Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:43]1[N:44]=[C:45]([NH2:48])[S:46][CH:47]=1)[C:5]([NH:7][CH:8]1[C:41](=[O:42])[N:10]2[C:11]([C:25]([O:27]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]#[CH:24])[N:21]=3)[CH2:13][S:14][C@H:9]12)=[O:6].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([C:43]1[N:44]=[C:45]([NH2:48])[S:46][CH:47]=1)[C:5]([NH:7][CH:8]1[C:41](=[O:42])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]#[CH:24])[N:21]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C#CCn1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOC)c4csc(N)n4)[C@H]3SC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: C#CCn1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(=NOC)c4csc(N)n4)[C@H]3SC2)n1
Yield: 65.5 %

Procedure:
To a mixture of benzhydryl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(2-propynyl)-2H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate (syn isomer)(1.9 g) in methylene chloride (19.0 ml) were added anisole (2.3 g) and trifluoroacetic acid (6.2 g) with stirring under ice-cooling and then the resulting mixture was stirred for an hour at room temperature. After the evaporation of the reaction mixture, to the residue were added water and ethyl acetate. The organic layer was separated and adjusted to pH 7.0 with an aqueous solution of sodium bicarbonate. The aqueous layer was separated, washed with ethyl acetate (x2) and then concentrated. The concentrate was adjusted to pH 3.0 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and then dried over phosphorus pentoxide to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(2-propynyl)-2H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.95 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH:42]([F:44])[F:43])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.[OH-].[K+].O.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH:42]([F:44])[F:43])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH2:32][CH2:33]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CCOC(=O)CCN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 3-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]propanoate (270 mg, 0.43 mmol) in ethanol (10 mL) was added KOH (200 mg, 3.56 mmol) and water (4 mL). The resulting solution was stirred at room temperature for 1 h and neutralized with 1 N HCl solution. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (27.0% up to 35.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 27.0% in 2 min); Detector, UV 254/220 nm. This resulted in 31.5 mg (11%) of the formic acid salt of 3-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-acetyl)piperazin-1-yl]propanoic acid as a off-white solid. LCMS (Method 28) [M+H]+=603.1, RT=0.81 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.4, 7.0 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.2, 7.0 Hz), 7.08 (t, 1H, J=73.6 Hz), 5.24 (s, 1H), 3.50-3.47 (m, 4H), 2.57 (t, 2H, J=7.2 Hz), 2.49-2.39 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N:13]3[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][CH2:14]3)[CH:12]=1)[NH:9][C:8]([C:21]([OH:23])=O)=[CH:7][C:6]2=[O:24].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[O:66]1[CH2:71][CH2:70][N:69]([C:72]2[CH:78]=[CH:77][C:75]([NH2:76])=[CH:74][CH:73]=2)[CH2:68][CH2:67]1>CN(C)C=O.CO>[N:69]1([C:72]2[CH:73]=[CH:74][C:75]([NH:76][C:21]([C:8]3[NH:9][C:10]4[C:5]([C:6](=[O:24])[CH:7]=3)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:11]=4[N:13]3[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][CH2:14]3)=[O:23])=[CH:77][CH:78]=2)[CH2:68][CH2:67][O:66][CH2:71][CH2:70]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COc1cc(N2CCCN(C)CC2)c2[nH]c(C(=O)O)cc(=O)c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(N2CCCN(C)CC2)c2[nH]c(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 69.2 %

