Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(S(NC1CCC(C(O)=O)CC1)(=O)=O)(C)(C)C.FC(F)(F)C1C=CC(N)=C(N)C=1.[NH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:55][C:54]=1[NH:63][C:64]([C@H:66]1[CH2:71][CH2:70][C@H:69]([NH:72][S:73]([C:76]([CH3:79])([CH3:78])[CH3:77])(=[O:75])=[O:74])[CH2:68][CH2:67]1)=O.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C.CN(C=O)C>[C:76]([S:73]([NH:72][C@H:69]1[CH2:68][CH2:67][C@H:66]([C:64]2[NH:63][C:54]3[CH:55]=[C:56]([C:59]([F:61])([F:62])[F:60])[CH:57]=[CH:58][C:53]=3[N:52]=2)[CH2:71][CH2:70]1)(=[O:75])=[O:74])([CH3:79])([CH3:78])[CH3:77]
Reactant: CC(C)(C)S(=O)(=O)N[C@H]1CC[C@H](C(=O)Nc2cc(C(F)(F)F)ccc2N)CC1
Agent: CC(C)(C)S(=O)(=O)NC1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)S(=O)(=O)N[C@H]1CC[C@H](c2nc3ccc(C(F)(F)F)cc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodimide (87 mg) and 1-hydroxybenzotriazole (90 mg) were added to a DMF solution (4.0 mL) containing 4-tert-butylsulfonylaminocyclohexanecarboxylic acid (99 mg) as prepared by the above-described preparation method and 4-trifluoromethyl-1,2-phenylenediamine (66 mg), followed by stirring at room temperature for 16 hrs. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with aqueous saturated sodium hydrogencarbonate and sodium chloride solutions, successively, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude amide containing trans-N-(2-amino-5-trifluoromethylphenyl)-4-tertbutylsulfonylaminocyclohexanecarboxamide. The crude amide was admixed with phosphorus oxychloride (1.0 mL), and the mixture was heated under stirring at 100° C. for 2 hrs. The excess phosphorus oxychloride was distilled off under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed with aqueous saturated sodium hydrogencarbonate and sodium chloride solutions successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was crystallized from isopropyl ether to give the title compound (48.2 mg).
Reaction SMILES: [NH:1]1CCCCC1.[CH3:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][N:14]([CH2:23][C:24]1[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>CN(C=O)C>[NH2:1][C@@H:19]([CH2:18][CH2:17][CH2:16][CH2:15][N:14]([CH2:13][C:9]1[N:8]([CH3:7])[CH:12]=[CH:11][N:10]=1)[CH2:23][C:24]1[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=1)[C:20]([OH:22])=[O:21]
Reactant: C1CCNCC1
Reactant: Cn1ccnc1CN(CCCCCC(=O)O)Cc1nccn1C
Solvent: CN(C)C=O
Product: Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)Cc1nccn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Piperidine (0.80 mL) was added to a solution of (S)-2-4(9H-fluoren-9-yl)methoxy)carbonylamino)-6-(bis((1-methyl-1H-imidazol-2-yl)methyl)amino)hexanoic acid (556 mg, 1.00 mmol) in DMF (4.0 mL). The mixture was stirred at room temperature for 2 hrs. Solvent was evaporated under reduce pressure to afford a residue, which was purified by Amberchrom to afford (S)-2-amino-6-(bis((1-methyl-1H-imidazol-2-yl)methyl)amino) hexanoic acid (330 mg, 99%). 1H NMR (400 MHz, DMSO-d6) 7.94 (s, 1H), 7.04 (d, J=3=1.2 Hz, 2H), 6.74 (d, J=1.2 Hz, 2H), 3.54 (s, 4H), 3.98 (brs, 1H), 2.88 (s, 3H), 2.72 (s, 3H), 2.35 (t, J=6.8 Hz, 2H), 1.60-1.54 (m, 1H), 1.43-1.29 (m, 3H), 1.16-1.11 (m, 2H); MS (ESI), 335 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:15]=[CH:14][N:13]=1.[NH2:23][C:24]1[S:25][C:26]([CH3:29])=[CH:27][N:28]=1.N1C=CC=C(C2C=CN=C(NC3C=CC(C(O)=O)=CC=3)N=2)C=1.CC1N=CN(C2C=C(N)C=C(C(F)(F)F)C=2)C=1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:23][C:24]2[S:25][C:26]([CH3:29])=[CH:27][N:28]=2)=[O:8])=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Cc1cnc(N)s1
