Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:20]1([CH2:23][C:24](N(OC)C)=[O:25])[CH2:22][CH2:21]1>C1COCC1>[CH:20]1([CH2:23][C:24](=[O:25])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)[CH2:22][CH2:21]1
Reactant: CSc1nccc(C)n1
Reactant: CON(C)C(=O)CC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1nccc(CC(=O)CC2CC2)n1
Temperature: 25 °C

Procedure:
To a solution of 4-methyl-2-(methylthio)pyrimidine (5.63 mL, 40.4 mmol) in THF (20 mL) at −10° C., LiHMDS (60.6 mL, 60.6 mmol) (1N in MBTE) was added dropwise under nitrogen. The reaction mixture coagulated, and stopped stirring. For this, additional THF (40 mL) was added to dissolve the highly viscous mixture. The reaction was warmed up to rt and was stirred for 30 minutes. The reaction mixture was re-cooled to −10° C., then 2-cyclopropyl-N-methoxy-N-methylacetamide (7.47 g, 40.4 mmol) was added dropwise. The reaction mixture was warmed up to rt, then stirred for an additional 2 hours. The reaction was partitioned between ammonium chloride solution and EtOAc. The organic layer was separated, and the aqueous layer was back-extracted. The organic extracts were combined, washed with brine, dried over sodium sulfate, then concentrated in vacuo. The crude product was purified by Biotage™ silica gel chromatography [100 g SNAP column, 10% EtOAc/heptane to 100% EtOAc] to obtain the desired product, which was still contaminated significantly with the starting material, 4-methyl-2-(methylthio)pyrimidine (5.63 g, 48% yield). The product was carried on to the next step without further purification. MS (ES+): m/z=223.2/224.3 (100/50) [MH+]. HPLC: tR=0.84 minute over 3 minutes. Purity: 77% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[CH3:26][C:27]1[NH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:28]3[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:35]=[C:27]3[CH3:26])=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Reactant: Cc1cc2ccccc2[nH]1
Product: Cc1cc2ccccc2n1Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2Cl)cc1
Yield: 81 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide (Intermediate 8), and 2-methyl-1-H-indole, the title compound was isolated as a yellow solid in 81% yield (96% purity by HPLC).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[C:11](OC(=O)C)(=[O:13])[CH3:12].O>N1C=CC=CC=1>[C:11]([NH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)(=[O:13])[CH3:12]
Reactant: NC1Cc2ccccc2C1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NC1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 71.1 %

Procedure:
2-aminoindan (6.0 g, 45 mmol) was dissolved in dry pyridine (7 ml), to which acetic anhydride (4.5 ml, 47.3 mmol) was added dropwise while cooling in ice water. After the reaction mixture was returned to room temperature and stirred for 20 minutes, water was added. The precipitate that deposited was filtered to obtain 2-acetamidoindan (5.6 g, 32 mmol).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](=O)[NH:13][C:12]([CH3:19])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:22])=[N:13][C:12]([CH3:19])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(c(=O)[nH]1)CCN(Cc1ccccc1)C2
Product: Cc1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Temperature: 25 °C

Procedure:
7-Benzyl-2-methyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one (prepared according to the method of Example 86, Step A, 17.1 g, 67.0 mmol) was suspended in phosphorus oxychloride (66 mL, 335 mmol). This mixture was stirred at reflux for 1 h, cooled to room temperature, evaporated, then chased with toluene. The residue was carefully diluted with ice/water/chloroform and the layers were separated. The aqueous phase was extracted with chloroform (3×) and the combined organic extracts were washed with saturated aqueous sodium bicarbonate (1×) and water (1×),dried over sodium sulfate, filtered, and evaporated to give the title compound of Example 86, Step B as a brown oil that was used without purification in the next step. 1H NMR (CDCl3, 250 MHz) δ 7.36-7.23 (c, 5H), 3.73 (s, 2H), 3.63 (s, 2H), 2.63 (app s, 4H), 2.36 (s, 3H); MS (APCI) 274, 276 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[C:19]([C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[F:27])#[N:20].N12CCN(CC1)CC2>C(#N)C>[C:19]([C:21]1[CH:22]=[C:23]([S:28]([N:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=2[O:2][CH3:1])[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[F:27])#[N:20]
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Yield: 19.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidine-4-amine (600 mg, 2.44 mmol) prepared in Example 14a, 3-cyano-4-fluorobenzenesulfonyl chloride (1.07 g, 4.87 mmol), 1,4-diazabicyclo[2.2.2]octane (549 mg, 4.89 mmol) and acetonitrile (12 mL), to yield the title compound (200 mg, 19%) as a colorless amorphous solid.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22]>C(Cl)Cl>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:20](=[O:24])[C:21]([CH3:23])=[CH2:22])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)c1ccc(O)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1ccc(S(=O)(=O)NC)cc1
Reaction time: 3 h
Yield: 79.3 %

