Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[OH:17])[C:6]1=[O:18])(=[O:3])[CH3:2].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH2:35][CH2:36]OC(=N)C(Cl)(Cl)Cl)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:1]([O:4][C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[O:17][CH2:36][CH2:35][C:29]2[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:28]=2)[C:6]1=[O:18])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC(=O)N([C@@H]2CCCC[C@H]2O)C1=O
Reactant: COc1ccc(CCOC(=N)C(Cl)(Cl)Cl)cc1OCc1ccccc1
Solvent: ClCCl
Product: COc1ccc(CCO[C@@H]2CCCC[C@H]2N2C(=O)C[C@@H](OC(C)=O)C2=O)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85.9 %

Procedure:
To a chilled (0° C.) solution of (3R)-1-((1R,2R)-2-hydroxylcyclohex-1-yl)-2,5-dioxopyrrolidin-3-yl acetate (15.0 g, 58.7 mmol) in anhydrous dichloromethane (100 mL) was added tetrafluoroboric acid diethyl ether complex (3.2 mL). The resultant reaction mixture was stirred at 0° C. for 20 minutes before adding a solution of 2-(3-benzyloxy-4-methoxy-phenyl)ethyl-2,2,2-trichloroacetimidate (24.8 g, 61.6 mmol, 1.05 equiv.) in dichloromethane (100 mL) via an addition funnel over 30 minutes. The reaction mixture was stirred at 0° C. until the reaction was judged complete by HPLC analysis. The reaction mixture was quenched with water (250 mL). The organic layer was separated from the aqueous layer and subsequently washed with dilute NaHCO3 (5% wt solution, 2×100 mL), and water (5×100 mL). The organic layer was dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure to −100 mL solution. The solution was cooled at −20° C. for 24 hours and the precipitate (trichloroacetamide) was removed by filtration. The filtrate was further concentrated to a volume of ˜40 mL. This process was repeated three times until the bulk of the by-product (trichloroacetamide) was removed. After the third filtration, the filtrate was concentrated in vacuo to give (1R,2R)-1-{2-[2-(3-benzyloxy-4-methoxy-phenyl)ethoxy]cyclohexyl}-2,5-dioxopyrrolidin-3-(R)-yl acetate as a pale yellow syrup (25 g, 86% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.C(N(CC)CC)C.Cl.[CH:21]1([NH:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:6]([N:27]([CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:28][CH:29]2[CH2:31][CH2:30]2)[N:7]=1
Reactant: C1CCC(NCC2CC2)CC1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(N(CC2CC2)C2CCCCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A cooled (0° C.) solution of methyl 2,4-dichloropyrimidine-6-carboxylate (Apollo, OR2558, 5.00 g; 24.1 mmol) in THF (50 mL) was treated triethylamine (7.38 ml; 53.1 mmol) and cyclohexyl(cyclopropylmethyl)amine hydrochloride (Chembridge, 4.58 g; 24.1 mmol. The reaction mixture was stirred for 2 days at RT. The solvent was evaporated under reduced pressure, the remaining residue was partitioned between 100 ml of ethyl acetate and a saturated aqueous solution of NH4Cl (50 mL). The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to obtain the crude product, which was purified by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc to give the title product as a yellow oil, which solidified upon standing (6.14 g, 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:13][CH2:14][C:15]1([OH:39])[C:20](=[O:21])[O:19][CH2:18][C:17]2[C:22]([N:24]3[C:28](=[CH:29][C:16]1=2)[C:27]1[N:30]=[C:31]2[C:36](=[CH:37][C:26]=1[CH2:25]3)[CH:35]=[CH:34][C:33]([NH2:38])=[CH:32]2)=[O:23]>[Pd]>[CH3:13][CH2:14][C:15]1([OH:39])[C:20](=[O:21])[O:19][CH2:18][C:17]2[C:22]([N:24]3[C:28](=[CH:29][C:16]1=2)[C:27]1[N:30]=[C:31]2[C:36](=[CH:37][C:26]=1[CH2:25]3)[CH:35]=[CH:34][C:33]([NH2:38])=[CH:32]2)=[O:23].[NH2:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Nc1cc([N+](=O)[O-])ccc1C=O
Agent: [Pd]
Agent: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(N)cc3nc2-1
Product: Nc1ccc(C=O)c(N)c1

