Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([OH:3])=[O:2].OS(O)(=O)=O.[CH2:21](O)[CH2:22][CH3:23]>>[C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([O:3][CH2:21][CH2:22][CH3:23])=[O:2]
Reactant: O=C(O)C=Nc1cc(Cl)ccc1C(=O)O
Reactant: CCCO
Agent: O=S(=O)(O)O
Product: CCCOC(=O)C=Nc1cc(Cl)ccc1C(=O)O
Temperature: 70 °C
Yield: 61 %

Procedure:
5 g (21.8 mmol) of N-carboxymethylene-4-chloro-anthranilic acid are dissolved in 40 ml of n-propanol, 108 mg (1.05 mmol) of concentrated H2SO4 are added and the mixture is heated at 70° C. for 4.5 hours. It is then cooled to room temperature and the product which has precipitated out is filtered off with suction and washed with n-propanol. After drying, 3.6 g (13.3 mmol; 61%) of N-carbopropoxymethylene-4-chloro-anthranilic acid are obtained as a pale yellow solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].[OH-].[K+].[I:22]I>CN(C=O)C>[I:22][C:14]1[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([C:9]3[CH:8]=[N:7][CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[N:10]=3)[CH:12]=2)[NH:16][CH:15]=1
Reactant: II
Reactant: CC(C)Oc1cncc(-c2ccc3[nH]ccc3c2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)Oc1cncc(-c2ccc3[nH]cc(I)c3c2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.6 %

Procedure:
To a solution of 5-(6-isopropoxy-pyrazin-2-yl)-1H-indole (32 g, 0.126 mol) in DMF (250 mL) was added KOH (17.8 g, 0.316 mol) and then stirred for 15 min at RT. I2 (35.3 g, 0.139 mol) was added to the reaction mixture and stirred at RT for another 1 h. Then reaction mixture was poured into ice water and excess of I2 was quenched with sodium thiosulfite. The resulting solid was collected by filtration, washed with water and dried under vacuum to afford crude 3-iodo-5-(6-isopropoxypyrazin-2-yl)-1H-indole (49 g) as pale brown solid. MS (ESI, m/z): 379.9 (M+1). This material was used to further step without purification.
Reaction SMILES: CN(C)C=O.[F:6][C:7]([F:17])([F:16])[C:8]([N:10]=[C:11]1[NH:15][CH2:14][CH2:13][S:12]1)=[O:9].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:18][C:19]1[N:20]=[CH:21][C:22]([CH2:25][N:15]2[CH2:14][CH2:13][S:12][C:11]2=[N:10][C:8](=[O:9])[C:7]([F:6])([F:16])[F:17])=[CH:23][CH:24]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=C(N=C1NCCS1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(N=C1SCCN1Cc1ccc(Cl)nc1)C(F)(F)F
Yield: 86.6 %

Procedure:
Dimethylformamide (2 mL) and tetrahydrofuran (18 mL) were added to 162 mg (0.82 mmol) of 2,2,2-trifluoro-N-(thiazolidin-2-ylidene)acetamide obtained by the above-described method, following which 198 mg of 2-chloro-5-chloromethylpyridine and 150 mg (1.09 mmol) of potassium carbonate were added, and the mixture was refluxed under heating for 20 hours. Following reaction completion, the reaction mixture was returned to room temperature, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was purified on a TLC plate (two 0.5 mm plates, developed with 100% ethyl acetate), giving 230 mg of the target compound (yield, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(Cl)cc1)C1CCN(c2cc(C(F)(F)F)ccn2)CC1
Yield: 31.9 %

