Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:12][CH2:13]2)=[O:7])=[CH:36][CH:37]=1
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)S(=O)(=O)c1ccc(CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)S(=O)(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
Activated manganese dioxide (870 mg, 10.0 mmol) was suspended in methylene chloride (10 ml), and N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-4-hydroxymethyl-N-(2-methoxyphenyl)benzene sulfonamide (259 mg, 0.492 mmol) dissolved in methylene chloride (3 ml) was added to the suspension. After 30 minutes of stirring at room temperature, the reaction mixture was filtered through silica gel (1 g) which was further subjected to elution with ethyl acetate. Thereafter, the filtrate and eluate were combined, and the solvent was removed by evaporation to obtain 211 mg (81.7%) of the title compound in a colorless amorphous form.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1.Br[CH2:33][CH2:34][OH:35].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[OH:35][CH2:34][CH2:33][N:3]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:4]1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)N[C@H]3CCNC3)ccc21
Reactant: OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)N[C@H]3CCN(CCO)C3)ccc21
Temperature: 50 °C

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [(S)-1-(2-hydroxy-ethyl)-pyrrolidin-3-yl]amide (20 mg) was prepared starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (S)-pyrrolidin-3-ylamide dihydrochloride (200 mg), 2-bromo-ethanol (50 uL) and Cs2CO3 (300 mg) in DMF (1 mL). The reaction was heated to 50° C. for 8 h. The reaction was filtered and purified with silica gel chromatography using DCM10% methanol in DCM (100:0 to 0:100) as an eluent system to give pure product. LC/MS: m/z 470.8.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.CN(C)[CH:42]=[O:43]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[F:28][C:22]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=1[CH:9]([S:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1)[C:5]1[C:6]([CH3:8])=[CH:7][C:2]([CH:42]=[O:43])=[N:3][CH:4]=1
Reactant: Cc1cc(Br)ncc1C(Sc1ccc(C(F)(F)F)cn1)c1cc(F)ccc1F
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)ncc1C(Sc1ccc(C(F)(F)F)cn1)c1cc(F)ccc1F
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
To a solution of 2-bromo-5-[(2,5-difluorophenyl)[[5-(trifluoromethyl)pyridin-2-yl]thio]methyl]-4-methylpyridine (1.97 g, 4.15 mmol) in toluene (45 ml), a hexane solution of n-butyllithium (1.54 M, 3.23 ml, 4.97 mmol) was added in an argon atmosphere at −78° C. The reaction mixture was stirred for 30 minutes at −40° C., and then cooled again to −78° C., and N,N-dimethylformamide (0.385 ml, 4.97 mmol) was added thereto. After completion of dropwise addition, the reaction mixture was allowed to warm to 0° C., and water was added thereto at the same temperature. Ethyl acetate was added to the reaction mixture, the organic layer was separated, and then the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=15:1 was concentrated under reduced pressure to obtain the title compound (1.07, 2.52 mmol, 61%) as a yellow oily substance.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].[NH2:19][C@H:20]([C:25]([OH:27])=[O:26])[CH2:21][CH2:22][CH2:23][NH2:24]>>[CH:17]1[C:18]2[CH:6]([CH2:5][O:4][C:2]([NH:19][C@H:20]([C:25]([OH:27])=[O:26])[CH2:21][CH2:22][CH2:23][NH:24][C:2]([O:4][CH2:5][CH:6]3[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[C:13]4[C:18]3=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:3])=[O:3])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: NCCC[C@H](N)C(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Product: O=C(NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 79 %

Procedure:
The reaction of 9-fluorenylmethyl chloroformate with L-ornithine according to the conditions described in example 2 provided the title product in 79% yield.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[I:7]I.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=1>S(=O)(=O)(O)O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:15]=1[I:7]
Reactant: II
Reactant: COC(=O)CCc1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Product: COC(=O)CCc1ccc(F)c(I)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium metaperiodate (0.971 g, 4.54 mmol) was slowly added to a solution of iodine (3.43 g, 13.5 mmol) in sulfuric acid (86 ml). This was stirred at room temperature for 30 minutes. This dark brown iodinating solution was then slowly added to a solution of methyl 3-(4-fluorophenyl)propanoate (5.20 g, 28.5 mmol) in sulfuric acid (28.5 ml) (pre-cooled to 0° C.) taking care not to let the temperature rise above 30° C. This was stirred for 50 min. further, and then the reaction was quenched by pouring onto 100 mL of stirring ice water. This was extracted with ethyl acetate (2×100 mL) and the combined organic layers were washed with water (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate and purified via column chromatography on a Biotage 40M column eluting with hexanes (1 CV) followed by a gradient of 0-50% ethyl acetate in hexanes to provide the desired product as a clear colorless liquid. 1H NMR (CDCl3, 500 MHz) δ 7.58 (dd, J=5.8 Hz, 1.9 Hz, 1H), 7.13 (m, 1H), 6.96 (t, J=8.2 Hz, 1H), 3.67 (s, 3H), 2.88 (t, J=7.7 Hz, 2H), 2.61 (t, J=7.7 Hz, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].CS[C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17]>>[N+:16]([NH:15][C:14]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[NH:19])([O-:18])=[O:17]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: NCCNCc1cnccn1
Product: N=C(NCCNCc1cnccn1)N[N+](=O)[O-]

