Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:28]2[CH:33]=[CH:32][N:31]=[C:30]([NH:34][CH3:35])[N:29]=2)[C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=2[CH3:27])[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=2)=[O:13])=[N:6][CH:7]=1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:21]([C:17]1[CH:16]=[C:15]([NH:14][C:12](=[O:13])[C:11]2[CH:24]=[CH:25][C:26]([CH3:27])=[C:9]([O:8][C:5]3[C:4]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([NH:34][CH3:35])[N:29]=4)=[CH:3][C:2]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:7][N:6]=3)[CH:10]=2)[CH:20]=[CH:19][CH:18]=1)([CH3:23])[CH3:22]
Reactant: C1CCNC1
Reactant: CNc1nccc(-c2cc(Cl)cnc2Oc2cc(C(=O)Nc3cccc(C(C)C)c3)ccc2C)n1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CNc1nccc(-c2cc(N3CCCC3)cnc2Oc2cc(C(=O)Nc3cccc(C(C)C)c3)ccc2C)n1
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
The title compound was prepared using the procedure of Harris et. al. [Organic Letters 2002, 4 (17), 2885-2888.]: In a N2-flushed sealing tube, 3-[5-Chloro-3-(2-methylamino-pyrimidin-4-yl)-pyridin-2-yloxy]-N-(3-isopropyl-phenyl)-4-methyl-benzamide (100 mg, 0.21 mmol), pyrrolidine (0.022 mL, 0.26 mmol), Pd2(dba)3 (5.1 mg, 0.0055 mmol), and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (5.2 mg, 0.13 mmol) were combined. The tube was flushed with argon, and 1 M Li(TMS)2 in THF (Aldrich, 0.67 ml) was added. The sealed tube was heated at 70° C. for 20 h. 1 N HCl was added, the mixture was stirred 5 minutes, then saturated aqueous NaHCO3 was added. After extraction, the organic layer was dried over Na2SO4. After concentration, the residue was purifed by HPLC (Gilson, acidic mobile phase), desalted by aqueous NaHCO3/EtOAc extraction, and purified by flash chromatography (2:1 to 1:1 hexanes/EtOAc. The resulting solid was triturated with a small amount of t-BuOMe to provide the product. MS m/z=523 [M+H]+. Calc'd for C31H34N6O2: 522.65.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[N:9]=2)[N:6]=[CH:5][C:4]=1[C:38]([O:40]CC)=[O:39].[OH-:45].[Li+].Cl.[O:48]1CCOCC1>>[C:3]([OH:48])([C:2]([F:44])([F:43])[F:1])=[O:45].[F:44][C:2]([F:1])([F:43])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=4)=[CH:26][CH:27]=3)[N:9]=2)[N:6]=[CH:5][C:4]=1[C:38]([OH:40])=[O:39]
Reactant: C1COCCO1
Reactant: [OH-]
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(-c4ccc(C(F)(F)F)nc4)cc3)n2)c1C(F)(F)F
Agent: Cl
Agent: [Li+]
Product: O=C(O)C(F)(F)F
Product: O=C(O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(-c4ccc(C(F)(F)F)nc4)cc3)n2)c1C(F)(F)F
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of the title compound from Example 14 Step B in 1,4-dioxane (0.500 mL) was added lithium hydroxide (0.5 mL, 2.0 M in water, 1.00 mmol), and the resulting mixture was stirred at 50° C. After 30 min, the reaction mixture was rendered acidic by addition of aqueous hydrochloric acid, then was diluted with 1,4-dioxane and passed through a 0.45 micron syringe filter. Purification by reverse phase HPLC (50 to 100% acetonitrile in water, each with 0.1% v/v TFA) provided the title compound: LCMS m/z 585.2 [M+H]+; 1H NMR (500 MHz, d6-DMSO) δ 9.09 (d, J=2.0 Hz, 1H), 8.36 (dd, J=8.0, 2.0 Hz, 1H), 8.30 (s, 1H), 8.18 (d, J=7.0 Hz, 1H), 8.14 (t, J=8.0 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.75 (dd, J=8.0, 2.0 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.47-7.43 (m, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 5.34 (s, 2H).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])(=[O:5])=[O:4].[N:13]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>>[CH3:2][S:3]([C:6]1[CH:7]=[C:8]([NH:9][NH2:13])[CH:10]=[CH:11][CH:12]=1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1cccc(NN)c1