Procedure:
In a manner similar to that described for 10-nitro-20(RS)-camptothecin, a mixture of 2-amino-4-nitrobenzaldehyde is treated with the tricyclic ketone 11 yielding 11-nitro-20(RS)-camptothecin which in turn is reduced to 11-amino-20(RS)-camptothecin by palladium/carbon. Alternatively, the 11-amino20(RS)-camptothecin is obtained by reaction of 2,4-diaminobenzaldehyde with ketone 11.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH2:16]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[CH3:29])[CH2:17][CH2:18][CH3:19].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1.Cl>[CH2:16]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:11]([C:6]2[C:5]([Cl:13])=[C:4]([Cl:14])[C:3]([Cl:15])=[C:2]([Cl:1])[C:7]=2[C:8]([OH:10])=[O:9])=[O:12])=[C:21]1[CH3:29])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCn1c(C)cc2ccccc21
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCCCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21

Procedure:
Proceeding in a manner similar to that described in part A of Example 2, 14.3 g (0.05 mole) of tetrachlorophthalic anhydride, 16.0 g (0.07 mole) of 76 percent active 1-n-butyl-2-methylindole and 13.3 g (0.10 mole) of aluminum chloride were interacted in 100 ml of benzene. The reaction mixture was drowned in 200 ml of five percent hydrochloric acid with stirring. The solid which formed was collected by filtration, washed with water and dried to obtain 2-[(1-n-butyl-2-methyl-3-indolyl)carbonyl]-3,4,5,6-tetrachlorobenzoic acid (Formula VIII: R0 =R1 =R2 =R3 =Y1 =H; R5 =CH3 ; R6 =(CH2)3CH3), a pale yellow solid melting at 162°-164° C. The nuclear magnetic resonance spectrum was in accord with the structure.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([C:8]#[N:9])=[N+:4]([O-:18])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1ncccc1Br
Solvent: ClC(Cl)Cl
Product: N#Cc1c(Br)ccc[n+]1[O-]
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromopicolinonitrile (1.0 eq.) in chloroform (0.3 M) was added 77% meta-chloroperbenzoic acid (mCPBA) (1.8 eq.) and heated at 60° C. for 2 days. After cooling to room temperature, Ca(OH)2 (2.5 eq.) was added, and the resulting precipitate was stirred for 30 minutes. The precipitate was filtered and washed with 5% methanol in dichloromethane. The filtrate was washed with saturated aqueous NaHCO3 solution. The aqueous layer was extracted several times with 3% methanol in dichloromethane. The combined organic layers were dried over anhydrous MgSO4 and concentrated en vacuo. The crude product was stiffed in hot hexane/ethyl acetate (1:1), filtered, and dried to give the desired product as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:15])[CH2:3][NH:4][C:5]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:14][C:12]1[CH:11]=[CH:10][C:6]2[C:7](=[O:8])[NH:1][C@@H:2]([CH3:15])[CH2:3][NH:4][C:5]=2[CH:13]=1
Reactant: C[C@H](N)CNc1cc(Br)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1CNc2cc(Br)ccc2C(=O)N1
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
To a solution of the crude (S)-2-((2-aminopropyl)amino)-4-bromobenzoic acid (544 mg, 2.0 mmol) and Et3N (731 mg, 7.24 mmol) in DMF was added HATU (829 mg, 2.18 mmol). After 30 min, the reaction mixture was concentrated and purified by flash chromatography on silica gel (2-10% MeOH/DCM eluent) to provide (S)-8-bromo-3-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepin-5(2H)-one as a white oily solid (464 mg, 91% yield). This material was dissolved in dioxane (20 mL), then treated with Pd2(dba)3 (83 mg, 0.09 mmol), PCy3 (121 mg, 0.43 mmol), diboron pinacol ester (595 mg, 2.35 mmol) and KOAc (532 mg, 5.43 mmol), then heated at 90° C. for 2 h. At completion, the reaction was cooled to room temperature, then filtered and concentrated. The crude material was flashed over silica gel (2-10% MeOH/DCM eluent) to provide (S)-3-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-benzo[e][1,4]diazepin-5(2H)-one (527 mg, 96% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[C:14]([O:18][C:19](=[O:34])[C@H:20]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])([CH3:17])([CH3:16])[CH3:15].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.Cl.C(OC(=O)[C@H](CC1C=CC=CC=1)N)(C)(C)C>CO.C(Cl)(Cl)Cl>[C:14]([O:18][C:19](=[O:34])[C@H:20]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[NH:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C

