Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]([NH2:27])[C:24]([Cl:28])=[CH:23][C:18]=1C(OC)=O.Cl[Si](C)(C)C.N1(CCCCC(O)=O)CCCCC1>C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>[ClH:28].[NH2:27][C:25]1[C:24]([Cl:28])=[CH:23][C:18]([C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][N:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[C:17]([O:16][CH3:15])[CH:26]=1
Reactant: COC(=O)c1cc(Cl)c(N)cc1OC
Reactant: O=C(O)CCCCN1CCCCC1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1C(=O)CCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 160 %

Procedure:
A suspension of 5-(piperdin-1-yl)valeric acid hydrochloride (6.6 g, 30 mmol) in 100 mL of THF was cooled in an ice bath and 100 mL of 1N lithium bis(trimethylsilyl)amide in THF was added. The ice bath was removed and the resulting solution was stirred at room temperature for 1 hour. A mixture of methyl 2-methoxy-4-amino-5-chlorobenzoate (2.15 g, 10 mmol) and chlorotrimethylsilane (2.5 mL, 20 mmol) in 25 mL of THF was cooled in an ice bath and 20 mL of lN lithium bis(trimethylsilyl)amide in THF was addled. The solution containing the 5-piperdin-1-ylvaleric acid and iN lithium bis(trimethylsilyl)amide was cooled in an ice bath and the mixture containing the methyl 2-methoxy-4-amino-5-chlorobenzoate was added over 5 minutes. The reaction mixture was removed from the ice bath and stirred at 50°-55° C. for 2 hours and then a solution of 25 mL of concentrated hydrochloric acid in 175 mL of water was added. The mixture was stirred at 50°-55° C. under a gentle stream of nitrogen and then 120 mL of ethyl acetate was added. The mixture was stirred in an ice bath for 1 hour giving a precipitate. The precipitate was isolated by filtration and washed with ethyl acetate. The precipitate was stirred in approximately 40 mL of boiling isopropanol for 30 minutes and then for 1 hour in an ice bath. The precipitate was isolated by filtration and washed with isopropanol. Drying in a vacuum oven at between 55 and 60° C. under a nitrogen gas bleed for 18 hours gave 1-(4-amino-5-chloro-2-methoxyphenyl)-5-piperidin-1-ylpentan-1-one hydrochloride (2.9 g, 8 mmol).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:26]2[O:30][N:29]=[C:28]([C:31]3[C:32]([C:37]([F:40])([F:39])[F:38])=[N:33][CH:34]=[CH:35][CH:36]=3)[N:27]=2)[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1.B(Br)(Br)Br>ClCCl>[N+:23]([C:13]1[CH:12]=[C:11]([C:26]2[O:30][N:29]=[C:28]([C:31]3[C:32]([C:37]([F:40])([F:39])[F:38])=[N:33][CH:34]=[CH:35][CH:36]=3)[N:27]=2)[CH:10]=[C:9]([OH:8])[C:14]=1[OH:15])([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cc(-c2nc(-c3cccnc3C(F)(F)F)no2)cc(OCc2ccccc2)c1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(-c2nc(-c3cccnc3C(F)(F)F)no2)cc(O)c1O
Temperature: -78 °C

