Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.[CH3:8][O:9][C:10]1[C:11](=[O:26])[CH:12]=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:15]=1.[C:27](#[N:29])[CH3:28]>O>[N:29]1[C:19]2[C:18](=[CH:17][CH:16]=[CH:21][CH:20]=2)[CH:22]=[CH:28][C:27]=1[CH2:8][O:9][C:10]1[C:11](=[O:26])[CH:12]=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)[CH:15]=1
Reactant: CC#N
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)ncc1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: O=c1cnn(-c2cccc(C(F)(F)F)c2)cc1OCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Sodium iodide (0.2772 g) and chlorotrimethylsilane (0.235 mL) were stirred in acetonitrile (1.85 mL) at room temperature for 30 min. A solution of 5-methoxy-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.100 g) in acetonitrile (3.7 mL) was added at room temperature. The reaction mixture was heated under reflux for 3 hr. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated, purified by silica gel column chromatography (ethyl acetate/hexane-methanol/ethyl acetate), and concentrated under reduced pressure. The obtained residue, potassium carbonate (0.1125 g) and 2-(chloromethyl)quinoline hydrochloride (0.0871 g) were suspended in N,N-dimethylformamide (2 mL), and the mixture was stirred at room temperature for 14 hr, and at 60° C. for 5 hr. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The residue was purified by NH silica gel column chromatography (ethyl acetate/hexane), silica gel column chromatography (ethyl acetate/hexane) and HPLC, and recrystallized from ethyl acetate/hexane to give the title compound (0.0527 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][N:3]=1.[CH2:10]1[CH2:12][CH:11]1[CH2:13][NH2:14]>>[CH:11]1([CH2:13][N:14]=[CH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)[CH2:12][CH2:10]1
Reactant: NCC1CC1
Reactant: Nc1nccc(C=O)n1
Product: Nc1nccc(C=NCC2CC2)n1

Procedure:
2-Aminopyrimidine-4-carboxaldehyde and 2-cyclopropylmethyl amine were reacted by the procedure of example 1(c) to afford the title compound as a yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N:15]2[C:19]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[S:26](=[O:29])(=[O:28])[CH2:27][C:18]=3[C:17]([C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:31])=[N:16]2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[N:32]1([C:30]([C:17]2[C:18]3[CH2:27][S:26](=[O:28])(=[O:29])[C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:19]=3[N:15]([C:11]3[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=3)[N:16]=2)=[O:31])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: [H][H]
Reactant: O=C(c1nn(-c2cccc(OCc3ccccc3)c2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: O=C(c1nn(-c2cccc(O)c2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Yield: 7.4 %

Procedure:
To a solution 1-[3-(benzyloxy)phenyl]-3-(morpholin-4-ylcarbonyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (8 g, 155 mmol) in MeOH (500 mL) is added 10% Pd/C (0.5 g) and the reaction mixture is hydrogenated at 12 Kg/cm2 pressure of hydrogen at RT for 20 h in Autoclave. The catalyst is filtered through celite and filtrate is concentrated to afford 4.9 g (89%) of the title compound as a brown solid. 1H NMR (DMSO-d6, 400 MHz): δ 10.08 (s, 1H), 8.02-8.00 (dd, J=2.4, 3.2 Hz, 1H), 7.65-7.59 (m, 2H), 7.42-7.38 (t, J=8.0 Hz, 1H), 7.01-6.99 (t, J=8.4 Hz, 1H), 6.93-6.88 (m, 3H), 4.88 (s, 2H), 3.95 (m, 2H), 3.66-3.61 (m, 4H), 3.56 (s, 2H). MS (ESI+): 426.0. HPLC (max plot): 96%; Rt 3.25 min.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:42]=[CH:41][C:13]([O:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][C@H:30]([NH:34]C(C(C)(C)C)=O)[C:31]([OH:33])=[O:32])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:34][C@@H:30]([CH2:29][CH2:28][O:27][C:21]1[CH:20]=[C:19]2[C:24]([C:15]([O:14][C:13]3[CH:41]=[CH:42][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:11][CH:12]=3)=[CH:16][CH:17]=[N:18]2)=[CH:23][C:22]=1[O:25][CH3:26])[C:31]([OH:33])=[O:32]
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ccnc2cc1OCC[C@H](NC(=O)C(C)(C)C)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ccnc2cc1OCC[C@H](N)C(=O)O
Reaction time: 6 h
Yield: 111.9 %

