Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)CCNC.C([Li])CCC.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=1[O:22][CH3:23].[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:24][C:16]1[C:15]([O:22][CH3:23])=[C:14]([F:13])[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]
Reactant: COc1cc(C=O)ccc1F
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CNCCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(F)ccc(C=O)c1Cl
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
A solution of N,N,N′-trimethylethylenediamine (20.3 mL, 156 mmol) in 75 mL of THF was cooled to −50° C. and a 2.5M solution of n-butyllithium in hexanes (62.5 mL, 156 mmol) was added dropwise with stirring during 15 minutes, keeping the internal temperature below −35° C. The temperature was maintained at 40° C. for 30 minutes, and then the reaction mixture was cooled to −70° C. A solution of 4-fluoro-3-methoxybenzaldehyde (24.09 g, 156.3 mmol) in 75 mL of THF was added dropwise during 15 minutes, keeping the reaction temperature below −50° C. When the addition was complete, the reaction was allowed to warm to −40° C. and held there for 25 minutes. The reaction was then re-cooled to −70° C. and a 2.5M solution of n-butyllithium in hexanes (62.5 mL, 156 mmol) was added dropwise. When the addition was complete, the reaction was allowed to warm to −20° C. and kept at that temperature overnight (12 hours). The reaction mixture was then cooled to −30° C. and the cold solution was added via cannula during 30 minutes to a room temperature solution of hexachloroethane (111 g, 469 mmol) in 200 mL of THF. After stirring at room temperature for 4 hours, the reaction mixture was poured into 500 mL of ice cold 4N HCl. Most of the THF was removed by rotary evaporation under reduced pressure and the residual mixture was extracted twice with 1:1 ethyl ether/hexanes. The organic layers were combined and washed successively with 1N NaOH, 1N HCl, water, and brine. After drying over sodium sulfate, removal of the solvent under vacuum gave a yellow solid. Flash chromatography on silica gel eluting with hexanes/dichloroethane (2:1 to 1:1) gave 2-chloro-4-fluoro-3-methoxybenzaldehyde as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12].[C:13]1(B(O)O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-]>CN(C)C(=O)C.C(O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl>[C:21]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][NH:6][C:5]3=[O:12])[C:22]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=c1[nH]cnc2ccc(Br)cc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]cnc2ccc(-c3cccc4ccccc34)cc12
Yield: 60.4 %

Procedure:
To a solution of 6-bromo-3H-quinazolin-4-one (45.2 mg, 0.2 mmol) dissolved in 2 ml N,N-dimethylacetamide in a 20 ml vial, naphthalene-1-boronic acid (69.4 mg, 0.4 mmol) dissolved in 1 ml ethanol and potassium carbonate (30.5 mg, 0.22 mmol) dissolved in 1 ml water were added. Tripenylphosphine (5.27 mg, 0.02 mmol) and tris(dibenzylideneacetone)dipalladium (0) (3.6 mg, 4 umol) was added to the mixture which refluxed overnight. The crude product was poured into 50 ml saturated bicarbonate solution and methylene chloride was used to extract the product. Solvent in the organic phase was removed under vacuum. The resulted residue was purified by preparative HPLC. 32.9 mg product was obtained. Yield: 62%; 1H NMR (500 MHz, DMSO-d6): δ 7.52083–7.54615(m, 2H), 7.56877–7.58461(dd, J=6.88 Hz, 1H), 7.61224–7.64281(dd, J1=8.255 Hz, J2=8.285 Hz, 1H), 7.78775–7.804 (d, J=8.125 Hz, 1H), 7.82384–7.84054(d, J=8.35 Hz, 1H), 7.93472–7.95545(dd, J1=8.365 Hz, J2=2 Hz, 1H), 8.00847–8.02533(d, J=8.43 Hz, 1H), 8.03829–8.05347(d, J=7.59 Hz, 1H), 8.15915–8.16300(d, J=1.925 Hz, 1H), 8.19218 (s, 1H); ESI-MS: m/z 273 (M++1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:6]([CH:21]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2.[CH3:38][NH:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:6]([CH:21]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([N:39]([CH3:38])[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:34])=[CH:36][CH:37]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2
Reactant: CCCCCCC(Nc1ccc(C(=O)O)cc1)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCC(Nc1ccc(C(=O)N(C)CCC(=O)OCC)cc1)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.7 %

