Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].Br[CH2:21][C:22]1[N:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:26][CH:27]=1.[H-].[Na+].C(O)(=O)C>C1COCC1>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:21][C:22]2[N:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:26][CH:27]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CCOC(=O)c1cnc(CBr)cn1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Temperature: 55 °C
Yield: 33.7 %

Procedure:
To a mixture of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (6.0 g, 0.018 mol) and ethyl 5-(bromomethyl)pyrazine-2-carboxylate (4.9 g, 0.02 mol) in THF (50.0 mL) was added NaH (0.5 g) and heated at 55° C. under argon atmosphere for 3 h. The reaction mixture was cooled added acetic acid (1.2 ml) and concentrated under reduced pressure. The residue was triturated with water and filtered the solid. It was washed with water, followed by ethanol and dried in vacuo to afford the title compound (3.0 g, 78%)as alight brown powder: 1H NMR (CD3OD/400 MHz) δ9.10 (d. 1H, J=1.2 Hz), 8.77 (d, 1H, J=1.2 Hz), 7.61 (m, 1H), 7.01 (m 2H), 6.54 (s, 1H), 5.54 (s, 2H), 5.30 (s, 2H), 4.43 (q, 2H, J=6.8 Hz), 2.52 (s, 3H), and 1.39 (t, 3H, J=6.8 Hz); 19F NMR (CD3OD/400 MHz) δ−111.64 (m), and −116.04 (m); ES-HRMS m/z 494.0482 (M+H C21H19N3O4BrF2 requires 494.0522).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:46]4[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=4)=[C:15]4[N:45]=[C:18]([C:19]([C:38]5[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=5)=[C:20]5[NH:37][C:23](=[C:24]([C:30]6[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:59](Br)[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67]>CN(C=O)C>[OH:52][C:49]1[CH:48]=[CH:47][C:46]([C:14]2[C:12]3[NH:13][C:9]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])=[CH:3][CH:4]=4)=[C:28]4[N:29]=[C:25]([C:24]([C:30]5[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=5)=[C:23]5[NH:37][C:20](=[C:19]([C:38]6[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=6)[C:18]6[CH:17]=[CH:16][C:15]=2[N:45]=6)[CH:21]=[CH:22]5)[CH:26]=[CH:27]4)=[CH:10][CH:11]=3)=[CH:51][CH:50]=1
Reactant: Oc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Reactant: CCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCOc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
5,10,15,20-tetrakis-(4-Hydroxy-phenyl)-porphyrin (200 mg, 0.294 mmol) is dissolved and potassium carbonate (487 mg, 3.53 mmol, 12 eqv.) is suspended under argon in absolute DMF (50 mL) and the mixture heated to 55° C. A solution nonyl bromide (49.4 μl, 0.206 mmol, 0.7 eqv.) in absolute DMF (10 mL) is added dropwise during 30 min. The mixture is stirred at 55° C. for 2 h. The solvent is removed in vacuo at 50° C., water (80 mL) is added and the mixture extracted with ethyl acetate (3×40 mL). The combined organic extracts are dried (Na2SO4) and solvent removed under reduced pressure. The product is isolated by chromatography on a column (300 g) of silica. Tetra-alkylated and tri-alkylated compounds are eluted with toluene:ethyl acetate (30:1 by vol.), di-substituted compound (trans-isomer) with toluene:ethyl acetate (15:1 by vol.), di-substituted compound (cis-isomer) with toluene:ethyl acetate (10:1 by vol.) and the desired product (mono-alkylated compound) is eluted with toluene:ethyl acetate (5:1 by vol.). The solvent is removed under reduced pressure and the residue dried at high vacuum to afford the product as a violet solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH2:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[O:20])=[CH:17][CH:16]=1)[CH:7]2O.C(N(S(F)(F)[F:37])CC)C.C([O-])(O)=O.[K+]>C(Cl)Cl>[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH2:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[O:20])=[CH:17][CH:16]=1)[CH:7]2[F:37]
Reactant: Cc1ccccc1NC(=O)c1ccc(CC2CCc3c(ccc(Cl)c3Cl)C2O)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)c1ccc(CC2CCc3c(ccc(Cl)c3Cl)C2F)cc1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
A solution containing 0.35 g of 4-[(5,6-dichloro-1-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]-N-(2-methylphenyl)benzamide and 10 cm3 of methylene chloride is cooled down to −65°C.±5° C. 142 mg of DAST (diethylaminosulfur trifluoride) was added. The solution was maintained under agitation for 1 hour at −65° C. The temperature was allowed to rise to 20° C. and the reaction medium was poured into an aqueous solution of potassium acid carbonate, followed by agitation for 30 minutes and extraction with methylene chloride. The organic phases were collected, dried, filtered and concentrated. In this way 340 mg of sought product was obtained.
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[Na+].Cl.[CH:16]#[CH:17]>CS(C)=O>[CH2:6]([O:5][CH2:4][C@@H:2]([OH:3])[CH2:1][C:16]#[CH:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: C#C
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C#CC[C@H](O)COCc1ccccc1
Temperature: 5 °C
Yield: 89 %

