Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]1[CH3:11].Cl.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[CH:8][C:7]([C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=2)=[C:6]1[CH3:11]
Reactant: O=C(Cl)c1cccnc1
Reactant: COCCn1c(C)ccc1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COCCn1c(C)cc(C(=O)c2cccnc2)c1C
Yield: 13.2 %

Procedure:
In 1,2-dichloroethane, 2-(2,5-dimethylpyrrol-1-yl)-ethyl methyl ether was reacted with nicotinoyl chloride hydrochloride in the presence of aluminum chloride. The reaction product was chromatographed on a column of silica gel using cyclohexane/ethyl acetate (1/1) as an eluent to afford compound (260) in a yield of 13.2%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5](=[C:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)[NH:6][CH:7]=[O:8])[CH3:2].[SH:23][CH2:24][CH2:25][OH:26].C[O-].[Na+]>>[CH2:15]([N:12]1[CH2:13][CH2:14][C:9]([CH:5]([NH:6][CH:7]=[O:8])[C:4]([O:3][CH2:1][CH3:2])=[O:22])([S:23][CH2:24][CH2:25][OH:26])[CH2:10][CH2:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(NC=O)=C1CCN(Cc2ccccc2)CC1
Reactant: OCCS
Agent: C[O-]
Agent: [Na+]
Product: CCOC(=O)C(NC=O)C1(SCCO)CCN(Cc2ccccc2)CC1
Temperature: 80 °C

Procedure:
A mixture of ethyl(1-benzyl-4-piperidinylidene)(formylamino)acetate (3.0 g, 10.0 mmol), 2-mercaptoethanol (2.7 g, 35 mmol) and sodium methoxide (1 g) was heated at 80° C. for 8 h under nitrogen. The reaction mixture was then cooled to room temperature and quenched with saturated ammonium chloride solution. It was extracted with chloroform, washed twice with brine and dried over anhydrous Na2SO4, filtered and concentrated. The oily residue was purified by silica gel column chromatography eluting with 5% methanol:chloroform to provide ethyl {1-benzyl-4-[(2-hydroxyethyl)sulfanyl]-4-piperidinyl}(formylamino)acetate as a yellow oil; Yield: 2.8 g (73%); Electrospray Mass Spec: 381 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[C:4](C)[CH:3]=1.[CH3:11]O.O>>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(Cl)sc1C(=O)O
Reactant: CO
Solvent: O
Product: Cc1cc(C(=O)O)sc1Cl

Procedure:
5-Chloro-3-methyl-thiophene-2-carboxylic acid, melting point (methanol/H2O) 149°-152° C. (90%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2Br)=[CH:2]1.C([Li])CCC.CCCCCC.[CH:25](N1CCCCC1)=[O:26]>O1CCCC1>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:25]=[O:26])=[CH:2]1
Reactant: Brc1ccccc1Cc1ccoc1
Reactant: O=CN1CCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccccc1Cc1ccoc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of Compound 3b (0.5 mmol) in tetrahydrofuran (2 mL) at -78° C. under nitrogen was added n-butyllithium in hexane (0.5 mmol). After 30 minutes, a solution of N- formylpiperidine (0.55 mmol) in tetrahydrofuran (0.5 mL) was added dropwise at -78° C. The reaction mixture was stirred for 5 hours while allowing it to warm to -10° C. The reaction was quenched with saturated aqueous ammonium chloride (1 mL) and diluted with diethyl ether (10 mL). The aqueous phase was extracted with diethyl ether (2×10 mL) and the combined organic phases were washed with saturated aqueous ammonium chloride (3×5 mL) and brine and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel eluted with ethyl acetate:hexane (2:98) to afford Compound 3c as an oil (Rf =0.2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:23][C:24]1([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:23][C:24]1([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)=[O:9]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CCC(c2ccccc2)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC(c4ccccc4)C3)CC2)cc1
Yield: 51.3 %

