Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].CCN(CC)CC.[Cl:17][C:18](Cl)=[CH2:19]>>[CH2:2]([O:3][C:4]([C:6]1[CH:19]=[C:18]([Cl:17])[O:8][N:7]=1)=[O:5])[CH3:1]
Reactant: C=C(Cl)Cl
Reactant: CCOC(=O)/C(Cl)=N\O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(Cl)on1
Temperature: 25 °C
Reaction time: 23 h
Yield: 35 %

Procedure:
To a solution of ethyl chlorooximidoacetate (11.0 g, 72.6 mmol, 1 equiv) in 1,1-dichloroethylene (350 mL) was added Et3N (25.3 mL, 181 mmol, 2.5 equiv) in 1,1-dichloroethylene (100 mL) via addition funnel over 30 min. The reaction mixture was stirred at room temperature for 23 h, then was partitioned between water (150 mL) and CH2Cl2 (2×150 mL). The combined organic layers were dried over Na2SO4 and were concentrated. The residue was purified by flash column chromatography (10% EtOAc in hexanes) to give the title intermediate (4.49 g, 35%) as a pale yellow oil: IR (cm−1) 1735, 1436, 1253; 1H NMR (CDCl3) δ 1.45 (t, 3H, J=7.2), 4.49 (q, 2H, J=7.2), 7.29 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]1[CH:25]=[C:24]([CH3:26])[O:23][N:22]=1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:10]([CH2:20][C:21]3[CH:25]=[C:24]([CH3:26])[O:23][N:22]=3)[C:4]=2[CH:3]=1
Reactant: Cc1cc(CBr)no1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Cn2c(-c3cnn(C)c3)cc3cnc(Br)cc32)no1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 0.060 g, 0.217) in anhydrous DMF (0.8 mL) was added sodium hydride 60% (0.013 g, 7.8 mg, 0.325 mmol). The reaction mixture was stirred at room temperature for 5 minutes under argon, then a solution of 3-(bromomethyl)-5-methylisoxazole (0.057 g, 0.325 mmol) in anhydrous DMF (0.3 mL) was added. The stirring was continued at room temp for 1 hour and 50 minutes. The reaction mixture was diluted with ethyl acetate (40 mL) and the solution was washed with water (10 mL), brine (2×10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified using preparative TLC eluting with 20% ethyl acetate in CH2Cl2. The product band was recovered and stirred with 5% MeOH in ethyl acetate. The silica was removed by filtration, washed with 5% MeOH in EtOAc (2×5 mL), acetone (2×8 mL). The title compound was obtained as an off-white solid (0.065 g, 80%). 1H-NMR (500 MHz, DMSO-d6) 2.31 (s, 3H), 3.89 (s, 3H), 5.58 (s, 2H), 5.89 (s, 1H), 6.75 (s, 1H), 7.78 (s, 1H), 7.83 (s, 1H), 8.12 (s, 1H), 8.57 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[C:5]1[NH:9][C:8](=[O:10])[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]1=[O:14])[CH3:3].[H-].[Na+].[H][H].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>CN(C)C=O>[CH3:3][N:2]([CH:4]=[C:5]1[N:9]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[C:8](=[O:10])[N:7]([CH:11]([CH3:12])[CH3:13])[C:6]1=[O:14])[CH3:1]
Reactant: [H][H]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)N1C(=O)NC(=CN(C)C)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)N(C(C)C)C(=O)C2=CN(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 100 mg of 5-dimethylaminomethylene-3-isopropylimidazolidine-2,4-dione in 2 ml of dimethylformamide was added 425 mg of sodium hydride (as a 60% dispersion in mineral oil). The mixture was stirred until evolution of hydrogen gas had ceased. The solution was then treated with 1.5 ml of 4-methoxybenzyl chloride and stirring continued overnight at rt. The mixture was partitioned between ethyl acetate and water and the organic layer dried, filtered and concentrated. The residue was purified by flash chromatography eluting with 1:1 ethyl acetate: haxane to give 85 mg of a colourless oil. 1H NMR (400 MHz, deuteriochloroform): δ=1.40 (6H, d, J=7 Hz), 3.02 (6H, s), 3.72 (3H, s), 4.38 (1H, septet, J=7 Hz), 4.60 (2H, s), 5.96 (1H, s), 6.80 (2H, d, J=8 Hz), 7.05 (2H, d, J=8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH3:15])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:18]I>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:14][CH3:15])[C:10](=[O:13])[N:11]([CH3:18])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCn1c(-c2ccc(Cl)cc2)n[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1c(-c2ccc(Cl)cc2)nn(C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, room