Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:23][CH3:24].Cl[C:26]1[N:31]=[C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]([CH3:41])[CH3:40])=[CH:35][C:34]=2[O:42][CH3:43])[C:29]([Cl:44])=[CH:28][N:27]=1>>[Cl:44][C:29]1[C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]([CH3:40])[CH3:41])=[CH:35][C:34]=2[O:42][CH3:43])=[N:31][C:26]([NH:1][C:2]2[CH:22]=[CH:21][C:5]3[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])[CH2:9][CH2:10][C:4]=3[C:3]=2[O:23][CH3:24])=[N:27][CH:28]=1
Reactant: CCN1C(=O)C(NC(=O)C(F)(F)F)CCc2c1ccc(N)c2OC
Reactant: COc1cc(N(C)C)ccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)C(NC(=O)C(F)(F)F)CCc2c1ccc(Nc1ncc(Cl)c(Nc3ccc(N(C)C)cc3OC)n1)c2OC
Yield: 42 %

Procedure:
Following a procedure analogous to Example 113, N-(7-Amino-1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-2,2,2-trifluoro-acetamide (78 mgs) and N(1)-(2,5-Dichloro-pyrimidin-4-yl)-2-methoxy-N(4),N(4)-dimethyl-benzene-1,4-diamine (60 mgs) were converted to the title compound as an off-white solid (50 mgs). 1H-NMR (CDCl3, 400 MHz): 8.39 (d, J=8.8 Hz, 1H), 8.05-8.04 (m, 2H), 7.59 (s, 1H), 7.43 (d, J=8.6 Hz, 2H), 6.90 (d, J=8.9 Hz, 1H), 6.41-6.39 (m, 2H), 4.49-4.41 (m, 1H), 4.34-4.28 (m, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.29-3.54 (m, 1H), 3.16-3.11 (m, 1H), 3.01 (s, 6H), 2.76-2.71 (m, 1H), 2.57-2.51 (m, 1H), 2.05-2.98 (m, 1H), 1.20 (t, J=7.3 Hz, 3H); LC/MS: found (M+H)+=622.52, MP: 192-193° C.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([CH2:12][CH3:13])S[C:10]=1N)=O)C.C(O[C:17]([C:19]1[N:20]=[C:21]([CH2:31][CH3:32])[S:22][C:23]=1[NH:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:18])C.C(C1SC(NC2C=NC=CC=2)=C(C(O)=O)[N:39]=1)C>>[CH3:10][C:6]1[N:7]=[C:8]([NH:39][C:17]([C:19]2[N:20]=[C:21]([CH2:31][CH3:32])[S:22][C:23]=2[NH:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:18])[CH:12]=[CH:13][CH:4]=1
Reactant: CCOC(=O)c1nc(CC)sc1N
Reactant: CCOC(=O)c1nc(CC)sc1Nc1cccnc1
Reactant: CCc1nc(C(=O)O)c(Nc2cccnc2)s1
Product: CCc1nc(C(=O)Nc2cccc(C)n2)c(Nc2cccnc2)s1

Procedure:
The title compound, MS (ISP): m/e=340.3 (M+H+), was prepared as for example 153, steps A to G. Step C was performed using propionyl chloride, and yielded cyano-propionylamino-acetic acid ethyl ester, which was cyclized to 5-amino-2-ethyl-thiazole-4-carboxylic acid ethyl ester in step D. This was used in step E to generate 2-ethyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester, which was hydrolized to 2-ethyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid in step F. Coupling as described in step G generated the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH:8]([OH:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].O>O1CCCC1>[C:25]([O:1][CH2:2][C:3]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH:8]([OH:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1)(=[O:27])[CH3:26]
Reactant: OCc1cccc2c1CCc1ccccc1C2O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OCc1cccc2c1CCc1ccccc1C2O
Reaction time: 72 h

Procedure:
4.0 g of 1-(hydroxymethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol prepared in Example 1-c was dissolved in 20 ml of tetrahydrofuran, and 1.2 ml of pyridine and 1.4 ml of acetic anhydride were added at room temperature, followed by stirring for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:9), to give 3.5 g of the title compound as a colorless powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]([CH3:31])([CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:29])[C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:23])[CH3:22])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[CH3:2].[BH4-].[Na+].O.ClCCl>CO>[CH2:1]([O:3][C:4](=[O:32])[C:5]([CH3:30])([CH3:31])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:23])[CH3:22])=[CH:18][CH:19]=2)[OH:29])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)Cc1ccc(C(=O)c2ccc(CC(C)(C)C(=O)OCC)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCOC(=O)C(C)(C)Cc1ccc(C(O)c2ccc(CC(C)(C)C(=O)OCC)cc2)cc1
Reaction time: 5 h
Yield: 82.4 %

