Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:11]=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1.NC1N=CC=CC=1C(O)=O.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C.P(=O)(O)(O)O>C(O)C.CO>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:4]2[C:5]3[CH:11]=[CH:10][CH:9]=[N:8][C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nc(Cl)c2cccnc2n1
Agent: Nc1ncccc1C(=O)O
Agent: O=P(O)(O)O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc3ncccc23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 40 %

Procedure:
A mixture of 2,4-dichloro-pyrido[2,3-d]pyrimidine (150 mg, 0.75 mmol, 1 eq) [prepared from 2-aminonicotinic acid by the methods of Robins et al. (J. Am. Chem. Soc. 1955, 77, 1045.) and Oakes et al. (J. Chem. Soc. 1956, 1045.)], N-t-butoxycarbonyl piperazine (147 mg, 0.787 mmol, 1.05 eq) and Hunig's base (0.39 mL, 2.25 mmol, 3 eq) in ethanol (2.5 mL) was stirred at rt for 17 hr. The white solid was collected by filtration, washed with water and cold ethanol, and dried to afford C1.1 (105 mg, 40% yield). LC/MS: 350.41 [M+H]+; HPLC: >95% at 1.44 min (Xterra 5 μm C18 column 4.6×30 mm, 10-90% aqueous methanol over 2 min containing 0.2% phosphoric acid, 5 mL/min, monitoring at 254 nm).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2)=O)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)[CH2:31][CH2:30]1.C[Al](C)C>C(Cl)Cl.CO>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:4]([C:6]3[CH:7]=[CH:8][C:9]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)=[O:3])=[N:40][CH:41]=2)[CH2:31][CH2:30]1
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2cccnc12
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3ncccc23)c1F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 5-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid ethyl ester (Step 174.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 2 h at 80° C. Title compound: ESI-MS: 534.1 [M+H]+; tR=3.56 min (System 1); TLC: Rf=0.14 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29]S(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][C:38]2[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Br)cc2)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2ccc(Cl)cc2)NS(=O)(=O)c2ccc(Br)cc2)cc1

Procedure:
The procedure described in Example 125 was repeated, except that ((RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (420 mg) was reacted with 4-chlorophenol (191.6 μl) to obtain (RS)-2-(4-bromobenzenesulfonylamino)-3-(4-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl) propanamide (242.12 mg).
Reaction SMILES: C([CH2:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH2:16])=[O:15])=[CH:7][CH:6]=1)(O)=O.[OH-:22].[Na+].Cl.C[OH:26]>>[C:4]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH2:16])=[O:15])=[CH:7][CH:6]=1)([OH:26])=[O:22]
Reactant: [OH-]
Reactant: NC(=O)c1cccc(OCc2ccc(CC(=O)O)cc2)c1
Reactant: CO
Agent: Cl
Agent: [Na+]
Product: NC(=O)c1cccc(OCc2ccc(C(=O)O)cc2)c1
Temperature: 40 °C

Procedure:
To 3-(4-carboxymethylbenzyloxy)benzamide (Compound NU1041) (0.03 g; 0.1 mmol) was added methanol (3 ml) and aqueous sodium hydroxide (1M; 3 ml). This was warmed to 40° C., and the reaction monitored. Upon the disappearance of the starting material the solution was acidified (aqueous HCl dropwise), and extracted into ethyl acetate (3×30 ml). The organics were pooled, dried over magnesium sulphate, and the solvent removed under reduced pressure. This yielded a white crystalline solid.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4](=[O:6])[CH3:5].O1[CH2:11][CH2:10][CH2:9][CH2:8]1.[H-].[Na+].BrCCCCBr>C(Cl)Cl>[CH3:1][S:2][C:3]1([S:4](=[O:6])[CH3:5])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CSCS(C)=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: BrCCCCBr
Product: CSC1(S(C)=O)CCCC1
Reaction time: 0.5 h
Yield: 46 %

