Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9]([CH:11]=O)=[O:10])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([NH2:30])([CH3:29])[CH3:28])=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16]>>[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([NH:30][CH2:11][CH:9]([OH:10])[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=2)([CH3:28])[CH3:29])=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccc(CCC(C)(C)N)cc1
Reactant: O=CC(=O)c1cccc(C(F)(F)F)c1
Product: COC(=O)c1ccc(CCC(C)(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared as in Example 1a from 3-trifluoromethylphenyl glyoxal (2.0 g) and 3-(4-carbomethoxyphenyl)-1,1-dimethylpropylamine (2.6 g) and isolated as the hydrochloride salt monohydrate m.p. 214°-219°. (methanol-ether). τ(DMSO d6) 8.6 (6H,s), 7.8-8.2 (2H,m), 6.6-7.4 (4H,m), 6.1 (3H,s), 5.8 (3H, broad, replaceable by D2O), 4.8 (1H,m), 2.55 (2H,d,J=8 Hz), 2.1-2.4 (4H,m), 2.07 (2H,d,J=8 Hz), 1.3 (1H, broad, replaceable by D2O), 0.33 (1H, broad, replaceable by D2O).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC=C)=[CH:9][CH:8]=1)[CH3:2].CN(C)[C:28]1[CH:33]=CC=C[CH:29]=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:33][CH:28]=[CH2:29])[CH:8]=1)[CH3:2]
Reactant: C=CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)OCC)cc1
Reactant: CN(C)c1ccccc1
Product: C=CCc1cc(CC(C)(Oc2ccccc2)C(=O)OCC)ccc1O
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of 3-(4-allyloxyphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (475 mg, 1.39 mmol) in dimethylaniline (1.5 mL) was heated at reflux for 18 h. After cooling to ambient temperature, the reaction mixture was partitioned between EtOAc and 1N H2SO4. The organic phase was dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (100 mL SiO2, hexanes to 30% EtOAc/hexanes) to provide the desired product (343 mg, 72%) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.23 (t, J=8.4 Hz, 2H), 7.02-6.96 (m, 3H), 6.83 (d, J=8.8 Hz, 2H), 6.72 (d, J=7.6 Hz, 1H), 6.05 (m, 1H), 5.16-5.09 (m, 2H), 4.21 (q, J=6.8 Hz, 2H), 3.38 (d, J=6.4 Hz, 2H), 3.25 (A of AB, J=13.6 Hz, 1H), 3.10 (B of AB, J=13.6 Hz, 1H), 1.41 (s, 3H), 1.23 (t, J=6.8 Hz, 3H).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])=[O:11])=[CH:8][CH:7]=1.N1C=CC=CC=1>C1C=CC=CC=1>[F:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([Cl:3])=[O:15])=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)c1ccccc1C(=O)c1ccc(F)cc1

Procedure:
Thionyl chloride (1.6 ml) was added to a solution of 2-(4-fluorobenzoyl)benzoic acid (3.6 g) and pyridine (0.03 ml) in benzene (40 ml), followed by refluxing for an hour. The solvent was distilled off to give 2-(4-fluorobenzoyl) benzoyl chloride (IRνmaxNujol : 1790 cm-1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:12][NH:13][CH3:14].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]([CH3:14])[CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of 4-bromobenzoyl chloride (2.00 g, 9.11 mmol) and dimethyl amine hydrochloride (892 mg, 10.90 mmol) in 20 mL of CH2Cl2 was added triethylamine (3.81 mL, 27.30 mmol). The mixture was stirred at room temperature for 2 h, quenched with water, extracted with 3×CHCl3, dried with Na2SO4, concentrated and purified by Biotage column chromatography with 1-4% MeOH in 1:1 EtOAc/CH2Cl2 to give a white solid (1.73 g, 83% yield). 1H NMR (400 MHz, CDCl3) δ 7.48-7.65 (m, 2 H) 7.20-7.37 (m, 2 H) 3.05 (d, J=50.78 Hz, 6 H); LCMS for C9H10BrNO m/z 228.00 and 230.00 (M+H)+
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[S:31][C:8]2[NH:9][C:10]([C:12]([NH:14][CH:15]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH2:25][C:26]([O:28]C)=O)[C:16]3=[O:30])=[O:13])=[CH:11][C:7]=2[CH:6]=1>CCO>[Cl:4][C:5]1[S:31][C:8]2[NH:9][C:10]([C:12]([NH:14][CH:15]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH2:25][C:26]([NH:2][NH2:3])=[O:28])[C:16]3=[O:30])=[O:13])=[CH:11][C:7]=2[CH:6]=1
Reactant: NN
Reactant: COC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Solvent: O
Solvent: CCO
Product: NNC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Yield: 76 %