Procedure:
Using the procedure from Example 1A, 4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2-chloro-4-(trifluoromethyl)pyridine (99 μl, 0.76 mmol), DIEA (0.27 ml, 1.52) and 1,4-dioxane (0.3 ml) at 190° C. to afford the title compound (49 mg), an off-white solid, in 32% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:35]([O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][N:39]=1)[CH3:36]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[N:29]=[C:30]([C:41]5[CH:40]=[N:39][C:38]([O:37][CH2:35][CH3:36])=[CH:43][CH:42]=5)[CH:31]=[CH:32][CH:33]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOc1ccc(B(O)O)cn1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccc(OCC)nc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-ethoxy-5-pyridineboronic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)=[O:12].[C:37]([O-:40])(=[O:39])[CH3:38].[Na+].[I-].[Na+]>C(O)(=O)C>[C:37]([O:40][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)=[O:12])(=[O:39])[CH3:38]
Reactant: CC(=O)[O-]
Reactant: O=C(Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1)c1ccccc1OCCCCCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCCCCCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Yield: 55.6 %

Procedure:
A mixture of 1-{4-[2-(6-bromohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (2.00 g), sodium acetate (0.36 g), sodium iodide (0.55 g) and acetic acid (20 ml) is refluxed for 1 day. The solvent is distilled off and the resulting residue is extracted with ethyl acetate. The organic layer is washed successively with 2N aqueous sodium hydroxide solution and saturated saline solution, and dried over magnesium sulfate. The solvent is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; chloroform: methanol=500:1), and recrystallized from ethanol to give 1-{4-[2-(6-acetyloxyhexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (1.07 g) as white powder, m.p. 145°-146° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][C:12]1[N:13]=[CH:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.[Cl:27]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:27][C:14]1[O:15][C:16]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=2)=[C:12]([CH3:11])[N:13]=1
Reactant: Cc1ncoc1-c1ccc(C(F)(F)F)cc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)oc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
Lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 19.4 mL, 19.4 mmol) was added dropwise to a solution of Example 12A (4.0 g, 17.6 mmol) in tetrahydrofuran (80 mL) at −78° C. After stirring 30 min, solid hexachloroethane (8.34 g, 35.2 mmol) was added in one portion, and the reaction was allowed to gradually warm to ambient temperature. After 16 hours the reaction was quenched with half-saturated NH4Cl solution. The product was extracted with diethyl ether, and the combined organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Analogix Intelliflash 280; 0% to 25% ethyl acetate/hexanes; SF65-600 g column; loading with hexane/CH2Cl2) to yield 4.69 g of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.87 (m, 2H), 7.82 (m, 2H), 2.40 (s, 3H). MS (DCI+) m/z 262 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=O)[CH2:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.Cl.[NH2:18]O>CO>[CH3:1][O:3][C:4]([C:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:14][N:18]=1)=[O:16]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(-c2ccccc2)on1
Yield: 78.6 %

Procedure:
To a stirred solution of 2,4-dioxo-4-phenyl-butyric acid ethyl ester (3.86 g, 0.01754 mole) in methanol (78 mL) was added hydroxylamine hydrochloride (3.657 g, 0.0526 mole) at ambient temperature. The resulting mixture was then heated to reflux overnight. Volatiles were then removed by evaporation and the resulting residue was diluted with water and the product extracted with chloroform. The chloroform layer was collected and washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (4% ethyl acetate in hexane) to afford 2.8 g (79%) of 5-phenyl-isoxazole-3-carboxylic acid methyl ester. LCMS: 204.06 (M+1)+, 97.58%. To a stirred solution of 5-phenyl-isoxazole-3-carboxylic acid methyl ester (2.8 g, 0.01379 mol) in a mixture of THF (10 mL), methanol (10 mL) and H2O (10 mL) was added LiOH.H2O (0.87 g, 0.02073 mol) and the resulting mixture was stirred at ambient temperature for 2.5 hours. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with concentrated HCl and extracted with ethyl acetate. The ethyl acetate layer was collected and washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 2.2 g (85%) of 5-phenyl-isoxazole-3-carboxylic acid. LCMS: 190.04 (M+1)+, 96.4%.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:15][CH:16]([Cl:20])[C:17](Cl)=[O:18]>C1C=CC=CC=1>[CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[C:17](=[O:18])[CH:16]([Cl:20])[Cl:15])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)NC(C)C
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)N(C(=O)C(Cl)Cl)C(C)C

