Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[NH:24][N:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[H-].[Na+].Br[CH2:44][CH2:45][O:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][O:48]1>CN(C=O)C>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:44][CH2:45][O:46][CH:47]5[CH2:52][CH2:51][CH2:50][CH2:49][O:48]5)[N:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: BrCCOC1CCCCO1
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCOC4CCCCO4)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
In a round-bottomed flask, 2-(6-chloro-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (see Example 23, 120 mg, 0.21 mmol) was dissolved in DMF (1.3 ml). The reaction mixture was cooled to 0° C. and sodium hydride (60% dispersion in mineral oil, 10 mg, 0.25 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min then 2-(2-bromoethoxy)tetrahydro-2H-pyran (47 μl, 0.31 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 4 h. The reaction mixture was quenched with water and extracted with ethyl acetate (2×). The combined organic layers were washed with water, sat LiCl, and brine then dried over MgSO4 and concentrated. The residue was chromatographed over silica gel with 50% to 100% EtOAc/heptane to afford 138 mg (94%) of 2-{6-chloro-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-indazol-3-yl}-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a viscous yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([N+:23]([O-])=O)[CH:17]=1.C(O)(=O)C>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH2:23])[C:19]([NH2:22])=[CH:20][CH:21]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(N)c(N)c3)c2cc1OC
Reaction time: 18 h

Procedure:
4-(6,7-Dimethoxyquinazolin-4-yloxy)-2-nitro-phenylamine (Step A, 1 g, 2.9 mmol) was dissolved in EtOH (200 mL) and glacial acetic acid (10 mL) and placed under nitrogen. Pd/C was added, the reaction mixture blanketed with H2, the mixture was shaken under H2 for 18 h at 55 psi. The catalyst was removed by filtration through Celite® and the solution was concentrated in vacuo. The residue was dissolved in MeOH/H2O and NH4OH was added to adjust to PH 10, and the solvent evaporated. Purification of the residue by column chromatography using a gradient of 0-100% of a 90:10:1 (CH2Cl2:MeOH: NH4OH) afforded the title compound as a orange solid. MS(MH+)=N/A; Calc'd 312.32 for C16H16N4O3.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([CH2:14][CH2:15][NH3+:16])[CH2:9][CH2:10][C:11]([O-:13])=[O:12]>C(O)(=O)C>[C:1]1(=[O:6])[N:16]([CH2:15][CH2:14][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[C:4](=[O:5])[CH:3]=[CH:2]1
Reactant: O=C1C=CC(=O)O1
Reactant: [NH3+]CCCCCC(=O)[O-]
Solvent: CC(=O)O
Product: O=C(O)CCCCCN1C(=O)C=CC1=O

Procedure:
The symmetrical anhydride of 6-Maleimidocaproic acid (Compound 24, FIG. 5) was prepared by the reaction of maleic anhydride and e-Amino-n-caproic acid in the presence of acetic acid to give 6-Maleimidocaproic acid (Compound 23) which was then converted to Compound 24 using dicyclohexyl carbodiimide (DCCl).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](O)=[O:6].B.C1COCC1.CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: O=C(O)c1cc(F)cc(Br)c1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-bromo-5-fluorobenzoic acid (4.51 g, 20.59 mmol) in THF (41.2 mL) at 0° C., BH3.THF (41.2 mL, 41.2 mmol) was added dropwise over 30 min, the reaction mixture was then allowed to return to room temperature and stirred at room temperature overnight. Methanol (40 mL) was added slowly and stirred at room temperature for 1 h. THF and Methanol was removed in vacuo. The residue was then extracted by EtOAc, and washed with sat.NaHCO3, The organic was dried and concentrated. The crude product was used in next step reaction without purification. LCMS (m/z): 187.2 (MH+−18), 0.66 min. 1H NMR (400 MHz, CDCl3) δ ppm 7.32 (s, 1H), 7.19-7.14 (m, 1H), 7.05 (tdd, J=0.7, 1.5, 9.1 Hz, 1H), 4.70 (br. s., 2H), 1.78 (br. s., 1H).
Reaction SMILES: [O:1]=[C:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)[CH:3]=[CH2:4].C(N(CC)CC)C.[SH:25][C:26]1[CH:27]=[C:28]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:29]([OH:38])=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:31]=1>CO>[OH:38][C:29]1[C:28]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:27][C:26]([S:25][CH2:4][CH2:3][C:2]([N:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][CH2:10]2)=[O:1])=[CH:31][C:30]=1[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C=CC(=O)N1CCN(Cc2ccccc2)CC1
Reactant: Oc1c(-c2ccccc2)cc(S)cc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(CCSc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1)N1CCN(Cc2ccccc2)CC1
Reaction time: 12 h
Yield: 29.5 %

