Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:15])[CH:9]2[O:14][CH:10]2[C:11]([O-:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].C(O)=O>O>[C:1]1([NH:7][C:8](=[O:15])[CH:9]2[O:14][CH:10]2[C:11]([OH:13])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])C1OC1C(=O)Nc1ccccc1
Agent: [K+]
Solvent: O=CO
Solvent: O
Product: O=C(O)C1OC1C(=O)Nc1ccccc1
Yield: 77.9 %

Procedure:
Potassium N-phenyl-2,3-epoxysuccinamate (Compound No. 95) (2.31 g) was dissolved in water (10 ml) and the solution was made acidic by addition of 25% HCOOH under ice-cooling with stirring. The reaction mixture was extracted with chloroform, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness. The residue was recrystallized from a mixture of n-hexane-acetone to give 1.52 g of N-phenyl-2,3-epoxysuccinamic acid (Compound No. 105) as colorless needles melting at 124°-128° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=2[C:22]([F:25])([F:24])[F:23])=[O:11])[CH2:3][CH2:2]1>CCOC(C)=O.CO.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10]([NH:9][CH2:8][CH2:7][N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[O:11])=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:15]=1
Reactant: O=C(NCCN1CCOCC1)Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(NC(=O)NCCN2CCOCC2)c(C(F)(F)F)c1

Procedure:
A mixture of 1-(2-morpholinoethyl)-3-(4-nitro-2-(trifluoromethyl)phenyl)urea (651 mg, 1.80 mmol, 1.0 equiv) and 10% Pd/C (20 mg) in EtOAc (25 mL) and MeOH (2 mL) was exposed to an atmosphere of H2 (balloon). Upon completion of the reduction, the reaction mixture was filtered through celite and concentrated in vacuo to afford 1-(4-amino-2-(trifluoromethyl)phenyl)-3-(2-morpholinoethyl)urea, which was advanced without further purification. MS m/z: 333 (M+H+); Calculated for C14H19F3N4O2: 332.2
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:38]([OH:40])=O)[CH2:13][C:14]2[N:18]=[CH:17][N:16]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.Cl.[NH2:52][C@@H:53]([CH2:62][CH:63]([CH3:65])[CH3:64])[CH:54]([OH:61])[C:55]([O:57]C(C)C)=[O:56].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:61][CH:54]([CH:53]([NH:52][C:38](=[O:40])[CH:12]([NH:11][C:9]([O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:10])[CH2:13][C:14]1[N:18]=[CH:17][N:16]([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:15]=1)[CH2:62][CH:63]([CH3:64])[CH3:65])[C:55]([OH:57])=[O:56]
Reactant: O=C(N[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)O)OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(O)C(=O)OC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CC(NC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.3 %

