Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[O:25][CH:26]([F:28])[F:27].Cl.N([O-])=O.[Na+].[I-:34].[K+].NC(N)=O.S([O-])([O-])=O.[Na+].[Na+]>O.C(#N)C>[Cl:24][C:19]1[CH:18]=[C:17]([C:11]2([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([I:34])=[C:3]([O:25][CH:26]([F:28])[F:27])[CH:4]=3)[CH2:12]2)[CH:22]=[C:21]([Cl:23])[CH:20]=1
Reactant: Nc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1OC(F)F
Reactant: [I-]
Agent: Cl
Agent: NC(N)=O
Agent: O=N[O-]
Solvent: CC#N
Solvent: O
Product: FC(F)Oc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1I
Yield: 47.9 %

Procedure:
In a solution of 1.00 g of 3-(4-amino-3-difluoromethoxyphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in a mixed solution of 10 mL of acetonitrile and 10 mL of water, 5 mL of concentrated hydrochloric acid was added, and a solution of 0.20 g of sodium nitrite in 2 mL of water was added dropwise slowly under cooling with ice and with stirring. After the completion of the addition dropwise, it was continued to stir at the same temperature further for 20 minutes. Then, a solution of 0.47 g of potassium iodide in 1 mL of water was added dropwise carefully. After the completion of the addition dropwise, it was continued to stir at room temperature further for 30 minutes. After the completion of the reaction, 0.041 g of urea was added in the reaction mixture, stirred at room temperature for 30 minutes, then a solution of 0.10 g of sodium sulfite in 5 mL of water was added, and extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with water, and then dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that were eluated with ethyl acetate-hexane (1:9) to obtain 0.60 g of the aimed product as yellow resinous substance.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=1
Reactant: Nc1cccnc1
Reactant: Brc1cccnc1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: c1cncc(Nc2cccnc2)c1
Reaction time: 15 h
Yield: 84.4 %

Procedure:
To a solution of 3-bromopyridine (4.75 gm, 30 mmol) and 3-aminopyridine (1.88 gm, 20 mmol) in dry toluene (8 mL) was added sodium t-butoxide (2.3 gm, 24 mmol), tris(dibenylideneacetone) dipalladium(0) (63 mg, 0.069 mmol), and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS) (183 mg, 0.317 mmol). The vessel was capped with a septum, degassed (3×), and heated at 100 C for ˜24 hours. The cooled reaction was diluted with methylene chloride, washed with NaHCO3 solution, water, and the organic layer dried over anhydrous sodium sulfate, filtered and the solvent concentrated to a small volume. Upon addition of diethyl ether and a few drops of methanol the product precipitated. After stirring this mixture for ˜15 hours the purified product was isolated by filtration to give 2.89 gm (84% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH:16]([CH3:21])[C:17]([NH:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:20][NH:19][C:17](=[O:18])[CH:16]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:21]
Reactant: CNC(=O)C(C)Br
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CNC(=O)C(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.29 g, 27.3 mmol), 2-bromo-N-methylpropanamide (9.05 g, 54.5 mmol) and potassium carbonate (5.65 g, 40.9 mmol) in 136 ml acetone was refluxed for 68 hours. The white suspension was filtered through Celite with acetone washes; and the filtrate was concentrated and purified via silica gel chromatography (80 mm; 1 L 65% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:24][CH:25]1[C:46](=[O:47])[N:27]2[C:28]([C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])=[C:29]([Cl:32])[CH2:30][S:31][C@H:26]12.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([NH:24][CH:25]2[C:46](=[O:47])[N:27]3[C:28]([C:33]([O:35][CH2:36][C:37]4[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=4)=[O:34])=[C:29]([Cl:32])[CH2:30][S:31][C@H:26]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Reactant: CCCCON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Yield: 81.9 %

Procedure:
A solution of 2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetic acid (syn isomer, 1.5 g.), N,N-dimethylformamide (440 mg.) and phosphoryl chloride (920 mg.) in ethyl acetate (12 ml.) and a solution of 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate (2.03 g.), trimethylsilylacetamide (7 g.) and bis(trimethylsilyl)acetamide (2 ml.) in ethyl acetate (25 ml.) were treated in a similar manner to that of Example 21-(1) to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 2.8 g.), yellow powder.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]1([CH:16]=[CH:17][CH:18]([OH:21])[C:19]#[CH:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[O:21]=[C:18](/[CH:17]=[CH:16]/[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)/[CH:19]=[CH:20]/[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: C#CC(O)C=Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(/C=C/C(=O)/C=C/c2ccccc2)cc1
Temperature: 120 °C