Reactant: Cc1ccc(C(=O)O)cc1Nc1nccc(-c2nccs2)n1
Agent: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Agent: O=C(O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Product: Cc1cnc(NC(=O)c2ccc(C)c(Nc3nccc(-c4nccs4)n3)c2)s1

Procedure:
4-methyl-3-(4-thiazol-2-yl-pyrimidin-2-ylamino)-benzoic acid and 2-amino-5-methylthiazole were used instead of 4-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzoic acid and 3-(4-methylimidazol-1-yl)-5-trifluoromethyl-phenylamine according to the similar procedure to Example 5 to give the titled compound as yellow brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N+:3]=1[O-:9].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([CH3:8])[N+:3]=1[O-:9]
Reactant: Cc1cccc(Cl)[n+]1[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])cc(Cl)[n+]1[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
2-Chloro-6-methyl-pyridine 1-oxide (5.0 g, 0.035 mol) was dissolved in concentrated sulfuric acid (20 ml) at 0° C. An ice-cooled mixture of concentrated nitric acid (12 ml) in concentrated sulfuric acid (20 ml) was added dropwise with stirring at 0° C. The cooling bath was removed, stirring was continued for 3 hours at 90° C. The mixture was poured into a mixture of icewater and ethyl acetate and the resulting precipitate was removed by filtration. The phases of the filtrate were separated, the aqueous phase was extracted several times with ethyl acetate, basified with NaOH and extracted again with ethyl acetate. The combined organic phases were dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was combined with the filtered residue above to yield 6.21 g of a yellow solid (0.033 mol, 94%). MS (ESI) m/z=189.0 [M+1]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][C:29]3([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:33][CH2:32][CH2:31][O:30]3)=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1.O>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][C:29]3([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:33][CH2:32][CH2:31][O:30]3)=[CH:21][CH:20]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCC3(c4ccccc4)OCCO3)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: [Br-]
Agent: [Zn+2]
Solvent: O
Solvent: ClCCl
Product: c1ccc(C2(CCCOc3ccc(C4CCNCC4OCc4ccc5ccccc5c4)cc3)OCCO2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.5 %

Procedure:
A mixture of 600 mg (0.962 mmol) of tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-{4-[3-(2-phenyl-[1,3]dioxolan-2-yl)-propoxy]-phenyl}-piperidine-1-carboxylate in 3.0 ml of methylene chloride and 433 mg (1.92 mmol, 2.0 eq.) of zinc bromide was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted three times with ethyl acetate. The organic phases were washed in each case once with water and with saturated sodium chloride solution, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The amorphous, slightly yellow crude product was separated on silica gel using a 95:5:0.1 mixture of methylene chloride, methanol and ammonia. There were obtained 355 mg (71% of theory) of (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-[3-(2-phenyl-[1,3]dioxolan-2-yl)-propoxy]-phenyl]-piperidine as a colourless resin; MS: 524 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([CH2:16][N:17]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:12][C:10]=3[CH:11]=2)=[CH:4][CH:3]=1.O1CCCC1.O.NN.C(=O)(O)[O-].[Na+]>C(O)C>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][C:10]=3[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc2oc(Cc3ccc(F)cc3)cc2c1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: NCc1ccc2oc(Cc3ccc(F)cc3)cc2c1