Procedure:
A mixture of 12.4 g (23.4 mmol) of N-[(phenylmethoxy)carbonyl]-1-(triphenylmethyl)-L-histidine, (Jones, J. H., et al, Synthesis, page 1110 (1987)) 3.3 g (24.6 mmol) of 1-hydroxybenzotriazole and 50 ml of dimethylformamide is cooled to <0° C. and treated with a mixture of 5.6 g (23.4 mmol) of (3S)-3-amino-2-hydroxy-5methylhexanoic acid, 1-methylethyl ester, monohydrochloride (mixture of isomers at hydroxy center) (Example B), and 2.5 g (25 mmol) of triethylamine in 30 ml of dimethylformamide at -5° C. The solution is stirred for five minutes, treated with 5.1 g (24.6 mmol) of dicyclohexylcarbodiimide in 30 ml of dimethylformamide and stirred for eight hours at -5 to 0° C., kept at -5° C. overnight, allowed to warm to room temperature under a nitrogen atmosphere and stirred for 24 hours. The mixture is treated with 1 g (10 mmol) of triethylamine, stirred at room temperature for 72 hours, filtered and the dimethylformamide evaporated in vacuo. The residue is dissolved in 200 ml of ethyl acetate, extracted with 200 ml of 1N citric acid solution, filtered, extracted with 200 ml of saturated sodium chloride solution, 200 ml of saturated solution of sodium bicarbonate and 200 ml of saturated solution of sodium chloride. The organic layer is separated, dried (magnesium sulfate) and the solvent evaporated in vacuo to give 14.1 g of the title compound as a tan foam.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][CH:14]([P:16](=[O:21])([O:19][CH3:20])[O:17][CH3:18])[F:15].[CH3:22][C:23]([CH3:37])=[CH:24][CH2:25][CH2:26]/[C:27](/[CH3:36])=[CH:28]/[CH2:29][CH2:30]/[C:31](/[CH3:35])=[CH:32]/[CH:33]=[O:34].Cl>O1CCCC1>[F:13][C:14]([P:16](=[O:21])([O:19][CH3:20])[O:17][CH3:18])([F:15])[CH:33]([OH:34])[CH:32]=[C:31]([CH3:35])[CH2:30][CH2:29][CH:28]=[C:27]([CH3:36])[CH2:26][CH2:25][CH:24]=[C:23]([CH3:22])[CH3:37]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Reactant: COP(=O)(OC)C(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COP(=O)(OC)C(F)(F)C(O)C=C(C)CCC=C(C)CCC=C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
Combine diisopropylamine (22.24 mL, 0.159 mol) with tetrahydrofuran (250 mL) and cool to -20° C. Add n-butyllithium (63.3 mL, 2.5N in hexane, 0.159 mol) dropwise to the solution. Stir for 30 minutes and cool to -78° C. Add dropwise a solution of dimethyl difluoromethylphosphonate (25.8 g, 0.159 mol) in tetrahydrofuran (20 mL) while maintaining the temperature below -75° C. After addition is complete, stir for 2 minutes and then slowly add a solution of trans, trans-farnesal [prepared according to Biller, S. A; Forster, C. Tetrahedron 1990, 46(19), 6645](14 g, 0.0636 mol) prepared in step a above, in tetrahydrofuran (10 mL) maintaining the temperature below -72° C. After addition is complete, stir for an additional 2 hours at -78° C. and then pour the reaction into 0.1N hydrochloric acid (500 mL). Extract the reaction with diethyl ether (2×1L). Combine the organic phases, dry over anhydrous magnesium sulfate, filter and concentrate under vacuum. Purify the residue by flash chromatography [40% ethyl acetate/hexane, Rf (50% ethyl acetate/hexane)=0.44] to provide the title compound (9.3 g, 39%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH2:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1.Br[C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH:18][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH:21]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Reactant: COc1ccccc1-c1cccn2nc(N)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: COc1ccccc1-c1cccn2nc(Nc3cccc(N4CCN(C)CC4)c3)nc12

Procedure:
[8-(2-Methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.312 mmol) and 1-(3-bromo-phenyl)-4-methyl-piperazine (90.0 mg, 0.353 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (34.0 mg, 0.0622 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a pale yellow foam (0.069 g, 53%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.40 (d, J=6.5 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.54 (d, J=7.3 Hz, 1H), 7.43-7.35 (m, 2H), 7.19 (d, J=7.9 Hz, 1H), 7.11-7.02 (m, 2H), 6.94-6.89 (m, 2H), 6.79 (s, 1H), 6.55 (d, J=7.9 Hz, 1H), 3.81 (s, 3H), 3.27-3.22 (m, 4H), 2.60-2.55 (m, 4H), 2.36 (s, 3H). MS=415 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([Cl:9])[CH:3]=1.[CH2:10]1[O:20][C:13]2([CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)[O:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:16]2[CH2:17][CH2:18][C:13]3([O:20][CH2:10][CH2:11][O:12]3)[CH2:14][CH2:15]2)=[C:4]([Cl:9])[CH:3]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Nc1ccc(Br)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Clc1cc(Br)ccc1NC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-bromo-2-chloro-phenylamine (6 g, 29.06 mmol), [CAS 38762-41-3], 1,4-cyclohexanedione monoethyleneketal [CAS 4746-97-8], (6.908 g, 43.59 mmol), and sodium triacetoxy-borohydride (9.239 g, 43.59 mmol) in DCE (100 ml) and acetic acid (0.2 ml) was stirred at r.t. for 2 days. The mixture was then filtered through a pad of diatomaceous earth and washed with DCM. The filtrate was washed with NaHCO3 (aqueous sat. solution), sodium chloride (aqueous sat. solution), dried (MgSO4) and concentrated in vacuo. The crude product thus obtained was purified by column chromatography (silica gel; DCM/AcOEt 4:1 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D38 (8.57 g, 85%).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH:15]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH2:15][N:28]2[CH2:27][CH2:26][N:25]([CH:24]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[C:21]3[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=3)[CH2:30][CH2:29]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CCCc1cc(CCC=O)nn1C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)nn1C(C)(C)C