Procedure:
Following the procedure of Example 4, 1-(1-oxo-2-propenyl-4-phenylmethyl)piperazine (Example 6) (2.30 g, 0.01 mole) was dissolved in methanol (150 ml) and triethylamine (1 ml) added to the solution. The solution was flushed with argon several times, 5'-mercapto [1,1':3',1"-terphenyl]-2'-ol (2.77 g, 0.01 mole) added and the reaction stirred for 12 hours. The solvent was removed and the product isolated by chromatography to yield 1.5 g of product after drying in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.CCN(C(C)C)C(C)C.[Cl:30][C:31]1[N:36]=[C:35](Cl)[N:34]=[CH:33][N:32]=1>C(O)C>[Cl:30][C:31]1[N:36]=[CH:35][N:34]=[C:33]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[N:32]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc2c(c1)CCN(C1CCN(c3ncnc(Cl)n3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.84 g (6.67 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 4.54 mL (26.7 mmol) DIPEA were placed in 50 mL ethanol. 1.00 g (6.67 mmol) 2,4-dichloro-[1,3,5]triazine were added and the reaction mixture was stirred overnight at RT. The precipitated solid was suction filtered and dried,
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C:20]([OH:22])=O)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:23][C:24]1(C)OC(=O)CC(=O)[O:25]1.S([O-])(O)(=O)=O.[K+]>CN(C1C=CN=CC=1)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:24](=[O:25])[CH:23]=[C:20]([OH:22])[CH:11]2[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: N#Cc1ccc(N[C@@H](Cc2ccc(F)cc2)C(=O)O)cc1Cl
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(N2C(=O)C=C(O)C2Cc2ccc(F)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
To a solution of N-(3-chloro-4-cyanophenyl)-4-fluorophenylalanine (3.67 g), Meldrum's acid (1.74 g) and 4-(N,N-dimethylamino)pyridine (2.11 g) in tetrahydrofuran (50 mL) was added N,N′-carbonyldiimidazole (2.24 g, 13.8 mmol) at 0° C., and the mixture was stirred at room temperature overnight. A 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous potassium hydrogen sulfate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), and the mixture was refluxed for 45 min. After allowing to room temperature, the organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate-isopropyl ether to give the title compound as colorless crystals (yield: 2.54 g, 64%).
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].N1C=CN=C1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][CH2:17][C@@H:18]([OH:21])[CH2:19][CH3:20]>ClCCl>[CH2:19]([C@@H:18]1[O:21][S:1](=[O:2])[N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=2)[CH2:17]1)[CH3:20]
Reactant: O=S(Cl)Cl
Reactant: CC[C@H](O)CNc1ccccn1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC[C@H]1CN(c2ccccn2)S(=O)O1

