Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][C:19]#[N:20]>>[C:19](/[C:18](/[C:17]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:15]([O:14][CH3:13])[CH:16]=1)=[CH:1]\[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)#[N:20]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: COc1ccc(CC#N)cc1OC
Product: COC(=O)c1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1
Yield: 30 %

Procedure:
Methyl 4-formylbenzoate (1.64 g) and 3,4-dimethoxybenzyl cyanide (1.77 g) were subjected to condensation in accordance with process B of (production process 2), to thereby produce the target product (0.97 g, yield: 30%).
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>>[Br:1][C:2]1[N:10]([CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[C:15]([F:14])([F:24])[F:25])[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccccc1C(F)(F)F
Yield: 69 %

Procedure:
8-Bromo-3-methyl-3,7-dihydropurine-2,6-dione and 2-(trifluoromethyl)benzyl bromide were reacted and purified as described in the General procedure G, step A, to afford 81A as white crystals in 69% yield.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]12[CH2:15][CH2:14][C:11]([C:16]([OH:18])=O)([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)(=[O:5])=[O:4])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:25][NH2:26]>C(Cl)Cl.CN(C=O)C>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]12[CH2:15][CH2:14][C:11]([C:16]([NH:26][CH3:25])=[O:18])([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)(=[O:5])=[O:4])[CH3:2]
Reactant: CN
Reactant: CCS(=O)(=O)CCC12CCC(C(=O)O)(CC1)CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCS(=O)(=O)CCC12CCC(C(=O)NC)(CC1)CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Carboxylic acid 10-4 (810 mg, 2.96 mmol) was dissolved in 12 mL of anhydrous methylene chloride under nitrogen atmosphere, treated with oxalyl chloride (2M in methylene chloride, 4.4 mL, 8.8 mmol) and subsequently with 5 drops of DMF. The reaction was stirred at room temperature under nitrogen atmosphere for 90 min, then evaporated and placed under vacuum for 20 mnin. The acid chloride was dissolved in anhydrous methylene chloride (12 mL), cooled in an ice-bath, and then treated dropwise with a solution of methylamine (2M in THF, 8.9 mL, 17.8 mmol). Upon addition of the amine, the cooling bath was removed and the reaction stirred at ambient temperature for 30 min. The mixture was diluted with 200 mL of methylene chloride and washed with 1N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was subjected to chromatography on silica gel eluting with a gradient from 0 to 3.5% methanol in methylene chloride to give 4-[2-(ethylsulfonyl)ethyl]-N-methylbicyclo[2.2.2]octane-1-carboxamide 10-5 as a white powder. MS (ESI+)=288 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[N:16]([CH2:20][CH3:21])[N:15]=3)[CH2:10][CH2:9]2)=[C:4]([F:22])[CH:3]=1.[N+:23]([C:26]1[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1)([O-:25])=[O:24]>CC(O)=O.CO>[CH2:20]([N:16]1[N:15]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2](/[N:1]=[CH:31]/[C:29]4[O:30][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=4)=[CH:3][C:4]=3[F:22])[CH2:9][CH2:10]2)[O:18][C:17]1=[O:19])[CH3:21]
Reactant: CCn1nc(C2CCN(c3ccc(N)cc3F)CC2)oc1=O
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Solvent: CO
Solvent: CC(=O)O
Product: CCn1nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3F)CC2)oc1=O
Yield: 87 %

Procedure:
5-[1-(4-Amino-2-fluorophenyl)-4-piperidyl]-3-ethyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7 g, 0.30 g, 1 mmol) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and re-crystallized in ethanol to obtain product 3-ethyl-5-[1-(2-fluoro-4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9 g, 373 mg, 87%).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:25]([Si:29]([O:32][CH2:33][CH2:34]I)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[C:25]([Si:29]([CH3:31])([CH3:30])[O:32][CH2:33][CH2:34][CH:6]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OCCI
Reactant: N#Cc1ccc(Cn2ccnc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCC(c1ccc(C#N)cc1)n1ccnc1
Temperature: -60 °C

Procedure:
4-Imidazol-1-ylmethyl-benzonitrile (5.5 gms, 30 mmol) was suspended in freshly distilled THF (150 mL) in dry glassware and stirred under argon in a -60° C. dry ice acetone bath then Lithium bis(trimethylsilyl)amide 1 molar in THF (33 mL) was added slowly. The mixture was stirred for 30 minutes and the temperature was reduced to -78° C. A suspension of tert-butyl-(2-iodo-ethoxy)-dimethyl-silane (9.5 gm, 33 mmol) in 20 mL of THF was cooled to -78° C. and added via cannula to the first solution and the resulting mixture was allowed to slowly warm to ambient temperature. After 16 hours the reaction was quenched by the addition of 10 mL of water and the solvent was removed in vacuo. The residue was suspended in ethyl acetate (200 mL) and extracted 2 times with saturated aqueous sodium bicarbonate (100 mL), then water (100 mL), then saturated sodium chloride solution (100 mL). The organic solvent was removed in vacuo and the residue was chromatographed on silica gel using 1:3 ethyl acatate: hexanes. The desired fractions were combined and the solvent was removed in vacuo to give the desired product.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:11]=[CH:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.ClCCl.[Br-].[Br-].[Br-]>C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:11]=[CH:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N=C(C=COc2ccccc2)Oc2ccccc2)cc1
Agent: [Br-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Oc1ccc(N=C(C=COc2ccccc2)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 20 %

