Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Li+].C([N:6]1[C:14]2[C:9](=[C:10]([CH3:20])[C:11](CC([O-])=O)=[CH:12][C:13]=2[CH3:15])[CH:8]=[N:7]1)(=O)C.[Cl-].[NH4+]>CO.O1CCCC1>[CH3:20][C:10]1[C:11]([OH:1])=[CH:12][C:13]([CH3:15])=[C:14]2[C:9]=1[CH:8]=[N:7][NH:6]2
Reactant: CC(=O)n1ncc2c(C)c(CC(=O)[O-])cc(C)c21
Reactant: [OH-]
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(O)cc(C)c2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
A 2N-aqueous lithium hydroxide solution (85 ml, 170 mmol) was added to a solution of (1-acetyl-4,7-dimethyl-1H-indazol-5-yl)acetate (20.3 g, 82.4 mmol) in methanol-tetrahydrofuran (1:1, 170 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was poured into the reaction solution, followed by extraction with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then distilled under reduced pressure to remove the solvent. The residue was washed with acetonitrile by repulping to obtain 4,7-dimethyl-1H-indazol-5-ol (13.0 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][CH:11]=[C:10]3[N:14]([CH3:18])[N:15]=[C:16]([NH2:17])[C:9]=23)=[CH:4][CH:3]=1.[N:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1)=[C:20]=[O:21].FC1C=CC(C)=CC=1N=C=O>>[NH2:17][C:16]1[C:9]2[C:10](=[CH:11][N:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:20]([NH:19][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)=[O:21])=[CH:7][CH:6]=2)[N:14]([CH3:18])[N:15]=1
Reactant: Cn1nc(N)c2c(-c3ccc(N)cc3)cncc21
Reactant: Cc1cccc(N=C=O)c1
Agent: Cc1ccc(F)c(N=C=O)c1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3cncc4c3c(N)nn4C)cc2)c1

Procedure:
The title compound was prepared using the procedure described in Example 1E using the product from Example 6A and 1-isocyanato-3-methyl-benzene instead of the product from Example 1D and 1-fluoro-2-isocyanato-4-methyl-benzene. MS (ESI(+)) m/e 373 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3H) 4.02 (s, 3H) 6.81 (d, J=7.12 Hz, 1H) 7.17 (t, J=7.80 Hz, 1H) 7.26 (d, J=8.14 Hz, 1H) 7.32 (s, 1H) 7.52 (d, J=8.82 Hz, 2H) 7.68 (d, J=8.82 Hz, 2H) 8.10 (s, 1H) 8.71 (s, 1H) 8.95 (s, 1H) 9.20 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].[Cl:8][C:9]1[N:14]=[CH:13][C:12](O)=[CH:11][N:10]=1>>[Cl:8][C:9]1[N:14]=[CH:13][C:12]([O:5][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])=[CH:11][N:10]=1
Reactant: Oc1cnc(Cl)nc1
Reactant: OCCC(F)(F)F
Product: FC(F)(F)CCOc1cnc(Cl)nc1
Yield: 92 %

Procedure:
Reactions similar to those of Reference Example 28 were performed except for using 3,3,3-trifluoro-1-propanol instead of 1-methyl-4-piperidinol, and from 100 mg (0.693 mmol) of 2-chloro-5-hydroxypyrimidine, 144 mg of the title compound as a colorless oil (yield: 92%).
Reaction SMILES: [C:1]([N:5]1[C:12]2[C@@H:11]3[CH2:13][C@@H:10]3[CH2:9][C:8]=2[C:7]([C:14](O)=[O:15])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[C:48]1([C:54]([NH2:57])([CH3:56])[CH3:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[CH3:55][C:54]([NH:57][C:14]([C:7]1[C:8]2[CH2:9][C@H:10]3[CH2:13][C@H:11]3[C:12]=2[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:6]=1)=[O:15])([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH3:56]
Reactant: CC(C)(C)n1nc(C(=O)O)c2c1[C@@H]1C[C@@H]1C2
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)c1nn(C(C)(C)C)c2c1C[C@H]1C[C@@H]21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.5 %