Procedure:
4-bromobenzonitrile (182 mg, 1 mmol), phenylpent-1-en-4-yn-3-ol (190 mg, 1.2 mmol), bis(triphenylphosphine)palladium(II)dichloride (14 mg, 0.02 mmol), copper iodide (3 mg, 0.03 mmol) and triphenylphosphine (52 mg, 0.2 mmol) were introduced in a 10 mL microwave vial flushed with argon. This was diluted with anhydrous triethylamine (700 μL, 4 mmol) in anhydrous degased 1,4-dioxane (1.3 mL). The solution was heated under microwave irradiation at 120° C. for 45 min. The reaction mixture was poured into a mix of 1M aqueous solution of hydrochloric acid (10 mL) and saturated aqueous ammonium chloride solution (10 mL), and this was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness to give crude product which was purified by flash chromatography (SiO2, 30% ethyl acetate in dichloromethane). This gave pure final compound TG007A82 (160 mg, 62%) as a light yellow powder.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:26])[CH2:14][C:15]1[CH:16]=[N:17][C:18]([N:21]2[CH:25]=[N:24][N:23]=[N:22]2)=[N:19][CH:20]=1)(C)(C)C>ClCCl>[N:21]1([C:18]2[N:17]=[CH:16][C:15]([CH2:14][C:13]([OH:26])=[O:12])=[CH:20][N:19]=2)[CH:25]=[N:24][N:23]=[N:22]1
Reactant: CC(C)(C)OC(=O)Cc1cnc(-n2cnnn2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1cnc(-n2cnnn2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (36 mL, 467 mmol) was added slowly to a solution of tert-butyl[2-(1H-tetrazol-1-yl)pyrimidin-5-yl]acetate (9.80 g, 37.4 mmol) in dichloromethane (36 mL) at RT. The reaction mixture was stirred at RT overnight then evaporated. The residue was triturated with ether:hexane (1:1) (100 mL). The solid was triturated with acetonitrile to afford title compound: 1H NMR 600 MHz (CD3OD) 10.01 (s, 1H); 8.94 (s, 2H); 3.88 (s, 2H); LC/MS (M+Na)+ at 229, (M+1)+ at 207, and (M+1-N2)+ at 179.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH2:28][NH2:29])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.C1C[O:35][CH2:34][CH2:33]1.C(Cl)(=O)C>C(N(CC)CC)C>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH2:28][NH:29][C:34](=[O:35])[CH3:33])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: CC(=O)NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(6-aminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (50 mg, 0.12 mmol) and THF (5 mL) is added acetyl chloride (50 mg) and triethylamine (50 mg). The solution is stirred at rt for 10 min before being partitioned between EtOAc and water. The organic layer is washed further with brine. The organic layer is then dried (Na2SO4), filtered, and concentrated under reduced pressure to give the title compound. MS (ESI) m/z 470.0 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.61 (d, J=1.01 Hz, 1H), 8.34 (d, J=9.09 Hz, 1H), 8.05 (s, 1H), 7.93 (d, J=3.54 Hz, 1H), 7.89 (d, J=7.83 Hz, 1H), 7.56 (t, J=7.96 Hz, 1H), 7.39-7.45 (m, 2H), 7.09 (dd, J=8.97, 2.40 Hz, 1H), 6.88 (s, 1H), 6.73 (d, J=3.79 Hz, 1H), 4.40 (s, 2H) 2.01 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1>CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([NH2:15])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1ccc(F)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of (5-fluoro-2-nitrophenyl)phenylamine (1.37 g, 5.90 mmol) in IMS (50 mL) and EtOAc (50 mL) was degassed with a stream of nitrogen prior to addition of 10% Pd/C (138 mg) and was stirred at RT under a hydrogen atmosphere for 4 h. The suspension was then filtered through a PTFE frit and the filtrate was concentrated in vacuo affording 4-Fluoro-N2-phenylbenzene-1,2-diamine as a red oil (1.19 g, quantitative). LCMS: RT 2.87 min [M+H]+ 203.1.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[C:32]5[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(F)cc1

