Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]([F:11])[C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].C(N(CC)CC)C.[CH3:20][C@H:21]1[O:26][C@H:25]([CH3:27])[CH2:24][NH:23][CH2:22]1.Cl>C(#N)C>[Br:1][C:2]1[C:3]([F:12])=[C:4]([F:11])[C:5]([N:23]2[CH2:22][CH:21]([CH3:20])[O:26][CH:25]([CH3:27])[CH2:24]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)c(F)c(F)c1F
Reactant: C[C@@H]1CNC[C@@H](C)O1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1CN(c2c(C=O)cc(Br)c(F)c2F)CC(C)O1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
5-Bromo-2,3,4-trifluoro-benzaldehyde (10 g, 41.8 mmol) was dissolved in dry acetonitrile (70 mL). Triethylamine (6.4 mL, 46.0 mmol) was added, followed by trans-2,6-dimethylmorpholine (BASF, 5.3 g, 46 mmol). The mixture was refluxed for 24 hours, then cooled to room temperature, and treated with 1N HCl (58 mL). The acetonitrile was removed by rotoevaporation and the resulting solids were filtered, washed with water then dissolved in THF (100 mL). The solution was dried over MgSO4 and concentrated to a yellow oil. Hexanes were added and the mixture was re-concentrated to give 12.66 g of a yellow powder. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.26 (d, J=6.4 Hz, 6H), 2.92 (m, 2H), 3.28 (d, J=11.7 Hz, 2H), 4.15 (m, 2H), 7.78 (dd, J=7.2, 2.3 Hz, 2H), 10.32 (s, 4H).
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][CH:20]=[CH:21][N:22]=3)=[CH:14][CH:13]=2)[CH2:7]1)(=O)=O.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>C(#N)C>[O:19]1[CH:20]=[CH:21][N:22]=[C:18]1[C:15]1[CH:16]=[CH:17][C:12]([N:8]2[CH2:9][CH2:10][CH2:11][CH:6]([NH:23][C@@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]3[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:7]2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)OC1CCCN(c2ccc(-c3ncco3)cc2)C1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc(-c3ncco3)cc2)C1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-(oxazol-2-yl)phenyl)piperidin-3-yl methane sulfonate (110 mg, 0.341 mmol) in acetonitrile (4 mL) was added tert-butyl (1R,2R)-2-aminocyclohexylcarbamate (110 mg, 0.512 mmol). The reaction was stirred in a microwave at 120° C. for 30 min. After this time, LC/MS showed two pairs of products formed. The reaction mixture was concentrated. The residue was diluted with EtOAc and washed with water. The remaining EtOAc organic layer was concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 50-100% EtOAc/Hex. Under these conditions, the two diastereomers separated and the desired diastereomer tert-butyl (1R,2R)-2-((1-(4-(oxazol-2-yl)phenyl)pyrrolidin-2-yl)methylamino)cyclohexylcarbamate (156 mg total) as a white foam.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:36])=[C:5]([C:27]([O:34]C)=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:31][O:30][C:29]1[C:3](=[O:2])[C:4]([CH3:36])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:11]([CH:20]=2)[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])[C:27](=[O:34])[C:28]=1[O:32][CH3:33]
Reactant: COC(=O)COc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1C(=O)N1CCOCC1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC(=O)COc1ccc(CC2=C(C)C(=O)C(OC)=C(OC)C2=O)cc1C(=O)N1CCOCC1
Yield: 79.7 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(methoxycarbonylmethyloxy)benzoyl]morpholine (0.240 g, 0.478 mmol) was dissolved in a mixed solution of acetonitrile (12 ml) and water (4 ml) and after adding thereto CAN (0.655 g, 1.20 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:3) to obtain the titled compound (0.180 g, 0.381 mmol, 80%).
Reaction SMILES: C([NH:8][CH:9]([CH:11]1[O:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH2:12]1)[CH3:10])C1C=CC=CC=1>CO.Cl.[Pd]>[O:16]1[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH:11]1[CH:9]([NH2:8])[CH3:10]
Reactant: CC(NCc1ccccc1)C1COc2ccccc2O1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(N)C1COc2ccccc2O1
Yield: 94.5 %

