Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[O:15][CH3:16])[N:6]=1.[C:23]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[C:35](O)=[O:36])(=[O:25])[CH3:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[C:23]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[C:35]([NH:1][C:2]1[S:3][C:4]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[O:15][CH3:16])[N:6]=1)=[O:36])(=[O:25])[CH3:24]
Reactant: CCOC(=O)Cc1sc(N)nc1-c1ccc(OC)cc1OC
Reactant: CC(=O)n1c(C(=O)O)cc2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1sc(NC(=O)c2cc3ccccc3n2C(C)=O)nc1-c1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.5 g of 2-amino-4-(2,4-dimethoxyphenyl)-5-ethoxycarbonylmethylthiazole, 1 g of 1-acetylindole-2carboxylic acid, 0.7 ml of triethylamine and 2.39 g of BOP are dissolved in 15 ml of dichloromethane. The reaction mixture is stirred overnight at room temperature and then concentrated under vacuum. The residue is taken up in ethyl acetate and the solution is successively washed with a buffer solution, pH=2, with a 5% solution of NaHCO3 and with water, and then the organic phase is dried over MgSO4 and concentrated under vacuum. The residue is purified by chromatography on a silica gel, eluent: dichloromethane/ethyl acetate 100/2.5 (v/v).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[C:5]#[N:6].Cl.[CH3:14][NH:15][OH:16].C(=O)([O-])[O-].[Na+].[Na+].[C:23]([C:30]([O:32][CH2:33][CH3:34])=[O:31])#[C:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(OCC)(=O)C.O.C(O)C>[CH2:33]([O:32][C:30]([C:23]1([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[O:16][N:15]([CH3:14])[C:5]([C:4]2[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:3]=2[O:2][CH3:1])=[N:6]1)=[O:31])[CH3:34]
Reactant: COc1cccc(OC)c1C#N
Reactant: CNO
Reactant: CCOC(=O)C#CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC1(C(=O)OCC)N=C(c2c(OC)cccc2OC)N(C)O1
Temperature: 80 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
To a stirred suspension of 2,6-dimethoxy-benzonitrile (0.82 g, 5 mmol) and N-methylhydroxylamine hydrochloride (1.66 g, 20 mmol) in 1:1 water/ethanol (20 mL) was added sodium carbonate (1.05 g, 10 mmol) in small portions and the resulting mixture stirred at 80° C. for 24 h. The reaction mixture was concentrated and the residue was re-dissolved into 1:1 water:ethanol (25 mL). To this solution was added diethyl acetylenedicarboxylate (0.96 mL, 6 mmol) and the resulting mixture stirred for 30 min at room temperature. The reaction mixture was then taken up in ethyl acetate (100 mL), washed successively with water and brine (50 mL each), dried (Na2SO4), filtered and concentrated to give a yellow oil. The crude product was purified on silica gel column (3:7 to 1:1 ethyl acetate/hexanes) to afford the title compound as a viscous yellow (1.5795 g, 83% yield). 1HNMR (500 MHz, CDCl3) δ: 7.32 (1H, t, J=8.24 Hz), 6.55 (2H, d, J=8.24 Hz), 4.38–4.24 (2H, m), 4.20–4.14 (2H, m), 3.80 (6H, s), 3.48 (1H, d, J=16.48 Hz), 3.03 (1H, d, J=16.48 Hz), 3.02 (3H, s), 1.33 (3H, t, J=7.02 Hz), 1.26 (3H, 7.02 Hz). HRMS (ESI) calcd for C18H25N2O7S (M+H): 381.1662; found: 381.1656.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][OH:29])=[CH:23][CH:22]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.N1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:29][CH2:28][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]#[C:19][C:16]2[CH:15]=[CH:14][C:13]([C:10]3[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=3)=[CH:18][N:17]=2)=[CH:26][CH:25]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Temperature: 0 °C

