Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C:29]1[C:33]([C:34](Cl)=[O:35])=[C:32]([CH3:37])[O:31][N:30]=1>ClCCl>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:34]([C:33]2[C:29]([C:23]3[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])=[N:30][O:31][C:32]=2[CH3:37])=[O:35])[N:10]=1)[CH3:20]
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: CCOC(=O)Cc1cccc(N)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cccc(NC(=O)c2c(-c3c(F)cccc3Cl)noc2C)n1
Reaction time: 8 h
Yield: 76.6 %

Procedure:
Add Et3N (0.7 ml, 5.06 mmol) to a solution of ethyl 2-(2-Aminopyridin-6-yl)acetate (for preparation see Goto, Jiro; Sakane, Kazuo; Nakai, Yoshiharu; Teraji, Tsutomu; Kamiya, Takashi. J. Antibiot. (1984), 37(5), 532–45) (0.6 g, 3.33 mmol) and 3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl chloride (0.694 g, 2.53 mmol) in dichloromethane (7 ml) and stir overnight. Dilute the reaction with dichloromethane, wash (H2O then brine), dry (MgSO4), filter, and concentrate. Column chromatography (silica gel, hexanes/EtOAc gradient) gives the title compound (0.81 g, 77%). Mass Spectrum (FIA) (m/z) 418.2 [M+1]
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1)[C:14](=[O:25])[N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:12]2=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:39].[Na+]>CO.CCO.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][S:22](=[O:39])[CH2:21][CH2:20]1)[C:14](=[O:25])[N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:12]2=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCSCC3)c2=O)cc1OC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCS(=O)CC3)c2=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.7 %

Procedure:
A mixture of 0.9 g of 6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-thiopyran-4-yl)quinazoline-2,4(1H,3H)-dione and 0.445 g of sodium periodate in 20 ml of an MeOH/EtOH/water mixture (5/5/1, v/v/v) is stirred overnight at room temperature. The resulting mixture is evaporated under reduced pressure. Water is added and the resulting mixture is extracted with DCM. The organic phase is dried over Na2SO4. The resulting mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/MeOH mixture from (100/0, v/v) to (95/5, v/v) to give 0.99 g of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:5].[Cl:17][C:18]1[CH:26]=[C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[CH:34][NH:35]3)=[O:28])[CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH:5][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[CH:34][NH:35]3)=[O:28])=[CH:26][C:18]=1[Cl:17]
Reactant: O=C(NCc1cccc2[nH]ccc12)c1ccc(C(=O)O)c(Cl)c1
Reactant: COC(=O)[C@@H](N)CNC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)c1ccccc1)NC(=O)c1ccc(C(=O)NCc2cccc3[nH]ccc23)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.2 %

Procedure:
3-(Benzoylamino)-L-alanine methyl ester (Example 299; 77 mg, 0.35 mmol) was mixed with 2-chloro-4-[[(1H-indol-4-yl-methyl)amino]carbonyl]benzoic acid (Example 36; 115 mg, 0.35 mmol), HOBT (57 mg, 0.42 mmol) and EDCI (80.5 mg, 0.42 mmol) in DMF (4 mL). The reaction mixture was stirred at room temperature for 16 h and then diluted with water (about 20 ml). The solution was extracted with ethyl acetate (3×10 ml) and the ethyl acetate layer was washed with dilute aqueous NaCl solution and then brine, dried (Na2SO4), concentrated, and chromatographed (40–80% ethyl acetate/hexanes) to give 3-(benzoylamino)-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine methyl ester (88 mg, 47%). A solution of the ester (51 mg, 0.096 mmol) and lithium hydroxide monohydrate (8 mg, 0.19 mmol) in tetrahydrofuran/methanol/water (3:1:1; 2 mL) was stirred at room temperature for 3 h. The solvent was removed and the product was purified by HPLC to give 3-(benzoylamino)-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine (37 mg, 75%) as a white fluffy powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:5]([F:18])[CH:4]=1)#[N:2].[NH2:19][OH:20]>CO>[NH2:2][C:1](=[N:19][OH:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[C:5]([F:18])[CH:4]=1
Reactant: CC(C)(C)OC(=O)CNc1ccc(C#N)cc1F
Reactant: NO
Solvent: CO