Reaction time: 3 h
Yield: 78.3 %

Procedure:
To a mixed solution of 2-(2-(4-fluoro-benzyl)-benzofuran-5-ylmethyl)-isoindole-1,3-dione (81 mg, 0.21 mmol) described in Production Example 76-1-3 in ethanol (5 mL) and tetrahydrofuran (3 mL) was added hydrazine monohydrate (52.6 mg, 1.05 mmol). This mixture was stirred for 3 hours while heating under reflux. After allowing the reaction mixture to cool on standing, saturated aqueous sodium bicarbonate solution was poured thereinto followed by extraction with ethyl acetate. The organic layer was separated followed by washing with sat. NaCl, drying over anhydrous magnesium sulfate and concentrating under a reduced pressure to obtain the title compound (42 mg, 78%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]([N:7]([C@H:26]([C:30]([OH:32])=[O:31])[CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:21]2[NH:22]N=NN=2)=[CH:13][CH:14]=1)=[O:6].[CH3:33]OC(=O)[C@H](C(C)C)NCC1C=CC(C2C=CC=CC=2C#N)=CC=1.C(Cl)(=O)CCCC.C(N(CC)CC)C>ClCCl>[CH3:33][O:32][C:30](=[O:31])[C@H:26]([CH:27]([CH3:28])[CH3:29])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:21]#[N:22])=[CH:11][CH:10]=1)[C:5](=[O:6])[CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Reactant: COC(=O)[C@@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C
Agent: CCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OC)C(C)C

Procedure:
Briefly, the process for the preparation of valsartan comprises of the condensation of N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester of Formula II with valeryl chloride of Formula III in the presence of triethylamine and dichloromethane, followed by flash chromatography, to give the compound N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester of Formula IV. The compound of Formula IV on tetrazole formation using tributyltin azide and subsequent hydrolysis using sodium hydroxide, followed by flash chromatography, gives valsartan of Formula I.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:23]([O-:25])=[O:24])[C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:22]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.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]>[CH3:10][C:8]1[N:7]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:22]=[C:2]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:3]=[C:4]([N+:23]([O-:25])=[O:24])[C:5]=2[N:9]=1
Reactant: Cc1nc2c([N+](=O)[O-])cc(Br)cc2n1Cc1cccc2ccccc12
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc2c([N+](=O)[O-])cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
A mixture of 6-bromo-2-methyl-1-(naphthalen-1-ylmethyl)-4-nitro-1H-benzo[d]imidazole (4.63 g), morpholine (3.05 g), Pd2(dba)3 (1.05 g), Cs2CO3 (5.72 g) and X-Phos (1.09 g) in dioxane (100 mL) was degassed with nitrogen and then stirred at 80° C. overnight. The mixture was cooled to room temperature and the solvent was removed in-vacuo. The residue was then purified by silica gel chromatography eluted with EtOAc:Petrolium ether=1:1 to afford the desired product as a yellow solid (2.8 g, 60%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.46 (s, 3H), 3.12 (t, 4H, J=4.8 Hz). 3.70 (t, 4H, J=4.8 Hz), 6.09 (s, 2H), 6.31 (d, 1H, J=7.5 Hz), 7.34 (t, 1H, J=7.5 Hz), 7.53 (d, 1H, J=2.1 Hz), 7.62-7.70 (m, 3H), 7.86 (d, 1H, J=8.1 Hz), 8.01 (d, 1H, J=7.5 Hz), 8.23 (d, 1H, J=8.1 Hz); LC-MS: m/e=403 [M+1]+.