Procedure:
The title compound (D143) (210 mg) was prepared according to the experimental procedure described in Description 142 starting from 5-chloro-2-(3-phenylpyrrolidin-1-yl)nicotinic acid (D99) (260 mg, 0.860 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (195 mg, 0.86 mmol).
Reaction SMILES: [Cl:1]/[C:2](/[CH3:7])=[CH:3]\[C:4](Cl)=[O:5].[NH2:8][C:9]1[CH:10]=[C:11]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])[CH:12]=[CH:13][CH:14]=1.C(N(CC)CC)C>O1CCCC1>[C:15]([C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[NH:8][C:4](=[O:5])/[CH:3]=[C:2](\[Cl:1])/[CH3:7])(=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC(=O)c1cccc(N)c1
Reactant: C/C(Cl)=C/C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)c1cccc(NC(=O)/C=C(/C)Cl)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 49.5 %

Procedure:
29.2 g of β-chlorocrotonyl chloride were added over one hour at 0° C to a mixture of 31 g of m-amino-butyrophenone 21.2 g of triethylamine and 300 ml of tetrahydrofuran and after stirring for 16 hours at 20° C, the mixture was vacuum filtered. The filtrate was concentrated to dryness and the residue was chromatographed over silica gel to obtain 25 g of m-butyryl-3-chlorocrotonanilide melting at 106° C.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=1.O>C(N(CC)CC)C.[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>[CH3:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=1
Reactant: Cc1ccnc(Br)c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccnc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenylacetylene (15.4 mL) is added to a mixture of 2-bromo-4-methyl-pyridine (20.0 g), CuI (2.2 g), and Pd(PPh3)2Cl2 (4.1 g) in triethylamine (600 mL) kept under argon atmosphere. The mixture is stirred at ambient temperature overnight. Then, water is added and the resulting mixture is extracted with diethyl ether. The combined organic extracts are washed with brine and dried (MgSO4). The solvent is removed under reduced pressure and the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 9:1->4:1) to give the product as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].[C:12]1([C:18]2[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:18]2[CH:19]=[CH:20][C:21]([NH:1][C:2]3[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=3[CH3:7])=[CH:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: COC(=S)c1cc(N)c(C)s1
Product: COC(=S)c1cc(Nc2ccc(-c3ccccc3)cc2)c(C)s1
Yield: 20 %

Procedure:
Using a procedure similar to Example 208, step (a), 74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed to react with 142.5 mg (2 equiv, 0.72 mmol) of 4-phenylphenyl boronic acid to give 24.5 mg (19.1%) of methyl 4-[(4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxylate. 1H NMR (CDCl3, 400 MHz) δ2.45 (s, 3H), 3.92 (s, 3H), 6.38 (bs, 1H), 7.08-7.14 (m, 2H), 7.33 (m, 1H), 7.43-7.46 (m, 2H), 7.54-7.60 (m, 4H), 7.82 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(OC)(C)C>CN(C=O)C.O>[CH2:20]([O:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)c1ccc(O)c(C=O)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(OCc2ccccc2)c(C=O)c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a stirred solution of compound 2 (614.5 g, 3.33 mol) in DMF (3.5 L) was added K2CO3 (953 g, 6.90 mol) and benzyl chloride (480 g, 3.80 mol). The mixture was heated to 90° C. and left stirring for 3 hours. The suspension was cooled to room temperature, then MTBE (2 L) was added, followed by water (12 L). The mixture was then stirred for 10 minutes and the aqueous layer was separated and extracted with MTBE (2 L×3). The organic layers were combined and washed with water (2 L×2) and brine (1.5 L×1) and concentrated to give compound 3 as a light-yellow solid. 1H NMR (DMSO-d6; 400 MHz) δ 10.42 (s), δ 7.71 (m), δ 7.51 (m), δ 7.43 (m), δ 7.35 (m), δ 7.24 (m), δ 5.27 (s), δ 1.26 (s).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][CH:11]([N:13]2[C:21](=[O:22])[C:20]3[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)[CH:18]=[N:17][C:16]=3[N:15]([CH3:31])[C:14]2=[O:32])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:40])C(=O)C1>CN(C=O)C>[CH2:1]([O:8][CH:9]1[CH2:10][CH:11]([N:13]2[C:21](=[O:22])[C:20]3[N:19]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[C:18]([Cl:40])=[N:17][C:16]=3[N:15]([CH3:31])[C:14]2=[O:32])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1c(=O)n(C2CC(OCc3ccccc3)C2)c(=O)c2c1ncn2Cc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C2CC(OCc3ccccc3)C2)c(=O)c2c1nc(Cl)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.5 %