Procedure:
A solution of 3-{4-[4-(2-ethoxycarbonyl-2-methylpropyl)-benzoyl]-phenyl}-2,2-dimethyl-propionic acid ethyl ester (4.40 g, 10.0 mmol) in methanol (80 mL) was cooled in an ice-water bath. Sodium borohydride (0.45 g, 13.7 mmol) was added and the mixture was stirred for 5 h. Water (150 mL) and dichloromethane (65 mL) were added and the layers were separated. The aqueous layer was washed with dichloromethane (2×65 mL). The combined organic layers were washed with saturated NaCl solution (100 mL), dried over MgSO4, and concentrated under vacuum. The residue was subjected to column chromatography on silica using hexanes/ethyl acetate (9:1 and 6:1) as eluent to afford 3-(4-{[4-(2-ethoxycarbonyl-2-methylpropyl)-phenyl]-hydroxymethyl}-phenyl)-2,2-dimethylpropionic acid ethyl ester (3.63 g, 82%) as a colorless oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.24 (d, 4H, J=8.0 Hz), 7.07 (d, 4H, J=8.0 Hz), 5.77 (s, 1H), 4.08 (q, 4H, J=7.1 Hz), 2.83 (s, 4H), 2.62 (s, 1H), 1.21 (t, 6H, J=7.1 Hz), 1.16 (s, 12H). 13C NMR (75 MHz, CDCl3=77.23 ppm): δ (ppm): 177.6, 142.2, 137.3, 130.3, 126.3, 75.9, 60.5, 46.0, 43.4, 25.1, 14.3. HRMS (LSIMS, nba): Calcd for C27H35O4 (M+H−H2O): 423.2535, found: 423.2520.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[NH:18][C:19](=O)[C:20]2[CH:25]=[CH:24][C:23]([S:26](=[O:29])(=[O:28])[NH2:27])=[CH:22][CH:21]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].P(Cl)(Cl)(Cl)=O.C(OCC)(=O)C>C(#N)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:7]([C:19]([C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:29])(=[O:28])[NH2:27])=[CH:22][CH:21]=3)=[N:18][C@@H:13]3[C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc([C@H]2CCCC[C@H]2NC(=O)c2ccc(S(N)(=O)=O)cc2)ccc1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOc1cc2c(cc1OC)C(c1ccc(S(N)(=O)=O)cc1)=N[C@H]1CCCC[C@@H]21
Yield: 62.6 %

Procedure:
700 mg of (+/-)-cis-N-[2-(3-ethoxy-4-methoxyphenyl)cyclohexyl]-4-sulfamoylbenzamide (compound A1) are dissolved in 100 ml of acetonitrile and 2.0 ml of phosphorus oxychloride and the solution is stirred at 80° C. overnight. The reaction mixture is treated with 60 ml of ethyl acetate and extracted with sodium hydrogencarbonate solution. The organic phase is dried using sodium sulfate and concentrated. The residue is recrystallized from ethanol. 420 mg of the title compound are obtained.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)#[N:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:38]3[CH:39]=[CH:40][C:35]([C:33]#[N:34])=[CH:36][CH:37]=3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)cc1
Yield: 19 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 4-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (19%).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH2:12]([O:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH:24]([CH:27]3[CH2:32][O:31][C:30](=[O:33])[CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[C:17]([F:36])[C:16]=1[F:37])[CH3:13].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:12]([O:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH:24]([CH:27]3[CH2:32][O:31][C:30]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])([OH:33])[CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[C:17]([F:36])[C:16]=1[F:37])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: CCOc1ccc(OCC2CCC(C3CCC(=O)OC3)CC2)c(F)c1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(OCC2CCC(C3CCC(O)(C#C[Si](C)(C)C)OC3)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
2.55 g of trimethylsilylacetylene was dissolved in 20 mL THF, and then 15.7 mL of a 1.66 M hexane solution of n-butyllithium was added dropwise thereto at −70° C., followed by stirring at that temperature for 1 hour. To the resulting solution, a solution containing 9.12 g of 5-[4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexyl]tetrahydropyran-2-one obtained in the twelfth step of Example 1 dissolved in 30 mL of THF was added dropwise at −70° C., followed by stirring at that temperature for 1 hour, and then the temperature of the solution was gradually increased to room temperature. The reaction product was poured into 50 mL of a saturated ammonium chloride aqueous solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and concentrated under reduced pressure. The resulting brown residue was purified by silica gel column chromatography to provide 10.7 g of 5-[4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexyl]-2-trimethylsilanylethynyltetrahydropyran-2-ol as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:26]=[CH:25][C:20]=1[C:21]([NH:23][NH2:24])=O.[Cl-].ClC1N(C)C=C[N+]=1C.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[O:15][C:21]([C:20]4[CH:25]=[CH:26][C:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[CH:28][C:19]=4[O:18][CH3:17])=[N:23][N:24]=3)=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(N2CCOCC2)ccc1C(=O)NN
Reactant: Cc1onc(-c2cccc(Cl)c2)c1C(=O)O
Agent: Cn1cc[n+](C)c1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3cccc(Cl)c3)noc2C)o1
Reaction time: 18 h
Yield: 61 %