Procedure:
To a solution of 6-methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid (2.10 mmol) (Reference Example 25b) and diisopropylethyl amine (1.4 mL, 8.6 mmol) in 34 mL dimethylformamide was added TBTU (1.40 g, 4.36 mmol) and HOBt (0.588 g, 4.35 mmol) followed by the addition of 4-morpholinoaniline (0.463 g, 2.60 mmol). The resulting dark brown solution was stirred at room temperature under nitrogen for 19 hours. The reaction was concentrated in vacuo and the resulting crude product was taken up in methylene chloride/methanol. Filtration of the resulting mixture afforded some product as a yellow solid. The filtrates were concentrated and partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated sodium bicarbonate, dried (MgSO4), and concentrated under vacuum to afford a brown solid. This was suspended in methanol and filtered to afford the desired product as a yellow solid (0.714 g, 69%). 1H NMR (300 MHz, DMSO, d6) δ 9.97 (bs, 1 H, NH), 7.67 (d, 2 H, Jo=8.8 Hz, ArH2′& H6′), 7.47 (bs, 1 H, ArH5), 7.00 (s, 1 H, C═CH), 6.99 (d, 2 H, Jo=8.8 Hz, ArH3′& H5′), 6.71 (bs, 1 H, ArH7), 3.85 (s, 3 H, OCH3), 3.75 (t, 4 H, J=4.6 Hz, OCH2CH2N), 3.70 (bs, 2 H, ArNCH2CH2CH2NCH3), 3.55 (bs, 2 H, ArNCH2CH2NCH3), 3.09 (t, 4 H, J=4.6 Hz, OCH2CH2N), 2.95 (bs, 2 H, ArNCH2CH2NCH3), 2.73 (bs, 2 H, ArNCH2CH2CH2NCH3), 2.36 (s, 3 H, NCH3), 2.07 (bs, 2 H ArNCH2CH2CH2NCH3); Mass Spec.: calc. for [C27H33N5O4+H]+ Theor. m/z=492; Obs. 492.
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=1.[SH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[K+].BrCC(=O)C([O-])=O>C(O)C>[N+:11]([C:5]1[C:6]2=[N:7][O:8][N:9]=[C:10]2[C:2]([S:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:3][CH:4]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c2nonc12
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])C(=O)CBr
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Sc2ccc(O)cc2)c2nonc12

Procedure:
A mixed solution of 4-chloro-7-nitro-2,1,3-benzoxadiazole (1 mmole) and 4-mercaptophenol (Sigma-Aldrich, Fine Chemicals) (2 mmoles) was made to react in 20 ml of ethanol: 1:1 potassium phosphate buffer, at pH 7.0 for 6 hours in a closed beaker, at 25° C. The pH was kept neutral by adding small quantities of KOH. At the end of the reaction, the excess 4-mercaptophenol was made to react with 1.5 mmoles of 3-bromopyruvate.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:21]=1)=[O:4].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([C:21]1[N:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[NH:5][C:3]([O:2][CH3:1])=[O:4])(=[O:24])[CH3:23]
Reactant: COC(=O)Nc1cn2cc(Sc3ccccc3)ccc2n1
Reactant: CC(=O)OC(C)=O
Product: COC(=O)Nc1nc2ccc(Sc3ccccc3)cn2c1C(C)=O

Procedure:
A suspension of 2-(methoxycarbonylamino)-6-(phenylthio) imidazo [1,2-a] pyridine (500 mg.) in 10 ml. of acetic anhydride is treated as in Example 7 to yield 3-acetyl-2-(methoxycarbonylamino)-6-(phenylthio) imidazo [1,2-a] pyridine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:27])([CH3:26])[C@@H:11]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])(=[O:7])=[O:6].[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O>[N:28]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:27])([CH3:26])[C@@H:11]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])(=[O:7])=[O:6])=[N+:29]=[N-:30]
Reactant: CC(C)OC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)OC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, isopropyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (25a) (0.61 g, 1.4 mmol) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 0.21 g (2.9 mmol) of sodium azide (NaN3). After work-up, the crude material (25b) was used in the next step without further purification or isolation. MS (ESI) m/z 450.13 (M+Na)+.
Reaction SMILES: ClC1C=CC=CC=1NN[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C.C(Cl)(Cl)(Cl)[Cl:42]>>[Cl:42][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]
Reactant: O=C(NNc1ccccc1Cl)c1ccccc1F
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C(Cl)c1ccccc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5.2 g of 2-fluorobenzoic acid, 2-(2-chlorophenyl)hydrazide, 64.3 g of triphenylphosphine, 500 ml of anhydrous acetonitrile and 19.3 ml of carbon tetrachloride was stirred at ambient temperature for 16 hours, concentrated in vacuo, and extracted with diethyl ether (4×200 ml). The extract was filtered and concentrated to an oil which, was flash chromatographed on silica utilizing hexane/ethyl acetate (25%) as the eluent. Concentration of the appropriate fractions yielded 47.5 g of α-chloro-2-fluorobenzaldehyde, (2-chlorophenyl)hydrazone.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12]([O-:15])(=O)=[O:13].[Na+]>CN(C)C=O>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12]([Cl:3])(=[O:15])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])CCCCCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)CCCCCCBr
Yield: 32.7 %