Procedure:
Hydrazine monohydrate (1 mL, 20.6 mmol) was added to a suspension of methyl[3-{[(2-chloro-6H-thieno[2,3-b]pyrrol-5-yl)carbonyl]amino}-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate (Example 1); 221 mg, 0.53 mmol) in EtOH (10 mL) and heated to reflux for 20 hours. On cooling the mixture was concentrated under reduced pressure and H2O (20 mL) added and the white precipitate filtered off and dried in vacuo to give the title product (169 mg, 76%) as an off white solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.CC(C)([O-])C.[K+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][C:30](=[O:32])[CH3:31])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>C(O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:28]2[CH2:29][C:30](=[O:32])[CH2:31][C:3](=[O:5])[CH:2]2[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(C=CC(C)=O)cc1OC
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1C(=O)CC(=O)CC1c1ccc(OC)c(OC)c1
Yield: 871.4 %

Procedure:
Diethyl malonate (73. 7 g) was dissolved in ethanol (700 ml), and then potassium tert-butoxide (51.6 g) was gradually added thereto. A solution of 4-(3,4-dimethoxyphenyl)-3-buten-2-one (79.1 g) in ethanol (500 ml) was added dropwise, and the mixture was refluxed for 1.5 hours. After distilling off the reaction solvent under reduced pressure, ice water was poured over it and it was adjusted to pH4 with concentrated hydrochloric acid. The deposited crystals were filtered by suction, washed with water and then air-dried to give 122 g of ethyl 2-(3,4-dimethoxyphenyl)-4,6-dioxocyclohexane carboxylate (99.6%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]1([S:17]([C:20]([CH3:32])([CH3:31])[CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH:26]([OH:30])[CH2:25]2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([S:17]([C:20]([CH3:32])([CH3:31])[CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH2:25]2)(=[O:18])=[O:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(CCCN1CCCC(O)C1)S(=O)(=O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(CCCN1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
Dimethylsulphoxide (1.2 ml, 16.6 mmol) was added to a solution of oxalyl chloride (1.5 ml, 16.6 mmol) in dichloromethane (200 ml) at −78° C. and stirred for 15 minutes. 1-(4-Benzenesulfonyl-4-methylpentyl)-3-hydroxypiperidine (3.5 g, 11.0 mmol) in dichloromethane (50 ml) was added and the reaction stirred at −20° C. for 15 minutes. Triethylamine (4.6 ml, 33 mmol) was added and the reaction stirred for 90 minutes, warming slowly to room temperature. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 5% methanol/dichloromethane to give the title compound (2.8 g, 80%).
Reaction SMILES: CS([C:4]1[S:5][C:6]2[CH:12]=[C:11]([CH2:13][N:14]3[C:18]4=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=[C:17]4[N:16]=[CH:15]3)[CH:10]=[CH:9][C:7]=2[N:8]=1)=O.[NH2:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]1[OH:34].CCN(C(C)C)C(C)C>CC(N(C)C)=O.CCOC(C)=O>[F:25][C:23]([F:24])([F:26])[C:21]1[CH:22]=[C:17]2[N:16]=[CH:15][N:14]([CH2:13][C:11]3[CH:10]=[CH:9][C:7]4[N:8]=[C:4]([NH:27][C@@H:28]5[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]5[OH:34])[S:5][C:6]=4[CH:12]=3)[C:18]2=[N:19][CH:20]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(C(F)(F)F)cnc43)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(C(F)(F)F)cnc43)cc2s1
Temperature: 130 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
A mixture of 2-(methylsulfinyl)-6-((6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazole (180 mg, 0.45 mmol), (1R,2R)-2-aminocyclohexanol (112 mg, 0.97 mmol) and DIEA (261 mg, 2 mmol) in DMA (2 mL) was stirred at 130° C. overnight. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford (1R,2R)-2-((6-((6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as a yellow solid (64 mg, 31.8%). 1H NMR (300 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.78 (d, J=1.2 Hz, 1H), 8.55 (d, J=1.5 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.68 (d, J=1.5 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.25-7.22 (m, 1H), 5.55 (s, 2H), 4.71 (d, J=5.1 Hz, 1H), 3.52-3.50 (m, 1H), 3.37-3.33 (m, 1H), 2.08-2.01 (m, 1H), 1.87-1.85 (m, 1H), 1.64-1.60 (m, 2H), 1.29-1.19 (m, 4H). LCMS (ESI) m/z 448 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O>>[O:29]=[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[C:32]([F:43])([F:42])[F:31])[CH:17]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20]1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Product: O=C(O)c1cnn(-c2nc3ccc(-c4ccccc4C(F)(F)F)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 2-trifluoromethylphenylboronic acid in step C. MS (ESI): mass calcd. for C19H11F3N4O3, 400.1; m/z found, 401.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.01 (br s, 2H), 8.99 (s, 1H), 8.42 (d, J=1.6 Hz, 1H), 8.31-8.25 (m, 2H), 8.13 (d, J=7.6 Hz, 1H), 8.10 (s, 1H), 7.83 (s, 1H), 7.77 (dt, J=15.3, 7.8 Hz, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[OH:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(#N)C>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:17][C:15]2[CH:14]=[CH:13][NH:12][C:11](=[O:10])[CH:16]=2)=[CH:4][CH:5]=1
Reactant: Oc1ccnc(O)c1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.40 g (7.41 mmol) 1-bromomethyl-4-fluoro-benzene in 20 mL acetonitrile is added 822 mg (7.40 mmol) 2,4-dihydroxy pyridine and 2.05 g (14.8 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT. 5 mL of DMF is added and the reaction is stirred overnight. After filtration and evaporation of the solvent, is the residue purified by HPLC (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]([N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1)([CH3:26])[CH3:25]>>[CH:24]([N:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:29][CH2:28]1)([CH3:26])[CH3:25]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)N1CCC(N)CC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCN(C(C)C)CC2)cn1
Yield: 73 %

