Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([I:16])[CH:14]=2)[NH:9][N:8]=1.Br.Br[CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[CH2:23]([N:22]([CH2:25][CH3:26])[CH2:21][CH2:20][CH2:19][NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([I:16])[CH:14]=2)[NH:9][N:8]=1)[CH3:24]
Reactant: Nc1n[nH]c2ccc(I)cc12
Reactant: CCN(CC)CCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)CCCNc1n[nH]c2ccc(I)cc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 63.6 %

Procedure:
To 80 ml of anhydrous N,N-dimethylformamide were added 9.7 g of 3-amino-5-iodoindazole as prepared in accordance with the method described in C. E. Kwartler et el., J. Am. Chem. Soc., 65 1804(1943), 8.3 g of 3-bromopropyldiethylamine hydrobromide and 8.3 g of anhydrous potassium carbonate. The mixture was stirred for 24 hours at 80° C. and condensed under reduced pressure. The condensed residue was added with 100 ml of chloroform and 50 ml of water. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography(alumina: 200 g) using chloroform as the developing solvent to give 7.15 g of 3-(3-diethylaminopropylamino)-5-iodoindazole having the following analytical values in a yield of 51%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH:20]([NH:23][C:24](=O)[CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:19][CH2:18]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].CS(C)=[O:33].C(=O)([O-])[O-].[K+].[K+].[H][H]>O>[CH3:29][O:28][CH2:27][CH2:26][CH2:25][CH2:24][NH:23][CH:20]1[CH2:19][CH2:18][CH:17]([CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[C:1]([NH2:2])=[O:33])[CH2:14][CH2:13]2)[CH2:22][CH2:21]1
Reactant: [H][H]
Reactant: COCCCC(=O)NC1CCC(CCN2CCN(c3cccc(C#N)c3)CC2)CC1
Reactant: CS(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCCCCNC1CCC(CCN2CCN(c3cccc(C(N)=O)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
A mixture of 85 mg (0.2 mmol) of N-(4-{2-[4-(3-cyanophenyl)piperazin-1-yl]ethyl}cyclohexyl)-4-methoxybutanamide, 2 mL of dimethyl sulfoxide, 16.5 mg of potassium carbonate and 0.12 mL of an aqueous 30% hydrogen peroxyde solution is stirred for 2 hours at room temperature. The suspension is poured into 50 mL of water. The solid is filtered, washed with water, dried under reduced pressure to give 15 mg (17%) of 3-(4-{2-[4-(4-methoxybutanylamino)cyclohexyl]ethyl}piperazin-1-yl)benzamide as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12]CC)=[O:11].[OH-].[Li+]>C1COCC1.O.C(OCC)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccccc2[nH]1
Reaction time: 8 h

Procedure:
Ethyl 1H-indole-2-carboxylate (3.0 g, 15.86 mmol) and lithium hydroxide, H2O (3.33 g, 79 mmol) were dissolved in THF (Ratio: 1.000, Volume: 10 ml) and Water (Ratio: 2, Volume: 20.00 ml). The reaction was stirred overnight. The reaction was diluted with water and diethyl ether. The water layer was washed with diethyl ether twice. The aqueous layer was acidified to pH 2 using 2N HCl. The suspension was extracted using ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to obtain product. (Yield: 2.39 g, white solid) 1H-NMR (400 MHz, DMSO-d6) 12.90, 11.70, 7.60, 7.40, 7.24-7.14, 7.07-6.98
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][N:14]([CH2:20][C:21]3[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=3[O:29][CH3:30])[C:15]([NH2:19])=[N:16]2)=[CH:11][CH:10]=1.C([O:33]CC)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:26]([O-:27])(=[O:33])[CH3:21].[NH:1]([C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][N:14]([CH2:20][C:21]3[C:22]([O:29][CH3:30])=[CH:23][CH:24]=[CH:25][C:26]=3[O:27][CH3:28])[C:15]([NH3+:19])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1CN1Cc2ccc(Br)cc2N=C1N
Reactant: Nc1ccccc1
Reactant: CCOCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)[O-]
Product: COc1cccc(OC)c1CN1Cc2ccc(Nc3ccccc3)cc2N=C1[NH3+]
Temperature: 25 °C

