Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([C:20]#[N:21])=[C:15]([CH:17]=[CH:18][CH:19]=2)[NH2:16])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].[CH2:28]([O:30][C:31](=[O:35])[C:32](Cl)=[O:33])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:35])[C:32]([NH:16][C:15]1[CH:17]=[CH:18][CH:19]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:22]=[CH:23][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([OH:27])[C:6]=2[CH2:24][CH2:25][CH3:26])[C:14]=1[C:20]#[N:21])=[O:33])[CH3:29]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCCc1c(OCCCOc2cccc(N)c2C#N)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCOc2cccc(NC(=O)C(=O)OCC)c2C#N)ccc(C(C)=O)c1O

Procedure:
In a manner analogous to that described in Examples 8 and 9, starting from 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-2-cyanoaniline, by reaction with chloro-oxalic acid ethyl ester there is obtained N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-2-cyanophenyl}-oxamic acid ethyl ester having a melting point of 158°-159°, and, by hydrolysis of that compound, N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-2-cyanophenyl}-oxamic acid is obtained in the form of the triethanolammonium salt having a melting point of 79°-81°.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[O:6]=[CH:7][C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9]>C1COCC1.C(OCC)(=O)C>[CH:1]1([CH:7]([OH:6])[C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH3:9])[CH2:3][CH2:2]1
Reactant: C[C@H](C=O)NC(=O)OC(C)(C)C
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(O)C1CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 54.5 %

Procedure:
Cyclopropylmagnesium bromide (32 mL, 16.00 mmol) was added dropwise to a solution of (R)-tert-butyl 1-oxopropan-2-ylcarbamate (1.10 g, 6.35 mmol) in anhydrous THF (Volume: 25.4 mL) at −78° C. The reaction mixture was then allowed to warm to 0° C. and stirred at this temp for 4 hrs before quenching with sat. ammonium chloride solution. The evaporated organic was then purified by column chromatography using hexane:ethyl acetate as eluent to give tert-butyl (2R)-1-cyclopropyl-1-hydroxypropan-2-ylcarbamate (745 mg, 3.46 mmol, 54.5% yield). 1H NMR (500 MHz, CCl3D) δ 4.80 (br. s., 1H), 3.94-3.66 (m, 1H), 3.07-2.90 (m, 1H), 2.87-2.65 (m, 1H), 2.44-2.13 (m, 1H), 1.48-1.37 (m, 9H), 1.24-1.12 (m, 3H), 1.06-0.91 (m, 1H), 0.91-0.78 (m, 1H), 0.64-0.46 (m, 2H), 0.42-0.15 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]([C:13](=[O:29])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[CH2:9][CH2:10]SC)([CH3:4])([CH3:3])[CH3:2].CI>>[C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]1[CH2:9][CH2:10][N:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[C:13]1=[O:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(OCc2ccccc2)cc1
Solvent: CI
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(OCc3ccccc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 0.1 %

Procedure:
A mixture of 0.35 g (0.81 mmol) of (S)-[1-(4-benzyloxy-phenylcarbamoyl)-3-methylsulfanyl-propyl]-carbamic acid tert-butyl ester and 8.79 g (62.0 mmol) of methyliodide is stirred at RT for 3 d. Thereafter, the methyliodide is evaporated, the intermediate sulfonium salt dissolved in 15 ml of THF and treated with 0.79 ml (0.79 ml) of lithium bis-(trimethylsilyl)amide (1 M solution in THF) at 0° C. After stirring at 0° C. for 2 h, the reaction mixture is evaporated under reduced pressure and the solid residue is directly submitted to chromatography on silica gel using a 2:1 mixture of n-hexane and ethyl acetate as the eluent. There are obtained 0.175 mg (56% of theory) of (S)-[1-(4-benzyloxy-phenyl)-2-oxo-pyrrolidin-3-yl]-carbamic acid tert-butyl ester as a white solid. MS: m/e=383 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][S:19][CH2:18][CH2:17]1>CO>[S:19]1[CH2:20][CH2:21][N:16]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:17][CH2:18]1
Reactant: COC(=O)c1ccc2c(Cl)ncnc2c1
Reactant: C1CSCCN1
Solvent: CO
Product: COC(=O)c1ccc2c(N3CCSCC3)ncnc2c1
Yield: 10.3 %

