Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[C:12]([C:20]#[N:21])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.[Li].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CN1CCOCC1>[C:20]([C:12]1[C:13]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[N:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:1][C:34](=[O:35])[C:33]3[CH:32]=[CH:31][C:30]([CH2:29][N:26]4[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]4)=[CH:38][CH:37]=3)[CH:7]=[CH:6][CH:5]=2)=[N:10][CH:11]=1)#[N:21]
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Reactant: N#Cc1cnc(Nc2cccc(N)c2)nc1-c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Li]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4ncc(C#N)c(-c5cccs5)n4)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of N-3-aminophenyl-5-cyano-4-thien-2-ylpyrimidine-2-amine (300 mg, 1.0 mmol) and 4-(4-methylpiperazin-1-yl)methylbenzoic acid, lithium salt (300 mg, 1.0 mmol) in DMF (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (307 mg, 1.6 mmol), 1-hydroxybenzotriazole (216 mg, 1.6 mmol) and N-methylmorpholine (350 ml, 3.2 μmol) and the resulting mixture was stirred at ambient temperature for 48 h. The reaction was then concentrated under reduced pressure and the resulting residue partitioned between ethyl acetate and saturated brine. The organic phase was dried (MgSO4), concentrated under reduced pressure and the resulting residue recrystallised from ethyl acetate-ether-MeOH (4:4:1) to give the title compound (312 mg) as a colourless solid, m.p. 208-209°. δH (d6 DMSO) 10.48 (1H, bs), 10.23 (1H, s), 8.89 (1h,s), 8.28 (1H, d, J 3.5 Hz), 8.13 (1H, m), 7.98 (1H, d, J 4.8 Hz), 7.90 (2H, d, J 8.2 Hz), 7.60 (1H, bs), 7.43 (3H, d, J 8.2 Hz), 7.36-7.30 (2H, s), 3.52 (2H, s), 2.37 (8H, bs) and 2.15 (3H,s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[CH:9][C:7]=2[CH:8]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=3)=[CH:9][C:7]=2[CH:8]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cccc(-c2ccc3oc(CCO)cc3c2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cc2cc(-c3cccc(C#N)c3)ccc2o1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The product from Example 112C (170 mg, 0.65 mmol) and triethylamine (100 μL, 0.72 mmol) were dissolved into CH2Cl2 (3 mL) and cooled to 0° C. The solution was treated with methanesulfonyl chloride (55 μL, 0.71 mmol), and after 10 minutes it was permitted to slowly warm to room temperature. More methanesulfonyl chloride (10 μL, 0.13 mmol) and triethylamine (10 μL, 0.072 mmol) were added. The mixture was stirred until the reaction was nearly complete and then washed consecutively with water and brine, dried (Na2SO4), concentrated, and used without further purification in the next step.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][N:13]=[CH:14][C:15]1[CH2:16][S:17][C@@H:18]2[CH:25]([NH:26][C:27](=[O:34])[CH2:28][C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)[C:24](=[O:35])[N:19]2[C:20]=1[C:21]([OH:23])=[O:22])=[O:11])=O)(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[NH2:8][CH2:9][C:10]([NH:12][N:13]=[CH:14][C:15]1[CH2:16][S:17][C@@H:18]2[CH:25]([NH:26][C:27](=[O:34])[CH2:28][C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)[C:24](=[O:35])[N:19]2[C:20]=1[C:21]([OH:23])=[O:22])=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)NN=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)NN=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 1 h
Yield: 61.8 %

Procedure:
A solution of 3-[2-(N-tertiary butoxycarbonylglycyl)hydrazono]methyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid (120 mg) in a mixture of anisole (0.6 ml) and trifluoroacetic acid (1.2 ml) is kept at 0° C for 1 hour. The reaction mixture is concentrated to remove trifluoroacetic acid, and the obtained residue is diluted with ether. The separated crystals are washed with ether and water and dried to give 3-(2-glycylhydrazono)methyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid (60 mg). m.p. 204°-209° C (decomposition). Yield: 62%. IR: νmax Nujol 3260, 1767, 1660, 1600, 1585cm-1. UV: νmaxEtOH 235nm; 316nm (Saturated solution). NMR: δd 6-DMSO 3.58s2H, 3.9dd2H, 5.17d(4Hz)1H, 5.75dd(8;4Hz)1H, 6.80-7.47m3H, 8.20s1H, 9.13d(8Hz)1H.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[O:16]1[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][NH:10][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:14][CH2:15]1
Reactant: N#Cc1ccccc1F
Reactant: NCCN1CCOCC1
Product: N#Cc1ccccc1NCCN1CCOCC1

