Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[C:11]([F:17])[CH:10]=1>C1C(Cl)=CC=C(Cl)C=1.O>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:11]([F:17])[CH:10]=1
Reactant: COCCO
Reactant: Fc1cc(Br)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Clc1ccc(Cl)cc1
Product: COCCOCc1ccc(Br)cc1F
Temperature: 60 °C
Reaction time: 12 h
Yield: 78.7 %

Procedure:
2-Methoxyethanol (5.0 g) was added to a stirred suspension of sodium hydride (2.64 g of a 60% mineral oil suspension) in DHF (200 ml) at room temperature and under a atmosphere of argon. The stirred mixture was heated to 60° C. and then cooled to 5° C. A solution of 4-bromo-2-fluorobenzyl bromide (15 g) in dichlorobenzene (75 ml) was added over 15 minutes. The mixture stirred for 12 hours at room temperature, then for 1 hour at 60° C. and cooled. The mixture was diluted with iced water (600 ml) and extracted with ethyl acetate (3×200 ml). The combined extracts were washed with 2M hydrochloric acid (100 ml), water (2×100 ml), saturated brine (100 ml) and dried (MgSO4). Evaporation of the solvents gave an oil which was distilled using a short path distillation apparatus to give 1-(4-bromo-2-fluorobenzyloxy)-2-methyoxyethane (11.6 g), furnace temperature 125° C./0.01 bar; NMR (CDCl3): 3.40(3H, s), 3.5-3.7(4H, m), 4.58(2H, s) and 7.2-7.4(3H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH:27]=[C:28]1[C:34]2[CH:35]=[CH:36][CH:37]=[N:38][C:33]=2[CH2:32][O:31][C:30]2[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]1=2>C(#N)C.O>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:6][CH2:7][N:8]([CH2:25][CH2:26][CH:27]=[C:28]2[C:34]3[CH:35]=[CH:36][CH:37]=[N:38][C:33]=3[CH2:32][O:31][C:30]3[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]2=3)[CH2:9][CH2:10]1)=[O:4]
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: COC(=O)C1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C1(c2ccc(Cl)cc2)CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4-(4-chloro-phenyl)-piperidine-4-carboxylic acid methyl ester in acetonitrile/water (4/1) was added potassium carbonate (221 mg, 1.6 mmol), followed by 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (150 mg, 0.4 mmol). The reaction mixture was stirred at room temperature for 48 hours and then concentrated in vacuo. The resulting residue was treated with water and extracted with ethyl acetate. Solvent was evaporate from the combined dried (MgSO4) organic extracts. Purification on silica gel chromatography using dichloromethane-methanol (9.6:0.4) afforded the title compound.
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][OH:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>N1C=CC=CC=1>[C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1ccccc1CO)C(=O)OCC
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCC(=O)C(=CNc1ccccc1COC(=O)c1ccc(OC)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
Ethyl 2-butyryl-3-(2-(hydroxymethyl)phenylamino)-acrylate (14.6 g, 50 mmol) was dissolved in pyridine (50 ml), cooled in ice, and p-anisoyl chloride (12.8 g, 75 mmol), added dropwise. The mixture was stirred 16 hours with warming to room temperature, then evaporated, taken up in dichloromethane, washed with aqueous sodium bicarbonate, dried and evaporated. Crystallization from ether gave ethyl 2-butyryl-3-(2-(4-methoxybenzoyloxymethyl)phenylamino)acrylate (12.3 g, 58%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:14]([N:15]=1)=[CH:13][C:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=1[CH:5]=2.[Cl:16][CH2:17][CH2:18][CH2:19][S:20][C:21]1[N:25]([CH3:26])[C:24]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[CH3:32])=[N:23][N:22]=1>>[ClH:16].[CH3:1][C:2]1[S:3][C:4]2[C:14]([N:15]=1)=[CH:13][C:7]1[CH2:8][CH2:9][N:10]([CH2:17][CH2:18][CH2:19][S:20][C:21]3[N:25]([CH3:26])[C:24]([C:27]4[O:31][CH:30]=[N:29][C:28]=4[CH3:32])=[N:23][N:22]=3)[CH2:11][CH2:12][C:6]=1[CH:5]=2
Reactant: Cc1nc2cc3c(cc2s1)CCNCC3
Reactant: Cc1ncoc1-c1nnc(SCCCCl)n1C
Product: Cc1nc2cc3c(cc2s1)CCN(CCCSc1nnc(-c2ocnc2C)n1C)CC3
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-methyl-6,7,8,9-tetrahydro-5H-[1,3]thiazolo[4,5-h][3]benzazepine (0.15 mmol) and 3-[(3-chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole (0.18 mmol) and was obtained as a colourless slightly hygroscopic solid (24 mg).
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.N1C=CC=CC=1.[CH3:19][O:20][C:21](Cl)=[O:22]>CN(C=O)C>[CH3:19][O:20][C:21]([O:12][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([O:11][C:21]([O:20][CH3:19])=[O:22])([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:22]
Reactant: COC(=O)Cl
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)OC12CC3CC(C1)CC(OC(=O)OC)(C3)C2
Temperature: 25 °C
Yield: 90 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1,3-adamantanediol and 24 mmole of pyridine were dissolved in 10 ml of DMF. To the mixture, 22 mmole of methoxycarbonyl chloride was added dropwise with stirring at room temperature. Cooling of the resultant mixture with ice was started at about the time exothermic reaction began. When the exothermic reaction is completed, the mixture was heated to 60° C. and then stirred for one hour. As a result, the conversion of 1,3-adamantanediol was 99% and 1,3-bis (methoxycarbonyloxy)adamantane (yield 90%) was formed.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][NH2:17].O>CO>[NH:16]([C:12](=[O:14])[CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[NH2:17]
Reactant: COC(=O)CCCNC(=O)OC(C)(C)C
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCC(=O)NN
Temperature: 65 °C
Reaction time: 12 h
Yield: 89.9 %