Procedure:
To chloroform (80 ml) solution of phenyl N-(4-methoxyphenyl)-3-(phenoxy)acrylimidate (2.4 g) was added dropwise with borone tribromide dichloromethane solution (1.0M: 14.0 ml) under ice-cooling and stirred for one hour at the same temperature and 2.5 hours at room temperature. Chloroform (200 ml) was added to the reaction solution and it was successively washed with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain phenyl N-(4-hydroxyphenyl)-3-(phenoxy)acrylimidate (0.46 g) as white crystal.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([OH:13])=O)[CH:8]=2)[NH:3]1.[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[NH:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[N:17]([C:11]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH2:10]3)=[O:13])[CH2:16][CH2:15]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C1Cc2cc(C(=O)N3CCC[C@@H]4c5ccccc5CC[C@@H]43)ccc2N1
Yield: 25 %

Procedure:
The title compound is prepared from 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 25% of theory; LC (method 4): tR=1.90 min; Mass spectrum (ESI+): m/z=347 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1)=O.[C:13]([NH2:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([C:13]2[O:20][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=3)[N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: NC(=O)c1ccccc1
Product: N#Cc1ccc(-c2coc(-c3ccccc3)n2)cc1
Temperature: 135 °C
Yield: 66 %

Procedure:
The mixture of the 2-bromo-1-(4-cyanophenyl)ethanone (4 g, 17.85 mmol) and benzamide (5.41 g, 44.6 mmol) was heated to 135° C. for 3 hours. Then the reaction mixture was cooled, and partitioned between diethyl ether and water. The aqueous layer was extracted with ether twice, and the combined organic layers were washed with 1N NaOH, 1N HCl, water, and brine, dried over MgSO4. After concentration, the solid residue was dissolved in CHCl3. The insoluable solid was filtered through a frits funnel and discarded. The CHCl3 solution was filtered through a pad of silica and evaporate to dryness to give 2.9 g (66% yield) of 4-(2-phenyl-1,3-oxazol-4-yl)benzonitrile. LCMS: m/z 247.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:22]I>CN(C=O)C>[Si:3]([O:10][CH2:11][C@@H:12]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: CI
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of NaH (60% dispersed in mineral oil, 60 mg, 1.49 mmol, 1.15 equiv.) in DMF (2.0 mL) was added (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)propan-2-ylcarbamate (360 mg, 1.3 mmol). The reaction mixture was stirred for 30 min followed by addition of methyl iodide (93 μL, 1.49 mmol, 1.15 equiv.) and stirred for 1 h. LC/MS indicated the reaction was complete. The reaction mixture was quenched with saturated NH4Cl and diluted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)propan-2-yl(methyl)carbamate as an oil, which was used in the next step without further purification. LRMS (M-Boc+H+) m/z 204.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Mg]Br.[O:13]1[CH:20]([CH3:21])[CH:14]1[C:15]([O:17]CC)=[O:16].Cl>ClCCl.C(OCC)C>[OH:13][CH:14]([CH:20]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH3:21])[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)C1OC1C
Reactant: c1ccc2[nH]ccc2c1
Agent: C[Mg]Br
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(c1c[nH]c2ccccc12)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 66.3 %