Procedure:
To a solution of (S)-4-[4-(4-benzoylamino-phenoxy)-6-methoxy-quinolin-7-yloxy]-2-tert-butylcarbonylamino-butyric acid (6.5 mg, 0.011 mmol) in DCM (1 ml) was added TFA (1 ml). The reaction was allowed to stir for 6 hours and then evaporated under reduced pressure to afford the title compound as an off-white solid (6.0 mg, 90% yield).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C([O-])([O-])=O.[K+].[K+].[I:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>CN(C=O)C.O>[I:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])=[CH:21][CH:20]=1
Reactant: BrCc1ccc(I)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(I)cc1
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 48.2 %

Procedure:
To a stirred solution of phthalimide (0.6 g, 4.0 mmol) in DMF (5 ml) was added K2CO3 (2.25 g, 16.00 mmol), followed by 4-iodobenzyl bromide (1.33 g, 4.4 mmol) at 0° C. and the reaction mixture was stirred at 20-35° C. for 16 h. The progress of the reaction was monitored by TLC. After 16 h of stirring, the mixture was diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (50 ml), followed by drying over anhydrous Na2SO4 and filtering. The filtrate was rotary evaporated to get residue which was washed with diethyl ether to get the desired compound as a white solid (700 mg, 50%). 1H NMR (400 MHz, DMSO-d6) δ 7.91-7.84 (m, 4H), 7.70-7.66 (m, 2H), 7.12 (d, J=8.3 Hz, 2H), 4.72 (s, 2H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]([OH:9])=[O:8])[C@@H:4]([CH3:6])[OH:5].[CH2:10](O)[CH3:11]>>[CH2:10]([O:8][C:7](=[O:9])[C@H:3]([C@@H:4]([CH3:6])[OH:5])[NH2:2])[CH3:11]
Reactant: CCO
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Agent: Cl
Product: CCOC(=O)[C@@H](N)[C@@H](C)O

Procedure:
A current of dry HCl was passed through a suspension of L-threonine (35.0 g, 0.29 mol) in absolute ethanol (350 ml), with shaking, until a clear solution formed. The solution then refluxed for 30 minutes, and was evaporated to dryness under reduced pressure, and the oily residue was taken up in absolute ethanol (175 mL) and, again, taken to dryness under reduced pressure. The oily residue was then treated with a saturated solution of ammonia in chloroform. The ammonium chloride was filtered off and the filtrate was taken to dryness at 0° C. under reduced pressure. A yellow solid was isolated (36.2 g. 85%); [α]29Na+0.82° (c 5.0, EtOH). Lit.12 [α]29D+0.95° (C 5.0 EtOH); m.p. 51-53° C. (Lit12 52-54° C.); 1H NMR (200 MHz, CDCl3 w/TMS) δ 4.82 (1H.m), 4.40 (1H,d), 4.05 (2H,q), 1.62 (3H,d), 1.21 (3H;t); FABMS 148.2 (M+H); HRFABMS Calcd for C6H14NO3 (M+H) 148-0974, found 148.0972.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][C:13]3[C:16]([CH:22]=[O:23])=[C:17]([OH:21])[CH:18]=[C:19]([CH3:20])[C:12]=3[C:11](=[O:24])[O:10][C:9]=2[C:8]([CH3:25])=[C:7]([OH:26])[CH:6]=1)=[O:4].[C:27]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][C:13]3[C:16]([CH:22]=[O:23])=[C:17]([OH:21])[CH:18]=[C:19]([CH3:20])[C:12]=3[C:11](=[O:24])[O:10][C:9]=2[C:8]([CH3:25])=[C:7]([O:26][CH3:27])[CH:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)c(C)c2c1Oc1c(C=O)c(O)cc(C)c1C(=O)O2
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(OC)c(C)c2c1Oc1c(C=O)c(O)cc(C)c1C(=O)O2
Yield: 84 %