temperature solution of 5-(4-chlorophenyl)-2,4-dihydro-4-ethyl-3H-1,2,4-triazol-3-one (6.00 g, 2.68×10-2 mole) and 1 molar aqueous NaOH (30.0 ml, 3.00×10-2 mole) was added a solution of methyl iodide (2.5 ml, 4.0×10-2 mole) and ethanol (10 ml). After stirring overnight at room temperature, the reaction mixture was transferred to a separatory funnel where it was extracted three times with EtOAc. The EtOAc extracts were combined, washed with saturated aqueous NaCl, and dried over Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving an oil which slowly solidified. Chromatography and crystallization from cyclohexane gave small colorless needles: 3.4 g (53%), mp 73°-75°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:9]2)([O-:3])=[O:2].C(Cl)CCl.[Cl:21][C:22]1[CH:23]=[N+:24]([O-:47])[CH:25]=[C:26]([Cl:46])[C:27]=1[CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH:32]=1)O.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[N+:24]([O-:47])[CH:25]=[C:26]([Cl:46])[C:27]=1[CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH:32]=1)[O:15][C:14](=[O:16])[CH2:13][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH:9]=[CH:10]1
Reactant: O=C(O)Cn1ccc2cccc([N+](=O)[O-])c21
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Cn1ccc2cccc([N+](=O)[O-])c21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.2 %

Procedure:
A mixture of 2-(7-nitro-1H-indol-1-yl)acetic acid (0.15 g, 0.681 mmol), EDC (0.131 g, 0.681 mmol), DMAP (0.128 g, 1.048 mmol) and (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.220 g, 0.524 mmol) in dry DCM (15 ml) was stirred at room temperature for 16 hours. Aqueous 2N HCl was added, and the organic phase was separated and dried over sodium sulfate; the solvent was removed and the crude was triturated with MeOH. The precipitate was filtered, washed with MeOH and dried affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(7-nitro-1H-indol-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.066 g, 0.106 mmol, 20% yield). MS/ESI+ 622.1 [MH]+; [αD]=−112.6, c=0.22, MeOH; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.44 (s, 2H), 8.00 (dd, 1H), 7.82 (dd, 1H), 7.52 (d, 1H), 7.22 (t, 1H), 7.16 (d, 1H), 7.05 (d, 1H), 6.92 (dd, 1H), 7.06 (t, 1H), 6.76 (d, 1H), 5.95 (dd, 1H), 5.30 (d, 1H), 5.17 (d, 1H), 3.90 (d, 2H), 3.33-3.54 (m, 1H), 3.18 (dd, 1H), 0.99-1.39 (m, 1H), 0.48-0.72 (m, 2H), 0.36 (q, 2H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[OH:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][C:20]#N)[CH2:12]1.C(O)(C(F)(F)F)=[O:23].CC#N>C1COCC1>[OH:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][C:20]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:8])=[O:23])[CH2:12]1
Reactant: Cc1ccccc1I
Reactant: O=C(O)C(F)(F)F
Reactant: N#CCCCN1CCCC(CO)C1
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1ccccc1C(=O)CCCN1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 50 mL oven-dried flask was added Mg turnings (780 mg, 32 mmol), which were activated by the use of a heat-gun under vacuum, followed by addition of anhydrous THF (7 mL). Under inert atmosphere was added a suspension of 2-iodotoluene (5.3 g, 24 mmol) in THF (10 mL) and the reaction mixture was allowed to reflux for 4 hours. A suspension of compound 6 (1.50 g, 8 mmol) in THF (5 mL) was added via a syringe followed by addition of CuBr (23 mg, 0.16 mmol, 2 mol %) and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched by addition of H2SO4 (20 mL, 2 M) and stirred at rt for 2 hours followed by addition of NaOH (8 mL, 2 M). Addition of THF (15 mL) was followed by extraction with CH2Cl2 (3×20 mL), and the organic phases were dried (MgSO4) and evaporated to dryness to produce 0.41 g of crude 7. The crude product was subjected to preparative HPLC CC [eluent: Buffer A: 0.1% TFA; Buffer B: 80% CH3CN+0.1%TFA] to produce an analytical pure sample of compound 7. LC-MS [M+H]+ 275 (cald. 275.2).