Product: CC(C)(C)OC(=O)CNc1ccc(C(N)=NO)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl N-(4-cyano-2-fluorophenyl)glycinate obtained in Step 1 (290 mg; 1.16 mmol; 1 eq.) was dissolved in MeOH (1 mL) and hydroxylamine (0.34 mL; 5.79 mmol; 5 eq.) was added. The mixture was stirred at RT overnight. Solvents were evaporated off, affording the title product as an off-white solid, which was used further without purification (302 mg, 92%). HPLC (Method A) Rt 2.23 min (Purity: 74.2%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:21])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:5]/[O:6][CH3:7].[Br:22]Br>C(Cl)(Cl)(Cl)Cl>[CH3:1][NH:2][C:3](=[O:21])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:16]=[CH:17][C:18]([Br:22])=[CH:19][CH:20]=1)=[N:5]/[O:6][CH3:7]
Reactant: BrBr
Reactant: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of (E)-N-methyl-2-(2-phenoxyphenyl)-2-methoxyiminoacetamide (500 mg) in carbon tetrachloride (3 ml) was cooled to 0° C., and bromine in carbon tetrachloride (1.27 mmol) was dropwise added thereto. The resulant mixture was stirred at the same temperature for 1 hour, washed with a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloroethane. The solvent was dried and evaporated, and the residue was subjected to HPLC with a mixture of hexane and ethyl acetate to give 200 mg of the objective compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:12])[CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19].N1C=CC=CC=1.O>C1COCC1.CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:12])[CH:11]=1)[C:5]([NH:7][NH:8][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([O:14][CH3:13])[CH:16]=1)=[O:6]
Reactant: NNC(=O)c1cc(I)cc(I)c1
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(C(=O)NNC(=O)c2cc(I)cc(I)c2)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of 3,5-Diiodobenzohydrazide (4.5 g, 11.60 mmol) in dry THF/DMF (100.0 ml:24.0 ml) was slowly added 3-methoxybenzoyl chloride (2.2 g, 12.90 mmol) at 0° C. under nitrogen. After addition of 3-methoxybenzoyl chloride, the reaction was warmed up to room temperature. The reaction mixture was stirred for 19 hours at room temperature and then pyridine (5.0 ml) was added and stirred for additional 1 h. Water (300.0 ml) was added to reaction mixture. The white solid was obtained and collected by filtration. After dried under vacuum, product was obtained as white powder in 5.05 g (83.3%). 1H NMR (400 MHz, DMSO-d6, δ): 10.72 (s, 1H, NH), 10.62 (s, br, 1H, NH), 8.33 (t, J=1.6 Hz, 1H), 8.23 (d, J=1.6 Hz, 2H), 7.50-7.41 (m, 3H), 7.15 (m, 1H), 3.81 (s, 3H, OCH3).
Reaction SMILES: N1C=CC=CC=1.[Br:7][C:8]1[CH:9]=[C:10]([C:14](Cl)=[O:15])[CH:11]=[N:12][CH:13]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.CN(C=O)C.O1CCCC1>[Br:7][C:8]1[CH:9]=[C:10]([C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH:11]=[N:12][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1cncc(Br)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1cncc(Br)c1
Reaction time: 3 h

Procedure:
Under argon and at RT, 32.4 ml (400 mmol, 2 eq.) of pyridine, 2.4 g (20 mmol, 0.1 eq.) of 4-dimethylaminopyridine and, dropwise, a solution of 44.1 g (200 mmol, 1.0 eq.) of 5-bromopyridine-3-carbonyl chloride in 200 ml of DMF were added to a solution of 18.6 g (200 mmol) of aniline in 500 ml of tetrahydrofuran. After 3 h, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water/dichloromethane and the solid was stirred well, washed repeatedly with water and dichloromethane and dried under reduced pressure. Yield: 35.7 g (52% of theory) After phase separation of the mother liquor, the organic phase was extracted twice with dichloromethane. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, dichloromethane/methanol 100:1), which gave 11.7 g (18% of theory) of Example 14A.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:38][CH2:39][CH3:40])=[C:5]([CH:31]=[CH:32][C:33]=1[C:34]([NH:36][CH3:37])=[O:35])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:27]=[CH:26][C:14]2[CH2:15][CH2:16][CH:17]([CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[O:18][C:13]=2[C:12]=1[CH2:28][CH2:29][CH3:30].[OH-].