Procedure:
107 mg (90%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50 mg, 0.225 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (65 mg, 0.225 mmol), DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: [OH-].[Na+].C=O.[CH3:5]CCCCC.[CH3:11][C:12]1[C:16]([CH3:18])([CH3:17])[CH:15]([CH2:19][CH:20]=[O:21])[CH2:14][CH:13]=1>CO.O>[CH3:18][C:16]1([CH3:17])[C:12]([CH3:11])=[CH:13][CH2:14][CH:15]1[C:19](=[CH2:5])[CH:20]=[O:21]
Reactant: CCCCCC
Reactant: CC1=CCC(CC=O)C1(C)C
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=C(C=O)C1CC=C(C)C1(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 215.6 %

Procedure:
A 3 liter 3 neck round bottomed flask was charged with 50 g of sodium hydroxide (1.25 moles) in 250 g of methanol. 200 g of paraformaldehyde, 500 g of hexane and 2.5 g of BHA were added and the flask was cooled to 0° C. With fast agitation 500 g of campholenic aldehyde at a purity of 88.9% (2.92 moles) were added dropwise over 70 minutes keeping the temperature at 0°-5° C. The batch was stirred for 3 hours at 0° C. Then 50 ml of water was added and the layers are separated. The water layer was back extracted with 250 ml of hexane. The hexane extracts were combined and washed with 2×500 ml of 10% sodium hydroxide and 3×500 ml of water. The batch was dried and afforded 1163 g of crude 2-(2,2,3-trimethylcyclopent-3-en-1-yl)propenal in hexane. A second batch was prepared analogously affording 1169 g of crude product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]1[N:15]([CH3:16])[C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[N:12]=1)(=[O:10])=[O:9].[F:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=1>>[F:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]=2)(=[O:10])=[O:9])[CH:25]=[CH:24][C:23]=1[C:37]1[CH:42]=[N:41][C:40]([NH2:43])=[N:39][CH:38]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: Cn1c(S(=O)(=O)c2ccccc2Br)nc2ccccc21
Product: Cn1c(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)nc2ccccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-((2-bromophenyl)sulfonyl)-1-methyl-1H-benzo[d]imidazole and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C24H18FN5O2S, 459.12; m/z found, 460.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 7.03-6.96 (dd, J=7.8, 1.5, 1H), 6.88-6.86 (d, J=1.4, 2H), 6.43-6.28 (m, 1.5, 2H), 6.15-6.09 (d, J=8.2, 1H), 6.08-5.99 (m, 2H), 5.97-5.86 (m, 2H), 5.64-5.53 (m, 1H), 5.34-5.30 (dd, J=7.8, 1.7, 1H), 5.30-5.23 (dd, J=11.3, 1.7, 1H), 2.22 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH2:8][CH2:9][O:10][CH2:11][CH3:12])[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[N:4]=1.[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1>>[CH2:11]([O:10][CH2:9][CH2:8][N:7]1[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[N:4]=[C:3]1[CH2:2][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1)[CH3:12]
Reactant: OCc1ccc(O)cc1
Reactant: CCOCCn1c(CCl)nc2ccccc21
Product: CCOCCn1c(COc2ccc(CO)cc2)nc2ccccc21
Yield: 83.4 %

