m, 1H), 7.38 (m, 2H), 7.76 (m, 4H), 7.92 (m, 2H), 10.30 (s, 1H).