Procedure:
A three-necked flask was heated under argon and then charged with sodium tert-butylate (0.178 g, 1.99 mol), (R/S)-1,1′-binaphthaline-2,2′-diylphosphate (0.092 g, 0.15 mmol) and tris(dibenzylidene acetone)dipalladium (0) (0.121 g, 0.13 mmol) under a protective atmosphere and suspended in 10 mL toluene. Aniline (0.25 mL, 2.79 mmol) and 7-bromo-3-(2,6-dimethoxybenzyl)-3,4-dihydroquinazolin-2-amine (0.500 g, 1.33 mmol), suspended in 20 mL toluene, were then added one after the other to the starting reagents. The reaction mixture was heated at reflux for 3 hours. The reaction was not yet complete, so that first the mixture had to heated at room temperature for 12 hours and then for 5 hours at reflux. After the reaction was concluded, the mixture was cooled to room temperature, diluted with diethyl ether and the resulting solids were filtered out. For purification, the solids were dissolved in acetonitrile/water (1:1) and acetic acid and purified by preparative HPLC (Merck, Chromolith RP18) with the eluents acetonitrile and water (0.1M % acetic acid) with a gradient of 20% to 50% acetonitrile in 30 minutes. After freeze drying, the desired product was isolated via the lyophilizer. Yield: 50 mg (0.129 mmol, 10%).
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].C(N(C(C)C)CC)(C)C>O1CCOCC1.C(OCC)(=O)C>[C:1]1([CH:7]2[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][N:12]2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(c2ccccc2)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(c2ccccc2)C1
Yield: 58.9 %

Procedure:
A solution of tert-butyl 3-phenylpiperazine-1-carboxylate (0.95 g, 3.6 mmol), benzyl chloroformate (0.85 g, 5.0 mmol) and diisopropylethylamine (1.0 g, 7.7 mmol) in dioxane (20 mL) was heated to 95° C. for 3 hours. After cooling, the reaction mixture was diluted with ethyl acetate (100 mL), and washed with saturated aqueous sodium bicarbonate (50 mL) and brine (25 mL). After drying over anhydrous sodium sulfate, filtration and concentration, the residue was purified by silica gel column chromatography (ethyl acetate/hexanes, 1:8) to give 1-benzyl 4-tert-butyl 2-phenylpiperazine-1,4-dicarboxylate (0.84 g, 59% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([CH3:19])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][O:30][CH3:31]>C(#N)C>[CH3:31][O:30][CH2:29][CH2:28][CH2:27][NH:8][CH2:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([CH3:19])[CH:12]=1
Reactant: Cc1cc(CCN)ccc1C#N
Reactant: COCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COCCCNCCc1ccc(C#N)c(C)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
A mixture of 500 mg 4-(2-Amino-ethyl)-2-methyl-benzonitrile trifluoro acetate and 756 mg potassium carbonate were stirred in 10 ml acetonitrile at 80° C. for fifteen minutes. Then 279 mg 1-bromo-3-methoxypropane, dissolved in 5 ml acetonitrile, were added dropwise at 80° C. The reaction mixture was stirred under micro wave irradiation at 120° C. for one hour. The cooled reaction mixture was filtered through a pad of celite to remove the salt. Then the solvent was removed in vacuo. The residue was purified by RP-HPLC to obtain 268 mg 4-[2-(3-Methoxy-propylamino)-ethyl]-2-methyl-benzonitrile as its trifluoroacetate salt.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:42]([O:44][C:45](=[O:49])[CH2:46][CH2:47][NH2:48])[CH3:43].C(N(CC)CC)C>ClCCl>[CH2:42]([O:44][C:45](=[O:49])[CH2:46][CH2:47][NH:48][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([CH:6]([CH:4]2[CH2:3][C:2]([CH3:1])([CH3:28])[CH2:5]2)[NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:8][CH:9]=1)[CH3:43]
Reactant: Cc1cc2ccccc2nc1NC(c1ccc(C(=O)O)cc1)C1CC(C)(C)C1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(C(Nc2nc3ccccc3cc2C)C2CC(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.8 %

