Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][OH:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:18]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=1[C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][OH:15])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)CCO)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(OCc2ccccc2)c(C(C)(C)CCO)c1
Temperature: 25 °C

Procedure:
To a solution of 4-tert-butyl-2-(3-hydroxy-1,1-dimethylpropyl)phenol (2 g, 8.5 mmol) and 1.1 mL benzyl bromide in 10 mL of DMF was added 1.75 g of potassium carbonate (K2CO3) and the reaction mixture stirred at room temperature until TLC indicated that the reaction was complete. After stirring overnight, the reaction mixture was diluted with ice and extracted with diethyl ether. The organics were combined, washed four times with water, washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified on COMBIFLASH® apparatus (0% to 30% ethyl acetate-hexanes) to give 1.7 g of 3-(2-benzyloxy-5-tert-butylphenyl)-3-methylbutan-1-ol as an oil.
Reaction SMILES: C(Cl)(=O)C.[CH3:5][C:6]1[C:7]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[C:8]([CH2:15][NH:16]C(=O)OC(C)(C)C)[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1>CO>[CH3:5][C:6]1[C:7]([N:24]2[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]2)=[C:8]([CH2:15][NH2:16])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1
Reactant: Cc1cc([N+](=O)[O-])cc(CNC(=O)OC(C)(C)C)c1N1CCN(C)CC1
Solvent: CO
Solvent: CC(=O)Cl
Product: Cc1cc([N+](=O)[O-])cc(CN)c1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
1.2 mL of acetyl chloride was slowly added to 10 mL of MeOH at 0° C. The solution was stirred for 30 min at room temperature and then tert-butyl N-{[3-methyl-2-(4-methylpiperazin-1-yl)-5-nitrophenyl]methyl}carbamate (300 mg, 0.82 mmol) dissolved in 5 mL of MeOH was added. The reaction mixture was stirred for 2 h and then evaporated. The residue was dissolved in 15 mL of water and washed with diethyl ether. The aqueous layer was made alkaline (pH=10) with an aqueous NaOH 1M and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated to yield expected compound as a pale yellow oil (216 mg, quantitative yield). m/z (ESI) 265.2 [M+H]+;
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[CH:23])=[N:20][CH:21]=2)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[C:23][C:2]3[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=3)=[N:20][CH:21]=2)=[CH:14][CH:15]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Nc1ccc(I)cc1
Product: Nc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1

Procedure:
Prepared according to general working method I from 4-iodoaniline (732 mg, 3.28 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (700 mg, 3.28 mmol).
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][O:7][C:8]1[CH:25]=[CH:24][C:11]([CH2:12][NH:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([Br:23])[CH:15]=2)=[CH:10][CH:9]=1>CCO>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][NH:13][C:14]2[CH:15]=[C:16]([Br:23])[N:17]=[CH:18][C:19]=2[NH2:20])=[CH:24][CH:25]=1
Reactant: COc1ccc(CNc2cc(Br)ncc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(CNc2cc(Br)ncc2N)cc1
Temperature: 70 °C
Yield: 88.1 %

Procedure:
Tin (II) chloride dihydrate (4.37 g, 19.4 mmol) was added portionwise to N-(4-methoxybenzyl)-2-bromo-5-nitropyridin-4-amine (1.31 g, 3.87 mmol) in absolute EtOH (10 mL) at room temperature. The mixture was then heated at 70° C. for 2 hours before being concentrated in vacuo. The residue was suspended in a mixture of ethyl acetate and saturated sodium bicarbonate solution and filtered. The insoluble solids were washed with EtOAc. The aqueous phase was re-extracted with ethyl acetate and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give the title compound as a brown solid (1.05 g, 3.41 mmol, 88%). 1H NMR (d6-DMSO, 400 MHz) δ 7.40 (s, 1H), 7.30 (d, 2H, 8.6 Hz), 6.90 (d, 2H, 8.6 Hz), 6.45 (s, 1H), 6.3 (br t, 1H, 5.5 Hz), 4.85 (br s, 2H), 4.3 (d, 2H, 5.5 Hz), 3.75 (s, 3H). LCMS (1) Rt=1.77 min; m/z (ESI−) 306, 308; (ESI+) 308, 310.
Reaction SMILES: N1C(C)=CC=CC=1C.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C@H:22]([OH:40])[CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:12][CH:11]=1.FC(F)(F)S(O[Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])(=O)=O>C(Cl)Cl>[Si:47]([O:40][C@@H:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=1)[CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:38][CH:39]=2)[CH2:25][CH2:24]1)([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)c1ccc(N2CCC([C@@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N2CCC([C@@H](O[Si](C)(C)C(C)(C)C)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C

