Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: Cc1cccc(CC(=O)O)c1
Reactant: CC(C)COC(=O)[C@H](C)N
Product: Cc1cccc(CC(=O)N[C@@H](C)C(=O)OCC(C)C)c1

Procedure:
Following General Procedure I above, and using 3-methylphenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tl c on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows:
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][CH3:19].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].[H-].[Na+]>CN(C=O)C>[CH3:31][O:30][C:28](=[O:29])[CH2:27][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH2:18][CH3:19])[N:8]2[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCc1cc2c(O)cccc2n1Cc1ccccc1-c1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc2c(OCC(=O)OC)cccc2n1Cc1ccccc1-c1ccccc1
Yield: 58.6 %

Procedure:
1-([1,1'-Biphenyl]-2-ylmethyl)-2-ethyl-4-hydroxy-1H-indole (911 mg, 2.8 mmol) was alkylated by treating with 0.26 mL (2.8 mmol) of methyl bromoacetate and 111 mg (2.8 mmol) of 60% NaH/mineral oil in DMF as described in Example 1, Part E. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 655 mg (59% yield) of [[1-([1,1'-biphenyl]-2-ylmethyl)-2-ethyl-1H-indol-4-yl]oxy]acetic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][S:7][C:6]=2[CH:10]=1.[Li]CCCC.[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][BH:19][O:18]1.[NH4+].[Cl-]>O1CCCC1>[O:9]1[C:5]2[CH:4]=[CH:3][C:2]([B:19]3[O:20][C:21]([CH3:23])([CH3:22])[C:17]([CH3:24])([CH3:16])[O:18]3)=[CH:10][C:6]=2[S:7][CH2:8]1
Reactant: Brc1ccc2c(c1)SCO2
Reactant: CC1(C)OBOC1(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc3c(c2)SCO3)OC1(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
5-Bromobenzo[d][1,3]oxathiole (1.0 g, 4.6 mmol, prepared as described in Cabiddu, Salvatore; Cerioni, Giovanni; Cocco, Maria Teresa; Maccioni, Antonio; Plumitallo, Antonio, Journal of Heterocyclic Chemistry 1982, 19, 135-139) was dissolved in dry tetrahydrofuran (12 mL), cooled to −70° C., treated in portions with n-BuLi (2.5 M; 1.9 mL, 4.8 mmol) and stirred at −70° C. for 30 min. 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (900 mg, 4.8 mmol) was added and stirring was continued for 1.5 h during which the temperature rose to −30° C. The mixture was treated with saturated NH4Cl (5 mL) and extracted with ethyl acetate (2×25 mL). The combined extracts were washed with saturated NaCl (10 mL), dried (Na2SO4) and evaporated to give the title compound which was used without further purification (1.2 g, 99%): 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=1.1 Hz, 1H), 7.48 (dd, J=8.0, 1.3 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H), 5.69 (s, 2H), 1.32 (s, 12H); EIMS m/z 264.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:8]([Cl:13])=[N:9][CH:10]=[CH:11][CH:12]=1)=O.N(O)=O.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH2:32])=[NH:31])[CH:26]=[CH:27][CH:28]=1)=[O:22])[CH3:19].[OH-].[Li+]>CC(O)CC>[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[C:25]([NH:29][C:30]2[N:32]=[C:5]([C:7]3[C:8]([Cl:13])=[N:9][CH:10]=[CH:11][CH:12]=3)[CH:4]=[CH:3][N:31]=2)[CH:26]=[CH:27][CH:28]=1)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1cccc(NC(=N)N)c1
Reactant: CN(C)C=CC(=O)c1cccnc1Cl
Agent: O=NO
Agent: [Li+]
Agent: [OH-]
Solvent: CCC(C)O
Product: CCOC(=O)c1cccc(Nc2nccc(-c3cccnc3Cl)n2)c1
Temperature: 25 °C
Yield: 84 %