Procedure:
1 mmol of 4-Formyl-3,8-dihydroxy-1,9-dimethyl-11-oxo-11H-dibenzo[b,e][1,4]dioxepine-6-carboxylic acid methyl ester was dissolved in 3 mL of acetone, 1 mmol K2CO3 was added and stirred for several minutes. Then, 1 mmol of CH3I in acetone was added from a pressure-equalizing dropping funnel. The reaction mixture was monitored by TLC. Upon completion, the reaction mixture was filtered to remove K2CO3 and evaporated by a rotatory evaporator to remove acetone. The residue was purified by column chromatography to give 4-formyl-3-hydroxy-8-methoxy-1,9-dimethyl-11-oxo-11H-dibenzo[b,e][1,4]dioxepine-6-carboxylic acid methyl ester (84%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C[O:20][C:21](=O)[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([N:29]2[CH:33]=[C:32]([C:34]3[CH:35]=[N:36][N:37]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:38]=3[CH2:39][CH3:40])[N:31]=[CH:30]2)[CH:23]=1>>[CH2:39]([C:38]1[N:37]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:36]=[CH:35][C:34]=1[C:32]1[N:31]=[CH:30][N:29]([C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=2[CH3:28])[C:21]([NH:1][C:2]2[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:3]=2[O:17][CH3:18])=[O:20])[CH:33]=1)[CH3:40]
Reactant: COc1c(N)cc(C(F)(F)F)cc1NS(C)(=O)=O
Reactant: CCc1c(-c2cn(-c3cc(C(=O)OC)ccc3C)cn2)cnn1-c1ccccc1
Product: CCc1c(-c2cn(-c3cc(C(=O)Nc4cc(C(F)(F)F)cc(NS(C)(=O)=O)c4OC)ccc3C)cn2)cnn1-c1ccccc1

Procedure:
Example 159 was prepared from N-(3-amino-2-methoxy-5-trifluoromethyl-phenyl)-methanesulfonamide and 3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (Example 151) in the same manner as Example 151. ESI MS m/z 639 [C31H29F3N6O4S+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CCCc2cc(OCCCCl)ccc21

Procedure:
In a 500 mL round bottom flask, 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (10 g, 61.0 mmol), 1-bromo-3-chloro-propane (9.6 g, 61.0 mmol), and potassium carbonate (9.3 g, 67.1 mmol) in acetonitrile (300 mL) was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. The slurry was partitioned between methylene chloride and water, separated, dried over MgSO4. Purification with silica gel chromatography eluting with hexanes/ethyl acetate (3:1) produced 10.6 g (73%). Mp 85-87° C. MS m/z 239 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][CH3:12])[CH:8]=[CH:7][C:6]=1I.[Br:16][C:17]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([F:25])[C:18]=1[NH2:19]>>[CH3:1][N:2]([CH3:15])[C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][CH3:12])[CH:8]=[CH:7][C:6]=1[NH:19][C:18]1[C:20]([F:25])=[CH:21][C:22]([Cl:24])=[CH:23][C:17]=1[Br:16]
Reactant: Nc1c(F)cc(Cl)cc1Br
Reactant: CCc1ccc(I)c(CC(=O)N(C)C)c1
Product: CCc1ccc(Nc2c(F)cc(Cl)cc2Br)c(CC(=O)N(C)C)c1

