Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)(=O)C.[N:25]([O-])=O.[Na+].C(=O)([O-])O.[Na+]>O>[N:1]1([CH:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:7]2[CH:12]=[CH:11][C:10]3[NH:13][N:25]=[N:14][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=N[O-]
Reactant: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(C(c2ccc3[nH]nnc3c2)n2ccnc2)cc1
Yield: 85.3 %

Procedure:
To a stirred and cooled (5° C.) solution of 5.2 parts of 4-[(1H-imidazol-1-yl)phenylmethyl]-1,2-benzenediamine in 4.8 parts of acetic acid and 20 parts of water was added a solution of 1.38 parts of sodium nitrite in 10 parts of water. The whole was stirred for 1 hour at room temperature. The reaction mixture was treated with a sodium hydrogen carbonate solution and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 64 parts of ethyl acetate. The product was filtered off and dried, yielding 4.7 parts (85.3%) of 5-[(1H-imidazol-1-yl)phenylmethyl]-1H-benzotriazole; mp. 178.8° C. (compound 146).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][NH2:4].OC1C=CC=CN=1.[C:14]([O:18][C:19](=[O:48])[NH:20][C@H:21]([C@@H:39]1[CH2:43][C@@H:42]([CH:44]([CH3:46])[CH3:45])[C:41](=[O:47])[O:40]1)[CH2:22][N:23]1[CH2:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH2:25][C:24]1([CH3:38])[CH3:37])([CH3:17])([CH3:16])[CH3:15]>O>[C:14]([O:18][C:19](=[O:48])[NH:20][C@@H:21]([CH2:22][N:23]1[CH2:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH2:25][C:24]1([CH3:38])[CH3:37])[C@@H:39]([OH:40])[CH2:43][C@H:42]([C:41](=[O:47])[NH:4][CH2:3][C@@H:2]([CH3:1])[CH2:5][CH3:6])[CH:44]([CH3:46])[CH3:45])([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Reactant: CC[C@H](C)CN
Agent: Oc1ccccn1
Solvent: O
Product: CC[C@H](C)CNC(=O)[C@@H](C[C@H](O)[C@H](CN1CC(=O)N(c2ccccc2Cl)CC1(C)C)NC(=O)OC(C)(C)C)C(C)C
Temperature: 80 °C
Reaction time: 4 h
Yield: 79.3 %

Procedure:
0.24 ml of (S)-2-methylbutylamine (2.0 mmol) and 37 mg of 2-hydroxypyridine (0.39 mmol) were added to 200 mg of {(S)-2-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (1m) (0.39 mmol), and the mixture was stirred at 80° C. for four hours. The reaction mixture was cooled and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/acetone=3/1) to obtain 184 mg of the title compound (yield: 79%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[CH3:22][C:23]1([CH3:29])[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1>[I-].[K+].CCCCCCC>[I:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:25]2[CH2:26][CH2:27][CH2:28][C:23]([CH3:29])([CH3:22])[CH2:24]2)=[CH:7][CH:8]=1
Reactant: CC1(C)CCCNC1
Reactant: ClCCCOc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCCCCCC
Product: CC1(C)CCCN(CCCOc2ccc(I)cc2)C1
Temperature: 30 °C
Reaction time: 0.08 h
Yield: 77.1 %