Procedure:
(+/−)-4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoic acid (Intermediate 26) (37 mg, 0.099 mmol) was combined with 1-hydrobenzotriazole hydrate (23.0 mg, 0.149 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (29.0 mg, 0.149 mmol), and beta-alanine ethyl ester hydrochloride (18.0 mg, 0.119 mmol). Anhydrous dichloromethane (5 mL) was added followed by triethylamine (0.027 mL, 0.198 mmol). The solution was stirred at room temperature for 3 d before partitioning between ethyl acetate and aq. sat. ammonium chloride. The separated aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave (+/−)-3-{4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid ethyl ester (37.9 mg) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J=8.2 Hz, 2 H) 7.59 (t, J=3.9 Hz, 2 H) 7.46-7.52 (m, 3 H) 7.37-7.45 (m, 1 H) 7.11-7.19 (m, 1 H) 6.75 (t, J=5.8 Hz, 1 H) 5.32 (dd, J=9.7, 6.7 Hz, 1 H) 4.75 (d, J=6.6 Hz, 1 H) 4.10-4.21 (m, 2 H) 3.70 (q, J=6.0 Hz, 2 H) 2.55-2.74 (m, 3 H) 2.29 (s, 3 H) 1.96 (ddd, J=11.1, 8.2, 2.9 Hz, 1 H) 1.75-1.84 (m, 1 H) 1.64-1.73 (m, 2 H) 1.26 (m, 3 H) 1.16 (s, 3 H) 1.09 (s, 3 H); MS (M+1): 474.7.
Reaction SMILES: [CH3:1]I.[NH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])=[S:5]>O1CCCC1>[NH:3]=[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11])[S:5][CH3:1]
Reactant: NC(=S)Nc1cccc(C(=O)O)c1
Reactant: CI
Solvent: C1CCOC1
Product: CSC(=N)Nc1cccc(C(=O)O)c1
Temperature: 75 °C

Procedure:
Methyl iodide (18 g; 127.4 mmol; 7.93 ml) is added at ambient temperature, under an argon atmosphere, to a solution of 3-[(aminocarbothioyl)amino]benzoic acid (25 g; 127.4 mmol) in 375 ml of anhydrous tetrahydrofuran, and then the reaction mixture is heated at 75° C. for 2 hours. After cooling and concentration, the residue is taken up in ether and the precipitate formed is filtered off to yield the expected product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@@H:16]3[O:17]C(C)(C)[O:19][C@@H:15]3[C@@H:14]([C:22]([NH:24]CC)=[O:23])[O:13]2)=[C:5]([NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:4]=1.C(N([CH2:47][CH3:48])CC)C.[CH2:49]([S:52](Cl)(=[O:54])=[O:53])[CH2:50][CH3:51]>ClCCl>[C:36]1([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][NH:27][C:5]2[N:4]=[C:3]([CH2:2][NH:1][S:52]([CH2:49][CH2:50][CH3:51])(=[O:54])=[O:53])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@@H:12]2[O:13][C@:14]([CH2:47][CH3:48])([C:22]([NH2:24])=[O:23])[C@@H:15]([OH:19])[C@H:16]2[OH:17])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCN(CC)CC
Reactant: CCCS(=O)(=O)Cl
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Solvent: ClCCl
Product: CCCS(=O)(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@](CC)(C(N)=O)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.7 %

Procedure:
A solution of (3aS,4S,6R,6aR)-6-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide (Preparation 10) (140 mg, 0.25 mmol) and triethylamine (0.05 ml, 0.36 mmol) in anhydrous dichloromethane (1 ml) was treated with a solution of 1-propanesulphonyl chloride (40 mg, 0.28 mmol) in anhydrous dichloromethane (1 ml). The mixture was stirred at room temperature for 18 hours during which time the solvent was allowed to evaporate off freely. The residue was dissolved in ethanol (1 ml), treated with hydrochloric acid (1 M, 1 ml) and heated at 60° C. for 4 hours. The solvent was removed under reduced pressure and the residue was azeotroped with ethanol (×2). The residue was then purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (95:5 by volume) gradually changing to dichloromethane:methanol (90:10 by volume) to give a solid which was triturated with diethyl ether, diluted with pentane, filtered and dried to afford the title compound as a solid (90 mg).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26](O)=[O:27])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.Cl.[CH3:61][O:62][C:63](=[O:66])[CH2:64][NH2:65]>C1COCC1.CN(C=O)C>[OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:23])([CH3:24])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([NH:65][CH2:64][C:63]([O:62][CH3:61])=[O:66])=[O:27])[CH:3]=1
Reactant: COC(=O)CN
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(C(=O)O)c4[C@]3(C)CC[C@@H]12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)c1cc(O)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.4 %

