Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S[N:8]2[C:12](=[O:13])[C:11]3=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]3[C:9]2=[O:18])CCCCC1>CCCCCCC>[C:12]1(=[O:13])[NH:8][C:9](=[O:18])[C:10]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]12
Reactant: O=C1c2ccccc2C(=O)N1SC1CCCCC1
Solvent: CCCCCCC
Product: O=C1NC(=O)c2ccccc21

Procedure:
13.1 Grams (0.05 mole) of N-(cyclohexylthio)phthalimide and 6.9 grams (0.05 mole) of benzoyl thiol(thiobenzoic acid) in 150 ml of heptane are stirred overnight at room temperature. The precipitate is recovered by filtration, washed with carbon tetrachloride and dried. 7.3 Grams of phthalimide (m.p. 234° C) are obtained. The solvent is removed from the filtrate by evaporation under reduced pressure. 12 Grams (95% yield) of product, a light brown liquid, are obtained. The identity of the benzoylcyclohexyl disulfide is confirmed by GLC and NMR analyses. Analysis gives 25.51% sulfur compared to 25.45% sulfur calculated for C13H16OS2. Similarly, except N-(2-benzothiazolylthio)phthalimide is one reactant, there is obtained benzoyl-2-benzothiazolyl disulfide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[S:25][C:26]([C:30](O)=[O:31])=[C:27]([CH3:29])[N:28]=2)[C:20](=[O:33])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[S:25][C:26]([C:30]([NH:9][CH2:8][C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:31])=[C:27]([CH3:29])[N:28]=2)[C:20](=[O:33])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1ccc(Cl)nc1
Yield: 60 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (6-chloropyridin-3-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 60% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.82 (t, J=5.8 Hz, 1H), 8.60 (d, J=8.1 Hz, 1H), 8.34 (d, J=2.1 Hz, 1H), 7.77 (dd, J=8.2, 2.5 Hz, 1H), 7.51-7.28 (m, 6H), 6.38 (dd, J=8.1, 2.7 Hz, 1H), 6.23 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.39 (d, J=5.8 Hz, 2H), 2.53 (s, 3H); MS (ES+) m/z 467.0 (M+1).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[N:5]=[CH:4][N:3]=1.[CH3:10][CH:11]1[CH2:16][CH:15]([CH3:17])[CH2:14][NH:13][CH2:12]1>C1(C)C=CC=CC=1>[F:9][C:6]1[C:7]([F:8])=[C:2]([N:13]2[CH2:14][CH:15]([CH3:17])[CH2:16][CH:11]([CH3:10])[CH2:12]2)[N:3]=[CH:4][N:5]=1
Reactant: CC1CNCC(C)C1
Reactant: Fc1ncnc(F)c1F
Solvent: Cc1ccccc1
Product: CC1CC(C)CN(c2ncnc(F)c2F)C1
Yield: 97.9 %