Procedure:
As described for example 34, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using N-isopropyl-4-aminopiperidine instead of 1-methylpiperidin-4-amine, to the title compound (110 mg, 73%) which was obtained as a white foam. MS: m/e=435.4 [M+H]+.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.O.[NH3:17]>O1CCCC1>[O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([S:12]([NH2:17])(=[O:14])=[O:13])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: N
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(-c2cnco2)cc1
Yield: 87 %

Procedure:
To a stirred solution of 4-(1,3-oxazol-5-yl)benzenesulfonyl chloride (1.00 g, 4.10 mmol) in tetrahydrofuran (15.0 mL) was added 25% ammonia water solution (5.00 mL) at room temperature. After 1 h the reaction mixture was partitioned between ethyl acetate (100.0 mL) and 1.0 N hydrochloric acid (10.0 mL) and separated. The organic layer was washed with water (2×40 mL), saturated sodium chloride (80 mL), dried (MgSO4), filtered. The filtrate was concentrated under reduced pressure to provide 4-(1,3-oxazol-5-yl)benzenesulfonamide (800 mg, 87%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1>>[ClH:1].[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[N:21]([C:2]2[N:11]=[C:10]([N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:20]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CCNCC
Reactant: Cc1cc(C)[nH]n1
Product: CCN(CC)c1nc(-n2nc(C)cc2C)nc2ccccc12
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, diethylamine and 3,5-dimethylpyrazole. Mp. 156.3° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[N:11]=[N:10][NH:9]1.[CH2:14]([N:17]([CH:21]1[CH2:25][CH2:24][O:23][CH2:22]1)[C:18](Cl)=[O:19])[CH2:15][CH3:16]>CN(C)C1C=CN=CC=1>[CH2:14]([N:17]([CH:21]1[CH2:25][CH2:24][O:23][CH2:22]1)[C:18]([N:11]1[C:12](=[O:13])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]=[N:10]1)=[O:19])[CH2:15][CH3:16]
Reactant: O=c1nn[nH]n1-c1ccccc1F
Reactant: CCCN(C(=O)Cl)C1CCOC1
Agent: CN(C)c1ccncc1
Product: CCCN(C(=O)n1nnn(-c2ccccc2F)c1=O)C1CCOC1

