Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:5])=[N+]=[N-]>CCOC(C)=O.[Pd]>[C:15]1([C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([S:21]([C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)(=[O:22])=[O:23])[C:6]=2[CH:4]([NH2:1])[CH3:5])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(C(C)N=[N+]=[N-])c(-c3ccccc3)c3ccccc32)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2c(C(C)N)c(-c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.3 %

Procedure:
A mixture of 2-(1-azidoethyl)-3-phenyl-1-(toluene-4-sulfonyl)-1H-indole (1.34 g, 3.22 mmol) and 10% Pd/C (200 mg) in EtOAc (80 mL) was degassed with a stream of nitrogen and stirred at RT under a hydrogen atmosphere for 20 h. The suspension was filtered and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) affording the title compound as a white solid (960 mg, 76%). 1H NMR (CDCl3, 400 MHz): δ 8.18 (1H, d, J=8.44 Hz), 7.73 (2H, d, J=8.44 Hz), 7.49-7.15 (10H, m), 4.72 (1H, q, J=6.96 Hz), 2.35 (3H, s), 1.45 (3H, d, J=7.40 Hz).
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][CH2:5][CH:6]([OH:12])[C:7]#[C:8][CH2:9][CH2:10][CH3:11]>CC(=O)CC>[OH:12][CH:6]([C:7]#[C:8][CH2:9][CH2:10][CH3:11])[CH2:5][CH2:4][I:1]
Reactant: CCCC#CC(O)CCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCC#CC(O)CCI
Reaction time: 18 h

Procedure:
A mixture of 15 g. of sodium iodide in 100 ml. of 2-butanone is stirred at the reflux temperature for 30 minutes. To the cooled mixture is added 12 g. of 1-chloro-3-hydroxy-4-octyne in 150 ml. of 2-butanone. The resulting mixture is stirred at the reflux temperature for 18 hours then cooled and filtered. The mother liquor is taken to dryness and the residue is triturated with benzene and filtered. The benzene is taken to dryness to give the subject product as an oil. The material is shown to be homogeneous by vapor phase chromatography and thin layer chromatography.
Reaction SMILES: N1(O[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([C:23]2[NH:27][N:26]=[C:25]([NH:28][C:29]3[CH:30]=[N:31][C:32]([N:37]4[CH:41]=[C:40]([Cl:42])[N:39]=[CH:38]4)=[C:33]([O:35][CH3:36])[CH:34]=3)[N:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CC(=O)CC>[Cl:42][C:40]1[N:39]=[CH:38][N:37]([C:32]2[N:31]=[CH:30][C:29]([NH:28][C:25]3[N:24]=[C:23]4[CH:15]([C:16]5[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=5)[CH2:14][CH2:13][CH2:12][CH2:11][N:27]4[N:26]=3)=[CH:34][C:33]=2[O:35][CH3:36])[CH:41]=1
Reactant: COc1cc(Nc2n[nH]c(C(CCCCOn3nnc4ccccc43)c3ccc(F)cc3)n2)cnc1-n1cnc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC(C)=O
Product: COc1cc(Nc2nc3n(n2)CCCCC3c2ccc(F)cc2)cnc1-n1cnc(Cl)c1
Temperature: 180 °C
Yield: 5.7 %

Procedure:
A microwave vial was charged with N-(5-(5-(1H-benzo[d][1,2,3]triazol-1-yloxy)-1-(4-fluorophenyl)pentyl)-1H-1,2,4-triazol-3-yl)-6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-amine (300 mg, 0.509 mmol), DIEA (0.089 mL, 0.509 mmol), and 2-butanone (5 mL). The mixture was heated in a microwave at 180° C. for 4 h. The reaction mixture was concentrated in vacuo. The crude product was purified using silica gel column chromatography (10-80% EtOAc/chloroform, linear gradient) to afford N-(6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-yl)-9-(4-fluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine (13 mg, 0.029 mmol, 6% yield) as white solid. LC-MS (M+H)+ 454.2. 1H NMR (500 MHz, chloroform-d) δ ppm 8.13 (d, J=1.53 Hz, 1 H) 8.03 (d, J=2.44 Hz, 1 H) 7.82 (d, J=2.44 Hz, 1 H) 7.58 (d, J=1.83 Hz, 1 H) 7.13-7.21 (m, 2H) 7.06 (t, J=8.70 Hz, 2H) 6.77 (s, 1 H) 4.16-4.34 (m, 3 H) 3.88 (s, 3 H) 1.78-2.28 (m, 6 H).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=4)[N:19]([CH3:33])[N:18]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[CH3:33][N:19]1[C:20]([C:22]2[CH:23]=[CH:24][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:26][CH:27]=2)=[CH:21][C:17]([CH2:16][O:15][C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:34])=[O:3])=[CH:10][CH:11]=2)=[N:18]1
Reactant: CCOC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)n(C)n3)cc21
Agent: [Li+]
Agent: [OH-]
Product: Cn1nc(COc2ccc3ccn(CC(=O)O)c3c2)cc1-c1ccc(OC(F)(F)F)cc1