Procedure:
To a solution of 3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid (200 mg, 0.85 mmol) in dichloromethane (4 mL) was added 2-methoxy-4-morpholin-4-yl-benzoic acid hydrazide (266 mg, 0.85 mmol) and 2-chloro-1,3-dimethylimidazolium chloride (313 mg, 1.85 mmol). After the solution was stirred for 15 min at ambient temperature triethylamine (0.59 ml, 4.21 mmol) was added over a period of 2 min and the reaction mixture was stirred for 18 h at this temperature. It was diluted with ethyl acetate (20 mL 1) and washed with aqueous sodium carbonate (half saturated). The aqueous layers were extracted with ethyl acetate. Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20) afforded the title compound (235 mg, 62%) as a white solid. MS: m/e=453.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]([F:14])([F:13])[F:12].[N+:17]([O-])([OH:19])=[O:18].S(=O)(=O)(O)O>>[F:1][C:2]([F:15])([F:16])[O:3][C:4]1[CH:9]=[C:8]([N+:17]([O-:19])=[O:18])[CH:7]=[CH:6][C:5]=1[O:10][C:11]([F:12])([F:13])[F:14]
Reactant: FC(F)(F)Oc1ccccc1OC(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(OC(F)(F)F)c(OC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
248 g of the 1,2-bistrifluoromethoxybenzene thus obtained were allowed to drop at 0° C. in the course of 2 hours into 250 g of a mixture of 33% by weight of nitric acid and 67% by weight of sulphuric acid. The mixture was subsequently stirred at 0° C. for 5 hours, then added to ice water, and the organic phase was separated off and distilled. 284 g of 99% strength 3,4-bistrifluoromethoxynitrobenzene were obtained.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@H:9]1[C:19]([OH:21])=O)=[O:7])(C)(C)C.[O:22]=[C:23]1[C:28](C(Cl)=O)=[CH:27][CH:26]=[C:25]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:24]1.[O:37]1[C:41]2[CH:42]=[CH:43][C:44]([CH2:46][N:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)=[CH:45][C:40]=2[O:39][CH2:38]1>>[C:15]([O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:19]([N:50]2[CH2:51][CH2:52][N:47]([CH2:46][C:44]3[CH:43]=[CH:42][C:41]4[O:37][CH2:38][O:39][C:40]=4[CH:45]=3)[CH2:48][CH2:49]2)=[O:21])[N:8]([C:6]([C:28]2[C:23](=[O:22])[O:24][C:25]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:26][CH:27]=2)=[O:7])[CH2:12]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)ON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Product: CCCCCc1ccc(C(=O)N2CC(=NOC(C)(C)C)C[C@H]2C(=O)N2CCN(Cc3ccc4c(c3)OCO4)CC2)c(=O)o1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 1-(1,3-benzodioxol-5-ylmethyl)piperazine the title compound was obtained in 59% purity by LC/MS. MS(ESI+): m/z=595.4.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[Na+].[CH2:6]([O:13][C:14]([N:16]1[CH2:20][C@H:19](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:18][C@H:17]1[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>CN(C)C=O>[CH2:6]([O:13][C:14]([N:16]1[CH2:20][C@@H:19]([S:3][C:1](=[O:4])[CH3:2])[CH2:18][C@H:17]1[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC([O-])=S
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCc3ccccc3)C2)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCc2ccccc2)C1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
29.34 g (257 mmol) of sodium thioacetate were added to a solution of 127.17 g (245 mmol) of (2S,4R)-1-benzyloxycarbonyl-2-(t-butyldimethylsilyloxy)methyl-4-(p-toluenesulfonyloxy)pyrrolidine [obtained as described in step (a) above] in 245 ml of dimethylformamide, and the resulting mixture was stirred for 1.5 hours at 60° C. After it was cooled to room temperature, water was added and it was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was purified by chromatography on a silica gel using an 8:1 by volume mixture of hexane and ethyl acetate as the eluant to afford 91.67 g (yield: 88%) of the title compound as an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([CH:9]=1)[CH:7]=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH2:11]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH2:7][NH:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)Cc1ccc(NCc2cc(Br)ccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-2-benzyloxybenzaldehyde (7.2 g) and ethyl 2-[4-aminophenyl]acetate (4.45 g) were heated on a steam bath for 2 hours. The mixture was cooled and dissolved in ethanol (100 ml) and NaBH4 (0.94 g) was added. The mixture was stirred at ambient temperature for 30 minutes, NaBH4 (0.5 g) added and stirred at ambient temperature for 2 hours. Acetic acid (2 ml) was added dropwise and the solvent evaporated to half volume. The mixture was partitioned between water (100 ml) and diethyl ether (3×75 ml) and the combined organic extracts washed with NaHCO3 (2×50 ml), dried (MgSO4) and evaporated. The residue was subjected to chromatography eluting with CH2Cl2 to give ethyl 2-[4-(2-benzyloxy-5-bromobenzylamino)phenyl]acetate: (yield 6.4 g, m.p. 73° C.).
Reaction SMILES: [Na].[O-]CC.[Br:5][C:6]1[C:7](=[O:15])[O:8][C:9](C)([CH3:13])[O:10][C:11]=1[CH3:12].Cl>C(O)C.CCOCC>[CH2:9]([O:8][C:7](=[O:15])[CH:6]([Br:5])[C:11]([CH3:12])=[O:10])[CH3:13]
Reactant: CC1=C(Br)C(=O)OC(C)(C)O1
Agent: CC[O-]
Agent: Cl
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(Br)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
Sodium metal (13.7 g, 0.59 mol) was dissolved in 500 ml of absolute ethanol, and the resulting ethoxide solution was cooled to 0° C. Crude 5-bromo-2,2,6-trimethyl-4H-1,3-dioxin-4-one (115.5 g, 0.5 mole at 95% purity) was then added, dropwise, to the chilled ethoxide solution over 30 minutes and the dark orange reaction mixture was stirred an additional 30 minutes at 0° C. The reaction was poured into 500 ml of ether and 550 ml of 1N HCl, and the organic layer was washed repeatedly with water (4×250 ml) and then dried over Na2SO4. Removal of solvent in vacuo (30° C., 2 Torr), followed by distillation on a 2-inch wiped-film molecular still (120° C. jacket, 0.2 Torr) afforded 68.7 g (71%) of a pale yellow oil (98% pure by gc).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.CI.[C:15](=O)([O-])[O-].[K+].[K+].CN(C)[CH:23]=[O:24]>>[CH3:15][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:24][CH3:23])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [K+]
Solvent: CI
Product: COC(=O)CCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 85 %