Procedure:
A solution of 5-(3,4-bis(benzyloxy)-5-nitrophenyl)-3-(2-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazole (0.099 g, 0.18 mmol) in dichloromethane (5 mL) was cooled to −78° C. with stirring under argon and treated with boron tribromide (0.18 g, 0.74 mmol) dropwise. The resulting deep purple suspension was then allowed to stir at room temperature for one hour before cooling again to −78° C. The mixture was quenched by the careful addition of methanol. After stirring at room temperature for thirty minutes, the volatiles were evaporated and the residue stirred with 2 N hydrochloric acid (5 mL) for thirty minutes. The resulting solid was filtered off, washed with water (25 mL) and then cold isopropanol (5 mL) to give 3-nitro-5-(3-(2-(trifluoromethyl)pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzene-1,2-diol as a yellow solid, 0.058 g (88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[BH4-].[Na+].C1CCCCC1.CCOC(C)=O>C(Cl)Cl.C(O)C>[OH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(CO)c(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 g of commercials 2,3,4-trimethoxybenzaldehyde are placed in a 100 ml three-necked flask equipped with a magnetic stirrer, a gas inlet and a thermometer and are dissolved in 15 ml of CH2Cl2 +5 ml of ethanol. 200 mg of NaBH4 (6 mmoles) are added in small portions, at ambient temperature. The contents are stirred for 30 minutes at ambient temperature. TLC (cyclohexane:AcOEt 6:4) indicates a single-spot product. The ethanol is evaporated off and the residue is taken up with ChCl3, the organic phases are washed with NaCl and then with H2O, dried over MgSO4 and evaporated. An analytically pure pale yellow oil is obtained (Y=98%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2O)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:19])=O.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[Cl:19])=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cn2ncnc(O)c2c1C
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn2ncnc(Cl)c2c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
A mixture of 4-hydroxy-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester (60.0 g, 271.2 mmol, for preparation see WO 0071129), phosphorus oxychloride (30.3 mL, 325.4 mmol) and diisopropylethyl amine (37.7 mL, 217 mmol) in toluene (800 mL) was heated to reflux under argon for 18 h and then cooled to room temperature. The mixture was concentrated on rotovap and the residue was diluted with dichloromethane (1000 mL) and cold sodium bicarbonate solution (300 mL). The resulting mixture was stirred at room temperature for 10 min. The separated organic layer was washed with cold brine (300 mL), dried, and concentrated in vacuo. The crude material was purified by chromatography on silica gel eluting with dichloromethane to provide the desired compound (64.8 g, 99%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:25])=[C:4](I)[C:5]([O:21][CH2:22][CH3:23])=[C:6]([CH:8]([N:10]2[C:14]3=[N:15][CH:16]=[N:17][C:18]([NH2:19])=[C:13]3[C:12]([CH3:20])=[N:11]2)[CH3:9])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]([O:49][CH3:50])(=[O:48])[CH:46]=[CH2:47].C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:19][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:10]([CH:8]([C:6]3[C:5]([O:21][CH2:22][CH3:23])=[C:4](/[CH:47]=[CH:46]/[C:45]([O:49][CH3:50])=[O:48])[C:3]([CH3:25])=[C:2]([Cl:1])[CH:7]=3)[CH3:9])[N:11]=[C:12]([CH3:20])[C:13]=12
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1I
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1/C=C/C(=O)OC
Temperature: 100 °C
Yield: 71.6 %

Procedure:
A suspension of 1-[1-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (peak 1 single isomer from step 2) (0.61 g, 1.3 mmol) in acetonitrile (7.4 mL) in a sealed tube was degassed with nitrogen and treated with triphenylphosphine (0.048 g, 0.18 mmol), methyl acrylate (0.41 mL, 4.5 mmol), and palladium acetate (0.029 g, 0.13 mmol) followed by triethylamine (0.54 mL, 3.9 mmol) and heated at 100° C. for 16 h. The reaction mixture was cooled to room temperature, filtered, and the solids washed with acetonitrile. The filtrate was concentrated to a residue. The crude material was purified by flash column chromatography using ethyl acetate (containing 3% methanol) in hexanes (0%-100%) to give the desired product (0.40 g, 72%). LCMS for C21H25ClN5O3 (M+H)+: m/z=430.2; Found: 430.2.
Reaction SMILES: [CH2:1]([NH:3][S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2].[H-].[Na+].F[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].O>CN(C=O)C>[CH2:1]([N:3]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19])[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCNS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(c1cc(F)ccc1[N+](=O)[O-])S(C)(=O)=O
Temperature: 55 °C
Reaction time: 8 h