Procedure:
In analogy to the procedure described for example 1 f], {6-[1-methyl-5-(4-trifluoromethoxy-phenyl)-1H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain {6-[1-methyl-5-(4-trifluoromethoxy-phenyl)-1H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid as colorless solid.
Reaction SMILES: C(O)C.C(O)(=O)C.[Cl:8][C:9]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[CH2:29][CH2:28]2)[C:24]([N+:41]([O-])=O)=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22])=[O:12]>[Fe]>[NH2:41][C:24]1[C:25]([N:27]2[CH2:28][CH2:29][N:30]([C:33]3[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[CH2:31][CH2:32]2)=[CH:26][C:9]([Cl:8])=[C:10]([CH:23]=1)[C:11]([NH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22])=[O:12]
Reactant: Cc1ccc(C)c(N2CCN(c3cc(Cl)c(C(=O)NCCCN4CCCC4=O)cc3[N+](=O)[O-])CC2)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(C)c(N2CCN(c3cc(Cl)c(C(=O)NCCCN4CCCC4=O)cc3N)CC2)c1
Temperature: 75 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stir bar and fitted with a septum with a nitrogen inlet, the iron powder (578.30 mg, 10.36 mmol) was suspended in clean, dry, reagent-grade ethanol (50.00 ml, 856.34 mmol) and was stirred vigorously at room temperature under nitrogen as the acetic acid (5.00 ml, 87.34 mmol) was added. The 2-chloro-4-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-5-nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide 12c (212.90 mg, 0.41 mmol) was added in one portion and the reaction was warmed to 75° C. The reaction was allowed to stir for 4 h. After 4 h, the reaction was cooled to room temperature and filtered through Celite, eluting with methanol. The solvent was then removed under reduced pressure and the ruby red oil was taken up in 100 ml of ethyl acetate. 100 ml of saturated NaHCO3 was added to the solution. The layers were separated and the aqueous layer was extracted twice with 75 ml of ethyl acetate. The organic phases were combined and washed with brine (1×100 ml) and dried over Na2SO4. The product solution was decanted and the solvent was removed under reduced pressure. The crude product, 5-amino-2-chloro-4-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide 12d (158.70 mg, 0.33 mmol), was isolated as a brown solid and was carried on without further purification. LCMS (m/e)=485 (M+H).
Reaction SMILES: [C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:13][CH:12]([NH:29]C(OC(C)(C)C)=O)[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C(C(CN1C2C=CC=CC=2N(C(=O)C(C)(C)C)CC(NC(OC(C)(C)C)=O)C1=O)=O)(C)(C)C>>[C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([C:21](=[O:28])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:13][CH:12]([NH2:29])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1C(=O)CN1C(=O)C(NC(=O)OC(C)(C)C)CN(C(=O)c2ccccc2)c2ccccc21
Agent: CC(C)(C)OC(=O)NC1CN(C(=O)C(C)(C)C)c2ccccc2N(CC(=O)C(C)(C)C)C1=O
Product: Cc1ccccc1C(=O)CN1C(=O)C(N)CN(C(=O)c2ccccc2)c2ccccc21

Procedure:
Step 2 of Example 10 was repeated except that 1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-benzoyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine that obtained from Step 2 of Example 22 was used instead of 1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine, to thereby obtain the title compound.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][N:3]=1.Cl.N.[OH2:12]>>[OH:12][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: O
Reactant: Fc1ncc(F)c(Cl)n1
Agent: Cl
Agent: N
Product: Oc1ncc(F)c(Cl)n1
Yield: 92.2 %