Procedure:
B-012 is prepared analogously to B-05 starting from 3-methylsulfonylaniline hydrochloride (2.50 g, 11.4 mmol), sodium nitrite (1.18 g, 17.1 mmol) and tin(II)chloride dihydrate (14.9 g, 66.0 mmol). The product is purified by precipitation from ethyl acetate with cyclohexane. Yield: 1.08 g.
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][CH2:10][CH2:11][N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:7][CH:6]=[CH:5][N:4]=1)#N.[CH3:18][OH:19].Cl.[OH2:21]>>[CH3:17][N:12]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:11][CH2:10][NH:9][C:8]1[C:3]([C:1]([O:19][CH3:18])=[O:21])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O
Reactant: CN(CCNc1cccnc1C#N)S(C)(=O)=O
Agent: Cl
Product: COC(=O)c1ncccc1NCCN(C)S(C)(=O)=O

Procedure:
In a manner similar to that described for Example 2, N-{2-[(2-cyanopyridin-3-yl)amino]ethyl}-N-methylmethanesulfonamide was treated with MeOH, HCl and water to give methyl 3-({2-[methyl(methylsulfonyl)amino]ethyl}amino)pyridine-2-carboxylate after aqueous workup. The crude product was then treated with NaH and methyl 3-chloro-3-oxopropionate as described in Example 2 and after aqueous workup the crude methyl 4-hydroxy-1-{2-[methyl(methylsulfonyl)amino]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate was obtained as a pink foam. A portion of the material was crystallized from EtOH to give the product as light brown crystals.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:20])[CH2:15][CH2:16][CH2:17][C:18]#[CH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Mg+2].[Cl-].[CH2:24](N(CC)CC)C.[Cl:31][C:32]1[N:37]=[CH:36][C:35]([CH:38]=[O:39])=[CH:34][CH:33]=1.Cl[Si](C)(C)C>C(OCC)(=O)C>[CH2:1]([C@H:8]1[CH2:24][CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:20])[C@@H:15]([C@@H:38]([C:35]1[CH:36]=[N:37][C:32]([Cl:31])=[CH:33][CH:34]=1)[OH:39])[CH2:16][CH2:17][C:18]#[CH:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: C#CCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: O=Cc1ccc(Cl)nc1
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: C#CCC[C@@H](C(=O)N1C(=O)OCC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(Cl)nc1
Reaction time: 72 h
Yield: 70.3 %

Procedure:
To a stirred solution of 23.0 g (837 mmol) of the title compound from step A above in 200 mL of anhydrous ethyl acetate at ambient temperature under an atmosphere of nitrogen was added 1.6 g (17 mmol) of anhydrous magnesium chloride, 23.0 mL (166 mmol) of triethylamine, 14.0 g (100 mmol) of 6-chloropyridine-3-carboxaldehyde and 16.0 mL (124 mmol) of chlorotrimethylsilane and the resulting mixture was stirred for 72 h. The heterogeneous reaction mixture was filtered through a 300 mL plug of silica gel eluting with an additional 1 L of ethyl acetate. The filtrate was evaporated to dryness in vacuo and the residue suspended in 200 mL of methanol and 5.0 mL of trifluoroacetic acid. The resulting mixture was stirred at ambient temperature under nitrogen for 5 h during which time the reaction became homogeneous. All volatiles were then removed in vacuo and the residue was purified by silica gel chromatography eluting with a 10-15% ethyl acetate in hexanes gradient to afford the title compound as a white solid (30 g, 88%). LC-MS: m/z (ES) 413.2 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH2:13])=[C:11]([C:14]([O:16][CH3:17])=[O:15])[N:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24]>CN(C)C=O>[ClH:1].[CH2:23]([N:22]([CH2:25][CH3:26])[CH2:21][CH2:20][CH2:19][N:9]1[N:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[C:12]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:13]1)[CH3:24]
Reactant: CCN(CC)CCCCl
Reactant: COC(=O)c1nnn(-c2ccc(Cl)cc2)c1N
Solvent: CN(C)C=O
Product: CCN(CC)CCCn1nc(Nc2ccc(Cl)cc2)c(C(=O)OC)n1
Product: Cl
Yield: 27.3 %

