Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:16]=1)[C:3](=[O:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C:33](Cl)(=[O:38])[O:34][CH:35]([CH3:37])[CH3:36].O>ClCCl>[C:8]([O:7][C:6]([NH:5][CH2:4][C:3]([N:2]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:34][CH:35]([CH3:37])[CH3:36])=[O:38])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:1])=[O:13])=[O:12])([CH3:11])([CH3:9])[CH3:10]
Reactant: CN(Cc1cccc(-c2cnc(N3CCNCC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: CC(C)OC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCN(c2ncc(-c3cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.8 %

Procedure:
tert-Butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (200 mg) and TEA (92 mg) were dissolved in dichloromethane, followed by ice-cooling. Isopropyl chlorocarbonate (83 mg) was added thereto, followed by stirring at room temperature for 4 hours. Water was added thereto, followed by extraction with chloroform. The organic layer was dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain isopropyl 4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazine-1-carboxylate (155 mg).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[Cl:16].[OH-].[Na+].Cl>CO.O>[Cl:16][C:5]1[CH:6]=[C:7]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1ccc(N2CCOCC2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(N2CCOCC2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.3 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-benzoic acid methyl ester (3.08 g, 12.0 mmol) and 6N NaOH (2.5 mL, 15 mmol) in methanol (50 mL) and water (7.5 mL) was stirred 24 h at room temperature, then acidified with 2N HCl. The precipitate was filtered off, washed with water and dried to provide 2-chloro-4-morpholin-4-yl-benzoic acid (2.56 g, 88% yield) as a white solid. This intermediate (10.6 mmol) was suspended in tert-butanol (20 mL), treated with diphenylphosphoryl azide (2.30 mL, 10.6 mmol), then with triethylamine (1.45 mL, 10.6 mmol), was stirred at reflux for 20 h and evaporated. Purification by flash chromatography (SiO2) eluted with 2:8 ethyl acetate:hexanes provided (2-chloro-4-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (2.84 g) as a mixture (˜1:1) with 2-chloro-4-morpholin-4-yl-benzoic acid tert-butyl ester. This mixture was carried on without further purification. 1H-NMR (CDCl3, 500 MHz) 8.0 (br, 1H), 7.80 (d, 1H), 7.4 (d, 1H), 6.90 (d, 1H), 6.87 (d, 1H), 6.84 (dd, 1H), 6.75 (dd, 1H), 3.87 (m, 8H), 3.26 (m, 4H), 3.11 (m, 4H), 1.61 (s, 9H), 1.55 (s, 9H) ppm; MS (FIA) 313.1 (M+H); HPLC (Method A) 3.70 min.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:8])[C:4](=[O:7])[CH:5]=[CH2:6].[C:9]([NH2:13])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([NH:13][CH2:6][CH2:5][C:4]([N:3]([O:2][CH3:1])[CH3:8])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)N
Reactant: C=CC(=O)N(C)OC
Product: CON(C)C(=O)CCNC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.8 %

Procedure:
N-Methoxy-N-methyl-acrylamide (5 g, 43.4 mmol, 1.0 equiv) was dissolved in t-butylamine (3.36 g, 46 mmol, 1.06 equiv). The resulting solution was stirred at room temperature for 48 h. The excess primary amine was removed in vacuo and the crude product was purified by flash chromatography on silica using 100% CH2Cl2 to 2% MeOH in CH2Cl2 to give the desired product as a light yellow oil (5.7 g, 70%); MS, m/z 189=M+1.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18](F)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18]([O:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: O=C1c2ccc(F)nc2OCCN1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccc(Oc3cccc(Cl)c3)nc2OCCN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
A mixture of the compound obtained in Example 28, step 1 (0.50 g), 3-chlorophenol (0.23 mL), potassium carbonate (0.76 g) and DMF (10 mL) was stirred at 100° C. for 16 hr. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give 4-benzyl-8-(3-chlorophenoxy)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (0.58 g, 83%) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[NH:6][CH:5]=1.N1C=CN=C1.[CH:19]([Si:22](Cl)([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])([CH3:21])[CH3:20]>CN(C)C=O.C(OCC)(=O)C>[CH:19]([Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]=[C:4]2[CH2:3][CH2:2][NH2:1])([CH3:21])[CH3:20]
Reactant: NCCc1c[nH]c2ccc(O)cc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1ccc2[nH]cc(CCN)c2c1)(C(C)C)C(C)C