Procedure:
To a solution of (1aR,5aR)-2-tert-butyl-1a,2,5,5a-tetrahydro-1H-2,3-diazacyclopropa[a]pentalene-4-carboxylic acid (30 mg, 0.136 mmol), HATU (55 mg, 0.143 mmol) in DMF (1 mL) was added Et3N (16 mg, 0.15 mmol). After stirring for 5 min at room temperature, 2-phenylpropan-2-amine (20 mg, 0.143 mmol) was added into the reaction. The reaction was stirred for 1 h at room temperature, and purified by preparative HPLC to give the title compound (25 mg). LCMS m/z=338.5 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.34 (td, J=4.5 and 3.4 Hz, 1H), 1.11 (td, J=7.8 and 4.5 Hz, 1H), 1.63 (s, 9H), 1.78 (s, 6H), 2.11-2.18 (m, 2H), 2.75 (d, J=16.7 Hz, 1H), 2.86 (dd, J=16.6 and 5.8 Hz, 1H), 7.21 (t, J=7.3 Hz, 1H), 7.32 (t, J=8.0 Hz, 2H), 7.36 (bs, 1H), 7.42-7.46 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[H+].[B-:11]([F:15])([F:14])([F:13])[F:12].[N:16]([O-])=O.[Na+].C(OCC)C>CCO>[F:12][B-:11]([F:15])([F:14])[F:13].[Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[N+:4]#[N:16]
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)cc1Br
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: N#[N+]c1ccc(Cl)cc1Br
Yield: 96 %

Procedure:
A solution of 2-bromo-4-chloroaniline (10.0 g, 48.4 mmol) and HBF4 in EtOH (60 mL) kept at 0° C. was treated with an aqueous solution (20 mL) of NaNO2 (3.34g, 48.4 mmol). After completion of the addition, diethyl ether (200 mL) was added to the mixture. The solid was collected by filtration, washed with water and dried under high vacuum affording the title compound (14.2 g, 96%) as white crystals.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH3:13][C:14]([CH3:24])([CH2:20][CH2:21][CH2:22][CH3:23])[C:15](OCC)=[O:16].C(O)(=O)C>C1COCC1>[CH3:13][C:14]([CH3:24])([CH2:20][CH2:21][CH2:22][CH3:23])[C:15](=[O:16])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCCCC(C)(C)C(=O)OCC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCC(C)(C)C(=O)CP(=O)(OC)OC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of dimethyl methylphosphonate (35.0 ml) in THF (300 ml) was cooled to -78° C., to which n-butyllithium (1.6 -M, 196 ml) was added dropwise. After stirring at -78° C. for one hour, a solution of ethyl 2,2-dimethylcaproate (27 g) in dry THF was added. The reaction solution was stirred at -78° C. for one hour, and then at room temperature for additional 2 hours. The reaction solution was cooled to 0° C. and acetic acid (18 ml) was added thereto. The crude product obtained after the conventional work-up was distilled under reduced pressure and the resulting fraction (>130° C.) was chromatographed to give dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate. Yield, 9.72 g (26%)
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:23]([CH3:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1>>[C:20]([C:19]1[CH:22]=[C:23]([CH3:24])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[C@H:26]([CH3:25])[CH2:30][O:29][C:28]4=[O:31])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)#[N:21]
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)nc2)CC1
Yield: 80.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using 6-[4-(6-bromopyridine-3-carbonyl)piperazin-1-yl]-5-methylnicotinonitrile (200 mg) described in Preparation Example 131 and (R)-4-methyloxazolidin-2-one (79 mg) described in Preparation Example 25, the title compound (170 mg) was obtained.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@@H:4]1[CH:6]1[CH2:11][CH2:10][N:9]([C:12](OC(C)(C)C)=O)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].ClC1[N:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][N:34]=1>ClCCl>[CH2:39]([C:36]1[CH:35]=[N:34][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C@H:4]3[CH2:5][C@H:3]3[CH2:2][OH:1])[CH2:11][CH2:10]2)=[N:38][CH:37]=1)[CH3:40]
Reactant: CCc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2CO)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3CO)CC2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.), stirred solution tert-butyl 4-[(1R,2R)-2-(hydroxymethyl)cyclopropyl]piperidine-1-carboxylate (intermediate 4, 5.0 g, 19.58 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (100 mL) slowly over 10 minutes. After being stirred at 0° C. for 1 h, the mixture was concentrated under vacuum. Residual TFA was further removed by stripping twice from dichloromethane followed by drying in vacuum. The resulting residue was dissolved in DMF (40 ml) followed by the addition of cesium carbonate (35.09 g, 107.69 mmol) and 2-chloro-5-ethylpyrimidine (5.6 g, 39.15 mmol). The mixture was stirred at RT for 15 h before being quenched with H2O. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with H2O (2×), brine (1×), dried over anhydrous MgSO4, filtered, and concentrated under vacuum to leave a residue which was purified by column chromatography on silica (elution with 2:1→1:1 hexane:ethyl acetate) to yield the title compound. H NMR (500 MHz, CDCl3) δ 8.18 (s, 2H), 4.74-4.65 (m, 2H), 3.74-3.67 (m, 2H), 2.89-2.81 (m, 2H), 2.47 (q, J 7.6 Hz, 2H), 1.91-1.82 (m, 2H), 1.46-1.34 (m, 2H), 1.23-1.16 (M, 4H), 1.16-1.07 (m 1H), 0.77-0.70 (m, 2H), 0.09-0.04 (m, 1H). MS (ESI) m/z 262 [M+H]+.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[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].[CH2:17]([O:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH3:19]>CC#N>[CH3:16][C@H:3]([CH2:2][N:24]1[CH2:25][CH2:26][CH:21]([O:20][CH2:17][CH2:18][CH3:19])[CH2:22][CH2:23]1)[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]
Reactant: CCCOC1CCNCC1
Reactant: C[C@H](CI)CN1C(=O)COc2ccccc21
Solvent: CC#N
Product: CCCOC1CCN(C[C@@H](C)CN2C(=O)COc3ccccc32)CC1
Yield: 64.4 %