Procedure:
To a solution of 15.00 g (0.08 mole) of N-methyl-4-hydroxybenzenesulfonamide, 8.11 g (0.08 mole) of triethylamine and 200 ml of methylene chloride cooled to 0° C. was added a solution of 8.37 g (0.08 mole) of methacryloyl chloride in 100 ml of methylene chloride over a period of approximately 30 minutes. The solution was then stirred for another 3 hours with cooling; washed once with 100 ml of 2 percent HCl solution, and twice with water; dried over magnesium sulfate and concentrated in vacuo in a warm water bath. The resultant solid was recrystallized from 150 ml of ethyl alcohol:water (1:1) with filtering through diatomaceous earth. Collection of the white solid and drying at room temperature in vacuo gave 16.20 g (79.9 percent of theory) of N-methyl-4-methacryloyloxybenzenesulfonamide; m.p.=106° to 107° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[Cl:13][C:14]1[CH:27]=[CH:26][C:25]2[CH:24]3[CH2:28][C:17]([CH2:29][N:30]4[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]4)([C:18]4[C:23]3=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16]=2[CH:15]=1>O1CCCC1>[Cl:13][C:14]1[CH:27]=[CH:26][C:25]2[CH:24]3[CH2:28][C:17]([CH2:29][N:30]4[CH2:31][CH2:32][C:33]([C:7]5[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=5)([OH:36])[CH2:34][CH2:35]4)([C:18]4[C:23]3=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16]=2[CH:15]=1
Reactant: Brc1cccnc1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2cccnc2)CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: -75 °C
Yield: 80.9 %

Procedure:
To a cooled solution (-90° C.) of n-butyllithium (2.5M in hexane, 2.40 mL, 6.0 mmol, 1.5 eq) in tetrahydrofuran (40 mL) under nitrogen was added freshly distilled 3-bromopyridine (0.540 mL, 5.6 mmol, 1.4 eq). The metal-halogen exchange reaction was warmed to -75° C. and maintained for 1.5 h. During that time a dark green solution evolved with the appearance of fine particulate. A solution of 1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (1.35 g, 4.0 mmol) in tetrahydrofuran (10 mL) was then added dropwise with considerable lightening of the solution color to a deep yellow. The reaction was warmed to room temperature over 1 h and quenched with water (50 mL). The aqueous phase was extracted with ethyl acetate (3×60 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The reaction mixture was purified by flash chromatography over silica gel (80 mL, eluent: ethyl acetate) to yield 1.35 g (81%) of the title compound as a white solid. TLC analysis (Rf 0.20, ethyl acetate). 1H NMR (D6 -DMSO, 300 MHz) 8.69 (br s, 1H), 8.41 (d, J=4.5 Hz, 1H), 7.83 (dt, J=8.0 Hz, 1H), 7.29 (m, 5H), 6.95 (m, 3H), 5.05 (s, 1H), 4.35 (s, 1H), 3.41 (m, 2H), 3.34 (s, 1H), 2.75 (m, 4H), 1.92 (m, 2H), 1.62 (m, 2H) MS (CI, CH4) m/z 417 (M+1,100), 419 (36), 445 (M+29,15), 399 (15) The free base was dissolved in diethyl ether containing a small amount of methylene chloride, acidified with ethereal HCl, and the hydrochloride salt suspension was diluted with additional ether. The salt was filtered, washed with fresh ether and dried in vacuo (50° C., 13 pascal, 18 h) to yield a white solid, mp 225°-228° C. (dec).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[CH3:13])(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:18](Cl)(=[O:20])[CH3:19]>C(=S)=S>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:18](=[O:20])[CH3:19])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[CH3:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)N1c2ccccc2CC1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)CC(C)N2C(C)=O
Temperature: 50 °C
Yield: 96.9 %

Procedure:
To a mixture of the compound from Step 1 (2.0 g, 11.4 mmol) and aluminum chloride (7.0 g, 52 mmol) in carbon disulfide (20 mL) is added acetyl chloride (1.2 mL, 17.1 mmol). The mixture is heated at 50° C. for 72 h, cooled, quenched with ice water then diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographed on silica gel eluting with 40-50% ethyl acetate in heptane to give 2.4 g (97%) of the title compound as a off-white solid. MS (ESI+) m/z 217.1 (M+H). Anal. Calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.78; H, 6.98; N, 6.43.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:11][CH:12]=1)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: N#CCC(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)CC#N)cc1
Temperature: 80 °C