Procedure:
N-ethyl-methanesulfonamide (Mijs et al. J. Chem. Soc. Chem. Com. 1972 p 412) (5 g 40.6 mmol) was added to a suspension of sodium hydride (1.9 g, 55% in mineral oil) in anhydrous DMF (100 mL) under nitrogen. The mixture was warmed to 55° C. for one hour and 2,4-difluoronitrobenzene (4.4 mL) was added dropwise. The reaction was stirred at 60° C. overnight, poured into water (500 mL) and the product extracted into CH2Cl2 (5×100 mL). The organic extracts were washed with water, dried over MgSO4 and evaporated to give an oily product. The remaining DMF was removed by trituration with petrol. The crude product was purified by flash chromatography (ethyl acetate:petrol 1:1) to yield the desired product which was recrystallised from ethanol. Yield 3.5 g (33%). Calculated N % 10,68 C % 41,22 S % 12,23H % 4,23; Found N % 10,68 C % 41,39 S % 12,22H % 4,17.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([O:21][C:22](=[O:32])[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([OH:3])=[O:2].[N+:33]([C:36]1[CH:41]=[CH:40][C:39]([O:42][C:43](=[O:46])[CH2:44]Br)=[CH:38][CH:37]=1)([O-:35])=[O:34].C(OC(C)C)(C)C>CC(C)=O.C(N(CC)CC)C>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([C:22]([O:21][C@@H:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]([O:3][CH2:44][C:43]([O:42][C:39]2[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:41][CH:40]=2)=[O:46])=[O:2])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:32])=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: O=C(CBr)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCC(CCCCCCCCCCC(=O)O)OC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CC(C)OC(C)C
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCC[C@H](CCCCCCCCCCC(=O)OCC(=O)Oc1ccc([N+](=O)[O-])cc1)OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-Nitro-benzoic acid 11-carboxy-1-hexyl-undecyl ester (500 g) in dry Acetone, triethylamine (232 mL) at 10-15° C. was added Bromoacetic acid 4-nitro-phenyl ester (347 g). The solution was stirred at room temperature for 8 hours. 75% of the solvent was distilled off and cooled to room temperature. The resulting solid was poured onto cold water and pH was adjusted to 4-5 with dilute HCl. The resulting solid was filtered off and washed with chilled water (100 mL). The slurry was prepared with 1 lit Di Isopropyl Ether and filtered off. The resulting solid was then dried in vacuum oven at 60-80° C. to yield pure (R)-18-(2-(4-nitrophenoxy)-2-oxoethoxy)-18-oxooctadecan-7-yl 4-nitrobenzoate product as off white powder with a melting point of 130-133° C. The resulting compound was characterized by 1H NMR (CDCl3) δ 0.86 (t, 3H, CH3), 1.2-1.5 (m, 28H, 14×CH2), 1.68 (m, 2H, CH2), 2.42 (t, 2H, COCH2), 3.52 (m, 1H, CH), 5.2 (s, 2H, CH2) 7.42 (m, 2H, Ar) 8.4-8.52 (m, 6H, Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:40]1([CH3:54])[CH:45]=[CH:44][C:43]([C:46]2([CH2:52][NH2:53])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[CH:7][C:3]=1[C:4]([NH:53][CH2:52][C:46]1([C:43]2[CH:42]=[CH:41][C:40]([CH3:54])=[CH:45][CH:44]=2)[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]1)=[O:6]
Reactant: Cc1ccc(-c2ccc(Cl)c(C(=O)O)c2)cn1
Reactant: Cc1ccc(C2(CN)CCCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C2(CNC(=O)c3cc(-c4ccc(C)nc4)ccc3Cl)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.9 %

Procedure:
To a solution of 2-chloro-5-(6-methyl-pyridin-3-yl)-benzoic acid (73 mg, 0.29 mmol) in N,N-dimethylformamide (4 mL) was added sequentially, stirring at room temperature for 10 minutes after each addition, 1-hydroxybenzotriazole (48 mg, 0.35 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (62 mg, 0.32 mmol), C-(1-p-tolyl-cyclohexyl)-methylamine (60 mg, 0.29 mmol) and triethylamine (31 mg, 0.31 mmol). The mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography to afford the title compound (35 mg). LCMS (m/z) 433.2 M+1.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[NH2:27][C:28]1[C:29](=[O:40])[NH:30][C:31](=[O:39])[N:32]([CH2:35][CH2:36][CH2:37][CH3:38])[C:33]=1[NH2:34]>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([NH:27][C:28]2[C:29](=[O:40])[NH:30][C:31](=[O:39])[N:32]([CH2:35][CH2:36][CH2:37][CH3:38])[C:33]=2[NH2:34])=[O:14])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCCCn1c(N)c(N)c(=O)[nH]c1=O
Reactant: CC(=O)Nc1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCn1c(N)c(NC(=O)Cc2ccc(NC(C)=O)cc2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.9 %

Procedure:
A solution of (4-acetylamino-phenyl)-acetic acid (348 mg, 1.65 mmol) in N,N-dimethylformamide (2.5 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (316 mg, 1.80 mmol). The resulting mixture was stirred at 25° C. for 20 min. At this time, the reaction was treated with 5,6-diamino-1-butyl-1H-pyrimidine-2,4-dione (300 mg, 1.5 mmol) followed by 4-dimethylaminopyridine (37 mg, 0.3 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was diluted with water (5.0 mL) and was brought to pH=5 with a 1N aqueous hydrochloric acid solution. The resulting solid was collected by filtration, washed with water, and dried in vacuo to afford 2-(4-acetylamino-phenyl)-N-(6-amino-1-butyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-acetamide (330 mg, 59%) as a light tan solid: LR-MS for C18H23N5O4 (M+H)+ at m/z=374
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][N:4]=1.[H][H]>[C].[Pd].C(O)C>[CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:12]([F:15])([F:13])[F:14])=[CH:5][N:4]=1
Reactant: [H][H]
Reactant: CNc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CNc1ncc(C(F)(F)F)cc1N
Yield: 83.8 %

