Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[BrH:14].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O>[Br:14][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: Br
Reactant: OCc1ccc2c(Cl)ccnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ccnc2cc(CBr)ccc12
Temperature: 120 °C

Procedure:
7-Hydroxymethyl-4-chloroquinoline (0.2 g, 0.97 mmol) is treated with 48% HBr and heated to 120° C. for 1 h. The resulting solution is cooled with ice, diluted with water and treated with ethyl acetate and sodium bicarbonate until basic to pH paper. The layers are separated and the organic layer is washed with water, dried (Na2SO4) and concentrated to give 7-Bromomethyl-4-chloroquinoline (0.23 g, 0.9 mmol). MS m/z: M+=255; 1H NMR (CDCl3, 300 MHz) δ8.75 (d, 1H), 8.1 (s, 1H), 7.7 (d, 1H), 7.5 (d, 1H), 4.7 (s. 2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27](Cl)=[O:28])=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.ClCCl>[N:1]1([C:27]([O:26][CH2:25][C:22]2[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=2)=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1CCCCN1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of ethyl piperidine-2-carboxylate (15 g, 95 mmol), triethylamine (27 ml, 191 mmol) and 4-dimethylaminopyridine (0.58 g, 4.8 mmol) in dichloromethane (100 ml) at 0° C. is added a solution of benzyl chloridocarbonate (17 g, 100 mmol) dropwise. The reaction is allowed to warm slowly to room temperature. It is stirred at room temperature overnight (16 h), then allowed to stand for 2 days. The crude product is extracted with dichloromethane, washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine. The organic phase is dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography over silica gel 60 (300 g) with cyclohexane/ethyl acetate as eluent to afford a pale yellow oil.
Reaction SMILES: [C:1]([CH:3]1[CH:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:5]([C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4]1)#[N:2].[CH2:19](N)[CH2:20][NH2:21].S.O>CCOCC>[NH:2]1[CH2:19][CH2:20][N:21]=[C:1]1[CH:3]1[CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH:5]([C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:4]1
Reactant: NCCN
Reactant: N#CC1CC2c3ccccc3C1c1ccccc12
Agent: S
Solvent: O
Solvent: CCOCC
Product: c1ccc2c(c1)C1CC(C3=NCCN3)C2c2ccccc21
Temperature: 130 °C
Reaction time: 20 h
Yield: 91.6 %