Procedure:
To a solution of 20.0 g (122 mmol) of (R)-O-benzylglycidol in dimethylsulfoxide (80 ml), 918.7 g (183 mmol) of a lithium acetylide-ethylenediamine complex (purity: 90%) was gradually added under stirring at a temperature of not higher than 5° C., and the mixture was stirred at the same temeprature for 40 minutes. To the reaction mixture, 150 ml of a saturated sodium chloride aqueous solution was added, and the mixture was acidified by an addition of concentrated hydrochloric acid. Then, the mixture was extracted with ethyl ether. The extract ether solution was washed with a 5% sodium bicarbonate aqueous solution and then with a saturated sodium chloride aqueous solution. The ether layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off from the ether layer. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain 20.69 g (yield: 89%) of the above identified terminal acetylene compound. Boiling point: 95° C. (0.3 Torr).
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@@H:14]([CH3:18])[C:15]([NH2:17])=[O:16])[C:7]2=[O:13].[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN(C)C=O>>[Cl:12][C:11]1[C:2]([NH:1][C:28](=[O:29])[CH2:27][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:31])([F:19])[F:32])=[CH:26][CH:25]=2)=[C:3]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:13])[N:6]([C@@H:14]([CH3:18])[C:15]([NH2:17])=[O:16])[CH:5]=[CH:4]2
Reactant: C[C@@H](C(N)=O)n1ccc2c(N)c(Cl)ccc2c1=O
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
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@@H](C(N)=O)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)cc3)c(Cl)ccc2c1=O
Temperature: 60 °C
Reaction time: 72 h

Procedure:
A mixture of (S)-2-(5-amino-6-chloro-1-oxoisoquinolin-2(1H)-yl)propanamide (100.0 mg, 0.0003764 mol), 2-(4-(trifluoromethyl)phenyl)acetic acid (115.2 mg, 0.0005646 mol), N,N-diisopropylethylamine (163.9 μL, 0.0009409 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (357.8 mg, 0.0009409 mol) and N,N-dimethylformamide (2 mL, 0.02 mol) was stirred at 60° C. for 3 days. the solvent was removed under reduced pressure and the residue purified by reverse phase preparative HPLC to afford the product as light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-])=O)[CH:4]=1.[C:13]1(=O)[C:23]2=[C:24]3[C:19](=[CH:20][CH:21]=[CH:22]2)[CH:18]=[CH:17][CH:16]=[C:15]3[C:14]1=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:8][CH:9]=1)[N:7]=[C:13]1[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:24]=3[C:15]([C:14]1=[N:10]2)=[CH:16][CH:17]=[CH:18]4
Reactant: O=C1C(=O)c2cccc3cccc1c23
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Product: COc1ccc2nc3c(nc2c1)-c1cccc2cccc-3c12
Yield: 91 %