Procedure:
To a solution of diisopropylamine (6.8 g) (0.068 mol) and 6.8 g. of triethylamine in 100 ml of anhydrous benzene was added dropwise at 15° C. with stirring and ice-bath cooling, dichloroacetyl chloride (10.0 g, 0.068 mol). The solution was stirred overnight at room temperature. The benzene solution was washed successively with 10% HCl, H2O sodium hydroxide and saturated NaCl solution and was dried over anhydrous MgSO4. The solvent was distilled off, yielding 4.9 g. of liquid product, which infrared absorption spectra indicated to be substantially pure. No further purification was considered to be necessary for the purpose of this invention.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14](O)=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([Cl:20])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(Cl)nc21
Product: CCn1cc(C(=O)Cl)c(=O)c2ccc(Cl)nc21

Procedure:
7-Chloro-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (29.5 g) and thionyl chloride (18 ml) in dry doluene (900 ml) were stirred and heated under reflux for 1 hour. The solution was cooled and the solid that separated was collected. It had m.p. 186.5°-188.5° (98%).
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.C1C(=O)N(Cl)C(=O)C1.[Cl:20][C:21]1[C:29]([F:30])=[C:28]2[C:24]([CH:25]=[C:26]([CH:38]3[CH2:40][CH2:39]3)[N:27]2[C:31]2[CH:32]=[N:33][N:34]([CH2:36][CH3:37])[CH:35]=2)=[CH:23][CH:22]=1>C(Cl)Cl>[Cl:20][C:21]1[C:29]([F:30])=[C:28]2[C:24]([C:25]([S:1][C:2]3[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=3)=[C:26]([CH:38]3[CH2:40][CH2:39]3)[N:27]2[C:31]2[CH:32]=[N:33][N:34]([CH2:36][CH3:37])[CH:35]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1cccc(S)n1
Reactant: CCn1cc(-n2c(C3CC3)cc3ccc(Cl)c(F)c32)cn1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CCn1cc(-n2c(C3CC3)c(Sc3cccc(C(=O)OC)n3)c3ccc(Cl)c(F)c32)cn1
Reaction time: 1 h
Yield: 32.2 %

Procedure:
To a stirred solution of methyl 6-mercaptopicolinate 6 (3.15 g, crude) in CH2Cl2 (50 mL) under inert atmosphere was added NCS (2.49 g, 18.63 mmol) at RT and stirred for 1 h. To this, indole 5 (5.6 g, 18.47 mmol) in CH2Cl2 (50 mL) was added at RT and stirred for 16 h. After completion of the reaction (TLC), the reaction mixture was diluted CH2Cl2 (100 mL) washed with water (3×100 mL). The organic extract was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel column chromatography; 10% EtOAc/hexanes) to afford 9 (2.8 g, 32%) as a pale brown solid. 1H NMR (500 MHz, DMSO-d6): δ 7.79 (d, J=7.5 Hz, 1H), 7.66 (d, J=10.5 Hz, 2H), 7.51 (t, J=7.5 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 7.10-7.07 (m, 1H), 6.78 (d, J=8.0 Hz, 1H), 4.28 (q, 2H), 4.00 (s, 3H), 1.75-1.69 (m, 1H), 1.58 (t, J=7.0 Hz, 3H), 1.09-1.08 (m, 2H), 0.87-0.84 (m, 2H); LC-MS: 98.4%; m/z 471.4 (M+H+); (column; X-select CSH C-18, (50×3.0 mm, 3.5 μm); RT 4.25 min. 5.0 mM NH4OAc (Aq): ACN; 0.8 mL/min); HPLC: 98.1%; (column: Acquity BEH C-18 (50×2.1 mm, 1.7μ); RT 3.02 min. ACN: 0.025% TFA (aq); 0.5 mL/min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:16]2[CH2:17][O:18][CH2:19][CH:9]1[C:10]1[CH:11]=[N:12][O:13][C:14]=1[CH:15]2O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:27])CC>C(Cl)Cl.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH:16]2[CH2:17][O:18][CH2:19][CH:9]1[C:10]1[CH:11]=[N:12][O:13][C:14]=1[CH:15]2[F:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C2COCC1C(O)c1oncc12
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2COCC1C(F)c1oncc12
Reaction time: 6 h