Procedure:
A mixture of 3-dimethylamino-1-(2-chloro-3-pyridyl)-2-propen-1-one (810 mg, 3.86 mmol), 3-ethoxycarbonyl-phenyl-guanidine nitrite (1.07 g, 3.96 mmol), lithium hydroxide (105 mg, 4.38 mmol) in 2-butanol (20 mL) is heated to reflux overnight. The reaction mixture is cooled to room temperature, the solvent is removed and water (40 mL) is added. The solid is collected by filtration and washed with water, isopropanol and dried to give N-[3-ethoxycarbonyl-phenyl]-4-(2-chloro-3-pyridyl)-2-pyrimidineamine (1.15 g); ESI-MS (m/z): 355.1 (M++H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][C:37]([F:41])([F:40])[CH2:36][CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:41][C:37]1([F:40])[CH2:38][CH2:39][N:34]([CH:32]2[CH2:33][N:30]([CH2:18][C:13]3[N:14]([CH3:17])[C:15]4[C:11]([N:12]=3)=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=[C:8]([N:7]3[C:6]5[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=5[N:4]=[C:3]3[CH2:1][CH3:2])[N:16]=4)[CH2:31]2)[CH2:35][CH2:36]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: FC1(F)CCN(C2CNC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCC(F)(F)CC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.6 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.1 g, 0.26 mmol), 1-azetidin-3-yl-4,4-difluoropiperidine (0.087 g, 0.38 mmol) and 4 Å molecular sieves (0.6 g) in DCE (6 mL)was stirred for 18 h at room temperature. Sodium triacetoxyborohydride (0.109 g, 0.51 mmol) was added and the reaction mixture was stirred for 5 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 3:97) to give 492 as a yellow solid (0.097 g, 69%). LCMS (Method I): RT=2.82 min, [M+H]+ 552.3. 1H NMR (400 MHz, DMSO-d6): δ 8.03-7.99 (m, 1 H); 7.65-7.61 (m, 1 H); 7.28-7.21 (m, 2 H); 4.30-4.23 (m, 4 H); 3.87 (s, 2 H); 3.80-3.75 (m, 7 H); 3.46-3.43 (m, 2 H); 3.25 (q, J=7.4 Hz, 2 H); 3.01-2.98 (m, 3 H); 2.37-2.33 (m, 4 H); 2.00-1.87 (m, 4 H); 1.33 (t, J=7.4 Hz, 3 H)
Reaction SMILES: N12CCCCC1C=NCCC2.[CH3:12][C:13]1([CH3:26])[O:17][C:16]2[C:18]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:19][CH:20]=[CH:21][C:15]=2[CH2:14]1.[CH3:27][N:28]=[C:29]=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:12][C:13]1([CH3:26])[O:17][C:16]2[C:18]([S:22]([NH:23][C:29]([NH:28][CH3:27])=[O:30])(=[O:25])=[O:24])=[CH:19][CH:20]=[CH:21][C:15]=2[CH2:14]1
Reactant: CC1(C)Cc2cccc(S(N)(=O)=O)c2O1
Reactant: CN=C=O
Agent: C1=NCCCN2CCCCC12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)NS(=O)(=O)c1cccc2c1OC(C)(C)C2
Reaction time: 2 h
Yield: 89.5 %