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][C:4]2[C@:8]([C:18]([F:21])([F:20])[F:19])([C:13]#[C:14][CH:15]3[CH2:17][CH2:16]3)[O:9][C:10]([NH:12][C:3]=2[CH:2]=1)=[O:11].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[C:30]([O:34][C:35](=[O:40])[CH2:36][CH2:37][CH2:38]Br)([CH3:33])([CH3:32])[CH3:31]>C1OCCOCCOCCOCCOCCOC1.CN(C=O)C>[C:30]([O:34][C:35](=[O:40])[CH2:36][CH2:37][CH2:38][N:12]1[C:3]2[CH:2]=[CH:1][C:6]([Cl:7])=[CH:5][C:4]=2[C:8]([C:13]#[C:14][CH:15]2[CH2:16][CH2:17]2)([C:18]([F:20])([F:21])[F:19])[O:9][C:10]1=[O:11])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCN1C(=O)OC(C#CC2CC2)(C(F)(F)F)c2cc(Cl)ccc21
Temperature: 125 °C
Yield: 91.3 %

Procedure:
To 250 mg (0.79 mmol) of efavirenz 1 was added 10 mL of anhydrous DMF, 600 mg (4.34 mmol) of potassium carbonate, 120 mg (0.80 mmol) of sodium iodide and 492 mg (2.2 mmol) of 4-bromo-butyric acid tert-butyl ester followed by 5 mg of 18-crown-6. The mixture was heated to 125° C. for 2 hours under argon atmosphere and concentrated under reduced pressure. To the residue 50 mL of chloroform was added, and the solid was filtered off. To the filtrate 50 mL of water was added. The organic layer was separated, washed with 50 mL of water, dried (Na2SO4), and concentrated. The residue was purified by silica gel flash column chromatography in 70% ethyl acetate in hexane to give 327 mg (0.721 mmol, 90% yield) of 2 (M+Na, 480).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[C:18]([O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([C:32]2[CH:37]=[CH:36][C:35](C(=O)C)=[CH:34][CH:33]=2)=[C:27]([CH3:41])[CH:26]=1)(=[O:20])[CH3:19].B(F)(F)F.CCOCC.CO>C(OCC)(=O)C.O.C(Cl)Cl>[CH3:5][O:3][C:1](=[O:4])[CH2:2][C:35]1[CH:34]=[CH:33][C:32]([C:28]2[C:27]([CH3:41])=[CH:26][C:25]([O:24][CH2:23][CH2:22][O:21][C:18](=[O:20])[CH3:19])=[CH:30][C:29]=2[CH3:31])=[CH:37][CH:36]=1
Reactant: CC(=O)OCCOc1cc(C)c(-c2ccc(C(C)=O)cc2)c(C)c1
Reactant: CC(=O)[O-]
Agent: FB(F)F
Agent: [Pb+4]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: COC(=O)Cc1ccc(-c2c(C)cc(OCCOC(C)=O)cc2C)cc1
Temperature: 0 °C
Yield: 43.3 %

Procedure:
Lead tetraacetate (1.369 g) was added to an ice-cooled mixture of 1-[4′-(2-acetoxyethoxy)-2′,6′-dimethylbiphenyl-4-yl]ethan-1-one (0.672 g), boron trifluoride diethyl etherate (1.56 mL), methanol (2 mL) and methylene chloride (20 mL) with stirring, and the mixture was stirred at room temperature for 4 hrs. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to afford methyl[4′-(2-acetoxyethoxy)-2′,6′-dimethylbiphenyl-4-yl]acetate (0.318 g).