Procedure:
To a solution of 1-(3-(benzyloxy)cyclobutyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (220 mg, 0.49 mmol) in DMF (3 mL) was added NCS (71.7 mg, 0.54 mmol) in portions at 0° C. The reaction was stirred at room temperature for 4 h. The reaction was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried and concentrated to give a crude product, which was purified by silica gel chromatography eluting with DCM/methanol (60:1) to give 1-(3-(benzyloxy)cyclobutyl)-8-chloro-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (170 mg, 71.8% yield) as yellow solid. LCMS retention time 2.079 min; LCMS MH+ 485.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=O)[CH2:5][CH2:4]1.S(Cl)([Cl:14])=O>>[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]([Cl:14])=[O:11])[CH2:5][CH2:4]1
Reactant: O=S(Cl)Cl
Reactant: CN1CCC(C(=O)O)CC1
Agent: Cl
Product: CN1CCC(C(=O)Cl)CC1
Temperature: 25 °C

Procedure:
1-Methylpiperidine-4-carboxylic acid hydrochloride salt 10 g (55.7 mmol) was added to thionyl chloride (25 ml) and resulting mixture stirred at room temperature until the solid dissolved completely. The reaction mixture was stirred for another 20 minutes and concentrated. The product was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[CH2:24]([N:28]([CH2:32][CH2:33]Cl)[CH2:29][CH2:30]Cl)[CH2:25][CH2:26][CH3:27]>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:33][CH2:32][N:28]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30]1)=[O:23])[CH3:2]
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CCCCN(CCCl)CCCl
Product: CCCCN1CCC(C(=O)OCC)(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC1