Procedure:
To a solution of methyl 4-(tert-butoxycarbonylamino)butanoate (21.0 g, 96.8 mmol) in MeOH (180 mL) was added NH2NH2.H2O (28.0 g, 483 mmol) at rt. The mixture was stirred at 65° C. for 12 hrs then concentrated under reduced pressure. The crude material was dissolved in DCM (400 mL). The organic layer was washed with water (2×), and saturated sodium chloride (2×), dried over Na2SO4, and concentrated to afford tert-butyl 4-hydrazinyl-4-oxobutylcarbamate (18.9 g, 90%) as a white solid. ESI-MS (EI+, m/z): 240 [M+Na]+.
Reaction SMILES: [CH3:1][Si:2]1([CH3:12])[CH2:11]OC2C(=CSC=2)O[CH2:3]1.[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([OH:23])[C:21]=1[OH:22])=[O:16].S1C=CC=C1.OC([SiH](C)C)O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[CH3:27][O:26][C:24]([C:19]1[S:18][C:17]([C:15]([O:14][CH3:13])=[O:16])=[C:21]2[C:20]=1[O:23][CH2:3][Si:2]([CH3:12])([CH3:11])[CH2:1][O:22]2)=[O:25]
Reactant: COC(=O)c1sc(C(=O)OC)c(O)c1O
Reactant: C[Si]1(C)COc2cscc2OC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: C[SiH](C)C(O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccsc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1sc(C(=O)OC)c2c1OC[Si](C)(C)CO2