Procedure:
When 0.05 mole each of 4-methoxy-2-nitroaniline and acenaphthenequinone were reacted by the method of Example 1, 12.9 g (91 percent yield) of 9-methoxyacenaphtho[1,2-b]-quinoxaline, mp = 194°-195° C. were obtained.
Reaction SMILES: [S:1]([C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][NH:11][CH2:12][C:13]2[N:14]([CH2:18][C:19]([N:21]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])[CH:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[S:40]1[CH:44]=[CH:43][N:42]=[C:41]1[CH:45]=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.O>[S:1]([C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][N:11]([CH2:12][C:13]2[N:14]([CH2:18][C:19]([N:21]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[O:20])[CH:15]=[CH:16][N:17]=2)[CH2:45][C:41]2[S:40][CH:44]=[CH:43][N:42]=2)=[CH:7][CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: O=Cc1nccs1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CNCCc1ccc(S(N)(=O)=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)Cc1nccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a solution of di-tert-butyl 2,2′-((2-(2-(((4-sulfamoylphenethyl)amino)methyl)-1H-imidazol-1-yl)acetyl)azanediyl)diacetate (244 mg, 0.43 mmol), thiazole-2-carbaldehyde (68 mg, 0.61 mmol), AcOH (0.05 mL) in DCE (10 mL) at 0° C. was treated with NaBH(OAc)3 (212 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 2 hrs and decomposed with water. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by biotage over silica gel to afford di-tert-butyl 2,2′-((2-(2-(((4-sulfamoylphenethyl)(thiazol-2-ylmethyl)amino)methyl)-1H-imidazol-1-yl)acetyl)azanediyl)diacetate as a colorless oil (200 mg, 70%). MS (ESI), 663.3 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=2[F:15])=[O:6])[CH2:3][CH2:2]1.[C:16]([CH2:18][C:19](O)=[O:20])#[N:17].CN(C)C=O.CS(Cl)(=O)=O>O.C(O)(C)C.O>[C:16]([CH2:18][C:19]([N:4]([CH:1]1[CH2:2][CH2:3]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=1[F:15])=[O:6])=[O:20])#[N:17]
Reactant: O=C(Nc1ccc(I)cc1F)NC1CC1
Reactant: N#CCC(=O)O
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: N#CCC(=O)N(C(=O)Nc1ccc(I)cc1F)C1CC1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
Under a nitrogen atmosphere, to 1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-urea 48 (167 g) and cyanoacetic acid 73 (80.0 g), was added N,N-dimethylformamide (836 ml), and methanesulfonyl chloride (72.8 ml) was added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 4 hrs. The reaction mixture was cooled with water, and water-isopropanol [2:1 (volume ratio), 1670 ml] was added dropwise. The mixture was stirred under water-cooling for 1 hr, and the precipitated crystals were collected by filtration and dried to give 1-(2-cyano-acetyl)-1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-urea 74 (192 g).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[C:3]=1[C:4]([NH:6][CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9])=[O:5]>CO.[Pd]>[NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[C:3]=1[C:4]([NH:6][CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9])=[O:5]
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)NC(Cc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(N)c1C(=O)NC(Cc1ccccc1)C(=O)O
Reaction time: 9 h

Procedure:
410 mg (1.25 mmol) 2-(2-amino-6-nitro-benzoylamino)-3-phenyl-propionic acid are dissolved in 50 ml of methanol and combined with 40 mg palladium on charcoal (10% Pd). The reaction mixture is hydrogenated for 9 h at 5 bar H2 pressure and 25° C. Then the catalyst is filtered off, the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and consists of 5% water and 95% acetonitrile at the finishing point.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(O[C:17](=O)[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25](=[O:30])N(OC)C)[CH2:21][CH2:20]1)(C)(C)C.[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1C=O>>[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[CH2:17][NH:18][C@H:19]1[CH2:20][CH2:21][C@H:22]([C:25]([C:10]2[S:11][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:30])[CH2:23][CH2:24]1
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: O=Cc1nc2ccccc2s1
Reactant: COc1cccc2scnc12
Product: COc1cccc2sc(C(=O)[C@H]3CC[C@H](NCc4nc5ccccc5s4)CC3)nc12