Procedure:
2,6-Lutidine (1.128 ml, 9.68 mmol) was added to a solution of (R)-ethyl 4-(4-((4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoate (INTERMEDIATE 11A (First Eluting Compound), 1.74 g, 3.87 mmol) in DCM (10 ml) at 0° C. tert-Butyldimethylsilyl trifluoromethanesulfonate (1.3 ml, 5.81 mmol) was added dropwise via syringe at 0° C. and the resulting mixture was allowed to warm up to room temperature for 10 minutes. Evaporation of the volatiles under reduced pressure gave a residue, which was purified by column chromatography (ISCO, 80 g silicon column, eluting with 0→10% EtOAc/hexanes) to give the title product (2.1 g, yield: almost quantitative).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:7]=2[CH:17]=1.[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH:32]=O)[CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:26][CH2:27][C@H:28]([CH2:31][CH2:32][N:14]2[CH2:13][CH2:12][N:11]([C:8]3[C:7]4[CH:17]=[C:3]([F:2])[CH:4]=[CH:5][C:6]=4[O:10][N:9]=3)[CH2:16][CH2:15]2)[CH2:29][CH2:30]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Fc1ccc2onc(N3CCNCC3)c2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3noc4ccc(F)cc34)CC2)CC1

Procedure:
The title compound, MS: m/e=447.1 (M+H+), can be prepared in accordance with the general method of example 1, step 1 from 5-fluoro-3-piperazin-1-yl-benzo[d]isoxazole hydrochloride and trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (intermediate A).
Reaction SMILES: C(O)(C(F)(F)F)=O.CC([N:12]([CH2:16][CH2:17][CH2:18][NH:19][C:20]1[N:21]=[C:22]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH2:39][NH2:40])[CH:33]=2)[C:23]2[C:29](=[O:30])[NH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)C(=O)[O-])(C)C>ClCCl>[NH2:40][CH2:39][CH2:38][C:34]1[CH:33]=[C:32]([NH:31][C:22]2[C:23]3[C:29](=[O:30])[NH:28][CH:27]=[CH:26][C:24]=3[N:25]=[C:20]([NH:19][CH2:18][CH2:17][CH2:16][NH2:12])[N:21]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)N(CCCNc1nc(Nc2cccc(CCN)c2)c2c(=O)[nH]ccc2n1)C(=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCNc1nc(Nc2cccc(CCN)c2)c2c(=O)[nH]ccc2n1
Reaction time: 0.5 h

Procedure:
To a premixed solution of TFA (0.5 mL, 6.49 mmol) and dichloromethane (0.5 mL) was added to 1,1-dimethylethyl{3-[(4-{[3-(2-aminoethyl)phenyl]amino}-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino]propyl}carbamate (11 mg, 0.024 mmol) and the reaction mixture was stirred for 30 min. It was concentrated and the product lypholized (4 mg, white solid).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][CH2:11][CH2:12]I.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:10][CH2:11][CH2:12][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: FCCI
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCF)cc1
Temperature: 70 °C

Procedure:
A mixture of commercially available 4-hydroxybenzaldehyde (2.000 g; 16.40 mmol), 1-fluoro-2-iodoethane (2.849 g; 16.40 mmol), and K2CO3 (4.527 g; 32.80 mmol) in anh. DMF (30 ml) was heated to 70° C., under nitrogen, for 2.5 h. After cooling to rt, the reaction mixture was filtered over a pad of celite. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 4-(2-fluoroethoxy)benzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.58 min.; no ionisation.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[O:12]1[CH2:13][CH2:14][N:9]([C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:10][CH2:11]1
Reactant: C1COCCN1
Reactant: Nc1nccnc1Cl
Product: Nc1nccnc1N1CCOCC1