Procedure:
15.05 g (0.1 mole) of 2,5-difluoro-4-chloropyrimidine were heated under reflux together with 30 ml of 37% strength aqueous hydrochloric acid for 2 hours. The volatile constituents were then stripped off in vacuo, the residue was taken up in 100 ml of water and this mixture was rendered weakly alkaline (pH 7.5) with 20% strength aqueous ammonia. The mixture was then again concentrated in vacuo down to 20% of the original volume. The solid obtained was filtered off with suction and dried. 13.7 g of product with a melting point of 176° to 177° C. (decomposition) were obtained, corresponding to a yield of 92.2%.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[C:12]([F:15])([F:14])[F:13])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CCN(Cc3ccccc3)CC2)c(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
7 g (31.5 mmol) of methyl 4-fluoro-3-trifluoromethyl-benzoate are dissolved in 60 ml of dry dimethylsulphoxide (DMSO) and combined with 5.55 g (31.5 mmol) of N-benzylpiperazine and 4.35 g (31.5 mmol) of potassium carbonate. The mixture is stirred for 12 hours at 90° C. After cooling, the reaction mixture is poured into 200 ml of water and extracted three times with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over magnesium sulphate and distilled off in vacuo. The residue is chromatographed on silica gel with a mixture of ethyl acetate and n-heptane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:17][N:18]1[CH2:23][C:22]([CH3:24])=[N:21][NH:20][C:19]1=[O:25].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C>[CH3:24][C:22]1[CH2:23][N:18]([NH:17][C:14]([C:11]2[CH:12]=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:16])[C:19](=[O:25])[NH:20][N:21]=1
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Reactant: CC1=NNC(=O)N(N)C1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC1=NNC(=O)N(NC(=O)c2cnc(-c3cccc(F)c3)nc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To a solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (0.317 g, 1.45 mmol) in anhydrous DMF (5 mL) is added 4-amino-6-methyl-4,5-dihydro-2H-[1,2,4]triazin-3-one (0.206 g, 1.45 mmol) followed by the addition of DMTMM (0.421 g, 1.52 mmol). The mixture is stirred at rt overnight. The mixture is partitioned between a saturated aqueous NaHCO3 solution and EtOAc. The organic phase is separated, dried (MgSO4), filtered and concentrated in vacuo to afford 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid (6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide (0.306 g) as a solid. MS: 329 (M+H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[F:12][C:13]1([F:24])[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][CH2:21][CH2:22][OH:23])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:5]([O:4][C:2](=[O:3])[N:20]([CH2:19][CH:16]1[CH2:15][CH2:14][C:13]([F:12])([F:24])[CH2:18][CH2:17]1)[CH2:21][CH2:22][OH:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCCNCC1CCC(F)(F)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N(CCO)CC1CCC(F)(F)CC1
Reaction time: 1 h
Yield: 83.7 %

Procedure:
Benzyl chloroformate (4.8 mL, 33.2 mmol) was added to a solution of 2-[(4,4-difluoro-cyclohexylmethyl)-amino]-ethanol (6.41 g, 33.2 mmol) and DIPEA (5.8 mL) in DCM (200 mL) and the reaction mixture was stirred for 1 h. The reaction mixture was washed with 0.1 N HCl (150 mL) and then with water (100 mL). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title product as a clear oil (9.1 g) which partially crystallized overnight.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]([Br:14])[C:11]([O:15][CH3:16])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)[CH3:2].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CN(C)C1C=CN=CC=1.O1CCCC1>[Br:14][C:12]1[C:11]([O:15][CH3:16])=[CH:10][C:6]2[C:7](=[O:9])[O:8][C:1]([CH3:2])=[N:4][C:5]=2[CH:13]=1
Reactant: COc1cc(C(=O)O)c(NC(C)=O)cc1Br
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2c(=O)oc(C)nc2cc1Br
Reaction time: 0.25 h
Yield: 87.1 %