Procedure:
Thionyl chloride (10.3 ml, 140.4 mmol) and N,N-dimethylformamide (one drop) were added to sodium 6-bromohexanesulfonate (5.00 g, 18.7 mmol) prepared by a process described in Org. Synth., Coll. Vol. II, 558 or WO95/19345 Pamphlet. The mixture was refluxed for 4 hours. The reaction mixture was concentrated in vacuo. The concentrate was diluted with benzene (50 ml). The resulting solution was washed twice with water (15 ml) and then with brine (10 ml), and thereafter dried over calcium chloride. The solvent was removed by evaporation in vacuo. Crude 6-bromohexanesulfonyl chloride (1.61 g) was obtained as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>CS(C)=O.O.N>[CH:9]1([NH:8][C:6]2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=[C:2]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1ccncc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1NC1CCCC1
Agent: N
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cnc(Nc2ccncc2)nc1NC1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.5 %

Procedure:
A mixture of 0.64 g (3 mmol) of 2-chloro-4-(cyclopentylamino)-5-nitropyrimidine and 0.62 g (6.6 mmol) of 4-aminopyridine in 5 mL of DMSO is stirred at room temperature for 15 minutes. The solution is diluted with water and basified with aqueous ammonia to give 0.41 g (44%) of the title compound: mp (EtOH) 219–221° C.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16](C)[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[Si]([O:32][C:33]([O:35][CH3:36])=[CH2:34])(C(C)(C)C)(C)C.C([Sn](F)(CCCC)CCCC)CCC>O1CCCC1.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([CH2:34][C:33]([O:35][CH3:36])=[O:32])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: C=C(OC)O[Si](C)(C)C(C)(C)C
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CCCC[Sn](F)(CCCC)CCCC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Temperature: 80 °C
Yield: 53.3 %

Procedure:
A mixture of 194 mg (0.500 mmol) of 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 411, 0.436 mL (2.00 mmol) of 1-(tert-butyldimethylsilyloxy)-1-methoxyethene, 19.6 mg (0.025 mmol) of dichlorobis(tri-o-tolylphosphine)palladium(II) (19.6 mg, 0.0250 mmol) and 309 mg (1.00 mmol) of tributyltin fluoride (309 mg, 1.00 mmol) in 3.0 ml of tetrahydrofuran was degassed and then heated for 18 hours at 80° C. The mixture was filtered through Celite, the filtrate mixed with 10 ml of water, the mixture was acidified to pH2 and extracted with ethyl acetate. The organic phases were combined, dried with MgSO4 and concentrated. The residue was purified by flash chromatography (0-5% gradient of methanol in dichloromethane) to afford 98 mg of Methyl 2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetate (51%). M/z 382.2. calc. 381.18.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)[C:5]2[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:7]=1.[CH3:35][N:36]1[CH:40]=[C:39]([NH2:41])[CH:38]=[N:37]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1>[CH3:35][N:36]1[CH:40]=[C:39]([NH:41][C:2]2[N:3]=[C:4]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=3)[C:5]3[C:10]([C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:22])[CH3:23])[C:6]=3[N:7]=2)[CH:38]=[N:37]1
Reactant: Cn1cc(N)cn1
Reactant: C[Si](C)(C)CCOCn1cc(-c2cccnc2)c2c(Oc3cccc([N+](=O)[O-])c3)nc(Cl)nc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Nc2nc(Oc3cccc([N+](=O)[O-])c3)c3c(-c4cccnc4)cn(COCC[Si](C)(C)C)c3n2)cn1
Temperature: 140 °C
Yield: 199.7 %

