Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][CH2:9][C:10]1[C:15]2[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=2[C:13]([O:21][CH3:22])=[CH:12][CH:11]=1.ClC1[CH:26]=[N:27]C=C(Cl)C=1CC(C1C2CC(C)(C)OC=2C(OC)=CC=1)O.C[Si](C#N)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:26]([CH:9]([C:10]1[C:15]2[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=2[C:13]([O:21][CH3:22])=[CH:12][CH:11]=1)[CH2:8][C:7]1[C:6]([Cl:23])=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1])#[N:27]
Reactant: COc1ccc(CCc2c(Cl)cncc2Cl)c2c1OC(C)(C)C2
Reactant: COc1ccc(C(O)Cc2c(Cl)cncc2Cl)c2c1OC(C)(C)C2
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(C#N)Cc2c(Cl)cncc2Cl)c2c1OC(C)(C)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 23.8 %

Procedure:
A solution (70 ml) obtained in Step A of Example 45 of Compound 45a (2.5 g) in methylene chloride was cooled to 0° C. and then trimethylsilylcyanide (5.4 ml) and boron trifluoride ether complex (2.5 ml) were successively added thereto, followed by stirring at 0° C. for 2 hours. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1) to give Compound 63 (0.61 g, 23.8%) as pale-yellow crystals.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Cl[CH2:7][CH:8]1[CH2:12][S:11][C:10]2([CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]2)[S:9]1>CN(C=O)C.O>[C:1]([S:3][CH2:7][CH:8]1[CH2:12][S:11][C:10]2([CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]2)[S:9]1)(=[O:4])[CH3:2]
Reactant: CCOC(=O)CC1CCC2(C1)SCC(CCl)S2
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1CCC2(C1)SCC(CSC(C)=O)S2
Yield: 103.5 %

Procedure:
A mixture of potassium thioacetate (5.4 g, 0.047 mole) and a solution of the product of Example E (4.0 g, 0.013 mole) in DMF (40 ml) was stirred under nitrogen for 2 days at room temperature. The reaction mixture was diluted with water (200 ml) and extracted twice with ethyl acetate. The organic phase was washed with brine and dried (Na2SO4). The drying agent was filtered and the filtrate stripped on the rotary evaporator to give 4.5 g of the titled compound. This material was a single spot on TLC.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]2[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:11][CH2:12][C:13]([O:15]CC)=[O:14])=[C:4]([OH:18])[CH:3]=1.O1CCCC1.O[Li].O.Cl>O>[Cl:1][C:2]1[C:7]([CH:8]2[CH2:10][CH2:9]2)=[CH:6][C:5]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[C:4]([OH:18])[CH:3]=1
Reactant: CCOC(=O)CNc1cc(C2CC2)c(Cl)cc1O
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNc1cc(C2CC2)c(Cl)cc1O
Temperature: 60 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
To a solution of ethyl 2-(4-chloro-5-cyclopropyl-2-hydroxyphenylamino)acetate (290 mg, 0.89 mmol) in of 4:1 mixture of tetrahydrofuran and water (30 mL) at RT, LiOH.H2O (226 mg, 5.34 mmol) was added and the resulting mixture was stirred for 2 h at 60° C. The mixture was acidified with aqueous HCl (1N) to adjust the pH to 3-5 and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the product (100 mg, 47% yield). 1H NMR (400 MHz, DMSO-d6) δ: 9.64 (s, 1H), 6.66 (s, 1H), 5.96 (s, 1H), 3.81 (s, 2H), 1.89-1.96 (m, 1H), 0.84-0.87 (m, 2H), 0.54-0.56 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:27]([O:29][CH2:30][CH3:31])=[CH2:28])CCC.N#N>CN(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>[CH2:30]([O:29][C:27]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1)=[CH2:28])[CH3:31]
Reactant: Clc1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: C=C(OCC)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Temperature: 100 °C

Procedure:
A solution of 6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline (intermediate O) (50 mg, 0.169 mmol) and tributyl(1-ethoxyvinyl)stannane (0.06 mL, 0.178 mmol) in DMF (6 mL) was purged with N2 for 30 min and then Pd(PPh3)4 (9.77 mg, 0.0085 mmol) was added. The resulting solution was heated at 100° C. for 3 h. The reaction mixture was quenched with water, extracted with EtOAc three times. The organic layers were combined, washed with KF solution and brine, dried over Na2SO4. After concentration, the crude was used in the next step without further purification. LCMS (method A): [MH]+=332.1, tR=4.969 min.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](Cl)=[O:20])=[CH:14][CH:13]=1>C(#N)C>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH:4][C:19](=[O:20])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: Cc1cc(C)c(N)c(Br)c1
Solvent: CC#N
Product: Cc1cc(C)c(NC(=O)Cc2ccc(F)cc2)c(Br)c1
Temperature: 150 °C
Yield: 66 %