Procedure:
A solution of methyl 4-chloroquinazoline-7-carboxylate 66a (1.01 mmol, 225 mg) and thiomorpholine 66b (2.02 mmol, 208 mg) in MeOH (1.6 mL) was refluxed overnight. Compound 66c (30 mg) was isolated after purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=O)[C:13]([OH:19])([CH3:18])[C:14]([F:17])([F:16])[F:15])(O)=[O:2].S(Cl)(Cl)=O.OC(C(F)(F)F)(C)C(O)=O.IC1C=C(C(O)=O)C([NH2:45])=CC=1.C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.O>[F:15][C:14]([F:17])([F:16])[C:13]([C:12]1[NH:45][C:1](=[O:2])[C:4]2[C:5](=[CH:6][CH:7]=[C:8]([I:10])[CH:9]=2)[N:11]=1)([OH:19])[CH3:18]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: CC(O)(C(=O)Nc1ccc(I)cc1C(=O)O)C(F)(F)F
Agent: CC(O)(C(=O)O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(O)(c1nc2ccc(I)cc2c(=O)[nH]1)C(F)(F)F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
N-(2-Carboxy-4-iodophenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.Thionyl chloride (5 g) was slowly added to a stirred solution of 2-hydroxy-2-trifluoromethyl propionic acid (6.64 g) in dimethylacetamide (100 mL) cooled to and maintained at -15° C. After 1 hour, 5-iodoanthranilic acid (10 g) was added in one portion and the temperature was allowed to slowly rise to ambient temperature. After stirring overnight, the reaction mixture was poured into water (1500 mL). The aqueous mixture was treated with solid sodium bicarbonate to pH 4, filtered, washed (water), and dried to give the amide (13.1 g) as a tan solid; mp 240°-243° C. Leaching with cold methylene chloride raises the mp to 247°-250° C.; NMR: 1.58 (s,3), 7.74 (s,1), 7.96 (d,1), 8.28 (s,1), 8.45 (d,1), 12.28 (s,1); MS: m/z=404(M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][CH2:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1)=[O:26]>CC(=O)CC.CN(C)C=O>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:23][CH2:24][C:25]([N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH2:28]2)=[O:26])[CH2:12][CH2:11]1
Reactant: O=C(CCCl)N1CCc2ccccc21
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: O=C(CCN1CCN(c2cccc(Cl)c2Cl)CC1)N1CCc2ccccc21
Temperature: 50 °C

Procedure:
A mixture of 1-(2,3-dichlorophenyl)piperazine, hydrochloride (8.0 g) and potassium carbonate (15 g) in a mixture of butanone (50 mL) and dimethyl formamide (5 mL) was heated to 50° C. followed by the addition of 3-chloro-1-(2,3-dihydro-1H-indol-1-yl)propan-1-one (6.0 g). The resulting mixture was boiled under reflux for 40 h and filtered hot. The remaining organic phase was left to crystallise, and a white crystalline material was collected by filtration and washed with acetone (8.5 g). Mp 157–158° C. 1H NMR (DMSO-d6): 2.60 (s, 4H); 2.60–2.80 (m, 4H); 3.00 (s, 4H); 3.15 (t, 2H); 4.10 (t, 2H); 6.95 (t, 1H); 7.10–7–15 (m, 2H); 7.20 (d, 1H); 7.25–7.35 (m, 2H); 8.10 (d, 1H). MS m/z: 404 (MH+), 243.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([F:16])[CH:8]=1.Cl.[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:17])=[CH:8][C:9]=4[F:16])=[O:13])[CH2:32][CH2:33]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1F
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2F)CC1
Yield: 62.9 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-fluorobenzoic acid (259 mg) described in Preparation Example 23 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (254 mg) described in Preparation Example 82 and by the reaction and treatment in the same manner as in Example 86, the title compound (288 mg) was obtained.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C@@H:20]3[CH:25]4[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([O-])=O>CO.Cl.[Pd]>[ClH:1].[ClH:1].[NH2:2][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([C@@H:20]3[CH:25]4[CH2:24][CH2:23][N:22]([CH2:27][CH2:26]4)[CH2:21]3)=[O:19])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1
Reactant: O=C(Nc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)[C@H]1CN2CCC1CC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1

