Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](/[N:8]=[CH:9]/N(C)C)=[N:6][CH:7]=1.Cl[CH2:14][C:15](=[O:17])[CH3:16].C([O-])(O)=O.[Na+]>CC(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:14]([C:15](=[O:17])[CH3:16])=[CH:9][N:8]=2)[CH:7]=1
Reactant: CC(=O)CCl
Reactant: CN(C)/C=N/c1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(=O)c1cnc2ccc(Br)cn12
Yield: 47.5 %

Procedure:
(E)-N′-(5-Bromopyridin-2-yl)-N,N-dimethylformimidamide (2.0 g, 8.8 mmol), 1-chloropropan-2-one (1.2 mL, 1.4 g, 15 mmol), NaHCO3 (1.3 g, 15.5 mmol) in 2-propanol (30 mL) were heated at 90° C. under nitrogen for 12 h. The dark reaction mixture was cooled and the dense heterogeneous suspension was diluted with water. The solid was collected by filtration, washed with water and dried to obtain 1.0 g of 1-(6-bromoimidazo[1,2-a]pyridin-3-yl)ethan-1-one. 1H NMR (300 MHz, DMSO-d6) δ 9.62 (d, J=1.9 Hz, 1H), 8.61 (s, 1H), 7.81 (d, J=9.5 Hz, 1H), 7.75 (dd, J=9.5, 1.9 Hz, 1H), 2.55 (s, 3H). See Bioorg. Med. Chem. Lett. 15(1), 403-412 (2007); Int'l Pat. App. Pub, no. 2009/158011.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[Br:20][C:21]1[CH:22]=[CH:23][C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[C:25]([NH2:27])[CH:26]=1.Cl>O1CCOCC1.CO>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[C:25]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:3]=2[CH3:19])[CH:26]=1
Reactant: Nc1cc(Br)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(Br)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 1 using 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (131 mg, 480 μmol), 5-bromo-2-morpholinobenzenamine (124 mg, 480 μmol) and 4.0N hydrochloric acid (0.12 mL, 480 μmol) solution in dioxane in MeOH (1.50 mL) to afford a yellow solid after purification by chromatography on silica gel, eluting with EtOAc-hexane solvent mixture. Mass Spectrum (ESI) m/e=493.0 & 495.0 (M+1).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.II.[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Br)[CH3:19].Cl>C1C=CC=CC=1.[Zn]>[OH:15][C:13]([C:10]1[CH:9]=[CH:8][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:12][CH:11]=1)([CH3:14])[CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:24]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1ccc(C2CCCCC2)cc1
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC(C)(O)c1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a refluxing mixture of 4′-cyclohexylacetophenone (25 g), I2 (5 mg) and Zn (17 g) in benzene (150 ml) was added ethylbromoacetate (20.7 ml) dropwise during 30 minutes. The mixture was refluxed for 2 h and then cooled to room temperature. It was acidified with 10% HCl (200 ml) an organic layer separated out. The organic phase was washed with water, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography using SiO2 as adsorbent and hexane-ethylacetate mixture as eluant to give 28 g (80% yield) of ethyl 3-hydroxy-3-(4-cyclohexylphenyl)-butanoate (2b, formula 2, R=cyclohexyl) m.p. 45° C.
Reaction SMILES: I[CH2:2][CH:3]1[O:7][CH:6]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH2:5][CH2:4]1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.CCOC(C)=O>[N:17]([CH2:2][CH:3]1[O:7][CH:6]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH2:5][CH2:4]1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC(CI)O1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ncc([N+](=O)[O-])c1C1CCC(CN=[N+]=[N-])O1
Temperature: 25 °C
Reaction time: 36 h
Yield: 100.2 %