Procedure:
A synthesis for 6,6-dimethy-6,7-dihydro-5H-4,8-dioxa-2-thia-6-sila-azulene, a silicon-containing EC monomer generally related to 3,4-alkylenedioxythiophene, is shown in FIG. 7. First, 3,4-Dihydroxy-thiophene-2,5-dicarboxylic acid dimethyl ester, the thiophene derivative labeled A7 in FIG. 7 (hereinafter referred to as compound A7) is synthesized from commercially available chemicals according to prior art techniques (see K. Zong, L. Madrigal, L. B. Groenendaal, R. Reynolds, Chem. Comm., 2498, 2002). Note that the same initial step is employed in the synthesis of FIG. 5. Then, a solution of compound A5, dihydroxylmethyldimethylsilane (labeled B7 in FIG. 7), PPh3 (labeled C7 in FIG. 7), and DEAD (labeled D7 in FIG. 7) is refluxed in THF for about 15-24 hours (preferably under an inert atmosphere). A small amount of water is then added to quench the reaction. The reaction mixture is evaporated to dryness. The resulting material is loaded into a silica gel column and eluded by hexane and dichloromethane (2:1, 1:1, volume ratio) to yield 6,6-Dimethyl-6,7-dihydro-5H-4,8-dioxa-2-thia-6-sila-azulene-1,3-dicarboxylic acid dimethyl ester, the silicon-containing thiophene derivative labeled E7 in FIG. 7 (hereinafter referred to as compound E7).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([CH3:19])([CH3:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[O:8][C:7]([CH2:21][O:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][CH:28]3[S:32][C:31](=[O:33])[NH:30][C:29]3=[O:34])=[CH:25][CH:24]=1)([CH3:20])[CH2:6][C:5]2=O.Cl.[NH2:39][OH:40].N1C=CC=CC=1>CO>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([CH3:19])([CH3:18])[CH2:13][C:14]([CH3:16])([CH3:17])[CH3:15])[O:8][C:7]([CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH:28]3[S:32][C:31](=[O:33])[NH:30][C:29]3=[O:34])=[CH:35][CH:36]=1)([CH3:20])[CH2:6]/[C:5]/2=[N:39]\[OH:40]
Reactant: NO
Reactant: CC(C)(C)CC(C)(C)c1cc2c(cc1O)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)(C)CC(C)(C)c1cc2c(cc1O)/C(=N/O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
The procedure described in Example 13 was repeated, but using 1.0 g of 5-{4-[6-hydroxy-2-methyl-4-oxo-7-(1,1,3,3-tetramethylbutyl)chroman -2-ylmethoxy]benzyl}thiazolidine-2,4-dione (prepared as described in Example 7), 0.26 g of hydroxylamine hydrochloride, 0.3 g of pyridine and 10 ml of methanol, to give the title compound as a white powder, softening at 115°-120° C.
Reaction SMILES: [C:1]1([C:11](=O)[CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C([O-])=O.[NH4+:24]>O>[C:1]1([CH:11]([NH2:24])[CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: [NH4+]
Reactant: O=C(CCC1CCNCC1)c1nccc2ccccc12
Agent: O=C[O-]
Solvent: O
Product: NC(CCC1CCNCC1)c1nccc2ccccc12
Temperature: 160 °C
Reaction time: 1 h
Yield: 5.2 %

Procedure:
A mixture of 1-(1-isoquinolyl)-3-(4-piperidyl)-1-propanone (2.5 g) and ammonium formate (7.5 g) is heated to 160° C. for 5 hours. The mixture is cooled, water (100 ml) is added, and the insoluble material is extracted with ethyl acetate (3×50 ml). After the solvent has been evaporated, the residue is taken up in 6N hydrochloric acid (35 ml) and boiled for 1 hour. The mixture is diluted with water (100 ml), the pH of the aqueous mixture is adjusted to 7, and the solution is extracted with ethyl acetate. The aqueous phase is made alkaline to pH 11, and extracted again with chloroform (3×100 ml). The organic phase is dried over magnesium sulphate and evaporated to dryness under reduced pressure. 1-(1-Isoquinolyl)-3-(4-piperidyl)-1-propanamine (0.13 g) is obtained, the proton NMR spectrum of which is deuterated chloroform has the following characteristics: ##STR8##
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:3]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=1[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:3]=1
Reactant: COc1cccc(OC)c1B(O)O
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(C(=O)N5CCOCC5)c4)cnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cccc(OC)c1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C(=O)N4CCOCC4)c3)cc12
Temperature: 120 °C