Procedure:
2-Bromo-4,6-dimethyl-aniline (600 mg) and (4-fluoro-phenyl)-acetyl chloride (543 mg) were dissolved in acetonitrile (6 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. The reaction was cooled to 0° C., the product filtered off and washed with cold acetonitrile (50 mL) affording 665 mg (66% yield) of the title compound as a white solid. LC-MS (m/z) 337 (MH+); tR=2.93, (UV, ELSD) 90%, 98%. 1H NMR (500 MHz, DMSO-d6): 2.05 (s, 6H), 2.25 (s, 3H), 3.63 (s, 2H), 7.05 (b, 1H), 7.15 (dt, 2H), 7.32 (b, 1H), 7.40 (dt, 2H), 9.67 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:61][CH3:62])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:19](=[O:40])[N:20]([CH3:39])CCOCCOCCOCCC(OC(C)(C)C)=O)[CH:16]=[CH:17][CH:18]=2)=[O:12])=[C:6]([C:41]2[CH:46]=[C:45]([C:47](=[O:60])[NH:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=3)[CH:44]=[CH:43][N:42]=2)[CH:5]=1)[CH3:2].[CH3:63][O:64][CH2:65][CH2:66][NH:67][C:68]([C@H:70]1[CH2:75][CH2:74][CH2:73]NC1)=[O:69]>>[CH2:1]([N:3]([CH2:61][CH3:62])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([N:20]3[CH2:73][CH2:74][CH2:75][C@H:70]([C:68](=[O:69])[NH:67][CH2:66][CH2:65][O:64][CH3:63])[CH2:39]3)=[O:40])[CH:14]=2)=[C:6]([C:41]2[CH:46]=[C:45]([CH:44]=[CH:43][N:42]=2)[C:47]([NH:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=2)=[O:60])[CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCOCCOCCOCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: COCCNC(=O)[C@H]1CCCNC1
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N3CCC[C@H](C(=O)NCCOC)C3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of tert-butyl 1-(3-((4-(diethylamino)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)phenyl)-2-methyl-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oate Example 188, using (S)—N-(2-methoxyethyl)piperidine-3-carboxamide 4.14a in place of tert-butyl 5,8,11-trioxa-2-azatetradecan-14-oate. MS (ES, m/z): 759.4 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:18][CH3:19].[CH2:20](I)[CH3:21].O>C1COCC1>[CH3:19][O:18][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[CH2:20][CH3:21]
Reactant: CCI
Reactant: COc1cc(C=Cc2ccccc2)cc(OC)c1Br
Solvent: O
Solvent: C1CCOC1
Product: CCc1c(OC)cc(C=Cc2ccccc2)cc1OC
Temperature: -78 °C
Yield: 70 %

Procedure:
To a solution of 1-(4-bromo-3,5-dimethoxyphenyl)-2-phenylethene (0.53 g, 1.7 mmol) in THF (10 mL) was added t-Butyl Li (1.1 mL, 1M in THF) at −78° C. After the addition complete, the solution was slowly heated to reflux for 30 min and then cooled down to −78° C. Ethyl iodide (1.2 eq, 0.27 mL) was added to the solution. Water (10 mL) was added after the completion of the reaction. THF was evaporated and the mixture was extracted with CH2Cl2 (3×5 mL). The extract was combined and dried over anhydrous magnesium sulfate. Evaporation of the solution followed by flash chromatography using 20% ether in hexane gave 1,3-dimethoxy-2-ethyl-5-(2-phenylethenyl)benzene in 70% yield. 1HNMR (CDCl3, ppm): δ 1.12 (t, J=7.2 Hz, 6H), 2.70 (q, J=7.2 Hz, 2H), 3.91 (s, 6H), 6.74 (s, 2H), 7.07 (s, 2H), 7.26 (m, 1H), 7.36 (m, 2H), 7.52 (m, 2H).
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].[OH:13][C:14]1([CH2:27][SH:28])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(#N)C>[O:11]=[C:2]1[C:1](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([S:28][CH2:27][C:14]2([OH:13])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)=[CH:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CS)CC1
Reactant: O=C1C=Cc2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(O)(CSC2=CC(=O)C(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 294.5 %