Procedure:
To a mixture of 4-[(1-{5-chloro-1-[3-(trifluoromethyl)phenyl]-1H-indol-2-yl}heptyl)amino]benzoic acid (250 mg) synthesized in Example A106(5), ethyl 3-(methylamino)propanoate (93.1 mg), 1-hydroxybenzotriazole monohydrate (109 mg), triethylamine (198 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (136 mg), and the mixture was stirred at room temperature for 3 days. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40% ethyl acetate/hexane) to give the title object compound (254 mg, 84%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:13])[CH:5]=[C:6]2[C:10]=1[NH:9]C(=O)[C:7]2=[O:12].[OH:14]O.Cl>[OH-].[Na+]>[NH2:9][C:10]1[C:2]([Cl:1])=[CH:3][C:4]([F:13])=[CH:5][C:6]=1[C:7]([OH:12])=[O:14]
Reactant: O=C1Nc2c(Cl)cc(F)cc2C1=O
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(Cl)cc(F)cc1C(=O)O
Reaction time: 1 h

Procedure:
A solution of 7-chloro-5-fluoro-1H-indole-2,3-dione (270 mg) in 1 M sodium hydroxide solution (5 mL) was treated with 30% hydrogen peroxide (5 mL) via dropwise addition. After one hour of stirring, the reaction was acidified with HCl to pH 1, and extracted three times with ethyl acetate. The combined organic layers were dried with sodium sulfate, and concentrated in vacuo to provide 200 mg of 2-amino-3-chloro-5-fluoro-benzoic acid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:38])[CH:20]([CH:21]=[C:22]([Cl:34])[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)[CH:19]1[C:35](Cl)=[O:36].N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[F:16][C:15]1[CH:14]=[CH:13][C:10]([CH2:11][O:12][C:35]([CH:19]2[CH:20]([CH:21]=[C:22]([Cl:34])[C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:31])[F:32])=[CH:25][CH:24]=3)[C:18]2([CH3:38])[CH3:17])=[O:36])=[CH:9][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Reactant: CC1(C)C(C=C(Cl)c2ccc(OC(F)(F)F)cc2)C1C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)C(C=C(Cl)c2ccc(OC(F)(F)F)cc2)C1C(=O)OCc1ccc(F)c(Oc2ccccc2)c1
Reaction time: 3 h
Yield: 81.3 %

Procedure:
4.4 g (0.02 mol) of 3-phenoxy-4-fluoro-benzyl alcohol and 7.1 g (0.02 mol) of 2,2-dimethyl-3-(2-chloro-2-(4-trifluoromethoxy-phenyl)-vinyl)-cyclopropanecarboxylic acid chloride were dissolved in 100 ml of anhydrous toluene, and 2.5 g of pyridine, dissolved in 50 ml of anhydrous toluene, were added dropwise at 20°-25° C., while stirring. Stirring was then continued at 25°-35° C. for 3 hours. The reaction mixture was poured into 150 ml of water, to which 10 ml of concentrated hydrochloric acid were added, and the organic phase was separated off and washed again with 100 ml of water. The toluene phase was then dried over sodium sulphate and the solvent was distilled off under a water-pump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 8.7 g (81.4% of theory) of 2,2-dimethyl-3-(2-chloro-2-(4 -trifluoromethoxy-phenyl)-vinyl)-cyclopropanecarboxylic acid 4-fluoro-3-phenoxy-benzyl ester were obtained as a yellow oil with the refractive index nD23 : 1.5443.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15]OS(C)(=O)=O)=[O:11])[CH2:5][CH2:4]1)[CH3:2].Cl.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.Cl.ClC1C=C(N2CCNCC2)C=CC=1>>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15][N:33]2[CH2:34][CH2:35][N:30]([C:24]3[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=3[CH3:22])[CH2:31][CH2:32]2)=[O:11])[CH2:5][CH2:4]1)[CH3:2]
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Reactant: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2COS(C)(=O)=O)CC1
Agent: Cl
Agent: Clc1cccc(N2CCNCC2)c1
Product: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CN2CCN(c3cc(C)ccc3C)CC2)CC1

