Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[N:11]O)[C:5]=2[CH:4]=[CH:3][N:2]=1>C(O)C.C(OCC)(=O)C.[Pd]>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: ON=C1CCCc2cnccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: NC1CCCc2cnccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 103.7 %

Procedure:
To a solution of 7,8-dihydroisoquinolin-5-(6H)-one oxime [Synth. Commun., 26(12), 2305-2308, (1996)] (1 g, 6.2 mmol) in ethanol (20 ml) and ethyl acetate (1 ml) was added 10% palladium on carbon (250 mg). The resulting slurry was stirred under a hydrogen balloon at room temperature for 20 hours. The catalyst was removed by filtration and the solvent evaporated to give the title compound as a brown oil (953 mg, 100%). m/z (ES+) 149 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].S=[C:12]1[CH2:16][S:15][C:14](=[O:17])[NH:13]1>C(O)C>[O:10]=[C:6]1[CH2:7][CH2:8][CH2:9][N:5]1[CH2:4][CH2:3][CH2:2][NH:1][C:12]1[CH2:16][S:15][C:14](=[O:17])[N:13]=1
Reactant: NCCCN1CCCC1=O
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: O=C1N=C(NCCCN2CCCC2=O)CS1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(3-aminopropyl)-2-pyrrolidone (1.12 mL) in ethanol (40 mL) was added 4-thioxo-1,3-thiazolidin-2-one (1.00 g), and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration and washed with ethyl acetate to give the title compound (1.56 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[O:26][C:25](=[O:27])[C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[N:22]=2)[CH2:13][CH2:12]1.[CH:32]([NH2:35])([CH3:34])[CH3:33]>O1CCCC1>[CH:32]([NH:35][C:25](=[O:27])[C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[NH:22][C:21](=[O:26])[CH2:20][CH2:19][CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][N:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH2:16][CH2:15]1)([CH3:34])[CH3:33]
Reactant: O=c1oc(CCCCN2CCN(c3ccc4ccccc4n3)CC2)nc2ccccc12
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1ccccc1NC(=O)CCCCN1CCN(c2ccc3ccccc3n2)CC1
Temperature: 80 °C
Yield: 58.1 %

Procedure:
In a glass tube, 414 mg of 2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-3,1-benzoxazin-4-one as synthesized in above Step 7-15-B, 590 mg of isopropylamine and 5 ml of tetrahydrofuran were hermetically sealed and stirred for an hour at the exterior temperature of 80° C. Cooling the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting residue was purified on silica gel column chromatography (dichloromethane:methanol=10:1) to provide 275 mg (58%) of N-isopropyl-2-[5-(4-quinolin-2-ylpiperazin-1-yl)pentanoylamino]benzamide.
Reaction SMILES: [CH2:1]([O:3]CC)C.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[N:11][CH:12]=1.C([Li])CCC.CN(C)C=O>O>[F:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][C:10]1[N:11]=[CH:12][C:7]([CH:1]=[O:3])=[CH:8][CH:9]=1
Reactant: Fc1cccc(Oc2ccc(Br)cn2)c1
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2cccc(F)c2)nc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 52 %