Procedure:
Into 6 ml of toluene solution of 0.5 g of 4,5,6-trifluoropyrimidine was added dropwise 1 ml toluene solution of 0.51 g of 3,5-dimethylpiperidine (cis/trans diastereomer=about 4/1) at 0° C., and the mixture was stirred for one-and-half hour at same temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.83 g of 4,5-difluoro-6-(3,5-dimethylpiperidino)pyrimidine. This compound had the cis/trans diastereomers originated two methyls on the piperidine ring. The ratio of the cis/trans diastereomer was about 5/1.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[CH2:17]([S:20]Cl)[CH2:18][CH3:19].C(SSCCC)CC.ClCl>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:20][CH2:17][CH2:18][CH3:19])=[C:7]([OH:11])[CH:6]=1
Reactant: CCCSCl
Reactant: Oc1cccc(Oc2ccc(Cl)cc2Cl)c1
Agent: CCCSSCCC
Agent: ClCl
Solvent: ClCCl
Product: CCCSc1ccc(Oc2ccc(Cl)cc2Cl)cc1O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
3-(2,4-Dichlorophenoxy)phenol (0.1 mole) and methylene chloride (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. The mixture is stirred until dissolved and cooled to about -20° C. A solution of propyl sulfenyl chloride freshly prepared by reacting dipropyl disulfide (0.15 mole) with chlorine (0.18 mole) in methylene chloride (100 ml) is then added dropwise to the reaction vessel over a period of about 40 minutes. After the addition is completed stirring is continued for 30 minutes with cooling and 30 minutes at room temperature. After this time the reaction mixture is washed with water (200 ml), with 5% aqueous sodium bicarbonate (200 ml) and again with water (200 ml). The washed solution is then dried by passing it through a phase separator. The dried solution is stripped of solvent under reduced pressure and the residue chromatographed using a clay column and hexane/ethyl acetate as the eluant. The fractions containing the product are combined and stripped of solvent to yield the desired product 5-(2,4-dichlorophenoxy) 2-(propylthio)phenol as the residue.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:4]([N:6]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=1)[CH2:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)=[O:5].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[CH3:26][C:21]1[CH:20]=[C:19]([N:6]([CH2:7][CH2:8][C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)[C:4](=[O:5])[C@@H:3]([NH:2][S:34]([CH3:33])(=[O:36])=[O:35])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][C:22]=1[CH3:25]
Reactant: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](N)c2ccccc2)cc1C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](NS(C)(=O)=O)c2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
A solution of (S)-2-amino-N-(3,4-dimethyl-phenyl)-2-phenyl-N-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-acetamide hydrochloride (40 mg, 0.086 mmol, derived from example 1) in dry CH2Cl2 (1.5 mL) was treated with methanesulphonyl chloride (10 mg, 0.087 mmol) under Argon and the mixture stirred at ambient temperature for 30 min then quenched with aqueous Na2CO3 (2 M, 1 mL), concentrated, then redissolved in EtOAc (15 mL) and washed with aqueous Na2CO3 (2 M, 3×15 mL). The combined aqueous layers were extracted with EtOAc (15 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (42 mg, 96%) as a light yellow oil. MS m/e: 506.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15](=O)[NH:16][CH2:17][C:18]([C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=3)=O)[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4].C([O-])(=O)C.[NH4+:32]>>[CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15]3[NH:32][C:18]([C:20]4[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=4)=[CH:17][N:16]=3)[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC(=O)N2C(CCC2C(=O)NCC(=O)c2ccc(Br)cc2)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: COC(=O)N1CC(=O)N2C(CCC2c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Temperature: 130 °C
Yield: 60 %

Procedure:
A mixture of 6-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester (110 mg, 0.25 mmol), ammonium acetate (193 mg, 2.5 mmol) and xylenes (8 mL) was heated to 130° C. After 1 hour the mixture was cooled and the xylenes were removed under reduced pressure. Dichloromethane was added to the resulting residue and the mixture was filtered. The solvent was removed under reduced pressure from the filtrate and the resulting residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide 6-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester (65 mg, 0.15 mmol, 60%). C18H19BrN4O3 calculated 418.1 observed [M+1]+419.1; rt=1.50 min.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:30]([F:33])([F:32])[F:31])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][NH2:25])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1>C(Cl)Cl>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:30]([F:31])([F:32])[F:33])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][NH:25][C:39]([CH:36]4[CH2:38][CH2:37]4)=[O:40])=[C:20]([C:26]([F:27])([F:28])[F:29])[CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(Cl)C1CC1
Reactant: NCc1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F)C1CC1
Reaction time: 8 h

Procedure:
1-[6-{3-[3,5-Bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-4-(trifluoromethyl)pyridin-3-yl]methanamine (0.18 g) was dissolved in methylene chloride (5 ml), and to the solution was added cyclopropane carbonyl chloride (0.036 ml) at room temperature. The reaction mixture was stirred overnight and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the target compound (0.15 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7]O.S(Cl)([Cl:15])=O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7][Cl:15]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc([N+](=O)[O-])c(CO)c1
Solvent: c1ccccc1
Product: Cc1ccc([N+](=O)[O-])c(CCl)c1
Reaction time: 18 h

Procedure:
The above reaction product obtained in step (a) is mixed with 600 ml of benzene and 60 ml of thionyl chloride, and left to stand for 18 hours at room temperature. The reaction solution is concentrated and subsequently partitioned between benzene and ice-water. After the organic phase is washed, dried and evaporated, the heading compound remains as an orange, semi-crystalline crude product, which is used in step (c) without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:19])[C:10]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.[Br:20]Br>ClC1C=CC=CC=1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH3:19])[C:10]([C:15]([F:18])([F:16])[F:17])=[C:11]([Br:20])[C:12]=2[C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Cn1c(C(F)(F)F)cc(C#N)c1-c1ccc(Cl)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: Cn1c(-c2ccc(Cl)cc2)c(C#N)c(Br)c1C(F)(F)F
Temperature: 80 °C
Yield: 89.4 %