Procedure:
A mixture of 11-cyano-9,10-dihydro-9,10-ethanoanthracene (4.6 g), ethylenediamine (1.5 g) and hydrogen sulfide (about 100 mg) is stirred at 130° C. for 20 hours. The reaction mixture is mixed with water and ether to be distributed in two layers. The ether layer is washed with water, dried, and evaporated to remove the ether. The residue is recrystallized from ether to give 11-(2-imidazolin-2-yl)-9,10-dihydro-9,10-ethanoanthracene (5.0 g) as crude crystals. IR (KBr), 1621 cm-1 (N--C=N).
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][C:34]([OH:36])=[O:35])[CH:27]=2)[S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])=[CH:10][CH:9]=1)([CH3:7])[CH3:6])C.O[Li].O>C1COCC1.O>[C:34]([CH2:33][O:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:37])=[O:3])=[CH:9][CH:10]=1)[S:16]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17])([OH:36])=[O:35]
Reactant: CCOC(=O)C(C)(C)c1ccc(CN(Cc2cccc(OCC(=O)O)c2)S(=O)(=O)c2cccnc2)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)c1ccc(CN(Cc2cccc(OCC(=O)O)c2)S(=O)(=O)c2cccnc2)cc1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
To a solution of 2-(4-{[(3-carboxymethoxy-benzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenyl)-2-methyl-propionic acid ethyl ester (83 mg, 0.157 mmol) in THF (10 mL) was added water (1 mL) and LiOH.H2O (66 mg, 1.58 mmol). The reaction was heated at reflux for 24 h. Additional LiOH.H2O (66 mg, 1.58 mmol) in water (2 mL) was added and the reaction was heated at reflux for 30 h. The mixture was concentrated in vacuo and to the residue was added THF (3 mL) and water (1.5 mL). The reaction was heated at reflux for 24 h and was cooled to room temperature. The solution was diluted with water and the pH was adjusted to about 5 by addition of 1N HCl. Sodium chloride was added and the aqueous solution was washed with EtOAc (3×). The combined organic solutions were dried (MgSO4), filtered, and concentrated to provide the title compound (74 mg). 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.73 (s, 1H), 8.13 (d, 1H), 7.55 (m, 1H), 7.23 (d, 2H), 7.11 (m, 3H), 6.78 (d, 1H), 6.73 (d, 1H), 6.68 (s, 1H), 4.90 (s, 2H), 4.39 (s, 2H), 3.30 (s, 2H), 1.50 (s, 6H); MS 497 (M−1).
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[C:9]([N:13]2[C:17]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[O:19])=[CH:16][C:15]([C:30]([F:33])([F:32])[F:31])=[N:14]2)[CH:10]=[CH:11][CH:12]=1>CC(O)=O.O>[CH:2]([C:7]1[CH:8]=[C:9]([N:13]2[C:17]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[O:19])=[CH:16][C:15]([C:30]([F:32])([F:33])[F:31])=[N:14]2)[CH:10]=[CH:11][CH:12]=1)=[O:1]
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(C2OCCCO2)c1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(C=O)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A stirred solution of 148 (105 mg, 0.228 mmol) in AcOH (1.8 mL) and water (0.5 mL) was allowed to stir at 90° C. for 2 h. After cooling to room temperature, water was added and the mixture was extracted with EtOAc and the extractis were dried over Na2SO4 and concentrated to give crude 149 (92 mg, 0.228 mmol, 100% yield) as a pale yellow solid. The material was used as is for the next step.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([N:8]2[C:17]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[CH:10]=[C:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:5]1([N:8]2[C:17]3[CH2:16][CH2:15][CH2:14][N:13]([C:1](=[O:3])[CH3:2])[CH2:12][C:11]=3[CH:10]=[C:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6][CH2:7]1
Reactant: CC(=O)Cl
Reactant: c1ccc(-c2cc3c(n2C2CC2)CCCNC3)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCCc2c(cc(-c3ccccc3)n2C2CC2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3.9 g. of acetyl chloride in 25 ml. of chloroform is added to a cooled solution of 11.0 g. of 1-cyclopropyl-2-phenyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine and 5.0 g. of triethylamine in 50 ml. of dry chloroform. The mixture is stirred at ambient temperature for 20 hours, washed with water, dried, and concentrated to provide 1-cyclopropyl-2-phenyl-5-acetyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine as an oil. The oil is treated according to the manipulative procedure described above in Example 2, to give crystals, m.p. 85°C. dec., of 1-cyclopropyl-2-phenyl-5-ethyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine oxalate.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N+:9]([C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)([O-:11])=[O:10]>CN(C=O)C>[Br:1][C:17]1[CH:18]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=[CH:14][C:15]=1[NH2:16]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1ccc([N+](=O)[O-])cc1Br
Temperature: 27.5 °C

Procedure:
N-Bromosuccinimide (26 g, 146 mmol) was added to a stirred solution of 4-nitro aniline (20 g, 145 mmol) in dry DMF (75 mL) in portions under stirring at temperature 25-30° C. Reaction mixture was stirred for 30 min. It was poured over crushed ice slowly under vigorous stirring, filtered and dried, to afford the title compound.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[F:9][C:10]([F:18])([F:17])[CH:11]([OH:16])[C:12](F)(F)F>>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][CH2:12][C@@H:11]([OH:16])[C:10]([F:18])([F:17])[F:9]
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccccc1N
Product: Nc1ccccc1NC[C@@H](O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.2 %

Procedure:
Benzene-1,2-diamine (4.83 g, 44.6 mmol) was dissolved in hexafluoroisopropanol (9.37 mL, 89 mmol), (R)-trifluoromethylepoxide (0.769 mL, 8.92 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 4 hours. The solution was concentrated and purified on a silica gel column with a 0-100% EtOAc/Hexanes gradient in a 100 g cartridge. (R)-3-[(2-aminophenyl)amino]-1,1,1-trifluoropropan-2-ol (1.30 g, 5.90 mmol) was obtained in 66.2% yield. 1H NMR (400 MHz, CDCl3) 83.32 (dd, J=13.4, 8.3 Hz, 1H), 3.55 (dd, J=13.5, 3.3 Hz, 1H), 3.55 (bs, 3H), 4.22 (m, 1H), 6.71 (d, J=7.7 Hz, 1H), 6.79 (m, 2H), 6.87 (d, d, J=7.7, 2.2 Hz, 1H). MS m/z=221.00
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3[CH:18]=[C:17](I)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24]>>[C:22](/[CH:23]=[CH:24]/[C:17]1[CH:16]=[N:15][C:9]2[N:10]([CH2:13][CH3:14])[C:11]3[N:12]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[N:6]([CH3:21])[C:7](=[O:20])[C:8]=2[CH:18]=1)([O:26][CH2:27][CH3:28])=[O:25]
Reactant: C=CC(=O)OCC
Reactant: CCN1c2ncc(I)cc2C(=O)N(C)c2ccc(Cl)nc21
Product: CCOC(=O)/C=C/c1cnc2c(c1)C(=O)N(C)c1ccc(Cl)nc1N2CC
Yield: 74.9 %