Procedure:
To a diethyl ether (100 mL) solution of 5-bromo-2-(3-fluoro-phenoxy)-pyridine (5.81 g, 21.7 mmol) described in Manufacturing Example 71-1-1 was added n-butyl lithium (13.8 mL, 1.57 M n-hexane solution, 21.7 mmol) under nitrogen atmosphere at −78° C., which was stirred for 40 minutes at −78° C. N,N-Dimethylformamide (2.02 mL, 26.0 mmol) was then added to the mixture at −78° C., and stirred for 25 minutes as the temperature was gradually raised to 0° C. Water was added to the reaction solution at 0° C., which was then extracted with ethyl acetate. The organic layer was separated, washed with 1 N aqueous sodium hydroxide solution and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=5:1) to obtain the title compound (2.47 g, 52%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1F)[CH2:3][OH:4].O1CCOCC1.CC([O-])(C)C.[K+].Cl>C(O)C>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH2:5][C@H:2]([NH2:1])[CH2:3]1
Reactant: N[C@H](CO)CSc1ccccc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Product: N[C@@H]1COc2ccccc2SC1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
In a round-bottom flask maintained under an inert atmosphere, 3.55 g (17.6 mmoles) of (2R)-2-amino-3-[(2-fluorophenyl)sulfanyl]propan-1-ol (4a-1) and 71 mL of dioxane are introduced. The solution is cooled to 0° C. then 9.90 g (88.2 mmoles) of potassium tert-butylate is added in portions, followed by stirring at ambient temperature for 12 hours. The mixture is then concentrated under reduced pressure and the residue taken up with water then extracted with ethyl acetate. The combined organic phases are washed with water, then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The brown oil thus obtained is taken up with a solution of 2.2 N HCl in ethanol (10.9 mL). The mixture is concentrated under reduced pressure and the chlorhydrate of the title compound is precipitated with the addition of isopropyl ether. The solid is filtered, washed with isopropyl ether, then dried under vacuum. The chlorhydrate of the title compound is obtained in the form of a solid cream (2.73 g, 12.5 mmoles).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.C(Cl)Cl.B(Br)(Br)Br>C(OCC)(=O)C>[OH:23][C:20]1[CH:19]=[CH:18][C:17]([CH:12]2[CH2:13][C:14]3[CH:15]=[CH:16][C:3]([OH:2])=[CH:4][C:5]=3[CH:6]3[CH:11]2[CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:22][CH:21]=1
Reactant: COc1ccc(C2Cc3ccc(OC)cc3C3CCCCC23)cc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Oc1ccc(C2Cc3ccc(O)cc3C3CCCCC23)cc1
Reaction time: 1.5 h
Yield: 71.8 %

Procedure:
Combine 6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthrene (132.1 mg, 0.41 mmol), methylene chloride (4.0 mL), boron tribromide (0.16 mL, 1.64 mmol) at 0° C., and stir under a nitrogen atmosphere. After 1.5 hours, add ethyl acetate to reaction mixture, quench reaction with sat ammonium chloride solution (aq). Wash organic layer with brine, dry over sodium sulfate, and concentrate in vacuo. Flash chromatograph to yield the titled compound (86.7 mg, 72%) as a white solid. 1H NMR (DMSO): 9.15 (s, 1H), 9.00 (s, 1H), 7.08 (d, 2H, J=8.8 Hz), 6.93 (d, 1H, J=8.4 Hz), 6.70 (m, 3H), 6.52 (dd, 1H, J=8.4, 2.2 Hz), 3.05 (m, 3H), 2.65 (m, 1H), 2.34 (d, 1H, J=12.8 Hz), 1.88 (m, 1H), 1.55 (m, 2H), 1.37 (m, 1H), 1.05 (m, 4H); MS m/z 293 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1.Cl[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]([OH:34])=[O:33])[CH:27]=1.C(N(CC)CC)C>C(O)C>[C:32]([C:28]1[CH:27]=[C:26]([N:21]2[CH2:20][CH2:19][CH:18]([CH2:17][NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:24])[CH2:23][CH2:22]2)[CH:31]=[CH:30][N:29]=1)([OH:34])=[O:33]
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(N2CCC(CNc3ccccc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Yield: 25 %

Procedure:
Using a similar procedure to that described in Example 52, N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (150 mg, 0.43 mmol), 4-chloropicolinic acid (95 mg, 0.60 mmol), triethylamine (87 mg, 0.86 mmol), and ethanol (2 mL) yielded 50 mg (25%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[C:24]([CH:28]=1)[C:25](O)=[O:26])(=[O:19])=[O:18]>>[F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:25](=[O:26])[C:24]3[CH:28]=[C:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:21]=[CH:22][C:23]=3[C:29]3[S:30][CH:31]=[CH:32][N:33]=3)[CH2:14][CH2:15]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(N2CCNCC2)cc1F
Reactant: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)N2CCN(c3ccc(C#N)c(F)c3)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 2-Fluoro-4-piperazin-1-yl-benzonitrile [204192-45-0] and 5-Methanesulfonyl-2-thiazol-2-yl-benzoic acid (Example O). MS (ISP): 471.0 MH+.
Reaction SMILES: [F:1][C:2]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:15](Cl)(Cl)=[O:16]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=[CH:5][C:3]=1[N:4]=[C:15]=[O:16]
Reactant: O=C(Cl)Cl
Reactant: CCOc1ccc(N)c(F)c1OCC
Solvent: Cc1ccccc1
Product: CCOc1ccc(N=C=O)c(F)c1OCC
Temperature: 25 °C