Procedure:
A solution of 739 mg (2.10 mmol) of (3R)—N-(4′-nitrobiphenyl-4-yl)quinuclidine-3-carboxamide (Example 6A) in 10 ml of methanol and 5 ml of 2 N hydrochloric acid is hydrogenated under atmospheric pressure in the presence of 448 mg (0.21 mmol) of 5% palladium on carbon for 2 h. Filtration through kieselgur is followed by washing with methanol and concentration of the filtrate and drying under high vacuum. 755 mg (89.2% of theory) of the title compound are obtained.
Reaction SMILES: N[C:2]1[C:10](C(F)(F)F)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].COC(=O)C1C=CC=CC=1I>CO.O>[C:4]([OH:6])(=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Agent: COC(=O)c1ccccc1I
Solvent: CO
Solvent: O
Product: O=C(O)c1ccccc1
Yield: 51 %

Procedure:
Similar reaction of 2-amino-3-trifluoromethylbenzoic acid and methyl-2-iodobenzoate by the reported method [Rewcastle and Denny, Synth. Comm, 1987, 17, 309] gave 3-trifluoromethyl-2-[(2-methoxycarbonyl)phenyl)amino]benzoic acid (51%), mp (MeOH/H2O) 113-115° C. 1H NMR [(CD3)2SO] δ 3.89 (s, 3 H, CO2CH3), 6.35 (d, J=8.5 Hz, 1 H, ArH), 6.78 (t, J=7.5 Hz, 1 H, ArH), 7.30 (ddd, J=7.8, 7.8, 1.6 Hz, 1 H, ArH), 7.59 (t, J=7.8 Hz, 1 H, ArH), 7.88 (dd, J=8.0, 1.5 Hz, 1 H, ArH), 8.03 (d, J=7.4 Hz, 1 H, ArH), 8.07 (d, J=8.07 Hz, 1 H, ArH), 9.49 (s, 1 H, NH), 13.15 (br s, 1 H, COOH). Anal. (C16H12F3NO2) C, H, N, F.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5](Cl)[C:4]=1[C:19]([O:21][CH3:22])=[O:20].[CH:24]1([SH:29])[CH2:28][CH2:27][CH2:26][CH2:25]1>C1COCC1>[CH:24]1([S:29][C:5]2[C:4]([C:19]([O:21][CH3:22])=[O:20])=[C:3]([CH:2]([F:23])[F:1])[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1Cl
Reactant: SC1CCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1SC1CCCC1
Yield: 107.1 %

Procedure:
This compound was prepared as described in Example 108: 3 g (0.0083 mol) of product of Example 103, 1.02 g (0.01 mol) of cyclopentylmercaptan and 0.36 g (0.009 mol) of 60NaH in 50 ml of dry THF were reacted affording 3.8 g of a red oil. Crude was purified by HPLC using 1ethyl acetate/cyclohexane as eluting solvent to give 2.5 g of a light yellow oil which gas chromatography showed to be 94% pure. This material was passed through a spinning plate preparative chromatograph in two different portions of 1.25 g each (eluting solvent: 40CH2Cl2 /cyclohexane) to give, after kugelrohr distillation at 105-125° C./106 Pa, 1.95 g (55%) of product as a clear oil; nD25 1.4831.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C)C=O.[CH2:19]([N:26]1[C:30]2[C:31]([Cl:35])=[N:32][CH:33]=[CH:34][C:29]=2[NH:28][CH:27]1Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C>[CH2:19]([N:26]1[C:30]2[C:31]([Cl:35])=[N:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nccc2c1N(Cc1ccccc1)C(Cl)N2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc3ccnc(Cl)c3n2Cc2ccccc2)CC1
Temperature: 150 °C
Yield: 14.9 %