Procedure:
Ullmann condensation of N,N-dimethyl-5-ethyl-2-iodo-phenylacetamide with 2-bromo-4-chloro-6-fluoroaniline according to the procedure described in Example 1 yields N,N-dimethyl-5-ethyl-2-(2′-bromo-4′-chloro-6′-fluoroanilino)phenylacetamide.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[N:17]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][N:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:6]2=[N:7][CH:8]=[CH:9][C:5]2=[C:4]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:23]([C:20]3[CH:21]=[CH:22][N:17]=[N:18][CH:19]=3)=[O:24])[CH2:14][CH2:15]2)[N:3]=[CH:2]1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Reactant: O=C(O)c1ccnnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCN(c2nc[nH]c3nccc2-3)CC1)c1ccnnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (100 mg), 4-pyridazinecarboxylic acid (57.1 mg, 0.460 mmol), HATU (210 mg, 0.552 mmol) and HOAt (37.60 mg, 0.276 mmol) in DMF (2.3 mL) was added DIPEA (386 μL, 2.209 mmol). The reaction mixture was stirred at room temperature for 2 hours then the solvent was removed in vacuo. The crude mixture was purified by MDAP using a formic acid method to afford E13 (44 mg), 1H NMR (d6-DMSO) δ 11.70 (1H, brs), 9.55 (1H, s), 9.42 (1H, d), 8.80 (1H, d), 8.17 (1H, s), 8.0 (1H, d), 7.20 (1H, d), 6.60 (1H, d), 4.70 (2H, dt), 4.15 (1H, m), 3.25 (2H, dt), 1.90 (2H, m), 1.60 (2H, m), MS(ES+) 324 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17].[CH3:20][C:21]([CH3:25])=[CH:22]CO.C[O-].[Na+]>>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH:20]=[C:21]([CH3:25])[CH3:22])=[O:17]
Reactant: CC(C)=CCO
Reactant: COC(=O)c1cnn(-c2c(Cl)cc(Cl)cc2Cl)c1N
Agent: C[O-]
Agent: [Na+]
Product: CC(C)=CCOC(=O)c1cnn(-c2c(Cl)cc(Cl)cc2Cl)c1N

Procedure:
12.0 parts by weight of methyl 5-amino-1-(2,4,6-trichlorophenyl)-pyrazole-4-carboxylate, 24.0 parts by weight of 3-methylbut-2-enol and 0.5 parts by weight of sodium methylate were refluxed for 2 hours (complete conversion), while dry nitrogen was passed over. The excess alcohol was removed under a reduced pressure of from 0.5 to 1.0 mbar/50° C., and the residue was dissolved in 100 ml of ether and precipitated with dry hydrogen chloride gas. The hydrochloride was filtered off with suction and stirred with saturated sodium bicarbonate solution, and the precipitate was filtered off with suction and dried under reduced pressure at 50° C. to give 10.6 g of 3-methylbut-2-enyl 5-amino-1-(2,4,6-trichlorophenyl)-pyrazole-4-carboxylate of melting point 102°-105° C. (active ingredient No.10).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]([OH:9])=O)=[N:4][NH:5][CH:6]=1.Cl.Cl.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:27])[CH2:20][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:3]([C:7]([N:24]2[CH2:23][CH2:22][N:21]([CH2:20][C:19]([C:16]3[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=3)=[O:27])[CH2:26][CH2:25]2)=[O:9])=[N:4][NH:5][CH:6]=1
Reactant: O=C(O)c1n[nH]cc1Cl
Reactant: O=C(CN1CCNCC1)c1ccc(F)cc1
Agent: Cl
Product: O=C(CN1CCN(C(=O)c2n[nH]cc2Cl)CC1)c1ccc(F)cc1
Yield: 65.3 %

Procedure:
The title compound was prepared in a similar manner as described in Example 1.2, using 4-chloro-1H-pyrazole-3-carboxylic acid (22.0 mg), and 1-(4-fluorophenyl)-2-(piperazin-1-yl)ethanone dihydrochloride (29.5 mg) as starting materials, to afford the title compound (22.9 mg) as a white solid. Exact mass calculated for C16H16ClFN4O2: 350.1. Found: LCMS m/z (%)=351.3 (M+H+35Cl, 100%), 353.3 (M+H+37Cl, 32%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](=[O:17])N(OC)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][Mg]Br>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12](=[O:17])[CH3:18])[CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Product: CC(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
To a solution of 3-(methoxy-methyl-carbamoyl)-azetidine-1-carboxylic acid tert-butyl ester (6.0 g, 24.56 mmol) in THF (15 mL) at −78° C. was added a solution of methymagnesium bromide (3M in toluene, 12.3 mL, 36.9 mmol). The reaction mixture was stirred at −78° C. for 1 h. The reaction mixture was warmed to ambient temperature gradually and stirred for 1 h. The reaction was quenched by the addition of aqueous KHSO4 solution (20 mL). The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether) to give 3-acetyl-azetidine-1-carboxylic acid tert-butyl ester (3.2 g, 65.4%). 1H NMR (DMSO-d6, 400 MHz): δ 3.88 (m, 4H), 3.53 (m, 1H), 2.08 (s, 3H), 1.34 (s, 9H).
Reaction SMILES: C(O[C:4]1[C:5](=[O:20])[C:6](=[O:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18])C.[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].C(OC(=O)C)C>CS(C)=O>[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:4]1[C:5](=[O:20])[C:6](=[O:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18]
Reactant: Nc1ccccc1Cl
Reactant: CCOc1c(Nc2ccc([N+](=O)[O-])cc2O)c(=O)c1=O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=c1c(Nc2ccc([N+](=O)[O-])cc2O)c(Nc2ccccc2Cl)c1=O
Temperature: 25 °C
Yield: 41.2 %