Procedure:
2-Chloro-5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.6 g, 1.45 mmol) was coupled with ethyl acrylate (0.19 mL, 1.75 mmol) by a procedure analogous to that described in Example 1h to give 0.42 g of the title compound as beige crystals, m.p. 192°-193° C. (ethyl acetate/hexanes). Hydrogenation, as described in Example 15, gave 0.22 g of a mixture of reduction products, which was used directly in the next step.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Br)C.CON(C)[C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[CH3:7][N:6]1[C:2]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[O:25])=[CH:3][N:4]=[CH:5]1
Reactant: Cn1cncc1Br
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC[Mg]Br
Solvent: ClCCl
Product: Cn1cncc1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-1-methyl-1H-imidazole (3.22 g, 19.982 mmol) in DCM (15 mL) was added ethyl magnesium bromide (6.66 mL, 19.982 mmol; 3.0 M in diethyl ether) dropwise over a 10 minute period. The resulting orange-red solution was stirred at room temperature for 15 minutes, cooled in an ice bath to 0° C. and N-methoxy-N-methyl-4-nitrobenzamide (3.5 g, 16.652 mmol, Intermediate 15: step a) dissolved in DCM (10 mL) was added dropwise. The cold bath was removed and the solid suspension stirred at room temperature for 48 hours. Water was added followed by 6 M aqueous HCl to a neutral pH (pH=6-7). The aqueous mixture was extracted with DCM, dried over Na2SO4, filtered and concentrated. Et2O was added and the mixture sonicated. The precipitate was collected by filtration and dried to provide the title compound as a tan solid.
Reaction SMILES: Cl.[CH2:2]1[C@H:6]2[CH2:7][CH:8]([CH2:10][OH:11])[CH2:9][C@H:5]2[CH2:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[C:30]([F:33])([F:32])[F:31].O>CN(C=O)C>[F:31][C:30]([F:32])([F:33])[C:21]1[CH:22]=[C:23]([C:26]([F:29])([F:27])[F:28])[CH:24]=[CH:25][C:20]=1[CH2:19][N:3]1[CH2:4][C@@H:5]2[CH2:9][CH:8]([CH2:10][OH:11])[CH2:7][C@@H:6]2[CH2:2]1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: OCC1C[C@H]2CNC[C@H]2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCC1C[C@@H]2CN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
To a solution of (3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-ylmethanol hydrochloride (0.79 g) and potassium carbonate (1.53 g) in DMF (15 ml) was added 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (1.5 g). The reaction mixture was stirred at room temperature for 3 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1O.[C:10](=O)([O-])[O-:11].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:11][CH3:10])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(Cl)c(O)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(Cl)ccc1C
Yield: 77.5 %