Procedure:
6.54 ml of 1,5-diazabicyclo(5,4,0)undec-5-ene are added to 9.9 g (0.0436 mole) of 2,3-dihydro-2,2-dimethyl-7-sulfamoylbenzo[b]furan (compound 1.4) in dioxan. While cooling with ice, 2.65 ml of methyl isocyanate are added dropwise. The reaction mixture is stirred for 2 hours at 20° to 25° C., then diluted with water, neutralised with 10 ml of 5% sodium carbonate solution, and filtered. Acidification of the filtrate yields 11.1 g (89.5% of theory) of N-(2,3-dihydro-2,2-dimethylbenzo[b]furan-7-ylsulfonyl)-N'-methylurea.
Reaction SMILES: [CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:19][CH2:20][C:21](=O)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1.[Na].O>ClCCCl.Cl[Ti](Cl)(Cl)Cl>[CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:19][CH2:20][CH:21]([NH:33][C:34]3[CH:35]=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:42][CH:43]=3)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: COC(=O)CCCCC(=O)CCc1ccccc1OCc1ccc(C2CCCCC2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na]
Solvent: O
Solvent: ClCCCl
Product: COC(=O)CCCCC(CCc1ccccc1OCc1ccc(C2CCCCC2)cc1)Nc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
At 0° C., 217 mg (1.15 mmol) of TiCl4 (1 M in CH2Cl2) were added to a solution of 500 mg (1.15 mmol) of methyl 8-{2-[(4-cyclohexylbenzyl)oxy]phenyl}-6-oxo-octanoate XIV and 190 mg (1.26 mmol) of methyl 4-aminobenzoate in 12.5 ml of 1,2-dichloroethane. The mixture was stirred at room temperature for 20 min, and 383 mg (1.72 mmol) of sodium triacetoxyborhydride were then added. The progress of the reaction was monitored by thin-layer chromatography, and after the reaction had ended, water was added. The mixture was extracted with ethyl acetate and the combined organic phases were dried over Na2SO4. The product was purified chromatographically (silica gel, gradient cyclohexane/ethyl acetate 10:1 to 0:100).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:26]([O-:28])=[O:27])=[C:6]([CH:25]=1)[C:7]([NH:9][C:10]1[NH:11][N:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:14]=1)=[O:8].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C)C=O.C(OCC)(=O)C>[N+:26]([C:5]1[CH:4]=[CH:3][C:2]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:6]=1[C:7]([NH:9][C:10]1[NH:11][N:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:14]=1)=[O:8])([O-:28])=[O:27]
Reactant: C1CCNCC1
Reactant: O=C(Nc1nc(-c2cccc(C(F)(F)F)c2)n[nH]1)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1nc(-c2cccc(C(F)(F)F)c2)n[nH]1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 5-chloro-2-nitro-N-(5-(3-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3-yl)benzamide (120 mg, 0.29 mmol, 1.00 equiv) in N,N-dimethylformamide (1 mL) was added piperidine (1 mL) and the resulting solution was stirred for 2 h at 100° C. in an oil bath. The mixture was diluted with 50 mL of ethyl acetate, washed with 2×20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to afford 130 mg (97%) of product as yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:34])[CH2:15][CH:16]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:4])([CH3:3])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:35](=[O:37])[CH3:36])=[CH:7][C:6]=1[NH:13][C:14](=[O:34])[CH2:15][CH:16]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(CC(=O)Nc1cc(CN)ccc1C(C)(C)C)c1cc(OC)c(OC)c(OC)c1
Product: CCCCCC(CC(=O)Nc1cc(CNC(C)=O)ccc1C(C)(C)C)c1cc(OC)c(OC)c(OC)c1

Procedure:
Following a similar procedure to that described in Example 144, but using N-(2-t-butyl-5-aminomethylphenyl)-3-(3,4,5-trimethoxyphenyl)octanamide (prepared as described in Preparation 72D) and acetic anhydride, the title compound was obtained as a colorless foam-like substance.
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:13][CH:12]=1>C1COCC1>[C:6]([O:5][C:3]([NH:1][N:2]=[C:17]([C:14]1[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=1)[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)CCCC(=O)c1ccc(F)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN=C(CCCC(=O)O)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 98.7 %

Procedure:
Step AAG (1): A mixture of tert-butyl hydrazinecarboxylate (1.45 g, 11.0 mmol) and 5-(4-fluorophenyl)-5-oxopentanoic acid (2.1 g, 10 mmol) in THF (20 mL) was stirred at 50° C. for 16 h. The reaction mixture was concentrated in vacuo to afford 5-(2-(tert-butoxycarbonyl)hydrazono)-5-(4-fluorophenyl)pentanoic acid (3.2 g, 9.87 mmol, 99% yield). LC-MS (M+H)+ 325.24. The crude product was used for subsequent chemistry without purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:28]4[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccncc4)cc32)N=C1N
Temperature: 120 °C
Yield: 12.6 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and pyridin-4-ylboronic acid (13 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure 2′-amino-1′-methyl-2-phenyl-6-(pyridin-4-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (2.51 mg, 10%). 1H-NMR (MeOD): 2.50 (t, 1H), 2.64 (dd, 1H), 3.37 (s, 3H), 5.91 (d, 1H), 7.26 (d, 1H), 7.45 (m, 5H), 7.82 (d, 1H), 7.94 (t, 1H), 8.16 (s, 2H), 8.71 (s, 2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C(N(CC)C(C)C)(C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>ClCCl>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1I
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To 3-iodo-4-methylaniline (500.0 mg, 2.145 mmol) was added dichloromethane (DCM) (10 mL) followed by N,N-diisopropylethylamine (DIPEA)(520 μL, 3.0 mmol) and 3-(trifluoromethyl)-benzoyl chloride (0.36 mL, 2.4 mmol). The reaction was stirred at 25° C. for 16 hours and was transferred to a separatory funnel and partitioned between water and dichloromethane (DCM). The organic phase was sequentially washed with 0.1N HCl, saturated aqueous NaHCO3, water, then saturated aqueous NaCl. The washed organic phase was then dried over MgSO4 and filtered and concentrated to leave the crude product. The crude product was triturated with hexanes to leave the product as an off-white solid, (797 mg, 92%). 1H NMR (400 MHz, CDCl3): δ 8.10 (m, 2H), 8.04 (d, 1H), 7.84 (bs, 1H), 7.81 (d, 1H), 7.63 (m, 1H), 7.58 (dd, 1H), 7.22 (d, 1H), 2.42 (s, 3H). MS (EI) m/z=274 (M+H).
Reaction SMILES: [Br:1]Br.[CH3:3][NH:4][N:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1>C(O)(=O)C.C(#N)C>[CH3:3][NH:4][N:5]=[C:6]([Br:1])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: CNN=Cc1ccc(Cl)cc1
Reactant: BrBr
Solvent: CC#N
Solvent: CC(=O)O
Product: CNN=C(Br)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 61 %