Procedure:
Formaldehyde dimethyl mercaptal S-oxide (1.49g) was dissolved in 15 ml. of tetrahydrofuran, and with ice cooling, 665 mg of sodium hydride was added. The mixture was stirred for 30 minutes with ice cooling, and then 2.936g of 1,4-dibromobutane was added. The mixture was stirred for 1 hour with ice cooling, for 24 hours at room temperature, and then for 44.5 hours at 50° C. Then, 100 ml. of methylene chloride was added, and the insoluble matter was separated. The filtrate was concentrated at reduced pressure, and the residue was separated by column chromatography (silica gel, eluted with 20% AcOEt-CH2Cl2, AcOEt, and MeOH) to afford 985 mg of cyclopentanone dimethyl mercaptal S-oxide. Also, 463 mg of formaldehyde dimethyl mercaptal S-oxide was recovered. The yield was 46%, and the conversion was 67%.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([N:14]1[C:18]2[N:19]=[C:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[NH:21][C:22](=[O:23])[C:17]=2[CH:16]=[N:15]1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.CS(C)=[O:42]>ClCCl>[C:3]([CH:4]([N:14]1[C:18]2[N:19]=[C:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[NH:21][C:22](=[O:23])[C:17]=2[CH:16]=[N:15]1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:42])[CH3:2]
Reactant: CS(C)=O
Reactant: COc1ccc(Cc2nc3c(cnn3C(CCO)CCCc3ccccc3)c(=O)[nH]2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cc2nc3c(cnn3C(CCCc3ccccc3)C(C)=O)c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
151 mg (0.35 mmol) of 1-[1-(-hydroxy-ethyl)-4-phenyl-butyl]-6-(4-methoxy-benzyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one are dissolved in 1 ml of DMSO and 3.5 ml of dichloromethane, and the solution is cooled to 0° C. 0.485 ml of triethylamine and 245 mg of SO3/pyridine complex are added, and the mixture is stirred for 15 hours at room temperature. The mixture is diluted with 20 ml of dichloromethane, extracted with 1N HCl and saturated NaHCO3 solution, the extract is dried over Na2SO4, and the solvent is removed in vacuo. Purification by chromatography (PE-EA=2:1) gives 115 mg (76%), M.p.: 129° C.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[H-].[Na+].ClC(OCC)=O.[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1.C(O)(=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH:20]([C:4]([C:3]1[C:2]([CH3:1])=[N:10][CH:9]=[CH:8][CH:7]=1)=[O:6])[C:19]([O:27][CH2:28][CH3:29])=[O:26])[CH3:25]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ncccc1C(=O)O
Agent: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cccnc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a slurry of 2-methyl-nicotinic acid (10.2 g, 74.45 mmol) in THF (30 mL) chilled to −10° C. was added sodium hydride (60% in mineral oil; 3.89 g, 89.3 mmol) portionwise and the reaction mixture stirred till no further gas evolution was noticed. Ethyl chloroformate (6.0 mL, 74.45 mmol) was added slowly at the same temperature and stirring continued for another 1 h, whereby a thick white slurry developed. Simultaneously, in a separate vessel, diethyl malonate (11.9 mL, 74.45 mmol) was added dropwise to a slurry of sodium hydride (60% in mineral oil; 3.24 g, 74.45 mmol)) in THF (20 mL) at −10° C., stirred for 30 min and slowly added to the slurry of the mixed anhydride. The reaction mixture was allowed to warm to r.t. and stirred overnight. The pH was adjusted to ˜pH 6 with acetic acid and evaporated to dryness. The residue was partitioned between water and ethyl acetate, the organics separated, then washed with water, brine, dried over sodium sulfate, filtered and concentrated to yield 2-(2-methyl-pyridine-3-carbonyl)-malonic acid diethyl ester (18.16 g, 87%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][C:12]3[N:11]=[C:10]([CH3:15])[NH:9][C:8](=[O:16])[C:7]=3[C:6]=2[CH:17]=1.BrN1C(=O)CCC1=O.N1C=CC=CC=1.NC1NC(=O)C2C3C=C(Br)C=CC=3C=CC=2N=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([CH3:15])[NH:9][C:8](=[O:16])[C:7]=3[C:6]=2[CH:17]=1
Reactant: Cc1nc2c(c(=O)[nH]1)-c1cc(Br)ccc1CC2
Agent: Nc1nc2ccc3ccc(Br)cc3c2c(=O)[nH]1
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: Cc1nc2ccc3ccc(Br)cc3c2c(=O)[nH]1