Procedure:
Thionyl chloride (18.98 millimoles) in dichloromethane (20 ml) is added dropwise to imidazole (4.7 g, 69 millimoles) in dichloromethane (50 ml) under argon. Then after 15 minutes the title compound of part (a) (17.26 millimoles) in 25 ml of dichloromethane was added slowly at a temperature maintained below 5° C. After an hour at a temperature range of 0° to 5° the temperature was allowed to warm up to room temperature. After 1 hour, water was added The organic layer was separated and the aqueous layer was subjected to extraction with dichloromethane. The combined organic portions were washed twice with water, dried (sodium sulphate) and evaporated to give the title compound as an orange oil (3.325 g, 15.66 millimoles), NMR data δ(400 MHz; CDCl3) 1.11 (1.5 H, t,J 8 Hz), 1.12 (1.5 H, t,J 8 Hz), 1.88-2.05 (1.5 H, m), 2.11-2.22 (0.5 H, m), 3.32 (0.5 H, dd, J 10 and 8 Hz), 3.74 (0.5 H, dd, J 10 and 7 Hz), 3.93-4.02 (1 H, m) 4.84-4.91 (0.5 H, m), 5.35-5.42 (0.5 H, m), 6.63 (0.5 H, d, J 8 Hz), 6.73 (0.5 H, d, j 8 Hz), 6.88-6.94 (1 H, m), 7.59-7.65 (1 H, m) and 8.25-8.30 (1 H, m).
Reaction SMILES: [C:1]1([CH:7]([O:16][C:17]2[CH:24]=[CH:23][C:20]([CH2:21]O)=[CH:19][CH:18]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Br-:31].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[C:1]1([CH:7]([O:16][C:17]2[CH:24]=[CH:23][C:20]([CH2:21][Br:31])=[CH:19][CH:18]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc(OC(CCc2ccccc2)c2ccccc2)cc1
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: BrCc1ccc(OC(CCc2ccccc2)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
To an ice cold solution of 6-5 (1.19 g, 6.0 mmol) in acetonitrile (15 ml) was added pyridine (0.76 g, 9.6 mmol) and then triphenylphosphine dibromide (3.29 g, 7.8 mmol). The mixture was stirred at ice bath temperature for 1/4 hr under N2 and at ambient temperature for 1 &3/4 hrs and then was filtered. Concentration of the filtrate in vacuo gave a crude oil. The pure product 6-6 was obtained after three silica gel chromatographic separations.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[NH:10][CH2:9][CH2:8][C:7]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:6]1=2)=[O:4].Cl.[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:21][CH:20]=1)=O.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[C:6]2[C:7](=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)[CH2:8][CH2:9][N:10]1[CH2:17][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:23][CH:24]=1)=[O:4]
Reactant: COC(=O)C1NCCc2cc(O)ccc21
Reactant: CC(=O)N[C@@H](C)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1c2ccc(O)cc2CCN1Cc1ccc([C@H](C)NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 200 mg (0.821 mmol) 7-hydroxy-1,2,3,4-tetrahydro-3-isoquinoline-4-carboxylic acid methyl ester hydrochloride and 157 mg (0.821 mmol) (S)—N-(1-(4-formylphenyl) ethyl) acetamide (example III) in 5 mL THF are added 141 μL (2.46 mmol) AcOH and the mixture is stirred at r.t. for 10 min. After that time, the resulting mixture is cooled to 0° C., 261 mg (1.23 mmol) sodium triacetoxyborohydride are added and the reaction mixture is stirred at r.t. for 2 h. After that time, the reaction is quenched by addition of 500 μL water and purified by HPLC (ACN/H2O/NH3).
Reaction SMILES: [CH3:1][C:2]([O:14][Si](C)(C)C)([CH3:13])[C:3]#[C:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:6].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[OH:14][C:2]([CH3:13])([CH3:1])[C:3]#[C:4][C:5]([C:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CC(C)(C#CC(=O)c1ccncc1)O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(O)C#CC(=O)c1ccncc1
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a stirred solution of 4-methyl-1-(pyridin-4-yl)-4-(trimethylsilyloxy) pent-2-yn-1-one (0.5 g, 1.915 mmol) in DCM (10 mL) was added PTSA (0.47 g, 2.49 mmol) at RT and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with DCM (50 mL). The organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered and then concentrated in vacuo to afford 4-hydroxy-4-methyl-1-(pyridin-4-yl) pent-2-yn-1-one (0.35 g, 96%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][Br:11]
Reactant: Cc1cc(Cl)c(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(Cl)c(CBr)cc1Cl
Temperature: 25 °C
Yield: 37.8 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 5.0 grams (0.026 mole) of 2,4,5-trichlorotoluene and 5.3 grams (0.030 mole) of N-bromosuccinimide in 30 ml of carbon tetrachloride was heated to reflux and then was irradiated with a sun lamp during a 10 minute period. The reaction mixture was allowed to cool to ambient temperature at which time it was filtered to remove excess succinimide. The filtrate was concentrated under reduced pressure to a residual oil. The oil was distilled under vacuum, yielding four fractions in the boiling point range of 130°-152° C./5 mm Hg. NMR analysis of the fractions indicated that two fractions, boiling point 140°-150° C./5 mm Hg., contained the majority of the reaction product. The two fractions were combined and diluted with 1 ml of petroleum ether. The mixture was filtered to remove unreacted starting material. The filtrate was diluted with 12 ml of petroleum ether, and the solution was cooled in dry-ice. The solvent was removed from the resultant solid by pipette. The solid was dried under reduced pressure, yielding 2.7 grams of 80% pure 2,4,5-trichlorophenylmethyl bromide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C.O>[CH:11]1[C:12]2[C:7](=[N:6][C:5]3[C:14]([N:13]=2)=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc2c(c1)Nc1ccccc1N2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc2nc3ccccc3nc2c1
Temperature: 25 °C
Yield: 40 %