Procedure:
0.094 g of t-butyl piperazine-1-carboxylate was added to a 1 ml N,N-dimethylformamide solution of 0.127 g of 3-benzyl-2,4-dichloro-1,3-dihydroimidazo[4,5-c]pyridine, and the mixture was heated at 150° C. for two hours. 25 ml of ethyl acetate was added to the mixture, and the organic layer was washed three times with 10 ml of water and then with 10 ml of an aqueous solution saturated with sodium chloride. The organic liquid was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.029 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (3:2).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C@H:11]([C:16](=[O:27])[NH:17][CH2:18][CH2:19][CH:20](OCC)[O:21]CC)[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1>[CH2:1]([O:8][C:9](=[O:28])[NH:10][C@H:11]([C:16](=[O:27])[NH:17][CH2:18][CH2:19][CH:20]=[O:21])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(CCNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)OCC
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC=O
Yield: 113.1 %

Procedure:
By using an analogous procedure to that described for Reference Example 14, [(1S)-1-(3,3-diethoxy-propylcarbamoyl)-3-methyl-butyl]-carbamic acid benzyl ester (1.0 g, 2.5 mmol, obtained from Reference Example 15) in tetrahydrofuran was reacted with 0.5N hydrochloric acid (5 mL) for 15 min, to provide [(1S)-3-methyl-1-(3-oxo-propylcarbamoyl)-butyl]-carbamic acid benzyl ester (906 mg, 100%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[CH2:22](O)[CH:23]=[CH2:24].S(=O)(=O)(O)O>O>[CH2:24]([O:12][C:11](=[O:13])[CH2:10][CH2:9][C:8]([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH3:14])[CH:23]=[CH2:22]
Reactant: C=CCO
Reactant: CC(CCC(=O)O)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: C=CCOC(=O)CCC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reaction time: 20 h

Procedure:
A mixture of 85.8 grams of 4,4-bis-(4-hydroxyphenyl)pentanoic acid, 200 ml. of allyl alcohol and 2 ml. of concentrated sulfuric acid was heated to 50° C. and maintained at the temperature, with stirring, for 20 hours. The mixture was then poured into 1500 ml. of water, with stirring. The oily layer was allowed to settle and the aqueous layer was removed by decantation. The oily layer was washed with water two additional times. Finally, a 1500 ml. portion of water was added to the oil and the mixture was stirred until the viscous oil solidified. The solid was separated from the water, pulverized and stirred one hour with 1000 ml. of water containing 16.8 grams of sodium bicarbonate. The product was filtered and washed with water until the filtrate was neutral. Yield: 86.6 grams (88.5%) of off white solid, m.p. 83°-85° C.
Reaction SMILES: C1COCC1.O.[C:7]([C:11]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14](=[O:21])[C:13](=[O:22])[C:12]=1[N+:23]([O-:25])=[O:24])([CH3:10])([CH3:9])[CH3:8].[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCOC(C)=O>[C:7]([C:11]1[C:12]([N+:23]([O-:25])=[O:24])=[C:13]([OH:22])[C:14]([OH:21])=[C:15]([C:17]([CH3:18])([CH3:19])[CH3:20])[CH:16]=1)([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)C1=CC(C(C)(C)C)=C([N+](=O)[O-])C(=O)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(C(C)(C)C)c([N+](=O)[O-])c(O)c1O
Reaction time: 0.03 h
Yield: 73.5 %