Procedure:
Following General Procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and N-(L-alaninyl)-L-phenylalanine tert-butyl ester hydrochloride (prepared from N-BOC-L-alanine (Sigma) and L-phenylalanine tert-butyl ester hydrochloride (Advanced Chemtech) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a gel. The reaction was monitored by tlc (Rf=0.5 in 4% MeOH/CHCl3) and the product was purified by silica gel chromatography using 4% MeOH/CHCl3 as the eluent.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([CH2:14]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])OCC.[N+](C1C=C([N+]([O-])=O)C=CC=1O)([O-])=O.[C:35]([O:38][CH2:39][CH3:40])(=[O:37])[CH3:36]>C1(C)C(C)=CC=CC=1>[CH2:39]([O:38][C:35](=[O:37])[CH2:36][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C:10]1=[CH2:14])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCC=C(CO)C1
Reactant: CCOC(C)=O
Agent: CCOC([O-])[O-]
Agent: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1C
Product: C=C1CN(C(=O)OC(C)(C)C)CCC1CC(=O)OCC
Temperature: 140 °C
Reaction time: 7 h

Procedure:
In 30 ml of xylene, 1.10 g of 1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-methanol (which had been prepared by the method described in Tetrahedron, Vol. 54, No. 25, p. 7045, 1998), 914 mg of ethyl orthoformate and 130 mg of 2,4-dinitrophenol were dissolved, and the formed solution was heated to 140° C. and stirred for 7 hours while removing the ethanol as formed. The reaction liquid was cooled, then ethyl acetate was added thereto and the organic layer was successively washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate and removed of the solvent by distillation. The resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate=10/1) to provide 692 mg of 1-tert-butoxycarbonyl-3-methylenepiperidine-4-acetic acid ethyl ester. The product was dissolved in 20 ml of tetrahydrofuran, cooled to 0° C., 111 mg of lithium aluminium hydride was added thereto, and stirred for an hour. Then an excessive amount of sodium sulfate decahydrate was added to the reaction liquid and stirred for 15 minutes. The resulting mixture was filtered, and the filtrate was concentrated to provide 558 mg of crude 1-tert-butoxycarbonyl-3-methylenepiperidine-4-ethanol.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH:19]2[OH:31])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7].[ClH:32].C(OCC)(=O)C>C(OCC)C>[ClH:32].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH:19]2[OH:31])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)C2(NC(=O)c3ccco3)CCCCC2)C(O)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(NC1(C(=O)NC2CCNCC2O)CCCCC1)c1ccco1

Procedure:
The solution of 4-{1-[N-(furan-2-ylcarbonyl)amino]cyclohexane carbonyl}amino-1-tert-butoxycarbonyl-3-piperidinol (30 g) obtained in Step 3 in 100 ml of 3N-hydrochloride/ethyl acetate was stirred for about 2 hours at room temperature. 100 ml of diethyl ether was added to the reaction mixture, and then the resulting white solid was filtered and dried to give 3.6 g of the titled compound.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][C:8]([CH3:38])([CH3:37])[CH2:9][C@@:10]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH3:18])[CH2:12][CH2:11]1.N1C=CC=CC=1.N>CN(C)C=O>[CH3:1][N:2]([CH3:6])[C:3]([N:28]1[CH2:29][CH2:30][CH:25]([C:22]2[CH:21]=[CH:20][C:19]([C@@H:17]([N:13]3[CH2:12][CH2:11][C@:10]([CH2:9][C:8]([OH:7])([CH3:37])[CH3:38])([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:15][C:14]3=[O:16])[CH3:18])=[CH:24][CH:23]=2)[CH2:26][CH2:27]1)=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: C[C@@H](c1ccc(C2CCNCC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: N
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(C2CCN(C(=O)N(C)C)CC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethylcarbamoyl chloride (26 μL) was added to a solution of (S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-[(S)-1-(4-piperidin-4-yl-phenyl)-ethyl]-[1,3]oxazinan-2-one (120 mg) and pyridine (40 μL) in N,N-dimethylformamide (2 mL) at room temperature. The solution was stirred at room temperature for 5 h, before another portion of dimethylcarbamoyl chloride (26 μL) and pyridine (20 μL) were added. The solution was stirred at room temperature overnight. Then, diluted aqueous ammonia solution was added and the resulting mixture was concentrated under reduced pressure. The residue was purified by HPLC on reversed phase (MeOH/H2O/NH3) to afford the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][C@@H:6]1[C@H:9]([NH:10][C:11](=[O:47])/[C:12](=[N:26]\[O:27][C:28]2([C:31]([O:33][CH:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:30][CH2:29]2)/[C:13]2[N:14]=[C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[S:16][CH:17]=2)[C:8](=[O:48])[NH:7]1.C1N=CN([C:54](N2C=NC=C2)=[O:55])C=1>C(Cl)(Cl)Cl>[C:22]([O:21][C:19]([NH:18][C:15]1[S:16][CH:17]=[C:13](/[C:12](=[N:26]/[O:27][C:28]2([C:31]([O:33][CH:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:32])[CH2:29][CH2:30]2)/[C:11](=[O:47])[NH:10][C@H:9]2[C@@H:6]([CH2:5][N:4]3[CH2:3][CH2:2][NH:1][C:54]3=[O:55])[NH:7][C:8]2=[O:48])[N:14]=1)=[O:20])([CH3:24])([CH3:23])[CH3:25]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CNCCN)cs1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CN2CCNC2=O)cs1
Reaction time: 12 h
Yield: 49.1 %