Procedure:
Reacting N-(2-pyrazinylmethyl)ethylenediamine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(2-pyrazinylmethyl-amino)ethyl]guanidine. Similarly, from the same starting material, according to the procedure of Example 2(iii), there is produced N-methyl-N'-nitro-N"-[2-(2-pyrazinyl-methylamino)ethyl]guanidine.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH3:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:25]=2[N:26]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:31][C:28]2[CH:29]=[CH:30][C:24]3[S:23][C:22]([CH3:21])=[N:26][C:25]=3[CH:27]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: Cc1nc2cc(O)ccc2s1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3sc(C)nc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and 2-methyl-benzothiazol-5-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid Example 285, Step 1), to produce a colorless oil.
Reaction SMILES: CI.[CH2:3]([O:5][C:6]([C:8]1[CH:9]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:27]=2[Br:34])[NH:10][C:11](=[O:25])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:13]=1[CH3:14])=[O:7])[CH3:4].[C:35](=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O.C(OCC)(=O)C>[CH2:3]([O:5][C:6]([C:8]1[CH:9]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:27]=2[Br:34])[N:10]([CH3:35])[C:11](=[O:25])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=2)[C:13]=1[CH3:14])=[O:7])[CH3:4]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1Br
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyliodide (c=2 mol/L, 1.1 mL, 17.7 mmol) is added to a solution 4-(2-Bromo-4-cyano-phenyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (intermediate 7. 47 g, 14.7 mmol) and cesium carbonate (7.9 g, 24.3 mmol) in N,N-dimethylformamide (80 mL). The mixture is stirred at room temperature overnight. Additional methyliodide (c=2 mol/L, 1.1 mL, 17.7 mmol) and cesium carbonate (5.0 g, 15.4 mmol) are added and the reaction is continued for 5 h. Water and ethyl acetate are added and the phases are separated. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution, dried over MgSO4 and concentrated. The residue is purified by reversed phase HPLC. Yield: 7.61 g. ESI mass spectrum: [M+H]+=522; Retention time HPLC: 1.20 min (HPLC method Z018_S04).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]Br.C(N(CC)CC)C.[F:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:6])[CH2:4][S:21][C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=1
Reactant: COC(=O)CBr
Reactant: Fc1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CSc1ccc(F)cc1

Procedure:
To a solution of bromo acetic acid methyl ester (1.53 g, 0.95 ml, 10.0 mmol) and triethylamine (3.0 ml) in dry THF (25 mL) was added 4-fluoro-benzenethiol (1.62 g, 12.6 mmol) in one portion at room temperature. The resulting mixture was heated to reflux and stirred until the TLC showed the completion of the reaction. The reaction mixture was diluted with EtOAc and washed sequentially with aqueous HCl, water and saturated NaCl solution. The organic phase was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to gave a crude material, which was then purified by a column chromatography with 0˜5% EtOAc in hexanes. MS: 201.3 (M+H)+.
Reaction SMILES: B([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(O)O.Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=2)[C:7]([OH:9])=[O:8])[CH:15]=1
Reactant: Brc1cccnc1
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1cccc(-c2cccnc2)c1
Yield: 83.7 %