Procedure:
To a solution of 7-Hydroxy-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene-12-carboxylic acid tert-butyl ester 106d (141 mg, 0.5 mmol, 1.0 eq) in DCM (5 mL) was added DAST (166 mg, 1 mmol, 2.0 eq) at −78° C. Then mixture was stirred for 6 h from −78° C. to room temperature. The reaction was diluted with EA (20 mL), and washed with aqueous NaHCO3 (5%, 20 mL). The organic layer was dried and concentrated to give 7-Fluoro-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene-12-carboxylic acid tert-butyl ester as an oil, 150 mg, crude yield: 100%. MS: calc'd (MH+) 285, measured (MH+) 285.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[S:28](Cl)(=[O:30])=[O:29].N12CCN(CC1)CC2>C(#N)C>[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[S:28]([N:6]([CH2:5][C:4]1[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=1[O:2][CH3:1])[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1)(=[O:30])=[O:29]
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1Cl
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(F)cc2Cl)c(OC)c1
Yield: 21.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (150 mg, 0.611 mmol) prepared in Example 14a, 2-Chloro-4,5-difluorobenzenesulfonyl chloride (302 mg, 1.22 mmol), 1,4-diazabicyclo[2.2.2]octane (137 mg, 1.22 mmol) and acetonitrile (5.0 mL), to yield the title compound (58.8 mg, 21%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1
Reactant: Oc1cccc(Cl)c1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(Oc3cccc(Cl)c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 3-chloro-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(3-chloro-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 352(MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[N+:15]([O-:17])=[O:16].C(O)C.CN(C)C(=N)N(C)C.[CH2:30](I)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>O>[N+:15]([C:5]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][C:12]([O:14][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH3:30])=[CH:13][C:4]=1[C:3]([O:2][CH3:1])=[O:18])([O-:17])=[O:16]
Reactant: CCCCCCCCCCCCCCCCCCI
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)c([N+](=O)[O-])c(C(=O)OC)c1

Procedure:
To a solution of 19.5 g. of dimethyl-5-hydroxy-2-nitroisophthalate in 150 ml. of dry ethanol are added 8.8 g. of tetramethylguanidine, followed by 29.1 g. of octadecyliodide. The mixture is refluxed for 16 hr., cooled, and poured into 700 ml. of water. The precipitate is collected and washed well with water. The dried crude product is triturated with methanol. The insoluble solid is collected, giving 32.6 g. of product, m.p. 65°-68° C., which is used without further purification.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:5]=[C:6]2[N:13]([CH3:14])[CH2:12][CH2:11][N:7]2[C:8](=[O:10])[N:9]=1.[OH:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[C:21]([CH:24]=1)[C:22]#[N:23].Cl>CN(C=O)C>[CH3:14][N:13]1[C:6]2[N:7]([C:8](=[O:10])[N:9]=[C:4]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=4)=[C:21]([CH:24]=3)[C:22]#[N:23])[CH:5]=2)[CH2:11][CH2:12]1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3cccc(C(F)(F)F)c3)c(C#N)c1)nc2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
NaH (28.8 mg, 60%, 0.72 mmol) was added to a solution of 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (44 mg, 0.24 mmol) and 5-(hydroxymethyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile (71 mg, 0.242 mmol) in DMF (1.8 mL). The reaction mixture was stirred at rt for 30 min. Aqueous HCl solution was added to adjust pH to ˜7. Purification by Mass Directed AutoPrep (MDAP) afforded the title compound as a white solid (60 mg, 56% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:18])[O:11][C:12]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1.Cl.[CH3:20]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH3:18])[O:11][C:12]=2[CH2:13][CH2:14][C:15]([O:17][CH3:20])=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Reactant: CO
Agent: Cl
Product: COC(=O)CCc1oc(C)nc1-c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
A mixture of 4-(4-chlorophenyl)-2-methyloxazole-5-propionic acid (10.0 g), methanol (50 ml) and 20% methanolic hydrogen chloride (50 ml) was allowed to stand at room temperature for 2 hours. The solvent was distilled off, followed by addition of water. The mixture was neutralized with potassium carbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was further distilled under reduced pressure to give crystals of methyl 4-(4-chlorophenyl)-2-methyloxazole-5-propionate, yield 7.7 g (68.8%), b.p. 162° C./0.7 mmHg, m.p. 74°-75° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[NH:6])[NH2:5].[Cl:7][CH2:8][C:9](=O)[CH2:10][C:11](OC)=[O:12]>>[Cl:7][CH2:8][C:9]1[CH:10]=[C:11]([OH:12])[N:5]=[C:4]([O:3][CH3:2])[N:6]=1
Reactant: COC(=N)N
Reactant: COC(=O)CC(=O)CCl
Agent: Cl
Product: COc1nc(O)cc(CCl)n1