Procedure:
A mixture of (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxylic acid (65) (0.20 g, 0.49 mmol), HATU (0.37 g, 0.98 mmol), N-methyl morpholine (0.2 mL, 3 mmol) and glycine methyl ester hydrochloride (0.09 g, 2 mmol) in THF (10 mL) and DMF (2.0 mL) was stirred at room temperature for 18 h. The THF was evaporated under reduced pressure, the residue was quenched with water and the resulting solid was collected by filtration. The crude product was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 10:1) to give methyl 2-{[(1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-yl]formamido}acetate (90) (0.05 g, 54%) as a cream solid. 1H NMR (CDCl3): δ 7.37 (s, 1H), 7.21 (d, 1H), 6.89 (d, 1H), 6.70 (m, 1H), 4.19 (m, 2H), 3.81 (s, 3H), 3.40 (m, 2H), 2.62 (m, 1H), 2.16 (m, 1H), 1.76-1.34 (m, 10H), 1.20-1.00 (m, 2H), 0.98-0.92 (m, 4H), 0.89 (s, 3H), 0.82 (s, 3H). MS m/z 476 (C25H35NO6S−H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=1.[NH2:23][C:24]1[C:25]([C:32](O)=[O:33])=[N:26][C:27]([Br:31])=[C:28]([F:30])[CH:29]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:23][C:24]1[C:25]([C:32]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH:9]=2)=[O:33])=[N:26][C:27]([Br:31])=[C:28]([F:30])[CH:29]=1
Reactant: Nc1cc(F)c(Br)nc1C(=O)O
Reactant: Cc1nc(NC(=O)OC(C)(C)C)cc(-c2ccncc2N)n1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)OC(C)(C)C)cc(-c2ccncc2NC(=O)c2nc(Br)c(F)cc2N)n1
Yield: 15 %

Procedure:
Method 27 was followed using tert-butyl 6-(3-aminopyridin-4-yl)-2-methylpyrimidin-4-ylcarbamate (1.0 equiv.), 3-amino-6-bromo-5-fluoropicolinic acid (1.0 equiv.), EDC (1.0 equiv.), and HOAt (1.0 equiv.) in DMF yielding tert-butyl 6-(3-(3-amino-6-bromo-5-fluoropicolinamido)pyridin-4-yl)-2-methylpyrimidin-4-ylcarbamate in 15% yield. LCMS (m/z): 520.1 (MH+); LC Rt=3.4 min.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]>>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:19]([O-:21])=[O:20])[CH:27]=3)[CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: O=c1[nH]c2ccc(Br)cc2n1Cc1ccccc1
Product: O=c1[nH]c2ccc(-c3cccc([N+](=O)[O-])c3)cc2n1Cc1ccccc1

Procedure:
Prepared from 1-benzyl-6-bromo-1,3-dihydro-benzoimidazol-2-one and 3-nitro-phenyl boronic acid in the same fashion as that of Example 5. White solid: mp 202-203° C.; 1H-NMR (DMSO-d6) δ 11.2 (s, 1H), 8.38 (t, 1H, J=1.97 Hz), 8.15 (dd, 1H, J=7.83, 1.97 Hz), 8.80 (d, 1H, J=7.83 Hz), 7.72 (t, 1H, J=7.83 Hz), 7.56 (bs, 1H), 7.43-7.22 (r, 6H), 7.13 (d, 1H, J=7.83 Hz), 5.1 (s, 2H); MS (ES) m/z 344([M−H]−, 100%); Anal. Calc. For C20H15N3O3.0.25H2O: C, 68.66, H, 4.46, N, 12.01. Found: C, 68.42, H, 4.44, N, 11.77.
Reaction SMILES: O.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+].[CH3:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-])=O>CO.CCOCC>[CH3:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]
Reactant: COCc1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: COCc1ccccc1N
Reaction time: 1 h
Yield: 101.8 %