Procedure:
In a manner similar to that of Production Example 9, the title compound (yield: 83.4%) was obtained as pale yellow prisms by use of 2-chloromethyl-N-(2-ethoxyethyl)benzimidazole and 4-Hydroxybenzyl alcohol.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]([NH:19][CH:20]3[CH2:25][CH2:24][CH2:23]C[CH2:21]3)=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N:11]2)=[CH:6][CH:5]=1.[N:26]([CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[C:27]=[O:28]>CN(C=O)C.[Cl-].[Na+].O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:18]([N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:21]3)[C:27]([NH:26][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:28])=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=C=NC1CCCC1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1CCCC1)N(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
To an ice cold suspension of NaH (6 mg, 160 umol) in DMF (2.5 ml) under an argon atmosphere was added a solution of [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (50 mg, 153 umol; example 11.1) in DMF (1 ml) within 10 min. The suspension was stirred for 1 h at 0° C. A solution of isocyanato-cyclopentane (34 mg, 306 umol; [4747-71-1]) in DMF (0.5 ml) was added within 5 min. The reaction mixture was stirred for 1 h at ambient temperature, poured onto ice water/1 N aqueous HCl solution/brine 1/1/1 and extracted two times with iPrOAc. The combined extracts were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative thin layer chromatography (silica gel, iPrOAc/heptane) to give the title compound (20 mg, 47 umol; 21%) as yellow foam. MS: m/e=423.1 [M+H+].
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]2[N:6]=[C:7]([NH:15][C:16]3[C:21]([Cl:22])=[CH:20][C:19]([C:23]4[NH:27][N:26]=[CH:25][CH:24]=4)=[CH:18][C:17]=3[Cl:28])[C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.[OH:31][C:32]([CH3:39])([CH3:38])/[CH:33]=[CH:34]/B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)(=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>[Cl:28][C:17]1[CH:18]=[C:19]([C:23]2[NH:27][N:26]=[CH:25][CH:24]=2)[CH:20]=[C:21]([Cl:22])[C:16]=1[NH:15][C:7]1[C:8]2[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=2[C:4]2[CH:3]=[C:2](/[CH:34]=[CH:33]/[C:32]([OH:31])([CH3:39])[CH3:38])[CH:30]=[CH:29][C:5]=2[N:6]=1
Reactant: O=c1[nH]ccc2c(Nc3c(Cl)cc(-c4ccn[nH]4)cc3Cl)nc3ccc(Br)cc3c12
Reactant: CC(C)(O)/C=C/B(O)O
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: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(O)/C=C/c1ccc2nc(Nc3c(Cl)cc(-c4ccn[nH]4)cc3Cl)c3cc[nH]c(=O)c3c2c1
Temperature: 80 °C

Procedure:
To a solution of 9-bromo-5-{[2,6-dichloro-4-(1H-pyrazol-5-yl)phenyl]amino}benzo[c]-2,6-naphthyridin-1(2H)-one (Example 100, Step 4) (125 mg, 0.25 mmol) in THF (4 mL) was added [(1E)-3-hydroxy-3-methylbut-1-en-1-yl]boronic acid (65 mg, 0.45 mmol), Pd(Ph3P)4 (58 mg, 0.05 mmol) and sodium carbonate (0.125 mL, 0.25 mmol, 2M in water). The reaction was heated to 80° C. for 16 h. The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in THF and methanol, filtered and purified by reverse phase HPLC to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>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.O>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccnc(Cl)c1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Clc1ccnc(-c2ccccc2)c1
Yield: 88.3 %

Procedure:
A 1 L round bottom flask was charged with 2,4-dichloropyridine (30 g, 203 mmol), phenylboronic acid (24.7 g, 203 mmol), potassium carbonate (84 g, 608 mmol), Pd(PPh3)4 (2.3 g, 2.0 mmol), dimethoxyethane (500 mL) and water (150 mL). The mixture was degassed and heated to reflux for 20 h. After cooling, the aqueous layer was extracted with EtOAc; the organic portion was combined and subjected to column chromatography (SiO2, 5% EtOAc in hexane to 10% EtOAc in hexane) to give 34 g (88%) of 4-chloro-2-phenylpyridine. The product was confirmed by GC/MS and NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[CH:8][CH:7]=[CH:6]2.[CH:14]([N:17]1[CH2:20][CH:19]([OH:21])[CH2:18]1)([CH3:16])[CH3:15].[OH-].[K+].[ClH:24]>>[ClH:24].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][CH2:20][CH:19]([OH:21])[CH2:18][NH:17][CH:14]([CH3:16])[CH3:15])=[CH:8][CH:7]=[CH:6]2
Reactant: CC(C)N1CC(O)C1
Reactant: COc1ccc2c(O)cccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COc1ccc2c(OCC(O)CNC(C)C)cccc2c1
Temperature: 140 °C
Yield: 57.5 %