Procedure:
A mixture of (3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (40 mg, 0.068 mmol), 2,6-dimethoxyphenylboronic acid (18.6 mg, 0.102 mmol), tetrakis(triphenylphosphine)palladium(0) (3.9 mg, 0.0034 mmol) and sodium carbonate (2M aqueous solution, 0.102 mL, 0.204 mmol) in acetonitrile (1 mL) was heated in a Personal microwave at 120° C. for 30 minutes. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness to afford crude (3-(3-(2,6-dimethoxyphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone, which was used in step 2 without further purification.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[NH2:3].[CH2:16]([O:18][C:19](=[O:26])[C:20](=O)[CH2:21][C:22](=O)[CH3:23])[CH3:17]>CC(O)=O>[CH2:16]([O:18][C:19]([C:20]1[CH:21]=[C:22]([CH3:23])[N:2]([C:4]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])[N:3]=1)=[O:26])[CH3:17]
Reactant: NNc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: CCOC(=O)C(=O)CC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2C(=O)O)n1
Yield: 55.9 %

Procedure:
To a solution of 2-hydrazinyl-5-nitrobenzoic acid hydrochloride (59.4 g, 255.1 mmol) in AcOH (500 mL) was added ethyl-2,4-dioxovalerate (31.0 g, 196.2 mmol). The reaction mixture was refluxed for 2 h. AcOH was evaporated invacuo and the residue was co-distilled with toluene (100 mL) twice. The residue was dissolved in EtOAc and washed with water until the aq. layer became neutral. The organic layer was dried over sodium sulphate and concentrated invacuo. The gummy material was triturated with diethyl ether to afford the title compound as a white solid 35 g (56%). Rf=0.30 (10% MeOH in DCM); 1H NMR (400 MHz, DMSO-d6): δ 13.90-13.60 (brs, 1H), 8.62 (d, J=2.5 Hz, 1H), 8.54 (dd, J=2.6 & 8.5 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 6.76 (s, 1H), 4.27 (q, J=7.0 Hz, 2H), 2.19 (s, 3H), 1.28 (t, J=7.1 Hz, 3H); LC-MS: m/z 320.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].Cl[C:19]1[S:20][C:21]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=2[N:23]=1>>[CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:19]3[S:20][C:21]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:12]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: Fc1ccc2nc(Cl)sc2c1
Reactant: CCOC(=O)c1cc(-c2cccc(N)c2)no1
Product: CCOC(=O)c1cc(-c2cccc(Nc3nc4ccc(F)cc4s3)c2)no1

