Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([CH:28]([CH3:30])[CH3:29])/[CH:4]=[CH:5]/[C@H:6]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@H:23]([OH:25])[CH2:24][C:19]4=[CH:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH3:7].S([C:35]1C=CC(C)=CC=1)([O-])(=O)=O.C([O-])(=O)C.[K+]>CO>[CH3:1][CH2:2][C@H:3]([CH:28]([CH3:29])[CH3:30])/[CH:4]=[CH:5]/[C@H:6]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][CH:23]([O:25][CH3:35])[CH2:24][C:19]4=[CH:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH3:7]
Reactant: CC[C@H](/C=C/[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: CC[C@@H](/C=C/[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4CC(OC)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Yield: 97.6 %

Procedure:
A suspension of stigmasterol tosylate (2) (64 g, 112.9 mmol) and potassium acetate (70 g, 713.19 mmol) in anhydrous methanol (1500 mL) was refluxed for 4.5 h under argon atmosphere. The methanol was evaporated in vacuo, and then ether (2 L) was added, washed with water (500 mL), 5% NaHCO3 (2×400 mL) and brine (400 mL) and dried (MgSO4). The solvent was evaporated in vacuo to afford 47 g (92%) of stigmasterol methyl ether (3) as a pale yellow viscous liquid.
Reaction SMILES: C[Al](C)C.C[Si]([N:9]=[N+:10]=[N-:11])(C)C.[C:12]([C:14]1[CH:15]=[C:16]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=3)[N:22]=2)[CH:17]=[C:18]([F:20])[CH:19]=1)#[N:13]>C1(C)C=CC=CC=1>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]2[N:22]=[C:21]([C:16]3[CH:15]=[C:14]([C:12]4[NH:13][N:11]=[N:10][N:9]=4)[CH:19]=[C:18]([F:20])[CH:17]=3)[O:25][N:24]=2)=[N:27][CH:28]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1cc(F)cc(-c2nc(-c3ccc(F)cn3)no2)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2noc(-c3cc(F)cc(-c4nnn[nH]4)c3)n2)nc1
Temperature: 80 °C
Yield: 36 %

Procedure:
To a mixture of 2 M trimethylaluminum (0.45 mL, 0.9 mmole, toluene) with toluene (1 mL) at 10° C., trimethylsilyl azide (0.119 mL, 0.9 mmole) was added, followed by the addition of 5-(3-cyano-5-fluorophenyl)-3-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazole. The reaction was heated at 80° C. for 2 hours and then quenched with 6 N hydrochloride (2 mL) and solid was collected by filtration. The product was recrystallized with dimethylformamide to give 59 mg (36%) of 3-(5-fluoro-pyrid-2-yl)-5-[3-fluoro-5-(1H-tetraazol-5-yl)-phenyl]-1,2,4-oxadiazole. 1H-NMR (DMSO-d 6), δ (ppm): 8.83 (d, 1H), 8.70 (s, 1H), 8.31 (m, 1H), 8.10 (m, 2H), 8.04 (dt, 1H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[CH2:15]Br>>[CH2:3]([N:2]([CH3:1])[CH2:15][C:14]1[CH:17]=[CH:18][C:19]([N+:20]([O-:22])=[O:21])=[C:12]([O:11][CH3:10])[CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1ccccc1
Reactant: COc1cc(CBr)ccc1[N+](=O)[O-]
Product: COc1cc(CN(C)Cc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
A solution of N-methyl-benzyl amine was alkylated with 3-methoxy-4-nitro-benzyl bromide as described above for compound 338. 1H NMR (400 MHz, CDCl3): δ7.83 (d, J=8.6 Hz, 1H), 7.35 (s, 4H), 7.26 (s, 1H), 7.17 (s, 1H), 7.01 (d, J=7.04 Hz, 1H), 3.97 (s, 3H), 3.55 (s, 4H), 2.22 (s, 3H).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.C([O:23][C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH2:30]Br)=[CH:26][C:25]=1[F:34])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[OH:23][C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH2:30][N:11]2[CH2:12][CH2:13][CH:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([CH3:2])=[CH:15][CH:14]=3)[CH2:9][CH2:10]2)=[CH:26][C:25]=1[F:34]