Procedure:
The title compound, white solid (100 mg, 88%), MS (ISP) m/z=453.3 [(M+H)+], mp 209.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-fluorobenzoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[C:11]([CH3:19])[N:12]=[C:13]([CH3:18])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].[Br:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[N:28]=1>CN(C)C=O>[Br:26][C:27]1[N:28]=[C:29]([CH2:33][N:9]2[C:10]3[C:15](=[CH:14][C:13]([CH3:18])=[N:12][C:11]=3[CH3:19])[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:20]=[CH:21][C:22]([CH3:23])=[C:2]([CH3:1])[CH:3]=3)=[CH:8]2)[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cc2c(=O)c(C(=O)c3ccc(C)c(C)c3)c[nH]c2c(C)n1
Reactant: BrCc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(=O)c(C(=O)c3ccc(C)c(C)c3)cn(Cc3cccc(Br)n3)c2c(C)n1
Yield: 12.1 %

Procedure:
Experimental conditions analogous to described for Step 3 of Example 1 were used with 42 mg (0.137 mmol) of 3-(3,4-Dimethyl-benzoyl)-6,8-dimethyl-1H-[1,7]naphthyridin-4-one, 6 mg (0.165 mmol, 60% dispersion in oil) of sodium hydride, 41.3 mg (0.165 mmol) of 2-bromo-6-bromomethyl-pyridine and 1.5 mL of N,N-dimethylformamide. The crude brown solid was purified by flash column chromatography using 30-100% ethyl acetate in hexane to yield 7.9 mg of 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-6,8-dimethyl-1H-[1,7]naphthyridin-4-one as an off white solid. LC-MSD, m/z for C25H22BrN3O2 [M+H]: 477.37 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.9 min
Reaction SMILES: [NH:1]1[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[NH:4][CH2:3][CH2:2]1.[H-].[Na+].[F:13][C:14]([F:25])([F:24])[CH2:15]OS(C(F)(F)F)(=O)=O>CN(C=O)C.CO>[F:13][C:14]([F:25])([F:24])[CH2:15][N:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[NH:4][CH2:3][CH2:2]1
Reactant: C1CC[C@H]2NCCN[C@H]2C1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: FC(F)(F)CN1CCNC2CCCCC21
Reaction time: 0.08 h
Yield: 144.7 %

Procedure:
cis-Decahydro-quinoxaline (0.104 g, 0.74 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 0.015 g, 0.37 mmol) was added. After 5 minutes, trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (0.137 g, 0.37 mmol) was dissolved in a small amount of DMF and added to the mixture. Stirring was continued for 1 hour at room temperature then the material was diluted slightly with methanol and applied to a 10 g SCX-2 cartridge. This was washed with methanol then eluted using 2 N ammonia in methanol to afford 1-(2,2,2-trifluoro-ethyl)-decahydro-quinoxaline as a pale yellow oil (0.119 g).
Reaction SMILES: C(Cl)Cl.[CH2:4]([CH:6]([C:9]1[C:10]2[N:11]([C:16]([C:20]3[O:21][CH:22]=[CH:23][C:24]=3[CH3:25])=[C:17]([CH3:19])[N:18]=2)[N:12]=[C:13]([CH3:15])[CH:14]=1)[CH2:7][CH3:8])[CH3:5].C1C(=O)N([Br:33])C(=O)C1>O>[Br:33][C:22]1[O:21][C:20]([C:16]2[N:11]3[N:12]=[C:13]([CH3:15])[CH:14]=[C:9]([CH:6]([CH2:7][CH3:8])[CH2:4][CH3:5])[C:10]3=[N:18][C:17]=2[CH3:19])=[C:24]([CH3:25])[CH:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(CC)c1cc(C)nn2c(-c3occc3C)c(C)nc12
Solvent: ClCCl
Solvent: O
Product: CCC(CC)c1cc(C)nn2c(-c3oc(Br)cc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.5 %