Procedure:
0.06 mL (0.75 mmol) of methanesulfonic acid chloride was added dropwise at 0° C. to a solution of 167 mg (0.50 mmol) of 2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenyl}ethanol and 0.08 mL (1.00 mmol) of pyridine in 5 mL of DCM and the mixture was then stirred for I hour at 0° C. It was combined again with pyridine (0.08 mL) and methanesulfonic acid chloride (0.06 mL) and stirred for 1 hour at RT. Then it was combined with 0.14 mL (1.00 mmol) of triethylamine and after 20 minutes at RT diluted with ice water. The organic phase was separated off, dried over magnesium sulfate, filtered, and the solvent was eliminated in vacuo. Yield: 185 mg (90% of theoretical); C22H18ClNO3S (M=411.902); calc.: molpeak (M+H)+:412/414 (Cl); found: molpeak (M+H)+:412/414 (Cl); HPLC-MS: 6.27 minutes (method H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][C:10](=[O:15])[NH:11][C:12](=[O:14])[CH2:13]2)=[CH:6][C:7]=1[Br:23]
Reactant: Nc1ccc(C2CC(=O)NC(=O)C2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1ccc(C2CC(=O)NC(=O)C2)cc1Br
Temperature: 0 °C
Yield: 93.9 %

Procedure:
A solution of 106 mg (0.519 mmol) of 4-(4-amino-phenyl)-piperidine-2,6-dione (as prepared in the previous step) in CH2Cl2 (20 mL) was cooled to 0° C. and treated with 92.4 mg (0.519 mmol) of NBS for 35 min. The mixture was diluted with CH2Cl2 (50 mL) and washed with saturated aqueous NaHCO3 (2×40 mL) and water (1×40 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 138 mg (94%) of the title compound as a tan solid: Mass spectrum (ESI, m/z): Calcd. for C11H11N2O2Br, 283.0/285.0 (M+H). found 283.1/285.1.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][Li]>C(OCC)C>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11](=[O:13])[CH3:14])[CH2:9][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: [Li]C
Solvent: CCOCC
Product: CC(=O)[C@H]1CC[C@H](C(C)(C)C)CC1

Procedure:
To trans-4-tert-butyl-cyclohexanecarboxylic acid (921 mg, 5.0 mmol) in ethyl ether (35 mL) was added methyl lithium (1.6 M in ethyl ether, 7.1 mL, 11.4 mmol) to produce 1-(trans-4-tert-butyl-cyclohexyl)-ethanone (769 mg, 4.22 mmol, 84%) following a method analogous to General Procedure A1. Workup involved treatment of the reaction mixture with water (50 mL), and the organic portion was washed with aq NaHCO3 and then brine, and dried over sodium sulfate. Solvent evaporation under reduced pressure gave the crude methyl ketone (769 mg). This crude ketone product was converted into the corresponding 2-bromoketone (525 mg, 2.01 mmol) following a method analogous to General Procedure B2 using bromine (0.228 mL, 4.43 mmol) and MeOH (about 10 mL).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.[C:17]([OH:22])(=[O:21])[C:18]([CH3:20])=O>C(O)C>[C:2]1([C:1]2[CH:20]=[C:18]([C:17]([OH:22])=[O:21])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(N)cc1
Reactant: CC(=O)C(=O)O
Solvent: CCO
Product: Cc1ccc2nc(-c3ccccc3)cc(C(=O)O)c2c1
Temperature: 25 °C
Yield: 9.7 %