Reactant: Cc1ccc(CC2CCNCC2)cc1
Reactant: Fc1cc(OCCBr)ccc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(CC2CCN(CCOc3ccc(O)c(F)c3)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-methylbenzyl)piperidine hydrochloride (347 mg, 1.54 mmol), 2-(4-benzoxy-3-fluorophenoxy)ethyl bromide (499 mg, 1.54 mmol) and potassium carbonate (531 mg, 3.85 mmol) in two steps as white-off solid (272 mg): mp 148-150° C. 1H NMR (CD3OD) 1.38 (m, 2 H), 1.699 (m, 3 H), 2.100 (s, 3 H), 2.375(d, J=6.3 Hz, 2 H), 2.834 (m, 2 H), 3.307 (m, 2 H), 3.427 (d, J=11.7 Hz, 2 H), 4.078 (t, J=4.8 Hz, 2 H), 6.48 (m, 1 H), 6.638 (m, 2 H), 6.844 (m, 4 H). Anal. Calcd for C21H27ClFNO2.0.3H2O: C, 65.45; H, 7.22; N, 3.64. Found: C, 65.54; H, 7.15; N, 3.60.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[C:34](Cl)[N:33]=[CH:32][N:31]=1.C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[C:34]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([S:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=4)[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:33]=[CH:32][N:31]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: COc1cccc(Sc2ccn3nc([C@H](C)N)n(-c4ccccc4)c(=O)c23)c1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(Sc2ccn3nc([C@H](C)Nc4ncnc(N)c4C#N)n(-c4ccccc4)c(=O)c23)c1
Yield: 57.1 %

Procedure:
(S)-2-(1-Aminoethyl)-5-((3-methoxyphenyl)thio)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (103 mg, 0.24 mmol) was treated with 4-amino-6-chloropyrimidine-5-carbonitrile (55 mg, 0.36 mmol),), N,N-diisopropylethylamine (126 μl, 0.72 mmol) and tert-butanol as a solvent according to the method described in Example 17. The crude was purified by reverse phase using SP1® Purification to give 70 mg (57% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([CH3:20])[C:17]([C:21]([O:23]CC)=[O:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O>CCO>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([CH3:20])[C:17]([C:21]([OH:23])=[O:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(N2CCN(Cc3ccccc3)CC2)ncc1C(=O)O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Added to a 1 l flask were 40 g (0.128 mol) of the ethyl 2-(4-benzylpiperazino)-4-methylpyrimidine-5-carboxylate, 11 g of KOH, 200 ml of H2O and 500 ml of EtOH. The contents were stirred at 100° C. for 0.5 hr. Thereafter, the solvent was distilled off under reduced pressure. One liter of H2O was then added to the residue and the resulting mixture was adjusted to pH 4 with conc. hydrochloric acid. The precipitated crystals were filtered off and the filtrate was dried under reduced pressure, thereby obtaining 36 g of the intended compound as a white solid substance (yield: 98%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>>[CH3:14][S:15]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:17])=[O:16]
Reactant: Cc1ccc(CCOCCO)cc1
Reactant: CS(=O)(=O)Cl
Product: Cc1ccc(CCOCCOS(C)(=O)=O)cc1
Yield: 83 %

Procedure:
The 2-[2-(4-methylphenyl)ethoxy]ethanol obtained according to the preceding paragraph was sulfonylated with methanesulfonyl chloride in a manner analogous to that described in Example 1(c) to give 7.8 g (83%) of 2-[2-(4-methylphenyl)ethoxy]ethyl methanesulfonate in the form of an oil which was homogeneous according to chromatography.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C:15](=[O:16])[C@H:14]2[CH2:17][C@:11]([OH:19])([C:12](=[O:18])[O:13]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH2:20].N1[CH:26]=[CH:25]C=CC=1>C(OC(=O)C)(=O)C.CCCCCC.C(OCC)(=O)C>[C:25]([O:19][C@@:11]12[CH2:17][C@@H:14]([O:13][C:12]1=[O:18])[C:15](=[O:16])[C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10]2)(=[O:20])[CH3:26]