Procedure:
The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[1,4]oxazin-3-one (108LM27-24) (0.202 g, 0.61 mmol) and 4-propoxy-piperidine (79KS66) (0.097 g, 0.67 mmol) in MeCN (½ mL) were reacted according to GP14 to give the title compound (108LM32-29) (0.136 g, 65%). 1H NMR (CDCl3) δ 7.15 (bd, J=7.3 Hz, 1H), 7.03-6.95 (m, 3H), 4.60 (ABq, J=13.9 Hz, J=31.6 Hz, CH2), 4.05-3.90 (m, 2H), 3.48 (t, J=7.0 Hz, CH2), 3.28-3.20 (m, 1H), 2.79 (bs, 1H), 2.63 (bs, 1H), 2.27-2.11 (m, 3H), 2.10-1.93 (m, 2H), 1.92-1.83 (m, 2H), 1.63-1.52 (m, 4H), 0.94-0.86 (m, 6H); 13C NMR (CDCl3) δ 164.5, 145.4, 128.5, 123.4, 122.3, 116.9, 115.2, 75.0, 69.4, 67.4, 63.2, 52.5, 51.5, 45.0, 31.6, 31.5, 29.1, 23.1, 16.6, 10.5; HPLC-MS (ammonium acetate) [M+H]+=347.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[C:24]3[C:19](=[C:20]([CH2:25][S:26][CH3:27])[CH:21]=[CH:22][CH:23]=3)[N:18](C(OC(C)(C)C)=O)[CH:17]=2)[CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[C:24]3[C:19](=[C:20]([CH2:25][S:26][CH3:27])[CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)C(c1ccc(Cl)cc1)c1cn(C(=O)OC(C)(C)C)c2c(CSC)cccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(C)C(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.85 g (1.69 mmol) of the compound from Example 31A was dissolved in 10 ml of dichloromethane, and 2.61 ml (33.86 mmol) of trifluoroacetic acid were added. After stirring at RT for 2 h, the reaction solution was concentrated and the residue was purified twice by preparative HPLC (mobile phase: acetonitrile-water gradient). 0.42 g (61% of theory) of the title compound was obtained as mixture of diasteromers.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH2:22][OH:23])=[CH:17][C:16]=2[CH3:24])[C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2].[OH-].[Na+].[CH2:28]1COCC1>>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:16]([CH3:24])=[CH:17][C:18]([CH2:22][O:23][CH3:28])=[CH:19][C:20]=2[CH3:21])[C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2]
Reactant: C1CCOC1
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(CO)cc2C)c1C
Agent: [Na+]
Agent: [OH-]
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(COC)cc2C)c1C
Reaction time: 0.08 h