Procedure:
A solution of compound 1a (10.0 g, 76.9 mmol) in morpholine (42.3 g, 486 mmol) was stirred at 120° C. overnight. The mixture was concentrated under reduced pressure. The residue was then treated with DCM (200 mL). The solids were collected by filtration and washed with Et2O. Compound 1b was obtained as a white solid (11.0 g, 74% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C8H12N4O: 181.1 (M+H). found: 181.2.
Reaction SMILES: [NH:1]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([O:16]CC1C=CC=CC=1)=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO>[Pd].CC(O)=O>[NH:1]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([OH:16])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O
Yield: 92.9 %

Procedure:
Boc-Phe-Gly-OBzl (6.2 g, 15 mmole) was suspended in the mixtured solvent of MeOH (80 ml) and AcOH (30 ml), and then H2 gas was passed through the solution in the presence of Pd-C for 4 hours. Pd-C was removed by filtration, and the solvent was distilled off. The thus-obtained residue was recrystalized two times with AcOEt/n-hexane to obtain the object product (4.49 g, 92.8%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH:14]1([N:20]=[C:21]=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C)C=O>[CH:14]1([NH:20][C:21](=[O:22])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: O=C=NC1CCCCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)NC2CCCCC2)n1

Procedure:
Following a procedure similar to that described in Preparation 1. the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 4.7 g of cyclohexyl isocyanate and 30 ml of dimethylformamide. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1([CH2:27][CH2:26][CH2:25][CH2:24]1)[NH:6][C:7]([C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:23])=[CH:14][N:15]=[C:16]2[NH:19][C:20]([NH2:22])=[NH:21])=[CH:11][CH:10]=1)=[O:8])C.[OH-].[Na+].Cl>O1CCOCC1>[Cl:23][C:13]1[C:12]2[C:17](=[CH:18][C:9]([C:7]([NH:6][C:5]3([C:4]([OH:28])=[O:3])[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:8])=[CH:10][CH:11]=2)[C:16]([NH:19][C:20]([NH2:22])=[NH:21])=[N:15][CH:14]=1
Reactant: CCOC(=O)C1(NC(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NC3(C(=O)O)CCCC3)cc12
Yield: 100 %

Procedure:
A partly heterogeneous solution of N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]cycloleucine ethyl ester (45 mg, 0.11 mmol) in dioxane (1.5 mL) was stirred with aqueous NaOH (1 mL, 2 M) for 2.5 h at 23° C. Dilute HCl (1 mL, 2 M) was added to give a cream suspension. The solid was collected by filtration and dried in vacuo to yield N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]cycloleucine (40 mg, 0.11 mmol).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[N:16][C:17]=4[NH2:19])[N:12]([CH3:20])[N:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](O)=[O:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[C:18]5[C:13](=[N:14][CH:15]=[N:16][C:17]=5[NH2:19])[N:12]([CH3:20])[N:11]=4)=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1cc(Cl)cc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(Cl)cc(Cl)c2)c2c(N)ncnc21
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (89 mg, 0.293 mmol), (3,5-dichlorophenyl)acetic acid (60 mg, 0.293 mmol), HATU (111 mg, 0.293 mmol), DIEA (0.204 mL, 1.171 mmol) was stirred at room temperature overnight. The crude was poured into water and stirred for 30 minutes. The precipitate that formed was collected by filtration, washed with water and dried at the pump for 30 minutes. The crude was adsorbed onto silica and purified by flash chromatography (0-10% methanol in DCM), concentrated and dried overnight in a vacuum oven to afford 3-{1-[(3,5-dichlorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg) as a white solid. LCMS (ES) m/z=453, 455 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.29 (t, J=9.60 Hz, 2H), 3.94 (s, 3H), 3.97 (s, 2H), 4.26 (t, J=8.59 Hz, 2H), 7.40 (d, J=2.02 Hz, 2H), 7.45 (d, J=8.08 Hz, 1H), 7.53 (d, J=1.77 Hz, 2H), 8.17 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[SH:17][CH2:18][CH2:19][CH2:20][OH:21]>C(#N)C>[Br:1][C:2]1[C:3]([S:17][CH2:18][CH2:19][CH2:20][OH:21])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: OCCCS
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: OCCCSc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2.47 g (10.8 mmol) of 5-Bromo-2,4-dichloropyrimidine in 30 ml of acetonitrile at −20° C. is mixed with 1.5 ml (10.8 mmol) of triethylamine and 1.00 g (10.8 mmol) of 3-Mercapto-propan-1-ol. The batch is slowly warmed to room temperature and stirred for 16 hours. The batch is filtrated to remove the solid precipitate. The filtrate is concentrated by evaporation. 2-Methoxy-2-methyl-propane is added to the remaining residue and the batch is stirred for 15 minutes. The batch is filtrated and the solid precipitate is dried. 3.03 g (10.6 mmol, corresponding to 98% of theory) of the product is obtained.
Reaction SMILES: CS[C:3]1[C:12]2[C:7]([CH:8]=[N:9][CH2:10][N:11]=2)=[CH:6][C:5]2=[N:13][CH:14]=[N:15][C:4]=12.[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].[ClH:24].BrC1C=C(C=CC=1)N>C(O)(C)C>[ClH:24].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:3]1[C:12]2[C:7]([CH:8]=[N:9][CH2:10][N:11]=2)=[CH:6][C:5]2=[N:13][CH:14]=[N:15][C:4]=12
Reactant: CSc1c2c(cc3c1=NCN=C3)=NC=N2
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CC(C)O
Product: Brc1cccc(Nc2c3c(cc4c2=NCN=C4)=NC=N3)c1
Yield: 104.5 %