Procedure:
A mixture of p-aminobenzoylacetonitrile, 1-bromohexadecane, potassium carbonate and hexamethylphosphoramide is heated to 80° C. for 20 hours and worked up as in Example 1, providing 4-hexadecylaminobenzoylacetonitrile. This material is dissolved in isopropanol and treated with an excess of sodium borohydride. After stirring at room temperature for 3 hours, the solution is concentrated, diluted with water and extracted with chloroform. The chloroform extract yields the crude carbinol which is heated to reflux for 1 hour with ethanol containing an equal volume of 2 N aqueous hydrochloric acid. The solution is then cooled, diluted with water and extracted with chloroform. The organic extract is washed successively with water and aqueous sodium bicarbonate, then dried and evaporated to afford 4-(hexadecylamino)cinnamonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N+:7]([O-])=O)=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1>[Pd].CO>[Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cn(-c2cccnc2)nc1Cl
Agent: [Pd]
Solvent: CO
Product: Nc1cn(-c2cccnc2)nc1Cl
Temperature: 20 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
A suspension of 3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (1.00 g, 4.45 mmol) and palladium on carbon (10 wt %, 0.05 g, 0.467 mmol) in methanol (20 mL) was purged with nitrogen (N2) three times, followed by hydrogen three times. The reaction was stirred at 20° C. under 40 psi of hydrogen for 4 hours. After which time the reaction was purged with nitrogen three times and analyzed by thin layer chromatography [Eluent: 10% methanol/dichloromethane], which indicated that the reaction was complete. The reaction mixture was filtered through a Celite® pad and the pad was rinsed with methanol (2×10 mL). The filtrates were concentrated to dryness to afford a slightly pink solid (0.82 g, 95%). The spectral characterization was in agreement with the product prepared previously.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1.Br[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[O:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]1[N:5]1[C:4](=[O:14])[CH:3]=[C:2]([O:1][CH2:16][C:17]2[CH:22]=[N:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=2)[CH:7]=[N:6]1
Reactant: O=c1cc(O)cnn1C1CCCCO1
Reactant: FC(F)(F)c1ccc(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1cc(OCc2ccc(C(F)(F)F)nc2)cnn1C1CCCCO1
Yield: 123.1 %

Procedure:
5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2.3 g, 12 mmol), 5-(bromomethyl)-2-(trifluoromethyl)pyridine (7.2 g, 30 mmol) and K2CO3 (8.4 g, 60 mmol) were stirred in DMF (40 ml) and CH2Cl2 (40 ml) for 48 h. The mixture was diluted with CH2Cl2, washed with 5% LiCl solution (4×) and concentrated. The residue was purified by column chromatography (40 g ISCO column column eluting with methylene chloride and a 10:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 95% methylene chloride) to yield the title compound (5.25 g, >100%) as a waxy white solid containing some DMF: 1H NMR (300 MHz, CDCl3) δ 8.78 (d, J=1.8 Hz, 1H), 7.97-7.88 (m, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.72 (m, 1H), 6.20 (d, J=2.9 Hz, 1H), 6.03-5.98 (d, J=10.9, 2.0 Hz, 1H), 5.11 (s, 2H), 4.16-4.08 (m, 1H), 3.79-3.69 (m, 1H), 2.24-1.96 (m, 2H), 1.83-1.48 (m, 4H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:29]=[CH:28][C:10]([C:11]2[O:12][C:13]3[C:18]([C:19](=[O:21])[CH:20]=2)=[C:17]([O:22]C)[C:16]([O:24]C)=[C:15]([O:26]C)[CH:14]=3)=[CH:9][CH:8]=1>ClCCl>[OH:6][C:7]1[CH:29]=[CH:28][C:10]([C:11]2[O:12][C:13]3[C:18]([C:19](=[O:21])[CH:20]=2)=[C:17]([OH:22])[C:16]([OH:24])=[C:15]([OH:26])[CH:14]=3)=[CH:9][CH:8]=1
Reactant: COc1ccc(-c2cc(=O)c3c(OC)c(OC)c(OC)cc3o2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1cc(-c2ccc(O)cc2)oc2cc(O)c(O)c(O)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.3 %