Procedure:
To a solution of benzhydryl 1-(((Z)-(2-(((2R,3S)-2-(((2-aminoethyl)amino)methyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (90 mg, 0.133 mmol) in chloroform (2.7 mL) was added CDI (43.1 mg, 0.266 mmol) and TEA (111 μl, 0.797 mmol). After 12 h, the reaction mixture was concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-100%) to afford the title compound (46 mg, 49%). LCMS: Rt=0.95 min, m/z=704.0 (M+1), Method 2m_acidic.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:38])=[C:4]([C:24]([NH:26][CH2:27][CH:28]([O:34]C(=O)C)[CH2:29][O:30]C(=O)C)=[O:25])[C:5]([I:23])=[C:6]([C:21]=1[I:22])[C:7]([NH:9][CH2:10][CH:11]([O:17]C(=O)C)[CH2:12][O:13]C(=O)C)=[O:8].[C:39](Cl)(=[O:62])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]#[C:49][C:50]#[C:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61].C(OCC)(=O)C>ClCCl>[OH:17][CH:11]([CH2:12][OH:13])[CH2:10][NH:9][C:7](=[O:8])[C:6]1[C:21]([I:22])=[C:2]([NH:1][C:39](=[O:62])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]#[C:49][C:50]#[C:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[C:3]([I:38])=[C:4]([C:24]([NH:26][CH2:27][CH:28]([OH:34])[CH2:29][OH:30])=[O:25])[C:5]=1[I:23]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Reactant: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-Amino,N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide (2.19 g, 2.5 mmol) and 10,12-tricosadiynoyl chloride (1.82 g, 5 mmol) were dissolved in 20 ml dichloromethane. The solution was stirred for 3 days at ambient temperature under a nitrogen atmosphere. TLC (ethyl acetate) indicated that the reaction was complete. The reaction mixture was evaporated and dissolved in a mixture of methanol (30 ml) and 1M sodium hydroxide solution (15 ml). After 1 hour TLC (methanol/chloroform) indicated that the reaction was complete. The solution was neutralized with concentrated hydrochloric acid. The residue was dissolved in chloroform and filtered. The solvent was removed and the reaction mixture was purified through silica gel with methanol/chloroform (1:3) to give the title compound. 1H NMR (300 MHz, DMSO): δ 0.8 (CH3, t), 1.2-1.7 (17×CH2, m), 2.2-2.3 (2×CH2, t) , 3.1-3.2 (2×CH2NH, m) , 3.3-3.5 (2×CH2OH, m), 3.6-3.8 (2×CHOH), 4.4-4.7 (4×OH, m), 8.4-8.5 (2×CONH, m), 9.8 (2×ArNHCO, s).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([Sn](C)(C)C)=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].I[N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH2:27]1>[Cu]I.C1COCC1>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:27]3[N:28]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:41])([CH3:42])[CH3:40])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[N:26]=3)=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)CCOCn1nc([Sn](C)(C)C)c2ccc([N+](=O)[O-])cc21
Reactant: C[Si](C)(C)CCOCN1CN(I)c2ccccc21
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c2ccc([N+](=O)[O-])cc21
Yield: 82.2 %