Procedure:
A mixture of 4-methylthio-6H-imidazo[4,5-g]quinazoline (0.5 g, 1.6 mmol) [Leonard, N. J.; Morrice, A. G.; Sprecker, M. A.; J. Org. Chem., 1975, 40, 356-363], 3-bromoaniline (0.35 g, 2.0 mmol), and 3-bromoaniline hydrochloride (0.4 g, 1.9 mmol) in isopropanol (200 mL) is heated under reflux for 1 h to give a precipitate of 4-(3-bromoanilino)-6H-imidazo[4,5-g]quinazoline hydrochloride (0.63 g, 72 %). 1H NMR (DMSO) δ9.93 (1H, brs), 9.01 (1H, s), 8.66 (2H, s), 8.39 (1H, s), 8.04 (2H, m), 7.39 (1H, t, J=7.9 Hz), 7.31 (1H, brd, J=8.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=O)[O:8][C:4]=2[CH:3]=1.[Cl:12]C1C=CC=CC=1Cl>>[Cl:12][C:7]1[O:8][C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2o1
Reactant: Clc1ccccc1Cl
Product: Clc1ccc2nc(Cl)oc2c1

Procedure:
lf the process is carried out as in Example 1, but only 500 ml of o-dichlorobenzene is initially introduced, and the 6-chlorobenzoxazolin-2-one is metered in as a suspension in 500 ml of o-dichlorobenzene, then 2,6-dichlorobenzoxazole is obtained in the same yield and purity as in Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1
Reactant: COc1ccc(C)c(O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C)c(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To a solution of 2-methyl-5-(methyloxy)phenol (Intermediate 12, 2 g) and 2-chloro-5-nitropyridine (2.1 g, 13.2 mmol) in DMF (50 mL) was added potassium carbonate (2.76 g, 20 mmol) and the reaction mixture was stirred at 100° C. overnight. The mixture was evaporated under vacuum and water (100 mL) was added. It was extracted with ethyl acetate (3 times 100 mL) and the combined organic layers were dried over sodium sulphate and evaporated to afford a brown oil, which was purified by column chromatography on silica gel (mobile phase: EtOAc/PE=1/50−1/20) to give the title compound (1.5 g).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[F:6][C:7]1[CH:8]=[C:9]([CH:11]=[C:12]([F:14])[CH:13]=1)[NH2:10]>Cl.O>[F:6][C:7]1[CH:13]=[C:12]([F:14])[CH:11]=[C:9]2[C:8]=1[CH:1]=[CH:2][C:3]([CH3:4])=[N:10]2
Reactant: C/C=C/C=O
Reactant: Nc1cc(F)cc(F)c1
Agent: Cl
Solvent: O
Product: Cc1ccc2c(F)cc(F)cc2n1
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
Crotonaldehyde (28 mL, 0.33 mol) was added dropwise to a refluxing solution of 3,5-difluoroaniline (10.75 g, 0.083 mol) in 5 N hydrochloric acid (450 mL) and reflux was continued for a further 0.5 h. Reaction mixture was cooled, diluted with water (200 mL) and washed with ether (200 mL). The aqueous layer was basified (pH 14) with 50% NaOH (aq) and extracted into MDC (3×200 mL). The combined organic phases were dried (Na2SO4) and evaporated in vacuo to give a dark oil which was purified by chromatography on silica gel (˜100 g) with 50-100% ethyl acetate in hexane gradient elution to give 5,7-difluoro-2-methylquinoline as a brown solid (6.57 g, 44%). A mixture of 5,7-difluoro-2-methylquinoline (1.0 g, 5.6 mmol) and sodium methoxide (1.69 g, 30 mmol) in methanol (50 mL), was stirred at reflux for 18 h, cooled, and most of the methanol removed in vacuo. The residue was partitioned between ethyl acetate (100 mL), and water (100 mL). The organic phase was dried (Na2SO4) and evaporated in vacuo to give a brown oil which was purified by chromatography on silica gel (˜60 g) with 20-30% ethyl acetate hexane gradient elution to give a yellow solid (0.57 g) which was suspended in 48% HBr (aq) (5 mL) and heated at reflux for 18 h. Reaction mixture was cooled and evaporated in vacuo to give the title compound as a brown solid (0.67 g, 46%).
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[C:7]([CH:9](Br)[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=O)[CH:6]=[CH:5][N:4]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33](=[S:35])[NH2:34])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[S:35][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([NH2:2])[CH:8]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[N:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: Nc1cc(C(Br)C(=O)c2cccc(Cl)c2)ccn1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(Cl)c3)c(-c3ccnc(N)c3)s2)CC1
Yield: 50 %