Procedure:
A mixture of 1-[(3-chloropropyl)oxy]-4-iodobenzene (100 g) and acetonitrile (600 ml) is stirred for about 5 min at 25-35° C., then potassium carbonate (93.07 g) followed by 3,3-dimethylpiperidine (49.53 g) are added over about 10 min. Potassium iodide (2.24 g) is added, then the mixture is stirred for about 15 min, before being heated to 78-82° C. for 22-24 h. The reaction mixture is cooled to 25-35° C., and the solid residue is filtered and washed with acetonitrile (200 ml). The filtrate and washings are concentrated under reduced pressure at 50-60° C. to give a thick liquid which is stirred with n-heptane (100 ml) for about 30 min at 25-30° C. The solution is then cooled to −5 to 10° C. and stirred for about 30 min. The solid is filtered, washed with chilled n-heptane (50 ml, 0-5° C.), then dried at 35-40° C. under vacuum for 6-10 h to give the title compound (97 g).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([I:9])=[CH:7][CH:8]=1)[NH2:2].[CH3:10][N:11]([C:13](Cl)=[N+](C)C)[CH3:12].F[P-](F)(F)(F)(F)F>CN(C=O)C>[I:9][C:6]1[CH:7]=[CH:8][C:3]2[N:4]([C:10]([N:11]([CH3:13])[CH3:12])=[N:2][N:1]=2)[N:5]=1
Reactant: CN(C)C(Cl)=[N+](C)C
Reactant: NNc1ccc(I)nn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN(C)c1nnc2ccc(I)nn12
Reaction time: 0.08 h
Yield: 82.4 %

Procedure:
The 3-hydrazinyl-6-iodopyridazine (1.00 g, 4.24 mmol, prepared using General Procedure D from Example #9, Step A with hydrazine) was dissolved in DMF (10 mL) then N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate(V) (1.31 g, 4.66 mmol, Fluka) was added. The solution was stirred for about 5 min and then TEA (1.30 mL, 9.32 mmol) was added. The mixture was stirred at ambient temperature for about 1 h then at about 60° C. for about 2 h. The reaction was concentrated under reduced pressure then the mixture was partitioned between DCM (20 mL) and saturated aqueous NaHCO3. The layers were separated then the organic solution was dried over MgSO4, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel with DCM/MeOH (95:5) as an eluent. The fractions were collected then concentrated under reduced pressure and the residue was triturated with Et2O (20 mL). The solid was collected by filtration and dried overnight under vacuum to give the title compound (1.01 g, 90%): LC/MS (Table 1, Method g) Rt=1.60 min; MS m/z: 289.8 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:13][CH2:14][CH2:15][CH3:16])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:17][NH2:18].[BH4-].[Na+].O>CO>[C:1]([C:5]1[C:6]([O:13][CH2:14][CH2:15][CH3:16])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][NH:18][CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCOc1c(C=O)cccc1C(C)(C)C
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCOc1c(CNC)cccc1C(C)(C)C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
3-tert-Butyl-2-propoxy-benzaldehyde (1.15 g, 5.21 mmol) was dissolved in anhydrous methanol (25 ml). Methylamine (2.00 ml of 33% solution in ethanol, 16.1 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a yellow oil and then dissolved in anhydrous methanol (25 ml). Sodium borohydride (198 mg, 5.23 mmol) was added and the mixture was stirred overnight at room temperature. Water (10 ml) was added and the solution was concentrated. Sodium hydroxide (30 ml, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×50 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford (3-tert-butyl-2-propoxy-benzyl)-methyl-amine (1.18 g, 96%) as a clear oil: 1H NMR (400 MHz, DMSO-d6) δ 7.28 (d, J=8.0 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 6.97 (y J=8.0, y1H), 3.79 (t, J=4.0 Hz, 2H), 3.61 (s, 2H), 2.28 (s, 3H), 1.80-1.75 (m, 2H), 1.33 (s, 9H), 1.03 (t, J=8.0 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH3:23])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:9])=[O:8])(=[O:3])[NH2:2].[OH-].[Na+].O>C(O)C>[C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]2[C:5]=1[N:13]=[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][CH3:23])[NH:9][C:7]2=[O:8])(=[O:3])[NH2:2]
Reactant: CCOc1ccccc1C(=O)Nc1c(C(N)=O)cccc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1ccccc1-c1nc2c(C(N)=O)cccc2c(=O)[nH]1
Yield: 77.6 %