Procedure:
To a solution of 3-boronobenzoic acid (1.5 g, 9 mmol) and 3-bromopyridine (1.5 g, 9.9 mmol) in acetonitrile (40 mL) and water (40 mL), potassium carbonate (5.5 g, 40 mmol), Bis(triphenylphosphine)palladium(II) chloride (400 mg, 0.37 mmol) was added. The mixture was stirred under reflux overnight. Then the hot suspension was filtered and concentrated to half of the original volume and washed with dichloromethane. The aquatic phase was adjusted to pH=3 with hydrochloric acid (1 M) and filtrated, washed with water. The residue was dried in vacuum to obtain 1.5 g of 3-(pyridin-3-yl)benzoic acid. Yield: 83%. LC-MS (ESI) m/z: 200 (M+1)+.
Reaction SMILES: [O:1]1[CH:3]2[C:4]3[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:5]=3[O:6][C:7]([CH3:9])([CH3:8])[CH:2]12.Cl.[Cl:18][CH2:19][CH2:20][CH2:21][NH2:22].[OH-].[Na+].O>O1CCOCC1.C(OCC)(=O)C>[ClH:18].[Cl:18][CH2:19][CH2:20][CH2:21][NH:22][C@H:3]1[C@H:2]([OH:1])[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:4]1=2
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C2OC21
Reactant: NCCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](NCCCCl)[C@@H]1O
Yield: 18.9 %

Procedure:
3,4-Epoxy-3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo[b]pyran (0.50g.), prepared as described in British Pat. No. 1,495,526, chloropropylamine hydrochloride (0.65g.), and sodium hydroxide pellets (0.20g.) in dioxan (25 ml) and water (3 ml) were stirred at room temperature for 6 days. Dilution with water and isolation via ethyl acetate gave a gum (0.62g.) which was separated, by application to silica gel plates and development with ethyl acetate- 60-80° petroleum ether mixture, into starting epoxide (0.34g.) and an amine fraction (0.25g.). The latter was dissolved in diethyl ether and treated with ethereal hydrogen chloride to give trans-4-(3-chloropropylamino)-3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo[b]-pyran-3-ol hydrochloride (0.15g.); m.p. 242°-243°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34]S[CH2:32][CH2:31]4)=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.O[O:38][S:39]([O-:41])=O.[K+]>CO.O>[O:38]=[S:39]1(=[O:41])[CH2:34][CH2:35][CH:30]([NH:29][C:27]([C:14]2[C:15](=[O:26])[N:16]([CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[C:17]3[C:12]([C:13]=2[OH:36])=[N:11][CH:10]=[C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:18]=3)=[O:28])[CH2:31][CH2:32]1
Reactant: O=S([O-])OO
Reactant: O=C(NC1CCSCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(Cc2cccnc2)c1=O
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(NC1CCS(=O)(=O)CC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(Cc2cccnc2)c1=O
Yield: 37.3 %

Procedure:
To a solution of 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-(3-pyridinylmethyl)-N-(tetrahydro-2H-thiopyran-4-yl)-1,2-dihydro-1,5-naphthyridine-3-carboxamide (24 mg, 0.05 mmol) in methanol (4 mL) was added Oxone (59.3 mg, 0.10 mmol) as a solution in water (1 mL). The resultant mixture was stirred overnight and then concentrated in vacuo. Ethyl acetate was added followed by water. The organics were washed with brine and the aqueous layer extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase preparative HPLC to give the title compound (10 mg, 38%) as a white solid as a format salt. 1H NMR (400 MHz, CDCl3) δ 10.41 (d, J=6.5 Hz, H), 8.58 (s, 1 H), 8.53 (d, J=4.3 Hz, 1 H), 8.41 (s, 1 H), 8.10 (s, 1 H), 7.36 (d, J=8.0 Hz, 1 H), 7.23 (m, 1 H), 7.16 (s, 1 H), 7.01-6.97 (m, 4 H), 5.37 (s, 2 H), 4.26 (m, 1 H), 4.04 (s, 2 H), 3.14 (m, 4 H), 2.49-2.29 (m, 4 H); HRMS m/z calcd for C27H26N4O5FS (M+H)+ 537.1608, found 537.1601.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[CH2:20]([N:22]([CH2:36][CH3:37])[C:23](=[O:35])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH3:21]>>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:31]([C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:23]([N:22]([CH2:36][CH3:37])[CH2:20][CH3:21])=[O:35])=[CH:30][CH:29]=2)(=[O:33])=[O:32])[C:3]1=[O:12]
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 30 from 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 4-(N',N'-diethylureido)benzenesulfonyl chloride. M.p.=195°-196° C.
Reaction SMILES: C([CH:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5])C.C(=O)([O-])[O-].[K+].[K+].[C:20]1([C:26]2[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[C:26]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:27]=[CH:28][C:29]([CH2:30][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:3][C:4]([OH:6])=[O:5])=[CH:12][CH:11]=2)=[CH:32][CH:33]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: CCC(C(=O)O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 84.4 %