Procedure:
In 50 ml of methanol was dissolved 7 g of pure N-benzyl-1-(1,4-benzodioxan-2-yl)ethylamine (i1 '). After adding one drop of ethanolic hydrochloric acid and 0.5 g of 10% palladium charcoal to the solution, and catalytic reduction was performed at normal pressure until the absorption of hydrogen gas stopped. Then, palladium charcoal was filtered away, the filtrate was acidified with the addition of ethanolic hydrochloric acid, and the solvent was distilled off. Then, 20 ml of isopropanol was added to the residue and the product formed was recovered by filtration to provide 4.4 g (75.7%) of 1-(1,4-benzodioxan-2-yl)ethylamine (i1 ') hydrochloride having a melting point of 234°-235° C. The product was then converted into a base by a conventional manner and distilled under reduced pressure to provide 2.9 g (62.3%) of 1-(1,4-benzodioxan-2-yl)ethylamine (i1 ') having a boiling point of 88°-90° C./0.1 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]5[NH:30][N:31]=[CH:32][C:25]=45)=[CH:19][CH:18]=3)=[O:15])=[CH:9][C:8]=2[C:33]([F:36])([F:35])[F:34])=[CH:4][CH:3]=1.CC[C:41]([C:43](Cl)=[O:44])=[O:42]>ClCCl.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C:41](=[O:42])[C:43](=[O:44])[N:16]([C:17]4[CH:18]=[CH:19][C:20]([O:23][C:24]5[CH:29]=[CH:28][N:27]=[C:26]6[NH:30][N:31]=[CH:32][C:25]=56)=[CH:21][CH:22]=4)[C:14]3=[O:15])=[CH:9][C:8]=2[C:33]([F:35])([F:36])[F:34])=[CH:37][CH:38]=1
Reactant: CCC(=O)C(=O)Cl
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]ncc23)cc1)Nc1ccc(Oc2ccc(F)cc2)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1C(=O)N(c2ccc(Oc3ccc(F)cc3)c(C(F)(F)F)c2)C(=O)N1c1ccc(Oc2ccnc3[nH]ncc23)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
1-[4-(4-Fluorophenoxy)-3-trifluoromethyl-phenyl]-3-[4-(1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl]urea (50 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL) and THF (3 mL), and ethyloxalyl chloride (70 μL) was added thereto. The resulting mixture was stirred at 70° C. for 3 hours. The reaction solution was concentrated and then purified by reverse-phase HPLC (ODS column, 0.05% TFA-containing water/acetonitrile system, 5% to 95% linear gradient) to give the target compound (9 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.Cl.[H][H]>>[CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:7]=[CH:8][CH:9]=1.[ClH:1]
Reactant: Clc1cccc2ccccc12
Reactant: [H][H]
Agent: Cl
Product: c1ccc2ccccc2c1

Procedure:
High conversions of 1-chloro- or 1-bromonaphthalene coupled with a long catalyst life can be achieved by the zeolites used according to the invention. The conversion of 1-chloronaphthalene over an amorphous aluminosilicate, in spite of an HCl atmosphere, dropped from 51 to 41% in the course of 4 hours (temperature 400° C., LHSV 0.2 h-1, N. N. Vorozhtsov, Jr. and A. M. Beskin, J. Gen. Chem. USSR, 24, 667/672 (1954) English edition). In contrast, an HEU-1 zeolite converted 56% of 1-chloro-naphthalene after 1 hour and 41% after 7 hours in a hydrogen atmosphere at the same temperature but 2.5 times the LHSV. The selectivity for the isomerization of 1-chloronaphthalene over HEU-1 is very high and is more than 98% at reaction temperatures of between 300° and 400° C. Naphthalene above all is formed as a by-product by elimination of HCl. Less than 0.05% of dichloronaphthalenes is formed. In the reaction of 1-bromonaphthalene, however, transbromination to naphthalene and dibromonaphthalenes occurs. The selectivity for 2-bromo-naphthalene is nevertheless very high, at 95% at 350° C. and 50% conversion.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[I-].[Na+].CS(O[CH2:12][C:13]1[CH:14]=[C:15]([NH:23][C:24]([N:26]2[C:34]3[C:29](=[CH:30][C:31]([O:35][C:36]4[C:37]5[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][C:38]=5[N:39]=[CH:40][N:41]=4)=[CH:32][CH:33]=3)[CH:28]=[CH:27]2)=[O:25])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)(=O)=O>C(Cl)Cl>[CH:1]([NH:4][CH2:12][C:13]1[CH:14]=[C:15]([NH:23][C:24]([N:26]2[C:34]3[C:29](=[CH:30][C:31]([O:35][C:36]4[C:37]5[CH2:45][CH2:44][NH:43][CH2:42][C:38]=5[N:39]=[CH:40][N:41]=4)=[CH:32][CH:33]=3)[CH:28]=[CH:27]2)=[O:25])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(COS(C)(=O)=O)cc(C(F)(F)F)c3)c2)C1
Reactant: CC(C)N
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)NCc1cc(NC(=O)n2ccc3cc(Oc4ncnc5c4CCNC5)ccc32)cc(C(F)(F)F)c1
Reaction time: 0.75 h