Procedure:
To a solution of 5-(5-(iodomethyl)tetrahydrofuran-2-yl)-1-methyl-4-nitro-1H-pyrazole (640 mg, 1.90 mmol, intermediate 60) in dry DMF (10 mL) was added sodium azide (250 mg, 3.80 mmol) and the mixture stirred at room temperature for 36 hr. The mixture was diluted with EtOAc (25 mL) and washed with water (2×10 mL) and brine (20 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure to give 5-(5-(azidomethyl)tetrahydrofuran-2-yl)-1-methyl-4-nitro-1H-pyrazole as a yellow oil (480 mg, 100%). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 5.84-5.70 (m, 1H), 4.49-4.45 (m, 1H), 4.03 (s, 3H), 3.56-3.39 (m, 2H), 2.66-2.65 (m, 1H), 2.29-2.22 (m, 1H), 2.02-1.92 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[NH:15]1[CH2:17][CH2:16]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([N:15]2[CH2:17][CH2:16]2)=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: C1CN1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(C(=O)N2CC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
13.0 g (55.6 mmol) of 4-[(methylsulfonyl)amino]benzoyl chloride is suspended in 150 mL of methylene chloride and cooled to about 0° C. 2.40 g (55.7 mmol) of aziridine and 7.75 mL (55.6 mmol) of triethylamine are added and the reaction allowed to warm to room temperature and stir for 2 hours. After 2 hours, the solution is washed with 100 mL of saturated aqueous sodium chloride and placed in the freezer. After 18 hours, the resulting white precipitate is filtered, washed with 50 mL of ether and dried to provide the title compound.
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15]2[C:24]([F:25])=[C:23]3[C:18]([C:19](=[O:32])[C:20]([C:29]([OH:31])=[O:30])=[CH:21][N:22]3[CH:26]3[CH2:28][CH2:27]3)=[CH:17][C:16]=2[F:33])[CH2:10]1)=O)(C)(C)C.[ClH:34]>C(O)C>[ClH:34].[NH2:8][C@H:9]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15]2[C:24]([F:25])=[C:23]3[C:18]([C:19](=[O:32])[C:20]([C:29]([OH:31])=[O:30])=[CH:21][N:22]3[CH:26]3[CH2:28][CH2:27]3)=[CH:17][C:16]=2[F:33])[CH2:10]1
Reactant: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H]1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-(cis-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.3 g) in ethanol (5 ml) and ethanolic hydrochloride (6 ml) was stirred for 2 hours at room temperature and then concentrated. To the residue was added ethanol and the resulting precipitate was collected by filtration and washed with ethanol to give the title compound (0.21 g) as pale yellowish powder, mp 274°-275° C. (decompd.).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].CC(C)=O.[C:9](Cl)(=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>N1C=CC=CC=1>[OH:3][CH2:2][CH2:1][O:4][C:9](=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: OCCO
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)OCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
Under cooling with ice, ethylene glycol (434 mg) was dissolved into acetone (20 ml), and pyridine (632 mg) was added thereto and then lauroyl chloride (1532 mg) was added dropwise thereto. The temperature of the solution was warmed to room temperature, and it was stirred for 2 hours. The mixture was evaporated. To the residue was added water, and the solution was extracted with ethyl acetate. The organic layer was washed with water (three times), dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (1.63 g) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C@@H:22]2[CH2:26][C@H:25]([F:27])[CH2:24][N:23]2[C:28]([O:30]CC2C=CC=CC=2)=O)[N:8](C)[C:9](=[O:20])[C:10]=1[O:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[C:38](OC(=O)C)(=O)C>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([OH:20])[N:8]=[C:7]([C@@H:22]2[CH2:26][C@H:25]([F:27])[CH2:24][N:23]2[C:28](=[O:30])[CH3:38])[N:6]=1)=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1nc([C@@H]2C[C@H](F)CN2C(=O)OCc2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1nc([C@@H]2C[C@H](F)CN2C(C)=O)nc(O)c1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl-5-(benzoyloxy)-2-{(2S,4S)-1-[(benzyloxy)carbonyl]-4-fluoropyrrolidin-2-yl}-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate, dissolved in ethyl acetate was treated with Pd/C 10% (10% w/w) and acetic anhydride (1 eq.) and submitted under H2 atmosphere at room temperature. The reaction mixture was stirred at room temperature for 18 hours and then the suspension was filtered over celite to give the title compound as a 7:3 mixture of rotamers by NMR.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][C:9](=O)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:15][C:9]1[CH2:10][CH2:11][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: O=C1CCN(c2ccccc2)N1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: ClC1=NN(c2ccccc2)CC1
Reaction time: 1 h