Procedure:
3-(4-Hydroxyphenyl)propionic acid (1.36 g, 8.18 mmol) and methyl iodide (1.20 ml, 19.3 mmol) were dissolved in N,N-dimethylformamide (20 ml) and potassium carbonate (3.40 g, 24.6 mmol) was added. The mixture was stirred at 50°-60° C. for 4 hours and at room temperature for 14 hours. The reaction mixture was filtrated and the filtarate was added to saturated brine (100 ml) and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give 1.35 g of methyl 3-(4-methoxyphenyl)propionate as a colorless solid (85%). This solid (1.30 g, 6.69 mmol) was dissolved in tetrahydrofuran (10 ml) and a 1N aqueous sodium hydroxide solution (7.0 ml, 7.0 mmol) was added. The mixture was stirred at room temperature for 2 hours. 1N Hydrochloric acid was added to the reaction mixture to adjust its pH to 2-3, and the resulting precipitate was collected by filtration and washed with water to give 1.11 g of 3-((4-methoxyphenyl)propionic acid as a colorless solid (92%).
Reaction SMILES: B(F)(F)F.CSC.[C:8]([C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[N:25][N:26]([CH2:37][C:38]#[N:39])[C:27]=3[C:28]3[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([O:35]C)[CH:29]=3)=[CH:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1)(=[O:10])[CH3:9]>ClCCl>[C:8]([C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[N:25][N:26]([CH2:37][C:38]#[N:39])[C:27]=3[C:28]3[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([OH:35])[CH:29]=3)=[CH:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1)(=[O:10])[CH3:9]
Reactant: COc1cc(C)cc(-c2c(-c3ccc(-c4cccc(C(C)=O)c4)nc3)cnn2CC#N)c1
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Product: CC(=O)c1cccc(-c2ccc(-c3cnn(CC#N)c3-c3cc(C)cc(O)c3)cn2)c1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.13 mL, 1.2 mmol) was dropwise added to a solution of the methoxy compound (50.7 mg, 0.12 mmol) prepared in Example 71 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL), and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (35 mg, 71%).
Reaction SMILES: C[C@@H:2]1[O:7][C@@H:6](OC)[C@H:5]([OH:10])[C@H:4](O)[C@H]1O.I([O-])(=O)(=O)=O.[Na+].[C:19](=[O:22])([O-])[OH:20].[Na+].[CH2:24](O)C>O>[CH3:4][C:5](=[O:10])[CH2:6][O:7][CH2:2][C:19]([O:20][CH3:24])=[O:22]
Reactant: CO[C@@H]1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O
Reactant: O=C([O-])O
Reactant: CCO
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: COC(=O)COCC(C)=O