Procedure:
A solution of 2-(2-amino-4-pyridyl)-2-bromo-1-(3-chlorophenyl)ethanone hydrobromide (2.74 g, 8.36 mmol) and 1-tert-butoxycarbonylpiperidine-4-carbothioamide in N,N-dimethylformamide (50 mL) was stirred at room temperature for 3 hours. Aqueous sodium hydrogen carbonate was added to the reaction mixture and extracted with ethyl acetate. The extracts were washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) and then purified by column chromatography (filler: Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd.), ethyl acetate). The obtained crude crystalline was recrystallized from ethyl acetate-hexane to give a title compound (1.94 g, yield 50%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][CH2:22][CH:21]([CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:20]1>>[CH3:18][N:19]1[CH2:24][CH2:23][CH2:22][CH:21]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:2]3[N:3]=[N:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[CH2:28][CH2:27]2)[CH2:20]1
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nn2)cc1
Reactant: CN1CCCC(CN2CCNCC2)C1
Product: CN1CCCC(CN2CCN(c3ccc(-c4ccc(C(F)(F)F)cc4)nn3)CC2)C1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(4-trifluoromethylphenyl)pyridazine and (1-methylpiperidin-3-ylmethyl)piperazine.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)[C:9]([O:11]C)=[O:10])=O.C([O-])([O-])=O.[K+].[K+].[CH2:28]([O:30][C:31](Cl)=[O:32])[CH3:29]>C1COCC1>[CH2:28]([O:30][C:31]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1)[C:9]([OH:11])=[O:10])=[O:32])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1cc(NC(=O)C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl 3-amino-5-(trifluoromethyl)benzoate (cf. procedures (116a) and (80a); 236 mg, 1.01 mmol) was dissolved in THF (11 mL) and the resulting solution was charged successively with K2CO3 (1.6 mL of a 2.0 M aq. solution) and ethylchloroformate (258 mg, 2.7 mmol). The reaction was stirred at RT for 48 h, concentrated in vacuo, and diluted with EtOAc. The organic phase was washed with sat. NaHCO3, water (2×), and brine before being dried (Na2SO4), filtered, and concentrated in vacuo. This product was dissolved in 3:1 THF/MeOH (8 mL) and the resultant solution was charged with lithium hydroxide (2 mL of a 1N solution). The reaction was stirred for 14 h, acidified with 1N HCl, and extracted with EtOAc (2×). The organic extracts were combined, washed with water, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide 3-(ethoxycarbonyl)amino-5-(trifluoromethyl)benzoic acid. MS found: (M−H)−=276.1.