Procedure:
To a solution of ethyl 4-hydroxyphenylacetic acid (3.6 g) in DMF (50 ml) were added potassium carbonate (2.5 g) and 4-phenylbenzyl chloride (4 g) sequentially. After stirring at 60° C. for 6 hr, the reaction mixture was poured onto water and the resulting crystals were suspended in ethyl acetate. The suspension was washed with water and concentrated. The resulting crude crystals were dissolved in THF (100 ml)/ethanol (50 ml) and 2 N sodium hydroxide (20 ml) was added to the solution. The reaction mixture was heated under stirring at 60° C. for 18 hr and concentrated. The residue was acidified with 2 N hydrochloric acid and the resulting crystals were collected by filtration and washed with ethyl ether to obtain the titled compound (5.3 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][C:23](F)=[CH:22][C:21]=2[O:27][CH:28]([CH3:30])[CH3:29])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[CH3:32][N:33]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][C:23]([N:36]3[CH2:37][CH2:38][CH2:39][N:33]([CH3:32])[CH2:34][CH2:35]3)=[CH:22][C:21]=2[O:27][CH:28]([CH3:30])[CH3:29])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: CN1CCCNCC1
Reactant: CC(C)Oc1cc(F)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Product: CC(C)Oc1cc(N2CCCN(C)CC2)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Yield: 99.9 %

Procedure:
Prepared from 5-fluoro-2-(4-fluoro-2-isopropoxybenzoylamino)-N-(5-chloropyridin-2-yl)benzamide (159 mg, 0.356 mmol) and 1-methyl-hexahydro-1,4-diazepine (203 mg, 1.77 mmol, 5 eq) to provide 192 mg (82%) of the title compound.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([O:29][CH:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)[C:9]=1[C:43]([O:45]CC)=[CH2:44].C(O)(C(F)(F)F)=O>O>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([O:29][CH:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]2)[C:9]=1[C:43](=[O:45])[CH3:44]
Reactant: C=C(OCC)c1c(OC2CCN(C(=O)OC(C)(C)C)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1c(OC2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Reaction time: 8 h

Procedure:
The crude tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)piperidine-1-carboxylate was treated with 50% TFA in H2O (6 mL) and stirred overnight. The reaction mixture was concentrated in vacuo. Purification with prep-LC provided 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yloxy)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone: LCMS tR=1.11 Min (5 min run, UV254nm). Mass calculated for, M+ 428.1, observed LC/MS m/z 429.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:28][C:29]([F:33])([F:32])[CH2:30][NH2:31].Cl.C(N(CC)CCCN=C=NCC)C>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=3)([C:16]([F:17])([F:18])[F:19])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:31][CH2:30][C:29]([F:33])([F:32])[F:28])=[O:6]
Reactant: Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 19.6 %

Procedure:
In a solution of 0.60 g of crude 2-amino-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]benzoic acid in 6 ml of chloroform, 0.20 g of 2,2,2-trifluoroethylamine, 0.02 g of 4-(N,N-dimethylamino) pyridine and 0.33 g of 1-[3-(diethylamino)propyl]-3-ethylcarbodiimide hydrochloride were added, and stirred at room temperature for 20 hours. After the completion of the reaction, the reaction mixture was subjected to purification with medium-pressure preparative liquid chromatography (Yamazen Corporation, medium pressure preparative system; YFLC-Wprep) that was eluted with ethyl acetate-hexane (1:4), and 0.14 g of the aimed product was obtained as pale yellow crystal.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[N:9][CH:10]=[CH:11][N:5]2[N:4]=[C:3]1SC>C(O)C.[Ni]>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[N:9][CH:10]=[CH:11][N:5]2[N:4]=[CH:3]1
Reactant: CSc1nn2ccnc2c(=O)n1C
Agent: [Ni]
Solvent: CCO
Product: Cn1cnn2ccnc2c1=O
Temperature: 40 °C
Yield: 24.4 %

Procedure:
3-Methyl-2-methylsulfanyl-3H-imidazo[2,1-f][1,2,4]triazin-4-one (0.81 g, 4.1 mmol) was suspended in ethanol (10 ml) and the mixture heated to 40° C. 6×1 ml pipette amounts of Raney-nickel (50 micron stored in water) were added in portions over 9 h. On complete addition the mixture was heated at 40° C. for a further 9 h. The mixture was allowed to cool to ambient temperature and the mixture filtered through Celite. The filtrate was evaporated and the residue purified by flash column chromatography on silica eluting with 2% methanol in dichloromethane. Collecting appropriate fractions gave 3-methyl-3H-imidazo[2,1-f][1,2,4]triazin-4-one (150 mg, 24%) as an off-white solid: δH (400 MHz, CDCl3) 3.59 (3H, s), 7.55 (1H, d, J1), 7.60 (1H, d, J1), 7.73 (1H, s).