Procedure:
To a microwave reaction vial was added 2-chloro-4-(3-nitrophenoxy)-5-(pyridin-3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (130 mg, 0.26 mmol), 1-methyl-1H-pyrazol-4-amine (28 mg, 0.29 mmol, 1.1 mol eq), 1,4-dioxane (5 mL), Cs2CO3 (ca. 170 mg), Xantphos (16 mg) and Pd2(dba)3 (24 mg). The reaction vial was flushed with nitrogen, capped, stirred and heated to 140° C. using microwave at high absorption level for 45 min. The reaction was diluted with EtOAc (120 mL) and water (20 mL). The organic layer was separated, washed with water (20 mL) and with brine (10 mL), dried over Na2SO4 and evaporated to give crude product (TLC: Rf 0.2 in 100 ethyl acetate). The crude product was purified on silica to give the title compound as a green gum (290 mg, 100% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 8.99 (s, 1H) 8.48 (d, J=3.78 Hz, 1H) 8.18-8.32 (m, 3H) 7.71-7.81 (m, 2H) 7.48-7.55 (m, 2H) 5.70 (s, 2H) 3.77-3.87 (m, 2H) 3.70-3.77 (m, 3H) 0.94-1.06 (m, 2H) 0.00 (s, 9H). m/z (APCI+) for C27H30N8O4Si 559.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:23][C@H:24]2[CH2:29][CH2:28][C@@H:27]([C:30](=[O:35])[NH:31][CH:32]([CH3:34])[CH3:33])[CH2:26][CH2:25]2)=[CH:4][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:36][C:37]1[CH:71]=[CH:70][C:40]([C:41](/[N:43]=[C:44]2/N([C@H]3CC[C@@H](C(=O)NC(C)C)CC3)C3C=C(OCCOC)N=CC=3N/2)=[O:42])=[CH:39][CH:38]=1>>[F:36][C:37]1[CH:38]=[CH:39][C:40]([C:41](/[N:43]=[C:44]2/[N:23]([C@H:24]3[CH2:25][CH2:26][C@@H:27]([C:30](=[O:35])[NH:31][CH:32]([CH3:33])[CH3:34])[CH2:28][CH2:29]3)[C:3]3[CH:4]=[C:5]([O:8][CH:9]4[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10]4)[N:6]=[CH:7][C:2]=3[NH:1]/2)=[O:42])=[CH:70][CH:71]=1
Reactant: COCCOc1cc2c(cn1)[nH]/c(=N\C(=O)c1ccc(F)cc1)n2[C@H]1CC[C@@H](C(=O)NC(C)C)CC1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OC3CCN(CC(=O)OC(C)(C)C)CC3)ncc2N)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3cnc(OC4CCN(CC(=O)OC(C)(C)C)CC4)cc32)CC1
Yield: 79 %

Procedure:
The title compound was prepared from tert-butyl 2-(4-(5-amino-4-(cis-4-(isopropylcarbamoyl)cyclohexylamino)pyridin-2-yloxy)piperidin-1-yl)acetate using a procedure analogous to that used for (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide. Isolated as an off-white solid (124 mg, 79% yield, last step). M/Z calc'd for C34H45FN6O5: 636.76. found 637 [M+H].
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][C:18]([F:21])([F:20])[F:19])=[N:7][O:8][C:9]=1[CH3:10])=[O:4].[OH-].[Na+]>CO>[CH3:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][C:18]([F:21])([F:19])[F:20])[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1c(-c2ccccc2OC(F)(F)F)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1onc(-c2ccccc2OC(F)(F)F)c1C(=O)O
Yield: 93.4 %

Procedure:
In a similar manner as described in Preparation Example 25, by using methanol (60 mL), methyl-5-methyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-carboxylate (6.0 g, 19.91 mmol) and 3% sodium hydroxide aqueous solution (60 mL), a white solid required compound (5.34 g, 18.59 mmol, 93%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7](Br)[N:6]=1)=[O:4].[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[N:30][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CN(C=O)C.[Cl-].[Na+].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.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:28]2[CH:29]=[N:30][CH:31]=[C:26]([F:25])[CH:27]=2)[N:6]=1)=[O:4]
Reactant: OB(O)c1cncc(F)c1
Reactant: COC(=O)c1nc(Br)c2ccc(=O)n(Cc3ccccc3)c2c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1nc(-c2cncc(F)c2)c2ccc(=O)n(Cc3ccccc3)c2c1O
Temperature: 100 °C
Yield: 61.7 %

