Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:12]([C:21]2[CH:26]=[C:25]([C:27]3[N:28]=[N:29][NH:30][N:31]=3)[CH:24]=[CH:23][N:22]=2)[N:11]=[CH:10]1.Cl[CH2:33][O:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>>[CH3:37][C:36]([CH3:39])([CH3:38])[C:35]([O:34][CH2:33][N:29]1[N:30]=[N:31][C:27]([C:25]2[CH:24]=[CH:23][N:22]=[C:21]([C:12]3[N:11]=[CH:10][N:9]([CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:13]=3[C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH:26]=2)=[N:28]1)=[O:40]
Reactant: Fc1ccc(-c2c(-c3cc(-c4nn[nH]n4)ccn3)ncn2Cc2ccccc2Cl)cc1
Reactant: CC(C)(C)C(=O)OCCl
Product: CC(C)(C)C(=O)OCn1nnc(-c2ccnc(-c3ncn(Cc4ccccc4Cl)c3-c3ccc(F)cc3)c2)n1
Yield: 24 %

Procedure:
The title compound was prepared in 24% yield from 2-[1-[(2-chlorophenyl)methyl]-5-(4-fluorophenyl)imidazol-4-yl]-4-(2H-tetrazol-5-yl)pyridine (Example 137) and 2,2-dimethyl-propionic acid chloromethyl ester according to the procedure for the preparation of Example 138. 1H NMR (300 MHz, CD3OD): δ 1.22 (9H, s), 5.30 (2H, s), 6.61 (2H, s), 6.61-6.62 (1H, m), 6.86-6.88 (2H, m), 7.09-7.39 (5H, m), 7.88 (1H, d, J=6.6 Hz), 7.96 (1H, s), 8.29 (1H, s), 8.55 (1H, d, J=5.1 Hz). [M+H] Calc'd for C28H25ClFN7O2, 546. Found, 546.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][NH:12]2)=[C:8]([NH2:15])[N:7]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)[CH2:27][P:28]([CH3:33])(=[O:32])[O:29][CH2:30][CH3:31]>CN(C=O)C>[NH2:15][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[CH2:23][C:24]1[CH:25]=[C:26]([CH2:27][P:28]([CH3:33])(=[O:32])[O:29][CH2:30][CH3:31])[CH:34]=[CH:35][CH:36]=1
Reactant: CCOP(C)(=O)Cc1cccc(CBr)c1
Reactant: CCCCOc1nc(N)c2nc[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2ncn(Cc3cccc(CP(C)(=O)OCC)c3)c2n1
Temperature: 25 °C
Yield: 33.7 %

Procedure:
A mixture of 59 (300.0 mg, 1.45 mmol) and K2CO3 (200.0 mg, 1.45 mmol) was dissolved in DMF (5 mL) and to it was added 65 (421.0 mg, 1.45 mmol). The mixture was left to stir over night at room temperature, solvent was evaporated by rotary evaporation. The remaining solid was taken up in water and the product extracted with DCM (3×50 mL). Combined organic layers were washed with water (1×50 mL) and brine (2×50 mL) and dried over Na2SO4. Product was purified by flash column eluting 0-10% methanol in ethyl acetate to give 204.0 mg (34%) 68 as a solid. 1H NMR (300 MHz, CDCl3) δ 0.923 (t, 3H), 1.19 (t, 3H), 1.31 (d, 3H), 1.44 (m, 2H), 1.73 (m, 2H), 3.07 (dd, 2H), 3.94 (m, 2H), 4.28 (t, 2H), 5.24 (s, 2H), 7.17 (m, 4H), 7.59 (s, 1H). LCMS: m/z for C20H28N5O3P++H observed 418.2 at 2.03 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].[CH:16]1([CH2:19][O:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:18][CH2:17]1.[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:16]1([CH2:19][O:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][N:5]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[O:8][CH2:7][C:6]3=[O:15])[CH2:23][CH2:22]2)[CH2:17][CH2:18]1
Reactant: O=C1COc2ccccc2N1CCCCl
Reactant: C1CC(OCC2CC2)CCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C1COc2ccccc2N1CCCN1CCC(OCC2CC2)CC1
Reaction time: 20 h
Yield: 73.5 %