Procedure:
To a solution of {4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl}-methanol in dry THF was added 60% NaOH in oil and stirred for 5 min. Excess of Mel was added and stirred at room temperature for 2 hr. After standard worked up procedure and purification, the title compound was obtained as a clear golden oil. 1H NMR(CDCl3) d 7.02(s,2H), 6.06(s,1H), 4.40(s,3H), 3.72(d,1H), 3.39(s,3H), 3.36(m,1H), 2.12(s,3H), 2.11(s,3H), 2.10(s,6H), 1.4-1.7(m,4H), 0.95(t,6H) ppm.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:11]([CH2:12][CH3:13])[C:10]([CH3:14])=[N:9][CH:8]=1)=O.C(=O)(O)O.[C:20]1([NH:26][C:27]([NH2:29])=[NH:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C[O-].[Na+].O>CC(N(C)C)=O>[NH:26]([C:27]1[N:29]=[C:5]([C:7]2[N:11]([CH2:12][CH3:13])[C:10]([CH3:14])=[N:9][CH:8]=2)[CH:4]=[CH:3][N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N=C(N)Nc1ccccc1
Reactant: CCn1c(C(=O)C=CN(C)C)cnc1C
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCn1c(-c2ccnc(Nc3ccccc3)n2)cnc1C
Temperature: 110 °C
Yield: 52.5 %

Procedure:
5-(3-Dimethylaminoprop-2-en-1-oyl)-1-ethyl-2-methylimidazole (Method 23; 2.10 g, 10.1 mmol), phenylguanidine hydrogen carbonate (2.2 g, 11.1 mmol) and sodium methoxide (1.2 g, 22.2 mmol) were suspended in anhydrous DMA (15 ml) and the mixture heated at 110° C. for 18 hours. The reaction mixture was allowed to cool to ambient temperature and poured into water (50 ml). The solution was extracted EtOAc (2×50 ml). The combined extracts were washed with water (2×50 ml) and then brine (2×50 ml), dried and the volatiles removed by evaporation. The residue was triturated with ether, collected by filtration and air dried to give the title compound (1.48 g, 53%) as a reddish brown solid. NMR 1.17 (t, 3H), 2.38 (s, 3H), 4.52 (q, 2H), 6.93 (t, 1H), 7.08 (d, 1H), 7.27 (t, 2H), 7.60 (s, 1H),7.62 (d, 2H), 8.35 (d, 1H), 9.35 (s, 1H); m/z 280.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[CH3:13])[CH:8]=O)(=[O:3])[CH3:2].N1CCCCC1.C(O)(=O)[CH2:21][C:22]([OH:24])=[O:23].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:21][C:22]([OH:24])=[O:23])[CH:10]=[CH:11][C:12]=1[CH3:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C=O)ccc1C
Reactant: O=C(O)CC(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(C=CC(=O)O)ccc1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To a solution of 3-acetamido-4-methylbenzaldehyde (14 g, 79 mmol) in pyridine (210 mL) is added piperidine (3.9 mL, 39.4 mmol) and malonic acid (15.26 g, 146.6 mmol). The mixture is heated to 100° C. for 4 hours, then stirred at room temperature overnight. The solution is concentrated in vacuo, then diluted with water. Cold 1 N HCl is added to the slurry until pH is ca. 4. The solid product (16.178 g, 73.8 mmol) is collected and washed generously with water. The title compound (16.178 g, 73.8 mmol) is then dried over P2O5 under vacuum overnight to yield a white solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][N:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1F)[CH:16]=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:9][C:6]1[CH:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[N:4][CH:5]=1)[CH:16]=[O:17]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1cnc(C(F)(F)F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Temperature: 130 °C
Yield: 83.4 %

Procedure:
To a solution of 2-(trifluoromethyl)pyrimidin-5-ol (1.5 g, 9.14 mmol) and 3,4-difluorobenzaldehyde (1.299 g, 9.14 mmol) in DMF (18 mL), was added K2CO3 (1.642 g, 11.88 mmol). The mixture was heated with a microwave condition at 130° C. for 1 h. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated to afford the title compound (2.18 g, 7.62 mmol, 83% yield) as a brown oil. LCMS: rt=3.08 min, [M+H+]=287
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH3:12][O:13][C:14](=[O:22])[CH2:15]P(OC)(OC)=O.C[O-].[Na+].Cl>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6](/[CH:7]=[CH:15]/[C:14]([O:13][CH3:12])=[O:22])[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1cccc([N+](=O)[O-])c1
Yield: 97.2 %