Procedure:
To a solution of naphthalene-1,2-dione (3.2 g, 2.02 mmol) and tert-butyl 4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate (5.0 g, 2.02 mmol) in anhydrous acetonitrile (400 ml) was added triethylamine (2.82 ml, 2.02 mmol). The reaction mixture was allowed to stir for 1 hour at room temperature and the solvents were evaporated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 40% EtOAc in hexanes to 70% EtOAc in hexanes). Fractions containing the product were concentrated and tritrated with ethyl acetate/ether to afford the desired product as a red solid (2.4 g, 29%). M.p.=156-157° C.; 400 MHz 1H NMR (CDCl3) δ: 8.17-8.12 (m, 1H), 7.87-7.83 (m, 1H), 7.69-7.62 (m, 1H), 7.59-7.52 (m, 1H), 6.49 (s, 1H), 4.0-3.85 (m, 2H), 3.25-3.14 (m, 4H), 1.84-1.78 (m, 2H), 1.76-1.66 (m, 2H), 1.47 (s, 9H); LCMS: 404 [M+H].
Reaction SMILES: O.[OH-].[Na+].[Cl:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=1>CO>[Cl:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]([C:11](=[O:16])[C:12]([CH3:14])([CH3:15])[CH3:13])=[CH:25][C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)C(=O)COc1ccc(Cl)cc1
Reactant: O=Cc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)C(=O)C(=Cc1cccnc1)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 72.2 %

Procedure:
100 ml of water, followed by 28 ml of 10% strength aqueous sodium hydroxide solution, were added to a stirred solution of 22.6 g (0.1 mol) of 1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one and 21.4 g (0.2 mol) of 3-pyridinealdehyde in 500 ml of methanol. The solution was subsequently stirred at room temperature for 4 days, the methanol was removed in vacuo and the aqueous residue was taken up in ether. The aqueous phase was separated off, the organic phase was extracted three times with 1 N hydrochloric acid and the hydrochloric acid extracts were neutralized with solid sodium bicarbonate and extracted three times with ethyl acetate. 22.8 g (72% of theory) Of 2-(4-chlorophenoxy)-4,4-dimethyl-1-pyridin-3-yl-1-penten-3-one of melting point 74°-76° C. were obtained from the ethyl acetate phase.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:7]([O:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]([C:24]([F:27])([F:26])[F:25])=[CH:5][CH:4]=1.[CH:28]([C:30]1[CH:35]=[C:34]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:33]=[CH:32][C:31]=1[C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1)=[O:29]>>[C:20]([O:19][C:17]([O:16][C:7]1[C:6]([C:24]([F:25])([F:26])[F:27])=[CH:5][CH:4]=[C:3]([CH2:2][O:47][C:44]2[CH:43]=[CH:42][C:41]([C:31]3[CH:32]=[CH:33][C:34]([CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:35][C:30]=3[CH:28]=[O:29])=[CH:46][CH:45]=2)[C:8]=1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:18])([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)c(C=O)c1
Product: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OC(=O)OC(C)(C)C)c3C(=O)OC(C)(C)C)cc2)c(C=O)c1
Yield: 61 %

Procedure:
According to a method similar to Example (2-3), from tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (3.60 g, 8.56 mmol) obtained in Example (28-5) and methyl (2-formyl-4′-hydroxy-1,1′-biphenyl-4-yl)acetate (2.10 g, 7.78 mmol) obtained in Example (45-1), tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[({2′-formyl-4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]-3-(trifluoromethyl)benzoate was obtained (3.06 g, yield: 61%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[CH:17]([C:20]([CH:22]=[CH2:23])=[O:21])([CH3:19])[CH3:18].C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:23][CH2:22][C:20](=[O:21])[CH:17]([CH3:19])[CH3:18])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: C=CC(=O)C(C)C
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)C(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The thiol of Example 2 (4.76 g, 0.02 mole) was reacted with isopropylvinyl ketone (3.6 g) and triethylamine (3 ml) in methanol (50 ml) by the method of Example 3 to give the title compound, m.p. ca. 50-53° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:33]([OH:35])=[O:34])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=1)=[O:10].C(=O)(O)[O-].[Na+].I[CH2:42][CH3:43].O>CN(C=O)C>[CH2:42]([O:34][C:33](=[O:35])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:28])([F:29])[F:27])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:10])[CH3:43]
Reactant: CCI
Reactant: Cc1cc(C(F)(F)F)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)c(=O)n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.5 %