Procedure:
A solution of 3-(2-amino-ethyl)-1H-indol-5-ol (3.0 g), imidazole (9.6 g), and triisopropylsilyl chloride (4.5 mL) was stirred in 20 mL N,N-dimethylformamide for 6 h. The solution was diluted with 100 mL of ethyl acetate and washed with 100 mL of sodium carbonate and 100 mL of saturated sodium chloride (3 times). The organic phase was dried over sodium sulfate and the solvent was evaporated. Silica gel chromatography (2% methyl alcohol in dichloromethane) gave 2-(5-triisopropylsilanyloxy-1H-indol-3-yl)-ethylamine (2.6 g). This compound was cyclized with formaldehyde by Procedure OO to afford 6-triisopropylsilanyloxy-2,3,4,9-tetrahydro-1H-β-carboline, which was protected with tert-butoxycarbonyl group by Procedure CC to give 6-triisopropylsilanyloxy-1,3,4,9-tetrahydro-β-carboline-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([NH:19][C:20](=[O:24])[CH2:21][CH2:22]Br)[C:14]=1[CH3:25].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:27].C(OCC)(=O)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([NH:19][C:20](=[O:24])[CH2:21][CH2:22][N:31]2[CH2:32][CH2:33][N:28]([CH2:26][CH3:27])[CH2:29][CH2:30]2)[C:14]=1[CH3:25]
Reactant: CCN1CCNCC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1NC(=O)CCBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN1CCN(CCC(=O)Nc2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(F)cc43)c2C)CC1
Temperature: 25 °C
Yield: 32 %

Procedure:
N-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-3-bromo-propionamide (548 mg, 1.0 eq) was dissolved in 4 ml of DMF, stirred at room temperature to obtain a solution. To the solution was added 4-ethylpiperazine (850 mg, 4.0 eq). The reaction mixture was heated to 50° C. and reacted for 4 h. Once the reaction was completed as indicated by TLC, the reaction solution was added to 200 ml of ethyl acetate. Solid product was formed, collected by filtration, washed with ethyl acetate, dried, and purified by column chromatograph to obtain the target compound of 312 mg (yield 32%).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)C.[ClH:32].[OH:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[OH:43])[CH2:37][CH2:38][NH2:39].C(O)CCC>O>[ClH:32].[CH2:22]([O:21][C:19]([N:6]([CH2:5][CH:4]1[C:40]2[C:36](=[CH:35][C:34]([OH:33])=[C:42]([OH:43])[CH:41]=2)[CH2:37][CH2:38][NH:39]1)[C:7]1[CH:8]=[C:9]([O:17][CH3:18])[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CCOC(CN(C(=O)OCc1ccccc1)c1cc(OC)c(OC)c(OC)c1)OCC
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: COc1cc(N(CC2NCCc3cc(O)c(O)cc32)C(=O)OCc2ccccc2)cc(OC)c1OC
Yield: 70.1 %

Procedure:
N-benzyloxycarbonyl-3,4,5-trimethoxyanilinoacetaldehyde diethyl acetal (21 g) and 3,4-dihydroxyphenethylamine hydrochloride (8.3 g) were added to a mixture of n-butyl alcohol (210 ml) and water (30 ml) and then the mixture was refluxed for 11 hours in a stream of nitrogen. In the course of the reaction, amounts of the above-mentioned acetal (2.1 g, 2.1 g and 4.2 g) were added to the mixture after 5 hours, 6 hours and 7 hours, respectively, from the beginning of the reaction, respectively. The reaction mixture was concentrated to dryness under reduced pressure and the residue was washed with ether and acetone to give 1-(N-benzyloxycarbonyl-3,4,5-trimethoxyanilinomethyl)-6,7-dihydroxy,1,2,3,4-tetrahydroisoquinoline hydrochloride (16.3 g). The product was recrystallized from a mixed solvent of ethanol and ether to give a pure product, mp 197° to 199° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[S:29][CH:30]=1)[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[Cl-].[CH2:38]([C:40]1[S:41][CH:42]=[C:43]([CH2:45][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:44]=1)[CH3:39].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:38]([C:40]1[S:41][CH:42]=[C:43](/[CH:45]=[CH:13]\[C:12]2[C:8]([O:7][CH2:6][C:5]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]4[N:27]=[C:28]([N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)[S:29][CH:30]=4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:9][N:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[N:44]=1)[CH3:39]
Reactant: CCc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1csc(N2CCCCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc(/C=C\c2cn(-c3ccccc3)nc2OCc2ccc(OCc3csc(N4CCCCC4)n3)c(OC)c2)cs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 17.8 %