Reactant: c1ccncc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@]2(O)C[C@@H](OC2=O)C1=O
Reactant: O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: CCCCCC
Product: CC(=O)O[C@@]12C[C@@H](OC1=O)C(=O)[C@H](O[Si](C)(C)C(C)(C)C)C2
Yield: 81 %

Procedure:
A solution of hydroxy ketone 3 (1.64 g, 5.8 mmol) in anhydrous pyridine (12 mL) and acetic anhydride (5.5 mL) was stirred for 3 hours at room temperature. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3, saturated CuSO4 and water, dried (MgSO4), and evaporated to give an oily residue which was dissolved in hexane/ethyl acetate (8:2) and filtered through short path of silica gel. Evaporation of solvents gave pure crystalline acetate 4 (1.51 g, 81%). Analytical sample was obtained by recrystallization from hexane/ethyl acetate. 4: m.p. 134-7° C.; [α]24D−78° (c 1.00 CHCl3); 1H NMR (400 MHz, CDCl3) δ0.046 and 0.141 (3H and 3H, each s, 2×SiCH3), 0.901 (9H, s, Si-t-Bu), 2.17 (3H, s, CH3CO), 2.28 (1H, dd, J=12.2, 10.4 Hz, 2α-H), 2.32 (1H, d, J=12.1 Hz, 8α-H), 2.65 (1H, ddd, J=12.2, 8.8, 3.9 Hz, 2β-H), 3.56 (1H, ddd ,J=12.1, 6.9, 3.9 Hz, 8β-H), 4.58 (1H, dd, J=10.4, 8.8 Hz, 3β-H), 4.80 (1H, d, J=6.9 Hz, 5α-H); 13C NMR (125 MHz) δ−5.8 (Si—CH3), −4.9 (Si—CH3), 18.2 [C(CH3)3], 20.9 (CH3—C═O), 25.6 [C(CH3)3], 38.3 (C8), 40.3 (C2), 70.4 (C3), 75.3 (C1), 78.4 (C5), 169.1 (CH3—C═O), 171.5 (C═O), 201.8 (C4); MS (EI) m/z (relative intensity) 328 (M+, 6), 271 (100), 256 (38), 229 (54), 211 (53); HRMS (ESI) exact mass calcd for C11H15O6Si (M+−t-Bu) 271.0638, measured 271.0646; Anal. Calcd for C15H24O6Si: C, 54.86, H, 7.37. Found: C, 54.88, H, 7.37.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)(O)=[O:2].CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([Cl:20])=[O:2])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1ccc(C(=O)Cl)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 4-carboxybenzaldehyde (4.50 g, 30 mmol) in CHCl3 (6 mL) and DCM (5 mL), containing a catalytic amount of DMF, was added oxalyl chloride (7.7 mL, 90 mmol). The mixture was stirred at 50° C. for 3 hours. The reaction was concentrated in vacuo and the residue was dried.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH2:3][C:4]#N.[OH-:17].[K+].C(O)C([OH:22])C>O>[CH3:1][CH:2]([CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH2:3][C:4]([OH:22])=[O:17]
Reactant: [OH-]
Reactant: CC(O)CO
Reactant: CC(C)=CCC/C(C)=C/CCC(C)CC#N
Agent: [K+]
Solvent: O
Product: CC(C)=CCC/C(C)=C/CCC(C)CC(=O)O
Temperature: 130 °C
Reaction time: 7 h

Procedure:
To 40 g of the compound obtained in step (b) above were added 35 g of potassium hydroxide, 15 ml of water and 80 ml of propylene glycol, and the mixture was stirred at 130° C. for 7 hours. The extract was washed with water and dried, then the solvent was removed by distillation and then the residue was purified by column chromatography using silica gel to obtain 36 g of the intended compound in the form of an oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)[NH2:4].[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[C:24]([C:28](O)=[O:29])[NH:25]2)=[CH:21][C:20]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.O>[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[C:24]([C:28](=[O:29])[NH:4][CH:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([F:13])([F:14])[F:15])[CH:6]=3)[C:2]([F:1])([F:16])[F:17])[NH:25]2)=[CH:21][C:20]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: NC(c1ccc(F)c(C(F)(F)F)c1)C(F)(F)F