Procedure:
A mixture of 9-Bromo-5,6-dihydro-3-methylbenzo[f]quinazolin-1(2H)-one (1.0 g, 3.4 mmoles), N-bromosuccinimide (0.63 g, 3.5 mmoles) and pyridine (0.3 ml, 3.7 mmoles) in dry benzene (350 ml) was reacted in the same manner as for the corresponding 3-pivalamide (Example 2). After cooling, benzene and excess pyridine were removed under reduced pressure. The residue was triturated with methanol:water (1:1) and filtered to leave a crude product which was recrystallized from methanol to give 9-bromo-3-methylbenzo[f]quinazolin-1(2H)-one as an off-white solid. (0.47 g, 37%) 1H NMR(DMSO-d6, 200 MHz) δ: 2.57(s, 3H, CH3); 7.73(d, J=9.0 Hz, 1H, Ar); 7.86(dd, J=8.6, 2.0 Hz, 1H, Ar); 8.09(d, J=8.7 Hz, 1H, Ar); 8.41(d, J=8.8 Hz, 1H, Ar); 9.92(d, J=2.0 Hz, 1H, Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([NH:26][NH2:27])=[O:25])(=[O:20])=[O:19])[CH2:14][CH2:13]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6](/[C:8](=[N:27]/[NH:26][C:24](=[O:25])[C:23]2[CH:28]=[CH:29][CH:30]=[C:21]([S:18]([N:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)(=[O:19])=[O:20])[CH:22]=2)/[CH3:9])[CH:7]=1
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: CC(=O)c1cc(Cl)ccc1F
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cc(Cl)ccc1F
Temperature: 120 °C
Yield: 19 %

Procedure:
1-(5-chloro-2-fluorophenyl)ethanone (20 mg, 0.116 mmol) and 3-(morpholinosulfonyl)benzohydrazide (33.1 mg, 0.116 mmol) was dissolved in Methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-N′-(1-(5-chloro-2-fluorophenyl)ethylidene)-3-(morpholinosulfonyl)benzohydrazide (10 mg, 0.022 mmol, 19.22% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.26 (m, 1H), 8.09 (m, 1H), 7.80 (d, 1H, J=7.6 Hz), 7.58 (t, 1H, J=7.6 Hz), 7.37 (m, 1H), 7.21 (m, 1H), 6.95 (m, 1H), 3.61 (m, 4H), 2.90 (m, 4H), 2.29 (s, 3H). Mass [M+H]+:440.1
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:5][C:4](=[O:6])[CH2:3][CH:2]([NH2:1])[C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: CO
Reactant: NC(CC(=O)O)c1ccc(O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
5.298 g (29.24 mmol) commercial 3-amino-3-(4-hydroxyphenyl)propionic acid were suspended in 136 ml methanol, the mixture cooled to 0° C. and 3.20 ml (43.86 mmol) thionyl chloride were slowly added. The mixture was stirred at room temperature for 20 hours and concentrated. The residue was treated with saturated sodium hydrogen carbonate solution and extracted with dichloromethane and dichloromethane/2-propanol 8:2. The organic part was concentrated to give 5.09 g (80%) 3-amino-3-(4-hydroxyphenyl)propionic acid methyl ester.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20](OC(C)(C)C)=[O:21])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[Cl:41][CH2:42]C(Cl)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:41][CH2:42][C:20]([N:17]1[CH2:16][CH2:15][N:14]([CH2:13][C@:2]2([CH3:1])[O:6][C:5]3=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]3[CH2:3]2)[CH2:19][CH2:18]1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(CN2CCN(C(=O)CCl)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.6 %