Procedure:
To a suspension of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine (145 mg, 0.275 mmol) and sodium bicarbonate (185 mg, 2.2 mmol) in DMF (2 mL) was added iodoethane (343 mg, 2.2 mmol) at room temperature. The mixture was stirred for 72 h at room temperature. Then, the reaction mixture was poured into water (30 mL) and was extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine solution (60 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the filtrate gave 129 mg (85% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine ethyl ester as a crystalline white solid: mp 86-91° C. ES-HRMS m/e calcd for C26H23Cl2F3N2O4 (M+Na) 577.0876. found 577.0887.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][O:17][C:18](=[O:30])[C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[C:21]([O:26][CH2:27][O:28][CH3:29])[CH:20]=1>N1C=CC=CC=1.[Cu]=O>[CH3:16][O:17][C:18](=[O:30])[C:19]1[CH:20]=[C:21]([O:26][CH2:27][O:28][CH3:29])[CH:22]=[C:23]([O:25][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:9])[CH:4]=2)[CH:24]=1
Reactant: COCOc1cc(O)cc(C(=O)OC)c1
Reactant: Fc1cc(I)ccc1Br
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Product: COCOc1cc(Oc2ccc(Br)c(F)c2)cc(C(=O)OC)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 6.4 %

Procedure:
After adding 20.4 g (0.68 mol) of 1-bromo-2-fluoro-4-iodobenzene, 20.8 g (0.64 mol) of cesium carbonate and 5.07 g (0.64 mol) of copper (II) oxide to a solution of 9.00 g (0.43 mol) of 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester in pyridine (50.0 ml), the mixture was stirred at 130° C. for 8 hours under a nitrogen atmosphere. The reaction mixture was filtered and then concentrated under reduced pressure, acetic acid ethyl ester and saturated aqueous ammonium chloride were added to the obtained residue, and the organic layer was washed with brine, dried and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester=9:1) to obtain 10.6 g of 3-(4-bromo-3-fluoro-phenoxy)-5-methoxymethoxybenzoic acid methyl ester (yield: 65%) as a yellow oil.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]([C:14]3([CH3:17])[CH2:16][CH2:15]3)O)=[CH:4][C:3]=2[O:2]1.P(Br)(Br)[Br:19].[Br-].[Li+]>[Br-].[Zn+2].[Br-]>[CH3:17][C:14](=[CH:12][CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[CH2:15][CH2:16][Br:19]
Reactant: BrP(Br)Br
Reactant: CC1(C(O)CCc2ccc3c(c2)OCO3)CC1
Agent: [Br-]
Agent: [Li+]
Agent: [Zn+2]
Product: CC(=CCCc1ccc2c(c1)OCO2)CCBr

Procedure:
3-Methyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl bromide [V; Ar is 3,4-methylenedioxyphenyl, R is CH3 ] was prepared from 17.6 g. of 2-(3,4-methylenedioxyphenyl)ethyl 1-methylcyclopropyl carbinol (Preparation B3), 20.3 g. of phosphorus tribromide, 18.5 g. of lithium bromide and 21 g. of zinc bromide according to the procedure given above the Preparation C1, affording 19 g. of product as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:12]N1C(C)(C)C(=O)N(Cl)C1=O>ClC(Cl)=C(Cl)Cl>[NH2:1][C:2]1[C:11]([Cl:12])=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccncc1N
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: ClC(Cl)=C(Cl)Cl
Product: COC(=O)c1ccnc(Cl)c1N
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 18 g (118 mmol) of methyl 3-aminoisonicotinate and 12 g (60 mmol) of 1,3-dichloro-5,5-dimethylhydantoin in 1500 mL of tetrachloroethylene was warmed slowly to 80° C. with stirring and held there for 3 hours. The solution was then cooled, filtered, washed with dilute aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a dark oil. This oil was purified by careful column chromatography to give 6.7 g (30 percent of theory) of the title compound as a colorless solid melting at 91°-92° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]1[CH2:24][CH3:25].S(Cl)([Cl:29])(=O)=O.O>C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:3]1([CH2:24][CH3:25])[Cl:29]
Reactant: CCC1C(=O)c2c(cc(OCC(=O)O)c(Cl)c2Cl)C1c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CCC1(Cl)C(=O)c2c(cc(OCC(=O)O)c(Cl)c2Cl)C1c1ccccc1
Temperature: 25 °C