Procedure:
A solution of 3-ethoxy-4-(2-Hydroxy-4-nitroanilino)-3-cyclobutene-1,2-dione (0.38 g, 1.37 mmol) and 2-chloroaniline (0.23 mL, 2.2 mmol) in 2 mL DMSO was heated at 110° C. for overnight. The reaction mixture was cooled to room temperature, and ethylacetate was added, and a precipitate formed. The filtrate was partitioned between ethylacetate and water. The organic layer was dried over sodium sulfate and concentrated. Recrystalized from ethylacetate and hexanes, 203 mg (41%) of 3-(2-chloroanilino)-4-(2-Hydroxy-4-nitroanilino)-3-cyclobutene-1,2-dione was obtained. LCMS(H+) 360.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][NH2:9].[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2O[C:26]([C:29]34[CH2:36][CH2:35][C:32]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)([CH2:33][CH2:34]3)[CH2:31][CH2:30]4)=[N:27][N:28]=2)=[C:20]([C:43]([F:46])([F:45])[F:44])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CO>>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:9]([CH3:8])[C:26]([C:29]34[CH2:36][CH2:35][C:32]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)([CH2:31][CH2:30]3)[CH2:33][CH2:34]4)=[N:27][N:28]=2)=[C:20]([C:43]([F:44])([F:45])[F:46])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN
Reactant: FC(F)(F)c1cc(OCc2ccccc2)ccc1-c1nnc(C23CCC(c4ccccc4)(CC2)CC3)o1
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Product: Cn1c(-c2ccc(OCc3ccccc3)cc2C(F)(F)F)nnc1C12CCC(c3ccccc3)(CC1)CC2
Temperature: 150 °C

Procedure:
The trifluoroacetate salt of methylamine (380 mg, 2.61 mmol) and 2-[4-(benzyloxy)-2-(trifluoromethyl)phenyl]-5-(4-phenylbicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole (8-D) were suspended in a 2 M solution of methylamine in methanol (1.3 mL, 2.61 mmol) and heated at 150° C. overnight. After being cooled to room temperature, the reaction mixture was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate (30 mL). The layers were separated and the aqueous layer extracted with twice with ethyl acetate (25 mL). The combined organic layers were washed with brine, dried (MgSO4), and solvent removed in vacuo. The residue was then dissolved in methanol (8 mL) and purified by reverse phase chromatography using gradient elution with 10% acetonitrile (0.1% TFA) /water (0.1% TFA) to 100% acetonitrile (0.1% TFA) over 10 min (20 mL/min). The fractions containing product were partitioned between saturated aqueous sodium bicarbonate (25 mL) and methylene chloride (15 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (15 mL) three times, dried (MgSO4), and the solvent removed in vacuo to afford 3-[4-(benzyloxy)-2-(trifluoromethyl)phenyl]-4-methyl-5-(4-phenylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazole (8-E). MS: m/z 518 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][NH:11][C:6]=2[CH:5]=[C:4]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].N#N.[CH2:29](Br)[CH:30]=[CH2:31]>CN(C=O)C.O>[CH2:31]([N:11]1[CH2:10][CH2:9][O:8][C:7]2[C:2]([F:1])=[CH:3][C:4]([B:12]3[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]3)=[CH:5][C:6]1=2)[CH:30]=[CH2:29]
Reactant: CC1(C)OB(c2cc(F)c3c(c2)NCCO3)OC1(C)C
Reactant: C=CCBr
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1CCOc2c(F)cc(B3OC(C)(C)C(C)(C)O3)cc21
Temperature: 70 °C
Yield: 76.9 %