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:8][CH:9]=1)([F:4])[CH3:3].[I:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][C:27]([CH3:29])=[N:26][C:25]=2[C:30](O)=[O:31])=[CH:20][C:19]=1[CH3:33]>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:30]([C:25]3[N:26]=[C:27]([CH3:29])[O:28][C:24]=3[C:21]3[CH:22]=[CH:23][C:18]([I:17])=[C:19]([CH3:33])[CH:20]=3)=[O:31])[CH:13]=[N:12]2)[O:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1coc(Cn2ncc(N)n2)n1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(I)c(C)c2)o1
Product: Cc1nc(C(=O)Nc2cnn(Cc3nc(C(C)(F)F)co3)n2)c(-c2ccc(I)c(C)c2)o1

Procedure:
Following general procedure A, starting from 2-((4-(1,1-difluoroethyl)oxazol-2-yl)methyl)-2H-1,2,3-triazol-4-amine and 5-(4-iodo-3-methylphenyl)-2-methyloxazole-4-carboxylic acid. LC-MS-conditions 07: tR=1.03 min; [M+H]+=555.03.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]=1[OH:14])[CH2:2][CH3:3].[C:15](Cl)(=[O:17])[CH3:16]>>[CH2:1]([C:4]1[CH:9]=[C:8]([C:15](=[O:17])[CH3:16])[CH:7]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]=1[OH:14])[CH2:2][CH3:3]
Reactant: CCCc1cccc(C(C)(C)C)c1O
Reactant: CC(=O)Cl
Product: CCCc1cc(C(C)=O)cc(C(C)(C)C)c1O

Procedure:
Intermediate 2-n-propyl-6-t-butylphenol is reacted with acetyl chloride, using the conditions outlined in Example 3 above, to give 2n-propyl-4-acetyl-6-t-butylphenol. This compound is then converted to 2-n-propyl-4-(6'-heptynoyl)-6-t-butylphenol according to the following procedure:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([NH2:12])[C:8]=2[CH:13]=1)([O-:3])=[O:2].[N:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:15]=[O:16]>C1COCC1>[CH2:17]([NH:14][C:15]([NH:12][C:9]1[C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[S:11][N:10]=1)=[O:16])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Nc1nsc2ccc([N+](=O)[O-])cc12
Reactant: CCCCCCN=C=O
Solvent: C1CCOC1
Product: CCCCCCNC(=O)Nc1nsc2ccc([N+](=O)[O-])cc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
100 mg (0.513 mmol) of 5-nitrobenzo[d]isothiazol-3-ylamine were suspended in 5 ml of THF. Addition of 78.1 mg (0.61 mmol) of 1-isocyanatohexane was followed by stirring at RT for 2 h and at 70° C. for 2 h. Then a further 0.3 mmol of 1-isocyanatohexane was added, and stirring was continued at 70° C. for 6 h. The reaction mixture was concentrated, and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 18 mg (11%), M+H+: 323.15.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:3]1.[CH2:25]([O:35][C:36]1[CH:48]=[CH:47][C:39]([C:40](C2NC=CN=2)=[O:41])=[CH:38][CH:37]=1)/[CH:26]=[C:27](/[CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])\[CH3:28]>O>[CH2:25]([O:35][C:36]1[CH:37]=[CH:38][C:39]([C:40]([NH:1][CH:2]2[CH2:6][N:5]([CH2:7][C:8]3[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=3)[N:4]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH2:3]2)=[O:41])=[CH:47][CH:48]=1)/[CH:26]=[C:27](/[CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])\[CH3:28]