Procedure:
A solution of 2-(p-chlorophenyl)-1-methyl-5-(trifluoromethyl)pyrrole-3-carbonitrile (5.70 g, 0.02 mol) in chlorobenzene is treated with bromine (3.52 g, 0.022 mol), heated at 80° C. for 20 hours, cooled to room temperature, treated with additional bromine (3.52 g, 0.022 mol) and heated at 100° C. until reaction is complete by HPLC analysis. The reaction mixture is cooled to room temperature and diluted with ethyl acetate and water. The organic phase is washed with aqueous sodium metabisulfite, dried (MgSO4) and concentrated in vacuo to afford a solid residue. The residue is recrystallized from ethyl acetate/heptane to give the title product as a white solid, 6.50 g (89.4% yield), mp 126°-129° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([C:12]([NH:14][NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=O)=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.S(Cl)(Cl)=O.CN(C=O)C>ClCCCl>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([C:12]3[O:21][C:16]([C:17]([F:18])([F:19])[F:20])=[N:15][N:14]=3)=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2cc(C(=O)NNC(=O)C(F)(F)F)oc12
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: COc1cccc2cc(-c3nnc(C(F)(F)F)o3)oc12
Yield: 17.5 %

Procedure:
To a solution (280 ml) of N′-(7-methoxybenzo(b)furan-2-ylcarbonyl)trifluoroacetohydrazide (14.6 g) in 1,2-dichloroethane were added thionyl chloride (4.2 ml) and DMF (0.1 ml) and the mixture was refluxed under heating for 4.5 hr. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to give the title compound (2.4 g) as pale-yellow crystals.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:9])[CH3:8].[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:20][C:21]1[C:22]([N:28]2[CH2:29][CH2:30][N:31]([C:14]([C:13]3[CH:12]=[CH:11][C:10]([C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:19])([CH3:8])[CH3:9])=[CH:18][CH:17]=3)=[O:16])[CH2:32][CH2:33]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: CC(C)(c1ccc(C(=O)O)cc1)N1CCCS1(=O)=O
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(C(C)(C)N4CCCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 98.6 %

Procedure:
Using 4-[1-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-1-methylethyl]benzoic acid (170 mg) described in Preparation Example 39 and 1-(3,5-dimethylpyridin-2-yl)piperazine (138 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (270 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([C@H:13]2[N:18]3[C:19](=[O:36])[C@@H:20]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:21][CH2:22][C:23](=[O:24])[N:17]3[CH2:16][CH2:15][CH2:14]2)=O)=[CH:4][CH:3]=1.O1CCOCC1.C([O-])(=O)C.[NH4+:48]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:48][C:11]([C@H:13]3[N:18]4[C:19](=[O:36])[C@@H:20]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:21][CH2:22][C:23](=[O:24])[N:17]4[CH2:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)NCC(=O)c3ccc(Br)cc3)N2C1=O)OCc1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](c3ncc(-c4ccc(Br)cc4)[nH]3)N2C1=O)OCc1ccccc1
Temperature: 110 °C
Yield: 34.1 %

Procedure:
In a 10 ml, seal tube, benzyl (4S,7S)-4-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-ylcarbamate (200 mg, 350 μmol) was combined with 1,4-dioxane (5 ml) to give a light yellow solution. Ammonium acetate (270 mg, 3.5 mmol) was added and the reaction mixture was heated at 110° C. for 12 hr. It was cooled and diluted with EtOAc (2×30 ml). The combined organic layers were washed with brine and H2O, dried with MgSO4 and concentrated in vacuo to afford a viscous oil. The crude was purified on a silica gel column (CH2Cl2, 2%, 4%, 6%, 8% MeOH/CH2Cl2) to afford benzyl (4S,7S)-4-(5-(4-bromophenyl)-1H-imidazol-2-yl)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-ylcarbamate as a yellow solid (66 mg, 34.1%). ESI-LRMS m/e calcd for C26H26BrN5O4 [M+] 552. found 553 [M+H+].
Reaction SMILES: C(O)(=O)CC.C(O)(=O)C1C=CC=CC=1.O.[C:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])[CH:17](C)[CH3:18]>>[C:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])[CH2:17][CH3:18]
Reactant: CC(C)C(=O)c1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: CCC(=O)O
Solvent: O
Product: CCC(=O)c1ccccc1
Reaction time: 4.5 h
Yield: 2360.1 %