Procedure:
Boron tribromide (0.7 mL) was added dropwise to a solution of the flavone 1c (68.4 mg, 0.2 mmol) in dichloromethane (3 mL) at 0° C. The mixture was allowed to warm to room temperature after 30 min and stirred at room temperature for 20 h. Then the mixture was poured into ice water (20 mL). The organic layer was separated and concentrated under reduce pressure. The aqueous layer was poured onto the organic residue. After stirring, the precipitate was filtered off and washed with water. Recrystallization from ethanol afforded the title compound (50 mg, 88%) as yellow crystals: 1H NMR (DMSO, 200 M Hz) δ 10.20 (br s, 2H), 7.90 (d, J=8.7 Hz, 2H), 6.90 (d, J=8.7 Hz, 2H), 6.72 (s 1H), 6.57 (s 1H), 3.75 (br s, 2H)); 13C NMR (DMSO, 50 M Hz) δ 182.1 (s), 163.6 (s), 161.0 (s), 153.3 (s), 149.7 (s), 147.1 (s), 129.2 (s), 128.4 (d, 2C), 121.5 (s), 116.0 (d, 2C), 104.1 (s), 102.3 (d), 93.9 (d).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[CH:16][C:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[N:28]=[CH:27][N:26](COCC[Si](C)(C)C)[N:25]=4)=[CH:20][CH:19]=3)=[C:11]2[N:10]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:26]1[CH:27]=[N:28][C:24]([C:21]2[CH:20]=[CH:19][C:18]([C:17]3[CH:16]=[N:15][N:12]4[CH:13]=[CH:14][C:9]([N:4]5[C@@H:3]([CH2:1][CH3:2])[CH2:7][O:6][C:5]5=[O:8])=[N:10][C:11]=34)=[CH:23][CH:22]=2)=[N:25]1
Reactant: CC[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)cc3)c2n1
Reaction time: 18 h
Yield: 45.3 %

Procedure:
A mixture of (S)-4-ethyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (0.024 g, 0.047 mmol) in DCM (1 mL) was treated with trifluoroacetic acid (0.4 mL) at ambient temperature. The mixture was stirred for 18 hours. The solvent was concentrated and the residue partitioned between EtOAc and aqueous satd. NaHCO3. The aqueous layer was further extracted with EtOAc. The combined organic extracts were washed with brine, dried (phase separator silicone treated filter paper), concentrated and purified on silica gel (1-5% 7N ammonia in MeOH/dichloromethane) to give (S)-3-(3-(4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-ethyloxazolidin-2-one (0.008 g, 45%) as a beige solid. MS (APCI+) m/z 376 [M+H]+.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:24][N:25]([CH3:31])[C:26](=[O:30])[CH2:27][NH:28][CH3:29].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:24][N:25]([CH3:31])[C:26](=[O:30])[CH2:27][N:28]([CH3:29])[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Reactant: CNCC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN(C)c1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Temperature: 135 °C

Procedure:
Into a 10 mL pressure vessel equipped with a magnetic stir bar was placed 0.1 g (0.266 mmol) 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (see Example 126), 0.031 g (0.27 mmol) N,N-dimethyl-2-(methylamino)acetamide, 0.726 mL (0.8 mmol) N,N-diisopropylethylamine and 5 mL DMF. The vessel was sealed and heated on an oil bath to 135° C. for 18 hrs., after which the mixture was cooled and the solvent removed in vacuo. The residue was purified by reverse phase HPLC on a C18 column using acetonitrile/water as eluent to give 5-[[2-(dimethylamino)-2-oxoethyl](methyl)amino]-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:11]1(=[O:20])[N:10]([CH2:9][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]12
Reactant: O=C1c2ccccc2C(=O)N1CCl
Reactant: Oc1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1COc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To a solution of 4.76 g (50 mmol) of 4-hydroxypyridine and 10.76 g (55 mmol) of N-chloromethylphthalimide in 80 ml of DMF, 8.23 ml (55 mmol) of 1,8-diazabicyclo[5,4,0]-7-undecene was added. The mixture was stirred at room temperature for 2 hours. After the solvent was distilled off, the reaction mixture was poured into water and extracted with ethyl acetate. The precipitate was filtered off. The aqueous layer was further extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 2.67 g of the desired compound (yield: 21%, colorless crystals).
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=1)[CH2:9][C:10]1[C:11]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[N:12][C:13]([NH2:17])=[N:14][C:15]=1[CH3:16]>CS(C)=O.CN(C=O)C.C([O-])(O)=O.[Na+]>[NH2:17][C:13]1[N:14]=[C:15]([CH3:16])[C:10]([CH2:9][C:8]2[CH:7]=[C:6]([CH2:5][C:1]#[N:2])[CH:26]=[CH:25][CH:24]=2)=[C:11]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[N:12]=1
Reactant: [C-]#N
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1cccc(CCl)c1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
Potassium cyanide (0.61 g) was added to a stirred solution of the product from step (v) (0.62 g) in DMSO (5 mL) and DMF (5 mL) and the mixture stirred at rt for 1 h. The reaction mixture was diluted with saturated aqueous NaHCO3 (10 mL) and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with water, dried and evaporated under reduced pressure to give the subtitle compound as a yellow oil 0.59 g that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:26]=[C:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:30]1[CH2:31][CH2:32][C:27](=[O:26])[CH2:28][CH2:29]1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C1CCNCC1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCC(=O)CC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from 2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 4-oxopiperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.04 minutes; C22H20Cl2N4O3 (459.33); mass spectrum: (M−H)−=458/460/462 (chlorine isotope).