Procedure:
Benzaldehyde (2.12 g) and 2.14 g of p-toluidine were dissolved in 50 ml of ethanol, and 1.76 g of pyruvic acid were added thereto dropwise. The reaction mixture was then heat-refluxed for 6 hours. The resulting reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in a 1N sodium hydroxide aqueous solution. This aqueous solution was extracted with ethyl ether, and the aqueous layer was acidified with dilute hydrochloric acid. The precipitate was collected by filtration, and dried to form 0.51 g of the above-mentioned compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21][O:22][C:23](=[O:32])[CH:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:21][O:22][C:23](=[O:32])[CH:24]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(Oc1cccc2c1cc(C)n2Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
1-Benzyl-2-methyl-1H-indol-4-ol 3 (0.3 g 1.26 mmole) was dissolved in anhydrous dimethylformamide (20 mL). To the solution sodium hydride 60% in mineral oil (66 mg 1.65 mmole) was added. The mixture was stirred at room temperature for 1 h. To the mixture bromo-phenyl-acetic acid methyl ester (0.24 mL, 1.512 mmole) was added. The mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (300 mL) and washed with H2O (4×100 mL) and brine (1×100 mL). The organic layer was separated, dried with magnesium sulfate and concentrated. The residue was purified by column chromatography (10:1 Hexane:EtOAc) to afford 8 (0.3 g, 62%) as a white solid.
Reaction SMILES: [C:1]1([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]([CH:29]=1)=[N:25][C:26](=[O:28])[N:27]=2.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(CC(C)C)=O>[C:1]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]4[C:24]([CH:29]=3)=[N:25][C:26](=[O:28])[N:27]=4)[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: O=C1N=c2ccc(CCBr)cc2=N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1N=c2ccc(CCN3CCN(c4cccc5ccccc45)CC3)cc2=N1
Yield: 14 %

Procedure:
To a 100 ml round-bottomed flask equipped with magnetic stirrer, condenser, and nitrogen inlet were added 2.64 grams (12.4 mmol) of N-(1-naphthyl)-piperazine, 3.0 grams (12.4 mmol) of 6-(2-bromoethyl)-benzimidazolone, 1.31 grams (12.4 mmol) sodium carbonate, 50 ml methylisobutylketone, and a catalytic amount of sodium iodide. The reaction was refluxed for 3 days, cooled, and evaporated to a brown gum. The gum was partitioned between 50 ml water and 75 ml ethyl acetate, and the ethyl acetate layer washed with brine, dried over sodium sulfate, and evaporated, then chromatographed on silica gel. Fractions containing the product were combined and evaporated, the residue taken up in tetrahydrofuran, treated with hydrochloric acid gas, and the resulting hydrochloride salt of the product filtered off to give a white solid, m.p. 260°-262° C., 716 mg (14% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]=O)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1([CH3:27])[CH2:26][C:24](=O)[CH2:23][C:21](=[O:22])[CH2:20]1.[NH2:28][C:29]1[NH:33][N:32]=[C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:30]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]3[C:23]4[C:21](=[O:22])[CH2:20][C:19]([CH3:18])([CH3:27])[CH2:26][C:24]=4[NH:28][C:29]4[NH:33][N:32]=[C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:30]3=4)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(N)[nH]n1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=C/C=C/c1ccc(-c2cccc(F)c2)cn1
Product: CCOC(=O)c1n[nH]c2c1C(/C=C/c1ccc(-c3cccc(F)c3)cn1)C1=C(CC(C)(C)CC1=O)N2

Procedure:
The title compound is prepared as a mixture of diastereomers according to procedure A from 150 mg of (E)-3-[5-(3-fluorophenyl)pyridin-2-yl]propenal, 93 mg of dimedone and 102 mg of ethyl 5-amino-1H-pyrazole-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:37][CH:38]=[CH2:39])=[C:5]([CH:27]=[CH:28][C:29]=1[C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([CH2:24][CH2:25][CH3:26])=[C:13]([CH:21]=[CH:22][CH:23]=1)[O:14][CH2:15][C:16]([O:18]CC)=[O:17].[OH-].[Li+].CO>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[C:4]([CH2:37][CH:38]=[CH2:39])=[C:5]([CH:27]=[CH:28][C:29]=1[C:30]([N:32]1[CH2:33][CH2:34][CH2:35][CH2:36]1)=[O:31])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([CH2:24][CH2:25][CH3:26])=[C:13]([CH:21]=[CH:22][CH:23]=1)[O:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: C=CCc1c(OCCCOc2cccc(OCC(=O)OCC)c2CCC)ccc(C(=O)N2CCCC2)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: C=CCc1c(OCCCOc2cccc(OCC(=O)O)c2CCC)ccc(C(=O)N2CCCC2)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound of Example 58 (95 mg, 0.176 mmol) and 352 μl (0.352 mmol) of 1M lithium hydroxide were added to 2.0 ml of methanol. The reaction mixture was stirred at room temperature for 4 hours and the solvent was removed under vacuum. Water (5.0 ml) was added to the residue, and the mixture was acidified with 10% hydrochloric acid then extracted three times with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed under vacuum to give a gum. Chromatography of the gum on silica gel with 50/50 ethyl acetate/hexane as eluant followed by drying under vacuum overnight gave the product.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.[CH2:11]1[C:16](=O)[CH2:15][C:13](=[O:14])[CH2:12]1.[NH2:18][C:19]1[N:23]([CH3:24])[NH:22][C:21](=[O:25])[CH:20]=1>>[I:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:20]3[C:21](=[O:25])[NH:22][N:23]([CH3:24])[C:19]=3[NH:18][C:16]3[CH2:11][CH2:12][C:13](=[O:14])[C:15]2=3)[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1ccc(C=O)cc1I
Reactant: Cn1[nH]c(=O)cc1N
Reactant: O=C1CCC(=O)C1
Product: Cc1ccc(C2C3=C(CCC3=O)Nc3c2c(=O)[nH]n3C)cc1I
Yield: 23.7 %