Procedure:
A 4 mL vial was charged with 4-(3-chloropropyl)-4H-benzo[1,4]oxazin-3-one (0.068 g, 0.3 mmol), 4-cyclopropylmethoxypiperidine (0.047 g, 0.3 mmol), NaI (0.075 g, 0.5 mmol), and K2CO3 (0.069 g, 0.5 mmol) in MeCN (1 mL) and shaken at 500 for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by cation exchange column chromatography to give the title compound (0.076 g, 74%). 1H NMR (CDCl3) δ 6.96-6.93 (m, 1H), 6.87-6.80 (m, 3H), 4.41 (s, 2H), 3.81 (t, J=7.4 Hz, 2H), 3.16-3.10 (m, 1H), 3.11 (d, J=6.8 Hz, 2H), 2.62-2.57 (m, 2H), 2.22 (t, J=7.0 Hz, 2H), 1.94-1.89 (m, 2H), 1.75-1.64 (m, 4H), 1.48-1.39 (m, 2H), 0.89-0.86 (m, 1H), 0.38-0.33 (m, 2H), 0.04-0.00 (m, 2H); 13C NMR (CDCl3) δ 164.2, 145.3, 128.6, 123.7, 122.7, 117.0, 115.0, 74.8, 72.6, 67.6, 55.3, 51.4, 39.5, 31.5, 24.8, 11.0, 3.0.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:17])[NH:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]n(-c2ccccc2)c2cc(Br)ccc12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1nn(-c2ccccc2)c2cc(Br)ccc12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 6-bromo-1-phenyl-1,2-dihydroindazol-3-one (5 g, 17.30 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL), potassium carbonate (3.7 g, 34.91 mmol, 2.00 equiv), CH3I (2.7 g, 19.01 mmol, 1.10 equiv). The resulting solution was stirred for 3 h at 80° C. in an oil bath. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×150 mL) and the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:40) to yield 6-bromo-3-methoxy-1-phenyl-1H-indazole as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[NH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH3:31].BrC1C=CC(F)=C(C2N=C(NC3C=CN=CC=3)C3C(=NC=CN=3)N=2)C=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:6]([C:8]2[N:17]=[C:16]([NH:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][C:26]=3[CH3:31])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: Cc1cnccc1N
Reactant: O=c1[nH]c(-c2cc(Br)ccc2N2CCCC2)nc2nccnc12
Agent: Fc1ccc(Br)cc1-c1nc(Nc2ccncc2)c2nccnc2n1
Product: Cc1cnccc1Nc1nc(-c2cc(Br)ccc2N2CCCC2)nc2nccnc12

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-pyrrolidin-1-yl-phenyl)pteridin-4-one 110 and 4-amino-3-methylpyridine following the procedure described for 4-(4-pyridylamino)-2-(5-bromo-2-fluorophenyl)pteridine 1 (LCMS analysis).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([O:23]COC)=[CH:18][C:17]=3[CH3:27])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:28][CH2:29][C:30]([OH:32])=[O:31].CS(O)(=O)=O>C(OCC)(=O)C.C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:17]([CH3:27])=[CH:18][C:19]([OH:23])=[CH:20][C:21]=3[CH3:22])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:28][CH2:29][C:30]([OH:32])=[O:31]
Reactant: COCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)O)c(F)c3)c2)c(C)c1
Agent: CS(=O)(=O)O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1cc(O)cc(C)c1-c1cccc(CNc2ccc(CCC(=O)O)c(F)c2)c1
Yield: 9.4 %

Procedure:
3-[2-Fluoro-4-({[4′-(methoxymethoxy)-2′,6′-dimethylbiphenyl-3-yl]methyl}amino)phenyl]propanoic acid (1.0 g, 2.29 mmol) was dissolved in ethyl acetate (2 mL) and diethyl ether (4 mL). To this solution was added methanesulfonic acid (0.16 mL, 2.47 mmol) and the solution was concentrated under reduced pressure. Aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (85 mg, yield 9%) as a colorless oil.
Reaction SMILES: [C:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[C:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:20])=[O:14])=[CH:11][CH:10]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)Oc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCC(=O)Oc1ccc(C(=O)Cl)cc1
Yield: 81.6 %

Procedure:
A mixture of 10 g of the resultant 4-hexanoyloxybenzoic acid, 8 g thionyl chloride and 100 ml toluene was stirred and externally heated to be refluxed for three hours. After distilling off the toluene from the mixture, the residue was distilled under reduced pressure to give 8.8 g 4-hexanoyloxybenzoic acid chloride in 82% yield based upon the amount of the 4-hexanoyloxybenzoic acid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([OH:17])(=O)[CH2:14][CH3:15].[CH2:18]([NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[CH3:19].CO>O1CCCC1.C(OCC)(=O)C>[CH2:18]([N:20]([C:13](=[O:17])[CH2:14][CH3:15])[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)[CH3:19]
Reactant: CCC(=O)O
Reactant: CCNCCc1ccc(O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(=O)N(CC)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.3 %