Procedure:
4-(Dimethylamino)pyridine (63 mg) and 2-(acetamido)-4-bromo-5-methoxybenzoic acid (0.49 g) were added to a tetrahydrofuran (1.5 mL) solution of di-tert-butyl dicarbonate (0.75 g) at room temperature, followed by stirring at the same temperature for 4 hours and 15 minutes. Tetrahydrofuran (2 mL) was added to the reaction mixture at room temperature, followed by stirring at the same temperature for 3 days. (Di-tert-butyl)dicarbonate (0.37 g) was added to the reaction mixture at room temperature, followed by stirring at the same temperature for one day. The solvent was evaporated under reduced pressure, and ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added to the residue. The organic layer was separated, washed with a 10% aqueous solution of citric acid and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue, and the solid substance was collected by filtration to obtain 0.40 g of 7-bromo-6-methoxy-2-methyl-4H-3,1-benzoxazin-4-one as a brown solid.
Reaction SMILES: [CH3:1][CH:2]([S:4]([NH2:7])(=[O:6])=[O:5])[CH3:3].CN(C)C=O.[H-].[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([N:23]=[C:24]=[O:25])[CH:19]=[CH:20][C:21]=1[Cl:22]>C1COCC1>[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][C:24]([NH:7][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])=[O:25])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: CC(C)S(N)(=O)=O
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)NC(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
2-propanesulfonamide (4.40 g) was combined with THF (150 ml) and then dimethylformamide (40 ml) and sodium hydride (2.1 g) were added and the mixture stirred two hours at room temperature. To the mixture was added 3,4-dichlorophenyl isocyanate (7.52 g) in THF (50 ml) and the mixture stirred overnight. The solvent was removed under vacuum, water was added and the mixture filtered. The filtrate was evaporated and then more water introduced when crystals did not form. The solution was made acidic and stirred overnight. The precipitated solid was recovered by filtration. Recrystallization from toluene provided 4.9 g of product with a melting point 151°-4° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][NH:16][C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.Br[C:18]1[N:23]=[C:22]([F:24])[C:21]([CH2:25][OH:26])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>O1CCOCC1.[Cu]I>[F:24][C:22]1[C:21]([CH2:25][OH:26])=[CH:20][CH:19]=[C:18]([N:16]2[C:10]3[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[N:13]=[CH:12][C:11]=3[CH:14]=[N:15]2)[N:23]=1
Reactant: Cc1cncc(-c2cc3[nH]ncc3cn2)n1
Reactant: OCc1ccc(Br)nc1F
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(CO)c(F)n2)n1
Temperature: 105 °C
Yield: 11.8 %

Procedure:
A mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (2.000 mmol; 422.4 mg), (6-bromo-2-fluoro-3-pyridyl)methanol (2.400 mmol; 494.4 mg), potassium carbonate (4.000 mmol; 552.8 mg), copper(I) iodide (2.000 mmol; 380.9 mg), and N,N′-Dimethylethylenediamine (0.2000 mmol; 17.81 mg; 0.0217 mL) in 1,4-Dioxane (15 mL) was purged with Argon then sealed in a pressure tube and heated at 105° C. overnight. The mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated and the residue was purified on silica eluted with 0 to 100% EtOAc in Heptane to afford [2-fluoro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-3-pyridyl]methanol (79.5 mg, 12%).
Reaction SMILES: [C:1]([C:3]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])#[N:2].[CH3:13][Si](Cl)(C)C>CO>[C:1]([C:3]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH3:13])=[O:6])#[N:2]
Reactant: Cc1cccc(C(=O)O)c1C#N
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)c1cccc(C)c1C#N
Temperature: 0 °C
Reaction time: 5 h
Yield: 81.3 %