Procedure:
(1-Oxo-2-ethyl-3-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (5.6 g., 0.0143 mole) is dissolved in warm acetic acid (70 ml.) and treated with sulfuryl chloride (1.3 ml., 0.016 mole). The solution is heated on a steam bath for two hours, cooled to room temperature and then added slowly to cold water (500 ml.) with stirring. The product precipitates and is collected by suction filtration, washed well with water and air-dried overnight to afford 5.9 g. of crude product. The crude product is recrystallized several times from ethanol (30 ml.) and water (20 ml.) and then from nitromethane to afford substantially pure (1-oxo-2-ethyl-3-phenyl-2,6,7-trichloro-5-indanyloxy)acetic acid, m.p. 190°-192° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH3:15])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][NH:21][C:22]2=[O:28].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:27][C:26]1[C:17]([NH:16][C:2]2[C:7]([C:8]3[CH:9]=[C:10]([NH:14][CH3:15])[N:11]=[CH:12][N:13]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:28])[NH:21][CH:20]=[CH:19]2
Reactant: CNc1cc(-c2cccnc2Cl)ncn1
Reactant: Cc1ccc2c(=O)[nH]ccc2c1N
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Product: CNc1cc(-c2cccnc2Nc2c(C)ccc3c(=O)[nH]ccc23)ncn1
Temperature: 150 °C
Yield: 25.9 %

Procedure:
6-(2-chloropyridin-3-yl)-N-methylpyrimidin-4-amine (897 mg, 4.1 mmol), 5-amino-6-methylisoquinolin-1(2H)-one (779 mg, 4.5 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl (128 mg, 0.33 mmol) and tris(dibenzylideneacetone) dipalladium (0) (149 mg, 0.16 mmol) were added to a microwave tube. The tube was capped and flushed with nitrogen, and then lithium bis(trimethylsilyl)amide (16.9 mL, 1.0 M solution in THF) was added. The mixture was heated in a microwave reactor at 150° C. for 15 min. The reaction mixture was quenched with saturated aqueous sodium bicarbonate then extracted with DCM. The DCM extracts were concentrated and purified by flash chromatography (0-10% 2 M ammonia in methanol) to give the title compound (380 mg, 26%). MS (M+H)+ 359.
Reaction SMILES: [NH2:1][C:2]1[S:11][C:5]2[CH2:6][O:7][CH:8]([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:19]([NH:27][C:28](=[S:29])[NH:1][C:2]1[S:11][C:5]2[CH2:6][O:7][CH:8]([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1Cc2c(sc(N)c2C(=O)OC(C)(C)C)CO1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCO
Product: CC1Cc2c(sc(NC(=S)NC(=O)c3ccccc3)c2C(=O)OC(C)(C)C)CO1
Yield: 34.2 %

Procedure:
To a solution of tert-butyl 2-amino-5-methyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.104 g, 0.386 mmol, 1 eq) in dry ethanol (1 mL) under argon was added benzoyl isothiocyanate (0.15 mL, 1.08 mmol, 2.8 eq). The mixture was heated at reflux for 16 hours. The solvent was evaporated in vacuo. Purification by reverse-phase chromatography (10-100% CH3CN: Water ramp over 20 min) afforded the desired product tert-butyl 2-(3-benzoylthioureido)-5-methyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate as a pale yellow oil (0.057 g, 0.132 mmol, 34% yield). 1H NMR (400 MHz, DMSO) δ 14.72 (s, 1H), 11.89 (s, 1H), 8.06-7.95 (m, 2H), 7.69 (t, J=7.4, 1H), 7.57 (t, J=7.7, 2H), 4.78 (d, J=14.8, 1H), 4.66 (d, J=15.0, 1H), 3.80-3.63 (m, 1H), 2.93 (d, J=16.7, 1H), 2.50-2.44 (m, 1H), 1.59 (s, 9H), 1.30 (d, J=6.1, 3H).
Reaction SMILES: [NH:1]1[C:5]2=[C:6]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:17]=1[C:18](Cl)=[O:19]>>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:17]=1[C:18]([C:3]1[C:4]2[C:5](=[C:6]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])[N:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)=[O:19]
Reactant: CCC(=O)Nc1nccc2cc[nH]c12
Reactant: O=C(Cl)c1c(F)cccc1Cl
Product: CCC(=O)Nc1nccc2c(C(=O)c3c(F)cccc3Cl)c[nH]c12

Procedure:
N-[3-(2-Chloro-6-fluorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]propanamide was synthesized using N-(1H-pyrrolo[2,3-c]pyridin-7-yl)propanamide and 2-chloro-6-fluoro benzoyl chloride (Compound No. 28).