Procedure:
According to a similar manner to that in Reference Example 3, the title compound was synthesized from 2-fluorobenzonitrile and 4-(2-aminoethyl)morpholine.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11](=[O:13])[CH3:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]Br>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:12][C:11](=[O:13])[CH2:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9]
Reactant: BrBr
Reactant: CC(=O)CS(=O)(=O)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CBr)CS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a stirred suspension of 100.0 g (0.504 mole) phenylsulfonylacetone in 500 ml carbon tetrachloride, 80 g [25.7 ml (0.5 mole)] bromine dissolved in 75 g carbon tetrachloride were added dropwise. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was filtered, and the precipitate was washed with hexane to give 139.8 g of the above-identified product.
Reaction SMILES: C(OC(C1C2C(=CC([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:18][CH:17]=3)=CC=2)C(C(OCC)=O)=CC=1)=O)C.[CH3:38][C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([CH3:49])=[CH:41][C:40]=1Br>>[CH3:38][C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([CH3:49])=[CH:41][C:40]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:18][CH:17]=1
Reactant: Cc1cc(Br)c(C)c2ccccc12
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c2cc(-c3ccc(OCCC(C)CCCC(C)C)cc3)ccc12
Product: Cc1cc(-c2ccc(OCCC(C)CCCC(C)C)cc2)c(C)c2ccccc12

Procedure:
1,4-dimethyl-2-(4-(3,7-dimethyloctyloxy)phenyl)naphthalene was prepared in accordance with the case of 6-(4-(3,7-dimethyloctyloxy)phenyl)naphthalene-1,4-dicarboxylic-acid diethyl ester described above, but using 1,4-dimethyl-2-bromonaphthalene, as a raw material, which was obtained by brominating 1,4-dimethylnaphtalene with Br2. 1,4-dimethyl-2-(4-(3,7-dimethyloctyloxy)phenyl)naphthalene was dissolved in carbon tetrachloride, and reacted to NBS to obtain 1,4-bis(bromomethyl)-2-{4-(3,7-dimethyloctyloxy)phenyl}naphthalene was obtained.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:17]([CH:18]=O)[C:16]=1[OH:24]>>[Cl:14][C:15]1[C:16]([OH:24])=[C:17]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cc(Cl)cc(Cl)c3O)CC2)nc[nH]1

Procedure:
6-[4-(3,5-Dichloro-2-hydroxy-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3,5-dichlorosalicylaldehyde. Mass spectrum (ES) MH+=355.
Reaction SMILES: [CH:1]1([C:7]2[N:15]3[C:10]([C:11](=[O:16])[NH:12][CH:13]=[N:14]3)=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I:17]N1C(=O)CCC1=O>CN(C=O)C.O>[CH:1]1([C:7]2[N:15]3[C:10]([C:11](=[O:16])[NH:12][CH:13]=[N:14]3)=[C:9]([I:17])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=c1[nH]cnn2c(C3CCCCC3)ncc12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]cnn2c(C3CCCCC3)nc(I)c12
Temperature: 55 °C
Reaction time: 20 h

Procedure:
To a solution of 7-cyclohexylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (130 mg, 0.6 mmol) in DMF (0.6 mL) was added N-iodosuccinimide (700 mg, 0.003 mol) and the reaction mixture stirred at 55° C. for 20 h. After this time the mixture was diluted with water (50 mL) and extracted with EtOAc (4×40 mL). The organic extracts were washed with water (4×40 mL), treated with sodium thiosulfate and brine, dried over Na2SO4 and concentrated in vacuo to afford 7-cyclohexyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4(3H)-one. 1H NMR (400 MHz-DMSO-d6) δ 1.34-1.37 (m, 3H), 1.52-1.56 (m, 2H), 1.76-1.88 (m, 5H), 3.06-3.08 (m, 1H) 7.87 (s, 1H) 11.78 (s, 1H); MS (ES+): m/z: 344.95 (100) [MH+]. HPLC: tr=2.95 min (OpenLynx: polar—5 min).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([C:33](=[O:35])[CH3:34])=[N:22][C:21]=1[CH3:36])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[OH:18][CH2:19][C:20]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[C:23]([C:33](=[O:35])[CH3:34])=[N:22][C:21]=1[CH3:36]
Reactant: CC(=O)c1nc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1nc(C)c(CO)n1COCC[Si](C)(C)C
Reaction time: 1 h