Procedure:
A mixture consisting of 5.1 gm (0.02 mol) of methyl 1-(4-chlorophenyl)-5-amino-1H-1,2,3-triazole-4-carboxylate, 100 ml of absolute dimethyl formamide and 7.5 gm (0.05 mol) of 1-chloro-3-diethylamino-propane was reacted analogous to Example 1, the reaction mixture was evaporated in vacuo, the residue was dissolved in 2N hydrochloric acid, and the solution was fractionally extracted with ether at stepwisely increasing pH values. After evaporation of the ether phases which were shown to be identical and pure by thin-layer chromatography, the residue was dissolved in ethyl acetate, and the hydrochloride was precipitated with ethereal hydrochloric acid and recrystallized twice, yielding 1.1 gm of the desired compound, corresponding to 13.7% of theory; melting point 181° C.
Reaction SMILES: C[C:2]1[C:6]([C:7]#[N:8])=[C:5]([S:9]([CH3:12])(=O)=O)[S:4][N:3]=1.[SH-].[K+].[CH2:15]([O:18]CCl)[C:16]#[CH:17].[CH2:21](COC)[O:22]C>O>[CH3:21][O:22][C:2]1[C:6]([C:7]#[N:8])=[C:5]([S:9][CH2:12][O:18][CH2:15][C:16]#[CH:17])[S:4][N:3]=1
Reactant: COCCOC
Reactant: C#CCOCCl
Reactant: Cc1nsc(S(C)(=O)=O)c1C#N
Agent: [K+]
Agent: [SH-]
Solvent: O
Product: C#CCOCSc1snc(OC)c1C#N

Procedure:
2.18 Grams of 3-methyl-4-cyano-5-methylsulfonylisothiazole was dissolved in 20 ml of dimethoxyethane, and a solution of 1.2 g of potassium hydrosulfide (KSH) in 5 ml of water was added at room temperature with stirring. After stirring for 10 minutes, 1.3 g of 2-propynyloxymethyl chloride was added, and the reaction solution was stirred for 3 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate. The extract was washed with water, dried and concentrated to obtain 2.1 g of an oily 3-methoxy-4-cyano-5-(2-propynyloxymethylthio)isothiazole. This product was dissolved in 20 ml of DMF and ice-cooled to 5° to 10° C. To this solution was added a solution of 5.1 g of iodine and 3.2 g of potassium iodide in 5 ml of water and 10 ml of DMF, and then 6.6 g of a 10% KOH was added dropwise. After addition, the reaction solution was stirred for 2 hours until the temperature reached room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate. The extract was washed with water, dried and concentrated under reduced pressure to obtain an oily product. This product was recrystallized from ether to obtain 2.7 g of white crystals having a melting point of 124° to 125° C. (yield 76%).
Reaction SMILES: [OH:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([C:16]2[O:17][C:18]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:19][C:20](=[O:22])[CH:21]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:35][O:36][C:37](=[O:40])[CH2:38]Br.O>CN(C)C=O>[CH3:35][O:36][C:37](=[O:40])[CH2:38][O:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([C:16]2[O:17][C:18]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:19][C:20](=[O:22])[CH:21]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: O=c1cc(-c2ccc(O)c3c2Sc2ccccc2S3)oc(N2CCOCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(-c2cc(=O)cc(N3CCOCC3)o2)c2c1Sc1ccccc1S2
Temperature: 60 °C

Procedure:
To a solution of 2-(4-Hydroxy-thianthren-1-yl)-6-morpholin-4-yl-pyran-4-one (130) (1.20 g, 2.91 mmol) in dimethylformamide (10 ml), under and inert atmosphere, was added powdered potassium carbonate (1.21 g, 8.75 mmol) and methylbromoacetate (0.55 ml, 5.82 mmol). The temperature of the reaction was raised to 60° C. for 48 hours and then cooled to room temperature before the addition of water (20 mL). The mixture was then extracted using ethyl acetate (3×30 ml). The combined organics were dried (MgSO4), filtered and concentrated in vacuo to give the title compound as an off white solid (1.40 g, 99%) that was suitably clan and required no further purification. m/z (LC-MS, ESP): RT=4.48 min, (M++1)=484
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>>[C:1]([NH:4][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C(=O)O)ccc1C
Reactant: O=[N+]([O-])O
Product: CC(=O)Nc1c(C)ccc(C(=O)O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
3-(acetylamino)-4-methylbenzoic acid (300 g, 1.55 mol) was added portionwise to fuming nitric acid (1200 mL) with stirring over a period of 1 h at 0˜5° C. The solution gradually turned into a heavy slurry during the addition. At the end of addition, an additional fuming nitric acid (200 mL) was added. The reaction mixture was stirred for an additional hour at 5° C., then allowed to warm to room temperature and poured into ice water. The solid formed was collected and washed with water (450 mL×3). The crude product was re-crystallized from acetic acid (1800 mL) to give the title compound (191.5 g, 51.8%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:5]=[C:4]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:3]=1.[CH2:18]([CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21]N)[CH3:19].[CH2:27](N)[CH2:28][CH2:29][CH3:30].N>>[CH2:16]([CH:15]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:14][NH:13][C:4]1[N:3]=[C:2]([NH:1][CH2:21][CH:20]([CH2:18][CH3:19])[CH2:23][CH2:24][CH2:25][CH3:26])[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:5]=1)[CH3:17]
Reactant: CCCCN
Reactant: CCCCC(CC)CN
Reactant: CCCCNc1nc(N)nc(NCCCC)n1
Agent: N
Product: CCCCNc1nc(NCC(CC)CCCC)nc(NCC(CC)CCCC)n1