Reactant: CCOC(=O)c1cc2cc(C(=O)O)[nH]c2cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)NC(c3ccc(F)c(C(F)(F)F)c3)C(F)(F)F)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
2,2,2-Trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanamine (0.82 g, 3.05 mmol) was dissolved in N,N-dimethylformamide (6 ml), and 6-chloro-5-(ethoxycarbonyl)-1H-indole-2-carboxylic acid (0.82 g, 3.05 mmol), N-[(1H-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate (1.16 g, 3.05 mmol) and 4-methylmorpholine (0.92 g, 9.10 mmol) were added. The reaction mixture was stirred at room temperature for 16 h and then water was added. The aqueous phase was extracted three times with ethyl acetate, dried over sodium sulphate, adsorbed on silica gel and chromatographed with cyclohexane/ethyl acetate (4/1). 1.29 g (65% of theory) of ethyl 6-chloro-2-({2,2,2-trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:13]([F:20])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O.C[O-].[Na+]>CO>[Cl:11][C:12]1[C:13]([F:20])=[C:14](/[CH:15]=[C:6](/[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)\[C:7]#[N:8])[CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1cccc(Cl)c1F
Reactant: N#CCc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1
Yield: 92.8 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chlorobenzyl cyanide (8.9 g, 59 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (Oakwood) (10 g, 63 mmol), methanolic solution (25 wt %) of sodium methoxide (15 mL, 66 mmol) in methanol (300 mL) at 40° C. for 5 h to give (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile as a white powder (16 g, 92%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([CH3:15])=[CH:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].ClC(OCC)=O.[CH3:22][CH:23]([NH2:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>ClCCl.C(N(CC)CC)C>[CH3:22][CH:23]([NH:33][C:12](=[O:14])[CH:11]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:15])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCC(C)N
Reactant: CC(=CC(=O)O)c1cccc([N+](=O)[O-])c1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCC(C)NC(=O)C=C(C)c1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
To a stirred slurry of 5.2 g. of the 3-(3-nitrophenyl)-2-butenoic acid from Preparation 12 having a melting point of 208°-210° C., in 100 ml. of dichloromethane, was added 2.8 g. of triethylamine in 10 ml. of dichloromethane. This was followed by the addition of a solution of 3.0 g. of ethyl chloroformate in 20 ml. of dichloromethane, during 20 minutes. Stirring was continued for 30 minutes, and then a solution of 1-methyldecylamine in 20 ml. of dichloromethane was added dropwise during 25 minutes. Stirring was continued overnight, and the the reaction mixture was washed successively with 1 N potassium carbonate, water and saturated sodium chloride. The resulting solution was dried using sodium sulfate, and then it was evaporated in vacuo leaving an oil which solidified on trituration under petroleum ether. This afforded 4.9 g. of the title compound, m.p. 72.5°-74° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:40][CH3:41])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:32][CH:31]5[CH:26]([CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][CH2:30]5)[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:40][CH3:41])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:32][CH:31]5[CH:26]([CH2:27][NH:28][CH2:29][CH2:30]5)[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2CCN(C(=O)OC(C)(C)C)CC2C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2CCNCC2C1
Yield: 90.5 %