Procedure:
The title compound was prepared by reacting 3-(3-amino-phenyl)-isoxazole-5-carboxylic acid ethyl ester with 2-chloro-6-fluoro-benzothiazole as described in Example 1, step 3. The solid was separated, filtered, washed with EtOH and dried to give the title compound in 90% yield. Mass (ES+), 384 (M++1); IR (KBr): 3423 (br), 2666 (br), 1723, 1629, 1598; 1H NMR (DMSO-d6) δ: 1.33 (t, 3H), 4.39 (q, 2H), 7.15 (m, 1H), 7.52 (m, 1H), 7.61 (m, 2H), 7.82 (s, 1H), 7.74 (m, 1H), 7.97 (m, 1H), 8.34 (m, 1H), 10.97 (br, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([C:13]([O-])=[O:14])=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.[K+].N1C=CC=CC=1.C(Cl)(=O)C([Cl:28])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([C:13]([Cl:28])=[O:14])=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2nnnc2C(=O)[O-])cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(Cn2nnnc2C(=O)Cl)cc1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
Potassium 1-(4-methoxybenzyl)-1H-tetrazole-5-carboxylate (10.0 g) and pyridine (1.8 ml) were stirred together in dry toluene (140 ml) at 10° C. Oxalyl chloride (30.7 ml) was added, and the mixture was stirred at 15° C. for 1 hour. The mixture was filtered and the residual solid was washed with dry toluene (100 ml). The filtrate and washings were combined and evaporated in vacuo to give crude 1-(4-methoxybenzyl)-1H-tetrazole-5-carbonyl chloride, which was used immediately in the next stage.
Reaction SMILES: [CH3:1]/[CH:2]=[C:3]1/[CH2:4][CH:5]2[N:16]([CH2:17]/1)[C:14](=[O:15])[C:13]1[C:8](=[CH:9][C:10]([OH:20])=[C:11]([O:18][CH3:19])[CH:12]=1)[N:7]=[CH:6]2.[C:21](=[O:24])([O-])[O-].[K+].[K+].[C:27]([O:31][C:32]([NH:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[C:43]([CH2:45][O:46]S(C2C=CC(C)=CC=2)(=O)=O)[N:42]=[C:41]([CH2:57]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:40]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O.[I-].[K+]>[C:27]([O:31][C:32]([NH:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:40]=[C:41]([CH2:57][O:20][C:10]2[C:11]([O:18][CH3:19])=[CH:12][C:13]3[C:14](=[O:15])[N:16]4[CH2:17][C:3](=[CH:2][CH3:1])[CH2:4][C@H:5]4[CH:6]=[N:7][C:8]=3[CH:9]=2)[N:42]=[C:43]([CH2:45][O:46][C:10]2[C:11]([O:24][CH3:21])=[CH:12][C:13]3[C:14](=[O:15])[N:16]4[CH2:17][C:3](=[CH:2][CH3:1])[CH2:4][C@H:5]4[CH:6]=[N:7][C:8]=3[CH:9]=2)[CH:44]=1)=[O:33])([CH3:28])([CH3:29])[CH3:30]
Reactant: C/C=C1/CC2C=Nc3cc(O)c(OC)cc3C(=O)N2C1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)OCc2cc(OCCCNC(=O)OC(C)(C)C)cc(COS(=O)(=O)c3ccc(C)cc3)n2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC=C1C[C@H]2C=Nc3cc(OCc4cc(OCCCNC(=O)OC(C)(C)C)cc(COc5cc6c(cc5OC)C(=O)N5CC(=CC)C[C@H]5C=N6)n4)c(OC)cc3C(=O)N2C1
Temperature: 30 °C
Reaction time: 20 h
Yield: 18.4 %

Procedure:
To a stirred solution of pre-tomaymycin (30 mg) in dimethylformamide (0.5 mL), were added potassium carbonate (45.7 mg), a solution of 4-(3-tert-butoxycarbonylamino-propoxy)-2,6-bis-(tosyloxymethyl)-pyridine (41 mg) in dimethylformamide (0.5 mL) and potassium iodide (18.3 mg). The reaction was stirred for 20 h at 30° C. Solids were filtered off and washed with dimethylformamide (0.2 mL). Water (0.5 mL) was added to the combined dimethylformamide solution and formic acid was added until complete dissolution of the precipitate. The resulting solution was injected for HPLC purification according to method B1. The appropriate fractions were combined and concentrated by centrifugal evaporation over a Jouan Model RC10.10. apparatus to afford 8,8′-[4-(3-tert-butoxycarbonylaminopropyloxy)-2,6-pyridine-diylbis(methylenoxy)]-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one] (8.3 mg).
Reaction SMILES: CC1(C)OC(=O)[CH:5]([C:9](=[O:20])[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4](=O)[O:3]1.CO>C(OCC)(=O)C.C(Cl)Cl>[O:3]=[C:4]1[CH2:5][C:9](=[O:20])[CH2:10][CH2:11][N:12]1[C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19]
Reactant: CC(C)(C)OC(=O)NCCC(=O)C1C(=O)OC(C)(C)OC1=O
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=O)CC1=O
Temperature: 105 °C
Yield: 82.8 %