Procedure:
A mixture of N-methyl-(3-nitro-5-trifluoromethyl-pyridin-2-yl)-amine (6.93 g), 5% of palladium-carbon (0.69 g), and ethanol was stirred under about 1 atm of hydrogen at room temperature for 10 hours. The reaction mixture was filtered through Celite®, and then the filtrate was concentrated under reduced pressure to give 5.02 g of N2-methyl-5-trifluoromethylpyridin-2,3-diamine (Compound (1F)-1).
Reaction SMILES: [F:1][B-](F)(F)F.[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[N:15]=2)[N:10]=[CH:9][C:8]=1[N+]#N>C1C2C(CCCC2)CCC1.C(Cl)(Cl)Cl>[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[N:15]=2)[N:10]=[CH:9][C:8]=1[F:1]
Reactant: COc1ccc2ncc([N+]#N)c(Br)c2n1
Reactant: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Solvent: C1CCC2CCCCC2C1
Product: COc1ccc2ncc(F)c(Br)c2n1
Temperature: 180 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
A suspension of 4-bromo-6-methoxy-[1,5]naphthyridine-3-diazonium tetrafluoroborate (31.42 g, 89.0 mmol) in decalin (mixed isomers, 500 mL) in a 2 L flask* was heated to 180° C. and held at this temperature for 5 min. The mixture was cooled and diluted with CHCl3 (500 mL, to keep the product in solution), and the resulting mixture was stirred vigorously for 30 min to break up a black solid by-product. The mixture was then poured onto a column of silica gel and the column was eluted with CHCl3 to remove decalin and then with 3% EtOAc/CHCl3 to afford the title compound (9.16 g, 40%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:11][CH2:10][CH2:9][N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: ClCCCN1CCCCC1
Reactant: O=C1CCNCC1
Product: O=C1CCN(CCCN2CCCCC2)CC1

Procedure:
1-(3-(1-Piperidinyl)propyl)-4-piperidone is prepared from 4-piperidone and 1-(3-chloropropyl)piperidine essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]1=[N:1][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc2ccccc2s1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N=c2[nH]c3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93 %

Procedure:
To a solution of 2-aminobenzothiazole (1.018 g, 6.78 mmol) in dry pyridine (4 mL) was added portion wise, p-toluene sulfonyl chloride (1.42 g, 7.48 mmol). The solution turned yellow upon addition. After 5 minutes of stirring at rt, the mixture was heated (70-80° C.) for 5 minutes. The mixture was poured on a bed of ice and the resulting precipitate was filtered off and dried overnight in a dessicator under vacuum to give a yellow powder in 93% yield: mp 246-249° C.; 1H-NMR (DMSO-d6) 2.36 (s, 3H), 7.26, (dt, 1H), 7.30 (d, 1H), 7.37 (d, 2H), 7.40 (dt, 1H), 7.75 (d, 2H), 7.81 (d, 1H); Anal. (C14H12N2O2S2) C, H, N.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C@@H:30]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]4)=[CH:25][CH:24]=3)[C:19](=[O:42])[CH:18]=2)=[N:13][CH:14]=1>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][N:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C@@H:30]4[CH2:34][CH2:33][NH:32][CH2:31]4)=[CH:27][CH:28]=3)[C:19](=[O:42])[CH:18]=2)=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(-n3ccc(OCc4ccc(Cl)cn4)cc3=O)cc2)C1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc(O[C@@H]2CCNC2)cc1
Temperature: 25 °C
Yield: 105.6 %

Procedure:
Trifluoroacetic acid (20 mL) was added to chloroform solution (20 mL) of 4-[(5-chloro-2-pyridinyl)methoxy]-1-(4-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy}phenyl)-1H-pyridin-2-one (3.14 g, Example 121), and stirred at room temperature for an hour. After concentrating the reaction liquid, 1N sodium hydroxide solution was added thereto, followed by extraction with chloroform two times. The organic layer was washed with saturated brine, dried over anhydrous potassium carbonate, and the solvent was concentrated under reduced pressure to provide the title compound (2.65 g, 83%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([C:21](=O)[CH:22]=[CH:23]N(C)C)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:29][C:30]([NH2:32])=[NH2+:31].[O-]CC.[Na+].NC(N)=N>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:20]([C:21]3[CH:22]=[CH:23][N:29]=[C:30]([NH2:32])[N:31]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:19])[F:18])=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Reactant: NC(N)=[NH2+]
Agent: CC[O-]
Agent: Cl
Agent: N=C(N)N
Solvent: CCO
Product: Nc1nccc(-c2c(-c3ccc(F)cc3)nn3cc(C(F)(F)F)ccc23)n1
Temperature: 0 °C