Procedure:
To a stirred solution of carbonyldiimidazole (14.13 g, 87.12 mmole) in tetrahydrofuran (109 ml) at 5° C., was added dropwise a solution of propionic acid (6.5 ml, 87.12 mmole) in tetrahydLrofuran (73 ml) over 30 minutes. After stirring for 20 minutes, N-ethyl tyramine (12.0 g, 72.6 mmole) in tetrahydlrofuran (73 ml) was added over 20 minutes. The reaction was allowed to warm to room temperature and stir for 4 hours. Methanol (7.3 ml) was added and stirring was continued for 30 minutes. The reaction was worked up by diluting with ethyl acetate and extracting with 1N hydrochloric acid, saturated sodium bicarbonate, then brine. The organic layer was dried over sodium sulfate, evaporated to dryness, and chromatographed on silica gel using a methylene chloride-methanol gradient to give N-ethyl,N-propionyl tyramine (6.95 g, 43%):
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1([C:27]([OH:29])=O)[CH2:18][C:17]2[C:12](=[C:13]([O:25][CH3:26])[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]=2[O:19][CH3:20])[CH2:11]1.[Cl-].C[NH3+].Cl.[CH2:34]([N:36]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C1COCC1>[CH3:34][NH:36][C:27]([C:10]1([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])[CH2:18][C:17]2[C:12](=[C:13]([O:25][CH3:26])[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]=2[O:19][CH3:20])[CH2:11]1)=[O:29]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCO)(C(=O)O)C2
Reactant: CCN=C=NCCCN(C)C
Agent: C[NH3+]
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C1(CCCCCCCCO)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Reaction time: 12 h
Yield: 89.5 %

Procedure:
A THF (3.0 ml) solution of 2-(8-hydroxyoctyl)-4,5,6,7-tetramethoxy-2-indan-carboxylic acid (300 mg, 0.731 mmols) was added to a THF (3.0 ml) suspension of methyl ammonium chloride (247 mg, 3.66 nmnols), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (420 mg, 2.19 mmols), 1-hydroxybenzotriazole monohydrate (335 mg, 2.19 mmols) and triethylamine (1.02 ml, 7.31 mmols), at room temperature. The reaction mixture was stirred for 12 hours, and then concentrated in vacuo. Water was added to the resulting residue, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by alumina column chromatography (ethyl acetate) to obtain the entitled compound (277 mg) as an oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11](=O)[CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:16]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1)#[N:17]>>[CH3:12][C:11](=[N:25][NH:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[CH:19][CH:20]=1)[CH2:10][O:9][C:8]1[CH:14]=[CH:15][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(NN)cc1
Reactant: CC(=O)COc1ccc(S(C)(=O)=O)cc1
Product: CC(COc1ccc(S(C)(=O)=O)cc1)=NNc1ccc(C#N)cc1

Procedure:
The sub-title compound was prepared by the method of example 20 step (ii), using the product from example 20 step (i) (700 mg) and 4-cyanophenylhydrazine (400 mg). Yield 900 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)([CH2:22][CH2:23]O)[O:18][C:17]3=[O:32])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:33]1[CH2:38][CH2:37][NH:36][CH2:35][C:34]1=[O:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)([CH2:22][CH2:23][N:36]4[CH2:37][CH2:38][NH:33][C:34](=[O:39])[CH2:35]4)[O:18][C:17]3=[O:32])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: O=C1CNCCN1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCN2CCNC(=O)C2)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 178 using piperazin-2-one in Step 2. LC-MS Method 2 tR=1.213 min, m/z=519.23; 1H NMR (CDCl3) 1.46 (d, 3H), 2.13-2.27 (m, 3H), 2.35 (m, 2H), 2.75 (m, 1H), 2.88 (m, 1H), 3.20-3.39 (m, 3H), 3.51 (s, 2H), 3.66 (s, 2H), 5.54 (m, 1H), 6.94-7.05 (m, 6H), 7.14 (m, 2H), 7.25 (d, 2H), 7.37 (m, 2H), 7.85 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[CH2:10]1[O:19][C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[O:12][CH2:11]1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.CCOCC.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]>[CH2:10]1[O:19][C:13]2([CH2:18][CH2:17][N:16]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[O:8][CH3:9])[CH2:15][CH2:14]2)[O:12][CH2:11]1
Reactant: COc1ccccc1Br
Reactant: C1CC2(CCN1)OCCO2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccccc1N1CCC2(CC1)OCCO2
Temperature: 100 °C