Procedure:
6-Nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-(trimethyl-stannanyl)-1-H-indazole (7.50 g, 16.4 mmol), 3-iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzimidazole (6.50 g, 17.4 mmol), and copper(I) iodide (313 mg, 1.64 mmol) were combined with dry THF (150 mL) in a flask purged with argon. Tetrakis(triphenylphosphine)palladium(0) was added, and the reaction stirred at reflux under argon for 23 h. The reaction was cooled and adsorbed directly onto silica gel (˜16 g). Purification by silica gel chromatography (4% to 15% ethyl acetate/hexanes) gave 7.28 g (82%) of 6-nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.91 (d, 1H, J=9.0 Hz), 8.59 (d, 1H, J=1.8 Hz), 8.22 (dd, 1H, J=8.7, 1.8 Hz), 7.92-7.89 (m, 1H), 7.66-7.62 (m, 1H), 7.40-7.36 (m, 2H), 6.24 (s, 2H), 5.90 (s, 2H), 3.68-3.59 (m, 4H), 0.94 (t, 2H, J=8.1 Hz), 0.86 (t, 2H, J=8.1 Hz), −0.04 (s, 9H), −0.15 (s, 9H). Anal. (C26H37N5O4Si2) C, H, N. Calculated: C, 57.85; H, 6.91; N, 12.97. Found: C, 57.60; H, 6.81; N, 12.82.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl>[CH:1]([O:4][CH2:5][CH2:6][O:7][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])([CH3:3])[CH3:2]
Reactant: CC(C)OCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOC(C)C)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
In a round bottom flask was placed 2-isopropoxy-ethanol (700 mg, 6.72 mmol) dissolved in methylene chloride (15 mL) and cooled to 0° C. in an ice bath. To this solution was added triethylamine (1.2 mL, 8.7 mmol) and para-toluenesulfonyl chloride (1.54 g, 8.06 mmol). The resulting solution was then slowly allowed to warm to 25° C. and was stirred for 16 h. After this time, the reaction was transferred to a separatory funnel and washed with water (15 mL). The aqueous layer was then extracted with methylene chloride (2×20 mL). The organic layers were combined and then dried over sodium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (40 g column, 25% ethyl acetate/hexanes) afforded toluene-4-sulfonic acid 2-isopropoxy-ethyl ester (1.41 g, 81%).
Reaction SMILES: [F:1][C:2]1[C:3]2[CH2:9][S:8][CH2:7][C:4]=2[S:5][CH:6]=1.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:25])(=O)=O)=CC=1>O1CCCC1.O=O>[F:25][C:6]1[S:5][C:4]2[CH2:7][S:8][CH2:9][C:3]=2[C:2]=1[F:1]
Reactant: Fc1csc2c1CSC2
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: O=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1sc2c(c1F)CSC2

Procedure:
In an alternate embodiment, a method is described of producing a monomer wherein the method begins by dissolving 3-fluoro-4,6 dihydrothieno[3,4-b]thiophene in tetrahydrofuran in a non-oxygen atmosphere to create a solution. An initiator of n-butyllithium is then added to the solution to produce an initiated solution. This is followed by adding N-fluorobenzenesulfonimide to the initiated solution to produce 2,3-difluoro-4,6-dihydrothieno[3,4-b]thiophene. 2,3-difluoro-4,6-dihydrothieno[3,4-b]thiophene is then oxidized with meta-chloroperoxybenzoic acid to produce 2,3-difluorothieno[3,4-b]thiophene. 2,3-difluorothieno[3,4-b]thiophene is then bromoated with N-bromosuccinimide to produce 4,6-dibromo-2,3-difluorothieno[2,3-c]thiophene. The final step involves debrominating 4,6-dibromo-2,3-difluorothieno[2,3-c]thiophene and adding an aryl group to produce the monomer
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.C1N2CN3CN(C2)CN1C3.Cl.C(Cl)Cl.C([OH:29])C>O>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[O:29]
Reactant: CCO
Reactant: O=C(O)Cc1ccc(CBr)cc1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc(CC(=O)O)cc1
Yield: 87 %

Procedure:
To a solution of 2-[4-(bromomethyl)phenyl]acetic acid (770 mg, 3.36 mmol) in ethanol (6 mL) and water (6 mL) was added hexamethylenetetramine (1.26 g, 9.0 mmol) and the mixture was heated to reflux for 4 hours. Concentrated HCl (1.5 mL) was added cautiously to the mixture at reflux. The mixture was heated to reflux for 30 minutes and then allowed to cool. Water (20 mL) and DCM (20 mL) were added and the organic phase was passed through a hydrophobic fit and the solvent was removed in vacuo to afford the title compound as an off-white solid (479 mg, 87%). 1H NMR (400 MHz, CDCl3): δ 10.01 (s, 1H), 7.86 (d, J=7.9 Hz, 2H), 7.47 (d, J=7.9 Hz, 2H), 3.75 (s, 2H).