Procedure:
528 g of 21.8% strength Na2[Fe(CO)4] solution (0.6 mol; 1 kg of the solution contains 633 g of water, 218 g of Na2[Fe(CO)4], 108 g of Na2CO3 and 41 g of NaOH) are added dropwise to 101 g (0.6 mol) of o-methoxymethylnitrobenzene (Example 3a) in 1 l of methanol at 20-30° C. Stirring is carried out for 1 hour at room temperature, after which the reaction mixture is diluted with ether. A brown oil separates out in the reaction vessel. The total reaction mixture is poured onto a silica gel column and is eluted with ether. Thereafter, the ether phase is evaporated, the residue is taken up in methylene chloride and the solution is dried over MgSO4. It is filtered under suction over silica gel and the solvent is then evaporated off under reduced pressure. The residue is purified by column chromatography with hexane and methylene chloride. 83.8 g of o-methoxymethylaniline are obtained as a brown oil, which is directly reacted further.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[N:21]=[C:20]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]3[C:14](=[CH:15][C:16]([O:29]C)=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].B(Br)(Br)Br>ClC(Cl)C.ClCCl>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[N:21]=[C:20]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]3[C:14](=[CH:15][C:16]([OH:29])=[CH:17][CH:18]=3)[N:13]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(Nc3cc(C)n[nH]3)nc(Sc3ccc(NC(C)=O)cc3)nc2c1
Agent: BrB(Br)Br
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)c3ccc(O)cc3n2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A solution of [2-(4-acetamidophenylsulfanyl)-7-methoxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (23 mg, 5.54.10−5 mol) in dichloroethane (3 mL) is treated with 1M BBr3 in dichloromethane (222 μL, 2.21.10−4 mol). The mixture os heated at 80° C. for 4 hours before 1M BBr3 in DCM (222 μL, 2.21.10−4 mol) is added. The reaction mixture is heated at 80° C. for a further 3 hours. The solvent is evaporated and methanol is added to the residue to quench residual BBr3. The solvent is evaporated in vacuo and this operation repeated 3 times. 1M HCl (2 mL) is added to the solid residue and the suspension stirred at room temperature for 15 hours. The solid is collected by filtration and suspended in a mixture water/EtOH (3/1, 8 mL). The mixture is neutralized with NaHCO3 and stirred for 2 hours at room temperature. The solid is then collected by filtration, rinsed with water and diethyl ether to give the desired [2-(4-acetamidophenylsulfanyl)-7-hydroxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [CH3:1][N:2](C(OC(C)(C)C)=O)[CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=1)[CH3:4].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[CH3:1][NH:2][CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=1)[CH3:4]
Reactant: CCOc1cncc(/C=C/CC(C)N(C)C(=O)OC(C)(C)C)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cncc(/C=C/CC(C)NC)c1
Temperature: 2.5 °C
Reaction time: 0.75 h
Yield: 99.9 %

Procedure:
Under a nitrogen atmosphere, a cold (0-5° C.), stirring solution of (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine (0.67 g, 2.09 mmol) in anisole (10 mL) was treated dropwise over 30 min with trifluoroacetic acid (10.40 g, 91.17 mmol). The resulting solution was stirred for 45 min at 0-5° C. and was then concentrated by rotary evaporation. The light-yellow oil was further dried under high vacuum at 0.5 mm Hg. The resulting oil was cooled (0-5° C.), basified with 10% NaOH solution (10 mL), treated with saturated NaCl solution (7.5 mL), and extracted with CHCl3 (4×10 mL). The combined light-yellow CHCl3 extracts were washed with saturated NaCl solution (20 mL), dried (Na2SO4), filtered, concentrated by rotary evaporation, followed by further drying at 0.5 mm Hg producing a brown oil (0.46 g). The crude product was purified by column chromatography on silica gel (56 g), eluting with CH3OH-Et3N (98:2, v/v). Selected fractions containing the product (Rf0.35) were combined and concentrated on a rotary evaporator. The residue was dissolved in CHCl3, and the CHCl3 solution was dried (Na2SO4), filtered, concentrated by rotary evaporation, and vacuum dried to give 327.5 mg (71.0%) of a light-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Br.[NH:11]1[CH2:21][CH2:20][CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][N:11]1[CH2:12][CH2:13][CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:20][CH2:21]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccc(CBr)cc1Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 17 h
Yield: 88.5 %

Procedure:
3,4-Dichlorobenzyl bromide (1.83 g, 7.63 mmol) was added to a solution of ethyl isonipecotate (1 g, 6.36 mmol) and triethylamine (1.33 ml, 9.54 mmol) in methylene chloride solution (10 ml) at room temperature. After 17 h, the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution (10 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated. Flash chromatography with 9:1, hexanes/ethyl acetate followed by 6:1 hexanes/ethyl acetate gave ethyl 1-(3,4-dichlorobenzyl)isonipecotate (1.78 g) as a pale yellow oil.