Procedure:
To a solution of the above mixture (0.15 g, 0.227 mmol) in 3 mL of DCM, isopropyl amine (0.06 mL, 0.680 mmol) is added followed by sodium iodide (0.1 g, 0.68 mmol). After 45 min, LC-MS shows that tert-butyl 4-(1-(3-((methylsulfonyloxy)methyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate is converted to desired product and the tert-butyl 4-(1-(3-(chloromethyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate left over. To the reaction 3 mL (0.227 mmol) of isopropyl amine is added followed by NaI (0.1 g, 0.68 mmol) and the mixture is heated to 45° C. for 2 h. The solvent is then removed and the residue diluted with EtOAc, washed with H2O, brine and the organic layer dried over Na2SO4. Following concentration the residue is separated by FCC (25-100% EtOAc/heptane). This product is then treated with 60 mL of 50% TFA/DCM at rt for 1.5 h. After concentration the residue is separated by semi-prep HPLC (C-18; 10-100% I/H2O with 0.1% NH4OH) to provide the title compound. MS (ESI) m/z 525.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (s, 1H), 8.40 (s, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.13 (d, J=3.8 Hz, 1H), 7.95 (d, J=15.2 Hz, 2H), 7.38-7.52 (m, 2H), 7.11 (dd, J=9.0, 2.4 Hz, 1H), 6.78 (d, J=3.8 Hz, 1H), 3.81 (d, J=7.6 Hz, 4H), 3.03 (t, J=5.8 Hz, 2H), 2.68-2.79 (m, 3H), 1.03 (d, J=6.1 Hz, 6H).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[N:24]([CH3:25])[CH:23]=[N:22][N:21]=1>>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[N:24]([CH3:25])[CH:23]=[N:22][N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: Cn1cnnc1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Product: Cn1cnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1

Procedure:
7-Amino-3-(4-methyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid was prepared from 7-ACA and 3-mercapto-4-methyl-1,2,4-triazole according to the first paragraph of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(F)c1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc(F)c1
Yield: 98.6 %

Procedure:
3-Fluorobenzaldehyde (5 g, 40.28 mmol) in pyridine (50 mL) was reacted with malonic acid (5.4 g, 52.3 mmol) and piperidine (343 mg, 4.0 mmol) at 75° C. for 12 hours to afford 6.6 g (96.9%) of the crude product which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].BrCC1CCCCO1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]2([C:25]3=[CH:26][C:27]4[O:31][CH2:30][O:29][C:28]=4[CH:32]=[C:24]3[O:23][CH2:22]2)[C:14]1=[O:33]>>[O:33]=[C:14]1[C:15]2([C:25]3=[CH:26][C:27]4[O:31][CH2:30][O:29][C:28]=4[CH:32]=[C:24]3[O:23][CH2:22]2)[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]1[CH2:2][C:3]#[N:4]
Reactant: N#CCCl
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: BrCC1CCCCO1
Product: N#CCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using chloroacetonitrile to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetonitrile was obtained (61%) as a colorless solid: mp 170-172° C.; 1H NMR (300 MHz, DMSO-d6) δ7.38 (dt, J=7.7, 1.2 Hz, 1H), 7.26 (d, J=7.7 Hz, 1H), 7.20 (d, J=7.3 Hz, 1H), 7.11 (dt, J=7.7, 1.1 Hz, 1H), 6.66 (s, 1H), 6.21 (s, 1H), 5.89 (d, J=1.5 Hz, 2H), 4.94 (ABq, J=17.9 Hz, 2H), 4.73 (ABq, J=9.5 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ176.8, 155.8, 148.9, 142.232, 141.0, 131.9, 129.4, 124.3, 124.3, 119.8, 116.0, 109.7, 103.5, 101.9, 93.8, 80.1, 57.8, 28.8; MS (ES+) m/z 321.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Cl[C:17]1([C:29]2[C:30]([O:35][CH2:36][CH3:37])=[N:31][CH:32]=[CH:33][CH:34]=2)[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=2)[NH:19][C:18]1=[O:28].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>ClCCl>[CH2:36]([O:35][C:30]1[C:29]([C:17]2([NH:15][C:12]3[CH:13]=[CH:14][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:10][CH:11]=3)[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=3)[NH:19][C:18]2=[O:28])=[CH:34][CH:33]=[CH:32][N:31]=1)[CH3:37]
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: CCOc1ncccc1C1(Cl)C(=O)Nc2ccc(C#N)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ncccc1C1(Nc2ccc(CN3CCN(C)CC3)cc2)C(=O)Nc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.1 %