Procedure:
5,10-dihydrophenazine in an amount of 10 g is dissolved in 100 ml ethanol and added to 2.6 g NaOH dissolved in 2 ml of water. The mixture was heated to reflux and O2 bubbled through for 30 minutes. TLC shows that the 5,10-dihydrophenazine is converted completely to phenazine. The mixture was stripped to a volume of 45 ml and 25 ml water added. After cooling in a refrigerator, 8.0 grams of crude phenazine is collected by filtration. The crude phenazine is dissolved in 80 ml toluene, filtered hot, and stripped to 25 ml. When cooled, 5.86 of still somewhat brown phenazine is collected. After an additional recrystallization from toluene, a further toluene solution (50 ml) is treated with 1.0 g charcoal, reduced to 20 ml, cooled to room temperature and then under refrigeration, to yield 4.0 g (40%) of yellow phenazine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[N:6]=[C:5]2[C:19](O)=[O:20].Cl.[CH3:23][O:24][C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][CH2:30]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[N:6]=[C:5]2[C:19]([N:29]1[CH2:28][CH2:27][C:26]2[C:31](=[CH:32][CH:33]=[CH:34][C:25]=2[O:24][CH3:23])[CH2:30]1)=[O:20]
Reactant: COc1cccc2c1CCNC2
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccc(F)cc12
Agent: Cl
Product: COc1cccc2c1CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3ccc(F)cc13)C2
Yield: 13.4 %

Procedure:
Reaction of 6-fluoro-2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 98 (13.4% yield). 1H NMR (400 MHz, CDCl3) δ 2.83 and 3.05 (2t, 2H), 3.61 and 4.20 (2t, 2H), 3.85 and 3.89 (2s, 3H), 4.57 and 5.12 (2s, 2H), 6.44-6.93 (m, 2H), 7.10-7.27 (m, 2H), 7.50-7.53 (m, 1H), 7.69-7.76 (m, 2H), 8.18-8.21 (m, 1H), 8.33-8.36 (m, 1H), 8.40-8.45 (m, 1H); MS (ESI) m/z 432 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][C:13](=[O:14])[N:5]([C:6]=23)[CH2:4][C:3]1=[O:15].[H-].[Na+].Br[CH2:19][C:20]#[N:21]>CN(C=O)C>[CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[N:12]([CH2:19][C:20]#[N:21])[C:13](=[O:14])[N:5]([C:6]=23)[CH2:4][C:3]1=[O:15]
Reactant: N#CCBr
Reactant: CN1C(=O)Cn2c(=O)[nH]c3cccc1c32
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)Cn2c(=O)n(CC#N)c3cccc1c32
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 6-methyl-4H-imidazo[1,5,4-de]quinoxaline-2,5(1H,6H)-dione (296 mg, 1.46 mmol, described in Intermediate 23) in DMF (5 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil; 78 mg, 1.96 mmol) and the resulting mixture was stirred for 5 min Bromoacetonitrile (0.122 mL, 1.75 mmol) in was added dropwise and the reaction mixture was allowed to warm to ambient temperature and was stirred for 3 h, then quenched with H2O (20 mL). The mixture was extracted with EtOAc (2×30 mL) and the combined organic extracts were washed with brine (10 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was partially purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 95:5, followed by trituration with CH2Cl2 to give the title compound. MS: m/z=243 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:22](O)=[O:23])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32](=[N:34]O)[NH2:33]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:22]3[O:23][N:34]=[C:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[F:25])[N:33]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCCC3)C2)cc1
Reactant: NC(=NO)c1ccccc1F
Product: CCc1ccc(C2CC(c3nc(-c4ccccc4F)no3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
73 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-carboxylic acid (Example 41A) and 47 mg (0.24 mmol, 1.1 eq.) of 2-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 46 mg (47% of theory)
Reaction SMILES: [CH:1]1([N:7]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[O:20][CH2:19][CH2:18][N:17]([C@@H](C4C=CC=CC=4)C)[CH2:16]3)=[CH:11][CH:10]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].C(O)C>[CH:1]1([N:7]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[O:20][CH2:19][CH2:18][NH:17][CH2:16]3)=[CH:11][CH:10]=2)[CH3:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N(C)C3CCCCC3)cc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(c1ccc([C@H]2CNCCO2)cc1)C1CCCCC1
Temperature: 50 °C
Reaction time: 10 h
Yield: 94.6 %