Procedure:
Using 4-methoxy-benzothiazole (5 mmol), [trans-4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (2.5 mmol) and benzothiazole-2-carbaldehyde (0.3 mmol) according to the same protocol as that described for example 1, steps 1.a to 1.c, the title compound was obtained as a yellow solid (66 mg).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][N:27]4[C:31](=[O:32])[C:30]5=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]5[C:28]4=[O:37])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (6.44 g, 29.1 mmole), K2CO3 (6.4 g, 46 mmol), N-(3-bromopropyl)phthalimide (8.4 g, 31 mmol) in acetonitrile (150 ml) was heated at reflux for 3.5 hours. The insolubles were filtered. The solvent was removed at reduced pressure and the residue was purified by silica gel column chromatography to give N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]phthalimide as a white solid. Recrystallization from ethanol yielded 9.8 g (83%) of off-white crystals, m.p.=129°-130° C.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[C:5]=1[CH:16](O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1.[C:30]([C:36]([O:38][CH3:39])=[O:37])#[C:31][C:32]([O:34][CH3:35])=[O:33].CO>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([C:16]2[C:5]3[C:4](=[CH:9][C:8]([O:10][CH3:11])=[C:7]([O:12][CH3:13])[C:6]=3[O:14][CH3:15])[C:3]([OH:2])=[C:31]([C:32]([O:34][CH3:35])=[O:33])[C:30]=2[C:36]([O:38][CH3:39])=[O:37])[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: COc1ccc(C(O)c2c(C(OC)OC)cc(OC)c(OC)c2OC)cc1OC
Reactant: COC(=O)C#CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: COC(=O)c1c(C(=O)OC)c(-c2ccc(OC)c(OC)c2)c2c(OC)c(OC)c(OC)cc2c1O
Reaction time: 8 h
Yield: 68.1 %

Procedure:
49.5 g of 2-(3,4-dimethoxy-α-hydroxybenzyl)-3,4,5-trimethoxybenzaldehyde dimethyl acetal are dissolved in 5 ml of toluene. 14.2 g of dimethyl acetylenedicarboxylate and 19 mg of p-toluenesulfonic acid monohydrate are added to the solution, and the mixture is refluxed for 3 hours. After cooling the reaction mixture, 200 ml of methanol are added thereto, and the mixture is allowed to stand at -30° C. overnight. The precipitated crystals are collected by filtration and recrystallized from ethyl acetate to give 33.1 g of 1-(3,4-dimethoxyphenyl)-2,3-bis(methoxycarbonyl)-4-hydroxy-6,7,8-trimethoxynaphthalene as colorless prisms.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][P:12]([O:16]CC)[O:13][CH2:14][CH3:15].CC(N=NC(C#N)(C)C)(C#N)C.C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[CH2:14]([O:13][P:12]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)([CH3:11])=[O:16])[CH3:15]
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: CCOP(C)OCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCOP(C)(=O)c1ccc(C(=O)O)cn1
Reaction time: 16 h

Procedure:
6-Bromonicotinic acid (150 mg, 0.74 mmol) and diethyl methylphosphonite (1.21 g, 8.91 mmol) were dissolved in toluene and the solution was purged with argon for several minutes. The mixture was brought to reflux and a solution of AIBN (40 mg, 0.22 mmol) and tris trimethylsilylsilane (220 mg, 0.89 mmol) in toluene was added dropwise over 4 hours via syringe pump. The initiator was added via syringe pump over 4 hours. The resulting mixture was reluxed for 16 hours then it was concentrated in vacuo and purified directly by MPLC (0-50% EtOAc:Hex). MS: cal'd 230 (MH+), exp 230 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14].[CH3:15][Sn](C)(C)C>ClCCCl.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>[NH2:1][C:2]1[C:7]([CH3:15])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14]
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1nc(Cl)c(I)c(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: COC(=O)c1nc(Cl)c(C)c(N)c1Cl
Yield: 82.4 %

Procedure:
A mixture of methyl 4-amino-3,6-dichloro-5-iodopicolinate (8.1 g, 23.4 mmol), tetramethylstannane (8.35 g, 46.7 mmol), and bis(triphenylphosphine)palladium(II) chloride (2.5 g, 3.5 mmol) in 1,2-dichloroethane (40 mL) was irradiated in a Biotage Initiator microwave at 120° C. for 30 min, with external infrared (IR)-sensor temperature monitoring from the side. The reaction mixture was loaded directly onto a silica gel cartridge and purified by flash chromatography (silica gel, 0-50% ethyl acetate/hexanes) to provide the title compound as an orange solid (4.53 g, 83%): mp 133-136° C.; 1H NMR (400 MHz, CDCl3) δ 4.92 (s, 2H), 3.96 (s, 3H), 2.29 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.34, 150.24, 148.69, 143.94, 117.01, 114.60, 53.02, 14.40; ESIMS m/z 236 ([M+H]+), 234 ([M−H]−).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4]O.P(Br)(Br)[Br:13].O>CCCCCC>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][Br:13]
Reactant: BrP(Br)Br
Reactant: CC(C)CCCC(C)CCO
Solvent: O
Solvent: CCCCCC
Product: CC(C)CCCC(C)CCBr
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To neat 3,7-dimethyloctanol (5 ml) was added phosphorus tribromide (1.01 ml). The mixture was stirred for 4 hours at 60° C. The reaction mixture was added to a mixture of water and n-hexane. The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 3,7-dimethyloctyl bromide (4.40 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([CH:8]2[CH2:13][C:12](=O)[CH2:11][C:10](=[O:15])[CH2:9]2)[CH:7]=1.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][C:12]1[CH2:13][CH:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:16])[CH2:9][C:10](=[O:15])[CH:11]=1
Reactant: [NH4+]
Reactant: Cc1ccc(F)cc1C1CC(=O)CC(=O)C1
Agent: CC(=O)[O-]
Solvent: CCO
Product: Cc1ccc(F)cc1C1CC(=O)C=C(N)C1