Procedure:
A mixture of 1-benzyl-5-bromo-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (70 mg, 0.18 mmol), 5-fluoro-pyridine-3-boronic acid (30 mg, 0.22 mmol), Pd(PPh3)4 (21 mg, 0.018 mmol) and Cs2CO3 (117 mg, 0.36 mmol) in DMF (4 mL) was heated at 100° C. for 16 h under nitrogen atmosphere. After cooling to r.t., EtOAc (50 mL) and brine (10 mL) were added. 1 M HCl was added until pH about 4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent, the crude product was purified by silica gel chromatography (0-70% EtOAc/hexanes+2% AcOH) to give 45 mg of the title compound. MS: (+) m/z 406.33 (M+1).
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:14](Cl)=[O:15])[CH3:9]>C1COCC1>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([C:14]([OH:15])=[C:4]([C:3]#[N:7])[C:5]#[N:6])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH3:9]
Reactant: N#CCC#N
Reactant: CCOc1cc(C(=O)Cl)ccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc(C(O)=C(C#N)C#N)ccc1OC
Reaction time: 1 h

Procedure:
NaH (2.2 g, 56 mmol, 60% dispersion in paraffin oil) was added to a solution of malononitrile (1.85 g, 28 mmol) in THF (30 mL) on ice. 3-ethoxy-4-methoxybenzoyl chloride (25.5 mmol) was dissolved in THF (50 mL) and added the first solution dropwise by syringe at 0° C. The ice was then removed and the reaction was allowed to proceed at RT for 60 min. 1N HCl (100 mL) was added and the solution was extracted three times with EtOAc. The organic phase was dried with MgSO4, filtered, and concentrated in vacuo to give an orange solid that was taken onto the next step without further characterization.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][C@@H:8]1[C:12](=[O:13])[N:11]([C@H:14]([C:23]2[NH:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([I:34])=[CH:30][CH:29]=3)=[CH:26][N:27]=2)[C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C:10](=[O:35])[NH:9]1)(C)(C)C.Cl.O1CCOCC1>>[I:34][C:31]1[CH:30]=[CH:29][C:28]([C:25]2[NH:24][C:23]([C@@H:14]([N:11]3[C:12](=[O:13])[C@@H:8]([CH2:7][C:6]([OH:36])=[O:5])[NH:9][C:10]3=[O:35])[C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[N:27][CH:26]=2)=[CH:33][CH:32]=1
Reactant: C[C@@H](c1ccccc1)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](c1ccccc1)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To ((R)-1-{(1S,2S)-1-[5-(4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-2,5-dioxo-imidazolidin-4-yl)-acetic acid tert-butyl ester (120 mg, 0.2 mmol) was added 4 N hydrogen chloride in p-dioxane (2 mL, 0.8 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and hexane was added to form a precipitate. The solid was collected by filtration and dried to give ((R)-1-{(1S,2S)-1-[5-(4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-2,5-dioxo-imidazolidin-4-yl)-acetic acid; hydrochloride salt as a light yellow solid (120 mg, 100%). LC-MS: calcd for C23H21IN4O4 [M+H+] 545. Found 545.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[CH:19]=[C:20]([N:23]6[CH:27]=[C:26]([C:28]([OH:30])=O)[CH:25]=[N:24]6)[CH:21]=[N:22][C:17]5=[N:16][CH:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:49]([CH3:51])[CH3:50])C2C=CC=CC=2N=N1.CNC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:50][N:49]([CH3:51])[C:28]([C:26]1[CH:25]=[N:24][N:23]([C:20]2[CH:21]=[N:22][C:17]3[N:18]([C:14]([C:11]4([C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[CH2:12][CH2:13]4)=[CH:15][N:16]=3)[CH:19]=2)[CH:27]=1)=[O:30]
Reactant: O=C(O)c1cnn(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cnn(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazole-4-carboxylic acid (50 mg, 0.13 mmol) in N,N-dimethylformamide (1.0 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (65 mg, 0.15 mmol), dimethylamine (2M in THF, 0.10 mL, 0.2 mmol) and N,N-diisopropylethylamine (0.10 mL). The mixture was stirred at RT for 2 h, and purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=424.1.