Procedure:
1-Butyl-4-[4-(4-chlorophenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(4-chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester (6 g, 18.3 mmol) and butyl-bis-(2-chloro-ethyl)-amine (5.2 g, 22 mmol). Yield 3.3 g (38%); yellow oil; MS: 480 (M+H)+
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CC([O-])(C)C.[K+].[F:36][C:37]1[CH:38]=[C:39]([C@H:47]2[CH2:52][CH2:51][C@H:50]([C@H:53]3[CH2:58][CH2:57][C@H:56]([CH:59]=O)[CH2:55][CH2:54]3)[CH2:49][CH2:48]2)[CH:40]=[CH:41][C:42]=1[C:43]([F:46])([F:45])[F:44]>C(OCC)(=O)C>[F:2][CH2:3][CH2:4][CH:5]=[CH:57][C@H:56]1[CH2:55][CH2:54][C@H:53]([C@H:50]2[CH2:49][CH2:48][C@H:47]([C:39]3[CH:40]=[CH:41][C:42]([C:43]([F:46])([F:44])[F:45])=[C:37]([F:36])[CH:38]=3)[CH2:52][CH2:51]2)[CH2:58][CH2:59]1
Reactant: FCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C(F)(F)F)c(F)c3)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FCCC=C[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C(F)(F)F)c(F)c3)CC2)CC1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A mixture of (3-fluoropropyl)triphenylphosphonium bromide (11.2 g, 27.8 millimols) with THF (50 ml) was cooled down to -20° C., followed by adding t-BuOK (3.1 g, 27.8 millimols) to the mixture, stirring for one hour, dropwise adding to the mixture, a THF (100 ml) solution of trans-4-(trans-4-(3-fluoro-4-trifluoromethylphenyl)cyclohexyl)cyclohexanecarbaldehyde (9.0 g, 25.3 millimols) so as to keep the temperature at -20° C. or lower, stirring the mixture at the same temperature for 2 hours, and treating the reaction product in the same manner as in Example 2 except that the quantity of ethyl acetate used for extraction was made 400 ml, to obtain raw (trans-4-(trans-4-(4-fluorobutenyl)cyclohexyl)cyclohexyl)-3-fluoro-4-trifluoromethylbenzene (8.9 g).
Reaction SMILES: [N:1]#[N:2].C(OC(=O)CN(C(=O)[C@H](CCCNC(=N)N)NS(C1C=CC2C(=CC(C)=C(C)C=2)C=1)(=O)=O)CCCC)(C)(C)C.[C:42]([O:46][C:47](=[O:54])[CH2:48][NH:49][CH2:50][CH2:51][CH2:52][CH3:53])([CH3:45])([CH3:44])[CH3:43].N#N.[CH3:57][O:58][C:59]1[CH:60]=[C:61]2[C:66](=[CH:67][C:68]=1[O:69][CH3:70])[CH:65]=[C:64]([S:71]([NH:74][C@H:75]([C:83](Cl)=[O:84])[CH2:76][CH2:77][CH2:78][NH:79][C:80](=[NH:82])[NH2:81])(=[O:73])=[O:72])[CH:63]=[CH:62]2>C(Cl)(Cl)Cl>[N:1]#[N:2].[C:42]([O:46][C:47](=[O:54])[CH2:48][N:49]([C:83](=[O:84])[C@H:75]([CH2:76][CH2:77][CH2:78][NH:79][C:80](=[NH:81])[NH2:82])[NH:74][S:71]([C:64]1[CH:63]=[CH:62][C:61]2[C:66](=[CH:67][C:68]([O:69][CH3:70])=[C:59]([O:58][CH3:57])[CH:60]=2)[CH:65]=1)(=[O:73])=[O:72])[CH2:50][CH2:51][CH2:52][CH3:53])([CH3:45])([CH3:44])[CH3:43]
Reactant: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)cc2cc1OC
Reactant: CCCCNCC(=O)OC(C)(C)C
Agent: CCCCN(CC(=O)OC(C)(C)C)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(C)c(C)cc2c1
Agent: N#N
Solvent: ClC(Cl)Cl
Product: CCCCN(CC(=O)OC(C)(C)C)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Reaction time: 1 h
Yield: 82 %

Procedure:
N2 -(6,7-dimethyl-2-naphthylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester: To a stirred solution of 2.64 g of N-butylglycine tert-butyl ester in 20 ml of chloroform was carefully added N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was allowed to stand at room temperature for one hour. At the end of this period, the reaction mixture was washed twice with 20 ml of saturated sodium chloride solution and evaporated to dryness. The residue was triturated with a small amount of water to give a crystalline material. This was collected by filtration and recrystallized from ethanol-ethyl ether to give 2.28 g (82 percent) of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-butylglycine tert-butyl ester, M.P. 164°-166° C, I.R. (KBr): 3,390, 3,165, 1,735, 1,370 cm-1.
Reaction SMILES: O.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[OH-].[Na+].[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>C(OCC)C>[C:19]([O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:8]=1)(=[O:22])[CH:20]=[CH2:21]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: C=CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: C=CC(=O)Oc1ccc(C(=O)c2ccccc2)cc1
Temperature: 9 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
A three-neck round-bottom flask fitted with an addition funnel, thermometer and a mechanical stirrer was charged with 100 ml of water, 40 g (0.20M) of p-hydroxybenzophenone and 8.8 g of sodium hydroxide. The flask was cooled in an ice bath to 8-10° C., then 20 g (0.22) of acryloyl chloride were added dropwise while holding the temperature at 8-10° C. When the addition was complete, the reaction mixture was stirred for an additional half hour. Then 150 ml of diethyl ether was added to dissolve the product of the reaction. The ether layer was separated from the water layer and washed twice with 3% sodium hydroxide and twice with water. The solution was dried over magnesium sulfate, filtered and stripped. An amount of 43.0 g of an oily product was obtained and purified by recrystallization from absolute ethanol, from which an amount of about 34.7 g of white crystalline product was isolated.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5](Br)[C:6]2[N:7]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:8]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.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>[Br:2][C:3]1[CH:4]=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:6]2[N:7]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:8]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cn2cc(Br)cc(Br)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Br
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn2cc(Br)cc(-c3ccccc3)c2n1
Temperature: 80 °C
Yield: 55.5 %