[Li+]>CO>[CH3:1][O:2][C:3]1[C:4]([CH2:38][CH2:39][CH3:40])=[C:5]([CH:31]=[CH:32][C:33]=1[C:34]([NH:36][CH3:37])=[O:35])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:27]=[CH:26][C:14]2[CH2:15][CH2:16][CH:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[O:18][C:13]=2[C:12]=1[CH2:28][CH2:29][CH3:30]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)NC)c(OC)c2CCC)ccc2c1OC(CCC(=O)OCC)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(C(=O)NC)c(OC)c2CCC)ccc2c1OC(CCC(=O)O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 13 (160 mg, 0.2877 mmol) was added to 2 ml of methanol and 432μl of 1 M lithium hydroxide was added. The reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum, water (5.0 ml) was added and the solution was acidified with I0% hydrochloric acid then extracted times with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed under vacuum to give a gum. Further drying under high vacuum overnight gave the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]([CH3:38])([C:22]2[N:26]([CH3:27])[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])=[N:24][N:23]=2)[CH3:21])=[C:6]([CH:18]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:15][O:14]C(C)(C)[O:12]1)=[O:8].Cl.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]([CH3:38])([C:22]2[N:26]([CH3:27])[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:36])([F:37])[F:35])=[N:24][N:23]=2)[CH3:21])=[C:6]([CH:18]=1)[C:7]([NH:9][CH2:10][CH:11]([OH:12])[CH2:15][OH:14])=[O:8]
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)NCC1COC(C)(C)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)NCC(O)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
5-chloro-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzamide (362 mg) was suspended in THF (10 ml), 1M hydrochloric acid (10 ml) was added thereto, followed by stirring at room temperature for 2 hours, warming to 50° C. and stirring for 30 minutes. The reaction solution was cooled to room temperature, and water and 1M hydrochloric acid were added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. The resulting solid was washed with diisopropylether to obtain, as a white solid, 5-chloro-N-(2,3-dihydroxypropyl)-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl}ethoxy)benzamide (293 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[PH4+]>C(#N)C>[Cl-:1].[C:3]1([CH2:2][P+:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1cccc2ccccc12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [PH4+]
Solvent: CC#N
Product: c1ccc([P+](Cc2cccc3ccccc23)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
340 g (1.93 mol) of 1-chloromethylnaphthalene (Aldrich) are dissolved together with 505.7 g (1.93 mol) of triphenylphosphine in 2 l of acetonitrile. The mixture is subsequently boiled at reflux with stirring for 5 hours. The phosphonium chloride begins to precipitate out after about 2 hours. The mixture is left to cool at room temperature and the crystals are filtered off with suction.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:9]([O:11][C:12]1[CH:21]=[C:20]([O:22][CH:23]2[CH2:40][CH:39]3[CH:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]4[C:36]([C:42]([OH:44])=[O:43])([NH:37][C:38]3=[O:41])[CH2:35]4)[CH2:24]2)C2C(=C(C)C(OC)=CC=2)N=1)[CH3:10]>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[C:12]([O:11][CH2:9][CH3:10])[CH:21]=[C:20]2[O:22][CH:23]1[CH2:40][CH:39]2[CH:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]3[C:36]([C:42]([OH:44])=[O:43])([NH:37][C:38]2=[O:41])[CH2:35]3)[CH2:24]1
Reactant: Nc1ccccc1Cl
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2cccc(Cl)c2n1

Procedure:
The title compound (10) was prepared from 2-chloroaniline following the procedure (Steps A-J) reported for synthesis of 17-[2-ethoxy-7-methoxy-8-methylquinolin-4-yl-oxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (2): m/z=556 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:21])([C:17]([F:20])([F:19])[F:18])[C:3]([F:16])([F:15])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[OH:14])=[O:5].N1C=CC=CC=1.C(#N)C.[C:31](Cl)(=[O:35])[C:32]([CH3:34])=[CH2:33]>O>[F:1][C:2]([F:21])([C:17]([F:18])([F:19])[F:20])[C:3]([F:16])([F:15])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:31](=[O:35])[C:32]([CH3:34])=[CH2:33])=[CH:9][C:8]=1[OH:14])=[O:5]
Reactant: C=C(C)C(=O)Cl
Reactant: Nc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)c(O)c1
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O
Product: C=C(C)C(=O)Nc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)c(O)c1
Yield: 61.8 %

Procedure:
To 64 g (0.2 mol) of 2-heptafluorobutanamido-5-aminophenol were added 18 g (0.22 mol) of pyridine and 500 ml of acetonitrile and mixture was cooled with stirring. To the solution was added dropwise 23 g (0.22 mol) of methacrylic chloride. After the completion of the reaction, 500 ml of water was added to the reaction solution and the crystals thus deposited were collected and recrystallized from acetonitrile to obtain 48 g of Monomer Coupler (15).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[O:14][C:15](=[O:17])[CH3:16].Cl.[C:19](Cl)(=[O:21])[CH3:20]>C(=S)=S>[C:19]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[CH2:5][CH:6]([O:14][C:15](=[O:17])[CH3:16])[CH2:7]2)(=[O:21])[CH3:20]
Reactant: CC(=O)OC1Cc2ccccc2C1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)OC1Cc2ccc(C(C)=O)cc2C1
Temperature: 5 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a mixture at 5-10° C. of aluminum chloride (AlCl3; 30.6 g, 0.229 mol) in carbon disulfide (CS2; 160 mL) was added acetyl chloride (12 mL, 13.2 g, 0.169 mol). To this mixture was added a solution of acetic acid indan-2-yl ester (19.9 g, 0.113 mol, prepared according to the method described in Can. J. Chem. 1967, 45, 1185) in acetyl chloride (12 mL) keeping the temperature below 11° C. The contents were stirred at 5° C. for 3 h and were then carefully added to ice-water (350 mL) containing concentrated HCl (60 mL). The mixture was extracted with CH2Cl2 (2×), and the combined extracts were washed with H2O and were dried over Na2SO4. Concentration gave the title compound (23.8 g, 97%) as a solid: 1H NMR δ 7.84 (s, 1H), 7.82 (m, 1H), 7.32 (d, J=7.0 Hz, 1H), 5.55 (m, 1H), 3.40-3.32 (m, 2H), 3.10-3.05 (m, 2H), 2.60 (s, 3H), 2.04 (s, 3H); EIMS m/z 158 ([M-AcOH]+, 42), 143 (100).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][Si](C(C)(C)C)(C)C)=[N:7][C:6]([O:20][Si](C(C)(C)C)(C)C)=[CH:5]2.[CH:28]1([Mg]Br)[CH2:32][CH2:31][CH2:30][CH2:29]1.CCOCC.Cl>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.O.C1COCC1>[CH:28]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][C:6](=[O:20])[CH2:5]3)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Br[Mg]C1CCCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc2cc(Br)ccc2c(O[Si](C)(C)C(C)(C)C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: O=C1Cc2cc(C3CCCC3)ccc2C(=O)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 6-bromo-1,3-bis-(tert-butyl-dimethyl-silanyloxy)-isoquinoline (1.76 g, 3.75 mmole) is added tetrakis(triphenylphosphine)palladium (110 mg, 0.095 mmole) and 2M cyclopentyl magnesium bromide in ether (3.0 mL, 6.0 mmole). This mixture is heated using a microwave reactor at 75° C. for 600 sec. The mixture is cooled to room temperature, transferred to a flask with THF and water, then 2M hydrochloric acid (20 mL) is added and stirred for 4 hours at room temperature. The organic solvents were removed in vacuo, the mixture extracted with ethyl acetate, the organic layer dried over sodium sulfate filtered, evaporated and chromatographed with hexanes-ethyl acetate on silica gel to give a white solid, 268 mg (31%) MS (ESI): m/z 230.2 (M+H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH2:28][CH2:29][CH3:30])[CH:25]=[C:24]4[CH2:31][CH2:32][C:33]([O:35]CCC)=[O:34])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>C1COCC1.C(O)(C)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH2:28][CH2:29][CH3:30])[CH:25]=[C:24]4[CH2:31][CH2:32][C:33]([OH:35])=[O:34])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCCOC(=O)CCc1cn(CCC)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: CCCn1cc(CCC(=O)O)c2cccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
Sodium hydroxide (130 mg) was added to a solution of propyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-propyl-1H-indol-3-yl]propanoate (D121) (166 mg) in THF (5 mL), isopropanol (4 mL) and water (2 mL). The reaction mixture was stirred at room temperature overnight. The mixture was neutralized with 2 M HCl till pH ˜6.0. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-propyl-1H-indol-3-yl]propanoic acid (E27) (98 mg). δH (DMSO-d6, 400 MHz): 0.54 (3H, t), 1.39 (8H, m), 2.62 (2H, t), 2.98 (2H, t), 4.08 (2H, t), 4.90 (1H, m), 7.17 (1H, t), 7.25 (1H, s), 7.44 (2H, m), 7.81 (1H, dd), 8.13 (1H, dd), 8.19 (1H, d), 12.07 (1H, br s); MS (ES): C26H26ClN3O4 requires 467; found 468.2 (M+H+).