Procedure:
2-Iodo-3-methylbenzoic acid (1.50 g, 5.70 mmol) was dissolved in DMF (15 mL) and treated with CuCN (0.625 g, 7.0 mmol). The solution was heated at 85° C. for 1 h, cooled and poured into water (25 mL). The solution was cooled to 0° C. and 2-cyano-3-methylbenzoic acid precipitated from the solution was isolated by filtration to yield 0.651 mg of a white solid (71%). Crude 2-cyano-3-methylbenzoic acid (0.50 g, 3.1 mmol) was dissolved in MeOH (10 mL) and cooled to 0° C. This solution was treated with excess trimethylsilyl chloride (5.0 mmol) and allowed to warm to RT where it was stirred for 5 h. The methanol was removed under vacuum and the residue was treated with water (20 mL) and extracted with ethyl acetate and concentrated to yield methyl 2-cyano-3-methylbenzoate (0.44 g, 2.52 mmol). To this solid was added DMF (5 mL), Sc(OTf)3 (0.01 g, 0.02 mmol), and diaminopropane (0.22 g, 3.0 mmol). The resulting mixture was heated at 85° C. for 0.5 h, cooled and the cyclic intermediate 5-Methyl-2,3-dihydro-1H-4,9a-diaza-fluoren-9-one was isolated by trituration with ether. This compound (0.112 g, 0.5 mmol) was dissolved in ethanol containing excess hydrazine hydrate (3.0 mmol). This solution was stirred at RT for 20 h and 4-(3-amino-propylamino)-5-methyl-2H-phthalazin-1-one was isolated by flash chromatography (MeOH/DCM/Et3N).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].N1C=CC=CC=1.[F:14][C@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[OH:21].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>ClCCl>[F:14][C@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[O:21][C:2](=[O:3])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: O[C@H]1CCCC[C@@H]1F
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)O[C@H]1CCCC[C@@H]1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-chloroethyl chloroformate (1.0 mL), pyridine (1.0 mL), and dichloromethane (30 mL), (1S,2S)-2-fluorocyclohexanol [CSA No. 292150-03-9] (900 mg) dissolved in dichloromethane (10 mL) was added at −78° C. After stirring the resulting mixture overnight at room temperature, dichloromethane (30 mL) was added to the mixture. The resulting mixture was sequentially washed with 0.5 N hydrochloric acid and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain the captioned compound (480 mg).
Reaction SMILES: [OH:1][C@H:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[O:21]1[CH2:23][CH:22]1[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1>>[OH:21][CH:22]([C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1)[CH2:23][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[C:10]2[C:11]([CH3:20])=[C:12]3[C:13](=[CH:18][CH:19]=2)[C:14](=[O:17])[O:15][CH2:16]3)[CH2:5][CH2:6]1
Reactant: Cc1c([C@@H](O)CN2CCNCC2)ccc2c1COC2=O
Reactant: N#Cc1ccc(C2CO2)cc1
Product: Cc1c(C(O)CN2CCN(CC(O)c3ccc(C#N)cc3)CC2)ccc2c1COC2=O

Procedure:
4-[1-Hydroxy-2-[4-[2-hydroxy-2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLES 2C and 28-29 starting from 5-[(1R)-1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one and 4-(oxiran-2-yl)benzonitrile.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]1[C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37][C:23]=3[N:24]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:25]=2[CH:26]=1.C(Cl)Cl.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>>[F:54][C:53]([F:56])([F:55])[C:51]([OH:57])=[O:52].[S:27]([N:24]1[C:25]2[CH:26]=[C:18]([N:3]3[CH:4]=[CH:5][C:6]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=4)=[CH:7][C:2]3=[O:1])[CH:19]=[CH:20][C:21]=2[C:22]2[CH2:40][NH:39][CH2:38][CH2:37][C:23]1=2)([C:30]1[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=1)(=[O:29])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(-n5ccc(-c6ccc(C(F)(F)F)cn6)cc5=O)cc42)CN(C(=O)OC(C)(C)C)CC3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(-n5ccc(-c6ccc(C(F)(F)F)cn6)cc5=O)cc42)CNCC3)cc1
Yield: 100 %

Procedure:
tert-Butyl 7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-5-tosyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (165 mg, 0.248 mmol) was stirred in TFA (3 mL) and methylene chloride (1 mL) for 3 h. Concentration of the solution under reduced pressure provided the title compound (164 mg, 100%) as a yellow oil; ESI MS m/z 565 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1.CCOC(C)=O>[CH3:21][S:22]([O:12][CH2:11][CH2:10][C@@H:9]([NH:13][C:14]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a stirred solution of 174 (1.327 g, 4.144 mmol) in THF (30 mL) at 0° C. was added TEA (0.6931 mL, 4.973 mmol) and MsCl (0.3528 mL, 4.559 mmol) and the solution stirred for 1 h at 0° C. The mixture was diluted with EtOAc, washed with dilute HCl solution, aq. satd. NaHCO3, and brine, dried (MgSO4) and concentrated to afford 1.51 grams (91%) of (R)-3-(tert-butoxycarbonylamino)-3-(3,4-dichlorophenyl)propyl methanesulfonate (364). The product may contain some of the corresponding chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[S:11]([N:14]=C=O)(=[O:13])=[O:12].C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][S:11](=[O:13])(=[O:12])[NH2:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1cc(Cl)cc(Cl)c1
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1cc(Cl)cc(Cl)c1
Yield: 83 %

Procedure:
The procedure used in Example 75 was used to prepare this compound from a mixture of 16.3 g (0.10 mole) of 3,5-dichlorophenol and 9.1 ml (0.105 mole) of chlorosulfonyl isocyanate in 75 ml of toluene. The compound was obtained in 83% yield as a white, fluffy solid, mp 146°-147° C. (benzene).