Procedure:
A solution of ethyl 6,8-dibromoimidazo[1,2-a]pyridine-2-carboxylate hydrobromide (0.5 g, 1.2 mmol) and phenylboronic acid (0.15 g, 1.2 mmol) in toluene (10 mL) and ethanol (2 mL) was bubbled nitrogen for 20 mins. The mixture was then treated with Pd(PPh3)4 (30 mg, 0.026 mmol) and K3PO4 (2 M, 1 mL, 2 mmol) and heated at 80° C. overnight. The reaction was cooled, poured into ethyl acetate (200 mL), washed with brine, separated, and concentrated. The residue was purified by column chromatography on silica gel using ethyl acetate in hexanes (10%) as eluent. The product containing fractions were concentrated to give 0.23 g (58% yield) of ethyl 6-bromo-8-phenylimidazo[1,2-a]pyridine-2-carboxylate as a white solid. LCMS (Conditions C): 3.41 min (RT); (M+H)+=347.24 (100%), 345.24 (100%). 1H NMR, 400 MHz, CDCl3: δ 8.27 (d, J=1.6 Hz, 1 H), 8.19 (s, 1 H), 8.02 (m, 2H), 7.52-7.41 (m, 4 H), 4.45 (q, J=7.1 Hz, 2 H), 1.42 (t, J=7.0 Hz, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@H:4]([CH2:15][OH:16])[NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:18]=O>CO>[CH3:1][O:2][C:3](=[O:17])[CH:4]([N:5]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:18])[CH2:15][OH:16]
Reactant: C=O
Reactant: COC(=O)[C@H](CO)NCCCc1ccccc1
Solvent: CO
Product: COC(=O)C(CO)N(C)CCCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of N-(3-phenylpropyl)serine methyl ester (6.4 g, 0.027 mol) in methanol (150 ml) is added with 10% Pd-on-carbon (0.7 g) and 40% formic aldehyde (3.0 ml 0.04 mol) dissolved in methanol (50 ml). The mixture is stirred at room temperature under hydrogen atmosphere, under a slight pressure (40 psi) until the absorption ceases. The mixture is filtered and the filtrate is evaporated under vacuum. The residue is taken up in ethyl ether (300 ml), washed with water (2×200 ml), dried over sodium sulfate and evaporated under vacuum. Yield: 6.6 g
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:16])[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].N1C=CN=C1.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Br:1][CH2:2][CH:3]([O:16][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27])[CH2:4][N:5]1[C:6](=[O:15])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]1=[O:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1c2ccccc2C(=O)N1CC(O)CBr
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC(CBr)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-(3-bromo-2-hydroxypropyl)isoindoline-1,3-dione (100 mg, 0.352 mmol) in DMF (0.5 mL) was added dropwise to a mixture of DMAP (43.0 mg, 0.352 mmol), imidazole (47.9 mg, 0.704 mmol) and tertbutyldimethylsilyl chloride (74.3 mg, 0.493 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with EtOAc (20 ml) and washed with saturated NaHCO3(aq) (20 ml) and brine (3×10 ml). The organic phase was dried over magnesium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-100% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[O:14][CH3:15]>CO.[C].[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: COC(=O)/C=C/c1ccc(O)c(OC)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.9 %

Procedure:
To a solution of methyl (E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoate (3.0 g, 14 mmol) in methanol (30 mL) was added 10% palladium carbon (50% water content, 0.20 g), and the mixture was stirred at room temperature for 4 hours under hydrogen atmosphere. The reaction solution was filtered, and then the filtrate was concentrated under reduced pressure to give the title compound (3.0 g, yield 97%) as an oily matter. The obtained compound was used in the next reaction without purification.