Procedure:
A stirred mixture of 3-carbamoyl-2-(2-ethoxybenzamido)benzamide (Preparation 18; 1 g, 0.003 mol) sodium hydroxide (0.61 g, 0.015 mol), water (30 ml) and ethanol (7 ml) was heated under reflux for 1 hour. The cool solution was washed with dichloromethane (3×30 ml), acidified to pH 1 with 2N hydrochloric acid and the resulting precipitate collected by filtration. The solid was suspended in saturated aqueous sodium carbonate solution (60 ml) and this suspension extracted with dichloromethane-methanol (98:2, 3×100 ml). The extracts were combined, dried (Na2SO4) and evaporated under vacuum, then the residue triturated with diethyl ether (50 ml) to give the title compound as a white solid (0.72 g, 78%), m.p. 252-254° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([O:16]CC)=O)=[C:5]2[OH:19].[C:20]([NH:29][NH2:30])(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([NH:30][NH:29][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:16])=[C:5]2[OH:19]
Reactant: CCOC(=O)c1c(O)c2cc(Cl)ccc2n(C)c1=O
Reactant: CCCCCCCC(=O)NN
Product: CCCCCCCC(=O)NNC(=O)c1c(O)c2cc(Cl)ccc2n(C)c1=O

Procedure:
Reagents: Comp 37 (0.36 mmols, 0.1 g); octanoyl hydrazine (0.39 mmols, 0.062 g). Yield: 0.12 g (86%), white solid, m.p.=187° C.-188° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:33])=[C:8]2[C:14]([Br:15])=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:12]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[CH3:34][C:35]([CH3:40])([CH3:39])[C:36](Cl)=[O:37].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:33][C:36](=[O:37])[C:35]([CH3:40])([CH3:39])[CH3:34])=[C:8]2[C:14]([Br:15])=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:12]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(-c1ccc(Cl)cc1)n2Cc1ccc2c(c1)OCO2
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncc2c(c(Br)c(-c3ccc(Cl)cc3)n2Cc2ccc3c(c2)OCO3)c1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a suspension mixture of 1-benzo[1,3]dioxol-5-ylmethyl-3-bromo-2-(4-chloro-phenyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (320 mg, 0.60 mmol)(from Example 35(e)) in CH2Cl2 (3 mL) at 0° C. was added 2,2-dimethyl-propionyl chloride (87.4 mg, 0.73 mmol) and triethylamine (122 mg, 1.20 mmol). Resulting mixture was stirred at room temperature for 1.5 h. It was diluted with CH2Cl2 and washed with 0.1 N HCl aqueous solution, water and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (eluting with 5%-20% EtOAc in CH2Cl2) to give the title compound 361 mg. MS-(+)-ion: M+1=614.98, 613.02.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:21])[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[CH:22]([Mg]Br)=[CH2:23].[Cl-].[NH4+]>O1CCCC1>[CH3:7][C:6]([OH:8])([CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:21])[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[CH:22]=[CH2:23]
Reactant: C=C[Mg]Br
Reactant: CC(=O)CCC=C(C)CCC=C(C)COC1CCCCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(C)(O)CCC=C(C)CCC=C(C)COC1CCCCO1
Temperature: 25 °C
Reaction time: 10 h
Yield: 70 %

Procedure:
A solution of 6,10-dimethyl-11-(2-tetrahydropyranyl) oxy-5,9-undecadien-2-one (80 mg, 0.27 mmol) in tetrahydrofuran (3 ml) was stirred on an ice bath under argon atmosphere. To the solution was added vinylmagnesium bromide in tetrahydrofuran (0.3 ml, 0.3 mmol, 1.0M), and the mixture was warmed to room temperature and stirred for 10 hours. After addition of saturated aqueous ammonium chloride (2 ml), the reaction mixture was extracted with ether. The extract was dried over Na2SO4 and evaporated in vacuo to remove the solvent to give a crude product, which was purified with silica gel column chromatography to obtain 3,7,11-trimethyl-12-(2-tetrahydropyranyl)oxy-1,6,10-dodecatrien-3-ol (61 mg, 70%).
Reaction SMILES: C[CH2:2][O-:3].[Na+].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:13][C:14]#[N:15].C(OCC)=O>C(O)C>[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:13]([CH:2]=[O:3])[C:14]#[N:15]
Reactant: CC[O-]
Reactant: N#CCc1cccc(Cl)c1Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC=O
Product: N#CC(C=O)c1cccc(Cl)c1Cl
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 45 %