Procedure:
A solution of 2-bromoanisole (6.00 g, 32.08 mmol) and 4-piperidone ethylene ketal (5.54 g, 38.69 mmol) in toluene (250 mL) was treated with sodium tert-butoxide (4.40 g, 45.76 mmol), tri-o-tolylphosphine (411 mg, 1.35 mmol), and tris(dibenzylideneacetone)dipalladium(0) (295 mg, 0.32 mmol) at room temperature. The mixture was heated in an oil bath (100° C., 2 h). The mixture was diluted with ether and the organics washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography on silica gel (20% ethyl acetate/hexane) afforded the title compound (19).
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.[C:40](=O)([O:51][CH2:52][C:53]1[S:57][CH:56]=[N:55][CH:54]=1)[O:41]C1C=CC([N+]([O-])=O)=CC=1.C(N(CC)CC)C>C(OCC)(=O)C>[S:57]1[C:53]([CH2:52][O:51][C:40]([N:13]([CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:12][C@@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]2[S:1][CH:2]=[N:3][CH:4]=2)=[O:9])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:41])=[CH:54][N:55]=[CH:56]1
Reactant: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(N[C@H](CNC[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](Cc1ccccc1)CN(C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)C(=O)OCc1cncs1)OCc1cncs1
Reaction time: 18 h
Yield: 35.8 %

Procedure:
The product from Example 35 (30 mg, 0.053 mmol) in ethyl acetate (2 mL) was treated with a solution of 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate [prepared from 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate hydrochloride salt (18 mg, 0.058 mmol) by extraction with aqueous NaHCO3], triethylamine (15 μl, 0.106 mmol), and N,N-dimethylaminopyridine (6 mg, 0.053 mmol) at ambient temperature. After stirring for 18 hours, the mixture was washed with aqueous 10% K2CO3 (5×2 mL), brine (2 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purify on a silica gel cartridge eluting with (chloroform:methanol, 99:1) to provide the title compound (13.4 mg, 36%). 1H NMR (CDCl3) δ 8.80-8.68 (m, 3H), 7.81 (m, 3H), 7.31-6.96 (m, 10H), 5.27-5.05 (m, 6H), 4.04-3.25 (m, 5H), 3.11-2.98 (m, 2H), 2.89-2.56 (m, 5H); MS (ESI+) m/z 707 (M+H)+.
Reaction SMILES: Br[C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[NH:29][N:28]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:26]=1.O1C=CC=C1C1N(C2C=C(C#N)SC=2)N=C(C(F)(F)F)C=1.O.NN>CN(C=O)C>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[N:29]([C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[N:28]=[C:27]([C:30]([F:33])([F:31])[F:32])[CH:26]=1
Reactant: FC(F)(F)c1cc(-c2ccco2)[nH]n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Br)C1
Agent: N#Cc1cc(-n2nc(C(F)(F)F)cc2-c2ccco2)cs1
Agent: NN
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2nc(C(F)(F)F)cc2-c2ccco2)C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a stirred solution of 72 (681 mg, 2.72 mmol) in DMF (9.894 mL) was added potassium carbonate (855 mg, 6.18 mmol), and then 5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (500 mg, 2.474 mmol) [made by following the procedure described above for the synthesis of compound 14 (scheme 2, example 1c, step 4), except using hydrazine hydrate instead of 13 as the starting material]. The resulting solution was allowed to stir at 100° C. for 1 h. The mixture was quenched with water and extracted with ethyl acetate, washed with brine, dried (MgSO4) filtered and concentrated. The residue was purified by silica gel column chromatography with gradient of EtOAc (10-20%) in hexanes to afford 73 (340 mg, 37%) as a colorless oil. LRMS (ESI): calc. 371.1; found 394.0 (MNa)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH2:21][C:22]4[S:26][C:25]([CH3:27])=[N:24][C:23]=4[CH3:28])=[C:12]([N+:17]([O-])=O)[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:29][CH3:30])=[C:5]([CH3:31])[O:4][N:3]=1.Cl.O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH2:21][C:22]4[S:26][C:25]([CH3:27])=[N:24][C:23]=4[CH3:28])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:29][CH3:30])=[C:5]([CH3:31])[O:4][N:3]=1
Reactant: COc1cc2c(NCc3sc(C)nc3C)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc2c(NCc3sc(C)nc3C)c(N)cnc2cc1-c1c(C)noc1C
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of 7-(3,5-dimethyl-4-isoxazolyl)-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-6-(methyloxy)-3-nitro-4-quinolinamine (for a preparation see intermediate 69, 1.13 g) in ethanol was added hydrochloric acid (2 ml, conc). Tin (II) chloride dihydrate (2.32 g) was added and the mixture was stirred at 40° C. for 1 h. The reaction mixture was cooled, diluted with water and basified using sodium hydroxide solution (1N). The formed precipitate was filtered through Celite and rinsed with DCM. The filtrate was washed with water and the organic was dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with DCM/methanol (98:2 then 93:7) to give 7-(3,5-dimethyl-4-isoxazolyl)-N4-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-6-(methyloxy)-3,4-quinolinediamine (0.6 g) as a beige foam.
Reaction SMILES: O[C:2]1([CH:7]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:8]2[N:12]=[CH:11][NH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O>ClCCl>[C:2]1(=[C:7]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:8]2[N:12]=[CH:11][NH:10][N:9]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1ccc(C(c2nc[nH]n2)C2(O)CCCC2)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(C(=C2CCCC2)c2nc[nH]n2)cc1
Reaction time: 2 h
Yield: 31.2 %