Procedure:
A mixture of 9.5 parts of 6-methoxy-1-naphthol, 5.8 parts of 1-(iso-propyl)-3-azetidinol and 0.3 part of potassium hydroxide was heated under nitrogen gas at 140° C. for 8 hours with agitation. The reaction mixture was treated in the same manner as in Example 1, and when the resulting hydrochloride was recrystallized from iso-propyl alcohol, there was obtained 17.7 parts of 1-(6'-methoxy-1-naphthoxy)-3-(iso-propylamino)-2-propanol hydrochloride melting at 165° - 167° C. The yield was 57.5%.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([CH2:19][C:20]#[N:21])=[CH:17][CH:16]=1)([O-:14])=[O:13].N1C=CC=CC=1>C(O)C>[C:20]([C:19]([C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=1)=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)#[N:21]
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: c1ccncc1
Product: N#CC(=Cc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1

Procedure:
A 1.5 g sample of p-nitrobenzaldehyde and 1.7 g of p-nitrobenzylcyanide were dissolved in 5 ml of hot ethanol, and 0.05 ml of pyridine was added. The mixture was heated for 10 minutes. After cooling overnight, the precipitated crystals were filtered and recrystallized from a mixture of acetone and ethanol to obtain 1-cyano-1,2-bis(p-nitrophenyl)ethylene having a melting point of 216.5°-217.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12](Br)=[CH:11][C:3]=1[C:4]([O:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5].[Cu](C#N)[C:18]#[N:19]>CN1CCCC1=O>[NH2:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12]([C:18]#[N:19])=[CH:11][C:3]=1[C:4]([O:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5]
Reactant: N#C[Cu]C#N
Reactant: COCCOC(=O)c1cc(Br)cc(C)c1N
Solvent: CN1CCCC1=O
Product: COCCOC(=O)c1cc(C#N)cc(C)c1N
Yield: 12.1 %

Procedure:
The above-described method (Example 2) was repeated to react 2-methoxyethyl 2-amino-5-bromo-3-methylbenzoate (5.00 g, 15.88 mmol) with copper cyanide (1.49 g, 16.67 mmol) in N-methylpyrrolidone at 170° C. for 6 hours. Following working up similar to Example 2 and additional extraction with ethyl acetate and washing with aqueous 5% ethylenediamine solution, 2-methoxyethyl 2-amino-5-cyano-3-methylbenzoate (0.45 g, 11.6% of theory, 95.6 area % LC) was obtained as a brown solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([CH2:8][C@H:9]([NH2:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])[CH3:3].[C:18]([O:22][C:23](=[O:52])[CH2:24][CH:25]([CH2:29][CH2:30][CH2:31][S:32][C:33]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:26](O)=[O:27])([CH3:21])([CH3:20])[CH3:19].C1C=CC2N(O)N=NC=2C=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:13]([O:12][C:10](=[O:11])[CH:9]([NH:17][C:26](=[O:27])[CH:25]([CH2:24][C:23]([O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:52])[CH2:29][CH2:30][CH2:31][S:32][C:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CC(CCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC(CCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 86.4 %

Procedure:
To H-Asp (OtBu)-OtBu hydrochloride salt (28 mg, 0.10 mmol) in dry DMF (2 mL) was sequentially added at room temperature 2-(3-tritylsulfanyl-propyl)-succinic acid 4-tert-butyl ester (50 mg, 0.10 mmol), HOBt (14 mg, 0.10 mmol), PYBOP (56 mg, 0.11 mmol) and DIPEA (37 μL, 0.20 mmol). The usual aqueous work up yielded the title compound (62 mg, 86%) as a colorless residue: 1H NMR (CDCl3, 400 MHz) δ 7.41–7.38 (m, 6H), 7.29–7.25 (m, 6H), 6.60–6.57 (m, 1H), 4.68–4.56 (m, 1H), 3.18–3.14 (m, 2H), 2.89–2.80 (m, 1H), 2.74–2.52 (m, 2H), 2.43–2.36 (m, 1H), 2.32–2.19 (m, 1H), 2.12–2.07 (m, 2H), 1.83–1.80 (m, 2H), 1.60–1.53 (m, 1H), 1.45–1.40 (m, 27H); 13C (DEPT) (CDCl3, 100 MHz) δ 129.4, 127.7, 126.4, 49.0, 48.7, 46.1, 42.5, 37.8, 37.6, 37.2, 31.6, 31.5, 29.6, 27.9, 27.8, 27.7, 26.3, 26.2, 26.0.