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH2:20][CH2:21][CH:22]=[CH2:23])([C:15](OCC)=[O:16])[C:10](OCC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].S([O-])([O-])(=O)=O.[Na+].[Na+].O>C1COCC1.CCOCC>[CH2:1]([NH:8][C:9]([CH2:20][CH2:21][CH:22]=[CH2:23])([CH2:10][OH:11])[CH2:15][OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCC(NCc1ccccc1)(C(=O)OCC)C(=O)OCC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(CO)(CO)NCc1ccccc1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
To a mixture of diethyl 2-(benzylamino)-2-but-3-enyl-propanedioate 81c (13.9 g, 43.6 mmol) in THF (200 mL) was added standard solution of 2 M LiAlH4 in THF (44 ml) dropwise at ice-bath. The mixture was allowed to warm to room temperature for 3 h. Then the reaction mixture was poured into a mixture of anhydrous sodium sulfate (500 g) and water (50 mL) in ether (300 mL), Then the insoluble solid was filtered off and the filtrate was concentrated in vacuo to afford 2-(benzylamino)-2-but-3-enyl-propane-1,3-diol (9.4 g, 91%) which was used for next step without further purification. MS: calc'd (MH+) 236, measured (MH+) 236.
Reaction SMILES: [C:1]1([C:7]([NH:9][C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)=[S:8])[CH:6]=[CH:5]C=C[CH:2]=1.C(Cl)(Cl)Cl.S(Cl)(Cl)(=O)=[O:20]>CO>[O:20]1[CH:5]=[CH:6][C:1]([C:7]2[S:8][N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[N:9]=2)=[CH:2]1
Reactant: S=C(Nc1ncc[nH]1)c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: c1cn2sc(-c3ccoc3)nc2n1

Procedure:
To 0.2 g. of 2-(3-furylthiocarbonylamino)-imidazole [(IV), R = 3-furyl] in 10 ml. of chloroform, at 20°-25°C, there is added dropwise 0.1 ml. of sulfuryl chloride in 2 ml. of chloroform. After 10 minutes the reaction mixture is concentrated at 10°-20°C. under vacuum to give a residue which is treated with methanol and filtered. The residue obtained following filtration is treated with dilute aqueous ammonia to give a precipitate which is filtered and dried to yield 2-(3-furyl)-1,2,4-thiadiazolo-[2,3-a]-imidazole.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:20]1([NH:19][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:10]=[CH:11][N:12]=3)[CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1
Reactant: Brc1cccc(-c2nccn2-c2ccccc2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: c1ccc(Nc2cccc(-c3nccn3-c3ccccc3)c2)cc1
Yield: 60.2 %

Procedure:
2-(3-bromophenyl)-1-phenyl-1H-imidazole (5.7 g, 19.05 mmol), aniline (0.85 g, 9.13 mmol), sodium tert-butoxide (2.55 g, 26.6 mmol), Pd2dba3 (0.167 g, 0.183 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (0.299 g, 0.730 mmol) were charged into the reaction flask with 150 mL of m-xylenes. This mixture was heated at reflux for 1 day. The reaction mixture was diluted with 100 mL of water then was filtered through a pad of Celite®. The m-xylene layer was separated and dried over magnesium sulfate. The organics were filtered and stripped under vacuum. The crude residue was passed through a silica gel column using 10-30% acetone/DCM yielding N-phenyl-3-(1-phenyl-1H-imidazol-2-yl)aniline (1.72 g, 5.5 mmol, 60.6% yield).