Procedure:
1-Phenylpyrazolidin-3-one (8.1 g) was suspended in dry toluene (100 ml), followed by addition of phosphoryl chloride (7.0 ml) and the mixture stirred for 1 hour at 85°. When cool the toluene was decanted from the solid and solvent removed in vacuo to give the sub-title compound, (6.9 g), mp 92°-93°.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])=[CH:10][CH:9]=1>N1C=CC=CC=1.CC(=O)OCC>[CH3:1][S:2]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:17])=[O:16])=[CH:10][CH:9]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(CS(=O)(=O)Oc2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(CS(=O)(=O)Oc2ccccc2)cc1
Reaction time: 20 h

Procedure:
Methanesulphonyl chloride (1.12 ml) was added to a cooled stirred solution of phenyl 4-aminobenzenemethanesulphonate, hydrochloride (3.0 g) in pyridine (9 ml). The resulting mixture was allowed to warm up to 20° and then stirred for 20 h. The reaction mixture was diluted with EA (150 ml) and washed with 8% NaHCO3 (400 ml), H2O (250 ml) and brine (250 ml). The organic extract was dried (MgSO4) and evaporated to leave a brown gum which was crystallised from toluene (100 ml) to give the crude title compound (as an off-white solid which was recrystallised from toluene (100 ml) to give the title compound (1.25 g) as a white solid m.p. 128°-129°.
Reaction SMILES: Br[Zn][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.Br[C:10]1[S:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=1>O1CCOCC1.O.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>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:10]1[S:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=1
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: Br[Zn]c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cnc(-c2ccccn2)s1
Reaction time: 0.17 h

Procedure:
A mixture of bromo(pyridine-2-yl)zinc (0.5 M in THF, 1.27 mL), ethyl 2-bromo-1,3-thiazole-5-carboxylate (0.063 mL, 0.42 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.02 mmol) in 1,4-dioxane (3 mL) and water (0.03 mL) was subjected to MWI at 120° C. for 10 min. The reaction mixture was diluted with water and extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, filtered, and concentrated to give ethyl 2-pyridin-2-yl-1,3-thiazole-5-carboxylate (0.12 g) which was used without further purification. LCMS: (FA) ES+ 235.
Reaction SMILES: [C:1]([NH:5][N:6]=[C:7]([CH:9]1[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:12]#[N:13]>>[C:1]([NH:5][NH:6][C:7]([C:12]#[N:13])([CH:9]1[CH2:10][CH2:11]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=NNC(C)(C)C)C1CC1
Reactant: C#N
Product: CC(C)(C)NNC(C)(C#N)C1CC1
Temperature: 0 °C

Procedure:
A solution of 8.7g methyl cyclopropyl ketone t-butylhydrazone in 20 ml liquid hydrocyanic acid was heated for 6 hours in a pressure bottle at 60°C. The solution was cooled, poured into ice water and the aqueous solution extracted twice with ether. The ether extracts were combined, washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and the ether evaporated off. The yield was 10.0g (99%) of a brown liquid. The infrared spectrum was consistent with the structure of the proposed product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:13])([P:9]([OH:12])(=[O:11])[OH:10])[P:5]([OH:8])(=[O:7])[OH:6].[OH-].[Na+:15]>O>[NH2:1][CH2:2][CH2:3][C:4]([OH:13])([P:5]([OH:8])(=[O:6])[OH:7])[P:9]([O-:12])(=[O:10])[O-:11].[Na+:15].[Na+:15]
Reactant: NCCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NCCC(O)(P(=O)([O-])[O-])P(=O)(O)O