Procedure:
A CH2Cl2 solution (4 mL) of 8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-furan-2-yl)-imidazo[1,2-b]pyridazine (32.4 mg, 0.11 mmol) is cooled to 0° C. under a CaSO4 drying tube and treated with NBS (20.1 mg, 0.11 mmol). After 15 minutes at 0° C., the mixture is warmed to room temperature. After an additional 10 minutes, the reaction mixture is poured into H2O (25 mL) and extracted into CH2Cl2 (2×25 mL). The combined organic extracts are washed with aq. brine, dried over Na2SO4, filtered, and concentrated. The crude product is purified by chromatography using hexane-ethyl acetate gradient (100% hexane to 10% ethyl acetate in hexane) to elute the title compound (26.3 mg, 64% yield) as a solid. ES-MS (m/z): calc'd for C18H22BrN3O: 375.1; found 376.2 (M+H); 1H NMR (400 mHz, CDCl3): δ 6.72 (s, 1H), 6.40 (s, 1H), 3.34 (m, 1H), 2.56 (s, 3H), 2.49 (s, 3H), 2.07 (s, 3H), 1.93-1.77 (m, 4H), 0.89 (t, J=7.5 Hz, 6H).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][CH2:9]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:11]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[Br:11][CH2:9][CH2:8][CH2:7][CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCCCC1CCCC1
Solvent: CC#N
Product: BrCCCCC1CCCC1
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A solution of 4-cyclopentyl-butan-1-ol (3.1 g, 22 mmol) in acetonitrile (200 mL) was treated with dibromotriphenylphosphorane (10.1 g, 23.9 mmol). The reaction was stirred for two hours and quenched with water (10 mL). The reaction was diluted with dichloromethane (300 mL) and washed with water (3×100 mL). The organic phase was dried (MgSO4), filtered, and concentrated to yield an oil. The product was passed through a pad of silica to yield (4-bromo-butyl)-cyclopentane as a colorless oil (3.37 g, 76%). 1H NMR (CDCl3, 300 MHz) δ 3.42 (t, 7.0 Hz, 2H), 1.9-1.7 (m, 4H), 1.6-1.3 (m, 9H), 1.07 (m, 2H).
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([CH3:22])=[CH:19][CH:20]=2)[C:15]2[C:23]3[C:28]([CH2:29][C:14]1=2)=[CH:27][CH:26]=[CH:25][CH:24]=3.N1C2C(C=CC3C=2C=C2C=3C=CC=C2)=CC=1.[Cl:46][Si:47](Cl)([CH3:49])[CH3:48]>C1COCC1>[Cl:46][Si:47]([CH3:49])([CH3:48])[CH:29]1[C:14]2[N:13]([CH3:12])[C:21]3[C:16]([C:15]=2[C:23]2[C:28]1=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][C:18]([CH3:22])=[CH:19][CH:20]=3
Reactant: Cc1ccc2c(c1)c1c(n2C)Cc2ccccc2-1
Reactant: C[Si](C)(Cl)Cl
Agent: C1=Nc2c3c(ccc2=C1)=c1ccccc1=C3
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2C)C([Si](C)(C)Cl)c2ccccc2-1
Temperature: -78 °C
Reaction time: 6 h

Procedure:
9.5 mL of a 2.5 M solution of n-BuLi in hexane (23.75 mmol) were added dropwise to a solution of 5.1 g of N-methyl-2-methyl-5,6-dihydroindeno[2,1-b]indole, obtained as reported above, (purity 98.2%, Mw=233.32, 21.46 mmol; indenoindole: n-BuLi=1:1.1) in 70 mL of THF, previously cooled to −78° C. At the end of the addition, the brown solution was allowed to warm up to room temperature and stirred for 6 hours. Then it was cooled again to −78° C. and added dropwise to a solution of dichlorodimethylsilane (Mw=129.06, d=1.064, 2.6 mL, 21.43 mmol; indenoindole: Me2SiCl2=1:1) in 20 mL of THF, previously cooled to −78° C. At the end of the addition, the reaction mixture was allowed to warm up to room temperature and stirred overnight. The solvents were evaporated under reduced pressure to give a brown sticky solid, which at the 1H-NMR analysis resulted to be the target product, with few by-products. The product was used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:15][C:14](=[O:16])[NH:13][NH:12]2)=[O:10])=[C:4]([C:17](=[O:24])[NH:18][CH:19]([CH:21]2[CH2:23][CH2:22]2)[CH3:20])[CH:3]=1.Cl[C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=1.[H-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:12]([C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=3)[N:13]=[C:14]([OH:16])[CH2:15]2)=[O:10])=[C:4]([C:17](=[O:24])[NH:18][CH:19]([CH:21]2[CH2:22][CH2:23]2)[CH3:20])[CH:3]=1
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(=O)NN1)C1CC1
Reactant: Clc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(O)=NN1c1ncccc1Cl)C1CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 87.3 %