Procedure:
A solution of 8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.507 g, 1.613 mmol, Ref. WO20100130034) and K2CO3 (0.512 g, 3.70 mmol) in dry DMF (5 mL) was sparged with N2 for 5 min, then treated with allyl bromide (0.8 mL, 9.17 mmol). The reaction tube was sealed and then heated (70° C.) for 22 h. The reaction was cooled then diluted with water (50 mL) and extracted into EtOAc (50 mL). The organic layer was then washed with water, brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by biotage column chromatography (12 g SiO2, 0% (3 CV); 0-40% (15 CV), 40% (2 CV), EtOAc in hexanes) to afford the desired product (0.396 g, 1.241 mmol, 77% yield) as a clear viscous oil. 1H NMR (500 MHz, CDCl3) δ 6.96-7.01 (m, 2H), 5.84-5.95 (m, 1H), 5.21-5.32 (m, 2H), 4.32-4.38 (m, 2H), 3.94 (d, J=5.8 Hz, 2H), 3.30-3.37 (m, 2H), 1.32 (s, 12H). LCMS (M+H)=320.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH2:12][CH2:13][CH3:14])=[C:6]2[CH:15]=O.[C:17]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)(=[O:19])[CH3:18].N1CCCCC1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH2:12][CH2:13][CH3:14])=[C:6]2/[CH:15]=[CH:18]/[C:17]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: CCCc1[nH]c2ccc(OC)cc2c1C=O
Reactant: CC(=O)c1ccncc1
Solvent: CO
Solvent: C1CCNCC1
Product: CCCc1[nH]c2ccc(OC)cc2c1/C=C/C(=O)c1ccncc1
Temperature: 40 °C
Yield: 85.8 %

Procedure:
5-Methoxy-2-propylindole-3-carboxaldehyde (200 mg, 0.92 mmol) was dissolved in anhydrous methanol (7.5 mL) under an atmosphere of Argon (g). 4-Acetylpyridine (167.17 mg, 1.38 mmol) and piperidine (117.5 mg, 1.38 mmol) were added to the reaction mixture and the solution was refluxed for 24 hours. A precipitate slowly formed which was collected, washed with cold MeOH (30 mL) and dried overnight in an oil driven vacuum pump equipped to a vacuum desiccator heated to 40° C. to yield a bright yellow powder (253 mg, 85%): TLC Rf 0.43 in 4:1 ethyl acetate/hexanes. Melting point=221-224° C. 1H NMR (600 MHz, d6-DMSO) δ 11.87 (s, 1H), 8.82-8.82 (m, 2H), 8.10-8.07 (d, 1H, J=15.24 Hz), 7.94-7.93 (m, 2H), 7.46-7.45 (d, 1H, J=2.34), 7.40-7.37 (d, 1H, J=15.24 Hz), 7.34-7.32 (d, 1H, J=8.7 Hz), 6.87-6.86 (dd, 1H, J1=2.4 Hz, J2=8.7 Hz), 3.87 (s, 3H), 2.92-2.89 (t, 2H, J=7.44 Hz) 1.74-1.70 (m, 2H) 0.95-0.92 (t, 3H, J=14.7 Hz); 13C NMR (150 MHz, d6-DMSO) δ 188.0, 155.1, 150.5, 149.7, 145.0, 139.4, 131.1, 126.2, 121.3, 112.8, 112.3, 111.0, 109.0, 103.7, 55.5, 27.6, 22.8, 13.5. Elemental analysis calculated for C20H20N2O2: C, 74.98; H, 6.29; N, 8.74. Found: C, 75.05; H, 6.32; N, 8.70.