Reaction SMILES: [CH3:1][N:2]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)[C:3](=[O:26])[CH2:4][N:5]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6](=[O:19])[CH2:7][N:8]1[C:12](=[O:13])C2=CC=CC=C2C1=O.O.NN.[CH3:37][C:38]1[CH:39]=[C:40]([N:44]=C=O)[CH:41]=[CH:42][CH:43]=1>>[CH3:1][N:2]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)[C:3](=[O:26])[CH2:4][N:5]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:6](=[O:19])[CH2:7][NH:8][C:12]([NH:44][C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([CH3:37])[CH:39]=1)=[O:13]
Reactant: Cc1cccc(N=C=O)c1
Reactant: Cc1cccc(N(C)C(=O)CN(C(=O)CN2C(=O)c3ccccc3C2=O)c2ccccc2)c1
Agent: NN
Solvent: O
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N(C)c2cccc(C)c2)c2ccccc2)c1
Yield: 32.2 %

Procedure:
The procedure is analogous to that described in Example 23, but 2.7 g of N-methyl-N-(3-methylphenyl)-2-(N-phenyl-2-phthalimidoacetamido)acetamide, 0.6 g of hydrazine hydrate and 0.8 g of 3-methylphenyl isocyanate are used as the starting material. The product obtained is purified by chromatography on 25 g of silica gel (0.065-0.200 mm) contained in a column 1.7 cm in diameter [eluent: methylene chloride/ethyl acetate (80-20 by volume)], collecting 25 cm3 fractions. Fractions 13 to 27 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from diethyl ether, 0.86 g of N-methyl-N-(3-methylphenyl)-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 165° C. is obtained.
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.[Cl:29]C1SC2C=CC(Cl)=CC=2N=1>>[Cl:29][C:28]1[CH:2]=[CH:3][C:4]2[S:8][C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)=[N:6][C:5]=2[CH:27]=1
Reactant: Clc1ccc2sc(Cl)nc2c1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cc(Cl)ccc2s1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2,5-dichloro-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.10-2.22 (m, 2H), 2.22-2.30 (m, 2H), 3.12 (q, J=11.1 Hz, 2H), 3.42 (d, J=12.4 Hz, 2H), 4.47-4.55 (m, 1H), 7.56 (d, J=8.4 Hz, 1H), 8.03 (s, 1H), 8.19-8.24 (m, 2H), 8.26 (br. s., 1H), 8.35 (s, 1H), 8.52 (s, 1H), MS (ES+): m/z=411.09/413.10 (3:1) [MH+]. HPLC: tR=2.18 min (ZQ2, polar—5 min).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14][CH:15]([CH2:19][CH2:20]Br)[C:16](Br)=[O:17]>CC#N>[CH2:7]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:20][CH2:19][C@@H:15]([Br:14])[C:16]2=[O:17])[CH2:9]1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Br)C(Br)CCBr
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Solvent: CC#N
Product: O=C1[C@H](Br)CCN1C1CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
A solution of 5.0 g of (R)-1-(phenylmethyl)-3-pyrrolidinamine in 50.0 ml CH3CN was treated at rt with 2.72 g of Na3PO4. The resulting fine light yellow suspension was cooled to 0° C. and treated with a solution of 10.07 g of 2,4-dibromobutyrylbromide (prepared according to Marinelli, E. R.; Arunachalam, T.; Diamantidis, G.; Emswiler, J.; Fan, H.; Neubeck, R.; Pillai, K. M. R.; Wagler, T. R.; Chen, C.-K.; et al. Tetrahedron (1996), 52(34), 11177-11214) in 5.0 ml of CH3CN over 20 min. After 30 min the very fine suspension was filtered and concentrated to a volume of 30 ml, and then treated with 130.1 ml of 0.497 M NaOH solution at room temperature. The resultant turbid orange solution was stirred for 2 h, concentrated and the resultant aqueous phase extracted with three portions of 50 ml of TBME. The combined organic phases were washed with H2O until neutral, dried over MgSO4 and concentrated to give 5.79 g (63%) of (R)-(1′-benzyl-3-bromo-[1,3′]bipyrrolidinyl-2-one) as yellow waxy crystals.