Reactant: COc1ccc(CN2CC(N)CN2Cc2ccc(OC)cc2)cc1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)c2ncc[nH]2)cc1
Solvent: O
Product: COc1ccc(CN2CC(NC(=O)c3ccc(OC/C=C(\C)CCC=C(C)C)cc3)CN2Cc2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
To a solution of 4-amino-1,2-bis(4-methoxyphenylmethyl)pyrazolidine (0.80 g) in tetrahydrofuran anhydride (20 ml) was added 4-geranyloxybenzoylimidazole (0.79 g). The mixture was stirred at room temperature for one night. The reaction solution, with water added thereto, was extracted with ethyl acetate. The extract was concentrated under a vacuum and the residue was purified by silica gel column chromatography (chloroform) and then recrystallized from ethyl acetate, thereby yielding 0.65 g (45%) of the aimed compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=3)=[O:19])=[CH:12][C:11]=12.[N+]([C:32]1[CH:40]=CC(C(O)=O)=C[CH:33]=1)([O-])=O>>[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:19])[C:20]3[CH:21]=[CH:22][C:23]([C:24]([N:5]4[CH2:40][CH2:32][CH2:33][CH:4]4[CH2:3][CH:2]([CH3:6])[CH3:1])=[O:26])=[CH:27][CH:28]=3)=[CH:12][C:11]=12
Reactant: O=C(O)c1ccc(C(=O)NCc2ccn3ccnc3c2)cc1
Reactant: CC(C)CCN
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: CC(C)CC1CCCN1C(=O)c1ccc(C(=O)NCc2ccn3ccnc3c2)cc1

Procedure:
The title compound was prepared as described in Example 1A, substituting 2-isobutylpyrrolidine for 3-methylbutan-1-amine and 4-(imidazo[1,2-a]pyridin-7-ylmethylcarbamoyl)benzoic acid for 4-nitrobenzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.17 (t, J=5.9 Hz, 1H), 8.49 (dd, J=6.9, 0.9 Hz, 1H), 7.95 (d, J=8.2 Hz, 2H), 7.89 (d, J=1.2 Hz, 1H), 7.56 (d, J=8.0 Hz, 2H), 7.52 (d, J=1.2 Hz, 1H), 7.40 (s, 1H), 6.86 (dd, J=7.0, 1.7 Hz, 1H), 4.52 (d, J=5.9 Hz, 2H), 4.25-4.14 (m, 1H), 3.58-3.51 (m, 1H), 3.51-3.38 (m, 1H), 2.09-1.53 (m, 5H), 1.33-1.17 (m, 2H), 0.94 (d, J=6.4 Hz, 6H); MS (ESI(+)) m/e 405 (M+H)+.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH:16]([N:20]2[CH:24]=[C:23]([C:25]3[C:26]4[CH:33]=[CH:32][N:31](COCC[Si](C)(C)C)[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:22]=[N:21]2)[CH2:17][C:18]#[N:19])[CH2:11][CH2:10]1.C(N(CC)CC)C.O>C(#N)C>[CH:1]1([S:4]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH:16]([N:20]3[CH:24]=[C:23]([C:25]4[C:26]5[CH:33]=[CH:32][NH:31][C:27]=5[N:28]=[CH:29][N:30]=4)[CH:22]=[N:21]3)[CH2:17][C:18]#[N:19])[CH2:11][CH2:10]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CC4CCNCC4)c3)ncnc21
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#CCC(CC1CCN(S(=O)(=O)C2CC2)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopropanesulfonyl chloride (77.0 mg, 0.548 mmol), 4-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (250 mg, 0.498 mmol), and triethylamine (208 μL, 0.00149 mol) were dissolved in acetonitrile (1.0 mL). The mixture was stirred at RT for 1 h, water was added to make a homogeneous solution and purified with preparative LCMS (pH=10) to provide the desired product. The product was treated with DCM (0.5 mL) and trifluoroacetic acid (0.5 mL, 0.006 mol) for 30 min. The reaction mixture was