Procedure:
To a solution of 3-nitro-benzaldehyde (15 g, 0.1 mol), (dimethoxy-phosphoryl)-acetic acid methyl ester (27 g, 0.148 mol) in DMF (100 ml) was added NaOMe (10.7 g 0.198 mol). The reaction was monitored by TLC. After reaction was completed, the reaction mixture was adjusted to pH=1 with aqueous HCl solution and evaporated. The resulting solid was washed with water to afford (E)-methyl 3-(3-nitrophenyl)acrylate as a yellow solid (20.14 g, 98%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[N:28]=2)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:25]2[CH:26]=[CH:21][CH:22]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[N:28]=3)[CH:24]=2)=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(B(O)O)ccc1OCc1ccccc1
Reactant: FC(F)(F)c1cccc(-c2cccc(Br)c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc(-c2cccc(-c3cccc(C(F)(F)F)n3)c2)ccc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-benzyloxy-3-methoxyphenylboronic acid (1.0 g, 3.87 mmol) and 2-(3-bromophenyl)-6-(trifluoromethyl)pyridine (1.063 g, 3.52 mmol) in toluene (10 mL) and ethanol (1 mL) at room temperature under argon was added 2 N aqueous sodium carbonate solution (5.41 mL, 10.82 mmol) followed by tetrakis(triphenylphosphine)palladium (0.22 g, 0.19 mmol). The resulting mixture was stirred at 90° C. for two hours and then allowed to cool to room temperature. The phases were separated and the aqueous phase was extracted with toluene (5 mL). The combined organic phases were washed with water and brine, then dried over anhydrous sodium sulphate and filtered. Evaporation of the solvent left a brown oil that was chromatographed over silica gel (petroleum ether/ethyl acetate, 9:1) to give 2-(4′-(benzyloxy)-3′-methoxybiphenyl-3-yl)-6-(trifluoromethyl)pyridine as a clear oil, 1.072 g (70%).
Reaction SMILES: C[Al](C)C.C1(C)C=CC=CC=1.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16].C([O:20][C:21]([C:23]1[N:24]=[C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:35]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=4)=[N:34][N:33]4[CH2:43][CH2:44][CH2:45][C:32]=34)=[CH:27][N:26]2[CH:46]=1)=O)C>ClCCl>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH:16][C:21]([C:23]1[N:24]=[C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:35]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=4)=[N:34][N:33]4[CH2:43][CH2:44][CH2:45][C:32]=34)=[CH:27][N:26]2[CH:46]=1)=[O:20]
Reactant: CCOC(=O)c1cn2cc(-c3c(-c4cccc(C)n4)nn4c3CCC4)ccc2n1
Reactant: CN(C)CCN
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2nn3c(c2-c2ccc4nc(C(=O)NCCN(C)C)cn4c2)CCC3)n1
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
Add 2M trimethylaluminum in toluene (0.38 mL, 0.38 mmol) to a solution of N,N-dimethylethylenediamine (0.034 g, 0.38 mmol) in dichloromethane (20 mL). Stir for 20 min and transfer via cannula to a solution of 6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (0.1 g, 0.26 mmol) in dichloromethane (20 mL). Heat at 45° C. and stir for 1.5 h. Add saturated aqueous sodium bicarbonate and extract into dichloromethane. Reversed phase chromatography gives the titled compound (0.067 g, 60%) as a white solid. MS ES+ m/e 430.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[C:10]([C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[CH:21][N:22]([CH3:24])[CH3:23]
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(CC(=O)c2ccc(Cl)cc2Cl)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=CN(C)C)C(=O)c2ccc(Cl)cc2Cl)cc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To a solution of the ketone product from Step A (11.79 g; 42.4 mmol) in DMF (150 mL) in an oven-dried round bottom flask was added N,N-dimethylformamide dimethyl acetal (22.5 mL; 169 mmol) under a nitrogen atmosphere. The reaction was stirred at 75° C. for 16 hours. Most of the volatiles were removed in vacuo to afford the crude product as a oil which was used in the next step without further purification.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=3)[C:13](=[O:23])[O:12][N:11]=2)=[N:7][O:8][N:9]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][C:5]1[C:6]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=3)[C:13](=[O:23])[O:12][N:11]=2)=[N:7][O:8][N:9]=1
Reactant: [N-]=[N+]=NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
3-[4-(Azidomethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (225 mg, 0.66 mmol) was dissolved in anhydrous THF (5.6 mL) and water (5.6 mL). The reaction was cooled to 0° C. followed by addition of triphenylphosphine (192 mg, 0.73 mmol). The reaction was allowed to warm to rt and was stirred overnight. The reaction was stripped to dryness, azeotroped with toluene and redissolved in MeOH. The crude residue was purified by preparative LCMS to yield the desired product (200 mg, 96%). MF=C11H7ClFN5O3; LCMS calculated for C11H8ClFN5O3(M+H)+: m/z=312.030.