Procedure:
A mixture of 3-[(3-methoxy-4-{[2-(piperidin-1-yl)-1,3-thiazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.60 g), [(2-ethyl-1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (0.76 g), potassium carbonate (0.17 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to give 1-[4-({4-[({4-[(Z)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-1,3-thiazol-2-yl]piperidine as colorless crystals (0.13 g, yield 18%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 93-94° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[C:5]=1[OH:18])[CH:2]=[CH2:3]>ClCCl.CC#N.CC#N.Cl[Pd]Cl>[Cl:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=1[C:6]1[C:5]([OH:18])=[C:4](/[CH:1]=[CH:2]/[CH3:3])[CH:9]=[CH:8][CH:7]=1
Reactant: C=CCc1cccc(-c2c(Cl)cccc2Cl)c1O
Agent: Cl[Pd]Cl
Solvent: ClCCl
Solvent: CC#N
Product: C/C=C/c1cccc(-c2c(Cl)cccc2Cl)c1O
Yield: 96.1 %

Procedure:
A mixture of 3-allyl-2′,6′-dichloro-1,1′-biphenyl-2-ol (2.922 g, 10.47 mmol) and bis(acetonitrile)dichloropalladium (II) (136 mg, 0.523 mmol) in anhydrous dichloromethane was heated to reflux under nitrogen for 1 hour. The cooled reaction mixture was then concentrated to a small volume under reduced pressure and directly pre-adsorbed onto silica gel. Purification by flash chromatography using a solvent gradient of 2 to 7.5% ethyl acetate in hexane gave 2.81 g (96%) of 2′,6′-dichloro-3-[(1E)-prop-1-enyl]-1,1′-biphenyl-2-ol as a colorless syrup. HRMS: calcd for C15H12Cl2O, 278.02652. found (EI, M+), 278.0262.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[N:9]=[C:10]([NH2:15])[N:11]=[C:12]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=3)[CH:13]=2)[CH:7]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Cc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Product: Cc1ccc(Br)cc1-c1cc(Nc2ccc(Br)cc2)nc(N)n1
Yield: 91 %

Procedure:
Following the method described in Example 26, 4-(5-bromo-2-methyl-phenyl)-6-chloro-pyrimidin-2-ylamine and 4-bromo-phenylamine provided the title compound (91% yield). 1H NMR (DMSO-d6) δ 2.34 (s, 3H, CH3), 6.37 (s, 1H, Ar), 7.40 (d, 1H, J=8.9 Hz, Ar), 7.59 (d, 2H, J=8.7 Hz, Ar), 7.70-7.71 (m, 2H, Ar), 7.82-7.84 (m, 2H, Ar), 10.89 (br s, 1H, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[CH3:23])[NH2:19]>>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:12]([NH2:14])=[O:13])[CH:20]=[CH:21][C:22]=1[CH3:23]
Reactant: Cc1ccc(N)cc1Cl
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(C)c(Cl)c1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 3-chloro-4-methylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:17]4[N:22]=[C:21]([N:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)[CH:20]=[CH:19][CH:18]=4)[C:10]=3[CH:9]=2)[CH:5]=[N:4]1)[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([N:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]5)[N:22]=4)[C:10]=3[CH:9]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCNCC3)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A mixture of tert-butyl 4-(6-(6-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate (0.2486 mmol; 118 mg) in DCM (5 mL) and TFA (5 mL) was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 6-(1-ethyl-1H-pyrazol-4-yl)-1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine 101 (47.5 mg, 50%). 1H NMR (400 MHz, DMSO) δ 9.15-9.11 (s, 1H), 8.67-8.65 (s, 1H), 8.54-8.51 (s, 1H), 8.27-8.24 (s, 1H), 7.91-7.88 (s, 1H), 7.78-7.72 (t, J=8.1 Hz, 1H), 7.24-7.18 (d, J=7.7 Hz, 1H), 6.80-6.74 (d, J=8.4 Hz, 1H), 4.26-4.17 (q, J=7.3 Hz, 2H), 3.65-3.56 (m, 4H), 2.96-2.86 (m, 4H), 1.46-1.41 (t, J=7.3 Hz, 3H); MS (ESI) m/z: 375.1 [M+H]+
Reaction SMILES: CN1CCCC1=O.[CH:8]1[C:20]2[N:19]([NH2:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1.[Cl:22][C:23]1[CH:28]=[C:27](Cl)[N:26]=[CH:25][N:24]=1>O>[Cl:22][C:23]1[N:24]=[CH:25][N:26]=[C:27]([NH:21][N:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[C:20]2=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:28]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nn1c2ccccc2c2ccccc21
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1cc(Nn2c3ccccc3c3ccccc32)ncn1
Temperature: 100 °C