Procedure:
3-Iodo-4-methylbenzaldehyde (0.37 g, 1.5 mmol) from Example 11A, 1,3-cyclopentadione (0.15 g, 1.5 mmol), and 5-amino-1-methyl-1,2-dihydropyrazol-3-one (0.17 g, 1.5 mmol) were processed as described in Example 1 to provide 0.15 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.25 (s, 3H) 2.3 (m, 2H), 2.68 (m, 2H), 3.49 (s, 3H), 4.6 (s, 1H), 7.05 (dd, 1H), 7.14 (d, 1H), 7.53 (d, 1H), 9.5 (bs, 1H), 10.35 (s, 1H); MS (ESI−) m/z 420 (M−H)−; Anal. calcd for C17H16N3IO2.0.75 C2H6O: C, 48.75;H, 4.53; N, 9.22. Found: C, 49.03;H, 4.50; N, 9.72.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl>ClCCl.[Cl-].[Na+].O>[I:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c[nH]nc1I
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn(COCC[Si](C)(C)C)nc1I
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 59A (1.3 g, 5 mmole) and diisopropyl-ethyl amine (1.3 mL, 7.5 mmole) in dichloromethane (20 mL) at ambient temperature was added 2-(trimethylsilyl)ethoxymethyl chloride (1.25 g, 7.5 mmole) dropwise. The solution was stirred overnight. Brine (20 mL) was added and the mixture was extracted with ethyl acetate. The mixture was dried with magnesium sulfate, filtered and concentrated. The residue was purified on a silica gel column eluting with 25% ethyl acetate in hexane. The two regioisomers were isolated as a mixture. MS (DCI) m/e 397 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]C.[K+].[Br-].Br[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1>C(#N)C>[Br-:10].[CH2:21]([C:35]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]([CH3:26])[C:36]=1[N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[NH:5][CH:4]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCCCCCCCCCCCBr
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCCCCCCCc1c(-[n+]2c[nH]c(Cl)c2Cl)c(C)cc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) will be dissolved into acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) will be added and the mixture will be allowed to stir for 0.5 h. 1-bromododecane (9 mmol) will be added and the solution will be allowed to reflux overnight. The solution will be filtered hot to remove a white precipitate (presumed to be KBr) and 2-bromomethylnaphthalene (1.98 g, 9 mmol) will be added and the mixture will be returned to reflux overnight. The mixture will be allowed to cool to room temperature, resulting in a yellow/white precipitate.
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:28][C@H:29]([C:36]([NH:38][C@H:39]([CH:44]=[N:45][NH:46][C:47]([NH2:49])=[O:48])[CH2:40][CH:41]([CH3:43])[CH3:42])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([NH:28][C@H:29]([C:36]([NH:38][C@H:39]([CH:44]=[N:45][NH:46][C:47]([NH2:49])=[O:48])[CH2:40][CH:41]([CH3:43])[CH3:42])=[O:37])[CH2:30][C:31]2[N:35]=[CH:34][NH:33][CH:32]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CC(Cc1cccc2ccccc12)C(=O)O)NCCc1ccccc1
Reactant: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C=NNC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)NCCc1ccccc1)Cc1cccc2ccccc12
Reaction time: 15 h