Procedure:
A solution of 5-(5-fluoro-2-methylphenyl)cyclohexane-1,3-dione (3.0 g) and ammonium acetate (3.1 g) in ethanol (50 ml) was heated under reflux for 14 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, washed successively with water and saturated brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1-amino-5-(5-fluoro-2-methylphenyl)cyclohexen-3-one. This was dissolved in ethanol (70 ml) and toluene (120 ml), combined with 3-oxobutylaldehyde dimethyl acetal (4.1 g) and potassium hydroxide powder (0.57 g), and then heated under reflux. The mixture was combined with potassium hydroxide powder (0.12 g) after 30 minutes and with potassium hydroxide powder (0.12 g) and 3-oxobutylaldehyde dimethylacetal (0.33 g) after 1 hour and further with potassium hydroxide powder (0.12 g) after 1 hour and 30 minutes, and then stirred at the same temperature for 2 hours. After cooling, the solvent was distilled off under reduced pressure, and ethyl acetate was added. The organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was subjected to a silica gel column (ethyl acetate-hexane) to obtain a crystal which was then recrystallized from ethyl acetate-hexane to obtain 7-(5-fluoro-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.5 g).
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].[CH2:10]([C:17]1[O:18][C:19]2[CH:52]=[CH:51][CH:50]=[CH:49][C:20]=2[C:21]=1[C:22]1[CH:48]=[CH:47][C:25]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][S:33][CH2:34][C@H:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:36]([OH:38])=[O:37])=[CH:28][CH:27]=2)=[CH:24][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C.C(OCC)(=O)C>[CH2:10]([C:17]1[O:18][C:19]2[CH:52]=[CH:51][CH:50]=[CH:49][C:20]=2[C:21]=1[C:22]1[CH:23]=[CH:24][C:25]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][S:33]([CH2:34][C@H:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:44])[CH3:45])=[O:41])[C:36]([OH:38])=[O:37])(=[O:6])=[O:5])=[CH:28][CH:27]=2)=[CH:47][CH:48]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1)C(=O)O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CS(=O)(=O)Cc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
Sodium perborate tetrahydrate (320 mg, 2.1 mmol) was added as a solid to a stirred solution of (2R)-3-[4′-(2-benzylbenzofuran-3-yl)biphen-4-ylmethylsulfanyl]-2-tert-butoxycarbonylamino-propionic acid (440 mg, 0.74 mmol) in acetic acid (10 mL) at 40° C. This solution was stirred at 40° C. for 2 hours (HPLC control) and then diluted with ethyl acetate (50 mL), washed with water, brine (2×), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 15% methanol in methylene chloride as eluent, afforded the title compound as a white solid (426 mg, 92%): mp. 202-203° C. Rf=0.40 (20% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz) δ 7.84 (2H, d, J=9 Hz, Ar—H), 7.74 (2H, d, J=9 Hz, Ar—H), 7.60 (4H, m, Ar—H), 7.48 (2H, d, J=9 Hz, Ar—H), 7.29 (5H, m, Ar—H), 7.22 (2H, d, J=8 Hz, Ar—H), 6.58 (1H, br s, NH), 4.51 (2H, s, PhCH2), 4.27 (2H, s, PhCH2S), 4.16 (1H, m, CHN), 3.56 (1H, dd, J=15, 5 Hz, CHHCHN), 3.20 (1H, dd, J=15, 8 Hz, CHHCHN), 1.37 (9H, s, tBu); ESI-LCMS e/z calcd for C36H35NO7S 625.739, found 626 (M+H)+.