Procedure:
Tert-butyl 3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-oxopropylcarbamate (I-59b: 50 g, 158.57 mmol) was dissolved in ethyl acetate (500 mL) at room temperature under nitrogen atmosphere and the resulting reaction mass was heated at 105° C. for 20 hours. The reaction was monitored by TLC (10% methanol in DCM). The reaction mass was cooled to room temperature and concentrated under reduced pressure to afford the crude product. Purification by ether-wash afforded 28 g of the product (83% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=[O:11].[C:13]1(Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCCCCC.CCOC(C)=O>[C:13]1([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([O:12][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)CCc1ccccc1O
Reactant: Brc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(CCc1ccccc1Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.5 %

Procedure:
A mixture of 3-(2-hydroxyphenyl)propionic acid (0.57 g, 3.4 mmol), phenylbromide (0.4 ml, 3.37 mmol), and K2CO3 (2.5 g) in acetone (10 ml) was stirred at room temperature for 2 days. The mixture was diluted with 1:1 hexane/EtOAc (100 ml), washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (5:1 then 4:1 hexane/EtOAc) to yield phenyl 3-(2-phenyloxyphenyl)propionate (0.45 g, 1.30 mmol, 77%).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:11]=2[CH:10]=1)=[O:8].[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[Cl:29])[C:23](Cl)=[O:24]>>[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([OH:17])[C:15]([C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:28]([Cl:29])=[C:20]([Cl:19])[CH:21]=3)=[CH:16][C:11]=2[CH:10]=1)=[O:8]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)C1=Cc2ccc(OC)cc21
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)C1=Cc2cc(C(=O)c3ccc(Cl)c(Cl)c3)c(O)cc21

Procedure:
In a manner analogous to that described in Example 5, starting from 26.6 g of aluminium trichloride, 9.61 g of 5-methoxybenzocyclobutene-1-carboxylic acid methyl ester and 20.95 g of 3,4-dichlorobenzoyl chloride there is obtained 4-(3,4-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid methyl ester having a melting point of 95°-96°.
Reaction SMILES: [CH3:1][C:2]1[NH:6][NH:5][C:4](=[O:7])[C:3]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[CH3:16][C:17]1[NH:21][N:20]=[C:19]([O:22][C@@H:23]2[O:40][C@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[C@@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]2[O:25][C:26](=[O:28])[CH3:27])[C:18]=1[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1>>[CH3:16][C:17]1[NH:21][N:20]=[C:19]([O:22][C@@H:23]2[O:40][C@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[C@@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]2[O:25][C:26](=[O:28])[CH3:27])[C:18]=1[CH2:46][C:47]1[CH:48]=[CH:49][C:50]([CH3:53])=[CH:51][CH:52]=1.[C@@H:23]1([O:7][C:4]2[C:3]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=3)=[C:2]([CH3:1])[NH:6][N:5]=2)[O:40][C@H:39]([CH2:41][OH:42])[C@@H:34]([OH:35])[C@H:29]([OH:30])[C@H:24]1[OH:25]
Reactant: Cc1ccc(Cc2c(C)[nH][nH]c2=O)cc1
Agent: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: Cc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1

Procedure:
5-Methyl-4-[(4-methylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole was prepared in a similar manner to that described in Reference Example 17 using 1,2-dihydro-5-methyl-4-[(4-methylphenyl)methyl]-3H-pyrazol-3-one instead of 1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one. Then, the title compound was prepared in a similar manner to that described in Reference Example 37 using 5-methyl-4-[(4-methylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole instead of 4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.