Procedure:
7.21 g of crude 4-[1-hydroxycyclopent-1-yl-1-(1,2,4-triazolyl) methyl]benzonitrile is dissolved in 50 ml of dichloromethane at 0° and stirred at 0° with 24 ml of thionyl chloride for 1 hour. Then the mixture is concentrated to dryness under vacuum, dissolved in 50 ml of dichloromethane, stirred for 2 hours with 32 ml of triethylamine, diluted with water, extracted four times with ethyl acetate, washed with sodium chloride solution, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, thus obtaining 2.1 g of 4-[1-cyclopentylidene-1- (1,2,4triazolyl)methyl]benzonitrile as the free base, mp 72°.
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:31])[CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH:20]([OH:22])[CH2:19][C@@H:18]3[C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[OH:30])=[N:13][C:12]=12)=[O:7].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:29][C:27]1[CH:26]=[CH:25][C:24]2[O:30][CH2:2][C@@H:3]([OH:31])[CH2:4][NH:5][C:6](=[O:7])[C:8]3=[C:12]4[N:13]=[C:14]([CH:15]=[CH:16][N:11]4[N:10]=[CH:9]3)[N:17]3[C@H:18]([CH2:19][C@@H:20]([OH:22])[CH2:21]3)[C:23]=2[CH:28]=1
Reactant: O=C(NC[C@H](O)CCl)c1cnn2ccc(N3CC(O)C[C@@H]3c3cc(F)ccc3O)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1NC[C@H](O)COc2ccc(F)cc2[C@H]2C[C@@H](O)CN2c2ccn3ncc1c3n2
Temperature: 85 °C
Yield: 16.2 %

Procedure:
A mixture of N-((S)-3-chloro-2-hydroxypropyl)-5-((R)-2-(5-fluoro-2-hydroxyphenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.0407 g, 0.0778 mmol) and Cs2CO3 (0.127 g, 0.389 mmol) in DMF (3.6 mL) was heated at 85° C. for 30 minutes. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to give the crude material which was purified by silica column chromatography, eluting with 0-20% MeOH/EtOAc to afford the crude product. The crude material was purified using chiral column chromatography (Chiral Tech OD-H column, 20% EtOH in hexanes). Isolation of the material having a retention time of about 21.8 minutes afforded the title compound (0.0052 g, 16.2% yield). The stereochemistry of the title compound was confirmed by 1H-NMR nOe experiment. LC/MS (ES+APCI) m/z=414.1 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([Li])CCC.[CH3:26][O:27][CH2:28][C:29](OCC)=[O:30].[NH4+].[Cl-]>C1COCC1>[CH3:26][O:27][CH2:28][C:29](=[O:30])[CH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CCOC(=O)COC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCC(=O)CS(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 72.7 %

Procedure:
A solution of 4-(4′-trifluoromethylphenyl)phenyl methyl sulfone (1.0 g, 3.33 mmol) in THF (50 mL) at −78° C. was treated with n-butyllithium (2.5M/hexanes, 1.4 mL, 3.50 mmol), stirred at −78° C. for 1.5 hours and then treated with ethyl methoxyacetate (0.78 mL, 6.66 mmol), stirred at −78° C. for three hours, treated with saturated NH4Cl solution, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), concentrated and purified on silica gel with 30-50% ethyl acetate/hexanes to provide 902 mg (73%) of the title compound as a white solid. MS (APCI) m/z 390 (M+NH4)+, 371 (M−H)−, 470 (M+Cl)−.