Procedure:
1.4 g (7.8 mmol) of 1,2-dihydro-1-(2-fluorophenyl)-5H-tetrazol-5-one, 1.5 g (7.8 mmol) of N-propyl-N-(tetrahydro-furan-3-yl)carbamoyl chloride and 1.29 g (10 mmol) of 4-dimethylaminopyridine were reacted by the method of the process described in Example 1. Yield 2.1 g.
Reaction SMILES: N(C(O[C:9](C)(C)[CH3:10])=O)=NC([O-])=O.[Cl:13][C:14]1[C:19]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([OH:39])=[CH:28][C:29]=3[O:31][CH:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)[N:24]=[CH:23][N:22]=2)=[C:18]2[O:40][CH2:41][O:42][C:17]2=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.N>C(Cl)Cl.C(OCC)C.C(O)C>[Cl:13][C:14]1[C:19]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:39][CH2:9][CH3:10])=[CH:28][C:29]=3[O:31][CH:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)[N:24]=[CH:23][N:22]=2)=[C:18]2[O:40][CH2:41][O:42][C:17]2=[CH:16][CH:15]=1
Reactant: CN1CCC(Oc2cc(O)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Reactant: CC(C)(C)OC(=O)N=NC(=O)[O-]
Agent: Cl
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: ClCCl
Solvent: CCOCC
Product: CCOc1cc(OC2CCN(C)CC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
A solution of di-(tert-butyl azodicarboxylate (0.26 g) in methylene chloride (1 ml) was added dropwise to a stirred mixture of 4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-(N-methylpiperidin-4-yloxy)quinazoline (0.12 g), ethanol (0.019 g), triphenylphosphine (0.15 g) and methylene chloride (2 ml) and the resultant mixture was stirred at ambient temperature for 1 hour. A 2M solution of hydrogen chloride in diethyl ether (3 ml) was added and the mixture was stirred at ambient temperature for 1.5 hours. Diethyl ether (1 ml) was added and the precipitate was isolated and dried under vacuum. The solid so obtained was dissolved in a 9:1 mixture of methylene chloride and a saturated methanolic ammonia solution. The mixture was filtered and the filtrate was evaporated. The residue was triturated under pentane and the resultant solid was isolated and dried under vacuum. There was thus obtained the title compound (0.092 g); NMR Spectrum: (CDCl3) 1.5 (t, 3H), 1.95-2.1 (m, 2H), 2.15-2.5 (m, 2H), 2.3 (s, 3H), 2.3-2.4 (m, 2H), 2.7 (br s, 2H), 4.15 (m, 2H), 4.6 (m, 1H), 6.05 (s, 2H), 6.5 (d, 1H), 6.7 (d, 1H), 6.8 (d, 1H), 6.95 (d, 1H), 8.5 (s, 1H), 9.25 (br s, 1H); Mass Spectrum: M+H+ 457 and 459.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:20])[CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([CH3:12])[CH2:8][CH:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19].Cl[CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:20])[CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([CH3:12])[CH2:8][CH:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:22][CH2:23][CH2:24][C:25]1=[O:26]
Reactant: O=C(Cl)CCCCl
Reactant: CN1Cc2c(Br)cc(Cl)cc2C(c2ccccc2N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1Cc2c(Br)cc(Cl)cc2C(c2ccccc2N2CCCC2=O)C1

Procedure:
Analogously to example 36, 2-(8-bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (80 mg) was reacted with 4-chlorobutyryl chloride (35 mg) and the resulting amide was subsequently ring-closed with potassium carbonate in DMSO.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]3[C:11]4([CH2:21][O:22][C:8]3=[CH:7][C:5]=2[N:6]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:13][C:12]4=[O:20].CC1C2C=C3C4([C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[NH:37]C4=O)COC3=CC=2ON=1.Br.BrCC1C=CC=CN=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]3[C:11]4([CH2:21][O:22][C:8]3=[CH:7][C:5]=2[N:6]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[N:13]([CH2:39][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:37]=1)[C:12]4=[O:20]
Reactant: Cc1nc2cc3c(cc2s1)C1(CO3)C(=O)Nc2ccccc21
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: Br
Agent: BrCc1ccccn1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: Cc1nc2cc3c(cc2s1)C1(CO3)C(=O)N(Cc2ccccn2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 2-methylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 2-methyl-1′-(pyridin-2-ylmethyl)spiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1H)-one was obtained (38%) as a colorless solid: mp 249-250° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ8.63-8.59 (m, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.85-7.70 (m, 2H), 7.38-7.31 (m, 1H), 7.27-7.1 (m, 3H), 7.02-6.95 (m, 1H), 6.85 (d, J=7.8 Hz, 1H), 5.31 (d, J=16.9 Hz, 1H), 4.96-4.84 (m, 3H), 2.67 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ176.4, 170.2, 160.2, 155.7, 149.3, 148.5, 142.3, 137.0, 131.9, 128.8, 128.1, 123.4, 123.1, 122.7, 120.7, 119.5, 109.3, 108.4, 81.0, 57.4, 45.6, 20.1; MS (ES+) m/z 400.0 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[Br:7][C:8]1[C:9](Cl)=[N:10][C:11](Cl)=[N:12][CH:13]=1.[OH2:16]>O1CCCC1>[Br:7][C:8]1[C:9]([O:16][C:2]([CH3:5])([CH3:3])[CH3:1])=[N:10][C:11]([O:4][C:2]([CH3:5])([CH3:3])[CH3:1])=[N:12][CH:13]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)[O-]
Reactant: O
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ncc(Br)c(OC(C)(C)C)n1
Reaction time: 1.5 h