Procedure:
The same procedures were repeated as in the N-substituted melamine (C1), except that mono-2-ethylhexylamine was employed in place of n-butyl amine, and further n-butyl amine was employed in place of the aqueous ammonia to obtain 2,4-bis(mono-2-ethylhexylamino)-6-monobutylamino-1,3,5-triazine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4].O.O.Cl[Sn]Cl>C(O)(=O)C.Cl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([NH2:14])=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2cccc([N+](=O)[O-])c2s1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc2cccc(N)c2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a mixture of 7-nitro-benzo[b]thiophene-2-carboxylic acid methyl ester (100 mg) in acetic acid (4 mL) was added a solution of SnCl2.2H2O (10 eq) in 1.5 mL of concentrated HCl. The reaction was stirred at room temperature 12 h. The excess acid was partially removed in vacuo, and the reaction mixture was then poured into a flask (250 mL) and was neutralized with saturated NaHCO3 solution at 0° C. The pH was brought up to pH 9 by adding solid NaHCO3. The resulting aqueous mixture was diluted with EtOAc, and the Tin-by product was removed by filtering through a pad of diatomaceous earth. The pad was rinsed with EtOAc and the combined filtrates were partitioned in a separatory funnel. The aqueous layer was extracted with EtOAc two times. The combined organics were dried over MgSO4, filtered and concentrated to give the desired 7-amino-benzo[b]thiophene-2-carboxylic acid methyl ester (100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.O=[C:20]1[CH2:25][CH2:24][N:23]([C@H:26]([CH3:30])[CH2:27][C:28]#[N:29])[CH2:22][CH2:21]1.[C-]#N.[Na+]>O.CO>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH:20]3[CH2:25][CH2:24][N:23]([C@H:26]([CH3:30])[CH2:27][CH2:28][NH2:29])[CH2:22][CH2:21]3)=[CH:13][CH:12]=2)=[CH:8][CH:9]=1
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Reactant: COC(=O)c1ccc(Oc2ccc(N)cc2)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(NC3CCN([C@H](C)CCN)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Using general procedure A with 4-(4-amino-phenoxy)-benzoic acid methyl ester (see EXAMPLE 96) (300 mg, 1.2 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (225 mg, 1.4 mmol) followed by general procedure J gave a green oil, which was subsequently treated with a solution of NaCN (175 mg) in H2O (5 mL) and MeOH (5 mL). The mixture was stirred at room temperature for 20 minutes to afford 4-{4-[1-((R)-3-amino-1-methyl-propyl)-piperidin-4-ylamino]-phenoxy}-benzoic acid methyl ester as a white solid (238 mg, 48% over 2 steps) following work-up and purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:24])[C:5]1=[O:34].C(N(C(C)C)CC)(C)C.[N:44]1([C:50](Cl)=[O:51])[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[O:24])[C:5](=[O:34])[N:4]3[CH2:3][CH2:2][NH:1][C:50]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[O:51])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: NCCn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCN1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)N2CCOCC2)c1=O