Procedure:
Indole (5.86 g) was dissolved in dichloromethane (50 ml) and to the solution was added dropwise 2.89 M solution of methyl magnesium bromide in diethyl ether (40 ml) over a period of 45 minutes at room temperature. After the dropwise addition was completed, the mixture was stirred for 45 minutes at room temperature. Under cooling at −10° C., a solution of ethyl (2RS,3SR)-2,3-epoxybutanoate (6.51 g) in dichloromethane (50 ml) was added dropwise over a period of 20 minutes. The mixture was stirred for 1 hour at −10 ° C. To the mixture was added 1 N aqueous solution of hydrochloric acid (150 ml). The organic layer was removed, and the aqueous layer was extracted with dichloromethane (50 ml). The organic layers were combined, and concentrated under reduced pressure. The residue was dissolved by adding ethanol (56 ml) and water (24 ml). To the solution was added 1 N aqueous solution of sodium hydroxide (50 ml) under ice cooling. The mixture was stirred for 3.5 hours under ice cooling and 12 hours at room temperature. To the mixture was added 1 N aqueous solution of sodium hydroxide (25 ml), and the mixture was stirred for 1 hour at room temperature. The ethanol was distilled off under reduced pressure, and aqueous layer was washed twice with ethyl acetate (70 ml). The aqueous layer was acidified by adding conc. hydrochloric acid (10 ml). The mixture was extracted twice with ethyl acetate (100 ml). The ethyl acetate layers were combined and dried over anhydrous magnesium sulfate. To the ethyl acetate layer was added activated carbon (1 g) and mixture was stirred. After filtration, the filtrate was concentrated under reduced pressure. The residue was recrystallized from water to give (2RS,3SR)-2-hydroxy-3-(indol-3-yl)butyric acid (7.27 g) as pale brown solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([N:21]=[C:22]=[O:23])[CH2:19][CH3:20]>>[CH2:18]([NH:21][C:22](=[O:23])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10]2)[CH2:19][CH3:20]
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: CCCN=C=O
Product: CCCNC(=O)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (15.0 mg, 66.6 μmol) using the same procedure employed for Example 2 (2), but with n-propylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (12.3 mg, 60%) having the following characteristics.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C)C=O>[N:31]([CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(Cl)c3ccccc32)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N=[N+]=[N-])c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
5-Chloro-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.8 g) is dissolved in dimethylformamide and thereto is added sodium azide (0.18 g) at room temperature. The mixture is stirred at room temperature overnight, and further reacted with heating at 50° C. for 5 hours. Water is added to the reaction mixture and the precipitated crystal is collected by filtration to give 5-azido-1-[4-(2-methylbenzoylamino)benzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.68 g) as light brown powder.
Reaction SMILES: C([N:4]([CH2:8][CH3:9])[CH:5]([CH3:7])[CH3:6])(C)C.[C:10]1(C)[CH:15]=CC=C[CH:11]=1.O>CO>[NH:4]1[C:5]2[C:6](=[CH:11][CH:10]=[CH:15][CH:7]=2)[CH:9]=[CH:8]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccccc1
Solvent: O
Solvent: CO
Product: c1ccc2[nH]ccc2c1

Procedure:
In Scheme VIII, Step 4, 4-Benzyloxypropiophenone is brominated in acetic acid with bromine. When the reaction is complete the mixture can be quenched with water and the resulting precipitate is washed with dilute acetic acid, water and heptane. The resulting solid is dried to give IV, 4-benzyloxyaniline hydrochloride. In Step 5, a mixture of IV, N,N-diisopropylethylamine and toluene is heated under reflux with removal of water. When the reaction is complete the mixture may be cooled and diluted with methanol. The solids produced can be collected, washed with methanol and dried to give compound indole V. A mixture of compounds V and III can be mixed in Step 6 with sodium tert-butoxide in N,N-dimethylformrnamide and stirred until the reaction is complete. Then the mixture may be quenched with brine and extracted with toluene. The extracts are concentrated and the residue diluted with methanol. The resulting solids may be collected, dissolved in ethyl acetate, clarified, and diluted with methanol. The solids may be collected from this dilution and dried to give compound VI.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[C:15](=[O:18])[NH:16][N:17]=[C:13]3[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11]([CH3:29])=[C:10]2[C:30](O)=[O:31])=[CH:5][CH:4]=1)#[N:2].[CH3:33][CH2:34][N:35](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)C>CN(C=O)C>[CH2:34]([NH:35][C:30]([C:10]1[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:14]2[C:15](=[O:18])[NH:16][N:17]=[C:13]2[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[C:11]=1[CH3:29])=[O:31])[CH3:33]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)n2c(n[nH]c2=O)N1c1cccc(C(F)(F)F)c1
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCNC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2n[nH]c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 49.2 %

Procedure:
To a solution of Example 9 (100 mg, 0.23 mmol) in DMF (3 ml), were added DIPEA (102 μL, 0.6 mmol) and HATU (133 mg, 0.35 mmol) and the reaction mixture was stirred at RT for 45 mins. Ethylamine (2 M in THF, 175 μL, 0.35 mmol) was then added, and stirring at RT was continued for 16 hours. Further ethylamine (2 M in THF, 175 μL, 0.35 mmol) was added, the temperature was raised to 60° C., and stirring was continued for 1.5 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 80-100% EtOAc in cyclohexane to yield the title compound as a white solid (53 mg).
Reaction SMILES: Br[C:2]1[C:3]([N:7]2[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]2=3)=[CH:4][S:5][CH:6]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.O>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[C:2]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)=[CH:6][S:5][CH:4]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: OB(O)c1cccnc1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cscc2Br)CCN(C)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cscc2-c2cccnc2)CCN(C)C1
Temperature: 95 °C
Yield: 25.3 %