Procedure:
In a separatory funnel was placed THF/H2O (1:1, 400 mL), 4,6-di-tert-butyl-3-nitrocyclohexa-3,5-diene-1,2-dione (4.59 g, 17.3 mmol) and Na2S2O4 (3 g, 17.3 mmol). The separatory funnel was stoppered and was shaken for 2 min. The mixture was diluted with EtOAc (20 mL). The layers were separated and the organic layer was washed with brine, dried over MgSO4 and concentrated to provide 4,6-di-tert-butyl-3-nitrobenzene-1,2-diol (3.4 g, 74%), which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.76 (s, 1H), 6.87 (s, 1H), 1.35 (s, 9H), 1.25 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:22][CH2:21][N:11]2[C:12]3[N:20]=[CH:19][CH:18]=[CH:17][C:13]=3[NH:14][CH2:15][CH2:16][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=[O:32])=[CH:26][CH:25]=1.CO>C(Cl)Cl>[CH2:1]([N:8]1[CH2:22][CH2:21][N:11]2[C:12]3[N:20]=[CH:19][CH:18]=[CH:17][C:13]=3[N:14]([C:31](=[O:32])[CH2:30][C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH2:15][CH2:16][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: c1ccc(CN2CCN3c4ncccc4NCCC3C2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)cc1)N1CCC2CN(Cc3ccccc3)CCN2c2ncccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of the product of Example 52 (135 mg, 0.367 mmol) in CH2Cl2 (3 mL) was added to 4-chlorophenylacetyl chloride (Aldrich, 0.058 mL, 0.38 mmol), and the resulting solution was stirred at room temperature for 45 minutes. Methanol (0.5 mL) was added and the mixture was stirred for 10 minutes and then concentrated under vacuum. The residue was crystallized from ethanol (4 mL) and water (0.2 mL) to provide the title compound as the HCl salt: 1H NMR (400 MHz, pyridine-d5) δ ppm 2.57-2.86 (m, 3H), 2.92-3.31 (m, 2H), 3.32-3.59 (m, 7H), 4.29-4.66 (m, 2H), 6.69-6.88 (m, 1H), 6.91-7.04 (m, 2H), 7.21 (d, J=8.2 Hz, 2H), 7.25 (d, J=7.3 Hz, 1H), 7.27-7.36 (m, J=7.3, 7.3 Hz, 3H), 7.37-7.44 (m, 2H), 8.23-8.33 (m, 1H), one proton obscured by solvent; MS (ESI) m/z 447/449 (M+H)+. Elemental analysis is calculated for C26H27N4OCl.HCl..0.4H2O: C, 63.65; H, 5.92; N, 11.42. Found: C, 63.72; H, 5.75; N, 11.26.
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:12][C:13](=O)[CH2:14][CH2:15][C:16](=O)[CH3:17]>[O-]S(C(F)(F)F)(=O)=O.[Sc+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH3:17][C:16]1[N:1]([C:2]2[S:6][CH:5]=[N:4][C:3]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:13]([CH3:12])=[CH:14][CH:15]=1
Reactant: CC(=O)CCC(C)=O
Reactant: CCOC(=O)c1ncsc1N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Product: CCOC(=O)c1ncsc1-n1c(C)ccc1C
Temperature: 180 °C

Procedure:
A mixture of ethyl 5-aminothiazole-4-carboxylate (91.3 mg, 0.53 mmol), scandium (III) triflate (2.61 mg, 0.005 mmol) and 2,5-hexanedione (1.5 mL) was heated up to 180° C. for 1 h by microwave. The reaction was then concentrated and purified with silica gel chromatography to give a tan solid of ethyl 5-(2,5-dimethyl-1H-pyrrol-1-yl)thiazole-4-carboxylate (104 mg). 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 5.92 (s, 2H), 4.25 (q, 2H), 2.01 (s, 6H), 1.20 (t, 3H). MS m/z 251.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][CH:13]([N:16]([C:20]4[CH:37]=[CH:36][C:23](C(N[C@H](C(O)=O)CCC(O)=O)=O)=[CH:22][CH:21]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1.NC(CO)(CO)CO.[C:46]([OH:49])(=[O:48])C>[Cl-].[Zn+2].[Cl-]>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][CH:13]([N:16]([C:20]4[CH:37]=[CH:36][C:23]([C:46]([OH:49])=[O:48])=[CH:22][CH:21]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1
Reactant: C#CCN(c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21
Reactant: CC(=O)O
Agent: NC(CO)(CO)CO
Agent: [Cl-]
Agent: [Zn+2]
Product: C#CCN(c1ccc(C(=O)O)cc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21
Temperature: 37 °C