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(4-morpholinyl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.052 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (5 mL) under nitrogen was treated with 4-morpholinecarbonyl chloride (0.008 mL, 0.068 mmol) at 40° C. for 1 h then 3½ h at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was triturated with Et2O:MeOH, filtered, washed with 2:1 Et2O:MeOH, and dried in vacuo to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.3 (s, 1 H), 3.10 (s, 2 H), 3.13-3.22 (m, 8 H), 3.27-3.33 (m, 1 H), 3.42-3.50 (m, 4 H), 3.55 (d, J=10.67 Hz, 2 H), 3.63-3.73 (m, 2 H), 3.78 (d, J=4.49 Hz, 1 H), 3.93-4.05 (m, 2 H), 4.14 (s, 2 H), 4.30 (t, J=6.67 Hz, 2 H), 7.11-7.19 (m, 2 H), 7.39-7.47 (m, 2 H), 8.34 (s, 1 H), 8.57 (d, J=1.12 Hz, 1 H), 9.88 (br. s., 1 H), 10.38-10.48 (m, 1 H); ES+ MS: 583 (M+H+).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C@H:27]([CH3:31])[CH2:28][C:29]#[N:30])[CH2:23][CH2:22]2)=[CH:16][CH:15]=1>>[C:29]([CH2:28][C@H:27]([N:24]1[CH2:23][CH2:22][CH:21]([N:20]([C:17]2[CH:18]=[CH:19][C:14]([S:13][CH3:12])=[CH:15][CH:16]=2)[C:9](=[O:11])[C:8]2[C:3]([CH3:2])=[CH:4][CH:5]=[N:6][CH:7]=2)[CH2:26][CH2:25]1)[CH3:31])#[N:30]
Reactant: Cc1ccncc1C(=O)O
Reactant: CSc1ccc(NC2CCN([C@H](C)CC#N)CC2)cc1
Agent: Cl
Product: CSc1ccc(N(C(=O)c2cnccc2C)C2CCN([C@H](C)CC#N)CC2)cc1
Yield: 67.4 %

Procedure:
Using general procedure F, 4-methylnicotinic acid hydrochloride (363 mg, 2.09 mmol) and (R)-3-[4-(4-methylsulfanyl-phenylamino)-piperidin-1-yl]-butyronitrile (see EXAMPLE 307) (304 mg, 0.93 mmol) afforded N-[1-((R)-2-cyano-1-methyl-ethyl)-piperidin-4-yl]-4-methyl-N-(4-methylsulfanyl-phenyl)-nicotinamide as a brown oil (256 mg, 70%).
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[N+:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)([O-:28])=[O:27]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:4]1([CH3:18])[C:3](=[O:19])[C:2]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([N+:26]([O-:28])=[O:27])[CH:34]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2cccc([N+](=O)[O-])c2)C1=O
Temperature: 90 °C
Reaction time: 12 h
Yield: 52.4 %

Procedure:
To a stirred solution of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (170 mg) in 30 ml toluene and 10 ml ethanol, were added 25 mg of tetrakis(triphenylphosphine)palladium(0), 10 ml of saturated aqueous sodium carbonate, and 120 mg of 3-nitrobenzeneboronic acid. The reaction solution was stirred at 90° C. for 12 hours. Then the solvent was removed under reduced pressure. The resulting residue was extracted with water and dichloromethane (50 ml×3). The organic layer was concentrated in vacuo and the resulting residue was separated by column chromatography (hexane/ethylacetate) to afford 100 mg of 2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-4-(3-nitrophenyl)-3(2H)-furanone as a solid. mp: 158-159° C. NMR: δ1.61 (s, 6H), 3.09 (s, 3H), 7.57 (t, J=7.8 Hz, 1H), 7.64 (m, 1 H), 7.81 (d, J=9.0 Hz, 2H), 7.98 (d, J=8.7 Hz, 2H), 8.19 (m, 2H). IR (cm−1): 2982, 1697, 1529, 1403, 1349, 1150, 959, 770.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([F:32])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.C([Sn]([C:46]#[N:47])(CCCC)CCCC)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:32][C:5]1[CH:4]=[N:3][C:2]([C:46]#[N:47])=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:31])[C:12](=[O:13])[N:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:23]=[N:22][N:21]=4)[CH2:18][CH2:19]3)[C:6]=12
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Reactant: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(Br)ncc(F)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: N#Cc1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Temperature: 100 °C
Yield: 31.4 %

Procedure:
To a sealable flask containing 1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (0.10 g, 0.20 mmol) in 1,4-dioxane (5 mL) was added tributyltin cyanide (0.07 g, 0.22 mmol) followed by Pd(PPh3)4 (0.07 g, 0.06 mmol). The mixture was flushed with N2, and the tube was sealed and heated to 100° C. After 16h of heating, the mixture was cooled to rt, and the solvent was removed in vacuo. The residue was dissolved in DMF and was filtered through a pad of celite to remove any remaining solids. The DMF solution was purified by prep HPLC to give the title compound as an off-white solid (0.028 g). LCMS: m/e 446.2 (M+H)+, ret time 1.81 min (method 2). 1H NMR (500 MHz, DMSO-D6) δ ppm 14.06 (s, 1 H) 8.66 (s, 1 H) 8.50 (d, J=2.14 Hz, 1 H) 7.56-7.70 (m, 5 H) 3.67-3.72 (m, 2 H) 3.33-3.50 (m, 4 H) 3.13-3.17 (m, 2 H).