Procedure:
In Example 1, using the reactor described above, together with ancillary equipment, a mixture containing 2 moles of propionic acid per mole of benzoic acid was fed to the reactor together with 4 moles of water per mole of benzoic acid at a rate of 249 ml/hr. for 4.5 hours. The reaction temperature was maintained between 445° C. and 450° C. Analysis of the condensed organic layer by gas chromatography indicated that 4.68 pounds of isobutyrophenone were produced per 100 pounds of propiophenone. These data are delineated in Table I. The instrument used was a Bendix Model 2300 dual column programmed temperature gas chromatograph having a thermal conductivity detector. The bridge current was 200 ma. with a 0-1 mv. recorder. The column consisted of two, 10 feet by 1/8 inch stainless steel tubing packed with silicone on an inert support. The column temperature was 190° C. The carrier gas was helium at 30 cc/minute.
Reaction SMILES: [Cl-].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2C=CC=CC=2[P+](C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:3]=1.C([Li])CCC.[CH3:33][C:34]([CH3:56])([CH2:39][CH:40]([CH2:53][CH:54]=O)[CH2:41][CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C:35]([O:37][CH3:38])=[O:36]>O1CCCC1.CCCCCC>[CH3:33][C:34]([CH3:56])([CH2:39][CH:40]([CH2:53][CH:54]=[CH:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)[CH2:41][CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C:35]([O:37][CH3:38])=[O:36]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1-c1cccnc1
Reactant: COC(=O)C(C)(C)CC(CC=O)CCCCO[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C(C)(C)CC(CC=Cc1cccnc1)CCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 8.8 g (22.6 mmol) 3-pyridyl-methyltriphenylphosphonium chloride in 40 mL dry tetrahydrofuran at 0° C. is added slowly 9.0 mL (22.5 mmol) of 2.5 M n-butyllithium in hexane. After stirring the resulting deep red solution at room temperature for 0.5 hour, a solution of 3.23 g (9 mmol) of methyl 2,2-dimethyl-4-(formylmethyl)-8-(t-butyldimethylsiloxy)octanoate in 10 mL dry tetrahydrofuran is added slowly and then stirred for 16 hours. The reaction is quenched by addition of saturated ammonium chloride solution and then extracted thrice with ether. The combined organic extracts are washed with water and brine, dried, filtered and concentrated. The residue is taken up in ether and the resulting precipitate is removed by filtration. The filtrate is evaporation and the residue is purified by silica gel chromatography using 1:1 hexane, ether to give methyl 2,2-dimethyl-4-[3-(3-pyridyl)-2-propenyl]-8-(t-butyldimethylsiloxy)octanoate; NMR (CDCl3): delta 5.7-6.4 (m,2H), 3.63 and 3.60 (two s,3H), 1.2 and 1.15 (two s,6H).
Reaction SMILES: Cl.[OH:2][NH2:3].C([O-])(=O)C.[Na+].O=[C:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1>O>[OH:2][N:3]=[C:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: NO
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1CCC(=NO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of hydroxyamine hydrochloride (15.3 g) and sodium acetate (24.1 g) in water (58.8 mL) was added dropwise ethyl 4-oxocyclohexanecarboxylate (25.0 g) over 20 min. The reaction mixture was stirred at room temperature overnight, and extracted with tert-butyl methyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (27.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][O:11][C:10](=[O:13])[N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]4[CH:35]=[CH:34][C:26]([C:27]([NH:29][NH:30][C:31](=[NH:33])[CH3:32])=O)=[CH:25][CH:24]=4)=[C:16]3[N:15]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOC(C)=O.C(Cl)Cl.C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:12][O:11][C:10](=[O:13])[N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]4[CH:35]=[CH:34][C:26]([C:27]5[NH:33][C:31]([CH3:32])=[N:30][N:29]=5)=[CH:25][CH:24]=4)=[C:16]3[N:15]=2)=[CH:6][CH:7]=1
Reactant: CC(=N)NNC(=O)c1ccc(-c2cnn3ccc(N4C(=O)OC[C@@H]4c4ccc(F)cc4)nc23)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccc(F)cc5)nc34)cc2)[nH]1
Temperature: 50 °C
Yield: 6.3 %