Procedure:
Follow the procedure of Example 11e, and substitute methane sulfonic acid 2-(trans-4-ethyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester (Example 13d) for 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester and 4-(2,5-dimethylphenyl)-piperazine hydrochloride for 1-(3-chloro-phenyl)-piperazine hydrochloride therein, to obtain the title compound LC/MS, m/z=398 (M+H)+.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[F:11][C:12]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][C:13]=1[C:14]#[N:15]>>[C:14]([C:13]1[CH:16]=[C:17]([CH:18]=[CH:19][C:12]=1[F:11])[CH2:20][NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])#[N:15]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Nc1ccccc1C(=O)O
Product: N#Cc1cc(CNc2ccccc2C(=O)O)ccc1F

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from anthranilic acid and 2-fluoro-5-formylbenzonitrile (Aldrich). 13C-NMR (DMSO-d6) δ 172.1, 161.3, 149.5, 138.7, 134.6, 131.9, 130.2, 121.4, 116.6, 114.2, 114.0, 110.0, 99.8, 44.8.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-:26])=O)=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[Cl:28][C:29]1[C:30]([N:35]2[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]2)=[N:31][CH:32]=[CH:33][CH:34]=1>>[Cl:28][C:29]1[C:30]([N:35]2[CH2:40][CH2:39][CH:38]([NH:41][C:24]([C:21]3[O:22][C:23]4[C:15]([N:12]5[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=6)[CH2:14][CH2:13]5)=[CH:16][CH:17]=[CH:18][C:19]=4[CH:20]=3)=[O:26])[CH2:37][CH2:36]2)=[N:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Reactant: NC1CCN(c2ncccc2Cl)CC1
Agent: [Li+]
Product: O=C(NC1CCN(c2ncccc2Cl)CC1)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (80 mg, 0.21 mmol) and 1-(3-chloropyridin-2-yl)piperidin-4-amine (57 mg, 0.27 mmol). Yield: 50 mg (40%).
Reaction SMILES: Br[CH2:2][C:3]([CH2:5][O:6][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:4].C[Si]([C:30]#[N:31])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>CC#N>[C:8]1([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:6][CH2:5][C:3](=[CH2:4])[CH2:2][C:30]#[N:31])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=C(CBr)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC#N
Product: C=C(CC#N)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
To a solution of 11 (1.45 g; 3.69 mmol) and in dry CH3CN (37 mL) was added trimethylsilyl cyanide (0.49 mL; 3.69 mmol). Then 1 M tetrabutylammonium fluoride (TBAF) in THF solution (3.69 mL, 3.69 mmol) was added slowly at room temperature and the reaction was stirred for 20 min. Most solvents were evaporated and ethyl acetate (100 mL) and saturated aqueous NaHCO3 (30 mL) were added. The organic layer was washed by saturated aqueous NaCl and dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was purified by flash column chromatography over silica gel using acetate-hexane (1:10) as the eluent to afford 12 as white solid (1.01 g; 64% yield): 1H NMR (400 MHz, CDCl3) δ 7.39-7.45 (m, 6H, six of ArH), 7.21-7.34 (m, 9H, nine of ArH), 5.31 (s, 2H, C═CH2), 3.64 (s, 2H, Ph3COCH2), 3.11 (s, 2H, CH2CN); 13C NMR (100 MHz, CDCl3) δ 143.3, 135.5, 128.2, 127.7, 126.9, 116.8, 114.7, 87.0, 65.7, 21.9, (10).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24](C)[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][NH:40][CH:41]=2)O1>[Pd].C(=O)([O-])[O-].[Na+].[Na+]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:37]1[CH:38]=[N:39][NH:40][CH:41]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@H](Nc1ncnc(N)c1-c1cn[nH]c1)c1nn2cccc2c(=O)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 28.8 %