Procedure:
To a solution of NaOEt (from 3.63 gms Na) in ethanol (500 ml) was added 2,3-dichlorophenylacetonitrile (Example 14.3) in ethanol (150 ml). Ethyl formate (16.67 gms) was then added and the mixture stirred at 80° C. for 45 minutes, before adding a further quantity of ethyl formate (2.78 gms). After stirring at 80° C. for a further 1.5 hours, the precipitate was filtered off and dried in vacuo. The solid was dissolved in water, filtered, acidified with concentrated hydrochloric acid and the precipitate filtered off and dried in vacuo, 14.35 gms, 45% yield.
Reaction SMILES: [OH-].[Na+].C[C:4]([CH:6]1[CH:8]([CH2:9][C:10](Cl)([Cl:12])[Cl:11])[C:7]1([CH3:15])[CH3:14])=[O:5].BrBr.S([O-])([O-])=[O:19].[Na+].[Na+]>O.CO>[CH3:14][C:7]1([CH3:15])[CH:8]([CH:9]=[C:10]([Cl:12])[Cl:11])[CH:6]1[C:4]([OH:5])=[O:19]
Reactant: O=S([O-])[O-]
Reactant: CC(=O)C1C(CC(Cl)(Cl)Cl)C1(C)C
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Temperature: 70 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To 250 ml of methanol solution containing 24 g of sodium hydroxide were added 17 g of 2,2-dimethyl-3-(2',2',2'-trichloroethyl)-cyclopropyl methyl ketone (purity: 97.9%, cis/trans ratio 91.5/8.5) under cooling with ice, and then 40 g of bromine were added dropwise at -10° C. to -5° C. for 20 minutes and after stirring the mixture at the same temperature for 2 hours, 25.2 g of sodium sulfite (7 hydrate) and 250 ml of water were added thereto, and the mixture was heated up to 70° C. and stirred for 47 hours with heating. Then the methanol was distilled off, water was added to the reaction mixture and neutral part was removed by extraction with ether. The water layer was acidified with conc. hydrochloric acid under cooling with ice. The deposited crystals were filtered, washed with water and dried to obtain 9.85 g of 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropanecarboxylic acid, cis/trans ratio 89.8/10.2, purity 91.8%, yield 72.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20](F)=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1.[CH3:25][C@H:26]1[CH2:30][CH2:29][C@H:28]([CH3:31])[NH:27]1.N12CCCN=C1CCCCC2.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:27]4[C@@H:28]([CH3:31])[CH2:29][CH2:30][C@@H:26]4[CH3:25])=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](C)N1
Reactant: COc1ccc(Cc2ccc(F)nc2)c(F)c1-c1cccc(Cl)c1
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(Cc2ccc(N3[C@@H](C)CC[C@@H]3C)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 160 °C