Procedure:
A solution of methyl-α-L-rhamnopyranoside (1.78 g, 10 mmol) in water (25 ml) was treated with sodium periodate (4.3 g) at 0° C. After 3 hours sodium hydrogen carbonate was cautiously added to neutralize the acid, the mixture was poured into ethanol (100 ml) and the insoluble material was filtered. The filtrate was concentrated to a syrup that was extracted with acetonitrile (15 ml). The extract was used for the next step without further purification.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]([CH:9]2[CH2:12][CH2:11][CH2:10]2)=[O:8])=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH:9]1([C:7]([C:4]2[CH:3]=[CH:2][C:1]([CH2:13][Br:14])=[CH:6][CH:5]=2)=[O:8])[CH2:10][CH2:11][CH2:12]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)C2CCC2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(CBr)cc1)C1CCC1

Procedure:
Cyclobutyl p-tolyl ketone (30 g) and N-bromosuccinimide (31 g) in carbon tetrachloride (200 ml) were irradiated and heated under reflux with a tungsten lamp for 1.5 hours, and cooled. The mixture was filtered and the filtrate was evaporated. The residue was distilled under reduced pressure and the fraction b.p. 120°-125°/0.015 mm was collected.
Reaction SMILES: N1C=CC=CC=1.B.[N+:8]([C:11]1[CH:33]=[CH:32][C:14]([CH2:15][CH:16]2[C:27](=O)[NH:26][CH2:25][C:24](=O)[NH:23][CH2:22][C:21](=O)[NH:20][CH2:19][C:18](=O)[NH:17]2)=[CH:13][CH:12]=1)([O-:10])=[O:9]>N1C=CC=CC=1>[N+:8]([C:11]1[CH:33]=[CH:32][C:14]([CH2:15][C@H:16]2[CH2:27][NH:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18][NH:17]2)=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=C1CNC(=O)CNC(=O)C(Cc2ccc([N+](=O)[O-])cc2)NC(=O)CN1
Agent: B
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(C[C@H]2CNCCNCCNCCN2)cc1
Temperature: 120 °C

Procedure:
Borane-pyridine (available from Aldrich) is added to a suspension of 2-(4-nitrobenzyl)-3,6,9,12-tetraoxo-1,4,7,10-tetraazacyclododecane in pyridine. The mixture is heated under reflux at 120° C. for 14 hours. The solvent is removed under reduced pressure. The residue is taken up in methanol and heated under reflux for 2 hours. The solvent is removed under reduced pressure. The residue is dissolved in methanol and re-evaporated. The solid residue is purified by chromatography on reverse phase Baker G18 silica gel available from J.T. Baker, Inc., Phillipsburg, N.J. Conversion of this product to nitro-benzyl-DOTA is accomplished via the procedure discussed in Renn et al., Bioconj. Chem., 3:563-569, 1992 or as set forth is subpart A above.