Procedure:
A suspension of (S)-4-(5-(4-(4-fluorophenyl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-N′-(1-iminoethyl)benzohydrazide (0.049 g, 0.104 mmol) in 1:1 DCM-acetonitrile (10 mL) was treated with carbon tetrachloride (0.040 mL, 0.414 mmol), triethylamine (0.1442 mL, 1.035 mmol) and triphenylphosphine (0.1086 g, 0.414 mmol) at ambient temperature. The mixture was heated at 50° C. for 2 hours. After cooing to ambient temperature, the mixture was treated with EtOAc, washed with water, dried (phase separator silicone treated filter paper), concentrated and purified on silica gel (2-5% MeOH in DCM) to provide (S)-4-(4-fluorophenyl)-3-(3-(4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (0.003 g, 6% yield) as a yellow oil. LCMS (APCI+) m/z 456 [M+H]+.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.Cl.[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.CO.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>[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH2:12][CH2:13][O:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[O:21][CH3:22])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:28][CH:27]=1
Reactant: NCc1ccc(B(O)O)cc1
Reactant: COc1ccccc1OCCNc1ccc2ncc(Br)n2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CC#N
Solvent: O
Product: COc1ccccc1OCCNc1ccc2ncc(-c3ccc(CN)cc3)n2n1
Temperature: 150 °C

Procedure:
A mixture of ((3-bromo-imidazo[1,2-b]pyridazin-6-yl)-[2-(2-methoxy-phenoxy)-ethyl]-amine (75 mg, 0.21 mmol), (4-aminomethylphenyl)boronic acid hydrochloride (51 mg, 0.27 mmol), K2CO3 (87 mg, 0.63 mmol) and dichlorobis(triphenylphosphine)palladium(II) (7.4 mg, 0.011 mmol) in MeCN/water (3.2 ml/0.8 ml) was heated in a microwave at 150° C. for 15 min. The reaction mixture was diluted with MeOH (3 ml) and filtered. The filtrate was subjected to preparative HPLC to give the titled compound as AcOH salt (59.6 mg). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.93 (s, 3H) 3.76-3.83 (m, 5H) 4.13 (s, 2H) 4.26 (t, J=5.56 Hz, 2H) 6.77 (d, J=9.60 Hz, 1H) 6.85-6.99 (m, 4H) 7.51 (d, J=8.34 Hz, 2H) 7.65 (d, J=9.60 Hz, 1H) 7.79 (s, 1H) 8.21 (d, J=8.34 Hz, 2H). LRMS (ESI) m/z 390.2 [(M+H)]+, calc'd for C22H23N5O2: 389.46.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]([C:19](=O)[CH:20]=[CH:21]N(C)C)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH:26]1([NH:29][C:30]([NH2:32])=[NH:31])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:26]1([NH:29][C:30]2[N:32]=[C:19]([C:18]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][N:10]4[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:11]=34)[CH:20]=[CH:21][N:31]=2)[CH2:28][CH2:27]1
Reactant: N=C(N)NC1CC1
Reactant: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C#N)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(F)cc3)nn2c1
Temperature: 100 °C

Procedure:
To a solution of 2-(4-fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)-6-cyanopyrazolo[1,5-a]pyridine (1.3 g, 3.9 mmol) in dimethylformamide (20 mL), under N2, was added N-cyclopropylguanidine (0.78 g, 7.8 mmol) and potassium carbonate (1.1 g, 7.8 mmol). The mixture was stirred and heated at 100° C. for 17 h and then additional N-cyclopropyl-guanidine (0.39 g, 3.9 mmol) and potassium carbonate (0.55 g, 3.9 mmol) were added. The mixture was heated at 100° C. for an additional 4 h and then the reaction mixture was cooled and water added. The resulting solid was collected by filtration. This solid was dissolved in diethyl ether and purified using chromatography to give the title compound as a yellow solid, 0.39 g (28%). 1H NMR (d6-DMSO) δ 0.50 (m, 2H), 0.69 (d, 2H, J=4.0 Hz), 2.69 (m, 1H), 6.29 (d, 1H, J=8.0 Hz), 7.34 (t, 2H, J=8.0 Hz), 7.47 (d, 1H, J=4.0 Hz), 7.69 (m, 3H), 8.11 (d, 1H, J=4.0 Hz), 8.56 (br 5,1H) MS (ES+) m/z 370 (M++H).