Procedure:
In an 8 mL vial equipped with a stir bar was placed 5-(3′Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (P-456, 100 mg, 0.289 mmol), (2S,5S)-2,5-dimethyl-pyrrolidine (176 mg, 1.30 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (367 uL, 2.60 mmol). The mixture was heated to 160° C. for 3 hours and then cooled to room temperature. The reaction mixture was treated with water (4 mL) and 1M HCl (6 mL). The aqueous portion was extracted with dichloromethane (2×30 mL), the organic portions were combined, washed with brine (15 mL), dried (MgSO4) and concentrated. The crude material was purified by silica gel column chromatography utilizing 5% acetone/dichloromethane as the eluent to produce 10 mg of P-577 as a pale viscous oil. 1H NMR (400 MHz, DMSO-d6) δ 1.05 (d, J=6 Hz, 6H), 1.56-1.61 (m, 4H), 3.72 (s, 3H), 3.75 (s, 2H), 4.07-4.12 (m, 2H), 6.38 (d, J=9 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 7.27-7.32 (m, 3H), 7.37 (s, 1H), 7.41-7.47 (m, 2H), 7.95 (d, J=2 Hz, 1H) ppm. MS (APCI+): 425.1 (M+1) LC-MS: 92%
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH2:6][CH2:7][C@@H:8]([NH:9][C:10](=[O:25])[C@H:11]([CH2:21][CH:22]([CH3:24])[CH3:23])[N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:13])[C@@H:4]2[CH2:3][NH:2]1.C(N(CC)CC)C.[F:33][C:34]([F:46])([F:45])[C:35]1[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1>ClCCl>[C:17]([O:16][C:14]([N:12]([CH3:13])[C@H:11]([C:10]([NH:9][C@H:8]1[C@H:4]2[C@H:5]([CH2:1][N:2]([S:41]([C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([C:34]([F:33])([F:45])[F:46])[CH:36]=3)(=[O:43])=[O:42])[CH2:3]2)[CH2:6][CH2:7]1)=[O:25])[CH2:21][CH:22]([CH3:23])[CH3:24])=[O:15])([CH3:18])([CH3:19])[CH3:20]
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CNC[C@H]21)N(C)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N1-[(3aS,4R,6aR)-Octahydrocyclopenta[c]pyrrol-4-yl]-N2-(tert-butyloxycarbonyl)-N2-methyl-L-leucinamide from Step A (220 mg, 0.622 mmol) in dichloromethane (5.0 mL) was added triethylamine (0.130 mL, 0.934 mmol) followed by 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.110 ml, 0.685 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction was reduced in volume and loaded onto a silica gel cartridge (Analogix®, Burlington, Wis., RS-24). The title compound was eluted with a gradient of 0% to 10% methanol (2 N ammonia)/dichloromethane over 20 minutes to give N2-(tert-butyloxycarbonyl)-N2-methyl-N1-((3aS,4R,6aR)-2-{[3-(trifluoromethyl)phenyl]sulfonyl}octahydrocyclopenta[c]pyrrol-4-yl)-L-leucinamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.32 (bs, 1H), 8.18-8.13 (m, 1H), 8.02-7.95 (m, 1H), 7.90-7.84 (m, 1H), 7.68 (t, J=7.9, 1H), 4.17-4.09 (m, 1H), 3.77-3.69 (m, 1H), 3.20-3.11 (m, 2H), 3.05-2.97 (m, 4H), 2.53-2.47 (m, 2H), 1.98-1.88 (m, 1H), 1.87-1.71 (m, 3H), 1.62-1.48 (m, 3H), 1.46 (s, 9H), 1.32-1.22 (m, 1H), 0.87 (dd, J=6.6, 15.5, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[C:5]([CH3:16])[CH:4]=1)#[N:2].C1C(=O)N([Br:24])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:16][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][C:6]=1[NH:9][C:10](=[O:15])[C:11]([F:13])([F:12])[F:14]
Reactant: Cc1cc(C#N)ccc1NC(=O)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(NC(=O)C(F)(F)F)c(CBr)c1
Temperature: 25 °C