Procedure:
A mixture of 2-(4-fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine (100 mg, 0.27 mmol), guanidinium hydrochloride (52 mg, 0.54 mmol), and sodium ethoxide (73 mg, 1.08 mmol) in EtOH (4 mL) was stirred at reflux for 21 h. Additional guanidine was added in portions to the mixture until starting material was consumed as evidenced by TLC. The reaction mixture was cooled to 0° C. and the resulting precipitate was collected by filtration washed with cold EtOH and dried under vacuum to afford the title compound as a tan solid, 93 mg (92%). 1H NMR (acetone-d6) δ 9.19 (s, 1H), 8.73 (d, 1H, J=9.4 Hz), 8.13 (d, 1H, J=5.2 Hz), 7.78 (m, 2H), 7.63 (d, 1H, J=9.5 Hz), 7.34 (m, 2H), 6.41 (d, 1H, J=5.2 Hz), 6.17 (s, 1H). MS (+ve ion electrospray) 374 (100), (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[N+:7]([C:10]1[CH:11]=[C:12]([CH2:16][SH:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].CS(O[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:25]=1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[N+:7]([C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[CH2:16][S:17][CH2:23][C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:32])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH:27]=[CH:28][CH:29]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cccc(CS)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(COS(C)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cccc(CSCc2cccc([N+](=O)[O-])c2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
A solution of cesium carbonate (0.57 g, 1.8 mmol) in N,N-dimethylformamide (1.8 mL) at 0° C. was treated with (3-nitrophenyl)methanethiol (0.22 mL, 1.6 mmol) dropwise and stirred at 0° C. for 10 min. The reaction mixture was treated with a solution of 3-[(tert-butoxycarbonyl)amino]benzyl methanesulfonate (0.41 g, 1.3 mmol) in N,N-dimethylformamide (2.4 mL) dropwise and stirred at 0° C. for 30 min. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (40 mL) and brine (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to a crude brown oil. This material was purified by flash column chromatography to give the desired product (0.42 g, 84% for 2 steps) as a yellow oil. LCMS for C19H22N2O4SNa (M+Na)+: m/z=396.7.
Reaction SMILES: C([CH:3]([C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][N:21]([S:32]([C:35]4[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=4)(=[O:34])=[O:33])[C:18]3=[N:19][CH:20]=2)[N:12]=[CH:11][N:10]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5])#N.C(OO)(=[O:44])C.S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:23]1[C:17]2[C:18](=[N:19][CH:20]=[C:15]([C:13]3[N:12]=[CH:11][N:10]=[C:9]([C:3](=[O:44])[C:4]([N:6]([CH3:8])[CH3:7])=[O:5])[CH:14]=3)[CH:16]=2)[N:21]([S:32]([C:35]2[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH:22]=1
Reactant: CC(=O)OO
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(C(C#N)C(=O)N(C)C)ncn3)cc12
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(C(=O)C(=O)N(C)C)ncn3)cc12
Temperature: 0 °C
Yield: 64.4 %

Procedure:
2-Cyano-2-{6-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrimidin-4-yl}-N,N-dimethyl-acetamide (500 mg, 0.88 mmole) was suspended in tetrahydrofuran (11 mL) and cooled to 0° C. in an ice bath. Peroxy acetic acid (32% in acetic acid, 174 mg, 2.29 mmole) was added and after 10 min, the heterogeneous solution was removed from the ice bath and maintained at ambient temperature for 6 h. Sodium bisulfite (918 mg, 8.83 mmole) in water (10 mL) was added, followed by saturated aqueous sodium bicarbonate (20 mL) and the mixture extracted with ethyl acetate (3×30 mL). The combined organic portions were dried over magnesium sulfate, filtered, and concentrated to dryness. Silica gel chromatography of the crude residue afforded 2-{6-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrimidin-4-yl}-N,N-dimethyl-2-oxo-acetamide (315 mg, 89% yield) as a clear residue. MS: m/z 402.2 (M+H+).