Procedure:
The title compound was prepared following the experimental procedure described in Example 3 from 100 mg (0.21 mmol) of (S)-2-(1-((6-amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one and 62 mg (0.32 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. The mixture was stirred at 80° C. for 18 hours and then an excess of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (62 mg), palladium catalyst (19 mg) and aqueous sodium carbonate solution (320 μl) were added and the reaction mixture was stirred at 80° C. for 24 hours more. The product was purified by flash chromatography (0% to 15%, dichloromethane-methanol) to obtain 25 mg (29% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]([C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:14][CH:13]2[C:35]([O:37]C(C)(C)C)=[O:36])(=[O:11])=[O:10])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]([C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=3)[CH2:14][CH:13]2[C:35]([OH:37])=[O:36])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3cccc(C(F)(F)F)c3)CC2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3cccc(C(F)(F)F)c3)CC2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
A mixture of 0.36 g (0.61 mmol) of 4-(4-methoxybenzenesulfonyl)-1-(3-trifluoromethylbenzoyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, tert-butyl ester and 3 ml of trifluoroacetic acid in 3 ml of CH2Cl2 was stirred at room temperature for 3 hours. The mixture was concentrated to dryness under vacuum and the residue extracted with CH2Cl2. The CH2Cl2 was washed with 1 N NaHCO3 and the aqueous layer (pH 8) was acidified with 2 N citric acid and extracted with ethyl acetate. The extract was dried (Na2SO4). The original CH2Cl2 extract was washed with 2 N citric acid, H2O, brine and dried with Na2SO4. The CH2Cl2 extract and the ethyl acetate extract were combined and the solvent removed under vacuum to give 0.31 g of solid, m.p. 105-110° C. Anal. for C25H21F3N2O6S: Calc'd: C, 56.2; H, 4.0; N, 5.2; Found: C, 55.1; H, 3.7; N, 5.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:7]([CH:8]=[CH:9][CH:10]=1)=[N:6][N:5]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)[CH:4]=2
Reactant: C1=COCCC1
Reactant: Clc1cccc2[nH]ncc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Clc1cccc2nn(C3CCCCO3)cc12
Temperature: 45 °C
Yield: 94.6 %

Procedure:
To a 1 L flask with mechanical stirrer was added 4-chloro-1H-indazole 12 (75.0 g, 0.492 mol), pyridinium p-toluenesulfonate (1.24 g, 4.92 mmol), CH2Cl2 (500 ml) and 3,4-dihydro-2H-pyran (98.6 ml, 1.08 mol). With stirring, this mixture was heated to 45° C. for 16 hours. Analysis of reaction mixture shows production of both isomers of product. Cooled reaction to 25° C. and added CH2Cl2 (200 ml). Washed the solution with water (300 ml) and saturated NaHCO3 (250 ml). Dried the organics with MgSO4 and concentrated to dryness. Purified the crude product by dissolving in EtOAc/Hexanes (4:6, 1 L) and adding SiO2 (1.2 L). The mixture was filtered and the cake was washed with EtOAc/Hexanes (4:6, 2 L). The organics were concentrated to yield 4-chloro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole 13 as an orange solid (110.2 g, 95%) and a minor amount (about 10%) of the THP regioisomer, 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. Isomer 1: 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=1 Hz, 1H), 7.50 (dd, J=9 Hz, 1 Hz 1H), 7.29 (dd, J=9 Hz, 8 Hz 1H), 7.15 (dd, J=8 Hz, 1 Hz 1H) 5.71 (dd, J=9 Hz, 3 Hz 1H) 4.02 (m, 1H) 3.55 (m, 1H) 2.51 (m, 1H) 2.02 (m, 2H) 1.55 (m, 3H). LCMS (ESI pos) m/e 237 (M+1); Isomer 2: 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=1 Hz, 1H), 7.62 (dd, J=9 Hz, 1 Hz 1H), 7.20 (dd, J=9 Hz, 8 Hz 1H), 7.06 (dd, J=8 Hz, 1 Hz 1H) 5.69 (dd, J=9 Hz, 3 Hz 1H) 4.15 (m, 1H) 3.80 (m, 1H) 2.22 (m, 2H) 2.05 (m, 1H) 1.75 (m, 3H). LCMS (ESI pos) m/e 237 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]1[C@H:26]([O:27][C:28](=O)[CH3:29])[NH:25][C:24]1=[O:31])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:32]CCO.O>C1C=CC=CC=1.C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]1[C@H:26]([O:27][CH2:28][CH2:29][Br:32])[NH:25][C:24]1=[O:31])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H]1C(=O)N[C@H]1OCCBr)OCc1ccccc1
Yield: 12 %