Procedure:
A mixture of tert-butyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-piperazine-1-carboxylate prepared in Example 393 (1.5 g, 4.1 mmol) and trifluoroacetic acid (20 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (20 ml), and the solution was added triethylamine (3 ml) and 4-dimethylaminopyridine (100 mg, 0.82 mmol) in this order. To the mixture, a solution of chloroacetyl chloride (0.49 ml, 6.2 mmol) in methylene chloride (2 ml) was added slowly with cooling on ice-bath followed by stirring at room temperature overnight. The reaction mixture was washed with water twice, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford (S)-2-chloro-1-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]ethanone (600 mg, yield 43%) as a light brown powder.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:8]=[C:9]([CH3:31])[C:10]2[O:16][C:15]3[C:17]([Cl:27])=[CH:18][C:19]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:20][C:14]=3[CH2:13][S:12](=[O:29])(=[O:28])[C:11]=2[CH:30]=1)=[O:6]>O.O1CCCC1>[Cl:27][C:17]1[C:15]2[O:16][C:10]3[C:9]([CH3:31])=[CH:8][C:7]([C:5]([OH:6])=[O:4])=[CH:30][C:11]=3[S:12](=[O:28])(=[O:29])[CH2:13][C:14]=2[CH:20]=[C:19]([N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)[CH:18]=1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N3CCNCC3)cc1CS2(=O)=O
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A solution of sodium hydroxide (0.22 g, 5.49 mmol) in water (15 mL) was added to a solution of 4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester (free base of example 16, 0.88 g, 1.83 mmol) in tetrahydrofuran (25 mL). The reaction mixture was stirred at 40° C. for 4 h, the solvent was removed under vacuum. The reaction mixture was acidified to pH 4-5 using 10% aqueous hydrochloric acid. The precipitate was filtered, washed with water and dried to obtain the title compound. Yield: 0.84 g, (98%); 1H NMR (DMSO-d6, 300 MHz): δ 2.65 (s, 3H, CH3), 3.26 (s, 4H, 2CH2), 3.43 (s, 4H, 2CH2), 5.16 (s, 2H, CH2), 7.20 (s, 2H, Ar), 8.08 (s, 1H, Ar), 8.18 (s, 1H, Ar); MS: m/e (ES−) 421 (M−1); analysis: C19H19ClN2O5S.2H2O requires C, 49.73; H, 5.05; N, 6.10; Cl, 7.73; S, 6.99. found: C, 50.27; H, 5.12; N, 6.12; Cl, 7.47; S, 6.92%.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([F:10])[CH:3]=1.[CH2:11]([S:13](Cl)(=[O:15])=[O:14])[CH3:12]>N1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][S:13]([CH2:11][CH3:12])(=[O:15])=[O:14])=[C:4]([F:10])[CH:3]=1
Reactant: NCc1ccc(Br)cc1F
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)NCc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Bromo-2-fluorobenzylamine (924 mg, 4.53 mmol) was dissolved in pyridine and ethane sulfonyl chloride (0.82 mL, 8.60 mmol) was added to the solution at 0° C. The mixture was stirred for 1 h at 0° C. Then, the mixture was quenched with 1N HCl and extracted with ethyl acetate (EtOAc). Drying (MgSO4) and evaporation of the ethyl acetate followed and the residue was purified by CC (eluent EtOAc/n-hexane) to yield N-(4-bromo-2-fluorobenzyl)ethanesulfonamide in pure form (1.06 g, 79%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:19][C:10]1[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[NH:12][N:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc(-c2[nH]ncc2-c2ccncc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2[nH]nc(Br)c2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72 %