Procedure:
4-(4-Methyl-piperazin-1-ylmethyl)phenylamine (425 mg, 2.07 mmol) was added to a solution of 3-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile (500 mg, 1.59 mmol) in dichloromethane (50 ml) and DIPEA (0.27 ml, 159 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h and then an aqueous NaHCO3 solution was added. The aqueous reaction mixture was extracted with dichloromethane. The combined organic phase was dried over magnesium sulfate, filtered and concentrated at reduced pressure. Purification by chromatography (silica gel, 0-20% methanol in dichloromethane) afforded 791 mg of the title compound (99% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[N:23]=[C:22]([CH2:24][C:25]#[N:26])[CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9]([C:18]3[N:23]=[C:22]([CH2:24][C:25]#[N:26])[CH:21]=[CH:20][CH:19]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: N#CCc1cccc(Br)n1
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(CC#N)n3)cc21

Procedure:
[6-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)pyridin-2-yl]acetonitrile was prepared, according to the procedure of Example 5 using (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and (6-bromo-2-pyridyl)acetonitrile (J. Org. Chem. 1988, 53, 786-790), as an off-white solid: mp 210-212.5° C.; 1H NMR (DMSO-d6) δ1.68 (s, 6H), 4.27 (s, 2H), 7.00 (d, 1H, J=8.3 Hz), 7.34 (d, 1H, J=7.1 Hz), 7.89-7.96 (m, 2H), 8.00-8.05 (m, 2H), 10.42 (s, 1H); MS (ESI) [M−H]−=292; Anal. Calcd. For C17H15N3O2: C, 69.61; H, 5.15; N, 14.33. Found: C, 68.49; H, 5.19; N, 13.74.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:21]=[C:22]([CH2:26][C:27]([OH:29])=[O:28])[CH:23]=[CH:24][CH:25]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[NH:13]1[C:14]2[C:10](=[C:9]([C:20]3[CH:21]=[C:22]([CH2:26][C:27]([OH:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)Cc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 70 °C
Yield: 84.3 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (15.52 g, 63.72 mmol), and 3-bromo-phenylacetic acid (13.78 g, 63.72 mmol) in THF (192 mL) were added Palladium catalyst Pd(PPh3)4 (2.21 g, 1.9 mmol) and the freshly prepared sodium hydroxide solution (7.65 g in 90 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen in a 70° C. oil bath for over the weekend. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The water layer was acidified with dil. HCl solution to pH 4-5 and extracted with ethyl acetate. The ethyl acetate solution was washed with water, brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified on a silica gel column to give 13.5 g (84%) of [3-(1H-indol-4-yl)-phenyl]-acetic acid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH3:11])[C:6]=2[C:5]([F:12])=[C:4]([F:13])[CH:3]=1.C1C(=O)[N:18](Br)[C:16](=O)C1.[C-]#N.[Na+].[OH-].[Na+]>O.C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][C:16]#[N:18])[C:6]=2[C:5]([F:12])=[C:4]([F:13])[CH:3]=1
Reactant: Cc1coc2c(Br)cc(F)c(F)c12
Reactant: O=C1CCC(=O)N1Br
Agent: [C-]#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#CCc1coc2c(Br)cc(F)c(F)c12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To the compound (98.8 mg, 0.400 mmol) of Step 1 of Example 21, NBS (78.3 mg, 0.440 mmol), and a catalytic amount of BPO, carbon tetrachloride (4 mL) was added, and heated under reflux overnight. The resultant was returned to room temperature, and the solvent was distilled away under reduced pressure. The resulting residue was diluted with dichloromethane, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was dissolved in acetonitrile (2 mL), and sodium cyanide (39.2 mg, 0.800 mmol) and water (0.2 mL) were added thereto, and stirred at 50° C. for 30 minutes. To the reaction solution, a 1 N sodium hydroxide aqueous solution was added. After concentrated under reduced pressure, the resultant was diluted with ethyl acetate, washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel chromatography to thus obtain the title compound.
Reaction SMILES: C([Li])CCC.[C:6]1([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN(C)[CH:21]=[O:22].OS(O)(=O)=O>CCOCC>[O:12]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[CH:21]=[O:22])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CN(C)C=O
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 68.7 %