Procedure:
A mixture of (3S,4S)-3-(N-benzyloxycarbonyl-L-phenylalanyl)amino-4-acetoxy-azetidin-2-one (4.57 g, 10.8 mmole), 2-bromoethanol (1479 mg, 11.83 mmole), and zinc acetate dihydrate (1.78 g, 8.128 mmole) in a mixture of benzene (150 ml) and toluene (150 ml) was refluxed for 7 hrs using Dean-Stark water separator. After cooling, the reaction mixture was partitioned between ethyl acetate (1000 ml), acetone (100 ml) and water (500 ml). The organic layer was washed with water, brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography using ethyl acetate-hexane (55:45) as eluent and (3S,4S)-3-(N-benzyloxycarbonyl-L-phenylalanyl)amino-4-bromoethoxy-azetidin-2-one was obtained (650 mg, 12% yield).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>C(#N)C>[CH2:25]([N:11]1[CH2:10][CH2:9][CH:8]([C:7]2[C:2]([F:1])=[C:3]([C:14](=[O:16])[CH3:15])[CH:4]=[CH:5][CH:6]=2)[CH2:13][CH2:12]1)[CH:24]=[CH2:23]
Reactant: CC(=O)c1cccc(C2CCNCC2)c1F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CCC(c2cccc(C(C)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 1-(2-fluoro-3-piperidin-4-ylphenyl)ethanone (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and allylbromide (0.01 g). MS m/z (rel. intensity, 70 eV) 261 (M+, 89), 260 (82), 234 (bp), 218 (25), 82 (32).
Reaction SMILES: [CH3:1][N:2]1CCC[CH2:3]1.C=C([O:10][C:11](=O)[NH:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[C:26]([NH:31][C:32]([NH:34][CH2:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:33])[CH:25]=3)[C:19]([CH3:23])=[N:20]2)=[CH:15][N:14]=1)C.Cl.CNC>O1CCOCC1>[CH3:39][C:37]([CH3:38])([CH3:40])[CH2:36][CH2:35][NH:34][C:32](=[O:33])[NH:31][C:26]1[CH:25]=[C:24]([C:18]2[C:19]([CH3:23])=[N:20][C:21]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:12][C:11](=[O:10])[N:2]([CH3:3])[CH3:1])[CH:22]=3)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: CN1CCCC1
Reactant: C=C(C)OC(=O)Nc1cc2nc(C)c(-c3ccc(F)c(NC(=O)NCCC(C)(C)C)c3)cc2cn1
Agent: CNC
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2cc(NC(=O)N(C)C)ncc2cc1-c1ccc(F)c(NC(=O)NCCC(C)(C)C)c1
Temperature: 60 °C
Yield: 50.9 %

Procedure:
Add 1-methylpyrrolidine (0.355 mL, 3.34 mmol) to a suspension of prop-1-en-2-yl(3-(3-(3-(3,3-dimethylbutyl)ureido)-4-fluorophenyl)-2-methyl-1,6-naphthyridin-7-yl)carbamate (0.2 g, 0.417 mmol) and dimethylamine hydrochloride (0.136 g, 1.668 mmol) in dioxane (4 mL) and heat at 60° C. overnight. Cool to RT, add satd. NaHCO3, extract with EtOAc (3×), dry the combined organics over MgSO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford 3-(3-(3-(3-(3,3-dimethylbutyl)ureido)-4-fluorophenyl)-2-methyl-1,6-naphthyridin-7-yl)-1,1-dimethylurea (99 mg, 51%). MS(ESI) m/z: 467.3 (M+H+). Treat the solid with MeCN (2 mL), add 0.1N HCl (2.33 mL, 0.233 mmol), freeze, lyophilize and dry to afford the title compound (76 mg, 71%). 1H NMR (400 MHz, DMSO-d6): δ 9.52 (s, 1H), 9.30 (s, 1H), 8.64 (s, 1H), 8.50 (s, 1H), 8.41 (s, 1H), 8.32 (dd, J=7.9, 2.4 Hz, 1H), 7.35 (dd, J=11.3, 8.4 Hz, 1H), 7.07 (m, 1H), 6.66 (m, 1H), 3.08 (m, 2H), 3.00 (s, 6H), 2.70 (s, 3H), 1.34 (m, 2H), 0.88 (s, 9H); MS(ESI) m/z: 467.3 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([NH:9]C(=O)C)=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].C(=O)([O-])[O-].[Na+].[Na+]>Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH2:9])=[CH:13][CH:14]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)c1ccc(NC(C)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCC(=O)c1ccc(N)cc1
Reaction time: 0.5 h

Procedure:
141 g (1 mole) of p-propionylacetanilide were dissolved while refluxing and stirring into 600 ml of 5 N hydrochloric acid. Refluxing was continued for 30 min, cooling was applied, and sodium carbonate (about 300 g) was added, until the reaction mixture was alkaline. The residue formed was sucked off, washed with water until neutral and recrystallized from 725 ml of isopropanol. The mixture was sucked off and washed with ether. After drying under vacuum, a yellow-brownish powder was obtained.