Procedure:
To 150 ml of 1-methyl-2-pyrrolidinone was added 10.0 g of 9H-carbazol-9-amine, and 8.2 g of 4,6-dichloropyrimidine, and the mixture was heated to 100° C. and stirred for eleven hours. The mixture was then poured into water and extracted with toluene. The organic layer was washed with water and dried (sat. NaCl, anhydrous MgSO4).
Reaction SMILES: [CH3:1][N:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=[N:3]1.Br[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([Cl:24])[CH:18]=1>COCCOC.CO>[Cl:24][C:19]1[CH:18]=[C:17]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:23]=[CH:22][C:20]=1[NH2:21]
Reactant: Nc1ccc(Br)cc1Cl
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Solvent: COCCOC
Solvent: CO
Product: Cn1nccc1-c1ccc(N)c(Cl)c1
Yield: 74 %

Procedure:
Prepared using Method C (Preparation 85) using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-bromo-2-chloroaniline in DME/MeOH 2/1 for 10 minutes at 150° C. under microwave irradiation. Purified using silica gel column chromatography eluting with 20% hexane in ethyl acetate to afford the title compound as a white powder (77 mg, 74%). 1H-NMR (500 MHz, CDCl3): δ 3.86 (s, 3H), 4.26 (s, br, 2H), 6.22 (d, J=2 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 7.1 (dd, J=2 Hz, 8.3 Hz. Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.48 (d, J=2 Hz, 1H).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=1)OC1C=CC=CC=1)#[N:2].[NH:27]([C:29]1[C:30]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][C:31]=2[N:32]=[CH:33][N:34]=1)[NH2:28]>C(O)(C)C>[N:32]1[C:31]2[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:30]=2[C:29]([N:27]2[C:1]([NH2:2])=[N:3][C:4]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26]4)=[CH:17][CH:18]=3)=[N:28]2)=[N:34][CH:33]=1
Reactant: N#CNC(=Nc1ccc(OCCN2CCCC2)cc1)Oc1ccccc1
Reactant: NNc1ncnc2c1CCCCCC2
Solvent: CC(C)O
Product: Nc1nc(Nc2ccc(OCCN3CCCC3)cc2)nn1-c1ncnc2c1CCCCCC2
Temperature: 150 °C
Yield: 78 %

Procedure:
A mixture of N-Cyano-N′-{[4-(pyrrolidin-1-yl-ethoxy)]phenyl}-O-phenylisourea (50 mg; 0.14 mmol; 1.0 equiv) and 4-hydrazino-5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine (28 mg; 0.14 mmol; 1 equiv) in 1 mL of isopropanol was heated in the microwave apparatus at 150° C. for 15 min. Purification by silica gel column chromatography eluted with CH2Cl2/MeOH/Et3N (95/5/1) gave 1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-4-yl)-N3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound #20, as a pale-yellow solid (50 mg; 78% yield); 1H-NMR (DMSO-d6, 300 MHz) 8.85 (br. s, 1H), 8.71 (s, 1H), 7.53 (br. s, 2H), 7.43 (d, J=9.0 Hz, 2H), 6.83 (d, J=8.7 Hs, 2H), 4.05-3.98 (m, 2H), 3.40-3.22 (m, 4H), 3.00-2.95 (m, 2H), 2.72-2.58 (m, 4H), 1.92-1.83 (m, 2H), 1.78-1.68 (m, 6H), 1.48-1.32 (m, 4H) ppm; MS (ES) 449.54 (M+H), 447.25 (M−H).
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:30]1[C:35]([Cl:36])=[CH:34][C:33]([C:37]([F:40])([F:39])[F:38])=[CH:32][N:31]=1.O>CN(C=O)C>[Cl:36][C:35]1[C:30]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C:7]3[N:11]([CH3:12])[N:10]=[C:9]([C:13]4[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=4[F:20])[N:8]=3)=[CH:21][CH:22]=2)=[N:31][CH:32]=[C:33]([C:37]([F:39])([F:38])[F:40])[CH:34]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Cn1nc(-c2c(F)cccc2F)nc1Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2c(F)cccc2F)nc1Cc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Temperature: 70 °C
Yield: 43.1 %