Procedure:
5-(4-Fluorophenyl)-4-(pyridin-4-yl)pyrazole (6.0 g (25 mmol), prepared as described in WO 00/31063) was dissolved in dimethylformamide (60 ml). To the solution was added N-bromosuccinimide (8.93 g, 50 mmol), and the resulting mixture was stirred at room temperature for 3 days. At the end of this time, water was added to the reaction mixture, and the precipitated crystals were collected by filtration and washed with diethyl ether, to give the title compound (5.73 g) as a white powder (yield 72%).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:22][N:14]1[C:15]2=[N:16][CH:17]=[N:18][C:19]([NH2:21])=[C:20]2[C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:3]([C:32](=[O:33])[CH2:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH3:23])[CH2:4][CH2:5]3)=[N:13]1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: COc1ccccc1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1CC(=O)N1CCc2cc(-c3nn(C)c4ncnc(N)c34)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (70 mg, 0.206 mmol), [2-(methyloxy)phenyl]acetic acid (34.3 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at room temperature for overnight. LCMS showed reaction was completed. The reaction was poured into water, off-white solid formed. The solid was filtered to give the title compound (78 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28 (m, 2H), 3.78 (s, 3H), 3.80 (s, 2H), 3.94 (s, 3H), 4.22-4.30 (m, 2H), 6.93 (t, J=7.45 Hz, 1H), 7.01 (d, J=7.83 Hz, 1H), 7.20 (dd, J=7.58, 1.52 Hz, 1H), 7.25-7.32 (m, 1H), 7.43 (d, J=8.34 Hz, 1H), 7.51 (s, 1H), 8.16 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: [CH2:1]1[N:12](CC(O)=O)[CH2:11][CH2:10][N:9](CC(O)=O)[CH2:8][CH2:7][N:6](CC(O)=O)[CH2:5][CH2:4][N:3](CC(O)=O)[CH2:2]1.[CH2:29]1[CH2:42][N:41](CC(O)=O)[CH2:40][CH2:39][N:38](CC(O)=O)[CH2:37][CH2:36][CH2:35][N:34](CC(O)=O)[CH2:33][CH2:32][N:31](CC(O)=O)[CH2:30]1>>[NH:3]1[CH2:4][CH2:5][NH:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][CH2:1][CH2:2]1.[NH:31]1[CH2:30][CH2:29][CH2:42][NH:41][CH2:40][CH2:39][NH:38][CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1
Reactant: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: O=C(O)CN1CCCN(CC(=O)O)CCN(CC(=O)O)CCCN(CC(=O)O)CC1
Product: C1CNCCNCCCNCCNC1
Product: C1CNCCNCCNCCN1

Procedure:
Accordingly, the invention provides a method for the synthesis of 1,4,7,10-tetraazacyclododecane N,N',N",N'"-tetraacetic acid (DOTA) and 1,4,8,11-tetraazacyclotetradecane N,N',N",N'"-tetraacetic acid (TETA) (Formula I). For this purpose 1,4,7,10-tetraazacyclododecane and 1,4,8,11-tetraazacyclotetradecane (Formula II) are provided and cyanomethylated using acid, formaldehyde, and cyanide compound yielding a tetranitrile (Formula III) which precipitates upon the addition of base.. The tetranitrile (Formula III) is hydrolyzed followed by acidification, evaporation to dryness, reconstitution and precipitation to give DOTA or TETA. ##STR5##
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.CCCCCC>[Si:20]([O:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: O=C1CCCCC1CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC1CCCCC1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.3 %

Procedure:
In dry DMF (200 ml) was dissolved 2-(2-hydroxyethyl)cyclohexanone (7.86 g) followed by addition of imidazole (9.53 g) and tert-butyldimethylchlorosilane (10 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with hexane (500 ml), washed successively with aqueous sodium hydrogen carbonate, diluted hydrochloric acid, aqueous sodium hydrogen carbonate, and aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was further subjected to vacuum distillation to give 7.55 g of 2-[2-(tert-butyldimethylsilyloxy)ethyl]cyclohexanone as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:18]([C:20]1[C:25]([N:26]=[C:27]=[S:28])=[C:24]([CH2:29][CH3:30])[N:23]=[C:22]([CH3:31])[N:21]=1)[CH3:19]>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:27](=[S:28])[NH:26][C:25]1[C:24]([CH2:29][CH3:30])=[N:23][C:22]([CH3:31])=[N:21][C:20]=1[CH2:18][CH3:19]
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Reactant: CCc1nc(C)nc(CC)c1N=C=S
Solvent: C1CCOC1
Product: CCc1nc(C)nc(CC)c1NC(=S)Nc1c(Cl)ccc(C(=O)OC)c1NCCCO
Temperature: 65 °C
Reaction time: 72 h
Yield: 54 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (3.30 g, 12.8 mmol) and 4,6-diethyl-5-isothiocyanato-2-methylpyrimidine (5.28 g, 25.5 mmol) in tetrahydrofuran (25 mL) was stirred at 65° C. for 3 days. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give methyl 4-chloro-3-{[(4,6-diethyl-2-methylpyrimidin-5-yl)carbamothioyl]amino}-2-[(3-hydroxypropyl)amino]benzoate as a yellow solid (3.22 g).