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]2=[O:13].[Li+].[Cl-].[CH:20]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Sn](C)(C)(C)C>CN(C)C=O.O.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>[CH2:14]([CH:5]1[CH2:4][C:3]2[C:7](=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:2]=2[CH3:20])[C:6]1=[O:13])[CH2:15][CH2:16][CH3:17]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCC1Cc2c(ccc(OC)c2Br)C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Sn](C)(C)C
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC1Cc2c(ccc(OC)c2C)C1=O
Temperature: 100 °C
Yield: 496.7 %

Procedure:
A solution of 4-bromo-2-butyl-5-methoxy-1-indanone (1.159 g, 3.90 mmol) in anhydrous dimethylformamide (39 mL) was treated with LiCl (455 mg, 10.73 mmol), PPh3 (205 mg, 0.78 mmol), PdCl2(PPh3)2 (205 mg, 0.292 mmol) and Me4Sn (1.08 mL, 7.80 mmol). The mixture was placed under a nitrogen atmosphere, then stirred and heated in an oil bath at 100° C. for 16.5 hours. After cooling to room temperature, the mixture was diluted with water (100 mL) and extracted with Et2O (100 mL, 2×25 mL). The ether extracts were washed with brine, dried over MgSO4, filtered and evaporated under vacuum to a yellow solid (1.29 g). This material was purified by chromatography on EM silica gel 60 (230-400 mesh, 130 mL dry, packed under CH2Cl2), using CH2Cl2 as eluting solvent, to afford a 92:3:5 mixture (0.90 g) of 2-butyl-5-methoxy-4-methyl-1-indanone, the 6-methyl isomer, and the desmethyl product. This material was used as is in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[Cl:15][C:16]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:17]=1[O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>N1C=CC=CC=1>[Cl:15][C:16]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:17]=1[O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)cc1
Temperature: 60 °C

Procedure:
A mixture of 4-nitrobenzenesulfonyl chloride (2.71 g, 12 mmol) and 2-(2,4-dichloro-phenoxy)aniline HCl (2.9 g, 10 mmol) were dissolved in pyridine (10 mL) at room temperature. After 1 hr the mixture was heated at 60° C. for 2 hour. The reaction mixture was concentrated under vacuum. The residue was diluted with EtOAc and washed sequentially with 1M aq. HCl and sat. aq. NaHCO3 and the organic extract dried over MgSO4, and the solvent removed in vacuo to afford the title compound as a solid. LCMS (ES MS, M+H+found: 439) and proton NMR (400 MHz, CDCl3) δ 6.54-6.62 (m, 2H), 7.02-7.18 (m, 4H), 7.43 (d, J=2.5 Hz, 1H), 7.73 (dd, J=8.1 and 1.6 Hz, 1H), 7.94 (d, J=8.6 Hz, 2H), 8.21 (d, J=8.6 Hz, 2H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C@H:10]([NH:21][C:22](=[O:24])[CH3:23])[CH2:9][C@@H:8]1[CH3:25])=[O:6])([CH3:3])[CH3:2].[F:26][C:27]([F:41])([F:40])[C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:31]Br.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=2)[C@H:10]([N:21]([C:22](=[O:24])[CH3:23])[CH2:31][C:30]2[CH:33]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:35]=[C:28]([C:27]([F:26])([F:40])[F:41])[CH:29]=2)[CH2:9][C@@H:8]1[CH3:25])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1C[C@H](C)N(C(=O)OC(C)C)c2ccc(C(F)(F)F)nc21
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C)N(C(=O)OC(C)C)c2ccc(C(F)(F)F)nc21
Yield: 30 %

Procedure:
Prepare the title compound by essentially following the procedure described in Example 49, Step 2, by replacing (+/−)-N-(1-cyclopently-6-methoxy-2-methyl-1,2,3,4-tetrahydro-[1,5]napthyridin-4-yl)-acetamide with cis-4-acetylamino-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (0.065 g, 0.018 mmol), and using 3,5-bis trifluoromethyl benzylbromide and lithium hexamethyldisilazide. Purify using silica gel column chromatography (gradient eluent, neat ethyl acetate) to afford the title compound (0.031 g, 30%). MS (ES+): 586 (M+H).