evaporated under reduced pressure. To the resulting residue was added methanol (5 mL) and ethylenediamine (0.5 mL, 0.007 mol) and the resultant mixture was stirred at RT for 30 min. The reaction mixture was concentrated under reduced pressure. The residue was purified on RP-HPLC (XBridge C-18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH, at flow rate 60 mL/min) to give the desired product (185 mg, 84.5%). LCMS calculated for C21H26N7O2S(M+H)+: m/z=440.2; Found: 440.0. 1H NMR (300 MHz, CD3OD): δ 8.98 (1H, s), 8.88 (1H, s), 8.53 (1H, s), 7.85 (1H, d, J=3.6 Hz), 7.28 (1H, d, J=3.6 Hz), 4.98 (1H, m), 3.68 (2H, m), 3.15 (2H, m), 2.73 (2H, m), 2.37 (1H, m), 2.23 (1H, m), 1.98 (1H, m), 1.87 (1H, m), 1.62 (1H, m), 1.29 (3H, m), 0.97 (4H, m) ppm.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])=[N:25][CH:26]=[N:27]2)=[CH:22][C:21]=1[O:39][CH3:40])([OH:15])=O.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>CN(C)C1C=CN=CC=1.CN(C=O)C>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:24]2[C:23]3[C:28](=[CH:29][C:20]([O:19][CH2:18][CH2:17][CH2:16][C:13]([N:45]4[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]4)=[O:15])=[C:21]([O:39][CH3:40])[CH:22]=3)[N:27]=[CH:26][N:25]=2)=[C:32]([F:38])[CH:33]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCC(=O)O
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (145 mg, 0.75 mmol) was added to a mixture of 7-(3-carboxypropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (250 mg, 0.62 mmol), (prepared as described for the starting material in Example 42), 1-methylpiperazine (0.21 ml, 2.32 mmol) and 4-dimethylaminopyridine (300 mg, 2.46 mol) in DMF (7.5 ml). The reaction mixture was stirred at ambient temperature for 24 hours and the volatiles were removed by evaporation. Water was added to the residue and the aqueous mixture was extracted with methylene chloride (3×30 ml). The combined organic extracts were washed with brine and the solvent was removed by evaporation. The residue was triturated with ether and the precipitate was collected by filtration. The solid was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (100/8/1). The purified product was triturated with ether collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(4-methylpiperazin-1-ylcarbonyl)propoxy)quinazoline (133 mg, 44%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:17][OH:18])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)=[N:4][O:5][N:6]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([O:18][N:17]=[C:7]([C:3]1[C:2]([NH2:1])=[N:6][O:5][N:4]=1)[NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=1)(=[O:21])[CH3:20]
Reactant: Nc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)ON=C(Nc1ccc(F)c(Cl)c1)c1nonc1N
Yield: 54 %

Procedure:
A solution of 4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (0.1 g, 0.37 mmol) in acetic anhydride was stirred for 2 h. The reaction mixture was concentrated and purified by preparative LCMS to give the desired product (625 mg, 54%). LCMS for C11H10ClFN5O3 (M+H)+: m/z=314.1.