Procedure:
To a solution of tert-butyl 2-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy) propyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate (0.40 g) in CH2Cl2 was added a solution of HCl in EtOAc (3 M, 10 mL). White solid was precipitated out after 2 h reaction. The resulted mixture was filtered and the residue was dried to give the title compound as a pale yellow solid (0.30 g, 80.00%), HPLC: 99.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 486.2 (M+1); 1H NMR (400 MHz, D2O) δ: 1.97-2.03 (m, 4H), 2.68-2.71 (m, 2H), 2.80-2.86 (m, 4H), 2.87-2.91 (m, 2H), 3.40-3.45 (m, 2H), 4.07-4.11 (m, 2H), 4.19 (s, 3H), 4.39-4.43 (m, 2H), 7.441 (s, 1H), 7.50 (t, J=8.6 Hz, 1H), 7.84 (s, 2H), 8.68 (t, J=4.6 Hz, 1H), 8.89 (s, 1H) ppm.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.CN.[N:24]1(C2C=CN=CC=2)CCC[CH2:25]1.C(N=C=NC(C)C)(C)C>C(O)C.ClCCl>[CH3:25][NH:24][C:17](=[O:18])[C:16]1[CH:15]=[CH:14][C:13]([C:3]2[C:4]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[NH:1][N:2]=2)=[CH:21][CH:20]=1
Reactant: c1cc(N2CCCC2)ccn1
Reactant: O=C(O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN
Solvent: ClCCl
Solvent: CCO
Product: CNC(=O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzoic acid (0.8 g), methylamine in ethanol (0.27 ml of a 33% w/w solution), 4-pyrrolidinopyridine (0.47 g), diisopropylcarbodiimide (0.5 ml) and dichloromethane (30 ml) was stirred at ambient temperature for 20 hours. More methylamine in ethanol (0.3 ml of a 33% w/w solution), 4-pyrrolidinopyridine (0.5 g) and diisopropylcarbodiimide (1 ml) were added and the mixture was stirred for 3 hours at ambient temperature. The solvent was removed under reduced pressure at 50° C. The mixture was kept under vacuum for 2 hours and then dichloromethane (50 ml) was added. The mixture was stirred at ambient temperature for 20 hours and then allowed to stand for 72 hours. A solid was removed by filtration and purified by flash column chromatography on silica using toluene/acetic acid (10:1) and then ethyl acetate as the mobile phase to give N-methyl-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, m.p. 182-188° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH:7]=[C:6]2[CH:14]=O)[CH2:3][CH2:2]1.[C:16]([O:20][C:21](=[O:44])[NH:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:43])[C:30]2[CH:35]=[C:34]([N+:36]([O-])=O)[C:33]([NH:39][CH3:40])=[C:32]([O:41][CH3:42])[CH:31]=2)[CH2:24]1)([CH3:19])([CH3:18])[CH3:17].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O.C(Cl)Cl>[C:16]([O:20][C:21](=[O:44])[NH:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([C:30]2[CH:31]=[C:32]([O:41][CH3:42])[C:33]3[N:39]([CH3:40])[C:14]([C:6]4[N:5]([CH2:4][CH:1]5[CH2:2][CH2:3]5)[C:9]5=[N:10][CH:11]=[CH:12][CH:13]=[C:8]5[CH:7]=4)=[N:36][C:34]=3[CH:35]=2)=[O:43])[CH2:24]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: O=Cc1cc2cccnc2n1CC1CC1
Reactant: CNc1c(OC)cc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc2nc(-c3cc4cccnc4n3CC3CC3)n(C)c12
Temperature: 25 °C
Yield: 74.8 %

Procedure:
A solution of 1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (0.743 g, 3.71 mmol) in ethanol (60 mL) was added to a round bottom flask containing (R)-tert-butyl(1-(3-methoxy-4-(methylamino)-5-nitrobenzoyl)piperidin-3-yl)carbamate (1.529 g, 3.74 mmol) and the resulting solution stirred at room temperature. A solution of sodium dithionite (1.375 g, 6.71 mmol) in water (30 mL) was added portionwise to the reaction mixture. The reaction mixture was heated to 100° C. and stirred under nitrogen for 4 hours. The reaction mixture was