Procedure:
At room temperature, under an argon atmosphere, n-butyllithium (15.45 mL of a 2.5M solution in hexanes, 38.61 mmol) was added to a solution of diphenyl ether (5.0 g; 29.38 mmol) in 100 mL of ether, and the reaction mixture was gently refluxed for 4 hrs. After cooling to 0° C., N,N-dimethylformamide (22.73 mL; 0.293 mol) was added dropwise and the reaction was stirred for 15 min at 0° C. and 1.5 hr at room temperature. After adding 10% H2SO4 to pH 1, it was stirred for 15 min and extracted into ethyl acetate. Chromatography of the crude product (10% ethyl acetate/hexane) provided 4.0 g (69%) of the aldehyde, 1H NMR (CDCl3): δ 6.97 (d, 1H); 7.02-7.11 (m, 2H); 7.18-7.22 (m, 2H); 7.29 (t, 1H); 7.39 (t, 1H); 7.43 (t, 1H); 7.95 (t, 1H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C:13]([O:14][CH3:15])=N[C@H](C(C)C)C(OC)=[N:9]1)=[N+:2]=[N-:3].Cl.[OH2:22].N>O1CCOCC1>[NH2:9][C@@H:8]([CH2:7][CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[C:13]([O:14][CH3:15])=[O:22]
Reactant: O
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1CCCCN=[N+]=[N-]
Agent: Cl
Agent: N
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)CCCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Azido-4-[(2R,5S)-3,6-dimethoxy-2-isopropyl-2,5-dihydro-5-pyrazinyl]butane (2.17 g, 7.72 mmol) was dissolved in 30 ml dioxane and a solution of 1.28 ml conc. HCl in 30 ml water (15.45 mmol) was added dropwise, the mixture stirred under argon at ambient temperature overnight. Ammonia solution was added until pH 9 was reached, the solution extracted with chloroform, dried (MgSO4), and the valine methyl ester was removed by bulb-to-bulb distillation (0.05 torr, 25° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[O:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)C=1.[C:23]1([CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:30](=[O:31])[CH:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:5][C:4]=1[O:10][CH2:11][C:12]1[C:19]2[C:20](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:21]=[CH:22][CH:13]=1
Reactant: COc1ccc(N)cc1OCCc1ccc2ccccc2c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)C(c2ccccc2)c2ccccc2)cc1OCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-[4-methoxy-3-(naphthylmethoxy)phenyl]-2,2-diphenylethanamide (Exemplary Compound 49) was prepared using the same experimental conditions used to prepare Example 52 (Scheme X). From 4-methoxy-3-(2-naphthylethoxy)phenylamine (350 mg, 1.25 mmol) and diphenylacetyl chloride (290 mg, 1.25 mmol) in 10 mL of dimethyl acetamide containing triethylamine (1 mL, 7.17 mmol) stirred at room temperature for 16 h., was obtained 375 mg of product in (64%) yield as a white solid after recrystallization from ethyl acetate/hexane: mp 170-172° C. 1H NMR (400 MHz, Me2SO-d6) δ3.69 (s, 3H); 5.13 (s, 1H); 5.46 (s, 2H); 6.93 (d, 1H, J=8.7); 7.20-7.37 (m, 10H); 7.50-7.65 (m, 5H); 7.94-8.09 (m, 3H); 10.28 (s, 1H). Anal. Calcd for C32H27NO3: C, 81.16; H, 5.75; N, 2.96. Found: C, 80.95; H, 5.76; N, 3.03.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])CC2C(F)=CC=CC=2Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:34]=1[CH2:35][Mg]Cl>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:35][C:34]2[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=[CH:41][C:33]=2[O:32][CH3:31])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(Cc1c(F)cccc1Cl)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Reactant: COc1ccc(OC)c(C[Mg]Cl)c1
Product: COc1ccc(OC)c(CC(O)(c2ccccc2)C2CN(Cc3ccccc3)CCO2)c1

Procedure:
The procedure for the synthesis of example 18a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-6-fluoro-phenyl)-1-phenyl-ethanol, using 2,5-dimethoxybenzyl magnesium chloride as starting material (available from Rieke Metals) was followed making non-critical variations, to yield the title compound. This material was used in step b) without further purification. LCMS (6 minutes method) [M+H]+=434 @ Rt 3.10 min. major peak.