Procedure:
To a de-aerated solution of 5-(4-bromo-thiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (160 mg, 0.44 mmol), 3-pyridinylboronic acid (81.9 mg, 0.66 mmol) and K3PO4 (235 mg, 1.11 mmol) in DMF-water (4.5:0.5 mL) was added dichlorobis(triphenylphosphine) palladium (II) (15.5 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(4-pyridin-3-yl-thiophen-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (40 mg). 1H NMR (Oxalate salt, CD3OD) d (ppm): 8.35 (bs, 1H), 8.10 (bs, 1H), 7.95 (s, 1H), 7.8 (s, 1H), 7.45 (bs, 1H), 7.3-7.2 (m, 2H), 6.95 (d, 1H), 6.9 (d, 1H), 4.5 (bs, 2H), 3.6-3.45 (m, 2H), 3.15-3.05 (m, 1H), 3.0 (s, 3H), 2.65-2.59 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:10]=[C:11]([C:25](=[O:27])[CH3:26])[CH:12]=[N:13][C:14]=2[NH:15][C:16]2[CH:17]=[N:18][C:19]([O:23][CH3:24])=[C:20]([F:22])[CH:21]=2)[CH:3]=1.[CH3:28][Mg]Br>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:10]=[C:11]([C:25]([OH:27])([CH3:28])[CH3:26])[CH:12]=[N:13][C:14]=2[NH:15][C:16]2[CH:17]=[N:18][C:19]([O:23][CH3:24])=[C:20]([F:22])[CH:21]=2)[CH:3]=1
Reactant: C[Mg]Br
Reactant: COc1ncc(Nc2ncc(C(C)=O)cc2-c2cc(N)nc(C)n2)cc1F
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc(C(C)(C)O)cc2-c2cc(N)nc(C)n2)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.9 %

Procedure:
A suspension of 1-(5-(6-amino-2-methylpyrimidin-4-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (88 mg, 0.24 mmol) in 2 mL of THF at 0° C. was treated with methylmagnesium bromide (0.55 mL of 3.0 M solution in diethyl ether, 1.67 mmol). It was stirred at 0° C. for 15 min, and quenched with 5 mL of sat. NH4Cl. The mixture was extracted with 2×15 mL of EtOAc. The organic extracts were dried and concentrated. The crude material was purified on a silica gel column and eluted with 20-70% EtOAc in DCM to give 2-(5-(6-amino-2-methylpyrimidin-4-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)propan-2-ol (58 mg, 63% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.23 (s, 1H), 8.35 (m, 1H), 8.32 (d, J=2.2 Hz, 1H), 8.17 (m, 2H), 7.02 (br, 2H), 6.03 (s, 1H), 5.18 (s, 1H), 3.92 (s, 3H), 2.47 (s, 3H), 1.48 (s, 6H). m/z (ESI, positive ion) 385.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][N:9]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:8]([C:28]([O:30][CH3:31])=[O:29])[CH2:7]1)=O.B.CO>O1CCCC1>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([N:9]2[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:6]([CH2:4][CH2:3][O:2][CH3:1])[CH2:7][CH:8]2[C:28]([O:30][CH3:31])=[O:29])(=[O:18])=[O:19])=[CH:21][CH:22]=1
Reactant: COCC(=O)N1CC(C(=O)OC)N(S(=O)(=O)c2ccc(OC)cc2)Cc2ccccc21
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: COCCN1CC(C(=O)OC)N(S(=O)(=O)c2ccc(OC)cc2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A mixture of 1.6 g (3.57 mmol) of methyl 1-(methoxyacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate and 32 ml of borane in tetrahydrofuran (1.0M) was refluxed under nitrogen overnight. Methanol was added and the solvent removed. To the residue was added 25 ml of CH2Cl2 and 25 ml of 2N HCl and the mixture stirred at room temperature for 1 hour. The organic layer was separated and washed with H2O and concentrated to dryness. The residue was triturated with ethyl acetate-hexane, cooled and filtered to give 1.2 g of white crystals, m.p. 86°-90° C.; Mass spectrum (ES) 435.4 (M+H). Anal. for C21H26N2O6S: Calc'd: C,58.1; H,6.0; N,6.5; Found: C.58.5; H,6.0: N,6.5.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.C1C([NH2:18])=CC=C(N)C=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:18]
Reactant: Oc1ccc2ccccc2c1
Reactant: Nc1ccc(N)cc1
Product: Nc1ccc2ccccc2c1
Yield: 94 %

Procedure:
In another run using a molar ratio of 4:1 of β-naphthol to p-phenylenediamine with 3% B2O3, based on the weight of β-naphthol, at 200° C., and a reaction time of 4 hours, a 94% yield was obtained with only 6 ppm β-naphthylamine being formed.