Procedure:
A mixture of N-{p-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoyl}-L-glutamic acid (6 g), carboxypeptidase G2 (2000 units) and tris buffer [prepared by mixing 2-amino-2-hydroxymethyl-1,3-propanediol (12.11 g), zinc chloride (0.035 g) and distilled water (950 ml), by adjusting the basicity of the mixture to pH 7.3 by the addition of 2N aqueous hydrochloric acid and by adding sufficient distilled water to give a final volume of 1 L; 750 ml] was stirred and heated to 37° C. for 30 hours. A second portion of carboxypeptidase G2 (2000 units) was added and the mixture was heated to 37° C. for a further 24 hours. The mixture was cooled to 0° C. and acidified to pH 4 by the addition of glacial acetic acid. The precipitate was isolated, washed with water and dried under vacuum. There was thus obtained p-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[a]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoic acid as a solid (4 g), m.p. 264° C.;
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-:10].[Na+]>C1COCC1>[Br:1][C:2]1[C:3]([OH:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (10 g, 44.2 mmol) in THF (135 mL) was added sodium hydroxide solution (3 M, 45 mL), and the mixture was stirred overnight at RT. The solvent was evaporated, and the residue was diluted with water (100 mL). The aqueous solution was cooled to 0° C., brought to pH 2-3 with 1 N HCl and then extracted with methanol/dichloromethane (5%, 5×100 mL). The organic layers were separated, combined, dried over sodium sulfate, filtered and concentrated to give 5-bromo-2-chloropyrimidin-4-ol (6.5 g, 71%) as a yellow solid. MS (ES+) C4H2BrClN2O requires: 208, 210, found: 209, 211 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Br:12][CH2:13][CH2:14][CH2:15]Br.O>CN(C=O)C>[Br:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCBr)cc1
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
A solution of 4-hydroxybenzaldehyde (3.7 g, 30 mmol) in DMF (10 ml) was added cautiously to a stirred solution of sodium hydride (60% in oil, 1.44 g) in DMF (80 ml). After 30 min., 1,3-dibromopropane (9.2 ml, 90 mmol) in DMF (10 ml) was added dropwise, the mixture stirred for 16 h, poured into water, extracted twice with ethyl acetate, and the combined extracts washed with water and saturated aqueous sodium chloride, dried over sodium sulphate and evaporated. The residue was purified by flash chromatography on silica, eluting with 25% diethyl ether in hexane, to afford 4-(3-bromopropyloxy)benzaldehyde (3.85 g). M+ 205; 360 MHz 1H n.m.r (CDCl3) 7.85 (2H, d, J 7.0 Hz), 7.01 (2H, d, J 7.0 Hz), 4.20 (2H, t, J 5.8 Hz), 3.62 (2H, t, J 6.4 Hz), 2.36 (2H, pentet, J 6.1 Hz).
Reaction SMILES: S([O:5][CH2:6][CH2:7][N:8]1[C:12]([NH2:13])=[C:11]([NH2:14])[CH:10]=[N:9]1)(O)(=O)=O.C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])C.C(O)=O>ClCCl.[Cl-].[Na+].O>[NH2:13][C:12]1[N:8]([CH2:7][CH2:6][OH:5])[N:9]=[CH:10][C:11]=1[NH:14][CH:22]=[O:24]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnn(CCOS(=O)(=O)O)c1N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=CO
Product: Nc1c(NC=O)cnn1CCO
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 2-(4,5-diamino-1H-pyrazol-1-yl)ethanol sulfate (5 g) in dichloromethane (50 ml) was added triethylamine (6.38 ml) at 0° C., and the mixture was stirred at 0° C. for 10 minutes. A mixture of acetic anhydride (2.16 ml) and formic acid (1.74 ml) was stirred at 40° C. for 30 minutes, cooled to 0° C. and added dropwise to the above solution at 0° C. The whole mixture was stirred at 0° C. for 2 hours. To the mixture was added brine, and the whole mixture was extracted with tetrahydrofuran. The extract was dried over magnesium sulfate and evaporated under reduced pressure to give crude [5-amino-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]formamide, which was used in the next reaction without further purification.