Procedure:
The compound (1.85 g) obtained in (3) was dissolved in THF (20 mL), followed by addition of TBAF (1.0 M THF solution, 3.54 mL) under stirring, and the stirring was continued for 1 hour. The reaction solution was diluted with water, followed by extraction with ethyl acetate. The combined extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=5%→70%) using amino column (product name: SNAP Cartridge NH 55 g, manufactured by Biotage, Ltd.) to afford the title compound (1.01 g).
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[NH2:26][C:20]1[C:19]([C:17]2[O:16][N:15]=[C:14]([CH2:13][C:12]3[CH:27]=[CH:28][C:9]([OH:8])=[CH:10][CH:11]=3)[CH:18]=2)=[CH:24][CH:23]=[C:22]([NH2:25])[N:21]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)cc3)no2)c(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 3-(3-(4-benzyloxy-benzyl)-isoxazol-5-yl)-pyridin-2,6-diamine (100 mg, 0.27 mmol) described in Example 13 in trifluoroacetic acid (3 mL) was added thioanisole (126 μL) at room temperature, which was stirred for 2 hours at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution at 0° C., which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (72.4 mg, 95%).
Reaction SMILES: [O:1]=[C:2]1[NH:16][C:15](=[O:17])[C:4]2([CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]2)[NH:3]1.[ClH:18]>O1CCOCC1>[CH2:5]1[C:4]2([C:15](=[O:17])[NH:16][C:2](=[O:1])[NH:3]2)[CH2:7][NH:6]1.[ClH:18]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)NC(=O)NC2=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1NC(=O)C2(CNC2)N1
Reaction time: 3 h

Procedure:
tert-Butyl 6,8-dioxo-2,5,7-triazaspiro[3.4]octane-2-carboxylate (Preparation 18A, 620 mg, 2.57 mmol) was dissolved in 15 mL of hot dioxane until a homogeneous yellow solution formed. To this solution was added 30 mL of 4 M hydrochloric acid in dioxane. The reaction was stirred for 3 h and then concentrated in vacuo to give 2,5,7-triazaspiro[3.4]octane-6,8-dione, hydrochloric acid (420 mg, 92%). MS (M+1)=142.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.9 (1H, s), 9.30 (2H, br d), 8.70 (1H, s), 4.15 (1H, br s), 4.05 (1H, br s), 3.39 (2H, br s).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.C(N1CCC(OC2C=CC=CN=2)CC1)(OC(C)(C)C)=O>>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Fc1ccncc1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2ccccn2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccncc2)CC1

Procedure:
Prepared from 1-Boc-4-hydroxypiperidine and 4-fluoropyridine using methods substantially equivalent to those described for the synthesis of 1-Boc-4-(pyridin-2-yloxy)piperidine. The product was purified by chromatography over silica gel, eluting with ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>C(#N)C>[C:13]1([S:19]([NH:1][C:2]2[C:3]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[N:4][CH:5]=[CH:6][CH:7]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N#CCCCc1ncccc1N
Solvent: CC#N
Solvent: c1ccncc1
Product: N#CCCCc1ncccc1NS(=O)(=O)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of 3-amino-2-(3-cyanopropyl)pyridine* (5 g, 0.031 mole) in acetonitrile (50 ml) was treated with benzenesulphonyl chloride (4 ml) and pyridine (6 ml). The solution was allowed to stand at room temperature overnight when the solvent was removed in vacuo. The residue was dissolved in dilute sodium hydroxide (100 ml) and was extracted with chloroform (4×100 ml) the chloroform extracts being discarded. The aqueous layer was adjusted to pH=4 and extracted with chloroform (3×100 ml). The combined chloroform extracts were dried over magnesium sulphate, the solvent was removed to give the title compound (7.12 g) as a cream coloured solid. m.p. 80°-81° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[CH3:23])[NH2:19]>>[CH3:15][C:16]1[CH:17]=[C:18]([NH:19][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:12]([NH2:14])=[O:13])[CH:20]=[CH:21][C:22]=1[CH3:23]
Reactant: Cc1ccc(N)cc1C
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(C)c(C)c1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 3,4-dimethylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[CH:13]=[CH:12][N:11]=2)[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:40][C:7]([C:6]3[C:2]([NH2:1])=[N:3][N:4]([C:10]4[N:15]=[C:14]([C:16]5[CH:17]=[CH:18][C:19]([N:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=5)[CH:13]=[CH:12][N:11]=4)[CH:5]=3)=[O:9])=[CH:38][CH:39]=2)[CH2:28][CH2:27]1
Reactant: CN(C)c1ccc(-c2ccnc(-n3cc(C(=O)O)c(N)n3)n2)cc1
Reactant: CN1CCN(CCc2ccc(N)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN1CCN(CCc2ccc(NC(=O)c3cn(-c4nccc(-c5ccc(N(C)C)cc5)n4)nc3N)cc2)CC1
Yield: 22.9 %