Procedure:
In a 500 mL round-bottomed flask N-(4-cyano-2-methylphenyl)-2,2,2-trifluoroacetamide (Intermediate 1; 7.3 g, 32.0 mmol), NBS (5.98 g, 33.6 mmol), and benzoyl peroxide (70%) (1.162 g, 4.80 mmol) were added to carbon tetrachloride (150 mL). The reaction mixture was then heated to reflux under argon for 4 days. The reaction mixture was cooled to room temperature then NBS (0.5 eq, 3 g) and benzoyl peroxide (0.075 eq, 0.581 g) were added. The reaction mixture was then heated to reflux for a further 18 hrs. The reaction mixture was allowed to cool to room temperature then poured into 2M NaOH (100 mL). The organic layer was collected then washed with a solution of sodium metabisulfite (10 g in 100 mL water), dried (MgSO4), filtered and the solvent removed. The resulting orange oil was then purified through a plug of silica gel eluting with 1-10% EtOAc:isoHexane. The desired fractions were then combined and evaporated to dryness to give a 1:1 mixture of the title compound and the starting material as an orange solid (9 g) which was then used in the next step without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C:17]3([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1.Cl.N[C:32](N)=N.ClC1C2C(=CC=C(S(NC3(C(OC)=O)CCOCC3)(=O)=O)C=2)C(Cl)=CN=1.NC(N)=N>CS(C)=O.O>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C:17]3([C:23]([O:25][CH3:32])=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1
Reactant: N=C(N)N
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)NC3(C(=O)O)CCOCC3)cc12
Agent: COC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CCOCC1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCOCC1
Temperature: 50 °C
Yield: 16.6 %

Procedure:
4-{[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}tetrahydro-2H-pyran-4-carboxylic acid hydrochloride ##STR55## NaH (33.5 mg, 80% dispersion by wt in mineral oil, 1.12 mmol) was added in one portion to a stirred solution of guanidine hydrochloride (176 mg, 1.84 mmol) in DMSO (3.0 mL) under N2 and the mixture was heated at 50° C. for 15 min. Methyl 4-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}tetrahydro-2H-pyran-4-carboxylate (187 mg, 0.446 mmol) was added in one portion and the mixture heated at 80° C. for 8 h. A second portion of guanidine (0.45 mmol) [prepared from guanidine hydrochloride and NaH] in DMSO (1.0 mL) was added and the mixture heated at 90° C. for an additional 4 h. The cooled mixture was poured into water (100 mL), extracted with EtOAc (3×50 mL) and the combined organic extracts were washed with brine, dried (Na2SO4). The solvents were evaporated in vacuo and the residue purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (95:5:0.5) as eluant, and then crystallised with EtOAc, to give to give methyl 4-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}tetrahydro-2H-pyran-4-carboxylate (83 mg, 0.186 mmol) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CN=C1.[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15].[NH4+].[Cl-]>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: ClCCCl
Product: CC(C)[Si](Oc1ccc(Br)cc1)(C(C)C)C(C)C
Reaction time: 12 h
Yield: 110.2 %

Procedure:
To a stirred solution of 4-bromophenol (25.1 g, 146 mmol), and imidazole (19.9 g, 292 mmol) in 1,2-dichloroethane (150 mL) at 23° C. was added triisopropylsilylchloride (34.4 mL, 161 mmol). The mixture was stirred for 12 h and poured onto saturated aqueous NH4Cl (400 mL), followed by extraction with CH2Cl2 (3×200 mL). The combined extracts were washed with brine (300 mL), dried (Na2SO4), and concentrated in vacuo to give a pale yellow oil which was crude oil was purified via short-path distillation (0.5 mmHg, 130° C.) to yield (4-Bromo-phenoxy)-triisopropylsilane as a colorless oil (53.0 g, 99% yield). Rf 0.81 (3:1 hexanes/EtOAc) IR (thin film) 2945, 2892, 2867 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.30 (2H, d, J=9 Hz), 6.75 (2H, d, J=9 Hz), 1.29-1.18 (3H, m), 1.08 (18H, d, J=7 Hz). 13C NMR (75 MHz, CDCl3) δ 155.0, 132.0, 121.5, 112.9, 17.6, 12.4. HRMS calcd. for C15H26OSiBr (MH+) 329.0936, found 329.0937.