Procedure:
70.0 kg of 3-amino-1-hydroxypropane-1,1-diphosphonic acid are suspended while stirring in 140 liters of demineralised water. The suspension is heated to 65°-70° and 59.9 liters (79.5 kg) of 30% aqueous sodium hydroxide solution are added at such a rate that the temperature of the reaction mixture rises to approximately 85° with the formation of a clear solution. The pH value of the solution should be between 7.2 and 7.5. It can be finely adjusted if necessary by the addition of small amounts of 30% sodium hydroxide solution or of 3-amino-1-hydroxypropane-1,1-diphosphonic acid. The solution is cleared by filtering through a filter that is coated with a small quantity of diatomaceous earth and has been preheated to 75°-80° into a vessel preheated to the same temperature. The solution is inoculated, and, while stirring, cooled in the course of 2 hours to 20°-25°, 70 liters of 96% ethanol are added in the course of a further 2 hours while stirring, the mixture is then cooled to 0°-5° in the course of 1 hour and the reaction is completed by stirring at this temperature for at least 1 hour. The mother liquor is then centrifuged off and the residue is washed in portions with a mixture of 25 liters of ethanol and 45 liters of demineralised water. The whole is centrifuged thoroughly and dried in a vacuum cabinet at 35°-40° until the weight is constant (approximately 24 hours). Disodium 3-amino-1-hydroxypropane-1,1-diphosphonate is obtained in the novel crystal form containing water of crystallisation (modification E), the IR spectrum of which is identical to that of the product obtained according to Example 1.
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29]C4C=CC([N+]([O-])=O)=CC=4)=O)[CH2:23][CH2:22]3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5]>C(O)C>[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27]([NH:1][NH2:2])=[O:29])[CH2:23][CH2:22]3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)(=[O:5])=[O:6]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)Oc4ccc([N+](=O)[O-])cc4)CC3)cn2)cc1
Reactant: NN
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)NN)CC3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
Hydrazine (0.140 mL, 4.45 mmol) was added to a mixture of 4-nitrophenyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (456 mg, 0.89 mmol) in ethanol (30 mL) at ambient temperature. The mixture was stirred at ambient temperature overnight. The mixture was charged with additional ethanol (30 mL) and hydrazine (5 mL, 159 mmol), stirred at reflux until homogeneous (15 min), then at ambient temperature overnight. The mixture was concentrated to dryness, charged with 4:1 EtOH:CH2Cl2 and MP-Carbonate (8 g). The mixture was stirred at ambient temperature for 2 h, filtered, washed with 4:1 EtOH:CH2Cl2, and the filtrate was concentrated to give 352 mg (98%) of 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarbohydrazide as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.43 (d, 1H, J=2.9 Hz), 8.28 (d, 2H, J=8.6 Hz), 8.06 (d, 1H, J=8.9 Hz), 7.99 (d, 2H, J=8.6 Hz), 7.61 (bs, 1H), 7.54 (dd, 1H, Ja=8.8 Hz, Jb=3.0 Hz), 4.03-3.92 (m, 4H), 3.84 (d, 2H, J=3.2 Hz), 3.25 (s, 3H), 2.74-2.64 (m, 2H), 2.05-1.88 (m, 1H), 1.79-1.67 (m, 2H), 1.23-1.09 (m, 2H); LRMS (ESI), m/z 405 (M+H).
Reaction SMILES: C(OC(N1CC2C([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[N:20]=[C:21]([Cl:32])[N:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:24]=4[N:25]=3)[CH2:13]2)C1)=O)(C)(C)C.[C:33]([O:37][C:38]([N:40]1[CH:45]2[CH2:46][CH2:47][CH:41]1CNC2)=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([N:40]1[CH:45]2[CH2:46][CH2:47][CH:41]1[CH2:11][N:12]([CH2:16][C:17]1[S:18][C:19]3[N:20]=[C:21]([Cl:32])[N:22]=[C:23]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[C:24]=3[N:25]=1)[CH2:13]2)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4s3)CC2C1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Product: CC(C)(C)OC(=O)N1C2CCC1CN(Cc1nc3c(N4CCOCC4)nc(Cl)nc3s1)C2