Procedure:
A mixture of 3-Amino-1-[4-(4-dimethylamino-phenyl)-pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid (35 mg, 0.108 mM) diisopropylethylamine (70 ul, 0.402 mM), 4-[2-(4-Methyl-piperazin-1-yl)-ethyl]-phenylamine (30 mg, 0.1369 mM) in DMF (1 ml) to which was added HBTU (60 mg, 0.1583 mM) and the stirred 16 hr at room temperature. The resulting suspension was filtered and the solid washed with water (1×1 ml) and dried in vacuo to afford 3-Amino-1-[4-(4-dimethylamino-phenyl)-pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid {4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenyl}-amide (13 mg, 21% yield). ES-MS MH+526.7. The filtrate may be purified via RP-HPLC 0.1% TFA to afford additional material.
Reaction SMILES: [CH3:1][Mg:2][Cl:3].C(Cl)(=O)CCC.Cl.[C:11]([S:15](CC(CCC)=O)(=[O:17])=[O:16])([F:14])([F:13])[F:12]>O1CCCC1>[C:11]([S:15]([CH2:1][Mg:2][Cl:3])(=[O:17])=[O:16])([F:14])([F:13])[F:12]
Reactant: C[Mg]Cl
Reactant: CCCC(=O)CS(=O)(=O)C(F)(F)F
Agent: CCCC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: O=S(=O)(C[Mg]Cl)C(F)(F)F
Reaction time: 2 h

Procedure:
The reagent CF3SO2CH2MgCl was prepared from 22.0 g. (0.15 mole) of methyl perfluoromethylsulfone and 0.2 mole of methylmagnesium chloride in tetrahydrofuran. Butyryl chloride (30.0 g.; 0.3 mole) was added at room temperature and the mixture stirred for two hours. The mixture was hydrolyzed with 3 N HCl, the tetrahydrofuran phase separated and heated to remove solvent. The residue was dissolved in diethyl ether and the solution (dried over MgSO4) heated to remove the ether, giving 14 g. of the novel fluoroalkylsulfonyl methane precursor, CF3SO2CH2COC3H7 b.p. 90° C. (5 mm.). A sample was recrystallized from water, m.p. 67.5°-68.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH2:12])[N:11]=1)[C:5]([NH:7][OH:8])=[NH:6].[C:13](OC(=O)C)(=O)[CH3:14]>>[CH3:13][C:14]1[O:8][N:7]=[C:5]([C:4]2[CH:3]=[C:2]([NH2:1])[N:11]=[C:10]([NH2:12])[CH:9]=2)[N:6]=1
Reactant: N=C(NO)c1cc(N)nc(N)c1
Reactant: CC(=O)OC(C)=O
Product: Cc1nc(-c2cc(N)nc(N)c2)no1

Procedure:
A solution of 0.134 g 2,6-diamino-N-hydroxy-isonicotinamidine (Example 108a) in 2.00 ml acetic acid anhydride was heated to reflux for 4 h. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was dried over magnesium sulfate dihydrate and evaporated. The residue was taken up in 2 ml 2N hydrochloric acid and heated to reflux for 1.5 h. The mixture neutralized by addition of 3 ml 1N sodium hydroxide and partitioned between water and ethyl acetate. The phases were separated and the organic phase was washed with brine and evaporated to yield 0.071 g of the title compound as brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[N:41]5[CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43][CH2:42]5)[CH2:33][O:32][C:31]4=[O:54])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][N:10](COCC[Si](C)(C)C)[N:9]=1.FC1C=C(C2C=NN3C=CC(N4C(C5C=CC=CC=5N5CCN(C(OC(C)(C)C)=O)CC5)COC4=O)=NC=23)C=CC=1C1N(COCC[Si](C)(C)C)N=CN=1>>[F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[N:41]5[CH2:42][CH2:43][NH:44][CH2:45][CH2:46]5)[CH2:33][O:32][C:31]4=[O:54])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][NH:10][N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C2COC(=O)N2c2ccn3ncc(-c4ccc(-c5ncn(COCC[Si](C)(C)C)n5)c(F)c4)c3n2)CC1
Agent: CC(C)(C)OC(=O)N1CCN(c2ccccc2C2COC(=O)N2c2ccn3ncc(-c4ccc(-c5ncnn5COCC[Si](C)(C)C)c(F)c4)c3n2)CC1
Product: O=C1OCC(c2ccccc2N2CCNCC2)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Yield: 43 %