Procedure:
Commercially available 2-chloro-5-methylphenol (19.8 g, 70 mmol) was dissolved in 450 ml acetone. Potassium carbonate (28.9 g, 209 mmol) was added, followed by iodomethane (29.7 g, 209 mmol), and the mixture was refluxed overnight with vigorous stirring. The mixture was then filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water, dried with sodium sulfate, and concentrated giving 8.5 g 4-Chloro-2-methoxy-1-methyl-benzene (100%). 1H NMR (300 MHz, CDCl3) •2.28 (s, CH3, 3H), 3.92 (s, —OCH3, 3H), 6.91 (d, Ar, 1H, J=2.0 Hz), 6.95 (dd, Ar, 1H, J=8.0, 2.0 Hz), 7.14 (m, Ar, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:28])(=[O:27])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[N:30]([CH2:33][C@@H:34]([C:36]1[CH:37]=[CH:38][C:39]([Cl:47])=[C:40]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:41]=1)[OH:35])=[N+]=[N-]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:21][CH2:22][CH:23]([NH:30][CH2:33][C@@H:34]([C:36]4[CH:37]=[CH:38][C:39]([Cl:47])=[C:40]([NH:42][S:43]([CH3:46])(=[O:44])=[O:45])[CH:41]=4)[OH:35])[CH2:24][CH2:25]3)=[CH:18][CH:19]=2)(=[O:27])=[O:28])=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN=[N+]=[N-])ccc1Cl
Reactant: COC(=O)COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: COC(=O)COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4ccc(Cl)c(NS(C)(=O)=O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from {4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenoxy}-acetic acid methyl ester (which was obtained in Example 232) and N-[5-((1R)-2-azido-1-hydroxy-ethyl)-2-chloro-phenyl]-methanesulfonamide (which was obtained in Example 25) according to the procedure of Example 95 as a pale grey solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.75–1.90 (m, 2 H), 2.50–2.80 (m, 5 H), 2.97 (s, 3 H), 3.40–3.55 (m, 2 H), 3.69 (s, 3 H), 4.63 (dd, J=8.0; 3.8 Hz, 1 H), 4.87(s, 2 H), 6.77 (d, J=9.0 Hz, 2 H), 6.87 (d, J=9.0 Hz, 2 H), 7.03 (d, J=9.0 Hz, 2 H), 7.17 (dd, J=8.3, 1.7 Hz, 1 H), 7.43 (d, J=8.3 Hz, 1 H), 7.43 (d, J=1.7 Hz, 1 H), 7.62 (d, J=9.0 Hz, 2 H); MS (ES) m/z: 667.0 (MH+); HRMS Calcd. for C29H36ClN4O8S2 (MH+): 667.1657. Found: 667.1651.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:13][CH2:14][OH:15])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.O.[CH2:17]([O:24]/[N:25]=[C:26]1\[CH2:27][CH2:28][C:29]2[C:34]\1=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:17]([O:24]/[N:25]=[C:26]1\[CH2:27][CH2:28][C:29]2[C:34]\1=[CH:33][CH:32]=[C:31]([C:2]1[CH:3]=[N:4][N:5]([CH2:13][CH2:14][OH:15])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH:30]=2)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: OB(O)c1ccc2c(c1)CC/C2=N\OCc1ccccc1
Reactant: OCCn1ncc(Br)c1-c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: OCCn1ncc(-c2ccc3c(c2)CC/C3=N\OCc2ccccc2)c1-c1ccncc1
Temperature: 75 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
To 2-(4-bromo-5-(pyridin-4-yl)-1H-pyrazol-1-yl)ethanol (0.050 g; Example 2, Step 2) dissolved in 5 mL acetonitrile was added 2 mL water, (E)-1-(benzyloxyimino)-2,3-dihydro-1H-inden-5-ylboronic acid (0.058 g; Example 2, Step 4), and 0.155 g potassium carbonate. The mixture was purged with nitrogen and about 20 mg tetrakis(triphenyphosphine)palladium(0) catalyst was added. The mixture was heated at 75° C. After 1 hour, the reaction mixture was filtered through celite, the filter cake washed with ethyl acetate, and the filtrate evaporated under vacuum. The residue was partitioned between ethyl acetate and water. The ethyl acetate was washed with saturated aqueous sodium carbonate, brine, dried over magnesium sulfate, filtered, and evaporated under vacuum to yield 0.05 g crude product as a colorless glass. The crude material was purified by chromatography, eluting with a mixture of 8:1 dichloromethane-methanol to afford 18.6 mg (23% yield) product as a colorless glass. 1H NMR (CDCl3) was consistent with the desired structure. LC/MS showed one peak with a M+1 molecular ion of m/z 425.2 by positive ESI.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[Br:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>>[Br:19][C:20]1[N:21]=[CH:22][N:23]([C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:3]=2)[CH:24]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: Brc1c[nH]cn1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.12) (2.73 g, 10.0 mmol) and commercially available 4-bromo-imidazole (2.21 g, 15.0 mmol) according to the general procedure IVa. Obtained as a light brown solid (3.20 g, 84%). MS (ISP) 383.0 [(M+H)+]; mp 166-168° C.
Reaction SMILES: NC1N=C(N)C2C(=CC=C(N)C=2)N=1.NC1N=C(N)C2C(=CC=C(N)C=2Cl)N=1.[NH2:28][C:29]1[N:38]=[C:37]([NH2:39])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[Cl:40])[N:30]=1.[N+:41]([O-])([OH:43])=[O:42].S(=O)(=O)(O)O>>[NH2:28][C:29]1[N:38]=[C:37]([NH2:39])[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([N+:41]([O-:43])=[O:42])[C:35]=2[Cl:40])[N:30]=1
Reactant: Nc1nc(N)c2c(Cl)cccc2n1
Reactant: O=[N+]([O-])O
Agent: Nc1ccc2nc(N)nc(N)c2c1
Agent: Nc1nc(N)c2c(Cl)c(N)ccc2n1
Agent: O=S(=O)(O)O
Product: Nc1nc(N)c2c(Cl)c([N+](=O)[O-])ccc2n1