Procedure:
To a solution of potassium tert-butoxide (67.5 g) in tetrahydrofuran (500 ml) was added dropwise a solution of 5-bromo-2,4-dichloropyrimidine (55 g) (J.Am.Chem.Soc. 1934,56,134) in tetrahydrofuran (100 ml). After 1.5 hours, water (100 ml) was added carefully and the mixture extracted with ethyl acetate. The combined extract was washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 5% triethylamine in isohexane. Yield 52.4 g.
Reaction SMILES: CC1C(/C=C/C(C)=O)C(C)(C)CCC=1.[C:15]1(=[O:30])[C:28]2[CH:27]=[CH:26][C:25]3[C:20](=CC=CC=3)[C:19]=2[CH:18]=[CH:17][C:16]1=[O:29]>>[CH:25]1[CH:20]=[C:19]2[CH:18]=[CH:17][C:16]([C:15](=[O:30])[C:28]2=[CH:27][CH:26]=1)=[O:29]
Reactant: O=C1C=Cc2c(ccc3ccccc23)C1=O
Agent: CC(=O)/C=C/C1C(C)=CCCC1(C)C
Product: O=C1C=Cc2ccccc2C1=O

Procedure:
In order to test and evaluate the equipment and methods of the present invention, pre-coated 10 cm×10 cm HPTLC plates (Whatman) and test compounds α-ionone, phenanthrenequinone and 1,2-naphthaquinone (Aldrich) were obtained. The test compounds were initially diluted with acetone to about 10 mg/ml and stock solutions stored below 4° C. The stock solutions were further diluted with acetone just before use. Ceric sulfate prepared by adding 42 g of (NH4)4Ce(SO4)4 and 56 ml of conc. H2SO4 in 1 liter of distilled water was the chromogenic reagent.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11]C(OCC1C=CC=CC=1)=O.O.[NH2:24][NH2:25]>C(O)C>[NH2:11][C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[C:3]([NH:24][NH2:25])=[O:2]
Reactant: NN
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)OCc1ccccc1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cc(Cl)ccc1N
Yield: 91.7 %

Procedure:
2-benzyloxycarbonylamino-5-chloro-benzoic acid methyl ester (3 g, 9.4 mmol) was dissolved in 30 mL ethanol. Hydrazine hydrate (1.5 mL, 30.0 mmol) was added and the resultant solution was heated at reflux under a nitrogen atmosphere for two hours, at which LCMS analysis showed complete conversion of the ester as well as the removal of the CBz protecting group. The reaction mixture was subsequently concentrated in vacuo to provide 1.6 g of 2-amino-5-chloro-benzoic acid hydrazide (light brown solid, 92% yield): HPLC retention time=2.21; MS (ES) M+H expected 186.0, found 186.0.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:49]=[N+:50]=[N-:51])(=O)=O)(C)C.C(O)(=O)C>C1COCC1>[CH3:20][O:19][C:17](=[O:18])[CH:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])=[CH:15][CH:14]=1)[N:49]=[N+:50]=[N-:51]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: COC(=O)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C(N=[N+]=[N-])c1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
A solution of methyl 4-(N-BOC-aminomethyl)phenylacetate (9.34 g; 0.033 mol) in THF (100 mL) was stirred under argon at −78° C. and potassium bis(trimethylsilyl)amide (16.7 g, 0.084 mol) in THF (50 mL) was added. After stirring for 30 minutes, 2,4,6-triisopropylbenzene-sulfonyl azide (31.1 g, 0.101 mol) was added as a solid. After 5 minutes, acetic acid (10 mL, 0.175 mol) was added and the reaction warmed to room temperature. The reaction mixture was then partitioned between ethyl acetate (500 mL) and water (500 mL), separated and the organic layer dried (MgSO4). Evaporation of the solvent and purification of the residue by silica gel chromatography afforded the azide (7.1 g, 67%).