Procedure:
1.0 g of N-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenyl)-5-oxopyrazolidine-3-carboxamide was dissolved in 10 mL of N,N-dimethylformamide, and 460 mg of 2,3-dichloropyridine and then 350 mg of sodium hydride were added, followed by stirring at about 70° C. for about 7 hours in a nitrogen atmosphere, and then the reaction liquid was left to cool. To the reaction liquid, water and ethyl acetate were added, followed by stirring and extraction with ethyl acetate. Then, concentration under reduced pressure was carried out to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate/ethanol=9/1) to obtain 1.15 g of the desired product (melting point: 165-167° C.).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13](=O)[CH3:14].C([O-])(=O)C.[Na+].Cl.[NH2:22][OH:23]>O>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13](=[N:22][OH:23])[CH3:14]
Reactant: NO
Reactant: CC(=O)c1nc(-c2ccncc2)[nH]c1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=NO)c1nc(-c2ccncc2)[nH]c1C
Temperature: 25 °C

Procedure:
To a 1.0 g (0.005 mole) amount of 1-[5-methyl-2-(4-pyridinyl)-1H-imidazol-4-yl]ethanone (prepared as described in Example 24) dissolved in 200 ml of boiling water were added 1.0 g (0.012 mole) of sodium acetate and 0.7 g (0.01 mole) of hydroxylamine hydrochloride. The mixture was stirred and heated for 2 hours, then cooled to room temperature. The resulting precipitate was collected by filtration and when dried at 60° C. for 18 hours gave 0.7 g of the product of the Example as white crystals, mp 253°-255° C. (dec.).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:29][C:28]3[C:27](=[O:30])[N:26]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]5(O)[CH2:42][C:41]([F:44])([F:43])[CH2:40]5)=[C:33]([O:46][CH3:47])[CH:32]=4)[CH:25]=[N:24][C:23]=3[CH:22]=2)=[CH:17][CH:16]=1.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH3:10])[C:11]([O:13][C:39]1([CH2:38][O:37][C:34]2[CH:35]=[CH:36][C:31]([N:26]3[C:27](=[O:30])[C:28]4[S:29][C:21]([C:18]5[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=5)=[CH:22][C:23]=4[N:24]=[CH:25]3)=[CH:32][C:33]=2[O:46][CH3:47])[CH2:40][C:41]([F:44])([F:43])[CH2:42]1)=[O:12])=[O:2])([CH3:7])([CH3:5])[CH3:6]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC1(O)CC(F)(F)C1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC1(OC(=O)[C@H](C)NC(=O)OC(C)(C)C)CC(F)(F)C1
Temperature: 40 °C
Reaction time: 18 h
Yield: 87.9 %

Procedure:
A mixture of Boc-alanine (94 mg, 0.495 mmol), 6-(4-chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (50 mg, 0.099 mmol) from Example 2,4-pyrrolidinopyridene (14.68 mg, 0.099 mmol) and N,N′-diisopropylcarbodiimide (0.077 mL, 0.495 mmol) in CH2Cl2 (4 mL) was stirred at 40° C. in a sealed tube for 18 hours. After cooling to RT and removal of the volatiles under vacuum, the crude product was subjected to gradient chromatography (silica gel/EtOAc/hexane 0 to 30%) to afford (S)-1-((4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)methyl)-3,3-difluorocyclobutyl 2-(tert-butoxycarbonylamino)propanoate (59 mg, 0.087 mmol, 88% yield) as off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.13 (1 H, s), 7.66 (2 H, d), 7.54 (1 H, s), 7.46 (2 H, d), 6.87-7.06 (3 H, m), 4.96 (1 H, br. s.), 4.34-4.48 (2H, m), 4.20-4.34 (1 H, m), 3.87 (3 H, s), 3.09-3.24 (2 H, m), 2.97 (2 H, broad s.), 1.45 (9 H, s), 1.38 (3 H, d, J=7.30 Hz). LC-MS: 2.72 min 677 (M+H). Luna 5 u C18 30×4.6 mm ID, flow rate=4 ml/min., gradient=0% A to 100% B in 2 min., A=90% H2O/10% MeOH/0.1% TFA, B=10% H2O/90% MeOH/0.1% TFA).