concentrated under vacuum then diluted with DCM (150 ml) and water (150 ml). The organic layer was collected and the aqueous layer washed with DCM (3×100 ml). Organic layers were collected, dried with Na2SO4, filtered through a hydrophobic frit and concentrated under vacuum to yield 2 g of crude product as yellow solid. This was dissolved in a minimum volume of DCM and purified using Biotage SP4 on a 50 g SNAP silica cartridge. The column was eluted with a gradient of 70-100% ethyl acetate in DCM for 10CV. Appropriate fractions were collected and concentrated under vacuum to yield the title compound as a yellow solid (1.55 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:7])[C:4]([OH:6])=[O:5].S(Cl)([Cl:10])=O.[CH3:12]O>>[ClH:10].[NH2:1][CH2:2][CH:3]([OH:7])[C:4]([O:6][CH3:12])=[O:5]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: NCC(O)C(=O)O
Product: COC(=O)C(O)CN
Product: Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 3-amino-2-hydroxypropanoic acid (0.7 g) in methanol (15 mL) was added thionyl chloride (2.5 mL) at 0° C., and the mixture was stirred at 0° C. for 2 hr and then at room temperature overnight. The solvent was evaporated under reduced pressure to give the title compound (1.6 g, 100%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][CH:16]([C:18]3[O:22][NH:21][C:20](=[O:23])[CH:19]=3)[CH2:15][CH2:14][N:13]2[C:24]([O:26][CH3:27])=[O:25])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CCCCCCC.CC(O)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:12]2[CH2:17][C@@H:16]([C:18]3[O:22][NH:21][C:20](=[O:23])[CH:19]=3)[CH2:15][CH2:14][N:13]2[C:24]([O:26][CH3:27])=[O:25])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10].[F:1][C:2]1[CH:3]=[C:4]([C@@H:12]2[CH2:17][C@H:16]([C:18]3[O:22][NH:21][C:20](=[O:23])[CH:19]=3)[CH2:15][CH2:14][N:13]2[C:24]([O:26][CH3:27])=[O:25])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: COC(=O)N1CCC(c2cc(=O)[nH]o2)CC1c1ccc(C(F)(F)F)c(F)c1
Solvent: CC#N
Solvent: CC(C)O
Solvent: CCCCCCC
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1c1ccc(C(F)(F)F)c(F)c1
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)c(F)c1
Yield: 49 %
Yield: 47 %

Procedure:
Methyl 2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (670 mg, 1.73 mmol) was subjected to chiral preparative HPLC (Column: CelluCoat (250×50), 10 μm particle size, mobile phase: Heptane/EtOH 50/50, flow rate 120 mL/min) to yield (2R,4S)-methyl 2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (319 mg, 47%), Chiral purity 99.9% ee, optical rotation [α]D20=+53.4 (acetonitrile, c=0.5) and (2S,4R)-methyl 2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (332 mg, 49%), Chiral purity 99.3% ee, Optical rotation [α]D20=−47.6 (acetonitrile, c=0.5).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[C:13](=[O:16])([O-])[O-].[K+].[K+].[OH2:19]>CS(C)=O>[CH:6]1[C:7]([N+:10]([O-:11])=[O:19])=[CH:8][CH:9]=[C:13]([O:16][C:4]2[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[CH:5]=1
Reactant: O
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 8 h
Yield: 63 %

Procedure:
1,4-Dinitrobenzene (3.52 g, 20.5 mmol) and potassium carbonate (1.38 g, 10 mmol) were heated in dimethylsulfoxide (8 mL) at about 100° C. for approximately 5.8 hours. The reaction was allowed to cool and was poured into water (20 mL). The reaction vessel was rinsed with an additional 10 mL of water and the rinses were combined. The combined aqueous suspensions were allowed to stand overnight. The solid was collected, washed with water, and dried to give 2.35 g (63% pure) of 4,4'-dinitrodiphenyl ether.