Procedure:
3-(3-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-(piperazin-1-yl)phenyl)oxazolidin-2-one (36 mg, 43%) was prepared by the procedure described in Example 1, Step 9, using a mixture of tert-butyl 4-(2-(3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-2-oxooxazolidin-4-yl)phenyl)piperazine-1-carboxylate and tert-butyl 4-(2-(3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-2-oxooxazolidin-4-yl)phenyl)piperazine-1-carboxylate. LCMS (APCI+) m/z 526.1 [M+H]+.
Reaction SMILES: [S:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:4]=2[O:3]1.Cl.[CH3:15][NH:16][CH3:17].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C)C=O.ClCCl>[CH3:15][N:16]([CH3:17])[C:11]([C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2](=[S:1])[O:3][C:4]=2[CH:10]=1)=[O:13]
Reactant: CNC
Reactant: O=C(O)c1ccc2[nH]c(=S)oc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc2[nH]c(=S)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Thioxo-2,3-dihydrobenzo[d]oxazole-6-carboxylic acid (Example 92B, 394 mg, 2.02 mmol), dimethylamine hydrochloride (181 mg, 2.22 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (844 mg, 2.22 mmol) were combined in tetrahydrofuran (20 mL) and dimethylformamide (2 mL). Diisopropylethylamine (1.5 mL, 8.68 mmol) was added and the mixture was stirred at ambient temperature overnight. The mixture was diluted with dichloromethane, washed with a 1 N aqueous solution of hydrochloric acid, and absorbed on silica gel. The crude mixture was purified with silica gel chromatography eluting with a gradient of methanol in dichloromethane (2-20%) to afford the title compound. MS (ESI+) m/z 222.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:41]=[CH:40][C:24]([CH2:25][CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][C:32](Cl)=[C:31]([N+:36]([O-:38])=[O:37])[CH:30]=2)=[CH:23][CH:22]=1>CS(C)=O.C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][CH2:26][NH:27][C:28]([C:29]2[CH:34]=[CH:33][C:32]([O:8][C:7]3[CH:6]=[CH:5][C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:3][C:2]=3[Cl:1])=[C:31]([N+:36]([O-:38])=[O:37])[CH:30]=2)=[O:39])=[CH:40][CH:41]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2[N+](=O)[O-])c(Cl)c1
Temperature: 85 °C
Reaction time: 12 h
Yield: 46.2 %

Procedure:
Methyl 2-(3-chloro-4-hydroxyphenyl)acetate (177 mg, 0.885 mmol) was diluted with DMSO (3 mL) followed by the addition of K2CO3 (122 mg, 0.885 mmol) and N-(4-chlorophenethyl)-4-chloro-3-nitrobenzamide (300 mg, 0.885 mmol) (synthesized in step C). The reaction was heated to 85° C. and stirred for 12 hours. The reaction was cooled, diluted with DCM and washed with 10% aq. sodium carbonate, water and brine. The layers were separated and the organic layer was dried over H2SO4, filtered and concentrated. The material was purified using a biotage 40S cartridge eluting with DCM:MeOH (99:1) to yield methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)-2-nitrophenoxy)-3-chlorophenyl)acetate (206 mg, 46.3% yield).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.ClCCl.C(Br)(Br)(Br)[Br:14]>C(#N)C>[Br:14][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cccc(O)c1
Solvent: ClCCl
Solvent: CC#N
Product: Oc1cccc(CBr)c1
Temperature: 2.5 °C

Procedure:
3-[(Hydroxy)methyl]phenol was dissolved in acetonitrile (300 ml) and dichloromethane (900 ml) and the resulting mixture was poured in the flask kept under argon; magnetic stirring was set on. The solution was then cooled with an ice bath and carbon tetrabromide and triphenilphosphine were added. The latter was added in small portions in order to maintain the temperature at ca. 2-3° C.