Procedure:
Analogously to the process described in Example 113, O-methylisourea hydrochloride or hydrosulphate is reacted with methyl 4-chloroacetoacetate in order to produce 4-chloromethyl-6-hydroxy-2-methoxy-pyrimidine, m.p. 154°-155° C., which is required as the starting material in Examples 68, 69 and 77.
Reaction SMILES: C(I)C.CI.[CH2:6]([N:8]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)C>>[CH3:6][N:8]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2
Reactant: CCn1c(=O)c2ccccc2c2ccccc21
Solvent: CI
Solvent: CCI
Product: Cn1c(=O)c2ccccc2c2ccccc21

Procedure:
By the use of ethyl iodide rather than methyl iodide, 5-ethyl-6 (5H)phenanthridone was prepared in 97% yield (m.p. 87°-90°).
Reaction SMILES: [CH3:1]I.[ClH:3].[Br:4][C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH:12]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:11][CH2:10][CH2:9][C:8]2=1.[H-].[Na+].Cl>C1COCC1>[ClH:3].[Br:4][C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:1])[C:13]1[CH:12]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:11][CH2:10][CH2:9][C:8]2=1
Reactant: CI
Reactant: Brc1ccc2[nH]c3c(c2c1)CCCC3NCCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c2c(c3cc(Br)ccc31)CCCC2NCCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
6-Bromo-9-methyl-N-(2-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt was prepared by addition of methyl iodide (0.016 mL, 0.25 mmol) to a solution of 6-bromo-N-(2-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt (0.05 g, 0.12 mmol) and sodium hydride (0.04 mL, 0.25 mmol) in THF (2.0 mL) that was under inert atmosphere and cooled to 0° C. The mixture was allowed to warm to room temperature and stirred for 12 hrs. The reaction was quenched with saturated (“sat.”) ammonium chloride (“NH4Cl”) (2.0 mL), ethyl acetate was added (10 mL), the organic layer was separated and washed with sat. NaCl (2.0 mL), dried over sodium sulfate (“Na2SO4”), filtered and evaporated to leave an oily residue. Purification by flash chromatography with 10-50% gradient ethyl acetate/hexanes eluent afforded a clear oil that was converted to the HCl salt to give a white solid (0.005 g, 9%). 1H-NMR (CDCl3): δ 7.57 (s, 1H), 7.31-7.21 (m, 7H), 7.09 (d, 1H), 3.86 (m, 1H), 3.53 (s, 3H), 3.19-3.13 (m, 1H), 2.94-2.87 (m, 1H), 2.84-2.80 (m, 2H), 2.74-2.67 (m, 1H), 2.55-2.47 (m, 1H), 2.17-2.11 (m, 1H), 1.83-1.70 (m, 3H); MS m/z 381, 383 (M−1).