Reaction SMILES: [CH2:1]([N:8]1[CH:14]([CH3:15])[CH2:13][CH2:12][CH2:11][CH:10]([CH2:16][OH:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][C:20]=1[CH3:26].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl>[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:17][CH2:16][CH:10]2[CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:14]([CH3:15])[CH2:13][CH2:12][CH2:11]2)=[CH:21][C:20]=1[CH3:26]
Reactant: Cc1cc(O)ccc1F
Reactant: CC1CCCC(CO)CN1Cc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(OCC2CCCC(C)N(Cc3ccccc3)C2)ccc1F
Temperature: 23 °C
Reaction time: 16 h

Procedure:
A mixture of (1-benzyl-7-methylazepan-3-yl)methanol (2-5, 500 mg, 2.1 mmol, 1.0 equiv), 4-fluoro-3-methylphenol (300 mg, 2.4 mmol, 1.1 equiv), and PS-triphenyl phosphine resin (1.2 g, 2.4 mmol, 1.1 equiv) in dichloromethane (25 mL) was treated with DIAD (0.46 mL, 480 mg, 2.4 mmol, 1.1 equiv) and the resulting suspension was stirred for 16 hours at 23° C. The mixture was filtered and filtrate was concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes gradient) to yield 6-[(4-fluoro-3-methylphenoxy)methyl]-1-benzyl-2-methylazepane (2-6) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 5H), 6.86 (m, 1H), 6.55 (m, 2H), 3.72-1.75 (m, 20H). LRMS m/z (M+H) 342.3 found, 242.2 required.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[CH:19][N:18]([CH2:21][C:22](O)=[O:23])[N:17]=3)=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:25]1[CH:30]=[C:29]([CH2:31][NH:32][CH2:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:28]=[CH:27][CH:26]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[N:28]1[CH:27]=[CH:26][CH:25]=[CH:30][C:29]=1[CH2:31][N:32]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][N:39]=1)[C:22](=[O:23])[CH2:21][N:18]1[CH:19]=[CH:20][C:16]([C:13]2[CH:12]=[CH:11][C:10]([C:2]3[N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][N:4]4[CH:3]=3)=[CH:15][CH:14]=2)=[N:17]1
Reactant: O=C(O)Cn1ccc(-c2ccc(-c3cn4ccccc4n3)cc2)n1
Reactant: c1ccc(CNCc2ccccn2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1ccc(-c2ccc(-c3cn4ccccc4n3)cc2)n1)N(Cc1ccccn1)Cc1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
2-[3-(4-Imidazo[1,2-a]pyridin-2-ylphenyl)-1H-1-pyrazolyl]acetic acid (51 mg), 2,2′-dipicolylamine (32 mg), and 1-hydroxybenzotriazole (27 mg) were dissolved in N,N-dimethylformamide (1 mL), and triethylamine (56 μL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (38 mg) were added to the solution, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with chloroform and then drying over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to flash column chromatography. Fractions eluted by dichloromethane-methanol (20:1) were concentrated under reduced pressure, and the solid was recovered through filtration by use of diethyl ether, to thereby yield the title compound (58 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C[N:14](C=O)C.[Br:18][CH2:19][C:20](Br)=[O:21]>O1CCOCC1>[Br:18][CH2:19][C:20]([NH:10][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])([NH2:14])[CH2:12][CH:11]=1)=[O:21]
Reactant: CCCCOc1ccc(N)cc1
Reactant: CN(C)C=O
Reactant: O=C(Br)CBr
Solvent: C1COCCO1
Product: CCCCOC1(N)C=CC(NC(=O)CBr)=CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A solution of 4-butoxyaniline (3.0 g, 18 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (3.68 g, 1.60 mL, 18 mmol) was added dropwise, keeping the internal temperature between 0° and 5° C. over a 1/2 h period. After the addition of the bromoacetyl bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water, causing a solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 3.38 g (65%) of the title compound as a pale purple solid, mp 131°-134° C.: 1H NMR (DMSO-d6) δ10.23 (s, 1H), 7.45 (d, J=8.8, 2H), 6.88 (d, J=9.2, 2H), 3.99 (s, 2H), 3.92 (t, J=6.4, 2H), 1.68-1.65 (m, 2H), 1.42-1.40 (m, 2H), 0.92 (t, J=7.2, 3H); 13C NMR (DMSO-d6) δ164.18, 155.01, 131.57, 120.70, 114.50, 67.22, 30.73, 30.38, 18.70, 13.66; MS (EI, m/z) 287 (M+).