Procedure:
In a similar manner 2,4,6-triaminoquinazoline and 2,4,6-triamino-5-chloroquinazoline can be prepared. This is accomplished by the nitration of, for example, 2,4-diamino-5-chloroquinazoline (above) with 90% nitric acid and sulfuric acid, yielding the corresponding 2,4-diamino-5-chloro-6-nitroquinazoline. The 6-nitroquinazoline is in turn reduced by either hydrogenation in the presence of 10% palladium on carbon or by treatment with stannous chloride dihydrate, affording the corresponding 2,4,6-triaminoquinazoline. Steps A and B of Example 15 describe in detail these two steps in the reaction sequence.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=2[Cl:1])[CH:18]=1
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccnc(N)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(NC(=O)COc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Yield: 71.6 %

Procedure:
To solution of (2,4-dichloro-phenoxyacetic acid (0.200 g, 0.9 mmol), 2-amino isonicotinic acid methyl ester (207 mg, 1.36 mmol) and DMAP (0.222 g, 1.81 mmol) in DMF 13 mL was added PyBOP (946 mg, 1.81 mmol) at room temperature. Reaction mixture was stirred at room temperature. Resulting mixture poured onto ice cold water, was diluted by ethyl acetate. The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by flash silica gel column chromatography (EtoAC:Hexane=1:9-4:6) to give 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-isonicotinic acid methyl ester as a colorless solid (0.229 g, 71% yield).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([CH3:34])=[N:12][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:33])OC4C=CC=CC=4)=[CH:18][CH:17]=3)[C:14]=2[CH3:15])[CH:7]=[CH:8][CH:9]=1)=[O:3].[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[S:43]([NH2:46])(=[O:45])=[O:44]>>[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[S:43]([NH:46][C:25]([NH:24][CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([N:13]2[C:14]([CH3:15])=[C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:2]([NH2:1])=[O:3])[C:11]([CH3:34])=[N:12]2)=[CH:21][CH:20]=1)=[O:33])(=[O:44])=[O:45]
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1cccc(C(N)=O)c1
Reactant: NS(=O)(=O)c1ccc(F)cc1F
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(F)cc3F)cc2)c(C)c1-c1cccc(C(N)=O)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-(4-{4-[3-(aminocarbonyl)phenyl]-3,5-dimethyl-1H-pyrazol-1-yl}phenyl)ethylcarbamate (step 6 of example 72) and 2,4-difluorobenzensulfonamide: MS (ESI) m/z 554 [M+H]+, 552 [M−H]−, 1H-NMR (CDCl3) δ 8.00-7.98 (1H, m), 7.83-7.73 (3H, m), 7.56-7.44 (2H, m), 7.22 (4H, s), 7.05-6.94 (1H, m), 6.20 (1H, br.s), 5.66 (1H, br.s), 3.47 (2H, t, J=6.2 Hz), 2.85 (2H, t, J=6.2 Hz), 2.21 (3H, s), 2.20 (3H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:11]=[C:10]([OH:20])[CH:9]=2)[CH:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC(O)(CC)C.[Cl-].[Zn+2].[Cl-]>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[N:11]=[C:10]([OH:20])[CH:9]=3)[CH:3]=2)[CH2:24][CH2:23]1
Reactant: Oc1cc(-c2cc(Cl)ccn2)nc(-c2ccccn2)n1
Reactant: CN1CCNCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCC(C)(C)O
Product: CN1CCN(c2ccnc(-c3cc(O)nc(-c4ccccn4)n3)c2)CC1

Procedure:
A mixture of 3.51 g (12.3 mmol) of 6-(4-chloropyrid-2-yl)-2-pyrid-2-yl-pyrimidin-4-ol, 27.4 ml (303 mmol, 20 equivalents, 30.38 g) of 1-methyl-piperazine and 84 mg (0.05 mmol, 0.05 equivalent) of zinc(II) chloride in 50 ml of 2-methyl-2-butanol is refluxed for 22 hours and concentrated to dryness using a rotary evaporator. 50 ml of water are added, 3.6 g of EDTA are added, and the pH is adjusted to 9 using dilute sodium hydroxide solution. Extraction is carried out three times using 150 ml of chloroform each time, and the organic extracts are combined and dried (sodium sulfate). Concentration is carried out using a rotary evaporator and the crude product is recrystallised from toluene. 6-[4-(4-Methyl-piperazin-1-yl)-pyrid-2-yl]-2-pyrid-2-yl-pyrimidin-4-ol is obtained in the form of a whitish solid.