Procedure:
2-Fluoro-3,4-diethoxyaniline (1.99 g) in toluene (20 ml) was dropwise added to a toluene solution containing 10 g of phosgene at 10° to 20° C. The resulting mixture was gradually heated and, after being refluxed for 30 minutes, cooled to room temperature. The solvent was removed by distillation under reduced pressure to give 2-fluoro-3,4-diethoxyphenyl isocyanate. The thus obtained crude substance was added to a toluene solution (50 ml) containing triethylamine (1.0 g) and isopropanol (1.0 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-(2-fluoro-3,4-diethoxyphenyl)carbamate (Compound No. 1) (1.99 g) in a yield of 69.8%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([CH3:11])[N:6](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:5]2.C1(O)C=CC=CC=1.C(O)(=O)CC.[H-].[Na+]>Br>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([CH3:11])[NH:6][CH2:5]2
Reactant: Cc1ccc(S(=O)(=O)N2Cc3cc(Br)ccc3C2C)cc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: Oc1ccccc1
Solvent: CCC(=O)O
Product: CC1NCc2cc(Br)ccc21
Yield: 89.7 %

Procedure:
67.46 g of 5-bromo-1-methyl-2-(p-toluene sulfonyl)isoindoline (3-8) was suspended in 325 ml of 47% hydrobromic acid and 48 ml of phenol and 197 ml of propionic acid were added thereto and the resulting mixture was heated under reflux for 4 hours. After the reaction was completed, the reaction mixture was adjusted to be alkaline with 8N sodium hydride solution and extracted with chloroform and the resulting organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel chromatopraphy (eluent; chloroform:methanol=19:1) to obtain 35.03 g of 5-bromo-1-methylisoindoline.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].[CH:14]1([NH2:17])[CH2:16][CH2:15]1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:14]1([NH:17][C:11]([C:8]2[N:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)NC2CC2)nc1
Yield: 42.4 %

Procedure:
5-(Methoxycarbonyl)pyridine-2-carboxylic acid (1.50 g, 8.28 mmol) was dissolved in DMF (25 mL) and cyclopropylamine (689 uL, 9.94 mmol), Et3N (4.66 mL, 33.1 mmol) and HBTU (3.30 g, 8.69 mmol) were added. The reaction mixture was stirred for 3d and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with sat aq Na2CO3 (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (774 mg, 42.4%) as a white solid. LCMS (ES+): 221.2 [MH]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[CH:13]=1)[C:8](O)=[O:9])([CH3:3])[CH3:2].S(Cl)([Cl:20])=O>C1C=CC=CC=1>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[CH:13]=1)[C:8]([Cl:20])=[O:9])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)Oc1cc(OC(C)C)cc(C(=O)O)c1
Solvent: c1ccccc1
Product: CC(C)Oc1cc(OC(C)C)cc(C(=O)Cl)c1
Temperature: 25 °C