Procedure:
9.5 g (0.06 mol) of bromine were added dropwise at (-5) to (-7)° C. to a solution of 10 g (0.06 mol) of 4-chlorobenzaldehyde (N-methyl)hydrazone in 50 ml of acetic acid and 20 ml of acetonitrile. After the mixture had been stirred for 3 hours, the product which had precipitated was separated off and washed with a small amount of pentane. Yield: 61%.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:22][N:23]([CH3:28])[S:24](Cl)(=[O:26])=[O:25].Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:22][N:23]([CH3:28])[S:24](=[O:26])(=[O:25])[O:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9](=[O:11])(=[O:10])[NH2:12])[S:8][C:4]=2[CH:3]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)Oc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 0 °C

Procedure:
To a stirred solution of 6-hydroxy-2-benzothiazolesulfonamide (2.3 g, 0.01 mole), triethylamine (1.4 ml) and 4-dimethylaminopyridine (200 mg) in dimethylformamide (20 ml) was added dimethylsulfamoyl chloride (1.1 ml). The reaction mixture was heated on a steam bath for 18 hours, poured into ice water and excess hydrochloric acid, extracted into ethyl acetate, washed with water and dried over magnesium sulfate. The ethyl acetate was evaporated and the (2-sulfamoyl-6-benzothiazolyl) N,N-dimethylsulfamate purified by chromatography on a 2 mm preparative silica gel TLC plate developed with chloroform/methanol 9:1 (v/v) m.p.=162°-164° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:9]([C:11]1([CH3:15])[CH2:14][CH2:13][NH:12]1)=[O:10].[CH3:25][C:26]1[CH:27]=[C:28]([N:33]=[C:34]=[O:35])[CH:29]=[C:30]([CH3:32])[CH:31]=1>C1COCC1>[CH3:2][O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)[C:9]([C:11]1([CH3:15])[CH2:14][CH2:13][N:12]1[C:34](=[O:35])[NH:33][C:28]1[CH:29]=[C:30]([CH3:32])[CH:31]=[C:26]([CH3:25])[CH:27]=1)=[O:10]
Reactant: COC(=O)CCCN(Cc1ccc(Cl)cc1)C(=O)C1(C)CCN1
Reactant: Cc1cc(C)cc(N=C=O)c1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)CCCN(Cc1ccc(Cl)cc1)C(=O)C1(C)CCN1C(=O)Nc1cc(C)cc(C)c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of 4-[(4-chloro-benzyl)-(2-methyl-azetidine-2-carbonyl)-amino]-butyric acid methyl ester hydrochloride, Intermediate 23 (1 eq.) and TEA (5 eq.) in THF under nitrogen was added 3,5-dimethyl-phenyl-isocyanate (1.5 eq.). The reaction was stirred for 15 h at 20° C. The crude was partitioned between a saturated aqueous solution of NaHCO3 and EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 75/25 to 40/60) to afford 4-{(4-chloro-benzyl)-[1-(3,5-dimethyl-phenylcarbamoyl)-2-methyl-azetidine-2-carbonyl]-amino}-butyric acid methyl ester.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1)=O.[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21].B(O)(O)O.O>C1(C)C(C)=CC=CC=1>[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[N:21]=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccccc1Cl
Reactant: O=Cc1ccc(-c2nc3ccccn3n2)cc1
Agent: OB(O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: Clc1ccccc1N=Cc1ccc(-c2nc3ccccn3n2)cc1
Temperature: 60 °C