Procedure:
A 300-ml flask containing a solution of (S)-2-(4-(N-cyclohexyl-N-methylamino)phenyl)-4-((R)-1-phenylethyl)morpholine (7.27 g, 19.07 mmol) and 10% palladium on carbon (3.0 g) in ethanol (30 ml) was charged with hydrogen. The reaction mixture was stirred vigorously at 50° C. for 10 hours. The catalyst was filtered off with a Celite pad, and the filtrate was concentrated under reduced pressure to yield (2S)-2-(4-(N-cyclohexyl-N-methylamino)phenyl)morpholine (4.95 g, 95%) as a clear oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=[O:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2ccc(Cl)cc2)c(NC(C)=O)c2ccc(Cl)cc21
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)Nc1c(C(=O)c2ccc(Cl)cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 2 (Method A) from 3-acetylamino-6-chloro-2-(4-chlorobenzoyl)-1-(ethoxycarbonyl)indole (step 1). m.p.: 175-176° C. (ethyl acetate/hexane)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:13])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(Br)c1
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1cccc(Br)c1

Procedure:
To CHCl3 is added 3-bromobenzoic acid (100 g) and thionyl chloride (109 ml) and refluxed overnight. The remaining thionyl chloride is evaporated off to afford 3-bromobenzoic acid chloride.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH:26][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: COc1cccc(CN)c1
Product: COc1cccc(CNc2nccc(-n3cnc4ccccc43)n2)c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3-methoxybenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. 1H NMR (500 MHz, CDCl3): δ 0.60 (br s, 1H); 8.44 (br s, 1H); 8.08 (br s, 1H); 7.86 (d, J=8.5 Hz, 1H); 7.3-7.5 (m, 3H); 7.02 (d, J=7.6 Hz; 1H); 6.98 (s, 1H); 6.85 (m, 2H); 5.86 (br s, 1H); 4.73 (d, J=5.7 Hz, 2H); 3.82 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[N:9][OH:10])=[N:6][CH:7]=1.[Cl:11]N1C(=O)CCC1=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([Cl:11])=[N:9][OH:10])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccc(Br)cn1
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccc(Br)cn1
Reaction time: 1 h
Yield: 94.8 %

Procedure:
5-Bromopyridine-2-carbaldehyde oxime (49.5 g, 246.3 mmol) was dissolved in DMF (150 ml) followed by addition of N-chlorosuccinimide (39.5 g, 295.5 mmol). HCl gas was then bubbled in the solution for 20 seconds to initiate the reaction, which was then allowed to stir for 1 hr. The reaction was poured into distilled water (1 L) and the precipitate was collected by vacuum filtration. The filter cake was washed with distilled water (2×500 ml) and then dried overnight in a vacuum oven at 60° C. (−30 inches Hg) to yield the product as a white powder (55 g).