Procedure:
Diisopropoxybenzoic acid (compound F, 10 g, 41 mmol) was dissolved in benzene (100 mL) in a 500 mL round bottom flask. Thionyl chloride (12.2 mL, 168 mmol) was added and the reaction heated at reflux for 1 hour. The mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was redissolved in dichloromethane and concentrated again to give 3,5-diisopropoxybenzoyl chloride. In a separate 200 mL flask, N,O-dimethylhydroxylamine-HCl (4.0 g, 42 mmol) was suspended in 80 mL dichloromethane at 0° C. Triethylamine (12.4 mL, 88 mmol) was added slowly, followed by crude 3,5-diisopropoxybenzoyl chloride. The reaction flask was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched with water and extracted with three portions of dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the resulting brown oil by column chromatography (30% acetone/hexane) gave the Weinreb amide (compound G) as a yellow oil in 60% yield from 3,5-dihydroxybenzoic acid: Rf 0.33 (30:70 acetone/hexane); IR (cm−1): 2977, 1647, 1590, 1441, 1374, 1184, 1155, 1113, 1037, 964; 1H NMR (250 MHz, C6D6): δ 1.06 (dd, J=2.5, 5.9 Hz, 12H), 3.00 (s, 3H), 3.05 (s, 3H), 4.19 (qn, J=6.2 Hz, 2H), 6.69 (t, J=2.5 Hz, 1H), 7.10 (d, J=2.5 Hz, 2H); 13C NMR (63 MHz, C6D6): 21.9 (4C), 33.4, 60.4, 69.8 (2C), 106.6, 108.1 (2C), 137.0, 159.3 (2C), 169.8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)(=[O:32])=[O:33])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)N1CCNCC1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCNCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)piperazine. MS (ESI): mass calcd. for C20H20FN5O2S, 413.13; m/z found, 414.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.39 (m, 1H), 8.21-8.13 (m, 2H), 8.01-7.95 (m, 1H), 7.79-7.74 (m, 1H), 7.69-7.63 (m, 1H), 7.50-7.46 (m, 1H), 7.37-7.30 (m, 2H), 3.14-3.08 (m, 4H), 3.06-2.99 (m, 4H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](C)=[CH:8][CH:7]=[CH:6]2.B(Br)(Br)Br.Cl[CH2:19]Cl>>[CH3:19][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]2
Reactant: COc1ccc2c(C)cccc2c1
Reactant: ClCCl
Agent: BrB(Br)Br
Product: Cc1ccc2cc(O)ccc2c1
Temperature: -60 °C
Reaction time: 3 h

Procedure:
To a solution of 6-methoxy-1-methylnaphthalene (6.4 g) in dichloromethanie (500 ml), cooled to -60° C., was added boron tribromide (45 ml of a 1M solution in dichloromethane). The resulting mixture was stirred at -60° C. for 3 hours. The reaction was quenched with water (500 ml) and extracted with dichloromethane (2x500 ml). The organic extracts were combined, dried (MgSO4) and evaporated to give a solid. Purification by flash column chromatography on silica, eluting with ethyl acctate/hexane (5:95 v/v) gave 6-methyl-2-naphthol (3.76 g) as a white solid. This was used without further characterisation.
Reaction SMILES: C(N(C(C)C)CC)(C)C.CN(C(O[N:18]1[N:26]=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.[Cl:44][C:45]1[CH:46]=[C:47]([CH:51]=[C:52]([N:54]2[CH2:59][CH2:58][CH:57]([NH:60][C:61]([C:63]3[NH:64][C:65]([CH3:70])=[C:66]([Cl:69])[C:67]=3[Cl:68])=[O:62])[CH2:56][CH2:55]2)[N:53]=1)[C:48]([OH:50])=O.NN>CN(C=O)C>[Cl:68][C:67]1[C:66]([Cl:69])=[C:65]([CH3:70])[NH:64][C:63]=1[C:61]([NH:60][CH:57]1[CH2:56][CH2:55][N:54]([C:52]2[CH:51]=[C:47]([C:48]([NH:18][NH2:26])=[O:50])[CH:46]=[C:45]([Cl:44])[N:53]=2)[CH2:59][CH2:58]1)=[O:62]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)cc(Cl)n3)CC2)c(Cl)c1Cl
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)NN)cc(Cl)n3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 56.1 %

Procedure:
Diisopropylethylamine (0.043 ml, 0.25 mmol), HATU (0.048 g, 0.12 mmol) and HOAT (0.017 g 0.12 mmol) were added to a stirred solution of 2-chloro-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)isonicotinic acid (Example 153; 0.055 g, 0.12 mmol) in DMF (2 ml). The resultant solution was stirred for 5 mins and hydrazine (0.04 ml, 0.12 mmol) was added. The mixture was stirred at room temperature for 14 h, partitioned between water and EtOAc. The layers were separated and the organic layer was washed with water two more times. The organic phase was dried over magnesium sulfate and concentrated to give the title compound (30 mg).
Reaction SMILES: [OH-].[K+].[C:3](=[S:5])=S.[Cl:6][C:7]1[CH:8]=[C:9]([NH2:15])[C:10]([NH2:14])=[CH:11][C:12]=1[I:13]>O.CCO>[Cl:6][C:7]1[C:12]([I:13])=[CH:11][C:10]2[NH:14][C:3](=[S:5])[NH:15][C:9]=2[CH:8]=1
Reactant: S=C=S
Reactant: Nc1cc(Cl)c(I)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: S=c1[nH]c2cc(Cl)c(I)cc2[nH]1