Procedure:
To a solution of 0.8 g of 5-(4-hydroxybenzyl)-3-(2,6-difluorophenyl)-1-methyl 1H-1,2,4-triazole in 10 ml of DMF at room temperature were added 0.4 g of anhydrous potassium carbonate and 0.63 g of 2,3-dichioro-5-trifluoromethylpyridine and then the suspension solution was heated to 70° C. or 1 hour. After cooling, the reaction mixture was poured into iced water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 0.55 g of 5-(4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-benzyl)-3-(2,6-difluorophenyl)-1-methyl-1H-1,2,4-triazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:23](O)=[O:24]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:23]=[O:24])=[C:4]([OH:10])[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(O)cc1Cl
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1cc(C=O)c(O)cc1Cl
Temperature: 85 °C

Procedure:
The above prepared 3-chloro-4-methoxy-phenol (2.379 g, 13.5 mmol, corrected for purity) was dissolved in 21 mL of trifluoroacetic acid and treated with hexamethylene tetramine (2.313 g, 1.25 eq.), and the mixture was then stirred at 85° C. over night. Cooling, pouring onto crashed ice, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, heptane/AcOiPr=82/18), followed by crystallization from heptane/AcOEt, produced finally 1.030 g of the title compound as yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9](CCCCCCCCCCCCCCC)[C:5]=1[C:6](O)=[O:7])[CH3:2].S(Cl)([Cl:30])=O.CN(C)C=O>CCCCCC>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([Cl:30])=[O:7])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOc1ccccc1C(=O)Cl

Procedure:
To a stirred solution of 2-Ethoxy-6-pentadecylbenzoic Acid (6.5 g, 16 mmol) in hexane (60 mL) were added thionyl chloride (2.5 g, 21 mmol) and N,N-dimethylformamide (0.5 mL). The reaction mixture was heated to reflux for 1 h. After the reaction was complete, the solvent was evaporated under reduced pressure to yield the desired 2-Ethoxy-benzoyl Chloride, which was redissolved in dichloromethane (50 mL) and used for the condensation with anilides.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH2:35][C:36]([O:38]C)=[O:37])=[O:33])=[CH:4][N:3]=1.[OH-].[Na+].O.Cl>O1CCOCC1>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:33])=[CH:4][N:3]=1
Reactant: COC(=O)CNC(=O)c1cnc(N)c2c(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)csc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2csc3c(C(=O)NCC(=O)O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 50 °C
Yield: 50.6 %

Procedure:
To a mixture of methyl ({[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)thieno[3,2-c]pyridin-7-yl]carbonyl}amino)acetate (0.130 g, 0.239 mmol) in 1,4 dioxane (10 mL) was added 2M sodium hydroxide in water (0.260 mL, 0.521 mmol). The resulting solution was heated at 50° C. for 3 hours. 1M hydrochloric acid was added until pH of the mixture was 4 and solvent was removed under reduced pressure. The resulting white solid was washed with water (2 mL) and filtered and dried to furnish the title compound (64 mg, 0.121 mmol): LCMS (Conditions b): MH+=530 RT=2.03 min; 1H NMR (DMSO-d6, 400 MHz) δ 12.65 (1H), 9.50 (1H), 8.95 (1H), 8.60 (1H), 8.02 (1H), 7.71 (2H), 7.58 (1H), 7.35 (2H), 7.21 (1H), 7.15 (1H), 7.09 (1H), 6.29 (2H), 4.04 (3H), 3.97 (2H), 3.92 (3H).