Procedure:
To a solution of 221 mg of (±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionic acid and 400 mg of bis-(p-toluenesulfonic acid) salt of L-histidyl-L-leucinal semicarbazone in 5 ml of dry N,N-dimethylformamide were successively added dropwise 202 mg of diphenylphosphoryl azide and 0.28 ml of triethylamine under ice-cooling, and then the mixture was stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1 by volume) to obtain 71 mg of N-[2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidyl-L-leucinal semicarbazone (isomer A) and 166 mg of isomer B.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[NH:11]1[CH2:14][CH:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12]1.Cl[C:24]1[O:25][C:26]2[C:27](=[C:29]([C:41]#[N:42])[C:30]([CH3:40])=[C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:32]=2[F:33])[N:28]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:41]([C:29]1[C:27]2[N:28]=[C:24]([N:11]3[CH2:14][CH:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:12]3)[O:25][C:26]=2[C:32]([F:33])=[C:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:30]=1[CH3:40])#[N:42]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(NC(=O)OC(C)(C)C)C3)nc2c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Diisopropylethylamine (787 μl, 4.63 mmol) and tert-butyl azetidin-3-ylcarbamate hydrochloride (483 mg, 2.31 mmol) were added to a dichloromethane (20 ml) solution of 2-chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (553 mg, 1.93 mmol), followed by stirring at room temperature for 30 minutes. With cooling with ice, aqueous 10% citric acid solution (10 ml) was added to the reaction liquid, followed by extraction with chloroform (50 ml), then the organic layer was washed with saturated brine (50 ml). After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to obtain the entitled compound (815 mg, 100%) as a colorless oily substance.
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=1>C(Cl)Cl>[F:26][C:27]([F:37])([F:36])[C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:6]/[C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:30][CH:29]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Yield: 71.1 %

Procedure:
To a solution of (carbethoxymethylene)triphenylphosphorane (55.3 g, 159 mmol) in 150 mL DCM, was added α,α,α-trifluoro-p-tolualdehyde (25.00 g, 144 mmol)(commercially available from 3B Scientific Corporation Product List (Order Number 3B4-3644)) in 75 mL DCM. The reaction was exothermic. The mixture was heated at reflux for 90 minutes. After removing the solvent, hexane was added to the resulting residue. A precipitate appeared and was collected by filtration through filter paper. The collected solid was subjected to silica gel chromatography with 100% hexane as the elutant to afford a white solid ((E)-ethyl 3-(4-(trifluoromethyl)phenyl)acrylate (25.0 g, yield=71%). LCMS (API-ES) m/z(%): 245.1 (100%, M++H); 1H NMR (400 MHz, CD3OD) δ ppm 1.35 (t, J=7.14 Hz, 3H) 4.28 (q, J=7.04 Hz, 2H) 6.68 (d, J=16.04 Hz, 1H) 7.70-7.77 (m, 3H) 7.80-7.84 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:40][CH3:41])[C:24]([F:42])=[CH:23][N:22]=1>>[F:42][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:29]=2[O:40][CH3:41])=[N:26][C:21]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1F
Reactant: CNC(=O)CN1CCc2cc(N)c(OC)cc2CC1
Product: CNC(=O)CN1CCc2cc(Nc3ncc(F)c(Nc4ccc(N5CCOCC5)cc4OC)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N-methyl-acetamide and (2-Chloro-5-fluoro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 61e. Product was isolated as a pale yellow solid (0.044 g, 48%). MP: 82-124° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.29 (d, 1H, J=8.6 Hz), 8.16 (s, 1H), 7.93-7.90 (m, 1H), 7.40 (s, 1H), 7.36-7.29 (m, 1H), 7.22-7.18 (m, 1H), 6.63 (s, 1H), 6.56-6.53 (m, 1H) 6.53-6.48 (m, 1H), 3.93-3.84 (m, 10H), 3.17-3.09 (m, 6H), 2.92-2.82 (m, 7H), 2.74-2.65 (m, 4H). MS: 566.30 (MH)+.