Procedure:
KOH (15.7 g, 238 mmol) in water (50 mL), followed by carbon disulfide (14.4 mL, 238 mmol), was added to a solution of 4-chloro-5-iodobenzene-1,2-diamine (50 g, 198 mmol) in EtOH (300 mL). The mixture was heated at reflux for 3 h, cooled and filtered. To the filtrate was added water (300 mL) and then AcOH (25 mL) in water (50 mL). The precipitate was collected, washed with water and a small amount of EtOH and dried to afford the desired product as a brown powder, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:14])[CH3:13])[CH2:8][CH2:7]1)=O.O.[NH2:21][NH2:22]>C(O)C>[C:12]([N:9]1[CH2:10][CH2:11][CH:6]([C:4](=[N:21][NH2:22])[C:3]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:2]=2[F:1])[CH2:7][CH2:8]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(=O)N1CCC(C(=NN)c2ccc(F)cc2F)CC1
Yield: 79.2 %

Procedure:
A solution of 15.0 g of 4-(2,4-difluorobenzoyl)-1-acetylpiperidine, 6.9 g of hydrazine hydrate and 140 ml of ethanol was heated under reflux for 4 hrs. The ethanol was removed in vacuo to give a solid. The solid was triturated with water, filtered and dried to yield 12.5 g (64%) of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine hydrazone, mp 139°-142° C.
Reaction SMILES: [CH3:1][N:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B1OC(C)(C)C(C)(C)O1)[S:3]([CH2:6][CH3:7])(=[O:5])=[O:4].Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=2)=[C:26]([F:37])[CH:25]=1>>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N:2]([CH3:1])[S:3]([CH2:6][CH3:7])(=[O:4])=[O:5])=[CH:25][C:26]=2[F:37])=[N:31][CH:32]=1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Reactant: CCS(=O)(=O)N(C)c1ccccc1B1OC(C)(C)C(C)(C)O1
Product: CCS(=O)(=O)N(C)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using N-methyl-N-(2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanesulfonamide and 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): mass calcd. C19H19FN4O2S, 386.12; m/z found, 387.1 [M+H]+. 1H NMR (400 MHz, CDC3) δ 8.63-8.57 (m, 1H), 8.13-8.09 (d, J=1.5, 1H), 8.04-7.95 (m, 1H), 7.72-7.62 (m, 0.75H), 7.59-7.51 (m, 0.25H), 7.50-7.39 (m, 3.75H), 7.37-7.32 (m, 1H), 7.31-7.28 (m, 0.25H), 4.69 (s, 2H), 3.16 (s, 3H), 2.89 (q, J=7.4, 2H), 1.25 (t, J=7.4, 3H).
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:17][CH:16]=3)=[C:8]([C:12]#[N:13])[C:9]=2[CH3:11])[C:4](=[O:26])[N:3]1[C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]1[OH:33].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[OH:33][C@@H:28]1[CH2:29][CH2:30][CH2:31][CH2:32][C@H:27]1[N:3]1[CH2:2][C:10]2[C:5](=[CH:6][C:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:17][CH:16]=3)=[C:8]([C:12]#[N:13])[C:9]=2[CH3:11])[C:4]1=[O:26]
Reactant: Cc1c(C#N)c(Cc2ccc(-n3cccn3)cc2)cc2c1C(O)N([C@@H]1CCCC[C@H]1O)C2=O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C#N)c(Cc2ccc(-n3cccn3)cc2)cc2c1CN([C@@H]1CCCC[C@H]1O)C2=O
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 20.8 %

Procedure:
To a solution of rac-3-hydroxy-2-(trans-2-hydroxycyclohexyl)-4-methyl-1-oxo-6-[4-(1H-pyrazol-1-yl)benzyl]-2,3-dihydro-1H-isoindole-5-carbonitrile (0.10 g) in dichloromethane (2.00 mL) was added trifluoroacetic acid (0.31 mL) under ice-cooling. After 15 min, triethylsilane (0.50 mL) was added thereto, and the mixture was stirred at 15° C. for 16 hr. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (×2). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by prep-HPLC, then lyophilized to give the title compound (0.02 g).