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a white solid (91 mg, 95%).
Reaction SMILES: [NH2:1][S:2]([CH2:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([N:10]([CH3:12])[CH3:11])=[O:9])(=[O:4])=[O:3].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[N:20]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([O:18][CH3:17])[N:20]=[C:21]([NH:27][C:28]([NH:1][S:2]([CH2:5][C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[C:8]([N:10]([CH3:12])[CH3:11])=[O:9])(=[O:3])=[O:4])=[O:29])[N:22]=1
Reactant: CN(C)C(=O)c1ccccc1CS(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Cc2ccccc2C(=O)N(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a solution of 0.48 g of the compound of Example 18 and 0.54 g of N-(4,6-dimethoxypyrimidin-2-yl)carbamic acid, phenyl ester in 25 ml of acetonitrile was added 0.3 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene, and the mixture was stirred overnight at room temperature. Ice (25.0 g) was added; the aqueous mixture acidified with concentrated hydrochloric acid and then extracted with two 75 ml portions of methylene chloride. The organic solution was washed with water, brine, dried (magnesium sulfate), filtered and concentrated in vacuo. Trituration of the oily residue with 1-chlorobutane gave 0.42 g of 2-[[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]methyl]-N,N-dimethylbenzamide, m.p. 141°-143°; IR (nujol): 1700 and 1600 cm-1 ; NMR (CDCl3): δ 2.93-3.13 (6H, N(CH3)2, 2 singlets), 3.83 (6H, OCH3, s), 5.0 (2H, CH2, s) and 5.76 (1H, CH, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(C2OCCO2)c1
Reactant: BrCCCCBr
Agent: [Li]C(C)(C)C
Product: BrCCCCc1cccc(C2OCCO2)c1
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
To a clean and dry 2000 ml round bottom flask equipped with a 500 ml addition funnel, low temperature thermometer and magnetic stir bar was transferred anhydrous tetrahydrofuran (800.0 ml) under nitrogen. 2-(3-bromophenyl)-1,3-dioxolane (33.0 ml, 0.2183 mol) was added to this flask by syringe. The reaction vessel was placed into a dry ice/acetone bath until a temperature of <−65° was achieved. The reaction mixture was then allowed to stir for 45 minutes at a stirring speed of 550 rpm in order to verify the integrity of the stirring apparatus at this temperature. Tert-butyllithium solution (257.0 ml, 0.4690 mol) was transferred to the addition funnel by cannula, then added dropwise to the reaction never allowing the temperature to rise above −65° C. Following addition, the reaction was allowed to stir for a period of 30 minutes. The vessel was then removed from the dry ice/acetone bath and allowed to warm to a temperature of −20° C. The vessel was then again placed into the dry ice/acetone bath until a temperature of <−65° was achieved. 1,4-dibromobutane (103.5 ml, 0.8740 mol) was added to the reaction dropwise via syringe, maintaining the current temperature. The reaction was allowed to stir for 30 minutes at this temperature following addition. The reaction was slowly warmed to room temperature over the following 12 hours. After warming, the reaction was quenched by the addition of isopropanol (20.0 ml) via syringe.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:13])=[N:6][N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12)([CH3:3])=[CH2:2].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([C:4]1[C:5]([CH3:13])=[N:6][N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12)([CH3:3])[CH3:2]
Reactant: C=C(C)c1c(C)nn2ccccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nn2ccccc2c1C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.6 %

Procedure:
A solution of 3-isopropenyl-2-methylpyrazolo[1,5-a]pyridine (0.43 g, 2.5 mmol) in CH2Cl2 (30 mL) was treated with triethylsilane (3 mL, 18.8 mmol) and TFA (6 mL). The reaction was stirred at room temperature for 15 hours then quenched with saturated NaHCO3.The layers were separated and the aqueous layer was extracted with CH2Cl2 and the combined organic layers was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (20% ethyl acetate/heptane) to give 0.19 g (44%) of a yellow oil as the title compound: 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J=7.0 Hz, 1H), 7.59 (d, J=8.9 Hz, 1H), 7.07–7.03 (m, 1H), 6.71–6.68 (m, 1H), 3.20–3.09 (m, 1H), 2.35 (s, 3H), 1.31 (d, J=7.1 Hz, 6H); 13CNMR (100 MHz, DMSO-d6)δ 147.5, 137.1, 128.1, 121.9, 116.6, 113.5, 110.2, 23.8, 22.7, 12.4; HRMS (FAB) calcd for C11H14N2+H 175.1235. found 175.1236.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccccc1F
Reactant: C1CCNC1
Product: N#Cc1ccccc1N1CCCC1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and pyrrolidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:23][C:24](=O)[CH2:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)[CH:28]=1)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:24](=[O:23])[CH2:25][C:26](=[O:38])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)[CH:28]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J14) (311 mg, 1.0 mmol) 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example K1) (259 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow oil (340 mg, 65%).