Procedure:
22.32 g of 2-(p-formylphenyl)-s-triazolo[1,5-a]pyridine (II), 14.03 g of o-chloroaniline and 1 g of boric acid in 350 ml of xylene are refluxed for 2 hours, the water formed being distilled off. The mixture is cooled to 60° C., 450 ml of methanol are added and the resulting mixture is further cooled to -10° C. The product which has precipitated is filtered off with suction, washed with 100 ml of cold methanol and dried. This gives 26.3 g (79.1% of theory) of compound (101) in the form of a pale beige powder with a melting point of 135° to 136° C. After recrystallising twice from methanol, 22.2 g (66.7% of theory) of small, pale yellow, glossy needles with a melting point of 135° to 136° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([O:22]CC)=[O:21])[C:11]3[CH:16]=[N:15][N:14]([CH:17]([CH3:19])[CH3:18])[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][NH:36][CH:37]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:19][CH:17]([N:14]1[C:12]2[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]4[CH:34]=[N:35][NH:36][CH:37]=4)=[CH:3][CH:4]=3)[CH:9]=[C:10]([C:20]([OH:22])=[O:21])[C:11]=2[CH:16]=[N:15]1)[CH3:18]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCOC(=O)c1cc(-c2ccc(Br)cc2)nc2c1cnn2C(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)n1ncc2c(C(=O)O)cc(-c3ccc(-c4cn[nH]c4)cc3)nc21
Yield: 34.9 %

Procedure:
To a 5-mL microwave vial were added ethyl 6-(4-bromophenyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (80 mg, 0.206 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (56.0 mg, 0.288 mmol), 1,4-dioxane (2 mL) and sodium carbonate (0.206 mL, 0.412 mmol), and the mixture was degassed with nitrogen for 10 min. Next added PdP(Ph3)4 (19.05 mg, 0.016 mmol) and the vial was sealed. The reaction mixture was irradiated (microwave) at 120° C. overnight. The reaction mixture was filtered and concentrated in vacuo. The residue was purified using reverse-phase HPLC to give 25 mg (35%) of product. LCMS E-S (M+H)=348.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (d, J=6.8 Hz, 6 H), 5.38 (quin, J=6.6 Hz, 1 H), 7.81 (d, J=8.3 Hz, 2 H), 8.14-8.30 (m, 4H), 8.36 (s, 1 H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[CH2:17]([C:19]1[NH:20][C:21]2[C:22]([N:29]=1)=[N:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])[CH3:18].O.[OH-].[Li+]>CN(C=O)C>[CH2:17]([C:19]1[N:29]([CH2:2][C:3]2[CH:16]=[CH:15][C:6]([C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:8])=[CH:5][CH:4]=2)[C:22]2=[N:23][C:24]([CH3:28])=[CH:25][C:26]([CH3:27])=[C:21]2[N:20]=1)[CH3:18]
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
Commercially available 4-bromomethylbenzophenone (5.00 g, 18.2 mmol) was dissolved in DMF (100 mL), and 2-ethyl-5,7-dimethylimidazo[4,5-b]pyridine (3.82 g, 21.8 mmol) and lithium hydroxide monohydrate (0.920 g, 21.9 mmol) was added to the solution, followed by stirring at room temperature for 3 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1), and recrystallized from ethanol to obtain Compound 1 (5.33 g, yield 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH2:13][C:12]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[O:14]2)[O:11][N:10]=1.OS(O)(=O)=O.[CH2:28](O)[CH3:29]>CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]([O:14][CH2:28][CH3:29])=[O:22])[O:11][N:10]=1
Reactant: CCO
Reactant: O=C1OC2(CC(c3ccc(Cl)cc3Cl)=NO2)c2ccccc21
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: CCOC(=O)c1ccccc1-c1cc(-c2ccc(Cl)cc2Cl)no1
Temperature: 0 °C

Procedure:
A solution of 4 g. (0.011 mole) of 3'-(2,4-dichlorophenyl)-spiro[isobenzofuran-1(3H),5'(4'H)-isoxazol]-3-one, 2 ml. of concentrated H2SO4 and 200 ml. of ethanol was held at reflux for 19 hours, cooled, and poured into ice water. The resultant mixture was extracted twice with ether. The ethereal solution was washed twice with water, dried over CaSO4 and concentrated under vacuum to give an oil. The oil was dissolved in hot hexane to afford 4.2 g. of a crystalline solid (96.9%). Recrystallization of the solid from hexane gave 3.1 g. of pure product; m.p. 85°-86° C.